FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Stapleton, CJ Kumar, JI Walcott, BP Torok, CM Agarwalla, PK Koch, MJ Patel, AB AF Stapleton, Christopher J. Kumar, Jay I. Walcott, Brian P. Torok, Collin M. Agarwalla, Pankaj K. Koch, Matthew J. Patel, Aman B. TI The effect of basilar artery bifurcation angle on rates of initial occlusion, recanalization, and retreatment of basilar artery apex aneurysms following coil embolization SO INTERVENTIONAL NEURORADIOLOGY LA English DT Article DE Arterial bifurcation angles; basilar artery; endovascular coil embolization; intracranial aneurysm; subarachnoid hemorrhage ID INTRACRANIAL ANEURYSMS; ENDOVASCULAR TREATMENT; CEREBRAL ANEURYSMS; TIP ANEURYSMS; GEOMETRY; OUTCOMES; TRENDS; AGE AB Background: Arterial bifurcations are common locations for aneurysm development given the altered hemodynamic forces and shear stress variations present at these locations. Recent reports indicate that a wide basilar artery bifurcation angle is an independent predictor of aneurysm development, growth, and subsequent rupture. Methods: To determine the effect of basilar artery bifurcation angle on rates of initial occlusion, recanalization, and retreatment of basilar artery apex aneurysms following coil embolization, the records of 46 patients with basilar artery apex aneurysms treated with endovascular coil embolization from 2007 to 2013 were analyzed. Results: A wide basilar artery bifurcation angle was associated with a Raymond-Roy Occlusion Classification (RROC) III occlusion in univariate analysis, but was not a statistically significant factor in multivariate modeling. An increasing basilar artery bifurcation angle was not associated with aneurysm recanalization or retreatment following coil embolization. Increasing packing density (p<.01) was the only statistically significant predictor of a RROC I or II closure. The initial RROC designation was the most powerful predictor of both eventual aneurysm recanalization (p=.01) and retreatment (p=.02). While increasing aneurysm size (p<.01), increasing aneurysm volume (p<.01), and increasing neck size (p<.01) were associated with wide basilar artery bifurcation angles, neck size (p=.03) was the only statistically significant predictor of basilar artery bifurcation angle on multivariate analyses. Conclusion: Basilar artery bifurcation angle fails to predict rates of initial occlusion, recanalization, and retreatment on multivariate modeling in our series. Basilar artery apex aneurysm neck size independently correlates with basilar artery bifurcation angle. C1 [Stapleton, Christopher J.; Kumar, Jay I.; Agarwalla, Pankaj K.; Koch, Matthew J.; Patel, Aman B.] Massachusetts Gen Hosp, Dept Neurosurg, 15 Parkman St,Wang 745, Boston, MA 02114 USA. [Stapleton, Christopher J.; Kumar, Jay I.; Torok, Collin M.; Agarwalla, Pankaj K.; Koch, Matthew J.; Patel, Aman B.] Harvard Med Sch, Boston, MA USA. [Walcott, Brian P.] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA USA. RP Patel, AB (reprint author), Massachusetts Gen Hosp, Dept Neurosurg, 15 Parkman St,Wang 745, Boston, MA 02114 USA. EM abpatel@mgh.harvard.edu NR 22 TC 0 Z9 0 U1 2 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1591-0199 EI 2385-2011 J9 INTERV NEURORADIOL JI Interv. Neuroradiol. PD AUG PY 2016 VL 22 IS 4 BP 389 EP 395 DI 10.1177/1591019916633243 PG 7 WC Clinical Neurology; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DS6UD UT WOS:000380917400003 PM 26922975 ER PT J AU De Guio, F Jouvent, E Biessels, GJ Black, SE Brayne, C Chen, C Cordonnier, C De Leeuw, FE Dichgans, M Doubal, F Duering, M Dufouil, C Duzel, E Fazekas, F Hachinski, V Ikram, MA Linn, J Matthews, PM Mazoyer, B Mok, V Norrving, B O'Brien, JT Pantoni, L Ropele, S Sachdev, P Schmidt, R Seshadri, S Smith, EE Sposato, LA Stephan, B Swartz, RH Tzourio, C van Buchem, M van der Lugt, A van Oostenbrugge, R Vernooij, MW Viswanathan, A Werring, D Wollenweber, F Wardlaw, JM Chabriat, H AF De Guio, Francois Jouvent, Eric Biessels, Geert Jan Black, Sandra E. Brayne, Carol Chen, Christopher Cordonnier, Charlotte De Leeuw, Frank-Eric Dichgans, Martin Doubal, Fergus Duering, Marco Dufouil, Carole Duzel, Emrah Fazekas, Franz Hachinski, Vladimir Ikram, M. Arfan Linn, Jennifer Matthews, Paul M. Mazoyer, Bernard Mok, Vincent Norrving, Bo O'Brien, John T. Pantoni, Leonardo Ropele, Stefan Sachdev, Perminder Schmidt, Reinhold Seshadri, Sudha Smith, Eric E. Sposato, Luciano A. Stephan, Blossom Swartz, Richard H. Tzourio, Christophe van Buchem, Mark van der Lugt, Aad van Oostenbrugge, Robert Vernooij, Meike W. Viswanathan, Anand Werring, David Wollenweber, Frank Wardlaw, Joanna M. Chabriat, Hugues TI Reproducibility and variability of quantitative magnetic resonance imaging markers in cerebral small vessel disease SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Review DE Magnetic resonance imaging; cerebral small vessel disease; marker; brain volume; atrophy; white matter hyperintensities; microbleeds; lacunes; perivascular spaces; reproducibility; repeatability; variability ID VIRCHOW-ROBIN SPACES; GRADIENT NONLINEARITY CORRECTION; WHITE-MATTER HYPERINTENSITY; MEASURING BRAIN ATROPHY; SURFACE-BASED ANALYSIS; MULTIPLE-SCLEROSIS; VASCULAR DEMENTIA; RATING-SCALE; ALZHEIMERS-DISEASE; VOLUME CHANGES AB Brain imaging is essential for the diagnosis and characterization of cerebral small vessel disease. Several magnetic resonance imaging markers have therefore emerged, providing new information on the diagnosis, progression, and mechanisms of small vessel disease. Yet, the reproducibility of these small vessel disease markers has received little attention despite being widely used in cross-sectional and longitudinal studies. This review focuses on the main small vessel disease-related markers on magnetic resonance imaging including: white matter hyperintensities, lacunes, dilated perivascular spaces, microbleeds, and brain volume. The aim is to summarize, for each marker, what is currently known about: (1) its reproducibility in studies with a scan-rescan procedure either in single or multicenter settings; (2) the acquisition-related sources of variability; and, (3) the techniques used to minimize this variability. Based on the results, we discuss technical and other challenges that need to be overcome in order for these markers to be reliably used as outcome measures in future clinical trials. We also highlight the key points that need to be considered when designing multicenter magnetic resonance imaging studies of small vessel disease. C1 [De Guio, Francois; Jouvent, Eric] Univ Paris Diderot, Sorbonne Paris Cite, UMRS INSERM 1161, Paris, France. [De Guio, Francois; Jouvent, Eric; Chabriat, Hugues] DHU NeuroVasc, Sorbonne Paris Cite, Paris, France. [Jouvent, Eric; Chabriat, Hugues] Lariboisiere Hosp, AP HP, Dept Neurol, Paris, France. [Biessels, Geert Jan] Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Dept Neurol, Utrecht, Netherlands. [Black, Sandra E.; Swartz, Richard H.] Univ Toronto, Dept Med Neurol, Sunnybrook Hlth Sci Ctr, Toronto, ON, Canada. [Brayne, Carol] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Chen, Christopher] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Pharmacol, Singapore, Singapore. [Cordonnier, Charlotte] Univ Lille, CHU Lille, INSERM, U1171, Lille, France. [De Leeuw, Frank-Eric] Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Med Ctr, Dept Neurol, Nijmegen, Netherlands. [Dichgans, Martin; Duering, Marco; Wollenweber, Frank] Univ Munich, Klinikum Univ Munchen, Inst Stroke & Dementia Res, Munich, Germany. [Dichgans, Martin] Munich Cluster Syst Neurol SyNergy, Munich, Germany. [Doubal, Fergus; Wardlaw, Joanna M.] Univ Edinburgh, Dept Neuroimaging Sci, Ctr Clin Brain Sci, Edinburgh, Midlothian, Scotland. [Dufouil, Carole; Tzourio, Christophe] Univ Bordeaux, Inserm UMR897, Bordeaux, France. [Duzel, Emrah] Univ Magdeburg, Dept Cognit Neurol & Dementia Res, Magdeburg, Germany. [Fazekas, Franz; Ropele, Stefan; Schmidt, Reinhold] Med Univ Graz, Dept Neurol, Graz, Austria. [Hachinski, Vladimir; Sposato, Luciano A.] Univ Western Ontario, Dept Clin Neurol Sci, London, ON, Canada. [Ikram, M. Arfan; van der Lugt, Aad; Vernooij, Meike W.] Univ Med Ctr Rotterdam, Dept Radiol, Erasmus MC, Rotterdam, Netherlands. [Ikram, M. Arfan; van der Lugt, Aad; Vernooij, Meike W.] Univ Med Ctr Rotterdam, Dept Epidemiol, Erasmus MC, Rotterdam, Netherlands. [Ikram, M. Arfan] Univ Med Ctr Rotterdam, Erasmus MC, Dept Neurol, Rotterdam, Netherlands. [Linn, Jennifer] Univ Hosp Munich, Dept Neuroradiol, Munich, Germany. [Matthews, Paul M.] Imperial Coll London, Div Brain Sci, Dept Med, London, England. [Mazoyer, Bernard] Univ Bordeaux, CNRS CEA UMR5296, Bordeaux, France. [Mok, Vincent] Chinese Univ Hong Kong, Dept Med & Therapeut, Hong Kong, Hong Kong, Peoples R China. [Norrving, Bo] Lund Univ, Dept Clin Sci, Neurol, Lund, Sweden. [O'Brien, John T.] Univ Cambridge, Dept Psychiat, Cambridge, England. [Pantoni, Leonardo] Univ Florence, Neurofarba Dept, Florence, Italy. [Sachdev, Perminder] Univ New S Wales, Sch Psychiat, Ctr Healthy Brain Ageing, Sydney, NSW, Australia. [Seshadri, Sudha] Boston Univ, Dept Neurol, Sch Med, Boston, MA USA. [Smith, Eric E.] Univ Calgary, Dept Clin Neurosci, Calgary, AB, Canada. [Smith, Eric E.] Univ Calgary, Hotchkiss Brain Inst, Calgary, AB, Canada. [Stephan, Blossom] Newcastle Univ, Inst Ageing, Inst Hlth & Soc, Newcastle, NSW, Australia. [van Buchem, Mark] Leiden Univ, Dept Radiol, Med Ctr, Leiden, Netherlands. [van Oostenbrugge, Robert] Maastricht Univ, Dept Neurol, Med Ctr, Maastricht, Netherlands. [Viswanathan, Anand] Harvard Univ, J Philip Kistler Stroke Res Ctr, Massachusetts Gen Hosp, Dept Neurol,Med Sch, Boston, MA USA. [Werring, David] UCL, Stroke Res Grp, Dept Brain Repair & Rehabil, London, England. [Wardlaw, Joanna M.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol CCACE, Edinburgh, Midlothian, Scotland. RP Chabriat, H (reprint author), Hop Lariboisiere, Dept Neurol, 2 Rue Ambroise Pare, F-75010 Paris, France. EM hugues.chabriat@aphp.fr RI Mok, Vincent /N-6421-2015; Tzourio, christophe/B-4015-2009; Chabriat, Hugues/G-5699-2010; de Leeuw, Frank-Erik/E-4795-2012; OI Tzourio, christophe/0000-0002-6517-2984; Chabriat, Hugues/0000-0001-8436-6074; De Guio, Francois/0000-0003-1809-4175 FU Fondation Avenir; Fondation Leducq (Transatlantic Network of Excellence on the Pathogenesis of Small Vessel Disease of the Brain); Centres of Excellence in Neurodegeneration (COEN) [MRC MR/J006971/1] FX This study was supported by grants from Fondation Avenir and Fondation Leducq (Transatlantic Network of Excellence on the Pathogenesis of Small Vessel Disease of the Brain, http://www.fondationleducq.org). This work follows from a project funded by the Centres of Excellence in Neurodegeneration (COEN), ref MRC MR/J006971/1, "Standards for determining the vascular contribution to neurodegeneration" in which many of the authors participated. NR 121 TC 4 Z9 4 U1 8 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X EI 1559-7016 J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD AUG PY 2016 VL 36 IS 8 BP 1319 EP 1337 DI 10.1177/0271678X16647396 PG 19 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA DU3ED UT WOS:000382092700001 PM 27170700 ER PT J AU Li, BQ Lee, J Boas, DA Lesage, F AF Li, Baoqiang Lee, Jonghwan Boas, David A. Lesage, Frederic TI Contribution of low- and high-flux capillaries to slow hemodynamic fluctuations in the cerebral cortex of mice SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE Capillaries; OCT; flux; low frequency; oscillation ID OPTICAL COHERENCE TOMOGRAPHY; FUNCTIONAL CONNECTIVITY; BLOOD-FLOW; RAT; OXYGENATION; ORIGIN; MRI AB We employed optical coherence tomography to measure cerebral cortical capillary red blood cell (RBC) flux in mice. The results suggest that baseline-flux weakly depends on cortical depth. Furthermore, under hypercapnia, low baseline-flux capillaries exhibit greater flux increases while the higher ones saturate, resulting in RBC-flux homogenization. Power-spectrum analysis indicates that higher flux capillaries saw greater flux variability in the low-frequency range (0.01-0.1 Hz) both at baseline and during hypercapnia. These results suggest that lower baseline-flux capillaries have more reserve to deliver oxygen with increased blood flow; but higher ones more strongly impact the low-frequency fluctuations associated with BOLD fMRI measurements of resting state functional connectivity. C1 [Li, Baoqiang; Lesage, Frederic] Ecole Polytech Montreal, Dept Elect Engn, Montreal, PQ, Canada. [Li, Baoqiang; Lee, Jonghwan; Boas, David A.] Harvard Med Sch, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Opt Div, 149 13th St,Room 2301, Charlestown, MA 02129 USA. RP Li, BQ (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Opt Div, 149 13th St,Room 2301, Charlestown, MA 02129 USA. EM baoqiang.li@mgh.harvard.edu FU CIHR [MOP-130253]; NIH [R01-EB021018, P01-NS055104] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: CIHR (MOP-130253) and NIH (R01-EB021018 and P01-NS055104). NR 15 TC 2 Z9 2 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X EI 1559-7016 J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD AUG PY 2016 VL 36 IS 8 BP 1351 EP 1356 DI 10.1177/0271678X16649195 PG 6 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA DU3ED UT WOS:000382092700003 PM 27165011 ER PT J AU Payne, GA Hage, FG Acharya, D AF Payne, Gregory A. Hage, Fadi G. Acharya, Deepak TI Transplant allograft vasculopathy: Role of multimodality imaging in surveillance and diagnosis SO JOURNAL OF NUCLEAR CARDIOLOGY LA English DT Article DE Cardiac allograft vasculopathy; myocardial perfusion imaging; coronary flow reserve; multimodality imaging ID DOBUTAMINE STRESS ECHOCARDIOGRAPHY; CORONARY-ARTERY-DISEASE; MYOCARDIAL-PERFUSION RESERVE; CARDIAC MAGNETIC-RESONANCE; COMPUTED-TOMOGRAPHY ANGIOGRAPHY; POSITRON-EMISSION-TOMOGRAPHY; HEART-TRANSPLANT; INTRAVASCULAR ULTRASOUND; LONG-TERM; ENDOTHELIAL DYSFUNCTION AB Cardiac allograft vasculopathy (CAV) is a challenging long-term complication of cardiac transplantation and remains a leading long-term cause of graft failure, re-transplantation, and death. CAV is an inflammatory vasculopathy distinct from traditional atherosclerotic coronary artery disease. Historically, the surveillance and diagnosis of CAV has been dependent on serial invasive coronary angiography with intravascular imaging. Although commonly practiced, angiography is not without significant limitations. Technological advances have provided sophisticated imaging techniques for CAV assessment. It is now possible to assess the vascular lumen, vessel wall characteristics, absolute blood flow, perfusion reserve, myocardial contractile function, and myocardial metabolism and injury in a noninvasive, expeditious manner with little risk. The current article will review key imaging modalities for the surveillance, diagnosis, and prognosis of CAV and discuss coronary physiology of transplanted hearts with emphasis on the clinical implications for provocative and vasodilator stress testing. C1 [Payne, Gregory A.; Hage, Fadi G.; Acharya, Deepak] Univ Alabama Birmingham, Sch Med, Div Cardiovasc Med, Tinsley Harrison Tower,Room 321, Birmingham, AL 35294 USA. [Hage, Fadi G.] Birmingham Vet Affairs Med Ctr, Cardiol Sect, Birmingham, AL USA. RP Acharya, D (reprint author), Univ Alabama Birmingham, Sch Med, Div Cardiovasc Med, Tinsley Harrison Tower,Room 321, Birmingham, AL 35294 USA. EM dacharya@uab.edu OI Hage, Fadi/0000-0002-1397-4942 NR 83 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1071-3581 EI 1532-6551 J9 J NUCL CARDIOL JI J. Nucl. Cardiol. PD AUG PY 2016 VL 23 IS 4 BP 713 EP 727 DI 10.1007/s12350-015-0373-3 PG 15 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA DS9DF UT WOS:000381082100013 PM 26711101 ER PT J AU Farag, AA Hage, FG AF Farag, Ayman A. Hage, Fadi G. TI Medical therapy for the treatment of myocardial ischemia SO JOURNAL OF NUCLEAR CARDIOLOGY LA English DT Editorial Material C1 [Farag, Ayman A.; Hage, Fadi G.] Univ Alabama Birmingham, Dept Med, Div Cardiovasc Dis, THT 311,1900 Univ BLVD, Birmingham, AL 35294 USA. [Hage, Fadi G.] Birmingham Vet Affairs Med Ctr, Cardiol Sect, Birmingham, AL USA. RP Hage, FG (reprint author), Univ Alabama Birmingham, Dept Med, Div Cardiovasc Dis, THT 311,1900 Univ BLVD, Birmingham, AL 35294 USA. EM fadihage@uab.edu OI Hage, Fadi/0000-0002-1397-4942 NR 5 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1071-3581 EI 1532-6551 J9 J NUCL CARDIOL JI J. Nucl. Cardiol. PD AUG PY 2016 VL 23 IS 4 BP 837 EP 839 DI 10.1007/s12350-015-0118-3 PG 3 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA DS9DF UT WOS:000381082100031 PM 25824020 ER PT J AU Keuroghlian, AS Palmer, BA Choi-Kain, LW Borba, CPC Links, PS Gunderson, JG AF Keuroghlian, Alex S. Palmer, Brian A. Choi-Kain, Lois W. Borba, Christina P. C. Links, Paul S. Gunderson, John G. TI THE EFFECT OF ATTENDING GOOD PSYCHIATRIC MANAGEMENT (GPM) WORKSHOPS ON ATTITUDES TOWARD PATIENTS WITH BORDERLINE PERSONALITY DISORDER SO JOURNAL OF PERSONALITY DISORDERS LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; DELIBERATE SELF-HARM; FOLLOW-UP; COUNTERTRANSFERENCE; COMORBIDITY; DIAGNOSIS; OUTCOMES; THERAPY; STEPPS AB The effect that attending a 1-day workshop on Good Psychiatric Management (GPM) had on attitudes about borderline personality disorder (BPD) was assessed among 297 clinicians. Change was recorded by comparing before and after scores on a 9-item survey previously developed to assess the effects of workshops on Systems Training for Emotional Predictability and Problem Solving (STEPPS). Participants reported decreased inclination to avoid borderline patients, dislike of borderline patients, and belief that BPD's prognosis is hopeless, as well as increased feeling of competence, belief that borderline patients have low self-esteem, feeling of being able to make a positive difference, and belief that effective psychotherapies exist. Less clinical experience was related to an increased feeling of competence and belief that borderline patients have low self-esteem. These findings were compared to those from the STEPPS workshop. This assessment demonstrates GPM's potential for training clinicians to meet population-wide needs related to borderline personality disorder. C1 [Keuroghlian, Alex S.; Choi-Kain, Lois W.; Gunderson, John G.] McLean Hosp, Dept Psychiat, Belmont, MA USA. [Keuroghlian, Alex S.; Borba, Christina P. C.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Keuroghlian, Alex S.; Choi-Kain, Lois W.; Borba, Christina P. C.; Gunderson, John G.] Harvard Med Sch, Dept Psychiat, Boston, MA USA. [Palmer, Brian A.] Mayo Clin, Dept Psychiat & Psychol, Rochester, MN USA. [Links, Paul S.] Univ Western Ontario, Schulich Sch Med & Dent, Dept Psychiat, London, ON N6A 3K7, Canada. RP Keuroghlian, AS (reprint author), Fenway Hlth, 1340 Boylston St,7th Floor, Boston, MA 02215 USA. EM akeuroghlian@partners.org FU National Institute of Mental Health [R25 MH 094612, 5K01MH100428-02] FX Dr. Keuroghlian was supported by grant R25 MH 094612 from the National Institute of Mental Health. Dr. Borba is supported by grant 5K01MH100428-02 from the National Institute of Mental Health. Funding sources had no role in designing this assessment; 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 30 TC 1 Z9 1 U1 4 U2 4 PU GUILFORD PUBLICATIONS INC PI NEW YORK PA 370 SEVENTH AVE, SUITE 1200, NEW YORK, NY 10001-1020 USA SN 0885-579X EI 1943-2763 J9 J PERS DISORD JI J. Pers. Disord. PD AUG PY 2016 VL 30 IS 4 BP 567 EP 576 PG 10 WC Psychiatry SC Psychiatry GA DT1JO UT WOS:000381238100009 PM 26111249 ER PT J AU Koofhethile, CK Ndhlovu, ZM Thobakgale-Tshabalala, C Prado, JG Ismail, N Mncube, Z Mkhize, L van der Stok, M Yende, N Walker, BD Goulder, PJR Ndung'u, T AF Koofhethile, Catherine K. Ndhlovu, Zaza M. Thobakgale-Tshabalala, Christina Prado, Julia G. Ismail, Nasreen Mncube, Zenele Mkhize, Lungile van der Stok, Mary Yende, Nonhlanhla Walker, Bruce D. Goulder, Philip J. R. Ndung'u, Thumbi TI CD8(+) T Cell Breadth and Ex Vivo Virus Inhibition Capacity Distinguish between Viremic Controllers with and without Protective HLA Class I Alleles SO JOURNAL OF VIROLOGY LA English DT Article ID REPLICATION-COMPETENT HIV; ELITE SUPPRESSORS; LYMPHOCYTE ESCAPE; IMMUNE CONTROL; VIRAL LOAD; DISEASE PROGRESSION; PRIMARY INFECTION; GAG PROTEIN; TYPE-1; RESPONSES AB The mechanisms of viral control and loss of viral control in chronically infected individuals with or without protective HLA class I alleles are not fully understood. We therefore characterized longitudinally the immunological and virological features that may explain divergence in disease outcome in 70 HIV-1 C-clade-infected antiretroviral therapy (ART)-naive South African adults, 35 of whom possessed protective HLA class I alleles. We demonstrate that, over 5 years of longitudinal study, 35% of individuals with protective HLA class I alleles lost viral control compared to none of the individuals without protective HLA class I alleles (P = 0.06). Sustained HIV-1 control in patients with protective HLA class I alleles was characteristically related to the breadth of HIV-1 CD8(+) T cell responses against Gag and enhanced ability of CD8(+) T cells to suppress viral replication ex vivo. In some cases, loss of virological control was associated with reduction in the total breadth of CD8(+) T cell responses in the absence of differences in HIV-1-specific CD8(+) T cell polyfunctionality or proliferation. In contrast, viremic controllers without protective HLA class I alleles possessed reduced breadth of HIV-1-specific CD8(+) T cell responses characterized by reduced ability to suppress viral replication ex vivo. These data suggest that the control of HIV-1 in individuals with protective HLA class I alleles may be driven by broad CD8(+) T cell responses with potent viral inhibitory capacity while control among individuals without protective HLA class I alleles may be more durable and mediated by CD8(+) T cell-independent mechanisms. IMPORTANCE Host mechanisms of natural HIV-1 control are not fully understood. In a longitudinal study of antiretroviral therapy (ART)naive individuals, we show that those with protective HLA class I alleles subsequently experienced virologic failure compared to those without protective alleles. Among individuals with protective HLA class I alleles, viremic control was associated with broad CD8(+) T cells that targeted the Gag protein, and CD8(+) T cells from these individuals exhibited superior virus inhibition capacity. In individuals without protective HLA class I alleles, HIV-1-specific CD8(+) T cell responses were narrow and poorly inhibited virus replication. These results suggest that broad, highly functional cytotoxic T cells (cytotoxic T lymphocytes [CTLs]) against the HIV-1 Gag protein are associated with control among those with protective HLA class I alleles and that loss of these responses eventually leads to viremia. A subset of individuals appears to have alternative, non-CTL mechanisms of viral control. These controllers may hold the key to an effective HIV vaccine. C1 [Koofhethile, Catherine K.; Ndhlovu, Zaza M.; Thobakgale-Tshabalala, Christina; Ismail, Nasreen; Mncube, Zenele; Mkhize, Lungile; van der Stok, Mary; Walker, Bruce D.; Goulder, Philip J. R.; Ndung'u, Thumbi] Univ KwaZulu Natal, Doris Duke Med Res Inst, HIV Pathogenesis Programme, Durban, South Africa. [Ndhlovu, Zaza M.; Walker, Bruce D.; Ndung'u, Thumbi] MIT, Ragon Inst, Massachusetts Gen Hosp, Boston, MA USA. [Ndhlovu, Zaza M.; Walker, Bruce D.; Ndung'u, Thumbi] Harvard Univ, Boston, MA 02115 USA. [Prado, Julia G.] Hosp Univ Germans TriasiPujol, AIDS Res Inst IrsiCaixa, Barcelona, Spain. [Yende, Nonhlanhla] Ctr AIDS Programme Res South Africa, Durban, South Africa. [Goulder, Philip J. R.] Univ Oxford, Dept Paediat, Peter Medawar Bldg Pathogen Res, Oxford, England. [Ndung'u, Thumbi] Univ KwaZulu Natal, KwaZulu Natal Res Inst TB & HIV RITH K, Durban, South Africa. [Ndung'u, Thumbi] Max Planck Inst Infect Biol, Berlin, Germany. RP Ndung'u, T (reprint author), Univ KwaZulu Natal, Doris Duke Med Res Inst, HIV Pathogenesis Programme, Durban, South Africa.; Ndung'u, T (reprint author), MIT, Ragon Inst, Massachusetts Gen Hosp, Boston, MA USA.; Ndung'u, T (reprint author), Harvard Univ, Boston, MA 02115 USA.; Ndung'u, T (reprint author), Univ KwaZulu Natal, KwaZulu Natal Res Inst TB & HIV RITH K, Durban, South Africa.; Ndung'u, T (reprint author), Max Planck Inst Infect Biol, Berlin, Germany. EM Ndungu@ukzn.ac.za FU South African Research Chairs Initiative of the Department of Science and Technology; National Research Foundation (NRF) [64809]; Victor Daitz Foundation; Howard Hughes Medical Institute (HHMI) [55007427]; Organization for Women in Science for the Developing World (OWSD); Mark and Lisa Schwartz Foundation FX This research was funded by grants from the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation (NRF) (64809), the Victor Daitz Foundation, and the Howard Hughes Medical Institute (HHMI) (55007427). Additional support was provided by the Organization for Women in Science for the Developing World (OWSD) and the Mark and Lisa Schwartz Foundation. NR 51 TC 3 Z9 3 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD AUG PY 2016 VL 90 IS 15 BP 6818 EP 6831 DI 10.1128/JVI.00276-16 PG 14 WC Virology SC Virology GA DU6EF UT WOS:000382306100017 PM 27194762 ER PT J AU Saito, A Henning, MS Serrao, E Dubose, BN Teng, S Huang, J Li, XM Saito, N Roy, SP Siddiqui, MA Ahn, J Tsuji, M Hatziioannou, T Engelman, AN Yamashita, M AF Saito, Akatsuki Henning, Matthew S. Serrao, Erik Dubose, Brittany N. Teng, Samantha Huang, Jing Li, Xiangming Saito, Namiko Roy, Saumendra Prasad Siddiqui, Mohammad Adnan Ahn, Jinwoo Tsuji, Moriya Hatziioannou, Theodora Engelman, Alan N. Yamashita, Masahiro TI Capsid-CPSF6 Interaction Is Dispensable for HIV-1 Replication in Primary Cells but Is Selected during Virus Passage In Vivo SO JOURNAL OF VIROLOGY LA English DT Article ID INTEGRATION SITE SELECTION; SIMIAN IMMUNODEFICIENCY VIRUS; NUCLEAR ENTRY; CYCLOPHILIN-A; DNA INTEGRATION; HUMANIZED MICE; HOST PROTEINS; TROPIC HIV-1; MONKEY CELLS; EARLY STEPS AB Cleavage and polyadenylation specificity factor subunit 6 (CPSF6), a host factor that interacts with the HIV-1 capsid (CA) protein, is implicated in diverse functions during the early part of the HIV-1 life cycle, including uncoating, nuclear entry, and integration targeting. Preservation of CA binding to CPSF6 in vivo suggests that this interaction is fine-tuned for efficient HIV-1 replication in physiologically relevant settings. Nevertheless, this possibility has not been formally examined. To assess the requirement for optimal CPSF6-CA binding during infection of primary cells and in vivo, we utilized a novel CA mutation, A77V, that significantly reduced CA binding to CPSF6. The A77V mutation rendered HIV-1 largely independent from TNPO3, NUP358, and NUP153 for infection and altered the integration site preference of HIV-1 without any discernible effects during the late steps of the virus life cycle. Surprisingly, the A77V mutant virus maintained the ability to replicate in monocyte-derived macrophages, primary CD4(+) T cells, and humanized mice at a level comparable to that for the wild-type (WT) virus. Nonetheless, revertant viruses that restored the WT CA sequence and hence CA binding to CPSF6 emerged in three out of four A77V-infected animals. These results suggest that the optimal interaction of CA with CPSF6, though not absolutely essential for HIV-1 replication in physiologically relevant settings, confers a significant fitness advantage to the virus and thus is strictly conserved among naturally circulating HIV-1 strains. IMPORTANCE CPSF6 interacts with the HIV-1 capsid (CA) protein and has been implicated in nuclear entry and integration targeting. Preservation of CPSF6-CA binding across various HIV-1 strains suggested that the optimal interaction between CA and CPSF6 is critical during HIV-1 replication in vivo. Here, we identified a novel HIV-1 capsid mutant that reduces binding to CPSF6, is largely independent from the known cofactors for nuclear entry, and alters integration site preference. Despite these changes, virus carrying this mutation replicated in humanized mice at levels indistinguishable from those of the wild-type virus. However, in the majority of the animals, the mutant virus reverted back to the wild-type sequence, hence restoring the wild-type level of CA-CPSF6 interactions. These results suggest that optimal binding of CA to CPSF6 is not absolutely essential for HIV-1 replication in vivo but provides a fitness advantage that leads to the widespread usage of CPSF6 by HIV-1 in vivo. C1 [Saito, Akatsuki; Henning, Matthew S.; Dubose, Brittany N.; Teng, Samantha; Huang, Jing; Li, Xiangming; Saito, Namiko; Siddiqui, Mohammad Adnan; Tsuji, Moriya; Hatziioannou, Theodora; Yamashita, Masahiro] Aaron Diamond AIDS Res Ctr, New York, NY 10016 USA. [Serrao, Erik; Engelman, Alan N.] Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02115 USA. [Roy, Saumendra Prasad; Ahn, Jinwoo] Univ Pittsburgh, Sch Med, Dept Biol Struct, Pittsburgh, PA USA. [Saito, Akatsuki] Osaka Univ, Microbial Dis Res Inst, Osaka, Japan. [Dubose, Brittany N.] Sloan Kettering Inst Canc Res, Ctr Stem Cell Biol, New York, NY USA. RP Yamashita, M (reprint author), Aaron Diamond AIDS Res Ctr, New York, NY 10016 USA. EM myamashi@adarc.org OI Tsuji, Moriya/0000-0001-8587-277X FU Mark S. Bertuch AIDS Research Fund; Leidos Inc.; HHS \ NIH \ National Institute of Allergy and Infectious Diseases (NIAID) [R01AI100720, R01AI078788, R01AI052014]; HHS \ NIH \ National Institute of General Medical Sciences (NIGMS) [R01GM116642]; Harvard University Center for AIDS Research (HU CFAR) [P30 AI060354]; Otsuka Pharmaceutical (OPC) FX This work, including the efforts of Moriya Tsuji, was funded by Mark S. Bertuch AIDS Research Fund. This work, including the efforts of Moriya Tsuji, was funded by Leidos Inc. This work, including the efforts of Masahiro Yamashita, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (R01AI100720). This work, including the efforts of Theodora Hatziioannou, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (R01AI078788). This work, including the efforts of Alan Engelman, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (R01AI052014). This work, including the efforts of Jinwoo Ahn, was funded by HHS vertical bar NIH vertical bar National Institute of General Medical Sciences (NIGMS) (R01GM116642). This work, including the efforts of Alan Engelman, was funded by Harvard University Center for AIDS Research (HU CFAR) (P30 AI060354). This work, including the efforts of Moriya Tsuji, was funded by Otsuka Pharmaceutical (OPC). NR 86 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD AUG PY 2016 VL 90 IS 15 BP 6918 EP 6935 DI 10.1128/JVI.00019-16 PG 18 WC Virology SC Virology GA DU6EF UT WOS:000382306100024 PM 27307565 ER PT J AU Rouleau, C Fernando, ATP Hwang, JH Faure, N Jiang, T White, EA Roberts, TM Schaffhausen, BS AF Rouleau, Cecile Fernando, Arun T. Pores Hwang, Justin H. Faure, Nathalie Jiang, Tao White, Elizabeth A. Roberts, Thomas M. Schaffhausen, Brian S. TI Transformation by Polyomavirus Middle T Antigen Involves a Unique Bimodal Interaction with the Hippo Effector YAP SO JOURNAL OF VIROLOGY LA English DT Article ID SIZED TUMOR-ANTIGEN; TRANSCRIPTIONAL COACTIVATOR; CELL-TRANSFORMATION; SIGNALING PATHWAY; PHOSPHATIDYLINOSITOL KINASE; TYROSINE PHOSPHORYLATION; MEDIATED TRANSFORMATION; PROTEIN PHOSPHATASE-2A; MURINE POLYOMAVIRUS; COMPLEX-FORMATION AB Murine polyomavirus has repeatedly provided insights into tumorigenesis, revealing key control mechanisms such as tyrosine phosphorylation and phosphoinositide 3-kinase (PI3K) signaling. We recently demonstrated that polyomavirus small T antigen (ST) binds YAP, a major effector of Hippo signaling, to regulate differentiation. Here we characterize YAP as a target of middle T antigen (MT) important for transformation. Through a surface including residues R103 and D182, wild-type MT binds to the YAPWW domains. Mutation of either R103 or D182 of MT abrogates YAP binding without affecting binding to other signaling molecules or the strength of PI3K or Ras signaling. Either genetic abrogation of YAP binding to MT or silencing of YAP via short hairpin RNA (shRNA) reduced MT transformation, suggesting that YAP makes a positive contribution to the transformed phenotype. MT targets YAP both by activating signaling pathways that affect it and by binding to it. MT signaling, whether from wild-type MT or the YAP-binding MT mutant, promoted YAP phosphorylation at S127 and S381/397 (YAP2/YAP1). Consistent with the known functions of these phosphorylated serines, MT signaling leads to the loss of YAP from the nucleus and degradation. Binding of YAP to MT brings it together with protein phosphatase 2A (PP2A), leading to the dephosphorylation of YAP in the MT complex. It also leads to the enrichment of YAP in membranes. Taken together, these results indicate that YAP promotes MT transformation via mechanisms that may depart from YAP's canonical oncogenic transcriptional activation functions. IMPORTANCE The highly conserved Hippo/YAP pathway is important for tissue development and homeostasis. Increasingly, changes in this pathway are being associated with cancer. Middle T antigen (MT) is the primary polyomavirus oncogene responsible for tumor formation. In this study, we show that MT signaling promotes YAP phosphorylation, loss from the nucleus, and increased turnover. Notably, MT genetics demonstrate that YAP binding to MT is important for transformation. Because MT also binds PP2A, YAP bound to MT is dephosphorylated, stabilized, and localized to membranes. Taken together, these results indicate that YAP promotes MT transformation via mechanisms that depart from YAP's canonical oncogenic transcriptional activation functions. C1 [Rouleau, Cecile; Hwang, Justin H.; Faure, Nathalie; Jiang, Tao; Schaffhausen, Brian S.] Tufts Univ, Sch Med, Dept Dev Mol & Chem Biol, Boston, MA 02111 USA. [Rouleau, Cecile; Hwang, Justin H.; Schaffhausen, Brian S.] Tufts Univ, Sackler Sch Grad Biomed Sci, Boston, MA 02111 USA. [Fernando, Arun T. Pores; Roberts, Thomas M.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Fernando, Arun T. Pores; Roberts, Thomas M.] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [White, Elizabeth A.] Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA USA. RP Schaffhausen, BS (reprint author), Tufts Univ, Sch Med, Dept Dev Mol & Chem Biol, Boston, MA 02111 USA.; Schaffhausen, BS (reprint author), Tufts Univ, Sackler Sch Grad Biomed Sci, Boston, MA 02111 USA.; Roberts, TM (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA.; Roberts, TM (reprint author), Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. EM thomas_roberts@dfci.harvard.edu; brian.schaffhausen@tufts.edu FU HHS \ NIH \ National Cancer Institute (NCI) [PO50661, CA34722, CA30002]; HHS \ National Institutes of Health (NIH) [CA50661] FX This work, including the efforts of Elizabeth A. White, was funded by HHS vertical bar NIH vertical bar National Cancer Institute (NCI) (PO50661). This work, including the efforts of Cecile Rouleau and Brian S. Schaffhausen, was funded by HHS vertical bar NIH vertical bar National Cancer Institute (NCI) (CA34722). This work, including the efforts of Arun T. Pores Fernando and Thomas M. Roberts, was funded by HHS vertical bar NIH vertical bar National Cancer Institute (NCI) (CA30002). This work, including the efforts of Thomas M. Roberts and Brian S. Schaffhausen, was funded by HHS vertical bar National Institutes of Health (NIH) (CA50661). NR 101 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 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD AUG PY 2016 VL 90 IS 16 BP 7032 EP 7045 DI 10.1128/JVI.00417-16 PG 14 WC Virology SC Virology GA DU6EJ UT WOS:000382306500003 PM 27194756 ER PT J AU Charidimou, A Soo, Y Heo, JH Srikanth, V AF Charidimou, Andreas Soo, Yannie Heo, Ji Hoe Srikanth, Velandai CA META-MICROBLEEDS Consortium TI A call for researchers to join the META-MICROBLEEDS Consortium SO LANCET NEUROLOGY LA English DT Letter ID CEREBRAL MICROBLEEDS C1 [Charidimou, Andreas] Massachusetts Gen Hosp, J Philip Kistler Stroke Res Ctr, Dept Neurol, Boston, MA 02114 USA. [Charidimou, Andreas] Harvard Med Sch, Boston, MA 02215 USA. [Soo, Yannie] Chinese Univ Hong Kong, Dept Med & Therapeut, Hong Kong, Hong Kong, Peoples R China. [Heo, Ji Hoe] Yonsei Univ, Coll Med, Dept Neurol, Seoul, South Korea. [Srikanth, Velandai] Monash Univ, Sch Clin Sci, Stroke & Ageing Res Ctr, Dept Med,Monash Hlth, Melbourne, Vic, Australia. [Srikanth, Velandai] Monash Hlth, Neurosci, Stroke Unit, Melbourne, Vic, Australia. RP Charidimou, A (reprint author), Massachusetts Gen Hosp, J Philip Kistler Stroke Res Ctr, Dept Neurol, Boston, MA 02114 USA.; Charidimou, A (reprint author), Harvard Med Sch, Boston, MA 02215 USA. EM acharidimou@mgh.harvard.edu NR 7 TC 2 Z9 2 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1474-4422 EI 1474-4465 J9 LANCET NEUROL JI Lancet Neurol. PD AUG PY 2016 VL 15 IS 9 BP 900 EP 900 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA DT1YY UT WOS:000381279200007 PM 27478945 ER PT J AU Lu, BY Thanawala, SU Zochowski, KC Burke, MJ Carroll, WL Bhatla, T AF Lu, Benjamin Y. Thanawala, Shivani U. Zochowski, Kelly C. Burke, Michael J. Carroll, William L. Bhatla, Teena TI Decitabine enhances chemosensitivity of early T-cell precursor-acute lymphoblastic leukemia cell lines and patient-derived samples SO LEUKEMIA & LYMPHOMA LA English DT Letter ID COMBINATION; PROGENITORS; INHIBITION; EXPRESSION; THERAPY; MODELS; LYL1 C1 [Lu, Benjamin Y.; Thanawala, Shivani U.; Zochowski, Kelly C.; Carroll, William L.; Bhatla, Teena] NYU, Perlmutter Canc Ctr, Langone Med Ctr, New York, NY 10012 USA. [Lu, Benjamin Y.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Burke, Michael J.] Med Coll Wisconsin, Dept Pediat, Div Hematol Oncol Blood & Marrow Transplant, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. [Burke, Michael J.] Childrens Hosp Wisconsin, Milwaukee, WI 53201 USA. RP Bhatla, T (reprint author), NYU, Perlmutter Canc Ctr, Langone Med Ctr, New York, NY 10012 USA. EM Teena.Bhatla@nyumc.org NR 17 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1042-8194 EI 1029-2403 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD AUG PY 2016 VL 57 IS 8 BP 1938 EP 1941 DI 10.3109/10428194.2015.1110747 PG 4 WC Oncology; Hematology SC Oncology; Hematology GA DT2DI UT WOS:000381290600025 PM 26726842 ER PT J AU Rashidi, A Wolach, O El-Jawahri, A Ho, VT DiPersio, JF Soiffer, R Stone, RM Chen, YB AF Rashidi, Armin Wolach, Ofir El-Jawahri, Areej Ho, Vincent T. DiPersio, John F. Soiffer, Robert Stone, Richard M. Chen, Yi-Bin TI The effect of FLT3-ITD and NPM1 mutation on survival in intensively treated elderly patients with cytogenetically normal acute myeloid leukemia SO LEUKEMIA & LYMPHOMA LA English DT Letter ID INTERNAL TANDEM DUPLICATION; TRANSPLANTATION; AML C1 [Rashidi, Armin; DiPersio, John F.] Washington Univ, Sch Med, Bone Marrow Transplantat & Leukemia Sect, Div Oncol, 660 S Euclid Ave,Campus Box 8056, St Louis, MO 63110 USA. [Wolach, Ofir; Stone, Richard M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [El-Jawahri, Areej; Ho, Vincent T.; Soiffer, Robert; Chen, Yi-Bin] Massachusetts Gen Hosp, Bone Marrow Transplant Unit, Boston, MA 02114 USA. RP Rashidi, A (reprint author), Washington Univ, Sch Med, Bone Marrow Transplantat & Leukemia Sect, Div Oncol, 660 S Euclid Ave,Campus Box 8056, St Louis, MO 63110 USA. EM arashidi@dom.wustl.edu NR 10 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1042-8194 EI 1029-2403 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD AUG PY 2016 VL 57 IS 8 BP 1977 EP 1979 DI 10.3109/10428194.2016.1161188 PG 3 WC Oncology; Hematology SC Oncology; Hematology GA DT2DI UT WOS:000381290600035 PM 27003236 ER PT J AU George, MD McGill, NK Baker, JF AF George, Michael D. McGill, Neilia-Kay Baker, Joshua F. TI Creatine kinase in the US population Impact of demographics, comorbidities, and body composition on the normal range SO MEDICINE LA English DT Article DE body composition; body mass index; CDC; Centers for Disease Control and Prevention; CK; creatine kinase; creatine phosphokinase; National Health and Nutrition Examination Survey; NHANES; race ID GENERAL-POPULATION; RACIAL-DIFFERENCES; GENDER; AGE AB Background: Creatine kinase (CK) values are a critical part of the workup of suspected myopathies and are often assessed in patients that develop myalgia on statin therapy. CK elevations may influence the initiation and cessation of statin treatment, and incidentally discovered CK elevation may lead to further testing. A number of factors influence CK levels in healthy patients, but current reference ranges do not incorporate important influencers of CK such as race. Objectives of this study were to evaluate clinical factors associated with CK among healthy individuals and to develop practical reference ranges for important subgroups to improve test interpretation. Methods: CK was evaluated in nonpregnant participants >= 20 years old from the cross-sectional National Health and Nutrition Examination Survey (NHANES) 2011-2014. Linear and logistic regression stratified by sex identified clinical factors associated with CK levels. Adjustment for anthropomorphic measures assessed whether age and race-ethnicity differences in CK were explained by differences in body composition. The 95th and 97.5th percentiles of CK in sex/race-ethnicity subgroups were calculated, excluding patients with recent strenuous exercise. Results: A total of 10,096 nonpregnant adults were studied. Black race was strongly associated with CK. The odds ratio of having an abnormal CK for black women was 5.08 (95% CI 3.65-7.08) and for black men was 8.39 (95% CI 6.11-11.52). CK was substantially lower in older men. Differences in CK by age but not race-ethnicity were largely explained by body composition. Women with low body mass index were less likely to have an elevated CK, and overweight or obese men had an almost 2-fold greater odds of having an elevated CK. The 97.5th percentile of CK was 382 (95% CI 295-469) in white men, 1001 (95% CI 718-1284) in black men, 295 (95% CI 216-374) in white women, and 487 (95% CI 310-664) in black women. Conclusion: CK is substantially higher in men and in black patients. Differences in body size and composition are also important but do not explain racial differences in CK. The 95th and 97.5th percentiles in sex and race-ethnicity subgroups provide a practical guide for clinicians interpreting CK values. C1 [George, Michael D.; McGill, Neilia-Kay; Baker, Joshua F.] Univ Penn, Div Rheumatol, Philadelphia, PA 19104 USA. [Baker, Joshua F.] Philadelphia VA Med Ctr, Philadelphia, PA USA. [Baker, Joshua F.] Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. RP George, MD (reprint author), Univ Penn, Div Rheumatol, Philadelphia, PA 19104 USA. EM michael.george@uphs.upenn.edu FU NIH [5T32AR007442-28]; Veterans Affairs Clinical Science Research & Development Career Development Award [IK2 CX000955] FX Dr. George is funded by an NIH T32 training grant (5T32AR007442-28). Dr. Baker is funded by a Veterans Affairs Clinical Science Research & Development Career Development Award (IK2 CX000955). The contents of this work do not represent the views of the Department of the Veterans Affairs or the United States Government. NR 18 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 0025-7974 EI 1536-5964 J9 MEDICINE JI Medicine (Baltimore) PD AUG PY 2016 VL 95 IS 33 AR e4344 DI 10.1097/MD.0000000000004344 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA DU5KR UT WOS:000382251100012 PM 27537560 ER PT J AU Clemons, PA Shamji, A Hon, C Wagner, BK Schreiber, SL Krasnitz, A Sordella, R Sander, C Lowe, SW Powers, S Smith, K Aburi, M Lavarone, A Lasorella, A Silva, J Stockwell, B Califano, A Boehm, JS Vazquez, F Weir, BA Golub, TR Hahn, WC Khuri, FR Moreno, CS Du, YH Cooper, L Ivanov, AA Johns, MA Fu, HA Nikolova, O Mendez, E Gadi, VK Margolin, AA Grandori, C Kemp, CJ Warren, EH Riddell, SR McIntosh, MW Gevaert, O Ji, HP Kuo, CJ Dhruv, H Finlay, D Kiefer, J Kim, S Vuori, K Berens, ME Weissman, J Bivona, T Bandyopadhyay, S Hangauer, M Boettcher, M McManus, M McCormick, F Aksoy, O Simonds, EF Zheng, TN Chen, J An, ZY Balmain, A Weiss, WA Chen, K Liang, H Scott, KL Mills, GB Posner, BA MacMillan, J Minna, J White, MA Roth, MG Jagu, S Mazerik, JN Gerhard, DS AF Clemons, Paul A. Shamji, Alykhan Hon, Cindy Wagner, Bridget K. Schreiber, Stuart L. Krasnitz, Alex Sordella, Raffaella Sander, Chris Lowe, Scott W. Powers, Scott Smith, Kenneth Aburi, Mahalaxmi Lavarone, Antonio Lasorella, Anna Silva, Jose Stockwell, Brent Califano, Andrea Boehm, Jesse S. Vazquez, Francisca Weir, Barbara A. Golub, Todd R. Hahn, William C. Khuri, Fadlo R. Moreno, Carlos S. Du, Yuhong Cooper, Lee Ivanov, Andrey A. Johns, Margaret A. Fu, Haian Nikolova, Olga Mendez, Eduardo Gadi, Vijayakrishna K. Margolin, Adam A. Grandori, Carla Kemp, Christopher J. Warren, Edus H. Riddell, Stanley R. McIntosh, Martin W. Gevaert, Olivier Ji, Hanlee P. Kuo, Calvin J. Dhruv, Harshil Finlay, Darren Kiefer, Jeffrey Kim, Seungchan Vuori, Kristiina Berens, Michael E. Weissman, Jonathan Bivona, Trever Bandyopadhyay, Sourav Hangauer, Matt Boettcher, Michael McManus, Michael McCormick, Frank Aksoy, Ozlem Simonds, Erin F. Zheng, Tina Chen, Justin An, Zhenyi Balmain, Allan Weiss, William A. Chen, Ken Liang, Han Scott, Kenneth L. Mills, Gordon B. Posner, Bruce A. MacMillan, John Minna, John White, Michael A. Roth, Michael G. Jagu, Subhashini Mazerik, Jessica N. Gerhard, Daniela S. CA Canc Target Discovery Dev Network TI Transforming Big Data into Cancer-Relevant Insight: An Initial, Multi-Tier Approach to Assess Reproducibility and Relevance The Cancer Target Discovery and Development Network SO MOLECULAR CANCER RESEARCH LA English DT Article ID DRUG-SENSITIVITY; INHIBITION; LANDSCAPE; TBK1 AB The Cancer Target Discovery and Development (CTD2) Network was established to accelerate the transformation of "Big Data" into novel pharmacologic targets, lead compounds, and biomarkers for rapid translation into improved patient outcomes. It rapidly became clear in this collaborative network that a key central issue was to define what constitutes sufficient computational or experimental evidence to support a biologically or clinically relevant finding. This article represents a first attempt to delineate the challenges of supporting and confirming discoveries arising from the systematic analysis of large-scale data resources in a collaborative work environment and to provide a framework that would begin a community discussion to resolve these challenges. The Network implemented a multi-tier framework designed to substantiate the biological and biomedical relevance as well as the reproducibility of data and insights resulting from its collaborative activities. The same approach can be used by the broad scientific community to drive development of novel therapeutic and biomarker strategies for cancer. (C) 2016 AACR. C1 [Jagu, Subhashini; Mazerik, Jessica N.; Gerhard, Daniela S.] NCI, 31 Ctr Dr, Bethesda, MD 20892 USA. [Clemons, Paul A.; Shamji, Alykhan; Hon, Cindy; Wagner, Bridget K.; Schreiber, Stuart L.] Broad Inst, Cambridge, MA USA. [Krasnitz, Alex; Sordella, Raffaella; Sander, Chris; Lowe, Scott W.; Powers, Scott] Cold Springs Harbor Lab, Cold Springs Harbor, NY USA. [Smith, Kenneth; Aburi, Mahalaxmi; Lavarone, Antonio; Lasorella, Anna; Silva, Jose; Stockwell, Brent; Califano, Andrea] Columbia Univ, New York, NY USA. [Boehm, Jesse S.; Vazquez, Francisca; Weir, Barbara A.; Golub, Todd R.; Hahn, William C.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Khuri, Fadlo R.; Moreno, Carlos S.; Du, Yuhong; Cooper, Lee; Ivanov, Andrey A.; Johns, Margaret A.; Fu, Haian] Emory Univ, Atlanta, GA 30322 USA. [Nikolova, Olga; Mendez, Eduardo; Gadi, Vijayakrishna K.; Margolin, Adam A.; Grandori, Carla; Kemp, Christopher J.; Warren, Edus H.; Riddell, Stanley R.; McIntosh, Martin W.] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Nikolova, Olga; Mendez, Eduardo; Gadi, Vijayakrishna K.; Margolin, Adam A.; Grandori, Carla; Kemp, Christopher J.] Cure First, Seattle, WA USA. [Nikolova, Olga; Mendez, Eduardo; Gadi, Vijayakrishna K.; Margolin, Adam A.; Grandori, Carla; Kemp, Christopher J.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Nikolova, Olga; Mendez, Eduardo; Gadi, Vijayakrishna K.; Margolin, Adam A.; Grandori, Carla; Kemp, Christopher J.] Univ Washington, Seattle, WA 98195 USA. [Gevaert, Olivier; Ji, Hanlee P.; Kuo, Calvin J.] Stanford Univ, Stanford, CA 94305 USA. [Dhruv, Harshil; Finlay, Darren; Kiefer, Jeffrey; Kim, Seungchan; Vuori, Kristiina; Berens, Michael E.] Translat Genom Res Inst, Phoenix, AZ USA. [Weissman, Jonathan; Bivona, Trever; Bandyopadhyay, Sourav; Hangauer, Matt; Boettcher, Michael; McManus, Michael; McCormick, Frank; Aksoy, Ozlem; Simonds, Erin F.; Zheng, Tina; Chen, Justin; An, Zhenyi; Balmain, Allan; Weiss, William A.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Chen, Ken; Liang, Han; Scott, Kenneth L.; Mills, Gordon B.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Posner, Bruce A.; MacMillan, John; Minna, John; White, Michael A.; Roth, Michael G.] Univ Texas Southwestern, Dallas, TX USA. RP Gerhard, DS (reprint author), NCI, 31 Ctr Dr, Bethesda, MD 20892 USA. EM gerhardd@mail.nih.gov RI Moreno, Carlos/B-3863-2009 OI Moreno, Carlos/0000-0002-5582-0028 FU NIH [CA176152, CA168409, CA168426, CA176058, CA168449, CA176303, CA176270, CA176299, CA168397, CA168370, CA176287, CA168394, CA176284] FX S.L. Schreiber was supported by NIH CA176152, S. Powers was supported by NIH CA168409, A. Califano was supported by NIH CA168426, W.C. Hahn was supported by NIH CA176058, H. Fu was supported by NIH CA168449, C.J. Kemp was supported by NIH CA176303, M. Mcintosh was supported by NIH CA176270, C.J. Kuo was supported by NIH CA176299, M. E. Berens was supported by NIH CA168397, M.T. Mcmanus was supported by NIH CA168370, W.A. Weiss was supported by NIH CA176287, G.B. Mills was supported by NIH CA168394, and M.G. Roth was supported by NIH CA176284. NR 20 TC 0 Z9 0 U1 12 U2 12 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1541-7786 EI 1557-3125 J9 MOL CANCER RES JI Mol. Cancer Res. PD AUG PY 2016 VL 14 IS 8 BP 675 EP 682 DI 10.1158/1541-7786.MCR-16-0090 PG 8 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DU5WJ UT WOS:000382283900001 ER PT J AU Alexandrov, V Brunner, D Menalled, LB Kudwa, A Watson-Johnson, J Mazzella, M Russell, I Ruiz, MC Torello, J Sabath, E Sanchez, A Gomez, M Filipov, I Cox, K Kwan, M Ghavami, A Ramboz, S Lager, B Wheeler, VC Aaronson, J Rosinski, J Gusella, JF MacDonald, ME Howland, D Kwak, S AF Alexandrov, Vadim Brunner, Dani Menalled, Liliana B. Kudwa, Andrea Watson-Johnson, Judy Mazzella, Matthew Russell, Ian Ruiz, Melinda C. Torello, Justin Sabath, Emily Sanchez, Ana Gomez, Miguel Filipov, Igor Cox, Kimberly Kwan, Mei Ghavami, Afshin Ramboz, Sylvie Lager, Brenda Wheeler, Vanessa C. Aaronson, Jeff Rosinski, Jim Gusella, James F. MacDonald, Marcy E. Howland, David Kwak, Seung TI Large-scale phenome analysis defines a behavioral signature for Huntington's disease genotype in mice SO NATURE BIOTECHNOLOGY LA English DT Article ID IN MOUSE MODEL; CAG-REPEAT LENGTH; DRUG DISCOVERY; EXPRESSION PROFILES; TRANSGENIC MOUSE; CONTROLLED-TRIAL; TIME-COURSE; ONSET; MOTOR; AGE AB Rapid technological advances for the frequent monitoring of health parameters have raised the intriguing possibility that an individual's genotype could be predicted from phenotypic data alone. Here we used a machine learning approach to analyze the phenotypic effects of polymorphic mutations in a mouse model of Huntington's disease that determine disease presentation and age of onset. The resulting model correlated variation across 3,086 behavioral traits with seven different CAG-repeat lengths in the huntingtin gene (Htt). We selected behavioral signatures for age and CAG-repeat length that most robustly distinguished between mouse lines and validated the model by correctly predicting the repeat length of a blinded mouse line. Sufficient discriminatory power to accurately predict genotype required combined analysis of >200 phenotypic features. Our results suggest that autosomal dominant disease-causing mutations could be predicted through the use of subtle behavioral signatures that emerge in large-scale, combinatorial analyses. Our work provides an open data platform that we now share with the research community to aid efforts focused on understanding the pathways that link behavioral consequences to genetic variation in Huntington's disease. C1 [Alexandrov, Vadim; Brunner, Dani; Menalled, Liliana B.; Kudwa, Andrea; Watson-Johnson, Judy; Mazzella, Matthew; Russell, Ian; Ruiz, Melinda C.; Torello, Justin; Sabath, Emily; Sanchez, Ana; Gomez, Miguel; Filipov, Igor; Cox, Kimberly; Kwan, Mei; Ghavami, Afshin; Ramboz, Sylvie] PsychoGenics Inc, Tarrytown, NY USA. [Lager, Brenda; Aaronson, Jeff; Rosinski, Jim; Howland, David; Kwak, Seung] CHDI Management CHDI Fdn, Princeton, NJ USA. [Wheeler, Vanessa C.; Gusella, James F.; MacDonald, Marcy E.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. RP Alexandrov, V (reprint author), PsychoGenics Inc, Tarrytown, NY USA. EM vadim.alexandrov@psychogenics.com FU CHDI Foundation, Inc. FX We are grateful to E. Leahy, V. Rivera, J. Rivera, K. Cheng, D. Lignore and L. Homa for their assistance. We thank S. Noble, D. Baker and J.-M. Lee for their thoughtful comments. This work was supported by CHDI Foundation, Inc., a nonprofit biomedical research organization exclusively dedicated to developing therapeutics that slow the progression of Huntington's disease. CHDI Foundation conducts research in a number of different ways; for the purposes of this manuscript, all research was conceptualized, planned and directed by all authors listed and conducted under a fee-for-service agreement at the contract research organization PsychoGenics, Inc. NR 47 TC 4 Z9 4 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 EI 1546-1696 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD AUG PY 2016 VL 34 IS 8 BP 838 EP + DI 10.1038/nbt.3587 PG 10 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA DT2VJ UT WOS:000381339600020 PM 27376585 ER PT J AU Kleinstiver, BP Tsai, SQ Prew, MS Nguyen, NT Welch, MM Lopez, JM McCaw, ZR Aryee, MJ Joung, JK AF Kleinstiver, Benjamin P. Tsai, Shengdar Q. Prew, Michelle S. Nguyen, Nhu T. Welch, Moira M. Lopez, Jose M. McCaw, Zachary R. Aryee, Martin J. Joung, J. Keith TI Genome-wide specificities of CRISPR-Cas Cpf1 nucleases in human cells SO NATURE BIOTECHNOLOGY LA English DT Article ID OFF-TARGET CLEAVAGE; RNA; SYSTEMS; ENDONUCLEASE; DELIVERY; TALENS; RANGE AB The activities and genome-wide specificities of CRISPR-Cas Cpf1 nucleases(1) are not well defined. We show that two Cpf1 nucleases from Acidaminococcus sp. BV3L6 and Lachnospiraceae bacterium ND2006 (AsCpf1 and LbCpf1, respectively) have on-target efficiencies in human cells comparable with those of the widely used Streptococcus pyogenes Cas9 (SpCas9)(2-5). We also report that four to six bases at the 3' end of the short CRISPR RNA (crRNA) used to program Cpf1 nucleases are insensitive to single base mismatches, but that many of the other bases in this region of the crRNA are highly sensitive to single or double substitutions. Using GUIDE-seq and targeted deep sequencing analyses performed with both Cpf1 nucleases, we were unable to detect off-target cleavage for more than half of 20 different crRNAs. Our results suggest that AsCpf1 and LbCpf1 are highly specific in human cells. C1 [Kleinstiver, Benjamin P.; Tsai, Shengdar Q.; Prew, Michelle S.; Nguyen, Nhu T.; Welch, Moira M.; Lopez, Jose M.; McCaw, Zachary R.; Aryee, Martin J.; Joung, J. Keith] Massachusetts Gen Hosp, Mol Pathol Unit, Charlestown, MA 02129 USA. [Kleinstiver, Benjamin P.; Tsai, Shengdar Q.; Prew, Michelle S.; Nguyen, Nhu T.; Welch, Moira M.; Lopez, Jose M.; McCaw, Zachary R.; Aryee, Martin J.; Joung, J. Keith] Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA 02129 USA. [Kleinstiver, Benjamin P.; Tsai, Shengdar Q.; Prew, Michelle S.; Nguyen, Nhu T.; Welch, Moira M.; Lopez, Jose M.; Joung, J. Keith] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Charlestown, MA 02129 USA. [Kleinstiver, Benjamin P.; Tsai, Shengdar Q.; Lopez, Jose M.; Aryee, Martin J.; Joung, J. Keith] Harvard Med Sch, Dept Pathol, Boston, MA 02115 USA. [McCaw, Zachary R.; Aryee, Martin J.] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. RP Kleinstiver, BP; Joung, JK (reprint author), Massachusetts Gen Hosp, Mol Pathol Unit, Charlestown, MA 02129 USA.; Kleinstiver, BP; Joung, JK (reprint author), Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA 02129 USA.; Kleinstiver, BP; Joung, JK (reprint author), Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Charlestown, MA 02129 USA.; Kleinstiver, BP; Joung, JK (reprint author), Harvard Med Sch, Dept Pathol, Boston, MA 02115 USA. EM bkleinstiver@mgh.harvard.edu; jjoung@mgh.harvard.edu OI Aryee, Martin/0000-0002-6848-1344 FU National Institutes of Health (NIH) Director's Pioneer Award [DP1 GM105378]; NIH [R01 GM107427]; Jim and Ann Orr Research Scholar Award; Natural Sciences and Engineering Research Council of Canada Postdoctoral Fellowship; Massachusetts General Hospital Collaborative Center for X-Linked Dystonia-Parkinsonism; MGH Tosteson Award FX 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., the Jim and Ann Orr Research Scholar Award (to J.K.J.), a Natural Sciences and Engineering Research Council of Canada Postdoctoral Fellowship (to B.P.K.), an award from the Massachusetts General Hospital Collaborative Center for X-Linked Dystonia-Parkinsonism, and an MGH Tosteson Award (to S.Q.T.). New reagents described in this work have been deposited with the non-profit plasmid distribution service Addgene (http://www.addgene.org/crispr-cas). NR 30 TC 17 Z9 18 U1 30 U2 32 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 EI 1546-1696 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD AUG PY 2016 VL 34 IS 8 BP 869 EP + DI 10.1038/nbt.3620 PG 7 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA DT2VJ UT WOS:000381339600025 PM 27347757 ER PT J AU Diakite, I Mooring, EQ Velasquez, GE Murray, MB AF Diakite, Ibrahim Mooring, Eric Q. Velasquez, Gustavo E. Murray, Megan B. TI Novel Ordered Stepped-Wedge Cluster Trial Designs for Detecting Ebola Vaccine Efficacy Using a Spatially Structured Mathematical Model SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID EPIDEMICS AB Background During the 2014 Ebola virus disease (EVD) outbreak, policy-makers were confronted with difficult decisions on how best to test the efficacy of EVD vaccines. On one hand, many were reluctant to withhold a vaccine that might prevent a fatal disease from study participants randomized to a control arm. On the other, regulatory bodies called for rigorous placebo-controlled trials to permit direct measurement of vaccine efficacy prior to approval of the products. A stepped-wedge cluster study (SWCT) was proposed as an alternative to a more traditional randomized controlled vaccine trial to address these concerns. Here, we propose novel "ordered stepped-wedge cluster trial" (OSWCT) designs to further mitigate tradeoffs between ethical concerns, logistics, and statistical rigor. Methodology/Principal Findings We constructed a spatially structured mathematical model of the EVD outbreak in Sierra Leone. We used the output of this model to simulate and compare a series of stepped-wedge cluster vaccine studies. Our model reproduced the observed order of first case occurrence within districts of Sierra Leone. Depending on the infection risk within the trial population and the trial start dates, the statistical power to detect a vaccine efficacy of 90% varied from 14% to 32% for standard SWCT, and from 67% to 91% for OSWCTs for an alpha error of 5%. The model's projection of first case occurrence was robust to changes in disease natural history parameters. Conclusions/Significance Ordering clusters in a step-wedge trial based on the cluster's underlying risk of infection as predicted by a spatial model can increase the statistical power of a SWCT. In the event of another hemorrhagic fever outbreak, implementation of our proposed OSWCT designs could improve statistical power when a step-wedge study is desirable based on either ethical concerns or logistical constraints. C1 [Diakite, Ibrahim; Murray, Megan B.] Harvard Med Sch, Dept Global Hlth & Social Med, Boston, MA 02115 USA. [Mooring, Eric Q.; Murray, Megan B.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Velasquez, Gustavo E.] Brigham & Womens Hosp, Div Infect Dis, 75 Francis St, Boston, MA 02115 USA. [Velasquez, Gustavo E.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Velasquez, Gustavo E.] Harvard Med Sch, Dept Med, Boston, MA USA. [Murray, Megan B.] Brigham & Womens Hosp, Div Global Hlth Equ, 75 Francis St, Boston, MA 02115 USA. [Murray, Megan B.] Partners Hlth, Boston, MA 02199 USA. RP Diakite, I; Murray, MB (reprint author), Harvard Med Sch, Dept Global Hlth & Social Med, Boston, MA 02115 USA.; Murray, MB (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.; Murray, MB (reprint author), Brigham & Womens Hosp, Div Global Hlth Equ, 75 Francis St, Boston, MA 02115 USA.; Murray, MB (reprint author), Partners Hlth, Boston, MA 02199 USA. EM ibrahim_diakite@hms.harvard.edu; megan_murray@hms.harvard.edu OI Velasquez, Gustavo/0000-0003-1438-0692 FU National Institute of Allergy and Infectious Diseases (NIH/NIAID) [U19 AI109755, T32 AI007535, T32 AI007433, L30 AI120170]; Abundance Foundation FX The project described was supported by the National Institute of Allergy and Infectious Diseases (NIH/NIAID grants U19 AI109755 to ID and MBM; T32 AI007535 to EQM.; T32 AI007433 to GEV; and L30 AI120170 to GEV) and MBM also acknowledges funding provided by a gift from the Abundance Foundation (Stephen Kahn). The project's contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. The funding sources 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 report for publication. NR 28 TC 0 Z9 0 U1 3 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD AUG PY 2016 VL 10 IS 8 AR e0004866 DI 10.1371/journal.pntd.0004866 PG 22 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA DU7JR UT WOS:000382390800019 PM 27509037 ER PT J AU Klase, ZA Khakhina, S Schneider, AD Callahan, MV Glasspool-Malone, J Malone, R AF Klase, Zachary A. Khakhina, Svetlana Schneider, Adriano De Bernardi Callahan, Michael V. Glasspool-Malone, Jill Malone, Robert TI Zika Fetal Neuropathogenesis: Etiology of a Viral Syndrome SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Review ID HERPES-SIMPLEX-VIRUS; WEST-NILE-VIRUS; HUMAN DENDRITIC CELLS; AICARDI-GOUTIERES SYNDROME; CENTRAL-NERVOUS-SYSTEM; HEPATITIS-C VIRUS; HUMAN CYTOMEGALOVIRUS-INFECTION; ANTIBODY-DEPENDENT ENHANCEMENT; CONGENITAL-RUBELLA SYNDROME; RECEPTOR TYROSINE KINASES AB The ongoing Zika virus epidemic in the Americas and the observed association with both fetal abnormalities (primary microcephaly) and adult autoimmune pathology (Guillain-Barre syndrome) has brought attention to this neglected pathogen. While initial case studies generated significant interest in the Zika virus outbreak, larger prospective epidemiology and basic virology studies examining the mechanisms of Zika viral infection and associated pathophysiology are only now starting to be published. In this review, we analyze Zika fetal neuropathogenesis from a comparative pathology perspective, using the historic metaphor of "TORCH" viral pathogenesis to provide context. By drawing parallels to other viral infections of the fetus, we identify common themes and mechanisms that may illuminate the observed pathology. The existing data on the susceptibility of various cells to both Zika and other flavivirus infections are summarized. Finally, we highlight relevant aspects of the known molecular mechanisms of flavivirus replication. C1 [Klase, Zachary A.; Khakhina, Svetlana] Univ Sci, Dept Biol Sci, Philadelphia, PA USA. [Schneider, Adriano De Bernardi] Univ North Carolina Charlotte, Dept Bioinformat & Genom, Charlotte, NC USA. [Callahan, Michael V.] Massachusetts Gen Hosp, Dept Med, Div Infect Dis, Boston, MA 02114 USA. [Callahan, Michael V.] Zika Fdn, College Stn, TX USA. [Glasspool-Malone, Jill; Malone, Robert] Ather Pharmaceut, Scottsville, VA 24590 USA. [Glasspool-Malone, Jill; Malone, Robert] Harvard Med Sch, Global Clin Scholars Res Training Program, Boston, MA 02115 USA. RP Malone, R (reprint author), Ather Pharmaceut, Scottsville, VA 24590 USA.; Malone, R (reprint author), Harvard Med Sch, Global Clin Scholars Res Training Program, Boston, MA 02115 USA. EM RWMaloneMD@gmail.com RI de Bernardi Schneider, Adriano/E-6252-2017; OI de Bernardi Schneider, Adriano/0000-0001-7487-266X; Malone, Robert/0000-0003-0340-7490 FU UNC Research Opportunities Initiative grant FX The authors received no specific funding for this work. Research reported in this publication was supported by a UNC Research Opportunities Initiative grant to UNC Charlotte, NC State University, and UNC-Chapel Hill. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 234 TC 6 Z9 6 U1 119 U2 122 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD AUG PY 2016 VL 10 IS 8 AR e0004877 DI 10.1371/journal.pntd.0004877 PG 32 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA DU7JR UT WOS:000382390800024 PM 27560129 ER PT J AU Makris, UE Paul, TM Holt, NE Latham, NK Ni, PS Jette, A Leveille, SG Bean, JF AF Makris, Una E. Paul, Tracy M. Holt, Nicole E. Latham, Nancy K. Ni, Pengsheng Jette, Alan Leveille, Suzanne G. Bean, Jonathan F. TI The Relationship Among Neuromuscular Impairments, Chronic Back Pain, and Mobility in Older Adults SO PM&R LA English DT Article ID LATE-LIFE FUNCTION; PHYSICAL PERFORMANCE BATTERY; LOWER-EXTREMITY FUNCTION; DISABILITY INSTRUMENT; SUBSEQUENT DISABILITY; RISK-ASSESSMENT; HEALTH-CARE; INCHIANTI; STRENGTH; DECLINE AB Background: For older adults with mobility problems, one focus of rehabilitation is treating the underlying neuromuscular impairment(s) that lead to functional decline and disability. Knowing which neuromuscular impairments contribute to basic mobility tasks among older adults with back pain will fill an important knowledge gap and is a critical step towards developing mechanistically based rehabilitative interventions. Objective: To evaluate the relationship of neuromuscular impairments with performance of mobility tasks among older adults with and without back pain. Design: Cross-sectional analysis of baseline data from the Boston Rehabilitative Impairment Study of the Elderly. Setting: Primary care based population. Patients: Participants (N = 430) were older primary care patients who completed assessments of neuromuscular impairments and mobility tasks. Methods: Back pain was assessed by the use of an established comorbidity questionnaire. Neuromuscular impairments included trunk extensor muscle endurance, kyphosis, leg strength, leg strength asymmetry, leg speed, mean reaction time, leg coordination, and knee and ankle range of motion. Main Outcome Measurements: Mobility tasks included gait speed, standing balance, chair stand, and patient-reported functional status. Analysis of covariance was used to generate adjusted means for neuromuscular impairments that differed significantly by back pain status. Separate multivariable regression models evaluated the association between neuromuscular impairments and mobility based on back pain status after we adjusted for sociodemographic factors and physiologic impairments. Results: Participants had an average age of 77 years, 68% were female, and 31% reported back pain. Trunk extensor muscle endurance, leg strength, and rapid leg coordination were significantly lower among those with back pain compared to those without (P < .01, P = .01, P = .04, respectively). Patterns of neuromuscular impairments that were associated with mobility tasks differed according to back pain status. Conclusions: The neuromuscular impairment profiles associated with mobility function among older adults with back pain vary compared with older adults without back pain. C1 [Makris, Una E.] UT Southwestern Med Ctr, Dept Internal Med, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. [Makris, Una E.] Dallas VAMC, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. [Paul, Tracy M.] Case Western Reserve Univ, Sch Med, Cleveland, OH USA. [Holt, Nicole E.] Spaulding Rehabil Hosp, Dept Phys Med & Rehabil, Boston, MA USA. [Latham, Nancy K.; Ni, Pengsheng; Jette, Alan] Boston Univ, Hlth Policy & Management, Boston, MA 02215 USA. [Leveille, Suzanne G.] Univ Massachusetts, Coll Nursing & Hlth Sci, Boston, MA 02125 USA. [Bean, Jonathan F.] VA Boston Healthcare Syst, New England GRECC, Dept Phys Med & Rehabil, Boston, MA USA. [Bean, Jonathan F.] Harvard Med Sch, Dept PM&R, Boston, MA USA. [Bean, Jonathan F.] Spaulding Rehabil Hosp, Boston, MA USA. RP Makris, UE (reprint author), UT Southwestern Med Ctr, Dept Internal Med, 5323 Harry Hines Blvd, Dallas, TX 75390 USA.; Makris, UE (reprint author), Dallas VAMC, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM una.makris@utsouthwestern.edu RI Bean, Jonathan/F-5798-2017 OI Bean, Jonathan/0000-0001-8385-8210 FU National Institute on Aging [5 R01 AG032052-03]; National Center for Research Resources [1 UL1 RR025758-01]; National Center for Medical Rehabilitation Research [5R24HD065688-04]; National Institutes of Health (NIH) [1K24HD070966-01]; Rheumatology Research Foundation/ASP Junior Career Development Award in Geriatric Medicine; NIA GEMSSTAR [R03AG040653]; Center for Translational Medicine; NIH/National Center for Advancing Translational Sciences Grants [KL2TR001103, UL1TR001105] FX This work was supported by the National Institute on Aging (5 R01 AG032052-03), the National Center for Research Resources in a grant to the Harvard Clinical and Translational Science Center (1 UL1 RR025758-01), and the National Center for Medical Rehabilitation Research (5R24HD065688-04). Dr Bean is supported by 1K24HD070966-01 from the National Institutes of Health (NIH). Dr Makris was supported by the Rheumatology Research Foundation/ASP Junior Career Development Award in Geriatric Medicine, NIA GEMSSTAR (R03AG040653) and the Center for Translational Medicine, and NIH/National Center for Advancing Translational Sciences Grants (KL2TR001103 and UL1TR001105). The content is solely the responsibility of the authors and does not necessarily represent the official views of the Center for Translational Medicine, UT Southwestern Medical Center and its affiliated academic and health care centers, the National Center for Advancing Translational Sciences, or the National Institutes of Health. NR 49 TC 0 Z9 0 U1 6 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1934-1482 EI 1934-1563 J9 PM&R JI PM&R PD AUG PY 2016 VL 8 IS 8 BP 738 EP 747 DI 10.1016/j.pmrj.2016.01.007 PG 10 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA DU3HV UT WOS:000382102300003 PM 26805908 ER PT J AU Vina, ER Ran, D Ashbeck, EL Ibrahim, SA Hannon, MJ Zhou, JJ Kwoh, CK AF Vina, Ernest R. Ran, Di Ashbeck, Erin L. Ibrahim, Said A. Hannon, Michael J. Zhou, Jin J. Kwoh, C. Kent TI Patient preferences for total knee replacement surgery: Relationship to clinical outcomes and stability of patient preferences over 2 years SO SEMINARS IN ARTHRITIS AND RHEUMATISM LA English DT Review DE Osteoarthritis; Knee replacement surgery; Treatment preference; Orthopedic consultation ID TOTAL JOINT ARTHROPLASTY; SOCIAL SUPPORT; OSTEOARTHRITIS; HIP; RECOMMENDATIONS; HEALTH; RACE; WILLINGNESS; MANAGEMENT; ARTHRITIS AB Objective: Evaluate the relationship between patient preferences for total knee replacement (TKR) with receipt of TKR, and assess participant characteristics that may influence change in willingness to undergo TKR. Methods: Structured interviews of knee osteoarthritis (OA) patients were conducted. Logistic regression models were conducted to assess the association between baseline willingness and eventual receipt of TKR, adjusted for sociodemographic and clinical variables. Mixed models for repeated measures were used to estimate the effects of sex, race, social support, Delta WOMAC, and orthopedic consult on change in willingness. Results: A total of 589 participants were willing, and 215 participants were unwilling to undergo TKR. Willing participants, compared to others, were more often White (69.4% vs. 48.4%), with more than a high school education (60.8% vs. 47.0%) and employed (39.1% vs. 26.5%). At follow-up, the odds of having TKR were twice as high among those who were willing to have the procedure at baseline, but this was no longer significant when adjusted for demographic variables (adjusted OR = 1.82, 95% CI: 0.89-3.69). Willingness to undergo TKR declined over 2 years. Among those who were willing to undergo TKR at baseline but did not obtain one, only 66.5% were still willing at the 2-year follow-up. This decline was less among those who had a greater increase (> median) in WOMAC disability (adjusted Delta = -0.34, 95% CI: -0.47 to -0.20) than those who had minimal change in their WOMAC disability (p = 0.08). The decline in willingness was also less among those who had seen an orthopedic surgeon (adjusted Delta = -0.32, 95% CI: -0.46 to -0.17) than those who did not (p = 0.05). Conclusions: Preference for TKR was consistent with TKR surgery utilization, but not after controlling for patient demographic characteristics. Willingness to undergo TKR declined over time, but this decrease was mitigated by worsening OA-related disability and by consultation with an orthopedic surgeon. (C) 2016 Elsevier Inc. All rights reserved. C1 [Vina, Ernest R.; Ran, Di; Ashbeck, Erin L.; Kwoh, C. Kent] Univ Arizona, Arthrit Ctr, Div Rheumatol, Dept Med, 1501 N Campbell Ave,POB 245093, Tucson, AZ 85724 USA. [Ibrahim, Said A.] Univ Penn, Dept Med, Ctr Hlth Equ Res & Promot, Philadelphia VA Med Ctr, Philadelphia, PA 19104 USA. [Hannon, Michael J.] Univ Pittsburgh, Dept Med, Div Rheumatol & Clin Immunol, Philadelphia, PA USA. [Ran, Di; Zhou, Jin J.] Univ Arizona, Mel & Enid Zuckerman Coll Publ Hlth, Epidemiol & Biostat Dept, Tucson, AZ USA. RP Vina, ER (reprint author), Univ Arizona, Arthrit Ctr, Div Rheumatol, Dept Med, 1501 N Campbell Ave,POB 245093, Tucson, AZ 85724 USA. EM evina@email.arizona.edu OI Vina, Ernest/0000-0001-8135-1731 FU NIAMS NIH HHS [P60 AR054731] NR 34 TC 0 Z9 0 U1 2 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0049-0172 EI 1532-866X J9 SEMIN ARTHRITIS RHEU JI Semin. Arthritis Rheum. PD AUG PY 2016 VL 46 IS 1 BP 27 EP 33 DI 10.1016/j.semarthrit.2016.03.012 PG 7 WC Rheumatology SC Rheumatology GA DT4JY UT WOS:000381447200003 PM 27132535 ER PT J AU Frey-Vogel, AS Scott-Vernaglia, SE Carter, LP Huang, GC AF Frey-Vogel, Ariel S. Scott-Vernaglia, Shannon E. Carter, Lindsay P. Huang, Grace C. TI Simulation for Milestone Assessment Use of a Longitudinal Curriculum for Pediatric Residents SO SIMULATION IN HEALTHCARE-JOURNAL OF THE SOCIETY FOR SIMULATION IN HEALTHCARE LA English DT Article DE Simulation; Residency education; Pediatric Milestones; Trainee assessment ID ACCREDITATION SYSTEM; RESUSCITATION; COMPETENCE; TOOL AB Introduction: Determining clinical competency on the milestones requires direct observation of residents, which is difficult for faculty members who are also providing patient care. Simulation can potentially represent an effective standardized tool for high-stakes assessment. Using a longitudinal simulation curriculum with formative and summative components, we conducted a pilot investigation to examine whether (1) performance on the formative cases predicted performance on the summative cases and (2) performance on the summative cases correlated with the clinical competency committee's (CCC) milestone placement. Methods: We developed 6 formative and 6 matched summative cases for pediatric interns that covered core pediatric topics. The interns progressed through the formative cases in pairs during the course of the academic year and then through the summative cases back to back individually at the end of the year. The interns were evaluated using a competency-based simulation evaluation. We determined the relationship between the formative and summative scores and between the summative scores and those from the CCC. Results: The relationship between formative and summative scores was not statistically significant. There was a statistically significant relationship between summative and CCC scores. Conclusions: Significant methodological limitations preclude definite conclusions about the predictive power of simulation cases for Pediatric Milestones-based assessment. However, our work is an example of how simulation is a potentially useful tool for assessing residents' skill development on the Pediatric Milestones. More rigorous research is needed to determine the extent to which simulation can be used for high-stakes, milestones-based assessment. C1 [Huang, Grace C.] Beth Israel Deaconess Med Ctr, Carl J Shapiro Inst Educ & Res, Boston, MA 02215 USA. [Frey-Vogel, Ariel S.; Scott-Vernaglia, Shannon E.; Carter, Lindsay P.] Harvard Med Sch, MassGen Hosp Children, Boston, MA USA. RP Frey-Vogel, AS (reprint author), MassGen Hosp Children, Dept Pediat, 175 Cambridge St,CPZS 592, Boston, MA 02114 USA. EM afrey@mgh.harvard.edu OI Huang, Grace/0000-0003-2965-0341 NR 22 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 1559-2332 EI 1559-713X J9 SIMUL HEALTHC JI Simul. Healthc. PD AUG PY 2016 VL 11 IS 4 BP 286 EP 292 DI 10.1097/SIH.0000000000000162 PG 7 WC Health Care Sciences & Services SC Health Care Sciences & Services GA DS6CV UT WOS:000380870200011 PM 27093513 ER PT J AU McFarland, LV Huang, Y Wang, L Malfertheiner, P AF McFarland, Lynne V. Huang, Ying Wang, Lin Malfertheiner, Peter TI Systematic review and meta-analysis: Multi-strain probiotics as adjunct therapy for Helicobacter pylori eradication and prevention of adverse events SO UNITED EUROPEAN GASTROENTEROLOGY JOURNAL LA English DT Review DE Probiotics; Helicobacter pylori; meta-analysis; adverse events; diarrhea ID RANDOMIZED-CONTROLLED-TRIALS; BIFIDOBACTERIUM-CONTAINING YOGURT; STANDARD TRIPLE THERAPY; QUADRUPLE THERAPY; PLUS LACTOFERRIN; SEQUENTIAL THERAPY; PUBLICATION BIAS; RESCUE THERAPY; LACTOBACILLUS; INFECTION AB Background Eradication rates with triple therapy for Helicobacter pylori infections have currently declined to unacceptable levels worldwide. Newer quadruple therapies are burdened with a high rate of adverse events. Whether multi-strain probiotics can improve eradication rates or diminish adverse events remains uncertain. Methods Relevant publications in which patients with H. pylori infections were randomized to a multi-strain probiotic or control were identified in PubMed, Cochrane Databases, and other sources from 1 January 1960-3 June 2015. Primary outcomes included eradication rates, incidence of any adverse event and the incidence of antibiotic-associated diarrhea. As probiotic efficacy is strain-specific, pooled relative risks and 95% confidence intervals were calculated using meta-analysis stratified by similar multi-strain probiotic mixtures. Results A total of 19 randomized controlled trials (20 treatment arms, n=2730) assessing one of six mixtures of strains of probiotics were included. Four multi-strain probiotics significantly improved H. pylori eradication rates, five significantly prevented any adverse reactions and three significantly reduced antibiotic-associated diarrhea. Only two probiotic mixtures (Lactobacillus acidophilus/Bifidobacterium animalis and an eight-strain mixture) had significant efficacy for all three outcomes. Conclusions Our meta-analysis found adjunctive use of some multi-strain probiotics may improve H. pylori eradication rates and prevent the development of adverse events and antibiotic-associated diarrhea, but not all mixtures were effective. C1 [McFarland, Lynne V.] Univ Washington, Dept Med Chem, Seattle, WA 98195 USA. [Huang, Ying; Wang, Lin] Fudan Univ, Childrens Hosp, Div Gastroenterol, Shanghai, Peoples R China. [Malfertheiner, Peter] Univ Klinikum Magdeburg AOR, Magdeburg, Germany. RP McFarland, LV (reprint author), VA Puget Sound Healthcare Syst, 1660 South Columbian Way,S-152, Seattle, WA 98108 USA. EM lvmcfarl@u.washington.edu NR 71 TC 0 Z9 0 U1 9 U2 10 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 2050-6406 EI 2050-6414 J9 UNITED EUR GASTROENT JI United European Gastroenterol. J. PD AUG PY 2016 VL 4 IS 4 BP 546 EP 561 DI 10.1177/2050640615617358 PG 16 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DS7EQ UT WOS:000380946200009 PM 27536365 ER PT J AU Tian, HJ Du, JJ Wen, J Liu, Y Montgomery, SR Scott, TP Aghdsi, B Xiong, CJ Suzuki, A Hayashi, T Ruangchainikom, M Phan, K Weintraub, G Raed, A Murray, SS Daubs, MD Yang, XJ Yuan, XB Wang, JC Lu, YF AF Tian, Haijun Du, Juanjuan Wen, Jing Liu, Yang Montgomery, Scott R. Scott, Trevor P. Aghdsi, Bayan Xiong, Chengjie Suzuki, Akinobu Hayashi, Tetsuo Ruangchainikom, Monchai Phan, Kevin Weintraub, Gil Raed, Alobaidaan Murray, Samuel S. Daubs, Michael D. Yang, Xianjin Yuan, Xu-bo Wang, Jeffrey C. Lu, Yunfeng TI Growth-Factor Nanocapsules That Enable Tunable Controlled Release for Bone Regeneration SO ACS NANO LA English DT Article DE protein nanocapsule; degradable polymer; controlled release; bone regeneration; inflammation ID CONTROLLED DRUG-DELIVERY; ANTERIOR CERVICAL-SPINE; MORPHOGENETIC PROTEIN; IN-VIVO; RODENT MODEL; HYDROGELS; MATRICES; THERAPY; FUSION; INFLAMMATION AB Growth factors are of great potential in regenerative medicine. However, their clinical applications are largely limited by the short in vivo half-lives and the narrow therapeutic window. Thus, a robust controlled release system remains an unmet medical need for growth factor-based therapies. In this research, a nanoscale controlled release system (degradable protein nanocapsule) is established via in situ polymerization on growth factor. The release rate can be finely tuned by engineering the surface polymer composition. Improved therapeutic outcomes can be achieved with growth factor nanocapsules, as illustrated in spinal cord fusion mediated by bone morphogenetic protein-2 nanocapsules. C1 [Tian, Haijun; Du, Juanjuan; Wen, Jing; Liu, Yang; Lu, Yunfeng] Univ Calif Los Angeles, Dept Chem & Biomol Engn, Los Angeles, CA 90095 USA. [Tian, Haijun; Montgomery, Scott R.; Scott, Trevor P.; Aghdsi, Bayan; Xiong, Chengjie; Suzuki, Akinobu; Hayashi, Tetsuo; Ruangchainikom, Monchai; Phan, Kevin; Weintraub, Gil; Raed, Alobaidaan; Wang, Jeffrey C.] Univ Calif Los Angeles, Dept Orthopaed Surg, Los Angeles, CA 90095 USA. [Yang, Xianjin; Yuan, Xu-bo] Tianjin Univ, Dept Mat Sci, Tianjin 300072, Peoples R China. [Tian, Haijun] Bethune Sch Medics, Dept Surg, Shijiazhuang 050000, Peoples R China. [Tian, Haijun] Second Mil Med Univ, Changzheng Hosp, Dept Orthopaed Surg, Shanghai 200003, Peoples R China. [Murray, Samuel S.] VA Greater Los Angeles Healthcare Syst, Res Serv, North Hills, CA 91343 USA. [Daubs, Michael D.] Univ Nevada, Sch Med, Dept Surg, Div Orthopaed Surg, Las Vegas, NV 89102 USA. [Wang, Jeffrey C.] Univ Southern Calif, Dept Orthopaed Surg, Los Angeles, CA 90033 USA. RP Lu, YF (reprint author), Univ Calif Los Angeles, Dept Chem & Biomol Engn, Los Angeles, CA 90095 USA.; Wang, JC (reprint author), Univ Calif Los Angeles, Dept Orthopaed Surg, Los Angeles, CA 90095 USA.; Yuan, XB (reprint author), Tianjin Univ, Dept Mat Sci, Tianjin 300072, Peoples R China.; Wang, JC (reprint author), Univ Southern Calif, Dept Orthopaed Surg, Los Angeles, CA 90033 USA. EM xbyuan@tju.edu.cn; Jeffrey.wang@med.usc.edu; luucla@ucla.edu FU National Nature Science Foundation of China [81402229]; International Science and Technology Cooperation Program of China [2012DFA51690] FX This work was supported by the National Nature Science Foundation of China (Grant No. 81402229) and International Science and Technology Cooperation Program of China (Grant No. 2012DFA51690). NR 45 TC 0 Z9 0 U1 22 U2 31 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1936-0851 EI 1936-086X J9 ACS NANO JI ACS Nano PD AUG PY 2016 VL 10 IS 8 BP 7362 EP 7369 DI 10.1021/acsnano.5b07950 PG 8 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Chemistry; Science & Technology - Other Topics; Materials Science GA DU1HP UT WOS:000381959100015 PM 27227573 ER PT J AU Qu, H Csordas, AT Wang, JP Oh, SS Eisenstein, MS Soh, HT AF Qu, Hao Csordas, Andrew T. Wang, Jinpeng Oh, Seung Soo Eisenstein, Michael S. Soh, Hyongsok Tom TI Rapid and Label-Free Strategy to Isolate Aptamers for Metal Ions SO ACS NANO LA English DT Article DE aptamers; molecular screening; metal ions; fluorescence-activated cell sorting ID DNA-POLYMERASE; SELECTION; MERCURY; SENSORS; HG2+ AB Generating aptamers that bind to specific metal ions is challenging because existing aptamer discovery methods typically require chemical labels or modifications that can alter the structure and properties of the ions. In this work, we report an aptamer discovery method that enables us to generate high-quality structure-switching aptamers (SSAs) that undergo a conformational change upon binding a metal ion target, without the requirement of labels or chemical modifications. Our method is more efficient than conventional selection methods because it enables direct measurement of target binding via fluorescence-activated cell sorting (FACS), isolating only the desired aptamers with the highest affinity. Using this strategy, we obtained a highly specific DNA SSA with similar to 30-fold higher affinity than the best aptamer for Hg2+ in the literature. We also discovered DNA aptamers that bind to Cu2+ with excellent affinity and specificity. Both aptamers were obtained within four rounds of screening, demonstrating the efficiency of our aptamer discovery method. Given the growing availability of FACS, we believe our method offers a general strategy for discovering high-quality aptamers for other ions and small-molecule targets in an efficient and reproducible manner. C1 [Qu, Hao] Hefei Univ Technol, Sch Biol & Med Engn, Hefei 230009, Anhui, Peoples R China. [Csordas, Andrew T.; Eisenstein, Michael S.] Univ Calif Santa Barbara, Dept Mat, Santa Barbara, CA 93111 USA. [Wang, Jinpeng] Aptitude Med Syst, Santa Barbara, CA 93105 USA. [Oh, Seung Soo] Harvard Med Sch, Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Soh, Hyongsok Tom] Stanford Univ, Dept Elect Engn, Stanford, CA 94305 USA. [Soh, Hyongsok Tom] Stanford Univ, Dept Radiol, Stanford, CA 94305 USA. RP Soh, HT (reprint author), Stanford Univ, Dept Elect Engn, Stanford, CA 94305 USA.; Soh, HT (reprint author), Stanford Univ, Dept Radiol, Stanford, CA 94305 USA. EM tsoh@stanford.edu RI Oh, Seung Soo/N-6315-2016 OI Oh, Seung Soo/0000-0001-8045-080X FU Garland Initiative; ARO Institute for Collaborative Biotechnologies [W911F-09-D-0001, W81XWH-09-0698]; DARPA [N66001-14-2-4055]; National Institutes of Health [U01 HL099773] FX We are grateful for the financial support of the Garland Initiative, ARO Institute for Collaborative Biotechnologies (W911F-09-D-0001, W81XWH-09-0698), DARPA (N66001-14-2-4055), and National Institutes of Health (U01 HL099773). We thank Prof. James A. Thomson, Prof. Peter Coffey, Dr. Susanne Meyer, and Dr. Monte Radeke for assistance with the cell sorter instrument. We thank Margaret A. Nakamoto for assistance in editing the manuscript. NR 34 TC 3 Z9 3 U1 33 U2 47 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1936-0851 EI 1936-086X J9 ACS NANO JI ACS Nano PD AUG PY 2016 VL 10 IS 8 BP 7558 EP 7565 DI 10.1021/acsnano.6b02558 PG 8 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Chemistry; Science & Technology - Other Topics; Materials Science GA DU1HP UT WOS:000381959100038 PM 27399153 ER PT J AU Jacobsson, J Borgquist, R Reitan, C Ghafoori, E Chatterjee, NA Kabir, M Platonov, PG Carlson, J Singh, JP Tereshchenko, LG AF Jacobsson, Jonatan Borgquist, Rasmus Reitan, Christian Ghafoori, Elyar Chatterjee, Neal A. Kabir, Muammar Platonov, Pyotr G. Carlson, Jonas Singh, Jagmeet P. Tereshchenko, Larisa G. TI Usefulness of the Sum Absolute QRST Integral to Predict Outcomes in Patients Receiving Cardiac Resynchronization Therapy SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID ACCF/AHA/HRS 2008 GUIDELINES; DEVICE-BASED THERAPY; HEART-FAILURE; FOCUSED UPDATE; ESC GUIDELINES; RHYTHM ABNORMALITIES; TASK-FORCE; DURATION; DIAGNOSIS; SOCIETY AB Cardiac resynchronization therapy (CRT) reduces mortality and morbidity in selected patients with heart failure (HF), but up to 1/3 of patients are nonresponders. Sum absolute QRST integral (SAI QRST) recently showed association with mechanical response on CRT. However, it is unknown whether SAI QRST is associated with all-cause mortality and HF hospitalizations in patients undergoing CRT. The study population included 496 patients undergoing CRT (mean age 69 +/- 10 years, 84% men, 65% left-bundle branch block [LBBB], left ventricular ejection, fraction 23 +/- 6%, 63% ischemic cardiomyopathy). Preimplant digital 12-lead electrocardiogram was transformed into orthogonal XYZ electrocardiogram. SAI QRST was measured as an arithmetic sum of areas under the QRST curve on XYZ leads and was dichotomized based on the median value (302 mV ms). All-cause mortality served as the primary end point. A composite of 2-year all-cause mortality, heart transplant, and HF hospitalization was a secondary end point. Cox regression models were adjusted for known predictors of CRT response. Patients with preimplant low mean SAI QRST had an increased risk of both the primary (hazard ratio [HR] 1.8, 95% CI 1.01 to 3.2) and secondary (HR 1.6, 95% CI 1.1 to 2.2) end points after multivariate adjustment. SAI QRST was associated with secondary outcome in subgroups of patients with LBBB (HR 2.1, 95% CI 1.5 to 3.0) and with non-LBBB (HR 1.7, 95% CI 1.0 to 2.6). In patients undergoing CRT, preimplant SAI QRST <302 mV ms was associated with an increased risk of all-cause mortality and HF hospitalization. After validation in another prospective cohort, SAI QRST may help to refine selection of CRT recipients. (C) 2016 Elsevier Inc. All rights reserved. C1 [Jacobsson, Jonatan; Borgquist, Rasmus; Reitan, Christian; Platonov, Pyotr G.; Carlson, Jonas] Lund Univ, Dept Cardiol, Clin Sci, Lund, Sweden. [Jacobsson, Jonatan; Borgquist, Rasmus; Reitan, Christian; Platonov, Pyotr G.; Carlson, Jonas] Skane Univ Hosp, Arrhythmia Clin, Lund, Sweden. [Borgquist, Rasmus; Chatterjee, Neal A.; Singh, Jagmeet P.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Ghafoori, Elyar; Kabir, Muammar; Tereshchenko, Larisa G.] Oregon Hlth & Sci Univ, Knight Cardiovasc Inst, Electrophysiol Chapter, Portland, OR 97201 USA. RP Tereshchenko, LG (reprint author), Oregon Hlth & Sci Univ, Knight Cardiovasc Inst, Electrophysiol Chapter, Portland, OR 97201 USA. EM tereshch@ohsu.edu OI Jacobsson, Jonatan/0000-0002-7400-7913; Tereshchenko, Larisa/0000-0002-6976-1313 FU National Institute of Health (Bethesda, MD) [1R0HL118277]; Swedish Heart-Lung Foundation; Per Westling Memorial Fund; Knut and Alice Wallenberg Fund; Maggie Stephen Fund; Swedish National Health Service FX This research was supported in part by the grant #1R0HL118277 from National Institute of Health (Bethesda, MD) (LGT). This research was supported by grants from the Swedish Heart-Lung Foundation (R.B., P.G.P.), by Per Westling Memorial Fund (R.B.), Knut and Alice Wallenberg Fund (R.B.), the Maggie Stephen Fund (R.B.) and by governmental funding of clinical research within the Swedish National Health Service (R.B., P.G.P.). NR 19 TC 0 Z9 0 U1 3 U2 3 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 AUG 1 PY 2016 VL 118 IS 3 BP 389 EP 395 DI 10.1016/j.amjcard.2016.05.017 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DS6BP UT WOS:000380867000013 PM 27265674 ER PT J AU Cheng, FW Li, YP Winkelman, JW Hu, FB Rimm, EB Gao, X AF Cheng, Feon W. Li, Yanping Winkelman, John W. Hu, Frank B. Rimm, Eric B. Gao, Xiang TI Probable insomnia is associated with future total energy intake and diet quality in men SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE cohort; diet quality; energy intake; insomnia; sleep disorders ID SHORT-SLEEP DURATION; NORMAL-WEIGHT INDIVIDUALS; CARDIOVASCULAR-DISEASE; POSTMENOPAUSAL WOMEN; PHYSICAL-ACTIVITY; JAPANESE WORKERS; NUTRIENT INTAKE; FOOD-INTAKE; RISK; SYMPTOMS AB Background: Insomnia is associated with several adverse health outcomes. Small clinical studies have suggested that an inferior nutrition status is a potential explanation, but to our knowledge, this possibility has not been examined in a large-scale, population-based cohort study. Objective: We examined whether individuals with probable insomnia and individual insomnia symptoms had greater energy intake and a lower diet quality as assessed with the use of the Alternate Healthy Eating Index (AHEI) 2 y later. Design: A cohort study of 15,273 US men aged 58-93 y who were free of cancer, cardiovascular diseases, and diabetes and were participating in the Health Professionals Follow-Up Study reported information on insomnia symptoms in 2004. Dietary intake was assessed with the use of a food-frequency questionnaire in 2002 and 2006. We calculated the adjusted mean differences of total energy intake in 2006 and the AHEI-component scores and their 95% CIs between subjects with and without probable insomnia in 2004 and also across categories for each insomnia symptom while adjusting for related covariates. Results: After dietary intake in 2002, major chronic conditions, and other potential confounders were controlled for, men with probable insomnia had a mean higher consumption of 35.8 kcal/d (95% CI: 17.4, 54.1 kcal/d) and had lower scores in 3 individual AHEI components (trans fat, vegetables, and sodium), which denoted higher consumption of trans fat and sodium and lower intake of vegetables (P <= 0.01 for all). For individual insomnia symptoms, nonrestorative sleep and a difficulty maintaining sleep were associated with higher energy intake (P-trend <= 0.007 for both). A similar trend was observed in men who had difficulty initiating sleep (P-trend = 0.07). We also observed a significant association between the difficulty of initiating sleep and a lower AHEI score 2 y later (P-trend = 0.004). Conclusion: Probable insomnia is associated with higher intakes of total energy, trans fat, and sodium and lower intake of vegetables. C1 [Cheng, Feon W.; Gao, Xiang] Penn State Univ, Dept Nutr Sci, University Pk, PA 16802 USA. [Li, Yanping; Hu, Frank B.; Rimm, Eric B.] Harvard Sch Publ Hlth, Dept Nutr, Boston, MA USA. [Winkelman, John W.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Hu, Frank B.; Rimm, Eric B.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Hu, Frank B.; Rimm, Eric B.] Harvard Med Sch, Boston, MA USA. RP Gao, X (reprint author), Penn State Univ, Dept Nutr Sci, University Pk, PA 16802 USA. EM xxg14@psu.edu FU National Institute of Neurological Disorders and Stroke [R01 NS062879-01A2]; NIH [UM1 CA167552] FX Supported in part by the National Institute of Neurological Disorders and Stroke (grant R01 NS062879-01A2) and the NIH (grant UM1 CA167552). NR 40 TC 1 Z9 1 U1 13 U2 13 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD AUG 1 PY 2016 VL 104 IS 2 BP 462 EP 469 DI 10.3945/ajcn.116.131060 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DU0CZ UT WOS:000381870200027 PM 27413124 ER PT J AU Buland, JR Wasserloos, KJ Tyurin, VA Tyurina, YY Amoscato, AA Mallampalli, RK Chen, BB Zhao, J Zhao, YT Ofori-Acquah, S Kagan, VE Pitt, BR AF Buland, Justin R. Wasserloos, Karla J. Tyurin, Vladimir A. Tyurina, Yulia Y. Amoscato, Andrew A. Mallampalli, Rama K. Chen, Bill B. Zhao, Jing Zhao, Yutong Ofori-Acquah, Solomon Kagan, Valerian E. Pitt, Bruce R. TI Biosynthesis of oxidized lipid mediators via lipoprotein-associated phospholipase A(2) hydrolysis of extracellular cardiolipin induces endothelial toxicity SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Article DE cardiolipin; pulmonary endothelium; octadecadienoic acid; lineolic acid; lipoprotein-associated phospholipase A(2) ID PLATELET-ACTIVATING-FACTOR; ACUTE LUNG INJURY; RESPIRATORY-DISTRESS-SYNDROME; MASS-SPECTROMETRIC CHARACTERIZATION; BRONCHOALVEOLAR LAVAGE FLUID; FACTOR ACETYLHYDROLASE; PHOSPHATIDYLSERINE PEROXIDATION; OXIDATIVE LIPIDOMICS; ACUTE-INFLAMMATION; DOUBLE-BLIND AB We (66) have previously described an NSAID-insensitive intramitochondrial biosynthetic pathway involving oxidation of the polyunsaturated mitochondrial phospholipid, cardiolipin (CL), followed by hydrolysis [by calcium-independent mitochondrial calcium-independent phospholipase A(2)-gamma (iPLA(2)gamma)] of oxidized CL (CLox), leading to the formation of lysoCL and oxygenated octadecadienoic metabolites. We now describe a model system utilizing oxidative lipidomics/mass spectrometry and bioassays on cultured bovine pulmonary artery endothelial cells (BPAECs) to assess the impact of CLox that we show, in vivo, can be released to the extracellular space and may be hydrolyzed by lipoprotein-associated PLA(2) (Lp-PLA(2)). Chemically oxidized liposomes containing bovine heart CL produced multiple oxygenated species. Addition of Lp-PLA(2) hydrolyzed CLox and produced (oxygenated) monolysoCL and dilysoCL and oxidized octadecadienoic metabolites including 9- and 13-hydroxyoctadecadienoic (HODE) acids. CLox caused BPAEC necrosis that was exacerbated by Lp-PLA(2). Lower doses of nonlethal CLox increased permeability of BPAEC monolayers. This effect was exacerbated by Lp-PLA(2) and partially mimicked by authentic monolysoCL or 9- or 13-HODE. Control mice plasma contained virtually no detectable CLox; in contrast, 4 h after Pseudomonas aeruginosa (P. aeruginosa) infection, 34 +/- 8 mol% (n = 6; P < 0.02) of circulating CL was oxidized. In addition, molar percentage of monolysoCL increased twofold after P. aeruginosa in a subgroup analyzed for these changes. Collectively, these studies suggest an important role for 1) oxidation of CL in proinflammatory environments and 2) possible hydrolysis of CLox in extracellular spaces producing lysoCL and oxidized octadecadienoic acid metabolites that may lead to impairment of pulmonary endothelial barrier function and necrosis. C1 [Buland, Justin R.] Childrens Hosp Pittsburgh, Pittsburgh, PA 15213 USA. [Wasserloos, Karla J.; Tyurin, Vladimir A.; Tyurina, Yulia Y.; Amoscato, Andrew A.; Kagan, Valerian E.; Pitt, Bruce R.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. [Buland, Justin R.; Zhao, Yutong; Ofori-Acquah, Solomon] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Buland, Justin R.; Zhao, Jing; Zhao, Yutong; Ofori-Acquah, Solomon] Vasc Med Inst, Pittsburgh, PA USA. [Mallampalli, Rama K.; Chen, Bill B.; Zhao, Jing; Zhao, Yutong] Univ Pittsburgh, Sch Med, Dept Med, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA 15213 USA. [Mallampalli, Rama K.; Chen, Bill B.; Zhao, Jing; Zhao, Yutong] Univ Pittsburgh, Sch Med, Acute Lung Injury Ctr Excellence, Pittsburgh, PA USA. [Mallampalli, Rama K.] VA Pittsburgh Hlth Care Syst, Pittsburgh, PA USA. [Mallampalli, Rama K.] Univ Pittsburgh, Sch Med, Dept Cell Biol & Physiol, Pittsburgh, PA USA. RP Pitt, BR (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, Dept Environm Occupat Hlth, Bridgeside Point 1,100 Technol Dr, Pittsburgh, PA 15219 USA. EM brucep@pitt.edu FU Children's Hospital of Pittsburgh Scholars Award; NIH [PO1 114,453, UL1 TR000005, K12HD052892]; University of Pittsburgh Vascular Medicine Institute FX This work was supported in part by grants from the University of Pittsburgh Vascular Medicine Institute, Children's Hospital of Pittsburgh Scholars Award, NIH PO1 114,453, UL1 TR000005, and K12HD052892. NR 73 TC 0 Z9 0 U1 6 U2 6 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1040-0605 EI 1522-1504 J9 AM J PHYSIOL-LUNG C JI Am. J. Physiol.-Lung Cell. Mol. Physiol. PD AUG 1 PY 2016 VL 311 IS 2 BP L303 EP L316 DI 10.1152/ajplung.00038.2016 PG 14 WC Physiology; Respiratory System SC Physiology; Respiratory System GA DT6XP UT WOS:000381628600011 PM 27233995 ER PT J AU Kohler, O Gasse, C Petersen, L Ingstrup, KG Nierenberg, AA Mors, O Ostergaard, SD AF Kohler, Ole Gasse, Christiane Petersen, Liselotte Ingstrup, Katja G. Nierenberg, Andrew A. Mors, Ole Ostergaard, Soren D. TI The Effect of Concomitant Treatment With SSRIs and Statins: A Population-Based Study SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID MAJOR DEPRESSIVE DISORDER; CENTRAL RESEARCH REGISTER; STAR-ASTERISK-D; DRUG-INTERACTIONS; CLINICAL-TRIAL; RISK-FACTORS; DANISH; SYMPTOMS; METAANALYSIS; FLUOXETINE AB Objective: Both preclinical studies and clinical trials have indicated that the combination of a selective serotonin re-uptake inhibitor (SSRI) and a statin may have superior antidepressant effects compared with SSRI treatment alone. The authors sought to assess whether this beneficial effect can be generalized to a more heterogeneous population of SSRI users. Method: In a nationwide cohort study that included all incident SSRI users in Denmark between 1997 and 2012, the authors compared people who had periods of concomitant use of SSRIs and statins with people who had periods of SSRI treatment alone. Outcomes included the rates of psychiatric hospital contacts (any cause), psychiatric hospital contacts due to depression, suicidal behavior, and all-cause mortality. Using Cox regression and competing risk analysis, the authors calculated crude and adjusted hazard ratios for these outcomes. Results: The authors identified 872,216 incident SSRI users, of whom 113,108 (13.0%) used a statin concomitantly. Compared with SSRI treatment alone, the combined use of an SSRI and a statin was associated with a significantly lower risk for both psychiatric hospital contacts (adjusted hazard ratio=0.75 (95% CI=0.69, 0.82) and psychiatric hospital contacts due to depression (adjusted hazard ratio=0.64, 95% CI=0.55, 0.75). Compared with SSRI treatment alone, the concomitant use of SSRIs and statins was not associated with significant increases in all-cause mortality (adjusted hazard ratio=1.04, 95% CI=0.96, 1.12) or suicidal behavior (adjusted hazard ratio=0.85, 95% CI=0.61, 1.18). Conclusions: In a large naturalistic cohort, concomitant treatment with SSRIs and statins resulted in robust advantages compared with SSRIs alone. C1 [Kohler, Ole] Aarhus Univ Hosp, Psychosis Res Unit, Risskov, Denmark. Lundbeck Fdn Initiat Integrat Psychiat Res iPSYCH, Aarhus, Denmark. Aarhus Univ, Natl Ctr Register Based Res, Aarhus, Denmark. Harvard Med Sch, Massachusetts Gen Hosp, Depress Clin & Res Program, Boston, MA USA. Harvard Med Sch, Massachusetts Gen Hosp, Bipolar Clin, Boston, MA USA. Harvard Med Sch, Massachusetts Gen Hosp, Res Program, Boston, MA USA. Aarhus Univ CIRRAU, Ctr Integrated Register Based Res, Aarhus, Denmark. Aarhus Univ, Dept Clin Med, Aarhus, Denmark. RP Kohler, O (reprint author), Aarhus Univ Hosp, Psychosis Res Unit, Risskov, Denmark. EM karlkoeh@rm.dk OI Ingstrup, Katja Glejsted/0000-0001-7288-5336; Ostergaard, Soren Dinesen/0000-0002-8032-6208; Kohler-Forsberg, Ole/0000-0001-5121-1287 FU Eli Lilly; Lundbeck; LASER Analytica; European Union Seventh Framework Programme [279227]; Innovative Medicines Initiative Joint Undertaking resources; American Foundation for Suicide Prevention; Agency for Healthcare Research and Quality; Brain and Behavior Research Foundation; Bristol-Myers Squibb; Cederroth; Cephalon; Cyberonics; Elan; Forest; GlaxoSmithKline; Janssen; Lichtwer Pharma; Marriott Foundation; Mylan; NIMH; Pamlab; Patient-Centered Outcomes Research Institute; Pfizer; Shire; Stanley Foundation; Takeda; Wyeth-Ayerst FX Dr. Gasse has received unrestricted research grants from Eli Lilly and Lundbeck, funding through research collaboration with LASER Analytica, funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement 279227, and support from the Innovative Medicines Initiative Joint Undertaking resources, which were composed of financial contributions from the European Union Seventh Framework Programme and in-kind contributions from members of the European Federation of Pharmaceutical Industries and Associations. Dr. Nierenberg has served as a consultant for Abbott Laboratories, the American Psychiatric Association, Appliance Computing, Inc. (Mindsite), Basilea, Brain Cells, Brandeis University, Bristol-Myers Squibb, Clintara, Corcept, Dey Pharmaceuticals, Dainippon Sumitomo (now Sunovion), Eli Lilly, EpiQ, L.P./Mylan, Forest, Genaissance, Genentech, GlaxoSmithKline, Healthcare Global Village, Hoffman-LaRoche, Infomedic, Lundbeck, Janssen, Jazz Pharmaceuticals, MedAvante, Merck, Methylation Sciences, Naurex, Novartis, Pamlab, Parexel, Pfizer, PGx Health, Otsuka, Ridge Diagnostics, Shire, Schering-Plough, Somerset, Sunovion, Takeda, Targacept, and Teva; he has also served as a consultant through the MGH Clinical Trials Network and Institute for AstraZeneca, Brain Cells, Dainippon Sumitomo/Sepracor, Johnson & Johnson, Labopharm, Merck, Methylation Sciences, Novartis, PGx Health, Shire, Schering-Plough, Targacept, and Takeda/Lundbeck; he has received grants or research support from the American Foundation for Suicide Prevention, the Agency for Healthcare Research and Quality, the Brain and Behavior Research Foundation, Bristol-Myers Squibb, Cederroth, Cephalon, Cyberonics, Elan, Eli Lilly, Forest, GlaxoSmithKline, Janssen, Lichtwer Pharma, the Marriott Foundation, Mylan, NIMH, Pamlab, the Patient-Centered Outcomes Research Institute, Pfizer, Shire, the Stanley Foundation, Takeda, and Wyeth-Ayerst; he has received honoraria from Belvoir Publishing, University of Texas Southwestern Dallas, Brandeis University, Bristol-Myers Squibb, Hillside Hospital, American Drug Utilization Review, the American Society for Clinical Psychopharmacology, Baystate Medical Center, Columbia University, CRICO, Dartmouth Medical School, Health New England, the Harold Grinspoon Charitable Foundation, IMEDEX, the International Society for Bipolar Disorder, the Israel Society for Biological Psychiatry, Johns Hopkins University, MJ Consulting, New York State, Medscape, MBL Publishing, MGH Psychiatry Academy, the National Association of Continuing Education, Physicians Postgraduate Press, SUNY Buffalo, University of Pisa, University of Michigan, University of Miami, University of Wisconsin at Madison, the American Professional Society of ADHD and Related Disorders, the International Society for Bipolar Disorders, SciMed, Slack Publishing, Wolters Kluwer Publishing, the American Society of Clinical Psychopharmacology, the New Clinical Drug Evaluation Unit, Rush Medical College, Yale University School of Medicine, the National Network of Depression Centers, Nova Southeastern University, NAMI, the Institute of Medicine, CME Institute, the International Society for CNS Clinical Trials and Methodology, the World Congress on Brain Behavior and Emotion, the Congress of the Hellenic Society for Basic and Clinical Pharmacology, and the Anxiety and Depression Association of America; he owns stock in Appliance Computing, Inc.; (MindSite), Brain Cells, and MedAvante; and he holds copyrights for the Clinical Positive Affect Scale and the MGH Structured Clinical Interview for the Montgomery-angstrom sberg Depression Rating Scale, exclusively licensed to the MGH Clinical Trials Network and Institute. The other authors report no financial relationships with commercial interests. NR 36 TC 2 Z9 2 U1 1 U2 2 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X EI 1535-7228 J9 AM J PSYCHIAT JI Am. J. Psychiat. PD AUG 1 PY 2016 VL 173 IS 8 BP 807 EP 815 DI 10.1176/appi.ajp.2016.15040463 PG 9 WC Psychiatry SC Psychiatry GA DT6WA UT WOS:000381624100011 PM 27138586 ER PT J AU Singh, JB Fedgchin, M Daly, EJ De Boer, P Cooper, K Lim, P Pinter, C Murrough, JW Sanacora, G Shelton, RC Kurian, B Winokur, A Fava, M Manji, H Drevets, WC Van Nueten, L AF Singh, Jaskaran B. Fedgchin, Maggie Daly, Ella J. De Boer, Peter Cooper, Kimberly Lim, Pilar Pinter, Christine Murrough, James W. Sanacora, Gerard Shelton, Richard C. Kurian, Benji Winokur, Andrew Fava, Maurizio Manji, Husseini Drevets, Wayne C. Van Nueten, Luc TI A Double-Blind, Randomized, Placebo-Controlled, Dose-Frequency Study of Intravenous Ketamine in Patients With Treatment-Resistant Depression SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID MAJOR DEPRESSION; SYMPTOMATOLOGY; VALIDATION; DISORDERS; INVENTORY; TRIAL AB Objective: Ketamine, an N-methyl-D-aspartate glutamate receptor antagonist, has demonstrated a rapid-onset antidepressant effect in patients with treatment-resistant depression. This study evaluated the efficacy of twice-and thrice-weekly intravenous administration of ketamine in sustaining initial antidepressant effects in patients with treatment-resistant depression. Method: In a multicenter, double-blind study, adults (ages 18-64 years) with treatment-resistant depression were randomized to receive either intravenous ketamine (0.5 mg/kg of body weight) or intravenous placebo, administered over 40 minutes, either two or three times weekly, for up to 4 weeks. Patients who discontinued double-blind treatment after at least 2 weeks for lack of efficacy could enter an optional 2-week open-label phase to receive ketamine with the same frequency as in the double-blind phase. The primary outcome measure was change from baseline to day 15 in total score on the Montgomery-angstrom sberg Depression Rating Scale (MADRS). Results: In total, 67 (45 women) of 68 randomized patients received treatment. In the twice-weekly dosing groups, the mean change in MADRS score at day 15 was -18.4 (SD=12.0) for ketamine and -5.7 (SD=10.2) for placebo; in the thrice-weekly groups, it was -17.7 (SD=7.3) for ketamine and -3.1 (SD=5.7) for placebo. Similar observations were noted for ketamine during the open-label phase (twice-weekly, -12.2 [SD=12.8] on day 4; thrice-weekly, -14.0 [SD=12.5] on day 5). Both regimens were generally well tolerated. Headache, anxiety, dissociation, nausea, and dizziness were the most common (>= 20%) treatment-emergent adverse events. Dissociative symptoms occurred transiently and attenuated with repeated dosing. Conclusions: Twice-weekly and thrice-weekly administration of ketamine at 0.5 mg/kg similarly maintained antidepressant efficacy over 15 days. C1 [Singh, Jaskaran B.] Janssen Res & Dev, Titusville, NJ USA. Janssen Res & Dev, Beerse, Belgium. Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA. Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. Univ Alabama Birmingham, Dept Psychiat & Behav Neurobiol, Sch Med, Birmingham, AL 35294 USA. Univ Texas Southwestern Med Ctr, Dept Psychiat, Dallas, TX USA. Inst Living, Hartford, CT USA. Univ Connecticut, Ctr Hlth, Farmington, CT USA. Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP Singh, JB (reprint author), Janssen Res & Dev, Titusville, NJ USA. EM jsingh25@its.jnj.com RI Murrough, James/J-7129-2013 OI Murrough, James/0000-0001-6286-1242 FU Janssen Research and Development; Johnson Johnson; Avanir; AstraZeneca; Bristol-Myers Squibb; Squibb; Eli Lilly; Janssen; Hoffman-La Roche; Merck; Naurex; Servier; Sanofi-Aventis; Alkermes; Assurex; Elan; Euthymics Bioscience; Forest; Novartis; Otsuka; Pamlab; Pfizer; Repligen; St. Jude Medical; Takeda; NIMH; Mitsubishi Tanabe Pharma; Roche; Shire; Acadia; AXSOME Therapeutics; Biogen; Cerecor; Dinippon Sumitomo Pharma; EnVivo; Forest Pharmaceuticals; FORUM Pharmaceuticals; GenOmind; GlaxoSmithKline; Indivior; Intracellular; Johnson & Johnson Pharmaceutical Research and Development; Lundbeck; Methylation Sciences; MSI Methylation Sciences; National Center for Complementary and Alternative Medicine; National Coordinating Center for Integrative Medicine; NIDA; Nestle Health Sciences; Neuralstem; NeuroRx; Novartis AG; Nutrition 21; Osmotica; Otsuka Pharmaceuticals; PharmoRx Therapeutics; Photothera; PPD; Puretech Ventures; PsychoGenics; RCT Logic; Reckitt Benckiser; Ridge Diagnostics; Roche Pharmaceuticals; Servier Laboratories; Stanley Medical Research Institute; Sunovion; Taisho; Tal Medical; VistaGen FX This study was funded by Janssen Research and Development, which also provided a formal review of the manuscript.; Drs. Singh, Fedgchin, Daly, De Boer, Lim, Manji, Drevets, Van Nueten, Ms. Cooper, and Ms. Pinter are employed by Janssen Research and Development and own stocks in the company. Dr. Manji reports a patent, which is assigned to Icahn School of Medicine at Mount Sinai, Yale University, and NIH, but he will not receive any financial benefit from this patent; the Icahn School of Medicine at Mount Sinai has entered into a licensing agreement with Johnson & Johnson and will receive payments related to the use of ketamine for the treatment of depression. Dr. Murrough has served as a consultant for Genentech, Impel Neuropharma, Janssen Research and Development, and Prophase and has received research funding from Avanir and Janssen Research and Development. Dr. Sanacora has served as a consultant for Allergan, Alkermes, AstraZeneca, Avanir, Bristol-Myers Squibb, Eli Lilly, Hoffman-La Roche, Janssen, Merck, Navigen, Naurex, Noven, Servier, Taisho, Takeda, Teva, and VistaGen Therapeutics; he has received research contracts from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, Hoffman-La Roche, Merck, Naurex, and Servier; he received medication from Sanofi-Aventis for an NIH-sponsored study; he holds shares in BioHaven Pharmaceuticals Holding Company; and he is named as a co-inventor on a U.S. patent held by Yale University. Dr. Shelton has served as a consultant for Bristol-Myers Squibb, Cerecor, Cyberonics, Eli Lilly, Forest, Janssen, Medtronic, Methylation Sciences, Naurex, Pamlab, Pfizer, Ridge Diagnostics, Shire Pic, and Takeda, and he has received research funding from Alkermes, Assurex, Avanir, Bristol-Myers Squibb, Eli Lilly, Elan, Euthymics Bioscience, Forest, Janssen, Naurex, Novartis, Otsuka, Pamlab, Pfizer, Repligen, St. Jude Medical, and Takeda. Dr. Kurian has received research funding from Janssen Research and Development, NIMH, and Naurex. Dr. Winokur received consulting fees from Mitsubishi Tanabe Pharma and research funding from Janssen, Pfizer, Roche, Forest, Shire, and Takeda. Dr.; Fava has received research support from and/or served as an adviser or consultant to Acadia, Alkermes, AstraZeneca, Avanir, AXSOME Therapeutics, Biogen, Bristol-Myers Squibb, Cerecor, Dinippon Sumitomo Pharma, Eli Lilly, EnVivo, Euthymics Bioscience, Forest Pharmaceuticals, FORUM Pharmaceuticals, GenOmind, GlaxoSmithKline, Indivior, Intracellular, Janssen Research and Development, Johnson & Johnson Pharmaceutical Research and Development, Lundbeck, Merck, Methylation Sciences, MSI Methylation Sciences, the National Center for Complementary and Alternative Medicine, the National Coordinating Center for Integrative Medicine, NIDA, NIMH, Naurex, Nestle Health Sciences, Neuralstem, NeuroRx, Novartis AG, Nutrition 21, Osmotica, Otsuka Pharmaceuticals, Pamlab, Pfizer, PharmoRx Therapeutics, Photothera, PPD, Puretech Ventures, PsychoGenics, RCT Logic (formerly Clinical Trials Solutions), Reckitt Benckiser, Ridge Diagnostics, Roche Pharmaceuticals, Sanofi-Aventis, Servier Laboratories, the Stanley Medical Research Institute, Sunovion, Taisho, Takeda, Tal Medical, and VistaGen; he has had speaking or publishing roles for the American Society of Clinical Psychopharmacology, Belvoir Media Group, CME Institute/Physicians Postgraduate Press, and MGH Psychiatry Academy; he has equity holdings in Compellis and PsyBrain; he is named on patents for sequential parallel comparison design, licensed by MGH to Pharmaceutical Product Development and a patent application for a combination of ketamine plus scopolamine in major depressive disorder, licensed by MGH to Biohaven; and he is a copyright holder for the MGH Cognitive and Physical Functioning Questionnaire, the Sexual Functioning Inventory, the Antidepressant Treatment Response Questionnaire, Discontinuation Emergent Signs and Symptoms, the Symptoms of Depression Questionnaire, and SAFER and has publications with Lippincott Williams & Wilkins, Wolters Kluwer, and World Scientific Publishing. NR 21 TC 16 Z9 16 U1 9 U2 10 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X EI 1535-7228 J9 AM J PSYCHIAT JI Am. J. Psychiat. PD AUG 1 PY 2016 VL 173 IS 8 BP 816 EP 826 DI 10.1176/appi.ajp.2016.16010037 PG 11 WC Psychiatry SC Psychiatry GA DT6WA UT WOS:000381624100012 PM 27056608 ER PT J AU Raja, AS Lanning, J Gower, A Langdorf, MI Nishijima, DK Baumann, BM Hendey, GW Medak, AJ Mower, WR Rodriguez, RM AF Raja, Ali S. Lanning, Jennifer Gower, Arian Langdorf, Mark I. Nishijima, Daniel K. Baumann, Brigitte M. Hendey, Gregory W. Medak, Anthony J. Mower, William R. Rodriguez, Robert M. TI Prevalence of Chest Injury With the Presence of NEXUS Chest Criteria: Data to Inform Shared Decisionmaking About Imaging Use SO ANNALS OF EMERGENCY MEDICINE LA English DT Article ID COMPUTED-TOMOGRAPHY; BLUNT TRAUMA; EMERGENCY-DEPARTMENTS; RADIOGRAPHY; INSTRUMENT AB Study objective: The NEXUS chest decision instrument identifies a very-low-risk population of patients with blunt trauma for whom chest imaging can be avoided. However, it requires that all 7 National Emergency X-Ray Utilization Study (NEXUS) chest criteria be absent. To inform patient and physician shared decisionmaking about imaging, we describe the test characteristics of individual criteria of the NEXUS chest decision instrument and provide the prevalence of injuries when 1, 2, or 3 of the 7 criteria are present. Methods: We conducted this secondary analysis of 2 prospectively collected cohorts of patients with blunt trauma who were older than 14 years and enrolled in NEXUS chest studies between December 2009 and January 2012. Physicians at 9 US Level I trauma centers recorded the presence or absence of the 7 NEXUS chest criteria. We calculated test characteristics of each criterion and combinations of criteria for the outcome measures of major clinical injuries and thoracic injury observed on chest imaging. Results: We enrolled 21,382 patients, of whom 992(4.6%) had major clinical injuries and 3,135(14.7%) had thoracic injuries observed on chest imaging. Sensitivities of individual test characteristics ranged from 15% to 56% for major clinical injury and 14% to 53% for thoracic injury observed on chest imaging, with specificities varying from 71% to 84% for major clinical injury and 67% to 84% for thoracic injury observed on chest imaging. Individual criteria were associated with a prevalence of major clinical injury between 1.9% and 3.8% and of thoracic injury observed on chest imaging between 5.3% and 11.5%. Conclusion: Patients with isolated NEXUS chest criteria have low rates of major clinical injury. The risk of major clinical injury for patients with 2 or 3 factors range from 1.7% to 16.6%, depending on the combination of criteria. Criteria specific risks could be used to inform shared decisionmaking about the need for imaging by patients and their physicians. C1 [Raja, Ali S.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02115 USA. [Lanning, Jennifer; Rodriguez, Robert M.] Univ Calif San Francisco, Dept Emergency Med, San Francisco, CA 94143 USA. [Gower, Arian] Rosalind Franklin Univ Med & Sci, Chicago Med Sch, N Chicago, IL USA. [Langdorf, Mark I.] Univ Calif Irvine, Dept Emergency Med, Irvine, CA USA. [Nishijima, Daniel K.] Univ Calif Davis, Dept Emergency Med, Davis, CA 95616 USA. [Baumann, Brigitte M.] Rowan Univ, Cooper Med Sch, Dept Emergency Med, Camden, NJ USA. [Hendey, Gregory W.] Univ Calif San Francisco, Dept Emergency Med, San Francisco Fresno Med Educ Program, San Francisco, CA 94143 USA. [Medak, Anthony J.] Univ Calif San Diego, San Diego Sch Med, Dept Emergency Med, San Diego, CA 92103 USA. [Mower, William R.] Univ Calif Los Angeles, Dept Emergency Med, Los Angeles, CA USA. RP Raja, AS (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02115 USA. EM asraja@partners.org OI Hendey, Gregory/0000-0002-0170-8743 FU University of California Center for Health Quality and Innovation FX By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). The authors have stated that no such relationships exist and provided the following details: Funded by University of California Center for Health Quality and Innovation. NR 10 TC 0 Z9 0 U1 2 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD AUG PY 2016 VL 68 IS 2 BP 222 EP 226 DI 10.1016/j.annemergmed.2015.09.024 PG 5 WC Emergency Medicine SC Emergency Medicine GA DT0II UT WOS:000381166800016 PM 26607334 ER PT J AU Fernandez, FG Kosinski, AS Burfeind, W Park, B DeCamp, MM Seder, C Marshall, B Magee, MJ Wright, CD Kozower, BD AF Fernandez, Felix G. Kosinski, Andrzej S. Burfeind, William Park, Bernard DeCamp, Malcolm M. Seder, Christopher Marshall, Blair Magee, Mitchell J. Wright, Cameron D. Kozower, Benjamin D. TI The Society of Thoracic Surgeons Lung Cancer Resection Risk Model: Higher Quality Data and Superior Outcomes SO ANNALS OF THORACIC SURGERY LA English DT Article; Proceedings Paper CT 62nd Annual Meeting of the Southern-Thoracic-Surgical-Association CY NOV 04-07, 2015 CL Orlando, FL SP So Thorac Surg Assoc ID PULMONARY RESECTION; MAJOR MORBIDITY; STS DATABASE; MORTALITY; PREDICTORS; LOBECTOMY; PNEUMONECTOMY; MEDICARE; IMPACT AB Background. The Society of Thoracic Surgeons (STS) creates risk-adjustment models for common cardiothoracic operations for quality improvement purposes. Our aim was to update the lung cancer resection risk model utilizing the STS General Thoracic Surgery Database (GTSD) with a larger and more contemporary cohort. Methods. We queried the STS GTSD for all surgical resections of lung cancers from January 1, 2012, through December 31, 2014. Logistic regression was used to create three risk models for adverse events: operative mortality, major morbidity, and composite mortality and major morbidity. Results. In all, 27,844 lung cancer resections were performed at 231 centers; 62% (n = 17,153) were performed by thoracoscopy. The mortality rate was 1.4% (n = 401), major morbidity rate was 9.1% (n = 2,545), and the composite rate was 9.5% (n = 2,654). Predictors of mortality included age, being male, forced expiratory volume in 1 second, body mass index, cerebrovascular disease, steroids, coronary artery disease, peripheral vascular disease, renal dysfunction, Zubrod score, American Society of Anesthesiologists rating, thoracotomy approach, induction therapy, reoperation, tumor stage, and greater extent of resection (all p < 0.05). For major morbidity and the composite measure, cigarette smoking becomes a risk factor whereas stage, renal dysfunction, congestive heart failure, and cerebrovascular disease lose significance. Conclusions. Operative mortality and complication rates are low for lung cancer resection among surgeons participating in the GTSD. Risk factors from the prior lung cancer resection model are refined, and new risk factors such as prior thoracic surgery are identified. The GTSD risk models continue to evolve as more centers report and data are audited for quality assurance. (C) 2016 by The Society of Thoracic Surgeons C1 Emory Univ, Atlanta, GA 30322 USA. Duke Clin Res Inst, Durham, NC USA. St Lukes Hlth Network, Allentown, PA USA. Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. Northwestern Univ, Chicago, IL 60611 USA. Rush Univ, Chicago, IL 60612 USA. Georgetown Univ, Washington, DC USA. Med City Hosp, Dallas, TX USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Virginia, Charlottesville, VA USA. RP Fernandez, FG (reprint author), Emory Clin, 1365 Clifton Rd NE,Ste A2214, Atlanta, GA 30322 USA. EM felix.fernandez@emoryhealthcare.org FU AHRQ HHS [R01 HS022279]; NCI NIH HHS [P30 CA008748] NR 20 TC 3 Z9 3 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-4975 EI 1552-6259 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD AUG PY 2016 VL 102 IS 2 BP 370 EP 377 DI 10.1016/j.athoracsur.2016.02.098 PG 8 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA DS4JY UT WOS:000380748600035 PM 27209606 ER PT J AU Edwards, FH Ferraris, VA Kurlansky, PA Lobdell, KW He, X O'Brien, SM Furnary, AP Rankin, JS Vassileva, CM Fazzalari, FL Magee, MJ Badhwar, V Xian, Y Jacobs, JP von Ballmoos, MCW Shahian, DM AF Edwards, Fred H. Ferraris, Victor A. Kurlansky, Paul A. Lobdell, Kevin W. He, Xia O'Brien, Sean M. Furnary, Anthony P. Rankin, J. Scott Vassileva, Christina M. Fazzalari, Frank L. Magee, Mitchell J. Badhwar, Vinay Xian, Ying Jacobs, Jeffrey P. von Ballmoos, Moritz C. Wyler Shahian, David M. TI Failure to Rescue Rates After Coronary Artery Bypass Grafting: An Analysis From The Society of Thoracic Surgeons Adult Cardiac Surgery Database SO ANNALS OF THORACIC SURGERY LA English DT Article; Proceedings Paper CT 52nd Annual Meeting of the Society-of-Thoracic-Surgeons CY JAN 23-27, 2016 CL Phoenix, AZ SP Soc Thorac Surg ID QUALITY-OF-CARE; TO-RESCUE; INPATIENT SURGERY; LUNG-CANCER; IMPROVEMENT; MORTALITY; RISK; COMPLICATIONS; OPPORTUNITY; RESECTION AB Background. Failure to rescue (FTR) is increasingly recognized as an important quality indicator in surgery. The Society of Thoracic Surgeons National Database was used to develop FTR metrics and a predictive FTR model for coronary artery bypass grafting (CABG). Methods. The study included 604,154 patients undergoing isolated CABG at 1,105 centers from January 2010 to January 2014. FTR was defined as death after four complications: stroke, renal failure, reoperation, and prolonged ventilation. FTR was determined for each complication and a composite of the four complications. A statistical model to predict FTR was developed. Results. FTR rates were 22.3% for renal failure, 16.4% for stroke, 12.4% for reoperation, 12.1% for prolonged ventilation, and 10.5% for the composite. Mortality increased with multiple complications and with specific combinations of complications. The multivariate risk model for prediction of FTR demonstrated a C index of 0.792 and was well calibrated, with a 1.0% average difference between observed/expected (O/E) FTR rates. With centers grouped into mortality terciles, complication rates increased modestly (11.4% to 15.7%), but FTR rates more than doubled (6.8% to 13.9%) from the lowest to highest terciles. Centers in the lowest complication rate tercile had an FTR O/E of 1.14, whereas centers in the highest complication rate tercile had an FTR O/E of 0.91. Conclusions. CABG mortality rates vary directly with FTR, but complication rates have little relation to death. FTR rates derived from The Society of Thoracic Surgeons data can serve as national benchmarks. Predicted FTR rates may facilitate patient counseling, and FTR O/E ratios have promise as valuable quality metrics. (C) 2016 by The Society of Thoracic Surgeons C1 Univ Florida, Dept Surg, Jacksonville, FL USA. Univ Kentucky, Dept Surg, Lexington, KY USA. Columbia Univ, Coll Phys & Surg, New York, NY USA. Carolinas Healthcare Syst, Sanger Heart & Vasc Inst, Charlotte, NC USA. Duke Clin Res Inst, Durham, NC USA. Starr Wood Cardiac Grp, Portland, OR USA. Cardiothorac Surg Associates, Nashville, TN USA. Southern Illinois Univ, Dept Surg, Springfield, IL USA. Univ Michigan, Sect Cardiac Surg, Rochester, MI USA. Baylor Univ, Med Ctr, Dept Surg, Dallas, TX 75246 USA. Univ Pittsburgh, Dept Surg, Pittsburgh, PA USA. Johns Hopkins All Childrens Heart Inst, St Petersburg, FL USA. Med Coll Wisconsin, Dept Surg, 8700 W Wisconsin Ave, Milwaukee, WI 53226 USA. Massachusetts Gen Hosp, Ctr Qual & Safety, Dept Surg, Boston, MA 02114 USA. RP Edwards, FH (reprint author), Univ Florida, 4646 Carlton Dunes 2, Amelia Isl, FL 32034 USA. EM fred.edwards@jax.ufl.edu NR 30 TC 4 Z9 4 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-4975 EI 1552-6259 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD AUG PY 2016 VL 102 IS 2 BP 458 EP 464 DI 10.1016/j.athoracsur.2016.04.051 PG 7 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA DS4JY UT WOS:000380748600047 PM 27344280 ER PT J AU Levesque, MH Aisagbonhi, O Digumarthy, S Wright, CD Ackman, JB AF Levesque, Marie-Helene Aisagbonhi, Omonigho Digumarthy, Subba Wright, Cameron D. Ackman, Jeanne B. TI Primary Paratracheal Leiomyoma: Increased Preoperative Diagnostic Specificity With Magnetic Resonance Imaging SO ANNALS OF THORACIC SURGERY LA English DT Editorial Material ID MEDIASTINAL LEIOMYOMA AB We report the case of a 47-year-old woman whose primary mediastinal leiomyoma was incidentally found during evaluation of her persistent cough. The pre-operative diagnosis of mediastinal leiomyoma is challenging because of its rarity and indeterminate features on chest radiography, computed tomography (CT), and positron emission tomography-CT. We highlight how magnetic resonance imaging can substantially contribute to mediastinal mass characterization and diagnostic specificity. (C) 2016 by The Society of Thoracic Surgeons C1 Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Ackman, JB (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Thorac Imaging & Intervent, Founders House 202,55 Fruit St, Boston, MA 02114 USA. EM jackman@mgh.harvard.edu NR 8 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 0003-4975 EI 1552-6259 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD AUG PY 2016 VL 102 IS 2 BP E151 EP E154 DI 10.1016/j.athoracsur.2016.01.015 PG 4 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA DS4JY UT WOS:000380748600021 PM 27449453 ER PT J AU Karanika, S Paudel, S Grigoras, C Kalbasi, A Mylonakis, E AF Karanika, Styliani Paudel, Suresh Grigoras, Christos Kalbasi, Alireza Mylonakis, Eleftherios TI Systematic Review and Meta-analysis of Clinical and Economic Outcomes from the Implementation of Hospital-Based Antimicrobial Stewardship Programs SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Review ID INTENSIVE-CARE-UNIT; ANTIBIOTIC USE; FLUOROQUINOLONE USE; TARGETING CEPHALOSPORIN; CLOSTRIDIUM-DIFFICILE; INTERVENTION PROGRAM; PRESCRIBING PRACTICE; CONFIDENCE-INTERVAL; MEDICAL-CENTER; COST SAVINGS AB The implementation of antimicrobial stewardship programs (ASPs) is a promising strategy to help address the problem of antimicrobial resistance. We sought to determine the efficacy of ASPs and their effect on clinical and economic parameters. We searched PubMed, EMBASE, and Google Scholar looking for studies on the efficacy of ASPs in hospitals. Based on 26 studies (extracted from 24,917 citations) with pre- and postimplementation periods from 6 months to 3 years, the pooled percentage change of total antimicrobial consumption after the implementation of ASPs was -19.1% (95% confidence interval [CI] = -30.1 to -7.5), and the use of restricted antimicrobial agents decreased by -26.6% (95% CI = -52.3 to -0.8). Interestingly, in intensive care units, the decrease in antimicrobial consumption was -39.5% (95% CI = -72.5 to -6.4). The use of broad-spectrum antibiotics (-18.5% [95% CI = -32 to -5.0] for carbapenems and -14.7% [95% CI = -27.7 to -1.7] for glycopeptides), the overall antimicrobial cost (-33.9% [95% CI = -42.0 to -25.9]), and the hospital length of stay (-8.9% [95% CI = -12.8 to -5]) decreased. Among hospital pathogens, the implementation of ASPs was associated with a decrease in infections due to methicillin-resistant Staphylococcus aureus (risk difference [RD] = -0.017 [95% CI = -0.029 to -0.005]), imipenem-resistant Pseudomonas aeruginosa (RD = -0.079 [95% CI = -0.114 to -0.040]), and extended-spectrum beta-lactamase Klebsiella spp. (RD = -0.104 [95% CI = -0.153 to -0.055]). Notably, these improvements were not associated with adverse outcomes, since the all-cause, infection-related 30-day mortality and infection rates were not significantly different after implementation of an ASP (RD = -0.001 [95% CI = -0.009 to 0.006], RD = -0.005 [95% CI = -0.016 to 0.007], and RD = -0.045% [95% CI = -0.241 to 0.150], respectively). Hospital ASPs result in significant decreases in antimicrobial consumption and cost, and the benefit is higher in the critical care setting. Infections due to specific antimicrobial-resistant pathogens and the overall hospital length of stay are improved as well. Future studies should focus on the sustainability of these outcomes and evaluate potential beneficial long-term effects of ASPs in mortality and infection rates. C1 [Karanika, Styliani; Paudel, Suresh; Grigoras, Christos; Mylonakis, Eleftherios] Brown Univ, Rhode Isl Hosp, Warren Alpert Med Sch, Div Infect Dis, Providence, RI 02912 USA. [Kalbasi, Alireza] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Mylonakis, E (reprint author), Brown Univ, Rhode Isl Hosp, Warren Alpert Med Sch, Div Infect Dis, Providence, RI 02912 USA. EM emylonakis@lifespan.org NR 67 TC 3 Z9 3 U1 5 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD AUG PY 2016 VL 60 IS 8 BP 4840 EP 4852 DI 10.1128/AAC.00825-16 PG 13 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA DS5AJ UT WOS:000380792600048 PM 27246783 ER PT J AU Lu, MT Park, J Ghemigian, K Mayrhofer, T Puchner, SB Liu, T Fleg, JL Udelson, JE Truong, QA Ferencik, M Hoffmann, U AF Lu, Michael T. Park, Jakob Ghemigian, Khristine Mayrhofer, Thomas Puchner, Stefan B. Liu, Ting Fleg, Jerome L. Udelson, James E. Truong, Quynh A. Ferencik, Maros Hoffmann, Udo TI Epicardial and paracardial adipose tissue volume and attenuation - Association with high-risk coronary plaque on computed tomographic angiography in the ROMICAT II trial SO ATHEROSCLEROSIS LA English DT Article DE Coronary CT angiography; High-risk coronary plaque; Coronary atherosclerosis; Epicardial adipose tissue; Paracardial adipose tissue ID ACUTE CHEST-PAIN; VISCERAL ABDOMINAL FAT; NAPKIN-RING SIGN; PERICARDIAL FAT; CT ANGIOGRAPHY; CARDIOVASCULAR-DISEASE; INTRATHORACIC FAT; ARTERY-DISEASE; INTRAVASCULAR ULTRASOUND; ATHEROSCLEROTIC LESIONS AB Background and aims: To determine whether epicardial (EAT) and paracardial adipose tissue (PAT) volume and attenuation are associated with high-risk coronary plaque features. Methods: In subjects with suspected acute coronary syndrome (ACS) enrolled in the ROMICAT II trial, EAT and PAT volumes indexed to body surface area (BSA) and attenuation were measured on non-contrast coronary artery calcium score (CACS) CT. High-risk plaque features (napkin-ring sign, positive remodeling, low density plaque, spotty calcium) and stenosis were assessed on coronary CT angiography (CTA). The association of EAT and PAT volume and attenuation with high-risk plaque and whether this was independent of clinical risk assessment, CACS and significant coronary artery disease (CAD) was determined. Results: Of 467 (mean 54 +/- 8 yrs, 53% male) with CACS and CTA, 167 (36%) had high-risk plaque features. Those with high-risk plaque had significantly higher indexed EAT (median 59 (Q1-Q3: 45-75) cc/m(2) vs. 49 (35-65) cc/m(2), p < 0.001) and PAT volume (median: 51 (36-73) cc/m(2) vs. 33 (22-52) cc/m(2), p < 0.001). Higher indexed EAT volume was associated with high-risk plaque [univariate OR 1.02 (95%-CI: 1.01-1.03) per cc/m(2) of EAT, p < 0.001], which remained significant [univariate OR 1.04 (95%-CI: 1.00 -1.08) per cc/m(2) of EAT, p = 0.040] after adjustment for risk factors, CACS, and stenosis >= 50%. Higher indexed PAT volume was associated with high-risk plaque in univariate analysis [OR 1.02 (1.01-1.03) per cc/m(2) of PAT, p < 0.001], though this was not significant in multivariate analysis. At a threshold of > 62.3 cc/m(2), EAT volume was associated with high-risk plaque [univariate OR 2.50 (95%-CI: 1.69-3.72), p < 0.001)], which remained significant [OR 1.83 (95%-CI: 1.10-3.05), p = 0.020] after adjustment. Subjects with high-risk plaque had lower mean attenuation EAT (-88.1 vs. -86.9 HU, p = 0.008) and PAT (-106 vs. -103 HU, p < 0.001), though this was not significant in multivariable analysis. Conclusions: Greater volumes of EAT are associated with high-risk plaque independent of risk factors, CACS and obstructive CAD. This observation supports possible local influence of EAT on development of high-risk coronary plaque. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Lu, Michael T.; Park, Jakob; Ghemigian, Khristine; Mayrhofer, Thomas; Ferencik, Maros; Hoffmann, Udo] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Boston, MA 02114 USA. [Lu, Michael T.; Park, Jakob; Ghemigian, Khristine; Mayrhofer, Thomas; Ferencik, Maros; Hoffmann, Udo] Harvard Med Sch, Boston, MA USA. [Park, Jakob] Heidelberg Univ, Heidelberg, Germany. [Mayrhofer, Thomas] Stralsund Univ Appl Sci, Sch Business Studies, Stralsund, Germany. [Puchner, Stefan B.] Univ Hosp Vienna, Div Cardiovasc & Intervent Radiol, Vienna, Austria. [Liu, Ting] China Med Univ, Affiliated Hosp 1, Shenyang, Peoples R China. [Fleg, Jerome L.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Udelson, James E.] Tufts Med Ctr, Div Cardiol, Boston, MA USA. [Udelson, James E.] Tufts Med Ctr, Ctr Cardiovasc, Boston, MA USA. [Truong, Quynh A.] Weill Cornell Med Coll, New York, NY USA. [Ferencik, Maros] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. RP Lu, MT (reprint author), Div Cardiovasc Imaging, 165 Cambridge St,Suite 400, Boston, MA 02114 USA. EM mlu@mgh.harvard.edu FU American Roentgen Ray Society FX The authors acknowledge NIH 5T32HL076136, the MGH Executive Committee on Research and the American Roentgen Ray Society Scholarship (MTL), the German Cardiac Society and German National Academic Foundation (JP), the American Heart Association 13FTF16450001 (MF), Siemens Healthcare, NIH/NHLBI 5K24HL113128 and 5U01HL092040-04 (UH). NR 52 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 EI 1879-1484 J9 ATHEROSCLEROSIS JI Atherosclerosis PD AUG PY 2016 VL 251 BP 47 EP 54 DI 10.1016/j.atherosclerosis.2016.05.033 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DT1SJ UT WOS:000381262100008 PM 27266821 ER PT J AU Giannopoulos, AA Chatzizisis, YS Maurovich-Horvat, P Antoniadis, AP Hoffmann, U Steigner, ML Rybicki, FJ Mitsouras, D AF Giannopoulos, Andreas A. Chatzizisis, Yiannis S. Maurovich-Horvat, Pal Antoniadis, Antonios P. Hoffmann, Udo Steigner, Michael L. Rybicki, Frank J. Mitsouras, Dimitrios TI Quantifying the effect of side branches in endothelial shear stress estimates SO ATHEROSCLEROSIS LA English DT Article DE Endothelial shear stress; Coronary computed tomography; Computational fluid dynamics; Side branches ID CORONARY-ARTERY-DISEASE; COMPUTATIONAL FLUID-DYNAMICS; OPTICAL COHERENCE TOMOGRAPHY; CARDIAC COMPUTED-TOMOGRAPHY; THIN-CAP FIBROATHEROMA; INTRAVASCULAR ULTRASOUND; CT ANGIOGRAPHY; ATHEROSCLEROTIC PLAQUE; VULNERABLE PLAQUE; NATURAL-HISTORY AB Background and aims: Low and high endothelial shear stress (ESS) is associated with coronary atherosclerosis progression and high-risk plaque features. Coronary ESS is currently assessed via computational fluid dynamic (CFD) simulation of coronary blood flow in the lumen geometry determined from invasive imaging such as intravascular ultrasound and optical coherence tomography. This process typically omits side branches of the target vessel in the CFD model as invasive imaging of those vessels is not usually clinically-indicated. The purpose of this study was to determine the extent to which this simplification affects the determination of those regions of the coronary endothelium subjected to pathologic ESS. Methods: We determined the diagnostic accuracy of ESS profiling without side branches to detect pathologic ESS in the major coronary arteries of 5 hearts imaged ex vivo with computed tomography angiography (CTA). ESS of the three major coronary arteries was calculated both without (test model), and with (reference model) inclusion of all side branches > 1.5 mm in diameter, using previously-validated CFD approaches. Diagnostic test characteristics (accuracy, sensitivity, specificity and negative and positive predictive value [NPV/PPV]) with respect to the reference model were assessed for both the entire length as well as only the proximal portion of each major coronary artery, where the majority of high-risk plaques occur. Results: Using the model without side branches overall accuracy, sensitivity, specificity, NPV and PPV were 83.4%, 54.0%, 96%, 95.9% and 55.1%, respectively to detect low ESS, and 87.0%, 67.7%, 90.7%, 93.7% and 57.5%, respectively to detect high ESS. When considering only the proximal arteries, test characteristics differed for low and high ESS, with low sensitivity (67.7%) and high specificity (90.7%) to detect low ESS, and low sensitivity (44.7%) and high specificity (95.5%) to detect high ESS. Conclusions: The exclusion of side branches in ESS vascular profiling studies greatly reduces the ability to detect regions of the major coronary arteries subjected to pathologic ESS. Single-conduit models can in general only be used to rule out pathologic ESS. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Giannopoulos, Andreas A.; Steigner, Michael L.; Rybicki, Frank J.; Mitsouras, Dimitrios] Harvard Med Sch, Brigham & Womens Hosp, Dept Radiol, Appl Imaging Sci Lab, Boston, MA USA. [Chatzizisis, Yiannis S.] Univ Nebraska Med Ctr, Div Cardiovasc, Omaha, NE USA. [Antoniadis, Antonios P.] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. [Maurovich-Horvat, Pal] Semmelweis Univ, MTA SE Lendulet Cardiovasc Imaging Res Grp, Heart & Vasc Ctr, Budapest, Hungary. [Antoniadis, Antonios P.] Guys & St Thomas NHS Fdn Trust, Cardiovasc Dept, London, England. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Rybicki, Frank J.] Univ Ottawa, Ottawa Hosp, Dept Radiol, Ottawa, ON K1N 6N5, Canada. RP Mitsouras, D (reprint author), Harvard Med Sch, Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM dmitsouras@partners.org OI Steigner, Michael/0000-0002-3742-4267 FU National Institutes of Health, National Institute of Biomedical Imaging and Bioengineering [K01-EB015868]; Behrakis Foundation; Toshiba America Medical Systems; Vital Images, A Toshiba Medical Systems Group Company FX Dr. Mitsouras receives grant support from the National Institutes of Health, National Institute of Biomedical Imaging and Bioengineering grant number K01-EB015868, Toshiba America Medical Systems, and Vital Images, A Toshiba Medical Systems Group Company. Drs Chatzizisis and Antoniadis received support from the Behrakis Foundation. NR 39 TC 0 Z9 0 U1 6 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 EI 1879-1484 J9 ATHEROSCLEROSIS JI Atherosclerosis PD AUG PY 2016 VL 251 BP 213 EP 218 DI 10.1016/j.atherosclerosis.2016.06.038 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DT1SJ UT WOS:000381262100031 PM 27372207 ER PT J AU Tsigkas, N Kidambi, S Tawakol, A Chatzizisis, YS AF Tsigkas, Nikolaos Kidambi, Srivatsan Tawakol, Ahmed Chatzizisis, Yiannis S. TI Drug-loaded particles: "Trojan horses" in the therapy of atherosclerosis SO ATHEROSCLEROSIS LA English DT Editorial Material DE Atherosclerosis; Imaging; High-density lipoproteins; Particles; Treatment ID CAROTID ATHEROSCLEROSIS; DELIVERY; DISEASE C1 [Tsigkas, Nikolaos; Chatzizisis, Yiannis S.] Univ Nebraska Med Ctr, Div Cardiovasc, Cardiovasc Biol & Biomech Lab, 982265 Nebraska Med Ctr, Omaha, NE 68198 USA. [Kidambi, Srivatsan] Univ Nebraska, Dept Chem Engn, Lincoln, NE 68588 USA. [Tawakol, Ahmed] Harvard Med Sch, Massachusetts Gen Hosp, Div Cardiovasc, Boston, MA USA. RP Chatzizisis, YS (reprint author), Univ Nebraska Med Ctr, Div Cardiovasc, Cardiovasc Biol & Biomech Lab, 982265 Nebraska Med Ctr, Omaha, NE 68198 USA. EM ychatzizisis@icloud.com OI Kidambi, Srivatsan/0000-0002-0282-0411 NR 17 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 EI 1879-1484 J9 ATHEROSCLEROSIS JI Atherosclerosis PD AUG PY 2016 VL 251 BP 528 EP 530 DI 10.1016/j.atherosclerosis.2016.06.050 PG 3 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DT1SJ UT WOS:000381262100085 PM 27401604 ER PT J AU DeFilipp, Z Duarte, RF Snowden, JA Majhail, NS Greenfield, DM Miranda, JL Arat, M Baker, KS Burns, LJ Duncan, CN Gilleece, M Hale, GA Hamadanin, M Hamilton, BK Hogan, WJ Hsu, JW Inamoto, Y Kamble, RT Lupo-Stanghellini, MT Malone, AK McCarthy, P Mohty, M Norkin, M Paplham, P Ramanathan, M Richart, JM Salooja, N Schouten, HC Schoemans, H Seber, A Steinberg, A Wirk, BM Wood, WA Battiwalla, M Flowers, MED Savani, BN Shaw, BE AF DeFilipp, Zachariah Duarte, Rafael F. Snowden, John A. Majhail, Navneet S. Greenfield, Diana M. Lopez Miranda, Jose Arat, Mutlu Baker, K. Scott Burns, Linda J. Duncan, Christine N. Gilleece, Maria Hale, Gregory A. Hamadanin, Mehdi Hamilton, Betty K. Hogan, William J. Hsu, Jack W. Inamoto, Yoshihiro Kamble, Rammurti T. Lupo-Stanghellini, Maria Teresa Malone, Adriana K. McCarthy, Philip Mohty, Mohamad Norkin, Maxim Paplham, Pamela Ramanathan, Muthalagu Richart, John M. Salooja, Nina Schouten, Harry C. Schoemans, Helene Seber, Adriana Steinberg, Amir Wirk, Baldeep M. Wood, William A. Battiwalla, Minoo Flowers, Mary E. D. Savani, Bipin N. Shaw, Bronwen E. CA CIBMTR Late Effects Quality EBMT Complications Quality Life TI Metabolic Syndrome and Cardiovascular Disease after Hematopoietic Cell Transplantation: Screening and Preventive Practice Recommendations from the CIBMTR and EBMT SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Metabolic syndrome; Cardiovascular disease; Hematopoietic cell transplantation; Survivorship; Late effects ID LONG-TERM SURVIVORS; BONE-MARROW-TRANSPLANTATION; BODY-COMPOSITION ABNORMALITIES; ACUTE LYMPHOBLASTIC-LEUKEMIA; IMPAIRED GLUCOSE-TOLERANCE; DIABETES-MELLITUS; RISK-FACTORS; SCIENTIFIC STATEMENT; GLOBAL BURDEN; FOLLOW-UP AB Metabolic syndrome (MetS) is a constellation of cardiovascular risk factors that increases the risk of cardiovascular disease, diabetes mellitus, and all-cause mortality. Long-term survivors of hematopoietic cell transplantation (HCT) have a substantial risk of developing MetS and cardiovascular disease, with an estimated prevalence of MetS of 31% to 49% among HCT recipients. Although MetS has not yet been proven to impact cardiovascular risk after HCT, an understanding of the incidence and risk factors for MetS in HCT recipients can provide the foundation to evaluate screening guidelines and develop interventions that may mitigate cardiovascular-related mortality. A working group was established through the Center for International Blood and Marrow Transplant Research and the European Group for Blood and Marrow Transplantation with the goal to review literature and recommend practices appropriate to HCT recipients. Here we deliver consensus recommendations to help clinicians provide screening and preventive care for MetS and cardiovascular disease among HCT recipients. All HCT survivors should be advised of the risks of MetS and encouraged to undergo recommended screening based on their predisposition and ongoing risk factors. (C) 2016 American Society for Blood and Marrow Transplantation. C1 [DeFilipp, Zachariah] Emory Univ, Winship Canc Inst, Dept Hematol & Med Oncol, Atlanta, GA 30322 USA. [Duarte, Rafael F.] Hosp Univ Puerta Hierro Majadahonda, Madrid, Spain. [Snowden, John A.] Sheffield Teaching Hosp NHS Fdn Trust, Dept Haematol, Sheffield, S Yorkshire, England. [Snowden, John A.] Univ Sheffield, Dept Oncol & Metab, Sheffield, S Yorkshire, England. [Majhail, Navneet S.; Hamilton, Betty K.] Cleveland Clin, Dept Hematol & Oncol, Cleveland, OH 44106 USA. [Greenfield, Diana M.] Sheffield Teaching Hosp NHS Fdn Trust, Specialized Canc Serv, Shefffied, England. [Lopez Miranda, Jose] Univ Cordoba, Maimonides Inst Biomed Res Cordoba IMIBIC, CIBER Fisiopatol Obesidad Nutr CIBEROBN, Dept Med,Reina Sofia Univ Hosp,Inst Salud Carlos, Cordoba, Spain. [Arat, Mutlu] Florence Nightingale Sisli Hosp, Hematopoiet Stem Cell Transplantat Unit, Istanbul, Turkey. [Baker, K. Scott; Flowers, Mary E. D.] Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA. [Burns, Linda J.] Univ Minnesota, Natl Marrow Donor Program, Minneapolis, MN 55417 USA. [Duncan, Christine N.] Dana Farber Canc Inst, Pediat Stem Cell Transplant, Boston, MA 02115 USA. [Gilleece, Maria] Leeds Teaching Hosp NHS Trust, Leeds, W Yorkshire, England. [Hale, Gregory A.] Univ S Florida, All Childrens Hosp, John Hopkins Med, St Petersburg, FL 33701 USA. [Hamadanin, Mehdi; Shaw, Bronwen E.] Med Coll Wisconsin, Dept Med, CIBMTR, Milwaukee, WI 53226 USA. [Hogan, William J.] Mayo Clin, Dept Internal Med, Div Hematol, Rochester, MN 55905 USA. [Hsu, Jack W.; Norkin, Maxim] Univ Florida, Dept Med, Div Hematol & Oncol, Gainesville, FL 32610 USA. [Inamoto, Yoshihiro] Natl Canc Ctr, Div Hematopoiet Stem Cell Transplantat, Tokyo, Japan. [Kamble, Rammurti T.] Baylor Coll Med, Ctr Cell & Gene Therapy, Div Hematol & Oncol, Houston, TX 77030 USA. [Lupo-Stanghellini, Maria Teresa] Ist Sci San Raffaele, Hematol & Bone Marrow Transplantat, I-20132 Milan, Italy. [Malone, Adriana K.; Steinberg, Amir] Icahn Sch Med Mt Sinai, Tisch Canc Inst, Div Hematol Oncol, New York, NY 10029 USA. [McCarthy, Philip; Paplham, Pamela] Roswell Pk Canc Inst, Dept Med, BMT Program, Buffalo, NY 14263 USA. [Mohty, Mohamad] Univ Paris 06, Paris, France. [Mohty, Mohamad] Hop St Antoine, AP HP, Paris, France. [Mohty, Mohamad] INSERM, UMRs 938, Paris, France. [Ramanathan, Muthalagu] UMass Mem Med Ctr, Dept Hematol Oncol & Bone Marrow Transplant, Worcester, MA USA. [Richart, John M.] St Louis Univ, Dept Internal Med, Div Hematol & Med Oncol, St Louis, MO 63103 USA. [Salooja, Nina] Ammersmith Hosp, London, England. [Schouten, Harry C.] Maastricht Univ Med Ctr, Maastricht, Netherlands. [Schoemans, Helene] Univ Hosp Leuven, Dept Hematol, Leuven, Belgium. [Schoemans, Helene] Katholieke Univ Leuven, Leuven, Belgium. [Seber, Adriana] Hosp Samaritan, Sao Paulo, Brazil. [Seber, Adriana] Assoc Medula Ossea AMEO, Sao Paulo, Brazil. RP Shaw, BE (reprint author), Med Coll Wisconsin, CIBMTR, Dept Med, 9200 W Wisconsin Ave, Milwaukee, WI 53226 USA. EM bshaw@doctors.org.uk FU NCI NIH HHS [U24 CA076518] NR 96 TC 2 Z9 2 U1 3 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD AUG PY 2016 VL 22 IS 8 BP 1493 EP 1503 DI 10.1016/j.bbmt.2016.05.007 PG 11 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DS1XC UT WOS:000380417400023 PM 27184625 ER PT J AU Abel, GA Albelda, R Khera, N Hahn, T Coronado, DYS Odejide, OO Bona, K Tucker-Seeley, R Soiffer, R AF Abel, Gregory A. Albelda, Randy Khera, Nandita Hahn, Theresa Coronado, Diana Y. Salas Odejide, Oreofe O. Bona, Kira Tucker-Seeley, Reginald Soiffer, Robert TI Financial Hardship and Patient-Reported Outcomes after Hematopoietic Cell Transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Stem cell transplantation; Financial hardship; Health-related quality of life; Perceived stress ID QUALITY-OF-LIFE; LONG-TERM SURVIVORS; CANCER-PATIENTS; HEALTH; COSTS; STRESS; BURDEN; CAREGIVERS; CHILDHOOD; MORTALITY AB Although hematopoietic cell transplantation (HCT) is the only curative therapy for many advanced hematologic cancers, little is known about the financial hardship experienced by HCT patients nor the association of hardship with patient-reported outcomes. We mailed a 43-item survey to adult patients approximately 180 days after their first autologous or allogeneic HCT at 3 high-volume centers. We assessed decreases in household income; difficulty with HCT-related costs, such as need to relocate or travel; and 2 types of hardship: hardship_1 (reporting 1 or 2 of the following: dissatisfaction with present finances, difficulty meeting monthly bill payments, or not having enough money at the end of the month) and "hardship_2" (reporting all 3). Patient-reported stress was measured with the Perceived Stress Scale-4, and 7-point scales were provided for perceptions of overall quality of life (QOL) and health. In total, 325 of 499 surveys (65.1%) were received. The median days since HCT was 173; 47% underwent an allogeneic HCT, 60% were male, 51% were > 60 years old, and 92% were white. Overall, 46% reported income decline after HCT, 56% reported hardship_1, and 15% reported hardship_2. In multivariable models controlling for income, those reporting difficulty paying for HCT-related costs were more likely to report financial hardship (odds ratio, 6.9; 95% confidence interval, 3.8 to 12.3). Hardship_1 was associated with QOL below the median (odds ratio, 2.9; 95% confidence interval, 1.7 to 4.9), health status below the median (odds ratio, 2.2; 95% confidence interval, 1.3 to 3.6), and stress above the median (odds ratio, 2.1; 95% confidence interval, 1.3 to 3.5). In this sizable cohort of HCT patients, financial hardship was prevalent and associated with worse QOL and higher levels of perceived stress. Interventions to address patient financial hardship especially those that ameliorate HCT-specific costs are likely to improve patient-reported outcomes. (C) 2016 American Society for Blood and Marrow Transplantation. C1 [Abel, Gregory A.; Coronado, Diana Y. Salas; Odejide, Oreofe O.; Bona, Kira; Tucker-Seeley, Reginald] Dana Farber Canc Inst, Div Populat Sci, Boston, MA 02115 USA. [Abel, Gregory A.; Odejide, Oreofe O.; Soiffer, Robert] Dana Farber Canc Inst, Div Hematol Oncol, Boston, MA 02115 USA. [Albelda, Randy] Univ Massachusetts, Dept Econ, Boston, MA 02125 USA. [Khera, Nandita] Mayo Clin, Dept Oncol Hematol, Phoenix, AZ USA. [Hahn, Theresa] Roswell Pk Canc Inst, Div Blood & Marrow Transplant, Buffalo, NY 14263 USA. [Coronado, Diana Y. Salas] Univ Massachusetts, Dept Publ Policy, Boston, MA 02125 USA. [Bona, Kira] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. RP Abel, GA (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM gregory_abel@dfci.harvard.edu FU NCI NIH HHS [K01 CA169041, U54 CA156732] NR 38 TC 2 Z9 2 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD AUG PY 2016 VL 22 IS 8 BP 1504 EP 1510 DI 10.1016/j.bbmt.2016.05.008 PG 7 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DS1XC UT WOS:000380417400024 PM 27184627 ER PT J AU Jain, A van der Meer, AD Papa, AL Barrile, R Lai, A Schlechter, BL Otieno, MA Louden, CS Hamilton, GA Michelson, AD Frelinger, AL Ingber, DE AF Jain, Abhishek van der Meer, Andries D. Papa, Anne-Laure Barrile, Riccardo Lai, Angela Schlechter, Benjamin L. Otieno, Monicah A. Louden, Calvert S. Hamilton, Geraldine A. Michelson, Alan D. Frelinger, Andrew L., III Ingber, Donald E. TI Assessment of whole blood thrombosis in a microfluidic device lined by fixed human endothelium SO BIOMEDICAL MICRODEVICES LA English DT Article ID IIB/IIIA RECEPTOR BLOCKADE; PLURIPOTENT STEM-CELLS; PLATELET-FUNCTION; HEMOSTASIS; TECHNOLOGY; ABCIXIMAB; DISEASES; SYSTEMS; FIBRIN; ALPHA AB The vascular endothelium and shear stress are critical determinants of physiological hemostasis and platelet function in vivo, yet current diagnostic and monitoring devices do not fully incorporate endothelial function under flow in their assessment and, therefore, they can be unreliable and inaccurate. It is challenging to include the endothelium in assays for clinical laboratories or point-of-care settings because living cell cultures are not sufficiently robust. Here, we describe a microfluidic device that is lined by a human endothelium that is chemically fixed, but still retains its ability to modulate hemostasis under continuous flow in vitro even after few days of storage. This device lined with a fixed endothelium supports formation of platelet-rich thrombi in the presence of physiological shear, similar to a living arterial vessel. We demonstrate the potential clinical value of this device by showing that thrombus formation and platelet function can be measured within minutes using a small volume (0.5 mL) of whole blood taken from subjects receiving antiplatelet medications. The inclusion of a fixed endothelial microvessel will lead to biomimetic analytical devices that can potentially be used for diagnostics and point-of-care applications. C1 [Jain, Abhishek; van der Meer, Andries D.; Papa, Anne-Laure; Barrile, Riccardo; Hamilton, Geraldine A.; Ingber, Donald E.] Harvard Univ, Wyss Inst Biol Inspired Engn, 3 Blackfan Circle,CLSB 5, Boston, MA 02115 USA. [Jain, Abhishek] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Med, Div Hemostasis & Thrombosis, Boston, MA USA. [Jain, Abhishek; Ingber, Donald E.] Boston Childrens Hosp, Vasc Biol Program, Boston, MA 02115 USA. [Jain, Abhishek; Ingber, Donald E.] Boston Childrens Hosp, Dept Surg, Boston, MA 02115 USA. [Jain, Abhishek; Ingber, Donald E.] Harvard Med Sch, Boston, MA 02115 USA. [van der Meer, Andries D.] Univ Twente, MIRA Inst Biomed Technol & Tech Med, Enschede, Netherlands. [Barrile, Riccardo] Cedars Sinai Med Ctr, Board Governors Regenerat Med Inst, Los Angeles, CA 90048 USA. [Lai, Angela] Carnegie Mellon Univ, Dept Biomed Engn, Pittsburgh, PA 15213 USA. [Schlechter, Benjamin L.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Div Hematol & Oncol, Dept Med, Boston, MA USA. [Otieno, Monicah A.; Louden, Calvert S.] Janssen Pharmaceut Res & Dev, Preclin Dev & Safety, Spring House, PA USA. [Hamilton, Geraldine A.] Emulate Inc, 210 Broadway St, Cambridge, MA USA. [Michelson, Alan D.; Frelinger, Andrew L., III] Harvard Med Sch, Dana Farber Canc Inst, Boston Childrens Hosp, Ctr Platelet Res Studies,Div Hematol Oncol, Boston, MA USA. [Ingber, Donald E.] Harvard John A Paulson Sch Engn & Appl Sci, Cambridge, MA 02138 USA. RP Ingber, DE (reprint author), Harvard Univ, Wyss Inst Biol Inspired Engn, 3 Blackfan Circle,CLSB 5, Boston, MA 02115 USA.; Ingber, DE (reprint author), Boston Childrens Hosp, Vasc Biol Program, Boston, MA 02115 USA.; Ingber, DE (reprint author), Boston Childrens Hosp, Dept Surg, Boston, MA 02115 USA.; Ingber, DE (reprint author), Harvard Med Sch, Boston, MA 02115 USA.; Ingber, DE (reprint author), Harvard John A Paulson Sch Engn & Appl Sci, Cambridge, MA 02138 USA. EM don.ingber@wyss.harvard.edu OI Jain, Abhishek/0000-0003-2235-5139 FU DARPA [N66001-11-1-4180, HR0011-N13-C-0025]; Wyss Institute for Biologically Inspired Engineering; Janssen Pharmaceuticals FX We thank M. Ingram and D. Wagner for their technical assistance support and feedback. SU8 masters were fabricated at the Center for Nanoscale Systems (CNS) facility at Harvard University. This work was supported by DARPA contracts N66001-11-1-4180, HR0011-N13-C-0025, the Wyss Institute for Biologically Inspired Engineering and Janssen Pharmaceuticals. NR 32 TC 2 Z9 2 U1 7 U2 10 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1387-2176 EI 1572-8781 J9 BIOMED MICRODEVICES JI Biomed. Microdevices PD AUG PY 2016 VL 18 IS 4 AR 73 DI 10.1007/s10544-016-0095-6 PG 7 WC Engineering, Biomedical; Nanoscience & Nanotechnology SC Engineering; Science & Technology - Other Topics GA DS9QE UT WOS:000381117500021 PM 27464497 ER PT J AU El-Jawahri, A Kim, HT Steensma, DP Cronin, AM Stone, RM Watts, CD Chen, YB Cutler, CS Soiffer, RJ Abel, GA AF El-Jawahri, A. Kim, H. T. Steensma, D. P. Cronin, A. M. Stone, R. M. Watts, C. D. Chen, Y-B Cutler, C. S. Soiffer, R. J. Abel, G. A. TI Does quality of life impact the decision to pursue stem cell transplantation for elderly patients with advanced MDS? SO BONE MARROW TRANSPLANTATION LA English DT Article ID ACUTE MYELOID-LEUKEMIA; MYELODYSPLASTIC SYNDROME MDS; INTERNET-BASED SURVEY; OLDER PATIENTS; EUROPEAN-ORGANIZATION; SCORING SYSTEM; INTENSITY; OUTCOMES; RISK; DISEASE AB The factors that influence utilization of reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (HCT) among medically fit older patients with advanced myelodysplastic syndromes (MDS) are largely unknown. The MDS Transplant-Associated Outcomes (MDS-TAO) study is an ongoing prospective observational study at the Dana-Farber Cancer Institute and Massachusetts General Hospital that enrolls transplant-eligible fit patients aged 60-75 years with advanced MDS and follows them through RIC HCT vs non-HCT treatment. In this analysis of 127 patients enrolled from May 2011 to June 2014, we examined the influence of age, gender, cytogenetics, International Prognostic Scoring System (IPSS) category, performance status, distance from HCT center and baseline patient-reported quality of life (QOL) from the EORTC QLQ-C30 (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire) on the likelihood of receiving RIC HCT using competing risk regression modeling. With a median follow-up of 16 months, 44 patients (35%) had undergone RIC HCT. In multivariable analyses, age (hazard ratio (HR) 0.87 per year, 95% confidence interval (CI): 0.81-0.92, P < 0.001) and higher IPSS (intermediate-2/high; HR 2.29, 95% CI: 1.25-4.19, P = 0.007) were significantly predictive of receipt of RIC HCT; neither global QOL score nor any QOL subscales scores were predictive. These data suggest that baseline patient-reported QOL has little influence on the decision to undergo RIC HCT for older patients with advanced MDS. C1 [El-Jawahri, A.; Chen, Y-B] Massachusetts Gen Hosp, Boston, MA 02114 USA. [El-Jawahri, A.; Steensma, D. P.; Stone, R. M.; Chen, Y-B; Cutler, C. S.; Soiffer, R. J.; Abel, G. A.] Harvard Med Sch, Boston, MA USA. [Kim, H. T.; Steensma, D. P.; Cronin, A. M.; Stone, R. M.; Watts, C. D.; Cutler, C. S.; Soiffer, R. J.; Abel, G. A.] Dana Farber Canc Inst, 450 Brookline Ave,Dana 1106, Boston, MA 02215 USA. RP Abel, GA (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,Dana 1106, Boston, MA 02215 USA. EM gregory_abel@dfci.harvard.edu FU National Palliative Care Research Center; Leukemia and Lymphoma Society FX This work was supported by National Palliative Care Research Center Career Development Award (to AEJ) and Leukemia and Lymphoma Society Research Scholar Grant (to GAA). NR 37 TC 3 Z9 3 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 EI 1476-5365 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD AUG PY 2016 VL 51 IS 8 BP 1121 EP 1126 DI 10.1038/bmt.2016.40 PG 6 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA DS4WB UT WOS:000380781200017 PM 26999469 ER PT J AU Ray, A Ravillah, D Das, DS Song, Y Nordstrom, E Gullbo, J Richardson, PG Chauhan, D Anderson, KC AF Ray, Arghya Ravillah, Durgadevi Das, Deepika S. Song, Yan Nordstrom, Eva Gullbo, Joachim Richardson, Paul G. Chauhan, Dharminder Anderson, Kenneth C. TI A novel alkylating agent Melflufen induces irreversible DNA damage and cytotoxicity in multiple myeloma cells SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE Myeloma; apoptosis; novel therapeutics; alkylating agents; melflufen; melphalan ID FLUOROPHENYLALANINE ETHYL-ESTER; IN-VITRO; MAINTENANCE THERAPY; ANTITUMOR-ACTIVITY; RANDOMIZED-TRIAL; PRODRUG J1; MELPHALAN; RESISTANCE; REPAIR; CHEMOTHERAPY AB Our prior study utilized both invitro and invivo multiple myeloma (MM) xenograft models to show that a novel alkylator melphalan-flufenamide (Melflufen) is a more potent anti-MM agent than melphalan and overcomes conventional drug resistance. Here we examined whether this potent anti-MM activity of melflufen versus melphalan is due to their differential effect on DNA damage and repair signalling pathways via -H2AX/ATR/CHK1/Ku80. Melflufen-induced apoptosis was associated with dose- and time-dependent rapid phosphorylation of -H2AX. Melflufen induces -H2AX, ATR, and CHK1 as early as after 2h exposure in both melphalan-sensitive and -resistant cells. However, melphalan induces -H2AX in melphalan-sensitive cells at 6h and 24h; no -H2AX induction was observed in melphalan-resistant cells even after 24h exposure. Similar kinetics was observed for ATR and CHK1 in meflufen- versus melphalan-treated cells. DNA repair is linked to melphalan-resistance; and importantly, we found that melphalan, but not melflufen, upregulates Ku80 that repairs DNA double-strand breaks. Washout experiments showed that a brief (2h) exposure of MM cells to melflufen is sufficient to initiate an irreversible DNA damage and cytotoxicity. Our data therefore suggest that melflufen triggers a rapid, robust, and an irreversible DNA damage which may account for its ability to overcome melphalan-resistance in MM cells. C1 [Ray, Arghya; Ravillah, Durgadevi; Das, Deepika S.; Song, Yan; Richardson, Paul G.; Chauhan, Dharminder; Anderson, Kenneth C.] Harvard Med Sch, Dept Med Oncol, LeBow Inst Myeloma Therapeut, Dana Farber Canc Inst, Boston, MA USA. [Ray, Arghya; Ravillah, Durgadevi; Das, Deepika S.; Song, Yan; Richardson, Paul G.; Chauhan, Dharminder; Anderson, Kenneth C.] Harvard Med Sch, Jerome Lipper Myeloma Ctr, Dana Farber Canc Inst, Boston, MA USA. [Nordstrom, Eva] Karolinska Inst, Oncopeptides AB, Sci Pk, Solna, Sweden. [Gullbo, Joachim] Uppsala Univ, Sect Oncol, Dept Immunol Genet & Pathol, Uppsala, Sweden. RP Chauhan, D; Anderson, KC (reprint author), Dana Farber Canc Inst, M561,450 Brookline Ave, Boston, MA 02115 USA. EM dharminder_chauhan@dfci.harvard.edu FU National Institutes of Health Specialized Programs of Research Excellence SPORE [P50100707, PO1-CA078378, RO1 CA050947] FX This investigation was supported by National Institutes of Health Specialized Programs of Research Excellence SPORE grant P50100707, PO1-CA078378, and RO1 CA050947 ( DC, and KCA); KCA is an American Cancer Society Clinical Research Professor NR 40 TC 0 Z9 0 U1 2 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 2016 VL 174 IS 3 BP 397 EP 409 DI 10.1111/bjh.14065 PG 13 WC Hematology SC Hematology GA DS4CO UT WOS:000380729200006 PM 27098276 ER PT J AU Trinh, QD Li, HH Meyer, CP Hanske, J Choueiri, TK Reznor, G Lipsitz, SR Kibel, AS Han, PK Nguyen, PL Menon, M Sammon, JD AF Quoc-Dien Trinh Li, Hanhan Meyer, Christian P. Hanske, Julian Choueiri, Toni K. Reznor, Gally Lipsitz, Stuart R. Kibel, Adam S. Han, Paul K. Nguyen, Paul L. Menon, Mani Sammon, Jesse D. TI Determinants of cancer screening in Asian-Americans SO CANCER CAUSES & CONTROL LA English DT Article DE Preventive services; Screening; Asian-American; Asian race; Racial disparities; Cancer; USPSTF ID COLORECTAL-CANCER; UNITED-STATES; CARE; DISPARITIES; HEALTH; SURVIVAL; RISK; RACE/ETHNICITY; POPULATION; CALIFORNIA AB Recent data suggest that Asian-Americans (AsAs) are more likely to present with advanced disease when diagnosed with cancer. We sought to determine whether AsAs are under-utilizing recommended cancer screening. Cross-sectional analysis of the 2012 Behavioral Risk Factor Surveillance System comprising of AsAs and non-Hispanic White (NHW) community-dwelling individuals (English and Spanish speaking) eligible for colorectal, breast, cervical, or prostate cancer screening according to the United States Preventive Services Task Force recommendations. Age, education and income level, residence location, marital status, health insurance, regular access to healthcare provider, and screening were extracted. Complex samples logistic regression models quantified the effect of race on odds of undergoing appropriate screening. Data were analyzed in 2015. Weighted samples of 63.3, 33.3, 47.9, and 30.3 million individuals eligible for colorectal, breast, cervical, and prostate cancer screening identified, respectively. In general, AsAs were more educated, more often married, had higher levels of income, and lived in urban/suburban residencies as compared to NHWs (all p < 0.05). In multivariable analyses, AsAs had lower odds of undergoing colorectal (odds ratio [OR] 0.78, 95 % confidence interval [CI] 0.63-0.96), cervical (OR 0.45, 95 % CI 0.36-0.55), and prostate cancer (OR 0.55, 95 % CI 0.39-0.78) screening and similar odds of undergoing breast cancer (OR 1.29, 95 % CI 0.92-1.82) screening as compared to NHWs. AsAs are less likely to undergo appropriate screening for colorectal, cervical, and prostate cancer. Contributing reasons include limitations in healthcare access, differing cultural beliefs on cancer screening and treatment, and potential physician biases. Interventions such as increasing healthcare access and literacy may improve screening rates. C1 [Quoc-Dien Trinh; Meyer, Christian P.; Hanske, Julian; Reznor, Gally; Lipsitz, Stuart R.; Kibel, Adam S.; Sammon, Jesse D.] Harvard Med Sch, Brigham & Womens Hosp, Div Urol Surg, Ctr Surg & Publ Hlth, 45 Francis St, Boston, MA 02115 USA. [Li, Hanhan; Menon, Mani; Sammon, Jesse D.] Henry Ford Hlth Syst, Ctr Outcomes Res, Vattikuti Urol Inst, Detroit, MI USA. [Choueiri, Toni K.] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA. [Han, Paul K.] Maine Med Ctr, Ctr Outcomes Res & Evaluat, Scarborough, ME USA. [Nguyen, Paul L.] Harvard Med Sch, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA USA. RP Trinh, QD (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Div Urol Surg, Ctr Surg & Publ Hlth, 45 Francis St, Boston, MA 02115 USA. EM trinh.qd@gmail.com OI Han, Paul/0000-0003-0165-1940 FU Vattikuti Urology Institute; Young Investigator Award from the Prostate Cancer Foundation; Career Development Award from the Conquer Cancer Foundation of the American Society of Clinical Oncology FX Quoc-Dien Trinh is supported by an unrestricted educational grant from the Vattikuti Urology Institute, a Young Investigator Award from the Prostate Cancer Foundation and a Career Development Award from the Conquer Cancer Foundation of the American Society of Clinical Oncology. NR 33 TC 0 Z9 0 U1 3 U2 3 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 2016 VL 27 IS 8 BP 989 EP 998 DI 10.1007/s10552-016-0776-8 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DS9RK UT WOS:000381120800004 PM 27372292 ER PT J AU Yang, M Zu, K Mucci, LA Rider, JR Fiorentino, M Clinton, SK Loda, M Stampfer, MJ Giovannucci, E AF Yang, Meng Zu, Ke Mucci, Lorelei A. Rider, Jennifer R. Fiorentino, Michelangelo Clinton, Steven K. Loda, Massimo Stampfer, Meir J. Giovannucci, Edward TI Vascular morphology differentiates prostate cancer mortality risk among men with higher Gleason grade SO CANCER CAUSES & CONTROL LA English DT Article DE Vessel morphology; Angiogenesis; Gleason grade; Prostate cancer mortality ID ANGIOGENESIS; EXPRESSION; GROWTH; COHORT; TARGET; SCORE AB Higher Gleason grade is associated with prostate cancer mortality; however, there is significant heterogeneity in this association. We evaluated whether vessel morphology, a biomarker of angiogenesis, aided in distinguishing mortality risks among men with high Gleason grading. We characterized vessel morphology (area and irregularity) among 511 patients diagnosed with prostate cancer during 1986 to 2000, re-reviewed Gleason grade, and followed men through 2012. Men were grouped according to integrated vessel lumen irregularity and vessel area across Gleason grade. The more angiogenic group was identified as those with more irregular vessel lumen and smaller vessel area. Crude rates (95 % confidence intervals) and survival probability were estimated across Gleason grade and vessel morphology. During a median 14-year follow-up, 62 men developed bone metastases or died of prostate cancer. Lethality rates were uniformly low within Gleason grade categories 6 and 7(3 + 4), regardless of vessel morphology. However, among men with Gleason grades of 7(4 + 3) or 8-10, the more angiogenic group was associated with fourfold higher risk of lethal outcomes compared to those with less angiogenic potential. Ten-year survival probability ranged from 95 to 74 % according to the extent of vessel morphology (p < 0.0001, log-rank test). Vessel morphology may aid Gleason grading in predicting prostate cancer mortality risks among men diagnosed with high-grade Gleason cancers. C1 [Yang, Meng; Zu, Ke; Stampfer, Meir J.; Giovannucci, Edward] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Mucci, Lorelei A.; Rider, Jennifer R.; Fiorentino, Michelangelo; Stampfer, Meir J.; Giovannucci, Edward] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Mucci, Lorelei A.; Rider, Jennifer R.; Stampfer, Meir J.; Giovannucci, Edward] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Mucci, Lorelei A.; Rider, Jennifer R.; Stampfer, Meir J.; Giovannucci, Edward] Harvard Med Sch, Boston, MA 02115 USA. [Fiorentino, Michelangelo] St Orsola Marcello Malpighi Hosp, Addarii Inst, Pathol Unit, I-40138 Bologna, Italy. [Clinton, Steven K.] Ohio State Univ, Dept Internal Med, Div Med Oncol, Columbus, OH 43210 USA. [Loda, Massimo] Harvard Med Sch, Dept Pathol, Boston, MA 02115 USA. [Loda, Massimo] Dana Farber Canc Inst, Dept Pathol, Boston, MA 02215 USA. RP Yang, M (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. EM meyang@hsph.harvard.edu FU National Institutes of Health [PO1 CA055075, CA141298, CA13389, UM1 CA167552]; US Army Prostate Cancer Research Program Idea Development Award [PC060389]; DF/HCC Prostate SPORE Career Development Award NIH/NCI [P50 CA90381]; Ohio State University NIH [P30 CA16058] FX This study was supported by funding from the National Institutes of Health (Grant Nos. PO1 CA055075, CA141298, and CA13389, UM1 CA167552), the US Army Prostate Cancer Research Program Idea Development Award PC060389, the DF/HCC Prostate SPORE Career Development Award NIH/NCI P50 CA90381, and the Ohio State University NIH P30 CA16058. JRR and LAM are Prostate Cancer Foundation Young Investigators. The funding bodies had no influence in the design or conduct of the study, analysis and interpretation of the data, or preparation of the article. We would like to thank the participants and staff of the Health Professionals Follow-up Study for their valuable contributions. We would also like to thank the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data. NR 15 TC 0 Z9 0 U1 2 U2 2 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 2016 VL 27 IS 8 BP 1043 EP 1047 DI 10.1007/s10552-016-0782-x PG 5 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DS9RK UT WOS:000381120800010 PM 27379990 ER PT J AU Brown, SM Grissom, CK Moss, M Rice, TW Schoenfeld, D Hou, PC Thompson, BT Brower, RG AF Brown, Samuel M. Grissom, Colin K. Moss, Marc Rice, Todd W. Schoenfeld, David Hou, Peter C. Thompson, B. Taylor Brower, Roy G. CA NIH NHLBI PETAL Network Collaborat TI Nonlinear Imputation of PaO2/FIO2 From SpO(2)/FIO2 Among Patients With Acute Respiratory Distress Syndrome SO CHEST LA English DT Article DE acute respiratory distress syndrome; pulse oximetry; respiratory failure; severity scores ID ACUTE LUNG INJURY; COMMUNITY-ACQUIRED PNEUMONIA; PULMONARY OXYGEN-TOXICITY; FAILURE ASSESSMENT SCORE; EMERGENCY-DEPARTMENT; DISEASE SEVERITY; CLINICAL-TRIAL; SATURATION; RATIO; ACCURACY AB BACKGROUND: ARDS is an important clinical problem. The definition of ARDS requires testing of arterial blood gas to define the ratio of PaO2 to FIO2 (PaO2/FIO2 ratio). However, many patients with ARDS do not undergo blood gas measurement, which may result in underdiagnosis of the condition. As a consequence, a method for estimating PaO2 on the basis of noninvasive measurements is desirable. METHODS: Using data from three ARDS Network studies, we analyzed the enrollment arterial blood gas measurements to compare nonlinear with linear and log-linear imputation methods of estimating PaO2 from percent saturation of hemoglobin with oxygen as measured by pulse oximetry (SpO(2)). We compared mortality on the basis of various measured and imputed PaO2/FIO2 ratio cutoffs to ensure clinical equivalence. RESULTS: We studied 1,184 patients, in 707 of whom the SpO(2) <= 96%. Nonlinear imputation from the SpO(2)/FIO2 ratio resulted in lower error than linear or log-linear imputation (P < .001) for patients with SpO(2) <= 96% but was equivalent to log-linear imputation in all patients. Ninety-day hospital mortality was 26% to 30%, depending on the PaO2/FIO2 ratio, whether nonlinearly imputed or measured. On multivariate regression, the association between imputed and measured PaO2 varied by use of vasopressors and SpO(2). CONCLUSIONS: A nonlinear equation more accurately imputes PaO2/FIO2 from SpO(2)/FIO2 than linear or log-linear equations, with similar observed hospital mortality depending on SpO(2)/FIO2 ratio vs measured PaO2/FIO2 ratios. While further refinement through prospective validation is indicated, a nonlinear imputation appears superior to prior approaches to imputation. C1 [Brown, Samuel M.; Grissom, Colin K.] Univ Utah, Sch Med, Intermt Med Ctr, Pulm & Crit Care Med Sect, Murray, UT USA. [Moss, Marc] Univ Colorado, Sch Med, Div Pulm Sci & Crit Care Med, Aurora, CO USA. [Rice, Todd W.] Vanderbilt Univ, Div Allergy Pulm & Crit Care Med, Sch Med, 221 Kirkland Hall, Nashville, TN 37235 USA. [Schoenfeld, David] Massachusetts Gen Hosp, Biostat Sect, Boston, MA 02114 USA. [Thompson, B. Taylor] Massachusetts Gen Hosp, Div Pulm & Crit Care Med, Boston, MA 02114 USA. [Hou, Peter C.] Harvard Med Sch, Brigham & Womens Hosp, Dept Emergency Med, Sect Emergency Med Crit Care, Boston, MA USA. [Brower, Roy G.] Johns Hopkins Univ, Sch Med, Pulm & Crit Med Sect, Baltimore, MD USA. RP Brown, SM (reprint author), Shock Trauma Intens Care Unit, 5121 S Cottonwood St, Murray, UT 84107 USA. EM samuel.brown@hsc.utah.edu RI Brown, Samuel/E-6846-2015 OI Brown, Samuel/0000-0003-1206-6261 FU National Institutes of Health, National Heart, Lung, and Blood Institute, Acute Respiratory Distress Syndrome Network [HHSN268200536171C, HHSN268200536165C, HHSN268200536179C]; Prevention and Early Treatment of Lung Injury Network [U01HL123010, U01HL123004, U01HL123022, U01HL122989, U01HL123008, U01HL123027, U01HL123020, U01HL123018, U01HL123031, U01HL123033, U01HL122998, U01HL123023, U01HL123009]; National Institutes of Health, National Institute of General Medical Sciences [K23GM094465]; National Heart, Lung, and Blood Institute [R21HL123433] FX This study was supported by the National Institutes of Health, National Heart, Lung, and Blood Institute, Acute Respiratory Distress Syndrome Network [contracts HHSN268200536171C, HHSN268200536165C, and HHSN268200536179C] and by the Prevention and Early Treatment of Lung Injury Network [contracts U01HL123010, U01HL123004, U01HL123022, U01HL122989, U01HL123008, U01HL123027, U01HL123020, U01HL123018, U01HL123031, U01HL123033, U01HL122998, U01HL123023, and U01HL123009]. S. M. B. is supported by the National Institutes of Health, National Institute of General Medical Sciences [grant K23GM094465] and National Heart, Lung, and Blood Institute [grant R21HL123433]. NR 31 TC 3 Z9 3 U1 1 U2 2 PU AMER COLL CHEST PHYSICIANS PI GLENVIEW PA 2595 PATRIOT BLVD, GLENVIEW, IL 60026 USA SN 0012-3692 J9 CHEST JI Chest PD AUG PY 2016 VL 150 IS 2 BP 307 EP 313 DI 10.1016/j.chest.2016.01.003 PG 7 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DS7AG UT WOS:000380934100019 PM 26836924 ER PT J AU Kabrhel, C Rosovsky, R Channick, R Jaff, MR Weinberg, I Sundt, T Dudzinski, DM Rodriguez-Lopez, J Parry, BA Harshbarger, S Chang, YC Rosenfield, K AF Kabrhel, Christopher Rosovsky, Rachel Channick, Richard Jaff, Michael R. Weinberg, Ido Sundt, Thoralf Dudzinski, David M. Rodriguez-Lopez, Josanna Parry, Blair A. Harshbarger, Savanah Chang, Yuchiao Rosenfield, Kenneth TI A Multidisciplinary Pulmonary Embolism Response Team Initial 30-Month Experience With a Novel Approach to Delivery of Care to Patients With Submassive and Massive Pulmonary Embolism SO CHEST LA English DT Article DE deep vein thrombosis; pulmonary embolism; rapid response team; thrombolysis; thrombosis ID VENOUS THROMBOEMBOLISM; CLINICAL-OUTCOMES; EMBOLECTOMY; MANAGEMENT; THROMBOLYSIS; REGISTRY; TRIAL; FRAGMENTATION; SUPPORT AB BACKGROUND: Integrating newly developed tests and treatments for severe pulmonary embolism (PE) into clinical care requires coordinated multispecialty collaboration. To meet this need, we developed a new paradigm: a multidisciplinary Pulmonary Embolism Response Team (PERT). In this report, we provide the first longitudinal analysis of patients treated by a PERT. METHODS: Our PERT includes specialists in cardiovascular medicine and surgery, emergency medicine, hematology, pulmonary/critical care, and radiology, and is organized as a rapid response team. We prospectively captured clinical, therapeutic, and outcome data at PERT activation and during follow-up periods up to 365 days. We analyzed data collectively, and as five mutually exclusive 6-month periods. We performed Fisher exact tests and regression analysis to test for trend. RESULTS: In 30 months, there were 394 unique PERT activations, 314 (80%) for confirmed PE. PERT activations increased by 16% every 6 months. Most confirmed PEs were submassive (n = 143, 46%) or massive (n = 80, 26%). The PERT treated a relatively large proportion of patients with PE and systemic or catheter-directed thrombolysis (n = 35, 11%), though the most common treatment was anticoagulation alone (n = 215, 69%). Hemorrhagic complications were rare overall, especially among patients treated with catheter-directed thrombolysis. The all-cause 30-day mortality of PERT patients with confirmed PE was 12%. CONCLUSIONS: We report our initial 30-month experience with a novel multidisciplinary PERT that rapidly engages multiple specialists to deliver efficient, organized, and evidence-based care to patients with high-risk PE. The PERT paradigm was rapidly adopted and may become a new standard of care for patients with PE. C1 [Kabrhel, Christopher; Rosovsky, Rachel; Dudzinski, David M.; Parry, Blair A.; Harshbarger, Savanah] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Vasc Emergencies, Dept Emergency Med, Boston, MA USA. [Rosovsky, Rachel; Rodriguez-Lopez, Josanna] Harvard Med Sch, Massachusetts Gen Hosp, Div Hematol & Oncol, Dept Med, Boston, MA USA. [Channick, Richard] Harvard Med Sch, Massachusetts Gen Hosp, Div Pulm & Crit Care, Dept Med, Boston, MA USA. [Jaff, Michael R.; Weinberg, Ido] Harvard Med Sch, Massachusetts Gen Hosp, Fireman Vasc Ctr, Boston, MA USA. [Jaff, Michael R.; Weinberg, Ido; Dudzinski, David M.; Rosenfield, Kenneth] Harvard Med Sch, Massachusetts Gen Hosp, Div Cardiol, Dept Med, Boston, MA USA. [Sundt, Thoralf] Harvard Med Sch, Massachusetts Gen Hosp, Div Cardiac Surg, Dept Surg, Boston, MA USA. [Dudzinski, David M.; Chang, Yuchiao] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Boston, MA USA. RP Kabrhel, C (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, Ctr Vasc Emergencies, Zero Emerson Pl,Ste 3B, Boston, MA 02114 USA. EM ckabrhel@partners.org OI Kabrhel, Christopher/0000-0002-8699-7176 FU Diagnostica Stago; Siemens Healthcare; Janssen Pharmaceuticals; Boehringer-Ingelheim; Abbott Vascular; Atrium; Lutonix/BARD; The Medicines Company FX The authors have reported to CHEST the following: C. K. discloses the following relationships: consultant to Diagnostica Stago, Janssen Pharmaceuticals, Siemens, Pfizer, and Portola Pharmaceuticals; grant recipient from Diagnostica Stago, Siemens Healthcare, Janssen Pharmaceuticals, and Boehringer-Ingelheim. M. J. discloses the following relationships: consultant to Abbott Vascular, Boston Scientific, Cardinal Health, Cordis Corporation, Covidien, Ekos Corporation, Medtronic, Micell, Inc., and Primacea; equity in Access Closure, Inc., I. C. Sciences, Inc., JanaCare, Inc., MC10, Northwind Medical, Inc., PQ Bypass, Inc., Primacea, Sano V, Inc., and Vascular Therapies, Inc.; board member with VIVA Physicians and CBSET. T. S. discloses the following relationship: consultant to Thrasos Therapeutics. R. discloses the following relationships: consultant to Cardinal Health and SurModics; grants/contracts with Abbott Vascular, Atrium; Lutonix/BARD, and The Medicines Company; equity with Access Closure, Inc., and AngioDynamics/Vortex; personal compensation from Cook, HCRI, and The Medicines Company; board member with VIVA Physicians. None declared (R. R., R. C., I. W., T. S., D. D., J. R.-L., B. P., S. H., Y. C.). NR 32 TC 0 Z9 0 U1 3 U2 3 PU AMER COLL CHEST PHYSICIANS PI GLENVIEW PA 2595 PATRIOT BLVD, GLENVIEW, IL 60026 USA SN 0012-3692 J9 CHEST JI Chest PD AUG PY 2016 VL 150 IS 2 BP 384 EP 393 DI 10.1016/j.chest.2016.03.011 PG 10 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DS7AG UT WOS:000380934100028 PM 27006156 ER PT J AU Nakamura, K Alba, GA Scheske, JA Meyersohn, NM Stone, JR Vlahakes, GJ Wright, CD Ghoshhajra, BB Dudzinski, DM AF Nakamura, Kenta Alba, George A. Scheske, Jonathan A. Meyersohn, Nandini M. Stone, James R. Vlahakes, Gus J. Wright, Cameron D. Ghoshhajra, Brian B. Dudzinski, David M. TI A 57-Year-Old Man With Insidious Dyspnea and Nonpleuritic Chest and Back Pain SO CHEST LA English DT Editorial Material ID THROMBOEMBOLIC PULMONARY-HYPERTENSION; PATENT FORAMEN OVALE; RIGHT HEART THROMBI; EMBOLISM REGISTRY; TASK-FORCE; DIAGNOSIS; MANAGEMENT; GUIDELINES; OUTCOMES; THERAPY AB A 57-year-old man with a history of DVT and pulmonary embolism, transient ischemic attacks, prior 60 pack-year smoking history, and oxygen-dependent COPD presented with insidiously worsening dyspnea associated with new pleuritic chest and back pain. C1 [Nakamura, Kenta; Dudzinski, David M.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA USA. [Alba, George A.; Dudzinski, David M.] Harvard Med Sch, Massachusetts Gen Hosp, Div Pulm & Crit Care Med, Dept Med, Boston, MA USA. [Scheske, Jonathan A.; Meyersohn, Nandini M.; Ghoshhajra, Brian B.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Cardiovasc Imaging, Boston, MA USA. [Stone, James R.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Boston, MA USA. [Wright, Cameron D.] Harvard Med Sch, Massachusetts Gen Hosp, Div Thorac Surg, Dept Surg, Boston, MA USA. [Vlahakes, Gus J.] Harvard Med Sch, Massachusetts Gen Hosp, Div Cardiothorac Surg, Dept Surg, Boston, MA USA. RP Dudzinski, DM (reprint author), Massachusetts Gen Hosp, Corrigan Minehan Heart Ctr, 55 Fruit St,Yawkey 5B, Boston, MA 02114 USA.; Dudzinski, DM (reprint author), Massachusetts Gen Hosp, Pulm Embolism Response Team, 55 Fruit St,Yawkey 5B, Boston, MA 02114 USA. EM ddudzinski@mgh.harvard.edu NR 31 TC 1 Z9 1 U1 1 U2 1 PU AMER COLL CHEST PHYSICIANS PI GLENVIEW PA 2595 PATRIOT BLVD, GLENVIEW, IL 60026 USA SN 0012-3692 J9 CHEST JI Chest PD AUG PY 2016 VL 150 IS 2 BP E41 EP E47 DI 10.1016/j.chest.2016.02.680 PG 7 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DS7AG UT WOS:000380934100004 PM 27502992 ER PT J AU Chu, CJ AF Chu, Catherine J. TI Quick and accurate quantification of the premature brain SO CLINICAL NEUROPHYSIOLOGY LA English DT Editorial Material ID PROGNOSTIC VALUE; FULL-TERM; PRETERM INFANTS; NEONATAL EEG; ENCEPHALOPATHY; ELECTROENCEPHALOGRAM; ASPHYXIA; SEIZURES; BIRTH; MATURATION C1 [Chu, Catherine J.] Harvard Med Sch, Massachusetts Gen Hosp, 175 Cambridge St,Suite 340, Boston, MA 02144 USA. RP Chu, CJ (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, 175 Cambridge St,Suite 340, Boston, MA 02144 USA. EM cjchu@mgh.harvard.edu FU NINDS NIH HHS [K23 NS092923] NR 27 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1388-2457 EI 1872-8952 J9 CLIN NEUROPHYSIOL JI Clin. Neurophysiol. PD AUG PY 2016 VL 127 IS 8 BP 2908 EP 2909 DI 10.1016/j.clinph.2016.04.024 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DS8VL UT WOS:000381061000032 PM 27236608 ER PT J AU Humphrey, MB Nakamura, MC AF Humphrey, Mary Beth Nakamura, Mary C. TI A Comprehensive Review of Immunoreceptor Regulation of Osteoclasts SO CLINICAL REVIEWS IN ALLERGY & IMMUNOLOGY LA English DT Review DE Osteoclast; Immunoreceptor; ITAM; Fc receptor; RANK; Osteoimmunology ID DAP12-ASSOCIATING LECTIN (MDL)-1; DNAX-ACTIVATING PROTEIN; HUMAN DENDRITIC CELLS; MYELOID CELLS; FCR-GAMMA; BONE LOSS; IMMUNE-SYSTEM; SIALIC-ACID; FUNCTIONAL OSTEOCLASTS; MEDIATED COSTIMULATION AB Osteoclasts require coordinated co-stimulation by several signaling pathways to initiate and regulate their cellular differentiation. Receptor activator for NF-kappa B ligand (RANKL or TNFSF11), a tumor necrosis factor (TNF) superfamily member, is the master cytokine required for osteoclastogenesis with essential co-stimulatory signals mediated by immunoreceptor tyrosine-based activation motif (ITAM)-signaling adaptors, DNAX-associated protein 12 kDa size (DAP12) and Fc epsilon RI gamma chain (FcR gamma). The ITAM-signaling adaptors do not have an extracellular ligand-binding domain and, therefore, must pair with ligand-binding immunoreceptors to interact with their extracellular environment. DAP12 pairs with a number of different immunoreceptors including triggering receptor expressed on myeloid cells 2 (TREM2), myeloid DAP12-associated lectin (MDL-1), and sialic acid-binding immunoglobulin-type lectin 15 (Siglec-15); while FcR gamma pairs with a different set of receptors including osteoclast-specific activating receptor (OSCAR), paired immunoglobulin receptor A (PIR-A), and Fc receptors. The ligands for many of these receptors in the bone microenvironment remain unknown. Here, we will review immunoreceptors known to pair with either DAP12 or FcR gamma that have been shown to regulate osteoclastogenesis. Co-stimulation and the effects of ITAM-signaling have turned out to be complex, and now include paradoxical findings that ITAM-signaling adaptor-associated receptors can inhibit osteoclastogenesis and immunoreceptor tyrosine-based inhibitory motif (ITIM) receptors can promote osteoclastogenesis. Thus, co-stimulation of osteoclastogenesis continues to reveal additional complexities that are important in the regulatory mechanisms that seek to maintain bone homeostasis. C1 [Humphrey, Mary Beth] Univ Oklahoma, Hlth Sci Ctr, Dept Med, Div Rheumatol Immunol & Allergy, 975 NE 10th St,BRC209, Oklahoma City, OK 73104 USA. [Nakamura, Mary C.] Univ Calif San Francisco, Dept Med, Div Rheumatol, San Francisco, CA USA. [Nakamura, Mary C.] San Francisco Vet Adm Med Ctr, Arthrit Immunol Sect, 4150 Clement St 111R, San Francisco, CA 94121 USA. RP Nakamura, MC (reprint author), Univ Calif San Francisco, Dept Med, Div Rheumatol, San Francisco, CA USA.; Nakamura, MC (reprint author), San Francisco Vet Adm Med Ctr, Arthrit Immunol Sect, 4150 Clement St 111R, San Francisco, CA 94121 USA. EM marybeth-humphrey@ouhsc.edu; mary.nakamura@ucsf.edu FU NIH [AR064211, AG046282]; VA Merit Review; UCSF-Stanford Arthritis Center of Excellence - Great Western Region of the Arthritis Foundation; Rheumatology Research Foundation; Russell/Engleman Rheumatology Research Center FX We thank T. P. Quinn for helpful suggestions and editing the manuscript. M. B. H. is supported by NIH grant AR064211. M. C. N. is supported by a VA Merit Review, NIH grant AG046282, the UCSF-Stanford Arthritis Center of Excellence funded by the Great Western Region of the Arthritis Foundation, the Rheumatology Research Foundation, and the Russell/Engleman Rheumatology Research Center. NR 81 TC 1 Z9 1 U1 7 U2 7 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1080-0549 EI 1559-0267 J9 CLIN REV ALLERG IMMU JI Clin. Rev. Allergy Immunol. PD AUG PY 2016 VL 51 IS 1 BP 48 EP 58 DI 10.1007/s12016-015-8521-8 PG 11 WC Allergy; Immunology SC Allergy; Immunology GA DS9BC UT WOS:000381075800004 PM 26573914 ER PT J AU Henin, A Berman, N AF Henin, Aude Berman, Noah TI The Promise and Peril of Emerging Adulthood: Introduction to the Special Issue SO COGNITIVE AND BEHAVIORAL PRACTICE LA English DT Article DE emerging adults; resilience; treatment; substance abuse ID MENTAL-HEALTH CONDITIONS; TRANSITION-AGE YOUTH; BIPOLAR DISORDER; ADOLESCENT BRAIN; RISK-TAKING; NEUROSCIENCE PERSPECTIVE; PREVALENCE; PATTERNS; LIFE; MATURATION AB Emerging adulthood, typically defined as the period between ages 18 and mid-to-late 20s, is gaining increased recognition, as a key developmental stage characterized by specific neurobiological changes and associated psychological and social characteristics. Of particular clinical importance, emerging adulthood is a period of elevated risk for psychiatric disorders and psythosocial dysfunction. At the same time, this developmental period may be an optimal time to intervene and facilitate the adoption of adaptive behaviors and coping strategies. This special section consists of 10 articles focusing on various topics of relevance to the study of and practice with emerging adults. These papers focus on the risks for a variety of psychological disorders in emerging adults and the adaptation of evidence-based interventions for use with this population. They also highlight common issues that clinicians face when working with emerging adults, and examine the impact of major psychosocial stressors, such as racial discrimination, on mental health in these youth. Together, these papers underscore both the tremendous challenges that some individuals face in transitioning to adulthood, as well as the possibility for great resilience and positive life trajectories. C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Med Sch, Boston, MA USA. RP Henin, A (reprint author), Massachusetts Gen Hosp, Child Cognit Behav Therapy Program, 151 Merrimac St,Suite 650, Boston, MA 02114 USA. EM ahenin@partners.org NR 70 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1077-7229 EI 1878-187X J9 COGN BEHAV PRACT JI Cogn. Behav. Pract. PD AUG PY 2016 VL 23 IS 3 BP 263 EP 269 PG 7 WC Psychology, Clinical SC Psychology GA DS8XK UT WOS:000381066100001 ER PT J AU Bergman, BG Kelly, JF Nargiso, JE McKowen, JW AF Bergman, Brandon G. Kelly, John F. Nargiso, Jessica E. McKowen, James W. TI "The Age of Feeling in-Between": Addressing Challenges in the Treatment of Emerging Adults With Substance Use Disorders SO COGNITIVE AND BEHAVIORAL PRACTICE LA English DT Article DE emerging adulthood; substance use disorders; addiction treatment; mutual-help organizations ID ALCOHOL-USE DISORDERS; LEEDS-DEPENDENCE-QUESTIONNAIRE; IDENTIFICATION TEST AUDIT; DRUG-TREATMENT OUTCOMES; RANDOMIZED CONTROLLED-TRIAL; ABUSE SCREENING-TEST; YOUNG-ADULTS; 12-STEP PARTICIPATION; DRINKING OUTCOMES; SELECTION BIAS AB Substance use and substance-related disorders are among the most prodigious public health problems in the United States. Emerging adults (ages 18-25) appear to carry a disproportionately large share of this societal burden, as they are more than twice as likely as adolescents and older adults to be diagnosed with substance use disorders (SUDs), and comprise more than 20% of SUD treatment seekers. Described as the "age of feeling in-between," emerging adulthood is associated with a biopsychosocial profile distinct from both adolescence and older adulthood, making members of this age group unique and challenging clinical cases. Data suggest that although emerging adults can benefit from cognitive-behavioral (CB) and other psychosocial treatments for SUD, they are likely to have poorer treatment response than their younger and older counterparts. Therefore, we propose several theoretically and empirically-grounded treatment modifications for this vulnerable group, such as parent counseling (or "coaching") to facilitate better treatment engagement and benefit via contingency management. A case example is used to illustrate challenges typical in SUD treatment for emerging adults and how a CB practitioner might choose to modify his/her approach based on the proposed modifications. We also offer several recommendations for practitioners who wish to address their patients' SUD or harmful substance use when it is not the primary focus of treatment. C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Med Sch, Boston, MA USA. RP Bergman, BG (reprint author), Recovery Res Inst, 151 Merrimac St,6th Floor, Boston, MA 02114 USA. EM bgbergman@mgh.harvard.edu NR 136 TC 2 Z9 2 U1 11 U2 16 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1077-7229 EI 1878-187X J9 COGN BEHAV PRACT JI Cogn. Behav. Pract. PD AUG PY 2016 VL 23 IS 3 BP 270 EP 288 PG 19 WC Psychology, Clinical SC Psychology GA DS8XK UT WOS:000381066100002 ER PT J AU Softic, S Boucher, J Solheim, MH Fujisaka, S Haering, MF Homan, EP Winnay, J Perez-Atayde, AR Kahn, CR AF Softic, Samir Boucher, Jeremie Solheim, Marie H. Fujisaka, Shiho Haering, Max-Felix Homan, Erica P. Winnay, Jonathon Perez-Atayde, Antonio R. Kahn, C. Ronald TI Lipodystrophy Due to Adipose Tissue-Specific Insulin Receptor Knockout Results in Progressive NAFLD SO DIABETES LA English DT Article ID FATTY LIVER-DISEASE; NONALCOHOLIC STEATOHEPATITIS; GENERALIZED LIPODYSTROPHY; PPAR-ALPHA; RESISTANCE; MODEL; MICE; FIBROBLAST-GROWTH-FACTOR-21; ASSOCIATION; METABOLISM AB Ectopic lipid accumulation in the liver is an almost universal feature of human and rodent models of generalized lipodystrophy and is also a common feature of type 2 diabetes, obesity, and metabolic syndrome. Here we explore the progression of fatty liver disease using a mouse model of lipodystrophy created by a fat-specific knockout of the insulin receptor (F-IRKO) or both IR and insulin-like growth factor 1 receptor (F-IR/IGFRKO). These mice develop severe lipodystrophy, diabetes, hyperlipidemia, and fatty liver disease within the first weeks of life. By 12 weeks of age, liver demonstrated increased reactive oxygen species, lipid peroxidation, histological evidence of balloon degeneration, and elevated serum alanine aminotransferase and aspartate aminotransferase levels. In these lipodystrophic mice, stored liver lipids can be used for energy production, as indicated by a marked decrease in liver weight with fasting and increased liver fibroblast growth factor 21 expression and intact ketogenesis. By 52 weeks of age, liver accounted for 25% of body weight and showed continued balloon degeneration in addition to inflammation, fibrosis, and highly dysplastic liver nodules. Progression of liver disease was associated with improvement in blood glucose levels, with evidence of altered expression of gluconeogenic and glycolytic enzymes. However, these mice were able to mobilize stored glycogen in response to glucagon. Feeding F-IRKO and F-IR/IGFRKO mice a high-fat diet for 12 weeks accelerated the liver injury and normalization of blood glucose levels. Thus, severe fatty liver disease develops early in lipodystrophic mice and progresses to advanced nonalcoholic steatohepatitis with highly dysplastic liver nodules. The liver injury is propagated by lipotoxicity and is associated with improved blood glucose levels. C1 [Softic, Samir; Boucher, Jeremie; Solheim, Marie H.; Fujisaka, Shiho; Haering, Max-Felix; Homan, Erica P.; Winnay, Jonathon; Kahn, C. Ronald] Harvard Med Sch, Joslin Diabet Ctr, Sect Integrat Physiol & Metab, Boston, MA 02115 USA. [Softic, Samir; Boucher, Jeremie; Solheim, Marie H.; Fujisaka, Shiho; Haering, Max-Felix; Homan, Erica P.; Winnay, Jonathon; Kahn, C. Ronald] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. [Softic, Samir] Boston Childrens Hosp, Div Gastroenterol Hepatol & Nutr, Boston, MA USA. [Solheim, Marie H.] Univ Bergen, KG Jebsen Ctr Diabet Res, Dept Clin Sci, Bergen, Norway. [Perez-Atayde, Antonio R.] Boston Childrens Hosp, Dept Pathol, Boston, MA USA. [Perez-Atayde, Antonio R.] Harvard Med Sch, Boston, MA USA. [Boucher, Jeremie] AstraZeneca R&D, Cardiovasc & Metab Dis iMed, Molndal, Sweden. RP Kahn, CR (reprint author), Harvard Med Sch, Joslin Diabet Ctr, Sect Integrat Physiol & Metab, Boston, MA 02115 USA.; Kahn, CR (reprint author), Harvard Med Sch, Dept Med, Boston, MA 02115 USA. EM c.ronald.kahn@joslin.harvard.edu FU Joslin Diabetes and Endocrinology Research Center Core Laboratories [P30-DK-036836]; National Institute of Diabetes and Digestive and Kidney Diseases [K12-HD-000850, R01-DK-031036, R01-DK-082659]; University of Bergen; KG Jebsen Foundation; Norwegian Society of Endocrinology; Eckbo's Foundation; T. Wilhelmsen Foundation; Norwegian Diabetes Association; Sunstar Foundation FX This work was supported by the Joslin Diabetes and Endocrinology Research Center Core Laboratories (P30-DK-036836) and by National Institute of Diabetes and Digestive and Kidney Diseases grants K12-HD-000850 to S.S. and R01-DK-031036 and R01-DK-082659 to C.R.K. M.H.S. was partly supported by funds from the University of Bergen, KG Jebsen Foundation, Norwegian Society of Endocrinology, Eckbo's Foundation, the T. Wilhelmsen Foundation, and the Norwegian Diabetes Association. The Sunstar Foundation supported S.F. NR 39 TC 4 Z9 4 U1 2 U2 2 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD AUG PY 2016 VL 65 IS 8 BP 2187 EP 2200 DI 10.2337/db16-0213 PG 14 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DS4KQ UT WOS:000380750400015 PM 27207510 ER PT J AU Boucher, J Softic, S El Ouaamari, A Krumpoch, MT Kleinridders, A Kulkarni, RN O'Neill, BT Kahn, CR AF Boucher, Jeremie Softic, Samir El Ouaamari, Abdelfattah Krumpoch, Megan T. Kleinridders, Andre Kulkarni, Rohit N. O'Neill, Brian T. Kahn, C. Ronald TI Differential Roles of Insulin and IGF-1 Receptors in Adipose Tissue Development and Function SO DIABETES LA English DT Article ID BETA-CELL PROLIFERATION; GROWTH-FACTOR-I; CONGENITAL LIPODYSTROPHY; GLUCOSE-INTOLERANCE; PPAR-GAMMA; RESISTANCE; MUSCLE; MICE; FAT; ADIPOCYTES AB To determine the roles of insulin and insulin-like growth factor 1 (IGF-1) action in adipose tissue, we created mice lacking the insulin receptor (IR), IGF-1 receptor (IGF1R), or both using Cre-recombinase driven by the adiponectin promoter. Mice lacking IGF1R only (F-IGFRKO) had a similar to 25% reduction in white adipose tissue (WAT) and brown adipose tissue (BAT), whereas mice lacking both IR and IGF1R (F-IR/IGFRKO) showed an almost complete absence of WAT and BAT. Interestingly, mice lacking only the IR (F-IRKO) had a 95% reduction in WAT, but a paradoxical 50% increase in BAT with accumulation of large unilocular lipid droplets. Both F-IRKO and F-IR/IGFRKO mice were unable to maintain body temperature in the cold and developed severe diabetes, ectopic lipid accumulation in liver and muscle, and pancreatic islet hyperplasia. Leptin treatment normalized blood glucose levels in both groups. Glucose levels also improved spontaneously by 1 year of age, despite sustained lipodystrophy and insulin resistance. Thus, loss of IR is sufficient to disrupt white fat formation, but not brown fat formation and/or maintenance, although it is required for normal BAT function and temperature homeostasis. IGF1R has only a modest contribution to both WAT and BAT formation and function. C1 [Boucher, Jeremie; Softic, Samir; Krumpoch, Megan T.; Kleinridders, Andre; O'Neill, Brian T.; Kahn, C. Ronald] Harvard Med Sch, Joslin Diabet Ctr, Sect Integrat Physiol & Metab, Boston, MA 02115 USA. [Boucher, Jeremie; Softic, Samir; El Ouaamari, Abdelfattah; Krumpoch, Megan T.; Kleinridders, Andre; Kulkarni, Rohit N.; O'Neill, Brian T.; Kahn, C. Ronald] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. [Softic, Samir] Boston Childrens Hosp, Div Gastroenterol Hepatol & Nutr, Boston, MA USA. [El Ouaamari, Abdelfattah; Kulkarni, Rohit N.] Harvard Med Sch, Joslin Diabet Ctr, Islet Cell & Regenerat Med, Boston, MA USA. [Boucher, Jeremie] AstraZeneca R&D, Cardiovasc & Metab Dis iMed, Molndal, Sweden. [Kleinridders, Andre] German Inst Human Nutr, Potsdam, Germany. [Kleinridders, Andre] German Ctr Diabet Res DZD, Neuherberg, Germany. RP Kahn, CR (reprint author), Harvard Med Sch, Joslin Diabet Ctr, Sect Integrat Physiol & Metab, Boston, MA 02115 USA.; Kahn, CR (reprint author), Harvard Med Sch, Dept Med, Boston, MA 02115 USA. EM c.ronald.kahn@joslin.harvard.edu FU Joslin Diabetes and Endocrinology Research Center Core Laboratories [P30-DK-036836]; National Institute of Diabetes and Digestive Kidney Diseases (NIDDK) [R01-DK-031036, R01-DK-082659, K12-HD-000850, R01-DK-67536, R01-DK-103215]; JDRF [3-APF-2014-182-A-N]; NIDDK [K08-DK-100543] FX This work was supported by the Joslin Diabetes and Endocrinology Research Center Core Laboratories (P30-DK-036836); National Institute of Diabetes and Digestive Kidney Diseases (NIDDK) grants R01-DK-031036 and R01-DK-082659 to C.R.K., K12-HD-000850 to S.S., and R01-DK-67536 and R01-DK-103215 to R.N.K.; JDRF 3-APF-2014-182-A-N to A.E.O.; and NIDDK K08 Training Award K08-DK-100543 to B.T.O. NR 38 TC 3 Z9 3 U1 3 U2 3 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD AUG PY 2016 VL 65 IS 8 BP 2201 EP 2213 DI 10.2337/db16-0212 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DS4KQ UT WOS:000380750400016 PM 27207537 ER PT J AU Luo, T Nocon, A Fry, J Sherban, A Rui, XL Jiang, BB Xu, XJ Han, JY Yan, Y Yang, Q Li, Q Zang, MW AF Luo, Ting Nocon, Allison Fry, Jessica Sherban, Alex Rui, Xianliang Jiang, Bingbing Xu, X. Julia Han, Jingyan Yan, Yun Yang, Qin Li, Qifu Zang, Mengwei TI AMPK Activation by Metformin Suppresses Abnormal Extracellular Matrix Remodeling in Adipose Tissue and Ameliorates Insulin Resistance in Obesity SO DIABETES LA English DT Article ID PROTEIN-KINASE; LIVER FIBROSIS; LIPID-METABOLISM; GENE-EXPRESSION; ADIPOCYTE; MICE; ATHEROSCLEROSIS; ROSIGLITAZONE; HOMEOSTASIS; MECHANISM AB Fibrosis is emerging as a hallmark of metabolically dysregulated white adipose tissue (WAT) in obesity. Although adipose tissue fibrosis impairs adipocyte plasticity, little is known about how aberrant extracellular matrix (ECM) remodeling of WAT is initiated during the development of obesity. Here we show that treatment with the antidiabetic drug metformin inhibits excessive ECM deposition in WAT of ob/ob mice and mice with diet-induced obesity, as evidenced by decreased collagen deposition surrounding adipocytes and expression of fibrotic genes including the collagen cross-linking regulator LOX. Inhibition of interstitial fibrosis by metformin is likely attributable to the activation of AMPK and the suppression of transforming growth factor-beta 1 (TGF-beta 1)/Smad3 signaling, leading to enhanced systemic insulin sensitivity. The ability of metformin to repress TGF-beta 1-induced fibrogenesis is abolished by the dominant negative AMPK in primary cells from the stromal vascular fraction. TGF-beta 1-induced insulin resistance is suppressed by AMPK agonists and the constitutively active AMPK in 3T3L1 adipocytes. In omental fat depots of obese humans, interstitial fibrosis is also associated with AMPK inactivation, TGF-beta 1/Smad3 induction, aberrant ECM production, myofibroblast activation, and adipocyte apoptosis. Collectively, integrated AMPK activation and TGF-beta 1/Smad3 inhibition may provide a potential therapeutic approach to maintain ECM flexibility and combat chronically uncontrolled adipose tissue expansion in obesity. C1 [Luo, Ting; Nocon, Allison; Fry, Jessica; Sherban, Alex; Rui, Xianliang; Jiang, Bingbing; Xu, X. Julia; Han, Jingyan; Zang, Mengwei] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Luo, Ting; Li, Qifu] Chongqing Med Univ, Dept Endocrinol, Affiliated Hosp 1, Chongqing, Peoples R China. [Yan, Yun] Childrens Mercy Hosp, Dept Pediat, Div Endocrinol, Kansas City, MO 64108 USA. [Yan, Yun] Univ Missouri, Kansas City, MO 64110 USA. [Yang, Qin] Univ Calif Irvine, Dept Med Physiol & Biophys, Ctr Diabet Res & Treatment, Irvine, CA USA. [Yang, Qin] Univ Calif Irvine, Ctr Epigenet & Metab, Irvine, CA USA. [Zang, Mengwei] Univ Texas Hlth Sci Ctr San Antonio, Ctr Hlth Aging, Barshop Inst Longev & Aging Studies, San Antonio, TX 78229 USA. [Zang, Mengwei] Univ Texas Hlth Sci Ctr San Antonio, Dept Mol Med, San Antonio, TX 78229 USA. [Zang, Mengwei] Audie L Murphy VA Hosp, Geriatr Res Educ & Clin Ctr, San Antonio, TX 78229 USA. [Zang, Mengwei] South Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. RP Zang, MW (reprint author), Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA.; Zang, MW (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Mol Med, San Antonio, TX 78229 USA.; Zang, MW (reprint author), Audie L Murphy VA Hosp, Geriatr Res Educ & Clin Ctr, San Antonio, TX 78229 USA.; Zang, MW (reprint author), South Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. EM zang@uthscsa.edu FU National Institutes of Health [R01 DK076942, R01 DK100603, R21AA021181]; American Diabetes Association [1-15-BS-216]; Boston University Clinical and Translational Science Award [1UL1TR001430] FX This work was supported by the National Institutes of Health (grant nos. R01 DK076942, R01 DK100603, and R21AA021181 [to M.Z.]) and the American Diabetes Association Award 1-15-BS-216 (to M.Z.). M.Z. also received a Boston University Clinical and Translational Science Award (1UL1TR001430). NR 44 TC 4 Z9 4 U1 13 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 2016 VL 65 IS 8 BP 2295 EP 2310 DI 10.2337/db15-1122 PG 16 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DS4KQ UT WOS:000380750400024 PM 27207538 ER PT J AU Mundinger, TO Mei, Q Foulis, AK Fligner, CL Hull, RL Taborsky, GJ AF Mundinger, Thomas O. Mei, Qi Foulis, Alan K. Fligner, Corinne L. Hull, Rebecca L. Taborsky, Gerald J., Jr. TI Human Type 1 Diabetes Is Characterized by an Early, Marked, Sustained, and Islet-Selective Loss of Sympathetic Nerves SO DIABETES LA English DT Article ID INSULIN-INDUCED HYPOGLYCEMIA; INCREASED GLUCAGON-SECRETION; AUTONOMIC NERVOUS-SYSTEM; PANCREATIC-POLYPEPTIDE; GLUCOSE COUNTERREGULATION; IMPAIRED GLUCAGON; MELLITUS; STIMULATION; EPINEPHRINE; NEUROPATHY AB In humans, the glucagon response to moderate-to-marked insulin-induced hypoglycemia (IIH) is largely mediated by the autonomic nervous system. Because this glucagon response is impaired early in type 1 diabetes, we sought to determine if these patients, like animal models of autoimmune diabetes, have an early and severe loss of islet sympathetic nerves. We also tested whether this nerve loss is a permanent feature of type 1 diabetes, is islet-selective, and is not seen in type 2 diabetes. To do so, we quantified pancreatic islet and exocrine sympathetic nerve fiber area from autopsy samples of patients with type 1 or 2 diabetes and control subjects without diabetes. Our central finding is that patients with either very recent onset (<2 weeks) or long duration (>10 years) of type 1 diabetes have a severe loss of islet sympathetic nerves (Delta = -88% and Delta = -79%, respectively). In contrast, patients with type 2 diabetes lose no islet sympathetic nerves. There is no loss of exocrine sympathetic nerves in either type 1 or type 2 diabetes. We conclude that patients with type 1, but not type 2, diabetes have an early, marked, sustained, and islet-selective loss of sympathetic nerves, one that may impair their glucagon response to IIH. C1 [Mundinger, Thomas O.; Mei, Qi; Hull, Rebecca L.; Taborsky, Gerald J., Jr.] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Foulis, Alan K.] Southern Gen Hosp, Dept Pathol, Glasgow, Lanark, Scotland. [Fligner, Corinne L.] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [Hull, Rebecca L.; Taborsky, Gerald J., Jr.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. RP Mundinger, TO (reprint author), Univ Washington, Dept Med, Seattle, WA 98195 USA. EM mundin@u.washington.edu FU U.S. National Institutes of Health [R01-DK-088082, R01-DK-050154]; Biomedical Laboratory Research and Development Service of the U.S. Department of Veterans Affairs; University of Washington Diabetes Research Center [P30-DK-017047] FX This work was supported by U.S. National Institutes of Health grants R01-DK-088082 (R.L.H.) and R01-DK-050154 (G.J.T.), the Biomedical Laboratory Research and Development Service of the U.S. Department of Veterans Affairs (G.J.T.), and University of Washington Diabetes Research Center grant P30-DK-017047. NR 56 TC 2 Z9 2 U1 2 U2 2 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD AUG PY 2016 VL 65 IS 8 BP 2322 EP 2330 DI 10.2337/db16-0284 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DS4KQ UT WOS:000380750400026 PM 27207540 ER PT J AU Zhang, W Wu, MR Kim, T Jariwala, RH Garvey, WJ Luo, NL Kang, MS Ma, E Tian, L Steverson, D Yang, QL Fu, YC Garvey, WT AF Zhang, Wei Wu, Mengrui Kim, Teayoun Jariwala, Ravi H. Garvey, W. John Luo, Nanlan Kang, Minsung Ma, Elizabeth Tian, Ling Steverson, Dennis Yang, Qinglin Fu, Yuchang Garvey, W. Timothy TI Skeletal Muscle TRIB3 Mediates Glucose Toxicity in Diabetes and High-Fat Diet-Induced Insulin Resistance SO DIABETES LA English DT Article ID GLUTAMINE-FRUCTOSE-6-PHOSPHATE AMIDOTRANSFERASE; TRIBBLES HOMOLOG; TRANSPORT SYSTEM; HEXOSAMINE BIOSYNTHESIS; INDUCED DESENSITIZATION; BIOCHEMICAL PATHWAYS; GLUT4 TRANSLOCATION; METABOLIC SYNDROME; TRANSGENIC MICE; TRB3 AB In the current study, we used muscle-specific TRIB3 over-expressing (MOE) and knockout (MKO) mice to determine whether TRIB3 mediates glucose-induced insulin resistance in diabetes and whether alterations in TRIB3 expression as a function of nutrient availability have a regulatory role in metabolism. In streptozotocin diabetic mice, TRIB3 MOE exacerbated, whereas MKO prevented, glucose-induced insulin resistance and impaired glucose oxidation and defects in insulin signal transduction compared with wild-type (WT) mice, indicating that glucose-induced insulin resistance was dependent on TRIB3. In response to a high-fat diet, TRIB3 MOE mice exhibited greater weight gain and worse insulin resistance in vivo compared with WT mice, coupled with decreased AKT phosphorylation, increased inflammation and oxidative stress, and upregulation of lipid metabolic genes coupled with downregulation of glucose metabolic genes in skeletal muscle. These effects were prevented in the TRIB3 MKO mice relative to WT mice. In conclusion, TRIB3 has a pathophysiological role in diabetes and a physiological role in metabolism. Glucose-induced insulin resistance and insulin resistance due to diet-induced obesity both depend on muscle TRIB3. Under physiological conditions, muscle TRIB3 also influences energy expenditure and substrate metabolism, indicating that the decrease and increase in muscle TRIB3 under fasting and nutrient excess, respectively, are critical for metabolic homeostasis. C1 [Zhang, Wei; Jariwala, Ravi H.; Garvey, W. John; Luo, Nanlan; Kang, Minsung; Ma, Elizabeth; Tian, Ling; Steverson, Dennis; Yang, Qinglin; Fu, Yuchang; Garvey, W. Timothy] Univ Alabama Birmingham, Dept Nutr Sci, Birmingham, AL 35294 USA. [Wu, Mengrui] Univ Alabama Birmingham, Dept Mol & Cellular Pathol, Birmingham, AL USA. [Kim, Teayoun] Univ Alabama Birmingham, Dept Med Endocrinol Diabet & Metab, Birmingham, AL USA. [Garvey, W. Timothy] Birmingham Vet Affairs Med Ctr, Birmingham, AL 35233 USA. RP Zhang, W; Garvey, WT (reprint author), Univ Alabama Birmingham, Dept Nutr Sci, Birmingham, AL 35294 USA.; Garvey, WT (reprint author), Birmingham Vet Affairs Med Ctr, Birmingham, AL 35233 USA. EM siweizh@uab.edu; garveyt@uab.edu FU National Institutes of Health [DK-038765, DK-083562]; Department of Veterans Affairs Merit Review Program; American Diabetes Association [1-13-IN-19]; National Institute of Diabetes and Digestive and Kidney Diseases [P60 DK079626] FX This work was supported by grants from the National Institutes of Health (DK-038765 and DK-083562), the Department of Veterans Affairs Merit Review Program, and the American Diabetes Association (1-13-IN-19) and by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases to the UAB Diabetes Research Center Core Facilities (P60 DK079626). NR 44 TC 0 Z9 0 U1 3 U2 3 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD AUG PY 2016 VL 65 IS 8 BP 2380 EP 2391 DI 10.2337/db16-0154 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DS4KQ UT WOS:000380750400031 PM 27207527 ER PT J AU Bind, MA Peters, A Koutrakis, P Coull, B Vokonas, P Schwartz, J AF Bind, Marie-Abele Peters, Annette Koutrakis, Petros Coull, Brent Vokonas, Pantel Schwartz, Joel TI Quantile Regression Analysis of the Distributional Effects of Air Pollution on Blood Pressure, Heart Rate Variability, Blood Lipids, and Biomarkers of Inflammation in Elderly American Men: The Normative Aging Study SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID MYOCARDIAL-INFARCTION SURVIVORS; AMBIENT-TEMPERATURE; ASSOCIATION; EXPOSURE; SUSCEPTIBILITY; CONSEQUENCES; HYPERTENSION; COAGULATION; METHYLATION; POPULATION AB BACKGROUND: Previous studies have observed associations between air pollution and heart disease. Susceptibility to air pollution effects has been examined mostly with a test of effect modification, but little evidence is available whether air pollution distorts cardiovascular risk factor distribution. OBJECTIVES: This paper aims to examine distributional and heterogeneous effects of air pollution on known cardiovascular biomarkers. METHODS: A total of 1,112 men from the Normative Aging Study and residents of the greater Boston, Massachusetts, area with mean age of 69 years at baseline were included in this study during the period 1995-2013. We used quantile regression and random slope models to investigate distributional effects and heterogeneity in the traffic-related responses on blood pressure, heart rate variability, repolarization, lipids, and inflammation. We considered 28-day averaged exposure to particle number, PM2.5 black carbon, and PM2.5 mass concentrations (measured at a single monitor near the site of the study visits). RESULTS: We observed some evidence suggesting distributional effects of traffic-related pollutants on systolic blood pressure, heart rate variability, corrected QT interval, low density lipoprotein (LDL) cholesterol, triglyceride, and intercellular adhesion molecule-1 (ICAM-1). For example, among participants with LDL cholesterol below 80 mg/dL, an interquartile range increase in PM2.5 black carbon exposure was associated with a 7-mg/dL (95% CI: 5, 10) increase in LDL cholesterol, while among subjects with LDL cholesterol levels close to 160 mg/dL, the same exposure was related to a 16-mg/dL (95% CI: 13, 20) increase in LDL cholesterol. We observed similar heterogeneous associations across low versus high percentiles of the LDL distribution for PM2.5 mass and particle number. CONCLUSIONS: These results suggest that air pollution distorts the distribution of cardiovascular risk factors, and that, for several outcomes, effects may be greatest among individuals who are already at high risk. C1 [Bind, Marie-Abele] Harvard Univ, Dept Stat, Cambridge, MA 02138 USA. [Peters, Annette] Helmholtz Zentrum Munchen German Res Ctr Environ, Inst Epidemiol 2, Neuherberg, Germany. [Koutrakis, Petros; Schwartz, Joel] Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA. [Koutrakis, Petros; Schwartz, Joel] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Coull, Brent] VA Boston Healthcare Syst, Boston, MA USA. [Vokonas, Pantel] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. RP Bind, MA (reprint author), Ctr Sci, Dept Stat, 7th Floor,One Oxford St, Cambridge, MA 02138 USA. EM ma.bind@mail.harvard.edu RI Peters, Annette/A-6117-2011 FU Ziff Fund at the Harvard University Center for the Environment; National Institutes of Health, National Institute of Environmental Health Sciences [RO1-ES015172, 2RO1-ES015172, ES014663]; Cooperative Studies Program/Epidemiology Research and Information Center of the U.S. Department of Veterans Affairs; U.S. Environmental Protection Agency (EPA) [RD-832416, RD-83479801] FX This work was supported by the Ziff Fund at the Harvard University Center for the Environment, and by the National Institutes of Health, National Institute of Environmental Health Sciences (grants RO1-ES015172, 2RO1-ES015172, and ES014663). The Normative Aging Study is supported by the Cooperative Studies Program/Epidemiology Research and Information Center of the U.S. Department of Veterans Affairs and is a component of the Massachusetts Veterans Epidemiology Research and Information Center, Boston, Massachusetts. In addition, this publication was made possible by U.S. Environmental Protection Agency (EPA) grants RD-832416 and RD-83479801. NR 37 TC 0 Z9 0 U1 6 U2 9 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD AUG PY 2016 VL 124 IS 8 BP 1189 EP 1198 DI 10.1289/ehp.1510044 PG 10 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA DS4KL UT WOS:000380749900017 PM 26967543 ER PT J AU Davison, BA Metra, M Senger, S Edwards, C Milo, O Bloomfield, DM Cleland, JG Dittrich, HC Givertz, MM O'Connor, CM Massie, BM Ponikowski, P Teerlink, JR Voors, AA Cotter, G AF Davison, Beth A. Metra, Marco Senger, Stefanie Edwards, Christopher Milo, Olga Bloomfield, Daniel M. Cleland, John G. Dittrich, Howard C. Givertz, Michael M. O'Connor, Christopher M. Massie, Barry M. Ponikowski, Piotr Teerlink, John R. Voors, Adriaan A. Cotter, Gad TI Patient journey after admission for acute heart failure: length of stay, 30-day readmission and 90-day mortality SO EUROPEAN JOURNAL OF HEART FAILURE LA English DT Article DE Acute heart failure; Length of stay; Prognosis; Regional differences; Global variation; Outcomes ID HOSPITALIZATION INSIGHTS; PROTECT TRIAL; ASCEND-HF; CARE; ROLOFYLLINE; ANTAGONIST; OUTCOMES; EUROPE; RATES AB AimsThe course of patients following admission for acute heart failure (AHF) is of major importance to patients and healthcare providers. We examined predictors and associations of length of stay (LOS), 30-day post-discharge readmission and 90-day post-discharge mortality in 1990 patients enrolled in the PROTECT study. Methods and resultsPROTECT was a randomized study that examined the effect of the adenosine blocker rolofylline in patients within 24h of admission for AHF with mild to moderate renal impairment. Geographic-region-adjusted multivariable models showed that LOS was only partly explained by the severity of heart failure (HF), comorbidities (diabetes mellitus, renal impairment, ischaemic heart disease) and degree of metabolic dysfunction (cholesterol and albumin) at baseline (adjusted R-2 0.27). Addition of in-hospital worsening heart failure (WHF) and changes in metabolic markers contributed significantly to prediction of LOS [R-2 difference 0.050, 95% confidence interval (CI) 0.0282-0.072]. Thirty-day HF readmission was associated with more severe HF and previous HF admission but not with LOS (odds ratios 1.00, 95% CI 0.97-1.04). Death within 90days after discharge was associated with older age, more severe HF, worse renal function, and lower sodium and bicarbonate at admission; LOS was a strong predictor of 90-day post-discharge mortality. ConclusionsIn patients admitted for AHF, LOS is not well-predicted by traditional markers of disease severity, but strongly associated with the occurrence of in-hospital WHF. Longer LOS is a strong predictor of early mortality after discharge but not of readmission. These findings may help focus efforts to reduce LOS and post-discharge outcomes on patients' subgroups at increased risk. C1 [Davison, Beth A.; Senger, Stefanie; Edwards, Christopher; Milo, Olga; Cotter, Gad] Momentum Res Inc, 3100 Tower Blvd,Suite 802, Durham, NC 27707 USA. [Metra, Marco] Univ Brescia, Brescia, Italy. [Bloomfield, Daniel M.] Merck Res Labs, Rahway, NJ USA. [Cleland, John G.] Univ Hull, Kingston Upon Hull, Yorks, England. [Cleland, John G.] Imperial Coll, Natl Heart & Lung Inst, London, England. [Dittrich, Howard C.] Univ Iowa, Carver Coll Med, Cardiovasc Res Ctr, Iowa City, IA USA. [Givertz, Michael M.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [O'Connor, Christopher M.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. [Massie, Barry M.; Teerlink, John R.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Massie, Barry M.; Teerlink, John R.] San Francisco VA Med Ctr, San Francisco, CA USA. [Ponikowski, Piotr] Klin Kardiol, Wroclaw, Poland. [Voors, Adriaan A.] Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands. RP Davison, BA (reprint author), Momentum Res Inc, 3100 Tower Blvd,Suite 802, Durham, NC 27707 USA. EM bethdavison@momentum-research.com RI Ponikowski, Piotr/O-6454-2015; OI Ponikowski, Piotr/0000-0002-3391-7064; Senger, Stefanie/0000-0003-4144-1040 FU Novacardia of Merck FX The PROTECT trials were sponsored by Novacardia, a subsidiary of Merck. No external funding was received for the preparation of this manuscript. NR 20 TC 4 Z9 4 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1388-9842 EI 1879-0844 J9 EUR J HEART FAIL JI Eur. J. Heart Fail. PD AUG PY 2016 VL 18 IS 8 BP 1041 EP 1050 DI 10.1002/ejhf.540 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DS8PL UT WOS:000381045200012 PM 27114058 ER PT J AU Bastu, E Buyru, F Ozsurmeli, M Demiral, I Dogan, M Yeh, J AF Bastu, Ercan Buyru, Faruk Ozsurmeli, Mehmet Demiral, Irem Dogan, Murat Yeh, John TI A randomized, single-blind, prospective trial comparing three different gonadotropin doses with or without addition of letrozole during ovulation stimulation in patients with poor ovarian response SO EUROPEAN JOURNAL OF OBSTETRICS & GYNECOLOGY AND REPRODUCTIVE BIOLOGY LA English DT Article DE Gonadotropins; Letrozole; Ovulation stimulation; Poor ovarian response ID IN-VITRO FERTILIZATION; HORMONE ANTAGONIST PROTOCOL; AROMATASE INHIBITORS; INVITRO FERTILIZATION; GNRH ANTAGONIST; IVF TREATMENT; FLARE-UP; AGONIST; WOMEN; MANAGEMENT AB Objective: The aim of this randomized controlled trial (RCT) was to investigate whether IVF outcomes would differ between patients with POR who received three different gonadotropin doses with or without the addition of letrozole during ovulation stimulation. Study design: Only those who fulfilled two of the three Bologna criteria were included to the study. 95 patients met the inclusion criteria and agreed to participate in the study. In the first group, 31 patients were treated with 450 IU gonadotropins. In the second group, 31 patients were treated with 300 IU gonadotropins. The third group comprised 33 patients and was treated with 150 IU gonadotropins in combination with letrozole. Results: The results indicate that differences in doses of hMG and rFSH in patients with POR result in a similar number of retrieved MII and fertilized oocytes, similar fertilization rates, number of transferred embryos, implantation, cancelation, chemical, clinical, and ongoing pregnancy rates. Conclusions: Increasing the dose of gonadotropins during ovulation stimulation is an intuitively appealing approach when the patient is a poor responder. However, increasing the dose does not necessarily improve the reproductive outcome. Using a mild stimulation with addition of letrozole was as effective as stimulation with higher doses of gonadotropins alone in this patient population. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Bastu, Ercan; Buyru, Faruk; Ozsurmeli, Mehmet; Demiral, Irem; Dogan, Murat] Istanbul Univ, Sch Med, Dept Obstet & Gynecol, Istanbul, Turkey. [Yeh, John] Harvard Med Sch, Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA USA. RP Bastu, E (reprint author), Istanbul Univ, Sch Med, Dept Obstet & Gynecol, Div Reprod Endocrinol & Infertil, TR-34093 Istanbul, Turkey. EM ercan.bastu@istanbul.edu.tr OI Bastu, Ercan/0000-0003-0810-6195 NR 37 TC 1 Z9 1 U1 6 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-2115 EI 1872-7654 J9 EUR J OBSTET GYN R B JI Eur. J. Obstet. Gynecol. Reprod. Biol. PD AUG PY 2016 VL 203 BP 30 EP 34 DI 10.1016/j.ejogrb.2016.05.027 PG 5 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA DU1EQ UT WOS:000381951400007 PM 27236602 ER PT J AU Strait, RT Camargo, CA AF Strait, Richard T. Camargo, Carlos A. TI Vitamin E and the risk of childhood asthma SO EXPERT REVIEW OF RESPIRATORY MEDICINE LA English DT Review DE Asthma; vitamin E; alpha-tocopherol; gamma-tocopherol; prevention; childhood; in utero ID INFLUENZA-VIRUS INFECTION; ALPHA-TOCOPHEROL; ANTIOXIDANT INTAKE; GAMMA-TOCOPHEROL; E SUPPLEMENTATION; ALLERGIC-ASTHMA; CELL RESPONSES; NEUTROPHIL RECRUITMENT; PULMONARY-FUNCTION; AIRWAY NEUTROPHIL AB Introduction: Asthma, a heterogeneous disease with multiple phenotypes, remains a significant health problem. Present treatments are not curative and prevention should be our ultimate goal. Vitamin E supplementation presents a potential easy and cheap preventive therapy but the results of studies are confusing and sometimes contradictory. Clarification is needed.Areas covered: Animal studies and research in pregnant women suggest enhanced lifetime resistance to asthma with appropriate fetal exposure to vitamin E. Vitamin E's preventive role is complex and includes functional variations of the different isoforms.Expert commentary: We review the most recent literature on the role of vitamin E isoforms on: lung inflammation, immune development, animal and clinical studies during pregnancy, and the potential influence of vitamin E isoforms on asthma development in offspring. We point out where data are seemingly contradictory, explain why this is so, and comment on where further clarifying research is needed and its future direction. C1 [Strait, Richard T.] Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati, OH 45220 USA. [Strait, Richard T.] Cincinnati Childrens Hosp Med Ctr, Div Emergency Med, Cincinnati, OH 45229 USA. [Camargo, Carlos A.] Harvard, Massachusetts Gen Hosp, Dept Emergency Med, Sch Med, Boston, MA USA. RP Strait, RT (reprint author), Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati, OH 45220 USA.; Strait, RT (reprint author), Cincinnati Childrens Hosp Med Ctr, Div Emergency Med, Cincinnati, OH 45229 USA. EM rick.strait@cchmc.org NR 91 TC 0 Z9 0 U1 3 U2 3 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1747-6348 EI 1747-6356 J9 EXPERT REV RESP MED JI Expert Rev. Respir. Med. PD AUG PY 2016 VL 10 IS 8 BP 881 EP 890 DI 10.1080/17476348.2016.1184090 PG 10 WC Respiratory System SC Respiratory System GA DS8QN UT WOS:000381048000006 PM 27123996 ER PT J AU Hasegawa, K Dumas, O Hartert, TV Camargo, CA AF Hasegawa, Kohei Dumas, Orianne Hartert, Tina V. Camargo, Carlos A. TI Advancing our understanding of infant bronchiolitis through phenotyping and endotyping: clinical and molecular approaches SO EXPERT REVIEW OF RESPIRATORY MEDICINE LA English DT Review DE Bronchiolitis; lower respiratory infection; infants; phenotypes; endotypes; immune response; genome; transcriptome; microbiome; systems biology ID RESPIRATORY SYNCYTIAL VIRUS; BLOOD GENE-EXPRESSION; LENGTH-OF-STAY; ASTHMA PHENOTYPES; DISEASE SEVERITY; VIRAL ETIOLOGY; PATHOGENIC BACTERIA; HUMAN RHINOVIRUSES; TRACT INFECTION; INCREASED RISK AB Introduction: Bronchiolitis is a major public health problem worldwide. However, no effective treatment strategies are available, other than supportive care.Areas covered: Although bronchiolitis has been considered a single disease diagnosed based on clinical characteristics, emerging evidence supports both clinical and pathobiological heterogeneity. The characterization of this heterogeneity supports the concept that bronchiolitis consists of multiple phenotypes or consistent grouping of characteristics.Expert commentary: Using unbiased statistical approaches, multidimentional clinical characteristics will derive bronchiolitis phenotypes. Furthermore, molecular and systems biology approaches will, by linking pathobiology to phenotype, identify endotypes. Large cohort studies of bronchiolitis with comprehensive clinical characterization and system-wide profiling of the -omics' data (e.g., host genome, transcriptome, epigenome, viral genome, microbiome, metabolome) should enhance our ability to molecularly understand these phenotypes and lead to more targeted and personalized approaches to bronchiolitis treatment. C1 [Hasegawa, Kohei; Camargo, Carlos A.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA USA. [Dumas, Orianne] Univ Versailles St Quentin En Yvelines, INSERM, VIMA Aging & Chron Dis, U1168,Epidemiol & Publ Hlth Approaches, Villejuif, France. [Hartert, Tina V.] Vanderbilt Univ, Sch Med, Div Allergy Pulm & Crit Care Med, Ctr Asthma & Environm Hlth Sci Res,Dept Med, Nashville, TN 37212 USA. RP Hasegawa, K (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, 125 Nashua St,Suite 920, Boston, MA 02114 USA. EM khasegawa1@partners.org FU National Institutes of Health (Bethesda, MD) [U01 AI-087881, R01 AI-114552, R21 HL-129909, U19 AI-095227, K24 AI-077930] FX This study was supported by the grants U01 AI-087881, R01 AI-114552, R21 HL-129909, U19 AI-095227, and K24 AI-077930 from the National Institutes of Health (Bethesda, MD). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 86 TC 0 Z9 0 U1 2 U2 2 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1747-6348 EI 1747-6356 J9 EXPERT REV RESP MED JI Expert Rev. Respir. Med. PD AUG PY 2016 VL 10 IS 8 BP 891 EP 899 DI 10.1080/17476348.2016.1190647 PG 9 WC Respiratory System SC Respiratory System GA DS8QN UT WOS:000381048000007 PM 27192374 ER PT J AU Kong, L Zhao, YP Tian, QY Feng, JQ Kobayashi, T Merregaert, J Liu, CJ AF Kong, Li Zhao, Yun-Peng Tian, Qing-Yun Feng, Jian-Quan Kobayashi, Tatsuya Merregaert, Joseph Liu, Chuan-Ju TI Extracellular matrix protein 1, a direct targeting molecule of parathyroid hormone-related peptide, negatively regulates chondrogenesis and endochondral ossification via associating with progranulin growth factor SO FASEB JOURNAL LA English DT Article DE ECM1; PTHrP; PGRN ID GRANULIN-EPITHELIN PRECURSOR; LICHEN-SCLEROSUS; LIPOID PROTEINOSIS; INDIAN HEDGEHOG; BONE-GROWTH; PLATE CHONDROCYTES; PTH/PTHRP RECEPTOR; PHOSPHOLIPASE-C; KNOCKOUT MICE; HOST-DEFENSE AB Chondrogenesis and endochondral ossification are precisely controlled by cellular interactions with surrounding matrix proteins and growth factors that mediate cellular signaling pathways. Here, we report that extracellular matrix protein 1 (ECM1) is a previously unrecognized regulator of chondrogenesis. ECM1 is induced in the course of chondrogenesis and its expression in chondrocytes strictly depends on parathyroid hormone-related peptide (PTHrP) signaling pathway. Overexpression of ECM1 suppresses, whereas suppression of ECM1 enhances, chondrocyte differentiation and hypertrophy in vitro and ex vivo. In addition, target transgene of ECM1 in chondrocytes or osteoblasts in mice leads to striking defects in cartilage development and endochondral bone formation. Of importance, ECM1 seems to be critical for PTHrP action in chondrogenesis, as blockage of ECM1 nearly abolishes PTHrP regulation of chondrocyte hypertrophy, and overexpression of ECM1 rescues disorganized growth plates of PTHrP-null mice. Furthermore, ECM1 and progranulin chondrogenic growth factor constitute an interaction network and act in concert in the regulation of chondrogenesis. C1 [Kong, Li; Zhao, Yun-Peng; Tian, Qing-Yun; Liu, Chuan-Ju] NYU, Sch Med, Dept Orthoped Surg, New York, NY USA. [Liu, Chuan-Ju] NYU, Sch Med, Dept Cell Biol, New York, NY 10016 USA. [Feng, Jian-Quan] Texas A&M Baylor Coll Dent, Dept Biomed Sci, Dallas, TX USA. [Kobayashi, Tatsuya] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Merregaert, Joseph] Univ Antwerp, Mol Biotechnol Lab, Antwerp, Belgium. RP Liu, CJ (reprint author), NYU, Med Ctr, Dept Orthoped Surg, Rm 1608,HJD,301 E 17th St, New York, NY 10003 USA. EM chuanju.liu@med.nyu.edu OI liu, chuanju/0000-0002-7181-8032 FU U.S. National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases [R01-AR062207, R01-AR061484]; Rheumatology Research Foundation FX The authors thank Dr. Brendan Lee (Baylor College of Medicine, Houston, TX, USA) for providing both Col II- and Col I-specific transgenic constructs used for generating ECM1 transgenic mice in this study, and Aubryanna Hettinghouse (New York University School of Medicine) for assistance in preparing the manuscript. This work was supported in part by U.S. National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases (Grants R01-AR062207 and R01-AR061484), and a Disease Targeted Research Grant from the Rheumatology Research Foundation (to C.-J.L.). NR 53 TC 0 Z9 0 U1 2 U2 5 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD AUG PY 2016 VL 30 IS 8 BP 2741 EP 2754 DI 10.1096/fj.201600261R PG 14 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA DS7WP UT WOS:000380994000011 PM 27075243 ER PT J AU Elajami, TK Colas, RA Dalli, J Chiang, N Serhan, CN Welty, FK AF Elajami, Tarec K. Colas, Romain A. Dalli, Jesmond Chiang, Nan Serhan, Charles N. Welty, Francine K. TI Specialized proresolving lipid mediators in patients with coronary artery disease and their potential for clot remodeling SO FASEB JOURNAL LA English DT Article DE metabololipidomics; resolvins; lipoxins; n-3 fatty acids; inflammation ID POLYUNSATURATED FATTY-ACIDS; RHEUMATOID-ARTHRITIS; CARDIOVASCULAR OUTCOMES; MYOCARDIAL-INFARCTION; RISK-FACTORS; OLIVE OIL; INFLAMMATION; RESOLUTION; SUPPLEMENTATION; TRIAL AB Inflammation in arterial walls leads to coronary artery disease (CAD). Because specialized proresolving lipid mediators (SPMs; lipoxins, resolvins, and protectins) stimulate resolution of inflammation in animal models, we tested whether n-3 fatty acids impact SPM profiles in patients with CAD and promote clot remodeling. Six patients with stable CAD were randomly assigned to either treatment with daily 3.36 g Lovaza for 1 yr or without. Targeted lipid mediator-metabololipidomics showed that both groups had absence of resolvin D1 (RvD1), RvD2, RvD3, RvD5 and resolvin E1-all of which are present in healthy patients. Those not taking Lovaza had an absence of aspirin-triggered resolvin D3 (AT-RvD3) and aspirin-triggered lipoxin B-4 (AT-LXB4). Lovaza treatment restored AT-RvD3 and AT-LXB4 and gave levels of RvD6 and aspirin-triggered protectin D1(AT-PD1) twice as high (resolvin E2 similar to 5 fold) as well as lower prostaglandins. Principal component analysis indicated positive relationships for patients with CAD who were receiving Lovaza with increased AT-RvD3, RvD6, AT-PD1, and AT-LXB4. SPMs identified in Lovaza-treated patients with CAD enhanced similar to 50% at 1 nM macrophage uptake of blood clots. These results indicate that patients with CAD have lower levels and/or absence of specific SPMs that were restored with Lovaza; these SPMs promote macrophage phagocytosis of blood clots. Together, they suggest that low vascular SPMs may enable progression of chronic vascular inflammation predisposing to coronary atherosclerosis and to thrombosis. C1 [Elajami, Tarec K.; Welty, Francine K.] Harvard Med Sch, Brigham & Womens Hosp, Beth Israel Deaconess Med Ctr, Div Cardiovasc Med,Dept Internal Med, Boston, MA USA. [Colas, Romain A.; Dalli, Jesmond; Chiang, Nan; Serhan, Charles N.] Harvard Med Sch, Brigham & Womens Hosp, Ctr Expt Therapeut & Reperfus Injury, Dept Anesthesiol Perioperat & Pain Med,Harvard In, Boston, MA USA. RP Welty, FK (reprint author), Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Med, Div Cardiovasc Med, 330 Brookline Ave,SL423, Boston, MA 02215 USA. EM fwelty@bidmc.harvard.edu FU U.S. National Institutes of Health (NIH) National Institute of General Medical Sciences [P01GM095467, RO1GM03865]; NIH National Heart, Lung, and Blood Institute [P50HL083813] FX This work was supported by U.S. National Institutes of Health (NIH) National Institute of General Medical Sciences Grants P01GM095467 and RO1GM03865 (to C.N.S.), and NIH National Heart, Lung, and Blood Institute Grant P50HL083813 (to F.K.W.). C.N.S. is an inventor of patents (resolvins) assigned to the Brigham and Women's Hospital, and licensed to Resolvyx Pharmaceuticals. C.N.S. is a scientific founder of Resolvyx Pharmaceuticals and owns equity in the company. The interests of C.N.S. were reviewed and are managed by the Brigham and Women's Hospital and Partners HealthCare in accordance with their conflicts of interest policies. The remaining authors declare no conflicts of interests. NR 50 TC 2 Z9 2 U1 2 U2 2 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD AUG PY 2016 VL 30 IS 8 BP 2792 EP 2801 DI 10.1096/fj.201500155R PG 10 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA DS7WP UT WOS:000380994000015 PM 27121596 ER PT J AU Wakefield, CE Hanlon, LV Tucker, KM Patenaude, AF Signorelli, C McLoone, JK Cohn, RJ AF Wakefield, Claire E. Hanlon, Lucy V. Tucker, Katherine M. Patenaude, Andrea F. Signorelli, Christina McLoone, Jordana K. Cohn, Richard J. TI The psychological impact of genetic information on children: a systematic review SO GENETICS IN MEDICINE LA English DT Review DE children; genetic; implications; information; psychological ID INHERITED CARDIOVASCULAR-DISEASES; QUALITY-OF-LIFE; BREAST-CANCER; HEREDITARY BREAST; PSYCHOSOCIAL-ASPECTS; DECISION-MAKING; OVARIAN-CANCER; ISSUES; ADOLESCENTS; RISK AB Purpose: This review assessed the psychological impact that acquiring personal and familial genetic information has on children. We also examined the concordance between the available empirical data and clinical guidance/perspectives articles. Methods: We screened 591 abstracts and identified 13 studies, representing 966 children. Ten studies assessed 386 children tested for familial adenomatous polyposis (n = 171), hereditary cardiac disease (n = 134), and other conditions (n = 81). Three studies addressed the impact of BRCA1/2 testing of a family member on 580 children. Results: Serious adverse psychological outcomes were uncommon. Most studies reported no significant increase in mean anxiety, depression, and distress scores (n = 8, 61.5%); however, some children experienced intrafamilial distress, discrimination, and guilt/regret. Some children were more concerned about their own health or their family members' health. There was limited consistency between anticipated adverse impact and empirical data. Conclusions: The review identified little conclusive evidence of deleterious psychological consequences for children acquiring genetic information. However, there is a lack of data regarding genetic testing for conditions that may not be treatable/modifiable, as well as a dearth of longitudinal studies. Therefore, clinical caution remains essential for the ethical integration of genetic testing into pediatrics. Further research assessing the potential positive and negative effects of genetic testing in childhood is warranted. C1 [Wakefield, Claire E.; Hanlon, Lucy V.; Signorelli, Christina; McLoone, Jordana K.; Cohn, Richard J.] Univ New South Wales, Sch Womens & Childrens Hlth, Discipline Paediat, UNSW Med, Sydney, NSW, Australia. [Wakefield, Claire E.; Signorelli, Christina; McLoone, Jordana K.] Sydney Childrens Hosp, Behav Sci Unit Proudly Supported Kids Canc Fdn, Kids Canc Ctr, Randwick, NSW, Australia. [Tucker, Katherine M.] Prince Wales Hosp, Dept Med Oncol, Hereditary Canc Clin, Randwick, NSW, Australia. [Tucker, Katherine M.] Univ New South Wales, Prince Wales Clin Sch, Sydney, NSW, Australia. [Patenaude, Andrea F.] Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, Boston, MA 02115 USA. [Patenaude, Andrea F.] Harvard Med Sch, Dept Psychiat, Boston, MA USA. [Cohn, Richard J.] Sydney Childrens Hosp, Kids Canc Ctr, Randwick, NSW, Australia. RP Wakefield, CE (reprint author), Univ New South Wales, Sch Womens & Childrens Hlth, Discipline Paediat, UNSW Med, Sydney, NSW, Australia.; Wakefield, CE (reprint author), Sydney Childrens Hosp, Behav Sci Unit Proudly Supported Kids Canc Fdn, Kids Canc Ctr, Randwick, NSW, Australia. EM c.wakefield@unsw.edu.au OI Signorelli, Christina/0000-0002-7091-0347; Hanlon, Lucy/0000-0002-8648-6165 FU National Health and Medical Research Council of Australia [APP1067501]; Cancer Institute of NSW [11/ECF/3-43]; Kids with Cancer Foundation FX C.E.W. is supported by a Career Development Fellowship from the National Health and Medical Research Council of Australia (APP1067501) and an Early Career Development fellowship from the Cancer Institute of NSW (ID: 11/ECF/3-43). The Behavioral Sciences Unit is proudly supported by the Kids with Cancer Foundation. We also acknowledge the contribution of Bridget Cavanagh (B.C.) in the process of article selection and review. NR 54 TC 2 Z9 2 U1 9 U2 11 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1098-3600 EI 1530-0366 J9 GENET MED JI Genet. Med. PD AUG PY 2016 VL 18 IS 8 BP 755 EP 762 DI 10.1038/gim.2015.181 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA DS9YZ UT WOS:000381140800001 PM 26741411 ER PT J AU Bunch, H Lawney, BP Burkholder, A Ma, DD Zheng, XF Motola, S Fargo, DC Levine, SS Wang, YYE Hue, G AF Bunch, Heeyoun Lawney, Brian P. Burkholder, Adam Ma, Duanduan Zheng, Xiaofeng Motola, Shmulik Fargo, David C. Levine, Stuart S. Wang, Yaoyu E. Hue, Guang TI RNA polymerase II promoter-proximal pausing in mammalian long non-coding genes SO GENOMICS LA English DT Article DE Long non-coding RNAs; RNA polymerase II promoter-proximal pausing; TRIM28 ID POL-II; TRANSCRIPTIONAL ELONGATION; DIVERGENT TRANSCRIPTION; MEDIATOR COMPLEX; PREPARES GENES; P-TEFB; EXPRESSION; INITIATION; DROSOPHILA; RELEASE AB Mammalian genomes encode a large number of non-coding RNAs (ncRNAs) that greatly exceed mRNA genes. While the physiological and pathological roles of ncRNAs have been increasingly understood, the mechanisms of regulation of ncRNA expression are less clear. Here, our genomic study has shown that a significant number of long non-coding RNAs (lncRNAs, >1000 nucleotides) harbor RNA polymerase II (Pol II) engaged with the transcriptional start site. A pausing and transcriptional elongation factor for protein-coding genes, tripartite motif-containing 28 (TRIM28) regulates the transcription of a subset of lncRNAs in mammalian cells. In addition, the majority of lncRNAs in human and murine cells regulated by Pol II promoter-proximal pausing appear to function in stimulus-inducible biological pathways. Our findings suggest an important role of Pol II pausing for the transcription of mammalian lncRNA genes. (C) 2016 Elsevier Inc. All rights reserved. C1 [Bunch, Heeyoun] Harvard Sch Publ Hlth, Dept Genet & Complex Dis, Boston, MA 02115 USA. [Lawney, Brian P.; Wang, Yaoyu E.] Dana Farber Canc Inst, Ctr Canc Computat Biol, Boston, MA 02130 USA. [Burkholder, Adam; Fargo, David C.] NIEHS, Integrat Bioinformat, NIH, Res Triangle Pk, NC 27705 USA. [Ma, Duanduan; Motola, Shmulik; Levine, Stuart S.] MIT, BioMicro Ctr, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Zheng, Xiaofeng; Hue, Guang] NIEHS, Epigenet & Stem Cell Biol Lab, NIH, Res Triangle Pk, NC 27705 USA. RP Bunch, H (reprint author), Harvard Med Sch, Dept Genet & Complex Dis, Harvard Sch Publ Hlth, Goldenson Bldg,Room 559,220 Longwood Ave, Boston, MA 02115 USA. EM heeyounbunch@gmail.com OI Bunch, Heeyoun/0000-0003-0038-1985 FU Harvard Joint Center for Radiation Therapy FX We appreciate S. K. Calderwood in Beth Israel Deaconess Medical Center & Harvard Medical School for discussions and reading the manuscript and P. J. Park and L. Jung in Brigham Women Hospital & Harvard Medical School for providing initial bioinformatics analysis and discussions. We are grateful to D. J. Taatjes in the University of Colorado, Boulder and to J. Rinn in the Broad Institute for their critical reading and helpful comments of the manuscript. H.B. is grateful to D. Bunch, Joy, R. Baker, M. Seaquist, K. Perkins, D. Verrengia, G. Hugenberger, and P.S.C. for their loving support and encouragement throughout the work. This study was supported by grants from the Harvard Joint Center for Radiation Therapy to H.B. NR 59 TC 0 Z9 0 U1 2 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 EI 1089-8646 J9 GENOMICS JI Genomics PD AUG PY 2016 VL 108 IS 2 BP 64 EP 77 DI 10.1016/j.ygeno.2016.07.003 PG 14 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA DT4UX UT WOS:000381477700003 PM 27432546 ER PT J AU Zhao, B Setsompop, K Ye, HH Cauley, SF Wald, LL AF Zhao, Bo Setsompop, Kawin Ye, Huihui Cauley, Stephen F. Wald, Lawrence L. TI Maximum Likelihood Reconstruction for Magnetic Resonance Fingerprinting SO IEEE TRANSACTIONS ON MEDICAL IMAGING LA English DT Article DE Augmented lagrangian; maximum likelihood estimation; quantitative magnetic resonance imaging; variable projection; variable splitting ID NONLINEAR LEAST-SQUARES; SPIN-ECHO MRI; FOURIER INVERSION; TOEPLITZ-SYSTEMS; SEQUENCES; FRAMEWORK; RECOVERY; SENSE; FIELD; MAP AB This paper introduces a statistical estimation framework for magnetic resonance (MR) fingerprinting, a recently proposed quantitative imaging paradigm. Within this framework, we present a maximum likelihood (ML) formalism to estimate multiple MR tissue parameter maps directly from highly undersampled, noisy k-space data. A novel algorithm, based on variable splitting, the alternating direction method of multipliers, and the variable projection method, is developed to solve the resulting optimization problem. Representative results from both simulations and in vivo experiments demonstrate that the proposed approach yields significantly improved accuracy in parameter estimation, compared to the conventional MR fingerprinting reconstruction. Moreover, the proposed framework provides new theoretical insights into the conventional approach. We show analytically that the conventional approach is an approximation to the ML reconstruction; more precisely, it is exactly equivalent to the first iteration of the proposed algorithm for the ML reconstruction, provided that a gridding reconstruction is used as an initialization. C1 [Zhao, Bo; Setsompop, Kawin; Ye, Huihui; Cauley, Stephen F.; Wald, Lawrence L.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Zhao, Bo; Setsompop, Kawin; Ye, Huihui; Cauley, Stephen F.; Wald, Lawrence L.] Harvard Med Sch, Dept Radiol, Boston, MA 02115 USA. [Wald, Lawrence L.] MIT, Harvard MIT Div Hlth Sci & Technol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. RP Zhao, B (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. EM bzhao4@mgh.harvard.edu; kawin@nmr.mgh.harvard.edu; yehuihuizju@gmail.com; stcauley@nmr.mgh.harvard.edu; wald@nmr.mgh.harvard.edu OI Zhao, Bo/0000-0002-3475-8739 FU [NIH-R01-EB017219]; [NIH-R01-EB017337]; [NIH-R01-EB013695]; [NIH-P41-EB015896]; [NIH-U01-MH093765]; [NIH-R00-EB012107]; [NIH-R24-MH106096] FX This work was supported in part by the following grants: NIH-R01-EB017219, NIH-R01-EB017337, NIH-R01-EB013695, NIH-P41-EB015896, NIH-U01-MH093765, NIH-R00-EB012107, and NIH-R24-MH106096. NR 60 TC 1 Z9 1 U1 3 U2 3 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0278-0062 EI 1558-254X J9 IEEE T MED IMAGING JI IEEE Trans. Med. Imaging PD AUG PY 2016 VL 35 IS 8 BP 1812 EP 1823 DI 10.1109/TMI.2016.2531640 PG 12 WC Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Engineering, Electrical & Electronic; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA DT4FR UT WOS:000381436000003 ER PT J AU Shen, Z Mannion, A Whary, MT Muthupalani, S Sheh, A Feng, Y Gong, G Vandamme, P Holcombe, HR Paster, BJ Fox, JG AF Shen, Z. Mannion, A. Whary, M. T. Muthupalani, S. Sheh, A. Feng, Y. Gong, G. Vandamme, P. Holcombe, H. R. Paster, B. J. Fox, J. G. TI Helicobacter saguini, a Novel Helicobacter Isolated from Cotton-Top Tamarins with Ulcerative Colitis, Has Proinflammatory Properties and Induces Typhlocolitis and Dysplasia in Gnotobiotic IL-10(-/-) Mice SO INFECTION AND IMMUNITY LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; COLON-CANCER; INTERLEUKIN-10-DEFICIENT MICE; DNA-DAMAGE; INTESTINAL ADENOCARCINOMA; CAMPYLOBACTER-FENNELLIAE; RAG2-DEFICIENT MICE; RHESUS-MONKEYS; DEFICIENT MICE; HEPATICUS AB A urease-negative, fusiform, novel bacterium named Helicobacter saguini was isolated from the intestines and feces of cotton-top tamarins (CTTs) with chronic colitis. Helicobacter sp. was detected in 69% of feces or intestinal samples from 116 CTTs. The draft genome sequence, obtained by Illumina MiSeq sequencing, for H. saguini isolate MIT 97-6194-5, consisting of similar to 2.9 Mb with a G+C content of 35% and 2,704 genes, was annotated using the NCBI Prokaryotic Genomes Automatic Annotation Pipeline. H. saguini contains homologous genes of known virulence factors found in other enterohepatic helicobacter species (EHS) and H. pylori. These include flagellin, gamma-glutamyl transpeptidase (ggt), collagenase, the secreted serine protease htrA, and components of a type VI secretion system, but the genome does not harbor genes for cytolethal distending toxin (cdt). H. saguini MIT 97-6194-5 induced significant levels of interleukin-8 (IL-8) in HT-29 cell culture supernatants by 4 h, which increased through 24 h. mRNAs for the proinflammatory cytokines IL-1 beta, tumor necrosis factor alpha (TNF-alpha), IL-10, and IL-6 and the chemokine CXCL1 were upregulated in cocultured HT-29 cells at 4 h compared to levels in control cells. At 3 months postinfection, all H. saguini-monoassociated gnotobiotic C57BL/129 IL-10(-/-) mice were colonized and had seroconverted to H. saguini antigen with a significant Th1-associated increase in IgG2c (P<0.0001). H. saguini induced a significant typhlocolitis, associated epithelial defects, mucosa-associated lymphoid tissue (MALT) hyperplasia, and dysplasia. Inflammatory cytokines IL-22, IL-17a, IL-1 beta, gamma interferon (IFN-gamma), and TNF-alpha, as well as inducible nitric oxide synthase (iNOS) were significantly upregulated in the cecal tissues of infected mice. The expression of the DNA damage response molecule gamma-H2AX was significantly higher in the ceca of H. saguini-infected gnotobiotic mice than in the controls. This model using a nonhuman primate Helicobacter sp. can be used to study the pathogenic potential of EHS isolated from primates with naturally occurring inflammatory bowel disease (IBD) and colon cancer. C1 [Shen, Z.; Mannion, A.; Whary, M. T.; Muthupalani, S.; Sheh, A.; Feng, Y.; Holcombe, H. R.; Fox, J. G.] MIT, Div Comparat Med, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Gong, G.; Fox, J. G.] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Vandamme, P.] Univ Ghent, Dept Biochem & Microbiol, Ghent, Belgium. [Paster, B. J.] Forsyth Inst, Cambridge, MA USA. RP Fox, JG (reprint author), MIT, Div Comparat Med, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Fox, JG (reprint author), MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM jgfox@mit.edu FU HHS \ National Institutes of Health (NIH) [P30-ES002109, R01-OD01141, T32-OD010978] FX This work, including the efforts of James G. Fox, was funded by HHS vertical bar National Institutes of Health (NIH) (P30-ES002109, R01-OD01141, and T32-OD010978). NR 52 TC 0 Z9 0 U1 3 U2 3 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 2016 VL 84 IS 8 BP 2307 EP 2316 DI 10.1128/IAI.00235-16 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DS4JC UT WOS:000380746400014 PM 27245408 ER PT J AU Perez-Brumer, AG Oldenburg, CE Biello, KB Novak, DS Rosenberger, JG Mimiaga, MJ AF Perez-Brumer, Amaya G. Oldenburg, Catherine E. Biello, Katie B. Novak, David S. Rosenberger, Joshua G. Mimiaga, Matthew J. TI HIV prevalence, sexual behaviours and engagement in HIV medical care among an online sample of sexually active MSM in Venezuela SO INTERNATIONAL JOURNAL OF STD & AIDS LA English DT Article DE Sexual behaviour; homosexual; men; Venezuela; men who have sex with men; HIV; AIDS; sexually transmitted infection; STI; Latin America ID VIRUS TYPE-2 INFECTION; TRANSGENDER WOMEN; LATIN-AMERICA; MEN; PERU; EPIDEMIOLOGY; RISK; SYPHILIS; HEALTH; LIMA AB In Venezuela, members of a social and sexual partner networking site for men who have sex with men (MSM) completed an online survey regarding sexual behaviours and HIV medical care. Among the 2851 respondents, self-reported HIV prevalence was 6.6%. Of participants living with HIV, 73.2% reported taking antiretroviral medication and 56.6% reported complete adherence within the past month. Participants living with HIV were more likely to be older (aOR = 1.04 per one-year increase in age, 95% CI: 1.02, 1.06) and diagnosed with a sexually transmitted infection in the previous year (aOR 3.26, 95% CI: 2.11, 5.04). These data provide further understanding of the HIV epidemic among MSM in Venezuela, and potential targets for HIV prevention interventions. C1 [Perez-Brumer, Amaya G.; Oldenburg, Catherine E.; Biello, Katie B.; Mimiaga, Matthew J.] Fenway Community Hlth, Fenway Inst, Boston, MA USA. [Perez-Brumer, Amaya G.] Columbia Univ, Mailman Sch Publ Hlth, Dept Sociomed Sci, 722 West 168th St, New York, NY 10032 USA. [Oldenburg, Catherine E.; Biello, Katie B.; Mimiaga, Matthew J.] Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Novak, David S.] Online Buddies Inc, OLB Res Inst, Cambridge, MA USA. [Rosenberger, Joshua G.] Penn State Univ, Dept Biobehav Hlth, University Pk, PA 16802 USA. [Mimiaga, Matthew J.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA USA. RP Perez-Brumer, AG (reprint author), Columbia Univ, Mailman Sch Publ Hlth, Dept Sociomed Sci, 722 West 168th St, New York, NY 10032 USA. EM agp2133@cumc.columbia.edu FU Eunice Kennedy Shriver National Institute of Child Health & Human Development [T32 HD049339]; National Institute of Allergy & Infectious Disease [T32AI007535] FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: APB is supported by a Eunice Kennedy Shriver National Institute of Child Health & Human Development T32 NRSA grant (T32 HD049339; PI: Nathanson). CEO is supported by a National Institute of Allergy & Infectious Disease T32 NRSA grant (T32AI007535, PI: Seage). NR 29 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0956-4624 EI 1758-1052 J9 INT J STD AIDS JI Int. J. STD AIDS PD AUG PY 2016 VL 27 IS 9 BP 790 EP 797 DI 10.1177/0956462415596298 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DS4TH UT WOS:000380773900009 PM 26378188 ER PT J AU Shahwan, KT Kimball, AB AF Shahwan, Kathryn T. Kimball, Alexa B. TI A Closer Inspection of the Number Needed to Biopsy Reply SO JAMA DERMATOLOGY LA English DT Letter ID SKIN-CANCER; AUSTRALIA C1 [Shahwan, Kathryn T.; Kimball, Alexa B.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Dermatol, Clin Unit Res Trials & Outcomes Skin CURTIS, 50 Staniford St,Ste 240, Boston, MA 02114 USA. RP Kimball, AB (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Dermatol, Clin Unit Res Trials & Outcomes Skin CURTIS, 50 Staniford St,Ste 240, Boston, MA 02114 USA. EM harvardskinstudies@partners.org NR 4 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 2168-6068 EI 2168-6084 J9 JAMA DERMATOL JI JAMA Dermatol. PD AUG PY 2016 VL 152 IS 8 BP 953 EP 953 DI 10.1001/jamadermatol.2016.0937 PG 1 WC Dermatology SC Dermatology GA DT1AY UT WOS:000381215300029 PM 27532360 ER PT J AU Hamilos, DL AF Hamilos, Daniel L. TI Chronic Rhinosinusitis in Patients with Cystic Fibrosis SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE LA English DT Review DE Chronic rhinosinusitis; Cystic fibrosis; Nasal polyposis; Histopathology; Medical treatment; Surgical treatment ID RANDOMIZED CONTROLLED-TRIAL; INHALED HYPERTONIC SALINE; SINUS SURGERY; INCREASED PREVALENCE; MEDICAL-MANAGEMENT; ENDOSCOPIC-SINUS; NASAL-POLYPOSIS; YOUNG-CHILDREN; DORNASE-ALPHA; MUTATION AB Chronic rhinosinusitis (CRS) is highly prevalent in patients with cystic fibrosis (CF) and accounts for significant morbidity and contribution to CF lung disease. Mutations of the cystic fibrosis transmembrane regulator gene occur with increased prevalence in patients with CRS without CF, suggesting some contribution to CRS pathophysiology. Nasal polyps (NPs) occur with increased prevalence in patients with CF of all ages and have a more neutrophilic appearance with fewer eosinophils and increased submucosal glandular elements in comparison to NPs from patients without CF. Mainstays of medical treatment include isotonic saline irrigations and topical intranasal glucocorticoids, with some evidence that topical intranasal glucocorticoids reduce NP size. Although inhaled hypertonic saline (7%) has been widely studied as a mucolytic agent for CF lung disease, there are no reports of its use in CF CRS. Mucolytics have also not been studied as a treatment for CRS in CF, and most evidence does not support their use for CF lung disease. Nasally nebulized dornase alfa (recombinant human deoxyribonuclease) following sinus surgery shows promise for treatment. Other unproven therapies include addition of baby shampoo to isotonic saline to potentially thin mucus and help prevent biofilm formation. There are no data to support the use of low-dose oral macrolide antibiotics or the use of prophylactic oral antibiotics for CRS in patients with CF. However, there is some support for the use of topical antibiotics, including colistimethate sodium or tobramycin, administered as a sinus irrigation or antral lavage in patients following sinus surgery when susceptible bacteria are cultured. Key components of CF sinus surgical management include extensive surgery to ensure that the maxillary, frontal, sphenoid, and ethmoid sinuses are all widely opened with smoothing of bony overhangs to prevent mucus retention and bacterial recolonization, postoperative meticulous daily nasal irrigations, and appropriate use of culture-directed topical antibiotics. There are no data yet on whether CF-targeted therapies, including ivacaftor or ivacaftor combined with lumacaftor, have an impact on CF CRS. (C) 2016 American Academy of Allergy, Asthma & Immunology C1 [Hamilos, Daniel L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Hamilos, DL (reprint author), Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, 55 Fruit St,Bulfinch 422, Boston, MA 02114 USA. EM dhamilos@partners.org FU Sanofi; Regeneron; Genentech; AstraZeneca; Med-IQ FX D. L. Hamilos has received consultancy fees from Sanofi, Regeneron, Genentech, and AstraZeneca; receives royalties from UpToDate; and has received payment for developing educational presentations from Med-IQ. NR 59 TC 0 Z9 0 U1 6 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2213-2198 EI 2213-2201 J9 J ALLER CL IMM-PRACT JI J. Allergy Clin. Immunol.-Pract. PD AUG PY 2016 VL 4 IS 4 BP 605 EP 612 DI 10.1016/j.jaip.2016.04.013 PG 8 WC Allergy; Immunology SC Allergy; Immunology GA DU0SZ UT WOS:000381916100006 PM 27393775 ER PT J AU Bachert, C Hamilos, DL AF Bachert, Claus Hamilos, Daniel L. TI Are Antibiotics Useful for Chronic Rhinosinusitis? SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE LA English DT Review ID STAPHYLOCOCCUS-AUREUS; CONTROLLED-TRIAL; NASAL POLYPS; NEBULIZED ANTIBIOTICS; CYTOKINE PRODUCTION; DOUBLE-BLIND; LONG-TERM; CLARITHROMYCIN; MICROBIOME; MACROLIDE C1 [Bachert, Claus] Univ Ghent, Upper Airways Res Lab, De Pintelaan 185, B-9000 Ghent, Belgium. [Hamilos, Daniel L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Bachert, C (reprint author), Univ Ghent, Upper Airways Res Lab, De Pintelaan 185, B-9000 Ghent, Belgium. EM claus.bachert@UGent.be FU Sanofi; Regeneron; Genentech; Merck FX D. L. Hamilos has received consultancy fees from Sanofi, Regeneron, and Genentech; has received research support from Merck; and receives royalties from UpToDate. C. Bachert declares no relevant conflicts of interest. NR 52 TC 4 Z9 4 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2213-2198 EI 2213-2201 J9 J ALLER CL IMM-PRACT JI J. Allergy Clin. Immunol.-Pract. PD AUG PY 2016 VL 4 IS 4 BP 629 EP 638 DI 10.1016/j.jaip.2015.12.008 PG 10 WC Allergy; Immunology SC Allergy; Immunology GA DU0SZ UT WOS:000381916100009 PM 26969267 ER PT J AU Kuhlen, JL Camargo, CA Balekian, DS Blumenthal, KG Guyer, A Morris, T Long, AD Banerji, A AF Kuhlen, James L., Jr. Camargo, Carlos A., Jr. Balekian, Diana S. Blumenthal, Kimberly G. Guyer, Autumn Morris, Theresa Long, Aidan Banerji, Aleena TI Antibiotics Are the Most Commonly Identified Cause of Perioperative Hypersensitivity Reactions SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE LA English DT Article DE Drug; Allergy; Hypersensitivity; Reaction; Anesthesia; Perioperative; Anaphylaxis; Tryptase; Cefazolin ID SKIN-TEST CONCENTRATIONS; ALLERGIC REACTIONS; RISK STRATIFICATION; REFERRAL CENTER; UNITED-STATES; HUMAN INSULIN; DRUG ALLERGY; ANAPHYLAXIS; ANESTHESIA; MASTOCYTOSIS AB BACKGROUND: Hypersensitivity reactions (HSRs) during the perioperative period are unpredictable and can be life threatening. Prospective studies for the evaluation of perioperative HSRs are lacking, and data on causative agents vary between different studies. OBJECTIVE: The objective of this study was to prospectively determine the success of a comprehensive allergy evaluation plan for patients with HSRs during anesthesia, including identification of a causative agent and outcomes during subsequent anesthesia exposure. METHODS: All patients referred for a perioperative HSR between November 2013 and March 2015, from a Boston teaching hospital, were evaluated using a standardized protocol with skin testing (ST) within 6 months of HSR. Comprehensive allergy evaluation included collection of patient information, including characteristics of HSR during anesthesia. We reviewed the results of ST and/or test doses for all potential causative medications Event-related tryptase levels were reviewed when available. RESULTS: Over 17 months, 25 patients completed the comprehensive allergy evaluation. Fifty-two percent (13 of 25) were female with a median age of 52 (interquartile range 43-66) years. The most frequently observed HSR systems were cutaneous (68%), cardiovascular (64%), and pulmonary (24%). A culprit drug, defined as a positive ST, was identified in 36% (9 of 25) of patients. The most common agent identified was cefazolin (6 of 9). After our comprehensive evaluation and management plan, 7 (7 of 8, 88%) patients tolerated subsequent anesthesia. CONCLUSIONS: Cefazolin was the most commonly identified cause of a perioperative HSR in our study population. Skin testing patients within 6 months of a perioperative HSR may improve the odds of finding a positive result. Tolerance of subsequent anesthesia is generally achieved in patients undergoing our comprehensive evaluation. (C) 2016 American Academy of Allergy, Asthma & Immunology C1 [Kuhlen, James L., Jr.; Camargo, Carlos A., Jr.; Balekian, Diana S.; Blumenthal, Kimberly G.; Long, Aidan; Banerji, Aleena] Massachusetts Gen Hosp, Dept Med, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. [Kuhlen, James L., Jr.; Camargo, Carlos A., Jr.; Balekian, Diana S.; Blumenthal, Kimberly G.; Long, Aidan; Banerji, Aleena] Harvard Med Sch, Dept Med, Boston, MA USA. [Camargo, Carlos A., Jr.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Blumenthal, Kimberly G.] Massachusetts Gen Hosp, Med Practice Evaluat Ctr, Boston, MA 02114 USA. [Guyer, Autumn] Beth Israel Deaconess Med Ctr, Dept Med, Div Allergy & Inflammat, Boston, MA 02215 USA. [Guyer, Autumn] Univ Calif San Francisco, Dept Med, Div Pulm Crit Care Allergy & Sleep Med, San Francisco, CA USA. [Morris, Theresa] Massachusetts Gen Hosp, Dept Anesthesia, Boston, MA 02114 USA. RP Kuhlen, JL (reprint author), Massachusetts Gen Hosp, Allergy Associates, Cox 201, Boston, MA 02114 USA. EM jameskuhlen@gmail.com FU NHLBI NIH HHS [T32 HL116275] NR 41 TC 2 Z9 2 U1 3 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2213-2198 EI 2213-2201 J9 J ALLER CL IMM-PRACT JI J. Allergy Clin. Immunol.-Pract. PD AUG PY 2016 VL 4 IS 4 BP 697 EP 704 DI 10.1016/j.jaip.2016.02.008 PG 8 WC Allergy; Immunology SC Allergy; Immunology GA DU0SZ UT WOS:000381916100020 PM 27039234 ER PT J AU Blumenthal, KG Kuhlen, JL Weil, AA Varughese, CA Kubiak, DW Banerji, A Shenoy, ES AF Blumenthal, Kimberly G. Kuhlen, James L., Jr. Weil, Ana A. Varughese, Christy A. Kubiak, David W. Banerji, Aleena Shenoy, Erica S. TI Adverse Drug Reactions Associated with Ceftaroline Use: A 2-Center Retrospective Cohort SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE LA English DT Article DE Ceftaroline; Adverse drug reaction; Hypersensitivity; allergy; beta-lactam; Drug ID SKIN-STRUCTURE INFECTIONS; COMPLICATED SKIN; PHASE-III; FOSAMIL; HYPERSENSITIVITY; CEPHALOSPORINS; NEUTROPENIA; THERAPY; ALLERGY; EVENTS AB BACKGROUND: Ceftaroline fosamil is a cephalosporin approved for treating skin and soft tissue infections (SSTIs), including those caused by methicillin-resistant Staphylococcus aureus and community-acquired pneumonia (CAP). OBJECTIVES: We aimed to study ceftaroline use and associated adverse drug reactions (ADRs), including hypersensitivity reactions (HSRs), among inpatients. METHODS: We performed a retrospective electronic health record review of inpatients from Massachusetts General Hospital and Brigham and Women's Hospital who received ceftaroline between May 2012 and February 2015. ADRs diagnosed by clinical providers during the course of clinical care were subsequently verified and classified. Risk factors for ADRs were identified. RESULTS: Among 96 patients (median age, 57 years; 54% females) who received a median of 28 (interquartile range, 6-63) ceftaroline doses, 54% were being treated for methicillin-resistant Staphylococcus aureus and treatment indications other than SSTI and CAP comprised 59% of care. There were 31 ADRs observed in 20 (21%) patients; hematologic (n =15) and cutaneous (n = 9) findings were most common. Observed HSRs included rash with mucosal lesions (n [ 1), rash with skin desquamation (n [ 1), and possible organ-specific HSRs (n = 2). Patients who suffered an ADR received more doses of ceftaroline (median, 46 vs 21; P = .013). There was no increased risk of ceftaroline ADR among patients with reported beta-lactam allergy history (P >.5). CONCLUSIONS: Ceftaroline is used to treat a range of infections beyond SSTI and CAP. We observed a high rate of ADRs from ceftaroline, including signs of severe HSRs. More data are needed to understand the frequency and predictors of ceftaroline ADRs and HSRs. (C) 2016 American Academy of Allergy, Asthma & Immunology C1 [Blumenthal, Kimberly G.; Banerji, Aleena] Massachusetts Gen Hosp, Dept Med, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. [Blumenthal, Kimberly G.; Weil, Ana A.; Banerji, Aleena; Shenoy, Erica S.] Harvard Med Sch, Dept Med, Boston, MA USA. [Blumenthal, Kimberly G.; Shenoy, Erica S.] Massachusetts Gen Hosp, Med Practice Evaluat Ctr, Boston, MA 02114 USA. [Kuhlen, James L., Jr.] Univ South Carolina, Sch Med, Dept Med, Acadia Allergy & Immunol, Greenville, SC USA. [Weil, Ana A.; Banerji, Aleena] Massachusetts Gen Hosp, Dept Med, Div Infect Dis, Boston, MA 02114 USA. [Varughese, Christy A.] Rush Univ, Med Ctr, Dept Pharm, Chicago, IL 60612 USA. [Kubiak, David W.] Brigham & Womens Hosp, Dept Med, Div Infect Dis, 75 Francis St, Boston, MA 02115 USA. [Kubiak, David W.] Brigham & Womens Hosp, Dept Pharm, 75 Francis St, Boston, MA 02115 USA. [Shenoy, Erica S.] Massachusetts Gen Hosp, Infect Control Unit, Boston, MA 02114 USA. RP Blumenthal, KG (reprint author), Massachusetts Gen Hosp, 50 Staniford St,9th Fl, Boston, MA 02114 USA. EM kblumenthal1@partners.org FU National Institutes of Health [T32 HL116275, UL1 TR001102, T32AI070611976, K01AI110524]; Harvard University and its affiliated academic health care centers FX This work was supported by the National Institutes of Health (grant nos. T32 HL116275 and UL1 TR001102 to K.G.B., T32AI070611976 to A.A.W., and K01AI110524 to E.S.S.) 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 29 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2213-2198 EI 2213-2201 J9 J ALLER CL IMM-PRACT JI J. Allergy Clin. Immunol.-Pract. PD AUG PY 2016 VL 4 IS 4 BP 740 EP 746 DI 10.1016/j.jaip.2016.03.008 PG 7 WC Allergy; Immunology SC Allergy; Immunology GA DU0SZ UT WOS:000381916100027 PM 27130709 ER PT J AU Collins, SP Levy, PD Martindale, JL Dunlap, ME Storrow, AB Pang, PS Albert, NM Felker, GM Fermann, GJ Fonarow, GC Givertz, MM Hollander, JE Lanfear, DJ Lenihan, DJ Lindenfeld, JM Peacock, WF Sawyer, DB Teerlink, JR Butler, J AF Collins, Sean P. Levy, Phillip D. Martindale, Jennifer L. Dunlap, Mark E. Storrow, Alan B. Pang, Peter S. Albert, Nancy M. Felker, G. Michael Fermann, Gregory J. Fonarow, Gregg C. Givertz, Michael M. Hollander, Judd E. Lanfear, David J. Lenihan, Daniel J. Lindenfeld, Joann M. Peacock, W. Frank Sawyer, Douglas B. Teerlink, John R. Butler, Javed TI Clinical and Research Considerations for Patients With Hypertensive Acute Heart Failure: A Consensus Statement from the Society of Academic Emergency Medicine and the Heart Failure Society of America Acute Heart Failure Working Group SO JOURNAL OF CARDIAC FAILURE LA English DT Article DE Heart failure; Hypertension; Emergency ID CARDIOGENIC PULMONARY-EDEMA; WORSENING RENAL-FUNCTION; SCANDINAVIAN ENALAPRIL SURVIVAL; HAND-CARRIED ULTRASOUND; BLOOD-PRESSURE; ISOSORBIDE-DINITRATE; NONINVASIVE VENTILATION; FLUID ACCUMULATION; TRANSDERMAL NITROGLYCERIN; INTRAVENOUS ENALAPRILAT AB Management approaches for patients in the emergency department (ED) who present with acute heart failure (AHF) have largely focused on intravenous diuretics. Yet, the primary pathophysiologic derangement underlying AHF in many patients is not solely volume overload. Patients with hypertensive AHF (H-AHF) represent a clinical phenotype with distinct pathophysiologic mechanisms that result in elevated ventricular filling pressures. To optimize treatment response and minimize adverse events in this subgroup, we propose that clinical management be tailored to a conceptual model of disease based on these mechanisms. This consensus statement reviews the relevant pathophysiology, clinical characteristics, approach to therapy, and considerations for clinical trials in ED patients with H-AHF. C1 [Collins, Sean P.; Storrow, Alan B.] Vanderbilt Univ, Dept Emergency Med, 1313 21st Ave South,312 Oxford House, Nashville, TN 37232 USA. [Levy, Phillip D.] Wayne State Univ, Dept Emergency Med, Detroit, MI USA. [Martindale, Jennifer L.] SUNY Downstate, Dept Emergency Med, New York, NY USA. [Dunlap, Mark E.] Case Western Univ, Dept Med, Cleveland, OH USA. [Pang, Peter S.] Indiana Univ, Dept Emergency Med, Indianapolis, IN 46204 USA. [Albert, Nancy M.] Cleveland Clin, Dept Med, Cleveland, OH 44106 USA. [Felker, G. Michael] Duke Univ, Dept Med, Raleigh, NC USA. [Fermann, Gregory J.] Univ Cincinnati, Dept Emergency Med, Cincinnati, OH USA. [Fonarow, Gregg C.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. [Givertz, Michael M.] Harvard Med Sch, Dept Med, Boston, MA USA. [Hollander, Judd E.] Thomas Jefferson Univ, Dept Emergency Med, Philadelphia, PA 19107 USA. [Lanfear, David J.] Henry Ford Hlth Syst, Dept Med, Detroit, MI USA. [Lenihan, Daniel J.; Lindenfeld, Joann M.] Vanderbilt Univ, Dept Med, Nashville, TN USA. [Peacock, W. Frank] Baylor Coll Med, Dept Emergency Med, Houston, TX 77030 USA. [Sawyer, Douglas B.] Maine Med Ctr, Dept Med, Portland, ME 04102 USA. [Teerlink, John R.] San Francisco VA Med Ctr, Dept Med, San Francisco, CA USA. [Butler, Javed] SUNY Stony Brook, Dept Med, Long Isl City, NY USA. RP Collins, SP (reprint author), Vanderbilt Univ, Dept Emergency Med, 1313 21st Ave South,312 Oxford House, Nashville, TN 37232 USA. EM sean.collins@vanderbilt.edu NR 91 TC 1 Z9 1 U1 2 U2 2 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1071-9164 EI 1532-8414 J9 J CARD FAIL JI J. Card. Fail. PD AUG PY 2016 VL 22 IS 8 BP 618 EP 627 DI 10.1016/j.cardfail.2016.04.015 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DS8WX UT WOS:000381064800007 PM 27262665 ER PT J AU Mattaini, KR Sullivan, MR Vander Heiden, MG AF Mattaini, Katherine R. Sullivan, Mark R. Vander Heiden, Matthew G. TI The importance of serine metabolism in cancer SO JOURNAL OF CELL BIOLOGY LA English DT Review ID PYRUVATE-KINASE M2; ONE-CARBON METABOLISM; CELL LUNG-CANCER; 3-PHOSPHOGLYCERATE DEHYDROGENASE; PHOSPHOGLYCERATE DEHYDROGENASE; ESCHERICHIA-COLI; RAT-LIVER; SYNTHESIS PATHWAY; MAMMALIAN-CELLS; HUMAN-MELANOMA AB Serine metabolism is frequently dysregulated in cancers; however, the benefit that this confers to tumors remains controversial. In many cases, extracellular serine alone is sufficient to support cancer cell proliferation, whereas some cancer cells increase serine synthesis from glucose and require de novo serine synthesis even in the presence of abundant extracellular serine. Recent studies cast new light on the role of serine metabolism in cancer, suggesting that active serine synthesis might be required to facilitate amino acid transport, nucleotide synthesis, folate metabolism, and redox homeostasis in a manner that impacts cancer. C1 [Mattaini, Katherine R.; Sullivan, Mark R.; Vander Heiden, Matthew G.] MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Mattaini, Katherine R.; Sullivan, Mark R.; Vander Heiden, Matthew G.] MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Vander Heiden, Matthew G.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Vander Heiden, Matthew G.] Broad Inst, Cambridge, MA 02139 USA. RP Vander Heiden, MG (reprint author), MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Vander Heiden, MG (reprint author), MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Vander Heiden, MG (reprint author), Dana Farber Canc Inst, Boston, MA 02215 USA.; Vander Heiden, MG (reprint author), Broad Inst, Cambridge, MA 02139 USA. EM mvh@mit.edu FU American Association for Cancer Research; Burroughs Wellcome Fund; Koch Institute; Ludwig Center at the Massachusetts Institute of Technology; Stand Up to Cancer; National Science Foundation Graduate Research Fellowship; National Institutes of Health [R21 CA198028] FX We acknowledge support from the American Association for Cancer Research, the Burroughs Wellcome Fund, the Koch Institute, the Ludwig Center at the Massachusetts Institute of Technology, Stand Up to Cancer, the National Science Foundation Graduate Research Fellowship Program, and the National Institutes of Health (grant R21 CA198028). M. Vander Heiden is a consultant and Science Advisory Board member for Agios Pharmaceuticals. NR 82 TC 4 Z9 4 U1 16 U2 20 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 AUG 1 PY 2016 VL 214 IS 3 BP 248 EP 257 DI 10.1083/jcb.201604085 PG 9 WC Cell Biology SC Cell Biology GA DS5OO UT WOS:000380831800006 ER PT J AU Lippincott, MF Chan, YM Delaney, A Rivera-Morales, D Butler, JP Seminara, SB AF Lippincott, Margaret F. Chan, Yee-Ming Delaney, Angela Rivera-Morales, Dianali Butler, James P. Seminara, Stephanie B. TI Kisspeptin Responsiveness Signals Emergence of Reproductive Endocrine Activity: Implications for Human Puberty SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID GONADOTROPIN-RELEASING-HORMONE; IDIOPATHIC HYPOGONADOTROPIC HYPOGONADISM; FOLLICLE-STIMULATING-HORMONE; LUTEINIZING-HORMONE; MENSTRUAL-CYCLE; KISS-1 PEPTIDE; GPR54; SECRETION; RECEPTOR; WOMEN AB Context: Some patients with idiopathic hypogonadotropic hypogonadism (IHH) undergo spontaneous activation of their hypothalamic-pituitary-gonadal axis resulting in normalization of steroidogenesis and/or gametogenesis, a phenomenon termed reversal. Objective: To assess the responsiveness of the GnRH neuronal network to exogenous kisspeptin administration in IHH patients who have undergone reversal. Participants: Six men with congenital IHH and evidence for reversal. Intervention: Subjects underwent q10 min blood sampling to measure GnRH-induced LH secretion at baseline and in response to iv boluses of kisspeptin (0.24-2.4 nmol/kg) and GnRH (75 ng/kg). Results: Individuals with sustained reversal of their hypogonadotropism (spontaneous LH pulses) responded to exogenous kisspeptin with a GnRH-induced LH pulse. Individuals who had reversal but then subsequently suffered relapse of their IHH (loss of spontaneous LH pulsatility) did not respond to kisspeptin. Conclusions: The ability of kisspeptin to stimulate a GnRH-induced LH pulse correlates with the presence of endogenous LH pulses. These data suggest that reversal of hypogonadotropism, and by extension sexual maturation, may be due to the acquisition of kisspeptin responsiveness. C1 [Lippincott, Margaret F.; Chan, Yee-Ming; Rivera-Morales, Dianali; Seminara, Stephanie B.] Massachusetts Gen Hosp, Dept Med, Harvard Reprod Sci Ctr, Boston, MA 02114 USA. [Lippincott, Margaret F.; Chan, Yee-Ming; Rivera-Morales, Dianali; Seminara, Stephanie B.] Massachusetts Gen Hosp, Dept Med, Reprod Endocrine Unit, Boston, MA 02114 USA. [Chan, Yee-Ming] Boston Childrens Hosp, Dept Med, Div Endocrinol, Boston, MA 02115 USA. [Butler, James P.] Brigham & Womens Hosp, Div Sleep Med, Boston, MA 02115 USA. Harvard Med Sch, Boston, MA 02115 USA. [Delaney, Angela] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Genet Puberty & Reprod, Bethesda, MD 20892 USA. RP Seminara, SB (reprint author), Massachusetts Gen Hosp, 55 Fruit St,BHX 5, Boston, MA 02114 USA. EM Seminara.Stephanie@mgh.harvard.edu FU Eunice Kennedy Shriver National Institute for Child Health and Human Development (NICHD) [R01 HD043341, P50 HD028138]; Harvard Catalyst Harvard Clinical and Translational Science Center (National Center for Research Resources, National Institutes of Health) [UL1 RR 025758, UL1 TR000170]; Harvard Catalyst Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health) [UL1 RR 025758, UL1 TR000170]; Harvard Catalyst Harvard Clinical and Translational Science Center (Harvard University and its affiliated academic health care centers); NIH NICHD Grant [K24 HD067388, F32 HD078083]; Doris Duke Clinical Scientist Development Award [2013110]; Postdoctoral Fellowship Award for Clinical Research from the Massachusetts General Hospital Executive Committee on Research Fund for Medical Discovery; NIH Intramural Research Program of NICHD FX This work was supported by grants R01 HD043341 and P50 HD028138 from the Eunice Kennedy Shriver National Institute for Child Health and Human Development (NICHD) and the Harvard Catalyst Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Awards UL1 RR 025758 and UL1 TR000170 and financial contributions from Harvard University and its affiliated academic health care centers). S.B.S. was supported by the NIH NICHD Grant K24 HD067388. Y.-M.C. was supported by a Doris Duke Clinical Scientist Development Award (Grant 2013110). M.F.L. was supported by the NIH NICHD Grant F32 HD078083 and by a Postdoctoral Fellowship Award for Clinical Research from the Massachusetts General Hospital Executive Committee on Research Fund for Medical Discovery. A.D. was supported by the NIH Intramural Research Program of NICHD. NR 44 TC 1 Z9 2 U1 3 U2 3 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD AUG PY 2016 VL 101 IS 8 BP 3061 EP 3069 DI 10.1210/jc.2016-1545 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DU0YF UT WOS:000381930200014 PM 27214398 ER PT J AU Shanbhogue, VV Finkelstein, JS Bouxsein, ML Yu, EW AF Shanbhogue, Vikram V. Finkelstein, Joel S. Bouxsein, Mary L. Yu, Elaine W. TI Association Between Insulin Resistance and Bone Structure in Nondiabetic Postmenopausal Women SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID QUANTITATIVE COMPUTED-TOMOGRAPHY; TYPE-2 DIABETES-MELLITUS; IN-VIVO ASSESSMENT; GROWTH-FACTOR-I; MINERAL DENSITY; STRENGTH FINDINGS; AFRICAN-AMERICAN; DISTAL RADIUS; FRACTURE RISK; HR-PQCT AB Context: The clinical consequences of insulin resistance and hyperinsulinemia on bone remain largely unknown. Objective: The objective of the study was to evaluate the effect of insulin resistance on peripheral bone geometry, volumetric bone mineral density (vBMD), bone microarchitecture, and estimated bone strength. Design, Setting, and Participants: This cross-sectional study included 146 postmenopausal, nondiabetic Caucasian women(mean age 60.3 +/- 2.7 y) who were participating in the Study of Women's Health Across the Nation. Interventions: There were no interventions. Main Outcome Measures: High-resolution peripheral quantitative computed tomography was used to assess bone density and microstructure at the distal radius and tibia. Fasting insulin and glucose were measured and insulin resistance was estimated using homeostasis model assessment of insulin resistance (HOMA-IR), with higher values indicating greater insulin resistance. Results: There was a negative association between HOMA-IR and bone size and a positive association between HOMA-IR and total vBMD, trabecular vBMD, trabecular thickness, and cortical thickness at the radius and tibia. These relationships remained, even after adjusting for body weight and other potential covariates (eg, time since menopause, cigarette smoking, physical activity, prior use of osteoporosis medications or glucocorticoids). Conclusions: In nondiabetic, postmenopausal women, insulin resistance was associated with smaller bone size, greater volumetric bone mineral density, and generally favorable bone microarchitecture at weight-bearing and nonweight-bearing skeletal sites. These associations were independent of body weight and other potential covariates, suggesting that hyperinsulinemia directly affects bone structure independent of obesity and may explain, in part, the higher trabecular bone density and favorable trabecular microarchitecture seen in individuals with type 2 diabetes mellitus. C1 [Shanbhogue, Vikram V.] Odense Univ Hosp, Dept Endocrinol, DK-5000 Odense C, Denmark. [Finkelstein, Joel S.; Bouxsein, Mary L.; Yu, Elaine W.] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Bouxsein, Mary L.] Beth Israel Deaconess Med Ctr, Ctr Adv Orthoped Studies, Boston, MA 02215 USA. RP Shanbhogue, VV (reprint author), Univ Southern Denmark, Odense Univ Hosp, Inst Clin Res, Dept Endocrinol, Kloevervaenget 6-1 Sal, DK-5000 Odense C, Denmark. EM vshanbhogue@health.sdu.dk FU National Institutes of Health (NIH), Department of Health and Human Services, through the National Institute on Aging; National Institute of Nursing Research; NIH Office of Research on Women's Health [U01NR004061, U01AG012505, U01AG012535, U01AG012531, U01AG012539, U01AG012546, U01AG012553, U01AG012554, U01AG012495]; NIH [1S10RR023405, DK093713] FX The Study of Women's Health Across the Nation has grant support from the National Institutes of Health (NIH), Department of Health and Human Services, through the National Institute on Aging, the National Institute of Nursing Research, and the NIH Office of Research on Women's Health Grants U01NR004061, U01AG012505, U01AG012535, U01AG012531, U01AG012539, U01AG012546, U01AG012553, U01AG012554, and U01AG012495. We are grateful to the Massachusetts General Hospital Bone Density Center and the Massachusetts General Hospital HR-pQCT Core Facility, which is supported by NIH Grant 1S10RR023405. E.W.Y. was supported by NIH Grant DK093713. NR 42 TC 1 Z9 1 U1 4 U2 4 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD AUG PY 2016 VL 101 IS 8 BP 3114 EP 3122 DI 10.1210/jc.2016-1726 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DU0YF UT WOS:000381930200020 PM 27243136 ER PT J AU Chung, DY Sadeghian, H Oka, F Qin, T Ayata, C AF Chung, David Y. Sadeghian, Homa Oka, Fumiaki Qin, Tao Ayata, Cenk TI Optogenetic Induction of Cortical Spreading Depressions SO JOURNAL OF GENERAL PHYSIOLOGY LA English DT Meeting Abstract CT 70th Annual Meeting of the Society-of-General-Physiologists - Genetic and Animal Models for Ion Channel Function in Physiology and Disease CY SEP 07-11, 2016 CL Marine Biol Lab, Woods Hole, MA SP Soc Gen Physiologists HO Marine Biol Lab C1 [Chung, David Y.; Sadeghian, Homa; Oka, Fumiaki; Qin, Tao; Ayata, Cenk] Harvard Med Sch, Massachusetts Gen Hosp, Neurovasc Res Unit, Dept Radiol, Boston, MA 02114 USA. [Chung, David Y.; Ayata, Cenk] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Stroke Serv & Neurosci Intens Care Unit, Boston, MA 02114 USA. [Oka, Fumiaki] Yamaguchi Univ, Sch Med, Dept Neurosurg, Ube, Yamaguchi, Japan. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0022-1295 EI 1540-7748 J9 J GEN PHYSIOL JI J. Gen. Physiol. PD AUG PY 2016 VL 148 IS 2 MA 9 BP 6A EP 6A PG 1 WC Physiology SC Physiology GA DS5OT UT WOS:000380832300019 ER PT J AU Sarkar, S Esserman, DA Skanderson, M Levin, FL Justice, AC Lim, JK AF Sarkar, Souvik Esserman, Denise A. Skanderson, Melissa Levin, Forrest L. Justice, Amy C. Lim, Joseph K. TI Disparities in hepatitis C testing in US veterans born 1945-1965 SO JOURNAL OF HEPATOLOGY LA English DT Article DE HCV; Hepatitis C virus; Epidemiology; Variances; Testing; Veterans; U.S ID SERVICES TASK-FORCE; VIRUS-INFECTION; UNITED-STATES; COST-EFFECTIVENESS; ANTIVIRAL THERAPY; NATIONAL-HEALTH; AFFAIRS CARE; GENOTYPE 1; PREVALENCE; SOFOSBUVIR AB Background & Aims: Universal one-time antibody testing for hepatitis C virus (HCV) infection has been recommended by the centers for disease control (CDC) and the United States preventative services task force (USPSTF) for Americans born 1945-1965 (birth cohort). Limited data exists addressing national HCV testing practices. We studied patterns and predictors of HCV testing across the U.S. within the birth cohort utilizing data from the national corporate data warehouse of the U.S. Veterans Administration(VA) health system. Methods: Testing was defined as any HCV test including antibody, RNA or genotype performed during 2000-2013. Results: Of 6,669,388 birth cohort veterans, 4,221,135 (63%) received care within the VA from 2000-2013 with two or more visits. Of this group, 2,139,935 (51%) had HCV testing with 8.1% HCV antibody and 5.4% RNA positive. Significant variation in testing was observed across centers (range: 7-83%). Older, male, African-Americans, with established risk factors and receiving care from urban centers of excellence were more likely to be tested. Among veterans free of other established risk factors (HIV negative, HBV negative, ALT <= 40 U/L, FIB-4 <= 1.45, or APRI < 0.5), HCV antibody and RNA were positive in 2.8% and 0.9%, respectively, comparable to established national average. At least 2.4-4.4% of veterans had scores suggesting advanced fibrosis (APRI P1.5 or FIB-4 > 3.25) with > 30-43% having positive HCV RNA but > 16-20% yet to undergo testing for HCV. Conclusions: Significant disparities are observed in HCV testing within the United States VA health system. Examination of the predictors of testing and HCV positivity may help inform national screening policies. Lay summary: Analysis of United States Veterans Administration data show significant disparities in hepatitis C virus testing of veterans born 1945-1965 (birth cohort). A fifth of those not tested had evidence of advanced liver fibrosis. Our data suggests some predictors for this disparity and will potentially help inform future policy measures in the era of universal birth cohort testing for HCV. (C) 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. C1 [Sarkar, Souvik; Lim, Joseph K.] Yale Univ, Sch Med, Sect Digest Dis, 333 Cedar St,1080 LMP, New Haven, CT USA. [Sarkar, Souvik] Univ Calif Davis, Div Gastroenterol & Hepatol, Davis, CA 95616 USA. [Esserman, Denise A.] Yale Sch Publ Hlth, Dept Biostat, New Haven, CT USA. [Skanderson, Melissa] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Levin, Forrest L.; Justice, Amy C.] VA Connecticut Healthcare Syst, Dept Internal Med, West Haven, CT USA. [Justice, Amy C.] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA. [Justice, Amy C.] Yale Sch Publ Hlth, Dept Hlth Policy & Management, New Haven, CT USA. RP Lim, JK (reprint author), Yale Univ, Sch Med, Sect Digest Dis, 333 Cedar St,1080 LMP, New Haven, CT USA. EM joseph.lim@yale.edu OI Sarkar, Souvik/0000-0002-9358-4257; Justice, Amy/0000-0003-0139-5502 FU Department of Veterans Affairs; Veterans Health Administration; Office of Research and Development; NIAAA [U24 AA020794, U01 AA020790, U10 AA01356]; NCATS [UL1TR000142]; NIDDK [P30 DK034989, 2T32DK007356-36] FX NIAAA U24 AA020794, U01 AA020790, U10 AA01356, completed (ACJ); NCATS UL1TR000142 (DAE); NIDDK P30 DK034989 (JKL); NIDDK 2T32DK007356-36 (SS). This material is based upon work supported by the Department of Veterans Affairs, Veterans Health Administration, and Office of Research and Development. We must disclaim that 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 35 TC 3 Z9 3 U1 1 U2 1 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 2016 VL 65 IS 2 BP 259 EP 265 DI 10.1016/j.jhep.2016.04.012 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DS2AH UT WOS:000380516900008 PM 27130843 ER PT J AU Zhu, AX Chen, D He, W Kanai, M Voi, M Chen, LT Daniele, B Furuse, J Kang, YK Poon, RTP Vogel, A Chiang, DY AF Zhu, Andrew X. Chen, David He, Wei Kanai, Masayuki Voi, Maurizio Chen, Li-Tzong Daniele, Bruno Furuse, Junji Kang, Yoon-Koo Poon, Ronnie T. P. Vogel, Arndt Chiang, Derek Y. TI Integrative biomarker analyses indicate etiological variations in hepatocellular carcinoma SO JOURNAL OF HEPATOLOGY LA English DT Article DE Everolimus; mTOR; c-Met; Tsc2; PI-3 kinase pathway; Next-generation sequencing ID ENDOTHELIAL GROWTH-FACTOR; C-MET EXPRESSION; THERAPEUTIC TARGETS; BREAST-CANCER; PHASE-II; EVEROLIMUS; MTOR; SORAFENIB; TUMOR; AMPLIFICATION AB Background & Aims: The purpose of this study was to determine whether biomarkers from baseline plasma and archival tissue specimens collected from patients enrolled in the EVOLVE-1 trial - a randomized phase 3 study of everolimus in hepatocellular carcinoma (HCC) - were associated with prognosis, etiology or ethnicity. Methods: Circulating plasma levels of bFGF, PLGF, VEGF, VEGF-D, c-Kit, collagen IV, sVEGFR1 and VEGFR2 were measured by ELISA (N = 503). Protein levels of IGF-1R, c-Met, mTOR, Tsc2 were assayed by immunohistochemistry (N = 125). Genomic DNA sequencing was conducted on a panel of 287 cancer-related genes (N = 69). Results: Patients with baseline plasma concentrations of VEGF or sVEGFR1 above the cohort median had significantly shorter overall survival. These plasma biomarkers retained prognostic significance in a multivariate Cox regression model with geographic region, macroscopic vascular invasion and alpha fetoprotein AFP levels. Membranous c-Met protein levels were significantly lower for Asian patients, as well as for hepatitis B viral etiology. The prevalence of genetic changes were similar to previous reports, along with a trend towards higher PTEN and TSC2 mutations among Asians. Conclusions: The angiogenesis biomarkers VEGF and sVEGFR1 were independent prognostic predictors of survival in patients with advanced HCC. Potential differences in c-Met and mTOR pathway activation between Asian and non-Asian patients should be considered in future clinical trials. Lay summary: Our study demonstrates that circulating angiogenesis biomarkers can predict the survival outcome in patients with advanced hepatocellular carcinoma independent of the clinical variables. There is etiology and ethnicity variation in molecular pathway activation in hepatocellular carcinoma, which should be considered for future clinical trial design of targeted therapy. (C) 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. C1 [Zhu, Andrew X.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Chen, David; He, Wei; Kanai, Masayuki; Voi, Maurizio] Novartis Pharmaceut, E Hanover, NJ USA. [Chen, Li-Tzong] Natl Inst Canc Res, Natl Hlth Res Inst, Tainan, Taiwan. [Chen, Li-Tzong] Natl Cheng Kung Univ Hosp, Dept Internal Med, Tainan, Taiwan. [Chen, Li-Tzong] Kaohsiung Med Univ Hosp, Dept Internal Med, Kaohsiung, Taiwan. [Daniele, Bruno] G Rummo Hosp, Dept Med Oncol, Benevento, Italy. [Furuse, Junji] Kyorin Univ, Sch Med, Dept Med Oncol, Tokyo, Japan. [Kang, Yoon-Koo] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Oncol, Seoul, South Korea. [Poon, Ronnie T. P.] Univ Hong Kong, Queen Mary Hosp, Dept Surg, Hong Kong, Hong Kong, Peoples R China. [Vogel, Arndt] Hannover Med Sch, Dept Gastroenterol Hepatol & Endocrinol, Hannover, Germany. [Chiang, Derek Y.] Novartis Inst Biomed Res, Cambridge, MA USA. RP Zhu, AX (reprint author), Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. EM azhu@partners.org RI Vogel, Arndt/A-8437-2012 FU Novartis Pharma AG FX This study was sponsored by Novartis Pharma AG. NR 56 TC 3 Z9 3 U1 2 U2 3 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 2016 VL 65 IS 2 BP 296 EP 304 DI 10.1016/j.jhep.2016.04.015 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DS2AH UT WOS:000380516900013 PM 27130844 ER PT J AU Chren, MM Arron, ST AF Chren, Mary-Margaret Arron, Sarah T. TI Research that Guides Clinical Decisions SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Editorial Material ID RANDOMIZED CONTROLLED-TRIAL; BASAL-CELL CARCINOMA; PHOTODYNAMIC THERAPY; MEDICAL LITERATURE; TOPICAL IMIQUIMOD; USERS GUIDES; PREVENTION; TIME; CARE AB The centerpiece of evidence-based medicine is the randomized controlled trial, a rigorous experiment. We use the study by Roozeboom et al. to illustrate how research guides clinical decisions. We describe levels of evidence, review criteria for assessing a trial regarding noninferiority of a therapy, and discuss challenges for evidence-based medicine in guiding care precisely targeted to an individual patient. C1 [Chren, Mary-Margaret; Arron, Sarah T.] Univ Calif San Francisco, Dept Dermatol, Program Clin Res, San Francisco, CA 94143 USA. [Chren, Mary-Margaret; Arron, Sarah T.] San Francisco VA Med Ctr, Dermatol Serv, San Francisco, CA USA. RP Chren, MM (reprint author), Univ Calif San Francisco, Dept Dermatol, Mt Zion Canc Res Bldg,2340 Sutter St,Room N412, San Francisco, CA 94143 USA. EM chrenm@derm.ucsf.edu NR 10 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2016 VL 136 IS 8 BP 1535 EP 1537 DI 10.1016/j.jid.2016.04.031 PG 3 WC Dermatology SC Dermatology GA DS2HE UT WOS:000380585200075 PM 27450497 ER PT J AU Binder, RL Hasturk, H Bascom, CC Isfort, RJ Klukowska, M Robinson, MK Tiesman, JP White, DJ Kantarci, A AF Binder, R. L. Hasturk, H. Bascom, C. C. Isfort, R. J. Klukowska, M. Robinson, M. K. Tiesman, J. P. White, D. J. Kantarci, A. TI Comparison of gene expression changes associated with intrinsic aging in healthy gingiva and sun-protected skin SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Investigative-Dermatology (SID) CY MAY 11-14, 2016 CL Scottsdale, AZ SP Soc Investigat Dermatol C1 [Binder, R. L.; Bascom, C. C.; Isfort, R. J.; Klukowska, M.; Robinson, M. K.; Tiesman, J. P.; White, D. J.] Procter & Gamble, Mason, OH USA. [Hasturk, H.; Kantarci, A.] Forsyth Inst, Cambridge, MA USA. NR 0 TC 0 Z9 0 U1 4 U2 4 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 2016 VL 136 IS 8 MA LB800 BP B9 EP B9 PG 1 WC Dermatology SC Dermatology GA DS2HE UT WOS:000380585200044 ER PT J AU Jakacki, RI Foley, MA Horan, J Wang, JZ Kieran, MW Bowers, DC Bouffet, E Zacharoulis, S Gill, SC AF Jakacki, Regina I. Foley, Margaret A. Horan, Julie Wang, Jiuzhou Kieran, Mark W. Bowers, Daniel C. Bouffet, Eric Zacharoulis, Stergios Gill, Stan C. TI Single-agent erlotinib versus oral etoposide in patients with recurrent or refractory pediatric ependymoma: a randomized open-label study SO JOURNAL OF NEURO-ONCOLOGY LA English DT Article DE Ependymoma; Epidermal growth factor receptor; EGFR; Pediatrics; Etoposide; Erlotinib ID MULTIINSTITUTIONAL RETROSPECTIVE ANALYSIS; CHILDRENS ONCOLOGY GROUP; PHASE-II; INTRACRANIAL EPENDYMOMA; PROGRESSIVE CANCER; CHEMOTHERAPY; SURVIVAL; MARKERS; TRIAL AB Overexpression of human epidermal growth factor receptor (HER/EGFR) is associated with various tumors, including ependymomas. To investigate whether EGFR inhibition was of benefit in pediatric patients with recurrent ependymoma, a multi-center, randomized, open-label, phase 2 study of oral erlotinib versus oral etoposide was undertaken. Twenty-five patients were randomized to receive erlotinib 85 mg/m(2) daily or etoposide 50 mg/m(2)/day for 21 consecutive days followed by a 7-day rest period. Courses were repeated every 28 days. In the erlotinib arm, no patient achieved a complete, partial, or minor response, and only 2 (15.4 %) patients showed stable disease as their best response. In the etoposide arm, 2 patients (16.7 %) demonstrated partial responses, 1 (8.3 %) patient demonstrated a minor response, and 2 (16.7 %) showed prolonged stable disease, for a prolonged disease control rate of 41.7 %. Three patients received at least nine cycles of etoposide (range 9-24 cycles) before discontinuing at the request of the physician and/or family. Four patients who failed etoposide in this study received erlotinib in a companion single arm study; none had a response. The futility criteria were met at the second interim analysis, and both studies were discontinued. Pharmacokinetics of erlotinib were similar to previous observations in pediatric patients. Overall, erlotinib was well tolerated and safety was consistent with its established profile in adults. The overall risk-benefit profile does not support the use of erlotinib in pediatric patients with recurrent ependymoma, whereas single-agent etoposide appears to have efficacy in a subset of patients. C1 [Jakacki, Regina I.] Univ Pittsburgh, Childrens Hosp Pittsburgh, 4401 Penn Ave, Pittsburgh, PA 15224 USA. [Foley, Margaret A.; Wang, Jiuzhou; Gill, Stan C.] Astellas Pharma Global Dev, 1 Astellas Way, Northbrook, IL 60062 USA. [Horan, Julie] Novella Clin, 4840 Pearl E Cir 100, Boulder, CO 80301 USA. [Kieran, Mark W.] Boston Childrens Hosp, Dana Farber Canc Inst, Pediat Neurooncol, 450 Brookline Ave,D-3154, Boston, MA 02215 USA. [Bowers, Daniel C.] Univ Texas Southwestern Med Sch, Dept Pediat, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. [Bouffet, Eric] Hosp Sick Kids, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. [Zacharoulis, Stergios] Royal Marsden Hosp, Downs Rd, Sutton SM2 5PT, Surrey, England. [Jakacki, Regina I.] AstraZeneca, One Medimmune Way, Gaithersburg, MD 20878 USA. RP Jakacki, RI (reprint author), Univ Pittsburgh, Childrens Hosp Pittsburgh, 4401 Penn Ave, Pittsburgh, PA 15224 USA.; Jakacki, RI (reprint author), AstraZeneca, One Medimmune Way, Gaithersburg, MD 20878 USA. EM regina.jakacki@astrazeneca.com FU Astellas Pharma, Inc.; Astellas FX This study was funded by Astellas Pharma, Inc. Medical writing support was provided by Tara N. Miller, PhD, and Sarah J. Knott, medical writers at Envision Scientific Solutions, and funded by Astellas. NR 19 TC 1 Z9 1 U1 2 U2 2 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 2016 VL 129 IS 1 BP 131 EP 138 DI 10.1007/s11060-016-2155-4 PG 8 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA DT0DE UT WOS:000381152000015 PM 27287856 ER PT J AU Dedmon, MM Locketz, GD Chambers, KJ Naunheim, MR Lin, DT Gray, ST AF Dedmon, Matthew M. Locketz, Garrett D. Chambers, Kyle J. Naunheim, Matthew R. Lin, Derrick T. Gray, Stacey T. TI Skull Base Surgery Training and Practice Patterns among Recent Otolaryngology Fellowship Graduates SO JOURNAL OF NEUROLOGICAL SURGERY PART B-SKULL BASE LA English DT Article DE endoscopic skull base surgery; practice patterns; otolaryngology fellowship; survey ID ENDOSCOPIC RESECTION; CHOLESTEATOMA; OUTCOMES; SOCIETY; EAR AB ObjectiveTo collect data on skull base surgery training experiences and practice patterns of otolaryngologists that recently completed fellowship training. DesignA 24-item survey was disseminated to physicians who completed otolaryngology fellowships in rhinology, head and neck oncology, or neurotology between 2010 and 2014. ResultsDuring a typical year, 50% of rhinologists performed more than 20 endoscopic anterior skull base cases, 83% performed fewer than 20 open cases, and were more confident performing advanced transplanum (p=0.02) and transclival (p=0.03) endoscopic approaches than head and neck surgeons. Head and neck surgeons performed fewer than 20 endoscopic and fewer than 20 open cases in 100% of respondents and were more confident with open approaches than rhinologists (p=0.02). Neurotologists performed more than 20 lateral skull base cases in 45% of respondents during a typical year, fewer than 20 endoscopic ear cases in 95%, and were very comfortable performing lateral skull base approaches. ConclusionMany recent otolaryngology fellowship graduates are integrating skull base surgery into their practices. Respondents reported high confidence levels performing a range of cranial base approaches. Exposure to endoscopic ear techniques is minimal in neurotology training, and rhinology training appears to offer increased exposure to skull base surgery compared with head and neck training. C1 [Dedmon, Matthew M.; Chambers, Kyle J.; Naunheim, Matthew R.; Lin, Derrick T.; Gray, Stacey T.] Harvard Med Sch, Dept Otol & Laryngol, Boston, MA USA. [Dedmon, Matthew M.; Chambers, Kyle J.; Naunheim, Matthew R.; Lin, Derrick T.; Gray, Stacey T.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol Head & Neck Surg, Boston, MA 02114 USA. [Locketz, Garrett D.] Stanford Univ, Dept Otolaryngol Head & Neck Surg, Stanford, CA 94305 USA. RP Dedmon, MM (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. EM matthew_dedmon@meei.harvard.edu NR 12 TC 0 Z9 0 U1 1 U2 1 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 2193-6331 EI 2193-634X J9 J NEUROL SURG PART B JI Journal of Neurol. Surg. Part B PD AUG PY 2016 VL 77 IS 4 BP 297 EP 303 DI 10.1055/s-0035-1567892 PG 7 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA DS8QK UT WOS:000381047700007 PM 27441153 ER PT J AU Naunheim, MR Goyal, N Dedmon, MM Chambers, KJ Sedaghat, AR Bleier, BS Holbrook, EH Curry, WT Gray, ST Lin, DT AF Naunheim, Matthew R. Goyal, Neerav Dedmon, Matthew M. Chambers, Kyle J. Sedaghat, Ahmad R. Bleier, Benjamin S. Holbrook, Eric H. Curry, William T. Gray, Stacey T. Lin, Derrick T. TI An Algorithm for Surgical Approach to the Anterior Skull Base SO JOURNAL OF NEUROLOGICAL SURGERY PART B-SKULL BASE LA English DT Article DE skull base surgery; sinonasal malignancy; CSF leak; sinocutaneous fistula ID TRANSNASAL ENDOSCOPIC RESECTION; GENERAL-HOSPITAL EXPERIENCE; PROTON-BEAM RADIATION; CRANIOFACIAL RESECTION; MALIGNANT-TUMORS; PARANASAL SINUSES; OLFACTORY NEUROBLASTOMA; MASSACHUSETTS EYE; ENDONASAL SURGERY; EAR INFIRMARY AB ObjectiveTo characterize our experience with the surgical management of anterior skull base malignancy, and to propose an algorithm for surgical approach to anterior skull base malignancies. DesignRetrospective review. SettingAcademic cranial base center. ParticipantsSixty-seven patients who underwent resection of paranasal sinus or anterior skull base malignancy with an endoscopic, cranioendoscopic, or traditional anterior craniofacial approach. Outcome MeasuresComplications, recurrence, and survival. ResultsThere were 48 males and 19 females, ranging from 6 to 88 years old. There were three groups: endonasal endoscopic resection (n=10), cranioendoscopic resection (n=12), and traditional craniofacial resection (n=45). The most common tumor pathologies included esthesioneuroblastoma, squamous cell carcinoma, and sinonasal undifferentiated carcinoma. Patients with T3/T4 disease were less likely to undergo endoscopic resection (p=0.007). The 5-year disease-free survival was 82.1% overall, with no statistically significant differences among approaches. There were no differences in orbital complications, meningitis, or cerebrospinal fluid leak. Use of a transfacial incisions predisposed patients to surgical site infection and sinocutaneous fistulae. An algorithm for surgical approach was developed based on these results. ConclusionSinonasal and skull base malignancies can be safely surgically addressed via several approaches. Surgical approach should be selected algorithmically based on preoperative clinical assessment of the tumor and known postoperative complication rates. C1 [Naunheim, Matthew R.; Goyal, Neerav; Dedmon, Matthew M.; Chambers, Kyle J.; Sedaghat, Ahmad R.; Bleier, Benjamin S.; Holbrook, Eric H.; Gray, Stacey T.; Lin, Derrick T.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol Head & Neck Surg, 243 Charles St, Boston, MA 02114 USA. [Naunheim, Matthew R.; Goyal, Neerav; Dedmon, Matthew M.; Chambers, Kyle J.; Sedaghat, Ahmad R.; Bleier, Benjamin S.; Holbrook, Eric H.; Gray, Stacey T.; Lin, Derrick T.] Harvard Med Sch, Dept Otol & Laryngol, Boston, MA USA. [Curry, William T.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. RP Naunheim, MR (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol Head & Neck Surg, 243 Charles St, Boston, MA 02114 USA. EM Matthew_Naunheim@meei.harvard.edu OI Goyal, Neerav/0000-0001-7783-1097 NR 36 TC 0 Z9 0 U1 1 U2 1 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 2193-6331 EI 2193-634X J9 J NEUROL SURG PART B JI Journal of Neurol. Surg. Part B PD AUG PY 2016 VL 77 IS 4 BP 364 EP 370 DI 10.1055/s-0036-1580598 PG 7 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA DS8QK UT WOS:000381047700017 PM 27441163 ER PT J AU Smith, KM Xie, SX Weintraub, D AF Smith, Kara M. Xie, Sharon X. Weintraub, Daniel TI Incident impulse control disorder symptoms and dopamine transporter imaging in Parkinson disease SO JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY LA English DT Article ID AGONIST WITHDRAWAL SYNDROME; COMPULSIVE DISORDERS; BEHAVIORS; MEDICATION; DEPRESSION; PET; QUESTIONNAIRE; ASSOCIATION; RELEASE; RISK AB Objective To describe the incidence of, and clinical and neurobiological risk factors for, new-onset impulse control disorder (ICD) symptoms and related behaviours in early Parkinson disease (PD). Methods The Parkinson's Progression Markers Initiative is an international, multicenter, prospective study of de novo patients with PD untreated at baseline and assessed annually, including serial dopamine transporter imaging (DAT-SPECT) and ICD assessment (Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease short form, QUIP). Participants were included if they screened negative on the QUIP at baseline. Kaplan-Meier curves and generalised estimating equations examined frequency and predictors of incident ICD symptoms. Results Participants were seen at baseline (n=320), year 1 (n=284), year 2 (n=217) and year 3 (n=96). Estimated cumulative incident rates of ICD symptoms and related behaviours were 8% (year 1), 18% (year 2) and 25% (year 3) and increased each year in those on dopamine replacement therapy (DRT) and decreased in those not on DRT. In participants on DRT, risk factors for incident ICD symptoms were younger age (OR=0.97, p=0.05), a greater decrease in right caudate (OR=4.03, p=0.01) and mean striatal (OR=6.90, p=0.04) DAT availability over the first year, and lower right putamen (OR=0.06, p=0.01) and mean total striatal (OR=0.25, p=0.04) DAT availability at any post-baseline visit. Conclusions The rate of incident ICD symptoms increases with time and initiation of DRT in early PD. In this preliminary study, a greater decrease or lower DAT binding over time increases risk of incident ICD symptoms, conferring additional risk to those taking DRT. C1 [Smith, Kara M.] Univ Penn, Dept Neurol, Perelman Sch Med, 330 S 9th St, Philadelphia, PA 19107 USA. [Xie, Sharon X.] Univ Penn, Dept Biostat & Epidemiol, Perelman Sch Med, Philadelphia, PA 19107 USA. [Weintraub, Daniel] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19107 USA. [Weintraub, Daniel] Philadelphia Vet Affairs Med Ctr, Parkinsons Dis Res Educ & Clin Ctr PADRECC, Philadelphia, PA USA. [Weintraub, Daniel] Philadelphia Vet Affairs Med Ctr, MIRECC, Philadelphia, PA USA. RP Smith, KM (reprint author), Univ Penn, Dept Neurol, Perelman Sch Med, 330 S 9th St, Philadelphia, PA 19107 USA. EM karasmi@gmail.com FU Michael J Fox Foundation for Parkinson's Research; Abbott; Avid Radiopharmaceuticals; Biogen Idec; Covance; Bristol-Myers Squibb; Meso Scale Discovery; Piramal; Eli Lilly and Co; F. Hoffman-La Roche Ltd; GE Healthcare; Genentech; GlaxoSmithKline; Merck and Co; Pfizer Inc; UCB Pharma SA FX Supported by the Michael J Fox Foundation for Parkinson's Research and funding partners: Abbott, Avid Radiopharmaceuticals, Biogen Idec, Covance, Bristol-Myers Squibb, Meso Scale Discovery, Piramal, Eli Lilly and Co, F. Hoffman-La Roche Ltd, GE Healthcare, Genentech, GlaxoSmithKline, Merck and Co, Pfizer Inc, and UCB Pharma SA. NR 36 TC 2 Z9 2 U1 2 U2 2 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 2016 VL 87 IS 8 BP 864 EP 870 DI 10.1136/jnnp-2015-311827 PG 7 WC Clinical Neurology; Psychiatry; Surgery SC Neurosciences & Neurology; Psychiatry; Surgery GA DS1VP UT WOS:000380392200011 PM 26534930 ER PT J AU Yao, Y Tan, YH Light, AR Mao, J Yu, ACH Fu, KY AF Yao, Yao Tan, Yong-Hui Light, Alan R. Mao, Jianren Yu, Albert Cheung Hoi Fu, Kai-Yuan TI Alendronate Attenuates Spinal Microglial Activation and Neuropathic Pain SO JOURNAL OF PAIN LA English DT Article DE Alendronate; chronic constriction injury; microglial activation; p38 mitogen-activated protein kinase; inflammatory cytokines ID PERIPHERAL-NERVE INJURY; CHRONIC CONSTRICTION INJURY; BONE CANCER PAIN; PROTEIN-KINASE; BISPHOSPHONATE ALENDRONATE; GLIAL ACTIVATION; CLINICAL PAIN; RAT MODEL; CORD; CONTRIBUTES AB Many derivatives of bisphosphonates, which are inhibitors of bone resorption, have been developed as promising agents for painful pathologies in patients with bone resorption-related diseases. The mechanism for pain relief by bisphosphonates remains uncertain. Studies have reported that bisphosphonates could reduce central neurochemical changes involved in the generation and maintenance of bone cancer pain. In this study, we hypothesized that bisphosphonates would inhibit spinal microglial activation and prevent the development of hyperalgesia caused by peripheral tissue injury. We investigated the effects of alendronate (a nitrogen-containing bisphosphonate) on the development of neuropathic pain and its role in modulating microglial activation in vivo and in vitro. Intrathecal and intraperitoneal administration of alendronate relieved neuropathic pain behaviors induced by chronic constriction sciatic nerve injury. Alendronate also significantly attenuated spinal microglial activation and p38 mitogen-activated protein kinase (MAPK) phosphorylation without affecting astrocytes. In vitro, alendronate downregulated phosphorylated p38 and phosphorylated extracellular signal regulated kinase expression in Iipopolysaccharide-stimulated primary microglia within 1 hour, and pretreatment with alendronate for 12 and 24 hours decreased the expression of inflammatory cytokines (tumor necrosis factor a, and interleukins 1 beta and 6). These findings indicate that alendronate could effectively relieve chronic constriction sciatic nerve injury induced neuropathic pain by at least partially inhibiting the activation of spinal microglia and the p38 MAPK signaling pathway. Perspective: Alendronate could relieve neuropathic pain behaviors in animals by inhibiting the activation of spinal cord microglia and the p38 MAPK cell signaling pathway. Therapeutic applications of alendronate may be extended beyond bone metabolism-related disease. (C) 2016 by the American Pain Society. Published by Elsevier Inc. All rights reserved C1 [Yao, Yao; Tan, Yong-Hui; Fu, Kai-Yuan] Peking Univ, Sch & Hosp Stomatol, Ctr TMD & Orofacial Pain, Beijing, Peoples R China. [Light, Alan R.] Univ Utah, Dept Anesthesiol & Neurobiol & Anat, Salt Lake City, UT USA. [Mao, Jianren] Harvard Med Sch, Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA USA. [Yu, Albert Cheung Hoi] Peking Univ, Neurosci Res Inst, Beijing, Peoples R China. [Yu, Albert Cheung Hoi] Peking Univ, Hlth Sci Ctr, Dept Neurobiol, Beijing, Peoples R China. RP Fu, KY (reprint author), Peking Univ, Sch & Hosp Stomatol, 22 Zhongguancun South Ave, Beijing 100081, Peoples R China. EM kqkyfu@bjmu.edu.cn OI Fu, Kai-Yuan/0000-0001-7049-9888 FU NSFC [30973337, 81271172] FX This research was supported by NSFC grant 30973337 (K.-Y.F.) and 81271172 (K.-Y.F.). NR 74 TC 0 Z9 0 U1 3 U2 5 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1526-5900 J9 J PAIN JI J. Pain PD AUG PY 2016 VL 17 IS 8 BP 889 EP 903 DI 10.1016/j.jpain.2016.03.008 PG 15 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DT1KQ UT WOS:000381241800003 PM 27063783 ER PT J AU Malavera, A Silva, FA Fregni, F Carrillo, S Garcia, RG AF Malavera, Alejandra Silva, Federico Arturo Fregni, Felipe Carrillo, Sandra Garcia, Ronald G. TI Repetitive Transcranial Magnetic Stimulation for Phantom Limb Pain in Land Mine Victims: A Double-Blinded, Randomized, Sham-Controlled Trial SO JOURNAL OF PAIN LA English DT Article DE Phantom limb pain; land mine victims; rTMS; neuropathic pain; noninvasive brain stimulation ID MOTOR CORTEX STIMULATION; CHRONIC NEUROPATHIC PAIN; SPINAL-CORD-INJURY; SENSATIONS; AMPUTATION; REORGANIZATION; MECHANISMS; PLASTICITY; GUIDELINES; EFFICACY AB We evaluated the effects of repetitive transcranial magnetic stimulation (rTMS) in the treatment of phantom limb pain (PLP) in land mine victims. Fifty-four patients with PLP were enrolled in a randomized, double-blinded, placebo-controlled, parallel group single-center trial. The intervention consisted of real or sham rTMS of M1 contralateral to the amputated leg. rTMS was given in series of 20 trains of 6-second duration (54-second intertrain, intensity 90% of motor threshold) at a stimulation rate of 10 Hz (1,200 pulses), 20 minutes per day, during 10 days. For the control group, a sham coil was used. The administration of active rTMS induced a significantly greater reduction in pain intensity (visual analogue scale scores) 15 days after treatment compared with sham stimulation (-53.38 +/- 53.12% vs -22.93 +/- 57.16%; mean between-group difference = 30.44%, 95% confidence interval, .30-60.58; P = .03). This effect was not significant 30 days after treatment. In addition, 19 subjects (70.3%) attained a clinically significant pain reduction (>30%) in the active group compared with 11 in the sham group (40.7%) 15 days after treatment (P =.03). The administration of 10 Hz rTMS on the contralateral primary motor cortex for 2 weeks in traumatic amputees with PLP induced significant clinical improvement in pain. Perspective: High-frequency rTMS on the contralateral primary motor cortex of traumatic amputees induced a clinically significant pain reduction up to 15 days after treatment without any major secondary effect. These results indicate that rTMS is a safe and effective therapy in patients with PLP caused by land mine explosions. (C) 2016 by the American Pain Society C1 [Malavera, Alejandra; Silva, Federico Arturo; Carrillo, Sandra; Garcia, Ronald G.] Fdn Cardiovasc Colombia, Neurovasc Sci Grp, Floridablanca, Colombia. [Malavera, Alejandra; Fregni, Felipe] Harvard Med Sch, Spaulding Rehabil Hosp, Spaulding Neuromodulat Ctr, Boston, MA USA. [Garcia, Ronald G.] Univ Santander, Sch Med, MASIRA Res Inst, Bucaramanga, Colombia. [Garcia, Ronald G.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Martinos Ctr Biomed Imaging, Boston, MA USA. RP Garcia, RG (reprint author), Martinos Ctr Biomed Imaging, Bldg 149,13th St,Suite 2301, Charlestown, MA 02129 USA. EM rgarcia@nmr.mgh.harvard.edu OI Malavera, Alejandra/0000-0002-8117-1367 FU Colombian Science and Technology Institute (COLCIENCIAS) [6566-49-326169]; NIH [5R01HD082302-02] FX This study was partially supported by a grant from the Colombian Science and Technology Institute (COLCIENCIAS, project code: 6566-49-326169). Felipe Fregni is the principal investigator at Spaulding Rehabilitation Hospital of a research grant funded by NIH (5R01HD082302-02). NR 51 TC 1 Z9 1 U1 6 U2 6 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1526-5900 J9 J PAIN JI J. Pain PD AUG PY 2016 VL 17 IS 8 BP 911 EP 918 DI 10.1016/j.jpain.2016.05.003 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DT1KQ UT WOS:000381241800005 PM 27260638 ER PT J AU Greer, JA Tramontano, AC McMahon, PM Pirl, WF Jackson, VA El-Jawahri, A Parikh, RB Muzikansky, A Gallagher, ER Temel, JS AF Greer, Joseph A. Tramontano, Angela C. McMahon, Pamela M. Pirl, William F. Jackson, Vicki A. El-Jawahri, Areej Parikh, Ravi B. Muzikansky, Alona Gallagher, Emily R. Temel, Jennifer S. TI Cost Analysis of a Randomized Trial of Early Palliative Care in Patients with Metastatic Nonsmall-Cell Lung Cancer SO JOURNAL OF PALLIATIVE MEDICINE LA English DT Article ID STANDARD ONCOLOGY CARE; HEALTH-CARE; CHEMOTHERAPY; INTEGRATION; SERVICES AB Background: Several trials have shown that integrated palliative and oncology care improves quality of life and mood in patients with advanced cancers. However, the degree to which early involvement of palliative care (PC) in the outpatient setting impacts the cost of care remains unknown. Methods: Data for this secondary analysis came from a trial of 151 patients with metastatic nonsmall-cell lung cancer (NSCLC) who were randomized to early PC integrated with standard oncology care (SC) or SC alone. We abstracted costs for hospital and outpatient care, including intravenous chemotherapy, from the hospital accounting system. Oral chemotherapy costs were estimated based on actual drug costs. To estimate hospice costs, we used Medicare reimbursement rates. We examined between-group differences in costs of care throughout the entire study period and during the last 30 days before death using the bootstrap-t method. Results: The analytic sample includes the 138/151 patients who died by July 15, 2013. Early PC was associated with a lower mean total cost per day of $117 (p = 0.13) compared to SC. In the final 30 days of life, patients in the early PC group incurred higher hospice care costs (mean difference = $1,053; p = 0.07), while expenses for chemotherapy were less (mean difference = $757; p = 0.03). Costs for emergency department visits and hospitalizations did not differ significantly between groups over the course of the study or at the end of life. Conclusions: The delivery of early PC does not appear to increase overall medical care expenses for patients with metastatic NSCLC. Larger, sufficiently powered cost studies of early PC are needed. C1 [Greer, Joseph A.; Tramontano, Angela C.; McMahon, Pamela M.; Pirl, William F.; Jackson, Vicki A.; El-Jawahri, Areej; Parikh, Ravi B.; Muzikansky, Alona; Gallagher, Emily R.; Temel, Jennifer S.] Harvard Med Sch, Massachusetts Gen Hosp, Yawkey Bldg,Suite 10B,55 Fruit St, Boston, MA 02114 USA. RP Greer, JA (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Yawkey Bldg,Suite 10B,55 Fruit St, Boston, MA 02114 USA. EM jgreer2@mgh.harvard.edu FU ASCO Career Development Award FX This study was supported by the ASCO Career Development Award (PI: Dr. Temel) and gifts from the Joanne Hill Monahan Cancer Fund and Golf Fights Cancer. NR 16 TC 2 Z9 2 U1 5 U2 6 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1096-6218 EI 1557-7740 J9 J PALLIAT MED JI J. Palliat. Med. PD AUG PY 2016 VL 19 IS 8 BP 842 EP 848 DI 10.1089/jpm.2015.0476 PG 7 WC Health Care Sciences & Services SC Health Care Sciences & Services GA DS5II UT WOS:000380814500011 PM 27167637 ER PT J AU Shin, JA El-Jawahri, A Parkes, A Schleicher, SM Knight, HP Temel, JS AF Shin, Jennifer A. El-Jawahri, Areej Parkes, Amanda Schleicher, Stephen M. Knight, Helen P. Temel, Jennifer S. TI Quality of Life, Mood, and Prognostic Understanding in Patients with Metastatic Breast Cancer SO JOURNAL OF PALLIATIVE MEDICINE LA English DT Article ID EARLY PALLIATIVE CARE; CELL LUNG-CANCER; TREATMENT PREFERENCES; NEAR-DEATH; COMMUNICATION; HEALTH; END; ASSOCIATIONS; INFORMATION; DISCUSSIONS AB Background: Although breast cancer is the second leading cause of cancer-related mortality in women in the United States, few studies focus on the supportive care needs of patients living with metastatic breast cancer (MBC). Objective: We studied quality of life (QOL), depression, anxiety, and prognostic understanding of patients with MBC. Design: We conducted a cross-sectional study of 140 patients with MBC, stratified by receipt of endocrine therapy or chemotherapy. Measurements: We evaluated anxiety and depression using the Hospital Anxiety and Depression Scale (HADS). We assessed QOL using the Functional Assessment of Cancer Therapy-Breast (FACT-B), specifically measuring the FACT-B Trial Outcome Index (TOI), which includes physical and functional well-being and breast cancer-specific symptoms. Higher FACT-B TOI scores represent better QOL. We used a 12-item questionnaire to assess patients' perceptions of their prognosis and goals of therapy. Results: Compared to those taking endocrine therapy (n = 40), patients receiving chemotherapy (n = 100) reported lower scores on the FACT-B TOI (66.1 versus 72.5, p < 0.01) and more depression symptoms (HADS-D > 7; 22% versus 7.5%, p = 0.03). Higher scores on the FACT-B TOI were associated with lower depression (beta, -0.16; p < 0.01) and anxiety (beta, -0.11; p < 0.01), and patients who reported frequent prognostic conversations with their oncologists had less depression (beta, -1.28; p < 0.01). Thirty-nine percent (54/140) reported that their cancer was likely curable. Conclusion: Patients with MBC, particularly those treated with chemotherapy, may benefit from interventions to address their physical, functional, and breast cancer-related symptoms. Many do not report accurate prognostic understanding, and more frequent prognostic conversations might address this information gap. C1 [Shin, Jennifer A.; El-Jawahri, Areej; Temel, Jennifer S.] Harvard Med Sch, Massachusetts Gen Hosp, Div Hematol & Oncol, Dept Med,Canc Ctr, Boston, MA USA. [Parkes, Amanda] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Schleicher, Stephen M.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Knight, Helen P.] Johns Hopkins Sch Med, Baltimore, MD USA. RP Shin, JA (reprint author), Massachusetts Gen Hosp, Div Hematol & Oncol, Ctr Canc, 55 Fruit St,Lawrence House 308, Boston, MA 02114 USA. EM jashin@partners.org FU National Cancer Institute at the National Institutes of Health [R25CA092203]; National Cancer Institute Career Development Award [K24CA181253] FX Research support: Dr. Shin was supported by R25CA092203 from the National Cancer Institute at the National Institutes of Health. Dr. Temel was supported by a National Cancer Institute Career Development Award K24CA181253. NR 29 TC 0 Z9 0 U1 3 U2 3 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1096-6218 EI 1557-7740 J9 J PALLIAT MED JI J. Palliat. Med. PD AUG PY 2016 VL 19 IS 8 BP 863 EP 869 DI 10.1089/jpm.2016.0027 PG 7 WC Health Care Sciences & Services SC Health Care Sciences & Services GA DS5II UT WOS:000380814500014 PM 27124211 ER PT J AU Lott, JP Elmore, JG Zhao, GA Knezevich, SR Frederick, PD Reisch, LM Chu, EY Cook, MG Duncan, LM Elenitsas, R Gerami, P Landman, G Lowe, L Messina, JL Mihm, MC van den Oord, JJ Rabkin, MS Schmidt, B Shea, CR Yun, SJ Xu, GX Piepkorn, MW Elder, DE Barnhill, RL AF Lott, Jason P. Elmore, Joann G. Zhao, Ge A. Knezevich, Stevan R. Frederick, Paul D. Reisch, Lisa M. Chu, Emily Y. Cook, Martin G. Duncan, Lyn M. Elenitsas, Rosalie Gerami, Pedram Landman, Gilles Lowe, Lori Messina, Jane L. Mihm, Martin C. van den Oord, Joost J. Rabkin, Michael S. Schmidt, Birgitta Shea, Christopher R. Yun, Sook Jung Xu, George X. Piepkorn, Michael W. Elder, David E. Barnhill, Raymond L. CA Int Melanoma Pathology Study Grp TI Evaluation of the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx) classification scheme for diagnosis of cutaneous melanocytic neoplasms: Results from the International Melanoma Pathology Study Group SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article DE classification; diagnosis; dysplastic nevus; melanoma; Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis; nevus; pathology; variability; variation AB Background: Pathologists use diverse terminology when interpreting melanocytic neoplasms, potentially compromising quality of care. Objective: We sought to evaluate the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx) scheme, a 5-category classification system for melanocytic lesions. Methods: Participants (n = 16) of the 2013 International Melanoma Pathology Study Group Workshop provided independent case-level diagnoses and treatment suggestions for 48 melanocytic lesions. Individual diagnoses (including, when necessary, least and most severe diagnoses) were mapped to corresponding MPATH-Dx classes. Interrater agreement and correlation between MPATH-Dx categorization and treatment suggestions were evaluated. Results: Most participants were board-certified dermatopathologists (n = 15), age 50 years or older (n = 12), male (n = 9), based in the United States (n = 11), and primary academic faculty (n = 14). Overall, participants generated 634 case-level diagnoses with treatment suggestions. Mean weighted kappa coefficients for diagnostic agreement after MPATH-Dx mapping (assuming least and most severe diagnoses, when necessary) were 0.70 (95% confidence interval 0.68-0.71) and 0.72 (95% confidence interval 0.71-0.73), respectively, whereas correlation between MPATH-Dx categorization and treatment suggestions was 0.91. Limitations: This was a small sample size of experienced pathologists in a testing situation. Conclusion: Varying diagnostic nomenclature can be classified into a concise hierarchy using the MPATH-Dx scheme. Further research is needed to determine whether this classification system can facilitate diagnostic concordance in general pathology practice and improve patient care. C1 [Lott, Jason P.] Cornell Scott Hill Hlth Ctr, New Haven, CT USA. [Elmore, Joann G.; Frederick, Paul D.; Reisch, Lisa M.] Univ Washington, Sch Med, Dept Internal Med, Seattle, WA 98195 USA. [Zhao, Ge A.; Piepkorn, Michael W.] Univ Washington, Sch Med, Div Dermatol, Seattle, WA 98195 USA. [Knezevich, Stevan R.] Pathol Associates Inc, Clovis, CA USA. [Chu, Emily Y.; Elenitsas, Rosalie] Univ Penn, Perelman Sch Med, Dept Dermatol, Philadelphia, PA 19104 USA. [Xu, George X.; Elder, David E.] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Cook, Martin G.] Univ Surrey, Div Clin Med, Guildford GU2 5XH, Surrey, England. [Duncan, Lyn M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Gerami, Pedram] Northwestern Univ, Feinberg Sch Med, Dept Dermatol, Chicago, IL 60611 USA. [Landman, Gilles] Univ Fed Sao Paulo, Escola Paulista Med, Dept Pathol, Sao Paulo, Brazil. [Lowe, Lori] Univ Michigan Hosp & Hlth Syst, Dept Pathol & Dermatol, Ann Arbor, MI USA. [Messina, Jane L.] Univ S Florida, Morsani Coll Med, Dept Anat Pathol, Moffitt Ctr, Tampa, FL 33620 USA. [Messina, Jane L.] Univ S Florida, Morsani Coll Med, Dept Cutaneous Oncol, Moffitt Ctr, Tampa, FL 33620 USA. [Gerami, Pedram] Univ S Florida, Morsani Coll Med, Dept Pathol & Cell Biol, Tampa, FL 33620 USA. [Mihm, Martin C.] Brigham & Womens Hosp, Dept Dermatol, 75 Francis St, Boston, MA 02115 USA. [Mihm, Martin C.; Schmidt, Birgitta] Harvard Med Sch, Boston, MA USA. [van den Oord, Joost J.] Katholieke Univ Leuven, Univ Hosp, Dept Pathol, Leuven, Belgium. [Rabkin, Michael S.] Rabkin Dermatopathol Lab PC, Tarentum, PA USA. [Schmidt, Birgitta] Boston Childrens Hosp, Dept Pathol, Boston, MA USA. [Shea, Christopher R.] Univ Chicago Med, Dermatol Sect, Chicago, IL USA. [Yun, Sook Jung] Chonnam Natl Univ, Sch Med, Dept Dermatol, Gwangju, South Korea. [Barnhill, Raymond L.] Univ Paris 05, Dept Pathol, Inst Curie, Paris, France. [Elmore, Joann G.; Barnhill, Raymond L.] Univ Paris 05, Fac Med, Paris, France. RP Elmore, JG (reprint author), Harborview Med Ctr, 325 Ninth Ave,Box 359780, Seattle, WA 98104 USA. EM jelmore@u.washington.edu FU National Cancer Institute [R01 CA151306, K05 CA104699] FX Supported by the National Cancer Institute (R01 CA151306 and K05 CA104699). NR 11 TC 1 Z9 1 U1 2 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD AUG PY 2016 VL 75 IS 2 BP 356 EP 363 DI 10.1016/j.jaad.2016.04.052 PG 8 WC Dermatology SC Dermatology GA DS4JV UT WOS:000380748300029 PM 27189823 ER PT J AU Kurtzman, DJB Thiede, R Erickson, C Curiel-Lewandrowski, C AF Kurtzman, Drew J. B. Thiede, Rebecca Erickson, Christopher Curiel-Lewandrowski, Clara TI An abrupt onset pustular eruption SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Editorial Material C1 [Kurtzman, Drew J. B.] VA Boston Healthcare Syst, Dept Dermatol, Boston, MA USA. [Kurtzman, Drew J. B.] Brigham & Womens Hosp, Boston, MA USA. [Thiede, Rebecca; Curiel-Lewandrowski, Clara] Univ Arizona, Coll Med, Div Dermatol, Tucson, AZ USA. [Erickson, Christopher] Dermpath Diagnost, Tucson, AZ USA. RP Kurtzman, DJB (reprint author), Brigham & Womens Hosp, Dept Dermatol, 221 Longwood Ave, Boston, MA 02115 USA. EM drewkurtzman@gmail.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD AUG PY 2016 VL 75 IS 2 BP E45 EP E46 DI 10.1016/j.jaad.2015.10.027 PG 2 WC Dermatology SC Dermatology GA DS4JV UT WOS:000380748300001 PM 27444083 ER PT J AU Stebbins, WG Neel, V AF Stebbins, William G. Neel, Victor TI Primary surgical closure versus second-intention healing (SIH) after Mohs micrographic surgery: Patient satisfaction and clinical implications SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Letter ID INTENTION C1 [Stebbins, William G.] Vanderbilt Univ, Med Ctr, Div Dermatol, 719 Thompson Ln,Suite 26300, Nashville, TN 37204 USA. [Neel, Victor] Harvard Med Sch, Massachusetts Gen Hosp, Dept Dermatol, Boston, MA USA. RP Stebbins, WG (reprint author), Vanderbilt Univ, Med Ctr, Div Dermatol, 719 Thompson Ln,Suite 26300, Nashville, TN 37204 USA. EM william.g.stebbins@vanderbilt.edu NR 8 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 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD AUG PY 2016 VL 75 IS 2 BP E71 EP E72 DI 10.1016/j.jaad.2016.02.1238 PG 2 WC Dermatology SC Dermatology GA DS4JV UT WOS:000380748300013 PM 27444095 ER PT J AU Tavri, S Ganguli, S Bryan, RG Goverman, J Liu, R Irani, Z Walker, TG AF Tavri, Sidhartha Ganguli, Suvranu Bryan, Roy G., Jr. Goverman, Jeremy Liu, Raymond Irani, Zubin Walker, T. Gregory TI Catheter-Directed Intraarterial Thrombolysis as Part of a Multidisciplinary Management Protocol of Frostbite Injury SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article ID TISSUE-PLASMINOGEN ACTIVATOR; AMPUTATION AB Purpose: To evaluate intraarterial catheter-directed thrombolysis for prediction and prevention of delayed surgical amputation as part of multidisciplinary management of frostbite injury. Materials and Methods: A retrospective review was performed of 13 patients (11 men, 2 women; median age, 33.4 y; range, 8-62 y) at risk of tissue loss secondary to frostbite injury and treated with catheter-directed tissue plasminogen activator (t-PA) thrombolysis. Amputation data were assessed on follow-up (mean, 23 mo; range, 9-83 mo). Angiographic findings were classified into complete, partial, and no angiographic response and assessed for association with follow-up amputation rates. Correlation between amputation outcome and duration of cold exposure (mean, 23 h; range, 5-96 h), time between exposure and rewarming therapy (mean, 25.5 range, 7-95 h); and time between exposure and t-PA thrombolysis (mean, 32 h; range, 12-96 h) was assessed. Complications were recorded. Results: Of 127 digits, at risk on baseline angiography that were treated with catheter-directed thrombolysis, complete recovery was seen in 106 (83.4%). Total mean t-PA dose per extremity was 27.5 mg (range, 12-48 mg) over a mean period of 34 hours (range, 12-72 h). Patients with complete angiographic response (8 patients; 79.5% of digits) did not require amputations; 4 of 5 patients (80%) with partial angiographic response (20.5% of digits) underwent amputation (P = .007). There was no significant correlation between amputation rates and duration of cold exposure (P = .9), time to rewarming therapy (P = .88), and time to thrombolysis (P = .56). Femoral access site bleeding in 2 patients was managed conservatively. One patient underwent surgical exploration for brachial artery hematoma. Conclusions: Intraarterial catheter-directed thrombolysis should be included in initial management of frostbite injury, as it may prevent delayed amputations. The degree of angiographic response to thrombolysis can potentially predict amputation outcomes. C1 [Tavri, Sidhartha] Univ Hosp, Dept Radiol, Div Vasc & Intervent Radiol, 11100 Euclid Ave,BSH 5056, Cleveland, OH 44106 USA. [Tavri, Sidhartha] Case Western Reserve Univ, Sch Med, 11100 Euclid Ave,BSH 5056, Cleveland, OH 44106 USA. [Ganguli, Suvranu; Bryan, Roy G., Jr.; Liu, Raymond; Irani, Zubin; Walker, T. Gregory] Massachusetts Gen Hosp, Div Intervent Radiol, Dept Radiol, Boston, MA 02114 USA. [Goverman, Jeremy] Massachusetts Gen Hosp, Div Burns, Dept Surg, Boston, MA USA. [Goverman, Jeremy] Harvard Med Sch, Boston, MA USA. RP Tavri, S (reprint author), Univ Hosp, Dept Radiol, Div Vasc & Intervent Radiol, 11100 Euclid Ave,BSH 5056, Cleveland, OH 44106 USA.; Tavri, S (reprint author), Case Western Reserve Univ, Sch Med, 11100 Euclid Ave,BSH 5056, Cleveland, OH 44106 USA. EM siddharth.tavri@gmail.com NR 13 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 1051-0443 EI 1535-7732 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD AUG PY 2016 VL 27 IS 8 BP 1228 EP 1235 DI 10.1016/j.jvir.2016.04.027 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA DT1HM UT WOS:000381232300019 PM 27363299 ER PT J AU Kwok, N Lee, LK Arellano, RS AF Kwok, Nathan Lee, Leslie K. Arellano, Ronald S. TI Use of Irreversible Electroporation to Treat Metastatic Pelvic Lymphadenopathy SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Letter ID SAFETY C1 [Kwok, Nathan] Tufts Univ, Sch Med, 145 Harrison Ave, Boston, MA 02111 USA. [Lee, Leslie K.] Massachusetts Gen Hosp, Dept Radiol, Div Nucl Med, Boston, MA 02114 USA. [Lee, Leslie K.] Massachusetts Gen Hosp, Dept Radiol, Div Mol Imaging, Boston, MA USA. [Arellano, Ronald S.] Massachusetts Gen Hosp, Intervent Radiol, Boston, MA 02114 USA. RP Kwok, N (reprint author), Tufts Univ, Sch Med, 145 Harrison Ave, Boston, MA 02111 USA. NR 4 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 1051-0443 EI 1535-7732 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD AUG PY 2016 VL 27 IS 8 BP 1257 EP 1258 DI 10.1016/j.jvir.2015.12.759 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA DT1HM UT WOS:000381232300023 PM 27449982 ER PT J AU Janeway, KA Gorlick, R AF Janeway, Katherine A. Gorlick, Richard TI The case for informative phase 2 trials in osteosarcoma SO LANCET ONCOLOGY LA English DT Editorial Material ID CHILDRENS ONCOLOGY GROUP; CHEMOTHERAPY; EURAMOS-1; SURVIVAL C1 [Janeway, Katherine A.] Childrens Hosp Boston, Dana Farber Canc Inst, Pediat Hematol Oncol, Boston, MA 02215 USA. [Gorlick, Richard] Childrens Hosp Montefiore, Bronx, NY USA. RP Janeway, KA (reprint author), Childrens Hosp Boston, Dana Farber Canc Inst, Pediat Hematol Oncol, Boston, MA 02215 USA. EM Katherine_janeway@dfci.harvard.edu NR 10 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD AUG PY 2016 VL 17 IS 8 BP 1022 EP 1023 PG 3 WC Oncology SC Oncology GA DS7BG UT WOS:000380936900030 PM 27511145 ER PT J AU Cramer, DW Elias, KM AF Cramer, Daniel W. Elias, Kevin M. TI A prognostically relevant miRNA signature for epithelial ovarian cancer SO LANCET ONCOLOGY LA English DT Editorial Material ID MICRORNAS; TARGETS C1 [Cramer, Daniel W.] Brigham & Womens Hosp, Dept Obstet & Gynecol & Reprod Biol, Obstet & Gynecol Epidemiol Ctr, 75 Francis St, Boston, MA 02115 USA. [Cramer, Daniel W.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Cramer, Daniel W.; Elias, Kevin M.] Harvard Med Sch, Boston, MA 02115 USA. [Elias, Kevin M.] Brigham & Womens Hosp, Dept Obstet & Gynecol & Reprod Biol, Div Gynecol Oncol, Boston, MA USA. [Elias, Kevin M.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Cramer, DW (reprint author), Brigham & Womens Hosp, Dept Obstet & Gynecol & Reprod Biol, Obstet & Gynecol Epidemiol Ctr, 75 Francis St, Boston, MA 02115 USA.; Cramer, DW (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.; Cramer, DW (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM dcramer@partners.org NR 10 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD AUG PY 2016 VL 17 IS 8 BP 1032 EP 1033 DI 10.1016/S1470-2045(16)30149-8 PG 3 WC Oncology SC Oncology GA DS7BG UT WOS:000380936900036 PM 27402146 ER PT J AU Kumar, S Paiva, B Anderson, KC Durie, B Landgren, O Moreau, P Munshi, N Lonial, S Blade, J Mateos, MV Dimopoulos, M Kastritis, E Boccadoro, M Orlowski, R Goldschmidt, H Spencer, A Hou, J Chng, WJ Usmani, SZ Zamagni, E Shimizu, K Jagannath, S Johnsen, HE Terpos, E Reiman, A Kyle, RA Sonneveld, P Richardson, PG McCarthy, P Ludwig, H Chen, W Cavo, M Harousseau, JL Lentzsch, S Hillengass, J Palumbo, A Orfao, A Rajkumar, SV Miguel, JS Avet-Loiseau, H AF Kumar, Shaji Paiva, Bruno Anderson, Kenneth C. Durie, Brian Landgren, Ola Moreau, Philippe Munshi, Nikhil Lonial, Sagar Blade, Joan Mateos, Maria-Victoria Dimopoulos, Meletios Kastritis, Efstathios Boccadoro, Mario Orlowski, Robert Goldschmidt, Hartmut Spencer, Andrew Hou, Jian Chng, Wee Joo Usmani, Saad Z. Zamagni, Elena Shimizu, Kazuyuki Jagannath, Sundar Johnsen, Hans E. Terpos, Evangelos Reiman, Anthony Kyle, Robert A. Sonneveld, Pieter Richardson, Paul G. McCarthy, Philip Ludwig, Heinz Chen, Wenming Cavo, Michele Harousseau, Jean-Luc Lentzsch, Suzanne Hillengass, Jens Palumbo, Antonio Orfao, Alberto Rajkumar, S. Vincent Miguel, Jesus San Avet-Loiseau, Herve TI International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma SO LANCET ONCOLOGY LA English DT Review ID STEM-CELL TRANSPLANTATION; MULTIPARAMETER FLOW-CYTOMETRY; FREE LIGHT-CHAIN; CIRCULATING PLASMA-CELLS; HIGH-DOSE THERAPY; POSITRON-EMISSION-TOMOGRAPHY; TIME QUANTITATIVE PCR; WHOLE-BODY MRI; BONE-MARROW; EXTRAMEDULLARY DISEASE AB Treatment of multiple myeloma has substantially changed over the past decade with the introduction of several classes of new effective drugs that have greatly improved the rates and depth of response. Response criteria in multiple myeloma were developed to use serum and urine assessment of monoclonal proteins and bone marrow assessment (which is relatively insensitive). Given the high rates of complete response seen in patients with multiple myeloma with new treatment approaches, new response categories need to be defined that can identify responses that are deeper than those conventionally defined as complete response. Recent attempts have focused on the identification of residual tumour cells in the bone marrow using flow cytometry or gene sequencing. Furthermore, sensitive imaging techniques can be used to detect the presence of residual disease outside of the bone marrow. Combining these new methods, the International Myeloma Working Group has defined new response categories of minimal residual disease negativity, with or without imaging-based absence of extramedullary disease, to allow uniform reporting within and outside clinical trials. In this Review, we clarify several aspects of disease response assessment, along with endpoints for clinical trials, and highlight future directions for disease response assessments. C1 [Kumar, Shaji; Kyle, Robert A.; Rajkumar, S. Vincent] Mayo Clin, Div Hematol, Rochester, MN 55905 USA. [Paiva, Bruno; Miguel, Jesus San] Univ Navarra Clin, CIMA, Pamplona, Spain. [Anderson, Kenneth C.; Munshi, Nikhil; Richardson, Paul G.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Durie, Brian] Cedars Sinai Comprehens Canc Ctr, Los Angeles, CA USA. [Landgren, Ola] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Moreau, Philippe; Harousseau, Jean-Luc] Univ Hosp, Nantes, France. [Lonial, Sagar] Emory Univ, Sch Med, Winship Canc Inst, Dept Hematol & Med Oncol, Atlanta, GA USA. [Mateos, Maria-Victoria; Orfao, Alberto] Univ Hosp Salamanca IBSAL, Salamanca, Spain. [Blade, Joan] Hosp Clin Barcelona, Barcelona, Spain. [Boccadoro, Mario; Palumbo, Antonio] Univ Turin, Azienda Osped Univ Citta Salute & Sci Torino, Div Hematol, Myeloma Unit, Turin, Italy. [Dimopoulos, Meletios; Kastritis, Efstathios; Terpos, Evangelos] Univ Athens, Sch Med, Dept Clin Therapeut, Athens, Greece. [Orlowski, Robert] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Goldschmidt, Hartmut; Hillengass, Jens] Heidelberg Univ, Dept Hematol Oncol & Rheumatol, Heidelberg, Germany. [Spencer, Andrew] Alfred Hosp, Melbourne, Vic, Australia. [Hou, Jian] Chang Zheng Hosp, Shanghai, Peoples R China. [Chng, Wee Joo] Natl Univ Hlth Syst, Singapore, Singapore. [Usmani, Saad Z.] Carolinas HealthCare Syst, Levine Canc Inst, Charlotte, NC USA. [Zamagni, Elena; Cavo, Michele] Univ Bologna, Sch Med, Seragnoli Inst Hematol, Bologna, Italy. [Shimizu, Kazuyuki] Tokai Cent Hosp, Kakamigahara, Japan. [Boccadoro, Mario; Jagannath, Sundar] Mt Sinai Canc Inst, New York, NY USA. [Johnsen, Hans E.] Aalborg Univ Hosp, Clin Canc Res Ctr, Dept Hematol, Aalborg, Denmark. [Reiman, Anthony] Dalhousie Univ, Sch Med, Dalhousie, NS, Canada. [Sonneveld, Pieter] Erasmus MC, Rotterdam, Netherlands. [McCarthy, Philip] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Ludwig, Heinz] Wilhelminenspital Stat Wien, Vienna, Austria. [Chen, Wenming] Beijing Chaoyang Hosp, Beijing, Peoples R China. [Lentzsch, Suzanne] Columbia Univ, New York, NY USA. [Avet-Loiseau, Herve] Univ Toulouse, Toulouse, France. RP Kumar, S (reprint author), Mayo Clin, Div Hematol, Rochester, MN 55905 USA. EM kumar.shaji@mayo.edu RI richard, chrystelle/K-8595-2015 FU Skyline Diagnostics; Noxxon Pharma; Kessios Pharma; Celgene; Millennium; Gilead; Bristol-Myers Squibb; Takeda Sanofi; EngMab; Takeda; Janssen; Novartis; Amgen; Onyx; Spectrum Pharma; Chugai; Karyopharm; Pharmamar; Oncopeptide; Binding Site; BMS; Boehringer Ingelheim; Genmab A/S; Merck; Sanofi; Janssen-Cilag FX SK reports personal fees for Skyline Diagnostics, Noxxon Pharma, and Kessios Pharma and serves on advisory boards for Takeda, Celgene, Janssen, Abbvie, Bristol-Myers Squibb, and Merck. KCA reports personal fees from Celgene, Millennium, Gilead, and Bristol-Myers Squibb. BP has been a consultant for Sanofi, serves on advisory boards and has received honoraria for Takeda, Celgene, Amgen, and Janssen, and reports grants from Celgene, Takeda Sanofi, and EngMab. PM reports personal fees from Celgene, Takeda, Janssen, Bristol-Myers Squibb, Novartis, and Amgen. NM has been a consultant for Celgene, Merck, Takeda, Pfizer, Amgen, and Janssen. M-VM reports personal fees from Janssen, Celgene, Bristol-Myers Squibb, and Amgen. MD has received personal fees from Celgene, Amgen, Janssen, and Novartis. EK has received honoraria from Janssen, Takeda, and Onyx. MB has received honoraria from Celgene, Onyx, Janssen-Cilag, Sanofi, and Amgen. RO reports grants from Bristol-Myers Squibb, Celgene, Takeda, Onyx, and Spectrum Pharma, and serves on advisory boards for Array BioPharma, Bristol-Myers Squibb, Celgene, FORMA Therapeutics, Janssen, Takeda, and Onyx. HG reports grants and personal fees from Celgene, Janssen, Chugai, Novartis, Onyx, Millennium, and reports grants from Bristol-Myers Squibb, Amgen, and Takeda. SJ serves on advisory boards for Celgene, Novartis, Bristol-Myers Squibb, and Merck. ET has received honoraria from Amgen, Celgene, Genesis, Takeda, Novartis, and Janssen-Cilag, serves on advisory boards for Amgen, Takeda, and Janssen-Cilag, and reports grants from Genesis, Amgen, and Janssen-Cilag. AR reports personal fees from Celgene. PS reports grants and personal fees from Celgene, Janssen, and Amgen, and reports grants from Karyopharm, Pharmamar, and Oncopeptide. PGR serves on advisory boards for Celgene, Takeda, and Johnson & Johnson. PM reports grants from Celgene and reports personal fees from Bristol-Myers Squibb, Celgene, Takeda, Karyopharm, Sanofi, Janssen, and The Binding Site. HL reports grants from Takeda and reports fees from BMS, Janssen-Cilag, Celgene, Onyx, and Boehringer Ingelheim. MC reports personal fees from Celgene, Janssen, Amgen, Takeda, and Bristol-Myers Squibb. SL serves on advisory boards for Celgene, Bristol-Myers Squibb, Novartis, and Celgene. JH reports grants from Novartis and Sanofi and reports personal fees from Amgen, Celgene, and Janssen. AP reports personal fees from Amgen, Novartis, Bristol-Myers Squibb, Genmab A/S, Celgene, Janssen-Cilag, Takeda, Sanofi, and Merck. JSM serves on advisory boards for Celgene, Novartis, Onyx, Janssen, Bristol-Myers Squibb, Takeda, and MSD. All other authors declare no competing interests. NR 120 TC 26 Z9 26 U1 10 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD AUG PY 2016 VL 17 IS 8 BP E328 EP E346 PG 19 WC Oncology SC Oncology GA DS7BG UT WOS:000380936900025 PM 27511158 ER PT J AU Sharma, A Lavie, CJ Sharma, SK Garg, A Vallakati, A Mukherjee, D Marmur, JD AF Sharma, Abhishek Lavie, Carl J. Sharma, Samin K. Garg, Akash Vallakati, Ajay Mukherjee, Debabrata Marmur, Jonathan D. TI Duration of Dual Antiplatelet Therapy After Drug-Eluting Stent Implantation in Patients With and Without Acute Coronary Syndrome: A Systematic Review of Randomized Controlled Trials SO MAYO CLINIC PROCEEDINGS LA English DT Article ID ST-SEGMENT ELEVATION; MYOCARDIAL-INFARCTION; STOPPING CLOPIDOGREL; ADVERSE EVENTS; METAANALYSIS; INTERVENTION; ASPIRIN; RISK; TERM; DISCONTINUATION AB In this systemic review we evaluated the efficacy and safety of long duration dual anti-platelet therapy (DAPT) (L-DAPT) compared with short duration DAPT (S-DAPT) after drug-eluting stent(DES) implantation in patients who presented with or without acute coronary syndromes (ACS). We identified 8 randomized controlled trials in which 30,975 patients were randomized to S-DAPT versus L-DAPT (12,421 ACS and 18,554 non-ACS). Short duration dual anti-platelet therapy was associated with an increase in target vessel revascularization (TVR) in ACS patients, but the difference was not significant for non-ACS patients (odds ratio [OR] 5.04 [95% CI, 1.28-19.76], and OR, 0.89 [95% CI, 0.51-1.55], respectively). The risk of cardiac mortality was not significantly different with S-DAPT and L-DAPT for ACS (OR, 1.69 [95% CI, 0.82-3.50]) and non-ACS patients (OR, 0.89 [95% CI, 0.57-1.37]). For all cause mortality, myocardial infarction, and stent thrombosis, most of the events were derived from the DAPT study, thus a meta-analysis was not performed for these end points. Based on our review of the literature, we conclude that S-DAPT was associated with higher rates of stent thrombosis and myocardial infarction, and non-significant differences in all-cause mortality, with no significant interactions according to ACS vs non-ACS. However, in non-ACS patients, the benefit-risk profile favored S-DAPT, with lower all-cause mortality, whereas the trends were reversed in ACS. Additional studies are required to determine if the benefit-risk profile of S-DAPT vs L-DAPT varies according to clinical syndrome. (C) 2016 Mayo Foundation for Medical Education and Research C1 [Sharma, Abhishek; Marmur, Jonathan D.] Suny Downstate Med Ctr, Div Cardiovasc Med, Brooklyn, NY USA. [Lavie, Carl J.] Univ Queensland, Dept Cardiovasc Dis, John Ochsner Heart & Vasc Inst, Ochsner Clin Sch,Sch Med, New Orleans, LA USA. [Sharma, Samin K.] Icahn Sch Med Mt Sinai, Mt Sinai Med Ctr, Inst Heart & Vasc, Dept Cardiovasc Med, New York, NY 10029 USA. [Garg, Akash] Icahn Sch Med Mt Sinai, Dept Med, James J Peters VA Med Ctr, New York, NY 10029 USA. [Vallakati, Ajay] Case Western Reserve Univ, Metrohlth Med Ctr, Div Cardiol, Cleveland, OH USA. [Mukherjee, Debabrata] Texas Tech Univ, Div Cardiol, El Paso, TX USA. RP Sharma, A (reprint author), 125 96th St,Apt 5B, Brooklyn, NY 11209 USA. EM abhisheksharma4mamc@gmail.com RI Lavie, Carl/A-6014-2011 NR 34 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0025-6196 EI 1942-5546 J9 MAYO CLIN PROC JI Mayo Clin. Proc. PD AUG PY 2016 VL 91 IS 8 BP 1084 EP 1093 DI 10.1016/j.mayocp.2016.06.004 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA DS4KN UT WOS:000380750100013 PM 27492914 ER PT J AU Swirski, FK Nahrendorf, M Libby, P AF Swirski, Filip K. Nahrendorf, Matthias Libby, Peter TI Mechanisms of Myeloid Cell Modulation of Atherosclerosis SO MICROBIOLOGY SPECTRUM LA English DT Article ID NEUTROPHIL EXTRACELLULAR TRAPS; SMOOTH-MUSCLE-CELL; ACUTE CORONARY SYNDROMES; MAST-CELLS; MACROPHAGE ACCUMULATION; CHOLESTEROL CONTROVERSY; CARDIOVASCULAR-DISEASE; INTERPRETIVE HISTORY; ADHESION MOLECULE-1; ADAPTIVE IMMUNITY AB Inflammation furnishes a series of pathogenic pathways that couple the risk factors for atherosclerosis with altered behavior of the intrinsic cells of the arterial wall, endothelium, and smooth muscle and promote the disease and its complications. Myeloid cells participate critically in all phases of atherosclerosis from initiation through progression, and ultimately the thrombotic consequences of this disease. Foam cells, lipid-laden macrophages, constitute the hallmark of atheromata. Much of the recent expansion in knowledge of the roles of myeloid cells in atherosclerosis revolves around the functional contributions of subsets of monocytes, precursors of macrophages, the most abundant myeloid cells in the atheroma. Proinflammatory monocytes preferentially accumulate in nascent atherosclerotic plaques. The most dramatic manifestations of atherosclerosis result from blood clot formation. Myocardial infarction, ischemic stroke, and abrupt limb ischemia all arise primarily from thrombi that complicate atherosclerotic plaques. Myeloid cells contribute pivotally to triggering thrombosis, for example, by elaborating enzymes that degrade the plaque's protective extracellular matrix, rendering it fragile, and by producing the potent procoagulant tissue factor. While most attention has focused on mononuclear phagocytes, the participation of polymorphonuclear leukocytes may aggravate local thrombus formation. Existing therapies such as statins may exert some of their protective effects by altering the functions of myeloid cells. The pathways of innate immunity that involve myeloid cells provide a myriad of potential targets for modifying atherosclerosis and its complications, and provide a fertile field for future attempts to address the residual burden of this disease, whose global prevalence is on the rise. C1 [Swirski, Filip K.; Nahrendorf, Matthias] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Libby, Peter] Harvard Med Sch, Brigham & Womens Hosp, Div Cardiovasc Med, Dept Med, Boston, MA 02115 USA. RP Libby, P (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Div Cardiovasc Med, Dept Med, Boston, MA 02115 USA. EM plibby@bwh.harvard.edu NR 84 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA EI 2165-0497 J9 MICROBIOL SPECTR JI Microbiol. Spectr. PD AUG PY 2016 VL 4 IS 4 AR UNSP MCHD-0026-2015 DI 10.1128/microbiolspec.MCHD-0026-2015 PG 11 WC Microbiology SC Microbiology GA DT9GI UT WOS:000381804000033 ER PT J AU McConnell, HL Schwartz, DL Richardson, BE Woltjer, RL Muldoon, LL Neuwelt, EA AF McConnell, Heather L. Schwartz, Daniel L. Richardson, Brian E. Woltjer, Randall L. Muldoon, Leslie L. Neuwelt, Edward A. TI Ferumoxytol nanoparticle uptake in brain during acute neuroinflammation is cell-specific SO NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE LA English DT Article DE Neuroinflammation; MRI; Iron oxide nanoparticles; Macrophages; Contrast agents ID IRON-OXIDE NANOPARTICLES; MRI; PSEUDOPROGRESSION; VISUALIZATION; GLIOBLASTOMA; GADOTERIDOL; ASTROCYTES; THERAPY; DISEASE; BARRIER AB Ferumoxytol ultrasmall superparamagnetic iron oxide nanoparticles can enhance contrast between neuroinflamed and normal-appearing brain tissue when used as a contrast agent for high-sensitivity magnetic resonance imaging (MRI). Here we used an anti-dextran antibody (Dx1) that binds the nanoparticle's carboxymethyldextran coating to differentiate ferumoxytol from endogenous iron and localize it unequivocally in brain tissue. Intravenous injection of ferumoxytol into immune-competent rats that harbored human tumor xenograft-induced inflammatory brain lesions resulted in heterogeneous and lesion-specific signal enhancement on MRI scans in vivo. We used Dx1 immunolocalization and electron microscopy to identify ferumoxytol in affected tissue post-MRI. We found that ferumoxytol nanoparticles were taken up by astrocyte endfeet surrounding cerebral vessels, astrocyte processes, and CD163(+)/CD68(+) macrophages, but not by tumor cells. These results provide a biological basis for the delayed imaging changes seen with ferumoxytol and indicate that ferumoxytol-MRI can be used to assess the inflammatory component of brain lesions in the clinic. Published by Elsevier Inc. C1 [McConnell, Heather L.; Muldoon, Leslie L.; Neuwelt, Edward A.] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA. [Schwartz, Daniel L.] Oregon Hlth & Sci Univ, Adv Imaging Res Ctr, Portland, OR 97201 USA. [Richardson, Brian E.] Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Portland, OR 97201 USA. [Woltjer, Randall L.] Oregon Hlth & Sci Univ, Dept Pathol, Portland, OR 97201 USA. [Neuwelt, Edward A.] Oregon Hlth & Sci Univ, Dept Neurosurg, Portland, OR 97201 USA. [Neuwelt, Edward A.] Portland VA Med Ctr, Dept Vet Affairs, Portland, OR USA. RP Neuwelt, EA (reprint author), Oregon Hlth & Sci Univ, Portland, OR 97239 USA. EM mcconneh@ohsu.edu; schwartd@ohsu.edu; brian@brianerichardson.com; woltjerr@ohsu.edu; muldoonl@ohsu.edu; neuwelte@ohsu.edu FU Walter S. and Lucienne Driskill Foundation; National Institutes of Health (NIH) [NS44687, CA137488, NS061800]; National Center for Advancing Translational Sciences at the NIH [TL1TR000129] FX This work was supported by the Walter S. and Lucienne Driskill Foundation and National Institutes of Health (NIH) grants NS44687 and CA137488 to EAN and NS061800 to Sue Aicher, and an Oregon Clinical and Translational Research Institute grant TL1TR000129 from the National Center for Advancing Translational Sciences at the NIH to HLM. Funding sources had no role in study design, collection or analysis of data, writing of the manuscript, or in the decision to submit the manuscript for publication. NR 28 TC 1 Z9 1 U1 6 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1549-9634 EI 1549-9642 J9 NANOMED-NANOTECHNOL JI Nanomed.-Nanotechnol. Biol. Med. PD AUG PY 2016 VL 12 IS 6 BP 1535 EP 1542 DI 10.1016/j.nano.2016.03.009 PG 8 WC Nanoscience & Nanotechnology; Medicine, Research & Experimental SC Science & Technology - Other Topics; Research & Experimental Medicine GA DT8DF UT WOS:000381718600011 PM 27071335 ER PT J AU Sieberts, SK Zhu, F Garcia-Garcia, J Stahl, E Pratap, A Pandey, G Pappas, D Aguilar, D Anton, B Bonet, J Eksi, R Fornes, O Guney, E Li, HD Marin, MA Panwar, B Planas-Iglesias, J Poglayen, D Cui, J Falcao, AO Suver, C Hoff, B Balagurusamy, VSK Dillenberger, D Neto, EC Norman, T Aittokallio, T Ammad-ud-din, M Azencott, CA Bellon, V Boeva, V Bunte, K Chheda, H Cheng, L Corander, J Dumontier, M Goldenberg, A Gopalacharyulu, P Hajiloo, M Hidru, D Jaiswal, A Kaski, S Khalfaoui, B Khan, SA Kramer, ER Marttinen, P Mezlini, AM Molparia, B Pirinen, M Saarela, J Samwald, M Stoven, V Tang, H Tang, J Torkamani, A Vert, JP Wang, B Wang, T Wennerberg, K Wineinger, NE Xiao, GH Xie, Y Yeung, R Zhan, XW Zhao, C Greenberg, J Kremer, J Michaud, K Barton, A Coenen, M Mariette, X Miceli, C Shadick, N Weinblatt, M de Vries, N Tak, PP Gerlag, D Huizinga, TWJ Kurreeman, F Allaart, CF Bridges, SL Criswell, L Moreland, L Klareskog, L Saevarsdottir, S Padyukov, L Gregersen, PK Friend, S Plenge, R Stolovitzky, G Oliva, B Guan, YF Mangravite, LM AF Sieberts, Solveig K. Zhu, Fan Garcia-Garcia, Javier Stahl, Eli Pratap, Abhishek Pandey, Gaurav Pappas, Dimitrios Aguilar, Daniel Anton, Bernat Bonet, Jaume Eksi, Ridvan Fornes, Oriol Guney, Emre Li, Hongdong Marin, Manuel Alejandro Panwar, Bharat Planas-Iglesias, Joan Poglayen, Daniel Cui, Jing Falcao, Andre O. Suver, Christine Hoff, Bruce Balagurusamy, Venkat S. K. Dillenberger, Donna Neto, Elias Chaibub Norman, Thea Aittokallio, Tero Ammad-ud-din, Muhammad Azencott, Chloe-Agathe Bellon, Victor Boeva, Valentina Bunte, Kerstin Chheda, Himanshu Cheng, Lu Corander, Jukka Dumontier, Michel Goldenberg, Anna Gopalacharyulu, Peddinti Hajiloo, Mohsen Hidru, Daniel Jaiswal, Alok Kaski, Samuel Khalfaoui, Beyrem Khan, Suleiman Ali Kramer, Eric R. Marttinen, Pekka Mezlini, Aziz M. Molparia, Bhuvan Pirinen, Matti Saarela, Janna Samwald, Matthias Stoven, Veronique Tang, Hao Tang, Jing Torkamani, Ali Vert, Jean-Phillipe Wang, Bo Wang, Tao Wennerberg, Krister Wineinger, Nathan E. Xiao, Guanghua Xie, Yang Yeung, Rae Zhan, Xiaowei Zhao, Cheng Greenberg, Jeff Kremer, Joel Michaud, Kaleb Barton, Anne Coenen, Marieke Mariette, Xavier Miceli, Corinne Shadick, Nancy Weinblatt, Michael de Vries, Niek Tak, Paul P. Gerlag, Danielle Huizinga, Tom W. J. Kurreeman, Fina Allaart, Cornelia F. Bridges, S. Louis, Jr. Criswell, Lindsey Moreland, Larry Klareskog, Lars Saevarsdottir, Saedis Padyukov, Leonid Gregersen, Peter K. Friend, Stephen Plenge, Robert Stolovitzky, Gustavo Oliva, Baldo Guan, Yuanfang Mangravite, Lara M. CA Rheumatoid Arth Challenge TI Crowdsourced assessment of common genetic contribution to predicting anti-TNF treatment response in rheumatoid arthritis SO NATURE COMMUNICATIONS LA English DT Article ID GENOME-WIDE ASSOCIATION; STACKED GENERALIZATION; MISSING HERITABILITY; NETWORK INFERENCE; CLINICAL-RESPONSE; COMPLEX TRAITS; DISEASE; RISK; METAANALYSIS; INFLIXIMAB AB Rheumatoid arthritis (RA) affects millions world-wide. While anti-TNF treatment is widely used to reduce disease progression, treatment fails in Bone-third of patients. No biomarker currently exists that identifies non-responders before treatment. A rigorous community-based assessment of the utility of SNP data for predicting anti-TNF treatment efficacy in RA patients was performed in the context of a DREAM Challenge (http://www.synapse.org/RA_Challenge). An open challenge framework enabled the comparative evaluation of predictions developed by 73 research groups using the most comprehensive available data and covering a wide range of state-of-the-art modelling methodologies. Despite a significant genetic heritability estimate of treatment non-response trait (h(2) = 0.18, P value = 0.02), no significant genetic contribution to prediction accuracy is observed. Results formally confirm the expectations of the rheumatology community that SNP information does not significantly improve predictive performance relative to standard clinical traits, thereby justifying a refocusing of future efforts on collection of other data. C1 [Sieberts, Solveig K.; Pratap, Abhishek; Cui, Jing; Suver, Christine; Hoff, Bruce; Neto, Elias Chaibub; Norman, Thea; Friend, Stephen; Mangravite, Lara M.] Sage Bionetworks, Seattle, WA 98109 USA. [Zhu, Fan; Eksi, Ridvan; Li, Hongdong; Panwar, Bharat; Guan, Yuanfang] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Garcia-Garcia, Javier; Pratap, Abhishek; Aguilar, Daniel; Anton, Bernat; Bonet, Jaume; Fornes, Oriol; Marin, Manuel Alejandro; Planas-Iglesias, Joan; Poglayen, Daniel; Oliva, Baldo] Univ Pompeu Fabra, Dept Cieecies Expt & Salut, Struct Bioinformat Grp GRIB IMIM, Barcelona 08003, Spain. [Stahl, Eli] Icahn Sch Med Mt Sinai, Div Psychiat Genom, Ctr Stat Genet, New York, NY 10029 USA. [Stahl, Eli; Pandey, Gaurav; Stolovitzky, Gustavo] Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, New York, NY 10029 USA. [Pandey, Gaurav; Stolovitzky, Gustavo] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Pappas, Dimitrios] Columbia Univ, Dept Med, Div Rheumatol, New York, NY 10032 USA. [Pappas, Dimitrios; Greenberg, Jeff] Corrona LLC, Southborough, MA 01772 USA. [Guney, Emre] Northeastern Univ, Ctr Complex Network Res, Boston, MA 02115 USA. Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02215 USA. [Shadick, Nancy; Weinblatt, Michael] Harvard Med Sch, Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. [Falcao, Andre O.; Stolovitzky, Gustavo] Univ Lisbon, Fac Sci, Dept Informat, P-1749016 Lisbon, Portugal. [Balagurusamy, Venkat S. K.; Dillenberger, Donna; Aittokallio, Tero] IBM TJ Watson Res Ctr, Yorktown Hts, NY 10598 USA. [Chheda, Himanshu; Cheng, Lu; Gopalacharyulu, Peddinti; Jaiswal, Alok; Khan, Suleiman Ali; Pirinen, Matti; Saarela, Janna; Tang, Jing; Wennerberg, Krister] Univ Helsinki, Inst Mol Med Finland FIMM, FI-00014 Helsinki, Finland. [Ammad-ud-din, Muhammad; Bunte, Kerstin; Cheng, Lu; Kaski, Samuel; Khan, Suleiman Ali; Marttinen, Pekka] Aalto Univ, Dept Comp Sci, Espoo 02150, Finland. [Ammad-ud-din, Muhammad; Bunte, Kerstin; Cheng, Lu; Corander, Jukka; Kaski, Samuel; Khan, Suleiman Ali; Marttinen, Pekka] Aalto Univ, Espoo 02150, Finland. [Azencott, Chloe-Agathe; Bellon, Victor; Boeva, Valentina; Stoven, Veronique; Vert, Jean-Phillipe] PSL Res Univ, CBIO Ctr Computat Biol, MINES ParisTech, F-77300 Fontainebleau, France. [Azencott, Chloe-Agathe; Bellon, Victor; Boeva, Valentina; Stoven, Veronique; Vert, Jean-Phillipe] Inst Curie, F-75248 Paris, France. [Azencott, Chloe-Agathe; Bellon, Victor; Boeva, Valentina; Stoven, Veronique; Vert, Jean-Phillipe] INSERM, U900, Biostat, Epidemiol & Computat Syst Biol Canc,Bioinformat, F-75248 Paris, France. [Corander, Jukka] Univ Helsinki, Dept Math & Stat, FI-00014 Helsinki, Finland. [Dumontier, Michel] Stanford Univ, Stanford Ctr Biomed Informat, Stanford, CA 94305 USA. [Goldenberg, Anna; Hidru, Daniel; Mezlini, Aziz M.; Zhao, Cheng] Univ Toronto, Dept Comp Sci, Toronto, ON M5G OA5, Canada. [Goldenberg, Anna; Hajiloo, Mohsen; Hidru, Daniel; Khalfaoui, Beyrem; Mezlini, Aziz M.; Zhao, Cheng] SickKids Res Inst, Genet & Genome Biol, Toronto, ON M5G 0A4, Canada. [Kaski, Samuel] Univ Helsinki, Dept Comp Sci, FI-00014 Helsinki, Finland. [Kramer, Eric R.; Molparia, Bhuvan; Torkamani, Ali; Wineinger, Nathan E.] Scripps Res Inst, Scripps Translat Sci Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA. [Samwald, Matthias] Med Univ Vienna, Ctr Med Stat Informat & Intelligent Syst, A-1090 Vienna, Austria. [Tang, Hao; Wang, Tao; Xiao, Guanghua; Xie, Yang; Zhan, Xiaowei] Univ Texas Southwestern Med Ctr Dallas, Quantitat Biomed Res Ctr, Dallas, TX 75390 USA. [Wang, Bo] Stanford Univ, Dept Comp Sci, Stanford, CA 94305 USA. [Xie, Yang] Univ Texas Southwestern Med Ctr Dallas, Harold C Simmons Comprehens Canc Ctr, Dallas, TX 75390 USA. [Yeung, Rae] Univ Toronto, Inst Med Sci, Dept Immunol, Dept Paediat, Toronto, ON M5S 1A8, Canada. [Yeung, Rae] SickKids Res Inst, Cell Biol, Toronto, ON M5G 0A4, Canada. [Zhan, Xiaowei] Univ Texas Southwestern Med Ctr, Ctr Genet Host Def, Dallas, TX 75390 USA. [Greenberg, Jeff] NYU, Sch Med, Dept Med, New York, NY 10003 USA. [Kremer, Joel] Albany Med Coll, Div Rheumatol, Dept Med, Albany, NY 12206 USA. [Michaud, Kaleb] Univ Nebraska, Med Ctr, Dept Med, 600 S 42nd St, Omaha, NE 68198 USA. [Michaud, Kaleb] Natl Data Bank Rheumat Dis, Wichita, KS 67214 USA. [Barton, Anne] Univ Manchester, Manchester Acad Hlth Sci Ctr, Ctr Musculoskeletal Res, Arthrit Res UK Ctr Genet & Genom, Manchester M13 9PT, Lancs, England. [Barton, Anne] Cent Manchester Fdn Trust, NIHR Manchester Musculoskeletal Biomed Res Unit, Manchester M13 9WU, Lancs, England. [Coenen, Marieke] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 GA Nijmegen, Netherlands. [Mariette, Xavier; Miceli, Corinne] Univ Paris 11, Dept Rheumatol, F-91400 Orsay, France. [Mariette, Xavier; Miceli, Corinne] INSERM, Hop Bicetre, AP HP,U1184, Ctr Immunol Viral Infect & Autoimmune Dis IMVA, F-94276 Paris, France. [de Vries, Niek; Tak, Paul P.; Gerlag, Danielle] Univ Amsterdam, Acad Med Ctr, Dept Clin Immunol & Rheumatol, NL-1105 AZ Amsterdam, Netherlands. [Tak, Paul P.] Univ Cambridge, Dept Med, Cambridge CB2 1TN, England. [Tak, Paul P.] Univ Ghent, Dept Rheumatol, B-9000 Ghent, Belgium. [Tak, Paul P.] GlaxoSmithKline, Stevenage SG1 2NY, Herts, England. [Gerlag, Danielle] GlaxoSmithKline, Clin Unit, Cambridge CB2 0QQ, England. [Huizinga, Tom W. J.; Kurreeman, Fina; Allaart, Cornelia F.] Leiden Univ, Med Ctr, Dept Rheumatol, NL-2300 RC Leiden, Netherlands. [Bridges, S. Louis, Jr.] Univ Alabama Birmingham, Dept Med, Div Clin Immunol & Rheumatol, Birmingham, AL 35294 USA. [Criswell, Lindsey] Univ Calif San Francisco, Dept Med, Div Rheumatol, Rosalind Russell Ephraim P Engleman Rheumatol Res, San Francisco, CA 94143 USA. [Moreland, Larry] Univ Pittsburgh, Div Rheumatol & Clin Immunol, Pittsburgh, PA 15261 USA. [Klareskog, Lars; Saevarsdottir, Saedis; Padyukov, Leonid] Karolinska Hosp, Dept Med, Rheumatol Unit, S-17176 Stockholm, Sweden. [Klareskog, Lars; Saevarsdottir, Saedis; Padyukov, Leonid] Karolinska Inst, S-17176 Stockholm, Sweden. [Gregersen, Peter K.] North Shore LIJ Hlth Syst, Feinstein Inst Med Res, Robert S Boas Ctr Genom & Human Genet, Manhasset, NY 11030 USA. [Plenge, Robert] Merck & Co Inc, Merck Res Labs, Boston, MA 02115 USA. RP Mangravite, LM (reprint author), Sage Bionetworks, Seattle, WA 98109 USA. EM lara.magravite@sagebase.org RI Boeva, Valentina/C-2855-2017; Falcao, Andre/A-3545-2010; Oliva, Baldomero/A-2690-2009; Bunte, Kerstin/A-6733-2012; Khan, Suleiman/F-3472-2017; Coenen, Marieke/A-2159-2010; Tang, Jing/H-4084-2012; Kaski, Samuel/B-6684-2008; Planas-Iglesias, Joan/O-8614-2016; Aittokallio, Tero/B-6583-2009; Gasull, Martina/A-6630-2013; Bonet, Jaume/C-5551-2011; Guney, Emre/B-2568-2017; OI Boeva, Valentina/0000-0002-4382-7185; Falcao, Andre/0000-0002-3588-8746; Oliva, Baldomero/0000-0003-0702-0250; Khan, Suleiman/0000-0002-0823-4042; Tang, Jing/0000-0001-7480-7710; Kaski, Samuel/0000-0003-1925-9154; Planas-Iglesias, Joan/0000-0002-6279-2483; Aittokallio, Tero/0000-0002-0886-9769; Bonet, Jaume/0000-0001-5210-4387; Guney, Emre/0000-0002-3466-6535; Pandey, Gaurav/0000-0003-1939-679X; Pirinen, Matti/0000-0002-1664-1350; Padyukov, Leonid/0000-0003-2950-5670; Wennerberg, Krister/0000-0002-1352-4220 FU NIH [R01GM114434, R01GM105857]; IBM faculty award; Corrona, LLC; Agency for Healthcare Research and Quality [R01HS018517]; Genentech; Eli Lilly; Momenta Pharmaceuticals; Pfizer; National Institute of Health [JRC AR053351, JDG AR054 412] FX G.P. is partially supported by NIH grant# R01GM114434 and an IBM faculty award. E.S. is funded by NIH R01GM105857. The Corrona CERTAIN study is sponsored by Corrona, LLC with support from the Agency for Healthcare Research and Quality (R01HS018517). The majority of funding for the planning and implementation of CERTAIN was derived from Genentech, with additional support for substudies from Eli Lilly, Momenta Pharmaceuticals and Pfizer. CERTAIN investigators also receive support from the National Institute of Health (JRC AR053351, JDG AR054 412). NR 48 TC 1 Z9 1 U1 12 U2 15 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD AUG PY 2016 VL 7 AR 12460 DI 10.1038/ncomms12460 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DU1DF UT WOS:000381947700001 PM 27549343 ER PT J AU Gibson, WJ Hoivik, EA Halle, MK Taylor-Weiner, A Cherniack, AD Berg, A Holst, F Zack, TI Werner, HMJ Staby, KM Rosenberg, M Stefansson, IM Kusonmano, K Chevalier, A Mauland, KK Trovik, J Krakstad, C Giannakis, M Hodis, E Woie, K Bjorge, L Vintermyr, OK Wala, JA Lawrence, MS Getz, G Carter, SL Beroukhim, R Salvesen, HB AF Gibson, William J. Hoivik, Erling A. Halle, Mari K. Taylor-Weiner, Amaro Cherniack, Andrew D. Berg, Anna Holst, Frederik Zack, Travis I. Werner, Henrica M. J. Staby, Kjersti M. Rosenberg, Mara Stefansson, Ingunn M. Kusonmano, Kanthida Chevalier, Aaron Mauland, Karen K. Trovik, Jone Krakstad, Camilla Giannakis, Marios Hodis, Eran Woie, Kathrine Bjorge, Line Vintermyr, Olav K. Wala, Jeremiah A. Lawrence, Michael S. Getz, Gad Carter, Scott L. Beroukhim, Rameen Salvesen, Helga B. TI The genomic landscape and evolution of endometrial carcinoma progression and abdominopelvic metastasis SO NATURE GENETICS LA English DT Article ID ESTROGEN-RECEPTOR; BREAST-CANCER; PANCREATIC-CANCER; MUTATIONS; HYPERPLASIA; THERAPY; REVEALS; ARID1A; ADENOCARCINOMA; INSTABILITY AB Recent studies have detailed the genomic landscape of primary endometrial cancers, but the evolution of these cancers into metastases has not been characterized. We performed whole-exome sequencing of 98 tumor biopsies including complex atypical hyperplasias, primary tumors and paired abdominopelvic metastases to survey the evolutionary landscape of endometrial cancer. We expanded and reanalyzed The Cancer Genome Atlas ( TCGA) data, identifying new recurrent alterations in primary tumors, including mutations in the estrogen receptor cofactor gene NRIP1 in 12% of patients. We found that likely driver events were present in both primary and metastatic tissue samples, with notable exceptions such as ARID1A mutations. Phylogenetic analyses indicated that the sampled metastases typically arose from a common ancestral subclone that was not detected in the primary tumor biopsy. These data demonstrate extensive genetic heterogeneity in endometrial cancers and relative homogeneity across metastatic sites. C1 [Gibson, William J.; Taylor-Weiner, Amaro; Cherniack, Andrew D.; Holst, Frederik; Zack, Travis I.; Rosenberg, Mara; Chevalier, Aaron; Giannakis, Marios; Hodis, Eran; Wala, Jeremiah A.; Lawrence, Michael S.; Getz, Gad; Carter, Scott L.; Beroukhim, Rameen] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. [Gibson, William J.; Holst, Frederik; Zack, Travis I.; Wala, Jeremiah A.; Beroukhim, Rameen] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Gibson, William J.; Zack, Travis I.; Giannakis, Marios; Hodis, Eran; Wala, Jeremiah A.; Beroukhim, Rameen] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Gibson, William J.; Zack, Travis I.; Hodis, Eran; Wala, Jeremiah A.; Beroukhim, Rameen] Harvard Med Sch, Harvard MIT Div Hlth Sci & Technol, Boston, MA 02115 USA. [Hoivik, Erling A.; Halle, Mari K.; Berg, Anna; Holst, Frederik; Werner, Henrica M. J.; Mauland, Karen K.; Trovik, Jone; Woie, Kathrine; Bjorge, Line; Salvesen, Helga B.] Univ Bergen, Dept Clin Sci, Ctr Canc Biomarkers, Bergen, Norway. [Hoivik, Erling A.; Halle, Mari K.; Berg, Anna; Holst, Frederik; Werner, Henrica M. J.; Kusonmano, Kanthida; Mauland, Karen K.; Trovik, Jone; Krakstad, Camilla; Bjorge, Line; Salvesen, Helga B.] Haukeland Hosp, Dept Gynecol & Obstet, Bergen, Norway. [Staby, Kjersti M.; Stefansson, Ingunn M.; Vintermyr, Olav K.] Haukeland Hosp, Dept Pathol, Bergen, Norway. [Stefansson, Ingunn M.; Vintermyr, Olav K.] Univ Bergen, Dept Clin Med, Bergen, Norway. [Kusonmano, Kanthida] Univ Bergen, Computat Biol Unit, Bergen, Norway. [Krakstad, Camilla] Univ Bergen, Dept Biomed, Bergen, Norway. [Carter, Scott L.] Brigham & Womens Hosp, Broad Inst, Dana Farber Canc Inst, Joint Ctr Canc Precis Med, 75 Francis St, Boston, MA 02115 USA. [Carter, Scott L.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Carter, Scott L.] Harvard TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Kusonmano, Kanthida] King Mongkuts Univ Technol, Bioinformat & Syst Biol Program, Computat Biol Unit, Sch Bioresources & Technol, Bangkok, Thailand. RP Carter, SL; Beroukhim, R (reprint author), Broad Inst Harvard & MIT, Cambridge, MA 02142 USA.; Beroukhim, R (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA.; Beroukhim, R (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA.; Beroukhim, R (reprint author), Harvard Med Sch, Harvard MIT Div Hlth Sci & Technol, Boston, MA 02115 USA.; Hoivik, EA (reprint author), Univ Bergen, Dept Clin Sci, Ctr Canc Biomarkers, Bergen, Norway.; Hoivik, EA (reprint author), Haukeland Hosp, Dept Gynecol & Obstet, Bergen, Norway.; Carter, SL (reprint author), Brigham & Womens Hosp, Broad Inst, Dana Farber Canc Inst, Joint Ctr Canc Precis Med, 75 Francis St, Boston, MA 02115 USA.; Carter, SL (reprint author), Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA.; Carter, SL (reprint author), Harvard TH Chan Sch Publ Hlth, Boston, MA 02115 USA. EM erling.hoivik@uib.no; scarter@broadinstitute.org; rameen_beroukhim@dfci.harvard.edu RI Bjorge, Line/C-1307-2017; salvesen, Helga/C-1187-2017; OI Bjorge, Line/0000-0002-0240-2770; salvesen, Helga/0000-0002-4438-8831; Holst, Frederik/0000-0002-5928-2175; Krakstad, Camilla/0000-0002-0174-8139 FU Research Council of Norway; Norwegian Cancer Society, Helse Vest; University of Bergen; Bergen Research Foundation; National Institutes of Health [T32GM007753, 5R01CA188228, 1F30CA192725]; Novartis Institutes for Biomedical Research FX We thank E. Valen, B. Edvardsen, K. Madissoo, R. Kopperud and B. Nordanger for excellent technical assistance. This study was supported by the Research Council of Norway, the Norwegian Cancer Society, Helse Vest, the University of Bergen, the Bergen Research Foundation, the National Institutes of Health (award numbers T32GM007753, 5R01CA188228 and 1F30CA192725) and the Novartis Institutes for Biomedical Research. NR 53 TC 6 Z9 6 U1 3 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD AUG PY 2016 VL 48 IS 8 BP 848 EP + DI 10.1038/ng.3602 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA DS4ML UT WOS:000380755100007 PM 27348297 ER PT J AU Gormley, P Anttila, V Winsvold, BS Palta, P Esko, T Pers, TH Farh, KH Cuenca-Leon, E Muona, M Furlotte, NA Kurth, T Ingason, A McMahon, G Ligthart, L Terwindt, GM Kallela, M Freilinger, TM Ran, C Gordon, SG Stam, AH Steinberg, S Borck, G Koiranen, M Quaye, L Adams, HHH Lehtimaki, T Sarin, AP Wedenoja, J Hinds, DA Buring, JE Schurks, M Ridker, PM Hrafnsdottir, MG Stefansson, H Ring, SM Hottenga, JJ Penninx, BWJH Farkkila, M Artto, V Kaunisto, M Vepsalainen, S Malik, R Heath, AC Madden, PAF Martin, NG Montgomery, GW Kurki, MI Kals, M Magi, R Parn, K Hamalainen, E Huang, HL Byrnes, AE Franke, L Huang, J Stergiakouli, E Lee, PH Sandor, C Webber, C Cader, Z Muller-Myhsok, B Schreiber, S Meitinger, T Eriksson, JG Salomaa, V Heikkila, K Loehrer, E Uitterlinden, AG Hofman, A van Duijn, CM Cherkas, L Pedersen, LM Stubhaug, A Nielsen, CS Mannikko, M Mihailov, E Milani, L Gobel, H Esserlind, AL Christensen, AF Hansen, TF Werge, T Kaprio, J Aromaa, AJ Raitakari, O Ikram, MA Spector, T Jarvelin, MR Metspalu, A Kubisch, C Strachan, DP Ferrari, MD Belin, AC Dichgans, M Wessman, M van den Maagdenberg, AMJM Zwart, JA Boomsma, DI Smith, GD Stefansson, K Eriksson, N Daly, MJ Neale, BM Olesen, J Chasman, DI Nyholt, DR Palotie, A AF Gormley, Padhraig Anttila, Verneri Winsvold, Bendik S. Palta, Priit Esko, Tonu Pers, Tune H. Farh, Kai-How Cuenca-Leon, Ester Muona, Mikko Furlotte, Nicholas A. Kurth, Tobias Ingason, Andres McMahon, George Ligthart, Lannie Terwindt, Gisela M. Kallela, Mikko Freilinger, Tobias M. Ran, Caroline Gordon, Scott G. Stam, Anine H. Steinberg, Stacy Borck, Guntram Koiranen, Markku Quaye, Lydia Adams, Hieab H. H. Lehtimaki, Terho Sarin, Antti-Pekka Wedenoja, Juho Hinds, David A. Buring, Julie E. Schurks, Markus Ridker, Paul M. Hrafnsdottir, Maria Gudlaug Stefansson, Hreinn Ring, Susan M. Hottenga, Jouke-Jan Penninx, Brenda W. J. H. Farkkila, Markus Artto, Ville Kaunisto, Mari Vepsalainen, Salli Malik, Rainer Heath, Andrew C. Madden, Pamela A. F. Martin, Nicholas G. Montgomery, Grant W. Kurki, Mitja I. Kals, Mart Magi, Reedik Parn, Kalle Hamalainen, Eija Huang, Hailiang Byrnes, Andrea E. Franke, Lude Huang, Jie Stergiakouli, Evie Lee, Phil H. Sandor, Cynthia Webber, Caleb Cader, Zameel Muller-Myhsok, Bertram Schreiber, Stefan Meitinger, Thomas Eriksson, Johan G. Salomaa, Veikko Heikkila, Kauko Loehrer, Elizabeth Uitterlinden, Andre G. Hofman, Albert van Duijn, Cornelia M. Cherkas, Lynn Pedersen, Linda M. Stubhaug, Audun Nielsen, Christopher S. Mannikko, Minna Mihailov, Evelin Milani, Lili Gobel, Hartmut Esserlind, Ann-Louise Christensen, Anne Francke Hansen, Thomas Folkmann Werge, Thomas Kaprio, Jaakko Aromaa, Arpo J. Raitakari, Olli Ikram, M. Arfan Spector, Tim Jarvelin, Marjo-Riitta Metspalu, Andres Kubisch, Christian Strachan, David P. Ferrari, Michel D. Belin, Andrea C. Dichgans, Martin Wessman, Maija van den Maagdenberg, Arn M. J. M. Zwart, John-Anker Boomsma, Dorret I. Smith, George Davey Stefansson, Kari Eriksson, Nicholas Daly, Mark J. Neale, Benjamin M. Olesen, Jes Chasman, Daniel I. Nyholt, Dale R. Palotie, Aarno CA Int Headache Genetics Consortium TI Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; FAMILIAL HEMIPLEGIC MIGRAINE; SINGLE-NUCLEOTIDE POLYMORPHISMS; RECEPTOR-RELATED PROTEIN-1; SMOOTH-MUSCLE-CELLS; GENE-EXPRESSION; MYOCARDIAL-INFARCTION; SPREADING DEPRESSION; GENOTYPE IMPUTATION; SYSTEMATIC ANALYSIS AB Migraine is a debilitating neurological disorder affecting around one in seven people worldwide, but its molecular mechanisms remain poorly understood. There is some debate about whether migraine is a disease of vascular dysfunction or a result of neuronal dysfunction with secondary vascular changes. Genome-wide association ( GWA) studies have thus far identified 13 independent loci associated with migraine. To identify new susceptibility loci, we carried out a genetic study of migraine on 59,674 affected subjects and 316,078 controls from 22 GWA studies. We identified 44 independent single-nucleotide polymorphisms ( SNPs) significantly associated with migraine risk ( P < 5 x 10(-8)) that mapped to 38 distinct genomic loci, including 28 loci not previously reported and a locus that to our knowledge is the first to be identified on chromosome X. In subsequent computational analyses, the identified loci showed enrichment for genes expressed in vascular and smooth muscle tissues, consistent with a predominant theory of migraine that highlights vascular etiologies. C1 [Gormley, Padhraig; Cuenca-Leon, Ester; Kurki, Mitja I.; Lee, Phil H.; Palotie, Aarno] Massachusetts Gen Hosp, Psychiat & Neurodevelopmental Genet Unit, Boston, MA 02114 USA. [Gormley, Padhraig; Anttila, Verneri; Farh, Kai-How; Cuenca-Leon, Ester; Kurki, Mitja I.; Huang, Hailiang; Byrnes, Andrea E.; Lee, Phil H.; Daly, Mark J.; Neale, Benjamin M.; Palotie, Aarno] Harvard Univ, Sch Med, Boston, MA 02138 USA. [Gormley, Padhraig; Anttila, Verneri; Esko, Tonu; Pers, Tune H.; Farh, Kai-How; Cuenca-Leon, Ester; Kurki, Mitja I.; Huang, Hailiang; Byrnes, Andrea E.; Lee, Phil H.; Daly, Mark J.; Neale, Benjamin M.; Palotie, Aarno] Broad Inst MIT & Harvard, Med & Populat Genet Program, Cambridge, MA 02139 USA. [Gormley, Padhraig; Anttila, Verneri; Cuenca-Leon, Ester; Kurki, Mitja I.; Huang, Hailiang; Byrnes, Andrea E.; Lee, Phil H.; Daly, Mark J.; Neale, Benjamin M.; Palotie, Aarno] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02139 USA. [Gormley, Padhraig; Huang, Jie; Palotie, Aarno] Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Hinxton, Cambs, England. [Anttila, Verneri; Farh, Kai-How; Huang, Hailiang; Byrnes, Andrea E.; Daly, Mark J.; Neale, Benjamin M.; Palotie, Aarno] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Winsvold, Bendik S.; Pedersen, Linda M.; Zwart, John-Anker] Oslo Univ Hosp, FORMI, Oslo, Norway. [Winsvold, Bendik S.; Zwart, John-Anker] Oslo Univ Hosp, Dept Neurol, Oslo, Norway. [Winsvold, Bendik S.; Zwart, John-Anker] Univ Oslo, Inst Clin Med, Oslo, Norway. [Palta, Priit; Muona, Mikko; Sarin, Antti-Pekka; Kaunisto, Mari; Kurki, Mitja I.; Hamalainen, Eija; Kaprio, Jaakko; Wessman, Maija; Palotie, Aarno] Univ Helsinki, FIMM, Helsinki, Finland. [Esko, Tonu; Kals, Mart; Magi, Reedik; Parn, Kalle; Mihailov, Evelin; Milani, Lili; Metspalu, Andres] Univ Tartu, Estonian Genome Ctr, Tartu, Estonia. [Esko, Tonu; Pers, Tune H.] Boston Childrens Hosp, Div Endocrinol, Boston, MA USA. [Pers, Tune H.] Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark. [Pers, Tune H.] Univ Copenhagen, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark. [Farh, Kai-How] Illumina, San Diego, CA USA. [Cuenca-Leon, Ester] Vall dHebron Res Inst, Pediat Neurol, Barcelona, Spain. [Muona, Mikko; Wessman, Maija] Folkhalsan Inst Genet, Helsinki, Finland. [Muona, Mikko] Univ Helsinki, Ctr Neurosci, Helsinki, Finland. [Muona, Mikko] Univ Helsinki, Res Programs Unit, Mol Neurol Res Program, Helsinki, Finland. [Furlotte, Nicholas A.; Hinds, David A.; Eriksson, Nicholas] 23andMe Inc, Mountain View, CA USA. [Kurth, Tobias] Charite, Inst Publ Hlth, D-13353 Berlin, Germany. [Kurth, Tobias; Buring, Julie E.; Ridker, Paul M.; Chasman, Daniel I.] Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA. [Ingason, Andres; Steinberg, Stacy; Stefansson, Hreinn; Stefansson, Kari] deCODE Genet, Reykjavik, Iceland. [McMahon, George; Ring, Susan M.; Stergiakouli, Evie; Smith, George Davey] Univ Bristol, MRC Integrat Epidemiol Unit, Bristol, Avon, England. [Ligthart, Lannie; Hottenga, Jouke-Jan; Boomsma, Dorret I.] Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands. [Terwindt, Gisela M.; Stam, Anine H.; Ferrari, Michel D.; van den Maagdenberg, Arn M. J. M.] Leiden Univ, Med Ctr, Dept Neurol, Leiden, Netherlands. [Kallela, Mikko; Farkkila, Markus; Artto, Ville; Vepsalainen, Salli] Univ Helsinki, Cent Hosp, Dept Neurol, Helsinki, Finland. [Freilinger, Tobias M.] Univ Tubingen, Hertie Inst Clin Brain Res, Dept Neurol & Epileptol, Tubingen, Germany. [Freilinger, Tobias M.; Malik, Rainer; Dichgans, Martin] Univ Munich, Klinikum Univ Munchen, Inst Stroke & Dementia Res, Munich, Germany. [Ran, Caroline; Belin, Andrea C.] Karolinska Inst, Dept Neurosci, Stockholm, Sweden. [Gordon, Scott G.; Martin, Nicholas G.; Montgomery, Grant W.] QIMR Berghofer Med Res Inst, Dept Genet & Computat Biol, Brisbane, Qld, Australia. [Borck, Guntram] Univ Ulm, Inst Human Genet, D-89069 Ulm, Germany. [Koiranen, Markku; Mannikko, Minna; Jarvelin, Marjo-Riitta] Univ Oulu, Ctr Life Course Epidemiol & Syst Med, Oulu, Finland. [Quaye, Lydia; Cherkas, Lynn; Spector, Tim] Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England. [Loehrer, Elizabeth; Hofman, Albert; van Duijn, Cornelia M.; Ikram, M. Arfan] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [Ikram, M. Arfan] Erasmus Univ, Med Ctr, Dept Radiol, Rotterdam, Netherlands. Univ Tampere, Sch Med, Fimlab Labs, Dept Clin Chem, Tampere, Finland. [Wedenoja, Juho; Kaprio, Jaakko] Univ Helsinki, Dept Publ Hlth, Helsinki, Finland. [Buring, Julie E.; Ridker, Paul M.; Chasman, Daniel I.] Harvard Med Sch, Boston, MA USA. [Schurks, Markus] Univ Duisburg Essen, Dept Neurol, Essen, Germany. [Hrafnsdottir, Maria Gudlaug] Landspitali Univ Hosp, Reykjavik, Iceland. [Penninx, Brenda W. J. H.] Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, Amsterdam, Netherlands. [Heath, Andrew C.; Madden, Pamela A. F.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. [Kurki, Mitja I.] Kuopio Univ Hosp, Dept Neurosurg, SF-70210 Kuopio, Finland. [Franke, Lude] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands. [Sandor, Cynthia; Webber, Caleb] Univ Oxford, Dept Physiol Anat & Genet, MRC Funct Genom Unit, Oxford, England. [Cader, Zameel] Univ Oxford, Nuffield Dept Clin Neurosci, Oxford, England. [Cader, Zameel] John Radcliffe Hosp, Oxford Headache Ctr, Oxford, England. [Muller-Myhsok, Bertram] Max Planck Inst Psychiat, Munich, Germany. [Schreiber, Stefan] Univ Kiel, Inst Clin Mol Biol, Kiel, Germany. [Meitinger, Thomas] Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany. [Meitinger, Thomas] Tech Univ Munich, Inst Human Genet, D-80290 Munich, Germany. [Eriksson, Johan G.] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland. [Eriksson, Johan G.] Helsinki Univ Hosp, Helsinki, Finland. [Eriksson, Johan G.; Salomaa, Veikko; Aromaa, Arpo J.] Natl Inst Hlth & Welf, Helsinki, Finland. [Heikkila, Kauko] Univ Helsinki, Inst Clin Med, Helsinki, Finland. [Loehrer, Elizabeth] Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA. [Uitterlinden, Andre G.] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands. [Stubhaug, Audun; Nielsen, Christopher S.] Oslo Univ Hosp, Dept Pain Management & Res, Oslo, Norway. [Stubhaug, Audun] Univ Oslo, Fac Med, Oslo, Norway. [Nielsen, Christopher S.] Norwegian Inst Publ Hlth, Dept Ageing & Hlth, Oslo, Norway. [Gobel, Hartmut] Kiel Pain & Headache Ctr, Kiel, Germany. [Esserlind, Ann-Louise; Christensen, Anne Francke; Olesen, Jes] Univ Copenhagen, Glostrup Hosp, Rigshosp, Dept Neurol,Danish Headache Ctr, Copenhagen, Denmark. [Hansen, Thomas Folkmann] Univ Copenhagen, Mental Hlth Ctr Sct Hans, Inst Biol Psychiat, Roskilde, Denmark. [Werge, Thomas] Mental Hlth Serv Copenhagen, MHC Sct Hans, Inst Biol Psychiat, Copenhagen, Denmark. [Werge, Thomas] Univ Copenhagen, Fac Med & Hlth Sci, Inst Clin Sci, Copenhagen, Denmark. [Werge, Thomas] iPSYCH, Copenhagen, Denmark. [Kaprio, Jaakko] Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland. [Raitakari, Olli] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland. [Raitakari, Olli] Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku, Finland. [Ikram, M. Arfan] Erasmus Univ, Med Ctr, Dept Neurol, Rotterdam, Netherlands. [Jarvelin, Marjo-Riitta] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, MRC Hlth Protect Agcy HPE Ctr Environm & Hlth, Dept Epidemiol & Biostat, London, England. [Jarvelin, Marjo-Riitta] Univ Oulu, Bioctr Oulu, Oulu, Finland. [Jarvelin, Marjo-Riitta] Oulu Univ Hosp, Unit Primary Care, Oulu, Finland. [Kubisch, Christian] Univ Med Ctr Hamburg Eppendorf, Inst Human Genet, Hamburg, Germany. [Strachan, David P.] St Georges Univ London, Populat Hlth Res Inst, London, England. [Muller-Myhsok, Bertram; Dichgans, Martin] Munich Cluster Syst Neurol SyNergy, Munich, Germany. [van den Maagdenberg, Arn M. J. M.] Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands. [Stefansson, Kari] Univ Iceland, Fac Med, Reykjavik, Iceland. [Nyholt, Dale R.] Queensland Univ Technol, Inst Hlth & Biomed Innovat, Stat & Genom Epidemiol Lab, Kelvin Grove, Qld, Australia. [Palotie, Aarno] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Palotie, A (reprint author), Massachusetts Gen Hosp, Psychiat & Neurodevelopmental Genet Unit, Boston, MA 02114 USA.; Palotie, A (reprint author), Harvard Univ, Sch Med, Boston, MA 02138 USA.; Palotie, A (reprint author), Broad Inst MIT & Harvard, Med & Populat Genet Program, Cambridge, MA 02139 USA.; Palotie, A (reprint author), Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02139 USA.; Palotie, A (reprint author), Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Hinxton, Cambs, England.; Palotie, A (reprint author), Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA.; Palotie, A (reprint author), Univ Helsinki, FIMM, Helsinki, Finland.; Palotie, A (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RI Kubisch, Christian/F-1893-2011; Kurth, Tobias/A-9243-2012; Franke, Lude/P-7036-2016; Davey Smith, George/A-7407-2013; OI Kaprio, Jaakko/0000-0002-3716-2455; vila-pueyo, marta/0000-0003-0652-2988; Palta, Priit/0000-0001-9320-7008; Pozo-Rosich, Patricia/0000-0003-0796-4702; Winsvold, Bendik Slagsvold/0000-0003-4171-8919; Kubisch, Christian/0000-0003-4220-0978; Kurth, Tobias/0000-0001-7169-2620; Franke, Lude/0000-0002-5159-8802; Davey Smith, George/0000-0002-1407-8314; Esko, Tonu/0000-0003-1982-6569; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Stergiakouli, Evangelia/0000-0003-3586-0927; Muona, Mikko/0000-0002-0949-6650; Olesen, Jes/0000-0002-6712-2702; Wedenoja, Juho/0000-0002-6155-0378; Kaunisto, Mari/0000-0002-6946-9195; Cormand, Bru/0000-0001-5318-4382 FU GTEx Consortium FX We thank the numerous individuals who contributed to sample collection, storage, handling, phenotyping, and genotyping for each of the individual cohorts. We also acknowledge the important contribution to research made by the study participants. We are grateful to H. Zhao (QIMR Berghofer Medical Research Institute) for helpful correspondence on the pathway analyses. We acknowledge the GTEx Consortium for support and contribution of pilot data. A list of study-specific acknowledgments and funding information can be found in the Supplementary Note. NR 91 TC 16 Z9 16 U1 9 U2 18 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD AUG PY 2016 VL 48 IS 8 BP 856 EP + DI 10.1038/ng.3598 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA DS4ML UT WOS:000380755100008 PM 27322543 ER PT J AU Abu Samra, K Maghsoudlou, A Roohipoor, R Valdes-Navarro, M Lee, S Foster, CS AF Abu Samra, Khawla Maghsoudlou, Armin Roohipoor, Ramak Valdes-Navarro, Manuel Lee, Stacey Foster, C. Stephen TI Current Treatment Modalities of JIA-associated Uveitis and its Complications: Literature Review SO OCULAR IMMUNOLOGY AND INFLAMMATION LA English DT Review DE Chronic JIA-associated uveitis; complication; corticosteroid; review; treatment ID JUVENILE IDIOPATHIC ARTHRITIS; CYSTOID MACULAR EDEMA; INTRAOCULAR-LENS IMPLANTATION; OPTICAL COHERENCE TOMOGRAPHY; CHRONIC CHILDHOOD UVEITIS; RHEUMATOID-ARTHRITIS; PHOTOTHERAPEUTIC KERATECTOMY; OCULAR COMPLICATIONS; SECONDARY GLAUCOMA; PEDIATRIC UVEITIS AB Uveitis is a common and serious complication of juvenile idiopathic arthritis. Up to 75% of all cases of anterior uveitis in childhood are associated with juvenile idiopathic arthritis. Despite the remarkable progress in early detection and treatment of inflammation, vision-threatening complications of uveitis still occur in almost 60% of patients. Structural complications include band keratopathy, maculopathy (macular edema, macular cysts, and epiretinal membrane), glaucomatous optic neuropathy, and cataracts. The management of complications in juvenile idiopathic arthritis is usually complex and requires early surgical intervention. In this paper, we review the general concepts of common ocular complications seen in patients with JIA-associated uveitis, with special attention to the recent diagnostic and preferred treatment approaches at the Massachusetts Eye Research and Surgery Institution. C1 [Abu Samra, Khawla; Maghsoudlou, Armin; Roohipoor, Ramak; Valdes-Navarro, Manuel; Lee, Stacey; Foster, C. Stephen] MERSI, Waltham, MA USA. [Abu Samra, Khawla; Maghsoudlou, Armin; Roohipoor, Ramak; Valdes-Navarro, Manuel; Lee, Stacey; Foster, C. Stephen] OIUF, Waltham, MA USA. [Maghsoudlou, Armin] Univ Penn, Sch Med, Scheie Eye Inst, Dept Ophthalmol, Philadelphia, PA 19104 USA. [Maghsoudlou, Armin; Foster, C. Stephen] Harvard Med Sch, Cambridge, MA USA. [Roohipoor, Ramak] Farabi Eye Hosp, Dept Ophthalmol, Tehran, Iran. [Roohipoor, Ramak] Univ Tehran Med Sci, Eye Res Ctr, Tehran, Iran. [Roohipoor, Ramak; Foster, C. Stephen] Massachusetts Eye & Ear Infirm, Cambridge, MA USA. RP Foster, CS (reprint author), Harvard Med Sch, Ocular Immunol & Uveitis Fdn, MERSI, 1440 Main St,Suite 201, Waltham, MA 02451 USA. EM sfoster@mersi.com FU Alcon (Aliso Viejo, CA); Aldeyra Therapeutics (Lexington, MA); Bausch & Lomb (Bridgewater, NJ); Clearside Biomedical (Alpharetta, GA); Dompe pharmaceutical (Milan, Italy); Eyegate Pharma (Waltham, MA); Mallinckrodt pharmaceuticals (Dublin, Ireland); Novartis Pharmaceuticals (Cambridge, MA); pSivida (Watertown, MA); Santen (Osaka, Japan); Allergan (Dublin, Ireland) FX Dr. C. Stephen Foster declares the following: Consultancies with Aldeyra Therapeutics (Lexington, MA), Bausch & Lomb Surgical, Inc (Rancho Cucamonga, CA), Eyegate Pharma (Waltham, MA), Novartis (Cambridge, MA), pSivida (Watertown, MA), and Xoma (Berkeley, CA). Grants or grants pending with Alcon (Aliso Viejo, CA), Aldeyra Therapeutics (Lexington, MA), Bausch & Lomb (Bridgewater, NJ), Clearside Biomedical (Alpharetta, GA), Dompe pharmaceutical (Milan, Italy), Eyegate Pharma (Waltham, MA), Mallinckrodt pharmaceuticals (Dublin, Ireland), Novartis Pharmaceuticals (Cambridge, MA), pSivida (Watertown, MA), Santen (Osaka, Japan). Payment for lectures including service on speaking bureaus: Alcon (Aliso Viejo, CA), Allergan (Dublin, Ireland) Stock or Stock Options: Eyegate Pharma (Waltham, MA). All other authors certify they have nothing to declare. NR 97 TC 0 Z9 0 U1 2 U2 3 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0927-3948 EI 1744-5078 J9 OCUL IMMUNOL INFLAMM JI Ocul. Immunol. Inflamm. PD AUG PY 2016 VL 24 IS 4 BP 431 EP 439 DI 10.3109/09273948.2015.1115878 PG 9 WC Ophthalmology SC Ophthalmology GA DU1HN UT WOS:000381958900011 PM 26765345 ER PT J AU Yonekawa, Y Wu, WC Kusaka, S Robinson, J Tsujioka, D Kang, KB Shapiro, MJ Padhi, TR Jain, L Sears, JE Kuriyan, AE Berrocal, AM Quiram, PA Gerber, AE Chan, RVP Jonas, KE Wong, SC Patel, CK Abbey, AM Spencer, R Blair, MP Chang, EY Papakostas, TD Vavvas, DG Sisk, RA Ferrone, PJ Henderson, RH Olsen, KR Hartnett, ME Chau, FY Mukai, S Murray, TG Thomas, BJ Meza, PA Drenser, KA Trese, MT Capone, A AF Yonekawa, Yoshihiro Wu, Wei-Chi Kusaka, Shunji Robinson, Joshua Tsujioka, Daishi Kang, Kai B. Shapiro, Michael J. Padhi, Tapas R. Jain, Lubhani Sears, Jonathan E. Kuriyan, Ajay E. Berrocal, Audina M. Quiram, Polly A. Gerber, Amanda E. Chan, R. V. Paul Jonas, Karyn E. Wong, Sui Chien Patel, C. K. Abbey, Ashkan M. Spencer, Rand Blair, Michael P. Chang, Emmanuel Y. Papakostas, Thanos D. Vavvas, Demetrios G. Sisk, Robert A. Ferrone, Philip J. Henderson, Robert H. Olsen, Karl R. Hartnett, M. Elizabeth Chau, Felix Y. Mukai, Shizuo Murray, Timothy G. Thomas, Benjamin J. Meza, P. Anthony Drenser, Kimberly A. Trese, Michael T. Capone, Antonio, Jr. TI Immediate Sequential Bilateral Pediatric Vitreoretinal Surgery An International Multicenter Study SO OPHTHALMOLOGY LA English DT Article; Proceedings Paper CT Club-Jules-Goning Meeting CY 2016 CL Bordeaux, FRANCE SP Club Jules Gonin ID CATARACT-SURGERY; FUNCTIONAL BLINDNESS; PRETERM INFANTS; ENDOPHTHALMITIS; PREMATURITY; RETINOPATHY; ANESTHESIA; VITRECTOMY; MORTALITY; RISK AB Purpose: To determine the feasibility and safety of bilateral simultaneous vitreoretinal surgery in pediatric patients. Design: International, multicenter, interventional, retrospective case series. Participants: Patients 17 years of age or younger from 24 centers worldwide who underwent immediate sequential bilateral vitreoretinal surgery (ISBVS)-defined as vitrectomy, scleral buckle, or lensectomy using the vitreous cutter-performed in both eyes sequentially during the same anesthesia session. Methods: Clinical history, surgical details and indications, time under anesthesia, and intraoperative and postoperative ophthalmic and systemic adverse events were reviewed. Main Outcome Measures: Ocular and systemic adverse events. Results: A total of 344 surgeries from 172 ISBVS procedures in 167 patients were included in the study. The mean age of the cohort was 1.3 +/- 2.6 years. Nonexclusive indications for ISBVS were rapidly progressive disease (74.6%), systemic morbidity placing the child at high anesthesia risk (76.0%), and residence remote from surgery location (30.2%). The most common diagnoses were retinopathy of prematurity (ROP; 72.7% [P < 0.01]; stage 3, 4.8%; stage 4A, 44.4%; stage 4B, 22.4%; stage 5, 26.4%), familial exudative vitreoretinopathy (7.0%), abusive head trauma (4.1%), persistent fetal vasculature (3.5%), congenital cataract (1.7%), posterior capsular opacification (1.7%), rhegmatogenous retinal detachment (1.7%), congenital X-linked retinoschisis (1.2%), Norrie disease (2.3%), and viral retinitis (1.2%). Mean surgical time was 143 +/- 59 minutes for both eyes. Higher ROP stage correlated with longer surgical time (P = 0.02). There were no reported intraoperative ocular complications. During the immediate postoperative period, 2 eyes from different patients demonstrated unilateral vitreous hemorrhage (0.6%). No cases of endophthalmitis, choroidal hemorrhage, or hypotony occurred. Mean total anesthesia time was 203 +/- 87 minutes. There were no cases of anesthesia-related death, malignant hyperthermia, anaphylaxis, or cardiac event. There was 1 case of reintubation (0.6%) and 1 case of prolonged oxygen desaturation (0.6%). Mean follow-up after surgery was 103 weeks, and anatomic success and globe salvage rates were 89.8% and 98.0%, respectively. Conclusions: This study found ISBVS to be a feasible and safe treatment paradigm for pediatric patients with bilateral vitreoretinal pathologic features when repeated general anesthesia is undesirable or impractical. (C) 2016 by the American Academy of Ophthalmology. C1 [Yonekawa, Yoshihiro; Thomas, Benjamin J.; Drenser, Kimberly A.; Trese, Michael T.; Capone, Antonio, Jr.] Oakland Univ, William Beaumont Sch Med, Associated Retinal Consultants, Royal Oak, MI USA. [Yonekawa, Yoshihiro; Papakostas, Thanos D.; Vavvas, Demetrios G.; Mukai, Shizuo] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Boston, MA USA. [Yonekawa, Yoshihiro; Vavvas, Demetrios G.; Mukai, Shizuo] Harvard Univ, Sch Med, Boston Childrens Hosp, Boston, MA USA. [Wu, Wei-Chi] Chang Gung Univ, Coll Med, Chang Gung Mem Hosp, Taipei, Taiwan. [Kusaka, Shunji; Tsujioka, Daishi] Kindai Univ, Fac Med, Sakai Hosp, Osaka, Japan. [Robinson, Joshua] Emory Eye Ctr, Emory Sch Med, Atlanta, GA USA. [Kang, Kai B.; Shapiro, Michael J.; Chan, R. V. Paul; Jonas, Karyn E.; Blair, Michael P.; Chau, Felix Y.] Univ Illinois, Coll Med, Illinois Eye & Ear Infirm, Chicago, IL USA. [Shapiro, Michael J.; Blair, Michael P.] Retinal Consultants, Des Plaines, IL USA. [Padhi, Tapas R.; Jain, Lubhani] LV Prasad Eye Inst, Bhubaneswar, Orissa, India. [Sears, Jonathan E.] Cleveland Clin Lerner, Coll Med, Cole Eye Inst, Cleveland, OH USA. [Kuriyan, Ajay E.; Berrocal, Audina M.] Miami Univ, Miller Sch Med, Bascom Palmer Eye Inst, Miami, FL USA. [Quiram, Polly A.; Gerber, Amanda E.] VitreoRetinal Surg, Minneapolis, MN USA. [Chan, R. V. Paul; Jonas, Karyn E.] Weill Cornell Med Coll, Dept Ophthalmol, New York, NY USA. [Wong, Sui Chien; Patel, C. K.; Henderson, Robert H.] Great Ormond St Hosp Sick Children, Dept Ophthalmol, London, England. [Wong, Sui Chien; Henderson, Robert H.] Moorfields Eye Hosp, Dept Vitreoretinal Surg, City Rd, London, England. [Patel, C. K.] John Radcliffe Hosp, Oxford Eye Hosp, Paediat Vitreoretinal Serv, Oxford OX3 9DU, England. [Abbey, Ashkan M.] Texas Retina Associates, Dallas, TX USA. [Abbey, Ashkan M.; Spencer, Rand] Univ Texas SW Med Ctr Dallas, Dept Ophthalmol, Dallas, TX 75390 USA. [Chang, Emmanuel Y.] Retina & Vitreous Texas, Houston, TX USA. [Sisk, Robert A.] Univ Cincinnati, Coll Med, Cincinnati Eye Inst, Cincinnati, OH USA. [Ferrone, Philip J.] North Shore Long Isl Jewish Med Ctr, Long Isl Vitreoretinal Consultants, New York, NY USA. [Olsen, Karl R.] Univ Pittsburg, Sch Med, Retina Vitreous Consultants, Pittsburgh, PA USA. [Hartnett, M. Elizabeth] Univ Utah, Sch Med, John A Moran Eye Ctr, Salt Lake City, UT USA. [Murray, Timothy G.] Murray Ocular Oncol & Retina, Miami, FL USA. [Thomas, Benjamin J.] Florida Retina Inst, Jacksonville, FL USA. [Meza, P. Anthony] Oakland Univ, William Beaumont Sch Med, Pediat Anesthesiol, Royal Oak, MI USA. [Capone, Antonio, Jr.] Oakland Univ, Associated Retinal Consultants, 3535 West Thirteen Mile, Royal Oak, MI 48073 USA. RP Capone, A (reprint author), Oakland Univ, Associated Retinal Consultants, 3535 West Thirteen Mile, Royal Oak, MI 48073 USA. EM acaponejr@arcpc.net OI Jonas, Karyn /0000-0001-9038-6979 NR 34 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD AUG PY 2016 VL 123 IS 8 BP 1802 EP 1808 DI 10.1016/j.ophtha.2016.04.033 PG 7 WC Ophthalmology SC Ophthalmology GA DS4MC UT WOS:000380754200040 PM 27221737 ER PT J AU Menon, S McCullough, LB Beyth, RJ Ford, ME Espadas, D Braun, UK AF Menon, Shailaja McCullough, Laurence B. Beyth, Rebecca J. Ford, Marvella E. Espadas, Donna Braun, Ursula K. TI Use of a values inventory as a discussion aid about end-of-life care: A pilot randomized controlled trial SO PALLIATIVE & SUPPORTIVE CARE LA English DT Article DE Advance care planning; Terminal care; Randomized controlled trial; Veterans; Outpatients; Ambulatory care ID QUESTION PROMPT LIST; DECISION-MAKING; ADVANCED CANCER; COMMUNICATION-SKILLS; ADVANCE DIRECTIVES; BREAST-CANCER; DISCUSSIONS; PHYSICIANS; PREFERENCES; CAREGIVERS AB Objective: We examined the utility of a brief values inventory as a discussion aid to elicit patients' values and goals for end-of-life (EoL) care during audiotaped outpatient physician -patient encounters. Method: Participants were seriously ill male outpatients (n = 120) at a large urban Veterans Affairs medical center. We conducted a pilot randomized controlled trial, randomizing 60 patients to either the intervention (with the values inventory) or usual care. We used descriptive statistics and qualitative methods to analyze the data. We coded any EoL discussions and recorded the length of such discussions. Results: A total of 8 patients (13%) in the control group and 13 (23%) in the intervention group had EoL discussions with a physician (p = 0.77). All EoL discussions in the control group were initiated by the physician, compared with only five (38%) in the intervention group. Because most EoL discussions took place toward the end of the encounter, discussions were usually brief. Significance of results: The outpatient setting has been promoted as a better place for discussing EoL care than a hospital during an acute hospitalization for a chronic serious illness. However, the low effectiveness of our intervention calls into question the feasibility of discussing EoL care during a single outpatient visit. Allowing extra time or an extra visit for EoL discussions might increase the efficacy of advance care planning. C1 [Menon, Shailaja; Espadas, Donna; Braun, Ursula K.] Michael E DeBakey VA Med Ctr, VA Hlth Serv Res & Dev Ctr Innovat Qual Effect &, Houston, TX USA. [Menon, Shailaja; Espadas, Donna] Baylor Coll Med, Dept Med, Sect Hlth Serv Res, Houston, TX 77030 USA. [McCullough, Laurence B.] Baylor Coll Med, Ctr Med Eth & Hlth Policy, Houston, TX 77030 USA. [Beyth, Rebecca J.] Univ Florida, Coll Med, Dept Med, Geriatr Res Educ Clin Ctr,North Florida South Geo, Gainesville, FL USA. [Ford, Marvella E.] Med Univ South Carolina, Hollings Canc Ctr, Dept Publ Hlth Sci & Canc Dispar, Charleston, SC 29425 USA. [Braun, Ursula K.] Baylor Coll Med, Dept Med, Sect Geriatr, Houston, TX 77030 USA. RP Menon, S (reprint author), VA Med Ctr, 152,2002 Holcombe Blvd, Houston, TX 77030 USA. EM smenon@bcm.edu FU Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service [IIR-02-224]; Geriatric Academic Career Award through the Health Resources and Services Administration [KO1HP20480]; VA Health Services Research and Development Center for Innovations in Quality, Effectiveness, and Safety at the Michael E. DeBakey VA Medical Center in Houston, Texas [CIN 13-413]; Keck Center's Agency for Healthcare Research and Quality training fellowship FX Thanks are extended to the patients and providers who took part in our study. This project was supported by the Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service, grant IIR-02-224 (Ursula Braun, Laurence McCullough). Dr. Braun was also supported by a Geriatric Academic Career Award (KO1HP20480) through the Health Resources and Services Administration. This research was also supported in part by resources at the VA Health Services Research and Development Center for Innovations in Quality, Effectiveness, and Safety (#CIN 13-413) at the Michael E. DeBakey VA Medical Center in Houston, Texas. Dr. Menon was supported by a Keck Center's Agency for Healthcare Research and Quality training fellowship in patient safety and quality. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs, the U.S. government, the Health Resources and Services Administration, or Baylor College of Medicine. NR 39 TC 0 Z9 0 U1 3 U2 3 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1478-9515 EI 1478-9523 J9 PALLIAT SUPPORT CARE JI Palliat. Support Care PD AUG PY 2016 VL 14 IS 4 BP 330 EP 340 DI 10.1017/S1478951515001091 PG 11 WC Health Policy & Services SC Health Care Sciences & Services GA DT2DH UT WOS:000381290500004 PM 26458331 ER PT J AU Kobraei, EM Bohnen, JD George, BC Mullen, JT Lillemoe, KD Austen, WG Liao, EC AF Kobraei, Edward M. Bohnen, Jordan D. George, Brian C. Mullen, John T. Lillemoe, Keith D. Austen, William G., Jr. Liao, Eric C. TI Uniting Evidence-Based Evaluation with the ACGME Plastic Surgery Milestones: A Simple and Reliable Assessment of Resident Operative Performance SO PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Article ID ACCREDITATION SYSTEM; EDUCATION AB Background: Milestones evaluations in plastic surgery reflect a shift toward competency-based training but have created a number of challenges. The authors have incorporated the smartphone application evaluation tool, System for Improving and Measuring Procedural Learning (SIMPL), that was recently developed by a multi-institutional research collaborative. In this pilot study, the authors hypothesize that SIMPL can improve resident evaluation and also collect granular performance data to simplify compliance with the plastic surgery Milestones. Methods: SIMPL was prospectively piloted with a plastic surgery resident and faculty surgeon at Massachusetts General Hospital in this institutional review board-approved study. The study period was a 2-month interval corresponding to the resident's rotation. Results: The resident-faculty combination performed 20 cases together. All cases were evaluated with SIMPL. SIMPL evaluations uniformly took under 1 minute to submit. The average time to completed evaluation from surgery completion was 5 hours (<0.5 hour to 12 hours). Concrete, objective, and specific data about resident performance were collected for every case and presented in a concise format. Conclusions: SIMPL is an innovative, evidence-based evaluation system that makes performance assessment feasible for every procedure in which a plastic surgery resident participates. SIMPL's competency-based framework can be easily scaled to facilitate data collection and reporting of mandatory Milestones evaluations at the program and national levels. This technology will support a shared vocabulary between residents and faculty to enhance intraoperative education. C1 Harvard Med Sch, Massachusetts Gen Hosp, Div Plast & Reconstruct Surg, Boston, MA USA. Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Boston, MA USA. Univ Washington, Harborview Med Ctr, Dept Surg, Seattle, WA 98195 USA. RP Liao, EC (reprint author), WACC Suite 435,15 Parkman St, Boston, MA 02114 USA. EM cliao@partners.org NR 12 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 0032-1052 EI 1529-4242 J9 PLAST RECONSTR SURG JI Plast. Reconstr. Surg. PD AUG PY 2016 VL 138 IS 2 BP 349E EP 357E DI 10.1097/PRS.0000000000002411 PG 9 WC Surgery SC Surgery GA DS5JE UT WOS:000380817200022 PM 27064228 ER PT J AU Trevino, KM Naik, AD Moye, J AF Trevino, Kelly M. Naik, Aanand D. Moye, Jennifer TI Perceived and Actual Change in Religion/Spirituality in Cancer Survivors: Longitudinal Relationships With Distress and Perceived Growth SO PSYCHOLOGY OF RELIGION AND SPIRITUALITY LA English DT Article DE anxiety; cancer survivor; depression; religion; spirituality ID QUALITY-OF-LIFE; LONG-TERM SURVIVORS; POSTTRAUMATIC GROWTH; BREAST-CANCER; COLORECTAL-CANCER; AFRICAN-AMERICAN; PSYCHOLOGICAL DISTRESS; TESTICULAR CANCER; PERSONAL GROWTH; POSITIVE CHANGE AB This observational cohort study examined the relationships between actual and perceived R/S change at 12 months post cancer diagnosis with depression, anxiety, and perceived growth 6 months later. Older adult military veteran cancer survivors (n = 111) completed self-report surveys at 6, 12, and 18 months post cancer diagnosis. Perceived R/S change was assessed at 12 months postdiagnosis with "Have your religious or spiritual beliefs changed as a result of your cancer" (more R/S, less R/S, other). Actual R/S change was assessed at 6 and 12 months postdiagnosis on a single item, "I have faith in God or a Higher Power" (no, somewhat, yes). A notable minority reported perceived (18.9%) and actual (14.4%) change. Greater perceived R/S change predicted more severe symptoms of depression and anxiety and greater perceived growth at 18 months postdiagnosis; perceived growth was positively associated with anxiety. Cancer survivors who report R/S changes may benefit from spiritual and/or psychological support. C1 [Trevino, Kelly M.] Weill Cornell Med Coll, Dept Med, 525 East 68th St,Box 39,1414 Baker Pavil, New York, NY 10065 USA. [Trevino, Kelly M.] NewYork Presbyterian Hosp, New York, NY USA. [Naik, Aanand D.] Michael E DeBakey VA Med Ctr, Ctr Innovat Qual Effectiveness & Safety IQuESt, Houston, TX USA. [Naik, Aanand D.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Moye, Jennifer] VA Boston Healthcare Syst, Boston, MA USA. [Moye, Jennifer] Harvard Med Sch, Dept Psychiat, Boston, MA USA. RP Trevino, KM (reprint author), Weill Cornell Med Coll, Dept Med, 525 East 68th St,Box 39,1414 Baker Pavil, New York, NY 10065 USA. EM ket2017@med.cornell.edu RI Moye, Jennifer/F-2240-2017 OI Moye, Jennifer/0000-0002-3434-347X FU Department of Veterans Affairs Rehabilitation Research and Development Service [5I01RX000104-02]; National Institute on Aging; American Federation for Aging Research [K23 AG048632] FX The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. Funding was provided by the Department of Veterans Affairs Rehabilitation Research and Development Service 5I01RX000104-02 (PI: Jennifer Moye). This material is the result of work supported with resources and the use of facilities at the Boston VA Medical Center and the Houston VA Center for Innovations in Quality, Effectiveness and Safety (CIN 13-413) at the Michael E DeBakey VA Medical Center. Dr. Kelly M. Trevino's time was supported by a grant from the National Institute on Aging and American Federation for Aging Research (K23 AG048632). We are indebted to the Veterans who have participated in our research studies and allow us to contribute to their healthcare. We thank the members of the Veterans Cancer Rehabilitation Study (Vetcares) Research team. NR 77 TC 0 Z9 0 U1 3 U2 6 PU EDUCATIONAL PUBLISHING FOUNDATION-AMERICAN PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST, NE, WASHINGTON, DC 20002-4242 USA SN 1941-1022 EI 1943-1562 J9 PSYCHOL RELIG SPIRIT JI Psychol. Relig. Spiritual. PD AUG PY 2016 VL 8 IS 3 BP 195 EP 205 DI 10.1037/rel0000030 PG 11 WC Psychology, Multidisciplinary; Religion SC Psychology; Religion GA DS9UM UT WOS:000381128900003 PM 27453768 ER PT J AU Becerra, MB Becerra, BJ Teodorescu, M AF Becerra, Monideepa B. Becerra, Benjamin J. Teodorescu, Mihaela TI Healthcare burden of obstructive sleep apnea and obesity among asthma hospitalizations: Results from the US-based Nationwide Inpatient Sample SO RESPIRATORY MEDICINE LA English DT Article DE Asthma; Obstructive sleep apnea; Obesity; Nationwide Inpatient Sample; Respiratory therapy ID BODY-MASS INDEX; QUALITY-OF-LIFE; GENDER-DIFFERENCES; INCREASED PREVALENCE; NOCTURNAL ASTHMA; ADULTS; RISK; POPULATION; WOMEN; ASSOCIATION AB Background: Studies have highlighted the significant comorbidities of both obesity and obstructive sleep apnea (OSA) among asthma patients in outpatient settings, but such data in the inpatient setting is sparse. Methods: Using 2009-2011 U.S. Nationwide Inpatient Sample; survey-weighted regression analyses were conducted to address the role of obesity, OSA, and both obesity and OSA on length of stay (LOS), total hospital charges, need for respiratory therapy, and disposition among adults with primary asthma hospitalization (n = 179,789). Results: Males had a higher prevalence of OSA than females (5.23% vs. 3.88%), while females had a higher prevalence of obesity (17.21% vs. 8.95%) and both obesity and OSA (7.11% vs. 6.19%). Increased hospital LOS was associated with presence of obesity (incidence rate ratio [IRR] males = 1.07, IRR females = 1.08), OSA (IRR males = 1.07, IRR females = 1.14), and both obesity and OSA (IRR males = 1.19, IRR females = 1.24). Increased total hospital charges was related to obesity (8.64% for males and 9.61% for females), OSA (15.39% for males and 19.13% for females), and both comorbidities (24.94% for males and 28.50% for females). Presence of OSA alone increased odds of need for respiratory therapy for males (odds ratio [OR] = 2.56) and females (OR = 3.22), as did presence of both comorbidities (OR males = 2.85, OR females = 3.60). Odds of routine disposition was lower among females with both comorbidities (OR = 0.82). Conclusion: Compared to obesity alone, OSA and both obesity and OSA are associated with increased health resource utilization and poorer inpatient outcomes. This demonstrates the need for further clinical investigations of early detection of OSA among such at-risk populations. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Becerra, Monideepa B.] Calif State Univ San Bernardino, Dept Hlth Sci & Human Ecol, San Bernardino, CA 92407 USA. [Becerra, Benjamin J.] Loma Linda Univ, Sch Allied Hlth Profess, Loma Linda, CA 92350 USA. [Teodorescu, Mihaela] William S Middleton Mem Vet Adm Med Ctr, Med Serv, James B Skatrud Pulm Sleep Res Lab, Madison, WI USA. [Teodorescu, Mihaela] Univ Wisconsin, Div Allergy Pulm & Crit Care Med, Sch Med & Publ Hlth, Madison, WI USA. RP Becerra, BJ (reprint author), Loma Linda Univ, Sch Allied Hlth Profess, Loma Linda, CA 92350 USA. EM bbecerra@llu.edu NR 45 TC 0 Z9 0 U1 1 U2 1 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0954-6111 EI 1532-3064 J9 RESP MED JI Respir. Med. PD AUG PY 2016 VL 117 BP 230 EP 236 DI 10.1016/j.rmed.2016.06.020 PG 7 WC Cardiac & Cardiovascular Systems; Respiratory System SC Cardiovascular System & Cardiology; Respiratory System GA DS5WM UT WOS:000380853700030 PM 27492536 ER PT J AU Hou, PC Filbin, MR Napoli, A Feldman, J Pang, PS Sankoff, J Lo, BM Dickey-White, H Birkhahn, RH Shapiro, NI AF Hou, Peter C. Filbin, Michael R. Napoli, Anthony Feldman, Joseph Pang, Peter S. Sankoff, Jeffrey Lo, Bruce M. Dickey-White, Howard Birkhahn, Robert H. Shapiro, Nathan I. TI Cardiac Output Monitoring Managing Intravenous Therapy (COMMIT) to Treat Emergency Department Patients with Sepsis SO SHOCK LA English DT Article DE Fluid resuscitation; sepsis; shock; stroke volume; volume responsiveness ID PREDICT FLUID RESPONSIVENESS; CRITICALLY-ILL PATIENTS; PRESSURE; EPIDEMIOLOGY; SURGERY; TRIAL AB Objective:Fluid responsiveness is proposed as a physiology-based method to titrate fluid therapy based on preload dependence. The objectives of this study were to determine if a fluid responsiveness protocol would decrease progression of organ dysfunction, and a fluid responsiveness protocol would facilitate a more aggressive resuscitation.Methods:Prospective, 10-center, randomized interventional trial. Inclusion criteria: suspected sepsis and lactate 2.0 to 4.0mmol/L. Exclusion criteria (abbreviated): systolic blood pressure more than 90mmHg, and contraindication to aggressive fluid resuscitation. Intervention: fluid responsiveness protocol using Non-Invasive Cardiac Output Monitor (NICOM) to assess for fluid responsiveness (>10% increase in stroke volume in response to 5mL/kg fluid bolus) with balance of a liter given in responsive patients. Control: standard clinical care. Outcomes: primarychange in Sepsis-related Organ Failure Assessment (SOFA) score at least 1 over 72h; secondaryfluids administered. Trial was initially powered at 600 patients, but stopped early due to a change in sponsor's funding priorities.Results:Sixty-four patients were enrolled with 32 in the treatment arm. There were no significant differences between arms in age, comorbidities, baseline vital signs, or SOFA scores (P>0.05 for all). Comparing treatment versus Standard of Carethere was no difference in proportion of increase in SOFA score of at least 1 point (30% vs. 33%) (note bene underpowered, P=1.0) or mean preprotocol fluids 1,050mL (95% confidence interval [CI]: 786-1,314) vs. 1,031mL (95% CI: 741-1,325) (P=0.93); however, treatment patients received more fluids during the protocol (2,633mL [95% CI: 2,264-3,001] vs. 1,002mL [95% CI: 707-1,298]) (P<0.001).Conclusions:In this study of a preshock population, there was no change in progression of organ dysfunction with a fluid responsiveness protocol. A noninvasive fluid responsiveness protocol did facilitate delivery of an increased volume of fluid. Additional properly powered and enrolled outcomes studies are needed. C1 [Hou, Peter C.] Brigham & Womens Hosp, Dept Emergency Med, 75 Francis St, Boston, MA 02115 USA. [Hou, Peter C.; Filbin, Michael R.; Shapiro, Nathan I.] Harvard Med Sch, Boston, MA USA. [Filbin, Michael R.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Napoli, Anthony] Brown Univ, Sch Med, Dept Emergency Med, Providence, RI 02912 USA. [Feldman, Joseph] Hackensack Univ, Med Ctr, Dept Emergency Med, Hackensack, NJ USA. [Pang, Peter S.] Indiana Univ Sch Med, Dept Emergency Med, Indianapolis, IN 46202 USA. [Sankoff, Jeffrey] Denver Gen Hosp, Dept Emergency Med, Denver, CO USA. [Lo, Bruce M.] Eastern Virginia Med Sch, Sentara Norfolk Gen, Dept Emergency Med, Norfolk, VA 23501 USA. [Dickey-White, Howard] Northeast Ohio Med Univ NEOMED, HMHP Mercy Hlth, Dept Emergency Med, Rootstown, OH USA. [Birkhahn, Robert H.] New York Methodist Hosp, Dept Emergency Med, Brooklyn, NY USA. [Shapiro, Nathan I.] Beth Israel Deaconess Med Ctr, Dept Emergency Med, Boston, MA 02215 USA. [Shapiro, Nathan I.] Beth Israel Deaconess Med Ctr, Vasc Biol Res Ctr, Div Mol & Vasc Med, Boston, MA 02215 USA. RP Shapiro, NI (reprint author), Beth Israel Deaconess Med Ctr, 1 Deaconess Rd,CC2-W, Boston, MA 02215 USA. EM nshapiro@bidmc.harvard.edu FU Cheetah Medical, Tel Aviv, Israel; Cheetah medical FX This study was sponsored by Cheetah Medical, Tel Aviv, Israel. The study investigators had primary input into the study design, data collection form creation, performed the analysis, and both drafted the primary manuscript and had final editorial decision-making. As the sponsor, Cheetah Medical had also input into the study design, assisted with data collection, and reviewed the final manuscript. They did not dictate journal submission.; The author reports no conflicts of interest. Since this was an industry sponsored trial, all authors received research funding from Cheetah medical (as described above). NR 15 TC 2 Z9 2 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1073-2322 EI 1540-0514 J9 SHOCK JI Shock PD AUG PY 2016 VL 46 IS 2 BP 132 EP 138 DI 10.1097/SHK.0000000000000564 PG 7 WC Critical Care Medicine; Hematology; Surgery; Peripheral Vascular Disease SC General & Internal Medicine; Hematology; Surgery; Cardiovascular System & Cardiology GA DS8NZ UT WOS:000381041400004 PM 26925867 ER PT J AU Pereira, NRP Beks, RB Janssen, SJ Harris, MB Hornicek, FJ Ferrone, ML Schwab, JH AF Pereira, Nuno Rui Paulino Beks, Reinier B. Janssen, Stein J. Harris, Mitchel B. Hornicek, Francis J. Ferrone, Marco L. Schwab, Joseph H. TI Are allogeneic blood transfusions associated with decreased survival after surgical treatment for spinal metastases? SO SPINE JOURNAL LA English DT Article DE Allogeneic blood transfusion; Bone metastases; Mortality; Spinal metastases; Spine; Survival ID PREOPERATIVE TRANSARTERIAL EMBOLIZATION; COLORECTAL LIVER METASTASES; HEPATIC RESECTION; CANCER RECURRENCE; SURGERY; RISK; PROGNOSIS; COMORBIDITY; PREDICTORS; OUTCOMES AB BACKGROUND CONTEXT: Perioperative allogeneic blood transfusions have been associated with decreased survival after surgical resection of primary and metastatic cancer. Studies investigating this association for patients undergoing resection of bone metastases are scarce and controversial. PURPOSE: We assessed (1) whether exposure to perioperative allogeneic blood transfusions was associated with decreased survival after surgery for spinal metastases and (2) if there was a dose-response relationship per unit of blood transfused. Additionally, we explored the risk factors associated with survival after surgery for spinal metastases. STUDY DESIGN/SETTING: This is a retrospective cohort study from two university medical centers. PATIENT SAMPLE: There were 649 patients who had operative treatment for metastatic disease of the spine between 2002 and 2014. Patients with lymphoma or multiple myeloma were also included. We excluded patients with a revision procedure, kyphoplasty, vertebroplasty, and radiosurgery alone. OUTCOME MEASURES: The outcome measure was survival after surgery. The date of death was obtained from the Social Security Death Index and medical charts. METHODS: Blood transfusions within 7 days before and 7 days after surgery were considered perioperative. Amultivariate Cox proportional hazard model was used to assess the relationship between allogeneic blood transfusion as exposure versus non-exposure, and subsequently as continuous value; we accounted for clinical, laboratory, and treatment factors. RESULTS: Four hundred fifty-three (70%) patients received perioperative blood transfusions, and the median number of units transfused was 3 (interquartile range: 2-6). Exposure to perioperative blood transfusion was not associated with decreased survival after accounting for all explanatory variables (hazard ratio [HR]: 1.03; 95% confidence interval [CI]: 0.80-1.31; p=.841). Neither did we find a dose-response relationship (HR: 1.01; 95% CI: 0.98-1.04; p=.420). Other factors associated with worse survival were older age, more severe comorbidity status, lower preoperative hemoglobin level, higher white blood cell count, higher calcium level, primary tumor type, previous systemic therapy, poor performance status, presence of lung, liver, or brain metastasis, and surgical approach. CONCLUSIONS: Perioperative allogeneic blood transfusions were not associated with decreased survival after surgery for spinal metastases. More liberal transfusion policies might be warranted for patients undergoing surgery for spinal metastasis, although careful consideration is needed as other complications may occur. (C) 2016 Elsevier Inc. All rights reserved. C1 [Pereira, Nuno Rui Paulino; Beks, Reinier B.; Janssen, Stein J.; Hornicek, Francis J.; Schwab, Joseph H.] Harvard Med Sch, Massachusetts Gen Hosp, Orthopaed Oncol Serv, Dept Orthopaed Surg, Room 3-946,Yawkey Bldg,55 Fruit St, Boston, MA 02114 USA. [Harris, Mitchel B.; Ferrone, Marco L.] Harvard Med Sch, Brigham & Womens Hosp, Orthopaed Oncol Serv, Dept Orthopaed Surg, 75 Francis St, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. RP Pereira, NRP (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Orthopaed Oncol Serv, Dept Orthopaed Surg, Room 3-946,Yawkey Bldg,55 Fruit St, Boston, MA 02114 USA. EM nunorui.pp@gmail.com OI Beks, Reinier/0000-0002-1839-0057 FU Stichting Anna Fonds; Stichting Michael van Vloten Fonds; Stichting de Drie Lichten; KWF Kankerfonds FX Dr Janssen has received funding from Stichting Anna Fonds, Stichting Michael van Vloten Fonds, Stichting de Drie Lichten, and the KWF Kankerfonds during the conduct of the study. The other authors have nothing to disclose. NR 40 TC 2 Z9 2 U1 1 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 PY 2016 VL 16 IS 8 BP 951 EP 961 DI 10.1016/j.spinee.2016.03.043 PG 11 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA DT8BS UT WOS:000381714300043 ER PT J AU Borges, CM Reichenbach, DK Kim, BS Misra, A Blazar, BR Turka, LA AF Borges, Christopher M. Reichenbach, Dawn K. Kim, Beom Seok Misra, Aditya Blazar, Bruce R. Turka, Laurence A. TI Regulatory T cell expressed MyD88 is critical for prolongation of allograft survival SO TRANSPLANT INTERNATIONAL LA English DT Article DE inflammation; T cells; transplantation; Treg ID TRANSPLANTATION TOLERANCE; BRONCHIOLITIS OBLITERANS; ADAPTER PROTEIN; CUTTING EDGE; MURINE MODEL; GRANZYME-B; IN-VIVO; RECEPTOR; REJECTION; GENERATION AB MyD88 signaling directly promotes T-cell survival and is required for optimal T-cell responses to pathogens. To examine the role of T-cell-intrinsic MyD88 signals in transplantation, we studied mice with targeted T-cell-specific MyD88 deletion. Contrary to expectations, we found that these mice were relatively resistant to prolongation of graft survival with anti-CD154 plus rapamycin in a class II-mismatched system. To specifically examine the role of MyD88 in Tregs, we created a Treg-specific MyD88-deficient mouse. Transplant studies in these animals replicated the findings observed with a global T-cell MyD88 knockout. Surprisingly, given the role of MyD88 in conventional T-cell survival, we found no defect in the survival of MyD88-deficient Tregs in vitro or in the transplant recipients and also observed intact cell homing and expression of Treg effector molecules. MyD88-deficient Tregs also fail to protect allogeneic bone marrow transplant recipients from chronic graft-versus-host disease, confirming the observations of defective regulation seen in a solid organ transplant system. Together, our data define MyD88 as having a divergent requirement for cell survival in non-Tregs and Tregs, and a yet-to-be defined survival-independent requirement for Treg function during the response to alloantigen. C1 [Borges, Christopher M.; Turka, Laurence A.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Ctr Transplantat Sci, Boston, MA USA. [Borges, Christopher M.] Harvard Univ, Program Immunol, Div Med Sci, Boston, MA 02115 USA. [Reichenbach, Dawn K.; Blazar, Bruce R.] Univ Minnesota, Dept Pediat, Div Blood & Marrow Transplantat, Minneapolis, MN 55455 USA. [Kim, Beom Seok] Yonsei Univ, Coll Med, Dept Internal Med, Seoul, South Korea. [Misra, Aditya] Harvard Univ, Summer Immunol Res Program, Boston, MA 02115 USA. [Misra, Aditya] Cornell Univ, Sch Chem & Biomol Engn, Ithaca, NY USA. RP Turka, LA (reprint author), Ctr Transplantat Sci, 149 13th St,Room 5101, Boston, MA 02129 USA. EM lturka@partners.org FU [P01 AI056299]; [HL011879]; [P01 CA142106]; [T32AI007529-14] FX We would like to thank members of the Turka laboratory for many helpful discussions, and Weihua Gong, and Gregory Whitcher for technical assistance. This work was funded by P01 AI056299 (LAT and BRB), HL011879 and P01 CA142106 (BRB), and T32AI007529-14 (CMB). NR 56 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0934-0874 EI 1432-2277 J9 TRANSPL INT JI Transpl. Int. PD AUG PY 2016 VL 29 IS 8 BP 930 EP 940 DI 10.1111/tri.12788 PG 11 WC Surgery; Transplantation SC Surgery; Transplantation GA DS8ZB UT WOS:000381070400011 PM 27112509 ER PT J AU Martin, DE Van Assche, K Dominguez-Gil, B Lopez-Fraga, M Budiani-Saberi, D Lavee, J Tibell, A Moazam, F Muller, E Danovitch, GM Codreanu, I Naicker, S Al Rukhaimi, M McGuinness, S Bakr, MA Moniruzzaman, M Capron, AM Delmonico, FL AF Martin, Dominique E. Van Assche, Kristof Dominguez-Gil, Beatriz Lopez-Fraga, Marta Budiani-Saberi, Debra Lavee, Jacob Tibell, Annika Moazam, Farhat Muller, Elmi Danovitch, Gabriel M. Codreanu, Igor Naicker, Saraladevi Al Rukhaimi, Mona McGuinness, Sheelagh Bakr, Mohamed A. Moniruzzaman, Monir Capron, Alexander M. Delmonico, Francis L. TI Prevention of Transnational Transplant-Related Crimes-What More Can be Done? SO TRANSPLANTATION LA English DT Article ID ORGAN-TRANSPLANTATION; KIDNEY VENDORS; MEDICAL GUIDELINES; TRAFFICKING; TOURISM; DECLARATION; ISTANBUL; PAKISTAN; DONATION; MARKETS AB Background. Many nations are able to prosecute transplant-related crimes committed in their territory, but transplant recipients, organ sellers and brokers, and transplant professionals may escape prosecution by engaging in these practices in foreign locations where they judge the risk of criminal investigation and prosecution to be remote. Methods. The Declaration of Istanbul Custodian Group convened an international working group to evaluate the possible role of extraterritorial jurisdiction in strengthening the enforcement of existing laws governing transplant-related crimes across national boundaries. Potential practical and ethical concerns about the use of extraterritorial jurisdiction were examined, and possible responses were explored. Results. Extraterritorial jurisdiction is a legitimate tool to combat transplant-related crimes. Further, development of a global registry of transnational transplant activities in conjunction with a standardized international referral system for legitimate travel for transplantation is proposed as a mechanism to support enforcement of national and international legal tools. Conclusions. States are encouraged to include provisions on extraterritorial jurisdiction in their laws on transplant-related crimes and to collaborate with professionals and international authorities in the development of a global registry of transnational transplant activities. These actions would assist in the identification and evaluation of illicit activities and provide information that would help in developing strategies to deter and prevent them. C1 [Martin, Dominique E.] Univ Melbourne, Ctr Hlth Equ, Parkville, Vic, Australia. [Van Assche, Kristof] Univ Ghent, Bioeth Inst Ghent, Ghent, Belgium. [Dominguez-Gil, Beatriz] Org Nacl Trasplantes, Madrid, Spain. [Lopez-Fraga, Marta] Council Europe, European Directorate Qual Med HealthCare, Strasbourg, France. [Budiani-Saberi, Debra] Coalit Organ Failure Solut, Washington, DC USA. [Lavee, Jacob] Tel Aviv Univ, Sheba Med Ctr, Tel Aviv, Israel. [Lavee, Jacob] Tel Aviv Univ, Sackler Fac Med, Tel Aviv, Israel. [Tibell, Annika] Karolinska Inst, Dept Learning Informat Management & Eth LIME, CHE, S-10401 Stockholm, Sweden. [Moazam, Farhat] SIUT, Ctr Biomed Eth & Culture, Karachi, Pakistan. [Muller, Elmi] Univ Cape Town, Cape Town, South Africa. [Danovitch, Gabriel M.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Codreanu, Igor] Transplant Agcy Moldova, Kishinev, Moldova. [Naicker, Saraladevi] Univ Witwatersrand, Johannesburg, South Africa. [Al Rukhaimi, Mona] Dubai Med Coll, Dubai, U Arab Emirates. [McGuinness, Sheelagh] Univ Birmingham, Birmingham, W Midlands, England. [Bakr, Mohamed A.] Mansoura Univ, Mansoura, Egypt. [Moniruzzaman, Monir] Michigan State Univ, E Lansing, MI 48824 USA. [Capron, Alexander M.] Univ Southern Calif, Pacific Ctr Hlth Policy & Eth, Los Angeles, CA USA. [Delmonico, Francis L.] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. RP Martin, DE (reprint author), Univ Melbourne, Ctr Hlth Equ, Sch Populat & Global Hlth, Level 4,207 Bouverie St, Melbourne, Vic 3010, Australia. EM dominique.martin@unimelb.edu.au FU Ghent University special research fund (UGent BOF) FX K.V.A. acknowledges financial support from the Ghent University special research fund (UGent BOF). The authors declare no other funding or conflicts of interest. NR 45 TC 6 Z9 6 U1 5 U2 5 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 AUG PY 2016 VL 100 IS 8 BP 1776 EP 1784 DI 10.1097/TP.0000000000001001 PG 9 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA DS5HB UT WOS:000380811200038 PM 26528771 ER PT J AU Celeng, C Takx, RAP Ferencik, M Maurovich-Horvat, P AF Celeng, Csilla Takx, Richard A. P. Ferencik, Maros Maurovich-Horvat, Pal TI Non-invasive and invasive imaging of vulnerable coronary plaque SO TRENDS IN CARDIOVASCULAR MEDICINE LA English DT Article DE Vulnerable plaque; Thin-cap fibroatheroma; Necrotic core; Coronary artery disease ID OPTICAL COHERENCE TOMOGRAPHY; NEAR-INFRARED SPECTROSCOPY; THIN-CAP FIBROATHEROMA; RADIOFREQUENCY DATA-ANALYSIS; MULTIDETECTOR COMPUTED-TOMOGRAPHY; ACUTE MYOCARDIAL-INFARCTION; HIGH-INTENSITY SIGNALS; NAPKIN-RING SIGN; INTRAVASCULAR-ULTRASOUND; IN-VIVO AB Vulnerable plaque is characterized by a large necrotic core and an overlying thin fibrous cap. Non-invasive imaging modalities such as computed tomography angiography (CTA) and magnetic resonance imaging (MRI) allow for the assessment of morphological plaque characteristics, while positron emission tomography (PET) enables the detection of metabolic activity within the atherosclerotic lesions. Invasive imaging modalities such as intravascular ultrasound (IVUS), optical-coherence tomography (OCT), and intravascular MRI (IV-MRI) display plaques at a high spatial resolution. Near-infrared spectroscopy (NIRS) allows for the detection of chemical components of atherosclerotic plaques. In this review, we describe state-of-the-art non-invasive and invasive imaging modalities and stress the combination of their advantages to identify vulnerable plaque features. C1 [Celeng, Csilla; Maurovich-Horvat, Pal] Semmelweis Univ, Heart & Vasc Ctr, MTA SE Cardiovasc Imaging Res Grp, Budapest, Hungary. [Takx, Richard A. P.] Massachusetts Gen Hosp, Div Cardiovasc Imaging, Cardiac MR PET CT Program, Boston, MA 02114 USA. [Takx, Richard A. P.] Harvard Med Sch, Boston, MA USA. [Takx, Richard A. P.] Univ Med Ctr Utrecht, Dept Radiol, Utrecht, Netherlands. [Ferencik, Maros] Oregon Hlth & Sci Univ, Knight Cardiovasc Inst, Portland, OR 97201 USA. RP Maurovich-Horvat, P (reprint author), Semmelweis Univ, Heart & Vasc Ctr, MTA SE Cardiovasc Imaging Res Grp, Budapest, Hungary. EM p.maurovich-horvat@cirg.hu NR 84 TC 3 Z9 3 U1 7 U2 9 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1050-1738 J9 TRENDS CARDIOVAS MED JI Trends Cardiovasc. Med. PD AUG PY 2016 VL 26 IS 6 BP 538 EP 547 DI 10.1016/j.tcm.2016.03.005 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DS8XF UT WOS:000381065600009 PM 27079893 ER PT J AU Chittle, MD Oklu, R Pino, RM He, P Sheridan, RM Martino, J Hirsch, JA AF Chittle, Melissa D. Oklu, Rahmi Pino, Richard M. He, Ping Sheridan, Robert M. Martino, Joanne Hirsch, Joshua A. TI Sedation shared decision-making in ambulatory venous access device placement: Effects on patient choice, satisfaction and recovery time SO VASCULAR MEDICINE LA English DT Article DE ambulatory vascular procedures; patient centered care; sedation; shared decision-making; venous access device ID INTERVENTIONAL RADIOLOGICAL PROCEDURES; CONSCIOUS SEDATION; ANALGESIA; PAIN; ANXIETY; CARE; ARTERIOGRAPHY; ANGIOGRAPHY; PERCEPTION; ANESTHESIA AB This study was undertaken to determine the impact of shared decision-making when selecting a sedation option, from no sedation (local anesthetic), minimal sedation (anxiolysis with a benzodiazepine) or moderate sedation (benzodiazepine and opiate), for venous access device placement (port-a-cath and tunneled catheters) on patient choice, satisfaction and recovery time. This is an IRB-approved, HIPPA-compliant, retrospective study of 198 patients (18-85 years old, 60% female) presenting to an ambulatory vascular interventional radiology department for venous access device placement between 22 October 2014 and 7 October 2015. Patients were educated about sedation options and given the choice of undergoing the procedure with no sedation (local anesthetic only), or minimal or moderate sedation. Satisfaction was assessed through three survey questions. No sedation was selected by 53/198 (27%), minimal sedation by 71/198 (36%) and moderate sedation by 74/198 (37%). All subjects would recommend the option to another patient and valued the opportunity to select a sedation option. Post-procedure recovery time differences were statistically significant (p<0.0001) with median recovery times of 0 minutes for no sedation, 38 minutes for minimal sedation and 64 minutes for moderate sedation. In conclusion, patient sedation preference for venous access device placement is variable, signifying there is a role for shared decision-making as it empowers the patient to select the option most aligned with his or her goals. The procedure is well-tolerated, associated with high satisfaction, and the impact on departmental flow is notable because patients choosing no or minimal sedation results in a decreased post-procedure recovery time burden. C1 [Chittle, Melissa D.; Pino, Richard M.; Sheridan, Robert M.; Martino, Joanne; Hirsch, Joshua A.] Massachusetts Gen Hosp, 55 Fruit St,Blake 290, Boston, MA 02113 USA. [Oklu, Rahmi] Mayo Clin Arizona, Scottsdale, AZ USA. [He, Ping] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. RP Chittle, MD (reprint author), Massachusetts Gen Hosp, 55 Fruit St,Blake 290, Boston, MA 02113 USA. EM mchittle@partners.org NR 24 TC 0 Z9 0 U1 3 U2 3 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1358-863X EI 1477-0377 J9 VASC MED JI Vasc. Med. PD AUG PY 2016 VL 21 IS 4 BP 355 EP 360 DI 10.1177/1358863X16643602 PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DS7KQ UT WOS:000380962800007 PM 27076197 ER PT J AU Vedantham, S Kahn, SR Goldhaber, SZ Comerota, AJ Parpia, S Meleth, S Earp, D Williams, R Sista, AK Marston, W Rathbun, S Magnuson, EA Razavi, MK Jaff, MR Kearon, C AF Vedantham, Suresh Kahn, Susan R. Goldhaber, Samuel Z. Comerota, Anthony J. Parpia, Sameer Meleth, Sreelatha Earp, Diane Williams, Rick Sista, Akhilesh K. Marston, William Rathbun, Suman Magnuson, Elizabeth A. Razavi, Mahmood K. Jaff, Michael R. Kearon, Clive TI Endovascular therapy for advanced post-thrombotic syndrome: Proceedings from a multidisciplinary consensus panel SO VASCULAR MEDICINE LA English DT Article DE deep vein thrombosis; endovascular therapy; post-thrombotic syndrome; quality of life; stent ID QUALITY-OF-LIFE; DEEP-VEIN THROMBOSIS; CHRONIC VENOUS DISEASE; CLINICAL SEVERITY SCORE; MAY-THURNER SYNDROME; QOL/SYM QUESTIONNAIRE; ILIAC VEIN; PREVENTION; LEG; RECANALIZATION AB Patients with advanced post-thrombotic syndrome (PTS) and chronic iliac vein obstruction suffer major physical limitations and impairment of health-related quality of life. Currently there is a lack of evidence-based treatment options for these patients. Early studies suggest that imaging-guided, catheter-based endovascular therapy can eliminate iliac vein obstruction and saphenous venous valvular reflux, resulting in reduced PTS severity; however, these observations have not been rigorously validated. A multidisciplinary expert panel meeting was convened to plan a multicenter randomized controlled clinical trial to evaluate endovascular therapy for the treatment of advanced PTS. This article summarizes the findings of the panel, and is expected to assist in developing a National Institutes of Health-sponsored clinical trial and other studies to improve the care of patients with advanced PTS. C1 [Vedantham, Suresh] Washington Univ, St Louis, MO USA. [Kahn, Susan R.] SMBD Jewish Gen Hosp, Montreal, PQ, Canada. [Goldhaber, Samuel Z.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Comerota, Anthony J.] Toledo Hosp, Toledo, OH USA. [Parpia, Sameer; Kearon, Clive] McMaster Univ, Hamilton, ON, Canada. [Meleth, Sreelatha; Earp, Diane; Williams, Rick] Res Triangle Int, Res Triangle Pk, NC USA. [Sista, Akhilesh K.] NYU, Sch Med, New York, NY USA. [Marston, William] Univ North Carolina Chapel Hill, Chapel Hill, NC USA. [Rathbun, Suman] OK Hlth Sci Ctr, Oklahoma City, OK USA. [Magnuson, Elizabeth A.] Mid Amer Heart Inst, Kansas City, MO USA. [Razavi, Mahmood K.] St Josephs Hosp, Orange, CA USA. [Jaff, Michael R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Vedantham, S (reprint author), Washington Univ, Sch Med, Mallinckrodt Inst Radiol, 510 S Kingshighway,Box 8131, St Louis, MO 63110 USA. EM vedanthams@mir.wustl.edu OI Sista, Akhilesh/0000-0001-5582-796X FU National Heart, Lung, and Blood Institute (NHLBI) [U34-HL123831, U24-HL114577] FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: the expert panel meeting and manuscript development were supported by grants U34-HL123831 and U24-HL114577 from the National Heart, Lung, and Blood Institute (NHLBI). The views expressed are those of the authors and do not represent the NHLBI or National Institutes of Health. NR 34 TC 6 Z9 6 U1 1 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1358-863X EI 1477-0377 J9 VASC MED JI Vasc. Med. PD AUG PY 2016 VL 21 IS 4 BP 400 EP 407 DI 10.1177/1358863X16650747 PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DS7KQ UT WOS:000380962800016 PM 27247235 ER PT J AU Masch, WR Wang, CL Davenport, MS AF Masch, William R. Wang, Carolyn L. Davenport, Matthew S. TI Severe allergic-like contrast reactions: epidemiology and appropriate treatment SO ABDOMINAL RADIOLOGY LA English DT Article DE Contrast media; Contrast reaction; Severe contrast reaction; Severe contrast reaction epidemiology; Severe contrast reaction treatment; Severe allergiclike reaction ID HIGH-FIDELITY SIMULATION; ADVERSE-REACTIONS; ANAPHYLACTIC REACTIONS; MEDIA REACTIONS; POSTMORTEM FINDINGS; 1ST-AID TREATMENT; EPINEPHRINE; MANAGEMENT; RISK; EMERGENCY AB Epinephrine is the most important treatment for severe allergic-like contrast reactions. The signs and symptoms of a severe reaction and the dose and methods of epinephrine administration are important for all radiologists to master. In this review article, we review the epidemiology of severe allergic-like contrast reactions, their common clinical manifestations, and their appropriate treatment, with a focus on correct epinephrine administration. We also discuss systematic limitations in the training of current and future radiologists, and recommend strategies for improvement. C1 [Masch, William R.] Massachusetts Gen Hosp, Div Abdominal Imaging, Dept Radiol, 55 Fruit St,White 270, Boston, MA 02114 USA. [Wang, Carolyn L.] Univ Washington, Div Abdominal Imaging, Dept Radiol, 1959 NE Pacific St, Seattle, WA 98195 USA. [Davenport, Matthew S.] Univ Michigan Hlth Syst, Dept Radiol, Div Abdominal Imaging, 1500 E Med Ctr Dr, Ann Arbor, MI 48108 USA. [Davenport, Matthew S.] Univ Michigan Hlth Syst, Michigan Radiol Qual Collaborat, 1500 E Med Ctr Dr, Ann Arbor, MI 48108 USA. RP Masch, WR (reprint author), Massachusetts Gen Hosp, Div Abdominal Imaging, Dept Radiol, 55 Fruit St,White 270, Boston, MA 02114 USA. EM mascwill@med.umich.edu NR 66 TC 0 Z9 0 U1 4 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 2366-004X EI 2366-0058 J9 ABDOM RADIOL JI Abdom. Radiol. PD AUG PY 2016 VL 41 IS 8 BP 1632 EP 1639 DI 10.1007/s00261-016-0723-x PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DS9OR UT WOS:000381113400023 PM 27039194 ER PT J AU Nierenberg, AA AF Nierenberg, A. A. TI Bipolar disorder: multiple pathways to neuroprogression SO ACTA PSYCHIATRICA SCANDINAVICA LA English DT Editorial Material ID BIOMARKERS; DISEASE; STRESS C1 [Nierenberg, A. A.] Harvard Med Sch, Massachusetts Gen Hosp, Bipolar Clin, Boston, MA 02115 USA. [Nierenberg, A. A.] Harvard Med Sch, Res Program, Boston, MA 02115 USA. RP Nierenberg, AA (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Bipolar Clin, Boston, MA 02115 USA.; Nierenberg, AA (reprint author), Harvard Med Sch, Res Program, Boston, MA 02115 USA. EM anierenberg@mgh.harvard.edu NR 8 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0001-690X EI 1600-0447 J9 ACTA PSYCHIAT SCAND JI Acta Psychiatr. Scand. PD AUG PY 2016 VL 134 IS 2 BP 89 EP 90 DI 10.1111/acps.12617 PG 2 WC Psychiatry SC Psychiatry GA DT7SY UT WOS:000381688700001 PM 27384497 ER PT J AU Foley, OW Rauh-Hain, JA Clark, RM Goodman, A Growdon, WB Boruta, DM Schorge, JO del Carmen, MG AF Foley, Olivia W. Rauh-Hain, Jose A. Clark, Rachel M. Goodman, Annekathryn Growdon, Whitfield B. Boruta, David M. Schorge, John O. del Carmen, Marcela G. TI Intraoperative Radiation Therapy in the Management of Gynecologic Malignancies SO AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS LA English DT Article DE intraoperative radiation therapy; surgery; recurrence ID ADVANCED CERVICAL-CANCER; PELVIC EXENTERATION; RADIOTHERAPY; EXPERIENCE; CARCINOMA; CISPLATIN; RESECTION; SURVIVAL; IORT AB Objective: The aim of this study was to review the experience with intraoperative radiation therapy (IORT) in the treatment of gynecologic cancers at the Massachusetts General Hospital. Methods: From January 1, 1994 to December 31, 2011, 32 patients were treated with IORT at Massachusetts General Hospital. Hospital, pathology, and office medical records and radiation oncology records were reviewed. The Kaplan-Meier method was used to generate disease-free survival and overall survival (OS) data. Results: In 27 patients (84.4), surgical resection margins were microscopically positive. In 5 patients (15.6%), margins were grossly positive. For patients with microscopic disease, 5-year disease-free survival was 40.9% (57 mo), compared with 9.1% (23 mo) for those with gross residual disease (P = 0.001). Five-year OS was also statistically improved for patients with microscopic residual disease, when compared with OS among patients with gross residual disease, 77.3% (93 mo) and 54.5% (40 mo), respectively (P = 0.001). The risk of distant metastases in patients with gross residual disease was 87%, compared with 28% in patients with microscopic disease (P = 0.02). Conclusions: Volume of residual disease before IORT is an important prognostic indicator. Local recurrence and distant metastases were more common among patients with gross residual disease left in situ at time of IORT. Our institutional experience with IORT further supports the importance of complete surgical resection. C1 [Foley, Olivia W.; Rauh-Hain, Jose A.; Clark, Rachel M.; Goodman, Annekathryn; Growdon, Whitfield B.; Boruta, David M.; Schorge, John O.; del Carmen, Marcela G.] Harvard Med Sch, Massachusetts Gen Hosp, Div Gynecol Oncol, Vincent Obstet & Gynecol, Boston, MA USA. RP del Carmen, MG (reprint author), Massachusetts Gen Hosp, Div Gynecol Oncol, Vincent Obstet & Gynecol, 55 Fruit St,Yawkey 9E, Boston, MA 02114 USA. EM mdelcarmen@partners.org NR 23 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 0277-3732 EI 1537-453X J9 AM J CLIN ONCOL-CANC JI Am. J. Clin. Oncol.-Cancer Clin. Trials PD AUG PY 2016 VL 39 IS 4 BP 329 EP 334 DI 10.1097/COC.0000000000000063 PG 6 WC Oncology SC Oncology GA DS5HH UT WOS:000380811800003 PM 24685883 ER PT J AU Burtness, B Powell, M Catalano, P Berlin, J Liles, DK Chapman, AE Mitchell, E Benson, A AF Burtness, Barbara Powell, Mark Catalano, Paul Berlin, Jordan Liles, Darla K. Chapman, Andrew E. Mitchell, Edith Benson, Al B. TI Randomized Phase II Trial of Irinotecan/Docetaxel or Irinotecan/Docetaxel Plus Cetuximab for Metastatic Pancreatic Cancer An Eastern Cooperative Oncology Group Study SO AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS LA English DT Article DE pancreatic cancer; docetaxel; irinotecan; cetuximab ID GROWTH-FACTOR RECEPTOR; ADVANCED SOLID TUMORS; CLINICAL-TRIALS; GEMCITABINE; ADENOCARCINOMA; DOCETAXEL; COMBINATION; CHEMOTHERAPY; CARCINOMA; CPT-11 AB Objectives: The primary objective was to determine the response rate in patients with metastatic pancreatic cancer treated in first line with irinotecan/docetaxel combination (Arm A) or with irinotecan/docetaxel/cetuximab combination (Arm B). Secondary endpoints were progression-free survival (PFS), overall survival (OS), toxicity, and the rate of thromboembolic events with prophylactic enoxaparin sodium. Patients and Methods: Patients were eligible who had measurable, metastatic adenocarcinoma of the pancreas, and normal bilirubin. All patients received anticoagulation. Docetaxel (35 mg/m(2)) and irinotecan (50 mg/m2) were administered once a week for 4 weeks followed by 2 weeks rest (Arm A) alone or with the addition of cetuximab (Arm B). The primary endpoint was response rate. Results: A total of 87 eligible patients were enrolled and treated. Grade 3/4 toxicity was observed in 74% of patients in Arm A and 76% in Arm B. The principal grade 3/4 toxicity was diarrhea. Response rates were 4.5% in Arm A and 7% in Arm B. Median PFS and OS were 3.9 and 6.5 months in Arm A and 4.5 and 5.4 months in Arm B. Conclusions: Docetaxel/irinotecan combination is associated with considerable toxicity. Objective responses were infrequent and addition of cetuximab in an unselected population was not beneficial, but PFS and OS were comparable with those achieved with other regimens. Docetaxel/irinotecan therapy is active in metastatic pancreatic cancer. C1 [Burtness, Barbara] Fox Chase Canc Ctr, Dept Med Oncol, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Chapman, Andrew E.; Mitchell, Edith] Thomas Jefferson Univ, Sch Med, Dept Internal Med, Philadelphia, PA 19107 USA. [Powell, Mark; Catalano, Paul] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Berlin, Jordan] Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, 221 Kirkland Hall, Nashville, TN 37235 USA. [Liles, Darla K.] East Carolina Univ, Sch Med, Greenville, NC USA. [Benson, Al B.] Northwestern Univ, Lurie Canc Ctr, Chicago, IL 60611 USA. RP Burtness, B (reprint author), Yale Univ, Sch Med, Sect Med Oncol, Dept Internal Med, 333 Cedar St,POB 208028,WWW225, New Haven, CT 06520 USA. EM barbara.burtness@yale.edu FU National Cancer Institute, DHHS [CA-23318]; Bristol-Myers Squibb; Sanofi; Pharmacia FX Supported by Grant CA-23318, awarded by the National Cancer Institute, DHHS; Bristol-Myers Squibb; Sanofi; and Pharmacia. NR 32 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 0277-3732 EI 1537-453X J9 AM J CLIN ONCOL-CANC JI Am. J. Clin. Oncol.-Cancer Clin. Trials PD AUG PY 2016 VL 39 IS 4 BP 340 EP 345 DI 10.1097/COC.0000000000000068 PG 6 WC Oncology SC Oncology GA DS5HH UT WOS:000380811800005 PM 24685886 ER PT J AU Bian, SX Kuban, DA Levy, LB Oh, J Choi, S McGuire, SE Frank, SJ Mahmood, U Nguyen, PL Pugh, TJ Lee, AK Hoffman, KE AF Bian, Shelly X. Kuban, Deborah A. Levy, Lawrence B. Oh, Jeong Choi, Seungtaek McGuire, Sean E. Frank, Steven J. Mahmood, Usama Nguyen, Paul L. Pugh, Thomas J. Lee, Andrew K. Hoffman, Karen E. TI The Influence of Age and Comorbidity on the Benefit of Adding Androgen Deprivation to Dose-escalated Radiation in Men With Intermediate-risk Prostate Cancer SO AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS LA English DT Article DE prostate cancer; radiotherapy; elderly; androgen-suppression therapy ID SUPPRESSION THERAPY; HORMONAL-THERAPY; ELDERLY-MEN; OLDER MEN; MORTALITY; SURVIVAL; HYPOGONADISM; ASSOCIATION; FAILURE; DISEASE AB Objective: Androgen deprivation therapy (ADT) can improve outcomes for men with intermediate-risk prostate cancer (IR-PrCa) receiving external-beam radiotherapy (EBRT). Older men and men with significant comorbidity may be more susceptible to the harms of ADT, therefore we aimed to determine whether these men benefit from ADT. Methods: The adult comorbidity evaluation-27 index categorized severity of comorbidity in 636 men treated for IR-PrCa with dose-escalated EBRT (> 75 Gy). The cohort was dichotomized at median age of 70. Multivariate Cox proportional hazard analysis evaluated the association of ADT with failure-free survival (FFS) for each age and comorbidity subgroup. Results: A total of 48% of men were 70 years and above. After adjustment for tumor characteristics, the addition of ADT to EBRT was associated with improved FFS for both men below 70 years of age (adjusted hazard ratio [AHR] 0.44; 95% confidence interval [CI], 0.190.99; P=0.046) and men 70 years and above (AHR 0.23; 95% CI, 0.060.91; P=0.035). ADT improved FFS for men below 70 years who had no or mild comorbidity (AHR 0.25; 95% CI, 0.09-0.73; P=0.011) but not for men below 70 years who had moderate or severe comorbidity (AHR 1.62; 95% CI, 0.35-7.49; P=0.537). Similarly, in men 70 years and above, there was a trend for improved FFS with ADT in healthy men (AHR 0.10; 95% CI, 0.01-1.08; P=0.058) but not in men with moderate to severe comorbidity (AHR 0.38; 95% CI, 0.06-2.56; P=0.318). Conclusions: The addition of ADT to dose-escalated EBRT can improve outcomes for both younger and older men with IR-PrCa. This benefit was more pronounced in healthy men. C1 [Bian, Shelly X.; Kuban, Deborah A.; Levy, Lawrence B.; Choi, Seungtaek; McGuire, Sean E.; Frank, Steven J.; Mahmood, Usama; Pugh, Thomas J.; Lee, Andrew K.; Hoffman, Karen E.] Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA. [Oh, Jeong] Univ Texas MD Anderson Canc Ctr, Dept Internal Med, Houston, TX 77030 USA. [Nguyen, Paul L.] Harvard Med Sch, Dana Farber Brigham & Womens Canc Ctr, Dept Radiat Oncol, Boston, MA USA. RP Hoffman, KE (reprint author), Univ Texas MD Anderson Canc Ctr, 1515 Holcombe Blvd,Unit 1202, Houston, TX 77030 USA. EM khoffman1@mdanderson.org FU NCI NIH HHS [P30 CA016672] NR 29 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0277-3732 EI 1537-453X J9 AM J CLIN ONCOL-CANC JI Am. J. Clin. Oncol.-Cancer Clin. Trials PD AUG PY 2016 VL 39 IS 4 BP 368 EP 373 DI 10.1097/COC.0000000000000071 PG 6 WC Oncology SC Oncology GA DS5HH UT WOS:000380811800010 PM 24732810 ER PT J AU Roberts, KB Younes, A Hodgson, DC Advani, R Dabaja, BS Dhakal, S Flowers, CR Ha, CS Hoppe, BS Mendenhall, NP Metzger, ML Plastaras, JP Shapiro, R Smith, SM Terezakis, SA Winkfield, KM Constine, LS AF Roberts, Kenneth B. Younes, Anas Hodgson, David C. Advani, Ranjana Dabaja, Bouthaina S. Dhakal, Sughosh Flowers, Christopher R. Ha, Chul S. Hoppe, Bradford S. Mendenhall, Nancy P. Metzger, Monika L. Plastaras, John P. Shapiro, Ronald Smith, Sonali M. Terezakis, Stephanie A. Winkfield, Karen M. Constine, Louis S. CA Expert Panel Radiation TI ACR Appropriateness Criteria (R) Hodgkin Lymphoma-Unfavorable Clinical Stage I and II SO AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS LA English DT Article DE early-stage classic Hodgkin lymphoma; unfavorable early-stage Hodgkin lymphoma; involved-site radiotherapy (ISRT); appropriateness criteria ID INVOLVED-FIELD RADIOTHERAPY; COMBINED-MODALITY THERAPY; POSITRON-EMISSION-TOMOGRAPHY; STEM-CELL TRANSPLANTATION; HIGH-DOSE CHEMOTHERAPY; BONE-MARROW-TRANSPLANTATION; CHILDRENS ONCOLOGY GROUP; TRIAL COMPARING CHEMOTHERAPY; GROUP HD14 TRIAL; RADIATION-THERAPY AB These guidelines review the historical evolution of treatment for early-stage Hodgkin lymphoma (HL) with current standards that rely on prognostic factors to risk stratify and direct current treatment schemes that includes differentiation of favorable and unfavorable presentations. The major clinical trials for unfavorable early-stage HL are reviewed. Patients in this heterogenous subgroup of classic HL are best managed with sequential chemotherapy and radiotherapy. The role of imaging response assessment as a means to modify therapy is a strategy under investigation. Tailoring the radiation treatment volume and radiation dose prescription along with selective use of modern conformal techniques is expected to help reduce long-term toxicities. Many patients are well served receiving involved-site radiotherapy to 30 Gy after appropriate systemic therapy intensity; but, there are nuances for which some variations in the chemotherapy and radiotherapy specifics are appropriately individualized. Following a discussion of the current evidence-based treatment algorithms, several different example cases are reviewed to help physicians make appropriate treatment decisions. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. C1 [Roberts, Kenneth B.] Yale Univ, Sch Med, New Haven, CT USA. [Younes, Anas] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Younes, Anas; Advani, Ranjana; Metzger, Monika L.] Amer Soc Clin Oncol, Alexandria, VA USA. [Dhakal, Sughosh] Univ Rochester, Med Ctr, Rochester, NY 14642 USA. [Hodgson, David C.] Princess Margaret Hosp, Toronto, ON, Canada. [Advani, Ranjana] Stanford Canc Ctr, Stanford, CA USA. [Dabaja, Bouthaina S.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Ha, Chul S.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Flowers, Christopher R.] Emory Univ, Atlanta, GA 30322 USA. [Hoppe, Bradford S.] Univ Florida, Proton Therapy Inst, Jacksonville, FL USA. [Mendenhall, Nancy P.] Univ Florida, Gainesville, FL USA. [Metzger, Monika L.] St Jude Childrens Res Hosp, 332 N Lauderdale St, Memphis, TN 38105 USA. [Plastaras, John P.] Univ Penn Hlth Syst, Philadelphia, PA USA. [Shapiro, Ronald] Indiana Univ Sch Med, Richard L Roudebush VA Med Ctr, Indianapolis, IN 46202 USA. [Smith, Sonali M.] Univ Chicago, Chicago, IL 60637 USA. [Smith, Sonali M.] Amer Soc Hematol, Washington, DC USA. [Terezakis, Stephanie A.] Johns Hopkins Univ Hosp, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21287 USA. [Winkfield, Karen M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Roberts, KB (reprint author), Amer Coll Radiol, 1891 Preston White Dr, Reston, VA 20191 USA. EM publications@acr.or RI Flowers, Christopher/F-1953-2010 OI Flowers, Christopher/0000-0002-9524-3990 FU PROCURE; Novartis FX B.S.H.: Travel expenses paid by PROCURE for a talks on using proton therapy for thoracic malignancies at a symposium in AZ. Travel expenses paid by US Oncology for a talk on using proton therapy for thoracic malignancies at a symposium in TX. A.Y.: Research support: Novartis, J & J, Curis Honorarium: Bayer, BMS, Cegene, Incyte, Janssen, Sanofi, Seattle Genetics, Takeda Millenium. C.R.F.: Optum RX-consultant. The other authors declare no conflicts of interest. NR 83 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 0277-3732 EI 1537-453X J9 AM J CLIN ONCOL-CANC JI Am. J. Clin. Oncol.-Cancer Clin. Trials PD AUG PY 2016 VL 39 IS 4 BP 384 EP 395 DI 10.1097/COC.0000000000000294 PG 12 WC Oncology SC Oncology GA DS5HH UT WOS:000380811800013 PM 27299425 ER PT J AU Askan, G Deshpande, V Klimstra, DS Adsay, V Sigel, C Shia, J Basturk, O AF Askan, Gokce Deshpande, Vikram Klimstra, David S. Adsay, Volkan Sigel, Carlie Shia, Jinru Basturk, Olca TI Expression of Markers of Hepatocellular Differentiation in Pancreatic Acinar Cell Neoplasms A Potential Diagnostic Pitfall SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE Pancreas; Acinar cell carcinoma; Hepatocellular carcinoma; Arginase 1; Glypican 3; Albumin ISH ID IN-SITU-HYBRIDIZATION; ALBUMIN MESSENGER-RNA; GLYPICAN-3 EXPRESSION; ALPHA-FETOPROTEIN; METASTATIC CARCINOMA; ONCOFETAL PROTEIN; SENSITIVE MARKER; HEP PAR-1; LIVER; TUMORS AB Objectives: Pancreatic acinar cell carcinoma (ACC) is a rare tumor that frequently metastasizes to the liver and may present a diagnostic challenge due to its morphologic similarity to hepatocellular carcinoma. We investigated (x-fetoprotein (AFP), hepatocyte paraffin antigen 1 (HepPar 1), glypican 3, arginase 1, and albumin messenger RNA (mRNA) in situ hybridization (ISH) in pancreatic neoplasms with ACC differentiation to assess their diagnostic value. Methods: AFP, HepPar 1, glypican 3, and arginase 1 immunohistochemical staining was performed on 28 ACCs using a tissue microarray. Albumin mRNA ISH was performed on full-faced sections. Results: Fifteen tumors were positive for at least one marker. Glypican 3 was positive in seven of 28, AFP in five 28, and albumin mRNA ISH in five of 20. None expressed arginase 1. Conclusions: Hepatocellular differentiation markers, including albumin mRNA ISH, may be positive in ACC, but arginase 1 appears to be uniformly negative. Thus, its use may improve the accuracy in distinguishing these neoplasms from hepatocellular carcinoma. If ACC diagnosis is considered, acinar differentiation can be reliably demonstrated by trypsin/chymotrypsin. C1 [Askan, Gokce; Klimstra, David S.; Sigel, Carlie; Shia, Jinru; Basturk, Olca] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10065 USA. [Deshpande, Vikram] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Adsay, Volkan] Emory Univ, Atlanta, GA 30322 USA. RP Basturk, O (reprint author), Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10065 USA. EM basturko@mskcc.org FU NCI NIH HHS [P30 CA008748] NR 49 TC 0 Z9 0 U1 2 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9173 EI 1943-7722 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD AUG PY 2016 VL 146 IS 2 BP 163 EP 169 DI 10.1093/ajcp/aqw096 PG 7 WC Pathology SC Pathology GA DT8WW UT WOS:000381777400003 PM 27425386 ER PT J AU Aaronson, EL Chang, YC Borczuk, P AF Aaronson, Emily L. Chang, Yuchiao Borczuk, Pierre TI A prediction model to identify patients without a concerning intraabdominal diagnosis SO AMERICAN JOURNAL OF EMERGENCY MEDICINE LA English DT Article ID ACUTE ABDOMINAL-PAIN; CLINICAL DECISION RULE; EMERGENCY-DEPARTMENT; ACUTE APPENDICITIS; ADVERSE OUTCOMES; DISCHARGE; CHILDREN; QUALITY; RISK AB Objective: Patients with abdominal diagnoses constitute 5% to 10% of all emergency department (ED) presentations. The goal of this study is to identify which of these patients will have a nonconcerning diagnosis based on demographic, physical examination, and basic laboratory testing. Methods: Consecutive patients from July 2013 to March 2014 discharged with a gastrointestinal (GI) diagnosis who presented to an urban, university-affiliated ED were identified. The cohort was split into a derivation set and a validation set. Using univariate and multivariable logistic regression analysis, a risk score was created based on the deviation data and then tested on the validation data. Results: There were 8852 patients with a GI diagnosis during the study period. A total of 7747 (87.5%) of them had a nonconcerning diagnosis. The logistic regression model identified 13 variables that predict a concerning GI diagnosis and created a scoring system ranging from 0 to 20. The area under the receiver operating characteristic was 0.81. When dichotomized at greater than or equal to 7 vs less than 7, the risk score has a sensitivity of 91% (95% confidence interval [CI], 88-94), specificity of 46% (95% CI, 44-48), positive predictive value of 17% (95% CI, 15-19) and negative predictive value of 98% (95% CI, 97-99). Conclusion: One can determine with a high degree of certainty, based only on an initial evaluation and screening laboratory work (excluding radiology) whether a patient who presents with a GI-related complaint has a nonconcerning diagnosis. This model could be used as a tool to aid in quality assurance when reviewing patients discharged with GI complaints and with future study, as a secondary triage instrument in a crowded ED environment, and aid in resource allocation. (C) 2016 Elsevier Inc. All rights reserved. C1 [Aaronson, Emily L.; Borczuk, Pierre] Harvard Med Sch, Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Chang, Yuchiao] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Aaronson, EL (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, Zero Emerson Pl,Suite 3B, Boston, MA 02114 USA. EM eaaronson@partners.org NR 31 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 2016 VL 34 IS 8 BP 1354 EP 1358 DI 10.1016/j.ajem.2016.03.063 PG 5 WC Emergency Medicine SC Emergency Medicine GA DS4LK UT WOS:000380752400005 PM 27113130 ER PT J AU Liu, SW Sri-On, J Tirrell, GP Nickel, C Bingisser, R AF Liu, Shan W. Sri-On, Jiraporn Tirrell, Gregory Philip Nickel, Christian Bingisser, Roland TI Serious conditions for ED elderly fall patients: a secondary analysis of the Basel Non-Specific Complaints study SO AMERICAN JOURNAL OF EMERGENCY MEDICINE LA English DT Article ID RISK-FACTORS; EMERGENCY-DEPARTMENT; OLDER-ADULTS; UNITED-STATES; COMMUNITY; PEOPLE; BENZODIAZEPINES; OUTCOMES; DEATH AB Objective: Falls among older adults are a public health problem and are multifactorial. We sought to determine whether falls predict more serious conditions in older adult patients presenting to the emergency department (ED) with a "nonspecific complaint" (NSC). A secondary objective was to examine what factors predicted serious conditions among older adult patients with a fall. Methods: This study was a secondary analysis of a prospective delayed-type cross-sectional diagnostic study that included a 30-day follow-up. We included patients 65 years and older who presented to the ED from May 2007 and July 2011 with a NSC and had an Emergency Severity Index score of 2 or 3. We then compared the serious conditions among older adults who presented to the ED with a fall with those who did not fall in a cohort of patients with NSC. Results: We had 1111 patients enrolled in our study; 518 (47%) of them had fallen. We found that 310 (60%) of elderly fall patients vs 349 (59%) of nonfall patients had a 30-day serious condition (P = .74). In multiple logistic regression analysis, falls did not predict serious conditions or 30-day mortality among all NSC patients. Among fall patients, male sex, diuretic use, and generalized weakness predicted serious conditions. Conclusion: Fall patients share many features with nonfall NSC patient. However, falls did not increase the risk of serious conditions. Falls in the elderly could be considered under the broader entity of NSC. (C) 2016 Elsevier Inc. All rights reserved. C1 [Liu, Shan W.; Tirrell, Gregory Philip] Massachusetts Gen Hosp, Emergency Dept, 55 Fruit St,Zero Emerson Pl,Room 346, Boston, MA 02114 USA. [Sri-On, Jiraporn] Navamindrahiraj Univ, Emergency Dept, Vajira Hosp, Bangkok, Thailand. [Nickel, Christian; Bingisser, Roland] Univ Basel Hosp, Emergency Dept, Basel, Switzerland. RP Liu, SW (reprint author), Massachusetts Gen Hosp, Emergency Dept, 55 Fruit St,Zero Emerson Pl,Room 346, Boston, MA 02114 USA. EM shanliu635@gmail.com; Jiraporn.rew@gmail.com; gregt89@yahoo.com; Christian.nickle@usb.ch; Roland.Bingisser@usb.ch OI Sri-on, Jiraporn/0000-0002-8853-2567 NR 29 TC 0 Z9 0 U1 6 U2 6 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 2016 VL 34 IS 8 BP 1394 EP 1399 DI 10.1016/j.ajem.2016.04.007 PG 6 WC Emergency Medicine SC Emergency Medicine GA DS4LK UT WOS:000380752400012 PM 27133925 ER PT J AU Prabhakar, AM Harvey, HB Brinegar, KN Raja, AS Kelly, JR Brink, JA Saini, S Oklu, R AF Prabhakar, Anand M. Harvey, H. Benjamin Brinegar, Katelyn N. Raja, Ali S. Kelly, James R. Brink, James A. Saini, Sanjay Oklu, Rahmi TI Critical access hospital ED to quaternary medical center: successful implementation of an integrated Picture Archiving and Communications System for patient transfers by air and sea SO AMERICAN JOURNAL OF EMERGENCY MEDICINE LA English DT Article ID CT ANGIOGRAPHY; SERVICES AB Purpose: The purpose of this study was to investigate the role of imaging in transfers between an island Critical Access Hospital (CAH) emergency department (ED) and a quaternary care hospital. Methods: Electronic medical records were reviewed to identify all patients who were transferred from an island CAH to our quaternary care hospital in 2012 and 2013. Medical history, transfer diagnosis, and the type of imaging performed at the CAH prior to transfer were reviewed. Results: During the study period, a total of 22 075 ED visits were made to the CAH and 696 (3.2%) of these patients were transferred for higher level of care, with 424 (60.9%) of the patients transferred to our quaternary care hospital. The most common reasons for transfer were cardiac (121; 28.5%), trauma (82; 19.3%), gastrointestinal (63; 14.9%), and neurologic conditions (54; 12.7%). 349 patients (82.3%) had imaging prior to transfer (56.4% radiograph, 33.5% computed tomography, 4.7% magnetic resonance imaging, 8.0% ultrasound). Of patients that had imaging, 53.6% had positive imaging findings related to the transfer diagnosis, and patients transferred for noncardiac etiologies were significantly more likely to have imaging findings related to their transfer diagnosis compared with patients transferred for cardiac etiologies (72.9% vs 6.9%, respectively; P<.0001). Conclusion: Approximately 3 of every 100 ED visits to the rural CAH required transfer for higher level of care, with nearly three-quarters of noncardiac transferred patients having a positive imaging finding related to the reason for transfer. (C) 2016 Elsevier Inc. All rights reserved. C1 [Prabhakar, Anand M.; Harvey, H. Benjamin; Brinegar, Katelyn N.; Brink, James A.; Saini, Sanjay] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Prabhakar, Anand M.; Harvey, H. Benjamin; Raja, Ali S.; Brink, James A.; Saini, Sanjay] Harvard Med Sch, Boston, MA USA. [Raja, Ali S.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Kelly, James R.] Nantucket Cottage Hosp, Nantucket, MA USA. [Oklu, Rahmi] Mayo Clin, Dept Radiol, Div Intervent Radiol, Scottsdale, AZ USA. RP Prabhakar, AM (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Div Cardiovasc Imaging, 55 Fruit St,Gray 2, Boston, MA 02114 USA. EM aprabhakar@mgh.harvard.edu NR 9 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0735-6757 EI 1532-8171 J9 AM J EMERG MED JI Am. J. Emerg. Med. PD AUG PY 2016 VL 34 IS 8 BP 1427 EP 1430 DI 10.1016/j.ajem.2016.04.015 PG 4 WC Emergency Medicine SC Emergency Medicine GA DS4LK UT WOS:000380752400018 PM 27130587 ER PT J AU Wilcox, SR Richards, JB Fisher, DF Sankoff, J Seigel, TA AF Wilcox, Susan R. Richards, Jeremy B. Fisher, Daniel F. Sankoff, Jeffrey Seigel, Todd A. TI Initial mechanical ventilator settings and lung protective ventilation in the ED SO AMERICAN JOURNAL OF EMERGENCY MEDICINE LA English DT Article ID RESPIRATORY-DISTRESS-SYNDROME; EMERGENCY-DEPARTMENT PATIENTS; LOWER TIDAL VOLUMES; CONTROLLED-TRIAL; INJURY; PRESSURE; SURGERY; PATIENT; RISK AB Objective: Mechanical ventilation with low tidal volumes has been shown to improve outcomes for patients both with and without acute respiratory distress syndrome. This study aims to characterize mechanically ventilated patients in the emergency department (ED), describe the initial ED ventilator settings, and assess for associations between lung protective ventilation strategies in the ED and outcomes. Methods: This was a multicenter, prospective, observational study of mechanical ventilation at 3 academic EDs. We defined lung protective ventilation as a tidal volume of less than or equal to 8mL/kg of predicted body weight and compared outcomes for patients ventilated with lung protective vs non-lung protective ventilation, including inhospital mortality, ventilator days, intensive care unit length of stay, and hospital length of stay. Results: Data from 433 patients were analyzed. Altered mental status without respiratory pathology was the most common reason for intubation, followed by trauma and respiratory failure. Two hundred sixty-one patients (60.3%) received lung protective ventilation, but most patients were ventilated with a low positive end-expiratory pressure, high fraction of inspired oxygen strategy. Patients were ventilated in the ED for a mean of 5 hours and 7 minutes but had few ventilator adjustments. Outcomes were not significantly different between patients receiving lung protective vs non-lung protective ventilation. Conclusions: Nearly 40% of ED patients were ventilated with non-lung protective ventilation as well as with low positive end-expiratory pressure and high fraction of inspired oxygen. Despite a mean ED ventilation time of more than 5 hours, few patients had adjustments made to their ventilators. (C) 2016 Elsevier Inc. All rights reserved. C1 [Wilcox, Susan R.] Med Univ South Carolina, Div Emergency Med, Div Pulm Crit Care Allergy & Sleep Med, Charleston, SC 29425 USA. [Richards, Jeremy B.] Med Univ South Carolina, Div Pulm Crit Care Allergy & Sleep Med, Charleston, SC USA. [Fisher, Daniel F.] Massachusetts Gen Hosp, Resp Care Serv, Boston, MA 02114 USA. [Sankoff, Jeffrey] Univ Colorado, Sch Med, Dept Emergency Med, Denver Hlth Med Ctr, Denver, CO USA. [Seigel, Todd A.] Kaiser Permanente East Bay, Dept Emergency Med & Crit Care, Oakland Med Ctr, Oakland, CA USA. [Seigel, Todd A.] Kaiser Permanente East Bay, Dept Emergency Med & Crit Care, Richmond Med Ctr, Richmond, CA USA. RP Wilcox, SR (reprint author), Med Univ South Carolina, Div Emergency Med, Div Pulm Crit Care Allergy & Sleep Med, Charleston, SC 29425 USA. EM susanrwilcoxmd@gmail.com; jeremyrichardsmd@gmail.com; dfisher2@mgh.harvard.edu; Jeffrey.sankoff@dhha.org; todd.a.seigel@gmail.com OI Wilcox, Susan/0000-0001-7477-7531 FU University Emergency Medicine Foundation; Rhode Island Hospital FX This study was supported by institutional funds. At Rhode Island Hospital, the work was funded in part by an institutional development grant from the University Emergency Medicine Foundation. NR 27 TC 1 Z9 1 U1 4 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0735-6757 EI 1532-8171 J9 AM J EMERG MED JI Am. J. Emerg. Med. PD AUG PY 2016 VL 34 IS 8 BP 1446 EP 1451 DI 10.1016/j.ajem.2016.04.027 PG 6 WC Emergency Medicine SC Emergency Medicine GA DS4LK UT WOS:000380752400022 PM 27139256 ER PT J AU Roberts, ES Belland, L Rivera-Reyes, L Hwang, U AF Roberts, Eleanor S. Belland, Laura Rivera-Reyes, Laura Hwang, Ula TI The effect of surgical consult in the treatment of abdominal pain in older adults in the ED SO AMERICAN JOURNAL OF EMERGENCY MEDICINE LA English DT Article ID EMERGENCY-DEPARTMENT; POSTOPERATIVE PAIN; ANALGESIA; QUALITY; IMPACT; CARE AB Objective: The objective was to determine whether need for surgical consult contributes to delayed or reduced analgesic administration in older adults presenting to the emergency department with abdominal pain. Methods: Secondary data analyses from a prospective cohort study consisting of adults >= 65 years in age presenting to the emergency department with a chief concern of abdominal pain from November 1, 2012, through October 31, 2014, were performed. Measurements included administration of analgesics, time to administration, type given, and pain score reduction. Covariates for adjusted analyses included age, sex, race/ethnicity, and Emergency Severity Index. Results: A total of 3522 patients were included, of which 281 (8.7%) received any consult. Consult patients were less likely to receive any analgesic medication (53.0%) compared with nonconsult patients (62.5%) (relative risk = 0.80; 95% confidence interval, 0.70-0.91). However, among those patients receiving analgesic medications, there were no differences in likelihood of receiving an opioid, time to administration, or pain score reduction. When analyzing patients who received a surgical consult (n = 154, 4.4%), these associations were notably stronger. Surgical consult patients had a lower rate of analgesic administration (46.8%) compared with nonconsult patients (62.4%) (relative risk = 0.75; 95% confidence interval, 0.63-0.89). Again, no differences were found in likelihood of receiving any opioid, time to administration, or pain score reduction. Conclusion: Need for abdominal surgical consult is associated with decreased administration of analgesics in older patients, possibly indicating a continued need to improve management in this setting. This difference, however, did not impact pain score reductions. (C) 2016 Elsevier Inc. All rights reserved. C1 [Roberts, Eleanor S.; Belland, Laura; Rivera-Reyes, Laura; Hwang, Ula] Icahn Sch Med Mt Sinai, Dept Emergency Med, 1 Gustave L Levy Pl,Box 1062, New York, NY 10029 USA. [Belland, Laura] Columbia Univ, Med Ctr, Ctr Family & Community Med, 610 W 158th St, New York, NY 10032 USA. [Hwang, Ula] Icahn Sch Med Mt Sinai, Brookdale Dept Geriatr & Palliat Med, New York, NY 10029 USA. [Hwang, Ula] James J Peters VAMC, Geriatr Res Educ & Clin Ctr, Bronx, NY USA. RP Roberts, ES (reprint author), 50 E 98th St Apt 8J-3, New York, NY 10029 USA. EM Eleanor.roberts@icahn.mssm.edu FU National Institutes of HealthR21 [AG040734]; Icahn School of Medicine Summer Student Research Stipend FX National Institutes of HealthR21 AG040734 (Hwang); Icahn School of Medicine Summer Student Research Stipend (Roberts). NR 17 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0735-6757 EI 1532-8171 J9 AM J EMERG MED JI Am. J. Emerg. Med. PD AUG PY 2016 VL 34 IS 8 BP 1524 EP 1527 DI 10.1016/j.ajem.2016.05.010 PG 4 WC Emergency Medicine SC Emergency Medicine GA DS4LK UT WOS:000380752400036 PM 27241564 ER PT J AU Chokengarmwong, N Ortiz, LA Raja, A Goldstein, JN Huang, F Yeh, DD AF Chokengarmwong, Nalin Ortiz, Luis Alfonso Raja, Ali Goldstein, Joshua N. Huang, Fei Yeh, D. Dante TI Outcome of patients receiving CPR in the ED of an urban academic hospital SO AMERICAN JOURNAL OF EMERGENCY MEDICINE LA English DT Article ID CHEST CARDIOPULMONARY-RESUSCITATION; TWO-DIMENSIONAL ECHOCARDIOGRAPHY; NONTRAUMATIC CARDIAC-ARREST; AMERICAN-HEART-ASSOCIATION; CLOSED-CHEST; BLOOD-FLOW; PERFUSION-PRESSURE; VALVE MOTION; MASSAGE; DOGS AB Background: The success of Closed Chest Cardiopulmonary Resuscitation (CC-CPR) degrades with prolonged times. Open Chest CPR (OC-CPR) is an alternative that may lead to superior coronary and cerebral perfusion. It is critical to determine when continued CC-CPR is unlikely to be successful to justify initiating OC-CPR as rescue therapy. The purpose of this study is to review CC-CPR outcomes to define a time threshold for attempting OC-CPR. Methods: We identified all adult non-trauma patients diagnosed with cardiac arrest, ventricular fibrillation, ventricular tachycardia and asystole from 1/1/10-12/31/14. We collected demographics, cardiac rhythm, resuscitation duration, survival to hospital discharge and neurological outcome. Using time to ROSC after ED arrival and good neurological outcome, we explored various times as triggers for attempting OC-CPR. Results: Among 242 cases of CPR, 205 cases were out-of-hospital cardiac arrest (OHCA). Mean age was 63.7 (+/- 16.9), woman comprised 29.8% (72/242), and median prehospital CPR time was 30 min (20-44). Patients suffering ED arrest had improved ROSC (54.1% vs. 12.7%, p<0.001) and survival to hospital discharge rates (37.8% vs. 2.9%, p<0.001) compared to OHCA. Patients achieving ROSC hadmedian total CPR duration of 18 minutes (10 minutes of pre-hospital CPR) compared with patients without ROSC who had 45 minutes (30 pre-hospital) respectively. No patient receiving > 10 minutes of CPR in the ED survived to hospital discharge. Conclusion: In patients suffering OHCA and requiring CC-CPR in the ED, overall survival rate to good neurologic function is low. OC-CPR could potentially be attempted after 10 minutes of CC-CPR in the ED. (C) 2016 Elsevier Inc. All rights reserved. C1 [Chokengarmwong, Nalin] Chulalongkorn Univ, King Chulalongkorn Mem Hosp, Thai Red Cross Soc, Bangkok, Thailand. [Chokengarmwong, Nalin] Chulalongkorn Univ, Fac Med, Dept Anesthesiol, Bangkok, Thailand. [Chokengarmwong, Nalin; Ortiz, Luis Alfonso; Yeh, D. Dante] Massachusetts Gen Hosp, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA 02114 USA. [Chokengarmwong, Nalin; Ortiz, Luis Alfonso; Raja, Ali; Goldstein, Joshua N.; Yeh, D. Dante] Harvard Med Sch, Boston, MA USA. [Raja, Ali; Goldstein, Joshua N.] Massachusetts Gen Hosp, Dept Emergency Medicinex, Boston, MA 02114 USA. [Huang, Fei] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Yeh, DD (reprint author), 165 Cambridge St 810, Boston, MA 02114 USA. EM dyeh2@partners.org NR 40 TC 0 Z9 0 U1 5 U2 5 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 2016 VL 34 IS 8 BP 1595 EP 1599 DI 10.1016/j.ajem.2016.05.060 PG 5 WC Emergency Medicine SC Emergency Medicine GA DS4LK UT WOS:000380752400050 PM 27339223 ER PT J AU Obaitan, I Dwyer, R Lipworth, AD Kupper, TS Camargo, CA Hooper, DC Murphy, GF Pallin, DJ AF Obaitan, Itegbemie Dwyer, Richard Lipworth, Adam D. Kupper, Thomas S. Camargo, Carlos A., Jr. Hooper, David C. Murphy, George F. Pallin, Daniel J. TI Failure of antibiotics in cellulitis trials: a systematic review and meta-analysis SO AMERICAN JOURNAL OF EMERGENCY MEDICINE LA English DT Review ID SKIN-STRUCTURE INFECTIONS; SOFT-TISSUE INFECTIONS; ACUTE BACTERIAL SKIN; RESISTANT STAPHYLOCOCCUS-AUREUS; RANDOMIZED CONTROLLED-TRIAL; COMPLICATED SKIN; DOUBLE-BLIND; UNCOMPLICATED SKIN; TRIMETHOPRIM-SULFAMETHOXAZOLE; NON-INFERIORITY AB Objectives: The objectives of the study are to quantify trial-to-trial variability in antibiotic failure rates, in randomized clinical trials of cellulitis treatment and to provide a point estimate for the treatment failure rate across trials. Methods: We conducted a structured search for clinical trials evaluating antibiotic treatment of cellulitis, indexed in PubMed by August 2015. We included studies published in English and excluded studies conducted wholly outside of developed countries because the pathophysiology of cellulitis is likely to be different in such settings. Two authors reviewed all abstracts identified for possible inclusion. Of studies identified initially, 5% met the selection criteria. Two reviewers extracted data independently, and data were pooled using the Freeman-Tukey transformation under a random-effects model. Our primary outcome was the summary estimate of treatment failure across intent-to-treat and clinically evaluable participants. Results: We included 19 articles reporting data from 20 studies, for a total of 3935 patients. Treatment failure was reported in 6% to 37% of participants in the 9 trials reporting intent-to-treat results, with a summary point estimate of 18% failing treatment (95% confidence interval, 15%-21%). In the 15 articles evaluating clinically evaluable participants, treatment failure rates ranged from 3% to 42%, and overall, 12% (95% confidence interval, 10%-14%) were designated treatment failures. Conclusions: Treatment failure rates vary widely across cellulitis trials, from 6% to 37%. This may be due to confusion of cellulitis with its mimics and perhaps problems with construct validity of the diagnosis of cellulitis. Such factors bias trials toward equivalence and, in routine clinical care, impair quality and antibiotic stewardship. Objective diagnostic tools are needed. (C) 2016 Elsevier Inc. All rights reserved. C1 [Obaitan, Itegbemie; Dwyer, Richard; Pallin, Daniel J.] Brigham & Womens Hosp, Dept Emergency Med, 75 Francis St, Boston, MA 02115 USA. [Lipworth, Adam D.; Kupper, Thomas S.] Brigham & Womens Hosp, Dept Dermatol, 75 Francis St, Boston, MA 02115 USA. [Camargo, Carlos A., Jr.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Hooper, David C.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Murphy, George F.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. RP Pallin, DJ (reprint author), 75 Francis St,Neville House 304-D, Boston, MA 02115 USA. EM dpallin@partners.org NR 39 TC 1 Z9 1 U1 3 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0735-6757 EI 1532-8171 J9 AM J EMERG MED JI Am. J. Emerg. Med. PD AUG PY 2016 VL 34 IS 8 BP 1645 EP 1652 DI 10.1016/j.ajem.2016.05.064 PG 8 WC Emergency Medicine SC Emergency Medicine GA DS4LK UT WOS:000380752400061 PM 27344098 ER PT J AU Baughmd, CW Brooks, GA Reust, AC Wang, TJ Caterino, JM Baker, ON Pallin, DJ AF Baughmd, Christopher W. Brooks, Gabriel A. Reust, Audrey C. Wang, Thomas J. Caterino, Jeffrey M. Baker, Olesya N. Pallin, Daniel J. TI Provider familiarity with specialty society guidelines for risk stratification and management of patients with febrile neutropenia SO AMERICAN JOURNAL OF EMERGENCY MEDICINE LA English DT Letter ID CLINICAL-PRACTICE GUIDELINE; EMERGENCY-DEPARTMENT C1 [Baughmd, Christopher W.; Reust, Audrey C.; Baker, Olesya N.; Pallin, Daniel J.] Brigham & Womens Hosp, Dept Emergency Med, Neville House 2nd Floor,75 Francis St, Boston, MA 02115 USA. [Brooks, Gabriel A.] Dana Farber Canc Inst, Gastrointestinal Canc Ctr, Boston, MA 02115 USA. [Wang, Thomas J.] Harvard Med Sch, Boston, MA USA. [Caterino, Jeffrey M.] Ohio State Univ, Dept Emergency Med, Wexner Med Ctr, Columbus, OH 43210 USA. RP Baughmd, CW (reprint author), Brigham & Womens Hosp, Dept Emergency Med, Neville House 2nd Floor,75 Francis St, Boston, MA 02115 USA. EM cbaugh@partners.org NR 10 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0735-6757 EI 1532-8171 J9 AM J EMERG MED JI Am. J. Emerg. Med. PD AUG PY 2016 VL 34 IS 8 BP 1704 EP 1705 DI 10.1016/j.ajem.2016.05.047 PG 3 WC Emergency Medicine SC Emergency Medicine GA DS4LK UT WOS:000380752400094 PM 27262602 ER PT J AU Zhong, F Mallipattu, SK Estrada, C Menon, M Salem, F Jain, MK Chen, HY Wang, YJ Lee, K He, JC AF Zhong, Fang Mallipattu, Sandeep K. Estrada, Chelsea Menon, Madhav Salem, Fadi Jain, Mukesh K. Chen, Hongyu Wang, Yongjun Lee, Kyung He, John C. TI Reduced Kruppel-Like Factor 2 Aggravates Glomerular Endothelial Cell Injury and Kidney Disease in Mice with Unilateral Nephrectomy SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID RENAL HEMODYNAMIC-RESPONSE; PROINFLAMMATORY ACTIVATION; TRANSCRIPTION FACTORS; NITRIC-OXIDE; KLF2; EXPRESSION; REGULATOR; DIFFERENTIATION; DEFICIENCY; PODOCYTES AB Loss of functional nephrons induces compensatory glomerular hyperfiltration and hypertrophy, leading to the progression of chronic kidney disease. Kruppel-like factor 2 (KLF2), a shear-stress inducible transcription factor, confers protection against endothelial injury. Because glomerular hyperfiltration is associated with shear stress, we hypothesized that KLF2 may be an important factor in the compensatory response to unilateral nephrectomy (UNX). To test this hypothesis, endothelial cell specific Klf2 heterozygous knockout mice (KO) and their wild-type Littermate control (WT) underwent either UNX or sham-operation. WT-UNX mice developed compensatory renal hypertrophy as expected, whereas K0-UNX mice did not. K0-UNX mice exhibited higher blood pressure, reduced glomerular filtration rate, and significant increase in proteinuria and glomerulosclerosis compared to WT-UNX. Expression of endothelial nitric oxide synthase (official name Nos3), a known transcriptional target gene of KLF2, was significantly reduced and dysregulation of other endothelial genes was also observed in the glomeruli of K0-UNX when compared to WT-UNX and sham-operated mice. Furthermore, both podocyte number and expression of podocyte markers were also significantly reduced in K0-UNX glomeruli, indicating a potential cross talk between glomerular endothelial cells and podocytes. Finally, decreased renal expression of KLF2 in nephrectomy patients was associated with the progression of kidney disease. Taken together, our data demonstrate a protective role of KLF2 against glomerular endothelial cell injury and progression of chronic kidney disease in the model of compensatory renal hypertrophy. C1 [Zhong, Fang; Menon, Madhav; Lee, Kyung; He, John C.] Icahn Sch Med Mt Sinai, Dept Med Nephrol, New York, NY USA. [Salem, Fadi] Icahn Sch Med Mt Sinai, Dept Pathol, New York, NY USA. [Zhong, Fang; Chen, Hongyu; Wang, Yongjun] Zhejiang Chinese Med Univ, Hang Zhou Hosp Tradit Chinese Med, Dept Nephrol, Hangzhou, Zhejiang, Peoples R China. [Mallipattu, Sandeep K.; Estrada, Chelsea] SUNY Stony Brook, Dept Med, Div Nephrol, Stony Brook, NY USA. [Jain, Mukesh K.] Case Western Reserve Univ, Case Cardiovasc Inst Res Inst, Dept Med, Cleveland, OH USA. [He, John C.] James J Peters Vet Affairs Med Ctr, Renal Sect, Bronx, NY USA. RP He, JC (reprint author), Mt Sinai Sch Med, Div Nephrol, Box 1243,One Gustave L Levy Pl, New York, NY 10029 USA. EM cijiang.he@mssm.edu FU Chinese 973 fund [2012CB517601]; VA Merit Award; NIH [1R01DK078897, 1R01DK088541, P01-DK-56492, K08DK102519] FX Supported by Chinese 973 fund 2012CB517601 (J.C.H.), VA Merit Award (J.C.H.), and NIH 1R01DK078897, 1R01DK088541, and P01-DK-56492 (J.C.H.) and K08DK102519 (S.K.M.). NR 37 TC 2 Z9 2 U1 3 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9440 EI 1525-2191 J9 AM J PATHOL JI Am. J. Pathol. PD AUG PY 2016 VL 186 IS 8 BP 2021 EP 2031 DI 10.1016/j.ajpath.2016.03.018 PG 11 WC Pathology SC Pathology GA DS2ON UT WOS:000380623500005 PM 27317905 ER PT J AU Moskowitz, A Andersen, LW Cocchi, M Donnino, MW AF Moskowitz, Ari Andersen, Lars W. Cocchi, Michael Donnino, Michael W. TI The Misapplication of Severity-of-Illness Scores toward Clinical Decision Making SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Editorial Material ID C-SPINE RULE; INTERNATIONAL CONSENSUS DEFINITIONS; SEPTIC SHOCK SEPSIS-3; CRITERIA; TRAUMA C1 [Moskowitz, Ari] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Andersen, Lars W.] Aarhus Univ Hosp, Res Ctr Emergency Med, Aarhus, Denmark. [Cocchi, Michael] Beth Israel Deaconess Med Ctr, Dept Anesthesia Crit Care, Boston, MA 02215 USA. [Donnino, Michael W.] Beth Israel Deaconess Med Ctr, Dept Emergency Med, Boston, MA 02215 USA. RP Moskowitz, A (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. OI Andersen, Lars Wiuff/0000-0001-5752-8082 NR 7 TC 3 Z9 3 U1 3 U2 3 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 AUG 1 PY 2016 VL 194 IS 3 BP 256 EP 258 PG 4 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DT7WA UT WOS:000381697700007 PM 27299379 ER PT J AU Blumenthal, KG Park, MA Macy, EM AF Blumenthal, Kimberly G. Park, Miguel A. Macy, Eric M. TI Redesigning the allergy module of the electronic health record SO ANNALS OF ALLERGY ASTHMA & IMMUNOLOGY LA English DT Article ID TOXIC EPIDERMAL NECROLYSIS; STEVENS-JOHNSON SYNDROME; ADVERSE DRUG EVENTS; PENICILLIN ALLERGY; HYPERSENSITIVITY REACTIONS; CROSS-REACTIVITY; KNOWLEDGE; ANTIBIOTICS; PREVALENCE; GUIDELINE C1 [Blumenthal, Kimberly G.] Massachusetts Gen Hosp, Dept Med, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. [Blumenthal, Kimberly G.] Harvard Med Sch, Boston, MA USA. [Blumenthal, Kimberly G.] Massachusetts Gen Hosp, Edward P Lawrence Ctr Qual & Safety, Boston, MA 02114 USA. [Blumenthal, Kimberly G.] Massachusetts Gen Profess Org, Boston, MA USA. [Park, Miguel A.] Mayo Clin, Allergy & Immunol, Rochester, MN USA. [Macy, Eric M.] San Diego Med Ctr, Southern Calif Permanente Med Grp, Dept Allergy, San Diego, CA USA. RP Blumenthal, KG (reprint author), Massachusetts Gen Hosp, 50 Staniford St,Ninth Floor, Boston, MA 02114 USA. EM kblumenthal1@partners.org FU ALK Abello Inc FX Dr Blumenthal reported creating clinical decision support for drug allergies used within Partners HealthCare Systems. Dr Macy reported being a partner in the Southern California Permanente Medical Group, receiving research grants from ALK Abello Inc to study adverse drug reactions, and being a member of clinical trial safety and monitoring committees for BioMarin Pharmaceutical Inc and Ultragenyx. NR 32 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 1081-1206 EI 1534-4436 J9 ANN ALLERG ASTHMA IM JI Ann. Allergy Asthma Immunol. PD AUG PY 2016 VL 117 IS 2 BP 126 EP 131 DI 10.1016/j.anai.2016.05.017 PG 6 WC Allergy; Immunology SC Allergy; Immunology GA DT7YS UT WOS:000381705100005 PM 27315742 ER PT J AU Sholl, LM Aisner, DL Allen, TC Beasley, MB Cagle, PT Capelozzi, VL Dacic, S Hariri, LP Kerr, KM Lantuejoul, S Mino-Kenudson, M Raparia, K Rekhtman, N Roy-Chowdhuri, S Thunnissen, E Tsao, M Vivero, M Yatabe, Y AF Sholl, Lynette M. Aisner, Dara L. Allen, Timothy Craig Beasley, Mary Beth Cagle, Philip T. Capelozzi, Vera L. Dacic, Sanja Hariri, Lida P. Kerr, Keith M. Lantuejoul, Sylvie Mino-Kenudson, Mari Raparia, Kirtee Rekhtman, Natasha Roy-Chowdhuri, Sinchita Thunnissen, Eric Tsao, Ming Vivero, Marina Yatabe, Yasushi TI Liquid Biopsy in Lung Cancer A Perspective From Members of the Pulmonary Pathology Society SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article ID CIRCULATING TUMOR-CELLS; RECEPTOR MUTATION STATUS; PLASMA DNA; EGFR MUTATIONS; ACQUIRED-RESISTANCE; COLORECTAL-CANCER; PROSTATE-CANCER; BREAST-CANCER; SURVIVAL; BIOMARKERS AB Liquid biopsy has received extensive media coverage and has been called the holy grail of cancer detection. Attempts at circulating tumor cell and genetic material capture have been progressing for several years, and recent financially and technically feasible improvements of cell capture devices, plasma isolation techniques, and highly sensitive polymerase chain reaction and sequencing-based methods have advanced the possibility of liquid biopsy of solid tumors. Although practical use of circulating RNA-based testing has been hindered by the need to fractionate blood to enrich for RNAs, the detection of circulating tumor cells has profited from advances in cell capture technology. In fact, the US Food and Drug Administration has approved one circulating tumor cell selection platform, the CellSearch System. Although the use of liquid biopsy in a patient population with a genomically defined solid tumor may potentially be clinically useful, it currently does not supersede conventional pretreatment tissue diagnosis of lung cancer. Liquid biopsy has not been validated for lung cancer diagnosis, and its lower sensitivity could lead to significant diagnostic delay if liquid biopsy were to be used in lieu of tissue biopsy. Ultimately, notwithstanding the enthusiasm encompassing liquid biopsy, its clinical utility remains unproven. C1 [Sholl, Lynette M.; Vivero, Marina] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Sholl, Lynette M.; Hariri, Lida P.; Mino-Kenudson, Mari; Vivero, Marina] Harvard Med Sch, Boston, MA USA. [Aisner, Dara L.] Univ Colorado, Ctr Canc, Dept Pathol, Denver, CO 80262 USA. [Allen, Timothy Craig] Univ Texas Med Branch, Dept Pathol, 301 Univ Blvd, Galveston, TX 77555 USA. [Beasley, Mary Beth] Icahn Sch Med Mt Sinai, Dept Pathol, New York, NY 10029 USA. [Cagle, Philip T.] Weill Cornell Med Coll, Dept Pathol, New York, NY USA. [Cagle, Philip T.] Houston Methodist Hosp, Dept Pathol & Genom Med, Houston, TX USA. [Capelozzi, Vera L.] Univ Sao Paulo, Sch Med, Dept Pathol, Sao Paulo, Brazil. [Dacic, Sanja] Univ Pittsburgh, Med Ctr, Dept Pathol, Pittsburgh, PA USA. [Hariri, Lida P.; Mino-Kenudson, Mari] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Kerr, Keith M.] Univ Aberdeen, Sch Med, Dept Pathol, Foresterhill, Aberdeen, Scotland. [Kerr, Keith M.] Aberdeen Royal Infirm, Foresterhill, Aberdeen, Scotland. [Lantuejoul, Sylvie] Ctr Leon Berard, Dept Biopathol, Lyon, France. [Lantuejoul, Sylvie] J Fourier Univ, INSERM U823, Inst Bonniot A, Grenoble, France. [Raparia, Kirtee] Northwestern Univ, Feinberg Sch Med, Dept Pathol, Chicago, IL 60611 USA. [Rekhtman, Natasha] Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA. [Roy-Chowdhuri, Sinchita] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Thunnissen, Eric] Vrije Univ Amsterdam Med Ctr, Dept Pathol, Amsterdam, Netherlands. [Tsao, Ming] Univ Hlth Network, Princess Margaret Canc Ctr, Dept Pathol, Toronto, ON, Canada. [Tsao, Ming] Univ Toronto, Toronto, ON, Canada. [Yatabe, Yasushi] Aichi Canc Ctr, Dept Pathol & Mol Diagnost, Nagoya, Aichi, Japan. RP Allen, TC (reprint author), Univ Texas Med Branch, Dept Pathol, 301 Univ Blvd, Galveston, TX 77555 USA. EM tcallen@utmb.edu FU AstraZeneca FX Dr Sholl previously served on the Genentech Scientific Advisory Board. Dr Tsao has received honorarium and a research grant from AstraZeneca. The other authors have no relevant financial interest in the products or companies described in this article. NR 53 TC 7 Z9 7 U1 4 U2 7 PU COLL AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 EI 1543-2165 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD AUG PY 2016 VL 140 IS 8 BP 825 EP 829 DI 10.5858/arpa.2016-0163-SA PG 5 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA DT7DF UT WOS:000381646600015 PM 27195432 ER PT J AU Kerr, DA Sweeney, B Arpin, RN Ring, M Pitman, MB Wilbur, DC Faquin, WC AF Kerr, Darcy A. Sweeney, Brenda Arpin, Ronald N., III Ring, Melissa Pitman, Martha B. Wilbur, David C. Faquin, William C. TI Automated Extraction of Formalin-Fixed, Paraffin-Embedded Tissue for High-Risk Human Papillomavirus Testing of Head and Neck Squamous Cell Carcinomas Using the Roche Cobas 4800 System SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article ID OROPHARYNGEAL CANCER; CYCLE CONTROL; HPV STATUS; IMMUNOHISTOCHEMISTRY; INVOLVEMENT; SPECIMEN; SURVIVAL; TRIALS; ISSUES AB Context.-Testing for high-risk human papillomavirus (HR-HPV) in head and neck squamous cell carcinomas (HNSCCs) is important for both prognostication and clinical management. Several testing platforms are available for HR-HPV; however, effective alternative automat. ed approaches are needed. Objective.-To assess the performance of the automated Roche cobas 4800 HPV real-time polymerase chain reaction-based system on formalin-fixed, paraffin-embedded HNSCC specimens and compare results with standard methods of in situ hybridization (ISH) and p16 immunohistochemistry. Design.-Formalin-fixed, paraffin-embedded samples of HNSCC were collected from archival specimens in the Department of Pathology, Massachusetts General Hospital (Boston), and prepared using the automated system by deparaffinization and dehydration followed by tissue lysis. Samples were integrated into routine cervical cytology testing runs by cobas. Corresponding formalin-fixed, paraffin-embedded samples were evaluated for HR-HPV by ISH and p16 by immunohistochemistry. Discrepant cases were adjudicated by polymerase chain reaction. Results.-Sixty-two HNSCC samples were analyzed using the automated cobas system, ISH, and immunohistochemistry. Fifty-two percent (n = 32 of 62) of formalin-fixed, paraffin-embedded tumors were positive for HR-HPV by cobas. Eighty-eight percent (n = 28 of 32) of cases were the HPV 16 subtype and 12% (n = 4 of 32) were other HR-HPV subtypes. Corresponding testing with ISH was concordant in 92% (n = 57 of 62) of cases. Compared with the adjudication polymerase chain reaction standard, there were 3 false-positive cases by cobas. Conclusions.-Concordance in HNSCC HR-HPV status between cobas and ISH was more than 90%. The cobas demonstrated a sensitivity of 100% and a specificity of 91% for detection of HR-HPV. Advantages favoring cobas include its automation, cost efficiency, objective results, and ease of performance. C1 [Faquin, William C.] Massachusetts Gen Hosp, Dept Pathol, Warren Bldg 225,55 Fruit St, Boston, MA 02114 USA. Harvard Med Sch, Boston, MA USA. RP Faquin, WC (reprint author), Massachusetts Gen Hosp, Dept Pathol, Warren Bldg 225,55 Fruit St, Boston, MA 02114 USA. EM wfaquin@mgh.harvard.edu NR 27 TC 0 Z9 0 U1 0 U2 0 PU COLL AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 EI 1543-2165 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD AUG PY 2016 VL 140 IS 8 BP 844 EP 848 DI 10.5858/arpa.2015-0272-OA PG 5 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA DT7DF UT WOS:000381646600018 PM 27031775 ER PT J AU Gerami-Naini, B Smith, A Maione, AG Kashpur, O Carpinito, G Veves, A Mooney, DJ Garlick, JA AF Gerami-Naini, Behzad Smith, Avi Maione, Anna G. Kashpur, Olga Carpinito, Gianpaolo Veves, Aristides Mooney, David J. Garlick, Jonathan A. TI Generation of Induced Pluripotent Stem Cells from Diabetic Foot Ulcer Fibroblasts Using a Nonintegrative Sendai Virus SO CELLULAR REPROGRAMMING LA English DT Article ID HUMAN IPS CELLS; CHRONIC WOUNDS; CELLULAR INFILTRATE; GENE-EXPRESSION; VENOUS ULCERS; LEG ULCERS; PYROSEQUENCING(TM); DIFFERENTIATION; REPAIR AB Diabetic foot ulcers (DFUs) are nonhealing chronic wounds that are a serious complication of diabetes. Since induced pluripotent stem cells (iPSCs) may offer a potent source of autologous cells to heal these wounds, we studied if repair-deficient fibroblasts, derived from DFU patients and age-and site-matched control fibroblasts, could be reprogrammed to iPSCs. To establish this, we used Sendai virus to successfully reprogram six primary fibroblast cell lines derived from ulcerated skin of two DFU patients (DFU8, DFU25), nonulcerated foot skin from two diabetic patients (DFF24, DFF9), and healthy foot skin from two nondiabetic patients (NFF12, NFF14). We confirmed reprogramming to a pluripotent state through three independent criteria: immunofluorescent staining for SSEA-4 and TRA-1-81, formation of embryoid bodies with differentiation potential to all three embryonic germ layers in vitro, and formation of teratomas in vivo. All iPSC lines showed normal karyotypes and typical, nonmethylated CpG sites for OCT4 and NANOG. iPSCs derived from DFUs were similar to those derived from site-matched nonulcerated skin from both diabetic and nondiabetic patients. These results have established for the first time that multiple, DFU-derived fibroblast cell lines can be reprogrammed with efficiencies similar to control fibroblasts, thus demonstrating their utility for future regenerative therapy of DFUs. C1 [Gerami-Naini, Behzad; Smith, Avi; Kashpur, Olga; Carpinito, Gianpaolo; Garlick, Jonathan A.] Tufts Univ, Sch Dent Med, Dept Diagnost Sci, 55 Kneeland St South Cove,Room 116, Boston, MA 02111 USA. [Maione, Anna G.] Tufts Univ, Dept Cell Mol & Dev Biol, Sackler Sch Grad Biomed Sci, Boston, MA 02111 USA. [Veves, Aristides] Harvard Univ, Beth Israel Deaconess Med Ctr, Microcirculat Lab, Boston, MA 02215 USA. [Veves, Aristides] Harvard Univ, Beth Israel Deaconess Med Ctr, Joslin Beth Israel Deaconess Foot Ctr, Boston, MA 02215 USA. [Mooney, David J.] Harvard Univ, Wyss Inst Biol Inspired Engn, Sch Engn & Appl Sci, Cambridge, MA 02138 USA. RP Gerami-Naini, B (reprint author), Tufts Univ, Sch Dent Med, Dept Diagnost Sci, 55 Kneeland St South Cove,Room 116, Boston, MA 02111 USA. EM behzad.gerami_naini@tufts.edu FU NIH [R01 DK98055-06] FX The authors gratefully acknowledge members of their laboratory, Dr. Benjamin Chan for his comments and input on the manuscript, and Ryan Imbriaco and Kamar Reda for their technical assistance. This project was supported by NIH Grant No. R01 DK98055-06 (J.A.G). NR 30 TC 0 Z9 0 U1 10 U2 10 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 2152-4971 EI 2152-4998 J9 CELL REPROGRAM JI Cell. Reprogramm. PD AUG PY 2016 VL 18 IS 4 BP 214 EP 223 DI 10.1089/cell.2015.0087 PG 10 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Genetics & Heredity SC Cell Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA DS5UC UT WOS:000380847100002 PM 27328415 ER PT J AU Choi, CJ Stagner, AM Freitag, SK Jakobiec, FA Lee, NG AF Choi, Catherine J. Stagner, Anna M. Freitag, Suzanne K. Jakobiec, Frederick A. Lee, Nahyoung Grace TI Atypical location of primary orbital conjunctival epithelial cysts: a case series SO CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY LA English DT Letter C1 [Choi, Catherine J.; Freitag, Suzanne K.; Lee, Nahyoung Grace] Massachusetts Eye & Ear Infirm, Ophthalm Plast Surg, Boston, MA 02114 USA. [Choi, Catherine J.; Stagner, Anna M.; Freitag, Suzanne K.; Jakobiec, Frederick A.; Lee, Nahyoung Grace] Harvard Med Sch, Dept Ophthalmol, Boston, MA 02115 USA. [Stagner, Anna M.; Jakobiec, Frederick A.] Massachusetts Eye & Ear Infirm, David G Cogan Ophthalm Pathol Lab, Boston, MA 02114 USA. RP Choi, CJ (reprint author), Massachusetts Eye & Ear Infirm, Ophthalm Plast Surg, Boston, MA 02114 USA.; Choi, CJ (reprint author), Harvard Med Sch, Dept Ophthalmol, Boston, MA 02115 USA. NR 6 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1442-6404 EI 1442-9071 J9 CLIN EXP OPHTHALMOL JI Clin. Exp. Ophthalmol. PD AUG PY 2016 VL 44 IS 6 BP 524 EP 526 DI 10.1111/ceo.12693 PG 3 WC Ophthalmology SC Ophthalmology GA DS4CH UT WOS:000380728500013 PM 26713538 ER PT J AU Mahoney, KM Jacobus, S Bhatt, RS Song, JX Carvo, I Cheng, SC Simpson, M Fay, AP Puzanov, I Michaelson, MD Atkins, MB McDermott, DF Signoretti, S Choueiri, TK AF Mahoney, Kathleen M. Jacobus, Susanna Bhatt, Rupal S. Song, Jiaxi Carvo, Ingrid Cheng, Su-Chun Simpson, Mekailah Fay, Andre P. Puzanov, Igor Michaelson, M. Dror Atkins, Michael B. McDermott, David F. Signoretti, Sabina Choueiri, Toni K. TI Phase 2 Study of Bevacizumab and Temsirolimus After VEGFR TKI in Metastatic Renal Cell Carcinoma SO CLINICAL GENITOURINARY CANCER LA English DT Article DE Bevacizumab; Renal cell carcinoma; Temsirolimus; TKI-refractory disease ID ENDOTHELIAL GROWTH-FACTOR; INTERFERON-ALPHA; III TRIAL; TARGETED THERAPY; EVEROLIMUS; CANCER; SORAFENIB; COMBINATION; SUNITINIB; SURVIVAL AB Combining bevacizumab and temsirolimus in metastatic renal cell carcinoma patients previously treated with vascular endothelial growth factor receptor tyrosine kinase inhibitor is possible, but with dose reductions and treatment discontinuations. This combination resulted in modest activity. Temsirolimus and bevacizumab combination is not recommended for use outside of a clinical trial. Background: Inhibiting VEGF and mammalian target of rapamycin (mTOR) pathways are standard treatment approaches for patients with metastatic renal cell carcinoma (mRCC). Here we report the activity and safety of the VEGF ligand inhibitor bevacizumab and the mTOR inhibitor temsirolimus combination in patients with clear cell (CC) and non-clear cell (NCC) mRCC whose disease had failed to respond to prior VEGF blockade. Patients and Methods: In this phase 2 investigator-initiated multicenter study, patients received bevacizumab and temsirolimus. The primary end point was 4-month progression-free survival (PFS) rate. Secondary end points included overall response rate, median overall survival (OS), toxicity, and correlative studies of biomarkers downstream of mTOR. Results: Forty patients received at least 1 dose of therapy. Thirty-three (82.5%) had favorable/intermediate risk disease according to International Metastatic Renal Cell Carcinoma Database Consortium criteria, 13 (32.5%) with nccRCC histology. Nineteen (48.7%) had primary vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI)-refractory disease. The 4-month PFS rate was 65%. Overall median PFS and OS were 5.6 and 12.2 months. Median PFS and OS were 6.5 and 9.6 months in patients with primary VEGFR TKI-refractory disease, and 5.6 months and 13.1 months in patients with nccRCC. Dose reductions were needed in 80% of patients. Most frequent toxicities included fatigue, hypertension, dyslipidemia, and proteinuria. Dose discontinuation due to adverse events occurred in 27.5% of patients. Baseline tumor immunohistochemistry for phospho-S6 protein was not associated with clinical benefit. Conclusion: Combining bevacizumab and temsirolimus in patients previously treated with VEGFR TKI was possible but with dose reductions and treatment discontinuations. This combination resulted in modest activity, including in patients with primary VEGF-refractory disease and NCC histology. (C) 2016 Elsevier Inc. All rights reserved. C1 [Mahoney, Kathleen M.; Bhatt, Rupal S.; Simpson, Mekailah; McDermott, David F.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Div Hematol Oncol, 450 Brookline Ave, Boston, MA 02215 USA. [Mahoney, Kathleen M.; Signoretti, Sabina; Choueiri, Toni K.] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. [Jacobus, Susanna; Cheng, Su-Chun] Harvard Med Sch, Dana Farber Canc Inst, Dept Stat, 450 Brookline Ave, Boston, MA 02215 USA. [Michaelson, M. Dror] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. [Song, Jiaxi; Carvo, Ingrid; Signoretti, Sabina] Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, 450 Brookline Ave, Boston, MA 02215 USA. [Fay, Andre P.] PUCRS Sch Med, Porto Alegre, RS, Brazil. [Puzanov, Igor] Vanderbilt Univ, Med Ctr, Div Hematol Oncol, Nashville, TN USA. [Atkins, Michael B.] Georgetown Univ, Sch Med, Dept Med Oncol, Georgetown Lombardi Comprehens Canc Ctr, Washington, DC USA. RP Choueiri, TK (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM toni_choueiri@dfci.harvard.edu FU DF/HCC Kidney Cancer [SPORE P50CA101942]; Claudia Adams Barr Program for Innovative Cancer Research, a AACR Basic Cancer Research Fellowship [14-40-01-MAHO]; ASCO Young Investigator Award - Kidney Cancer Association; Genentech; Pfizer FX We thank the patients and their families, the Kidney Cancer Program, the clinical research coordinators and nursing staff, and Pfizer. Supported in part by DF/HCC Kidney Cancer SPORE P50CA101942 (T.C., S.S., D.F.M., M.B.A.). Research supported by the Claudia Adams Barr Program for Innovative Cancer Research, a 2014 AACR Basic Cancer Research Fellowship (grant 14-40-01-MAHO), and the ASCO Young Investigator Award supported by Kidney Cancer Association (K.M.). Supported in part by Genentech and Pfizer. NR 33 TC 0 Z9 0 U1 5 U2 5 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 2016 VL 14 IS 4 BP 304 EP + DI 10.1016/j.clgc.2016.02.007 PG 16 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA DS4ON UT WOS:000380760500008 PM 27036973 ER PT J AU Mullane, SA Werner, L Guancial, EA Lis, RT Stack, EC Loda, M Kantoff, PW Choueiri, TK Rosenberg, J Bellmunt, J AF Mullane, Stephanie A. Werner, Lillian Guancial, Elizabeth A. Lis, Rosina T. Stack, Edward C. Loda, Massimo Kantoff, Philip W. Choueiri, Toni K. Rosenberg, Jonathan Bellmunt, Joaquim TI Expression Levels of DNA Damage Repair Proteins Are Associated With Overall Survival in Platinum-Treated Advanced Urothelial Carcinoma SO CLINICAL GENITOURINARY CANCER LA English DT Article DE Bladder cancer; DNA damage; Immunohistochemistry; Platinum chemotherapy ID CELL LUNG-CANCER; CISPLATIN-BASED CHEMOTHERAPY; NUCLEOTIDE EXCISION-REPAIR; MESSENGER-RNA EXPRESSION; LONG-TERM-SURVIVAL; INVASIVE BLADDER-CANCER; PHASE-III TRIAL; PROGNOSTIC-FACTORS; OVARIAN-CANCER; BREAST-CANCER AB In a cohort of 104 patients with metastatic urothelial carcinoma (mUC) who had received platinum therapy, we examined the correlation between ERCC1, RAD51, PARP-1, PAR, BRCA1, and BRCA2 and overall survival (OS). A greater percentage of nuclear staining of ERCC1 (hazard ratio [HR], 2.7; 95% confidence interval [CI], 1.5-4.9; P = .0007), RAD51 (HR, 5.6; 95% CI, 1.7-18.3; P = .005), and PAR (HR, 2.2; 95% CI, 1.1-4.4; P = .026) was associated with worse OS. Background: Combination platinum chemotherapy is standard first-line therapy for metastatic urothelial carcinoma (mUC). Defining the platinum response biomarkers for patients with mUC could establish personalize medicine and provide insights into mUC biology. Although DNA repair mechanisms have been hypothesized to mediate the platinum response, we sought to analyze whether increased expression of DNA damage genes would correlate with worse overall survival (OS) in patients with mUC. Patients and Methods: We retrospectively identified a clinically annotated cohort of patients with mUC, who had been treated with first-line platinum combination chemotherapy. A tissue microarray was constructed from formalin-fixed paraffin-embedded tissue from the primary tumor before treatment. Immunohistochemical analysis of the following DNA repair proteins was performed: ERCC1, RAD51, BRCA1/2, PAR, and PARP-1. Nuclear and cytoplasmic expression was analyzed using multispectral imaging. Nuclear staining was used for the survival analysis. Cox regression analysis was used to evaluate the associations between the percentage of positive nuclear staining and OS in multivariable analysis, controlling for known prognostic variables. Results: In a cohort of 104 patients with mUC, a greater percentage of nuclear staining of ERCC1 (hazard ratio [HR], 2.7; 95% confidence interval [CI], 1.5-4.9; P = .0007), RAD51 (HR, 5.6; 95% CI, 1.7-18.3; P = .005), and PAR (HR, 2.2; 95% CI, 1.1-4.4; P = .026) was associated with worse OS. BRCA1, BRCA2, and PARP-1 expression was not associated with OS (P = .76, P = .38, and P = .09, respectively). A greater percentage of combined ERCC1 and RAD51 nuclear staining was strongly associated with worse OS (P = .005). Conclusion: A high percentage of nuclear staining of ERCC1, RAD51, and PAR, assessed by immunohistochemistry, correlated with worse OS for patients with mUC treated with first-line platinum combination chemotherapy, supporting the evidence of the DNA repair pathways' role in the prognosis of mUC. We also report new evidence that RAD51 and PAR might play a role in the platinum response. Additional prospective studies are required to determine the prognostic or predictive nature of these biomarkers in mUC. (C) 2015 Elsevier Inc. All rights reserved. C1 [Mullane, Stephanie A.; Kantoff, Philip W.; Choueiri, Toni K.; Bellmunt, Joaquim] Brigham & Womens Hosp, Dana Farber Canc Inst, Bladder Canc Ctr, 75 Francis St, Boston, MA 02115 USA. [Werner, Lillian] Dana Farber Canc Inst, Biostat & Computat Biol, 450 Brookline Ave, Boston, MA 02215 USA. [Guancial, Elizabeth A.] Univ Rochester, Dept Med, Wilmot Canc Inst, Rochester, NY USA. [Lis, Rosina T.; Stack, Edward C.] Dana Farber Canc Inst, Ctr Mol Oncol Pathol, 450 Brookline Ave, Boston, MA 02215 USA. [Loda, Massimo] Brigham & Womens Hosp, Dept Pathol, Dana Farber Canc Inst, 75 Francis St, Boston, MA 02115 USA. [Loda, Massimo; Kantoff, Philip W.; Choueiri, Toni K.; Bellmunt, Joaquim] Harvard Med Sch, Boston, MA USA. [Rosenberg, Jonathan] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. RP Bellmunt, J (reprint author), Dana Farber Canc Inst, Bladder Canc Ctr, 450 Brookline Ave, Boston, MA 02215 USA. EM joaquim_bellmunt@dfci.harvard.edu NR 60 TC 1 Z9 1 U1 6 U2 6 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 2016 VL 14 IS 4 BP 352 EP 359 DI 10.1016/j.clgc.2015.12.029 PG 8 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA DS4ON UT WOS:000380760500014 PM 26778300 ER PT J AU Muralidhar, V Regan, MM Werner, L Nakabayashi, M Evan, CP Bellmunt, J Choueiri, TK Elfiky, AA Harshman, LC McKay, RR Pomerantz, MM Sweeney, CJ Taplin, ME Kantoff, PW Nguyen, PL AF Muralidhar, Vinayak Regan, Meredith M. Werner, Lillian Nakabayashi, Mari Evan, Carolyn P. Bellmunt, Joaquim Choueiri, Toni K. Elfiky, Aymen A. Harshman, Lauren C. McKay, Rana R. Pomerantz, Mark M. Sweeney, Christopher J. Taplin, Mary-Ellen Kantoff, Philip W. Nguyen, Paul L. TI Duration of Androgen Deprivation Therapy for High-Risk Prostate Cancer: Application of Randomized Trial Data in a Tertiary Referral Cancer Center SO CLINICAL GENITOURINARY CANCER LA English DT Article DE ADT; Discontinuation; Side effects; Toxicity ID RADICAL PROSTATECTOMY; SUPPRESSION; PREDICTORS; RADIATION; MORTALITY; FAILURE; DISEASE; MEN AB We evaluated the patterns of androgen deprivation therapy (ADT) use for high-risk prostate cancer at a tertiary referral cancer center. Genitourinary oncology specialists tended to prescribe longer course ADT after the 2008-2009 trial publications supporting long-course ADT. However, specialists have continued to weigh the risks and benefits of ADT: 49.4% of patients diagnosed starting in 2010 received shorter course ADT, most often because of side effects, comorbidities, or age. Introduction: We evaluated the incidence and predictors of the use of long-term (2-3 years) versus shorter term androgen deprivation therapy (ADT) in radiation-managed men with high-risk prostate cancer. Patients and Methods: We identified 302 patients from the Dana-Farber Cancer Institute patient registry who had been diagnosed with high-risk prostate cancer (T3a or prostate-specific antigen [PSA] > 20 ng/mL or Gleason score 8-10) from 1993 to 2015. We assessed the intended duration of ADT and used multivariable Cox regression to evaluate the predictors of receiving a shorter course of ADT than recommended by the guidelines (< 2 years). Results: The course of ADT intended by physicians increased after the 2008/2009 publication of trials showing the superiority of long-term versus short-term ADT, with 43.5% intending >= 2 years before versus 61.4% after (P = .014). Starting in 2010, 49.4% of patients actually received < 2 years of ADT. The most common reasons for receipt of shorter course ADT were intolerance of ADT side effects, patient comorbidity/age, the presence of T3a on magnetic resonance imaging only as the sole high-risk feature, or participation in a clinical trial. Moderate to severe comorbidity assessed using the Adult Comorbidity Evaluation-27 (adjusted hazard ratio [AHR] = 2.94), Gleason score < 8 (AHR = 5.66), and PSA < 20 ng/mL (AHR = 4.19) all predicted for receipt of shorter course ADT (P < .05 for all). Conclusion: In a tertiary-care setting, the rates of long-course ADT for high-risk disease have increased since the 2008/2009 trials supporting its use. However, approximately one half of patients continued to receive shorter course ADT, often because of intolerance of side effects, underlying comorbidity, or physician judgment about the aggressiveness of the disease. C1 [Muralidhar, Vinayak] Harvard Med Sch, Harvard MIT Div Hlth Sci & Technol, 75 Francis St, Boston, MA 02115 USA. [Regan, Meredith M.; Werner, Lillian] Harvard Med Sch, Dana Farber Canc Inst, Dept Biostat & Computat Biol, 75 Francis St, Boston, MA 02115 USA. [Nakabayashi, Mari; Evan, Carolyn P.] Harvard Med Sch, Dana Farber Canc Inst, Gelb Ctr Translat Oncol, 75 Francis St, Boston, MA 02115 USA. [Bellmunt, Joaquim; Choueiri, Toni K.; Elfiky, Aymen A.; Harshman, Lauren C.; McKay, Rana R.; Pomerantz, Mark M.; Sweeney, Christopher J.; Taplin, Mary-Ellen; Kantoff, Philip W.] Harvard Med Sch, Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, 75 Francis St, Boston, MA 02115 USA. [Nguyen, Paul L.] Harvard Med Sch, Dana Farber Canc Inst, Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. RP Nguyen, PL (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. EM pnguyen@LROC.harvard.edu FU Health Sciences and Technology IDEA2 Program - Peter C. Farrell Fund; Prostate Cancer Foundation; Scott Forbes and Gina Ventre Fund; anonymous family foundation FX This work was supported by grants from the Health Sciences and Technology IDEA2 Program supported by the Peter C. Farrell (1967) Fund, The Prostate Cancer Foundation, Fitz's Cancer Warriors, David and Cynthia Chapin, Hugh Simons in Honor of Frank and Anne Simons, The Scott Forbes and Gina Ventre Fund, and a grant from an anonymous family foundation. NR 22 TC 2 Z9 2 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 2016 VL 14 IS 4 BP E299 EP E305 DI 10.1016/j.clgc.2015.12.008 PG 7 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA DS4ON UT WOS:000380760500017 PM 26778006 ER PT J AU White, MB Rajagopalan, S Yoshikawa, TT AF White, Mary B. Rajagopalan, Shobita Yoshikawa, Thomas T. TI Infectious Diarrhea Norovirus and Clostridium difficile in Older Adults SO CLINICS IN GERIATRIC MEDICINE LA English DT Article DE Norovirus; Gastroenteritis; Long-term care; Elderly; Clostridium difficile infection; Infectious diarrhea; Long-term care facilities; Aging ID TERM-CARE FACILITIES; HEALTH-CARE; UNITED-STATES; RISK-FACTORS; NORWALK VIRUS; GASTROENTERITIS; OUTBREAKS; PREVENTION; MORTALITY; DISEASE AB Norovirus infection usually results in acute gastroenteritis, often with incapacitating nausea, vomiting, and diarrhea. It is highly contagious and resistant to eradication with alcohol-based hand sanitizer. Appropriate preventative and infection control measures can mitigate the morbidity and mortality associated with norovirus infection. Clostridium difficile infection is the leading cause of health care-associated diarrhea in the United States. Antibiotic use is by far the most common risk factor for C difficile colonization and infection. Appropriate preventive measures and judicious use of antibiotics can help mitigate the morbidity and mortality associated with C difficile infection. C1 [White, Mary B.; Yoshikawa, Thomas T.] VA Greater Los Angeles Healthcare Syst, Dept Vet Affairs, 11300 Wilshire Blvd, Los Angeles, CA 90073 USA. [Rajagopalan, Shobita] Cty Los Angeles Dept Publ Hlth, Curtis Tucker Hlth Ctr, 123 West Manchester Blvd, Inglewood, CA 90301 USA. RP Rajagopalan, S (reprint author), 123 West Manchester Blvd,Suite 220C, Inglewood, CA 90301 USA. EM srajagopalan@ph.lacounty.gov NR 58 TC 0 Z9 0 U1 7 U2 7 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0749-0690 EI 1879-8853 J9 CLIN GERIATR MED JI Clin. Geriatr. Med. PD AUG PY 2016 VL 32 IS 3 BP 509 EP + DI 10.1016/j.cger.2016.02.008 PG 15 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA DS7NA UT WOS:000380969000008 PM 27394020 ER PT J AU Scott, J Goetz, MB AF Scott, Jake Goetz, Matthew Bidwell TI Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome in Older Adults SO CLINICS IN GERIATRIC MEDICINE LA English DT Article DE Human immunodeficiency virus; Acquired immunodeficiency syndrome; Antiretroviral therapy; Immunocompromised host; Epidemiology ID COMBINATION ANTIRETROVIRAL THERAPY; HIV MEDICINE ASSOCIATION; METABOLIC SYNDROME; MYOCARDIAL-INFARCTION; INCREASED RISK; UNITED-STATES; INFECTION; DIAGNOSIS; DISEASES; COLLABORATION AB Improved survival with combination antiretroviral therapy has led to a dramatic increase in the number of human immunodeficiency virus (HIV)-infected individuals 50 years of age or older such that by 2020 more than 50% of HIV -infected persons in the United States will be above this age. Recent studies confirm that antiretroviral therapy should be offered to all HIV -infected patients regardless of age, symptoms, CD4+ cell count, or HIV viral load. However, when compared with HIV-uninfected populations, even with suppression of measurable HIV replication, older individuals are at greater risk for cardiovascular disease, malignancies, liver disease, and other comorbidities. C1 [Scott, Jake; Goetz, Matthew Bidwell] Univ Calif Los Angeles, David Geffen Sch Med, Infect Dis Sect, VA Greater Los Angeles Healthcare Syst,Dept Med, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. RP Goetz, MB (reprint author), VA Greater Los Angeles Healthcare Syst, Infect Dis, 111-F,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM Matthew.Goetz@va.gov NR 35 TC 0 Z9 0 U1 1 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 0749-0690 EI 1879-8853 J9 CLIN GERIATR MED JI Clin. Geriatr. Med. PD AUG PY 2016 VL 32 IS 3 BP 571 EP + DI 10.1016/j.cger.2016.02.010 PG 14 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA DS7NA UT WOS:000380969000012 PM 27394024 ER PT J AU Noonan, HR Metelo, AM Kamei, CN Peterson, RT Drummond, IA Iliopoulos, O AF Noonan, Haley R. Metelo, Ana M. Kamei, Caramai N. Peterson, Randall T. Drummond, Iain A. Iliopoulos, Othon TI Loss of vhl in the zebrafish pronephros recapitulates early stages of human clear cell renal cell carcinoma SO DISEASE MODELS & MECHANISMS LA English DT Article DE VHL disease; HIF2a; Renal cell carcinoma; Zebrafish cancer model; Pronephros ID LINDAU TUMOR-SUPPRESSOR; DISEASE; GENE; INHIBITION; EXPRESSION; CANCER; MODEL; DIFFERENTIATION; IDENTIFICATION; INACTIVATION AB Patients with von Hippel-Lindau (VHL) disease harbor a germline mutation in the VHL gene leading to the development of several tumor types including clear cell renal cell carcinoma (ccRCC). In addition, the VHL gene is inactivated in over 90% of sporadic ccRCC cases. 'Clear cell' tumors contain large, proliferating cells with 'clear cytoplasm', and a reduced number of cilia. VHL inactivation leads to the stabilization of hypoxia inducible factors 1a and 2a [HIF1a and HIF2a (HIF2a is also known as EPAS1)] with consequent upregulation of specific target genes involved in cell proliferation, angiogenesis and erythropoiesis. A zebrafish model with a homozygous inactivation in the VHL gene (vhl(-/-)) recapitulates several aspects of the human disease, including development of highly vascular lesions in the brain and the retina and erythrocytosis. Here, we characterize for the first time the epithelial abnormalities present in the kidney of the vhl(-/-) zebrafish larvae as a first step in building a model of ccRCC in zebrafish. Our data show that the vhl(-/-) zebrafish kidney is characterized by an increased tubule diameter, disorganized cilia, the dramatic formation of cytoplasmic lipid vesicles, glycogen accumulation, aberrant cell proliferation and abnormal apoptosis. This phenotype of the vhl(-/-) pronephros is reminiscent of clear cell histology, indicating that the vhl(-/-) mutant zebrafish might serve as a model of early stage RCC. Treatment of vhl(-/-) zebrafish embryos with a small-molecule HIF2a inhibitor rescued the pronephric abnormalities, underscoring the value of the zebrafish model in drug discovery for treatment of VHL disease and ccRCC. C1 [Noonan, Haley R.; Metelo, Ana M.; Peterson, Randall T.; Iliopoulos, Othon] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA. [Metelo, Ana M.; Peterson, Randall T.; Iliopoulos, Othon] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. [Metelo, Ana M.] Univ Coimbra, Fac Sci & Technol, Dept Life Sci, P-3001401 Coimbra, Portugal. [Kamei, Caramai N.; Drummond, Iain A.] Massachusetts Gen Hosp, Dept Med, Div Nephrol, Boston, MA 02114 USA. [Kamei, Caramai N.; Drummond, Iain A.] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. [Peterson, Randall T.] Massachusetts Gen Hosp, Dept Med, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Peterson, Randall T.] Broad Inst Harvard & MIT, Cambridge, MA 02114 USA. [Iliopoulos, Othon] Massachusetts Gen Hosp, Dept Med, Div Hematol Oncol, Boston, MA 02142 USA. RP Iliopoulos, O (reprint author), Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA.; Iliopoulos, O (reprint author), Harvard Med Sch, Dept Med, Boston, MA 02115 USA.; Iliopoulos, O (reprint author), Massachusetts Gen Hosp, Dept Med, Div Hematol Oncol, Boston, MA 02142 USA. EM oiliopoulos@partners.org FU Massachusetts General Hospital federal share of program income [C06 CA059267]; VHL Alliance Research Award; Fundacao para a Ciencia e a Tecnologia, Portugal - POPH/FSE; Programa Operacional e da Uniao Europeia [SFRH/BD/70002/2010]; National Institutes of Health [RO1 DK053093, RO1 DK082971, R01CA160458] FX This work was supported by the Massachusetts General Hospital federal share of program income [grant number C06 CA059267 to O.I.]; the 2014 VHL Alliance Research Award (to O.I.); the Fundacao para a Ciencia e a Tecnologia, Portugal funded by POPH/FSE, Programa Operacional e da Uniao Europeia [grant number SFRH/BD/70002/2010 to A.M.M.]; and the National Institutes of Health [grant numbers RO1 DK053093 to I.A.D., RO1 DK082971 to R.T.P. and R01CA160458 to O.I.]. NR 53 TC 0 Z9 0 U1 3 U2 3 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 1754-8403 EI 1754-8411 J9 DIS MODEL MECH JI Dis. Model. Mech. PD AUG 1 PY 2016 VL 9 IS 8 BP 873 EP 884 DI 10.1242/dmm.024380 PG 12 WC Cell Biology; Pathology SC Cell Biology; Pathology GA DT8PW UT WOS:000381754600005 PM 27491085 ER PT J AU Zhang, HH Zhao, HT Yang, XX Xue, QS Cotten, JF Feng, HJ AF Zhang, Honghai Zhao, Haiting Yang, Xiaoxuan Xue, Qingsheng Cotten, Joseph F. Feng, Hua-Jun TI 5-Hydroxytryptophan, a precursor for serotonin synthesis, reduces seizure-induced respiratory arrest SO EPILEPSIA LA English DT Article DE SUDEP; Generalizedseizures; Pentylenetetrazole; 5-HT; Therapeutics ID SUDDEN UNEXPECTED DEATH; EPILEPSY SUDEP; DBA/1 MICE; ANTIEPILEPTIC DRUGS; ICTAL HYPOXEMIA; RISK-FACTORS; MOUSE MODEL; MECHANISMS; GENE; 5-HYDROXY-L-TRYPTOPHAN AB Objective: The DBA/1 mouse is a relevant animal model of sudden unexpected death in epilepsy (SUDEP), as it exhibits seizure-induced respiratory arrest (S-IRA) evoked by acoustic stimulation, followed by cardiac arrhythmia and death. Defects in serotonergic neurotransmission may contribute to S-IRA. The tryptophan hydroxylase-2 (TPH2) enzyme converts L-tryptophan to 5-hydroxytryptophan (5-HTP), a precursor for central nervous system (CNS) serotonin (5-HT) synthesis; and DBA/1 mice have a polymorphism that decreases TPH2 activity. We, therefore, hypothesized that supplementation with 5-HTP may bypass TPH2 and suppress S-IRA in DBA/1 mice. Methods: TPH2 expression was examined by Western blot in the brainstem of DBA/1 and C57BL/6J mice both with and without acoustic stimulation. Changes in breathing and cardiac electrical activity in DBA/1 and C57BL/6J mice that incurred sudden death during generalized seizures evoked by pentylenetetrazole (PTZ) were studied by plethysmography and electrocardiography. The effect of 5-HTP administration on seizure-induced mortality evoked by acoustic stimulation or by PTZ was investigated in DBA/1 mice. Results: Repetitive acoustic stimulation resulted in reduced TPH2 protein in the brainstem of DBA/1 mice as compared with C57BL/6J mice. S-IRA evoked by acoustic stimulation in DBA/1 mice was significantly reduced by 5-HTP. Following S-IRA, cardiac electrical activity could be detected for minutes before terminal asystole and death in both DBA/1 and C57BL/6J mice after PTZ treatment. The incidence of S-IRA by PTZ administration was greater in DBA/1 than in C57BL/6J mice, and administration of 5-HTP also significantly reduced S-IRA by PTZ in DBA/1 mice. Significance: Our data suggest that S-IRA is the primary event leading to death incurred in most DBA/1 and some C57BL/6J mice during PTZ-evoked seizures. Suppression of S-IRA by 5-HTP suggests that 5-HT transmission contributes to the pathophysiology of S-IRA, and that 5-HTP, an over-the-counter supplement available for human consumption, may be clinically useful in preventing SUDEP. C1 [Zhang, Honghai; Zhao, Haiting; Yang, Xiaoxuan; Cotten, Joseph F.; Feng, Hua-Jun] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA. [Zhang, Honghai; Zhao, Haiting; Yang, Xiaoxuan; Cotten, Joseph F.; Feng, Hua-Jun] Harvard Med Sch, 55 Fruit St, Boston, MA 02114 USA. [Zhang, Honghai] Nanjing Med Univ, Hangzhou Peoples Hosp 1, Dept Anesthesia, Hangzhou, Zhejiang, Peoples R China. [Zhao, Haiting] Xiamen Univ, Affiliated Hosp 1, Dept Neurol, Xiamen, Peoples R China. [Zhao, Haiting] Cent S Univ, Xiangya Hosp, Dept Neurol, Changsha, Hunan, Peoples R China. [Yang, Xiaoxuan; Xue, Qingsheng] Shanghai Jiao Tong Univ, Sch Med, Dept Anesthesiol, Ruijin Hosp, Shanghai, Peoples R China. RP Feng, HJ (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA.; Feng, HJ (reprint author), Harvard Med Sch, 55 Fruit St, Boston, MA 02114 USA. EM feng.huajun@mgh.harvard.edu FU CURE (Citizens United for Research in Epilepsy) foundation; Massachusetts General Hospital Department of Anesthesia, Critical Care and Pain Medicine; China Scholarship Council [CSC 201506370075]; Chinese Medical Association (CMA); [R03NS078591]; [R01HL117871] FX We thank Dr. Han Lu (in Dr. Zhongcong Xie's lab) for help with Western blot experiments. This work was supported by R03NS078591 and CURE (Citizens United for Research in Epilepsy) foundation to HJF, and R01HL117871 to JFC. We thank the support from the Massachusetts General Hospital Department of Anesthesia, Critical Care and Pain Medicine. Haiting Zhao is a recipient of fellowship from China Scholarship Council (CSC 201506370075). Xiaoxuan Yang is partly supported by Chinese Medical Association (CMA). NR 48 TC 2 Z9 2 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0013-9580 EI 1528-1167 J9 EPILEPSIA JI Epilepsia PD AUG PY 2016 VL 57 IS 8 BP 1228 EP 1235 DI 10.1111/epi.13430 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA DS4KP UT WOS:000380750300011 PM 27302625 ER PT J AU Fortuna, LR Alvarez, K Ortiz, ZR Wang, Y Alegria, XM Cook, BL Alegria, M AF Fortuna, L. R. Alvarez, K. Ortiz, Z. Ramos Wang, Y. Mozo Alegria, X. Cook, B. L. Alegria, M. TI Mental health, migration stressors and suicidal ideation among Latino immigrants in Spain and the United States SO EUROPEAN PSYCHIATRY LA English DT Article DE Suicide; Unipolar depression; Posttraumatic stress disorder; Social and cross-cultural psychiatry; Addiction ID PRIMARY-CARE PATIENTS; PTSD CHECKLIST PCL; RISK-FACTORS; PSYCHOMETRIC PROPERTIES; ACCULTURATIVE STRESS; MAJOR DEPRESSION; BEHAVIOR; PREVALENCE; ADOLESCENTS; AMERICAN AB Background: Immigration stress appears to augment the risk for suicide behaviors for Latinos. Yet, specific risk factors that contribute to suicidal ideation (SI) among diverse Latino immigrant populations are not well established. Methods: Data were collected in Boston, Madrid and Barcelona using a screening battery assessing mental health, substance abuse risk, trauma exposure, demographics, and sociocultural factors. Prevalence rates of lifetime and 30-day SI were compared across sites. Logistic regression modeling was used to identify sociodemographic, clinical, and sociocultural-contextual factors associated with 30-day SI. Results: Five hundred and sixty-seven Latino patients from primary care, behavioral health and HIV clinics and community agencies participated. Rates of lifetime SI ranged from 29-35%; rates for 30-day SI were 21-23%. Rates of SI were not statistically different between sites. Factors associated with SI included exposure to discrimination, lower ethnic identity, elevated family conflict, and low sense of belonging (P < 0.01). In the adjusted model, higher scores on depression, posttraumatic stress disorder, and trauma exposure were significantly associated with 30-day SI (OR = 1.14, 1.04, and 7.76, respectively). Greater number of years living in the host country was significantly associated with increased odds of having SI (OR = 2.22) while having citizenship status was associated with lower odds (OR = 0.45). Conclusion: Latinos suffering depression, trauma exposure, and immigration stressors are more likely to experience SI. Despite differences in country of origin, education, and other demographic factors between countries, rates of SI did not differ. Recommendations for prevention and clinical practice for addressing suicidal ideation risk among Latino immigrants are discussed. (C) 2016 Elsevier Masson SAS. All rights reserved. C1 [Fortuna, L. R.] Boston Univ, Sch Med, Boston Med Ctr, Child & Adolescent Psychiat, 850 Harrison Ave,Dowling Bldg,7th Floor, Boston, MA 02118 USA. [Fortuna, L. R.; Alvarez, K.; Ortiz, Z. Ramos; Wang, Y.; Alegria, M.] Massachusetts Gen Hosp, Dept Med, Dispar Res Unit, 50 Staniford St,Suite 830, Boston, MA 02114 USA. [Fortuna, L. R.; Alvarez, K.; Ortiz, Z. Ramos; Wang, Y.; Cook, B. L.; Alegria, M.] Harvard Med Sch, 50 Staniford St,Suite 830, Boston, MA 02114 USA. [Mozo Alegria, X.] Hosp Univ Vall dHebron, Paseo Vall dHebron 119-129, Barcelona 08035, Spain. [Cook, B. L.] Cambridge Hlth Alliance, Hlth Equ Res Lab, 1035 Cambridge St, Cambridge, MA 02141 USA. RP Alegria, M (reprint author), Massachusetts Gen Hosp, Dept Med, Dispar Res Unit, 50 Staniford St,Suite 830, Boston, MA 02114 USA.; Alegria, M (reprint author), Harvard Med Sch, 50 Staniford St,Suite 830, Boston, MA 02114 USA. EM malegria@mgh.harvard.edu FU National Institute on Drug Abuse [R01DA034952]; NIH Research Grant - National Institute of Mental Health [R01MH098374, R01MH100155]; National Institute of Mental Health [R01MH098374-03S1] FX This study is supported by Research Grant R01DA034952, funded by the National Institute on Drug Abuse. This study was also supported by NIH Research Grant R01MH098374 and R01MH100155 funded by the National Institute of Mental Health. Dr. Alvarez was supported by Research Grant R01MH098374-03S1, funded by the National Institute of Mental Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 69 TC 0 Z9 0 U1 11 U2 14 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0924-9338 EI 1778-3585 J9 EUR PSYCHIAT JI Eur. Psychiat. PD AUG PY 2016 VL 36 BP 15 EP 22 DI 10.1016/j.eurpsy.2016.03.001 PG 8 WC Psychiatry SC Psychiatry GA DS2EI UT WOS:000380556000003 PM 27311103 ER PT J AU Wang, Z Mandel, H Levingston, CA Young, MRI AF Wang, Zhewu Mandel, Howard Levingston, Corinne A. Young, M. Rita I. TI An exploratory approach demonstrating immune skewing and a loss of coordination among cytokines in plasma and saliva of Veterans with combat-related PTSD SO HUMAN IMMUNOLOGY LA English DT Article DE Cytokines; Immune regulation; Inflammation; Plasma; Post-traumatic stress disorder; PTSD; Saliva ID POSTTRAUMATIC-STRESS-DISORDER; DSM-IV; BRAIN; INFLAMMATION; DISEASE; MODEL; INTERLEUKIN-6; PREVALENCE; DEPRESSION; BIOMARKERS AB Studies have suggested PTSD to be associated with an inflammatory state, although few studies have examined the balances between stimulatory and inhibitory immune mediators in PTSD. An exploratory approach was taken to assess the immune imbalances between Th1 stimulatory, inflammatory and inhibitory mediators associated with PTSD. This approach focused on a tightly-controlled and relatively homogeneous population of Veterans, all with similar levels of combat exposure in the Afghanistan and Iraq wars, but some testing negative and others testing positive for PTSD. Although the sample size was small (6 controls and 7 with PTSD) and a limitation of this study, the results showed significant imbalances in immune cytokines favoring a Th1 and inflammatory state, with reduced levels of inhibitory cytokines in Veterans with PTSD. This was particularly prominent in the saliva of PTSD subjects compared to in their plasma. Published by Elsevier Inc. C1 [Wang, Zhewu; Mandel, Howard; Levingston, Corinne A.; Young, M. Rita I.] Ralph H Johnson VA Med Ctr, 109 Bee St, Charleston, SC 29401 USA. [Wang, Zhewu; Young, M. Rita I.] Med Univ South Carolina, Charleston, SC USA. RP Young, MRI (reprint author), Ralph H Johnson VA Med Ctr, 109 Bee St, Charleston, SC 29401 USA. EM youngmr@musc.edu FU Clinical Sciences Research & Development Program of the Department of Veterans Affairs (Merit Review Grants) [1 I01 CX000851, 1 I01 CX000487] FX This work was supported by the Clinical Sciences Research & Development Program of the Department of Veterans Affairs (Merit Review Grants 1 I01 CX000851 to MRIY and 1 I01 CX000487 to ZW). NR 42 TC 0 Z9 0 U1 5 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0198-8859 EI 1879-1166 J9 HUM IMMUNOL JI Hum. Immunol. PD AUG PY 2016 VL 77 IS 8 BP 652 EP 657 DI 10.1016/j.humimm.2016.05.018 PG 6 WC Immunology SC Immunology GA DS7NV UT WOS:000380971100009 PM 27216157 ER PT J AU Morinelli, TA Luttrell, LM Strungs, EG Ullian, ME AF Morinelli, Thomas A. Luttrell, Louis M. Strungs, Erik G. Ullian, Michael E. TI Angiotensin II receptors and peritoneal dialysis-induced peritoneal fibrosis SO INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY LA English DT Article DE Angiotensin II; Arrestin; AT1R; Fibrosis; Peritoneal mesothelial cells ID SMOOTH-MUSCLE-CELLS; PROTEIN-COUPLED RECEPTORS; GROWTH-FACTOR-BETA; NF-KAPPA-B; TYPE-1 RECEPTOR; AT(1) RECEPTOR; MESOTHELIAL CELLS; BLOOD-PRESSURE; HIGH GLUCOSE; NUCLEAR-LOCALIZATION AB The vasoactive hormone angiotensin II initiates its major hemodynamic effects through interaction with AT1 receptors, a member of the class of G protein-coupled receptors. Acting through its AT1R, angiotensin II regulates blood pressure and renal salt and water balance. Recent evidence points to additional pathological influences of activation of AT1R, in particular inflammation, fibrosis and atherosclerosis. The transcription factor nuclear factor kappa B, a key mediator in inflammation and atherosclerosis, can be activated by angiotensin II through a mechanism that may involve arrestin-dependent AT1 receptor internalization. Peritoneal dialysis is a therapeutic modality for treating patients with end-stage kidney disease. The effectiveness of peritoneal dialysis at removing waste from the circulation is compromised over time as a consequence of peritoneal dialysis-induced peritoneal fibrosis. The non-physiological dialysis solution used in peritoneal dialysis, i.e. highly concentrated, hyperosmotic glucose, acidic pH as well as large volumes infused into the peritoneal cavity, contributes to the development of fibrosis. Numerous trials have been conducted altering certain components of the peritoneal dialysis fluid in hopes of preventing or delaying the fibrotic response with limited success. We hypothesize that structural activation of AT1R by hyperosmotic peritoneal dialysis fluid activates the internalization process and subsequent signaling through the transcription factor nuclear factor kappa B, resulting in the generation of pro-fibrotic/pro-inflammatory mediators producing peritoneal fibrosis. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Morinelli, Thomas A.; Ullian, Michael E.] Med Univ South Carolina, Dept Med, Div Nephrol, Charleston, SC 29425 USA. [Luttrell, Louis M.; Strungs, Erik G.] Med Univ South Carolina, Div Endocrinol, Dept Med, Charleston, SC 29425 USA. [Luttrell, Louis M.; Ullian, Michael E.] Ralph H Johnson Vet Affairs Med Ctr, Res Serv, Charleston, SC 29401 USA. RP Morinelli, TA (reprint author), Med Univ South Carolina, Dept Med, Div Nephrol, Charleston, SC 29425 USA. EM morinelt@musc.edu FU Dialysis Clinic, Incorporated; National Institutes of Health [R01 DK55524, GM095497]; Research Service of the Charleston, SC Veterans Affairs Medical Center FX The work was supported by Dialysis Clinic, Incorporated (T.A.M./M.E.U.), National Institutes of Health Grant R01 DK55524 AND GM095497 (L.M.L.) and the Research Service of the Charleston, SC Veterans Affairs Medical Center (L.M.L./M.E.U.). The contents of this article do not represent the views of the Department of Veterans Affairs or the United States Government NR 127 TC 0 Z9 0 U1 2 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1357-2725 EI 1878-5875 J9 INT J BIOCHEM CELL B JI Int. J. Biochem. Cell Biol. PD AUG PY 2016 VL 77 BP 240 EP 250 DI 10.1016/j.biocel.2016.04.016 PN B PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DT7EN UT WOS:000381650000009 PM 27167177 ER PT J AU Million, L Yi, EJ Wu, F Von Eyben, R Campbell, BA Dabaja, B Tsang, RW Ng, A Wilson, LD Ricardi, U Kirova, Y Hoppe, RT AF Million, Lynn Yi, Esther J. Wu, Frank Von Eyben, Rie Campbell, Belinda A. Dabaja, Bouthaina Tsang, Richard W. Ng, Andrea Wilson, Lynn D. Ricardi, Umberto Kirova, Youlia Hoppe, Richard T. TI Radiation Therapy for Primary Cutaneous Anaplastic Large Cell Lymphoma: An International Lymphoma Radiation Oncology Group Multi-institutional Experience SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID CD30-POSITIVE LYMPHOPROLIFERATIVE DISORDERS; EORTC; CLASSIFICATION; PAPULOSIS; SURVIVAL; ISCL AB Purpose: To collect response rates of primary cutaneous anaplastic large cell lymphoma, a rare cutaneous T-cell lymphoma, to radiation therapy (RT), and to determine potential prognostic factors predictive of outcome. Methods and Materials: The study was a retrospective analysis of patients with primary cutaneous anaplastic large cell lymphoma who received RT as primary therapy or after surgical excision. Data collected include initial stage of disease, RT modality (electron/photon), total dose, fractionation, response to treatment, and local recurrence. Radiation therapy was delivered at 8 participating International Lymphoma Radiation Oncology Group institutions worldwide. Results: Fifty-six patients met the eligibility criteria, and 63 tumors were treated: head and neck (27%), trunk (14%), upper extremities (27%), and lower extremities (32%). Median tumor size was 2.25 cm (range, 0.6-12 cm). T classification included T1, 40 patients (71%); T2, 12 patients (21%); and T3, 4 patients (7%). The median radiation dose was 35 Gy (range, 6-45 Gy). Complete clinical response (CCR) was achieved in 60 of 63 tumors (95%) and partial response in 3 tumors (5%). After CCR, 1 tumor recurred locally (1.7%) after 36 Gy and 7 months after RT. This was the only patient to die of disease. Conclusions: Primary cutaneous anaplastic large cell lymphoma is a rare, indolent cutaneous lymphoma with a low death rate. This analysis, which was restricted to patients selected for treatment with radiation, indicates that achieving CCR was independent of radiation dose. Because there were too few failures (<2%) for statistical analysis on dose response, 30 Gy seems to be adequate for local control, and even lower doses may suffice. (C) 2016 Elsevier Inc. All rights reserved. C1 [Million, Lynn; Yi, Esther J.; Wu, Frank; Von Eyben, Rie; Hoppe, Richard T.] Stanford Canc Inst, 875 Blake Wilbur Dr, Stanford, CA 94305 USA. [Campbell, Belinda A.] Peter MacCallum Canc Ctr, Dept Radiat Oncol & Canc Imaging, East Melbourne, Australia. [Dabaja, Bouthaina] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Tsang, Richard W.] Princess Margaret Canc Ctr, Dept Radiat Oncol, Toronto, ON, Canada. [Ng, Andrea] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Wilson, Lynn D.] Yale Sch Med, Dept Therapeut Radiol Radiat Oncol, Yale Canc Ctr, New Haven, CT USA. [Ricardi, Umberto] Univ Turin, Dept Oncol, Turin, Italy. [Kirova, Youlia] Inst Curie, Paris, France. RP Million, L (reprint author), Stanford Canc Inst, 875 Blake Wilbur Dr, Stanford, CA 94305 USA. EM lmillion@stanford.edu OI Ricardi, Umberto/0000-0003-4406-7621 FU NCI NIH HHS [P30 CA124435] NR 13 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD AUG 1 PY 2016 VL 95 IS 5 BP 1454 EP 1459 DI 10.1016/j.ijrobp.2016.03.023 PG 6 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DS2EN UT WOS:000380562300017 PM 27315663 ER PT J AU Kalkhoran, S Lisha, NE Neilands, TB Jordan, JW Ling, PM AF Kalkhoran, Sara Lisha, Nadra E. Neilands, Torsten B. Jordan, Jeffrey W. Ling, Pamela M. TI Evaluation of Bar and Nightclub Intervention to Decrease Young Adult Smoking in New Mexico SO JOURNAL OF ADOLESCENT HEALTH LA English DT Article DE Cigarette smoking; Young adult; Tobacco use disorder/prevention and control; Social marketing ID HARD-TO-REACH; MISSING DATA; CESSATION INTERVENTIONS; TOBACCO PROMOTIONS; CIGARETTE-SMOKING; UNITED-STATES; PATRONS; PEER; POPULATIONS; PREVENTION AB Purpose: Over 20% of young adults in New Mexico currently smoke. We evaluated cigarette smoking prevalence of young adult bar patrons during an anti-tobacco Social Branding intervention. Methods: The Social Branding intervention used a smoke-free brand, "HAVOC," to compete with tobacco marketing within the "Partier" young adult peer crowd. A series of cross-sectional surveys were collected from adults aged 18-26 in bars and nightclubs in Albuquerque, New Mexico, from 2009 to 2013 using randomized time-location sampling. Multivariable multinomial regression using full information maximum likelihood estimation to account for missing data evaluated differences in daily and nondaily smoking during the intervention, controlling for demographics, other risk behaviors, and tobacco-related attitudes. Results: Data were collected from 1,069 individuals at Time 1, and 720, 1,142, and 1,149 participants at Times 2, 3, and 4, respectively. Current smoking rates decreased from 47.5% at Time 1 to 37.5% at Time 4 (p < .001). Among Partiers, the odds of daily smoking decreased significantly, but nondaily smoking was unchanged. Partiers that recalled, liked, and understood the smoke-free message of HAVOC had lower odds of nondaily (odds ratio:.48, 95% CI: .31-.75) and daily (odds ratio: .31, 95% CI: .14-.68) smoking than those who did not recall HAVOC. HAVOC recall was associated with attitudes that were also associated with smoking behavior. Conclusions: The significant decrease in daily smoking among young adult Partiers in New Mexico was associated with HAVOC recall and understanding. Social Branding interventions efficiently target and may decrease tobacco use among young adult bar patrons. (C) 2016 Society for Adolescent Health and Medicine. All rights reserved. C1 [Kalkhoran, Sara; Lisha, Nadra E.; Ling, Pamela M.] Univ Calif San Francisco, Dept Med, Div Gen Internal Med, San Francisco, CA USA. [Neilands, Torsten B.] Univ Calif San Francisco, Dept Med, Ctr AIDS Prevent Studies, San Francisco, CA USA. [Jordan, Jeffrey W.] Rescue, San Diego, CA USA. [Ling, Pamela M.] Univ Calif San Francisco, Ctr Tobacco Control Res & Educ, San Francisco, CA USA. [Kalkhoran, Sara] Massachusetts Gen Hosp, Dept Med, Div Gen Internal Med, Boston, MA 02114 USA. [Kalkhoran, Sara] Harvard Med Sch, Boston, MA 02114 USA. RP Ling, PM (reprint author), Univ Calif San Francisco, Div Gen Internal Med, Dept Med, Ctr Tobacco Control Res & Educ, 530 Parnassus Ave,Suite 366, San Francisco, CA 94143 USA. EM pling@medicine.ucsf.edu FU NIH NRSA [T32HP19025]; National Cancer Institute [U01-154240]; New Mexico Department of Health's Tobacco Use Prevention and Control Program FX This work was supported by NIH NRSA T32HP19025 (Kalkhoran), National Cancer Institute (U01-154240), and New Mexico Department of Health's Tobacco Use Prevention and Control Program. NR 40 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1054-139X EI 1879-1972 J9 J ADOLESCENT HEALTH JI J. Adolesc. Health PD AUG PY 2016 VL 59 IS 2 BP 222 EP 229 DI 10.1016/j.jadohealth.2016.04.003 PG 8 WC Psychology, Developmental; Public, Environmental & Occupational Health; Pediatrics SC Psychology; Public, Environmental & Occupational Health; Pediatrics GA DS4NF UT WOS:000380757100014 PM 27265423 ER PT J AU Papathanasiou, E Kantarci, A Konstantinidis, A Gao, H Van Dyke, TE AF Papathanasiou, E. Kantarci, A. Konstantinidis, A. Gao, H. Van Dyke, T. E. TI SOCS-3 Regulates Alveolar Bone Loss in Experimental Periodontitis SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE inflammation; Porphyromonas gingivalis; animal model; osteoclasts; macrophages; cytokines ID CYTOKINE SIGNALING SOCS; PORPHYROMONAS-GINGIVALIS; SUPPRESSORS; ACTIVATION; MICE; INFLAMMATION; MACROPHAGES; INVOLVEMENT; EXPRESSION; INFECTION AB The host immune response plays a key role in bacteria-induced alveolar bone resorption. Endogenous control of the magnitude and duration of inflammatory signaling is considered an important determinant of the extent of periodontal pathology. Suppressor of cytokine signaling (SOCS) proteins are inhibitors of cytokine signaling pathways and may play a role in restraining periodontal inflammation. We hypothesized that SOCS-3 regulates alveolar bone loss in experimental periodontitis. Periodontal bone loss was induced in 16-wkold myeloid-specific SOCS-3-knockout and wild-type (WT) C57Bl6-B. 129 mice by oral inoculation 9 times with 109 colony-forming units of Porphyromonas gingivalis A7436 through an oral gavage model for periodontitis. Sham controls for both types of mice received vehicle without bacteria. The mice were euthanized 6 wk after the last oral inoculation. Increased bone loss was demonstrated in P. gingivalis-infected SOCS-3-knockout mice as compared with P. gingivalis-infected WT mice by direct morphologic measurements, micro-computed tomography analyses, and quantitative histology. Loss of SOCS-3 function resulted in an increased number of alveolar bone osteoclasts and increased RANKL expression after P. gingivalis infection. SOCS-3 deficiency in myeloid cells also promotes a higher P. gingivalis lipopolysaccharide-induced inflammatory response with higher secretion of IL-I beta, IL- 6, and KC (IL- 8) by peritoneal macrophages as compared with WT controls. Our data implicate SOCS-3 as a critical negative regulator of alveolar bone loss in periodontitis. C1 [Papathanasiou, E.; Kantarci, A.; Van Dyke, T. E.] Forsyth Inst, Ctr Periodontol, Dept Appl Oral Sci, Cambridge, MA USA. [Papathanasiou, E.] Tufts Univ, Sch Dent Med, Dept Periodontol, Boston, MA 02111 USA. [Papathanasiou, E.; Konstantinidis, A.] Aristotle Univ Thessaloniki, Sch Dent, Dept Prevent Dent Periodontol & Implant Biol, Thessaloniki, Greece. [Gao, H.] Harvard Med Sch, Brigham & Womens Hosp, Dept Anesthesiol Perioperat & Pain Med, Ctr Expt Therapeut & Reperfus Injury, Boston, MA USA. RP Van Dyke, TE (reprint author), Ctr Periodontol, Clin & Translat Res Chair, Dept Appl Oral Sci, 245 First St, Cambridge, MA 02142 USA. EM tvandyke@forsyth.org FU National Institute of Dental and Craniofacial Research, U.S. Public Health Service [DE25020, DE020906] FX The authors of this study thank the veterinary and technical personnel of the Forsyth Institute Animal Center for assistance during animal handling and experimental procedures. The authors also thank Justine Dobeck for assisting in the process of histologic samples, Daniel Nguyen for technical support, and Steven Wilbert and Jordan Briscoe for assisting in micro-computed tomography analysis. This study was partly supported by grants from the National Institute of Dental and Craniofacial Research, U.S. Public Health Service (DE25020 to T.E. Van Dyke; DE020906 to A. Kantarci). The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article. NR 29 TC 0 Z9 0 U1 2 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-0345 EI 1544-0591 J9 J DENT RES JI J. Dent. Res. PD AUG PY 2016 VL 95 IS 9 BP 1018 EP 1025 DI 10.1177/0022034516645332 PG 8 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA DS5IQ UT WOS:000380815400007 PM 27126447 ER PT J AU Syed, ZA Chen, TC AF Syed, Zeba A. Chen, Teresa C. TI New Ultrasound Biomicroscopy Iris Findings in Juvenile Xanthogranuloma SO JOURNAL OF GLAUCOMA LA English DT Article DE juvenile xanthogranuloma; hyphema; pediatric glaucoma AB We report a case of juvenile xanthogranuloma in a 12-month-old girl presenting with heterochromia, hyphema, and elevated intraocular pressure. This case demonstrates new ultrasound biomicroscopy iris findings of a generalized bumpy iris contour, suggesting diffuse heterogeneous involvement. This imaging finding has not been previously described. Untreated, iris juvenile xanthogranuloma may lead to corneal blood staining, glaucoma, and amblyopia. An understanding of the full range of ultrasound features of juvenile xanthogranuloma expands our appreciation for the clinical findings in this condition. C1 [Syed, Zeba A.; Chen, Teresa C.] Harvard Med Sch, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA USA. RP Chen, TC (reprint author), Massachusetts Eye & Ear Infirm, Glaucoma Serv, 243 Charles St, Boston, MA 02114 USA. EM teresa_chen@meei.harvard.edu NR 5 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1057-0829 EI 1536-481X J9 J GLAUCOMA JI J. Glaucoma PD AUG PY 2016 VL 25 IS 8 BP E759 EP E760 DI 10.1097/IJG.0000000000000443 PG 2 WC Ophthalmology SC Ophthalmology GA DS4QE UT WOS:000380765000010 PM 27483333 ER PT J AU Senders, A Sando, K Wahbeh, H Hiller, AP Shinto, L AF Senders, Angela Sando, Kelsi Wahbeh, Helane Hiller, Amie Peterson Shinto, Lynne TI Managing psychological stress in the multiple sclerosis medical visit: Patient perspectives and unmet needs SO JOURNAL OF HEALTH PSYCHOLOGY LA English DT Article DE health psychology; patient satisfaction; psychological distress; qualitative methods; verbal communication ID PRIMARY-CARE; RANDOMIZED-TRIAL; LIFE EVENTS; HEALTH; MS; MANAGEMENT; METAANALYSIS; DEPRESSION; ILLNESS; LESIONS AB Psychological stress can negatively impact multiple sclerosis. To further understand how stress is addressed in the multiple sclerosis medical visit, 34 people with multiple sclerosis participated in focus groups. Transcripts were analyzed by inductive thematic analysis. The majority of participants did not discuss stress with their provider, citing barriers to communication such as lack of time, poor coordination between specialties, physician reliance on pharmaceutical prescription, and patient lack of self-advocacy. Participants recommended several ways to better manage psychological well-being in the clinical setting. These findings provide a foundation for future studies aimed at minimizing the detrimental effect of stress in multiple sclerosis. C1 [Senders, Angela; Wahbeh, Helane; Hiller, Amie Peterson; Shinto, Lynne] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Senders, Angela; Sando, Kelsi] Natl Coll Nat Med, Portland, OR USA. [Hiller, Amie Peterson] Portland VA Med Ctr, Portland, OR USA. RP Senders, A (reprint author), Oregon Hlth & Sci Univ, Dept Neurol, 3181 SW Sam Jackson Pk Rd,Mail Code CR120, Portland, OR 97239 USA. EM senders@ohsu.edu FU Oregon Clinical & Translational Research Institute from the National Center for Research Resources [UL1 RR024140]; National Center for Advancing Translational Sciences of the National Institutes of Health); National Center for Complementary and Alternative Medicine of the National Institutes of Health [AT002688, 2R25AT002878-05A1]; Agency for Healthcare Research Quality [5T32HS017582-05] FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Oregon Clinical & Translational Research Institute (grant number UL1 RR024140 from the National Center for Research Resources and the National Center for Advancing Translational Sciences of the National Institutes of Health); the National Center for Complementary and Alternative Medicine of the National Institutes of Health (grant numbers AT002688 and 2R25AT002878-05A1); and the Agency for Healthcare Research Quality (grant number 5T32HS017582-05). NR 42 TC 2 Z9 2 U1 4 U2 4 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1359-1053 EI 1461-7277 J9 J HEALTH PSYCHOL JI J. Health Psychol. PD AUG PY 2016 VL 21 IS 8 BP 1676 EP 1687 DI 10.1177/1359105314562084 PG 12 WC Psychology, Clinical SC Psychology GA DS7UL UT WOS:000380988300017 PM 25527612 ER PT J AU Gavlovsky, PJ Tonnerre, P Gerard, N Nedellec, S Daman, AW McFarland, BJ Charreau, B AF Gavlovsky, Pierre-Jean Tonnerre, Pierre Gerard, Nathalie Nedellec, Steven Daman, Andrew W. McFarland, Benjamin J. Charreau, Beatrice TI Alternative Splice Transcripts for MHC Class I-like MICA Encode Novel NKG2D Ligands with Agonist or Antagonist Functions SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ENDOTHELIAL-CELLS; T-CELLS; TRANSMEMBRANE REGION; KIDNEY ALLOGRAFTS; HIV CONTROL; NK CELLS; GENE; EXPRESSION; ACTIVATION; POLYMORPHISM AB MHC class I chain-related proteins A and B (MICA and MICB) and UL16-binding proteins are ligands of the activating NKG2D receptor involved in cancer and immune surveillance of infection. Structurally, MICA/B proteins contain an alpha 3 domain, whereas UL16-binding proteins do not. We identified novel alternative splice transcripts for MICA encoding five novel MICA isoforms: MICA-A, -B1, -B2, -C, and -D. Alternative splicing associates with MICA*015 and *017 and results from a point deletion (G) in the 59 splice donor site of MICA intron 4 leading to exon 3 and exon 4 skipping and/or deletions. These changes delete the alpha 3 domain in all isoforms, and the alpha 2 domain in the majority of isoforms (A, B1, C, and D). Endothelial and hematopoietic cells contained endogenous alternative splice transcripts and isoforms. MICA-B1, -B2, and -D bound NKG2D by surface plasmon resonance and were expressed at the cell surface. Functionally, MICA-B2 contains two extracellular domains (alpha 1 and alpha 2) and is a novel potent agonist ligand for NKG2D. We found that MICA-D is a new truncated form of MICA with weak affinity for NKG2D despite lacking alpha 2 and alpha 3 domains. MICA-D may functionally impair NKG2D activation by competing with full-length MICA or MICA-B2 for NKG2D engagement. Our study established NKG2D binding for recombinant MICA-B1 but found no function for this isoform. New truncated MICA isoforms exhibit a range of functions that may drive unexpected immune mechanisms and provide new tools for immunotherapy. C1 [Gavlovsky, Pierre-Jean; Tonnerre, Pierre; Gerard, Nathalie; Charreau, Beatrice] INSERM, UMR1064, LabEx Transplantex, LabEx Immunol Graft Oncol, F-44000 Nantes, France. [Gavlovsky, Pierre-Jean; Tonnerre, Pierre; Gerard, Nathalie; Charreau, Beatrice] Hospital Univ Inst European Ctr Transplantat & Im, F-44000 Nantes, France. [Gavlovsky, Pierre-Jean; Tonnerre, Pierre; Gerard, Nathalie; Charreau, Beatrice] Ctr Hosp Univ Nantes, Inst Transplantat & Rech Transplantat Urol Nephro, F-44000 Nantes, France. [Gavlovsky, Pierre-Jean; Tonnerre, Pierre; Gerard, Nathalie; Nedellec, Steven; Charreau, Beatrice] Univ Nantes, Univ Nantes Angers Le Mans, Fac Med, F-44000 Nantes, France. [Nedellec, Steven] Inst Rech Therapeut, Plateforme MicroPICell Struct Federat Rech Sante, F-44000 Nantes, France. [Daman, Andrew W.; McFarland, Benjamin J.] Seattle Pacific Univ, Dept Chem & Biochem, Seattle, WA 98119 USA. [Tonnerre, Pierre] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Tonnerre, Pierre] Harvard Med Sch, Boston, MA USA. [Daman, Andrew W.] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. RP Charreau, B (reprint author), INSERM, UMR1064, 30 Blvd Jean Monnet, F-44093 Nantes 01, France. EM Beatrice.Charreau@univ-nantes.fr NR 55 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD AUG 1 PY 2016 VL 197 IS 3 BP 736 EP 746 DI 10.4049/jimmunol.1501416 PG 11 WC Immunology SC Immunology GA DS1EM UT WOS:000380338600008 PM 27342847 ER PT J AU Ng, LC Petruzzi, LJ Greene, MC Mueser, KT Borba, CPC Henderson, DC AF Ng, Lauren C. Petruzzi, Liana J. Greene, M. Claire Mueser, Kim T. Borba, Christina P. C. Henderson, David C. TI Posttraumatic Stress Disorder Symptoms and Social and Occupational Functioning of People With Schizophrenia SO JOURNAL OF NERVOUS AND MENTAL DISEASE LA English DT Article DE Functioning; interpersonal; occupational; PTSD; schizophrenia ID SEVERE MENTAL-ILLNESS; COGNITIVE-BEHAVIORAL TREATMENT; NATIONAL COMORBIDITY SURVEY; QUALITY-OF-LIFE; CHILDHOOD TRAUMA; SCHIZOAFFECTIVE DISORDER; PSYCHIATRIC-INPATIENTS; CLINICIAN PERSPECTIVES; 1ST-EPISODE PSYCHOSIS; SPECTRUM DISORDERS AB This study sought to clarify the contribution of posttraumatic stress disorder (PTSD) to interpersonal and occupational functioning in people with schizophrenia. Self-report questionnaires and semistructured interviews were used to evaluate PTSD and brain injury, positive symptoms, depression, substance abuse, occupational and social functioning, and intelligence. Multiple regressions assessed the relationship between predictors and functional impairment. Posttraumatic stress disorder symptoms were present in 76% of participants, with 12% of participants meeting diagnostic criteria for PTSD. Participants with PTSD had higher rates of depression and more severe positive symptoms. Results of multiple regressions indicated that PTSD symptoms were the only significant predictor of patient-rated interpersonal and occupational functioning. Posttraumatic stress disorder symptoms were not associated with interviewer-rated interpersonal or occupational functioning or employment. While more research is needed, screening and treatment for exposure to traumatic events and PTSD symptoms might be indicated for individuals with schizophrenia. Availability of PTSD assessment and evidence-based treatments for people with schizophrenia is a crucial and often unmet health service need. C1 [Ng, Lauren C.; Petruzzi, Liana J.; Greene, M. Claire; Borba, Christina P. C.; Henderson, David C.] Massachusetts Gen Hosp, Dept Psychiat, Schizophrenia Clin & Res Program, Boston, MA 02114 USA. [Ng, Lauren C.; Borba, Christina P. C.; Henderson, David C.] Harvard Med Sch, Dept Psychiat, Boston, MA USA. [Petruzzi, Liana J.] Univ Texas Austin, Sch Social Work, Austin, TX 78712 USA. [Greene, M. Claire] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Mueser, Kim T.] Boston Univ, Ctr Psychiat Rehabil, Dept Occupat Therapy, Boston, MA 02215 USA. [Mueser, Kim T.] Boston Univ, Dept Psychol, Ctr Psychiat Rehabil, 64 Cummington St, Boston, MA 02215 USA. [Mueser, Kim T.] Boston Univ, Dept Psychiat, Ctr Psychiat Rehabil, Boston, MA 02215 USA. RP Ng, LC (reprint author), Freedom Trail Clin, 25 Staniford St,2nd Floor, Boston, MA 02114 USA. EM lng4@mgh.harvard.edu FU National Institute of Mental Health at the National Institutes of Health [T32 MH093310] FX This work was supported by the National Institute of Mental Health at the National Institutes of Health (grant T32 MH093310). NR 63 TC 1 Z9 1 U1 7 U2 10 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 AUG PY 2016 VL 204 IS 8 BP 590 EP 598 DI 10.1097/NMD.0000000000000523 PG 9 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DS4PF UT WOS:000380762300006 PM 27105458 ER PT J AU Rogers, JT Venkataramani, V Washburn, C Liu, YY Tummala, V Jiang, H Smith, A Cahill, CM AF Rogers, Jack T. Venkataramani, Vivek Washburn, Cecilia Liu, Yanyan Tummala, Vinusha Jiang, Hong Smith, Ann Cahill, Catherine M. TI A role for amyloid precursor protein translation to restore iron homeostasis and ameliorate lead (Pb) neurotoxicity SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE APP; ferritin; iron retention; iron-responsive element; lead toxicity; neuronal cell ID MESSENGER-RNA TRANSLATION; LOW-LEVEL LEAD; ALZHEIMERS-DISEASE; REGULATORY PROTEIN-1; 5'-UNTRANSLATED REGION; RESPONSIVE ELEMENT; FERRITIN EXPRESSION; ENDOTHELIAL-CELLS; CELLULAR IRON; SH-SY5Y CELLS AB Iron supplementation ameliorates the neurotoxicity of the environmental contaminant lead (Pb); however, the mechanism remains undefined. Iron is an essential nutrient but high levels are toxic due to the catalytic generation of destructive hydroxyl radicals. Using human neuroblastoma SH-SY5Y cells to model human neurons, we investigated the effect of Pb on proteins of iron homeostasis: the Alzheimer's amyloid precursor protein (APP), which stabilizes the iron exporter ferroportin 1; and, the heavy subunit of the iron-storage protein, ferritin (FTH). Lead (Pb(II) and Pb(IV) inhibited APP translation and raised cytosolic iron(II). Lead also increased iron regulatory protein-1 binding to the cognate 5untranslated region-specific iron-responsive element (IRE) of APP and FTH mRNAs. Concurrent iron treatment rescued cells from Pb toxicity by specifically restoring APP synthesis, i.e. levels of the APP-related protein, APLP-2, were unchanged. Significantly, iron/IRE-independent over-expression of APP(695)protected SH-SY5Y cells from Pb toxicity, demonstrating that APP plays a key role in maintaining safe levels of intracellular iron. Overall, our data support a model of neurotoxicity where Pb enhances iron regulatory protein/IRE-mediated repression of APP and FTH translation. We propose novel treatment options for Pb poisoning to include chelators and the use of small molecules to maintain APP and FTH translation. C1 [Rogers, Jack T.; Washburn, Cecilia; Liu, Yanyan; Tummala, Vinusha; Cahill, Catherine M.] Harvard Med Sch, Massachusetts Gen Hosp East, Dept Psychiat Neurosci, Neurochem Lab, Charlestown, MA USA. [Venkataramani, Vivek] Univ Med Ctr, Dept Hematol & Med Oncol, Gottingen, Germany. [Jiang, Hong] Qingdao Univ, State Key Disciplines Physiol, Coll Med, Qingdao, Peoples R China. [Smith, Ann] Univ Missouri KC, Sch Biol Sci, Kansas City, MO USA. RP Rogers, JT; Cahill, CM (reprint author), Massachusetts Gen Hosp, Dept Psychiat Neurosci, 149 13th St, Charlestown, MA 02129 USA. EM jrogers@partners.org; ccahill@helix.mgh.harvard.edu FU National Institute for Neurological diseases [NINDS 077079]; Zenith grant from the Alzheimer's association FX We thank Sohan Mikkilineni (MGH) for sequence comparisons of the 5'untranslated regions of the ferritin and amyloid precursor protein transcripts and JTR thanks Prof. Maurizio Fava for expert support during the course of this work. J.T.R., A.S. and H.J. designed the study; C.C., V.V. and C.W. carried out experiments; Y.L. and V.T carried out western blots and APP-IRE luciferase experiments. J.T.R., A.S., C.C. and V.V. analyzed and interpreted data and wrote the paper. This work was funded by grants to JTR from the National Institute for Neurological diseases (NINDS 077079) and from a Zenith grant from the Alzheimer's association. The authors state no conflict of interest. NR 99 TC 0 Z9 0 U1 6 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2016 VL 138 IS 3 BP 479 EP 494 DI 10.1111/jnc.13671 PG 16 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA DS6SW UT WOS:000380914000011 PM 27206843 ER PT J AU Rodriguez, EK Zurakowski, D Herder, L Hall, A Walley, KC Weaver, MJ Appleton, PT Vrahas, M AF Rodriguez, Edward K. Zurakowski, David Herder, Lindsay Hall, Amber Walley, Kempland C. Weaver, Mike J. Appleton, Paul T. Vrahas, Mark TI Mechanical Construct Characteristics Predisposing to Non-union After Locked Lateral Plating of Distal Femur Fractures SO JOURNAL OF ORTHOPAEDIC TRAUMA LA English DT Article; Proceedings Paper CT Annual Meeting of the Orthopaedic-Trauma-Association CY OCT 14-18, 2014 CL Tampa, FL SP Orthopaed Trauma Assoc DE distal femur fracture; nonunion; construct stiffness; rigidity score; screw density ID FAR CORTICAL LOCKING; INVASIVE STABILIZATION SYSTEM; TOTAL KNEE ARTHROPLASTY; FEMORAL FRACTURES; FIXATION; PLATES; STIFFNESS; OUTCOMES AB Objectives: To identify discrete construct characteristics related to overall construct rigidity that may be independent predictors of nonunion after lateral locked plate (LLP) fixation of distal femur fractures. Design: Retrospective case-control study. Setting: Three level-1 urban trauma centers. Patients/Participants: Two hundred and seventy-one supracondylar femoral fractures treated with LLP at 3 affiliated level 1 urban trauma centers between August 2004 and December 2010. Methods: Nonunion was defined as a secondary procedure for poor healing. Construct variables included: (1) combined plate design and material variable, (2) Plate length, (3) # screws proximal to fracture, (4) total screw density (TSD), (5) proximal screw density (PSD), (6) presence of a screw crossing the main fracture, and (7) rigidity score multivariable analysis was performed using logistic regression to identify independent risk factors for nonunion. Intervention: LLP fixation. Main Outcome Measure: Nonunion. Results: Nonunion rate was 13.3% (n = 36). There was a significant association between plate design/material and nonunion with 41% of stainless constructs and 10% of titanium constructs resulting in a non-union (P < 0.001). Rigidity scores reached significance (P = 0.001) with constructs resulting in a nonunion having higher scores. No significant univariate differences with respect to number of proximal screws, plate length, total screw density, or proximal screw density were observed between healed fractures and those with nonunion. Results of the multivariate analysis confirmed that the primary significant independent predictor of nonunion was plate design/material (odds ratio, 6.8; 95% CI, 2.9-16.1; P < 0.001). Conclusions: When treating distal femur fractures with LLP, combined plate design and material variable has a highly significant influence on the risk of nonunion independent of any other construct variable. C1 [Rodriguez, Edward K.; Herder, Lindsay; Walley, Kempland C.; Appleton, Paul T.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Rodriguez, Edward K.; Weaver, Mike J.; Appleton, Paul T.; Vrahas, Mark] Harvard Med Sch, Orthoped Trauma Initiat, Boston, MA USA. [Zurakowski, David; Hall, Amber] Childrens Hosp, 300 Longwood Ave, Boston, MA 02115 USA. [Weaver, Mike J.; Vrahas, Mark] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Vrahas, Mark] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Rodriguez, EK (reprint author), Beth Israel Deaconess Med Ctr, Dept Orthopaed Surg, 330 Brookline Ave,Stoneman 10, Boston, MA 02215 USA. EM ekrodrig@bidmc.harvard.edu OI Walley, Kempland/0000-0003-4488-0663 NR 31 TC 0 Z9 0 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0890-5339 EI 1531-2291 J9 J ORTHOP TRAUMA JI J. Orthop. Trauma PD AUG PY 2016 VL 30 IS 8 BP 403 EP 408 DI 10.1097/BOT.0000000000000593 PG 6 WC Orthopedics; Sport Sciences SC Orthopedics; Sport Sciences GA DS5HI UT WOS:000380811900009 PM 27027801 ER PT J AU Stuver, SO McNiff, K Fraile, B Odejide, O Abel, GA Dodek, A Jacobson, JO AF Stuver, Sherri O. McNiff, Kristen Fraile, Belen Odejide, Oreofe Abel, Gregory A. Dodek, Anton Jacobson, Joseph O. TI Novel Data Sharing Between a Comprehensive Cancer Center and a Private Payer to Better Understand Care at the End of Life SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Article DE End-of-life care; claims data; oncology patients; quality improvement ID POPULATION-BASED INDICATORS; OF-LIFE; MEDICARE BENEFICIARIES; ADMINISTRATIVE DATA; MENTAL-HEALTH; LAST YEAR; QUALITY; DEATH; AGGRESSIVENESS; INTENSITY AB Context. Understanding end-of-life (EOL) care patterns is a prerequisite to improving the experience for cancer patients. EOL measures endorsed by the National Quality Forum (NQF) have been examined in older patients using Medicare claims. Objectives. To evaluate EOL care for patients treated at a comprehensive cancer center, using private payer claims data. Methods. A retrospective cohort study was conducted of Dana-Farber Cancer Institute ( DFCI) patients who died between July 2010 and December 2012, and were insured by Blue Cross Blue Shield of Massachusetts. Primary data sources included Blue Cross Blue Shield of Massachusetts claims information and DFCI administrative data. We assessed NQF-endorsed measures of EOL care related to emergency department visits, hospitalizations, and intensive care unit admissions in the last 30 days, chemotherapy in the last 14 days, hospice stay, and death in an acute care setting. Patterns of care by cancer type and service location were determined. Results. Among 674 patients ( mean age 58 years), event rates for NQF-endorsed EOL measures were similar to those reported using Medicare claims. Decedents with hematologic malignancies received significantly more intensive care and were less likely to have enrolled in hospice, compared to decedents with solid tumors. Thirty to 45% of EOL events occurred outside of DFCI and its affiliated hospitals. Conclusion. Data sharing between a private payer and a large cancer center proved feasible and informative. High rates of hospital service use outside of our sites of care were unexpected. The findings suggest opportunities to better manage care at the end of life. (C) 2016 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved. C1 [Stuver, Sherri O.; McNiff, Kristen; Fraile, Belen; Odejide, Oreofe; Abel, Gregory A.; Jacobson, Joseph O.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Stuver, Sherri O.] Boston Univ, Sch Publ Hlth, Boston, MA 02215 USA. [Dodek, Anton] Blue Cross & Blue Shield Massachusetts, Boston, MA USA. RP Stuver, SO (reprint author), Dana Farber Canc Inst, Dept Qual & Patient Safety, 450 Brookline Ave, Boston, MA 02215 USA. EM Sherri_Stuver@dfci.harvard.edu NR 41 TC 1 Z9 1 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0885-3924 EI 1873-6513 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD AUG PY 2016 VL 52 IS 2 BP 161 EP 169 DI 10.1016/j.jpainsymman.2016.02.004 PG 9 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA DT7RD UT WOS:000381683000004 PM 27033156 ER PT J AU Just, E Casarett, DJ Asch, DA Dai, DW Feudtner, C AF Just, Erica Casarett, David J. Asch, David A. Dai, Dingwei Feudtner, Chris TI Differences in Terminal Hospitalization Care Between US Men and Women SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Article DE Sex differences; end-of-life care ID SEX-BASED DISPARITIES; OF-LIFE CARE; UNITED-STATES; MEDICATION USE; OUTCOMES; GENDER; RATES AB Context. In many settings, men and women receive different care. Objectives. We sought to determine whether men and women receive different care during terminal hospitalizations. Methods. We analyzed data of 98,314 adult patients who died while hospitalized in 458 acute care hospitals in the U.S. during 2011. We examined sex-based differences in lengths of stay (LOS), resuscitation status, and intensive interventions and processes of care, adjusting for patient-and hospital-level characteristics. Results. Women represented half of the sample (48,509; 49.34%), were older than men (73.8 vs. 70.6 years, P < 0.0001), and less likely to be married (27.7% vs. 48.3%, P < 0.001). Among all patients, median LOS was four days (interquartile range 2-10); 19.1% of subjects received cardiopulmonary resuscitation; 37.6% had a do-not-resuscitate order during the admission; and 51.6% received mechanical ventilation. Compared with men, women had slightly shorter hospitalizations (adjusted LOS: - 0.16 days; 95% CI - 0.19, - 0.12) and were more likely to have a do-not-resuscitate order (odds ratio [ OR] 1.08; 95% CI 1.05, 1.11). Women remained less likely to receive care in an intensive care unit (OR 0.95; 95% CI 0.93, 0.98), cardiopulmonary resuscitation (OR 0.83; 95% CI 0.80, 0.86), mechanical ventilation (OR 0.94; 95% CI 0.91, 0.97), hemodialysis (adjusted OR 0.81; 95% CI 0.78, 0.86), or surgical procedures (OR 0.88; 95% CI 0.84, 0.93). Conclusion. Men who die in hospitals receive more aggressive care than women. Further research should examine potential causes of this overall pattern. (C) 2016 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved. C1 [Just, Erica] Tulane Univ, Sch Med, Dept Med, New Orleans, LA 70112 USA. [Just, Erica] Tulane Univ, Sch Med, Dept Pediat, New Orleans, LA 70112 USA. [Casarett, David J.; Asch, David A.] Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Casarett, David J.] Univ Penn, Dept Med Eth & Hlth Policy, Perelman Sch Med, Philadelphia, PA 19104 USA. [Feudtner, Chris] Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Casarett, David J.; Asch, David A.; Feudtner, Chris] Univ Penn, Leonard Davis Inst, Philadelphia, PA 19104 USA. [Asch, David A.] Philadelphia VA Med Ctr, VA Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Dai, Dingwei; Feudtner, Chris] Childrens Hosp Philadelphia, CHOP North Room 1523,34th & Civ Ctr Blvd, Philadelphia, PA 19104 USA. RP Feudtner, C (reprint author), Childrens Hosp Philadelphia, CHOP North Room 1523,34th & Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM feudtner@email.chop.edu OI Feudtner, Chris/0000-0002-5879-0434 FU Health Resources and Services Administration (HRSA) [T32 HP10026]; AHRQ [R01HS018425] FX This study was supported by Health Resources and Services Administration (HRSA) T32 HP10026 and AHRQ R01HS018425. The funding organizations had no role in the design of the study beyond the critique offered by the peer-review process and had no role in the conduct of the study, including the collection, analysis, and preparation of the data or the drafting, editing, review, or approval of the manuscript. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Agency for Healthcare Research and Quality. The authors declare that they have no relevant financial relationships to disclose. The authors thank Wenjun Zhong for assistance with the preparation of the manuscript. NR 23 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0885-3924 EI 1873-6513 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD AUG PY 2016 VL 52 IS 2 BP 205 EP 211 DI 10.1016/j.jpainsymman.2016.01.013 PG 7 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA DT7RD UT WOS:000381683000009 PM 27220946 ER PT J AU Rosenberg, AR Orellana, L Ullrich, C Kang, T Geyer, JR Feudtner, C Dussel, V Wolfe, J AF Rosenberg, Abby R. Orellana, Liliana Ullrich, Christina Kang, Tammy Geyer, J. Russell Feudtner, Chris Dussel, Veronica Wolfe, Joanne TI Quality of Life in Children With Advanced Cancer: A Report From the PediQUEST Study SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Article DE Quality of life; pediatric cancer; palliative care; end of life; patient-reported outcomes; symptom distress ID ACUTE LYMPHOBLASTIC-LEUKEMIA; RANDOMIZED CONTROLLED-TRIAL; GENERIC CORE SCALES; CHILDHOOD-CANCER; PEDIATRIC CANCER; CONCEPTUAL-MODEL; TUMOR SURVIVORS; ONCOLOGY GROUP; FOLLOW-UP; HEALTH AB Context. Modifiable factors of health-related quality of life (HRQOL) are poorly described among children with advanced cancer. Symptom distress may be an important factor for intervention. Objectives. We aimed to describe patient-reported HRQOL and its relationship to symptom distress. Methods. Prospective, longitudinal data from the multicenter Pediatric Quality of Life and Symptoms Technology study included primarily patient-reported symptom distress and HRQOL, measured at most weekly with the Memorial Symptoms Assessment Scale and Pediatric Quality of Life inventory, respectively. Associations were evaluated using linear mixed-effects models adjusting for sex, age, cancer type, intervention arm, treatment intensity, and time since disease progression. Results. Of 104 enrolled patients, 49% were female, 89% were white, and median age was 12.6 years. Nine hundred and twenty surveys were completed over nine months of follow-up (84% by patients). The median total Pediatric Quality of Life score was 74 (interquartile range 63-87) and was ``poor/ fair'' (e.g., <70) 38% of the time. ``Poor/ fair'' categories were highest in physical (53%) and school (48%) compared to emotional (24%) and social (16%) subscores. Thirteen of 24 symptoms were independently associated with reductions in overall or domain-specific HRQOL. Patients commonly reported distress from two or more symptoms, corresponding to larger HRQOL score reductions. Neither cancer type, time since progression, treatment intensity, sex, nor age was associated with HRQOL scores in multivariable models. Among 25 children completing surveys during the last 12 weeks of life, 11 distressing symptoms were associated with reductions in HRQOL. Conclusion. Symptom distress is strongly associated with HRQOL. Future research should determine whether alleviating distressing symptoms improves HRQOL in children with advanced cancer. (C) 2016 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved. C1 [Rosenberg, Abby R.; Geyer, J. Russell] Univ Washington, Sch Med, Seattle Childrens Hosp, Canc & Blood Disorders Ctr, Seattle, WA USA. [Rosenberg, Abby R.; Geyer, J. Russell] Univ Washington, Sch Med, Dept Pediat, Seattle, WA 98195 USA. [Rosenberg, Abby R.; Geyer, J. Russell] Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA. [Rosenberg, Abby R.] Seattle Childrens Res Inst, Treuman Katz Ctr Pediat Bioeth, Seattle, WA USA. [Orellana, Liliana] Deakin Univ, Fac Hlth, Biostat Unit, Geelong, Vic, Australia. [Ullrich, Christina; Wolfe, Joanne] Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, 450 Brookline Ave, Boston, MA 02215 USA. [Ullrich, Christina; Wolfe, Joanne] Dana Farber Canc Inst, Ctr Outcomes & Policy Res, Boston, MA 02115 USA. [Ullrich, Christina; Dussel, Veronica; Wolfe, Joanne] Boston Childrens Hosp, Dept Med, Boston, MA USA. [Ullrich, Christina; Wolfe, Joanne] Harvard Med Sch, Boston, MA USA. [Kang, Tammy; Feudtner, Chris] Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA. [Kang, Tammy; Feudtner, Chris] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Dussel, Veronica] Inst Clin Effectiveness & Hlth Policy, Ctr Res & Implementat Palliat Care, Buenos Aires, DF, Argentina. RP Wolfe, J (reprint author), Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, 450 Brookline Ave, Boston, MA 02215 USA. EM joanne_wolfe@dfci.harvard.edu RI Orellana, Liliana/S-3302-2016 OI Orellana, Liliana/0000-0003-3736-4337 FU NIH/NCI [1K07 CA096746-01, L40 CA170049]; Charles H. Hood Foundation Child Health Research Award; American Cancer Society; NIH/NCATS [KL2 TR000421] FX The PediQUEST study (Evaluation of Pediatric Quality of Life and Evaluation of Symptoms Technology in Children with Cancer) was supported by grants NIH/NCI 1K07 CA096746-01, Charles H. Hood Foundation Child Health Research Award, and American Cancer Society Pilot and Exploratory Project Award in Palliative Care of Cancer Patients and Their Families. Dr. Rosenberg was supported by the grants NIH/NCATS KL2 TR000421 and NIH/NCI L40 CA170049. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors have no financial relationships relevant to this article to disclose. NR 62 TC 1 Z9 1 U1 8 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0885-3924 EI 1873-6513 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD AUG PY 2016 VL 52 IS 2 BP 243 EP 253 DI 10.1016/j.jpainsymman.2016.04.002 PG 11 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA DT7RD UT WOS:000381683000014 PM 27220948 ER PT J AU Smith, AK Ritchie, CS Wallhagen, ML AF Smith, Alexander K. Ritchie, Christine S. Wallhagen, Margaret L. TI Hearing Loss in Hospice and Palliative Care: A National Survey of Providers SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Article DE Hearing loss; aging; hospice; palliative care; communication ID OLDER-ADULTS; AID USE; PREVALENCE; EPIDEMIOLOGY; IMPAIRMENT AB Context. Age-related hearing loss can impair patient-provider communication about symptom management, goals of care, and end-of-life decision-making. Objectives. To determine whether hospice and palliative care providers screen for or received training about hearing loss, believe it impacts patient care, and use strategies to optimize communication. Methods. This was a national survey of hospice and palliative care providers conducted via email and social media. Survey questions were pilot tested with multidisciplinary providers in San Francisco. Results. Of 510 responses (55% age 50+ years, 65% female, 64% in practice 5+ years, 57% practiced hospital-based palliative care, 45% hospice), 315 were physicians, 50 nurses, 48 nurse practitioners, 58 social workers, and 39 chaplains. Ninety-one percent reported that hearing loss has some or great impact on the quality of care for older adults. Eighty-eight percent recalled a situation where hearing loss created a communication problem with a patient and 56% a communication problem with a caregiver. Eighty-seven percent of physicians, nurses, and nurse practitioners reported not screening for hearing loss. Although 61% felt comfortable with their communication skills for patients with hearing loss, only 21% reported having received formal training in its management, 31% were unfamiliar with resources for patients with hearing loss, and 38% had never heard of a pocket talker amplification device. Conclusion. Hospice and palliative medicine providers believe age-related hearing loss impacts care yet most do not screen. Although they feel they are managing well, few have formal training. Knowledge about management approaches and resources is suboptimal. (C) 2016 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved. C1 [Smith, Alexander K.; Ritchie, Christine S.] Univ Calif San Francisco, Div Geriatr, San Francisco, CA 94143 USA. [Wallhagen, Margaret L.] Univ Calif San Francisco, Dept Physiol Nursing, San Francisco, CA USA. [Smith, Alexander K.] Vet Affairs Med Ctr, Geriatr Palliat & Extended Care, San Francisco, CA 94121 USA. [Ritchie, Christine S.] Jewish Home San Francisco, San Francisco, CA USA. RP Smith, AK (reprint author), UCSF, San Francisco VA Med Ctr, Div Geriatr, 4150 Clement St,181G, San Francisco, CA 94121 USA. EM aksmith@ucsf.edu FU National Institute on Aging [1K23AG040772]; American Federation for Aging Research FX Dr. Smith was funded by a K23 Beeson award from the National Institute on Aging (1K23AG040772) and the American Federation for Aging Research. The authors have no other disclosures. NR 12 TC 1 Z9 1 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0885-3924 EI 1873-6513 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD AUG PY 2016 VL 52 IS 2 BP 254 EP 258 DI 10.1016/j.jpainsymman.2016.02.007 PG 5 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA DT7RD UT WOS:000381683000015 PM 27046300 ER PT J AU Back, AL Steinhauser, KE Kamal, AH Jackson, VA AF Back, Anthony L. Steinhauser, Karen E. Kamal, Arif H. Jackson, Vicki A. TI Building Resilience for Palliative Care Clinicians: An Approach to Burnout Prevention Based on Individual Skills and Workplace Factors SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Article DE Resilience; burnout; well-being; work engagement; palliative care ID POSITIVE PSYCHOLOGY; COMPASSION FATIGUE; JOB-SATISFACTION; MEDICAL ERRORS; SELF-CARE; PHYSICIANS; EMPATHY; MINDFULNESS; HEALTH; LIFE AB For palliative care (PC) clinicians, the work of caring for patients with serious illness can put their own well-being at risk. What they often do not learn in training, because of the relative paucity of evidence-based programs, are practical ways to mitigate this risk. Because a new study indicates that burnout in PC clinicians is increasing, we sought to design an acceptable, scalable, and testable intervention tailored to the needs of PC clinicians. In this article, we describe our paradigm for approaching clinician resilience, our conceptual model, and curriculum for a workplace resilience intervention for hospital-based PC teams. Our paradigm for approaching resilience is based on upstream, early intervention. Our conceptual model posits that clinician well-being is influenced by personal resources and work demands. Our curriculum for increasing clinician resilience is based on training in eight resilience skills that are useful for common challenges faced by clinicians. To address workplace issues, our intervention also includes material for the team leader and a clinician perception survey of work demands and workplace engagement factors. The intervention will focus on individual skill building and will be evaluated with measures of resilience, coping, and affect. For PC clinicians, resilience skills are likely as important as communication skills and symptom management as foundations of expertise. Future work to strengthen clinician resilience will likely need to address system issues more directly. (C) 2016 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved. C1 [Back, Anthony L.] Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle, WA 98195 USA. [Steinhauser, Karen E.] Duke Univ, Ctr Hlth Serv Res Primary Care, Durham VA Med Ctr, Durham, NC USA. [Kamal, Arif H.] Duke Univ, Dept Med, Div Gen Internal Med, Durham, NC USA. [Kamal, Arif H.] Duke Univ, Durham, NC USA. [Jackson, Vicki A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Back, AL (reprint author), Harborview Med Ctr, Cambia Palliat Care Ctr Excellence, 325 9th Ave, Seattle, WA 98104 USA. EM tonyback@uw.edu OI Back, Anthony/0000-0002-7903-0477 FU National Palliative Care Research Center; Arnold P. Gold Foundation; American Academy of Hospice and Palliative Medicine FX The authors gratefully acknowledge funding from the National Palliative Care Research Center, Arnold P. Gold Foundation and support from the American Academy of Hospice and Palliative Medicine. The authors declare no conflicts of interest. NR 63 TC 3 Z9 3 U1 19 U2 25 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0885-3924 EI 1873-6513 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD AUG PY 2016 VL 52 IS 2 BP 284 EP 291 DI 10.1016/j.jpainsymman.2016.02.002 PG 8 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA DT7RD UT WOS:000381683000019 PM 26921494 ER PT J AU Ozcan, E Saygun, NI Serdar, MA Bengi, VU Kantarci, A AF Ozcan, Erkan Saygun, N. Isil Serdar, Muhittin A. Bengi, V. Umut Kantarci, Alpdogan TI Non-Surgical Periodontal Therapy Reduces Saliva Adipokine and Matrix Metalloproteinase Levels in Periodontitis SO JOURNAL OF PERIODONTOLOGY LA English DT Article DE Adipokines; chronic periodontitis; matrix metalloproteinases; periodontal debridement; saliva ID GINGIVAL CREVICULAR FLUID; TYPE-2 DIABETES-MELLITUS; SERUM VISFATIN CONCENTRATION; ENDOTHELIAL-CELLS; LUNG INJURY; INFLAMMATION; PROGRANULIN; EXPRESSION; CHEMERIN; DISEASE AB Background: Adipokines enhance the synthesis of proinflammatory cytokines and matrix metalloproteinases (MMPs), which play a role in extracellular matrix degeneration. The aim of this study is to determine the levels of some adipokines, proinflammatory cytokines, and MMPs in the saliva of patients with periodontitis and healthy individuals and to evaluate the changes after non-surgical periodontal therapy (NSPT). Methods: Of 32 individuals included in the study, 17 had periodontitis and 15 had healthy gingiva. Saliva samples were obtained from all individuals. In patients with periodontitis, samples were recollected 3 and 6 months after NSPT. Visfatin, chemerin, progranulin, interleukin (IL)-1 beta, IL-8, MMP-8, and MMP-13 levels were measured using enzyme-linked immunosorbent assay. Results: In patients with periodontitis, all of the parameters measured in the saliva were higher than those of healthy individuals. At 3 months, visfatin, progranulin, IL-8, and MMP-8 levels were significantly decreased compared with baseline values. The levels of other biochemical parameters, chemerin and IL-1 beta, were significantly decreased compared with baseline values at 6 months, and the levels became similar to those in healthy individuals. In the periodontitis group, positive correlations were found among visfatin and IL-8 (r = 0.909, P < 0.01), MMP-8 (r = 0.702, P = 0.02), and MMP-13 (r = 0.781, P = 0.01); chemerin and IL-8 (r = 0.913, P < 0.01), MMP-8 (r = 0.770, P < 0.01), and MMP-13 (r = 0.788, P < 0.01); and progranulin and IL-8 (r = 0.762, P < 0.01), MMP-8 (r = 0.845, P < 0.01), and MMP-13 (r = 0.813, P < 0.01). Conclusion: Adipokines may contribute to the breakdown of periodontal tissue in periodontitis by stimulating the expression of proinflammatory cytokines and MMPs. C1 [Ozcan, Erkan; Saygun, N. Isil; Bengi, V. Umut] Gulhane Mil Hosp, Dept Periodontol, Ctr Oral Hlth, Ankara, Turkey. [Serdar, Muhittin A.] Acibadem Univ, Dept Biochem, Ankara, Turkey. [Kantarci, Alpdogan] Forsyth Inst, Ctr Periodontol, Dept Appl Oral Sci, Cambridge, MA USA. RP Ozcan, E (reprint author), Gulhane Mil Med Acad, Dept Periodontol, Dent Sci Ctr, TR-06018 Ankara, Turkey. EM eozcan@gata.edu.tr FU Gulhane Military Medical Academy Research Board [AR-2014/31] FX This project was financially supported by Gulhane Military Medical Academy Research Board, project number AR-2014/31. The authors report no conflicts of interest related to this study. NR 50 TC 1 Z9 1 U1 2 U2 2 PU AMER ACAD PERIODONTOLOGY PI CHICAGO PA 737 NORTH MICHIGAN AVENUE, SUITE 800, CHICAGO, IL 60611-2690 USA SN 0022-3492 EI 1943-3670 J9 J PERIODONTOL JI J. Periodont. PD AUG PY 2016 VL 87 IS 8 BP 934 EP 943 DI 10.1902/jop.2016.160046 PG 10 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA DS5SZ UT WOS:000380843900013 PM 26991485 ER PT J AU Brink, JA AF Brink, James A. TI Life Lessons for Successful Leadership SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Editorial Material C1 [Brink, James A.] Massachusetts Gen Hosp, FND 216, 55 Fruit St, Boston, MA 02114 USA. RP Brink, JA (reprint author), Massachusetts Gen Hosp, FND 216, 55 Fruit St, Boston, MA 02114 USA. EM jabrink@partners.org NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD AUG PY 2016 VL 13 IS 8 BP 887 EP 888 DI 10.1016/j.jacr.2016.06.025 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DS7NQ UT WOS:000380970600001 PM 27493084 ER PT J AU McCarthy, CJ Zhu, AX Alansari, SA Oklu, R AF McCarthy, Cohn J. Zhu, Andrew X. Alansari, Shehab A. Oklu, Rahmi TI Transarterial Chemoembolization in the Coming Era of Decreased Reimbursement for Readmissions SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Article DE TACE; chemoembolization; transarterial; oncology; readmissions ID UNRESECTABLE HEPATOCELLULAR-CARCINOMA; HOSPITAL READMISSIONS; HEART-FAILURE; PROGRAM; REHOSPITALIZATION; ABLATION; OUTCOMES; TUMORS AB Purpose: CMS has identified readmission of patients within 30 days of discharge as a targeted quality metric and has instituted financial penalties to encourage hospitals to reduce readmissions. The aims of this study were to examine the rate of 30-day admissions after transarterial chemoembolization (TACE) at a single institution and to identify potential factors associated with readmission. Methods: A total of 275 patients were identified who underwent a total of 457 TACE procedures over a 21-year period. Their electronic medical records were reviewed to evaluate the 30-day readmission rate in all patients undergoing TACE, and multiple logistic regression analysis was used to ascertain any clinical or demographic factors affecting the risk for readmission. Results: Nineteen patients (4.2%) required readmission to the hospital within 30 days; 11 of these readmissions were directly attributable to TACE, with inpatient stays upon readmission ranging from 2 to 27 days. Fourteen patients (3.1%) returned to the emergency department (ED) within 30 days of TACE. Medicare patients were more likely to be readmitted to the hospital or require emergency department treatment within 30 days than patients with private health insurance (P = .006). Patients with worse performance status (Eastern Cooperative Oncology Group) were also more likely to require emergency department care within 30 days (P = .04). Conclusions: TACE patients are at risk for readmission, often related to underlying medical comorbidities. Although extensively studied in other specialties, the Hospital Readmissions Reduction Program has received little attention in the radiology literature, and radiologists should familiarize themselves with this continually expanding initiative. C1 [McCarthy, Cohn J.; Alansari, Shehab A.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Imaging, Div Vasc & Intervent Radiol, Boston, MA USA. [Zhu, Andrew X.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Div Hematol Oncol, Boston, MA USA. [Oklu, Rahmi] Harvard Med Sch, Brigham & Womens Hosp, Biomat Innovat Res Ctr, Dept Med, Cambridge, MA USA. [Oklu, Rahmi] Mayo Clin, Div Vasc & Intervent Radiol, Scottsdale, AZ USA. RP Oklu, R (reprint author), Mayo Clin, Div Intervent Radiol, 13400 E Shea Blvd, Scottsdale, AZ 85259 USA. EM oklu.rahmi@mayo.edu FU National Institutes of Health grant [RO3CA172738, R21EB021148] FX This study was supported by National Institutes of Health grant RO3CA172738 and R21EB021148 (R.O.). The authors have no conflicts of interest related to the material discussed in this article. NR 29 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD AUG PY 2016 VL 13 IS 8 BP 915 EP 921 DI 10.1016/j.jacr.2016.04.030 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DS7NQ UT WOS:000380970600011 PM 27325468 ER PT J AU Westra, SJ Karmazyn, BK Alazraki, AL Dempsey, ME Dillman, JR Garber, M Moore, SG Raske, ME Rice, HE Rigsby, CK Safdar, N Simoneaux, SF Strouse, PJ Trout, AT Wootton-Gorges, SL Coley, BD AF Westra, Sjirk J. Karmazyn, Boaz K. Alazraki, Adina L. Dempsey, Molly E. Dillman, Jonathan R. Garber, Matthew Moore, Sheila G. Raske, Molly E. Rice, Henry E. Rigsby, Cynthia K. Safdar, Nabile Simoneaux, Stephen F. Strouse, Peter J. Trout, Andrew T. Wootton-Gorges, Sandra L. Coley, Brian D. TI ACR Appropriateness Criteria Fever Without Source or Unknown Origin-Child SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Article DE Appropriateness Criteria; infants and children imaging; fever without source; fever of unknown origin; occult pneumonia; sepsis workup ID ROUTINE CHEST RADIOGRAPHY; WHOLE-BODY MRI; FEBRILE CHILDREN; PEDIATRIC-PATIENTS; PROLONGED FEVER; YOUNG-CHILDREN; BACTERIAL-INFECTIONS; CLINICAL EXAMINATION; UNEXPLAINED FEVER; DIAGNOSTIC-VALUE AB The cause of fever in a child can often be determined from history, physical examination, and laboratory tests; infections account for the majority of cases. Yet in 20%, no apparent cause can be found, designated as fever without source (FWS). The yield of chest radiography in children with FWS is low, and it is usually not appropriate. However, in children with respiratory signs, high fever (>39 degrees C), or marked leukocytosis (>= 20,000/mm(3)), chest radiography is usually appropriate, as it has a higher yield in detecting clinically occult pneumonia. In newborns with FWS, there is higher risk for serious bacterial infection, and the routine use of chest radiography is controversial. In children with neutropenia, fever is a major concern. In some clinical circumstances, such as after hematopoietic stem cell transplantation, chest CT scan may be appropriate even if the results of chest radiography are negative or nonspecific, as it has higher sensitivity and can demonstrate specific findings (such as lung nodule and "halo sign") that can guide management. In a child with prolonged fever of unknown origin despite extensive medical workup (fever of unknown origin), diagnosis is usually dependent on clinical and laboratory studies, and imaging tests have low yield. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. C1 [Westra, Sjirk J.] Massachusetts Gen Hosp, Boston, MA USA. [Karmazyn, Boaz K.] Indiana Univ, Riley Hosp Children, Indianapolis, IN USA. [Alazraki, Adina L.; Simoneaux, Stephen F.] Childrens Healthcare Atlanta, Atlanta, GA USA. [Dempsey, Molly E.] Texas Scottish Rite Hosp Children, Dallas, TX USA. [Dillman, Jonathan R.; Strouse, Peter J.] CS Mott Childrens Hosp, Ann Arbor, MI USA. [Garber, Matthew] Amer Acad Pediat, Div Gen & Hosp Pediat, Columbia, SC USA. [Moore, Sheila G.] Childrens Hosp Wisconsin, Milwaukee, WI USA. [Raske, Molly E.] Childrens Hosp & Clin Minnesota, Minneapolis, MN USA. [Rice, Henry E.] Duke Univ, Med Ctr, Amer Pediat Surg Assoc, Durham, NC USA. [Rigsby, Cynthia K.] Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL USA. [Safdar, Nabile] Emory Univ Hosp, Atlanta, GA USA. [Trout, Andrew T.; Coley, Brian D.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USA. [Wootton-Gorges, Sandra L.] Univ Calif Davis, Med Ctr, Sacramento, CA USA. RP Westra, SJ (reprint author), Massachusetts Gen Hosp, Dept Radiol, 199 Cambridge St, Boston, MA 02114 USA. EM swestra@partners.org OI Trout, Andrew/0000-0003-1431-4054 FU GE; Yottalook FX Dr Safdar has received research funding from GE and has financial interest in Yottalook. The other authors have no conflicts of interest related to the material discussed in this article. NR 80 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD AUG PY 2016 VL 13 IS 8 BP 922 EP 930 DI 10.1016/j.jacr.2016.04.028 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DS7NQ UT WOS:000380970600012 ER PT J AU Yee, J Chang, KJ Dachman, AH Kim, DH McFarland, EG Pickhardt, PJ Cash, BD Bruining, DH Zalis, ME AF Yee, Judy Chang, Kevin J. Dachman, Abraham H. Kim, David H. McFarland, Elizabeth G. Pickhardt, Perry J. Cash, Brooks D. Bruining, David H. Zalis, Michael E. TI The Added Value of the CT Colonography Reporting and Data System SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Editorial Material ID COMPUTED TOMOGRAPHIC COLONOGRAPHY; CLINICAL SCREENING-PROGRAM; EXTRACOLONIC FINDINGS; COLORECTAL-CANCER; NATURAL-HISTORY; POLYPS; COLONOSCOPY; GROWTH; POPULATION; PREVALENCE C1 [Yee, Judy] Univ Calif San Francisco, 4150 Clement St, San Francisco, CA 94121 USA. [Chang, Kevin J.] Brown Univ, Warren Alpert Med Sch, Providence, RI USA. [Dachman, Abraham H.] Univ Chicago, Med Ctr, Chicago, IL USA. [Kim, David H.; Pickhardt, Perry J.] Univ Wisconsin, Hosp & Clin, Madison, WI USA. [McFarland, Elizabeth G.] Ctr Diagnost Imaging, St Louis, MO USA. [Cash, Brooks D.] Univ S Alabama, Mobile, AL USA. [Bruining, David H.] Mayo Clin, Rochester, MN USA. [Zalis, Michael E.] Massachusetts Gen Hosp, Boston, MA USA. [Zalis, Michael E.] Harvard Med Sch, Boston, MA USA. RP Yee, J (reprint author), Univ Calif San Francisco, 4150 Clement St, San Francisco, CA 94121 USA. EM judy.yee@ucsf.edu NR 23 TC 1 Z9 1 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD AUG PY 2016 VL 13 IS 8 BP 931 EP 935 DI 10.1016/j.jacr.2016.04.031 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DS7NQ UT WOS:000380970600013 PM 27260486 ER PT J AU Anderson, JE Li, ZM Romano, PS Parker, J Chang, DC AF Anderson, Jamie E. Li, Zhongmin Romano, Patrick S. Parker, Joseph Chang, David C. TI Should Risk Adjustment for Surgical Outcomes Reporting Include Sociodemographic Status? A Study of Coronary Artery Bypass Grafting in California SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Article ID READMISSION RATES; SURGERY; CARE; MORTALITY; PROGRAM; RACE AB BACKGROUND: Public reporting of surgical outcomes must adjust for patient risk. However, whether patient sociodemographic status (SDS) should be included is debatable. Our objective was to empirically compare risk-adjustment models and hospital ratings with or without SDS factors for patients undergoing coronary artery bypass grafting. STUDY DESIGN: This is a retrospective analysis of the California Coronary Artery Bypass Grafting Outcomes Reporting Program, 2011-2012. Outcomes included 30-day or in-hospital mortality, peri-operative stroke, and 30-day readmission. Sociodemographic status factors included race, language, insurance, ZIP code-based median income, and percent that were a college graduate. The c-statistic and goodness-of-fit were compared between models with and without SDS factors. Differences in hospital performance rating when adjusting for SDS were also compared. RESULTS: None of the SDS factors predicted mortality. Income, education, and language had no impact on any outcomes. Insurance predicted stroke (MediCal vs private insurance, odds ratio [OR] = 1.91; 95% CI, 1.11-3.31; p = 0.020) and readmissions (Medicare vs private insurance, OR = 1.36; 95% CI, 1.16-1.61; p < 0.001; MediCal vs private insurance, OR = 1.56; 95% CI, 1.26-1.94; p < 0.001). Race also predicted stroke (Asian vs white, OR = 2.26; p < 0.001). Adding SDS factors improved the c-statistic in readmission only (0.652 vs 0.645; p = 0.008). Goodness-of-fit worsened when adding SDS factors to mortality models, but was no different in stroke or readmissions. Hospital performance rating only changed in readmissions; of 124 hospitals, only 1 hospital moved from "better" to "average" when adjusting for SDS. CONCLUSIONS: Adjusting for insurance improves statistical models when analyzing readmissions after coronary artery bypass grafting, but does not impact hospital performance ratings substantially. Deciding whether SDS should be included in a patient's risk profile depends on valid measurements of SDS and requires a nuanced approach to assessing how these variables improve risk-adjusted models. (C) 2016 by the American College of Surgeons. Published by Elsevier Inc. All rights reserved. C1 [Anderson, Jamie E.] Univ Calif Davis, Med Ctr, Dept Surg, 2315 Stockton Blvd,OP 512, Sacramento, CA 95817 USA. [Li, Zhongmin; Romano, Patrick S.] Univ Calif Davis, Med Ctr, Dept Internal Med, Sacramento, CA 95817 USA. [Romano, Patrick S.] Univ Calif Davis, Med Ctr, Ctr Healthcare Policy & Res, Sacramento, CA 95817 USA. [Parker, Joseph] Calif Off Statewide Hlth Planning & Dev, Sacramento, CA USA. [Chang, David C.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Anderson, JE (reprint author), Univ Calif Davis, Med Ctr, Dept Surg, 2315 Stockton Blvd,OP 512, Sacramento, CA 95817 USA. EM jeanderson@ucdavis.edu NR 13 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 EI 1879-1190 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD AUG PY 2016 VL 223 IS 2 BP 221 EP 230 DI 10.1016/j.jamcollsurg.2016.05.008 PG 10 WC Surgery SC Surgery GA DS4KY UT WOS:000380751200006 PM 27216572 ER PT J AU Liu, YM Cohen, ME Hall, BL Ko, CY Bilimoria, KY AF Liu, Yaoming Cohen, Mark E. Hall, Bruce L. Ko, Clifford Y. Bilimoria, Karl Y. TI Evaluation and Enhancement of Calibration in the American College of Surgeons NSQIP Surgical Risk Calculator SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Article ID PREDICTION MODELS; REGRESSION-MODELS; ADJUSTMENT; INDIVIDUALS; QUALITY AB BACKGROUND: The American College of Surgeon (ACS) NSQIP Surgical Risk Calculator has been widely adopted as a decision aid and informed consent tool by surgeons and patients. Previous evaluations showed excellent discrimination and combined discrimination and calibration, but model calibration alone, and potential benefits of recalibration, were not explored. Because lack of calibration can lead to systematic errors in assessing surgical risk, our objective was to assess calibration and determine whether spline-based adjustments could improve it. STUDY DESIGN: We evaluated Surgical Risk Calculator model calibration, as well as discrimination, for each of 11 outcomes modeled from nearly 3 million patients (2010 to 2014). Using independent random subsets of data, we evaluated model performance for the Development (60% of records), Validation (20%), and Test (20%) datasets, where prediction equations from the Development dataset were recalibrated using restricted cubic splines estimated from the Validation dataset. We also evaluated performance on data subsets composed of higher-risk operations. RESULTS: The nonrecalibrated Surgical Risk Calculator performed well, but there was a slight tendency for predicted risk to be overestimated for lowest- and highest-risk patients and underestimated for moderate-risk patients. After recalibration, this distortion was eliminated, and p values for miscalibration were most often nonsignificant. Calibration was also excellent for subsets of higher-risk operations, though observed calibration was reduced due to instability associated with smaller sample sizes. CONCLUSIONS: Performance of NSQIP Surgical Risk Calculator models was shown to be excellent and improved with recalibration. Surgeons and patients can rely on the calculator to provide accurate estimates of surgical risk. (C) 2016 by the American College of Surgeons. Published by Elsevier Inc. All rights reserved. C1 [Liu, Yaoming; Cohen, Mark E.; Hall, Bruce L.; Ko, Clifford Y.; Bilimoria, Karl Y.] Amer Coll Surg, Div Res & Optimal Patient Care, Chicago, IL USA. [Bilimoria, Karl Y.] Northwestern Univ, SOQIC, Dept Surg, Chicago, IL 60611 USA. [Bilimoria, Karl Y.] Northwestern Univ, Ctr Healthcare Studies, Feinberg Sch Med, Chicago, IL 60611 USA. [Bilimoria, Karl Y.] Northwestern Univ, Northwestern Med, Chicago, IL 60611 USA. [Hall, Bruce L.] Washington Univ, Dept Surg, St Louis, MO USA. [Hall, Bruce L.] Washington Univ, Ctr Hlth Policy, St Louis, MO USA. [Hall, Bruce L.] Washington Univ, Olin Business Sch, St Louis, MO USA. [Hall, Bruce L.] John Cochran Vet Affairs Med Ctr, St Louis, MO USA. [Hall, Bruce L.] BJC Healthcare, St Louis, MO USA. [Ko, Clifford Y.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Ko, Clifford Y.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RP Cohen, ME (reprint author), Amer Coll Surg, 633 N St Clair St,22nd Floor, Chicago, IL 60611 USA. EM markcohen@facs.org NR 18 TC 4 Z9 4 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 EI 1879-1190 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD AUG PY 2016 VL 223 IS 2 BP 231 EP 239 DI 10.1016/j.jamcollsurg.2016.03.040 PG 9 WC Surgery SC Surgery GA DS4KY UT WOS:000380751200007 PM 27212006 ER PT J AU Fathi, R Sheehan, OC Garrigues, SK Saliba, D Leff, B Ritchie, CS AF Fathi, Roya Sheehan, Orla C. Garrigues, Sarah K. Saliba, Debra Leff, Bruce Ritchie, Christine S. TI Development of an Interdisciplinary Team Communication Framework and Quality Metrics for Home-Based Medical Care Practices SO JOURNAL OF THE AMERICAN MEDICAL DIRECTORS ASSOCIATION LA English DT Article DE Long-term care; interdisciplinary access; home care; house calls; communication; care coordination ID JUST-IN-TIME; PALLIATIVE CARE; HEALTH-CARE; APPROPRIATENESS METHOD; DECISION-MAKING; UNITED-STATES; IMPACT; STANDARDS; OUTCOMES; RECORD AB Background: The unique needs of homebound adults receiving home-based medical care (HBMC) (ie, home-based primary care and home-based palliative care services) are ideally provided by interdisciplinary care teams (IDTs) that provide coordinated care. The composition of team members from an array of organizations and the unique dimension of providing care in the home present specific challenges to timely access and communication of patient care information. The objective of this work was to develop a conceptual framework and corresponding quality indicators (QIs) that assess how IDT members for HBMC practices access and communicate key patient information with each other. Methods: A systematic review of peer-reviewed and gray literature was performed to inform a framework for care coordination in the home and the development of candidate QIs to assess processes by which all IDT members optimally access and use patient information. A technical expert panel (TEP) participated in a modified Delphi process to assess the validity and feasibility of each QI and to identify which would be most suitable for testing in the field. Results: Thematic analysis of literature revealed 4 process themes for how HBMC practices might engage in high-quality care coordination: using electronic medical records, conducting interdisciplinary team meetings, sharing standardized patient assessments, and communicating via secure e-messaging. Based on these themes, 9 candidate QIs were developed to reflect these processes. Three candidate QIs were assessed by the TEP as valid and feasible to measure in an HBMC practice setting. These indicators focused on use of IDT meetings, standardized patient assessments, and secure e-messaging. Conclusion: Translating the complex issue of care coordination into QIs will improve care delivered to vulnerable home-limited adults who receive HBMC. Guided by the literature, we developed a framework to reflect optimal care coordination in the home setting and identified 3 candidate QIs to field-test in HBMC practices. Published by Elsevier Inc. on behalf of AMDA - The Society for Post-Acute and Long-Term Care Medicine. This is an open access article under the CC BY-NC-ND license. C1 [Fathi, Roya; Garrigues, Sarah K.; Ritchie, Christine S.] Univ Calif San Francisco, Div Geriatr, 3333 Calif St,Suite 380, San Francisco, CA 94145 USA. [Fathi, Roya] San Francisco VA Med Ctr, VA Qual Scholars Fellowship Program, San Francisco, CA USA. [Sheehan, Orla C.] Johns Hopkins Univ, Sch Med, Ctr Aging & Hlth, Div Geriatr Med & Gerontol, Baltimore, MD USA. [Saliba, Debra] Univ Calif Los Angeles, JH Borun Ctr, Los Angeles, CA USA. [Saliba, Debra] Los Angeles VA GRECC, Los Angeles, CA USA. [Leff, Bruce] Johns Hopkins Univ, Sch Med, Div Geriatr Med & Gerontol, Baltimore, MD USA. [Ritchie, Christine S.] Jewish Home San Francisco, San Francisco, CA USA. RP Fathi, R (reprint author), Univ Calif San Francisco, Div Geriatr, 3333 Calif St,Suite 380, San Francisco, CA 94145 USA. EM roya.fathi@ucsf.edu FU Commonwealth Fund [20140041] FX This work was supported by the Commonwealth Fund (20140041), a national private foundation based in New York City that supports independent research on health care and makes grants to improve health care practice and policy. The views presented here are those of the authors and not necessarily those of the Commonwealth Fund, its directors, officers, or staff. NR 60 TC 0 Z9 0 U1 14 U2 14 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-8610 EI 1538-9375 J9 J AM MED DIR ASSOC JI J. Am. Med. Dir. Assoc. PD AUG 1 PY 2016 VL 17 IS 8 BP 725 EP + DI 10.1016/j.jamda.2016.03.018 PG 15 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA DS4OF UT WOS:000380759700010 PM 27217093 ER PT J AU Ramey, L Goldstein, R Zafonte, R Ryan, C Kazis, L Schneider, J AF Ramey, Lindsay Goldstein, Richard Zafonte, Ross Ryan, Colleen Kazis, Lewis Schneider, Jeffrey TI Variation in 30-Day Readmission Rates Among Medically Complex Patients at Inpatient Rehabilitation Facilities and Contributing Factors SO JOURNAL OF THE AMERICAN MEDICAL DIRECTORS ASSOCIATION LA English DT Article DE Inpatient rehabilitation facilities; readmission rates; variation; quality measures; post-acute care; health policy ID HOSPITAL READMISSION; DISCHARGE AB Objective: Few studies have focused on 30-day readmission rates in inpatient rehabilitation facilities (IRFs) and factors that contribute to this. The purpose of this study was to examine the variation in 30-day readmission rates among medically complex patients at IRFs nationally and explore how patient and facility characteristics are associated with this variation. Design: Retrospective review of an administrative database. Setting: IRFs throughout the United States. Participants: Patients from the medically complex impairment group treated at IRFs nationwide represented in the Uniform Data System for Medical Rehabilitation (UDSMR) from 2002 to 2011. Measurements: Using multilevel logistic regression analysis, 16 patient and facility characteristics were examined to identify and adjust for variables with a significant effect on readmission rates. Unadjusted and adjusted readmission rates were plotted by facility rank. Facilities were grouped by decile, based on readmission rates, and the mean unadjusted and adjusted rates for the lowest and highest deciles were compared to quantify the variation due to adjustment. Patient and facility characteristics for the highest and lowest deciles were compared. Results: A total of 117,156 medically complex patients from 682 IRFs nationwide were included. Patients were 46% male and 84% white with an average age of 71.5 years. Nine of 16 characteristics were identified that significantly increased the odds of readmission, including older age, male gender, poorer admission motor function, longer duration of impairment, higher Elixhauser comorbidity index, unemployed or retired status, larger facility size, lower mean facility admission motor function, and eastern or western geographic area. The average unadjusted and adjusted readmission rates for all facilities were 15.63% and 15.86%, respectively. The unadjusted readmission rates for the lowest and highest deciles were 6.71% and 26.48%, respectively. After adjustment, this narrowed to 10.33% and 21.91%, respectively. Patient and facility characteristics accounted for 41% of the variation seen in the readmission rates for these groups. Facilities with the highest readmission rates (highest decile) more commonly cared for patients at highest risk for readmission: unemployed, male patients with higher comorbidity index and poorer motor function on admission. Conclusion: This study shows significant variation in readmission rates for medically complex patients across IRFs. However, nearly half (41.4%) of this variation was attributed to 9 patient and facility characteristics, suggesting the need for risk adjustment if readmission rates are to be used as a quality indicator for IRFs. (C) 2016 AMDA - The Society for Post-Acute and Long-Term Care Medicine. C1 [Ramey, Lindsay; Goldstein, Richard; Zafonte, Ross; Schneider, Jeffrey] Spaulding Rehabil Hosp, 300 First Ave, Charlestown, MA 02129 USA. [Ramey, Lindsay] Harvard Med Sch, Boston, MA USA. [Ryan, Colleen] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Kazis, Lewis] Boston Univ, Sch Publ Hlth, Boston, MA USA. RP Schneider, J (reprint author), Spaulding Rehabil Hosp, 300 First Ave, Charlestown, MA 02129 USA. EM JCSCHNEIDER@PARTNERS.ORG NR 22 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-8610 EI 1538-9375 J9 J AM MED DIR ASSOC JI J. Am. Med. Dir. Assoc. PD AUG 1 PY 2016 VL 17 IS 8 BP 730 EP 736 DI 10.1016/j.jamda.2016.03.019 PG 7 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA DS4OF UT WOS:000380759700011 PM 27161849 ER PT J AU Nitschmann, C May, T Mirkovic, J Feldman, S AF Nitschmann, Caroline May, Taymaa Mirkovic, Jelena Feldman, Sarah TI Screening History Among Women with Invasive Cervical Cancer in an Academic Medical Center: Will We Miss Cancers Following Updated Guidelines? SO JOURNAL OF WOMENS HEALTH LA English DT Article ID ADENOCARCINOMA IN-SITU; SQUAMOUS-CELL CARCINOMA; PAPANICOLAOU SMEAR SENSITIVITY; UTERINE CERVIX; UNITED-STATES; YOUNGER WOMEN; CARE; INCREASE; ACCESS; RISK AB Objective: Updated guidelines for the screening and management of cervical cancer in the United States recommend starting Papanicolaou (Pap) testing at age 21 and screening less frequently with less aggressive management for abnormalities. We sought to examine updated Pap test screening guidelines and how they may affect the detection of invasive cervical cancer, especially among women <30 years of age. Materials and Methods: Patients diagnosed at Brigham and Women's Hospital with invasive cervical cancer between 2002 and 2012 were retrospectively identified. Prior screening history was obtained and patients were divided into two groups based on age <30 years or age >= 30 years. The two groups were then compared with respect to demographics, pathological findings, and time to diagnosis. Results: A total of 288 patients with invasive cervical carcinoma were identified. Among these patients, 109 had adequate information on prior screening history. Invasive adenocarcinoma (IAC) was diagnosed in 37 (33.94%) patients, whereas 64 (58.72%) patients were diagnosed with invasive squamous cell carcinoma (ISCC). The remaining eight patients were diagnosed with other types of cancers of the cervix. A total of 13 patients were younger than 30 while 96 patients were 30 or older. The mean time from normal Pap to diagnosis of IAC was 15 months in patients younger than 30 years of age compared to 56 months in patients aged 30 and older (p < 0.001). The mean time from normal Pap to diagnosis of ISCC was 38 months in patients younger than 30 years of age and 82 months in patients aged 30 and older (p = 0.018). Conclusion: In this small retrospective study, updated Pap test screening guidelines would not have missed invasive cancer on average among screened women age 30 and older. However, young patients aged 21-29 years may be at increased risk of developing IAC of the cervix between the recommended screening intervals. C1 [Nitschmann, Caroline] Mayo Clin, Div Gynecol Surg, Dept Obstet & Gynecol, 200 First St SW, Rochester, MN 55905 USA. [May, Taymaa] Princess Margaret Canc Ctr, Div Gynecol Oncol, Dept Obstet & Gynecol, Toronto, ON, Canada. [Mirkovic, Jelena] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Feldman, Sarah] Brigham & Womens Hosp, Dept Obstet & Gynecol, Div Gynecol Oncol, 75 Francis St, Boston, MA 02115 USA. [Feldman, Sarah] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Nitschmann, C (reprint author), Mayo Clin, Div Gynecol Surg, Dept Obstet & Gynecol, 200 First St SW, Rochester, MN 55905 USA. EM nitschmann.caroline@mayo.edu NR 29 TC 0 Z9 0 U1 2 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 EI 1931-843X J9 J WOMENS HEALTH JI J. Womens Health PD AUG PY 2016 VL 25 IS 8 BP 826 EP 831 DI 10.1089/jwh.2015.5394 PG 6 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA DS5GE UT WOS:000380808600010 PM 26859535 ER PT J AU Huang, G Wharton, W Bhasin, S Harman, SM Pencina, KM Tsitouras, P Li, ZY Hally, KA Asthana, S Storer, TW Basaria, S AF Huang, Grace Wharton, Whitney Bhasin, Shalender Harman, S. Mitchell Pencina, Karol M. Tsitouras, Panayiotis Li, Zhuoying Hally, Kathleen A. Asthana, Sanjay Storer, Thomas W. Basaria, Shehzad TI Effects of long-term testosterone administration on cognition in older men with low or low-to-normal testosterone concentrations: a prespecified secondary analysis of data from the randomised, double-blind, placebo-controlled TEAAM trial SO LANCET DIABETES & ENDOCRINOLOGY LA English DT Article ID HEALTH INITIATIVE MEMORY; ESTROGEN PLUS PROGESTIN; ALZHEIMER-DISEASE; ELDERLY-MEN; VISUOSPATIAL COGNITION; POSTMENOPAUSAL WOMEN; SERUM TESTOSTERONE; BRAIN; SUPPLEMENTATION; DECLINE AB Background The effects of testosterone on cognitive function in older men are incompletely understood. We aimed to establish the effects of long-term testosterone administration on multiple domains of cognitive function in older men with low or low-to-normal testosterone concentrations. Methods We did the randomised, double-blind, placebo-controlled, parallel-group TEAAM trial at three medical centres in Boston, Phoenix, and Los Angeles, USA. Men aged 60 years and older with low or low-to-normal testosterone concentrations (3.47-13.9 nmol/L, or free testosterone <173 pmol/L) were randomly assigned (1: 1), via computer-generated randomisation, to receive either 7.5 g of 1% testosterone gel or placebo gel daily for 3 years. Randomisation was stratified by age (60-75 years vs >75 years) and study site. The testosterone dose was adjusted to achieve concentrations of 17.3-31.2 nmol/L. Participants and all study personnel were masked to treatment allocation. Multiple domains of cognitive function were assessed as prespecified secondary outcomes by use of standardised tests at baseline and months 6, 18, and 36. We did analyses by intention to treat (in men who had baseline assessments of cognitive function) and per protocol (restricted to participants who completed the study drug and had both baseline and 36 month assessments of cognitive function). The TEAAM trial is registered with ClinicalTrials.gov, number NCT00287586. Findings Between Sept 1, 2004, and Feb 12, 2009, we randomly assigned 308 participants to receive either testosterone (n=156) or placebo (n=152). 280 men had baseline cognitive assessments (n=140 per group). Mean follow-up time was 29.0 months (SD 11.5) in the testosterone group and 31.1 months (9.5) in the placebo group. The last participant completed the study on May 11, 2012. In the testosterone group, mean concentrations of serum total testosterone increased from 10.6 nmol/L (SD 2.2) to 19.7 nmol/L (9.2) and free testosterone concentrations increased from 222 pmol/L (62) to 364 pmol/L (222). In the placebo group, mean concentrations of serum total testosterone were 10.7 nmol/L (SD 2.3) at baseline and 11.1 nmol/L (3.2) post-intervention and free testosterone concentrations were 210 pmol/L (61) and 172 pmol/L (49), respectively. We recorded no between-group differences in changes in visuospatial ability (mean difference: Complex Figure Test -0.51, 95% CI -2.0 to 1.0), phonemic or category verbal fluency (phonemic fluency test 0.90, -1.3 to 3.1; categorical fluency test 1.1, -0.3 to 2.6), verbal memory (paragraph recall test 0.29, -1.2 to 1.8), manual dexterity (Grooved Pegboard Test 4.2, -1.3 to 9.7), and attention or executive function (Stroop Interference Test -2.6, -7.4 to 2.3) after adjustment for age, education, and baseline cognitive function. In both the intention-to-treat and per-protocol (n=86 per group) populations, changes in cognitive function scores were not related significantly to changes in total or free testosterone, or oestradiol concentrations. Interpretation Testosterone administration for 36 months in older men with low or low-to-normal testosterone concentrations did not improve cognitive function. Future long-term trials are needed to investigate the efficacy of testosterone replacement in patients with impaired cognition, such as people with Alzheimer's disease. C1 [Huang, Grace; Bhasin, Shalender; Pencina, Karol M.; Li, Zhuoying; Hally, Kathleen A.; Storer, Thomas W.; Basaria, Shehzad] Harvard Med Sch, Brigham & Womens Hosp, Sect Mens Hlth Aging & Metab, Boston, MA 02115 USA. [Wharton, Whitney] Emory Univ, Dept Neurol, Atlanta, GA 30322 USA. [Harman, S. Mitchell; Tsitouras, Panayiotis] Kronos Longev Res Inst, Phoenix, AZ USA. [Harman, S. Mitchell] Phoenix VA Hlth Care Syst, Phoenix, AZ USA. [Tsitouras, Panayiotis] Univ Oklahoma, Hlth Sci Ctr, Dept Geriatr Med, Oklahoma City, OK USA. [Asthana, Sanjay] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI USA. [Asthana, Sanjay] William S Middleton Mem Vet Adm Med Ctr, Geriatr Res Educ & Clin Ctr, Madison, WI USA. [Asthana, Sanjay] Wisconsin Alzheimers Dis Res Ctr, Madison, WI USA. RP Huang, G (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Sect Mens Hlth Aging & Metab, Boston, MA 02115 USA. EM ghuang7@partners.org FU AbbVie Pharmaceuticals; Aurora Foundation; Boston Claude D Pepper Older Americans Independence Center; Boston University's Clinical and Translational Science Institute FX AbbVie Pharmaceuticals, Aurora Foundation, Boston Claude D Pepper Older Americans Independence Center, and Boston University's Clinical and Translational Science Institute. NR 32 TC 1 Z9 1 U1 7 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2213-8587 J9 LANCET DIABETES ENDO JI Lancet Diabetes Endocrinol. PD AUG PY 2016 VL 4 IS 8 BP 657 EP 665 DI 10.1016/S2213-8587(16)30102-4 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DS4OY UT WOS:000380761600019 PM 27377542 ER PT J AU Wang, HD Wolock, TM Carter, A Nguyen, G Kyu, HH Gakidou, E Hay, SI Mills, EJ Trickey, A Msemburi, W Coates, MM Mooney, MD Fraser, MS Sligar, A Salomon, J Larson, HJ Friedman, J Abajobir, AA Abate, KH Abbas, KM Abd El Razek, MM Abd-Allah, F Abdulle, AM Abera, SF Abubakar, I Abu-Raddad, LJ Abu-Rmeileh, NME Abyu, GY Adebiyi, AO Adedeji, IA Adelekan, AL Adofo, K Adou, AK Ajala, ON Akinyemiju, TF Akseer, N Al Lami, FH Al-Aly, Z Alam, K Alam, NKM Alasfoor, D Aldhahri, SFS Aldridge, RW Alegretti, MA Aleman, AV Alemu, ZA Alfonso-Cristancho, R Ali, R Alkerwi, A Alla, F Al-Raddadi, RMS Alsharif, U Alvarez, E Alvis-Guzman, N Amare, AT Amberbir, A Amegah, AK Ammar, W Amrock, SM Antonio, CAT Anwari, P Auml;rnlov, J Al Artaman, Asayesh, H Asghar, RJ Assadi, R Atique, S Atkins, LS Avokpaho, EFGA Awasthi, A Quintanilla, BPA Bacha, U Badawi, A Barac, A Barnighausen, T Basu, A Bayou, TA Bayou, YT Bazargan-Hejazi, S Beardsley, J Bedi, N Bennett, DA Bensenor, IM Betsu, BD Beyene, AS Bhatia, E Bhutta, ZA Biadgilign, S Bikbov, B Birlik, SM Bisanzio, D Brainin, M Brazinova, A Breitborde, NJK Brown, A Burch, M Butt, ZA Campuzano, JC Cardenas, R Carrero, JJ Castaneda-Orjuela, CA Rivas, JC Catala-Lopez, F Chang, HY Chang, JC Chavan, L Chen, WQ Chiang, PPC Chibalabala, M Chisumpa, VH Choi, JYJ Christopher, DJ Ciobanu, LG Cooper, C Dahiru, T Damtew, SA Dandona, L Dandona, R das Neves, J de Jager, P De Leo, D Degenhardt, L Dellavalle, RP Deribe, K Deribew, A Jarlais, DCD Dharmaratne, SD Ding, EL Doshi, PP Driscoll, TR Dubey, M Elshrek, YM Elyazar, I Endries, AY Ermakov, SP Eshrati, B Esteghamati, A Faghmous, IDA Sofia e Sa Farinha, C Faro, A Farvid, MS Farzadfar, F Fereshtehnejad, SM Fernandes, JC Fischer, F Fitchett, JRA Foigt, N Fullman, N Furst, T Gankpe, FG Gebre, T Gebremedhin, AT Gebru, AA Geleijnse, JM Gessner, BD Gething, PW Ghiwot, TT Giroud, M Gishu, MD Glaser, E Goenka, S Goodridge, A Gopalani, SV Goto, A Gugnani, HC Guimaraes, MDC Gupta, R Gupta, R Gupta, V Haagsma, J Hafezi-Nejad, N Hagan, H Hailu, GB Hamadeh, RR Hamidi, S Hammami, M Hankey, GJ Hao, YT Harb, HL Harikrishnan, S Haro, JM Harun, KM Havmoeller, R Hedayati, MT Heredia-Pi, IB Hoek, HW Horino, M Horita, N Hosgood, HD Hoy, DG Hsairi, M Hu, GQ Huang, H Huang, JJ Iburg, KM Idrisov, BT Innos, K Iyer, VJ Jacobsen, KH Jahanmehr, N Jakovljevic, MB Javanbakht, M Jayatilleke, AU Jeemon, P Jha, V Jiang, GH Jiang, Y Jibat, T Jonas, JB Kabir, Z Kamal, R Kan, HD Karch, A Karema, CK Karletsos, D Kasaeian, A Kaul, A Kawakami, N Kayibanda, JF Keiyoro, PN Kemp, AH Kengne, AP Kesavachandran, CN Khader, YS Khalil, I Khan, AR Khan, EA Khang, YH Khubchandani, J Kim, YJ Kinfu, Y Kivipelto, M Kokubo, Y Kosen, S Koul, PA Koyanagi, A Defo, BK Bicer, BK Kulkarni, VS Kumar, GA Lal, DK Lam, H Lam, JO Langan, SM Lansingh, VC Larsson, A Leigh, J Leung, R Li, YM Lim, SS Lipshultz, SE Liu, SW Lloyd, BK Logroscino, G Lotufo, PA Lunevicius, R Abd El Razek, HM Mahdavi, M Majdan, M Majeed, A Makhlouf, C Malekzadeh, R Mapoma, CC Marcenes, W Martinez-Raga, J Marzan, MB Masiye, F Mason-Jones, AJ Mayosi, BM Mckee, M Meaney, PA Mehndiratta, MM Mekonnen, AB Melaku, YA Memiah, P Memish, ZA Mendoza, W Meretoja, A Meretoja, TJ Mhimbira, FA Miller, TR Mikesell, J Mirarefin, M Mohammad, KA Mohammed, S Mokdad, AH Monasta, L Moradi-Lakeh, M Mori, R Mueller, UO Murimira, B Murthy, GVS Naheed, A Naldi, L Nangia, V Nash, D Nawaz, H Nejjari, C Ngalesoni, FN Ngirabega, JDD Le Nguyen, Q Nisar, MI Norheim, OF Norman, RE Nyakarahuka, L Ogbo, FA Oh, IH Ojelabi, FA Olusanya, BO Olusanya, JO Opio, JN Oren, E Ota, E Padukudru, MA Park, HY Park, JH Patil, ST Patten, SB Paul, VK Pearson, K Peprah, EK Pereira, CC Perico, N Pesudovs, K Petzold, M Phillips, MR Pillay, JD Plass, D Polinder, S Pourmalek, F Prokop, DM Qorbani, M Rafay, A Rahimi, K Rahimi-Movaghar, V Rahman, M Rahman, MHU Rahman, SU Rai, RK Rajsic, S Ram, U Rana, SM Rao, PV Remuzzi, G Rojas-Rueda, D Ronfani, L Roshandel, G Roy, A Ruhago, GM Saeedi, MY Sagar, R Saleh, MM Sanabria, JR Santos, IS Sarmiento-Suarez, R Sartorius, B Sawhney, M Schutte, AE Schwebel, DC Seedat, S Sepanlou, SG Servan-Mori, EE Shaikh, MA Sharma, R She, J Sheikhbahaei, S Shen, JB Shibuya, K Shin, HH Sigfusdottir, ID Silpakit, N Silva, DAS Silveira, DGA Simard, EP Sindi, S Singh, JA Singh, OP Singh, PK Skirbekk, V Sliwa, K Soneji, S Sorensen, RJD Soriano, JB Soti, DO Sreeramareddy, CT Stathopoulou, V Steel, N Sunguya, BF Swaminathan, S Sykes, BL Tabares-Seisdedos, R Talongwa, RT Tavakkoli, M Taye, B Tedla, BA Tekle, T Shifa, GT Temesgen, AM Terkawi, AS Tesfay, FH Tessema, GA Thapa, K Thomson, AJ Thorne-Lyman, AL Tobe-Gai, R Topor-Madry, R Towbin, JA Tran, BX Dimbuene, ZT Tsilimparis, N Tura, AK Ukwaja, KN Uneke, CJ Uthman, OA Venketasubramanian, N Vladimirov, SK Vlassov, VV Vollset, SE Wang, LH Weiderpass, E Weintraub, RG Werdecker, A Westerman, R Wijeratne, T Wilkinson, JD Wiysonge, CS Wolfe, CDA Won, SH Wong, JQ Xu, GL Yadav, AK Yakob, B Yalew, AZ Yano, YC Yaseri, M Yebyo, HG Yip, P Yonemoto, N Yoon, SJ Younis, MZ Yu, CH Yu, SC Zaidi, Z Zaki, ME Zeeb, H Zhang, H Zhao, Y Zodpey, S Zoeckler, L Zuhlke, LJ Lopez, AD Murray, CJL AF Wang, Haidong Wolock, Tim M. Carter, Austin Nguyen, Grant Kyu, Hmwe Hmwe Gakidou, Emmanuela Hay, Simon I. Mills, Edward J. Trickey, Adam Msemburi, William Coates, Matthew M. Mooney, Meghan D. Fraser, Maya S. Sligar, Amber Salomon, Joshua Larson, Heidi J. Friedman, Joseph Abajobir, Amanuel Alemu Abate, Kalkidan Hassen Abbas, Kaja M. Abd El Razek, Mohamed Magdy Abd-Allah, Foad Abdulle, Abdishakur M. Abera, Semaw Ferede Abubakar, Ibrahim Abu-Raddad, Laith J. Abu-Rmeileh, Niveen M. E. Abyu, Gebre Yitayih Adebiyi, Akindele Olupelumi Adedeji, Isaac Akinkunmi Adelekan, Ademola Lukman Adofo, Koranteng Adou, Arsene Kouablan Ajala, Oluremi N. Akinyemiju, Tomi F. Akseer, Nadia Al Lami, Faris Hasan Al-Aly, Ziyad Alam, Khurshid Alam, Noore K. M. Alasfoor, Deena Aldhahri, Saleh Fahed S. Aldridge, Robert William Alegretti, Miguel Angel Aleman, Alicia V. Alemu, Zewdie Aderaw Alfonso-Cristancho, Rafael Ali, Raghib Alkerwi, Ala'a Alla, Francois Al-Raddadi, Rajaa Mohammad Salem Alsharif, Ubai Alvarez, Elena Alvis-Guzman, Nelson Amare, Azmeraw T. Amberbir, Alemayehu Amegah, Adeladza Kofi Ammar, Walid Amrock, Stephen Marc Antonio, Carl Abelardo T. Anwari, Palwasha Arnlov, Johan Al Artaman Asayesh, Hamid Asghar, Rana Jawad Assadi, Reza Atique, Suleman Atkins, Lydia S. Avokpaho, Euripide Frinel G. Arthur Awasthi, Ashish Quintanilla, Beatriz Paulina Ayala Bacha, Umar Badawi, Alaa Barac, Aleksandra Barnighausen, Till Basu, Arindam Bayou, Tigist Assefa Bayou, Yibeltal Tebekaw Bazargan-Hejazi, Shahrzad Beardsley, Justin Bedi, Neeraj Bennett, Derrick A. Bensenor, Isabela M. Betsu, Balem Demtsu Beyene, Addisu Shunu Bhatia, Eesh Bhutta, Zulfiqar A. Biadgilign, Sibhatu Bikbov, Boris Birlik, Sait Mentes Bisanzio, Donal Brainin, Michael Brazinova, Alexandra Breitborde, Nicholas J. K. Brown, Alexandria Burch, Michael Butt, Zahid A. Campuzano, Julio Cesar Cardenas, Rosario Carrero, Juan Jesus Castaneda-Orjuela, Carlos A. Rivas, Jacqueline Castillo Catala-Lopez, Ferran Chang, Hsing-Yi Chang, Jung-chen Chavan, Laxmikant Chen, Wanqing Chiang, Peggy Pei-Chia Chibalabala, Mirriam Chisumpa, Vesper Hichilombwe Choi, Jee-Young Jasmine Christopher, Devasahayam Jesudas Ciobanu, Liliana G. Cooper, Cyrus Dahiru, Tukur Damtew, Solomon Abreha Dandona, Lalit Dandona, Rakhi das Neves, Jose de Jager, Pieter De Leo, Diego Degenhardt, Louisa Dellavalle, Robert P. Deribe, Kebede Deribew, Amare Jarlais, Don C. Des Dharmaratne, Samath D. Ding, Eric L. Doshi, Pratik Pinal Driscoll, Tim R. Dubey, Manisha Elshrek, Yousef Mohamed Elyazar, Iqbal Endries, Aman Yesuf Ermakov, Sergey Petrovich Eshrati, Babak Esteghamati, Alireza Faghmous, Imad D. A. Sofia e Sa Farinha, Carla Faro, Andre Farvid, Maryam S. Farzadfar, Farshad Fereshtehnejad, Seyed-Mohammad Fernandes, Joao C. Fischer, Florian Fitchett, Joseph Robert Ander Foigt, Nataliya Fullman, Nancy Furst, Thomas Gankpe, Fortune Gbetoho Gebre, Teshome Gebremedhin, Amanuel Tesfay Gebru, Alemseged Aregay Geleijnse, Johanna M. Gessner, Bradford D. Gething, Peter W. Ghiwot, Tsegaye Tewelde Giroud, Maurice Gishu, Melkamu Dedefo Glaser, Elizabeth Goenka, Shifalika Goodridge, Amador Gopalani, Sameer Vali Goto, Atsushi Gugnani, Harish Chander Guimaraes, Mark D. C. Gupta, Rahul Gupta, Rajeev Gupta, Vipin Haagsma, Juanita Hafezi-Nejad, Nima Hagan, Holly Hailu, Gessessew Bugssa Hamadeh, Randah Ribhi Hamidi, Samer Hammami, Mouhanad Hankey, Graeme J. Hao, Yuantao Harb, Hilda L. Harikrishnan, Sivadasanpillai Haro, Josep Maria Harun, Kimani M. Havmoeller, Rasmus Hedayati, Mohammad T. Heredia-Pi, Ileana Beatriz Hoek, Hans W. Horino, Masako Horita, Nobuyuki Hosgood, H. Dean Hoy, Damian G. Hsairi, Mohamed Hu, Guoqing Huang, Hsiang Huang, John J. Iburg, Kim Moesgaard Idrisov, Bulat T. Innos, Kaire Iyer, Veena J. 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CA GBD 2015 HIV Collaborators TI Estimates of global, regional, and national incidence, prevalence, and mortality of HIV, 1980-2015: the Global Burden of Disease Study 2015 SO LANCET HIV LA English DT Article ID PROJECTION PACKAGE; SYSTEMATIC ANALYSIS; UNAIDS ESTIMATION; MALE CIRCUMCISION; 188 COUNTRIES; INFECTION; PREVENTION; EPIDEMIC; MODEL; TRIAL AB Background Timely assessment of the burden of HIV/AIDS is essential for policy setting and programme evaluation. In this report from the Global Burden of Disease Study 2015 (GBD 2015), we provide national estimates of levels and trends of HIV/AIDS incidence, prevalence, coverage of antiretroviral therapy (ART), and mortality for 195 countries and territories from 1980 to 2015. Methods For countries without high-quality vital registration data, we estimated prevalence and incidence with data from antenatal care clinics and population-based seroprevalence surveys, and with assumptions by age and sex on initial CD4 distribution at infection, CD4 progression rates (probability of progression from higher to lower CD4 cell-count category), on and off antiretroviral therapy (ART) mortality, and mortality from all other causes. Our estimation strategy links the GBD 2015 assessment of all-cause mortality and estimation of incidence and prevalence so that for each draw from the uncertainty distribution all assumptions used in each step are internally consistent. We estimated incidence, prevalence, and death with GBD versions of the Estimation and Projection Package (EPP) and Spectrum software originally developed by the Joint United Nations Programme on HIV/AIDS (UNAIDS). We used an open-source version of EPP and recoded Spectrum for speed, and used updated assumptions from systematic reviews of the literature and GBD demographic data. For countries with high-quality vital registration data, we developed the cohort incidence bias adjustment model to estimate HIV incidence and prevalence largely from the number of deaths caused by HIV recorded in cause-of-death statistics. We corrected these statistics for garbage coding and HIV misclassification. Findings Global HIV incidence reached its peak in 1997, at 3.3 million new infections (95% uncertainty interval [UI] 3.1-3.4 million). Annual incidence has stayed relatively constant at about 2.6 million per year (range 2.5-2.8 million) since 2005, after a period of fast decline between 1997 and 2005. The number of people living with HIV/AIDS has been steadily increasing and reached 38.8 million (95% UI 37.6-40.4 million) in 2015. At the same time, HIV/AIDS mortality has been declining at a steady pace, from a peak of 1.8 million deaths (95% UI 1.7-1.9 million) in 2005, to 1.2 million deaths (1.1-1.3 million) in 2015. We recorded substantial heterogeneity in the levels and trends of HIV/AIDS across countries. Although many countries have experienced decreases in HIV/AIDS mortality and in annual new infections, other countries have had slowdowns or increases in rates of change in annual new infections. Interpretation Scale-up of ART and prevention of mother-to-child transmission has been one of the great successes of global health in the past two decades. However, in the past decade, progress in reducing new infections has been slow, development assistance for health devoted to HIV has stagnated, and resources for health in low-income countries have grown slowly. Achievement of the new ambitious goals for HIV enshrined in Sustainable Development Goal 3 and the 90-90-90 UNAIDS targets will be challenging, and will need continued efforts from governments and international agencies in the next 15 years to end AIDS by 2030. Copyright (C) The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY license C1 [Wang, Haidong; Wolock, Tim M.; Carter, Austin; Nguyen, Grant; Kyu, Hmwe Hmwe; Gakidou, Emmanuela; Hay, Simon I.; Msemburi, William; Coates, Matthew M.; Mooney, Meghan D.; Fraser, Maya S.; Sligar, Amber; Larson, Heidi J.; Friedman, Joseph; Brown, Alexandria; Dandona, Lalit; Fullman, Nancy; Haagsma, Juanita; Khalil, Ibrahim; Lim, Stephen S.; Mikesell, Joseph; Mokdad, Ali H.; Moradi-Lakeh, Maziar; Pearson, Katherine; Silpakit, Naris; Sorensen, Reed J. D.; Temesgen, Awoke Misganaw; Vollset, Stein Emil; Zoeckler, Leo; Murray, Christopher J. L.] Inst Hlth Metr & Evaluat, Seattle, WA 98121 USA. 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[Dellavalle, Robert P.] Colorado Sch Publ Hlth, Aurora, CO USA. [Deribe, Kebede] Brighton & Sussex Med Sch, Brighton, E Sussex, England. [Deribew, Amare] KEMRI Wellcome Trust Res Programme, Kilifi, Kenya. [Jarlais, Don C. Des] Mt Sinai Beth Israel, New York, NY USA. [Jarlais, Don C. Des] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Dharmaratne, Samath D.] Univ Peradeniya, Dept Community Med, Fac Med, Peradeniya, Sri Lanka. [Doshi, Pratik Pinal] Univ Southern Calif, Los Angeles, CA USA. [Dubey, Manisha; Rahman, Mahfuzar; Ram, Usha; Yadav, Ajit Kumar] Int Inst Populat Sci, Bombay, Maharashtra, India. [Elyazar, Iqbal] Univ Tripoli, Dept Food Sci, Fac Agr, Tripoli, Libya. [Elyazar, Iqbal] Eijkman Oxford Clin Res Unit, Jakarta, Indonesia. [Endries, Aman Yesuf; Shifa, Girma Temam] Arba Minch Univ, Arba Minch, Ethiopia. [Ermakov, Sergey Petrovich] Russian Acad Sci, Inst Social & Econ Studies Populat, Moscow, Russia. [Ermakov, Sergey Petrovich] Minist Hlth Russian Federat, Fed Res Inst Hlth Org & Informat, Moscow, Russia. [Eshrati, Babak] Minist Hlth & Med Educ, Tehran, Iran. [Eshrati, Babak] Arak Univ Med Sci, Arak, Iran. [Esteghamati, Alireza; Hafezi-Nejad, Nima; Sheikhbahaei, Sara] Univ Tehran Med Sci, Endocrinol & Metab Res Ctr, Terhan, Iran. [Farzadfar, Farshad] Univ Tehran Med Sci, Noncommunicable Dis Res Ctr, Endocrinol & Metab Populat Sci Inst, Terhan, Iran. [Kasaeian, Amir] Univ Tehran Med Sci, Hematol Oncol & Stem Cell Transplantat Res Ctr, Terhan, Iran. [Malekzadeh, Reza; Roshandel, Gholamreza; Sepanlou, Sadaf G.] Univ Tehran Med Sci, Digest Dis Res Inst, Terhan, Iran. [Rahimi-Movaghar, Vafa] Univ Tehran Med Sci, Sina Trauma & Surg Res Ctr, Terhan, Iran. [Yaseri, Mehdi] Univ Tehran Med Sci, Terhan, Iran. [Faghmous, Imad D. A.; Langan, Sinead M.; Mckee, Martin; Murthy, Gudlavalleti Venkata Satyanarayana] London Sch Hyg & Trop Med, Dept Infect Dis Epidemiol, London, England. [Sofia e Sa Farinha, Carla] DGS Directorate Gen Hlth, Lisbon, Portugal. [Sofia e Sa Farinha, Carla] Univ Aberta, Lisbon, Portugal. [Faro, Andre] Univ Fed Sergipe, Aracaju, Brazil. [Farvid, Maryam S.] Inst Hlth Policy, Boston, MA USA. [Fernandes, Joao C.] Univ Coimbra, Pharmacol & Expt Therapeut, Inst Biomed Imaging & Life Sci, Fac Med, Coimbra, Portugal. [Fischer, Florian] Univ Bielefeld, Bielefeld, Germany. [Foigt, Nataliya] Acad Med Sci, Inst Gerontol, Kiev, Ukraine. [Furst, Thomas] Imperial Coll London, Dept Infect Dis Epidemiol, London, England. [Majeed, Azeem] Imperial Coll London, London, England. [Gankpe, Fortune Gbetoho] Leras Afrique, Cotonou, Benin. [Gankpe, Fortune Gbetoho] CHU Hassan II, Fes, Morocco. [Gebre, Teshome] Task Force Global Hlth, Decatur, GA USA. [Gebremedhin, Amanuel Tesfay] Univ Munich, Munich, Germany. [Geleijnse, Johanna M.] Wageningen Univ, Div Human Nutr, Wageningen, Netherlands. [Jibat, Tariku] Wageningen Univ, Wageningen, Netherlands. [Gessner, Bradford D.] Agence Medecine Prevent, Paris, France. [Giroud, Maurice] Univ Hosp Dijon, Dijon, France. [Gishu, Melkamu Dedefo; Tura, Abera Kenay] Haramaya Univ, Dire Dawa, Ethiopia. [Gishu, Melkamu Dedefo] Kersa Hlth & Demog Surveillance Syst, Harar, Ethiopia. [Glaser, Elizabeth] Brandeis Univ, Heller Sch Social Policy & Management, Waltham, MA USA. [Goodridge, Amador] INDICASAT AIP, Inst Invest Cientif, City Of Knowledge, Panama. [Goodridge, Amador] INDICASAT AIP, Serv Alta Tecnol, City Of Knowledge, Panama. [Gopalani, Sameer Vali] Govt Federated States Micronesia, Dept Hlth & Social Aff airs, Palikir, Micronesia. [Goto, Atsushi] Tokyo Womens Med Univ, Dept Publ Hlth, Tokyo, Japan. [Gugnani, Harish Chander] St James Sch Med, Dept Microbiol, The Quarter, Anguilla. [Gugnani, Harish Chander] St James Sch Med, Dept Epidemiol & Biostat, The Quarter, Anguilla. [Guimaraes, Mark D. C.] Univ Fed Minas Gerais, Belo Horizonte, MG, Brazil. West Virginia Bur Publ Hlth, Charleston, WV USA. Eternal Heart Care Ctr, Jaipur, Rajasthan, India. Res Inst, Jaipur, Rajasthan, India. [Gupta, Vipin] Univ Delhi, Delhi, India. [Hagan, Holly] NYU, New York, NY USA. [Hamadeh, Randah Ribhi] Arabian Gulf Univ, Manama, Bahrain. [Hamidi, Samer] Hamdan Bin Mohammed Smart Univ, Dubai, U Arab Emirates. [Hammami, Mouhanad] Wayne Cty Dept Hlth & Human Serv, Detroit, MI USA. [Hankey, Graeme J.] Univ Western Australia, Sch Med & Pharmacol, Perth, WA, Australia. [Hankey, Graeme J.] Harry Perkins Inst Med Res, Nedlands, WA, Australia. [Hankey, Graeme J.] Western Australian Neurosci Res Inst, Nedlands, WA, Australia. [Hao, Yuantao] Sun Yat Sen Univ, Sch Publ Hlth, Guangzhou, Guangdong, Peoples R China. [Harikrishnan, Sivadasanpillai] Sree Chitra Tirunal Inst Med Sci & Technol, Trivandrum, Kerala, India. [Koyanagi, Ai] Res & Dev Unit, Barcelona, Spain. [Haro, Josep Maria] Parc Sanitari Sant Joan de Deu CIBERSAM, Barcelona, Spain. [Haro, Josep Maria] Univ Barcelona, Barcelona, Spain. [Harun, Kimani M.] Kenyatta Univ, Nairobi, Kenya. [Hedayati, Mohammad T.] Mazandaran Univ Med Sci, Sari, Iran. [Hoek, Hans W.] Columbia Univ, Dept Epidemiol, New York, NY USA. [Skirbekk, Vegard] Columbia Univ, New York, NY USA. [Horino, Masako] Nevada Div Behav & Publ Hlth, Carson City, NV USA. [Horino, Masako] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Los Angeles, CA USA. [Horita, Nobuyuki] Yokohama City Univ, Sch Med, Yokohama, Kanagawa, Japan. [Hosgood, H. Dean] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Hoy, Damian G.] Secretariat Pacific Commun, Publ Hlth Div, Noumea, New Caledonia. [Hsairi, Mohamed] Natl Inst Publ Hlth, Tunis, Tunisia. [Hu, Guoqing] Cent S Univ, Dept Epidemiol & Hlth Stat, Sch Publ Hlth, Changsha, Hunan, Peoples R China. [Huang, Hsiang] Cambridge Hlth Alliance, Cambridge, MA USA. [Huang, John J.] Yale Univ, New Haven, CT USA. [Iburg, Kim Moesgaard] Aarhus Univ, Aarhus, Denmark. [Idrisov, Bulat T.] Bashkir State Med Univ, Ufa, Russia. [Idrisov, Bulat T.] Boston Univ, Boston Med Ctr, Boston, MA 02215 USA. Boston Univ, Boston Med Ctr, Boston, MA 02215 USA. [Innos, Kaire] Natl Inst Hlth Dev, Tallinn, Estonia. [Iyer, Veena J.] Indian Inst Publ Hlth Gandhinagar, Ahmadabad, Gujarat, India. [Jacobsen, Kathryn H.] George Mason Univ, Dept Global & Community Hlth, Fairfax, VA 22030 USA. [Jahanmehr, Nader] Shahid Beheshti Med Univ, Tehran, Iran. [Jakovljevic, Mihajlo B.] Univ Kragujevac, Fac Med Sci, Kragujevac, Serbia. [Javanbakht, Mehdi] Univ Aberdeen, Aberdeen, Scotland. [Jayatilleke, Achala Upendra] Postgrad Inst Med, Colombo, Sri Lanka. [Jayatilleke, Achala Upendra] Inst Violence & Injury Prevent, Colombo, Sri Lanka. [Jha, Vivekanand] Postgrad Inst Med Educ & Res, Chandigarh, India. [Jiang, Guohong] Tianjin Ctr Dis Control & Prevent, Tianjin, Peoples R China. [Jiang, Ying] Univ Occupat & Environm Hlth, Dept Hlth Dev, Inst Ind Ecol Sci, Dept Environm Epidemiol, Kitakyushu, Fukuoka, Japan. [Deribe, Kebede] Univ Addis Ababa, Sch Publ Hlth, Debre Zeit, Ethiopia. [Jibat, Tariku] Univ Addis Ababa, Debre Zeit, Ethiopia. [Jonas, Jost B.] Heidelberg Univ, Dept Ophthalmol, Med Fac Mannheim, Mannheim, Germany. [Kabir, Zubair] Univ Coll Cork, Cork, Ireland. [Kamal, Ritul; Kesavachandran, Chandrasekharan Nair] CSIR, Indian Inst Toxicol Res, Lucknow, Uttar Pradesh, India. [She, Jun] Fudan Univ, Zhongshan Hosp, Shanghai, Peoples R China. [Zhang, Hao] Fudan Univ, Zhongshan Hosp, Dept Nephrol, Shanghai, Peoples R China. [Kan, Haidong] Fudan Univ, Shanghai, Peoples R China. [Karch, Andre] Helmholtz Ctr Infect Res, Epidemiol & Stat Methods Res Grp, Braunschweig, Germany. [Karch, Andre] German Ctr Infect Res, Hannover Braunschweig Site, Braunschweig, Germany. [Karletsos, Dimitris] Clinton Hlth Access Initiat, Boston, MA USA. [Kaul, Anil] Oklahoma State Univ, Tulsa, OK USA. [Kawakami, Norito] Univ Tokyo, Sch Publ Hlth, Tokyo, Japan. [Shibuya, Kenji] Univ Tokyo, Tokyo, Japan. [Kayibanda, Jeanne Francoise] Ottawa Hlth Res Inst, Ottawa, ON, Canada. [Keiyoro, Peter Njenga] Inst Trop & Infect Dis, Nairobi, Kenya. [Keiyoro, Peter Njenga] Sch Continuing & Distance Educ, Nairobi, Kenya. [Kengne, Andre Pascal] South African Med Res Council, Cape Town, South Africa. [Sliwa, Karen] Univ Cape Town, Fac Hlth Sci, Hatter Inst Cardiovascular Res Africa, Cape Town, South Africa. [Kengne, Andre Pascal; Mayosi, Bongani M.] Univ Cape Town, Cape Town, South Africa. [Khader, Yousef Saleh] Jordan Univ Sci & Technol, Irbid, Jordan. [Khan, Abdur Rahman] Univ Louisville, Louisville, KY 40292 USA. [Khan, Ejaz Ahmad] Hlth Serv Acad, Islamabad, Pakistan. [Khan, Ejaz Ahmad] Expanded Programme Immunizat, Islamabad, Pakistan. [Khubchandani, Jagdish] Ball State Univ, Muncie, IN 47306 USA. [Kim, Yun Jin] SouthernUniv Coll, Skudai, Malaysia. [Kinfu, Yohannes] Univ Canberra, Canberra, ACT, Australia. [Kokubo, Yoshihiro] Natl Cerebral & Cardiovasc Ctr, Dept Prevent Cardiol, Suita, Osaka, Japan. [Kosen, Soewarta] NIHRD, Ctr Community Empowerment Hlth Policy & Humanitie, Jakarta, Indonesia. [Koul, Parvaiz A.] Sherikashmir Inst Med Sci, Srinagar, Jammu & Kashmir, India. [Defo, Barthelemy Kuate] Univ Montreal, Dept Demog, Montreal, PQ, Canada. [Defo, Barthelemy Kuate] Univ Montreal, Publ Hlth Res Inst, Montreal, PQ, Canada. [Defo, Barthelemy Kuate] Univ Montreal, Dept Social & Prevent Med, Sch Publ Hlth, Montreal, PQ, Canada. [Bicer, Burcu Kucuk] Hacettepe Univ, Inst Publ Hlth, Ankara, Turkey. [Kulkarni, Veena S.] Univ Arkansas, State Univ, Fayetteville, AR 72701 USA. [Lam, Hilton] Natl Inst Hlth, Inst Hlth Policy & Dev Studies, Manila, Philippines. [Lam, Jennifer O.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Bach Xuan Tran] Johns Hopkins Univ, Baltimore, MD USA. [Lansingh, Van C.] Help Me See Inc, New York, NY USA. [Lansingh, Van C.] Inst Mexicano Oftalmol, Queretaro, Mexico. [Leung, Ricky] SUNY Albany, Rensselaer, NY USA. [Li, Yongmei] San Francisco VA Med Ctr, San Francisco, CA USA. Wayne State Univ, Sch Med, Miami, FL USA. [Lipshultz, Steven E.; Wilkinson, James D.] Childrens Hosp Michigan, Detroit, MI 48201 USA. [Liu, Shiwei; Wang, Linhong] Natl Ctr Chron & Noncommunicable Dis Control & Pr, Beijing, Peoples R China. [Yu, Shicheng] Chinese Ctr Dis Control & Prevent, Beijing, Peoples R China. [Lloyd, Belinda K.] Monash Univ, Eastern Hlth Clin Sch, Fitzroy, Vic, Australia. [Lloyd, Belinda K.] Eastern Hlth, Turning Point, Melbourne, Vic, Australia. [Logroscino, Giancarlo] Univ Bari, Bari, Italy. [Lunevicius, Raimundas] Aintree Univ Hosp Natl Hlth Serv Fdn Trust, Liverpool, Merseyside, England. [Lunevicius, Raimundas] Univ Liverpool, Sch Med, Liverpool, Merseyside, England. [Abd El Razek, Hassan Magdy; Zaki, Maysaa El Sayed] Mansoura Fac Med, Mansoura, Egypt. [Polinder, Suzanne] Erasmus Univ, Dept Publ Hlth, Univ Med Ctr, Rotterdam, Netherlands. [Mahdavi, Mahdi] Erasmus Univ, Rotterdam, Netherlands. [Mahdavi, Mahdi] Iranian Minist Hlth, Tehran, Iran. [Marcenes, Wagner] Queen Mary Univ London, London, England. [Martinez-Raga, Jose] Hosp Univ Doctor Peset, Valencia, Spain. [Martinez-Raga, Jose] Univ CEU UCH, Moncada, Spain. [Marzan, Melvin Barrientos] Univ East Ramon Magsaysay, Mem Med Ctr, Quezon City, Philippines. [Mason-Jones, Amanda J.] Univ York, Dept Hlth Sci, York, N Yorkshire, England. [Meaney, Peter A.] Univ Penn, Pereleman Sch Med, Philadelphia, PA 19104 USA. [Meaney, Peter A.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Mehndiratta, Man Mohan] Janakpuri Superspecialty Hosp, New Delhi, India. [Mekonnen, Alemayehu B.; Tedla, Bemnet Amare; Tessema, Gizachew Assefa] Univ Gondar, Gondar, Ethiopia. [Memish, Ziad A.] Univ West Florida, Pensacola, FL 32514 USA. [Memish, Ziad A.] Saudi Minist Hlth, Riyadh, Saudi Arabia. [Memish, Ziad A.] Alfaisal Univ, Coll Med, Riyadh, Saudi Arabia. [Mendoza, Walter] United Nations Populat Fund, Lima, Peru. [Meretoja, Atte] Univ Helsinki, Cent Hosp, Dept Neurol, Helsinki, Finland. [Meretoja, Tuomo J.] Helsinki Univ Hosp, Ctr Comprehens Canc, Breast Surg Unit, Helsinki, Finland. [Meretoja, Tuomo J.] Univ Helsinki, Helsinki, Finland. [Mhimbira, Francis Apolinary] Ifakara Hlth Inst, Bagamoyo, Tanzania. [Miller, Ted R.] Pacific Inst Res & Evaluat, Calverton, MD USA. [Miller, Ted R.] Curtin Univ, Ctr Populat Hlth, Perth, WA, Australia. [Mirarefin, Mojde] Hunger Act Los Angeles, Los Angeles, CA USA. [Mohammad, Karzan Abdulmuhsin] Univ Salahaddin, Erbil, Iraq. [Mohammed, Shafiu] Heidelberg Univ, Inst Publ Hlth, Heidelberg, Germany. [Monasta, Lorenzo; Ronfani, Luca] IRCCS Burlo Garofolo, Inst Maternal & Child Hlth, Trieste, Italy. [Moradi-Lakeh, Maziar] Iran Univ Med Sci, Dept Community Med, Gastrointestinal & Liver Dis Res Ctr, Tehran, Iran. [Mori, Rintaro] Natl Ctr Child Hlth & Dev, Tokyo, Japan. [Werdecker, Andrea] Fed Inst Populat Res, Competence Ctr Mortal Follow Up German Natl Cohor, Wiesbaden, Germany. [Mueller, Ulrich O.; Westerman, Ronny] Fed Inst Populat Res, Wiesbaden, Germany. [Murimira, Brighton] Minist Hlth & Child Care, AIDS & TB Unit, Bindura, Zimbabwe. [Murimira, Brighton] Zimbabwe Natl Family Planning Council, Harare, Zimbabwe. [Naheed, Aliya] Int Ctr Diarrhoeal Dis Res, Dhaka, Bangladesh. [Naldi, Luigi] Azienda Osped Papa Giovanni XXIII, Bergamo, Italy. [Nangia, Vinay] Suraj Eye Inst, Nagpur, Maharashtra, India. [Nash, Denis] CUNY, Sch Publ Hlth, New York, NY 10021 USA. [Nawaz, Haseeb] Southern Illinois Univ, Springfield, IL USA. [Nejjari, Chakib] Fac Med, Fes, Morocco. [Ngalesoni, Frida Namnyak] Minist Hlth & Social Welf, Dar Es Salaam, Tanzania. [Ngirabega, Jean De Dieu] East African Community Hlth Res Commiss, Kigali, Rwanda. [Quyen Le Nguyen] Duy Tan Univ, Inst Global Hlth Innovat, Da Nang, Vietnam. [Vollset, Stein Emil] Univ Bergen, Dept Global Publ Hlth & Primary Care, Bergen, Norway. [Norheim, Ole F.] Univ Bergen, Bergen, Norway. [Norman, Rosana E.] Queensland Univ Technol, Inst Hlth & Biomed Innovat, Brisbane, Qld, Australia. [Nyakarahuka, Luke] Makerere Univ, Kampala, Uganda. Amer Univ Beirut, Ctr Res Populat & Hlth, Fac Hlth Sci, Beirut, Lebanon. [Ogbo, Felix Akpojene] Univ Western Sydney, Sydney, NSW, Australia. [Oh, In-Hwan] Kyung Hee Univ, Dept Prevent Med, Sch Med, Seoul, South Korea. [Olusanya, Bolajoko Olubukunola] Ctr Healthy Start Initiat, Ikoyi, Nigeria. [Olusanya, Jacob Olusegun] Ctr Healthy Start Initiat, Lagos, Nigeria. [Opio, John Nelson] Lira Dist Local Govt, Lira Municipal Council, Lira, Uganda. [Ota, Erika] Natl Res Inst Child Hlth & Dev, Tokyo, Japan. [Padukudru, Mahesh Anand] JSS Univ, JSS Med Coll, Mysore, Karnataka, India. [Park, Hye-Youn] Calif Air Resources Board, Sacramento, CA USA. [Park, Jae-Hyun] Sungkyunkwan Univ, Dept Social & Prevent Med, Samsung Biomed Res Inst, Sch Med, Suwon, South Korea. Univ Calgary, Calgary, AB, Canada. [Patil, Snehal T.] Sch Dent Sci, Karad, India. [Patten, Scott B.] Univ Calgary, Dept Community Hlth Sci, Calgary, AB, Canada. [Paul, Vinod K.; Roy, Ambuj; Sagar, Rajesh] All India Inst Med Sci, New Delhi, India. [Peprah, Emmanuel Kwame] NHLBI, Bldg 10, Bethesda, MD 20892 USA. [Pereira, Claudia C.] Fiocruz MS, Rio De Janeiro, Brazil. [Perico, Norberto; Remuzzi, Giuseppe] IRCCS Mario Negri Inst Pharmacol Res, Ctr Anna Maria Astori, Bergamo, Italy. [Pesudovs, Konrad; Tesfay, Fisaha Haile] Flinders Univ S Australia, Adelaide, SA, Australia. [Petzold, Max] Hlth Metr Unit, Gothenburg, Sweden. [Phillips, Michael Robert] Shanghai Jiao Tong Univ, Sch Med, Shanghai, Peoples R China. [Simard, Edgar P.] Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Phillips, Michael Robert] Emory Univ, Atlanta, GA 30322 USA. [Pillay, Julian David] Durban Univ Technol, Durban, South Africa. [Plass, Dietrich] Sect Exposure Assessment & Environm Hlth Indicato, Berlin, Germany. [Pourmalek, Farshad] Univ British Columbia, Vancouver, BC, Canada. [Qorbani, Mostafa] Alborz Univ Med Sci, Dept Community Med, Sch Med, Karaj, Iran. [Rafay, Anwar; Rana, Saleem M.] Contech Int Hlth Consultants, Lahore, Pakistan. [Rafay, Anwar; Rana, Saleem M.] Contech Sch Publ Hlth, Lahore, Pakistan. [Rahman, Mahfuzar] BRAC, Res & Evaluat Div, Dhaka, Bangladesh. [Rahman, Sajjad Ur] Hamad Med Corp, Doha, Qatar. [Rai, Rajesh Kumar] Soc Hlth & Demog Surveillance, Suri, India. [Rajsic, Sasa] UMIT, ERAWEB Program, Hall In Tirol, Austria. [Rao, Paturi Vishnupriya] Diabet Res Soc, Hyderabad, Andhra Pradesh, India. [Rao, Paturi Vishnupriya] Diabet Res Ctr, Hyderabad, Andhra Pradesh, India. [Remuzzi, Giuseppe] Azienda Osped Papa Giovanni XXIII, Bergamo, Italy. [Rojas-Rueda, David] ISGlobal, Ctr Res Environm Epidemiol, Barcelona, Spain. [Roshandel, Gholamreza] Golestan Univ Med Sci, Golestan Res Ctr Gastroenterol & Hepatol, Gorgan, Iran. [Ruhago, George Mugambage; Sunguya, Bruno F.] Muhimbili Univ Hlth & Allied Sci, Dar Es Salaam, Tanzania. [Saleh, Muhammad Muhammad] Dev Res & Projects Ctr, Abuja, Nigeria. [Sanabria, Juan R.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Sanabria, Juan R.] RFU Chicago Med Sch, Canc Treatment Centers Amer, N Chicago, IL USA. [Sarmiento-Suarez, Rodrigo] Univ Ciencias Aplicadas & Ambient, Bogota, DC, Colombia. [Sartorius, Benn; Yakob, Bereket] Univ KwaZulu Natal, Durban, South Africa. [Sawhney, Monika] Marshall Univ, Huntington, WV USA. [Schutte, Aletta E.] North West Univ, Hypertens Africa Res Team, Potchefstroom, South Africa. [Seedat, Soraya; Wiysonge, Charles Shey] Univ Stellenbosch, Cape Town, South Africa. [Sharma, Rajesh] Indian Inst Technol Ropar, Roopnagar, India. [Shen, Jiabin] Res Inst Nationwide Childrens Hosp, Columbus, OH USA. [Shen, Jiabin] Ohio State Univ, Coll Med, Columbus, OH 43210 USA. [Shin, Hwashin Hyun] Hlth Canada, Ottawa, ON, Canada. [Sigfusdottir, Inga Dora] Reykjavik Univ, Reykjavik, Iceland. [Santos Silva, Diego Augusto] Univ Fed Santa Catarina, Florianopolis, SC, Brazil. [Alves Silveira, Dayane Gabriele] Univ Brasilia, Brasilia, DF, Brazil. [Singh, Om Prakash] Banaras Hindu Univ, Dept Med, Inst Med Sci, Varanasi, Uttar Pradesh, India. [Singh, Prashant Kumar] Inst Human Dev, New Delhi, India. [Skirbekk, Vegard] Norwegian Inst Publ Hlth, Oslo, Norway. [Soneji, Samir] Dartmouth Coll, 1 Med Ctr Dr, Lebanon, NH 03756 USA. [Soriano, Joan B.] Univ Autonoma Madrid, Inst Invest Hosp Univ Princesa, Catedra UAM Linde, Palma de Mallorca, Spain. [Karema, Corine Kakizi] Minist Hlth, Malaria & Other Parasit Dis Div, Nairobi, Kenya. [Soti, David O.] Minist Hlth, Nairobi, Kenya. [Sreeramareddy, Chandrashekhar T.] Int Med Univ, Dept Community Med, Kuala Lumpur, Malaysia. [Stathopoulou, Vasiliki] Attikon Univ Hosp, Athens, Greece. [Steel, Nicholas] Univ East Anglia, Norwich, Norfolk, England. [Steel, Nicholas] Publ Hlth England, London, England. [Swaminathan, Soumya] Natl Inst Res TB, Madras, Tamil Nadu, India. [Sykes, Bryan L.] Univ Calif Irvine, Dept Criminol, Irvine, CA USA. [Sykes, Bryan L.] Univ Calif Irvine, Dept Law & Soc, Irvine, CA USA. [Sykes, Bryan L.] Univ Calif Irvine, Dept Sociol, Irvine, CA USA. [Sykes, Bryan L.] Univ Calif Irvine, Dept Publ Hlth, Irvine, CA USA. [Talongwa, Roberto Tchio] MINSANTE, Minist Hlth, Yaounde, Cameroon. [Tavakkoli, Mohammad] Westchester Med Ctr, Valhalla, NY USA. [Taye, Bineyam] Univ Addis Ababa, Addis Ababa, Ethiopia. [Tedla, Bemnet Amare] James Cook Univ, Cairns, Qld, Australia. [Terkawi, Abdullah Sulieman] Univ Virginia, Dept Anesthesiol, Charlottesville, VA USA. [Terkawi, Abdullah Sulieman] Cleveland Clin, Outcomes Res Consortium, Cleveland, OH USA. [Thapa, Kiran] Inst Med, Kathmandu, Nepal. [Thomson, Alan J.] Adapt Knowledge Management, Victoria, BC, Canada. [Thorne-Lyman, Andrew L.] WorldFish, Bayan Lepas, Penang, Malaysia. [Tobe-Gai, Ruoyan] Natl Ctr Child Hlth & Dev, Tokyo, Japan. [Topor-Madry, Roman] Jagiellonian Univ, Inst Publ Hlth, Krakow, Poland. [Topor-Madry, Roman] Casimir Great Fdn Innovat & Dev, Krakow, Poland. [Towbin, Jeffrey Allen] Le Bonheur Childrens Hosp, Memphis, TN USA. [Towbin, Jeffrey Allen] Univ Tennessee, Hlth Sci Ctr, Memphis, TN USA. [Towbin, Jeffrey Allen] St Jude Childrens Res Hosp, 332 N Lauderdale St, Memphis, TN 38105 USA. [Bach Xuan Tran] Hanoi Med Univ, Hanoi, Vietnam. [Dimbuene, Zacharie Tsala] Univ Kinshasa, Dept Populat Sci & Dev, Fac Econ & Management, Kinshasa, Zaire. [Tsilimparis, Nikolaos] Univ Heart Ctr Hamburg, Hamburg, Germany. [Ukwaja, Kingsley Nnanna] Fed Teaching Hosp, Dept Internal Med, Abakaliki, Nigeria. [Uneke, Chigozie Jesse] Ebonyi State Univ, Abakaliki, Nigeria. [Uthman, Olalekan A.] Univ Warwick, Warwick Med Sch, Coventry, W Midlands, England. [Venketasubramanian, N.] Raffles Hosp, Raffles Neurosci Ctr, Singapore, Singapore. [Vladimirov, Sergey K.] Fed Res Inst Hlth Org & Informat, Moscow, Russia. [Vlassov, Vasiliy Victorovich] Natl Res Univ, Higher Sch Econ, Moscow, Russia. [Vollset, Stein Emil] Norwegian Inst Publ Hlth, Bergen, Norway. [Weiderpass, Elisabete] Norway Inst Populat Based Canc Res, Dept Res, Canc Registry, Oslo, Norway. [Weiderpass, Elisabete] Univ Tromso, Fac Hlth Sci, Dept Community Med, Tromso, Norway. [Weiderpass, Elisabete] Folkhalsan Res Ctr, Genet Epidemiol Grp, Helsinki, Finland. [Weintraub, Robert G.] Royal Childrens Hosp, Melbourne, Vic, Australia. [Weintraub, Robert G.] German Natl Cohort Consortium, Heidelberg, Germany. [Wijeratne, Tissa] Western Hlth Footscray, Footscray, Vic, Australia. [Wilkinson, James D.] Wayne State Univ, Sch Med, Detroit, MI USA. [Wolfe, Charles D. A.] Kings Coll London, Div Hlth & Social Care Res, London, England. [Wolfe, Charles D. A.] Guys & St Thomas NHS Fdn Trust, Natl Inst Hlth Res, Comprehens Biomed Res Ctr, London, England. [Wolfe, Charles D. A.] Kings Coll London, London, England. [Wong, John Q.] Manila Univ, Ateneo Sch Med & Publ Hlth, Pasig, Philippines. [Xu, Gelin] Nanjing Univ, Sch Med, Dept Neurol, Jinling Hosp, Nanjing, Jiangsu, Peoples R China. [Yano, Yuichiro] Northwestern Univ, Dept Prevent Med, Chicago, IL 60611 USA. [Yaseri, Mehdi] Ophthalm Res Ctr, Tehran, Iran. [Yebyo, Henock Gebremedhin] Univ Zurich, Zurich, Switzerland. [Yip, Paul] Univ Hong Kong, Social Work & Social Adm Dept, Hong Kong, Hong Kong, Peoples R China. [Yip, Paul] Univ Hong Kong, Hong Kong Jockey Club Ctr Suicide Res & Prevent, Hong Kong, Hong Kong, Peoples R China. [Yonemoto, Naohiro] Kyoto Univ, Dept Biostat, Sch Publ Hlth, Kyoto, Japan. [Yoon, Seok-Jun] Korea Univ, Dept Prevent Med, Coll Med, Seoul, South Korea. [Younis, Mustafa Z.] Jackson State Univ, Jackson, MS USA. [Yu, Chuanhua] Wuhan Univ, Dept Epidemiol & Biostat, Sch Publ Hlth, Wuhan, Peoples R China. [Yu, Chuanhua] Wuhan Univ, Global Hlth Inst, Wuhan, Peoples R China. [Zaidi, Zoubida] Univ Hosp, Setif, Algeria. [Zeeb, Hajo] Leibniz Inst Prevent Res & Epidemiol, Bremen, Germany. [Zhang, Hao] Shanghai Inst Kidney Dis & Dialysis, Shanghai, Peoples R China. [Zhao, Yong] Chongqing Med Univ, Chongqing, Peoples R China. [Zuhlke, Liesl Joanna] Red Cross War Mem Childrens Hosp, Cape Town, South Africa. RP Wang, HD (reprint author), Inst Hlth Metr & Evaluat, Seattle, WA 98121 USA.; Wang, HD (reprint author), Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98121 USA. EM haidong@uw.edu RI Gishu, Melkamu Dedefo/C-3747-2017; Alsharif, Ubai/C-6527-2017; Lotufo, Paulo/A-9843-2008; Karch, Andre/D-6973-2017; Hedayati, Mohammad T./E-2304-2017; Patten, Scott/B-4434-2011; Abbas, Kaja/E-6590-2017; Pereira, David/M-9286-2013; Beyene, Tariku Jibat/A-6875-2017; Roshandel, gholamreza/N-2260-2016; Martinez-Raga, Jose/B-6251-2017; Majdan, Marek/K-5017-2012; Weiderpass, Elisabete/M-4029-2016; das Neves, Jose/J-8369-2013; Jacobsen, Kathryn/B-5857-2008; Hankey, Graeme /H-4968-2014; Degenhardt, Louisa/D-4515-2012; Ronfani, Luca/B-6668-2013; NORMAN, ROSANA/F-2774-2010; Salomon, Joshua/D-3898-2009; Monasta, Lorenzo/B-1388-2012; OI Olusanya, Bolajoko/0000-0002-3826-0583; Sreeramareddy, Chandrashekhar/0000-0002-5693-7631; Castaneda-Orjuela, Carlos/0000-0002-8735-6223; Heredia-Pi, Ileana Beatriz/0000-0002-9998-9239; Goenka, Shifalika/0000-0001-6993-2883; Miller, Ted/0000-0002-0958-2639; Xu, Gelin/0000-0002-6194-0341; GEBREMDHIN, AMANUEL TESFAY/0000-0003-2459-1805; Al-Aly, Ziyad/0000-0002-2600-0434; assadi, reza/0000-0002-5016-2994; Gishu, Melkamu Dedefo/0000-0002-3466-1232; Alsharif, Ubai/0000-0002-4024-3950; Lotufo, Paulo/0000-0002-4856-8450; Karch, Andre/0000-0003-3014-8543; Hedayati, Mohammad T./0000-0001-6415-4648; Patten, Scott/0000-0001-9871-4041; Abbas, Kaja/0000-0003-0563-1576; Pereira, David/0000-0003-0384-7592; Wiysonge, Charles/0000-0002-1273-4779; Vlassov, Vasiliy/0000-0001-5203-549X; Birlik, Sait Mentes/0000-0002-9889-8837; Santos, Itamar/0000-0003-3212-8466; Alkerwi, Ala'a/0000-0002-7448-3936; Schutte, Aletta/0000-0001-9217-4937; Sindi, Shireen/0000-0002-3786-0552; Leung, Ricky/0000-0002-2852-6771; Pesudovs, Konrad/0000-0002-6322-9369; Aldridge, Robert/0000-0003-0542-0816; Catala-Lopez, Ferran/0000-0002-3833-9312; Javanbakht, Mehdi/0000-0002-8661-8439; Beyene, Tariku Jibat/0000-0002-7474-1966; Roshandel, gholamreza/0000-0002-5494-0722; Martinez-Raga, Jose/0000-0002-2856-6562; Majdan, Marek/0000-0001-8037-742X; Weiderpass, Elisabete/0000-0003-2237-0128; das Neves, Jose/0000-0002-2317-2759; Jacobsen, Kathryn/0000-0002-4198-6246; Hankey, Graeme /0000-0002-6044-7328; Degenhardt, Louisa/0000-0002-8513-2218; Ronfani, Luca/0000-0001-5710-3914; NORMAN, ROSANA/0000-0002-9742-1957; Salomon, Joshua/0000-0003-3929-5515; Monasta, Lorenzo/0000-0001-7774-548X; Gething, Peter/0000-0001-6759-5449; Langan, Sinead/0000-0002-7022-7441; Deribe, Kebede/0000-0002-8526-6996; Uthman, Olalekan/0000-0002-8567-3081; Khang, Young-Ho/0000-0002-9585-8266; Kemp, Andrew/0000-0003-1146-3791; Kamal, Ritul/0000-0001-9741-1698; Glaser, Elizabeth/0000-0002-1918-057X; Awasthi, Ashish/0000-0002-9308-9782; Amegah, A Kofi/0000-0001-5868-6402; Atique, Suleman/0000-0002-5149-0703; Norheim, Ole F./0000-0002-5748-5956; Hoek, Hans/0000-0001-6353-5465; Hay, Simon/0000-0002-0611-7272; Moradi-Lakeh, Maziar/0000-0001-7381-5305 FU Bill AMP; Melinda Gates Foundation; National Institute of Mental Health, National Institutes of Health (NIH) [R01MH110163]; National Institute on Aging, NIH [P30AG047845]; Qatar National Research Fund (NPRP) [04-924-3-251]; Bill AMP; Melinda Gates Foundation [OPP1068048]; Fundacao para a Ciencia e a Tecnologia, Portugal [SFRH/BPD/92934/2013]; Wellcome Trust Fellowship in Public Health and Tropical Medicine [099876]; Swiss National Science Foundation (SNSF) [P300P3-154634]; Sistema Nacional de Investigadores de Panama-SNI; Wellcome Trust-DBT India Alliance Clinical and Public Health Intermediate Fellowship; Academy of Finland; Swedish Research Council; Alzheimerfonden; Alzheimer's Research AMP; Prevention Foundation; Center for Innovative Medicine (CIMED) at Karolinska Institutet South Campus; AXA Research Fund; Wallenberg Clinical Scholars Award from the Knut och Alice Wallenbergs Foundation; Sheika Salama Bint Hamdan Al Nahyan Foundation; ISCIII (General Branch Evaluation and Promotion of Health Research); European Regional Development Fund (ERDF-FEDER); National Institute for Health Research (NIHR) Clinician Scientist Fellowship [NIHR/CS/010/014]; NIHR; EU Innovative Medicines Initiative; Centre for Strategic AMP; International Studies; WHO; German National Cohort Consortium [O1ER1511D]; NIHR Oxford Biomedical Research Centre; NIHR Career Development Fellowship; Oxford Martin School; International Society of Nephrology (ISN); FAPESP (Brazilian public agency); Fonds de la recherche en sante du Quebec (FRSQ); Generalitat Valenciana [PROMETEOII/2015/021]; ISCIII-FEDER [PI14/00894]; Strategic Public Policy Research [HKU7003-SPPR-12]; [CP13/00150]; [PI15/00862] FX We thank the countless individuals who have contributed to the Global Burden of Disease (GBD) Study 2015 in various capacities. We specifically thank Jeffrey Eaton and John Stover. HW and CJLM received funding for this study from the Bill & Melinda Gates Foundation; the National Institute of Mental Health, National Institutes of Health (NIH; R01MH110163); and the National Institute on Aging, NIH (P30AG047845). LJAR acknowledges the support of Qatar National Research Fund (NPRP 04-924-3-251) who provided the main funding for generating the data provided to the GBD-Institute for Health Metrics and Evaluation effort. BPAQ acknowledges institutional support from PRONABEC (National Program of Scholarship and Educational Loan), provided by the Peruvian government. DB is supported by the Bill & Melinda Gates Foundation (grant number OPP1068048). JDN was supported in his contribution to this work by a Fellowship from Fundacao para a Ciencia e a Tecnologia, Portugal (SFRH/BPD/92934/2013). KD is supported by a Wellcome Trust Fellowship in Public Health and Tropical Medicine (grant number 099876). TF received financial support from the Swiss National Science Foundation (SNSF; project number P300P3-154634). AG acknowledges funding from Sistema Nacional de Investigadores de Panama-SNI. PJ is supported by Wellcome Trust-DBT India Alliance Clinical and Public Health Intermediate Fellowship. MK receives research support from the Academy of Finland, the Swedish Research Council, Alzheimerfonden, Alzheimer's Research & Prevention Foundation, Center for Innovative Medicine (CIMED) at Karolinska Institutet South Campus, AXA Research Fund, Wallenberg Clinical Scholars Award from the Knut och Alice Wallenbergs Foundation, and the Sheika Salama Bint Hamdan Al Nahyan Foundation. AK's work was supported by the Miguel Servet contract financed by the CP13/00150 and PI15/00862 projects, integrated into the National R&D&I and funded by the ISCIII (General Branch Evaluation and Promotion of Health Research), and the European Regional Development Fund (ERDF-FEDER). SML is funded by a National Institute for Health Research (NIHR) Clinician Scientist Fellowship (grant number NIHR/CS/010/014). HJL reports grants from the NIHR, EU Innovative Medicines Initiative, Centre for Strategic & International Studies, and WHO. WM is Program analyst, Population and Development, in the Peru Country Office of the United Nations Population Fund, which does not necessarily endorse this study. For UOM, funding from the German National Cohort Consortium (O1ER1511D) is gratefully acknowledged. KR reports grants from NIHR Oxford Biomedical Research Centre, NIHR Career Development Fellowship, and Oxford Martin School during the conduct of the study. GR acknowledges that work related to this paper has been done on the behalf of the GBD Genitourinary Disease Expert Group supported by the International Society of Nephrology (ISN). ISS reports grants from FAPESP (Brazilian public agency). RSS receives institutional support from Universidad de Ciencias Aplicadas y Ambientales, UDCA, Bogota Colombia. SS receives postdoctoral funding from the Fonds de la recherche en sante du Quebec (FRSQ), including its renewal. RTS was supported in part by grant number PROMETEOII/2015/021 from Generalitat Valenciana and the national grant PI14/00894 from ISCIII-FEDER. PY acknowledges support from Strategic Public Policy Research (HKU7003-SPPR-12). NR 54 TC 13 Z9 14 U1 51 U2 64 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 2352-3018 J9 LANCET HIV JI Lancet HIV PD AUG PY 2016 VL 3 IS 8 BP E361 EP E387 DI 10.1016/S2352-3018(16)30087-X PG 27 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DS5SK UT WOS:000380842400010 ER PT J AU Wells, JM Farris, RF Gosdin, TA Dransfield, MT Wood, ME Bell, SC Rowe, SM AF Wells, J. Michael Farris, Roopan F. Gosdin, Taylor A. Dransfield, Mark T. Wood, Michelle E. Bell, Scott C. Rowe, Steven M. TI Pulmonary artery enlargement and cystic fibrosis pulmonary exacerbations: a cohort study SO LANCET RESPIRATORY MEDICINE LA English DT Article ID TRANSMEMBRANE CONDUCTANCE REGULATOR; LUNG-DISEASE; CARDIAC-FUNCTION; HYPERTENSION; COPD; CFTR; ECHOCARDIOGRAPHY; PATHOPHYSIOLOGY; EXPRESSION; MANAGEMENT AB Background Acute pulmonary exacerbations are associated with progressive lung function decline and increased mortality in cystic fibrosis. The role of pulmonary vascular disease in pulmonary exacerbations is unknown. We aimed to assess the association between pulmonary artery enlargement (defined as pulmonary artery diameter to ascending aorta diameter [PA:A] ratio >1), a marker of pulmonary vascular disease, and exacerbations. Methods In this cohort study, we used clinical, CT imaging, and prospective exacerbation data from a previous prospective clinical trial (derivation cohort) and from The Prince Charles Hospital (TPCH; Brisbane, QLD, Australia) cystic fibrosis registry (validation cohort). In our derivation cohort, we included adults aged 18 years or older with cystic fibrosis and at least one CFTR nonsense mutation, who were enrolled in the trial between Sept 8, 2009, and Nov 30, 2010, randomly assigned to receive placebo, and had baseline CT imaging. Our validation cohort included adult patients with cystic fibrosis who had CT imaging performed between Jan 1, 2002, and Dec 31, 2014. We measured the PA: A ratio at the level of the pulmonary artery bifurcation on CT scans. Patients in each cohort were separated into two groups on the basis of PA: A ratio (>1 or <= 1) and were followed up for 1 year in the derivation cohort and 2 years in the validation cohort. The primary endpoint was the development of one or more acute pulmonary exacerbations during follow-up. We used linear and logistic regression models to determine associations between clinical factors, the PA: A ratio, and pulmonary exacerbations. We used Cox regression to determine the time to first exacerbation in the validation cohort. Findings 37 (50%) of 74 patients in the derivation cohort and 89 (47%) of 190 patients in the validation cohort had enlarged pulmonary arteries (PA: A>1). 50 (68%) patients in the derivation cohort had one or more exacerbations at 1 year and 133 (70%) patients in the validation cohort had one or more exacerbations at 2 years. At baseline, patients with pulmonary artery enlargement were younger than those without enlargement in both cohorts and had elevated sweat chloride concentrations in the derivation cohort (100.5 mmol/L [SD 10.9] vs 90.4 mmol/L [19.9]; difference 10.1 mmol/L [95% CI 2.5- 177], p=0.017). Pulmonary artery enlargement was associated with exacerbations in the derivation cohort (odds ratio 3.49 [95% CI 1.18-10.3], p=0.023) when adjusted for sex, body-mass index (BMI), forced expiratory volume in 1 s (FEV1), and PA: A greater than 1, and in the validation cohort (2.41 [1.06-5.52], p=0.037) when adjusted for sex, BMI, chronic Pseudomonas aeruginosa infection, FEV1/FVC (forced vital capacity), PA: A greater than 1, and previous exacerbation. The time to first exacerbation was shorter in patients with enlarged pulmonary arteries than in those with normal-sized pulmonary arteries in the validation cohort (hazard ratio 1.66 [95% CI 1.18-2.34], p=0.0038) in unadjusted analysis, but not when adjusted for sex, BMI, exacerbations within 1 year before index CT scan, FEV1/FVC, and chronic Paeruginosa infection (1.14 [0.80-1.62], p=0.82). Interpretation Pulmonary artery enlargement is prevalent in adult patients with cystic fibrosis and was associated with acute pulmonary exacerbation risk in two well characterised cohorts. The PA: A ratio could be a predictive marker in cystic fibrosis. C1 [Wells, J. Michael; Farris, Roopan F.; Dransfield, Mark T.; Rowe, Steven M.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Wells, J. Michael; Gosdin, Taylor A.; Dransfield, Mark T.; Rowe, Steven M.] Univ Alabama Birmingham, Div Pulm Allergy & Crit Care, Birmingham, AL USA. [Wells, J. Michael; Gosdin, Taylor A.; Dransfield, Mark T.; Rowe, Steven M.] Univ Alabama Birmingham, UAB Lung Hlth Ctr, Birmingham, AL USA. [Wells, J. Michael; Dransfield, Mark T.; Rowe, Steven M.] Univ Alabama Birmingham, Cyst Fibrosis Res Ctr, Birmingham, AL USA. [Wells, J. Michael; Dransfield, Mark T.] Birmingham VA Med Ctr, Birmingham, AL USA. [Wood, Michelle E.; Bell, Scott C.] Prince Charles Hosp Brisbane, Adult Cyst Fibrosis Ctr, Brisbane, Qld, Australia. [Wood, Michelle E.; Bell, Scott C.] Berghofer Med Res Inst, QIMR, Brisbane, Qld, Australia. [Wood, Michelle E.; Bell, Scott C.] Univ Queensland, Sch Med, Brisbane, Qld, Australia. RP Wells, JM (reprint author), Univ Alabama Birmingham, Div Pulm Allergy & Crit Care Med, 1900 Univ Blvd,THT 422, Birmingham, AL 35294 USA. EM jmwells@uabmc.edu FU US National Heart, Lung, and Blood Institute/National Institutes of Health; Cystic Fibrosis Foundation; University of Alabama at Birmingham; Queensland Health Fellowship FX US National Heart, Lung, and Blood Institute/National Institutes of Health, Cystic Fibrosis Foundation, the University of Alabama at Birmingham, and the Queensland Health Fellowship. NR 37 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2213-2600 J9 LANCET RESP MED JI Lancet Resp. Med. PD AUG PY 2016 VL 4 IS 8 BP 636 EP 645 DI 10.1016/S2213-2600(16)30105-9 PG 10 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DS5QI UT WOS:000380836800027 PM 27298019 ER PT J AU Reich, A Werth, VP Furukawa, F Kuhn, A Szczech, J Samotij, D Szepietowski, JC AF Reich, A. Werth, V. P. Furukawa, F. Kuhn, A. Szczech, J. Samotij, D. Szepietowski, J. C. TI Treatment of cutaneous lupus erythematosus: current practice variations SO LUPUS LA English DT Article DE CLE; CCLE; DLE; ICLE; LET; SCLE; therapy ID DOUBLE-BLIND; CLOBETASOL PROPIONATE; CONTROLLED-TRIAL; TACROLIMUS; EFFICACY; OINTMENT; SPECTRUM; SAFETY AB The treatment of cutaneous lupus erythematous (CLE) remains a challenge. Most of the therapeutic options used in CLE have not been tested in randomized controlled studies and to date no agent has been approved. Therefore, CLE treatment is mostly based on personal experience. To better characterize therapeutic habits among physicians treating CLE patients, a questionnaire-based study about various aspects of topical and systemic treatment for CLE has been performed. The questionnaire was distributed among CLE experts, mostly from Japan, the USA, and Europe. A total of 82 completed questionnaires were assessed. High-potent and potent corticosteroids as well as calcineurin inhibitors were the most often recommended topical treatment for all CLE subtypes. The most relevant factors for initiation of systemic therapy were severity of skin lesions, concomitant involvement of internal organs, CLE subtype and lack of response to topical therapies. Corticosteroids and antimalarials were considered as the most suitable and effective systemic drugs for CLE patients. However, significant differences were observed between various CLE subtypes and between different countries regarding the assessment of various topical and systemic treatment options. In conclusion, great variability of obtained answers underlines the need of development of CLE treatment guidelines suitable for different disease subtypes. C1 [Reich, A.; Szczech, J.; Samotij, D.; Szepietowski, J. C.] Wroclaw Med Univ, Dept Dermatol Venereol & Allergol, Ul Chalubinskiego 1, PL-50368 Wroclaw, Poland. [Werth, V. P.] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. [Werth, V. P.] Univ Penn, Sch Med, Dept Dermatol, Philadelphia, PA 19104 USA. [Furukawa, F.] Wakayama Med Univ, Dept Dermatol, Wakayama, Japan. [Kuhn, A.] Univ Med Ctr, Interdisciplinary Ctr Clin Trials, Mainz, Germany. RP Reich, A (reprint author), Wroclaw Med Univ, Dept Dermatol Venereol & Allergol, Ul Chalubinskiego 1, PL-50368 Wroclaw, Poland. EM adam.reich@umed.wroc.pl NR 15 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0961-2033 EI 1477-0962 J9 LUPUS JI Lupus PD AUG PY 2016 VL 25 IS 9 BP 964 EP 972 DI 10.1177/0961203316628997 PG 9 WC Rheumatology SC Rheumatology GA DS7RV UT WOS:000380981500003 PM 26821963 ER PT J AU Graetz, I Gordon, N Fung, V Hamity, C Reed, ME AF Graetz, Ilana Gordon, Nancy Fung, Vick Hamity, Courtnee Reed, Mary E. TI The Digital Divide and Patient Portals Internet Access Explained Differences in Patient Portal Use for Secure Messaging by Age, Race, and Income SO MEDICAL CARE LA English DT Article DE access to care; consumer behavior; disparities; health care technology; patient behavior; patient preference; patient surveys; physician/patient communication ID HEALTH INFORMATION EXCHANGE; QUALITY-OF-CARE; MEDICAL-RECORD; OLDER-ADULTS; DISPARITIES; ADOPTION; GENDER; RACE/ETHNICITY; SERVICES; COSTS AB Background: Online access to health records and the ability to exchange secure messages with physicians can improve patient engagement and outcomes; however, the digital divide could limit access to web-based portals among disadvantaged groups. Objectives: To understand whether sociodemographic differences in patient portal use for secure messaging can be explained by differences in internet access and care preferences. Research Design: Cross-sectional survey to examine the association between patient sociodemographic characteristics and internet access and care preferences; then, the association between sociodemographic characteristics and secure message use with and without adjusting for internet access and care preference. Subjects: One thousand forty-one patients with chronic conditions in a large integrated health care delivery system (76% response rate). Measures: Internet access, portal use for secure messaging, preference for in-person or online care, and sociodemographic and health characteristics. Results: Internet access and preference mediated some of the differences in secure message use by age, race, and income. For example, using own computer to access the internet explained 52% of the association between race and secure message use and 60% of the association between income and use (Sobel-Goodman mediation test, P < 0.001 for both). Education and sex-related differences in portal use remained statistically significant when controlling for internet access and preference. Conclusions: As the availability and use of patient portals increase, it is important to understand which patients have limited access and the barriers they may face. Improving internet access and making portals available across multiple platforms, including mobile, may reduce some disparities in secure message use. C1 [Graetz, Ilana] Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, 66 N Pauline St,Suite 633, Memphis, TN 38163 USA. [Graetz, Ilana; Gordon, Nancy; Hamity, Courtnee; Reed, Mary E.] Kaiser Permanente Northern Calif, Div Res, Oakland, CA USA. [Fung, Vick] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. [Fung, Vick] Harvard Med Sch, Dept Med, Boston, MA USA. RP Graetz, I (reprint author), Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, 66 N Pauline St,Suite 633, Memphis, TN 38163 USA. EM igraetz@uthsc.edu RI Graetz, Ilana/N-1189-2016 OI Graetz, Ilana/0000-0003-3664-5815 FU Kaiser Foundation Research Institute FX Supported by the Kaiser Foundation Research Institute. The content, findings, and conclusions of this paper are the sole responsibility of the authors; the sponsors were not involved in any way in the determination of the content of this paper. NR 28 TC 1 Z9 1 U1 6 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0025-7079 EI 1537-1948 J9 MED CARE JI Med. Care PD AUG PY 2016 VL 54 IS 8 BP 772 EP 779 DI 10.1097/MLR.0000000000000560 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA DS1ZM UT WOS:000380502800008 PM 27314262 ER PT J AU Popescu, I Schrag, D Ang, A Wong, M AF Popescu, Ioana Schrag, Deborah Ang, Alfonso Wong, Mitchell TI Racial/Ethnic and Socioeconomic Differences in Colorectal and Breast Cancer Treatment Quality The Role of Physician-level Variations in Care SO MEDICAL CARE LA English DT Article DE race; socioeconomic status; disparities; colorectal breast cancer ID ADJUVANT CHEMOTHERAPY; RACIAL DISPARITIES; CONSERVING SURGERY; RECTAL-CANCER; COLON-CANCER; HEALTH-CARE; RADIATION-THERAPY; UNITED-STATES; STAGE-II; MEDICARE AB Background: Despite a large body of research showing racial/ethnic and socioeconomic disparities in cancer treatment quality, the relative role of physician-level variations in care is unclear. Objective: To examine the effect of physicians on disparities in breast and colorectal cancer care. Subjects: Linked SEER Medicare data were used to identify Medicare beneficiaries diagnosed with colorectal and breast cancer during 1995-2007 and their treating physicians. Research Design: We identified treating physicians from Medicare claims data. We measured the use of NIH guideline-recommended therapies from SEER and Medicare claims data, and used logistic models to examine the relationship between race/ethnicity, socioeconomic status, and cancer quality of care. We used physician fixed effects to account for between-physician variations in treatment. Results: Minority and low socioeconomic status beneficiaries with breast and colorectal cancer were less likely to receive any recommended treatments as compared with whites. Overall, between-physician variation explained <20% of the total variation in quality of care. After accounting for between-physician differences, median household income explained 14.3%, 18.4%, and 13.2% of the variation in use of breast-conserving surgery, chemotherapy, and radiation for breast cancer, and 13.7%, 12.9%, and 12.6% of the within-physician variation in use of colorectal surgery, chemotherapy, and radiation for colorectal cancer, whereas race and ethnicity explained <2% of the within-physician variation in cancer care. Conclusions: Between-physician variations partially explain racial disparities in cancer care. Residual within-physician disparities may be due to differences in patient-provider communication, patient preferences and treatment adherence, or unmeasured clinical severity. C1 [Popescu, Ioana; Ang, Alfonso; Wong, Mitchell] David Geffen Sch Med, Div Gen Internal Med & Hlth Serv Res, Los Angeles, CA USA. [Schrag, Deborah] Dana Farber Canc Inst, Div Populat Sci, Boston, MA 02115 USA. [Schrag, Deborah] Harvard Med Sch, Boston, MA USA. RP Popescu, I (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Div Gen Internal Med & Hlth Serv Res, 911 Broxton Ave,Suite 316, Los Angeles, CA 90024 USA. EM ipopescu@mednet.ucla.edu FU American Cancer Society [114115-RSGT-07-231-01-CPHPS]; NHLBI [R01 HL118410] FX Supported by award #114115-RSGT-07-231-01-CPHPS from the American Cancer Society. I.P. was supported by R01 HL118410 from the NHLBI. NR 45 TC 0 Z9 0 U1 4 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0025-7079 EI 1537-1948 J9 MED CARE JI Med. Care PD AUG PY 2016 VL 54 IS 8 BP 780 EP 788 DI 10.1097/MLR.0000000000000561 PG 9 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA DS1ZM UT WOS:000380502800009 PM 27326547 ER PT J AU Warren, JL Mariotto, A Melbert, D Schrag, D Doria-Rose, P Penson, D Yabroff, KR AF Warren, Joan L. Mariotto, Angela Melbert, Danielle Schrag, Deborah Doria-Rose, Paul Penson, David Yabroff, K. Robin TI Sensitivity of Medicare Claims to Identify Cancer Recurrence in Elderly Colorectal and Breast Cancer Patients SO MEDICAL CARE LA English DT Article DE Medicare; SEER; health claims; recurrence; outcomes; disease-free progression ID PROSTATE-CANCER; UNITED-STATES; SURVIVAL; DEATH; SURVEILLANCE; POPULATION; UTILITY AB Background: Researchers are increasingly interested in using observational data to evaluate cancer outcomes following treatment, including cancer recurrence and disease-free survival. Because population-based cancer registries do not collect recurrence data, recurrence is often imputed from health claims, primarily by identifying later cancer treatments after initial treatment. The validity of this approach has not been established. Research Design: We used the linked Surveillance, Epidemiology, and End Results-Medicare data to assess the sensitivity of Medicare claims for cancer recurrence in patients very likely to have had a recurrence. We selected newly diagnosed stage II/III colorectal (n = 6910) and female breast cancer (n = 3826) patients during 1994-2003 who received initial cancer surgery, had a treatment break, and then died from cancer in 1994-2008. We reviewed all claims from the treatment break until death for indicators of recurrence. We focused on additional cancer treatment (surgery, chemotherapy, radiation therapy) as the primary indicator, and used multivariate logistic regression analysis to evaluate patient factors associated with additional treatment. We also assessed metastasis diagnoses and end-of-life care as recurrence indicators. Results: Additional treatment was the first indicator of recurrence for 38.8% of colorectal patients and 35.2% of breast cancer patients. Patients aged 70 and older were less likely to have additional treatment (P < 0.05), in adjusted analyses. Over 20% of patients either had no recurrence indicator before death or had end-of-life care as their first indicator. Conclusions: Identifying recurrence through additional cancer treatment in Medicare claims will miss a large percentage of patients with recurrences; particularly those who are older. C1 [Warren, Joan L.; Mariotto, Angela; Doria-Rose, Paul; Yabroff, K. Robin] NCI, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,Room 3E428, Bethesda, MD 20892 USA. [Melbert, Danielle] Informat Management Serv Inc, Beltsville, MD USA. [Schrag, Deborah] Dana Farber Canc Inst, Dept Med, Boston, MA 02115 USA. [Penson, David] Vanderbilt Ingram Canc Ctr, Ctr Surg Qual & Outcomes Res, Nashville, TN USA. RP Warren, JL (reprint author), NCI, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,Room 3E428, Bethesda, MD 20892 USA. EM joan_warren@nih.gov OI Doria-Rose, Vincent/0000-0002-8802-5143 FU Intramural NIH HHS [Z99 CA999999] NR 24 TC 2 Z9 2 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0025-7079 EI 1537-1948 J9 MED CARE JI Med. Care PD AUG PY 2016 VL 54 IS 8 BP E47 EP E54 DI 10.1097/MLR.0000000000000058 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA DS1ZM UT WOS:000380502800001 PM 24374419 ER PT J AU Wong, ES Wang, V Liu, CF Hebert, PL Maciejewski, ML AF Wong, Edwin S. Wang, Virginia Liu, Chuan-Fen Hebert, Paul L. Maciejewski, Matthew L. TI Do Veterans Health Administration Enrollees Generalize to Other Populations? SO MEDICAL CARE RESEARCH AND REVIEW LA English DT Article DE veterans; comparative research; propensity score models; Medicare; Medicaid ID OBSTRUCTIVE PULMONARY-DISEASE; RANDOMIZED CONTROLLED-TRIAL; NURSE FOLLOW-UP; CARE-SYSTEM; BEHAVIORAL-MODEL; MEDICAL-CARE; AUTOMATED CALLS; GLUCOSE CONTROL; AFFAIRS; OUTCOMES AB The Veterans Health Administration (VHA) has historically served a disproportionately male patient population with lower income and greater rates of mental illness than non-VHA populations. The generalizability of research based on VHA enrollees is unknown because the overlap between VHA and non-VHA populations has never been empirically examined. This study used 2013 National Health Interview Survey data to examine the extent to which VHA enrollees had similar demographic and health characteristics as individuals with Medicaid, Medicare, or private insurance coverage, based on propensity score models. A majority of male VHA enrollees were similar to Medicare beneficiaries suggesting greater generalizability of VHA studies than commonly hypothesized. Overlap declined when comparing with Medicaid enrollees or privately insured individuals, suggesting more limited generalizability of VHA studies to these populations. C1 [Wong, Edwin S.; Liu, Chuan-Fen; Hebert, Paul L.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Wong, Edwin S.; Liu, Chuan-Fen; Hebert, Paul L.] Univ Washington, Seattle, WA 98195 USA. [Wang, Virginia; Maciejewski, Matthew L.] Durham VA Med Ctr, Durham, NC USA. [Wang, Virginia; Maciejewski, Matthew L.] Duke Univ, Durham, NC USA. RP Wong, ES (reprint author), VA Puget Sound Hlth Care Syst, Ctr Innovat Vet Ctr & Value Driven Care, 1660 S Columbian Way,HSR&D MS-152, Seattle, WA 98108 USA. EM edwin.wong@va.gov FU U.S. Department of Veterans Affairs Health Services Research & Development Career Development Award [CDA 13-024] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Dr. Wong is supported by a U.S. Department of Veterans Affairs Health Services Research & Development Career Development Award (CDA 13-024). Dr. Maciejewski is a Department of Veterans Affairs Research Career Scientist (RCS 10-391). NR 29 TC 1 Z9 1 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1077-5587 EI 1552-6801 J9 MED CARE RES REV JI Med. Care Res. Rev. PD AUG PY 2016 VL 73 IS 4 BP 493 EP 507 DI 10.1177/1077558715617382 PG 15 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA DS7JI UT WOS:000380959200006 PM 26589675 ER PT J AU Wang, SA Tam, W Tsai, AG Arber, DA Hasserjian, RP Geyer, JT George, TI Czuchlewski, DR Foucar, K Rogers, HJ Hsi, ED Rea, BB Bagg, A Dal Cin, P Zhao, C Kelley, TW Verstovsek, S Bueso-Ramos, C Orazi, A AF Wang, Sa A. Tam, Wayne Tsai, Albert G. Arber, Daniel A. Hasserjian, Robert P. Geyer, Julia T. George, Tracy I. Czuchlewski, David R. Foucar, Kathryn Rogers, Heesun J. Hsi, Eric D. Rea, B. Bryan Bagg, Adam Dal Cin, Paola Zhao, Chong Kelley, Todd W. Verstovsek, Srdan Bueso-Ramos, Carlos Orazi, Attilio TI Targeted next-generation sequencing identifies a subset of idiopathic hypereosinophilic syndrome with features similar to chronic eosinophilic leukemia, not otherwise specified SO MODERN PATHOLOGY LA English DT Article ID CHRONIC NEUTROPHILIC LEUKEMIA; WORLD-HEALTH-ORGANIZATION; CLONAL HEMATOPOIESIS; MYELOPROLIFERATIVE NEOPLASMS; SOMATIC MUTATIONS; UNDETERMINED SIGNIFICANCE; MYELOID-LEUKEMIA; CALR MUTATIONS; HIGH-RISK; DISTINCT AB The distinction between chronic eosinophilic leukemia, not otherwise specified and idiopathic hypereosinophilic syndrome largely relies on clonality assessment. Prior to the advent of next-generation sequencing, clonality was usually determined by cytogenetic analysis. We applied targeted next-generation sequencing panels designed for myeloid neoplasms to bone marrow specimens from a cohort of idiopathic hypereosinophilic syndrome patients (n=51), and assessed the significance of mutations in conjunction with clinicopathological features. The findings were further compared with those of 17 chronic eosinophilic leukemia, not otherwise specified patients defined by their abnormal cytogenetics and/or increased blasts. Mutations were detected in 14/51 idiopathic hypereosinophilic syndrome patients (idiopathic hypereosinophilic syndrome/next-generation sequencing-positive) (28%), involving single gene in 7 and >= 2 in 7 patients. The more frequently mutated genes included ASXL1 (43%), TET2 (36%), EZH2 (29%), SETBP1 (22%), CBL (14%), and NOTCH1 (14%). Idiopathic hypereosinophilic syndrome/next-generation sequencing-positive patients showed a number of clinical features and bone marrow findings resembling chronic eosinophilic leukemia, not otherwise specified. Chronic eosinophilic leukemia, not otherwise specified patients showed a disease-specific survival of 14.4 months, markedly inferior to idiopathic hypereosinophilic syndrome/next-generation sequencing-negative (P<0.001), but not significantly different from idiopathic hypereosinophilic syndrome/next-generation sequencing-positive (P=0.117). These data suggest that targeted next-generation sequencing helps to establish clonality in a subset of patients with hypereosinophilia that would otherwise be classified as idiopathic hypereosinophilic syndrome. In conjunction with other diagnostic features, mutation data can be used to establish a diagnosis of chronic eosinophilic leukemia, not otherwise specified in patients presenting with hypereosinophilia. C1 [Wang, Sa A.; Zhao, Chong; Bueso-Ramos, Carlos] Univ Texas MD Anderson Canc Ctr, Dept Hematopathol, 1515 Holcombe Blvd,Unit 72, Houston, TX 77030 USA. [Tam, Wayne; Geyer, Julia T.; Orazi, Attilio] Weill Cornell Med Coll, Dept Pathol, New York, NY USA. [Tsai, Albert G.; Arber, Daniel A.] Stanford Univ, Dept Pathol, Stanford, CA 94305 USA. [Hasserjian, Robert P.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [George, Tracy I.; Czuchlewski, David R.; Foucar, Kathryn] Univ New Mexico, Dept Pathol, Albuquerque, NM 87131 USA. [Rogers, Heesun J.; Hsi, Eric D.] Cleveland Clin, Dept Lab Med, Cleveland, OH 44106 USA. [Rea, B. Bryan; Bagg, Adam] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA USA. [Dal Cin, Paola] Brigham & Women Hosp, Dept Pathol, Boston, MA USA. [Kelley, Todd W.] Univ Utah, Dept Pathol, Salt Lake City, UT USA. [Verstovsek, Srdan] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA. RP Wang, SA (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Hematopathol, 1515 Holcombe Blvd,Unit 72, Houston, TX 77030 USA. EM swang5@mdanderson.org FU NCI NIH HHS [P30 CA016672] NR 42 TC 3 Z9 3 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD AUG PY 2016 VL 29 IS 8 BP 854 EP 864 DI 10.1038/modpathol.2016.75 PG 11 WC Pathology SC Pathology GA DS5KR UT WOS:000380821400007 PM 27174585 ER PT J AU Ritterhouse, LL Nowak, JA Strickland, KC Garcia, EP Jia, YH Lindeman, NI Macconaill, LE Konstantinopoulos, PA Matulonis, UA Liu, J Berkowitz, RS Nucci, MR Crum, CP Sholl, LM Howitt, BE AF Ritterhouse, Lauren L. Nowak, Jonathan A. Strickland, Kyle C. Garcia, Elizabeth P. Jia, Yonghui Lindeman, Neal I. Macconaill, Laura E. Konstantinopoulos, Panagiotis A. Matulonis, Ursula A. Liu, Joyce Berkowitz, Ross S. Nucci, Marisa R. Crum, Christopher P. Sholl, Lynette M. Howitt, Brooke E. TI Morphologic correlates of molecular alterations in extrauterine Mullerian carcinomas SO MODERN PATHOLOGY LA English DT Article ID EPITHELIAL OVARIAN-CANCER; GRADE SEROUS CARCINOMA; BRCA-MUTATION-STATUS; DNA-SEQUENCING DATA; GERMLINE MUTATIONS; FALLOPIAN-TUBE; COPY NUMBER; SURVIVAL; RECOMBINATION; PATTERNS AB Extrauterine high-grade serous carcinomas can exhibit various histologic patterns including (1) classic architecture that is papillary, micropapillary and infiltrative and (2) solid, endometrioid, and transitional (ie, SET) patterns. Although the SET pattern has been associated with germline BRCA mutations, potential molecular underpinnings have not been fully investigated. DNA was isolated from 174 carcinomas of the fallopian tube, ovary, or peritoneum. Targeted next-generation sequencing was performed and single-nucleotide and copy number variants were correlated with morphologic subtype. Overall, 79% of tumors were classified as high-grade serous carcinoma (n = 138), and the most common mutations in high-grade serous carcinomas were TP53 (94%), BRCA1 (25%), BRCA2 (11%), and ATM (7%). Among chemotherapy-naive high-grade serous carcinomas, 40 cases exhibited classic morphology and 40 cases had non-classic morphology (SET or ambiguous features). Mutations in homologous recombination pathways were seen across all tumor histotypes. High-grade serous carcinomas with homologous recombination mutations were six times more likely to be associated with nonclassic histology (P = 0.002) and were significantly more likely to be platinum sensitive and have improved progression-free survival (PFS) (P = 0.007 and P = 0.004, respectively). In a multivariate analysis adjusted for age, homologous recombination mutation status and increased copy number variants were independently associated with improved PFS (P = 0.008 and P = 0.005, respectively). These findings underscore the potential significance of variant morphologic patterns and comprehensive genomic analysis in high-grade serous carcinomas with potential implications for pathogenesis, as well as response to targeted therapies. C1 [Ritterhouse, Lauren L.; Nowak, Jonathan A.; Strickland, Kyle C.; Lindeman, Neal I.; Sholl, Lynette M.; Howitt, Brooke E.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Ritterhouse, Lauren L.; Nowak, Jonathan A.; Strickland, Kyle C.; Garcia, Elizabeth P.; Jia, Yonghui; Lindeman, Neal I.; Macconaill, Laura E.; Berkowitz, Ross S.; Nucci, Marisa R.; Crum, Christopher P.; Sholl, Lynette M.; Howitt, Brooke E.] Harvard Med Sch, Boston, MA USA. [Garcia, Elizabeth P.; Jia, Yonghui; Lindeman, Neal I.; Macconaill, Laura E.; Sholl, Lynette M.] Brigham & Womens Hosp, Ctr Adv Mol Diagnost, 75 Francis St, Boston, MA 02115 USA. [Konstantinopoulos, Panagiotis A.; Matulonis, Ursula A.; Liu, Joyce] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA USA. [Berkowitz, Ross S.] Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Biol, Div Gynecol Oncol, 75 Francis St, Boston, MA 02115 USA. [Nucci, Marisa R.; Crum, Christopher P.] Brigham & Womens Hosp, Dept Pathol, Womens & Perinatal Pathol Div, 75 Francis St, Boston, MA 02115 USA. RP Howitt, BE (reprint author), Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. EM bhowitt@partners.org NR 33 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD AUG PY 2016 VL 29 IS 8 BP 893 EP 903 DI 10.1038/modpathol.2016.82 PG 11 WC Pathology SC Pathology GA DS5KR UT WOS:000380821400011 PM 27150160 ER PT J AU Valcz, G Galamb, O Krenacs, T Spisak, S Kalmar, A Patai, AV Wichmann, B Dede, K Tulassay, Z Molnar, B AF Valcz, Gabor Galamb, Orsolya Krenacs, Tibor Spisak, Sandor Kalmar, Alexandra Patai, Arpad V. Wichmann, Barna Dede, Kristof Tulassay, Zsolt Molnar, Bela TI Exosomes in colorectal carcinoma formation: ALIX under the magnifying glass SO MODERN PATHOLOGY LA English DT Article ID CANCER CELL-LINE; MULTIVESICULAR BODY FORMATION; MESSENGER-RNA EXPRESSION; COLON-CANCER; STEM-CELLS; SIGNAL-TRANSDUCTION; GENE-EXPRESSION; PROTEINS; MARKER; STROMA AB Exosomes are small membrane vesicles that have important roles in transporting a great variety of bioactive molecules between epithelial compartment and their microenvironment during tumor formation including colorectal adenoma-carcinoma sequence. We tested the mRNA expression of the top 25 exosome-related markers based on ExoCharta database in healthy (n = 49), adenoma (n = 49) and colorectal carcinoma (n = 49) patients using Affymetrix HGU133 Plus2.0 microarrays. Most related genes showed significantly elevated expression including PGK1, PKM, ANXA5, ENO1, HSP90AB1 and MSN during adenoma-carcinoma sequence. Surprisingly, the expression of ALIX (ALG 2-interacting protein X), involved in multivesicular body (MVB) and exosome formation, was significantly reduced in normal vs adenoma (P = 5.02 x 10(-13)) and in normal vs colorectal carcinoma comparisons (P = 1.51 x 10(-10)). ALIX also showed significant reduction (P < 0.05) at the in situ protein level in the epithelial compartment of adenoma (n = 35) and colorectal carcinoma (n = 37) patients compared with 27 healthy individuals. Furthermore, significantly reduced ALIX protein levels were accompanied by their gradual transition from diffuse cytoplasmic expression to granular signals, which fell into the 0.6-2 mu m diameter size range of MVBs. These ALIX-positive particles were seen in the tumor nests, including tumor-stroma border, which suggest their exosome function. MVB-like structures were also detected in tumor microenvironment including alpha-smooth muscle actin-positive stromal cells, budding off cancer cells in the tumor front as well as in cancer cells entrapped within lymphoid vessels. In conclusion, we determined the top aberrantly expressed exosome-associated markers and revealed the transition of diffuse ALIX protein signals into a MVB-like pattern during adenoma-carcinoma sequence. These tumor-associated particles seen both in the carcinoma and the surrounding microenvironment can potentially mediate epithelial-stromal interactions involved in the regulation of tumor growth, metastatic invasion and therapy response. C1 [Valcz, Gabor; Galamb, Orsolya; Wichmann, Barna; Tulassay, Zsolt; Molnar, Bela] Hungarian Acad Sci, Mol Med Res Unit, Budapest, Hungary. [Krenacs, Tibor] Semmelweis Univ, Dept Pathol & Expt Canc Res 1, Budapest, Hungary. [Krenacs, Tibor] MTA SE Tumor Progress Res Grp, Budapest, Hungary. [Spisak, Sandor] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Kalmar, Alexandra; Patai, Arpad V.; Tulassay, Zsolt; Molnar, Bela] Semmelweis Univ, Dept Internal Med 2, Budapest, Hungary. [Dede, Kristof] Uzsoki Teaching Hosp, Dept Gen Surg & Surg Oncol, Budapest, Hungary. RP Valcz, G (reprint author), Semmelweis Univ, Hungarian Acad Sci, Mol Med Res Unit, Dept Med 2, Szentkiralyi St 46, H-1088 Budapest, Hungary. EM valczg@yahoo.com FU Research and Technology Innovation Fund, Hungary [KMR_12-1-2012-0216]; Hungarian Scientific Research Fund [OTKA-K111743] FX This study was funded by the Research and Technology Innovation Fund, Hungary, KMR_12-1-2012-0216 and Hungarian Scientific Research Fund (OTKA-K111743 grant). We would like to thank to Marcell Szasz for his help in sample collection. We also thank our assistants Gabriella Konyane Farkas (Cell Analysis Laboratory, 2nd Department of Medicine, Semmelweis University) and Zita Bratu (1st Department of Pathology and Experimental Cancer Research, Semmelweis University) for their hard work in this field. We also thank Zoltan Szallasi and Theo deVos for language revision. NR 65 TC 0 Z9 0 U1 3 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD AUG PY 2016 VL 29 IS 8 BP 928 EP 938 DI 10.1038/modpathol.2016.72 PG 11 WC Pathology SC Pathology GA DS5KR UT WOS:000380821400014 PM 27150162 ER PT J AU Qiao, DH Meyer, K Friedl, A AF Qiao, Dianhua Meyer, Kristy Friedl, Andreas TI Glypican 1 Stimulates S Phase Entry and DNA Replication in Human Glioma Cells and Normal Astrocytes (Retraction of vol 33, pg 4408, 2013) SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Correction C1 [Qiao, Dianhua; Meyer, Kristy; Friedl, Andreas] Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI 53706 USA. [Friedl, Andreas] William S Middleton Mem Vet Adm Med Ctr, Pathol & Lab Med Serv, Dept Vet Affairs Med Ctr, 2500 Overlook Terrace, Madison, WI 53705 USA. [Friedl, Andreas] Univ Wisconsin, Carbone Canc Ctr, Madison, WI USA. RP Qiao, DH (reprint author), Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI 53706 USA. NR 1 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD AUG PY 2016 VL 36 IS 15 BP 2105 EP 2105 DI 10.1128/MCB.00321-16 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DS1QL UT WOS:000380371200009 PM 27418536 ER PT J AU Laurenti, M Al Subaie, A Abdallah, MN Cortes, ARG Ackerman, JL Vali, H Basu, K Zhang, YL Murshed, M Strandman, S Zhu, J Makhoul, N Barralet, JE Tamimi, F AF Laurenti, Marco Al Subaie, Ahmed Abdallah, Mohamed-Nur Cortes, Arthur R. G. Ackerman, Jerome L. Vali, Hojatollah Basu, Kaustuv Zhang, Yu Ling Murshed, Monzur Strandman, Satu Zhu, Julian Makhoul, Nicholas Barralet, Jake E. Tamimi, Faleh TI Two-Dimensional Magnesium Phosphate Nanosheets Form Highly Thixotropic Gels That Up-Regulate Bone Formation SO NANO LETTERS LA English DT Article DE 2D nanomaterial; nanocrystalline magnesium phosphate; injectable; biocompatible; bone tissue engineering ID IN-VIVO; AQUEOUS SUSPENSIONS; CALCIUM; HYDROGELS; CLAY; DIFFERENTIATION; OSTEOBLAST; GRAPHENE; REGENERATION; DELIVERY AB Hydrogels composed of two-dimensional (2D) nanomaterials have become an important alternative to replace traditional inorganic scaffolds for tissue engineering. Here, we describe a novel nanocrystalline material with 2D morphology that was synthesized by tuning the crystallization of the sodium-magnesium-phosphate system. We discovered that the sodium ion can regulate the precipitation of magnesium phosphate by interacting with the crystal's surface causing a preferential crystal growth that results in 2D morphology. The 2D nanomaterial gave rise to a physical hydrogel that presented extreme thixotropy, injectability, biocompatibility, bioresorption, and long-term stability. The nanocrystalline material was characterized in vitro and in vivo and we discovered that it presented unique biological properties. Magnesium phosphate nanosheets accelerated bone healing and osseointegration by enhancing collagen formation, osteoblasts differentiation, and osteoclasts proliferation through up-regulation of COL1A1, RunX2, ALP, OCN, and OPN. In summary, the 2D magnesium phosphate nanosheets could bring a paradigm shift in the field of minimally invasive orthopedic and craniofacial interventions because it is the only material available that can be injected through high gauge needles into bone defects in order to accelerate bone healing and osseointegration. C1 [Laurenti, Marco; Al Subaie, Ahmed; Abdallah, Mohamed-Nur; Zhang, Yu Ling; Murshed, Monzur; Makhoul, Nicholas; Barralet, Jake E.; Tamimi, Faleh] McGill Univ, Fac Dent, 3640 Univ St, Montreal, PQ H3A 0C7, Canada. [Vali, Hojatollah; Basu, Kaustuv] McGill Univ, Fac Med, Dept Anat & Cell Biol, 3640 Univ St, Montreal, PQ H3A 0C7, Canada. [Al Subaie, Ahmed] Univ Dammam, Coll Dent, POB 1982, Dammam 31441, Saudi Arabia. [Strandman, Satu; Zhu, Julian] Univ Montreal, Dept Chem, CP 6128,Succursale Ctr Ville, Montreal, PQ H3C 3J7, Canada. [Zhang, Yu Ling; Barralet, Jake E.] McGill Univ, Fac Med, Montreal Gen Hosp, Dept Surg, 1650 Cedar Ave, Montreal, PQ H3G 1A4, Canada. [Cortes, Arthur R. G.; Ackerman, Jerome L.] Massachusetts Gen Hosp, Dept Radiol, Martinos Ctr Biomed Imaging, Biomat Lab, 73 High St, Charlestown, MA 02129 USA. [Cortes, Arthur R. G.; Ackerman, Jerome L.] Harvard Med Sch, 73 High St, Charlestown, MA 02129 USA. RP Barralet, JE; Tamimi, F (reprint author), McGill Univ, Fac Dent, 3640 Univ St, Montreal, PQ H3A 0C7, Canada.; Barralet, JE (reprint author), McGill Univ, Fac Med, Montreal Gen Hosp, Dept Surg, 1650 Cedar Ave, Montreal, PQ H3G 1A4, Canada. EM jake.barralet@mcgill.ca; faleh.tamimimarino@mcgill.ca RI Cortes, Arthur/C-8738-2013; Abdallah, Mohamed-Nur/D-9303-2017; OI Cortes, Arthur/0000-0001-6591-7256; Abdallah, Mohamed-Nur/0000-0003-1179-6270; Barralet, jake/0000-0003-3543-6042; Ackerman, Jerome/0000-0001-5176-7496 FU Canadian Institutes of Health Research Proof of Principle [CIHR PPP-125781]; Canada Research Chair FX We acknowledge the financial support of the Canadian Institutes of Health Research Proof of Principle (CIHR PPP-125781). M.L. and M.N.A. acknowledge the Network for Oral and Bone Health Research (RSBO). A.A.S. acknowledges the University of Dammam and Saudi Arabian Cultural Bureau in Canada. M.N.A. acknowledges the Fonds de recherche du Quebec - Nature et technologies (FRQNT), A.R.G.C. acknowledges the National Council for Scientific and Technological Development (CNPq) Science without Borders in Brazil. F.T. was supported by Canada Research Chair. We kindly acknowledge Dr. S. Komarova and Dr. D. Le Nihouannen for providing mouse-derived bone marrow cells, Dr. C. Doillon for providing the human fibroblast cells, and Mr. A. Golsztajn, Mr. R. Roy, and Ms. L. Harrison for their technical support. NR 63 TC 1 Z9 1 U1 39 U2 58 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1530-6984 EI 1530-6992 J9 NANO LETT JI Nano Lett. PD AUG PY 2016 VL 16 IS 8 BP 4779 EP 4787 DI 10.1021/acs.nanolett.6b00636 PG 9 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 DT2SY UT WOS:000381331900007 PM 27280476 ER PT J AU Yu, B Kang, SY Akthakul, A Ramadurai, N Pilkenton, M Patel, A Nashat, A Anderson, DG Sakamoto, FH Gilchrest, BA Anderson, RR Langer, R AF Yu, Betty Kang, Soo-Young Akthakul, Ariya Ramadurai, Nithin Pilkenton, Morgan Patel, Alpesh Nashat, Amir Anderson, Daniel G. Sakamoto, Fernanda H. Gilchrest, Barbara A. Anderson, R. Rox Langer, Robert TI An elastic second skin SO NATURE MATERIALS LA English DT Article ID MECHANICAL-PROPERTIES; MODEL; ELECTRONICS; PROGRESS; DISEASE; DEVICES; INVIVO AB We report the synthesis and application of an elastic, wearable crosslinked polymer layer (XPL) that mimics the properties of normal, youthful skin. XPL is made of a tunable polysiloxane-based material that can be engineered with specific elasticity, contractility, adhesion, tensile strength and occlusivity. XPL can be topically applied, rapidly curing at the skin interface without the need for heat-or light-mediated activation. In a pilot human study, we examined the performance of a prototype XPL that has a tensile modulus matching normal skin responses at low strain (<40%), and that withstands elongations exceeding 250%, elastically recoiling with minimal strain-energy loss on repeated deformation. The application of XPL to the herniated lower eyelid fat pads of 12 subjects resulted in an average 2-grade decrease in herniation appearance in a 5-point severity scale. The XPL platform may offer advanced solutions to compromised skin barrier function, pharmaceutical delivery and wound dressings. C1 [Yu, Betty; Kang, Soo-Young; Pilkenton, Morgan; Patel, Alpesh] Living Proof Inc, Cambridge, MA 02142 USA. [Akthakul, Ariya; Ramadurai, Nithin; Nashat, Amir] Olivo Labs LLC, Cambridge, MA 02142 USA. [Anderson, Daniel G.; Langer, Robert] MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Anderson, Daniel G.; Anderson, R. Rox; Langer, Robert] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Anderson, Daniel G.; Langer, Robert] MIT, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Anderson, Daniel G.; Langer, Robert] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Sakamoto, Fernanda H.; Anderson, R. Rox] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Sakamoto, Fernanda H.; Gilchrest, Barbara A.; Anderson, R. Rox] Harvard Med Sch, Boston, MA 02114 USA. [Sakamoto, Fernanda H.; Gilchrest, Barbara A.; Anderson, R. Rox] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. RP Langer, R (reprint author), MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Langer, R (reprint author), MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA.; Langer, R (reprint author), MIT, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Langer, R (reprint author), MIT, Dept Chem Engn, Cambridge, MA 02139 USA. EM rlanger@mit.edu NR 32 TC 7 Z9 7 U1 55 U2 73 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1476-1122 EI 1476-4660 J9 NAT MATER JI Nat. Mater. PD AUG PY 2016 VL 15 IS 8 BP 911 EP + DI 10.1038/NMAT4635 PG 10 WC Chemistry, Physical; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Materials Science; Physics GA DS5UV UT WOS:000380849200027 PM 27159017 ER PT J AU Fryer, SL Roach, BJ Wiley, K Loewy, RL Ford, JM Mathalon, DH AF Fryer, Susanna L. Roach, Brian J. Wiley, Katherine Loewy, Rachel L. Ford, Judy M. Mathalon, Daniel H. TI Reduced Amplitude of Low-Frequency Brain Oscillations in the Psychosis Risk Syndrome and Early Illness Schizophrenia SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID RESTING-STATE FMRI; NAIVE 1ST-EPISODE SCHIZOPHRENIA; FUNCTIONAL CONNECTIVITY; INTERRATER RELIABILITY; PREDICTIVE-VALIDITY; PRODROMAL SYNDROMES; CLINICAL RISK; FLUCTUATIONS; MRI; CHILDREN AB Low-frequency oscillations (LFOs) of the blood oxygen level-dependent (BOLD) signal are gaining interest as potential biomarkers sensitive to neuropsychiatric pathology. Schizophrenia has been associated with alterations in intrinsic LFOs that covary with cognitive deficits and symptoms. However, the extent to which LFO dysfunction is present before schizophrenia illness onset remains unknown. Resting-state FMRI data were collected from clinical high-risk (CHR; n = 45) youth, early illness schizophrenia (ESZ; n = 74) patients, and healthy controls (HCs; n = 85) aged 12-35 years. Age-adjusted voxelwise fractional amplitude of low-frequency fluctuations (fALFF; 0.01 - 0.08 Hz) of the BOLD signal was compared among the three groups. Main effects of Group (p<0.005 height threshold, familywise error cluster-level corrected p<0.05) were followed up via Tukey-corrected pairwise comparisons. Significant main effects of Group (p<0.05) revealed decreased fALFF in ESZ and CHR groups relative to HCs, with values in the CHR group falling between those of ESZ and HC groups. These differences were identified primarily in posterior cortex, including temporoparietal regions, extending into occipital and cerebellar lobes. Less LFO activity was related to greater symptom severity in both CHR and ESZ groups in several of these posterior cortical regions. These data support an intermediate phenotype of reduced posterior cortical LFO amplitude in CHR individuals, with resting fALFF values smaller than in HCs but higher than in ESZ patients. Findings indicate that LFO magnitude alterations relate to clinical symptoms and predate psychosis onset but are more pronounced in the early stages of schizophrenia. C1 [Fryer, Susanna L.; Loewy, Rachel L.; Ford, Judy M.; Mathalon, Daniel H.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Fryer, Susanna L.; Roach, Brian J.; Wiley, Katherine; Ford, Judy M.; Mathalon, Daniel H.] San Francisco VA Med Ctr, San Francisco, CA USA. RP Mathalon, DH (reprint author), San Francisco VA Med Ctr, Psychiat Serv 116D, 4150 Clement St, San Francisco, CA 94121 USA. EM daniel.mathalon@ucsf.edu FU [NIMH: MH076989]; [VA: CX001028] FX This research was supported by NIMH: MH076989 (to DH Mathalon) and VA: CX001028 (to SL Fryer). We thank Nicholas Diaz for assistance with manuscript preparation. NR 50 TC 3 Z9 3 U1 8 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 2016 VL 41 IS 9 BP 2388 EP 2398 DI 10.1038/npp.2016.51 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DS1SC UT WOS:000380377300021 PM 27067126 ER PT J AU Eryilmaz, H Tanner, AS Ho, NF Nitenson, AZ Silverstein, NJ Petruzzi, LJ Goff, DC Manoach, DS Roffman, JL AF Eryilmaz, Hamdi Tanner, Alexandra S. Ho, New Fei Nitenson, Adam Z. Silverstein, Noah J. Petruzzi, Liana J. Goff, Donald C. Manoach, Dara S. Roffman, Joshua L. TI Disrupted Working Memory Circuitry in Schizophrenia: Disentangling fMRI Markers of Core Pathology vs Other Aspects of Impaired Performance SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID DORSOLATERAL PREFRONTAL CORTEX; EVENT-RELATED FMRI; FUNCTIONAL CONNECTIVITY; MEDIODORSAL NUCLEUS; DEFAULT NETWORK; ACTIVATION; THALAMUS; DYSFUNCTION; ABNORMALITIES; CINGULATE AB Working memory (WM) impairment, a core feature of schizophrenia, is often associated with aberrant dorsolateral prefrontal cortex (dlPFC) activation. Reduced resting-state connectivity within the frontoparietal control network (FPCN) has also been reported in schizophrenia. However, interpretation of WM-related dlPFC dysfunction has been limited by performance differences between patients and controls, and by uncertainty over the relevance of resting-state connectivity to network engagement during task. We contrasted brain activation in 40 schizophrenia patients and 40 controls during verbal WM performance, and evaluated underlying functional connectivity during rest and task. During correct trials, patients demonstrated normal FPCN activation, despite an inverse relationship between positive symptoms and activation. FPCN activation differed between the groups only during error trials (controls>patients). In contrast, controls demonstrated stronger deactivation of the ventromedial prefrontal cortex (vmPFC) during correct and error trials. Functional connectivity analysis indicated impaired resting-state FPCN connectivity in patients, but normal connectivity during task. However, patients showed abnormal connectivity among regions such as vmPFC, lateral orbitofrontal cortex, and parahippocampal gyrus (PHG) during both rest and task. During task, patients also exhibited altered thalamic connectivity to PHG and FPCN. Activation and connectivity patterns that were more characteristic of controls generally correlated with better performance. In summary, patients demonstrated normal FPCN activation when they remained on-task, and exhibited normal FPCN connectivity during WM, whereas vmPFC deactivation differences persisted regardless of WM performance. Our findings suggest that altered FPCN activation in patients reflects performance difference, and that limbic and thalamic dysfunction is critically involved in WM deficits in schizophrenia. C1 [Eryilmaz, Hamdi; Tanner, Alexandra S.; Ho, New Fei; Nitenson, Adam Z.; Silverstein, Noah J.; Petruzzi, Liana J.; Manoach, Dara S.; Roffman, Joshua L.] Massachusetts Gen Hosp, Dept Psychiat, 149 13th St,Room 2606, Charlestown, MA 02129 USA. [Eryilmaz, Hamdi; Tanner, Alexandra S.; Ho, New Fei; Nitenson, Adam Z.; Silverstein, Noah J.; Petruzzi, Liana J.; Manoach, Dara S.; Roffman, Joshua L.] Harvard Med Sch, 149 13th St,Room 2606, Charlestown, MA 02129 USA. [Goff, Donald C.] NYU, Dept Psychiat, Langone Med Ctr, 550 1St Ave, New York, NY 10016 USA. [Goff, Donald C.] Nathan S Kline Inst Psychiat Res, New York, NY USA. RP Eryilmaz, H (reprint author), Massachusetts Gen Hosp, Dept Psychiat, 149 13th St,Room 2606, Charlestown, MA 02129 USA.; Eryilmaz, H (reprint author), Harvard Med Sch, 149 13th St,Room 2606, Charlestown, MA 02129 USA. EM hamdi.eryilmaz@mgh.harvard.edu FU NIH [K23MH084059, R01MH101425, 1S10RR023043, 1S10RR023401]; HHMI (Physician-Scientist Early Career Award); Pamlab FX This work was supported by NIH (K23MH084059, R01MH101425, 1S10RR023043, and 1S10RR023401), HHMI (Physician-Scientist Early Career Award), and Pamlab. JLR has previously received grant support and consulting fees from Pamlab. The remaining authors declare no conflict of interest. NR 50 TC 3 Z9 3 U1 4 U2 4 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 2016 VL 41 IS 9 BP 2411 EP 2420 DI 10.1038/npp.2016.55 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DS1SC UT WOS:000380377300023 PM 27103065 ER PT J AU Xu, Q Wu, X Li, M Huang, H Minica, C Yi, Z Wang, G Shen, L Xing, Q Shi, Y He, L Qin, S AF Xu, Q. Wu, X. Li, M. Huang, H. Minica, C. Yi, Z. Wang, G. Shen, L. Xing, Q. Shi, Y. He, L. Qin, S. TI Association studies of genomic variants with treatment response to risperidone, clozapine, quetiapine and chlorpromazine in the Chinese Han population SO PHARMACOGENOMICS JOURNAL LA English DT Article ID O-METHYLTRANSFERASE COMT; VAL(108/158) MET GENOTYPE; THERAPEUTIC RESPONSE; GENE POLYMORPHISMS; 1ST-EPISODE SCHIZOPHRENIA; ANTIPSYCHOTIC MEDICATION; VAL108/158MET GENOTYPE; OLANZAPINE TREATMENT; CLINICAL-RESPONSE; WIDE ASSOCIATION AB Schizophrenia is a widespread mental disease with a prevalence of about 1% in the world population. Continuous long-term treatment is required to maintain social functioning and prevent symptom relapse of schizophrenia patients. However, there are considerable individual differences in response to the antipsychotic drugs. There is a pressing need to identify more drug-response-related markers. But most pharmacogenomics of schizophrenia have typically focused on a few candidate genes in small sample size. In this study, 995 subjects were selected for discovering the drug-response-related markers. A total of 77 single-nucleotide polymorphisms of 25 genes have been investigated for four commonly used antipsychotic drugs in China: risperidone, clozapine, quetiapine, and chlorpromazine. Significant associations with treatment response for several genes, such as CYP2D6, CYP2C19, COMT, ABCB1, DRD3 and HTR2C have been verified in our study. Also, we found several new candidate genes (TNIK, RELN, NOTCH4 and SLC6A2) and combinations (haplotype rs1544325-rs5993883-rs6269-rs4818 in COMT) that are associated with treatment response to the four drugs. Also, multivariate interactions analysis demonstrated the combination of rs6269 in COMT and rs3813929 in HTR2C may work as a predictor to improve the clinical antipsychotic response. So our study is of great significance to improve current knowledge on the pharmacogenomics of schizophrenia, thus promoting the implementation of personalized medicine in schizophrenia. C1 [Xu, Q.; Wu, X.; Li, M.; Shen, L.; Shi, Y.; He, L.; Qin, S.] Shanghai Jiao Tong Univ, Bio X Inst, Key Lab Genet Dev & Neuropsychiat Disorders, Minist Educ, Little White House Bldg 1954 Hua Shan Rd, Shanghai 200030, Peoples R China. [Huang, H.; Qin, S.] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA USA. [Huang, H.; Qin, S.] Harvard Med Sch, Boston, MA USA. [Huang, H.; Qin, S.] Broad Inst Harvard & MIT, Cambridge, MA USA. [Minica, C.] Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands. [Yi, Z.] Shanghai Inst Mental Hlth, Shanghai, Peoples R China. [Wang, G.] Nanjing Med Univ, Affiliated Wuxi Mental Hlth Ctr, Wuxi, Peoples R China. [Xing, Q.; He, L.] Fudan Univ, Inst Biomed Sci, Shanghai, Peoples R China. [He, L.; Qin, S.] Shanghai Key Lab Psychot Disorders, Shanghai, Peoples R China. RP Qin, S (reprint author), Shanghai Jiao Tong Univ, Bio X Inst, Key Lab Genet Dev & Neuropsychiat Disorders, Minist Educ, Little White House Bldg 1954 Hua Shan Rd, Shanghai 200030, Peoples R China. EM chinsir@sjtu.edu.cn FU 863 Program [2012AA02A515, 2012AA021802]; 973 Program [2010CB529600]; National Key Technology RD Program [2012BAI01B09]; National Nature Science Foundation of China [81121001, 81273596, J1210047, 30900799, 30972823, 81171272]; Public Science and Technology Research Funds [201210056]; Shanghai Jiaotong University Interdisciplinary Research fund; Shanghai Leading Academic Discipline Project [B205] FX This work was supported by grants from the 863 Program (2012AA02A515, 2012AA021802), the 973 Program (2010CB529600), the National Key Technology R&D Program (2012BAI01B09), the National Nature Science Foundation of China (81121001, 81273596, J1210047, 30900799, 30972823, 81171272), Public Science and Technology Research Funds (201210056), the Shanghai Jiaotong University Interdisciplinary Research fund and the Shanghai Leading Academic Discipline Project (B205). NR 83 TC 1 Z9 1 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1470-269X EI 1473-1150 J9 PHARMACOGENOMICS J JI Pharmacogenomics J. PD AUG PY 2016 VL 16 IS 4 BP 357 EP 365 DI 10.1038/tpj.2015.61 PG 9 WC Genetics & Heredity; Pharmacology & Pharmacy SC Genetics & Heredity; Pharmacology & Pharmacy GA DS4SW UT WOS:000380772700009 PM 26282453 ER PT J AU Blonstein, AC Lv, N Camargo, CA Wilson, SR Buist, AS Rosas, LG Strub, P Ma, J AF Blonstein, Andrea C. Lv, Nan Camargo, Carlos A., Jr. Wilson, Sandra R. Buist, A. Sonia Rosas, Lisa G. Strub, Peg Ma, Jun TI Acceptability and feasibility of the 'DASH for Asthma' intervention in a randomized controlled trial pilot study SO PUBLIC HEALTH NUTRITION LA English DT Article DE DASH diet; Behaviour change; Randomized controlled trial; Social Cognitive Theory; Asthma ID SOCIAL COGNITIVE THEORY; QUALITATIVE CONTENT-ANALYSIS; LIFE-STYLE MODIFICATION; BLOOD-PRESSURE; SELF-EFFICACY; WEIGHT-LOSS; OUTCOME EXPECTATIONS; MEDITERRANEAN DIET; BEHAVIOR-CHANGE; ADHERENCE AB Objective: 'DASH for Asthma' (n 90) was a 6-month randomized controlled trial that demonstrated potential benefits of a DASH (Dietary Approaches to Stop Hypertension) behavioural intervention for improving diet quality and asthma control by comparing intervention to usual care in adults with uncontrolled asthma. The present study examined acceptability and feasibility of the intervention from the perspective of intervention participants and lifestyle coaches. Design: Grounded in Social Cognitive Theory, the 3-month intensive stage, including three individual and eight group sessions, focused on diet modifications and behavioural self-regulation. The 3-month maintenance stage contained telephone consultations. Participants and lifestyle coaches completed surveys including 5-point Likert scales and open-ended questions. We analysed data using descriptive and inductive content analyses. Subjects: Forty-six intervention participants (survey response rate was 65-72 %) and two lifestyle coaches. Results: Participants and lifestyle coaches were highly satisfied (all mean ratings >4) with individual and group sessions. Participants identified mastery of knowledge and skills (awareness, goal setting, self-monitoring, problem solving), social learning (class members sharing experiences and ideas) and good coaching skills (reflective listening, empathy, motivational counselling) as important contributors to self-efficacy and programme satisfaction. Participants also valued personalized feedback received in individual sessions. Lifestyle coaches viewed participant engagement as a facilitator to effective sessions. Finally, participants and lifestyle coaches identified food tasting as beneficial for observational learning and facilitation of participant engagement. High class attendance and self-monitoring rate also reflected the high engagement among participants. Conclusions: The DASH behavioural intervention was feasible and highly acceptable to participants with uncontrolled asthma and lifestyle coaches. C1 [Blonstein, Andrea C.; Lv, Nan; Wilson, Sandra R.; Rosas, Lisa G.; Ma, Jun] Palo Alto Med Fdn, Res Inst, Palo Alto, CA 94301 USA. [Camargo, Carlos A., Jr.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA USA. [Wilson, Sandra R.; Rosas, Lisa G.; Ma, Jun] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. [Buist, A. Sonia] Oregon Hlth & Sci Univ, Pulm Crit & Care Med, Portland, OR 97201 USA. [Strub, Peg] San Francisco Med Ctr, Permanente Med Grp, Dept Allergy Asthma & Immunol, San Francisco, CA USA. [Ma, Jun] Univ Illinois, Sch Publ Hlth, Dept Hlth Policy & Adm, Chicago, IL 60607 USA. RP Ma, J (reprint author), Palo Alto Med Fdn, Res Inst, Palo Alto, CA 94301 USA.; Ma, J (reprint author), Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA.; Ma, J (reprint author), Univ Illinois, Sch Publ Hlth, Dept Hlth Policy & Adm, Chicago, IL 60607 USA. EM maj2015@uic.edu FU National Heart, Lung, and Blood Institute [R34 HL108753]; Palo Alto Medical Foundation Research Institute FX This research was supported by the National Heart, Lung, and Blood Institute (grant number R34 HL108753) and internal funding from the Palo Alto Medical Foundation Research Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute. No sponsor or funding source had a role in the design or conduct of the study; collection, management, analysis or interpretation of the data; or preparation, review or approval of the manuscript. NR 42 TC 0 Z9 0 U1 7 U2 9 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 1368-9800 EI 1475-2727 J9 PUBLIC HEALTH NUTR JI Public Health Nutr. PD AUG PY 2016 VL 19 IS 11 BP 2049 EP 2059 DI 10.1017/S136898001500350X PG 11 WC Public, Environmental & Occupational Health; Nutrition & Dietetics SC Public, Environmental & Occupational Health; Nutrition & Dietetics GA DS6MY UT WOS:000380897300015 PM 26653101 ER PT J AU Ikeda, K Liu, XW Kida, K Marutani, E Hirai, S Sakaguchi, M Andersen, LW Bagchi, A Cocchi, MN Berg, KM Ichinose, F Donnino, MW AF Ikeda, Kohei Liu, Xiaowen Kida, Kotaro Marutani, Eizo Hirai, Shuichi Sakaguchi, Masahiro Andersen, Lars W. Bagchi, Aranya Cocchi, Michael N. Berg, Katherine M. Ichinose, Fumito Donnino, Michael W. TI Thiamine as a neuroprotective agent after cardiac arrest SO RESUSCITATION LA English DT Article DE Cardiopulmonary resuscitation; Heart arrest; Neurological function; Mitochondria; Thiamine; Pyruvate dehydrogenase ID PYRUVATE-DEHYDROGENASE COMPLEX; MICROPLATE-BASED ACTIVITY; FOREBRAIN ISCHEMIA; OXIDATIVE STRESS; BLOOD-FLOW; RESUSCITATION; BRAIN; MITOCHONDRIA; DEATH; IMMUNOCAPTURE AB Aims: Reduction of pyruvate dehydrogenase (PDH) activity in the brain is associated with neurological deficits in animals resuscitated from cardiac arrest. Thiamine is an essential co-factor of PDH. The objective of this study was to examine whether administration of thiamine improves outcomes after cardiac arrest in mice. Secondarily, we aimed to characterize the impact of cardiac arrest on PDH activity in mice and humans. Methods: Animal study: Adult mice were subjected to cardiac arrest whereupon cardiopulmonary resuscitation was performed. Thiamine or vehicle was administered 2 min before resuscitation and daily thereafter. Mortality, neurological outcome, and metabolic markers were evaluated. Human study: In a convenience sample of post-cardiac arrest patients, we measured serial PDH activity from peripheral blood mononuclear cells and compared them to healthy controls. Results: Animal study: Mice treated with thiamine had increased 10-day survival (48% versus 17%,P< 0.01) and improved neurological function when compared to vehicle-treated mice. In addition, thiamine markedly improved histological brain injury compared to vehicle. The beneficial effects of thiamine were accompanied by improved oxygen consumption in mitochondria, restored thiamine pyrophosphate levels, and increased PDH activity in the brain at 10 days. Human study: Post-cardiac arrest patients had lower PDH activity in mononuclear cells than did healthy volunteers (estimated difference: -5.8 O.D./min/mg protein, P < 0.001). Conclusions: The provision of thiamine after cardiac arrest improved neurological outcome and 10-day survival in mice. PDH activity was markedly depressed in post-cardiac arrest patients suggesting that this pathway may represent a therapeutic target. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Ikeda, Kohei; Kida, Kotaro; Marutani, Eizo; Hirai, Shuichi; Sakaguchi, Masahiro; Bagchi, Aranya; Ichinose, Fumito] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Anesthesia Ctr Crit Care Res, Boston, MA 02114 USA. [Liu, Xiaowen; Andersen, Lars W.; Cocchi, Michael N.; Berg, Katherine M.; Donnino, Michael W.] Beth Israel Deaconess Med Ctr, Dept Emergency Med, Ctr Resuscitat Sci, 330 Brookline Ave W CC2, Boston, MA 02215 USA. [Andersen, Lars W.] Aarhus Univ Hosp, Dept Anaesthesiol, Aarhus, Denmark. [Andersen, Lars W.] Aarhus Univ Hosp, Res Ctr Emergency Med, Aarhus, Denmark. [Cocchi, Michael N.] Beth Israel Deaconess Med Ctr, Dept Anesthesia Crit Care, Boston, MA 02215 USA. [Berg, Katherine M.; Donnino, Michael W.] Beth Israel Deaconess Med Ctr, Div Pulm & Crit Care, Dept Med, Boston, MA 02215 USA. RP Donnino, MW (reprint author), Beth Israel Deaconess Med Ctr, Dept Emergency Med, Ctr Resuscitat Sci, 330 Brookline Ave W CC2, Boston, MA 02215 USA.; Ichinose, F (reprint author), Massachusetts Gen Hosp, Anesthesia Ctr Crit Care Res, Dept Anesthesia Crit Care & Pain Med, 149 13th St,CNY 149,Room 4315, Charlestown, MA 02129 USA. EM fichinose@mgh.harvard.edu; mdonnino@bidmc.harvard.edu OI IKEDA, KOHEI/0000-0002-0961-1532; Marutani, Eizo/0000-0001-7031-7386; Andersen, Lars Wiuff/0000-0001-5752-8082 FU NIH [HL101930, HL107447] FX This work was supported by NIH R01 grant HL101930 (FI) and NIH K02 grant HL107447 (MWD). NR 27 TC 1 Z9 1 U1 3 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0300-9572 J9 RESUSCITATION JI Resuscitation PD AUG PY 2016 VL 105 BP 138 EP 144 DI 10.1016/j.resuscitation.2016.04.024 PG 7 WC Critical Care Medicine; Emergency Medicine SC General & Internal Medicine; Emergency Medicine GA DT7DS UT WOS:000381647900037 PM 27185216 ER PT J AU Weber, D McCarthy, D Pathmanathan, J AF Weber, Daniel McCarthy, David Pathmanathan, Jay TI An effective automated method for teaching EEG interpretation to neurology residents SO SEIZURE-EUROPEAN JOURNAL OF EPILEPSY LA English DT Article DE Education; EEG; Residency ID EDUCATION; MISDIAGNOSIS; INSTRUCTION; EPILEPSY AB Purpose: EEG interpretation is a fundamental procedural skill in the practice of neurology, but there is no standardized method for educating residents. One-to-one instruction is commonly employed, but is time intensive for supervising physicians, provides arbitrary exposure to normal and abnormal EEG patterns, and often lacks immediate and detailed feedback on performance. Here, we investigated the effectiveness of a novel automated program to assist in educating neurology residents in EEG interpretation. Methods: An EEG teaching program was developed to provide neurology residents EEG training less dependent on attending supervision. Residents enter interpretations of full-length pre-selected EEGs and receive immediate feedback based on consensus interpretation of supervising epileptologists. Resident learning was assessed based on performance on matched pre- and post-tests covering common EEG findings including artifacts, normal variants, and abnormalities. Results: Twenty residents were included in this analysis: 12 post-graduate year (PGY) 3 and eight PGY 4 neurology residents. All residents showed improvement, from a mean score of 42.7% (95% CI 36.9-48.5%) on the pre-test to 75.4% (95% CI 70.7-80.2%) on the post-test (p < 0.001). No significant difference was noted between the classes. Residents reported taking 16-30 h to complete this teaching module spread over a 3-week rotation. Conclusion: This pilot study demonstrated the effectiveness of an automated EEG teaching program used by neurology residents in training. This tool could serve as an effective method of supplementing resident education. (C) 2016 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. C1 [Weber, Daniel; McCarthy, David; Pathmanathan, Jay] VABHS, Boston, MA USA. [Weber, Daniel] Univ Massachusetts, Worcester, MA 01605 USA. [McCarthy, David] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [McCarthy, David; Pathmanathan, Jay] Harvard Med Sch, Boston, MA USA. [Pathmanathan, Jay] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Weber, D (reprint author), 55 Lake Ave North, Worcester, MA 01655 USA. EM daniel.weber@umassmemorial.org; david.mccarthy@va.gov; jay.pathmanathan@va.gov NR 7 TC 0 Z9 0 U1 1 U2 1 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 1059-1311 EI 1532-2688 J9 SEIZURE-EUR J EPILEP JI Seizure PD AUG PY 2016 VL 40 BP 10 EP 12 DI 10.1016/j.seizure.2016.05.009 PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DT7FY UT WOS:000381653700003 PM 27295562 ER PT J AU Hotan, GC Struck, AF Bianchi, MT Eskandar, EN Cole, AJ Westover, MB AF Hotan, G. C. Struck, A. F. Bianchi, M. T. Eskandar, E. N. Cole, A. J. Westover, M. B. TI Decision analysis of intracranial monitoring in non-lesional epilepsy SO SEIZURE-EUROPEAN JOURNAL OF EPILEPSY LA English DT Article DE Epilepsy Surgery; Decision Analysis; Non-lesional Epilepsy; Intracranial EEG ID TEMPORAL-LOBE EPILEPSY; SUBDURAL GRID ELECTRODES; VAGUS-NERVE-STIMULATION; PARTIAL-ONSET SEIZURES; QUALITY-OF-LIFE; REFRACTORY EPILEPSY; SURGERY PROCEDURES; CONTROLLED-TRIAL; PRESURGICAL EVALUATION; CLINICAL ARTICLE AB Purpose: Up to one third of epilepsy patients develop pharmacoresistant seizures and many benefit from resective surgery. However, patients with non-lesional focal epilepsy often require intracranial monitoring to localize the seizure focus. Intracranial monitoring carries operative morbidity risk and does not always succeed in localizing the seizures, making the benefit of this approach less certain. We performed a decision analysis comparing three strategies for patients with non-lesional focal epilepsy: (1) intracranial monitoring, (2) vagal nerve stimulator (VNS) implantation and (3) medical management to determine which strategy maximizes the expected quality-adjusted life years (QALYs) for our base cases. Method: We constructed two base cases using parameters reported in the medical literature: (1) a young, otherwise healthy patient and (2) an elderly, otherwise healthy patient. We constructed a decision tree comprising strategies for the treatment of non-lesional epilepsy and two clinical outcomes: seizure freedom and no seizure freedom. Sensitivity analyses of probabilities at each branch were guided by data from the medical literature to define decision thresholds across plausible parameter ranges. Results: Intracranial monitoring maximizes the expected QALYs for both base cases. The sensitivity analyses provide estimates of the values of key variables, such as the surgical risk or the chance of localizing the focus, at which intracranial monitoring is no longer favored. Conclusion: Intracranial monitoring is favored over VNS and medical management in young and elderly patients over a wide, clinically-relevant range of pertinent model variables such as the chance of localizing the seizure focus and the surgical morbidity rate. (C) 2016 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. C1 [Hotan, G. C.] MIT, Dept Brain & Cognit Sci, E25-618, Cambridge, MA 02139 USA. [Struck, A. F.; Bianchi, M. T.; Cole, A. J.; Westover, M. B.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Eskandar, E. N.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. RP Struck, AF (reprint author), Fruit St Wang 7, Boston, MA 02114 USA. EM astruck@mgh.harvard.edu FU Center for Integration of Medicine and Innovative Technology; Milton Family Foundation; DARPA; NIH-NINDS [K23 NS090900]; Rappaport Foundation; Andrew David Heitman Neuroendovascular Research Fund; [NINDSR01NS086422] FX Gladia Hotan has no relevant disclosures. Dr. Struck has no relevant disclosures. Dr. Bianchi receives funding from the Center for Integration of Medicine and Innovative Technology and the Milton Family Foundation. Dr. Eskandar is supported by grants from DARPA and NINDSR01NS086422. Dr. Cole has no relevant disclosures. Dr. Westover receives funding from NIH-NINDS (K23 NS090900), the Rappaport Foundation, and the Andrew David Heitman Neuroendovascular Research Fund (MBW). NR 56 TC 1 Z9 1 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 1059-1311 EI 1532-2688 J9 SEIZURE-EUR J EPILEP JI Seizure PD AUG PY 2016 VL 40 BP 59 EP 70 DI 10.1016/j.seizure.2016.06.010 PG 12 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DT7FY UT WOS:000381653700013 PM 27348062 ER PT J AU Thordardottir, EB Hansdottir, I Valdimarsdottir, UA Shipherd, JC Resnick, H Gudmundsdottir, B AF Thordardottir, Edda Bjork Hansdottir, Ingunn Valdimarsdottir, Unnur Anna Shipherd, Jillian C. Resnick, Heidi Gudmundsdottir, Berglind TI The Manifestations of Sleep Disturbances 16 Years Post-Trauma SO SLEEP LA English DT Article DE trauma; sleep; posttraumatic stress; development; children ID STRESS-DISORDER; QUALITY INDEX; TRAUMA; SURVIVORS; PTSD; SCALE; REM AB Study Objectives: Limited data exist on the association between trauma and sleep across developmental stages, particularly trauma experienced in childhood and sleep in adulthood. We assessed sleep quality across the developmental spectrum among avalanche survivors 16 years after exposure as compared to a matched comparison cohort. Methods: Participants were survivors of two avalanche-affected towns (n = 286) and inhabitants of non-exposed towns (n = 357). Symptoms were assessed with respect to the survivors' developmental stage at the time of the disaster: childhood (2-12), adolescence (13-19), young adult (20-39), and adult (= 40). The Posttraumatic Diagnostic Scale, Pittsburgh Sleep Quality Index and Pittsburgh Sleep Quality Index PTSD Addendum were used. Results: Overall PTSD symptoms were not associated with avalanche exposure in any age groups under study. However, survivors who were children at the time of the disaster were 2.58 times (95% CI 1.33-5.01) more likely to have PTSD-related sleep disturbances (PSQI-A score = 4) in adulthood than their non-exposed peers, especially symptoms of acting out dreams (aRR = 3.54; 95% CI 1.15-10.87). Those who were adults at time of the exposure had increased risk of trauma-related nightmares (aRR = 2.69; 95% CI 1.07-6.79 for young adults aRR = 3.07; 95% CI 1.51-6.24 for adults) compared to their non-exposed peers. Conclusions: Our data indicate a chronicity of PTSD-related sleep disturbances, particularly among childhood trauma survivors. REM sleep disturbances may have different manifestations depending on the developmental stage at the time of trauma exposure. C1 [Thordardottir, Edda Bjork; Valdimarsdottir, Unnur Anna] Univ Iceland, Sch Hlth Sci, Fac Med, Ctr Publ Hlth Sci, Reykjavik, Iceland. [Hansdottir, Ingunn] Univ Iceland, Sch Hlth Sci, Fac Psychol, Reykjavik, Iceland. [Valdimarsdottir, Unnur Anna] Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Valdimarsdottir, Unnur Anna] Karolinska Inst, Dept Med Epidemiol & Biostat, Solna, Sweden. [Shipherd, Jillian C.] VA Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA USA. [Shipherd, Jillian C.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Resnick, Heidi] Med Univ South Carolina, Dept Psychiat & Behav Sci, Charleston, SC USA. [Gudmundsdottir, Berglind] Natl Univ Hosp Iceland, Mental Hlth Serv, Reykjavik, Iceland. [Gudmundsdottir, Berglind] Univ Iceland, Sch Hlth Sci, Fac Med, Reykjavik, Iceland. RP Thordardottir, EB (reprint author), Univ Iceland, Ctr Publ Hlth Sci, IS-101 Reykjavik, Iceland. EM eddat@hi.is FU University of Iceland Research Fund; Icelandic Research Fund for Graduate Students (Rannis); Landspitali University Hospital Research Fund; Nordic Centre of Excellence for Resilience and Societal Security (NORDRESS) - Nordic Societal Security Programme FX This was not an industry supported study. This study was funded by the University of Iceland Research Fund, the Icelandic Research Fund for Graduate Students (Rannis), the Landspitali University Hospital Research Fund, and the Nordic Centre of Excellence for Resilience and Societal Security (NORDRESS), which is funded by the Nordic Societal Security Programme. The authors have indicated no financial conflicts of interest. NR 18 TC 1 Z9 1 U1 5 U2 9 PU AMER ACAD SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CTR, STE 920, WESTCHESTER, IL 60154 USA SN 0161-8105 EI 1550-9109 J9 SLEEP JI Sleep PD AUG 1 PY 2016 VL 39 IS 8 BP 1551 EP 1554 DI 10.5665/sleep.6018 PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DT8NF UT WOS:000381746800010 PM 27166232 ER PT J AU Shaw, ND McHill, AW Schiavon, M Kangarloo, T Mankowski, PW Cobelli, C Klerman, EB Hall, JE AF Shaw, Natalie D. McHill, Andrew W. Schiavon, Michele Kangarloo, Tairmae Mankowski, Piotr W. Cobelli, Claudio Klerman, Elizabeth B. Hall, Janet E. TI Effect of Slow Wave Sleep Disruption on Metabolic Parameters in Adolescents SO SLEEP LA English DT Article DE glucose; insulin; puberty; slow wave sleep ID BETA-CELL FUNCTION; EYE-MOVEMENT SLEEP; INSULIN-RESISTANCE; GLUCOSE-TOLERANCE; OBESE ADOLESCENTS; APNEA SYNDROME; CHILDREN; DURATION; ARCHITECTURE; ASSOCIATION AB Study Objectives: Cross-sectional studies report a correlation between slow wave sleep (SWS) duration and insulin sensitivity (SI) in children and adults. Suppression of SWS causes insulin resistance in adults but effects in children are unknown. This study was designed to determine the effect of SWS fragmentation on SI in children. Methods: Fourteen pubertal children (11.3-14.1 y, body mass index 29th to 97th percentile) were randomized to sleep studies and mixed meal (MM) tolerance tests with and without SWS disruption. Beta-cell responsiveness (F) and SI were determined using oral minimal modeling. Results: During the disruption night, auditory stimuli (68.1 +/- 10.7/night; mean +/- standard error) decreased SWS by 40.0 +/- 8.0%. SWS fragmentation did not affect fasting glucose (non-disrupted 76.9 +/- 2.3 versus disrupted 80.6 +/- 2.1 mg/dL), insulin (9.2 +/- 1.6 versus 10.4 +/- 2.0 mu IU/mL), or C-peptide (1.9 +/- 0.2 versus 1.9 +/- 0.1 ng/mL) levels and did not impair SI (12.9 +/- 2.3 versus 10.1 +/- 1.6 10(-4) dL/kg/min per mu IU/mL) or Phi (73.4 +/- 7.8 versus 74.4 +/- 8.4 10(-9) min(-1)) to a MM challenge. Only the subjects in the most insulin-sensitive tertile demonstrated a consistent decrease in SI after SWS disruption. Conclusion: Pubertal children across a range of body mass indices may be resistant to the adverse metabolic effects of acute SWS disruption. Only those subjects with high SI (i.e., having the greatest "metabolic reserve") demonstrated a consistent decrease in SI. These results suggest that adolescents may have a unique ability to adapt to metabolic stressors, such as acute SWS disruption, to maintain euglycemia. Additional studies are necessary to confirm that this resiliency is maintained in settings of chronic SWS disruption. C1 [Shaw, Natalie D.; Kangarloo, Tairmae; Hall, Janet E.] Massachusetts Gen Hosp, Dept Med, Reprod Endocrine Unit, Boston, MA 02114 USA. [Shaw, Natalie D.; Hall, Janet E.] NIEHS, Clin Res Branch, POB 12233, Res Triangle Pk, NC 27709 USA. [McHill, Andrew W.; Mankowski, Piotr W.; Klerman, Elizabeth B.] Brigham & Womens Hosp, Div Sleep & Circadian Disorders, 75 Francis St, Boston, MA 02115 USA. [McHill, Andrew W.; Mankowski, Piotr W.; Klerman, Elizabeth B.] Harvard Med Sch, Div Sleep Med, Boston, MA USA. [Schiavon, Michele; Cobelli, Claudio] Univ Padua, Dept Informat Engn, Padua, Italy. RP Shaw, ND (reprint author), NIEHS, Bldg 101,A349,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM natalie.shaw@nih.gov OI Shaw, Natalie/0000-0002-0847-9170; Hall, Janet/0000-0003-4644-3061 FU NIH [K23HD073304-02, T32HL007901, K24HL105664, R01HL114088, R01GM105018, P01AG009975, R21HD086392, NSBRI HFP02802, HFP04201, R01 DK-78646, R01 DK-82396]; NIH (National Institute of Diabetes and Digestive Diseases [NIDDK]-Boston Area Diabetes Endocrinology Research Center Pilot Research Grant Award); Pediatric Endocrine Society; Harvard Catalyst (The Harvard Clinical and Translational Science Center) [1UL1TR001102-01]; Harvard University; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [NIEHS] (Lasker Clinical Research Scholar Award) [1SI2ES025429-01]; Marathon Pharmaceuticals FX This was not an industry supported study. Dr. Shaw received support from the NIH (K23HD073304-02 and the National Institute of Diabetes and Digestive Diseases [NIDDK]-sponsored Boston Area Diabetes Endocrinology Research Center Pilot Research Grant Award), the Pediatric Endocrine Society, and Harvard Catalyst (The Harvard Clinical and Translational Science Center [Award #1UL1TR001102-01] 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, the National Center for Research Resources or the National Institutes of Health). Drs. McHill, Klerman, and Cobelli are funded by the NIH (T32HL007901; K24HL105664, R01HL114088, R01GM105018, P01AG009975, R21HD086392, NSBRI HFP02802, HFP04201; and R01 DK-78646 and R01 DK-82396, respectively). This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [NIEHS] (1SI2ES025429-01, Lasker Clinical Research Scholar Award to Dr. Shaw). Dr. Hall has received research support from Marathon Pharmaceuticals. Dr. Vienne has consulted for Celgene International Sarl. The other authors have indicated no financial conflicts of interest. Clinical studies were conducted in the Clinical Research Unit at Massachusetts General Hospital, Boston, MA. Analyses were performed at NIEHS, Brigham and Women's Hospital, and the University of Padova. This study does not meet the FDAAA 801 definition of an "applicable clinical trial" and as such was not registered at clinicaltrials.gov. NR 51 TC 2 Z9 2 U1 3 U2 3 PU AMER ACAD SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CTR, STE 920, WESTCHESTER, IL 60154 USA SN 0161-8105 EI 1550-9109 J9 SLEEP JI Sleep PD AUG 1 PY 2016 VL 39 IS 8 BP 1591 EP 1599 DI 10.5665/sleep.6028 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DT8NF UT WOS:000381746800015 PM 27166229 ER PT J AU Lima, FO Silva, GS Furie, KL Frankel, MR Lev, MH Camargo, ECS Haussen, DC Singhal, AB Koroshetz, WJ Smith, WS Nogueira, RG AF Lima, Fabricio O. Silva, Gisele S. Furie, Karen L. Frankel, Michael R. Lev, Michael H. Camargo, Erica C. S. Haussen, Diogo C. Singhal, Aneesh B. Koroshetz, Walter J. Smith, Wade S. Nogueira, Raul G. TI Field Assessment Stroke Triage for Emergency Destination A Simple and Accurate Prehospital Scale to Detect Large Vessel Occlusion Strokes SO STROKE LA English DT Article DE cerebrovascular occlusion; scale; stroke, acute, prehospital emergency care; triage ID ACUTE ISCHEMIC-STROKE; SEVERITY SCALE; THROMBECTOMY; ANGIOGRAPHY; VALIDATION; DESIGN; SCORE; TIME AB Background and Purpose-Patients with large vessel occlusion strokes (LVOS) may be better served by direct transfer to endovascular capable centers avoiding hazardous delays between primary and comprehensive stroke centers. However, accurate stroke field triage remains challenging. We aimed to develop a simple field scale to identify LVOS. Methods-The Field Assessment Stroke Triage for Emergency Destination (FAST-ED) scale was based on items of the National Institutes of Health Stroke Scale (NIHSS) with higher predictive value for LVOS and tested in the Screening Technology and Outcomes Project in Stroke (STOPStroke) cohort, in which patients underwent computed tomographic angiography within the first 24 hours of stroke onset. LVOS were defined by total occlusions involving the intracranial internal carotid artery, middle cerebral artery-M1, middle cerebral artery-2, or basilar arteries. Patients with partial, bihemispheric, and anterior+posterior circulation occlusions were excluded. Receiver operating characteristic curve, sensitivity, specificity, positive predictive value, and negative predictive value of FAST-ED were compared with the NIHSS, Rapid Arterial Occlusion Evaluation (RACE) scale, and Cincinnati Prehospital Stroke Severity (CPSS) scale. Results-LVO was detected in 240 of the 727 qualifying patients (33%). FAST-ED had comparable accuracy to predict LVO to the NIHSS and higher accuracy than RACE and CPSS (area under the receiver operating characteristic curve: FAST-ED=0.81 as reference; NIHSS=0.80, P=0.28; RACE=0.77, P=0.02; and CPSS=0.75, P=0.002). A FAST-ED >= 4 had sensitivity of 0.60, specificity of 0.89, positive predictive value of 0.72, and negative predictive value of 0.82 versus RACE >= 5 of 0.55, 0.87, 0.68, and 0.79, and CPSS >= 2 of 0.56, 0.85, 0.65, and 0.78, respectively. Conclusions-FAST-ED is a simple scale that if successfully validated in the field, it may be used by medical emergency professionals to identify LVOS in the prehospital setting enabling rapid triage of patients. C1 [Lima, Fabricio O.] Univ Fortaleza, Ctr Ciencias Saude, Curso Med, Fortaleza, CE, Brazil. [Silva, Gisele S.] Univ Fed Sao Paulo, Dept Neurol, Neurovasc Serv, Sao Paulo, SP, Brazil. [Furie, Karen L.] Brown Univ, Dept Neurol, Providence, RI USA. [Frankel, Michael R.; Haussen, Diogo C.; Nogueira, Raul G.] Emory Univ, Sch Med, Grady Mem Hosp, Marcus Stroke & Neurosci Ctr,Neuroendovasc & Neur, Atlanta, GA USA. [Lev, Michael H.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Camargo, Erica C. S.; Singhal, Aneesh B.] Massachusetts Gen Hosp, Dept Neurol, Stroke Serv, Boston, MA USA. [Koroshetz, Walter J.] NINDS, NIH, Bethesda, MD USA. [Smith, Wade S.] Univ Calif San Francisco, Dept Neurol, Neurovasc Serv, San Francisco, CA USA. RP Nogueira, RG (reprint author), 49 Jesse Hill Dr,SE Room 333, Atlanta, GA 30303 USA. EM raul.g.nogueira@emory.edu FU NIH [R01NS051412, P50NS051343, R21NS077442, R21-NS085574, U10NS086729]; Biogen; Boehringer Ingelheim; Stryker Neurovascular-modest FX Dr Lev reports working as consultant for GE Healthcare, MLNM Pharm, MedyMatch, and D-Pharm. He also reports receiving institution research support from GE Healthcare. Dr Singhal is a deputy PI of the New England Regional Coordinating Center for the National Institutes of Health (NIH) StrokeNet. He reports receiving partial support from the following NIH grants during the conduct of the study: R01NS051412, P50NS051343, R21NS077442, R21-NS085574, and U10NS086729. He is on ACTION (A Multicenter, Double-Blind, Placebo-Controlled, Randomized, Parallel-Group Study to Evaluate the Safety and Efficacy of Intravenous Natalizumab on Reducing Infarct Volume in Acute Ischemic Stroke) trial Advisory Board sponsored by Biogen. He is the site PI of stroke clinical trial sponsored by Boehringer Ingelheim. Dr Smith is a consultant for Stryker Neurovascular, DSMB board. Dr Nogueira is the PI for Trevo-2 Trial (sponsored by Stryker Neurovascular-modest) and the DAWN (Diffusion Weighted Imaging [DWI] or Computerized Tomography Perfusion [CTP] Assessment With Clinical Mismatch in the Triage of Wake Up and Late Presenting Strokes Undergoing Neurointervention) trial (no compensation). He is on the Steering Committee of SWIFT Trial (modest) and SWIFT Prime (no compensation). He receives compensation from the STAR (Solitaire FR Thrombectomy for Acute Revascularisation) trial (Angiographic Core Lab-significant). He is also part of the Executive Committee for the Penumbra 3D separator Trial (no compensation). He is also an Editor-In-Chief of the Interventional Neurology Journal (no compensation). The other authors report no conflicts. NR 19 TC 6 Z9 6 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD AUG PY 2016 VL 47 IS 8 BP 1997 EP 2002 DI 10.1161/STROKEAHA.116.013301 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA DS5GC UT WOS:000380808400017 PM 27364531 ER PT J AU Di Tullio, MR Qian, M Thompson, JLP Labovitz, AJ Mann, DL Sacco, RL Pullicino, PM Freudenberger, RS Teerlink, JR Graham, S Lip, GYH Levin, B Mohr, JP Buchsbaum, R Estol, CJ Lok, DJ Ponikowski, P Anker, SD Homma, S AF Di Tullio, Marco R. Qian, Min Thompson, John L. P. Labovitz, Arthur J. Mann, Douglas L. Sacco, Ralph L. Pullicino, Patrick M. Freudenberger, Ronald S. Teerlink, John R. Graham, Susan Lip, Gregory Y. H. Levin, Bruce Mohr, J. P. Buchsbaum, Richard Estol, Conrado J. Lok, Dirk J. Ponikowski, Piotr Anker, Stefan D. Homma, Shunichi CA WARCEF Investigators TI Left Ventricular Ejection Fraction and Risk of Stroke and Cardiac Events in Heart Failure Data From the Warfarin Versus Aspirin in Reduced Ejection Fraction Trial SO STROKE LA English DT Article DE aspirin; echocardiography; heart failure; heart ventricles; stroke; warfarin ID BLOOD-PRESSURE; SINUS RHYTHM; THROMBOEMBOLIC EVENTS; BROAD-SPECTRUM; MORTALITY; INSIGHTS; OUTCOMES; ASSOCIATION; SURVIVAL; EFFICACY AB Background and Purpose-In heart failure (HF), left ventricular ejection fraction (LVEF) is inversely associated with mortality and cardiovascular outcomes. Its relationship with stroke is controversial, as is the effect of antithrombotic treatment. We studied the relationship of LVEF with stroke and cardiovascular events in patients with HF and the effect of different antithrombotic treatments. Methods-In the Warfarin Versus Aspirin in Reduced Ejection Fraction (WARCEF) trial, 2305 patients with systolic HF (LVEF <= 35%) and sinus rhythm were randomized to warfarin or aspirin and followed for 3.5 +/- 1.8 years. Although no differences between treatments were observed on primary outcome (death, stroke, or intracerebral hemorrhage), warfarin decreased the stroke risk. The present report compares the incidence of stroke and cardiovascular events across different LVEF and treatment subgroups. Results-Baseline LVEF was inversely and linearly associated with primary outcome, mortality and its components (sudden and cardiovascular death), and HF hospitalization, but not myocardial infarction. A relationship with stroke was only observed for LVEF of <15% (incidence rates: 2.04 versus 0.95/100 patient-years; P=0.009), which more than doubled the adjusted stroke risk (adjusted hazard ratio, 2.125; 95% CI, 1.182-3.818; P=0.012). In warfarin-treated patients, each 5% LVEF decrement significantly increased the stroke risk (adjusted hazard ratio, 1.346; 95% CI, 1.044-1.737; P=0.022; P value for interaction=0.04). Conclusions-In patients with systolic HF and sinus rhythm, LVEF is inversely associated with death and its components, whereas an association with stroke exists for very low LVEF values. An interaction with warfarin treatment on stroke risk may exist. C1 [Di Tullio, Marco R.; Homma, Shunichi] Columbia Univ, Dept Med, Div Cardiol, Med Ctr, New York, NY USA. [Qian, Min; Thompson, John L. P.; Levin, Bruce; Buchsbaum, Richard] Columbia Univ, Med Ctr, Dept Biostat, Mailman Sch Publ Hlth, New York, NY USA. [Mohr, J. P.] Columbia Univ, Med Ctr, Dept Neurol, New York, NY USA. [Labovitz, Arthur J.] Univ S Florida, Dept Cardiovasc Med, Tampa, FL USA. [Mann, Douglas L.] Washington Univ, Dept Med, Cardiovasc Div, St Louis, MO USA. [Sacco, Ralph L.] Univ Miami, Dept Neurol, Miami, FL USA. [Sacco, Ralph L.] Univ Miami, Dept Epidemiol, Miami, FL USA. [Sacco, Ralph L.] Univ Miami, Dept Publ Hlth, Miami, FL USA. [Pullicino, Patrick M.] Kent Inst Med & Hlth Sci, Canterbury, Kent, England. [Freudenberger, Ronald S.] Lehigh Valley Hosp, Dept Med, Div Cardiol, Allentown, PA USA. [Teerlink, John R.] Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, Cardiol Sect, San Francisco, CA 94143 USA. [Graham, Susan] SUNY Upstate Med Univ, Dept Med, Div Cardiol, Buffalo, NY USA. [Lip, Gregory Y. H.] Univ Birmingham, Ctr Cardiovasc Sci, City Hosp, Birmingham, W Midlands, England. [Estol, Conrado J.] Ctr Neurol Tratamiento & Rehabil, Buenos Aires, DF, Argentina. [Mann, Douglas L.] Deventer Hosp, Dept Cardiol, Deventer, Netherlands. [Ponikowski, Piotr] Wroclaw Med Univ, Mil Hosp, Dept Heart Dis, Wroclaw, Poland. [Anker, Stefan D.] Univ Med Gottingen, Dept Innovat Clin Trials, Gottingen, Germany. RP Di Tullio, MR (reprint author), Div Cardiol, PH 3-342,622 W,168th St, New York, NY 10032 USA. EM md42@cumc.columbia.edu RI Ponikowski, Piotr/O-6454-2015 OI Ponikowski, Piotr/0000-0002-3391-7064 FU National Institute of Neurological Diseases and Stroke (NINDS) [U01-NS-043975, U01-NS-039143] FX The study was funded by U01-NS-043975 (Dr Homma) and U01-NS-039143 (Dr Thompson) from the National Institute of Neurological Diseases and Stroke (NINDS). NR 17 TC 4 Z9 4 U1 2 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD AUG PY 2016 VL 47 IS 8 BP 2031 EP 2037 DI 10.1161/STROKEAHA.116.013679 PG 7 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA DS5GC UT WOS:000380808400022 PM 27354224 ER PT J AU Myint, PK Hellkamp, AS Fonarow, GC Reeves, MJ Schwamm, LH Schulte, PJ Xian, Y Suter, RE Bhatt, DL Saver, JL Peterson, ED Smith, EE AF Myint, Phyo K. Hellkamp, Anne S. Fonarow, Gregg C. Reeves, Matthew J. Schwamm, Lee H. Schulte, Phillip J. Xian, Ying Suter, Robert E. Bhatt, Deepak L. Saver, Jeffrey L. Peterson, Eric D. Smith, Eric E. TI Prior Antithrombotic Use Is Associated With Favorable Mortality and Functional Outcomes in Acute Ischemic Stroke SO STROKE LA English DT Article DE antiplatelet agents; antithrombotic agents; mortality; prognosis; stroke ID GUIDELINES-STROKE; ANTIPLATELET USE; SEVERITY; REGISTRY; PREVENTION; THERAPY; SUBTYPE; PROGRAM; ATTACK AB Background and Purpose-Antithrombotics are the mainstay of treatment in primary and secondary prevention of stroke, and their use before an acute event may be associated with better outcomes. Methods-Using data from Get With The Guidelines-Stroke with over half a million acute ischemic strokes recorded between October 2011 and March 2014 (n=540 993) from 1661 hospitals across the United States, we examined the unadjusted and adjusted associations between previous antithrombotic use and clinical outcomes. Results-There were 250 104 (46%) stroke patients not receiving any antithrombotic before stroke; of whom approximately one third had a documented previous vascular indication. After controlling for clinical and hospital factors, patients who were receiving antithrombotics before stroke had better outcomes than those who did not, regardless of whether a previous vascular indication was present or not: adjusted odds ratio (95% confidence intervals) were 0.82 (0.80-0.84) for in-hospital mortality, 1.18 (1.16-1.19) for home as the discharge destination, 1.15 (1.13-1.16) for independent ambulatory status at discharge, and 1.15 (1.12-1.17) for discharge modified Rankin Scale score of 0 or 1. Conclusions-Previous antithrombotic therapy was independently associated with improved clinical outcomes after acute ischemic stroke. Ensuring the use of antithrombotics in appropriate patient populations may be associated with benefits beyond stroke prevention. C1 [Myint, Phyo K.] Univ Aberdeen, Sch Med & Med Sci & Nutr, Inst Appl Hlth Sci, Epidemiol Grp, Aberdeen AB9 1FX, Scotland. [Hellkamp, Anne S.; Schulte, Phillip J.; Xian, Ying] Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC USA. [Peterson, Eric D.] Duke Univ, Sch Med, Div Cardiol, Dept Med, Durham, NC USA. [Fonarow, Gregg C.] Univ Calif Los Angeles, David Geffen Sch Med, Div Cardiol, Los Angeles, CA 90024 USA. [Reeves, Matthew J.] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Schwamm, Lee H.] Massachusetts Gen Hosp, Stroke Serv, Dept Neurol, Boston, MA 02114 USA. [Suter, Robert E.] Univ Texas Southwestern, IFEM, Amer Heart Assoc, Dallas, TX USA. [Bhatt, Deepak L.] Harvard Med Sch, Brigham & Womens Hosp, Heart & Vasc Ctr, Boston, MA USA. [Saver, Jeffrey L.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Stroke Program, Los Angeles, CA 90024 USA. [Smith, Eric E.] Univ Calgary, Clin Neurosci, Calgary, AB T2N 1N4, Canada. [Smith, Eric E.] Univ Calgary, Hotchkiss Brain Inst, Calgary, AB T2N 1N4, Canada. RP Myint, PK (reprint author), Univ Aberdeen, Sch Med Med Sci & Nutr, Inst Appl Hlth Sci, Aberdeen Gerontol & Epidemiol INterdisciplinary R, Epidemiol Grp Room 4 013,Polwarth Bldg, Aberdeen AB25 2ZD, Scotland. EM phyo.myint@abdn.ac.uk FU Boehringer-Ingelheim; Merck; Bristol-Myers Squibb/Sanofi Pharmaceutical Partnership; American Heart Association Pharmaceutical Roundtable FX The Get With The Guidelines (GWTG)-Stroke program is currently supported, in part, by a charitable contribution from Bristol-Myers Squibb/Sanofi Pharmaceutical Partnership and the American Heart Association Pharmaceutical Roundtable. GWTG-Stroke has been funded in the past through support from Boehringer-Ingelheim and Merck. These funding agencies did not participate in design or analysis, article preparation, or approval of this study. NR 22 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 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD AUG PY 2016 VL 47 IS 8 BP 2066 EP 2074 DI 10.1161/STROKEAHA.115.012414 PG 9 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA DS5GC UT WOS:000380808400027 PM 27435402 ER PT J AU Rost, NS Giugliano, RP Ruff, CT Murphy, SA Crompton, AE Norden, AD Silverman, S Singhal, AB Nicolau, JC SomaRaju, B Mercuri, MF Antman, EM Braunwald, E AF Rost, Natalia S. Giugliano, Robert P. Ruff, Christian T. Murphy, Sabina A. Crompton, Andrea E. Norden, Andrew D. Silverman, Scott Singhal, Aneesh B. Nicolau, Jose C. SomaRaju, Bhupathi Mercuri, Michele F. Antman, Elliott M. Braunwald, Eugene CA ENGAGE AF-TIMI 48 Investigators TI Outcomes With Edoxaban Versus Warfarin in Patients With Previous Cerebrovascular Events Findings From ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) SO STROKE LA English DT Article DE atrial fibrillation; clinical trial; hemorrhage; risk factors; stroke ID ANTITHROMBOTIC THERAPY; PREDICTING STROKE; ISCHEMIC-STROKE; RISK-FACTORS; HEMORRHAGE; PREVENTION; METAANALYSIS; RIVAROXABAN; EFFICACY; TRIALS AB Background and Purpose-Patients with atrial fibrillation and previous ischemic stroke (IS)/transient ischemic attack (TIA) are at high risk of recurrent cerebrovascular events despite anticoagulation. In this prespecified subgroup analysis, we compared warfarin with edoxaban in patients with versus without previous IS/TIA. Methods-ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) was a double-blind trial of 21 105 patients with atrial fibrillation randomized to warfarin (international normalized ratio, 2.0-3.0; median time-in-therapeutic range, 68.4%) versus once-daily edoxaban (higher-dose edoxaban regimen [HDER], 60/30 mg; lower-dose edoxaban regimen, 30/15 mg) with 2.8-year median follow-up. Primary end points included all stroke/systemic embolic events (efficacy) and major bleeding (safety). Because only HDER is approved, we focused on the comparison of HDER versus warfarin. Results-Of 5973 (28.3%) patients with previous IS/TIA, 67% had CHADS 2 (congestive heart failure, hypertension, age, diabetes, prior stroke/transient ischemic attack) > 3 and 36% were >= 75 years. Compared with 15 132 without previous IS/TIA, patients with previous IS/TIA were at higher risk of both thromboembolism and bleeding (stroke/systemic embolic events 2.83% versus 1.42% per year; P<0.001; major bleeding 3.03% versus 2.64% per year; P<0.001; intracranial hemorrhage, 0.70% versus 0.40% per year; P<0.001). Among patients with previous IS/TIA, annualized intracranial hemorrhage rates were lower with HDER than with warfarin (0.62% versus 1.09%; absolute risk difference, 47 [8-85] per 10 000 patient-years; hazard ratio, 0.57; 95% confidence interval, 0.36-0.92; P=0.02). No treatment subgroup interactions were found for primary efficacy (P=0.86) or for intracranial hemorrhage (P=0.28). Conclusions-Patients with atrial fibrillation with previous IS/TIA are at high risk of recurrent thromboembolism and bleeding. HDER is at least as effective and is safer than warfarin, regardless of the presence or the absence of previous IS or TIA. C1 [Rost, Natalia S.; Silverman, Scott; Singhal, Aneesh B.] Massachusetts Gen Hosp, 175 Cambridge St,Suite 300, Boston, MA 02114 USA. [Giugliano, Robert P.; Ruff, Christian T.; Murphy, Sabina A.; Crompton, Andrea E.; Norden, Andrew D.; Antman, Elliott M.; Braunwald, Eugene] Brigham & Womens Hosp, Cardiovasc Med, TIMI Study Grp, 75 Francis St, Boston, MA 02115 USA. [Nicolau, Jose C.] Univ Sao Paulo, Sch Med, Heart Inst InCor, BR-05508 Sao Paulo, Brazil. [SomaRaju, Bhupathi] CARE Musheerabad, Hyderabad, Andhra Pradesh, India. [Mercuri, Michele F.] Daiichi Sankyo Pharma Dev, Edison, NJ USA. RP Rost, NS (reprint author), Massachusetts Gen Hosp, 175 Cambridge St,Suite 300, Boston, MA 02114 USA. EM nrost@partners.org RI Nicolau, Jose/E-1487-2012 FU Daiichi-Sankyo Pharma Development, Edison, NJ FX This study was supported by Daiichi-Sankyo Pharma Development, Edison, NJ. NR 23 TC 4 Z9 4 U1 4 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD AUG PY 2016 VL 47 IS 8 BP 2075 EP 2082 DI 10.1161/STROKEAHA.116.013540 PG 8 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA DS5GC UT WOS:000380808400028 PM 27387994 ER PT J AU Castro, LNG Colorado, RA Botelho, AA Freitag, SK Rabinov, JD Silverman, SB AF Castro, Luis Nicolas Gonzalez Colorado, Rene A. Botelho, Alyssa A. Freitag, Suzanne K. Rabinov, James D. Silverman, Scott B. TI Carotid-Cavernous Fistula A Rare but Treatable Cause of Rapidly Progressive Vision Loss SO STROKE LA English DT Editorial Material C1 [Castro, Luis Nicolas Gonzalez; Colorado, Rene A.; Silverman, Scott B.] Massachusetts Gen Hosp, Dept Neurol, 55 Fruit St, Boston, MA 02114 USA. [Rabinov, James D.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Botelho, Alyssa A.] Harvard Med Sch, Boston, MA USA. [Freitag, Suzanne K.] Massachusetts Eye & Ear Infirm, Ophthalm Plast Surg Serv, Boston, MA 02114 USA. RP Silverman, SB (reprint author), Massachusetts Gen Hosp, Dept Neurol, 55 Fruit St, Boston, MA 02114 USA. EM sbsilverman@partners.org NR 8 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 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD AUG PY 2016 VL 47 IS 8 BP E207 EP E209 DI 10.1161/STROKEAHA.116.013428 PG 3 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA DS5GC UT WOS:000380808400002 ER PT J AU Beste, LA Mattox, EA Pichler, R Young, BA Au, DH Kirsh, SF Germani, MW Hedeen, A Harp, BK Chang, MF AF Beste, Lauren A. Mattox, Elizabeth A. Pichler, Raimund Young, Bessie A. Au, David H. Kirsh, Susan F. Germani, Maureen W. Hedeen, Ashley Harp, Bonnie K. Chang, Michael F. TI Primary Care Team Members Report Greater Individual Benefits from Long- Versus Short-Term Specialty Telemedicine Mentorship SO TELEMEDICINE AND E-HEALTH LA English DT Article DE telehealth; ECHO; veterans; education; professional development ID GENERALIST-SUBSPECIALIST COMMUNICATION; PROJECT ECHO; OUTCOMES; ACCESS; SATISFACTION; EXTENSION; CHILDREN; COMPLEX AB Background: Primary care providers who participate in structured specialty telemedicine mentorship report improvements in clinical content mastery, professional satisfaction, and specialist communication. Introduction: Although these programs require investments of infrastructure resources and time, the duration of participation required to accrue optimal benefits is not known. We aimed to assess whether duration of participation is related to improved benefits of a longitudinal telemedicine-based mentorship program, specifically regarding perceived specialty care access, acquisition of new knowledge and skills, team integration, and overall job satisfaction. Materials and Methods: We conducted an e-mail survey of Veterans Affairs-based primary care team members in the United States' Pacific Northwest region who engaged in a longitudinal telemedicine mentorship program (n = 78). Results: After adjustment for potential confounding factors, respondents who engaged in telemedicine mentorship for >= 1 year were significantly more likely to strongly agree that telemedicine mentorship improved patient access to specialty care (adjusted odds ratio [AOR] = 9.3, p < 0.005) and was useful in treating other patients on their panels (AOR = 3.7, p = 0.04). Participation >= 1 year was also associated with higher self-reported knowledge and competencies (AOR = 4.0, p = 0.03) and with perception of integration into a clinical team (AOR = 5.6, p = 0.01), but not with overall job satisfaction. Conclusion: Telemedicine-based specialty mentorship programs are highly valued by primary care-based participants, and self-reported benefits accumulate beyond 1 year of participation. C1 [Beste, Lauren A.] VA Puget Sound Hlth Care Syst, Gen Med Serv, 1660 S Columbian Way, Seattle, WA 98108 USA. [Beste, Lauren A.; Young, Bessie A.; Au, David H.; Germani, Maureen W.; Hedeen, Ashley; Harp, Bonnie K.] VA Puget Sound Hlth Care Syst, Hlth Serv Res & Dev Ctr Innovat, Seattle, WA USA. [Beste, Lauren A.] Univ Washington, Div Gen Internal Med, Seattle, WA 98195 USA. [Mattox, Elizabeth A.; Au, David H.] VA Puget Sound Hlth Care Syst, Pulm & Crit Care Sect, Hosp & Specialty Med, Seattle, WA USA. [Pichler, Raimund; Young, Bessie A.] VA Puget Sound Hlth Care Syst, Hosp & Specialty Med, Nephrol Sect, Seattle, WA USA. [Pichler, Raimund; Young, Bessie A.; Harp, Bonnie K.] Univ Washington, Div Nephrol, Seattle, WA 98195 USA. [Pichler, Raimund; Young, Bessie A.; Harp, Bonnie K.] Univ Washington, Kidney Res Inst, Seattle, WA 98195 USA. [Au, David H.] Univ Washington, Div Pulm & Crit Care, Seattle, WA 98195 USA. [Kirsh, Susan F.] Dept Vet Hlth Adm, Off Specialty Care Serv, Patient Care Serv, Washington, DC USA. [Kirsh, Susan F.] Louis Stokes Cleveland VA Med Ctr, Cleveland, OH USA. [Kirsh, Susan F.] Case Western Reserve Univ, Sch Med, Cleveland, OH USA. [Chang, Michael F.] VA Portland Hlth Care Syst, Gastroenterol & Hepatol Serv, Portland, OR USA. [Chang, Michael F.] Oregon Hlth & Sci Univ, Div Gastroenterol & Hepatol, Portland, OR 97201 USA. RP Beste, LA (reprint author), VA Puget Sound Hlth Care Syst, Gen Med Serv, 1660 S Columbian Way, Seattle, WA 98108 USA. EM lauren.beste@va.gov FU VA Office of Patient Care Services, Specialty Care Services program office; VA Office of Rural Health FX 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. This material is the result of work supported by resources from the VA Puget Sound Health Care System (Seattle, Washington) and the VA Portland Health Care System (Portland, OR). Funding support was provided by the VA Office of Patient Care Services, Specialty Care Services program office, and by the VA Office of Rural Health. NR 26 TC 0 Z9 0 U1 3 U2 3 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1530-5627 EI 1556-3669 J9 TELEMED E-HEALTH JI Telemed. e-Health PD AUG PY 2016 VL 22 IS 8 BP 699 EP 706 DI 10.1089/tmj.2015.0185 PG 8 WC Health Care Sciences & Services SC Health Care Sciences & Services GA DS5EZ UT WOS:000380805400011 PM 26959098 ER PT J AU Blackney, KA Zavodni, ZJ Saddawi-Konefka, D AF Blackney, Kevin A. Zavodni, Zachary J. Saddawi-Konefka, Daniel TI The Anesthetic Implications of Aqueous Drainage Devices and Glaucoma: A Report of a Patient Undergoing Urgent Prone Cervical Decompression and Fusion SO A & A Case Reports LA English DT Article ID PERIOPERATIVE VISUAL-LOSS; OPEN-ANGLE GLAUCOMA; CEREBROSPINAL-FLUID PRESSURE; TREATMENT OUTCOMES; CLOSURE GLAUCOMA; AHMED GLAUCOMA; SURGERY; PROGRESSION; BAERVELDT; TRIAL AB The pathophysiology of glaucoma and perioperative visual loss is similar. A patient with glaucoma may be at increased risk of perioperative visual loss. For both, goals of management include optimizing ocular perfusion pressure and oxygen delivery. One treatment for refractory glaucoma is an aqueous drainage device; however, there is no published literature on the anesthetic management of patients with these devices. We present the case of a patient with recalcitrant glaucoma treated with an Ahmed Glaucoma Valve who underwent urgent prone surgery. Anesthetic implications of aqueous drainage devices and glaucoma are discussed, and recommendations are made. C1 [Blackney, Kevin A.] Stanford Univ, Med Ctr, Dept Anesthesiol Perioperat & Pain Med, Stanford, CA 94305 USA. [Zavodni, Zachary J.] Eye Inst Utah, Salt Lake City, UT USA. [Zavodni, Zachary J.] Univ Utah, John A Moran Eye Ctr, Salt Lake City, UT USA. [Saddawi-Konefka, Daniel] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Blackney, KA (reprint author), Stanford Univ, Med Ctr, Dept Anesthesiol Perioperat & Pain Med, 300 Pasteur Dr,Room H3580, Stanford, CA 94305 USA. EM KABlackney@gmail.com NR 29 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 AUG 1 PY 2016 VL 7 IS 3 BP 63 EP 66 DI 10.1213/XAA.0000000000000346 PG 4 WC Anesthesiology SC Anesthesiology GA DT4YD UT WOS:000381486600004 PM 27258174 ER PT J AU Roh, M Yasa, C Cho, H Nicholson, L Uchiyama, E Young, LHY Lobo, AM Papaliodis, GN Durand, ML Sobrin, L AF Roh, Miin Yasa, Cagla Cho, Heeyoon Nicholson, Laura Uchiyama, Eduardo Young, Lucy H. Y. Lobo, Ann-Marie Papaliodis, George N. Durand, Marlene L. Sobrin, Lucia TI The role of serological titres in the diagnosis of ocular toxoplasmosis SO ACTA OPHTHALMOLOGICA LA English DT Article C1 [Roh, Miin; Yasa, Cagla; Cho, Heeyoon; Nicholson, Laura; Uchiyama, Eduardo; Lobo, Ann-Marie; Papaliodis, George N.; Sobrin, Lucia] Harvard Med Sch, Dept Ophthalmol, Uveitis Serv, Massachusetts Eye & Ear Infirm, Boston, MA USA. [Yasa, Cagla] Koc Univ, Sch Med, Istanbul, Turkey. [Cho, Heeyoon; Sobrin, Lucia] Hanyang Univ, Dept Ophthalmol, Coll Med, Seoul, South Korea. [Young, Lucy H. Y.] Harvard Med Sch, Dept Ophthalmol, Retina Serv, Massachusetts Eye & Ear Infirm, Boston, MA USA. [Durand, Marlene L.] Harvard Med Sch, Dept Med & Ophthalmol, Boston, MA USA. RP Sobrin, L (reprint author), Harvard Med Sch, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, 243 Charles St,12th Floor, Boston, MA 02114 USA. EM Lucia_Sobrin@meei.harvard.edu NR 5 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1755-375X EI 1755-3768 J9 ACTA OPHTHALMOL JI Acta Ophthalmol. PD AUG PY 2016 VL 94 IS 5 BP 521 EP 522 DI 10.1111/aos.12851 PG 2 WC Ophthalmology SC Ophthalmology GA DR8IZ UT WOS:000380142900044 PM 26426456 ER PT J AU Wolach, O Stevenson, KE Wadleigh, M DeAngelo, DJ Steensma, DP Ballen, KK Soiffer, RJ Antin, JH Neuberg, DS Ho, VT Stone, RM AF Wolach, Ofir Stevenson, Kristen E. Wadleigh, Martha DeAngelo, Daniel J. Steensma, David P. Ballen, Karen K. Soiffer, Robert J. Antin, Joseph H. Neuberg, Donna S. Ho, Vincent T. Stone, Richard M. TI Allogeneic transplantation is not superior to chemotherapy in most patients over 40years of age with Philadelphia-negative acute lymphoblastic leukemia in first remission SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article ID HEMATOPOIETIC-CELL TRANSPLANTATION; REDUCED-INTENSITY; ADULT PATIENTS; OLDER PATIENTS; JAPAN SOCIETY; STANDARD-RISK; WORKING GROUP; B-CELL; TRIAL; SURVIVAL AB Survival of patients 40years of age with Philadelphia-negative acute lymphoblastic leukemia (ALL) remains poor with current therapeutic approaches. It is unknown whether allogeneic hematopoietic stem-cell transplantation (HSCT) in first remission confers a survival benefit compared to a chemotherapy-only approach. We retrospectively compared the outcome of patients >40years treated with HSCT or chemotherapy alone in first remission (n=40 in each cohort). Three-year overall survival (OS) and disease-free survival (DFS) were not significantly different between the chemotherapy-only and HSCT groups (OS, 46% [31-68] vs. 40% [27-59], P=0.35; DFS, 31% [18-52] vs. 40% [27-59], P=0.98). The 3-year cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were 61% [41-76] and 9% [2-21] for the chemotherapy-only group and 28% [15-43] and 32% [17-47] for the transplant group (CIR, P=0.011; NRM, P=0.014). Allogeneic transplantation for patients 40years with Ph-negative ALL in first remission is associated with a lower CIR, but this benefit is offset by considerable NRM as compared with chemotherapy-only approach. HSCT may be beneficial in patients with high-risk disease features. Am. J. Hematol. 91:793-799, 2016. (c) 2016 Wiley Periodicals, Inc. C1 [Wolach, Ofir; Wadleigh, Martha; DeAngelo, Daniel J.; Steensma, David P.; Soiffer, Robert J.; Antin, Joseph H.; Ho, Vincent T.; Stone, Richard M.] Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02115 USA. [Stevenson, Kristen E.; Neuberg, Donna S.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Ballen, Karen K.] Massachusetts Gen Hosp, Dept Hematol Oncol, Boston, MA 02114 USA. RP Wolach, O (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02115 USA. EM Ofir_wolaj@dfci.harvard.edu NR 36 TC 1 Z9 1 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 EI 1096-8652 J9 AM J HEMATOL JI Am. J. Hematol. PD AUG PY 2016 VL 91 IS 8 BP 793 EP 799 DI 10.1002/ajh.24410 PG 7 WC Hematology SC Hematology GA DS0CE UT WOS:000380262100016 PM 27153389 ER PT J AU Brunner, AM Steensma, DP AF Brunner, Andrew M. Steensma, David P. TI Myelodysplastic syndrome associated with acquired beta thalassemia: "BTMDS" SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Letter ID MDS C1 [Brunner, Andrew M.] Massachusetts Gen Hosp, Div Hematol & Oncol, Boston, MA 02114 USA. [Steensma, David P.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Brunner, AM (reprint author), Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. EM abrunner@mgh.harvard.edu FU NCI NIH HHS [K12 CA087723, T32 CA071345] NR 6 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 EI 1096-8652 J9 AM J HEMATOL JI Am. J. Hematol. PD AUG PY 2016 VL 91 IS 8 BP E325 EP E327 DI 10.1002/ajh.24400 PG 3 WC Hematology SC Hematology GA DS0CE UT WOS:000380262100003 PM 27121565 ER PT J AU Marini, C Baldaia, H Trigo, F Castillo, JJ AF Marini, Carolina Baldaia, Helena Trigo, Fernanda Castillo, Jorge J. TI Transformation of a previously diagnosed diffuse large B-cell lymphoma to plasmablastic lymphoma SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Letter C1 [Marini, Carolina; Trigo, Fernanda] Univ Porto, Dept Clin Haematol, Ctr Hosp Sao Joao, Sch Med, Oporto, Portugal. [Baldaia, Helena] Univ Porto, Dept Pathol, Ctr Hosp Sao Joao, Sch Med, Oporto, Portugal. [Castillo, Jorge J.] Harvard Med Sch, Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA USA. RP Marini, C (reprint author), Dept Haematol, Alameda Prof Hernani Monteiro, P-4200319 Oporto, Portugal. EM carolinamarini@gmail.com OI Castillo, Jorge/0000-0001-9490-7532 NR 6 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 EI 1096-8652 J9 AM J HEMATOL JI Am. J. Hematol. PD AUG PY 2016 VL 91 IS 8 BP E324 EP E325 DI 10.1002/ajh.24375 PG 4 WC Hematology SC Hematology GA DS0CE UT WOS:000380262100002 PM 27012155 ER PT J AU Cohen, RA Jackson, VA Norwich, D Schell, JO Schaefer, K Ship, AN Sullivan, AM AF Cohen, Robert A. Jackson, Vicki A. Norwich, Diana Schell, Jane O. Schaefer, Kristen Ship, Amy N. Sullivan, Amy M. TI A Nephrology Fellows' Communication Skills Course: An Educational Quality Improvement Report SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Communication skills; nephrology fellows; dialysis decision-making; conservative management; dialysis withdrawal; end of life; physician training; quality improvement; patient-centered care; kidney disease ID OF-LIFE CARE; DIALYSIS DECISION-MAKING; TEACHING COMMUNICATION; ELDERLY-PATIENTS; NATIONAL-SURVEY; KIDNEY-DISEASE; END; PROGRAM; ONCOLOGISTS; MODEL AB Background: Nephrology fellows need expertise navigating challenging conversations with patients throughout the course of advanced kidney disease. However, evidence shows that nephrologists receive inadequate training in this area. This study assessed the effectiveness of an educational quality improvement intervention designed to enhance fellows' communication with patients who have advanced kidney disease. Study Design: Quality improvement project. Setting & Participants: Full-day annual workshops (2013-2014) using didactics, discussion, and practice with simulated patients. Content focused on delivering bad news, acknowledging emotion, discussing care goals in dialysis decision making when prognosis is uncertain, and addressing dialysis therapy withdrawal and end of life. Participants were first-year nephrology fellows from 2 Harvard-affiliated training programs (N = 26). Quality Improvement Plan: Study assessed the effectiveness of an intervention designed to enhance fellows' communication skills. Outcomes: Primary outcomes were changes in self-reported patient communication skills, attitudes, and behaviors related to discussing disease progression, prognostic uncertainty, dialysis therapy withdrawal, treatments not indicated, and end of life; responding to emotion; eliciting patient goals and values; and incorporating patient goals into recommendations. Measurements: Surveys measured prior training, pre- and postcourse perceived changes in skills and values, and reported longer term (3-month) changes in communication behaviors, using both closed-and open-ended items. Results: Response rates were 100% (pre-and postsurveys) and 68% (follow-up). Participants reported improvement in all domains, with an overall mean increase of 1.1 (summed average scores: precourse, 2.8; postcourse, 3.9 [1-5 scale; 5 = "extremely well prepared"]; P < 0.001), with improvement sustained at 3 months. Participants reported meaningful changes integrating into practice specific skills taught, such as "Ask-Tell-Ask" and using open-ended questions. Limitations: Self-reported data may overestimate actual changes; small sample size and the programs' affiliation with a single medical school may limit generalizability. Conclusions: A day-long course addressing nephrology fellows' communication competencies across the full course of patients' illness experience can enhance fellows' self-reported skills and practices. (C) 2016 by the National Kidney Foundation, Inc. C1 [Cohen, Robert A.] Harvard Med Sch, Div Nephrol, Dept Med, Beth Israel Deaconess Med Ctr, Boston, MA USA. [Jackson, Vicki A.] Harvard Med Sch, Massachusetts Gen Hosp, Palliat Care Div, Dept Med, Boston, MA USA. [Norwich, Diana; Sullivan, Amy M.] Harvard Med Sch, Dept Med, Beth Israel Deaconess Med Ctr, Boston, MA USA. [Schell, Jane O.] Univ Pittsburgh, Med Ctr, Sch Med, Sect Palliat Care & Med Eth, Pittsburgh, PA USA. [Schell, Jane O.] Univ Pittsburgh, Med Ctr, Sch Med, Renal Div,Electrolyte Div, Pittsburgh, PA USA. [Schaefer, Kristen] Harvard Med Sch, Dana Farber Canc Inst, Div Psychosocial Med & Palliat Care, Boston, MA USA. [Ship, Amy N.] Harvard Med Sch, Div Gen Med, Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA USA. RP Cohen, RA (reprint author), Beth Israel Deaconess Med Ctr, Div Nephrol, W Libby 2,171 Pilgrim Rd, Boston, MA 02215 USA. EM rcohen@bidmc.harvard.edu FU Arnold P. Gold Foundation; Stanley J. Bernstein Memorial Fund at BIDMC [0102642] FX Funding for the development and implementation of this course, as well as study design, data collection, and analysis, was provided by a grant from the Arnold P. Gold Foundation and the Stanley J. Bernstein Memorial Fund at BIDMC (clinical trials account 0102642). Study sponsors had no role in study design; collection, analysis, and interpretation of data; writing the report; and the decision to submit the report for publication. NR 33 TC 2 Z9 2 U1 4 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 EI 1523-6838 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD AUG PY 2016 VL 68 IS 2 BP 203 EP 211 DI 10.1053/j.ajkd.2016.01.025 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA DS4LZ UT WOS:000380753900011 PM 26994686 ER PT J AU Young, BA Katz, R Boulware, LE Kestenbaum, B de Boer, IH Wang, W Fulop, T Bansal, N Robinson-Cohen, C Griswold, M Powe, NR Himmelfarb, J Correa, A AF Young, Bessie A. Katz, Ronit Boulware, L. Ebony Kestenbaum, Bryan de Boer, Ian H. Wang, Wei Fueloep, Tibor Bansal, Nisha Robinson-Cohen, Cassianne Griswold, Michael Powe, Neil R. Himmelfarb, Jonathan Correa, Adolfo TI Risk Factors for Rapid Kidney Function Decline Among African Americans: The Jackson Heart Study (JHS) SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Chronic kidney disease (CKD); African American; ethnic differences; kidney disease progression; disease trajectory; rapid kidney function decline; estimated glomerular filtration rate (eGFR); risk factor; renal failure; Jackson Heart Study (JHS) ID BODY-MASS INDEX; STAGE RENAL-DISEASE; UNITED-STATES; ETHNIC-DIFFERENCES; RACIAL-DIFFERENCES; APOL1 VARIANTS; YOUNG-ADULTS; ASSOCIATION; POPULATION; PREVALENCE AB Background: Racial differences in rapid kidney function decline exist, but less is known regarding factors associated with rapid decline among African Americans. Greater understanding of potentially modifiable risk factors for early kidney function loss may help reduce the burden of kidney failure in this high-risk population. Study Design: Prospective cohort study. Setting & Participants: 3,653 African American participants enrolled in the Jackson Heart Study (JHS) with kidney function data from 2 of 3 examinations (2000-2004 and 2009-2013). Estimated glomerular filtration rate (eGFR) was calculated from serum creatinine using the CKD-EPI creatinine equation. Predictors: Demographics, socioeconomic status, lifestyle, and clinical risk factors for kidney failure. Outcomes: Rapid decline was defined as a >= 30% decline in eGFR during follow-up. We quantified the association of risk factors with rapid decline in multivariable models. Measurements: Clinical (systolic blood pressure and albuminuria [albumin-creatinine ratio]) and modifiable risk factors. Results: Mean age was 54 +/- 12 (SD) years, 37% weremen, average body mass index was 31.8 +/- 7.1 kg/m(2), 19% had diabetes mellitus (DM), and mean eGFR was 96.0 +/- 20 mL/min/1.73 m(2) with an annual rate of decline of 1.27 mL/min/1.73 m(2). Those with rapid decline (11.5%) were older, were more likely to be of low/middle income, and had higher systolic blood pressures and greater DM than those with nonrapid decline. Factors associated with >= 30% decline were older age (adjusted OR per 10 years older, 1.51; 95% CI, 1.34-1.71), cardiovascular disease (adjusted OR, 1.53; 95% CI, 1.12-2.10), higher systolic blood pressure (adjusted OR per 17 mm Hg greater, 1.22; 95% CI, 1.06-1.41), DM (adjusted OR, 2.63; 95% CI, 2.02-3.41), smoking (adjusted OR, 1.60; 95% CI, 1.10-2.31), and albumin-creatinine ratio >30 mg/g (adjusted OR, 1.55; 95% CI, 1.08-1.21). Conversely, results did not support associations of waist circumference, C-reactive protein level, and physical activity with rapid decline. Limitations: No midstudy creatinine measurement at examination 2 (2005-2008). Conclusions: Rapid decline heterogeneity exists among African Americans in JHS. Interventions targeting potentially modifiable factors may help reduce the incidence of kidney failure. Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. This is a US Government Work. There are no restrictions on its use. C1 [Young, Bessie A.] Vet Affairs Puget Sound Hlth Care Syst, Ctr Innovat, Seattle, WA USA. [Young, Bessie A.; de Boer, Ian H.] Vet Affairs Puget Sound Hlth Care Syst, Hosp & Specialty Med, Seattle, WA USA. [Young, Bessie A.; Katz, Ronit; Kestenbaum, Bryan; de Boer, Ian H.; Bansal, Nisha; Robinson-Cohen, Cassianne; Himmelfarb, Jonathan] Univ Washington, Kidney Res Inst, Seattle, WA 98195 USA. [Young, Bessie A.; Katz, Ronit; Kestenbaum, Bryan; de Boer, Ian H.; Bansal, Nisha; Robinson-Cohen, Cassianne; Himmelfarb, Jonathan] Univ Washington, Div Nephrol, Seattle, WA 98195 USA. [Boulware, L. Ebony] Duke Univ, Dept Med, Durham, NC USA. [Wang, Wei; Griswold, Michael] Univ Mississippi, Med Ctr, Ctr Biostat & Bioinformat, Jackson, MS 39216 USA. [Fueloep, Tibor; Correa, Adolfo] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Powe, Neil R.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. RP Young, BA (reprint author), VA Puget Sound Hlth Care Syst, Hosp & Specialty Med, 1660 Columbian Way S,RDU 111A, Seattle, WA 98108 USA.; Young, BA (reprint author), VA Puget Sound Hlth Care Syst, Ctr Innovat Vet Ctr & Value Driven Care COIN, 1660 Columbian Way S,RDU 111A, Seattle, WA 98108 USA. EM youngb@uw.edu OI Robinson-Cohen, Cassianne/0000-0003-4783-7046 FU Dr Young's National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases [1R01DK102134-01]; National Heart, Lung and Blood Institute (NHLBI) [HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201 300049C, HHSN268201300050C]; National Institute on Minority Health and Health Disparities; Veterans Affairs Puget Sound Health Care System FX This study was supported by Dr Young's National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases grant 1R01DK102134-01. The JHS is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201 300049C, and HHSN268201300050C from the National Heart, Lung and Blood Institute (NHLBI) and the National Institute on Minority Health and Health Disparities. Drs Young and de Boer are also supported in part by funding from the Veterans Affairs Puget Sound Health Care System. NR 43 TC 3 Z9 3 U1 2 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 0272-6386 EI 1523-6838 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD AUG PY 2016 VL 68 IS 2 BP 229 EP 239 DI 10.1053/j.ajkd.2016.02.046 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA DS4LZ UT WOS:000380753900014 PM 27066930 ER PT J AU Sabharwal, S Kumbhare, D AF Sabharwal, Sunil Kumbhare, Dinesh TI Second-Order Peer Reviews of Clinically Relevant Articles for the Physiatrist Is Venlafaxine XR Effective for Major Depression in People with Spinal Cord Injury? SO AMERICAN JOURNAL OF PHYSICAL MEDICINE & REHABILITATION LA English DT Review DE PREP; Critical Appraisal; Spinal Cord Injury; Venlafaxine ID CONTROLLED-TRIAL; EFFICACY; METAANALYSIS C1 [Sabharwal, Sunil] Harvard Med Sch, Dept Phys Med & Rehabil, VA Boston Hlth Care Syst, Spinal Cord Injury Serv, Boston, MA USA. [Kumbhare, Dinesh] Univ Toronto, Dept Med, Div Phys Med & Rehabil, Toronto, ON, Canada. RP Kumbhare, D (reprint author), Univ Toronto, Dept Med, Div Phys Med & Rehabil, Toronto, ON, Canada. NR 12 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0894-9115 EI 1537-7385 J9 AM J PHYS MED REHAB JI Am. J. Phys. Med. Rehabil. PD AUG PY 2016 VL 95 IS 8 BP E121 EP E124 DI 10.1097/PHM.0000000000000475 PG 4 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA DR9NH UT WOS:000380222900002 PM 27088461 ER PT J AU Kang, SK Huang, WC Skolnik, EY Gervais, DA Braithwaite, RS Pandharipande, PV AF Kang, Stella K. Huang, William C. Skolnik, Edward Y. Gervais, Debra A. Braithwaite, R. Scott Pandharipande, Pari V. TI Tumor Anatomy Scoring and Renal Function for Nephron-Sparing Treatment Selection in Patients With Small Renal Masses: A Microsimulation-Based Decision Analysis SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE chronic kidney disease; nephrometry score; partial nephrectomy; renal mass ID CHRONIC KIDNEY-DISEASE; NORMAL CONTRALATERAL KIDNEY; COST-EFFECTIVENESS ANALYSIS; OPEN PARTIAL NEPHRECTOMY; CELL CARCINOMA; RADIOFREQUENCY ABLATION; PERCUTANEOUS ABLATION; LIFE EXPECTANCY; CONVENIENT APPROXIMATION; EXTIRPATIVE TECHNIQUES AB OBJECTIVE. The purpose of this article is to compare the effectiveness of a treatment algorithm for small renal tumors incorporating the nephrometry score, a renal tumor anatomy scoring system developed by urologists, with the current standard of uniformly recommended partial nephrectomy in patients with mild-to-moderate chronic kidney disease (CKD). MATERIALS AND METHODS. We developed a state-transition microsimulation model to project life expectancy (LE) in hypothetic patients with baseline mild or moderate CKD undergoing treatment of small renal masses. Our model incorporated the nephrometry score, which is predictive of postsurgical renal function loss. The two tested strategies were uniform treatment with partial nephrectomy and selective treatment based on nephrometry score and CKD stage, including percutaneous ablation for CKD stages 2 or 3a and intermediate-to-high nephrometry score or stage 3b CKD and any nephrometry score; otherwise, partial nephrectomy was assumed for other CKD stages and nephrometry scores. The model accounted for benign and malignant lesions, renal function decline, recurrence, and metastatic disease rates specific to each treatment, mortality by CKD stage, and comorbidities. Sensitivity analysis tested the stability of results when varying key parameters. RESULTS. Selective treatment with partial nephrectomy resulted in an average LE benefit of 0.48 year (95% interpercentile range, 0.42-0.54 year) in 65-year-old men and 0.37 year (95% interpercentile range, 0.30-0.43 year) in 65-year-old women relative to nondiscriminatory surgery, due to worsening CKD and cardiovascular mortality associated with partial nephrectomy. Model results were most sensitive to the rate of renal function decline and CKD-related mortality. CONCLUSION. Nephron-sparing treatment selection for small renal masses based on nephrometry score may improve LE in patients with mild or moderate CKD. C1 [Kang, Stella K.] NYU, Sch Med, Dept Radiol, 550 First Ave, New York, NY 10016 USA. [Kang, Stella K.; Braithwaite, R. Scott] NYU, Sch Med, Dept Populat Hlth, New York, NY 10016 USA. [Huang, William C.] NYU, Sch Med, Dept Urol, New York, NY 10003 USA. [Skolnik, Edward Y.] NYU, Sch Med, Dept Med, Div Nephrol, New York, NY USA. [Gervais, Debra A.; Pandharipande, Pari V.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Braithwaite, R. Scott] NYU, Med Ctr, Dept Med, New York, NY 10016 USA. [Pandharipande, Pari V.] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. RP Kang, SK (reprint author), NYU, Sch Med, Dept Radiol, 550 First Ave, New York, NY 10016 USA.; Kang, SK (reprint author), NYU, Sch Med, Dept Populat Hlth, New York, NY 10016 USA. EM stella.kang@nyumc.org OI Kang, Stella/0000-0003-2402-3787; Huang, William/0000-0001-5261-0650 FU Association of University Radiologists-GE Radiology Research Academic Fellowship Award; Medical Imaging and Technology Alliance FX S. K. Kang and this investigation were supported in part by an Association of University Radiologists-GE Radiology Research Academic Fellowship Award. P. V. Pandharipande receives research funding from the Medical Imaging and Technology Alliance for unrelated research. NR 58 TC 0 Z9 0 U1 0 U2 0 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X EI 1546-3141 J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD AUG PY 2016 VL 207 IS 2 BP 344 EP 353 DI 10.2214/AJR.15.15823 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DS5CN UT WOS:000380798400023 PM 27305103 ER PT J AU Ulano, A Bredella, MA Burke, P Chebib, I Simeone, FJ Huang, AJ Torriani, M Chang, CY AF Ulano, Adam Bredella, Miriam A. Burke, Patrick Chebib, Ivan Simeone, F. Joseph Huang, Ambrose J. Torriani, Martin Chang, Connie Y. TI Distinguishing Untreated Osteoblastic Metastases From Enostoses Using CT Attenuation Measurements SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE attenuation; bone island; CT; enostosis; osteoblastic metastatic disease; sclerotic ID BONE ISLAND ENOSTOSIS; BREAST-CANCER; UNITED-STATES; CYTOKINES; PROSTATE; DISEASE AB OBJECTIVE. The purpose of this study was to determine whether CT attenuation thresholds can be used to distinguish untreated osteoblastic metastases from enostoses. MATERIALS AND METHODS. The study group comprised 62 patients with 279 sclerotic bone lesions found at CT (126 enostoses in 37 patients and 153 metastases in 25 patients). The cause of sclerotic lesions was assessed histologically or by clinical and imaging follow-up. None of the patients had undergone prior treatment for the metastases. The mean and maximum attenuation were measured in Hounsfield units. ROC analysis was performed to determine sensitivity, specificity, AUC, 95% CIs, and cutoff values of CT attenuation to differentiate metastases from enostoses. Interreader reproducibility was assessed using an intraclass correlation coefficient with 95% CI. RESULTS. The mean and maximum CT attenuation values of enostoses were 1190 +/- 239 HU and 1323 +/- 234 HU, respectively, and those of osteoblastic metastases were 654 +/- 176 HU and 787 +/- 194 HU, respectively. Using a cutoff of 885 HU for mean attenuation, the AUC was 0.982, sensitivity was 95%, and specificity was 96%. Using a cutoff of 1060 HU for maximum CT attenuation, the AUC was 0.976, sensitivity was 95%, and specificity was 96%. The mean attenuation intraclass correlation coefficient was 0.987 for enostoses and 0.81 for metastases. The maximum attenuation intraclass correlation coefficient was 0.814 for enostoses and 0.980 for metastases. CONCLUSION. CT attenuation measurements can be used to distinguish untreated osteoblastic metastases from enostoses. A mean attenuation of 885 HU and a maximum attenuation of 1060 HU provide reliable thresholds below which a metastatic lesion is the favored diagnosis. C1 [Ulano, Adam; Bredella, Miriam A.; Simeone, F. Joseph; Huang, Ambrose J.; Torriani, Martin; Chang, Connie Y.] Massachusetts Gen Hosp, Dept Radiol, Div Musculoskeletal Imaging & Intervent, 55 Fruit St,YAW6033, Boston, MA 02114 USA. [Burke, Patrick] Massachusetts Gen Hosp, Dept Radiol, Div Abdominal Imaging & Intervent, Boston, MA USA. [Chebib, Ivan] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Chang, CY (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Musculoskeletal Imaging & Intervent, 55 Fruit St,YAW6033, Boston, MA 02114 USA. EM cychang@mgh.harvard.edu NR 40 TC 0 Z9 0 U1 1 U2 1 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X EI 1546-3141 J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD AUG PY 2016 VL 207 IS 2 BP 362 EP 368 DI 10.2214/AJR.15.15559 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DS5CN UT WOS:000380798400025 PM 27101076 ER PT J AU Lopez, J Juan, I Wu, A Samaha, G Cho, B Luck, JD Soni, A Milton, J May, JW Tufaro, AP Dorafshar, AH AF Lopez, Joseph Juan, Ilona Wu, Adela Samaha, Georges Cho, Brian Luck, J. D. Soni, Ashwin Milton, Jacqueline May, James W., Jr. Tufaro, Anthony P. Dorafshar, Amir H. TI The Impact of Financial Conflicts of Interest in Plastic Surgery Are They All Created Equal? SO ANNALS OF PLASTIC SURGERY LA English DT Article DE conflicts of interest; plastic surgery; sunshine act; publication bias; biomedical industry ID ACELLULAR DERMAL MATRIX; BIOMEDICAL-RESEARCH; CLINICAL-TRIALS; NATIONAL-SURVEY; DRUG TRIALS; INDUSTRY; ASSOCIATION; CONCLUSIONS; RECONSTRUCTION; SPONSORSHIP AB Background: Recently, several studies have demonstrated that articles that disclose conflicts of interests (COI) are associated with publication of positive results. The purpose of this study was to learn more about the different types of COI as they relate to the general topic of COI in plastic surgery. Specifically, we aimed to examine whether different types of COI are more likely than others to be associated with the presentation of positive findings. Methods: We reviewed all original articles in Annals of Plastic Surgery, Journal of Plastic, Reconstructive, and Aesthetic Surgery, and Plastic & Reconstructive Surgery from January 1, 2012, to December 31, 2013. All scientific articles were analyzed, and several article characteristics were extracted. Disclosed COI were categorized into the following categories: consultant/employee, royalties/stock options, and research support. The findings reported in each article abstract were blindly graded as reporting a positive, negative, neutral, or not applicable result. A multivariable analysis was performed to determine whether an association existed between certain types of COI and publication of positive conclusions. Results: A total of 3124 articles were identified of which 1185 fulfilled the inclusion criteria. Financial COI were reported in 153 studies (12.9%). The most common type of COI was "research support" (7.3%), whereas the least common was "royalties/stock options" (1.2%). Rates of different types of COI varied significantly by plastic surgery subspecialty field (P < 0.001). In the multivariable analysis, authors who disclosed COI related to research support, consultant/employee, and royalties/stock options were 1.31, 6.62, and 8.72 times more likely, respectively, to publish positive findings when compared with authors that disclosed no COI after correcting for potential confounding factors. However, consultancy/employee status was the only COI category statistically associated with publication of positive results (P < 0.001). Conclusions: Self-reported COI are uncommon in plastic surgery research. Our results provide evidence that certain types of financial COI are more likely than others to be associated with the presentation of positive findings. This analysis suggests that certain investigators may be more biased, consciously or unconsciously, by the type of financial benefit offered by industry. C1 [Lopez, Joseph; Juan, Ilona; Wu, Adela; Cho, Brian; Luck, J. D.; Tufaro, Anthony P.; Dorafshar, Amir H.] Johns Hopkins Univ Hosp, Dept Plast & Reconstruct Surg, Baltimore, MD USA. [Samaha, Georges] Johns Hopkins Univ Hosp, Dept Gen Surg, Baltimore, MD USA. [Soni, Ashwin] Univ Washington, Med Ctr, Div Plast Surg, Seattle, WA 98195 USA. [Milton, Jacqueline] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [May, James W., Jr.] Massachusetts Gen Hosp, Div Plast & Reconstruct Surg, Boston, MA 02114 USA. RP Lopez, J (reprint author), Univ Maryland, Med Ctr, Dept Plast Surg, Johns Hopkins Hosp, 1780 E Fayette St,7th Floor,Rm 7314, Baltimore, MD 21231 USA. EM jlopez37@jhmi.edu FU De Puy Synthes; KLS Martin FX Dr. James W. May Jr is a consultant for TEI Biosciences and an educational consultant for Johnson-Johnson - Mentor. Dr. Amir Dorafshar receives indirect research support and is entitled to royalties from KLS Martin. Dr. Amir Dorafshar also receives research support from De Puy Synthes. NR 36 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 0148-7043 EI 1536-3708 J9 ANN PLAS SURG JI Ann. Plast. Surg. PD AUG PY 2016 VL 77 IS 2 BP 226 EP 230 DI 10.1097/SAP.0000000000000834 PG 5 WC Surgery SC Surgery GA DR9PH UT WOS:000380228100026 PM 27220019 ER PT J AU Loehrer, AP Chang, DC Hutter, MM Warshaw, AL AF Loehrer, Andrew P. Chang, David C. Hutter, Matthew M. Warshaw, Andrew L. TI Surgical Quality and Equity: Revisiting the Class of 1895 SO ANNALS OF SURGERY LA English DT Editorial Material C1 [Loehrer, Andrew P.; Chang, David C.; Hutter, Matthew M.; Warshaw, Andrew L.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 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 NR 6 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD AUG PY 2016 VL 264 IS 2 BP 235 EP 236 DI 10.1097/SLA.0000000000001733 PG 2 WC Surgery SC Surgery GA DS1ZQ UT WOS:000380504400014 PM 27058945 ER PT J AU McMillan, MT Soi, S Asbun, HJ Ball, CG Bassi, C Beane, JD Behrman, SW Berger, AC Bloomston, M Callery, MP Christein, JD Dixon, E Drebin, JA Fernandez-del Castillo, C Fisher, WE Fong, ZV House, MG Hughes, SJ Kent, TS Kunstman, JW Malleo, G Miller, BC Salem, RR Soares, K Valero, V Wolfgang, CL Vollmer, CM AF McMillan, Matthew T. Soi, Sameer Asbun, Horacio J. Ball, Chad G. Bassi, Claudio Beane, Joal D. Behrman, Stephen W. Berger, Adam C. Bloomston, Mark Callery, Mark P. Christein, John D. Dixon, Elijah Drebin, Jeffrey A. Fernandez-del Castillo, Carlos Fisher, William E. Fong, Zhi Ven House, Michael G. Hughes, Steven J. Kent, Tara S. Kunstman, John W. Malleo, Giuseppe Miller, Benjamin C. Salem, Ronald R. Soares, Kevin Valero, Vicente Wolfgang, Christopher L. Vollmer, Charles M., Jr. TI Risk-adjusted Outcomes of Clinically Relevant Pancreatic Fistula Following Pancreatoduodenectomy: A Model for Performance Evaluation SO ANNALS OF SURGERY LA English DT Article DE Fistula Risk Score; pancreatic fistula; pancreatoduodenectomy; performance assessment; risk adjustment ID MULTIINSTITUTIONAL EXTERNAL VALIDATION; ISGPF CLASSIFICATION SCHEME; QUALITY IMPROVEMENT PROGRAM; INTERNATIONAL STUDY-GROUP; PLACEBO-CONTROLLED TRIAL; SURGICAL QUALITY; RANDOMIZED-TRIAL; ACS-NSQIP; POSTOPERATIVE MORBIDITY; PROPHYLACTIC OCTREOTIDE AB Objective: To evaluate surgical performance in pancreatoduodenectomy using clinically relevant postoperative pancreatic fistula (CR-POPF) occurrence as a quality indicator. Background: Accurate assessment of surgeon and institutional performance requires (1) standardized definitions for the outcome of interest and (2) a comprehensive risk-adjustment process to control for differences in patient risk. Methods: This multinational, retrospective study of 4301 pancreatoduodenectomies involved 55 surgeons at 15 institutions. Risk for CR-POPF was assessed using the previously validated Fistula Risk Score, and pancreatic fistulas were stratified by International Study Group criteria. CR-POPF variability was evaluated and hierarchical regression analysis assessed individual surgeon and institutional performance. Results: There was considerable variability in both CR-POPF risk and occurrence. Factors increasing the risk for CR-POPF development included increasing Fistula Risk Score (odds ratio 1.49 per point, P < 0.00001) and octreotide (odds ratio 3.30, P < 0.00001). When adjusting for risk, performance outliers were identified at the surgeon and institutional levels. Of the top 10 surgeons (>= 15 cases) for nonrisk-adjusted performance, only 6 remained in this high-performing category following risk adjustment. Conclusions: This analysis of pancreatic fistulas following pancreatoduodenectomy demonstrates considerable variability in both the risk and occurrence of CR-POPF among surgeons and institutions. Disparities in patient risk between providers reinforce the need for comprehensive, risk-adjusted modeling when assessing performance based on procedure-specific complications. Furthermore, beyond inherent patient risk factors, surgical decision-making influences fistula outcomes. C1 [McMillan, Matthew T.; Drebin, Jeffrey A.; Miller, Benjamin C.; Vollmer, Charles M., Jr.] Univ Penn, Sch Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Soi, Sameer] Mayo Clin, Dept Surg, Jacksonville, FL 32224 USA. [Asbun, Horacio J.; Dixon, Elijah] Univ Calgary, Dept Surg, Calgary, AB, Canada. [Ball, Chad G.; Bassi, Claudio; Malleo, Giuseppe] Univ Verona, Dept Surg, Verona, Italy. [Beane, Joal D.; House, Michael G.] Indiana Univ Sch Med, Dept Surg, Indianapolis, IN 46202 USA. [Behrman, Stephen W.] Univ Tennessee, Ctr Hlth Sci, Dept Surg, Memphis, TN 38163 USA. [Berger, Adam C.] Jefferson Med Coll, Dept Surg, Philadelphia, PA USA. [Bloomston, Mark] Ohio State Univ, Dept Surg, Wexner Med Ctr, Columbus, OH 43210 USA. [Callery, Mark P.; Kent, Tara S.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Surg, Boston, MA USA. [Christein, John D.] Univ Alabama Birmingham, Sch Med, Dept Surg, Birmingham, AL 35294 USA. [Fernandez-del Castillo, Carlos; Fong, Zhi Ven] Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Boston, MA USA. [Fisher, William E.] Baylor Coll Med, Dept Surg, Houston, TX 77030 USA. [Hughes, Steven J.] Univ Florida, Coll Med, Dept Surg, Gainesville, FL USA. [Kunstman, John W.; Salem, Ronald R.] Yale Sch Med, Dept Surg, New Haven, CT USA. [Soares, Kevin; Valero, Vicente; Wolfgang, Christopher L.] Johns Hopkins Sch Med, Dept Surg, Baltimore, MD USA. RP Vollmer, CM (reprint author), Univ Penn, Sch Med, Perelman Sch Med, Philadelphia, PA 19104 USA. EM Charles.Vollmer@uphs.upenn.edu NR 53 TC 5 Z9 5 U1 1 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 AUG PY 2016 VL 264 IS 2 BP 344 EP 352 DI 10.1097/SLA.0000000000001537 PG 9 WC Surgery SC Surgery GA DS1ZQ UT WOS:000380504400031 PM 26727086 ER PT J AU de Jong, MAC Ladha, KS Melo, MFV Staehr-Rye, AK Bittner, EA Kurth, T Eikermann, M AF de Jong, Myrthe A. C. Ladha, Karim S. Melo, Marcos F. Vidal Staehr-Rye, Anne Kathrine Bittner, Edward A. Kurth, Tobias Eikermann, Matthias TI Differential Effects of Intraoperative Positive End-expiratory Pressure (PEEP) on Respiratory Outcome in Major Abdominal Surgery Versus Craniotomy SO ANNALS OF SURGERY LA English DT Article ID INDUCED LUNG INJURY; POSTOPERATIVE PULMONARY COMPLICATIONS; PROTECTIVE MECHANICAL VENTILATION; GENERAL-ANESTHESIA; RISK-FACTORS; VOLUME; HETEROGENEITY; STRATEGIES; BIOTRAUMA; PREVENTS AB Objectives: In this study, we examined whether (1) positive end-expiratory pressure (PEEP) has a protective effect on the risk of major postoperative respiratory complications in a cohort of patients undergoing major abdominal surgeries and craniotomies, and (2) the effect of PEEP is differed by surgery type. Background: Protective mechanical ventilation with lower tidal volumes and PEEP reduces compounded postoperative complications after abdominal surgery. However, data regarding the use of intraoperative PEEP is conflicting. Methods: In this observational study, we included 5915 major abdominal surgery patients and 5063 craniotomy patients. Analysis was performed using multivariable logistic regression. The primary outcome was a composite of major postoperative respiratory complications (respiratory failure, reintubation, pulmonary edema, and pneumonia) within 3 days of surgery. Results: Within the entire study population (major abdominal surgeries and craniotomies), we found an association between application of PEEP >= 5 cmH(2)O and a decreased risk of postoperative respiratory complications compared with PEEP <5cmH(2)O. Application of PEEP >5cmH(2)O was associated with a significant lower odds of respiratory complications in patients undergoing major abdominal surgery (odds ratio 0.53, 95% confidence interval 0.39 - 0.72), effects that translated to deceased hospital length of stay [median hospital length of stay : 6 days (4-9 days), incidence rate ratios for each additional day: 0.91 (0.84 - 0.98)], whereas PEEP >5cmH(2)O was not significantly associated with reduced odds of respiratory complications or hospital length of stay in patients undergoing craniotomy. Conclusions: The protective effects of PEEP are procedure specific with meaningful effects observed in patients undergoing major abdominal surgery. Our data suggest that default mechanical ventilator settings should include PEEP of 5-10cmH(2)O during major abdominal surgery. C1 [de Jong, Myrthe A. C.; Ladha, Karim S.; Melo, Marcos F. Vidal; Staehr-Rye, Anne Kathrine; Bittner, Edward A.; Eikermann, Matthias] Harvard Med Sch, Massachusetts Gen Hosp, Dept Anesthesia, Crit Care,Pain Med, Boston, MA USA. [Staehr-Rye, Anne Kathrine] Univ Copenhagen, Herlev Hosp, Dept Anesthesiol, Copenhagen, Denmark. [Kurth, Tobias] Team Neuroepidemiol, Res Ctr Epidemiol & Biostat, INSERM, U897, Bordeaux, France. [Kurth, Tobias] Univ Bordeaux, Coll Hlth Sci, Bordeaux, France. Harvard Med Sch, Brigham & Womens Hosp, Div Prevent Med, Boston, MA USA. [Eikermann, Matthias] Essen Duisburg Univ, Essen, Germany. RP Melo, MFV (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA. EM mvidalmelo@partners.org RI Kurth, Tobias/A-9243-2012 OI Kurth, Tobias/0000-0001-7169-2620 FU NIH [R01 HL 121228] FX This study was funded by a grant of Judy and Jeff Buzen to Matthias Eikermann and by NIH grant R01 HL 121228 to Marcos Vidal Melo. This project received approval from the Partners Institutional Review Board, protocol number: 2014P002718. The authors declare no conflict of interest. NR 41 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 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD AUG PY 2016 VL 264 IS 2 BP 362 EP 369 DI 10.1097/SLA.0000000000001499 PG 8 WC Surgery SC Surgery GA DS1ZQ UT WOS:000380504400033 PM 26496082 ER PT J AU Aranson, NJ Lancaster, RT Ergul, EA Conrad, MF LaMuraglia, GM Kwolek, CJ Cambria, RP Patel, VI AF Aranson, Nathan J. Lancaster, Robert T. Ergul, Emel A. Conrad, Mark F. LaMuraglia, Glenn M. Kwolek, Christopher J. Cambria, Richard P. Patel, Virendra I. TI Chronic Kidney Disease Class Predicts Mortality After Abdominal Aortic Aneurysm Repair in Propensity-matched Cohorts From the Medicare Population SO ANNALS OF SURGERY LA English DT Article DE abdominal aortic aneurysm; chronic kidney disease; Medicare ID GLOMERULAR-FILTRATION-RATE; SERUM CREATININE; POSTOPERATIVE MORTALITY; RENAL-DISEASE; SURGERY; EXPERIENCE; OUTCOMES; IMPACT; INTACT; UNFIT AB Introduction: Chronic kidney disease (CKD) predicts mortality after abdominal aortic aneurysm (AAA) repair. Few studies are adequately powered to stratify outcomes by CKD severity. This study assesses the effect of CKD severity on survival after AAA repair. Methods: Patients who underwent AAA repair from 2006 to 2007 were retrospectively identified in the Medicare database and stratified by CKD class as follows: normal (CKD class 1 and 2), moderate (CKD class 3), and severe (CKD class 4 and 5). Propensity matching (30: 1) by clinical factors and procedure type was performed to derive well-matched comparative cohorts. Primary outcomes were 30-day and long-term mortality; secondary outcomes included hospital length of stay and cost. Results: A total of 47,715 patients were included (96.7% normal, 1.88% moderate, and 1.65% severe). Propensity matching was corrected for differences between cohorts. Thirty-day mortality was higher in moderate (5.7% vs normal 2.5%; P < 0.01) and severe (9.9% vs normal 1.8%; P < 0.01) groups. Hospital length of stay increased with CKD severity (4.4 +/- 3.7 days normal vs 6.5 +/- 4.2 days moderate CKD; P < 0.01/4.7 +/- 3.8 days normal vs 9.1 +/- 4.5 days severe CKD; P < 0.01) as did cost ($23 +/- 14K normal vs $25 +/- 16K moderate; P < 0.01 /$22 +/- 11K normal vs $29 +/- 22K severe; P < 0.01). Three-year survival favored the normal cohort (80% vs 64% moderate; log rank P < 0.01 /82% normal vs 44% severe; log rank P < 0.01). Conclusions: CKD severity is an important predictor of perioperative mortality and long-term survival after AAA repair in propensity-matched cohorts. The 5-fold increase in 30-day mortality and 44% in 3-year survival suggest that elective AAA repair is contraindicated in most severe CKD patients. C1 [Aranson, Nathan J.; Lancaster, Robert T.; Ergul, Emel A.; Conrad, Mark F.; LaMuraglia, Glenn M.; Kwolek, Christopher J.; Cambria, Richard P.; Patel, Virendra I.] Massachusetts Gen Hosp, Dept Surg, Div Vasc & Endovasc Surg, 15 Parkman St,Wang ACC 440, Boston, MA 02114 USA. RP Patel, VI (reprint author), Massachusetts Gen Hosp, Dept Surg, Div Vasc & Endovasc Surg, 15 Parkman St,Wang ACC 440, Boston, MA 02114 USA. EM vpatel4@partners.org NR 37 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 AUG PY 2016 VL 264 IS 2 BP 386 EP 391 DI 10.1097/SLA.0000000000001519 PG 6 WC Surgery SC Surgery GA DS1ZQ UT WOS:000380504400036 PM 27414155 ER PT J AU Li, J Brock, J Jack, B Mittman, B Naylor, M Sorra, J Mays, G Williams, MV AF Li, Jing Brock, Jane Jack, Brian Mittman, Brian Naylor, Mary Sorra, Joann Mays, Glen Williams, Mark V. CA Project ACHIEVE Team TI Project ACHIEVE - using implementation research to guide the evaluation of transitional care effectiveness (vol 16, 70, 2016) SO BMC HEALTH SERVICES RESEARCH LA English DT Correction C1 [Li, Jing] Univ Kentucky, Ctr Hlth Serv Res, Lexington, KY USA. [Li, Jing] Univ Kentucky, Internal Med, Lexington, KY USA. [Brock, Jane] Telligen, Care Transit Theme Support Ctr, Englewood, CO USA. [Jack, Brian] Boston Univ, Sch Med, Family Med, Boston, MA 02118 USA. [Mittman, Brian] Kaiser Permanente, Res & Evaluat, Pasadena, CA USA. [Mittman, Brian] US Dept Vet Affairs, Greater Los Angeles Healthcare Syst, VA Ctr Implementat Practice & Res, Los Angeles, CA USA. [Mittman, Brian] Univ Calif Los Angeles, Clin Translat Sci Inst, Sch Med, Los Angeles, CA USA. [Naylor, Mary] Univ Penn, Sch Nursing, NewCourtland Ctr Transit & Hlth, Philadelphia, PA 19104 USA. [Sorra, Joann] Westat Corp, Washington, DC USA. [Mays, Glen] Univ Kentucky, Natl Coordinating Ctr Publ Hlth Serv & Syst Res, Lexington, KY USA. [Williams, Mark V.] Univ Kentucky, Dept Internal Med, Ctr Hlth Serv Res, Kentucky Clin J525, Lexington, KY 40536 USA. RP Williams, MV (reprint author), Univ Kentucky, Dept Internal Med, Ctr Hlth Serv Res, Kentucky Clin J525, Lexington, KY 40536 USA. EM mark.will@uky.edu NR 2 TC 0 Z9 0 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6963 J9 BMC HEALTH SERV RES JI BMC Health Serv. Res. PD AUG 1 PY 2016 VL 16 AR 326 DI 10.1186/s12913-016-1560-x PG 1 WC Health Care Sciences & Services SC Health Care Sciences & Services GA DS2XX UT WOS:000380648300002 ER PT J AU Halpern, MT Schrag, D AF Halpern, Michael T. Schrag, Deborah TI Effects of state-level medicaid policies and patient characteristics on time to breast cancer surgery among medicaid beneficiaries SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Breast neoplasms; Medicaid; Time factors; Mastectomy; Breast conserving surgery ID ADJUVANT CHEMOTHERAPY; CLAIMS DATA; ACCESS; INSURANCE; DIAGNOSIS; CARE; INITIATION; IMPACT; DELAYS; WOMEN AB Medicaid beneficiaries with cancer are less likely to receive timely and high-quality care. This study examined whether differences in state-level Medicaid policies affect delays in time to surgery (TTS) among women diagnosed with breast cancer. Using 2006-2008 Medicaid data, we identified women aged 18-64 enrolled in Medicaid diagnosed with breast cancer. Analyses examined associations of state-specific Medicaid surgery reimbursements, Medicaid eligibility recertification period (annually vs. shorter) and required patient copayment on time from breast cancer diagnosis to receipt of breast surgery. Patients receiving neoadjuvant therapy were excluded. Separate multivariable regression analyses controlling for patient demographic characteristics and clustering by state were performed for breast conserving surgery (BCS), inpatient mastectomy, and outpatient mastectomy. The study included 7542 Medicaid beneficiaries with breast cancer: 3272 received BCS, 2156 outpatient mastectomy, and 2115 inpatient mastectomy. Higher Medicaid reimbursements for BCS were associated with decreased time from diagnosis to surgery. A 12-month (vs. < 12 month) Medicaid eligibility recertification period was associated with decreased TTS for BCS and outpatient mastectomy. Black Medicaid beneficiaries (compared with non-Hispanic White beneficiaries) were more likely to experience delays for all three types of surgery, while Hispanic beneficiaries were more likely to experience delays only for outpatient mastectomy. State-level Medicaid policies and patient characteristics can affect receipt of timely surgery among Medicaid beneficiaries with breast cancer. As delays in surgery can increase morbidity and mortality, changes to state Medicaid policies and health system programs are needed to improve access to care for this vulnerable population. C1 [Halpern, Michael T.] RTI Int, Washington, DC 20005 USA. [Halpern, Michael T.] Temple Univ, Hlth Serv Adm & Policy, Coll Publ Hlth, 1301 Cecil B Moore Ave 533, Philadelphia, PA 19122 USA. [Schrag, Deborah] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Halpern, MT (reprint author), RTI Int, Washington, DC 20005 USA.; Halpern, MT (reprint author), Temple Univ, Hlth Serv Adm & Policy, Coll Publ Hlth, 1301 Cecil B Moore Ave 533, Philadelphia, PA 19122 USA. EM michael.halpern@temple.edu FU American Cancer Society [RSGI-12-009-01-CHPS] FX This study was supported by the American Cancer Society (Grant # RSGI-12-009-01-CHPS). NR 35 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 EI 1573-7217 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD AUG PY 2016 VL 158 IS 3 BP 573 EP 581 DI 10.1007/s10549-016-3879-8 PG 9 WC Oncology SC Oncology GA DS3VV UT WOS:000380711700016 PM 27422241 ER PT J AU Albertini, MR Ranheim, EA Zuleger, CL Sondel, PM Hank, JA Bridges, A Newton, MA McFarland, T Collins, J Clements, E Henry, MB Neuman, HB Weber, S Whalen, G Galili, U AF Albertini, Mark R. Ranheim, Erik A. Zuleger, Cindy L. Sondel, Paul M. Hank, Jacquelyn A. Bridges, Alan Newton, Michael A. McFarland, Thomas Collins, Jennifer Clements, Erin Henry, Mary Beth Neuman, Heather B. Weber, Sharon Whalen, Giles Galili, Uri TI Phase I study to evaluate toxicity and feasibility of intratumoral injection of alpha-gal glycolipids in patients with advanced melanoma SO CANCER IMMUNOLOGY IMMUNOTHERAPY LA English DT Article DE Immunotherapy; alpha-Gal glycolipids; Cancer vaccines; Melanoma ID CARCINOMA-SPECIFIC IMMUNOTHERAPY; ANTI-GAL; INCREASED IMMUNOGENICITY; CANCER-IMMUNOTHERAPY; UNTREATED MELANOMA; GALACTOSYL EPITOPE; IGG ANTIBODY; T-CELLS; VACCINE; SURVIVAL AB Effective uptake of tumor cell-derived antigens by antigen-presenting cells is achieved pre-clinically by in situ labeling of tumor with alpha-gal glycolipids that bind the naturally occurring anti-Gal antibody. We evaluated toxicity and feasibility of intratumoral injections of alpha-gal glycolipids as an autologous tumor antigen-targeted immunotherapy in melanoma patients (pts). Pts with unresectable metastatic melanoma, at least one cutaneous, subcutaneous, or palpable lymph node metastasis, and serum anti-Gal titer a parts per thousand yen1:50 were eligible for two intratumoral alpha-gal glycolipid injections given 4 weeks apart (cohort I: 0.1 mg/injection; cohort II: 1.0 mg/injection; cohort III: 10 mg/injection). Monitoring included blood for clinical, autoimmune, and immunological analyses and core tumor biopsies. Treatment outcome was determined 8 weeks after the first alpha-gal glycolipid injection. Nine pts received two intratumoral injections of alpha-gal glycolipids (3 pts/cohort). Injection-site toxicity was mild, and no systemic toxicity or autoimmunity could be attributed to the therapy. Two pts had stable disease by RECIST lasting 8 and 7 months. Tumor nodule biopsies revealed minimal to no change in inflammatory infiltrate between pre- and post-treatment biopsies except for 1 pt (cohort III) with a post-treatment inflammatory infiltrate. Two and four weeks post-injection, treated nodules in 5 of 9 pts exhibited tumor cell necrosis without neutrophilic or lymphocytic inflammatory response. Non-treated tumor nodules in 2 of 4 evaluable pts also showed necrosis. Repeated intratumoral injections of alpha-gal glycolipids are well tolerated, and tumor necrosis was seen in some tumor nodule biopsies after tumor injection with alpha-gal glycolipids. C1 [Albertini, Mark R.; Ranheim, Erik A.; Zuleger, Cindy L.; Sondel, Paul M.; Hank, Jacquelyn A.; Newton, Michael A.; McFarland, Thomas; Collins, Jennifer; Clements, Erin; Neuman, Heather B.; Weber, Sharon] Univ Wisconsin, Carbone Canc Ctr, Madison, WI USA. [Albertini, Mark R.; Zuleger, Cindy L.; Bridges, Alan; McFarland, Thomas] Univ Wisconsin, Sch Med & Publ Hlth, Dept Med, Madison, WI USA. [Albertini, Mark R.; Bridges, Alan] William S Middleton Mem Vet Adm Med Ctr, Med Serv, Madison, WI USA. [Ranheim, Erik A.] Univ Wisconsin, Dept Pathol, Sch Med & Publ Hlth, Madison, WI 53706 USA. [Sondel, Paul M.; Hank, Jacquelyn A.] Univ Wisconsin, Dept Human Oncol, Sch Med & Publ Hlth, Madison, WI USA. [Sondel, Paul M.] Univ Wisconsin, Dept Pediat, Sch Med & Publ Hlth, Madison, WI USA. [Newton, Michael A.] Univ Wisconsin, Dept Biostat & Med Informat, Sch Med & Publ Hlth, Madison, WI USA. [Henry, Mary Beth; Neuman, Heather B.; Weber, Sharon] Univ Wisconsin, Dept Surg, Sch Med & Publ Hlth, Madison, WI USA. [Whalen, Giles; Galili, Uri] Univ Massachusetts, Dept Surg, Sch Med, Worcester, MA USA. [Albertini, Mark R.] Univ Wisconsin, Ctr Clin Sci, Room K6-530,600 Highland Ave, Madison, WI 53792 USA. RP Albertini, MR (reprint author), Univ Wisconsin, Carbone Canc Ctr, Madison, WI USA.; Albertini, MR (reprint author), Univ Wisconsin, Sch Med & Publ Hlth, Dept Med, Madison, WI USA.; Albertini, MR (reprint author), William S Middleton Mem Vet Adm Med Ctr, Med Serv, Madison, WI USA.; Albertini, MR (reprint author), Univ Wisconsin, Ctr Clin Sci, Room K6-530,600 Highland Ave, Madison, WI 53792 USA. EM mralbert@wisc.edu FU NIH from the National Cancer Institute [CA130295, P30 CA014520]; Clinical and Translational Science Award (CTSA) program, through the NIH National Center for Advancing Translational Sciences (NCATS) [UL1TR000427]; Ann's Hope Foundation; Tim Eagle Memorial; Jay Van Sloan Memorial from the Steve Leuthold Family; Gretchen and Andrew Dawes Melanoma Research Fund; Agalimmune FX Support was provided by NIH Grants CA130295, P30 CA014520 from the National Cancer Institute, by resources at the William S. Middleton Memorial Veterans Hospital, Madison, WI, and by the Clinical and Translational Science Award (CTSA) program, through the NIH National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000427. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the views of the Department of Veterans Affairs or the US Government. Additional support was provided by Ann's Hope Foundation, the Tim Eagle Memorial, the Jay Van Sloan Memorial from the Steve Leuthold Family, the Gretchen and Andrew Dawes Melanoma Research Fund, and Agalimmune. NR 41 TC 0 Z9 0 U1 4 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-7004 EI 1432-0851 J9 CANCER IMMUNOL IMMUN JI Cancer Immunol. Immunother. PD AUG PY 2016 VL 65 IS 8 BP 897 EP 907 DI 10.1007/s00262-016-1846-1 PG 11 WC Oncology; Immunology SC Oncology; Immunology GA DS1OW UT WOS:000380366800002 PM 27207605 ER PT J AU Yende, S Austin, S Rhodes, A Finfer, S Opal, S Thompson, T Bozza, FA LaRosa, SP Ranieri, VM Angus, DC AF Yende, Sachin Austin, Shamly Rhodes, Andrew Finfer, Simon Opal, Steven Thompson, Taylor Bozza, Fernando A. LaRosa, Steven P. Ranieri, V. Marco Angus, Derek C. TI Long-Term Quality of Life Among Survivors of Severe Sepsis: Analyses of Two International Trials SO CRITICAL CARE MEDICINE LA English DT Editorial Material DE quality of life; sepsis ID SEPTIC SHOCK; CRITICAL ILLNESS; ADULTS; BURDEN; CARE AB Objectives: To describe the quality of life among sepsis survivors. Design: Secondary analyses of two international, randomized clinical trials (A Controlled Comparison of Eritoran and placebo in patients with Severe Sepsis [derivation cohort] and PROWESS-SHOCK [validation cohort]). Setting: ICUs in North and South America, Europe, Africa, Asia, and Australia. Patients: Adults with severe sepsis. We analyzed only patients who were functional and living at home without help before sepsis hospitalization (n = 1,143 and 987 from A Controlled Comparison of Eritoran and placebo in patients with Severe Sepsis and PROWESS-SHOCK, respectively). Interventions: None. Measurements and Main Results: In A Controlled Comparison of Eritoran and placebo in patients with Severe Sepsis and PROWESS-SHOCK, the average age of patients living at home independently was 63 and 61 years; 400 (34.9%) and 298 (30.2%) died by 6 months. In A Controlled Comparison of Eritoran and placebo in patients with Severe Sepsis, 580 patients had a quality of life measured using EQ-5D at 6 months. Of these, 41.6% could not live independently (22.7% were home but required help, 5.1% were in nursing home or rehabilitation facilities, and 5.3% were in acute care hospitals). Poor quality of life at 6 months, as evidenced by problems in mobility, usual activities, and self-care domains were reported in 37.4%, 43.7%, and 20.5%, respectively, and the high incidence of poor quality of life was also seen in patients in PROWESS-SHOCK. Over 45% of patients with mobility and self-care problems at 6 months in A Controlled Comparison of Eritoran and placebo in patients with Severe Sepsis died or reported persistent problems at 1 year. Conclusions: Among individuals enrolled in a clinical trial who lived independently prior to severe sepsis, one third had died and of those who survived, a further one third had not returned to independent living by 6 months. Both mortality and quality of life should be considered when designing new interventions and considering endpoints for sepsis trials. C1 [Yende, Sachin; Austin, Shamly; Bozza, Fernando A.; Angus, Derek C.] Univ Pittsburgh, Clin Res Invest & Syst Modeling Acute Illnes CRIS, Dept Crit Care Med, Pittsburgh, PA 15260 USA. [Yende, Sachin] Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA 15261 USA. [Austin, Shamly] Gateway Hlth, Res & Dev, Qual Improvement Dept, Pittsburgh, PA USA. [Rhodes, Andrew] NHS Fdn Trust, St Georges Univ Hosp, Adult Crit Care, London, England. [Finfer, Simon] Univ Sydney, George Inst Global Hlth, Sydney, NSW, Australia. [Opal, Steven] Brown Univ, Alpert Med Sch, Div Infect Dis, Pawtucket, RI USA. [Thompson, Taylor] Massachusetts Gen Hosp, Pulm & Crit Care Div, Boston, MA 02114 USA. [Bozza, Fernando A.] Fundacao Oswaldo Cruz FIOCRUZ, Evandro Chagas Natl Inst Infect Dis, Rio De Janeiro, Brazil. [LaRosa, Steven P.] Lahey Hlth Syst, Beverly Hosp, Beverly, MA USA. [Ranieri, V. Marco] Univ Sapienza Rome, Policlin Umberto I Hosp, Dept Anesthesia & Intens Care Med, Rome, Italy. RP Yende, S (reprint author), Univ Pittsburgh, Clin Res Invest & Syst Modeling Acute Illnes CRIS, Dept Crit Care Med, Pittsburgh, PA 15260 USA.; Yende, S (reprint author), Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA 15261 USA. EM yendes@upmc.edu FU NIGMS NIH HHS [R01 GM097471] NR 13 TC 8 Z9 9 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0090-3493 EI 1530-0293 J9 CRIT CARE MED JI Crit. Care Med. PD AUG PY 2016 VL 44 IS 8 BP 1461 EP 1467 DI 10.1097/CCM.0000000000001658 PG 7 WC Critical Care Medicine SC General & Internal Medicine GA DS2RK UT WOS:000380631000002 PM 26992066 ER PT J AU Dai, XP Bragina, O Zhang, TS Yang, YR Rao, GR Bragin, DE Statom, G Nemoto, EM AF Dai, Xingping Bragina, Olga Zhang, Tongsheng Yang, Yirong Rao, Gutti R. Bragin, Denis E. Statom, Gloria Nemoto, Edwin M. TI High Intracranial Pressure Induced Injury in the Healthy Rat Brain SO CRITICAL CARE MEDICINE LA English DT Article DE cerebral arteriovenous oxygen difference; cerebral blood flow; Fluoro-Jade stain; intracranial hypertension; ischemia; microvascular shunting ID CEREBRAL PERFUSION-PRESSURE; METABOLIC-RATE; VENOUS SYSTEM; HYPERTENSION; OXYGEN; HYPOTHERMIA; VOLUME; FLOW AB Objectives: We recently showed that increased intracranial pressure to 50 mm Hg in the healthy rat brain results in microvascular shunt flow characterized by tissue hypoxia, edema, and increased blood-brain barrier permeability. We now determined whether increased intracranial pressure results in neuronal injury by Fluoro-Jade stain and whether changes in cerebral blood flow and cerebral metabolic rate for oxygen suggest nonnutritive microvascular shunt flow. Design: Intracranial pressure was elevated by a reservoir of artificial cerebrospinal fluid connected to the cisterna magna. Arterial blood gases, cerebral arterial-venous oxygen content difference, and cerebral blood flow by MRI were measured. Fluoro-Jade stain neurons were counted in histologic sections of the right and left dorsal and lateral cortices and hippocampus. Setting: University laboratory. Subjects: Male Sprague Dawley rats. Interventions: Arterial pressure support if needed by IV dopamine infusion and base deficit corrected by sodium bicarbonate. Measurements and Main Results: Fluoro-Jade stain neurons increased 2.5- and 5.5-fold at intracranial pressures of 30 and 50 mm Hg and cerebral perfusion pressures of 57 +/- 4 (mean +/- sem) and 47 +/- 6 mm Hg, respectively (p < 0.001) (highest in the right and left cortices). Voxel frequency histograms of cerebral blood flow showed a pattern consistent with microvascular shunt flow by dispersion to higher cerebral blood flow at high intracranial pressure and decreased cerebral metabolic rate for oxygen. Conclusions: High intracranial pressure likely caused neuronal injury because of a transition from normal capillary flow to nonnutritive microvascular shunt flow resulting in tissue hypoxia and edema, and it is manifest by a reduction in the cerebral metabolic rate for oxygen. C1 [Dai, Xingping] Cent S Univ, Xiangya Hosp, Integrated Tradit Chinese & Western Med, Changsha, Hunan, Peoples R China. [Dai, Xingping; Bragina, Olga; Zhang, Tongsheng; Bragin, Denis E.; Statom, Gloria; Nemoto, Edwin M.] Univ New Mexico, Dept Neurosurg, Albuquerque, NM 87131 USA. [Yang, Yirong] Univ New Mexico, Coll Pharm, BRaIN Imaging Ctr, Dept Pharmaceut Sci, Albuquerque, NM 87131 USA. [Rao, Gutti R.] VA Pittsburgh Hlth Care Syst, Dept Pathol & Lab Med, Pittsburgh, PA USA. RP Nemoto, EM (reprint author), Univ New Mexico, Dept Neurosurg, BRaIN Ctr, 1101 Yale Blvd NE,Domenici Hall,Rm 1131B, Albuquerque, NM 87131 USA. EM ENemoto@salud.unm.edu RI Bragin, Denis/E-5494-2016 OI Bragin, Denis/0000-0003-4894-0061 FU National Institutes of Health (NIH) [NS061216, NS051639]; China Scholarship Council [201206375041]; AHA [12BGIA11730011UNM, 12BGIA11730011]; HSC COBRE program [P20 RR15636]; NIH-NINDS CoBRE Pilot Project [P30GM103400]; UNM SOM Dedicated Health Research Fund Pilot Project; Department of Neurosurgery; UNM HSC COBRE program [P20 RR15636]; AHA Chinese Govt. UNM COBRE FX Dr. Nemoto received support for article research from the National Institutes of Health (NIH), The China Scholarship Council Grant (#201206375041 to Dr. Xingping Dai), AHA 12BGIA11730011UNM HSC COBRE program (P20 RR15636), NIH-NINDS CoBRE Pilot Project P30GM103400, UNM SOM Dedicated Health Research Fund Pilot Project, and the Department of Neurosurgery. Dr. Dai disclosed other support from the AHA 12BGIA11730011; NIH Grants NS061216, NS051639 and UNM HSC COBRE program (P20 RR15636); NIH-NINDS CoBRE Pilot Project P30GM103400; UNM SOM Dedicated Health Research Fund Pilot Project; and the Department of Neurosurgery. He received funding from The China Scholarship Council Grant (#201206375041). Dr. Zhang received support for article research from the NIH and received funding from the China Scholarship Council Grant (#201206375041 for Dr. Dai). Dr. Yang received support for article research from the NIH and disclosed work for hire. Dr. Statom received support for article research from the NIH and AHA Chinese Govt. UNM COBRE. The remaining authors have disclosed that they do not have any potential conflicts of interest. NR 28 TC 0 Z9 0 U1 4 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0090-3493 EI 1530-0293 J9 CRIT CARE MED JI Crit. Care Med. PD AUG PY 2016 VL 44 IS 8 BP E633 EP E638 DI 10.1097/CCM.0000000000001625 PG 6 WC Critical Care Medicine SC General & Internal Medicine GA DS2RK UT WOS:000380631000037 PM 26974548 ER PT J AU Smith, JA Mayeux, PR Schnellmann, RG AF Smith, Joshua A. Mayeux, Philip R. Schnellmann, Rick G. TI Delayed Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Inhibition by Trametinib Attenuates Systemic Inflammatory Responses and Multiple Organ Injury in Murine Sepsis SO CRITICAL CARE MEDICINE LA English DT Article DE inflammation; mitogen-activated protein kinase/extracellular signal-regulated kinase; multiple organ failure; sepsis; trametinib ID ACUTE KIDNEY INJURY; ACUTE-RENAL-FAILURE; PERITUBULAR CAPILLARY DYSFUNCTION; MITOCHONDRIAL BIOGENESIS; ANIMAL-MODELS; MICROVASCULAR DYSFUNCTION; POLYMICROBIAL SEPSIS; MOUSE MODEL; INDUCTION; IMPROVES AB Objective: The mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathway is an essential component of innate immunity necessary for mediating proinflammatory responses in the setting of sepsis. We previously demonstrated that the mitogen-activated protein kinase 1/2 inhibitor trametinib prevents endotoxin-induced renal injury in mice. We therefore assessed efficacy of trametinib in a more clinically relevant experimental model of sepsis. Design: Controlled in vivo laboratory study. Setting: University animal research laboratory. Subjects: Male C57BL/6 mice. Interventions: Mice were subjected to cecal ligation and puncture to induce sepsis or underwent sham operation as controls. Six hours after cecal ligation and puncture, mice were randomized to four experimental groups as follows: 1) sham control; 2) sham control + trametinib (1 mg/kg, IP); 3) cecal ligation and puncture; and 4) cecal ligation and puncture + trametinib. All animals received buprenorphine (0.05 mg/kg, SC) and imipenem/cilastatin (14 mg/kg, SC) in 1.5 mL of warm saline (40 mL/kg) at the 6-hour time point. Mice were euthanized at 18 hours after induction of cecal ligation and puncture. Measurements and Main Results: Trametinib inhibition of mitogen-activated protein kinase/extracellular signal-regulated kinase signaling 6 hours after cecal ligation and puncture attenuated increases in circulating proinflammatory cytokines (tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6, and granulocyte macrophage colony-stimulating factor) and hypothermia at 18 hours. Trametinib also attenuated multiple organ injury as determined by serum creatinine, alanine aminotransferase, lactate dehydrogenase, and creatine kinase. At the organ level, trametinib completely restored peritubular capillary perfusion in the kidney. Restoration of microvascular perfusion was associated with reduced messenger RNA expression of well-characterized markers of proximal tubule injury. mitogen-activated protein kinase/extracellular signal-regulated kinase blockade attenuated cecal ligation and puncture-mediated up-regulation of cytokines (tumor necrosis factor-alpha, interleukin-1 beta) and restored interleukin-6 to control levels in the renal cortex, indicating the protective effects on the proximal tubule occur primarily through modulation of the proinflammatory response in sepsis. Conclusions: These data reveal that the mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor trametinib attenuates systemic inflammation and multiple organ damage in a clinically relevant model of sepsis. Because trametinib has been safely used in humans, we propose that this drug might represent a translatable approach to limit organ injury in septic patients. C1 [Smith, Joshua A.; Schnellmann, Rick G.] Univ Colorado Denver, Dept Med, Aurora, CO 80045 USA. [Mayeux, Philip R.] Univ Arkansas Med Sci, Dept Pharmacol & Toxicol, Little Rock, AR 72205 USA. [Schnellmann, Rick G.] Ralph H Johnson Vet Adm Med Ctr, Charleston, SC USA. RP Schnellmann, RG (reprint author), Univ Colorado Denver, Dept Med, Aurora, CO 80045 USA.; Schnellmann, RG (reprint author), Ralph H Johnson Vet Adm Med Ctr, Charleston, SC USA. EM schnell@musc.edu FU National Institute of General Medical Sciences; National Center for Research Resources [UL1-RR029882, C06-RR015455]; South Carolina Clinical and Translational Research Institute at the Medical University of South Carolina; National Institutes of Health (NIH); NIH, National Institute of General Medical Sciences (NIGMS); Biomedical Laboratory Research, and Development Program of the Department of Veterans Affairs; NIH [R01 GM106419, P20GM103542-02]; Journal of Pharmacology and Experimental Therapeutics; NIGMS [GM084147]; Biomedical Laboratory Research and Development Program of the Department of Veterans Affairs [5I01 BX-000851] FX Supported, in part, by National Institute of General Medical Sciences; National Center for Research Resources (UL1-RR029882); and the South Carolina Clinical and Translational Research Institute at the Medical University of South Carolina. Animal facilities were funded by National Center for Research Resources (C06-RR015455).; Mr. Smith received support for article research from the National Institutes of Health (NIH). His institution received grant support from the NIH, National Institute of General Medical Sciences (NIGMS), and Biomedical Laboratory Research, and Development Program of the Department of Veterans Affairs. Dr. Mayeux received support for article research from the NIH and received funding from the Journal of Pharmacology and Experimental Therapeutics (Associate Editor). His institution received grant support from the NIH R01 GM106419. Dr. Schnellmann received support for article research from the NIH. His institution received funding from the NIH ((and P20GM103542-02 [to South Carolina COBRE in Oxidants, Redox Balance, and Stress Signaling), NIGMS (GM084147), and the Biomedical Laboratory Research and Development Program of the Department of Veterans Affairs (5I01 BX-000851). NR 50 TC 3 Z9 3 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0090-3493 EI 1530-0293 J9 CRIT CARE MED JI Crit. Care Med. PD AUG PY 2016 VL 44 IS 8 BP E711 EP E720 DI 10.1097/CCM.0000000000001672 PG 10 WC Critical Care Medicine SC General & Internal Medicine GA DS2RK UT WOS:000380631000044 PM 27031380 ER PT J AU Nguyen, KL Hu, P Ennis, DB Shao, JX Pham, KA Chen, JJ AF Nguyen, Kim-Lien Hu, Peng Ennis, Daniel B. Shao, Jiaxin Pham, Kimberly A. Chen, Joseph J. TI Cardiac MRI: a Translational Imaging Tool for Characterizing Anthracycline-Induced Myocardial Remodeling SO CURRENT ONCOLOGY REPORTS LA English DT Review DE Cardiac magnetic resonance imaging; Cardiotoxicity; Cardio-oncology; Anthracyclines; Translational imaging ID CARDIOVASCULAR MAGNETIC-RESONANCE; CORONARY-HEART-DISEASE; EMISSION COMPUTED-TOMOGRAPHY; SENSITIVE INVERSION-RECOVERY; STEADY-STATE PRECESSION; LONG-TERM SURVIVORS; EXTRACELLULAR VOLUME; CHILDHOOD-CANCER; CE-MARC; INTERSTUDY REPRODUCIBILITY AB Cardiovascular side effects of cancer therapeutics are the leading causes of morbidity and mortality in cancer survivors. Anthracyclines (AC) serve as the backbone of many anti-cancer treatment strategies, but dose-dependent myocardial injury limits their use. Cumulative AC exposure can disrupt the dynamic equilibrium of the myocardial microarchitecture while repeated injury and repair leads to myocyte loss, interstitial myocardial fibrosis, and impaired contractility. Although children are assumed to have greater myocardial plasticity, AC exposure at a younger age portends worse prognosis. In older patients, there is lower overall survival once they develop cardiovascular disease. Because aberrations in the myocardial architecture predispose the heart to a decline in function, early detection with sensitive imaging tools is crucial and the implications for resource utilization are substantial. As a comprehensive imaging modality, cardiac magnetic resonance (CMR) imaging is able to go beyond quantification of ejection fraction and myocardial deformation to characterize adaptive microstructural and microvascular changes that are important to myocardial tissue health. Herein, we describe CMR as an established translational imaging tool that can be used clinically to characterize ACassociated myocardial remodeling. C1 [Nguyen, Kim-Lien; Hu, Peng; Shao, Jiaxin] Univ Calif Los Angeles, David Geffen Sch Med, Diagnost Cardiovasc Imaging Lab, Los Angeles, CA 90095 USA. [Nguyen, Kim-Lien; Hu, Peng; Shao, Jiaxin; Pham, Kimberly A.; Chen, Joseph J.] VA Greater Los Angeles Healthcare Syst, 11301 Wilshire Blvd,MC 111E, Los Angeles, CA 90024 USA. [Nguyen, Kim-Lien; Shao, Jiaxin; Pham, Kimberly A.; Chen, Joseph J.] Univ Calif Los Angeles, David Geffen Sch Med, Div Cardiol, 11301 Wilshire Blvd,MC 111E, Los Angeles, CA 90024 USA. [Hu, Peng; Ennis, Daniel B.; Shao, Jiaxin] Univ Calif Los Angeles, David Geffen Sch Med, Dept Radiol Sci, Los Angeles, CA 90095 USA. RP Nguyen, KL (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Diagnost Cardiovasc Imaging Lab, Los Angeles, CA 90095 USA.; Nguyen, KL (reprint author), VA Greater Los Angeles Healthcare Syst, 11301 Wilshire Blvd,MC 111E, Los Angeles, CA 90024 USA.; Nguyen, KL (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Div Cardiol, 11301 Wilshire Blvd,MC 111E, Los Angeles, CA 90024 USA. EM klnguyen@ucla.edu RI Shao, Jiaxin/S-3993-2016; OI Shao, Jiaxin/0000-0001-9998-3622; Nguyen, Kim-Lien/0000-0002-8854-2976 FU UCLA Jonsson Comprehensive Cancer Foundation; UCLA CTSI grant [UL1TR000124] FX This work is supported by pilot grants from the UCLA Jonsson Comprehensive Cancer Foundation and UCLA CTSI grant UL1TR000124. NR 100 TC 2 Z9 2 U1 3 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3790 EI 1534-6269 J9 CURR ONCOL REP JI Curr. Oncol. Rep. PD AUG PY 2016 VL 18 IS 8 AR 48 DI 10.1007/s11912-016-0533-x PG 14 WC Oncology SC Oncology GA DS3GE UT WOS:000380670300002 PM 27292153 ER PT J AU Simone, M Chitnis, T AF Simone, Marta Chitnis, Tanuja TI Use of Disease-Modifying Therapies in Pediatric MS SO Current Treatment Options in Neurology LA English DT Review DE Pediatric; Multiple sclerosis; Treatment; Interferon; Glatiramer acetate; Monoclonal antibody; Relapse; Disability; Safety; Efficacy; Randomized controlled trial ID ONSET MULTIPLE-SCLEROSIS; PLACEBO-CONTROLLED PHASE-3; DOUBLE-BLIND; NATALIZUMAB TREATMENT; BACLOFEN WITHDRAWAL; INTERFERON BETA-1A; CONTROLLED-TRIAL; CHILDHOOD-ONSET; ORAL BG-12; OPEN-LABEL AB Pediatric multiple sclerosis (PedMS) is a rare disease with a more severe prognosis compared to adult-onset MS. It remains a challenging condition to treat because of the highly inflammatory nature of the disease, the prominent cognitive issues, and the limited knowledge about the efficacy and safety of current available disease-modifying therapies. Over the past decade, there has been a dramatic increase in the number of drugs licensed for adult-onset MS and several of them, although not tested in PedMS, are currently being used off-label in this population. To date, interferon-beta and glatiramer acetate are the most commonly used first-line treatments in children, although the efficacy and safety of these drugs have only been studied in observational cohorts and in unblinded randomized controlled trials. For children with breakthrough disease, escalation to higher efficacious second-line therapies, such as natalizumab, fingolimod, dimethyl fumarate, mitoxantrone, cyclophosphamide, rituximab, and daclizumab may be considered. Large observational studies showed natalizumab is an effective treatment with safety and efficacy comparable to those in adult populations. The safety, efficacy, and tolerability of the other second-line treatments in PedMS have been reported only in small size retrospective case series. Large phase III studies are underway which will provide important information regarding the efficacy and safety of fingolimod, teriflunomide, and dimethyl fumarate in PedMS. Symptomatic treatments for fatigue, spasticity, depression, bladder and bowel dysfunction, and neuropathic pain should be considered in PedMS, especially when these symptoms impact the quality of life. Further work is needed to ensure that new trials best address treatment outcomes tailored to PedMS. C1 [Simone, Marta; Chitnis, Tanuja] Massachusetts Gen Hosp, Partners Pediat MS Ctr, 55 Fruit St,ACC708, Boston, MA 02114 USA. RP Chitnis, T (reprint author), Massachusetts Gen Hosp, Partners Pediat MS Ctr, 55 Fruit St,ACC708, Boston, MA 02114 USA. EM tchitnis@partners.org FU Biogen-Idec; Serono; Verily FX Tanuja Chitnis is a member of the Steering committee for pediatric clinical trials for Novartis and Sanofi-Genzyme. She has provided one-time consultation for Genzyme-Sanofi, Biogen-Idec, Novartis, Genentech-Roche, and Bayer Pharmaceuticals. She receives grant support from Biogen-Idec, Serono, and Verily. NR 85 TC 1 Z9 1 U1 2 U2 4 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1092-8480 EI 1534-3138 J9 CURR TREAT OPTION NE JI Curr. Treat. Options Neurol. PD AUG PY 2016 VL 18 IS 8 AR 36 DI 10.1007/s11940-016-0420-7 PG 14 WC Clinical Neurology SC Neurosciences & Neurology GA DS3GY UT WOS:000380672300002 PM 27314428 ER PT J AU Kan, MY Auer, PL Wang, GT Bucasas, KL Hooker, S Rodriguez, A Li, B Ellis, J Cupples, LA Chen, YDI Dupuis, J Fox, CS Gross, MD Smith, JD Heard-Costa, N Meigs, JB Pankow, JS Rotter, JI Siscovick, D Wilson, JG Shendure, J Jackson, R Peters, U Zhong, H Lin, DY Hsu, L Franceschini, N Carlson, C Abecasis, G Gabriel, S Bamshad, MJ Altshuler, D Nickerson, DA North, KE Lange, LA Reiner, AP Leal, SM AF Kan, Mengyuan Auer, Paul L. Wang, Gao T. Bucasas, Kristine L. Hooker, Stanley Rodriguez, Alejandra Li, Biao Ellis, Jaclyn Cupples, L. Adrienne Chen, Yii-Der Ida Dupuis, Josee Fox, Caroline S. Gross, Myron D. Smith, Joshua D. Heard-Costa, Nancy Meigs, James B. Pankow, James S. Rotter, Jerome I. Siscovick, David Wilson, James G. Shendure, Jay Jackson, Rebecca Peters, Ulrike Zhong, Hua Lin, Danyu Hsu, Li Franceschini, Nora Carlson, Chris Abecasis, Goncalo Gabriel, Stacey Bamshad, Michael J. Altshuler, David Nickerson, Deborah A. North, Kari E. Lange, Leslie A. Reiner, Alexander P. Leal, Suzanne M. CA NHLBI-Exome Sequencing Project TI Rare variant associations with waist-to-hip ratio in European-American and African-American women from the NHLBI-Exome Sequencing Project SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article ID BODY-FAT DISTRIBUTION; NF-KAPPA-B; INDUCED INSULIN-RESISTANCE; GENOME-WIDE ASSOCIATION; CORONARY-HEART-DISEASE; IKK-BETA; ABDOMINAL ADIPOSITY; GENERAL FRAMEWORK; QUALITY-CONTROL; OBESITY AB Waist-to-hip ratio (WHR), a relative comparison of waist and hip circumferences, is an easily accessible measurement of body fat distribution, in particular central abdominal fat. A high WHR indicates more intra-abdominal fat deposition and is an established risk factor for cardiovascular disease and type 2 diabetes. Recent genome-wide association studies have identified numerous common genetic loci influencing WHR, but the contributions of rare variants have not been previously reported. We investigated rare variant associations with WHR in 1510 European-American and 1186 African-American women from the National Heart, Lung, and Blood Institute-Exome Sequencing Project. Association analysis was performed on the gene level using several rare variant association methods. The strongest association was observed for rare variants in IKBKB (P = 4.0 x 10(-8)) in European-Americans, where rare variants in this gene are predicted to decrease WHRs. The activation of the IKBKB gene is involved in inflammatory processes and insulin resistance, which may affect normal food intake and body weight and shape. Meanwhile, aggregation of rare variants in COBLL1, previously found to harbor common variants associated with WHR and fasting insulin, were nominally associated (P = 2.23 x 10(-4)) with higher WHR in European-Americans. However, these significant results are not shared between African-Americans and European-Americans that may be due to differences in the allelic architecture of the two populations and the small sample sizes. Our study indicates that the combined effect of rare variants contribute to the inter-individual variation in fat distribution through the regulation of insulin response. C1 [Kan, Mengyuan; Wang, Gao T.; Bucasas, Kristine L.; Hooker, Stanley; Rodriguez, Alejandra; Li, Biao; Leal, Suzanne M.] Baylor Coll Med, Dept Mol & Human Genet, Ctr Stat Genet, One Baylor Plaza 700D, Houston, TX 77030 USA. [Kan, Mengyuan] Chinese Acad Sci, Grad Sch, Shanghai Inst Biol Sci, Inst Nutr Sci, Shanghai, Peoples R China. [Auer, Paul L.; Peters, Ulrike; Hsu, Li; Carlson, Chris; Reiner, Alexander P.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Ellis, Jaclyn; Lange, Leslie A.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Cupples, L. Adrienne; Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Cupples, L. Adrienne; Dupuis, Josee; Fox, Caroline S.; Heard-Costa, Nancy] NHLBI, Framingham Heart Study, Framingham, MA USA. [Chen, Yii-Der Ida; Rotter, Jerome I.] Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Los Angeles Biomed Res Inst, Torrance, CA 90509 USA. [Chen, Yii-Der Ida; Rotter, Jerome I.] Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90509 USA. [Chen, Yii-Der Ida] Harbor UCLA Med Ctr, Dept Med, Torrance, CA 90509 USA. [Gross, Myron D.; Pankow, James S.; Nickerson, Deborah A.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Smith, Joshua D.; Shendure, Jay; Bamshad, Michael J.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Heard-Costa, Nancy] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Meigs, James B.] Harvard Med Sch, Boston, MA USA. [Siscovick, David] Univ Washington, Dept Med, Seattle, WA USA. [Siscovick, David; Reiner, Alexander P.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Jackson, Rebecca] Ohio State Univ, Ctr Clin & Translat Sci, Columbus, OH 43210 USA. [Zhong, Hua] NYU, Langone Med Ctr, Dept Environm Med, Div Biostat, New York, NY USA. [Zhong, Hua] NYU, Langone Med Ctr, Dept Populat Hlth, New York, NY USA. [Lin, Danyu] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Franceschini, Nora; North, Kari E.] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [Abecasis, Goncalo] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Gabriel, Stacey; Altshuler, David] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [Auer, Paul L.] Univ Wisconsin, Sch Publ Hlth, Milwaukee, WI 53201 USA. [Rodriguez, Alejandra] Univ Antioquia, Gene Mapping Grp, Medellin 050010, Colombia. RP Leal, SM (reprint author), Baylor Coll Med, Dept Mol & Human Genet, Ctr Stat Genet, One Baylor Plaza 700D, Houston, TX 77030 USA. EM sleal@bcm.edu FU NHLBI [RC2 HL-103010, RC2 HL-102923, RC2 HL-102924, RC2 HL-102925, RC2 HL-102926] FX We thank the support of NHLBI and the contributions of the research institutions, study investigators, field staff and study participants in creating this resource for biomedical research. Funding for GO ESP was provided by NHLBI grants RC2 HL-103010 (HeartGO), RC2 HL-102923 (LungGO) and RC2 HL-102924 (WHISP). The exome sequencing was performed through NHLBI grants RC2 HL-102925 (BroadGO) and RC2 HL-102926 (SeattleGO). NR 51 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1018-4813 EI 1476-5438 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD AUG PY 2016 VL 24 IS 8 BP 1181 EP 1187 DI 10.1038/ejhg.2015.272 PG 7 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA DS1VI UT WOS:000380390300017 PM 26757982 ER PT J AU Fadista, J Manning, AK Florez, JC Groop, L AF Fadista, Joao Manning, Alisa K. Florez, Jose C. Groop, Leif TI The (in)famous GWAS P-value threshold revisited and updated for low-frequency variants SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article ID ASSOCIATION; GENOMEWIDE; MAP AB Genome-wide association studies (GWAS) have long relied on proposed statistical significance thresholds to be able to differentiate true positives from false positives. Although the genome-wide significance P-value threshold of 5 x 10(-8) has become a standard for common-variant GWAS, it has not been updated to cope with the lower allele frequency spectrum used in many recent array-based GWAS studies and sequencing studies. Using a whole-genome- and -exome-sequencing data set of 2875 individuals of European ancestry from the Genetics of Type 2 Diabetes (GoT2D) project and a whole-exome-sequencing data set of 13 000 individuals from five ancestries from the GoT2D and T2D-GENES (Type 2 Diabetes Genetic Exploration by Next-generation sequencing in multi-Ethnic Samples) projects, we describe guidelines for genome-and exome-wide association P-value thresholds needed to correct for multiple testing, explaining the impact of linkage disequilibrium thresholds for distinguishing independent variants, minor allele frequency and ancestry characteristics. We emphasize the advantage of studying recent genetic isolate populations when performing rare and low-frequency genetic association analyses, as the multiple testing burden is diminished due to higher genetic homogeneity. C1 [Fadista, Joao] Statens Serum Inst, Dept Epidemiol Res, 5 Artillerivej,Bldg 206, DK-2300 Copenhagen S, Denmark. [Fadista, Joao; Groop, Leif] Lund Univ, Ctr Diabet, Dept Clin Sci, Malmo, Sweden. [Manning, Alisa K.; Florez, Jose C.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Manning, Alisa K.; Florez, Jose C.] Massachusetts Gen Hosp, Dept Med, Ctr Human Genet Res, Boston, MA 02114 USA. [Florez, Jose C.] Massachusetts Gen Hosp, Dept Med, Diabet Res Ctr, Diabet Unit, Boston, MA 02114 USA. [Florez, Jose C.] Harvard Med Sch, Dept Med, Boston, MA USA. [Groop, Leif] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland. RP Fadista, J (reprint author), Statens Serum Inst, Dept Epidemiol Res, 5 Artillerivej,Bldg 206, DK-2300 Copenhagen S, Denmark. EM joaofadista@gmail.com NR 16 TC 5 Z9 5 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1018-4813 EI 1476-5438 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD AUG PY 2016 VL 24 IS 8 BP 1202 EP 1205 DI 10.1038/ejhg.2015.269 PG 4 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA DS1VI UT WOS:000380390300020 PM 26733288 ER PT J AU O'Grady, GL Ma, A Sival, D Wong, MTY Peduto, T Menezes, MP Young, H Waddell, L Ghaoui, R Needham, M Lek, M North, KN MacArthur, DG van Ravenswaaij-Arts, CMA Clarke, NF AF O'Grady, Gina L. Ma, Alan Sival, Deborah Wong, Monica T. Y. Peduto, Tony Menezes, Manoj P. Young, Helen Waddell, Leigh Ghaoui, Roula Needham, Merrilee Lek, Monkol North, Kathryn N. MacArthur, Daniel G. van Ravenswaaij-Arts, Conny M. A. Clarke, Nigel F. TI Prominent scapulae mimicking an inherited myopathy expands the phenotype of CHD7-related disease SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article ID NEURAL CREST CELLS; CHARGE-SYNDROME; CHD7 GENE; MUTATIONS; VARIANTS; UPDATE; FAMILY AB CHD7 variants are a well-established cause of CHARGE syndrome, a disabling multi-system malformation disorder that is often associated with deafness, visual impairment and intellectual disability. Less severe forms of CHD7-related disease are known to exist, but the full spectrum of phenotypes remains uncertain. We identified a de novo missense variant in CHD7 in a family presenting with musculoskeletal abnormalities as the main manifestation of CHD7-related disease, representing a new phenotype. The proband presented with prominent scapulae, mild shoulder girdle weakness and only subtle dysmorphic features. Investigation revealed hypoplasia of the trapezius and sternocleidomastoid muscles and semicircular canal defects, but he did not fulfill diagnostic criteria for CHARGE syndrome. Although the shoulders are often sloping and anteverted in CHARGE syndrome, the underlying neuromuscular cause has never been investigated. This report expands the phenotypes associated with CHD7 mutations to include a musculoskeletal presentation, with hypoplasia of the shoulder and neck muscles. CHD7 should be considered in patients presenting in childhood with stable scapular winging, particularly if accompanied by dysmorphic features and balance difficulties. C1 [O'Grady, Gina L.; Menezes, Manoj P.; Young, Helen; Waddell, Leigh; Ghaoui, Roula; Lek, Monkol; North, Kathryn N.; Clarke, Nigel F.] Childrens Hosp Westmead, Kids Res Inst, Inst Neurosci & Muscle Res, Locked Bag 4001, Sydney, NSW 2145, Australia. [O'Grady, Gina L.; Ma, Alan; Menezes, Manoj P.; Ghaoui, Roula; Lek, Monkol; Clarke, Nigel F.] Univ Sydney, Fac Med, Discipline Paediat & Child Hlth, Sydney, NSW, Australia. [Ma, Alan] Nepean Hosp, Dept Clin Genet, Sydney, NSW, Australia. [Sival, Deborah] Univ Groningen, Univ Med Ctr Groningen, Beatrix Childrens Hosp, Dept Pediat, Groningen, Netherlands. [Wong, Monica T. Y.; van Ravenswaaij-Arts, Conny M. A.] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, POB 30-001, NL-9700 RB Groningen, Netherlands. [Peduto, Tony] Westmead Hosp, Med Imaging, Sydney, NSW, Australia. [Needham, Merrilee] Fiona Stanley Hosp, Dept Neurol, Perth, WA, Australia. [Needham, Merrilee] Murdoch Univ, Inst Immunol & Infect Dis, Perth, WA, Australia. [Lek, Monkol; MacArthur, Daniel G.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Lek, Monkol; MacArthur, Daniel G.] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [North, Kathryn N.] Murdoch Childrens Res Inst, Melbourne, Vic, Australia. [North, Kathryn N.] Univ Melbourne, Fac Med, Dept Paediat, Melbourne, Vic, Australia. RP O'Grady, GL (reprint author), Childrens Hosp Westmead, Kids Res Inst, Inst Neurosci & Muscle Res, Locked Bag 4001, Sydney, NSW 2145, Australia.; van Ravenswaaij-Arts, CMA (reprint author), Univ Groningen, Univ Med Ctr Groningen, Dept Genet, POB 30-001, NL-9700 RB Groningen, Netherlands. EM gina.ogrady@health.nsw.gov.au; c.m.a.van.ravenswaaij@umcg.nl FU National Health and Medical Research Council of Australia [1022707, 1031893, 1056285]; National Human Genome Research Institute of the US National Institutes of Health (Medical Sequencing Program) [U54 HG003067]; Fund Nuts Ohra [1202-023] FX We thank the families for their invaluable contributions. This work was funded by the National Health and Medical Research Council of Australia grants 1022707 and 1031893 (NFC and KNN), and 1056285 (GO). Exome sequencing was supported by grants from the National Human Genome Research Institute of the US National Institutes of Health (Medical Sequencing Program grant U54 HG003067 to the Broad Institute principal investigator, Lander). Grant 1202-023 was provided by Fund Nuts Ohra to MTYW. NR 21 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1018-4813 EI 1476-5438 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD AUG PY 2016 VL 24 IS 8 BP 1216 EP 1219 DI 10.1038/ejhg.2015.276 PG 4 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA DS1VI UT WOS:000380390300023 PM 26813943 ER PT J AU Fu, ZL Li, ZA Huang, J Zhang, J Liu, M Li, Q Li, Y AF Fu, Zhanli Li, Ziao Huang, Jia Zhang, Jin Liu, Meng Li, Qian Li, Yi TI High F-18-FDG uptake in urinary calculi on PET/CT: An unrecognized non-malignant accumulation SO EUROPEAN JOURNAL OF RADIOLOGY LA English DT Article DE F-18-Fluorodeoxyglucose; Positron emission tomography; Computed tomography; Urinary calculus ID FDG-PET/CT; TOMOGRAPHY; TRACER AB Aim: To assess the high F-18-fluorodeoxyglucose (F-18-FDG) uptake in urinary calculi on positron -emission tomography/computed tomography (PET/CT). Methods: In this study, F-18-FDG PET/CT examinations were retrospectively reviewed from November 2013 to February 2016 in a single center, and patients with high F-18-FDG uptake in urinary calculi were identified. The following data were collected from each patient, including age, sex, primary disease, method to verify the urinary calculus, and imaging characteristics of the calculus. Results: A total of 2758 PET/CT studies (2567 patients) were reviewed, and 52 patients with urinary calculi were identified, in which 6 (11.5%, 6/52) patients (5 males, 1 female, age 34-73 years, median age 60.5 years) demonstrated high F-18-FDG uptake in the urinary calculi. Among the 6 patients, 3 patients had bladder calculi, 2 patients had renal calculi, and 1 patient had both bladder and renal calculi. The size of the urinary calculi varied from sandy to 19 mm on CT. The maximal Hounsfield units of the calculi ranged from 153 to 1078. The SUVmax of the calculi on the routine PET/CT scan ranged from 11.7 to 143.0. Delayed PET/CT scans were performed on 4 patients, which showed the calculi SUVmaX increasing in 2 patients, while decreasing in the other 2 patients. One patient with bladder calculus underwent a follow-up PET/CT, which showed enlargement of the calculus as well as the increased SUVI-nax. Conclusion: This study shows an uncommon high F-18-FDG uptake in urinary calculi. Recognition of this non-malignant accumulation in urinary calculi is essential for correct interpretation of PET/CT findings. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Fu, Zhanli; Li, Ziao; Liu, Meng] Peking Univ, Hosp 1, Dept Nucl Med, 8 Xishiku St West Dist, Beijing 100034, Peoples R China. [Huang, Jia] Zhejiang Jinhua Guangfu Hosp, Dept Nucl Med, Jinhua 321000, Peoples R China. [Zhang, Jin] Beijing Univ Chinese Med, Dongzhimen Hosp, Dept Nucl Med, Beijing 100700, Peoples R China. [Li, Qian] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Li, Yi] Good Samaritan Hosp, Dept Med Imaging Serv, Cent Islips, NY 11722 USA. RP Fu, ZL (reprint author), Peking Univ, Hosp 1, Dept Nucl Med, 8 Xishiku St West Dist, Beijing 100034, Peoples R China. EM fuzhanli2002@163.com NR 16 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0720-048X EI 1872-7727 J9 EUR J RADIOL JI Eur. J. Radiol. PD AUG PY 2016 VL 85 IS 8 BP 1395 EP 1399 DI 10.1016/j.ejrad.2016.05.010 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DS2AK UT WOS:000380518200007 PM 27423678 ER PT J AU Sadow, CA Maurer, AN Prevedello, LM Sweeney, CJ Silverman, SG AF Sadow, Cheryl A. Maurer, Amma N. Prevedello, Luciano M. Sweeney, Christopher J. Silverman, Stuart G. TI CT restaging of testicular germ cell tumors: The incidence of isolated pelvic metastases SO EUROPEAN JOURNAL OF RADIOLOGY LA English DT Article DE Testicular cancer; Restaging CT; Radiation reduction ID RADIATION-INDUCED CANCER; LYMPH-NODE DISSECTION; STAGE-I SEMINOMA; PROGNOSTIC-FACTORS; TESTIS CANCER; SURVEILLANCE; EXPOSURE; RISK; MANAGEMENT; RELAPSE AB Purpose: We determined the incidence of isolated pelvic metastases at restaging computed tomography (CT) in patients with testicular germ cell tumors to consider if imaging the pelvis could be omitted. Methods: After receiving IRB approval for this HIPAA-compliant retrospective study, medical records of 560 men (mean age 32.8) with 583 testicular germ cell tumors who underwent 3683 restaging CT scans of the abdomen and pelvis were reviewed to determine the proportion of patients with metastatic disease in the pelvis alone, as verified by histology or by resolution after therapy. Chi-square statistical analysis tested the association between factors currently thought to predispose patients to pelvic metastases. Patients were also categorized by clinical stage, tumor histology, and initial treatment. Results: Isolated pelvic metastases were detected in nine (1.6%) of 560 men. Neither bulky abdominal disease (p = 0.85) nor extratesticular invasion by the primary tumor (p = 0.37) were statistically significant in predicting which patients were more likely to have isolated pelvic metastases. Among the nine patients with isolated pelvic recurrence, only three (0.7%) of 408 men with no known pelvic disease at initial staging and no tumor marker elevation at restaging had isolated pelvic metastases. Isolated pelvic recurrence was not statistically different when analyzed by initial stage and treatment. Conclusion: The incidence of isolated pelvic metastases in testicular germ cell tumors at restaging CT is low, but no group of patients was found to be without risk. Therefore, given the small, if any, risk of radiation-induced harm, the decision about whether to include routine pelvic CT in surveillance protocols should be individualized. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Sadow, Cheryl A.; Maurer, Amma N.; Silverman, Stuart G.] Brigham & Womens Hosp, Dept Radiol, Div Abdominal Imaging & Intervent, 75 Francis St, Boston, MA 02115 USA. [Maurer, Amma N.] Medstar Georgetown Univ Hosp, Dept Radiol, 3800 Reservoir Rd, Washington, DC 20007 USA. [Prevedello, Luciano M.] Brigham & Womens Hosp, Dept Radiol, 75 Francis St, Boston, MA 02115 USA. [Prevedello, Luciano M.] Brigham & Womens Hosp, Ctr Evidenced Based Imaging, 75 Francis St, Boston, MA 02115 USA. [Prevedello, Luciano M.] Ohio State Wexner Med Ctr, Dept Radiol, 395 W 12th Ave, Columbus, OH 43210 USA. [Sweeney, Christopher J.] Dana Farber Canc Inst, Dept Oncol, Div Genitourinary Oncol, 450 Brookline Ave, Boston, MA 02215 USA. RP Sadow, CA (reprint author), Brigham & Womens Hosp, Dept Radiol, Div Abdominal Imaging & Intervent, 75 Francis St, Boston, MA 02115 USA. EM csadow@partners.org NR 29 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0720-048X EI 1872-7727 J9 EUR J RADIOL JI Eur. J. Radiol. PD AUG PY 2016 VL 85 IS 8 BP 1439 EP 1444 DI 10.1016/j.ejrad.2016.06.002 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DS2AK UT WOS:000380518200014 PM 27423685 ER PT J AU Bockorny, B Pectasides, E AF Bockorny, Bruno Pectasides, Eirini TI The emerging role of immunotherapy in gastric and esophageal adenocarcinoma SO FUTURE ONCOLOGY LA English DT Review ID EPSTEIN-BARR-VIRUS; INDUCED KILLER-CELLS; LEVEL MICROSATELLITE INSTABILITY; PROGRAMMED DEATH-1 LIGAND-1; ENDOTHELIAL GROWTH-FACTOR; T-CELLS; CLINICAL-SIGNIFICANCE; PD-L1 EXPRESSION; CTLA-4 BLOCKADE; DENDRITIC CELLS AB Gastric and esophageal adenocarcinomas are aggressive malignancies. Systemic therapy for these tumors relies primarily on cytotoxic chemotherapy but outcomes remain poor. In recent years, immunotherapy has emerged as a new, promising therapeutic approach for a variety of solid tumors. Characterization of gastroesophageal cancers has revealed genomic and immune features of these tumors that may predict response to immunotherapy. Indeed, preliminary results from the initial trials of immune checkpoint inhibitors have been encouraging, with objective response rates of 20% in heavily pretreated patient populations. Based on these results, additional trials of single-agent checkpoint inhibitors as well as combinations with chemotherapy and targeted therapies are currently ongoing. Further work to identify predictive biomarkers will be crucial for the successful implementation of immunotherapy. C1 [Bockorny, Bruno; Pectasides, Eirini] Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Boston, MA 02215 USA. [Bockorny, Bruno; Pectasides, Eirini] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Pectasides, E (reprint author), Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Boston, MA 02215 USA.; Pectasides, E (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM eirini_pectasides@dfci.harvard.edu NR 103 TC 2 Z9 2 U1 1 U2 4 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1479-6694 EI 1744-8301 J9 FUTURE ONCOL JI Future Oncol. PD AUG PY 2016 VL 12 IS 15 BP 1833 EP 1846 DI 10.2217/fon-2016-0103 PG 14 WC Oncology SC Oncology GA DS1QH UT WOS:000380370500011 PM 27166503 ER PT J AU Joshi, AD Andersson, C Buch, S Stender, S Noordam, R Weng, LC Weeke, PE Auer, PL Boehm, B Chen, C Choi, H Curhan, G Denny, JC De Vivo, I Eicher, JD Ellinghaus, D Folsom, AR Fuchs, C Gala, M Haessler, J Hofman, A Hu, F Hunter, DJ Janssen, HLA Kang, JH Kooperberg, C Kraft, P Kratzer, W Lieb, W Lutsey, PL Murady, SD Nordestgaard, BG Pasquale, LR Reiner, AP Ridker, PM Rirnribi, E Rose, LM Shaffer, CM Schafmayer, C Tamimi, RM Uitterlinden, AG Volker, U Volzke, H Wakabayashi, Y Wiggs, JL Zhu, J Roden, DM Stricker, BH Tang, WH Teumer, A Hampe, J Tybjmrg-Hansen, A Chasman, DI Andrew, T Andrew, D AF Joshi, Amit D. Andersson, Charlotte Buch, Stephan Stender, Stefan Noordam, Raymond Weng, Lu-Chen Weeke, Peter E. Auer, Paul L. Boehm, Bernhard Chen, Constance Choi, Hyon Curhan, Gary Denny, Joshua C. De Vivo, Immaculata Eicher, John D. Ellinghaus, David Folsom, Aaron R. Fuchs, Charles Gala, Manish Haessler, Jeffrey Hofman, Albert Hu, Frank Hunter, David J. Janssen, Harry L. A. Kang, Jae H. Kooperberg, Charles Kraft, Peter Kratzer, Wolfgang Lieb, Wolfgang Lutsey, Pamela L. Murady, Sarwa Darwish Nordestgaard, Borge G. Pasquale, Louis R. Reiner, Alex P. Ridker, Paul M. Rirnribi, Eric Rose, Lynda M. Shaffer, Christian M. Schafmayer, Clemens Tamimi, Rulla M. Uitterlinden, Andre G. Volker, Uwe Volzke, Henry Wakabayashi, Yoshiyuki Wiggs, Janey L. Zhu, Jun Roden, Dan M. Stricker, Bruno H. Tang, Weihong Teumer, Alexander Hampe, Jochen Tybjmrg-Hansen, Anne Chasman, Daniel I. Chan, Andrew T. Johnson, Andrew D. TI Four Susceptibility Loci for Gallstone Disease Identified in a Meta-analysis of Genome-Wide Association Studies SO GASTROENTEROLOGY LA English DT Article DE Genetics; Risk Factors; SNP; GWAS ID HUMAN PREFRONTAL CORTEX; CORONARY-HEART-DISEASE; GENE-EXPRESSION; BREAST-CANCER; BILIRUBIN LEVELS; CANDIDATE GENES; HUMAN BRAIN; CHOLESTEROL TRANSPORTER; ENDOMETRIAL CANCER; PERIPHERAL-BLOOD AB BACKGROUND & AIMS: A genome-wide association study (GWAS) of 280 cases identified the hepatic cholesterol transporter ABCG8 as a locus associated with risk for gallstone disease, but findings have not been reported from any other GWAS of this phenotype. We performed a large-scale, meta-analysis of GWASs of individuals of European ancestry with available prior genotype data, to identify additional genetic risk factors for gallstone disease. METHODS: We obtained per-allele odds ratio (OR) and standard error estimates using age- and sex-adjusted logistic regression models within each of the 10 discovery studies (8720 cases and 55,152 controls). We performed an inverse variance weighted, fixed-effects meta-analysis of study specific estimates to identify single-nucleotide polymorphisms that were associated independently with gallstone disease. Associations were replicated in 6489 cases and 62,797 controls. RESULTS: We observed independent associations for 2 single-nucleotide polymorphisms at the ABCG8 locus: rs11887534 (OR, 1.69; 95% confidence interval [CI], 1.54-1.86; P = 2.44 x 10(-60)) and rs4245791 (OR, 1.27; P = 1.90 x 10(-34)). We also identified and/or replicated associations for rs9843304 in TM4SF4 (OR, 1.12; 95% CI, 1.08-1.16; P = 6.09 x 10(-11)), rs2547231 in SULT2A1 (encodes a sulfoconjugation enzyme that acts on hydroxysteroids and cholesterol-derived sterol bile acids) (OR, 1.17; 95% CI, 1.12-1.21; P = 2.24 x 10-11, rs1260326 in glucokinase regulatory protein (OR, 1.12; 95% CI, 1.07-1.17; P = 2.55 x 10(-10)), and rs6471717 near CYP7A1 (encodes an enzyme that catalyzes conversion of cholesterol to primary bile acids) (OR, 1.11; 95% CI, 1.08-1.15; P = 8.84 x 10(-9)). Among individuals of African American and Hispanic American ancestry, rs11887534 and rs4245791 were associated positively with gallstone disease risk, whereas the association for the rs1260326 variant was inverse. CONCLUSIONS: In this large-scale GWAS of gallstone disease, we identified 4 loci in genes that have putative functions in cholesterol metabolism and transport, and sulfonylation of bile acids or hydroxysteroids. C1 [Joshi, Amit D.; Chen, Constance; De Vivo, Immaculata; Gala, Manish; Hunter, David J.; Kraft, Peter; Chan, Andrew T.] Harvard Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA USA. [De Vivo, Immaculata; Hu, Frank; Hunter, David J.; Kraft, Peter; Rirnribi, Eric; Tamimi, Rulla M.] Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Hu, Frank; Rirnribi, Eric] Harvard Sch Publ Hlth, Dept Nutr, Boston, MA USA. [Joshi, Amit D.; Gala, Manish; Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Joshi, Amit D.; Chan, Andrew T.] Massachusetts Gen Hosp, Clin & Translat Epidemiol Unit, Dept Med, Boston, MA 02114 USA. [Joshi, Amit D.; Chan, Andrew T.] Harvard Med Sch, Boston, MA USA. [Andersson, Charlotte; Eicher, John D.; Johnson, Andrew D.] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. [Buch, Stephan; Hampe, Jochen] Tech Univ Dresden, Univ Hosp Dresden, Med Dept 1, Dresden, Germany. [Stender, Stefan; Tybjmrg-Hansen, Anne] Rigshosp, Ctr Heart, Dept Clin Biochem, Copenhagen, Denmark. [Weeke, Peter E.] Rigshosp, Ctr Heart, Dept Cardiol, Copenhagen, Denmark. [Noordam, Raymond; Uitterlinden, Andre G.; Stricker, Bruno H.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Noordam, Raymond; Hofman, Albert; Uitterlinden, Andre G.; Stricker, Bruno H.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Janssen, Harry L. A.; Murady, Sarwa Darwish] Erasmus MC, Dept Gastroenterol & Hepatol, Rotterdam, Netherlands. [Janssen, Harry L. A.; Murady, Sarwa Darwish] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN 55455 USA. [Weng, Lu-Chen; Folsom, Aaron R.; Lutsey, Pamela L.; Tang, Weihong] Vanderbilt Univ, Dept Med, Nashville, TN USA. [Weeke, Peter E.; Denny, Joshua C.; Shaffer, Christian M.; Roden, Dan M.] Vanderbilt Univ, Depat Biomed Informat, Nashville, TN USA. [Denny, Joshua C.] Univ Wisconsin, Joseph J Zilber Sch Publ Hlth, Milwaukee, WI 53201 USA. [Auer, Paul L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Auer, Paul L.; Haessler, Jeffrey; Kooperberg, Charles; Reiner, Alex P.] Ulm Univ Hosp, Dept Internal Med 1, Ulm, Germany. [Boehm, Bernhard; Kratzer, Wolfgang] Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. [Choi, Hyon] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA USA. [Curhan, Gary; De Vivo, Immaculata; Fuchs, Charles; Kang, Jae H.; Pasquale, Louis R.; Rirnribi, Eric; Tamimi, Rulla M.; Chan, Andrew T.] Brigham & Womens Hosp, Boston, MA USA. [Curhan, Gary; De Vivo, Immaculata; Fuchs, Charles; Kang, Jae H.; Pasquale, Louis R.; Rirnribi, Eric; Tamimi, Rulla M.; Chan, Andrew T.] Harvard Med Sch, Boston, MA USA. [Curhan, Gary] Brigham & Womens Hosp, Dept Med, Div Renal, 75 Francis St, Boston, MA 02115 USA. [Eicher, John D.; Johnson, Andrew D.] NHLBI, Populat Sci Branch, NIH, Framingham, MA USA. [Ellinghaus, David] Univ Kiel, Inst Clin Mol Biol, Kiel, Germany. [Lieb, Wolfgang] Univ Kiel, Inst Epidemiol, Kiel, Germany. [Fuchs, Charles] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Fuchs, Charles; Ridker, Paul M.; Rose, Lynda M.; Chasman, Daniel I.] Harvard Med Sch, Boston, MA USA. [Janssen, Harry L. A.] Toronto Western & Gen Hosp, Univ Hlth Network, Toronto Ctr Liver Dis, Toronto, ON, Canada. [Nordestgaard, Borge G.] Herlev Hosp, Copenhagen Gen Populat Study, Herlev, Denmark. [Nordestgaard, Borge G.; Tybjmrg-Hansen, Anne] Herlev Hosp, Dept Clin Biochem, Herlev, Denmark. [Nordestgaard, Borge G.] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark. [Ridker, Paul M.; Rose, Lynda M.; Chasman, Daniel I.] Harvard Med Sch, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA USA. [Ridker, Paul M.; Rose, Lynda M.; Chasman, Daniel I.] Brigham & Womens Hosp, Dept Med, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA. [Schafmayer, Clemens] Univ Kiel, Dept Gen Abdominal Thorac & Transplantat, Kiel, Germany. [Volker, Uwe] Univ Med Greifswald, Interfaculty Inst Genet & Funct Gen, Dept Funct Gen, Greifswald, Germany. [Volzke, Henry; Teumer, Alexander] Univ Med Greifswald, Inst Community Med, Greifswald, Germany. [Volzke, Henry] German Ctr Cardiovasc Res, Greifswald, Germany. [Volzke, Henry] German Ctr Diabet Res, Greifswald, Germany. [Wakabayashi, Yoshiyuki; Zhu, Jun] NHLBI, DNA Sequencing Core Lab, Bldg 10, Bethesda, MD 20892 USA. RP Joshi, AD (reprint author), Massachusetts Gen Hosp, Div Gastroenterol, Clin & Translat Epidemiol Unit, 55 Fruit St, Boston, MA USA.; Andersson, C (reprint author), Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave, Framingham, MA 01702 USA.; Andrew, T (reprint author), Massachusetts Gen Hosp, GRJ-825C, Boston, MA 02114 USA.; Andrew, T (reprint author), Harvard Med Sch, Clin & Translat Epidemiol Unit, Div Gastroenterol, GRJ-825C, Boston, MA 02114 USA.; Andrew, D (reprint author), NHLBI, Cardiovasc Epidemiol & Human Genom Branch, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM ajoshi@hsph.harvard.edu; achan@mgh.harvard.edu; johnsonad2@nhibimih.gov RI Johnson, Andrew/G-6520-2013; Ellinghaus, David/G-4467-2012; Lieb, Wolfgang/C-1990-2012; OI Hampe, Jochen/0000-0002-2421-6127 FU Intramural NIH HHS [Z99 HL999999]; NEI NIH HHS [R01 EY015473]; NHGRI NIH HHS [U01 HG006378, U01 HG008672]; NIDDK NIH HHS [K24 DK098311]; NIH HHS [S10 OD020069] NR 144 TC 3 Z9 3 U1 6 U2 8 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD AUG PY 2016 VL 151 IS 2 BP 351 EP + DI 10.1053/j.gastro.2016.04.007 PG 41 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DS4KK UT WOS:000380749800030 PM 27094239 ER PT J AU Buckley, B Chan, VO Mitchell, DP McDermott, S Eisenberg, RL Heffernan, EJ Ridge, CA AF Buckley, Bryan Chan, Victoria O. Mitchell, David P. McDermott, Shaunagh Eisenberg, Ron L. Heffernan, Eric J. Ridge, Carole A. TI The clothes maketh the sign SO INSIGHTS INTO IMAGING LA English DT Review DE Pattern recognition; Visual; Radiography; Tomography; X-ray Computed; Magnetic resonance imaging; Ultrasonography ID BONE-SCINTIGRAPHY; MENISCUS; SPINE; KNEE; CT AB Pattern recognition is a key tool that enables radiologists to evoke certain diagnoses based on a radiologic appearance. In Shakespeare's Hamlet, Polonius tells his son Laertes to dress well because "apparel oft proclaims the man"; this phrase is now expressed in modern parlance as "the clothes maketh the man". Similarly in radiology, appearances are everything, and in the case of radiologic signs, occasionally "the clothes maketh the sign". The radiologic signs described in this pictorial review resemble items of clothing, fabric types, headwear, or accessories and are found in the musculoskeletal, pulmonary, gastrointestinal, and genitourinary systems. These "clothing signs" serve as a useful visual trigger to help radiologists to identify particular disease entities. aEuro cent Pattern recognition enables radiologists to evoke a diagnosis based on radiologic appearance. aEuro cent The radiologic signs described in this review resemble clothing, fabric, or accessories. aEuro cent These "clothing signs" serve as visual triggers that evoke particular disease entities. C1 [Buckley, Bryan; Chan, Victoria O.; Mitchell, David P.; Ridge, Carole A.] Mater Misericordiae Univ Hosp, Dept Radiol, Dublin, Ireland. [McDermott, Shaunagh] Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St, Boston, MA 02114 USA. [Eisenberg, Ron L.] Beth Israel Deaconess Med Ctr, Dept Radiol, 330 Brookline Ave, Boston, MA 02215 USA. [Heffernan, Eric J.] St Vincents Univ Hosp, Dept Radiol, Elm Pk, Dublin, Ireland. RP Ridge, CA (reprint author), Mater Misericordiae Univ Hosp, Dept Radiol, Dublin, Ireland. EM cridge@mater.ie NR 27 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1869-4101 J9 INSIGHTS IMAGING JI Insights Imaging PD AUG PY 2016 VL 7 IS 4 BP 629 EP 640 DI 10.1007/s13244-016-0507-4 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DR8SL UT WOS:000380167500013 PM 27271510 ER PT J AU Andre, E Isaacs, C Affolabi, D Alagna, R Brockmann, D de Jong, BC Cambau, E Churchyard, G Cohen, T Delmee, M Delvenne, JC Farhat, M Habib, A Holme, R Keshavjee, S Khan, A Lightfoot, P Moore, D Moreno, Y Mundade, Y Pai, M Patel, S Nyaruhirira, AU Rocha, LEC Takle, J Trebucq, A Creswell, J Boehme, C AF Andre, E. Isaacs, C. Affolabi, D. Alagna, R. Brockmann, D. de Jong, B. C. Cambau, E. Churchyard, G. Cohen, T. Delmee, M. Delvenne, J. -C. Farhat, M. Habib, A. Holme, R. Keshavjee, S. Khan, A. Lightfoot, P. Moore, D. Moreno, Y. Mundade, Y. Pai, M. Patel, S. Nyaruhirira, A. U. Rocha, L. E. C. Takle, J. Trebucq, A. Creswell, J. Boehme, C. TI Connectivity of diagnostic technologies: improving surveillance and accelerating tuberculosis elimination SO INTERNATIONAL JOURNAL OF TUBERCULOSIS AND LUNG DISEASE LA English DT Article DE laboratory; connectivity; tuberculosis; surveillance; data ID COUNTRIES; POINT; TB AB In regard to tuberculosis (TB) and other major global epidemics, the use of new diagnostic tests is increasing dramatically, including in resource-limited countries. Although there has never been as much digital information generated, this data source has not been exploited to its full potential. In this opinion paper, we discuss lessons learned from the global scale-up of these laboratory devices and the pathway to tapping the potential of laboratory-generated information in the field of TB by using connectivity. Responding to the demand for connectivity, innovative third-party players have proposed solutions that have been widely adopted by field users of the Xpert MTB/RIF assay. The experience associated with the utilisation of these systems, which facilitate the monitoring of wide laboratory networks, stressed the need for a more global and comprehensive approach to diagnostic connectivity. In addition to SUMMARY facilitating the reporting of test results, the mobility of digital information allows the sharing of information generated in programme settings. When they become easily accessible, these data can be used to improve patient care, disease surveillance and drug discovery. They should therefore be considered as a public health good. We list several examples of concrete initiatives that should allow data sources to be combined to improve the understanding of the epidemic, support the operational response and, finally, accelerate TB elimination. With the many opportunities that the pooling of data associated with the TB epidemic can provide, pooling of this information at an international level has become an absolute priority. C1 [Andre, E.; Delmee, M.] Catholic Univ Louvain, Inst Rech Expt & Clin, Pole Microbiol Med, B-1200 Brussels, Belgium. [Andre, E.; Delmee, M.] Clin Univ St Luc, Dept Biol Clin, Serv Microbiol, Brussels, Belgium. [Andre, E.] ESCMID, European Soc Clin Microbiol & Infect Dis ESCMID, Study Grp Mycobacterial Infect ESGMYC, Basel, Switzerland. [Lightfoot, P.; Boehme, C.] Fdn Innovat New Diagnost, Geneva, Switzerland. [Affolabi, D.] Abomey Calavi Univ, Fac Hlth Sci, Cotonou, Benin. [Affolabi, D.] Natl TB Programme, Cotonou, Benin. [Alagna, R.] Ist Ricovero & Cura Carattere Sci San Raffaele Sc, TB Supranat Reference Lab, Milan, Italy. [Brockmann, D.] Humboldt Univ, Inst Theoret Biol, Dept Biol, Berlin, Germany. [Brockmann, D.] Robert Koch Inst, Epidemiol Modelling Infect Dis, Berlin, Germany. [de Jong, B. C.] Inst Trop Med, Dept Biomed Sci, Unit Mycobacteriol, Ghent, Belgium. [Cambau, E.] Univ Paris Diderot, Inst Natl Sante & Rech Med, UMR 1137, Infect Antimicrobiens Modelisat Evolut, Paris, France. [Cambau, E.] Hop Lariboisiere, AP HP, Bacteriol, Paris, France. [Churchyard, G.] Aurum Inst, Johannesburg, South Africa. [Cohen, T.] Yale Univ, Yale Sch Publ Hlth, New Haven, CT USA. [Delvenne, J. -C.] Catholic Univ Louvain, Inst Informat & Commun Technol Elect & Appl Math, Louvain, Belgium. [Delvenne, J. -C.] Catholic Univ Louvain, Ctr Operat Res & Econometr, Louvain, Belgium. [Farhat, M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Habib, A.] Interact Hlth Solut, Karachi, Pakistan. [Holme, R.] Sungkyunkwan Univ, Seoul, South Korea. [Keshavjee, S.] Harvard Med Sch, Ctr Global Hlth Delivery, Dubai, U Arab Emirates. [Khan, A.] Interact Res & Dev, Karachi, Pakistan. [Moore, D.] London Sch Hyg & Trop Med, TB Ctr, London, England. [Moreno, Y.] Univ Zaragoza, Inst Biocomputat & Phys Complex Syst BIFI, Zaragoza, Spain. [Rocha, L. E. C.] Univ Zaragoza, Dept Theoret Phys, Fac Sci, Zaragoza, Spain. [Mundade, Y.] UNITAID, Geneva, Switzerland. [Pai, M.] McGill Univ, McGill Int TB Ctr, Montreal, PQ, Canada. [Pai, M.] McGill Univ, McGill Global Hlth Programs, Montreal, PQ, Canada. [Patel, S.] Univ Hosp Southampton NHS Fdn Trust, Southampton, Hants, England. [Nyaruhirira, A. U.] Management Sci Hlth, Gauteng, South Africa. [Rocha, L. E. C.] Karolinska Inst, Stockholm, Sweden. [Rocha, L. E. C.] Univ Namur, Namur, Belgium. [Takle, J.] Global Connect LLC, Somerville, MA USA. [Trebucq, A.] Int Union TB & Lung Dis, Paris, France. [Creswell, J.] Stop TB Partnership, Geneva, Switzerland. RP Andre, E (reprint author), Catholic Univ Louvain, Pole Microbiol, Inst Rech Expt & Clin, 10 Ave Hippocrate, B-1200 Brussels, Belgium. EM emmanuel.andre@uclouvain.be RI Moreno, Yamir/A-1076-2009 OI Moreno, Yamir/0000-0002-0895-1893 NR 16 TC 3 Z9 3 U1 0 U2 0 PU INT UNION AGAINST TUBERCULOSIS LUNG DISEASE (I U A T L D) PI PARIS PA 68 BOULEVARD SAINT-MICHEL,, 75006 PARIS, FRANCE SN 1027-3719 EI 1815-7920 J9 INT J TUBERC LUNG D JI Int. J. Tuberc. Lung Dis. PD AUG PY 2016 VL 20 IS 8 BP 999 EP 1003 DI 10.5588/ijtld.16.0015 PG 5 WC Infectious Diseases; Respiratory System SC Infectious Diseases; Respiratory System GA DS0PC UT WOS:000380298200004 PM 27393530 ER PT J AU Menendez, ME Park, KJ Barnes, CL AF Menendez, Mariano E. Park, Kwan J. Barnes, C. Lowry TI Early Postoperative Outcomes After Total Joint Arthroplasty in Patients With Multiple Myeloma SO JOURNAL OF ARTHROPLASTY LA English DT Article DE total joint arthroplasty; multiple myeloma; outcome; perioperative; mortality ID DEEP VENOUS THROMBOSIS; TOTAL HIP-ARTHROPLASTY; LONG-TERM SURVIVAL; UNITED-STATES; ORTHOPEDIC-SURGERY; METASTATIC-DISEASE; KNEE ARTHROPLASTY; 30-DAY MORTALITY; COMPLICATIONS; MORBIDITY AB Background: Multiple myeloma is the most common primary bone malignancy and is increasingly becoming a chronic condition, but little is known about its impact in the perioperative arthroplasty setting. We sought to determine whether patients with multiple myeloma undergoing elective total joint arthroplasty would be at increased risk for in-hospital complications and death, prolonged length of stay, and nonroutine discharge. Methods: Using discharge records from the Nationwide Inpatient Sample (2002-2011), we identified 6,054,344 patients undergoing elective primary total joint arthroplasty, of whom 2381 (0.039%) with multiple myeloma. Comparisons of perioperative outcomes were performed by multivariable logistic regression modeling. Results: Patients with multiple myeloma were more likely to suffer several postoperative complications, including thromboembolic events (odds ratio [OR]: 2.97, 95% CI: 2.32-3.81), surgical site infection (OR: 2.82, 95% CI: 1.59-5.01), acute renal failure (OR: 1.93, 95% CI: 1.59-2.37), and induced mental disorder (OR: 1.57, 95% CI: 1.21-2.04). A diagnosis of multiple myeloma was also associated with higher risk for blood transfusion (OR: 2.14, 95% CI: 1.97-2.33), prolonged hospital stay (OR: 2.04, 95% CI: 1.86-2.23), and nonroutine discharge (OR: 1.33, 95% CI: 1.21-1.45) but was not associated with greater in-hospital mortality. Conclusion: Patients with multiple myeloma are at increased risk for early postoperative complications (especially surgical site infection and thromboembolic events) and resource utilization after elective joint arthroplasty. Greater awareness of multiple myeloma and its health consequences may contribute to improvements in the perioperative management of total joint arthroplasty patients. (C) 2016 Elsevier Inc. All rights reserved. C1 [Menendez, Mariano E.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA USA. [Park, Kwan J.; Barnes, C. Lowry] Univ Arkansas Med Sci, Dept Orthopaed Surg, Little Rock, AR 72205 USA. RP Barnes, CL (reprint author), Outpatient Ctr Bldg,1st Floor, Little Rock, AR 72205 USA. NR 31 TC 0 Z9 0 U1 1 U2 1 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 2016 VL 31 IS 8 BP 1645 EP 1648 DI 10.1016/j.arth.2016.01.029 PG 4 WC Orthopedics SC Orthopedics GA DS0AS UT WOS:000380258100008 PM 26895818 ER PT J AU Liow, MHL Urish, KL Preffer, FI Nielson, GP Kwon, YM AF Liow, Ming Han Lincoln Urish, Kenneth L. Preffer, Frederic I. Nielson, Gunnlaugur P. Kwon, Young-Min TI Metal Ion Levels Are Not Correlated With Histopathology of Adverse Local Tissue Reactions in Taper Corrosion of Total Hip Arthroplasty SO JOURNAL OF ARTHROPLASTY LA English DT Article DE metal ion levels; intraoperative tissue damage; ALVAL score; histopathology; taper corrosion; total hip arthroplasty ID HEAD-NECK TAPER; ON-METAL; MODULAR-NECK; PSEUDOTUMOR FORMATION; RHEUMATOID-ARTHRITIS; FLOW-CYTOMETRY; FEMORAL STEMS; UP-REGULATION; SERUM-METAL; REJUVENATE AB Background: The underlying biological mechanism in the formation of adverse local tissue reaction in taper corrosion of total hip arthroplasty (THA) remains unknown. This study evaluated whether there was a dose-dependent relationship between metal ion levels, intraoperative tissue damage and ALVAL (aseptic lymphocyte-dominated vasculitis-associated lesion) scores in dual taper THA patients who underwent revisions for taper corrosion. Methods: We performed a retrospective review of 31 dual taper THA patients who underwent revision surgery from May 2013 to October 2013. Preoperative serum metal ion levels, intraoperative tissue damage grading, and ALVAL scores were reviewed. Multivariate analysis was performed to determine if an association existed between metal ion levels, intraoperative tissue damage, and ALVAL scores. Results: Findings consistent with adverse local tissue reaction were found in all cases. We noted 10 patients with low, 8 with moderate, and 13 with high ALVAL scores, respectively. For intraoperative tissue damage, we recorded 2 (grade 1), 22 (grade 2) and 7 (grade 3) cases. Preoperatively, there was preferential elevation of serum cobalt (3.8 ng/mL, 2.3-17.0) compared to serum chromium (1.0 ng/mL, 0.2-5.8). There was no correlation between preoperative metal ion levels and intraoperative tissue damage (R = -0.06, P = .74) or ALVAL scores (R = -0.04, P = .481). There was also no correlation between intraoperative tissue damage and ALVAL score (R = -0.06, P = .73). Conclusion: There was no significant correlation between ALVAL scores and prerevision surgery metal ion levels or intraoperative tissue damage, suggesting that the biological mechanism of histologic morphology cannot be solely attributed to elevated metal ion levels and is likely multifactorial, reflecting a complex interplay between implant and patient factors. (C) 2016 Elsevier Inc. All rights reserved. C1 [Liow, Ming Han Lincoln; Urish, Kenneth L.; Kwon, Young-Min] Harvard Med Sch, Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA USA. [Preffer, Frederic I.; Nielson, Gunnlaugur P.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Boston, MA USA. RP Kwon, YM (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Orthopaed Surg, Yawkey Ctr Outpatient Care, Suite 3B,55 Fruit St, Boston, MA 02114 USA. NR 43 TC 2 Z9 2 U1 0 U2 0 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 2016 VL 31 IS 8 BP 1797 EP 1802 DI 10.1016/j.arth.2016.01.041 PG 6 WC Orthopedics SC Orthopedics GA DS0AS UT WOS:000380258100037 PM 26923497 ER PT J AU Kwon, YM Dimitriou, D Liow, MHL Tsai, TY Li, GA AF Kwon, Young-Min Dimitriou, Dimitris Liow, Ming Han Lincoln Tsai, Tsung-Yuan Li, Guoan TI Is Ultrasound As Useful As Metal Artifact Reduction Sequence Magnetic Resonance Imaging in Longitudinal Surveillance of Metal-on-Metal Hip Arthroplasty Patients? SO JOURNAL OF ARTHROPLASTY LA English DT Article DE metal-on-metal; ultrasound; MARS MRI; soft tissue reaction; bearings ID DIAGNOSTIC-ACCURACY; PSEUDOTUMORS; MANAGEMENT; PROSTHESES; MRI AB Background: Current guidelines recommend longitudinal monitoring of at-risk metal-on-metal (MoM) arthroplasty patients with cross-sectional imaging such as metal artifact reduction sequence (MARS) magnetic resonance imaging (MRI) or ultrasound. During follow-up evaluations, the clinical focus is on the relative interval changes in symptoms, radiographs, laboratory tests, and cross-sectional imaging modalities. Although MRI has the capacity for the detection of adverse local soft tissue reactions (ALTRs), the potential disadvantages of MARS MRI include the obscuration of periprosthetic tissues by metal artifacts and the cost. The aim of this study was to evaluate the diagnostic accuracy of ultrasound in comparison with MARS MRI in detecting ALTR in MoM patients during consecutive follow-up. Methods: Thirty-five MoM patients (42 hips) were recruited prospectively to evaluate the sensitivity and specificity of the ultrasound for detecting ALTR in relation to MARS MRI during 2 longitudinal follow-up scans. The agreement between ultrasound and MARS MRI in ALTR grade, size, and size change was calculated. Results: At the initial evaluation and at the subsequent follow-up, ultrasound had a sensitivity of 81% and 86% and a specificity of 92% and 88%, respectively. At the follow-up evaluations, ultrasound was able to detect the "change" in the lesions size with -0.3 cm(2) average bias from the MARS MRI with higher agreement (k = 0.85) with MARS MRI compared to the initial evaluation in detecting any "change" in ALTR size or grade. Conclusion: Ultrasound detected the interval change in the ALTR size and grade with higher accuracy and higher agreement with MARS MRI compared with the initial evaluation, suggesting ultrasound is a valid and useful. (C) 2016 Elsevier Inc. All rights reserved. C1 [Kwon, Young-Min; Dimitriou, Dimitris; Liow, Ming Han Lincoln; Tsai, Tsung-Yuan; Li, Guoan] Harvard Med Sch, Massachusetts Gen Hosp, Dept Orthopaed Surg, 55 Fruit St, Boston, MA 02114 USA. RP Kwon, YM (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Orthopaed Surg, 55 Fruit St, Boston, MA 02114 USA. OI LIOW, MING HAN LINCOLN/0000-0002-4496-8035; Dimitriou, Dimitris/0000-0002-9558-7080 FU Biomet Inc. FX Partial funding from Biomet Inc. NR 17 TC 0 Z9 0 U1 1 U2 1 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 2016 VL 31 IS 8 BP 1821 EP 1827 DI 10.1016/j.arth.2016.01.033 PG 7 WC Orthopedics SC Orthopedics GA DS0AS UT WOS:000380258100041 PM 26895821 ER PT J AU Herrera, JA Herrera, JE D'Empaire, G Octavio, JA Finizola, B Garcia, E Velasco, L Torres, W Cubeddu, R Levine, R Palacios, I AF Herrera, Jose A. Herrera, Jose E. D'Empaire, Gabriel Octavio, Jose A. Finizola, Bartolome Garcia, Eleazar Velasco, Luis Torres, William Cubeddu, Robert Levine, Robert Palacios, Igor TI Echocardiographic Data in the First 6 Heart Failure Patients with Caval Counterpulsation Balloon SO JOURNAL OF CARDIAC FAILURE LA English DT Meeting Abstract CT 20th Annual Scientific Meeting of the Heart-Failure-Society-of-America CY SEP 17-20, 2016 CL Kissimmee, FL SP Heart Failure Soc Amer C1 [Herrera, Jose A.; Finizola, Bartolome; Garcia, Eleazar; Velasco, Luis; Torres, William; Cubeddu, Robert] ASCARDIO, Barquisimeto, Bolivarian, Venezuela. [Herrera, Jose E.] ASCARDIO, Porlamar, Bolivarian, Venezuela. [D'Empaire, Gabriel; Octavio, Jose A.] Hosp Clin Caracas, Caracas, Bolivarian, Venezuela. [Cubeddu, Robert] Adventure Hosp, Miami, FL USA. [Levine, Robert; Palacios, Igor] Mass Gen Hosp, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1071-9164 EI 1532-8414 J9 J CARD FAIL JI J. Card. Fail. PD AUG PY 2016 VL 22 IS 8 SU S MA 170 BP S63 EP S63 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DS8WW UT WOS:000381064700167 ER PT J AU LeMond, LM Grady, K Goodlin, S AF LeMond, Lisa M. Grady, Kathleen Goodlin, Sarah TI Certain Uncertainties: Provider Decision-Making for Destination Therapy Left Ventricular Assist Devices SO JOURNAL OF CARDIAC FAILURE LA English DT Meeting Abstract CT 20th Annual Scientific Meeting of the Heart-Failure-Society-of-America CY SEP 17-20, 2016 CL Kissimmee, FL SP Heart Failure Soc Amer C1 [LeMond, Lisa M.] Univ Colorado Hosp, Aurora, CO USA. [Grady, Kathleen] Northwestern Univ, Chicago, IL 60611 USA. [Goodlin, Sarah] Portland VA Med Ctr, Portland, OR USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1071-9164 EI 1532-8414 J9 J CARD FAIL JI J. Card. Fail. PD AUG PY 2016 VL 22 IS 8 SU S MA 044 BP S17 EP S18 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DS8WW UT WOS:000381064700044 ER PT J AU Sommerfeld, AJ Althouse, AD Prince, J Hickey, GW AF Sommerfeld, Alex J. Althouse, Andrew D. Prince, Jennifer Hickey, Gavin W. TI Obstructive Sleep Apnea is Associated with Increased Readmissions in CHF Patients SO JOURNAL OF CARDIAC FAILURE LA English DT Meeting Abstract CT 20th Annual Scientific Meeting of the Heart-Failure-Society-of-America CY SEP 17-20, 2016 CL Kissimmee, FL SP Heart Failure Soc Amer C1 [Sommerfeld, Alex J.; Althouse, Andrew D.; Hickey, Gavin W.] Univ Pittsburgh, Pittsburgh, PA USA. [Sommerfeld, Alex J.; Althouse, Andrew D.; Prince, Jennifer; Hickey, Gavin W.] VA Pittsburgh Hlth Syst, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1071-9164 EI 1532-8414 J9 J CARD FAIL JI J. Card. Fail. PD AUG PY 2016 VL 22 IS 8 SU S MA 255 BP S88 EP S88 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DS8WW UT WOS:000381064700247 ER PT J AU Burton, KR Mellema, JJ Menendez, ME Ring, D Chen, NC AF Burton, Kyle R. Mellema, Jos J. Menendez, Mariano E. Ring, David Chen, Neal C. TI The yield of subsequent radiographs during nonoperative treatment of radial head and neck fractures SO JOURNAL OF SHOULDER AND ELBOW SURGERY LA English DT Article DE Radiographs; radial head; fractures; nonoperative treatment; quality improvement; orthopedic trauma ID MANAGEMENT; FIXATION AB Objectives: After diagnosis of an isolated radial head or neck fracture and selection of nonoperative treatment, the value of subsequent radiographs is uncertain. This study tested the null hypothesis that there are no patient, surgeon, or injury factors associated with alteration in patient management based on subsequent radiographs. Secondarily, we tested the null hypothesis that the use of subsequent radiographs is not associated with patient, surgeon, and fracture characteristics. Methods: We identified 415 adult patients with nonoperative treatment for isolated Broberg and Morrey modified Mason type 1 or 2 fractures at a large urban hospital system during years 2013 and 2014. Patient demographics, fracture characteristics, provider characteristics, and treatment details were obtained from a hospital database. Bivariate analysis and multivariable logistic regression modeling were performed. Results: One of 255 patients with 262 fractures that had subsequent radiographs (0.4%) was offered surgery but declined. In multivariable analysis, displaced fractures were more likely to have subsequent radiographs, but surgeon-to-surgeon variation was a far more influential factor. Conclusions: Radiographs subsequent to diagnosis do not alter treatment of radial head fractures with no associated ligament injuries or fractures. The substantial surgeon-to-surgeon variation in the use of subsequent radiographs suggests that this may be a good focus for quality improvement initiatives. Level of evidence: Level II; Retrospective Design; Prognosis Study (C) 2016 Journal of Shoulder and Elbow Surgery Board of Trustees. All rights reserved. C1 [Burton, Kyle R.; Mellema, Jos J.; Chen, Neal C.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Orthoped Surg, Hand & Upper Extrem Serv, Boston, MA USA. [Menendez, Mariano E.; Ring, David] Univ Texas Austin, Dell Med Sch, Dept Surg & Perioperat Care, 1400 Barbara Jordan Blvd,Ste 2-834,MC R1800, Austin, TX 78723 USA. RP Ring, D (reprint author), Univ Texas Austin, Dell Med Sch, Dept Surg & Perioperat Care, 1400 Barbara Jordan Blvd,Ste 2-834,MC R1800, Austin, TX 78723 USA. EM david.ring@austin.utexas.edu OI Ring, David/0000-0002-6506-4879 NR 17 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 1058-2746 J9 J SHOULDER ELB SURG JI J. Shoulder Elbow Surg. PD AUG PY 2016 VL 25 IS 8 BP 1216 EP 1222 DI 10.1016/j.jse.2016.03.007 PG 7 WC Orthopedics; Sport Sciences; Surgery SC Orthopedics; Sport Sciences; Surgery GA DS1QK UT WOS:000380371000010 PM 27282736 ER PT J AU Beks, RB Claessen, FMAP Oh, LS Ring, D Chen, NC AF Beks, Reinier B. Claessen, Femke M. A. P. Oh, Luke S. Ring, David Chen, Neal C. TI Factors associated with adverse events after distal biceps tendon repair or reconstruction SO JOURNAL OF SHOULDER AND ELBOW SURGERY LA English DT Article DE Distal biceps; tendinopathy; rupture; surgical repair; reconstruction; second surgery; adverse events ID MODIFIED 2-INCISION TECHNIQUE; RUPTURES; COMPLICATIONS; BRACHII; SINGLE AB Background: Factors associated with adverse events after distal biceps tendon repair or reconstruction are incompletely understood. This study examined factors associated with adverse events, prevalence of adverse events, and rate of second surgeries after distal biceps repair or reconstruction. Methods: Between January 2002 and March 2015, 373 adult patients who underwent repair or reconstruction of the distal biceps tendon at 1 of 3 area hospitals were analyzed to determine factors associated with adverse events after surgical repair or reconstruction of the distal biceps tendon. Results: Of 373 distal biceps tendon repairs or reconstructions, 82 (22%) had an adverse event; 5.3% were major adverse events. In multivariable analysis, a single-incision anterior approach and obesity were associated with a higher rate of adverse events. Fifteen patients (18% of patients with an adverse event and 4% of all patients) had a second surgery after distal biceps tendon surgery. Conclusion: Patients should be counseled that 1 in 5 patients will have a minor complication and 1 in 20 patients will have a major complication after surgery on the distal biceps tendon. The most common adverse event is lateral antebrachial cutaneous neurapraxia. (C) 2016 Journal of Shoulder and Elbow Surgery Board of Trustees. All rights reserved. C1 [Beks, Reinier B.; Claessen, Femke M. A. P.] Harvard Med Sch, Massachusetts Gen Hosp, Hand & Upper Extrem Serv, Dept Orthopaed Surg, Boston, MA USA. [Oh, Luke S.] Massachusetts Gen Hosp, Dept Orthopaed Surg, Sports Med Serv, Boston, MA 02114 USA. [Ring, David] Univ Texas Austin, Dell Med Sch, Dept Surg & Perioperat Care, 1400 Barbara Jordan Blvd,Suite 1-114AC,MC R1800, Austin, TX 78723 USA. [Chen, Neal C.] Massachusetts Gen Hosp, Dept Orthopaed Surg, Hand & Upper Extrem Serv, Boston, MA 02114 USA. RP Ring, D (reprint author), Univ Texas Austin, Dell Med Sch, Dept Surg & Perioperat Care, 1400 Barbara Jordan Blvd,Suite 1-114AC,MC R1800, Austin, TX 78723 USA. EM david.ring@austin.utexas.edu OI Beks, Reinier/0000-0002-1839-0057; Ring, David/0000-0002-6506-4879 NR 19 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 1058-2746 J9 J SHOULDER ELB SURG JI J. Shoulder Elbow Surg. PD AUG PY 2016 VL 25 IS 8 BP 1229 EP 1234 DI 10.1016/j.jse.2016.02.032 PG 6 WC Orthopedics; Sport Sciences; Surgery SC Orthopedics; Sport Sciences; Surgery GA DS1QK UT WOS:000380371000012 PM 27107731 ER PT J AU Calzo, JP Horton, NJ Sonneville, KR Swanson, SA Crosby, RD Micali, N Eddy, KT Field, AE AF Calzo, Jerel P. Horton, Nicholas J. Sonneville, Kendrin R. Swanson, Sonja A. Crosby, Ross D. Micali, Nadia Eddy, Kamryn T. Field, Alison E. TI Male Eating Disorder Symptom Patterns and Health Correlates From 13 to 26 Years of Age SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE eating disorder; body image; gender; adolescence; longitudinal analysis ID LATENT CLASS ANALYSIS; BODY-MASS INDEX; ADOLESCENT GIRLS; DSM-IV; BOYS; MUSCULARITY; COMORBIDITY; WEIGHT; MEN; CLASSIFICATION AB Objective: Research on the manifestations and health correlates of eating disorder symptoms among males is lacking. This study identified patterns of appearance concerns and eating disorder behaviors from adolescence through young adulthood and their health correlates. Method: Participants were 7,067 males from the prospective Growing Up Today Study. Surveys from 1999 to 2007 (spanning ages 13 26 years) provided repeated measures data on muscularity and leanness concerns, eating disorder behaviors (purging, overeating, binge eating, use of muscle-building products), and health correlates (obesity, non-marijuana drug use, binge drinking, and depressive symptoms). Results: Latent class analyses of observations at ages 13 to 15, 16 to 18, 19 to 22, and 23 to 26 years identified 1 large Asymptomatic class and 4 symptomatic patterns: Body Image Disturbance (high appearance concerns, low eating disorder behaviors; 1.0%-6.0% per age period); Binge Eating/Purging (binge eating and purging, use of muscle-building products, low appearance concerns; 0.1%-2.5%); Mostly Asymptomatic (low levels of muscularity concern, product use, and overeating; 3.5%-5.0%); and Muscularity Concerns (high muscularity concerns and use of products; 0.6%-1.0%). The Body Image Disturbance class was associated with high estimated prevalence of depressive symptoms. Males in the Binge Eating/Purging and Muscularity Concerns classes had high prevalence of binge drinking and drug use. Despite exhibiting modestly greater appearance concerns and eating disorder behaviors than the Asymptomatic class, being in the Mostly Asymptomatic class was prospectively associated with adverse health outcomes. Conclusion: Results underscore the importance of measuring concerns about leanness, muscularity, and use of muscle-building products when assessing eating disorder presentations among males in research and clinical settings. C1 [Calzo, Jerel P.; Sonneville, Kendrin R.; Field, Alison E.] Boston Childrens Hosp, Div Adolescent Young Adult Med, 300 Longwood Ave,AU Box 17,BCH3189, Boston, MA 02115 USA. [Calzo, Jerel P.; Sonneville, Kendrin R.; Eddy, Kamryn T.; Field, Alison E.] Harvard Med Sch, Boston, MA USA. [Sonneville, Kendrin R.] Univ Michigan, Sch Publ Hlth, Ann Arbor, MI 48109 USA. [Swanson, Sonja A.; Field, Alison E.] Harvard TH Chan Sch Publ Hlth, Boston, MA USA. [Field, Alison E.] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Field, Alison E.] Brown Univ, Providence, RI 02912 USA. [Horton, Nicholas J.] Amherst Coll, Amherst, MA 01002 USA. [Swanson, Sonja A.] Erasmus MC, Rotterdam, Netherlands. [Crosby, Ross D.] Neuropsychiat Res Inst, Fargo, ND USA. [Crosby, Ross D.] Univ North Dakota, Sch Med & Hlth Sci, Fargo, ND USA. [Micali, Nadia] UCL, Inst Child Hlth, Behav & Brain Sci Unit, London WC1E 6BT, England. [Micali, Nadia] Great Ormond St Hosp Sick Children, London, England. [Micali, Nadia] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Eddy, Kamryn T.] Massachusetts Gen Hosp, Eating Disorders Clin & Res Program, Boston, MA 02114 USA. RP Calzo, JP (reprint author), Boston Childrens Hosp, Div Adolescent Young Adult Med, 300 Longwood Ave,AU Box 17,BCH3189, Boston, MA 02115 USA. EM jerel.calzo@childrens.harvard.edu FU National Institutes of Health (NIH) [HD045763, HD057368, DK46834, HL03533, MH087786]; National Institute on Drug Abuse (NIDA) [K01DA034753]; National Institute of Mental Health (NIMH) [R01MH087786] FX The Growing Up Today Study (GUTS) was funded by National Institutes of Health (NIH) grants HD045763, HD057368, DK46834, HL03533, and MH087786. Dr. Calzo-was supported by K01DA034753 from the National Institute on Drug Abuse (NIDA). Drs. Field, Horton, Crosby, and Micali were supported by R01MH087786 from the National Institute of Mental Health (NIMH). NR 41 TC 1 Z9 1 U1 11 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0890-8567 EI 1527-5418 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD AUG PY 2016 VL 55 IS 8 BP 693 EP 700 DI 10.1016/j.jaac.2016.05.011 PG 8 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA DS2GP UT WOS:000380580900009 PM 27453083 ER PT J AU Carliner, H Keyes, KM McLaughlin, KA Meyers, JL Dunn, EC Martins, SS AF Carliner, Hannah Keyes, Katherine M. McLaughlin, Katie A. Meyers, Jacquelyn L. Dunn, Erin C. Martins, Silvia S. TI Childhood Trauma and Illicit Drug Use in Adolescence: A Population-Based National Comorbidity Survey Replication Adolescent Supplement Study SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE substance use; illicit drugs; adolescents; childhood trauma; maltreatment ID POSTTRAUMATIC-STRESS-DISORDER; SUBSTANCE USE DISORDERS; ADULT PSYCHIATRIC-DISORDERS; DSM-IV-DISORDERS; NCS-A; INTERGENERATIONAL TRANSMISSION; PROTECTIVE FACTORS; MENTAL-DISORDERS; MARIJUANA USE; LIFE EVENTS AB Objective: Although potentially traumatic events (PTEs) are established risk factors for substance use disorders among adults, little is known about associations with drug use during adolescence, an important developmental stage for drug use prevention. We examined whether childhood PTEs were associated with illicit drug use among a representative sample of US adolescents. Method: Data were drawn from the National Comorbidity Survey Replication Adolescent Supplement (NCS-A), which included adolescents aged 13 to 18 years (N = 9,956). Weighted logistic regression models estimated risk ratios for lifetime use of marijuana, cocaine, nonmedical prescription drugs, other drugs, and multiple drugs. Results: Exposure to any PTE before age 11 years was reported by 36% of the sample and was associated with higher risk for use of marijuana (risk ratio [RR] = 1.50), cocaine (RR = 2.78), prescription drugs (RR = 1.80), other drugs (RR = 1.90), and multiple drugs (RR = 1.74). A positive monotonic relationship was observed between number of PTEs and marijuana, other drug, and multiple drug use. Interpersonal violence was associated with all drug use outcomes. Accidents and unspecified events were associated with higher risk for marijuana, cocaine, and prescription drug use. Conclusion: Potentially traumatic events in childhood are associated with risk for illicit drug use among US adolescents. These findings add to the literature by illustrating a potentially modifiable health behavior that may be a target for intervention. The results also highlight that adolescents with a trauma history are a high-risk group for illicit drug use and may benefit from trauma-focused prevention efforts that specifically address traumatic memories and coping strategies for dealing with stressful life events. C1 [Carliner, Hannah; Keyes, Katherine M.; Martins, Silvia S.] Columbia Univ, New York, NY 10032 USA. [McLaughlin, Katie A.] Univ Washington, Seattle, WA 98195 USA. [Meyers, Jacquelyn L.] Suny Downstate Med Ctr, Brooklyn, NY 11203 USA. [Dunn, Erin C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Carliner, H (reprint author), Columbia Univ, Mailman Sch Publ Hlth, 722 West 168th St,1030-F, New York, NY 10032 USA. EM hcarliner@mail.harvard.edu FU National Institutes of Health [T32DA031099, MH102403, AA021511, R01DA037866, R01HD060072, MH106482, MH103291] FX This work is supported in part by National Institutes of Health grants T32DA031099 (Carliner, PI: Hasin), MH102403 (Dunn), AA021511 (Keyes), R01DA037866 (Martins), R01HD060072 (Martins), MH106482 (McLaughlin), and MH103291 (McLaughlin). NR 65 TC 1 Z9 1 U1 8 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0890-8567 EI 1527-5418 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD AUG PY 2016 VL 55 IS 8 BP 701 EP 708 DI 10.1016/j.jaac.2016.05.010 PG 8 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA DS2GP UT WOS:000380580900010 PM 27453084 ER PT J AU Coit, DG Thompson, JA Algazi, A Andtbacka, R Bichakjian, CK Carson, WE Daniels, GA DiMaio, D Fields, RC Fleming, MD Gastman, B Gonzalez, R Guild, V Johnson, D Joseph, RW Lange, JR Martini, MC Materin, MA Olszanski, AJ Ott, P Gupta, AP Ross, MI Salama, AK Skitzki, J Swetter, SM Tanabe, KK Torres-Roca, JF Trisal, V Urist, MM McMillian, N Engh, A AF Coit, Daniel G. Thompson, John A. Algazi, Alain Andtbacka, Robert Bichakjian, Christopher K. Carson, William E., III Daniels, Gregory A. DiMaio, Dominick Fields, Ryan C. Fleming, Martin D. Gastman, Brian Gonzalez, Rene Guild, Valerie Johnson, Douglas Joseph, Richard W. Lange, Julie R. Martini, Mary C. Materin, Miguel A. Olszanski, Anthony J. Ott, Patrick Gupta, Aparna Priyanath Ross, Merrick I. Salama, April K. Skitzki, Joseph Swetter, Susan M. Tanabe, Kenneth K. Torres-Roca, Javier F. Trisal, Vijay Urist, Marshall M. McMillian, Nicole Engh, Anita TI NCCN Guidelines (R) Insights Melanoma, Version 3.2016 Featured Updates to the NCCN Guidelines SO Journal of the National Comprehensive Cancer Network LA English DT Article ID BRAF-MUTANT MELANOMA; MUTATED METASTATIC MELANOMA; RANDOMIZED CONTROLLED-TRIAL; EXTENDED FOLLOW-UP; OPEN-LABEL; UNTREATED MELANOMA; MEK INHIBITION; IMPROVED SURVIVAL; PHASE-2 TRIAL; IPILIMUMAB AB The NCCN Guidelines for Melanoma have been significantly revised over the past few years in response to emerging data on a number of novel agents and treatment regimens. These NCCN Guidelines Insights summarize the data and rationale supporting extensive changes to the recommendations for systemic therapy in patients with metastatic or unresectable melanoma. C1 [Coit, Daniel G.] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. [Thompson, John A.] Fred Hutchinson Canc Res Ctr, Seattle Canc Care Alliance, Seattle, WA USA. [Algazi, Alain] UCSF, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA. [Andtbacka, Robert] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT 84112 USA. [Bichakjian, Christopher K.] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Carson, William E., III] Ohio State Univ, Ctr Comprehens Canc, James Canc Hosp, Columbus, OH 43210 USA. [Carson, William E., III] Solove Res Inst, Columbus, OH USA. [Daniels, Gregory A.] UC San Diego Moores Canc Ctr, La Jolla, CA USA. [DiMaio, Dominick] Fred & Pamela Buffett Canc Ctr, Omaha, NE USA. [Fields, Ryan C.] Barnes Jewish Hosp, Siteman Canc Ctr, St Louis, MO USA. [Fields, Ryan C.] Washington Univ, Sch Med, St Louis, MO 63130 USA. [Fleming, Martin D.] Univ Tennessee, Hlth Sci Ctr, Knoxville, TN 37996 USA. [Gastman, Brian] Univ Hosp Seidman Canc Ctr, Case Comprehens Canc Ctr, Cleveland, OH USA. [Gastman, Brian] Cleveland Clin, Taussig Canc Inst, Cleveland, OH USA. [Gonzalez, Rene] Univ Colorado, Ctr Canc, Boulder, CO 80309 USA. [Guild, Valerie] Aim Melanoma, Plano, TX USA. [Johnson, Douglas] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Joseph, Richard W.] Mayo Clin, Ctr Canc, Rochester, MN USA. [Lange, Julie R.] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD USA. [Martini, Mary C.; Gupta, Aparna Priyanath] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Evanston, IL 60208 USA. [Materin, Miguel A.] Yale Canc Ctr, Smilow Canc Hosp, New Haven, CT USA. [Olszanski, Anthony J.] Fox Chase Canc Ctr, Philadelphia, PA USA. [Ott, Patrick] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Ross, Merrick I.] Univ Texas MD Anderson Canc Ctr, Houston, TX USA. [Salama, April K.] Duke Canc Inst, Durham, NC USA. [Skitzki, Joseph] Roswell Pk Canc Inst, Buffalo, NY USA. [Swetter, Susan M.] Stanford Canc Inst, Stanford, CA USA. [Tanabe, Kenneth K.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Torres-Roca, Javier F.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Trisal, Vijay] City Hope Comprehens Canc Ctr, Duarte, CA USA. [Urist, Marshall M.] Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL USA. [McMillian, Nicole; Engh, Anita] Natl Comprehens Canc Network, Ft Washington, PA USA. RP Coit, DG (reprint author), Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. FU Eisai Inc.; Genentech, Inc.; Seattle Genetics; Acerta; Amgen Inc.; AstraZeneca Pharmaceuticals LP; Bristol-Myers Squibb Company; Corvus; GlaxoSmithKline; MedImmune Inc.; Merck Co, Inc.; Novartis Pharmaceuticals Corporation; Merck Co., Inc.; Roche Laboratories, Inc.; X4 Pharmaceuticals; AstraZeneca Pharmaceuticals/MedImmune; Celldex Therapeutics FX John A. Thompson, MD, Panel Vice Chair, has disclosed that he is a scientific advisor for Celldex Therapeutics; and receives consulting fees/honoraria from Eisai Inc., Genentech, Inc., and Seattle Genetics.; Alain Algazi, MD, Panel Member, has disclosed that he receives grant/research support from Acerta; Amgen Inc.; AstraZeneca Pharmaceuticals LP; Bristol-Myers Squibb Company; Corvus; GlaxoSmithKline; MedImmune Inc.; Merck & Co, Inc.; and Novartis Pharmaceuticals Corporation. He is also a consultant for Taylor Blessey LLC.; Richard W. Joseph, MD, Panel Member, has disclosed that he receives grant/research support from Amgen Inc., Bristol-Myers Squibb Company, Merck & Co., Inc., Roche Laboratories, Inc., and X4 Pharmaceuticals; he also serves as a scientific advisor for Bristol-Myers Squibb Company, Castle Biosciences, Inc., Eisai Inc., and Nektar Therapeutics.; Patrick Ott, MD, PhD, Panel Member, has disclosed that he receives grant/research support from AstraZeneca Pharmaceuticals/MedImmune, Celldex Therapeutics, Merck & Co., Inc., and Bristol-Myers Squibb Company; and that he is on the advisory board for Alexion Pharmaceuticals, Genentech, Inc., and Celldex Therapeutics. NR 50 TC 5 Z9 5 U1 1 U2 4 PU HARBORSIDE PRESS PI COLD SPRING HARBOR PA 37 MAIN ST, COLD SPRING HARBOR, NY 11724 USA SN 1540-1405 EI 1540-1413 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD AUG 1 PY 2016 VL 14 IS 8 BP 945 EP 958 PG 14 WC Oncology SC Oncology GA DS5JP UT WOS:000380818400004 PM 27496110 ER PT J AU Provenzale, D Gupta, S Ahnen, DJ Bray, T Cannon, JA Cooper, G David, DS Early, DS Erwin, D Ford, JM Giardiello, FM Grady, W Halverson, AL Hamilton, SR Hampel, H Ismail, MK Klapman, JB Larson, DW Lazenby, AJ Lynch, PM Mayer, RJ Ness, RM Regenbogen, SE Samadder, NJ Shike, M Steinbach, G Weinberg, D Dwyer, M Darlow, S AF Provenzale, Dawn Gupta, Samir Ahnen, Dennis J. Bray, Travis Cannon, Jamie A. Cooper, Gregory David, Donald S. Early, Dayna S. Erwin, Deborah Ford, James M. Giardiello, Francis M. Grady, William Halverson, Amy L. Hamilton, Stanley R. Hampel, Heather Ismail, Mohammad K. Klapman, Jason B. Larson, David W. Lazenby, Audrey J. Lynch, Patrick M. Mayer, Robert J. Ness, Reid M. Regenbogen, Scott E. Samadder, Niloy Jewel Shike, Moshe Steinbach, Gideon Weinberg, David Dwyer, Mary Darlow, Susan TI Genetic/Familial High-Risk Assessment: Colorectal Version 1.2016 SO Journal of the National Comprehensive Cancer Network LA English DT Article ID REVISED BETHESDA GUIDELINES; MISMATCH REPAIR DEFICIENCY; CANCER-INSTITUTE WORKSHOP; LYNCH SYNDROME CARRIERS; SMALL-BOWEL CANCER; MICROSATELLITE INSTABILITY; ENDOMETRIAL CANCER; GERMLINE MUTATIONS; GASTRIC-CANCER; COLON-CANCER AB This is a focused update highlighting the most current NCCN Guidelines for diagnosis and management of Lynch syndrome. Lynch syndrome is the most common cause of hereditary colorectal cancer, usually resulting from a germline mutation in 1 of 4 DNA mismatch repair genes (MLH1, MSH2, MSH6, or PMS2), or deletions in the EPCAM promoter. Patients with Lynch syndrome are at an increased lifetime risk, compared with the general population, for colorectal cancer, endometrial cancer, and other cancers, including of the stomach and ovary. As of 2016, the panel recommends screening all patients with colorectal cancer for Lynch syndrome and provides recommendations for surveillance for early detection and prevention of Lynch syndrome- associated cancers. C1 [Provenzale, Dawn] Duke Canc Inst, Durham, NC USA. [Gupta, Samir] UC San Diego Moores Canc Ctr, La Jolla, CA USA. [Ahnen, Dennis J.] Univ Colorado, Ctr Canc, Boulder, CO 80309 USA. [Bray, Travis] Hereditary Colon Canc Fdn, Park City, UT USA. [Cannon, Jamie A.] Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL USA. [Cooper, Gregory] Univ Hosp Seidman Canc Ctr, Case Comprehens Canc Ctr, Cleveland, OH USA. [Cooper, Gregory] Cleveland Clin, Taussig Canc Inst, Cleveland, OH USA. [David, Donald S.] City Hope Natl Med Ctr, Ctr Comprehens Canc, Duarte, CA USA. [Early, Dayna S.] Barnes Jewish Hosp, Siteman Canc Ctr, St Louis, MO USA. [Early, Dayna S.] Washington Univ, Sch Med, St Louis, MO 63130 USA. [Erwin, Deborah] Roswell Pk Canc Inst, Buffalo, NY USA. [Ford, James M.] Stanford Canc Inst, Stanford, CA USA. [Giardiello, Francis M.] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD USA. [Grady, William; Steinbach, Gideon] Fred Hutchinson Canc Res Ctr, Seattle Canc Care Alliance, Seattle, WA USA. [Halverson, Amy L.] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Evanston, IL 60208 USA. [Hamilton, Stanley R.; Lynch, Patrick M.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Hampel, Heather] Ohio State Univ, Ctr Comprehens Canc, James Canc Hosp, Columbus, OH 43210 USA. [Hampel, Heather] Ohio State Univ, Solove Res Inst, Columbus, OH 43210 USA. [Ismail, Mohammad K.] Univ Tennessee, Hlth Sci Ctr, St Jude Childrens Res Hosp, Knoxville, TN 37996 USA. [Klapman, Jason B.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Larson, David W.] Mayo Clin, Ctr Canc, Rochester, MN USA. [Lazenby, Audrey J.] Fred & Pamela Buffett Canc Ctr, Omaha, NE USA. [Mayer, Robert J.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Ness, Reid M.] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Regenbogen, Scott E.] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Samadder, Niloy Jewel] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT 84112 USA. [Shike, Moshe] Mem Sloan Kettering Canc Ctr, New York, NY USA. [Weinberg, David] Fox Chase Canc Ctr, Philadelphia, PA USA. RP Provenzale, D (reprint author), Duke Canc Inst, Durham, NC USA. NR 84 TC 2 Z9 4 U1 0 U2 3 PU HARBORSIDE PRESS PI COLD SPRING HARBOR PA 37 MAIN ST, COLD SPRING HARBOR, NY 11724 USA SN 1540-1405 EI 1540-1413 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD AUG 1 PY 2016 VL 14 IS 8 BP 1010 EP 1030 PG 21 WC Oncology SC Oncology GA DS5JP UT WOS:000380818400011 PM 27496117 ER PT J AU Albadawi, H Oklu, R Malley, RER O'Keefe, RM Uong, TP Cormier, NR Watkins, MT AF Albadawi, Hassan Oklu, Rahmi Malley, Rita Elise Raacke O'Keefe, Ryan M. Uong, Thuy P. Cormier, Nicholas R. Watkins, Michael T. TI Effect of DNase I treatment and neutrophil depletion on acute limb ischemia-reperfusion injury in mice SO JOURNAL OF VASCULAR SURGERY LA English DT Article ID DEEP-VEIN THROMBOSIS; EXTRACELLULAR TRAPS; SKELETAL-MUSCLE; DEOXYRIBONUCLEASE-I; ISCHEMIA/REPERFUSION INJURY; ACTIN; HISTONES; INFLAMMATION; CHROMATIN; CELLS AB Objective: Extracellular traps (ETs) consisting of DNA-protein complexes formed after tissue injury contribute to the inflammatory and thrombosis cascades, thereby exacerbating injury. Exogenous DNase I has been suggested as a therapeutic strategy to limit injury in the brain and myocardium. These studies were designed to evaluate the effects of exogenous DNase I treatment on skeletal muscle injury after acute hindlimb ischemia-reperfusion (IR) injury in mice and to determine whether neutrophils are a major source of ETs in postischemic muscle tissue. Methods: C57BL6 mice were subjected to 1.5 hours of tourniquet ischemia and 24 hours of reperfusion with and without human recombinant DNase I treatment. A separate set of mice was subjected to neutrophil depletion (ND), followed by the same intervals of IR. Laser Doppler imaging and tissue harvesting were done at 24 hours for assessment of limb perfusion, muscle fiber injury, adenosine triphosphate (ATP) level, markers of inflammation, thrombosis, and formation of ETs. Results: DNase I treatment significantly reduced detection of ETs in postischemic muscle but did not alter skeletal muscle fiber injury, levels of proinflammatory molecules, or ATP level. DNase I treatment did enhance postischemic hindlimb perfusion, decreased infiltrating inflammatory cells, and reduced the expression of thrombin-antithrombin III. ND resulted in a significant yet small reduction in ETs in the postischemic muscle. ND did not alter skeletal muscle fiber injury, hindlimb perfusion, or ATP levels. Conclusions: These data suggest that neither DNase I treatment nor ND was protective against IR injury, even though both decreased detection of ETs in skeletal muscle after IR. Neutrophils are not the only source of ETs after IR. Clinical Relevance: Acute muscle ischemia-reperfusion injury that follows a traumatic event or thrombotic occlusion of a major artery due to vascular disease in the lower extremities can lead to extensive tissue inflammation and necrosis. DNase I was recently proposed as a treatment strategy to degrade neutrophil extracellular traps, which consist of protein-DNA complexes accumulating after tissue injury or thrombosis. Investigators believe that these complexes can enhance the prothrombogenic and proinflammatory milieu in the tissue, thereby exacerbating injury. In this study, we investigate the benefit of DNase I treatment as a tool to degrade these complexes, aiming to ameliorate muscle ischemia-reperfusion injury. C1 [Albadawi, Hassan; Malley, Rita Elise Raacke; O'Keefe, Ryan M.; Uong, Thuy P.; Cormier, Nicholas R.; Watkins, Michael T.] Massachusetts Gen Hosp, Dept Surg, Div Vasc & Endovasc Surg, Boston, MA 02114 USA. [Oklu, Rahmi] Massachusetts Gen Hosp, Dept Radiol, Div Vasc Imaging & Intervent, Boston, MA 02114 USA. [Albadawi, Hassan; Oklu, Rahmi; Watkins, Michael T.] Harvard Med Sch, Boston, MA USA. RP Albadawi, H (reprint author), Massachusetts Gen Hosp, Vasc Res Lab, Dept Surg, Div Vasc & Endovasc Surg, 70 Blossom St Edwards 301, Boston, MA 02114 USA. EM halbadawi@partners.org OI Albadawi, Hassan/0000-0001-5913-8571 FU NIAMS NIH HHS [R01 AR055843] NR 38 TC 1 Z9 1 U1 3 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 2016 VL 64 IS 2 BP 484 EP 493 DI 10.1016/j.jvs.2015.01.031 PG 10 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA DS4LT UT WOS:000380753300033 PM 26704988 ER PT J AU Zanetti, KA Wang, ZM Aldrich, M Amos, CI Blot, WJ Bowman, ED Burdette, L Cai, QY Caporaso, N Chung, CC Gillanders, EM Haiman, CA Hansen, HM Henderson, BE Kolonel, LN Le Marchand, L Li, SC McNeil, LH Ryan, BM Schwartz, AG Sison, JD Spitz, MR Tucker, M Wenzlaff, AS Wiencke, JK Wilkens, L Wrensch, MR Wu, XF Zheng, W Zhou, WY Christiani, D Palmer, JR Penning, TM Rieber, AG Rosenberg, L Ruiz-Narvaez, EA Su, L Vachani, A Wei, YY Whitehead, AS Chanock, SJ Harris, CC AF Zanetti, Krista A. Wang, Zhaoming Aldrich, Melinda Amos, Christopher I. Blot, William J. Bowman, Elise D. Burdette, Laurie Cai, Qiuyin Caporaso, Neil Chung, Charles C. Gillanders, Elizabeth M. Haiman, Christopher A. Hansen, Helen M. Henderson, Brian E. Kolonel, Laurence N. Le Marchand, Loic Li, Shengchao McNeil, Lorna Haughton Ryan, Brid M. Schwartz, Ann G. Sison, Jennette D. Spitz, Margaret R. Tucker, Margaret Wenzlaff, Angela S. Wiencke, John K. Wilkens, Lynne Wrensch, Margaret R. Wu, Xifeng Zheng, Wei Zhou, Weiyin Christiani, David Palmer, Julie R. Penning, Trevor M. Rieber, Alyssa G. Rosenberg, Lynn Ruiz-Narvaez, Edward A. Su, Li Vachani, Anil Wei, Yongyue Whitehead, Alexander S. Chanock, Stephen J. Harris, Curtis C. TI Genome-wide association study confirms lung cancer susceptibility loci on chromosomes 5p15 and 15q25 in an African-American population SO LUNG CANCER LA English DT Article DE Genome-wide association study; Lung neoplasms; Smoking; African Americans; Telomerase; Receptors, Cholinergic ID ACETYLCHOLINE-RECEPTOR GENES; NICOTINE DEPENDENCE; EUROPEAN-AMERICANS; RACIAL-DIFFERENCES; SMOKING-BEHAVIOR; CIGARETTE-SMOKING; HEAVY SMOKING; IDENTIFIES 2; RISK; VARIANTS AB Objectives: Genome-wide association studies (GWAS) of lung cancer have identified regions of common genetic variation with lung cancer risk in Europeans who smoke and never-smoking Asian women. This study aimed to conduct a GWAS in African Americans, who have higher rates of lung cancer despite smoking fewer cigarettes per day when compared with Caucasians. This population provides a different genetic architecture based on underlying African ancestry allowing the identification of new regions and exploration of known regions for finer mapping. Materials and methods: We genotyped 1,024,001 SNPs in 1737 cases and 3602 controls in stage 1, followed by a replication phase of 20 SNPs (p < 1.51 x 10(-8)) in an independent set of 866 cases and 796 controls in stage 2. Results and conclusion: In the combined analysis, we confirmed two loci to be associated with lung cancer that achieved the threshold of genome-wide significance: 15q25.1 marked by rs2036527 (p =1.3 x 10(-9); OR =1.32; 95% CI =1.20-1.44) near CHRNA5, and 5p15.33 marked by rs2853677 (p = 2.8 x 10(-9); OR =1.28; 95% CI = 1.18-1.39) near TERT. The association with rs2853677 is driven by the adenocarcinoma subtype of lung cancer (p =1.3 x 10(-8); OR= 1.37; 95% CI= 1.23-1.54). No SNPs reached genome-wide significance for either of the main effect models examining smoking - cigarettes per day and current or former smoker. Our study was powered to identify strong risk loci for lung cancer in African Americans; we confirmed results previously reported in African Americans and other populations for two loci near plausible candidate genes, CHRNA5 and TERT, on 15825.1 and 5p15.33 respectively, are associated with lung cancer. Additional work is required to map and understand the biological underpinnings of the strong association of these loci with lung cancer risk in African Americans. Published by Elsevier Ireland Ltd. C1 [Zanetti, Krista A.; Gillanders, Elizabeth M.] NCI, Div Canc Control & Populat Sci, 9609 Med Ctr Dr, Rockville, MD 20892 USA. [Wang, Zhaoming; Burdette, Laurie; Caporaso, Neil; Chung, Charles C.; Li, Shengchao; Tucker, Margaret; Zhou, Weiyin; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr, Rockville, MD 20892 USA. [Aldrich, Melinda; Blot, William J.; Cai, Qiuyin; Zheng, Wei] Vanderbilt Univ, Med Ctr, Div Epidemiol, 1161 21st Ave South,D-3100 Med Ctr North, Nashville, TN 37232 USA. [Aldrich, Melinda] Vanderbilt Univ, Med Ctr, Dept Thorac Surg, 609 Oxford House,1313 21st Ave South, Nashville, TN 37232 USA. [Amos, Christopher I.] Geisel Sch Med, Dept Biomed Data Sci, 1 Rope Ferry Rd, Lebanon, NH 03755 USA. [Bowman, Elise D.; Ryan, Brid M.; Harris, Curtis C.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, Bldg 37,Room 3068A, Bethesda, MD 20892 USA. [Haiman, Christopher A.; Henderson, Brian E.] Univ Southern Calif, Keck Sch Med, Dept Prevent Med, 1975 Zonal Ave, Los Angeles, CA 90033 USA. [Haiman, Christopher A.; Henderson, Brian E.] Norris Comprehens Canc Ctr, 1975 Zonal Ave, Los Angeles, CA 90033 USA. [Hansen, Helen M.; Sison, Jennette D.; Wiencke, John K.; Wrensch, Margaret R.] Univ Calif San Francisco, Dept Neurol Surg, 505 Parnassus Ave,Room 779, San Francisco, CA 94143 USA. [Kolonel, Laurence N.; Le Marchand, Loic; Wilkens, Lynne] Univ Hawaii, Canc Res Ctr, Program Epidemiol, Honolulu, HI 96813 USA. [McNeil, Lorna Haughton] Univ Texas MD Anderson Canc Ctr, Div OVP Canc Prevent & Populat Sci, Dept Hlth Dispar Res, 1515 Holcombe Blvd,Unit 91, Houston, TX 77030 USA. [Schwartz, Ann G.; Wenzlaff, Angela S.] Wayne State Univ, Sch Med, Karmanos Canc Inst, Dept Oncol, 4100 John R, Detroit, MI 48201 USA. [Wilkens, Lynne] Baylor Coll Med, Dept Mol & Cellular Biol, One Baylor Plaza,Mail Stop BCM225, Houston, TX 77030 USA. [Wu, Xifeng] Univ Texas MD Anderson Canc Ctr, Div OVP Canc Prevent & Populat Sci, Dept Epidemiol, Unit 1340,POB 301439, Houston, TX 77230 USA. [Christiani, David; Su, Li; Wei, Yongyue] Harvard Med Sch, Massachusetts Gen Hosp, Harvard Sch Publ Hlth, 25 Shattuck St, Boston, MA 02115 USA. [Palmer, Julie R.; Rosenberg, Lynn; Ruiz-Narvaez, Edward A.] Boston Univ, Slone Epidemiol Canc Ctr, 1010 Commonwealth Ave,4th Floor, Boston, MA 02215 USA. [Penning, Trevor M.; Vachani, Anil; Whitehead, Alexander S.] Univ Penn, Perelman Sch Med, Ctr Excellence Environm Toxicol, 3535 Market St, Philadelphia, PA 19104 USA. [Penning, Trevor M.; Whitehead, Alexander S.] Univ Penn, Perelman Sch Med, Dept Pharmacol, 3535 Market St, Philadelphia, PA 19104 USA. [Rieber, Alyssa G.] Univ Texas MD Anderson Canc Ctr, Div Canc Med, Dept Gen Oncol, 1515 Holcombe Blvd, Houston, TX 77030 USA. [Vachani, Anil] Univ Penn, Perelman Sch Med, Dept Med, 3535 Market St, Philadelphia, PA 19104 USA. RP Chanock, SJ (reprint author), NCI, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr, Rockville, MD 20892 USA.; Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, Ctr Canc Res, Bldg 37,Room 3068A, Bethesda, MD 20892 USA. EM zanettik@mail.nih.gov; wangzha@mail.nih.gov; melinda.aldrich@Vanderbilt.Edu; Christopher.I.Amos@Dartmouth.edu; blotw@iei.us; bowmane@intra.nci.nih.gov; burdettl@mail.nih.gov; qiuyin.cai@Vanderbilt.Edu; caporasn@mail.nih.gov; chungcc@mail.nih.gov; lgilland@mail.nih.gov; haiman@usc.edu; helen.hansen@ucsf.edu; lkolonel@cc.hawaii.edu; Loic@cc.hawaii.edu; shengchao.li@nih.gov; lmcneill@mdanderson.org; ryanb@mail.nih.gov; schwarta@karmanos.org; jennette.sison@ucsf.edu; spitz@bcm.edu; tuckerp@mail.nih.gov; wenzlaff@karmanos.org; john.wiencke@ucsf.edu; lynne@cc.hawaii.edu; Margaret.Wrensch@ucsf.edu; xwu@mdanderson.org; wei.zheng@vanderbilt.edu; zhouw@mail.nih.gov; dchris@hsph.harvard.edu; jpalmer@bu.edu; PENNING@UPENN.EDU; arieber@mdanderson.org; Irosenbe@bu.edu; eruiznar@bu.edu; lisu@hsph.harvard.edu; avachani@mail.med.upenn.edu; ywei@hsph.harvard.edu; aswhiteh@mail.med.upenn.edu; chanocks@mail.nih.gov; Curtis_Harris@nih.gov RI Zheng, Wei/O-3351-2013 OI Zheng, Wei/0000-0003-1226-070X FU Black Women's Health Study (BWHS): NIH grants [R01CA098663, R01CA05842]; National Institutes of Health [CA63464, CA54281, CA1326792, CA164973, CA148085, CA138338, CA148127, HG004726]; Department of Defense Breast Cancer Research Program Era of Hope Scholar Award [W81XWH-08-1-0383]; Pennsylvania Department of Health [PA4100038714]; NCI [R21CA156087]; NIH-NIEHS grant [P30ES013508]; intramural research program of the National Institutes of Health, National Cancer Institute; federal funds from the National Cancer Institute, National Institutes of Health; National Institutes of Health through MD Anderson's Cancer Center Support Grant [CA016672]; NIH [R01CA092447]; Vanderbilt-Ingram Cancer Center [P30CA068485]; NIH/NCI grant [K07CA172294]; Karmanos Cancer Institute at Wayne State University: NIH [R01CA060691, R01CA87895, N01-PC35145, P30CA22453]; Department of Health and Human Services [HHSN261201000028C] FX The Black Women's Health Study (BWHS): NIH grants R01CA098663 and R01CA05842.; The Multiethnic Cohort Study (MEC): The MEC study, blood collection, DNA extraction and genotyping was supported by National Institutes of Health grants CA63464, CA54281, CA1326792, CA164973, CA148085, CA138338, CA148127 and HG004726 and a Department of Defense Breast Cancer Research Program Era of Hope Scholar Award to CAH (W81XWH-08-1-0383).; Philadelphia Lung Cancer Study on Gene Environment Interactions (Plus-Gene): This work was funded by grant PA4100038714 from the Pennsylvania Department of Health, NCI R21CA156087, and NIH-NIEHS grant P30ES013508 for the Center of Excellence in Environmental Toxicology.; Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO): The NCI African American lung cancer GWAS was supported by the intramural research program of the National Institutes of Health, National Cancer Institute. This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health.; Project CHURCH (Creating a Higher Understanding of Cancer Research & Community Health): University Cancer Foundation, the Duncan Family Institute through the Center for Community Engaged Translational Research, the Ms. Regina J. Rogers Gift: Health Disparities Research Program, the Cullen Trust for Health Care Endowed Chair Funds for Health Disparities Research, the Morgan Foundation Funds for Health Disparities Research and Educational Programs, and the National Institutes of Health through MD Anderson's Cancer Center Support Grant (CA016672).; The Southern Community Cohort Study (SCCS): Funding for the SCCS research was provided by NIH grant R01CA092447. DNA Sample preparation was conducted at the Survey and Biospecimen Shared Resources, which is supported in part by Vanderbilt-Ingram Cancer Center (P30CA068485), and Dr. Melinda Aldrich's effort was supported by NIH/NCI grant K07CA172294. Karmanos Cancer Institute at Wayne State University: NIH grants R01CA060691, R01CA87895, contracts N01-PC35145 and P30CA22453, Department of Health and Human Services contract HHSN261201000028C, and the Herrick Foundation. NR 70 TC 1 Z9 1 U1 7 U2 8 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0169-5002 EI 1872-8332 J9 LUNG CANCER JI Lung Cancer PD AUG PY 2016 VL 98 BP 33 EP 42 DI 10.1016/j.lungcan.2016.05.008 PG 10 WC Oncology; Respiratory System SC Oncology; Respiratory System GA DS2JS UT WOS:000380596400006 PM 27393504 ER PT J AU Readhead, B Haure-Mirande, JV Zhang, B Haroutunian, V Gandy, S Schadt, EE Dudley, JT Ehrlich, ME AF Readhead, B. Haure-Mirande, J-V Zhang, B. Haroutunian, V. Gandy, S. Schadt, E. E. Dudley, J. T. Ehrlich, M. E. TI Molecular systems evaluation of oligomerogenic APP(E693Q) and fibrillogenic APP(KM670/671NL)/PSEN1(Delta exon9) mouse models identifies shared features with human Alzheimer's brain molecular pathology SO MOLECULAR PSYCHIATRY LA English DT Article ID AMYLOID PRECURSOR PROTEIN; A-BETA OLIGOMER; GENE SET ENRICHMENT; MICROGLIAL ACTIVATION; TRANSGENIC MICE; DISEASE; EXPRESSION; TRANSCRIPTION; SP1; METAANALYSIS AB Identification and characterization of molecular mechanisms that connect genetic risk factors to initiation and evolution of disease pathophysiology represent major goals and opportunities for improving therapeutic and diagnostic outcomes in Alzheimer's disease (AD). Integrative genomic analysis of the human AD brain transcriptome holds potential for revealing novel mechanisms of dysfunction that underlie the onset and/or progression of the disease. We performed an integrative genomic analysis of brain tissue-derived transcriptomes measured from two lines of mice expressing distinct mutant AD-related proteins. The first line expresses oligomerogenic mutant APP(E693Q) inside neurons, leading to the accumulation of amyloid beta (A beta) oligomers and behavioral impairment, but never develops parenchymal fibrillar amyloid deposits. The second line expresses APP(KM670/671NL)/PSEN1(Delta exon9) in neurons and accumulates fibrillar A beta amyloid and amyloid plaques accompanied by neuritic dystrophy and behavioral impairment. We performed RNA sequencing analyses of the dentate gyrus and entorhinal cortex from each line and from wild-type mice. We then performed an integrative genomic analysis to identify dysregulated molecules and pathways, comparing transgenic mice with wild-type controls as well as to each other. We also compared these results with datasets derived from human AD brain. Differential gene and exon expression analysis revealed pervasive alterations in APP/A beta metabolism, epigenetic control of neurogenesis, cytoskeletal organization and extracellular matrix (ECM) regulation. Comparative molecular analysis converged on FMR1 (Fragile X Mental Retardation 1), an important negative regulator of APP translation and oligomerogenesis in the post-synaptic space. Integration of these transcriptomic results with human postmortem AD gene networks, differential expression and differential splicing signatures identified significant similarities in pathway dysregulation, including ECM regulation and neurogenesis, as well as strong overlap with AD-associated co-expression network structures. The strong overlap in molecular systems features supports the relevance of these findings from the AD mouse models to human AD. C1 [Readhead, B.; Zhang, B.; Schadt, E. E.; Dudley, J. T.; Ehrlich, M. E.] Icahn Sch Med Mt Sinai, Dept Genet, New York, NY 10029 USA. [Readhead, B.; Zhang, B.; Schadt, E. E.; Dudley, J. T.] Icahn Sch Med Mt Sinai, Dept Genom Sci, New York, NY 10029 USA. [Readhead, B.; Zhang, B.; Schadt, E. E.; Dudley, J. T.; Ehrlich, M. E.] Icahn Sch Med Mt Sinai, Icahn Inst Genom Sci & Multiscale Biol, New York, NY 10029 USA. [Haure-Mirande, J-V; Gandy, S.; Ehrlich, M. E.] Icahn Sch Med Mt Sinai, Alzheimers Dis Res Ctr, Dept Neurol, One Gustave L Levy Pl Box 1137, New York, NY 10029 USA. [Haroutunian, V.; Gandy, S.] Icahn Sch Med Mt Sinai, Alzheimers Dis Res Ctr, Dept Psychiat, New York, NY 10029 USA. [Haroutunian, V.; Gandy, S.] James J Peters VA Med Ctr, New York, NY USA. [Gandy, S.] Ctr Cognit Hlth & NFL Neurol Care, Dept Neurol, New York, NY USA. [Gandy, S.] Icahn Sch Med Mt Sinai, Dept Pediat, New York, NY 10029 USA. RP Ehrlich, ME (reprint author), Icahn Sch Med Mt Sinai, Alzheimers Dis Res Ctr, Dept Neurol, One Gustave L Levy Pl Box 1137, New York, NY 10029 USA.; Dudley, JT (reprint author), Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, 770 Lexington Ave, New York, NY 10065 USA. EM joel.dudley@mssm.edu; michelle.ehrlich@mssm.edu FU NIH [multi-PI U01 AG046170, multi-PI R34 AG049649, R01 NS075685, P50 AG005138, R01 DK098242, U54 CA189201, HHSN271201300031C]; VA MERIT [RRD MERIT I01RX000684, BLRD MERIT I01BX000348]; Cure Alzheimer's Fund Research Consortium FX We thank the Mount Sinai Genomics Core Facility for carrying out the RNA sequencing. We would like to recognize the federal and foundation support that made this research possible. NIH support for this work included multi-PI U01 AG046170 (to EES, SG, VH, MEE), multi-PI R34 AG049649 (JTD, SG), R01 NS075685 (SG), P50 AG005138 to Mary Sano (SG), R01 DK098242 to JTD, U54 CA189201 to JTD, and HHSN271201300031C to VH. VA MERIT support included RRD MERIT I01RX000684 (SG) and BLRD MERIT I01BX000348 (SG). The Cure Alzheimer's Fund Research Consortium also supported this work (SG). The computational resources and staff expertise provided by the Department of Scientific Computing at the Icahn School of Medicine at Mount Sinai also contributed to the performance of this research. Data for the human LOAD DEX analysis were generated from postmortem brain tissue collected through the Mount Sinai VA Medical Center Brain Bank (generously provided by Dr. Eric Schadt), and the Mount Sinai NIH Brain and Tissue Repository (generously provided by Dr. Vahram Haroutunian). The results published here are based on data obtained from the Accelerating Medicines Partnership for Alzheimer's Disease (AMP-AD) Target Discovery Consortium data portal and can be accessed at doi:10.7303/syn2580853. NR 89 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD AUG PY 2016 VL 21 IS 8 BP 1099 EP 1111 DI 10.1038/mp.2015.167 PG 13 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA DS4GN UT WOS:000380739500014 PM 26552589 ER PT J AU Cox, AG Hwang, KL Brown, KK Evason, KJ Beltz, S Tsomides, A O'Connor, K Galli, GG Yimlamai, D Chhangawala, S Yuan, M Lien, EC Wucherpfennig, J Nissim, S Minami, A Cohen, DE Camargo, FD Asara, JM Houvras, Y Stainier, DYR Goessling, W AF Cox, Andrew G. Hwang, Katie L. Brown, Kristin K. Evason, Kimberley J. Beltz, Sebastian Tsomides, Allison O'Connor, Keelin Galli, Giorgio G. Yimlamai, Dean Chhangawala, Sagar Yuan, Min Lien, Evan C. Wucherpfennig, Julia Nissim, Sahar Minami, Akihiro Cohen, David E. Camargo, Fernando D. Asara, John M. Houvras, Yariv Stainier, Didier Y. R. Goessling, Wolfram TI Yap reprograms glutamine metabolism to increase nucleotide biosynthesis and enable liver growth SO NATURE CELL BIOLOGY LA English DT Article ID NOVO PYRIMIDINE SYNTHESIS; AMPK-MEDIATED REGULATION; HIPPO PATHWAY ACTIVITY; ZEBRAFISH DANIO-RERIO; L-FABP GENE; CELL-GROWTH; TRANSGENIC ZEBRAFISH; BETA-CATENIN; RAT-LIVER; IN-VIVO AB The Hippo pathway is an important regulator of organ size and tumorigenesis. It is unclear, however, how Hippo signalling provides the cellular building blocks required for rapid growth. Here, we demonstrate that transgenic zebrafish expressing an activated form of the Hippo pathway effector Yap1 (also known as YAP) develop enlarged livers and are prone to liver tumour formation. Transcriptomic and metabolomic profiling identify that Yap1 reprograms glutamine metabolism. Yap1 directly enhances glutamine synthetase (glul) expression and activity, elevating steady-state levels of glutamine and enhancing the relative isotopic enrichment of nitrogen during de novo purine and pyrimidine biosynthesis. Genetic or pharmacological inhibition of GLUL diminishes the isotopic enrichment of nitrogen into nucleotides, suppressing hepatomegaly and the growth of liver cancer cells. Consequently, Yap-driven liver growth is susceptible to nucleotide inhibition. Together, our findings demonstrate that Yap1 integrates the anabolic demands of tissue growth during development and tumorigenesis by reprogramming nitrogen metabolism to stimulate nucleotide biosynthesis. C1 [Cox, Andrew G.; Hwang, Katie L.; Beltz, Sebastian; Tsomides, Allison; O'Connor, Keelin; Wucherpfennig, Julia; Nissim, Sahar; Minami, Akihiro; Cohen, David E.; Goessling, Wolfram] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA 02115 USA. [Hwang, Katie L.] Harvard Med Sch, Harvard MIT MD PhD Program, Boston, MA 02115 USA. [Brown, Kristin K.; Yuan, Min; Lien, Evan C.; Asara, John M.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. [Evason, Kimberley J.] Univ Utah, Salt Lake City, UT 84112 USA. [Galli, Giorgio G.; Yimlamai, Dean; Camargo, Fernando D.] Harvard Med Sch, Boston Childrens Hosp, Boston, MA 02115 USA. [Chhangawala, Sagar; Houvras, Yariv] Weill Cornell Med Coll, New York, NY 10065 USA. [Camargo, Fernando D.; Goessling, Wolfram] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Stainier, Didier Y. R.] Max Planck Inst, D-61231 Bad Nauheim, Germany. [Goessling, Wolfram] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA 02115 USA. [Goessling, Wolfram] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Galli, Giorgio G.] Novartis Inst BioMed Res, Dis Area Oncol, CH-4056 Basel, Switzerland. RP Goessling, W (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Boston, MA 02115 USA.; Goessling, W (reprint author), Harvard Stem Cell Inst, Cambridge, MA 02138 USA.; Goessling, W (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Boston, MA 02115 USA.; Goessling, W (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. EM wgoessling@partners.org OI Lien, Evan/0000-0001-7866-4761; Yimlamai, Dean/0000-0002-7936-7168; Chhangawala, Sagar/0000-0001-9626-1034 FU Irwin Arias Postdoctoral Fellowship American Liver Foundation; Liver Scholar Award from the American Liver Foundation; HDDC Pilot Feasibility Grant from the Harvard Digestive Disease Center [P30 DK034854]; NIH NIGMS [T32GM007753]; NIH NCI [5K08CA172288, 5P01CA120964, 5P30CA006516]; NIH NIDDK [RO1DK60322, RO1DK090311]; NIH [K08DK105351, R01AR064036, R01DK099559]; Packard Foundation; American-Italian Cancer Foundation; Damon Runyon Cancer Research Foundation [DRG-10910]; Claudia Adams Barr Program for Innovative Cancer Research; Pew Scholar in the Biomedical Sciences FX This work was supported by an Irwin Arias Postdoctoral Fellowship (A.G.C.) and Liver Scholar Award (A.G.C.) from the American Liver Foundation, an HDDC Pilot Feasibility Grant from the Harvard Digestive Disease Center, P30 DK034854 (A.G.C., D.Y), NIH NIGMS T32GM007753 (K.L.H.), NIH NCI 5K08CA172288 (K.J.E.), NIH NIDDK RO1DK60322 (D.YR.S.), NIH NIDDK RO1DK090311 (W.G.), NIH K08DK105351 (D.Y.), R01AR064036 (F.D.C.) and R01DK099559 (F.D.C.), and the Packard Foundation (D.Y.R.S.). J.M.A. is partially supported by NIH NCI 5P01CA120964 and 5P30CA006516. G.G.G. is supported by an American-Italian Cancer Foundation postdoctoral research fellowship. K.J.E. was a Robert Black Fellow supported by the Damon Runyon Cancer Research Foundation (DRG-10910). D.Y. is a Gilead Sciences Scholar in Liver Disease. W.G. is supported by the Claudia Adams Barr Program for Innovative Cancer Research, and is a Pew Scholar in the Biomedical Sciences. NR 70 TC 3 Z9 3 U1 10 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 EI 1476-4679 J9 NAT CELL BIOL JI Nat. Cell Biol. PD AUG PY 2016 VL 18 IS 8 BP 886 EP + DI 10.1038/ncb3389 PG 22 WC Cell Biology SC Cell Biology GA DS5NO UT WOS:000380829200009 PM 27428308 ER PT J AU Georgopoulos, K AF Georgopoulos, Katia TI Induction of Bcl11b during T cell commitment through a tripartite mechanism SO NATURE IMMUNOLOGY LA English DT Editorial Material ID DIFFERENTIATION; LINEAGE; SPECIFICATION; CHECKPOINT; EXPRESSION AB Induction of the transcription factor Bcl11b in early T cell precursors is supported by three positive forces: signaling via the transmembrane receptor Notch1 provides stochastic permissivity; the transcription factors TCF-1 and GATA-3 poise the locus for expression; and the transcription factor Runx1 steps in to raise expression. C1 [Georgopoulos, Katia] Harvard Med Sch, Massachusetts Gen Hosp, Biol Res Ctr, Charlestown, MA 02129 USA. RP Georgopoulos, K (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Biol Res Ctr, Charlestown, MA 02129 USA. EM katia.georgopoulos@cbrc2.mgh.harvard.edu NR 13 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 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD AUG PY 2016 VL 17 IS 8 BP 903 EP 904 PG 2 WC Immunology SC Immunology GA DS2XK UT WOS:000380647000006 PM 27434004 ER PT J AU Robinson, PC Choi, HK Do, R Merriman, TR AF Robinson, Philip C. Choi, Hyon K. Do, Ron Merriman, Tony R. TI Insight into rheumatological cause and effect through the use of Mendelian randomization SO Nature Reviews Rheumatology LA English DT Review ID CORONARY-HEART-DISEASE; SERUM URIC-ACID; MULTIPLE GENETIC-VARIANTS; C-REACTIVE PROTEIN; ISCHEMIC CARDIOVASCULAR-DISEASE; CHRONIC KIDNEY-DISEASE; MIDDLE-AGED MEN; RHEUMATOID-ARTHRITIS; BLOOD-PRESSURE; VITAMIN-D AB Establishing causality of risk factors is important to determine the pathogenetic mechanisms underlying rheumatic diseases, and can facilitate the design of interventions to improve care for affected patients. The presence of unmeasured confounders, as well as reverse causation, is a challenge to the assignment of causality in observational studies. Alleles for genetic variants are randomly inherited at meiosis. Mendelian randomization analysis uses these genetic variants to test whether a particular risk factor is causal for a disease outcome. In this Review of the Mendelian randomization technique, we discuss published results and potential applications in rheumatology, as well as the general clinical utility and limitations of the approach. C1 [Robinson, Philip C.] Univ Queensland, Fac Med & Biomed Sci, Sch Med, Herston Rd, Brisbane, Qld 4006, Australia. [Robinson, Philip C.] Royal Brisbane & Womens Hosp, Dept Rheumatol, Butterfield St & Bowen Bridge Rd, Brisbane, Qld 4029, Australia. [Choi, Hyon K.] Harvard Med Sch, Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, 55 Fruit St, Boston, MA 02114 USA. [Do, Ron] Mt Sinai Sch Med, Genet & Genome Sci, 1 Gustav L Levy Pl, New York, NY 10029 USA. [Merriman, Tony R.] Univ Otago, Dept Biochem, 710 Cumberland St, Dunedin 9054, New Zealand. RP Merriman, TR (reprint author), Univ Otago, Dept Biochem, 710 Cumberland St, Dunedin 9054, New Zealand. EM tony.merriman@otago.ac.nz OI Merriman, Tony/0000-0003-0844-8726 FU Menarini; AstraZeneca; Ardea Biosciences; Takeda FX P.R. declares that he has received speaking and consulting fees from Menarini and speaking fees and research funding from AstraZeneca. T.R.M. declares that he has received consulting fees and research funding from Ardea Biosciences and AstraZeneca. H.K.C. declares that he has received consulting fees from AstraZeneca and Takeda. R.D. declares no competing interests. NR 117 TC 3 Z9 3 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4790 EI 1759-4804 J9 NAT REV RHEUMATOL JI Nat. Rev. Rheumatol. PD AUG PY 2016 VL 12 IS 8 BP 486 EP 496 DI 10.1038/nrrheum.2016.102 PG 11 WC Rheumatology SC Rheumatology GA DS5VG UT WOS:000380850500008 PM 27411906 ER PT J AU Vasudeva, VS Chi, JH Groff, MW AF Vasudeva, Viren S. Chi, John H. Groff, Michael W. TI Surgical treatment of aggressive vertebral hemangiomas SO Neurosurgical Focus LA English DT Article DE aggressive vertebral hemangioma; vertebral hemangioma; cavernous hemangioma; vertebral angioma; primary spinal column tumor ID SPINAL-CORD COMPRESSION; OF-THE-LITERATURE; N-BUTYL CYANOACRYLATE; PERCUTANEOUS EMBOLIZATION; INTRALESIONAL INJECTION; SYMPTOMATIC HEMANGIOMA; METHYL-METHACRYLATE; FOLLOW-UP; RADIOTHERAPY; MANAGEMENT AB OBJECTIVE Vertebral hemangiomas are common tumors that are benign and generally asymptomatic. Occasionally these lesions can exhibit aggressive features such as bony expansion and erosion into the epidural space resulting in neurological symptoms. Surgery is often recommended in these cases, especially if symptoms are severe or rapidly progressive. Some surgeons perform decompression alone, others perform gross-total resection, while others perform en bloc resection. Radiation, embolization, vertebroplasty, and ethanol injection have also been used in combination with surgery. Despite the variety of available treatment options, the optimal management strategy is unclear because aggressive vertebral hemangiomas are uncommon lesions, making it difficult to perform large trials. For this reason, the authors chose instead to report their institutional experience along with a comprehensive review of the literature. METHODS A departmental database was searched for patients with a pathological diagnosis of "hemangioma" between 2008 and 2015. Medical records were reviewed to identify patients with aggressive vertebral hemangiomas, and these cases were reviewed in detail. RESULTS Five patients were identified who underwent surgery for treatment of aggressive vertebral hemangiomas during the specified time period. There were 2 lumbar and 3 thoracic lesions. One patient underwent en bloc spondylectomy, 2 patients had piecemeal gross-total resection, and the remaining 2 had subtotal tumor resection. Intraoperative vertebroplasty was used in 3 cases to augment the anterior column or to obliterate residual tumor. Adjuvant radiation was used in 1 case where there was residual tumor as well. The patient who underwent en bloc spondylectomy experienced several postoperative complications requiring additional medical care and reoperation. At an average follow-up of 31 months ( range 3-65 months), no patient had any recurrence of disease and all were clinically asymptomatic, except the patient who underwent en bloc resection who continued to have back pain. CONCLUSIONS Gross-total resection or subtotal resection in combination with vertebroplasty or adjuvant radiation therapy to treat residual tumor seems sufficient in the treatment of aggressive vertebral hemangiomas. En bloc resection appears to provide a similar oncological benefit, but it carries higher morbidity to the patient. C1 [Vasudeva, Viren S.; Chi, John H.; Groff, Michael W.] Harvard Med Sch, Brigham & Womens Hosp, 75 Francis St,AB 136, Boston, MA 02115 USA. [Chi, John H.; Groff, Michael W.] Dana Farber Canc Inst, Ctr Neurooncol, Boston, MA 02115 USA. RP Vasudeva, VS (reprint author), Harvard Med Sch, Brigham & Womens Hosp, 75 Francis St,AB 136, Boston, MA 02115 USA. EM vvasudeva@partners.org NR 74 TC 2 Z9 2 U1 2 U2 2 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 1092-0684 J9 NEUROSURG FOCUS JI Neurosurg. Focus PD AUG PY 2016 VL 41 IS 2 AR E7 DI 10.3171/2016.5.FOCUS16169 PG 12 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA DS4MW UT WOS:000380756200007 PM 27476849 ER PT J AU Putman, MS Greenblatt, LB Sicilian, L Uluer, A Lapey, A Sawicki, G Gordon, CM Bouxsein, ML Finkelstein, JS AF Putman, M. S. Greenblatt, L. B. Sicilian, L. Uluer, A. Lapey, A. Sawicki, G. Gordon, C. M. Bouxsein, M. L. Finkelstein, J. S. TI Young adults with cystic fibrosis have altered trabecular microstructure by ITS-based morphological analysis SO OSTEOPOROSIS INTERNATIONAL LA English DT Article DE Bone microarchitecture; Cystic fibrosis; Dual-energy X-ray absorptiometry; High-resolution peripheral quantitative computed tomography; Individual trabecula segmentation ID BONE-MINERAL DENSITY; QUANTITATIVE COMPUTED-TOMOGRAPHY; TRANSMEMBRANE CONDUCTANCE REGULATOR; CHINESE-AMERICAN; POSTMENOPAUSAL WOMEN; F508DEL MUTATION; DISTAL RADIUS; WHITE WOMEN; RESOLUTION; MICROARCHITECTURE AB Young adults with cystic fibrosis have compromised plate-like trabecular microstructure, altered axial alignment of trabeculae, and reduced connectivity between trabeculae that may contribute to the reduced bone strength and increased fracture risk observed in this patient population. The risk of fracture is increased in patients with cystic fibrosis (CF). Individual trabecular segmentation (ITS)-based morphological analysis of high-resolution peripheral quantitative computed tomography (HR-pQCT) images segments trabecular bone into individual plates and rods of different alignment and connectivity, which are important determinants of trabecular bone strength. We sought to determine whether alterations in ITS variables are present in patients with CF and may help explain their increased fracture risk. Thirty patients with CF ages 18-40 years underwent DXA scans of the hip and spine and HR-pQCT scans of the radius and tibia with further assessment of trabecular microstructure by ITS. These CF patients were compared with 60 healthy controls matched for age (+/- 2 years), race, and gender. Plate volume fraction, thickness, and density as well as plate-plate and plate-rod connectivity were reduced, and axial alignment of trabeculae was lower in subjects with CF at both the radius and the tibia (p < 0.05 for all). At the radius, adjustment for BMI eliminated most of these differences. At the tibia, however, reductions in plate volume fraction and number, axially aligned trabeculae, and plate-plate connectivity remained significant after adjustment for BMI alone and for BMI and aBMD (p < 0.05 for all). Young adults with CF have compromised plate-like and axially aligned trabecular morphology and reduced connectivity between trabeculae. ITS analysis provides unique information about bone integrity, and these trabecular deficits may help explain the increased fracture risk in adults with CF not accounted for by BMD and/or traditional bone microarchitecture measurements. C1 [Putman, M. S.; Greenblatt, L. B.; Bouxsein, M. L.; Finkelstein, J. S.] Massachusetts Gen Hosp, Dept Med, Endocrine Unit, 50 Blossom St,THR 1051, Boston, MA 02114 USA. [Putman, M. S.] Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Sicilian, L.] Massachusetts Gen Hosp, Dept Med, Div Pulm, Boston, MA 02114 USA. [Uluer, A.; Sawicki, G.] Boston Childrens Hosp, Div Resp Dis, Boston, MA USA. [Lapey, A.] Massachusetts Gen Hosp, Dept Pediat, Div Pulm, Boston, MA 02114 USA. [Gordon, C. M.] Cincinnati Childrens Hosp Med Ctr, Div Adolescent & Transit Med, Cincinnati, OH 45229 USA. [Bouxsein, M. L.] Beth Israel Deaconess Med Ctr, Ctr Adv Orthoped Studies, Boston, MA 02215 USA. [Bouxsein, M. L.] Harvard Med Sch, Dept Orthoped Surg, Boston, MA USA. RP Putman, MS (reprint author), Massachusetts Gen Hosp, Dept Med, Endocrine Unit, 50 Blossom St,THR 1051, Boston, MA 02114 USA.; Putman, MS (reprint author), Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. EM msputman@partners.org OI Greenblatt, Logan/0000-0002-8764-8576 FU Endocrine Society Amgen Fellowship Award [NIH T32 DK007699-29, NIH K23 DK102600-01A1]; NCRR [1S10RR023405-01]; Harvard Clinical and Translational Science Center [8 UL1 TR000170-05, 1 UL1TR001102-01, 1 UL1RR025758-04]; Vertex Pharmaceuticals Investigator Initiated Studies Grant FX ITS images were generously created by X. Edward Guo, PhD, and Ji Wang, PhD, at Columbia University. This study was supported in part by an Endocrine Society Amgen Fellowship Award, NIH T32 DK007699-29, and NIH K23 DK102600-01A1. A Vertex Pharmaceuticals Investigator Initiated Studies Grant provided partial support for procedures in this study. The HR-pQCT measurements were made possible by an NCRR Shared Equipment Grant (1S10RR023405-01). This project was also supported by the Harvard Clinical and Translational Science Center (Grant Numbers 8 UL1 TR000170-05, 1 UL1TR001102-01, and 1 UL1RR025758-04). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The authors gratefully acknowledge the support of the dedicated staff of the MGH Clinical Research Center, and the Research Groups of the MGH and BCH CF Centers. NR 43 TC 1 Z9 1 U1 1 U2 1 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0937-941X EI 1433-2965 J9 OSTEOPOROSIS INT JI Osteoporosis Int. PD AUG PY 2016 VL 27 IS 8 BP 2497 EP 2505 DI 10.1007/s00198-016-3557-z PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DR7YE UT WOS:000380114800010 PM 26952010 ER PT J AU Pross, SE Bourne, AL Cheung, SW AF Pross, Seth E. Bourne, Andrea L. Cheung, Steven W. TI TeleAudiology in the Veterans Health Administration SO OTOLOGY & NEUROTOLOGY LA English DT Article DE Hearing aids; TeleAudiology; TeleHealth; Veterans administration ID INTERNATIONAL OUTCOME INVENTORY; HEARING-AID USE; UNITED-STATES; OLDER-ADULTS AB Objective: To assess effectiveness of TeleAudiology for hearing aid services. Study Design: Retrospective case-control. Setting: Ambulatory Veterans Health Administration and Community-Based Outpatient Clinics (CBOCs). Patients: 42,697 veterans who received hearing aids from January through September, 2014. Intervention(s): TeleAudiology (TA) and conventional in-person (IP) audiology care. Main Outcome Measure(s): International Outcome Inventory for Hearing Aids (IOI-HA) outcomes data. The IOI-HA is a 7-item survey used to assess hearing aid effectiveness. Scored from 7 to 35 points, higher scores are more favorable. Results: Among veterans nationwide who received hearing aids and completed the IOI-HA survey, 1,009 received TA and 41,688 received IP care. TA and IP groups have comparable mean IOI-HA values (TA = 29.6, SD = 3.9; IP = 28.7, SD = 4.2). Although comparison showed a statistically significant difference (p<0.0001, t test), principally because of large sample size, the distinction is not clinically meaningful. Subgroup analysis of veterans from San Francisco and six affiliated CBOCs showed 169 received TA and 338 received IP care. TA and IP groups have similar mean age (TA = 74, SD = 9.8; IP = 76, SD = 10.3) and sex distribution (TA male = 100%; IP male = 96%) with statistically significant (p<0.01, t test) but clinically insignificant differences. Mean IOI-HA scores (TA = 30.7, SD = 3.6; IP = 30.5, SD = 3.1) are not different between groups (p>0.05, t test). Conclusion: TA and IP encounters to provide hearing aid services to veterans are comparable, as both are highly effective based on IOI-HA results. The noninferiority of TA suggests its adoption to non-veterans may improve access while preserving high satisfaction. Financial impact of migration to TA will require future econometric analysis. C1 [Pross, Seth E.] Johns Hopkins Univ, Dept Otolaryngol Head & Neck Surg, Baltimore, MD USA. [Bourne, Andrea L.] San Francisco VA Med Ctr, Audiol & Speech Pathol Serv, San Francisco, CA USA. [Cheung, Steven W.] Univ Calif San Francisco, Dept Otolaryngol Head & Neck Surg, San Francisco, CA USA. RP Cheung, SW (reprint author), 2233 Post St,3rd Floor, San Francisco, CA 94115 USA. EM Steven.Cheung@ucsf.edu FU Coleman Memorial and Hearing Research, Inc. FX Coleman Memorial and Hearing Research, Inc. Funds. NR 14 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 1531-7129 EI 1537-4505 J9 OTOL NEUROTOL JI Otol. Neurotol. PD AUG PY 2016 VL 37 IS 7 BP 847 EP 850 DI 10.1097/MAO.0000000000001058 PG 4 WC Clinical Neurology; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA DS2NQ UT WOS:000380621200020 PM 27273404 ER PT J AU Nadol, JB AF Nadol, Joseph B., Jr. TI Focal Endolymphatic Hydrops as Seen in the Pars Inferior of the Human Inner Ear SO OTOLOGY & NEUROTOLOGY LA English DT Article DE Cochlear inflammation; Human histopathology; Meniere's disease ID GUINEA-PIG COCHLEA; MENIERES-DISEASE; MAMMALIAN COCHLEA; FLOW; HISTOPATHOLOGY; OBLITERATION; PERILYMPH; PATHOLOGY; MEMBRANE; DEAFNESS AB Hypothesis: Endolymphatic hydrops of the human inner ear may be localized focally in the pars inferior of the human inner ear. Background: Endolymphatic hydrops may be found in the human inner ear in patients who in life had suffered from Meniere's syndrome or a variety of other disorders. The degree of endolymphatic hydrops may differ based on location in the inner ear. Methods: A computer-assisted search of all cases in the collection of the Massachusetts Eye and Ear Infirmary in which endolymphatic hydrops was found in the inner ear yielded 13 specimens in which there was good evidence for focal endolymphatic hydrops in the pars inferior. Temporal bones were prepared for light microscopy. Semi-serial sections were reviewed to generate localization data for endolymphatic hydrops and also to search for evidence of a previous inflammatory process, including fibrosis or new bone formation. Results: Endolymphatic hydrops was present in the saccule in 10 of 13 specimens. In the cochlear duct, there were segments of the cochlea in which there was no cochlear hydrops juxtaposed to other regions in which there was severe endolymphatic hydrops. Transition between hydropic and non-hydropic status in the cochlear duct was often abrupt. Evidence for a previous inflammation process was found in 6 of 13 specimens including fibrosis because of temporal bone fracture, or traumatic stapedectomy and in those cases in which the cause of hearing loss was idiopathic, fibrosis, and osteoid between the labyrinthine surface of the footplate and the hydropic saccular wall, and/or osteoid in the scala vestibuli, or in the proximate Rosenthal's canal. Evidence of a previous inflammatory process was uniformly seen in the perilymphatic compartment. Conclusions: Endolymphatic hydrops of the pars inferior in the human may have a focal distribution. This study suggests that the pathogenesis of endolymphatic hydrops is unlikely to be because of distal obstruction of longitudinal flow and was more consistent with the hypothesis that homeostasis of the endolymphatic and perilymphatic volumes occurs all along the cochlear duct. Other factors including variable distensibility of Reissner's membrane or disturbance of local solute homeostatic mechanisms may be responsible for wide variations in the degree of hydrops. A focal inflammatory process during life may be one cause of focal endolymphatic hydrops as seen histopathologically. C1 [Nadol, Joseph B., Jr.] Harvard Med Sch, Dept Otolaryngol, Otopathol Lab, Massachusetts Eye & Ear Infirm, Boston, MA USA. RP Nadol, JB (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM joseph_nadol@meei.harvard.edu FU National Institute on Deafness and Other Communication Disorders (NIH) [U24DC013983] FX Supported by: National Institute on Deafness and Other Communication Disorders (NIH Grant U24DC013983). NR 31 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 1531-7129 EI 1537-4505 J9 OTOL NEUROTOL JI Otol. Neurotol. PD AUG PY 2016 VL 37 IS 7 BP 859 EP 864 DI 10.1097/MAO.0000000000001094 PG 6 WC Clinical Neurology; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA DS2NQ UT WOS:000380621200022 PM 27273408 ER PT J AU van Tilburg, MJ Herrmann, BS Guinan, JJ Rauch, SD AF van Tilburg, Mark J. Herrmann, Barbara S. Guinan, John J., Jr. Rauch, Steven D. TI Increasing the Stimulation Rate Reduces cVEMP Testing Time by More Than Half With No Significant Difference in Threshold SO OTOLOGY & NEUROTOLOGY LA English DT Article DE Cervical vestibular evoked myogenic potential; Peak-to-peak amplitude; Stimulation rate; Threshold ID EVOKED MYOGENIC POTENTIALS; REPETITION RATE AB Objective: Assessing the effect of a higher stimulation rate in cervical vestibular evoked myogenic potential (cVEMP) outcome measurements. Study Design: Prospective cohort study. Setting: Large specialty hospital, Department of otolaryngology. Subjects: Eleven healthy subjects were used in this study. Intervention: All subjects underwent a cervical vestibular evoked myogenic potential test at 500, 750, and 1000 Hz using 5 and 13 Hz stimulation rates. Main Outcome Measures: Threshold, peak-to-peak (PP) amplitude, and interaural asymmetry ratio (IAR). Results: PP cVEMP amplitudes were larger at 5/s than at 13/s. The 5/s to 13/s differences were statistically significant at 500 and 750 Hz (p<0.02). The coefficient of variation in PP amplitudes across subjects, was not significantly different at any frequency for 5/s versus 13/s stimuli. No significant difference was found in the IAR at any frequency. The cVEMP thresholds were similar between stimulation rates. Conclusion: In healthy young subjects no significant differences in threshold were found between 5/s and 13/s stimulation rates, though intrasubject PP amplitude was significantly lower at the faster stimulation rate. Increasing stimulation rate reduces test time and burden. Additional studies are needed to verify that these conclusions are also true for patients. C1 [van Tilburg, Mark J.; Rauch, Steven D.] Harvard Med Sch, Dept Otolaryngol, Boston, MA USA. [Herrmann, Barbara S.; Guinan, John J., Jr.; Rauch, Steven D.] Harvard Med Sch, Dept Otol & Laryngol, Boston, MA USA. [Herrmann, Barbara S.] Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. [Guinan, John J., Jr.] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. RP Rauch, SD (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM steven_rauch@meei.harvard.edu NR 8 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 1531-7129 EI 1537-4505 J9 OTOL NEUROTOL JI Otol. Neurotol. PD AUG PY 2016 VL 37 IS 7 BP 933 EP 936 DI 10.1097/MAO.0000000000001096 PG 4 WC Clinical Neurology; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA DS2NQ UT WOS:000380621200034 PM 27295442 ER PT J AU Hur, C Tramontano, AC Dowling, EC Brooks, GA Jeon, A Brugge, WR Gazelle, GS Kong, CY Pandharipande, PV AF Hur, Chin Tramontano, Angela C. Dowling, Emily C. Brooks, Gabriel A. Jeon, Alvin Brugge, William R. Gazelle, G. Scott Kong, Chung Yin Pandharipande, Pari V. TI Early Pancreatic Ductal Adenocarcinoma Survival Is Dependent on Size Positive Implications for Future Targeted Screening SO PANCREAS LA English DT Article DE pancreatic cancer; SEER registry; survival; pancreas; adenocarcinoma; pancreatic neoplasms ID HIGH-RISK INDIVIDUALS; CANCER; MORTALITY; PANCREATICODUODENECTOMY; LESIONS; RATES; CELLS AB Objectives: Pancreatic ductal adenocarcinoma (PDAC) has not experienced a meaningful mortality improvement for the past few decades. Successful screening is difficult to accomplish because most PDACs present late in their natural history, and current interventions have not provided significant benefit. Our goal was to identify determinants of survival for early PDAC to help inform future screening strategies. Methods: Early PDACs from the National Cancer Institute's Surveillance, Epidemiology, and End Results Program database (2000-2010) were analyzed. We stratified by size and included carcinomas in situ (Tis). Overall cancer-specific survival was calculated. A Cox proportional hazards model was developed and the significance of key covariates for survival prediction was evaluated. Results: A Kaplan-Meier plot demonstrated significant differences in survival by size at diagnosis; these survival benefits persisted after adjustment for key covariates in the Cox proportional hazards analysis. In addition, relatively weaker predictors of worse survival included older age, male sex, black race, nodal involvement, tumor location within the head of the pancreas, and no surgery or radiotherapy. Conclusions: For early PDAC, we found tumor size to be the strongest predictor of survival, even after adjustment for other patient characteristics. Our findings suggest that early PDAC detection can have clinical benefit, which has positive implications for future screening strategies. C1 [Hur, Chin; Tramontano, Angela C.; Dowling, Emily C.; Jeon, Alvin; Brugge, William R.; Gazelle, G. Scott; Kong, Chung Yin; Pandharipande, Pari V.] Inst Technol Assessment, 101 Merrimac St,10th Floor, Boston, MA 02114 USA. [Hur, Chin; Jeon, Alvin; Brugge, William R.] Massachusetts Gen Hosp, Dept Med, Div Gastroenterol, Boston, MA 02114 USA. [Hur, Chin; Brooks, Gabriel A.; Brugge, William R.; Gazelle, G. Scott; Kong, Chung Yin; Pandharipande, Pari V.] Harvard Med Sch, Boston, MA USA. [Tramontano, Angela C.; Dowling, Emily C.; Gazelle, G. Scott; Kong, Chung Yin; Pandharipande, Pari V.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Brooks, Gabriel A.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Hur, C (reprint author), Inst Technol Assessment, 101 Merrimac St,10th Floor, Boston, MA 02114 USA.; Hur, C (reprint author), Massachusetts Gen Hosp, Div Gastroenterol, 101 Merrimac St,10th Floor, Boston, MA 02114 USA. EM chur@mgh-ita.org OI Hur, Chin/0000-0002-2819-7576 FU National Cancer Institute [K07CA133097]; Medical Imaging and Technology Alliance; Lustgarten; Celgene; RedPath FX This study was supported by the National Cancer Institute (Award Number K07CA133097 to P.V.P.). P.V.P. received research funding from the Medical Imaging and Technology Alliance. W.R.B. received research funding from Lustgarten, Celgene, and RedPath and is a consultant to Boston Scientific. For the remaining authors none were declared. NR 24 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 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD AUG PY 2016 VL 45 IS 7 BP 1062 EP 1066 DI 10.1097/MPA.0000000000000587 PG 5 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DR9OL UT WOS:000380225900027 PM 26692444 ER PT J AU Rosenberg, AR Bona, K AF Rosenberg, Abby R. Bona, Kira TI The Power of Personal Narrative: A Reply to "The Reality of Relapse: Impact of Cancer Relapse on Survivorship Interventions and Patient-Reported Outcomes Data" SO PEDIATRIC BLOOD & CANCER LA English DT Letter ID ADOLESCENTS; CARE C1 [Rosenberg, Abby R.] Seattle Childrens Hosp, Canc & Blood Disorders Ctr, 4800 Sand Point Way NE,M-S MB 8-501,POB 5371, Seattle, WA 98145 USA. [Rosenberg, Abby R.] Seattle Childrens Res Inst, Ctr Clin & Translat Res, Seattle, WA USA. [Rosenberg, Abby R.] Seattle Childrens Hosp, Treuman Katz Ctr Pediat Bioeth, Seattle, WA USA. [Rosenberg, Abby R.] Univ Washington, Dept Pediat, Seattle, WA 98195 USA. [Bona, Kira] Boston Childrens Hosp, Dept Med, Boston, MA USA. [Bona, Kira] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Bona, Kira] Harvard Med Sch, Dept Pediat Hematol Oncol, Boston, MA USA. RP Rosenberg, AR (reprint author), Seattle Childrens Hosp, Canc & Blood Disorders Ctr, 4800 Sand Point Way NE,M-S MB 8-501,POB 5371, Seattle, WA 98145 USA. EM abby.rosenberg@seattlechildrens.org FU NCATS NIH HHS [KL2 TR000421]; NCI NIH HHS [L40 CA170049] NR 7 TC 0 Z9 0 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD AUG PY 2016 VL 63 IS 8 BP 1494 EP 1494 DI 10.1002/pbc.26007 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA DR7VU UT WOS:000380108600034 PM 27082716 ER PT J AU Dumas, O Mansbach, JM Jartti, T Hasegawa, K Sullivan, AF Piedra, PA Camargo, CA AF Dumas, Orianne Mansbach, Jonathan M. Jartti, Tuomas Hasegawa, Kohei Sullivan, Ashley F. Piedra, Pedro A. Camargo, Carlos A., Jr. TI A clustering approach to identify severe bronchiolitis profiles in children SO THORAX LA English DT Article ID RESPIRATORY SYNCYTIAL VIRUS; LENGTH-OF-STAY; VIRAL-ETIOLOGY; RISK-FACTORS; EARLY-LIFE; INHALED EPINEPHRINE; CHILDHOOD ASTHMA; MANAGEMENT; INFECTIONS; PHENOTYPES AB Objective Although bronchiolitis is generally considered a single disease, recent studies suggest heterogeneity. We aimed to identify severe bronchiolitis profiles using a clustering approach. Methods We analysed data from two prospective, multicentre cohorts of children younger than 2 years hospitalised with bronchiolitis, one in the USA (2007-2010 winter seasons, n=2207) and one in Finland (2008-2010 winter seasons, n=408). Severe bronchiolitis profiles were determined by latent class analysis, classifying children based on clinical factors and viral aetiology. Results In the US study, four profiles were identified. Profile A (12%) was characterised by history of wheezing and eczema, wheezing at the emergency department (ED) presentation and rhinovirus infection. Profile B (36%) included children with wheezing at the ED presentation, but, in contrast to profile A, most did not have history of wheezing or eczema; this profile had the largest probability of respiratory syncytial virus infection. Profile C (34%) was the most severely ill group, with longer hospital stay and moderate-to-severe retractions. Profile D (17%) had the least severe illness, including non-wheezing children with shorter length of stay. Two of these profiles (A and D) were replicated in the Finnish cohort; a third group ('BC') included Finnish children with characteristics of profiles B and/ or C in the US population. Conclusions Several distinct clinical profiles (phenotypes) were identified by a clustering approach in two multicentre studies of children hospitalised for bronchiolitis. The observed heterogeneity has important implications for future research on the aetiology, management and long-term outcomes of bronchiolitis, such as future risk of childhood asthma. C1 [Dumas, Orianne; Hasegawa, Kohei; Sullivan, Ashley F.; Camargo, Carlos A., Jr.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Dumas, Orianne; Mansbach, Jonathan M.; Hasegawa, Kohei; Camargo, Carlos A., Jr.] Harvard Med Sch, Boston, MA USA. [Dumas, Orianne] INSERM, U1168, VIMA, Aging & Chron Dis Epidemiol & Publ Hlth Approache, Villejuif, France. [Dumas, Orianne] Univ Versailles St Quentin En Yvelines, UMR S 1168, Montigny Le Bretonneux, France. [Mansbach, Jonathan M.] Boston Childrens Hosp, Dept Med, Boston, MA USA. [Jartti, Tuomas] Turku Univ Hosp, Dept Pediat, Turku, Finland. [Piedra, Pedro A.] Baylor Coll Med, Dept Mol Virol & Microbiol, Houston, TX 77030 USA. [Piedra, Pedro A.] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. RP Dumas, O (reprint author), Inserm UMRS 1168, VIMA, Aging & Chron Dis Epidemiol & Publ Hlth Approache, 16 Ave Paul Vaillant Couturier, F-94807 Villejuif, France. EM orianne.dumas@inserm.fr FU National Institutes of Health [AI-67693, AI-87881]; Academy of Finland [132595, 114034]; Sigrid Juselius Foundation, Helsinki, Finland; Foundation for Pediatric Research, Helsinki, Finland FX This work was supported by the National Institutes of Health (AI-67693 and AI-87881); the Academy of Finland (132595 and 114034); the Sigrid Juselius Foundation, Helsinki, Finland; and the Foundation for Pediatric Research, Helsinki, Finland. NR 37 TC 4 Z9 4 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0040-6376 EI 1468-3296 J9 THORAX JI Thorax PD AUG PY 2016 VL 71 IS 8 BP 712 EP 718 DI 10.1136/thoraxjnl-2016-208535 PG 7 WC Respiratory System SC Respiratory System GA DS1SB UT WOS:000380377100008 PM 27339060 ER PT J AU Panagiotou, G Pazaitou-Panayiotou, K Paschou, SA Komninou, D Kalogeris, N Vryonidou, A Mantzoros, CS AF Panagiotou, Grigorios Pazaitou-Panayiotou, Kalliopi Paschou, Stavroula A. Komninou, Despina Kalogeris, Nikolaos Vryonidou, Andromachi Mantzoros, Christos S. TI Changes in Thyroid Hormone Levels Within the Normal and/or Subclinical Hyper- or Hypothyroid Range Do Not Affect Circulating Irisin Levels in Humans SO THYROID LA English DT Article ID BROWN ADIPOSE-TISSUE; RECOMBINANT HUMAN THYROTROPIN; MESSENGER-RNA; PHYSICAL-ACTIVITY; OBESE CHILDREN; EXERCISE; METABOLISM; RECEPTOR; CANCER; ACTIVATION AB Background: Both thyroid hormones and irisin increase energy expenditure and induce browning of adipose tissue. However, irisin physiology and regulation remain largely unknown, and existing data are mainly derived from observational studies. In this study, we aimed to elucidate whether changes in thyroid-axis hormones alter circulating irisin levels in humans, thereby exerting a direct downstream effect on serum irisin. Subjects and methods: Samples from a cross-sectional evaluation and two interventions were utilized, including patients who had previously undergone thyroidectomy. In the cross-sectional study, 96 consecutively enrolled subjects were divided into a euthyroid group and a subclinical hyperthyroid group, according to their serum thyrotropin (TSH) levels (TSH cutoff 0.3 mIU/L). In interventional study A, 34 patients who had undergone thyroidectomy due to thyroid cancer were withdrawn from their thyroxine replacement treatment for five weeks. In interventional study B, 13 patients underwent a recombinant human TSH stimulation protocol, and blood samples were drawn at baseline, day 3 (i.e., at least 24 hours after the second intramuscular injection), day 5, and day 10. Results: Irisin concentrations were not associated with thyroid-axis hormones (i.e., TSH, free thyroxine, and free triiodiothyronine) cross-sectionally in either the overall cohort or in the euthyroid and/or subclinical hyperthyroid subgroups (p > 0.05). There was no significant difference between euthyroid and subclinical hyperthyroid subjects (p = 0.60). Levothyroxine withdrawal did not result in any changes in irisin concentrations (p = 0.33). Recombinant human TSH stimulation did not induce any significant changes in circulating irisin (p = 0.60). Conclusions: Changes in thyroid-axis hormone levels within the physiological or supraphysiological range do not affect circulating irisin levels in humans. Therefore, their metabolic effects are most likely independent of each other. Other regulators of irisin levels should be identified in the future. C1 [Panagiotou, Grigorios; Paschou, Stavroula A.; Komninou, Despina; Mantzoros, Christos S.] Beth Israel Deaconess Med Ctr, Dept Internal Med, Div Endocrinol Diabet & Metab, Boston, MA 02215 USA. [Mantzoros, Christos S.] Boston VA Healthcare Syst, Endocrinol Sect, Boston, MA USA. [Mantzoros, Christos S.] Harvard Med Sch, Boston, MA 02215 USA. [Panagiotou, Grigorios; Pazaitou-Panayiotou, Kalliopi] Theagenio Canc Hosp, Dept Endocrinol Endocrine Oncol, Thessaloniki, Greece. [Paschou, Stavroula A.; Kalogeris, Nikolaos; Vryonidou, Andromachi] Hellen Red Cross Hosp, Dept Endocrinol & Diabet, Athens, Greece. RP Mantzoros, CS (reprint author), Harvard Med Sch, Beth Israel Deaconess Med Ctr, 330 Brookline Ave, Boston, MA 02215 USA. EM cmantzor@bidmc.harvard.edu NR 45 TC 1 Z9 1 U1 2 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1050-7256 EI 1557-9077 J9 THYROID JI Thyroid PD AUG PY 2016 VL 26 IS 8 BP 1039 EP 1045 DI 10.1089/thy.2016.0098 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DS5DZ UT WOS:000380802400006 PM 27267080 ER PT J AU Giugliano, RP Ruff, CT Wiviott, SD Nordio, F Murphy, SA Kappelhof, JAN Shi, M Mercuri, MF Antman, EM Braunwald, E AF Giugliano, Robert P. Ruff, Christian T. Wiviott, Stephen D. Nordio, Francesco Murphy, Sabina A. Kappelhof, Johannes A. N. Shi, Minggao Mercuri, Michele F. Antman, Elliott M. Braunwald, Eugene TI Mortality in Patients with Atrial Fibrillation Randomized to Edoxaban or Warfarin: Insights from the ENGAGE AF-TIMI 48 Trial SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE Anticoagulant; Bleeding; Death; Edoxaban; Factor Xa inhibitor; Hemorrhage; Warfarin ID ANTICOAGULATION THERAPY; CHA(2)DS(2)-VASC SCORE; MYOCARDIAL-INFARCTION; ORAL ANTICOAGULATION; RISK-FACTOR; STROKE; METAANALYSIS; RIVAROXABAN; PREVENTION; DABIGATRAN AB BACKGROUND: When compared with warfarin, edoxaban significantly reduced cardiovascular mortality in the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillatione-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial. We studied the possible reasons leading to this reduction. METHODS: ENGAGE AF-TIMI 48 was a double-blind, double-dummy comparison of warfarin with 2 regimens of once-daily edoxaban in 21,105 patients with atrial fibrillation followed for 2.8 years (median). Causes of deaths in the intention-to-treat population were classified as cardiovascular (including fatal bleeding and ischemic stroke), malignancy, or noncardiovascular/nonmalignancy by an independent, blinded, clinical endpoint committee. Deaths also were adjudicated as directly due to bleeding (ie, fatal), or bleeding contributing to death, or neither. RESULTS: There were 839 total deaths (4.35%/y) in the warfarin arm, compared with 773 (3.99%/y, P = .08) with the higher-dose edoxaban regimen, and 737 (3.80%/ y, P = .006) with the lower-dose edoxaban regimen. No significant differences between treatments were observed in (1) any of the 3 most common causes of cardiovascular death (sudden cardiac, heart failure, ischemic stroke), (2) fatal malignancies, (3) other noncardiovascular death. There were 124 fatal bleeds, 65 with warfarin, significantly fewer with the higher-dose (n = 35, P =.003) and lower-dose (n = 24, P <.001) edoxaban regimens. There were 101 bleeding events with warfarin that were either fatal or that contributed to death. There were significantly fewer with the higher-dose (n = 59, P =.001) and lower-dose (n = 54, P <.001) edoxaban regimens. CONCLUSIONS: Fewer total and cardiovascular deaths were observed with edoxaban as compared with warfarin in the ENGAGE AF-TIMI 48 trial, and this predominantly resulted from the significantly lower rate of major bleeding with edoxaban. Edoxaban reduces mortality both directly (less fatal bleeding) and indirectly (fewer bleeding-related complications and interruptions in therapy after nonfatal bleeding). (C) 2016 The Authors. Published by Elsevier Inc. C1 [Giugliano, Robert P.; Ruff, Christian T.; Wiviott, Stephen D.; Nordio, Francesco; Murphy, Sabina A.; Antman, Elliott M.; Braunwald, Eugene] Brigham & Womens Hosp, TIMI Study Grp, Cardiovasc Med, Boston, MA USA. [Kappelhof, Johannes A. N.; Shi, Minggao; Mercuri, Michele F.] Daiichi Sankyo Pharma Dev, Edison, NJ USA. RP Giugliano, RP (reprint author), TIMI Study Grp, 350 Longwood Ave,1st Floor Off, Boston, MA 02115 USA. EM rgiugliano@partners.org FU Daiichi Sankyo Pharma Development FX The ENGAGE AF-TIMI 48 trial was supported by a research grant from Daiichi Sankyo Pharma Development, who participated in the design and conduct of this trial, and in the preparation of this article. NR 25 TC 5 Z9 5 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 EI 1555-7162 J9 AM J MED JI Am. J. Med. PD AUG PY 2016 VL 129 IS 8 BP 850 EP + DI 10.1016/j.amjmed.2016.02.028 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA DR9YU UT WOS:000380253000040 PM 26994510 ER PT J AU Liow, MHL Goh, GSH Pang, HN Tay, DKJ Lo, NN Yeo, SJ AF Liow, Ming Han Lincoln Goh, Graham Seow-Hng Pang, Hee-Nee Tay, Darren Keng Jin Lo, Ngai Nung Yeo, Seng Jin TI Computer-assisted stereotaxic navigation improves the accuracy of mechanical alignment and component positioning in total knee arthroplasty SO ARCHIVES OF ORTHOPAEDIC AND TRAUMA SURGERY LA English DT Article DE Total knee arthroplasty; Computer-assisted; Stereotaxic; Accelerometer; Navigation; iASSIST; Mechanical axis ID ACCELEROMETER-BASED NAVIGATION; RANDOMIZED CONTROLLED-TRIAL; NO DIFFERENCE; PINLESS NAVIGATION; TIBIAL RESECTION; CORONAL ALIGNMENT; AXIS ALIGNMENT; BLOOD-LOSS; OUTCOMES; SYSTEM AB This study reports on a novel computer-assisted stereotaxic navigation (CASN) system that attempts to combine the accuracy of computer navigation with familiarity of conventional methods. We hypothesize that CASN would improve mechanical alignment and component positioning when compared to conventional instrumentation. 145 patients (192 knees) retrospectively matched for age, BMI, gender and pre-operative scores, underwent total knee arthroplasty (TKA) using CASN (n = 92) or conventional instrumentation (n = 100). Pre- and post-operative radiological alignment [Acceptable ranges: mechanical axis (MA) 0A degrees A A +/- A 3A degrees, coronal femoral-component angle (CFA) and coronal tibia-component angle (CTA) 90A degrees A A +/- A 3A degrees] and clinical outcomes (Knee Society Scores, Oxford Knee Score and Short Form-36) at 6 months were examined. The CASN group had significantly improved mean MA (1.9A degrees A A +/- A 1.4A degrees, versus 2.8A degrees A A +/- A 2.0A degrees in the conventional group, p = 0.001), CFA (1.6A degrees A A +/- A 1.3A degrees, versus 2.1A degrees A A +/- A 1.5A degrees in the conventional group, p = 0.035) and CTA (1.6A degrees A A +/- A 1.2A degrees, versus 2.1A degrees A A +/- A 1.5A degrees in the conventional group, p = 0.024). 91.3 % of knees in the CASN group were within 3A degrees of a neutral mechanical axis, versus 74 % in the conventional group (p < 0.001). The duration of surgery was significantly longer in the CASN group (84 +/- A 22 vs 73 +/- A 15 min, p = 0.001) and cost an additional USD 850 per operation. There were no significant differences in clinical outcomes or satisfaction rates at 6 months post-operatively (p > 0.05). CASN improved TKA mechanical alignment and component positioning, however, resulted in longer and costlier surgery with no benefits in short-term functional outcomes, despite providing familiarity to surgeons accustomed to conventional instrumentation. III. C1 [Liow, Ming Han Lincoln; Goh, Graham Seow-Hng; Pang, Hee-Nee; Tay, Darren Keng Jin; Lo, Ngai Nung; Yeo, Seng Jin] Singapore Gen Hosp, Dept Orthopaed Surg, 20 Coll Rd,Level 4, Singapore 169865, Singapore. [Liow, Ming Han Lincoln] Harvard Med Sch, Massachusetts Gen Hosp, Dept Orthopaed Surg, 55 Fruit St, Boston, MA 02114 USA. RP Liow, MHL (reprint author), Singapore Gen Hosp, Dept Orthopaed Surg, 20 Coll Rd,Level 4, Singapore 169865, Singapore.; Liow, MHL (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Orthopaed Surg, 55 Fruit St, Boston, MA 02114 USA. EM dr.lincoln.liow@gmail.com NR 53 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0936-8051 EI 1434-3916 J9 ARCH ORTHOP TRAUM SU JI Arch. Orthop. Trauma Surg. PD AUG PY 2016 VL 136 IS 8 BP 1173 EP 1180 DI 10.1007/s00402-016-2483-z PG 8 WC Orthopedics; Surgery SC Orthopedics; Surgery GA DR8CN UT WOS:000380126100017 PM 27349233 ER PT J AU Yip, WK Bonetti, M Cole, BF Barcella, W Wang, XV Lazar, A Gelber, RD AF Yip, Wai-Ki Bonetti, Marco Cole, Bernard F. Barcella, William Wang, Xin Victoria Lazar, Ann Gelber, Richard D. TI Subpopulation Treatment Effect Pattern Plot (STEPP) analysis for continuous, binary, and count outcomes SO CLINICAL TRIALS LA English DT Article DE Generalized linear model; randomized clinical trial; subgroup analysis; Subpopulation Treatment Effect Pattern Plot (STEPP) ID TREATMENT-COVARIATE INTERACTIONS; TREATMENT-EFFECT HETEROGENEITY; CLINICAL-TRIALS; SUBGROUP ANALYSES; COMPETING RISK; BREAST-CANCER; SUBSETS; SAMPLE; MODEL AB Background: For the past few decades, randomized clinical trials have provided evidence for effective treatments by comparing several competing therapies. Their successes have led to numerous new therapies to combat many diseases. However, since their conclusions are based on the entire cohort in the trial, the treatment recommendation is for everyone, and may not be the best option for an individual. Medical research is now focusing more on providing personalized care for patients, which requires investigating how patient characteristics, including novel biomarkers, modify the effect of current treatment modalities. This is known as heterogeneity of treatment effects. A better understanding of the interaction between treatment and patient-specific prognostic factors will enable practitioners to expand the availability of tailored therapies, with the ultimate goal of improving patient outcomes. The Subpopulation Treatment Effect Pattern Plot (STEPP) approach was developed to allow researchers to investigate the heterogeneity of treatment effects on survival outcomes across values of a (continuously measured) covariate, such as a biomarker measurement. Methods: Here, we extend the Subpopulation Treatment Effect Pattern Plot approach to continuous, binary, and count outcomes, which can be easily modeled using generalized linear models. With this extension of Subpopulation Treatment Effect Pattern Plot, these additional types of treatment effects within subpopulations defined with respect to a covariate of interest can be estimated, and the statistical significance of any observed heterogeneity of treatment effect can be assessed using permutation tests. The desirable feature that commonly used models are applied to well-defined patient subgroups to estimate treatment effects is retained in this extension. Results: We describe a simulation study to confirm that the proper Type I error rate is maintained when there is no treatment heterogeneity, and a power study to show that the statistics have power to detect treatment heterogeneity under alternative scenarios. As an illustration, we apply the methods to data from the Aspirin/Folate Polyp Prevention Study, a clinical trial evaluating the effect of oral aspirin, folic acid, or both as a chemoprevention agent against colorectal adenomas. The pre-existing R software package stepp has been extended to handle continuous, binary, and count data using Gaussian, Bernoulli, and Poisson models, and it is available on the Comprehensive R Archive Network. Conclusion: The extension of the method and the availability of new software now permit STEPP to be applied to the full range of clinical trial end points. C1 [Yip, Wai-Ki; Wang, Xin Victoria; Gelber, Richard D.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, 450 Brookline Ave,CLS 11007, Boston, MA 02115 USA. [Yip, Wai-Ki; Wang, Xin Victoria; Gelber, Richard D.] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Bonetti, Marco] Bocconi Univ, Carlo F Dondena Ctr Res Social Dynam & Publ Polic, Milan, Italy. [Cole, Bernard F.] Univ Vermont, Dept Math & Stat, Burlington, VT 05405 USA. [Barcella, William] UCL, Dept Stat Sci, London, England. [Lazar, Ann] Univ Calif San Francisco, Div Oral Epidemiol, Dept Prevent & Restorat Dent Sci, San Francisco, CA 94143 USA. [Lazar, Ann] Univ Calif San Francisco, Dept Epidemiol & Biostat, Div Biostat, San Francisco, CA 94143 USA. RP Yip, WK (reprint author), Dana Farber Canc Inst, Dept Biostat & Computat Biol, 450 Brookline Ave,CLS 11007, Boston, MA 02115 USA. EM wyip@jimmy.harvard.edu FU US National Cancer Institute [CA-075362]; Italian Ministry of Education, University, and Research [P30 DE020752, 2007AYHZWC]; Clinical Epidemiology of Lung Diseases Training Grant [T32 HL007427]; (2 of 2) Genetic Epidemiology of COPD Grant [5R01HL089856-08] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Partial support for the development of the STEPP methodology was provided by Grant No. CA-075362 from the US National Cancer Institute, and Grant Nos P30 DE020752 and 2007AYHZWC from the Italian Ministry of Education, University, and Research. We would also like to acknowledge the support to Wai-Ki Yip by the Clinical Epidemiology of Lung Diseases Training Grant (T32 HL007427) and (2 of 2) Genetic Epidemiology of COPD Grant (5R01HL089856-08). NR 21 TC 0 Z9 0 U1 6 U2 6 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD AUG PY 2016 VL 13 IS 4 BP 382 EP 390 DI 10.1177/1740774516643297 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DR8DV UT WOS:000380129500004 PM 27094489 ER PT J AU Gilman, JM Schuster, RM Curran, MT Calderon, V van der Kouwe, A Evins, AE AF Gilman, Jodi M. Schuster, Randi M. Curran, Max T. Calderon, Vanessa van der Kouwe, Andre Evins, A. Eden TI Neural mechanisms of sensitivity to peer information in young adult cannabis users SO COGNITIVE AFFECTIVE & BEHAVIORAL NEUROSCIENCE LA English DT Article DE Social influence; Reward; Peer groups; Marijuana; Cannabis; Nucleus accumbens ID REWARD-CIRCUITRY; SOCIAL-INFLUENCE; DECISION-MAKING; MARIJUANA USE; RISK-TAKING; INTERPERSONAL INFLUENCES; COMPARING CANNABIS; NUCLEUS-ACCUMBENS; DORSAL STRIATUM; WORKING-MEMORY AB Though social influence is a critical factor in the initiation and maintenance of marijuana use, the neural correlates of influence in those who use marijuana are unknown. In this study, marijuana-using young adults (MJ; n = 20) and controls (CON; n = 23) performed a decision-making task in which they made a perceptual choice after viewing the choices of unknown peers via photographs, while they underwent functional magnetic resonance imaging scans. The MJ and CON groups did not show differences in the overall number of choices that agreed with versus opposed group influence, but only the MJ group showed reaction time slowing when deciding against group choices. Longer reaction times were associated with greater activation of frontal regions. The MJ goup, compared to CON, showed significantly greater activation in the caudate when presented with peer information. Across groups, caudate activation was associated with self-reported susceptibility to influence. These findings indicate that young adults who use MJ may exhibit increased effort when confronted with opposing peer influence, as well as exhibit greater responsivity of the caudate to social information. These results not only better define the neural basis of social decisions, but also suggest that marijuana use is associated with exaggerated neural activity during decision making that involves social information. C1 [Gilman, Jodi M.; Schuster, Randi M.; Curran, Max T.; Calderon, Vanessa; Evins, A. Eden] Massachusetts Gen Hosp, Dept Psychiat, Ctr Addict Med, Boston, MA 02114 USA. [Gilman, Jodi M.; van der Kouwe, Andre] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Gilman, Jodi M.; Schuster, Randi M.; van der Kouwe, Andre; Evins, A. Eden] Harvard Med Sch, Boston, MA 02115 USA. RP Gilman, JM (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Ctr Addict Med, Boston, MA 02114 USA.; Gilman, JM (reprint author), Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA.; Gilman, JM (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM jgilman1@partners.org FU NIDA [K01 DA034093, K24 DA030443] FX This work was supported by Grants NIDA K01 DA034093 (J.M.G.) and NIDA K24 DA030443 (A.E.E.). These funding sources had no role in the study design, collection, analysis or interpretation of the data, writing the manuscript, or the decision to submit the manuscript for publication. NR 96 TC 0 Z9 0 U1 12 U2 15 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1530-7026 EI 1531-135X J9 COGN AFFECT BEHAV NE JI Cogn. Affect. Behav. Neurosci. PD AUG PY 2016 VL 16 IS 4 BP 646 EP 661 DI 10.3758/s13415-016-0421-8 PG 16 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA DR7YQ UT WOS:000380116000007 PM 27068178 ER PT J AU Raz, G Touroutoglou, A Wilson-Mendenhall, C Gilam, G Lin, T Gonen, T Jacob, Y Atzil, S Admon, R Bleich-Cohen, M Maron-Katz, A Hendler, T Barrett, LF AF Raz, Gal Touroutoglou, Alexandra Wilson-Mendenhall, Christine Gilam, Gadi Lin, Tamar Gonen, Tal Jacob, Yael Atzil, Shir Admon, Roee Bleich-Cohen, Maya Maron-Katz, Adi Hendler, Talma Barrett, Lisa Feldman TI Functional connectivity dynamics during film viewing reveal common networks for different emotional experiences SO COGNITIVE AFFECTIVE & BEHAVIORAL NEUROSCIENCE LA English DT Article DE Stimulus-induced functional connectivity; Network cohesion; Amygdala; Emotions ID VOXEL-BASED METAANALYSIS; LARGE-SCALE BRAIN; ANTERIOR INSULA; BASIC EMOTIONS; MODEL; ARCHITECTURE; ATTENTION; COGNITION; FEELINGS; SYSTEMS AB Recent theoretical and empirical work has highlighted the role of domain-general, large-scale brain networks in generating emotional experiences. These networks are hypothesized to process aspects of emotional experiences that are not unique to a specific emotional category (e.g., "sadness," "happiness"), but rather that generalize across categories. In this article, we examined the dynamic interactions (i.e., changing cohesiveness) between specific domain-general networks across time while participants experienced various instances of sadness, fear, and anger. We used a novel method for probing the network connectivity dynamics between two salience networks and three amygdala-based networks. We hypothesized, and found, that the functional connectivity between these networks covaried with the intensity of different emotional experiences. Stronger connectivity between the dorsal salience network and the medial amygdala network was associated with more intense ratings of emotional experience across six different instances of the three emotion categories examined. Also, stronger connectivity between the dorsal salience network and the ventrolateral amygdala network was associated with more intense ratings of emotional experience across five out of the six different instances. Our findings demonstrate that a variety of emotional experiences are associated with dynamic interactions of domain-general neural systems. C1 [Raz, Gal; Wilson-Mendenhall, Christine; Gilam, Gadi; Lin, Tamar; Gonen, Tal; Jacob, Yael; Admon, Roee; Bleich-Cohen, Maya; Maron-Katz, Adi; Hendler, Talma] Tel Aviv Sourasky Med Ctr, Wohl Inst Adv Imaging, Tel Aviv Ctr Brain Funct, Tel Aviv, Israel. [Raz, Gal; Maron-Katz, Adi; Hendler, Talma] Tel Aviv Univ, Sackler Fac Med, Tel Aviv, Israel. [Raz, Gal] Tel Aviv Univ, Steve Tisch Sch Film & Televis, Tel Aviv, Israel. [Touroutoglou, Alexandra] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Touroutoglou, Alexandra] Harvard Med Sch, Boston, MA USA. [Touroutoglou, Alexandra; Wilson-Mendenhall, Christine; Atzil, Shir; Barrett, Lisa Feldman] Massachusetts Gen Hosp, MGH HST Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Touroutoglou, Alexandra; Wilson-Mendenhall, Christine; Atzil, Shir; Barrett, Lisa Feldman] Harvard Med Sch, Charlestown, MA 02129 USA. [Wilson-Mendenhall, Christine; Atzil, Shir; Barrett, Lisa Feldman] Northeastern Univ, Dept Psychol, 125 Nightingale Hall, Boston, MA 02115 USA. [Gilam, Gadi; Lin, Tamar; Gonen, Tal; Hendler, Talma] Tel Aviv Univ, Sch Psychol Sci, Tel Aviv, Israel. [Jacob, Yael] Tel Aviv Univ, Sagol Sch Neurosci, Tel Aviv, Israel. [Admon, Roee] Harvard Med Sch, McLean Hosp, Ctr Depress Anxiety & Stress Res, Belmont, MA USA. [Barrett, Lisa Feldman] Massachusetts Gen Hosp, Dept Psychiat, Div Psychiat Neuroimaging, Charlestown, MA 02129 USA. RP Barrett, LF (reprint author), Massachusetts Gen Hosp, MGH HST Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA.; Barrett, LF (reprint author), Harvard Med Sch, Charlestown, MA 02129 USA.; Barrett, LF (reprint author), Northeastern Univ, Dept Psychol, 125 Nightingale Hall, Boston, MA 02115 USA.; Barrett, LF (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Div Psychiat Neuroimaging, Charlestown, MA 02129 USA. EM l.barrett@neu.edu FU National Institutes of Health Director's Pioneer Award [DP1OD003312]; National Institute on Aging grant [R01 AG030311-06A1]; National Center for Research Resources [1S10RR023401, 1S10RR019307, 1S10RR023043]; University of Chicago's Arete Initiative "The Science of Virtues,"; Israeli Defense Forces Medical Corps; U.S Department of Defense [W81XWH-11-2-0008]; BRAINTRAIN under the EU FP7 Health Cooperation Work Program [602186]; National Institutes of Health; National Institute on Aging FX We thank Alaina Baker for her assistance with editing the manuscript. This work was supported by a National Institutes of Health Director's Pioneer Award (DP1OD003312) to L.F.B., a National Institute on Aging grant (R01 AG030311-06A1) to L.F.B., and Shared Instrumentation grants (1S10RR023401, 1S10RR019307, and 1S10RR023043) from the National Center for Research Resources. This study was also supported by a Dan David Scholarship to G.R., and by grants from the University of Chicago's Arete Initiative "The Science of Virtues," to T.H., G.R., and G.G.; the Israeli Defense Forces Medical Corps, to T.H. and R.A.; the U.S Department of Defense (W81XWH-11-2-0008) to T.H.; and BRAINTRAIN under the EU FP7 Health Cooperation Work Program (602186), to T.H. and G.R. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources, the National Institutes of Health, or the National Institute on Aging. G.R., A.T., C.W.-M., S.A., T.H., and L.F.B. designed the study. G.R., A.T., T.H., and L.F.B. wrote the manuscript. G.R., A.T., T.H., L.F.B., G.G., C.W.-M., T.L., T.G., Y.J., S.A., R.A., and A.M.-K. analyzed the data. L.F.B. and T.H. contributed to the grant funding. The authors declare no conflicts of interest. NR 64 TC 3 Z9 3 U1 5 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1530-7026 EI 1531-135X J9 COGN AFFECT BEHAV NE JI Cogn. Affect. Behav. Neurosci. PD AUG PY 2016 VL 16 IS 4 BP 709 EP 723 DI 10.3758/s13415-016-0425-4 PG 15 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA DR7YQ UT WOS:000380116000011 PM 27142636 ER PT J AU Flanagan, JC Korte, KJ Killeen, TK Back, SE AF Flanagan, Julianne C. Korte, Kristina J. Killeen, Therese K. Back, Sudie E. TI Concurrent Treatment of Substance Use and PTSD SO CURRENT PSYCHIATRY REPORTS LA English DT Review DE Substance use disorders; Addiction; Posttraumatic stress disorder; Clinical trials; Integrated intervention ID POSTTRAUMATIC-STRESS-DISORDER; COMORBID ALCOHOL DEPENDENCE; RANDOMIZED CONTROLLED-TRIAL; COGNITIVE-BEHAVIORAL THERAPY; SOCIAL ANXIETY DISORDER; PROLONGED EXPOSURE; FUNCTIONAL CONNECTIVITY; PILOT TRIAL; ALPHA-1-ADRENERGIC ANTAGONIST; PHARMACOLOGICAL-TREATMENT AB Substance use disorders (SUD) and posttraumatic stress disorder (PTSD) are chronic, debilitating conditions that frequently co-occur. Individuals with co-occurring SUD and PTSD suffer a more complicated course of treatment and less favorable treatment outcomes compared to individuals with either disorder alone. The development of effective psychosocial and pharmacological interventions for co-occurring SUD and PTSD is an active and critically important area of investigation. Several integrated psychosocial treatments for cooccurring SUD and PTSD have demonstrated promising outcomes. While recent studies examining medications to treat co-occurring SUD and PTSD have yielded encouraging findings, there remain substantial gaps in the evidence base regarding the treatment of co-occurring SUD and PTSD. This review will summarize the findings from clinical trials targeting a reduction in SUD and PTSD symptoms simultaneously. These results may improve our knowledge base and subsequently enhance our ability to develop effective interventions for this complex comorbid condition. C1 [Flanagan, Julianne C.; Korte, Kristina J.; Killeen, Therese K.; Back, Sudie E.] Med Univ South Carolina, 5 Charleston Ctr Dr,Suite 151, Charleston, SC 29455 USA. [Back, Sudie E.] Ralph H Johnson VAMC, 109 Bee St, Charleston, SC 29401 USA. RP Flanagan, JC (reprint author), Med Univ South Carolina, 5 Charleston Ctr Dr,Suite 151, Charleston, SC 29455 USA. EM Hellmuth@musc.edu FU National Institute on Child Health and Human Development; Office of Research on Women's Health [K12HD055885]; National Institute of Alcohol Abuse and Alcoholism [T32AA007474] FX This manuscript is the result of work supported, in part, by the National Institute on Child Health and Human Development and the Office of Research on Women's Health (K12HD055885) and the National Institute of Alcohol Abuse and Alcoholism (T32AA007474). NR 100 TC 3 Z9 3 U1 11 U2 16 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3812 EI 1535-1645 J9 CURR PSYCHIAT REP JI Curr. Psychiatry Rep. PD AUG PY 2016 VL 18 IS 8 AR 70 DI 10.1007/s11920-016-0709-y PG 9 WC Psychiatry SC Psychiatry GA DR8HR UT WOS:000380139500003 PM 27278509 ER PT J AU Finckh, A Escher, M Liang, MH Bansback, N AF Finckh, Axel Escher, Monica Liang, Matthew H. Bansback, Nick TI Preventive Treatments for Rheumatoid Arthritis: Issues Regarding Patient Preferences SO CURRENT RHEUMATOLOGY REPORTS LA English DT Article DE Rheumatoid arthritis (RA); Preventive therapy; Prevention; Population at risk; Patient preferences; Decision making ID CYCLIC CITRULLINATED PEPTIDE; BODY-MASS INDEX; ALCOHOL-CONSUMPTION; BLOOD-DONORS; RISK; POPULATION; MEDICATION; AUTOANTIBODIES; ANTIBODIES; DECISIONS AB The detection of biomarkers in the preclinical phase of rheumatoid arthritis (RA) and recent therapeutic advances suggest that it may be possible to identify and treat persons at high risk and to prevent the development of RA. Several trials are ongoing to test the efficacy of a therapeutic intervention in primary prevention. This paper reviews potential populations that might be considered for preventative medication. Further, we review the medications that are being explored to treat individuals considered at high risk of developing RA. Finally, in a group of asymptomatic individuals at high risk of developing RA, we assessed which factors mattered most when considering a preventive therapeutic intervention and what type of preventive treatment would be most acceptable to them. Understanding subjects' perceptions of risks and benefits and willingness to undergo preventive therapy will be important in designing and implementing screening and preventive strategies. C1 [Finckh, Axel] Univ Hosp Geneva HUG, Div Rheumatol, 26 Av Beau Sejour, CH-1211 Geneva 14, Switzerland. [Escher, Monica] Univ Hosp Geneva, Div Clin Pharmacol & Toxicol, Pain & Palliat Care Consultat, Geneva, Switzerland. [Liang, Matthew H.] Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. [Liang, Matthew H.] VA Boston Healthcare Syst, Rheumatol Sect, Boston, MA USA. [Bansback, Nick] Univ British Columbia, Sch Populat & Publ Hlth, Vancouver, BC, Canada. RP Finckh, A (reprint author), Univ Hosp Geneva HUG, Div Rheumatol, 26 Av Beau Sejour, CH-1211 Geneva 14, Switzerland. EM axel.finckh@hcuge.ch OI Bansback, Nick/0000-0002-1510-3462 FU Swiss National Science Foundation [3200B0_120639/1] FX This work was supported by the Swiss National Science Foundation [3200B0_120639/1]. NR 68 TC 0 Z9 1 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3774 EI 1534-6307 J9 CURR RHEUMATOL REP JI Curr. Rheumatol. Rep. PD AUG PY 2016 VL 18 IS 8 AR 51 DI 10.1007/s11926-016-0598-4 PG 10 WC Rheumatology SC Rheumatology GA DR8QT UT WOS:000380163100003 PM 27402108 ER PT J AU Randall, TC Armstrong, K AF Randall, Thomas C. Armstrong, Katrina TI Health Care Disparities in Hereditary Ovarian Cancer: Are We Reaching the Underserved Population? SO CURRENT TREATMENT OPTIONS IN ONCOLOGY LA English DT Review DE BRCA1/2; Hereditary ovarian cancer; Disparities; Genetic counseling ID BRCA2 MUTATION CARRIERS; BREAST-CANCER; PATIENT NAVIGATION; ORAL-CONTRACEPTIVES; CONTROLLED-TRIAL; AMERICAN WOMEN; RISK; PREVALENCE; MORTALITY; METAANALYSIS AB Ovarian cancer is an uncommon but deadly disease. There is no effective screening for the disease, and the majority of women with ovarian cancer present in advanced stage and eventually die from their disease. The majority of families with multiple cases of breast and ovarian cancer are found to carry germline mutations in BRCA1/2. Recent, more sensitive sequencing techniques have shown that nearly 20 % of ovarian cancer is associated with germline mutations in cancer susceptibility genes, with approximately 15 % accounted for by deleterious mutations in BRCA1/2. Women found to have mutations in BRCA1/2 can be empowered to make decisions on reproduction, cancer prevention, or treatment that may either avoid cancer or prolong survival. Though initial studies suggested that African American (AA) women were significantly less likely than White women to have mutations in BRCA1/2, this has been found to be untrue. Despite this revelation, and the clear importance of BRCA1/2 mutation status to appropriate clinical management, AA women still undergo genetic counseling and testing at much lower rates than do comparable White women. This disparity is not explained by factors such as calculated risk of a mutation, insurance coverage, or previous knowledge of the availability of testing. To date, no effective strategies have been identified that can overcome this disparity. Possible approaches include use of patient navigators, online social media, or EMR-based decision support aids. Funders should support research in this area, as it represents an actionable means to decrease the burden of ovarian and breast cancer in AA women. C1 [Randall, Thomas C.] Massachusetts Gen Hosp, Dept Obstet & Gynecol, 55 Fruit St,Founders 520B, Boston, MA 02108 USA. [Armstrong, Katrina] Massachusetts Gen Hosp, Dept Med, 55 Fruit St, Boston, MA 02108 USA. RP Randall, TC (reprint author), Massachusetts Gen Hosp, Dept Obstet & Gynecol, 55 Fruit St,Founders 520B, Boston, MA 02108 USA. EM trandall@mgh.harvard.edu NR 43 TC 1 Z9 1 U1 3 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1527-2729 EI 1534-6277 J9 CURR TREAT OPTION ON JI Curr. Treat. Options Oncol. PD AUG PY 2016 VL 17 IS 8 AR 39 DI 10.1007/s11864-016-0417-1 PG 8 WC Oncology SC Oncology GA DR8RP UT WOS:000380165300004 PM 27315065 ER PT J AU Fuller, H Justo, F Nearing, BD Kahlig, KM Rajamani, S Belardinelli, L Verrier, RL AF Fuller, Henrique Justo, Fernanda Nearing, Bruce D. Kahlig, Kristopher M. Rajamani, Sridharan Belardinelli, Luiz Verrier, Richard L. TI Eleclazine, a new selective cardiac late sodium current inhibitor, confers concurrent protection against autonomically induced atrial premature beats, repolarization alternans and heterogeneity, and atrial fibrillation in an intact porcine model SO HEART RHYTHM LA English DT Article DE Atrial fibrillation; Repolarization; Alternans; Heterogeneity; Atrial premature beats; Epinephrine; Acetylcholine; Late sodium current ID T-WAVE ALTERNANS; VENTRICULAR-TACHYCARDIA; NERVOUS-SYSTEM; GS-458967; VULNERABILITY; ARRHYTHMIAS; HEARTS; POTENT AB BACKGROUND The cardiac late sodium current (INa) has been increasingly implicated in the initiation of atrial fibrillation (AF). Eledazine (formerly known as GS-6615) is a new selective late INa inhibitor and is undergoing clinical testing for the treatment of cardiac arrhythmias. OBJECTIVE We tested whether late INa inhibition by eledazine confers protection against atrial premature beats (APBs) and AF. METHODS In dosed-chest anesthetized Yorkshire pigs, epinephrine (2.0 mu g/kg, intravenous, bolus over 1 minute) was administered alone to induce APBs (n = 6) or in combination with intrapericardial acetylcholine (0.5-4 mL of 12.5 mM solution) to induce spontaneous AF (n = 11). Effects of eledazine (0.3 and 0.9 mg/kg, intravenous, over 15 minutes) on APBs and AF were determined. RESULTS Epinephrine-induced APBs were reduced >3-fold (P <.04) after eledazine (0.9 mg/kg) infusion. The combined administration of epinephrine and acetylcholine resulted in AF in all animals tested, which was invariably preceded by APBs. Eledazine pretreatment suppressed AF in all 7 animals in at least 1 test episode during the 60- to 150-minute observation period (P =.04). The plasma eledazine level at 120 minutes was 828 45.8 nM, within exposure range evaluated clinically. Eledazine shortened ventricular QT and atrial PTa intervals by 7% (P <.001 for both) and reduced atrial repolarization alternans (P =.003) and heterogeneity (P =.021) without attenuation of the inotropic response to catecholamine (P =.56). The drug inhibited the enhanced late INa of single atrial myocytes with a potency of 736 67 nM. CONCLUSION Selective cardiac late INa inhibition with eledazine suppresses autonomically mediated atrial repolarization alternans and heterogeneity, APBs, and AF in an intact porcine model. C1 [Fuller, Henrique; Justo, Fernanda; Nearing, Bruce D.; Verrier, Richard L.] Beth Israel Deaconess Med Ctr, Boston, MA USA. [Fuller, Henrique; Justo, Fernanda] Univ Sao Paulo, Fac Med, Sao Paulo, Brazil. [Nearing, Bruce D.; Verrier, Richard L.] Harvard Med Sch, Boston, MA USA. [Kahlig, Kristopher M.; Rajamani, Sridharan; Belardinelli, Luiz] Gilead Sci Inc, Foster City, CA USA. RP Verrier, RL (reprint author), Harvard Med Sch, Harvard Thorndike Electrophysiol Inst, Beth Israel Deaconess Med Ctr, Div Cardiovasc Med, 99 Brookline Ave,Room 301, Boston, MA 02215 USA. EM rverrier@bidmc.harvard.edu FU Science Without Borders Program of Brazil FX Mr Fuller and Ms Justo received support from the Science Without Borders Program of Brazil administered by CAPES, the Brazilian Coordinating Office for the Advancement of Higher Education. Dr Rajamani, Dr Kahlig, and Dr Belardinelli are employees of Gilead Sciences. Dr. Rajamani is currently at Amgen, Inc., 1120 Veterans Blvd, South San Francisco CA 94080. Dr Verrier and Dr Nearing have received royalties from Georgetown University and Beth Israel Deaconess Medical Center for intellectual property on the Modified Moving Average method for T-wave alternans analysis, which was licensed to GE Healthcare and was used in this study. This study was funded by a grant from Gilead Sciences to Beth Israel Deaconess Medical Center (Dr Verrier, principal investigator). NR 24 TC 2 Z9 2 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1547-5271 EI 1556-3871 J9 HEART RHYTHM JI Heart Rhythm PD AUG PY 2016 VL 13 IS 8 BP 1679 EP 1686 DI 10.1016/j.hrthm.2016.04.015 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DR9JI UT WOS:000380212500016 PM 27108587 ER PT J AU Castellanos, A Scangas, GA Naunheim, MR Raol, N Cohen, MS AF Castellanos, Angela Scangas, George A. Naunheim, Matthew R. Raol, Nikhila Cohen, Michael S. TI Avoiding surgical pitfalls during resection of a "hybrid" first and second branchial cleft cyst - A case report SO INTERNATIONAL JOURNAL OF PEDIATRIC OTORHINOLARYNGOLOGY LA English DT Article DE Branchial cleft cyst; Branchial cleft anomalies; Branchial arches; Facial nerve; Congenital head and neck anomalies ID MANAGEMENT; ANOMALIES C1 [Castellanos, Angela; Scangas, George A.; Naunheim, Matthew R.; Raol, Nikhila; Cohen, Michael S.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol Head & Neck Surg, 243 Charles St, Boston, MA 02114 USA. [Castellanos, Angela; Scangas, George A.; Naunheim, Matthew R.; Raol, Nikhila; Cohen, Michael S.] Harvard Med Sch, Dept Otol & Laryngol, Boston, MA USA. [Castellanos, Angela] Childrens Hosp Philadelphia, Dept Pediat, 9NW 34th & Civ Ctr Blvd, Philadelphia, PA 19104 USA. RP Cohen, MS (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM Michael_Cohen@meei.harvard.edu NR 9 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-5876 EI 1872-8464 J9 INT J PEDIATR OTORHI JI Int. J. Pediatr. Otorhinolaryngol. PD AUG PY 2016 VL 87 BP 91 EP 93 DI 10.1016/j.ijporl.2016.06.012 PG 3 WC Otorhinolaryngology; Pediatrics SC Otorhinolaryngology; Pediatrics GA DR7LU UT WOS:000380082000017 PM 27368450 ER PT J AU Engel, PA AF Engel, Peter A. TI Is age-related failure of metabolic reprogramming a principal mediator in idiopathic Parkinson's disease? Implications for treatment and inverse cancer risk SO MEDICAL HYPOTHESES LA English DT Article ID MITOCHONDRIAL-DNA DELETIONS; SUBSTANTIA-NIGRA NEURONS; ALPHA-SYNUCLEIN; COMPLEX I; DOPAMINERGIC-NEURONS; MALIGNANT-MELANOMA; OXIDATIVE STRESS; ASSOCIATION; EXPRESSION; MUTATIONS AB Idiopathic Parkinson's disease (IPD) is a neurodegenerative disorder characterized by selective degeneration of the substantia nigra pars compacta (SNc), dorsal motor nucleus of the vagus and other vulnerable nervous system regions characterized by extensive axonal arborization and intense energy requirements. Systemic age-related depression of mitochondrial function, oxidative phosphorylation (OXPHOS) and depressed expression of genes supporting energy homeostasis is more severe in IPD than normal aging such that energy supply may exceed regional demand. In IPD, the overall risk of malignancy is reduced. Cancer is a collection of proliferative diseases marked by malignant transformation, dysregulated mitosis, invasion and metastasis. Many cancers demonstrate normal mitochondrial function, preserved OXPHOS, competent mechanisms of energy homeostasis, and metabolic reprogramming capacities that are lacking in IPD. Metabolic reprogramming adjusts OXPHOS and glycolytic pathways in response to changing metabolic needs. These opposite metabolic features form the basis of a two component hypothesis. First, that depressed mitochondrial function, OXPHOS deficiency and impaired metabolic reprogramming contribute to focal energy failure, neurodegeneration and disease expression in IPD. Second, that the same systemic metabolic deficits inhibit development and proliferation of malignancies in IPD. Studies of mitochondrial aging, familial PD (FPD), the lysosomal storage disorder, Gaucher's disease, Parkinson's disease cybrids, the mitochondrial cytopathies, and disease-related metabolic reprogramming both in IPD and cancer provide support for this model. (C) 2016 Published by Elsevier Ltd. C1 [Engel, Peter A.] VA Boston Healthcare Syst, Geriatr Res Educ & Clin Ctr, Boston, MA USA. [Engel, Peter A.] Harvard Med Sch, Boston, MA USA. RP Engel, PA (reprint author), VA Boston Healthcare Syst, 150 S Huntington Ave, Boston, MA 02130 USA. EM penge1443@gmail.com NR 84 TC 1 Z9 1 U1 1 U2 2 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0306-9877 EI 1532-2777 J9 MED HYPOTHESES JI Med. Hypotheses PD AUG PY 2016 VL 93 BP 154 EP 160 DI 10.1016/j.mehy.2016.05.033 PG 7 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DR7KG UT WOS:000380077900033 PM 27372878 ER PT J AU Morotti, A Jessel, MJ Brouwers, HB Falcone, GJ Schwab, K Ayres, AM Vashkevich, A Anderson, CD Viswanathan, A Greenberg, SM Gurol, ME Romero, JM Rosand, J Goldstein, JN AF Morotti, Andrea Jessel, Michael J. Brouwers, H. Bart Falcone, Guido J. Schwab, Kristin Ayres, Alison M. Vashkevich, Anastasia Anderson, Christopher D. Viswanathan, Anand Greenberg, Steven M. Gurol, M. Edip Romero, Javier M. Rosand, Jonathan Goldstein, Joshua N. TI CT Angiography Spot Sign, Hematoma Expansion, and Outcome in Primary Pontine Intracerebral Hemorrhage SO NEUROCRITICAL CARE LA English DT Article DE CT angiography; Spot sign; Brainstem; Pontine; Prognosis; Intracerebral hemorrhage ID ASSOCIATION/AMERICAN STROKE ASSOCIATION; HEALTH-CARE PROFESSIONALS; IDENTIFIES PATIENTS; HIGHEST RISK; SCORE AB The computed tomography angiography (CTA) spot sign is a validated predictor of hematoma expansion and poor outcome in supratentorial intracerebral hemorrhage (ICH), but patients with brainstem ICH have typically been excluded from the analyses. We investigated the frequency of spot sign and its relationship with hematoma expansion and outcome in patients with primary pontine hemorrhage (PPH). We performed a retrospective analysis of PPH cases obtained from a prospectively collected cohort of consecutive ICH patients who underwent CTA. CTA first-pass readings for spot sign presence were analyzed by two trained readers. Baseline and follow-up hematoma volumes on non-contrast CT scans were assessed by semi-automated computer-assisted volumetric analysis. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive and negative likelihood ratio, and accuracy of spot sign for prediction of in-hospital mortality were calculated. 49 subjects met the inclusion criteria of whom 11 (22.4 %) showed a spot sign. In-hospital mortality was higher in spot sign-positive versus spot sign-negative subjects (90.9 vs 47.4 %, p = 0.020). Spot sign showed excellent specificity (95 %) and PPV (91 %) in predicting in-hospital mortality. Absolute hematoma growth, defined as parenchymal and intraventricular hematoma expansion of any amount, was significantly higher in spot sign-positive versus spot sign-negative subjects (13.72 +/- 20.93 vs 3.76 +/- 8.55 mL, p = 0.045). As with supratentorial ICH, the CTA spot sign is a common finding and is associated with higher risk of hematoma expansion and mortality in PPH. This marker may assist clinicians in prognostic stratification. C1 [Morotti, Andrea] Univ Brescia, Dept Clin & Expt Sci, Neurol Clin, Brescia, Italy. [Morotti, Andrea; Jessel, Michael J.; Falcone, Guido J.; Anderson, Christopher D.; Rosand, Jonathan; Goldstein, Joshua N.] Massachusetts Gen Hosp, Dept Neurol, Div Neurocrit Care & Emergency Neurol, Boston, MA 02114 USA. [Morotti, Andrea; Jessel, Michael J.; Falcone, Guido J.; Schwab, Kristin; Ayres, Alison M.; Vashkevich, Anastasia; Anderson, Christopher D.; Viswanathan, Anand; Greenberg, Steven M.; Gurol, M. Edip; Rosand, Jonathan; Goldstein, Joshua N.] Massachusetts Gen Hosp, Hemorrhag Stroke Res Grp, Boston, MA 02114 USA. [Brouwers, H. Bart] Rudolf Magnus Univ, Med Ctr, Brain Ctr, Dept Neurosurg, Utrecht, Netherlands. [Romero, Javier M.] Massachusetts Gen Hosp, Dept Radiol, Serv Neuroradiol, Boston, MA 02114 USA. [Goldstein, Joshua N.] Massachusetts Gen Hosp, Dept Emergency Med, Zero Emerson Pl,Suite 3B, Boston, MA 02114 USA. RP Goldstein, JN (reprint author), Massachusetts Gen Hosp, Dept Neurol, Div Neurocrit Care & Emergency Neurol, Boston, MA 02114 USA.; Goldstein, JN (reprint author), Massachusetts Gen Hosp, Hemorrhag Stroke Res Grp, Boston, MA 02114 USA.; Goldstein, JN (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, Zero Emerson Pl,Suite 3B, Boston, MA 02114 USA. EM jgoldstein@partners.org RI Gurol, Edip/J-2279-2014; OI Gurol, Edip/0000-0002-2169-4457; Anderson, Christopher/0000-0002-0053-2002 FU NINDS [5R01NS073344, K23AG02872605, K23 NS086873, R01NS059727] FX This study was supported by the following awards from the NINDS: 5R01NS073344, K23AG02872605, K23 NS086873, R01NS059727. None of the funding entities had any involvement in study design; data collection, analysis, and interpretation; writing of the manuscript; or decision to submit the study for publication. NR 23 TC 1 Z9 1 U1 2 U2 2 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1541-6933 EI 1556-0961 J9 NEUROCRIT CARE JI Neurocrit. Care PD AUG PY 2016 VL 25 IS 1 BP 79 EP 85 DI 10.1007/s12028-016-0241-2 PG 7 WC Critical Care Medicine; Clinical Neurology SC General & Internal Medicine; Neurosciences & Neurology GA DR8LZ UT WOS:000380150700011 PM 26759226 ER PT J AU Boland, T Henderson, GV Gibbons, FK Brouwers, HB Greenberg, SM Raffeld, M Kourkoulis, CE Rosand, J Christopher, KB AF Boland, Torrey Henderson, Galen V. Gibbons, Fiona K. Brouwers, H. Bart Greenberg, Steven M. Raffeld, Miriam Kourkoulis, Christina E. Rosand, Jonathan Christopher, Kenneth B. TI Hypernatremia at Hospital Discharge and Out of Hospital Mortality Following Primary Intracerebral Hemorrhage SO NEUROCRITICAL CARE LA English DT Article DE Sodium; Hypernatremia; Critical care; Intensive care; Mortality; Intracerebral hemorrhage ID CRITICALLY-ILL PATIENTS; ACUTE KIDNEY INJURY; UNITED-STATES; CRITICAL-CARE; SCORE; COHORT; ASSOCIATION; FAILURE; EPIDEMIOLOGY; PREDICTION AB In patients with intracerebral hemorrhage (ICH), it is not clear if hypernatremia is merely a marker of disease severity or if elevated sodium levels are harmful. We hypothesized that hypernatremia at hospital discharge in primary ICH patients would be associated with increased mortality following discharge. We performed a two-center observational study of critically ill ICH patients in Boston. We studied 5100 patients, age a parts per thousand yen18 years, who were diagnosed with ICH (ICD-9 code 431), received medical or surgical critical care between 1997 and 2011 and survived hospitalization. The exposure of interest was serum sodium within 24 h of hospital discharge, categorized as Na a parts per thousand currency sign 145 mmol/L and Na > 145 mmol/L. The primary outcome was 30-day post-discharge mortality. Odds ratios were estimated by logistic regression models adjusted for age, race, gender, Deyo-Charlson Index, patient type (medical versus surgical) and sepsis. In ICH patients who received critical care and survived hospitalization, the serum sodium at discharge was a predictor of post-discharge mortality. Patients with a discharge Na > 145 mmol/L have an OR for mortality in the 30 days following hospital discharge of 1.82 (95 %CI 1.38-2.38; P < 0.001) and an adjusted OR of 1.87 (95 %CI 1.40-2.48; P < 0.001) both relative to patients with a discharge Na a parts per thousand currency sign 145 mmol/L. The adjusted model showed good discrimination AUC 0.77 (95 %CI 0.74-0.79) and calibration (Hosmer-Lemeshow chi (2) P = 0.68). In critically ill ICH patients who survive hospitalization, hypernatremia at the time of discharge is a robust predictor of post-discharge mortality. C1 [Boland, Torrey] Rush Univ, Dept Neurol, Med Ctr, Chicago, IL 60612 USA. [Henderson, Galen V.] Brigham & Womens Hosp, Dept Neurol, 75 Francis St, Boston, MA 02115 USA. [Gibbons, Fiona K.] Massachusetts Gen Hosp, Dept Med, Div Pulm & Crit Care Med, Boston, MA 02114 USA. [Brouwers, H. Bart] Univ Med Ctr Utrecht, Dept Neurosurg, Brain Ctr Rudolf Magnus, Utrecht, Netherlands. [Greenberg, Steven M.; Raffeld, Miriam; Kourkoulis, Christina E.; Rosand, Jonathan] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Raffeld, Miriam; Kourkoulis, Christina E.; Rosand, Jonathan] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Christopher, Kenneth B.] Brigham & Womens Hosp, Nathan E Hellman Mem Lab, Div Renal, Dept Med, 75 Francis St,MRB 418, Boston, MA 02115 USA. RP Christopher, KB (reprint author), Brigham & Womens Hosp, Nathan E Hellman Mem Lab, Div Renal, Dept Med, 75 Francis St,MRB 418, Boston, MA 02115 USA. EM kbchristopher@partners.org FU NIH [R01 NS059727] FX NIH R01 NS059727. NR 32 TC 0 Z9 0 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1541-6933 EI 1556-0961 J9 NEUROCRIT CARE JI Neurocrit. Care PD AUG PY 2016 VL 25 IS 1 BP 110 EP 116 DI 10.1007/s12028-015-0234-6 PG 7 WC Critical Care Medicine; Clinical Neurology SC General & Internal Medicine; Neurosciences & Neurology GA DR8LZ UT WOS:000380150700015 PM 26842718 ER PT J AU Boehme, AK Hays, AN Kicielinski, KP Arora, K Kapoor, N Lyerly, MJ Gadpaille, A Shiue, H Albright, K Miller, D Elkind, MSV Harrigan, MR AF Boehme, Amelia K. Hays, Angela N. Kicielinski, Kimberly P. Arora, Kanika Kapoor, Niren Lyerly, Michael J. Gadpaille, Alissa Shiue, Harn Albright, Karen Miller, David Elkind, Mitchell S. V. Harrigan, Mark R. TI Systemic Inflammatory Response Syndrome and Outcomes in Intracerebral Hemorrhage SO NEUROCRITICAL CARE LA English DT Article DE Intracerebral hemorrhage; Stroke; Inflammation; Epidemiology; Systemic inflammatory response syndrome ID SUBARACHNOID HEMORRHAGE; ISCHEMIC-STROKE; PLASMINOGEN ACTIVATOR; RISK-FACTORS; THROMBOLYSIS; PREDICTORS; INFARCTION; VASOSPASM; MORTALITY; SEVERITY AB To identify the patients at greatest odds for systemic inflammatory response syndrome (SIRS) and examine the association between SIRS and outcomes in patients presenting with intracerebral hemorrhage (ICH). We retrospectively reviewed consecutive patients presenting to a tertiary care center from 2008 to 2013 with ICH. SIRS was defined according to standard criteria as 2 or more of the following: (1) body temperature < 36 or > 38 A degrees C, (2) heart rate > 90 beats per minute, (3) respiratory rate > 20, or (4) white blood cell count < 4000/mm(3) or > 12,000/mm(3) or > 10 % polymorphonuclear leukocytes for > 24 h in the absence of infection. The outcomes of interest, discharge modified Rankin Scale (mRS 4-6), death, and poor discharge disposition (discharge anywhere but home or inpatient rehab) were assessed using logistic regression. A total of 249 ICH patients met inclusion criteria and 53 (21.3 %) developed SIRS during their hospital stay. A score was developed (ranging from 0 to 3) to identify patients at greatest risk for developing SIRS. Adjusting for stroke severity, SIRS was associated with mRS 4-6 (OR 5.25, 95 %CI 2.09-13.2) and poor discharge disposition (OR 3.74, 95 %CI 1.58-4.83) but was not significantly associated with death (OR 1.75, 95 %CI 0.58-5.32). We found that 33 % of the effect of ICH score on poor functional outcome at discharge was explained by the development of SIRS in the hospital (Sobel 2.11, p = 0.03). We observed that approximately 20 % of patients with ICH develop SIRS, and that patients with SIRS were at increased risk of having poor functional outcome at discharge. C1 [Boehme, Amelia K.; Elkind, Mitchell S. V.] Columbia Univ, Dept Neurol, Coll Phys & Surg, New York, NY 10032 USA. [Hays, Angela N.; Arora, Kanika; Lyerly, Michael J.; Gadpaille, Alissa; Shiue, Harn] Univ Alabama Birmingham, Dept Neurol, UAB Stn, Birmingham, AL 35294 USA. [Kicielinski, Kimberly P.; Harrigan, Mark R.] Univ Alabama Birmingham, Dept Neurosurg, Birmingham, AL 35294 USA. [Kapoor, Niren] Univ Penn, Dept Neurol, Div Neurocrit Care, Philadelphia, PA 19104 USA. [Albright, Karen] Birmingham VA Med Ctr, GRECC, Birmingham, AL 35233 USA. [Albright, Karen] Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35249 USA. [Hays, Angela N.; Miller, David] Univ Alabama Birmingham, Dept Anesthesiol, Birmingham, AL 35294 USA. [Elkind, Mitchell S. V.] Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, New York, NY 10032 USA. [Boehme, Amelia K.] Columbia Univ, Dept Neurol, Gertrude Sergievsky Ctr, 710 W 168th St,Room 612, New York, NY 10032 USA. RP Boehme, AK (reprint author), Columbia Univ, Dept Neurol, Coll Phys & Surg, New York, NY 10032 USA.; Boehme, AK (reprint author), Columbia Univ, Dept Neurol, Gertrude Sergievsky Ctr, 710 W 168th St,Room 612, New York, NY 10032 USA. EM akb2188@cumc.columbia.edu OI Lyerly, Michael/0000-0003-4236-1018 FU NINDS NIH [T32 NS007153-31] FX Dr. Boehme is supported by NINDS NIH T32 NS007153-31. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NINDS or the NIH. NR 38 TC 1 Z9 1 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1541-6933 EI 1556-0961 J9 NEUROCRIT CARE JI Neurocrit. Care PD AUG PY 2016 VL 25 IS 1 BP 133 EP 140 DI 10.1007/s12028-016-0255-9 PG 8 WC Critical Care Medicine; Clinical Neurology SC General & Internal Medicine; Neurosciences & Neurology GA DR8LZ UT WOS:000380150700018 PM 26920909 ER PT J AU Balbale, SN Locatelli, SM LaVela, SL AF Balbale, Salva N. Locatelli, Sara M. LaVela, Sherri L. TI Through Their Eyes: Lessons Learned Using Participatory Methods in Health Care Quality Improvement Projects SO QUALITATIVE HEALTH RESEARCH LA English DT Article DE health care; guided tours; participatory action research (PAR); photography; photovoice; qualitative; United States ID PATIENT-CENTERED CARE; PUBLIC-HEALTH; MOBILE METHODS; PHOTOVOICE; REFLECTIONS; SYSTEM; PERCEPTIONS; EXPLORE; NEEDS; TRANSFORMATION AB In this methodological article, we examine participatory methods in depth to demonstrate how these methods can be adopted for quality improvement (QI) projects in health care. We draw on existing literature and our QI initiatives in the Department of Veterans Affairs to discuss the application of photovoice and guided tours in QI efforts. We highlight lessons learned and several benefits of using participatory methods in this area. Using participatory methods, evaluators can engage patients, providers, and other stakeholders as partners to enhance care. Participant involvement helps yield actionable data that can be translated into improved care practices. Use of these methods also helps generate key insights to inform improvements that truly resonate with stakeholders. Using participatory methods is a valuable strategy to harness participant engagement and drive improvements that address individual needs. In applying these innovative methodologies, evaluators can transcend traditional approaches to uniquely support evaluations and improvements in health care. C1 [Balbale, Salva N.; Locatelli, Sara M.; LaVela, Sherri L.] US Dept Vet Affairs, Ctr Evaluat Practices & Experiences Patient Ctr C, Hines, IL USA. RP Balbale, SN (reprint author), Northwestern Univ, Feinberg Sch Med, 633 N St Clair St,20th Floor, Chicago, IL 60611 USA. EM salva.balbale@northwestern.edu FU Department of Veterans Affairs, Office of Patient-Centered Care and Cultural Transformation; Office of Research and Development Health Services Research and Development, Quality Enhancement Research Initiative [PEC-13-002] FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Funding was received from the Department of Veterans Affairs, Office of Patient-Centered Care and Cultural Transformation, and the Office of Research and Development Health Services Research and Development, Quality Enhancement Research Initiative (PEC-13-002). NR 75 TC 1 Z9 1 U1 4 U2 6 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1049-7323 EI 1552-7557 J9 QUAL HEALTH RES JI Qual. Health Res. PD AUG PY 2016 VL 26 IS 10 SI SI BP 1382 EP 1392 DI 10.1177/1049732315618386 PG 11 WC Information Science & Library Science; Social Sciences, Interdisciplinary; Social Sciences, Biomedical SC Information Science & Library Science; Social Sciences - Other Topics; Biomedical Social Sciences GA DR7FT UT WOS:000380066100007 PM 26667882 ER PT J AU Spence, RT Zargaran, E Hameed, M Nicol, A Navsaria, P AF Spence, Richard Trafford Zargaran, Eiman Hameed, Morad Nicol, Andrew Navsaria, Pradeep TI An Objective Assessment of the Surgical Trainee in an Urban Trauma Unit in South Africa: A Pilot Study SO WORLD JOURNAL OF SURGERY LA English DT Article ID MORTALITY; SURGERY; CARE; OUTCOMES; QUALITY; PROGRAM; VOLUME AB Surgical outcomes are provider specific. This prospective audit describes the surgical activity of five general surgery residents on their trauma surgery rotation. It was hypothesized that the operating surgical trainee is an independent risk factor for adverse outcomes following major trauma. This is a prospective cohort study. All patients admitted, over a 6-month period (August 2014-January 2015), following trauma requiring a major operation performed by a surgical trainee at Groote Schuur Hospital's trauma unit in South Africa were included. Multiple logistic regression models were built to compare risk-adjusted surgical outcomes between trainees. The primary outcome measure was major in-hospital complications. A total of 320 major operations involving 341 procedures were included. The mean age was 28.49 years (range 13-64), 97.2 % were male with a median ISS of 9 (IQR 1-41). Mechanism of injury was penetrating in 93.42 % of cases of which 51.86 % were gunshot injuries. Surgeon A consistently had the lowest risk-adjusted outcomes and was used as the reference for all outcomes in the regression models. Surgeon B, D, and E had statistically significant higher rates of major in-hospital complications than Surgeon A and C, after adjusting for multiple confounders. The final model used to calculate the risk estimates for the primary outcome had a ROC of 0.8649. Risk-adjusted surgical outcomes vary by operating surgical trainee. The analysis thereof can add value to the objective assessment of a surgical trainee. C1 [Spence, Richard Trafford] Massachusetts Gen Hosp, Codman Ctr, Dept Gen Surg, Boston, MA 02114 USA. [Spence, Richard Trafford; Nicol, Andrew; Navsaria, Pradeep] Univ Cape Town, Dept Gen Surg, Cape Town, South Africa. [Zargaran, Eiman; Hameed, Morad] Vancouver Gen Hosp, Dept Gen Surg, Vancouver, BC, Canada. [Zargaran, Eiman; Hameed, Morad] Univ British Columbia, Dept Gen Surg, Vancouver, BC, Canada. [Nicol, Andrew; Navsaria, Pradeep] Groote Schuur Hosp, Dept Trauma Surg, Cape Town, South Africa. RP Spence, RT (reprint author), Massachusetts Gen Hosp, Codman Ctr, Dept Gen Surg, Boston, MA 02114 USA.; Spence, RT (reprint author), Univ Cape Town, Dept Gen Surg, Cape Town, South Africa. EM spnric004@myuct.ac.za NR 23 TC 1 Z9 1 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-2313 EI 1432-2323 J9 WORLD J SURG JI World J.Surg. PD AUG PY 2016 VL 40 IS 8 BP 1815 EP 1822 DI 10.1007/s00268-016-3503-4 PG 8 WC Surgery SC Surgery GA DR7BC UT WOS:000380054000004 PM 27091205 ER PT J AU Ng-Kamstra, JS Riesel, JN Arya, S Weston, B Kreutzer, T Meara, JG Shrime, MG AF Ng-Kamstra, Joshua S. Riesel, Johanna N. Arya, Sumedha Weston, Brad Kreutzer, Tino Meara, John G. Shrime, Mark G. TI Surgical Non-governmental Organizations: Global Surgery's Unknown Nonprofit Sector SO WORLD JOURNAL OF SURGERY LA English DT Article ID WORKFORCE AB Charitable organizations may play a significant role in the delivery of surgical care in low- and middle-income countries (LMICs). However, in order to quantify their collective contribution, to account for the care they provide in national surgical plans, and to maximize coordination between organizations, a comprehensive database of these groups is required. We aimed to create such a database using web-available data. We searched for organizations that meet the United Nations Rule of Law definition of non-governmental organizations and provide surgery in LMICs. We termed these surgical non-governmental organizations (s-NGOs). We screened multiple sources including a listing of disaster relief organizations, medical volunteerism databases, charity commissions, and the results of a literature search. We performed a secondary review of each eligible organization's website to verify inclusion criteria and extracted data. We found 403 s-NGOs providing surgery in all 139 LMICs, with most (61 %) incorporating surgery into a broader spectrum of health services. Over 80 % of s-NGOs had an office in the USA, the UK, Canada, India, or Australia, and they most commonly provided surgery in India (87 s-NGOs), Haiti (71), Kenya (60), and Ethiopia (55). The most common specialties provided were general surgery (184), obstetrics and gynecology (140), and plastic surgery (116). This new catalog includes the largest number of s-NGOs to date, but this is likely to be incomplete. This list will be made publicly available to promote collaboration between s-NGOs, national health systems, and global health policymakers. C1 [Ng-Kamstra, Joshua S.; Riesel, Johanna N.; Meara, John G.; Shrime, Mark G.] Harvard Med Sch, Program Global Surg & Social Change, 641 Huntington Ave, Boston, MA 02115 USA. [Ng-Kamstra, Joshua S.; Riesel, Johanna N.; Meara, John G.; Shrime, Mark G.] Boston Childrens Hosp, Dept Plast & Oral Surg, Boston, MA 02115 USA. [Ng-Kamstra, Joshua S.] Univ Toronto, Dept Surg, Toronto, ON, Canada. [Riesel, Johanna N.] Harvard Plast Surg Combined Residency Program, Boston, MA USA. [Arya, Sumedha; Weston, Brad] Univ Toronto, Fac Med, Toronto, ON, Canada. [Kreutzer, Tino] Brigham & Womens Hosp, Dept Emergency Med, 75 Francis St, Boston, MA 02115 USA. [Kreutzer, Tino] Harvard Humanitarian Initiat, Cambridge, MA USA. [Shrime, Mark G.] Massachusetts Eye & Ear Infirm, Dept Otol & Laryngol, Boston, MA 02114 USA. [Shrime, Mark G.] Massachusetts Eye & Ear Infirm, Off Global Surg, Boston, MA 02114 USA. RP Ng-Kamstra, JS (reprint author), Harvard Med Sch, Program Global Surg & Social Change, 641 Huntington Ave, Boston, MA 02115 USA.; Ng-Kamstra, JS (reprint author), Boston Childrens Hosp, Dept Plast & Oral Surg, Boston, MA 02115 USA.; Ng-Kamstra, JS (reprint author), Univ Toronto, Dept Surg, Toronto, ON, Canada. EM Josh.ng@mail.harvard.edu NR 23 TC 1 Z9 1 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-2313 EI 1432-2323 J9 WORLD J SURG JI World J.Surg. PD AUG PY 2016 VL 40 IS 8 BP 1823 EP 1841 DI 10.1007/s00268-016-3486-1 PG 19 WC Surgery SC Surgery GA DR7BC UT WOS:000380054000005 PM 27008646 ER PT J AU Kohrt, BA Marienfeld, CB Panter-Brick, C Tsai, AC Wainberg, ML AF Kohrt, Brandon A. Marienfeld, Carla B. Panter-Brick, Catherine Tsai, Alexander C. Wainberg, Milton L. TI Global Mental Health: Five Areas for Value-Driven Training Innovation SO ACADEMIC PSYCHIATRY LA English DT Article DE Curriculum development; Cross-cultural psychiatry; Global mental health; Medical education; Training innovation ID COMPETENCE; PROGRAM AB Objective In the field of global mental health, there is a need for identifying core values and competencies to guide training programs in professional practice as well as in academia. This paper presents the results of interdisciplinary discussions fostered during an annual meeting of the Society for the Study of Psychiatry and Culture to develop recommendations for value-driven innovation in global mental health training. Methods Participants (n = 48), who registered for a dedicated workshop on global mental health training advertised in conference proceedings, included both established faculty and current students engaged in learning, practice, and research. They proffered recommendations in five areas of training curriculum: values, competencies, training experiences, resources, and evaluation. Results Priority values included humility, ethical awareness of power differentials, collaborative action, and "deep accountability" when working in low-resource settings in low- and middle-income countries and high-income countries. Competencies included flexibility and tolerating ambiguity when working across diverse settings, the ability to systematically evaluate personal biases, historical and linguistic proficiency, and evaluation skills across a range of stakeholders. Training experiences included didactics, language training, self-awareness, and supervision in immersive activities related to professional or academic work. Resources included connections with diverse faculty such as social scientists and mentors in addition to medical practitioners, institutional commitment through protected time and funding, and sustainable collaborations with partners in low resource settings. Finally, evaluation skills built upon community-based participatory methods, 360-degree feedback from partners in low-resource settings, and observed structured clinical evaluations (OSCEs) with people of different cultural backgrounds. Conclusions Global mental health training, as envisioned in this workshop, exemplifies an ethos of working through power differentials across clinical, professional, and social contexts in order to form longstanding collaborations. If incorporated into the ACGME/ABPN Psychiatry Milestone Project, such recommendations will improve training gained through international experiences as well as the everyday training of mental health professionals, global health practitioners, and social scientists. C1 [Kohrt, Brandon A.] Duke Univ, Duke Global Hlth Inst, Durham, NC USA. [Marienfeld, Carla B.] Yale Univ, Sch Med, New Haven, CT USA. [Panter-Brick, Catherine] Yale Univ, New Haven, CT USA. [Tsai, Alexander C.] Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA USA. [Wainberg, Milton L.] Columbia Univ, New York State Psychiat Inst, Global Mental Hlth Program, New York, NY USA. RP Kohrt, BA (reprint author), Duke Univ, Duke Global Hlth Inst, Durham, NC USA. EM brandon.kohrt@duke.edu FU [K01MH104310]; [K23M096620] FX The authors acknowledge salary support for Dr. Kohrt through K01MH104310 and Dr. Tsai through K23M096620. NR 25 TC 1 Z9 1 U1 8 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1042-9670 EI 1545-7230 J9 ACAD PSYCHIATR JI Acad. Psych. PD AUG PY 2016 VL 40 IS 4 BP 650 EP 658 DI 10.1007/s40596-016-0504-4 PG 9 WC Education & Educational Research; Psychiatry SC Education & Educational Research; Psychiatry GA DR2BE UT WOS:000379709200019 PM 26983416 ER PT J AU Ng, LC Magidson, JF Hock, RS Joska, JA Fekadu, A Hanlon, C Galler, JR Safren, SA Borba, CPC Fricchione, GL Henderson, DC AF Ng, Lauren C. Magidson, Jessica F. Hock, Rebecca S. Joska, John A. Fekadu, Abebaw Hanlon, Charlotte Galler, Janina R. Safren, Steven A. Borba, Christina P. C. Fricchione, Gregory L. Henderson, David C. TI Proposed Training Areas for Global Mental Health Researchers SO ACADEMIC PSYCHIATRY LA English DT Article ID MIDDLE-INCOME COUNTRIES; DEVELOPING-WORLD; RURAL ETHIOPIA; SCHIZOPHRENIA; DISORDERS; SERVICES; ANXIETY; NEED; COMPETENCE; CHALLENGES C1 [Ng, Lauren C.; Magidson, Jessica F.; Hock, Rebecca S.; Galler, Janina R.; Safren, Steven A.; Borba, Christina P. C.; Fricchione, Gregory L.; Henderson, David C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Joska, John A.] Univ Cape Town, Cape Town, South Africa. [Fekadu, Abebaw; Hanlon, Charlotte] Univ Addis Ababa, Addis Ababa, Ethiopia. RP Ng, LC (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM lng4@mgh.harvard.edu OI Ng, Lauren/0000-0001-5988-008X FU National Institute of Mental Health [5T32MH093310, 5K24MH094214, 1K01MH100428] FX This manuscript was supported by grant numbers 5T32MH093310, 5K24MH094214, and 1K01MH100428 from the National Institute of Mental Health. NR 40 TC 1 Z9 1 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1042-9670 EI 1545-7230 J9 ACAD PSYCHIATR JI Acad. Psych. PD AUG PY 2016 VL 40 IS 4 BP 679 EP 685 DI 10.1007/s40596-016-0518-y PG 7 WC Education & Educational Research; Psychiatry SC Education & Educational Research; Psychiatry GA DR2BE UT WOS:000379709200023 PM 26976395 ER PT J AU Magidson, JF Stevenson, A Ng, LC Hock, RS Borba, CPC Namey, LB Carney, J Joska, JA Kagee, A Fekadu, A Bangsberg, DR Safren, SA Fricchione, GL Henderson, DC AF Magidson, Jessica F. Stevenson, Anne Ng, Lauren C. Hock, Rebecca S. Borba, Christina P. C. Namey, Leah Beth Carney, Julia Joska, John A. Kagee, Ashraf Fekadu, Abebaw Bangsberg, David R. Safren, Steven A. Fricchione, Gregory L. Henderson, David C. TI Massachusetts General Hospital Global Psychiatric Clinical Research Training Program: A New Fellowship in Global Mental Health SO ACADEMIC PSYCHIATRY LA English DT Editorial Material C1 [Magidson, Jessica F.; Ng, Lauren C.; Hock, Rebecca S.; Borba, Christina P. C.; Bangsberg, David R.; Fricchione, Gregory L.; Henderson, David C.] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. [Stevenson, Anne; Namey, Leah Beth; Carney, Julia] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Joska, John A.] Univ Cape Town, Cape Town, South Africa. [Kagee, Ashraf] Univ Stellenbosch, Stellenbosch, South Africa. [Fekadu, Abebaw] Univ Addis Ababa, Addis Ababa, Ethiopia. [Safren, Steven A.] Univ Miami, Miami, FL USA. RP Magidson, JF (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. EM jmagidson@mgh.harvard.edu FU NIH [T32MH093310]; [5K24MH094214]; [K01MH100428] FX We would like to acknowledge the NIH for funding the MGH fellowship (T32MH093310). SS' time mentoring for the fellowship is supported by 5K24MH094214. CB is supported by K01MH100428. We would like to acknowledge Shayna Schor for all of her organizational support of the fellowship. We would also like to acknowledge the MGH Center for Global Health and the Partners Center for Excellence (CoE) for providing additional travel support to the fellows. NR 4 TC 1 Z9 1 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1042-9670 EI 1545-7230 J9 ACAD PSYCHIATR JI Acad. Psych. PD AUG PY 2016 VL 40 IS 4 BP 695 EP 697 DI 10.1007/s40596-015-0388-8 PG 3 WC Education & Educational Research; Psychiatry SC Education & Educational Research; Psychiatry GA DR2BE UT WOS:000379709200026 PM 26108399 ER PT J AU Sweetland, AC Oquendo, MA Carlson, C Magidson, JF Wainberg, ML AF Sweetland, Annika C. Oquendo, Maria A. Carlson, Catherine Magidson, Jessica F. Wainberg, Milton L. TI Mental Health Research in the Global Era: Training the Next Generation SO ACADEMIC PSYCHIATRY LA English DT Article ID IMPLEMENTATION RESEARCH; HIV PREVENTION; LOW-INCOME; SCIENCE; INTERVENTIONS; DEPRESSION; SERVICES; GAP C1 [Sweetland, Annika C.; Oquendo, Maria A.; Carlson, Catherine; Wainberg, Milton L.] Columbia Univ, New York State Psychiat Inst, New York, NY USA. [Magidson, Jessica F.] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. RP Sweetland, AC (reprint author), Columbia Univ, New York State Psychiat Inst, New York, NY USA. EM acs2124@cumc.columbia.edu FU NIMH [T32 MH096724, T32 MH 093310]; [D43 TW009675] FX This manuscript was supported in part by NIMH T32 MH096724, NIMH T32 MH 093310, and D43 TW009675. NR 30 TC 1 Z9 1 U1 2 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1042-9670 EI 1545-7230 J9 ACAD PSYCHIATR JI Acad. Psych. PD AUG PY 2016 VL 40 IS 4 BP 715 EP 720 DI 10.1007/s40596-015-0437-3 PG 6 WC Education & Educational Research; Psychiatry SC Education & Educational Research; Psychiatry GA DR2BE UT WOS:000379709200031 PM 26497971 ER PT J AU Keane, FK D'Amico, AV AF Keane, Florence K. D'Amico, Anthony V. TI Androgen deprivation therapy use and risk of death in men treated with high-dose radiation for intermediate-risk prostate cancer SO CANCER LA English DT Editorial Material ID RADICAL PROSTATECTOMY; RANDOMIZED-TRIAL; CARDIOVASCULAR-DISEASE; RADIOTHERAPY; SUPPRESSION; METAANALYSIS C1 [Keane, Florence K.] Harvard Med Sch, Harvard Radiat Oncol Program, Boston, MA USA. [D'Amico, Anthony V.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [D'Amico, Anthony V.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. RP Keane, FK (reprint author), Massachusetts Gen Hosp, Harvard Radiat Oncol Program, 100 Blossom St,Cox 3, Boston, MA 02114 USA. EM fkeane@partners.org NR 20 TC 0 Z9 0 U1 3 U2 3 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 AUG 1 PY 2016 VL 122 IS 15 BP 2296 EP 2298 DI 10.1002/cncr.30048 PG 3 WC Oncology SC Oncology GA DR7CY UT WOS:000380058800004 PM 27191800 ER PT J AU Belani, CP Dahlberg, SE Rudin, CM Fleisher, M Chen, HX Takebe, N Velasco, MR Tester, WJ Sturtz, K Hann, CL Shanks, JC Monga, M Ramalingam, SS Schiller, JH AF Belani, Chandra P. Dahlberg, Suzanne E. Rudin, Charles M. Fleisher, Martin Chen, Helen X. Takebe, Naoko Velasco, Mario R. Tester, William J. Sturtz, Keren Hann, Christine L. Shanks, James C. Monga, Manish Ramalingam, Suresh S. Schiller, Joan H. TI Vismodegib or cixutumumab in combination with standard chemotherapy for patients with extensive-stage small cell lung cancer: A trial of the ECOG-ACRIN Cancer Research Group (E1508) SO CANCER LA English DT Article DE circulating tumor cell (CTC); cixutumumab; small cell lung cancer; extensive disease; vismodegib ID HEDGEHOG PATHWAY; INHIBITION; EFFICACY; GROWTH; SAFETY AB BACKGROUNDPreclinical targeting of the hedgehog pathway by vismodegib and of insulin-like growth factor 1 receptor by cixutumumab enhances the efficacy of chemotherapy and also demonstrates activity against the tumor cell fraction responsible for disease recurrence in small cell lung cancer. METHODSPatients with newly diagnosed extensive-stage small cell lung cancer (SCLC-ED) were randomized to receive four 21-day cycles of cisplatin and etoposide alone (cisplatin at 75 mg/m(2) on day 1 and etoposide at 100 mg/m(2) on days 1-3; arm A) or in combination with either vismodegib (150 mg/d by mouth; arm B) or cixutumumab (6 mg/kg/wk intravenously on day 1; arm C). The primary endpoint was progression-free survival (PFS). Circulating tumor cells (CTCs) were isolated/enumerated with the Veridex CellSearch platform at the baseline. RESULTSOne hundred fifty-two eligible patients were treated. Patient demographics and disease characteristics were well balanced between the 3 arms except for the higher rate with a performance status of 0 in arm B (P = .03). The median PFS times in arms A, B, and C were 4.4, 4.4, and 4.6 months, respectively; the median overall survival (OS) times were 8.8, 9.8, and 10.1 months, respectively; and the response rates were 48%, 56%, and 50%, respectively. None of the comparisons of these outcomes were statistically significant. The median OS was 10.5 months for those with low CTC counts (100/7.5 mL) at baseline and 7.2 months for those with high CTC counts (hazard ratio, 1.74; P = .006). CONCLUSIONSThere was no significant improvement in PFS or OS with the addition of either vismodegib or cixutumumab to chemotherapy in patients with SCLC-ED. A low baseline CTC count was associated with a favorable prognosis. Cancer 2016;122:2371-2378. (c) 2016 American Cancer Society. C1 [Belani, Chandra P.] Penn State Hershey Canc Inst, 500 Univ Dr,CH72, Hershey, PA 17033 USA. [Dahlberg, Suzanne E.] Dana Farber Canc Inst, ECOG ACRIN Biostat Ctr, Boston, MA 02115 USA. [Rudin, Charles M.; Fleisher, Martin; Hann, Christine L.] Johns Hopkins Univ, Baltimore, MD USA. [Fleisher, Martin] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Chen, Helen X.; Takebe, Naoko] NCI, Rockville, MD USA. [Velasco, Mario R.] Decatur Mem Hosp, Decatur, IL USA. [Tester, William J.] Albert Einstein Canc Ctr, Philadelphia, PA USA. [Sturtz, Keren] Colorado Canc Res Program, Denver, CO USA. [Shanks, James C.] HealthEast Canc Care, Maplewood, MN USA. [Monga, Manish] West Virginia Univ, Morgantown, WV USA. [Ramalingam, Suresh S.] Emory Univ, Atlanta, GA 30322 USA. [Schiller, Joan H.] Univ Texas Southwestern Med Ctr, Dallas, TX USA. RP Belani, CP (reprint author), Penn State Hershey Canc Inst, 500 Univ Dr,CH72, Hershey, PA 17033 USA. EM cbelani@psu.edu FU Public Health Service Grants from the National Cancer Institute (National Institutes of Health, Department of Health and Human Services) [CA180794, CA180820, CA180802, CA180791, CA189830, CA180790, CA189805, CA189863, CA180844, CA180864, CA180870] FX This study was coordinated by the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Research Group (Robert L. Comis, MD, and Mitchell D. Schnall, MD, PhD, group cochairs) and was supported in part by Public Health Service Grants CA180794, CA180820, CA180802, CA180791, CA189830, CA180790, CA189805, CA189863, CA180844, CA180864, and CA180870 from the National Cancer Institute (National Institutes of Health, Department of Health and Human Services). This article's content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute. NR 18 TC 4 Z9 4 U1 2 U2 2 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 AUG 1 PY 2016 VL 122 IS 15 BP 2371 EP 2378 DI 10.1002/cncr.30062 PG 8 WC Oncology SC Oncology GA DR7CY UT WOS:000380058800013 PM 27163943 ER PT J AU Fathi, AT DeAngelo, DJ Stevenson, KE Kolitz, JE Asch, JD Amrein, PC Attar, EC Steensma, DP Wadleigh, M Foster, J Connolly, C Galinsky, I Devoe, CE Stone, RM Neuberg, DS Ballen, KK AF Fathi, Amir T. DeAngelo, Daniel J. Stevenson, Kristen E. Kolitz, Jonathan E. Asch, Julie D. Amrein, Philip C. Attar, Eyal C. Steensma, David P. Wadleigh, Martha Foster, Julia Connolly, Christine Galinsky, Ilene Devoe, Craig E. Stone, Richard M. Neuberg, Donna S. Ballen, Karen K. TI Phase 2 study of intensified chemotherapy and allogeneic hematopoietic stem cell transplantation for older patients with acute lymphoblastic leukemia SO CANCER LA English DT Article DE acute lymphoblastic leukemia; chemotherapy; older adults; Philadelphia chromosome; stem cell transplant ID ACUTE MYELOID-LEUKEMIA; 1ST COMPLETE REMISSION; PEDIATRIC-PATIENTS; ADULT PATIENTS; REDUCED-INTENSITY; ELDERLY-PATIENTS; ONCOLOGY-GROUP; YOUNG-ADULTS; B-PRECURSOR; CLOFARABINE AB BACKGROUNDOutcomes among older patients with acute lymphoblastic leukemia remain poor. This study sought to determine the efficacy of an intensified, multi-agent approach derived from a Dana-Farber consortium trial in younger adults for patients older than 50 years (trial identifier NCT00973752). METHODSThe primary endpoint was overall survival (OS) at 1 year. Patients received induction chemotherapy with vincristine, prednisone, doxorubicin, and pegylated asparaginase. Imatinib was incorporated for Philadelphia chromosome-positive disease. After induction, the first consolidation incorporated clofarabine. Patients in remission could proceed to allogeneic hematopoietic cell transplantation (HCT) after induction and consolidation I. Those not receiving HCT went on to receive central nervous system, consolidation II, and continuation phases of treatment. RESULTSThirty patients were enrolled: 19 achieved a complete remission (CR) after induction and 1 achieved CR after consolidation I for a CR rate of 67%. Sixteen patients underwent HCT. The proportion surviving at 1 year was 63%, and this met the primary endpoint. The 2-year OS rate was 52% (n = 30), and the 2-year disease-free survival rate was 52% for patients achieving CR (n = 20). There was no survival advantage among those undergoing HCT. Therapy-related hyperbilirubinemia prompted adjustments and limitations to asparaginase dosing. CONCLUSIONSIntensified chemotherapy can result in improved outcomes in comparison with historical data. Additional studies of similarly intensive regimens are warranted in this population. Cancer 2016;122:2379-2388. (c) 2016 American Cancer Society. C1 [Fathi, Amir T.; Amrein, Philip C.; Attar, Eyal C.; Foster, Julia; Connolly, Christine; Ballen, Karen K.] Massachusetts Gen Hosp, Ctr Canc, Zero Emerson Pl,Suite 118, Boston, MA 02114 USA. [DeAngelo, Daniel J.; Stevenson, Kristen E.; Steensma, David P.; Wadleigh, Martha; Galinsky, Ilene; Stone, Richard M.; Neuberg, Donna S.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Kolitz, Jonathan E.; Devoe, Craig E.] North Shore Long Isl Jewish Hlth Syst, Monter Canc Ctr, Lake Success, NY USA. [Asch, Julie D.] Latter Day St Hosp, Salt Lake City, UT USA. RP Ballen, KK (reprint author), Massachusetts Gen Hosp, Ctr Canc, Zero Emerson Pl,Suite 118, Boston, MA 02114 USA. EM kballen@partners.org FU Genzyme (Sanofi); Sigma Tau Pharmaceuticals (Enzon) FX This study received funding from by Genzyme (Sanofi), which also provided clofarabine, and from Sigma Tau Pharmaceuticals (Enzon). NR 44 TC 0 Z9 0 U1 3 U2 3 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 AUG 1 PY 2016 VL 122 IS 15 BP 2379 EP 2388 DI 10.1002/cncr.30037 PG 10 WC Oncology SC Oncology GA DR7CY UT WOS:000380058800014 PM 27171984 ER PT J AU McKay, RR De Velasco, G Werner, L Bellmunt, J Harshman, L Sweeney, C Rosenberg, JE Hirsch, M Signoretti, S Van Allen, EM Walsh, M Vaishampayan, U McDermott, DF Choueiri, TK AF McKay, Rana R. De Velasco, Guillermo Werner, Lillian Bellmunt, Joaquim Harshman, Lauren Sweeney, Christopher Rosenberg, Jonathan E. Hirsch, Michelle Signoretti, Sabina Van Allen, Eliezer M. Walsh, Meghara Vaishampayan, Ulka McDermott, David F. Choueiri, Toni K. TI A phase 1 study of buparlisib and bevacizumab in patients with metastatic renal cell carcinoma progressing on vascular endothelial growth factor-targeted therapies SO CANCER LA English DT Article DE bevacizumab; buparlisib; phase 1; phosphatidylinositol-3 kinase (PI3K) inhibitor; renal cell carcinoma ID CLINICAL TUMOR SAMPLES; ADVANCED SOLID TUMORS; KINASE INHIBITORS; SIGNALING PATHWAY; DOSE-ESCALATION; DOUBLE-BLIND; III TRIAL; CANCER; SUNITINIB; TEMSIROLIMUS AB BACKGROUNDThe phosphatidylinositol-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is dysregulated in patients with metastatic renal cell carcinoma (mRCC). Buparlisib is a pan-PI3K inhibitor with activity in advanced solid tumors. The primary objective of the current study was to determine the maximum tolerated dose (MTD) and dose-limiting toxicities of buparlisib and bevacizumab in patients with mRCC. Secondary objectives included efficacy, biomarker discovery, and additional toxicity. METHODSThis was a standard 3 + 3 dose escalation study of buparlisib (at a dose of 60-100 mg/day) and bevacizumab (at a dose of 10 mg/kg every 2 weeks). After the MTD was defined, 15 patients were accrued to the expansion cohort. RESULTSThirty-two patients were accrued (3 were treated at 60 mg/day, 21 were treated at 80 mg/day, 6 were treated at 100 mg/day, and 2 patients never received therapy). The majority of patients had clear cell histology (87%) and 50% had received 2 prior lines of therapy. The MTD of buparlisib was 80 mg/day and that of bevacizumab was 10 mg/kg every 2 weeks. A total of 28 patients discontinued therapy: 17 because of disease progression, 7 because of toxicity, and 4 for other reasons. Dose-limiting toxicities included rash/pruritis, elevated lipase/amylase, anorexia, and psychiatric disorders (suicidal ideation, depression, and cognitive disturbances). Of the 30 patients who received at least 1 dose, 13% achieved a partial response (95% confidence interval, 4%-31%). Two patients harboring activating PI3KA mutations achieved 42% and 16% maximal tumor shrinkage, respectively. CONCLUSIONSBuparlisib at a dose of 80 mg/day with bevacizumab was found to be a tolerable regimen with preliminary activity in vascular endothelial growth factor-refractory mRCC. The benefit of this combination may be of interest for future mRCC trials, possibly in a selected patient population. Cancer 2016;122:2389-2398. (c) 2016 American Cancer Society. The phosphatidylinositol-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is dysregulated in patients with metastatic renal cell carcinoma (mRCC), and targeting this pathway, in addition to the vascular endothelial growth factor (VEGF) pathway, is a potential therapeutic strategy in the management of RCC. Buparlisib at a dose of 80 mg/day with bevacizumab appears to be a tolerable regimen with preliminary activity in patients with vascular endothelial growth factor-refractory mRCC. C1 [McKay, Rana R.; De Velasco, Guillermo; Bellmunt, Joaquim; Harshman, Lauren; Sweeney, Christopher; Van Allen, Eliezer M.; Walsh, Meghara; Choueiri, Toni K.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Werner, Lillian] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Rosenberg, Jonathan E.] Mem Sloan Kettering Canc Ctr, Deparment Med Oncol, 1275 York Ave, New York, NY 10021 USA. [Hirsch, Michelle; Signoretti, Sabina] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Vaishampayan, Ulka] Wayne State Univ, Karmanos Canc Inst, Dept Hematol Oncol, Detroit, MI USA. [McDermott, David F.] Beth Israel Deaconess Med Ctr, Dept Med Oncol, Boston, MA 02215 USA. RP Choueiri, TK (reprint author), Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM toni_choueiri@dfci.harvard.edu FU Novartis; Dana-Farber/Harvard Cancer Center Kidney SPORE; Trust Family; Loker Pinard Funds for Kidney Cancer Research at Dana-Farber Cancer Institute FX Funded in part by Novartis. In addition, this research was funded in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE (to David F. McDermott and Toni K. Choueiri) and the Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at Dana-Farber Cancer Institute (to Toni K. Choueiri). NR 44 TC 3 Z9 3 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 AUG 1 PY 2016 VL 122 IS 15 BP 2389 EP 2398 DI 10.1002/cncr.30056 PG 10 WC Oncology SC Oncology GA DR7CY UT WOS:000380058800015 PM 27198170 ER PT J AU Budczies, J Bockmayr, M Denkert, C Klauschen, F Groschel, S Darb-Esfahani, S Pfarr, N Leichsenring, J Onozato, ML Lennerz, JK Dietel, M Frohling, S Schirmacher, P Iafrate, AJ Weichert, W Stenzinger, A AF Budczies, Jan Bockmayr, Michael Denkert, Carsten Klauschen, Frederick Groeschel, Stefan Darb-Esfahani, Silvia Pfarr, Nicole Leichsenring, Jonas Onozato, Maristela L. Lennerz, Jochen K. Dietel, Manfred Froehling, Stefan Schirmacher, Peter Iafrate, A. John Weichert, Wilko Stenzinger, Albrecht TI Pan-Cancer Analysis of Copy Number Changes in Programmed Death-Ligand 1 (PD-L1, CD274) - Associations with Gene Expression, Mutational Load, and Survival SO GENES CHROMOSOMES & CANCER LA English DT Article ID CELL LUNG-CANCER; BREAST-CANCER; ADVANCED MELANOMA; NEXT-GENERATION; IMMUNOTHERAPY; AMPLIFICATION; JAK2; ADENOCARCINOMA; INTERLEUKIN-2; COMBINATIONS AB Inhibition of the PD-L1 (CD274) - PD-1 axis has emerged as a powerful cancer therapy that prevents evasion of tumor cells from the immune system. While immunohistochemical detection of PD-L1 was introduced as a predictive biomarker with variable power, much less is known about copy number alterations (CNA) affecting PD-L1 and their associations with expression levels, mutational load, and survival. To gain insight, we employed The Cancer Genome Atlas (TCGA) datasets to comprehensively analyze 22 major cancer types for PD-L1 CNAs. We observed a diverse landscape of PD-L1 CNAs, which affected focal regions, chromosome 9p or the entire chromosome 9. Deletions of PD-L1 were more frequent than gains (31% vs. 12%) with deletions being most prevalent in melanoma and non-small cell lung cancer. Copy number gains most frequently occurred in ovarian cancer, head and neck cancer, bladder cancer, cervical and endocervical cancer, sarcomas, and colorectal cancers. Fine-mapping of the genetic architecture revealed specific recurrently amplified and deleted core regions across cancers with putative biological and clinical consequences. PD-L1 CNAs correlated significantly with PD-L1 mRNA expression changes in many cancer types, and tumors with PD-L1 gains harbored significantly higher mutational load compared to non-amplified cases (median: 78 non-synonymous mutations vs. 40, P = 7.1e-69). Moreover, we observed that, in general, both PD-L1 amplifications and deletions were associated with dismal prognosis. In conclusion, PD-L1 CNAs, in particular PD-L1 copy number gains, represent frequent genetic alterations across many cancers, which influence PD-L1 expression levels, are associated with higher mutational loads, and may be exploitable as predictive biomarker for immunotherapy regimens. (C) 2016 Wiley Periodicals, Inc. C1 [Budczies, Jan; Bockmayr, Michael; Denkert, Carsten; Klauschen, Frederick; Darb-Esfahani, Silvia; Dietel, Manfred] Charite, Inst Pathol, Berlin, Germany. [Budczies, Jan; Denkert, Carsten; Groeschel, Stefan; Dietel, Manfred; Froehling, Stefan; Schirmacher, Peter; Weichert, Wilko] German Canc Consortium DKTK, Dresden, Germany. [Groeschel, Stefan; Froehling, Stefan] Natl Ctr Tumor Dis NCT Heidelberg, Dept Translat Oncol, Heidelberg, Germany. [Groeschel, Stefan; Froehling, Stefan] German Canc Res Ctr, Heidelberg, Germany. [Groeschel, Stefan; Froehling, Stefan] Univ Heidelberg Hosp, Sect Personalized Oncol, Heidelberg, Germany. [Pfarr, Nicole] Tech Univ Munich, Inst Pathol, Munich, Germany. [Leichsenring, Jonas; Schirmacher, Peter; Stenzinger, Albrecht] Univ Heidelberg Hosp, Inst Pathol, Heidelberg, Germany. [Onozato, Maristela L.; Lennerz, Jochen K.; Iafrate, A. John; Weichert, Wilko; Stenzinger, Albrecht] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Integrated Diagnost, Dept Pathol, Cambridge, MA USA. [Stenzinger, Albrecht] Natl Ctr Tumor Dis NCT, Heidelberg, Germany. RP Budczies, J (reprint author), Inst Pathol, Charitepl 1, D-10117 Berlin, Germany.; Stenzinger, A (reprint author), Inst Pathol, Neuenheimer Feld 224, D-69120 Heidelberg, Germany. EM jan.budczies@charite.de; albrecht.stenzinger@med.uni-heidelberg.de FU German Cancer Consortium (DKTK); NCT-Heidelberg School of Oncology (HSO) FX Supported by: The German Cancer Consortium (DKTK) and the NCT-Heidelberg School of Oncology (HSO). NR 60 TC 7 Z9 7 U1 7 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1045-2257 EI 1098-2264 J9 GENE CHROMOSOME CANC JI Gene Chromosomes Cancer PD AUG PY 2016 VL 55 IS 8 BP 626 EP 639 DI 10.1002/gcc.22365 PG 14 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA DR5PI UT WOS:000379954500002 PM 27106868 ER PT J AU Niimi, A Yamauchi, M Limsirichaikul, S Sekine, R Oike, T Sato, H Suzuki, K Held, KD Nakano, T Shibata, A AF Niimi, Atsuko Yamauchi, Motohiro Limsirichaikul, Siripan Sekine, Ryota Oike, Takahiro Sato, Hiro Suzuki, Keiji Held, Kathryn D. Nakano, Takashi Shibata, Atsushi TI Identification of DNA Double Strand Breaks at Chromosome Boundaries Along the Track of Particle Irradiation SO GENES CHROMOSOMES & CANCER LA English DT Article ID END-RESECTION; HUMAN-CELLS; HOMOLOGOUS RECOMBINATION; MAMMALIAN-CELLS; REPAIR; TRANSLOCATIONS; PATHWAY; RADIATION; DAMAGE; ATM AB Chromosomal translocations arise from misrejoining of DNA double strand breaks (DSBs) between loci located on two chromosomes. One current model suggests that spatial proximity of potential chromosomal translocation partners influences translocation probability. Ionizing radiation (IR) is a potent inducer of translocations. Accumulating evidence demonstrates that particle irradiation more frequently causes translocations compared with X-ray irradiation. This observation has led to the hypothesis that the high frequency of translocations after particle irradiation may be due to the formation of DSBs at chromosome boundaries along the particle track, because such DSBs can be misrejoined between distinct chromosomes. In this study, we simultaneously visualized the site of IR-induced DSBs and chromosome position by combining Immunofluorescence and fluorescence in situ hybridization. Importantly, the frequency of gamma H2AX foci at the chromosome boundary of chromosome 1 after carbon-ion irradiation was >4-fold higher than that after X-ray irradiation. This observation is consistent with the idea that particle irradiation generates DSBs at the boundaries of two chromosomes along the track. Further, we showed that resolution of gamma H2AX foci at chromosome boundaries is prevented by inhibition of DNA-PKcs activity, indicating that the DSB repair is NHEJ-dependent. Finally, we found that gamma H2AX foci at chromosome boundaries after carbon-ion irradiation contain DSBs undergoing DNA-end resection, which promotes repair utilizing microhomology mediated end-joining during translocation. Taken together, our study suggests that the frequency of DSB formation at chromosome boundaries is associated with the incidence of chromosomal translocations, supporting the notion that the spatial proximity between breaks is an important factor in translocation formation. (C) 2016 Wiley Periodicals, Inc. C1 [Niimi, Atsuko; Nakano, Takashi] Gunma Univ, Initiat Adv Res GIAR, Div Integrated Oncol Res, Res Program Heavy IonTherapy, Gunma, Japan. [Yamauchi, Motohiro] Nagasaki Univ, Atom Bomb Dis Inst, Div Radiat Biol & Protect, Nagasaki, Japan. [Limsirichaikul, Siripan] Silpakorn Univ, Fac Pharm, Nakhon Pathom, Thailand. [Sekine, Ryota; Shibata, Atsushi] Gunma Univ, Adv Sci Res Leaders Dev Unit, Gunma, Japan. [Oike, Takahiro; Sato, Hiro; Nakano, Takashi] Gunma Univ, Dept Radiat Oncol, Gunma, Japan. [Suzuki, Keiji] Nagasaki Univ, Atom Bomb Dis Inst, Dept Radiat Med Sci, Nagasaki, Japan. [Held, Kathryn D.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA USA. [Held, Kathryn D.] Gunma Univ, Initiat Adv Res GIAR, Int Open Lab, Gunma, Japan. RP Shibata, A (reprint author), 3-39-22 Showa Machi, Maebashi, Gunma 3718511, Japan. EM shibata.at@gunma-u.ac.jp FU JSPS KAKENHI [26701005, 26670549, 15H02816, 15K15447]; Takeda Science Foundation; Uehara Memorial Foundation; Suzuken Memorial Foundation; Cooperative Research Grant of the Atomic Bomb Disease Institute at Nagasaki University, Nagasaki, Japan FX Supported by: JSPS KAKENHI, Grant numbers: 26701005, 26670549, 15H02816, 15K15447, the Takeda Science Foundation, the Uehara Memorial Foundation, the Suzuken Memorial Foundation, and the 2015 Cooperative Research Grant of the Atomic Bomb Disease Institute at Nagasaki University, Nagasaki, Japan. NR 36 TC 1 Z9 1 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1045-2257 EI 1098-2264 J9 GENE CHROMOSOME CANC JI Gene Chromosomes Cancer PD AUG PY 2016 VL 55 IS 8 BP 650 EP 660 DI 10.1002/gcc.22367 PG 11 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA DR5PI UT WOS:000379954500004 PM 27113385 ER PT J AU Barry, CL Epstein, AJ Fiellin, DA Fraenkel, L Busch, SH AF Barry, Colleen L. Epstein, Andrew J. Fiellin, David A. Fraenkel, Liana Busch, Susan H. TI Estimating demand for primary care-based treatment for substance and alcohol use disorders SO ADDICTION LA English DT Article DE Alcohol use disorders; collaborative care; economics; financing; primary care; substance use disorders ID LATE-LIFE DEPRESSION; COLLABORATIVE CARE; COST-EFFECTIVENESS; BRIEF INTERVENTION; RANDOMIZED-TRIAL; DRUG-USE; DRINKING; MANAGEMENT; HEALTH; METAANALYSIS AB Background and AimsWhile there is broad recognition of the high societal costs of substance use disorders (SUD), treatment rates are low. We examined whether, in the United States, participants with substance or alcohol use disorder would report a greater willingness to enter SUD treatment located in a primary care setting (primary care) or more commonly found specialty care setting in the United States (usual care). DesignRandomized survey-embedded experiment. SettingUS web-based research panel in which participants were randomized to read one-paragraph vignettes describing treatment in usual care (specialty drug or alcohol treatment center), primary care or collaborative care within a primary care setting. ParticipantsA total of 42451 panelists aged 18+ were screened for substance or alcohol use disorder using validated diagnostic criteria. Participants included 344 with a substance use disorder and 634 with an alcohol use disorder not in treatment with no prior treatment history. MeasuresWillingness to enter treatment across vignettes by condition. FindingsAmong participants with a substance use disorder, 24.6% of those randomized to usual care reported being willing to enter drug treatment compared with 37.2% for primary care [12.6 percentage point difference; 95% confidence interval (CI)=0.8, 24.4) and 34.0% for collaborative care (9.4 percentage point difference; 95% CI=-2.0, 20.8). Among participants with an alcohol use disorder, 17.6% of those randomized to usual care reported being willing to enter alcohol treatment compared with 20.3% for primary care (2.6 percentage point difference; 95% CI=-4.9, 10.1) and 20.8% for collaborative care (3.1 percentage point difference; 95% CI=-4.3, 10.6). The most common reason for not being willing to enter drug (63%) and alcohol (78%) treatment was the belief that treatment was not needed. ConclusionsIn the United States, people diagnosed with substance or alcohol use disorders appear to be more willing to enter treatment in a primary care setting than in a specialty drug treatment center. Expanding availability of primary care-based substance use disorder treatment could increase treatment rates in the United States. C1 [Barry, Colleen L.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Policy & Management, 624 North Broadway,Hampton House 403, Baltimore, MD 21205 USA. [Barry, Colleen L.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD USA. [Barry, Colleen L.; Epstein, Andrew J.] Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. [Epstein, Andrew J.] Univ Penn, Dept Med, Perelman Sch Med, Div Gen Internal Med, Philadelphia, PA 19104 USA. [Epstein, Andrew J.] Philadelphia Vet Affairs Med Ctr, Dept Vet Affairs, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Fiellin, David A.; Fraenkel, Liana] Yale Sch Med, Dept Gen Internal Med, New Haven, CT USA. [Fiellin, David A.; Busch, Susan H.] Yale Sch Publ Hlth, Dept Hlth Policy & Management, New Haven, CT USA. [Fraenkel, Liana] VA Connecticut Healthcare Syst, West Haven, CT USA. RP Barry, CL (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Policy & Management, 624 North Broadway,Hampton House 403, Baltimore, MD 21205 USA. EM cbarry@jhu.edu OI Fiellin, David/0000-0002-4006-010X FU National Institute on Drug Abuse [R01DA026414] FX The authors gratefully acknowledge funding from the National Institute on Drug Abuse (R01DA026414). NR 43 TC 1 Z9 1 U1 4 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0965-2140 EI 1360-0443 J9 ADDICTION JI Addiction PD AUG PY 2016 VL 111 IS 8 BP 1376 EP 1384 DI 10.1111/add.13364 PG 9 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA DR5NE UT WOS:000379948900012 PM 26899802 ER PT J AU Ling, W Hillhouse, MP Saxon, AJ Mooney, LJ Thomas, CM Ang, A Matthews, AG Hasson, A Annon, J Sparenborg, S Liu, DS McCormack, J Church, S Swafford, W Drexler, K Schuman, C Ross, S Wiest, K Korthuis, PT Lawson, W Brigham, GS Knox, PC Dawes, M Rotrosen, J AF Ling, Walter Hillhouse, Maureen P. Saxon, Andrew J. Mooney, Larissa J. Thomas, Christie M. Ang, Alfonso Matthews, Abigail G. Hasson, Albert Annon, Jeffrey Sparenborg, Steve Liu, David S. McCormack, Jennifer Church, Sarah Swafford, William Drexler, Karen Schuman, Carolyn Ross, Stephen Wiest, Katharina Korthuis, P. Todd Lawson, William Brigham, Gregory S. Knox, Patricia C. Dawes, Michael Rotrosen, John TI Buprenorphine plus naloxone plus naltrexone for the treatment of cocaine dependence: the Cocaine Use Reduction with Buprenorphine (CURB) study SO ADDICTION LA English DT Article DE Buprenorphine plus naloxone; cocaine use disorder; double-blind; multi-site trial; naltrexone; pharmacotherapy; placebo-controlled; treatment ID ABUSE CLINICAL-TRIALS; OPIOID DEPENDENCE; RANDOMIZED-TRIAL; ADDICTION; ANTAGONIST; MODULATION; METHADONE; MODELS AB AimsTo examine the safety and effectiveness of buprenorphine+naloxone sublingual tablets (BUP, as Suboxone((R))) provided after administration of extended-release injectable naltrexone (XR-NTX, as Vivitrol((R))) to reduce cocaine use in participants who met DSM-IV criteria for cocaine dependence and past or current opioid dependence or abuse. MethodsThis multi-centered, double-blind, placebo-controlled study, conducted under the auspices of the National Drug Abuse Treatment Clinical Trials Network, randomly assigned 302 participants at sites in California, Oregon, Washington, Colorado, Texas, Georgia, Ohio, New York and Washington DC, USA to one of three conditions provided with XR-NTX: 4mg/day BUP (BUP4, n=100), 16mg/day BUP (BUP16, n=100, or no buprenorphine (placebo; PLB, n=102). Participants received pharmacotherapy for 8weeks, with three clinic visits per week. Cognitive behavioral therapy was provided weekly. Follow-up assessments occurred at 1 and 3months post-intervention. The planned primary outcome was urine drug screen (UDS)-corrected, self-reported cocaine use during the last 4weeks of treatment. Planned secondary analyses assessed cocaine use by UDS, medication adherence, retention and adverse events. ResultsNo group differences were found between groups for the primary outcome (BUP4 versus PLB, P=0.262; BUP16 versus PLB, P=0.185). Longitudinal analysis of UDS data during the evaluation period using generalized linear mixed equations found a statistically significant difference between BUP16 and PLB [P=0.022, odds ratio (OR)=1.71] but not for BUP4 (P=0.105, OR=1.05). No secondary outcome differences across groups were found for adherence, retention or adverse events. ConclusionsBuprenorphine+naloxone, used in combination with naltrexone, may be associated with reductions in cocaine use among people who meet DSM-IV criteria for cocaine dependence and past or current opioid dependence or abuse. C1 [Ling, Walter; Hillhouse, Maureen P.; Mooney, Larissa J.; Thomas, Christie M.; Ang, Alfonso; Hasson, Albert; Annon, Jeffrey] Univ Calif Los Angeles, Los Angeles, CA USA. [Saxon, Andrew J.] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. [Sparenborg, Steve; Liu, David S.] NIDA, Bethesda, MD 20892 USA. [Matthews, Abigail G.; McCormack, Jennifer] Emmes Corp, Rockville, MD USA. [Church, Sarah] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Swafford, William] ARTS, Denver, CO USA. [Drexler, Karen] Atlanta VA Med Ctr, Atlanta, GA USA. [Schuman, Carolyn] BAART Programs, San Francisco, CA USA. [Ross, Stephen] Bellevue Hosp Ctr, New York, NY 10016 USA. [Wiest, Katharina] CODA, Portlad, OR USA. [Korthuis, P. Todd] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Lawson, William] Howard Univ, Washington, DC 20059 USA. [Brigham, Gregory S.] Maryhaven Treatment Ctr, Columbus, OH USA. [Knox, Patricia C.] RCKC, Kent, WA USA. [Dawes, Michael] South Texas Vet Hlth Care Syst, San Antonio, TX USA. [Rotrosen, John] NYU, Sch Med, New York, NY USA. RP Ling, W (reprint author), UCLA Integrated Subst Abuse Programs, 1640 South Sepulveda Blvd,Suite 120, Los Angeles, CA 90025 USA. EM lwalter@ucla.edu FU National Institute on Drug Abuse [DA13045, DA13035, DA13046, DA015815, HHSN271200900034C / N01DA-92217, HHSN271201200017C / N01DA-12-2229, HHSN271201400028C / N01DA-14-2237]; Reckitt Benckiser Pharmaceuticals; Alkermes Pharmaceuticals FX Support provided through the National Institute on Drug Abuse (DA13045; DA13035; DA13046, DA015815, HHSN271200900034C / N01DA-92217, HHSN271201200017C / N01DA-12-2229, HHSN271201400028C / N01DA-14-2237); Reckitt Benckiser Pharmaceuticals, Alkermes Pharmaceuticals. NR 27 TC 1 Z9 1 U1 5 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0965-2140 EI 1360-0443 J9 ADDICTION JI Addiction PD AUG PY 2016 VL 111 IS 8 BP 1416 EP 1427 DI 10.1111/add.13375 PG 12 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA DR5NE UT WOS:000379948900017 PM 26948856 ER PT J AU Schuster, RM Mermelstein, RJ Hedeker, D AF Schuster, Randi Melissa Mermelstein, Robin J. Hedeker, Donald TI Ecological momentary assessment of working memory under conditions of simultaneous marijuana and tobacco use SO ADDICTION LA English DT Article DE Alcohol; cannabis; ecological momentary assessment; tobacco; working memory; young adults ID NICOTINE-SEEKING BEHAVIOR; CB1 RECEPTOR ANTAGONIST; ASSESSMENT EMA DATA; ACETYLCHOLINE-RELEASE; ALCOHOL-INTOXICATION; CIGARETTE-SMOKING; COGNITIVE CONTROL; CANNABIS USERS; TURNOVER RATE; RATS AB Background and aimsThe neuropsychological correlates of simultaneous marijuana and tobacco use are largely unknown, which is surprising as both substances have similar neural substrates and have opposing influences on working memory (WM). This study examined the effects of marijuana alone, tobacco alone and simultaneous marijuana and tobacco use on WM. DesignPrimary aims were tested using a within-subject design, controlling for multiple subject- and momentary-level confounds via ecological momentary assessment (EMA). SettingData collection occurred in the Chicago, USA area in participants' natural environments. ParticipantsParticipants were 287 community young adults from a larger natural history study, oversampled for ever smoking, all of whom event-recorded at least one substance use occasion during the study week. MeasurementsMomentary tobacco, marijuana and alcohol use were recorded during multiple EMA across 1 week of data capture. WM was assessed at the end of each EMA assessment. Contextual variables that may influence WM were recorded via EMA. FindingsThere were main effects for marijuana and tobacco: WM was poorer with marijuana [odds ratio (OR)=0.91, 95% confidence interval (CI)=0.84-0.99] and better with tobacco (OR=1.11, 95% CI=1.04-1.18). These effects were not qualified by an interaction (OR=1.03, 95% CI=0.84-1.26). Alcohol also reduced WM (OR=0.87, 95% CI=0.79-0.95), and the tobaccoxalcohol interaction was significant (OR=0.81, 95% CI=0.66-0.99), indicating that the facilitative effect of tobacco disappeared with concurrent alcohol use. ConclusionsRelative to when individuals did not use these substances, working memory decreased with acute marijuana and alcohol use and increased with acute tobacco use. However, the putative effect of marijuana on working memory and the facilitative effect of tobacco on working memory were no longer present when used simultaneously with tobacco and alcohol, respectively. Data suggest that tobacco use may compensate for working memory decrements from marijuana among young adults and highlight the importance of investigating further the negative impact of alcohol use on cognition. C1 [Schuster, Randi Melissa] Massachusetts Gen Hosp, Dept Psychiat, Ctr Addict Med, 60 Stanford St, Boston, MA 02114 USA. [Schuster, Randi Melissa] Harvard Med Sch, Boston, MA USA. [Mermelstein, Robin J.] Univ Illinois, Dept Psychol, Chicago, IL 60680 USA. [Mermelstein, Robin J.] Inst Hlth Res & Policy, Chicago, IL USA. [Hedeker, Donald] Univ Chicago, Dept Publ Hlth Sci, Chicago, IL 60637 USA. RP Schuster, RM (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Ctr Addict Med, 60 Stanford St, Boston, MA 02114 USA. EM rschuster@mgh.harvard.edu FU National Cancer Institute of the National Institutes of Health [5P01CA098262]; Massachusetts General Hospital; Harvard Medical School FX This research was supported by the National Cancer Institute of the National Institutes of Health under award number 5P01CA098262 (Principle Investigator: R.J.M.), as well as the following fellowships from Massachusetts General Hospital and Harvard Medical School (Principle Investigator: R.M.S.): Norman E. Zinberg Fellowship in Addiction Psychiatry, Livingston Fellowship and Louis V. Gerstner III Research Scholar Award. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of NCI, the National Institutes of Health, Massachusetts General Hospital or Harvard Medical School. We thank Dr Kathi Diviak and John O'Keefe for their work recruiting and maintaining study participants. NR 89 TC 2 Z9 2 U1 12 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0965-2140 EI 1360-0443 J9 ADDICTION JI Addiction PD AUG PY 2016 VL 111 IS 8 BP 1466 EP 1476 DI 10.1111/add.13342 PG 11 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA DR5NE UT WOS:000379948900023 PM 26857917 ER PT J AU Uebelacker, LA Weisberg, RB Herman, DS Bailey, GL Pinkston-Camp, MM Garnaat, SL Stein, MD AF Uebelacker, Lisa A. Weisberg, Risa B. Herman, Debra S. Bailey, Genie L. Pinkston-Camp, Megan M. Garnaat, Sarah L. Stein, Michael D. TI Pilot Randomized Trial of Collaborative Behavioral Treatment for Chronic Pain and Depression in Persons Living with HIV/AIDS SO AIDS AND BEHAVIOR LA English DT Article DE HIV/AIDS; Chronic pain; Depression; Behavioral medicine ID THERAPY AB In this pilot study, we assessed feasibility and acceptability of a behavior therapy intervention for pain and depressive symptoms in persons living with HIV/AIDS (PLWH). We randomly assigned 23 participants to HIV-PASS (HIV-Pain and Sadness Study) or a health education control arm for 3 months. On average, participants attended more than 5 sessions (of 7 possible) in both arms. Qualitative data suggest HIV-PASS participants understood key messages and made concrete behavioral changes. HIV-PASS was associated with effects in the expected direction for three of four outcomes, including the primary outcome (pain-related interference with functioning). Findings suggest that HIV-PASS is promising. C1 [Uebelacker, Lisa A.; Herman, Debra S.; Garnaat, Sarah L.] Butler Hosp, 345 Blackstone Blvd, Providence, RI 02906 USA. [Uebelacker, Lisa A.; Weisberg, Risa B.; Herman, Debra S.; Bailey, Genie L.; Pinkston-Camp, Megan M.; Garnaat, Sarah L.; Stein, Michael D.] Brown Univ, Alpert Med Sch, Providence, RI 02912 USA. [Weisberg, Risa B.] Boston VA Healthcare Syst, Boston, MA USA. [Bailey, Genie L.] Stanley St Treatment & Resources, Fall River, MA USA. [Pinkston-Camp, Megan M.; Stein, Michael D.] Miriam Hosp, Providence, RI 02906 USA. RP Uebelacker, LA (reprint author), Butler Hosp, 345 Blackstone Blvd, Providence, RI 02906 USA.; Uebelacker, LA (reprint author), Brown Univ, Alpert Med Sch, Providence, RI 02912 USA. EM luebelacker@butler.org FU National Institute of Nursing Research of the National Institutes of Health [R21NR013438] FX Research reported in this publication was supported by the National Institute of Nursing Research of the National Institutes of Health under Award Number R21NR013438 to Drs. Uebelacker and Stein. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 13 TC 0 Z9 0 U1 1 U2 3 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 EI 1573-3254 J9 AIDS BEHAV JI AIDS Behav. PD AUG PY 2016 VL 20 IS 8 BP 1675 EP 1681 DI 10.1007/s10461-016-1397-7 PG 7 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA DR2OD UT WOS:000379742900010 PM 27115400 ER PT J AU Nguyen, LH Hoang, J Nguyen, NH Vu, VD Wang, C Trinh, HN Li, J Zhang, JQ Nguyen, MH AF Nguyen, L. H. Hoang, J. Nguyen, N. H. Vu, V. D. Wang, C. Trinh, H. N. Li, J. Zhang, J. Q. Nguyen, M. H. TI Ethnic differences in incidence of hepatitis B surface antigen seroclearance in a real-life multicenter clinical cohort of 4737 patients with chronic hepatitis B infection SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article ID TERM-FOLLOW-UP; POSITIVE CHRONIC HEPATITIS; ALANINE AMINOTRANSFERASE LEVELS; LONG-TERM; HBSAG SEROCLEARANCE; HEPATOCELLULAR-CARCINOMA; ADEFOVIR DIPIVOXIL; NATURAL-HISTORY; VIRUS-INFECTION; PEGINTERFERON ALPHA-2B AB BackgroundHepatitis B surface antigen (HBsAg) positivity is associated with increased risk for cirrhosis and hepatocellular carcinoma (HCC). HBsAg seroclearance is thought to be rare in general, but cohort data from US patients are limited. AimTo determine the incidence of HBsAg seroclearance in a real-life US cohort. MethodsIn total, 4737 patients with chronic hepatitis B from five primary care, gastroenterology and multispecialty centres, and a university medical centre were retrospectively enrolled between 2001 and 2014 with data obtained by manual review of individual patient medical records. Seroclearance was determined by loss of HBsAg seropositivity. Persistent HBsAg was confirmed by direct serology or by proxy with positive hepatitis B e-antigen (HBeAg) or HBV DNA levels. ResultsHBsAg seroclearance occurred in 52 patients over 16 844 person-years (0.31% annually, 1.2% overall). Median follow-up was 32 months, and mean age 45 14 years. Incidence of HBsAg seroclearance was higher in non-Asians, age >45, males, and those with baseline HBV DNA 10 000 IU/mL. On multivariate Cox proportional modelling, non-Asian ethnicity (HR 2.8), male sex (HR 2.1), baseline HBVDNA 10 000 (HR 2.0) and age >45 (HR 1.8) were significant independent predictors of seroclearance. ConclusionHBsAg seroclearance rates were lower than previously described in this real-life cohort of patients with chronic hepatitis B, especially among Asian, female and younger patients. C1 [Nguyen, L. H.] Stanford Univ, Med Ctr, Dept Med, Palo Alto, CA 94304 USA. [Nguyen, L. H.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Hoang, J.; Vu, V. D.; Wang, C.; Nguyen, M. H.] Stanford Univ, Med Ctr, Div Gastroenterol & Hepatol, 750 Welch Rd,Suite 210, Palo Alto, CA 94304 USA. [Nguyen, N. H.] Univ Calif San Diego, Dept Med, San Diego, CA 92103 USA. [Trinh, H. N.] San Jose Gastroenterol, San Jose, CA USA. [Li, J.] Palo Alto Med Fdn, Dept Gastroenterol, Mountain View, CA USA. [Zhang, J. Q.] Chinese Hosp, San Francisco, CA USA. RP Nguyen, MH (reprint author), Stanford Univ, Med Ctr, Div Gastroenterol & Hepatol, 750 Welch Rd,Suite 210, Palo Alto, CA 94304 USA. EM mindiehn@stanford.edu FU Stanford NIH/NCCR CTSA grant [TLI RR025742]; Digestive Disease Research Foundation, New York, NY, USA FX This project was supported in part by the Stanford NIH/NCCR CTSA grant number TLI RR025742 and a research training grant from the Digestive Disease Research Foundation, New York, NY, USA (LN). NR 63 TC 1 Z9 1 U1 3 U2 5 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 2016 VL 44 IS 4 BP 390 EP 399 DI 10.1111/apt.13709 PG 10 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA DR5QI UT WOS:000379957100007 PM 27363288 ER PT J AU Stevenson, DA Schill, L Schoyer, L Andresen, BS Bakker, A Bayrak-Toydemir, P Burkitt-Wright, E Chatfield, K Elefteriou, F Elgersma, Y Fisher, MJ Franz, D Gelb, BD Goriely, A Gripp, KW Hardan, AY Keppler-Noreuil, KM Kerr, B Korf, B Leoni, C McCormick, F Plotkin, SR Rauen, KA Reilly, K Roberts, A Sandler, A Siegel, D Walsh, K Widemann, BC AF Stevenson, David A. Schill, Lisa Schoyer, Lisa Andresen, Brage S. Bakker, Annette Bayrak-Toydemir, Pinar Burkitt-Wright, Emma Chatfield, Kathryn Elefteriou, Florent Elgersma, Ype Fisher, Michael J. Franz, David Gelb, Bruce D. Goriely, Anne Gripp, Karen W. Hardan, Antonio Y. Keppler-Noreuil, Kim M. Kerr, Bronwyn Korf, Bruce Leoni, Chiara McCormick, Frank Plotkin, Scott R. Rauen, Katherine A. Reilly, Karlyne Roberts, Amy Sandler, Abby Siegel, Dawn Walsh, Karin Widemann, Brigitte C. TI The Fourth International Symposium on Genetic Disorders of the Ras/MAPK pathway SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE RASopathy; Ras; MAPK; cancer; rare disorders; clinical trials; experimental models ID NEUROFIBROMATOSIS TYPE-1; PLEXIFORM NEUROFIBROMAS; CLINICAL-TRIALS; YOUNG-ADULTS; CHILDREN; INHIBITION; SPECTRUM; NOONAN AB The RASopathies are a group of disorders due to variations of genes associated with the Ras/MAPK pathway. Some of the RASopathies include neurofibromatosis type 1 (NF1), Noonan syndrome, Noonan syndrome with multiple lentigines, cardiofaciocutaneous (CFC) syndrome, Costello syndrome, Legius syndrome, and capillary malformation-arteriovenous malformation (CM-AVM) syndrome. In combination, the RASopathies are a frequent group of genetic disorders. This report summarizes the proceedings of the 4th International Symposium on Genetic Disorders of the Ras/MAPK pathway and highlights gaps in the field. (c) 2016 Wiley Periodicals, Inc. C1 [Stevenson, David A.; Hardan, Antonio Y.] Stanford Univ, Stanford, CA 94305 USA. [Schill, Lisa; Schoyer, Lisa] RASopathies Network, Berkeley, CA USA. [Andresen, Brage S.] Univ Southern Denmark, Odense, Denmark. [Bakker, Annette] Childrens Tumor Fdn, New York, NY USA. [Bayrak-Toydemir, Pinar] Univ Utah, Dept Pathol, Salt Lake City, UT USA. [Burkitt-Wright, Emma; Kerr, Bronwyn] Univ Manchester, Manchester M13 9PL, Lancs, England. [Chatfield, Kathryn] Univ Colorado, Denver, CO 80202 USA. [Elefteriou, Florent] Baylor Coll Med, Houston, TX 77030 USA. [Elgersma, Ype] Erasmus Univ, Med Ctr, Rotterdam, Netherlands. [Fisher, Michael J.] Univ Penn, Childrens Hosp Philadelphia, Perelman Sch Med, Philadelphia, PA 19104 USA. [Franz, David] Univ Cincinnati, Cincinnati, OH USA. [Gelb, Bruce D.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA. [Goriely, Anne] Univ Oxford, Oxford, England. [Gripp, Karen W.] Alfred I DuPont Hosp Children, Div Med Genet, Wilmington, DE USA. [Keppler-Noreuil, Kim M.] NHGRI, NIH, Bethesda, MD 20892 USA. [Korf, Bruce] Univ Alabama Birmingham, Birmingham, AL USA. [Leoni, Chiara] Fdn Policlin Univ A Gemelli, Rome, Italy. [McCormick, Frank; Reilly, Karlyne; Sandler, Abby; Widemann, Brigitte C.] NCI, NIH, Bethesda, MD 20892 USA. [Plotkin, Scott R.] Massachussets Gen Hosp, Boston, MA USA. [Rauen, Katherine A.] Univ Calif Davis, Dept Pediat, Div Genom Med, Sacramento, CA USA. [Roberts, Amy] Boston Childrens Hosp, Boston, MA USA. [Siegel, Dawn] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Walsh, Karin] George Washington Univ, Sch Med, Washington, DC USA. RP Stevenson, DA (reprint author), Stanford Univ, Div Med Genet, 300 Pasteur Dr H315, Stanford, CA 94305 USA. EM dasteven@stanford.edu RI Andresen, Brage/D-2515-2012; OI Andresen, Brage/0000-0001-7488-3035; Goriely, Anne/0000-0001-9229-7216 FU National Institutes of Health [1R13TR001272-01]; International Costello Syndrome; March of Dimes; Noonan Syndrome Foundation; Children's Tumor Foundation; NF Network; NCI CCR intramural research program; CFC International; Costello Syndrome Family Network; National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Disease [5RO1AR062165] FX Grant sponsor: National Institutes of Health; Grant number: 1R13TR001272-01; Grant sponsor: International Costello Syndrome; Grant sponsor: March of Dimes; Grant sponsor: Noonan Syndrome Foundation; Grant sponsor: Children's Tumor Foundation; Grant sponsor: NF Network; Grant sponsor: NCI CCR intramural research program; Grant sponsor: CFC International; Grant sponsor: Costello Syndrome Family Network; Grant sponsor: National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Disease; Grant number: 5RO1AR062165. NR 16 TC 1 Z9 1 U1 6 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD AUG PY 2016 VL 170 IS 8 BP 1959 EP 1966 DI 10.1002/ajmg.a.37723 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA DR5MZ UT WOS:000379948400003 PM 27155140 ER PT J AU Fishman, JA Feng, S AF Fishman, J. A. Feng, S. TI Advancing Transplant Care in AIDS: Encouraging Innovation in Transplantation SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Editorial Material DE editorial; personal viewpoint; ethics and public policy; infectious disease; law; legislation; organ transplantation in general; ethics; infection and infectious agents; viral; infection and infectious; agents; viral: hepatitis C; clinical trial design ID RECIPIENTS; LIVER; HAART AB Transplantation of organs from HIV-positive donors exemplifies an innovative approach to increasing organ availability, and the transplant community should embrace such research efforts and reconsider oversight mechanisms that may impede creative approaches to care. See page 2473 for the case report from Calmy et al. C1 [Fishman, J. A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Fishman, J. A.] Harvard Med Sch, Boston, MA 02115 USA. [Feng, S.] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Fishman, JA (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA.; Fishman, JA (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM jfishman@partners.org NR 8 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD AUG PY 2016 VL 16 IS 8 BP 2252 EP 2253 DI 10.1111/ajt.13841 PG 2 WC Surgery; Transplantation SC Surgery; Transplantation GA DR6QR UT WOS:000380026900006 PM 27108538 ER PT J AU Kaminski, H Fishman, JA AF Kaminski, H. Fishman, J. A. TI The Cell Biology of Cytomegalovirus: Implications for Transplantation SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Review DE translational research; science; basic (laboratory) research; science; immunobiology; infectious disease; organ transplantation in general; infection and infectious agents; viral: Cytomegalovirus (CMV); innate immunity; graft survival; T cell biology ID DELTA-T-CELLS; TUMOR-NECROSIS-FACTOR; CARDIAC ALLOGRAFT VASCULOPATHY; HEART-LUNG TRANSPLANTATION; SMOOTH-MUSCLE-CELLS; BRONCHIOLITIS OBLITERANS SYNDROME; ANTIBODY-MEDIATED REJECTION; SOLID-ORGAN TRANSPLANTATION; INFECTED ENDOTHELIAL-CELLS; GROWTH-FACTOR RECEPTOR AB Interpretation of clinical data regarding the impact of cytomegalovirus (CMV) infection on allograft function is complicated by the diversity of viral strains and substantial variability of cellular receptors and viral gene expression in different tissues. Variation also exists in nonspecific (monocytes and dendritic cells) and specific (NK cells, antibodies) responses that augment T cell antiviral activities. Innate immune signaling pathways and expanded pools of memory NK cells and T cells also serve to amplify host responses to infection. The clinical impact of specific memory T cell anti-CMV responses that cross-react with graft antigens and alloantigens is uncertain but appears to contribute to graft injury and to the abrogation of allograft tolerance. These responses are modified by diverse immunosuppressive regimens and by underlying host immune deficits. The impact of CMV infection on the transplant recipient reflects cellular changes and corresponding host responses, the convergence of which has been termed the indirect effects of CMV infection. Future studies will clarify interactions between CMV infection and allograft injury and will guide interventions that may enhance clinical outcomes in transplantation. Cytomegalovirus infection reflects a variety of cellular changes and host responses, and this review examines the variability of cellular receptors, viral gene expression in different tissues, and innate and adaptive immune responses that may contribute to graft injury and the abrogation of allograft tolerance. C1 [Kaminski, H.] CHU Bordeaux Pellegrin, Kidney Transplant Unit, Pl Raba Leon, Bordeaux, France. [Fishman, J. A.] Massachusetts Gen Hosp, Transplant Infect Dis & Immunocompromised Host Pr, Boston, MA 02114 USA. [Fishman, J. A.] Massachusetts Gen Hosp, MGH Transplant Ctr, Boston, MA 02114 USA. RP Fishman, JA (reprint author), Massachusetts Gen Hosp, Transplant Infect Dis & Immunocompromised Host Pr, Boston, MA 02114 USA.; Fishman, JA (reprint author), Massachusetts Gen Hosp, MGH Transplant Ctr, Boston, MA 02114 USA. EM jfishman@mgh.harvard.edu NR 199 TC 2 Z9 2 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD AUG PY 2016 VL 16 IS 8 BP 2254 EP 2269 DI 10.1111/ajt.13791 PG 16 WC Surgery; Transplantation SC Surgery; Transplantation GA DR6QR UT WOS:000380026900007 PM 26991039 ER PT J AU Grasing, K Mathur, D DeSouza, C Newton, TF Moody, DE Sturgill, M AF Grasing, Kenneth Mathur, Deepan DeSouza, Cherilyn Newton, Thomas F. Moody, David E. Sturgill, Marc TI Cocaine cardiovascular effects and pharmacokinetics after treatment with the acetylcholinesterase inhibitor donepezil SO AMERICAN JOURNAL ON ADDICTIONS LA English DT Article ID ALZHEIMERS-DISEASE; CHOLINESTERASE ACTIVITY; MASS-SPECTROMETRY; CARBOXYLESTERASE; METABOLITES; PATHOLOGY; ACCUMBENS; TOXICITY; PLASMA; SAFETY AB BackgroundIn rodents, cholinesterase inhibitors can cause sustained decreases in the reinforcing effects of cocaine. Nonetheless, cocaine is metabolized by butyrylcholinesterase (BuChE), raising concerns that cholinesterase inhibition could increase its peripheral concentrations, perhaps augmenting toxicity. Although donepezil is approved for use in patients and selective for inhibiting acetylcholinesterase over BuChE, no studies have reported cocaine bioavailability in human subjects receiving donepezil. MethodsTwelve cocaine-dependent veterans received three days of treatment with either oral placebo or 5mg daily of donepezil, followed by cross-over to the opposite treatment. During both oral treatments, double-blind intravenous cocaine was administered at .0, .18, and .36mg/kg in a laboratory setting, followed by determinations of heart rate, blood pressure, and plasma concentrations of cocaine and major metabolites. ResultsIntravenous cocaine produced dose-related increases in systolic blood pressure that were most pronounced over the initial 30minutes after treatment. Oral donepezil attenuated drug-induced elevations of systolic blood pressure following low-dose cocaine (.18mg/kg). No significant difference in blood pressure following treatment with placebo or donepezil after high-dose cocaine (.36mg/kg). Peak values of blood pressure and heart rate were unaffected by donepezil. Plasma concentrations of cocaine and metabolites did not differ in donepezil- and placebo-treated participants. Conclusions and Scientific SignificanceWe conclude that donepezil can attenuate drug-induced increases in systolic blood pressure following low-dose cocaine, but does not otherwise modify the cardiovascular effects of intravenous cocaine. Clinically significant changes in cocaine bioavailability and cardiovascular effects do not occur following this dose of donepezil. (Am J Addict 2016;25:392-399) C1 [Grasing, Kenneth; Mathur, Deepan; DeSouza, Cherilyn] Kansas City Vet Affairs Med Ctr, Subst Abuse Res Lab, Kansas City, MO USA. [Grasing, Kenneth] Univ Kansas, Sch Med, Dept Med, Div Clin Pharmacol, Kansas City, KS USA. [DeSouza, Cherilyn] Univ Kansas, Sch Med, Dept Psychiat, Kansas City, KS USA. [Newton, Thomas F.] Baylor Coll Med, Dept Psychiat & Behav Sci, Houston, TX 77030 USA. [Newton, Thomas F.] Baylor Coll Med, Michael E DeBakey Dept Vet Affairs Med Ctr, Houston, TX 77030 USA. [Moody, David E.] Univ Utah, Dept Pharmacol & Toxicol, Ctr Human Toxicol, 112 Skaggs Hall, Salt Lake City, UT 84112 USA. [Sturgill, Marc] Rutgers State Univ, Ernest Mario Sch Pharm, Dept Pharm Practice & Adm, Piscataway, NJ USA. RP Grasing, K (reprint author), Kansas City VA Med Ctr, Subst Abuse Res Lab, 4801 Linwood Blvd, Kansas City, MO 64128 USA. EM kgrasing@kumc.edu FU National Institutes of Health, Institute on Drug Abuse, Bethesda, MD [R21-DA029787]; Medical Research Service, Department of Veterans Affairs, Washington, DC [589-KG-0012] FX This study was supported by grant R21-DA029787 issued to KG by the National Institutes of Health, Institute on Drug Abuse, Bethesda, MD 20892-9581; and grant 589-KG-0012 issued to KG by the Medical Research Service, Department of Veterans Affairs, Washington, DC, 20420. NR 36 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1055-0496 EI 1521-0391 J9 AM J ADDICTION JI Am. J. Addict. PD AUG PY 2016 VL 25 IS 5 BP 392 EP 399 DI 10.1111/ajad.12402 PG 8 WC Substance Abuse SC Substance Abuse GA DR6RM UT WOS:000380029000006 PM 27392137 ER PT J AU Manders, P Joshua, AM Kefford, R Robert, C Ribas, A Hamid, O Daud, A Wolchok, JD Hwu, WJ Weber, JS Gangadhar, TC Joseph, R Dronca, R Patnaik, A Zarour, H Hersey, P Li, XN Diede, SJ Ebbinghaus, S Hodi, FS AF Manders, P. Joshua, A. M. Kefford, R. Robert, C. Ribas, A. Hamid, O. Daud, A. Wolchok, J. D. Hwu, W-J Weber, J. S. Gangadhar, T. C. Joseph, R. Dronca, R. Patnaik, A. Zarour, H. Hersey, P. Li, X. N. Diede, S. J. Ebbinghaus, S. Hodi, F. S. TI THREE-YEAR OVERALL SURVIVAL FOR PATIENTS WITH ADVANCED MELANOMA TREATED WITH PEMBROLIZUMAB IN KEYNOTE-001 SO ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 [Manders, P.] Kinghorn Canc Ctr, Sydney, NSW, Australia. [Manders, P.] St Vincents Hosp, Sydney, NSW, Australia. [Joshua, A. M.] Princess Margaret Canc Ctr, Toronto, ON, Canada. [Kefford, R.] Westmead Hosp, Melanoma Inst Australia, Crown Princess Mary Canc Ctr, Sydney, NSW, Australia. [Kefford, R.] Macquarie Univ, Sydney, NSW, Australia. [Robert, C.] Gustave Roussy Canc Campus, Villejuif Paris Sud, France. [Robert, C.] Univ Paris Sud, Villejuif Paris Sud, France. [Ribas, A.] Univ Calif Los Angeles, Los Angeles, CA USA. [Hamid, O.] Angeles Clin & Res Inst, Los Angeles, CA USA. [Daud, A.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Wolchok, J. D.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Hwu, W-J] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Weber, J. S.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Weber, J. S.] NYU, Langone Med Ctr, Perlmutter Canc Ctr, New York, NY USA. [Gangadhar, T. C.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Joseph, R.] Mayo Clin, Jacksonville, FL 32224 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. [Hersey, P.] Univ Sydney, Sydney, NSW, Australia. [Li, X. N.; Diede, S. J.; Ebbinghaus, S.] Merck & Co Inc, Kenilworth, NJ USA. [Hodi, F. S.] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 3 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 2016 VL 12 SU 4 SI SI BP 47 EP 48 PG 2 WC Oncology SC Oncology GA DR6IH UT WOS:000380005100012 ER PT J AU Long, G Atkinson, V Cebon, JS Jameson, MB Fitzharris, BM McNeil, CM Hill, AG Ribas, A Atkins, MB Thompson, JA Hwu, WJ Hodi, FS Menzies, AM Guminski, AD Kefford, R Shu, X Ebbinghaus, S Ibrahim, N Carlino, M AF Long, G. Atkinson, V. Cebon, J. S. Jameson, M. B. Fitzharris, B. M. McNeil, C. M. Hill, A. G. Ribas, A. Atkins, M. B. Thompson, J. A. Hwu, W-J Hodi, F. S. Menzies, A. M. Guminski, A. D. Kefford, R. Shu, X. Ebbinghaus, S. Ibrahim, N. Carlino, M. TI PEMBROLIZUMAB PLUS IPILIMUMAB FOR ADVANCED MELANOMA: RESULTS OF THE KEYNOTE-029 EXPANSION COHORT SO ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 [Long, G.; Menzies, A. M.; Guminski, A. D.] Univ Sydney, Melanoma Inst Australia, Mater Hosp, Sydney, NSW, Australia. [Long, G.; Menzies, A. M.; Guminski, A. D.] Royal North Shore Hosp, Sydney, NSW, Australia. [Atkinson, V.] Greenslopes Private Hosp, Gallipoli Med Res Fdn, Brisbane, Qld, Australia. [Cebon, J. S.] Olivia Newton John Canc Res Inst, Heidelberg, Vic, Australia. [Jameson, M. B.] Waikato Hosp, Reg Canc Ctr, Hamilton, New Zealand. [Fitzharris, B. M.] Canterbury Dist Hlth Board, Christchurch, New Zealand. [McNeil, C. M.] Royal Prince Alfred Hosp, Melanoma Inst Australia, Chris OBrien Lifehouse, Sydney, NSW, Australia. [McNeil, C. M.] Univ Sydney, Sydney, NSW, Australia. [Hill, A. G.] Tasman Oncol Res, Southport, Qld, Australia. [Ribas, A.] Univ Calif Los Angeles, Los Angeles, CA USA. [Atkins, M. B.] Georgetown Lombardi Comprehens Canc Ctr, Washington, DC USA. [Thompson, J. A.] Univ Washington, Seattle, WA 98195 USA. [Hwu, W-J] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Hodi, F. S.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Kefford, R.; Carlino, M.] Westmead Hosp, Melanoma Inst Australia, Sydney, NSW, Australia. [Kefford, R.] Macquarie Univ, Sydney, NSW, Australia. [Shu, X.; Ebbinghaus, S.; Ibrahim, N.] Merck & Co Inc, Kenilworth, NJ USA. [Carlino, M.] Blacktown Hosp, Melanoma Inst Australia, Sydney, NSW, Australia. [Carlino, M.] Univ Sydney, Sydney, NSW, Australia. NR 0 TC 0 Z9 0 U1 5 U2 5 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 2016 VL 12 SU 4 SI SI BP 60 EP 61 PG 2 WC Oncology SC Oncology GA DR6IH UT WOS:000380005100046 ER PT J AU Muralidhar, V Mahal, BA Nezolosky, MD Beard, CJ Feng, FY Martin, NE Efstathiou, JA Choueiri, TK Pomerantz, MM Sweeney, CJ Trinh, QD Vander Heiden, MG Nguyen, PL AF Muralidhar, Vinayak Mahal, Brandon A. Nezolosky, Michelle D. Beard, Clair J. Feng, Felix Y. Martin, Neil E. Efstathiou, Jason A. Choueiri, Toni K. Pomerantz, Mark M. Sweeney, Christopher J. Trinh, Quoc-Dien Vander Heiden, Matthew G. Nguyen, Paul L. TI Association between very small tumour size and increased cancer-specific mortality after radical prostatectomy in lymph node-positive prostate cancer SO BJU INTERNATIONAL LA English DT Article DE prostate cancer; tumour size; node-positive prostate cancer; microscopic tumour ID RACIAL DISPARITIES; AMERICAN VETERANS; SURVIVAL; RISK; VOLUME; LYMPHADENECTOMY; METASTASIS; PERCENTAGE; SPECIMENS; OUTCOMES AB Objective To determine whether very small prostate cancers present in patients who also have lymph node (LN) metastases represent a particularly aggressive disease variant compared with larger LN-positive tumours. Patients and Methods We identified 37 501 patients diagnosed with prostate cancer between 1988 and 2001 treated with radical prostatectomy within the Surveillance, Epidemiology, and End Results database. The primary study variables were tumour size by largest dimension (stratified into: (i) microscopic focus only or 1 mm; (ii) 2-15 mm; (iii) 16-30 mm; (iv) >30 mm), regional LN involvement, and the corresponding interaction term. We evaluated the risk of 10-year prostate cancer-specific mortality (PCSM) using the Fine and Gray model for competing risks after controlling for race, tumour grade, T stage, receipt of radiation, number of dissected LNs, number of positive LNs, year of diagnosis, and age at diagnosis. Results The median follow-up was 11.8 years. There was a significant interaction between tumour size and LN involvement (P-interaction <0.001). In the absence of LN involvement (36 561 patients), the risk of 10-year PCSM increased monotonically with increasing tumour size. Among patients with LN involvement (940), those with the smallest tumours had increased 10-year PCSM compared with patients with tumours sized 2-15 mm (24.7% vs 11.8%; adjusted hazard ratio [AHR] 2.84, 95% confidence interval [CI] 1.21-6.71; P = 0.017) or 16-30 mm (24.7% vs 15.5%; AHR 3.12, 95% CI 1.51-6.49; P = 0.002), and similar 10-year PCSM as those with tumours >30 mm (24.7% vs 24.9%; P = 0.156). Conclusion In patients with prostate cancer with LN involvement, very small tumour size may predict for higher PCSM compared with some larger tumours, even after controlling for other prognostic variables. These tumours might be particularly aggressive, beyond what is captured by pathological assessment of tumour grade and stage. C1 [Muralidhar, Vinayak] Harvard MIT Div Hlth Sci & Technol, Boston, MA USA. [Mahal, Brandon A.] Harvard Med Sch, Boston, MA USA. [Nezolosky, Michelle D.; Beard, Clair J.; Martin, Neil E.; Nguyen, Paul L.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Nezolosky, Michelle D.; Beard, Clair J.; Martin, Neil E.; Choueiri, Toni K.; Pomerantz, Mark M.; Sweeney, Christopher J.; Nguyen, Paul L.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Feng, Felix Y.] Univ Michigan, Dept Radiat Oncol, Ann Arbor, MI 48109 USA. [Efstathiou, Jason A.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Choueiri, Toni K.; Pomerantz, Mark M.; Sweeney, Christopher J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Trinh, Quoc-Dien] Brigham & Womens Hosp, Dept Urol, 75 Francis St, Boston, MA 02115 USA. [Vander Heiden, Matthew G.] MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. RP Nguyen, PL (reprint author), 75 Francis St, Boston, MA 02115 USA. EM pnguyen@LROC.harvard.edu FU Health Sciences and Technology IDEA2 Program - Peter C. Farrell Fund; Prostate Cancer Foundation; Fitz's Cancer Warriors; David and Cynthia Chapin, Hugh Simons in Honor of Frank and Anne Simons, The Scott Forbes and Gina Ventre Fund FX This work was supported by grants from the Health Sciences and Technology IDEA2 Program supported by the Peter C. Farrell (1967) Fund, The Prostate Cancer Foundation, Fitz's Cancer Warriors, David and Cynthia Chapin, Hugh Simons in Honor of Frank and Anne Simons, The Scott Forbes and Gina Ventre Fund, and a grant from an anonymous family foundation. NR 33 TC 1 Z9 1 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-4096 EI 1464-410X J9 BJU INT JI BJU Int. PD AUG PY 2016 VL 118 IS 2 SI SI BP 279 EP 285 DI 10.1111/bju.13248 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA DR7CN UT WOS:000380057700020 PM 26235660 ER PT J AU Dalela, D Krishna, N Okwara, J Preston, MA Abdollah, F Choueiri, TK Reznor, G Sammon, JD Schmid, M Kibel, AS Nguyen, PL Menon, M Trinh, QD AF Dalela, Deepansh Krishna, Nandita Okwara, James Preston, Mark A. Abdollah, Firas Choueiri, Toni K. Reznor, Gally Sammon, Jesse D. Schmid, Marianne Kibel, Adam S. Nguyen, Paul L. Menon, Mani Trinh, Quoc-Dien TI Suicide and accidental deaths among patients with non-metastatic prostate cancer SO BJU INTERNATIONAL LA English DT Article DE prostate cancer; primary treatment; suicide; accidental death; SEER ID QUALITY-OF-LIFE; RISK-FACTORS; RADICAL PROSTATECTOMY; CARDIOVASCULAR DEATH; HEALTH OUTCOMES; UNITED-STATES; DIAGNOSIS; MEN; DEPRESSION; SURVIVORS AB Objective To determine if American men with prostate cancer are at increased risk of suicide/accidental death compared with other cancers and if the receipt of definitive treatment alters this association, as patients with cancer are at increased risk of suicide and evidence suggests a relationship between suicides and deaths due to accidents and externally caused injuries. Patients and Methods Demographic, socio-economic and tumour characteristics of men with prostate cancer and men with other solid malignancies were extracted from the Surveillance, Epidemiology and End Results (SEER) database (1988-2010). Poisson regression models were fitted to compare the incidence of suicidal and accidental deaths in prostate cancer vs other solid cancers. Multivariate Cox regression was used to determine if receipt of definitive primary treatment impacted the risk of suicide or accidental death in men with localised/regional prostate cancer. Results Risk of suicidal and accidental death was significantly lower in men with prostate cancer (1 165 [0.2%] and 3 199 [0.6%]) than men with other cancers (2 232 [0.2%] and 4 501 [0.5%], respectively), except within the first year of diagnosis (adjusted relative risk [ARR] 3.98, 95% confidence interval [CI] 3.02-5.23 and ARR 4.22, 95% CI 3.24-5.51, respectively, 0-3 months after diagnosis). Men with non-metastatic prostate cancer who were White, uninsured, or recommended but did not receive treatment (hazard ratio vs treated 1.44, 95% CI 1.20-1.72, and 1.44, 95% CI 1.30-1.59, both P < 0.001) were at increased risk of suicidal and accidental mortality, respectively. Absence of data about previous co-morbidities and drug addictions in the SEER dataset was an important limitation. Conclusions Relative to other cancers, men with prostate cancer were at increased risk of suicide and accidental deaths within the first year of diagnosis and when definitive treatment was recommended but not received, suggesting the need for close monitoring and coordination with mental health professionals in at-risk men with potentially curable disease. C1 [Dalela, Deepansh; Krishna, Nandita; Okwara, James; Preston, Mark A.; Reznor, Gally; Schmid, Marianne; Kibel, Adam S.; Trinh, Quoc-Dien] Harvard Med Sch, Brigham & Womens Hosp, Dana Farber Canc Inst, Div Urol Surg, Boston, MA USA. [Dalela, Deepansh; Krishna, Nandita; Okwara, James; Preston, Mark A.; Reznor, Gally; Schmid, Marianne; Kibel, Adam S.; Trinh, Quoc-Dien] Harvard Med Sch, Brigham & Womens Hosp, Dana Farber Canc Inst, Ctr Surg & Publ Hlth, Boston, MA USA. [Dalela, Deepansh; Abdollah, Firas; Sammon, Jesse D.] Henry Ford Hlth Syst, Vattikuti Urol Inst, VUI Ctr Outcomes Res Analyt & Evaluat, Detroit, MI USA. [Choueiri, Toni K.] Harvard Med Sch, Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA. [Choueiri, Toni K.] Harvard Med Sch, Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA USA. RP Trinh, QD (reprint author), Ctr Surg & Publ Hlth, 45 Francis St,ASB 2-3, Boston, MA 02115 USA. EM qtrinh@partners.org FU Vattikuti Urology Institute; Professor Walter Morris-Hale Distinguished Chair in Urologic Oncology at Brigham and Women's Hospital FX Adam S. Kibel is a consultant on Advisory Boards of Sanofi-Aventis, Dendreon, and Myriad. Paul L. Nguyen is a consultant for Ferring and for Medivation. Quoc-Dien Trinh has received honorarium from Intuitive Surgical and an unrestricted educational grant from Vattikuti Urology Institute. He is supported by the Professor Walter Morris-Hale Distinguished Chair in Urologic Oncology at Brigham and Women's Hospital. NR 44 TC 2 Z9 2 U1 2 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-4096 EI 1464-410X J9 BJU INT JI BJU Int. PD AUG PY 2016 VL 118 IS 2 SI SI BP 286 EP 297 DI 10.1111/bju.13257 PG 12 WC Urology & Nephrology SC Urology & Nephrology GA DR7CN UT WOS:000380057700021 PM 26305451 ER PT J AU Cheng, G AF Cheng, Gang TI A Case of Lung Squamous Cell Carcinoma With Duodenal Metastasis on FDG PET/CT SO CLINICAL NUCLEAR MEDICINE LA English DT Editorial Material DE non-small cell lung cancer; duodenum; metastasis; FDG PET ID SMALL-BOWEL METASTASES; RARE COMPLICATION C1 [Cheng, Gang] Philadelphia VA Med Ctr, Dept Radiol, 3900 Woodland Ave, Philadelphia, PA 19104 USA. [Cheng, Gang] Hosp Univ Penn, Dept Radiol, 3400 Spruce St, Philadelphia, PA 19104 USA. RP Cheng, G (reprint author), Philadelphia VA Med Ctr, Dept Radiol, 3900 Woodland Ave, Philadelphia, PA 19104 USA. EM gangcheng99@yahoo.com NR 10 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0363-9762 EI 1536-0229 J9 CLIN NUCL MED JI Clin. Nucl. Med. PD AUG PY 2016 VL 41 IS 8 BP 659 EP 660 DI 10.1097/RLU.0000000000001225 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DR1LE UT WOS:000379666200027 PM 27055139 ER PT J AU Osborn, TM AF Osborn, Timothy M. TI The surgical management of cephalalgia SO CURRENT OPINION IN OTOLARYNGOLOGY & HEAD AND NECK SURGERY LA English DT Review DE chronic migraine; surgical management of cephalalgia; trigger site decompression ID CORRUGATOR SUPERCILII MUSCLE; OCCIPITAL NERVE-STIMULATION; CHRONIC CLUSTER HEADACHE; PRIMARY SENSORY NEURONS; MIGRAINE HEADACHES; PREMONITORY SYMPTOMS; NOCICEPTIVE NEURONS; SUPRAORBITAL NERVE; TRIGEMINAL NERVE; PAIN AB Purpose of review Management of headache disorders is not part of most craniomaxillofacial surgery practices; however there are certain indications for surgical management of headaches by the craniomaxillofacial surgeon. Recent findings Migraine headaches are the most amenable to surgical management and while the exact mechanism of migraine is unknown, a central or peripheral trigger such as compressive neuropathy of trigeminal nerve branches leading to neurogenic inflammation has been suggested. The primary management for episodic migraine headache should be lifestyle modification and medication, whereas for chronic migraine (>15 headache days/month) use of medication and botulinum neurotoxin is effective, whereas some patients may choose to explore surgical options. Trigger site decompression for chronic migraine surgically relieves anatomic impingement at various sites and has been shown to reduce by at least 50% the frequency, intensity, and duration of headaches in over 85% and elimination of headaches in almost 60%. Trigger points may also lead to exacerbation of cluster headaches and treatment with botulinum neurotoxin may reduce attacks. Summary Trigger site decompression is an effective treatment for chronic migraine, as are botulinum neurotoxin injections in reducing attacks in cluster headaches. The craniomaxillofacial surgeon is uniquely qualified to treat these primary headache disorders. C1 [Osborn, Timothy M.] Boston Med Ctr, Dept Oral & Maxillofacial Surg, 100 East Newton St,Suite G-407, Boston, MA 02118 USA. [Osborn, Timothy M.] Boston Univ, Beth Israel Deaconness Med Ctr, 100 East Newton St,Suite G-407, Boston, MA 02118 USA. RP Osborn, TM (reprint author), Boston Med Ctr, Dept Oral & Maxillofacial Surg, 100 East Newton St,Suite G-407, Boston, MA 02118 USA.; Osborn, TM (reprint author), Boston Univ, Beth Israel Deaconness Med Ctr, 100 East Newton St,Suite G-407, Boston, MA 02118 USA. EM tiosborn@bu.edu NR 59 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 1068-9508 EI 1531-6998 J9 CURR OPIN OTOLARYNGO JI Curr. Opin. Otolaryngol. Head Neck Surg. PD AUG PY 2016 VL 24 IS 4 BP 359 EP 367 DI 10.1097/MOO.0000000000000273 PG 9 WC Otorhinolaryngology SC Otorhinolaryngology GA DR1LB UT WOS:000379665900014 PM 27138357 ER PT J AU Altawil, Z Arawi, T AF Altawil, Zaid Arawi, Thalia TI Uterine Transplantation: Ethical Considerations within Middle Eastern Perspectives SO DEVELOPING WORLD BIOETHICS LA English DT Article DE Uterine transplant; ethics; Middle East; religion; Arab society ID UTERUS TRANSPLANTATION; MONTREAL-CRITERIA; FEASIBILITY; PREGNANCY; LEBANON AB The field of reproductive medicine witnessed a breakthrough in September 2014 with the first successful live birth post uterine transplantation. This success represents the culmination of decades' worth of research on infertility and reproductive medicine. This subject of infertility gathers special attention in the Middle East, as childbearing is given paramount importance in the family unit. And as with any new medical advancement, Middle Eastern people look to their religious authorities for guidance. This paper describes the various ethical quandaries related to uterine transplantation, from a perspective of the religious and societal factors that are unique to the Middle East, and embeds them within the conversation of its alternative solutions. C1 [Arawi, Thalia] Amer Univ Beirut, Fac Med, Salim El Hoss Bioeth & Professionalism Program, POB 11-0236, Beirut 11072020, Lebanon. [Arawi, Thalia] Amer Univ Beirut, Med Ctr, POB 11-0236, Beirut 11072020, Lebanon. [Altawil, Zaid] Massachusetts Gen Hosp, Dept Emergency Med, Div Global Hlth & Human Rights, Boston, MA 02114 USA. RP Arawi, T (reprint author), Amer Univ Beirut, Fac Med, Salim El Hoss Bioeth & Professionalism Program, POB 11-0236, Beirut 11072020, Lebanon.; Arawi, T (reprint author), Amer Univ Beirut, Med Ctr, POB 11-0236, Beirut 11072020, Lebanon. EM ta16@aub.edu.lb NR 40 TC 1 Z9 1 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1471-8731 EI 1471-8847 J9 DEV WORLD BIOETH JI Dev. World Bioeth. PD AUG PY 2016 VL 16 IS 2 BP 91 EP 97 DI 10.1111/dewb.12085 PG 7 WC Ethics; Medical Ethics SC Social Sciences - Other Topics; Medical Ethics GA DR5HY UT WOS:000379935300005 PM 25982588 ER PT J AU Patorno, E Everett, BM Goldfine, AB Glynn, RJ Liu, J Gopalakrishnan, C Kim, SC AF Patorno, E. Everett, B. M. Goldfine, A. B. Glynn, R. J. Liu, J. Gopalakrishnan, C. Kim, S. C. TI Comparative cardiovascular safety of glucagon-like peptide-1 receptor agonists versus other antidiabetic drugs in routine care: a cohort study SO DIABETES OBESITY & METABOLISM LA English DT Article DE cardiovascular disease; DPP-4 inhibitor; GLP-1 analogue; insulin therapy; pharmaco-epidemiology; sulphonylureas ID TYPE-2 DIABETES-MELLITUS; ADMINISTRATIVE DATA; CLINICAL-TRIALS; METAANALYSIS; DISEASE; RISK; ASSOCIATION; EXENATIDE; OUTCOMES; EVENTS AB Aims: To evaluate the comparative cardiovascular disease (CVD) safety of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in head-to-head comparisons with dipeptidyl peptidase-4 (DPP-4) inhibitors, sulphonylureas or insulin, when added to metformin, as used in 'real-world' patients with type 2 diabetes mellitus (T2DM). Methods: Within a large US commercial health plan database linked to laboratory test results, we identified three pairwise 1 : 1 propensity-score-matched cohorts of patients with T2DM aged >= 18 years treated with metformin who initiated a GLP-1 RA or a comparator, i.e. DPP-4 inhibitor (n=35 534), second-generation sulphonylureas (n=28 138) or insulin (n=47 068), between 2005 and 2013. We examined the association between drug initiation and a composite CVD endpoint, comprising hospitalizations for acute myocardial infarction, unstable angina, stroke or coronary revascularization. Results: During the course of 1 year, there were 13.9 and 13.7 CVD events per 1000 person-years among propensity-score-matched initiators of GLP-1 RAs versus DPP-4 inhibitors [hazard ratio (HR) 1.02; 95% confidence interval (CI) 0.84-1.24]; and 12.1 versus 14.0 events among initiators of GLP-1 RAs versus sulphonylureas (HR 0.86; 95% CI 0.69-1.08). The effect estimates for GLP-1 RAs versus insulin were sensitive to the adjustment for glycated haemoglobin, after which the HR was 1.01 (95% CI 0.73-1.41). Results were robust across several sensitivity analyses, including an as-treated analysis considering up to 8.7 years of follow-up. Conclusions: This large study, performing head-to-head comparisons of GLP-1 RAs with other antidiabetic agents in real-world patients, provides estimates of relative safety precise enough to exclude large differences in CVD risk and adds further understanding to results from recent clinical trials. C1 [Patorno, E.; Glynn, R. J.; Liu, J.; Gopalakrishnan, C.; Kim, S. C.] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, Boston, MA 02120 USA. [Everett, B. M.] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Div Cardiovasc, Boston, MA 02120 USA. [Everett, B. M.] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Div Prevent Med, Boston, MA 02120 USA. [Goldfine, A. B.] Harvard Med Sch, Joslin Diabet Ctr, Clin Res, Boston, MA 02120 USA. [Kim, S. C.] Harvard Med Sch, Brigham & Womens Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02120 USA. RP Patorno, E (reprint author), Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, Med, 1620 Tremont St Suite 3030, Boston, MA 02120 USA.; Patorno, E (reprint author), Harvard Med Sch, 1620 Tremont St Suite 3030, Boston, MA 02120 USA. EM epatorno@partners.org FU Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA FX This study was funded by the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. NR 39 TC 3 Z9 3 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1462-8902 EI 1463-1326 J9 DIABETES OBES METAB JI Diabetes Obes. Metab. PD AUG PY 2016 VL 18 IS 8 BP 755 EP 765 DI 10.1111/dom.12665 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DR4WR UT WOS:000379904300003 PM 27003762 ER PT J AU Mukherjee, R Mareninova, OA Odinokova, IV Huang, W Murphy, J Chvanov, M Javed, MA Wen, L Booth, DM Cane, MC Awais, M Gavillet, B Pruss, RM Schaller, S Molkentin, JD Tepikin, AV Petersen, OH Pandol, SJ Gukovsky, I Criddle, DN Gukovskaya, AS Sutton, R AF Mukherjee, Rajarshi Mareninova, Olga A. Odinokova, Irina V. Huang, Wei Murphy, John Chvanov, Michael Javed, Muhammad A. Wen, Li Booth, David M. Cane, Matthew C. Awais, Muhammad Gavillet, Bruno Pruss, Rebecca M. Schaller, Sophie Molkentin, Jeffery D. Tepikin, Alexei V. Petersen, Ole H. Pandol, Stephen J. Gukovsky, Ilya Criddle, David N. Gukovskaya, Anna S. Sutton, Robert CA NIHR Pancreas Biomedical Res Unit TI Mechanism of mitochondrial permeability transition pore induction and damage in the pancreas: inhibition prevents acute pancreatitis by protecting production of ATP SO GUT LA English DT Article ID INOSITOL TRISPHOSPHATE RECEPTORS; ACINAR-CELLS; TRYPSINOGEN ACTIVATION; CA2+ RELEASE; BILE-ACIDS; INTRACELLULAR ACTIVATION; HEREDITARY PANCREATITIS; ENDOPLASMIC-RETICULUM; ZYMOGEN ACTIVATION; MOUSE MODEL AB Objective Acute pancreatitis is caused by toxins that induce acinar cell calcium overload, zymogen activation, cytokine release and cell death, yet is without specific drug therapy. Mitochondrial dysfunction has been implicated but the mechanism not established. Design We investigated the mechanism of induction and consequences of the mitochondrial permeability transition pore (MPTP) in the pancreas using cell biological methods including confocal microscopy, patch clamp technology and multiple clinically representative disease models. Effects of genetic and pharmacological inhibition of the MPTP were examined in isolated murine and human pancreatic acinar cells, and in hyperstimulation, bile acid, alcoholic and choline-deficient, ethionine-supplemented acute pancreatitis. Results MPTP opening was mediated by toxin-induced inositol trisphosphate and ryanodine receptor calcium channel release, and resulted in diminished ATP production, leading to impaired calcium clearance, defective autophagy, zymogen activation, cytokine production, phosphoglycerate mutase 5 activation and necrosis, which was prevented by intracellular ATP supplementation. When MPTP opening was inhibited genetically or pharmacologically, all biochemical, immunological and histopathological responses of acute pancreatitis in all four models were reduced or abolished. Conclusions This work demonstrates the mechanism and consequences of MPTP opening to be fundamental to multiple forms of acute pancreatitis and validates the MPTP as a drug target for this disease. C1 [Mukherjee, Rajarshi; Huang, Wei; Murphy, John; Chvanov, Michael; Javed, Muhammad A.; Wen, Li; Booth, David M.; Awais, Muhammad; Tepikin, Alexei V.; Criddle, David N.; Sutton, Robert; NIHR Pancreas Biomedical Res Unit] Royal Liverpool Univ Hosp, NIHR Liverpool Pancreas Biomed Res Unit, 5th Floor UCD,Daulby St, Liverpool L69 3GA, Merseyside, England. [Mukherjee, Rajarshi; Huang, Wei; Murphy, John; Chvanov, Michael; Javed, Muhammad A.; Wen, Li; Booth, David M.; Cane, Matthew C.; Awais, Muhammad; Tepikin, Alexei V.; Criddle, David N.; Sutton, Robert] Univ Liverpool, Inst Translat Med, Liverpool, Merseyside, England. [Mareninova, Olga A.; Odinokova, Irina V.; Pandol, Stephen J.; Gukovsky, Ilya; Gukovskaya, Anna S.] Univ Calif Los Angeles, Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Mareninova, Olga A.; Odinokova, Irina V.; Pandol, Stephen J.; Gukovsky, Ilya; Gukovskaya, Anna S.] Southern Calif Res Ctr Alcohol Liver & Pancreat D, Los Angeles, CA USA. [Odinokova, Irina V.] Russian Acad Sci, Inst Theoret & Expt Biophys, Pushchino, Russia. [Huang, Wei] Sichuan Univ, West China Hosp, Dept Integrated Tradit & Western Med, Sichuan Prov Pancreatitis Ctr, Chengdu, Peoples R China. [Gavillet, Bruno] Debiopharm Res & Mfg SA, Lausanne, Switzerland. [Pruss, Rebecca M.; Schaller, Sophie] Trophos SA, Marseille, France. [Molkentin, Jeffery D.] Childrens Hosp, Med Ctr, Howard Hughes Med Inst, Cincinnati, OH 45229 USA. [Petersen, Ole H.] Cardiff Univ, Cardiff Sch Biosci, Cardiff, S Glam, Wales. RP Sutton, R (reprint author), Royal Liverpool Univ Hosp, NIHR Liverpool Pancreas Biomed Res Unit, 5th Floor UCD,Daulby St, Liverpool L69 3GA, Merseyside, England.; Gukovskaya, AS (reprint author), UCLA Vet Affairs Greater Los Angeles Healthcare S, West Los Angeles Vet Affairs Healthcare Ctr, 11301 Wilshire Blvd,Blg 258,Rm 340, Los Angeles, CA 90073 USA. EM agukovsk@ucla.edu; r.sutton@liverpool.ac.uk OI Cane, Matthew/0000-0002-7874-294X FU US Veterans Administration Merit Review; NIH [R01DK59936, R01AA19730]; Southern California Research Center for Alcoholic Liver and Pancreatic Diseases; American Gastroenterological Association Foundation Designated Research Scholar Award in Pancreatitis; Russian Federation BR grant [09-04-00739]; UK/China Postgraduate Research Scholarship for Excellence; Liverpool China Scholarship Council Award; CORE, UK; UK Medical Research Council; Royal College of Surgeons of England; UK NIHR Biomedical Research Unit Funding Scheme FX This work was supported by US Veterans Administration Merit Review (ASG), NIH grants R01DK59936 (ASG) and R01AA19730 (IG and OAM), Southern California Research Center for Alcoholic Liver and Pancreatic Diseases (SJP and ASG), American Gastroenterological Association Foundation Designated Research Scholar Award in Pancreatitis (OAM), Russian Federation BR grant 09-04-00739 (IVO), UK/China Postgraduate Research Scholarship for Excellence (WH), Liverpool China Scholarship Council Award (LW), CORE, UK (RM, JM, MAJ), UK Medical Research Council (DMB, MC, MCC, OHP, AVT, DNC and RS), Royal College of Surgeons of England (MAJ) and UK NIHR Biomedical Research Unit Funding Scheme (MA, AVT, DNC and RS). NR 59 TC 8 Z9 8 U1 9 U2 14 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 2016 VL 65 IS 8 BP 1333 EP 1346 DI 10.1136/gutjnl-2014-308553 PG 14 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DR2TL UT WOS:000379756700014 PM 26071131 ER PT J AU Gildener-Leapman, N Kim, J Abberbock, S Choby, GW Mandal, R Duvvuri, U Ferris, RL Kim, S AF Gildener-Leapman, Neil Kim, Jeehong Abberbock, Shira Choby, Garret W. Mandal, Rajarsi Duvvuri, Umamaheswar Ferris, Robert L. Kim, Seungwon TI Utility of up-front transoral robotic surgery in tailoring adjuvant therapy SO HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK LA English DT Article; Proceedings Paper CT Triological-Society 118th Annual Meeting at the Combined Otolaryngology Spring Meetings (COSM) / Spring Meeting of the American-Rhinologic-Society (ARS) / Meeting of the American-Society-of-Head-and-Neck-Surgery CY APR 22-26, 2015 CL Boston, MA SP Triol Soc, Amer Rhinol Soc DE transoral robotic surgery (TORS); adjuvant therapy; oropharyngeal squamous cell carcinoma (OPSCC); oropharynx; decision-making ID SQUAMOUS-CELL CARCINOMA; OROPHARYNGEAL CANCER; LASER MICROSURGERY; ASSISTED SURGERY; NECK-CANCER; HEAD; OUTCOMES AB BackgroundThe purpose of this study was to describe how the up-front transoral robotic surgery (TORS) approach could be used to individually tailor adjuvant therapy based on surgical pathology. MethodsBetween January 2009 and December 2013, 76 patients received TORS for oropharyngeal squamous cell carcinoma (OPSCC). Clinical predictors of adjuvant therapy were analyzed and comparisons were made between recommended treatment guidelines for up-front surgery versus definitive nonsurgical approaches. ResultsAdvanced N classification, human papillomavirus (HPV)-positive tumor, extracapsular spread (ECS; 26 of 76), perineural invasion (PNI; 14 of 76), and positive margins (7 of 76) were significant predictors of adjuvant chemoradiotherapy (CRT) (p < .05). Up-front TORS deintensified adjuvant therapy; 76% of stage I/II and 46% of stage III/IV patients avoided CRT. Conversely, pathologic staging resulted in 33% of patients who would have received radiotherapy (RT) alone based on clinical staging, to be intensified to receive adjuvant CRT. ConclusionThe TORS approach deintensifies adjuvant therapy and provides valuable pathologic information to intensify treatment in select patients. TORS may be less effective in deintensification of adjuvant therapy in patients with clinically advanced N classification disease. (c) 2016 Wiley Periodicals, Inc. Head Neck 38:1201-1207, 2016 C1 [Gildener-Leapman, Neil] Albany Med Coll, Dept Surg, Div Otolaryngol Head & Neck Surg, Albany, NY 12208 USA. [Kim, Jeehong] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Abberbock, Shira] Univ Pittsburgh, Biostat Facil, Inst Canc, Pittsburgh, PA USA. [Choby, Garret W.; Mandal, Rajarsi; Duvvuri, Umamaheswar; Ferris, Robert L.; Kim, Seungwon] Univ Pittsburgh, Med Ctr, Dept Otolaryngol Head & Neck Surg, Pittsburgh, PA USA. [Duvvuri, Umamaheswar] VA Pittsburgh Hlth Syst, Dept Otolaryngol, Pittsburgh, PA USA. RP Kim, S (reprint author), Univ Pittsburgh, Dept Otolaryngol, Med Ctr, 200 Lothrop St,EEI 500, Pittsburgh, PA 15213 USA. EM kimsw2@upmc.edu FU NCI NIH HHS [T32 CA060397] NR 15 TC 1 Z9 1 U1 2 U2 3 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 2016 VL 38 IS 8 BP 1201 EP 1207 DI 10.1002/hed.24390 PG 7 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA DR5JY UT WOS:000379940500014 PM 27225507 ER PT J AU Alkire, BC Bergmark, RW Chambers, K Lin, DT Deschler, DG Cheney, ML Meara, JG AF Alkire, Blake C. Bergmark, Regan W. Chambers, Kyle Lin, Derrick T. Deschler, Daniel G. Cheney, Mack L. Meara, John G. TI Head and neck cancer in South Asia: Macroeconomic consequences and the role of the head and neck surgeon SO HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK LA English DT Article DE economic burden; head and neck cancer; global surgery; South Asia; economic analysis ID ADJUSTED LIFE YEARS; GLOBAL BURDEN; HUMAN-PAPILLOMAVIRUS; SYSTEMATIC ANALYSIS; STATISTICAL LIFE; ORAL-CANCER; INDIA; HEALTH; DISEASES; CARE AB BackgroundHead and neck cancer constitutes a substantial portion of the burden of disease in South Asia, and there is an undersupply of surgical capacity in this region. The purpose of this study was to estimate the economic welfare losses due to head and neck cancer in India, Pakistan, and Bangladesh in 2010. MethodsWe used publicly available estimates of head and neck cancer morbidity and mortality along with a concept termed the value of a statistical life to estimate economic welfare losses in the aforementioned countries in 2010.Results. Economic losses because of head and neck cancer in India, Pakistan, and Bangladesh totaled $16.9 billion (2010 US dollars [USD]), equivalent to 0.26% of the region's economic output. Bangladesh, the poorest country, experienced the greatest proportional losses. ConclusionThe economic consequences of head and neck cancer in South Asia are significant, and building surgical capacity is essential to begin to address this burden. (c) 2016 Wiley Periodicals, Inc. Head Neck 38:1242-1247, 2016 C1 [Alkire, Blake C.; Bergmark, Regan W.; Chambers, Kyle; Cheney, Mack L.] Massachusetts Eye & Ear Infirm, Off Global Surg, Boston, MA 02114 USA. [Alkire, Blake C.; Cheney, Mack L.; Meara, John G.] Harvard Med Sch, Dept Global Hlth & Social Med, Program Global Surg & Social Change, Boston, MA USA. [Alkire, Blake C.; Bergmark, Regan W.; Chambers, Kyle; Lin, Derrick T.; Deschler, Daniel G.; Cheney, Mack L.] Harvard Med Sch, Dept Otolaryngol, Boston, MA USA. [Meara, John G.] Boston Childrens Hosp, Dept Plast & Oral Surg, Boston, MA USA. [Lin, Derrick T.; Deschler, Daniel G.] Massachusetts Eye & Ear Infirm, Div Head & Neck Surg, Boston, MA 02114 USA. RP Alkire, BC (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. EM blakealkire@gmail.com NR 47 TC 0 Z9 0 U1 4 U2 5 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 2016 VL 38 IS 8 BP 1242 EP 1247 DI 10.1002/hed.24430 PG 6 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA DR5JY UT WOS:000379940500020 PM 27028850 ER PT J AU Stavrinou, S Clark, A Irving, J Lee, CH Oliva, E Young, R Sriraksa, R Magdy, N Van Noorden, S McCluggage, WG El-Bahrawy, M AF Stavrinou, Stavroula Clark, Ashleigh Irving, Julie Lee, Cheng-Han Oliva, Esther Young, Robert Sriraksa, Ruethairat Magdy, Nesreen Van Noorden, Susan McCluggage, W. Glenn El-Bahrawy, Mona TI Differential expression of E-cadherin and catenins in ovarian sex cord stromal tumours SO HISTOPATHOLOGY LA English DT Article DE catenin; E-cadherin; ovary; sex cord; stromal; tumour ID GRANULOSA-CELL TUMOR; BETA-CATENIN; NUCLEAR-LOCALIZATION; ALPHA-CATENIN; HUMAN CANCER; ADHESION; MUTATION; SUPPRESSOR; MOLECULES; COMPLEX AB AimsSex cord stromal tumours (SCSTs) of the ovary encompass several histological tumour subtypes that are defined by characteristic histological features. Some can show morphological overlap with other subtypes of SCSTs, as well as with non-SCSTs. The E-cadherin/catenin complex constitutes the adherens junction, which is well developed in epithelial tissue, but the constituent molecules are also expressed in several non-epithelial tumours. The aim of this study was to determine whether the expression patterns of E-cadherin and catenins in ovarian SCSTs can be of diagnostic utility. Methods and resultsWe studied the expression of E-cadherin, -, - and -catenin in 55 tumours using immunohistochemistry. We found that all tumour subtypes showed nuclear expression of E-cadherin, while only microcystic stromal tumours (MCSTs) displayed a distinct profile, with nuclear localization of all three catenins in almost all cases. ConclusionsWe conclude that the E-cadherin expression profile in SCSTs can assist in distinguishing between SCSTs and non-SCSTs in which there is no nuclear expression of E-cadherin. The nuclear localization of catenins may be of potential use in distinguishing MCST from other subtypes of SCST. C1 [Stavrinou, Stavroula; Clark, Ashleigh; Magdy, Nesreen; Van Noorden, Susan; El-Bahrawy, Mona] Imperial Coll London, Dept Histopathol, London, England. [Irving, Julie] Royal Jubilee Hosp, Dept Lab Med Pathol & Med Genet, Victoria, BC, Canada. [Irving, Julie] Univ British Columbia, Dept Pathol, Vancouver, BC, Canada. [Lee, Cheng-Han] Univ Alberta, Dept Lab Med & Pathol, Edmonton, AB, Canada. [Lee, Cheng-Han] Royal Alexandra Hosp, Edmonton, AB, Canada. [Oliva, Esther; Young, Robert] Massachusetts Gen Hosp, James Homer Wright Pathol Labs, Boston, MA USA. [Oliva, Esther; Young, Robert] Harvard Med Sch, Dept Pathol, Boston, MA USA. [Sriraksa, Ruethairat] Khon Kaen Univ, Liver Fluke & Cholangiocarcinoma Res Ctr, Khon Kaen, Thailand. [Magdy, Nesreen; El-Bahrawy, Mona] Cairo Univ, Natl Canc Inst, Dept Pathol, Giza, Egypt. [McCluggage, W. Glenn] Belfast Hlth & Social Care Trust, Dept Pathol, Belfast, Antrim, North Ireland. RP El-Bahrawy, M (reprint author), Imperial Coll London, Hammersmith Hosp, Dept Histopathol, DuCane Rd, London W12 0HS, England. EM m.elbahrawy@imperial.ac.uk NR 32 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0309-0167 EI 1365-2559 J9 HISTOPATHOLOGY JI Histopathology PD AUG PY 2016 VL 69 IS 2 BP 298 EP 306 DI 10.1111/his.12937 PG 9 WC Cell Biology; Pathology SC Cell Biology; Pathology GA DR5MJ UT WOS:000379946800013 PM 27097978 ER PT J AU Saunier, C Stove, SI Popp, B Gerard, B Blenski, M AhMew, N de Bie, C Goldenberg, P Isidor, B Keren, B Leheup, B Lampert, L Mignot, C Tezcan, K Mancini, GMS Nava, C Wasserstein, M Bruel, AL Thevenon, J Masurel, A Duffourd, Y Kuentz, P Huet, F Riviere, JB van Slegtenhorst, M Faivre, L Piton, A Reis, A Arnesen, T Thauvin-Robinet, C Zweier, C AF Saunier, Chloe Stove, Svein Isungset Popp, Bernt Gerard, Benedicte Blenski, Marina AhMew, Nicholas de Bie, Charlotte Goldenberg, Paula Isidor, Bertrand Keren, Boris Leheup, Bruno Lampert, Laetitia Mignot, Cyril Tezcan, Kamer Mancini, Grazia M. S. Nava, Caroline Wasserstein, Melissa Bruel, Ange-Line Thevenon, Julien Masurel, Alice Duffourd, Yannis Kuentz, Paul Huet, Frederic Riviere, Jean-Baptiste van Slegtenhorst, Marjon Faivre, Laurence Piton, Amelie Reis, Andre Arnesen, Thomas Thauvin-Robinet, Christel Zweier, Christiane TI Expanding the Phenotype Associated with NAA10-Related N-Terminal Acetylation Deficiency SO HUMAN MUTATION LA English DT Article DE NAA10; X-linked; intellectual disability; N-terminal acetylation ID X-CHROMOSOME INACTIVATION; MEMBRANE-PROTEIN SYS1P; INTELLECTUAL DISABILITY; MISSENSE MUTATIONS; GTPASE ARL3P; ACETYLTRANSFERASE; COMPLEX; IDENTIFICATION; REQUIRES; FEMALES AB N-terminal acetylation is a common protein modification in eukaryotes associated with numerous cellular processes. Inherited mutations in NAA10, encoding the catalytic subunit of the major N-terminal acetylation complex NatA have been associated with diverse, syndromic X-linked recessive disorders, whereas de novo missense mutations have been reported in one male and one female individual with severe intellectual disability but otherwise unspecific phenotypes. Thus, the full genetic and clinical spectrum of NAA10 deficiency is yet to be delineated. We identified three different novel and one known missense mutation in NAA10, de novo in 11females, and due to maternal germ line mosaicism in another girl and her more severely affected and deceased brother. In vitro enzymatic assays for the novel, recurrent mutations p.(Arg83Cys) and p.(Phe128Leu) revealed reduced catalytic activity. X-inactivation was random in five females. The core phenotype of X-linked NAA10-related N-terminal-acetyltransferase deficiency in both males and females includes developmental delay, severe intellectual disability, postnatal growth failure with severe microcephaly, and skeletal or cardiac anomalies. Genotype-phenotype correlations within and between both genders are complex and may include various factors such as location and nature of mutations, enzymatic stability and activity, and X-inactivation in females. C1 [Saunier, Chloe; Thevenon, Julien; Masurel, Alice; Faivre, Laurence; Thauvin-Robinet, Christel] CHU, Hop Enfants, Ctr Reference Malad Rares Anomalies Dev & Syndrom, Dijon, France. [Saunier, Chloe; Huet, Frederic] CHU Dijon, Hop Enfants, Serv Pediat, Dijon, France. [Stove, Svein Isungset; Blenski, Marina; Arnesen, Thomas] Univ Bergen, Dept Mol Biol, Thormoehlensgate 55, N-5020 Bergen, Norway. [Stove, Svein Isungset; Arnesen, Thomas] Haukeland Hosp, Dept Surg, Bergen, Norway. [Popp, Bernt; Reis, Andre; Zweier, Christiane] Univ Erlangen Nurnberg, Inst Human Genet, Erlangen, Germany. [Gerard, Benedicte; Piton, Amelie] CHRU, Genet Mol Lab, Strasbourg, France. [AhMew, Nicholas] Childrens Natl Med Ctr, Div Genet & Metab, Washington, DC 20010 USA. [de Bie, Charlotte] UMC Utrecht, Dept Genet, Utrecht, Netherlands. [Goldenberg, Paula] Massachusetts Gen Hosp, Med Genet, Boston, MA 02114 USA. [Isidor, Bertrand] CHU Nantes, Serv Genet Med, Nantes, France. [Isidor, Bertrand] INSERM, UMR S 957, Nantes, France. [Keren, Boris; Nava, Caroline] Hop La Pitie Salpetriere, AP HP, Dept Genet, Paris, France. [Keren, Boris; Nava, Caroline] ICM, CNRS, UMR 7225, UPMC,Inserm,UM 75,U1127, F-75013 Paris, France. [Leheup, Bruno; Lampert, Laetitia] CHU Nancy, Hop Brabois, Serv Genet Med, Nancy, France. [Mignot, Cyril] Grp Hosp Pitie Salpetriere, APHP, Dept Genet, Paris, France. [Mignot, Cyril] Grp Hosp Pitie Salpetriere, Ctr Reference Deficiences Intellectuelles Causes, Paris, France. [Tezcan, Kamer] Kaiser Permanente, Dept Genet, Sacramento, CA USA. [Mancini, Grazia M. S.; van Slegtenhorst, Marjon] Erasmus Univ, Med Ctr, Dept Clin Genet, Rotterdam, Netherlands. [Wasserstein, Melissa] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Wasserstein, Melissa] Icahn Sch Med Mt Sinai, Dept Pediat, New York, NY 10029 USA. [Bruel, Ange-Line; Thevenon, Julien; Masurel, Alice; Duffourd, Yannis; Kuentz, Paul; Huet, Frederic; Riviere, Jean-Baptiste; Faivre, Laurence; Thauvin-Robinet, Christel] Univ Bourgogne, CHU Dijon, FHU TRANSLAD, Dijon, France. [Bruel, Ange-Line; Thevenon, Julien; Duffourd, Yannis; Kuentz, Paul; Huet, Frederic; Riviere, Jean-Baptiste; Faivre, Laurence; Thauvin-Robinet, Christel] Univ Bourgogne, Equipe GAD EA4271, Dijon, France. [Riviere, Jean-Baptiste] CHU Dijon, PTB, Genet Mol Lab, Dijon, France. RP Arnesen, T (reprint author), Univ Bergen, Dept Mol Biol, Thormoehlensgate 55, N-5020 Bergen, Norway.; Zweier, C (reprint author), Inst Human Genet, Schwabachanlage 10, D-91054 Erlangen, Germany. EM Thomas.Arnesen@uib.no; christiane.zweier@uk-erlangen.de RI Zweier, Christiane/F-2202-2015; piton, amelie/F-1201-2013; Reis, Andre/D-2309-2009; OI piton, amelie/0000-0003-0408-7468; Reis, Andre/0000-0002-6301-6363; Arnesen, Thomas/0000-0002-3005-147X FU Dijon University Hospital; Regional Council of Burgundy; Interdisciplinary Center for Clinical Research (IZKF) Erlangen [E16, E26]; German Research Foundation DFG [Zw184/1-2]; Norwegian Cancer Society; Bergen Research Foundation BFS; Research Council of Norway [230865]; Western Norway Regional Health Authority FX Contract grant sponsors: Dijon University Hospital; Regional Council of Burgundy; Interdisciplinary Center for Clinical Research (IZKF) Erlangen (projects E16 and E26); German Research Foundation DFG (Zw184/1-2); Norwegian Cancer Society; The Bergen Research Foundation BFS; Research Council of Norway(grant 230865); Western Norway Regional Health Authority. NR 33 TC 2 Z9 2 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1059-7794 EI 1098-1004 J9 HUM MUTAT JI Hum. Mutat. PD AUG PY 2016 VL 37 IS 8 BP 755 EP 764 DI 10.1002/humu.23001 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA DR5GU UT WOS:000379932300006 PM 27094817 ER PT J AU Gupta, M Babic, A Beck, AH Terry, K AF Gupta, Mamta Babic, Ana Beck, Andrew H. Terry, Kathryn TI TNF-alpha expression, risk factors, and inflammatory exposures in ovarian cancer: evidence for an inflammatory pathway of ovarian carcinogenesis? SO HUMAN PATHOLOGY LA English DT Article DE Ovary; Carcinoma; Cytokines; TNF-alpha; Parity; Smoking ID TUMOR-NECROSIS-FACTOR; C-REACTIVE PROTEIN; MUCINOUS TUMORS; SERUM-LEVELS; FLUID LEVELS; CARCINOMA; CYTOKINES; INVOLVEMENT; ORIGIN; INTERLEUKIN-6 AB Inflammatory cytokines, like tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), are elevated in ovarian cancer. Differences in cytokine expression by histologic subytpe or ovarian cancer risk factors can provide useful insight into ovarian cancer risk and etiology. We used ribonucleic acid in situ hybridization to assess TNF-alpha and IL-6 expression on tissue microarray slides from 78 epithelial ovarian carcinomas (51 serous, 12 endometrioid, 7 clear cell, 2 mucinous, 6 other) from a population-based case-control study. Cytokine expression was scored semiquantitatively, and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using polytomous logistic regression. TNF-alpha was expressed in 46% of the tumors, whereas sparse IL-6 expression was seen in only 18% of the tumors. For both markers, expression was most common in high-grade serous carcinomas followed by endometrioid carcinomas. Parity was associated with a reduced risk of TNF-alpha-positive (OR, 0.3; 95% CI, 0.1-0.7 for 3 or more children versus none) but not TNF-alpha-negative tumors (P heterogeneity = .02). In contrast, current smoking was associated with a nearly 3-fold increase in risk of TNF-alpha-negative (OR, 2.8; 95% CI, 1.2-6.6) but not TNF-alpha-positive tumors (P heterogeneity = .06). Our data suggest that TNF-alpha expression in ovarian carcinoma varies by histologic subtype and provides some support for the role of inflammation in ovarian carcinogenesis. The novel associations detected in our study need to be validated in a larger cohort of patients in future studies. (C) 2016 Elsevier Inc. All rights reserved. C1 [Gupta, Mamta; Beck, Andrew H.] Beth Israel Deaconess Med Ctr, Dept Pathol, 330 Brookline Ave, Boston, MA 02215 USA. [Babic, Ana] Dana Farber Canc Inst, Boston, MA 02215 USA. [Babic, Ana; Terry, Kathryn] Harvard Med Sch, Boston, MA 02215 USA. [Terry, Kathryn] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02215 USA. [Terry, Kathryn] Brigham & Womens Hosp, Obstet & Gynecol Epidemiol Ctr, Boston, MA 02215 USA. RP Gupta, M (reprint author), Beth Israel Deaconess Med Ctr, Dept Pathol, 330 Brookline Ave, Boston, MA 02215 USA. EM mgupta5@bidmc.harvard.edu FU National Institutes of Health [R01 CA054419-10, P50 CA105009]; DOD [W81XWH-10-1-0280, 5T32CA009001-38] FX This work was supported in part by the following grants: National Institutes of Health R01 CA054419-10 and P50 CA105009, DOD W81XWH-10-1-0280, and 5T32CA009001-38 (Harvard T.H. Chan School of Public Health, Boston, MA). NR 40 TC 1 Z9 1 U1 6 U2 6 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0046-8177 EI 1532-8392 J9 HUM PATHOL JI Hum. Pathol. PD AUG PY 2016 VL 54 BP 82 EP 91 DI 10.1016/j.humpath.2016.03.006 PG 10 WC Pathology SC Pathology GA DR6CP UT WOS:000379990000011 PM 27068525 ER PT J AU Rowell, SL Muratoglu, OK AF Rowell, Shannon L. Muratoglu, Orhun K. TI Investigation of surgically retrieved, vitamin E-stabilized, crosslinked UHMWPE implants after short-term in vivo service SO JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART B-APPLIED BIOMATERIALS LA English DT Article DE antioxidant; vitamin E; total joint arthroplasty; polyethylene (UHMWPE); implant retrieval ID MOLECULAR-WEIGHT POLYETHYLENE; TOTAL JOINT REPLACEMENT; ALPHA-TOCOPHEROL; MECHANICAL-PROPERTIES; IRRADIATED UHMWPE; ACETABULAR LINERS; OXIDATION; COMPONENTS; WEAR; PARTICLES AB BackgroundAntioxidant stabilized highly crosslinked ultra-high molecular weight polyethylene (UHMWPE) components have been in clinical use since 2008. In vitro testing has shown excellent oxidation resistance, wear resistance, mechanical properties, and fatigue strength. In this study, we analyzed surgically retrieved components to investigate in vivo behavior and changes in the material. MethodsFifteen surgically retrieved, vitamin E-stabilized, and radiation crosslinked UHMWPE components were analyzed to determine their oxidative stability, extent of lipid absorption in vivo, free radical content, hydroperoxide index, and extent of visible wear damage after in vivo service (0.1-36.6 months). ResultsRetrievals showed no significant carbonyls at the time of surgical removal, while free radical content was observed to decay with increasing in vivo duration. There was no increase in hydroperoxide index. Lipid penetration increased with time. Ex vivo oxidation was not observed after 18 months of aging in air at room temperature. ConclusionsThe free-radical scavenging activity of the vitamin E appears to successfully prevent both in vivo and ex vivo oxidation for short durations, while reducing free radical content overall. Without an increase in hydroperoxides, the oxidation cascade initiated by radiation-induced and lipid-derived free radicals appears to have been inhibited. Further investigation is required with longer duration implants. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1132-1140, 2016. C1 [Rowell, Shannon L.; Muratoglu, Orhun K.] Massachusetts Gen Hosp, Harris Orthopaed Lab, Boston, MA 02114 USA. [Muratoglu, Orhun K.] Harvard Med Sch, Dept Orthopaed Surg, Boston, MA 02115 USA. RP Muratoglu, OK (reprint author), Massachusetts Gen Hosp, Harris Orthopaed Lab, Boston, MA 02114 USA.; Muratoglu, OK (reprint author), Harvard Med Sch, Dept Orthopaed Surg, Boston, MA 02115 USA. EM omuratoglu@partners.org FU Zimmer; Stryker; DePuy; Biomet; Renovis FX The author and/or co-authors report the following conflicts of interest: royalties from Zimmer, Biomet, Corin, Iconacy, Renovis, Conformis, Aston Medical, Ceramtech, Maxx Orthopedix, Arthrex; stocks or stock options in Cambridge Polymer Group, Orthopedic Technology Group; research support from Zimmer, Stryker, DePuy, Biomet, Renovis; financial/material support from Biomet. NR 30 TC 0 Z9 0 U1 8 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4973 EI 1552-4981 J9 J BIOMED MATER RES B JI J. Biomed. Mater. Res. Part B PD AUG PY 2016 VL 104 IS 6 BP 1132 EP 1140 DI 10.1002/jbm.b.33465 PG 9 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA DR6ST UT WOS:000380032300009 PM 26039944 ER PT J AU Amorim, E McDade, EM AF Amorim, Edilberto McDade, Eric M. TI Rapidly-progressive catatonia responsive to zolpidem in a patient with ovarian teratoma-associated paraneoplastic encephalitis SO JOURNAL OF CLINICAL NEUROSCIENCE LA English DT Article DE Catatonia; Ovarian teratoma; Paraneoplastic encephalitis; Zolpidem ID LIMBIC ENCEPHALITIS AB Psychiatric symptoms and catatonia are key components of the clinical presentation of paraneoplastic encephalitis; additionally symptoms can be long-lasting and often difficult to treat. We report a 73-year-old patient with rapidly progressive catatonia not responsive to immunotherapy, tumor resection, electroconvulsive therapy, or benzodiazepines who had significant improvement after zolpidem administration. This report suggests that zolpidem is an option in the treatment of patients with refractory catatonia and paraneoplastic encephalitis. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Amorim, Edilberto] Massachusetts Gen Hosp, Dept Neurol, Boston, MA USA. [Amorim, Edilberto] Brigham & Womens Hosp, Boston, MA USA. [McDade, Eric M.] Washington Univ, Dept Neurol, 600 South Euclid,Box 8111, St Louis, MO 63110 USA. RP McDade, EM (reprint author), Washington Univ, Dept Neurol, 600 South Euclid,Box 8111, St Louis, MO 63110 USA. EM mcdadee@neuro.wustl.edu OI Amorim, Edilberto/0000-0001-6972-5622 NR 8 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0967-5868 EI 1532-2653 J9 J CLIN NEUROSCI JI J. Clin. Neurosci. PD AUG PY 2016 VL 30 BP 136 EP 138 DI 10.1016/j.jocn.2016.01.028 PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DR4QY UT WOS:000379888500027 PM 26964475 ER PT J AU Kalpathy-Cramer, J Zhao, BS Goldgof, D Gu, YH Wang, XW Yang, H Tan, YQ Gillies, R Napel, S AF Kalpathy-Cramer, Jayashree Zhao, Binsheng Goldgof, Dmitry Gu, Yuhua Wang, Xingwei Yang, Hao Tan, Yongqiang Gillies, Robert Napel, Sandy TI A Comparison of Lung Nodule Segmentation Algorithms: Methods and Results from a Multi-institutional Study SO JOURNAL OF DIGITAL IMAGING LA English DT Article DE Segmentation; Infrastructure; Lung cancer; Computed tomography; Quantitative imaging ID CONCORDANCE CORRELATION-COEFFICIENT; DATABASE-CONSORTIUM LIDC; ASSESSING AGREEMENT; CT SCANS; IMAGING BIOMARKERS; CANCER; VARIABILITY; MANAGEMENT; VOLUME; TUMORS AB Tumor volume estimation, as well as accurate and reproducible borders segmentation in medical images, are important in the diagnosis, staging, and assessment of response to cancer therapy. The goal of this study was to demonstrate the feasibility of a multi-institutional effort to assess the repeatability and reproducibility of nodule borders and volume estimate bias of computerized segmentation algorithms in CT images of lung cancer, and to provide results from such a study. The dataset used for this evaluation consisted of 52 tumors in 41 CT volumes (40 patient datasets and 1 dataset containing scans of 12 phantom nodules of known volume) from five collections available in The Cancer Imaging Archive. Three academic institutions developing lung nodule segmentation algorithms submitted results for three repeat runs for each of the nodules. We compared the performance of lung nodule segmentation algorithms by assessing several measurements of spatial overlap and volume measurement. Nodule sizes varied from 29 mu l to 66 ml and demonstrated a diversity of shapes. Agreement in spatial overlap of segmentations was significantly higher for multiple runs of the same algorithm than between segmentations generated by different algorithms (p < 0.05) and was significantly higher on the phantom dataset compared to the other datasets (p < 0.05). Algorithms differed significantly in the bias of the measured volumes of the phantom nodules (p < 0.05) underscoring the need for assessing performance on clinical data in addition to phantoms. Algorithms that most accurately estimated nodule volumes were not the most repeatable, emphasizing the need to evaluate both their accuracy and precision. There were considerable differences between algorithms, especially in a subset of heterogeneous nodules, underscoring the recommendation that the same software be used at all time points in longitudinal studies. C1 [Kalpathy-Cramer, Jayashree] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Kalpathy-Cramer, Jayashree] Harvard Med Sch, Boston, MA USA. [Zhao, Binsheng; Yang, Hao; Tan, Yongqiang] Columbia Univ, Med Ctr, Dept Radiol, New York, NY USA. [Goldgof, Dmitry] Univ S Florida, Dept Comp Sci & Engn, Tampa, FL USA. [Gu, Yuhua; Gillies, Robert] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Imaging, Tampa, FL 33612 USA. [Gu, Yuhua; Gillies, Robert] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Metab, Tampa, FL 33612 USA. [Wang, Xingwei; Napel, Sandy] Stanford Univ, Sch Med, Dept Radiol, James H Clark Ctr S323 318 Campus Dr, Stanford, CA 94305 USA. RP Napel, S (reprint author), Stanford Univ, Sch Med, Dept Radiol, James H Clark Ctr S323 318 Campus Dr, Stanford, CA 94305 USA. EM snapel@stanford.edu FU NCI NIH HHS [U24 CA180918, R01 CA149490, R01 CA160251, U01 CA140207, U01 CA143062, U01 CA154601, U24 CA180927] NR 43 TC 5 Z9 5 U1 8 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0897-1889 EI 1618-727X J9 J DIGIT IMAGING JI J. Digit. Imaging PD AUG PY 2016 VL 29 IS 4 BP 476 EP 487 DI 10.1007/s10278-016-9859-z PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DR2RI UT WOS:000379751200011 PM 26847203 ER PT J AU Romo, RD Lee, SJ AF Romo, Rafael D. Lee, Sei J. TI Changes in Social Function as a Trigger to Screen for Cognitive Impairment SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Editorial Material C1 [Romo, Rafael D.; Lee, Sei J.] San Francisco VA Med Ctr, Geriatr Serv, 4150 Clement St 181G, San Francisco, CA 94121 USA. [Romo, Rafael D.; Lee, Sei J.] San Francisco VA Med Ctr, Palliat Serv, 4150 Clement St 181G, San Francisco, CA 94121 USA. [Romo, Rafael D.; Lee, Sei J.] San Francisco VA Med Ctr, Extended Care Serv, 4150 Clement St 181G, San Francisco, CA 94121 USA. [Romo, Rafael D.; Lee, Sei J.] Univ Calif San Francisco, Div Geriatr, San Francisco, CA 94143 USA. RP Romo, RD (reprint author), San Francisco VA Med Ctr, Geriatr Serv, 4150 Clement St 181G, San Francisco, CA 94121 USA.; Romo, RD (reprint author), San Francisco VA Med Ctr, Palliat Serv, 4150 Clement St 181G, San Francisco, CA 94121 USA.; Romo, RD (reprint author), San Francisco VA Med Ctr, Extended Care Serv, 4150 Clement St 181G, San Francisco, CA 94121 USA. EM Rafael.Romo@ucsf.edu NR 9 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD AUG PY 2016 VL 31 IS 8 BP 826 EP 827 DI 10.1007/s11606-016-3755-6 PG 2 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA DR4KY UT WOS:000379871600004 PM 27245052 ER PT J AU Petrillo, LA Dzeng, E Smith, AK AF Petrillo, Laura A. Dzeng, Elizabeth Smith, Alexander K. TI California's End of Life Option Act: Opportunities and Challenges Ahead SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Editorial Material DE end of life care; palliative care; physician-assisted death; aging; health policy ID CARE C1 [Petrillo, Laura A.; Smith, Alexander K.] Univ Calif San Francisco, Dept Med, Div Geriatr, San Francisco, CA USA. [Petrillo, Laura A.; Smith, Alexander K.] San Francisco VA Med Ctr, San Francisco, CA USA. [Dzeng, Elizabeth] Univ Calif San Francisco, Dept Med, Div Hosp Med, San Francisco, CA USA. RP Petrillo, LA (reprint author), UCSF, Div Geriatr, 4150 Clement St 181G, San Francisco, CA 94141 USA. EM laura.petrillo@ucsf.edu FU NIA NIH HHS [K23 AG040772] NR 5 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD AUG PY 2016 VL 31 IS 8 BP 828 EP 829 DI 10.1007/s11606-016-3713-3 PG 2 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA DR4KY UT WOS:000379871600005 PM 27114358 ER PT J AU Danan, ER Joseph, AM Sherman, SE Burgess, DJ Noorbaloochi, S Clothier, B Japuntich, SJ Taylor, BC Fu, SS AF Danan, Elisheva R. Joseph, Anne M. Sherman, Scott E. Burgess, Diana J. Noorbaloochi, Siamak Clothier, Barbara Japuntich, Sandra J. Taylor, Brent C. Fu, Steven S. TI Does Motivation Matter? Analysis of a Randomized Trial of Proactive Outreach to VA Smokers SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE smoking cessation; motivation; veterans ID SMOKING-CESSATION; CLINICAL-TRIAL; TRANSTHEORETICAL MODEL; TOBACCO TREATMENT; QUIT SMOKING; INTEGRATIVE MODEL; STAGE; PREDICTORS; TIME; CONTEMPLATION AB Current guidelines advise providers to assess smokers' readiness to quit, then offer cessation therapies to smokers planning to quit and motivational interventions to smokers not planning to quit. We examined the relationship between baseline stage of change (SOC), treatment utilization, and smoking cessation to determine whether the effect of a proactive smoking cessation intervention was dependent on smokers' level of motivation to quit. Secondary analysis of a multicenter randomized controlled trial. A total of 3006 current smokers, aged 18-80 years, at four Veterans Affairs (VA) medical centers. Interventions: Proactive care included proactive outreach (mailed invitation followed by telephone outreach), offer of smoking cessation services (telephone or face-to-face), and access to pharmacotherapy. Usual care participants had access to VA smoking cessation services and state telephone quitlines. Baseline SOC measured with Readiness to Quit Ladder, and 6-month prolonged abstinence self-reported at 1 year. At baseline, 35.8 % of smokers were in preparation, 38.2 % in contemplation, and 26.0 % in precontemplation. The overall interaction between SOC and treatment arm was not statistically significant (p = 0.30). Among smokers in preparation, 21.1 % of proactive care participants achieved 6-month prolonged abstinence, compared to 13.1 % of usual care participants (OR, 1.8 [95 % CI, 1.2-2.6]). Similarly, proactive care increased abstinence among smokers in contemplation (11.0 % vs. 6.5 %; OR, 1.8 [95 % CI, 1.1-2.8]). Smokers in precontemplation quit smoking at similar rates (5.3 % vs. 5.6 %; OR, 0.9 [95 % CI, 0.5-1.9]). Within each stage, uptake of smoking cessation treatments increased with higher SOC and with proactive care as compared with usual care. Mostly male participants limits generalizability. Randomization was not stratified by SOC. Proactive care increased treatment uptake compared to usual care across all SOC. Proactive care increased smoking cessation among smokers in preparation and contemplation but not in precontemplation. Proactively offering cessation therapies to smokers at all SOC will increase treatment utilization and population-level smoking cessation. C1 [Danan, Elisheva R.; Burgess, Diana J.; Noorbaloochi, Siamak; Clothier, Barbara; Taylor, Brent C.; Fu, Steven S.] Minneapolis VA Hlth Care Syst, VA HSR & D Ctr Chron Dis Outcomes Res, Minneapolis, MN 55417 USA. [Danan, Elisheva R.; Joseph, Anne M.; Burgess, Diana J.; Noorbaloochi, Siamak; Taylor, Brent C.; Fu, Steven S.] Univ Minnesota, Sch Med, Dept Med, Minneapolis, MN 55455 USA. [Sherman, Scott E.] VA New York Harbor Healthcare Syst, New York, NY USA. [Sherman, Scott E.] NYU, Sch Med, Dept Populat Hlth, New York, NY USA. [Japuntich, Sandra J.] VA Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA USA. [Japuntich, Sandra J.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. RP Fu, SS (reprint author), Minneapolis VA Hlth Care Syst, VA HSR & D Ctr Chron Dis Outcomes Res, Minneapolis, MN 55417 USA. EM Steven.Fu@va.gov RI Taylor, Brent/A-8069-2009; OI Taylor, Brent/0000-0002-2140-8377; Sherman, Scott/0000-0003-1752-7303 FU US Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, and Health Services Research and Development [IAB-05-303]; Clinical Sciences Research and Development Service of the US Department of Veterans Affairs Office of Research and Development [1IK2CX000918-01A1] FX This study was funded by the US Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, and Health Services Research and Development (IAB-05-303), and was registered on ClinicalTrials.gov (NCT00608426). This work was supported in part by Career Development Award (Japuntich) no. 1IK2CX000918-01A1 from the Clinical Sciences Research and Development Service of the US Department of Veterans Affairs Office of Research and Development. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the US Department of Veterans Affairs or the US government. NR 50 TC 2 Z9 2 U1 3 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 2016 VL 31 IS 8 BP 878 EP 887 DI 10.1007/s11606-016-3687-1 PG 10 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA DR4KY UT WOS:000379871600014 PM 27071399 ER PT J AU Kimerling, R Iverson, KM Dichter, ME Rodriguez, AL Wong, A Pavao, J AF Kimerling, Rachel Iverson, Katherine M. Dichter, Melissa E. Rodriguez, Allison L. Wong, Ava Pavao, Joanne TI Prevalence of Intimate Partner Violence among Women Veterans who Utilize Veterans Health Administration Primary Care SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE domestic violence; women's health; veterans; primary care ID FEMALE VHA PATIENTS; HOUSING INSTABILITY; DOMESTIC VIOLENCE; SCREENING TOOL; REVICTIMIZATION; VICTIMIZATION; HOMELESSNESS; CONTINUITY; SURVIVORS; ACCURACY AB The objectives of this study were to identify the prevalence of past-year intimate partner violence (IPV) among women Veterans utilizing Veterans Health Administration (VHA) primary care, and to document associated demographic, military, and primary care characteristics. This was a retrospective cohort design, where participants completed a telephone survey in 2012 (84% participation rate); responses were linked to VHA administrative data for utilization in the year prior to the survey. A national stratified random sample of 6,287 women Veteran VHA primary care users participated in the study. Past-year IPV was assessed using the HARK screening tool. Self-report items and scales assessed demographic and military characteristics. Primary care characteristics were assessed via self-report and VHA administrative data. The prevalence of past-year IPV among women Veterans was 18.5% (se = 0.5%), with higher rates (22.2% - 25.5%) among women up to age 55. Other demographic correlates included indicators of economic hardship, lesbian or bisexual orientation, and being a parent/guardian of a child less than 18 years old. Military correlates included service during Vietnam to post-Vietnam eras, less than 10 years of service, and experiences of Military Sexual Trauma (MST). Most (77.3%, se = 1.2%) women who experienced IPV identified a VHA provider as their usual provider. Compared with women who did not report past-year IPV, women who reported IPV had more primary care visits, yet experienced lower continuity of care across providers. The high prevalence of past-year IPV among women beyond childbearing years, the majority of whom primarily rely on VHA as a source of health care, reinforces the importance of screening all women for IPV in VHA primary care settings. Key considerations for service implementation include sensitivity with respect to sexual orientation, race/ethnicity, and other aspects of diversity, as well as care coordination and linkages with social services and MST-related care. C1 [Kimerling, Rachel; Rodriguez, Allison L.; Pavao, Joanne] VA Palo Alto Hlth Care Syst, Dept Vet Affairs, Natl Ctr PTSD, Menlo Pk, CA USA. [Kimerling, Rachel; Wong, Ava] VA Palo Alto Hlth Care Syst, Dept Vet Affairs, Ctr Innovat Implementat, Menlo Pk, CA 94550 USA. [Iverson, Katherine M.] VA Boston Healthcare Syst, Dept Vet Affairs, Natl Ctr PTSD, Boston, MA USA. [Iverson, Katherine M.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Dichter, Melissa E.] Philadelphia VA Med Ctr, Dept Vet Affairs, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Dichter, Melissa E.] Univ Penn, Dept Family Med & Community Hlth, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Kimerling, R (reprint author), VA Palo Alto Hlth Care Syst, Dept Vet Affairs, Ctr Innovat Implementat, Menlo Pk, CA 94550 USA. EM Rachel.Kimerling@va.gov OI Wong, Ava/0000-0003-1777-219X FU National Center for PTSD; VA HSRD SDR [12-196]; VA HSRD CDA [10-202]; CDA [10-029] FX This study was funded by the National Center for PTSD and VA HSR&D SDR 12-196. The contributions of Drs. Dichter and Iverson to this manuscript were supported by VA HSR&D CDA 10-202 (MD) and CDA 10-029 (KI). NR 50 TC 1 Z9 1 U1 4 U2 7 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 2016 VL 31 IS 8 BP 888 EP 894 DI 10.1007/s11606-016-3701-7 PG 7 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA DR4KY UT WOS:000379871600015 PM 27130619 ER PT J AU Pamuk, F Cetinkaya, BO Keles, GC Balli, U Koyuncuoglu, CZ Cintan, S Kantarci, A AF Pamuk, F. Cetinkaya, B. O. Keles, G. C. Balli, U. Koyuncuoglu, C. Z. Cintan, S. Kantarci, A. TI Ankaferd blood stopper enhances healing after osseous grafting in patients with intrabony periodontal defects SO JOURNAL OF PERIODONTAL RESEARCH LA English DT Article DE blood stopper; intrabony defects; periodontal regeneration; VEGF ID ENDOTHELIAL GROWTH-FACTOR; GUIDED TISSUE REGENERATION; PLATELET-RICH PLASMA; VASCULAR-PERMEABILITY FACTOR; INTRAOSSEOUS DEFECTS; FURCATION DEFECTS; AUTOGENOUS BONE; BIOACTIVE GLASS; HUMANS; ANGIOGENESIS AB Background and ObjectiveThe aim of this clinical study were to compare the clinical efficacy of ankaferd blood stopper (ABS) when used in combination with autogenous cortical bone graft (ACB) in the treatment of intrabony periodontal defects. Material and MethodsThe study was planned as a split-mouth design. Fifteen patients with chronic periodontitis at 30 sites (six men, nine women; 42 7 years) were included. Treatment sites had probing pocket depths (PPD) of 6 mm and osseous defect depths of 4 mm as radiographically assessed. Following the initial periodontal therapy, patients were randomly assigned to two treatments in contralateral areas of the dentition: ACB + ABS or ACB alone. At baseline and 6 mo after surgery, clinical parameters of plaque index, gingival index, PPD, clinical attachment level and gingival recession (GR) were recorded. The primary outcome variable was the change in clinical attachment level between baseline and 24 wk after surgery. Gingival crevicular fluid samples were collected immediately before surgery and at 2, 4, 6, 12 and 24 wk after the surgery. Gingival crevicular fluid volume was calculated and vascular endothelial growth factor levels in gingival crevicular fluid were measured. ResultsPPD decreased, clinical attachment level improved and gingival index decreased significantly in response to both modes of treatment (p < 0.05). Both treatment modalities resulted in a significant gain in radiographic bone levels compared to baseline (p < 0.05). Intergroup comparisons showed that there was a significantly higher gain in clinical attachment level in the ABS/ACB group compared to ACB group (p < 0.05) with significantly less GR (p < 0.05). Similarly, vascular endothelial growth factor concentration in gingival crevicular fluid was significantly higher in the ABS/ACB group at postoperative weeks 2 and 4 compared to the ACB group (p < 0.01). ConclusionsThe findings suggest that ABS enhances the soft tissue healing during the periodontal defect fill by the ACB by stimulating angiogenesis and vascular endothelial cell function, prevents GR and thereby increases the clinical attachment gain. C1 [Pamuk, F.; Koyuncuoglu, C. Z.] Istanbul Aydin Univ, Fac Dent, Dept Periodontol, Besyol Mahallesi,Inonu Cad 38, TR-34295 Istanbul, Turkey. [Cetinkaya, B. O.; Keles, G. C.] Ondokuz Mayis Univ, Fac Dent, Dept Periodontol, Samsun, Turkey. [Balli, U.] Bulent Ecevit Univ, Fac Dent, Dept Periodontol, Zonguldak, Turkey. [Cintan, S.] Istanbul Univ, Fac Dent, Dept Periodontol, Istanbul, Turkey. [Kantarci, A.] Forsyth Inst, Dept Periodontol, Cambridge, MA USA. RP Pamuk, F (reprint author), Istanbul Aydin Univ, Fac Dent, Dept Periodontol, Besyol Mahallesi,Inonu Cad 38, TR-34295 Istanbul, Turkey. EM pamukferda@yahoo.com NR 64 TC 0 Z9 0 U1 6 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3484 EI 1600-0765 J9 J PERIODONTAL RES JI J. Periodont. Res. PD AUG PY 2016 VL 51 IS 4 BP 540 EP 547 DI 10.1111/jre.12334 PG 8 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA DR5AH UT WOS:000379914800013 PM 26547514 ER PT J AU Polyzos, SA Mantzoros, CS AF Polyzos, Stergios A. Mantzoros, Christos S. TI Nonalcoholic fatty future disease SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Article DE Noninvasive indices; Nonalcoholic fatty liver disease; Nonalcoholic steatohepatitis; Simple steatosis; Treatment ID LIVER-DISEASE; INSULIN SENSITIVITY; HEPATIC STEATOSIS; OXIDATIVE STRESS; LIPID-METABOLISM; UNITED-STATES; MICE; STEATOHEPATITIS; ACCUMULATION; EXPRESSION C1 [Polyzos, Stergios A.] Aristotle Univ Thessaloniki, Med Clin 2, Ippokration Hosp, Thessaloniki, Greece. [Mantzoros, Christos S.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Internal Med, Div Endocrinol Diabet & Metab, Boston, MA USA. [Mantzoros, Christos S.] Boston VA Healthcare Syst, Boston, MA USA. RP Mantzoros, CS (reprint author), Harvard Med Sch, Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. EM cmantzor@bidmc.harvard.edu NR 46 TC 2 Z9 2 U1 1 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 0026-0495 EI 1532-8600 J9 METABOLISM JI Metab.-Clin. Exp. PD AUG PY 2016 VL 65 IS 8 BP 1007 EP 1016 DI 10.1016/j.metabol.2015.12.009 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DR4RH UT WOS:000379889400001 PM 26805015 ER PT J AU Polyzos, SA Kountouras, J Mantzoros, CS AF Polyzos, Stergios A. Kountouras, Jannis Mantzoros, Christos S. TI Adipokines in in nonalcoholic fatty liver disease SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Article DE Adipokines; Adiponectin; Leptin; Nonalcoholic fatty liver disease; Nonalcoholic steatohepatitis; Resistin ID HEPATIC STELLATE CELLS; RETINOL-BINDING-PROTEIN; MORBIDLY OBESE-PATIENTS; MESSENGER-RNA EXPRESSION; VISCERAL ADIPOSE-TISSUE; COLONY-ENHANCING FACTOR; INSULIN-RESISTANCE; NICOTINAMIDE PHOSPHORIBOSYLTRANSFERASE; SERUM RETINOL-BINDING-PROTEIN-4; BARIATRIC SURGERY AB Since the discovery of adipose tissue as a higly active endocrine tissue, adipokines, peptides produced by adipose tissue and exerting autocrine, paracrine and endocrine function, have gained increasing interest in various obesity-related diseases, including nonalcoholic fatty liver disease (NAFLD). Data regarding the association between NAFLD and circulating leptin and adiponectin levels are generally well documented: leptin levels increase, whereas adiponectin levels decrease, by increasing the severity of NAFLD. Data regarding other adipokines in histologically confirmed NAFLD populations are inconclusive (e.g., resistin, visfatin, retinol-binding protein-4, chemerin) or limited (e.g., adipsin, obestatin, omentin, vaspin etc.). This review summarizes evidence on the association between adipokines and NAFLD. The first part of the review provides general consideration on the interplay between adipokines and NAFLD, and the second part provides evidence on specific adipokines possibly involved in NAFLD pathogenesis. A thorough insight into the pathophysiologic mechanisms linking adipokines with NAFLD may result in the design of studies investigating the combined adipokine use as noninvasive diagnostic markers of NAFLD and new clinical trials targeting the treatment of NAFLD. (C) 2016 Elsevier Inc. All rights reserved. C1 [Polyzos, Stergios A.; Kountouras, Jannis] Aristotle Univ Thessaloniki, Ippokrat Hosp, Dept Med, Med Clin 2, Thessaloniki, Greece. [Mantzoros, Christos S.] Harvard Med Sch, Div Endocrinol Diabet & Metab, Beth Israel Deaconess Med Ctr, Dept Internal Med, Boston, MA USA. [Mantzoros, Christos S.] Harvard Med Sch, Boston VA Healthcare Syst, Endocrinol Sect, Boston, MA USA. RP Polyzos, SA (reprint author), 13 Simou Lianidi, Thessaloniki 55134, Macedonia, Greece. EM stergios@endo.gr NR 191 TC 9 Z9 9 U1 7 U2 20 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 2016 VL 65 IS 8 BP 1062 EP 1079 DI 10.1016/j.metabol.2015.11.006 PG 18 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DR4RH UT WOS:000379889400006 PM 26725002 ER PT J AU Cristofaro, V Carey, SD Yalla, SV Sullivan, MP AF Cristofaro, V Carey, S. D. Yalla, S., V Sullivan, M. P. TI LOSS OF DETRUSOR SMOOTH MUSCLE CAVEOLAE ALTERS ALPHA-1 ADRENERGIC SIGNALING IN OVERACTIVE BLADDERS FROM SPONTANEOUSLY HYPERTENSIVE RATS SO NEUROUROLOGY AND URODYNAMICS LA English DT Meeting Abstract CT Annual Meeting of the International-Continence-Society (ICS) CY SEP 13-16, 2016 CL Tokyo, JAPAN SP Int Continence Soc C1 [Cristofaro, V; Carey, S. D.; Yalla, S., V; Sullivan, M. P.] Harvard Med Sch, Boston VA Healthcare Syst, 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 2016 VL 35 SU 4 MA 447 BP S402 EP S403 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA DR4XQ UT WOS:000379907200270 ER PT J AU Akers, SR Werner, TJ Rubello, D Alavi, A Cheng, G AF Akers, Scott R. Werner, Thomas J. Rubello, Domenico Alavi, Abass Cheng, Gang TI F-18-FDG uptake and clearance in patients with compromised renal function SO NUCLEAR MEDICINE COMMUNICATIONS LA English DT Article DE clearance; delayed imaging; F-18-FDG PET; renal function; standardized uptake value ID DUAL TIME-POINT; FDG-PET; NORMAL-TISSUES; GLUCOSE AB ObjectiveThe aim of this study is to evaluate whether compromised renal function has an effect on the uptake and clearance of 2-deoxy-2-[F-18]fluoro-d-glucose (F-18-FDG) in normal tissues on F-18-FDG PET/CT imaging.Patients and methodsPatients were divided into three groups on the basis of their renal function status: 25 patients with normal renal function [estimated glomerular filtration rate (eGFR)>90ml/min], 21 patients with mildly compromised renal function (90eGFR60ml/min), and 12 patients with moderate or severe compromised renal function (eGFR<60ml/min). All patients underwent F-18-FDG PET/CT imaging at 1, 2, and 3h after tracer injection. Maximum standardized uptake values (SUVmax) were obtained in regions of interest for multiple tissue types.ResultsSerial SUV values from 1 to 3h were measured for different tissues including the aortic blood pool, liver, spleen, lung, lymph nodes, and skeletal muscles. The SUV values of F-18-FDG uptake showed significantly decreased activity from 1 to 2h as well as from 2 to 3h for each tissue type, irrespective of renal function. There was no significant difference in SUVmean values between patients with normal and compromised renal functions, which was consistently observed for each tissue type and at each time point. In fact, the variance in individual SUV values within a group was more than the variance of SUV means between the groups with different renal functions for all tissue types and at 1-, 2-, or 3-h time points. Finally, the lack of dependence of SUV values in normal tissues on renal function is shown by very low r(2) values when comparing SUV and eGFR.ConclusionOur data suggest that compromised renal function does not significantly compromise clearance of background activity of F-18-FDG PET imaging. As a result, adjustment of F-18-FDG dose or imaging time is not necessary in renal-impaired patients to achieve optimal imaging. C1 [Akers, Scott R.; Cheng, Gang] Philadelphia VA Med Ctr, Dept Radiol, 3900 Woodland Ave, Philadelphia, PA 19104 USA. [Werner, Thomas J.; Alavi, Abass; Cheng, Gang] Hosp Univ Penn, Dept Radiol, 3400 Spruce St, Philadelphia, PA 19104 USA. [Rubello, Domenico] Santa Maria della Misericordia Hosp, Dept Nucl Med, Intervent Radiol NeuroRadiol,Pathol,Microbiol, PET CT Ctr,Radiol,Med Phys,Clin Lab,Biomarkers La, Rovigo, Italy. RP Cheng, G (reprint author), Philadelphia VA Med Ctr, Dept Radiol, 3900 Woodland Ave, Philadelphia, PA 19104 USA. EM gangcheng99@yahoo.com FU Department of Veterans Affairs (VISN 4 CPPF Grant) FX This study was supported in part by a pilot grant from the Department of Veterans Affairs (VISN 4 CPPF Grant). The content of this article does not necessarily reflect the views of the Department of Veterans Affairs or of the US Government. NR 12 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 0143-3636 EI 1473-5628 J9 NUCL MED COMMUN JI Nucl. Med. Commun. PD AUG PY 2016 VL 37 IS 8 BP 825 EP 832 DI 10.1097/MNM.0000000000000513 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DR7WN UT WOS:000380110500007 PM 27058366 ER PT J AU Carlson, LC Lafta, R Al-Shatari, S Stewart, BT Burnham, G Kushner, AL AF Carlson, Lucas C. Lafta, Riyadh Al-Shatari, Sahar Stewart, Barclay T. Burnham, Gilbert Kushner, Adam L. TI Pediatric injury during conflict and prolonged insecurity in Iraq from 2003-2014 SO SURGERY LA English DT Article ID MIDDLE-INCOME COUNTRIES; TRAUMA CARE; CHILDHOOD INJURIES; GHANA; AFRICA; BURDEN; HEALTH AB Background. Injury disproportionately affects low- and middle-income countries, and in Iraq, this risk has been compounded by conflict and insecurity since the Coalition invasion in 2003. Children in such settings are particularly vulnerable; yet, the epidemiology of pediatric injury during conflict has not been previously described. This study aimed to characterize the pattern and outcomes of pediatric injury in Baghdad, Iraq from 2003-2014. Methods. We conducted a cluster-randomized, cross-sectional, community-based survey in Baghdad in 2014 to determine the epidemiology and impact of injuries since 2003. This study details the injury patterns and outcomes among children (ie, <18 years of age) as well as care sought and provided. Results. A total of 900 households, which represented 5,148 persons, were surveyed. There were 152 pediatric injuries from 2003-2014 (28% of all injuries). The incidence of childhood injury during the study period was 6.5 per 1,000 life years. The most common cause of injury was fall (52 injuries; 34% of pediatric injuries) followed by road traffic crash (32; 22%). Fifteen percent of pediatric injuries were directly related to conflict (22 injuries). There were 10 reported deaths (7% of pediatric injuries). Conclusion. Although falls and road traffic crashes were the most common causes of childhood injury, conflict was directly responsible for 1 in 6 injuries. The number of pediatric injuries that resulted in death far exceeded that of low- and middle-income countries unaffected by conflict. These findings reflect the importance of pediatric injury prevention, protection of vulnerable populations, and essential trauma care during conflict. C1 [Carlson, Lucas C.] Brigham & Womens Hosp, Dept Emergency Med, Boston, MA USA. [Carlson, Lucas C.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA USA. [Lafta, Riyadh] Al Munstansiriya Univ, Coll Med, Baghdad, Iraq. [Al-Shatari, Sahar] Minist Hlth, Human Dev & Training Ctr, Baghdad, Iraq. [Stewart, Barclay T.] Univ Washington, Dept Surg, Seattle, WA USA. [Stewart, Barclay T.] Kwame Nkrumah Univ Sci & Technol, Sch Med Sci, Kumasi, Ghana. [Stewart, Barclay T.] Univ Stellenbosch, Dept Interdisciplinary Hlth Sci, Cape Town, South Africa. [Burnham, Gilbert; Kushner, Adam L.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD 21205 USA. [Kushner, Adam L.] Surg OverSeas SOS, New York, NY USA. RP Kushner, AL (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD 21205 USA. EM akushne1@jhu.edu OI Kushner, Adam/0000-0002-7797-4837 FU Surgeons OverSeas; Fogarty International Center, US National Institutes of Health [R25-TW009345] FX Supported by Surgeons OverSeas. Data analysis and manuscript preparation was partially supported by grant R25-TW009345 from the Fogarty International Center, US National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 29 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 0039-6060 J9 SURGERY JI Surgery PD AUG PY 2016 VL 160 IS 2 BP 493 EP 500 DI 10.1016/j.surg.2016.03.022 PG 8 WC Surgery SC Surgery GA DR4QT UT WOS:000379888000027 PM 27155907 ER PT J AU Kelley-Cook, E Nguyen, G Lee, S Edwards, TM Sanchez-Reilly, S AF Kelley-Cook, Esther Nguyen, George Lee, Shuko Edwards, Tressia M. Sanchez-Reilly, Sandra TI Medication Needs Vary for Terminally Ill Vietnam Era Veterans With and Without a Diagnosis of PTSD SO AMERICAN JOURNAL OF HOSPICE & PALLIATIVE MEDICINE LA English DT Article DE posttraumatic stress disorder (PTSD); end of life; Vietnam Veterans; palliative care; terminal care; pharmacotherapy ID POSTTRAUMATIC-STRESS-DISORDER; INTIMATE PARTNER; COMBAT VETERANS; US VETERANS; DEPRESSION; INSOMNIA; RISK; LIFE; END AB This retrospective pilot study aims to evaluate the clinical impact of palliative care in the treatment of terminally ill Vietnam Veterans with a history of posttraumatic stress disorder (PTSD) versus those without PTSD, as it pertains to medications for symptom control at the end of life (EOL). Active prescriptions for benzodiazepines, hypnotics, antidepressants, and antipsychotic medications at the EOL were recorded. During EOL care, 28 (72%) participants with PTSD used these medications versus 55 (40%) of the non-PTSD participants (P = .0005). There was significant correlation between a lifetime diagnosis of PTSD with antidepressant use (P = .0002) and hypnotics (P = .0085) during EOL care but not with benzodiazepines or antipsychotics. The higher utilization of certain medication classes among participants with PTSD may indicate that PTSD treatment should continue at the EOL to improve care. C1 [Kelley-Cook, Esther; Sanchez-Reilly, Sandra] Univ Texas Hlth Sci Ctr San Antonio, 7400 Merton Minter Blvd, San Antonio, TX 78229 USA. [Nguyen, George] Baylor Scott & White Hlth Care Syst, Temple, TX USA. [Lee, Shuko; Edwards, Tressia M.; Sanchez-Reilly, Sandra] South Texas Vet Hlth Care Syst, San Antonio, TX USA. RP Sanchez-Reilly, S (reprint author), Univ Texas Hlth Sci Ctr San Antonio, 7400 Merton Minter Blvd, San Antonio, TX 78229 USA.; Sanchez-Reilly, S (reprint author), South Texas Vet Hlth Care Syst GRECC 182, 7400 Merton Minter Blvd, San Antonio, TX 78229 USA. EM Sanchezreill@uthscsa.edu FU South Texas Veterans Health Care System, San Antonio, Texas FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study is the result of work supported with resources and the use of facilities at the South Texas Veterans Health Care System, San Antonio, Texas. NR 16 TC 0 Z9 0 U1 1 U2 3 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 2016 VL 33 IS 7 BP 625 EP 632 DI 10.1177/1049909115586556 PG 8 WC Health Care Sciences & Services SC Health Care Sciences & Services GA DR3MR UT WOS:000379807800002 PM 25991568 ER PT J AU Thai, JN Barnhart, CE Cagle, J Smith, AK AF Thai, Julie N. Barnhart, Caroline E. Cagle, John Smith, Alexander K. TI "It Just Consumes Your Life": Quality of Life for Informal Caregivers of Diverse Older Adults With Late-Life Disability SO AMERICAN JOURNAL OF HOSPICE & PALLIATIVE MEDICINE LA English DT Article DE caregiving; geriatrics; quality of life; disability; palliative care; informal caregivers ID LARGE SOCIAL NETWORK; LONG-TERM-CARE; FAMILY CAREGIVERS; STRESS PROCESS; TRANSITIONS; LONELINESS; SPREAD; HEALTH AB Little is known about the quality of life (QoL) for informal caregivers of disabled older adults aged 65+ with diverse backgrounds. Forty-two caregivers were interviewed in English and Cantonese about their caregiving experiences, their recollections of QoL over time, and the factors influencing their appraisals. Overall, 52% of caregivers experienced a decline in QoL. Factors associated with decreased QoL were less time for self, competing financial demands, and the physical and emotional impact of the patient's illness. Factors associated with no change in QoL were minimal caregiving responsibilities, a sense of filial duty, and QoL being consistently poor over time. Factors associated with improved QoL were perceived rewards in caregiving, receiving institutional help, and increased experience. Chinese caregivers were more likely to cite filial duty as their motivator for continued caregiving than were Caucasian caregivers. In conclusion, informal caregivers take on a huge burden in enabling older adults to age in the community. These caregivers need more support in maintaining their QoL. C1 [Thai, Julie N.; Barnhart, Caroline E.; Smith, Alexander K.] Univ Calif San Francisco, Dept Med, Div Geriatr, San Francisco, CA USA. [Barnhart, Caroline E.; Smith, Alexander K.] San Francisco VA Med Ctr, Geriatr Palliat & Extended Care, San Francisco, CA USA. [Cagle, John] Univ Maryland, Sch Social Work, 525 W Redwood St, Baltimore, MD 21201 USA. RP Smith, AK (reprint author), Univ Calif San Francisco, Div Geriatr, 4250 Clement St,Bldg 1,Room 181G, San Francisco, CA 94121 USA. EM aksmith@ucsf.edu FU "Medical Student Training in Aging Research (MSTAR)" Program - National Institute on Aging [T35AG026736]; John A. Hartford Foundation; MetLife Foundation; Lillian R. Gleitsman Foundation; National Institute on Aging (NIA) [5T32AG000212]; Beeson Career Development Award from National Institute on Aging; American Federation of Aging Research [K23AG040772]; ASP-T FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Julie Thai's effort on this project was supported by the "Medical Student Training in Aging Research (MSTAR)" Program funded by the National Institute on Aging (T35AG026736), the John A. Hartford Foundation, the MetLife Foundation, and the Lillian R. Gleitsman Foundation. Dr Cagle's efforts were supported by a training grant from the National Institute on Aging (NIA), 5T32AG000212. Dr Smith's effort on this project was supported by the Beeson Career Development Award from the National Institute on Aging and the American Federation of Aging Research (K23AG040772) and by the ASP-T. Franklin Williams Society of General Internal Medicine Scholars Award in Geriatrics. NR 21 TC 1 Z9 1 U1 9 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 2016 VL 33 IS 7 BP 644 EP 650 DI 10.1177/1049909115583044 PG 7 WC Health Care Sciences & Services SC Health Care Sciences & Services GA DR3MR UT WOS:000379807800005 PM 25948041 ER PT J AU Curigliano, G Pardo, PG Meric-Bernstam, F Conte, P Lolkema, MP Beck, JT Bardia, A Garcia, MM Penault-Llorca, F Dhuria, S Tang, Z Solovieff, N Miller, M Di Tomaso, E Hurvitz, SA AF Curigliano, G. Gomez Pardo, P. Meric-Bernstam, F. Conte, P. Lolkema, M. P. Beck, J. T. Bardia, A. Martinez Garcia, M. Penault-Llorca, F. Dhuria, S. Tang, Z. Solovieff, N. Miller, M. Di Tomaso, E. Hurvitz, S. A. TI Ribociclib plus letrozole in early breast cancer: A presurgical, window-of-opportunity study SO BREAST LA English DT Article DE Breast cancer; CDK4/6; Letrozole; Ribociclib ID CIRCULATING TUMOR-CELLS; ENDOCRINE THERAPY; PROGNOSTIC VALUE; CONTROLLED-TRIAL; PLACEBO; PROLIFERATION; PALBOCICLIB; CDK4/6; DNA AB Objectives: Cyclin D-cyclin-dependent kinase (CDK) 4/6-inhibitor of CDK4/6-retinoblastoma (Rb) pathway hyperactivation is associated with hormone receptor-positive (HR+) breast cancer (BC). This study assessed the biological activity of ribociclib (LEE011; CDK4/6 inhibitor) plus letrozole compared with single-agent letrozole in the presurgical setting. Materials and methods: Postmenopausal women (N = 14) with resectable, HR+, human epidermal growth factor receptor 2-negative (HER2-) early BC were randomized 1:1:1 to receive 2.5 mg/day letrozole alone (Arm 1), or with 400 or 600 mg/day ribociclib (Arm 2 or 3). Circulating tumor DNA and tumor biopsies were collected at baseline and, following 14 days of treatment, prior to or during surgery. The primary objective was to assess antiproliferative response per Ki67 levels in Arms 2 and 3 compared with Arm 1. Additional assessments included safety, pharmacokinetics, and genetic profiling. Results: Mean decreases in the Ki67-positive cell fraction from baseline were: Arm 1 69% (range 38-100%; n = 2), Arm 2 96% (range 78-100%; n = 6), Arm 3 92% (range 75-100%; n = 3). Decreased phosphorylated Rb levels and CDK4, CDK6, CCND2, CCND3, and CCNE1 gene expression were observed following ribociclib treatment. Ribociclib and letrozole pharmacokinetic parameters were consistent with single-agent data. The ribociclib plus letrozole combination was well tolerated, with no Grade 3/4 adverse events over the treatment. Conclusion: The results suggest absence of a drug-drug interaction between ribociclib and letrozole and indicate ribociclib plus letrozole may reduce Ki67 expression in HR+, HER2- BC (NCT01919229). (C) 2016 The Authors. Published by Elsevier Ltd. C1 [Curigliano, G.] Ist Europeo Oncol, Via Ripamonti 435, I-20141 Milan, Italy. [Gomez Pardo, P.] Vall dHebron Univ Hosp, Med Oncol Serv, Vall dHebron 119-129, Barcelona 08035, Spain. [Meric-Bernstam, F.] Univ Texas MD Anderson Canc Ctr, 1400 Holcombe Blvd, Houston, TX 77030 USA. [Conte, P.] Ist Oncol Veneto, Via Gattamelata 64, I-35128 Padua, Italy. [Conte, P.] Univ Padua, Via Giustiniani 22, I-35121 Padua, Italy. [Lolkema, M. P.] Univ Med Ctr Utrecht, Heidelberglaan 100, NL-3584 CX Utrecht, Netherlands. [Lolkema, M. P.] Erasmus MC, Erasmus Med Ctr Canc Inst, S Gravendijkwal 230, NL-3015 CE Rotterdam, Netherlands. [Beck, J. T.] Highlands Oncol Grp, 3232 N North Hills Blvd, Fayetteville, AR 72703 USA. [Bardia, A.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc, 55 Fruit St, Boston, MA 02114 USA. [Martinez Garcia, M.] Hosp del Mar, Oncol Med, Passeig Maritim 25-29, Barcelona 08003, Spain. [Penault-Llorca, F.] Univ Auvergne, Ctr Jean Perrin, Unicanc, 58 Rue Montalembert, F-63011 Clermont Ferrand, France. [Penault-Llorca, F.] Univ Auvergne, EA 4677, 58 Rue Montalembert, F-63011 Clermont Ferrand, France. [Dhuria, S.; Tang, Z.; Miller, M.] Novartis Pharmaceut, One Hlth Plaza, E Hanover, NJ 07936 USA. [Solovieff, N.; Di Tomaso, E.] Novartis Inst BioMed Res, 230 Massachusetts Ave, Cambridge, MA 02139 USA. [Hurvitz, S. A.] Univ Calif Los Angeles, 2825 Santa Monica Blvd,Suite 211, Santa Monica, CA 90404 USA. RP Curigliano, G (reprint author), Ist Europeo Oncol, Via Ripamonti 435, I-20141 Milan, Italy. EM giuseppe.curigliano@ieo.it RI CONTE, PIERFRANCO/F-7418-2014 OI CONTE, PIERFRANCO/0000-0002-5210-5344 FU Novartis Pharmaceuticals Corporation; Novartis FX This study was initiated, funded, and sponsored by Novartis Pharmaceuticals Corporation, who also provided financial support for medical editorial assistance. S. Dhuria, Z. Tang, N. Solovieff, M. Miller, and E. Di Tomaso are Novartis employees; Z. Tang holds Novartis stock and options. F. Meric-Bernstam served as a consultant to, and received research funding from, Novartis. Outside the submitted work, F. Meric-Bernstam served as a consultant to Celgene, Genentech, Inflection Biosciences, and Roche, received research funding from Aileron Therapeutics, AstraZeneca, Bayer, Calithera, CytomX Therapeutics, Debiopharm, Puma Biotechnology, Taiho, and Veastem, and honoraria from Genentech and Roche. M.P. Lolkema received research funding from Astellas Pharma and Johnson & Johnson outside the submitted work. A. Bardia acted as a consultant for Novartis outside the submitted work. S.A. Hurvitz received related research funding from Novartis and institute research funding from Bayer, Lilly, and OBI Pharma outside the submitted work. G. Curigliano, P. Gomez Pardo, P. Conte, J.T. Beck, and F. Penault-Llorca declare no conflicts of interest. NR 34 TC 1 Z9 1 U1 2 U2 9 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0960-9776 EI 1532-3080 J9 BREAST JI Breast PD AUG PY 2016 VL 28 BP 191 EP 198 DI 10.1016/j.breast.2016.06.008 PG 8 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA DR1RT UT WOS:000379683300029 PM 27336726 ER PT J AU Vina, ER Richardson, D Medvedeva, E Kwoh, CK Collier, A Ibrahim, SA AF Vina, Ernest R. Richardson, Diane Medvedeva, Elina Kwoh, C. Kent Collier, Aliya Ibrahim, Said A. TI Does a Patient-centered Educational Intervention Affect African-American Access to Knee Replacement? A Randomized Trial SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID TOTAL JOINT REPLACEMENT; RACE/ETHNICITY DISPARITIES; PHYSICIANS PERCEPTIONS; PROVIDER CONTRIBUTION; SOCIOECONOMIC-STATUS; RACIAL DISPARITIES; DECISION-MAKING; UNITED-STATES; OSTEOARTHRITIS; HEALTH AB A TKA is the most effective and cost-effective surgical option for moderate to severe osteoarthritis (OA) of the knee. Yet, black patients are less willing to undergo knee replacement surgery than white patients. Decision aids help people understand treatment options and consider the personal importance of possible benefits and harms of treatments, including TKA. We asked: (1) Does a patient-centered intervention consisting of a decision aid for knee OA and motivational interviewing improve the proportion of referrals of blacks with knee OA to orthopaedic surgery? (2) Does the intervention increase patients' willingness to undergo TKA? Adults who self-identified as black who were at least 50 years old with moderate to severe knee OA were enrolled from urban primary care clinics in a two-group randomized, controlled trial. A total of 1253 patients were screened for eligibility, and 760 were excluded for not meeting inclusion criteria, declining to participate, or other reasons. Four hundred ninety-three patients were randomized and completed the intervention; three had missing referral data at followup. The mean age of the patients was 61 years, and 51% were women. The majority had an annual household income less than USD 15,000. Participants in the treatment group were shown a decision-aid video and had a brief session with a trained counselor in motivational interviewing. Participants in the control group received an educational booklet about OA that did not mention joint replacement. The two groups had comparable demographic and socioeconomic characteristics. The primary outcome was referral to orthopaedic surgery 12 months after treatment exposure. Receipt of referral was defined as the receipt of a recommendation or prescription from a primary care provider for orthopaedic evaluation. The secondary outcome was change in patient willingness to undergo TKA based on patient self-report. The odds of receiving a referral to orthopaedic surgery did not differ between the two study groups (36%, 90 of 253 of the control group; 32%, 76 of 240 of the treatment group; odds ratio [OR], 0.81; 95% CI, 0.56-1.18; p = 0.277). At 2 weeks followup, there was no difference between the treatment and the control groups in terms of increased willingness to consider TKA relative to baseline (34%, 67 of 200 patients in the treatment group; 33%, 68 of 208 patients in the control group; OR, 1.06; p = 0.779). At 12 months followup, the percent increase in willingness to undergo TKA still did not differ between patients in the treatment and control groups (29%, 49 of 174 in the treatment group; 27%, 51 of 191 in the control group; OR, 1.10; p = 0.679). A combination decision aid and motivational interviewing strategy was no better than an educational pamphlet in improving patients' preferences toward joint replacement surgery for knee OA. The type of intervention treatment also did not affect access to surgical evaluation. Other tools that target patient knowledge, beliefs, and attitudes regarding surgical treatments for OA may be further developed and tested in the future. Level I, therapeutic study. C1 Univ Penn, Philadelphia, PA 19104 USA. Philadelphia VA Med Ctr, Philadelphia, PA USA. Univ Pittsburgh, Pittsburgh, PA USA. [Vina, Ernest R.; Kwoh, C. Kent] Univ Arizona, Sch Med, 1501 N Campbell Ave, Tucson, AZ 85724 USA. [Vina, Ernest R.; Kwoh, C. Kent] Univ Arizona, Arthrit Ctr, 1501 N Campbell Ave, Tucson, AZ 85724 USA. [Richardson, Diane; Medvedeva, Elina; Ibrahim, Said A.] Philadelphia VA Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Collier, Aliya; Ibrahim, Said A.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Vina, ER (reprint author), Univ Arizona, Sch Med, 1501 N Campbell Ave, Tucson, AZ 85724 USA.; Vina, ER (reprint author), Univ Arizona, Arthrit Ctr, 1501 N Campbell Ave, Tucson, AZ 85724 USA. EM evina@email.arizona.edu OI Vina, Ernest/0000-0001-8135-1731 FU NIH/National Institute of Arthritis and Musculoskeletal Skin Diseases [1-RO1-AR-054474-5, K24AR055259] FX Funding was received from the NIH/National Institute of Arthritis and Musculoskeletal Skin Diseases Grant# 1-RO1-AR-054474-5 (SI) and K24AR055259 (SI). NR 39 TC 1 Z9 1 U1 4 U2 4 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 2016 VL 474 IS 8 BP 1755 EP 1764 DI 10.1007/s11999-016-4834-z PG 10 WC Orthopedics; Surgery SC Orthopedics; Surgery GA DQ1WW UT WOS:000378992200003 PM 27075333 ER PT J AU Ring, DC AF Ring, David C. TI Clinical Faceoff: Routine Electrodiagnostic Testing is Not Helpful in the Management of Carpal Tunnel Syndrome SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Editorial Material C1 [Ring, David C.] Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. RP Ring, DC (reprint author), Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. EM dring@partners.org NR 0 TC 0 Z9 0 U1 2 U2 4 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 2016 VL 474 IS 8 BP 1770 EP 1774 DI 10.1007/s11999-015-4183-3 PG 5 WC Orthopedics; Surgery SC Orthopedics; Surgery GA DQ1WW UT WOS:000378992200005 PM 25690166 ER PT J AU Nota, SPFT Spit, SA Oosterhoff, TCH Hageman, MGJS Ring, DC Vranceanu, AM AF Nota, Sjoerd P. F. T. Spit, Silke A. Oosterhoff, Thijs C. H. Hageman, Michiel G. J. S. Ring, David C. Vranceanu, Ana-Maria TI Is Social Support Associated With Upper Extremity Disability? SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID INFORMATION-SYSTEM PROMIS; POSTTRAUMATIC GROWTH; PHYSICAL FUNCTION; HEALTH-STATUS; PAIN; DEPRESSION; QUICKDASH; ARM; QUESTIONNAIRE; ARTHRITIS AB Pain intensity and disability correlate with psychosocial factors such as depression and pain interference (the degree to which pain interferes with activities of daily living) as much or more than pathophysiology in upper extremity illness. However, other factors like emotional support (perception of being cared for and valued as a person), instrumental support (perception of availability of tangible assistance when needed), positive psychosocial impact (perception and focus on the positive side of a difficult situation, sometimes characterized as posttraumatic growth, benefit-finding, or meaning making), also might be associated with disability in patients with upper extremity orthopaedic illness. This is the first published study, to our knowledge, addressing the potential association of emotional support, instrumental support, and positive psychosocial illness impact with disability in patients with upper extremity illness. We asked: (1) Is there a correlation between the QuickDASH and the Patient-reported Outcomes Measurement Information System (PROMISA (R)) emotional support Computer Adaptive Testing (CAT)? (2) Is there a correlation between the QuickDASH and PROMISA (R) instrumental support CAT? (3) Is there a correlation between the QuickDASH and PROMISA (R) positive psychosocial illness impact CAT? (4) Among the PROMISA (R) measures of depression, emotional support, instrumental support, positive illness impact, and pain interference, which accounts for the most variance in QuickDASH scores? One hundred ninety-three patients with upper extremity illness (55% women; average age, 51 +/- 18 years) of 213 approached (91% recruitment rate) completed the QuickDASH, and five different PROMISA (R) CATs: pain interference (the degree to which pain interferes with accomplishing one's goals), depression, emotional support, psychosocial illness impact, and instrumental support. We recruited patients from the practice of three surgeons in hand service of the department of orthopaedic surgery at a major urban university hospital. Pearson Product Moment Correlations showed that emotional support (r = -0.18; p = 0.014) and instrumental support (r = -0.19; p = 0.008) were weakly and inversely associated with the QuickDASH), while positive psychosocial illness impact was moderately and inversely associated with the QuickDASH (r = -0.36; p < 0.001). In multivariable analyses, pain interference, but not the social support measures, was the only psychosocial factor associated with the QuickDASH and alone explained 66% of variance. Emotional support, instrumental support and positive psychosocial illness impact are all individually associated with disability to a small degree, but pain interference (the degree to which pain interferes with accomplishing one's goals) has the strongest influence on magnitude of disability. Level 1, prognostic study. C1 [Nota, Sjoerd P. F. T.; Spit, Silke A.; Oosterhoff, Thijs C. H.; Hageman, Michiel G. J. S.; Ring, David C.] Massachusetts Gen Hosp, Orthopaed Hand & Upper Extrem Serv, Boston, MA 02114 USA. [Vranceanu, Ana-Maria] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Ring, David C.] Dell Med Sch, Dept Surg & Perioperat Care, 1400 Barbara Jordan Blvd,Suite 2-834,MC R1800, Austin, TX 78723 USA. RP Ring, DC (reprint author), Dell Med Sch, Dept Surg & Perioperat Care, 1400 Barbara Jordan Blvd,Suite 2-834,MC R1800, Austin, TX 78723 USA. EM david.ring@austin.utexas.edu NR 29 TC 0 Z9 0 U1 2 U2 4 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 2016 VL 474 IS 8 BP 1830 EP 1836 DI 10.1007/s11999-016-4892-2 PG 7 WC Orthopedics; Surgery SC Orthopedics; Surgery GA DQ1WW UT WOS:000378992200016 PM 27172821 ER PT J AU Palthe, ODRV Neuhaus, V Janssen, SJ Guitton, TG Ring, D AF Palthe, Olivier D. R. van Wulfften Neuhaus, Valentin Janssen, Stein J. Guitton, Thierry G. Ring, David CA Sci Variation Grp TI Among Musculoskeletal Surgeons, Job Dissatisfaction Is Associated With Burnout SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID QUALITY-OF-LIFE; CAREER SATISFACTION; AMERICAN SURGEONS; PATIENT-CARE; RISK; DISTRESS; PHYSICIANS; PROGRAM; DISEASE AB Burnout is common in professions such as medicine in which employees have frequent and often stressful interpersonal interactions where empathy and emotional control are important. Burnout can lead to decreased effectiveness at work, negative health outcomes, and less job satisfaction. A relationship between burnout and job satisfaction is established for several types of physicians but is less studied among surgeons who treat musculoskeletal conditions. We asked: (1) For surgeons treating musculoskeletal conditions, what risk factors are associated with worse job dissatisfaction? (2) What risk factors are associated with burnout symptoms? Two hundred ten (52% of all active members of the Science of Variation Group [SOVG]) surgeons who treat musculoskeletal conditions (94% orthopaedic surgeons and 6% trauma surgeons; in Europe, general trauma surgeons do most of the fracture surgery) completed the Global Job Satisfaction instrument, Shirom-Malamed Burnout Measure, and provided practice and surgeon characteristics. Most surgeons were male (193 surgeons, 92%) and most were academically employed (186 surgeons, 89%). Factors independently associated with job satisfaction and burnout were identified with multivariable analysis. Greater symptoms of burnout (beta, -7.13; standard error [SE], 0.75; 95% CI, -8.60 to -5.66; p < 0.001; adjusted R-2, 0.33) was the only factor independently associated with lower job satisfaction. Having children (beta, -0.45; SE, 0.0.21; 95% CI, -0.85 to -0.043; p = 0.030; adjusted R-2, 0.046) was the only factor independently associated with fewer symptoms of burnout. Among an active research group of largely academic surgeons treating musculoskeletal conditions, most are satisfied with their job. Efforts to limit burnout and job satisfaction by optimizing engagement in and deriving meaning from the work are effective in other settings and merit attention among surgeons. Level II, prognostic study. C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. [Palthe, Olivier D. R. van Wulfften; Janssen, Stein J.; Ring, David] Harvard Med Sch, Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA USA. [Neuhaus, Valentin] Univ Zurich Hosp, Dept Traumatol, Zurich, Switzerland. [Guitton, Thierry G.] Univ Groningen, Univ Med Ctr Groningen, Dept Plast Surg, Groningen, Netherlands. [Ring, David] Univ Texas Austin, Dell Med Sch, 1400 Barbara Jordan Blvd,Suite 2-834,MC R1800, Austin, TX 78723 USA. RP Ring, D (reprint author), Univ Texas Austin, Dell Med Sch, 1400 Barbara Jordan Blvd,Suite 2-834,MC R1800, Austin, TX 78723 USA. EM david.ring@austin.utexas.edu FU Tornier (Bloomington, IN, USA) FX One of the authors certifies that he (DR) has received payments, during the study period, of less than USD 10,000 from Tornier (formerly Wright Medical), (Bloomington, IN, USA). NR 33 TC 0 Z9 0 U1 2 U2 4 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 2016 VL 474 IS 8 BP 1857 EP 1863 DI 10.1007/s11999-016-4848-6 PG 7 WC Orthopedics; Surgery SC Orthopedics; Surgery GA DQ1WW UT WOS:000378992200021 ER PT J AU Lin, KJ Schneeweiss, S AF Lin, K. J. Schneeweiss, S. TI Considerations for the Analysis of Longitudinal Electronic Health Records Linked to Claims Data to Study the Effectiveness and Safety of Drugs SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Review ID SULFAMETHOXAZOLE-INDUCED HYPERKALEMIA; ATRIAL-FIBRILLATION; CATHETER ABLATION; GLYCEMIC CONTROL; VENOUS THROMBOEMBOLISM; ORAL RIVAROXABAN; PHARMACY CLAIMS; CARE DATABASES; HEART-FAILURE; THERAPY AB Health insurance claims and electronic health records (EHR) databases have been considered the preferred data sources with which to study drug safety and effectiveness in routine care. Linking claims data to EHR allows researchers to leverage the complementary advantages of each data source to enhance study validity. We propose a framework to evaluate the need for supplementing claims data with EHR and vice versa to optimize outcome ascertainment, exposure assessment, and confounding adjustment. C1 [Lin, K. J.; Schneeweiss, S.] Harvard Med Sch, Brigham & Womens Hosp, Div Pharmacoepidemiol & Pharmacoecon, Dept Med, Boston, MA 02115 USA. [Lin, K. J.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Boston, MA USA. [Lin, K. J.; Schneeweiss, S.] Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. RP Lin, KJ (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Div Pharmacoepidemiol & Pharmacoecon, Dept Med, Boston, MA 02115 USA.; Lin, KJ (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Boston, MA USA.; Lin, KJ (reprint author), Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. EM jklin@mgh.harvard.edu RI Schneeweiss, Sebastian/C-2125-2013 FU Takeda training Fellowship; Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine at Brigham and Women's Hospital FX Dr. Lin was supported by a Takeda training Fellowship and a training grant from the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine at Brigham and Women's Hospital. We thank Paul Bain who helped with the search of existing literature. NR 62 TC 1 Z9 1 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD AUG PY 2016 VL 100 IS 2 BP 147 EP 159 DI 10.1002/cpt.359 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DQ6TA UT WOS:000379336900017 PM 26916672 ER PT J AU Kaunitz, JD AF Kaunitz, Jonathan D. TI DDS Elementary Style: A Brief Guide for Authors SO DIGESTIVE DISEASES AND SCIENCES LA English DT Editorial Material C1 [Kaunitz, Jonathan D.] UCLA Sch Med, Greater Los Angeles VA Healthcare Syst, Dept Med & Surg, Los Angeles, CA 90073 USA. RP Kaunitz, JD (reprint author), UCLA Sch Med, Greater Los Angeles VA Healthcare Syst, Dept Med & Surg, Los Angeles, CA 90073 USA. EM jake@ucla.edu NR 2 TC 0 Z9 0 U1 3 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0163-2116 EI 1573-2568 J9 DIGEST DIS SCI JI Dig. Dis. Sci. PD AUG PY 2016 VL 61 IS 8 BP 2147 EP 2150 DI 10.1007/s10620-016-4223-1 PG 4 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DR3FE UT WOS:000379787200001 PM 27312030 ER PT J AU Paul, S Shuja, A Tam, I Kim, EM Kang, S Kapulsky, L Viveiros, K Lee, H AF Paul, Sonali Shuja, Asim Tam, Idy Kim, Eun Min Kang, Sandra Kapulsky, Leonid Viveiros, Kathleen Lee, Hannah TI Gastroenterologists Have Suboptimal Hepatitis B Virus Screening Rates in Patients Receiving Immunosuppressive Therapy SO DIGESTIVE DISEASES AND SCIENCES LA English DT Article DE Hepatitis B; Reactivation; Screening; Gastroenterologist; Rituximab ID BREAST-CANCER PATIENTS; LAMIVUDINE PROPHYLAXIS; CHEMOTHERAPY PATIENTS; REACTIVATION; METAANALYSIS; INFECTION; AWARENESS; ONCOLOGISTS; PREVENTION; MORTALITY AB Hepatitis B reactivation in patients undergoing immunosuppressive therapy can lead to liver failure and death. Prior studies have shown suboptimal hepatitis B screening rates, but few have compared screening rates across specialties or factors associated with screening. A retrospective study was performed using a hospital-based chemotherapy database and outpatient pharmacy records from January 1999 to December 2013. HBV screening rates prior to initiation of immunosuppression were determined. Multivariate analysis was used to determine predictors of HBV screening. Of the 4008 study patients, 47 % were screened prior to receiving immunosuppressive therapy; only 48 % on rituximab and 45 % of those on anti-TNF therapy were screened. Transplant specialists screened most frequently (85 %) while gastroenterologists screened the least (34 %). Factors significantly associated with HBV screening were younger age, Asian race, use of anti-rejection therapy, and treatment by a transplant specialist (p < 0.001). HBV screening prior to immunosuppressive therapy is suboptimal, especially among gastroenterologists. Efforts to improve screening rates in at risk populations are needed. C1 [Paul, Sonali] Massachusetts Gen Hosp, Div Gastroenterol & Hepatol, 55 Fruit St,Blake 4, Boston, MA 02114 USA. [Shuja, Asim] Univ Florida, Coll Med, Dept Gastroenterol, 655 West 8th St, Jacksonville, FL 32209 USA. [Tam, Idy; Kim, Eun Min; Viveiros, Kathleen] Tufts Med Ctr, Dept Gastroenterol & Hepatol, 800 Washington St,Box 233, Boston, MA 02111 USA. [Kang, Sandra; Kapulsky, Leonid] Tufts Univ, Sch Med, 145 Harrison St, Boston, MA 02111 USA. [Lee, Hannah] Virginia Commonwealth Univ, Med Ctr, Div Gastroenterol & Hepatol, 1101 East Marshall St, Richmond, VA 23298 USA. RP Paul, S (reprint author), Massachusetts Gen Hosp, Div Gastroenterol & Hepatol, 55 Fruit St,Blake 4, Boston, MA 02114 USA. EM sonali.paul2@gmail.com; asimshuja@gmail.com; idyxtam@gmail.com; emk282@nyu.edu; smkang2012@gmail.com; lkap13@gmail.com; kviveiros@tuftsmedicalcenter.org; hannah.lee@vcuhealth.org FU Bristol-Myers Squibb Virology Research Training Program; National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH) [UL1 TR001064, UL1 TR000073] FX S. Paul received grant support through the 2013-2014 Bristol-Myers Squibb Virology Research Training Program. This project was also supported by the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Grant Nos. UL1 TR001064 and UL1 TR000073. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. NR 31 TC 2 Z9 2 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0163-2116 EI 1573-2568 J9 DIGEST DIS SCI JI Dig. Dis. Sci. PD AUG PY 2016 VL 61 IS 8 BP 2236 EP 2241 DI 10.1007/s10620-016-4118-1 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DR3FE UT WOS:000379787200015 PM 26993822 ER PT J AU Clowse, MEB Feldman, SR Isaacs, JD Kimball, AB Strand, V Warren, RB Xibille, D Chen, Y Frazier, D Geier, J Proulx, J Marren, A AF Clowse, Megan E. B. Feldman, Steven R. Isaacs, John D. Kimball, Alexandra B. Strand, Vibeke Warren, Richard B. Xibille, Daniel Chen, Yan Frazier, Donald Geier, Jamie Proulx, James Marren, Amy TI Pregnancy Outcomes in the Tofacitinib Safety Databases for Rheumatoid Arthritis and Psoriasis SO DRUG SAFETY LA English DT Article ID PROSPECTIVE MULTICENTER COHORT; CHRONIC PLAQUE PSORIASIS; JANUS KINASE INHIBITOR; LOW-DOSE METHOTREXATE; ANTIRHEUMATIC DRUGS; CONTROLLED-TRIAL; 1ST TRIMESTER; DISEASE; BIRTH; PLACEBO AB Introduction Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA), and is being investigated for the treatment of psoriasis. Both conditions can present in women of child-bearing potential, but pregnancy was an exclusion and discontinuation criterion in tofacitinib randomized controlled trials (RCTs) because of the unknown effects of tofacitinib on mother and child. Tofacitinib is a small molecule that has the potential to cross the placenta. Objective The objective was to report outcomes of pregnancy cases identified through April 2014 from tofacitinib RA/psoriasis RCTs, RA post-approval non-interventional studies, and spontaneous adverse-event reporting. Methods Pregnancy outcomes were categorized as follows: healthy newborn, medical termination, fetal death, congenital malformation, spontaneous abortion, or pending/lost to follow-up. Results Out of 9815 patients, 1821 female patients of child-bearing age were enrolled in the RA/psoriasis RCTs; 47 women became pregnant, including 33 who received tofacitinib monotherapy, 13 who received combination therapy with methotrexate (RA patients only), and one patient whose therapy was still blinded. No fetal deaths were reported. One congenital pulmonary valve stenosis (monotherapy, n = 1), seven spontaneous abortions (monotherapy, n = 4; combination therapy, n = 3), and eight medical terminations (monotherapy, n = 4; combination therapy, n = 3; blinded therapy, n = 1) were identified. Remaining cases reported healthy newborns (n = 25) or were pending/lost to follow-up (n = 6). Forty-four cases of paternal exposure to tofacitinib were reported (monotherapy, n = 43; combination therapy, n = 1), including five spontaneous abortions (monotherapy, n = 4; combination therapy, n = 1), 23 healthy newborns, and 16 pending/lost to follow-up. Conclusions The pregnancy outcomes reported in this small number of RA/psoriasis patients appear similar to those observed in the general population and in patients treated with biologic therapies for inflammatory diseases. However, definitive conclusions cannot be drawn, and pregnancy outcomes in patients receiving tofacitinib will continue to be monitored. C1 [Clowse, Megan E. B.] Duke Univ, Sch Med, Durham, NC USA. [Feldman, Steven R.] Wake Forest Univ, Bowman Gray Sch Med, Dept Dermatol, Winston Salem, NC 27103 USA. [Isaacs, John D.] Newcastle Univ, NIHR Newcastle Biomed Res Ctr, Newcastle Upon Tyne, Tyne & Wear, England. [Isaacs, John D.] Newcastle Tyne Hosp NHS Fdn Trust, Newcastle Upon Tyne, Tyne & Wear, England. [Kimball, Alexandra B.] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Kimball, Alexandra B.] Harvard Med Sch, Boston, MA USA. [Strand, Vibeke] Stanford Univ, Sch Med, Div Immunol Rheumatol, Palo Alto, CA 94304 USA. [Warren, Richard B.] Univ Manchester, Manchester Acad Hlth Sci Ctr, Dermatol Ctr, Manchester, Lancs, England. [Xibille, Daniel] Hosp Gen Cuernavaca, Cuernavaca, Morelos, Mexico. [Chen, Yan; Marren, Amy] Pfizer Inc, 500 Arcola Rd, Collegeville, PA 19426 USA. [Frazier, Donald; Proulx, James] Pfizer Inc, Groton, CT 06340 USA. [Geier, Jamie] Pfizer Inc, New York, NY USA. RP Marren, A (reprint author), Pfizer Inc, 500 Arcola Rd, Collegeville, PA 19426 USA. EM Amy.marren@pfizer.com FU Pfizer Inc. FX The studies reported in this manuscript were sponsored by Pfizer Inc. Medical writing support for the development of this manuscript, under direction from the authors, was provided by Alice Palmer, PhD, and Sandrine M. Dupre, PhD, of Complete Medical Communications, and funded by Pfizer Inc. NR 36 TC 1 Z9 1 U1 8 U2 11 PU ADIS INT LTD PI NORTHCOTE PA 5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND SN 0114-5916 EI 1179-1942 J9 DRUG SAFETY JI Drug Saf. PD AUG PY 2016 VL 39 IS 8 BP 755 EP 762 DI 10.1007/s40264-016-0431-z PG 8 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy; Toxicology GA DQ8UG UT WOS:000379486100006 PM 27282428 ER PT J AU Flax-Goldenberg, R Kulkarni, KS Carson, KA Pinto, JM Martin-Harris, B Lefton-Greif, MA AF Flax-Goldenberg, Renee Kulkarni, Kopal S. Carson, Kathryn A. Pinto, Jeanne M. Martin-Harris, Bonnie Lefton-Greif, Maureen A. TI Concordance Between Aspiration Detected on Upper Gastrointestinal Series and Videofluoroscopic Swallow Study in Bottle-Fed Children SO DYSPHAGIA LA English DT Article DE Aspiration; Radiation dosage; UGI; VFSS; Deglutition; Children AB The increasing incidence of pediatric dysphagia has raised questions about how to identify children at risk for aspiration. Multiple investigative imaging modalities are considered in diagnostic algorithms, since dysphagia may involve any or all phases of swallowing. Although upper gastrointestinal (UGI) series and videofluoroscopic swallow study (VFSS) are common procedures, the utility of UGI for detection of aspiration and the impact of oropharyngeal imaging during UGI on radiation exposure have not been well described. We hypothesized that diagnosis of aspiration on UGI would be predictive of aspiration on VFSS and screening swallows during UGI would increase radiation exposure. A retrospective review was completed of bottle-fed children undergoing UGI series within 1 month before/after standardized VFSS. UGI was imaged at 3 frames per second (fps) pulsed and VFSS at 30 fps continuous fluoroscopy. Cumulative radiation dose (CD) and dose area product (DAP) were recorded. VFSS and UGI were performed in 49 patients; however, only 21 (43 %) had documentation of swallow function on an UGI series. All children with aspiration on UGI demonstrated thin liquid aspiration on VFSS; however, 53 % without aspiration on UGI aspirated on VFSS. CD for UGI with versus without swallowing documentation was significantly higher (median = 0.33 vs. 0.21 mGy, p = 0.02) but within variability ranges reported for fluoroscopy equipment. DAP was not significantly higher for UGI with documentation of swallowing compared to without documentation of swallowing (median = 4.11 vs. 3.02 mu Gy cm(2), p = 0.09). UGI findings are specific but not sensitive markers for aspiration on VFSS. Imaging of swallowing on UGI may have an appreciable increase on radiation exposure. C1 [Flax-Goldenberg, Renee] Johns Hopkins Univ, Sch Med, Div Pediat Radiol, Russell H Morgan Dept Radiol & Radiol Sci, Sheikh Zayed Tower,Room 4174,1800 Orleans St, Baltimore, MD 21287 USA. [Kulkarni, Kopal S.] Johns Hopkins Univ Hosp, Russell H Morgan Dept Radiol & Radiol Sci, 601 N Caroline St,Room 4210, Baltimore, MD 21287 USA. [Carson, Kathryn A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Welch Ctr Prevent Epidemiol & Clin Res, 2024 East Monument St,Suite 2-500, Baltimore, MD 21287 USA. [Pinto, Jeanne M.; Lefton-Greif, Maureen A.] Johns Hopkins Univ, Sch Med, Dept Pediat, Eudowood Div Pediat Resp Sci, David M Rubenstein Bldg,200 North Wolfe St, Baltimore, MD 21287 USA. [Martin-Harris, Bonnie] Med Univ South Carolina, Coll Med, Dept Otolaryngol Head & Neck Surg, 135 Rutledge Ave,MSC 550, Charleston, SC 29425 USA. [Martin-Harris, Bonnie] Med Univ South Carolina, Evelyn Trammell Inst Voice & Swallowing, Charleston, SC 29425 USA. [Martin-Harris, Bonnie] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29425 USA. [Lefton-Greif, Maureen A.] Johns Hopkins Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, Baltimore, MD 21287 USA. [Lefton-Greif, Maureen A.] Johns Hopkins Univ, Sch Med, Dept Phys Med & Rehabil, Baltimore, MD 21287 USA. RP Lefton-Greif, MA (reprint author), Johns Hopkins Univ, Sch Med, Dept Pediat, Eudowood Div Pediat Resp Sci, David M Rubenstein Bldg,200 North Wolfe St, Baltimore, MD 21287 USA.; Lefton-Greif, MA (reprint author), Johns Hopkins Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, Baltimore, MD 21287 USA.; Lefton-Greif, MA (reprint author), Johns Hopkins Univ, Sch Med, Dept Phys Med & Rehabil, Baltimore, MD 21287 USA. EM mlefton@jhmi.edu FU NIDCD NIH HHS [R01 DC011290] NR 16 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0179-051X EI 1432-0460 J9 DYSPHAGIA JI Dysphagia PD AUG PY 2016 VL 31 IS 4 BP 505 EP 510 DI 10.1007/s00455-016-9705-y PG 6 WC Otorhinolaryngology SC Otorhinolaryngology GA DR2LJ UT WOS:000379735700003 PM 27048206 ER PT J AU Cruz-Romero, C Agarwal, S Abujudeh, HH Thrall, J Hahn, PF AF Cruz-Romero, Cinthia Agarwal, Sheela Abujudeh, Hani H. Thrall, James Hahn, Peter F. TI Spleen volume on CT and the effect of abdominal trauma SO EMERGENCY RADIOLOGY LA English DT Article DE Spleen volume; Trauma; Shrink; Hemocontraction; CT; Blunt abdominal trauma ID NORMAL SPLENIC VOLUME; COMPUTED-TOMOGRAPHY; HEMOGLOBIN CONCENTRATION; CONTRACTION; EXERCISE; LIVER; AGE; SEGMENTATION; INCREASE; STRESS AB The aim of this study is to determine the magnitude of change in spleen volume on CT in subjects sustaining blunt abdominal trauma without hemorrhage relative to patients without disease and how the spleen volumes are distributed. Sixty-seven subjects with blunt abdominal trauma and 101 control subjects were included in this retrospective single-center, IRB-approved, and HIPAA-compliant study. Patients with an injured spleen were excluded. Using a semiautomatic segmentation program, two readers computed spleen volumes from CT. Spleen volume distribution in male and female trauma and control cohorts were compared nonparametrically. Spleen volume plotted against height, weight, and age were analyzed by linear regression. The number of females and males are, respectively, 35 and 32 in trauma subjects and 69 and 32 among controls. Female trauma patients (49.6 years) were older than males (39.8 years) (p = 0.02). Distributions of spleen volume were not normal, skewed above their means, requiring a nonparametric comparison. Spleen volumes in trauma patients were smaller than those in controls with medians of 230 vs 294 mL in males(p < 0.006) and 163 vs 191 mL in females(p < 0.04). Spleen volume correlated positively with weight in females and with height in male controls, and negatively with age in male controls (p < 0.01). Variation in reproducibility and repeatability was acceptable at 1.5 and 4.9 %, respectively. Reader variation was 1.7 and 4.6 % for readers 1 and 2, respectively. The mean spleen volume in controls was 245 mL, the largest ever reported. Spleen volume decreases in response to blunt abdominal trauma. Spleen volumes are not normally distributed. Our population has the largest spleen volume reported in the literature, perhaps a consequence of the obesity epidemic. C1 [Cruz-Romero, Cinthia; Agarwal, Sheela; Abujudeh, Hani H.; Thrall, James; Hahn, Peter F.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Cruz-Romero, C (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM ccruzromero@mgh.harvard.edu NR 35 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1070-3004 EI 1438-1435 J9 EMERG RADIOL JI Emerg. Radiol. PD AUG PY 2016 VL 23 IS 4 BP 315 EP 323 DI 10.1007/s10140-016-1402-5 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DR1BQ UT WOS:000379641400001 PM 27166964 ER PT J AU Young, JY Duhaime, AC Caruso, PA Rincon, SP AF Young, Joseph Yeen Duhaime, Ann-Christine Caruso, Paul Albert Rincon, Sandra Patricia TI Comparison of non-sedated brain MRI and CT for the detection of acute traumatic injury in children 6 years of age or less SO EMERGENCY RADIOLOGY LA English DT Article DE Rapid MRI; CT; Brain; Pediatric; Trauma ID HEAD-INJURY; HYDROCEPHALUS; EVENTS AB CT is considered the first-line study for acute intracranial injury in children because of its availability, detection of acute hemorrhage, and lack of sedation. An MRI study with rapidly acquired sequences can obviate the need for sedation and radiation. We compared the detection rate of rapid non-sedated brain MRI to CT for traumatic head injury in young children. We reviewed a series of children 6 years of age or less who presented to our ED during a 5-year period with head trauma and received a non-sedated brain MRI and CT within 24 h of injury. Most MRI studies were limited to triplane T2 and susceptibility sequences. Two neuroradiologists reviewed the MRIs and CTs and assessed the following findings: fracture, epidural hematoma (EDH)/subdural hematoma (SDH), subarachnoid hemorrhage (SAH), intraventricular hemorrhage (IVH), and parenchymal injury. Thirty of 33 patients had radiologically identified traumatic injuries. There was an overall agreement of 82 % between the two modalities. Skull fracture was the only injury subtype which had a statistically significant difference in detection between CT and MRI (p = 0.0001), with MRI missing 14 of 21 fractures detected on CT. While not statistically significant, MRI had a higher detection rate of EDH/SDH (p = 0.34), SAH (p = 0.07), and parenchymal injuries (p = 0.50). Non-sedated MRI has similar detection rates to CT for intracranial injury in young children presenting with acute head trauma and may be an alternative to CT in select patients. C1 [Young, Joseph Yeen; Caruso, Paul Albert; Rincon, Sandra Patricia] Massachusetts Gen Hosp, Neuroradiol Sect, Dept Radiol, 55 Fruit St,Gray 273A, Boston, MA 02114 USA. [Duhaime, Ann-Christine] Massachusetts Gen Hosp, Dept Neurosurg, 55 Fruit St,Gray 273A, Boston, MA 02114 USA. RP Young, JY (reprint author), Massachusetts Gen Hosp, Neuroradiol Sect, Dept Radiol, 55 Fruit St,Gray 273A, Boston, MA 02114 USA. EM joseph.y.young@gmail.com NR 22 TC 0 Z9 0 U1 4 U2 4 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1070-3004 EI 1438-1435 J9 EMERG RADIOL JI Emerg. Radiol. PD AUG PY 2016 VL 23 IS 4 BP 325 EP 331 DI 10.1007/s10140-016-1392-3 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DR1BQ UT WOS:000379641400002 PM 27166965 ER PT J AU Hammoud, K Lanfranchi, M Li, SX Mehan, WA AF Hammoud, Khaled Lanfranchi, Michael Li, Sean X. Mehan, William A. TI What is the diagnostic value of head MRI after negative head CT in ED patients presenting with symptoms atypical of stroke? SO EMERGENCY RADIOLOGY LA English DT Article DE Stroke; Atypical stroke; Vague neurologic symptoms; Emergency department; MRI; CT; Ischemia; Occult ID COMPUTED-TOMOGRAPHY; EMERGENCY; DIZZINESS AB The diagnostic value of head magnetic resonance imaging after negative head computed tomography for emergency department patients with vague neurologic symptoms, such as dizziness and altered mental status, remains an ongoing discussion. The objective of this study is to detect the subgroup of patients with such presentations having minor strokes whom may benefit from primary and secondary stroke prevention. We conducted a retrospective analysis and stratified patient risk factors associated with positive findings on subsequent head MRI ordered by the emergency department physician following a normal head CT. Two hundred fifty-two patients presenting with atypical stroke symptoms to the emergency department had a negative head CT followed by head MRI within 24 h ordered by emergency department clinician (123 males and 129 females; mean age of 59.4). Twenty nine of the 252 patients (11.5 %) had findings of acute to subacute infarct on the subsequent MRI. Positive MRI findings were statistically correlated with the following variables: age (p < 0.001), history of hyperlipidemia (p = 0.019), hypertension (p < 0.001), diabetes (p = 0.004), anticoagulation use (p = 0.029), and prior transient ischemic attack or stroke (p < 0.001). The mean age of the MRI-positive group was 74.1 years, with a mean difference of 16.7 +/- 2.4 years more than the MRI-negative group (95 % CI, 11.8-21.5 years) (t = 6.8, p < 0.001). Emergency physicians caring for patients with vague neurologic complaints should maintain a lower threshold for ordering a head MRI despite a negative head CT for elderly patients with a history of prior stroke or transient ischemic attack to exclude a CT occult or minor ischemic stroke. C1 [Hammoud, Khaled; Mehan, William A.] Tufts Med Ctr, Dept Radiol, Boston, MA 02111 USA. [Lanfranchi, Michael] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Li, Sean X.] Tufts Univ, Sch Med, Boston, MA 02111 USA. RP Hammoud, K (reprint author), Tufts Med Ctr, Dept Radiol, Boston, MA 02111 USA. EM khammoud@tuftsmedicalcenter.org NR 11 TC 1 Z9 1 U1 4 U2 5 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1070-3004 EI 1438-1435 J9 EMERG RADIOL JI Emerg. Radiol. PD AUG PY 2016 VL 23 IS 4 BP 339 EP 344 DI 10.1007/s10140-016-1408-z PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DR1BQ UT WOS:000379641400004 PM 27220652 ER PT J AU Koutroumpakis, E Dasyam, AK Furlan, A Slivka, A Gougol, A Zeh, HJ Lee, KK Zureikat, AH Whitcomb, DC Yadav, D Papachristou, GI AF Koutroumpakis, Efstratios Dasyam, Anil K. Furlan, Alessandro Slivka, Adam Gougol, Amir Zeh, Herbert J., III Lee, Kenneth K. Zureikat, Amer H. Whitcomb, David C. Yadav, Dhiraj Papachristou, Georgios I. TI Isolated Peripancreatic Necrosis in Acute Pancreatitis Is Infrequent and Leads to Severe Clinical Course Only When Extensive A Prospective Study From a US Tertiary Center SO JOURNAL OF CLINICAL GASTROENTEROLOGY LA English DT Article DE acute pancreatitis; pancreatic necrosis; peripancreatic necrosis ID DETERMINANT-BASED CLASSIFICATION; NECROTIZING PANCREATITIS; ATLANTA CLASSIFICATION; REVISION; SYSTEMS AB Goals: To explore the diagnostic challenges, management, and clinical outcomes of patients with isolated peripancreatic necrosis (PPN), with emphasis on the extent of involvement, and compare them to pancreatic necrosis (PN). Background: PPN, a relatively new term, has been included as a separate entity in the Revised Atlanta Classification. Study: Clinical data of recruited acute pancreatitis patients were recorded prospectively. Contrast-enhanced computed tomographic scans were reviewed by expert radiologists blinded to clinical outcomes. Results: In total, 271 of the 400 acute pancreatitis patients underwent contrast-enhanced computed tomography, of which 29 (11%) had PPN (14: limited; 15: extensive) and 124 (46%) PN (40: <30%, 16: 30% to 50%, 68: >50% of parenchyma). Patients with PPN were similar to PN in age (56 y), gender (55% male), and body mass index (29 kg/m(2)). Nutritional support was provided in 18 (62%) patients with PPN and 97 (78%) with PN (P=0.12). Drainage/debridement was required in 2 patients (7%) with PPN and 64 (53%) with parenchymal necrosis (P<0.001). Persistent organ failure rates did not differ significantly (34% vs. 51%, P=0.17), but hospital stay was shorter in patients with PPN (15 vs. 20 d, P=0.05). Limited PPN required no intervention and had similar persistent organ failure rates and hospitalization length with interstitial pancreatitis (both P>0.12). Extensive PPN mainly developed in patients with persistent organ failure (60%) and rarely required drainage (2/15). Conclusions: PPN prevalence was lower than PN with a ratio of 1:4. PPN rarely required intervention. Utilizing the extent of involvement has the potential to classify PPN and PN with escalating clinical significance and guide management. C1 [Koutroumpakis, Efstratios; Slivka, Adam; Gougol, Amir; Whitcomb, David C.; Yadav, Dhiraj; Papachristou, Georgios I.] Univ Pittsburgh, Med Ctr, Div Gastroenterol Hepatol & Nutr, Dept Med, Pittsburgh, PA USA. [Dasyam, Anil K.; Furlan, Alessandro] Univ Pittsburgh, Med Ctr, Div Abdominal Imaging, Dept Radiol, Pittsburgh, PA USA. [Zeh, Herbert J., III; Lee, Kenneth K.; Zureikat, Amer H.] Univ Pittsburgh, Med Ctr, Div Surg Oncol, Dept Surg, Pittsburgh, PA USA. [Papachristou, Georgios I.] Vet Affairs Pittsburgh Hlth Syst, Div Gastroenterol & Hepatol, Dept Med, Pittsburgh, PA USA. RP Papachristou, GI (reprint author), UPMC Presbyterian, 200 Lothrop St,3rd Floor, Pittsburgh, PA 15213 USA. EM papachri@pitt.edu FU Veterans Affairs Merit Review Award [PRO00000496] FX Supported by a Veterans Affairs Merit Review Award (PRO00000496; PI: G.I.P.) NR 21 TC 1 Z9 1 U1 4 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0192-0790 EI 1539-2031 J9 J CLIN GASTROENTEROL JI J. Clin. Gastroenterol. PD AUG PY 2016 VL 50 IS 7 BP 589 EP 595 DI 10.1097/MCG.0000000000000482 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DR1MI UT WOS:000379669200012 PM 26828244 ER PT J AU Baty, BJ Trepanier, A Bennett, RL Davis, C Erby, L Hippman, C Lerner, B Matthews, A Myers, MF Robbins, CB Singletary, CN AF Baty, Bonnie J. Trepanier, Angela Bennett, Robin L. Davis, Claire Erby, Lori Hippman, Catriona Lerner, Barbara Matthews, Anne Myers, Melanie F. Robbins, Carol B. Singletary, Claire N. TI Developing a Model of Advanced Training to Promote Career Advancement for Certified Genetic Counselors: An Investigation of Expanded Skills, Advanced Training Paths, and Professional Opportunities SO JOURNAL OF GENETIC COUNSELING LA English DT Article DE Advanced training; Genetic counselors; Career development; Career advancement ID EDUCATION; LADDERS AB There are currently multiple paths through which genetic counselors can acquire advanced knowledge and skills. However, outside of continuing education opportunities, there are few formal training programs designed specifically for the advanced training of genetic counselors. In the genetic counseling profession, there is currently considerable debate about the paths that should be available to attain advanced skills, as well as the skills that might be needed for practice in the future. The Association of Genetic Counseling Program Directors (AGCPD) convened a national committee, the Committee on Advanced Training for Certified Genetic Counselors (CATCGC), to investigate varied paths to post-master's training and career development. The committee began its work by developing three related grids that view career advancement from the viewpoints of the skills needed to advance (skills), ways to obtain these skills (paths), and existing genetic counselor positions that offer career change or advancement (positions). Here we describe previous work related to genetic counselor career advancement, the charge of the CATCGC, our preliminary work in developing a model through which to view genetic counselor advanced training and career advancement opportunities, and our next steps in further developing and disseminating the model. C1 [Baty, Bonnie J.] Univ Utah, Hlth Sci Ctr, Dept Pediat, Div Med Genet, SOM 2C454, Salt Lake City, UT 84132 USA. [Trepanier, Angela] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. [Bennett, Robin L.] Univ Washington, Dept Med, Div Med Genet, Seattle, WA 98195 USA. [Davis, Claire] Sarah Lawrence Coll, Joan H Marks Grad Program Human Genet, Bronxville, NY 10708 USA. [Erby, Lori] NHGRI, Social & Behav Res Branch, Bethesda, MD 20892 USA. [Hippman, Catriona] Univ British Columbia, Dept Psychiat, Vancouver, BC, Canada. [Hippman, Catriona] BC Womens Hosp & Hlth Ctr, Womens Hlth Res Inst, Vancouver, BC, Canada. [Lerner, Barbara] VA Boston Healthcare Syst, Ctr Healthcare Org & Implementat Res, Boston, MA USA. [Matthews, Anne] Case Western Reserve Univ, Dept Genet & Genome Sci, Cleveland, OH 44106 USA. [Myers, Melanie F.] Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Cincinnati, OH 45229 USA. [Robbins, Carol B.] Fac Dev & Adult Learning Consultant, New York, NY USA. [Singletary, Claire N.] Univ Texas Hlth, Dept Pediat & Obstet Gynecol & Reprod Sci, Houston, TX USA. RP Baty, BJ (reprint author), Univ Utah, Hlth Sci Ctr, Dept Pediat, Div Med Genet, SOM 2C454, Salt Lake City, UT 84132 USA. EM bonnie.baty@hsc.utah.edu FU Association of Genetic Counseling Program Directors FX The authors would like to acknowledge the help of Susan Manley, who is also a member of the CATCGC, and the Association of Genetic Counseling Program Directors, which provided the impetus to form the committee and paid for conference calls enabling the committee to meet. NR 22 TC 1 Z9 1 U1 3 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1059-7700 EI 1573-3599 J9 J GENET COUNS JI J. Genet. Couns. PD AUG PY 2016 VL 25 IS 4 BP 625 EP 634 DI 10.1007/s10897-015-9916-7 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA DQ8XR UT WOS:000379495500004 PM 26739839 ER PT J AU Rautiainen, S Wang, L Lee, IM Manson, JE Gaziano, JM Buring, JE Sesso, HD AF Rautiainen, Susanne Wang, Lu Lee, I-Min Manson, Joann E. Gaziano, J. Michael Buring, Julie E. Sesso, Howard D. TI Multivitamin use and the risk of hypertension in a prospective cohort study of women SO JOURNAL OF HYPERTENSION LA English DT Article DE blood pressure; cohort; epidemiology; hypertension; multivitamins ID FOOD FREQUENCY QUESTIONNAIRE; CORONARY-HEART-DISEASE; CARDIOVASCULAR-DISEASE; BLOOD-PRESSURE; UNITED-STATES; VITAMIN-E; DIETARY-SUPPLEMENTS; PRIMARY PREVENTION; HEALTH; MORTALITY AB Objective: Despite the widespread use of multivitamin supplements, little is known regarding their effects on blood pressure (BP) and the development of hypertension. We, therefore, sought to prospectively investigate how multivitamin use was associated with incident hypertension among middle-aged and older women. Methods: We studied 28 157 women from the Women's Health Study aged at least 45 years and free of cardiovascular disease, cancer, and hypertension at baseline. Women reported information on a wide range of lifestyle, clinical, and dietary factors, including multivitamin and other supplement use at baseline. Hypertension was identified on baseline and annual follow-up questionnaires. Incident hypertension was defined as either a new diagnosis of hypertension by a physician, initiation of antihypertensive medication, newly reported SBP at least 140 mmHg, or DBP at least 90 mmHg during follow-up. Results: During a mean follow-up of 11.5 years, we identified 16 316 cases of incident hypertension. We found that neither baseline (hazard ratio = 1.03, 95% confidence interval: 1.00, 1.07) nor time-varying multivitamin use (hazard ratio = 0.97, 95% confidence interval: 0.94-1.00) were associated with the risk of incident hypertension in multivariable-adjusted models. When we investigated the duration of multivitamin use reported at baseline, we also observed no association with the risk of hypertension. Conclusion: The results from this prospective study of middle-aged and older women suggest that neither baseline multivitamin use nor time-varying multivitamin use is associated with the risk of developing hypertension. C1 [Rautiainen, Susanne; Wang, Lu; Lee, I-Min; Manson, Joann E.; Gaziano, J. Michael; Buring, Julie E.; Sesso, Howard D.] Brigham & Womens Hosp, Dept Med, Div Prevent Med, 900 Commonwealth Ave, Boston, MA 02115 USA. [Rautiainen, Susanne; Wang, Lu; Lee, I-Min; Manson, Joann E.; Gaziano, J. Michael; Buring, Julie E.; Sesso, Howard D.] Harvard Med Sch, 900 Commonwealth Ave, Boston, MA 02115 USA. [Rautiainen, Susanne] Karolinska Inst, Inst Environm Med, Stockholm, Sweden. [Lee, I-Min; Manson, Joann E.; Buring, Julie E.; Sesso, Howard D.] Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Gaziano, J. Michael] VA Boston Healthcare Syst, Boston, MA USA. [Gaziano, J. Michael; Sesso, Howard D.] Brigham & Womens Hosp, Dept Med, Div Aging, 75 Francis St, Boston, MA 02115 USA. RP Rautiainen, S (reprint author), Brigham & Womens Hosp, Dept Med, Div Prevent Med, 900 Commonwealth Ave, Boston, MA 02115 USA.; Rautiainen, S (reprint author), Harvard Med Sch, 900 Commonwealth Ave, Boston, MA 02115 USA. EM susanne.rautiainen@ki.se FU NIH, Bethesda, MD [CA047988, HL043851, HL080467]; COFAS Marie Curie Fellowship, Sweden; Pfizer Inc.; Council for Responsible Nutrition Foundation FX The study was supported by research grants CA047988, HL043851, and HL080467 from the NIH, Bethesda, MD, and COFAS Marie Curie Fellowship, Sweden.; J.E.M. has received investigator-initiated grants from Pfizer Inc. J.M.G. has received investigator-initiated grants from Pfizer Inc. and the Council for Responsible Nutrition Foundation. H.D.S. has received investigator-initiated grants from Pfizer Inc. and the Council for Responsible Nutrition Foundation. NR 38 TC 0 Z9 0 U1 2 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0263-6352 EI 1473-5598 J9 J HYPERTENS JI J. Hypertens. PD AUG PY 2016 VL 34 IS 8 BP 1513 EP 1519 DI 10.1097/HJH.0000000000000973 PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DQ8GW UT WOS:000379448100013 PM 27327440 ER PT J AU Jhunjhunwala, S Alvarez, D Aresta-DaSilva, S Tang, K Tang, BC Greiner, DL Newburger, PE von Andrian, UH Langer, R Anderson, DG AF Jhunjhunwala, Siddharth Alvarez, David Aresta-DaSilva, Stephanie Tang, Katherine Tang, Benjamin C. Greiner, Dale L. Newburger, Peter E. von Andrian, Ulrich H. Langer, Robert Anderson, Daniel G. TI Frontline Science: Splenic progenitors aid in maintaining high neutrophil numbers at sites of sterile chronic inflammation SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE granulocyte; hematopoietic stem cells; biomaterials; devices; peritoneal cavity ID TUMOR-INDUCED NEUTROPHILIA; FOREIGN-BODY REACTION; BONE-MARROW; G-CSF; MICE; MACROPHAGES; CELLS; MONOCYTES; BLOOD; GRANULOPOIESIS AB Neutrophils are constantly generated from hematopoietic stem and progenitor cells in the bone marrow to maintain high numbers in circulation. A considerable number of neutrophils and their progenitors have been shown to be present in the spleen too; however, their exact role in this organ remains unclear. Herein, we sought to study the function of splenic neutrophils and their progenitors using a mouse model for sterile, peritoneal inflammation. In this microcapsule device implantationmodel, we show chronic neutrophil presence at implant sites, with recruitment from circulation as the primary mechanism for their prevalence in the peritoneal exudate. Furthermore, we demonstrate that progenitor populations in the spleen play a key role in maintaining elevated neutrophil numbers. Our results provide new insight into the role for splenic neutrophils and their progenitors and establish a model to study neutrophil function during sterile inflammation. C1 [Jhunjhunwala, Siddharth; Aresta-DaSilva, Stephanie; Tang, Katherine; Tang, Benjamin C.; Langer, Robert; Anderson, Daniel G.] MIT, David H Koch Inst Integrat Canc Res, 500 Main St, Cambridge, MA 02139 USA. [Langer, Robert; Anderson, Daniel G.] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Langer, Robert; Anderson, Daniel G.] MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Langer, Robert; Anderson, Daniel G.] MIT, Harvard Massachusetts Inst Technol Div Hlth Sci &, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Jhunjhunwala, Siddharth; Aresta-DaSilva, Stephanie; Tang, Katherine; Tang, Benjamin C.; Langer, Robert; Anderson, Daniel G.] Boston Childrens Hosp, Dept Anesthesiol, Boston, MA USA. [Alvarez, David; von Andrian, Ulrich H.] Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA USA. [Greiner, Dale L.] Univ Massachusetts, Sch Med, Dept Mol Med, Diabet Ctr Excellence, Worcester, MA USA. [Newburger, Peter E.] Univ Massachusetts, Sch Med, Dept Pediat, Worcester, MA USA. [Newburger, Peter E.] Univ Massachusetts, Sch Med, Dept Canc Biol, Worcester, MA USA. [von Andrian, Ulrich H.] Ragon Inst Massachusetts Gen Hosp Massachusetts I, Cambridge, MA USA. RP Anderson, DG (reprint author), MIT, David H Koch Inst Integrat Canc Res, 500 Main St, Cambridge, MA 02139 USA. EM dgander@mit.edu OI Newburger, Peter/0000-0002-8615-673X FU Mazumdar-Shaw International Oncology Fellowship; U.S. Juvenile Diabetes Research Foundation [17-2007-1063]; Leona M. and Harry B. Helmsley Charitable Trust Foundation [09PG-T1D027]; U.S. National Institutes of Health (NIH) National Institute of Biomedical Imaging and Bioengineering (NIBIB) [EB000244, EB000351]; NIH National Institute of Dental and Craniofacial Research [DE013023]; NIH National Cancer Institute [CA151884]; NIH National Institute of Allergy and Infectious Diseases (NIAID) [P01-AI111595]; NIH National Heart, Lung, and Blood Institute [5T32 HL066987]; NIH NIAID [U19AI095261]; Ragon Institute at Massachusetts General Hospital, Massachusetts Institute of Technology (MIT), and Harvard; NIH NCI [P30-CA14051] FX S.J. is supported by the Mazumdar-Shaw International Oncology Fellowship. This work was supported by the U.S. Juvenile Diabetes Research Foundation Grant 17-2007-1063; Leona M. and Harry B. Helmsley Charitable Trust Foundation Grant 09PG-T1D027; U.S. National Institutes of Health (NIH) National Institute of Biomedical Imaging and Bioengineering (NIBIB) Grants EB000244 and EB000351; NIH National Institute of Dental and Craniofacial Research Grant DE013023; NIH National Cancer Institute CA151884; and through a generous gift from the Tayebati Family Foundation. This work was partly supported by NIH National Institute of Allergy and Infectious Diseases (NIAID) Grant P01-AI111595; NIH National Heart, Lung, and Blood Institute Grant 5T32 HL066987 (to U.H.v.A.); NIH NIAID Grant U19AI095261 (D.A. and U.H.v.A.); and the Ragon Institute at Massachusetts General Hospital, Massachusetts Institute of Technology (MIT), and Harvard. The authors thank Nicki Watson for assistance with transmission electron microscopy, the W.M. Keck Microscopy Facility at the Whitehead Institute, and the Flow Cytometry Core Facility at MIT (supported by NIH NCI Core Grant P30-CA14051). NR 36 TC 1 Z9 1 U1 1 U2 3 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 EI 1938-3673 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD AUG PY 2016 VL 100 IS 2 BP 253 EP 260 DI 10.1189/jlb.1HI0615-248RR PG 8 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA DR2MM UT WOS:000379738600002 PM 26965635 ER PT J AU Irimia, D Ellett, F AF Irimia, Daniel Ellett, Felix TI Big insights from small volumes: deciphering complex leukocyte behaviors using microfluidics SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Review DE nanotechnology; inflammation; neutrophils; dendritic cells; monocytes ID BLOOD POLYMORPHONUCLEAR LEUKOCYTES; DENDRITIC CELL-MIGRATION; NEUTROPHIL EXTRACELLULAR TRAPS; IN-VITRO; WALDENSTROMS MACROGLOBULINEMIA; PROMYELOCYTIC LEUKEMIA; INFLAMMATORY RESPONSE; CONFINED ENVIRONMENTS; RHEUMATOID-ARTHRITIS; COMPETING GRADIENT AB Inflammation is an indispensable component of the immune response, and leukocytes provide the first line of defense against infection. Although the major stereotypic leukocyte behaviors in response to infection are well known, the complexities and idiosyncrasies of these phenotypes in conditions of disease are still emerging. Novel tools are indispensable for gaining insights into leukocyte behavior, and in the past decade, microfluidic technologies have emerged as an exciting development in the field. Microfluidic devices are readily customizable, provide tight control of experimental conditions, enable high precision of ex vivo measurements of individual as well as integrated leukocyte functions, and have facilitated the discovery of novel leukocyte phenotypes. Here, we review some of the most interesting insights resulting from the application of microfluidic approaches to the study of the inflammatory response. The aim is to encourage leukocyte biologists to integrate these new tools into increasingly more sophisticated experimental designs for probing complex leukocyte functions. C1 [Irimia, Daniel; Ellett, Felix] Harvard Med Sch, Massachusetts Gen Hosp, Shriners Burns Hosp,Dept Surg, BioMEMS Resource Ctr,Div Surg Innovat & Bioengn, Boston, MA USA. RP Irimia, D; Ellett, F (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Shriners Burns Hosp,Dept Surg,MGH CNY, BioMEMS Resource Ctr,Div Surg Innovat & Bioengn, 114 16th St,1404, Boston, MA 02129 USA. EM dirimia@hms.harvard.edu; fellett@mgh.harvard.edu FU U.S. National Institutes of Health [GM092804, EB002503] FX This work was supported, in part, by the U.S. National Institutes of Health (Grant Nos. GM092804 and EB002503). NR 160 TC 1 Z9 1 U1 8 U2 16 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 EI 1938-3673 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD AUG PY 2016 VL 100 IS 2 BP 291 EP 304 DI 10.1189/jlb.5RU0216-056R PG 14 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA DR2MM UT WOS:000379738600005 PM 27194799 ER PT J AU Smith, RE Reyes, NJ Khandelwal, P Schlereth, SL Lee, HS Masli, S Saban, DR AF Smith, R. E. Reyes, N. J. Khandelwal, P. Schlereth, S. L. Lee, H. S. Masli, S. Saban, D. R. TI Secondary allergic T cell responses are regulated by dendritic cell-derived thrombospondin-1 in the setting of allergic eye disease SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE AED; conjunctivitis; Th2 ID GROWTH-FACTOR-BETA; IMMUNE-MEDIATED BLEPHAROCONJUNCTIVITIS; OCULAR SURFACE INFLAMMATION; VERNAL CONJUNCTIVITIS; IN-VIVO; ATOPIC KERATOCONJUNCTIVITIS; CYTOKINE PRODUCTION; INTERFERON-GAMMA; MURINE MODEL; MAST-CELLS AB Allergic eye disease, as in most forms of atopy, ranges in severity among individuals from immediate hypersensitivity to a severe and debilitating chronic disease. Dendritic cells play a key role in stimulating pathogenic T cells in allergen re-exposure, or secondary responses. However, molecular cues by dendritic cells underpinning allergic T cell response levels and the impact that this control has on consequent severity of allergic disease are poorly understood. Here, we show that a deficiency in thrombospondin-1, a matricellular protein known to affect immune function, has subsequent effects on downstream T cell responses during allergy, as revealed in an established mouse model of allergic eye disease. More specifically, we demonstrate that a thrombospondin-1 deficiency specific to dendritic cells leads to heightened secondary T cell responses and consequent clinical disease. Interestingly, whereas thrombospondin-1-deficient dendritic cells augmented activity of allergen-primed T cells, this increase was not recapitulated with naive T cells in vitro. The role of dendritic cell-derived thrombospondin-1 in regulating secondary allergic T cell responses was confirmed in vivo, as local transfer of thrombospondin-1-sufficient dendritic cells to the ocular mucosa of thrombospondin-1 null hosts prevented the development of augmented secondary T cell responses and heightened allergic eye disease clinical responses. Finally, we demonstrate that topical instillation of thrombospondin-1-derived peptide reduces T cell activity and clinical progression of allergic eye disease. Taken together, this study reveals an important modulatory role of dendritic cell-derived thrombospondin-1 on secondary allergic T cell responses and suggests the possible dysregulation of dendritic cell-derived thrombospondin-1 expression as a factor in allergic eye disease severity. C1 [Smith, R. E.; Reyes, N. J.; Saban, D. R.] Duke Univ, Sch Med, Dept Ophthalmol, 2351 Erwin Rd, Durham, NC 27705 USA. [Saban, D. R.] Duke Univ, Sch Med, Dept Immunol, 2351 Erwin Rd, Durham, NC 27705 USA. [Khandelwal, P.; Schlereth, S. L.; Lee, H. S.] Boston Univ, Med Ctr, Dept Ophthalmol, Boston, MA USA. [Masli, S.] Harvard Med Sch, Massachusetts Eye & Ear Infirm, Schepens Eye Res Inst, Boston, MA USA. [Schlereth, S. L.] Univ Cologne, Cologne, Germany. [Lee, H. S.] Catholic Univ Korea, Coll Med, Seoul, South Korea. [Lee, H. S.] Seoul St Marys Hosp, Seoul, South Korea. RP Saban, DR (reprint author), Duke Univ, Sch Med, Dept Ophthalmol, 2351 Erwin Rd, Durham, NC 27705 USA.; Saban, DR (reprint author), Duke Univ, Sch Med, Dept Immunol, 2351 Erwin Rd, Durham, NC 27705 USA. EM daniel.saban@duke.edu FU U.S. National Institutes of Health National Eye Institute (Bethesda, MD, USA) [R01EY021798, P30EY005722]; Research to Prevent Blindness (New York, NY, USA) FX Funding sources were provided by the U.S. National Institutes of Health National Eye Institute (Bethesda, MD, USA; R01EY021798 to D.R.S. and P30EY005722) and Research to Prevent Blindness (New York, NY, USA; to D.R.S.). The authors thank Dr. Darlene Dartt (Harvard Medical School) for excellent discussions that contributed to this manuscript. NR 50 TC 0 Z9 0 U1 4 U2 4 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 EI 1938-3673 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD AUG PY 2016 VL 100 IS 2 BP 371 EP 380 DI 10.1189/jlb.3A0815-357RR PG 10 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA DR2MM UT WOS:000379738600012 PM 26856994 ER PT J AU Hanninen, T Tuominen, M Parkkari, J Vartiainen, M Ohman, J Iverson, GL Luoto, TM AF Hanninen, Timo Tuominen, Markku Parkkari, Jari Vartiainen, Matti Ohman, Juha Iverson, Grant L. Luoto, Teemu M. TI Sport concussion assessment tool-3rd edition - normative reference values for professional ice hockey players SO JOURNAL OF SCIENCE AND MEDICINE IN SPORT LA English DT Article DE Brain concussion; Head injuries; Baseline survey; Clinical assessment ID TRAUMATIC BRAIN-INJURY; BASE-LINE VALUES; INTERNATIONAL-CONFERENCE; POSTURAL STABILITY; HIGH-SCHOOL; STATEMENT; HISTORY; SCAT2; SIDELINE; MENS AB Objectives: To determine normative reference values for the Sport Concussion Assessment Tool-3rd Edition (SCAT3) using a large sample of professional male ice hockey players. Design: A descriptive cross-sectional study. Methods: Preseason baseline testing was administered individually to 304 professional male ice hockey players. Results: The participants were aged between 16 and 40 with a mean (M) age of 25.3 years. Over 60% of the athletes reported previous concussion, almost 20% had been hospitalized or medically imaged following a head trauma. Of the players, 48% reported no symptoms. The symptom score median (Md) was 1.0 (M=1.5) and severity median was 1.0 (M=2.3). The median of the SAC score was 27.0 (M= 27.0). The median of the M-BESS was 1.0 (M=2.0). The Tandem gait median was 10.9 s (M=10.8 s). The most common baseline symptom was neck pain (24%). Delayed recall was the most difficult component of the SAC (Md=4); only 24% performed it flawlessly. All athletes completed the double-leg stance of the M-BESS without errors, but there was performance variability in the tandem stance (Md=0, M=0.6, range = 0-10) and single-leg stance (Md=1.0, M = 1.4, range = 0-10). Conclusions: Representative normative reference values for the SCAT3 among professional male ice hockey players are provided. (C) 2015 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved. C1 [Hanninen, Timo; Parkkari, Jari] UKK Inst Hlth Promot Res, Tampere Res Ctr Sports Med, Tampere, Finland. [Tuominen, Markku] Int Ice Hockey Federat IIHF, Med Comm, Zurich, Switzerland. [Tuominen, Markku] Liiga Finnish Ice Hockey Assoc, Liiga, Finland. [Tuominen, Markku] Medisport Ltd, Tampere, Finland. [Vartiainen, Matti] Univ Helsinki, Div Cognit Psychol & Neuropsychol, Inst Behav Sci, Helsinki, Finland. [Ohman, Juha; Luoto, Teemu M.] Tampere Univ Hosp, Dept Neurosurg, Tampere, Finland. [Iverson, Grant L.] Harvard Med Sch, Spaulding Rehabil Hosp, Dept Phys Med & Rehabil, Boston, MA USA. [Iverson, Grant L.] Massachusetts Gen Hosp, Children Sport Concuss Program, Boston, MA 02114 USA. [Iverson, Grant L.] Red Sox Fdn, Boston, MA USA. [Iverson, Grant L.] Massachusetts Gen Hosp, Home Base Program, Boston, MA 02114 USA. RP Hanninen, T (reprint author), UKK Inst Hlth Promot Res, Tampere Res Ctr Sports Med, Tampere, Finland. EM timo.hanninen@fimnet.fi OI Ohman, Juha/0000-0002-6592-1367; Luoto, Teemu/0000-0002-7329-3284 FU Finnish Ministry of Education and Culture and Finnish Hockey League; Finnish Hockey League; Finnish Ice Hockey Association (FIHA); Finnish Hockey Player Association (FHPA) FX This study was financially supported by the Finnish Ministry of Education and Culture and Finnish Hockey League. We greatly appreciate the cooperation of all the team physicians and physiotherapists (Davies Paul, Huttunen Jussi, Hyde Jacob, Hamalainen Jari, Ikonen Juhani, Isotupa Juha, Kuosmanen Mika, Kuutamoinen Ville, Lahtinen Teppo, Mali Hero, Piekkola Ville, Pihkoluoma Tomi, Pohjonen Veli-Matti, Puustinen Vesa, Tikanto Jukka, Toivanen Tero, Tahkapaa Mikko, Uotila Toni, Vahtera Ville, Virtala Mika, Vaisanen Jonne) who volunteered their time to collect the data for this project. We sincerely thank Mr. Kari Tokola, M.Sc., for the statistical advice, Ms. Birgitta Jarvinen, M.Sc. for help in conducting literature searches and research assistant Anne Simi for her contribution in data collection. We would like to thank the Finnish Hockey League, Finnish Ice Hockey Association (FIHA) and Finnish Hockey Player Association (FHPA) for all their support. This study was partly presented at the Ice Hockey Summit II-Action on Concussion in Rochester, MN, USA, in October 2013. NR 29 TC 0 Z9 0 U1 1 U2 9 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1440-2440 EI 1878-1861 J9 J SCI MED SPORT JI J. Sci. Med. Sport PD AUG PY 2016 VL 19 IS 8 BP 636 EP 641 DI 10.1016/j.jsams.2015.08.005 PG 6 WC Sport Sciences SC Sport Sciences GA DQ7FI UT WOS:000379371900007 PM 26383876 ER PT J AU Ellingson, LD Schwabacher, IJ Kim, Y Welk, GJ Cook, DB AF Ellingson, Laura D. Schwabacher, Isaac J. Kim, Youngwon Welk, Gregory J. Cook, Dane B. TI Validity of an Integrative Method for Processing Physical Activity Data SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE ActiGraph; activPAL; SOJOURNS; MACHINE LEARNING; SEDENTARY; MEASUREMENT ID SEDENTARY BEHAVIOR; ENERGY-EXPENDITURE; ACCELEROMETER DATA; WEARABLE MONITORS; HEALTH; TIME; PREDICTION; WRIST; VALIDATION; SYSTEMS AB Accurate assessments of both physical activity and sedentary behaviors are crucial to understand the health consequences of movement patterns and to track changes over time and in response to interventions. Purpose: The study evaluates the validity of an integrative, machine learning method for processing activity monitor data in relation to a portable metabolic analyzer (Oxycon mobile [OM]) and direct observation (DO). Methods: Forty-nine adults (age 18-40 yr) each completed 5-min bouts of 15 activities ranging from sedentary to vigorous intensity in a laboratory setting while wearing ActiGraph (AG) on the hip, activPAL on the thigh, and OM. Estimates of energy expenditure (EE) and categorization of activity intensity were obtained from the AG processed with Lyden's sojourn (SOJ) method and from our new sojourns including posture (SIP) method, which integrates output from the AG and activPAL. Classification accuracy and estimates of EE were then compared with criterion measures (OM and DO) using confusion matrices and comparisons of the mean absolute error of log-transformed data (MAE ln Q). Results: The SIP method had a higher overall classification agreement (79%, 95% CI = 75%-82%) than the SOJ (56%, 95% CI = 52%-59%) based on DO. Compared with OM, estimates of EE from SIP had lower mean absolute error of log-transformed data than SOJ for light-intensity (0.21 vs 0.27), moderate-intensity (0.33 vs 0.42), and vigorous-intensity (0.16 vs 0.35) activities. Conclusions: The SIP method was superior to SOJ for distinguishing between sedentary and light activities as well as estimating EE at higher intensities. Thus, SIP is recommended for research in which accuracy of measurement across the full range of activity intensities is of interest. C1 [Ellingson, Laura D.; Kim, Youngwon; Welk, Gregory J.] Iowa State Univ, Dept Kinesiol, 239 Forker, Ames, IA 50011 USA. [Ellingson, Laura D.; Schwabacher, Isaac J.; Cook, Dane B.] Univ Wisconsin, Dept Kinesiol, Madison, WI USA. [Schwabacher, Isaac J.; Cook, Dane B.] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. [Kim, Youngwon] Univ Cambridge, Epidemiol Unit, MRC, Cambridge, England. RP Ellingson, LD (reprint author), Iowa State Univ, Dept Kinesiol, 239 Forker, Ames, IA 50011 USA. EM ellingl@iastate.edu FU Bodymedia/Jawbone FX The authors thank all the participants for their participation in the current study. They also thank Rachel Devick and Paul Hibbing for their assistance in data collection. Authors Y. Kim and G. J. Welk declare that they have had ongoing research support from Bodymedia/Jawbone to assist in cross validation of algorithms and in testing of new prototype monitors. The data reported here were collected as part of a larger study designed to test new monitoring technologies, but the new devices were not reported in the present study. The present study was conducted independently from Bodymedia/Jawbone, but the authors acknowledge that funding from Bodymedia/Jawbone supported the data collection. The SIP software detailed in this article was developed by Isaac Schwabacher in the laboratory of Dr. Cook at the University of Wisconsin-Madison. The contents of this study do not represent the views of the U.S. Department of Veterans Affairs or the United States Government. The findings of the current study do not constitute endorsement by the American College of Sports Medicine. NR 41 TC 0 Z9 0 U1 10 U2 14 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 2016 VL 48 IS 8 BP 1629 EP 1638 DI 10.1249/MSS.0000000000000915 PG 10 WC Sport Sciences SC Sport Sciences GA DR2TP UT WOS:000379757100024 PM 27015380 ER PT J AU Yang, S Leone, D Frydenlund, N Hoang, M Deng, A Hernandez-Perez, M Biswas, A Singh, R Yaar, R Mahalingam, M AF Yang, Shi Leone, Dominick Frydenlund, Noah Hoang, Mai Deng, April Hernandez-Perez, Marier Biswas, Asok Singh, Rajendra Yaar, Ron Mahalingam, Meera TI Frequency of telomerase reverse transcripter promoter mutations in desmoplastic melanoma subtypes: analyses of 76 cases SO MELANOMA RESEARCH LA English DT Article DE desmoplastic melanoma subtypes; genetic drivers; telomerase reverse transcripter mutations ID TERT-PROMOTER; MALIGNANT-MELANOMA; PURE; SUBCLASSIFICATION; VARIANTS; CANCER AB Estimates of the frequency of telomerase reverse transcripter (TERT) mutations in desmoplastic melanoma (DM) are limited. DM is categorized into subtypes, pure and mixed, differing in prognosis, suggesting genetic heterogeneity. Given this, our aims were to determine the incidence of TERT promoter mutations in DM subtypes and to evaluate its relationship with established histopathologic prognosticators, BRAF and RETp status, and neurofibromin protein expression. Of the archival annotated samples retrieved, 76 cases of DM (48 pure and 28 mixed) fulfilled the criteria for inclusion. PCR amplification of the TERT promoter region was performed on DNA extracted from formalin-fixed paraffin-embedded tissue using primers 5'-GCCGATTCGACCTCTCTCC-3' (forward) and 5'-CAGCGCTGCCTGAAACTC-3' (reverse). For each case, appropriate C>T mutations were identified on the electropherograms. Univariate analysis using chi(2)-test was carried out to identify potential confounders; a nested case-control study of demographic, clinical, histopathological, and genetic determinants was carried out using multiple logistic regression. Significant differences in TERT promoter mutation frequencies were noted in the subtypes (mixed vs. pure; 15/28, 54% vs. 11/48, 23%, respectively, P=0.0066). After adjusting for potential confounding, multivariate analyses indicated a three-fold increase in the odds of the TERT mutation for those with the mixed subtype compared with the pure subtype (P=0.04, adjusted odds ratio = 3.32). No other significant associations were noted (sex/junctional component/Breslow depth/ulceration/mitoses/host response/RETp, BRAF status, and neurofibromin protein expression). Our findings, the largest to date investigating TERT promoter mutations in DM, support the hypothesis that the subtypes have distinct genetic drivers and underscore the relevance of telomere integrity in the etiopathogenesis of the mixed variant. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved. C1 [Yang, Shi] Boston Univ Med, Dept Pathol, Boston, MA USA. [Leone, Dominick] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Leone, Dominick] Ragon Inst MGH MIT & Harvard, Boston, MA USA. [Hoang, Mai] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Hernandez-Perez, Marier] Miraca Life Sci, Newton Upper Falls, MA USA. [Deng, April] Univ Massachusetts, Sch Med, Dept Pathol, Worcester, MA 01605 USA. [Mahalingam, Meera] VA Integrated Syst Network VISN1, Dermatopathol Sect, Dept Pathol & Lab Med, West Roxbury, MA USA. [Frydenlund, Noah] Univ Iowa, Carver Coll Med, Iowa City, IA USA. [Singh, Rajendra] Icahn Sch Med Mt Sinai, Dept Pathol & Dermatol, New York, NY 10029 USA. [Yaar, Ron] Aurora Diagnost GPA Labs, Greensboro, NC USA. [Biswas, Asok] Western Gen Hosp, Dept Pathol, Edinburgh, Midlothian, Scotland. RP Mahalingam, M (reprint author), VA Integrated Syst Network VISN1, Dermatopathol Sect, Dept Pathol & Lab Med 113, 1400 VFW PKWY, West Roxbury, MA 02132 USA. EM me@meeramahalingam.com NR 22 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 0960-8931 EI 1473-5636 J9 MELANOMA RES JI Melanoma Res. PD AUG PY 2016 VL 26 IS 4 BP 361 EP 366 DI 10.1097/CMR.0000000000000272 PG 6 WC Oncology; Dermatology; Medicine, Research & Experimental SC Oncology; Dermatology; Research & Experimental Medicine GA DQ8GQ UT WOS:000379447500006 PM 27244099 ER PT J AU Wei, ZQ Yan, L Chen, YX Bao, CH Deng, J Deng, JG AF Wei, Zhiquan Yan, Li Chen, Yixin Bao, Chuanhong Deng, Jing Deng, Jiagang TI Mangiferin inhibits macrophage classical activation via downregulating interferon regulatory factor 5 expression SO MOLECULAR MEDICINE REPORTS LA English DT Article DE mangiferin; macrophage classical activation; interferon regulatory factor 5; anti-inflammation; M1 macrophage; THP-1 cells ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; NF-KAPPA-B; AIRWAY INFLAMMATION; IRF5 POLYMORPHISMS; GENETIC-VARIANTS; DENDRITIC CELLS; EXTRACT; DISEASE; BRONCHITIS; BETA AB Mangiferin is a natural polyphenol and the predominant effective component of Mangifera indica Linn. leaves. For hundreds of years, Mangifera indica Linn. leaf has been used as an ingredient in numerous traditional Chinese medicine preparations for the treatment of bronchitis. However, the pharmacological mechanism of mangiferin in the treatment of bronchitis remains to be elucidated. Macrophage classical activation is important role in the process of bronchial airway inflammation, and interferon regulatory factor 5 (IRF5) has been identified as a key regulatory factor for macrophage classical activation. The present study used the THP-1 human monocyte cell line to investigate whether mangiferin inhibits macrophage classical activation via suppressing IRF5 expression in vitro. THP-1 cells were differentiated to macrophages by phorbol 12-myristate 13-acetate. Macrophages were polarized to M1 macrophages following stimulation with lipopolysaccharide (LPS)/interferon-gamma (IFN-gamma). Flow cytometric analysis was conducted to detect the M1 macrophages. Reverse transcription-quantitative polymerase chain reaction was used to investigate cellular IRF5 gene expression. Levels of proinflammatory cytokines and IRF5 were assessed following cell culture and cellular homogenization using enzyme-linked immunosorbent assay. IRF5 protein and nuclei co-localization was performed in macrophages with laser scanning confocal microscope immunofluorescence analysis. The results of the present study demonstrated that mangiferin significantly inhibits LPS/IFN-gamma stimulation-induced classical activation of macrophages in vitro and markedly decreases proinflammatory cytokine release. In addition, cellular IRF5 expression was markedly downregulated. These results suggest that the inhibitory effect of mangiferin on classical activation of macrophages may be exerted via downregulation of cellular IRF5 expression levels. C1 [Wei, Zhiquan] Guangxi Univ Chinese Med, Zhuang Med Coll, Guangxi Sci Expt Ctr Tradit Chinese Med, Nanning 530001, Guangxi, Peoples R China. [Yan, Li] Guangxi Univ Chinese Med, Zhuang Med Coll, Lab Basis & Applicat Res Zhuang Med Formulas, Nanning 530001, Guangxi, Peoples R China. [Chen, Yixin; Deng, Jiagang] Guangxi Key Lab Pharmacodynam Studies Tradit Chie, 179 Mingxiudong Rd, Nanning 530001, Guangxi, Peoples R China. [Bao, Chuanhong] Guangxi Univ Chinese Med, Ruikang Affiliated Hosp, Dept Pharm, Nanning 530012, Guangxi, Peoples R China. [Deng, Jing] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Deng, JG (reprint author), Guangxi Key Lab Pharmacodynam Studies Tradit Chie, 179 Mingxiudong Rd, Nanning 530001, Guangxi, Peoples R China. EM jg_deng@hotmail.com FU National Natural Science Foundation of China [81260666]; Guangxi Key Laboratory of Pharmacodynamics Studies of Traditional Chinese Medicine [14-A-01-03] FX The present study was supported by the National Natural Science Foundation of China (grant no. 81260666), the Guangxi Key Laboratory of Pharmacodynamics Studies of Traditional Chinese Medicine (grant no. 14-A-01-03). The authors would also like to thank all the staff of Guangxi College and University Laboratory of Basis and Application Research of Zhuang Medicine Formulas for their helpful technical assistance. NR 60 TC 0 Z9 0 U1 2 U2 5 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1791-2997 EI 1791-3004 J9 MOL MED REP JI Mol. Med. Rep. PD AUG PY 2016 VL 14 IS 2 BP 1091 EP 1098 DI 10.3892/mmr.2016.5352 PG 8 WC Oncology; Medicine, Research & Experimental SC Oncology; Research & Experimental Medicine GA DQ9UK UT WOS:000379554600007 PM 27277156 ER PT J AU Sagvand, BT Khairi, S Haghshenas, A Swearingen, B Tritos, NA Miller, KK Klibanski, A Nachtigall, LB AF Sagvand, Babak Torabi Khairi, Shafaq Haghshenas, Arezoo Swearingen, Brooke Tritos, Nicholas A. Miller, Karen K. Klibanski, Anne Nachtigall, Lisa B. TI Monotherapy with lanreotide depot for acromegaly: long-term clinical experience in a pituitary center SO PITUITARY LA English DT Article DE Acromegaly; Somatostatin analogs; Somatostatin receptor ligands; Lanreotide depot; IGF-1 ID ACTING SOMATOSTATIN ANALOG; OCTREOTIDE-LAR; TUMOR SHRINKAGE; GLUCOSE-TOLERANCE; SANDOSTATIN-LAR; GROWTH-HORMONE; EFFICACY; THERAPY; AUTOGEL; MACROADENOMAS AB Long-acting somatostatin analogs are one of the main classes of medical therapy used for acromegaly and most patients require ongoing treatment. Few studies have evaluated the long-term efficacy and safety of lanreotide depot beyond 2 years. The goal of this study was to provide a long-term longitudinal assessment of efficacy and safety of lanreotide depot in lanreotide responders compared to a surgically cured control group. In this retrospective longitudinal case-control study, patients with acromegaly receiving lanreotide depot monotherapy continuously for at least 24 months (N = 24) and surgically cured patients (N = 39) were compared. Serum IGF-1, pituitary MRIs, lanreotide dose, co-morbidities and adverse effects were assessed longitudinally. In the lanreotide group, IGF-1 remained normal and unchanged over 6 years; comparable to the surgery only group. There was no difference in prevalence of normal IGF-1 between the lanreotide and surgery only groups at 6 months (100 vs. 97 %), 6 years (89 vs. 90 %) and at last follow-up (96 vs. 92 %). Tumor size remained stable (79 %) or decreased (21 %) in the lanreotide group. In the surgery only group, tumor size remained unchanged in all patients. Hemoglobin A(1C) did not differ between lanreotide and surgery only groups (baseline 5.8 vs. 6.1 %; last follow-up 6.0 vs. 5.7 %). Two (8 %) of the lanreotide and none of the surgery only group developed new diabetes mellitus. Lanreotide depot maintains normalization of IGF-1 in 89 % of responders after 6 years, comparable to surgically cured controls, and controlled tumor size in all without significant adverse effects. C1 [Sagvand, Babak Torabi; Khairi, Shafaq; Haghshenas, Arezoo; Tritos, Nicholas A.; Miller, Karen K.; Klibanski, Anne; Nachtigall, Lisa B.] Harvard Med Sch, Massachusetts Gen Hosp, Neuroendocrine Unit, Neuroendocrine Clin Ctr, Zero Emerson Pl,Suite 112, Boston, MA 02114 USA. [Swearingen, Brooke] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. RP Nachtigall, LB (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Neuroendocrine Unit, Neuroendocrine Clin Ctr, Zero Emerson Pl,Suite 112, Boston, MA 02114 USA. EM lnachtigall@mgh.harvard.edu FU Ipsen FX This study was supported by an investigator-initiated grant from Ipsen. NR 41 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1386-341X EI 1573-7403 J9 PITUITARY JI Pituitary PD AUG PY 2016 VL 19 IS 4 BP 437 EP 447 DI 10.1007/s11102-016-0724-3 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DQ6XP UT WOS:000379350000013 PM 27155600 ER PT J AU Campbell, DG Bonner, LM Bolkan, CR Lanto, AB Zivin, K Waltz, TJ Klap, R Rubenstein, LV Chaney, EF AF Campbell, Duncan G. Bonner, Laura M. Bolkan, Cory R. Lanto, Andrew B. Zivin, Kara Waltz, Thomas J. Klap, Ruth Rubenstein, Lisa V. Chaney, Edmund F. TI Stigma Predicts Treatment Preferences and Care Engagement Among Veterans Affairs Primary Care Patients with Depression SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Article DE Depression; Stigma; Treatment preferences; Treatment engagement; Primary care; Veterans ID MENTAL-HEALTH TREATMENT; COMORBIDITY SURVEY REPLICATION; POSTTRAUMATIC-STRESS-DISORDER; NATIONAL-GUARD SOLDIERS; PERCEIVED STIGMA; HELP-SEEKING; SELF-STIGMA; MILITARY PERSONNEL; COGNITIVE THERAPY; MAJOR DEPRESSION AB Whereas stigma regarding mental health concerns exists, the evidence for stigma as a depression treatment barrier among patients in Veterans Affairs (VA) primary care (PC) is mixed. This study tests whether stigma, defined as depression label avoidance, predicted patients' preferences for depression treatment providers, patients' prospective engagement in depression care, and care quality. We conducted cross-sectional and prospective analyses of existing data from 761 VA PC patients with probable major depression. Relative to low-stigma patients, those with high stigma were less likely to prefer treatment from mental health specialists. In prospective controlled analyses, high stigma predicted lower likelihood of the following: taking medications for mood, treatment by mental health specialists, treatment for emotional concerns in PC, and appropriate depression care. High stigma is associated with lower preferences for care from mental health specialists and confers risk for minimal depression treatment engagement. C1 [Campbell, Duncan G.] Univ Montana, Dept Psychol, Missoula, MT 59812 USA. [Bonner, Laura M.] VA Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA USA. [Bonner, Laura M.; Chaney, Edmund F.] VA Puget Sound Hlth Care Syst, Hlth Serv Res & Dev Serv, Seattle, WA USA. [Bonner, Laura M.; Chaney, Edmund F.] Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Bolkan, Cory R.] Washington State Univ Vancouver, Dept Human Dev, Vancouver, WA USA. [Lanto, Andrew B.; Klap, Ruth; Rubenstein, Lisa V.] VA Greater Los Angeles Healthcare Syst, VA HSR&D Ctr Study Healthcare Innovat Implementat, Los Angeles, CA USA. [Zivin, Kara; Waltz, Thomas J.] VA Ann Arbor Hlth Care Syst, Ctr Clin Management Res Hlth Serv Res & Dev Serv, Ann Arbor, MI USA. [Zivin, Kara] Univ Michigan, Sch Med, Dept Psychiat, Ann Arbor, MI USA. [Zivin, Kara] Univ Michigan, Inst Social Res, Ann Arbor, MI USA. [Waltz, Thomas J.] Eastern Michigan Univ, Dept Psychol, Ypsilanti, MI 48197 USA. [Rubenstein, Lisa V.] Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. [Rubenstein, Lisa V.] RAND, Hlth Program, Santa Monica, CA USA. RP Campbell, DG (reprint author), Univ Montana, Dept Psychol, Missoula, MT 59812 USA. EM duncan.campbell@umontana.edu OI Waltz, Thomas/0000-0001-7976-430X FU Intramural VA [VA999999] NR 66 TC 0 Z9 0 U1 4 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 EI 1532-4796 J9 ANN BEHAV MED JI Ann. Behav. Med. PD AUG PY 2016 VL 50 IS 4 BP 533 EP 544 DI 10.1007/s12160-016-9780-1 PG 12 WC Psychology, Multidisciplinary SC Psychology GA DQ3DH UT WOS:000379082500006 PM 26935310 ER PT J AU Primo, V Graham, M Bigger-Allen, AA Chick, JM Ospina, C Quiroz, YT Manent, J Gygi, SP Lopera, F D'Amore, PA Arboleda-Velasquez, JF AF Primo, Vincent Graham, Mark Bigger-Allen, Alexander A. Chick, Joel M. Ospina, Carolina Quiroz, Yakeel T. Manent, Jan Gygi, Steven P. Lopera, Francisco D'Amore, Patricia A. Arboleda-Velasquez, Joseph F. TI Blood biomarkers in a mouse model of CADASIL SO BRAIN RESEARCH LA English DT Article DE CADASIL; Biomarker; Vascular smooth muscle; Stroke; Notch 3 mouse mutant; Endostatin; HTRA1 ID SMALL-VESSEL DISEASE; AUTOSOMAL-DOMINANT ARTERIOPATHY; SUBCORTICAL INFARCTS; NOTCH3 MUTATIONS; ISCHEMIC-STROKE; LEUKOENCEPHALOPATHY; PROTEOMICS; IMPAIRMENT; EXPRESSION; MEMBERS AB Mutations in NOTCH 3 are the cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a neurological disorder characterized by stroke, and vascular cognitive impairment and dementia. Loss of vascular smooth muscle cells (VSMC) and accumulation of granular osmiophilic material (GOM) deposits are hallmarks of CADASIL. There are no therapies for CADASIL and experimental endpoints to examine the preclinical efficacy of potential drugs are lacking. This study aims to use a mouse carrying the C455R mutation in Notch 3 to identify biomarkers associated with CADASIL. Mass spectrometry and antibody arrays were used to explore the aorta and blood proteomes of CADASIL mice, ELISA assays were utilized for biomarker validation, a ligand-dependent assay was applied to examine the relationship between Notch signaling and biomarker expression, and retinal histology was performed for quantification of VSMC loss in arteries. Two-hundred day-old mice with the C455R CADASIL mutation in Notch 3 mice display robust VSMC loss in retinal arteries and had increased plasma levels of collagen18 alpha 1/endostatin (col18 alpha 1) and high-temperature requirement A serine peptidase 1 (HTRA1) and reduced levels of Notch 3 extracellular domain (N3ECD), compared to control wild type mice. Measurements of plasma endostatin, HTRA1 and N3ECD, along with VSMC quantification in retinal arteries, may serve as surrogate endpoints for assessing efficacy in preclinical therapeutic studies of CADASIL using mice. (C) 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). C1 [Primo, Vincent; Graham, Mark; Bigger-Allen, Alexander A.; D'Amore, Patricia A.; Arboleda-Velasquez, Joseph F.] Harvard Med Sch, Dept Ophthalmol, Schepens Eye Res Inst, Massachusetts Eye & Ear, Boston, MA 02115 USA. [Chick, Joel M.; Gygi, Steven P.] Harvard Med Sch, Dept Cell Biol, Boston, MA USA. [Ospina, Carolina; Quiroz, Yakeel T.; Lopera, Francisco] Univ Antioquia, Grp Neurociencias Antioquia, Medellin, Colombia. [Quiroz, Yakeel T.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA USA. [Quiroz, Yakeel T.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Boston, MA USA. [Manent, Jan] La Trobe Univ, La Trobe Inst Mol Sci, Dept Biochem & Genet, Bundoora, Vic, Australia. [D'Amore, Patricia A.] Harvard Med Sch, Dept Pathol, Boston, MA USA. RP D'Amore, PA; Arboleda-Velasquez, JF (reprint author), Harvard Med Sch, Dept Ophthalmol, Schepens Eye Res Inst, Massachusetts Eye & Ear, Boston, MA 02115 USA. EM patricia_damore@meei.harvard.edu; joseph_arboleda@meei.harvard.edu FU cureCADASIL Association; NIH [R01EY005318, R00EY021624]; COLCIENCIAS Colombia [111565740694] FX The authors thank Magali Saint-Geniez, Ph.D., Leo Kim, M.D., Ph.D., and Eric Ng, Ph.D. for valuable discussions, and advice and Sandy Michaud, Dhanesh Armani and Daniel Oh for expert technical assistance. The authors would especially like to thank the cureCADASIL Association for their continued interest, enthusiasm and financial support. This work performed was supported by the cureCADASIL Association's 2014 summer fellowship (M.J.G.) and a cureCADASIL Association research grant (M.J.G. and J.F.A.-V), NIH grants R01EY005318 (P.A.D.), and R00EY021624 (J.F.A.-V.), COLCIENCIAS Colombia (grant 111565740694; F.L. Universidad de Antioquia). NR 40 TC 1 Z9 1 U1 6 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 EI 1872-6240 J9 BRAIN RES JI Brain Res. PD AUG 1 PY 2016 VL 1644 BP 118 EP 126 DI 10.1016/j.brainres.2016.05.008 PG 9 WC Neurosciences SC Neurosciences & Neurology GA DQ3MB UT WOS:000379105300014 PM 27174004 ER PT J AU Wang, Z Cho, YS Soeda, T Minami, Y Xing, L Jia, HB Aguirre, A Vergallo, R Lee, H Fujimoto, JG Yu, B Jang, IK AF Wang, Zhao Cho, Young-Seok Soeda, Tsunenari Minami, Yoshiyasu Xing, Lei Jia, Haibo Aguirre, Aaron Vergallo, Rocco Lee, Hang Fujimoto, James G. Yu, Bo Jang, Ik-Kyung TI Three-dimensional morphological response of lipid-rich coronary plaques to statin therapy: a serial optical coherence tomography study SO CORONARY ARTERY DISEASE LA English DT Article DE fibrous cap; optical coherence tomography; statin therapy ID FIBROUS CAP THICKNESS AB Objective Previous studies have suggested that intensive statin therapy, compared with moderate statin therapy, provided greater reduction of LDL and better protection against major cardiovascular events. However, the exact dose-dependent mechanism of plaque stabilization remains unclear. The aim of this study is to investigate the three-dimensional (3D) response of fibrous caps overlying lipid plaques to statin therapy. Methods We applied a novel computer algorithm to investigate the fibrous cap 3D morphological change over time in patients with coronary artery disease. Patients were treated with either atorvastatin 20 mg/day (moderate intensity) or atorvastatin 60 mg/day (high intensity). Optical coherence tomography was performed at baseline, 6, and 12 months. A total of 31 lipid plaques from 21 patients were analyzed. Results Conventional metrics such as the minimum fibrous cap thickness change between the two treatment groups were not significantly different between the baseline and the 12-month follow-up. In contrast, the 3D metric thin cap (<80 mu m) surface area change between the baseline and the 12-month follow-up showed dose-dependent, significant differences between the statin treatment groups (P<0.001). 3D reconstructions of fibrous caps further indicated that fibrous caps showed diverse (scattered vs. confluent) patterns and could evolve in a complex manner. Conclusion High-intensity statin therapy more effectively stabilized fibrous caps at follow-up. The new 3D algorithm provided more comprehensive and detailed information on the changes in plaque phenotype in response to statin therapy. Coron Artery Dis 27:350-356 Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved. C1 [Wang, Zhao; Fujimoto, James G.] MIT, Elect Res Lab, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA. [Cho, Young-Seok; Soeda, Tsunenari; Minami, Yoshiyasu; Aguirre, Aaron; Vergallo, Rocco; Jang, Ik-Kyung] Harvard Med Sch, Massachusetts Gen Hosp, Cardiol Div, Boston, MA USA. [Lee, Hang] Harvard Med Sch, Massachusetts Gen Hosp, MGH Biostat Ctr, Boston, MA USA. [Xing, Lei; Jia, Haibo; Yu, Bo] Harbin Med Univ, Affiliated Hosp 2, Dept Cardiol, Harbin, Peoples R China. [Jang, Ik-Kyung] Kyung Hee Univ, Div Cardiol, Seoul, South Korea. RP Jang, IK (reprint author), Massachusetts Gen Hosp, Div Cardiol, 55 Fruit St, Boston, MA 02114 USA. EM ijang@mgh.harvard.edu FU National Science Foundation of China; National Institutes of Health (NIH) [R01-CA075289-18] FX This study was funded by the National Science Foundation of China (H.J., L.X. and B.Y.). Ik-Kyung Jang was supported by Michael A. Park and by Gill and Allan Gray. Zhao Wang and James G. Fujimoto were supported by National Institutes of Health (NIH) R01-CA075289-18 research grant. NR 11 TC 0 Z9 0 U1 4 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0954-6928 EI 1473-5830 J9 CORONARY ARTERY DIS JI Coronary Artery Dis. PD AUG PY 2016 VL 27 IS 5 BP 350 EP 356 DI 10.1097/MCA.0000000000000370 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DQ2MR UT WOS:000379036900003 PM 27105047 ER PT J AU Liu, Y He, ZX Zhang, Y Dong, ZX Bi, YY Kou, JJ Zhou, J Shi, JL AF Liu, Yan He, Zhangxiu Zhang, Yan Dong, Zengxiang Bi, Yayan Kou, Junjie Zhou, Jin Shi, Jialan TI Dissimilarity of increased phosphatidylserine-positive microparticles and associated coagulation activation in acute coronary syndromes SO CORONARY ARTERY DISEASE LA English DT Article DE acute coronary syndromes; lactadherin; microparticles; phosphatidylserine; procoagulant activity ID ELEVATION MYOCARDIAL-INFARCTION; PLATELET-DERIVED MICROPARTICLES; SHED MEMBRANE-PARTICLES; PROCOAGULANT ACTIVITY; THROMBIN GENERATION; ARTERY-DISEASE; BLOOD-CELLS; EXPOSURE; EXPRESSION; ERYTHROCYTES AB Objective We evaluated cellular origin, numbers, and procoagulant activity of phosphatidylserine-positive microparticles (MPs) among subgroups in acute coronary syndromes (ACS). Materials and methods Parameters were measured on admission, days 1 (within 24 h of admission), 2, 3, and 7. All ST-elevated myocardial infarction (STEMI) patients presented more than 3 h from symptom onset and received fibrinolysis treatment; controls included unstable angina and non-STEMI patients as well as healthy controls. Phosphatidylserine-positive MPs were detected by flow cytometry, whereas procoagulant activity was assessed by coagulation time, purified coagulation complex assays, and fibrin formation. MP-induced fibrins were visualized by confocal microscopy. Results On admission, the total MP count was similar to 2.5-fold higher in the ACS groups compared with the healthy controls (P<0.05), primarily originating from platelets and endothelial cells, and there were no significant differences among ACS subgroups. Specifically, leukocyte-derived and erythrocyte-derived MPs were higher in the STEMI group compared with unstable angina and non-STEMI groups (both P<0.05). Further, MPs from the ACS groups reduced coagulation time by 27.5% and induced intrinsic and extrinsic FXase, prothrombinase, and fibrin formation by 2.8-, 2.3-, 2.5-, and 1.7-fold, respectively (P<0.05 for all), whereas blocking phosphatidylserine with lactadherin inhibited similar to 70% of procoagulant activity. MP number and concomitant coagulation decreased significantly by day 2 and continued to decrease gradually during the recovery period. Conclusion This study shows that MP characteristics from circulating blood may be used as prognostic indicators to reflect the origin cell of activation and thrombophilic states found in ACS subgroups. Coron Artery Dis 27:365-375 Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved. C1 [Liu, Yan; He, Zhangxiu; Zhang, Yan; Zhou, Jin; Shi, Jialan] Harbin Med Univ, Hosp 1, Dept Hematol, 23 Youzheng St, Harbin 150001, Peoples R China. [Dong, Zengxiang; Bi, Yayan] Harbin Med Univ, Hosp 1, Dept Cardiol, Harbin 150001, Peoples R China. [Kou, Junjie] Harbin Med Univ, Hosp 2, Dept Cardiol, Harbin 150001, Peoples R China. [Shi, Jialan] Harvard Med Sch, VA Boston Healthcare Syst, Brigham & Womens Hosp, Dept Surg, Boston, MA USA. RP Shi, JL (reprint author), Harbin Med Univ, Hosp 1, Dept Hematol, 23 Youzheng St, Harbin 150001, Peoples R China. EM shijialan12345@163.com FU National Natural Science Foundation of China [81270588, 81470301] FX This work was supported by grants from the National Natural Science Foundation of China (81270588 and 81470301). NR 52 TC 0 Z9 0 U1 2 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0954-6928 EI 1473-5830 J9 CORONARY ARTERY DIS JI Coronary Artery Dis. PD AUG PY 2016 VL 27 IS 5 BP 365 EP 375 DI 10.1097/MCA.0000000000000368 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DQ2MR UT WOS:000379036900005 PM 27058313 ER PT J AU Raynor, W Houshmand, S Gholami, S Emamzadehfard, S Rajapakse, CS Blomberg, BA Werner, TJ Hoilund-Carlsen, PF Baker, JF Alavi, A AF Raynor, William Houshmand, Sina Gholami, Saeid Emamzadehfard, Sahra Rajapakse, Chamith S. Blomberg, Bjorn Alexander Werner, Thomas J. Hoilund-Carlsen, Poul F. Baker, Joshua F. Alavi, Abass TI Evolving Role of Molecular Imaging with F-18-Sodium Fluoride PET as a Biomarker for Calcium Metabolism SO CURRENT OSTEOPOROSIS REPORTS LA English DT Review DE 18F-sodiumfluoride; Metabolic bone disease; Positron emission tomography; Quantitative radionuclide imaging; Regional bone formation ID POSITRON-EMISSION-TOMOGRAPHY; REGIONAL BONE METABOLISM; EARLY-STAGE OSTEOARTHRITIS; CORONARY-ARTERY-DISEASE; F-18-FLUORIDE PET; PARATHYROID-HORMONE; POSTMENOPAUSAL WOMEN; ANKYLOSING-SPONDYLITIS; RISK-FACTORS; ATHEROSCLEROTIC PLAQUE AB F-18-sodium fluoride (NaF) as an imaging tracer portrays calcium metabolic activity either in the osseous structures or in soft tissue. Currently, clinical use of NaF-PET is confined to detecting metastasis to the bone, but this approach reveals indirect evidence for disease activity and will have limited use in the future in favor of more direct approaches that visualize cancer cells in the read marrow where they reside. This has proven to be the case with FDG-PET imaging in most cancers. However, a variety of studies support the application of NaF-PET to assess benign osseous diseases. In particular, bone turnover can be measured from NaF uptake to diagnose osteoporosis. Several studies have evaluated the efficacy of bisphosphonates and their lasting effects as treatment for osteoporosis using bone turnover measured by NaF-PET. Additionally, NaF uptake in vessels tracks calcification in the plaques at the molecular level, which is relevant to coronary artery disease. Also, NaF-PET imaging of diseased joints is able to project disease progression in osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis. Further studies suggest potential use of NaF-PET in domains such as back pain, osteosarcoma, stress-related fracture, and bisphosphonate-induced osteonecrosis of the jaw. The critical role of NaF-PET in disease detection and characterization of many musculoskeletal disorders has been clearly demonstrated in the literature, and these methods will become more widespread in the future. The data from PET imaging are quantitative in nature, and as such, it adds a major dimension to assessing disease activity. C1 [Raynor, William; Houshmand, Sina; Gholami, Saeid; Emamzadehfard, Sahra; Alavi, Abass] Hosp Univ Penn, Dept Radiol, 3400 Spruce St, Philadelphia, PA 19104 USA. [Rajapakse, Chamith S.] Hosp Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. [Blomberg, Bjorn Alexander; Hoilund-Carlsen, Poul F.] Odense Univ Hosp, Dept Nucl Med, Odense, Denmark. [Blomberg, Bjorn Alexander] Univ Med Ctr Utrecht, Dept Radiol & Nucl Med, Utrecht, Netherlands. [Baker, Joshua F.] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. [Baker, Joshua F.] Hosp Univ Penn, Dept Med, Div Rheumatol, Philadelphia, PA 19104 USA. [Baker, Joshua F.] Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. RP Alavi, A (reprint author), Hosp Univ Penn, Dept Radiol, 3400 Spruce St, Philadelphia, PA 19104 USA. EM abass.alavi@uphs.upenn.edu NR 87 TC 2 Z9 2 U1 7 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1544-2241 J9 CURR OSTEOPOROS REP JI Curr. Osteoporos. Rep. PD AUG PY 2016 VL 14 IS 4 BP 115 EP 125 DI 10.1007/s11914-016-0312-5 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DQ2FZ UT WOS:000379019100001 PM 27301549 ER PT J AU Schulz, TJ Graja, A Huang, TL Xue, RD An, D Poehle-Kronawitter, S Lynes, MD Tolkachov, A O'Sullivan, LE Hirshman, MF Schupp, M Goodyear, LJ Mishina, Y Tseng, YH AF Schulz, Tim J. Graja, Antonia Huang, Tian Lian Xue, Ruidan An, Ding Poehle-Kronawitter, Sophie Lynes, Matthew D. Tolkachov, Alexander O'Sullivan, Lindsay E. Hirshman, Michael F. Schupp, Michael Goodyear, Laurie J. Mishina, Yuji Tseng, Yu-Hua TI Loss of BMP receptor type 1A in murine adipose tissue attenuates age-related onset of insulin resistance SO DIABETOLOGIA LA English DT Article DE Adipose tissue; Ageing; Bone morphogenetic proteins; Insulin sensitivity; Macrophage infiltration ID BONE MORPHOGENETIC PROTEIN-7; GLUCOSE-HOMEOSTASIS; ENERGY-EXPENDITURE; WHITE FAT; OBESITY; MACROPHAGES; MICE; DIFFERENTIATION; INFLAMMATION; PROGENITORS AB Aims/hypothesis Adipose tissue dysfunction is a prime risk factor for the development of metabolic disease. Bone morphogenetic proteins (BMPs) have previously been implicated in adipocyte formation. Here, we investigate the role of BMP signalling in adipose tissue health and systemic glucose homeostasis. Methods We employed the Cre/loxP system to generate mouse models with conditional ablation of BMP receptor 1A in differentiating and mature adipocytes, as well as tissue-resident myeloid cells. Metabolic variables were assessed by glucose and insulin tolerance testing, insulin-stimulated glucose uptake and gene expression analysis. Results Conditional deletion of Bmpr1a using the aP2 (also known as Fabp4)-Cre strain resulted in a complex phenotype. Knockout mice were clearly resistant to age-related impairment of insulin sensitivity during normal and high-fat-diet feeding and showed significantly improved insulin-stimulated glucose uptake in brown adipose tissue and skeletal muscle. Moreover, knockouts displayed significant reduction of variables of adipose tissue inflammation. Deletion of Bmpr1a in myeloid cells had no impact on insulin sensitivity, while ablation of Bmpr1a in mature adipocytes partially recapitulated the initial phenotype from aP2-Cre driven deletion. Co-cultivation of macrophages with pre-adipocytes lacking Bmpr1a markedly reduced expression of proinflammatory genes. Conclusions/interpretation Our findings show that altered BMP signalling in adipose tissue affects the tissue's metabolic properties and systemic insulin resistance by altering the pattern of immune cell infiltration. The phenotype is due to ablation of Bmpr1a specifically in pre-adipocytes and maturing adipocytes rather than an immune cell-autonomous effect. Mechanistically, we provide evidence for a BMP-mediated direct crosstalk between pre-adipocytes and macrophages. C1 [Schulz, Tim J.; Graja, Antonia; Poehle-Kronawitter, Sophie] German Inst Human Nutr Potsdam Rehbrucke, Dept Adipocyte Dev & Nutr, 114-116 Arthur Scheunert Allee, D-14558 Potsdam, Germany. [Schulz, Tim J.; Huang, Tian Lian; Xue, Ruidan; An, Ding; Lynes, Matthew D.; O'Sullivan, Lindsay E.; Hirshman, Michael F.; Goodyear, Laurie J.; Tseng, Yu-Hua] Harvard Med Sch, Joslin Diabet Ctr, Sect Integrat Physiol & Metab, One Joslin Pl, Boston, MA 02215 USA. [Schulz, Tim J.] German Ctr Diabet Res DZD, Munich, Germany. [Tolkachov, Alexander; Schupp, Michael] Charite Univ Sch Med, Inst Pharmacol, Cardiovasc Res Ctr, Berlin, Germany. [Mishina, Yuji] Univ Michigan, Sch Dent, Dept Biol & Mat Sci, Ann Arbor, MI 48109 USA. [Tseng, Yu-Hua] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Schulz, TJ (reprint author), German Inst Human Nutr Potsdam Rehbrucke, Dept Adipocyte Dev & Nutr, 114-116 Arthur Scheunert Allee, D-14558 Potsdam, Germany.; Schulz, TJ; Tseng, YH (reprint author), Harvard Med Sch, Joslin Diabet Ctr, Sect Integrat Physiol & Metab, One Joslin Pl, Boston, MA 02215 USA.; Schulz, TJ (reprint author), German Ctr Diabet Res DZD, Munich, Germany.; Tseng, YH (reprint author), Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. EM Tim.Schulz@dife.de; Yu-Hua.Tseng@joslin.harvard.edu FU National Institutes of Health grants NIDDK [R01DK077097, P30DK036836]; Harvard Stem Cell Institute; American Diabetes Association [ADA7-12-BS-191]; Mary K. Iacocca Foundation; German Research Foundation [SCHU 2445/1-1, SCHU 2445/2-1]; European Research Council [ERC-StG-2012-311082]; German Center for Diabetes Research (DZD); National Institutes of Health [R01 DK099511] FX This work was supported by National Institutes of Health grants NIDDK, R01DK077097 (to Y-HT) and P30DK036836 (to Joslin Diabetes Center's Diabetes Research Center). Y-HT was also supported by a grant from the Harvard Stem Cell Institute and the American Diabetes Association (ADA7-12-BS-191). TJS was supported by a research fellowship from the Mary K. Iacocca Foundation, the German Research Foundation (SCHU 2445/1-1 and SCHU 2445/2-1), the European Research Council (ERC-StG-2012-311082) and the German Center for Diabetes Research (DZD). LJG was supported by a National Institutes of Health grant, R01 DK099511. NR 47 TC 0 Z9 0 U1 3 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD AUG PY 2016 VL 59 IS 8 BP 1769 EP 1777 DI 10.1007/s00125-016-3990-8 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DQ4FH UT WOS:000379158800024 PM 27209464 ER PT J AU Kassis, EB Loring, SH Talmor, D AF Kassis, Elias Baedorf Loring, Stephen H. Talmor, Daniel TI Mortality and pulmonary mechanics in relation to respiratory system and transpulmonary driving pressures in ARDS SO INTENSIVE CARE MEDICINE LA English DT Article DE ARDS; Driving pressure; Esophageal manometry; Transpulmonary driving pressure; Respiratory system driving pressure; Mortality ID ACUTE LUNG INJURY; END-EXPIRATORY PRESSURE; RANDOMIZED CONTROLLED-TRIAL; DISTRESS-SYNDROME; VENTILATION STRATEGY; ESOPHAGEAL PRESSURE; TIDAL VOLUMES; BABY LUNG; FAILURE; RECRUITMENT AB The driving pressure of the respiratory system has been shown to strongly correlate with mortality in a recent large retrospective ARDSnet study. Respiratory system driving pressure [plateau pressure-positive end-expiratory pressure (PEEP)] does not account for variable chest wall compliance. Esophageal manometry can be utilized to determine transpulmonary driving pressure. We have examined the relationships between respiratory system and transpulmonary driving pressure, pulmonary mechanics and 28-day mortality. Fifty-six patients from a previous study were analyzed to compare PEEP titration to maintain positive transpulmonary end-expiratory pressure to a control protocol. Respiratory system and transpulmonary driving pressures and pulmonary mechanics were examined at baseline, 5 min and 24 h. Analysis of variance and linear regression were used to compare 28 day survivors versus non-survivors and the intervention group versus the control group, respectively. At baseline and 5 min there was no difference in respiratory system or transpulmonary driving pressure. By 24 h, survivors had lower respiratory system and transpulmonary driving pressures. Similarly, by 24 h the intervention group had lower transpulmonary driving pressure. This decrease was explained by improved elastance and increased PEEP. The results suggest that utilizing PEEP titration to target positive transpulmonary pressure via esophageal manometry causes both improved elastance and driving pressures. Treatment strategies leading to decreased respiratory system and transpulmonary driving pressure at 24 h may be associated with improved 28 day mortality. Studies to clarify the role of respiratory system and transpulmonary driving pressures as a prognosticator and bedside ventilator target are warranted. C1 [Kassis, Elias Baedorf] Harvard Med Sch, Div Pulm & Crit Care, Beth Israel Deaconess Med Ctr, 55 Fruit St,Bulfinch 108, Boston, MA 02114 USA. [Kassis, Elias Baedorf] Harvard Med Sch, Massachusetts Gen Hosp, 55 Fruit St,Bulfinch 108, Boston, MA 02114 USA. [Loring, Stephen H.; Talmor, Daniel] Harvard Med Sch, Dept Anesthesia Crit Care & Pain Med, Beth Israel Deaconess Med Ctr, 330 Brookline Ave, Boston, MA 02215 USA. RP Kassis, EB (reprint author), Harvard Med Sch, Div Pulm & Crit Care, Beth Israel Deaconess Med Ctr, 55 Fruit St,Bulfinch 108, Boston, MA 02114 USA.; Kassis, EB (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, 55 Fruit St,Bulfinch 108, Boston, MA 02114 USA. EM ekassis@partners.org FU Stephen Lorings RO1 Grant [HL-52586] FX The authors acknowledge Robert Gerber for assistance in making the figures and Victor Novak for assistance with statistical analysis. There was no separate funding source for this study, however the original EPVent study was funded under Stephen Lorings RO1 Grant HL-52586. NR 29 TC 4 Z9 4 U1 4 U2 7 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 2016 VL 42 IS 8 BP 1206 EP 1213 DI 10.1007/s00134-016-4403-7 PG 8 WC Critical Care Medicine SC General & Internal Medicine GA DQ4GD UT WOS:000379161200002 ER PT J AU Arem, H Sorkin, M Cartmel, B Fiellin, M Capozza, S Harrigan, M Ercolano, E Zhou, Y Sanft, T Gross, C Schmitz, K Neogi, T Hershman, D Ligibel, J Irwin, ML AF Arem, Hannah Sorkin, Mia Cartmel, Brenda Fiellin, Martha Capozza, Scott Harrigan, Maura Ercolano, Elizabeth Zhou, Yang Sanft, Tara Gross, Cary Schmitz, Kathryn Neogi, Tuhina Hershman, Dawn Ligibel, Jennifer Irwin, Melinda L. TI Exercise adherence in a randomized trial of exercise on aromatase inhibitor arthralgias in breast cancer survivors: the Hormones and Physical Exercise (HOPE) study SO JOURNAL OF CANCER SURVIVORSHIP LA English DT Article DE Physical activity; Exercise; Breast cancer; Aromatase inhibitors; Arthralgia ID POSTMENOPAUSAL WOMEN; AMERICAN-COLLEGE; SPORTS-MEDICINE; RECOMMENDATIONS; PREDICTORS; THERAPY; HEALTH AB Up to 50 % of postmenopausal breast cancer survivors taking aromatase inhibitors (AIs) experience AI-associated arthralgias, or joint pain, which causes many to stop taking AIs and may inhibit exercise, despite known health benefits. We thus evaluated exercise adherence and factors associated with better exercise adherence in breast cancer survivors experiencing AI-induced arthralgia in the (HOPE) year long randomized controlled trial. We included 61 HOPE women randomized to exercise (150 min/week of moderate-intensity aerobic exercise and twice-weekly supervised strength training). Our main outcomes were aerobic exercise measured with daily activity logs, attendance at supervised exercise sessions, and changes in cardiorespiratory fitness, measured maximal oxygen consumption (VO(2)max). We examined means and standard deviations (SDs) for exercise adherence by demographic and medical characteristics and used the t test for mean differences. We also examined predictors of adherence using linear regression. On average, at the end of the year long trial, women reported 119 (SD 78) min/week of moderate-intensity aerobic exercise and participated in 70 % of supervised exercise training sessions. After adjustment for other factors that influence adherence, at 6 months postrandomization, only baseline VO(2)max was associated with higher aerobic exercise levels and at 12 months, only older age predicted better supervised exercise training attendance. Breast cancer survivors taking AIs and experiencing arthralgia are able to initiate and maintain a year long exercise program, regardless of other factors that influence activity levels. Breast cancer survivors can exercise at levels that have been shown to improve AI-associated arthralgia. C1 [Arem, Hannah] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Sorkin, Mia; Cartmel, Brenda; Fiellin, Martha; Capozza, Scott; Harrigan, Maura; Ercolano, Elizabeth; Irwin, Melinda L.] Yale Sch Publ Hlth, New Haven, CT 06510 USA. [Cartmel, Brenda; Ercolano, Elizabeth; Zhou, Yang; Sanft, Tara; Gross, Cary; Irwin, Melinda L.] Yale Canc Ctr, New Haven, CT 06510 USA. [Schmitz, Kathryn] Univ Penn, Philadelphia, PA 19104 USA. [Neogi, Tuhina] Boston Univ, Sch Med, Boston, MA 02118 USA. [Hershman, Dawn] Columbia Univ, New York, NY USA. [Ligibel, Jennifer] Dana Farber Canc Inst, Boston, MA 02115 USA. [Irwin, Melinda L.] Yale Sch Publ Hlth, Dept Chron Dis Epidemiol, POB 208034, New Haven, CT 06520 USA. RP Irwin, ML (reprint author), Yale Sch Publ Hlth, New Haven, CT 06510 USA.; Irwin, ML (reprint author), Yale Canc Ctr, New Haven, CT 06510 USA.; Irwin, ML (reprint author), Yale Sch Publ Hlth, Dept Chron Dis Epidemiol, POB 208034, New Haven, CT 06520 USA. EM melinda.irwin@yale.edu FU intramural research program at the National Cancer Institute; NCI [R01 CA132931]; Breast Cancer Research Foundation; Yale Cancer Center Support Grant (CCSG) [P30 CA016359]; CTSA from the National Center for Advancing Translational Science (NCATS), a component of the National Institutes of Health (NIH) [UL1 TR000142] FX HA is supported by the intramural research program at the National Cancer Institute. HOPE was supported by NCI R01 CA132931 and in part by a grant from the Breast Cancer Research Foundation. This study was also supported in part by the Yale Cancer Center Support Grant (CCSG) P30 CA016359 and the CTSA Grant Number UL1 TR000142 from the National Center for Advancing Translational Science (NCATS), a component of the National Institutes of Health (NIH). Certain data used in this study were obtained from the Connecticut Tumor Registry located in the Connecticut Department of Public Health. The authors assume full responsibility for analyses and interpretation of these data. NR 23 TC 1 Z9 1 U1 3 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1932-2259 EI 1932-2267 J9 J CANCER SURVIV JI J. Cancer Surviv.-Res. Pract. PD AUG PY 2016 VL 10 IS 4 BP 654 EP 662 DI 10.1007/s11764-015-0511-6 PG 9 WC Oncology; Social Sciences, Biomedical SC Oncology; Biomedical Social Sciences GA DP7WS UT WOS:000378710500005 PM 26782031 ER PT J AU Oluloro, A Petrik, AF Turner, A Kapka, T Rivelli, J Carney, PA Saha, S Coronado, GD AF Oluloro, Ann Petrik, Amanda F. Turner, Ann Kapka, Tanya Rivelli, Jennifer Carney, Patricia A. Saha, Somnath Coronado, Gloria D. TI Timeliness of Colonoscopy After Abnormal Fecal Test Results in a Safety Net Practice SO JOURNAL OF COMMUNITY HEALTH LA English DT Article DE Colorectal cancer; Federally qualified health center; Hispanic/Latino; Colonoscopy; Gastroenterology referral ID OCCULT BLOOD-TEST; CANCER SCREENING-PROGRAM; COLORECTAL-CANCER; FOLLOW-UP; UNITED-STATES; BARRIERS; IMPROVEMENT AB Fecal testing can only reduce colorectal cancer mortality if patients with an abnormal test result receive a follow-up colonoscopy. As part of the Strategies and Opportunities to STOP Colon Cancer in Priority Populations (STOP CRC) project, we examined factors associated with adherence to follow-up colonoscopy among patients with abnormal fecal test results. As part of STOP CRC outreach, Virginia Garcia Memorial Health Center staff distributed 1753 fecal immunochemical tests (FIT), of which 677 (39 %) were completed, and 56 had an abnormal result (8 %). Project staff used logistic regression analyses to examine factors associated with colonoscopy referral and completion. Of the 56 patients with abnormal FIT results; 45 (80 %) had evidence of a referral for colonoscopy, 32 (57 %) had evidence of a completed colonoscopy within 18 months, and 14 (25 %) within 60 days of an abnormal fecal test result. In adjusted analysis, Hispanics had lower odds of completing follow-up colonoscopy within 60 days than non-Hispanic whites (adjusted OR 0.20; 95 % CI 0.04, 0.92). Colonoscopy within 60 days trended lower for women than for men (adjusted OR 0.25; 95 % CI 0.06-1.04). Among the 24 patients lacking medical record evidence of a colonoscopy, 19 (79 %) had a documented reason, including clinician did not pursue, patient refused, and colonoscopy not indicated. No reason was found for 21 %. Improvements are needed to increase rates of follow-up colonoscopy completion, especially among female and Hispanic patients. C1 [Oluloro, Ann; Petrik, Amanda F.; Kapka, Tanya; Rivelli, Jennifer; Coronado, Gloria D.] Kaiser Permanente Northwest, Ctr Hlth Res, 3800 N Interstate Ave, Portland, OR 97227 USA. [Oluloro, Ann; Carney, Patricia A.; Saha, Somnath] Oregon Hlth & Sci Univ, 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. [Turner, Ann; Kapka, Tanya] Virginia Garcia Mem Hlth Ctr, 226 SE 8th Ave, Hillsboro, OR 97123 USA. [Saha, Somnath] Portland VA Med Ctr, Gen Internal Med Sect, 3710 SW US Vet Hosp Rd P3HSRD, Portland, OR 97239 USA. RP Oluloro, A (reprint author), Kaiser Permanente Northwest, Ctr Hlth Res, 3800 N Interstate Ave, Portland, OR 97227 USA.; Oluloro, A (reprint author), Oregon Hlth & Sci Univ, 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM oluloroa@ohsu.edu FU National Institutes of Health through National Center for Complementary & Alternative Medicine [UH2AT007782]; National Cancer Institute [4UH3CA188640-02] FX Research reported in this publication was supported by the National Institutes of Health through the National Center for Complementary & Alternative Medicine under Award Number UH2AT007782 and the National Cancer Institute under Award Number 4UH3CA188640-02. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Complementary & Alternative Medicine or the National Cancer Institute. Dr. Saha's contribution to this work was supported with resources and the use of facilities at the VA Portland Health Care System. NR 31 TC 2 Z9 2 U1 1 U2 1 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 2016 VL 41 IS 4 BP 864 EP 870 DI 10.1007/s10900-016-0165-y PG 7 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA DQ4HC UT WOS:000379163700023 PM 26874943 ER PT J AU Gerlock, AA Szarka, JG Cox, K Harel, O AF Gerlock, April A. Szarka, Jackie G. Cox, Koriann Harel, Ofer TI Comparing Intimately Violent to Non-violent Veterans in Treatment for Posttraumatic Stress Disorder SO JOURNAL OF FAMILY VIOLENCE LA English DT Article DE PTSD; Abuse; Veterans; Couples; Treatment ID ADMINISTERED PTSD SCALE; ABUSE SCREENING-TEST; US ARMY SOLDIERS; PARTNER VIOLENCE; COMBAT VETERANS; DOMESTIC VIOLENCE; MILITARY VETERANS; VIETNAM VETERANS; ALCOHOL-USE; AGGRESSION AB The impact on relationships and adjustment to life after warzone deployments is a major concern, especially when the Veteran also struggles with posttraumatic stress disorder (PTSD). In this manuscript, we describe and compare Veterans who are intimately violent to non-violent Veterans who are in treatment for PTSD. In order to accurately identify the presence of intimate partner violence (IPV) we relied on both Veterans' and their partners' reports in the form of interviews and questionnaires. Additionally, we examined the following variables to determine if PTSD severity, childhood witnessing of inter-parental IPV, substance use/abuse, mutuality, and demographic variables could reliably differentiate Veterans perpetrating IPV from those who were not. Of the overall sample (N = 882; Veterans and partners), 43% of the male Veterans met our operationally defined criteria for IPV. Among the variables identified above, only the level of relationship mutuality significantly differentiated the intimately violent from non-violent. C1 [Gerlock, April A.; Szarka, Jackie G.; Cox, Koriann] VA Puget Sound Hlth Care Syst, Seattle Denver Ctr Innovat Vet Ctr & Value Driven, Hlth Serv Res & Dev, 1100 Olive Way,Suite 1400, Seattle, WA 98101 USA. [Harel, Ofer] Univ Connecticut, Dept Stat, Storrs, CT 06269 USA. RP Gerlock, AA (reprint author), VA Puget Sound Hlth Care Syst, Seattle Denver Ctr Innovat Vet Ctr & Value Driven, Hlth Serv Res & Dev, 1100 Olive Way,Suite 1400, Seattle, WA 98101 USA. EM April.Gerlock@va.gov NR 50 TC 0 Z9 0 U1 7 U2 10 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0885-7482 EI 1573-2851 J9 J FAM VIOLENCE JI J. Fam. Violence PD AUG PY 2016 VL 31 IS 6 BP 667 EP 678 DI 10.1007/s10896-016-9814-2 PG 12 WC Psychology, Clinical; Family Studies SC Psychology; Family Studies GA DQ5CQ UT WOS:000379222400001 ER PT J AU Crossley, KM Agnihotri, S Chaganti, J Rodriguez, ML McNally, LP Venna, N Turbett, SE Gutman, M Morey, A Koralnik, IJ Brew, BJ AF Crossley, Kate M. Agnihotri, Shruti Chaganti, Joga Rodriguez, Michael L. McNally, Leon Patrick Venna, Nagagopal Turbett, Sarah E. Gutman, Matthew Morey, Adrienne Koralnik, Igor J. Brew, Bruce J. TI Recurrence of progressive multifocal leukoencephalopathy despite immune recovery in two HIV seropositive individuals SO JOURNAL OF NEUROVIROLOGY LA English DT Article DE Progressive multifocal leukoencephalopathy; Neuroimmunology; Neurovirology ID JC VIRUS; INFECTION; DISEASE; NEUROPATHOLOGY AB We present two cases of recurrent progressive multifocal leukoencephalopathy (PML) in patients with long standing virally suppressed human immunodeficiency virus (HIV) and normal CD4+ T cell count who were taking stable regimens of highly active antiretroviral therapy (HAART). This has significant implications for other patients with a past history of PML, not just those with HIV but also those on medications such as natalizumab or fumarates. C1 [Crossley, Kate M.; Brew, Bruce J.] St Vincents Hosp, Dept Neurol, Level 4 Xavier Bldg, Sydney, NSW 2010, Australia. [Agnihotri, Shruti; Koralnik, Igor J.] Beth Deaconess Med Ctr, Ctr Virol & Vaccine Res, Div Neuro Immunol, Boston, MA USA. [Chaganti, Joga] St Vincents Hosp, Dept Radiol, Sydney, NSW, Australia. [Rodriguez, Michael L.] St Vincents Hosp, Dept Neuropathol, Sydney, NSW, Australia. [McNally, Leon Patrick] St Vincents Hosp, Dept Mol Med, Sydney, NSW, Australia. [Venna, Nagagopal] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Turbett, Sarah E.] Massachusetts Gen Hosp, Dept Infect Dis, Boston, MA 02114 USA. [Gutman, Matthew] St Vincents Hosp, Dept Neurosurg, Sydney, NSW, Australia. [Morey, Adrienne] St Vincents Hosp, Dept Anat Pathol, Sydney, NSW, Australia. [Brew, Bruce J.] St Vincents Ctr Appl Med Res, Neurosci Program, Peter Duncan Neurosci Unit, Sydney, NSW, Australia. [Brew, Bruce J.] St Vincents Hosp, Dept Infect Dis & Immunol, Sydney, NSW, Australia. RP Crossley, KM (reprint author), St Vincents Hosp, Dept Neurol, Level 4 Xavier Bldg, Sydney, NSW 2010, Australia. EM kate.crossley@health.nsw.gov.au OI Crossley, Kate/0000-0003-0553-1903 FU NIH [R01 047029, R01 074995] FX Igor J. Koralnik was supported in part by NIH grants R01 047029 and R01 074995. The other authors all declare that they have no conflict of interest. NR 11 TC 3 Z9 3 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-0284 EI 1538-2443 J9 J NEUROVIROL JI J. Neurovirol. PD AUG PY 2016 VL 22 IS 4 BP 541 EP 545 DI 10.1007/s13365-015-0419-y PG 5 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA DQ1YA UT WOS:000378995700017 PM 26727910 ER PT J AU Xie, Y LaFleur, J Kamauu, A Knippenberg, K DuVail, SL Haselkorn, J Nelson, RE AF Xie, Yan LaFleur, Joanne Kamauu, Aaron Knippenberg, Kristin DuVail, Scott L. Haselkorn, Jodie Nelson, Richard E. TI Rates of Early Treatment for US Veterans With Multiple Sclerosis SO JOURNAL OF PHARMACY TECHNOLOGY LA English DT Article AB Background: Early treatment of patients with multiple sclerosis (MS) may prevent neurological damage and reduce the risk of disability. However, little is known about the timing of treatment initiation following diagnosis and long-term outcomes in the general population of the Department of Veterans Affairs (VA) benefits-eligible patients. Objective: Our objective was to characterize treatment for MS patients in the VA at various time points following diagnosis date. Methods: In our historical database cohort study of US veterans, we calculated the proportion of MS patients from 1999 through 2010 with at least one prescription for a medication used to treat the condition at 6, 12, 24, 36, 48, 60, and 72 months following the index date. We also stratified the treatments given into 3 categories based on their role within the course of the disease: disease modifying, relapse, and symptom. Finally, we performed our calculations separately by MS subtype: relapsing-remitting, secondary-progressive, primary-progressive, and progressive-relapsing. Results: A total of 6803 patients were included in the analysis. Only 27.4% of MS patients received a prescription for MS medication within the first 6 months after diagnosis. The most common treatments were interferon beta-I a, glatiramer, amantadine, and prednisone, with disease-modifying agents being more than twice as frequently prescribed as medications for relapse or symptoms. Patients with relapsing-remitting MS were the most likely to be treated, followed by progressive-relapsing MS. Conclusions: Our results suggest that treatment rates are low in VA MS patients in the 6 years following their first diagnosis of MS. C1 [Xie, Yan] Abbvie Inc, N Chicago, IL USA. [LaFleur, Joanne; Knippenberg, Kristin; DuVail, Scott L.; Nelson, Richard E.] Salt Lake City Vet Affairs Hlth Care Syst, Salt Lake City, UT USA. [LaFleur, Joanne; Knippenberg, Kristin; DuVail, Scott L.] Univ Utah, Coll Pharm, Salt Lake City, UT 84112 USA. [Kamauu, Aaron] Anolinx LLC, Salt Lake City, UT USA. [DuVail, Scott L.; Nelson, Richard E.] Univ Utah, Sch Med, Salt Lake City, UT 84112 USA. [Haselkorn, Jodie] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. [Haselkorn, Jodie] Univ Washington, Sch Publ Hlth, Seattle, WA 98195 USA. RP Nelson, RE (reprint author), 500 Foothill Blvd, Salt Lake City, UT 84148 USA. EM richard.nelson@utah.edu NR 0 TC 0 Z9 0 U1 2 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 8755-1225 EI 1549-4810 J9 J PHARM TECHNOL JI J. Pharm. Technol. PD AUG PY 2016 VL 32 IS 4 BP 143 EP 149 DI 10.1177/8755122516640297 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DQ5YZ UT WOS:000379282500002 ER PT J AU Annunziata, R Kheirkhah, A Aggarwal, S Hamrah, P Trucco, E AF Annunziata, Roberto Kheirkhah, Ahmad Aggarwal, Shruti Hamrah, Pedram Trucco, Emanuele TI A fully automated tortuosity quantification system with application to corneal nerve fibres in confocal microscopy images SO MEDICAL IMAGE ANALYSIS LA English DT Article DE Tortuosity; Cornea; Multiscale; Segmentation; Curvature; Automated ID RETINAL VASCULAR TORTUOSITY; VESSEL TORTUOSITY; STRUCTURE SEGMENTATION; BLOOD-VESSELS; KERATITIS; CLASSIFICATION; RETINOPATHY; NEUROPATHY; FEATURES; FILTERS AB Recent clinical research has highlighted important links between a number of diseases and the tortuosity of curvilinear anatomical structures like corneal nerve fibres, suggesting that tortuosity changes might detect early stages of specific conditions. Currently, clinical studies are mainly based on subjective, visual assessment, with limited repeatability and inter-observer agreement. To address these problems, we propose a fully automated framework for image-level tortuosity estimation, consisting of a hybrid segmentation method and a highly adaptable, definition-free tortuosity estimation algorithm. The former combines an appearance model, based on a Scale and Curvature-Invariant Ridge Detector (SCIRD), with a context model, including multi-range learned context filters. The latter is based on a novel tortuosity estimation paradigm in which discriminative, multi-scale features can be automatically learned for specific anatomical objects and diseases. Experimental results on 140 in vivo confocal microscopy images of corneal nerve fibres from healthy and unhealthy subjects demonstrate the excellent performance of our method compared to state-of-the-art approaches and ground truth annotations from 3 expert observers. (C) 2016 Elsevier B.V. All rights reserved. C1 [Annunziata, Roberto; Trucco, Emanuele] Univ Dundee, Sch Sci & Engn Comp, VAMPIRE Project, Comp Vis & Image Proc Grp, Dundee, Scotland. [Hamrah, Pedram] Tufts Med Ctr, New England Eye Ctr, Boston Image Reading Ctr & Cornea Serv, Boston, MA USA. [Kheirkhah, Ahmad; Aggarwal, Shruti; Hamrah, Pedram] Harvard Med Sch, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Ocular Surface Imaging Ctr,Cornea Serv, Boston, MA USA. RP Annunziata, R (reprint author), Univ Dundee, Sch Sci & Engn Comp, VAMPIRE Project, Comp Vis & Image Proc Grp, Dundee, Scotland. EM r.annunziata@dundee.ac.uk FU EU Marie Curie Initial Training Network (ITN) "REtinal VAscular Modelling, Measurement And Diagnosis" (REVAMMAD) [316990]; National Eye Institute [R01EY022695]; Falk Medical Research Trust; Research to Prevent Career Development Award FX R. Annunziata is supported by the EU Marie Curie Initial Training Network (ITN) "REtinal VAscular Modelling, Measurement And Diagnosis" (REVAMMAD), project number 316990. P. Hamrah is supported by the National Eye Institute Grant R01EY022695, Falk Medical Research Trust and Research to Prevent Career Development Award. We thank the VAMPIRE project members for useful discussions. We are also grateful to the anonymous reviewers for their valuable comments and suggestions, which contributed to improve this paper. NR 65 TC 1 Z9 1 U1 7 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1361-8415 EI 1361-8423 J9 MED IMAGE ANAL JI Med. Image Anal. PD AUG PY 2016 VL 32 BP 216 EP 232 DI 10.1016/j.media.2016.04.006 PG 17 WC Computer Science, Artificial Intelligence; Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Radiology, Nuclear Medicine & Medical Imaging GA DQ1OC UT WOS:000378969300015 PM 27136674 ER PT J AU Kopacz, MS Morley, SW Wozniak, BM Simons, KV Bishop, TM Vance, CG AF Kopacz, Marek S. Morley, Sybil W. Wozniak, Barbara M. Simons, Kelsey V. Bishop, Todd M. Vance, C. Garland TI Religious Well-Being and Suicide Ideation in Veterans - An Exploratory Study SO PASTORAL PSYCHOLOGY LA English DT Article DE Veterans; Suicide ideation; Religious practice; Religious well-being ID POSTTRAUMATIC-STRESS-DISORDER; RISK-FACTORS; HEALTH; CARE; PREVALENCE; PTSD; ORIENTATION; PREVENTION; SEEKING; SAMPLE AB Religious well-being is a multi-faceted construct posited as a protective factor against suicidal thoughts and behaviors. This cross-sectional, exploratory study used religious practice data collected from n = 5378 U.S. military veterans to create composite measures of private and public religious practice. These composite measures were subsequently used to determine the probability of being identified with a history of suicide ideation. Data analysis was conducted using logistic regression. Veterans with a history of suicide ideation made up 10.2 % (n = 549) of the sample. Such veterans had significantly lower mean public and private religiosity scores compared to those without ideation. Differences between these two composite measures of religiosity were associated with a higher probability of being identified with a history of suicide ideation. The present study adds to the extant literature by presenting a framework for interpreting religious well-being in the context of religious practice. Quantitative differences in engagement between private and public practices may be indicative of a decreased sense of religious well-being, conferring less protection against suicidal behavior. C1 [Kopacz, Marek S.; Morley, Sybil W.; Simons, Kelsey V.; Bishop, Todd M.] VISN 2 Ctr Excellence Suicide Prevent, US Dept Vet Affairs, 400 Ft Hill Ave, Canandaigua, NY 14424 USA. [Wozniak, Barbara M.] Jagiellonian Univ, Coll Med, Dept Med Sociol, Kopernika 7a, PL-31034 Krakow, Poland. [Bishop, Todd M.] Univ Rochester, Med Ctr, Rochester, NY USA. [Vance, C. Garland] Charles George VA Med Ctr, US Dept Vet Affairs, Asheville, NC USA. RP Kopacz, MS (reprint author), VISN 2 Ctr Excellence Suicide Prevent, US Dept Vet Affairs, 400 Ft Hill Ave, Canandaigua, NY 14424 USA. EM marek.kopacz@va.gov NR 55 TC 1 Z9 1 U1 2 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0031-2789 EI 1573-6679 J9 PASTOR PSYCHOL JI Pastor. Psychol. PD AUG PY 2016 VL 65 IS 4 BP 481 EP 491 DI 10.1007/s11089-016-0699-z PG 11 WC Psychology, Clinical; Psychology, Multidisciplinary SC Psychology GA DQ0OP UT WOS:000378899600004 ER PT J AU Boltze, J Wagner, DC Henninger, N Plesnila, N Ayata, C AF Boltze, Johannes Wagner, Daniel-Christoph Henninger, Nils Plesnila, Nikolaus Ayata, Cenk TI Phase III Preclinical Trials in Translational Stroke Research: Community Response on Framework and Guidelines SO TRANSLATIONAL STROKE RESEARCH LA English DT Article DE Animal models; Experimental; Focal ischemia; Randomized controlled trials; Multicenter preclinical trials; Regeneration and recovery AB The multicenter phase III preclinical trial concept is currently discussed to enhance the predictive value of preclinical stroke research. After public announcement, we collected a community feedback on the concept with emphasis on potential design features and guidelines by an anonymous survey. Response analysis was conducted after plausibility checks by applying qualitative and quantitative measures. Most respondents supported the concept, including the implementation of a centralized steering committee. Based on received feedback, we suggest careful, stepwise implementation and to leave selected competencies and endpoint analysis at the discretion of participating centers. Strict application of quality assurance methods is accepted, but should be harmonized. However, received responses also indicate that the application of particular quality assurance models may require more attention throughout the community. Interestingly, clear and pragmatic preferences were given regarding publication and financing, suggesting the establishing of writing committees similar to large-scale clinical trials and global funding resources for financial support. The broad acceptance among research community encourages phase III preclinical trial implementation. C1 [Boltze, Johannes] Univ Lubeck, Fraunhofer Res Inst Marine Biotechnol, Monkhofer Weg 239a, D-23562 Lubeck, Germany. [Boltze, Johannes] Univ Lubeck, Inst Med & Marine Biotechnol, Monkhofer Weg 239a, D-23562 Lubeck, Germany. [Boltze, Johannes; Wagner, Daniel-Christoph] Fraunhofer Inst Cell Therapy & Immunol, Leipzig, Germany. [Henninger, Nils] Univ Massachusetts, Sch Med, Dept Neurol, Worcester, MA USA. [Plesnila, Nikolaus] Univ Munich, Med Ctr, Inst Stroke & Dementia Res, Munich, Germany. [Ayata, Cenk] Massachusetts Gen Hosp, Neurovasc Res Lab, Boston, MA 02114 USA. [Ayata, Cenk] Harvard Med Sch, Boston, MA USA. RP Boltze, J (reprint author), Univ Lubeck, Fraunhofer Res Inst Marine Biotechnol, Monkhofer Weg 239a, D-23562 Lubeck, Germany.; Boltze, J (reprint author), Univ Lubeck, Inst Med & Marine Biotechnol, Monkhofer Weg 239a, D-23562 Lubeck, Germany.; Boltze, J (reprint author), Fraunhofer Inst Cell Therapy & Immunol, Leipzig, Germany. EM johannes.boltze@emb.fraunhofer.de NR 9 TC 5 Z9 5 U1 2 U2 2 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 2016 VL 7 IS 4 BP 241 EP 247 DI 10.1007/s12975-016-0474-6 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DQ2OR UT WOS:000379042500001 PM 27297402 ER PT J AU Brotherton, JML Jit, M Gravitt, PE Brisson, M Kreimer, AR Pai, SI Fakhry, C Monsonego, J Franceschi, S AF Brotherton, Julia M. L. Jit, Mark Gravitt, Patti E. Brisson, Marc Kreimer, Aimee R. Pai, Sara I. Fakhry, Carole Monsonego, Joseph Franceschi, Silvia TI Eurogin Roadmap 2015: How has HPV knowledge changed our practice: Vaccines SO INTERNATIONAL JOURNAL OF CANCER LA English DT Review DE HPV; vaccine; cervical cancer; oropharyngeal cancer ID HUMAN-PAPILLOMAVIRUS VACCINATION; HPV-16/18 AS04-ADJUVANTED VACCINE; SQUAMOUS-CELL CARCINOMA; OF-STUDY ANALYSIS; P16-POSITIVE OROPHARYNGEAL CANCER; INCOMPLETELY ADDRESSES ISSUES; CROSS-PROTECTIVE EFFICACY; LONG-TERM IMMUNOGENICITY; POPULATION-LEVEL IMPACT; BLIND PATRICIA TRIAL AB This review is one of two complementary reviews that have been prepared in the framework of the Eurogin Roadmap 2015 to evaluate how knowledge about HPV is changing practices in HPV infection and disease control through vaccination and screening. In this review of HPV vaccine knowledge, we present the most significant findings of the past year which have contributed to our knowledge of the two HPV prophylactic vaccines currently in widespread use and about the recently licensed nonavalent HPV vaccine. Whereas anal cancer is dealt with in the companion mini-review on screening, we also review here the rapidly evolving evidence regarding HPV-associated head and neck cancer and priority research areas. C1 [Brotherton, Julia M. L.] VCS Registries, Natl HPV Vaccinat Program, East Melbourne, Vic, Australia. [Brotherton, Julia M. L.] Univ Melbourne, Sch Populat & Global Hlth, Melbourne, Vic, Australia. [Jit, Mark] Publ Hlth England, Modelling & Econ Unit, London, England. [Jit, Mark] London Sch Hyg & Trop Med, Dept Infect Dis Epidemiol, London WC1, England. [Gravitt, Patti E.] Univ New Mexico, Hlth Sci Ctr, Dept Pathol, Albuquerque, NM 87131 USA. [Brisson, Marc] Univ Laval, Dept Med Sociale & Prevent, Quebec City, PQ, Canada. [Kreimer, Aimee R.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Pai, Sara I.] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Fakhry, Carole] Johns Hopkins Outpatient Ctr, Johns Hopkins Sch Med, Dept Otolaryngol Head & Neck Surg, Baltimore, MD USA. [Monsonego, Joseph] Inst Col, 174 Rue Courcelles, F-75017 Paris, France. [Franceschi, Silvia] Int Agcy Res Canc, 150 Cours Albert Thomas, F-69372 Lyon 08, France. RP Brotherton, JML (reprint author), POB 310, East Melbourne, Vic 8002, Australia. EM jbrother@vcs.org.au FU bioCSL/Merck; Merck Frosst FX JMLB has been an investigator on investigator designed unrestricted epidemiological research grants partially funded through bioCSL/Merck but has received no personal financial benefits. In the past 3 years, MB received an unrestricted grant from Merck Frosst related to Zoster burden of illness (no grants ongoing). JM reports having received honorarium as a member of the scientific advisory board of Sanofi Pasteur MSD, Merck, Roche Diagnostics, Gen-Probe and Genticel and compensation from Merck and Glaxo Smith Kline to conduct vaccine trials. NR 110 TC 4 Z9 4 U1 10 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD AUG 1 PY 2016 VL 139 IS 3 BP 510 EP 517 DI 10.1002/ijc.30063 PG 8 WC Oncology SC Oncology GA DP3TK UT WOS:000378418100003 PM 26916230 ER PT J AU Wang, P Yoo, B Sherman, S Mukherjee, P Ross, A Pantazopoulos, P Petkova, V Farrar, C Medarova, Z Moore, A AF Wang, Ping Yoo, Byunghee Sherman, Sarah Mukherjee, Pinku Ross, Alana Pantazopoulos, Pamela Petkova, Victoria Farrar, Christian Medarova, Zdravka Moore, Anna TI Predictive imaging of chemotherapeutic response in a transgenic mouse model of pancreatic cancer SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE underglycosylated mucin 1 tumor antigen (uMUC1); pancreatic cancer; in vivo imaging; nanoparticles ID TUMOR PROGRESSION; EXPRESSION; ADENOCARCINOMA; THERAPY; ANTIGEN; CELLS AB The underglycosylated mucin 1 tumor antigen (uMUC1) is a biomarker that forecasts the progression of adenocarcinomas. In this study, we evaluated the utility of a dual-modality molecular imaging approach based on targeting uMUC1 for monitoring chemotherapeutic response in a transgenic murine model of pancreatic cancer (KCM triple transgenic mice). An uMUC1-specific contrast agent (MN-EPPT) was synthesized for use with magnetic resonance imaging (MRI) and fluorescence optical imaging. It consisted of dextran-coated iron oxide nanoparticles conjugated to the near infrared fluorescent dye Cy5.5 and to a uMUC1-specific peptide (EPPT). KCM triple transgenic mice were given gemcitabine as chemotherapy while control animals received saline injections following the same schedule. Changes in uMUC1 levels following chemotherapy were monitored using T2-weighted MRI and optical imaging before and 24 hr after injection of the MN-EPPT. uMUC1 expression in tumors from both groups was evaluated by histology and qRT-PCR. We observed that the average delta-T2 in the gemcitabine-treated group was significantly reduced compared to the control group indicating lower accumulation of MN-EPPT, and correspondingly, a lower level of uMUC1 expression. In vivo optical imaging confirmed the MRI findings. Fluorescence microscopy of pancreatic tumor sections showed a lower level of uMUC1 expression in the gemcitabine-treated group compared to the control, which was confirmed by qRT-PCR. Our data proved that changes in uMUC1 expression after gemcitabine chemotherapy could be evaluated using MN-EPPT-enhanced in vivo MR and optical imaging. These results suggest that the uMUC1-targeted imaging approach could provide a useful tool for the predictive assessment of therapeutic response. C1 [Wang, Ping; Yoo, Byunghee; Sherman, Sarah; Ross, Alana; Pantazopoulos, Pamela; Medarova, Zdravka; Moore, Anna] Massachusetts Gen Hosp, Mol Imaging Lab, MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Dept Radiol, Charlestown, MA USA. [Wang, Ping; Yoo, Byunghee; Sherman, Sarah; Ross, Alana; Pantazopoulos, Pamela; Farrar, Christian; Medarova, Zdravka; Moore, Anna] Harvard Univ, Sch Med, Charlestown, MA USA. [Mukherjee, Pinku] Univ N Carolina, Dept Biol Sci, Chapel Hill, NC USA. [Mukherjee, Pinku] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Petkova, Victoria] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Mol Med Core, Boston, MA 02215 USA. [Farrar, Christian] Massachusetts Gen Hosp, Dept Radiol, MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Charlestown, MA USA. RP Medarova, Z; Moore, A (reprint author), Massachusetts Gen Hosp, Dept Radiol, MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Radiol,Mol Imaging Lab, 13th St, Boston, MA 02129 USA.; Medarova, Z; Moore, A (reprint author), Harvard Univ, Sch Med, 13th St, Boston, MA 02129 USA. EM zmedarova@partners.org; amoore@helix.mgh.harvard.edu OI Wang, Ping/0000-0001-6712-8939 FU National Institute of Health [R01CA135650, R01CA163461] FX Grant sponsor: National Institute of Health; Grant numbers: R01CA135650, R01CA163461 NR 19 TC 2 Z9 2 U1 4 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD AUG 1 PY 2016 VL 139 IS 3 BP 712 EP 718 DI 10.1002/ijc.30098 PG 7 WC Oncology SC Oncology GA DP3TK UT WOS:000378418100025 PM 26996122 ER PT J AU Toro, JJ Gushiken, FC Schneider, D Lee, S Haile, DJ Freytes, CO AF Toro, Juan Jose Gushiken, Francisca Cecilia Schneider, Deanna Lee, Shuko Haile, David Johannes Freytes, Cesar Ovidio TI Edentulism and transplant-associated complications in patients with multiple myeloma undergoing autologous hematopoietic stem cell transplantation SO SUPPORTIVE CARE IN CANCER LA English DT Article DE Multiple myeloma; Autologous hematopoietic stem cell transplantation; Edentulous; Dentate; Oral complications; Post-transplant toxicities ID MARROW-TRANSPLANTATION; PERIODONTAL PATHOGENS; ORAL MUCOSITIS; MELPHALAN; RECIPIENTS; THERAPY; DISEASE; CANCER; CHEMOTHERAPY; GUIDELINES AB Patients undergoing autologous hematopoietic stem cell transplantation (HSCT) are at risk for oral complications which may cause significant morbidity. The aim of this study was to compare the incidence of toxicities and complications in edentulous and dentate patients undergoing autologous HSCT for multiple myeloma. We conducted a retrospective case-control study to analyze the incidence of bacteremia, fever, and oral mucositis, between edentulous and dentate patients. All patients underwent dental evaluation, received dental treatment if indicated, and were cleared before transplantation. The two groups were matched for age, gender, ethnicity, disease stage, time from diagnosis to transplant, performance status, and conditioning regimen. A total of 45 edentulous and 90 dentate patients were enrolled. All patients were male with a median age of 60 years and a mean performance status by Karnofsky score of 90 %. Two thirds had stage III MM with a median time from diagnosis to transplantation of 12 months, and all received melphalan as part of the conditioning regimen. The incidence of bacteremia (p = 0.553), fever (p = 0.245), severity of oral mucositis (p = 0.465), and other post-transplant toxicities were similar between both groups. There were no significant differences in the incidence of bacteremia, fever, severity of oral mucositis, or other complications between edentulous and dentate patients with multiple myeloma after autologous HSCT. C1 [Toro, Juan Jose; Gushiken, Francisca Cecilia; Schneider, Deanna; Lee, Shuko; Haile, David Johannes; Freytes, Cesar Ovidio] South Texas Vet Hlth Care Syst, Audie L Murphy Mem Vet Hosp, 7400 Merton Minter Blvd, San Antonio, TX 78229 USA. RP Toro, JJ (reprint author), South Texas Vet Hlth Care Syst, Audie L Murphy Mem Vet Hosp, 7400 Merton Minter Blvd, San Antonio, TX 78229 USA. EM Juan.toro2@va.gov NR 22 TC 0 Z9 0 U1 4 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 2016 VL 24 IS 8 BP 3411 EP 3415 DI 10.1007/s00520-016-3168-4 PG 5 WC Oncology; Health Care Sciences & Services; Rehabilitation SC Oncology; Health Care Sciences & Services; Rehabilitation GA DQ0JE UT WOS:000378884400025 PM 26984247 ER PT J AU Brand, SR Chordas, C Liptak, C Manley, P Recklitis, C AF Brand, Sarah R. Chordas, Christine Liptak, Cori Manley, Peter Recklitis, Christopher TI Screening for fatigue in adolescent and young adult pediatric brain tumor survivors: accuracy of a single-item screening measure SO SUPPORTIVE CARE IN CANCER LA English DT Article DE Brain tumors; Late effects; Psychosocial; Quality of life; Support care; Outcomes research ID QUALITY-OF-LIFE; CHILDHOOD-CANCER SURVIVORS; BRIEF SYMPTOM INVENTORY-18; PROJECT REACH; FEASIBILITY; VALIDITY; RELIABILITY; THERMOMETER; PEDSQL(TM); OUTCOMES AB Cancer-related fatigue (CRF) is one of the most commonly reported and distressing symptoms experienced by adolescent and young adult (AYA) cancer survivors. While national guidelines have recommended screening for CRF during routine follow-up appointments, the validity of using a one-item screening measure for fatigue has not been examined with AYA brain tumor survivors. The purpose of this study is to assess how well a single-item fatigue screen could identify clinically significant fatigue in childhood brain tumor survivors. A single-item measure, the Fatigue Thermometer (FT), was compared with a more in-depth measure, the Multidimensional Fatigue Scale (MFS), in a cohort of AYA pediatric brain tumor survivors. One hundred and forty-two survivors (aged 12-32 years) completed the two instruments. Forty-two survivors were identified on the MFS as having clinically significant fatigue, but the FT was not found to be an accurate tool for identifying these cases. Although receiver operating characteristic curve analysis of FT ratings against the MFS criterion indicated good concordance between measures, no cutoff score on the FT was identified that resulted in acceptable sensitivity and specificity. Results from this study suggest that a single-item screening measure for fatigue is not able to reliably identify clinically significant fatigue in AYA brain tumor survivors. C1 [Brand, Sarah R.; Liptak, Cori] Dana Farber Canc Inst, Dept Psychosocial Oncol, 450 Brookline Ave, Boston, MA 02115 USA. [Chordas, Christine; Manley, Peter; Recklitis, Christopher] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. RP Brand, SR (reprint author), Dana Farber Canc Inst, Dept Psychosocial Oncol, 450 Brookline Ave, Boston, MA 02115 USA. EM SarahR_Brand@dfci.harvard.edu NR 31 TC 0 Z9 0 U1 0 U2 1 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 2016 VL 24 IS 8 BP 3581 EP 3587 DI 10.1007/s00520-016-3150-1 PG 7 WC Oncology; Health Care Sciences & Services; Rehabilitation SC Oncology; Health Care Sciences & Services; Rehabilitation GA DQ0JE UT WOS:000378884400045 PM 27029475 ER PT J AU Bose-O'Reilly, S Schierl, R Nowak, D Siebert, U William, JF Owi, FT Ir, YI AF Bose-O'Reilly, Stephan Schierl, Rudolf Nowak, Dennis Siebert, Uwe William, Jossep Frederick Owi, Fradico Teorgi Ir, Yuyun Ismawati TI A preliminary study on health effects in villagers exposed to mercury in a small-scale artisanal gold mining area in Indonesia SO ENVIRONMENTAL RESEARCH LA English DT Article DE Mercury; Rice; Artisanal small-scale gold mining; Intoxication; Indonesia ID HUMAN BIOMONITORING COMMISSION; METHYLMERCURY EXPOSURE; FISH CONSUMPTION; PUBLIC-HEALTH; RICE; INTOXICATION; PROVINCE; GUIZHOU; CHINA AB Cisitu is a small-scale gold mining village in Indonesia. Mercury (Hg) is used to extract gold from ore, heavily polluting air, soil, fish and rice paddy fields with Hg. Rice in Cisitu is burdened with mercury. The main staple food of the inhabitants of Cisitu is this polluted rice. Villagers were concerned that the severe diseases they observed in the community might be related to their mining activities, including high mercury exposure. Case report of the medical examinations and the mercury levels in urine and hair of 18 people with neurological symptoms. Typical signs and symptoms of chronic mercury intoxication were found (excessive salivation, sleep disturbances, tremor, ataxia, dysdiadochokinesia, pathological coordination tests, gray to bluish discoloration of the oral cavity and proteinuria). Mercury levels in urine were increased in eight patients ( > 7 mu g Hg/L urine). All 18 people had increased hair levels ( > 1 mu g Hg/g hair). 15 patients exhibited several, and sometimes numerous, symptoms in addition to having moderately to highly elevated levels of mercury in their specimens. These patients were classified as intoxicated. The situation in Cisitu is special, with rice paddy fields being irrigated with mercury-contaminated water and villagers consuming only local food, especially mercury-contaminated rice. Severe neurological symptoms and increased levels of mercury in urine and hair support are possibly caused by exposure to inorganic mercury in air, and the consumption of mercury-contaminated fish and rice. The mercury exposure needs to be reduced and treatment provided. Further research is needed to test the hypothesis that mercury-contaminated rice from small-scale gold mining areas might cause mercury intoxication. (C) 2016 Elsevier Inc. All rights reserved. C1 [Bose-O'Reilly, Stephan; Schierl, Rudolf; Nowak, Dennis] Univ Hosp Munich, Inst & Outpatient Clin Occupat Social & Environm, WHO Collaborating Ctr Occupat Hlth, Ziemssenstr 1, D-80336 Munich, Germany. [Bose-O'Reilly, Stephan; Siebert, Uwe] Univ Hlth Sci Med Informat & Technol UMIT, Dept Publ Hlth & Hlth Technol Assessment, Inst Publ Hlth Med Decis Making & Hlth Technol As, Eduard Wallnoefer Ctr 1, A-6060 Hall In Tirol, Austria. [Siebert, Uwe] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Inst Technol Assessment, Boston, MA USA. [Siebert, Uwe] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Siebert, Uwe] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Ctr Hlth Decis Sci, Boston, MA 02115 USA. [William, Jossep Frederick; Owi, Fradico Teorgi] Medicuss Fdn, Ruko A45,Hypersq,Jalan Pasirkaliki, Bandung 40114, Indonesia. [William, Jossep Frederick; Ir, Yuyun Ismawati] BaliFokus Fdn, Mandalawangi 5,Jalan Tukad Tegalwangi, Denpasar 80223, Bali, Indonesia. RP Bose-O'Reilly, S (reprint author), Univ Hosp Munich, Inst & Outpatient Clin Occupat Social & Environm, WHO Collaborating Ctr Occupat Hlth, Paediat Environm Epidemiol, Ziemssenstr 1, D-80336 Munich, Germany. EM stephan.boeseoreilly@med-uni-muenchen.de; Rudolf.Schierl@med.uni-muenchen.de; Dennis.Nowak@med.uni-muenchen.de; uwe.siebert@umit.at; medicuss.foundation@gmail.com FU US Department of States [S-LMAQM-11-GR-0027]; IPEN (International POPs Elimination Network) through International Mercury Enabling Activity Program (IMEAP) FX US Department of States funded this project with US dollars 10,000 as part of the Grant award no. S-LMAQM-11-GR-0027.; IPEN (International POPs Elimination Network), an international non-governmental organization (www.ipen.org) provided a small grant, amounted US dollars 5000.00 through the International Mercury Enabling Activity Program (IMEAP) for the field visit and training for health workers and NGOs. NR 37 TC 1 Z9 1 U1 19 U2 25 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0013-9351 EI 1096-0953 J9 ENVIRON RES JI Environ. Res. PD AUG PY 2016 VL 149 BP 274 EP 281 DI 10.1016/j.envres.2016.04.007 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA DP3AY UT WOS:000378366000031 PM 27174690 ER PT J AU King, MR Anderson, TA Sui, JH He, GL Poon, KYT Cote, CJ AF King, Michael R. Anderson, T. Anthony Sui, Jinghu He, Guoluo Poon, Kwun Yee T. Cote, Charles J. TI Age-related incidence of desaturation events and the cardiac responses on stroke index, cardiac index, and heart rate measured by continuous bioimpedance noninvasive cardiac output monitoring in infants and children undergoing general anesthesia SO JOURNAL OF CLINICAL ANESTHESIA LA English DT Article DE Cardiac output; Anesthesia, general; Hypoxemia; Electric impedance; Hemodynamics; Monitoring, physiologic ID ELECTRICAL CARDIOMETRY; NEWBORN PIGLETS; PULSE OXIMETRY; SINGLE-BLIND; HYPOXEMIA AB Study objective: To assess the effects of desaturation on stroke index (SI), cardiac index (CI), and heart rate (HR) using the ICON continuous noninvasive cardiac output monitor in children undergoing general anesthesia. Design: Retrospective analysis of a prospectively collected data set. Setting: Pediatric operating rooms in a tertiary academic medical center. Patients: Children younger than 20 years who experienced desaturation while undergoing general anesthesia. Intervention: All records were retrospectively searched for desaturation events defined as a recorded Spo(2) <= 90%. We compared the data from the prior 4 minutes (baseline) with mild, moderate, and severe levels of desaturation. Measurements: The relationship between Spo2 and percent change in SI, CI, and HR from baseline was assessed using a generalized linear model with repeated measures and the least-squares method. Main results: Data from 446 patients were reviewed; 38 events were eligible for analysis after exclusions. There were significant decreases in SI at all saturation ranges below 95%: 6.5% (P <.001) for 85%-95%, 8.9% (P =.002) for 71%-84%, and -11% (P <.001) for 70%. Based on the result from the regression, Spo2 was associated with change in SI with borderline significance (P=.053) but not that of HR and CI. There was a strong relationship to desaturation events with young age (P <.001), particularly infants younger than 6 months. Conclusion: Events associated with desaturation in children under general anesthesia were significantly associated with decreased SI with a greater effect with lower saturation nadirs. It is unclear if other concurrent events could have also contributed to adverse hemodynamic responses during desaturation. In most children, a compensatory increase in HR generally offsets concurrent decreases in CI. It would appear that bradycardia is a late manifestation of hypoxemia. (C) 2016 Elsevier Inc. All rights reserved. C1 [King, Michael R.] Childrens Hosp Philadelphia, Dept Anesthesiol & Crit Care, 3401 Civ Ctr Blvd, Philadelphia, PA 19104 USA. [Anderson, T. Anthony; Poon, Kwun Yee T.; Cote, Charles J.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Anderson, T. Anthony; Poon, Kwun Yee T.; Cote, Charles J.] Harvard Univ, Sch Med, Boston, MA USA. [Sui, Jinghu] Chinese Acad Med Sci, Plast Surg Hosp, Dept Anesthesiol, Beijing 100730, Peoples R China. [He, Guoluo] Jiangxi Prov Gen Hosp, Dept Anesthesia, Nanchang, Peoples R China. RP King, MR (reprint author), Childrens Hosp Philadelphia, Dept Anesthesiol & Crit Care, 3401 Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM mrking1@gmail.com FU People's Republic of China FX Drs Jinghu sin and Guoluo He were supported as research fellows at Massachusetts General Hospital by a grant from the People's Republic of China. Osypka Medical provided no financial support and had no role in the data collection or analysis, but did provide an ICON monitor with which to conduct the study. NR 18 TC 0 Z9 0 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0952-8180 EI 1873-4529 J9 J CLIN ANESTH JI J. Clin. Anesth. PD AUG PY 2016 VL 32 BP 181 EP 188 DI 10.1016/j.jclinane.2016.02.026 PG 8 WC Anesthesiology SC Anesthesiology GA DP3AU UT WOS:000378365600039 PM 27290971 ER PT J AU Yesavage, JA Taylor, JL Friedman, L Rosenberg, PB Lazzeroni, LC Leoutsakos, JMS Kinoshita, LM Perlow, MJ Munro, CA Devanand, DP Drye, LT Mintzer, JE Pollock, BG Porsteinsson, AP Schneider, LS Shade, DM Weintraub, D Lyketsos, CG Noda, A AF Yesavage, Jerome A. Taylor, Joy L. Friedman, Leah Rosenberg, Paul B. Lazzeroni, Laura C. Leoutsakos, Jeannie-Marie S. Kinoshita, Lisa M. Perlow, Mark J. Munro, Cynthia A. Devanand, D. P. Drye, Lea T. Mintzer, Jacobo E. Pollock, Bruce G. Porsteinsson, Anton P. Schneider, Lon S. Shade, David M. Weintraub, Daniel Lyketsos, Constantine G. Noda, Art CA CitAD Res Grp TI Principal components analysis of agitation outcomes in Alzheimer's disease SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Agitation; Alzheimer's disease; Principal component analysis ID CITALOPRAM AB Background: We developed a composite measure of agitation as a secondary outcome of change over time in the Citalopram for Agitation in Alzheimer's disease study (CitAD). CitAD demonstrated a positive effect of citalopram on agitation on the Neurobehavioral Rating Scale agitation subscale (NBRS-A). CitAD included additional agitation measures such as the Cohen-Mansfield Agitation Inventory and the Neuropsychiatric Inventory. Methods: We performed principal components analyses on change in individual item of these scales for the same, original CitAD subjects. Results: The first principal component accounted for 12.6% of the observed variance and was composed of items that appear to reflect agitation. The effect size for citalopram calculated using this component was 0.53 (95% CI 0.22-0.83) versus 0.32 for the NBRS-A (95% CI 0.01-0.62). Conclusions: Results suggest that a composite measure of change in agitation might be more sensitive than change in a single primary agitation measure. Published by Elsevier Ltd. C1 [Yesavage, Jerome A.; Taylor, Joy L.; Kinoshita, Lisa M.; Perlow, Mark J.] Dept Vet Affairs Hlth Care Syst, Palo Alto, CA 94304 USA. [Yesavage, Jerome A.; Taylor, Joy L.; Friedman, Leah; Lazzeroni, Laura C.; Noda, Art] Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. [Yesavage, Jerome A.] Stanford Univ, Sch Med, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA. [Rosenberg, Paul B.; Leoutsakos, Jeannie-Marie S.; Munro, Cynthia A.; Lyketsos, Constantine G.] Johns Hopkins Sch Med, Johns Hopkins Bayview Med Ctr, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Devanand, D. P.] New York State Psychiat Inst & Hosp, Div Geriatr Psychiat, New York, NY 10032 USA. [Devanand, D. P.] Columbia Univ, Coll Phys & Surg, New York, NY 10032 USA. [Drye, Lea T.; Shade, David M.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Mintzer, Jacobo E.] Roper St Francis Healthcare, Clin Biotechnol Res Inst, Charleston, SC 29401 USA. [Mintzer, Jacobo E.] Ralph H Johnson VA Med Ctr, Charleston, SC 29401 USA. [Pollock, Bruce G.] Univ Toronto, CAMH, Campbell Inst, Toronto, ON M5S 2S1, Canada. [Porsteinsson, Anton P.] Univ Rochester, Sch Med & Dent, Rochester, NY 14642 USA. [Schneider, Lon S.] Univ So Calif, Keck Sch Med, Los Angeles, CA 90089 USA. [Weintraub, Daniel] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Weintraub, Daniel] Dept Vet Affairs, Philadelphia, PA 19104 USA. RP Yesavage, JA (reprint author), Palo Alto VA Hlth Care Syst, 3801 Miranda Ave 151Y, Palo Alto, CA 94304 USA. EM yesavage@stanford.edu FU NIA; NIMH [R01AG031348]; NIH [P50, AG05142]; Sierra-Pacific Mental Illness Research, Education, and Clinical Center (MIRECC); Medical Research Service of the Department of Veterans Affairs FX This work was supported by NIA and NIMH, R01AG031348 and in part by NIH P50, AG05142 (USC, LSS). and by the Sierra-Pacific Mental Illness Research, Education, and Clinical Center (MIRECC) and the Medical Research Service of the Department of Veterans Affairs. The funding sources had a 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 article for publication. NR 12 TC 0 Z9 0 U1 4 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 EI 1879-1379 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD AUG PY 2016 VL 79 BP 4 EP 7 DI 10.1016/j.jpsychires.2016.04.004 PG 4 WC Psychiatry SC Psychiatry GA DP0KP UT WOS:000378179000002 PM 27115509 ER PT J AU Corbo, V Amick, MA Milberg, WP McGlinchey, RE Salat, DH AF Corbo, Vincent Amick, Melissa A. Milberg, William P. McGlinchey, Regina E. Salat, David H. TI Early life trauma is associated with altered white matter integrity and affective control SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Trauma; Childhood; Fractional anisotropy; Executive function; PTSD; Attention ID POSTTRAUMATIC-STRESS-DISORDER; FRACTIONAL ANISOTROPY; BRAIN-DEVELOPMENT; ATTENTION BIAS; MALTREATED CHILDREN; ANTERIOR CINGULATE; PREFRONTAL CORTEX; CHILDHOOD TRAUMA; REACTION-TIME; SEXUAL-ABUSE AB Early life trauma (ELT) has been shown to impair affective control and attention well into adulthood. Neuroimaging studies have further shown that ELT was associated with decreased white matter integrity in the prefrontal areas in children and adults. However, no study to date has looked at the relationship between white matter integrity and affective control in individuals with and without a history of ELT. To examine this, we tested 240 Veterans with (ELT N = 80) and without (NoELT N = 160) a history of childhood sexual abuse, physical abuse or family violence. Affective control was measured with the Affective Go/No-Go (AGN) and attention was indexed with the Test of Variable Attention (TOVA). White matter integrity was measured using fractional anisotropy (FA). Results showed greater number of errors on the AGN in ELT compared to NoELT. There was no difference on the TOVA. While there were no mean differences in FA, there was an interaction between FA and reaction time to positive stimuli on the AGN where the ELT group showed a positive relationship between FA and reaction time in right frontal and prefrontal areas, whereas the NoELT group showed a negative or no association between FA and reaction time. This suggests that ELT may be associated with a distinct brain-behavior relationship that could be related to other determinants of FA than those present in healthy adults. Published by Elsevier Ltd. C1 [Corbo, Vincent; Amick, Melissa A.; Milberg, William P.; McGlinchey, Regina E.; Salat, David H.] VA Boston Healthcare Syst, Translat Res Ctr TBI & Stress Disorders, GRECC, Boston, MA USA. [Corbo, Vincent] Boston Univ, Sch Med, Boston, MA 02118 USA. [Milberg, William P.; McGlinchey, Regina E.] Harvard Univ, Sch Med, Dept Psychiat, Cambridge, MA 02138 USA. [Salat, David H.] Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. RP Corbo, V (reprint author), 150 South Huntington Ave,C-11-36, Boston, MA 02120 USA. EM Vincent.corbo@va.gov RI McGlinchey, Regina/R-1971-2016 FU VA Rehabilitation, Research and Development; National Institute of Health FX The funding agencies (VA Rehabilitation, Research and Development & the National Institute of Health) were not involved in the study development, data analysis, writing of report or in the decision to submit this manuscript for publication. NR 63 TC 0 Z9 0 U1 11 U2 22 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 EI 1879-1379 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD AUG PY 2016 VL 79 BP 70 EP 77 DI 10.1016/j.jpsychires.2016.05.001 PG 8 WC Psychiatry SC Psychiatry GA DP0KP UT WOS:000378179000011 PM 27214523 ER PT J AU Thames, AD Sayegh, P Terashima, K Foley, JM Cho, A Arentoft, A Hinkin, CH Bookheimer, SY AF Thames, April D. Sayegh, Philip Terashima, Kevin Foley, Jessica M. Cho, Andrew Arentoft, Alyssa Hinkin, Charles H. Bookheimer, Susan Y. TI Increased subcortical neural activity among HIV plus individuals during a lexical retrieval task SO NEUROBIOLOGY OF DISEASE LA English DT Article DE Lexical retrieval; Verbal fluency; HIV; Neuroimaging; Immunosuppression ID IMMUNODEFICIENCY-VIRUS TYPE-1; VERBAL FLUENCY EVIDENCE; NEUROCOGNITIVE IMPAIRMENT; ANTIRETROVIRAL THERAPY; FUNCTIONAL MRI; BASAL GANGLIA; CD4 NADIR; INFECTION; BRAIN; ADULTS AB Background: Deficits in lexical retrieval, present in approximately 40% of HIV + patients, are thought to reflect disruptions to frontal-striatal functions and may worsen with immunosuppression. Coupling frontal-striatal tasks such as lexical retrieval with functional neuroimaging may help delineate the pathophysiologic mechanisms underlying HIV-associated neurological dysfunction. Objective: We examined whether HIV infection confers brain functional changes during lexical access and retrieval. It was expected that HIV + individuals would demonstrate greater brain activity in frontal-subcortical regions despite minimal differences between groups on neuropsychological testing. Within the HIV + sample, we examined associations between indices of immunosuppression (recent and nadir CD4+ count) and task-related signal change in frontostriatal structures. Method 16 HIV+ participants and 12 HIV - controls underwent fMRI while engaged in phonemic/letter and semantic fluency tasks. Participants also completed standardized measures of verbal fluency Results: HIV status groups performed similarly on phonemic and semantic fluency tasks prior to being scanned. fMRI results demonstrated activation differences during the phonemic fluency task as a function of HIV status, with HIV + individuals demonstrating significantly greater activation in BG structures than HIV individuals. There were no significant differences in frontal brain activation between HIV status groups during the phonemic fluency task, nor were there significant brain activation differences during the semantic fluency task. Within the HIV+ group, current CD4+ count, though not nadir, was positively correlated with increased activity in the inferior frontal gyrus and basal ganglia. Conclusion: During phonemic fluency performance, HIV+ patients recruit subcortical structures to a greater degree than HIV controls despite similar task performances suggesting that fMRI may be sensitive to neurocompromise before overt cognitive declines can be detected. Among HIV + individuals, reduced activity in the frontal-subcortical structures was associated with lower CD4+ count. (C) 2015 Elsevier Inc. All rights reserved. C1 [Thames, April D.; Sayegh, Philip; Terashima, Kevin; Cho, Andrew; Arentoft, Alyssa; Hinkin, Charles H.; Bookheimer, Susan Y.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, 740 Westwood Plaza C8-746, Los Angeles, CA 90095 USA. [Foley, Jessica M.] Univ Calif San Francisco, Med Ctr, 505 Parnassus Ave, San Francisco, CA 94143 USA. [Arentoft, Alyssa] Calif State Univ Northridge, Dept Psychol, 18111 Nordhoff St, Northridge, CA 91330 USA. [Hinkin, Charles H.] VA Greater Los Angeles Healthcare Syst, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. RP Thames, AD (reprint author), Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, 740 Westwood Plaza, Los Angeles, CA 90095 USA. EM athames@mednet.ucla.edu FU UCLA Academic Senate Grant; National Institute of Health (NIH/NIMH) Career Development Award [K23 MH095661] FX We would like to thank Vanessa Streiff and Darryl Stallworth for assistance with MRI data collection. We would like to acknowledge the following funding sources: UCLA Academic Senate Grant (PI: S.Y. Bookheimer). Center For AIDS Research (CFAR) (AI28697; PI: A. Thames). Dr. Thames is supported by a National Institute of Health (NIH/NIMH) Career Development Award (K23 MH095661). NR 50 TC 0 Z9 0 U1 4 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 EI 1095-953X J9 NEUROBIOL DIS JI Neurobiol. Dis. PD AUG PY 2016 VL 92 SI SI BP 175 EP 182 DI 10.1016/j.nbd.2015.10.017 PN B PG 8 WC Neurosciences SC Neurosciences & Neurology GA DP4IQ UT WOS:000378460000008 PM 26484382 ER PT J AU Hwang, K Ghuman, AS Manoach, DS Jones, SR Luna, B AF Hwang, Kai Ghuman, Avniel S. Manoach, Dara S. Jones, Stephanie R. Luna, Beatriz TI Frontal preparatory neural oscillations associated with cognitive control: A developmental study comparing young adults and adolescents SO NEUROIMAGE LA English DT Article DE Adolescence; Antisaccade; Frontal cortex; Inhibitory control; Neural oscillations ID WHITE-MATTER DEVELOPMENT; SIGNAL-SPACE SEPARATION; ANTI-SACCADE TASK; PRIMARY SOMATOSENSORY CORTEX; POSTERIOR PARIETAL CORTICES; SURFACE-BASED ANALYSIS; EVENT-RELATED FMRI; INHIBITORY CONTROL; PREFRONTAL CORTEX; ALPHA-OSCILLATIONS AB Functional magnetic resonance imaging (fMRI) studies suggest that age-related changes in the frontal cortexmay underlie developmental improvements in cognitive control. In the present study we used magnetoencephalography (MEG) to identify frontal oscillatory neurodynamics that support age-related improvements in cognitive control during adolescence. We characterized the differences in neural oscillations in adolescents and adults during the preparation to suppress a prepotent saccade (antisaccade trials-AS) compared to preparing to generate a more automatic saccade (prosaccade trials-PS). We found that for adults, AS were associated with increased beta-band (16-38 Hz) power in the dorsal lateral prefrontal cortex (DLPFC), enhanced alpha-to low betaband (10-18 Hz) power in the frontal eye field (FEF) that predicted performance, and increased cross-frequency alpha-beta (10-26 Hz) amplitude coupling between the DLPFC and the FEF. Developmental comparisons between adults and adolescents revealed similar engagement of DLPFC beta-band power but weaker FEF alpha-band power, and lower cross-frequency coupling between the DLPFC and the FEF in adolescents. These results suggest that lateral prefrontal neural activity associated with cognitive control is adult-like by adolescence; the development of cognitive control from adolescence to adulthood is instead associated with increases in frontal connectivity and strengthening of inhibition signaling for suppressing task-incompatible processes. (C) 2016 Elsevier Inc. All rights reserved. C1 [Hwang, Kai] Univ Calif Berkeley, Helen Wills Neurosci Inst, Berkeley, CA 94720 USA. [Hwang, Kai; Ghuman, Avniel S.; Luna, Beatriz] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. [Hwang, Kai; Luna, Beatriz] Univ Pittsburgh, Dept Psychol, Pittsburgh, PA 15260 USA. [Hwang, Kai; Ghuman, Avniel S.; Luna, Beatriz] Carnegie Mellon Univ, Ctr Neural Basis Cognit, Pittsburgh, PA 15213 USA. [Hwang, Kai; Ghuman, Avniel S.; Luna, Beatriz] Univ Pittsburgh, Pittsburgh, PA USA. [Ghuman, Avniel S.] Univ Pittsburgh, Dept Neurol Surg, Pittsburgh, PA 15260 USA. [Manoach, Dara S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA USA. [Manoach, Dara S.] Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Jones, Stephanie R.] Brown Univ, Dept Neurosci, Providence, RI 02912 USA. RP Hwang, K (reprint author), Univ Calif Berkeley, 132 Barker Hall, Berkeley, CA 94720 USA. EM kai.hwang@berkeley.edu OI Ghuman, Avniel/0000-0003-1746-4656 FU National Institutes of Mental Health [R01 MH067924]; MEG Research Seed Fund from the UPMC-Brain Mapping Center FX This work was supported by National Institutes of Mental Health grant R01 MH067924 and the MEG Research Seed Fund from the UPMC-Brain Mapping Center. We thank Soma Chatterji, Natalie Nawarawong, and Amanda Wright for assistance in data collection; TJ Amdurs, Anna Haridis, and Erika Taylor for technical support; and Dr. Michael Hallquist for statistical consulting. NR 106 TC 0 Z9 0 U1 3 U2 3 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 2016 VL 136 BP 139 EP 148 DI 10.1016/j.neuroimage.2016.05.017 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DO8QI UT WOS:000378048000013 PM 27173759 ER PT J AU Labenski, V Suerth, JD Barczak, E Heckl, D Levy, C Bernadin, O Charpentier, E Williams, DA Fehse, B Verhoeyen, E Schambach, A AF Labenski, Verena Suerth, Julia D. Barczak, Elke Heckl, Dirk Levy, Camille Bernadin, Ornellie Charpentier, Emmanuelle Williams, David A. Fehse, Boris Verhoeyen, Els Schambach, Axel TI Alpharetroviral self-inactivating vectors produced by a superinfection-resistant stable packaging cell line allow genetic modification of primary human T lymphocytes SO BIOMATERIALS LA English DT Article DE Alpharetroviral SIN vector; Immunotherapy; Stable packaging cell line; TK007; CRISPR-Cas9; Superinfection ID AMINO-ACID TRANSPORTER; LARGE-SCALE PRODUCTION; BROAD-HOST-RANGE; RETROVIRAL VECTORS; HIGH-TITER; LENTIVIRAL VECTORS; TRANSGENE EXPRESSION; CANCER-IMMUNOTHERAPY; HEMATOPOIETIC STEM; ENVELOPE PROTEIN AB Primary human T lymphocytes represent an important cell population for adoptive immunotherapies, including chimeric-antigen and T-cell receptor applications, as they have the capability to eliminate non self, virus-infected and tumor cells. Given the increasing numbers of clinical immunotherapy applications, the development of an optimal vector platform for genetic T lymphocyte engineering, which allows cost-effective high-quality vector productions, remains a critical goal. Alpharetroviral self-inactivating vectors (ARV) have several advantages compared to other vector platforms, including a more random genomic integration pattern and reduced likelihood for inducing aberrant splicing of integrated pro viruses. We developed an ARV platform for the transduction of primary human T lymphocytes. We demonstrated functional transgene transfer using the clinically relevant herpes-simplex-virus thymidine kinase variant TK.007. Proof-of-concept of alpharetroviral-mediated T-lymphocyte engineering was shown in vitro and in a humanized transplantation model in vivo. Furthermore, we established a stable, human alpharetroviral packaging cell line in which we deleted the entry receptor (SLC1A5) for RD114/TR-pseudotyped ARVs to prevent superinfection and enhance genomic integrity of the packaging cell line and viral particles. We showed that superinfection can be entirely prevented, while maintaining high recombinant virus titers. Taken together, this resulted in an improved production platform representing an economic strategy for translating the promising features of ARVs for therapeutic T-lymphocyte engineering. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Labenski, Verena; Suerth, Julia D.; Barczak, Elke; Schambach, Axel] Hannover Med Sch, Inst Expt Hematol, Carl Neuberg Str 1, D-30625 Hannover, Germany. [Heckl, Dirk] Hannover Med Sch, Dept Pediat Hematol & Oncol, D-30625 Hannover, Germany. [Heckl, Dirk; Charpentier, Emmanuelle] Helmholtz Ctr Infect Res, Dept Regulat Infect Biol, Braunschweig, Germany. [Levy, Camille; Bernadin, Ornellie; Verhoeyen, Els] Univ Lyon 1, ENS Lyon, INSERM, U1111,CIRI,EVIR Team,CNRS,UMR5308, Lyon, France. [Williams, David A.; Schambach, Axel] Harvard Univ, Sch Med, Boston Childrens Hosp, Div Hematol Oncol, Boston, MA USA. [Williams, David A.] Harvard Univ, Sch Med, Boston, MA USA. [Williams, David A.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Fehse, Boris] Univ Med Ctr Hamburg Eppendorf, Dept Stem Cell Transplantat, Res Dept Cell & Gene Therapy, Hamburg, Germany. [Verhoeyen, Els] Fac Med Nice, INSERM, U1065, Equipe Controle Metab Morts Cellulaires,C3M, U210, F-06034 Nice, France. RP Schambach, A (reprint author), Harvard Univ, Sch Med, Boston Childrens Hosp, Div Hematol Oncol, Boston, MA USA. EM schambach.axel@mh-hannover.de RI Verhoeyen, Els/H-6360-2016 FU Deutsche Forschungsgemeinschaft [SFB738]; Deutsche Forschungsgemeinschaft (Cluster of Excellence REBIRTH) [EXC 62/1]; Bundesministerium fur Bildung and Forschung (BMBF); DAAD (Modern Applications in Biotechnology); European Union (PERSIST); European Union (CELLPID); European Union (SCIDNET); Rentschler Biotechnologie FX This work was supported by grants from the Deutsche Forschungsgemeinschaft (SFB738, Cluster of Excellence REBIRTH (EXC 62/1)), the Bundesministerium fur Bildung and Forschung (BMBF, Joint Research Project IFB-Tx, PidNet), the DAAD (Modern Applications in Biotechnology), the European Union (FP7 projects PERSIST and CELLPID, Horizon 2020 project SCIDNET) and Rentschler Biotechnologie. We would like to thank Johann Meyer, Christian Konecke, Solaiman Raha and Tobias Matzig for helpful experimental advice and support as well as Michael Morgan and Hildegard Buning for proofreading of the manuscript. Furthermore, we are thankful to the Central Research Facility Cell Sorting of Hannover Medical School for excellent support in cell sorting. NR 62 TC 0 Z9 0 U1 7 U2 29 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 2016 VL 97 BP 97 EP 109 DI 10.1016/j.biomaterials.2016.04.019 PG 13 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA DO4EY UT WOS:000377735800009 PM 27162078 ER PT J AU Sridhar, SS Sweeney, CJ AF Sridhar, Srikala S. Sweeney, Christopher J. TI It Is Time to Harmonize the Design and Conduct of Clinical Trials in Metastatic Hormone-sensitive Prostate Cancer SO EUROPEAN UROLOGY LA English DT Editorial Material ID DOCETAXEL; THERAPY C1 [Sridhar, Srikala S.] Princess Margaret Canc Ctr, Toronto, ON, Canada. [Sweeney, Christopher J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. RP Sweeney, CJ (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM christopher_sweeney@dfci.harvard.edu NR 7 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 EI 1873-7560 J9 EUR UROL JI Eur. Urol. PD AUG PY 2016 VL 70 IS 2 BP 263 EP 264 DI 10.1016/j.eururo.2015.11.025 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA DP0UY UT WOS:000378206600023 PM 26683759 ER PT J AU Templeton, AJ Knox, JJ Lin, X Simantov, R Xie, WL Lawrence, N Broom, R Fay, AP Rini, B Donskov, F Bjarnason, GA Smoragiewicz, M Kollmannsberger, C Kanesvaran, R Alimohamed, N Hermanns, T Wells, JC Amir, E Choueiri, TK Heng, DYC AF Templeton, Arnoud J. Knox, Jennifer J. Lin, Xun Simantov, Ronit Xie, Wanling Lawrence, Nicola Broom, Reuben Fay, Andre P. Rini, Brian Donskov, Frede Bjarnason, Georg A. Smoragiewicz, Martin Kollmannsberger, Christian Kanesvaran, Ravindran Alimohamed, Nimira Hermanns, Thomas Wells, J. Connor Amir, Eitan Choueiri, Toni K. Heng, Daniel Y. C. TI Change in Neutrophil-to-lymphocyte Ratio in Response to Targeted Therapy for Metastatic Renal Cell Carcinoma as a Prognosticator and Biomarker of Efficacy SO EUROPEAN UROLOGY LA English DT Article DE Change; Conversion; Renal cell carcinoma; Prognosis; Neutrophil-to-lymphocyte ratio; Targeted therapy ID TUMOR-INFILTRATING LYMPHOCYTES; PRETREATMENT NEUTROPHIL; SOLID TUMORS; SUNITINIB; CANCER; HYPERTENSION; EVEROLIMUS; SURVIVAL; TRIAL AB Background: Neutrophil-to-lymphocyte ratio (NLR), if elevated, is associated with worse outcomes in several malignancies. Objective: Investigation of NLR at baseline and during therapy for metastatic renal cell carcinoma. Design, setting, and participants: Retrospective analysis of 1199 patients from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC cohort) and 4350 patients from 12 prospective randomized trials (validation cohort). Intervention: Targeted therapies for metastatic renal cell carcinoma. Outcome measurements and statistical analysis: NLR was examined at baseline and 6 (+/- 2) wk later. A landmark analysis at 8 wk was conducted to explore the prognostic value of relative NLR change on overall survival (OS), progression-free survival (PFS), and objective response rate using Cox or logistic regression models, adjusted for variables in IMDC score and NLR values at baseline. Results and limitations: Higher NLR at baseline was associated with shorter OS and PFS (Hazard Ratios [HR] per 1 unit increase in log-transformed NLR = 1.69 [95% confidence interval {CI} = 1.46-1.95] and 1.30 [95% CI = 1.15-1.48], respectively). Compared with no change (decrease <25% to increase <25%, reference), increase NLR at Week 6 by 25-50% and >75% was associated with poor OS (HR = 1.55 [95% CI = 1.10-2.18] and 2.31 [95% CI = 1.64-3.25], respectively), poor PFS (HR = 1.46 [95% CI = 1.04-2.03], 1.76 [95% CI = 1.23-2.52], respectively), and reduced objective response rate (odds ratios = 0.77 [95% CI = 0.37-1.63] and 0.24 [95% CI = 0.08-0.72], respectively). By contrast, a decrease of 25-50% was associated with improved outcomes. Findings were confirmed in the validation cohort. The study is limited by its retrospective design. Conclusions: Compared with no change, early decline of NLR is associated with favorable outcomes, whereas an increase is associated with worse outcomes. Patient summary: We found that the proportion of immune cells in the blood is of prognostic value, namely that a decrease of the proportion of neutrophils-to-lymphocytes is associated with more favorable outcomes while an increase had the opposite effect. (C) 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved. C1 [Templeton, Arnoud J.; Knox, Jennifer J.; Alimohamed, Nimira; Amir, Eitan] Princess Margaret Canc Ctr, Div Med Oncol, Toronto, ON, Canada. [Templeton, Arnoud J.] Kantonsspital St Gallen, Dept Med Oncolgoy & Hematol, St Gallen, Switzerland. [Lin, Xun; Simantov, Ronit] Pfizer Inc, Pfizer Oncol, New York, NY USA. [Xie, Wanling; Fay, Andre P.; Choueiri, Toni K.] Dana Farber Canc Inst, Biostat & Computat Biol, Boston, MA 02115 USA. [Lawrence, Nicola; Broom, Reuben] Auckland City Hosp, Auckland, New Zealand. [Rini, Brian] Cleveland Clin, Taussig Canc Ctr, Cleveland, OH 44106 USA. [Donskov, Frede] Aarhus Univ Hosp, DK-8000 Aarhus, Denmark. [Bjarnason, Georg A.] Sunnybrook Odette Canc Ctr, Toronto, ON, Canada. [Smoragiewicz, Martin] British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. [Kollmannsberger, Christian] Natl Canc Ctr, Singapore, Singapore. [Kanesvaran, Ravindran; Alimohamed, Nimira; Wells, J. Connor; Heng, Daniel Y. C.] Tom Baker Canc Clin, Dept Med Oncol, Calgary, AB, Canada. RP Heng, DYC (reprint author), Univ Calgary, Tom Baker Canc Ctr, 1331-29th St North West, Calgary, AB T2N 4N2, Canada. EM daniel.heng@albertahealthservices.ca OI Alimohamed, Nimira/0000-0002-2930-4206 FU Pfizer; AstraZeneca; Roche; Novartis; GSK; BMS; Merck; Exilixis; Tracon FX Daniel Y.C. Heng certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Templeton: consultancy (without personal compensation) Sanofi, Astellas, BMS; Knox: research support Pfizer, AstraZeneca; Lin: employment Pfizer, stock ownership Pfizer; Simantov: employment Pfizer, stock ownership Pfizer; Lawrence: travel grant Roche; Rini: consultancy and research funding Pfizer; Donskov: research funding Novartis, GSK, Pfizer; Kanesvaran: speaker bureau Pfizer and GKS, advisory board GSK and Bayer; Choueiri: research funding Pfizer, GSK, Novartis, BMS, Merck, Exilixis, Roche, AstraZeneca, Tracon, and consultancy Pfizer, GSK, Novartis, Merck, Bayer, AstraZeneca; Heng: consultancy Pfizer, Novartis. NR 29 TC 5 Z9 5 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 EI 1873-7560 J9 EUR UROL JI Eur. Urol. PD AUG PY 2016 VL 70 IS 2 BP 358 EP 364 DI 10.1016/j.eururo.2016.02.033 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA DP0UY UT WOS:000378206600036 PM 26924770 ER PT J AU Otero, TMN Canales, C Yeh, DD Hou, PC Belcher, DM Quraishi, SA AF Otero, Tiffany M. N. Canales, Cecilia Yeh, D. Dante Hou, Peter C. Belcher, Donna M. Quraishi, Sadeq A. TI Elevated red cell distribution width at initiation of critical care is associated with mortality in surgical intensive care unit patients SO JOURNAL OF CRITICAL CARE LA English DT Article DE RDW; Red cell distribution width; Mortality; ICU; Critical care ID ACUTE PHYSIOLOGY SCORE; C-REACTIVE PROTEIN; OF-LIFE CARE; HEART-FAILURE; ILL PATIENTS; GLUCOCORTICOID-RECEPTOR; STRESS ERYTHROPOIESIS; ICU PATIENTS; MEDICAL ICU; APACHE-II AB Purpose: Recent evidence suggests that red cell distribution width (RDW) is associated with mortality in mixed cohorts of critically ill patients. Our goal was to investigate whether elevated RDW at initiation of critical care in the intensive care unit (ICU) is associated with 90-day mortality in surgical patients. Methods: We performed a retrospective, single-center cohort study. Normal RDW was defined as 11.5%-14.5%. To investigate the association of admission RDW with 90-day mortality, we performed a logistic regression analysis, controlling for age, sex, race, body mass index, Nutrition Risk Screening 2002 score, Acute Physiology and Chronic Health Evaluation II score, hospital length of stay, as well as levels of creatinine, albumin, and mean corpuscular volume. Results: 500 patients comprised the analytic cohort; 47% patients had elevated RDW and overall 90-day mortality was 28%. Logistic regression analysis demonstrated that patients with elevated RDW had a greater than two-fold increased odds of mortality (OR 2.28: 95% CI 1.20-4.33) compared to patients with normal RDW. Conclusions: Elevated RDW at initiation of care is associated with increased odds of 90-day mortality in surgical ICU patients. These data support the need for prospective studies to determine whether RDW can improve risk stratification in surgical ICU patients. Published by Elsevier Inc. C1 [Otero, Tiffany M. N.] Tufts Univ, Sch Med, 136 Harrison Ave, Boston, MA 02111 USA. [Otero, Tiffany M. N.; Canales, Cecilia; Quraishi, Sadeq A.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA. [Canales, Cecilia] Univ Calif Irvine, 252 Irvine Hall, Irvine, CA USA. [Yeh, D. Dante] Massachusetts Gen Hosp, Dept Surg, 55 Fruit St, Boston, MA 02114 USA. [Yeh, D. Dante; Hou, Peter C.; Quraishi, Sadeq A.] Harvard Univ, Sch Med, 25 Shattuck St, Boston, MA 02115 USA. [Hou, Peter C.] Brigham & Womens Hosp, Dept Emergency Med, 75 Francis St, Boston, MA 02115 USA. [Belcher, Donna M.] Massachusetts Gen Hosp, Dept Nutr & Food Serv, 55 Fruit St, Boston, MA 02114 USA. RP Quraishi, SA (reprint author), Dept Anesthesia Crit Care & Pain Med, 55 Fruit St,GRJ 402, Boston, MA 02114 USA. EM totero@partners.org; canalesc@uci.edu; dyeh2@mgh.harvard.edu; phou@bwh.harvard.edu; dmbelcher@partners.org; squraishi@mgh.harvard.edu FU National Center for Advancing Translational Sciences, National Institutes of Health [TL1TR001062]; Nestle Foundation [226, 280]; National Institutes of Health [T32 GM007592, UL1 RR025758, L30 GM102903, L30 TR00125] FX Tiffany M.N. Otero received support from the National Center for Advancing Translational Sciences, National Institutes of Health, Award Number TL1TR001062. D. Dante Yeh received support from the Nestle Foundation, Award Number 226,280. Sadeq A. Quraishi received support from the National Institutes of Health grants T32 GM007592, UL1 RR025758, L30 GM102903, and L30 TR00125. NR 39 TC 1 Z9 1 U1 3 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0883-9441 EI 1557-8615 J9 J CRIT CARE JI J. Crit. Care PD AUG PY 2016 VL 34 BP 7 EP 11 DI 10.1016/j.jcrc.2016.03.005 PG 5 WC Critical Care Medicine SC General & Internal Medicine GA DO3TK UT WOS:000377704200003 PM 27288601 ER PT J AU Warren, T Dickey, MW Lei, CM AF Warren, Tessa Dickey, Michael Walsh Lei, Chia-Ming TI Structural prediction in aphasia: Evidence from either SO JOURNAL OF NEUROLINGUISTICS LA English DT Article DE Sentence processing; Language comprehension; Prediction; Syntax; Reading; Aphasia; Aging ID LANGUAGE COMPREHENSION; SENTENCE PRODUCTION; SYNTACTIC COMPREHENSION; READING-COMPREHENSION; AGRAMMATIC APHASIA; BROCAS APHASIA; INTEGRATION; INFORMATION; IMPLICIT; ACTIVATION AB Young neurotypical adults engage in prediction during language comprehension (e.g., Altmann & Kamide, 1999; Staub & Clifton, 2006; Yoshida, Dickey & Sturt, 2013). The role of prediction in aphasic comprehension is less clear. Some evidence suggests that lexical prediction may be spared in aphasia (Dickey, Warren, Hayes, & Milburn, 2014; Love & Webb, 1977; cf. Mack, Ji, & Thompson, 2013), and there is even indication that structural prediction may be spared in some people with aphasia (PWA; e.g. Hanne, Burchert, De Bleser, & Vashishth, 2015). The current self-paced reading experiment manipulated the presence of either to examine structural prediction among PWA and a set of similar-aged neurotypical control participants. Consistent with intact structural prediction for both groups of participants, when either preceded a disjunction, reading times were faster on the or and second disjunct (cf. Staub & Clifton, 2006). For neurotypical controls, this effect of the presence vs. absence of either shrank reliably as more experimental items were encountered, whereas for PWA there was a non-significant trend for it to grow as more experimental items were encountered. These findings indicate that PWA and older neurotypical individuals can use a lexical cue to predict the structural form of upcoming material during comprehension, but that on-line adaptation to patterns in the local context may be different for the two groups. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Warren, Tessa] Univ Pittsburgh, Learning Res & Dev Ctr, Pittsburgh, PA 15260 USA. [Warren, Tessa] Univ Pittsburgh, Dept Psychol, Pittsburgh, PA 15260 USA. [Dickey, Michael Walsh; Lei, Chia-Ming] Univ Pittsburgh, Dept Commun Sci & Disorders, Pittsburgh, PA 15260 USA. [Dickey, Michael Walsh] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. RP Warren, T (reprint author), 635 LRDC,3939 OHara St, Pittsburgh, PA 15260 USA. EM tessa@pitt.edu OI Dickey, Michael Walsh/0000-0002-9068-3313 FU NIH [R01DC011520]; [UL1TR000005] FX This research was supported by NIH grant R01DC011520 to the first and second authors and by grant number UL1TR000005 to the Clinical and Translational Science Institute of the University of Pittsburgh. It is the result of work supported with resources and the use of facilities at the VA Pittsburgh Healthcare System. We thank Mandy Simons for helpful discussion and for her work helping develop the original set of stimuli from which the ones in the current study were adapted; Rebecca Hayes, Michelle Holcomb, Evelyn Milburn, and Teljer Liburd for help running participants; and Dominique Walker for help with language testing. NR 51 TC 1 Z9 1 U1 2 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0911-6044 J9 J NEUROLINGUIST JI J. Neurolinguist. PD AUG PY 2016 VL 39 BP 38 EP 48 DI 10.1016/j.jneuroling.2016.01.001 PG 11 WC Linguistics; Neurosciences; Psychology, Experimental SC Linguistics; Neurosciences & Neurology; Psychology GA DO5NL UT WOS:000377829700004 PM 27041821 ER PT J AU Ruben, MA Hall, JA AF Ruben, Mollie A. Hall, Judith A. TI A Lens Model Approach to the Communication of Pain SO HEALTH COMMUNICATION LA English DT Article ID FACIAL EXPRESSIONS; DETECTING DECEPTION; ACCURACY; EMPATHY; METAANALYSIS; PERCEPTION; FRAMEWORK; GENUINE AB Two studies examined the expression and detection of suppressed, genuine, and exaggerated pain. In Study 1, videotaped participants underwent an acute laboratory pain stressor and completed pain ratings. In Study 2, the lens model examined the cues encoders displayed while in pain (facial expressions of pain and viewers' global impressions), the cues decoders used to infer pain in the videotaped encoders, and decoders' accuracy in making judgments of pain. Results revealed expression differences between the suppressed, genuine, and exaggerated pain such that exaggerated expressions contained more tightened facial expressions while genuine expressions of pain contained more open facial expressions of pain. Decoders were accurate at detecting pain only in the exaggerated pain expressions. These results highlight the need for improving providers' accuracy in detecting pain intensity for suppressed, genuine, and exaggerated pain displays. Trainings should focus on teaching providers that patients who appear more agitated and less composed may be suppressing pain, while patients who appear more tense and determined may be exaggerating pain. Finally, patients who seem to not be in that much pain because they are not showing tightened facial expressions may actually be experiencing higher intensities of genuine pain. C1 [Ruben, Mollie A.] US Dept Vet Affairs, Ctr Healthcare Org & Implementat Res, 150 S Huntington Ave,Bdg 9, Boston, MA 02130 USA. [Hall, Judith A.] Northeastern Univ, Dept Psychol, Boston, MA USA. RP Ruben, MA (reprint author), US Dept Vet Affairs, Ctr Healthcare Org & Implementat Res, 150 S Huntington Ave,Bdg 9, Boston, MA 02130 USA. EM Mollie.Ruben@va.gov NR 49 TC 0 Z9 0 U1 5 U2 5 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1041-0236 EI 1532-7027 J9 HEALTH COMMUN JI Health Commun. PD AUG PY 2016 VL 31 IS 8 BP 934 EP 945 DI 10.1080/10410236.2015.1020261 PG 12 WC Communication; Health Policy & Services SC Communication; Health Care Sciences & Services GA DN7YH UT WOS:000377295600003 PM 26752199 ER PT J AU Bigman, CA Nagler, RH Viswanath, K AF Bigman, Cabral A. Nagler, Rebekah H. Viswanath, K. TI Representation, Exemplification, and Risk: Resonance of Tobacco Graphic Health Warnings Across Diverse Populations SO HEALTH COMMUNICATION LA English DT Article ID MASS-MEDIA CAMPAIGNS; RACIAL/ETHNIC DISPARITIES; SMOKING-CESSATION; TELEVISION-NEWS; COMMUNICATION; PERCEPTION; ISSUES; INTERVENTIONS; SEGMENTATION; METAANALYSIS AB As countries implement Article 11 of the World Health Organization (WHO) Framework Convention on Tobacco Control, graphic warning labels that use images of people and their body parts to illustrate the consequences of smoking are being added to cigarette packs. According to exemplification theory, these case examples-exemplars-can shape perceptions about risk and may resonate differently among demographic subpopulations. Drawing on data from eight focus groups (N = 63) with smokers and nonsmokers from vulnerable populations, this qualitative study explores whether people considered exemplars in their reactions to and evaluations of U.S. graphic health warning labels initially proposed by the Food and Drug Administration. Participants made reference to prior and concurrent mass media messages and exemplars during the focus groups and used demographic cues in making sense of the images on the warning labels. Participants were particularly sensitive to age of the exemplars and how it might affect label effectiveness and beliefs about smoking. Race and socioeconomic status also were salient for some participants. We recommend that exemplars and exemplification be considered when selecting and evaluating graphic health warnings for tobacco labels and associated media campaigns. C1 [Bigman, Cabral A.] Univ Illinois, Dept Commun, 3001 Lincoln Hall,702 South Wright St, Urbana, IL 61801 USA. [Nagler, Rebekah H.] Univ Minnesota, Sch Journalism & Mass Commun, Minneapolis, MN 55455 USA. [Viswanath, K.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Social & Behav Sci, Cambridge, MA 02138 USA. [Viswanath, K.] Ctr Community Based Res, Washington, DC USA. [Viswanath, K.] Dana Farber Canc Inst, Boston, MA USA. RP Bigman, CA (reprint author), Univ Illinois, Dept Commun, 3001 Lincoln Hall,702 South Wright St, Urbana, IL 61801 USA. EM cbigman@illinois.edu FU Yerby postdoctoral fellowship at the Harvard T.H. Chan School of Public Health; National Cancer Institute [5 R25-CA057711, 3P50-CA148596-03S1]; Eunice Kennedy Shriver National Institutes of Child Health and Human Development [2 K12-HD055887]; Office of Research on Women's Health; National Institute on Aging FX This article was supported by the Yerby postdoctoral fellowship at the Harvard T.H. Chan School of Public Health (C.A.B.), the National Cancer Institute-funded Harvard Education Program in Cancer Prevention (5 R25-CA057711) (R.H.N.), and National Cancer Institute grant 3P50-CA148596-03S1 (K.V., PI). R.H.N. also acknowledges support from the Building Interdisciplinary Research Careers in Women's Health Grant (2 K12-HD055887) from the Eunice Kennedy Shriver National Institutes of Child Health and Human Development, the Office of Research on Women's Health, and the National Institute on Aging, administered by the University of Minnesota Deborah E. Powell Center for Women's Health. The content is solely the responsibility of the authors and does not represent the official views of the National Institutes of Health. NR 50 TC 1 Z9 1 U1 4 U2 12 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1041-0236 EI 1532-7027 J9 HEALTH COMMUN JI Health Commun. PD AUG PY 2016 VL 31 IS 8 BP 974 EP 987 DI 10.1080/10410236.2015.1026430 PG 14 WC Communication; Health Policy & Services SC Communication; Health Care Sciences & Services GA DN7YH UT WOS:000377295600007 PM 26757354 ER PT J AU Denny, BT Fan, J Liu, X Guerreri, S Mayson, SJ Rimsky, L McMaster, A Alexander, H New, AS Goodman, M Perez-Rodriguez, M Siever, LJ Koenigsberg, HW AF Denny, Bryan T. Fan, Jin Liu, Xun Guerreri, Stephanie Mayson, Sarah Jo Rimsky, Liza McMaster, Antonia Alexander, Heather New, Antonia S. Goodman, Marianne Perez-Rodriguez, Mercedes Siever, Larry J. Koenigsberg, Harold W. TI Brain structural anomalies in borderline and avoidant personality disorder patients and their associations with disorder-specific symptoms SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Borderline personality disorder; Avoidant personality disorder; Voxel-based morphometry; Anxiety; Affective instability ID MAJOR DEPRESSIVE DISORDER; MEDIAL PREFRONTAL CORTEX; AMYGDALA; METAANALYSIS; MEMORY; VOLUME; ATLAS; SELF; HIPPOCAMPUS; COMORBIDITY AB Background: Borderline personality disorder (BPD) and avoidant personality disorder (AvPD) are characterized by hyper-reactivity to negatively-perceived interpersonal cues, yet they differ in degree of affective instability. Recent work has begun to elucidate the neural (structural and functional) and cognitive-behavioral underpinnings of BPD, although some initial studies of brain structure have reached divergent conclusions. AvPD, however, has been almost unexamined in the cognitive neuroscience literature. Methods: In the present study we investigated group differences among 29 BPD patients, 27 AvPD patients, and 29 healthy controls (HC) in structural brain volumes using voxel-based morphometry (VBM) in five anatomically-defined regions of interest: amygdala, hippocampus, medial prefrontal cortex (MPFC), dorsolateral prefrontal cortex (DLPFC), and anterior cingulate cortex (ACC). We also examined the relationship between individual differences in brain structure and self-reported anxiety and affective instability in each group. Results: We observed reductions in MPFC and ACC volume in BPD relative to HC, with no significant difference among patient groups. No group differences in amygdala volume were found. However, BPD and AvPD patients each showed a positive relationship between right amygdala volume and state-related anxiety. By contrast, in HC there was an inverse relationship between MPFC volume and state and trait related anxiety as well as between bilateral DLPFC volume and affective instability. Limitations: Current sample sizes did not permit examination of gender effects upon structure-symptom correlations. Conclusions: These results shed light on potentially protective, or compensatory, aspects of brain structure in these populations namely, relatively reduced amygdala volume or relatively enhanced MPFC and DLPFC volume. Published by Elsevier B.V. C1 [Denny, Bryan T.; Fan, Jin; Guerreri, Stephanie; Mayson, Sarah Jo; Rimsky, Liza; McMaster, Antonia; Alexander, Heather; New, Antonia S.; Goodman, Marianne; Perez-Rodriguez, Mercedes; Siever, Larry J.; Koenigsberg, Harold W.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Fan, Jin] Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA. [Fan, Jin] CUNY Queens Coll, Dept Psychol, Flushing, NY 11367 USA. [Liu, Xun] Chinese Acad Sci, Inst Psychol, Beijing 100101, Peoples R China. [New, Antonia S.; Goodman, Marianne; Siever, Larry J.; Koenigsberg, Harold W.] James J Peters VA Med Ctr, Bronx, NY 10468 USA. RP Koenigsberg, HW (reprint author), James J Peters VA Med Ctr, Mental Hlth Patient Care Ctr, 130 West Kingsbridge Rd, Bronx, NY 10468 USA. EM HWarrenK@nyc.rr.com FU National Institute of Mental Health (NIH) [R01 MH077813]; NIH [F32 MH105119]; National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH) [UL1TR000067]; James J Peters Veterans Affairs Medical Center FX This work was supported by the National Institute of Mental Health (NIH grant R01 MH077813 to Dr. Koenigsberg and NIH grant F32 MH105119 to Dr. Denny), by the James J Peters Veterans Affairs Medical Center, and Grant UL1TR000067 from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH). NR 51 TC 0 Z9 0 U1 4 U2 12 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 AUG PY 2016 VL 200 BP 266 EP 274 DI 10.1016/j.jad.2016.04.053 PG 9 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DN9IH UT WOS:000377392400036 PM 27155069 ER PT J AU Kopacz, MS Feldstein, BD Asekoff, CA Kaprow, MS Smith-Coggins, R Rasmussen, KA AF Kopacz, Marek S. Feldstein, Bruce D. Asekoff, Cecille Allman Kaprow, Maurice S. Smith-Coggins, Rebecca Rasmussen, Kathy A. TI How Involved are Non-VA Chaplains in Supporting Veterans? SO JOURNAL OF RELIGION & HEALTH LA English DT Article DE Veterans; Non-VA; Community health ID MENTAL-HEALTH-SERVICES AB In terms of supporting veteran populations, little is known of the experiences of chaplains professionally active outside of Department of Veterans Affairs (VA) healthcare settings. The present study looks to examine how involved non-VA chaplains are in supporting veterans as well as their familiarity with the VA. An online survey was distributed in a convenience sample of chaplains, of which n = 39 met the inclusion criterion for this study (i.e., no past or present VA affiliation). The results find that most of the non-VA chaplains encounter veteran service users either on a weekly or monthly basis. Though familiar with VA services, non-VA chaplains were not sure of their veteran service users' VA enrollment status nor did they feel able to adequately advise their veteran service users on VA enrollment. The results suggest that non-VA chaplains actively support veteran populations. Opportunities for enhancing chaplaincy services and VA outreach programs are discussed. C1 [Kopacz, Marek S.; Rasmussen, Kathy A.] US Dept Vet Affairs, VISN Ctr Excellence Suicide Prevent 2, 400 Ft Hill Ave, Canandaigua, NY 14424 USA. [Feldstein, Bruce D.; Smith-Coggins, Rebecca] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Feldstein, Bruce D.; Asekoff, Cecille Allman; Kaprow, Maurice S.] Neshama Assoc Jewish Chaplains, Whippany, NJ USA. [Rasmussen, Kathy A.] Univ Rochester, Med Ctr, Rochester, NY 14642 USA. RP Kopacz, MS (reprint author), US Dept Vet Affairs, VISN Ctr Excellence Suicide Prevent 2, 400 Ft Hill Ave, Canandaigua, NY 14424 USA. EM marek.kopacz@va.gov FU Office of Academic Affiliations, Advanced Fellowship Program in Mental Illness Research and Treatment, US Department of Veterans Affairs, VISN 2 Center of Excellence for Suicide Prevention FX Dr. Rasmussen was supported by the Office of Academic Affiliations, Advanced Fellowship Program in Mental Illness Research and Treatment, US Department of Veterans Affairs, VISN 2 Center of Excellence for Suicide Prevention. Institutional support for this study was provided by the VISN 2 Center of Excellence for Suicide Prevention (Canandaigua, NY) and Neshama: Association of Jewish Chaplains (Whippany, NJ). The views expressed are those of the authors and do not reflect the official policy or position of the Department of Veterans Affairs or the US Government. NR 13 TC 1 Z9 1 U1 2 U2 2 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 2016 VL 55 IS 4 BP 1206 EP 1214 DI 10.1007/s10943-016-0223-x PG 9 WC Public, Environmental & Occupational Health; Religion SC Public, Environmental & Occupational Health; Religion GA DN2FW UT WOS:000376880500008 PM 27023459 ER PT J AU Krakauer, EL Rajagopal, MR AF Krakauer, Eric L. Rajagopal, M. R. TI End-of-life care across the world: a global moral failing SO LANCET LA English DT Editorial Material C1 [Krakauer, Eric L.] Harvard Med Sch, Ctr Palliat Care, Boston, MA 02115 USA. [Krakauer, Eric L.] Massachusetts Gen Hosp, Div Palliat Care, Boston, MA 02114 USA. [Rajagopal, M. R.] WHO Collaborating Ctr Training & Policy Access Pa, Pallium India, Thiruvananthapuram, Kerala, India. RP Krakauer, EL (reprint author), Harvard Med Sch, Ctr Palliat Care, Boston, MA 02115 USA.; Krakauer, EL (reprint author), Massachusetts Gen Hosp, Div Palliat Care, Boston, MA 02114 USA. EM eric_krakauer@hms.harvard.edu NR 9 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD JUL 30 PY 2016 VL 388 IS 10043 BP 444 EP 446 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA DS2EK UT WOS:000380559400007 PM 27507744 ER PT J AU Castillo, JJ Glezerman, IG Boklage, SH Chiodo, J Tidwell, BA Lamerato, LE Schulman, KL AF Castillo, Jorge J. Glezerman, Ilya G. Boklage, Susan H. Chiodo, Joseph, III Tidwell, Beni A. Lamerato, Lois E. Schulman, Kathy L. TI The occurrence of hyponatremia and its importance as a prognostic factor in a cross-section of cancer patients SO BMC CANCER LA English DT Article DE Hyponatremia; Euvolemic; Hypervolemic; Cancer; Survival ID CELL LUNG-CANCER; SINGLE INSTITUTION; MORTALITY; DISORDERS; DIAGNOSIS; IMPACT AB Background: Hyponatremia is prognostic of higher mortality in some cancers but has not been well studied in others. We used a longitudinal design to determine the incidence and prognostic importance of euvolemic and hypervolemic hyponatremia in patients following diagnosis with lymphoma, breast (BC), colorectal (CRC), small cell lung (SCLC), or non-small cell lung cancer (NSCLC). Methods: Medical record and tumor registry data from two large integrated delivery networks were combined for patients diagnosed with lymphoma, BC, CRC, or lung cancers (2002-2010) who had >= 1 administration of radiation/ chemotherapy within 6 months of diagnosis and no evidence of hypovolemic hyponatremia. Hyponatremia incidence was measured per 1000 person-years (PY). Cox proportional hazard models assessed the prognostic value of hyponatremia as a time-varying covariate on overall survival (OS) and progression-free survival (PFS). Results: Hyponatremia incidence (%, rate) was 76 % each, 1193 and 2311 per 1000 PY, among NSCLC and SCLC patients, respectively; 37 %, 169 in BC; 64 %, 637 in CRC, and 60 %, 395 in lymphoma. Hyponatremia was negatively associated with OS in BC (HR 3.7; P = <. 01), CRC (HR 2.4; P <.01), lung cancer (HR 2.4; P <.01), and lymphoma (HR 4.5; P <.01). Hyponatremia was marginally associated with shorter PFS (HR 1.3, P =.07) across cancer types. Conclusions: The incidence of hyponatremia is higher than previously reported in lung cancer, is high in lymphoma, BC, and CRC and is a negative prognostic indicator for survival. Hyponatremia incidence in malignancy may be underestimated. The effects of hyponatremia correction on survival in cancer patients require further study. C1 [Castillo, Jorge J.] Dana Farber Canc Inst, 450 Brookline Ave,M221, Boston, MA 02215 USA. [Glezerman, Ilya G.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Boklage, Susan H.; Chiodo, Joseph, III] Otsuka Amer Pharmaceut Inc, Princeton, NJ USA. [Tidwell, Beni A.; Schulman, Kathy L.] Outcomes Res Solut Inc, Waltham, MA USA. [Lamerato, Lois E.] Henry Ford Hlth Syst, Detroit, MI USA. RP Castillo, JJ (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,M221, Boston, MA 02215 USA. EM jorgej_castillo@dfci.harvard.edu OI Castillo, Jorge/0000-0001-9490-7532 FU Otsuka America Pharmaceutical, Inc., Princeton, NJ, USA FX This study was sponsored by Otsuka America Pharmaceutical, Inc., Princeton, NJ, USA. NR 26 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD JUL 29 PY 2016 VL 16 AR 564 DI 10.1186/s12885-016-2610-9 PG 9 WC Oncology SC Oncology GA DT1AX UT WOS:000381215200008 PM 27473121 ER PT J AU Yamoah, K Zeigler-Johnson, CM Jeffers, A Malkowicz, B Spangler, E Park, JY Whittemore, A Rebbeck, TR AF Yamoah, Kosj Zeigler-Johnson, Charnita M. Jeffers, Abra Malkowicz, Bruce Spangler, Elaine Park, Jong Y. Whittemore, Alice Rebbeck, Timothy R. TI The impact of body mass index on treatment outcomes for patients with low-intermediate risk prostate cancer SO BMC CANCER LA English DT Article DE Body mass index; Biochemical failure; Tumor pathology; Prostate cancer treatment ID EXTERNAL-BEAM RADIOTHERAPY; RANDOMIZED CLINICAL-TRIAL; POSITIVE SURGICAL MARGINS; QUALITY-OF-LIFE; TERM-FOLLOW-UP; RADICAL PROSTATECTOMY; ADJUVANT RADIOTHERAPY; AFRICAN-AMERICAN; PATHOLOGICAL VARIABLES; ACTIVE SURVEILLANCE AB Background: Little is known about the relationship between preoperative body mass index and need for adjuvant radiation therapy (RT) following radical prostatectomy. The goal of this study was to evaluate the utility of body mass index in predicting adverse clinical outcomes which require adjuvant RT among men with organ-confined prostate cancer (PCa). Methods: We used a prospective cohort of 1,170 low-intermediate PCa risk men who underwent radical prostatectomy and evaluated the effect of body mass index on adverse pathologic features and freedom from biochemical failure (FFbF). Clinical and pathologic variables were compared across the body mass index groups using an analysis of variance model for continuous variables or X-2 for categorical variables. Factors related to adverse pathologic features were examined using logistic regression models. Time to biochemical recurrence was compared across the groups using a log-rank survivorship analysis. Multivariable analysis predicting biochemical recurrence was conducted with a Cox proportional hazards model. ` Results: Patients with elevated body mass index (defined as body mass index >= 25 kg/m(2)) had greater extraprostatic extension (p = 0.004), and positive surgical margins (p = 0.01). Elevated body mass index did not correlate with preoperative risk groupings (p = 0.94). However, when compared with non-obese patients (body mass index < 30 kg/m2), obese patients (body mass index >= 30 kg/m(2)) were much more likely to have higher rate of adverse pathologic features (p = 0.006). In patients with low-and intermediate-risk disease, obesity was strongly associated with rate of pathologic upgrading of tumors (p = 0.01 and p = 0.02), respectively. After controlling for known preoperative risk factors, body mass index was independently associated with >= 2 adverse pathologic features (p = 0.002), an indicator for adjuvant RT as well as FFbF (p = 0.001). Conclusions: Body mass index of >= 30 kg/m(2) is independently associated with adverse pathologic features, which is an indicator for additional RT, particularly in patients with low-intermediate risk disease. Future studies may determine if this select group of patients may be best treated with definitive RT to reduce toxicity from additional RT following radical prostatectomy. We propose including body mass index in clinical decision-making for appropriate treatment recommendation for patients with low-intermediate risk PCa. C1 [Yamoah, Kosj; Park, Jong Y.] H Lee Moffitt Canc Ctr & Res Inst, Dept Radiat Oncol & Canc Epidemiol, 12902 USF Magnolia Dr, Tampa, FL 33612 USA. [Zeigler-Johnson, Charnita M.] Thomas Jefferson Univ, Jefferson Med Coll, Philadelphia, PA 19107 USA. [Zeigler-Johnson, Charnita M.] Thomas Jefferson Univ, Kimmel Canc Ctr, Philadelphia, PA 19107 USA. [Jeffers, Abra; Whittemore, Alice] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Malkowicz, Bruce; Spangler, Elaine] Univ Penn, Perelman Sch Med, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Rebbeck, Timothy R.] Dana Farber Canc Inst, Boston, MA USA. [Rebbeck, Timothy R.] Harvard TH Chan Sch Publ Hlth, Boston, MA USA. RP Yamoah, K (reprint author), H Lee Moffitt Canc Ctr & Res Inst, Dept Radiat Oncol & Canc Epidemiol, 12902 USF Magnolia Dr, Tampa, FL 33612 USA. EM Kosj.Yamoah@moffitt.org FU PHS grants [R01-CA085074, P50-CA10564, P60-MD-006900]; DOD grant [PC-121189]; Prostate Cancer Foundation Young Investigator Award FX This work was funded in part by PHS grants R01-CA085074, P50-CA105641, P60-MD-006900 (to T.R.R.), and DOD grant PC-121189, and the Prostate Cancer Foundation Young Investigator Award (to K.Y.). NR 68 TC 1 Z9 1 U1 1 U2 1 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 29 PY 2016 VL 16 AR 557 DI 10.1186/s12885-016-2572-y PG 11 WC Oncology SC Oncology GA DT1AX UT WOS:000381215200001 PM 27473687 ER PT J AU Esterman, M Grosso, M Liu, GY Mitko, A Morris, R DeGutis, J AF Esterman, Michael Grosso, Mallory Liu, Guanyu Mitko, Alex Morris, Rachael DeGutis, Joseph TI Anticipation of Monetary Reward Can Attenuate the Vigilance Decrement SO PLOS ONE LA English DT Article ID SUSTAINED ATTENTION; DEFAULT NETWORK; STRENGTH MODEL; EGO DEPLETION; SELF-CONTROL; ABSENT MIND; MEMORY LOAD; TASK; RESOURCE; PERFORMANCE AB Motivation and reward can have differential effects on separate aspects of sustained attention. We previously demonstrated that continuous reward/punishment throughout a sustained attention task improves overall performance, but not vigilance decrements. One interpretation of these findings is that vigilance decrements are due to resource depletion, which is not overcome by increasing overall motivation. However, an alternative explanation is that as one performs a continuously rewarded task there are less potential gains/losses as the task progresses, which could decrease motivation over time, producing a vigilance decrement. This would predict that keeping future gains/losses consistent throughout the task would reduce the vigilance decrement. In the current study, we examined this possibility by comparing two versions (continuous-small loss vs. anticipate-large loss) of a 10-minute gradual onset continuous performance task (gradCPT), a challenging go/no-go sustained attention task. Participants began each task with the potential to keep $ 18. In the continuous-small-loss version, small monetary losses were accrued continuously throughout the task for each error. However, in the anticipate-large-loss version, participants lost all $ 18 if they erroneously responded to one target that always appeared toward the end of the vigil. Typical vigilance decrements were observed in the continuous-small-loss condition. In the anticipate-large-loss condition, vigilance decrements were reduced, particularly when the anticipate-large loss condition was completed second. This suggests that the looming possibility of a large loss can attenuate the vigilance decrement and that this attenuation may occur most consistently after sufficient task experience. We discuss these results in the context of current theories of sustained attention. C1 [Esterman, Michael; Grosso, Mallory; Liu, Guanyu; Mitko, Alex; DeGutis, Joseph] VA Boston Healthcare Syst, Boston Attent & Learning Lab, Boston, MA 02130 USA. [Esterman, Michael; DeGutis, Joseph] Boston Div VA Healthcare Syst, GRECC, Boston, MA 02130 USA. [Esterman, Michael] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Esterman, Michael; DeGutis, Joseph] Harvard Med Sch, Dept Psychiat, Boston, MA 02115 USA. [Morris, Rachael] Univ Kent, Sch Psychol, Canterbury, Kent, England. RP Esterman, M (reprint author), VA Boston Healthcare Syst, Boston Attent & Learning Lab, Boston, MA 02130 USA.; Esterman, M (reprint author), Boston Div VA Healthcare Syst, GRECC, Boston, MA 02130 USA.; Esterman, M (reprint author), Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA.; Esterman, M (reprint author), Harvard Med Sch, Dept Psychiat, Boston, MA 02115 USA. EM esterman@bu.edu FU VA Clinical Science R&D Career Development Award [1IK2CX000706-01A2] FX This research was supported by a VA Clinical Science R&D Career Development Award to Michael Esterman (1IK2CX000706-01A2). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 0 Z9 0 U1 5 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 29 PY 2016 VL 11 IS 7 AR e0159741 DI 10.1371/journal.pone.0159741 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT5IM UT WOS:000381516300017 PM 27472785 ER PT J AU Lingren, T Chen, P Bochenek, J Doshi-Velez, F Manning-Courtney, P Bickel, J Welchons, LW Reinhold, J Bing, N Ni, YZ Barbaresi, W Mentch, F Basford, M Denny, J Vazquez, L Perry, C Namjou, B Qiu, HJ Connolly, J Abrams, D Holm, IA Cobb, BA Lingren, N Solti, I Hakonarson, H Kohane, IS Harley, J Savova, G AF Lingren, Todd Chen, Pei Bochenek, Joseph Doshi-Velez, Finale Manning-Courtney, Patty Bickel, Julie Welchons, Leah Wildenger Reinhold, Judy Bing, Nicole Ni, Yizhao Barbaresi, William Mentch, Frank Basford, Melissa Denny, Joshua Vazquez, Lyam Perry, Cassandra Namjou, Bahram Qiu, Haijun Connolly, John Abrams, Debra Holm, Ingrid A. Cobb, Beth A. Lingren, Nataline Solti, Imre Hakonarson, Hakon Kohane, Isaac S. Harley, John Savova, Guergana TI Electronic Health Record Based Algorithm to Identify Patients with Autism Spectrum Disorder SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; MEDICAL-RECORDS; DISEASE; CLASSIFICATION; INFORMATICS; COMORBIDITY; SELECTION; CHILDREN; CLUSTERS; TODDLERS AB Objective Cohort selection is challenging for large-scale electronic health record (EHR) analyses, as International Classification of Diseases 9th edition (ICD-9) diagnostic codes are notoriously unreliable disease predictors. Our objective was to develop, evaluate, and validate an automated algorithm for determining an Autism Spectrum Disorder (ASD) patient cohort from EHR. We demonstrate its utility via the largest investigation to date of the co-occurrence patterns of medical comorbidities in ASD. Methods We extracted ICD-9 codes and concepts derived from the clinical notes. A gold standard patient set was labeled by clinicians at Boston Children's Hospital (BCH) (N = 150) and Cincinnati Children's Hospital and Medical Center (CCHMC) (N = 152). Two algorithms were created: (1) rule-based implementing the ASD criteria from Diagnostic and Statistical Manual of Mental Diseases 4th edition, (2) predictive classifier. The positive predictive values (PPV) achieved by these algorithms were compared to an ICD-9 code baseline. We clustered the patients based on grouped ICD-9 codes and evaluated subgroups. Results The rule-based algorithm produced the best PPV: (a) BCH: 0.885 vs. 0.273 (baseline); (b) CCHMC: 0.840 vs. 0.645 (baseline); (c) combined: 0.864 vs. 0.460 (baseline). A validation at Children's Hospital of Philadelphia yielded 0.848 (PPV). Clustering analyses of comorbidities on the three-site large cohort (N = 20,658 ASD patients) identified psychiatric, developmental, and seizure disorder clusters. Conclusions In a large cross-institutional cohort, co-occurrence patterns of comorbidities in ASDs provide further hypothetical evidence for distinct courses in ASD. The proposed automated algorithms for cohort selection open avenues for other large-scale EHR studies and individualized treatment of ASD. C1 [Lingren, Todd; Ni, Yizhao; Solti, Imre] Cincinnati Childrens Hosp Med Ctr, Div Biomed Informat, Cincinnati, OH 45229 USA. [Chen, Pei] Boston Childrens Hosp, Ctr Syst Biol, Boston, MA USA. [Bochenek, Joseph; Denny, Joshua] Vanderbilt Univ, Sch Med, Biomed Informat, Nashville, TN 37212 USA. [Doshi-Velez, Finale] Harvard Med Sch, Ctr Biomed Informat, Boston, MA USA. [Manning-Courtney, Patty; Reinhold, Judy; Bing, Nicole; Harley, John] Univ Cincinnati, Dept Pediat, Cincinnati, OH USA. [Manning-Courtney, Patty; Reinhold, Judy; Bing, Nicole] Cincinnati Childrens Hosp Med Ctr, Div Dev & Behav Pediat, Cincinnati, OH 45229 USA. [Bickel, Julie; Welchons, Leah Wildenger] Boston Childrens Hosp, Pediat, Boston, MA USA. [Bickel, Julie; Welchons, Leah Wildenger] Boston Childrens Hosp, Dev Med, Boston, MA USA. [Welchons, Leah Wildenger] Boston Childrens Hosp, Neurol, Boston, MA USA. [Welchons, Leah Wildenger] Boston Childrens Hosp, Ctr Commun Enhancement, Boston, MA USA. [Barbaresi, William; Holm, Ingrid A.] Childrens Hosp, Div Med, 300 Longwood Ave, Boston, MA 02115 USA. [Mentch, Frank; Vazquez, Lyam; Qiu, Haijun; Connolly, John; Abrams, Debra; Hakonarson, Hakon] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA. [Basford, Melissa] Vanderbilt Univ, Med Ctr, Vanderbilt Inst Clin & Translat Res, Nashville, TN USA. [Perry, Cassandra; Holm, Ingrid A.] Boston Childrens Hosp, Div Genet & Genom, Boston, MA USA. [Namjou, Bahram; Cobb, Beth A.; Harley, John] Cincinnati Childrens Hosp Med Ctr, Ctr Autoimmune Genom & Etiol, Cincinnati, OH 45229 USA. [Namjou, Bahram; Solti, Imre] Univ Cincinnati, Coll Med, Cincinnati, OH USA. [Holm, Ingrid A.; Kohane, Isaac S.; Savova, Guergana] Harvard Med Sch, Pediat, Boston, MA USA. [Holm, Ingrid A.] Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Boston, MA USA. [Lingren, Nataline] Cincinnati Childrens Hosp Med Ctr, Emergency Med, Cincinnati, OH 45229 USA. [Hakonarson, Hakon] Perelman Sch Med, Pediat, Philadelphia, PA USA. [Kohane, Isaac S.; Savova, Guergana] Boston Childrens Hosp, Childrens Hosp Informat Program, Boston, MA USA. [Harley, John] US Dept Vet Affairs, Med Ctr, Med, Cincinnati, OH USA. RP Lingren, T (reprint author), Cincinnati Childrens Hosp Med Ctr, Div Biomed Informat, Cincinnati, OH 45229 USA. EM todd.lingren@cchmc.org OI Lingren, Todd/0000-0003-0311-7100 FU collaborative sites in the eMERGE Network; National Human Genome Research Institute (NHGRI) [U01HG006828, U01HG006830, U01HG006378, U01HG008666] FX This work was supported by collaborative sites in the eMERGE Network and funded by National Human Genome Research Institute (NHGRI) through the following grants: U01HG006828 (Cincinnati Children's Hospital Medical Center/Boston Children's Hospital); U01HG006830 (Children's Hospital of Philadelphia); U01HG006378 (Vanderbilt University Medical Center) and U01HG008666 (Cincinnati Children's Hospital Medical Center). NR 40 TC 1 Z9 1 U1 4 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 29 PY 2016 VL 11 IS 7 AR e0159621 DI 10.1371/journal.pone.0159621 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT5IM UT WOS:000381516300015 PM 27472449 ER PT J AU Stenroos, M Nummenmaa, A AF Stenroos, Matti Nummenmaa, Aapo TI Incorporating and Compensating Cerebrospinal Fluid in Surface-Based Forward Models of Magneto- and Electroencephalography SO PLOS ONE LA English DT Article ID VOLUME CONDUCTOR; HEAD MODELS; EEG; STIMULATION; BRAIN; MAGNETOENCEPHALOGRAPHY; RECONSTRUCTION; ROBUST; SKULL; FIELD AB MEG/EEG source imaging is usually done using a three-shell (3-S) or a simpler head model. Such models omit cerebrospinal fluid (CSF) that strongly affects the volume currents. We present a four-compartment (4-C) boundary-element (BEM) model that incorporates the CSF and is computationally efficient and straightforward to build using freely available software. We propose a way for compensating the omission of CSF by decreasing the skull conductivity of the 3-S model, and study the robustness of the 4-C and 3-S models to errors in skull conductivity. We generated dense boundary meshes using MRI datasets and automated Sim NIBS pipeline. Then, we built a dense 4-C reference model using Galerkin BEM, and 4-C and 3-S test models using coarser meshes and both Galerkin and collocation BEMs. We compared field topographies of cortical sources, applying various skull conductivities and fitting conductivities that minimized the relative error in 4-C and 3-S models. When the CSF was left out from the EEG model, our compensated, unbiased approach improved the accuracy of the 3-S model considerably compared to the conventional approach, where CSF is neglected without any compensation (mean relative error < 20% vs. > 40%). The error due to the omission of CSF was of the same order in MEG and compensated EEG. EEG has, however, large overall error due to uncertain skull conductivity. Our results show that a realistic 4-C MEG/EEG model can be implemented using standard tools and basic BEM, without excessive workload or computational burden. If the CSF is omitted, compensated skull conductivity should be used in EEG. C1 [Stenroos, Matti] Aalto Univ, Sch Sci, Dept Neurosci & Biomed Engn, POB 12200, FI-00076 Aalto, Finland. [Nummenmaa, Aapo] Harvard Med Sch, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02129 USA. RP Stenroos, M (reprint author), Aalto Univ, Sch Sci, Dept Neurosci & Biomed Engn, POB 12200, FI-00076 Aalto, Finland. EM matti.stenroos@aalto.fi FU National Institutes of Health under National Institute of Biomedical Imaging and Bioengineering [R00EB015445] FX AN received funding from the National Institutes of Health under National Institute of Biomedical Imaging and Bioengineering (http://www.nibib.nih.gov/) award number R00EB015445. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 2 Z9 2 U1 2 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 29 PY 2016 VL 11 IS 7 AR e0159595 DI 10.1371/journal.pone.0159595 PG 23 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT5IM UT WOS:000381516300013 PM 27472278 ER PT J AU Greenzang, KA Kesselheim, J AF Greenzang, Katie A. Kesselheim, Jennifer TI The Importance of Fostering Ownership During Medical Training: Working 9-5 Isn't the Only Issue SO AMERICAN JOURNAL OF BIOETHICS LA English DT Editorial Material ID RESIDENT AUTONOMY; PATIENT-CARE; SUPERVISION C1 [Greenzang, Katie A.; Kesselheim, Jennifer] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Greenzang, KA (reprint author), Dana Farber Boston Childrens Hosp, Pediat Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM katie_greenzang@dfci.harvard.edu NR 11 TC 0 Z9 0 U1 0 U2 0 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1526-5161 EI 1536-0075 J9 AM J BIOETHICS JI Am. J. Bioeth. PD JUL 29 PY 2016 VL 16 IS 9 BP 17 EP 18 DI 10.1080/15265161.2016.1197339 PG 4 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA DT8QB UT WOS:000381755600007 PM 27471930 ER PT J AU Fischer, MJ Stroupe, KT Kaufman, JS O'Hare, AM Browning, MM Sohn, MW Huo, ZP Hynes, DM AF Fischer, Michael J. Stroupe, Kevin T. Kaufman, James S. O'Hare, Ann M. Browning, Margaret M. Sohn, Min-Woong Huo, Zhiping Hynes, Denise M. TI Predialysis nephrology care and dialysis-related health outcomes among older adults initiating dialysis SO BMC NEPHROLOGY LA English DT Article DE Dialysis; Elderly; Nephrology care ID CHRONIC KIDNEY-DISEASE; OF-VETERANS-AFFAIRS; ELDERLY-PATIENTS; PERITONEAL-DIALYSIS; VASCULAR ACCESS; REFERRED LATE; MORTALITY; PATIENT; AGE; TRANSPLANTATION AB Background: Predialysis nephrology care is associated with lower mortality and rates of hospitalization following chronic dialysis initiation. Whether more frequent predialysis nephrology care is associated with other favorable outcomes for older adults is not known. Methods: Retrospective cohort study of patients >= 66 years who initiated chronic dialysis in 2000-2001 and were eligible for VA and/or Medicare-covered services. Nephrology visits in VA and/or Medicare during the 12-month predialysis period were identified and classified by low intensity (<3 visits), moderate intensity (3-6 visits), and high intensity (>6 visits). Outcome measures included very low estimated glomerular filtration rate, severe anemia, use of peritoneal dialysis, and receipt of permanent vascular access at dialysis initiation and death and kidney transplantation within two years of initiation. Generalized linear models with propensity score weighting were used to examine the association between nephrology care and outcomes. Results: Among 58,014 patients, 46 % had none, 22 % had low, 13 % had moderate, and 19 % had high intensity predialysis nephrology care. Patients with a greater intensity of predialysis nephrology care had more favorable outcomes (all p < 0.001). In adjusted models, patients with high intensity predialysis nephrology care were less likely to have severe anemia (RR = 0.70, 99 % CI: 0.65-0.74) and more likely to have permanent vascular access (RR = 3.60, 99 % CI: 3.42-3.79) at dialysis initiation, and less likely to die within two years of dialysis initiation (RR = 0.80, 99 % CI: 0.77-0.82). Conclusion: In a large cohort of older adults treated with chronic dialysis, greater intensity of predialysis nephrology care was associated with more favorable outcomes. C1 [Fischer, Michael J.] Univ Illinois, Med Ctr, Jesse Brown VA Med Ctr, Med Nephrol, Chicago, IL 60607 USA. [Fischer, Michael J.; Stroupe, Kevin T.; Browning, Margaret M.; Sohn, Min-Woong; Huo, Zhiping; Hynes, Denise M.] Edward Hines Jr VA Hosp, Ctr Innovat Complex Chron Care, Hines, IL 60141 USA. [Stroupe, Kevin T.] Loyola Univ Chicago, Dept Publ Hlth Sci, Maywood, IL USA. [Browning, Margaret M.; Hynes, Denise M.] Edward Hines Jr VA Hosp, VA Informat Resource Ctr, Hines, IL USA. [Kaufman, James S.] VA New York Harbor Healthcare Syst, Med Nephrol, New York, NY USA. [Kaufman, James S.] NYU, Sch Med, New York, NY USA. [O'Hare, Ann M.] VA Puget Sound Healthcare Syst, Med Nephrol, Seattle, WA USA. [O'Hare, Ann M.] Univ Washington, Grp Hlth Res Inst, Med Nephrol, Seattle, WA 98195 USA. [Sohn, Min-Woong] Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA USA. [Hynes, Denise M.] Univ Illinois, Sch Publ Hlth, Med Hlth Promot Res, Chicago, IL USA. RP Fischer, MJ (reprint author), Univ Illinois, Med Ctr, Jesse Brown VA Med Ctr, Med Nephrol, Chicago, IL 60607 USA.; Fischer, MJ (reprint author), Edward Hines Jr VA Hosp, Ctr Innovat Complex Chron Care, Hines, IL 60141 USA. EM fischerm@uic.edu FU Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service (VA HSRD) [IIR 02-244, IIR 20-016]; NIH [K23AG28980]; VA Information Resource Center (VA HSRD) [SDR 02-237] FX The authors received funding support for this research project from: Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service (VA HSR&D IIR 02-244 and IIR 20-016 - K. Stroupe, D. Hynes, M. Browning; VA HSR&D Research Career Scientist Award - D, Hynes; VA HSR&D Career Development Award - M. Fischer); NIH K23AG28980 - A. O'Hare. USRDS and Medicare data for this project were provided by the VA Information Resource Center (VA HSR&D SDR 02-237). NR 45 TC 1 Z9 1 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2369 J9 BMC NEPHROL JI BMC Nephrol. PD JUL 29 PY 2016 VL 17 AR 103 DI 10.1186/s12882-016-0324-5 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA DS5WP UT WOS:000380854000002 PM 27473684 ER PT J AU Thijssen, R ter Burg, J Garrick, B van Bochove, GGW Brown, JR Fernandes, SM Rodriguez, MS Michot, JM Hallek, M Eichhorst, B Reinhardt, HC Bendell, J Derks, IAM van Kampen, RJW Hege, K Kersten, MJ Trowe, T Filvaroff, EH Eldering, E Kater, AP AF Thijssen, Rachel ter Burg, Johanna Garrick, Brett van Bochove, Gregor G. W. Brown, Jennifer R. Fernandes, Stacey M. Sole Rodriguez, Maria Michot, Jean-Marie Hallek, Michael Eichhorst, Barbara Reinhardt, Hans Christian Bendell, Johanna Derks, Ingrid A. M. van Kampen, Roel J. W. Hege, Kristen Kersten, Marie Jose Trowe, Torsten Filvaroff, Ellen H. Eldering, Eric Kater, Arnon P. TI Dual TORK/DNA-PK inhibition blocks critical signaling pathways in chronic lymphocytic leukemia SO BLOOD LA English DT Article ID DEPENDENT PROTEIN-KINASE; DNA-DAMAGE RESPONSE; CELL-CYCLE; CLL CELLS; B-CELLS; REPAIR PATHWAYS; IN-VITRO; IONIZING-RADIATION; T-CELLS; RESISTANCE AB Inhibition of B-cell receptor (BCR) signaling pathways in chronic lymphocytic leukemia (CLL) provides significant clinical benefit to patients, mainly by blocking adhesion of CLL cells in the lymph node microenvironment. The currently applied inhibitors ibrutinib and idelalisib have limited capacity however to induce cell death as monotherapy and are unlikely to eradicate the disease. Acquired resistance to therapy in CLL is often caused by mutations in the response network being targeted, both for DNA damage or BCR signaling pathways. Thus, drugswith dual targeting capacity could offer improved therapeutic value. Here, the potency of CC-115, a novel inhibitor of mammalian target of rapamycin kinase (TORK) and DNA-dependent proteinkinase (DNA-PK), was evaluated in primary CLL cells in vitro and in CLL patients. Combined TORK and DNA-PK inhibition in vitro resulted in caspase-dependent cell killing irrespective of p53, ATM, NOTCH1, or SF3B1 status. Proliferation induced by CD40(+) interleukin-21 stimulation was completely blocked by CC-115, and CD40-mediated resistance to fludarabine and venetoclax could be reverted by CC-115. BCR-mediated signaling was inhibited by CC-115 and also in CLL samples obtained from patients with acquired resistance to idelalisib treatment. Clinical efficacy of CC-115 was demonstrated in 8 patients with relapsed/refractory CLL/small lymphocytic lymphoma harboring ATM deletions/mutations; all but 1 patient had a decrease in lymphadenopathy, resulting in 1 IWCLL partial response (PR) and 3 PRs with lymphocytosis. In conclusion, these preclinical results, along with early promising clinical activity, suggest that CC-115 may be developed further for treatment of CLL. C1 [Thijssen, Rachel; ter Burg, Johanna; van Bochove, Gregor G. W.; Derks, Ingrid A. M.; Eldering, Eric] Univ Amsterdam, Acad Med Ctr, Dept Expt Immunol, Amsterdam, Netherlands. [Thijssen, Rachel; ter Burg, Johanna; van Bochove, Gregor G. W.; Kersten, Marie Jose; Kater, Arnon P.] Univ Amsterdam, Acad Med Ctr, Dept Hematol, Amsterdam, Netherlands. [Garrick, Brett; Hege, Kristen; Trowe, Torsten; Filvaroff, Ellen H.] Celgene, San Francisco, CA USA. [Brown, Jennifer R.; Fernandes, Stacey M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Sole Rodriguez, Maria] Hosp Univ Virgen del Rocio, Dept Hematol, Seville, Spain. [Michot, Jean-Marie] Inst Gustave Roussy, Dept Hematol, Villejuif, France. [Hallek, Michael; Eichhorst, Barbara; Reinhardt, Hans Christian] Univ Hosp, Dept Hematol, Cologne, Germany. [Bendell, Johanna] Tennessee Oncol, Sarah Cannon Res Inst, Nashville, TN USA. [van Kampen, Roel J. W.] Orbis Med Ctr, Sittard, Netherlands. [Kersten, Marie Jose; Eldering, Eric; Kater, Arnon P.] Lymphoma & Myeloma Ctr Amsterdam, Amsterdam, Netherlands. RP Kater, AP (reprint author), Acad Med Ctr, Dept Hematol, NL-1105 AZ Amsterdam, Netherlands. EM a.p.kater@amc.uva.nl FU Dutch Cancer Society clinical fellowship; German Research Foundation [KFO-286-RP2] FX The authors thank the CLL patients for blood donations and Marjolein Spiering and Dieuwertje Luijks for database management and CLL cell phenotyping. A.P.K. is a recipient of a Dutch Cancer Society clinical fellowship. H.C.R. received funding through the German Research Foundation (KFO-286-RP2). NR 64 TC 4 Z9 4 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUL 28 PY 2016 VL 128 IS 4 BP 574 EP 583 DI 10.1182/blood-2016-02-700328 PG 10 WC Hematology SC Hematology GA DW9AQ UT WOS:000383947300015 PM 27235137 ER PT J AU Fu, HJ Hussaini, SA Wegmann, S Profaci, C Daniels, JD Herman, M Emrani, S Figueroa, HY Hyman, BT Davies, P Duff, KE AF Fu, Hongjun Hussaini, S. Abid Wegmann, Susanne Profaci, Caterina Daniels, Jacob D. Herman, Mathieu Emrani, Sheina Figueroa, Helen Y. Hyman, Bradley T. Davies, Peter Duff, Karen E. TI 3D Visualization of the Temporal and Spatial Spread of Tau Pathology Reveals Extensive Sites of Tau Accumulation Associated with Neuronal Loss and Recognition Memory Deficit in Aged Tau Transgenic Mice SO PLOS ONE LA English DT Article ID LATERAL ENTORHINAL CORTEX; EARLY ALZHEIMERS-DISEASE; MICROGLIAL ACTIVATION; NEUROFIBRILLARY TANGLES; OBJECT RECOGNITION; PERIRHINAL CORTEX; MOUSE MODEL; RAT MODEL; BRAIN; MUTANT AB 3D volume imaging using iDISCO+ was applied to observe the spatial and temporal progression of tau pathology in deep structures of the brain of a mouse model that recapitulates the earliest stages of Alzheimer's disease (AD). Tau pathology was compared at four timepoints, up to 34 months as it spread through the hippocampal formation and out into the neocortex along an anatomically connected route. Tau pathology was associated with significant gliosis. No evidence for uptake and accumulation of tau by glia was observed. Neuronal cells did appear to have internalized tau, including in extrahippocampal areas as a small proportion of cells that had accumulated human tau protein did not express detectible levels of human tau mRNA. At the oldest timepoint, mature tau pathology in the entorhinal cortex (EC) was associated with significant cell loss. As in human AD, mature tau pathology in the EC and the presence of tau pathology in the neocortex correlated with cognitive impairment. 3D volume imaging is an ideal technique to easily monitor the spread of pathology over time in models of disease progression. C1 [Fu, Hongjun; Hussaini, S. Abid; Profaci, Caterina; Daniels, Jacob D.; Herman, Mathieu; Emrani, Sheina; Figueroa, Helen Y.; Duff, Karen E.] Columbia Univ, Med Ctr, Taub Inst Res Alzheimers Dis & Aging Brain, New York, NY 10027 USA. [Fu, Hongjun; Hussaini, S. Abid; Profaci, Caterina; Daniels, Jacob D.; Herman, Mathieu; Emrani, Sheina; Figueroa, Helen Y.; Duff, Karen E.] Columbia Univ, Dept Pathol & Cell Biol, Med Ctr, New York, NY USA. [Wegmann, Susanne; Hyman, Bradley T.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA USA. [Davies, Peter] North Shore LIJ Hlth Syst, Feinstein Inst Med Res, Litwin Zucker Ctr Res Alzheimers Dis, Manhasset, NY USA. RP Duff, KE (reprint author), Columbia Univ, Med Ctr, Taub Inst Res Alzheimers Dis & Aging Brain, New York, NY 10027 USA.; Duff, KE (reprint author), Columbia Univ, Dept Pathol & Cell Biol, Med Ctr, New York, NY USA. EM ked2115@cumc.columbia.edu OI Davies, Peter/0000-0002-8015-1997 FU National Institute of Neurological Disorders and Stroke [NS074874]; National Institute on Aging [AG050425] FX Support was provided by the National Institute of Neurological Disorders and Stroke NS074874 (KED) [https://projectreporter.nih.gov/project_info_details.cfm?aid=8824979&ic de=27538292] and NS081555 (to KED) [https://projectreporter.nih.gov/project_info_details.cfm?aid=8842723 & National Institute on Aging AG050425 (to KED and SAH) [https://projectreporter.nih.gov/project_info_details.cfm?aid=9118863&ic de=30215735]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 65 TC 0 Z9 0 U1 2 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 28 PY 2016 VL 11 IS 7 AR e0159463 DI 10.1371/journal.pone.0159463 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT5IL UT WOS:000381516100033 PM 27466814 ER PT J AU Vahidy, F Nguyen, C Albright, KC Boehme, AK Mir, O Sands, KA Savitz, SI AF Vahidy, Farhaan Nguyen, Claude Albright, Karen C. Boehme, Amelia K. Mir, Osman Sands, Kara A. Savitz, Sean I. TI Transferring Patients with Intracerebral Hemorrhage Does Not Increase In-Hospital Mortality SO PLOS ONE LA English DT Article ID ASSOCIATION/AMERICAN-STROKE-ASSOCIATION; INTENSIVE-CARE-UNIT; OUTCOMES; IMPACT; POPULATION; PREVENTION; GUIDELINES; ADMISSION; STATEMENT; REGISTRY AB Introduction Comprehensive stroke centers (CSCs) accept transferred patients from referring hospitals in a given regional area. The transfer process itself has not been studied as a potential factor that may impact outcome. We compared in-hospital mortality and severe disability or death at CSCs between transferred and directly admitted intracerebral hemorrhage (ICH) patients of matched severity. Materials and Methods We retrospectively reviewed all primary ICH patients from a prospectively-collected stroke registry and electronic medical records, at two tertiary care sites. Patients meeting inclusion criteria were divided into two groups: patients transferred in for a higher level of care and direct presenters. We used propensity scores (PS) to match 175 transfer patients to 175 direct presenters. These patients were taken from a pool of 530 eligible patients, 291 (54.9%) of whom were transferred in for a higher level of care. Severe disability or death was defined as a modified Rankin Scale (mRS) sore of 4-6. Mortality and morbidity were compared between the 2 groups using Pearson chi-squared test and Student t test. We fit logistic regression models to estimate odds ratios (OR) and 95% confidence intervals (CI) for association between transfer status and in-hospital mortality and severe disability or death in full and PS-matched patients. Results There were no significant differences in the PS-matched transfer and direct presentation groups. Patients transferred to a regional center were not at higher odds of in-hospital mortality (OR: 0.93, 95% CI: 0.50-1.71) and severe disability or death (OR: 0.77, 95% CI: 0.39-1.50), than direct presenters, even after adjustment for PS, age, baseline NIHSS score, and glucose on admission. Conclusion Our observation suggests that transfer patients of similar disease burden are not at higher risk of in-hospital mortality than direct presenters. C1 [Vahidy, Farhaan; Nguyen, Claude; Mir, Osman; Savitz, Sean I.] Univ Texas Hlth Sci Ctr Houston, McGovern Med Sch, Dept Neurol, Houston, TX USA. [Albright, Karen C.] Birmingham VA Med Ctr, Geriatr Res Educ & Clin Ctr, Birmingham, AL USA. [Albright, Karen C.] Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA. [Boehme, Amelia K.] Columbia Univ, Gertrude H Sergievsky Ctr, Dept Neurol, New York, NY 10027 USA. [Sands, Kara A.] Univ Alabama Birmingham, Dept Neurol, UAB Stn, Birmingham, AL 35294 USA. RP Vahidy, F (reprint author), Univ Texas Hlth Sci Ctr Houston, McGovern Med Sch, Dept Neurol, Houston, TX USA. EM farhaan.vahidy@uth.tmc.edu FU National Institutes of Health Training Grant [5 T32 NS007412-12]; NINDS [T32 NS007153 31] FX Financial support for this study was provided in part by National Institutes of Health Training Grant 5 T32 NS007412-12. Dr. Boehme is supported by NINDS T32 NS007153 31. The funding agreement ensured the authors' independence in designing the study, interpreting the data, writing and publishing the report.; The authors acknowledge technical and infrastructural research supported provided by the Center for Clinical Research and Evidence Based Medicine at the McGovern Medical School at University of Texas in Houston for this work. This work was supported by National Institutes of Health Training Grant 5 T32 NS007412-12. Dr. Boehme is supported by NINDS T32 NS007153 31. NR 37 TC 0 Z9 0 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 28 PY 2016 VL 11 IS 7 AR e0159174 DI 10.1371/journal.pone.0159174 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT5IL UT WOS:000381516100020 PM 27467594 ER PT J AU Barnett, ML Mehrotra, A Jena, AB AF Barnett, Michael L. Mehrotra, Ateev Jena, Anupam B. TI Adverse inpatient outcomes during the transition to a new electronic health record system: observational study SO BMJ-British Medical Journal LA English DT Article ID PHYSICIAN ORDER ENTRY; DIFFERENCE-IN-DIFFERENCES; US HOSPITALS; INFORMATION-TECHNOLOGY; MYOCARDIAL-INFARCTION; INCREASED MORTALITY; MEDICAL-RECORD; MEANINGFUL USE; IMPLEMENTATION; IMPACT AB OBJECTIVE To assess the short term association of inpatient implementation of electronic health records (EHRs) with patient outcomes of mortality, readmissions, and adverse safety events. Design Observational study with difference-in-differences analysis. Setting Medicare, 2011-12. Participants Patients admitted to 17 study hospitals with a verifiable "go live" date for implementation of inpatient EHRs during 2011-12, and 399 control hospitals in the same hospital referral region. Main outcome measures All cause readmission within 30 days of discharge, all cause mortality within 30 days of admission, and adverse safety events as defined by the patient safety for selected indicators (PSI)-90 composite measure among Medicare beneficiaries admitted to one of these hospitals 90 days before and 90 days after implementation of the EHRs (n=28 235 and 26 453 admissions), compared with the control group of all contemporaneous admissions to hospitals in the same hospital referral region (n=284 632 and 276 513 admissions). Analyses were adjusted for beneficiaries' sociodemographic and clinical characteristics. Results Before and after implementation, characteristics of admissions were similar in both study and control hospitals. Among study hospitals, unadjusted 30 day mortality (6.74% to 7.15%, P=0.06) and adverse safety event rates (10.5 to 11.4 events per 1000 admissions, P=0.34) did not significantly change after implementation of EHRs. There was an unadjusted decrease in 30 day readmission rates, from 19.9% to 19.0% post-implementation (P=0.02). In difference-indifferences analysis, however, there was no significant change in any outcome between pre-implementation and post-implementation periods (all P >= 0.13). Conclusions Despite concerns that implementation of EHRs might adversely impact patient care during the acute transition period, we found no overall negative association of such implementation on short term inpatient mortality, adverse safety events, or readmissions in the Medicare population across 17 US hospitals. C1 [Barnett, Michael L.] Harvard TH Chan Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Barnett, Michael L.] Brigham & Womens Hosp, Dept Med, Div Gen Internal Med & Primary Care, 75 Francis St, Boston, MA 02115 USA. [Mehrotra, Ateev; Jena, Anupam B.] Harvard Med Sch, Dept Hlth Care Policy, Boston, MA 02115 USA. [Mehrotra, Ateev] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Jena, Anupam B.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Jena, AB (reprint author), Harvard Med Sch, Dept Hlth Care Policy, Boston, MA 02115 USA.; Jena, AB (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. EM jena@hcp.med.harvard.edu FU Office of the Director, National Institutes of Health (NIH early independence award) [1DP5OD017897-01]; Health Resources and Services Administration [T32-HP10251] FX This study was supported by grants from the Office of the Director, National Institutes of Health (ABJ, NIH early independence award, grant 1DP5OD017897-01) and Health Resources and Services Administration (MLB, T32-HP10251). NR 44 TC 1 Z9 1 U1 4 U2 4 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 28 PY 2016 VL 354 AR i3835 DI 10.1136/bmj.i3835 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA DS6ZO UT WOS:000380932300002 PM 27471242 ER PT J AU Hayakawa, K Esposito, E Wang, XH Terasaki, Y Liu, Y Xing, CH Ji, XM Lo, EH AF Hayakawa, Kazuhide Esposito, Elga Wang, Xiaohua Terasaki, Yasukazu Liu, Yi Xing, Changhong Ji, Xunming Lo, Eng H. TI Transfer of mitochondria from astrocytes to neurons after stroke SO NATURE LA English DT Article ID STROMAL CELLS; CD38; RECOVERY; INJURY; VULNERABILITY; INHIBITION; ISCHEMIA; VESICLES; PROTECTS; DISEASE AB Neurons can release damaged mitochondria and transfer them to astrocytes for disposal and recycling(1). This ability to exchange mitochondria may represent a potential mode of cell-to-cell signalling in the central nervous system. Here we show that astrocytes in mice can also release functional mitochondria that enter neurons. Astrocytic release of extracellular mitochondrial particles was mediated by a calcium-dependent mechanism involving CD38 and cyclic ADP ribose signalling. Transient focal cerebral ischaemia in mice induced entry of astrocytic mitochondria into adjacent neurons, and this entry amplified cell survival signals. Suppression of CD38 signalling by short interfering RNA reduced extracellular mitochondria transfer and worsened neurological outcomes. These findings suggest a new mitochondrial mechanism of neuroglial crosstalk that may contribute to endogenous neuroprotective and neurorecovery mechanisms after stroke. C1 [Hayakawa, Kazuhide; Esposito, Elga; Wang, Xiaohua; Terasaki, Yasukazu; Liu, Yi; Xing, Changhong; Lo, Eng H.] Massachusetts Gen Hosp, Dept Radiol, Neuroprotect Res Lab, Charlestown, MA 02129 USA. [Hayakawa, Kazuhide; Esposito, Elga; Wang, Xiaohua; Terasaki, Yasukazu; Liu, Yi; Xing, Changhong; Lo, Eng H.] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA. [Hayakawa, Kazuhide; Esposito, Elga; Wang, Xiaohua; Terasaki, Yasukazu; Liu, Yi; Xing, Changhong; Lo, Eng H.] Harvard Med Sch, Charlestown, MA 02129 USA. [Wang, Xiaohua; Liu, Yi; Ji, Xunming] Capital Med Univ, Xuanwu Hosp, Cerebrovasc Res Ctr, Beijing 100053, Peoples R China. RP Hayakawa, K; Lo, EH (reprint author), Massachusetts Gen Hosp, Dept Radiol, Neuroprotect Res Lab, Charlestown, MA 02129 USA.; Hayakawa, K; Lo, EH (reprint author), Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA.; Hayakawa, K; Lo, EH (reprint author), Harvard Med Sch, Charlestown, MA 02129 USA.; Ji, XM (reprint author), Capital Med Univ, Xuanwu Hosp, Cerebrovasc Res Ctr, Beijing 100053, Peoples R China. EM khayakawa1@mgh.harvard.edu; jixunming@vip.163.com; Lo@helix.mgh.harvard.edu FU National Institutes of Health (NIH); Rappaport Foundation; China National Natural Science Foundation Award For Distinguished Young Scholars FX fThis work was supported in part by grants from the National Institutes of Health (NIH), the Rappaport Foundation, and the China National Natural Science Foundation Award For Distinguished Young Scholars. Electron microscopy was performed in the Center for Systems Biology. Cytometric assessments were supported by the Department of Pathology Flow and Image Cytometry Core. The authors thank J. Felton and J. Zwicker for assistance with qNano analysis. NR 37 TC 13 Z9 13 U1 18 U2 39 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 28 PY 2016 VL 535 IS 7613 BP 551 EP + DI 10.1038/nature18928 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DS5XP UT WOS:000380856600029 PM 27466127 ER PT J AU Scheid, JF Horwitz, JA Bar-On, Y Kreider, EF Lu, CL Lorenzi, JCC Feldmann, A Braunschweig, M Nogueira, L Oliveira, T Shimeliovich, I Patel, R Burke, L Cohen, YZ Hadrigan, S Settler, A Witmer-Pack, M West, AP Juelg, B Keler, T Hawthorne, T Zingman, B Gulick, RM Pfeifer, N Learn, GH Seaman, MS Bjorkman, PJ Klein, F Schlesinger, SJ Walker, BD Hahn, BH Nussenzweig, MC Caskey, M AF Scheid, Johannes F. Horwitz, Joshua A. Bar-On, Yotam Kreider, Edward F. Lu, Ching-Lan Lorenzi, Julio C. C. Feldmann, Anna Braunschweig, Malte Nogueira, Lilian Oliveira, Thiago Shimeliovich, Irina Patel, Roshni Burke, Leah Cohen, Yehuda Z. Hadrigan, Sonya Settler, Allison Witmer-Pack, Maggi West, Anthony P., Jr. Juelg, Boris Keler, Tibor Hawthorne, Thomas Zingman, Barry Gulick, Roy M. Pfeifer, Nico Learn, Gerald H. Seaman, Michael S. Bjorkman, Pamela J. Klein, Florian Schlesinger, Sarah J. Walker, Bruce D. Hahn, Beatrice H. Nussenzweig, Michel C. Caskey, Marina TI HIV-1 antibody 3BNC117 suppresses viral rebound in humans during treatment interruption SO NATURE LA English DT Article ID BROADLY NEUTRALIZING ANTIBODIES; ANTIRETROVIRAL THERAPY; MONOCLONAL-ANTIBODIES; GENETIC-DETERMINANTS; PASSIVE TRANSFER; CD4 BINDING; POTENT; INFECTION; SEQUENCE; REPLICATION AB Interruption of combination antiretroviral therapy in HIV-1-infected individuals leads to rapid viral rebound. Here we report the results of a phase IIa open label clinical trial evaluating 3BNC117, a broad and potent neutralizing antibody against the CD4 binding site of the HIV-1 Env protein(1), during analytical treatment interruption in 13 HIV-1-infected individuals. Participants with 3BNC117-sensitive virus outgrowth cultures were enrolled. Results show that two or four 30 mg kg(-1) 3BNC117 infusions, separated by 3 or 2 weeks, respectively, are generally well tolerated. Infusions are associated with a delay in viral rebound of 5-9 weeks after two infusions, and up to 19 weeks after four infusions, or an average of 6.7 and 9.9 weeks, respectively, compared with 2.6 weeks for historical controls (P < 0.00001). Rebound viruses arise predominantly from a single provirus. In most individuals, emerging viruses show increased resistance, indicating escape. However, 30% of participants remained suppressed until antibody concentrations waned below 20 mu g ml(-1), and the viruses emerging in all but one of these individuals showed no apparent resistance to 3BCN117, suggesting failure to escape over a period of 9-19 weeks. We conclude that the administration of 3BNC117 exerts strong selective pressure on HIV-1 emerging from latent reservoirs during analytical treatment interruption in humans. C1 [Scheid, Johannes F.; Horwitz, Joshua A.; Bar-On, Yotam; Lu, Ching-Lan; Lorenzi, Julio C. C.; Braunschweig, Malte; Nogueira, Lilian; Oliveira, Thiago; Shimeliovich, Irina; Patel, Roshni; Cohen, Yehuda Z.; Hadrigan, Sonya; Settler, Allison; Witmer-Pack, Maggi; Klein, Florian; Schlesinger, Sarah J.; Nussenzweig, Michel C.; Caskey, Marina] Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. [Scheid, Johannes F.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Scheid, Johannes F.] Harvard Med Sch, Boston, MA 02114 USA. [Kreider, Edward F.; Learn, Gerald H.; Hahn, Beatrice H.] Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Kreider, Edward F.; Learn, Gerald H.; Hahn, Beatrice H.] Univ Penn, Dept Microbiol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Feldmann, Anna; Pfeifer, Nico] Max Planck Inst Informat, Dept Computat Biol & Appl Algorithm, Campus E1 4, D-66123 Saarbrcken, Germany. [Burke, Leah; Gulick, Roy M.] Cornell Univ, Div Infect Dis, Weill Med Coll, New York, NY 10065 USA. [West, Anthony P., Jr.; Bjorkman, Pamela J.] CALTECH, Div Biol, Pasadena, CA 91125 USA. [Juelg, Boris; Walker, Bruce D.] Ragon Inst MGH MIT & Harvard, Cambridge, MA 02139 USA. [Keler, Tibor; Hawthorne, Thomas] Celldex Therapeut Inc, Hampton, NJ 08827 USA. [Zingman, Barry] Montefiore Med Ctr, Albert Einstein Coll Med, Bronx, NY 10467 USA. [Seaman, Michael S.] Beth Israel Deaconess Med Ctr, Ctr Virol & Vaccine Res, Boston, MA 02215 USA. [Klein, Florian] Univ Cologne, Ctr Mol Med Cologne CMMC, Lab Expt Immunol, D-50931 Cologne, Germany. [Klein, Florian] Univ Hosp Cologne, Ctr Integrated Oncol Cologne Bonn, Dept Internal Med 1, D-50937 Cologne, Germany. [Walker, Bruce D.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. [Nussenzweig, Michel C.] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10065 USA. RP Nussenzweig, MC; Caskey, M (reprint author), Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA.; Nussenzweig, MC (reprint author), Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10065 USA. EM nussen@rockefeller.edu; mcaskey@rockefeller.edu RI Pfeifer, Nico/G-1559-2016; OI Pfeifer, Nico/0000-0002-4647-8566 FU Rockefeller University Hospital Clinical Research Support Office; AIDS Clinical Trials Group grant [UM1 AI068636]; Statistical and Data Management Center [UM1 AI068634]; Collaboration for AIDS Vaccine Discovery grant [OPP1033115, OPP1032144]; National Center for Advancing Translational Sciences (NCATS) [8 UL1 TR000043]; NIH Clinical and Translational Science Award (CTSA) program; NIH Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) [1UM1 AI100663-01, 5UM1 AI100645-03, 1UM1 AI00645]; Bill and Melinda Gates Foundation [OPP1092074, OPP1124068]; NIH HIVRAD [P01 AI100148]; Robertson Foundation; Ruth L. Kirschstein National Research Service Award [F30 AI112426, F31 AI118555]; University of Pennsylvania Center for AIDS Research (CFAR) Single Genome Amplification Service Center [P30 AI045008]; NIH Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) [1UM1-AI100663] FX We would like to thank the trial participants for their invaluable support. We thank the Rockefeller University Hospital Clinical Research Support Office and nursing staff for help with recruitment and study implementation, especially N. Buckley, A. Hurley, S. B. A. Shulman and L. Corregano; all members of the Nussenzweig laboratory, especially T. Schoofs, A. Halper-Stromberg, M. and Z. Jankovic; C. Unson-O'Brien, J. Dizon, R. Baptiste and R. Levin for sample processing and study coordination; A. Louie for regulatory support; P. Fast and H. Park for clinical monitoring; E. Giorgi and W. Fischer from Los Alamos National Laboratory; R. T. Gandhi, J. Li and The AIDS Clinical Trials Group (grant UM1 AI068636) and its Statistical and Data Management Center (grant UM1 AI068634). This study was supported by the following grants: Collaboration for AIDS Vaccine Discovery grant OPP1033115 (M. C. N.) and OPP1032144 (M. S. S.). Grant 8 UL1 TR000043 from the National Center for Advancing Translational Sciences (NCATS); NIH Clinical and Translational Science Award (CTSA) program; NIH Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) 1UM1 AI100663-01 (M. C. N.) and 5UM1 AI100645-03 (B. H. H.); Bill and Melinda Gates Foundation grants OPP1092074 and OPP1124068 (M. C. N.); NIH HIVRAD P01 AI100148 (P. J. B. and M. C. N.); the Robertson Foundation to M. C. N. M. C. N. is a Howard Hughes Medical Institute Investigator. Ruth L. Kirschstein National Research Service Award F30 AI112426 (E.F.K.); F31 AI118555 (J. A. H.); The NIH Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) 1UM1 AI00645 (B. H. H.); The University of Pennsylvania Center for AIDS Research (CFAR) Single Genome Amplification Service Center P30 AI045008 (B. H. H.); The NIH Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID and 1UM1-AI100663) (B.D.W.). NR 52 TC 21 Z9 21 U1 8 U2 13 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 28 PY 2016 VL 535 IS 7613 BP 556 EP + DI 10.1038/nature18929 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DS5XP UT WOS:000380856600030 PM 27338952 ER PT J AU Iorio, F Knijnenburg, TA Vis, DJ Bignell, GR Menden, MP Schubert, M Aben, N Goncalves, E Barthorpe, S Lightfoot, H Cokelaer, T Greninger, P van Dyk, E Chang, H de Silva, H Heyn, H Deng, XM Egan, RK Liu, QS Mironenko, T Mitropoulos, X Richardson, L Wang, JH Zhang, TH Moran, S Sayols, S Soleimani, M Tamborero, D Lopez-Bigas, N Ross-Macdonald, P Esteller, M Gray, NS Haber, DA Stratton, MR Benes, CH Wessels, LFA Saez-Rodriguez, J McDermott, U Garnett, MJ AF Iorio, Francesco Knijnenburg, Theo A. Vis, Daniel J. Bignell, Graham R. Menden, Michael P. Schubert, Michael Aben, Nanne Goncalves, Emanuel Barthorpe, Syd Lightfoot, Howard Cokelaer, Thomas Greninger, Patricia van Dyk, Ewald Chang, Han de Silva, Heshani Heyn, Holger Deng, Xianming Egan, Regina K. Liu, Qingsong Mironenko, Tatiana Mitropoulos, Xeni Richardson, Laura Wang, Jinhua Zhang, Tinghu Moran, Sebastian Sayols, Sergi Soleimani, Maryam Tamborero, David Lopez-Bigas, Nuria Ross-Macdonald, Petra Esteller, Manel Gray, Nathanael S. Haber, Daniel A. Stratton, Michael R. Benes, Cyril H. Wessels, Lodewyk F. A. Saez-Rodriguez, Julio McDermott, Ultan Garnett, Mathew J. TI A Landscape of Pharmacogenomic Interactions in Cancer SO CELL LA English DT Article ID GENE-EXPRESSION PATTERNS; DRUG-SENSITIVITY; TUMOR TYPES; LUNG-CANCER; IDENTIFICATION; ADENOCARCINOMA; INHIBITOR; MUTATIONS; DISCOVERY; GENOME AB Systematic studies of cancer genomes have provided unprecedented insights into the molecular nature of cancer. Using this information to guide the development and application of therapies in the clinic is challenging. Here, we report how cancer-driven alterations identified in 11,289 tumors from 29 tissues (integrating somatic mutations, copy number alterations, DNA methylation, and gene expression) can be mapped onto 1,001 molecularly annotated human cancer cell lines and correlated with sensitivity to 265 drugs. We find that cell lines faithfully recapitulate oncogenic alterations identified in tumors, find that many of these associate with drug sensitivity/resistance, and highlight the importance of tissue lineage in mediating drug response. Logic-based modeling uncovers combinations of alterations that sensitize to drugs, while machine learning demonstrates the relative importance of different data types in predicting drug response. Our analysis and datasets are rich resources to link genotypes with cellular phenotypes and to identify therapeutic options for selected cancer sub-populations. C1 [Iorio, Francesco; Menden, Michael P.; Schubert, Michael; Goncalves, Emanuel; Cokelaer, Thomas; Saez-Rodriguez, Julio] European Bioinformat Inst, European Mol Biol Lab, Wellcome Genome Campus, Cambridge CB10 1SA, England. [Iorio, Francesco; Bignell, Graham R.; Barthorpe, Syd; Lightfoot, Howard; Cokelaer, Thomas; Mironenko, Tatiana; Richardson, Laura; Soleimani, Maryam; Stratton, Michael R.; McDermott, Ultan; Garnett, Mathew J.] Wellcome Trust Sanger Inst, Wellcome Genome Campus, Cambridge CB10 1SA, England. [Knijnenburg, Theo A.] Inst Syst Biol, Seattle, WA 98109 USA. [Knijnenburg, Theo A.; Vis, Daniel J.; Aben, Nanne; van Dyk, Ewald; Wessels, Lodewyk F. A.] Netherlands Canc Inst, Div Mol Carcinogenesis, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands. [Menden, Michael P.; Saez-Rodriguez, Julio] Rhein Westfal TH Aachen, Joint Res Ctr Computat Biomed, Fac Med, D-52057 Aachen, Germany. [Aben, Nanne; Wessels, Lodewyk F. A.] Delft Univ Technol, Dept EEMCS, NL-2628 CD Delft, Netherlands. [Greninger, Patricia; Egan, Regina K.; Mitropoulos, Xeni; Haber, Daniel A.; Benes, Cyril H.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA 02129 USA. [Chang, Han; de Silva, Heshani; Ross-Macdonald, Petra] Bristol Myers Squibb Res & Dev, Genetically Defined Dis & Genom, Hopewell, NJ 08534 USA. [Heyn, Holger; Moran, Sebastian; Sayols, Sergi; Esteller, Manel] Bellvitge Biomed Res Inst IDIBELL, PEBC, Barcelona CATALONIA, Spain. [Deng, Xianming; Liu, Qingsong; Wang, Jinhua; Zhang, Tinghu; Gray, Nathanael S.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Deng, Xianming; Liu, Qingsong; Wang, Jinhua; Zhang, Tinghu; Gray, Nathanael S.] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02215 USA. [Tamborero, David; Lopez-Bigas, Nuria] IMIM Hosp del Mar Med Res Inst, Res Program Biomed Informat, Barcelona 08003, Spain. [Tamborero, David; Lopez-Bigas, Nuria] Univ Pompeu Fabra, Barcelona 08003, Spain. [Lopez-Bigas, Nuria; Esteller, Manel] ICREA, Barcelona 08010, Catalonia, Spain. [Esteller, Manel] Univ Barcelona, Sch Med, Dept Physiol Sci 2, Barcelona 08908, Catalonia, Spain. [Haber, Daniel A.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Wessels, Lodewyk F. A.] Canc Genom Netherlands, Uppsalalaan 8, NL-3584 CT Utrecht, Netherlands. [Cokelaer, Thomas] Inst Pasteur, USR IP CNRS 3756, C3BI, Bioinformat & Biostat Hub, F-75015 Paris, France. [Deng, Xianming] Xiamen Univ, Sch Life Sci, Innovat Ctr Cell Signaling Network, Xiamen 361102, Peoples R China. [Sayols, Sergi] Inst Mol Biol, D-55128 Mainz, Germany. RP McDermott, U; Garnett, MJ (reprint author), Wellcome Trust Sanger Inst, Wellcome Genome Campus, Cambridge CB10 1SA, England. EM um1@sanger.ac.uk; mg12@sanger.ac.uk RI Moran, Sebastian /G-5293-2013; Gasull, Martina/A-6630-2013; Lopez-Bigas, Nuria/F-6193-2011; OI Moran, Sebastian /0000-0003-4192-8983; Lopez-Bigas, Nuria/0000-0003-4925-8988; Schubert, Michael/0000-0002-6862-5221; Goncalves, Emanuel/0000-0002-9967-5205; McDermott, Ultan/0000-0001-9032-4700; Heyn, Holger/0000-0002-3276-1889 FU Wellcome Trust [086375, 102696]; European Bioinformatics Institute; Wellcome Trust Sanger Institute post-doctoral (ESPOD) program; National Cancer Institute [U24CA143835]; Netherlands Organization for Scientific Research; People Programme (Marie Curie Actions) of the 7th Framework Programme of the European Union [600388]; Agency of Competitiveness for Companies of the Government of Catalonia (ACCIO); La Fundacio la Marato de TV3; European Research Council [268626]; Ministerio de Ciencia e Innovacion [SAF2011-22803]; Institute of Health Carlos III (ISCIII) under the Integrated Project of Excellence [PIE13/00022]; Spanish Cancer Research Network [RD12/0036/0039]; Health Department of the Catalan Government Generalitat de Catalunya [2014-SGR 633]; Science Department of the Catalan Government Generalitat de Catalunya [2014-SGR 633]; Cellex Foundation; Cancer Research UK Clinician Scientist Fellowship; AstraZeneca FX This work was funded by the Wellcome Trust (086375 and 102696). F.I. was supported by the European Bioinformatics Institute and Wellcome Trust Sanger Institute post-doctoral (ESPOD) program. T.A.K. was supported by the National Cancer Institute (U24CA143835) and the Netherlands Organization for Scientific Research. D.T. was supported by the People Programme (Marie Curie Actions) of the 7th Framework Programme of the European Union (FP7/2007-2013; 600388) and the Agency of Competitiveness for Companies of the Government of Catalonia (ACCIO). N.L.-B. was supported by La Fundacio la Marato de TV3. M.E. was funded by the European Research Council (268626), the Ministerio de Ciencia e Innovacion (SAF2011-22803), the Institute of Health Carlos III (ISCIII) under the Integrated Project of Excellence (PIE13/00022), the Spanish Cancer Research Network (RD12/0036/0039), the Health and Science Departments of the Catalan Government Generalitat de Catalunya 2014-SGR 633, and the Cellex Foundation. U.M. was supported by a Cancer Research UK Clinician Scientist Fellowship. We thank Aiqing He for expression data and Ilya Shmulevich for assistance with the LOBICO framework. We thank P. Campbell, M. Ranzani, J. Brammeld, M. Petljak, F. Behan, C. Alsinet Armengol, H. Francies, V. Grinkevich, and A. "Lilla" Mupo for useful comments. P. R.-M., H. C., and H.d.S. are employees and shareholders of Bristol-Myers Squibb. Research in the M.J.G. lab is supported in part with funding from AstraZeneca. NR 34 TC 22 Z9 22 U1 18 U2 20 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 28 PY 2016 VL 166 IS 3 BP 740 EP 754 DI 10.1016/j.cell.2016.06.017 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DS2ED UT WOS:000380546500023 PM 27397505 ER PT J AU Marso, SP Daniels, GH Brown-Frandsen, K Kristensen, P Mann, JFE Nauck, MA Nissen, SE Pocock, S Poulter, NR Ravn, LS Steinberg, WM Stockner, M Zinman, B Bergenstal, RM Buse, JB AF Marso, Steven P. Daniels, Gilbert H. Brown-Frandsen, Kirstine Kristensen, Peter Mann, Johannes F. E. Nauck, Michael A. Nissen, Steven E. Pocock, Stuart Poulter, Neil R. Ravn, Lasse S. Steinberg, William M. Stockner, Mette Zinman, Bernard Bergenstal, Richard M. Buse, John B. CA LEADER Steering Comm LEADER Trial Investigators TI Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID CLINICAL-TRIAL; PANCREATITIS; THERAPIES; CANCER; DRUGS AB BACKGROUND The cardiovascular effect of liraglutide, a glucagon-like peptide 1 analogue, when added to standard care in patients with type 2 diabetes, remains unknown. METHODS In this double-blind trial, we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo. The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome, with a margin of 1.30 for the upper boundary of the 95% confidence interval of the hazard ratio. No adjustments for multiplicity were performed for the prespecified exploratory outcomes. RESULTS A total of 9340 patients underwent randomization. The median follow-up was 3.8 years. The primary outcome occurred in significantly fewer patients in the liraglutide group (608 of 4668 patients [13.0%]) than in the placebo group (694 of 4672 [14.9%]) (hazard ratio, 0.87; 95% confidence interval [CI], 0.78 to 0.97; P<0.001 for noninferiority; P = 0.01 for superiority). Fewer patients died from cardiovascular causes in the liraglutide group (219 patients [4.7%]) than in the placebo group (278 [6.0%]) (hazard ratio, 0.78; 95% CI, 0.66 to 0.93; P = 0.007). The rate of death from any cause was lower in the liraglutide group (381 patients [8.2%]) than in the placebo group (447 [9.6%]) (hazard ratio, 0.85; 95% CI, 0.74 to 0.97; P = 0.02). The rates of nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure were nonsignificantly lower in the liraglutide group than in the placebo group. The most common adverse events leading to the discontinuation of liraglutide were gastrointestinal events. The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group. CONCLUSIONS In the time-to-event analysis, the rate of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo. (Funded by Novo Nordisk and the National Institutes of Health; LEADER ClinicalTrials.gov number, NCT01179048.) C1 [Marso, Steven P.] Univ Texas Southwestern Med Ctr, Dallas, TX USA. [Daniels, Gilbert H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Brown-Frandsen, Kirstine; Kristensen, Peter; Ravn, Lasse S.; Stockner, Mette] Novo Nordisk, Bagsvaerd, Denmark. [Mann, Johannes F. E.] Univ Erlangen Nurnberg, Erlangen, Germany. [Nauck, Michael A.] Ruhr Univ, St Josef Hosp, Bochum, Germany. [Nissen, Steven E.] Cleveland Clin, Cleveland, OH 44106 USA. [Pocock, Stuart] London Sch Hyg & Trop Med Med, Stat Unit, London, England. [Poulter, Neil R.] Imperial Coll London, London, England. [Steinberg, William M.] George Washington Univ, Med Ctr, Washington, DC 20037 USA. [Zinman, Bernard] Univ Toronto, Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada. [Bergenstal, Richard M.] Int Diabet Ctr Pk Nicollet, Minneapolis, MN USA. [Buse, John B.] Univ N Carolina, Sch Med, CB7172, Chapel Hill, NC 27599 USA. RP Buse, JB (reprint author), Univ N Carolina, Sch Med, CB7172, Chapel Hill, NC 27599 USA. EM john_buse@med.unc.edu RI Saravanan, Ponnusamy/M-6142-2016; Hukkanen, Janne/C-7292-2013; BALCI, Mustafa Kemal/C-2979-2016; Krizova, Jarmila/B-2601-2017; Trachta, Pavel/B-2602-2017; Anderlova, Katerina/D-9334-2017; OI Saravanan, Ponnusamy/0000-0002-9566-2626; Hukkanen, Janne/0000-0003-4981-0525; BALCI, Mustafa Kemal/0000-0002-6494-3249; Krizova, Jarmila/0000-0001-7287-5672; Trachta, Pavel/0000-0002-2218-3157; Anderlova, Katerina/0000-0001-8794-6496; buscemi, silvio/0000-0003-0730-7649; English, Patrick/0000-0001-6268-8400; Huang, Chung-Huei/0000-0001-6736-1423; Camafort-Babkowski, Miguel/0000-0002-8669-6410 FU Novo Nordisk; National Institutes of Health FX Funded by Novo Nordisk and the National Institutes of Health; LEADER ClinicalTrials.gov number, NCT01179048. NR 27 TC 209 Z9 212 U1 28 U2 48 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 28 PY 2016 VL 375 IS 4 BP 311 EP 322 DI 10.1056/NEJMoa1603827 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA DS0UV UT WOS:000380313200005 PM 27295427 ER PT J AU Chiappa, V Gonzalez, RG Manian, FA Deshpande, V AF Chiappa, Victor Gonzalez, R. Gilberto Manian, Farrin A. Deshpande, Vikram TI Case 23-2016: A 46-Year-Old Man with Somnolence after Orthopedic Surgery SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID FAT-EMBOLISM SYNDROME C1 [Chiappa, Victor; Manian, Farrin A.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Gonzalez, R. Gilberto] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Deshpande, Vikram] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Chiappa, Victor; Manian, Farrin A.] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. [Gonzalez, R. Gilberto] Harvard Med Sch, Dept Radiol, Boston, MA USA. [Deshpande, Vikram] Harvard Med Sch, Dept Pathol, Boston, MA USA. RP Chiappa, V (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA.; Chiappa, V (reprint author), Harvard Med Sch, Dept Med, Boston, MA 02115 USA. NR 7 TC 0 Z9 0 U1 1 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 28 PY 2016 VL 375 IS 4 BP 370 EP 378 DI 10.1056/NEJMcpc1601840 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA DS0UV UT WOS:000380313200011 PM 27464205 ER PT J AU Saukkonen, K Sharma, A AF Saukkonen, Kai Sharma, Amita TI Case 8-2016: A Man with Recurrent Fevers, Hypoxemia, and Lung Infiltrates REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID ASPERGILLOSIS C1 [Saukkonen, Kai; Sharma, Amita] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Saukkonen, K (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 3 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 28 PY 2016 VL 375 IS 4 BP 392 EP 393 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DS0UV UT WOS:000380313200028 PM 27464217 ER PT J AU Fischer, M Grossmann, P Padi, M DeCaprio, JA AF Fischer, Martin Grossmann, Patrick Padi, Megha DeCaprio, James A. TI Integration of TP53, DREAM, MMB-FOXM1 and RB-E2F target gene analyses identifies cell cycle gene regulatory networks SO NUCLEIC ACIDS RESEARCH LA English DT Article ID EMBRYONIC STEM-CELLS; DNA-DAMAGE; TRANSCRIPTIONAL REPRESSION; B-MYB; RETINOBLASTOMA PROTEIN; IONIZING-RADIATION; TOPOISOMERASE-II; G(2) CHECKPOINT; DOWN-REGULATION; GROWTH ARREST AB Cell cycle (CC) and TP53 regulatory networks are frequently deregulated in cancer. While numerous genome-wide studies of TP53 and CC-regulated genes have been performed, significant variation between studies has made it difficult to assess regulation of any given gene of interest. To overcome the limitation of individual studies, we developed a meta-analysis approach to identify high confidence target genes that reflect their frequency of identification in independent datasets. Gene regulatory networks were generated by comparing differential expression of TP53 and CC-regulated genes with chromatin immunoprecipitation studies for TP53, RB1, E2F, DREAM, B-MYB, FOXM1 and MuvB. RNA-seq data from p21-null cells revealed that gene down-regulation by TP53 generally requires p21 (CDKN1A). Genes downregulated by TP53 were also identified as CC genes bound by the DREAM complex. The transcription factors RB, E2F1 and E2F7 bind to a subset of DREAM target genes that function in G1/S of the CC while B-MYB, FOXM1 and MuvB control G2/M gene expression. Our approach yields high confidence ranked target gene maps for TP53, DREAM, MMB-FOXM1 and RB-E2F and enables prediction and distinction of CC regulation. A web-based atlas at www. targetgenereg. org enables assessing the regulation of any human gene of interest. C1 [Fischer, Martin] Univ Leipzig, Sch Med, Mol Oncol, D-04103 Leipzig, Germany. [Fischer, Martin; DeCaprio, James A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Fischer, Martin; Padi, Megha; DeCaprio, James A.] Harvard Med Sch, Dept Med, Boston, MA 02215 USA. [Grossmann, Patrick] Harvard Med Sch, Dana Farber Canc Inst, Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02215 USA. [Grossmann, Patrick; Padi, Megha] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. RP Fischer, M (reprint author), Univ Leipzig, Sch Med, Mol Oncol, D-04103 Leipzig, Germany.; Fischer, M (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA.; Fischer, M (reprint author), Harvard Med Sch, Dept Med, Boston, MA 02215 USA. EM Martin.Fischer@medizin.uni-leipzig.de RI Fischer, Martin/I-4825-2014 OI Fischer, Martin/0000-0002-3429-1876 FU Fritz Thyssen Foundation; German National Academy of Sciences Leopoldina Postdoctoral Fellowship; Add-On Fellowship for Interdisciplinary Science by the Joachim Herz Foundation; NIH [K25 HG006031]; US Public Health Service grants [R01CA63113, R01CA173023]; German Research Foundation (DFG); University of Leipzig FX Postdoctoral fellowship provided by the Fritz Thyssen Foundation; German National Academy of Sciences Leopoldina Postdoctoral Fellowship; Add-On Fellowship for Interdisciplinary Science by the Joachim Herz Foundation [to M.F.]; NIH [K25 HG006031 to M.P.]; US Public Health Service grants [R01CA63113, R01CA173023 to J.A.D., in part]. Funding for page charges: Fritz Thyssen Foundation [through M.F.]. Funding for open access charge: German Research Foundation (DFG) and University of Leipzig within the program of Open Access Publishing. NR 76 TC 5 Z9 5 U1 7 U2 7 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 27 PY 2016 VL 44 IS 13 BP 6070 EP 6086 DI 10.1093/nar/gkw523 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DV5VR UT WOS:000382999300011 PM 27280975 ER PT J AU Vigorito, E Kuchenbaecker, KB Beesley, J Adlard, J Agnarsson, BA Andrulis, IL Arun, BK Barjhoux, L Belotti, M Benitez, J Berger, A Bojesen, A Bonanni, B Brewer, C Caldes, T Caligo, MA Campbell, I Chan, SB Claes, KBM Cohn, DE Cook, J Daly, MB Damiola, F Davidson, R de Pauw, A Delnatte, C Diez, O Domchek, SM Dumont, M Durda, K Dworniczak, B Easton, DF Eccles, D Ardnor, CE Eeles, R Ejlertsen, B Ellis, S Evans, DG Feliubadalo, L Fostira, F Foulkes, WD Friedman, E Frost, D Gaddam, P Ganz, PA Garber, J Garcia-Barberan, V Gauthier-Villars, M Gehrig, A Gerdes, AM Giraud, S Godwin, AK Goldgar, DE Hake, CR Hansen, TVO Healey, S Hodgson, S Hogervorst, FBL Houdayer, C Hulick, PJ Imyanitov, EN Isaacs, C Izatt, L Izquierdo, A Jacobs, L Jakubowska, A Janavicius, R Jaworska-Bieniek, K Jensen, UB John, EM Vijai, J Karlan, BY Kast, K Khan, S Kwong, A Laitman, Y Lester, J Lesueur, F Liljegren, A Lubinski, J Mai, PL Manoukian, S Mazoyer, S Meindl, A Mensenkamp, AR Montagna, M Nathanson, KL Neuhausen, SL Nevanlinna, H Niederacher, D Olah, E Olopade, OI Ong, KR Osorio, A Park, SK Paulsson-Karlsson, Y Pedersen, IS Peissel, B Peterlongo, P Pfeiler, G Phelan, CM Piedmonte, M Poppe, B Pujana, MA Radice, P Rennert, G Rodriguez, GC Rookus, MA Ross, EA Schmutzler, RK Simard, J Singer, CF Slavin, TP Soucy, P Southey, M Steinemann, D Stoppa-Lyonnet, D Sukiennicki, G Sutter, C Szabo, CI Tea, MK Teixeira, MR Teo, SH Terry, MB Thomassen, M Tibiletti, MG Tihomirova, L Tognazzo, S van Rensburg, EJ Varesco, L Varon-Mateeva, R Vratimos, A Weitzel, JN McGuffog, L Kirk, J Toland, AE Hamann, U Lindor, N Ramus, SJ Greene, MH Couch, FJ Offit, K Pharoah, PDP Chenevix-Trench, G Antoniou, AC AF Vigorito, Elena Kuchenbaecker, Karoline B. Beesley, Jonathan Adlard, Julian Agnarsson, Bjarni A. Andrulis, Irene L. Arun, Banu K. Barjhoux, Laure Belotti, Muriel Benitez, Javier Berger, Andreas Bojesen, Anders Bonanni, Bernardo Brewer, Carole Caldes, Trinidad Caligo, Maria A. Campbell, Ian Chan, Salina B. Claes, Kathleen B. M. Cohn, David E. Cook, Jackie Daly, Mary B. Damiola, Francesca Davidson, Rosemarie de Pauw, Antoine Delnatte, Capucine Diez, Orland Domchek, Susan M. Dumont, Martine Durda, Katarzyna Dworniczak, Bernd Easton, Douglas F. Eccles, Diana Ardnor, Christina Edwinsdotter Eeles, Ros Ejlertsen, Bent Ellis, Steve Evans, D. Gareth Feliubadalo, Lidia Fostira, Florentia Foulkes, William D. Friedman, Eitan Frost, Debra Gaddam, Pragna Ganz, Patricia A. Garber, Judy Garcia-Barberan, Vanesa Gauthier-Villars, Marion Gehrig, Andrea Gerdes, Anne-Marie Giraud, Sophie Godwin, Andrew K. Goldgar, David E. Hake, Christopher R. Hansen, Thomas V. O. Healey, Sue Hodgson, Shirley Hogervorst, Frans B. L. Houdayer, Claude Hulick, Peter J. Imyanitov, Evgeny N. Isaacs, Claudine Izatt, Louise Izquierdo, Angel Jacobs, Lauren Jakubowska, Anna Janavicius, Ramunas Jaworska-Bieniek, Katarzyna Jensen, Uffe Birk John, Esther M. Vijai, Joseph Karlan, Beth Y. Kast, Karin Khan, Sofia Kwong, Ava Laitman, Yael Lester, Jenny Lesueur, Fabienne Liljegren, Annelie Lubinski, Jan Mai, Phuong L. Manoukian, Siranoush Mazoyer, Sylvie Meindl, Alfons Mensenkamp, Arjen R. Montagna, Marco Nathanson, Katherine L. Neuhausen, Susan L. Nevanlinna, Heli Niederacher, Dieter Olah, Edith Olopade, Olufunmilayo I. Ong, Kai-ren Osorio, Ana Park, Sue Kyung Paulsson-Karlsson, Ylva Pedersen, Inge Sokilde Peissel, Bernard Peterlongo, Paolo Pfeiler, Georg Phelan, Catherine M. Piedmonte, Marion Poppe, Bruce Angel Pujana, Miquel Radice, Paolo Rennert, Gad Rodriguez, Gustavo C. Rookus, Matti A. Ross, Eric A. Schmutzler, Rita Katharina Simard, Jacques Singer, Christian F. Slavin, Thomas P. Soucy, Penny Southey, Melissa Steinemann, Doris Stoppa-Lyonnet, Dominique Sukiennicki, Grzegorz Sutter, Christian Szabo, Csilla I. Tea, Muy-Kheng Teixeira, Manuel R. Teo, Soo-Hwang Terry, Mary Beth Thomassen, Mads Tibiletti, Maria Grazia Tihomirova, Laima Tognazzo, Silvia van Rensburg, Elizabeth J. Varesco, Liliana Varon-Mateeva, Raymonda Vratimos, Athanassios Weitzel, Jeffrey N. McGuffog, Lesley Kirk, Judy Toland, Amanda Ewart Hamann, Ute Lindor, Noralane Ramus, Susan J. Greene, Mark H. Couch, Fergus J. Offit, Kenneth Pharoah, Paul D. P. Chenevix-Trench, Georgia Antoniou, Antonis C. CA Kconfab Investigators TI Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; BREAST; INVESTIGATORS; CONSORTIUM; PATHOLOGY; CENTLEIN AB Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95% CI: 0.68 to 0.79, p-value 2x 10-16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95% CI: 0.59 to 0.80, p-value 1.0 x 10-6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population. C1 [Vigorito, Elena; Kuchenbaecker, Karoline B.; Easton, Douglas F.; McGuffog, Lesley; Antoniou, Antonis C.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Beesley, Jonathan; Healey, Sue; Chenevix-Trench, Georgia] QIMR Berghofer Med Res Inst, Dept Genet, Herston Rd, Brisbane, Qld 4029, Australia. [Adlard, Julian] Chapel Allerton Hosp, Yorkshire Reg Genet Serv, Leeds, W Yorkshire, England. [Agnarsson, Bjarni A.] Univ Hosp Landspitali, Dept Pathol, IS-101 Reykjavik, Iceland. [Agnarsson, Bjarni A.] Univ Iceland, Sch Med, IS-101 Reykjavik, Iceland. [Andrulis, Irene L.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada. [Arun, Banu K.] Univ Texas MD Anderson Canc Ctr, Dept Breast Med Oncol, 1515 Pressler St,CBP 5, Houston, TX USA. [Arun, Banu K.] Univ Texas MD Anderson Canc Ctr, Clin Canc Genet Program, 1515 Pressler St,CBP 5, Houston, TX USA. [Barjhoux, Laure; Damiola, Francesca; Mazoyer, Sylvie] Ctr Leon Berard, Batiment Cheney D,28 Rue Laennec, Lyon, France. [Belotti, Muriel; de Pauw, Antoine; Gauthier-Villars, Marion; Houdayer, Claude; Stoppa-Lyonnet, Dominique] Inst Curie, Serv Geneit Oncol, 26 Rue Ulm, Paris 05, France. [Benitez, Javier] Spanish Natl Canc Ctr CNIO, Human Genet Grp, Madrid, Spain. [Benitez, Javier] Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Program, Human Genotyping CEGEN Unit, Madrid, Spain. [Berger, Andreas] Med Univ Vienna, Dept OB GYN, Vienna, Austria. [Bojesen, Anders] Vejle Hosp, Dept Clin Genet, Kabbeltoft 25, Vejle, Denmark. [Bonanni, Bernardo] IEO, Div Canc Prevent & Genet, Via Ripamonti 435, I-20141 Milan, Italy. [Brewer, Carole] Royal Devon & Exeter Hosp, Dept Clin Genet, Exeter, Devon, England. [Caldes, Trinidad; Garcia-Barberan, Vanesa] Hosp Clin San Carlos, IdISSC Inst Invest Sanitaria, Mol Oncol Lab, Martin Lagos S-N, Madrid, Spain. [Caligo, Maria A.] Univ Pisa, Dept Lab Med, Sect Genet Oncol, Pisa, Italy. [Caligo, Maria A.] Univ Hosp Pisa, Pisa, Italy. [Campbell, Ian] Peter MacCallum Canc Ctr, Div Res, Locked Bag 1,ABeckett St, Melbourne, Vic 8006, Australia. [Chan, Salina B.] 1600 Div St,C415, San Francisco, CA 94143 USA. [Claes, Kathleen B. M.; Poppe, Bruce] Univ Ghent, Ctr Med Genet, De Pintelaan 185, B-9000 Ghent, Belgium. [Cohn, David E.] Ohio State Univ, Columbus Canc Council GYN Oncol, 3651 Ridge Mill Dr, Columbus, OH 43026 USA. [Cook, Jackie] Sheffield Childrens Hosp, Sheffield Clin Genet Serv, Sheffield, S Yorkshire, England. [Daly, Mary B.] Fox Chase Canc Ctr, Dept Clin Oncol, 333 Cottman Ave, Philadelphia, PA USA. [Davidson, Rosemarie] South Glasgow Univ Hosp, Dept Clin Genet, Glasgow, Lanark, Scotland. [Delnatte, Capucine] ICO Ctr Rene Gauducheau, Unite Oncogenet, Blvd Jacques Monod, F-44805 St Herblain, France. [Diez, Orland] Vall Hebron Univ Hosp, VHIO, Oncogenet Grp, Passeig Vall Hebron 119-129, Barcelona, Spain. [Diez, Orland] Univ Autonoma Barcelona, Passeig Vall Hebron 119-129, Barcelona, Spain. [Domchek, Susan M.; Nathanson, Katherine L.] Univ Penn, Dept Med, Abramson Canc Ctr, Perelman Sch Med, 3400 Civic Ctr Blvd, Philadelphia, PA 19104 USA. [Dumont, Martine; Simard, Jacques; Soucy, Penny] CHU, Quebec Res Ctr, Genom Ctr, 2705 Laurier Blvd, Quebec City, PQ, Canada. [Dumont, Martine; Simard, Jacques; Soucy, Penny] Univ Laval, 2705 Laurier Blvd, Quebec City, PQ, Canada. [Durda, Katarzyna; Jakubowska, Anna; Jaworska-Bieniek, Katarzyna; Lubinski, Jan; Sukiennicki, Grzegorz] Pomeranian Med Univ, Dept Genet & Pathol, Polabska 4, Szczecin, Poland. [Dworniczak, Bernd] Univ Munster, Inst Human Genet, Munster, Germany. [Eccles, Diana] Southampton Univ Hosp NHS Trust, Fac Med, Southampton, Hants, England. [Ardnor, Christina Edwinsdotter] Umea Univ, Dept Radiat Sci, Oncol, Umea, Sweden. [Eeles, Ros] Inst Canc Res, Oncogenet Team, Sutton, Surrey, England. [Eeles, Ros] Royal Marsden NHS Fdn Trust, Sutton, Surrey, England. [Ejlertsen, Bent] Univ Copenhagen Hosp, Dept Oncol, Rigshosp, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. [Ellis, Steve; Frost, Debra] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Strangeways Res Lab, Cambridge, England. [Evans, D. Gareth] Univ Manchester, Cent Manchester Univ Hosp NHS Fdn Trust, Inst Human Dev, Genom Med,Manchester Acad Hlth Sci Ctr, Manchester, Lancs, England. [Feliubadalo, Lidia] Catalan Inst Oncol, Hereditary Canc Program, Mol Diagnost Unit, IDIBELL Bellvitge Biomed Res Inst, Gran Via lHospitalet,199-203, Barcelona 08908, Spain. [Fostira, Florentia; Vratimos, Athanassios] Natl Ctr Sci Res Demokritos, INRASTES Inst Nucl & Radiol Sci & Technol, Mol Diagnost Lab, Patriarchou Gregoriou & Neapoleos Str, Athens, Greece. [Foulkes, William D.] McGill Univ, Dept Human Genet, Program Canc Genet, Montreal, PQ, Canada. [Foulkes, William D.] McGill Univ, Dept Oncol, Montreal, PQ, Canada. [Friedman, Eitan] Chaim Sheba Med Ctr, Inst Human Genet, Susanne Levy Gertner Oncogenet Unit, IL-52621 Ramat Gan, Israel. [Friedman, Eitan] Tel Aviv Univ, Sackler Fac Med, IL-69978 Ramat Aviv, Israel. [Gaddam, Pragna] Mem Sloane Kettering Canc Ctr, Clin Canc Genet Lab, New York, NY USA. [Ganz, Patricia A.] Jonsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, UCLA Sch Med, 650 Charles Young Dr South,Room A2-125 HS, Los Angeles, CA 90095 USA. [Ganz, Patricia A.] Jonsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, UCLA Sch Publ Hlth, 650 Charles Young Dr South,Room A2-125 HS, Los Angeles, CA 90095 USA. [Garber, Judy] Dana Farber Canc Inst, Canc Risk & Prevent Clin, 450 Brookline Ave, Boston, MA 02115 USA. [Gehrig, Andrea] Univ Wurzburg, Inst Human Genet, Dept Med Genet, Ctr Familial Breast & Ovarian Canc, Wurzburg, Germany. [Gerdes, Anne-Marie] Rigshosp 4062, Dept Clin Genet, Blegdamsvej 9, Copenhagen O, Denmark. [Giraud, Sophie] Hospices Civils Lyon, Serv Genet Mol & Clin, Lyon 04, France. [Godwin, Andrew K.] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, 3901 Rainbow Blvd,4019 Wahl Hall East,MS 3040, Kansas City, KS USA. [Goldgar, David E.] Univ Utah, Sch Med, Dept Dermatol, 30 North 1900 East,SOM 4B454, Salt Lake City, UT 84132 USA. [Hake, Christopher R.] City Hope Natl Med Ctr, Clin Canc Genet Community Res Network, 1500 East Duarte Rd, Duarte, CA 91010 USA. [Hansen, Thomas V. O.] Univ Copenhagen Hosp, Ctr Genom Med, Rigshosp, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. [Hodgson, Shirley] St Georges Univ London, Med Genet Unit, London, England. [Hogervorst, Frans B. L.] Netherlands Canc Inst, Family Canc Clin, POB 90203, NL-1000 BE Amsterdam, Netherlands. [Hulick, Peter J.] Univ Chicago, Pritzker Sch Med, Ctr Med Genet, NorthShore Univ Hlth Syst, 1000 Cent St,Suite 620, Evanston, IL 60201 USA. [Imyanitov, Evgeny N.] NN Petrov Inst Oncol, St Petersburg 197758, Russia. [Isaacs, Claudine] Georgetown Univ, Lombardi Comprehens Canc Ctr, 3800 Reservoir Rd NW, Washington, DC USA. [Izatt, Louise] Guys & St Thomas NHS Fdn Trust, Clin Genet, London, England. [Izquierdo, Angel] Catalan Inst Oncol, Genet Counseling Unit, Hereditary Canc Program, IDIBGI Inst Invest Biomed Girona, Av Franca S-N, Girona 1707, Spain. [Jacobs, Lauren; Vijai, Joseph] Mem Sloan Kettering Canc Ctr, Dept Med, Clin Genet Res Lab, 1275 York Ave, New York, NY 10044 USA. [Janavicius, Ramunas] Vilnius Univ Hosp Santariskiu Clin, Hematol Oncol & Transfus Med Ctr, Dept Mol & Regenerat Med, State Res Inst Ctr Innovat Med, Santariskiu St,Zygymantu St 9, Vilnius, Lithuania. [Jensen, Uffe Birk] Aarhus Univ Hosp, Dept Clin Genet, Brendstrupgaardsvej 21C, Aarhus N, Denmark. [John, Esther M.] Canc Prevent Inst Calif, Dept Epidemiol, 2201 Walnut Ave,Suite 300, Fremont, CA 94538 USA. [Karlan, Beth Y.; Lester, Jenny] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, 8700 Beverly Blvd,Suite 290W, Los Angeles, CA 90048 USA. [Kast, Karin] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Dept Obstet & Gynaecol, Dresden, Germany. [Kconfab Investigators] Peter MacCallum Canc Inst, Kathleen Cuningham Consortium Res Familial Breast, Melbourne, Australia. [Khan, Sofia; Nevanlinna, Heli] Univ Helsinki, Dept Obstet & Gynecol, POB 700,Haartmaninkatu 8, Helsinki 00029, Finland. [Khan, Sofia; Nevanlinna, Heli] Helsinki Univ Hosp, Biomed Helsinki, POB 700,Haartmaninkatu 8, Helsinki 00029, Finland. [Kwong, Ava] Hong Kong Sanat & Hosp, Canc Genet Ctr, Hong Kong Hereditary Breast Canc Family Registry, Hong Kong, Hong Kong, Peoples R China. [Laitman, Yael] Chaim Sheba Med Ctr, Inst Human Genet, Susanne Levy Gertner Oncogenet Unit, IL-52621 Tel Hashomer, Israel. Inst Curie, Inserm U900, Genet Epidemiol Canc team, Mines ParisTech,26 Rue Ulm, F-75248 Paris 05, France. [Liljegren, Annelie] Karolinska Univ Hosp, Dept Oncol, Stockholm, Sweden. [Mai, Phuong L.; Greene, Mark H.] NCI, DCEG, Clin Genet Branch, NIH, 9609 Med Ctr Dr,Room 6E-454, Bethesda, MD 20892 USA. [Manoukian, Siranoush; Peissel, Bernard] Ist Nazl Tumori, Fdn IRCCS Ist Ricovero Cura & Caratter Sci, Dept Prevent & Predict Med, Unit Med Genet, Via Giacomo Venezian 1, I-20133 Milan, Italy. [Meindl, Alfons] Tech Univ Munich, Klinikum Rechts Isar, Div Tumor Genet, Dept Obstet & Gynaecol, Munich, Germany. [Mensenkamp, Arjen R.] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, POB 9101, NL-6500 HB Nijmegen, Netherlands. [Montagna, Marco; Tognazzo, Silvia] Veneto Inst Oncol IOV IRCCS, Immunol & Mol Oncol Unit, Via Gattamelata 64, Padua, Italy. [Neuhausen, Susan L.] City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Duarte, CA USA. [Niederacher, Dieter] Univ Dusseldorf, Univ Hosp Dusseldorf, Dept Obstet & Gynaecol, Dusseldorf, Germany. [Olah, Edith] Natl Inst Oncol, Dept Mol Genet, Budapest, Hungary. [Olopade, Olufunmilayo I.] Univ Chicago Med, 5841 South Maryland Ave,MC 2115, Chicago, IL 60637 USA. [Ong, Kai-ren] Birmingham Womens Hosp Healthcare NHS Trust, West Midlands Reg Genet Serv, Birmingham, W Midlands, England. [Osorio, Ana] Spanish Natl Canc Ctr CNIO, Human Genet Grp, Madrid, Spain. [Park, Sue Kyung] Seoul Natl Univ, Grad Sch, Dept Biomed Sci, Dept Prevent Med,Coll Med, 103 Daehak Ro, Seoul 110799, South Korea. [Park, Sue Kyung] Seoul Natl Univ, Canc Res Inst, 103 Daehak Ro, Seoul 110799, South Korea. [Paulsson-Karlsson, Ylva] Uppsala Univ, Dept Immunol Genet & Pathol, SE-75185 Uppsala, Sweden. [Pedersen, Inge Sokilde] Aalborg Univ Hosp, Sect Mol Diagnost, Dept Biochem, Reberbansgade 15, Aalborg, Denmark. [Peterlongo, Paolo] Inst Mol Oncol, IFOM, FIRC Italian Fdn Canc Res, IFOM-IEO Campus,Via Adamello 16, I-20139 Milan, Italy. [Pfeiler, Georg] Med Univ Vienna, Wahringer Gurtel 18-20, A-1090 Vienna, Austria. [Phelan, Catherine M.] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL USA. [Piedmonte, Marion] Roswell Pk Canc Inst, NRG Oncol, Stat & Data Management Ctr, Elm St & Carlton St, Buffalo, NY 14263 USA. [Angel Pujana, Miquel] Catalan Inst Oncol, IDIBELL Bellvitge Biomed Res Inst, Translat Res Lab, Barcelona, Spain. [Radice, Paolo] Ist Nazl Tumori, Unit Mol Bases Genet Risk & Genet Testing, Dept Prevent & Predicted Med, Fdn IRCCS Ist Ricovero Cura Caratter Sci, Amaedeolab,Via GA Amadeo 42, I-20133 Milan, Italy. [Rennert, Gad] Clalit Natl Israeli Canc Control Ctr, 7 Michal St, IL-34362 Haifa, Israel. [Rennert, Gad] Carmel Hosp, Dept Community Med & Epidemiol, 7 Michal St, IL-34362 Haifa, Israel. [Rennert, Gad] B Rappaport Fac Med, 7 Michal St, IL-34362 Haifa, Israel. [Rodriguez, Gustavo C.] Univ Chicago, NorthShore Univ HealthSyst, Div Gynecol Oncol, 2650 Ridge Ave Suite 1507 Walgreens, Evanston, IL 60201 USA. [Rookus, Matti A.] Netherlands Canc Inst, Dept Epidemiol, POB 90203, NL-1000 BE Amsterdam, Netherlands. [Ross, Eric A.] Fox Chase Canc Ctr, Biostat & Bioinformat Facil, 333 Coltman Ave, Philadelphia, PA 19111 USA. [Schmutzler, Rita Katharina] Univ Hosp Cologne, Fac Med, Ctr Hereditary Breast & Ovarian Canc, Cologne, Germany. [Singer, Christian F.; Tea, Muy-Kheng] Med Univ Vienna, Dept OB GYN, A-1090 Vienna, Austria. [Singer, Christian F.; Tea, Muy-Kheng] Waehringer Guertel 18-20, A-1090 Vienna, Austria. [Slavin, Thomas P.; Weitzel, Jeffrey N.] City Hope Natl Med Ctr, Clin Canc Genet, 1500 East Duarte Rd, Duarte, CA 91010 USA. [Southey, Melissa] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Parkville, Vic, Australia. [Steinemann, Doris] Hannover Med Sch, Inst Cell & Mol Pathol, Hannover, Germany. [Sutter, Christian] Univ Heidelberg Hosp, Dept Human Genet, Inst Human Genet, Heidelberg, Germany. [Szabo, Csilla I.] NHGRI, NIH, Bldg 50,Room 5312,50 South Dr,MSC 004, Bethesda, MD 20892 USA. [Teixeira, Manuel R.] Portuguese Oncol Inst, Dept Genet, Rua Dr Antonio Bernardino de Almeida, P-4200072 Oporto, Portugal. [Teo, Soo-Hwang] Sime Darby Med Ctr, Canc Res Initiat Fdn, 1 Jalan SS12-1A, Subang Jaya 47500, Malaysia. [Terry, Mary Beth] Columbia Univ, Dept Epidemiol, New York, NY USA. [Thomassen, Mads] Odense Univ Hosp, Dept Clin Genet, Sonder Blvd 29, Odense C, Denmark. [Tibiletti, Maria Grazia] Osped Circolo Univ Insubria, UO Anat Patol, Via O Rossi 9, I-21100 Varese, Italy. [Tihomirova, Laima] Latvian Biomed Res & Study Ctr, Ratsupites Str 1, Riga, Latvia. [van Rensburg, Elizabeth J.] Univ Pretoria, Dept Genet, Canc Genet Lab, Private Bag X323, ZA-0007 Arcadia, South Africa. [Varesco, Liliana] AOU San Martino IST Ist Nazl Ric Cancro, IRCCS, Dept Epidemiol Prevent & Special Funct, Unit Hereditary Canc, Largo Rosanna Benzi 10, I-16132 Genoa, Italy. [Varon-Mateeva, Raymonda] Charite, Inst Human Genet, Campus Virchov Klinikum, Berlin, Germany. [Kirk, Judy] Westmead Hosp, Familial Canc Serv, Hawkesbury Rd,POB 533, Wentworthville, NSW 2145, Australia. [Toland, Amanda Ewart] Ohio State Univ, Dept Internal Med, Div Human Canc Genet, 998 Biomed Res Tower, Columbus, OH 43210 USA. [Toland, Amanda Ewart] Ohio State Univ, Ctr Comprehens Canc, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA. [Hamann, Ute] German Canc Res Ctr, Mol Genet Breast Canc, Neuenheimer Feld 580, D-69120 Heidelberg, Germany. [Lindor, Noralane] Mayo Clin, Dept Hlth Sci Res, 13400 E Scottsdale Blvd, Scottsdale, AZ USA. [Ramus, Susan J.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol, 200 First St SW, Rochester, MN USA. [Couch, Fergus J.] Mayo Clin, Hlth Sci Res, 200 First St SW, Rochester, MN USA. [Offit, Kenneth] Mem Sloan Kettering Canc Ctr, Clin Genet Res Lab, Dept Med Canc Biol & Genet, 1275 York Ave, New York, NY 10044 USA. [Pharoah, Paul D. P.] Univ Cambridge, Dept Oncol, Cambridge, England. RP Antoniou, AC (reprint author), Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. EM antonis@srl.cam.ac.uk RI Osorio, Ana/I-4324-2014; Teo, Soo-hwang/H-2353-2014; Jansen van Rensburg, Elizabeth (Lizette)/B-9104-2011; Peissel, Bernard/E-8187-2017; montagna, marco/E-2225-2012; OI Osorio, Ana/0000-0001-8124-3984; Peissel, Bernard/0000-0001-9233-3571; montagna, marco/0000-0002-4929-2150; Khan, Sofia/0000-0003-4185-8882; Evans, Gareth/0000-0002-8482-5784 FU Cancer Research - UK [C12292/A11174, C1287/A10118]; MRC Advanced Studentship award; NHMRC; National Breast Cancer Foundation; Cancer Australia; National Institute of Health (USA) FX The CIMBA data management and data analysis were supported by Cancer Research - UK grants C12292/A11174 and C1287/A10118. EV was supported by an MRC Advanced Studentship award. Details of the funding of individual studies participating in CIMBA are included in S1 Text of the manuscript.; BCFR-AU acknowledges Maggie Angelakos, Judi Maskiell, Gillian Dite, Helen Tsimiklis. BCFR-NY wishes to thank members and participants in the New York site of the Breast Cancer Family Registry for their contributions to the study. BCFR-ON wishes to thank members and participants in the Ontario Familial Breast Cancer Registry for their contributions to the study. BFBOCC-LT acknowledges Vilius Rudaitis, Laimonas Grigkeviequs. BMBSA We wish to thank the families who contribute to the BMBSA study. BRICOH wishes to thank Yuan Chun Ding and Linda Steele for their work in participant enrollment and biospecimen and data management. CBCS thanks Bent Ejlertsen for the recruitment and genetic counseling of participants. CNIO thanks Alicia Barroso, Rosario Alonso and Guillermo Pita for their assistance. CONSIT TEAM acknowledges Daniela Zaffaroni of the Fondazione IRCCS Istituto Nazionale deti Tumori, Milano, Italy: Monica Barile and Irene Feroce of the Istituto Europeo di Oncologia, Milano, Italy; Alessandra Viel and Riccardo Dolcetti of the CRO Aviano National Cancer Institute, Aviano (PN), Italy; Laura Papi and Gabriele Capone of the University of Florence, Florence, Italy; Laura Ottini and Giuseppe Giannini of the "Sapienza" University, Rome, Italy; Antonella Savarese and Alyne Martayan of the Istituto Nazionale Tumori Regina Elena, Rome, Italy; Stefania Tommasi of the Istituto Nazionale Tumori "Giovanni Paolo II" Bari, Italy. GCHBOC thanks Ms. JoEllen Weaver and Dr. Betsy Bove for their technical support. GEMO wishes to pay a tribute to Olga M. Sinilnikova, who with Dominique Stoppa-Lyonnet initiated and coordinated GEMO until she sadly passed away on the 30th June 2014, and to thank all the GEMO collaborating groups for their contribution to this study. GEMO Collaborating Centers are: Coordinating Centres, Unite Mixte de Genetique Constitutionnelle des Cancers Frequents, Hospices Civils de Lyon Centre Leon Berard, & Equipe Genetique du cancer du sein, Centre de Recherche en Cancerologie de Lyon: Olga Sinilnikovat, Sylvie Mazoyer, Francesca Damiola, Laure Barjhoux, Carole Verny-Pierre, Melanie Leone, Nadia Boutry-Kryza, Alain Calender, Sophie Giraud; and Service de Genetique Oncologique, Institut Curie, Paris: Dominique Stoppa-Lyonnet, Marion Gauthier-Villars, Bruno Buecher, Claude Houdayer, Etienne Rouleau, Lisa Golmard, Agnes Collet, Virginie Moncoutier, Muriel Belotti, Antoine de Pauw, Camille Elan, Catherine Nogues, Emmanuelle Fourme, Anne -Marie Birot. Institut Gustave Roussy, Villejuif: Brigitte Bressac-de-Paillerets, Olivier Caron, Marine Guillaud-Bataille. Centre Jean Perrin, Clermont-Ferrand: Yves -Jean Bignon, Nancy Uhrhammer. Centre Leon Berard, Lyon: Christine Lasset, Valerie Bonadona, Sandrine Handallou. Centre Francois Baclesse, Caen: Agnes Hardouin, Pascaline Berthet, Dominique Vaur, Laurent Castera. Institut Paoli Calmettes, Marseille: Hagay Sobol, Violaine Bourdon, Tetsuro Noguchi, Audrey Remenieras, Francois Eisinger. CHU Arnaud -de -Villeneuve, Montpellier: Isabelle Coupier, Pascal Pujol. Centre Oscar Lambret, Lille: Jean -Philippe Peyrat, Joelle Fournier, Francoise Revillion, Philippe Vennint, Claude Adenis. Centre Paul Strauss, Strasbourg: Daniele Muller, Jean-Pierre Fricker. Institut Bergonie, Bordeaux: Emmanuelle Barouk-Simonet, Francoise Bonnet, Virginie Bubien, Nicolas Sevenet, Michel Longy. Institut Claudius Regaud, Toulouse: Christine Toulas, Rosine Guimbaud, Laurence Gladieff, Viviane Feillel. CHU Grenoble: Dominique Leroux, Helene Dreyfus, Christine Rebischung, Magalie Peysselon.; CHU Dijon: Fanny Coron, Laurence Faivre. CHU St -Etienne: Fabienne Prieur, Marine Lebrun, Caroline Kientz. Hotel Dieu Centre Hospitalier, Chambery: Sandra Fert Ferrer. Centre Antoine Lacassagne, Nice: Marc Frenay. CHU Limoges: Laurence Venat-Bouvet. CHU Nantes: Capucine Delnatte. CHU Bretonneau, Tours: Isabelle Mortemousque. Groupe Hospitalier Pitie-Salpetriere, Paris: Florence Coulet, Chrystelle Colas, Florent Soubrier, Mathilde Warcoin. CHU Vandoeuvre-les-Nancy: Johanna Sokolowska, Myriam Bronner. CHU Besancon: Marie -Agnes Collonge-Rame, Alexandre Damette. Creighton University, Omaha, USA: Henry T. Lynch, Carrie L. Snyder. HCSC acknowledges Alicia Tosar and Paula Diaque for their technical assistance. HEBCS would like to thank Dr. Kristiina Aittomaki, Taru A. Muranen, Drs. Carl Blomqvist and Kirsimari Aaltonen and RNs Irja Erkkila and Virpi Palola for their help with the HEBCS data and samples. HEBON thanks the registration teams of the Comprehensive Cancer Centre Netherlands and Comprehensive Centre South (together the Netherlands Cancer Registry) and PALGA (Dutch Pathology Registry) for part of the data collection. The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) consists of the following Collaborating Centers: Coordinating center: Netherlands Cancer Institute, Amsterdam, NL: M.A. Rookus, F.B.L. Hogervorst, F.E. van Leeuwen, S. Verhoef, M.K. Schmidt, N.S. Russell, J.L. de Lange, R. Wijnands; Erasmus Medical Center, Rotterdam, NL: J.M. Collee, A.M.W. van den Ouweland, M.J. Hooning, C. Seynaeve, C.H.M. van Deurzen, I.M. Obdeijn; Leiden University Medical Center, NL: C. J. van Asperen, J.T. Wijnen, R.A.E.M. Tollenaar, P. Devilee, T.C.T.E.F. van Cronenburg; Radboud University Nijmegen Medical Center, NL: C.M. Kets, A.R. Mensenkamp; University Medical Center Utrecht, NL: M.G.E.M. Ausems, R.B. van der Luijt, C.C. van der Pol; Amsterdam Medical Center, NL: C.M. Aalfs, T.A.M. van Os; VU University Medical Center, Amsterdam, NL: J.J.P. Gille, Q. Waisfisz, H.E.J. Meijers-Heijboer; University Hospital Maastricht, NL: E.B. Gomez -Garcia, M.J. Blok; University Medical Center Groningen, NL: J.C. Oosterwijk, A. H. van der Hout, M.J. Mourits, G.H. de Bock; The Netherlands Foundation for the detection of hereditary tumours, Leiden, NL: H.F. Vasen; The Netherlands Comprehensive Cancer Organization (IKNL): S. Siesling, J.Verloop; The Dutch Pathology Registry (PALGA): L.I.H. Overbeek. HEBON thanks the registration teams of IKNL and PALGA for part of the data collection. HRBCP wishes to thank Hong Kong Sanatorium and Hospital for their continued support. HUNBOCS wishes to thank the Hungarian Breast and Ovarian Cancer Study Group members (Janos Papp, Tibor Vaszko, Aniko Bozsik, Timea Pocza, Judit Franko, Maria Balogh, Gabriella Domokos, Judit Ferenczi, Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary) and the clinicians and patients for their contributions to this study. ICO wishes to thank the ICO Hereditary Cancer Program team led by Dr. Gabriel Capella. INHERIT would like to thank Dr Martine Dumont, Martine Tranchant for sample management and skilful technical assistance. J.S. is Chairholder of the Canada Research Chair in Oncogenetics. J.S. and P.S. were part of the QC and Genotyping coordinating group of iCOGS (BCAC and CIMBA). IPOBCS wishes to thank Drs. Ana Peixoto, Catarina Santos, Patricia Rocha and Pedro Pinto for their skilful contribution to the study.; KCONFAB wishes to thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study (which has received funding from the NHMRC, the National Breast Cancer Foundation, Cancer Australia, and the National Institute of Health (USA)) for their contributions to this resource, and the many families who contribute to kConFab. MCGILL Jewish General Hospital Weekend to End Breast Cancer, Quebec Ministry of Economic Development, Innovation and Export Trade. MODSQUAD acknowledges ModSQuaD members Csilla Szabo (National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA); Lenka Foretova and Eva Machackova (Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute and MF MU, Brno, Czech Republic); and Michal Zikan, Petr Pohlreich and Zdenek Kleibl (Oncogynecologic Center and Department of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic). NICCC wishes to thank the NICCC National Familial Cancer Consultation Service team led by Sara Dishon, the lab team led by Dr. Flavio Lejbkowicz, and the research field operations team led by Dr. Mila Pinchev. OCGN We wish to thank members and participants in the Ontario Cancer Genetics Network for their contributions to the study. OSU CCG Leigha Senter, Kevin Sweet, Caroline Craven, and Michelle O'Conor were instrumental in accrual of study participants, ascertainment of medical records and database management. Samples were processed by the OSU Human Genetics Sample Bank. SEABASS would like to thank Yip Cheng Har, Nur Aishah Mohd Taib, Phuah Sze Yee, Norhashimah Hassan and all the research nurses, research assistants and doctors involved in the MyBrCa Study for assistance in patient recruitment, data collection and sample preparation. In addition, we thank Philip Iau, Sng Jen-Hwei and Sharifah Nor Akmal for contributing samples from the Singapore Breast Cancer Study and the HUKM-HKL Study respectively. SMC team wishes to acknowledge the assistance of the Meirav Comprehensive breast cancer center team at the Sheba Medical Center for assistance in this study. SWE-BRCA Swedish scientists participating as SWE-BRCA collaborators are: from Lund University and University Hospital: Ake Borg, Hakan Olsson, Helena Jernstrom, Karin Henriksson, Katja Harbst, Maria Soller, Ulf Kristoffersson; from Gothenburg Sahlgrenska University Hospital: Anna Ofverholm, Margareta Nordling, Per Karlsson, Zakaria Einbeigi; from Stockholm and Karolinska University Hospital: Anna von Wachenfeldt, Annelie Liljegren, Annika Lindblom, Brita Arver, Gisela Barbany Bustinza, Johanna Rantala; from Ume5. University Hospital: Beatrice Melin, Christina Edwinsdotter Ardnor, Monica Emanuelsson; from Uppsala University: Hans Ehrencrona, Maritta Hellstrom Pigg, Richard Rosenquist; from Linkoping University Hospital: Marie Stenmark-Askmalm, Sigrun Liedgren. UCHICAGO wishes to thank Cecilia Zvocec, Qun Niu, physicians, genetic counselors, research nurses and staff of the Cancer Risk Clinic for their contributions to this resource, and the many families who contribute to our program. UCLA thanks Joyce Seldon MSGC and Lorna Kwan, MPH for assembling the data for this study. UCSF would like to thank Dr Robert Nussbaum and the following genetic counsellors for participant recruitment: Beth Crawford, Kate Loranger, Julie Mak, Nicola Stewart, Robin Lee, Amie Blanco and Peggy Conrad. And thanks to Ms. Salina Chan for her data management.; UKFOCR thanks Simon Gayther, Carole Pye, Patricia Harrington and Eva Wozniak for their contributions towards the UKFOCR. UPENN Breast Cancer Research Foundation; Susan G. Komen Foundation for the cure, Basser Research Center for BRCA. VFCTG acknowledges Geoffrey Lindeman, Marion Harris, Martin Delatycki of the Victorian Familial Cancer Trials Group. We thank Sarah Sawyer and Rebecca Driessen for assembling this data and Ella Thompson for performing all DNA amplification NR 21 TC 0 Z9 0 U1 11 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 27 PY 2016 VL 11 IS 7 AR e0158801 DI 10.1371/journal.pone.0158801 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT5IJ UT WOS:000381515900021 PM 27463617 ER PT J AU Marcum, ZA Bellon, JE Li, J Gellad, WF Donohue, JM AF Marcum, Zachary A. Bellon, Johanna E. Li, Jie Gellad, Walid F. Donohue, Julie M. TI New chronic disease medication prescribing by nurse practitioners, physician assistants, and primary care physicians: a cohort study SO BMC HEALTH SERVICES RESEARCH LA English DT Article DE Health services research; Pharmacoepidemiology; Primary care; Work force ID ATRIAL-FIBRILLATION; RISK-FACTORS; DABIGATRAN; INHIBITORS; MANAGEMENT; KNOWLEDGE; MORTALITY; WARFARIN; TRENDS; DRUGS AB Background: Medications to treat and prevent chronic disease have substantially reduced morbidity and mortality; however, their diffusion has been uneven. Little is known about prescribing of chronic disease medications by nurse practitioners (NPs) and physician assistants (PAs), despite their increasingly important role as primary care providers. Thus, we sought to conduct an exploratory analysis to examine prescribing of new chronic disease medications by NPs and PAs compared to primary care physicians (PCPs). Methods: We obtained prescribing data from IMS Health's Xponent (TM) on all NPs, PAs, and PCPs in Pennsylvania regularly prescribing anticoagulants, antihypertensives, oral hypoglycemics, and/or HMG-Co-A reductase inhibitors pre- and post-introduction of five new drugs in these classes that varied in novelty (i.e., dabigatran, aliskiren, sitagliptin or saxagliptin, and pitavastatin). We constructed three measures of prescriber adoption during the 15-month post-FDA approval period: 1) any prescription of the medication, 2) proportion of prescriptions in the class for the medication, and 3) time to adoption (first prescription) of the medication. Results: From 2007 to 2011, the proportion of antihypertensive prescriptions prescribed by NPs and PAs approximately doubled from 2.0 to 4.2 % and 2.2 to 4.9 %, respectively. Similar trends were found for anticoagulants, oral hypoglycemics, and HMG-Co-A reductase inhibitors. By 2011, more PCPs had prescribed each of the newly approved medications than NPs and PAs (e.g., 44.3 % vs. 18.5 % vs. 20 % for dabigatran among PCPs, NPs, and PAs). Across all medication classes, the newly approved drugs accounted for a larger share of prescriptions in the class for PCPs followed by PAs, followed by NPs (e.g., dabigatran: 4.9 % vs. 3.2 % vs. 2.8 %, respectively). Mean time-to-adoption for the newly approved medications was shorter for PCPs compared to NPs and PAs (e.g., dabigatran, 7.3 vs. 8.2 vs. 8.5 months; P all medications < 0.001). Conclusions: PCPs were more likely to prescribe each of the newly approved medications per each measure of drug adoption, regardless of drug novelty. Differences in the rate and speed of drug adoption between PCPs, NPs, and PAs may have important implications for care and overall costs at the population level as NPs and PAs continue taking on a larger role in prescribing. C1 [Marcum, Zachary A.] Univ Washington, Sch Pharm, Dept Pharm, 1959 NE Pacific St,Box 357630, Seattle, WA 98102 USA. [Bellon, Johanna E.] UPMC, Wolff Ctr, Ross Bldg,Room 219,4601 Baum Blvd, Pittsburgh, PA 15213 USA. [Li, Jie; Donohue, Julie M.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Hlth Policy & Management, 130 De Soto St, Pittsburgh, PA 15261 USA. [Gellad, Walid F.] Univ Pittsburgh, Sch Med, VA Pittsburgh Healthcare Syst, 200 Meyran Ave,Parkvale Bldg, Pittsburgh, PA 15213 USA. [Gellad, Walid F.] Univ Pittsburgh, Sch Med, Dept Gen Internal Med, 200 Meyran Ave,Parkvale Bldg, Pittsburgh, PA 15213 USA. RP Marcum, ZA (reprint author), Univ Washington, Sch Pharm, Dept Pharm, 1959 NE Pacific St,Box 357630, Seattle, WA 98102 USA. EM zmarcum@uw.edu FU NHLBI [R01HL119246]; VA HSR&D Career Development Award [CDA 09-207]; RAND-University of Pittsburgh Health Institute (RUPHI); National Center for Research Resources (NCRR), a component of the National Institutes of Health [UL1 RR024153] FX This work was supported by R01HL119246 from NHLBI (Drs. Donohue and Gellad). Dr. Gellad was also supported by a VA HSR&D Career Development Award (CDA 09-207). Drs. Donohue and Gellad were partially supported by a pilot grant from the RAND-University of Pittsburgh Health Institute (RUPHI) and Grant Number UL1 RR024153 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health. NR 28 TC 0 Z9 0 U1 9 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6963 J9 BMC HEALTH SERV RES JI BMC Health Serv. Res. PD JUL 27 PY 2016 VL 16 AR 312 DI 10.1186/s12913-016-1569-1 PG 8 WC Health Care Sciences & Services SC Health Care Sciences & Services GA DS2WY UT WOS:000380645800005 PM 27464570 ER PT J AU Wang, P Farmer, ME Huo, X Jain, P Shen, PX Ishoey, M Bradner, JE Wisniewski, SR Eastgate, MD Yu, JQ AF Wang, Peng Farmer, Marcus E. Huo, Xing Jain, Pankaj Shen, Peng-Xiang Ishoey, Mette Bradner, James E. Wisniewski, Steven R. Eastgate, Martin D. Yu, Jin-Quan TI Ligand-Promoted Meta-C-H Arylation of Anilines, Phenols, and Heterocycles SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID AMINO-ACID LIGANDS; BOND ACTIVATION; DIRECTING GROUP; FUNCTIONALIZATION; PALLADIUM; NORBORNENE; TEMPLATE; ARENES; OLEFINATION; ALKYLATION AB Here we report the development of a versatile 3-acetylamino-2-hydroxypyridine class of ligands that promote meta-C-H arylation of anilines, heterocyclic aromatic amines, phenols, and 2-benzyl heterocycles using norbornene as a transient mediator. More than 120 examples are presented, demonstrating this ligand scaffold enables a wide substrate and coupling partner scope. Meta-C-H arylation with heterocyclic aryl iodides as coupling partners is also realized for the first time using this ligand. The utility for this transformation for drug discovery is showcased by allowing the meta-C-H arylation of a lenalidomide derivative. The first steps toward a silver-free protocol for this reaction are also demonstrated. C1 [Wang, Peng; Farmer, Marcus E.; Huo, Xing; Jain, Pankaj; Shen, Peng-Xiang; Yu, Jin-Quan] Scripps Res Inst, Dept Chem, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA. [Ishoey, Mette; Bradner, James E.] Dana Farber Canc Inst, Dept Med Oncol, 360 Longwood Ave, Boston, MA 02115 USA. [Wisniewski, Steven R.; Eastgate, Martin D.] Bristol Myers Squibb, Chem Dev, 1 Squibb Dr, New Brunswick, NJ 08903 USA. RP Yu, JQ (reprint author), Scripps Res Inst, Dept Chem, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA. EM Yu200@scripps.edu RI Wang, Peng/F-3646-2015; OI Wang, Peng/0000-0002-6442-3008; Shen, Peng-Xiang/0000-0002-6941-4741 FU Scripps Research Institute; NIH (NIGMS) [1R01 GM102265] FX We gratefully acknowledge The Scripps Research Institute and the NIH (NIGMS, 1R01 GM102265) for financial support. NR 44 TC 11 Z9 11 U1 37 U2 49 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD JUL 27 PY 2016 VL 138 IS 29 BP 9269 EP 9276 DI 10.1021/jacs.6b04966 PG 8 WC Chemistry, Multidisciplinary SC Chemistry GA DS4CW UT WOS:000380730000047 PM 27384126 ER PT J AU Zhang, Q Dong, TT Li, PY Wu, MX AF Zhang, Qi Dong, Tingting Li, Peiyu Wu, Mei X. TI Noninvasive low-level laser therapy for thrombocytopenia SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID CHEMOTHERAPY-INDUCED THROMBOCYTOPENIA; PLATELET PRODUCTION; BONE-MARROW; MEGAKARYOCYTES; THROMBOPOIESIS; CELLS; DIFFERENTIATION; MECHANISMS; APOPTOSIS; FAILURE AB Thrombocytopenia is a common hematologic disorder that is managed primarily by platelet transfusions. We report here that noninvasive whole-body illumination with a special near-infrared laser cures acute thrombocytopenia triggered by gamma-irradiation within 2 weeks in mice, as opposed to a 5-week recovery time required in controls. The low-level laser (LLL) also greatly accelerated platelet regeneration in the presence of anti-CD41 antibody that binds and depletes platelets, and prevented a severe drop in platelet count caused by a common chemotherapeutic drug. Mechanistically, LLL stimulated mitochondrial biogenesis specifically in megakaryocytes owing to polyploidy of the cells. LLL also protected megakaryocytes from mitochondrial injury and apoptosis under stress. The multifaceted effects of LLL on mitochondria bolstered megakaryocyte maturation; facilitated elongation, branching, and formation of proplatelets; and doubled the number of platelets generated from individual megakaryocytes in mice. LLL-mediated platelet biogenesis depended on megakaryopoiesis and was inversely correlated with platelet counts, which kept platelet biogenesis in check and effectively averted thrombosis even after repeated uses, in sharp contrast to all current agents that stimulate the differentiation of megakaryocyte progenitors from hematopoietic stem cells independently of platelet counts. This safe, drug-free, donor-independent modality represents a paradigm shift in the prophylaxis and treatment of thrombocytopenia. C1 [Zhang, Qi; Dong, Tingting; Li, Peiyu; Wu, Mei X.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Zhang, Qi; Dong, Tingting; Li, Peiyu; Wu, Mei X.] Harvard Med Sch, Dept Dermatol, Boston, MA 02114 USA. [Wu, Mei X.] Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02115 USA. RP Wu, MX (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA.; Wu, MX (reprint author), Harvard Med Sch, Dept Dermatol, Boston, MA 02114 USA.; Wu, MX (reprint author), Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02115 USA. EM mwu5@mgh.harvard.edu FU Department of Defense/Air Force Office of Scientific Research Military Photomedicine Program [FA9550-13-1-0068]; Bullock-Wellman postdoctoral fellowship FX This study was supported in part by FA9550-13-1-0068, Department of Defense/Air Force Office of Scientific Research Military Photomedicine Program, department funds (to M.X.W.), and a Bullock-Wellman postdoctoral fellowship (to Q.Z.). NR 38 TC 1 Z9 1 U1 3 U2 3 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD JUL 27 PY 2016 VL 8 IS 349 AR 349ra101 DI 10.1126/scitranslmed.aaf4964 PG 12 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA DS4VO UT WOS:000380779900005 PM 27464749 ER PT J AU Wu, XH Liu, W Duan, ZF Gao, Y Li, S Wang, K Song, Y Shao, ZW Yang, SH Yang, C AF Wu, Xinghuo Liu, Wei Duan, Zhenfeng Gao, Yong Li, Shuai Wang, Kun Song, Yu Shao, Zengwu Yang, Shuhua Yang, Cao TI The Involvement of Protease Nexin-1 (PN1) in the Pathogenesis of Intervertebral Disc (IVD) Degeneration SO Scientific Reports LA English DT Article ID MATRIX METALLOPROTEINASES; EXTRACELLULAR-MATRIX; PLASMINOGEN-ACTIVATOR; INCREASED EXPRESSION; ASPARTIC-ACID; TNF-ALPHA; CELLS; THROMBIN; TISSUE; OSTEOARTHRITIS AB Protease nexin-1 (PN-1) is a serine protease inhibitor belonging to the serpin superfamily. This study was undertaken to investigate the regulatory role of PN-1 in the pathogenesis of intervertebral disk (IVD) degeneration. Expression of PN-1 was detected in human IVD tissue of varying grades. Expression of both PN-1 mRNA and protein was significantly decreased in degenerated IVD, and the expression levels of PN-1 were correlated with the grade of disc degeneration. Moreover, a decrease in PN-1 expression in primary NP cells was confirmed. On induction by IL-1 beta, the expression of PN-1 in NP cells was decreased at day 7, 14, and 21, as shown by western blot analysis and immunofluorescence staining. PN-1 administration decreased IL-1 beta-induced MMPs and ADAMTS production and the loss of Agg and Col II in NP cell cultures through the ERK1/2/NF-kB signaling pathway. The changes in PN-1 expression are involved in the pathogenesis of IVD degeneration. Our findings indicate that PN-1 administration could antagonize IL-1 beta-induced MMPs and ADAMTS, potentially preventing degeneration of IVD tissue. This study also revealed new insights into the regulation of PN-1 expression via the ERK1/2/NF-kB signaling pathway and the role of PN-1 in the pathogenesis of IVD degeneration. C1 [Wu, Xinghuo; Liu, Wei; Gao, Yong; Li, Shuai; Wang, Kun; Song, Yu; Shao, Zengwu; Yang, Shuhua; Yang, Cao] Huazhong Univ Sci & Technol, Tongji Med Coll, Union Hosp, Dept Orthopaed Surg, Wuhan 430022, Peoples R China. [Duan, Zhenfeng] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. [Duan, Zhenfeng] Harvard Med Sch, Boston, MA 02114 USA. RP Yang, C (reprint author), Huazhong Univ Sci & Technol, Tongji Med Coll, Union Hosp, Dept Orthopaed Surg, Wuhan 430022, Peoples R China. EM yangcaom@gmail.com FU National Science Foundation of China (NSFC) [81201393, 81541056, 2013YGYL015] FX This study was supported by grants from the financial support of the National Science Foundation of China (NSFC, 81201393, 81541056; 2013YGYL015). NR 68 TC 1 Z9 1 U1 35 U2 35 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 27 PY 2016 VL 6 AR 30563 DI 10.1038/srep30563 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DS6ID UT WOS:000380884600001 PM 27460424 ER PT J AU Xiao, LJ Feng, Q Zhang, Z Wang, F Lydon, JP Ittmann, MM Xin, L Mitsiades, N He, B AF Xiao, Lijuan Feng, Qin Zhang, Zheng Wang, Fen Lydon, John P. Ittmann, Michael M. Xin, Li Mitsiades, Nicholas He, Bin TI The essential role of GATA transcription factors in adult murine prostate SO ONCOTARGET LA English DT Article DE GATA2; GATA3; FoxA1; androgen receptor; prostate cancer ID ACUTE MYELOID-LEUKEMIA; ANDROGEN RECEPTOR; CELL-DIFFERENTIATION; REGULATORY LOOP; GENE-EXPRESSION; MOUSE PROSTATE; MAMMARY-GLAND; BREAST-CANCER; STEM-CELLS; FOXA1 AB GATA transcription factors are essential in mammalian cell lineage determination and have a critical role in cancer development. In cultured prostate cancer cells, GATA2 coordinates with androgen receptor (AR) to regulate gene transcription. In the murine prostate, among six GATA members, GATA2 and GATA3 are expressed. Immunofluorescence staining revealed that both GATA factors predominantly localize in the nuclei of luminal epithelial cells. The pioneer factor FoxA1 is exclusively detected in the luminal cells, whereas AR is detected in both luminal and basal cells. Using genetic engineering, we generated prostate-specific GATA2 and GATA3 knockout (KO) mice. Ablation of single GATA gene had marginal effect on prostate morphology and AR target gene expression, likely due to their genetic compensation. Double KO mice exhibited PIN III to IV lesions, but decreased prostate to body weight ratio, altered AR target gene expression, and expansion of p63-positive basal cells. However, deletion of GATA2 and GATA3 did not reduce the mRNA or protein levels of AR or FoxA1, indicating that GATA factors are not required for AR or FoxA1 expression in adult prostate. Surprisingly, GATA2 and GATA3 exhibit minimal expression in the ventral prostatic (VP) lobe. In contrast, FoxA1 and AR expression levels in VP are at least as high as those in anterior prostatic (AP) and dorsal-lateral prostatic (DLP) lobes. Together, our results indicate that GATA2 and GATA3 are essential for adult murine prostate function and in vivo AR signaling, and the lack of the GATA factor expression in the VP suggests a fundamental difference between VP and other prostatic lobes. C1 [Xiao, Lijuan; Mitsiades, Nicholas; He, Bin] Baylor Coll Med, Dept Med Hematol & Oncol, Houston, TX 77030 USA. [Feng, Qin; Zhang, Zheng; Lydon, John P.; Xin, Li; Mitsiades, Nicholas; He, Bin] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. [Wang, Fen] Texas A&M Hlth Sci Ctr, Inst Biosci & Technol, Ctr Canc & Stem Cell Biol, Houston, TX USA. [Ittmann, Michael M.] Baylor Coll Med, Dept Pathol & Immunol, Houston, TX 77030 USA. [Ittmann, Michael M.] US Dept Vet Affairs, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX USA. RP Mitsiades, N; He, B (reprint author), Baylor Coll Med, Dept Med Hematol & Oncol, Houston, TX 77030 USA.; Mitsiades, N; He, B (reprint author), Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. EM mitsiade@bcm.edu; bhe@bcm.edu FU NIH [K01DK081446, R01HD042311, R21AI122418]; American Cancer Society [RSG-13-061-01-TBE]; Department of Defense [BC122115] FX We thank the Genetically Engineered Mouse Core for their assistance (P30CA125123). This work has been supported by NIH K01DK081446 (B.H.), American Cancer Society RSG-13-061-01-TBE (B.H.), NIH R01HD042311 (J.L.P.), Department of Defense BC122115 (Q.F.), and NIH R21AI122418 (Q.F.). NR 58 TC 0 Z9 0 U1 0 U2 0 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 26 PY 2016 VL 7 IS 30 BP 47891 EP 47903 DI 10.18632/oncotarget.10294 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DY8WP UT WOS:000385413000082 PM 27374105 ER PT J AU Lefort, K Ostano, GP Mello-Grand, M Calpini, V Scatolini, M Farsetti, A Dotto, GP Chiorino, G AF Lefort, Karine Ostano, Gian Paola Mello-Grand, Maurizia Calpini, Valerie Scatolini, Maria Farsetti, Antonella Dotto, G. Paolo Chiorino, Giovanna TI Dual tumor suppressing and promoting function of Notch1 signaling in human prostate cancer SO ONCOTARGET LA English DT Article DE notch; prostate cancer ID GENE-EXPRESSION ANALYSIS; NEGATIVE REGULATION; CELL-LINES; DIFFERENTIATION; PROGRESSION; ACTIVATION; GROWTH; BETA; INHIBITION; PATHWAY AB Adenocarcinomas of the prostate arise as multifocal heterogeneous lesions as the likely result of genetic and epigenetic alterations and deranged cell-cell communication. Notch signaling is an important form of intercellular communication with a role in growth/differentiation control and tumorigenesis. Contrasting reports exist in the literature on the role of this pathway in prostate cancer (PCa) development. We show here that i) compared to normal prostate tissue, Notch1 expression is significantly reduced in a substantial fraction of human PCas while it is unaffected or even increased in others; ii) acute Notch activation both inhibits and induces process networks associated with prostatic neoplasms; iii) down-modulation of Notch1 expression and activity in immortalized normal prostate epithelial cells increases their proliferation potential, while increased Notch1 activity in PCa cells suppresses growth and tumorigenicity through a Smad3-dependent mechanism involving p21(WAF1/CIP1); iv) prostate cancer cells resistant to Notch growth inhibitory effects retain Notch1-induced upregulation of pro-oncogenic genes, like EPAS1 and CXCL6, also overexpressed in human PCas with high Notch1 levels. Taken together, these results reconcile conflicting data on the role of Notch1 in prostate cancer. C1 [Lefort, Karine; Calpini, Valerie; Dotto, G. Paolo] Univ Lausanne, Dept Biochem, Lausanne, Switzerland. [Ostano, Gian Paola; Mello-Grand, Maurizia; Chiorino, Giovanna] Fdn Edo & Elvo Tempia Valenta, Lab Canc Genom, Biella, Italy. [Scatolini, Maria] Fdn Edo & Elvo Tempia Valenta, Lab Mol Oncol, Biella, Italy. [Farsetti, Antonella] CNR, Inst Cell Biol & Neurobiol, Rome, Italy. [Farsetti, Antonella] Goethe Univ Frankfurt, Internal Med Clin 3, Frankfurt, Germany. [Dotto, G. Paolo] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA USA. RP Lefort, K (reprint author), Univ Lausanne, Dept Biochem, Lausanne, Switzerland. EM karine.lefort@unil.ch; giovanna.chiorino@fondazionetempia.org FU Swiss National Science Foundation [310030_156191/1]; National Institute of Arthritis and Musculoskeletal and Skin Diseases [R01AR039190, R01AR064786]; European Research Council [26075083]; Swiss Cancer Research [OCS-2922-02-2012, KFS-330108-2013]; AIRC (MFAG) [11742]; Lauretana SpA; Fondazione Boschetto Colombo; Compagnia di San Paolo FX This work was supported by grants from the Swiss National Science Foundation (310030_156191/1), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR039190; R01AR064786; the content not necessarily representing the official views of NIH), European Research Council (26075083) and Swiss Cancer Research (OCS-2922-02-2012 and KFS-330108-2013) for G.P.D. and K.L., a grant by AIRC (MFAG 2011 grant N.11742) to G.C., grants from Lauretana SpA and Fondazione Boschetto Colombo to P.O. and a grant by Compagnia di San Paolo to M.M.G. NR 66 TC 0 Z9 0 U1 0 U2 0 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 26 PY 2016 VL 7 IS 30 BP 48011 EP 48026 DI 10.18632/oncotarget.10333 PG 16 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DY8WP UT WOS:000385413000092 PM 27384993 ER PT J AU Glass, JD Hertzberg, VS Boulis, NM Riley, J Federici, T Polak, M Bordeau, J Fournier, C Johe, K Hazel, T Cudkowicz, M Atassi, N Borges, LF Rutkove, SB Duell, J Patil, PG Goutman, SA Feldman, EL AF Glass, Jonathan D. Hertzberg, Vicki S. Boulis, Nicholas M. Riley, Jonathan Federici, Thais Polak, Meraida Bordeau, Jane Fournier, Christina Johe, Karl Hazel, Tom Cudkowicz, Merit Atassi, Nazem Borges, Lawrence F. Rutkove, Seward B. Duell, Jayna Patil, Parag G. Goutman, Stephen A. Feldman, Eva L. TI Transplantation of spinal cord-derived neural stem cells for ALS: Analysis of phase 1 and 2 trials SO NEUROLOGY LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; TRANSGENIC RATS; SAFETY OUTCOMES; I TRIAL; DISEASE; PROGRESSION; SURVIVAL; GRAFTS AB Objective:To test the safety of spinal cord transplantation of human stem cells in patients with amyotrophic lateral sclerosis (ALS) with escalating doses and expansion of the trial to multiple clinical centers.Methods:This open-label trial included 15 participants at 3 academic centers divided into 5 treatment groups receiving increasing doses of stem cells by increasing numbers of cells/injection and increasing numbers of injections. All participants received bilateral injections into the cervical spinal cord (C3-C5). The final group received injections into both the lumbar (L2-L4) and cervical cord through 2 separate surgical procedures. Participants were assessed for adverse events and progression of disease, as measured by the ALS Functional Rating Scale-Revised, forced vital capacity, and quantitative measures of strength. Statistical analysis focused on the slopes of decline of these phase 2 trial participants alone or in combination with the phase 1 participants (previously reported), comparing these groups to 3 separate historical control groups.Results:Adverse events were mostly related to transient pain associated with surgery and to side effects of immunosuppressant medications. There was one incident of acute postoperative deterioration in neurologic function and another incident of a central pain syndrome. We could not discern differences in surgical outcomes between surgeons. Comparisons of the slopes of decline with the 3 separate historical control groups showed no differences in mean rates of progression.Conclusions:Intraspinal transplantation of human spinal cord-derived neural stem cells can be safely accomplished at high doses, including successive lumbar and cervical procedures. The procedure can be expanded safely to multiple surgical centers.Classification of evidence:This study provides Class IV evidence that for patients with ALS, spinal cord transplantation of human stem cells can be safely accomplished and does not accelerate the progression of the disease. This study lacks the precision to exclude important benefit or safety issues. C1 [Glass, Jonathan D.; Polak, Meraida; Bordeau, Jane; Fournier, Christina] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA. [Boulis, Nicholas M.; Riley, Jonathan; Federici, Thais] Emory Univ, Sch Med, Dept Neurosurg, Atlanta, GA USA. [Hertzberg, Vicki S.] Emory Univ, Nell Hodgson Woodruff Sch Nursing, Ctr Nursing Data Sci, Atlanta, GA 30322 USA. [Johe, Karl; Hazel, Tom] Neuralstem Inc, Germantown, MD USA. [Cudkowicz, Merit; Atassi, Nazem] Massachusetts Gen Hosp, Dept Neurol, Neurol Clin Res Inst, Boston, MA 02114 USA. [Borges, Lawrence F.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Rutkove, Seward B.] Beth Israel Hosp, Dept Neurol, Boston, MA USA. [Patil, Parag G.] Univ Michigan, Dept Neurosurg, Ann Arbor, MI 48109 USA. [Duell, Jayna; Patil, Parag G.; Goutman, Stephen A.; Feldman, Eva L.] Univ Michigan, Dept Neurol, Ann Arbor, MI USA. RP Glass, JD (reprint author), Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA. EM Jglas03@emory.edu FU National Institute of Neurological Disorders and Stroke [1R01NS077982]; ALS Association; Neuralstem, Inc. FX National Institute of Neurological Disorders and Stroke 1R01NS077982, the ALS Association, and Neuralstem, Inc. NR 20 TC 2 Z9 2 U1 9 U2 9 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 26 PY 2016 VL 87 IS 4 BP 392 EP 400 DI 10.1212/WNL.0000000000002889 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA DT4SU UT WOS:000381472000018 PM 27358335 ER PT J AU Singh, JA Yu, SH AF Singh, Jasvinder A. Yu, Shaohua TI Emergency Department and Inpatient Healthcare utilization due to Hypertension SO BMC HEALTH SERVICES RESEARCH LA English DT Article DE Emergency department; Hospitalization; Health care utilization; Charges; Hypertension; Predictors; Hospital discharge; Predictors ID UNITED-STATES; HOSPITALIZATION; BURDEN; RISK AB Background: Hypertension is one of the commonest chronic diseases, yet limited data are available for related health care utilization. Our study objective was to describe the emergency department (ED) and subsequent hospitalization related health care utilization and charges due to hypertension in the U.S. Methods: We used the National ED sample (NEDS) to study hypertension-related utilization and charges. Multivariable-adjusted linear or logistic regression was used to assess hypertension-associated ED and hospitalization outcomes (disposition, length of stay, charges), adjusted for patient demographic, comorbidity and hospital characteristics. Results: There were 0.92, 0.97 and 1.04 million ED visits (0.71-0.77 % of all ED visits) with hypertension as the primary diagnosis in 2009, 2010 and 2012, respectively; 23 % resulted in hospitalization. ED charges were $2.00, $2.27 and $2.86 billion, and for those hospitalized, total charges (ED plus inpatient) were $6.62, $7.09 and $7.94 billion, in 2009, 2010 and 2012, respectively. Older age (50 to 65 years), female sex, metropolitan area residence, South or West U.S. hospital location, private insurance and the presence of congestive heart failure were each associated with higher charges for an ED visit with hypertension as the primary diagnosis. Younger age, metropolitan residence, Medicaid insurance, hospital location in the Northeast and co-existing diabetes, gout, coronary heart disease, chronic obstructive pulmonary disease, hyperlipidemia and osteoarthritis were associated with higher risk, whereas male sex was associated with lower risk of hospitalization after ED visit for hypertension. In 2012, 71.6 % of all patients hospitalized with hypertension as the primary diagnosis were discharged home. Older age, metropolitan residence and most comorbidities were associated with lower odds, whereas male sex, payer other than Medicare, South or West U.S. hospital location were associated with higher odds of discharge to home. Conclusions: Hypertension is associated with significant healthcare burden in the U.S. Future studies should assess strategies to reduce hypertension-associated cost and health care burden. C1 [Singh, Jasvinder A.] Birmingham VA Med Ctr, Med Serv, Birmingham, AL 35233 USA. [Singh, Jasvinder A.; Yu, Shaohua] Univ Alabama Birmingham, Dept Med, Sch Med, Birmingham, AL 35294 USA. [Singh, Jasvinder A.; Yu, Shaohua] Univ Alabama Birmingham, Sch Publ Hlth, Div Epidemiol, Birmingham, AL 35294 USA. [Singh, Jasvinder A.] Mayo Clin, Coll Med, Dept Orthoped Surg, Rochester, MN USA. RP Singh, JA (reprint author), Birmingham VA Med Ctr, Med Serv, Birmingham, AL 35233 USA.; Singh, JA (reprint author), Univ Alabama Birmingham, Dept Med, Sch Med, Birmingham, AL 35294 USA.; Singh, JA (reprint author), Univ Alabama Birmingham, Sch Publ Hlth, Div Epidemiol, Birmingham, AL 35294 USA. EM Jasvinder.md@gmail.com FU Division of Rheumatology at the University of Alabama at Birmingham FX This material is the result of work supported by research funds from the Division of Rheumatology at the University of Alabama at Birmingham and the resources and use of facilities at the Birmingham VA Medical Center, Birmingham, Alabama, USA. The funding body did not play any role in design, in the collection, analysis, and interpretation of data; in the writing of the manuscript; and in the decision to submit the manuscript for publication. NR 17 TC 0 Z9 0 U1 5 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6963 J9 BMC HEALTH SERV RES JI BMC Health Serv. Res. PD JUL 26 PY 2016 VL 16 AR 303 DI 10.1186/s12913-016-1563-7 PG 11 WC Health Care Sciences & Services SC Health Care Sciences & Services GA DS2WS UT WOS:000380645200005 PM 27461237 ER PT J AU Singh, SK Fiorelli, R Kupp, R Rajan, S Szeto, E Lo Cascio, C Maire, CL Sun, Y Alberta, JA Eschbacher, JM Ligon, KL Berens, ME Sanai, N Mehta, S AF Singh, Shiv K. Fiorelli, Roberto Kupp, Robert Rajan, Sindhu Szeto, Emily Lo Cascio, Costanza Maire, Cecile L. Sun, Yu Alberta, John A. Eschbacher, Jennifer M. Ligon, Keith L. Berens, Michael E. Sanai, Nader Mehta, Shwetal TI Post-translational Modifications of OLIG2 Regulate Glioma Invasion through the TGF-beta Pathway SO CELL REPORTS LA English DT Article ID EPITHELIAL-MESENCHYMAL TRANSITION; MALIGNANT GLIOMA; BRAIN-TUMORS; NEURAL PROGENITORS; CELL-POPULATION; STEM-CELLS; GLIOBLASTOMA; MIGRATION; BIOLOGY; GROWTH AB In glioblastoma, invasion and proliferation are presumed to be mutually exclusive events; however, the molecular mechanisms that mediate this switch at the cellular level remain elusive. Previously, we have shown that phospho-OLIG2, a central-nervous-system-specific transcription factor, is essential for tumor growth and proliferation. Here, we show that the modulation of OLIG2 phosphorylation can trigger a switch between proliferation and invasion. Glioma cells with unphosphorylated OLIG2 (S10, S13, S14) are highly migratory and invasive, both in vitro and in vivo. Mechanistically, unphosphorylated OLIG2 induces TGF-beta 2 expression and promotes invasive mesenchymal properties in glioma cells. Inhibition of the TGF-beta 2 pathway blocks this OLIG2-dependent invasion. Furthermore, ectopic expression of phosphomimetic Olig2 is sufficient to block TGF-beta 2-mediated invasion and reduce expression of invasion genes (ZEB1 and CD44). Our results not only provide a mechanistic insight into how cells switch from proliferation to invasion but also offer therapeutic opportunities for inhibiting dissemination of gliomas. C1 [Singh, Shiv K.; Fiorelli, Roberto; Kupp, Robert; Rajan, Sindhu; Szeto, Emily; Lo Cascio, Costanza; Sanai, Nader; Mehta, Shwetal] St Josephs Hosp, Barrow Neurol Inst, Barrow Brain Tumor Res Ctr, Div Neurobiol, Phoenix, AZ 85013 USA. [Maire, Cecile L.; Ligon, Keith L.] Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Sun, Yu; Alberta, John A.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Eschbacher, Jennifer M.] St Josephs Hosp, Barrow Neurol Inst, Div Neuropathol, Phoenix, AZ 85013 USA. [Berens, Michael E.] Translat Genom Inst, Canc & Cell Biol Div, Phoenix, AZ 85004 USA. RP Mehta, S (reprint author), St Josephs Hosp, Barrow Neurol Inst, Barrow Brain Tumor Res Ctr, Div Neurobiol, Phoenix, AZ 85013 USA. EM shwetal.mehta@dignityhealth.org FU Arizona Biomedical Research Commission; Barrow Neurological Foundation; NIH/NINDS grant [R01 NS088648A]; Bear Necessities Pediatric Cancer Foundation; NIH [R01 NS082745, R01 CA175391] FX Patient-derived glioma cells were provided by the Biobank Core Facility at St. Joseph's Hospital and Barrow Neurological Institute and the Living Tissue Bank at Dana-Farber Cancer Institute. The biobank is funded by the Arizona Biomedical Research Commission and the Barrow Neurological Foundation. We are grateful to Dr. Mythreye Karthikeyan (University of South Carolina at Columbia) for useful suggestions for the ELISA and the TGF-beta signaling, in general. We thank Timothy Troxel, Dr. Sara Bowen, Jonathan Yamaguchi, Lior Shtayer, Nicole Giannonatti, Laura Belmont, and Padhmavathy Yuvaraj for their technical assistance. Dr. Harshil Dhruv and Brock Armstrong (TGen) provided the reagents and technical advice for the glioma tissue microarray. We thank the Neuro publications department at the Barrow Neurological Institute for their help with the illustrations. This work was supported by the Barrow Neurological Foundation (to S.M.). S.M is also supported by an NIH/NINDS grant (R01 NS088648A) and the Bear Necessities Pediatric Cancer Foundation. N.S. is supported by NIH grants (R01 NS082745 and R01 CA175391). NR 46 TC 2 Z9 2 U1 3 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 26 PY 2016 VL 16 IS 4 BP 950 EP 966 DI 10.1016/j.celrep.2016.06.045 PG 17 WC Cell Biology SC Cell Biology GA DS0DL UT WOS:000380265500006 PM 27396340 ER PT J AU Wang, WK Yang, M Kenfield, SA Hu, FB Stampfer, MJ Willett, WC Fuchs, CS Giovannucci, EL Bao, Y AF Wang, Weike Yang, Meng Kenfield, Stacey A. Hu, Frank B. Stampfer, Meir J. Willett, Walter C. Fuchs, Charles S. Giovannucci, Edward L. Bao, Ying TI Nut consumption and prostate cancer risk and mortality SO BRITISH JOURNAL OF CANCER LA English DT Article DE nut consumption; prostate cancer; overall mortality; prospective cohort study ID HEART-DISEASE; HEALTH; DIET; ASSOCIATION; PREVENTION; FOODS AB Background: Little is known of the association between nut consumption, and prostate cancer (PCa) incidence and survivorship. Methods: We conducted an incidence analysis and a case-only survival analysis in the Health Professionals Follow-up Study on the associations of nut consumption (updated every 4 years) with PCa diagnosis, and PCa-specific and overall mortality. Results: In 26 years, 6810 incident PCa cases were identified from 47 299 men. There was no association between nut consumption and being diagnosed with PCa or PCa-specific mortality. However, patients who consumed nuts five or more times per week after diagnosis had a significant 34% lower rate of overall mortality than those who consumed nuts less than once per month (HR = 0.66, 95% CI: 0.52-0.83, P-trend = 0.0005). Conclusions: There were no statistically significant associations between nut consumption, and PCa incidence or PCa-specific mortality. Frequent nut consumption after diagnosis was associated with significantly reduced overall mortality. C1 [Wang, Weike; Hu, Frank B.; Stampfer, Meir J.; Willett, Walter C.; Giovannucci, Edward L.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave, Boston, MA 02115 USA. [Yang, Meng; Hu, Frank B.; Stampfer, Meir J.; Willett, Walter C.; Giovannucci, Edward L.] Harvard TH Chan Sch Publ Hlth, Dept Nutr, 677 Huntington Ave, Boston, MA 02115 USA. [Kenfield, Stacey A.] Univ Calif San Francisco, Dept Urol, 550 16th St, San Francisco, CA 94143 USA. [Hu, Frank B.; Stampfer, Meir J.; Willett, Walter C.; Fuchs, Charles S.; Giovannucci, Edward L.; Bao, Ying] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 181 Longwood Ave, Boston, MA 02115 USA. [Hu, Frank B.; Stampfer, Meir J.; Willett, Walter C.; Fuchs, Charles S.; Giovannucci, Edward L.; Bao, Ying] Harvard Med Sch, 181 Longwood Ave, Boston, MA 02115 USA. [Fuchs, Charles S.] Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. RP Bao, Y (reprint author), Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 181 Longwood Ave, Boston, MA 02115 USA.; Bao, Y (reprint author), Harvard Med Sch, 181 Longwood Ave, Boston, MA 02115 USA. EM ying.bao@channing.harvard.edu FU National Institutes of Health [UM1 CA167552, U54CA155626, P30DK046200]; International Tree Nut Council Nutrition Research & Education Foundation; 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); Harvard Catalyst: The Harvard Clinical and Translational Science Center (National Institutes of Health) [KL2 TR001100] FX We would like to thank the participants and staff of the HPFS for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, and WY. This study was supported by the grants UM1 CA167552, U54CA155626, and P30DK046200 from the National Institutes of Health and by a grant from the International Tree Nut Council Nutrition Research & Education Foundation. This work was also conducted with the support of a KL2/Catalyst Medical Research Investigator Training award (an appointed KL2 award) from Harvard Catalyst: The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, and National Institutes of Health Award KL2 TR001100). 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 centres, or the National Institutes of Health. NR 20 TC 1 Z9 1 U1 6 U2 10 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 26 PY 2016 VL 115 IS 3 BP 371 EP 374 DI 10.1038/bjc.2016.181 PG 4 WC Oncology SC Oncology GA DS1SS UT WOS:000380380400013 PM 27280637 ER PT J AU Maffazioli, GD Stanford, FC Reyes, KJC Stanley, TL Singhal, V Corey, KE Pratt, JS Bredella, MA Misra, M AF Maffazioli, Giovana D. Stanford, Fatima Cody Reyes, Karen J. Campoverde Stanley, Takara L. Singhal, Vibha Corey, Kathleen E. Pratt, Janey S. Bredella, Miriam A. Misra, Madhusmita TI Comparing Outcomes of Two Types of Bariatric Surgery in an Adolescent Obese Population: Roux-en-Y Gastric Bypass vs. Sleeve Gastrectomy SO FRONTIERS IN PEDIATRICS LA English DT Article DE bariatric surgery; adolescence; Roux-en-Y gastric bypass; sleeve gastrectomy; obesity ID NONALCOHOLIC STEATOHEPATITIS; COMMITTEE; CHILDREN; OVERWEIGHT; PREVENTION; AGE AB Background: Obesity is prevalent among adolescents and is associated with serious health consequences. Roux-en-Y Gastric Bypass (RYGB) and Sleeve Gastrectomy (SG) are bariatric procedures that cause significant weight loss in adults and are increasingly being performed in adolescents with morbid obesity. Data comparing outcomes of RYGB vs. SG in this age-group are scarce. This study aims to compare short-term (1-6 months) and longer-term (7-18 months) body mass index (BMI) and biochemical outcomes following RYGB and SG in adolescents/young adults. Methods: A retrospective study using data extracted from medical records of patients 16-21 years who underwent RYGB or SG between 2012 and 2014 at a tertiary care academic medical center. Results: Forty-six patients were included in this study: 24 underwent RYGB and 22 underwent SG. Groups did not differ for baseline age, sex, race, or BMI. BMI reductions were significant at 1-6 months and 7-18 months within groups (p < 0.0001), but did not differ by surgery type (p = 0.65 and 0.09, for 1-6 months and 7-18 months, respectively). Over 7-18 months, within-group improvement in low-density lipoprotein (LDL) (-24 6 in RYGB, p = 0.003, vs. 7 9 mg/dl in SG, p = 0.50) and non-high-density lipoprotein (non-HDL) cholesterol (-23 8 in RYGB, p = 0.02, vs. 12 7 in SG, p = 0.18) appeared to be of greater magnitude following RYGB. However, differences between groups did not reach statistical significance. When divided by non-alcoholic steatohepatitis stages (NASH), patients with Stage II III NASH had greater reductions in alanine aminotransferase levels vs. those with Stage 0 I NASH (-45 18 vs. 9 3, p = 0.01) after 7-18 months. RYGB and SG groups did not differ for the magnitude of post-surgical changes in liver enzymes. Conclusion: RYGB and SG did not differ for the magnitude of BMI reduction across groups, though changes trended higher following RYGB. Further prospective studies are needed to confirm these findings. C1 [Maffazioli, Giovana D.; Reyes, Karen J. Campoverde; Stanley, Takara L.; Singhal, Vibha; Misra, Madhusmita] Harvard Med Sch, Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02115 USA. [Stanford, Fatima Cody; Stanley, Takara L.; Singhal, Vibha; Misra, Madhusmita] Harvard Med Sch, Massachusetts Gen Hosp Children, Pediat Endocrine Unit, Boston, MA USA. [Stanford, Fatima Cody; Pratt, Janey S.] Massachusetts Gen Hosp, Weight Ctr, Boston, MA 02114 USA. [Stanford, Fatima Cody; Corey, Kathleen E.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med Gastroenterol, Boston, MA USA. [Pratt, Janey S.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Boston, MA USA. [Bredella, Miriam A.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. RP Stanford, FC (reprint author), Harvard Med Sch, Massachusetts Gen Hosp Children, Pediat Endocrine Unit, Boston, MA USA.; Stanford, FC (reprint author), Massachusetts Gen Hosp, Weight Ctr, Boston, MA 02114 USA.; Stanford, FC (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Med Gastroenterol, Boston, MA USA. EM fstanford@mgh.harvard.edu OI Stanford, Fatima/0000-0003-4616-533X FU NICHD NIH HHS [K24 HD071843] NR 28 TC 0 Z9 0 U1 5 U2 7 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 2296-2360 J9 FRONT PEDIATR JI Front. Pediatr. PD JUL 26 PY 2016 VL 4 AR 78 DI 10.3389/fped.2016.00078 PG 7 WC Pediatrics SC Pediatrics GA DS1FT UT WOS:000380341900001 PM 27508205 ER PT J AU Winslow, BD Chadderdon, GL Dechmerowski, SJ Jones, DL Kalkstein, S Greene, JL Gehrman, P AF Winslow, Brent D. Chadderdon, George L. Dechmerowski, Sara J. Jones, David L. Kalkstein, Solomon Greene, Jennifer L. Gehrman, Philip TI Development and Clinical Evaluation of an mHealth Application for Stress Management SO FRONTIERS IN PSYCHIATRY LA English DT Article DE stress; electrodermal response; heart rate; mobile applications; wearable devices; cognitive behavioral therapy; telemedicine ID COGNITIVE-BEHAVIORAL THERAPY; DEPRESSION; ANXIETY; METAANALYSIS; DISORDERS; IMPAIRMENT; PREVALENCE; RESPONSES; DROPOUT; CARE AB A large number of individuals experience mental health disorders, with cognitive behavioral therapy (CBT) emerging as a standard practice for reduction in psychiatric symptoms, including stress, anger, anxiety, and depression. However, CBT is associated with significant patient dropout and lacks the means to provide objective data regarding a patient's experience and symptoms between sessions. Emerging wearables and mobile health (mHealth) applications represent an approach that may provide objective data to the patient and provider between CBT sessions. Here, we describe the development of a classifier of real-time physiological stress in a healthy population (n = 35) and apply it in a controlled clinical evaluation for armed forces veterans undergoing CBT for stress and anger management (n = 16). Using cardiovascular and electrodermal inputs from a wearable device, the classifier was able to detect physiological stress in a non-clinical sample with accuracy greater than 90%. In a small clinical sample, patients who used the classifier and an associated mHealth application were less likely to discontinue therapy (p = 0.016, d = 1.34) and significantly improved on measures of stress (p = 0.032, d = 1.61), anxiety (p = 0.050, d = 1.26), and anger (p = 0.046, d = 1.41) compared to controls undergoing CBT alone. Given the large number of individuals that experience mental health disorders and the unmet need for treatment, especially in developing nations, such mHealth approaches have the potential to provide or augment treatment at low cost in the absence of in-person care. C1 [Winslow, Brent D.; Chadderdon, George L.; Dechmerowski, Sara J.] Design Interact Inc, Orlando, FL USA. [Jones, David L.] Quantified Design Solut LLC, Orlando, FL USA. [Kalkstein, Solomon; Greene, Jennifer L.; Gehrman, Philip] Univ Penn, Philadelphia VA Med Ctr, Philadelphia, PA 19104 USA. RP Winslow, BD (reprint author), Design Interact Inc, Orlando, FL USA. EM brent.winslow@designinteractive.net RI Emchi, Karma/Q-1952-2016 FU US Army Medical Research and Materiel Command (USA MRMC) [W81XWH-12-C-0071] FX Portions of the classifier study were reported at the 49th Annual Meeting of the Interservice/Industry Training, Simulation & Education Conference (I/ITSEC), as SD, BW, GC, T. Schmidt-Daly, DJ (2014) Classifying stress in a mobile environment (14.195). This work was funded by the US Army Medical Research and Materiel Command (USA MRMC) grant W81XWH-12-C-0071. NR 50 TC 0 Z9 0 U1 13 U2 19 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-0640 J9 FRONT PSYCHIATRY JI Front. Psychiatry PD JUL 26 PY 2016 VL 7 AR 130 DI 10.3389/fpsyt.2016.00130 PG 8 WC Psychiatry SC Psychiatry GA DS1KV UT WOS:000380355400001 PM 27507949 ER PT J AU Dobbins, J Gagnon, E Godec, J Pyrdol, J Vignali, DAA Sharpe, AH Wucherpfennig, KW AF Dobbins, Jessica Gagnon, Etienne Godec, Jernej Pyrdol, Jason Vignali, Dario A. A. Sharpe, Arlene H. Wucherpfennig, Kai W. TI Binding of the cytoplasmic domain of CD28 to the plasma membrane inhibits Lck recruitment and signaling SO Science Signaling LA English DT Article ID T-CELL COSTIMULATION; KINASE-C-THETA; SRC-FAMILY KINASES; TYROSINE PHOSPHORYLATION; PROTEIN-KINASE; PHOSPHATIDYLINOSITOL 3-KINASE; RECEPTOR ZETA; PYAP MOTIFS; ACTIVATION; MICE AB The T cell costimulatory receptor CD28 is required for the full activation of naive T cells and for the development and maintenance of Foxp3(+) regulatory T (T-reg) cells. We showed that the cytoplasmic domain of CD28 was bound to the plasma membrane in resting cells and that ligand binding to CD28 resulted in its release. Membrane binding by the CD28 cytoplasmic domain required two clusters of basic amino acid residues, which interacted with the negatively charged inner leaflet of the plasma membrane. These same clusters of basic residues also served as interaction sites for Lck, a Src family kinase critical for CD28 function. This signaling complex was further stabilized by the Lck-mediated phosphorylation of CD28 Tyr(207) and the subsequent binding of the Src homology 2 (SH2) domain of Lck to this phosphorylated tyrosine. Mutation of the basic clusters in the CD28 cytoplasmic domain reduced the recruitment to the CD28-Lck complex of protein kinase C theta (PKC theta), which serves as a key effector kinase in the CD28 signaling pathway. Consequently, mutation of either a basic cluster or Tyr(207) impaired CD28 function in mice as shown by the reduced thymic differentiation of FoxP3(+) T-reg cells. On the basis of these results, we propose a previously undescribed model for the initiation of CD28 signaling. C1 [Dobbins, Jessica; Gagnon, Etienne; Pyrdol, Jason; Wucherpfennig, Kai W.] Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02115 USA. [Dobbins, Jessica; Godec, Jernej; Sharpe, Arlene H.; Wucherpfennig, Kai W.] Harvard Med Sch, Program Immunol, Boston, MA 02115 USA. [Godec, Jernej; Sharpe, Arlene H.; Wucherpfennig, Kai W.] Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. [Vignali, Dario A. A.] Univ Pittsburgh, Sch Med, Dept Immunol, Pittsburgh, PA 15261 USA. [Vignali, Dario A. A.] Univ Pittsburgh, Inst Canc, Tumor Microenvironm Ctr, Pittsburgh, PA 15232 USA. [Gagnon, Etienne] Inst Rech Immunol & Cancerol, Dept Microbiol Infectiol & Immunol, Montreal, PQ H3T 1J4, Canada. RP Wucherpfennig, KW (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02115 USA.; Wucherpfennig, KW (reprint author), Harvard Med Sch, Program Immunol, Boston, MA 02115 USA.; Wucherpfennig, KW (reprint author), Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. EM kai_wucherpfennig@dfci.harvard.edu FU NIH [R01AI054520, PO1 AI045757, F31AI091155, P01 AI108545, R01 AI091977, R01 AI52199, R01 DK089125, P50 SPORE CA097190, P30 CA047904] FX This work was supported by a grant from the NIH (R01AI054520 and PO1 AI045757 to K.W.W.), a fellowship from the NIH (F31AI091155 to J.D.), and grants P01 AI108545, R01 AI091977, R01 AI52199, R01 DK089125, P50 SPORE CA097190, and P30 CA047904 (to D.A.A.V.). NR 54 TC 1 Z9 1 U1 4 U2 4 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1945-0877 EI 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD JUL 26 PY 2016 VL 9 IS 438 AR ra75 DI 10.1126/scisignal.aaf0626 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DS4VG UT WOS:000380779100002 PM 27460989 ER PT J AU Wilcox, SL Veggeberg, R Lemme, J Hodkinson, DJ Scrivani, S Burstein, R Becerra, L Borsook, D AF Wilcox, Sophie L. Veggeberg, Rosanna Lemme, Jordan Hodkinson, Duncan J. Scrivani, Steven Burstein, Rami Becerra, Lino Borsook, David TI Increased Functional Activation of Limbic Brain Regions during Negative Emotional Processing in Migraine SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE migraine; headache; fMRI; emotion; IAPS; limbic ID PSYCHIATRIC COMORBIDITIES; CEREBRAL-CORTEX; DAILY HASSLES; PAIN; RESPONSES; AMYGDALA; CONNECTIVITY; STRESS; HEADACHE; FMRI AB Pain is both an unpleasant sensory and emotional experience. This is highly relevant in migraine where cortical hyperexcitability in response to sensory stimuli (including pain, light, and sound) has been extensively reported. However, migraine may feature a more general enhanced response to aversive stimuli rather than being sensory-specific. To this end we used functional magnetic resonance imaging to assess neural activation in migraineurs interictaly in response to emotional visual stimuli from the International Affective Picture System. Migraineurs, compared to healthy controls, demonstrated increased neural activity in response to negative emotional stimuli. Most notably in regions overlapping in their involvement in both nociceptive and emotional processing including the posterior cingulate, caudate, amygdala, and thalamus (cluster corrected, p < 0.01). In contrast, migraineurs and healthy controls displayed no and minimal differences in response to positive and neutral emotional stimuli, respectively. These findings support the notion that migraine may feature more generalized altered cerebral processing of aversive/negative stimuli, rather than exclusively to sensory stimuli. A generalized hypersensitivity to aversive stimuli may be an inherent feature of migraine, or a consequential alteration developed over the duration of the disease. This proposed cortical-limbic hypersensitivity may form an important part of the migraine pathophysiology, including psychological comorbidity, and may represent an innate sensitivity to aversive stimuli that underpins attack triggers, attack persistence and (potentially) gradual headache chronification. C1 [Wilcox, Sophie L.; Veggeberg, Rosanna; Hodkinson, Duncan J.; Becerra, Lino; Borsook, David] Harvard Med Sch, Boston Childrens Hosp, PAIN Res Grp, Ctr Pain & Brain, Boston, MA USA. [Wilcox, Sophie L.; Lemme, Jordan; Hodkinson, Duncan J.; Becerra, Lino; Borsook, David] Harvard Med Sch, Boston Childrens Hosp, Dept Anesthesiol Perioperat & Pain Med, Boston, MA USA. [Veggeberg, Rosanna; Becerra, Lino; Borsook, David] Harvard Med Sch, McLean Hosp, Brain imaging Center, Dept Psychiat,PAIN Res Grp, Belmont, MA USA. [Scrivani, Steven] Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Boston, MA 02114 USA. [Burstein, Rami] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Anesthesia Crit Care & Pain Med, Boston, MA USA. RP Wilcox, SL (reprint author), Harvard Med Sch, Boston Childrens Hosp, PAIN Res Grp, Ctr Pain & Brain, Boston, MA USA.; Wilcox, SL (reprint author), Harvard Med Sch, Boston Childrens Hosp, Dept Anesthesiol Perioperat & Pain Med, Boston, MA USA. EM sophie.wilcox@childrens.harvard.edu FU National Institutes of Health (NIH) [R01 NS073977, K24 NS064050] FX Research reported in this publication was supported by the National Institutes of Health (NIH) under award number R01 NS073977 and K24 NS064050. NR 77 TC 0 Z9 0 U1 2 U2 4 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 26 PY 2016 VL 10 AR 366 DI 10.3389/fnhum.2016.00366 PG 10 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA DR9HW UT WOS:000380208700001 PM 27507939 ER PT J AU Garofalo, A Sholl, L Reardon, B Taylor-Weiner, A Amin-Mansour, A Miao, D Liu, D Oliver, N MacConaill, L Ducar, M Rojas-Rudilla, V Giannakis, M Ghazani, A Gray, S Janne, P Garber, J Joffe, S Lindeman, N Wagle, N Garraway, LA Van Allen, EM AF Garofalo, Andrea Sholl, Lynette Reardon, Brendan Taylor-Weiner, Amaro Amin-Mansour, Ali Miao, Diana Liu, David Oliver, Nelly MacConaill, Laura Ducar, Matthew Rojas-Rudilla, Vanesa Giannakis, Marios Ghazani, Arezou Gray, Stacy Janne, Pasi Garber, Judy Joffe, Steve Lindeman, Neal Wagle, Nikhil Garraway, Levi A. Van Allen, Eliezer M. TI The impact of tumor profiling approaches and genomic data strategies for cancer precision medicine SO GENOME MEDICINE LA English DT Article DE Genomics; Precision medicine; Disparities; Immuno-oncology; Neoantigens; Panel testing ID GENERATION SEQUENCING ASSAY; NONSMALL CELL LUNG; PD-1 BLOCKADE; SOMATIC MUTATIONS; GENETIC-VARIATION; TARGETED CAPTURE; CTLA-4 BLOCKADE; VALIDATION; MELANOMA; SAMPLES AB Background: The diversity of clinical tumor profiling approaches (small panels to whole exomes with matched or unmatched germline analysis) may engender uncertainty about their benefits and liabilities, particularly in light of reported germline false positives in tumor-only profiling and use of global mutational and/or neoantigen data. The goal of this study was to determine the impact of genomic analysis strategies on error rates and data interpretation across contexts and ancestries. Methods: We modeled common tumor profiling modalities-large (n = 300 genes), medium (n = 48 genes), and small (n = 15 genes) panels-using clinical whole exomes (WES) from 157 patients with lung or colon adenocarcinoma. We created a tumor-only analysis algorithm to assess germline false positive rates, the impact of patient ancestry on tumor-only results, and neoantigen detection. Results: After optimizing a germline filtering strategy, the germline false positive rate with tumor-only large panel sequencing was 14 % (144/1012 variants). For patients whose tumor-only results underwent molecular pathologist review (n = 91), 50/54 (93 %) false positives were correctly interpreted as uncertain variants. Increased germline false positives were observed in tumor-only sequencing of non-European compared with European ancestry patients (p < 0.001; Fisher's exact) when basic germline filtering approaches were used; however, the ExAC database (60,706 germline exomes) mitigated this disparity (p = 0.53). Matched and unmatched large panel mutational load correlated with WES mutational load (r(2) = 0.99 and 0.93, respectively; p < 0.001). Neoantigen load also correlated (r(2) = 0.80; p < 0.001), though WES identified a broader spectrum of neoantigens. Small panels did not predict mutational or neoantigen load. Conclusions: Large tumor-only targeted panels are sufficient for most somatic variant identification and mutational load prediction if paired with expanded germline analysis strategies and molecular pathologist review. Paired germline sequencing reduced overall false positive mutation calls and WES provided the most neoantigens. Without patient-matched germline data, large germline databases are needed to minimize false positive mutation calling and mitigate ethnic disparities. C1 [Garofalo, Andrea; Reardon, Brendan; Miao, Diana; Liu, David; Oliver, Nelly; MacConaill, Laura; Giannakis, Marios; Ghazani, Arezou; Gray, Stacy; Janne, Pasi; Garber, Judy; Wagle, Nikhil; Garraway, Levi A.; Van Allen, Eliezer M.] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02115 USA. [Garofalo, Andrea; Reardon, Brendan; Taylor-Weiner, Amaro; Amin-Mansour, Ali; Miao, Diana; Liu, David; Giannakis, Marios; Wagle, Nikhil; Garraway, Levi A.; Van Allen, Eliezer M.] Broad Inst MIT & Harvard, 7 Cambridge Ctr, Cambridge, MA 02142 USA. [Sholl, Lynette; MacConaill, Laura; Ducar, Matthew; Rojas-Rudilla, Vanesa; Lindeman, Neal] Brigham & Womens Hosp, Dept Pathol, Boston, MA USA. [Joffe, Steve] Univ Penn, Dept Med Eth & Hlth Policy, Philadelphia, PA USA. [Wagle, Nikhil; Garraway, Levi A.; Van Allen, Eliezer M.] Dana Farber Canc Inst, Ctr Canc Precis Med, 450 Brookline Ave, Boston, MA 02115 USA. RP Garraway, LA; Van Allen, EM (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02115 USA.; Garraway, LA; Van Allen, EM (reprint author), Broad Inst MIT & Harvard, 7 Cambridge Ctr, Cambridge, MA 02142 USA.; Garraway, LA; Van Allen, EM (reprint author), Dana Farber Canc Inst, Ctr Canc Precis Med, 450 Brookline Ave, Boston, MA 02115 USA. EM Levi_Garraway@dfci.harvard.edu; Eliezerm_vanallen@dfci.harvard.edu FU NIH [U01HG006492]; BroadNext10; [K08 CA188615-02] FX This work was supported by NIH U01HG006492. This work was also supported by K08 CA188615-02 (E.M.V.) and BroadNext10 (E.M.V.). The funding organizations were not responsible for design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. NR 49 TC 7 Z9 7 U1 6 U2 8 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 26 PY 2016 VL 8 AR 79 DI 10.1186/s13073-016-0333-9 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA DR9IN UT WOS:000380210400001 PM 27460824 ER PT J AU Millstein, RA Woodruff, SI Linton, LS Edwards, CC Sallis, JF AF Millstein, Rachel A. Woodruff, Susan I. Linton, Leslie S. Edwards, Christine C. Sallis, James F. TI Development of measures to evaluate youth advocacy for obesity prevention SO INTERNATIONAL JOURNAL OF BEHAVIORAL NUTRITION AND PHYSICAL ACTIVITY LA English DT Article DE Built environment; Food environment; Physical activity environment; Adolescent; Psychometrics ID RANDOMIZED CONTROLLED-TRIAL; SCHOOL PHYSICAL-EDUCATION; HEALTH-PROMOTION; SELF-EFFICACY; CHILDHOOD OBESITY; STRUCTURAL MODELS; SCREENING MEASURE; TOBACCO CONTROL; PRIMARY-CARE; FIT INDEXES AB Background: Youth advocacy has been successfully used in substance use prevention but is a novel strategy in obesity prevention. As a precondition for building an evidence base for youth advocacy for obesity prevention, the present study aimed to develop and evaluate measures of youth advocacy mediator, process, and outcome variables. Methods: The Youth Engagement and Action for Health (YEAH!) program (San Diego County, CA) engaged youth and adult group leaders in advocacy for school and neighborhood improvements to nutrition and physical activity environments. Based on a model of youth advocacy, scales were developed to assess mediators, intervention processes, and proximal outcomes of youth advocacy for obesity prevention. Youth (baseline n = 136) and adult group leaders (baseline n = 47) completed surveys before and after advocacy projects. With baseline data, we created youth advocacy and adult leadership subscales using confirmatory factor analysis (CFA) and described their psychometric properties. Results: Youth came from 21 groups, were ages 9-22, and most were female. Most youth were non-White, and the largest ethnic group was Hispanic/Latino (35.6 %). The proposed factor structure held for most (14/20 youth and 1/2 adult) subscales. Modifications were necessary for 6 of the originally proposed 20 youth and 1 of the 2 adult multi-item subscales, which involved splitting larger subscales into two components and dropping low-performing items. Conclusions: Internally consistent scales to assess mediators, intervention processes, and proximal outcomes of youth advocacy for obesity prevention were developed. The resulting scales can be used in future studies to evaluate youth advocacy programs. C1 [Millstein, Rachel A.] San Diego State Univ Univ Calif San Diego Joint D, San Diego, CA 92103 USA. [Millstein, Rachel A.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Woodruff, Susan I.] San Diego State Univ, Sch Social Work, San Diego, CA 92182 USA. [Linton, Leslie S.; Edwards, Christine C.] Hlth Policy Consulting Grp, San Diego, CA 92182 USA. [Sallis, James F.] Univ Calif San Diego, Dept Family Med & Publ Hlth, San Diego, CA 92013 USA. RP Millstein, RA (reprint author), San Diego State Univ Univ Calif San Diego Joint D, San Diego, CA 92103 USA.; Millstein, RA (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. EM ramillstein@mgh.harvard.edu FU Active Living Research program of the Robert Wood Johnson Foundation [68508]; California Endowment; Kaiser Permanente FX This work was supported by a grant (# 68508) from the Active Living Research program of the Robert Wood Johnson Foundation. Program funding for YEAH! was provided by The California Endowment and Kaiser Permanente. NR 40 TC 0 Z9 0 U1 10 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5868 J9 INT J BEHAV NUTR PHY JI Int. J. Behav. Nutr. Phys. Act. PD JUL 26 PY 2016 VL 13 AR 84 DI 10.1186/s12966-016-0410-x PG 13 WC Nutrition & Dietetics; Physiology SC Nutrition & Dietetics; Physiology GA DS0RB UT WOS:000380303300001 PM 27461189 ER PT J AU Tawakol, A Tardif, JC AF Tawakol, Ahmed Tardif, Jean-Claude TI Early Detection of Cardiac Allograft Vasculopathy and Long-Term Risk After Heart Transplantation SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE cardiac transplantation; intravascular ultrasound; plaque instability; plaque instability; rejection; risk assessment ID INTRAVASCULAR ULTRASOUND; PLAQUE; INSIGHTS; DISEASE C1 [Tawakol, Ahmed] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Tawakol, Ahmed] Harvard Med Sch, Boston, MA USA. [Tardif, Jean-Claude] Univ Montreal, Montreal Heart Inst, Montreal, PQ, Canada. RP Tawakol, A (reprint author), Massachusetts Gen Hosp, Div Cardiol, 165 Cambridge St,Suite 400, Boston, MA 02114 USA. EM atawakol@mgh.harvard.edu NR 11 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUL 26 PY 2016 VL 68 IS 4 BP 393 EP 395 DI 10.1016/j.jacc.2016.05.046 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DR7JT UT WOS:000380076600010 PM 27443436 ER PT J AU Wee, B Pietras, A Ozawa, T Bazzoli, E Podlaha, O Antczak, C Westermark, B Nelander, S Uhrbom, L Forsberg-Nilsson, K Djaballah, H Michor, F Holland, EC AF Wee, Boyoung Pietras, Alexander Ozawa, Tatsuya Bazzoli, Elena Podlaha, Ondrej Antczak, Christophe Westermark, Bengt Nelander, Sven Uhrbom, Lene Forsberg-Nilsson, Karin Djaballah, Hakim Michor, Franziska Holland, Eric C. TI ABCG2 regulates self-renewal and stem cell marker expression but not tumorigenicity or radiation resistance of glioma cells SO SCIENTIFIC REPORTS LA English DT Article ID SIDE-POPULATION PHENOTYPE; HUMAN GLIOBLASTOMA; BRAIN-TUMORS; GROWTH; NOTCH; PATHWAY; MODELS AB Glioma cells with stem cell traits are thought to be responsible for tumor maintenance and therapeutic failure. Such cells can be enriched based on their inherent drug efflux capability mediated by the ABC transporter ABCG2 using the side population assay, and their characteristics include increased self-renewal, high stem cell marker expression and high tumorigenic capacity in vivo. Here, we show that ABCG2 can actively drive expression of stem cell markers and self-renewal in glioma cells. Stem cell markers and self-renewal was enriched in cells with high ABCG2 activity, and could be specifically inhibited by pharmacological and genetic ABCG2 inhibition. Importantly, despite regulating these key characteristics of stem-like tumor cells, ABCG2 activity did not affect radiation resistance or tumorigenicity in vivo. ABCG2 effects were Notch-independent and mediated by diverse mechanisms including the transcription factor Mef. Our data demonstrate that characteristics of tumor stem cells are separable, and highlight ABCG2 as a potential driver of glioma stemness. C1 [Wee, Boyoung] Canc Biol & Genet Program, New York, NY 10021 USA. [Wee, Boyoung] Brain Tumor Ctr, New York, NY 10021 USA. [Pietras, Alexander; Ozawa, Tatsuya; Holland, Eric C.] Fred Hutchinson Canc Res Ctr, Human Biol Div, Solid Tumor & Translat Res, Seattle, WA 98109 USA. [Pietras, Alexander; Ozawa, Tatsuya; Holland, Eric C.] Univ Washington, Neurosurg & Alvord Brain Tumor Ctr, Seattle, WA 98104 USA. [Pietras, Alexander] Lund Univ, Dept Lab Med, Translat Canc Res, SE-22363 Lund, Sweden. [Bazzoli, Elena] IRCCS, Ctr San Giovanni Di Dio Fatebenefratelli, I-25123 Bs, Italy. [Podlaha, Ondrej; Michor, Franziska] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Podlaha, Ondrej; Michor, Franziska] Harvard Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Antczak, Christophe; Djaballah, Hakim] Mem Sloan Kettering Canc Ctr, HTS Core Facil, New York, NY 10021 USA. [Westermark, Bengt; Nelander, Sven; Uhrbom, Lene; Forsberg-Nilsson, Karin] Uppsala Univ, Dept Immunol Genet & Pathol, Sci Life Lab, Rudbeck Lab, S-75185 Uppsala, Sweden. [Antczak, Christophe] Novartis Inst Biomed Res, Ctr Prote Chem, 250 Massachusetts Ave, Cambridge, MA 02139 USA. RP Holland, EC (reprint author), Fred Hutchinson Canc Res Ctr, Human Biol Div, Solid Tumor & Translat Res, Seattle, WA 98109 USA.; Holland, EC (reprint author), Univ Washington, Neurosurg & Alvord Brain Tumor Ctr, Seattle, WA 98104 USA. EM eholland@fhcrc.org OI Westermark, Bengt/0000-0001-7153-5545; Pietras, Alexander/0000-0002-5783-9347 FU NIH [U01 CA141502, U54 CA143798, U54CA163167, RO1 CA94842]; Commonwealth Foundation for Cancer Research; Experimental Therapeutics Center of MSKCC; William Randolph Hearst Fund in Experimental Therapeutics; Lillian S Wells Foundation; NIH/NCI Cancer Center [5 P30 CA008748-44]; Tegger Foundation; Swedish Research Council; Swedish Childhood Cancer Foundation; Swedish Cancer Society; Italian Ministry of Health [GR 2010 2312023] FX We thank J. Finney and Q. Zhang for their technical assistance, Mrs. A. Hermansson for cell culture, M. Menon, P. Anderson, Dr. J. Hendrix, and Dr. J. Wilshire at Memorial Sloan-Kettering FACS Core Facility for their technical assistance and Dr. R. Benezra for plasmids. This work was supported by NIH grants U01 CA141502, U54 CA143798, U54CA163167, and RO1 CA94842. The HTS Core Facility is partially supported by Mr. William H. Goodwin and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research, the Experimental Therapeutics Center of MSKCC, the William Randolph Hearst Fund in Experimental Therapeutics, the Lillian S Wells Foundation and by an NIH/NCI Cancer Center Support Grant 5 P30 CA008748-44. AP was supported by fellowships from the Tegger Foundation, the Swedish Research Council, and the Swedish Childhood Cancer Foundation. B.W., S.N., L.U. and K.F-.N. were supported by grants from the Swedish Cancer Society and the Swedish Research Council. EB was supported by the Italian Ministry of Health grant GR 2010 2312023. NR 28 TC 1 Z9 1 U1 2 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 26 PY 2016 VL 6 AR 25956 DI 10.1038/srep25956 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DR9HT UT WOS:000380208400001 PM 27456282 ER PT J AU Yang, ZJ Concannon, J Ng, KS Seyb, K Mortensen, LJ Ranganath, S Gu, FQ Levy, O Tong, ZX Martyn, K Zhao, WA Lin, CP Glicksman, MA Karp, JM AF Yang, Zijiang Concannon, John Ng, Kelvin S. Seyb, Kathleen Mortensen, Luke J. Ranganath, Sudhir Gu, Fangqi Levy, Oren Tong, Zhixiang Martyn, Keir Zhao, Weian Lin, Charles P. Glicksman, Marcie A. Karp, Jeffrey M. TI Tetrandrine identified in a small molecule screen to activate mesenchymal stem cells for enhanced immunomodulation SO SCIENTIFIC REPORTS LA English DT Article ID NF-KAPPA-B; NECROSIS-FACTOR-ALPHA; UMBILICAL-CORD BLOOD; STROMAL CELLS; PROSTAGLANDIN E-2; TNF-ALPHA; HEMATOPOIETIC STEM; BONE-MARROW; STEM/STROMAL CELLS; ENDOTHELIAL-CELLS AB Pre-treatment or priming of mesenchymal stem cells (MSC) prior to transplantation can significantly augment the immunosuppressive effect of MSC-based therapies. In this study, we screened a library of 1402 FDA-approved bioactive compounds to prime MSC. We identified tetrandrine as a potential hit that activates the secretion of prostaglandin E2 (PGE2), a potent immunosuppressive agent, by MSC. Tetrandrine increased MSC PGE2 secretion through the NF-kappa B/COX-2 signaling pathway. When co-cultured with mouse macrophages (RAW264.7), tetrandrine-primed MSC attenuated the level of TNF-alpha secreted by RAW264.7. Furthermore, systemic transplantation of primed MSC into a mouse ear skin inflammation model significantly reduced the level of TNF-alpha in the inflamed ear, compared to unprimed cells. Screening of small molecules to pre-condition cells prior to transplantation represents a promising strategy to boost the therapeutic potential of cell therapy. C1 [Yang, Zijiang; Ng, Kelvin S.; Ranganath, Sudhir; Gu, Fangqi; Levy, Oren; Tong, Zhixiang; Martyn, Keir; Karp, Jeffrey M.] Harvard MIT Hlth Sci & Technol, Cambridge, MA 02139 USA. [Yang, Zijiang; Ng, Kelvin S.; Ranganath, Sudhir; Gu, Fangqi; Levy, Oren; Tong, Zhixiang; Martyn, Keir; Lin, Charles P.; Glicksman, Marcie A.; Karp, Jeffrey M.] Harvard Med Sch, Brigham & Womens Hosp, Div Biomed Engn, Dept Med, Boston, MA 02115 USA. [Yang, Zijiang; Ng, Kelvin S.; Ranganath, Sudhir; Gu, Fangqi; Levy, Oren; Tong, Zhixiang; Martyn, Keir; Karp, Jeffrey M.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Yang, Zijiang; Lin, Charles P.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Yang, Zijiang] Shanghai Jiao Tong Univ, Adv Ind Technol Res Inst, Shanghai, Peoples R China. [Concannon, John; Seyb, Kathleen; Glicksman, Marcie A.] Harvard Med Sch, Brigham & Womens Hosp, Harvard NeuroDiscovery Ctr, Lab Drug Discovery Neurodegenerat, Cambridge, MA 02115 USA. [Mortensen, Luke J.] Univ Georgia, Dept Anim & Dairy Sci, Regenerat Biosci Ctr, Athens, GA 30602 USA. [Mortensen, Luke J.] Univ Georgia, Coll Engn, Athens, GA 30602 USA. [Ranganath, Sudhir] Siddaganga Inst Technol, Dept Chem Engn, Tumkur, India. [Zhao, Weian] Univ Calif Irvine, Dept Pharmaceut Sci, Sue & Bill Gross Stem Cell Res Ctr, Irvine, CA USA. [Zhao, Weian] Univ Calif Irvine, Dept Biomed Engn, Chao Family Comprehens Canc Ctr, Irvine, CA USA. [Zhao, Weian] Univ Calif Irvine, Edwards Lifesci Ctr Adv Cardiovasc Technol, Irvine, CA USA. RP Karp, JM (reprint author), Harvard MIT Hlth Sci & Technol, Cambridge, MA 02139 USA.; Glicksman, MA; Karp, JM (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Div Biomed Engn, Dept Med, Boston, MA 02115 USA.; Karp, JM (reprint author), Harvard Stem Cell Inst, Cambridge, MA 02138 USA.; Glicksman, MA (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Harvard NeuroDiscovery Ctr, Lab Drug Discovery Neurodegenerat, Cambridge, MA 02115 USA. EM mglicksman@rics.bwh.harvard.edu; jeffkarp.bwh@gmail.com FU National Institutes of Health (NIH) R01 [HL095722]; Department of Defense grant [W81XWH-13-1-0305] FX The authors wish to thank Cheryl H. Cui, Grace Sock Leng Teo, Sarah LeBlanc, Tara Stratton for their technical support. This work was funded in part by the National Institutes of Health (NIH) R01 grant HL095722 and a Department of Defense grant # W81XWH-13-1-0305 to JMK. NR 71 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUL 26 PY 2016 VL 6 AR 30263 DI 10.1038/srep30263 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DR9MA UT WOS:000380219600001 PM 27457881 ER PT J AU Zang, CZ Luyten, A Chen, J Liu, XS Shivdasani, RA AF Zang, Chongzhi Luyten, Annouck Chen, Justina Liu, X. Shirley Shivdasani, Ramesh A. TI NF-E2, FLI1 and RUNX1 collaborate at areas of dynamic chromatin to activate transcription in mature mouse megakaryocytes SO SCIENTIFIC REPORTS LA English DT Article ID HEMATOPOIETIC STEM-CELLS; GENOME-WIDE ANALYSIS; CHIP-SEQ; HISTONE MODIFICATIONS; ADULT HEMATOPOIESIS; PLATELET PRODUCTION; OCCUPANCY ANALYSIS; MICE LACKING; BONE-MARROW; DIFFERENTIATION AB Mutations in mouse and human Nfe2, Fli1 and Runx1 cause thrombocytopenia. We applied genome-wide chromatin dynamics and ChIP-seq to determine these transcription factors' (TFs) activities in terminal megakaryocyte (MK) maturation. Enhancers with H3K4me2-marked nucleosome pairs were most enriched for NF-E2, FLI and RUNX sequence motifs, suggesting that this TF triad controls much of the late MK program. ChIP-seq revealed NF-E2 occupancy near previously implicated target genes, whose expression is compromised in Nfe2-null cells, and many other genes that become active late in MK differentiation. FLI and RUNX were also the motifs most enriched near NF-E2 binding sites and ChIP-seq implicated FLI1 and RUNX1 in activation of late MK, including NF-E2-dependent, genes. Histones showed limited activation in regions of single TF binding, while enhancers that bind NF-E2 and either RUNX1, FLI1 or both TFs gave the highest signals for TF occupancy and H3K4me2; these enhancers associated best with genes activated late in MK maturation. Thus, three essential TFs co-occupy late-acting cis-elements and show evidence for additive activity at genes responsible for platelet assembly and release. These findings provide a rich dataset of TF and chromatin dynamics in primary MK and explain why individual TF losses cause thrombopocytopenia. C1 [Zang, Chongzhi; Liu, X. Shirley] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Zang, Chongzhi; Liu, X. Shirley] Harvard TH Chan Sch Publ Hlth, Boston, MA 02215 USA. [Zang, Chongzhi; Luyten, Annouck; Chen, Justina; Liu, X. Shirley; Shivdasani, Ramesh A.] Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02215 USA. [Luyten, Annouck; Chen, Justina; Shivdasani, Ramesh A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Luyten, Annouck; Shivdasani, Ramesh A.] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. [Shivdasani, Ramesh A.] Boston Childrens Hosp, Dept Pediat Hematol Oncol, Boston, MA 02115 USA. [Shivdasani, Ramesh A.] Harvard Med Sch, Boston, MA 02115 USA. RP Shivdasani, RA (reprint author), Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02215 USA.; Shivdasani, RA (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA.; Shivdasani, RA (reprint author), Harvard Med Sch, Dept Med, Boston, MA 02115 USA.; Shivdasani, RA (reprint author), Boston Childrens Hosp, Dept Pediat Hematol Oncol, Boston, MA 02115 USA.; Shivdasani, RA (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM ramesh_shivdasani@dfci.harvard.edu RI Zang, Chongzhi/D-1445-2011 FU US National Institutes of Health [R01 HL63143, R01 GM099409]; Leukemia & Lymphoma Society FX The authors thank Hui Huang and Alan B. Cantor for mutant mice and valuable discussions. This work was supported by US National Institutes of Health grants R01 HL63143 to R.A.S. and R01 GM099409 to X.S.L., and a fellowship from the Leukemia & Lymphoma Society to C.Z. NR 55 TC 0 Z9 0 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUL 26 PY 2016 VL 6 AR 30255 DI 10.1038/srep30255 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DR9LZ UT WOS:000380219500001 PM 27457419 ER PT J AU Ngo, D Sinha, S Shen, DX Kuhn, EW Keyes, MJ Shi, X Benson, MD O'Sullivan, JF Keshishian, H Farrell, LA Fifer, MA Vasan, RS Sabatine, MS Larson, MG Carr, SA Wang, TJ Gerszten, RE AF Ngo, Debby Sinha, Sumita Shen, Dongxiao Kuhn, Eric W. Keyes, Michelle J. Shi, Xu Benson, Mark D. O'Sullivan, John F. Keshishian, Hasmik Farrell, Laurie A. Fifer, Michael A. Vasan, Ramachandran S. Sabatine, Marc S. Larson, Martin G. Carr, Steven A. Wang, Thomas J. Gerszten, Robert E. TI Aptamer-Based Proteomic Profiling Reveals Novel Candidate Biomarkers and Pathways in Cardiovascular Disease SO CIRCULATION LA English DT Editorial Material DE aptamer, nucleotides; cardiovascular diseases; mass spectrometry; myocardial infarction; proteomics ID HYPERTROPHIC OBSTRUCTIVE CARDIOMYOPATHY; ACUTE MYOCARDIAL-INFARCTION; CORONARY-HEART-DISEASE; ACID-BINDING PROTEIN; MASS-SPECTROMETRY; SEPTAL REDUCTION; GROWTH-FACTOR; HUMAN PLASMA; FACTOR-I; RISK AB BACKGROUND: Single-stranded DNA aptamers are oligonucleotides of approximate to 50 base pairs in length selected for their ability to bind proteins with high specificity and affinity. Emerging DNA aptamer-based technologies may address limitations of existing proteomic techniques, including low sample throughput, which have hindered proteomic analyses of large cohorts. METHODS: To identify early biomarkers of myocardial injury, we applied an aptamer-based proteomic platform that measures 1129 proteins to a clinically relevant perturbational model of planned myocardial infarction (PMI), patients undergoing septal ablation for hypertrophic cardiomyopathy. Blood samples were obtained before and at 10 and 60 minutes after PMI, and protein changes were assessed by repeated-measures analysis of variance. The generalizability of our PMI findings was evaluated in a spontaneous myocardial infarction cohort (Wilcoxon rank-sum). We then tested the platform's ability to detect associations between proteins and Framingham Risk Score components in the Framingham Heart Study, performing regression analyses for each protein versus each clinical trait. RESULTS: We found 217 proteins that significantly changed in the peripheral vein blood after PMI in a derivation cohort (n=15; P<5.70E-5). Seventy-nine of these proteins were validated in an independent PMI cohort (n=15; P<2.30E-4); >85% were directionally consistent and reached nominal significance. We detected many protein changes that are novel in the context of myocardial injury, including Dickkopf-related protein 4, a WNT pathway inhibitor (peak increase 124%, P=1.29E-15) and cripto, a growth factor important in cardiac development (peak increase 64%, P=1.74E-4). Among the 40 validated proteins that increased within 1 hour after PMI, 23 were also elevated in patients with spontaneous myocardial infarction (n=46; P<0.05). Framingham Heart Study analyses revealed 156 significant protein associations with the Framingham Risk Score (n=899), including aminoacylase 1 (beta=0.3386, P=2.54E-22) and trigger factor 2 (beta=0.2846, P=5.71E-17). Furthermore, we developed a novel workflow integrating DNA-based immunoaffinity with mass spectrometry to analytically validate aptamer specificity. CONCLUSIONS: Our results highlight an emerging proteomics tool capable of profiling >1000 low-abundance analytes with high sensitivity and high precision, applicable both to well-phenotyped perturbational studies and large human cohorts, as well. C1 [Gerszten, Robert E.] Beth Israel Deaconess Med Ctr, Div Cardiovasc Med, 330 Brookline Ave, Boston, MA 02115 USA. [Kuhn, Eric W.; Keshishian, Hasmik; Carr, Steven A.; Gerszten, Robert E.] Broad Inst Harvard & MIT, 415 Main St, Cambridge, MA 02142 USA. [Ngo, Debby] Harvard Med Sch, Massachusetts Gen Hosp, Div Pulm & Crit Care Med, Dept Med, Boston, MA USA. [Ngo, Debby; Sinha, Sumita; Shen, Dongxiao; Keyes, Michelle J.; Shi, Xu; Benson, Mark D.; O'Sullivan, John F.; Farrell, Laurie A.; Gerszten, Robert E.] Harvard Med Sch, Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA USA. [Benson, Mark D.; Sabatine, Marc S.] Brigham & Womens Hosp, Div Cardiovasc, 75 Francis St, Boston, MA 02115 USA. [Fifer, Michael A.; Sabatine, Marc S.; Gerszten, Robert E.] Harvard Med Sch, Massachusetts Gen Hosp, Div Cardiol, Boston, MA USA. [Vasan, Ramachandran S.] Boston Univ, Dept Med, Prevent Med Sect, Sch Med, Boston, MA 02215 USA. [Larson, Martin G.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Larson, Martin G.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Wang, Thomas J.] Vanderbilt Univ, Div Cardiovasc Med, 221 Kirkland Hall, Nashville, TN 37235 USA. RP Gerszten, RE (reprint author), Beth Israel Deaconess Med Ctr, Div Cardiovasc Med, 330 Brookline Ave, Boston, MA 02115 USA.; Carr, SA (reprint author), Broad Inst Harvard & MIT, 415 Main St, Cambridge, MA 02142 USA. EM scarr@broadinstitute.org; rgerszte@bidmc.harvard.edu OI Ramachandran, Vasan/0000-0001-7357-5970 FU [R01HL132320]; NCI NIH HHS [U24 CA160034]; NHLBI NIH HHS [HHSN268201000033C, N01HC25195, R01 HL132320, T32 HL007208]; NIGMS NIH HHS [K01 GM103817] NR 40 TC 6 Z9 6 U1 4 U2 10 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 26 PY 2016 VL 134 IS 4 BP 270 EP + DI 10.1161/CIRCULATIONAHA.116.021803 PG 145 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DR8GP UT WOS:000380136700008 PM 27444932 ER PT J AU Bohula, EA Bonaca, MP Braunwald, E Aylward, PE Corbalan, R De Ferrari, GM He, P Lewis, BS Merlini, PA Murphy, SA Sabatine, MS Scirica, BM Morrow, DA AF Bohula, Erin A. Bonaca, Marc P. Braunwald, Eugene Aylward, Philip E. Corbalan, Ramon De Ferrari, Gaetano M. He, Ping Lewis, Basil S. Merlini, Piera A. Murphy, Sabina A. Sabatine, Marc S. Scirica, Benjamin M. Morrow, David A. TI Atherothrombotic Risk Stratification and the Efficacy and Safety of Vorapaxar in Patients With Stable Ischemic Heart Disease and Previous Myocardial Infarction SO CIRCULATION LA English DT Article DE atherosclerosis; receptors, thrombin; risk assessment; secondary prevention ID ASSOCIATION TASK-FORCE; SECONDARY PREVENTION; PRACTICE GUIDELINES; AMERICAN-COLLEGE; 50 TRIAL; MANAGEMENT; EVENTS; SCORE AB BACKGROUND: Patients with stable ischemic heart disease and previous myocardial infarction (MI) vary in their risk for recurrent cardiovascular events. Atherothrombotic risk assessment may be useful to identify high-risk patients who have the greatest potential to benefit from more intensive secondary preventive therapy such as treatment with vorapaxar. METHODS: We identified independent clinical indicators of atherothrombotic risk among 8598 stable, placebo-treated patients with a previous MI followed up for 2.5 years (median) in TRA 2 degrees P-TIMI 50 [Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events-TIMI 50]. The efficacy and safety of vorapaxar (SCH 530348; MK-5348) were assessed by baseline risk among patients with previous MI without prior stroke or transient ischemic attack for whom there is a clinical indication for vorapaxar. End points were cardiovascular death, MI, or ischemic stroke and GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) severe bleeding. RESULTS: The 9 independent risk predictors were age, diabetes mellitus, hypertension, smoking, peripheral arterial disease, previous stroke, previous coronary bypass grafting, heart failure, and renal dysfunction. A simple integer-based scheme using these predictors showed a strong graded relationship with the rate of cardiovascular death/MI/ischemic stroke and the individual components (P for trend <0.001 for all). High-risk patients (>= 3 risk indicators; 20% of population) had a 3.2% absolute risk reduction in cardiovascular disease/MI/ischemic stroke with vorapaxar, and intermediate-risk patients (1-2 risk indicators; 61%) had a 2.1% absolute risk reduction (P<0.001 each), translating to a number needed to treat of 31 and 48. Bleeding increased across risk groups (P for trend <0.01); however, net clinical outcome was increasingly favorable with vorapaxar across risk groups. Fatal bleeding or intracranial hemorrhage was 0.9% with both treatments in high-risk patients. CONCLUSIONS: Stratification of baseline atherothrombotic risk can assist with therapeutic decision making for vorapaxar use for secondary prevention after MI. C1 [Bohula, Erin A.; Bonaca, Marc P.; Braunwald, Eugene; He, Ping; Murphy, Sabina A.; Sabatine, Marc S.; Scirica, Benjamin M.; Morrow, David A.] Harvard Med Sch, Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp,Dept Med, Boston, MA USA. [Aylward, Philip E.] Flinders Univ & Med Ctr, South Australian Hlth & Res Inst, Adelaide, SA, Australia. [Corbalan, Ramon] Pontificia Univ Catolica Chile, Sch Med, Div Cardiovasc Dis, Alameda 340, Santiago, Chile. [De Ferrari, Gaetano M.] Fdn IRCCS Policlin San Matteo, Dept Cardiol, Pavia, Italy. [Lewis, Basil S.] Technion, Lady Davis Carmel Med Ctr, Haifa, Israel. [Lewis, Basil S.] Technion, Ruth & Bruce Rappaport Sch Med, Haifa, Israel. [Merlini, Piera A.] Azienda Osped Niguarda Ca Granda, Div Cardiol 4, Milan, Italy. RP Bohula, EA (reprint author), Brigham & Womens Hosp, TIMI Study Grp, Div Cardiovasc, 350 Longwood Ave,First Off Floor, Boston, MA 02115 USA. EM ebohula@partners.org FU Merck and Co. FX The TRA2 degrees P-TIMI 50 Trial was sponsored by Merck and Co. NR 17 TC 3 Z9 3 U1 1 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 26 PY 2016 VL 134 IS 4 BP 304 EP + DI 10.1161/CIRCULATIONAHA.115.019861 PG 22 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DR8GP UT WOS:000380136700012 PM 27440003 ER PT J AU Peralta, CA McClure, LA Scherzer, R Odden, MC White, CL Shlipak, M Benavente, O Pergola, PE AF Peralta, Carmen A. McClure, Leslie A. Scherzer, Rebecca Odden, Michelle C. White, Carole L. Shlipak, Michael Benavente, Oscar Pergola, Pablo E. TI Response by Peralta et al to Letter Regarding Article, "Effect of Intensive Versus Usual Blood Pressure Control on Kidney Function Among Individuals With Prior Lacunar Stroke: A Post Hoc Analysis of the Secondary Prevention of Small Subcortical Strokes (SPS3) Randomized Trial" SO CIRCULATION LA English DT Letter C1 [Peralta, Carmen A.; Scherzer, Rebecca; Shlipak, Michael] Univ Calif San Francisco, Kidney Hlth Res Collaborat, San Francisco, CA 94143 USA. [Peralta, Carmen A.; Scherzer, Rebecca; Shlipak, Michael] San Francisco VA Med Ctr, San Francisco, CA USA. [McClure, Leslie A.] Univ Alabama Birmingham, Birmingham, AL USA. [Odden, Michelle C.] Oregon State Univ, Corvallis, OR 97331 USA. [White, Carole L.; Pergola, Pablo E.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Benavente, Oscar] Univ British Columbia, Vancouver, BC, Canada. RP Peralta, CA (reprint author), Univ Calif San Francisco, Kidney Hlth Res Collaborat, San Francisco, CA 94143 USA.; Peralta, CA (reprint author), San Francisco VA Med Ctr, San Francisco, CA USA. FU NIA NIH HHS [R01 AG046206] NR 3 TC 0 Z9 0 U1 1 U2 3 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 26 PY 2016 VL 134 IS 4 BP E26 EP E27 DI 10.1161/CIRCULATIONAHA.116.022942 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DR8GP UT WOS:000380136700005 PM 27462061 ER PT J AU Tsao, H Weinstock, MA AF Tsao, Hensin Weinstock, Martin A. TI Visual Inspection and the US Preventive Services Task Force Recommendation on Skin Cancer Screening SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID MELANOMA MORTALITY; GERMANY; PROGRAM C1 [Tsao, Hensin] Massachusetts Gen Hosp, Dept Dermatol, Wellman Ctr Photomed, 50 Blossom St, Boston, MA 02114 USA. [Weinstock, Martin A.] Brown Univ, Dept Dermatol, Warren Alpert Med Sch, Providence, RI 02912 USA. [Weinstock, Martin A.] Vet Affairs Med Ctr, Div Dermatol, Providence, RI USA. RP Tsao, H (reprint author), Massachusetts Gen Hosp, Dept Dermatol, Wellman Ctr Photomed, 50 Blossom St, Boston, MA 02114 USA. EM htsao@mgh.harvard.edu NR 24 TC 2 Z9 2 U1 1 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 26 PY 2016 VL 316 IS 4 BP 398 EP 400 DI 10.1001/jama.2016.9850 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA DR9MV UT WOS:000380221700017 PM 27458944 ER PT J AU Brown, PD Jaeckle, K Ballman, KV Farace, E Cerhan, JH Anderson, SK Carrero, XW Barker, FG Deming, R Burri, SH Menard, C Chung, C Stieber, VW Pollock, BE Galanis, E Buckner, JC Asher, AL AF Brown, Paul D. Jaeckle, Kurt Ballman, Karla V. Farace, Elana Cerhan, Jane H. Anderson, S. Keith Carrero, Xiomara W. Barker, Fred G., II Deming, Richard Burri, Stuart H. Menard, Cynthia Chung, Caroline Stieber, Volker W. Pollock, Bruce E. Galanis, Evanthia Buckner, Jan C. Asher, Anthony L. TI Effect of Radiosurgery Alone vs Radiosurgery With Whole Brain Radiation Therapy on Cognitive Function in Patients With 1 to 3 Brain Metastases A Randomized Clinical Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID QUALITY-OF-LIFE; PHASE-III TRIAL; NEUROCOGNITIVE FUNCTION; STEREOTACTIC RADIOSURGERY; SURGICAL RESECTION; RADIOTHERAPY; CANCER; TUMORS AB IMPORTANCE Whole brain radiotherapy (WBRT) significantly improves tumor control in the brain after stereotactic radiosurgery (SRS), yet because of its association with cognitive decline, its role in the treatment of patients with brain metastases remains controversial. OBJECTIVE To determine whether there is less cognitive deterioration at 3 months after SRS alone vs SRS plus WBRT. DESIGN, SETTING, AND PARTICIPANTS At 34 institutions in North America, patients with 1 to 3 brain metastases were randomized to receive SRS or SRS plus WBRT between February 2002 and December 2013. INTERVENTIONS The WBRT dose schedule was 30 Gy in 12 fractions; the SRS dose was 18 to 22 Gy in the SRS plus WBRT group and 20 to 24 Gy for SRS alone. MAIN OUTCOMES AND MEASURES The primary end pointwas cognitive deterioration (decline >1 SD from baseline on at least 1 cognitive test at 3 months) in participants who completed the baseline and 3-month assessments. Secondary end points included time to intracranial failure, quality of life, functional independence, long-term cognitive status, and overall survival. RESULTS There were 213 randomized participants (SRS alone, n=111; SRS plus WBRT, n=102) with a mean age of 60.6 years (SD, 10.5 years); 103 (48%) were women. There was less cognitive deterioration at 3 months after SRS alone (40/63 patients [63.5%]) than when combined with WBRT (44/48 patients [91.7%]; difference, -28.2%; 90% CI, -41.9% to -14.4%; P<.001). Quality of life was higher at 3 months with SRS alone, including overall quality of life (mean change from baseline, -0.1 vs -12.0 points; mean difference, 11.9; 95% CI, 4.8-19.0 points; P=.001). Time to intracranial failure was significantly shorter for SRS alone compared with SRS plus WBRT (hazard ratio, 3.6; 95% CI, 2.2-5.9; P<.001). There was no significant difference in functional independence at 3 months between the treatment groups (mean change from baseline, -1.5 points for SRS alone vs -4.2 points for SRS plus WBRT; mean difference, 2.7 points; 95% CI, -2.0 to 7.4 points; P=.26). Median overall survival was 10.4 months for SRS alone and 7.4 months for SRS plus WBRT (hazard ratio, 1.02; 95% CI, 0.75-1.38; P=.92). For long-term survivors, the incidence of cognitive deterioration was less after SRS alone at 3 months (5/11 [45.5%] vs 16/17 [94.1%]; difference, -48.7%; 95% CI, -87.6% to -9.7%; P=.007) and at 12 months (6/10 [60%] vs 17/18 [94.4%]; difference, -34.4%; 95% CI, -74.4% to 5.5%; P=.04). CONCLUSIONS AND RELEVANCE Among patients with 1 to 3 brain metastases, the use of SRS alone, compared with SRS combined with WBRT, resulted in less cognitive deterioration at 3 months. In the absence of a difference in overall survival, these findings suggest that for patients with 1 to 3 brainmetastases amenable to radiosurgery, SRS alone may be a preferred strategy. C1 [Brown, Paul D.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Brown, Paul D.; Cerhan, Jane H.; Pollock, Bruce E.; Galanis, Evanthia; Buckner, Jan C.] Mayo Clin, Rochester, MI USA. [Jaeckle, Kurt] Mayo Clin, Jacksonville, FL 32224 USA. [Ballman, Karla V.; Anderson, S. Keith; Carrero, Xiomara W.] Mayo Clin, Alliance Stat & Data Ctr, Rochester, MN USA. [Farace, Elana] Penn State Hershey Med Ctr, Hershey, PA USA. [Barker, Fred G., II] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Deming, Richard] Mercy Med Ctr, Des Moines, IA USA. [Burri, Stuart H.; Asher, Anthony L.] Carolinas Healthcare Syst, Levine Canc Inst, Charlotte, NC USA. [Menard, Cynthia; Chung, Caroline] Princess Margaret Canc Ctr, Toronto, ON, Canada. [Menard, Cynthia] Ctr Hosp Univ Montreal, Montreal, PQ, Canada. [Stieber, Volker W.] Novant Hlth Forsyth Med Ctr, Winston Salem, NC USA. [Asher, Anthony L.] Carolina Neurosurg & Spine Associates, Charlotte, NC USA. RP Brown, PD (reprint author), Mayo Clin, Dept Radiat Oncol, 200 First St SW, Rochester, MN 55905 USA. EM brown.paul@mayo.edu FU NCI [U10CA180821, U10CA180882, CA076001, CA025224, RTOG U10CA21661, NRG U10CA180868] FX This trial was conducted by the NCCTG (Alliance for Clinical Trials in Oncology) in collaboration with other cooperative groups including the Radiation Therapy Oncology Group, and was supported by grants U10CA180821, U10CA180882, CA076001, CA025224, RTOG U10CA21661, and NRG U10CA180868 from the NCI. There were no commercial sponsors of this study. Data confidentiality was governed by National Institutes of Health policy. NR 25 TC 18 Z9 18 U1 4 U2 9 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 26 PY 2016 VL 316 IS 4 BP 401 EP 409 DI 10.1001/jama.2016.9839 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA DR9MV UT WOS:000380221700018 PM 27458945 ER PT J AU Bibbins-Domingo, K Grossman, DC Curry, SJ Davidson, KW Ebell, M Epling, JW Garcia, FAR Gillman, MW Kemper, AR Krist, AH Kurth, AE Landefeld, CS Mangione, CM Phillips, WR Phipps, MG Pignone, MP Siu, AL AF Bibbins-Domingo, Kirsten Grossman, David C. Curry, Susan J. Davidson, Karina W. Ebell, Mark Epling, John W., Jr. Garcia, Francisco A. R. Gillman, Matthew W. Kemper, Alex R. Krist, Alex H. Kurth, Ann E. Landefeld, C. Seth Mangione, Carol M. Phillips, William R. Phipps, Maureen G. Pignone, Michael P. Siu, Albert L. CA US Preventive Serv Task Force TI Screening for Skin Cancer US Preventive Services Task Force Recommendation Statement SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Review ID MELANOMA; DERMATOLOGISTS; PROGRAM AB IMPORTANCE Basal and squamous cell carcinoma are the most common types of cancer in the United States and represent the vast majority of all cases of skin cancer; however, they rarely result in death or substantial morbidity, whereas melanoma skin cancer has notably higher mortality rates. In 2016, an estimated 76 400 US men and women will develop melanoma and 10 100 will die from the disease. OBJECTIVE To update the 2009 US Preventive Services Task Force (USPSTF) recommendation on screening for skin cancer. EVIDENCE REVIEW The USPSTF reviewed the evidence on the effectiveness of screening for skin cancer with a clinical visual skin examination in reducing skin cancer morbidity and mortality and death from any cause; its potential harms, including any harms resulting from associated diagnostic follow-up; its test characteristics when performed by a primary care clinician vs a dermatologist; and whether its use leads to earlier detection of skin cancer compared with usual care. FINDINGS Evidence to assess the net benefit of screening for skin cancer with a clinical visual skin examination is limited. Direct evidence on the effectiveness of screening in reducing melanoma morbidity and mortality is limited to a single fair-quality ecologic study with important methodological limitations. Information on harms is similarly sparse. The potential for harm clearly exists, including a high rate of unnecessary biopsies, possibly resulting in cosmetic or, more rarely, functional adverse effects, and the risk of overdiagnosis and overtreatment. CONCLUSIONS AND RECOMMENDATION The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of visual skin examination by a clinician to screen for skin cancer in adults (I statement). C1 [Bibbins-Domingo, Kirsten] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Grossman, David C.] Grp Hlth Res Inst, Seattle, WA USA. [Curry, Susan J.] Univ Iowa, Iowa City, IA USA. [Davidson, Karina W.] Columbia Univ, New York, NY USA. [Ebell, Mark] Univ Georgia, Athens, GA 30602 USA. [Epling, John W., Jr.] SUNY Upstate Med Univ, Syracuse, NY 13210 USA. [Garcia, Francisco A. R.] Pima Cty Dept Hlth, Tucson, AZ USA. [Gillman, Matthew W.] Harvard Med Sch, Boston, MA USA. [Gillman, Matthew W.] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Kemper, Alex R.] Duke Univ, Durham, NC USA. [Krist, Alex H.] Fairfax Family Practice Residency, Fairfax, VA USA. [Krist, Alex H.] Virginia Commonwealth Univ, Richmond, VA 23284 USA. [Kurth, Ann E.] Yale Univ, New Haven, CT USA. [Landefeld, C. Seth] Univ Alabama, Tuscaloosa, AL 35487 USA. [Mangione, Carol M.] Univ Calif Los Angeles, Los Angeles, CA USA. Univ Washington, Seattle, WA 98195 USA. Brown Univ, Providence, RI 02912 USA. [Pignone, Michael P.] Univ Texas Austin, Austin, TX 78712 USA. [Siu, Albert L.] Mt Sinai Sch Med, New York, NY USA. [Siu, Albert L.] James J Peters Vet Affairs Med Ctr, Bronx, NY USA. RP Bibbins-Domingo, K (reprint author), Univ Calif San Francisco, San Francisco, CA 94143 USA. EM chair@uspstf.net OI Epling, John W/0000-0001-9445-8669 NR 21 TC 7 Z9 7 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 26 PY 2016 VL 316 IS 4 BP 429 EP 435 DI 10.1001/jama.2016.8465 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA DR9MV UT WOS:000380221700021 ER PT J AU Jacob, T Snyder, W Feng, J Choi, H AF Jacob, Theju Snyder, Wesley Feng, Jing Choi, HeeSun TI A neural model for straight line detection in the human visual cortex SO NEUROCOMPUTING LA English DT Article DE Hough transform; Straight line detection; Primary visual cortex; Oja's rule; Orientation columns ID MONKEY STRIATE CORTEX; FUNCTIONAL ARCHITECTURE; RECEPTIVE FIELDS; NATURAL IMAGES; NETWORK MODEL; RECOGNITION; ORIENTATION; EMERGENCE; COLUMNS; FILTERS AB Building a computational model for how the visual cortex identifies objects is a problem that has attracted much attention over the years. Generally, the interest has been in creating models that are translation, rotation, and luminance invariant. In this paper, we utilize the philosophy of Hough Transform to create a model for detecting straight lines under conditions of discontinuity and noise. A neural network that can learn to perform a Hough Transform-like computation in an unsupervised manner is the main takeaway from this work. Performance of the network when presented with straight lines is compared with that of human subjects. Optical illusions like the Poggendorff illusion could potentially find an explanation in the framework of our model. (C) 2016 Elsevier B.V. All rights reserved. C1 [Jacob, Theju; Snyder, Wesley] NC State Univ, Dept Elect & Comp Engn, Raleigh, NC USA. [Feng, Jing; Choi, HeeSun] NC State Univ, Dept Psychol, Raleigh, NC USA. RP Jacob, T (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. EM theju.jacob@mgh.harvard.edu NR 42 TC 0 Z9 0 U1 4 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-2312 EI 1872-8286 J9 NEUROCOMPUTING JI Neurocomputing PD JUL 26 PY 2016 VL 199 BP 185 EP 196 DI 10.1016/j.neucom.2016.03.023 PG 12 WC Computer Science, Artificial Intelligence SC Computer Science GA DN7BN UT WOS:000377230400018 ER PT J AU McMahan, RH Porsche, CE Edwards, MG Rosen, HR AF McMahan, Rachel H. Porsche, Cara E. Edwards, Michael G. Rosen, Hugo R. TI Free Fatty Acids Differentially Downregulate Chemokines in Liver Sinusoidal Endothelial Cells: Insights into Non-Alcoholic Fatty Liver Disease SO PLOS ONE LA English DT Article ID LIPID-ACCUMULATION; INSULIN-RESISTANCE; HEPATIC STEATOSIS; CXC CHEMOKINE; INJURY; MODEL; STEATOHEPATITIS; RECRUITMENT; ACTIVATION; LIPOTOXICITY AB Non-alcoholic fatty liver disease is a prevalent problem throughout the western world. Liver sinusoidal endothelial cells (LSEC) have been shown to play important roles in liver injury and repair, but their role in the underlying pathogenetic mechanisms of non-alcoholic fatty liver disease remains undefined. Here, we evaluated the effects of steatosis on LSEC gene expression in a murine model of non-alcoholic fatty liver disease and an immortalized LSEC line. Using microarray we identified distinct gene expression profiles following exposure to free fatty acids. Gene pathway analysis showed a number of differentially expressed genes including those involved in lipid metabolism and signaling and inflammation. Interestingly, in contrast to hepatocytes, fatty acids led to decreased expression of pro-inflammatory chemokines including CCL2 (MCP-1), CXCL10 and CXCL16 in both primary and LSEC cell lines. Chemokine downregulation translated into a significant inhibition of monocyte migration and LSECs isolated from steatotic livers demonstrated a similar shift towards an antiinflammatory phenotype. Overall, these pathways may represent a compensatory mechanism to reverse the liver damage associated with non-alcoholic fatty liver disease. C1 [McMahan, Rachel H.; Porsche, Cara E.; Rosen, Hugo R.] Univ Colorado Denver, Div Gastroenterol & Hepatol, Dept Med, Aurora, CO 80045 USA. [Edwards, Michael G.] Univ Colorado Denver, Div Pulm Sci & Crit Care Med, Dept Med, Aurora, CO USA. [Rosen, Hugo R.] Univ Colorado Denver, Dept Microbiol & Immunol, Aurora, CO 80045 USA. [Rosen, Hugo R.] Denver Vet Affairs Med Ctr, Denver, CO 80220 USA. RP Rosen, HR (reprint author), Univ Colorado Denver, Div Gastroenterol & Hepatol, Dept Med, Aurora, CO 80045 USA.; Rosen, HR (reprint author), Univ Colorado Denver, Dept Microbiol & Immunol, Aurora, CO 80045 USA.; Rosen, HR (reprint author), Denver Vet Affairs Med Ctr, Denver, CO 80220 USA. EM Hugo.Rosen@ucdenver.edu FU NIH/NIDDK [K01DKO96025]; VA Merit Review Grant FX RHM was funded by NIH/NIDDK K01DKO96025. HRR was funded by a VA Merit Review Grant. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 2 Z9 2 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 25 PY 2016 VL 11 IS 7 AR e0159217 DI 10.1371/journal.pone.0159217 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DT5ID UT WOS:000381515200013 PM 27454769 ER PT J AU Wilhelm, C Harrison, OJ Schmitt, V Pelletier, M Spencer, SP Urban, JF Ploch, M Ramalingam, TR Siegel, RM Belkaid, Y AF Wilhelm, Christoph Harrison, Oliver J. Schmitt, Vanessa Pelletier, Martin Spencer, Sean P. Urban, Joseph F., Jr. Ploch, Michelle Ramalingam, Thirumalai R. Siegel, Richard M. Belkaid, Yasmine TI Critical role of fatty acid metabolism in ILC2-mediated barrier protection during malnutrition and helminth infection SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID INNATE LYMPHOID-CELLS; RETINOIC ACID; T-CELLS; IMMUNITY; ALPHA; INFLAMMATION; ADAPTATION; ACTIVATION; LIPOLYSIS; TISSUE AB Innate lymphoid cells (ILC) play an important role in many immune processes, including control of infections, inflammation, and tissue repair. To date, little is known about the metabolism of ILC and whether these cells can metabolically adapt in response to environmental signals. Here we show that type 2 innate lymphoid cells (ILC2), important mediators of barrier immunity, predominantly depend on fatty acid (FA) metabolism during helminth infection. Further, in situations where an essential nutrient, such as vitamin A, is limited, ILC2 sustain their function and selectively maintain interleukin 13 (IL-13) production via increased acquisition and utilization of FA. Together, these results reveal that ILC2 preferentially use FAs to maintain their function in the context of helminth infection or malnutrition and propose that enhanced FA usage and FA-dependent IL-13 production by ILC2 could represent a host adaptation to maintain barrier immunity under dietary restriction. C1 [Wilhelm, Christoph; Harrison, Oliver J.; Spencer, Sean P.; Belkaid, Yasmine] NIAID, Mucosal Immunol Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Ramalingam, Thirumalai R.] NIAID, Immunopathogenesis Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Pelletier, Martin; Ploch, Michelle; Siegel, Richard M.] NIAMSD, Immunoregulat Sect, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. [Wilhelm, Christoph; Schmitt, Vanessa] Univ Bonn, Univ Hosp Bonn, Inst Clin Chem & Clin Pharmacol, D-53127 Bonn, Germany. [Spencer, Sean P.] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Inst Immunol, Philadelphia, PA 19104 USA. [Urban, Joseph F., Jr.] ARS, Diet Genom & Immunol Lab, Beltsville Human Nutr Res Ctr, USDA, Beltsville, MD 20705 USA. [Pelletier, Martin] Univ Laval, CHU Quebec, Ctr Rech, Dept Microbiol & Immunol, Quebec City, PQ G1V 4G2, Canada. [Spencer, Sean P.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Wilhelm, C; Belkaid, Y (reprint author), NIAID, Mucosal Immunol Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.; Wilhelm, C (reprint author), Univ Bonn, Univ Hosp Bonn, Inst Clin Chem & Clin Pharmacol, D-53127 Bonn, Germany. EM christoph.wilhelm@uni-bonn.de; ybelkaid@niaid.nih.gov OI Spencer, Sean/0000-0002-7328-5399; Wilhelm, Christoph/0000-0002-9839-0291; Pelletier, Martin/0000-0001-5033-4947; Ploch, Michelle/0000-0003-2565-1750 FU Division of Intramural Research of the NIAID; Ministry for Science and Education of North-Rhine-Westfalia; Deutsche Forschungsgemeinschaft Excellence Cluster ImmunoSensation; Human Frontier Science Program; U.S. Department of Agriculture/Agricultural Research Service Project Plan [8040-51000-058-00D] FX This work was supported by the Division of Intramural Research of the NIAID, the Ministry for Science and Education of North-Rhine-Westfalia (C. Wilhelm), the Deutsche Forschungsgemeinschaft Excellence Cluster ImmunoSensation (C. Wilhelm), and the Human Frontier Science Program and by funds from the U.S. Department of Agriculture/Agricultural Research Service Project Plan #8040-51000-058-00D (J.F. Urban Jr.). The NIAID Division of Intramural Research Animal Care and Use Program, as part of the National Institutes of Health Intramural Research Program, approved all of the experimental procedures (protocol LP3D-7E). NR 32 TC 2 Z9 2 U1 3 U2 3 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 25 PY 2016 VL 213 IS 8 BP 1409 EP 1418 DI 10.1084/jem.20151448 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA DS5VN UT WOS:000380851200004 PM 27432938 ER PT J AU Shimizu, T Kubovcakova, L Nienhold, R Zmajkovic, J Meyer, SC Hao-Shen, H Geier, F Dirnhofer, S Guglielmelli, P Vannucchi, AM Feenstra, JDM Kralovics, R Orkin, SH Skoda, RC AF Shimizu, Takafumi Kubovcakova, Lucia Nienhold, Ronny Zmajkovic, Jakub Meyer, Sara C. Hao-Shen, Hui Geier, Florian Dirnhofer, Stephan Guglielmelli, Paola Vannucchi, Alessandro M. Feenstra, Jelena D. Milosevic Kralovics, Robert Orkin, Stuart H. Skoda, Radek C. TI Loss of Ezh2 synergizes with JAK2-V617F in initiating myeloproliferative neoplasms and promoting myelofibrosis SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID HEMATOPOIETIC STEM-CELLS; WORLD-HEALTH-ORGANIZATION; TYROSINE KINASE JAK2; REPRESSIVE COMPLEX 2; GROUP GENE EZH2; MYELOID METAPLASIA; POLYCYTHEMIA-VERA; SOMATIC MUTATIONS; MYELODYSPLASTIC SYNDROMES; ACTIVATING MUTATION AB Myeloproliferative neoplasm (MPN) patients frequently show co-occurrence of JAK2-V617F and mutations in epigenetic regulator genes, including EZH2. In this study, we show that JAK2-V617F and loss of Ezh2 in hematopoietic cells contribute synergistically to the development of MPN. The MPN phenotype induced by JAK2-V617F was accentuated in JAK2-V617F;Ezh2(-/-) mice, resulting in very high platelet and neutrophil counts, more advanced myelofibrosis, and reduced survival. These mice also displayed expansion of the stem cell and progenitor cell compartments and a shift of differentiation toward megakaryopoiesis at the expense of erythropoiesis. Single cell limiting dilution transplantation with bone marrow from JAK2-V617F; Ezh2(+/-) mice showed increased reconstitution and MPN disease initiation potential compared with JAK2-V617F alone. RNA sequencing in Ezh2-deficient hematopoietic stem cells (HSCs) and megakaryocytic erythroid progenitors identified highly up-regulated genes, including Lin28b and Hmga2, and chromatin immunoprecipitation (ChIP)-quantitative PCR (qPCR) analysis of their promoters revealed decreased H3K27me3 deposition. Forced expression of Hmga2 resulted in increased chimerism and platelet counts in recipients of retrovirally transduced HSCs. JAK2-V617F-expressing mice treated with an Ezh2 inhibitor showed higher platelet counts than vehicle controls. Our data support the proposed tumor suppressor function of EZH2 in patients with MPN and call for caution when considering using Ezh2 inhibitors in MPN. C1 [Shimizu, Takafumi; Kubovcakova, Lucia; Nienhold, Ronny; Zmajkovic, Jakub; Meyer, Sara C.; Hao-Shen, Hui; Skoda, Radek C.] Univ Basel Hosp, Dept Biomed, Expt Hematol, CH-4031 Basel, Switzerland. [Shimizu, Takafumi; Kubovcakova, Lucia; Nienhold, Ronny; Zmajkovic, Jakub; Meyer, Sara C.; Hao-Shen, Hui; Skoda, Radek C.] Univ Basel, CH-4031 Basel, Switzerland. [Geier, Florian] Univ Basel Hosp, Bioinformat Core Facil, Dept Biomed, CH-4031 Basel, Switzerland. [Dirnhofer, Stephan] Univ Basel Hosp, Inst Pathol, CH-4031 Basel, Switzerland. [Guglielmelli, Paola; Vannucchi, Alessandro M.] Univ Florence, Dept Clin & Expt Med, I-50134 Florence, Italy. [Feenstra, Jelena D. Milosevic; Kralovics, Robert] Austrian Acad Sci, CeMM Res Ctr Mol Med, A-1090 Vienna, Austria. [Orkin, Stuart H.] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Orkin, Stuart H.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. [Orkin, Stuart H.] Harvard Med Sch, Howard Hughes Med Inst, Boston, MA 02215 USA. RP Skoda, RC (reprint author), Univ Basel Hosp, Dept Biomed, Expt Hematol, CH-4031 Basel, Switzerland.; Skoda, RC (reprint author), Univ Basel, CH-4031 Basel, Switzerland. EM radek.skoda@unibas.ch OI Guglielmelli, Paola/0000-0003-1809-284X FU Swiss National Science Foundation [310000-120724/1, 32003BB_135712/1]; Swiss Cancer League [KLS-2950-02-2012, KFS-3655-02-2015]; SystemsX.ch (Medical Research and Development grant) [2014/266]; Associazione Italiana per la Ricerca sul Cancro (AIRC; Milan, Italy) [1005]; AIRC [IG2014-15967]; Ministero della Salute [GR-2011-02352109] FX This work was supported by the Swiss National Science Foundation (grants 310000-120724/1 and 32003BB_135712/1), the Swiss Cancer League (KLS-2950-02-2012 and KFS-3655-02-2015), and SystemsX.ch (Medical Research and Development grant 2014/266) to R.C. Skoda. A.M. Vannucchi and P. Guglielmelli were supported by a grant from Associazione Italiana per la Ricerca sul Cancro (AIRC; Milan, Italy), Special Program Molecular Clinical Oncology 5x1000 to AIRC-Gruppo Italiano Malattie Mieloproliferative (AGI MM) project #1005. P. Guglielmelli was also supported by the AIRC (IG2014-15967) and Ministero della Salute (project code GR-2011-02352109). NR 47 TC 4 Z9 4 U1 0 U2 0 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 25 PY 2016 VL 213 IS 8 BP 1479 EP 1496 DI 10.1084/jem.20151136 PG 18 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA DS5VN UT WOS:000380851200009 PM 27401344 ER PT J AU Rowe, RG Wang, LD Coma, S Han, A Mathieu, R Pearson, DS Ross, S Sousa, P Nguyen, PT Rodriguez, A Wagers, AJ Daley, GQ AF Rowe, R. Grant Wang, Leo D. Coma, Silvia Han, Areum Mathieu, Ronald Pearson, Daniel S. Ross, Samantha Sousa, Patricia Nguyen, Phi T. Rodriguez, Antony Wagers, Amy J. Daley, George Q. TI Developmental regulation of myeloerythroid progenitor function by the Lin28b-let-7-Hmga2 axis SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID HEMATOPOIETIC STEM-CELLS; GENE-EXPRESSION; SELF-RENEWAL; PROMOTES TRANSFORMATION; MYELOID PROGENITORS; GLUCOSE-METABOLISM; LIN28 PROMOTES; TGF-BETA; FETAL; HMGA2 AB For appropriate development, tissue and organ system morphogenesis and maturation must occur in synchrony with the overall developmental requirements of the host. Mistiming of such developmental events often results in disease. The hematopoietic system matures from the fetal state, characterized by robust erythrocytic output that supports prenatal growth in the hypoxic intrauterine environment, to the postnatal state wherein granulocytes predominate to provide innate immunity. Regulation of the developmental timing of these myeloerythroid states is not well understood. In this study, we find that expression of the heterochronic factor Lin28b decreases in common myeloid progenitors during hematopoietic maturation to adulthood in mice. This decrease in Lin28b coincides with accumulation of mature let-7 microRNAs, whose biogenesis is regulated by Lin28 proteins. We find that inhibition of let-7 in the adult hematopoietic system recapitulates fetal erythroid-dominant hematopoiesis. Conversely, deletion of Lin28b or ectopic activation of let-7 microRNAs in the fetal state induces a shift toward adult-like myeloid-dominant output. Furthermore, we identify Hmga2 as an effector of this genetic switch. These studies provide the first detailed analysis of the roles of endogenous Lin28b and let-7 in the timing of hematopoietic states during development. C1 [Rowe, R. Grant; Wang, Leo D.; Coma, Silvia; Han, Areum; Pearson, Daniel S.; Ross, Samantha; Sousa, Patricia; Daley, George Q.] Boston Childrens Hosp, Div Pediat Hematol Oncol, Stem Cell Transplantat Program, Stem Cell Program, Boston, MA 02215 USA. [Rowe, R. Grant; Wang, Leo D.; Coma, Silvia; Han, Areum; Pearson, Daniel S.; Ross, Samantha; Sousa, Patricia; Daley, George Q.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Wang, Leo D.; Mathieu, Ronald; Nguyen, Phi T.; Wagers, Amy J.; Daley, George Q.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Mathieu, Ronald] Boston Childrens Hosp, Flow Cytometry Lab, Boston, MA 02115 USA. [Wang, Leo D.; Nguyen, Phi T.; Wagers, Amy J.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Han, Areum; Daley, George Q.] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Rodriguez, Antony] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Daley, George Q.] Howard Hughes Med Inst, Boston, MA 02115 USA. [Wagers, Amy J.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Daley, George Q.] Brigham & Womens Hosp, Div Hematol, Boston, MA 02115 USA. [Daley, George Q.] Manton Ctr Orphan Dis Res, Boston, MA 02115 USA. [Nguyen, Phi T.] Univ Calif San Francisco, Sch Med, San Francisco, CA 94143 USA. [Rodriguez, Antony] Univ Texas Med Branch, Dept Phys Therapy, Galveston, TX 77555 USA. RP Daley, GQ (reprint author), Boston Childrens Hosp, Div Pediat Hematol Oncol, Stem Cell Transplantat Program, Stem Cell Program, Boston, MA 02215 USA.; Daley, GQ (reprint author), Dana Farber Canc Inst, Boston, MA 02215 USA.; Daley, GQ (reprint author), Harvard Stem Cell Inst, Cambridge, MA 02138 USA.; Daley, GQ (reprint author), Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA.; Daley, GQ (reprint author), Howard Hughes Med Inst, Boston, MA 02115 USA.; Daley, GQ (reprint author), Brigham & Womens Hosp, Div Hematol, Boston, MA 02115 USA.; Daley, GQ (reprint author), Manton Ctr Orphan Dis Res, Boston, MA 02115 USA. EM george.daley@childrens.harvard.edu FU US National Institutes of Health: National Institute for Diabetes and Digestive and Kidney Diseases [R24-DK092760, R24-DK49216]; US National Institutes of Health: National Heart, Lung, and Blood Institute (NHBLI Progenitor Cell Biology Consortium) [UO1-HL100001]; US National Institutes of Health: National Institute of General Medical Sciences [RO1GM107536, PN2 EY018244, P30DK036836]; NHLBI [5T32HL007574-34]; Damon Runyon-Sohn Foundation Pediatric Cancer Research fellowship [DSRG 02-12]; Alex's Lemonade Stand Foundation for Childhood Cancer Young Investigator award [31582]; St. Baldrick's Foundation PALS Scholar award [243625] FX This work is supported by grants from the US National Institutes of Health: National Institute for Diabetes and Digestive and Kidney Diseases (R24-DK092760 and R24-DK49216), the National Heart, Lung, and Blood Institute (NHBLI Progenitor Cell Biology Consortium grant UO1-HL100001), and the National Institute of General Medical Sciences (RO1GM107536; PN2 EY018244 and P30DK036836 to A.J. Wagers). G.Q. Daley is an associate member of the Broad Institute and an investigator of the Howard Hughes Medical Institute and the Manton Center for Orphan Disease Research. R.G. Rowe was supported by NHLBI (5T32HL007574-34). L.D. Wang was supported by a Damon Runyon-Sohn Foundation Pediatric Cancer Research fellowship (DSRG 02-12), an Alex's Lemonade Stand Foundation for Childhood Cancer Young Investigator award (31582), and a St. Baldrick's Foundation PALS Scholar award (243625). NR 66 TC 2 Z9 2 U1 1 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 25 PY 2016 VL 213 IS 8 BP 1497 EP 1512 DI 10.1084/jem.20151912 PG 16 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA DS5VN UT WOS:000380851200010 PM 27401346 ER PT J AU Minnings, K Fiore, M Mosco, M Ferguson, R Leatherman, S Kerns, E Kaufman, J Fiore, M Brooks, D Amador, JJ Paulsen, H Ernstberger, Z Trejo, B Sullivan, E Lichtman, A Nobil, K Lawlor, M Parker, C Parekh, R Fiore, L AF Minnings, Kailey Fiore, Madeline Mosco, Martha Ferguson, Ryan Leatherman, Sarah Kerns, Eric Kaufman, James Fiore, Melissa Brooks, Daniel Amador, Juan Jose Paulsen, Hillary Ernstberger, Zachary Trejo, Bricia Sullivan, Elyse Lichtman, Amos Nobil, Keriann Lawlor, Matthew Parker, Cassandra Parekh, Rulan Fiore, Louis TI The Rivas Cohort Study: design and baseline characteristics of a Nicaraguan cohort SO BMC NEPHROLOGY LA English DT Article DE Cohort studies; Nicaragua; Central America; Renal insufficiency; Public health; Public health surveillance; Data collection; Baseline Survey; Creatinine ID CHRONIC KIDNEY-DISEASE; GLOMERULAR-FILTRATION-RATE; RISK-FACTORS; EL SALVADOR; PREVALENCE; CREATININE AB Background: A lack of advanced healthcare information systems and validated scientific cohorts in Nicaragua makes it difficult to estimate disease prevalences and other public health statistics. Although there is concern of an "epidemic" of chronic kidney disease (CKD) in this country, statistics regarding its magnitude are derived from only a small number of non--representative studies. Budgetary constraints and the logistical problems of maintaining a study cohort make longitudinal studies difficult. The Rivas Cohort was created to measure disease burden of CKD and other public health priorities in the Department of Rivas, Nicaragua. Using primarily volunteer research students and technologic innovation including GPS, digital photography and point of care biochemical analysis, the ability to establish a longitudinal chronic disease cohort is demonstrated. Methods: Subjects were recruited from consecutive adjacent households in thirty-two randomly selected communities in the ten municipalities that comprise the Department of Rivas in southern Pacific coastal Nicaragua. The study was conducted in two phases. In the first phase, subjects were enrolled into the cohort and consented for future re-contact. In Phase II, conducted two years later, attempts were made to re-contact 400 of these subjects for additional data collection. Demographic, lifestyle, occupational, exposure and health data was collected for both phases of the study. Blood and urine testing and height, weight and blood pressure measurements were also performed. GPS coordinates of homes were recorded and maps of remote communities created. Results: Of 1397 adults living in 533 households approached for participation a total of 1242 (89 %) were enrolled in the cohort. The median age is 41 years and 43 % are male, demographics in agreement with Nicaraguan census data for the Department of Rivas. During Phase II we attempted to re-contact 400 subjects for a follow-up study of CKD. It was possible to re-contact 84 % of these participants and of those re-contacted 95 % agreed to participate in the follow-up study. Of subjects that were not successfully re-contacted the majority had either moved (32) or were not at home (22) at the time of the study team visits. Conclusion: The Rivas Cohort Study enrolled a representative sample of 1242 adults living in the Department of Rivas, Nicaragua. The high re-contact and participation rates at two years suggests that the cohort is suitable for long-term studies and presents opportunities for investigations of disease prevalence, incidence, treatment and other public health matters. GPS coordinates and maps are available for future researchers who wish to use the cohort for additional studies. C1 [Minnings, Kailey] Univ Toronto, Fac Med, 1 Kings Coll Circle, Toronto, ON M5S 1A8, Canada. [Fiore, Madeline] UMass Med Sch, 55 N Lake Ave, Chestnut St,Apt 21, Worcester, MA 01604 USA. [Fiore, Madeline] UMass Med Sch, 55 N Lake Ave,Chestnut St Apt 21, Worcester, MA 01609 USA. [Mosco, Martha] Beth Israel Deaconess Med Ctr, 330 Brookline Ave, Boston, MA 02215 USA. [Mosco, Martha] Beth Israel Deaconess Med Ctr, 16 Oak Manor Dr, Barrington, RI 02806 USA. [Ferguson, Ryan] Massachusetts Vet Epidemiol Res & Informat Ctr Hl, 150 South Huntington Ave, Boston, MA 02130 USA. [Leatherman, Sarah] VA Boston Healthcare Syst, 150 South Huntington Ave, Boston, MA 02130 USA. [Kerns, Eric] Brown Univ, Warren Alpert Med Sch, 593 Eddy St,APC 9, Providence, RI 02903 USA. [Kaufman, James] VA New York Healthcare Syst, 423 East 23rd St, New York, NY 10010 USA. [Brooks, Daniel] Boston Univ, Sch Publ Hlth, 715 Albany St,T317E, Boston, MA 02118 USA. [Amador, Juan Jose] Boston Univ, 715 Albany St,Talbot 3 East, Boston, MA 02118 USA. [Fiore, Melissa] Athena Hlth, 311 Arsenal St, Watertown, MA 02472 USA. [Fiore, Melissa] Athena Hlth, 18 Parker St, Cambridge, MA 02138 USA. [Paulsen, Hillary] Boston Childrens Hosp, 401 Pk Dr,6th Floor,Landmark Ctr, Boston, MA 02115 USA. [Paulsen, Hillary] Boston Childrens Hosp, 12 Greenway Ct Apt 3, Brookline, MA 02446 USA. [Ernstberger, Zachary] Indiana Univ Sch Med, 340 West 10th St,Suite 6200, Indianapolis, IN 46202 USA. [Ernstberger, Zachary] Indiana Univ Sch Med, 1547 N Coll Ave, Indianapolis, IN 46202 USA. [Trejo, Bricia] Boston Univ, Sch Publ Hlth, 801 Massachusetts Ave 4th Floor, Boston, MA 02118 USA. [Trejo, Bricia] Boston Univ, Sch Publ Hlth, 60 Pkwy Rd, Newton, MA 02460 USA. [Sullivan, Elyse] Northeastern Univ, 350 Huntington Ave, Boston, MA 02115 USA. [Sullivan, Elyse] Northeastern Univ, 255 Newbury St,Aprl R, Boston, MA 02116 USA. [Lichtman, Amos] UMass Med Sch, 55 N Lake Ave, Worcester, MA 01604 USA. [Lichtman, Amos] UMass Med Sch, 60 Pkwy Rd, Newton, MA 02460 USA. [Nobil, Keriann] Univ Massachusetts, Sch Med, 55 N Lake Ave, Worcester, MA 01605 USA. [Nobil, Keriann] Univ Massachusetts, Sch Med, 285 Plantat St Apt 522, Worcester, MA 01604 USA. [Lawlor, Matthew; Fiore, Louis] Boston Univ, Sch Med, 72 E Concord St, Boston, MA 02118 USA. [Lawlor, Matthew; Fiore, Louis] Boston Univ, Sch Publ Hlth, 72 E Concord St, Boston, MA 02118 USA. [Lawlor, Matthew] Boston Univ, Sch Med, 255 Newbury St 1R, Boston, MA 02116 USA. [Lawlor, Matthew] Boston Univ, Sch Publ Hlth, 255 Newbury St 1R, Boston, MA 02116 USA. [Parker, Cassandra] Boston Univ, Sch Med, 160 E Berkeley St Apt 304, Boston, MA 02118 USA. [Parker, Cassandra] Boston Univ, Sch Publ Hlth, 160 E Berkeley St Apt 304, Boston, MA 02118 USA. [Parekh, Rulan] Univ Hlth Network, Hosp Sick Children, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. [Parekh, Rulan] Univ Toronto, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. RP Fiore, L (reprint author), Boston Univ, Sch Med, 72 E Concord St, Boston, MA 02118 USA.; Fiore, L (reprint author), Boston Univ, Sch Publ Hlth, 72 E Concord St, Boston, MA 02118 USA. EM lfiore@bu.edu FU Newton-San Juan Del Sur Sister City Project FX This project was funded pimarily by private donations and the work done in collaboration with the 'Newton-San Juan Del Sur Sister City Project' (http://sanjuandesursistercityproject.wordpress.com/). NR 16 TC 0 Z9 0 U1 2 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2369 J9 BMC NEPHROL JI BMC Nephrol. PD JUL 25 PY 2016 VL 17 AR 93 DI 10.1186/s12882-016-0320-9 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA DS0MB UT WOS:000380288700001 PM 27456863 ER PT J AU Carmona-Moran, CA Zavgorodnya, O Penman, AD Kharlampieva, E Bridges, SL Hergenrother, RW Singh, JA Wick, TM AF Carmona-Moran, Carlos A. Zavgorodnya, Oleksandra Penman, Andrew D. Kharlampieva, Eugenia Bridges, S. Louis, Jr. Hergenrother, Robert W. Singh, Jasvinder A. Wick, Timothy M. TI Development of gellan gum containing formulations for transdermal drug delivery: Component evaluation and controlled drug release using temperature responsive nanogels SO INTERNATIONAL JOURNAL OF PHARMACEUTICS LA English DT Article DE Transdermal drug transport; Transdermal formulation development; Diclofenac; Semisolid gel; Hydrogel film; Nanogels; Synthetic membrane ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; VITRO PERCUTANEOUS PENETRATION; IN-VIVO EVALUATION; DICLOFENAC SODIUM; TOPICAL DELIVERY; PHARMACEUTICAL APPLICATIONS; ISOPROPYL MYRISTATE; PROPYLENE-GLYCOL; RAT SKIN; HYDROGELS AB Enhancing skin permeation is important for development of new transdermal drug delivery formulations. This is particularly relevant for non-steroidal anti-inflammatory drugs (NSAIDs). To address this, semisolid gel and solid hydrogel film formulations containing gellan gum as a gelling agent were developed and the effects of penetration enhancers (dimethyl sulfoxide, isopropyl alcohol and propylene glycol) on transport of the NSAID diclofenac sodium was quantified. A transwell diffusion system was used to accelerate formulation development. After 4 h, diclofenac flux from a superior formulation of the semisolid gel or the solid hydrogel film was 130 +/- 11 mu g/cm(2) h and 108 +/- 7 mu g/cm(2) h, respectively, and significantly greater than that measured for a currently available diclofenac sodium topical gel (30 +/- 4 mu g/cm(2) h, p < 0.05) or solution formulation (44 +/- 6 mu g/cm(2) h, p < 0.05) under identical conditions. Over 24 h diclofenac transport from the solid hydrogel film was greater than that measured for any new or commercial diclofenac formulation. Entrapment of temperature-responsive nanogels within the solid hydrogel film provides temperature-activated prolonged release of diclofenac. Diclofenac transport was minimal at 22 degrees C, when diclofenac is entrapped within temperature-responsive nanogels incorporated into the solid hydrogel film, but increased 6-fold when the temperature was increased to skin surface temperature of 32 degrees C. These results demonstrate the feasibility of the semisolid gel and solid hydrogel film formulations that can include thermo-responsive nanogels for development of transdermal drug formulations with adjustable drug transport kinetics. (C) 2016 Elsevier B.V. All rights reserved. C1 [Carmona-Moran, Carlos A.; Wick, Timothy M.] Univ Alabama Birmingham, Dept Biomed Engn, Birmingham, AL 35294 USA. [Zavgorodnya, Oleksandra; Kharlampieva, Eugenia] Univ Alabama Birmingham, Dept Chem, Birmingham, AL 35294 USA. [Bridges, S. Louis, Jr.; Singh, Jasvinder A.] Univ Alabama Birmingham, Dept Med, Div Clin Immunol & Rheumatol, Birmingham, AL 35294 USA. [Hergenrother, Robert W.] Southern Res, Birmingham, AL USA. [Singh, Jasvinder A.] Birmingham VA Med Ctr, Med Serv, Birmingham, AL USA. [Singh, Jasvinder A.] Mayo Clin, Coll Med, Dept Orthoped Surg, Rochester, MN USA. RP Wick, TM (reprint author), Univ Alabama Birmingham, Sch Engn, 115G Hoehn Engn Bldg,1075 13th St South, Birmingham, AL 35233 USA. EM tmwick@uab.edu OI Wick, Timothy/0000-0001-8922-0939; Zavgorodnya, Oleksandra/0000-0001-8296-6340 FU University of Alabama at Birmingham; Southern Research Institute; NSF CAREER [1350370] FX This research was supported by the University of Alabama at Birmingham and the Southern Research Institute, and by NSF CAREER 1350370 (EK). We thank Dr. Veronika Kozlovskaya (UAB) for SEM imaging and technical assistance. NR 82 TC 2 Z9 2 U1 15 U2 21 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5173 EI 1873-3476 J9 INT J PHARMACEUT JI Int. J. Pharm. PD JUL 25 PY 2016 VL 509 IS 1-2 BP 465 EP 476 DI 10.1016/j.ijpharm.2016.05.062 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DQ1GP UT WOS:000378949800048 PM 27260133 ER PT J AU Nahrendorf, M Swirski, FK AF Nahrendorf, Matthias Swirski, Filip K. TI Abandoning M1/M2 for a Network Model of Macrophage Function SO CIRCULATION RESEARCH LA English DT Article DE atherosclerosis; bone marrow; macrophage; myocardial; infarction; monocyte ID MYOCARDIAL-INFARCTION; CARDIAC MACROPHAGES; DENDRITIC CELLS; STEADY-STATE; SPI-C; MONOCYTES; HOMEOSTASIS; ACTIVATION; ONTOGENY; HEART AB The heart and blood vessels of a healthy individual contain resident immune cells, the majority of which are macrophages that have seeded these organs early in the development. In the mouse, approximate to 10% of noncardiomyocytes are macrophages, 1,2 and humans may have comparable numbers. 1 After myocardial infarction, macrophage numbers increase in the heart through the combined effects of massive recruitment of bone marrow-derived cells and local self-renewal. 1,3 Likewise, in atherosclerosis, the chronic lipid-driven inflammatory disease that is the underlying cause of myocardial infarction, macrophage numbers increase in the vessel wall, again because of recruitment and local proliferation. 4 Although many of these insights have been generated in mouse models, compelling evidence from genome-wide association studies have associated innate immunity mediators with myocardial infarction, 5 whereas prospective human studies have shown that blood monocyte levels can predict cardiovascular events in patients. 6 C1 [Nahrendorf, Matthias; Swirski, Filip K.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. RP Nahrendorf, M; Swirski, FK (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. EM mnahrendorf@mgh.harvard.edu; fswirski@mgh.harvard.edu FU National Institutes of Health (NIH) [HL096576, HL095629, NS084863, HL128264, HL095612] FX This work was supported by National Institutes of Health (NIH) grants HL096576, HL095629, NS084863, HL128264, HL095612, HL128264, and HL095612. NR 40 TC 1 Z9 1 U1 6 U2 6 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 22 PY 2016 VL 119 IS 3 BP 414 EP 417 DI 10.1161/CIRCRESAHA.116.309194 PG 4 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA DS5CS UT WOS:000380798900009 PM 27458196 ER PT J AU Safdar, N Musuuza, JS Xie, AP Hundt, AS Hall, M Wood, K Carayon, P AF Safdar, Nasia Musuuza, Jackson S. Xie, Anping Hundt, Ann Schoofs Hall, Matthew Wood, Kenneth Carayon, Pascale TI Management of ventilator-associated pneumonia in intensive care units: a mixed methods study assessing barriers and facilitators to guideline adherence SO BMC INFECTIOUS DISEASES LA English DT Article DE Ventilator-associated pneumonia; VAP; Guidelines; Systems Engineering Initiative for Patient Safety; Barriers and facilitators ID CLINICAL-PRACTICE GUIDELINES; HOSPITAL-ACQUIRED PNEUMONIA; CRITICALLY-ILL PATIENTS; ACUTE OTITIS-MEDIA; ANTIBIOTIC-THERAPY; IMPLEMENTATION; PHYSICIANS; IMPACT; MORTALITY; PATTERNS AB Background: Guidelines from the Infectious Diseases Society of America/The American Thoracic Society (IDSA/ATS) provide recommendations for diagnosis and treatment of ventilator-associated pneumonia (VAP). However, the mere presence of guidelines is rarely sufficient to promote widespread adoption and uptake. Using the Systems Engineering Initiative for Patient Safety (SEIPS) model framework, we undertook a study to understand barriers and facilitators to the adoption of the IDSA/ATS guidelines. Methods: We conducted surveys and focus group discussions of different health care providers involved in the management of VAP. The setting was medical-surgical ICUs at a tertiary academic hospital and a large multispecialty rural hospital in Wisconsin, USA. Results: Overall, we found that 55 % of participants indicated that they were aware of the IDSA/ATS guideline. The top ranked barriers to VAP management included: 1) having multiple physician groups managing VAP, 2) variation in VAP management by differing ICU services, 3) physicians and level of training, and 4) renal failure complicating doses of antibiotics. Facilitators to VAP management included presence of multidisciplinary rounds that include nurses, pharmacist and respiratory therapists, and awareness of the IDSA/ATS guideline. This awareness was associated with receiving effective training on management of VAP, keeping up to date on nosocomial infection literature, and belief that performing a bronchoscopy to diagnose VAP would help with expeditious diagnosis of VAP. Conclusions: Findings from our study complement existing studies by identifying perceptions of the many different types of healthcare workers in ICU settings. These findings have implications for antibiotic stewardship teams, clinicians, and organizational leaders. C1 [Safdar, Nasia] William S Middleton Mem Vet Adm Med Ctr, Madison, WI 53705 USA. [Safdar, Nasia] Univ Wisconsin, Sch Med & Publ Hlth, Dept Med, Madison, WI 53706 USA. [Safdar, Nasia] Univ Wisconsin Hosp & Clin, Dept Infect Dis, Madison, WI 53792 USA. [Musuuza, Jackson S.] Univ Wisconsin, Inst Clin & Translat Res, Madison, WI USA. [Xie, Anping] Johns Hopkins Univ, Sch Med, Armstrong Inst Patient Safety & Qual, Baltimore, MD USA. [Hundt, Ann Schoofs; Carayon, Pascale] Univ Wisconsin, Ctr Qual & Prod Improvement, Madison, WI USA. [Hall, Matthew] Marshfield Clin Fdn Med Res & Educ, Dept Infect Med, Marshfield, WI USA. [Wood, Kenneth] Univ Maryland, Sch Med, R Adams Cowley Shock Trauma Ctr, Baltimore, MD 21201 USA. RP Safdar, N (reprint author), William S Middleton Mem Vet Adm Med Ctr, Madison, WI 53705 USA.; Safdar, N (reprint author), Univ Wisconsin, Sch Med & Publ Hlth, Dept Med, Madison, WI 53706 USA. EM ns2@medicine.wisc.edu FU Clinical and Translational Science Award (CTSA) program, through the NIH National Center for Advancing Translational Sciences (NCATS) [UL1TR000427]; United States Department of Veterans Affairs MERIT award FX The project described was supported by the Clinical and Translational Science Award (CTSA) program, through the NIH National Center for Advancing Translational Sciences (NCATS), grant UL1TR000427. NS is supported by a United States Department of Veterans Affairs MERIT award. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the Department of Veterans Affairs. There are no conflicts of interest for any of the authors. NR 46 TC 1 Z9 1 U1 6 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2334 J9 BMC INFECT DIS JI BMC Infect. Dis. PD JUL 22 PY 2016 VL 16 AR 349 DI 10.1186/s12879-016-1665-1 PG 9 WC Infectious Diseases SC Infectious Diseases GA DS7WW UT WOS:000380994700001 PM 27448800 ER PT J AU Sosa, MAG De Gasperi, R Hof, PR Elder, GA AF Sosa, Miguel A. Gama De Gasperi, Rita Hof, Patrick R. Elder, Gregory A. TI Fibroblast growth factor rescues brain endothelial cells lacking presenilin 1 from apoptotic cell death following serum starvation SO SCIENTIFIC REPORTS LA English DT Article ID AMYLOID BETA-PEPTIDE; ALZHEIMERS-DISEASE; PROGENITOR CELLS; PC12 CELLS; ACTIVATION; MICE; SURVIVAL; CATENIN; DIFFERENTIATION; CYTOPROTECTION AB Presenilin 1 (Psen1) is important for vascular brain development and is known to influence cellular stress responses. To understand the role of Psen1 in endothelial stress responses, we investigated the effects of serum withdrawal on wild type (wt) and Psen1-/- embryonic brain endothelial cells. Serum starvation induced apoptosis in Psen1-/- cells but did not affect wt cells. PI3K/AKT signaling was reduced in serum-starved Psen1-/- cells, and this was associated with elevated levels of phospho-p38 consistent with decreased pro-survival AKT signaling in the absence of Psen1. Fibroblast growth factor (FGF1 and FGF2), but not vascular endothelial growth factor (VEGF) rescued Psen1-/- cells from serum starvation induced apoptosis. Inhibition of FGF signaling induced apoptosis in wt cells under serum withdrawal, while blocking gamma-secretase activity had no effect. In the absence of serum, FGF2 immunoreactivity was distributed diffusely in cytoplasmic and nuclear vesicles of wt and Psen1-/- cells, as levels of FGF2 in nuclear and cytosolic fractions were not significantly different. Thus, sensitivity of Psen1-/- cells to serum starvation is not due to lack of FGF synthesis but likely to effects of Psen1 on FGF release onto the cell surface and impaired activation of the PI3K/AKT survival pathway. C1 [Sosa, Miguel A. Gama] James J Peters Dept Vet Affairs Med Ctr, Gen Med Res Serv, Bronx, NY 10468 USA. [Sosa, Miguel A. Gama; De Gasperi, Rita; Elder, Gregory A.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Sosa, Miguel A. Gama; De Gasperi, Rita; Hof, Patrick R.; Elder, Gregory A.] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA. [De Gasperi, Rita] James J Peters Dept Vet Affairs Med Ctr, Res & Dev Serv, Bronx, NY USA. [Hof, Patrick R.] Icahn Sch Med Mt Sinai, Fishberg Dept Neurosci, New York, NY 10029 USA. [Hof, Patrick R.] Icahn Sch Med Mt Sinai, Dept Geriatr & Palliat Care, New York, NY 10029 USA. [Elder, Gregory A.] James J Peters Dept Vet Affairs Med Ctr, Neurol Serv, Bronx, NY USA. [Elder, Gregory A.] Icahn Sch Med Mt Sinai, Dept Neurol, New York, NY 10029 USA. RP Sosa, MAG (reprint author), James J Peters Dept Vet Affairs Med Ctr, Gen Med Res Serv, Bronx, NY 10468 USA.; Sosa, MAG (reprint author), Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA.; Sosa, MAG (reprint author), Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA. EM miguel.gama-sosa@mssm.edu FU Department of Veterans Affairs [1I01BX000342-01, 1I01RX000996-01, I21RX002069]; General Medical Research Service of the James J. Peters Department of Veterans Affairs Medical Center FX This work was supported in part by funds from the Department of Veterans Affairs, Awards 1I01BX000342-01, 1I01RX000996-01 and I21RX002069. MAGS was supported in part by the General Medical Research Service of the James J. Peters Department of Veterans Affairs Medical Center. NR 49 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JUL 22 PY 2016 VL 6 AR 30267 DI 10.1038/srep30267 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DR9OO UT WOS:000380226200001 ER PT J AU Shimomura, Y Suga, M Kuriyama, N Nakamura, T Sakai, T Kato, Y Hara, Y Yamashita, C Nagasaki, H Kaneki, M Nishida, O AF Shimomura, Yasuyo Suga, Mika Kuriyama, Naohide Nakamura, Tomoyuki Sakai, Toshikazu Kato, Yu Hara, Yoshitaka Yamashita, Chizuru Nagasaki, Hiroshi Kaneki, Masao Nishida, Osamu TI Recombinant human thrombomodulin inhibits neutrophil extracellular trap formation in vitro SO JOURNAL OF INTENSIVE CARE LA English DT Article DE Disseminated intravascular coagulation; Innate immunity; Neutrophil extracellular traps; Sepsis; Thrombomodulin ID DISSEMINATED INTRAVASCULAR COAGULATION; SOLUBLE THROMBOMODULIN; BACTERIA; SEPSIS AB The aim of this study was to investigate the effects of recombinant human-soluble thrombomodulin (rTM) on lipopolysaccharide (LPS)-induced, platelet-dependent neutrophil extracellular trap (NET) formation (NETosis). Human peripheral blood neutrophils and platelets were co-incubated with or without LPS (0.2 mu g/ml) in the presence and absence of rTM (2 mu g/ml). NETosis was confirmed by immunostaining and confocal microscopy. In the absence of platelets, LPS did not induce NETosis in the neutrophils. NETosis, however, was induced by LPS when neutrophils were co-cultured with platelets (64 % of neutrophils). Notably, rTM was able to fully inhibit NETosis in neutrophils cultured with platelets and in the presence of LPS. rTM did not induce NETosis in this co-culture system (p < 0.01 versus LPS in the absence of rTM). These results show that rTM can suppress LPS-induced platelet-dependent NETosis in vitro. C1 [Shimomura, Yasuyo; Suga, Mika; Kuriyama, Naohide; Nakamura, Tomoyuki; Sakai, Toshikazu; Kato, Yu; Hara, Yoshitaka; Yamashita, Chizuru; Nishida, Osamu] Fujita Hlth Univ, Sch Med, Dept Anesthesiol & Crit Care Med, 1-98 Dengakugakubo,Kutsukake Cho, Toyoake, Aichi 4701192, Japan. [Nagasaki, Hiroshi] Fujita Hlth Univ, Sch Med, Dept Physiol 1, 1-98 Dengakugakubo,Kutsukake Cho, Toyoake, Aichi 4701192, Japan. [Kuriyama, Naohide; Kaneki, Masao] Harvard Med Sch, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 149 13th St, Charlestown, MA 02129 USA. RP Shimomura, Y (reprint author), Fujita Hlth Univ, Sch Med, Dept Anesthesiol & Crit Care Med, 1-98 Dengakugakubo,Kutsukake Cho, Toyoake, Aichi 4701192, Japan. EM yasuyo@fujita-hu.ac.jp NR 12 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 2052-0492 J9 J INTENSIVE CARE JI J. Intensive Care PD JUL 22 PY 2016 VL 4 AR 48 DI 10.1186/s40560-016-0177-9 PG 5 WC Critical Care Medicine SC General & Internal Medicine GA DR8MX UT WOS:000380153100001 PM 27453785 ER PT J AU Villar, J Belda, J Anon, JM Blanco, J Perez-Mendez, L Ferrando, C Martinez, D Soler, JA Ambros, A Munoz, T Rivas, R Corpas, R Diaz-Dominguez, FJ Soro, M Garcia-Bello, MA Fernandez, RL Kacmarek, RM AF Villar, Jesus Belda, Javier Manuel Anon, Jose Blanco, Jesus Perez-Mendez, Lina Ferrando, Carlos Martinez, Domingo Alfonso Soler, Juan Ambros, Alfonso Munoz, Tomas Rivas, Rosana Corpas, Ruth Diaz-Dominguez, Francisco J. Soro, Marina Angel Garcia-Bello, Miguel Lidia Fernandez, Rosa Kacmarek, Robert M. CA DEXA-ARDS Network TI Evaluating the efficacy of dexamethasone in the treatment of patients with persistent acute respiratory distress syndrome: study protocol for a randomized controlled trial SO TRIALS LA English DT Article DE Acute respiratory distress syndrome; Dexamethasone; Corticoids; Positive end-expiratory pressure; Lung-protective ventilation ID ACUTE LUNG INJURY; SEPTIC SHOCK PATIENTS; CLINICAL-TRIALS; CORTICOSTEROIDS; ARDS; METHYLPREDNISOLONE; METAANALYSIS; DEFINITION; MECHANISMS; MORTALITY AB Background: Although much has evolved in our understanding of the pathogenesis and factors affecting outcome of patients with acute respiratory distress syndrome (ARDS), still there is no specific pharmacologic treatment for ARDS. Several clinical trials have evaluated the utility of corticoids but none of them has demonstrated a definitive benefit due to small sample sizes, selection bias, patient heterogeneity, and time of initiation of treatment or duration of therapy. We postulated that adjunctive treatment of persistent ARDS with intravenous dexamethasone might change the pulmonary and systemic inflammatory response and thereby reduce morbidity, leading to a decrease in duration of mechanical ventilation and a decrease in mortality. Methods/design: This is a prospective, multicenter, randomized, controlled trial in 314 patients with persistent moderate/severe ARDS. Persistent ARDS is defined as maintaining a PaO2/FiO(2) <= 200 mmHg on PEEP >= 10 cmH(2)O and FiO(2) >= 0.5 after 24 hours of routine intensive care. Eligible patients will be randomly allocated to two arms: (i) conventional treatment without dexamethasone, (ii) conventional treatment plus dexamethasone. Patients in the dexamethasone group will be treated with a daily dose of 20 mg iv from day 1 to day 5, and 10 mg iv from day 6 to day 10. Primary outcome is the number of ventilator-free days, defined as days alive and free from mechanical ventilation at day 28 after intubation. Secondary outcome is all-cause mortality at day 60 after enrollment. Discussion: This study will be the largest randomized controlled clinical trial to assess the role of dexamethasone in patients with persistent ARDS. C1 [Villar, Jesus; Blanco, Jesus; Perez-Mendez, Lina; Lidia Fernandez, Rosa] Inst Salud Carlos III, CIBER Enfermedades Resp, Madrid, Spain. [Villar, Jesus; Lidia Fernandez, Rosa] Hosp Univ Dr Negrin, Res Unit, Multidisciplinary Organ Dysfunct Evaluat Res Net, Barranco Ballena S-N,4th Floor,South Wing, Las Palmas Gran Canaria 35019, Spain. [Villar, Jesus] St Michaels Hosp, Li Ka Shing Knowledge Inst, Keenan Res Ctr Biomed Sci, Toronto, ON, Canada. [Belda, Javier; Ferrando, Carlos; Soro, Marina] Hosp Clin Univ Valencia, Dept Anesthesiol, Valencia, Spain. [Manuel Anon, Jose] Hosp Virgen de La Luz, Intens Care Unit, Cuenca, Spain. [Blanco, Jesus] Hosp Univ Rio Hortega, Intens Care Unit, Valladolid, Spain. [Perez-Mendez, Lina] Hosp Univ NS de Candelaria, Res Unit, Div Clin Epidemiol & Biostat, Santa Cruz De Tenerife, Spain. [Martinez, Domingo] Hosp Virgen La Arrixaca, Intens Care Unit, Murcia, Spain. [Alfonso Soler, Juan] Hosp Morales Meseguer, Intens Care Unit, Murcia, Spain. [Ambros, Alfonso] Hosp Gen Ciudad Real, Intens Care Unit, Ciudad Real, Spain. [Munoz, Tomas] Hosp Univ Cruces, Intens Care Unit, Baracaldo, Vizcaya, Spain. [Rivas, Rosana] Hosp Galdakao Usansolo, Intens Care Unit, Usansolo, Vizcaya, Spain. [Corpas, Ruth] Hosp NS del Prado, Intens Care Unit, Talavera De La Reina, Toledo, Spain. [Diaz-Dominguez, Francisco J.] Hosp Gen Leon, Intens Care Unit, Leon, Spain. [Angel Garcia-Bello, Miguel] Hosp Univ Dr Negrin, Res Unit, Biostat, Las Palmas Gran Canaria, Spain. [Kacmarek, Robert M.] Massachusetts Gen Hosp, Dept Resp Care, Boston, MA 02114 USA. [Kacmarek, Robert M.] Harvard Univ, Dept Anesthesiol, Boston, MA 02115 USA. RP Villar, J (reprint author), Inst Salud Carlos III, CIBER Enfermedades Resp, Madrid, Spain.; Villar, J (reprint author), Hosp Univ Dr Negrin, Res Unit, Multidisciplinary Organ Dysfunct Evaluat Res Net, Barranco Ballena S-N,4th Floor,South Wing, Las Palmas Gran Canaria 35019, Spain.; Villar, J (reprint author), St Michaels Hosp, Li Ka Shing Knowledge Inst, Keenan Res Ctr Biomed Sci, Toronto, ON, Canada. EM jesus.villar54@gmail.com NR 39 TC 1 Z9 1 U1 1 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6215 J9 TRIALS JI Trials PD JUL 22 PY 2016 VL 17 AR 342 DI 10.1186/s13063-016-1456-4 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DR7TX UT WOS:000380103700008 PM 27449641 ER PT J AU Bawadekar, M Gendron-Fitzpatrick, A Rebernick, R Shim, D Warner, TF Nicholas, AP Lundblad, LKA Thompson, PR Shelef, MA AF Bawadekar, Mandar Gendron-Fitzpatrick, Annette Rebernick, Ryan Shim, Daeun Warner, Thomas F. Nicholas, Anthony P. Lundblad, Lennart K. A. Thompson, Paul R. Shelef, Miriam A. TI Tumor necrosis factor alpha, citrullination, and peptidylarginine deiminase 4 in lung and joint inflammation SO ARTHRITIS RESEARCH & THERAPY LA English DT Article DE Rheumatoid arthritis; Citrullination; Peptidylarginine deiminase 4; Lung; TNF-alpha; Experimental arthritis ID POSITIVE RHEUMATOID-ARTHRITIS; SYNOVIAL-FLUID; AUTOIMMUNE ARTHRITIS; DISEASE; MICE; EXPRESSION; MODEL; PROTEIN; ASSOCIATION; SELECTION AB Background: The relationship between lung and joint inflammation in rheumatoid arthritis is poorly understood. Lung inflammation with resultant protein citrullination may trigger anti-citrullinated protein antibodies, inflammation, and arthritis. Alternatively, lung and joint inflammation may be two manifestations of a single underlying pathology. The lung has increased citrullination and TNF-alpha levels are high in rheumatoid arthritis; however, it is unknown if TNF-alpha can induce lung protein citrullination. The citrullinating enzyme peptidylarginine deiminase 4 (PAD4) exacerbates TNF-alpha-induced arthritis, but a role for PAD4 in lung citrullination and TNF-alpha-induced lung inflammation has not been explored. Our aim was to use TNF-alpha-overexpressing mice to clarify the intersection of TNF-alpha, citrullination, PAD4, arthritis, and lung inflammation. Methods: Lung protein citrullination in wild-type mice, mice that overexpress TNF-alpha systemically (TNF+), TNF(+)PAD4(+/+), and TNF(+)PAD4(-/-) mice was quantified by both gel electrophoresis using a citrulline probe and western blot. Hematoxylin and eosin (H&E)-stained lung sections from TNF(+)PAD4(+/+) and TNF(+)PAD4(-/-) mice were scored for lung inflammation. H&E-stained ankle joint sections from mice that overexpress TNF-a only in the lungs were assessed for arthritis. Results: TNF+ mice have increased lung protein citrullination. TNF(+)PAD4(-/-) mice do not have significantly reduced lung protein citrullination, but do have decreased lung inflammation compared to TNF(+)PAD4(+/+) mice. Mice that overexpress TNF-alpha only in the lungs do not develop arthritis. Conclusions: PAD4 exacerbates lung inflammation downstream of TNF-alpha without having a major role in generalized protein citrullination in inflamed lungs. Also, TNF-alpha-induced lung inflammation is not sufficient to drive murine arthritis. C1 [Bawadekar, Mandar; Rebernick, Ryan; Shim, Daeun; Shelef, Miriam A.] Univ Wisconsin, Dept Med, Madison, WI 53706 USA. [Gendron-Fitzpatrick, Annette] Univ Wisconsin, Sch Vet Med, Res Anim Resource Ctr Comparat Pathol Lab, Madison, WI 53706 USA. [Gendron-Fitzpatrick, Annette] Univ Wisconsin, Sch Vet Med, Dept Pathobiol Sci, Madison, WI 53706 USA. [Warner, Thomas F.] Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI USA. [Nicholas, Anthony P.] Univ Alabama Birmingham, Dept Neurol, UAB Stn, Birmingham, AL 35294 USA. [Nicholas, Anthony P.] Univ Alabama Birmingham, Ctr Neurodegenerat & Expt Therapeut, Birmingham, AL USA. [Nicholas, Anthony P.] Birmingham VA Med Ctr, Birmingham, AL USA. [Lundblad, Lennart K. A.] Univ Vermont, Dept Med, Burlington, VT USA. [Thompson, Paul R.] Univ Massachusetts, Sch Med, Dept Biochem, Worcester, MA 01655 USA. [Thompson, Paul R.] Univ Massachusetts, Sch Med, Dept Mol Pharmacol, Worcester, MA USA. [Shelef, Miriam A.] William S Middleton Mem Vet Adm Med Ctr, Madison, WI 53705 USA. RP Shelef, MA (reprint author), Univ Wisconsin, Dept Med, Madison, WI 53706 USA.; Shelef, MA (reprint author), William S Middleton Mem Vet Adm Med Ctr, Madison, WI 53705 USA. EM mshelef@medicine.wisc.edu FU Rheumatology Research Foundation via a Scientist Development Award; National Institutes of Health (NIH) [K08 AR065500]; NIH/National Center for Research Resources (NCRR) [P30 GM103532]; NIH [R01 GM079357] FX Funding for this research was made possible by the Rheumatology Research Foundation via a Scientist Development Award as well as awards from the National Institutes of Health (NIH) K08 AR065500 to MAS, NIH/National Center for Research Resources (NCRR) P30 GM103532 to LKAL, and NIH R01 GM079357 to PRT. NR 45 TC 0 Z9 0 U1 4 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1478-6354 EI 1478-6362 J9 ARTHRITIS RES THER JI Arthritis Res. Ther. PD JUL 22 PY 2016 VL 18 AR 173 DI 10.1186/s13075-016-1068-0 PG 9 WC Rheumatology SC Rheumatology GA DR6EW UT WOS:000379996000001 PM 27450561 ER PT J AU Moore, SA Abbara, S Mak, GS Mark, EJ Stone, JR AF Moore, Stephanie A. Abbara, Suhny Mak, Gary S. Mark, Eugene J. Stone, James R. TI Case 22-2016: A 65-Year-Old Man with Syncope, Dyspnea, and Leg Edema SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID SUBAORTIC SEPTAL MYECTOMY; HYPERTROPHIC CARDIOMYOPATHY; CARDIAC SARCOIDOSIS; PULMONARY-HYPERTENSION; ENDOMYOCARDIAL BIOPSY; SURGICAL PATHOLOGY; CONVERTING ENZYME; HEART; DIAGNOSIS; CORRELATE C1 [Moore, Stephanie A.; Mak, Gary S.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Abbara, Suhny] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Mark, Eugene J.; Stone, James R.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Moore, Stephanie A.; Mak, Gary S.] Harvard Med Sch, Dept Med, Boston, MA USA. [Abbara, Suhny] Harvard Med Sch, Dept Radiol, Boston, MA USA. [Mark, Eugene J.; Stone, James R.] Harvard Med Sch, Dept Pathol, Boston, MA USA. RP Moore, SA (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA.; Moore, SA (reprint author), Harvard Med Sch, Dept Med, Boston, MA USA. FU Glaxo-SmithKline; USP Labs; Alnylam Pharmaceuticals FX Dr. Mark reports receiving payments from law firms for providing expert testimony on behalf of patients in asbestos-related cases; and Dr. Stone, receiving consulting fees from Glaxo-SmithKline, fees for providing expert testimony from USP Labs, and lecture fees from Alnylam Pharmaceuticals outside the submitted work. No other potential conflict of interest relevant to this article was reported. NR 24 TC 0 Z9 0 U1 2 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 21 PY 2016 VL 375 IS 3 BP 262 EP 272 DI 10.1056/NEJMcpc1601838 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA DS0ZL UT WOS:000380325400011 PM 27468063 ER PT J AU Minter, MR Zhang, C Leone, V Ringus, DL Zhang, XQ Oyler-Castrillo, P Musch, MW Liao, F Ward, JF Holtzman, DM Chang, EB Tanzi, RE Sisodia, SS AF Minter, Myles R. Zhang, Can Leone, Vanessa Ringus, Daina L. Zhang, Xiaoqiong Oyler-Castrillo, Paul Musch, Mark W. Liao, Fan Ward, Joseph F. Holtzman, David M. Chang, Eugene B. Tanzi, Rudolph E. Sisodia, Sangram S. TI Antibiotic-induced perturbations in gut microbial diversity influences neuro-inflammation and amyloidosis in a murine model of Alzheimer's disease SO SCIENTIFIC REPORTS LA English DT Article ID GENOME-WIDE ASSOCIATION; IN-VIVO; MOUSE MODEL; BETA; MICROGLIA; PATHOLOGY; VARIANTS; DEMENTIA; CELLS; ONSET AB Severe amyloidosis and plaque-localized neuro-inflammation are key pathological features of Alzheimer's disease (AD). In addition to astrocyte and microglial reactivity, emerging evidence suggests a role of gut microbiota in regulating innate immunity and influencing brain function. Here, we examine the role of the host microbiome in regulating amyloidosis in the APPSWE/PS1.E9 mouse model of AD. We show that prolonged shifts in gut microbial composition and diversity induced by long-term broadspectrum combinatorial antibiotic treatment regime decreases A beta plaque deposition. We also show that levels of soluble A beta are elevated and that levels of circulating cytokine and chemokine signatures are altered in this setting. Finally, we observe attenuated plaque-localised glial reactivity in these mice and significantly altered microglial morphology. These findings suggest the gut microbiota community diversity can regulate host innate immunity mechanisms that impact A beta amyloidosis. C1 [Minter, Myles R.; Zhang, Xiaoqiong; Oyler-Castrillo, Paul; Sisodia, Sangram S.] Univ Chicago, Dept Neurobiol, Chicago, IL 60637 USA. [Minter, Myles R.; Leone, Vanessa; Ringus, Daina L.; Musch, Mark W.; Chang, Eugene B.; Sisodia, Sangram S.] Univ Chicago, Microbiome Ctr, Chicago, IL 60637 USA. [Zhang, Can; Ward, Joseph F.; Tanzi, Rudolph E.] Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Dept Neurol, Genet & Aging Res Unit, Charlestown, MA 02114 USA. [Leone, Vanessa; Ringus, Daina L.; Musch, Mark W.; Chang, Eugene B.] Univ Chicago, Dept Med, 5841 S Maryland Ave, Chicago, IL 60637 USA. [Liao, Fan; Holtzman, David M.] Washington Univ, Hope Ctr Neurol Disorders, Charles F & Joanne Knight Alzheimers Dis Res Ctr, Dept Neurol,Sch Med, St Louis, MO 63110 USA. RP Sisodia, SS (reprint author), Univ Chicago, Dept Neurobiol, Chicago, IL 60637 USA.; Sisodia, SS (reprint author), Univ Chicago, Microbiome Ctr, Chicago, IL 60637 USA. EM ssisodia@bsd.uchicago.edu FU Cure Alzheimer's Fund (CAF); National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [DK42086] FX This study was supported by the Cure Alzheimer's Fund (CAF, to S.S.S) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) P30 program funding the Digestive Disease Research Core Center (DDRCC) at the University of Chicago (DK42086, to E.B.C.). The authors would like to thank Dr. Christine Labno, Ms. Shirley Bond and Dr. Vytas Bindokas (University of Chicago Integrated Light Microscopy Facility) for aid in microscopy and IMARIS-based processing, Ms. Sarah M. Owens (Argonne National Laboratory) for running the Illumina (R) MiSeq deep sequencing, and, Dr. Xulun Zhang and Mr. Manish Aryal (Department of Neurobiology, University of Chicago) for technical expertise. NR 54 TC 10 Z9 11 U1 9 U2 9 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 21 PY 2016 VL 6 DI 10.1038/srep30028 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH9IT UT WOS:000392085700001 PM 27443609 ER PT J AU Tai, YT Anderson, KC AF Tai, Yu-Tzu Anderson, Kenneth C. TI A new era of immune therapy in multiple myeloma SO BLOOD LA English DT Editorial Material ID DARATUMUMAB MONOTHERAPY C1 [Tai, Yu-Tzu; Anderson, Kenneth C.] Dana Farber Canc Inst, Boston, MA 02215 USA. RP Tai, YT (reprint author), Dana Farber Canc Inst, Boston, MA 02215 USA. NR 8 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUL 21 PY 2016 VL 128 IS 3 BP 318 EP 319 DI 10.1182/blood-2016-06-719856 PG 4 WC Hematology SC Hematology GA DX0TN UT WOS:000384078200002 PM 27445408 ER PT J AU Wang, H Bierie, B Li, AG Pathania, S Toomire, K Dimitrov, SD Liu, B Gelman, R Giobbie-Hurder, A Feunteun, J Polyak, K Livingston, DM AF Wang, Hua Bierie, Brian Li, Andrew G. Pathania, Shailja Toomire, Kimberly Dimitrov, Stoil D. Liu, Ben Gelman, Rebecca Giobbie-Hurder, Anita Feunteun, Jean Polyak, Kornelia Livingston, David M. TI BRCA1/FANCD2/BRG1-Driven DNA Repair Stabilizes the Differentiation State of Human Mammary Epithelial Cells SO MOLECULAR CELL LA English DT Article ID CROSS-LINK REPAIR; BREAST-CANCER; STEM-CELLS; HOMOLOGOUS RECOMBINATION; GENOMIC INSTABILITY; MUTATION CARRIERS; TUMOR-FORMATION; IN-VIVO; BRCA1; DAMAGE AB An abnormal differentiation state is common in BRCA1-deficient mammary epithelial cells, but the underlying mechanism is unclear. Here, we report a convergence between DNA repair and normal, cultured human mammary epithelial (HME) cell differentiation. Surprisingly, depleting BRCA1 or FANCD2 (Fanconi anemia [FA] proteins) or BRG1, a mSWI/SNF subunit, caused HME cells to undergo spontaneous epithelial-to-mesenchymal transition (EMT) and aberrant differentiation. This also occurred when wild-type HMEs were exposed to chemicals that generate DNA interstrand crosslinks (repaired by FA proteins), but not in response to double-strand breaks. Suppressed expression of Delta NP63 also occurred in each of these settings, an effect that links DNA damage to the aberrant differentiation outcome. Taken together with somatic breast cancer genome data, these results point to a breakdown in a BRCA/FA-mSWI/SNF-Delta NP63-mediated DNA repair and differentiation maintenance process in mammary epithelial cells that may contribute to sporadic breast cancer development. C1 [Wang, Hua; Li, Andrew G.; Pathania, Shailja; Toomire, Kimberly; Dimitrov, Stoil D.; Liu, Ben; Livingston, David M.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Wang, Hua; Li, Andrew G.; Pathania, Shailja; Toomire, Kimberly; Liu, Ben; Livingston, David M.] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. [Bierie, Brian] Nine Cambridge Ctr, Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Gelman, Rebecca; Giobbie-Hurder, Anita] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Feunteun, Jean] Univ Paris 11, Stabilite Genet & Oncogenese, CNRS, UMR8200, F-94805 Villejuif, France. [Polyak, Kornelia] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Polyak, Kornelia] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. [Polyak, Kornelia] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Wang, H; Livingston, DM (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.; Wang, H; Livingston, DM (reprint author), Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. EM hua_wang@dfci.harvard.edu; david_livingston@dfci.harvard.edu FU National Cancer Institute (NCI) Mechanisms of Breast Development and Carcinogenesis [2PO1CA80111-16]; BRCA1 Function in Post Damage Foci [5R01CA136512-05]; Susan B. Komen Foundation for the Cure; Breast Cancer Research Foundation; BRCA Foundation FX We thank all D.M.L. laboratory members for numerous helpful discussions. We are grateful to Drs. Robert Weinberg and Qiufu Ma for important suggestions and other valuable input along the way. We also thank Dr A. D'Andrea for the generous gifts of valuable reagents and helpful insights and the DFCI flow cytometry facility for excellent technical support. This work was supported by grants from the National Cancer Institute (NCI) Mechanisms of Breast Development and Carcinogenesis (2PO1CA80111-16), BRCA1 Function in Post Damage Foci (5R01CA136512-05), and grants from the Susan B. Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the BRCA Foundation (to D.M.L.). NR 66 TC 0 Z9 0 U1 5 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 EI 1097-4164 J9 MOL CELL JI Mol. Cell PD JUL 21 PY 2016 VL 63 IS 2 BP 277 EP 292 DI 10.1016/j.molcel.2016.05.038 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DT6UI UT WOS:000381619300011 PM 27373334 ER PT J AU Halbert, CH McDonald, J Vadaparampil, S Rice, L Jefferson, M AF Halbert, Chanita Hughes McDonald, Jasmine Vadaparampil, Susan Rice, LaShanta Jefferson, Melanie TI Conducting Precision Medicine Research with African Americans SO PLOS ONE LA English DT Article ID CANCER GENETICS RESEARCH; RESEARCH PARTICIPATION; DIETARY INTERVENTIONS; PHYSICAL-ACTIVITY; PROSTATE-CANCER; INCREASED RISK; RETENTION; RECRUITMENT; INTENTIONS; TRIAL AB Importance Precision medicine is an approach to detecting, treating, and managing disease that is based on individual variation in genetic, environmental, and lifestyle factors. Precision medicine is expected to reduce health disparities, but this will be possible only if studies have adequate representation of racial minorities. Objective It is critical to anticipate the rates at which individuals from diverse populations are likely to participate in precision medicine studies as research initiatives are being developed. We evaluated the likelihood of participating in a clinical study for precision medicine. Design, Setting, Participants Observational study conducted between October 2010 and February 2011 in a national sample of African Americans. Main Outcome Measure Intentions to participate in a government sponsored study that involves providing a biospecimen and generates data that could be shared with other researchers to conduct future studies. Results One third of respondents would participate in a clinical study for precision medicine. Only gender had a significant independent association with participation intentions. Men had a 1.86 (95% CI = 1.11, 3.12, p = 0.02) increased likelihood of participating in a precision medicine study compared to women in the model that included overall barriers and facilitators. In the model with specific participation barriers, distrust was associated with a reduced likelihood of participating in the research described in the vignette (OR = 0.57, 95% CI = 0.34, 0.96, p = 0.04). Conclusion and Relevance African Americans may have low enrollment in PMI research. As PMI research is implemented, extensive efforts will be needed to ensure adequate representation. Additional research is needed to identify optimal ways of ethically describing precision medicine studies to ensure sufficient recruitment of racial minorities. C1 [Halbert, Chanita Hughes; Rice, LaShanta] Med Univ South Carolina, Dept Psychiat & Behav Sci, 171 Ashley Ave, Charleston, SC 29425 USA. [Halbert, Chanita Hughes; Rice, LaShanta] Med Univ South Carolina, Hollings Canc Ctr, Charleston, SC 29425 USA. [Halbert, Chanita Hughes; Rice, LaShanta] Ralph H Johnson Vet Adm Med Ctr, Charleston, SC 29401 USA. [McDonald, Jasmine; Jefferson, Melanie] Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, New York, NY USA. [Vadaparampil, Susan] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. RP Halbert, CH (reprint author), Med Univ South Carolina, Dept Psychiat & Behav Sci, 171 Ashley Ave, Charleston, SC 29425 USA.; Halbert, CH (reprint author), Med Univ South Carolina, Hollings Canc Ctr, Charleston, SC 29425 USA.; Halbert, CH (reprint author), Ralph H Johnson Vet Adm Med Ctr, Charleston, SC 29401 USA. EM hughesha@musc.edu FU National Human Genome Research Institute [R01HG004346]; American Cancer Society [RSG-11-268-01-CPPB]; National Cancer Institute [UG1CA189848]; National Center for Advancing Translational Science [UL1TR001450] FX This research was supported by National Human Genome Research Institute grant #R01HG004346, grant #RSG-11-268-01-CPPB from the American Cancer Society, grant #UG1CA189848 from the National Cancer Institute, and grant #UL1TR001450 from the National Center for Advancing Translational Science. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 TC 0 Z9 0 U1 2 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 21 PY 2016 VL 11 IS 7 AR e0154850 DI 10.1371/journal.pone.0154850 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DS5CG UT WOS:000380797500003 PM 27441706 ER PT J AU Zimering, JH Dong, YL Fang, F Huang, LN Zhang, YY Xie, ZC AF Zimering, Jeffrey H. Dong, Yuanlin Fang, Fang Huang, Lining Zhang, Yiying Xie, Zhongcong TI Anesthetic Sevoflurane Causes Rho-Dependent Filopodial Shortening in Mouse Neurons SO PLOS ONE LA English DT Article ID DENDRITIC SPINE MORPHOGENESIS; AMYLOID PROTEIN-LEVELS; ACTIN-BINDING PROTEIN; SYNAPTIC PLASTICITY; ELECTRICAL-ACTIVITY; NEONATAL EXPOSURE; TRANSGENIC MICE; F-ACTIN; DREBRIN; ACTIVATION AB Early postnatal anesthesia causes long-lasting learning and memory impairment in rodents, however, evidence for a specific neurotoxic effect on early synaptogenesis has not been demonstrated. Drebrin A is an actin binding protein whose localization in dendritic protrusions serves an important role in dendritic spine morphogenesis, and is a marker for early synaptogenesis. We therefore set out to investigate whether clinically-relevant concentrations of anesthetic sevoflurane, widely-used in infants and children, alters dendritic morphology in cultured fetal day 16 mouse hippocampal neurons. After 7 days in vitro, mouse hippocampal neurons were exposed to four hours of 3% sevoflurane in 95% air/5% CO2 or control condition (95% air/5% CO2). Neurons were fixed in 4% paraformaldehyde and stained with Alexa Fluor555-Phalloidin, and/or rabbit anti-mouse drebrin A/E antibodies which permitted subcellular localization of filamentous (F)-actin and/or drebrin immunoreactivity, respectively. Sevoflurane caused acute significant length-shortening in filopodia and thin dendritic spines in days-in-vitro 7 neurons, an effect which was completely rescued by co-incubating neurons with ten micromolar concentrations of the selective Rho kinase inhibitor Y27632. Filopodia and thin spine recovered in length two days after sevoflurane exposure. Yet cluster-type filopodia (a precursor to synaptic filopodia) were persistently significantly decreased in number on day-in-vitro 9, in part owing to preferential localization of drebrin immunoreactivity to dendritic shafts versus filopodial stalks. These data suggest that sevoflurane induces F-actin depolymerization leading to acute, reversible length-shortening in dendritic protrusions through a mechanism involving (in part) activation of RhoA/Rho kinase signaling and impairs localization of drebrin A to filopodia required for early excitatory synapse formation. C1 [Zimering, Jeffrey H.] Univ Rochester, Sch Med & Dent, Rochester, NY USA. [Zimering, Jeffrey H.; Dong, Yuanlin; Fang, Fang; Huang, Lining; Zhang, Yiying; Xie, Zhongcong] Massachusetts Gen Hosp, Geriatr Anesthesia Res Unit, Dept Anesthesia Crit Care & Pain Med, Charlestown, MA 02129 USA. [Zimering, Jeffrey H.; Dong, Yuanlin; Fang, Fang; Huang, Lining; Zhang, Yiying; Xie, Zhongcong] Harvard Med Sch, Charlestown, MA 02129 USA. [Zimering, Jeffrey H.] Harvard Med Sch, Howard Hughes Med Inst, Boston, MA USA. [Fang, Fang] Fudan Univ, Dept Anesthesiol, Zhongshan Hosp, Shanghai, Peoples R China. [Huang, Lining] Hebei Med Univ, Hosp 2, Dept Anesthesiol, Shijiazhuang, Hebei Province, Peoples R China. RP Xie, ZC (reprint author), Massachusetts Gen Hosp, Geriatr Anesthesia Res Unit, Dept Anesthesia Crit Care & Pain Med, Charlestown, MA 02129 USA.; Xie, ZC (reprint author), Harvard Med Sch, Charlestown, MA 02129 USA. EM zxie@mgh.harvard.edu FU Howard Hughes Medical Institute Medical Research Fellowship, Chevy Chase, Maryland; Harvard Medical School, Boston, Massachusetts; National Institutes of Health, Bethesda, Maryland [R01 GM088801, R01 AG041274]; Alzheimer's Association, Chicago, Illinois FX Supported by Howard Hughes Medical Institute Medical Research Fellowship, Chevy Chase, Maryland and Harvard Medical School, Boston, Massachusetts to JHZ. This research was supported by R01 GM088801 and R01 AG041274 from National Institutes of Health, Bethesda, Maryland, Investigator-initiated Research grant from Alzheimer's Association, Chicago, Illinois to ZX. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 0 Z9 0 U1 3 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 21 PY 2016 VL 11 IS 7 AR e0159637 DI 10.1371/journal.pone.0159637 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DS5CG UT WOS:000380797500109 PM 27441369 ER PT J AU Quinti, L Casale, M Moniot, S Pais, TF Van Kanegan, MJ Kaltenbach, LS Pallos, J Lim, RG Naidu, SD Runne, H Meisel, L Rauf, NA Leyfer, D Maxwell, MM Saiah, E Landers, JE Luthi-Carter, R Abagyan, R Dinkova-Kostova, AT Steegborn, C Marsh, JL Lo, DC Thompson, LM Kazantsev, AG AF Quinti, Luisa Casale, Malcolm Moniot, Sebastien Pais, Teresa F. Van Kanegan, Michael J. Kaltenbach, Linda S. Pallos, Judit Lim, Ryan G. Naidu, Sharadha Dayalan Runne, Heike Meisel, Lisa Rauf, Nazifa Abdul Leyfer, Dmitriy Maxwell, Michele M. Saiah, Eddine Landers, John E. Luthi-Carter, Ruth Abagyan, Ruben Dinkova-Kostova, Albena T. Steegborn, Clemens Marsh, J. Lawrence Lo, Donald C. Thompson, Leslie M. Kazantsev, Aleksey G. TI SIRT2-and NRF2-Targeting Thiazole-Containing Compound with Therapeutic Activity in Huntington's Disease Models SO CELL CHEMICAL BIOLOGY LA English DT Article ID SIRTUIN 2; BRAIN INFLAMMATION; OXIDATIVE STRESS; SCREENING ASSAY; NITRIC-OXIDE; CELL-DEATH; NEURODEGENERATION; DEACETYLASE; GENE; NRF2 AB There are currently no disease-modifying therapies for the neurodegenerative disorder Huntington's disease (HD). This study identified novel thiazole-containing inhibitors of the deacetylase sirtuin-2 (SIRT2) with neuroprotective activity in ex vivo brain slice and Drosophila models of HD. A systems biology approach revealed an additional SIRT2-independent property of the lead-compound, MIND4, as an inducer of cytoprotective NRF2 (nuclear factor-erythroid 2 p45-derived factor 2) activity. Structure-activity relationship studies further identified a potent NRF2 activator (MIND4-17) lacking SIRT2 inhibitory activity. MIND compounds induced NRF2 activation responses in neuronal and non-neuronal cells and reduced production of reactive oxygen species and nitrogen intermediates. These drug-like thiazole-containing compounds represent an exciting opportunity for development of multi-targeted agents with potentially synergistic therapeutic benefits in HD and related disorders. C1 [Quinti, Luisa; Rauf, Nazifa Abdul; Leyfer, Dmitriy; Maxwell, Michele M.; Kazantsev, Aleksey G.] Harvard Med Sch, Dept Neurol, Boston, MA 02114 USA. [Quinti, Luisa; Rauf, Nazifa Abdul; Leyfer, Dmitriy; Maxwell, Michele M.; Kazantsev, Aleksey G.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Casale, Malcolm; Thompson, Leslie M.] Univ Calif Irvine, Dept Neurobiol & Behav, Irvine, CA 92697 USA. [Moniot, Sebastien; Meisel, Lisa; Steegborn, Clemens] Univ Bayreuth, Dept Biochem, D-95447 Bayreuth, Germany. [Pais, Teresa F.] Inst Med Mol, Cell & Mol Neurosci Unit, Ave Prof Egas Moniz, P-1649028 Lisbon, Portugal. [Van Kanegan, Michael J.; Kaltenbach, Linda S.; Lo, Donald C.] Duke Univ, Med Ctr, Ctr Drug Discovery, Dept Neurobiol, Durham, NC 27710 USA. [Pallos, Judit; Marsh, J. Lawrence] Univ Calif Irvine, Dept Dev & Cell Biol, Irvine, CA 92697 USA. [Lim, Ryan G.; Thompson, Leslie M.] Univ Calif Irvine, Dept Biol Chem, Irvine, CA 92697 USA. [Naidu, Sharadha Dayalan; Dinkova-Kostova, Albena T.] Univ Dundee, Sch Med, Div Canc Res, Dundee DD1 9SY, Scotland. [Runne, Heike; Luthi-Carter, Ruth] Ecole Polytech Fed Lausanne, Brain Mind Inst, Funct Neurogen, CH-1015 Lausanne, Switzerland. [Saiah, Eddine] Pfizer Worldwide Med Chem, BioTherapeut Chem, 200 Cambridge Pk Dr, Cambridge, MA 02140 USA. [Landers, John E.] Univ Massachusetts, Sch Med, Dept Neurol, Worcester, MA 01655 USA. [Abagyan, Ruben] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, San Diego, CA 92093 USA. [Dinkova-Kostova, Albena T.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Dinkova-Kostova, Albena T.] Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA. [Thompson, Leslie M.] Univ Calif Irvine, Dept Psychiat & Human Behav, Irvine, CA 92697 USA. RP Kazantsev, AG (reprint author), Harvard Med Sch, Dept Neurol, Boston, MA 02114 USA.; Kazantsev, AG (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM akazantsev47@gmail.com OI Faria Pais, Teresa/0000-0002-8855-4395 FU NIH [U01-NS066912, R01NS04528, NS078370, NS080514]; NIGMS [GM080356]; Biotechnology and Biological Sciences Research Council [BB/J007498/1, BB/L01923X/1]; Alzheimer Forschung Initiative [14834]; Cancer Research UK [C20953/A18644]; RJG foundation; American Heart Association; Optical Biology Shared Resource of the Cancer Center Support Grant [CA-62203] FX This work was supported by grants from the NIH U01-NS066912, R01NS04528, NIH NS078370, NIH NS080514, and NIGMS grant GM080356, the Biotechnology and Biological Sciences Research Council (BB/J007498/1, BB/L01923X/1), Alzheimer Forschung Initiative (grant 14834 to C.S.) and Cancer Research UK (C20953/A18644). We also acknowledge support from the RJG foundation to L.Q and A.G.K and from the American Heart Association to R.G.L. This work was made possible in part by the availability of the Optical Biology Shared Resource of the Cancer Center Support Grant (CA-62203) at the University of California, Irvine. We thank Michael McMahon (University of Dundee) for plasmids encoding wild-type Keap1. NR 51 TC 4 Z9 4 U1 4 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2451-9448 J9 CELL CHEM BIOL JI Cell Chem. Biol. PD JUL 21 PY 2016 VL 23 IS 7 BP 849 EP 861 DI 10.1016/j.chembiol.2016.05.015 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DT5GH UT WOS:000381509200013 PM 27427231 ER PT J AU Li, H Lim, KS Kim, H Hinds, TR Jo, U Mao, HB Weller, CE Sun, J Chatterjee, C D'Andrea, AD Zheng, N AF Li, Heng Lim, Kah Suan Kim, Hyungjin Hinds, Thomas R. Jo, Ukhyun Mao, Haibin Weller, Caroline E. Sun, Ji Chatterjee, Champak D'Andrea, Alan D. Zheng, Ning TI Allosteric Activation of Ubiquitin-Specific Proteases by beta-Propeller Proteins UAF1 and WDR20 SO MOLECULAR CELL LA English DT Article ID SMALL-MOLECULE INHIBITOR; FANCONI-ANEMIA PATHWAY; OVERCOMES BORTEZOMIB RESISTANCE; DEUBIQUITINATING ENZYME USP12; PAPAIN-LIKE PROTEASE; STRUCTURAL INSIGHTS; ANDROGEN RECEPTOR; CRYSTAL-STRUCTURE; MULTIPLE-MYELOMA; COMPLEX AB Ubiquitin-specific proteases (USPs) constitute the largest family of deubiquitinating enzymes, whose catalytic competency is often modulated by their binding partners through unknown mechanisms. Here we report on a series of crystallographic and biochemical analyses of an evolutionarily conserved deubiquitinase, USP12, which is activated by two beta-propeller proteins, UAF1 and WDR20. Our structures reveal that UAF1 and WDR20 interact with USP12 at two distinct sites far from its catalytic center. Without increasing the substrate affinity of USP12, the two beta-propeller proteins potentiate the enzyme through different allosteric mechanisms. UAF1 docks at the distal end of the USP12 Fingers domain and induces a cascade of structural changes that reach a critical ubiquitin-contacting loop adjacent to the catalytic cleft. By contrast, WDR20 anchors at the base of this loop and remotely modulates the catalytic center of the enzyme. Our results provide a mechanistic example for allosteric activation of USPs by their regulatory partners. C1 [Li, Heng; Hinds, Thomas R.; Mao, Haibin; Sun, Ji; Zheng, Ning] Univ Washington, Dept Pharmacol, Seattle, WA 98195 USA. [Weller, Caroline E.; Chatterjee, Champak] Univ Washington, Dept Chem, Seattle, WA 98195 USA. [Li, Heng; Mao, Haibin; Zheng, Ning] Univ Washington, Howard Hughes Med Inst, Box 357280, Seattle, WA 98195 USA. [Lim, Kah Suan; D'Andrea, Alan D.] Harvard Med Sch, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Kim, Hyungjin; Jo, Ukhyun] SUNY Stony Brook, Dept Pharmacol Sci, Stony Brook, NY 11794 USA. RP Zheng, N (reprint author), Univ Washington, Dept Pharmacol, Seattle, WA 98195 USA.; Zheng, N (reprint author), Univ Washington, Howard Hughes Med Inst, Box 357280, Seattle, WA 98195 USA. EM nzheng@uw.edu FU Wong Family Award; Howard Hughes Medical Institute; NIH [R01GM110430, R01DK43889, R37HL052725] FX We thank the beamline staff of the Advanced Light Source at Lawrence Berkeley National Laboratory. We also thank members of the N.Z. and Wenqing Xu laboratories for discussion and help. This work is supported by the Wong Family Award (K.S.L.), the Howard Hughes Medical Institute (N.Z.), and NIH (R01GM110430 to C.C. and R01DK43889 and R37HL052725 to A.D.D.) NR 48 TC 1 Z9 1 U1 4 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 EI 1097-4164 J9 MOL CELL JI Mol. Cell PD JUL 21 PY 2016 VL 63 IS 2 BP 249 EP 260 DI 10.1016/j.molcel.2016.05.031 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DT6UI UT WOS:000381619300009 PM 27373336 ER PT J AU Zash, R Souda, S Leidner, J Ribaudo, H Binda, K Moyo, S Powis, KM Petlo, C Mmalane, M Makhema, J Essex, M Lockman, S Shapiro, R AF Zash, Rebecca Souda, Sajini Leidner, Jean Ribaudo, Heather Binda, Kelebogile Moyo, Sikhulile Powis, Kathleen M. Petlo, Chipo Mmalane, Mompati Makhema, Joe Essex, Max Lockman, Shahin Shapiro, Roger TI HIV-exposed children account for more than half of 24-month mortality in Botswana SO BMC PEDIATRICS LA English DT Article DE HIV-exposed uninfected; Child mortality; Breastfeeding; HIV-infected children; PMTCT; Sub-Saharan Africa ID ACTIVE ANTIRETROVIRAL THERAPY; INFECTED MOTHERS; UNINFECTED CHILDREN; INFANTS BORN; MORBIDITY; AFRICA; OUTCOMES; WOMEN; HEALTH; AGE AB Background: The contribution of HIV-exposure to childhood mortality in a setting with widespread antiretroviral treatment (ART) availability has not been determined. Methods: From January 2012 to March 2013, mothers were enrolled within 48 h of delivery at 5 government postpartum wards in Botswana. Participants were followed by phone 1-3 monthly for 24 months. Risk factors for 24-month survival were assessed by Cox proportional hazards modeling. Results: Three thousand mothers (1499 HIV-infected) and their 3033 children (1515 HIV-exposed) were enrolled. During pregnancy 58 % received three-drug ART, 23 % received zidovudine alone, 11 % received no antiretrovirals (8 % unknown); 2.1 % of children were HIV-infected by 24 months. Vital status at 24 months was known for 3018 (99.5 %) children; 106 (3.5 %) died including 12 (38 %) HIV-infected, 70 (4.7 %) HIV-exposed uninfected, and 24 (1.6 %) HIV-unexposed. Risk factors for mortality were child HIV-infection (aHR 22.6, 95 % CI 10.7, 47.5 %), child HIV-exposure (aHR 2.7, 95 % CI 1.7, 4.5) and maternal death (aHR 8.9, 95 % CI 2.1, 37.1). Replacement feeding predicted mortality when modeled separately from HIV-exposure (aHR 2.3, 95 % CI 1.5, 3.6), but colinearity with HIV-exposure status precluded investigation of its independent effect. Applied at the population level (26 % maternal HIV prevalence), an estimated 52 % of child mortality occurs among HIV-exposed or HIV-infected children. Conclusions: In a programmatic setting with high maternal HIV prevalence and widespread maternal and child ART availability, HIV-exposed and HIV-infected children still account for most deaths at 24 months. Lack of breastfeeding was a likely contributor to excess mortality among HIV-exposed children. C1 [Zash, Rebecca] Beth Israel Deaconess Med Ctr, 110 Francis St,Suite GB, Boston, MA 02215 USA. [Zash, Rebecca; Binda, Kelebogile; Moyo, Sikhulile; Powis, Kathleen M.; Mmalane, Mompati; Makhema, Joe; Essex, Max; Lockman, Shahin; Shapiro, Roger] Botswana Harvard AIDS Inst Parternship, Private Bag BO320, Gaborone, Botswana. [Zash, Rebecca; Ribaudo, Heather; Powis, Kathleen M.; Essex, Max; Lockman, Shahin; Shapiro, Roger] Harvard TH Chan Sch Publ Hlth, 651 Huntington Ave, Boston, MA 02115 USA. [Souda, Sajini] Univ Botswana, Fac Hlth Sci, Gaborone, Botswana. [Leidner, Jean] Goodtables Data Consulting, Norman, OK USA. [Powis, Kathleen M.] Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. [Petlo, Chipo] Minist Hlth, Gaborone, Botswana. [Essex, Max] Harvard Med Sch, Boston, MA USA. [Lockman, Shahin] Brigham & Womens Hosp, Div Infect Dis, 75 Francis St, Boston, MA 02115 USA. RP Zash, R (reprint author), Beth Israel Deaconess Med Ctr, 110 Francis St,Suite GB, Boston, MA 02215 USA.; Zash, R (reprint author), Botswana Harvard AIDS Inst Parternship, Private Bag BO320, Gaborone, Botswana.; Zash, R (reprint author), Harvard TH Chan Sch Publ Hlth, 651 Huntington Ave, Boston, MA 02115 USA. EM rzash@bidmc.harvard.edu FU CDC [U2GPS000941]; NIH/NIAID [T32 5T32AI007433-21] FX This study was funded by the CDC (U2GPS000941). Additional funds to support RZ were provided by NIH/NIAID (T32 5T32AI007433-21). NR 29 TC 4 Z9 4 U1 4 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2431 J9 BMC PEDIATR JI BMC Pediatr. PD JUL 21 PY 2016 VL 16 AR 103 DI 10.1186/s12887-016-0635-5 PG 9 WC Pediatrics SC Pediatrics GA DR9UP UT WOS:000380241900001 PM 27439303 ER PT J AU Bonner-Weir, S Aguayo-Mazzucato, C AF Bonner-Weir, Susan Aguayo-Mazzucato, Cristina TI PHYSIOLOGY Pancreatic beta-cell heterogeneity revisited SO NATURE LA English DT Editorial Material ID INSULIN-SECRETION; B-CELLS; SUBPOPULATIONS; MASS C1 [Bonner-Weir, Susan; Aguayo-Mazzucato, Cristina] Harvard Med Sch, Joslin Diabet Ctr, Boston, MA 02215 USA. RP Bonner-Weir, S (reprint author), Harvard Med Sch, Joslin Diabet Ctr, Boston, MA 02215 USA. EM susan.bonner-weir@joslin.harvard.edu FU NIDDK NIH HHS [P30 DK036836, R01 DK093909] NR 17 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD JUL 21 PY 2016 VL 535 IS 7612 BP 365 EP 366 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DS1GQ UT WOS:000380344200029 PM 27398615 ER PT J AU Chaudhuri, AR Callen, E Ding, X Gogola, E Duarte, AA Lee, JE Wong, N Lafarga, V Calvo, JA Panzarino, NJ John, S Day, A Crespo, AV Shen, BH Starnes, LM de Ruiter, JR Daniel, JA Konstantinopoulos, PA Cortez, D Cantor, SB Fernandez-Capetillo, O Ge, K Jonkers, J Rottenberg, S Sharan, SK Nussenzweig, A AF Chaudhuri, Arnab Ray Callen, Elsa Ding, Xia Gogola, Ewa Duarte, Alexandra A. Lee, Ji-Eun Wong, Nancy Lafarga, Vanessa Calvo, Jennifer A. Panzarino, Nicholas J. John, Sam Day, Amanda Crespo, Anna Vidal Shen, Binghui Starnes, Linda M. de Ruiter, Julian R. Daniel, Jeremy A. Konstantinopoulos, Panagiotis A. Cortez, David Cantor, Sharon B. Fernandez-Capetillo, Oscar Ge, Kai Jonkers, Jos Rottenberg, Sven Sharan, Shyam K. Nussenzweig, Andre TI Replication fork stability confers chemoresistance in BRCA-deficient cells SO NATURE LA English DT Article ID HOMOLOGY-DIRECTED REPAIR; LYSINE-4 METHYLTRANSFERASE COMPLEX; CONDITIONAL MOUSE MODEL; DNA-REPAIR; BREAST-CANCER; END RESECTION; MUTANT-CELLS; RECOMBINATION; 53BP1; RESISTANCE AB Cells deficient in the Brca1 and Brca2 genes have reduced capacity to repair DNA double-strand breaks by homologous recombination and consequently are hypersensitive to DNA-damaging agents, including cisplatin and poly(ADP-ribose) polymerase (PARP) inhibitors. Here we show that loss of the MLL3/4 complex protein, PTIP, protects Brca1/2-deficient cells from DNA damage and rescues the lethality of Brca2-deficient embryonic stem cells. However, PTIP deficiency does not restore homologous recombination activity at double-strand breaks. Instead, its absence inhibits the recruitment of the MRE11 nuclease to stalled replication forks, which in turn protects nascent DNA strands from extensive degradation. More generally, acquisition of PARP inhibitors and cisplatin resistance is associated with replication fork protection in Brca2-deficient tumour cells that do not develop Brca2 reversion mutations. Disruption of multiple proteins, including PARP1 and CHD4, leads to the same end point of replication fork protection, highlighting the complexities by which tumour cells evade chemotherapeutic interventions and acquire drug resistance. C1 [Chaudhuri, Arnab Ray; Callen, Elsa; Wong, Nancy; John, Sam; Day, Amanda; Crespo, Anna Vidal; Nussenzweig, Andre] NCI, Lab Genome Integr, NIH, Bethesda, MD 20892 USA. [Ding, Xia; Sharan, Shyam K.] NCI, Mouse Canc Genet Program, NIH, Frederick, MD 21702 USA. [Gogola, Ewa; Duarte, Alexandra A.; de Ruiter, Julian R.; Jonkers, Jos; Rottenberg, Sven] Netherlands Canc Inst, Div Mol Pathol, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands. [Ding, Xia; Gogola, Ewa; de Ruiter, Julian R.; Jonkers, Jos; Rottenberg, Sven] Netherlands Canc Inst, Canc Genom Ctr, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands. [Lee, Ji-Eun; Ge, Kai] NIDDK, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20892 USA. [Lafarga, Vanessa; Fernandez-Capetillo, Oscar] Spanish Natl Canc Res Ctr CNIO, Genom Instabil Grp, Madrid 28029, Spain. [Calvo, Jennifer A.; Panzarino, Nicholas J.; Cantor, Sharon B.] Univ Massachusetts, Sch Med, UMASS Mem Canc Ctr, Dept Mol Cell & Canc Biol, Worcester, MA 01605 USA. [Shen, Binghui] City Hope Natl Med Ctr, Beckman Res Inst, Dept Radiat Biol, 1500 East Duarte Rd, Duarte, CA 91010 USA. [Starnes, Linda M.; Daniel, Jeremy A.] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Prot Res, DK-2200 Copenhagen, Denmark. [Konstantinopoulos, Panagiotis A.] Harvard Med Sch, Dana Farber Canc Inst, Dept Gynecol Med Oncol, Boston, MA 02215 USA. [Cortez, David] Vanderbilt Univ, Dept Biochem, Sch Med, 2215 Garland Ave, Nashville, TN 37232 USA. [Rottenberg, Sven] Univ Bern, Vetsuisse Fac, Inst Anim Pathol, Langgassstr 122, CH-3012 Bern, Switzerland. RP Nussenzweig, A (reprint author), NCI, Lab Genome Integr, NIH, Bethesda, MD 20892 USA. EM andre_nussenzweig@nih.gov RI Daniel, Jeremy/S-4729-2016; OI Daniel, Jeremy/0000-0002-1981-5571; Ge, Kai/0000-0002-7442-5138 FU Intramural Research Program of the National Institutes of Health (NIH), the National Cancer Institute; Center for Cancer Research; Department of Defense [11557134]; Netherlands Organization for Scientific Research; Dutch Cancer Society; Swiss National Science Foundation; Swiss National Science Foundation [PBZHP3 147302]; Human Frontier Science Program Long-Term Fellowship [LT000393/2013]; NIH [R01 CA176166-01A1, R01CA085344]; Novo Nordisk Foundation [NNF14CC0001] FX We thank A. Bhandoola for discussions; K. Wolcott for flow cytometry; R. Faryabi for help with statistical analysis; T. de Lange for Rif1f/f mice, J. Tainer for PFM39, R. Brosh for WRNi and J. Petrini for Mre11 antibodies. This work was supported by the Intramural Research Program of the National Institutes of Health (NIH), the National Cancer Institute and the Center for Cancer Research, and by a Department of Defense grant to A.N. (BCRP DOD Idea Expansion Award, grant 11557134), and the Netherlands Organization for Scientific Research, the Dutch Cancer Society and the Swiss National Science Foundation to S.V. A.R.C. was supported by a Prospective Researcher Award from Swiss National Science Foundation (PBZHP3 147302) and Human Frontier Science Program Long-Term Fellowship (LT000393/2013). S.C. was supported by NIH grant R01 CA176166-01A1; B.S. was supported by NIH grant R01CA085344; and J.A.D. was supported by a grant to the Center for Protein Research from the Novo Nordisk Foundation (NNF14CC0001). NR 44 TC 19 Z9 19 U1 10 U2 22 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 21 PY 2016 VL 535 IS 7612 BP 382 EP + DI 10.1038/nature18325 PG 24 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DS1GQ UT WOS:000380344200032 ER PT J AU Brito, IL Yilmaz, S Huang, K Xu, L Jupiter, SD Jenkins, AP Naisilisili, W Tamminen, M Smillie, CS Wortman, JR Birren, BW Xavier, RJ Blainey, PC Singh, AK Gevers, D Alm, EJ AF Brito, I. L. Yilmaz, S. Huang, K. Xu, L. Jupiter, S. D. Jenkins, A. P. Naisilisili, W. Tamminen, M. Smillie, C. S. Wortman, J. R. Birren, B. W. Xavier, R. J. Blainey, P. C. Singh, A. K. Gevers, D. Alm, E. J. TI Mobile genes in the human microbiome are structured from global to individual scales SO NATURE LA English DT Article ID LEVEL MUPIROCIN RESISTANCE; TRANSFER-RNA-SYNTHETASES; HUMAN GUT MICROBIOME; STAPHYLOCOCCUS-AUREUS; SEQUENCES; BACTERIA; PLASMID; METAGENOMES; ANNOTATION; COMMUNITY AB Recent work has underscored the importance of the microbiome in human health, and has largely attributed differences in phenotype to differences in the species present among individuals(1-5). However, mobile genes can confer profoundly different phenotypes on different strains of the same species. Little is known about the function and distribution of mobile genes in the human microbiome, and in particular whether the gene pool is globally homogenous or constrained by human population structure. Here, we investigate this question by comparing the mobile genes found in the microbiomes of 81 metropolitan North Americans with those of 172 agrarian Fiji islanders using a combination of single-cell genomics and metagenomics. We find large differences in mobile gene content between the Fijian and North American microbiomes, with functional variation that mirrors known dietary differences such as the excess of plant-based starch degradation genes found in Fijian individuals. Notably, we also observed differences between the mobile gene pools of neighbouring Fijian villages, even though microbiome composition across villages is similar. Finally, we observe high rates of recombination leading to individual-specific mobile elements, suggesting that the abundance of some genes may reflect environmental selection rather than dispersal limitation. Together, these data support the hypothesis that human activities and behaviours provide selective pressures that shape mobile gene pools, and that acquisition of mobile genes is important for colonizing specific human populations. C1 [Brito, I. L.; Smillie, C. S.; Alm, E. J.] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Brito, I. L.; Huang, K.; Xu, L.; Wortman, J. R.; Birren, B. W.; Xavier, R. J.; Blainey, P. C.; Gevers, D.; Alm, E. J.] Broad Inst MIT & Harvard, Cambridge, MA 02139 USA. [Yilmaz, S.; Singh, A. K.] Sandia Natl Labs, Livermore, CA 94608 USA. [Jupiter, S. D.; Naisilisili, W.] Wildlife Conservat Soc, Suva, Fiji. [Jenkins, A. P.] Edith Cowan Univ, Joondalup, WA 6027, Australia. [Tamminen, M.] Eawag, Dept Aquat Ecol, CH-8600 Dubendorf, Switzerland. [Tamminen, M.] ETH, Dept Environm Syst Sci, CH-8092 Zurich, Switzerland. [Xavier, R. J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Xavier, R. J.; Alm, E. J.] MIT, Ctr Microbiome Informat & Therapeut, 77 Massachusetts Ave, Cambridge, MA 02139 USA. RP Alm, EJ (reprint author), MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Alm, EJ (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02139 USA.; Alm, EJ (reprint author), MIT, Ctr Microbiome Informat & Therapeut, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM ejalm@mit.edu OI Blainey, Paul/0000-0002-4889-8783 FU National Human Genome Research Institute [U54HG003067]; Center for Environmental Health Sciences at MIT; Center for Microbiome Informatics and Therapeutics at MIT; Fijian Ministry of Health; Columbia University Earth Institute Fellowship; Broad Institute Lawrence Summers Fellowship; Burroughs Wellcome Fund Career Award at the Scientific Interface; NIDCR [R01 DE020891]; ENIGMA; US Department of Energy, Office of Science, Office of Biological and Environmental Research; United States Department of Energy [DE-AC04-94AL85000] FX We thank our field collaborators in the Fiji Islands: the Wildlife Conservation Society, Fiji, Wetlands International-Oceania, K. Jenkins, S. Korovou, N. Litidamu, and K. Kishore. We thank T. Poon for sample, sequencing, and data coordination, and A. Materna (QIAGEN) for technical assistance. This work was supported by grants from the National Human Genome Research Institute (U54HG003067) to the Broad Institute, the Center for Environmental Health Sciences at MIT, the Center for Microbiome Informatics and Therapeutics at MIT, and the Fijian Ministry of Health. Additional support was provided by a Columbia University Earth Institute Fellowship (I.L.B.); a Broad Institute Lawrence Summers Fellowship (L.X.); a Burroughs Wellcome Fund Career Award at the Scientific Interface (P.C.B.); and an R01 DE020891 funded by the NIDCR and ENIGMA and a Lawrence Berkeley National Laboratory Scientific Focus Area Program supported by the US Department of Energy, Office of Science, Office of Biological and Environmental Research (S.Y. and A.K.S.). Sandia is a multi-program laboratory operated by Sandia Corp., a Lockheed Martin Co., for the United States Department of Energy under Contract DE-AC04-94AL85000. NR 62 TC 5 Z9 5 U1 18 U2 30 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 21 PY 2016 VL 535 IS 7612 BP 435 EP + DI 10.1038/nature18927 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DS1GQ UT WOS:000380344200043 PM 27409808 ER PT J AU Goss, PE Ingle, JN Pritchard, KI Robert, NJ Muss, H Gralow, J Gelmon, K Whelan, T Strasser-Weippl, K Rubin, S Sturtz, K Wolff, AC Winer, E Hudis, C Stopeck, A Beck, JT Kaur, JS Whelan, K Tu, D Parulekar, WR AF Goss, P. E. Ingle, J. N. Pritchard, K. I. Robert, N. J. Muss, H. Gralow, J. Gelmon, K. Whelan, T. Strasser-Weippl, K. Rubin, S. Sturtz, K. Wolff, A. C. Winer, E. Hudis, C. Stopeck, A. Beck, J. T. Kaur, J. S. Whelan, K. Tu, D. Parulekar, W. R. TI Extending Aromatase-Inhibitor Adjuvant Therapy to 10 Years SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID POSITIVE BREAST-CANCER; QUALITY-OF-LIFE; POSTMENOPAUSAL WOMEN; TAMOXIFEN THERAPY; ENDOCRINE THERAPY; RANDOMIZED-TRIAL; ADHERENCE; LETROZOLE AB BACKGROUND Treatment with an aromatase inhibitor for 5 years as up-front monotherapy or after tamoxifen therapy is the treatment of choice for hormone-receptor-positive early breast cancer in postmenopausal women. Extending treatment with an aromatase inhibitor to 10 years may further reduce the risk of breast-cancer recurrence. METHODS We conducted a double-blind, placebo-controlled trial to assess the effect of the extended use of letrozole for an additional 5 years. Our primary end point was disease-free survival. RESULTS We enrolled 1918 women. After a median follow-up of 6.3 years, there were 165 events involving disease recurrence or the occurrence of contralateral breast cancer (67 with letrozole and 98 with placebo) and 200 deaths (100 in each group). The 5-year disease-free survival rate was 95% (95% confidence interval [CI], 93 to 96) with letrozole and 91% (95% CI; 89 to 93) with placebo (hazard ratio for disease recurrence or the occurrence of contralateral breast cancer, 0.66; P = 0.01 by a two-sided log-rank test stratified according to nodal status, prior adjuvant chemotherapy, the interval from the last dose of aromatase-inhibitor therapy, and the duration of treatment with tamoxifen). The rate of 5-year overall survival was 93% (95% CI, 92 to 95) with letrozole and 94% (95% CI, 92 to 95) with placebo (hazard ratio, 0.97; P = 0.83). The annual incidence rate of contralateral breast cancer in the letrozole group was 0.21% (95% CI, 0.10 to 0.32), and the rate in the placebo group was 0.49% (95% CI, 0.32 to 0.67) (hazard ratio, 0.42; P = 0.007). Bone-related toxic effects occurred more frequently among patients receiving letrozole than among those receiving placebo, including a higher incidence of bone pain, bone fractures, and new-onset osteoporosis. No significant differences between letrozole and placebo were observed in scores on most subscales measuring quality of life. CONCLUSIONS The extension of treatment with an adjuvant aromatase inhibitor to 10 years resulted in significantly higher rates of disease-free survival and a lower incidence of contralateral breast cancer than those with placebo, but the rate of overall survival was not higher with the aromatase inhibitor than with placebo. ( Funded by the Canadian Cancer Society and others;) C1 [Goss, P. E.] Massachusetts Gen Hosp, Ctr Canc, Avon Int Breast Canc Res Program, 55 Fruit St,LRH 302, Boston, MA 02114 USA. [Goss, P. E.; Winer, E.] Harvard Med Sch, Boston, MA USA. [Winer, E.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Ingle, J. N.; Kaur, J. S.] Mayo Clin, Dept Oncol, Rochester, MN USA. [Pritchard, K. I.] Sunnybrook Odette Canc Ctr, Toronto, ON, Canada. [Gelmon, K.] British Columbia Canc Agcy, Vancouver, BC, Canada. [Whelan, K.; Tu, D.; Parulekar, W. R.] Queens Univ, Canadian Canc Trials Grp, Kingston, ON, Canada. [Whelan, T.] McMaster Univ, Dept Oncol, Hamilton, ON, Canada. [Rubin, S.] Dalhousie Univ, Fac Med, Moncton Hosp, Moncton, NB, Canada. [Robert, N. J.] Virginia Canc Specialists US Oncol Network, Fairfax, VA USA. [Muss, H.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC USA. [Gralow, J.] Univ Washington, Sch Med, Seattle, WA USA. [Strasser-Weippl, K.] Wilheminen Hosp, Ctr Oncol & Hematol, Vienna, Austria. [Sturtz, K.] Colorado Canc Res Program, Denver, CO USA. [Wolff, A. C.] Johns Hopkins Kimmel Canc Ctr, Baltimore, MD USA. [Hudis, C.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Stopeck, A.] Univ Arizona, Tucson, AZ USA. [Beck, J. T.] Highlands Oncol Grp, Fayetteville, AR USA. RP Goss, PE (reprint author), Massachusetts Gen Hosp, Ctr Canc, Avon Int Breast Canc Res Program, 55 Fruit St,LRH 302, Boston, MA 02114 USA. EM pgoss@mgh.harvard.edu RI Whelan, Timothy/D-3185-2017 FU Canadian Cancer Society Research Institute [021039, 015469]; National Cancer Institute [CA180888, CA189953, CA180828, CA13612, CA37981, CA077202, CA180863, CA67753, CA189805, CA16116, CA180802]; Canadian Cancer Trials Group [CA077202, CA180863]; ECOG-ACRIN Cancer Research Group [CA180820, CA21115]; Novartis Pharmaceuticals; Avon Foundation; AstraZeneca; Pfizer; Roche; Amgen; Novartis; Glaxo-SmithKline; Eisai; Genomic Health; NanoString; Genentech; BioMarin FX Supported by grants from the Canadian Cancer Society Research Institute (021039 and 015469), the National Cancer Institute (CA180888, CA189953, CA180828, CA13612, CA37981, CA077202, CA180863, CA67753, CA189805 [to Dr. Sturtz], CA16116, CA180802 [to Dr. Wolff], CA16116, and CA180802 [to Dr. Robert]), the Canadian Cancer Trials Group (CA077202 and CA180863), the ECOG-ACRIN Cancer Research Group (CA180820 and CA21115), and Novartis Pharmaceuticals. Dr. Goss was funded in part by the Avon Foundation.; Dr. Pritchard reports receiving fees for serving on advisory boards from AstraZeneca, Pfizer, Roche, Amgen, Novartis, Glaxo-SmithKline and Eisai, consulting fees from Pfizer and Novartis, and lecture fees from Novartis; Dr. Muss, serving as an uncompensated consultant and advisor to Pfizer and HarborPath and serving on the board of directors of HarborPath; Dr. Gralow, serving on data safety and monitoring committees for Novartis and Roche-Genentech and on a steering committee for Roche-Genentech; Dr. Whelan, receiving fees for serving on an advisory board from Genomic Health and fees for testing reagents from NanoString; Dr. Winer, receiving grant support through his institution from Novartis; Dr. Hudis, receiving consulting fees and fees for serving on advisory boards from Novartis, Pfizer, and AstraZeneca; and Dr. Stopeck, receiving consulting fees from Amgen, Genentech, and BioMarin and honoraria from Amgen and serving on a data safety and monitoring committee for Pfizer and a steering committee for Sandoz. No other potential conflict of interest relevant to this article was reported. NR 15 TC 34 Z9 34 U1 10 U2 17 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 21 PY 2016 VL 375 IS 3 BP 209 EP 219 DI 10.1056/NEJMoa1604700 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA DS0ZL UT WOS:000380325400004 PM 27264120 ER PT J AU Alshikho, MJ Talas, JM Noureldine, SI Zazou, S Addas, A Kurabi, H Nasser, M AF Alshikho, Mohamad J. Talas, Joud M. Noureldine, Salem I. Zazou, Saf Addas, Aladdin Kurabi, Haitham Nasser, Mahmoud TI Intestinal Lymphangiectasia: Insights on Management and Literature Review SO AMERICAN JOURNAL OF CASE REPORTS LA English DT Review DE Lymphangiectasis, Intestinal; Octreotide; Protein-Losing Enteropathies; Cellulitis ID SLOW-RELEASE OCTREOTIDE; PROTEIN-LOSING ENTEROPATHY; ANTIPLASMIN THERAPY; EFFUSIONS; ASCITES AB Objective: Rare disease Background: Intestinal lymphangiectasia (IL) is a rare disease characterized by a dilatation of the intestinal lymphatics and loss of lymph fluid into the gastrointestinal tract leading to hypoproteinemia, edema, lymphocytopenia, hypogammaglobinemia, and immunological abnormalities. Iron, calcium, and other serum components (e.g., lipids, fat soluble vitamins) may also be depleted. A literature search revealed more than 200 reported cases of IL. Herein, we report our observations of a patient diagnosed with IL; we also present our conclusion for our review of the published literature. Case Report: A 24-year-old male was admitted to Aleppo University Hospital with the complaints of abdominal pain, headache, arthralgia, fever, and rigors. His past medical history was remarkable for frequent episodes of diarrhea, recurrent infections, and swelling in the lower limbs. In addition, he had been hospitalized several times in non-academic hospitals due to edema in his legs, cellulitis, and recurrent infections. In the emergency department, a physical examination revealed a patient in distress. He was weak, dehydrated, pale, and had a high-grade fever. His lower extremities were edematous, swollen, and extremely tender to touch. The overlying skin was erythematous and warm. Moreover, the patient was tachycardic, tacypneic, and moderately hypotensive. The patient was resuscitated with IV fluids, and Tylenol was administered to bring the temperature down. Blood tests showed anemia and high levels of inflammatory markers. The patient's white blood cell count was elevated with an obvious left shift. However, subsequent investigations showed that the patient had IL. Suitable diet modification plans were applied as a long-term management plan. Conclusions: IL is a rare disease of challenging nature due to its systematic effects and lack of comprehensive studies that can evaluate the effectiveness of specific treatments in a large cohort of patients. Medium-chain triglyceride (MCT) oils and diet modification strategies are effective in reducing the loss of body proteins and in maintaining near-normal blood levels of immunoglobulins. However, octreotide and MCT oils had no proven role in reducing lymphedema in our patient. C1 [Alshikho, Mohamad J.] Harvard Univ, Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02115 USA. [Talas, Joud M.] Aleppo Univ, Dept Dermatol, Aleppo, Syria. [Noureldine, Salem I.] Johns Hopkins Univ, Dept Otolaryngol Head & Neck Surg, Baltimore, MD USA. [Zazou, Saf; Addas, Aladdin; Kurabi, Haitham] Aleppo Univ, Dept Gen Internal Med, Aleppo, Syria. [Nasser, Mahmoud] Aleppo Univ, Dept Gastroenterol, Aleppo, Syria. RP Alshikho, MJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02115 USA. EM malshikho@mgh.harvard.edu NR 24 TC 0 Z9 0 U1 1 U2 1 PU INT SCIENTIFIC LITERATURE, INC PI SMITHTOWN PA 361 FOREST LANE, SMITHTOWN, NY 11787 USA SN 1941-5923 J9 AM J CASE REP JI Am. J. Case Rep. PD JUL 21 PY 2016 VL 17 DI 10.12659/AJCR.899636 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA DR5LR UT WOS:000379945000001 ER PT J AU Chirgwin, JH Giobbie-Hurder, A Coates, AS Price, KN Ejlertsen, B Debled, M Gelber, RD Goldhirsch, A Smith, I Rabaglio, M Forbes, JF Neven, P Lang, I Colleoni, M Thurlimann, B AF Chirgwin, Jacquie H. Giobbie-Hurder, Anita Coates, Alan S. Price, Karen N. Ejlertsen, Bent Debled, Marc Gelber, Richard D. Goldhirsch, Aron Smith, Ian Rabaglio, Manuela Forbes, John F. Neven, Patrick Lang, Istvan Colleoni, Marco Thurlimann, Beat TI Treatment Adherence and Its Impact on Disease-Free Survival in the Breast International Group 1-98 Trial of Tamoxifen and Letrozole, Alone and in Sequence SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ADJUVANT ENDOCRINE THERAPY; PATIENT SELF-REPORT; POSTMENOPAUSAL WOMEN; HORMONAL-THERAPY; RANDOMIZED-TRIAL; CANCER PATIENTS; COMPARING LETROZOLE; AROMATASE INHIBITOR; COMPETING RISK; DOUBLE-BLIND AB Purpose To investigate adherence to endocrine treatment and its relationship with disease-free survival (DFS) in the Breast International Group (BIG) 1-98 clinical trial. Methods The BIG 1-98 trial is a double-blind trial that randomly assigned 6,193 postmenopausal women with hormone receptor-positive early breast cancer in the four-arm option to 5 years of tamoxifen (Tam), letrozole (Let), or the agents in sequence (Let-Tam, Tam-Let). This analysis included 6,144 women who received at least one dose of study treatment. Conditional landmark analyses and marginal structural Cox proportional hazards models were used to evaluate the relationship between DFS and treatment adherence (persistence [duration] and compliance with dosage). Competing risks regression was used to assess demographic, disease, and treatment characteristics of the women who stopped treatment early because of adverse events. Results Both aspects of low adherence (early cessation of letrozole and a compliance score of < 90%) were associated with reduced DFS (multivariable model hazard ratio, 1.45; 95% CI, 1.09 to 1.93; P = .01; and multivariable model hazard ratio, 1.61; 95% CI, 1.08 to 2.38; P = .02, respectively). Sequential treatments were associated with higher rates of nonpersistence (Tam-Let, 20.8%; Let-Tam, 20.3%; Tam 16.9%; Let 17.6%). Adverse events were the reason for most trial treatment early discontinuations (82.7%). Apart from sequential treatment assignment, reduced adherence was associated with older age, smoking, node negativity, or prior thromboembolic event. Conclusion Both persistence and compliance are associated with DFS. Toxicity management and, for sequential treatments, patient and physician awareness, may improve adherence. (C) 2016 by American Society of Clinical Oncology C1 [Chirgwin, Jacquie H.; Forbes, John F.] Univ Newcastle, Newcastle, NSW, Australia. [Forbes, John F.] Calvary Mater Newcastle, Newcastle, NSW, Australia. [Coates, Alan S.] Univ Sydney, Sch Publ Hlth, Sydney, NSW 2006, Australia. [Chirgwin, Jacquie H.] Box Hill Hosp, Melbourne, Vic, Australia. [Chirgwin, Jacquie H.] Maroondah Hosp, Melbourne, Vic, Australia. [Chirgwin, Jacquie H.] Monash Univ, Melbourne, Vic, Australia. [Giobbie-Hurder, Anita; Price, Karen N.; Gelber, Richard D.] Dana Farber Canc Inst, Int Breast Canc Study Grp Stat Ctr, Boston, MA 02115 USA. [Price, Karen N.; Gelber, Richard D.] Frontier Sci & Technol Res Fdn Inc, Boston, MA USA. [Gelber, Richard D.] Harvard Med Sch, Boston, MA USA. [Ejlertsen, Bent] Rigshosp, Copenhagen, Denmark. [Debled, Marc] Inst Bergonie, Bordeaux, France. [Goldhirsch, Aron; Colleoni, Marco] European Inst Oncol, Milan, Italy. [Smith, Ian] Royal Marsden Hosp, London, England. [Smith, Ian] Inst Canc Res, London, England. [Rabaglio, Manuela] Inselspital Bern, Bern, Switzerland. [Thurlimann, Beat] Kantonsspital, St Gallen, Switzerland. [Neven, Patrick] Univ Leuven, Leuven, Belgium. [Neven, Patrick] Univ Hosp Leuven, Leuven, Belgium. [Lang, Istvan] Natl Inst Oncol, Budapest, Hungary. RP Chirgwin, JH (reprint author), Univ Newcastle, Newcastle, NSW, Australia.; Chirgwin, JH (reprint author), Maroondah Breast Clin, 20 Grey St, Ringwood, Vic 3135, Australia. EM chirgwin@tpg.com.au FU Novartis; Swedish Cancer Society; Cancer Council Australia; Australian New Zealand Breast Cancer Trials Group; Frontier Science and Technology Research Foundation; Swiss Group for Clinical Cancer Research; National Cancer Institute [CA-75362]; Cancer Research Switzerland/Oncosuisse; Foundation for Clinical Cancer Research of Eastern Switzerland FX The Breast International Group 1-98 trial was financed by Novartis and coordinated by the International Breast Cancer Study Group. Support for the International Breast Cancer Study Group was provided by Swedish Cancer Society, The Cancer Council Australia, Australian New Zealand Breast Cancer Trials Group, Frontier Science and Technology Research Foundation, Swiss Group for Clinical Cancer Research, National Cancer Institute Grant CA-75362, Cancer Research Switzerland/Oncosuisse, and the Foundation for Clinical Cancer Research of Eastern Switzerland. NR 52 TC 2 Z9 2 U1 9 U2 9 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 2016 VL 34 IS 21 BP 2452 EP + DI 10.1200/JCO.2015.63.8619 PG 12 WC Oncology SC Oncology GA DT5BZ UT WOS:000381497000004 PM 27217455 ER PT J AU Khorana, AA Mangu, PB Berlin, J Engebretson, A Hong, TS Maitra, A Mohile, SG Mumber, M Schulick, R Shapiro, M Urba, S Zeh, HJ Katz, MHG AF Khorana, Alok A. Mangu, Pamela B. Berlin, Jordan Engebretson, Anitra Hong, Theodore S. Maitra, Anirban Mohile, Supriya G. Mumber, Matthew Schulick, Richard Shapiro, Marc Urba, Susan Zeh, Herbert J. Katz, Matthew H. G. TI Potentially Curable Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID PHASE-III TRIAL; GEMCITABINE-BASED CHEMORADIATION; RANDOMIZED CONTROLLED-TRIAL; LONG-TERM SURVIVAL; ADJUVANT CHEMOTHERAPY; DUCTAL ADENOCARCINOMA; CURATIVE RESECTION; COST-EFFECTIVENESS; MULTIDISCIPLINARY MANAGEMENT; POSTOPERATIVE COMPLICATIONS AB PurposeTo provide evidence-based recommendations to oncologists and others on potentially curative therapy for patients with localized pancreatic cancer.MethodsASCO convened a panel of medical oncology, radiation oncology, surgical oncology, palliative care, and advocacy experts and conducted a systematic review of literature from January 2002 to June 2015. Outcomes included overall survival, disease-free survival, progression-free survival, and adverse events.ResultsNine randomized controlled trials met the systematic review criteria.RecommendationsA multiphase computed tomography scan of the abdomen and pelvis or magnetic resonance imaging should be performed for all patients to assess the anatomic relationships of the primary tumor and for the presence of intra-abdominal metastases. Baseline performance status, comorbidity profile, and goals of care should be evaluated and established. Primary surgical resection is recommended for all patients who have no metastases, appropriate performance and comorbidity profiles, and no radiographic interface between primary tumor and mesenteric vasculature. Preoperative therapy is recommended for patients who meet specific characteristics. All patients with resected pancreatic cancer who did not receive preoperative therapy should be offered 6 months of adjuvant chemotherapy in the absence of contraindications. Adjuvant chemoradiation may be offered to patients who did not receive preoperative therapy with microscopically positive margins (R1) after resection and/or who had node-positive disease after completion of 4 to 6 months of systemic adjuvant chemotherapy. Patients should have a full assessment of symptoms, psychological status, and social supports and should receive palliative care early. Patients who have completed treatment and have no evidence of disease should be monitored. Additional information is available at www.asco.org/guidelines/PCPC and www.asco.org/guidelineswiki. C1 [Khorana, Alok A.; Shapiro, Marc] Cleveland Clin, Cleveland, OH 44106 USA. [Mangu, Pamela B.] Amer Soc Clin Oncol, 2318 Mill Rd,Ste 800, Alexandria, VA 22314 USA. [Berlin, Jordan] Vanderbilt Univ, 221 Kirkland Hall, Nashville, TN 37235 USA. [Hong, Theodore S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Maitra, Anirban; Katz, Matthew H. G.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Mohile, Supriya G.] Univ Rochester, Rochester, NY USA. [Mumber, Matthew] Harbin Clin, Rome, GA USA. [Schulick, Richard] Univ Colorado, Denver, CO 80202 USA. [Urba, Susan] Univ Michigan, Ann Arbor, MI 48109 USA. [Zeh, Herbert J.] Univ Pittsburgh, Pittsburgh, PA USA. RP Khorana, AA (reprint author), Amer Soc Clin Oncol, 2318 Mill Rd,Ste 800, Alexandria, VA 22314 USA. EM guidelines@asco.org NR 86 TC 11 Z9 13 U1 5 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 2016 VL 34 IS 21 BP 2541 EP + DI 10.1200/JCO.2016.67.5553 PG 18 WC Oncology SC Oncology GA DT5BZ UT WOS:000381497000015 PM 27247221 ER PT J AU Ren, XY Weisgerber, DW Bischoff, D Lewis, MS Reid, RR He, TC Yamaguchi, DT Miller, TA Harley, BAC Lee, JC AF Ren, Xiaoyan Weisgerber, Daniel W. Bischoff, David Lewis, Michael S. Reid, Russell R. He, Tong-Chuan Yamaguchi, Dean T. Miller, Timothy A. Harley, Brendan A. C. Lee, Justine C. TI Nanoparticulate Mineralized Collagen Scaffolds and BMP-9 Induce a Long-Term Bone Cartilage Construct in Human Mesenchymal Stem Cells SO ADVANCED HEALTHCARE MATERIALS LA English DT Article ID BMP9-INDUCED OSTEOGENIC DIFFERENTIATION; MORPHOGENETIC PROTEIN-9; ACTIVATION; STIMULATION; DELIVERY; P38; REGENERATION; RECEPTORS; SYSTEMS; ERK1/2 AB Engineering the osteochondral junction requires fabrication of a micro-environment that supports both osteogenesis and chondrogenesis. Multiphasic scaffold strategies utilizing a combination of soluble factors and extracellular matrix components are ideally suited for such applications. In this work, the contribution of an osteogenic nanoparticulate mineralized glycosaminoglycan scaffold (MC-GAG) and a dually chondrogenic and osteogenic growth factor, BMP-9, in the differentiation of primary human mesenchymal stem cells (hMSCs) is evaluated. Although 2D cultures demonstrate alkaline phosphatase activity and mineralization of hMSCs induced by BMP-9, MC-GAG scaffolds do not demonstrate significant differences in the collagen I expression, osteopontin expression, or mineralization. Instead, BMP-9 increases expression of collagen II, Sox9, aggrecan (ACAN), and cartilage oligomeric protein. However, the hypertrophic chondrocyte marker, collagen X, is not elevated with BMP-9 treatment. In addition, histologic analyses demonstrate that while BMP-9 does not increase mineralization, BMP-9 treatment results in an increase of sulfated glycosaminoglycans. Thus, the combination of BMP-9 and MC-GAG stimulates chondrocytic and osteogenic differentiation of hMSCs. C1 [Ren, Xiaoyan; Miller, Timothy A.; Lee, Justine C.] Univ Calif Los Angeles, David Geffen Sch Med, Div Plast & Reconstruct Surg, Los Angeles, CA 90095 USA. [Ren, Xiaoyan; Bischoff, David; Yamaguchi, Dean T.; Miller, Timothy A.; Lee, Justine C.] Greater Los Angeles VA Healthcare Syst, Res Serv, Los Angeles, CA 90073 USA. [Weisgerber, Daniel W.; Harley, Brendan A. C.] Univ Illinois, Inst Genom Biol, Dept Chem & Biomol Engn, Urbana, IL 61801 USA. [Lewis, Michael S.] Greater Los Angeles VA Healthcare Syst, Dept Pathol, Los Angeles, CA 90073 USA. [Reid, Russell R.] Univ Chicago, Sect Plast & Reconstruct Surg, Chicago, IL 60637 USA. [He, Tong-Chuan] Univ Chicago, Dept Orthopaed Surg, Chicago, IL 60637 USA. RP Lee, JC (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Div Plast & Reconstruct Surg, Los Angeles, CA 90095 USA.; Lee, JC (reprint author), Greater Los Angeles VA Healthcare Syst, Res Serv, Los Angeles, CA 90073 USA. EM justine@ucla.edu OI Harley, Brendan/0000-0001-5458-154X FU US Department of Veterans Affairs [IK2 BX002442-01A2, 1I01BX001367-01A2]; Jean Perkins Foundation; Aramont Foundation; Bernard G. Sarnat Endowment for Craniofacial Biology; National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health [R21 AR063331]; UIUC from National Science Foundation (NSF) [0965918] FX This work was supported by the US Department of Veterans Affairs under award numbers IK2 BX002442-01A2 (JCL) and 1I01BX001367-01A2 (TAM), the Jean Perkins Foundation (JCL), the Aramont Foundation (TAM), and the Bernard G. Sarnat Endowment for Craniofacial Biology (JCL). Research reported in this publication was also supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under award number R21 AR063331 (BACH). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. D.W.W. was funded at UIUC from National Science Foundation (NSF) under Grant 0965918 IGERT: Training the Next Generation of Researchers in Cellular & Molecular Mechanics and BioNanotechnology. NR 35 TC 0 Z9 0 U1 10 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2192-2640 EI 2192-2659 J9 ADV HEALTHC MATER JI Adv. Healthc. Mater. PD JUL 20 PY 2016 VL 5 IS 14 BP 1821 EP 1830 DI 10.1002/adhm.201600187 PG 10 WC Engineering, Biomedical; Nanoscience & Nanotechnology; Materials Science, Biomaterials SC Engineering; Science & Technology - Other Topics; Materials Science GA DV2RT UT WOS:000382769400011 PM 27275929 ER PT J AU Mazzulli, JR Zunke, F Tsunemi, T Toker, NJ Jeon, S Burbulla, LF Patnaik, S Sidransky, E Marugan, JJ Sue, CM Krainc, D AF Mazzulli, Joseph R. Zunke, Friederike Tsunemi, Taiji Toker, Nicholas J. Jeon, Sohee Burbulla, Lena F. Patnaik, Samarjit Sidransky, Ellen Marugan, Juan J. Sue, Carolyn M. Krainc, Dimitri TI Activation of beta-Glucocerebrosidase Reduces Pathological alpha-Synuclein and Restores Lysosomal Function in Parkinson's Patient Midbrain Neurons SO JOURNAL OF NEUROSCIENCE LA English DT Article DE alpha-synuclein; glucocerebrosidase; induced pluripotent stem cells; lysosomes; Parkinson's disease; synucleinopathy ID GAUCHER-DISEASE; DOPAMINE NEURONS; LEWY BODIES; MOUSE MODEL; DYSFUNCTION; AGGREGATION; MUTATIONS; INHIBITION; DEFECTS; CELLS AB Parkinson's disease (PD) is characterized by the accumulation of alpha-synuclein (alpha-syn) within Lewy body inclusions in the nervous system. There are currently no disease-modifying therapies capable of reducing alpha-syn inclusions in PD. Recent data has indicated that loss-of-function mutations in the GBA1 gene that encodes lysosomal beta-glucocerebrosidase (GCase) represent an important risk factor for PD, and can lead to alpha-syn accumulation. Here we use a small-molecule modulator of GCase to determine whether GCase activation within lysosomes can reduce alpha-syn levels and ameliorate downstream toxicity. Using induced pluripotent stem cell (iPSC)-derived human midbrain dopamine (DA) neurons from synucleinopathy patients with different PD-linked mutations, wefind that a non-inhibitory small molecule modulator of GCase specifically enhanced activity within lysosomal compartments. This resulted in reduction of GCase substrates and clearance of pathological alpha-syn, regardless of the disease causing mutations. Importantly, the reduction of alpha-syn was sufficient to reverse downstream cellular pathologies induced by alpha-syn, including perturbations in hydrolase maturation and lysosomal dysfunction. These results indicate that enhancement of a single lysosomal hydrolase, GCase, can effectively reduce alpha-syn and provide therapeutic benefit in human midbrain neurons. This suggests that GCase activators may prove beneficial as treatments for PD and related synucleinopathies. C1 [Mazzulli, Joseph R.; Tsunemi, Taiji; Burbulla, Lena F.; Krainc, Dimitri] Massachusetts Gen Hosp, Harvard Med Sch, MassGen Inst Neurodegenerat, Dept Neurol, Charlestown, MA 02129 USA. [Mazzulli, Joseph R.; Zunke, Friederike; Tsunemi, Taiji; Toker, Nicholas J.; Jeon, Sohee; Burbulla, Lena F.; Krainc, Dimitri] Northwestern Univ, Feinberg Sch Med, Ken & Ruth Davee Dept Neurol, 303 East Chicago Ave,Ward 12-140, Chicago, IL 60611 USA. [Patnaik, Samarjit; Marugan, Juan J.] NIH, Dept Preclin Innovat, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA. [Sidransky, Ellen] NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Sue, Carolyn M.] Royal North Shore Hosp, Kolling Inst Med Res, Dept Neurogenet, St Leonards, NSW 2065, Australia. [Sue, Carolyn M.] Univ Sydney, St Leonards, NSW 2065, Australia. RP Mazzulli, JR; Krainc, D (reprint author), Northwestern Univ, Feinberg Sch Med, Ken & Ruth Davee Dept Neurol, 303 East Chicago Ave,Ward 12-140, Chicago, IL 60611 USA. EM jmazzulli@northwestern.edu; krainc@northwestern.edu FU Human Embryonic and Induced Pluripotent Stem Cell Facility at Northwestern University; NIH [P30 NS081774]; Lipidomics Shared Resource, Hollings Cancer Center, Medical University of South Carolina [P30 CA138313]; Lipidomics Core in the South Carolina Lipidomics and Pathobiology Center of Biomedical Research Excellence, Department Biochemistry, Medical University of South Carolina [P20 RR017677]; German Academic Exchange Service (DAAD); Intramural Research Programs of the National Human Genome Research Institute; Intramural Research Program of the National Center for Advancing Translational Sciences of the National Institutes of Health; NHMRC Practitioner Fellowship [1008433]; National Institute of Neurological Disorders and Stroke [R01NS092823, R01NS076054, U24NS078338]; PDNSW Association FX This work was supported in part by the Human Embryonic and Induced Pluripotent Stem Cell Facility at Northwestern University and NIH core support Grant P30 NS081774; lipid measurements were supported in part by the Lipidomics Shared Resource, Hollings Cancer Center, Medical University of South Carolina (P30 CA138313) and the Lipidomics Core in the South Carolina Lipidomics and Pathobiology Center of Biomedical Research Excellence, Department Biochemistry, Medical University of South Carolina (P20 RR017677); L.F.B. was supported by a fellowship within the postdoctoral program of the German Academic Exchange Service (DAAD); E.S. was supported by the Intramural Research Programs of the National Human Genome Research Institute; S.P. and J.J.M. by the Intramural Research Program of the National Center for Advancing Translational Sciences, both of the National Institutes of Health; C.M.S. by the NHMRC Practitioner Fellowship (1008433); National Institute of Neurological Disorders and Stroke Grants R01NS092823 (J.R.M.), R01NS076054, U24NS078338 (D.K.); and the PDNSW Association (C.M.S.). We thank Kana Hamada and Haris Dzaferbegovic for excellent technical assistance, Nick Blair and Ernst Wolvetang for advice and characterization of PARK9 iPSC line, R. Jaenisch (MIT) for generously providing the A53T alpha-syn iPSC lines, and Johannes Aerts (University of Leiden) for generously providing the anti-glucocerebrosidase antibody (8E4). NR 48 TC 10 Z9 10 U1 6 U2 11 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 20 PY 2016 VL 36 IS 29 BP 7693 EP 7706 DI 10.1523/JNEUROSCI.0628-16.2016 PG 14 WC Neurosciences SC Neurosciences & Neurology GA DU6AX UT WOS:000382296300013 PM 27445146 ER PT J AU Ishizawa, Y Ahmed, OJ Patel, SR Gale, JT Sierra-Mercado, D Brown, EN Eskandar, EN AF Ishizawa, Yumiko Ahmed, Omar J. Patel, Shaun R. Gale, John T. Sierra-Mercado, Demetrio Brown, Emery N. Eskandar, Emad N. TI Dynamics of Propofol-Induced Loss of Consciousness Across Primate Neocortex SO JOURNAL OF NEUROSCIENCE LA English DT Article DE general anesthesia; local field potential; loss of consciousness; primate; sensory premotor network; single-neuron activity ID VENTRAL PREMOTOR CORTEX; GENERAL-ANESTHESIA; INDUCED UNCONSCIOUSNESS; BEHAVIORAL-CONTROL; COHERENCE ANALYSIS; BETA-OSCILLATIONS; BRAIN ACTIVATION; NETWORK; RHYTHMS; SYSTEMS AB The precise neural mechanisms underlying transitions between consciousness and anesthetic-induced unconsciousness remain unclear. Here, we studied intracortical neuronal dynamics leading to propofol-induced unconsciousness by recording single-neuron activity and local field potentials directly in the functionally interconnecting somatosensory (S1) and frontal ventral premotor (PMv) network during a gradual behavioral transition from full alertness to loss of consciousness (LOC) and on through a deeper anesthetic level. Macaque monkeys were trained for a behavioral task designed to determine the trial-by-trial alertness and neuronal response to tactile and auditory stimulation. Weshow that disruption of coherent beta oscillations between S1 and PMv preceded, but did not coincide with, the LOC. LOC appeared to correspond to pronounced but brief gamma-/high-beta-band oscillations (lasting similar to 3 min) in PMv, followed by a gamma peak in S1. We also demonstrate that the slow oscillations appeared after LOC in S1 and then in PMv after a delay, together suggesting that neuronal dynamics are very different across S1 versus PMv during LOC. Finally, neurons in both S1 and PMv transition from responding to bimodal (tactile and auditory) stimulation before LOC to only tactile modality during unconsciousness, consistent with an inhibition of multisensory integration in this network. Our results show that propofol-induced LOC is accompanied by spatiotemporally distinct oscillatory neuronal dynamics across the somatosensory and premotor network and suggest that a transitional state from wakefulness to unconsciousness is not a continuous process, but rather a series of discrete neural changes. C1 [Ishizawa, Yumiko; Brown, Emery N.] Massachusetts Gen Hosp, Harvard Med Sch, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA. [Ahmed, Omar J.] Massachusetts Gen Hosp, Harvard Med Sch, Dept Neurol, Boston, MA 02114 USA. [Patel, Shaun R.; Gale, John T.; Sierra-Mercado, Demetrio; Eskandar, Emad N.] Massachusetts Gen Hosp, Harvard Med Sch, Dept Neurosurg, Boston, MA 02114 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 Ishizawa, Y (reprint author), Massachusetts Gen Hosp, Harvard Med Sch, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA. EM yishizawa@mgh.harvard.edu FU Foundation for Anesthesia Education and Research; National Institutes of Health [5T32GM007592]; Harvard Medical School (Eleanor and Miles Shore 50th Anniversary Fellowship Scholars in Medicine) FX This work was supported by the Foundation for Anesthesia Education and Research, the National Institutes of Health (Grant 5T32GM007592), and Harvard Medical School (Eleanor and Miles Shore 50th Anniversary Fellowship Scholars in Medicine). We thank T. Kawai, C.-S. Kwon, F. Girgis, M. K. Mian, and S. Abdel-Aziz for help with primate surgeries; A. Uchida for assistance in animal experiments; and W.M. Zapol for expert advice. NR 46 TC 0 Z9 0 U1 3 U2 3 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 20 PY 2016 VL 36 IS 29 BP 7718 EP 7726 DI 10.1523/JNEUROSCI.4577-15.2016 PG 9 WC Neurosciences SC Neurosciences & Neurology GA DU6AX UT WOS:000382296300015 PM 27445148 ER PT J AU Vanduffel, W Arsenault, JT AF Vanduffel, Wim Arsenault, John T. TI Should I Stay or Should I Go? SO NEURON LA English DT Editorial Material ID CORTEX AB In this issue of Neuron, Lee et al. (2016) assessed the brain-wide effects of stimulating the direct and indirect pathway by optogenetic activation of D1 and D2 striatal neurons. This work demonstrates the exquisite power of combining cell-type-specific perturbation methods with focal and whole-brain measurements of brain activity. C1 [Vanduffel, Wim; Arsenault, John T.] Katholieke Univ Leuven, Sch Med, Dept Neurosci, Lab Neuro & Psychophysiol, B-3000 Leuven, Belgium. [Vanduffel, Wim; Arsenault, John T.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Vanduffel, Wim] Harvard Med Sch, Dept Radiol, Boston, MA 02114 USA. RP Vanduffel, W (reprint author), Katholieke Univ Leuven, Sch Med, Dept Neurosci, Lab Neuro & Psychophysiol, B-3000 Leuven, Belgium.; Vanduffel, W (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA.; Vanduffel, W (reprint author), Harvard Med Sch, Dept Radiol, Boston, MA 02114 USA. EM wim@nmr.mgh.harvard.edu NR 9 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD JUL 20 PY 2016 VL 91 IS 2 BP 207 EP 210 DI 10.1016/j.neuron.2016.07.012 PG 5 WC Neurosciences SC Neurosciences & Neurology GA DU7LH UT WOS:000382395200002 PM 27477011 ER PT J AU Williamson, RS Ahrens, MB Linden, JF Sahani, M AF Williamson, Ross S. Ahrens, Misha B. Linden, Jennifer F. Sahani, Maneesh TI Input-Specific Gain Modulation by Local Sensory Context Shapes Cortical and Thalamic Responses to Complex Sounds SO NEURON LA English DT Article ID PRIMARY AUDITORY-CORTEX; SPECTROTEMPORAL RECEPTIVE-FIELDS; STIMULUS-SPECIFIC ADAPTATION; MEDIAL GENICULATE-BODY; COMBINATION-SENSITIVE NEURONS; NATURAL SOUNDS; POPULATION RESPONSES; SPECTRAL INTEGRATION; INFERIOR COLLICULUS; INFORMATION-TRANSMISSION AB Sensory neurons are customarily characterized by one or more linearly weighted receptive fields describing sensitivity in sensory space and time. We show that in auditory cortical and thalamic neurons, the weight of each receptive field element depends on the pattern of sound falling within a local neighborhood surrounding it in time and frequency. Accounting for this change in effective receptive field with spectrotemporal context improves predictions of both cortical and thalamic responses to stationary complex sounds. Although context dependence varies among neurons and across brain areas, there are strong shared qualitative characteristics. In a spectrotemporally rich soundscape, sound elements modulate neuronal responsiveness more effectively when they coincide with sounds at other frequencies, and less effectively when they are preceded by sounds at similar frequencies. This local-context-driven lability in the representation of complex sounds-a modulation of "input-specific gain" rather than "output gain"-may be a widespread motif in sensory processing. C1 [Williamson, Ross S.; Sahani, Maneesh] UCL, Gatsby Computat Neurosci Unit, London W1T 4JG, England. [Williamson, Ross S.] UCL, Ctr Math & Phys Life Sci & Expt Biol, London WC1E 6BT, England. [Ahrens, Misha B.] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. [Ahrens, Misha B.] Univ Cambridge, Dept Engn, Computat & Biol Learning Lab, Cambridge CB2 1PZ, England. [Linden, Jennifer F.] UCL, Ear Inst, London WC1X 8EE, England. [Linden, Jennifer F.] UCL, Dept Neurosci Physiol & Pharmacol, London WC1E 6BT, England. [Williamson, Ross S.] Massachusetts Eye & Ear Infirm, Eaton Peabody Labs, Boston, MA 02114 USA. [Williamson, Ross S.] Boston Univ, Ctr Computat Neurosci & Neural Technol, Boston, MA 02115 USA. [Ahrens, Misha B.] Howard Hughes Med Inst, Janelia Res Campus, Ashburn, VA 20147 USA. RP Sahani, M (reprint author), UCL, Gatsby Computat Neurosci Unit, London W1T 4JG, England.; Linden, JF (reprint author), UCL, Ear Inst, London WC1X 8EE, England.; Linden, JF (reprint author), UCL, Dept Neurosci Physiol & Pharmacol, London WC1E 6BT, England. EM j.linden@ucl.ac.uk; maneesh@gatsby.ucl.ac.uk FU Centre for Mathematics and Physics in the Life Sciences and Experimental Biology at University College London; Wellcome Trust; National Institutes of Health; Gatsby Charitable Foundation FX We thank Lucy Anderson for expert guidance and assistance with histology and thalamic recording procedures, including design and fabrication of custom electrodes. This work was supported by the Centre for Mathematics and Physics in the Life Sciences and Experimental Biology at University College London (R.S.W.), the Wellcome Trust (M.B.A. and J.F.L.), the National Institutes of Health (J.F.L.), and the Gatsby Charitable Foundation (M.S. and J.F.L.). NR 89 TC 2 Z9 2 U1 3 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD JUL 20 PY 2016 VL 91 IS 2 BP 467 EP 481 DI 10.1016/j.neuron.2016.05.041 PG 15 WC Neurosciences SC Neurosciences & Neurology GA DU7LH UT WOS:000382395200022 PM 27346532 ER PT J AU Kwong, TC Hsing, M Lin, YT Thayer, D Unlu, MB Su, MY Gulsen, G AF Kwong, Tiffany C. Hsing, Mitchell Lin, Yuting Thayer, David Unlu, Mehmet Burcin Su, Min-Ying Gulsen, Gultekin TI Differentiation of tumor vasculature heterogeneity levels in small animals based on total hemoglobin concentration using magnetic resonance-guided diffuse optical tomography in vivo SO APPLIED OPTICS LA English DT Article ID NEOADJUVANT CHEMOTHERAPY; BREAST-CANCER; FLUORESCENCE TOMOGRAPHY; TREATMENT RESPONSE; DISRUPTING AGENTS; NEXT-GENERATION; MRI; SYSTEM; CONTRAST; ANGIOGENESIS AB Insight into the vasculature of the tumor in small animals has the potential to impact many areas of cancer research. The heterogeneity of the vasculature of a tumor is directly related to tumor stage and disease progression. In this small scale animal study, we investigated the feasibility of differentiating tumors with different levels of vasculature heterogeneity in vivo using a previously developed hybrid magnetic resonance imaging (MRI) and diffuse optical tomography (DOT) system for small animal imaging. Cross-sectional total hemoglobin concentration maps of 10 Fisher rats bearing R3230 breast tumors are reconstructed using multi-wavelength DOT measurements both with and without magnetic resonance (MR) structural a priori information. Simultaneously acquired MR structural images are used to guide and constrain the DOT reconstruction, while dynamic contrast-enhanced MR functional images are used as the gold standard to classify the vasculature of the tumor into two types: high versus low heterogeneity. These preliminary results show that the stand-alone DOT is unable to differentiate tumors with low and high vascular heterogeneity without structural a priori information provided by a high resolution imaging modality. The mean total hemoglobin concentrations comparing the vasculature of the tumors with low and high heterogeneity are significant (p-value 0.02) only when MR structural a priori information is utilized. (C) 2016 Optical Society of America C1 [Kwong, Tiffany C.; Hsing, Mitchell; Lin, Yuting; Thayer, David; Su, Min-Ying; Gulsen, Gultekin] Univ Calif Irvine, Dept Radiol Sci, Tu & Yuen Ctr Funct Oncoimaging, Irvine, CA 92697 USA. [Hsing, Mitchell] MIT, Dept Elect & Elect Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Lin, Yuting] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02144 USA. [Lin, Yuting] Harvard Med Sch, Boston, MA 02144 USA. [Thayer, David] Washington Univ, Sch Med St Louis, Mallinckrodt Inst Radiol, St Louis, MO 63110 USA. [Unlu, Mehmet Burcin] Bogazici Univ, Dept Phys, Istanbul, Turkey. RP Gulsen, G (reprint author), Univ Calif Irvine, Dept Radiol Sci, Tu & Yuen Ctr Funct Oncoimaging, Irvine, CA 92697 USA. EM ggulsen@uci.edu FU National Institutes of Health (NIH) [R21 EB013387, R21CA191389, R01EB008716, R21EB013387, R33CA120175, P30CA062203]; Ruth L. Kirschstein National Research Service Award [F31CA171915-01A1]; UCI Eugene Cota-Robles Fellowship FX National Institutes of Health (NIH) (R21 EB013387, R21CA191389, R01EB008716, R21EB013387, R33CA120175, P30CA062203); Ruth L. Kirschstein National Research Service Award (F31CA171915-01A1); UCI Eugene Cota-Robles Fellowship. NR 54 TC 0 Z9 0 U1 3 U2 3 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1559-128X EI 2155-3165 J9 APPL OPTICS JI Appl. Optics PD JUL 20 PY 2016 VL 55 IS 21 BP 5479 EP 5487 DI 10.1364/AO.55.005479 PG 9 WC Optics SC Optics GA DS4HD UT WOS:000380741100002 PM 27463894 ER PT J AU Blumenthal, KG Shenoy, ES Huang, MS Kuhlen, JL Ware, WA Parker, RA Walensky, RP AF Blumenthal, Kimberly G. Shenoy, Erica S. Huang, Mingshu Kuhlen, James L. Ware, Winston A. Parker, Robert A. Walensky, Rochelle P. TI The Impact of Reporting a Prior Penicillin Allergy on the Treatment of Methicillin-Sensitive Staphylococcus aureus Bacteremia SO PLOS ONE LA English DT Article ID INFECTIOUS-DISEASE CONSULTATION; HEMODIALYSIS-DEPENDENT PATIENTS; QUALITY-OF-CARE; ANTIMICROBIAL THERAPY; CLINICAL MANAGEMENT; ANTIBIOTIC-THERAPY; DRUG ALLERGY; BETA-LACTAMS; CEPHALOSPORINS; OUTCOMES AB Background Methicillin-sensitive Staphylococcus aureus (MSSA) bacteremia is a morbid infection with mortality benefit from receipt of parenteral beta-lactam therapy. A substantial portion of MSSA bacteremia patients report penicillin allergy, but infrequently have true allergy. Objective To determine the frequency and predictors of optimal and adequate therapy in patients with MSSA bacteremia. Design Retrospective cohort. Participants Adult inpatients with MSSA bacteremia, January 2009 through October 2013. Main Measures The primary measure was a trial of optimal therapy (OT), defined as >= 3 inpatient days or discharge on any first-line agents (nafcillin, oxacillin, cefazolin, or penicillin G, if susceptible). The secondary measure was completion of adequate therapy (AT), defined as >= 10 inpatient days or discharge on an agent appropriate for MSSA bacteremia. Data were electronically gathered with key variables manually validated through chart review. Logbinomial regression models were used to determine the frequency and predictors of outcomes. Key Results Of 456 patients, 346 (76%) received a trial of OT. Patients reporting penicillin allergy (13%) were less likely to receive OT trial than those without penicillin allergy (47% vs. 80%, p<0.001). Adjusting for other factors, penicillin allergy was the largest negative predictor of OT trial (RR 0.64 [0.49, 0.83]). Infectious Disease (ID) consultation was the largest positive predictor of OT trial across all patients (RR 1.34 [1.14, 1.57]). Allergy/Immunology consultation was the single most important predictor of OT trial among patients reporting penicillin allergy (RR 2.33 [1.44, 3.77]). Of 440 patients, 391 (89%) completed AT, with ID consultation the largest positive predictor of the outcome (RR 1.28 [1.15, 1.43]). Conclusions Nearly 25% of patients with MSSA bacteremia did not receive OT trial and about 10% did not receive AT completion. Reported penicillin allergy reduced, and ID consult increased, the likelihood of OT. Allergy evaluation, coupled with ID consultation, may improve outcomes in MSSA bacteremic patients. C1 [Blumenthal, Kimberly G.] Massachusetts Gen Hosp, Dept Med, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. [Blumenthal, Kimberly G.; Shenoy, Erica S.; Huang, Mingshu; Parker, Robert A.; Walensky, Rochelle P.] Massachusetts Gen Hosp, Dept Med, Med Practice Evaluat Ctr, Boston, MA 02114 USA. [Blumenthal, Kimberly G.; Shenoy, Erica S.; Parker, Robert A.; Walensky, Rochelle P.] Harvard Med Sch, Boston, MA 02115 USA. [Blumenthal, Kimberly G.; Ware, Winston A.] Massachusetts Gen Hosp, Edward P Lawrence Ctr Qual & Safety, Boston, MA 02114 USA. [Shenoy, Erica S.; Walensky, Rochelle P.] Massachusetts Gen Hosp, Dept Med, Div Infect Dis, Boston, MA 02114 USA. [Shenoy, Erica S.] Massachusetts Gen Hosp, Infect Control Unit, Boston, MA 02114 USA. [Huang, Mingshu; Parker, Robert A.] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Kuhlen, James L.] Univ South Carolina, Sch Med, Dept Med, Acadia Allergy & Immunol, Greenville, SC USA. RP Blumenthal, KG (reprint author), Massachusetts Gen Hosp, Dept Med, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA.; Blumenthal, KG (reprint author), Massachusetts Gen Hosp, Dept Med, Med Practice Evaluat Ctr, Boston, MA 02114 USA.; Blumenthal, KG (reprint author), Harvard Med Sch, Boston, MA 02115 USA.; Blumenthal, KG (reprint author), Massachusetts Gen Hosp, Edward P Lawrence Ctr Qual & Safety, Boston, MA 02114 USA. EM kblumenthal1@partners.org OI Blumenthal, Kimberly/0000-0003-4773-9817 FU National Institutes of Health [T32 HL116275]; 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 This work was supported by the National Institutes of Health T32 HL116275 and 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 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 52 TC 0 Z9 0 U1 2 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 20 PY 2016 VL 11 IS 7 AR e0159406 DI 10.1371/journal.pone.0159406 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DR8TL UT WOS:000380170100042 PM 27438379 ER PT J AU Nana, A Nelson, SB McLaren, A Chen, AF AF Nana, Arvind Nelson, Sandra B. McLaren, Alex Chen, Antonia F. TI What's New in Musculoskeletal Infection: Update on Biofilms SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Article ID STAPHYLOCOCCUS-AUREUS BIOFILMS; PERIPROSTHETIC JOINT INFECTIONS; CLINICAL-PRACTICE GUIDELINES; PULSATILE LAVAGE IRRIGATION; SENSING-MEDIATED VIRULENCE; AMERICAN-HEART-ASSOCIATION; PSEUDOMONAS-AERUGINOSA; OPEN FRACTURES; ACINETOBACTER-BAUMANNII; ESCHERICHIA-COLI C1 [Nana, Arvind] Univ North Texas, Hlth Sci Ctr, Ft Worth, TX 76203 USA. [Nelson, Sandra B.] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. [McLaren, Alex] Univ Arizona, Coll Med, Orthopaed Surg Residency, Phoenix, AZ USA. [Chen, Antonia F.] Thomas Jefferson Univ, Sidney Kimmel Med Coll, Rothman Inst, Philadelphia, PA 19107 USA. RP Nana, A (reprint author), Univ North Texas, Hlth Sci Ctr, Ft Worth, TX 76203 USA. EM arvind.nana@unthsc.edu FU JBJS FX The authors of this work received a stipend from JBJS for writing this work. NR 120 TC 1 Z9 1 U1 3 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0021-9355 EI 1535-1386 J9 J BONE JOINT SURG AM JI J. Bone Joint Surg.-Am. Vol. PD JUL 20 PY 2016 VL 98 IS 14 BP 1226 EP 1234 DI 10.2106/JBJS.16.00300 PG 9 WC Orthopedics; Surgery SC Orthopedics; Surgery GA DR5JB UT WOS:000379938200017 PM 27440572 ER PT J AU VanEpps, EM Volpp, KG Halpern, SD AF VanEpps, Eric M. Volpp, Kevin G. Halpern, Scott D. TI A nudge toward participation: Improving clinical trial enrollment with behavioral economics SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Editorial Material AB Interventions informed by behavioral economics can address barriers to patient enrollment in clinical trials and improve recruitment efforts. C1 [VanEpps, Eric M.; Volpp, Kevin G.] Corporal Michael J Crescenz Vet Affairs Med Ct, Ctr Hlth Equity Res & Promot, 3900 Woodland Ave, Philadelphia, PA 19104 USA. [VanEpps, Eric M.; Volpp, Kevin G.; Halpern, Scott D.] Univ Penn, Dept Med Eth & Hlth Policy, 3401 Market St, Philadelphia, PA 19104 USA. [Volpp, Kevin G.; Halpern, Scott D.] Univ Penn, Dept Med, 3400 Spruce St, Philadelphia, PA 19104 USA. [Volpp, Kevin G.] Univ Penn, Dept Hlth Care Management, 3641 Locust Walk, Philadelphia, PA 19104 USA. [Halpern, Scott D.] Univ Penn, Dept Biostat & Epidemiol, 423 Guardian Dr, Philadelphia, PA 19104 USA. RP VanEpps, EM (reprint author), Corporal Michael J Crescenz Vet Affairs Med Ct, Ctr Hlth Equity Res & Promot, 3900 Woodland Ave, Philadelphia, PA 19104 USA.; VanEpps, EM (reprint author), Univ Penn, Dept Med Eth & Hlth Policy, 3401 Market St, Philadelphia, PA 19104 USA. EM vanepps@mail.med.upenn.edu NR 8 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD JUL 20 PY 2016 VL 8 IS 348 AR 348fs13 DI 10.1126/scitranslmed.aaf0946 PG 3 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA DR6SC UT WOS:000380030600001 PM 27440726 ER PT J AU Peng, M Zhang, C Dong, YL Zhang, YY Nakazawa, H Kaneki, M Zheng, H Shen, Y Marcantonio, ER Xie, ZC AF Peng, Mian Zhang, Ce Dong, Yuanlin Zhang, Yiying Nakazawa, Harumasa Kaneki, Masao Zheng, Hui Shen, Yuan Marcantonio, Edward R. Xie, Zhongcong TI Battery of behavioral tests in mice to study postoperative delirium SO SCIENTIFIC REPORTS LA English DT Article ID MITOCHONDRIAL PERMEABILITY TRANSITION; PRECURSOR PROTEIN MUTATION; INDUCED CELL-DEATH; CYCLOSPORINE-A; COGNITIVE DYSFUNCTION; OXIDATIVE STRESS; NONCARDIAC SURGERY; ELDERLY-PATIENTS; KNOCKOUT MICE; OPEN-FIELD AB Postoperative delirium is associated with increased morbidity, mortality and cost. However, its neuropathogenesis remains largely unknown, partially owing to lack of animal model(s). We therefore set out to employ a battery of behavior tests, including natural and learned behavior, in mice to determine the effects of laparotomy under isoflurane anesthesia (Anesthesia/Surgery) on these behaviors. The mice were tested at 24 hours before and at 6, 9 and 24 hours after the Anesthesia/Surgery. Composite Z scores were calculated. Cyclosporine A, an inhibitor of mitochondria permeability transient pore, was used to determine potential mitochondria-associated mechanisms of these behavioral changes. Anesthesia/Surgery selectively impaired behaviors, including latency to eat food in buried food test, freezing time and time spent in the center in open field test, and entries and duration in the novel arm of Y maze test, with acute onset and various timecourse. The composite Z scores quantitatively demonstrated the Anesthesia/Surgery-induced behavior impairment in mice. Cyclosporine A selectively ameliorated the Anesthesia/Surgery-induced reduction in ATP levels, the increases in latency to eat food, and the decreases in entries in the novel arm. These findings suggest that we could use a battery of behavior tests to establish a mouse model to study postoperative delirium. C1 [Peng, Mian] Wuhan Univ, Zhongnan Hosp, Dept Anesthesia, Wuhan 430071, Peoples R China. [Peng, Mian; Zhang, Ce; Dong, Yuanlin; Zhang, Yiying; Xie, Zhongcong] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Geriatr Anesthesia Res Unit, Charlestown, MA 02129 USA. [Peng, Mian; Zhang, Ce; Dong, Yuanlin; Zhang, Yiying; Nakazawa, Harumasa; Kaneki, Masao; Xie, Zhongcong] Harvard Med Sch, Charlestown, MA 02129 USA. [Zhang, Ce] Jilin Univ, China Japan Union Hosp, Dept Anesthesia, Changchun 130033, Jilin, Peoples R China. [Nakazawa, Harumasa; Kaneki, Masao] Massachusetts Gen Hosp, Shriners Hosp Children, Dept Anesthesia Crit Care & Pain Med, Charlestown, MA 02129 USA. [Zheng, Hui] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Zheng, Hui] Harvard Med Sch, Boston, MA 02114 USA. [Shen, Yuan] Tongji Univ, Peoples Hosp 10, Dept Psychiat, Shanghai 200072, Peoples R China. [Marcantonio, Edward R.] Beth Israel Deaconess Med Ctr, Dept Med, Div Gen Med & Primary Care & Gerontol, Boston, MA 02215 USA. [Marcantonio, Edward R.] Harvard Med Sch, Boston, MA 02215 USA. RP Xie, ZC (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Geriatr Anesthesia Res Unit, Charlestown, MA 02129 USA.; Xie, ZC (reprint author), Harvard Med Sch, Charlestown, MA 02129 USA. EM zxie@mgh.harvard.edu FU National Institutes of Health, Bethesda, Maryland [R01GM088801, R01AG041274, R01HD 086977]; National Institute on Aging [P01 AG031720, R01AG030618, K24AG035075, R01AG051658] FX This research was supported by R01GM088801, R01AG041274 and R01HD 086977 from National Institutes of Health, Bethesda, Maryland (to Z. X.). Dr. Marcantonio was funded by the following grants from the National Institute on Aging: P01 AG031720, R01AG030618, K24AG035075, and R01AG051658. The costs of isoflurane and EMLA cream (2.5% lidocaine and 2.5% prilocaine) were generously provided by the Department of Anesthesia, Critical Care and Pain Medicine at Massachusetts General Hospital. The studies were performed in the Geriatric Anesthesia Research Unit in the Department of Anesthesia, Critical Care and Pain Medicine at Massachusetts General Hospital, Boston, MA. These works should be attributed to the Department of Anesthesia, Critical Care and Pain Medicine at Massachusetts General Hospital and Harvard Medical School. NR 72 TC 0 Z9 0 U1 2 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 20 PY 2016 VL 6 AR 29874 DI 10.1038/srep29874 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DR5AK UT WOS:000379915100001 PM 27435513 ER PT J AU Zhang, Z Liu, L Gomez-Casal, R Wang, XH Hayashi, R Appella, E Kopelovich, L DeLeo, AB AF Zhang, Zhan Liu, Ling Gomez-Casal, Roberto Wang, Xinhui Hayashi, Ryo Appella, Ettore Kopelovich, Levy DeLeo, Albert B. TI Targeting cancer stem cells with p53 modulators SO ONCOTARGET LA English DT Article DE CP-31398; PRIMA-1; cancer stem cells; P53 vaccine; T cells ID TUMOR-SUPPRESSOR FUNCTION; ALDEHYDE DEHYDROGENASE 1; HSP90 ATPASE ACTIVITY; BREAST-CANCER; MUTANT P53; RETINOIC ACID; CP-31398; ANTIGEN; PRIMA-1; MARKER AB Cancer stem cells (CSC) typically over-express aldehyde dehydrogenase (ALDH). Thus, ALDH(bright) tumor cells represent targets for developing novel cancer prevention/treatment interventions. Loss of p53 function is a common genetic event during cancer development wherein small molecular weight compounds (SMWC) that restore p53 function and reverse tumor growth have been identified. Here, we focused on two widely studied p53 SMWC, CP-31398 and PRIMA-1, to target ALDHbright CSC in human breast, endometrial and pancreas carcinoma cell lines expressing mutant or wild type (WT) p53. CP-31398 and PRIMA-1 significantly reduced CSC content and sphere formation by these cell lines in vitro. In addition, these agents were more effective in vitro against CSC compared to cisplatin and gemcitabine, two often-used chemotherapeutic agents. We also tested a combinatorial treatment in methylcholantrene (MCA)-treated mice consisting of p53 SMWC and p53-based vaccines. Yet using survival end-point analysis, no increased efficacy in the presence of either p53 SMWC alone or with vaccine compared to vaccine alone was observed. These results may be due, in part, to the presence of immune cells, such as activated lymphocytes expressing WT p53 at levels comparable to some tumor cells, wherein further increase of p53 expression by p53 SMWC may alter survival of these immune cells and negatively impact an effective immune response. Continuous exposure of mice to MCA may have also interfered with the action of these p53 SMWC, including potential direct interaction with MCA. Nonetheless, the effect of p53 SMWC on CSC and cancer treatment remains of great interest. C1 [Zhang, Zhan; Liu, Ling] Zhengzhou Univ, Affiliated Hosp 3, Dept Obstet & Gynecol, Zhengzhou, Henan, Peoples R China. [Liu, Ling; Wang, Xinhui] Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Div Surg Oncol, Boston, MA 02115 USA. [Gomez-Casal, Roberto; DeLeo, Albert B.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Gomez-Casal, Roberto; DeLeo, Albert B.] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA USA. [Hayashi, Ryo; Appella, Ettore] NCI, Bethesda, MD 20892 USA. [Kopelovich, Levy] Weill Cornell Med Coll, Dept Med, New York, NY USA. RP Wang, XH (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Div Surg Oncol, Boston, MA 02115 USA. EM xwang30@mgh.harvard.edu FU NCI [CN-433008]; Massachusetts General Hospital ECOR Deliberative Interim Support Funding [NCI R21 CA181851]; China Scholarship Council (CSC) [201407040027] FX Funded by NCI contract CN-433008 (A.B.D.), Massachusetts General Hospital ECOR Deliberative Interim Support Funding (X.W.), NCI R21 CA181851 (X.W.) and China Scholarship Council (CSC No. 201407040027) (L.L.). NR 44 TC 0 Z9 0 U1 1 U2 1 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 19 PY 2016 VL 7 IS 29 BP 45079 EP 45093 DI 10.18632/oncotarget.8650 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DY8SX UT WOS:000385402300020 PM 27074569 ER PT J AU Li, J Lei, KC Wu, ZR Li, WH Liu, GX Liu, JW Cheng, FX Tang, Y AF Li, Jie Lei, Kecheng Wu, Zengrui Li, Weihua Liu, Guixia Liu, Jianwen Cheng, Feixiong Tang, Yun TI Network-based identification of microRNAs as potential pharmacogenomic biomarkers for anticancer drugs SO ONCOTARGET LA English DT Article DE pharmacogenomics; miRNA; network-based inference; metformin; breast cancer ID PROTEIN-INTERACTION NETWORKS; BREAST-CANCER CELLS; SMALL MOLECULES; TARGET INTERACTIONS; SAFETY ASSESSMENT; DATABASE; PREDICTION; EXPRESSION; ASSOCIATIONS; INTEGRATION AB As the recent development of high-throughput technologies in cancer pharmacogenomics, there is an urgent need to develop new computational approaches for comprehensive identification of new pharmacogenomic biomarkers, such as microRNAs (miRNAs). In this study, a network-based framework, namely the SMiR-NBI model, was developed to prioritize miRNAs as potential biomarkers characterizing treatment responses of anticancer drugs on the basis of a heterogeneous network connecting drugs, miRNAs and genes. A high area under the receiver operating characteristic curve of 0.820 +/- 0.013 was yielded during 10-fold cross validation. In addition, high performance was further validated in identifying new anticancer mechanism-of-action for natural products and non-steroidal anti-inflammatory drugs. Finally, the newly predicted miRNAs for tamoxifen and metformin were experimentally validated in MCF-7 and MDA-MB-231 breast cancer cell lines via qRT-PCR assays. High success rates of 60% and 65% were yielded for tamoxifen and metformin, respectively. Specifically, 11 oncomiRNAs (e.g. miR-20a-5p, miR-27a-3p, miR-29a-3p, and miR-146a-5p) from the top 20 predicted miRNAs were experimentally verified as new pharmacogenomic biomarkers for metformin in MCF-7 or MDA-MB-231 cell lines. In summary, the SMiR-NBI model would provide a powerful tool to identify potential pharmacogenomic biomarkers characterized by miRNAs in the emerging field of precision cancer medicine, which is available at http://lmmd.ecust.edu.cn/database/smir-nbi/. C1 [Li, Jie; Lei, Kecheng; Wu, Zengrui; Li, Weihua; Liu, Guixia; Liu, Jianwen; Tang, Yun] East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai, Peoples R China. [Cheng, Feixiong] Sichuan Univ, West China Med Sch, West China Hosp, Collaborat Innovat Ctr Biotherapy,State Key Lab B, Chengdu, Peoples R China. [Cheng, Feixiong] Harvard Med Sch, Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA USA. [Cheng, Feixiong] Northeastern Univ, Ctr Complex Networks Res, Boston, MA 02115 USA. RP Liu, JW; Tang, Y (reprint author), East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai, Peoples R China.; Cheng, FX (reprint author), Sichuan Univ, West China Med Sch, West China Hosp, Collaborat Innovat Ctr Biotherapy,State Key Lab B, Chengdu, Peoples R China.; Cheng, FX (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA USA.; Cheng, FX (reprint author), Northeastern Univ, Ctr Complex Networks Res, Boston, MA 02115 USA. EM liujian@ecust.edu.cn; fxcheng1985@gmail.com; ytang234@ecust.edu.cn FU National Natural Science Foundation of China [81373329, 81573020]; 863 Project [2012AA020308]; Fundamental Research Funds for the Central Universities [WY1113007]; 111 Project [B07023] FX This work was supported by the National Natural Science Foundation of China (Grant 81373329 and 81573020), the 863 Project (Grant 2012AA020308), the Fundamental Research Funds for the Central Universities (Grant WY1113007), and the 111 Project (Grant B07023). NR 57 TC 0 Z9 0 U1 2 U2 2 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD JUL 19 PY 2016 VL 7 IS 29 BP 45584 EP 45596 DI 10.18632/oncotarget.10052 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DY8SX UT WOS:000385402300057 PM 27329603 ER PT J AU Cotter, K Liberman, R Sun-Wada, G Wada, Y Sgroi, D Naber, S Brown, D Breton, S Forgac, M AF Cotter, Kristina Liberman, Rachel Sun-Wada, GeHong Wada, Yoh Sgroi, Dennis Naber, Stephen Brown, Dennis Breton, Sylvie Forgac, Michael TI The a3 isoform of subunit a of the vacuolar ATPase localizes to the plasma membrane of invasive breast tumor cells and is overexpressed in human breast cancer SO ONCOTARGET LA English DT Article DE vacuolar ATPase; proton transport; acidification; invasion; migration; breast cancer ID V-ATPASE; H+-ATPASE; PROTON PUMP; OSTEOCLAST DIFFERENTIATION; DRUG-RESISTANCE; CATHEPSIN-B; IN-VIVO; METASTASIS; EXPRESSION; INHIBITION AB The vacuolar (H+)-ATPases (V-ATPases) are a family of ATP-driven proton pumps that acidify intracellular compartments and transport protons across the plasma membrane. Previous work has demonstrated that plasma membrane V-ATPases are important for breast cancer invasion in vitro and that the V-ATPase subunit a isoform a3 is upregulated in and critical for MDA-MB231 and MCF10CA1a breast cancer cell invasion. It has been proposed that subunit a3 is present on the plasma membrane of invasive breast cancer cells and is overexpressed in human breast cancer. To test this, we used an a3-specific antibody to assess localization in breast cancer cells. Subunit a3 localizes to the leading edge of migrating breast cancer cells, but not the plasma membrane of normal breast epithelial cells. Furthermore, invasive breast cancer cells express a3 throughout all intracellular compartments tested, including endosomes, the Golgi, and lysosomes. Moreover, subunit a3 knockdown in MB231 breast cancer cells reduces in vitro migration. This reduction is not enhanced upon addition of a V-ATPase inhibitor, suggesting that a3-containing V-ATPases are critical for breast cancer migration. Finally, we have tested a3 expression in human breast cancer tissue and mRNA prepared from normal and cancerous breast tissue. a3 mRNA was upregulated 2.5-47 fold in all breast tumor cDNA samples tested relative to normal tissue, with expression generally correlated to cancer stage. Furthermore, a3 protein expression was increased in invasive breast cancer tissue relative to noninvasive cancer and normal breast tissue. These studies suggest that subunit a3 plays an important role in invasive human breast cancer. C1 [Cotter, Kristina; Forgac, Michael] Tufts Univ, Sch Med, Dept Dev Mol & Chem Biol, Boston, MA 02111 USA. [Cotter, Kristina; Forgac, Michael] Tufts Univ, Sackler Sch Grad Biomed Sci, Program Cellular & Mol Physiol, Boston, MA 02111 USA. [Liberman, Rachel; Brown, Dennis; Breton, Sylvie] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Syst Biol, Program Membrane Biol,Nephrol Div, Boston, MA 02114 USA. [Sun-Wada, GeHong] Doshisha Womens Coll, Fac Pharmaceut Sci, Dept Biochem, Kyoto 6100395, Japan. [Wada, Yoh] Osaka Univ, Inst Sci & Ind Res, Div Biol Sci, Ibaraki, Osaka 5670047, Japan. [Sgroi, Dennis] Massachusetts Gen Hosp, Mol Pathol Unit, Dept Pathol, Charlestown, MA 02129 USA. [Naber, Stephen] Tufts Med Ctr, Dept Pathol, Boston, MA 02111 USA. RP Forgac, M (reprint author), Tufts Univ, Sch Med, Dept Dev Mol & Chem Biol, Boston, MA 02111 USA.; Forgac, M (reprint author), Tufts Univ, Sackler Sch Grad Biomed Sci, Program Cellular & Mol Physiol, Boston, MA 02111 USA. EM michael.forgac@tufts.edu FU National Institutes of Health [GM34478]; Sackler Families Collaborative Cancer Biology Award from Tufts University; predoctoral Ruth L. Kirschstein National Research Service Award [CA192500-01A1]; National Institutes of Health Training Grant [T32CA079443] FX This work was supported by National Institutes of Health Grant GM34478 (to M.F.); K.C was supported in part by a Sackler Families Collaborative Cancer Biology Award from Tufts University and by a predoctoral Ruth L. Kirschstein National Research Service Award CA192500-01A1.; R.L. was supported in part by National Institutes of Health Training Grant T32CA079443. NR 62 TC 0 Z9 0 U1 0 U2 0 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 19 PY 2016 VL 7 IS 29 BP 46142 EP 46157 DI 10.18632/oncotarget.10063 PG 16 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DY8SX UT WOS:000385402300100 PM 27323815 ER PT J AU Toniolo, PA Liu, SH Yeh, JE Ye, DQ Barbuto, JAM Frank, DA AF Toniolo, Patricia A. Liu, Suhu Yeh, Jennifer E. Ye, Darwin Q. Barbuto, Jose Alexandre M. Frank, David A. TI Deregulation of SOCS5 suppresses dendritic cell function in chronic lymphocytic leukemia SO ONCOTARGET LA English DT Article DE monocytes; dendritic cells; SOCS5; CLL; STAT3 ID REGULATORY T-CELLS; COLONY-STIMULATING FACTOR; BREAST-CANCER; VACCINATION; ACTIVATION; MATURATION; DIFFERENTIATION; IMMUNITY; STAT3; PATHOGENESIS AB One cause of morbidity and mortality in chronic lymphocytic leukemia (CLL) is infection, which results from defects in a number of components of the immune system. In particular, dendritic cells (DCs) are functionally defective in patients with CLL. To understand the molecular mechanism for this abnormality, we focused on signal transduction pathways that regulate the function of monocyte-derived dendritic cells (Mo-DCs). Monocytes from CLL patients exhibit high IL-4Ra expression due to the enhanced activation of STAT3. However, IL-4R signaling is decoupled from activation of its downstream mediator STAT6 by enhanced levels of the negative regulator SOCS5. This impairs differentiation of functionally mature DCs leading to decreased expression of HLA-DR and costimulatory molecules, and reduced secretion of pro-inflammatory cytokines in LPS-activated DCs. Moreover, Mo-DCs from CLL patients display a decreased ability to induce pro-inflammatory T-cell responses. IL-10- treatment of monocytes from healthy donors mimics the alteration in signaling observed in CLL patients, through enhanced STAT3-dependent expression of SOCS5. The higher level of SOCS5 inhibits STAT6 activation and leads to defective DC differentiation. These findings indicate that SOCS5 mediates the impaired function of DCs in CLL patients, and has the potential to be a new therapeutic target for reversing cancer-associated immune suppression. C1 [Toniolo, Patricia A.; Liu, Suhu; Yeh, Jennifer E.; Ye, Darwin Q.; Frank, David A.] Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Med Oncol, 75 Francis St, Boston, MA 02115 USA. [Toniolo, Patricia A.; Liu, Suhu; Yeh, Jennifer E.; Ye, Darwin Q.; Frank, David A.] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Toniolo, Patricia A.; Liu, Suhu; Yeh, Jennifer E.; Ye, Darwin Q.; Frank, David A.] Harvard Med Sch, Boston, MA 02115 USA. [Toniolo, Patricia A.; Barbuto, Jose Alexandre M.] Univ Sao Paulo, Inst Biomed Sci, Dept Immunol, Sao Paulo, Brazil. RP Frank, DA (reprint author), Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Med Oncol, 75 Francis St, Boston, MA 02115 USA.; Frank, DA (reprint author), Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA.; Frank, DA (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM david_frank@dfci.harvard.edu FU National Cancer Institute [R01-CA160979]; Lymphoma Research Foundation; Joan Harris Cancer Foundation; CLL Foundation; Brent Leahey Fund; Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [09/54599-5, 12/01623-9, 10/15312-0]; CNPq FX This work was supported by grants from the National Cancer Institute (R01-CA160979), the Lymphoma Research Foundation, the Joan Harris Cancer Foundation, the CLL Foundation, the Brent Leahey Fund, the Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP; grants #09/54599-5, #12/01623-9 and #10/15312-0), and CNPq. NR 47 TC 0 Z9 0 U1 1 U2 1 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 19 PY 2016 VL 7 IS 29 BP 46301 EP 46314 DI 10.18632/oncotarget.10093 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DY8SX UT WOS:000385402300112 PM 27317770 ER PT J AU Chong, DQ Zhu, AX AF Chong, Dawn Q. Zhu, Andrew X. TI The landscape of targeted therapies for cholangiocarcinoma: current status and emerging targets SO ONCOTARGET LA English DT Review DE cholangiocarcinoma; genetics; IDH; FGFR2 ID BILIARY-TRACT CANCER; PHASE-II TRIAL; ISOCITRATE DEHYDROGENASE 1; GROWTH-FACTOR-RECEPTOR; REVERSES MULTIDRUG-RESISTANCE; INTRAHEPATIC CHOLANGIOCARCINOMA; SOLID TUMORS; C-MET; PROGNOSTIC-SIGNIFICANCE; GALLBLADDER CARCINOMA AB Cholangiocarcinoma (CCA) is a relatively rare malignancy that arises from the epithelial cells of the intrahepatic, perihilar and distal biliary tree. Intrahepatic CCA (ICC) represents the second most common primary liver cancer, after hepatocellular cancer. Two-thirds of the patients with ICC present with locally advanced or metastatic disease. Despite standard treatment with gemcitabine and cisplatin, prognosis remains dismal with a median survival of less than one year. Several biological plausibilities can account for its poor clinical outcomes. First, despite the advent of next generation and whole exome sequencing, no oncogenic addiction loops have been validated as clinically actionable targets. Second, the anatomical, pathological and molecular heterogeneity, and rarity of CCA confer an ongoing challenge of instituting adequately powered clinical trials. Last, most of the studies were not biomarker-driven, which may undermine the potential benefit of targeted therapy in distinct subpopulations carrying the unique molecular signature. Recent whole genome sequencing efforts have identified known mutations in genes such as epidermal growth factor receptor (EGFR), kirsten rat sarcoma viral oncogene homolog (KRAS), v-raf murine sarcoma viral oncogene homolog (BRAF) and tumor protein p53 (TP53), novel mutations in isocitrate dehydrogenase (IDH), BRCA1-Associated Protein 1 (BAP1) and AT-rich interactive domain-containing protein 1A (ARID1A), and novel fusions such as fibroblast growth factor receptor 2 (FGFR2) and ROS proto-oncogene 1 (ROS1). In this review, we will discuss the evolving genetic landscape of CCA, with an in depth focus on novel fusions (e.g. FGFR2 and ROS1) and somatic mutations (e.g. IDH1/2), which are promising actionable molecular targets. C1 [Chong, Dawn Q.; Zhu, Andrew X.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02115 USA. [Chong, Dawn Q.] Natl Canc Ctr, Div Med Oncol, Singapore, Singapore. RP Zhu, AX (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02115 USA. EM azhu@partners.org FU V Foundation for Cancer Research; Target Cancer Foundation; National Medical Research Council FX Andrew X. Zhu received research funding support from the V Foundation for Cancer Research and Target Cancer Foundation.; Dawn Q. Chong received research funding support from the National Medical Research Council. NR 105 TC 0 Z9 1 U1 6 U2 6 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD JUL 19 PY 2016 VL 7 IS 29 BP 46750 EP 46767 DI 10.18632/oncotarget.8775 PG 18 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DY8SX UT WOS:000385402300147 PM 27102149 ER PT J AU Pinilla-Vera, M Xiong, ZY Zhao, YT Zhao, J Donahoe, MP Barge, S Horne, WT Kolls, JK McVerry, BJ Birukova, A Tighe, RM Foster, WM Hollingsworth, J Ray, A Mallampalli, R Ray, P Lee, JS AF Pinilla-Vera, Miguel Xiong, Zeyu Zhao, Yutong Zhao, Jing Donahoe, Michael P. Barge, Suchitra Horne, William T. Kolls, Jay K. McVerry, Bryan J. Birukova, Anastasiya Tighe, Robert M. Foster, W. Michael Hollingsworth, John Ray, Anuradha Mallampalli, Rama Ray, Prabir Lee, Janet S. TI Full Spectrum of LPS Activation in Alveolar Macrophages of Healthy Volunteers by Whole Transcriptomic Profiling SO PLOS ONE LA English DT Article ID OBSTRUCTIVE PULMONARY-DISEASE; BACTERIAL PNEUMONIA; MYCOBACTERIUM-TUBERCULOSIS; ISOPEPTIDASE ACTIVITY; ENDOTOXIN TOLERANCE; SIGNALING PATHWAY; IL-10 PRODUCTION; I INTERFERONS; RECEPTOR; CELLS AB Despite recent advances in understanding macrophage activation, little is known regarding how human alveolar macrophages in health calibrate its transcriptional response to canonical TLR4 activation. In this study, we examined the full spectrum of LPS activation and determined whether the transcriptomic profile of human alveolar macrophages is distinguished by a TIR-domain-containing adapter-inducing interferon-beta (TRIF)-dominant type I interferon signature. Bronchoalveolar lavage macrophages were obtained from healthy volunteers, stimulated in the presence or absence of ultrapure LPS in vitro, and whole transcriptomic profiling was performed by RNA sequencing (RNA-Seq). LPS induced a robust type I interferon transcriptional response and Ingenuity Pathway Analysis predicted interferon regulatory factor (IRF) 7 as the top upstream regulator of 89 known gene targets. Ubiquitin-specific peptidase (USP)-18, a negative regulator of interferon alpha/beta responses, was among the top up-regulated genes in addition to IL10 and USP41, a novel gene with no known biological function but with high sequence homology to USP18. We determined whether IRF-7 and USP-18 can influence downstream macrophage effector cytokine production such as IL-10. We show that IRF-7 siRNA knockdown enhanced LPS-induced IL-10 production in human monocyte-derived macrophages, and USP-18 overexpression attenuated LPS-induced production of IL-10 in RAW264.7 cells. Quantitative PCR confirmed upregulation of USP18, USP41, IL10, and IRF7. An independent cohort confirmed LPS induction of USP41 and IL10 genes. These results suggest that IRF-7 and predicted downstream target USP18, both elements of a type I interferon gene signature identified by RNA-Seq, may serve to fine-tune early cytokine response by calibrating IL-10 production in human alveolar macrophages. C1 [Pinilla-Vera, Miguel; Xiong, Zeyu; Zhao, Yutong; Zhao, Jing; Donahoe, Michael P.; Barge, Suchitra; McVerry, Bryan J.; Ray, Anuradha; Ray, Prabir; Lee, Janet S.] Univ Pittsburgh, Dept Med, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA 15260 USA. [Horne, William T.; Kolls, Jay K.] Univ Pittsburgh, Dept Pediat, Pittsburgh, PA USA. [Birukova, Anastasiya; Tighe, Robert M.; Foster, W. Michael; Hollingsworth, John] Duke Univ, Dept Med, Durham, NC USA. [Hollingsworth, John] Ohio State Univ, Dept Med, Div Pulm & Crit Care Med, Columbus, OH USA. [Mallampalli, Rama] Vet Affairs Pittsburgh Healthcare Syst, Med Specialty Serv Line, Pittsburgh, PA USA. [Zhao, Yutong; Zhao, Jing; Lee, Janet S.] Univ Pittsburgh, Vasc Med Inst, Pittsburgh, PA USA. RP Lee, JS (reprint author), Univ Pittsburgh, Dept Med, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA 15260 USA.; Lee, JS (reprint author), Univ Pittsburgh, Vasc Med Inst, Pittsburgh, PA USA. EM leejs3@upmc.edu OI Tighe, Robert/0000-0002-3465-9861 FU Breathe Pennsylvania; National Institute of Health [R01 HL086884, R21AI119042, K08 HL105537, P01 HL114453]; Flight Attendant Medical Research Institute; Pilot Project Program in Hemostasis and Vascular Biology; Vascular Medicine Institute; Hemophilia Center of Western Pennsylvania; Institute for Transfusion Medicine FX This study was supported by Breathe Pennsylvania (JSL, MPD); National Institute of Health R01 HL086884 and R21AI119042 (JSL), K08 HL105537 (RMT), P01 HL114453 (RKM, PR); Flight Attendant Medical Research Institute (JSL); Pilot Project Program in Hemostasis and Vascular Biology, the Vascular Medicine Institute, the Hemophilia Center of Western Pennsylvania, Institute for Transfusion Medicine (JSL). The funders had no role in study design, data collection, decision to publish, or preparation of the manuscript. NR 59 TC 0 Z9 0 U1 3 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 19 PY 2016 VL 11 IS 7 AR e0159329 DI 10.1371/journal.pone.0159329 PG 22 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DR8TG UT WOS:000380169600047 PM 27434537 ER PT J AU Mark, DB Federspiel, JJ Cowper, PA Anstrom, KJ Hoffmann, U Patel, MR Davidson-Ray, L Daniels, MR Cooper, LS Knight, JD Lee, KL Douglas, PS AF Mark, Daniel B. Federspiel, Jerome J. Cowper, Patricia A. Anstrom, Kevin J. Hoffmann, Udo Patel, Manesh R. Davidson-Ray, Linda Daniels, Melanie R. Cooper, Lawton S. Knight, J. David Lee, Kerry L. Douglas, Pamela S. CA PROMISE Investigators TI Economic Outcomes With Anatomical Versus Functional Diagnostic Testing for Coronary Artery Disease SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID ANGIOGRAPHY; METAANALYSIS; ACCURACY; ECHOCARDIOGRAPHY; MANAGEMENT; ANGINA AB Background: PROMISE (PROspective Multicenter Imaging Study for Evaluation of Chest Pain) found that initial use of at least 64-slice multidetector computed tomography angiography (CTA) versus functional diagnostic testing strategies did not improve clinical outcomes in stable symptomatic patients with suspected coronary artery disease (CAD) requiring noninvasive testing. Objective: To conduct an economic analysis for PROMISE (a major secondary aim of the study). Design: Prospective economic study from the U.S. perspective. Comparisons were made according to the intention-to-treat principle, and CIs were calculated using bootstrap methods. (ClinicalTrials.gov: NCT01174550) Setting: 190 U.S. centers. Patients: 9649 U.S. patients enrolled in PROMISE between July 2010 and September 2013. Median follow-up was 25 months. Measurements: Technical costs of the initial (outpatient) testing strategy were estimated from Premier Research Database data. Hospital-based costs were estimated using hospital bills and Medicare cost-charge ratios. Physician fees were taken from the Medicare Physician Fee Schedule. Costs were expressed in 2014 U.S. dollars, discounted at 3% annually, and estimated out to 3 years using inverse probability weighting methods. Results: The mean initial testing costs were $174 for exercise electrocardiography; $404 for CTA; $501 to $514 for pharmacologic and exercise stress echocardiography, respectively; and $946 to $1132 for exercise and pharmacologic stress nuclear testing, respectively. Mean costs at 90 days were $2494 for the CTA strategy versus $2240 for the functional strategy (mean difference, $254 [95% CI, -$634 to $906]). The difference was associated with more revascularizations and catheterizations (4.25 per 100 patients) with CTA use. After 90 days, the mean cost difference between the groups out to 3 years remained small. Limitation: Cost weights for test strategies were obtained from sources outside PROMISE. Conclusion: Computed tomography angiography and functional diagnostic testing strategies in patients with suspected CAD have similar costs through 3 years of follow-up. C1 Duke Univ, Med Ctr, Duke Clin Res Inst, Outcomes Res Grp, Durham, NC USA. Duke Univ, Durham, NC USA. Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. [Cooper, Lawton S.] NHLBI, RKL2 BG RM 10108,6701 Rockledge Dr, Bethesda, MD 20817 USA. [Mark, Daniel B.; Federspiel, Jerome J.; Cowper, Patricia A.; Anstrom, Kevin J.; Patel, Manesh R.; Davidson-Ray, Linda; Daniels, Melanie R.; Knight, J. David; Lee, Kerry L.; Douglas, Pamela S.] Duke Clin Res Inst, POB 17969, Durham, NC 27715 USA. [Hoffmann, Udo] Radiol Associates, 55 Fruit St, Boston, MA 02114 USA. RP Mark, DB (reprint author), Duke Clin Res Inst, POB 17969, Durham, NC 27715 USA. OI Picard, Michael/0000-0002-9264-3243 FU National Heart, Lung, and Blood Institute FX National Heart, Lung, and Blood Institute. NR 13 TC 6 Z9 6 U1 1 U2 2 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 19 PY 2016 VL 165 IS 2 BP 94 EP + DI 10.7326/M15-2639 PG 18 WC Medicine, General & Internal SC General & Internal Medicine GA DS2GY UT WOS:000380583100016 PM 27214597 ER PT J AU Qaseem, A Kansagara, D Forciea, MA Cooke, M Denberg, TD AF Qaseem, Amir Kansagara, Devan Forciea, Mary Ann Cooke, Molly Denberg, Thomas D. CA Clinical Guidelines Comm Amer TI Management of Chronic Insomnia Disorder in Adults: A Clinical Practice Guideline From the American College of Physicians SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; COGNITIVE-BEHAVIORAL THERAPY; SELF-HELP TREATMENT; LATE-LIFE INSOMNIA; GENERAL MEDICAL-PRACTICE; OLDER-ADULTS; DOUBLE-BLIND; LONG-TERM; PSYCHOLOGICAL TREATMENT; COMORBID INSOMNIA AB Description: The American College of Physicians (ACP) developed this guideline to present the evidence and provide clinical recommendations on the management of chronic insomnia disorder in adults. Methods: This guideline is based on a systematic review of randomized, controlled trials published in English from 2004 through September 2015. Evaluated outcomes included global outcomes assessed by questionnaires, patient-reported sleep outcomes, and harms. The target audience for this guideline includes all clinicians, and the target patient population includes adults with chronic insomnia disorder. This guideline grades the evidence and recommendations by using the ACP grading system, which is based on the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Recommendation 1: ACP recommends that all adult patients receive cognitive behavioral therapy for insomnia (CBT-I) as the initial treatment for chronic insomnia disorder. (Grade: strong recommendation, moderate-quality evidence) Recommendation 2: ACP recommends that clinicians use a shared decision-making approach, including a discussion of the benefits, harms, and costs of short-term use of medications, to decide whether to add pharmacological therapy in adults with chronic insomnia disorder in whom cognitive behavioral therapy for insomnia (CBT-I) alone was unsuccessful. (Grade: weak recommendation, low-quality evidence) C1 [Qaseem, Amir] Amer Coll Physicians, 190 N Independence Mall West, Philadelphia, PA 19106 USA. [Forciea, Mary Ann] Penn Hlth Syst, 3615 Chestnut St, Philadelphia, PA 19104 USA. [Kansagara, Devan] Portland VA Med Ctr, 3805 NE 34th Ave, Portland, OR 97212 USA. [Cooke, Molly] Univ Calif San Francisco, 550 16th St, San Francisco, CA 94158 USA. [Qaseem, Amir; Denberg, Thomas D.] Caril Clin, POB 13727, Roanoke, VA 24036 USA. RP Qaseem, A (reprint author), Amer Coll Physicians, 190 N Independence Mall West, Philadelphia, PA 19106 USA. EM aqaseem@acponline.org NR 78 TC 22 Z9 22 U1 7 U2 12 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 19 PY 2016 VL 165 IS 2 BP 125 EP + DI 10.7326/M15-2175 PG 15 WC Medicine, General & Internal SC General & Internal Medicine GA DS2GY UT WOS:000380583100019 PM 27136449 ER PT J AU Beck, TN Korobeynikov, VA Kudinov, AE Georgopoulos, R Solanki, NR Andrews-Hoke, M Kistner, TM Pepin, D Donahoe, PK Nicolas, E Einarson, MB Zhou, Y Boumber, Y Proia, DA Serebriiskii, IG Golemis, EA AF Beck, Tim N. Korobeynikov, Vladislav A. Kudinov, Alexander E. Georgopoulos, Rachel Solanki, Nehal R. Andrews-Hoke, Magda Kistner, Timothy M. Pepin, David Donahoe, Patricia K. Nicolas, Emmanuelle Einarson, Margret B. Zhou, Yan Boumber, Yanis Proia, David A. Serebriiskii, Ilya G. Golemis, Erica A. TI Anti-Mullerian Hormone Signaling Regulates Epithelial Plasticity and Chemoresistance in Lung Cancer SO CELL REPORTS LA English DT Article ID TO-MESENCHYMAL TRANSITION; TGF-BETA; INHIBITING SUBSTANCE; OVARIAN-CANCER; II RECEPTOR; STEM-CELLS; PATHWAY; ADENOCARCINOMA; PROGRESSION; ACTIVATION AB Anti-Mullerian hormone (AMH) and its type II receptor AMHR2, both previously thought to primarily function in gonadal tissue, were unexpectedly identified as potent regulators of transforming growth factor (TGF-beta)/bone morphogenetic protein (BMP) signaling and epithelial-mesenchymal transition (EMT) in lung cancer. AMH is a TGF-beta/BMP superfamily member, and AMHR2 heterodimerizes with type I receptors (ALK2, ALK3) also used by the type II receptor for BMP (BMPR2). AMH signaling regulates expression of BMPR2, ALK2, and ALK3, supports protein kinase B-nuclear factor kappa B (AKTNF-kappa B) and SMAD survival signaling, and influences BMP-dependent signaling in non-small cell lung cancer (NSCLC). AMH and AMHR2 are selectively expressed in epithelial versus mesenchymal cells, and loss of AMH/AMHR2 induces EMT. Independent induction of EMT reduces expression of AMH and AMHR2. Importantly, EMT associated with depletion of AMH or AMHR2 results in chemoresistance but sensitizes cells to the heat shock protein 90 (HSP90) inhibitor ganetespib. Recognition of this AMH/AMHR2 axis helps to further elucidate TGF-beta/BMP resistance-associated signaling and suggests new strategies for therapeutic targeting of EMT. C1 [Beck, Tim N.; Korobeynikov, Vladislav A.; Kudinov, Alexander E.; Nicolas, Emmanuelle; Einarson, Margret B.; Boumber, Yanis; Serebriiskii, Ilya G.; Golemis, Erica A.] Fox Chase Canc Ctr, Program Mol Therapeut, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Beck, Tim N.; Golemis, Erica A.] Drexel Univ, Coll Med, Program Mol & Cell Biol & Genet, Philadelphia, PA 19129 USA. [Korobeynikov, Vladislav A.] Novosibirsk State Univ, Dept Med, Novosibirsk 630090, Russia. [Georgopoulos, Rachel] Temple Univ, Sch Med, Philadelphia, PA 19140 USA. [Solanki, Nehal R.] Fox Chase Canc Ctr, Immune Cell Dev & Host Def Program, Philadelphia, PA 19111 USA. [Solanki, Nehal R.] Drexel Univ, Coll Med, Program Microbiol & Immunol, Philadelphia, PA 19129 USA. [Andrews-Hoke, Magda] Yale Univ, New Haven, CT 06520 USA. [Kistner, Timothy M.] Johns Hopkins Univ, Baltimore, MD 21218 USA. [Pepin, David; Donahoe, Patricia K.] Harvard Med Sch, Massachusetts Gen Hosp, Pediat Surg Res Labs, Boston, MA 02114 USA. [Pepin, David; Donahoe, Patricia K.] Harvard Med Sch, Dept Surg, Boston, MA 02114 USA. [Zhou, Yan] Fox Chase Canc Ctr, Dept Biostat & Bioinformat, Philadelphia, PA 19140 USA. [Proia, David A.] Synta Pharmaceut, Lexington, MA 02421 USA. [Serebriiskii, Ilya G.] Kazan Fed Univ, Kazan 420000, Russia. RP Golemis, EA (reprint author), Fox Chase Canc Ctr, Program Mol Therapeut, 7701 Burholme Ave, Philadelphia, PA 19111 USA.; Golemis, EA (reprint author), Drexel Univ, Coll Med, Program Mol & Cell Biol & Genet, Philadelphia, PA 19129 USA. EM erica.golemis@fccc.edu OI Korobeynikov, Vlad/0000-0002-9127-292X FU NIH [U54 CA149147, R21 CA181287, R21 CA191425, P50 CA083638]; Ruth L. Kirschstein NRSA F30 fellowship from the NIH [F30 CA180607]; NCI Core Grant [P30 CA006927]; Russian Ministry of Science and Education; Russian Government to support the Program for Competitive Growth of Kazan Federal University FX We thank Drs. Jonathan Chernoff, Jeffrey Peterson, Mauricio Reginato, and Mark Lemmon for critical reading of the manuscript. We also thank current and former members of the E.A.G. lab, and the facilities and our colleagues at Fox Chase Cancer Center. Jean-Marc Barret and Jean-Francois Prost from GamaMabs Pharma deserve special thanks for generously sharing reagents and ideas. The authors were supported by U54 CA149147, R21 CA181287, R21 CA191425, and P50 CA083638 from the NIH (to E.A.G.), the Ruth L. Kirschstein NRSA F30 fellowship (F30 CA180607) from the NIH (to T.N.B.), NCI Core Grant P30 CA006927 (to Fox Chase Cancer Center), the Russian Ministry of Science and Education, as task #17.1891.2014/K (to V.A.K.), and the Russian Government to support the Program for Competitive Growth of Kazan Federal University (to I.G.S.). NR 65 TC 0 Z9 0 U1 7 U2 7 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 19 PY 2016 VL 16 IS 3 BP 657 EP 671 DI 10.1016/j.celrep.2016.06.043 PG 15 WC Cell Biology SC Cell Biology GA DS0CY UT WOS:000380264200007 PM 27396341 ER PT J AU Revelo, XS Ghazarian, M Chng, MHY Luck, H Kim, JH Zeng, KJ Shi, SY Tsai, S Lei, H Kenkel, J Liu, CL Tangsombatvisit, S Tsui, H Sima, C Xiao, CT Shen, L Li, XY Jin, TR Lewis, GF Woo, M Utz, PJ Glogauer, M Engleman, E Winer, S Winer, DA AF Revelo, Xavier S. Ghazarian, Magar Chng, Melissa Hui Yen Luck, Helen Kim, Justin H. Zeng, Kejing Shi, Sally Y. Tsai, Sue Lei, Helena Kenkel, Justin Liu, Chih Long Tangsombatvisit, Stephanie Tsui, Hubert Sima, Corneliu Xiao, Changting Shen, Lei Li, Xiaoying Jin, Tianru Lewis, Gary F. Woo, Minna Utz, Paul J. Glogauer, Michael Engleman, Edgar Winer, Shawn Winer, Daniel A. TI Nucleic Acid-Targeting Pathways Promote Inflammation in Obesity-Related Insulin Resistance SO CELL REPORTS LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; PLASMACYTOID DENDRITIC CELLS; NEUTROPHIL EXTRACELLULAR TRAPS; DIET-INDUCED OBESITY; METABOLIC SYNDROME; ADIPOSE-TISSUE; PEPTIDYLARGININE DEIMINASE; AUTOANTIBODY PRODUCTION; MITOCHONDRIAL-DNA; INNATE IMMUNITY AB Obesity-related inflammation of metabolic tissues, including visceral adipose tissue (VAT) and liver, are key factors in the development of insulin resistance (IR), though many of the contributing mechanisms remain unclear. We show that nucleic-acid-targeting pathways downstream of extracellular trap (ET) formation, unmethylated CpG DNA, or ribonucleic acids drive inflammation in IR. High-fat diet (HFD)-fed mice show increased release of ETs in VAT, decreased systemic clearance of ETs, and increased autoantibodies against conserved nuclear antigens. In HFD-fed mice, this excess of nucleic acids and related protein antigens worsens metabolic parameters through a number of mechanisms, including activation of VAT macrophages and expansion of plasmacytoid dendritic cells (pDCs) in the liver. Consistently, HFD-fed mice lacking critical responders of nucleic acid pathways, Toll-like receptors (TLR)7 and TLR9, show reduced metabolic inflammation and improved glucose homeostasis. Treatment of HFD-fed mice with inhibitors of ET formation or a TLR7/9 antagonist improves metabolic disease. These findings reveal a pathogenic role for nucleic acid targeting as a driver of metabolic inflammation in IR. C1 [Revelo, Xavier S.; Ghazarian, Magar; Luck, Helen; Kim, Justin H.; Zeng, Kejing; Shi, Sally Y.; Tsai, Sue; Lei, Helena; Jin, Tianru; Woo, Minna; Winer, Shawn; Winer, Daniel A.] Univ Hlth Network, Toronto Gen Res Inst, Diabet Res Grp, Div Cellular & Mol Biol, Toronto, ON M5G 1L7, Canada. [Chng, Melissa Hui Yen; Kenkel, Justin; Engleman, Edgar] Stanford Univ, Dept Pathol, Sch Med, Palo Alto, CA 94305 USA. [Zeng, Kejing] Sun Yat Sen Univ, Affiliated Hosp 3, Dept Endocrinol & Metab, Guangzhou 510630, Guangdong, Peoples R China. [Liu, Chih Long; Tangsombatvisit, Stephanie; Utz, Paul J.] Stanford Univ, Sch Med, Div Rheumatol & Immunol, Dept Med, Palo Alto, CA 94305 USA. [Tsui, Hubert; Winer, Daniel A.] Univ Hlth Network, Dept Pathol, Toronto, ON M5G 2C4, Canada. [Sima, Corneliu] Forsyth Inst, Dept Appl Oral Sci, Cambridge, MA 02142 USA. [Xiao, Changting; Lewis, Gary F.; Woo, Minna] Univ Hlth Network, Div Endocrinol & Metab, Dept Med, Toronto, ON M5G 2C4, Canada. [Shen, Lei] Shanghai Jiao Tong Univ, Shanghai Inst Immunol, Sch Med, Shanghai 200240, Peoples R China. [Li, Xiaoying] Fudan Univ, Zhongshan Hosp, Dept Endocrinol, Shanghai 200011, Peoples R China. [Glogauer, Michael] Univ Toronto, Matrix Dynam Grp, Fac Dent, Toronto, ON M5G 1G6, Canada. [Winer, Shawn] St Michaels Hosp, Dept Lab Med, Toronto, ON M5B 1W8, Canada. [Winer, Shawn; Winer, Daniel A.] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5S 1A8, Canada. [Winer, Daniel A.] Univ Toronto, Dept Immunol, Toronto, ON M5S 1A8, Canada. RP Revelo, XS; Winer, DA (reprint author), Univ Hlth Network, Toronto Gen Res Inst, Diabet Res Grp, Div Cellular & Mol Biol, Toronto, ON M5G 1L7, Canada.; Winer, DA (reprint author), Univ Hlth Network, Dept Pathol, Toronto, ON M5G 2C4, Canada.; Winer, DA (reprint author), Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5S 1A8, Canada.; Winer, DA (reprint author), Univ Toronto, Dept Immunol, Toronto, ON M5S 1A8, Canada. EM xrevelo@uhnresearch.ca; dan.winer@uhn.ca FU Canadian Institutes of Health Research (CIHR) [119414, 132562, 142708]; Canadian Diabetes Association (CDA) [OG-3-15-5014, CS-5-12-3886]; NIH [HL075462]; University of Toronto Banting and Best Diabetes Centre Sun Life New Investigator Award; CDA Postdoctoral Fellowship FX We thank Battista Calvieri (Microscopy Imaging Lab, University of Toronto) for assistance with electron microscopy and Paul Taylor (SPARC BioCentre, The Hospital for Sick Children) for assistance with protein MS analysis. We thank the Hirano laboratory for assistance with our ELISPOT assays. This work was supported in part by Canadian Institutes of Health Research (CIHR) grants 119414, 132562, and 142708 (D.A.W.); Canadian Diabetes Association (CDA) grants OG-3-15-5014 and CS-5-12-3886 (D.A.W.); NIH grant HL075462 (E.E.); and the University of Toronto Banting and Best Diabetes Centre Sun Life New Investigator Award (D.A.W.). X.S.R. is the recipient of a CDA Postdoctoral Fellowship. NR 68 TC 1 Z9 1 U1 4 U2 9 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 19 PY 2016 VL 16 IS 3 BP 717 EP 730 DI 10.1016/j.celrep.2016.06.024 PG 14 WC Cell Biology SC Cell Biology GA DS0CY UT WOS:000380264200012 PM 27373163 ER PT J AU Sok, D Pauthner, M Briney, B Lee, JH Saye-Francisco, KL Hsueh, J Ramos, A Le, KM Jones, M Jardine, JG Bastidas, R Sarkar, A Liang, CH Shivatare, SS Wu, CY Schief, WR Wong, CH Wilson, IA Ward, AB Zhu, J Poignard, P Burton, DR AF Sok, Devin Pauthner, Matthias Briney, Bryan Lee, Jeong Hyun Saye-Francisco, Karen L. Hsueh, Jessica Ramos, Alejandra Le, Khoa M. Jones, Meaghan Jardine, Joseph G. Bastidas, Raiza Sarkar, Anita Liang, Chi-Hui Shivatare, Sachin S. Wu, Chung-Yi Schief, William R. Wong, Chi-Huey Wilson, Ian A. Ward, Andrew B. Zhu, Jiang Poignard, Pascal Burton, Dennis R. TI A Prominent Site of Antibody Vulnerability on HIV Envelope Incorporates a Motif Associated with CCR5 Binding and Its Camouflaging Glycans SO IMMUNITY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; BROADLY NEUTRALIZING ANTIBODIES; HEPATITIS-C VIRUS; HUMAN MONOCLONAL-ANTIBODIES; CRYO-EM STRUCTURE; GP41-GP120 INTERFACE; DEPENDENT EPITOPE; CRYSTAL-STRUCTURE; VACCINE DESIGN; POTENT AB The dense patch of high-mannose-type glycans surrounding the N332 glycan on the HIV envelope glycoprotein (Env) is targeted by multiple broadly neutralizing antibodies (bnAbs). This region is relatively conserved, implying functional importance, the origins of which are not well understood. Here we describe the isolation of new bnAbs targeting this region. Examination of these and previously described antibodies to Env revealed that four different bnAb families targeted the (324)GDIR(327) peptide stretch at the base of the gp120 V3 loop and its nearby glycans. We found that this peptide stretch constitutes part of the CCR5 co-receptor binding site, with the high-mannose patch glycans serving to camouflage it from most antibodies. GDIR-glycan bnAbs, in contrast, bound both (324)GDIR(327) peptide residues and high-mannose patch glycans, which enabled broad reactivity against diverse HIV isolates. Thus, as for the CD4 binding site, bnAb effectiveness relies on circumventing the defenses of a critical functional region on Env. C1 [Sok, Devin; Pauthner, Matthias; Briney, Bryan; Saye-Francisco, Karen L.; Hsueh, Jessica; Ramos, Alejandra; Le, Khoa M.; Jones, Meaghan; Jardine, Joseph G.; Bastidas, Raiza; Liang, Chi-Hui; Schief, William R.; Zhu, Jiang; Poignard, Pascal; Burton, Dennis R.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Sok, Devin; Pauthner, Matthias; Briney, Bryan; Lee, Jeong Hyun; Saye-Francisco, Karen L.; Hsueh, Jessica; Ramos, Alejandra; Le, Khoa M.; Jones, Meaghan; Jardine, Joseph G.; Bastidas, Raiza; Sarkar, Anita; Liang, Chi-Hui; Schief, William R.; Wilson, Ian A.; Ward, Andrew B.; Zhu, Jiang; Poignard, Pascal; Burton, Dennis R.] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA. [Sok, Devin; Pauthner, Matthias; Briney, Bryan; Lee, Jeong Hyun; Saye-Francisco, Karen L.; Hsueh, Jessica; Ramos, Alejandra; Le, Khoa M.; Jones, Meaghan; Jardine, Joseph G.; Bastidas, Raiza; Sarkar, Anita; Liang, Chi-Hui; Schief, William R.; Wilson, Ian A.; Ward, Andrew B.; Zhu, Jiang; Poignard, Pascal; Burton, Dennis R.] Scripps Res Inst, Collaborat AIDS Vaccine Discovery, La Jolla, CA 92037 USA. [Sok, Devin; Pauthner, Matthias; Briney, Bryan; Lee, Jeong Hyun; Saye-Francisco, Karen L.; Hsueh, Jessica; Ramos, Alejandra; Le, Khoa M.; Jones, Meaghan; Jardine, Joseph G.; Bastidas, Raiza; Sarkar, Anita; Liang, Chi-Hui; Schief, William R.; Wilson, Ian A.; Ward, Andrew B.; Poignard, Pascal; Burton, Dennis R.] Scripps Res Inst, Ctr HIV AIDS Vaccine Immunol & Immunogen Discover, La Jolla, CA 92037 USA. [Sok, Devin; Ramos, Alejandra; Poignard, Pascal] Int AIDS Vaccine Initiat, New York, NY 10004 USA. [Shivatare, Sachin S.; Wu, Chung-Yi; Wong, Chi-Huey] Acad Sinica, Genom Res Ctr, 128 Acad Rd,Sect 2, Taipei 115, Taiwan. [Lee, Jeong Hyun; Sarkar, Anita; Wilson, Ian A.; Ward, Andrew B.; Zhu, Jiang] Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA. [Wilson, Ian A.] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA. [Schief, William R.; Burton, Dennis R.] MIT, Massachusetts Gen Hosp, Ragon Inst, Cambridge, MA 02139 USA. [Schief, William R.; Burton, Dennis R.] Harvard Univ, Cambridge, MA 02139 USA. RP Burton, DR (reprint author), Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA.; Burton, DR (reprint author), Scripps Res Inst, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA.; Burton, DR (reprint author), Scripps Res Inst, Collaborat AIDS Vaccine Discovery, La Jolla, CA 92037 USA.; Burton, DR (reprint author), Scripps Res Inst, Ctr HIV AIDS Vaccine Immunol & Immunogen Discover, La Jolla, CA 92037 USA.; Burton, DR (reprint author), MIT, Massachusetts Gen Hosp, Ragon Inst, Cambridge, MA 02139 USA.; Burton, DR (reprint author), Harvard Univ, Cambridge, MA 02139 USA. EM burton@scripps.edu RI Ward, Andrew/F-9203-2014 OI Ward, Andrew/0000-0001-7153-3769 FU International AIDS Vaccine Initiative Neutralizing Antibody Consortium through Collaboration for AIDS Vaccine Discovery grant [OPP1084519]; NIH [R01 AI033292]; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery Grant [UM1AI100663]; California HIV/AIDS Research Program Basic Biomedical Sciences Training Award [D13-SRI-391]; James and Jessie Minor Chair in Immunology; IAVI FX The CCR5 N-terminal peptide Fc constructs were kindly provided by Michael Farzan. This work was supported by the International AIDS Vaccine Initiative Neutralizing Antibody Consortium through the Collaboration for AIDS Vaccine Discovery grant OPP1084519 (D.R.B., I.A.W., A.B.W.), NIH grants R01 AI033292 (D.R.B.), and Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery Grant UM1AI100663 (D.R.B., I.A.W., A.B.W.). Funding was also provided by the California HIV/AIDS Research Program Basic Biomedical Sciences Training Award D13-SRI-391 (M.P.). D.R.B. acknowledges the support of the James and Jessie Minor Chair in Immunology. This work was funded in part by IAVI and made possible by the support of many donors, including: the Bill & Melinda Gates Foundation, the Ministry of Foreign Affairs of Denmark, Irish Aid, the Ministry of Finance of Japan, the Ministry of Foreign Affairs of the Netherlands, the Norwegian Agency for Development Cooperation (NORAD), the United Kingdom Department for International Development (DFID), and the United States Agency for International Development (USAID). The full list of IAVI donors is available at http://www.iavi.org. The contents of this manuscript are the responsibility of IAVI and do not necessarily reflect the views of USAID or the US Government. NR 71 TC 4 Z9 4 U1 3 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD JUL 19 PY 2016 VL 45 IS 1 BP 31 EP 45 DI 10.1016/j.immuni.2016.06.026 PG 15 WC Immunology SC Immunology GA DS4KC UT WOS:000380749000008 PM 27438765 ER PT J AU Najjar, M Saleh, D Zelic, M Nogusa, S Shah, S Tai, A Finger, JN Polykratis, A Gough, PJ Bertin, J Whalen, MJ Pasparakis, M Balachandran, S Kelliher, M Poltorak, A Degterev, A AF Najjar, Malek Saleh, Danish Zelic, Matija Nogusa, Shoko Shah, Saumil Tai, Albert Finger, Joshua N. Polykratis, Apostolos Gough, Peter J. Bertin, John Whalen, Michael J. Pasparakis, Manolis Balachandran, Siddharth Kelliher, Michelle Poltorak, Alexander Degterev, Alexei TI RIPK1 and RIPK3 Kinases Promote Cell-Death-Independent Inflammation by Toll-like Receptor 4 SO IMMUNITY LA English DT Article ID KAPPA-B ACTIVATION; PROGRAMMED NECROSIS; TRANSFORMING ACTIVITY; TNF-ALPHA; C-FOS; NECROPTOSIS; APOPTOSIS; PHOSPHORYLATION; TRIF; INHIBITOR AB Macrophages are a crucial component of the innate immune system in sensing pathogens and promoting local and systemic inflammation. RIPK1 and RIPK3 are homologous kinases, previously linked to activation of necroptotic death. In this study, we have described roles for these kinases as master regulators of pro-inflammatory gene expression induced by lipopolysaccharide, independent of their well-documented cell death functions. In primary macrophages, this regulation was elicited in the absence of caspase-8 activity, required the adaptor molecule TRIF, and proceeded in a cell autonomous manner. RIPK1 and RIPK3 kinases promoted sustained activation of Erk, cFos, and NF-kappa B, which were required for inflammatory changes. Utilizing genetic and pharmacologic tools, we showed that RIPK1 and RIPK3 account for acute inflammatory responses induced by lipopolysaccharide in vivo; notably, this regulation did not require exogenous manipulation of caspases. These findings identified a new pharmacologically accessible pathway that may be relevant to inflammatory pathologies. C1 [Najjar, Malek; Degterev, Alexei] Tufts Univ, Sackler Grad Sch, Program Pharmacol & Expt Therapeut, Boston, MA 02111 USA. [Saleh, Danish] Tufts Univ, Sackler Grad Sch, Med Scientist Training Program, Boston, MA 02111 USA. [Saleh, Danish] Tufts Univ, Sackler Grad Sch, Program Neurosci, Boston, MA 02111 USA. [Zelic, Matija; Kelliher, Michelle] Univ Massachusetts, Sch Med, Dept Mol Cell & Canc Biol, Worcester, MA 01605 USA. [Nogusa, Shoko; Balachandran, Siddharth] Fox Chase Canc Ctr, Blood Cell Dev & Funct Program, Philadelphia, PA 19111 USA. [Shah, Saumil; Degterev, Alexei] Tufts Univ, Sch Med, Dept Dev Mol & Chem Biol, Boston, MA 02111 USA. [Tai, Albert; Poltorak, Alexander] Tufts Univ, Sch Med, Dept Integrat Physiol & Pathobiol, Boston, MA 02111 USA. [Finger, Joshua N.; Gough, Peter J.; Bertin, John] GlaxoSmithKline, Pattern Recognit Receptor Discovery Performance U, Immunoinflammat Therapeut Area, Collegeville, PA 19426 USA. [Polykratis, Apostolos; Pasparakis, Manolis] Univ Cologne, Ctr Mol Med, Inst Genet, D-50674 Cologne, Germany. [Polykratis, Apostolos; Pasparakis, Manolis] Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, D-50674 Cologne, Germany. [Whalen, Michael J.] Massachusetts Gen Hosp, Neurosci Ctr, Charlestown, MA 02129 USA. [Whalen, Michael J.] Massachusetts Gen Hosp, Dept Pediat, Charlestown, MA 02129 USA. [Whalen, Michael J.] Harvard Med Sch, Charlestown, MA 02129 USA. RP Degterev, A (reprint author), Tufts Univ, Sackler Grad Sch, Program Pharmacol & Expt Therapeut, Boston, MA 02111 USA.; Degterev, A (reprint author), Tufts Univ, Sch Med, Dept Dev Mol & Chem Biol, Boston, MA 02111 USA. EM alexei.degterev@tufts.edu FU NIH [R01GM080356, R01GM084205, R01CA190542, R01AI07118, R01NS047447] FX This work was supported in part by grants from NIH to A.D. (R01GM080356 and R01GM084205), to S.B. and A.D. (R01CA190542), to M.K. (R01AI07118), and to M.J.W. (R01NS047447). We thank Drs. Vishva Dixit, Francis K.M. Chan, Stan Krajewski, Katherine Fitzgerald, and Sergei Nedospasov for providing the reagents. P.J.G., J.B., and J.N.F. are employees of GlaxoSmithKline. A.D. is a consultant for Denali Therapeutics. NR 57 TC 10 Z9 10 U1 4 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD JUL 19 PY 2016 VL 45 IS 1 BP 46 EP 59 DI 10.1016/j.immuni.2016.06.007 PG 14 WC Immunology SC Immunology GA DS4KC UT WOS:000380749000009 PM 27396959 ER PT J AU Lam, WY Becker, AM Kennerly, KM Wong, R Curtis, JD Llufrio, EM McCommis, KS Fahrmann, J Pizzato, HA Nunley, RM Lee, J Wolfgang, MJ Patti, GJ Finck, BN Pearce, EL Bhattacharya, D AF Lam, Wing Y. Becker, Amy M. Kennerly, Krista M. Wong, Rachel Curtis, Jonathan D. Llufrio, Elizabeth M. McCommis, Kyle S. Fahrmann, Johannes Pizzato, Hannah A. Nunley, Ryan M. Lee, Jieun Wolfgang, Michael J. Patti, Gary J. Finck, Brian N. Pearce, Erika L. Bhattacharya, Deepta TI Mitochondrial Pyruvate Import Promotes Long-Term Survival of Antibody-Secreting Plasma Cells SO IMMUNITY LA English DT Article ID MEMORY B-CELLS; BONE-MARROW; GERMINAL-CENTERS; FATTY-ACIDS; RESPIRATORY CAPACITY; GLUCOSE-METABOLISM; IMMUNE-RESPONSE; CARRIER 2; DIFFERENTIATION; GROWTH AB Durable antibody production after vaccination or infection is mediated by long-lived plasma cells (LLPCs). Pathways that specifically allow LLPCs to persist remain unknown. Through bioenergetic profiling, we found that human and mouse LLPCs could robustly engage pyruvate-dependent respiration, whereas their short-lived counterparts could not. LLPCs took up more glucose than did short-lived plasma cells (SLPCs) in vivo, and this glucose was essential for the generation of pyruvate. Glucose was primarily used to glycosylate antibodies, but glycolysis could be promoted by stimuli such as low ATP levels and the resultant pyruvate used for respiration by LLPCs. Deletion of Mpc2, which encodes an essential component of the mitochondrial pyruvate carrier, led to a progressive loss of LLPCs and of vaccine-specific antibodies in vivo. Thus, glucose uptake and mitochondrial pyruvate import prevent bioenergetic crises and allow LLPCs to persist. Immunizations that maximize these plasma cell metabolic properties might thus provide enduring antibody-mediated immunity. C1 [Lam, Wing Y.; Becker, Amy M.; Kennerly, Krista M.; Wong, Rachel; Curtis, Jonathan D.; Pizzato, Hannah A.; Pearce, Erika L.; Bhattacharya, Deepta] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Llufrio, Elizabeth M.; Patti, Gary J.] Washington Univ, Sch Med, Dept Chem, St Louis, MO 63110 USA. [McCommis, Kyle S.; Finck, Brian N.] Washington Univ, Sch Med, Ctr Human Nutr, St Louis, MO 63110 USA. [Fahrmann, Johannes] Univ Calif Davis, West Coast Metabol Ctr, Davis, CA 95616 USA. [Nunley, Ryan M.] Washington Univ Orthoped, Barnes Jewish Hosp, St Louis, MO 63110 USA. [Lee, Jieun; Wolfgang, Michael J.] Johns Hopkins Univ, Sch Med, Ctr Metab & Obes Res, Dept Biol Chem, Baltimore, MD 21205 USA. [Becker, Amy M.] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Curtis, Jonathan D.; Pearce, Erika L.] Max Planck Inst Immunobiol & Epigenet, D-79108 Freiburg, Germany. [Fahrmann, Johannes] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. RP Bhattacharya, D (reprint author), Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. EM deeptab@wustl.edu FU NIH [R01AI099108, R01AI091965, R01DK104735, R42AA021228, R01NS072241, K01DK099395, U24 DK-097154, P30CA91842, UL1TR000448]; New York Stem Cell Foundation; American Cancer Society [125091-RSG-13-252-01-LIB]; Diabetes Research Postdoctoral Training Program [T32 DK07296, DK007120]; National Science Foundation [DGE-1143954]; Biocomposites; Cardinal Health; CardioMEMS; DePUy; Johnson & Johnson Company; Integra Sciences; Medtronic; Smith Nephew; Wright Medical Technology, Inc. FX This work was supported by NIH grants R01AI099108 (D.B.), R01AI091965 (E.L.P.), R01DK104735 (B.N.F.), R42AA021228 (B.N.F.), R01NS072241 (M.J.W.), and K01DK099395 (A.M.B.). This work was also supported by the New York Stem Cell Foundation and a Research Scholar grant from the American Cancer Society (125091-RSG-13-252-01-LIB, to D.B.). D.B. is a New York Stem Cell Foundation-Robertson Investigator. K.S.M. is a Diabetes Research Postdoctoral Training Program fellow (T32 DK07296 and DK007120). R.W. is supported by a predoctoral fellowship from the National Science Foundation (DGE-1143954). The West Coast Metabolomics Center is supported by NIH grant U24 DK-097154. RNA-seq analysis was performed by the Genome Technology Access Center at Washington University, supported by NIH grants P30CA91842 (Siteman Cancer Center) and UL1TR000448 (ICTS/CTSA). G.J.P. is a scientific advisory board member for Cambridge Isotope Laboratories. R.M.N. is a paid consultant for Biocomposites, Cardinal Health; CardioMEMS; DePUy, A Johnson & Johnson Company; Integra Sciences; Medtronic; Smith & Nephew; and Wright Medical Technology, Inc. NR 63 TC 4 Z9 4 U1 3 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD JUL 19 PY 2016 VL 45 IS 1 BP 60 EP 73 DI 10.1016/j.immuni.2016.06.011 PG 14 WC Immunology SC Immunology GA DS4KC UT WOS:000380749000010 PM 27396958 ER PT J AU Poissonnier, A Sanseau, D Le Gallo, M Malleter, M Levoin, N Viel, R Morere, L Penna, A Blanco, P Dupuy, A Poizeau, F Fautrel, A Seneschal, J Jouan, F Ritz, J Forcade, E Rioux, N Contin-Bordes, C Ducret, T Vacher, AM Barrow, PA Flynn, RJ Vacher, P Legembre, P AF Poissonnier, Amanda Sanseau, Doriane Le Gallo, Matthieu Malleter, Marine Levoin, Nicolas Viel, Roselyne Morere, Lucie Penna, Aubin Blanco, Patrick Dupuy, Alain Poizeau, Florence Fautrel, Alain Seneschal, Julien Jouan, Florence Ritz, Jerome Forcade, Edouard Rioux, Nathalie Contin-Bordes, Cecile Ducret, Thomas Vacher, Anne-Marie Barrow, Paul A. Flynn, Robin J. Vacher, Pierre Legembre, Patrick TI CD95-Mediated Calcium Signaling Promotes T Helper 17 Trafficking to Inflamed Organs in Lupus-Prone Mice SO IMMUNITY LA English DT Article ID AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME; FAS GENE-MUTATIONS; SH3 DOMAIN; PROTEIN; APOPTOSIS; RECEPTOR; CD95; PATHWAY; LIGAND; DEATH AB CD95 ligand (CD95L) is expressed by immune cells and triggers apoptotic death. Metalloprotease-cleaved CD95L (cl-CD95L) is released into the bloodstream but does not trigger apoptotic signaling. Hence, the pathophysiological role of cl-CD95L remains unclear. We observed that skin-derived endothelial cells from systemic lupus erythematosus (SLE) patients expressed CD95L and that after cleavage, cl-CD95L promoted T helper 17 (Th17) lymphocyte transmigration across the endothelial barrier at the expense of T regulatory cells. T cell migration relied on a direct interaction between the CD95 domain called calcium-inducing domain (CID) and the Src homology 3 domain of phospholipase C gamma 1. Th17 cells stimulated with cl-CD95L produced sphingosine-1-phosphate (S1P), which promoted endothelial transmigration by activating the S1P receptor 3. We generated a cell-penetrating CID peptide that prevented Th17 cell transmigration and alleviated clinical symptoms in lupus mice. Therefore, neutralizing the CD95 non-apoptotic signaling pathway could be an attractive therapeutic approach for SLE treatment. C1 [Poissonnier, Amanda; Sanseau, Doriane; Le Gallo, Matthieu; Malleter, Marine; Morere, Lucie; Poizeau, Florence; Jouan, Florence; Legembre, Patrick] Ctr Eugene Marquis, Rue Bataille Flandres Dunkerque, F-35042 Rennes, France. [Poissonnier, Amanda; Sanseau, Doriane; Le Gallo, Matthieu; Malleter, Marine; Morere, Lucie; Poizeau, Florence; Jouan, Florence; Legembre, Patrick] INSERM, ERL440 OSS, Equipe Labellisee, F-35042 Rennes, France. [Poissonnier, Amanda; Sanseau, Doriane; Le Gallo, Matthieu; Malleter, Marine; Viel, Roselyne; Morere, Lucie; Penna, Aubin; Dupuy, Alain; Fautrel, Alain; Jouan, Florence; Rioux, Nathalie; Legembre, Patrick] Univ Rennes 1, 2 Ave Prof Leon Bernard, F-35043 Rennes, France. [Levoin, Nicolas] Bioprojet Biotech, Rue Chesnay Beauregard, F-35760 St Gregoire, France. [Malleter, Marine; Viel, Roselyne; Fautrel, Alain; Legembre, Patrick] Biosit, Plateforme H2P2, Biogenouest, 2 Ave Prof Leon Bernard, F-35043 Rennes, France. [Penna, Aubin; Rioux, Nathalie] INSERM, U1085, 2 Ave Prof Leon Bernard, F-35043 Rennes, France. [Blanco, Patrick; Seneschal, Julien; Forcade, Edouard; Contin-Bordes, Cecile; Ducret, Thomas; Vacher, Anne-Marie; Vacher, Pierre] Univ Bordeaux, CHU Bordeaux, 146 Rue Leo Saignat, F-33076 Bordeaux, France. [Blanco, Patrick; Forcade, Edouard; Contin-Bordes, Cecile] CNRS, UMR 5164, 146 Rue Leo Saignat, F-33076 Bordeaux, France. [Dupuy, Alain; Poizeau, Florence] Ctr Hosp Univ Rennes, 2 Rue Henri Le Guilloux, F-35022 Rennes, France. [Seneschal, Julien; Rioux, Nathalie] INSERM, U1035, 146 Rue Le Saignat, F-33076 Bordeaux, France. [Ritz, Jerome; Forcade, Edouard] Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA 02115 USA. [Ritz, Jerome; Forcade, Edouard] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Ducret, Thomas] INSERM, U1045, 146 Rue Le Saignat, F-33076 Bordeaux, France. [Vacher, Anne-Marie; Vacher, Pierre] INSERM, U1218, Inst Bergonie, F-33076 Bordeaux, France. [Barrow, Paul A.; Flynn, Robin J.] Univ Nottingham, Sch Vet Med & Sci, Loughborough LE12 5RD, Leics, England. RP Legembre, P (reprint author), Ctr Eugene Marquis, Rue Bataille Flandres Dunkerque, F-35042 Rennes, France.; Legembre, P (reprint author), INSERM, ERL440 OSS, Equipe Labellisee, F-35042 Rennes, France.; Legembre, P (reprint author), Univ Rennes 1, 2 Ave Prof Leon Bernard, F-35043 Rennes, France. EM patrick.legembre@inserm.fr OI Flynn, Dr Robin/0000-0001-5304-3088 FU INCa PLBIO; Ligue Contre le Cancer; INSERM Transfert; Fondation ARC; Region Bretagne; Rennes Metropole; University of Nottingham Faculty of Medicine; Biotechnology and Biological Sciences Research Council [BB/M018369/1]; ANR [ANR-12-JSV2-0004-001] FX We are grateful to the H2P2 facility of Biosit (Rennes) for its technical assistance. This work was supported by INCa PLBIO, Ligue Contre le Cancer, INSERM Transfert, Fondation ARC, Region Bretagne, Rennes Metropole. We would like to thank the University of Nottingham Faculty of Medicine for funding of BSU pump priming. R.J.F. was supported by the Biotechnology and Biological Sciences Research Council award BB/M018369/1. AP was supported by ANR (ANR-12-JSV2-0004-001). NR 38 TC 2 Z9 2 U1 3 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD JUL 19 PY 2016 VL 45 IS 1 BP 209 EP 223 DI 10.1016/j.immuni.2016.06.028 PG 15 WC Immunology SC Immunology GA DS4KC UT WOS:000380749000022 PM 27438772 ER PT J AU Richardson, K Bennion, OT Tan, SM Hoang, AN Cokol, M Aldridge, BB AF Richardson, Kirill Bennion, Owen T. Tan, Shumin Hoang, Anh N. Cokol, Murat Aldridge, Bree B. TI Temporal and intrinsic factors of rifampicin tolerance in mycobacteria SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE antibiotic susceptibility; single cell; mathematical modeling; mycobacteria; cell biology ID BACTERIAL-CELL CYCLE; TUBERCULOSIS; GROWTH; PERSISTERS; DIVISION; SUSCEPTIBILITY; RESISTANCE; MECHANISMS; DYNAMICS; DORMANCY AB Mycobacteria grow and divide asymmetrically, creating variability in growth pole age, growth properties, and antibiotic susceptibilities. Here, we investigate the importance of growth pole age and other growth properties in determining the spectrum of responses of Mycobacterium smegmatis to challenge with rifampicin. We used a combination of live-cell microscopy and modeling to prospectively identify subpopulations with altered rifampicin susceptibility. We found two subpopulations that had increased susceptibility. At the initiation of treatment, susceptible cells were either small and at early stages of the cell cycle, or large and in later stages of their cell cycle. In contrast to this temporal window of susceptibility, tolerance was associated with factors inherited at division: long birth length and mature growth poles. Thus, rifampicin response is complex and due to a combination of differences established from both asymmetric division and the timing of treatment relative to cell birth. C1 [Richardson, Kirill; Bennion, Owen T.; Tan, Shumin; Cokol, Murat; Aldridge, Bree B.] Tufts Univ, Sch Med, Dept Mol Biol & Microbiol, Boston, MA 02111 USA. [Richardson, Kirill; Aldridge, Bree B.] Tufts Univ, Sch Engn, Dept Biomed Engn, Medford, MA 02155 USA. [Hoang, Anh N.] Massachusetts Gen Hosp, Ctr Engn Med, Boston, MA 02114 USA. [Cokol, Murat] Sabanci Univ, Fac Engn & Nat Sci, Mol Biol Genet & Bioengn Program, TR-34956 Istanbul, Turkey. [Cokol, Murat; Aldridge, Bree B.] Harvard Med Sch, Lab Syst Pharmacol, Boston, MA 02115 USA. RP Aldridge, BB (reprint author), Tufts Univ, Sch Med, Dept Mol Biol & Microbiol, Boston, MA 02111 USA.; Aldridge, BB (reprint author), Tufts Univ, Sch Engn, Dept Biomed Engn, Medford, MA 02155 USA.; Aldridge, BB (reprint author), Harvard Med Sch, Lab Syst Pharmacol, Boston, MA 02115 USA. EM bree.aldridge@tufts.edu FU Alfred P. Sloan Foundation Research Fellowship; NIH Director's New Innovator Award [1DP2LM011952-01]; Harvard Laboratory of Systems Pharmacology Center [P50GM107618]; NIH [K99AI114952, 5P41EB002503-12]; Turkish Academy of Sciences GEBIP Fellowship; TUBITAK Grant [115S934] FX We thank members of the B.B.A. laboratory, A. Sonenshein, S. Fortune, and E. Rubin for feedback and helpful discussions. This work was supported by an Alfred P. Sloan Foundation Research Fellowship and NIH Director's New Innovator Award 1DP2LM011952-01 (to B.B.A.); the Harvard Laboratory of Systems Pharmacology Center Grant P50GM107618 (to B.B.A. and M.C.); an NIH K99AI114952 Grant (to S.T.); and Turkish Academy of Sciences GEBIP Fellowship and TUBITAK 115S934 Grant (to M.C.). The work for the making of the microfluidic devices at the BioMEMS Resource Center was supported by NIH 5P41EB002503-12. NR 24 TC 1 Z9 1 U1 3 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 19 PY 2016 VL 113 IS 29 BP 8302 EP 8307 DI 10.1073/pnas.1600372113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DR9NX UT WOS:000380224500082 PM 27357669 ER PT J AU Yazaki, J Galli, M Kim, AY Nito, K Aleman, F Chang, KN Carvunis, AR Quan, R Nguyen, H Song, L Alvarez, JM Huang, SSC Chen, HM Ramachandran, N Altmann, S Gutierrez, RA Hill, DE Schroeder, JI Chory, J LaBaer, J Vidal, M Braun, P Ecker, JR AF Yazaki, Junshi Galli, Mary Kim, Alice Y. Nito, Kazumasa Aleman, Fernando Chang, Katherine N. Carvunis, Anne-Ruxandra Quan, Rosa Hien Nguyen Song, Liang Alvarez, Jose M. Huang, Shao-shan Carol Chen, Huaming Ramachandran, Niroshan Altmann, Stefan Gutierrez, Rodrigo A. Hill, David E. Schroeder, Julian I. Chory, Joanne LaBaer, Joshua Vidal, Marc Braun, Pascal Ecker, Joseph R. TI Mapping transcription factor interactome networks using HaloTag protein arrays SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE protein arrays; interactome; hormone; systems biology; Arabidopsis thaliana ID APICAL HOOK DEVELOPMENT; GLOBAL ANALYSIS; ARABIDOPSIS SEEDLINGS; GENE-EXPRESSION; MICROARRAYS; RESPONSES; TARGETS; NITRATE; GENOME; DNA AB Protein microarrays enable investigation of diverse biochemical properties for thousands of proteins in a single experiment, an unparalleled capacity. Using a high-density system called HaloTag nucleic acid programmable protein array (HaloTag-NAPPA), we created high-density protein arrays comprising 12,000 Arabidopsis ORFs. We used these arrays to query protein-protein interactions for a set of 38 transcription factors and transcriptional regulators (TFs) that function in diverse plant hormone regulatory pathways. The resulting transcription factor interactome network, TF-NAPPA, contains thousands of novel interactions. Validation in a benchmarked in vitro pull-down assay revealed that a random subset of TF-NAPPA validated at the same rate of 64% as a positive reference set of literature-curated interactions. Moreover, using a bimolecular fluorescence complementation (BiFC) assay, we confirmed in planta several interactions of biological interest and determined the interaction localizations for seven pairs. The application of HaloTag-NAPPA technology to plant hormone signaling pathways allowed the identification of many novel transcription factor-protein interactions and led to the development of a proteome-wide plant hormone TF interactome network. C1 [Yazaki, Junshi; Galli, Mary; Kim, Alice Y.; Quan, Rosa; Hien Nguyen; Chen, Huaming; Ecker, Joseph R.] Salk Inst Biol Studies, Genom Anal Lab, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA. [Yazaki, Junshi; Nito, Kazumasa; Chang, Katherine N.; Song, Liang; Huang, Shao-shan Carol; Chory, Joanne; Ecker, Joseph R.] Salk Inst Biol Studies, Plant Biol Lab, La Jolla, CA 92037 USA. [Yazaki, Junshi] RIKEN Ctr Integrat Med Sci, Yokohama, Kanagawa 2300045, Japan. [Aleman, Fernando; Schroeder, Julian I.] Univ Calif San Diego, Div Biol Sci, Cell & Dev Biol Sect, La Jolla, CA 92093 USA. [Carvunis, Anne-Ruxandra; Hill, David E.; Vidal, Marc] Dana Farber Canc Inst, CCSB, Boston, MA 02215 USA. [Carvunis, Anne-Ruxandra; Hill, David E.; Vidal, Marc] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Carvunis, Anne-Ruxandra; Hill, David E.; Vidal, Marc] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. [Alvarez, Jose M.; Gutierrez, Rodrigo A.] Pontificia Univ Catolica Chile, Dept Mol Genet & Microbiol, Millennium Nucleus Ctr Plant Syst & Synthet Biol, Ctr Genome Regulat,Fondo Financiamiento Ctr Inves, Santiago 340, Chile. [Ramachandran, Niroshan] Life Technol, Carlsbad, CA 92008 USA. [Altmann, Stefan; Braun, Pascal] Tech Univ Munich, Sch Life Sci Weihenstephan WZW, Plant Syst Biol, D-85354 Freising Weihenstephan, Germany. [Chory, Joanne; Ecker, Joseph R.] Salk Inst Biol Studies, Howard Hughes Med Inst, La Jolla, CA 92037 USA. [LaBaer, Joshua] Arizona State Univ, Biodesign Inst, Personalized Diagnost, Tempe, AZ 85287 USA. [Braun, Pascal] Tech Univ Munich, Inst Adv Study, D-85748 Garching, Germany. [Galli, Mary] Rutgers State Univ, Waksman Inst, Piscataway, NJ 08854 USA. [Aleman, Fernando] Scripps Res Inst, La Jolla, CA 92037 USA. [Carvunis, Anne-Ruxandra] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. RP Ecker, JR (reprint author), Salk Inst Biol Studies, Genom Anal Lab, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA.; Ecker, JR (reprint author), Salk Inst Biol Studies, Plant Biol Lab, La Jolla, CA 92037 USA.; Braun, P (reprint author), Tech Univ Munich, Sch Life Sci Weihenstephan WZW, Plant Syst Biol, D-85354 Freising Weihenstephan, Germany.; Ecker, JR (reprint author), Salk Inst Biol Studies, Howard Hughes Med Inst, La Jolla, CA 92037 USA.; Braun, P (reprint author), Tech Univ Munich, Inst Adv Study, D-85748 Garching, Germany. EM pbraun@wzw.tum.de; ecker@salk.edu RI Aleman , Fernando/A-4293-2012; OI Aleman , Fernando/0000-0003-0327-1343; Carvunis, Anne-Ruxandra/0000-0002-6474-6413; Schroeder, Julian/0000-0002-3283-5972 FU NSF Plant Genome Research Program [DBI-0703905]; Gordon and Betty Moore Foundation [GBMF 3034]; NIH [R01GM060396-ES010337]; Sumitomo Foundation, Grant for Basic Science Research Project [140384]; Deutsche Forschungs Germeinschaft [SFB924]; European Research Council under the European Union's Horizon Research and Innovation Programme [648420]; Caja Madrid Foundation FX We thank Shoji Mano for the generous gifts of BiFC vectors. We also thank Mattia Pelizzola for assistance with data analysis and Mark Zander, Mathew G. Lewsey, Matija Dreze, Samuel J. Pevzner, and Michael E. Cusick for critical reading of the manuscript. We thank Kenichi Hitomi for creation of 3D modeling of the Halo and PYL6 proteins and Rosa Castanon and Anna Bartlett for technical help. This work was supported by grants from the NSF Plant Genome Research Program (DBI-0703905; to M.V. and J.R.E.), Gordon and Betty Moore Foundation (GBMF 3034; to J.R.E.), and NIH (R01GM060396-ES010337; to J.I.S.). J.Y. is supported by the Sumitomo Foundation, Grant for Basic Science Research Project (140384). P.B. is supported by the Deutsche Forschungs Germeinschaft (SFB924) and has received funding from the European Research Council under the European Union's Horizon 2020 Research and Innovation Programme (Grant Agreement 648420). F.A. was supported by a Caja Madrid Foundation Fellowship. J.C. and J.R.E. are investigators of the Howard Hughes Medical Institute. NR 63 TC 3 Z9 3 U1 12 U2 22 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 19 PY 2016 VL 113 IS 29 BP E4238 EP E4247 DI 10.1073/pnas.1603229113 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DR9NX UT WOS:000380224500017 PM 27357687 ER PT J AU Miller, CL Romero, M Karna, SLR Chen, T Heeb, S Leung, KP AF Miller, Christine L. Romero, Manuel Karna, S. L. Rajasekhar Chen, Tsute Heeb, Stephan Leung, Kai P. TI RsmW, Pseudomonas aeruginosa small non-coding RsmA-binding RNA upregulated in biofilm versus planktonic growth conditions SO BMC MICROBIOLOGY LA English DT Article ID INTEGRATION HOST FACTOR; FLUORESCENS CHA0; ESCHERICHIA-COLI; TRANSCRIPTIONAL REGULATOR; GLOBAL REGULATION; EXPRESSION; GENES; VIRULENCE; PROTEIN; IDENTIFICATION AB Background: Biofilm development, specifically the fundamentally adaptive switch from acute to chronic infection phenotypes, requires global regulators and small non-coding regulatory RNAs (sRNAs). This work utilized RNA-sequencing (RNA-seq) to detect sRNAs differentially expressed in Pseudomonas aeruginosa biofilm versus planktonic state. Results: A computational algorithm was devised to detect and categorize sRNAs into 5 types: intergenic, intragenic, 5'-UTR, 3'-UTR, and antisense. Here we report a novel RsmY/RsmZ-type sRNA, termed RsmW, in P. aeruginosa up-transcribed in biofilm versus planktonic growth. RNA-Seq, 5'-RACE and Mfold predictions suggest RsmW has a secondary structure with 3 of 7 GGA motifs located on outer stem loops. Northern blot revealed two RsmW binding bands of 400 and 120 bases, suggesting RsmW is derived from the 3'-UTR of the upstream hypothetical gene, PA4570. RsmW expression is elevated in late stationary versus logarithmic growth phase in PB minimal media, at higher temperatures (37 degrees C versus 28 degrees C), and in both gacA and rhlR transposon mutants versus wild-type. RsmW specifically binds to RsmA protein in vitro and restores biofilm production and reduces swarming in an rsmY/rsmZ double mutant. PA4570 weakly resembles an RsmA/RsmN homolog having 49 % and 51 % similarity, and 16 % and 17 % identity to RsmA and RsmN amino acid sequences, respectively. PA4570 was unable to restore biofilm and swarming phenotypes in Delta rsmA deficient strains. Conclusion: Collectively, our study reveals an interesting theme regarding another sRNA regulator of the Rsm system and further unravels the complexities regulating adaptive responses for Pseudomonas species. C1 [Miller, Christine L.; Karna, S. L. Rajasekhar; Leung, Kai P.] Inst Surg Res, Dental & Craniofacial Trauma Res & Tissue Regener, Jbsa Ft Sam Houston, TX 78234 USA. [Romero, Manuel; Heeb, Stephan] Univ Nottingham, Ctr Biomol Sci, Sch Life Sci, Univ Pk, Nottingham NG7 2RD, England. [Chen, Tsute] Forsyth Inst, Cambridge, MA USA. RP Leung, KP (reprint author), Inst Surg Res, Dental & Craniofacial Trauma Res & Tissue Regener, Jbsa Ft Sam Houston, TX 78234 USA. EM kai.p.leung.civ@mail.mil FU Naval Medical Research Center's Advanced Medical Development Program [MIPR N3239815MHX040]; US Army Medical Research and Materiel Command, Dental and Craniofacial Trauma Research and Tissue Regeneration Directorate; fellowship "Apoio a formacion posdoutoral do PLAN I2C da Xunta de Galicia"; [NIH P30 DK089507] FX This work was supported in part by the Naval Medical Research Center's Advanced Medical Development Program (MIPR N3239815MHX040) and US Army Medical Research and Materiel Command, Dental and Craniofacial Trauma Research and Tissue Regeneration Directorate. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense. Manuel Romero was supported by a fellowship "Apoio a formacion posdoutoral do PLAN I2C da Xunta de Galicia". Grant # NIH P30 DK089507 supported the production of the transposon mutant library [76] where we utilized strains PW6883, PW5341, and PAO1-UW. RNA Sequencing was performed by SeqWright Genomic Services, Houston, Texas. NR 76 TC 2 Z9 2 U1 5 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2180 J9 BMC MICROBIOL JI BMC Microbiol. PD JUL 19 PY 2016 VL 16 AR 155 DI 10.1186/s12866-016-0771-y PG 16 WC Microbiology SC Microbiology GA DR4SX UT WOS:000379893900002 PM 27430253 ER PT J AU Gammie, JS Wilson, P Bartus, K Gackowski, A Hung, J D'Ambra, MN Kolsut, P Bittle, GJ Szymanski, P Sadowski, J Kapelak, B Bilewska, A Kusmierczyk, M Ghoreishi, M AF Gammie, James S. Wilson, Peter Bartus, Krzysztof Gackowski, Andrzej Hung, Judy D'Ambra, Michael N. Kolsut, Piotr Bittle, Gregory J. Szymanski, Piotr Sadowski, Jerzy Kapelak, Boguslaw Bilewska, Agata Kusmierczyk, Mariusz Ghoreishi, Mehrdad TI Transapical Beating-Heart Mitral Valve Repair With an Expanded Polytetrafluoroethylene Cordal Implantation Device Initial Clinical Experience SO CIRCULATION LA English DT Article DE mitral valve; regurgitation; valvuloplasty; surgery; echocardiography ID CHORDAL REPLACEMENT; ECHOCARDIOGRAPHY; RECOMMENDATIONS; REGURGITATION; GUIDELINES; PREDICTORS AB BACKGROUND: Degenerative mitral valve (MV) disease is a common cause of severe mitral regurgitation (MR) and accounts for the majority of MV operations. Conventional MV surgery requires cardiopulmonary bypass, aortic cross-clamping, cardioplegia, and a thoracotomy or sternotomy and, therefore, is associated with significant disability, risks, and unpredictable rates of MV repair. Transesophageal echocardiography-guided beating-heart MV repair with expanded polytetrafluoroethylene cordal insertion has the potential to significantly reduce surgical morbidity. We report the first-in-human clinical experience with a novel preformed expanded polytetrafluoroethylene knot implantation device (Harpoon TSD-5) designed to treat degenerative MR. METHODS: Through a small left thoracotomy, the device was inserted into the heart and guided by transesophageal echocardiography to the ventricular surface of the prolapsed leaflet. Multiple expanded polytetrafluoroethylene cords were anchored in the leaflet and then adjusted to the correct length to restore MV leaflet coaptation and secured at the epicardium. RESULTS: Eleven patients with posterior leaflet prolapse and severe MR, with mean +/- SD age of 65 +/- 13 years and mean ejection fraction of 69 +/- 7%, were treated with 100% procedural success. Immediate postprocedural mean MR grade was trace. At 1 month, the mean MR grade was mild with significant decreases in end-diastolic volume (139 to 107 mL; P = 0.03) and left atrial volume (118 to 85 mL; P = 0.04). CONCLUSIONS: A novel device used for beating-heart image-guided MV repair demonstrates a significant reduction in MR with favorable left ventricular and left atrial reverse remodeling. This approach has the potential to decrease invasiveness and surgical morbidity. Further follow-up is necessary to assess long-term efficacy. C1 [Gammie, James S.; Bittle, Gregory J.; Ghoreishi, Mehrdad] Univ Maryland, Sch Med, Div Cardiac Surg, 110 S Paca St,7th Floor, Baltimore, MD 21201 USA. [Bartus, Krzysztof; Gackowski, Andrzej; Sadowski, Jerzy; Kapelak, Boguslaw] Jagiellonian Univ, Coll Med, John Paul II Hosp, Krakow, Poland. [Kolsut, Piotr; Szymanski, Piotr; Bilewska, Agata; Kusmierczyk, Mariusz] Inst Cardiol, Warsaw, Poland. [D'Ambra, Michael N.] Harvard Med Sch, Div Cardiac Anesthesiol, Brigham & Womens Hosp, Boston, MA USA. [Hung, Judy] Harvard Med Sch, Massachusetts Gen Hosp, Div Cardiol, Boston, MA USA. [Wilson, Peter] Harpoon Med, Baltimore, MD USA. RP Gammie, JS (reprint author), Univ Maryland, Sch Med, Div Cardiac Surg, 110 S Paca St,7th Floor, Baltimore, MD 21201 USA. EM Jsgammiemd@gmail.com FU Harpoon Medical, Inc. FX Funding for this study was provided by Harpoon Medical, Inc. NR 14 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 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD JUL 19 PY 2016 VL 134 IS 3 BP 189 EP + DI 10.1161/CIRCULATIONAHA.116.022010 PG 15 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DR8EH UT WOS:000380130700009 PM 27436878 ER PT J AU Bittencourt, MS Hulten, E Polonsky, TS Hoffman, U Nasir, K Abbara, S Di Carli, M Blankstein, R AF Bittencourt, Marcio Sommer Hulten, Edward Polonsky, Tamar S. Hoffman, Udo Nasir, Khurram Abbara, Suhny Di Carli, Marcelo Blankstein, Ron TI European Society of Cardiology-Recommended Coronary Artery Disease Consortium Pretest Probability Scores More Accurately Predict Obstructive Coronary Disease and Cardiovascular Events Than the Diamond and Forrester Score The Partners Registry SO CIRCULATION LA English DT Article DE chest pain; coronary artery disease; risk assessment; prognosis ID AMERICAN-HEART-ASSOCIATION; COMPUTED TOMOGRAPHIC ANGIOGRAPHY; APPROPRIATE USE CRITERIA; TASK-FORCE; MAGNETIC-RESONANCE; NUCLEAR CARDIOLOGY; THORACIC SURGEONS; PROGNOSTIC VALUE; COLLEGE; ECHOCARDIOGRAPHY AB BACKGROUND: The most appropriate score for evaluating the pretest probability of obstructive coronary artery disease (CAD) is unknown. We sought to compare the Diamond-Forrester (DF) score with the 2 CAD consortium scores recently recommended by the European Society of Cardiology. METHODS: We included 2274 consecutive patients (age, 56 +/- 13 years; 57% male) without prior CAD referred for coronary computed tomographic angiography. Computed tomographic angiography findings were used to determine the presence or absence of obstructive CAD (>= 50% stenosis). We compared the DF score with the 2 CAD consortium scores with respect to their ability to predict obstructive CAD and the potential implications of these scores on the downstream use of testing for CAD, as recommended by current guidelines. RESULTS: The DF score did not satisfactorily fit the data and resulted in a significant overestimation of the prevalence of obstructive CAD (P < 0.001); the CAD consortium basic score had no significant lack of fitness; and the CAD consortium clinical provided adequate goodness of fit (P = 0.39). The DF score had a lower discrimination for obstructive CAD, with an area under the receiver-operating characteristics curve of 0.713 versus 0.752 and 0.791 for the CAD consortium models (P < 0.001 for both). Consequently, the use of the DF score was associated with fewer individuals being categorized as requiring no additional testing (8.3%) compared with the CAD consortium models (24.6% and 30.0%; P < 0.001). The proportion of individuals with a high pretest probability was 18% with the DF and only 1.1% with the CAD consortium scores (P < 0.001) CONCLUSIONS: Among contemporary patients referred for noninvasive testing, the DF risk score overestimates the risk of obstructive CAD. On the other hand, the CAD consortium scores offered improved goodness of fit and discrimination; thus, their use could decrease the need for noninvasive or invasive testing while increasing the yield of such tests. C1 [Bittencourt, Marcio Sommer] Univ Sao Paulo, Ctr Clin & Epidemiol Res, Univ Hosp, Sch Med, Sao Paulo, Brazil. [Bittencourt, Marcio Sommer] Univ Sao Paulo, Sao Paulo State Canc Inst, Sch Med, Sao Paulo, Brazil. [Bittencourt, Marcio Sommer; Hulten, Edward; Di Carli, Marcelo; Blankstein, Ron] Harvard Med Sch, Dept Med, Cardiovasc Imaging Program, Boston, MA USA. [Bittencourt, Marcio Sommer; Hulten, Edward; Di Carli, Marcelo; Blankstein, Ron] Harvard Med Sch, Dept Radiol, Brigham & Womens Hosp, Boston, MA USA. [Bittencourt, Marcio Sommer] Hosp Israelita Albert Einstein, Prevent Med Ctr, Sao Paulo, Brazil. [Hulten, Edward] Walter Reed Natl Mil Med Ctr, Serv Cardiol, Dept Internal Med, Bethesda, MD USA. [Polonsky, Tamar S.] Univ Chicago, Dept Med, 5841 S Maryland Ave, Chicago, IL 60637 USA. [Hoffman, Udo; Abbara, Suhny] Harvard Med Sch, Massachusetts Gen Hosp, Cardiac MR PET CT Program, Dept Radiol,Div Cardiac Imaging, Boston, MA USA. [Nasir, Khurram] Baptist Hlth South Florida, Miami, FL USA. [Abbara, Suhny] Univ Texas Southwestern, Dept Radiol, Dallas, TX USA. RP Blankstein, R (reprint author), Brigham & Womens Hosp, Cardiovasc Div, 75 Francis St, Boston, MA 02115 USA.; Blankstein, R (reprint author), Brigham & Womens Hosp, Dept Radiol, 75 Francis St, Boston, MA 02115 USA. EM rblankstein@partners.org RI Bittencourt, Marcio/C-1444-2011 OI Bittencourt, Marcio/0000-0002-3711-1754 FU J.P. Lemann Foundation FX Dr Bittencourt was supported by the J.P. Lemann Foundation as a Jorge Paulo Lemann Harvard Medical School Cardiovascular Fellow at Brigham and Women's Hospital. NR 30 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 19 PY 2016 VL 134 IS 3 BP 201 EP + DI 10.1161/CIRCULATIONAHA.116.023396 PG 13 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DR8EH UT WOS:000380130700011 PM 27413052 ER PT J AU Ruff, CT Giugliano, RP Antman, EM AF Ruff, Christian T. Giugliano, Robert P. Antman, Elliott M. TI Management of Bleeding With Non-Vitamin K Antagonist Oral Anticoagulants in the Era of Specific Reversal Agents SO CIRCULATION LA English DT Article DE anticoagulants; atrial fibrillation; hemorrhage; venous thromboembolism ID PROTHROMBIN COMPLEX CONCENTRATE; NONVALVULAR ATRIAL-FIBRILLATION; ACTIVATED FACTOR-VII; ACUTE VENOUS THROMBOEMBOLISM; DRESDEN NOAC REGISTRY; STAGE RENAL-DISEASE; FACTOR XA INHIBITOR; DABIGATRAN ETEXILATE; IN-VITRO; RABBIT MODEL AB Vitamin K antagonists are commonly used by clinicians to provide anticoagulation to patients who have or are at risk of having thrombotic events. In addition to familiarity with the dosing and monitoring of vitamin K antagonists, clinicians are accustomed to using vitamin K if there is a need to reverse the anticoagulant effect of vitamin K antagonists. There are now 4 new non-vitamin K antagonist oral anticoagulants (NOACs) that are attractive alternatives to vitamin K antagonists. Despite similar or lower rates of serious bleeding with NOACs in comparison with warfarin, there is a pressing need for strategies to manage bleeding when it does occur with NOACs and to reverse the pharmacological effect of these agents if needed. Important steps in minimizing bleeding risks with NOACs include dose adjustment of the agents in the setting of renal dysfunction and avoidance of the concomitant use of other antithrombotic agents if feasible. Laboratory measurement of the anticoagulant effect of NOACs is best accomplished with specialized assays, although some of the more widely available coagulation tests can provide information that is potentially useful to clinicians. Nonspecific hemostatic agents such as prothrombin complex concentrates and recombinant factor VIIa can be used to reverse the effect of NOACs. More specific reversing agents include the approved humanized monoclonal antibody fragment idarucizumab for reversing the effects of dabigatran, the investigational factor Xa decoy andexanet alfa, and the synthetic small molecule ciraparantag. Both andexanet and ciraparantag have been reported to reverse the effects of the anti-Xa NOACs (rivaroxaban, apixaban, and edoxaban), and a number of other anticoagulant agents in common clinical use, as well. C1 Brigham & Womens Hosp, Cardiovasc Med Div, TIMI Study Grp, 75 Francis St, Boston, MA 02115 USA. Harvard Med Sch, Boston, MA USA. RP Ruff, CT (reprint author), TIMI Study Grp, 350 Longwood Ave,1st Floor Off, Boston, MA 02115 USA. EM cruff@partners.org FU Daiichi Sankyo; Merck; Johnson Johnson; Sanofi; AstraZeneca FX Dr Ruff reports grant support through his institution (Brigham and Women's Hospital) from Daiichi Sankyo and has served as a consultant and received honoraria from Daiichi Sankyo, Boehringer Ingelheim, Bayer, and Portola. Dr Giugliano reports grant support through his institution (Brigham and Women's Hospital) from Daiichi Sankyo and has served as a consultant and has received honoraria from American College of Cardiology, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Daiichi Sankyo, Pfizer, Portola, Merck, and Sanofi; and grant support through his institution from Daiichi Sankyo, Merck, Johnson & Johnson, Sanofi, and AstraZeneca. Dr Antman reports receiving grant support through his institution (Brigham and Women's Hospital) from Daiichi Sankyo. NR 85 TC 5 Z9 5 U1 4 U2 4 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 19 PY 2016 VL 134 IS 3 BP 248 EP 261 DI 10.1161/CIRCULATIONAHA.116.021831 PG 14 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DR8EH UT WOS:000380130700015 PM 27436881 ER PT J AU Grecco, LAC Oliveira, CS Galli, M Cosmo, C Duarte, NDC Zanon, N Edwards, DJ Fregni, F AF Collange Grecco, Luanda A. Oliveira, Claudia Santos Galli, Manuela Cosmo, Camila Carvalho Duarte, Natalia de Almeida Zanon, Nelci Edwards, Dylan J. Fregni, Felipe TI Spared Primary Motor Cortex and The Presence of MEP in Cerebral Palsy Dictate the Responsiveness to tDCS during Gait Training SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE cerebral palsy; neuromodulation; non-invasive brain stimulation; gait training; motor evoked potential ID DIRECT-CURRENT STIMULATION; NONINVASIVE BRAIN-STIMULATION; 6-MINUTE WALK TEST; CLINICAL-TRIAL; DOUBLE-BLIND; CHILDREN; STROKE; EXCITABILITY; RELIABILITY; IMPAIRMENT AB The current priority of investigations involving transcranial direct current stimulation (tDOS) and neurorehabilitation is to identify biomarkers associated with the positive results of the interventions such that respondent and non-respondent patients can be identified in the early phases of treatment. The aims were to determine whether: (1) present motor evoked potential (MEP); and (2) injuries involving the primary motor cortex, are associated with tDCS-enhancement in functional outcome following gait training in children with cerebral palsy (CP). We reviewed the data from our parallel, randomized, sham-controlled, double-blind studies. Fifty-six children with spastic CP received gait training (either treadmill training or virtual reality training) and tDCS (active or sham). Univariate and multivariate logistic regression analyses were employed to identify clinical, neurophysiologic and neuroanatomic predictors associated with the responsiveness to treatment with tDCS. MEP presence during the initial evaluation and the subcortical injury were associated with positive effects in the functional results. The logistic regression revealed that present MEP was a significant predictor for the six minute walk test (6MWT; p = 0.003) and gait speed (p = 0.028), whereas the subcortical injury was a significant predictor of gait kinematics (p = 0.013) and gross motor function (p = 0.021). In this preliminary study involving children with CP, two important prediction factors of good responses to anodal tDCS combined with gait training were identified. Apparently, MEP (integrity of the corticospinal tract) and subcortical location of the brain injury exerted different influences on aspects related to gait, such as velocity and kinematics. C1 [Collange Grecco, Luanda A.; Zanon, Nelci] CENEPE Rehabil, Ctr Pediat Neurosurg, Sao Paulo, Brazil. [Collange Grecco, Luanda A.; Oliveira, Claudia Santos; Carvalho Duarte, Natalia de Almeida] Univ Nove de Julho, Dept Rehabil Sci, Movement Anal Lab, Sao Paulo, Brazil. [Galli, Manuela] Politecn Milan, Dept Elect Comp Sci & Bioengn DEIB, Milan, Italy. [Galli, Manuela] IRCCS San Raffaele Pisana, Rome, Italy. [Cosmo, Camila] Univ Fed Bahia, Hlth Sci Inst, PostGrad Program Interact Proc Organs & Syst, Salvador, BA, Brazil. [Edwards, Dylan J.] Comel Univ, Weill Med Coll, Dept Neurol, Burke Med Res Inst, White Plains, NY USA. [Edwards, Dylan J.] Comel Univ, Weill Med Coll, Dept Neurosci, Burke Med Res Inst, White Plains, NY USA. [Fregni, Felipe] Harvard Med Sch, Massachusetts Gen Hosp, Spaulding Rehabil Hosp, Dept Phys Med & Rehabil, Boston, MA USA. RP Grecco, LAC (reprint author), CENEPE Rehabil, Ctr Pediat Neurosurg, Sao Paulo, Brazil.; Grecco, LAC (reprint author), Univ Nove de Julho, Dept Rehabil Sci, Movement Anal Lab, Sao Paulo, Brazil. EM luandagrecco@hotmail.com RI Duarte, Natalia/K-5260-2016 OI Duarte, Natalia/0000-0003-1486-1330 FU Brazilian fostering agencie Conselho Nacional de Desenvolvimento Cientifico e Tecnologico [CNPq-3 07998/2011-8]; Coordenacao de Aperfeicoamento de Pessoa de Nivel Superior [CAPES-99999.011513/2013-06]; Fundacao de Amparo a Pesquisa [FAPESP-2015/14952-9]; NICHD [R03HD084971] FX The authors gratefully acknowledge financial support from the Brazilian fostering agencie Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq-3 07998/2011-8), Coordenacao de Aperfeicoamento de Pessoa de Nivel Superior (CAPES-99999.011513/2013-06) and Fundacao de Amparo a Pesquisa (FAPESP-2015/14952-9). DJE is supported by the NICHD under award number R03HD084971. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 29 TC 3 Z9 3 U1 5 U2 10 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 19 PY 2016 VL 10 AR 361 DI 10.3389/fnhum.2016.00361 PG 11 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA DR4PB UT WOS:000379882500001 PM 27486393 ER PT J AU Raff, AB Kroshinsky, D AF Raff, Adam B. Kroshinsky, Daniela TI Cellulitis A Review SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Review ID SOFT-TISSUE INFECTIONS; RESISTANT STAPHYLOCOCCUS-AUREUS; LOWER-EXTREMITY CELLULITIS; SKIN-STRUCTURE INFECTIONS; GRAM-NEGATIVE CELLULITIS; LOWER-LIMB CELLULITIS; DEEP-VEIN THROMBOSIS; ACUTE BACTERIAL SKIN; RISK-FACTORS; NECROTIZING FASCIITIS AB IMPORTANCE Cellulitis is an infection of the deep dermis and subcutaneous tissue, presenting with expanding erythema, warmth, tenderness, and swelling. Cellulitis is a common global health burden, with more than 650 000 admissions per year in the United States alone. OBSERVATIONS In the United States, an estimated 14.5 million cases annually of cellulitis account for $3.7 billion in ambulatory care costs alone. The majority of cases of cellulitis are nonculturable and therefore the causative bacteria are unknown. In the 15% of cellulitis cases in which organisms are identified, most are due to beta-hemolytic Streptococcus and Staphylococcus aureus. There are no effective diagnostic modalities, and many clinical conditions appear similar. Treatment of primary and recurrent cellulitis should initially cover Streptococcus and methicillin-sensitive S aureus, with expansion for methicillin-resistant S aureus (MRSA) in cases of cellulitis associated with specific risk factors, such as athletes, children, men who have sex with men, prisoners, military recruits, residents of long-term care facilities, those with prior MRSA exposure, and intravenous drug users. Five days of treatment is sufficient with extension if symptoms are not improved. Addressing predisposing factors can minimize risk of recurrence. CONCLUSIONS AND RELEVANCE The diagnosis of cellulitis is based primarily on history and physical examination. Treatment of uncomplicated cellulitis should be directed against Streptococcus and methicillin-sensitive S aureus. Failure to improve with appropriate first-line antibiotics should prompt consideration for resistant organisms, secondary conditions that mimic cellulitis, or underlying complicating conditions such as immunosuppression, chronic liver disease, or chronic kidney disease. C1 [Raff, Adam B.; Kroshinsky, Daniela] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. RP Kroshinsky, D (reprint author), 50 Staniford St,200, Boston, MA 02114 USA. EM dkroshinsky@partners.org NR 119 TC 9 Z9 9 U1 8 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 19 PY 2016 VL 316 IS 3 BP 325 EP 337 DI 10.1001/jama.2016.8825 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA DR3LN UT WOS:000379804800020 PM 27434444 ER PT J AU Radomski, TR Fine, MJ Gellad, WF AF Radomski, Thomas R. Fine, Michael J. Gellad, Walid F. TI Outcome After Admission at Veterans Affairs vs Non-Veterans Affairs Hospitals SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID SYSTEM C1 [Radomski, Thomas R.] Univ Pittsburgh, Sch Med, Div Gen Internal Med, Pittsburgh, PA USA. [Fine, Michael J.; Gellad, Walid F.] VA Pittsburgh Healthcare Syst, Ctr Hlth Equity Res & Promot, Univ Dr,151C, Pittsburgh, PA 15240 USA. RP Radomski, TR (reprint author), VA Pittsburgh Healthcare Syst, Ctr Hlth Equity Res & Promot, Univ Dr,151C, Pittsburgh, PA 15240 USA. EM radomskitr@upmc.edu NR 4 TC 0 Z9 0 U1 1 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 19 PY 2016 VL 316 IS 3 BP 345 EP 346 DI 10.1001/jama.2016.5391 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DR3LN UT WOS:000379804800024 PM 27434448 ER PT J AU Bonaca, MP O'Malley, RG Jarolim, P Scirica, BM Murphy, SA Conrad, MJ Cannon, CP White, HD Braunwald, E Morrow, DA Sabatine, MS AF Bonaca, Marc P. O'Malley, Ryan G. Jarolim, Petr Scirica, Benjamin M. Murphy, Sabina A. Conrad, Michael J. Cannon, Christopher P. White, Harvey D. Braunwald, Eugene Morrow, David A. Sabatine, Marc S. TI Serial Cardiac Troponin Measured Using a High-Sensitivity Assay in Stable Patients With Ischemic Heart Disease SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Letter ID MYOCARDIAL-INFARCTION; EVENTS C1 [Bonaca, Marc P.] Brigham & Womens Hosp, TIMI Study Grp, Div Cardiovasc, 75 Francis St, Boston, MA 02115 USA. RP Bonaca, MP (reprint author), Brigham & Womens Hosp, TIMI Study Grp, Div Cardiovasc, 75 Francis St, Boston, MA 02115 USA. EM mbonaca@partners.org NR 5 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUL 19 PY 2016 VL 68 IS 3 BP 322 EP 323 DI 10.1016/j.jacc.2016.04.046 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DQ9GO UT WOS:000379518600013 PM 27417011 ER PT J AU Murphy, SA Cannon, CP Blazing, MA Giugliano, RP Tershakovec, AM Braunwald, E AF Murphy, Sabina A. Cannon, Christopher P. Blazing, Michael A. Giugliano, Robert P. Tershakovec, Andrew M. Braunwald, Eugene TI REPLY: Personalize and Optimize Lipid-Lowering Therapies SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Letter C1 [Murphy, Sabina A.; Cannon, Christopher P.; Blazing, Michael A.; Giugliano, Robert P.; Tershakovec, Andrew M.; Braunwald, Eugene] TIMI Study Grp, 350 Longwood Ave,1st Floor, Boston, MA 02115 USA. RP Murphy, SA (reprint author), TIMI Study Grp, 350 Longwood Ave,1st Floor, Boston, MA 02115 USA. EM smurphy15@partners.org NR 1 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUL 19 PY 2016 VL 68 IS 3 BP 326 EP 326 DI 10.1016/j.jacc.2016.04.043 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DQ9GO UT WOS:000379518600016 PM 27417014 ER PT J AU Liu, N Yu, ZY Xun, Y Li, MM Peng, XN Xiao, Y Hu, X Sun, Y Yang, MJ Gan, SQ Yuan, SS Wang, XY Xiang, SL Zhang, J AF Liu, Ning Yu, Zhanyang Xun, Yu Li, Miaomiao Peng, Xiaoning Xiao, Ye Hu, Xiang Sun, Yi Yang, Manjun Gan, Shiquan Yuan, Shishan Wang, Xiaoying Xiang, Shuanglin Zhang, Jian TI TNFAIP1 contributes to the neurotoxicity induced by A beta(25-35) in Neuro2a cells SO BMC NEUROSCIENCE LA English DT Article DE TNFAIP1; Amyloid-beta; Alzheimer's disease; Neurotoxicity; Neuro2a cells ID ACTIVATED PROTEIN-KINASE; ALZHEIMERS-DISEASE; CORTICAL-NEURONS; IN-VITRO; APOPTOSIS; MODEL; GENE; MECHANISMS; CASPASE-3; PATHOLOGY AB Background: Amyloid-beta (A beta) accumulation is a hallmark of Alzheimer's disease (AD) that can lead to neuronal dysfunction and apoptosis. Tumor necrosis factor, alpha-induced protein 1 (TNFAIP1) is an apoptotic protein that was robustly induced in the transgenic C. elegans AD brains. However, the roles of TNFAIP1 in AD have not been investigated. Results: We found TNFAIP1 protein and mRNA levels were dramatically elevated in primary mouse cortical neurons and Neuro2a (N2a) cells exposed to A beta(25-35). Knockdown and overexpression of TNFAIP1 significantly attenuated and exacerbated A beta(25-35)-induced neurotoxicity in N2a cells, respectively. Further studies showed that TNFAIP1 knockdown significantly blocked A beta(25-35)-induced cleaved caspase 3, whereas TNFAIP1 overexpression enhanced A beta(25-35)-induced cleaved caspase 3, suggesting that TNFAIP1 plays an important role in A beta(25-35)-induced neuronal apoptosis. Moreover, we observed that TNFAIP1 was capable of inhibiting the levels of phosphorylated Akt and CREB, and also anti-apoptotic protein Bcl-2. TNFAIP1 overexpression enhanced the inhibitory effect of A beta(25-35) on the levels of p-CREB and Bcl-2, while TNFAIP1 knockdown reversed A beta(25-35)-induced attenuation in the levels of p-CREB and Bcl-2. Conclusion: These results suggested that TNFAIP1 contributes to A beta(25-35)-induced neurotoxicity by attenuating Akt/CREB signaling pathway, and Bcl-2 expression. C1 [Liu, Ning; Xun, Yu; Li, Miaomiao; Xiao, Ye; Hu, Xiang; Yang, Manjun; Gan, Shiquan; Xiang, Shuanglin; Zhang, Jian] Hunan Normal Univ, Coll Life Sci, Key Lab Prot Chem & Dev Biol State Educ, Minist China, Changsha 410081, Hunan, Peoples R China. [Liu, Ning; Peng, Xiaoning; Yuan, Shishan] Hunan Normal Univ, Coll Med, Changsha, Hunan, Peoples R China. [Yu, Zhanyang; Wang, Xiaoying] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol & Radiol, Neurosci Program,Neuroprotect Res Lab, Boston, MA USA. [Sun, Yi] Cent S Univ, Xiangya Hosp 2, Dept Pathol, Changsha, Hunan, Peoples R China. RP Xiang, SL; Zhang, J (reprint author), Hunan Normal Univ, Coll Life Sci, Key Lab Prot Chem & Dev Biol State Educ, Minist China, Changsha 410081, Hunan, Peoples R China. EM xshlin@hunnu.edu.cn; zhangjian@hunnu.edu.cn FU China Scholarships Council [2009672005]; China Postdoctoral Science Foundation [2014M552139]; Scientific Research Fund of Hunan Provincial Education Department [2014RS4008]; AHA FDA Summer Postdoctoral Fellowship [12POST9720007] FX This work was supported in part by the financial support from the program of China Scholarships Council (No. 2009672005), the China Postdoctoral Science Foundation (2014M552139), Scientific Research Fund of Hunan Provincial Education Department (2014RS4008) (to N. Liu), and AHA FDA Summer 2011 Postdoctoral Fellowship (12POST9720007) (to Z. Yu). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 32 TC 0 Z9 0 U1 5 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2202 J9 BMC NEUROSCI JI BMC Neurosci. PD JUL 18 PY 2016 VL 17 AR 51 DI 10.1186/s12868-016-0286-3 PG 10 WC Neurosciences SC Neurosciences & Neurology GA DR3TK UT WOS:000379825300002 PM 27430312 ER PT J AU Di Saverio, S Birindelli, A Kelly, MD Catena, F Weber, DG Sartelli, M Sugrue, M De Moya, M Gomes, CA Bhangu, A Agresta, F Moore, EE Soreide, K Griffiths, E De Castro, S Kashuk, J Kluger, Y Leppaniemi, A Ansaloni, L Andersson, M Coccolini, F Coimbra, R Gurusamy, KS Campanile, FC Biffl, W Chiara, O Moore, F Peitzman, AB Fraga, GP Costa, D Maier, RV Rizoli, S Balogh, ZJ Bendinelli, C Cirocchi, R Tonini, V Piccinini, A Tugnoli, G Jovine, E Persiani, R Biondi, A Scalea, T Stahel, P Ivatury, R Velmahos, G Andersson, R AF Di Saverio, Salomone Birindelli, Arianna Kelly, Micheal D. Catena, Fausto Weber, Dieter G. Sartelli, Massimo Sugrue, Michael De Moya, Mark Gomes, Carlos Augusto Bhangu, Aneel Agresta, Ferdinando Moore, Ernest E. Soreide, Kjetil Griffiths, Ewen De Castro, Steve Kashuk, Jeffry Kluger, Yoram Leppaniemi, Ari Ansaloni, Luca Andersson, Manne Coccolini, Federico Coimbra, Raul Gurusamy, Kurinchi S. Campanile, Fabio Cesare Biffl, Walter Chiara, Osvaldo Moore, Fred Peitzman, Andrew B. Fraga, Gustavo P. Costa, David Maier, Ronald V. Rizoli, Sandro Balogh, Zsolt J. Bendinelli, Cino Cirocchi, Roberto Tonini, Valeria Piccinini, Alice Tugnoli, Gregorio Jovine, Elio Persiani, Roberto Biondi, Antonio Scalea, Thomas Stahel, Philip Ivatury, Rao Velmahos, George Andersson, Roland TI WSES Jerusalem guidelines for diagnosis and treatment of acute appendicitis SO WORLD JOURNAL OF EMERGENCY SURGERY LA English DT Review DE Acute Appendicitis; Guidelines; Consensus Conference; Alvarado Score; Appendicitis diagnosis score; Non-operative management; Antibiotics; Complicated appendicitis; Appendectomy; Laparoscopic appendectomy; Phlegmon; Appendiceal abscess ID RANDOMIZED CONTROLLED-TRIALS; INFLAMMATORY RESPONSE SCORE; COMPLICATED ACUTE APPENDICITIS; LOWER QUADRANT PAIN; UNCOMPLICATED ACUTE APPENDICITIS; PREDICTING ACUTE APPENDICITIS; COMPUTED-TOMOGRAPHY USE; ILIAC FOSSA PAIN; LAPAROSCOPIC-APPENDECTOMY; PERFORATED APPENDICITIS AB Acute appendicitis (AA) is among the most common cause of acute abdominal pain. Diagnosis of AA is challenging; a variable combination of clinical signs and symptoms has been used together with laboratory findings in several scoring systems proposed for suggesting the probability of AA and the possible subsequent management pathway. The role of imaging in the diagnosis of AA is still debated, with variable use of US, CT and MRI in different settings worldwide. Up to date, comprehensive clinical guidelines for diagnosis and management of AA have never been issued. In July 2015, during the 3rd World Congress of the WSES, held in Jerusalem (Israel), a panel of experts including an Organizational Committee and Scientific Committee and Scientific Secretariat, participated to a Consensus Conference where eight panelists presented a number of statements developed for each of the eight main questions about diagnosis and management of AA. The statements were then voted, eventually modified and finally approved by the participants to The Consensus Conference and lately by the board of co-authors. The current paper is reporting the definitive Guidelines Statements on each of the following topics: 1) Diagnostic efficiency of clinical scoring systems, 2) Role of Imaging, 3) Non-operative treatment for uncomplicated appendicitis, 4) Timing of appendectomy and in-hospital delay, 5) Surgical treatment 6) Scoring systems for intra-operative grading of appendicitis and their clinical usefulness 7) Non-surgical treatment for complicated appendicitis: abscess or phlegmon 8) Pre-operative and post-operative antibiotics. C1 [Di Saverio, Salomone] AUSL, Emergency & Trauma Surg Maggiore Hosp, Bologna, Italy. [Birindelli, Arianna; Tonini, Valeria] Univ Bologna, S Orsola Malpighi Univ Hosp, Bologna, Italy. [Kelly, Micheal D.] Canberra Hosp, Acute Surg Unit, Canberra, ACT, Australia. [Catena, Fausto] Maggiore Hosp Parma, Emergency & Trauma Surg Dept, Parma, Italy. [Weber, Dieter G.] Trauma & Gen Surgeon Royal Perth Hosp, Perth, WA, Australia. [Weber, Dieter G.] Univ Western Australia, Perth, WA, Australia. [Sartelli, Massimo] Macerata Hosp, Macerata, Italy. [Sugrue, Michael] Letterkenny Hosp, Donegal, Ireland. [De Moya, Mark] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. [Gomes, Carlos Augusto] Univ Gen Juiz de Fora, Univ Hosp, Dept Surg, Juiz De Fora, Brazil. [Bhangu, Aneel] Univ Hosp Birmingham NHS Fdn Trust, Acad Dept Surg, Birmingham, W Midlands, England. [Agresta, Ferdinando] Civil Hosp, Gen Surg, ULSS19, Adria, RO, Italy. [Moore, Ernest E.; Stahel, Philip] Denver Hlth Med Ctr, Denver Hlth Syst, Denver, CO USA. [Soreide, Kjetil] Stavanger Univ Hosp, Dept Gastrointestinal Surg, Stavanger, Norway. [Griffiths, Ewen] Univ Hosp Birmingham NHS Fdn Trust, Queen Elizabeth Hosp, Birmingham, W Midlands, England. [De Castro, Steve] OLVG, Dept Surg, Amsterdam, Netherlands. [Kashuk, Jeffry] Univ Jerusalem, Dept Surg, Jerusalem, Israel. [Kluger, Yoram] Rambam Hlth Care Campus, Div Gen Surg, Haifa, Israel. [Leppaniemi, Ari] Univ Helsinki, Abdominal Ctr, Helsinki, Finland. [Ansaloni, Luca; Coccolini, Federico] Papa Giovanni XXIII Hosp, Gen Surg 1, Bergamo, Italy. [Andersson, Manne; Andersson, Roland] Linkoping Univ, Dept Surg, Linkoping, Sweden. [Coimbra, Raul] UCSD Hlth Syst, Hillcrest Campus Dept Surg, Div Trauma Surg Crit Care Burns & Acute Care Surg, San Diego, CA USA. [Gurusamy, Kurinchi S.] UCL, Royal Free Campus, London, England. [Campanile, Fabio Cesare] San Giovanni Decollato Andosilla Hosp, Dept Surg, Viterbo, Italy. [Biffl, Walter] Univ Hawaii, Queens Med Ctr, Honolulu, HI USA. [Chiara, Osvaldo] Osped Niguarda Ca Granda, Milan, Italy. [Moore, Fred] Univ Florida, Gainesville, FL USA. [Peitzman, Andrew B.] Univ Pittsburgh, UPMC Presbyterian, Sch Med, Dept Surg, Pittsburgh, PA USA. [Fraga, Gustavo P.] Univ Estadual Campinas, FCM, Campinas, SP, Brazil. [Maier, Ronald V.] Univ Washington, Harborview Med Ctr, Dept Surg, Seattle, WA USA. [Rizoli, Sandro] St Michaels Hosp, Toronto, ON, Canada. [Balogh, Zsolt J.; Bendinelli, Cino] John Hunter Hosp, Dept Traumatol, Newcastle, NSW, Australia. [Cirocchi, Roberto] Univ Perugia, Terni Hosp, Dept Surg, Terni, Italy. [Piccinini, Alice; Tugnoli, Gregorio] AUSL, Maggiore Hosp, Trauma Surg Unit, Bologna, Italy. [Jovine, Elio] AUSL, Maggiore Hosp, Dept Surg, Bologna, Italy. [Persiani, Roberto] Catholic Univ, A Gemelli Univ Hosp, Rome, Italy. [Biondi, Antonio] Univ Catania, Dept Surg, Catania, Italy. [Scalea, Thomas] R Adams Cowley Trauma Ctr, Baltimore, MD USA. [Ivatury, Rao] Virginia Commonwealth Univ, Richmond, VA USA. [Velmahos, George] Harvard Med Sch, Massachusetts Gen Hosp, Trauma Emergency Surg & Surg Crit Care, Boston, MA USA. RP Di Saverio, S (reprint author), AUSL, Emergency & Trauma Surg Maggiore Hosp, Bologna, Italy. EM salo75@inwind.it OI Di Saverio, Salomone/0000-0001-5685-5022 NR 162 TC 3 Z9 3 U1 8 U2 14 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1749-7922 J9 WORLD J EMERG SURG JI World J. Emerg. Surg. PD JUL 18 PY 2016 VL 11 AR 34 DI 10.1186/s13017-016-0090-5 PG 25 WC Emergency Medicine; Surgery SC Emergency Medicine; Surgery GA DR5WG UT WOS:000379972500001 PM 27437029 ER PT J AU Lee, GQ Lachowski, C Cai, E Lima, VD Boum, Y Muzoora, C Mocello, AR Hunt, PW Martin, JN Bangsberg, DR Harrigan, PR AF Lee, Guinevere Q. Lachowski, Chris Cai, Eric Lima, Viviane D. Boum, Yap Muzoora, Conrad Mocello, Adrienne Rain Hunt, Peter W. Martin, Jeffrey N. Bangsberg, David R. Harrigan, P. Richard TI Non-R5-tropic HIV-1 in subtype A1 and D infections were associated with lower pretherapy CD4(+) R cell count but not with PI/(N)NRTI therapy outcomes in Mbarara, Uganda SO AIDS LA English DT Article DE Africa; clinical outcome; consequence; HIV-1; non-B tropism; subtype A1; subtype D; Uganda; virologic outcome ID INITIATING ANTIRETROVIRAL THERAPY; IMMUNODEFICIENCY-VIRUS TYPE-1; NON-B SUBTYPES; CORECEPTOR USAGE; DRUG-RESISTANCE; DISEASE PROGRESSION; SEQUENCE-ANALYSIS; CXCR4 TROPISM; EPIDEMIOLOGY; PREVALENCE AB Background: Previous studies suggest that infection with non-R5-tropic subtype B HIV-1, compared with R5, is associated with a more rapid decline in CD4(+) cell count, but does not affect PI/(N) NRTI therapy outcome. Here, we explored clinical correlates associated with viral tropism in subtype A1 and D infections. Methods: HIV-1 subtype A1 (n = 196) and D (n = 143) pretherapy plasma samples and up to 7.5 years of posttherapy virologic and CD4(+) data were collected from a crosssectional cohort in Mbarara, Uganda. Tropism and subtype were inferred using env V3 (geno2pheno) and gp41 (RIP) Sanger sequences. For each subtype, R5 infection was compared with non-R5 in terms of: pretherapy viral load and CD4(+) cell count (Mann-Whitney tests), and therapy outcomes, including time to virologic suppression, postsuppression virologic rebound, CD4(+) decline and CD4(+) recovery (log-rank tests). Results: A 94% of all patients in this study achieved virologic suppression within median 3 months posttherapy. In both subtypes, non-R5 infection was associated with lower pretherapy CD4(+) cell count (non-R5 vs. R5; A: median 57 vs. 147 cells/ml P = 0.005; D: 80 vs. 128 cells/mu l P = 0.006). Multivariable linear regression confirmed that tropism, not subtype nor the interaction between subtype and tropism, was a significant predictor of pretherapy CD4(+) cell count (P<0.0001). None of pretherapy viral load, time to virologic suppression, virologic rebound, CD4(+) decline nor CD4(+) recovery was significantly different (all P>0.09). Conclusion: Regardless of HIV-1 subtype or tropism, the majority of patients in this Ugandan cohort responded to therapy, even though non-R5 infection was associated with lower pretherapy CD4(+) cell count. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved. C1 [Lee, Guinevere Q.; Lachowski, Chris; Cai, Eric; Lima, Viviane D.; Harrigan, P. Richard] BC Ctr Excellence HIV AIDS, 603-1081 Burrard St, Vancouver, BC V6Z 1Y6, Canada. [Boum, Yap; Muzoora, Conrad; Bangsberg, David R.] Mbarara Univ Sci & Technol, Mbarara, Uganda. [Mocello, Adrienne Rain; Hunt, Peter W.; Martin, Jeffrey N.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Bangsberg, David R.] Harvard Med Sch, Boston, MA USA. [Bangsberg, David R.] Harvard Sch Publ Hlth, Boston, MA USA. [Bangsberg, David R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Lee, GQ (reprint author), BC Ctr Excellence HIV AIDS, 603-1081 Burrard St, Vancouver, BC V6Z 1Y6, Canada. EM glee@cfenet.ubc.ca RI Lee, Guinevere/D-4436-2017 OI Lee, Guinevere/0000-0002-9412-886X FU Canadian Institutes of Health Research (CIHR); National Institutes of Health (NIH) Centers for AIDS Research (CFAR) Program; National Institute of Mental Health [R01MH054907, P30AI027763, U01CA066529]; National Institute on Alcohol Abuse and Alcoholism [R21AA014784] FX This work was funded by the Canadian Institutes of Health Research (CIHR), National Institutes of Health (NIH) Centers for AIDS Research (CFAR) Program, National Institute of Mental Health R01MH054907, P30AI027763, U01CA066529 and National Institute on Alcohol Abuse and Alcoholism R21AA014784. NR 32 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD JUL 17 PY 2016 VL 30 IS 11 BP 1781 EP 1788 DI 10.1097/QAD.0000000000001128 PG 8 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA DR1KT UT WOS:000379665100012 PM 27124899 ER PT J AU Park, LS Tate, JP Sigel, K Rimland, D Crothers, K Gibert, C Rodriguez-Barradas, MC Goetz, MB Bedimo, RJ Brown, ST Justice, AC Dubrow, R AF Park, Lesley S. Tate, Janet P. Sigel, Keith Rimland, David Crothers, Kristina Gibert, Cynthia Rodriguez-Barradas, Maria C. Goetz, Matthew Bidwell Bedimo, Roger J. Brown, Sheldon T. Justice, Amy C. Dubrow, Robert TI Time trends in cancer incidence in persons living with HIV/AIDS in the antiretroviral therapy era: 1997-2012 SO AIDS LA English DT Article DE AIDS; cancer; HIV infections; neoplasms; veterans ID HIV-INFECTED PATIENTS; AIDS-DEFINING CANCERS; FORCE RECOMMENDATION STATEMENT; HUMAN-PAPILLOMAVIRUS VACCINE; UNITED-STATES; NORTH-AMERICA; LUNG-CANCER; ANAL CANCER; HIV-1-INFECTED PATIENTS; CHANGING PATTERNS AB Objective: Utilizing the Veterans Aging Cohort Study, the largest HIV cohort in North America, we conducted one of the few comprehensive comparisons of cancer incidence time trends in HIV-infected (HIV+) versus uninfected persons during the antiretroviral therapy (ART) era. Design: Prospective cohort study. Methods: We followed 44 787 HIV+ and 96 852 demographically matched uninfected persons during 1997-2012. We calculated age-, sex-, and race/ethnicity-standardized incidence rates and incidence rate ratios (IRR, HIV+ versus uninfected) over four calendar periods with incidence rate and IRR period trend P values for cancer groupings and specific cancer types. Results: We observed 3714 incident cancer diagnoses in HIV+ and 5760 in uninfected persons. The HIV+ all-cancer crude incidence rate increased between 1997-2000 and 2009-2012 (P trend = 0.0019). However, after standardization, we observed highly significant HIV+ incidence rate declines for all cancer (25% decline; P trend <0.0001), AIDS-defining cancers (55% decline; P trend <0.0001), nonAIDS-defining cancers (NADC; 15% decline; P trend = 0.0003), and nonvirus-related NADC (20% decline; P trend<0.0001); significant IRRdeclines for all cancer (from 2.0 to 1.6; P trend<0.0001), AIDS-defining cancers (from 19 to 5.5; P trend <0.0001), and nonvirus-related NADC (from 1.4 to 1.2; P trend = 0.049); and borderline significant IRR declines for NADC(from 1.6 to 1.4; P trend = 0.078) and virus-related NADC (from 4.9 to 3.5; P trend = 0.071). Conclusion: Improved HIV care resulting in improved immune function most likely contributed to the HIV+ incidence rate and the IRR declines. Further promotion of early and sustained ART, improved ART regimens, reduction of traditional cancer risk factor (e.g. smoking) prevalence, and evidence-based screening could contribute to future cancer incidence declines among HIV+ persons. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved. C1 [Park, Lesley S.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Tate, Janet P.; Justice, Amy C.] Vet Affairs Connecticut Healthcare Syst, West Haven, CT USA. [Tate, Janet P.; Justice, Amy C.; Dubrow, Robert] Yale Sch Med, New Haven, CT USA. [Sigel, Keith; Brown, Sheldon T.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Rimland, David] Atlanta Vet Affairs Med Ctr, Atlanta, GA USA. [Rimland, David] Emory Univ, Sch Med, Atlanta, GA USA. [Crothers, Kristina] Univ Washington, Sch Med, Seattle, WA USA. [Gibert, Cynthia] Washington DC Vet Affairs Med Ctr, Washington, DC USA. [Gibert, Cynthia] George Washington Univ, Sch Med & Hlth Sci, Washington, DC 20052 USA. [Rodriguez-Barradas, Maria C.] Michael E DeBakey VA Med Ctr, Houston, TX USA. [Rodriguez-Barradas, Maria C.] Baylor Coll Med, Houston, TX 77030 USA. [Goetz, Matthew Bidwell] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Goetz, Matthew Bidwell] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Bedimo, Roger J.] Vet Affairs North Texas Healthcare Syst, Dallas, TX USA. [Bedimo, Roger J.] Univ Texas Southwestern Med Ctr, Dallas, TX USA. [Brown, Sheldon T.] James J Peters Vet Affairs Med Ctr, New York, NY USA. [Dubrow, Robert] Yale Sch Publ Hlth, New Haven, CT USA. RP Park, LS (reprint author), Stanford Univ, Sch Med, Ctr Hlth Policy, Ctr Primary Care & Outcomes Res, 117 Encina Commons, Stanford, CA 94305 USA. EM lesley.park@stanford.edu OI Sigel, Keith/0000-0002-4051-4861 FU US Veterans Health Administration; National Institute on Alcohol Abuse and Alcoholism [U01-AA020790, U24-AA020794, U10-AA013566]; National Institute of Mental Health [T32-MH020031, P30-MH062294]; National Institute of Allergy and Infectious Diseases [U01-A1069918]; National Cancer Institute [F31-CA180775, R01-CA165937, R01-CA173754]; National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health [3T32-DK007217] FX This research was supported by the US Veterans Health Administration and by grants from the National Institute on Alcohol Abuse and Alcoholism (U01-AA020790, U24-AA020794, U10-AA013566), National Institute of Mental Health (T32-MH020031, P30-MH062294), National Institute of Allergy and Infectious Diseases (U01-A1069918), National Cancer Institute (F31-CA180775, R01-CA165937, R01-CA173754), and National Institute of Diabetes and Digestive and Kidney Diseases (3T32-DK007217) of the National Institutes of Health. NR 67 TC 4 Z9 4 U1 2 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD JUL 17 PY 2016 VL 30 IS 11 BP 1795 EP 1806 DI 10.1097/QAD.0000000000001112 PG 12 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA DR1KT UT WOS:000379665100014 PM 27064994 ER PT J AU Rochard, L Monica, SD Ling, ITC Kong, Y Roberson, S Harland, R Halpern, M Liao, EC AF Rochard, Lucie Monica, Stefanie D. Ling, Irving T. C. Kong, Yawei Roberson, Sara Harland, Richard Halpern, Marnie Liao, Eric C. TI Roles of Wnt pathway genes wls, wnt9a, wnt5b, frzb and gpc4 in regulating convergent-extension during zebrafish palate morphogenesis SO DEVELOPMENT LA English DT Article DE Wnt; Convergent-extension; Zebrabow; Palate; Morphogenesis ID PLANAR CELL POLARITY; CRANIOFACIAL DEVELOPMENT; GASTRULATION MOVEMENTS; LIPOPROTEIN PARTICLES; ARTICULAR-CARTILAGE; GRADIENT FORMATION; AXIS FORMATION; KNOCKOUT MICE; EXPRESSION; SECRETION AB The Wnt signaling pathway is crucial for tissue morphogenesis, participating in cellular behavior changes, notably during the process of convergent-extension. Interactions between Wnt-secreting and receiving cells during convergent-extension remain elusive. We investigated the role and genetic interactions of Wnt ligands and their trafficking factors Wls, Gpc4 and Frzb in the context of palate morphogenesis in zebrafish. We describe that the chaperon Wls and its ligands Wnt9a and Wnt5b are expressed in the ectoderm, whereas juxtaposed chondrocytes express Frzb and Gpc4. Using wls, gpc4, frzb, wnt9a and wnt5b mutants, we genetically dissected the Wnt signals operating between secreting ectoderm and receiving chondrocytes. Our analysis delineates that non-canonical Wnt signaling is required for cell intercalation, and that wnt5b and wnt9a are required for palate extension in the anteroposterior and transverse axes, respectively. C1 [Rochard, Lucie; Ling, Irving T. C.; Kong, Yawei; Liao, Eric C.] Harvard Med Sch, Harvard Stem Cell Inst, Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Monica, Stefanie D.; Harland, Richard] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. [Roberson, Sara; Halpern, Marnie] Johns Hopkins Univ, Carnegie Inst Sci, Dept Embryol, 3520 San Martin Dr, Baltimore, MD 21218 USA. [Roberson, Sara; Halpern, Marnie] Johns Hopkins Univ, Dept Biol, 3520 San Martin Dr, Baltimore, MD 21218 USA. RP Liao, EC (reprint author), Harvard Med Sch, Harvard Stem Cell Inst, Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. EM cliao@partners.org FU National Institute of Dental and Craniofacial Research [RO3DE024490]; Shriners Hospital for Children; Shriners Hospital; Ford Foundation; National Institutes of Health [GM42341] FX This work was funded by the National Institute of Dental and Craniofacial Research [RO3DE024490] and Shriners Hospital for Children (E.C.L); L.R. is supported by a research fellowship from Shriners Hospital; and S.D.M. was supported by the Ford Foundation and the National Institutes of Health [GM42341]. Deposited in PMC for release after 12 months. NR 57 TC 1 Z9 1 U1 0 U2 0 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 EI 1477-9129 J9 DEVELOPMENT JI Development PD JUL 15 PY 2016 VL 143 IS 14 BP 2541 EP 2547 DI 10.1242/dev.137000 PG 7 WC Developmental Biology SC Developmental Biology GA EI7WR UT WOS:000392715600007 PM 27287801 ER PT J AU Ghandi, M Mohammad-Noori, M Ghareghani, N Lee, D Garraway, L Beer, MA AF Ghandi, Mahmoud Mohammad-Noori, Morteza Ghareghani, Narges Lee, Dongwon Garraway, Levi Beer, Michael A. TI gkmSVM: an R package for gapped-kmer SVM SO BIOINFORMATICS LA English DT Article ID STRING KERNELS; DNA-SEQUENCE; ENHANCERS AB We present a new R package for training gapped-kmer SVM classifiers for DNA and protein sequences. We describe an improved algorithm for kernel matrix calculation that speeds run time by about 2 to 5-fold over our original gkmSVM algorithm. This package supports several sequence kernels, including: gkmSVM, kmer-SVM, mismatch kernel and wildcard kernel. Availability and Implementation: gkmSVM package is freely available through the Comprehensive R Archive Network (CRAN), for Linux, Mac OS and Windows platforms. The C++ implementation is available at www.beerlab.org/gkmsvm C1 [Ghandi, Mahmoud; Garraway, Levi] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Mohammad-Noori, Morteza] Univ Tehran, Coll Sci, Sch Math Stat & Comp Sci, Tehran, Iran. [Ghareghani, Narges] Univ Tehran, Coll Engn, Dept Engn Sci, Tehran, Iran. [Ghareghani, Narges] Inst Res Fundamental Sci IPM, Tehran, Iran. [Lee, Dongwon; Beer, Michael A.] Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Garraway, Levi] Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. [Beer, Michael A.] Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD USA. RP Ghandi, M (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.; Beer, MA (reprint author), Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Baltimore, MD USA.; Beer, MA (reprint author), Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD USA. EM mghandi@gmail.com; mbeer@jhu.edu OI Ghandi, Mahmoud/0000-0003-1897-2265 FU NIH [R01 HG0007348]; IPM [CS1391-4-02, 94050016] FX M.A.B. was supported by NIH grant R01 HG0007348. M.M-N and N.G. were supported by grants from IPM (No. CS1391-4-02 and No. 94050016). NR 14 TC 1 Z9 1 U1 2 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 EI 1460-2059 J9 BIOINFORMATICS JI Bioinformatics PD JUL 15 PY 2016 VL 32 IS 14 BP 2205 EP 2207 DI 10.1093/bioinformatics/btw203 PG 3 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA DT1SZ UT WOS:000381263700019 PM 27153639 ER EF