FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Jelly, CA Jiang, YD Hoeft, M Liang, YF AF Jelly, Christina Anne Jiang, Yandong Hoeft, Mark Liang, Yafen TI Transesophageal Echocardiography Assisting in the Diagnosis of Intraabdominal Hemorrhage During Cardiac Arrest SO A & A CASE REPORTS LA English DT Article ID NONCARDIAC SURGERY AB Transesophageal echocardiography (TEE) has been frequently used to identify potential etiologies of intraoperative cardiac arrest for noncardiac surgical patients. However, rescue TEE to assist in the diagnosis of intraabdominal hemorrhage has never been reported. We present a patient who developed cardiac arrest on emergence after an elective abdominal surgery. Intraoperative TEE revealed hypovolemia with hyperdynamic left and right ventricles. It also demonstrated a 3.3- by 13.2-cm circular perihepatic fluid collection on transgastric views raising concern for major intraabdominal hemorrhage as the cause for the cardiac arrest. This prompted surgical reexploration, which confirmed the diagnosis. We suggest that transgastric views to identify intraabdominal fluid collections should be considered during a rescue TEE if intraabdominal hemorrhage is suspected. C1 [Jelly, Christina Anne; Hoeft, Mark] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Jiang, Yandong; Liang, Yafen] Vanderbilt Univ, Med Ctr, Dept Anesthesiol, Nashville, TN 37232 USA. RP Liang, YF (reprint author), Vanderbilt Univ, Med Ctr, Dept Anesthesiol, Nashville, TN 37232 USA. EM yafen.liang@vanderbilt.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 2325-7237 J9 A A CASE REP JI A A Case Rep. PD APR 1 PY 2016 VL 6 IS 7 BP 201 EP 203 DI 10.1213/XAA.0000000000000284 PG 3 WC Anesthesiology SC Anesthesiology GA DI6FV UT WOS:000373595500008 PM 26795911 ER PT J AU Tipps, ME Raybuck, JD Kozell, LB Lattal, KM Buck, KJ AF Tipps, Megan E. Raybuck, Jonathan D. Kozell, Laura B. Lattal, K. Matthew Buck, Kari J. TI G Protein-Gated Inwardly Rectifying Potassium Channel Subunit 3 Knock-Out Mice Show Enhanced Ethanol Reward SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE GIRK Channels; Reward; Conditioned Place Preference; Fear Conditioning; Ethanol ID CONDITIONED PLACE PREFERENCE; VENTRAL TEGMENTAL AREA; NULL MUTANT MICE; GIRK CHANNELS; ALCOHOL ADDICTION; DOPAMINE SYSTEM; DRUG-ADDICTION; K+ CHANNELS; HYBRID MICE; NEURONS AB BackgroundG protein-gated inwardly rectifying potassium (GIRK) channels contribute to the effects of a number of drugs of abuse, including ethanol. However, the roles of individual subunits in the rewarding effects of ethanol are poorly understood. MethodsWe compare conditioned place preference (CPP) in GIRK3 subunit knock-out (GIRK3(-/-)), heterozygote (GIRK3(+/-)), and wild-type (WT) mice. In addition, the development of locomotor tolerance/sensitization and the effects of EtOH intoxication on associative learning (fear conditioning) are also assessed. ResultsOur data show significant EtOH CPP in GIRK3(-/-) and GIRK3(+/-) mice, but not in the WT littermates. In addition, we demonstrate that these effects are not due to differences in EtOH metabolism, the development of EtOH tolerance/sensitivity, or associative learning abilities. While there were no consistent genotype differences in the fear conditioning assay, our data do show a selective sensitization of the impairing effects of EtOH intoxication on contextual learning, but no effect on cued learning. ConclusionsThese findings suggest that GIRK3 plays a role in EtOH reward. Furthermore, the selectivity of this effect suggests that GIRK channels could be an effective therapeutic target for the prevention and/or treatment of alcoholism. C1 [Tipps, Megan E.; Kozell, Laura B.; Buck, Kari J.] Portland VA Med Ctr, Portland Alcohol Res Ctr, Portland, OR USA. [Tipps, Megan E.; Raybuck, Jonathan D.; Kozell, Laura B.; Lattal, K. Matthew; Buck, Kari J.] Oregon Hlth & Sci Univ, Dept Behav Neurosci, 3181 SW Sam Jackson Pk Rd,Mail Code L470, Portland, OR 97239 USA. RP Tipps, ME (reprint author), Oregon Hlth & Sci Univ, Dept Behav Neurosci, 3181 SW Sam Jackson Pk Rd,Mail Code L470, Portland, OR 97239 USA. EM metipps@gmail.com OI Kozell, Laura/0000-0003-3059-2046 FU NIH [F32 AA022011, T32 AA07468, F32DA031537, T32 DA07262, R01 AA011114, P60 AA10760, R24 AA020245, R01 DA005228, R01 DA025922]; VA; U.S. Department of the Army/DOD-TATRC [W81XWH-12-2-0048] FX This work was supported by NIH F32 AA022011 and T32 AA07468 (MET); NIH F32DA031537 and T32 DA07262 (JDR); NIH R01 AA011114, P60 AA10760, R24 AA020245, R01 DA005228, and the VA (KJB); NIH R01 DA025922 and U.S. Department of the Army/DOD-TATRC: W81XWH-12-2-0048 (KML). NR 52 TC 2 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD APR PY 2016 VL 40 IS 4 BP 857 EP 864 DI 10.1111/acer.13012 PG 8 WC Substance Abuse SC Substance Abuse GA DI8GK UT WOS:000373739300023 PM 27012303 ER PT J AU Berg, DD Bonaca, MP Braunwald, E Corbalan, R Goto, S Kiss, RG Murphy, SA Scirica, BM Spinar, J Morrow, DA AF Berg, David D. Bonaca, Marc P. Braunwald, Eugene Corbalan, Ramon Goto, Shinya Kiss, Robert G. Murphy, Sabina A. Scirica, Benjamin M. Spinar, Jindrich Morrow, David A. TI Outcomes in Stable Patients With Previous Atherothrombotic Events Receiving Vorapaxar Who Experience a New Acute Coronary Event (from TRA2 degrees P-TIMI 50) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID THROMBIN-RECEPTOR ANTAGONIST; SECONDARY PREVENTION AB Vorapaxar is a first-in-class protease-activated receptor-1 antagonist indicated for secondary prevention in stable patients with previous myocardial infarction (MI) or peripheral artery disease and no cerebrovascular disease. Vorapaxar is not recommended for initiation in the acute phase of acute coronary syndromes (ACS) because of an unfavorable balance between bleeding and efficacy when started in that setting. The aim of this analysis was to investigate outcomes in patients who experienced a new ACS while receiving vorapaxar for long-term secondary prevention. Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic ischemic Events-Thrbmbolysis In Myocardial Infarction 50 was a randomized, double-blind, placebo-controlled trial of vorapaxar (n = 26,449). We evaluated bleeding and ischemic events during the acute care of patients with a new ACS during the trial. During a median follow-up of 30 months, 799 patients (8.9%) randomized to vorapaxar and 913 (10.0%) to placebo had a new ACS event (p = 0.003); 87% and 86%, respectively, were on study therapy at the time of the event. In a landmark analysis through 7 days after ACS, the rates of Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) severe bleeding were 0.8% versus 0.8% (hazard ratio [HR] 0.99, 95% CI 0.33 to 2.94) and GUSTO moderate/severe bleeding were 2.5% versus 1.6% (HR 1.59, 95% CI 0.78 to 3.24) with vorapaxar versus placebo. The effect of vorapaxar on cardiovascular death, MI, or stroke (2.4% vs 4.4%; HR 0.54, 95% CI 0,31 to 0.93; p = 0.027) was consistent with the, overall trial result. In conclusion, in patients who experience a new ACS event while receiving vorapaxar for secondary prevention, continuing therapy was associated with favorable efficacy without excess severe bleeding during the period of acute ACS management. (C) 2016 Elsevier Inc. All rights reserved. C1 [Berg, David D.; Bonaca, Marc P.; Braunwald, Eugene; Murphy, Sabina A.; Scirica, Benjamin M.; Morrow, David A.] Harvard Univ, Brigham & Womens Hosp, Cardiovasc Div, TIMI Study Grp,Dept Med,Med Sch, Boston, MA 02115 USA. [Corbalan, Ramon] Catholic Univ Chile, Dept Cardiol, Sch Med, Santiago, Chile. [Goto, Shinya] Tokai Univ, Sch Med, Dept Med, Isehara, Kanagawa 25911, Japan. [Kiss, Robert G.] Mil Hosp, Dept Cardiol, Budapest, Hungary. [Spinar, Jindrich] Univ Hosp, Dept Cardiol, Brno, Czech Republic. RP Morrow, DA (reprint author), Harvard Univ, Brigham & Womens Hosp, Cardiovasc Div, TIMI Study Grp,Dept Med,Med Sch, Boston, MA 02115 USA. EM dmorrow@partners.org FU Merck and Co. FX TRA2 degrees P-TIMI 50 (http://www.clinicaltrials.gov, NCT00526474) was supported by Merck and Co. NR 5 TC 2 Z9 2 U1 4 U2 5 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 APR 1 PY 2016 VL 117 IS 7 BP 1055 EP 1058 DI 10.1016/j.amjcard.2015.12.052 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DI5FH UT WOS:000373523800004 PM 26876014 ER PT J AU Vaduganathan, M Marti, CN Mentz, RJ Greene, SJ Ambrosy, AP Subacius, HP Fonarow, GC Chioncel, O Bazari, H Maggioni, AP Zannad, F Konstam, MA Sato, N Gheorghiade, M Butler, J AF Vaduganathan, Muthiah Marti, Catherine N. Mentz, Robert J. Greene, Stephen J. Ambrosy, Andrew P. Subacius, Hans P. Fonarow, Gregg C. Chioncel, Ovidiu Bazari, Hasan Maggioni, Aldo P. Zannad, Faiez Konstam, Marvin A. Sato, Naoki Gheorghiade, Mihai Butler, Javed CA EVEREST Trial Investigators TI Serum Osmolality and Postdischarge Outcomes After Hospitalization for Heart Failure SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID LEFT-VENTRICULAR DYSFUNCTION; EVEREST; TOLVAPTAN; TRIAL; ACTIVATION AB Serum osmolality may fluctuate with neurohormonal activation and in response to certain therapeutics in patients with heart failure (HF). The clinical relevance of osmolality in patients with HF has not been defined. In this post hoc analysis of the Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan trial, we analyzed serum osmolality measured at discharge in 3,744 patients hospitalized for HF and reduced ejection fraction (EF <= 40%). Median follow-up was 9.9 months. The association between discharge osmolality and all-cause mortality (ACM) and composite cardiovascular mortality or HF hospitalization was nonlinear; and thus, patients were divided into low (<= 284), normal (285 to 300), and high (>= 300 mOsm/kg) osmolality. Median serum osmolality at discharge was 297 (290 to 304) mOsm/kg. Patients in the low osmolality group (n = 454,12.1%) were more likely to be younger, men, have lower rates of hypertension, coronary artery disease, chronic kidney disease, diabetes, and have lower serum sodium, creatinine, systolic blood pressure, and EF (all p <0.001). Low discharge osmolality was associated with higher ACM (low 29.3%; normal 23.6%; high 25.2%; p = 0.04) and the composite endpoint (low 45.6%; normal 39.3%; high 41.8%; p = 0.04). After risk adjustment, a 15 mOsm/kg decrease in osmolality was predictive of higher ACM (hazard ratio 1.61, 95% CI 1.19 to 2.17) and the composite endpoint (hazard ratio 1.37, 95% CI 1.06 to 1.75) in the low osmolality group. These associations were not seen in patients with normal or high osmolality. Interaction analyses for tolvaptan treatment were nonsignificant (p >0.4). In conclusion, low discharge serum osmolality was independently predictive of worse postdischarge mortality and readmission. Further study is required to clarify the clinical utility of serum osmolality in hospitalized patients with HF. (C) 2016 Elsevier Inc. All rights reserved. C1 [Vaduganathan, Muthiah] Harvard Univ, Brigham & Womens Hosp, Heart & Vasc Ctr, Sch Med, Boston, MA 02115 USA. [Bazari, Hasan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. [Marti, Catherine N.] Emory Univ, Sch Med, Div Cardiol, Atlanta, GA 30322 USA. [Mentz, Robert J.; Greene, Stephen J.; Ambrosy, Andrew P.] Duke Univ, Med Ctr, Durham, NC USA. [Subacius, Hans P.] Northwestern Univ, Dept Med, Div Cardiol, Feinberg Sch Med, Chicago, IL 60611 USA. [Fonarow, Gregg C.] Ronald Reagan Univ Calif Los Angeles Med Ctr, Ahmanson Univ Calif Los Angeles Cardiomyopathy Ct, Los Angeles, CA USA. [Chioncel, Ovidiu] Inst Cardiovasc Dis Prof C Iliescu, Cardiol, Bucharest, Romania. [Maggioni, Aldo P.] Italian Assoc Hosp Cardiologists Res Ctr, Florence, Italy. [Zannad, Faiez] Nancy Univ, Dept Cardiol, Nancy, France. [Konstam, Marvin A.] Tufts Med Ctr, Boston, MA USA. [Sato, Naoki] Musashi Kosugi Hosp, Nippon Med Sch, Tokyo, Japan. [Gheorghiade, Mihai] Northwestern Univ, Ctr Cardiovasc Innovat, Feinberg Sch Med, Chicago, IL 60611 USA. [Butler, Javed] SUNY Stony Brook, Div Cardiol, Stony Brook, NY 11794 USA. RP Butler, J (reprint author), SUNY Stony Brook, Div Cardiol, Stony Brook, NY 11794 USA. EM javed.butler@stonybrookmedicine.edu OI chioncel, ovidiu/0000-0002-3197-3628; Vaduganathan, Muthiah/0000-0003-0885-1953; Maggioni, Aldo Pietro/0000-0003-2764-6779 FU Otsuka Inc. (Rockville, Maryland) FX Otsuka Inc. (Rockville, Maryland) provided financial and material support for the EVEREST trial. Database management was performed by the sponsor. NR 10 TC 3 Z9 3 U1 1 U2 2 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 EI 1879-1913 J9 AM J CARDIOL JI Am. J. Cardiol. PD APR 1 PY 2016 VL 117 IS 7 BP 1144 EP 1150 DI 10.1016/j.amjcard.2015.12.059 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DI5FH UT WOS:000373523800018 PM 26851146 ER PT J AU Quraishi, SA Camargo, CA Manson, JE AF Quraishi, Sadeq A. Camargo, Carlos A., Jr. Manson, JoAnn E. TI Low vitamin D status in Europe: moving from evidence to sound public health policies SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Editorial Material ID D-BINDING PROTEIN; D DEFICIENCY C1 [Quraishi, Sadeq A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA USA. [Camargo, Carlos A., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA USA. [Manson, JoAnn E.] Harvard Univ, Sch Med, Dept Med, Brigham & Womens Hosp, Boston, MA USA. RP Manson, JE (reprint author), Harvard Univ, Sch Med, Dept Med, Brigham & Womens Hosp, Boston, MA USA. EM jmanson@rics.bwh.harvard.edu FU NCI NIH HHS [R01 CA138962]; NIAMS NIH HHS [R01 AR059775] NR 12 TC 0 Z9 0 U1 2 U2 6 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 APR PY 2016 VL 103 IS 4 BP 957 EP 958 DI 10.3945/ajcn.116.132274 PG 2 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DI3VI UT WOS:000373426400001 PM 26984486 ER PT J AU Rosendorff, C AF Rosendorff, Clive CA Writing Comm TI Treatment of Hypertension in Patients with Coronary Artery Disease. A Case-Based Summary of the 2015 AHA/ACC/ASH Scientific Statement SO AMERICAN JOURNAL OF MEDICINE LA English DT Review DE Acute Coronary Syndrome; Coronary Artery Disease; Heart Failure; Hypertension; Myocardial Infarction; Stable Angina; Unstable Angina ID COLLEGE-OF-CARDIOLOGY; LEFT-VENTRICULAR DYSFUNCTION; CONVERTING-ENZYME-INHIBITOR; ACUTE MYOCARDIAL-INFARCTION; AMERICAN-HEART-ASSOCIATION; PREVENTIVE-CARDIOVASCULAR-NURSES; BLOOD-PRESSURE CONTROL; HIGH-RISK PATIENTS; RANDOMIZED-TRIAL; PRACTICE GUIDELINES AB The 2015 American Heart Association/American College of Cardiology/American Society of Hypertension Scientific Statement "Treatment of Hypertension in Patients with Coronary Artery Disease" is summarized in the context of a clinical case. The Statement deals with target blood pressures, and the optimal agents for the treatment of hypertension in patients with stable angina, in acute coronary syndromes, and in patients with ischemic heart failure. In all cases, the recommended blood pressure target is < 140/90 mm Hg, but < 130/80 mm Hg may be appropriate, especially in those with a history of a previous myocardial infarction or stroke, or at high risk for developing either. These numbers may need to be revised after the publication of the SPRINT data. Appropriate management should include beta-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and in the case of heart failure, aldosterone antagonists. Thiazide or thiazide-like (chlorthalidone) diuretics and calcium channel blockers can be used for the management of hypertension, but the evidence for improved outcomes compared with other agents in hypertension with coronary artery disease is meager. Loop diuretics should be reserved for patients with New York Heart Association Class III and IV heart failure or with a glomerular filtration rate of < 30 mL/min. Published by Elsevier Inc. C1 Mt Sinai Heart, New York, NY USA. Icahn Sch Med Mt Sinai, Dept Med, New York, NY 10029 USA. James J Peters VA Med Ctr, Bronx, NY 10468 USA. RP Rosendorff, C (reprint author), James J Peters VA Med Ctr, Med 111, 130 West Kingsbridge Rd, Bronx, NY 10468 USA. EM clive.rosendorff@va.gov OI Allison, Matthew/0000-0003-0777-8272 NR 37 TC 2 Z9 2 U1 2 U2 9 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 APR PY 2016 VL 129 IS 4 BP 372 EP 378 DI 10.1016/j.amjmed.2015.10.045 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA DI4RH UT WOS:000373486500021 PM 26655222 ER PT J AU Lin, BM Curhan, SG Wang, M Eavey, R Stankovic, KM Curhan, GC AF Lin, Brian M. Curhan, Sharon G. Wang, Molin Eavey, Roland Stankovic, Konstantina M. Curhan, Gary C. TI Hypertension, Diuretic Use, and Risk of Hearing Loss SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE Furosemide; Hearing loss; Hypertension; Prospective study; Thiazide diuretics ID FOOD FREQUENCY QUESTIONNAIRE; NUTRITION EXAMINATION SURVEY; STRIA-VASCULARIS; OLDER-ADULTS; NATIONAL-HEALTH; IMPAIRMENT; FUROSEMIDE; WOMEN; PREVALENCE; REPRODUCIBILITY AB BACKGROUND: Hearing loss is highly prevalent among adults in the United States. Hypertension also is common and often treated with diuretics. Hypertension may increase the risk of hearing loss by decreasing vascular supply to the stria vascularis. Use of thiazides has been anecdotally associated with hearing loss. In small studies, furosemide use has been associated with hearing loss that is usually reversible, but can be permanent. We investigated the relation among hypertension, diuretic use, and hearing loss in a prospective cohort of 54,721 women in the Nurses' Health Study I, 1994 to 2012. METHODS: Eligible participants included 54,721 female nurses aged 48 to 73 years in 1994 who provided information on thiazide diuretic and furosemide use in 1994, answered the question on hearing loss over their lifetime in 2012, and did not report hearing loss with date of onset before date of onset of hypertension diagnosis or medication use. The outcome was self-reported hearing loss. Cox proportional hazards regression was used to adjust for potential confounders. RESULTS: During 774,096 person-years of follow-up, 19,296 cases of hearing loss were reported (incidence rate, 25 cases per 1000 person-years). At baseline in 1994, the mean age was 57.9 years and mean body mass index was 26.3 kg/m2. Some 30.8% of participants had a history of hypertension. History of hypertension was independently associated with a modestly higher risk of hearing loss (multivariable adjusted relative risk, 1.04 [1.01-1.07]). Among women with a history of hypertension, neither thiazide diuretic (multivariable adjusted relative risk, 1.07 [0.99-1.16]) nor furosemide use (multivariable adjusted relative risk, 0.91 [0.75-1.09]) was significantly associated with risk of hearing loss when compared with women not taking antihypertensive medications. There was no significant effect modification by age. CONCLUSIONS: History of hypertension was associated with a small increased risk of hearing loss. Thiazide diuretic use and furosemide use were not associated with risk of hearing loss among women with a history of hypertension. (C) 2016 Elsevier Inc. All rights reserved. C1 [Lin, Brian M.; Stankovic, Konstantina M.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol Head & Neck Surg, Boston, MA 02114 USA. [Lin, Brian M.; Curhan, Sharon G.; Wang, Molin; Curhan, Gary C.] Brigham & Womens Hosp, Channing Div Network Med, 181 Longwood Ave, Boston, MA 02115 USA. [Lin, Brian M.; Curhan, Sharon G.; Wang, Molin; Stankovic, Konstantina M.; Curhan, Gary C.] Harvard Univ, Sch Med, Boston, MA USA. [Wang, Molin; Curhan, Gary C.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Wang, Molin] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Eavey, Roland] Vanderbilt Univ, Sch Med, Vanderbilt Bill Wilkerson Ctr Otolaryngol & Commu, Nashville, TN 37212 USA. [Curhan, Gary C.] Brigham & Womens Hosp, Dept Med, Div Renal, 75 Francis St, Boston, MA 02115 USA. RP Lin, BM (reprint author), Brigham & Womens Hosp, Channing Div Network Med, 181 Longwood Ave, Boston, MA 02115 USA. EM brian_lin@meei.harvard.edu FU National Institutes of Health [U01 DC010811, UM1 CA176726] FX This work was supported by Grants U01 DC010811 and UM1 CA176726 from the National Institutes of Health. The sponsors of this study had no role in the study design, data collection, data analysis, data interpretation, or writing of the manuscript. This study was approved by the Partners Healthcare Institutional Review Board. Completion of the self-administered questionnaire was considered implied informed consent. NR 50 TC 3 Z9 3 U1 1 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 APR PY 2016 VL 129 IS 4 BP 416 EP 422 DI 10.1016/j.amjmed.2015.11.014 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA DI4RH UT WOS:000373486500028 PM 26656761 ER PT J AU Carbo, AR Goodman, EB Totte, C Clardy, P Feinbloom, D Kim, H Kriegel, G Dierks, M Weingart, SN Sands, K Aronson, M Tess, A AF Carbo, Alexander R. Goodman, Elaine Besancon Totte, Cheryle Clardy, Peter Feinbloom, David Kim, Hans Kriegel, Gila Dierks, Meghan Weingart, Saul N. Sands, Ken Aronson, Mark Tess, Anjala TI Resident Case Review at the Departmental Level: A Win-Win Scenario SO AMERICAN JOURNAL OF MEDICINE LA English DT Review ID QUALITY IMPROVEMENT; INTERNAL-MEDICINE; PATIENT SAFETY; EXPERIENCE; MORBIDITY; PROGRAMS AB Adverse event review using root cause analysis is a cornerstone of the peer review process. As stated in the landmark Institute of Medicine publication To Err is Human, "Adequate attention and resources must be devoted to analyzing reports and taking appropriate follow-up action to hold health care organizations accountable. Sufficient attention must be devoted to analyzing and understanding the causes of errors in order to make improvements." 1 In response to this call to action and to state regulatory requirements, hospitals have established internal processes to collect events, analyze them, and report findings as they occur. Given that residents and fellows are integral members of academic medical centers, the Accreditation Council for Graduate Medical Education (ACGME) has emphasized the importance of training the future workforce in safety science as well. Originally, this was codified indirectly within the framework of 6 core competencies and within milestone reporting. 2 Through the Clinical Learning Environment Review program, institutions are now also being asked to provide opportunities for trainees to participate in hands-on investigation of events.(3-5) Despite these increased requirements for safety training, most published work in quality improvement and safety education tend to focus on resident integration into quality improvement work and medical morbidity conferences rather than event review or root cause analysis.(6-15) Few describe resident involvement in the peer review process itself.(16) In this paper we describe the structured approach to event review by residents in our Department of Medicine and share descriptive outcomes over the past several years. C1 [Carbo, Alexander R.; Totte, Cheryle; Clardy, Peter; Feinbloom, David; Kim, Hans; Kriegel, Gila; Dierks, Meghan; Sands, Ken; Aronson, Mark; Tess, Anjala] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Carbo, Alexander R.; Goodman, Elaine Besancon; Clardy, Peter; Feinbloom, David; Kim, Hans; Kriegel, Gila; Dierks, Meghan; Sands, Ken; Aronson, Mark; Tess, Anjala] Harvard Univ, Sch Med, Boston, MA USA. [Goodman, Elaine Besancon] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Weingart, Saul N.] Tufts Med Ctr, Boston, MA USA. [Weingart, Saul N.] Tufts Univ, Sch Med, Boston, MA 02111 USA. RP Carbo, AR (reprint author), Beth Israel Deaconess Med Ctr, Hosp Med Program, Span 2nd Floor,330 Brookline Ave, Boston, MA 02215 USA. EM acarbo@bidmc.harvard.edu NR 22 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 EI 1555-7162 J9 AM J MED JI Am. J. Med. PD APR PY 2016 VL 129 IS 4 BP 448 EP 452 DI 10.1016/j.amjmed.2015.12.003 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA DI4RH UT WOS:000373486500035 PM 26721634 ER PT J AU Kempen, JH Gewaily, DY Newcomb, CW Liesegang, TL Kacmaz, RO Levy-Clarke, GA Nussenblatt, RB Rosenbaum, JT Sen, HN Suhler, EB Thorne, JE Foster, CS Jabs, DA Payal, A Fitzgerald, TD AF Kempen, John H. Gewaily, Dina Y. Newcomb, Craig W. Liesegang, Teresa L. Kacmaz, R. Oktay Levy-Clarke, Grace A. Nussenblatt, Robert B. Rosenbaum, James T. Sen, H. Nida Suhler, Eric B. Thorne, Jennifer E. Foster, C. Stephen Jabs, Douglas A. Payal, Abhishek Fitzgerald, Tonetta D. CA Systemic Immunosuppressive Therapy TI Remission of Intermediate Uveitis: Incidence and Predictive Factors SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID PARS-PLANA VITRECTOMY; OCULAR INFLAMMATORY DISEASES; CLINICAL-FEATURES; PLANITIS; THERAPY; PANUVEITIS; POSTERIOR; OUTCOMES; RISK; EYE AB PURPOSE: To evaluate the incidence of remission among patients with intermediate uveitis; to identify factors potentially predictive of remission. DESIGN: Retrospective cohort study. METHODS: Involved eyes of patients with primary noninfectious intermediate uveitis at 4 academic ocular inflammation subspecialty practices, followed sufficiently long to meet the remission outcome definition, were studied retrospectively by standardized chart review data. Remission of intermediate uveitis was defined as a lack of inflammatory activity at >= 2 visits spanning >= 90 days in the absence of any corticosteroid or immunosuppressant medications. Factors potentially predictive of intermediate uveitis remission were evaluated using survival analysis. RESULTS: Among 849 eyes (of 510 patients) with intermediate uveitis followed over 1934 eye-years, the incidence of intermediate uveitis remission was 8.6/100 eye-years (95% confidence interval [CI], 7.4-10.1). Factors predictive of disease remission included prior pars plana vitrectomy (PPV) (hazard ratio [HR] [vs no PPV] = 2.39; 95% CI, 1.42-4.00), diagnosis of intermediate uveitis within the last year (HR [vs diagnosis >5 years ago] = 3.82; 95% CI, 1.91-7.63), age >= 45 years (HR [vs age <45 years] = 1.79; 95% CI, 1.03-3.11), female sex (HR = 1.61; 95% CI, 1.04-2.49), and Hispanic race/ethnicity (HR [vs white race] = 2.81; 95% CI, 1.23-6.41). Presence/absence of a systemic inflammatory disease, laterality of uveitis, and smoking status, were not associated with differential incidence. CONCLUSIONS: Our results suggest that intermediate uveitis is a chronic disease with an overall low rate of remission. Recently diagnosed patients and older, female, and Hispanic patients were more likely to remit. With regard to management, pars plana vitrectomy was associated with increased probability of remission. (C) 2016 by Elsevier Inc. All rights reserved. C1 [Kempen, John H.; Gewaily, Dina Y.; Payal, Abhishek; Fitzgerald, Tonetta D.] Univ Penn, Perelman Sch Med, Dept Ophthalmol, Philadelphia, PA 19104 USA. [Kempen, John H.; Newcomb, Craig W.] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Kempen, John H.; Newcomb, Craig W.] Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Gewaily, Dina Y.] Deglin & Greene Retinal Ctr, Wynnewood, PA USA. [Liesegang, Teresa L.; Rosenbaum, James T.; Suhler, Eric B.] Oregon Hlth & Sci Univ, Dept Ophthalmol, Portland, OR 97201 USA. [Rosenbaum, James T.; Payal, Abhishek] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97201 USA. [Kacmaz, R. Oktay; Foster, C. Stephen] Massachusetts Eye Res & Surg Inst, Waltham, MA USA. [Kacmaz, R. Oktay] Allergan Pharmaceut Inc, Dublin, Ireland. [Levy-Clarke, Grace A.; Nussenblatt, Robert B.; Sen, H. Nida] NEI, Immunol Lab, Bldg 10, Bethesda, MD 20892 USA. [Levy-Clarke, Grace A.] Tampa Bay Uveitis Ctr, Tampa, FL USA. [Rosenbaum, James T.] Devers Eye Inst, Portland, OR USA. [Suhler, Eric B.; Payal, Abhishek] Portland VA Med Ctr, Portland, OR USA. [Thorne, Jennifer E.] Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21205 USA. [Thorne, Jennifer E.; Jabs, Douglas A.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Foster, C. Stephen] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Jabs, Douglas A.] Icahn Sch Med Mt Sinai, Dept Ophthalmol, New York, NY USA. [Jabs, Douglas A.] Icahn Sch Med Mt Sinai, Dept Med, New York, NY 10029 USA. RP Kempen, JH (reprint author), Univ Penn, Dept Ophthalmol, Ctr Prevent Ophthalmol & Biostat, 3535 Market St,Suite 700, Philadelphia, PA 19104 USA. EM john.kempen@uphs.upenn.edu OI Payal, Abhishek/0000-0002-4484-8279 FU NATIONAL EYE INSTITUTE (BETHESDA, MD, USA) [EY014943]; Research to Prevent Blindness (New York, NY, USA); Paul and Evanina Mackall Foundation (New York, NY, USA); Lois Pope Life Foundation (New York, NY, USA); Veteran's Affairs Administration (Washington, DC, USA); National Eye Institute; Research to Prevent Blindness FX SUPPORTED PRIMARILY BY NATIONAL EYE INSTITUTE (BETHESDA, MD, USA) GRANT EY014943 (JOHN H. Kempen). Additional support was provided by Research to Prevent Blindness (New York, NY, USA), the Paul and Evanina Mackall Foundation (New York, NY, USA), and the Lois Pope Life Foundation (New York, NY, USA). During the course of the study, John H. Kempen was a Research to Prevent Blindness James S. Adams Special Scholar Award recipient, Jennifer E. Thorne was a Research to Prevent Blindness Harrington Special Scholar Award recipient, and Douglas A. Jabs and James T. Rosenbaum were Research to Prevent Blindness Senior Scientific Investigator Award recipients. Eric B. Suhler receives support from the Veteran's Affairs Administration (Washington, DC, USA). Grace A. Levy-Clarke was previously supported by and Robert B. Nussenblatt and H. Nida Sen continue to be supported by intramural funds of the National Eye Institute. The funding organizations had no role in the design or conduct of this research. NR 34 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 EI 1879-1891 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD APR PY 2016 VL 164 BP 110 EP 117 DI 10.1016/j.ajo.2015.12.034 PG 8 WC Ophthalmology SC Ophthalmology GA DI7CS UT WOS:000373657300014 PM 26772874 ER PT J AU Gao, S Jakobs, TC AF Gao, Shan Jakobs, Tatjana C. TI Mice Homozygous for a Deletion in the Glaucoma Susceptibility Locus INK4 Show Increased Vulnerability of Retinal Ganglion Cells to Elevated Intraocular Pressure SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID OPEN-ANGLE GLAUCOMA; OPTIC-NERVE HEAD; GENOME-WIDE ASSOCIATION; INDUCED OCULAR HYPERTENSION; MOUSE MODEL; NONCODING RNA; AQUEOUS-HUMOR; TGF-BETA; COMMON VARIANTS; GENE-EXPRESSION AB A genomic region Located on chromosome 9p21 is associated with primary open-angle glaucoma and normal tension glaucoma in genome-wide association studies. The genomic region contains the gene for a Long noncoding RNA called CDKN2B-AS, two genes that code for cyclin-dependent kinase inhibitors 2A and 2B (CDKN2A/p16(INK4A) and CDKN2B/p15(INK4B)) and an additional protein (p14(ARF)). We used a trans genic mouse model in which 70 kb of murine chromosome 4, syntenic to human chromosome 9p21, are deleted to study whether this deletion leads to a discernible phenotype in ocular structures implicated in glaucoma. Homozygous mice of this strain were previously reported to show persistent hyperplastic primary vitreous. Fundus photography and optical coherence tomography confirmed that finding but showed no abnormalities for heterozygous mice. Optokinetic response, eletroretinogram, and histology indicated that the heterozygous and mutant retinas were normal functionally and morphologically, whereas glial cells were activated in the retina and optic nerve head of mutant eyes. In quantitative PCR, CDKN2B expression was reduced by approximately 50% in the heterozygous mice and by 90% in the homozygous mice, which suggested that the CDKN2B knock down had no deleterious consequences for the retina under normal conditions. However, compared with wild-type and heterozygous animals, the homozygous mice are more vulnerable to retinal ganglion cell loss in response to elevated intraocular pressure. C1 [Gao, Shan] Xi An Jiao Tong Univ, Hlth Sci Ctr, Affiliated Hosp 1, Dept Ophthalmol, Xian 710049, Shaanxi, Peoples R China. [Gao, Shan; Jakobs, Tatjana C.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol,Schepens Eye Res Inst, Boston, MA USA. RP Jakobs, TC (reprint author), Schepens Eye Res Inst, 20 Staniford St, Boston, MA 02114 USA. EM tatjana_jakobs@meei.harvard.edu OI Jakobs, Tatjana/0000-0002-8104-9206 FU NIH [R01EY019703, R01EY022092, SP30EY003790-34]; Chinese Scholarship Council; Massachusetts Lions Eye Research Fund; Ellison Foundation FX Supported by NIH grants R01EY019703 and R01EY022092, a grant from the Chinese Scholarship Council, and grants from the Massachusetts Lions Eye Research Fund and the Ellison Foundation. The morphology core facility at the Massachusetts Eye and Ear Infirmary/Schepens Eye Research Institute is supported by the NIH core grant for vision research SP30EY003790-34. NR 99 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 0002-9440 EI 1525-2191 J9 AM J PATHOL JI Am. J. Pathol. PD APR PY 2016 VL 186 IS 4 BP 985 EP 1005 DI 10.1016/j.ajpath.2015.11.026 PG 21 WC Pathology SC Pathology GA DI3QP UT WOS:000373413900022 PM 26883755 ER PT J AU Shahrabi-Farahani, S Gallottini, M Martins, F Li, E Mudge, DR Nakayama, H Hida, K Panigrahy, D D'Amore, PA Bielenberg, DR AF Shahrabi-Farahani, Shokoufeh Gallottini, Marina Martins, Fabiana Li, Erik Mudge, Dayna R. Nakayama, Hironao Hida, Kyoko Panigrahy, Dipak D'Amore, Patricia A. Bielenberg, Diane R. TI Neuropilin 1 Receptor Is Up-Regulated in Dysplastic Epithelium and Oral Squamous Cell Carcinoma SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; SEMAPHORIN 3A; TUMOR-CELLS; PROSTATE-CANCER; UNITED-STATES; SKIN-CANCER; LYMPH-NODE; EXPRESSION; ANGIOGENESIS; IDENTIFICATION AB Neuropilins are receptors for disparate ligands, including proangiogenic factors such as vascular endothelial growth factor and inhibitory class 3 semaphorin (SEMA3) family members. Differentiated cells in skin epithelium and cutaneous squamous ceLL carcinoma highly express the neuropilin-1 (NRP1) receptor. We examined the expression of NRP1 in human and mouse oral mucosa. NRP1 was significantly up-regulated in oral epithelial dysplasia and oral squamous cell carcinoma (OSCC). NRP1 receptor localized to the outer suprabasal epithelial layers in normal tongue, an expression pattern similar to the normal skin epidermis. However, dysplastic tongue epithelium and OSCC up regulated NRP1 in basal and proliferating epithelial layers, a profile unseen in cutaneous squamous cell carcinoma. NRP1 up-regulation is observed in a mouse carcinogen-induced OSCC model and in human tongue OSCC biopsies. Human OSCC cell Lines express NRP1 protein in vitro and in mouse tongue xenografts. Sites of capillary infiltration into orthotopic OSCC tumors correlate with high NRP1 expression. HSC3 xenografts, which express the highest NRP1 Levels of the cell lines examined, showed massive intratumoral lymphangiogenesis. SEMA3A inhibited OSCC cell migration, suggesting that the NRP1 receptor was bioactive in OSCC. In conclusion, NRP1 is regulated in the oral epithelium and is selectively up-regulated during epithelial dysplasia. NRP1 may function as a reservoir to sequester proangiogenic ligands within the neoplastic compartment, thereby recruiting neovessels toward tumor cells. C1 [Shahrabi-Farahani, Shokoufeh; Li, Erik; Nakayama, Hironao; Bielenberg, Diane R.] Boston Childrens Hosp, Vasc Biol Program, Boston, MA 02115 USA. [Gallottini, Marina; Martins, Fabiana] Univ Sao Paulo, Dept Stomatol, Sch Dent, BR-05508 Sao Paulo, Brazil. [Mudge, Dayna R.; Panigrahy, Dipak] Beth Israel Deaconess Med Ctr, Ctr Vasc Biol Res, Boston, MA USA. [Nakayama, Hironao; Bielenberg, Diane R.] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Panigrahy, Dipak] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [D'Amore, Patricia A.] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Hida, Kyoko] Hokkaido Univ, Inst Med Genet, Vasc Biol, Sapporo, Hokkaido, Japan. [D'Amore, Patricia A.] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Bielenberg, DR (reprint author), Boston Childrens Hosp, 300 Longwood Ave, Boston, MA 02115 USA. EM bielenberg@childrens.harvard.edu RI gallottini, marina/B-8893-2011 OI gallottini, marina/0000-0001-6071-5110 FU Vascular Biology Program at Boston Children's Hospital; NIH National Cancer Institute; National Eye Institute [K01CA118732, R21CA155728, R01CA148633, R01EY015435]; L-Core, Center for Oral Health Research, Medical University of South Carolina - NIH National Institute of General Medical Sciences [P30GM103331] FX Supported by the Vascular Biology Program at Boston Children's Hospital and NIH National Cancer Institute and National Eye Institute grants K01CA118732 and R21CA155728 (D.R.B.), R01CA148633 (D.P.), and R01EY015435 (P.A.D.). Generation and production of the murine oral cancer tissue microarray was supported in part by the L-Core, Center for Oral Health Research, Medical University of South Carolina, funded by NIH National Institute of General Medical Sciences grant P30GM103331. NR 54 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 0002-9440 EI 1525-2191 J9 AM J PATHOL JI Am. J. Pathol. PD APR PY 2016 VL 186 IS 4 BP 1055 EP 1064 DI 10.1016/j.ajpath.2015.11.021 PG 10 WC Pathology SC Pathology GA DI3QP UT WOS:000373413900028 PM 26877262 ER PT J AU Capurso, NA Petrakis, I AF Capurso, Noah A. Petrakis, Ismene TI Dyslipidemia associated with heavy alcohol use SO AMERICAN JOURNAL ON ADDICTIONS LA English DT Article ID CORONARY-HEART-DISEASE; SEVERE HYPERTRIGLYCERIDEMIA; LIPOPROTEIN-LIPASE; RISK; CONSUMPTION; MEN; MORTALITY; DRINKING AB Background and ObjectivesAlcohol has many effects on lipid metabolism and has been associated with elevated triglycerides. The purpose of this paper is to report a case of globally dysregulated lipids secondary to alcohol use and to describe the natural history of this phenomenon after drinking cessation. MethodsWe present a case of an otherwise healthy patient (N=1) who was admitted to our facility for alcohol detoxification and found to have extreme lipid dysregulation. He was treated with benzodiazepines for alcohol withdrawal but no hypolipidemic agents were given. ResultsLipid indices self-corrected and were found to be normal following just several weeks of sobriety in the absence of treatment with any hypolipidemic agents. DiscussionThe literature regarding the effects of alcohol on lipid metabolism is briefly reviewed followed by a discussion of how these findings might apply to this patient in particular as well as implications for broader clinical practice. Conclusion and Scientific SignificanceAlcohol has the ability to dysregulate several lipid indices in addition to elevating triglycerides. The rapid resolution of dyslipidemia suggests that additional treatment may not be necessary for patients who are able to abstain from alcohol but that hypolipidemic agents may be indicated for those patients who continue to drink. Additionally, clinicians should consider checking lipid panels in patients who present with alcohol intoxication and are found to have other laboratory abnormalites or those who have risk factors for hyperlipidemia. (Am J Addict 2016;25:188-190) C1 [Capurso, Noah A.; Petrakis, Ismene] Yale Univ, Sch Med, Dept Psychiat, 300 George St,Suite 901, New Haven, CT 06511 USA. [Petrakis, Ismene] VA Connecticut Healthcare Syst, US Dept Vet Affairs, West Haven, CT USA. RP Capurso, NA (reprint author), Yale Univ, Sch Med, Dept Psychiat, 300 George St,Suite 901, New Haven, CT 06511 USA. EM noah.capurso@yale.edu NR 19 TC 0 Z9 0 U1 0 U2 3 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 APR PY 2016 VL 25 IS 3 BP 188 EP 190 DI 10.1111/ajad.12347 PG 3 WC Substance Abuse SC Substance Abuse GA DI5UA UT WOS:000373564800002 PM 26991470 ER PT J AU Freitas, CRD Malbouisson, LMS Benicio, A Negri, EM Bini, FM Massoco, CO Otsuki, DA Melo, MFV Carmona, MJC AF da Costa Freitas, Claudia Regina Sa Malbouisson, Luiz Marcelo Benicio, Anderson Negri, Elnara Marcia Bini, Filipe Minussi Massoco, Cristina Oliveira Otsuki, Denise Aya Vidal Melo, Marcos Francisco Carvalho Carmona, Maria Jose TI Lung Perfusion and Ventilation During Cardiopulmonary Bypass Reduces Early Structural Damage to Pulmonary Parenchyma SO ANESTHESIA AND ANALGESIA LA English DT Article ID MECHANICAL VENTILATION; INFLAMMATORY RESPONSE; GENERAL-ANESTHESIA; ABDOMINAL-SURGERY; TIDAL-VOLUME; INJURY; ATELECTASIS; DYSFUNCTION; HYPOTHERMIA; HYPOXEMIA AB BACKGROUND: It is unclear whether maintaining pulmonary perfusion and ventilation during cardiopulmonary bypass (CPB) reduces pulmonary inflammatory tissue injury compared with standard CPB where the lungs are not ventilated and are minimally perfused. In this study, we tested the hypothesis that maintenance of lung perfusion and ventilation during CPB decreases regional lung inflammation, which may result in less pulmonary structural damage. METHODS: Twenty-seven pigs were randomly allocated into a control group only submitted to sternotomy (n = 8), a standard CPB group (n = 9), or a lung perfusion group (n = 10), in which lung perfusion and ventilation were maintained during CPB. Hemodynamics, gas exchanges, respiratory mechanics, and systemic interleukins (ILs) were determined at baseline (T0), at the end of 90 minutes of CPB (T90), and 180 minutes after CPB (T180). Bronchoalveolar lavage (BAL) ILs were obtained at T0 and T180. Dorsal and ventral left lung tissue samples were examined for optical and electron microscopy. RESULTS: At T90, there was a transient reduction in Pao(2)/Fio(2) in CPB (126 64 mm Hg) compared with the control and lung perfusion groups (296 +/- 46 and 244 +/- 57 mm Hg; P < 0.001), returning to baseline at T180. Serum ILs were not different among the groups throughout the study, whereas there were significant increases in BAL IL-6 (P < 0.001), IL-8 (P < 0.001), and IL-10 (P < 0.001) in both CPB and lung perfusion groups compared with the control group. Polymorphonuclear counts within the lung tissue were smaller in the lung perfusion group than in the CPB group (P = 0.006). Electron microscopy demonstrated extrusion of surfactant vesicles into the alveolar spaces and thickening of the alveolar septa in the CPB group, whereas alveolar and capillary histoarchitecture was better preserved in the lung perfusion group. CONCLUSIONS: Maintenance of lung perfusion and ventilation during CPB attenuated early histologic signs of pulmonary inflammation and injury compared with standard CPB. Although increased compared with control animals, there were no differences in serum or BAL IL in animals receiving lung ventilation and perfusion during CPB compared with standard CPB. C1 [da Costa Freitas, Claudia Regina; Sa Malbouisson, Luiz Marcelo; Bini, Filipe Minussi; Otsuki, Denise Aya; Carvalho Carmona, Maria Jose] Univ Sao Paulo, Discipline Anesthesiol, LIM Lab Anesthesiol 8, Fac Med, Sao Paulo, Brazil. [Benicio, Anderson] Univ Sao Paulo, Dept Cardiothorac Surg, Inst Coracao, Fac Med,Hosp Clin, Sao Paulo, Brazil. [Negri, Elnara Marcia] Univ Sao Paulo, Dept Pathol, Fac Med, Sao Paulo, Brazil. [Massoco, Cristina Oliveira] Univ Sao Paulo, Dept Vet Pathol, Fac Med Vet, Sao Paulo, Brazil. [Vidal Melo, Marcos Francisco] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA USA. RP Carmona, MJC (reprint author), Ave Dr Eneas de Carvalho Aguiar 155,8 Andar, BR-05403001 Sao Paulo, SP, Brazil. EM maria.carmona@incor.usp.br RI Carmona, Maria Jose/G-3653-2014; massoco, cristina/N-2634-2015 OI Carmona, Maria Jose/0000-0002-3031-2924; massoco, cristina/0000-0001-8030-0609 FU Brazilian National Council for Scientific and Technological Development (CNPQ) [478485/2004-2] FX This study was supported by grants from Brazilian National Council for Scientific and Technological Development (CNPQ; grant number 478485/2004-2). NR 43 TC 1 Z9 1 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD APR PY 2016 VL 122 IS 4 BP 943 EP 952 DI 10.1213/ANE.0000000000001118 PG 10 WC Anesthesiology SC Anesthesiology GA DG8OH UT WOS:000372343000003 PM 26991612 ER PT J AU Eisenach, JC Warner, DS Houle, TT AF Eisenach, James C. Warner, David S. Houle, Timothy T. TI Reporting of Preclinical Research in Anesthesiology Transparency and Enforcement SO ANESTHESIOLOGY LA English DT Editorial Material C1 [Eisenach, James C.] Wake Forest Sch Med, Dept Anesthesiol, Winston Salem, NC 27109 USA. [Warner, David S.] Duke Univ, Sch Med, Dept Anesthesiol, Durham, NC USA. [Houle, Timothy T.] Massachusetts Gen Hosp, Dept Anaesthesiol & Crit Care, Boston, MA 02114 USA. RP Eisenach, JC (reprint author), Wake Forest Sch Med, Dept Anesthesiol, Winston Salem, NC 27109 USA. EM editor-in-chief@anesthesiology.org FU NIGMS NIH HHS [R37-GM48085, R37 GM048085] NR 13 TC 2 Z9 2 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-3022 EI 1528-1175 J9 ANESTHESIOLOGY JI Anesthesiology PD APR PY 2016 VL 124 IS 4 BP 763 EP 765 DI 10.1097/ALN.0000000000001044 PG 3 WC Anesthesiology SC Anesthesiology GA DI2TO UT WOS:000373352000008 PM 26845144 ER PT J AU Yang, YS Rivera, AJ Fortier, CR Abernathy, JH AF Yang, Yushi Rivera, Antonia Joy Fortier, Christopher R. Abernathy, James H., III TI A Human Factors Engineering Study of the Medication Delivery Process during an Anesthetic Self-filled Syringes versus Prefilled Syringes SO ANESTHESIOLOGY LA English DT Article ID PATIENT SAFETY; SYSTEMS; CARE; PERFORMANCE; WORKLOAD; QUALITY; DESIGN; ERRORS AB Background: Prefilled syringes (PFS) have been recommended by the Anesthesia Patient Safety Foundation. However, aspects in PFS systems compared with self-filled syringes (SFS) systems have never been explored. The aim of this study is to compare system vulnerabilities (SVs) in the two systems and understand the impact of PFS on medication safety and efficiency in the context of anesthesiology medication delivery in operating rooms. Methods: This study is primarily qualitative research, with a quantitative portion. A work system analysis was conducted to analyze the complicated anesthesia work system using human factors principles and identify SVs. Anesthesia providers were shadowed: (1) during general surgery cases (n = 8) exclusively using SFS and (2) during general surgery cases (n = 9) using all commercially available PFS. A proactive risk assessment focus group was followed to understand the risk of each identified SV. Results: PFS are superior to SFS in terms of the simplified work processes and the reduced number and associated risk of SVs. Eight SVs were found in the PFS system versus 21 in the SFS system. An SV example with high risk in the SFS system was a medication might need to be drawn-up during surgery while completing other requests simultaneously. This SV added cognitive complexity during anesthesiology medication delivery. However, it did not exist in the PFS system. Conclusions: The inclusion of PFS into anesthesiology medication delivery has the potential to improve system safety and work efficiency. However, there were still opportunities for further improvement by addressing the remaining SVs and newly introduced complexity. C1 [Yang, Yushi] Clemson Univ, Dept Ind Engn, Clemson, SC USA. [Rivera, Antonia Joy] Childrens Hosp Wisconsin, Dept Informat Management Serv, Milwaukee, WI 53201 USA. [Fortier, Christopher R.] Massachusetts Gen Hosp, Dept Pharm, Boston, MA 02114 USA. [Abernathy, James H., III] Med Univ S Carolina, Dept Anesthesia & Perioperat Med, Ashley River Tower, Charleston, SC 29425 USA. RP Abernathy, JH (reprint author), Med Univ S Carolina, Dept Anesthesia & Perioperat Med, Ashley River Tower, Charleston, SC 29425 USA. EM abernatj@musc.edu FU Pharmedium (Lake Forest, Illinois) FX Pharmedium (Lake Forest, Illinois) provided support in the form of an unrestricted grant to the Medical University of South Carolina (Charleston, South Carolina) to cover the costs of performing the study and analyzing the results. This funding came at the request of our group of researchers. NR 33 TC 1 Z9 1 U1 5 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-3022 EI 1528-1175 J9 ANESTHESIOLOGY JI Anesthesiology PD APR PY 2016 VL 124 IS 4 BP 795 EP 803 DI 10.1097/ALN.0000000000001040 PG 9 WC Anesthesiology SC Anesthesiology GA DI2TO UT WOS:000373352000013 PM 26845139 ER PT J AU Ladha, KS Patorno, E Huybrechts, KF Liu, J Rathmell, JP Bateman, BT AF Ladha, Karim S. Patorno, Elisabetta Huybrechts, Krista F. Liu, Jun Rathmell, James P. Bateman, Brian T. TI Variations in the Use of Perioperative Multimodal Analgesic Therapy SO ANESTHESIOLOGY LA English DT Article ID MAJOR NONCARDIAC SURGERY; POSTOPERATIVE PAIN; POSTSURGICAL PAIN; PATIENT SATISFACTION; SURGICAL-PATIENTS; NATIONAL-SURVEY; ADVERSE EVENTS; OPEN COLECTOMY; HIP FRACTURE; OUTCOMES AB Background: Practice guidelines for perioperative pain management recommend that multimodal analgesic therapy should be used for all postsurgical patients. However, the proportion of patients who actually receive this evidence-based approach is unknown. The objective of this study was to describe hospital-level patterns in the utilization of perioperative multimodal analgesia. Methods: Data for the study were obtained from the Premier Research Database. Patients undergoing below-knee amputation, open lobectomy, total knee arthroplasty, and open colectomy between 2007 and 2014 were included in the analysis. Patients were considered to have multimodal therapy if they received one or more nonopioid analgesic therapies. Mixed-effects logistic regression models were used to estimate the hospital-specific frequency of multimodal therapy use while adjusting for the case mix of patients and hospital characteristics and accounting for random variation. Results: The cohort consisted of 799,449 patients who underwent a procedure at 1 of 315 hospitals. The mean probability of receiving multimodal therapy was 90.4%, with 95% of the hospitals having a predicted probability between 42.6 and 99.2%. A secondary analysis examined whether patients received two or more nonopioid analgesics, which gave an average predicted probability of 54.2%, with 95% of the hospitals having a predicted probability between 9.3 and 93.2%. Conclusions: In this large nationwide sample of surgical admissions in the United States, the authors observed tremendous variation in the utilization of multimodal therapy not accounted for by patient or hospital characteristics. Efforts should be made to identify why there are variations in the use of multimodal analgesic therapy and to promote its adoption in appropriate patients. C1 [Ladha, Karim S.; Patorno, Elisabetta; Huybrechts, Krista F.; Liu, Jun; Bateman, Brian T.] Brigham & Womens Hosp, Div Pharmacoepidemiol & Pharmacoecon, Dept Med, 1620 Tremont St,Suite 3030, Boston, MA 02120 USA. [Ladha, Karim S.; Bateman, Brian T.] Harvard Univ, Sch Med, Dept Anesthesiol Crit Care & Pain Med, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Ladha, Karim S.] Toronto Gen Hosp, Dept Anesthesia, Toronto, ON, Canada. [Ladha, Karim S.] Univ Toronto, Toronto, ON, Canada. [Rathmell, James P.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Anesthesiol Perioperat & Pain Med, Boston, MA 02115 USA. RP Ladha, KS (reprint author), Brigham & Womens Hosp, Div Pharmacoepidemiol & Pharmacoecon, Dept Med, 1620 Tremont St,Suite 3030, Boston, MA 02120 USA. EM karim.ladha@post.harvard.edu FU Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health (Bethesda, Maryland) [K08HD075831]; National Institute of Mental Health [K01MH099141] FX This study was supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health (Bethesda, Maryland) under Award Number K08HD075831 (to Dr. Bateman); a career development grant K01MH099141 from the National Institute of Mental Health (to Dr. Huybrechts). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the National Institute of Mental Health. NR 45 TC 4 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-3022 EI 1528-1175 J9 ANESTHESIOLOGY JI Anesthesiology PD APR PY 2016 VL 124 IS 4 BP 837 EP 845 DI 10.1097/ALN.0000000000001034 PG 9 WC Anesthesiology SC Anesthesiology GA DI2TO UT WOS:000373352000017 PM 26835644 ER PT J AU Emery, MJ Groves, CC Kruse, TN Shi, C Terman, GW AF Emery, Michael J. Groves, Chase C. Kruse, Timothy N. Shi, Chen Terman, Gregory W. TI Ventilation and the Response to Hypercapnia after Morphine in Opioid-naive and Opioid-tolerant Rats SO ANESTHESIOLOGY LA English DT Article ID INDUCED RESPIRATORY DEPRESSION; ADMINISTERED MORPHINE; POSTNATAL-DEVELOPMENT; RECURRENT HYPOXIA; CHRONIC PAIN; RECEPTORS; SLEEP; OVERDOSE; MECHANISMS; ANALGESIA AB Background: Opioid-related deaths are a leading cause of accidental death, with most occurring in patients receiving chronic pain therapy. Respiratory arrest is the usual cause of death, but mechanisms increasing that risk with increased length of treatment remain unclear. Repeated administration produces tolerance to opioid analgesia, prompting increased dosing, but depression of ventilation may not gain tolerance to the same degree. This study addresses differences in the degree to which chronic morphine (1) produces tolerance to ventilatory depression versus analgesia and (2) alters the magnitude and time course of ventilatory depression. Methods: Juvenile rats received subcutaneous morphine for 3 days (n = 116) or vehicle control (n = 119) and were then tested on day 4 following one of a range of morphine doses for (a) analgesia by paw withdraw from heat or (b) respiratory parameters by plethysmography-respirometry. Results: Rats receiving chronic morphine showed significant tolerance to morphine sedation and analgesia (five times increased ED50). When sedation was achieved for all animals in a dose group (lowest effective doses: opioid-tolerant, 15 mg/kg; opioid-naive, 3 mg/kg), the opioid-tolerant showed similar magnitudes of depressed ventilation (-41.4 7.0%, mean +/- SD) and hypercapnic response (-80.9 +/- 15.7%) as found for morphine-naive (-35.5 +/- 16.9% and -67.7 +/- 15.1%, respectively). Ventilation recovered due to tidal volume without recovery of respiratory rate or hypercapnic sensitivity and more slowly in morphine-tolerant. Conclusions: In rats, gaining tolerance to morphine analgesia does not reduce ventilatory depression effects when sedated and may inhibit recovery of ventilation. C1 [Emery, Michael J.; Groves, Chase C.; Kruse, Timothy N.; Shi, Chen; Terman, Gregory W.] Univ Washington, Sch Med, Dept Anesthesiol & Pain Med, Seattle, WA 98195 USA. [Emery, Michael J.] Vet Affairs Puget Sound Hlth Care Syst, Pulm & Crit Care Med, Seattle, WA USA. RP Emery, MJ (reprint author), Univ Washington, Sch Med, Dept Anesthesiol & Pain Med, Seattle, WA 98195 USA. EM mjemery@u.washington.edu FU University of Washington Alcohol and Drug Abuse Institute (Seattle, Washington) FX This study was supported by the University of Washington Alcohol and Drug Abuse Institute (Seattle, Washington). NR 56 TC 2 Z9 2 U1 3 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-3022 EI 1528-1175 J9 ANESTHESIOLOGY JI Anesthesiology PD APR PY 2016 VL 124 IS 4 BP 945 EP 957 DI 10.1097/ALN.0000000000000997 PG 13 WC Anesthesiology SC Anesthesiology GA DI2TO UT WOS:000373352000027 PM 26734964 ER PT J AU Datta, M Via, LE Chen, W Baish, JW Xu, L Barry, CE Jain, RK AF Datta, Meenal Via, Laura E. Chen, Wei Baish, James W. Xu, Lei Barry, Clifton E., III Jain, Rakesh K. TI Mathematical Model of Oxygen Transport in Tuberculosis Granulomas SO ANNALS OF BIOMEDICAL ENGINEERING LA English DT Article DE Diffusion; Mycobacterium tuberculosis; Michaelis-Menten kinetics; Rabbit model; Pimonidazole ID MYCOBACTERIUM-BOVIS BCG; AVASCULAR TUMOR-GROWTH; IN-VITRO MODEL; NONREPLICATING PERSISTENCE; IMMUNE-RESPONSE; HYPOXIA MARKER; DRUG-DELIVERY; STRATEGIES; PIMONIDAZOLE; VASCULATURE AB Pulmonary granulomas-the hallmark of Mycobacterium tuberculosis (MTB) infection-are dense cellular lesions that often feature regions of hypoxia and necrosis, partially due to limited transport of oxygen. Low oxygen in granulomas can impair the host immune response, while MTB are able to adapt and persist in hypoxic environments. Here, we used a physiologically based mathematical model of oxygen diffusion and consumption to calculate oxygen profiles within the granuloma, assuming Michaelis-Menten kinetics. An approximate analytical solution-using a priori and newly estimated parameters from experimental data in a rabbit model of tuberculosis-was able to predict the size of hypoxic and necrotic regions in agreement with experimental results from the animal model. Such quantitative understanding of transport limitations can inform future tuberculosis therapeutic strategies that may include adjunct host-directed therapies that facilitate oxygen and drug delivery for more effective treatment. C1 [Datta, Meenal; Chen, Wei; Xu, Lei; Jain, Rakesh K.] Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Labs, Cox 7,100 Blossom St, Boston, MA 02114 USA. [Datta, Meenal; Chen, Wei; Xu, Lei; Jain, Rakesh K.] Harvard Univ, Sch Med, Cox 7,100 Blossom St, Boston, MA 02114 USA. [Datta, Meenal] Tufts Univ, Dept Chem & Biol Engn, Medford, MA 02155 USA. [Via, Laura E.; Barry, Clifton E., III] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Via, Laura E.; Barry, Clifton E., III] Univ Cape Town, Fac Hlth Sci, Dept Clin Lab Sci, ZA-7701 Cape Town, South Africa. [Chen, Wei] Sun Yat Sen Univ, Affiliated Hosp 1, Dept Pancreatobiliary Surg, Guangzhou 510080, Guangdong, Peoples R China. [Baish, James W.] Bucknell Univ, Dept Biomed, Lewisburg, PA 17837 USA. [Baish, James W.] Bucknell Univ, Dept Mech Engn, Lewisburg, PA 17837 USA. RP Jain, RK (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Labs, Cox 7,100 Blossom St, Boston, MA 02114 USA.; Jain, RK (reprint author), Harvard Univ, Sch Med, Cox 7,100 Blossom St, Boston, MA 02114 USA. EM jain@steele.mgh.harvard.edu FU Bill and Melinda Gates Foundation; Imperial College; NIH, NIAID FX We thank Drs. Jerry Meldon and Stephen Matson for their insightful comments, and Drs. Vasileios Askoxylakis, Dai Fukumura, Giorgio Seano, Triantafyllos Stylianopoulos, and Joshua Tam for their assistance in manuscript editing. We would like to acknowledge Kathleen England, Daniel Schimel, and Danielle Weiner (Tuberculosis Research Section, Laboratory of Clinical Infectious Disease, National Institutes of Health/National Institute of Allergy and Infectious Diseases) for their technical assistance in the previously performed animal studies. Thanks to Carolyn Smith (Edwin L. Steele Laboratories, Massachusetts General Hospital/Harvard Medical School) for her support in the immunohistochemistry studies. This study was supported in part by Grants from the Bill and Melinda Gates Foundation (to R.K.J.), through the Grand Challenges in Global Health Program to Douglas Young, Imperial College (to C.E.B.), and from the Intramural Research Program of the NIH, NIAID (to C.E.B). NR 56 TC 3 Z9 3 U1 3 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0090-6964 EI 1573-9686 J9 ANN BIOMED ENG JI Ann. Biomed. Eng. PD APR PY 2016 VL 44 IS 4 BP 863 EP 872 DI 10.1007/s10439-015-1415-3 PG 10 WC Engineering, Biomedical SC Engineering GA DI8HJ UT WOS:000373741800003 PM 26253038 ER PT J AU MacGillivray, TE AF MacGillivray, Thomas E. TI How I Teach Hemi-Arch Replacement SO ANNALS OF THORACIC SURGERY LA English DT Editorial Material C1 [MacGillivray, Thomas E.] Massachusetts Gen Hosp, Dept Surg, Div Cardiac Surg, Boston, MA 02114 USA. RP MacGillivray, TE (reprint author), Massachusetts Gen Hosp, Dept Surg, Div Cardiac Surg, Boston, MA 02114 USA.; MacGillivray, TE (reprint author), Massachusetts Gen Hosp, Div Cardiac Surg, 55 Fruit St,Cox 650, Boston, MA 02114 USA. EM tmacgillivray@partners.org NR 4 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 0003-4975 EI 1552-6259 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD APR PY 2016 VL 101 IS 4 BP 1251 EP 1254 DI 10.1016/j.athoracsur.2016.02.047 PG 4 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA DH1CT UT WOS:000372522700015 PM 27000566 ER PT J AU Sihag, S Kosinski, AS Gaissert, HA Wright, CD Schipper, PH AF Sihag, Smita Kosinski, Andrzej S. Gaissert, Henning A. Wright, Cameron D. Schipper, Paul H. TI Minimally Invasive Versus Open Esophagectomy for Esophageal Cancer: A Comparison of Early Surgical Outcomes From The Society of Thoracic Surgeons National Database SO ANNALS OF THORACIC SURGERY LA English DT Article ID IVOR-LEWIS ESOPHAGECTOMY; SHORT-TERM OUTCOMES; PERIOPERATIVE OUTCOMES; VOLUME; MORTALITY; LOBECTOMY AB Background. Open esophagectomy results in significant morbidity and mortality. Minimally invasive esophagectomy (MIE) has become increasingly popular at specialized centers with the aim of improving perioperative outcomes. Numerous single-institution studies suggest MIE may offer lower short-term morbidity. The two approaches are compared using a large, multi institutional database. Methods. The Society of Thoracic Surgeons (STS) National Database (v2.081) was queried for all resections performed for esophageal cancer between 2008 and 2011 (n = 3,780). Minimally invasive approaches included both transhiatal (n = 214) and Ivor Lewis (n = 600), and these were compared directly with open transhiatal (n = 1,065) and Ivor Lewis (n = 1,291) procedures, respectively. Thirty-day outcomes were examined using nonparametric statistical testing. Results. Both open and MIE groups were similar in terms of preoperative risk factors. Morbidity and all cause mortality were equivalent at 62.2% and 3.8%. MIE was associated with longer median procedure times (443.0 versus 312.0 minutes; p < 0.001), but a shorter median length of hospital stay (9.0 versus 10.0 days; p < 0.001). Patients who underwent MIE had higher rates of reoperation (9.9% versus 4.4%; p < 0.001) and empyema (4.1% versus 1.8%; p < 0.001). Open technique led to an increased rate of wound infections (6.3% versus 2.3%; p < 0.001), postoperative transfusion (18.7% versus 14.1%; p = 0.002), and ileus (4.5% versus 2.2%; p = 0.002). Propensity score-matched analysis confirmed these findings. High-and low-volume centers had similar outcomes. Conclusions. Early results from the STS National Database indicate that MIE is safe, with comparable rates of morbidity and mortality as open technique. Longer procedure times and a higher rate of reoperation following MIE may reflect a learning curve. (C) 2016 by The Society of Thoracic Surgeons C1 Massachusetts Gen Hosp, Dept Thorac Surg, Boston, MA 02114 USA. Duke Univ, Med Ctr, Dept Biostat & Bioinformat, Durham, NC USA. Duke Clin Res Inst, Durham, NC USA. Oregon Hlth & Sci Univ, Med Ctr, Dept Cardiothorac Surg, Portland, OR 97201 USA. RP Sihag, S (reprint author), 55 Fruit St,Blake 1570, Boston, MA 02114 USA. EM ssihag@partners.org FU TSFRE Research Fellowship FX This work is partially supported by a TSFRE Research Fellowship (S.S.). NR 24 TC 9 Z9 11 U1 2 U2 3 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 APR PY 2016 VL 101 IS 4 BP 1281 EP 1289 DI 10.1016/j.athoracsur.2015.09.095 PG 9 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA DH1CT UT WOS:000372522700019 PM 26704412 ER PT J AU Kozower, BD O'Brien, SM Kosinski, AS Magee, MJ Dokholyan, R Jacobs, JP Shahian, DM Wright, CD Fernandez, FG AF Kozower, Benjamin D. O'Brien, Sean M. Kosinski, Andrzej S. Magee, Mitchell J. Dokholyan, Rachel Jacobs, Jeffery P. Shahian, David M. Wright, Cameron D. Fernandez, Felix G. TI The Society of Thoracic Surgeons Composite Score for Rating Program Performance for Lobectomy for Lung Cancer SO ANNALS OF THORACIC SURGERY LA English DT Article ID MEASUREMENT TASK-FORCE; DATABASE; OUTCOMES; MORTALITY; RESECTION; QUALITY; RELIABILITY AB Background. The Society of Thoracic Surgeons (STS) has developed multidimensional composite quality measures for common cardiac surgery procedures. This first composite measure for general thoracic surgery evaluates STS participant performance for lobectomy in lung cancer patients. Methods. The STS lobectomy composite score is composed of two outcomes: risk-adjusted mortality; and any-or-none, risk-adjusted major complications. General Thoracic Surgery Database data were included from 2011 to 2014 to provide adequate sample size, and 95% Bayesian credible intervals were used to determine "star ratings." The STS participants were also compared with national benchmarks (including non-STS participants) using the National Inpatient Sample. Comparisons of discharge mortality, postoperative length of stay, and percent of stage I lung cancers resected using minimally invasive approaches are not included in star ratings but will be reported to participants in STS feedback reports. Results. The study population included 20,657 lobectomy patients from 231 participating centers. Operative mortality was 1.5%, major complication rate was 9.6%, and median postoperative length of stay was 4 days. Risk-adjusted mortality and major complication rates varied threefold from highest performing (three-star) to lowest performing (one-star) programs. Approximately 5% of participants were one star, 7% were three-star, and 88% were two-star programs. Conclusions. The STS has developed the first general thoracic surgery quality composite measure to compare programs performing lobectomy for lung cancer. This measure will be used for quality assessment and provider feedback, and will be made available for voluntary public reporting. (C) 2016 by The Society of Thoracic Surgeons C1 [Kozower, Benjamin D.] Univ Virginia, Box 800679, Charlottesville, VA 22908 USA. Duke Clin Res Inst, Durham, NC USA. Med City Dallas Hosp, Dallas, TX USA. Johns Hopkins Univ, All Childrens Hosp, St Petersburg, FL USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Emory Univ, Atlanta, GA 30322 USA. RP Kozower, BD (reprint author), Univ Virginia, Box 800679, Charlottesville, VA 22908 USA. EM bdk8g@virginia.edu NR 22 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 0003-4975 EI 1552-6259 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD APR PY 2016 VL 101 IS 4 BP 1379 EP 1387 DI 10.1016/j.athoracsur.2015.10.081 PG 9 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA DH1CT UT WOS:000372522700032 PM 26785936 ER PT J AU Park, M Shlipak, MG Thiessen-Philbrook, H Garg, AX Koyner, JL Coca, SG Parikh, CR AF Park, Meyeon Shlipak, Michael G. Thiessen-Philbrook, Heather Garg, Amit X. Koyner, Jay L. Coca, Steven G. Parikh, Chirag R. CA TRIBE-AKI Consortium TI Association of Peak Changes in Plasma Cystatin C and Creatinine With Death After Cardiac Operations SO ANNALS OF THORACIC SURGERY LA English DT Article ID GLOMERULAR-FILTRATION-RATE; ACUTE KIDNEY INJURY; SERUM CREATININE; CARDIOTHORACIC SURGERY; RISK; BIOMARKERS; EQUATION; FAILURE; MARKER AB Background. Acute kidney injury is a risk factor for death in cardiac surgical patients. Plasma cystatin C and creatinine have different temporal profiles in the postoperative setting, but the associations of simultaneous changes in both filtration markers compared with change in only one marker with prognosis after hospital discharge are not well described. Methods. This is a longitudinal study of 1,199 high-risk adult cardiac surgical patients in the TRIBE-AM (Translational Research Investigating Biomarker Endpoints for Acute Kidney Injury) Consortium who survived hospitalization. We examined in-hospital peak changes of cystatin C and creatinine in the 3 days after cardiac operations. We evaluated associations of these filtration markers with death, adjusting for demographics, operative characteristics, medical comorbidities, preoperative estimated glomerular filtration rate, preoperative urinary albumin-to-creatinine ratio, and site. Results. During the first 3 days of hospitalization, nearly twice as many patients had a 25% or higher rise in creatinine (30%) compared with a 25% or higher peak rise in cystatin C (15%). The risk of death was higher in those with elevations in cystatin C (adjusted hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.4 to 2.37) or creatinine (adjusted HR, 1.90; 95% CI, 1.32 to 2.72) compared with patients who experienced a postoperative decrease in either filtration marker. Patients who had simultaneous elevations of 25% or higher in cystatin C and creatinine were at similar adjusted risk for 3-year mortality (HR, 1.79; 95% CI, 1.03 to 3.1) as those with a 25% or higher increase in cystatin C alone (HR, 2.2; 95% CI, 1.09 to 4.47). Conclusions. Elevations in creatinine postoperatively are more common than elevations in cystatin C. However, elevations in cystatin C appeared to be associated with a higher risk of death after hospital discharge. (C) 2016 by The Society of Thoracic Surgeons C1 Univ Calif San Francisco, Div Nephrol, San Francisco, CA 94143 USA. Univ Calif San Francisco, Div Gen Internal Med, San Francisco VA Med Ctr, San Francisco, CA 94143 USA. Univ Western Ontario, Dept Med, Div Nephrol, London, ON, Canada. Inst Clin Evaluat Sci, Toronto, ON, Canada. Univ Chicago, Dept Med, Nephrol Sect, 5841 S Maryland Ave, Chicago, IL 60637 USA. Mt Sinai Sch Med, Div Nephrol, New York, NY USA. Yale Univ, Sch Med, Nephrol Sect, New Haven, CT USA. RP Park, M (reprint author), 521 Parnassus Ave,C443,Box 0532, San Francisco, CA 94143 USA. EM meyeon.park@ucsf.edu FU Institute for Clinical Evaluative Sciences; Ontario Ministry of Health and Long-Term Care; National Institutes of Health (NIH) [R01-HL085757]; NIH National Institute of Diabetes and Digestive and Kidney Diseases [K23-DK099238]; Adam Linton Chair in Kidney Health Analytics; NIH [K23-DK081616, K23-DK080132, K24-DK090203, U01-DK082185]; Abbott Diagnostics; Sekisui Diagnostics Inc FX This study was supported by the Institute for Clinical Evaluative Sciences, funded by an annual grant from the Ontario Ministry of Health and Long-Term Care. The opinions, results, and conclusions reported in this paper are those of the authors and are independent from the funding sources. No endorsement by Institute for Clinical Evaluative Sciences or the Ontario Ministry of Health and Long-Term Care is intended or should be inferred. This study was supported by National Institutes of Health (NIH) (R01-HL085757 C.R.P.) to fund the TRIBE-AKI Consortium to study novel biomarkers of AKI in cardiac surgery. Other support: NIH National Institute of Diabetes and Digestive and Kidney Diseases grant K23-DK099238 (M.P.), Adam Linton Chair in Kidney Health Analytics (A.X.G.), and NIH K23-DK081616 (J.L.K.), K23-DK080132 (S.G.C.), and K24-DK090203 (C.R.P.). S.G.C., A.X.G., and C.R.P. are also members of the NIH-sponsored Assess, Serial Evaluation, and Subsequent Sequelae in Acute Kidney Injury Consortium (U01-DK082185). The granting agencies, Abbott Diagnostics and Sekisui Diagnostics Inc, did not participate in the design or conduct of the study, collection, management, analysis, interpretation of data, or preparation, review, or approval of the manuscript. NR 21 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 APR PY 2016 VL 101 IS 4 BP 1395 EP 1401 DI 10.1016/j.athoracsur.2015.12.010 PG 7 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA DH1CT UT WOS:000372522700034 PM 26921980 ER PT J AU Allen, MS Calhoon, JH Fullerton, D Shemin, R Naunheim, K Verrier, E Doty, J Mathisen, DJ AF Allen, Mark S. Calhoon, John H. Fullerton, David Shemin, Richard Naunheim, Keith Verrier, Edward Doty, John Mathisen, Douglas J. TI Outcome of the Joint Council of Thoracic Surgery Education's Early Review Course Project SO ANNALS OF THORACIC SURGERY LA English DT Article ID PERFORMANCE AB Background. The Joint Council on Thoracic Surgical Education was formed in 2008 to improve cardiothoracic education. Resident learning has been a concern as reflected in declining passing rates on the American Board of Thoracic Surgery examinations. The Joint Council on Thoracic Surgical Education piloted a program to determine whether early exposure to a cardiothoracic curriculum through participation in a board review course would improve learning. The purpose of this paper is to report the results of this project. Methods. Residents from the incoming classes of traditional 5-2 or 5-3 cardiothoracic training programs were randomly selected to attend a 3-day board review course (University of Utah) in September of their first year. For the 2012 and 2013 classes of cardiothoracic residents, we asked all incoming residents to take the prior spring in-training examination in July of their first year and then take the in-training examination in the spring of their first year. We combined the results of the incoming class of 2012 and 2013 and analyzed the results. Results. There were 171 residents who participated in either 2012 or 2013. There were 38 residents (78.9% were men) who attended the board review course and 133 (79.7% men) who did not. Questionnaires completed by the program directors and the residents who took the review course showed a favorable opinion of the program. The number of correct answers on the in-training examination, the percentage correct, and the percentile rank score increased more for the residents who took the review course, but was not statistically significant. When only the general thoracic surgery questions were analyzed, there was a statistically significant increase in the rank change between residents who attended the review course and residents who did not (8.4% increase versus 2.0% decrease, respectively; p = 0.042, Student t test). Conclusions. This pilot study established for the first time the baseline level of knowledge of incoming residents assessed by the in-training examination. Participation in a board review type course early in the residency training program may increase learning by cardiothoracic residents, but there was not a clear statistical difference between the two groups. The program was viewed as favorable by both the participating residents and the program directors. (C) 2016 by The Society of Thoracic Surgeons C1 Mayo Clin, Dept Surg, Div Gen Thorac Surg, Rochester, MN USA. Univ Texas Hlth Sci Ctr San Antonio, Dept Cardiothorac Surg, San Antonio, TX 78229 USA. Univ Colorado Denver, Aurora, CO USA. Univ Calif Los Angeles, Div Cardiac Surg, Los Angeles, CA USA. St Louis Univ, Hlth Sci Ctr, Div Thorac Surg, St Louis, MO 63103 USA. Univ Washington, Div Cardiothorac Surg, Seattle, WA 98195 USA. Intermt Med Ctr, Murray, UT USA. Massachusetts Gen Hosp, Div Thorac Surg, Boston, MA 02114 USA. RP Allen, MS (reprint author), Mayo Clin, Div Gen Thorac Surg, 200 First St SW, Rochester, MN 55905 USA. EM allen.mark@mayo.edu FU Joint Council on Thoracic Surgical Education FX This study was supported by a grant from the Joint Council on Thoracic Surgical Education. NR 8 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 0003-4975 EI 1552-6259 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD APR PY 2016 VL 101 IS 4 BP 1564 EP 1568 DI 10.1016/j.athoracsur.2015.11.027 PG 5 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA DH1CT UT WOS:000372522700057 PM 26897319 ER PT J AU Naqvi, M Muniappan, A Modest, V Mathisen, DJ Madapu, M Bryant, A Kaimal, A AF Naqvi, Mariam Muniappan, Ashok Modest, Vicki Mathisen, Douglas J. Madapu, Manokanth Bryant, Allison Kaimal, Anjali TI Tracheal Resection for Symptomatic Tracheal Stenosis During Pregnancy SO ANNALS OF THORACIC SURGERY LA English DT Editorial Material ID PARTURIENT AB A 31-year-old multipara was diagnosed with tracheal stenosis that developed after intubation after an intentional benzodiazepine overdose in the first trimester of pregnancy. Tracheal dilations only temporarily improved her dyspnea at rest. A definitive repair by tracheal resection and reconstruction was performed at 28 weeks' gestation. Her symptoms resolved, and she delivered vaginally at 36 weeks' gestation after spontaneous labor. (C) 2016 by The Society of Thoracic Surgeons C1 Massachusetts Gen Hosp, Dept Surg, Dept Obstet & Gynecol, Div Maternal Fetal Med,Div Thorac Surg, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Anesthesiol, Boston, MA 02114 USA. RP Naqvi, M (reprint author), 55 Fruit St,Founders 460, Boston, MA 02114 USA. EM mnaqvi@partners.org 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 APR PY 2016 VL 101 IS 4 BP 1589 EP 1591 DI 10.1016/j.athoracsur.2015.05.134 PG 4 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA DH1CT UT WOS:000372522700068 PM 27000585 ER PT J AU Sng, GGR Wright, CD AF Sng, Gerald G. R. Wright, Cameron D. TI An Aneurysmal Abdominal Aortic Branch Supplying an Intralobar Pulmonary Sequestration SO ANNALS OF THORACIC SURGERY LA English DT Editorial Material C1 [Sng, Gerald G. R.] Natl Univ Singapore, Yong Loo Lin Sch Med, 1E Kent Ridge Rd, Singapore 119228, Singapore. Massachusetts Gen Hosp, Div Thorac Surg, Boston, MA 02114 USA. RP Sng, GGR (reprint author), Natl Univ Singapore, Yong Loo Lin Sch Med, 1E Kent Ridge Rd, Singapore 119228, Singapore. EM geraldsng@gmail.com 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 0003-4975 EI 1552-6259 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD APR PY 2016 VL 101 IS 4 BP E123 EP E123 DI 10.1016/j.athoracsur.2015.11.012 PG 1 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA DH1CT UT WOS:000372522700009 PM 27000616 ER PT J AU Sholl, LM Aisner, DL Allen, TC Beasley, MB Borczuk, AC Cagle, PT Capelozzi, V Dacic, S Hariri, L Kerr, KM Lantuejoul, S Mino-Kenudson, M Raparia, K Rekhtman, N Roy-Chowdhuri, S Thunnissen, E Tsao, MS Yatabe, Y AF Sholl, Lynette M. Aisner, Dara L. Allen, Timothy Craig Beasley, Mary Beth Borczuk, Alain C. Cagle, Philip T. Capelozzi, Vera Dacic, Sanja Hariri, Lida Kerr, Keith M. Lantuejoul, Sylvie Mino-Kenudson, Mari Raparia, Kirtee Rekhtman, Natasha Roy-Chowdhuri, Sinchita Thunnissen, Eric Tsao, Ming Sound Yatabe, Yasushi CA Pulm Pathology Soc TI Programmed Death Ligand-1 Immunohistochemistry-A New Challenge for Pathologists A Perspective From Members of the Pulmonary Pathology Society SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article ID CELL LUNG-CANCER; PD-1 BLOCKADE; ANTIBODY; IMMUNOTHERAPY; EXPRESSION; NIVOLUMAB; DOCETAXEL AB The binding of programmed death ligand-1 and ligand-2 (PD-L1 and PD-L2) to PD-1 blocks T-cell-mediated immune response to tumor. Antibodies that target programmed death receptor-1 (PD-1) will block the ligand-receptor interface, thereby allowing T cells to attack the tumor and increase antitumor immune response. In clinical trials, PD-1 inhibitors have been associated with an approximately 20% overall response rate in unselected patients with non-small cell lung cancer, with sustained tumor response in a subset of patients treated by these immune checkpoint inhibitors. Facing a proliferation of PD-L1 immunohistochemistry clones, staining platforms, and scoring criteria, the pathologist must decide on the feasibility of introducing a newly approved companion diagnostic assay that may require purchase not only of a specific antibody kit but of a particular staining platform. Given the likely reality that clinical practice may, in the near future, demand access to 4 different PD-L1 antibodies coupled with different immunohistochemistry platforms, laboratories will be challenged with deciding among this variety of testing methods, each with its own potential benefits. Another immediate challenge to PD-L1 testing in lung cancer patients is that of access to adequate tumor tissue, given that non-small cell lung cancer samples are often extremely limited in size. With PD-L1 testing it has become clear that the historically used US regulatory approach of one assay-one drug will not be sustainable. One evolving concept is that of complementary diagnostics, a novel regulatory pathway initiated by the US Food and Drug Administration, which is distinct from companion diagnostics in that it may present additional flexibility. Although pathologists need to face the practical reality that oncologists will be asking regularly for the PD-L1 immunohistochemistry status of their patients' tumors, we should also keep in mind that there may be room for improvement of biomarkers for immunotherapy response. The field is rich with opportunities for investigation into biomarkers of immunotherapy response, particularly in the form of collaborative, multidisciplinary studies that incorporate oncologists, pathologists, and basic scientists. Pathologists must take the lead in the rational incorporation of these biomarkers into clinical practice. C1 [Sholl, Lynette M.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Sholl, Lynette M.; Hariri, Lida; Mino-Kenudson, Mari] Harvard Univ, Sch Med, 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. [Borczuk, Alain C.; 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] Univ Sao Paulo, Sch Med, Dept Pathol, Sao Paulo, Brazil. [Dacic, Sanja] Univ Pittsburgh, Med Ctr, Dept Pathol, Pittsburgh, PA USA. [Hariri, Lida; Mino-Kenudson, Mari] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Kerr, Keith M.] Univ Aberdeen, Sch Med, Dept Pathol, Aberdeen AB9 2ZD, Scotland. [Kerr, Keith M.] Aberdeen Royal Infirm, Aberdeen, Scotland. [Lantuejoul, Sylvie] Ctr Leon Berard, Dept Biopathol, F-69373 Lyon, France. [Lantuejoul, Sylvie] Univ Grenoble 1, Inst Bonniot A, INSERM, U 823, Grenoble, France. [Raparia, Kirtee] Northwestern Univ, Dept Pathol, Feinberg Sch Med, 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 Sound] Princess Margaret Canc Ctr, Univ Hlth Network, Dept Pathol, Toronto, ON, Canada. [Tsao, Ming Sound] Univ Toronto, Toronto, ON, Canada. [Yatabe, Yasushi] Aichi Canc Ctr, Dept Pathol & Mol Diagnost, Nagoya, Aichi 464, Japan. RP Allen, TC (reprint author), Univ Texas Med Branch, Dept Pathol, 301 Univ Blvd, Galveston, TX 77555 USA. EM tcallen@utmb.edu FU Astra-Zeneca; Roche-Genentech; Bristol-Myers Squibb; Merck; Pfizer FX Dr Sholl received consultancy honoraria from Genentech. Dr Rekhtman received consultancy honoraria from Bristol-Myers Squibb. Dr Beasley is a member of the Genentech Scientific Advisory Board. Dr Kerr receives lecture fees and/or advisory fees from Astra-Zeneca, Roche-Genentech, Bristol-Myers Squibb, Merck, and Pfizer. Dr Tsao received consultancy honoraria from Pfizer, Merck Canada, AstraZeneca, and Roche-Genentech. Dr Thunnissen is on the Global Advisory Board for Merck and only receives cost for travel. The other authors have no relevant financial interest in the products or companies described in this article. NR 22 TC 12 Z9 13 U1 2 U2 8 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 APR PY 2016 VL 140 IS 4 BP 341 EP 344 DI 10.5858/arpa.2015-0506-SA PG 4 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA DI7TJ UT WOS:000373704600010 PM 26780537 ER PT J AU Balasubramanian, CK Li, CY Bowden, MG Duncan, PW Kautz, SA Velozo, CA AF Balasubramanian, Chitralakshmi K. Li, Chih-Ying Bowden, Mark G. Duncan, Pamela W. Kautz, Steven A. Velozo, Craig A. TI Dimensionality and Item-Difficulty Hierarchy of the Lower Extremity Fugl-Meyer Assessment in Individuals With Subacute and Chronic Stroke SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article DE Lower extremity; Rehabilitation; Stroke ID ASSESSMENT SCALE; HEMIPLEGIC PATIENT; OUTCOME MEASURES; MOTOR RECOVERY; PERFORMANCE; POSTSTROKE; WALKING; REHABILITATION; COORDINATION; RELIABILITY AB Objective: To investigate the dimensionality and item-difficulty hierarchy of the Fugl-Meyer Assessment of the lower extremity (FMA-LE). Design: Secondary analyses of data pooled from 4 existing datasets: a phase III randomized controlled trial investigating the effectiveness of body weight support and a treadmill for rehabilitation of walking poststroke, and 3 cross-sectional studies investigating the link between impaired motor performance poststroke and walking. Setting: University research centers and rehabilitation centers. Participants: A pooled sample of individuals with a stroke (N=535, men = 313; mean age +/- SD, 61.91 +/- 12.42y). Interventions: Not applicable. Main Outcome Measures: Confirmatory factor analyses (CFA) and Rasch residual principal component analysis (PCA) investigated the dimensionality of the FMA-LE. The Rasch analysis rating scale model investigated item-difficulty hierarchy of the FMA-LE. Results: The CFA showed adequate fit of a 3-factor model, with 2 out of 3 indices (CFA=.95; Tucker-Lewis Index=.94; root mean square error of approximation=.124) showing good model fit. Rasch PCA showed that removal of the reflex and coordination items explained 90.8% of variance in the data, suggesting that the abnormal synergy items contributed to the measurement of a unidimensional construct. However, rating scale model results revealed deviations in the item-difficulty hierarchy of the unidimensional abnormal synergy items from the originally proposed stepwise sequence of motor recovery. Conclusions: Our findings suggest that the FMA-LE might represent a multidimensional construct, challenging the use of a total score of the FMA-LE to predict lower extremity motor recovery. Removal of the misfit items resulted in creation of a unidimensional scale composed of the abnormal synergy items. However, this unidimensional scale deviates from the originally proposed hierarchical ordering. (C) 2016 by the American Congress of Rehabilitation Medicine C1 [Balasubramanian, Chitralakshmi K.] Univ N Florida, Dept Clin & Appl Movement Sci, 1 UNF Dr, Jacksonville, FL 32224 USA. [Li, Chih-Ying; Bowden, Mark G.; Kautz, Steven A.] Med Univ S Carolina, Coll Hlth Profess, Dept Hlth Sci & Res, Charleston, SC 29425 USA. [Li, Chih-Ying; Bowden, Mark G.; Kautz, Steven A.] Med Univ S Carolina, Coll Hlth Profess, Div Phys Therapy, Charleston, SC 29425 USA. [Bowden, Mark G.; Kautz, Steven A.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. [Duncan, Pamela W.] Wake Forest Univ, Dept Neurol, Winston Salem, NC 27109 USA. [Velozo, Craig A.] Med Univ S Carolina, Coll Hlth Profess, Div Occupat Therapy, Charleston, SC 29425 USA. RP Balasubramanian, CK (reprint author), Univ N Florida, Dept Clin & Appl Movement Sci, 1 UNF Dr, Jacksonville, FL 32224 USA. EM c.k-balasubramanian@unf.edu FU National Institute of Neurologic Diseases and Stroke; National Center for Medical Rehabilitation Research [RO1 NS050506]; National Institutes of Health [HD46820]; Rehabilitation Research and Development Service of the U.S. Department of Veterans Affairs [B2748R]; Institutional Development Award from the National Institute of General Medical Sciences of the National Institutes of Health [P20-GM109040] FX Support for study 1 by the National Institute of Neurologic Diseases and Stroke and the National Center for Medical Rehabilitation Research (grant no. RO1 NS050506); for study 2, by the National Institutes of Health (grant no. HD46820); for study 3, by the Rehabilitation Research and Development Service of the U.S. Department of Veterans Affairs (grant no. B2748R); and for study 4, by an Institutional Development Award from the National Institute of General Medical Sciences of the National Institutes of Health (grant no. P20-GM109040). NR 47 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 0003-9993 EI 1532-821X J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD APR PY 2016 VL 97 IS 4 BP 582 EP 589 DI 10.1016/j.apmr.2015.12.012 PG 8 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA DI5EM UT WOS:000373521700012 PM 26740065 ER PT J AU Moreno, F Dussel, V Orellana, L AF Moreno, Florencia Dussel, Veronica Orellana, Liliana CA ROHA Network TI Childhood cancer in Argentina: Survival 2000-2007 (vol 39, pg 505, 2015) SO CANCER EPIDEMIOLOGY LA English DT Correction C1 [Moreno, Florencia] Natl Canc Inst, Argentinean Oncopaediat Registry, Buenos Aires, DF, Argentina. [Dussel, Veronica] Ctr Res & Implementat Palliat Care, Inst Clin Effectiveness & Hlth Policy, Buenos Aires, DF, Argentina. [Dussel, Veronica] Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, Boston, MA 02115 USA. [Orellana, Liliana] Natl Canc Inst, Buenos Aires, DF, Argentina. [Orellana, Liliana] Deakin Univ, Fac Hlth, Biostat Unit, Burwood, Australia. RP Moreno, F (reprint author), Natl Canc Inst, Argentinean Oncopaediat Registry ROHA, Av Julio A Roca 781 10th Floor, Buenos Aires, DF, Argentina. EM roha@roha.org.ar; veronica_dussel@dfci.harvard.edu; l.orellana@deakin.edu.au RI Orellana, Liliana/S-3302-2016 OI Orellana, Liliana/0000-0003-3736-4337 NR 1 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 1877-7821 EI 1877-783X J9 CANCER EPIDEMIOL JI Cancer Epidemiol. PD APR PY 2016 VL 41 BP 165 EP 165 DI 10.1016/j.canep.2015.11.011 PG 1 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DI7ZZ UT WOS:000373721800023 ER PT J AU Rebbeck, TR AF Rebbeck, Timothy R. TI Defining Priorities for Reducing Disparities in Cancer Mortality SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Editorial Material C1 [Rebbeck, Timothy R.] Dana Farber Canc Inst, 1101 Dana Bldg,450 Brookline Ave, Boston, MA 02215 USA. [Rebbeck, Timothy R.] Harvard Univ, TH Chan Sch Publ Hlth, 1101 Dana Bldg,450 Brookline Ave, Boston, MA 02215 USA. RP Rebbeck, TR (reprint author), Dana Farber Canc Inst, 1101 Dana Bldg,450 Brookline Ave, Boston, MA 02215 USA.; Rebbeck, TR (reprint author), Harvard Univ, TH Chan Sch Publ Hlth, 1101 Dana Bldg,450 Brookline Ave, Boston, MA 02215 USA. EM Timothy_Rebbeck@dfci.harvard.edu NR 2 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2016 VL 25 IS 4 BP 570 EP 572 DI 10.1158/1055-9965.EPI-15-1244 PG 3 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DI4RB UT WOS:000373485900001 PM 27196088 ER PT J AU Nagler, RH Bigman, CA Ramanadhan, S Ramamurthi, D Viswanath, K AF Nagler, Rebekah H. Bigman, Cabral A. Ramanadhan, Shoba Ramamurthi, Divya Viswanath, K. TI Prevalence and Framing of Health Disparities in Local Print News: Implications for Multilevel Interventions to Address Cancer Inequalities SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID NEWSPAPER CONTENT-ANALYSIS; SOCIAL DETERMINANTS; BLACK NEWSPAPERS; COMMUNITY TIES; COVERAGE; MEDIA; JOURNALISTS; INTEGRATION; TELEVISION; STRATEGIES AB Background: Americans remain under-informed about cancer and other health disparities and the social determinants of health (SDH). The news media may be contributing to this knowledge deficit, whether by discussing these issues narrowly or ignoring them altogether. Because local media are particularly important in influencing public opinion and support for public policies, this study examines the prevalence and framing of disparities/SDH in local mainstream and ethnic print news. Methods: We conducted a multi-method content analysis of local mainstream (English language) and ethnic (Spanish language) print news in two lower income cities in New England with substantial racial/ethnic minority populations. After establishing intercoder reliability (kappa = 0.63-0.88), coders reviewed the primary English and Spanish language newspaper in each city, identifying both disparities and non-disparities health stories published between February 2010 and January 2011. Results: Local print news coverage of cancer and other health disparities was rare. Of 650 health stories published across four newspapers during the one-year study period, only 21 (3.2%) discussed disparities/SDH. Although some stories identified causes of and solutions for disparities, these were often framed in individual (e.g., poor dietary habits) rather than social contextual terms (e.g., lack of food availability/affordability). Cancer and other health stories routinely missed opportunities to discuss disparities/SDH. Conclusion: Local mainstream and ethnic media may be ideal targets for multilevel interventions designed to address cancer and other health inequalities. Impact: By increasing media attention to and framing of health disparities, we may observe important downstream effects on public opinion and support for structural solutions to disparities, particularly at the local level. (C) 2016 AACR. C1 [Nagler, Rebekah H.] Univ Minnesota, Sch Journalism & Mass Commun, 111 Murphy Hall,206 Church St SE, Minneapolis, MN 55455 USA. [Bigman, Cabral A.] Univ Illinois, Dept Commun, Urbana, IL 61801 USA. [Ramanadhan, Shoba; Viswanath, K.] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. [Ramanadhan, Shoba; Viswanath, K.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02115 USA. [Ramamurthi, Divya] Stanford Sch Med, Stanford Res Impact Tobacco Advertising, Palo Alto, CA USA. RP Nagler, RH (reprint author), Univ Minnesota, Sch Journalism & Mass Commun, 111 Murphy Hall,206 Church St SE, Minneapolis, MN 55455 USA. EM nagle026@umn.edu FU NCI at the NIH [5 P50-CA148596]; NCI through the Harvard Education Program in Cancer Prevention [3 R25-CA057711]; Building Interdisciplinary Research Careers in Women's Health Grant from the Eunice Kennedy Shriver National Institutes of Child Health and Human Development; Office of Research on Women's Health; National Institute on Aging, administered by the University of Minnesota Deborah E. Powell Center for Women's Health [2 K12-HD055887]; Yerby postdoctoral fellowship at the Harvard T.H. Chan School of Public Health FX This work was supported by the NCI at the NIH [grant number 5 P50-CA148596 to K. Viswanath (principal investigator for Project 1)]. Funding support for R.H. Nagler was provided by the NCI through the Harvard Education Program in Cancer Prevention (grant number 3 R25-CA057711). R.H. Nagler also acknowledges support from the Building Interdisciplinary Research Careers in Women's Health Grant 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 (grant number 2 K12-HD055887). C.A. Bigman acknowledges support from the Yerby postdoctoral fellowship at the Harvard T.H. Chan School of Public Health. NR 55 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2016 VL 25 IS 4 BP 603 EP 612 DI 10.1158/1055-9965.EPI-15-1247 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DI4RB UT WOS:000373485900007 PM 27196094 ER PT J AU Yamashita, T Koretsune, Y Yang, YJ Chen, SA Chung, N Shimada, YJ Kimura, T Miyazaki, K Abe, K Mercuri, M Ruff, CT Giugliano, RP AF Yamashita, Takeshi Koretsune, Yukihiro Yang, Yuejin Chen, Shih-Ann Chung, Namsik Shimada, Yuichi J. Kimura, Tetsuya Miyazaki, Koichi Abe, Kenji Mercuri, Michele Ruff, Christian T. Giugliano, Robert P. TI Edoxaban vs. Warfarin in East Asian Patients With Atrial Fibrillation - An ENGAGE AF-TIMI 48 Subanalysis - SO CIRCULATION JOURNAL LA English DT Article DE Anticoagulant; Asian; Atrial fibrillation; Edoxaban; Factor Xa inhibitor ID FACTOR XA INHIBITOR; INTERNATIONAL NORMALIZED RATIO; J-RHYTHM REGISTRY; JAPANESE PATIENTS; RISK-FACTORS; ROCKET AF; RIVAROXABAN; PREVALENCE; STROKE; POPULATION AB Background: In the multinational, double-blind, double-dummy ENGAGE AF-TIMI 48 phase 3 study, once-daily edoxaban was non-inferior to warfarin for prevention of stroke or systemic embolism event (SEE) in patients with non-valvular atrial fibrillation (AF). Here, we evaluated the efficacy and safety of edoxaban in patients from East Asia. Methods and Results: Patients aged >= 21 years with documented AF and CHADS score >= 2 were randomized to receive once-daily edoxaban higher-dose (60 mg) or lower-dose (30 mg) regimen or warfarin dose-adjusted to an international normalized ratio of 2.0-3.0. Patients with a creatinine clearance of 30-50 ml/min, weighing <= 60 kg, or receiving strong p-glycoprotein inhibitors at randomization or during the study received a 50% dose reduction of edoxaban or matched placebo. This prespecified subanalysis included 1,943 patients from Japan, China, Taiwan, and South Korea. The annualized rate of stroke/SEE for higher-dose edoxaban was 1.34% vs. 2.62% for warfarin (hazard ratio [HR], 0.53; 95% confidence interval [CI]: 0.31-0.90, P=0.02) and 2.52% for lower-dose edoxaban (HR, 0.98; 95% CI: 0.63-1.54, P=0.93). Compared with warfarin (4.80%), major bleeding was significantly reduced for the higher-dose (2.86%; HR, 0.61; 95% CI: 0.41-0.89, P=0.011) and lower-dose regimens (1.59%; HR, 0.34; 95% CI: 0.21-0.54, P<0.001). Conclusions: Once-daily edoxaban provided similar efficacy to warfarin while reducing major bleeding risk in the East Asian population. C1 [Yamashita, Takeshi] Cardiovasc Inst, Tokyo, Japan. [Koretsune, Yukihiro] Osaka Natl Hosp, Natl Hosp Org, Clin Res Inst, Osaka, Japan. [Yang, Yuejin] Chinese Acad Med Sci, Cardiovasc Inst, Beijing 100730, Peoples R China. [Yang, Yuejin] Chinese Acad Med Sci, Natl Ctr Cardiovasc Dis, Fuwai Hosp, Beijing 100730, Peoples R China. [Yang, Yuejin] Peking Union Med Coll, Beijing 100021, Peoples R China. [Chen, Shih-Ann] Taipei Vet Gen Hosp, Taipei, Taiwan. [Chung, Namsik] Yonsei Univ, Coll Med, Severance Hosp, Seoul 120749, South Korea. [Shimada, Yuichi J.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Kimura, Tetsuya; Miyazaki, Koichi; Abe, Kenji] Daiichi Sankyo Co Ltd, Tokyo, Japan. [Mercuri, Michele] Daiichi Sankyo Pharma Dev, Edison, NJ USA. [Ruff, Christian T.; Giugliano, Robert P.] Brigham & Womens Hosp, TIMI Study Grp, 75 Francis St, Boston, MA 02115 USA. RP Yamashita, T (reprint author), Cardiovasc Inst, Minato Ku, 3-2-19 Nishiazabu, Tokyo 1060031, Japan. EM yamt-tky@umin.ac.jp OI Shimada, Yuichi/0000-0002-3494-307X FU Daiichi Sankyo Co, Ltd (Tokyo, Japan); Daiichi Sankyo FX This study was sponsored by Daiichi Sankyo Co, Ltd (Tokyo, Japan). Medical writing and editorial support was provided by Terri Schochet, PhD, and Meryl Gersh, PhD, of AlphaBioCom, LLC (King of Prussia, PA, USA), and funded by Daiichi Sankyo. NR 23 TC 11 Z9 11 U1 0 U2 1 PU JAPANESE CIRCULATION SOC PI TOYKO PA 18TH FLOOR IMPERIAL HOTEL TOWER, 1-1-1 UCHISAIWAI-CHO CHIYODA-KU, TOYKO, 100-0011, JAPAN SN 1346-9843 EI 1347-4820 J9 CIRC J JI Circ. J. PD APR PY 2016 VL 80 IS 4 BP 860 EP + DI 10.1253/circj.CJ-15-1082 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DI3MD UT WOS:000373401900016 PM 26888149 ER PT J AU Melanson, SEF Griggs, D Bixho, I Khaliq, T Flood, JG AF Melanson, Stacy E. F. Griggs, David Bixho, Ida Khaliq, Tahira Flood, James G. TI 7-Aminoclonazepam is superior to clonazepam for detection of clonazepam use in oral fluid by LC-MS/MS SO CLINICA CHIMICA ACTA LA English DT Article DE Oral fluid; Clonazepam; 7-Aminoclonazepam; Addiction management; Compliance ID TANDEM MASS-SPECTROMETRY; MS-MS; DRUGS; ABUSE; BENZODIAZEPINES; URINE; SAMPLES; MATRIX AB Background: Clonazepam (CLON) is not only frequently prescribed in addiction management but is also commonly abused. Therefore many addiction clinics perform oral fluid (OF) testing, which unlike urine is not subject to adulteration, to monitor CLON compliance. However, CLON and other benzodiazepines can be challenging to detect in OF due to their weakly acidic nature and their presence in low concentrations. We determined the optimal technical and clinical approach for the detection of CLON use using OF. Methods: We measured CLON and its primary metabolite 7-aminoclonazepam (7AC) by liquid chromatography tandem mass spectrometry in OF specimens over a 2 month period. The samples were collected using the Orasure Intercept OF sample collection device. Results: One hundred samples were presumptive-positive for 7AC and/or CLON. 91(91.0%) confirmed positive for 7AC (median, range: 42, 0.5-316.7 ng/ml) using the ion ratio test, while only 44 of the 100 (44.0%) samples confirmed positive for CLON (median, range: 3.7, 0.5-217.2 ng/ml) using the ion ratio test. In OF the levels of 7AC were approximately 2.4-fold higher than CLON. The use of 7AC as an analyte for the detection of both CLON compliance and undisclosed use is also recommended. Conclusions: 7AC should be the analyte measured in OF for the detection of CLON use. (C) 2016 Elsevier B.V. All rights reserved. C1 [Melanson, Stacy E. F.; Bixho, Ida] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol,Clin Labs Div, 75 Francis St, Boston, MA 02115 USA. [Griggs, David; Khaliq, Tahira; Flood, James G.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St, Boston, MA 02114 USA. RP Melanson, SEF (reprint author), Brigham & Womens Hosp, 75 Francis St,Amory 2, Boston, MA 02115 USA. EM semelanson@partners.org NR 20 TC 0 Z9 0 U1 2 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0009-8981 EI 1873-3492 J9 CLIN CHIM ACTA JI Clin. Chim. Acta PD APR 1 PY 2016 VL 455 BP 128 EP 133 DI 10.1016/j.cca.2016.01.027 PG 6 WC Medical Laboratory Technology SC Medical Laboratory Technology GA DI7BW UT WOS:000373655100023 PM 26826393 ER PT J AU Freedman, RA Kouri, EM West, DW Rosenberg, S Partridge, AH Lii, J Keating, NL AF Freedman, Rachel A. Kouri, Elena M. West, Dee W. Rosenberg, Shoshana Partridge, Ann H. Lii, Joyce Keating, Nancy L. TI Higher Stage of Disease Is Associated With Bilateral Mastectomy Among Patients With Breast Cancer: A Population-Based Survey SO CLINICAL BREAST CANCER LA English DT Article DE Bilateral mastectomy; Breast cancer; Contralateral prophylactic mastectomy; Reconstruction; Stage ID CONTRALATERAL PROPHYLACTIC MASTECTOMY; CARCINOMA-IN-SITU; YOUNG-WOMEN; FOLLOW-UP; SURGICAL-TREATMENT; FAMILY-HISTORY; INCREASING USE; RECONSTRUCTION; TRENDS; KNOWLEDGE AB We examined factors that were associated with bilateral mastectomy and reconstruction in a population-based survey. In addition to other previously described factors, having stage III disease (vs. stage 0) was associated with bilateral mastectomy. Given the lack of clear medical benefit for this procedure, our findings highlight the need for interventions to assure women are making informed surgical decisions. Background: The reasons for increasing rates of bilateral mastectomy for unilateral breast cancer are incompletely understood, and associations of disease stage with bilateral surgery have been inconsistent. We examined associations of clinical and sociodemographic factors, including stage, with surgery type and reconstruction receipt among women with breast cancer. Patients and Methods: We surveyed a diverse population-based sample of women from Northern California cancer registries with stage 0 to III breast cancer diagnosed during 2010-2011 (participation rate, 68.5%). Using multinomial logistic regression, we examined factors associated with bilateral and unilateral mastectomy (vs. breast-conserving surgery), adjusting for tumor and sociodemographic characteristics. In a second model, we examined factors associated with reconstruction for mastectomy-treated patients. Results: Among 487 participants, 58% had breast-conserving surgery, 32% had unilateral mastectomy, and 10% underwent bilateral mastectomy. In adjusted analyses, women with stage III (vs. stage 0) cancers had higher odds of bilateral mastectomy (odds ratio [OR], 8.28; 95% confidence interval, 2.32-29.50); women with stage II and III (vs. stage 0) disease had higher odds of unilateral mastectomy. Higher (vs. lower) income was also associated with bilateral mastectomy, while age >= 60 years (vs. < 50 years) was associated with lower odds of bilateral surgery. Among mastectomy-treated patients (n = 206), bilateral mastectomy, unmarried status, and higher education and income were all associated with reconstruction (P < .05). Conclusion: In this population-based cohort, women with the greatest risk of distant recurrence were most likely to undergo bilateral mastectomy despite a lack of clear medical benefit, raising concern for overtreatment. Our findings highlight the need for interventions to assure women are making informed surgical decisions. (C) 2016 Elsevier Inc. All rights reserved. C1 [Freedman, Rachel A.; Rosenberg, Shoshana; Partridge, Ann H.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Kouri, Elena M.; Keating, Nancy L.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [West, Dee W.] Canc Registry Greater Calif, Inst Publ Hlth, Sacramento, CA USA. [Lii, Joyce] Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, 75 Francis St, Boston, MA 02115 USA. [Keating, Nancy L.] Brigham & Womens Hosp, Dept Med, Div Gen Internal Med, 75 Francis St, Boston, MA 02115 USA. RP Freedman, RA (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM rafreedman@partners.org FU Susan G. Komen; National Cancer Institute [K24CA181510]; California Department of Public Health [103885]; National Cancer Institute's Surveillance, Epidemiology, and End Results Program [HHSN261201000140C, HHSN261201000035C, HHSN261201000034C]; US Centers for Disease Control and Prevention's National Program of Cancer Registries [U58DP003862-01] FX We thank all women who participated in interviews, the Cancer Registry of Greater California, and Ana Guerrero for assistance with interviews. Supported in part by Susan G. Komen. Support was also received by an American Cancer Society Mentored Research Scholar Grant (RAF) and a K24CA181510 (NLK) from the National Cancer Institute.; The collection of cancer incidence data used in this study was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885; the National Cancer Institute's Surveillance, Epidemiology, and End Results Program under contract HHSN261201000140C awarded to the Cancer Prevention Institute of California, contract HHSN261201000035C awarded to the University of Southern California, and contract HHSN261201000034C awarded to the Public Health Institute; and the US Centers for Disease Control and Prevention's National Program of Cancer Registries, under agreement U58DP003862-01 awarded to the California Department of Public Health. The ideas and opinions expressed herein are those of the authors, and endorsement by the State of California, Department of Public Health the National Cancer Institute, and the Centers for Disease Control and Prevention or their Contractors and Subcontractors is not intended nor should be inferred. NR 51 TC 2 Z9 2 U1 2 U2 2 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1526-8209 EI 1938-0666 J9 CLIN BREAST CANCER JI Clin. Breast Cancer PD APR PY 2016 VL 16 IS 2 BP 105 EP 112 DI 10.1016/j.clbc.2015.08.004 PG 8 WC Oncology SC Oncology GA DI8LS UT WOS:000373753100006 PM 26410475 ER PT J AU Bachireddy, P Wu, CJ AF Bachireddy, Pavan Wu, Catherine J. TI Arresting the Inflammatory Drive of Chronic Lymphocytic Leukemia with Ibrutinib SO CLINICAL CANCER RESEARCH LA English DT Editorial Material ID INHIBITOR; THERAPY; CELLS; ITK AB The clinical success of agents targeting the B-cell receptor signaling pathway in chronic lymphocytic leukemia (CLL) may also derive from disrupting the CLL microenvironment. Investigation of the immunomodulatory effects of these agents illuminates the unique immunobiology of CLL and highlights potential targets for dismantling the chronic inflammatory drive. (C) 2016 AACR. C1 [Bachireddy, Pavan; Wu, Catherine J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Bachireddy, Pavan; Wu, Catherine J.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Bachireddy, Pavan; Wu, Catherine J.] Harvard Univ, Sch Med, Boston, MA USA. [Bachireddy, Pavan; Wu, Catherine J.] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. RP Wu, CJ (reprint author), Dana Farber Canc Inst, Dana 540,44 Binney St, Boston, MA 02115 USA. EM cwu@partners.org FU NCI NIH HHS [R01 CA184922, U10 CA180861, R01 CA182461, R01 CA155010]; NHLBI NIH HHS [R01 HL116452, R01HL116452, R01HL103532, R01 HL103532] NR 12 TC 2 Z9 2 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD APR 1 PY 2016 VL 22 IS 7 BP 1547 EP 1549 DI 10.1158/1078-0432.CCR-15-3106 PG 3 WC Oncology SC Oncology GA DI2WT UT WOS:000373360600001 PM 26847060 ER PT J AU Andronesi, OC Loebel, F Bogner, W Marjanska, M Vander Heiden, MG Iafrate, AJ Dietrich, J Batchelor, TT Gerstner, ER Kaelin, WG Chi, AS Rosen, BR Cahill, DP AF Andronesi, Ovidiu C. Loebel, Franziska Bogner, Wolfgang Marjanska, Malgorzata Vander Heiden, Matthew G. Iafrate, A. John Dietrich, Jorg Batchelor, Tracy T. Gerstner, Elizabeth R. Kaelin, William G. Chi, Andrew S. Rosen, Bruce R. Cahill, Daniel P. TI Treatment Response Assessment in IDH-Mutant Glioma Patients by Noninvasive 3D Functional Spectroscopic Mapping of 2-Hydroxyglutarate SO CLINICAL CANCER RESEARCH LA English DT Article ID MAGNETIC-RESONANCE-SPECTROSCOPY; DIFFUSION MAPS FDMS; LOW-GRADE GLIOMA; ONCOMETABOLITE 2-HYDROXYGLUTARATE; VINCRISTINE CHEMOTHERAPY; RANDOMIZED-TRIAL; IN-VIVO; GLIOBLASTOMA; MUTATIONS; SURVIVAL AB Purpose: Measurements of objective response rates are critical to evaluate new glioma therapies. The hallmark metabolic alteration in gliomas with mutant isocitrate dehydrogenase (IDH) is the overproduction of oncometabolite 2-hydroxyglutarate (2HG), which plays a key role in malignant transformation. 2HG represents an ideal biomarker to probe treatment response in IDH-mutant glioma patients, and we hypothesized a decrease in 2HG levels would be measureable by in vivo magnetic resonance spectroscopy (MRS) as a result of antitumor therapy. Experimental Design: We report a prospective longitudinal imaging study performed in 25 IDH-mutant glioma patients receiving adjuvant radiation and chemotherapy. A newly developed 3D MRS imaging was used to noninvasively image 2HG. Paired Student t test was used to compare pre- and posttreatment tumor 2HG values. Test-retest measurements were performed to determine the threshold for 2HG functional spectroscopic maps (fSM). Univariate and multivariate regression were performed to correlate 2HG changes with Karnofsky performance score (KPS). Results: We found that mean 2HG (2HG/Cre) levels decreased significantly (median = 48.1%; 95% confidence interval = 27.3%-56.5%; P = 0.007) in the posttreatment scan. The volume of decreased 2HG correlates (R-2 = 0.88, P = 0.002) with clinical status evaluated by KPS. Conclusions: We demonstrate that dynamic measurements of 2HG are feasible by 3D fSM, and the decrease of 2HG levels can monitor treatment response in patients with IDH-mutant gliomas. Our results indicate that quantitative in vivo 2HG imaging maybe used for precision medicine and early response assessment in clinical trials of therapies targeting IDH-mutant gliomas. (C) 2015 AACR. C1 [Andronesi, Ovidiu C.; Loebel, Franziska; Bogner, Wolfgang; Rosen, Bruce R.] Harvard Univ, Sch Med, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging,Massachus, Boston, MA 02115 USA. [Loebel, Franziska; Cahill, Daniel P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurosurg, Boston, MA USA. [Loebel, Franziska] Charite, Dept Neurosurg, D-13353 Berlin, Germany. [Bogner, Wolfgang] Med Univ Vienna, High Field MR Ctr, Dept Biomed Imaging & Imageguided Therapy, A-1090 Vienna, Austria. [Marjanska, Malgorzata] Univ Minnesota, Ctr Magnet Resonance Res, Minneapolis, MN USA. [Vander Heiden, Matthew G.] MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Iafrate, A. John] Harvard Univ, Sch Med, Dept Pathol, Ctr Integrated Diagnost,Massachusetts Gen Hosp, Boston, MA 02115 USA. [Dietrich, Jorg; Batchelor, Tracy T.; Gerstner, Elizabeth R.; Chi, Andrew S.] Harvard Univ, Sch Med, Dept Neurol,Massachusetts Gen Hosp, Stephen E & Catherine Pappas Ctr Neurooncol,Div H, Boston, MA 02115 USA. [Kaelin, William G.] Dana Farber Harvard Canc Ctr, Boston, MA USA. RP Andronesi, OC (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Bldg 149,Thirteenth St, Charlestown, MA 02129 USA. EM ovidiu@nmr.mgh.harvard.edu; cahill@mgh.harvard.edu OI Cahill, Daniel/0000-0003-2552-6546; Bogner, Wolfgang/0000-0002-0130-3463 FU NCI/NIH K22 Career Award [1K22CA178269-01]; Burroughs-Wellcome Career Award; DFHCC/MIT Koch Institute Bridge Foundation; NIH Brain Cancer SPORE; NIH [R01CA129371, K24CA125440A, S10RR013026, S10RR021110, S10RR023401]; Austrian Science Fund (FWF) [KLI-61]; Biotechnology Research Center (BTRC) [P41 RR008079, P41 EB015894]; NCC [P30 NS057091] FX This work was supported by NCI/NIH K22 Career Award 1K22CA178269-01 (to O.C. Andronesi); Burroughs-Wellcome Career Award, DFHCC/MIT Koch Institute Bridge Foundation and NIH Brain Cancer SPORE (to D.P. Cahill); NIH R01CA129371 and K24CA125440A (to T.T. Batchelor); Austrian Science Fund (FWF) KLI-61 (to W. Bogner); Biotechnology Research Center (BTRC) grant P41 RR008079 and P41 EB015894 (NIBIB), and NCC P30 NS057091 (M. Marjanska); NIH S10RR013026, S10RR021110, S10RR023401 (to B. Rosen). NR 50 TC 12 Z9 13 U1 2 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD APR 1 PY 2016 VL 22 IS 7 BP 1632 EP 1641 DI 10.1158/1078-0432.CCR-15-0656 PG 10 WC Oncology SC Oncology GA DI2WT UT WOS:000373360600012 PM 26534967 ER PT J AU Ferreiro-Neira, I Torres, NE Liesenfeld, LF Chan, CHF Penson, T Landesman, Y Senapedis, W Shacham, S Hong, TS Cusack, JC AF Ferreiro-Neira, Isabel Torres, Nancy E. Liesenfeld, Lukas F. Chan, Carlos H. F. Penson, Tristan Landesman, Yosef Senapedis, William Shacham, Sharon Hong, Theodore S. Cusack, James C. TI XPO1 Inhibition Enhances Radiation Response in Preclinical Models of Rectal Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID CRM1-MEDIATED NUCLEAR EXPORT; THERAPEUTIC TARGET; COLORECTAL-CANCER; PREOPERATIVE RADIOCHEMOTHERAPY; SURVIVIN EXPRESSION; DRUG-RESISTANCE; CRM1; APOPTOSIS; RADIOTHERAPY; PROTEINS AB Purpose: Combination of radiation with radiosensitizing chemotherapeutic agents improves outcomes for locally advanced rectal cancer. Current treatment includes 5-fluorouracil-based chemoradiation prior to surgical resection; however pathologic complete response varies from 15% to 20%, prompting the need to identify new radiosensitizers. Exportin 1 (XPO1, also known as chromosome region 1, CRM1) mediates the nuclear export of critical proteins required for rectal cancer proliferation and treatment resistance. We hypothesize that inhibition of XPO1 may radiosensitize cancer cells by altering the function of these critical proteins resulting in decreased radiation resistance and enhanced antitumoral effects. Experimental Design: To test our hypothesis, we used the selective XPO1 inhibitor, selinexor, to inhibit nuclear export in combination with radiation fractions similar to that given in clinical practice for rectal cancer: hypofractionated short-course radiation dosage of 5 Gy per fraction or the conventional long-course radiation dosage of 1 Gy fractions. Single and combination treatments were tested in colorectal cancer cell lines and xenograft tumor models. Results: Combination treatment of radiotherapy and selinexor resulted in an increase of apoptosis and decrease of proliferation compared with single treatment, which correlated with reduced tumor size. We found that the combination promoted nuclear survivin accumulation and subsequent depletion, resulting in increased apoptosis and enhanced radiation antitumoral effects. Conclusions: Our findings suggest a novel therapeutic option for improving radiation sensitivity in the setting of rectal cancer and provide the scientific rationale to evaluate this combination strategy for clinical trials. (C) 2015 AACR. C1 [Ferreiro-Neira, Isabel; Torres, Nancy E.; Liesenfeld, Lukas F.; Chan, Carlos H. F.; Penson, Tristan; Hong, Theodore S.; Cusack, James C.] Massachusetts Gen Hosp, Div Surg Oncol, Yawkey 7,55 Fruit St, Boston, MA 02114 USA. [Ferreiro-Neira, Isabel; Torres, Nancy E.; Liesenfeld, Lukas F.; Chan, Carlos H. F.; Penson, Tristan; Cusack, James C.] Harvard Univ, Sch Med, Boston, MA USA. [Landesman, Yosef; Senapedis, William; Shacham, Sharon] Karyopharm Therapeut, Natick, MA USA. [Hong, Theodore S.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Ferreiro-Neira, I; Cusack, JC (reprint author), Massachusetts Gen Hosp, Div Surg Oncol, Yawkey 7,55 Fruit St, Boston, MA 02114 USA.; Ferreiro-Neira, I (reprint author), Harvard Univ, Sch Med, Boston, MA USA. EM isabel.ferreironeira@gmail.com; jcusack@partners.org FU Karyopharm Therapeutics Incorporated FX The research was supported by Karyopharm Therapeutics Incorporated. NR 50 TC 1 Z9 1 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD APR 1 PY 2016 VL 22 IS 7 BP 1663 EP 1673 DI 10.1158/1078-0432.CCR-15-0978 PG 11 WC Oncology SC Oncology GA DI2WT UT WOS:000373360600015 PM 26603256 ER PT J AU Zhao, SG Evans, JR Kothari, V Sun, G Larm, A Mondine, V Schaeffer, EM Ross, AE Klein, EA Den, RB Dicker, AP Karnes, RJ Erho, N Nguyen, PL Davicioni, E Feng, FY AF Zhao, Shuang G. Evans, Joseph R. Kothari, Vishal Sun, Grace Larm, Ashley Mondine, Victor Schaeffer, Edward M. Ross, Ashley E. Klein, Eric A. Den, Robert B. Dicker, Adam P. Karnes, R. Jeffrey Erho, Nicholas Nguyen, Paul L. Davicioni, Elai Feng, Felix Y. TI The Landscape of Prognostic Outlier Genes in High-Risk Prostate Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID AAA-ATPASE NVL2; CAPRA-S SCORE; RADICAL PROSTATECTOMY; TISSUE BIOMARKER; CONSERVATIVE MANAGEMENT; BIOCHEMICAL RECURRENCE; GENOMIC CLASSIFIER; DISEASE RECURRENCE; LIVER-CANCER; EXPRESSION AB Purpose: There is a clear need to improve risk stratification and to identify novel therapeutic targets in aggressive prostate cancer. The goal of this study was to investigate genes with outlier expression with prognostic association in high-risk prostate cancer patients as potential biomarkers and drug targets. Experimental Design: We interrogated microarray gene expression data from prostatectomy samples from 545 high-risk prostate cancer patients with long-term follow-up (mean 13.4 years). Three independent clinical datasets totaling an additional 545 patients were used for validation. Novel prognostic outlier genes were interrogated for impact on oncogenic phenotypes in vitro using siRNA-based knockdown. Association with clinical outcomes and comparison with existing prognostic instruments was assessed with multivariable models using a prognostic outlier score. Results: Analysis of the discovery cohort identified 20 prognostic outlier genes. Three top prognostic outlier genes were novel prostate cancer genes; NVL, SMC4, or SQLE knockdown reduced migration and/or invasion and outlier expression was significantly associated with poor prognosis. Increased prognostic outlier score was significantly associated with poor prognosis independent of standard clinicopathologic variables. Finally, the prognostic outlier score prognostic association is independent of, and adds to existing genomic and clinical tools for prognostication in prostate cancer (Decipher, the cell-cycle progression signature, and CAPRA-S). Conclusions: To our knowledge, this study represents the first unbiased high-throughput investigation of prognostic outlier genes in prostate cancer and demonstrates the potential biomarker and therapeutic importance of this previously unstudied class of cancer genes. (C) 2015 AACR. C1 [Zhao, Shuang G.; Evans, Joseph R.; Kothari, Vishal; Sun, Grace; Larm, Ashley; Mondine, Victor; Feng, Felix Y.] Univ Michigan, Dept Radiat Oncol, UH B2C490,SPC 5010, Ann Arbor, MI 48109 USA. [Zhao, Shuang G.] Beaumont Hosp, Transit Year Program, Dearborn, MI USA. [Schaeffer, Edward M.; Ross, Ashley E.] Johns Hopkins Med Inst, James Buchanan Brady Urol Inst, Baltimore, MD 21205 USA. [Klein, Eric A.] Cleveland Clin, Glickman Urol & Kidney Inst, Cleveland, OH 44106 USA. [Den, Robert B.; Dicker, Adam P.] Thomas Jefferson Univ, Dept Radiat Oncol, Sidney Kimmel Med Coll, Philadelphia, PA 19107 USA. [Karnes, R. Jeffrey] Mayo Clin, Dept Urol, Rochester, MN USA. [Erho, Nicholas; Davicioni, Elai] GenomeDx Biosci Inc, Vancouver, BC, Canada. [Nguyen, Paul L.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, 44 Binney St, Boston, MA 02115 USA. [Nguyen, Paul L.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Feng, Felix Y.] Univ Michigan, Michigan Ctr Translat Pathol, Ann Arbor, MI 48109 USA. [Feng, Felix Y.] Univ Michigan, Comprehens Canc Ctr, Ann Arbor, MI 48109 USA. RP Feng, FY (reprint author), Univ Michigan, Dept Radiat Oncol, UH B2C490,SPC 5010, Ann Arbor, MI 48109 USA. EM ffeng@med.umich.edu FU Prostate Cancer Foundation; Evans Foundation FX This research was supported by Challenge Grants awarded (to F.Y. Feng and J.R. Evans) by the Prostate Cancer Foundation and the Evans Foundation. NR 52 TC 7 Z9 7 U1 1 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD APR 1 PY 2016 VL 22 IS 7 BP 1777 EP 1786 DI 10.1158/1078-0432.CCR-15-1250 PG 10 WC Oncology SC Oncology GA DI2WT UT WOS:000373360600025 PM 26631616 ER PT J AU Johansen, KL Dalrymple, LS Glidden, D Delgado, C Kaysen, GA Grimes, B Chertow, GM AF Johansen, Kirsten L. Dalrymple, Lorien S. Glidden, David Delgado, Cynthia Kaysen, George A. Grimes, Barbara Chertow, Glenn M. TI Association of Performance-Based and Self-Reported Function-Based Definitions of Frailty with Mortality among Patients Receiving Hemodialysis SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID MAINTENANCE HEMODIALYSIS; CONSENSUS; DIALYSIS; DISEASE; HEALTH; OLDER AB Background and objectives Frailty is common among patients on dialysis and increases vulnerability to dependency and death. Design, setting, participants, & measurements We examined the predictive ability of frailty on the basis of physical performance and self-reported function in participants of a US Renal Data System special study that enrolled a convenience sample of 771 prevalent patients on hemodialysis from 14 facilities in the Atlanta and northern California areas from 2009 to 2011. Performance-based frailty was assessed using direct measures of grip strength (weakness) and gait speed along with weight loss, exhaustion, and low physical activity; poor self reported function was substituted for weakness and slow gait speed in the self reported function based definition. For both definitions, patients meeting three or more criteria were considered frail. Results The mean age of 762 patients included in analyses was 57.1 +/- 14.2 years old; 240 patients (31%) met the physical performance-based definition of frailty, and 396 (52%) met the self reported function-based definition. There were 106 deaths during 1.7 (interquartile range, 1.4-2.4) years of follow-up. After adjusting for demographic and clinical characteristics, the hazard ratio (HR) for mortality for the performance-based definition (2.16; 95% confidence interval [95% CI], 1.41 to 3.29) was slightly higher than that of the self reported function based definition (HR, 1.93; 95% CI, 1.24 to 3.00). Patients who met the self-report based definition but not the physical performance definition of frailty (n=192) were not at statistically significantly higher risk of mortality than those who were not frail by either definition (n=330; HR, 1.41; 95% CI, 0.81 to 2.45), but those who met both definitions of frailty (n=204) were at significantly higher risk (HR, 2.46; 95% CI, 1.51 to 4.01). Conclusions Frailty, defined using either direct tests of physical performance or self reported physical function, was associated with higher mortality among patients receiving hemodialysis. Future studies are needed to determine the utility of assessing frailty in clinical practice. C1 [Johansen, Kirsten L.; Delgado, Cynthia] Univ Calif San Francisco, Div Nephrol, San Francisco, CA 94143 USA. [Johansen, Kirsten L.; Glidden, David; Grimes, Barbara] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Johansen, Kirsten L.; Delgado, Cynthia] San Francisco VA Med Ctr, Nephrol Sect, 111J,4150 Clement St, San Francisco, CA 94121 USA. [Dalrymple, Lorien S.; Kaysen, George A.] Univ Calif Davis, Div Nephrol, Davis, CA 95616 USA. [Chertow, Glenn M.] Stanford Univ, Sch Med, Div Nephrol, Stanford, CA 94305 USA. RP Johansen, KL (reprint author), San Francisco VA Med Ctr, Nephrol Sect, 111J,4150 Clement St, San Francisco, CA 94121 USA. EM Kirsten.johansen@ucsf.edu FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [N01-DK-7-005, K24DK085153, K23DK093584, K24DK085446]; Career Development Award from US Department of Veterans Affairs [1K2CX000527]; Clinical Research and Development Program; National Center for Advancing Translational Sciences, National Institutes of Health through University of California; San Francisco-Clinical & Translational Science Institute grant [UL1 TR000004] FX This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Contract N01-DK-7-005 and NIDDK Grants K24DK085153 (to K.L.J.), K23DK093584 (to L.S.D.), and K24DK085446 (to G.M.C.). In addition, C.D. was supported by Career Development Award 1K2CX000527 from the US Department of Veterans Affairs, Clinical Research and Development Program. This publication was supported by the National Center for Advancing Translational Sciences, National Institutes of Health through University of California, San Francisco-Clinical & Translational Science Institute grant UL1 TR000004. NR 20 TC 3 Z9 3 U1 1 U2 3 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 EI 1555-905X J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD APR PY 2016 VL 11 IS 4 BP 626 EP 632 DI 10.2215/CJN.03710415 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA DI5EV UT WOS:000373522600013 PM 26792529 ER PT J AU Mueller, JL King, LY Johnson, KB Gao, T Nephew, LD Kothari, D Simpson, MA Zheng, H Wei, L Corey, KE Misdraji, J Lee, JH Lin, MV Gogela, NA Fuchs, BC Tanabe, KK Gordon, FD Curry, MP Chung, RT AF Mueller, Jessica L. King, Lindsay Y. Johnson, Kara B. Gao, Tian Nephew, Lauren D. Kothari, Darshan Simpson, Mary Ann Zheng, Hui Wei, Lan Corey, Kathleen E. Misdraji, Joseph Lee, Joon Hyoek Lin, M. Valerie Gogela, Neliswa A. Fuchs, Bryan C. Tanabe, Kenneth K. Gordon, Fredric D. Curry, Michael P. Chung, Raymond T. TI Impact of EGF, IL28B, and PNPLA3 polymorphisms on the outcome of allograft hepatitis C: a multicenter study SO CLINICAL TRANSPLANTATION LA English DT Article DE cirrhosis; hepatitis C virus; single nucleotide polymorphism; sustained virological response; transplantation ID GROWTH-FACTOR GENE; LIVER-TRANSPLANTATION; HEPATOCELLULAR-CARCINOMA; FIBROSIS PROGRESSION; ANTIVIRAL THERAPY; RECIPIENT IL28B; FUNCTIONAL POLYMORPHISM; VIRUS; DONOR; ASSOCIATION AB Hepatitis C virus (HCV) infection is accelerated following liver transplantation (LT). Single nucleotide polymorphisms (SNPs) near the epidermal growth factor (EGF) (rs4444903), IL28B (rs12979860), and PNPLA3 (rs738409) loci are associated with treatment response, fibrosis, and hepatocellular carcinoma in non-transplant hepatitis C, but allograft population data are limited. We sought to determine the role of these SNPs in 264 patients with HCV who underwent LT between 1990 and 2008. Genotypes were determined from donor wedge/allograft biopsies and recipient explants. Cox proportional hazards model was used to assess time to cirrhosis, liver-related death, and retransplantation, adjusting for donor age and sustained virological response (SVR). Over a median follow-up of 6.3 yr, a trend toward increased progression to graft cirrhosis was observed among recipients of an EGF non-AA vs. AA donor liver (adjusted HR 2.01; 95% CI 0.93-4.34; p = 0.08). No other genotypes predicted cirrhosis development or graft survival. The CC IL28B variant in both recipients and donors was associated with increased rate of SVR (R-CC/D-CC 8/12[67%], R-non-CC/D-CC or R-CC/D-non-CC 23/52[44%], R-non-CC/D-non-CC 12/45[27%], p linear trend = 0.009). Recipient EGF, IL28B, and PNPLA3, and donor IL28B and PNPLA3 genotypes do not predict adverse outcomes in HCV LT recipients. A potential association exists between donor EGF genotype and cirrhosis. C1 [Mueller, Jessica L.; King, Lindsay Y.; Johnson, Kara B.; Corey, Kathleen E.; Lin, M. Valerie; Gogela, Neliswa A.; Chung, Raymond T.] Massachusetts Gen Hosp, Dept Med, Div Gastroenterol, 55 Fruit St, Boston, MA 02114 USA. [Mueller, Jessica L.; King, Lindsay Y.; Johnson, Kara B.; Kothari, Darshan; Corey, Kathleen E.; Lin, M. Valerie; Gogela, Neliswa A.; Fuchs, Bryan C.; Tanabe, Kenneth K.; Gordon, Fredric D.; Curry, Michael P.; Chung, Raymond T.] Harvard Univ, Sch Med, Boston, MA USA. [Gao, Tian] Boston Med Ctr, Dept Med, Div Gastroenterol, Boston, MA USA. [Nephew, Lauren D.] Univ Penn Hlth Syst, Dept Med, Div Gastroenterol, Philadelphia, PA USA. [Kothari, Darshan; Curry, Michael P.] Beth Israel Deaconness Med Ctr, Dept Med, Div Gastroenterol, Boston, MA USA. [Simpson, Mary Ann; Gordon, Fredric D.] Lahey Hosp & Med Ctr, Dept Med, Div Gastroenterol, Burlington, MA USA. [Zheng, Hui] Massachusetts Gen Hosp, Ctr Biostat, 55 Fruit St, Boston, MA 02114 USA. [Wei, Lan; Fuchs, Bryan C.; Tanabe, Kenneth K.] Massachusetts Gen Hosp, Dept Surg, Div Surg Oncol, 55 Fruit St, Boston, MA 02114 USA. [Misdraji, Joseph] Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St, Boston, MA 02114 USA. [Lee, Joon Hyoek] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Med, Seoul, South Korea. RP Chung, RT (reprint author), Massachusetts Gen Hosp, Dept Med, Div Gastroenterol, 55 Fruit St, Boston, MA 02114 USA. EM rtchung@partners.org FU NIDDK NIH HHS [K23 DK099422] NR 30 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0902-0063 EI 1399-0012 J9 CLIN TRANSPLANT JI Clin. Transplant. PD APR PY 2016 VL 30 IS 4 BP 452 EP 460 DI 10.1111/ctr.12710 PG 9 WC Surgery; Transplantation SC Surgery; Transplantation GA DI7KT UT WOS:000373679200015 PM 26854475 ER PT J AU Bitzer, C AF Bitzer, Carolynn TI Evidence-Based Practice Research on Pole- vs Patient-Mounted Transducer Placement SO CRITICAL CARE NURSE LA English DT Meeting Abstract C1 [Bitzer, Carolynn] Dept Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CRITICAL CARE NURSES PI ALISO VIEJO PA 101 COLUMBIA, ALISO VIEJO, CA 92656 USA SN 0279-5442 EI 1940-8250 J9 CRIT CARE NURSE JI Crit. Care Nurse PD APR PY 2016 VL 36 IS 2 MA EB66 BP E27 EP E28 PG 2 WC Critical Care Medicine; Nursing SC General & Internal Medicine; Nursing GA DI4CQ UT WOS:000373448300030 ER PT J AU Scully, E Alter, G AF Scully, Eileen Alter, Galit TI NK Cells in HIV Disease SO CURRENT HIV/AIDS REPORTS LA English DT Article DE HIV; Innate immunity; NK cell; Antibody-dependent cellular cytotoxicity; NK cell memory; Natural killer (NK); Viral immunity; HIV pathogenesis; Review ID NATURAL-KILLER-CELLS; DEPENDENT CELLULAR CYTOTOXICITY; HUMAN CYTOMEGALOVIRUS-INFECTION; ANTIVIRAL T-CELLS; IN-VIVO; HLA-B; EPISTATIC INTERACTION; PERSISTENT INFECTION; EFFECTOR FUNCTIONS; ADAPTIVE IMMUNITY AB Natural killer (NK) cells play a critical role in viral immunity. In the setting of HIV infection, epidemiologic and functional evidence support a role for NK cells in both protection from new infection and in viral control. Specifically, NK cells directly mediate immune pressure leading to virus evolution, and NK cell receptor genotypic profiles, clonal repertoires, and functional capacity have all been implicated in virus containment. In addition, indirect NK cell-mediated antibody-dependent cellular cytotoxicity has been linked to vaccine-induced protective immunity against HIV infection. With recent advances in our understanding of NK cell deficiency, development, memory-like responses, and editing of the adaptive immune system, the opportunities to direct and exploit NK cell antiviral immunity to target HIV have exponentially grown. In this review, we seek to highlight the intersections between discoveries in basic NK cell biology and the challenges of HIV chronic infection, vaccine development, and cure/eradication strategies. C1 [Scully, Eileen; Alter, Galit] MIT, Massachusetts Gen Hosp, Ragon Inst, 400 Technol Sq, Cambridge, MA 02139 USA. [Scully, Eileen; Alter, Galit] Harvard Univ, 400 Technol Sq, Cambridge, MA 02139 USA. [Scully, Eileen] Brigham & Womens Hosp, Dept Med, Div Infect Dis, Boston, MA 02130 USA. RP Alter, G (reprint author), MIT, Massachusetts Gen Hosp, Ragon Inst, 400 Technol Sq, Cambridge, MA 02139 USA.; Alter, G (reprint author), Harvard Univ, 400 Technol Sq, Cambridge, MA 02139 USA. EM escully@partners.org; galter@partners.org FU NIAID NIH HHS [P30 AI027763] NR 98 TC 4 Z9 4 U1 4 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1548-3568 EI 1548-3576 J9 CURR HIV-AIDS REP JI Curr. Hiv/Aids Rep. PD APR PY 2016 VL 13 IS 2 BP 85 EP 94 DI 10.1007/s11904-016-0310-3 PG 10 WC Infectious Diseases SC Infectious Diseases GA DI6WI UT WOS:000373640500002 PM 27002078 ER PT J AU Katz, IT Bangsberg, DR AF Katz, Ingrid T. Bangsberg, David R. TI Cascade of Refusal-What Does It Mean for the Future of Treatment as Prevention in Sub-Saharan Africa? SO CURRENT HIV/AIDS REPORTS LA English DT Article DE Antiretroviral medications; Treatment refusal; Global epidemic; HIV/AIDS; HIV prevention; Science of prevention; ART refusal; Point of testing; Review ID CLUSTER-RANDOMIZED-TRIAL; RURAL SOUTH-AFRICA; HIV-RELATED STIGMA; ANTIRETROVIRAL THERAPY; FOLLOW-UP; CARE; UGANDA; INITIATION; RETENTION; OUTCOMES AB Recent recommendations by the World Health Organization support treatment for all people living with HIV (PLWH) globally to be initiated at the point of testing. While there has been marked success in efforts to identify and expand treatment for PLWH throughout sub-Saharan Africa, the goal of universal treatment may prove challenging to achieve. The pre-ART phase of the care cascade from HIV testing to HIV treatment initiation includes several social and structural barriers. One such barrier is antiretroviral therapy (ART) treatment refusal, a phenomenon in which HIV-infected individuals choose not to start treatment upon learning their ART eligibility. Our goal is to provide further understanding of why treatment-eligible adults may choose to present for HIV testing but not initiate ART when indicated. In this article, we will discuss factors driving pre-ART loss and present a framework for understanding the impact of decision-making on early losses in the care cascade, with a focus on ART refusal. C1 [Katz, Ingrid T.] Brigham & Womens Hosp, Dept Med, Div Womens Hlth, 1620 Tremont St, Boston, MA 02120 USA. [Katz, Ingrid T.; Bangsberg, David R.] Harvard Univ, Sch Med, Boston, MA USA. [Katz, Ingrid T.; Bangsberg, David R.] Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02114 USA. RP Katz, IT (reprint author), Brigham & Womens Hosp, Dept Med, Div Womens Hlth, 1620 Tremont St, Boston, MA 02120 USA.; Katz, IT (reprint author), Harvard Univ, Sch Med, Boston, MA USA.; Katz, IT (reprint author), Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02114 USA. EM IKatz2@Partners.org FU US National Institute for Mental Health [K23 MH097667] FX This publication was made possible with funding from US National Institute for Mental Health K23 MH097667 (Katz). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 77 TC 2 Z9 2 U1 3 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1548-3568 EI 1548-3576 J9 CURR HIV-AIDS REP JI Curr. Hiv/Aids Rep. PD APR PY 2016 VL 13 IS 2 BP 125 EP 130 DI 10.1007/s11904-016-0309-9 PG 6 WC Infectious Diseases SC Infectious Diseases GA DI6WI UT WOS:000373640500006 PM 26894487 ER PT J AU Dunn, EC Wiste, A Radmanesh, F Almli, LM Gogarten, SM Sofer, T Faul, JD Kardia, SLR Smith, JA Weir, DR Zhao, W Soare, TW Mirza, SS Hek, K Tiemeier, H Goveas, JS Sarto, GE Snively, BM Cornelis, M Koenen, KC Kraft, P Purcell, S Ressler, KJ Rosand, J Wassertheil-Smoller, S Smoller, JW AF Dunn, Erin C. Wiste, Anna Radmanesh, Farid Almli, Lynn M. Gogarten, Stephanie M. Sofer, Tamar Faul, Jessica D. Kardia, Sharon L. R. Smith, Jennifer A. Weir, David R. Zhao, Wei Soare, Thomas W. Mirza, Saira S. Hek, Karin Tiemeier, Henning Goveas, Joseph S. Sarto, Gloria E. Snively, Beverly M. Cornelis, Marilyn Koenen, Karestan C. Kraft, Peter Purcell, Shaun Ressler, Kerry J. Rosand, Jonathan Wassertheil-Smoller, Sylvia Smoller, Jordan W. TI GENOME-WIDE ASSOCIATION STUDY (GWAS) AND GENOME-WIDE BY ENVIRONMENT INTERACTION STUDY (GWEIS) OF DEPRESSIVE SYMPTOMS IN AFRICAN AMERICAN AND HISPANIC/LATINA WOMEN SO DEPRESSION AND ANXIETY LA English DT Article DE genome-wide association study; gene-environment interaction; depression; stressful life events; social support ID STRESSFUL LIFE EVENTS; COMORBIDITY SURVEY REPLICATION; SEROTONIN TRANSPORTER GENE; MAJOR DEPRESSION; POSTMENOPAUSAL WOMEN; POLYGENIC RISK; SOCIAL SUPPORT; HEALTH; DISORDER; METAANALYSIS AB BackgroundGenome-wide association studies (GWAS) have made little progress in identifying variants linked to depression. We hypothesized that examining depressive symptoms and considering gene-environment interaction (GxE) might improve efficiency for gene discovery. We therefore conducted a GWAS and genome-wide by environment interaction study (GWEIS) of depressive symptoms. MethodsUsing data from the SHARe cohort of the Women's Health Initiative, comprising African Americans (n = 7,179) and Hispanics/Latinas (n = 3,138), we examined genetic main effects and GxE with stressful life events and social support. We also conducted a heritability analysis using genome-wide complex trait analysis (GCTA). Replication was attempted in four independent cohorts. ResultsNo SNPs achieved genome-wide significance for main effects in either discovery sample. The top signals in African Americans were rs73531535 (located 20 kb from GPR139, P = 5.75 x 10(-8)) and rs75407252 (intronic to CACNA2D3, P = 6.99 x 10(-7)). In Hispanics/Latinas, the top signals were rs2532087 (located 27 kb from CD38, P = 2.44 x 10(-7)) and rs4542757 (intronic to DCC, P = 7.31 x 10(-7)). In the GEWIS with stressful life events, one interaction signal was genome-wide significant in African Americans (rs4652467; P = 4.10 x 10(-10); located 14 kb from CEP350). This interaction was not observed in a smaller replication cohort. Although heritability estimates for depressive symptoms and stressful life events were each less than 10%, they were strongly genetically correlated (rG = 0.95), suggesting that common variation underlying self-reported depressive symptoms and stressful life event exposure, though modest on their own, were highly overlapping in this sample. ConclusionsOur results underscore the need for larger samples, more GEWIS, and greater investigation into genetic and environmental determinants of depressive symptoms in minorities. C1 [Dunn, Erin C.; Radmanesh, Farid; Soare, Thomas W.; Rosand, Jonathan; Smoller, Jordan W.] Massachusetts Gen Hosp, Ctr Human Genet Res, 185 Cambridge St,Simches Res Bldg 6th Floor, Boston, MA 02114 USA. [Dunn, Erin C.; Soare, Thomas W.; Smoller, Jordan W.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Dunn, Erin C.; Soare, Thomas W.; Smoller, Jordan W.] Broad Inst Harvard & MIT, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Wiste, Anna] Massachusetts Gen Hosp, Ctr Expt Drugs & Diagnost, Dept Psychiat, 185 Cambridge St,Simches Res Bldg 6th Floor, Boston, MA 02114 USA. [Radmanesh, Farid; Rosand, Jonathan] Massachusetts Gen Hosp, Dept Neurol, Div Neurocrit Care, 185 Cambridge St,Simches Res Bldg 6th Floor, Boston, MA 02114 USA. [Radmanesh, Farid; Rosand, Jonathan] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [Almli, Lynn M.; Ressler, Kerry J.] Emory Univ, Sch Med, Dept Psychiat & Behav Sci, Atlanta, GA USA. [Gogarten, Stephanie M.; Sofer, Tamar] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Faul, Jessica D.; Weir, David R.] Univ Michigan, Inst Social Res, Ann Arbor, MI USA. [Kardia, Sharon L. R.; Smith, Jennifer A.; Zhao, Wei] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Mirza, Saira S.; Hek, Karin; Tiemeier, Henning] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Hek, Karin; Tiemeier, Henning] Erasmus MC, Dept Psychiat, Rotterdam, Netherlands. [Goveas, Joseph S.] Med Coll Wisconsin, Dept Psychiat & Behav Med, Milwaukee, WI 53226 USA. [Sarto, Gloria E.] Univ Wisconsin, Dept Obstet & Gynecol, Sch Med & Publ Hlth, Ctr Womens Hlth & Hlth Dispar Res, Madison, WI 53706 USA. [Snively, Beverly M.] Wake Forest Sch Med, Dept Biostat Sci, Div Publ Hlth Sci, Winston Salem, NC USA. [Cornelis, Marilyn] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Koenen, Karestan C.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. [Kraft, Peter] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Purcell, Shaun] Icahn Sch Med Mt Sinai, Inst Genom & Multiscale Biol, New York, NY 10029 USA. [Dunn, Erin C.; Wassertheil-Smoller, Sylvia] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. RP Dunn, EC (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, 185 Cambridge St,Simches Res Bldg 6th Floor, Boston, MA 02114 USA. EM edunn2@mgh.harvard.edu OI Gogarten, Stephanie/0000-0002-7231-9745; Smith, Jennifer/0000-0002-3575-5468; Sofer, Tamar/0000-0001-8520-8860 FU National Institute of Mental Health of the National Institutes of Health [K01MH102403, K24MH094614]; NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation; National Heart, Lung, and Blood Institute; U.S. Department of Health and Human Services [HHSN268201100046C, HHSN268201100001C, HHSN 268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C]; National Institute on Aging [NIA U01AG009740, RC2 AG036495, RC4 AG039029] FX Contract grant sponsor: National Institute of Mental Health of the National Institutes of Health; Contract grant numbers: K01MH102403 and K24MH094614; Contract grant sponsor: NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation. Contract grant sponsor: the National Heart, Lung, and Blood Institute; Contract grant sponsor: U.S. Department of Health and Human Services; Contract grant numbers: HHSN268201100046C, HHSN268201100001C, HHSN 268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. Contract grant sponsor: National Institute on Aging; Contract grant number: NIA U01AG009740, RC2 AG036495, and RC4 AG039029. NR 89 TC 3 Z9 3 U1 5 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1091-4269 EI 1520-6394 J9 DEPRESS ANXIETY JI Depress. Anxiety PD APR PY 2016 VL 33 IS 4 BP 265 EP 280 DI 10.1002/da.22484 PG 16 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA DI7XS UT WOS:000373715900001 PM 27038408 ER PT J AU Sadeh, N Wolf, EJ Logue, MW Hayes, JP Stone, A Griffin, LM Schichman, SA Miller, MW AF Sadeh, Naomi Wolf, Erika J. Logue, Mark W. Hayes, Jasmeet P. Stone, Annjanette Griffin, L. Michelle Schichman, Steven A. Miller, Mark W. TI EPIGENETIC VARIATION AT SKA2 PREDICTS SUICIDE PHENOTYPES AND INTERNALIZING PSYCHOPATHOLOGY SO DEPRESSION AND ANXIETY LA English DT Article DE DNA methylation; PTSD; externalizing; suicide risk; trauma; veterans ID POSTTRAUMATIC-STRESS-DISORDER; COMMON MENTAL-DISORDERS; EXTERNALIZING PSYCHOPATHOLOGY; GENETIC-VARIATION; LIFE EVENTS; RISK; SAMPLE; POPULATION; VETERANS; RECEPTOR AB BackgroundDNA methylation of the SKA2 gene has recently been implicated as a biomarker of suicide risk and posttraumatic stress disorder (PTSD). To examine the specificity and reliability of these findings, we examined associations between SKA2 DNA methylation, broad dimensions of psychiatric symptoms, and suicide phenotypes in adults with high levels of trauma exposure. MethodsA total of 466 White, non-Hispanic veterans and their intimate partners (65% male) underwent clinical assessment and had blood drawn for genotyping and methylation analysis. DNA methylation of the CpG locus cg13989295 and genotype at the methylation-associated single-nucleotide polymorphism (SNP) rs7208505 were examined in relation to current and lifetime PTSD, internalizing and externalizing psychopathology, and suicide phenotypes (ideation, plans, and attempts). ResultsDNA methylation at the previously implicated SKA2 CpG locus (cg13989295) was associated with current and lifetime symptoms of internalizing (but not externalizing) disorders. SKA2 methylation levels also predicted higher rates of current suicidal thoughts and behaviors, even after including well-established psychiatric risk factors for suicide in the model. Associations between PTSD and SKA2 were not significant, and genetic variation at the methylation-associated SNP (rs7208505) was not related to any of the phenotypes examined. ConclusionsSKA2 methylation may index a general propensity to experience stress-related psychopathology, including internalizing disorders and suicidal thoughts and behaviors. This study demonstrates that SKA2 methylation levels explain unique variance in suicide risk not captured by clinical symptom interviews, providing further evidence of its potential utility as a biomarker of suicide risk and stress-related psychopathology. C1 [Sadeh, Naomi; Wolf, Erika J.; Hayes, Jasmeet P.; Miller, Mark W.] VA Boston Healthcare Syst, Behav Sci Div, Natl Ctr PTSD, 150 South Huntington Ave, Boston, MA 02130 USA. [Sadeh, Naomi; Wolf, Erika J.; Hayes, Jasmeet P.; Miller, Mark W.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Logue, Mark W.] VA Boston Healthcare Syst, Res Serv, Boston, MA USA. [Logue, Mark W.] Boston Univ, Sch Med, Biomed Genet, Boston, MA 02118 USA. [Logue, Mark W.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Stone, Annjanette; Griffin, L. Michelle; Schichman, Steven A.] Cent Arkansas Vet Healthcare Syst, Res Serv, Pharmacogen Anal Lab, Little Rock, AR USA. RP Sadeh, N (reprint author), VA Boston Healthcare Syst, Behav Sci Div, Natl Ctr PTSD, 150 South Huntington Ave, Boston, MA 02130 USA. EM Naomi.SamimiSadeh@va.gov FU National Institute of Mental Health award FX Contract grant sponsor: National Institute of Mental Health award. NR 33 TC 2 Z9 2 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1091-4269 EI 1520-6394 J9 DEPRESS ANXIETY JI Depress. Anxiety PD APR PY 2016 VL 33 IS 4 BP 308 EP 315 DI 10.1002/da.22480 PG 8 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA DI7XS UT WOS:000373715900005 PM 27038412 ER PT J AU Ito, N Hendriks, WT Dhakal, J Vaine, CA Liu, C Shin, D Shin, K Wakabayashi-Ito, N Dy, M Multhaupt-Buell, T Sharma, N Breakefield, XO Bragg, DC AF Ito, Naoto Hendriks, William T. Dhakal, Jyotsna Vaine, Christine A. Liu, Christina Shin, David Shin, Kyle Wakabayashi-Ito, Noriko Dy, Marisela Multhaupt-Buell, Trisha Sharma, Nutan Breakefield, Xandra O. Bragg, D. Cristopher TI Decreased N-TAF1 expression in X-linked dystonia-parkinsonism patient-specific neural stem cells SO DISEASE MODELS & MECHANISMS LA English DT Article DE X-linked dystonia-parkinsonism; Induced pluripotent stem cells; TAF1 ID BILATERAL PALLIDAL STIMULATION; DOMINANT CEREBELLAR-ATAXIA; MULTIPLE TRANSCRIPT SYSTEM; BINDING PROTEIN; SYNDROME XDP; SVA RETROTRANSPOSONS; STRUCTURAL INSIGHTS; HUMAN TAF(II)250; PHILIPPINES XDP; SYNDROME LOCUS AB X-linked dystonia-parkinsonism(XDP) is a hereditary neurodegenerative disorder involving a progressive loss of striatal medium spiny neurons. The mechanisms underlying neurodegeneration are not known, in part because there have been few cellular models available for studying the disease. The XDP haplotype consists of multiple sequence variations in a region of the X chromosome containing TAF1, a large gene with at least 38 exons, and a multiple transcript system (MTS) composed of five unconventional exons. A previous study identified an XDP-specific insertion of a SINE-VNTR-Alu (SVA)-type retrotransposon in intron 32 of TAF1, as well as a neural-specific TAF1 isoform, N-TAF1, which showed decreased expression in post-mortem XDP brain compared with control tissue. Here, we generated XDP patient and control fibroblasts and induced pluripotent stem cells (iPSCs) in order to further probe cellular defects associated with this disease. As initial validation of the model, we compared expression of TAF1 and MTS transcripts in XDP versus control fibroblasts and iPSC-derived neural stem cells (NSCs). Compared with control cells, XDP fibroblasts exhibited decreased expression of TAF1 transcript fragments derived from exons 32-36, a region spanning the SVA insertion site. N-TAF1, which incorporates an alternative exon (exon 34'), was not expressed in fibroblasts, but was detectable in iPSC-differentiated NSCs at levels that were similar to threefold lower in XDP cells than in controls. These results support the previous findings that N-TAF1 expression is impaired in XDP, but additionally indicate that this aberrant transcription might occur in neural cells at relatively early stages of development that precede neurodegeneration. C1 [Ito, Naoto; Hendriks, William T.; Dhakal, Jyotsna; Vaine, Christine A.; Liu, Christina; Shin, David; Shin, Kyle; Wakabayashi-Ito, Noriko; Dy, Marisela; Multhaupt-Buell, Trisha; Sharma, Nutan; Breakefield, Xandra O.; Bragg, D. Cristopher] Massachusetts Gen Hosp, Dept Neurol, Collaborat Ctr X Linked Dystonia Parkinsonism, Boston, MA 02129 USA. [Ito, Naoto; Hendriks, William T.; Dhakal, Jyotsna; Vaine, Christine A.; Liu, Christina; Shin, David; Shin, Kyle; Wakabayashi-Ito, Noriko; Breakefield, Xandra O.; Bragg, D. Cristopher] Harvard Univ, Sch Med, Harvard Brain Sci Initiat, Boston, MA 02114 USA. [Breakefield, Xandra O.] Massachusetts Gen Hosp, Dept Radiol, Ctr Mol Imaging Res, Charlestown, MA 02129 USA. RP Breakefield, XO; Bragg, DC (reprint author), Massachusetts Gen Hosp, Dept Neurol, Collaborat Ctr X Linked Dystonia Parkinsonism, Boston, MA 02129 USA.; Breakefield, XO; Bragg, DC (reprint author), Harvard Univ, Sch Med, Harvard Brain Sci Initiat, Boston, MA 02114 USA.; Breakefield, XO (reprint author), Massachusetts Gen Hosp, Dept Radiol, Ctr Mol Imaging Res, Charlestown, MA 02129 USA. EM breakefield@hms.harvard.edu; bragg@helix.mgh.harvard.edu OI Liu, Christina/0000-0001-7023-6578 FU Massachusetts General Hospital Collaborative Center for X-Linked Dystonia-Parkinsonism FX The study was supported by the Massachusetts General Hospital Collaborative Center for X-Linked Dystonia-Parkinsonism (D.C.B., N.S. and X.O.B.). NR 74 TC 0 Z9 0 U1 4 U2 8 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 APR 1 PY 2016 VL 9 IS 4 BP 451 EP 462 DI 10.1242/dmm.022590 PG 12 WC Cell Biology; Pathology SC Cell Biology; Pathology GA DI4TA UT WOS:000373491000009 PM 26769797 ER PT J AU Justice, AC McGinnis, KA Tate, JP Braithwaite, RS Bryant, KJ Cook, RL Edelman, EJ Fiellin, LE Freiberg, MS Gordon, AJ Kraemer, KL Marshall, BDL Williams, EC Fiellin, DA AF Justice, Amy C. McGinnis, Kathleen A. Tate, Janet P. Braithwaite, R. Scott Bryant, Kendall J. Cook, Robert L. Edelman, E. Jennifer Fiellin, Lynn E. Freiberg, Matthew S. Gordon, Adam J. Kraemer, Kevin L. Marshall, Brandon D. L. Williams, Emily C. Fiellin, David A. TI Risk of mortality and physiologic injury evident with lower alcohol exposure among HIV infected compared with uninfected men SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Alcohol; Mortality; Morbidity; VACS Index; AUDIT-C; Veteran; HIV ID VETERANS AGING COHORT; ALL-CAUSE MORTALITY; J-SHAPED CURVE; ANTIRETROVIRAL THERAPY; PRIMARY-CARE; AUDIT-C; MEDICATION ADHERENCE; ADMINISTRATIVE DATA; SCREENING SCORES; PROBLEM DRINKING AB Background: HIV infected (HIV+) individuals may be more susceptible to alcohol-related harm than uninfected individuals. Methods: We analyzed data on HIV+ and uninfected individuals in the Veterans Aging Cohort Study (VACS) with an Alcohol Use Disorders Identification Test-Consumption AUDIT-C score from 2008 to 2012. We used Cox proportional hazards models to examine the association between alcohol exposure and mortality through July, 2014; and linear regression models to assess the association between alcohol exposure and physiologic injury based on VACS Index Scores. Models were adjusted for age, race/ethnicity, smoking, and hepatitis C infection. Results: The sample included 18,145 HIV+ and 42,228 uninfected individuals. Among HIV+ individuals, 76% had undetectable HIV-1 RNA (<500 copies/ml). The threshold for an association of alcohol use with mortality and physiologic injury differed by HIV status. Among HIV+ individuals, AUDIT-C score >= 4 (hazard ratio [HR] 1.25, 95% CI 1.09-1.44) and >= 30 drinks per month (HR, 1.30, 95% CI 1.14-1.50) were associated with increased risk of mortality. Among uninfected individuals, AUDIT-C score >= 5 (HR, 1.19, 95% CI 1.07-1.32) and >= 70 drinks per month (HR 1.13, 95% CI 1.00-1.28) were associated with increased risk. Similarly, AUDIT-C threshold scores of 5-7 were associated with physiologic injury among HIV+ individuals (beta 0.47, 95% CI 0.22, 0.73) and a score of 8 or more was associated with injury in uninfected (beta 0.29, 95% CI 0.16, 0.42) individuals. Conclusions: Despite antiretroviral therapy, HIV+ individuals experienced increased mortality and physiologic injury at lower levels of alcohol use compared with uninfected individuals. Alcohol consumption limits should be lower among HIV+ individuals. Published by Elsevier Ireland Ltd. C1 [Justice, Amy C.; Tate, Janet P.; Edelman, E. Jennifer; Fiellin, David A.] West Haven VA Healthcare Syst, Vet Aging Cohort Study Coordinating Ctr, 950 Campbell Ave, West Haven, CT 06516 USA. [Justice, Amy C.; Tate, Janet P.; Edelman, E. Jennifer; Fiellin, Lynn E.; Fiellin, David A.] Yale Univ, Yale Sch Med, Dept Internal Med, 367 Cedar St, New Haven, CT 06510 USA. [Justice, Amy C.; Tate, Janet P.; Edelman, E. Jennifer; Fiellin, Lynn E.; Fiellin, David A.] Yale Univ, Yale Sch Med, CIRA, 367 Cedar St, New Haven, CT 06510 USA. [McGinnis, Kathleen A.; Gordon, Adam J.; Kraemer, Kevin L.] VA Pittsburgh Healthcare Syst, Univ Dr C, Pittsburgh, PA 15240 USA. [Braithwaite, R. Scott] NYU, Sch Med, Dept Populat Hlth, 227 East 30th St, New York, NY 10016 USA. [Bryant, Kendall J.] NIAAA, 5635 Fishers Lane,MSC 9304, Bethesda, MD 20892 USA. [Cook, Robert L.] Univ Florida, Dept Epidemiol, POB 100231, Gainesville, FL USA. [Freiberg, Matthew S.] Vanderbilt Univ, Sch Med, Div Cardiovasc Med, Nashville, TN 37212 USA. [Freiberg, Matthew S.] Vet Affairs Tennessee Valley Healthcare Syst, Geriatr Res Educ & Clin Ctr, 2525 West End Ave, Nashville, TN USA. [Gordon, Adam J.; Kraemer, Kevin L.] Univ Pittsburgh, Sch Med, Div Gen Internal Med, Suite 600,230 McKee Pl, Pittsburgh, PA 15213 USA. [Marshall, Brandon D. L.] Brown Univ, Sch Publ Hlth, Dept Epidemiol, 121 South Main St, Providence, RI 02912 USA. [Williams, Emily C.] Univ Washington, Sch Publ Hlth, 325 Ninth Ave,Box 359762, Seattle, WA 98195 USA. RP Justice, AC (reprint author), Yale Univ, Sch Med, VA Connecticut Healthcare Syst, 950 Campbell Ave,Bldg 35a Room 2-212 11 ACSLG, West Haven, CT 06516 USA. EM amy.Justice2@va.gov OI Fiellin, David/0000-0002-4006-010X; Justice, Amy/0000-0003-0139-5502 FU NHLBI NIH HHS [R01 HL090342, R01 HL095136, R01-HL090342, R01-HL095136, RC1 HL100347, RCI-HL100347]; NIA NIH HHS [R01 AG029154, R01-AG029154]; NIAAA NIH HHS [U10-AA13566, U10 AA013566, U13 AA022864, U24 AA022000, U24 AA022002, U24AA02002]; PHS HHS [U01-A1069918] NR 60 TC 13 Z9 13 U1 3 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD APR 1 PY 2016 VL 161 BP 95 EP 103 DI 10.1016/j.drugalcdep.2016.01.017 PG 9 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA DI3SP UT WOS:000373419100013 PM 26861883 ER PT J AU Okita, K Ghahremani, DG Payer, DE Robertson, CL Dean, AC Mandelkern, MA London, ED AF Okita, Kyoji Ghahremani, Dara G. Payer, Doris E. Robertson, Chelsea L. Dean, Andy C. Mandelkern, Mark A. London, Edythe D. TI Emotion dysregulation and amygdala dopamine D2-type receptor availability in methamphetamine users SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Methamphetamine; Amygdala; Emotion dysregulation; Dopamine; [F-18]Fallypride; PET ID BORDERLINE PERSONALITY-DISORDER; REFERENCE TISSUE MODEL; HUMAN BRAIN; NEURAL MECHANISMS; IMPULSE CONTROL; ABSTINENCE; DEPENDENCE; CORTEX; DIFFICULTIES; INHIBITION AB Background: Individuals who use methamphetamine chronically exhibit emotional and dopaminergic neurochemical deficits. Although the amygdala has an important role in emotion processing and receives dopaminergic innervation, little is known about how dopamine transmission in this region contributes to emotion regulation. This investigation aimed to evaluate emotion regulation in subjects who met DSM-IV criteria for methamphetamine dependence, and to test for a relationship between self-reports of difficulty in emotion regulation and D2-type dopamine receptor availability in the amygdala. Method: Ninety-four methamphetamine-using and 102 healthy-control subjects completed the Difficulties in Emotion Regulation Scale (DERS); 33 of those who used methamphetamine completed the Addiction Severity Index (ASI). A subset of 27 methamphetamine-group and 20 control-group subjects completed positron emission tomography with [F-18]fallypride to assay amygdala D2-type dopamine receptor availability, measured as binding potential (BPND). Results: The methamphetamine group scored higher than the control group on the DERS total score (p < 0.001), with DERS total score positively correlated with the Drug Composite Score on the ASI (p = 0.02) in the methamphetamine group. The DERS total score was positively correlated with amygdala BPND in both groups and the combined group of participants (combined: r= 0.331, p= 0.02), and the groups did not differ in this relationship. Conclusion: These findings highlight problems with emotion regulation linked to methamphetamine use, possibly contributing to personal and interpersonal behavioral problems. They also suggest that D2-type dopamine receptors in the amygdala contribute to emotion regulation in both healthy and methamphetamine-using subjects. (c) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Okita, Kyoji; Ghahremani, Dara G.; Dean, Andy C.; London, Edythe D.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. [Robertson, Chelsea L.; London, Edythe D.] Dept Mol & Med Pharmacol, Los Angeles, CA 90024 USA. [London, Edythe D.] Univ Calif Los Angeles, Brain Res Inst, Los Angeles, CA 90024 USA. [Payer, Doris E.] Ctr Addict & Mental Hlth, Addict Imaging Res Grp, Toronto, ON M5T 1R8, Canada. [Payer, Doris E.] Univ Toronto, Dept Psychiat, Toronto, ON M5T 1R8, Canada. [Okita, Kyoji; Robertson, Chelsea L.; Mandelkern, Mark A.; London, Edythe D.] VA Greater Los Angeles Healthcare Syst, Dept Res, Los Angeles, CA 90073 USA. [Mandelkern, Mark A.] Univ Calif Irvine, Dept Phys, Irvine, CA 92697 USA. RP London, ED (reprint author), Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, 760 Westwood Plaza,POB 175919, Los Angeles, CA 90095 USA. EM elondon@mednet.ucla.edu OI Payer, Doris/0000-0001-9313-2587 FU National Institute on Drug Abuse [R01 DA015179, R01 DA020726, P20 DA022539, T32 DA024635, K23 DA027734, R21 DA034928]; National Center for Research Resources [M01 RR00865]; Thomas P and Katherine K Pike Chair in Addiction Studies; Marjorie M Greene Trust; Department of Psychiatry, Chiba University, DOMONKAI fund FX This research was supported, in part, by grants from the National Institute on Drug Abuse (R01 DA015179, R01 DA020726, P20 DA022539, T32 DA024635, EDL; K23 DA027734, R21 DA034928, ACD) and the National Center for Research Resources (M01 RR00865), and endowments from the Thomas P and Katherine K Pike Chair in Addiction Studies and the Marjorie M Greene Trust. KO was partly supported by Department of Psychiatry, Chiba University, DOMONKAI fund. NR 68 TC 0 Z9 0 U1 8 U2 14 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD APR 1 PY 2016 VL 161 BP 163 EP 170 DI 10.1016/j.drugalcdep.2016.01.029 PG 8 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA DI3SP UT WOS:000373419100021 PM 26880595 ER PT J AU Chavez, LJ Bradley, K Tefft, N Liu, CF Hebert, P Devine, B AF Chavez, Laura J. Bradley, Katharine Tefft, Nathan Liu, Chuan-Fen Hebert, Paul Devine, Beth TI Preference weights for the spectrum of alcohol use in the US Population SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Alcohol consumption; Health-related quality of life; preference weights ID QUALITY-OF-LIFE; RANDOMIZED CONTROLLED-TRIAL; REPORTED HEALTH-STATUS; USE DISORDER SEVERITY; UNITED-STATES; GENERAL-POPULATION; PRIMARY-CARE; SCREENING SCORES; RISK-FACTORS; AUDIT-C AB Background: Little is known about the cost-utility of population-based alcohol interventions. One barrier to research has been the lack of preference weights needed to calculate Quality Adjusted Life Years (QALYs). Preference weights can be estimated from measures of health-related quality of life (HRQOL). The objective of this study was to describe preference weights for the full spectrum of alcohol use. Methods: This cross-sectional study included participants in both the National Health Interview Survey (NHIS; 1999-2002) and the Medical Expenditure Panel Survey (MEPS; 2000-2003). The AUDIT-C alcohol screen was derived from NHIS with scores categorized into 6 groups (0,1-3, 4-5, 6-7, 8-9,10-12 points), ranging from nondrinking (0) to very severe unhealthy alcohol use (10-12). AUDIT-C scores were mapped to EQ-5D and SF-6D preference weights using the linked datasets and analyses adjusted for demographics. Results: Among 17,440 participants, mean EQ-5D and SF-6D preference weights were 0.82 (95% CI 0.82-0.83) and 0.79 (95% CI 0.79-0.80), respectively. Adjusted EQ-5D preference weights for nondrinking (0.80; 95% CI 0.79-0.81) and moderate unhealthy drinking (0.85; 95% CI 0.84-0.86) were significantly different from low-risk drinking (0.83; 95% CI 0.83-0.84), but no other differences were significant. Results for the SF-GD were similar. Conclusions: This study provides EQ-5D and SF-6D preference weights for various alcohol use categories in a representative U.S. adult sample. However, neither measure suggested meaningful differences in HRQOL based on AUDIT-C categories. Self-reported alcohol consumption may not be associated with preference weights or generic instruments may not capture alcohol-related differences in HRQOL. (c) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Chavez, Laura J.; Bradley, Katharine; Liu, Chuan-Fen; Hebert, Paul] Vet Affairs Puget Sound Hlth Care Syst, Seattle Ctr Innovat Vet Ctr & Value Driven Care, Hlth Serv Res & Dev, 1660 S Columbian Way, Seattle, WA 98108 USA. [Bradley, Katharine] Vet Affairs Puget Sound Hlth Care Syst, Ctr Excellence Subst Abuse Treatment & Educ, 1660 S Columbian Way, Seattle, WA 98108 USA. [Chavez, Laura J.; Bradley, Katharine; Liu, Chuan-Fen; Hebert, Paul; Devine, Beth] Univ Washington, Dept Hlth Serv, 1959 NE Pacific St,Box 357660, Seattle, WA 98195 USA. [Bradley, Katharine] Univ Washington, Dept Med, 1959 NE Pacific St, Seattle, WA 98195 USA. [Devine, Beth] Univ Washington, Dept Pharm, 1959 NE Pacific St, Seattle, WA 98195 USA. [Tefft, Nathan] Bates Coll, 2 Andrews Rd, Lewiston, ME 04240 USA. [Bradley, Katharine] Grp Hlth Res Inst, 1730 Minor Ave,Suite 1600, Seattle, WA 98101 USA. RP Chavez, LJ (reprint author), Univ Washington, Dept Hlth Serv, 1959 NE Pacific St,Box 357660, Seattle, WA 98195 USA. EM ljchavez@u.washington.edu OI Bradley, Katharine/0000-0003-1933-4425; Tefft, Nathan/0000-0002-2758-8700 FU Agency for Healthcare Research and Quality (AHRQ) [NIH 1R36HS022800-01]; University of Washington Center of Excellence in Comparative Effectiveness Research; Pharmaceutical Researcher and Manufacturer's Association (PhRMA) Foundation FX Ms. Chavez's work on this study was supported by an Agency for Healthcare Research and Quality (AHRQ) Dissertation Grant (NIH 1R36HS022800-01) and a predoctoral fellowship from the University of Washington Center of Excellence in Comparative Effectiveness Research, sponsored by the Pharmaceutical Researcher and Manufacturer's Association (PhRMA) Foundation. Dr. Bradley's time on this study was supported by the Center of Excellence for Substance Abuse Treatment and Education (CESATE) at VA Puget Sound. NR 50 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD APR 1 PY 2016 VL 161 BP 206 EP 213 DI 10.1016/j.drugalcdep.2016.02.004 PG 8 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA DI3SP UT WOS:000373419100026 PM 26900145 ER PT J AU Ben-Shlomo, Y Scharf, JM Miller, LL Mathews, CA AF Ben-Shlomo, Y. Scharf, J. M. Miller, L. L. Mathews, C. A. TI Parental mood during pregnancy and post-natally is associated with offspring risk of Tourette syndrome or chronic tics: prospective data from the Avon Longitudinal Study of Parents and Children (ALSPAC) SO EUROPEAN CHILD & ADOLESCENT PSYCHIATRY LA English DT Article DE Tourette syndrome; Anxiety; Depression; Cohort studies; Risk factors; ALSPAC ID PRENATAL ANXIETY; COHORT; EPIDEMIOLOGY; DISORDER; DEPRESSION; CORTISOL; SMOKING AB Little is known about risk factors for Tourette syndrome (TS) and chronic tic disorders (CT) but maternal psychological morbidity in pregnancy may be associated with TS/CT. We examined whether pre- and post-natal parental anxiety and/or depression are associated with risk of TS/CT in the Avon Longitudinal Study of Parents and Children. We compared self-reported anxiety and depression measures collected prospectively at four time points (18 and 32 weeks prenatally, and 8 weeks and 8 months post-natally) among parents of children who subsequently met criteria for TS/CT at 13 years of age as compared to other children from the cohort. We adjusted for various socioeconomic measures and tested both for time period-specific exposure and chronic exposure using multivariable logistic regression models. 122 children had TS/CT (50 TS, 72 CT) and 5968 children had no tics. In crude analyses, both pre- and post-natal maternal anxiety and depression, but only post-natal paternal depression at 8 months, showed associations with TS/CT. In the final, adjusted multivariable models, chronic maternal anxiety (odds ratio 2.17, 95 % CI 1.23, 3.84, p = 0.007) and pre-natal maternal depression (odds ratio 1.86, 95 % CI 1.02, 3.39, p = 0.04) showed associations with TS/CT though the latter was consistent with chance (p = 0.07) after adjustment for past maternal depression. We find associations between maternal psychological morbidity pre- and post-natally and risk of future TS/CT in offspring. These associations may reflect either shared genetic susceptibility or a pre-natal exposure. Further work is required to see if these findings can be replicated in larger datasets. C1 [Ben-Shlomo, Y.; Miller, L. L.] Univ Bristol, Sch Social & Community Med, 39 Whatley Rd, Bristol BS8 2PS, Avon, England. [Scharf, J. M.] Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Scharf, J. M.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Scharf, J. M.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Scharf, J. M.] Brigham & Womens Hosp, Dept Neurol, Div Cognit & Behav Neurol, 75 Francis St, Boston, MA 02115 USA. [Mathews, C. A.] Univ Calif San Francisco, Dept Psychiat, Program Genet & Epidemiol Neuropsychiat Symptoms, San Francisco, CA 94143 USA. RP Ben-Shlomo, Y (reprint author), Univ Bristol, Sch Social & Community Med, 39 Whatley Rd, Bristol BS8 2PS, Avon, England. EM y.ben-shlomo@bristol.ac.uk FU Wellcome Trust [102215/2/13/2]; Tourette Syndrome Association (USA) FX We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The UK Medical Research Council and the Wellcome Trust (Grant ref: 102215/2/13/2) and the University of Bristol provided core support for ALSPAC. This publication is the work of the authors and Yoav Ben-Shlomo will serve as guarantor for the contents of this paper. This research was specifically funded by the Tourette Syndrome Association (USA). NR 22 TC 2 Z9 2 U1 5 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1018-8827 EI 1435-165X J9 EUR CHILD ADOLES PSY JI Eur. Child Adolesc. Psych. PD APR PY 2016 VL 25 IS 4 BP 373 EP 381 DI 10.1007/s00787-015-0742-0 PG 9 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA DI6WU UT WOS:000373641700005 PM 26174227 ER PT J AU Ovaska, MT Madanat, R Makinen, TJ AF Ovaska, Mikko T. Madanat, Rami Maekinen, Tatu J. TI Predictors of Postoperative Wound Necrosis Following Primary Wound Closure of Open Ankle Fractures SO FOOT & ANKLE INTERNATIONAL LA English DT Article DE trauma; ankle fracture; open fracture; wound necrosis; wound closure ID OPERATIVE TREATMENT; CANCELLOUS BONE; RISK-FACTORS; IRRIGATION; COMPLICATIONS; INFECTION; PRESSURE; DEBRIDEMENT; MANAGEMENT; TRAUMA AB Background: Most open malleolar ankle fracture wounds can be closed primarily after meticulous debridement. However, the development of wound necrosis following operative treatment of open malleolar ankle fractures can have catastrophic consequences. The aim of this study was to identify risk factors predisposing to postoperative wound necrosis following primary wound closure of open malleolar ankle fractures. Methods: A total of 137 patients with open malleolar ankle fractures were identified. The open fracture wound was primarily closed in 110 of 137 (80%) patients, and postoperative wound necrosis occurred in 18 (16%) of these patients. These patients were compared to the open fracture patients without wound necrosis. Twenty possible risk factors for the development of wound necrosis were studied with logistic regression analysis. Results: The variables that were independently associated with an increased risk for postoperative wound necrosis included ASA class 2, Gustilo grade III open injury, and the use of pulsatile lavage at index surgery. Conclusions: Our study showed that ASA class 2, Gustilo grade III open injury, and the use of pulsatile lavage at index surgery were the most important factors predisposing to postoperative wound necrosis following primary wound closure of open malleolar ankle fractures. The findings warrant a further study specifically comparing primary and delayed wound closure in patients with Gustilo grade III open malleolar ankle fractures and different ASA classes. Also, the role of pulsatile lavage should be re-evaluated. Level of Evidence: Level III, retrospective comparative series. C1 [Ovaska, Mikko T.] Helsinki Univ Hosp, Dept Orthopaed & Traumatol, Topeliuksenkatu 5, Helsinki 00260, Finland. [Ovaska, Mikko T.] Univ Helsinki, Helsinki, Finland. [Madanat, Rami] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Madanat, Rami] Harvard Univ, Sch Med, Boston, MA USA. [Maekinen, Tatu J.] Mt Sinai Hosp, Toronto, ON M5G 1X5, Canada. [Maekinen, Tatu J.] Univ Toronto, Toronto, ON, Canada. RP Ovaska, MT (reprint author), Helsinki Univ Hosp, Dept Orthopaed & Traumatol, Topeliuksenkatu 5, Helsinki 00260, Finland. EM mikko.ovaska@hus.fi FU HUS EVO; Maud Kuistila Memorial Foundation; Biomedicum Foundation; Paivikki and Sakari Sohlberg Foundation FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by grants from the HUS EVO, the Maud Kuistila Memorial Foundation, the Biomedicum Foundation, and the Paivikki and Sakari Sohlberg Foundation. Mikko T. Ovaska, MD, PhD, reports grants from HUS EVO, during the conduct of the study. Rami Madanat, MD, PhD, reports grants from the Paivikki and Sakari Sohlberg Foundation and the Biomedicum Foundation, during the conduct of the study. Tatu J. Makinen, MD, PhD, reports grants from the Maud Kuistila Memorial Foundation and the Biomedicum Foundation, during the conduct of the study. NR 25 TC 3 Z9 3 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1071-1007 EI 1944-7876 J9 FOOT ANKLE INT JI Foot Ankle Int. PD APR PY 2016 VL 37 IS 4 BP 401 EP 406 DI 10.1177/1071100715609182 PG 6 WC Orthopedics SC Orthopedics GA DI7GY UT WOS:000373668700008 PM 26830839 ER PT J AU Gonzalez, TA Watkins, C Drummond, R Wolf, JC Toomey, EP DiGiovanni, CW AF Gonzalez, Tyler A. Watkins, Colyn Drummond, Rosa Wolf, Jonathon C. Toomey, E. Pepper DiGiovanni, Christopher W. TI Transfibular Approach to Posterior Malleolus Fracture Fixation: Technique Tip SO FOOT & ANKLE INTERNATIONAL LA English DT Editorial Material DE ankle fracture; transfibular approach; posterior malleolus; ankle fracture ORIF ID POSTEROLATERAL APPROACH; ANKLE FRACTURES; OPERATIVE TREATMENT; INTERNAL-FIXATION; OPEN REDUCTION C1 [Gonzalez, Tyler A.; Watkins, Colyn] Massachusetts Gen Hosp, Harvard Combined Orthopaed Residency Program, Yawkey Ctr Outpatient Care, Dept Orthopaed Surg, 3F,Suite 3300,55 Fruit St, Boston, MA 02114 USA. [Drummond, Rosa] Massachusetts Gen Hosp, Foot & Ankle Serv, Dept Orthopaed Surg, Yawkey Ctr Outpatient Care, Boston, MA 02114 USA. [Drummond, Rosa] Massachusetts Gen Hosp, Fellowship Program, Dept Orthopaed Surg, Yawkey Ctr Outpatient Care, Boston, MA 02114 USA. [Wolf, Jonathon C.] Massachusetts Gen Hosp, Yawkey Ctr Outpatient Care, Dept Orthopaed Surg, Harvard Combined Orthopaed Surg Prog, Boston, MA 02114 USA. [Toomey, E. Pepper] Orthoped Phys Associates, Seattle, WA USA. [DiGiovanni, Christopher W.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [DiGiovanni, Christopher W.] Newton Wellesley Hosp, Massachusetts Gen Hosp, MGH Comprehens Foot & Ankle Ctr, Foot & Ankle Serv, Waltham, MA USA. [DiGiovanni, Christopher W.] Newton Wellesley Hosp, Massachusetts Gen Hosp, MGH Comprehens Foot & Ankle Ctr, Fellowship Program, Waltham, MA USA. [DiGiovanni, Christopher W.] Massachusetts Gen Hosp, Yawkey Ctr Outpatient Care, Dept Orthopaed Surg, Boston, MA USA. RP Gonzalez, TA (reprint author), Massachusetts Gen Hosp, Harvard Combined Orthopaed Residency Program, Yawkey Ctr Outpatient Care, Dept Orthopaed Surg, 3F,Suite 3300,55 Fruit St, Boston, MA 02114 USA. EM tagonzalez@partners.org NR 14 TC 1 Z9 1 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1071-1007 EI 1944-7876 J9 FOOT ANKLE INT JI Foot Ankle Int. PD APR PY 2016 VL 37 IS 4 BP 440 EP 445 DI 10.1177/1071100715617760 PG 6 WC Orthopedics SC Orthopedics GA DI7GY UT WOS:000373668700014 PM 26596796 ER PT J AU Liang, JJ Cade, BE Wang, HM Chen, H Gleason, KJ Larkin, EK Saxena, R Lin, XH Redline, S Zhu, XF AF Liang, Jingjing Cade, Brian E. Wang, Heming Chen, Han Gleason, Kevin J. Larkin, Emma K. Saxena, Richa Lin, Xihong Redline, Susan Zhu, Xiaofeng TI Comparison of Heritability Estimation and Linkage Analysis for Multiple Traits Using Principal Component Analyses SO GENETIC EPIDEMIOLOGY LA English DT Article DE principal components; principal components of heritability; heritability; estimation; linkage analysis; sleep apnea ID OBSTRUCTIVE SLEEP-APNEA; GENOME-WIDE ASSOCIATION; BODY-MASS INDEX; BLOOD-PRESSURE; RISK-FACTORS; PLEIOTROPY; PHENOTYPES; FAMILY; GENES; POWER AB A disease trait often can be characterized by multiple phenotypic measurements that can provide complementary information on disease etiology, physiology, or clinical manifestations. Given that multiple phenotypes may be correlated and reflect common underlying genetic mechanisms, the use of multivariate analysis of multiple traits may improve statistical power to detect genes and variants underlying complex traits. The literature, however, has been unclear as to the optimal approach for analyzing multiple correlated traits. In this study, heritability and linkage analysis was performed for six obstructive sleep apnea hypopnea syndrome (OSAHS) related phenotypes, as well as principal components of the phenotypes and principal components of the heritability (PCHs) using the data from Cleveland Family Study, which include both African and European American families. Our study demonstrates that principal components generally result in higher heritability and linkage evidence than individual traits. Furthermore, the PCHs can be transferred across populations, strongly suggesting that these PCHs reflect traits with common underlying genetic mechanisms for OSAHS across populations. Thus, PCHs can provide useful traits for using data on multiple phenotypes and for genetic studies of trans-ethnic populations. C1 [Liang, Jingjing; Wang, Heming; Zhu, Xiaofeng] Case Western Reserve Univ, Sch Med, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Cade, Brian E.; Gleason, Kevin J.; Saxena, Richa; Redline, Susan] Brigham & Womens Hosp, Div Sleep & Circadian Disorders, 75 Francis St, Boston, MA 02115 USA. [Cade, Brian E.; Gleason, Kevin J.; Saxena, Richa; Redline, Susan] Harvard Univ, Sch Med, Div Sleep Med, Boston, MA USA. [Lin, Xihong] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Larkin, Emma K.] Vanderbilt Univ, Med Ctr, Dept Med, Div Allergy Pulm & Crit Care, Nashville, TN USA. [Saxena, Richa] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Saxena, Richa] Massachusetts Gen Hosp, Dept Anesthesia Pain & Crit Care Med, Boston, MA 02114 USA. [Saxena, Richa] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Redline, Susan] Beth Israel Deaconess Med Ctr, Div Pulm Crit Care & Sleep Med, Boston, MA 02215 USA. RP Zhu, XF (reprint author), Case Western Reserve Univ, Sch Med, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. EM xiaofeng.zhu@case.edu OI Chen, Han/0000-0002-9510-4923 FU NCRR NIH HHS [P41 RR003655, KL2 RR024990, RR024990, RR03655]; NHGRI NIH HHS [HG003054, R01 HG003054]; NHLBI NIH HHS [HL046380, HL113338, R01 HL046380, R01 HL113338, T32 HL007567]; NIEHS NIH HHS [P30 ES000002] NR 33 TC 1 Z9 1 U1 3 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD APR PY 2016 VL 40 IS 3 BP 222 EP 232 DI 10.1002/gepi.21957 PG 11 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA DI6HQ UT WOS:000373600200005 PM 27027516 ER PT J AU Wang, S Zhao, JH An, P Guo, XQ Jensen, RA Marten, J Huffman, JE Meidtner, K Boeing, H Campbell, A Rice, KM Scott, RA Yao, J Schulze, MB Wareham, NJ Borecki, IB Province, MA Rotter, JI Hayward, C Goodarzi, MO Meigs, JB Dupuis, J AF Wang, Shuai Zhao, Jing Hua An, Ping Guo, Xiuqing Jensen, Richard A. Marten, Jonathan Huffman, Jennifer E. Meidtner, Karina Boeing, Heiner Campbell, Archie Rice, Kenneth M. Scott, Robert A. Yao, Jie Schulze, Matthias B. Wareham, Nicholas J. Borecki, Ingrid B. Province, Michael A. Rotter, Jerome I. Hayward, Caroline Goodarzi, Mark O. Meigs, James B. Dupuis, Josee TI General Framework for Meta-Analysis of Haplotype Association Tests SO GENETIC EPIDEMIOLOGY LA English DT Article DE meta-analysis; haplotype association tests; family samples; linear mixed effects model ID GENOME-WIDE ASSOCIATION; FASTING GLUCOSE; EM ALGORITHM; TRAITS; LOCI; SUSCEPTIBILITY; REGRESSION; LASSO AB For complex traits, most associated single nucleotide variants (SNV) discovered to date have a small effect, and detection of association is only possible with large sample sizes. Because of patient confidentiality concerns, it is often not possible to pool genetic data from multiple cohorts, and meta-analysis has emerged as the method of choice to combine results from multiple studies. Many meta-analysis methods are available for single SNV analyses. As new approaches allow the capture of low frequency and rare genetic variation, it is of interest to jointly consider multiple variants to improve power. However, for the analysis of haplotypes formed by multiple SNVs, meta-analysis remains a challenge, because different haplotypes may be observed across studies. We propose a two-stage meta-analysis approach to combine haplotype analysis results. In the first stage, each cohort estimate haplotype effect sizes in a regression framework, accounting for relatedness among observations if appropriate. For the second stage, we use a multivariate generalized least square meta-analysis approach to combine haplotype effect estimates from multiple cohorts. Haplotype-specific association tests and a global test of independence between haplotypes and traits are obtained within our framework. We demonstrate through simulation studies that we control the type-I error rate, and our approach is more powerful than inverse variance weighted meta-analysis of single SNV analysis when haplotype effects are present. We replicate a published haplotype association between fasting glucose-associated locus (G6PC2) and fasting glucose in seven studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium and we provide more precise haplotype effect estimates. C1 [Wang, Shuai; Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Zhao, Jing Hua] Univ Cambridge, MRC, Epidemiol Unit, Sch Clin Med,Inst Metab Sci, Box 285,Cambridge Biomed Campus, Cambridge, England. [An, Ping; Borecki, Ingrid B.; Province, Michael A.] Washington Univ, Sch Med, Dept Genet, Div Stat Gen, St Louis, MO 63110 USA. [Guo, Xiuqing; Yao, Jie; Rotter, Jerome I.] Univ Calif Los Angeles, Med Ctr, LABioMed Harbor, Dept Pediat,Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA. [Jensen, Richard A.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Jensen, Richard A.; Hayward, Caroline] Univ Washington, Dept Med, Seattle, WA USA. [Marten, Jonathan; Huffman, Jennifer E.] Univ Edinburgh, Human Genet Unit, MRC, MRC IGMM, Edinburgh EH8 9YL, Midlothian, Scotland. [Meidtner, Karina; Schulze, Matthias B.] German Inst Human Nutr Potsdam Rehbrucke, Dept Mol Epidemiol, Nuthetal, Germany. [Boeing, Heiner] German Inst Human Nutr Potsdam Rehbrucke, Dept Epidemiol, Nuthetal, Germany. [Campbell, Archie; Hayward, Caroline] Univ Edinburgh, Ctr Genom & Expt Med, Inst Genet & Mol Med, Generat Scotland,Western Gen Hosp, Edinburgh, Midlothian, Scotland. [Rice, Kenneth M.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Schulze, Matthias B.] German Ctr Diabet Res DZD, Munich, Germany. [Goodarzi, Mark O.] Cedars Sinai Med Ctr, Div Endocrinol Diabet & Metab, Los Angeles, CA 90048 USA. [Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Meigs, James B.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Dupuis, Josee] NHLBI, Framingham Heart Study, Framingham, MA USA. RP Dupuis, J (reprint author), 3rd Floor,801 Massachusetts Ave, Boston, MA 02118 USA. EM dupuis@bu.edu OI Meidtner, Karina/0000-0001-5810-4062; Schulze, Matthias B./0000-0002-0830-5277 FU Chief Scientist Office [CZD/16/6, CZD/16/6/4]; Intramural NIH HHS; Medical Research Council [MC_PC_U127561128, MC_U106179471]; NCATS NIH HHS [UL1 TR000040, UL1 TR000124, UL1 TR001079, UL1-TR-000040, UL1-TR-001079, UL1TR000124]; NCRR NIH HHS [UL1-RR-025005, UL1 RR025005]; NHLBI NIH HHS [HHSN268200800007C, HHSN268201200036C, HL068986, HL080295, HL087652, HL103612, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, N01HC95159, N01HC95160, N01HC95161, N01HC95162, N01HC95163, N01HC95164, N01HC95165, N01HC95166, N01HC95167, N01HC95168, N01HC95169, N02HL64278, R01 HL068986, R01 HL071205, R01 HL071250, R01 HL071252, R01 HL071258, R01 HL071259, R01 HL080295, R01 HL087652, R01 HL087700, R01 HL088215, R01 HL103612, R01-HL-071051, R01-HL-071205, R01-HL-071250, R01-HL-071251, R01-HL-071252, R01-HL-071258, R01-HL-071259, R01-HL-087700, R01-HL-088215, U01 HL080295]; NIA NIH HHS [AG023629, R01 AG023629, R56 AG023629]; NIDDK NIH HHS [DK063491, K24 DK080140, P30 DK063491, R01 DK075681, R01 DK078616, R01 DK089256, R01-DK-075681, R01-DK-8925601, U01 DK078616]; PHS HHS [HHSN268200800007C, HHSN268201200036C]; Wellcome Trust NR 26 TC 0 Z9 0 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD APR PY 2016 VL 40 IS 3 BP 244 EP 252 DI 10.1002/gepi.21959 PG 9 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA DI6HQ UT WOS:000373600200007 PM 27027517 ER PT J AU Ananthakrishnan, AN Cagan, A Cai, TX Gainer, VS Shaw, SY Savova, G Churchill, S Karlson, EW Kohane, I Liao, KP Murphy, SN AF Ananthakrishnan, Ashwin N. Cagan, Andrew Cai, Tianxi Gainer, Vivian S. Shaw, Stanley Y. Savova, Guergana Churchill, Susanne Karlson, Elizabeth W. Kohane, Isaac Liao, Katherine P. Murphy, Shawn N. TI Comparative Effectiveness of Infliximab and Adalimumab in Crohn's Disease and Ulcerative Colitis SO INFLAMMATORY BOWEL DISEASES LA English DT Article DE infliximab; ulcerative colitis; treatment response; biologic; Crohn's disease ID ELECTRONIC HEALTH RECORDS; ANTI-TNF AGENTS; NETWORK METAANALYSIS; COMPARATIVE EFFICACY; MAINTENANCE THERAPY; CERTOLIZUMAB PEGOL; CLINICAL-RESPONSE; TRIAL; GASTROENTEROLOGY; GOLIMUMAB AB Background: The availability of monoclonal antibodies to tumor necrosis factor alpha has revolutionized management of Crohn's disease (CD) and ulcerative colitis. However, limited data exist regarding comparative effectiveness of these agents to inform clinical practice. Methods: This study consisted of patients with CD or ulcerative colitis initiation either infliximab (IFX) or adalimumab (ADA) between 1998 and 2010. A validated likelihood of nonresponse classification score using frequency of narrative mentions of relevant symptoms in the electronic health record was applied to assess comparative effectiveness at 1 year. Inflammatory bowel disease-related surgery, hospitalization, and use of steroids were determined during this period. Results: Our final cohort included 1060 new initiations of IFX (68% for CD) and 391 of ADA (79% for CD). In CD, the likelihood of nonresponse was higher in ADA than IFX (odds ratio, 1.62 and 95% CI, 1.21-2.17). Similar differences favoring efficacy of IFX were observed for the individual symptoms of diarrhea, pain, bleeding, and fatigue. However, there was no difference in inflammatory bowel disease-related surgery, hospitalizations, or prednisone use within 1 year after initiation of IFX or ADA in CD. There was no difference in narrative or codified outcomes between the 2 agents in ulcerative colitis. Conclusions: We identified a modestly higher likelihood of symptomatic nonresponse at 1 year for ADA compared with IFX in patients with CD. However, there were no differences in inflammatory bowel disease-related surgery or hospitalizations, suggesting these treatments are broadly comparable in effectiveness in routine clinical practice. C1 [Ananthakrishnan, Ashwin N.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Ananthakrishnan, Ashwin N.; Shaw, Stanley Y.; Karlson, Elizabeth W.; Kohane, Isaac; Liao, Katherine P.; Murphy, Shawn N.] Harvard Univ, Sch Med, Boston, MA USA. [Ananthakrishnan, Ashwin N.; Shaw, Stanley Y.; Murphy, Shawn N.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Cagan, Andrew; Gainer, Vivian S.] Partners HealthCare, Res IS & Comp, Charlestown, MA USA. [Cai, Tianxi] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Shaw, Stanley Y.] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Savova, Guergana] Boston Childrens Hosp, Childrens Hosp, Informat Program, Boston, MA USA. [Churchill, Susanne; Kohane, Isaac; Murphy, Shawn N.] Harvard Univ, Sch Med, Ctr Biomed Informat, Boston, MA USA. [Karlson, Elizabeth W.; Liao, Katherine P.] Brigham & Womens Hosp, Div Rheumatol Allergy & Immunol, 75 Francis St, Boston, MA 02115 USA. [Kohane, Isaac] Childrens Hosp Boston, Boston, MA USA. [Murphy, Shawn N.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Ananthakrishnan, AN (reprint author), Massachusetts Gen Hosp, Crohns & Colitis Ctr, Div Gastroenterol, 165 Cambridge St,9th Floor, Boston, MA 02114 USA. EM aananthakrishnan@mgh.harvard.edu FU NIH [U54-LM008748, K08 AR060257, K24 AR052403, P60 AR047782, R01 AR049880]; US National Institutes of Health [K23 DK097142]; Amgen; Harold and Duval Bowen Fund; Cubist FX Supported by NIH U54-LM008748. A. N. Ananthakrishnan is supported by funding from the US National Institutes of Health (K23 DK097142) and Amgen. K. P. Liao is supported by NIH K08 AR060257 and the Harold and Duval Bowen Fund. E. W. Karlson is supported by grants from the NIH (K24 AR052403, P60 AR047782, R01 AR049880).; A. N. Ananthakrishnan and S. Churchill received funding from Amgen; A. N. Ananthakrishnan has received research support from Cubist and has served on the scientific advisory boards for Cubist, AbbVie, and Exact Sciences. The other authors have no conflict of interest to disclose. NR 31 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 1078-0998 EI 1536-4844 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD APR PY 2016 VL 22 IS 4 BP 880 EP 885 DI 10.1097/MIB.0000000000000754 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DH7VR UT WOS:000373002500012 PM 26933751 ER PT J AU Adappa, ND Workman, AD Hadjiliadis, D Dorgan, DJ Frame, D Brooks, S Doghramji, L Palmer, JN Mansfield, C Reed, DR Cohen, NA AF Adappa, Nithin D. Workman, Alan D. Hadjiliadis, Denis Dorgan, Daniel J. Frame, Danielle Brooks, Steven Doghramji, Laurel Palmer, James N. Mansfield, Corrine Reed, Danielle R. Cohen, Noam A. TI T2R38 genotype is correlated with sinonasal quality of life in homozygous F508 cystic fibrosis patients SO INTERNATIONAL FORUM OF ALLERGY & RHINOLOGY LA English DT Article DE chronic rhinosinusitis; cystic fibrosis; T2R38; SNOT-22; bitter taste receptor; genetics ID TASTE RECEPTOR T2R38; SINUS SURGERY; CHRONIC RHINOSINUSITIS; PSEUDOMONAS-AERUGINOSA; PARANASAL SINUSES; INFECTION; DISEASE; NASAL; MECHANISMS; PHENOTYPE AB BackgroundChronic rhinosinusitis (CRS) is very prevalent in the cystic fibrosis (CF) patient population, and leads to high morbidity and markedly decreased quality of life (QOL). Identification of genetic markers that contribute to CRS symptoms in these patients can allow for risk stratification and tailoring of medical and surgical treatments. T2R38 is a bitter taste receptor expressed in the sinonasal tract, and nonfunctional alleles of this receptor have been implicated in treatment-refractory CRS in non-CF patients. The purpose of this study is to investigate the significance of T2R38 genotype in the variability of sinonasal QOL and CRS disease severity in a sample of CF patients. MethodsF508 homozygous CF patients were recruited from the University of Pennsylvania Cystic Fibrosis Center and were genotyped for the TAS2R38 locus. To assess sinonasal symptom severity, a 22-item Sino-Nasal Outcome Test (SNOT-22) was collected from each patient. Additional demographic and medical history data was obtained at the time of patient enrollment. ResultsA total of 49 F508 homozygous CF patients aged 18 to 32 years were included in the final SNOT-22 score analysis. Individuals with 2 functional T2R38 alleles (PAV/PAV) had significantly lower SNOT-22 scores (n = 49, p < 0.05). On further breakdown of SNOT-22 subcategories, rhinologic symptoms specifically were less severe in PAV/PAV patients than patients with other genotypes (n = 47, p < 0.05). ConclusionOur investigation indicates that T2R38 genotype correlates both with SNOT-22 scores and rhinologic-specific QOL in F508 homozygous CF patients. C1 [Adappa, Nithin D.; Workman, Alan D.; Brooks, Steven; Doghramji, Laurel; Palmer, James N.; Cohen, Noam A.] Univ Penn, Perelman Sch Med, Dept Otorhinolaryngol Head & Neck Surg, 5th Floor Ravdin Bldg,3400 Spruce St, Philadelphia, PA 19104 USA. [Hadjiliadis, Denis; Dorgan, Daniel J.; Frame, Danielle] Univ Penn, Dept Med, Perelman Sch Med, Paul Harron Jr Lung Ctr, 5th Floor Ravdin Bldg,3400 Spruce St, Philadelphia, PA 19104 USA. [Mansfield, Corrine; Reed, Danielle R.; Cohen, Noam A.] Monell Smell & Taste Ctr, Philadelphia, PA USA. [Cohen, Noam A.] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. RP Adappa, ND (reprint author), Univ Penn, Med Ctr, Dept Otorhinolaryngol Head & Neck Surg, 5th Floor Ravdin Bldg,3400 Spruce St, Philadelphia, PA 19104 USA. EM Nithin.Adappa@uphs.upenn.edu FU American Rhinology Society; Cystic Fibrosis Foundation FX American Rhinology Society (to N.D.A.); Cystic Fibrosis Foundation (to N.D.A.). NR 31 TC 6 Z9 6 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2042-6976 EI 2042-6984 J9 INT FORUM ALLERGY RH JI Int. Forum Allergy Rhinol. PD APR PY 2016 VL 6 IS 4 BP 356 EP 361 DI 10.1002/alr.21675 PG 6 WC Otorhinolaryngology SC Otorhinolaryngology GA DI6OH UT WOS:000373618500003 PM 26678226 ER PT J AU Bandyopadhaya, A Constantinou, C Psychogios, N Ueki, R Yasuhara, S Martyn, JAJ Wilhelmy, J Mindrinos, M Rahme, LG Tzika, AA AF Bandyopadhaya, Arunava Constantinou, Caterina Psychogios, Nikolaos Ueki, Ryusuke Yasuhara, Shingo Martyn, J. A. Jeevendra Wilhelmy, Julie Mindrinos, Michael Rahme, Laurence G. Tzika, A. Aria TI Bacterial-excreted small volatile molecule 2-aminoacetophenone induces oxidative stress and apoptosis in murine skeletal muscle SO INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE LA English DT Article DE Pseudomonas aeruginosa; 2-aminoacetophenone; skeletal muscle; oxidative stress; apoptosis; mitochondria; nuclear magnetic resonance; microarrays; genomics ID PROGRAMMED CELL-DEATH; IN-VIVO DETECTION; PSEUDOMONAS-AERUGINOSA; MITOCHONDRIAL DYSFUNCTION; CYSTIC-FIBROSIS; PROTEIN-METABOLISM; VIRUS-INFECTION; BURN-TRAUMA; PATHWAYS; SPECTROSCOPY AB Oxidative stress induces mitochondrial dysfunction and facilitates apoptosis, tissue damage or metabolic alterations following infection. We have previously discovered that the Pseudomonas aeruginosa (PA) quorum sensing (QS)-excreted small volatile molecule, 2-aminoacetophenone (2-AA), which is produced in infected human tissue, promotes bacterial phenotypes that favor chronic infection, while also compromising muscle function and dampens the pathogen-induced innate immune response, promoting host tolerance to infection. In this study, murine whole-genome expression data have demonstrated that 2-AA affects the expression of genes involved in reactive oxygen species (ROS) homeostasis, thus producing an oxidative stress signature in skeletal muscle. The results of the present study demonstrated that the expression levels of genes involved in apoptosis signaling pathways were upregulated in the skeletal muscle of 2-AA-treated mice. To confirm the results of our transcriptome analysis, we used a novel high-resolution magic-angle-spinning (HRMAS), proton (H-1) nuclear magnetic resonance (NMR) method and observed increased levels of bisallylic methylene fatty acyl protons and vinyl protons, suggesting that 2-AA induces skeletal muscle cell apoptosis. This effect was corroborated by our results demonstrating the downregulation of mitochondrial membrane potential in vivo in response to 2-AA. The findings of the present study indicate that the bacterial infochemical, 2-AA, disrupts mitochondrial functions by inducing oxidative stress and apoptosis signaling and likely promotes skeletal muscle dysfunction, which may favor chronic/persistent infection. C1 [Bandyopadhaya, Arunava; Constantinou, Caterina; Rahme, Laurence G.] Harvard Univ, Sch Med, Dept Surg Microbiol & Immunobiol, Boston, MA 02114 USA. [Bandyopadhaya, Arunava; Constantinou, Caterina; Rahme, Laurence G.] Massachusetts Gen Hosp, Ctr Surg Innovat & Bioengn, Dept Surg, Mol Surg Lab, Boston, MA 02114 USA. [Bandyopadhaya, Arunava; Constantinou, Caterina; Rahme, Laurence G.] Shriners Burns Hosp, Boston, MA 02114 USA. [Bandyopadhaya, Arunava; Constantinou, Caterina; Psychogios, Nikolaos; Rahme, Laurence G.; Tzika, A. Aria] Massachusetts Gen Hosp, Ctr Surg Innovat & Bioengn, Dept Surg, NMR Surg Lab, Boston, MA 02114 USA. [Bandyopadhaya, Arunava; Constantinou, Caterina; Psychogios, Nikolaos; Rahme, Laurence G.; Tzika, A. Aria] Harvard Univ, Sch Med, Shriners Burns Hosp, Boston, MA 02114 USA. [Psychogios, Nikolaos; Tzika, A. Aria] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02129 USA. [Psychogios, Nikolaos; Ueki, Ryusuke; Yasuhara, Shingo; Martyn, J. A. Jeevendra; Tzika, A. Aria] Harvard Univ, Sch Med, Boston, MA 02129 USA. [Ueki, Ryusuke; Yasuhara, Shingo; Martyn, J. A. Jeevendra] Massachusetts Gen Hosp, Dept Anesthesiol & Crit Care, Boston, MA 02114 USA. [Wilhelmy, Julie; Mindrinos, Michael] Stanford Univ, Dept Biochem, Sch Med, Stanford, CA 94305 USA. RP Rahme, LG (reprint author), Harvard Univ, Sch Med, Dept Surg Microbiol & Immunobiol, Boston, MA 02114 USA.; Rahme, LG (reprint author), Massachusetts Gen Hosp, Ctr Surg Innovat & Bioengn, Dept Surg, Mol Surg Lab, Boston, MA 02114 USA.; Tzika, AA (reprint author), Massachusetts Gen Hosp, Ctr Surg Innovat & Bioengn, Dept Surg, NMR Surg Lab, Boston, MA 02114 USA.; Tzika, AA (reprint author), Harvard Univ, Sch Med, Shriners Burns Hosp, Boston, MA 02114 USA. EM rahme@molbio.mgh.harvard.edu; atzika@hms.harvard.edu OI Constantinou, Caterina/0000-0003-3589-0739 FU Shriner's Hospital for Children research grants [87100, 85200]; Basic Research Award; US Army Medical Research Acquisition Act of US Department of Defense, Congressionally Directed Medical Research Programs (CDMRP) [W81XWH-10-DMRDP-BRA]; Defense Medical Research and Development Program (DMRDP); Center grant of the National Institutes of Health (NIH); NIH [AI105902] FX This study was supported in part by Shriner's Hospital for Children research grants (nos. 87100 and 85200), and Basic Research Award, W81XWH-10-DMRDP-BRA from US Army Medical Research Acquisition Act of US Department of Defense, Congressionally Directed Medical Research Programs (CDMRP), Defense Medical Research and Development Program (DMRDP) to Laurence G. Rahme, and by a Center grant of the National Institutes of Health (NIH) to the Stanford Genome Technology Cente, as well as by NIH grant AI105902. We acknowledge Dr Damien Maura at the Massachusetts General Hospital and Harvard Medical School for his insightful comments on the manuscript. NR 85 TC 2 Z9 2 U1 1 U2 1 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1107-3756 EI 1791-244X J9 INT J MOL MED JI Int. J. Mol. Med. PD APR PY 2016 VL 37 IS 4 BP 867 EP 878 DI 10.3892/ijmm.2016.2487 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DI4TS UT WOS:000373492900001 PM 26935176 ER PT J AU Schmid, M Hanske, J Ravi, P Krishna, N Reznor, G Meyer, CP Fisch, M Noldus, J Nguyen, PL Trinh, QD AF Schmid, Marianne Hanske, Julian Ravi, Praful Krishna, Nandita Reznor, Gally Meyer, Christian P. Fisch, Margit Noldus, Joachim Nguyen, Paul L. Quoc-Dien Trinh TI Relationship between androgen deprivation therapy and community-acquired respiratory infections in patients with prostate cancer SO INTERNATIONAL JOURNAL OF UROLOGY LA English DT Article DE androgen deprivation therapy; pneumonia; prostate cancer; respiratory infections; Surveillance; Epidemiology and End Results-Medicare ID HORMONE AGONISTS; RISK; HOSPITALIZATIONS; POPULATION; FRACTURE; DISEASE; MEN AB Objectives: To investigate the dose-dependent effect of androgen deprivation therapy on community-acquired respiratory infections in patients with localized prostate cancer. Methods: We identified 52 905 men diagnosed with localized prostate cancer within the Surveillance, Epidemiology and End Results-Medicare database between 1991 and 2006. We compared those who did not receive androgen deprivation therapy with those who received androgen deprivation therapy within 2 years of diagnosis, calculated as monthly equivalent doses (< 7, 7-11, > 11 doses), or orchiectomy. Adjusted Cox hazard models were fitted to predict the risk of community-acquired respiratory infections (acute sinusitis, acute bronchitis, [severe] pneumonia) in patients treated with medical androgen deprivation therapy versus orchiectomy versus none. Results: Overall, 43.4% received medical androgen deprivation therapy. These patients more likely experienced respiratory events compared with those who did not receive androgen deprivation therapy or who underwent orchiectomy (62.2% vs 54.5% vs 47.8%, P < 0.001). The risk of experiencing any respiratory event increased with the number of doses received. For example, men receiving > 11 doses of androgen deprivation therapy were at greatest risk of acute sinusitis, acute bronchitis and pneumonia (HR 1.13, 1.26 and 1.15, respectively, all P < 0.001), except severe pneumonia. Furthermore, we did not detect any relationship between orchiectomy and respiratory events. Study limitations include the utilization of a retrospective population-based dataset. Conclusions: Increased exposure to medical androgen deprivation therapy for men with localized prostate cancer is associated with a higher risk of community-acquired respiratory infections. Our results suggest that respiratory complications represent potentially underreported complications of medical androgen deprivation therapy. C1 [Schmid, Marianne; Hanske, Julian; Krishna, Nandita; Reznor, Gally; Meyer, Christian P.; Quoc-Dien Trinh] Harvard Univ, Sch Med, Brigham & Womens Hosp, Ctr Surg & Publ Hlth, 45 Francis St,ASB II-3, Boston, MA 02115 USA. [Schmid, Marianne; Hanske, Julian; Krishna, Nandita; Reznor, Gally; Meyer, Christian P.; Quoc-Dien Trinh] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Urol Surg, 45 Francis St,ASB II-3, Boston, MA 02115 USA. [Schmid, Marianne; Meyer, Christian P.; Fisch, Margit] Univ Med Ctr Hamburg Eppendorf, Dept Urol, Hamburg, Germany. [Hanske, Julian; Noldus, Joachim] Ruhr Univ Bochum, Marien Hosp, Dept Urol, Herne, Germany. [Ravi, Praful] Mayo Clin, Dept Med, Rochester, MN USA. [Nguyen, Paul L.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dana Farber Canc Inst,Dept Radiat Oncol, 45 Francis St,ASB II-3, Boston, MA 02115 USA. RP Trinh, QD (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Ctr Surg & Publ Hlth,Div Urol Surg, 45 Francis St,ASB II-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; University Medical Center Hamburg-Eppendorf; Heinrich Hertz-Stiftung FX Quoc-Dien Trinh is supported by an unrestricted educational grant from the Vattikuti Urology Institute and the Professor Walter Morris-Hale Distinguished Chair in Urologic Oncology at Brigham and Women's Hospital. Marianne Schmid is supported by the Equal Opportunity Grant for Women of the University Medical Center Hamburg-Eppendorf. Julian Hanske is supported by a grant from the Heinrich Hertz-Stiftung. NR 30 TC 2 Z9 2 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0919-8172 EI 1442-2042 J9 INT J UROL JI Int. J. Urol. PD APR PY 2016 VL 23 IS 4 BP 305 EP 311 DI 10.1111/iju.13043 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA DI8TZ UT WOS:000373776200003 PM 26763083 ER PT J AU Hemal, K Pagidipati, NJ Coles, A Dolor, RJ Mark, DB Pellikka, PA Hoffmann, U Litwin, SE Daubert, MA Shah, SH Ariani, K Bullock-Palmer, RP Martinez, B Lee, KL Douglas, PS AF Hemal, Kshipra Pagidipati, Neha J. Coles, Adrian Dolor, Rowena J. Mark, Daniel B. Pellikka, Patricia A. Hoffmann, Udo Litwin, Sheldon E. Daubert, Melissa A. Shah, Svati H. Ariani, Kevin Bullock-Palmer, Renee P. Martinez, Beth Lee, Kerry L. Douglas, Pamela S. TI Sex Differences in Demographics, Risk Factors, Presentation, and Noninvasive Testing in Stable Outpatients With Suspected Coronary Artery Disease SO JACC-CARDIOVASCULAR IMAGING LA English DT Article DE angina; CAD; risk factors; sex ID AMERICAN-HEART-ASSOCIATION; GENDER-DIFFERENCES; MYOCARDIAL-INFARCTION; SYMPTOM PRESENTATION; EXERCISE ECHOCARDIOGRAPHY; CARDIOVASCULAR RISK; CHEST-PAIN; MANAGEMENT; DIAGNOSIS; OUTCOMES AB OBJECTIVES The aim of this study was to determine whether presentation, risk assessment, testing choices, and results differ by sex in stable symptomatic outpatients with suspected coronary artery disease (CAD). BACKGROUND Although established CAD presentations differ by sex, little is known about stable, suspected CAD. METHODS The characteristics of 10,003 men and women in the PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) trial were compared using chi-square and Wilcoxon rank-sum tests. Sex differences in test selection and predictors of test positivity were examined using logistic regression. RESULTS Women were older (62.4 years of age vs. 59.0 years of age) and were more likely to be hypertensive (66.6% vs. 63.2%), dyslipidemic (68.9% vs. 66.3%), and to have a family history of premature CAD (34.6% vs. 29.3) (all p values<0.005). Women were less likely to smoke (45.6% vs. 57.0%; p<0.001), although their prevalence of diabetes was similar to that in men(21.8% vs. 21.0%; p = 0.30). Chest pain was the primary symptomin 73.2% of women versus 72.3% of men (p = 0.30), and was characterized as "crushing/pressure/ squeezing/tightness" in 52.5% of women versus 46.2% of men (p<0.001). Compared with men, all risk scores characterized women as being at lower risk, and providers were more likely to characterize women as having a low (<30%) pre-test probability of CAD (40.7% vs. 34.1%; p < 0.001). Compared with men, women were more often referred to imaging tests (adjusted odds ratio: 1.21; 95% confidence interval: 1.01 to 1.44) than nonimaging tests. Women were less likely to have a positive test (9.7% vs. 15.1%; p < 0.001). Although univariate predictors of test positivity were similar, in multivariable models, age, body mass index, and Framingham risk score were predictive of a positive test in women, whereas Framingham and Diamond and Forrester risk scores were predictive in men. CONCLUSIONS Patient sex influences the entire diagnostic pathway for possible CAD, from baseline risk factors and presentation to noninvasive test outcomes. These differences highlight the need for sex-specific approaches for the evaluation of CAD. (C) 2016 by the American College of Cardiology Foundation. C1 [Hemal, Kshipra; Pagidipati, Neha J.; Coles, Adrian; Dolor, Rowena J.; Mark, Daniel B.; Daubert, Melissa A.; Shah, Svati H.; Martinez, Beth; Lee, Kerry L.; Douglas, Pamela S.] Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC 27715 USA. [Dolor, Rowena J.; Shah, Svati H.] Duke Univ, Sch Med, Dept Med, Durham, NC 27715 USA. [Pellikka, Patricia A.] Mayo Clin, Coll Med, Rochester, MN USA. [Hoffmann, Udo] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Litwin, Sheldon E.] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. [Ariani, Kevin] Northridge Hosp, Med Ctr, Northridge, CA USA. [Bullock-Palmer, Renee P.] Deborah Heart & Lung Ctr, Browns Mills, NJ USA. RP Douglas, PS (reprint author), Duke Univ, Sch Med, 7022 North Pavil DUMC,POB 17969, Durham, NC 27715 USA. EM pamela.douglas@duke.edu FU National Heart, Lung, and Blood Institute [R01 HL098237, R01 HL098236, R01 HL098305, R01 HL098235]; Medtronic; CardioDx; St. Jude Medical; Eli Lilly; Bristol-Myers Squibb; Gilead Sciences; AGA Medical; Merck; Oxygen Biotherapeutics; AstraZeneca; Siemens Healthcare; HeartFlow FX From the aDuke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina; bDepartment of Medicine, Duke University School of Medicine, Durham, North Carolina; cMayo Clinic College of Medicine, Rochester, Minnesota; dMassachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; eDepartment of Medicine, Medical University of South Carolina, Charleston, South Carolina; fNorthridge Hospital Medical Center, Northridge, California; and the gDeborah Heart and Lung Center, Browns Mills, New Jersey. The PROMISE trial was funded by National Heart, Lung, and Blood Institute grants R01 HL098237, R01 HL098236, R01 HL098305, and R01 HL098235. The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The views expressed in this paper do not necessarily represent the official views of the National Heart, Lung, and Blood Institute. Dr. Mark has received personal fees from Medtronic, CardioDx, and St. Jude Medical; and grant support from Eli Lilly, Bristol-Myers Squibb, Gilead Sciences, AGA Medical, Merck, Oxygen Biotherapeutics, and AstraZeneca. Dr. Hoffmann has received grant support from Siemens Healthcare and HeartFlow. Dr. Douglas has received grant support from HeartFlow; and serves on a data and safety monitoring board for General Electric Healthcare. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 35 TC 7 Z9 7 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-878X EI 1876-7591 J9 JACC-CARDIOVASC IMAG JI JACC-Cardiovasc. Imag. PD APR PY 2016 VL 9 IS 4 BP 337 EP 346 DI 10.1016/j.jcmg.2016.02.001 PG 10 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA DI8AE UT WOS:000373722300001 PM 27017234 ER PT J AU Shi, L Dorbala, S Paez, D Shaw, LJ Zukotynski, KA Pascual, TNB Karthikeyan, G Vitola, JV Better, N Bokhari, N Rehani, MM Kashyap, R Dondi, M Mercuri, M Einstein, AJ AF Shi, Lynn Dorbala, Sharmila Paez, Diana Shaw, Leslee J. Zukotynski, Katherine A. Pascual, Thomas N. B. Karthikeyan, Ganesan Vitola, Joao V. Better, Nathan Bokhari, Nadia Rehani, Madan M. Kashyap, Ravi Dondi, Maurizio Mercuri, Mathew Einstein, Andrew J. CA INCAPS Investigators Grp TI Gender Differences in Radiation Dose From Nuclear Cardiology Studies Across the World Findings From the INCAPS Registry SO JACC-CARDIOVASCULAR IMAGING LA English DT Article DE gender; nuclear cardiology; radiation exposure ID MYOCARDIAL-PERFUSION SPECT; RISK STRATIFICATION; PROGNOSTIC VALUE; WOMEN; EXPOSURE; TOMOGRAPHY; MANAGEMENT; MEDICINE; DISEASE; SEX AB OBJECTIVES The aim of this study was to investigate gender-based differences in nuclear cardiology practice globally, with a particular focus on laboratory volume, radiation dose, protocols, and best practices. BACKGROUND It is unclear whether gender-based differences exist in radiation exposure for nuclear cardiology procedures. METHODS In a large, multicenter, observational, cross-sectional study encompassing 7,911 patients in 65 countries, radiation effective dose was estimated for each examination. Patient-level best practices relating to radiation exposure were compared between genders. Analysis of covariance was used to determine any difference in radiation exposure according to gender, region, and the interaction between gender and region. Linear, logistic, and hierarchical regression models were developed to evaluate gender-based differences in radiation exposure and laboratory adherence to best practices. The study also included the United Nations Gender Inequality Index and Human Development Index as covariates in multivariable models. RESULTS The proportion of myocardial perfusion imaging studies performed in women varied among countries; however, there was no significant correlation with the Gender Inequality Index. Globally, mean effective dose for nuclear cardiology procedures was only slightly lower in women (9.6 +/- 4.5 mSv) than in men (10.3 +/- 4.5 mSv; p < 0.001), with a difference of only 0.3 mSv in a multivariable model adjusting for patients' age and weight. Stress-only imaging was performed more frequently in women (12.5% vs. 8.4%; p < 0.001); however, camera-based dose reduction strategies were used less frequently in women (58.6% vs. 65.5%; p < 0.001). \CONCLUSIONS Despite significant worldwide variation in best practice use and radiation doses from nuclear cardiology procedures, only small differences were observed between genders worldwide. Regional variations noted in myocardial perfusion imaging use and radiation dose offer potential opportunities to address gender-related differences in delivery of nuclear cardiology care. (C) 2016 by the American College of Cardiology Foundation. C1 [Shi, Lynn] Columbia Univ, Coll Phys & Surg, New York, NY USA. [Dorbala, Sharmila] Harvard Univ, Brigham & Womens Hosp, Dept Med, Div Cardiol, Boston, MA 02115 USA. [Paez, Diana; Pascual, Thomas N. B.; Kashyap, Ravi; Dondi, Maurizio] IAEA, Div Human Hlth, Sect Nucl Med & Diagnost Imaging, A-1400 Vienna, Austria. [Shaw, Leslee J.] Emory Univ, Sch Med, Dept Med, Div Cardiol, Atlanta, GA USA. [Shaw, Leslee J.] Emory Univ, Sch Med, Emory Clin Cardiovasc Res Inst, Atlanta, GA USA. [Zukotynski, Katherine A.] McMaster Univ, Dept Med, Hamilton, ON, Canada. [Zukotynski, Katherine A.] McMaster Univ, Dept Radiol, Hamilton, ON, Canada. [Karthikeyan, Ganesan] All India Inst Med Sci, Dept Cardiol, New Delhi, India. [Vitola, Joao V.] Quanta Diagnost & Terapia, Curitiba, Parana, Brazil. [Better, Nathan] Royal Melbourne Hosp, Dept Cardiol, Melbourne, Vic, Australia. [Better, Nathan] Royal Melbourne Hosp, Dept Nucl Med, Melbourne, Vic, Australia. [Bokhari, Nadia; Mercuri, Mathew; Einstein, Andrew J.] Columbia Univ, Med Ctr, Dept Med, Div Cardiol, New York, NY USA. [Rehani, Madan M.] IAEA, Radiat Protect Patients Unit, A-1400 Vienna, Austria. [Rehani, Madan M.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Einstein, Andrew J.] New York Presbyterian Hosp, New York, NY USA. [Einstein, Andrew J.] Columbia Univ, Dept Radiol, Med Ctr, New York, NY USA. RP Einstein, AJ (reprint author), Columbia Univ, Med Ctr, Div Cardiol, 622 West 168th St PH 10-203, New York, NY 10032 USA. EM andrew.einstein@columbia.edu RI Lahoutte, Tony/O-6381-2016; Maffioli, Lorenzo Stefano/Q-4985-2016; OI Maffioli, Lorenzo Stefano/0000-0002-8867-2447; Murthy, Venkatesh/0000-0002-7901-1321; florimonte, luigia/0000-0002-5254-6852; Al-Mallah, Mouaz/0000-0003-2348-0484 FU National Institutes of Health-National Heart, Lung, and Blood Institute Summer Research Program at Columbia University [5T35HL007616-34]; International Atomic Energy Agency; Margaret Q. Landenberger Research Foundation in memory of Professor A; Astellas; GE Healthcare; Philips Healthcare; Spectrum Dynamics; Toshiba America Medical Systems FX From the aCollege of Physicians and Surgeons, Columbia University, New York, New York; bDivision of Cardiology, Department of Medicine, Brigham and Women's Hospital, Harvard University, Boston, Massachusetts; cSection of Nuclear Medicine and Diagnostic Imaging, Division of Human Health, International Atomic Energy Agency, Vienna, Austria; dDivision of Cardiology, Department of Medicine, and Emory Clinical Cardiovascular Research Institute, Emory University School of Medicine, Atlanta, Georgia; eDepartments of Medicine and Radiology, McMaster University, Hamilton, Ontario, Canada; fDepartment of Cardiology, All India Institute of Medical Sciences, New Delhi, India; gQuanta Diagnostico & Terapia, Curitiba, Brazil; hDepartments of Cardiology and Nuclear Medicine, Royal Melbourne Hospital, Melbourne, Australia; iDepartment of Medicine, Cardiology Division, Columbia University Medical Center, New York, New York; jRadiation Protection of Patients Unit, International Atomic Energy Agency, Vienna, Austria; kDepartment of Radiology, Massachusetts General Hospital, Boston, Massachusetts; lDepartment of Medicine, Cardiology Division, Columbia University Medical Center and New York-Presbyterian Hospital, New York, New York; and the mDepartment of Radiology, Columbia University Medical Center and New York-Presbyterian Hospital, New York, New York. Funding was provided by the National Institutes of Health-National Heart, Lung, and Blood Institute Summer Research Program at Columbia University (5T35HL007616-34); the International Atomic Energy Agency; and the Margaret Q. Landenberger Research Foundation in memory of Professor A. Donny Strosberg; and the Irving Scholars Program. Dr. Dorbala has received an institutional research grant from Astellas; and owns stock in GE. Dr. Einstein has received institutional research grants for other research from GE Healthcare, Philips Healthcare, Spectrum Dynamics, and Toshiba America Medical Systems. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Heinrich Schelbert, MD, served as the Guest Editor for this article. NR 26 TC 2 Z9 2 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-878X EI 1876-7591 J9 JACC-CARDIOVASC IMAG JI JACC-Cardiovasc. Imag. PD APR PY 2016 VL 9 IS 4 BP 376 EP 384 DI 10.1016/j.jcmg.2016.01.001 PG 9 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA DI8AE UT WOS:000373722300007 PM 27056156 ER PT J AU Reeves, GR Forman, DE AF Reeves, Gordon R. Forman, Daniel E. TI Gait Speed: Stepping Towards Improved Assessment of Heart Failure Patients SO JACC-HEART FAILURE LA English DT Editorial Material DE frailty; gait speed; heart failure; hospitalization; prognosis ID PRESERVED EJECTION FRACTION; CARDIOVASCULAR HEALTH; ELDERLY-PATIENTS; OLDER PERSONS; RISK-FACTORS; ADULTS; OUTCOMES; IMPACT; CARE C1 [Reeves, Gordon R.] Thomas Jefferson Univ, Dept Med, Sidney Kimmel Med Coll, Philadelphia, PA 19107 USA. [Forman, Daniel E.] Univ Pittsburgh, Med Ctr, Geriatr Cardiol Sect, Div Cardiol, Pittsburgh, PA 15213 USA. [Forman, Daniel E.] Univ Pittsburgh, Med Ctr, Geriatr Cardiol Sect, Div Geriatr, Pittsburgh, PA 15213 USA. [Forman, Daniel E.] VA Pittsburgh Healthcare Syst, Ctr Geriatr Res Educ & Clin, Pittsburgh, PA USA. [Forman, Daniel E.] Univ Pittsburgh, Dept Med, 930 Scaife Hall, Pittsburgh, PA 15213 USA. RP Forman, DE (reprint author), Univ Pittsburgh, Geriatr Cardiol Sect, 3471 Fifth Ave,Suite 500, Pittsburgh, PA 15213 USA. EM formand@pitt.edu NR 16 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 2213-1779 EI 2213-1787 J9 JACC-HEART FAIL JI JACC-Heart Fail. PD APR PY 2016 VL 4 IS 4 BP 299 EP 300 DI 10.1016/j.jchf.2016.02.002 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DI8KT UT WOS:000373750600010 PM 27033017 ER PT J AU Auerbach, AD Kripalani, S Vasilevskis, EE Sehgal, N Lindenauer, PK Metlay, JP Fletcher, G Ruhnke, GW Flanders, SA Kim, C Williams, MV Thomas, L Giang, V Herzig, SJ Patel, K Boscardin, WJ Robinson, EJ Schnipper, JL AF Auerbach, Andrew D. Kripalani, Sunil Vasilevskis, Eduard E. Sehgal, Neil Lindenauer, Peter K. Metlay, Joshua P. Fletcher, Grant Ruhnke, Gregory W. Flanders, Scott A. Kim, Christopher Williams, Mark V. Thomas, Larissa Giang, Vernon Herzig, Shoshana J. Patel, Kanan Boscardin, W. John Robinson, Edmondo J. Schnipper, Jeffrey L. TI Preventability and Causes of Readmissions in a National Cohort of General Medicine Patients SO JAMA INTERNAL MEDICINE LA English DT Article ID ADVERSE DRUG EVENTS; HOSPITAL READMISSIONS; PHARMACIST INTERVENTION; RANDOMIZED-TRIAL; CARE; RISK; QUALITY; TRANSITIONS; STRATEGIES; RATIONALE AB IMPORTANCE Readmission penalties have catalyzed efforts to improve care transitions, but few programs have incorporated viewpoints of patients and health care professionals to determine readmission preventability or to prioritize opportunities for care improvement. OBJECTIVES To determine preventability of readmissions and to use these estimates to prioritize areas for improvement. DESIGN, SETTING, AND PARTICIPANTS An observational studywas conducted of 1000 general medicine patients readmitted within 30 days of discharge to 12 US academic medical centers between April 1, 2012, and March 31, 2013. We surveyed patients and physicians, reviewed documentation, and performed 2-physician case review to determine preventability of and factors contributing to readmission. We used bivariable statistics to compare preventable and nonpreventable readmissions, multivariable models to identify factors associated with potential preventability, and baseline risk factor prevalence and adjusted odds ratios (aORs) to determine the proportion of readmissions affected by individual risk factors. MAIN OUTCOME AND MEASURE Likelihood that a readmission could have been prevented. RESULTS The study cohort comprised 1000 patients (median age was 55 years). Of these, 269 (26.9%) were considered potentially preventable. In multivariable models, factors most strongly associated with potential preventability included emergency department decision making regarding the readmission (aOR, 9.13; 95% CI, 5.23-15.95), failure to relay important information to outpatient health care professionals (aOR, 4.19; 95% CI, 2.17-8.09), discharge of patients too soon (aOR, 3.88; 95% CI, 2.44-6.17), and lack of discussions about care goals among patients with serious illnesses (aOR, 3.84; 95% CI, 1.39-10.64). The most common factors associated with potentially preventable readmissions included emergency department decision making (affecting 9.0%; 95% CI, 7.1%-10.3%), inability to keep appointments after discharge (affecting 8.3%; 95% CI, 4.1%-12.0%), premature discharge from the hospital (affecting 8.7%; 95% CI, 5.8%-11.3%), and patient lack of awareness of whom to contact after discharge (affecting 6.2%; 95% CI, 3.5%-8.7%). CONCLUSIONS AND RELEVANCE Approximately one-quarter of readmissions are potentially preventable when assessed using multiple perspectives. High-priority areas for improvement efforts include improved communication among health care teams and between health care professionals and patients, greater attention to patients' readiness for discharge, enhanced disease monitoring, and better support for patient self-management. C1 [Auerbach, Andrew D.; Sehgal, Neil] Univ Calif San Francisco, Dept Med, Div Hosp Med, 505 Parnassus Ave,POB 0131, San Francisco, CA 94143 USA. [Kripalani, Sunil; Vasilevskis, Eduard E.] Vanderbilt Univ, Dept Med, Sect Hosp Med Vanderbilt, Nashville, TN USA. [Kripalani, Sunil; Vasilevskis, Eduard E.] Vanderbilt Univ, Ctr Clin Qual & Implementat Res, 221 Kirkland Hall, Nashville, TN 37235 USA. [Lindenauer, Peter K.] Tufts Univ, Sch Med, Dept Med, Ctr Qual Care Res,Baystate Med Ctr, Boston, MA 02111 USA. [Metlay, Joshua P.] Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. [Fletcher, Grant] Univ Washington, Harborview Med Ctr, Div Gen Internal Med, 325 9th Ave, Seattle, WA 98104 USA. [Ruhnke, Gregory W.] Univ Chicago, Dept Med, Sect Hosp Med, 5841 S Maryland Ave, Chicago, IL 60637 USA. [Flanders, Scott A.; Kim, Christopher] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Williams, Mark V.] Univ Kentucky, Coll Med, Ctr Hlth Serv Res, Louisville, KY USA. [Thomas, Larissa] San Francisco Gen Hosp, Div Gen Internal Med, San Francisco, CA 94110 USA. [Giang, Vernon] Calif Pacific Med Ctr, Dept Med, San Francisco, CA USA. [Herzig, Shoshana J.] Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care, Boston, MA 02215 USA. [Patel, Kanan] Univ Calif San Francisco, Dept Med, Div Geriatr, 505 Parnassus Ave,POB 0131, San Francisco, CA 94143 USA. [Boscardin, W. John] Univ Calif San Francisco, Dept Med, 505 Parnassus Ave,POB 0131, San Francisco, CA 94143 USA. [Boscardin, W. John] Univ Calif San Francisco, Dept Epidemiol & Biostat, 505 Parnassus Ave,POB 0131, San Francisco, CA 94143 USA. [Robinson, Edmondo J.] Christiana Care Hlth Syst, Value Inst, Wilmington, DE USA. [Robinson, Edmondo J.] Christiana Care Hlth Syst, Dept Med, Wilmington, DE USA. [Schnipper, Jeffrey L.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Hosp Med Serv,Div Gen Med, Boston, MA 02115 USA. RP Auerbach, AD (reprint author), Univ Calif San Francisco, Dept Med, Div Hosp Med, 505 Parnassus Ave,POB 0131, San Francisco, CA 94143 USA. EM andrew.auerbach@ucsf.edu OI Robinson, Edmondo/0000-0001-9625-6235 FU National Heart, Lung, and Blood Institute [K24HL098372]; American Association of Medical Colleges; National Institute on Aging [2 UL1 TR000445-06] FX Dr Auerbach is supported by grant K24HL098372 from the National Heart, Lung, and Blood Institute. This work was supported by an unrestricted research grant from the American Association of Medical Colleges and in part by grant 2 UL1 TR000445-06 from the National Institute on Aging. NR 38 TC 19 Z9 19 U1 2 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD APR PY 2016 VL 176 IS 4 BP 484 EP 493 DI 10.1001/jamainternmed.2015.7863 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA DI3EG UT WOS:000373380600017 PM 26954564 ER PT J AU Atkins, D Kansagara, D AF Atkins, David Kansagara, Devan TI Reducing Readmissions-Destination or Journey? SO JAMA INTERNAL MEDICINE LA English DT Editorial Material ID CARE TRANSITIONS; RATES C1 [Atkins, David] US Dept Vet Affairs, Off Res & Dev, Hlth Serv Res & Dev, 10P9H,810 Vermont Ave NW, Washington, DC 20420 USA. [Kansagara, Devan] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97201 USA. [Kansagara, Devan] Vet Affairs Portland Healthcare Syst, Portland, OR USA. RP Atkins, D (reprint author), US Dept Vet Affairs, Off Res & Dev, Hlth Serv Res & Dev, 10P9H,810 Vermont Ave NW, Washington, DC 20420 USA. EM David.atkins@va.gov NR 8 TC 1 Z9 1 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD APR PY 2016 VL 176 IS 4 BP 493 EP 495 DI 10.1001/jamainternmed.2015.8603 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA DI3EG UT WOS:000373380600018 PM 26954103 ER PT J AU Donze, JD Williams, MV Robinson, EJ Zimlichman, E Aujesky, D Vasilevskis, EE Kripalani, S Metlay, JP Wallington, T Fletcher, GS Auerbach, AD Schnipper, JL AF Donze, Jacques D. Williams, Mark V. Robinson, Edmondo J. Zimlichman, Eyal Aujesky, Drahomir Vasilevskis, Eduard E. Kripalani, Sunil Metlay, Joshua P. Wallington, Tamara Fletcher, Grant S. Auerbach, Andrew D. Schnipper, Jeffrey L. TI International Validity of the HOSPITAL Score to Predict 30-Day Potentially Avoidable Hospital Readmissions SO JAMA INTERNAL MEDICINE LA English DT Article ID ATRIAL-FIBRILLATION; RISK PREDICTION; ANTICOAGULATED PATIENTS; MEDICAL PATIENTS; BLEEDING RISK; VALIDATION; MODELS; CHADS(2); TRIAL AB IMPORTANCE Identification of patients at a high risk of potentially avoidable readmission allows hospitals to efficiently direct additional care transitions services to the patients most likely to benefit. OBJECTIVE To externally validate the HOSPITAL score in an international multicenter study to assess its generalizability. DESIGN, SETTING, AND PARTICIPANTS International retrospective cohort study of 117 065 adult patients consecutively discharged alive from the medical department of 9 large hospitals across 4 different countries between January 2011 and December 2011. Patients transferred to another acute care facility were excluded. EXPOSURES The HOSPITAL score includes the following predictors at discharge: hemoglobin, discharge from an oncology service, sodium level, procedure during the index admission, index type of admission (urgent), number of admissions during the last 12 months, and length of stay. MAIN OUTCOMES AND MEASURES 30-day potentially avoidable readmission to the index hospital using the SQLape algorithm. RESULTS Overall, 117 065 adults consecutively discharged alive from a medical department between January 2011 and December 2011 were studied. Of all medical discharges, 16 992 of 117 065 (14.5%) were followed by a 30-day readmission, and 11 307 (9.7%) were followed by a 30-day potentially avoidable readmission. The discriminatory power of the HOSPITAL score to predict potentially avoidable readmission was good, with a C statistic of 0.72 (95% CI, 0.72-0.72). As in the derivation study, patients were classified into 3 risk categories: low (n = 73 031 [62.4%]), intermediate (n = 27 612 [23.6%]), and high risk (n = 16 422 [14.0%]). The estimated proportions of potentially avoidable readmission for each risk category matched the observed proportion, resulting in an excellent calibration (Pearson.2 test P = .89). CONCLUSIONS AND RELEVANCE The HOSPITAL score identified patients at high risk of 30-day potentially avoidable readmission with moderately high discrimination and excellent calibration when applied to a large international multicenter cohort of medical patients. This score has the potential to easily identify patients in need of more intensive transitional care interventions to prevent avoidable hospital readmissions. C1 [Donze, Jacques D.; Aujesky, Drahomir] Univ Hosp Bern, Div Gen Internal Med, CH-3010 Bern, Switzerland. [Donze, Jacques D.; Schnipper, Jeffrey L.] Brigham & Womens Hosp, Div Gen Med, Boston, MA 02115 USA. [Donze, Jacques D.; Schnipper, Jeffrey L.] Harvard Univ, Sch Med, Boston, MA USA. [Williams, Mark V.] Univ Kentucky, Ctr Hlth Serv Res, Lexington, KY 40506 USA. [Robinson, Edmondo J.] Christiana Care Hlth Syst, Value Inst, Wilmington, DE USA. [Zimlichman, Eyal] Chaim Sheba Med Ctr, IL-52621 Tel Hashomer, Israel. [Vasilevskis, Eduard E.; Kripalani, Sunil] Vanderbilt Univ, Med Ctr, Sect Hosp Med, Nashville, TN USA. [Vasilevskis, Eduard E.; Kripalani, Sunil] Vanderbilt Univ, Med Ctr, Ctr Clin Qual & Implementat Res, Nashville, TN USA. [Vasilevskis, Eduard E.] Vet Affairs Tennessee Valley Geriatr Res Educ & C, Nashville, TN USA. [Metlay, Joshua P.] Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. [Wallington, Tamara] William Osler Hlth Syst, Toronto, ON, Canada. [Fletcher, Grant S.] Univ Washington, Harborview Med Ctr, Dept Med, Seattle, WA 98104 USA. [Auerbach, Andrew D.] Univ Calif San Francisco, Div Hosp Med, San Francisco, CA 94143 USA. RP Donze, JD (reprint author), Univ Hosp Bern, Inselspital, Univ Klin Allgemeine Innere Med, CH-3010 Bern, Switzerland. EM donze.author@gmail.com OI Robinson, Edmondo/0000-0001-9625-6235 FU Swiss National Science Foundation; Swiss Foundation for Medical-Biological Scholarships [PASMP3-142734]; National Institute on Aging of the National Institutes of Health [K23AG040157]; Veterans Affairs Clinical Research Center of Excellence, the Geriatric Research, Education, and Clinical Center (GRECC) FX Dr Donze was supported by the Swiss National Science Foundation and the Swiss Foundation for Medical-Biological Scholarships (grant No. PASMP3-142734). Dr Vasilevskis was supported by the National Institute on Aging of the National Institutes of Health (award No. K23AG040157) and the Veterans Affairs Clinical Research Center of Excellence, the Geriatric Research, Education, and Clinical Center (GRECC). NR 28 TC 11 Z9 11 U1 2 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD APR PY 2016 VL 176 IS 4 BP 496 EP 502 DI 10.1001/jamainternmed.2015.8462 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA DI3EG UT WOS:000373380600019 PM 26954698 ER PT J AU Blumenthal, D Hsiao, W Blumenthal, DM AF Blumenthal, David Hsiao, William Blumenthal, Daniel M. TI Caring for Coronary Artery Disease in China Managing Modernization SO JAMA INTERNAL MEDICINE LA English DT Editorial Material C1 [Blumenthal, David] Commonwealth Fund, One E 75th St, New York, NY 11201 USA. [Hsiao, William] Harvard Univ, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Blumenthal, Daniel M.] Massachusetts Gen Hosp, Dept Cardiol, Boston, MA 02114 USA. RP Blumenthal, D (reprint author), Commonwealth Fund, One E 75th St, New York, NY 11201 USA. EM db@cmwf.org NR 5 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD APR PY 2016 VL 176 IS 4 BP 521 EP 523 DI 10.1001/jamainternmed.2016.0198 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA DI3EG UT WOS:000373380600023 PM 26974368 ER PT J AU McIlvennan, CK Jones, J Allen, LA Swetz, KM Nowels, C Matlock, DD AF McIlvennan, Colleen K. Jones, Jacqueline Allen, Larry A. Swetz, Keith M. Nowels, Carolyn Matlock, Daniel D. TI Bereaved Caregiver Perspectives on the End-of-Life Experience of Patients With a Left Ventricular Assist Device SO JAMA INTERNAL MEDICINE LA English DT Article ID DESTINATION THERAPY; SUPPORT AB IMPORTANCE For patients and their loved ones, decisions regarding the end of life in the setting of chronic progressive illness are among the most complex in health care. Complicating these decisions are increasingly available, invasive, and potentially life-prolonging technologies such as the left ventricular assist device (LVAD). OBJECTIVE To understand the experience of bereaved caregivers and patients at the end of life who have an LVAD. DESIGN, SETTING, AND PARTICIPANTS Semistructured, in-depth interviews were conducted between September 10 and November 21, 2014, with 8 bereaved caregivers of patients with an LVAD who were recruited from a single institution. Data were analyzed from December 13, 2014, to February 18, 2015, using a mixed inductive and deductive approach. MAIN OUTCOMES AND MEASURES Themes from semistructured interviews. RESULTS The 8 caregivers (6 females) described 3 main themes that coalesced around feelings of confusion in the final weeks with their loved ones: (1) the process of death with an LVAD, (2) the legal and ethically permissible care of patients with an LVAD approaching death, and (3) fragmented integration of palliative and hospice care. CONCLUSIONS AND RELEVANCE Despite increasing use of LVADs in patients with advanced heart failure, bereaved caregivers of patients with an LVAD describe a high level of confusion at the end of life. There remains a need for the health care community to develop clear guidance on the management of patients with an LVAD at the end of life. Future work will focus on the educational process and the ideal timing and reiteration of such information to patients and families. C1 [McIlvennan, Colleen K.; Allen, Larry A.] Univ Colorado, Sch Med, Div Cardiol, Sect Adv Heart Failure & Transplantat, 12631 E 17th Ave,Mail Code B130, Aurora, CO 80045 USA. [McIlvennan, Colleen K.; Allen, Larry A.; Matlock, Daniel D.] Univ Colorado, Sch Med, Colorado Cardiovasc Outcomes Res Consortium, 12631 E 17th Ave,Mail Code B130, Aurora, CO 80045 USA. [Jones, Jacqueline] Univ Colorado, Sch Nursing, 12631 E 17th Ave,Mail Code B130, Aurora, CO 80045 USA. [Nowels, Carolyn; Matlock, Daniel D.] Univ Colorado, Sch Med, Div Gen Internal Med, 12631 E 17th Ave,Mail Code B130, Aurora, CO 80045 USA. [Swetz, Keith M.] Birmingham VA Med Ctr, Dept Vet Affairs, Birmingham Atlanta Geriatr Res Educ & Clin Ctr, Birmingham, AL USA. [Swetz, Keith M.] Univ Alabama Birmingham, Ctr Palliat & Support Care, Birmingham, AL USA. RP McIlvennan, CK (reprint author), Univ Colorado, Sch Med, Div Cardiol, Sect Adv Heart Failure & Transplantat, 12631 E 17th Ave,Mail Code B130, Aurora, CO 80045 USA. EM colleen.mcilvennan@ucdenver.edu NR 28 TC 5 Z9 5 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD APR PY 2016 VL 176 IS 4 BP 534 EP 539 DI 10.1001/jamainternmed.2015.8528 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA DI3EG UT WOS:000373380600026 PM 26998594 ER PT J AU Kerlikowske, K AF Kerlikowske, Karla TI Progress Toward Consensus on Breast Cancer Screening Guidelines and Reducing Screening Harms Reply SO JAMA INTERNAL MEDICINE LA English DT Letter ID WOMEN C1 [Kerlikowske, Karla] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Kerlikowske, Karla] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Kerlikowske, Karla] Univ Calif San Francisco, Dept Vet Affairs, Gen Internal Med Sect, San Francisco, CA 94143 USA. RP Kerlikowske, K (reprint author), San Francisco VA Med Ctr, Gen Internal Med Sect, 4150 Clement St,111A1, San Francisco, CA 94121 USA. EM karla.kerlikowske@ucsf.edu FU NCI NIH HHS [P01 CA154292, P01CA154292] NR 6 TC 0 Z9 0 U1 2 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD APR PY 2016 VL 176 IS 4 BP 562 EP 563 DI 10.1001/jamainternmed.2016.0225 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DI3EG UT WOS:000373380600043 PM 27043108 ER PT J AU Silverberg, ND Mannix, R Iverson, GL AF Silverberg, Noah D. Mannix, Rebekah Iverson, Grant L. TI Attribution of Concussion-Like Symptoms and History of Collision Sports Exposure Reply SO JAMA PEDIATRICS LA English DT Letter C1 [Silverberg, Noah D.] Univ British Columbia, Div Phys Med & Rehabil, Vancouver, BC V5Z 1M9, Canada. [Silverberg, Noah D.] GF Strong Rehabil Ctr, 4255 Laurel St, Vancouver, BC V5Z 2G9, Canada. [Mannix, Rebekah] Boston Childrens Hosp, Div Emergency Med, Boston, MA USA. [Silverberg, Noah D.; Iverson, Grant L.] Harvard Univ, Sch Med, Dept Phys Med & Rehabil, Boston, MA USA. [Iverson, Grant L.] Spaulding Rehabil Hosp, Boston, MA USA. [Silverberg, Noah D.; Iverson, Grant L.] Massachusetts Gen Hosp, Children Sports Concuss Program, Boston, MA 02114 USA. [Silverberg, Noah D.; Iverson, Grant L.] Red Sox Fdn, Boston, MA USA. [Silverberg, Noah D.; Iverson, Grant L.] Massachusetts Gen Hosp, Home Base Program, Boston, MA 02114 USA. RP Silverberg, ND (reprint author), GF Strong Rehabil Ctr, 4255 Laurel St, Vancouver, BC V5Z 2G9, Canada. EM noah.silverberg@vch.ca 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 2168-6203 EI 2168-6211 J9 JAMA PEDIATR JI JAMA Pediatr. PD APR PY 2016 VL 170 IS 4 BP 401 EP 401 PG 1 WC Pediatrics SC Pediatrics GA DI3EI UT WOS:000373380800026 ER PT J AU Hauberg, ME Roussos, P Grove, J Borglum, AD Mattheisen, M AF Hauberg, Mads Engel Roussos, Panos Grove, Jakob Borglum, Anders Dupont Mattheisen, Manuel CA Psychiat Genomics Consortium TI Analyzing the Role of MicroRNAs in Schizophrenia in the Context of Common Genetic Risk Variants SO JAMA PSYCHIATRY LA English DT Article ID GENOME-WIDE ASSOCIATION; SYNAPTIC PLASTICITY; TARGET GENES; BRAIN; LOCI; NEUROGENESIS; ARCHITECTURE; ENRICHMENT; DATABASE; DISEASE AB IMPORTANCE The recent implication of 108 genomic loci in schizophrenia marked a great advancement in our understanding of the disease. Against the background of its polygenic nature there is a necessity to identify how schizophrenia risk genes interplay. As regulators of gene expression, microRNAs (miRNAs) have repeatedly been implicated in schizophrenia etiology. It is therefore of interest to establish their role in the regulation of schizophrenia risk genes in disease-relevant biological processes. OBJECTIVE To examine the role of miRNAs in schizophrenia in the context of disease-associated genetic variation. DESIGN, SETTING, AND PARTICIPANTS The basis of this study was summary statistics from the largest schizophrenia genome-wide association study meta-analysis to date (83 550 individuals in a meta-analysis of 52 genome-wide association studies) completed in 2014 along with publicly available data for predicted miRNA targets. We examined whether schizophrenia risk genes were more likely to be regulated by miRNA. Further, we used gene set analyses to identify miRNAs that are regulators of schizophrenia risk genes. MAIN OUTCOMES AND MEASURES Results from association tests for miRNA targetomes and related analyses. RESULTS In line with previous studies, we found that similar to other complex traits, schizophrenia risk genes were more likely to be regulated by miRNAs (P < 2 x 10(-16)). Further, the gene set analyses revealed several miRNAs regulating schizophrenia risk genes, with the strongest enrichment for targets of miR-9-5p (P = .0056 for enrichment among the top 1% most-associated single-nucleotide polymorphisms, corrected for multiple testing). It is further of note that MIR9-2 is located in a genomic region showing strong evidence for association with schizophrenia (P = 7.1 x 10(-8)). The second and third strongest gene set signals were seen for the targets of miR-485-5p and miR-137, respectively. CONCLUSIONS AND RELEVANCE This study provides evidence for a role of miR-9-5p in the etiology of schizophrenia. Its implication is of particular interest as the functions of this neurodevelopmental miRNA tie in with established disease biology: it has a regulatory loop with the fragile X mental retardation homologue FXR1 and regulates dopamine D-2 receptor density. C1 [Hauberg, Mads Engel; Grove, Jakob; Borglum, Anders Dupont; Mattheisen, Manuel] Aarhus Univ, Dept Biomed, Wilhelm Meyers Alle 1, DK-8000 Aarhus C, Denmark. [Hauberg, Mads Engel; Grove, Jakob; Borglum, Anders Dupont; Mattheisen, Manuel] Lundbeck Fdn Initiat Integrat Psychiat Res, Lundbeck, Denmark. [Hauberg, Mads Engel; Grove, Jakob; Borglum, Anders Dupont; Mattheisen, Manuel] Aarhus Univ, Ctr Integrat Sequencing, DK-8000 Aarhus C, Denmark. [Roussos, Panos] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Roussos, Panos] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Roussos, Panos] Icahn Sch Med Mt Sinai, Inst Genom & Multiscale Biol, New York, NY 10029 USA. [Roussos, Panos] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA. [Roussos, Panos] James J Peters VA Med Ctr, Mental Illness Res Educ & Clin Ctr, Bronx, NY USA. [Grove, Jakob] Aarhus Univ, Bioinformat Res Ctr, DK-8000 Aarhus C, Denmark. [Borglum, Anders Dupont] Aarhus Univ Hosp, Res Dept P, Risskov, Denmark. [Borglum, Anders Dupont] Aarhus Univ, Dept Clin Med, Translat Neuropsychiat Unit, DK-8000 Aarhus C, Denmark. RP Mattheisen, M (reprint author), Aarhus Univ, Dept Biomed, Wilhelm Meyers Alle 1, DK-8000 Aarhus C, Denmark. EM mm@biomed.au.dk RI Roussos, Panos/J-7090-2013; OI Roussos, Panos/0000-0002-4640-6239; Grove, Jakob/0000-0003-2284-5744 FU Lundbeck Foundation; Centre for Integrative Sequencing, Aarhus University; Faculty of Health, Aarhus University FX This work was supported by the Lundbeck Foundation; the Centre for Integrative Sequencing, Aarhus University; and the Faculty of Health, Aarhus University. NR 47 TC 4 Z9 4 U1 1 U2 7 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-622X EI 2168-6238 J9 JAMA PSYCHIAT JI JAMA Psychiatry PD APR PY 2016 VL 73 IS 4 BP 369 EP 377 DI 10.1001/jamapsychiatry.2015.3018 PG 9 WC Psychiatry SC Psychiatry GA DI4BI UT WOS:000373444700012 PM 26963595 ER PT J AU Camprodon, JA Pascual-Leone, A AF Camprodon, Joan A. Pascual-Leone, Alvaro TI Multimodal Applications of Transcranial Magnetic Stimulation for Circuit-Based Psychiatry SO JAMA PSYCHIATRY LA English DT Editorial Material C1 [Camprodon, Joan A.] Harvard Univ, Massachusetts Gen Hosp, Lab Neuropsychiat & Neuromodulat, Dept Psychiat,Med Sch, 149 13th St,Ste 2654, Boston, MA 02129 USA. [Camprodon, Joan A.] Harvard Univ, Massachusetts Gen Hosp, Transcranial Magnet Stimulat Clin Serv, Dept Psychiat,Med Sch, 149 13th St,Ste 2654, Boston, MA 02129 USA. [Pascual-Leone, Alvaro] Harvard Univ, Beth Israel Deaconess Med Ctr, Berenson Allen Ctr Noninvas Neuromodulat, Div Cognit Neurol,Dept Neurol,Med Sch, Boston, MA 02215 USA. RP Camprodon, JA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Lab Neuropsychiat & Neuromodulat, Dept Psychiat,Med Sch, 149 13th St,Ste 2654, Boston, MA 02129 USA.; Camprodon, JA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Transcranial Magnet Stimulat Clin Serv, Dept Psychiat,Med Sch, 149 13th St,Ste 2654, Boston, MA 02129 USA. EM jcamprodon@mgh.harvard.edu NR 10 TC 1 Z9 1 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-622X EI 2168-6238 J9 JAMA PSYCHIAT JI JAMA Psychiatry PD APR PY 2016 VL 73 IS 4 BP 407 EP 408 DI 10.1001/jamapsychiatry.2015.3127 PG 2 WC Psychiatry SC Psychiatry GA DI4BI UT WOS:000373444700016 PM 26981644 ER PT J AU Pineles, SL Nillni, YI King, MW Patton, SC Bauer, MR Mostoufi, SM Gerber, MR Hauger, R Resick, PA Rasmusson, AM Orr, SP AF Pineles, Suzanne L. Nillni, Yael I. King, Matthew W. Patton, Samantha C. Bauer, Margaret R. Mostoufi, Sheeva M. Gerber, Megan R. Hauger, Richard Resick, Patricia A. Rasmusson, Ann M. Orr, Scott P. TI Extinction Retention and the Menstrual Cycle: Different Associations for Women With Posttraumatic Stress Disorder SO JOURNAL OF ABNORMAL PSYCHOLOGY LA English DT Article DE extinction retention; menstrual cycle; estradiol; progesterone; PTSD ID SEX-DIFFERENCES; RECEPTOR; TRAUMA; PTSD AB The propensity to acquire and retain conditioned fear responses may contribute to the risk of developing and maintaining posttraumatic stress disorder (PTSD) following a traumatic event. There is growing evidence that the gonadal hormones estrogen and progesterone are associated with how well women retain extinction of previously conditioned fear responses. Thus, sex steroid effects may contribute to the increased prevalence of PTSD in women. For the current study, 32 nonmedicated female trauma survivors with and without PTSD completed a differential fear conditioning task both during the early follicular phase of the menstrual cycle when estradiol and progesterone levels are low, and during the midluteal phase when estradiol and progesterone levels are high. Skin conductance served as the measure of conditioned fear. Women with PTSD, compared to those without, showed impaired retention of extinction learning in the midluteal phase of the menstrual cycle. Therefore, the impact of menstrual phase on extinction retention may differ between women with and without PTSD. These findings raise potential considerations regarding the coordination of psychopharmacologic and trauma exposure-based treatments for PTSD with specific phases of the menstrual cycle. C1 [Pineles, Suzanne L.; Nillni, Yael I.] VA Boston Healthcare Syst, Natl Ctr Posttraumat Stress Disorder PTSD, Boston, MA USA. [Pineles, Suzanne L.; Nillni, Yael I.; Rasmusson, Ann M.] Boston Univ, Dept Psychiat, Sch Med, Boston, MA 02215 USA. [King, Matthew W.; Rasmusson, Ann M.] VA Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA USA. [Patton, Samantha C.] Univ Louisville, Dept Psychol & Brain Sci, Louisville, KY 40292 USA. [Bauer, Margaret R.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA USA. [Mostoufi, Sheeva M.] Univ Calif San Diego, San Diego State Univ, Joint Doctoral Program Clin Psychol, San Diego, CA 92103 USA. [Gerber, Megan R.] VA Boston Healthcare Syst, Women Vet Program, Boston, MA USA. [Gerber, Megan R.] Boston Univ, Dept Med, Sch Med, Boston, MA 02215 USA. [Hauger, Richard] San Diego VA Healthcare Syst, Ctr Excellence Stress & Mental Hlth, San Diego, CA USA. [Hauger, Richard] Univ Calif San Diego, Dept Psychiat, Sch Med, San Diego, CA 92103 USA. [Resick, Patricia A.] Duke Univ, Dept Psychiat & Behav Sci, Durham, NC 27706 USA. [Orr, Scott P.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Orr, Scott P.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Pineles, SL (reprint author), Vet Affairs Boston Healthcare Syst 116B 3, Boston, MA 02130 USA. EM suzanne.pineles@va.gov FU U.S. Department of Veterans Affairs Career Development Award FX Support for this research was provided to Suzanne Pineles through a U.S. Department of Veterans Affairs Career Development Award. NR 21 TC 4 Z9 4 U1 6 U2 9 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0021-843X EI 1939-1846 J9 J ABNORM PSYCHOL JI J. Abnorm. Psychol. PD APR PY 2016 VL 125 IS 3 BP 349 EP 355 DI 10.1037/abn0000138 PG 7 WC Psychology, Clinical; Psychology, Multidisciplinary SC Psychology GA DI7XE UT WOS:000373714500003 PM 26866677 ER PT J AU Painter, JM Kring, AM AF Painter, Janelle M. Kring, Ann M. TI Toward an Understanding of Anticipatory Pleasure Deficits in Schizophrenia: Memory, Prospection, and Emotion Experience SO JOURNAL OF ABNORMAL PSYCHOLOGY LA English DT Article DE schizophrenia; memory; prospection; emotion; narratives ID MENTAL TIME-TRAVEL; AUTOBIOGRAPHICAL MEMORY; NEGATIVE SYMPTOMS; COGNITIVE NEUROSCIENCE; AFFECTIVE REACTIVITY; FUTURE; IMAGINE; THINKING; EVENTS; BRAIN AB Anticipatory pleasure deficits have been observed in people with schizophrenia. Less is known about the extent to which interrelated processes that comprise anticipatory pleasure, including memory, prospection, and emotion experience are disrupted. We asked people with (n = 32) and without (n = 29) schizophrenia or schizoaffective disorder to provide memory and prospection narratives in response to specific cues. Half of the prospections followed a memory task, and half followed a control task. People with schizophrenia generated memories similar in content and experience as controls even as they described them less clearly. However, people with schizophrenia were less likely to explicitly reference the past in their prospections, and their prospections were less detailed and richly experienced than controls, regardless of the task completed before prospection. People with schizophrenia reported similar levels of positive emotion (current and predicted) in positive prospections that followed the memory task, but less positive emotion than controls in positive prospections that followed the control task. Taken together, these results suggest that people with schizophrenia experience difficulties drawing from past experiences and generating detailed prospections. However, asking people with schizophrenia to recall and describe memories prior to prospection may increase the likelihood of drawing from the past in prospections, and may help boost current and predicted pleasure. C1 [Painter, Janelle M.; Kring, Ann M.] Univ Calif Berkeley, Berkeley, CA 94720 USA. [Painter, Janelle M.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. RP Painter, JM (reprint author), Vet Affairs Puget Sound Hlth Care Syst, 1660 South Columbian Way S-116, Seattle, WA 98108 USA. EM janelle.painter@va.gov FU National Institutes of Health Grant [1R01MH082890] FX This study was supported in part by National Institutes of Health Grant 1R01MH082890 to Ann M. Kring. NR 46 TC 0 Z9 0 U1 4 U2 5 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0021-843X EI 1939-1846 J9 J ABNORM PSYCHOL JI J. Abnorm. Psychol. PD APR PY 2016 VL 125 IS 3 BP 442 EP 452 DI 10.1037/abn0000151 PG 11 WC Psychology, Clinical; Psychology, Multidisciplinary SC Psychology GA DI7XE UT WOS:000373714500012 PM 26950753 ER PT J AU Moschetti, WE Konopka, JF Rubash, HE Genuario, JW AF Moschetti, Wayne E. Konopka, Joseph F. Rubash, Harry E. Genuario, James W. TI Can Robot-Assisted Unicompartmental Knee Arthroplasty Be Cost-Effective? A Markov Decision Analysis SO JOURNAL OF ARTHROPLASTY LA English DT Article DE unicompartmental arthroplasty; robotic assistance; cost; economic analysis; cost-effectiveness ID UNITED-STATES; MEDICARE POPULATION; HOSPITAL-VOLUME; FOLLOW-UP; REPLACEMENT; OSTEOARTHRITIS; PROSTHESIS; REVISION; HEALTH; REGISTER AB Background: Unicompartmental knee arthroplasty (UKA) is a treatment option for single-compartment knee osteoarthritis. Robotic assistance may improve survival rates of UKA, but the cost-effectiveness of robot-assisted UKA is unknown. The purpose of this study was to delineate the revision rate, hospital volume, and robotic system costs for which this technology would be cost-effective. Methods: We created a Markov decision analysis to evaluate the costs, outcomes, and incremental cost-effectiveness of robot-assisted UKA in 64-year-old patients with end-stage unicompartmental knee osteoarthritis. Results: Robot-assisted UKA was more costly than traditional UKA, but offered a slightly better outcome with 0.06 additional quality-adjusted life-years at an incremental cost of $47,180 per quality-adjusted life-years, given a case volume of 100 cases annually. The system was cost-effective when case volume exceeded 94 cases per year, 2-year failure rates were below 1.2%, and total system costs were <$1.426 million. Conclusion: Robot-assisted UKA is cost-effective compared with traditional UKA when annual case volume exceeds 94 cases per year. It is not cost-effective at low-volume or medium-volume arthroplasty centers. (C) 2016 Elsevier Inc. All rights reserved. C1 [Moschetti, Wayne E.] Dartmouth Hitchcock Med Ctr, Dept Orthopaed Surg, Lebanon, NH 03766 USA. [Konopka, Joseph F.; Rubash, Harry E.] Massachusetts Gen Hosp, Dept Orthoped Surg, 55 Fruit St, Boston, MA 02114 USA. [Genuario, James W.] Steadman Hawkins Clin, Denver, CO USA. RP Konopka, JF (reprint author), Massachusetts Gen Hosp, Dept Orthoped Surg, 55 Fruit St, Boston, MA 02114 USA. NR 46 TC 3 Z9 4 U1 0 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 APR PY 2016 VL 31 IS 4 BP 759 EP 765 DI 10.1016/j.arth.2015.10.018 PG 7 WC Orthopedics SC Orthopedics GA DI6QS UT WOS:000373625600004 PM 26706836 ER PT J AU Gromov, K Greene, ME Huddleston, JI Emerson, R Gebuhr, P Malchau, H Troelsen, A AF Gromov, Kirill Greene, Meridith E. Huddleston, James I. Emerson, Roger Gebuhr, Peter Malchau, Henrik Troelsen, Anders TI Acetabular Dysplasia and Surgical Approaches Other Than Direct Anterior Increases Risk for Malpositioning of the Acetabular Component in Total Hip Arthroplasty SO JOURNAL OF ARTHROPLASTY LA English DT Article DE total hip arthroplasty; component positioning; dysplasia; anteversion; Martell analysis ID OBESE-PATIENTS; ACCURACY; LIGAMENT; REPLACEMENT; POSITION; OSTEOARTHRITIS; ORIENTATION; VARIABILITY; ANTEVERSION; WEAR AB Background: Persistent acetabular dysplasia (AD) after periacetabular osteotomy has been hypothesized to increase the risk for malpositioning of the acetabular component. In this study, we investigate whether AD is an independent risk factor for cup malpositioning during primary total hip arthroplasty (THA). Methods: Patient demographics, surgical approach, presence of AD assessed using the lateral center-edge angle, and acetabular cup positioning determined using Martell Hip Analysis Suite were investigated in 836 primary THA patients enrolled in a prospective multicenter study. Results: We found that presence of AD, defined as the lateral center-edge angle of <25 degrees, is an independent risk factor for malpositioning of the acetabular component during primary THA. Surgical approach other than direct anterior was also independently associated with malpositioned cups. Conclusions: Surgeons should therefore take special care during placement of the acetabular component in patients with AD. (C) 2016 Elsevier Inc. All rights reserved. C1 [Gromov, Kirill; Greene, Meridith E.; Malchau, Henrik] Massachusetts Gen Hosp, Harris Orthopaed Lab, Boston, MA 02114 USA. [Gromov, Kirill; Gebuhr, Peter; Troelsen, Anders] Copenhagen Hosp, Dept Orthopaed Surg, Copenhagen, Denmark. [Huddleston, James I.] Stanford Univ, Med Ctr, Dept Orthopaed Surg, Stanford, CA 94305 USA. [Emerson, Roger] Texas Ctr Joint Replacement, Plano, TX USA. RP Gromov, K (reprint author), Univ Copenhagen Hosp, Dept Orthopaed Surg, DK-2100 Copenhagen, Denmark. NR 35 TC 1 Z9 1 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 APR PY 2016 VL 31 IS 4 BP 835 EP 841 DI 10.1016/j.arth.2015.10.045 PG 7 WC Orthopedics SC Orthopedics GA DI6QS UT WOS:000373625600018 PM 26706838 ER PT J AU Karmon, AE Cardozo, ER Souter, I Gold, J Petrozza, JC Styer, AK AF Karmon, Anatte E. Cardozo, Eden R. Souter, Irene Gold, Julie Petrozza, John C. Styer, Aaron K. TI Donor TSH level is associated with clinical pregnancy among oocyte donation cycles SO JOURNAL OF ASSISTED REPRODUCTION AND GENETICS LA English DT Article; Proceedings Paper CT 70th Annual Scientific Meeting of the American-Society-for-Reproductive-Medicine CY OCT 18-22, 2014 CL Honolulu, HI SP Amer Soc Reprod Med DE Thyroid-stimulating hormone; Oocyte donation; Infertility; In vitro fertilization ID IN-VITRO FERTILIZATION; THYROID-HORMONE RECEPTORS; INFERTILE WOMEN; HUMAN GRANULOSA; HYPOTHYROIDISM; CELLS AB The purpose of the study is to evaluate the association between donor TSH level (independent of recipient TSH level) and recipient pregnancy outcome among fresh donor oocyte IVF cycles. This is a retrospective cohort study investigating 232 consecutive fresh donor-recipient cycles (200 total oocyte donors) at an academic medical center. Main outcome measures include clinical pregnancy and live birth. Cycles were categorized into two groups based on donor TSH level (< 2.5 and a parts per thousand yen 2.5 mIU/L). After controlling for multiple donor and recipient characteristics, the probability of clinical pregnancy was significantly lower among donors with TSH levels a parts per thousand yen2.5 mIU/L compared to those with TSH values < 2.5 mIU/L (43.1 %, 95 % CI 28.5-58.9, versus 66.7 %, 95 % CI 58.6-73.9, respectively, p = 0.01). The difference in live birth rates between the two groups did not achieve statistical significance (43.1 %, 95 % CI 28.8-58.6, versus 58.0 %, 95 % CI 50.0-65.6, respectively, p = 0.09). Donor TSH level, independent of recipient TSH level, is associated with recipient clinical pregnancy. These findings suggest that thyroid function may impact the likelihood of pregnancy at the level of the oocyte. C1 [Karmon, Anatte E.; Cardozo, Eden R.; Souter, Irene; Gold, Julie; Petrozza, John C.; Styer, Aaron K.] Massachusetts Gen Hosp, Vincent Reprod Med & IVF, Vincent Dept Obstet & Gynecol, Yawkey 10A 55 Fruit St, Boston, MA 02114 USA. [Karmon, Anatte E.; Cardozo, Eden R.; Souter, Irene; Petrozza, John C.; Styer, Aaron K.] Harvard Univ, Sch Med, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. RP Karmon, AE (reprint author), Massachusetts Gen Hosp, Vincent Reprod Med & IVF, Vincent Dept Obstet & Gynecol, Yawkey 10A 55 Fruit St, Boston, MA 02114 USA.; Karmon, AE (reprint author), Harvard Univ, Sch Med, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. EM anatte@gmail.com NR 22 TC 0 Z9 0 U1 0 U2 3 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1058-0468 EI 1573-7330 J9 J ASSIST REPROD GEN JI J. Assist. Reprod. Genet. PD APR PY 2016 VL 33 IS 4 BP 489 EP 494 DI 10.1007/s10815-016-0668-6 PG 6 WC Genetics & Heredity; Obstetrics & Gynecology; Reproductive Biology SC Genetics & Heredity; Obstetrics & Gynecology; Reproductive Biology GA DI5XG UT WOS:000373573200010 PM 26847132 ER PT J AU Chamoto, K Guo, TX Imataki, O Tanaka, M Nakatsugawa, M Ochi, T Yamashita, Y Saito, AM Saito, TI Butler, MO Hirano, N AF Chamoto, Kenji Guo, Tingxi Imataki, Osamu Tanaka, Makito Nakatsugawa, Munehide Ochi, Toshiki Yamashita, Yuki Saito, Akiko M. Saito, Toshiki I. Butler, Marcus O. Hirano, Naoto TI CDR3 beta sequence motifs regulate autoreactivity of human invariant MKT cell receptors SO JOURNAL OF AUTOIMMUNITY LA English DT Article DE iNKT; Autoreactivity; TCR; CDR3 beta ID KILLER T-CELLS; LIPID-ANTIGEN PRESENTATION; TCR ALPHA-CHAIN; NKT CELLS; SELF-ANTIGENS; V-BETA; RECOGNITION; ACTIVATION; GLYCOSYLCERAMIDES; IDENTIFICATION AB Invariant natural killer T (INKT) cells are a subset of T lymphocytes that recognize lipid ligands presented by monomorphic CD1d. Human iNICT T cell receptor (TCR) is largely composed of invariant V alpha 24 (V alpha 24i) TCR alpha chain and semi-variant V beta 11 TCR beta chain, where complementarity-determining region (CDR)3 beta is the sole variable region. One of the characteristic features of iNKT cells is that they retain autoreactivity even after the thymic selection. However, the molecular features of human iNKT TCR CDR3 beta sequences that regulate autoreactivity remain unknown. Since the numbers of iNKT cells with detectable autoreactivity in peripheral blood is limited, we introduced the V alpha 24i gene into peripheral T cells and generated a de novo human iNKT TCR repertoire. By stimulating the transfected T cells with artificial antigen presenting cells (aAPCs) presenting self-ligands, we enriched strongly autoreactive iNKT TCRs and isolated a large panel of human iNKT TCRs with a broad range autoreactivity. From this panel of unique iNKT TCRs, we deciphered three CDR3 beta sequence motifs frequently encoded by strongly-autoreactive iNKT TCRs: a VD region with 2 or more acidic amino acids, usage of the J beta 2-5 allele, and a CDR beta region of 13 amino acids in length. iNKT TCRs encoding 2 or 3 sequence motifs also exhibit higher autoreactivity than those encoding 0 or 1 motifs. These data facilitate our understanding of the molecular basis for human iNKT cell autoreactivity involved in immune responses associated with human disease. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Chamoto, Kenji; Guo, Tingxi; Nakatsugawa, Munehide; Ochi, Toshiki; Yamashita, Yuki; Butler, Marcus O.; Hirano, Naoto] Princess Margaret Canc Ctr, Campbell Family Canc Res Inst, Campbell Family Inst Breast Canc Res, Univ Hlth Network,Tumor Immunotherapy Program, Toronto, ON M5G 2M9, Canada. [Guo, Tingxi; Butler, Marcus O.; Hirano, Naoto] Univ Toronto, Dept Immunol, 100 Coll St, Toronto, ON M5S 1A8, Canada. [Saito, Akiko M.; Saito, Toshiki I.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Butler, Marcus O.] Univ Toronto, Dept Med, Toronto, ON M5S 1A8, Canada. RP Hirano, N (reprint author), Princess Margaret Canc Ctr, 610 Univ Ave, Toronto, ON M5G 2M9, Canada. EM naoto.hirano@utoronto.ca FU NIH [R01 CA148673]; Ontario Institute for Cancer Research Clinical Investigator Award [IA-039]; Princess Margaret Cancer Foundation; Knudson Postdoctoral Fellowship; Canadian Institutes of Health Research Canada Graduate Scholarship; Guglietti Fellowship Award FX This work was supported by NIH grant R01 CA148673 (NH); the Ontario Institute for Cancer Research Clinical Investigator Award IA-039 (NH); The Princess Margaret Cancer Foundation (MOB, NH); Knudson Postdoctoral Fellowship (KC); Canadian Institutes of Health Research Canada Graduate Scholarship (TG); and Guglietti Fellowship Award (TO). NR 42 TC 3 Z9 3 U1 0 U2 3 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0896-8411 EI 1095-9157 J9 J AUTOIMMUN JI J. Autoimmun. PD APR PY 2016 VL 68 BP 39 EP 51 DI 10.1016/j.jaut.2015.12.005 PG 13 WC Immunology SC Immunology GA DI5NP UT WOS:000373546200005 PM 26748722 ER PT J AU Zappulli, V Friis, KP Fitzpatrick, Z Maguire, CA Breakefield, XO AF Zappulli, Valentina Friis, Kristina Pagh Fitzpatrick, Zachary Maguire, Casey A. Breakefield, Xandra O. TI Extracellular vesicles and intercellular communication within the nervous system SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Review ID MESENCHYMAL STEM-CELLS; ALZHEIMERS-DISEASE; ALPHA-SYNUCLEIN; L1 RETROTRANSPOSITION; AMYLOID-BETA; CEREBROSPINAL-FLUID; EXOSOME RELEASE; IN-VIVO; GLIOBLASTOMA-MULTIFORME; TRANSPOSABLE ELEMENTS AB Extracellular vesicles (EVs, including exosomes) are implicated in many aspects of nervous system development and function, including regulation of synaptic communication, synaptic strength, and nerve regeneration. They mediate the transfer of packets of information in the form. of nonsecreted proteins and DNA/RNA protected within a membrane compartment. EVs are essential for the packaging and transport of many cell-fate proteins during development as well as many neurotoxic misfolded proteins during pathogenesis. This form of communication provides another dimension of cellular crosstalk, with the ability to assemble a "kit" of directional instructions made up of different molecular entities and address it to specific recipient cells. This multidimensional form of communication has special significance in the nervous system. How EVs help to orchestrate the wiring of the brain while allowing for plasticity associated with learning and memory and contribute to regeneration and degeneration are all under investigation. Because they carry specific disease-related RNAs and proteins, practical applications of EVs include potential uses as biomarlcers and therapeutics. This Review describes our current understanding of EVs and serves as a springboard for future advances, which may reveal new important mechanisms by which EVs in coordinate brain and body function and dysfunction. C1 [Zappulli, Valentina] Univ Padua, Dept Comparat Biomed & Food Sci, Legnaro, Italy. [Friis, Kristina Pagh; Fitzpatrick, Zachary; Maguire, Casey A.; Breakefield, Xandra O.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Breakefield, Xandra O.] Harvard Univ, Sch Med, Dept Radiol, Ctr Mol Imaging Res,Massachusetts Gen Hosp, Boston, MA 02115 USA. [Breakefield, Xandra O.] Harvard Univ, Sch Med, NeuroDiscovery Ctr, Boston, MA USA. RP Breakefield, XO (reprint author), Massachusetts Gen Hosp, CNY Bldg 149,Room 6203,149 13th St, Charlestown, MA 02129 USA. EM xandra_breakefield@hms.harvard.edu FU NIH Common Fund through the Office of Strategic Coordination/Office of the NIH Director [NCI U19 CA179563, NIH/NCI P01 CA069246]; Alfred Benzon Foundation; Fulbright Visiting Scholar Program Institute of International Education; American Brain Tumor Association Discovery Grant FX We thank Suzanne McDavitt for skilled editorial assistance, Lawrence Rajendran for insights into the role of EVs in neuro-degeneration, and Sybren Maas for insights into the role of EVs in brain tumors. This work was supported by the NIH Common Fund through the Office of Strategic Coordination/Office of the NIH Director (NCI U19 CA179563 and NIH/NCI P01 CA069246 to X.O. Breakefield); the Alfred Benzon Foundation (to K.P. Friis); the Fulbright Visiting Scholar Program Institute of International Education (to V. Zappulli); and an American Brain Tumor Association Discovery Grant (to C.A. Maguire). NR 148 TC 6 Z9 8 U1 3 U2 15 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD APR PY 2016 VL 126 IS 4 BP 1198 EP 1207 DI 10.1172/JCI81134 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DI5ES UT WOS:000373522300009 PM 27035811 ER PT J AU Lee, D Wang, YH Kalaitzidis, D Ramachandran, J Eda, H Sykes, DB Raje, N Scadden, DT AF Lee, Dongjun Wang, Ying-Hua Kalaitzidis, Demetrios Ramachandran, Janani Eda, Homare Sykes, David B. Raje, Noopur Scadden, David T. TI Endogenous transmembrane protein UT2 inhibits pSTAT3 and suppresses hematological malignancy SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID MULTIPLE-MYELOMA CELLS; SIGNAL TRANSDUCER; STAT3 ACTIVATION; IN-VIVO; CONSTITUTIVE EXPRESSION; LEUKEMIA-CELLS; GROWTH-HORMONE; CANCER; INTERLEUKIN-6; TRANSCRIPTION-3 AB Regulation of STAT3 activation is critical for normal and malignant hematopoietic cell proliferation. Here, we have reported that the endogenous transmembrane protein upstream-of-mTORC2 (UT2) negatively regulates activation of STAT3. Specifically, we determined that UT2 interacts directly with GP130 and inhibits phosphorylation of STAT3 on tyrosine 705 (STAT3'05). This reduces cytokine signaling including IL6 that is implicated in multiple myeloma and other hematopoietic malignancies. Modulation of UT2 resulted in inverse effects on animal survival in myeloma models. Samples from multiple myeloma patients also revealed a decreased copy number of UT2 and decreased expression of UT2 in genomic and transcriptomic analyses, respectively. Together, these studies identify a transmembrane protein that functions to negatively regulate cytokine signaling through GP130 and pSTAT3(Y705) and is molecularly and mechanistically distinct from the suppressors of cytokine signaling (SOCS) family of genes. Moreover, this work provides evidence that perturbations of this activation-dampening molecule participate in hematologic malignancies and may serve as a key determinant of multiple myeloma pathophysiology. UT2 is a negative regulator shared across STAT3 and mTORC2 signaling cascades, functioning as a tumor suppressor in hematologic malignancies driven by those pathways. C1 [Lee, Dongjun; Wang, Ying-Hua; Kalaitzidis, Demetrios; Sykes, David B.; Scadden, David T.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Lee, Dongjun; Wang, Ying-Hua; Kalaitzidis, Demetrios; Ramachandran, Janani; Eda, Homare; Sykes, David B.; Raje, Noopur; Scadden, David T.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Lee, Dongjun; Wang, Ying-Hua; Kalaitzidis, Demetrios; Sykes, David B.; Scadden, David T.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Lee, Dongjun; Wang, Ying-Hua; Kalaitzidis, Demetrios; Sykes, David B.; Scadden, David T.] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Scadden, DT (reprint author), 185 Cambridge St, Boston, MA 02114 USA. EM david_scadden@harvard.edu OI lee, dongjun/0000-0001-6828-401X FU NIH NHLBI [U01HL100402, HL97794, HL044851]; Ellison Medical Foundation; MGH Fund for Medical Discovery fellowship; MGH/HSCI CRM flow cytometry core FX We thank those who funded this work: NIH NHLBI U01HL100402, HL97794, HL044851, and the Ellison Medical Foundation (to D. Lee and D.T. Scadden); MGH Fund for Medical Discovery fellowship (D. Lee); and the MGH/HSCI CRM flow cytometry core (L. Prickett, A. Galvin, M. Handley, and M. Weglarz). We thank Scadden lab members for advice and helpful comments and IH Oh (Catholic High Performance Cell Therapy Center, Catholic University, Seoul, South Korea) for MIG-STAT3C plasmid. The data reported in this manuscript are tabulated in the main paper and in the supplementary materials. NR 94 TC 0 Z9 0 U1 1 U2 2 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD APR PY 2016 VL 126 IS 4 BP 1300 EP 1310 DI 10.1172/JCI84620 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DI5ES UT WOS:000373522300022 PM 26927669 ER PT J AU Winnay, JN Solheim, MH Dirice, E Sakaguchi, M Noh, HL Kang, HJ Takahashi, H Chudasama, KK Kim, JK Molven, A Kahn, CR Njolstad, PR AF Winnay, Jonathon N. Solheim, Marie H. Dirice, Ercument Sakaguchi, Masaji Noh, Hye-Lim Kang, Hee Joon Takahashi, Hirokazu Chudasama, Kishan K. Kim, Jason K. Molven, Anders Kahn, C. Ronald Njolstad, Pal R. TI PI3-kinase mutation linked to insulin and growth factor resistance in vivo SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID TYROSINE-PHOSPHATASE 1B; PHOSPHOINOSITIDE 3-KINASE; PHOSPHATIDYLINOSITOL 3-KINASE; RECEPTOR SUBSTRATE-1; SHORT STATURE; PARTIAL LIPODYSTROPHY; POSTNATAL-GROWTH; MICE LACKING; BETA-CELLS; PROTEIN AB The phosphatidylinositol 3-kinase (PI3K) signaling pathway is central to the action of insulin and many growth factors. Heterozygous mutations in the gene encoding the p85 alpha regulatory subunit of PI3K (PIK3R1) have been identified in patients with SHORT syndrome a disorder characterized by short stature, partial lipodystrophy, and insulin resistance. Here, we evaluated whether SHORT syndrome-associated PIK3R1 mutations account for the pathophysiology that underlies the abnormalities by generating knockin mice that are heterozygous for the Pik3r1(Arg649TrP) mutation, which is homologous to the mutation found in the majority of affected individuals. Similar to the patients, mutant mice exhibited a reduction in body weight and length, partial lipodystrophy, and systemic insulin resistance. These derangements were associated with a reduced capacity of insulin and other growth factors to activate PI3K in liver, muscle, and fat; marked insulin resistance in liver and fat of mutation-harboring animals; and insulin resistance in vitro in cells derived from these mice. In addition, mutant mice displayed defective insulin secretion and GLP-1 action on islets in vivo and in vitro. These data demonstrate the ability of this heterozygous mutation to alter PI3K activity in vivo and the central role of PI3K in insulin/growth factor action, adipocyte function, and glucose metabolism. C1 [Winnay, Jonathon N.; Solheim, Marie H.; Dirice, Ercument; Sakaguchi, Masaji; Takahashi, Hirokazu; Kahn, C. Ronald] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. [Solheim, Marie H.; Chudasama, Kishan K.; Molven, Anders; Njolstad, Pal R.] Univ Bergen, Dept Clin Sci, KG Jebsen Ctr Diabet Res, Bergen, Norway. [Noh, Hye-Lim; Kang, Hee Joon; Kim, Jason K.] Univ Massachusetts, Sch Med, Div Endocrinol Metab & Diabet, Worcester, MA USA. [Chudasama, Kishan K.] Oslo Univ Hosp, Inst Canc Res, Dept Canc Immunol, Oslo, Norway. [Molven, Anders] Univ Bergen, Dept Clin Med, Gade Lab Pathol, Bergen, Norway. [Molven, Anders] Haukeland Hosp, Dept Pathol, N-5021 Bergen, Norway. [Njolstad, Pal R.] Haukeland Hosp, Dept Pediat, N-5021 Bergen, Norway. RP Kahn, CR (reprint author), Joslin Diabet Ctr, Sect Integrat Physiol & Metab, One Joslin Pl, Boston, MA 02215 USA.; Njolstad, PR (reprint author), Univ Bergen, Dept Clin Sci, Dept Pediat, Haukeland Univ Hosp, N-5021 Bergen, Norway. EM c.ronald.kahn@joslin.harvard.edu; pal.njolstad@uib.no RI Dirice, Ercument/B-2825-2017 FU National Institute of Digestive and Diabetes and Kidney Diseases [R01 DK055545]; NIH [U24-DK093000]; European Research Council [293574]; Research Council of Norway; University of Bergen; Western Regional Health Authorities; KG Jebsen Foundation; Norwegian Society of Endocrinology; Eckbo's Foundation; Tom Wilhelmsen Foundation; Norwegian Diabetes Association FX We would like to thank Rohit Kulkarni at the Joslin Diabetes Center for helpful discussion. We would like to thank the Physiology Core at the Joslin Diabetes Center for performing and interpreting the comprehensive lab animal monitoring system and dual energy X-ray absorptiometry analysis and the National Mouse Metabolic Phenotyping Center at the University of Massachusetts Medical School for performing the hyperinsulinemic-euglycemic clamp study. This work was supported by R01 DK055545 (to C.R. Kahn) from the National Institute of Digestive and Diabetes and Kidney Diseases. The National Mouse Metabolic Phenotyping Center at the University of Massachusetts is funded by NIH grant U24-DK093000. This work was also supported by the European Research Council (293574 to P.R. Njolstad), the Research Council of Norway (to P.R. Njolstad), the University of Bergen, and the Western Regional Health Authorities. M.H. Solheim was supported in part by funds from the University of Bergen, the KG Jebsen Foundation, the Norwegian Society of Endocrinology, Eckbo's Foundation, Tom Wilhelmsen Foundation, and the Norwegian Diabetes Association. NR 48 TC 2 Z9 2 U1 1 U2 1 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD APR PY 2016 VL 126 IS 4 BP 1401 EP 1412 DI 10.1172/JCI84005 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DI5ES UT WOS:000373522300029 PM 26974159 ER PT J AU Riedel, SS Haladyna, JN Bezzant, M Stevens, B Polyea, DA Sinha, AU Armstrong, SA Wei, Q Pollock, RM Daigle, SR Jordan, CT Ernst, P Neff, T Bernt, KM AF Riedel, Simone S. Haladyna, Jessica N. Bezzant, Matthew Stevens, Brett Polyea, Daniel A. Sinha, Amit U. Armstrong, Scott A. Wei, Qi Pollock, Roy M. Daigle, Scott R. Jordan, Craig T. Ernst, Patricia Neff, Tobias Bernt, Kathrin M. TI MLL1 and DOT1L cooperate with meningioma-1 to induce acute myeloid leukemia SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID RXR-MEDIATED TRANSCRIPTION; H3K79 METHYLATION; GENE-EXPRESSION; MICRORNA EXPRESSION; STEM-CELLS; MN1 GENE; AML; FUSION; TRANSFORMATION; HEMATOPOIESIS AB Meningioma-1 (MN1) overexpression is frequently observed in patients with acute myeloid leukemia (AML) and is predictive of poor prognosis. In murine models, forced expression of MN1 in hematopoietic progenitors induces an aggressive myeloid leukemia that is strictly dependent on a defined gene expression program in the cell of origin, which includes the homeobox genes Hoxa9 and Meis1 as key components. Here, we have shown that this program is controlled by two histone methyltransferases, MLL1 and DOT1L, as deletion of either MII1 or Dot1l in MN1-expressing cells abrogated the cell of origin derived gene expression program, including the expression of Hoxa cluster genes. In murine models, genetic inactivation of either Mill or Dot1l impaired MN1-mediated leukemogenesis. We determined that HOXA9 and MEIS1 are coexpressed with MN1 in a subset of clinical MN1(hi) leukemia, and human MN1(hi)/HOXA9(hi) leukemias were sensitive to pharmacologic inhibition of DOT1L. Together, these data point to DOT1L as a potential therapeutic target in MN1(hi) AML. In addition, our findings suggest that epigenetic modulation of the interplay between an oncogenic lesion and its cooperating developmental program has therapeutic potential in AML. C1 [Riedel, Simone S.; Haladyna, Jessica N.; Bezzant, Matthew; Ernst, Patricia; Neff, Tobias; Bernt, Kathrin M.] Univ Colorado, Sch Med, Div Pediat Hematol Oncol BMT, Aurora, CO USA. [Riedel, Simone S.; Haladyna, Jessica N.; Bezzant, Matthew; Ernst, Patricia; Neff, Tobias; Bernt, Kathrin M.] Childrens Hosp Colorado, Aurora, CO USA. [Stevens, Brett; Polyea, Daniel A.; Jordan, Craig T.] Univ Colorado Denver, Div Hematol, Aurora, CO USA. [Sinha, Amit U.; Armstrong, Scott A.] Harvard Univ, Childrens Hosp, Div Hematol Oncol, Sch Med,Dana Farber Canc Inst, Boston, MA 02115 USA. [Sinha, Amit U.; Armstrong, Scott A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, 44 Binney St, Boston, MA 02115 USA. [Wei, Qi] Childrens Hosp Colorado, Dept Pathol, Aurora, CO USA. [Pollock, Roy M.; Daigle, Scott R.] Epizyme Inc, Cambridge, MA USA. [Sinha, Amit U.] Basepair, New York, NY USA. [Armstrong, Scott A.] Mem Sloan Kettering Canc Ctr, Dept Med, Dept Pediat, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10021 USA. [Armstrong, Scott A.] Mem Sloan Kettering Canc Ctr, Dept Med, Leukemia Serv, 1275 York Ave, New York, NY 10021 USA. RP Neff, T; Bernt, KM (reprint author), Univ Colorado, Ctr Canc & Blood Disorders, Childrens Hosp Colorado, 13123 East 16th Ave,Box B115, Aurora, CO 80045 USA. EM Tobias.Neff@ucdenver.edu; Kathrin.Bernt@ucdenver.edu RI Bernt, Kathrin/L-1826-2016; OI Bernt, Kathrin/0000-0002-5400-0482; Neff, Tobias/0000-0002-0188-8393 FU University of Colorado Denver, Hematology/Oncology Section; Children's Hospital Colorado Research Institute; NHLBI [K08HL102264]; Sidney-Kimmel Foundation [141761]; Doris-Duke Charitable Foundation [2014104]; NCI [K08CA154777, P30CA046934]; ASCO career development grant FX We thank Ellen C. Zwarthoff (Erasmus University, Rotterdam, the Netherlands) for providing the MN1 plasmid. We thank Karen Helm and the staff at the flow cytometry core for assistance with cell sorting, and we thank Katrina Diener, Bifeng Gao, Ted Shade, and Kenneth Jones from the genomics and bioinformatics cores for assistance with the RNA-Seq experiment. This work was supported by start-up funds from University of Colorado Denver, Hematology/Oncology Section and the Children's Hospital Colorado Research Institute (to K.M. Bernt), as well as NHLBI K08HL102264 (to K.M. Bernt), Sidney-Kimmel Foundation 141761 (to K.M. Bernt), Doris-Duke Charitable Foundation 2014104 (to K.M. Bernt, for human cell line and patient sample work only; no funds from the Doris Duke Charitable Foundation were used to support research that used non-human animal models), NCI K08CA154777 (to T. Neff), ASCO career development grant (to D.A. Pollyea), and NCI P30CA046934 (Shared Resource of the University of Colorado Cancer Center). NR 43 TC 0 Z9 0 U1 0 U2 5 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD APR PY 2016 VL 126 IS 4 BP 1438 EP 1450 DI 10.1172/JCI80825 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DI5ES UT WOS:000373522300032 PM 26927674 ER PT J AU Demehri, S Cunningham, TJ Manivasagam, S Ngo, KH Tuchayi, SM Reddy, R Meyers, MA DeNardo, DG Yokoyama, WM AF Demehri, Shadmehr Cunningham, Trevor J. Manivasagam, Sindhu Ngo, Kenneth H. Tuchayi, Sara Moradi Reddy, Rasika Meyers, Melissa A. DeNardo, David G. Yokoyama, Wayne M. TI Thymic stromal lymphopoietin blocks early stages of breast carcinogenesis SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID CARCINOMA IN-SITU; CANCER-IMMUNOTHERAPY; PANCREATIC-CANCER; ATOPIC-DERMATITIS; T-CELLS; MOUSE; SKIN; KERATINOCYTES; ALLERGY; RISK AB Advances in the field of cancer immunology, including studies on tumor-infiltrating CD8(+) cytotoxic T lymphocytes (CTLs), have led to new immunotherapeutics with proven efficacy against late-stage cancers. However, the antitumor potential of the immune system in targeting early-stage cancers remains uncertain. Here, we demonstrated that both genetic and chemical induction of thymic stromal lymphopoietin (TSLP) at a distant site leads to robust antitumor immunity against spontaneous breast carcinogenesis in mice. Breast tumors exposed to high circulating levels of TSLP were arrested at an early adenoma-like stage and were prevented from advancing to late carcinoma and metastasis. Additionally, CD4(+) Th2 cells mediated the antitumor effects of TSLP, challenging the notion that Th2 cells only promote cancer. We also discovered that TSLP is expressed by the breast tumor cells themselves and acts to block breast cancer promotion. Moreover, TSLP-induced immunity also blocked early stages of pancreatic cancer development. Together, our findings demonstrate that TSLP potently induces immunity directed against early stages of breast cancer development without causing inflammation in the normal breast tissue. Moreover, our results highlight a previously unappreciated function of the immune system in controlling the early development of cancer and establish a fundamental role for TSLP and Th2 cells in tumor immunity against early-stage cancers. C1 [Demehri, Shadmehr; Cunningham, Trevor J.; Ngo, Kenneth H.; Tuchayi, Sara Moradi] Harvard Univ, Sch Med, Dept Dermatol, Ctr Canc Immunol,Massachusetts Gen Hosp, Boston, MA 02115 USA. [Demehri, Shadmehr; Cunningham, Trevor J.; Ngo, Kenneth H.; Tuchayi, Sara Moradi] Harvard Univ, Sch Med, Dept Dermatol, Cutaneous Biol Res Ctr,Massachusetts Gen Hosp, Boston, MA 02115 USA. [Demehri, Shadmehr; Cunningham, Trevor J.; Ngo, Kenneth H.; Tuchayi, Sara Moradi] Harvard Univ, Massachusetts Gen Hosp, Sch Med, MGH Canc Ctr, Boston, MA USA. [Demehri, Shadmehr; Cunningham, Trevor J.; Reddy, Rasika] Washington Univ, Sch Med, Div Dermatol, St Louis, MO 63110 USA. [Demehri, Shadmehr; Cunningham, Trevor J.; Manivasagam, Sindhu; Reddy, Rasika; Yokoyama, Wayne M.] Washington Univ, Sch Med, Div Rheumatol, St Louis, MO USA. [Meyers, Melissa A.; DeNardo, David G.] Washington Univ, Sch Med, Dept Med, Div Oncol, St Louis, MO 63110 USA. [Yokoyama, Wayne M.] Washington Univ, Sch Med, Howard Hughes Med Inst, St Louis, MO 63110 USA. RP Demehri, S (reprint author), Bldg 149 13th St,3rd Floor, Charlestown, MA 02129 USA. EM sdemehri1@mgh.harvard.edu FU Washington University Digestive Diseases Research Core Center (NIH) [P30DK052574]; Washington University Rheumatic Diseases Core Center (NIH) [P03AR048335]; NIH [S10-RR0227552, 1DP5OD021353]; American Skin Association; Dermatology Foundation FX We thank the Yokoyama and DeNardo laboratory members Emil R. Unanue and Herbert W. Virgin for their critical reading of the manuscript. We thank Andrew Farr for the K14-TSLPtg mice, Warren Leonard for the Tslpr-/- mice, and Raphael Kopan and Ahu Turkoz for their assistance with the early generation of the animal models used in this study (NIH RO1 CA163353 and NIH P50 CA094056-07, to R. Kopan). We thank the Washington University Digestive Diseases Research Core Center (NIH grant P30DK052574) for assistance with IHC studies and the Washington University Rheumatic Diseases Core Center (NIH grant P03AR048335) for the Abs used in the depletion studies. The NanoZoomer imaging facility is supported by NIH Shared Instrumentation grant S10-RR0227552. W.M. Yokoyama is an Investigator of the Howard Hughes Medical Institute. S. Demehri is supported by grants from the American Skin Association, the Dermatology Foundation, and the NIH (1DP5OD021353). NR 37 TC 6 Z9 7 U1 0 U2 2 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD APR PY 2016 VL 126 IS 4 BP 1458 EP 1470 DI 10.1172/JCI83724 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DI5ES UT WOS:000373522300034 PM 26927668 ER PT J AU Grogg, KS Toole, T Ouyang, JS Zhu, XP Normandin, MD Li, QZ Johnson, K Alpert, NM El Fakhri, G AF Grogg, Kira S. Toole, Terrence Ouyang, Jinsong Zhu, Xuping Normandin, Marc D. Li, Quanzheng Johnson, Keith Alpert, Nathaniel M. El Fakhri, Georges TI National Electrical Manufacturers Association and Clinical Evaluation of a Novel Brain PET/CT Scanner SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE PET/CT; instrumentation; NEMA standard ID ECAT EXACT HR+; ATTENUATION COEFFICIENTS; PERFORMANCE; CT AB The aim of this study was to determine the performance of a novel mobile human brain/small-animal PET/CT system. The scanner has a 35.7-cm-diameter bore and a 22-cm axial extent. The detector ring has 7 modules each with 3 x 4 cerium-doped lutetium yttrium orthosilicate crystal blocks, each consisting of 22 x 22 outer-layer and 21 x 21 inner-layer crystals, each layer 1-cm thick. Light is collected by 12 x 12 silicon photomultipliers. The integrated CT can be used for attenuation correction and anatomic localization. The scanner was designed as a low-cost device that nevertheless produces high-quality PET images with the unique capability of battery-powered propulsion, enabling use in many settings. Methods: Spatial resolution, sensitivity, and noise-equivalent counting rate were measured based on the National Electrical Manufacturers Association NU2-2012 procedures. Reconstruction was done with tight energy and timing cuts-400-650 keV and 7 ns-and loose cuts-350-700 keV and 10 ns. Additional image quality measurements were made from phantom, human, and animal studies. Performance was compared with a reference scanner with comparable imaging properties. Results: The full width at half maximum transverse resolution at a 1-cm (10-cm) radius was 3.2 mm (5.2-mm radial, 3.1-mm tangential), and the axial resolution was 3.5 mm (4.0 mm). A sensitivity of 7.5 and 11.7 kcps/MBq at the center for tight and loose cuts, respectively, increased to 8.8 and 13.9 kcps/MBq, respectively, at a 10-cm radial offset. The maximum noise-equivalent counting rate of 19.5 and 22.7 kcps for tight and loose cuts, respectively, was achieved for an activity concentration of 2.9 kBq/mL. Contrast recovery for 4: 1 hot cylinder to warm background was 76% for the 25-mm-diameter cylinder but decreased with decreasing cylinder size. The quantitation agreed within 2% of the known activity distribution and concentration. Brain phantom and human scans have shown agreement in SUVs and image quality with the reference scanner. Conclusion: We characterized the performance of the NeuroPET/CT and showed images from the first human studies. The study shows that this scanner achieves good performance when spatial resolution, sensitivity, counting rate, and image quality along with a low cost and unique mobile capabilities are considered. C1 [Grogg, Kira S.; Ouyang, Jinsong; Zhu, Xuping; Normandin, Marc D.; Li, Quanzheng; Alpert, Nathaniel M.; El Fakhri, Georges] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gordon Ctr Med Imaging,Dept Radiol, Boston, MA USA. [Toole, Terrence] Photo Diagnost Syst Inc, Boxboro, MA USA. [Johnson, Keith] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Nucl Med & Mol Imaging,Dept Radiol, Boston, MA USA. RP El Fakhri, G (reprint author), Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. EM elfakhri.georges@mgh.harvard.edu FU NIH [S10RR028110, T32EB013180, R21EB012823, R01EB019959, C06CA059267] FX The costs of publication of this article were defrayed in part by the payment of page charges. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 USC section 1734. This work was supported by NIH grants S10RR028110, T32EB013180, R21EB012823, R01EB019959, and C06CA059267. Terrence Toole is an employee of PDSi. No other potential conflict of interest relevant to this article was reported. NR 17 TC 0 Z9 0 U1 1 U2 4 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD APR 1 PY 2016 VL 57 IS 4 BP 646 EP 652 DI 10.2967/jnumed.115.159723 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DI6RN UT WOS:000373627800036 PM 26697961 ER PT J AU Gaskins, AJ Rich-Edwards, JW Williams, PL Toth, TL Missmer, SA Chavarro, JE AF Gaskins, Audrey J. Rich-Edwards, Janet W. Williams, Paige L. Toth, Thomas L. Missmer, Stacey A. Chavarro, Jorge E. TI Prepregnancy Low to Moderate Alcohol Intake Is Not Associated with Risk of Spontaneous Abortion or Stillbirth SO JOURNAL OF NUTRITION LA English DT Article DE alcohol; ethanol; miscarriage; pregnancy loss; stillbirth; spontaneous abortion ID BINGE DRINKING; CONSUMPTION; PREGNANCY; QUESTIONNAIRE; REPRODUCIBILITY; MISCARRIAGE; RECALL; VALIDATION; CIGARETTE; CAFFEINE AB Background: Numerous studies have documented the negative effects of maternal alcohol consumption during pregnancy on risk of pregnancy loss, yet whether prepregnancy alcohol intake affects the risk of spontaneous abortion is still unclear. Objective: This study aimed to assess prepregnancy alcohol intake and risk of spontaneous abortion and stillbirth. Methods: Our prospective cohort study included 27,580 pregnancies reported by 17,929 women in the Nurses' Health Study II between 1990 and 2009. Alcohol intake was assessed in 1989 and 1991 and every 4 y thereafter with the use of a validated questionnaire. Women were classified into 5 categories of consumption: 0, 0.1-1.9, 2-4.9, 5-9.9, and >= 10 g/d (1 serving = similar to 12 g). Pregnancies were self-reported, with case pregnancies lost spontaneously (spontaneous abortion after gestation of < 20 wk and stillbirth after gestation of >= 20 wk) and comparison pregnancies not ending in fetal loss (live birth, ectopic pregnancy, or induced abortion). Multivariable log-binomial regression models with generalized estimating equations were used to estimate RRs and 95% CIs. Results: Incident spontaneous abortion and stillbirth were reported in 4326 (15.7%) and 205 (0.7%) pregnancies, respectively. Prepregnancy alcohol intake was not associated with spontaneous abortion. Compared with women who did not consume alcohol, the multivariable RRs (95% CIs) for increasing categories of alcohol intake among women who did consume alcohol were 1.04 (0.97, 1.12) for 0.1-1.9 g/d, 1.02 (0.94, 1.11) for 2-4.9 g/d, 1.01 (0.92, 1.10) for 5-9.9 g/d, and 0.98 (0.88, 1.09) for >= 10 g/d (P-trend = 0.45). Women who consumed >= 2 servings beer/wk before pregnancy had a 9% (95% CI: 1%, 17%) lower risk of spontaneous abortion than did women who consumed < 1 serving beer/mo; however, this association did not persist in various sensitivity analyses. Prepregnancy consumption of wine and liquor were not associated with spontaneous abortion. Total alcohol and specific alcohol beverage intake before pregnancy were not associated with stillbirth. Conclusion: Prepregnancy alcohol intake was not related to risk of incident spontaneous abortion or stillbirth in women with no history of pregnancy loss. Our results provide reassuring evidence that low to moderate alcohol intake (<= 12 g/d) before pregnancy initiation does not affect risk of pregnancy loss. C1 [Gaskins, Audrey J.; Chavarro, Jorge E.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Rich-Edwards, Janet W.; Williams, Paige L.; Missmer, Stacey A.; Chavarro, Jorge E.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Williams, Paige L.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Rich-Edwards, Janet W.; Missmer, Stacey A.; Chavarro, Jorge E.] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Rich-Edwards, Janet W.] Brigham & Womens Hosp, Dept Med, Connors Ctr Womens Hlth & Gender Biol, 75 Francis St, Boston, MA 02115 USA. [Missmer, Stacey A.] Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Biol, 75 Francis St, Boston, MA 02115 USA. [Toth, Thomas L.; Missmer, Stacey A.] Harvard Univ, Sch Med, Boston, MA USA. [Toth, Thomas L.] Massachusetts Gen Hosp, Vincent Obstet & Gynecol, Boston, MA 02114 USA. [Missmer, Stacey A.] Beth Israel Deaconess Med Ctr, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02215 USA. RP Gaskins, AJ (reprint author), Harvard Univ, TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. EM agaskins@hsph.harvard.edu FU NIH [T32DK007703-16, P30DK46200, UM1 CA176726] FX Supported by NIH grants T32DK007703-16, P30DK46200, and UM1 CA176726. NR 40 TC 0 Z9 0 U1 4 U2 8 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 EI 1541-6100 J9 J NUTR JI J. Nutr. PD APR PY 2016 VL 146 IS 4 BP 799 EP 805 DI 10.3945/jn.115.226423 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DI3RA UT WOS:000373415000019 ER PT J AU Langlois, J Zaoui, A Bichara, DA Nich, C Bensidhoum, M Petite, H Muratoglu, OK Hamadouche, M AF Langlois, Jean Zaoui, Amine Bichara, David A. Nich, Christophe Bensidhoum, Morad Petite, Herve Muratoglu, Orhun K. Hamadouche, Moussa TI Biological reaction to polyethylene particles in a murine calvarial model is highly influenced by age SO JOURNAL OF ORTHOPAEDIC RESEARCH LA English DT Article DE orthopaedic implants; aging; bone histomorphometry; bone micro-CT; luminescence ID MICRO-COMPUTED TOMOGRAPHY; TOTAL HIP-ARTHROPLASTY; ALTERNATIVE MACROPHAGE ACTIVATION; MOLECULAR-WEIGHT POLYETHYLENE; WEAR DEBRIS PARTICLES; INNATE IMMUNE-SYSTEM; PERIPROSTHETIC OSTEOLYSIS; BONE-FORMATION; IN-VIVO; RAT MODEL AB Particle-induced osteolysis is driven by multiple factors including bone metabolism, inflammation, and age. The objective of this study was to determine the influence of age on polyethylene (PE) particle-induced osteolysis in a murine calvarial model comparing 2-month-old (young) versus 24-month-old (old) mice. After PE particle implantation, calvaria were assessed at days (D) 3, D7, D14, and D21 via chemoluminescent imaging for inflammation (L-012 probe). In addition micro-computed tomography (micro-CT) and histomorphometry end points addressed the bone reaction. Inflammation peaked at D7 in young mice and D14 in old mice. Using micro-CT, a nadir of mature bone was recorded at D7 for young mice, versus D21 for old mice. Besides, regenerating bone peaked at distinct timepoints: D7 for young mice versus D21 for old mice. In the young mice group, the histomorphometric findings correlated with micro-CT regenerating bone findings at D7, associated with ample osteoid deposition. No osteoid could be histologically quantified in the old mice group at D7. This study demonstrated that the biological reaction to polyethylene particles is highly influenced by age. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:574-580, 2016. C1 [Langlois, Jean; Bichara, David A.; Muratoglu, Orhun K.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Harris Orthopaed Lab, 55 Fruit St,GRJ 1231, Boston, MA 02114 USA. [Langlois, Jean; Zaoui, Amine; Nich, Christophe; Bensidhoum, Morad; Petite, Herve; Hamadouche, Moussa] Paris 7 Denis Diderot, Fac Med, Lab Bioingn & Biomecan Osteoarticulaires, UMR CNRS 7052, 10 Ave Verdun, F-75010 Paris, France. RP Langlois, J (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Harris Orthopaed Lab, 55 Fruit St,GRJ 1231, Boston, MA 02114 USA.; Langlois, J (reprint author), Paris 7 Denis Diderot, Fac Med, Lab Bioingn & Biomecan Osteoarticulaires, UMR CNRS 7052, 10 Ave Verdun, F-75010 Paris, France. EM jeangast@gmail.com RI Petite, Herve/E-3478-2016 OI Petite, Herve/0000-0003-1694-5060 FU APHP; Fulbright Program; Arthur Sachs; Harvard French Scholarship Fund grant FX Grant sponsor: APHP (concours de la medaille); Grant sponsor: Fulbright Program; Grant sponsor: Arthur Sachs; Grant sponsor: Harvard French Scholarship Fund grant. NR 55 TC 1 Z9 1 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0736-0266 EI 1554-527X J9 J ORTHOP RES JI J. Orthop. Res. PD APR PY 2016 VL 34 IS 4 BP 574 EP 580 DI 10.1002/jor.23050 PG 7 WC Orthopedics SC Orthopedics GA DI4ST UT WOS:000373490300004 PM 26375608 ER PT J AU Zhai, X Sun, CL Rong, PJ Li, SY McCabe, MF Wang, X Mao, JR Wang, SX AF Zhai, Xu Sun, Chunli Rong, Peijing Li, Shaoyuan McCabe, Michael F. Wang, Xing Mao, Jianren Wang, Shuxing TI A Correlative Relationship Between Chronic Pain and Insulin Resistance in Zucker Fatty Rats: Role of Downregulation of Insulin Receptors SO JOURNAL OF PAIN LA English DT Article DE Chronic hypersensitivity; insulin resistance; type 2 diabetes; constriction injury of a unilateral sciatic nerve; hemoglobiri Alc; insulin receptor; Zucker Diabetic Fatty rats ID PERIPHERAL MONONEUROPATHY; BETA-CELL; HYPERALGESIA; GLUCOSE; NERVE; HYPERINSULINEMIA; PREVALENCE; NEUROPATHY; ALLODYNIA; SENSATION AB Epidemiological studies and meta-analyses report a strong relationship between chronic pain and abnormalities in glucose metabolism, but the exact relationship between chronic pain and insulin resistance in type 2 diabetes (T2D) remains unknown. Using a model of neuropathic thermal and tactile hypersensitivity induced by chronic constriction injury (CCI) of the sciatic nerve in Zucker Diabetic Fatty (ZDF) and Zucker Lean (ZL) littermates, we compared the recovery period of hypersensitivity and the progression of T2D and studied the possible involvement of insulin receptors (IRs) in the comorbidity of these 2 conditions. We found that the nociceptive thresholds to thermal and mechanical stimulation in naive ZDF rats were lower than in ZL littermates at 6 weeks of age. Although ZDF and ZL rats developed thermal and tactile hypersensitivity after CCI, it took a longer time nociceptive sensitivity to be restored in ZDF rats. Nerve injury accelerated the progression of T2D in ZDF rats, shown by an earlier onset of hyperglycemia, more severe hyperinsulinemia, and a higher concentration of glycosylated hemoglobin Alc 6 weeks after CCI, compared with those in naive ZDF and ZL rats. IR-immunoreactive cells were located across the central nervous system and skeletal muscles. In the central nervous system, IR coexpressed with a neuronal marker (neuronal nuclei) but not a glial marker (glial fibrillary acidic protein). There was a low level of IR expression in skeletal muscles of naive ZDF rats. In contrast, CCI reduced the IR expression in skeletal muscles as well as the ipsilateral spinal cord, primarily in the dorsal horn. In conclusion, our data suggest that the relationship between insulin resistance and chronic pain in ZDF rats is bidirectional and an impaired IR signaling system might be implicated in this reciprocal relationship. Perspective: Nerve injuries in genetically susceptible individuals might accelerate the development of insulin resistance as in T2D. A downregulated expression of IRs in the skeletal muscle innervated by the injured nerve is one of the underlying mechanisms. (C) 2016 The Authors. Published by Elsevier Inc. on behalf of the American Pain Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). C1 [Zhai, Xu; Sun, Chunli; Wang, Xing] Xinxiang Med Univ, Dept Anat, Xinxiang, Henan Province, Peoples R China. [Zhai, Xu; Rong, Peijing; Li, Shaoyuan] China Acad Chinese Med Sci, Inst Acupuncture & Moxibust, Dept Physiol, Beijing, Peoples R China. [McCabe, Michael F.; Mao, Jianren] Harvard Univ, Massachusetts Gen Hosp, Sch Med, MGH Ctr Translat Pain Res,Dept Anesthesia Crit Ca, Boston, MA USA. [Wang, Shuxing] Guangdong Inst Appl Biol Resources, Guangzhou 510260, Guangdong, Peoples R China. [Wang, Shuxing] Guangdong Publ Lab Wild Anim Conservat & Utilizat, Guangzhou, Guangdong, Peoples R China. RP Rong, PJ (reprint author), China Acad Chinese Med Sci, Inst Acupuncture & Moxibust, Dept Physiol, Beijing, Peoples R China.; Wang, SX (reprint author), Guangdong Inst Appl Biol Resources, Guangzhou 510260, Guangdong, Peoples R China. EM rongpj@hotmail.com; shuxingw@gmail.com FU National Natural Science Foundation of China [81271243, 81571085, 81473780]; National Basic Research Program of China (973 Program) [2012CB518503]; Project Supported National Science and Technology Ministry [2012BAF14B10]; Guangdong Entomological Institute [GDEI-gjrc201501] FX This work was supported by the National Natural Science Foundation of China-81271243 and 81571085 (S.W.), and 81473780 (P.R.); National Basic Research Program of China (973 Program) - 2012CB518503 and Project Supported National Science and Technology Ministry-2012BAF14B10 (ER.); and Institutional fund of Guangdong Entomological Institute-GDEI-gjrc201501 (S.W.). The funding sources had no role in the experimental design, procedures, writing, and decision to submit the work for publication. NR 30 TC 0 Z9 0 U1 0 U2 4 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 APR PY 2016 VL 17 IS 4 BP 404 EP 413 DI 10.1016/j.jpain.2015.12.003 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DI5EY UT WOS:000373522900002 PM 26705975 ER PT J AU Higgins, D Buta, E Heapy, A Driscoll, M Kerns, R Masheb, R Becker, W Burgess, D Hausmann, L Bair, M Justice, A Wandner, L Krein, S Brandt, C Goulet, J AF Higgins, D. Buta, E. Heapy, A. Driscoll, M. Kerns, R. Masheb, R. Becker, W. Burgess, D. Hausmann, L. Bair, M. Justice, A. Wandner, L. Krein, S. Brandt, C. Goulet, J. TI The relationship among BMI, pain intensity, and musculoskeletal diagnoses SO JOURNAL OF PAIN LA English DT Meeting Abstract C1 [Higgins, D.; Buta, E.; Heapy, A.; Driscoll, M.; Kerns, R.; Masheb, R.; Becker, W.; Burgess, D.; Hausmann, L.; Bair, M.; Justice, A.; Wandner, L.; Krein, S.; Brandt, C.; Goulet, J.] Boston Univ, Sch Med, VA Boston Healthcare Syst, Boston, MA 02118 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 APR PY 2016 VL 17 IS 4 SU 1 MA 208 BP S28 EP S28 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DI5EZ UT WOS:000373523000110 PM 28162438 ER PT J AU Jackson, W Kulich, R Malacarne, A Lapidow, A Vranceanu, A AF Jackson, W. Kulich, R. Malacarne, A. Lapidow, A. Vranceanu, A. TI Physical functioning and mindfulness based interventions in chronic pain: a systematic review SO JOURNAL OF PAIN LA English DT Meeting Abstract C1 [Jackson, W.; Kulich, R.; Malacarne, A.; Lapidow, A.; Vranceanu, A.] Tufts Univ, Sch Dent Med, Harvard Univ, Massachusetts Gen Hosp,Sch Med, Boston, MA 02111 USA. NR 0 TC 0 Z9 0 U1 2 U2 3 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 APR PY 2016 VL 17 IS 4 SU 1 MA 497 BP S99 EP S99 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DI5EZ UT WOS:000373523000395 PM 28162752 ER PT J AU Lonberger, C McSheffrey, S Allsup, K Sluice, M Driscoll, M Higgins, D Tyzik, A Gerber, M Scioli-Salter, E AF Lonberger, C. McSheffrey, S. Allsup, K. Sluice, M. Driscoll, M. Higgins, D. Tyzik, A. Gerber, M. Scioli-Salter, E. TI Potential barriers for achieving exercise maintenance among trauma exposed female veterans with Fibromyalgia SO JOURNAL OF PAIN LA English DT Meeting Abstract C1 [Lonberger, C.; McSheffrey, S.; Allsup, K.; Sluice, M.; Driscoll, M.; Higgins, D.; Tyzik, A.; Gerber, M.; Scioli-Salter, E.] VA Boston Healthcare Syst, Womens Hlth Sci Div, Natl Ctr PTSD, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 APR PY 2016 VL 17 IS 4 SU 1 MA 517 BP S104 EP S104 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DI5EZ UT WOS:000373523000415 PM 28162324 ER PT J AU Mawla, I Loggia, M Schmithorst, V Ortiz, A Gerber, J Protsenko, E Lee, J Kim, J Kim, H Berna, C Kaptchuk, T Kong, J Gollub, R Rosen, B Edwards, R Wasan, A Napadow, V AF Mawla, I. Loggia, M. Schmithorst, V. Ortiz, A. Gerber, J. Protsenko, E. Lee, J. Kim, J. Kim, H. Berna, C. Kaptchuk, T. Kong, J. Gollub, R. Rosen, B. Edwards, R. Wasan, A. Napadow, V. TI Investigating the neural circuitry supporting clinical pain perception in chronic low back pain - the importance of cardiorespiratory artifact correction with arterial spin labeling fMRI SO JOURNAL OF PAIN LA English DT Meeting Abstract C1 [Mawla, I.; Loggia, M.; Schmithorst, V.; Ortiz, A.; Gerber, J.; Protsenko, E.; Lee, J.; Kim, J.; Kim, H.; Berna, C.; Kaptchuk, T.; Kong, J.; Gollub, R.; Rosen, B.; Edwards, R.; Wasan, A.; Napadow, V.] Massachusetts Gen Hosp, Charlestown, MA USA. NR 0 TC 0 Z9 0 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 1526-5900 J9 J PAIN JI J. Pain PD APR PY 2016 VL 17 IS 4 SU 1 MA 336 BP S59 EP S60 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DI5EZ UT WOS:000373523000236 PM 28162572 ER PT J AU Rudd-Barnard, G Walbom, A Pangarkar, S Baria, A AF Rudd-Barnard, G. Walbom, A. Pangarkar, S. Baria, A. TI A case study investigating opioid medication utilization in patients with complex regional pain syndrome before and after ketamine infusion therapy SO JOURNAL OF PAIN LA English DT Meeting Abstract C1 [Rudd-Barnard, G.; Walbom, A.; Pangarkar, S.; Baria, A.] Univ Calif Los Angeles, Greater Los Angeles VA Hlth Syst, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 APR PY 2016 VL 17 IS 4 SU 1 MA 406 BP S76 EP S76 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DI5EZ UT WOS:000373523000305 PM 28162651 ER PT J AU Rudd-Barnard, G Pangarkar, S Moaleji, N Glassman, P AF Rudd-Barnard, G. Pangarkar, S. Moaleji, N. Glassman, P. TI Epidemiology of naloxone use for opioid overdose in a tertiary care medical center SO JOURNAL OF PAIN LA English DT Meeting Abstract C1 [Rudd-Barnard, G.; Pangarkar, S.; Moaleji, N.; Glassman, P.] Greater Los Angeles VA Hlth Syst, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 APR PY 2016 VL 17 IS 4 SU 1 MA 141 BP S11 EP S11 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DI5EZ UT WOS:000373523000043 PM 28162348 ER PT J AU Stegner, A Cook, D AF Stegner, A. Cook, D. TI Resistance exercise training in Gulf War Veterans with chronic unexplained muscle pain: impact on pain, fatigue, mood and global impression of change SO JOURNAL OF PAIN LA English DT Meeting Abstract C1 [Stegner, A.; Cook, D.] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 APR PY 2016 VL 17 IS 4 SU 1 MA 484 BP S95 EP S96 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DI5EZ UT WOS:000373523000382 PM 28162735 ER PT J AU Charidimou, A AF Charidimou, Andreas TI Cerebral Microbleeds Meta-analyses of Prospective Studies: The Need to Consider Both Ischemic and Hemorrhagic Stroke Outcomes SO JOURNAL OF STROKE & CEREBROVASCULAR DISEASES LA English DT Letter C1 [Charidimou, Andreas] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp,Stroke Res Ctr,Hemorrhag S, Boston, MA 02115 USA. RP Charidimou, A (reprint author), Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp,Stroke Res Ctr,Hemorrhag S, Boston, MA 02115 USA. EM andreas.charidimou.09@ucl.ac.uk NR 5 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1052-3057 EI 1532-8511 J9 J STROKE CEREBROVASC JI J. Stroke Cerebrovasc. Dis. PD APR PY 2016 VL 25 IS 4 BP 1007 EP 1007 DI 10.1016/j.jstrokecerebrovasdis.2015.12.012 PG 1 WC Neurosciences; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA DI7ZJ UT WOS:000373720200045 PM 26794263 ER PT J AU Kennedy, JG van Dijk, PAD Murawski, CD Duke, G Newman, H DiGiovanni, CW Yasui, Y AF Kennedy, John G. van Dijk, Pim A. D. Murawski, Christopher D. Duke, Gavin Newman, Hunter DiGiovanni, Christopher W. Yasui, Youichi TI Functional outcomes after peroneal tendoscopy in the treatment of peroneal tendon disorders SO KNEE SURGERY SPORTS TRAUMATOLOGY ARTHROSCOPY LA English DT Article DE Peroneal tendon; Ankle; Tendoscopy; Tendon injury; Tendinosis; Magnetic resonance imaging ID LATERAL ANKLE INSTABILITY; PLATELET-RICH PLASMA; TEARS; RETINACULUM; MANAGEMENT; INJURIES; FOOT; MRI; TENDINOPATHY; DISLOCATION AB The primary purpose of this study was to evaluate clinical outcomes following peroneal tendoscopy for the treatment of peroneal pathology. Correlation between pre-operative magnetic resonance imaging (MRI) and peroneal tendoscopic diagnostic findings was also assessed. Twenty-three patients with a mean age of 34 +/- A 8.8 years undergoing peroneal tendoscopy were pre- and post-operatively assessed with the foot and ankle outcome score (FAOS) and the Short Form-12 (SF-12) outcome questionnaires. Follow-up was over 24 months in all patients. The sensitivity and specificity of MRI were calculated in comparison with peroneal tendoscopy, including the positive predictive value (PPV). Both the FAOS and the SF-12 improved significantly (p < 0.05) at a mean follow-up of 33 +/- A 7.3 months significantly. MRI showed an overall sensitivity of 0.90 (95 % confidence interval (CI) = 0.82-0.95) and specificity of 0.72 (95 % CI 0.62-0.80). The PPV for MRI diagnosis of peroneal tendon pathology was 0.76 (95 % CI 0.68-0.83). The current study found good clinical outcomes in patients with peroneal tendon disorders, treated with peroneal tendoscopy. Although a relatively small number of patients were included, the study suggests good correlation between tendoscopic findings and pre-operative MRI findings of peroneal tendon pathology, supporting the use of MRI as a useful diagnostic modality for suspected peroneal tendon disorders. Level IV, retrospective case series. C1 [Kennedy, John G.; van Dijk, Pim A. D.; Newman, Hunter; Yasui, Youichi] Hosp Special Surg, 535 E 70th St, New York, NY 10021 USA. [van Dijk, Pim A. D.] Univ Amsterdam, Acad Med Ctr, Dept Orthoped Surg, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. [van Dijk, Pim A. D.] ACHSS, Acad Ctr Evidence Based Sports Med ACES, Amsterdam, Netherlands. [Duke, Gavin] East River Med Imaging, New York, NY USA. [Murawski, Christopher D.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [DiGiovanni, Christopher W.] Harvard Univ, Dept Orthopaed Surg, Sch Med, Massachusetts Gen Hosp, Boston, MA USA. [Yasui, Youichi] Teikyo Univ, Sch Med, Dept Orthopaed Surg, Tokyo 173, Japan. RP Kennedy, JG (reprint author), Hosp Special Surg, 535 E 70th St, New York, NY 10021 USA. EM KennedyJ@hss.edu NR 40 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0942-2056 EI 1433-7347 J9 KNEE SURG SPORT TR A JI Knee Surg. Sports Traumatol. Arthrosc. PD APR PY 2016 VL 24 IS 4 BP 1148 EP 1154 DI 10.1007/s00167-016-4012-6 PG 7 WC Orthopedics; Sport Sciences; Surgery SC Orthopedics; Sport Sciences; Surgery GA DI7SX UT WOS:000373703400028 PM 26846655 ER PT J AU van Dijk, PAD Lubberts, B Verheul, C DiGiovanni, CW Kerkhoffs, GMMJ AF van Dijk, Pim A. D. Lubberts, Bart Verheul, Claire DiGiovanni, Christopher W. Kerkhoffs, Gino M. M. J. TI Rehabilitation after surgical treatment of peroneal tendon tears and ruptures SO KNEE SURGERY SPORTS TRAUMATOLOGY ARTHROSCOPY LA English DT Article DE Physical therapy; Rehabilitation; Peroneal tendon; Tear; Tendon; Rupture; Tendon healing ID CHRONIC ANKLE INSTABILITY; BREVIS TENDON; LONGUS TENDON; OS PERONEUM; ALLOGRAFT RECONSTRUCTION; ACTIVE MOBILIZATION; SPLIT LESIONS; REPAIR; INJURIES; FRACTURE AB The purpose of this study was to provide an overview of the available evidence on rehabilitation programmes after operatively treated patients with peroneal tendon tearsand ruptures. A systematic review was performed, and PubMed and EMBASE were searched for relevant studies. Information regarding the rehabilitation programme after surgical management of peroneal tendon tears and ruptures was extracted from all included studies. In total, 49 studies were included. No studies were found with the primary purpose to report on rehabilitation of surgically treated peroneal tendon tears or ruptures. The median duration of the total immobilization period after primary repair was 6.0 weeks (range 0-12), 7.0 weeks (range 3.0-13) after tenodesis, 6.3 weeks (range 3.0-13) after grafting, and 8.0 weeks (range 6.0-11) after end-to-end suturing. Forty one percent of the studies that reported on the start of range of motion exercises initiated range of motion within 4 weeks after surgery. No difference was found in duration of immobilization or start of range of motion between different types of surgical treatment options. Appropriate directed rehabilitation appears to be an important factor in the clinical success of surgically treated peroneal tendon tears and ruptures. There seems to be a trend towards shorter immobilization time and early range of motion, although there is no consensus in the literature on best practice recommendations for optimizing rehabilitation after surgical repair of peroneal tendon tears or ruptures. It is important to adjust the rehabilitation protocol to every specific patient for an optimal rehabilitation. Level of evidence Systematic Review, Level IV. C1 [van Dijk, Pim A. D.; Kerkhoffs, Gino M. M. J.] Univ Amsterdam, Acad Med Ctr, Orthopaed Res Ctr Amsterdam, Dept Orthopaed Surg, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. [van Dijk, Pim A. D.; Verheul, Claire; Kerkhoffs, Gino M. M. J.] Acad Ctr Evidence Based Sports Med ACES, Amsterdam, Netherlands. [van Dijk, Pim A. D.; Verheul, Claire; Kerkhoffs, Gino M. M. J.] ACHSS, Amsterdam, Netherlands. [van Dijk, Pim A. D.; Lubberts, Bart; DiGiovanni, Christopher W.] Massachusetts Gen Hosp, Dept Orthopaed Surg, Foot & Ankle Serv, Boston, MA 02114 USA. [Verheul, Claire] Orthopaed Manual Therapy & Sport Physiotherapy, Amsterdam, Netherlands. RP van Dijk, PAD (reprint author), Univ Amsterdam, Acad Med Ctr, Orthopaed Res Ctr Amsterdam, Dept Orthopaed Surg, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands.; van Dijk, PAD (reprint author), Acad Ctr Evidence Based Sports Med ACES, Amsterdam, Netherlands.; van Dijk, PAD (reprint author), ACHSS, Amsterdam, Netherlands.; van Dijk, PAD (reprint author), Massachusetts Gen Hosp, Dept Orthopaed Surg, Foot & Ankle Serv, Boston, MA 02114 USA. EM p.a.vandijk@amc.uva.nl; g.m.kerkhoffs@amc.uva.nl NR 69 TC 1 Z9 1 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0942-2056 EI 1433-7347 J9 KNEE SURG SPORT TR A JI Knee Surg. Sports Traumatol. Arthrosc. PD APR PY 2016 VL 24 IS 4 BP 1165 EP 1174 DI 10.1007/s00167-015-3944-6 PG 10 WC Orthopedics; Sport Sciences; Surgery SC Orthopedics; Sport Sciences; Surgery GA DI7SX UT WOS:000373703400030 PM 26803783 ER PT J AU Claessen, FMAP Meijer, DT van den Bekerom, MPJ Deynoot, BDJG Mallee, WH Doornberg, JN van Dijk, CN AF Claessen, Femke M. A. P. Meijer, Diederik T. van den Bekerom, Michel P. J. Deynoot, Barend D. J. Gevers Mallee, Wouter H. Doornberg, Job N. van Dijk, C. Niek TI Reliability of classification for post-traumatic ankle osteoarthritis SO KNEE SURGERY SPORTS TRAUMATOLOGY ARTHROSCOPY LA English DT Article DE Ankle trauma; Post-traumatic ankle fracture osteoarthritis; Classification system; Interobserver study ID PROXIMAL HUMERAL FRACTURES; OF-THE-LITERATURE; INTEROBSERVER RELIABILITY; DECISION-MAKING; OSTEOCHONDRAL DEFECTS; PATIENT PREFERENCES; 3-DIMENSIONAL CT; ARTHRITIS; PRIORITIES; OSTEOTOMY AB The purpose of this study was to identify the most reliable classification system for clinical outcome studies to categorize post-traumatic-fracture-osteoarthritis. A total of 118 orthopaedic surgeons and residents-gathered in the Ankle Platform Study Collaborative Science of Variation Group-evaluated 128 anteroposterior and lateral radiographs of patients after a bi- or trimalleolar ankle fracture on a Web-based platform in order to rate post-traumatic osteoarthritis according to the classification systems coined by (1) van Dijk, (2) Kellgren, and (3) Takakura. Reliability was evaluated with the use of the Siegel and Castellan's multirater kappa measure. Differences between classification systems were compared using the two-sample Z-test. Interobserver agreement of surgeons who participated in the survey was fair for the van Dijk osteoarthritis scale (k = 0.24), and poor for the Takakura (k = 0.19) and the Kellgren systems (k = 0.18) according to the categorical rating of Landis and Koch. This difference in one categorical rating was found to be significant (p < 0.001, CI 0.046-0.053) with the high numbers of observers and cases available. This study documents fair interobserver agreement for the van Dijk osteoarthritis scale, and poor interobserver agreement for the Takakura and Kellgren osteoarthritis classification systems. Because of the low interobserver agreement for the van Dijk, Kellgren, and Takakura classification systems, those systems cannot be used for clinical decision-making. Development of diagnostic criteria on basis of consecutive patients, Level II. C1 [Claessen, Femke M. A. P.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Orthopaed Hand & Upper Extrem Serv,Yawkey Ctr, 55 Fruit St, Boston, MA 02114 USA. [Claessen, Femke M. A. P.] Univ Amsterdam, Sch Med, 55 Fruit St, Boston, MA 02114 USA. [Meijer, Diederik T.; Deynoot, Barend D. J. Gevers; Mallee, Wouter H.; Doornberg, Job N.] Univ Amsterdam, Acad Med Ctr, Orthotrauma Res Ctr Amsterdam, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. [van den Bekerom, Michel P. J.] Onze Lieve Vrouw Hosp, Shoulder & Elbow Unit, Amsterdam, Netherlands. [van Dijk, C. Niek] Univ Amsterdam, Acad Med Ctr, Dept Orthopaed Surg, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. RP Claessen, FMAP (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Orthopaed Hand & Upper Extrem Serv,Yawkey Ctr, 55 Fruit St, Boston, MA 02114 USA.; Claessen, FMAP (reprint author), Univ Amsterdam, Sch Med, 55 Fruit St, Boston, MA 02114 USA. EM femke__claessen@hotmail.com FU Marti-Keuning Eckhart Foundation; Prins Bernhard Cultuur foundation; Trust foundation; VSB foundation; Van Beek-Donner foundation FX DT. Meijer and J. N. Doornberg have received an unrestricted research grant from the Marti-Keuning Eckhart Foundation. F. M. A. P Claessen has received a research grant from the Prins Bernhard Cultuur foundation, Trust foundation, VSB foundation, and Van Beek-Donner foundation. For the remaining authors, none were declared. NR 36 TC 0 Z9 0 U1 1 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0942-2056 EI 1433-7347 J9 KNEE SURG SPORT TR A JI Knee Surg. Sports Traumatol. Arthrosc. PD APR PY 2016 VL 24 IS 4 BP 1332 EP 1337 DI 10.1007/s00167-015-3871-6 PG 6 WC Orthopedics; Sport Sciences; Surgery SC Orthopedics; Sport Sciences; Surgery GA DI7SX UT WOS:000373703400051 PM 26611896 ER PT J AU Claessen, FMAP Meijer, DT van den Bekerom, MPJ Deynoot, BDJG Mallee, WH Doornberg, JN van Dijk, CN AF Claessen, Femke M. A. P. Meijer, Diederik T. van den Bekerom, Michel P. J. Deynoot, Barend D. J. Gevers Mallee, Wouter H. Doornberg, Job N. van Dijk, C. Niek CA Ankle Platform Study Collaborative TI Reliability of classification for post-traumatic ankle osteoarthritis (vol 24, pg 1332, 2016) SO KNEE SURGERY SPORTS TRAUMATOLOGY ARTHROSCOPY LA English DT Correction C1 [Claessen, Femke M. A. P.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Orthopaed Hand & Upper Extrem Serv,Yawkey Ctr, 55 Fruit St, Boston, MA 02114 USA. [Claessen, Femke M. A. P.] Univ Amsterdam, Sch Med, 55 Fruit St, Boston, MA 02114 USA. [Meijer, Diederik T.; Deynoot, Barend D. J. Gevers; Mallee, Wouter H.; Doornberg, Job N.] Univ Amsterdam, Acad Med Ctr, Orthotrauma Res Ctr Amsterdam, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. [van den Bekerom, Michel P. J.] Onze Lieve Vrouw Hosp, Shoulder & Elbow Unit, Amsterdam, Netherlands. [van Dijk, C. Niek] Univ Amsterdam, Acad Med Ctr, Dept Orthopaed Surg, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. RP Claessen, FMAP (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Orthopaed Hand & Upper Extrem Serv,Yawkey Ctr, 55 Fruit St, Boston, MA 02114 USA.; Claessen, FMAP (reprint author), Univ Amsterdam, Sch Med, 55 Fruit St, Boston, MA 02114 USA. EM femke__claessen@hotmail.com NR 1 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0942-2056 EI 1433-7347 J9 KNEE SURG SPORT TR A JI Knee Surg. Sports Traumatol. Arthrosc. PD APR PY 2016 VL 24 IS 4 BP 1338 EP 1338 DI 10.1007/s00167-016-3986-4 PG 1 WC Orthopedics; Sport Sciences; Surgery SC Orthopedics; Sport Sciences; Surgery GA DI7SX UT WOS:000373703400052 PM 26814893 ER PT J AU Chan, AT AF Chan, Andrew T. TI Metformin for cancer prevention: a reason for optimism SO LANCET ONCOLOGY LA English DT Editorial Material ID DIABETIC-PATIENTS; RISK C1 [Chan, Andrew T.] Massachusetts Gen Hosp, Clin & Translat Epidemiol Unit, 55 Fruit St,GRJ-825C, Boston, MA 02114 USA. [Chan, Andrew T.] Harvard Univ, Sch Med, 55 Fruit St,GRJ-825C, Boston, MA 02114 USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Chan, Andrew T.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. RP Chan, AT (reprint author), Massachusetts Gen Hosp, Clin & Translat Epidemiol Unit, 55 Fruit St,GRJ-825C, Boston, MA 02114 USA.; Chan, AT (reprint author), Harvard Univ, Sch Med, 55 Fruit St,GRJ-825C, Boston, MA 02114 USA.; Chan, AT (reprint author), Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA.; Chan, AT (reprint author), Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. EM achan@mgh.harvard.edu NR 10 TC 2 Z9 2 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD APR PY 2016 VL 17 IS 4 BP 407 EP 409 DI 10.1016/S1470-2045(16)00006-1 PG 4 WC Oncology SC Oncology GA DI4VN UT WOS:000373497600033 PM 26947330 ER PT J AU Kim, DW Mehra, R Tan, DSW Felip, E Chow, LQM Camidge, DR Vansteenkiste, J Sharma, S De Pas, T Riely, GJ Solomon, BJ Wolf, J Thomas, M Schuler, M Liu, G Santoro, A Sutradhar, S Li, SY Szczudlo, T Yovine, A Shaw, AT AF Kim, Dong-Wan Mehra, Ranee Tan, Daniel S. W. Felip, Enriqueta Chow, Laura Q. M. Camidge, D. Ross Vansteenkiste, Johan Sharma, Sunil De Pas, Tommaso Riely, Gregory J. Solomon, Benjamin J. Wolf, Juergen Thomas, Michael Schuler, Martin Liu, Geoffrey Santoro, Armando Sutradhar, Santosh Li, Siyu Szczudlo, Tomasz Yovine, Alejandro Shaw, Alice T. TI Activity and safety of ceritinib in patients with ALK-rearranged non-small-cell lung cancer (ASCEND-1): updated results from the multicentre, open-label, phase 1 trial SO LANCET ONCOLOGY LA English DT Article ID TYROSINE KINASE INHIBITORS; ACQUIRED-RESISTANCE; BRAIN METASTASES; CSF CONCENTRATION; CLINICAL BENEFIT; CRIZOTINIB; CHEMOTHERAPY; DISEASE; ALECTINIB; THERAPY AB Background ALK-rearranged non-small-cell lung cancer (NSCLC) is sensitive to ALK tyrosine kinase inhibitors (ALK inhibitors) such as crizotinib, but resistance invariably develops, often with progression in the brain. Ceritinib is a more potent ALK inhibitor than crizotinib in vitro, crosses the blood-brain barrier in vivo, and shows clinical responses in patients with crizotinib-resistant disease. We aimed to assess whole-body activity of ceritinib in both ALK inhibitor-pretreated and ALK inhibitor-naive patients with ALK-rearranged NSCLC. Methods ASCEND-1 was an open-label, phase 1 trial that recruited patients from 20 academic hospitals or cancer centres in 11 countries in Europe, North America, and Asia-Pacific. Eligible patients were aged 18 years or older with ALK-rearranged locally advanced or metastatic cancer that had progressed despite standard therapy (or for which no effective standard therapy existed), who had at least one measurable lesion at baseline. The primary objective (to determine the maximum tolerated dose) has been reported previously. This updated analysis includes all patients with ALK-rearranged NSCLC given oral ceritinib at the recommended dose of 750 mg/ day in the dose-escalation and expansion phases. Here we report the secondary outcomes of overall response, duration of response, and progression-free survival, analysed in all patients who received at least one 750 mg dose of ceritinib. Exploratory analyses included retrospective analysis of intracranial activity by independent neuroradiologists, in patients with untreated or locally treated neurologically stable brain metastases at baseline. Safety was assessed in all patients who received at least one dose of ceritinib. This study is no longer recruiting patients; however, treatment and follow-up are ongoing. This study is registered with ClinicalTrials.gov, number NCT01283516. Findings Between Jan 24, 2011, and July 31, 2013, 255 patients were enrolled and received at least one dose of ceritinib 750 mg/ day, of whom 246 had ALK-rearranged NSCLC. At data cutoff (April 14, 2014), median follow-up was 11.1 months (IQR 6.7-15.2) and 147 (60%) patients had discontinued treatment, 98 (40%) as a result of disease progression. An overall response was reported in 60 (72% [95% CI 61-82]) of 83 ALK inhibitor-naive patients and 92 (56% [49-64]) of 163 ALK inhibitor-pretreated patients. Median duration of response was 17.0 months (95% CI 11.3-non-estimable [NE]) in ALK inhibitor-naive patients and 8.3 months (6.8-9.7) in ALK inhibitor-pretreated patients. Median progression-free survival was 18.4 months (95% CI 11.1-NE) in ALK inhibitor-naive patients and 6.9 months (5.6-8.7) in ALK inhibitor-pretreated patients. Of 94 patients with retrospectively confirmed brain metastases and at least one post-baseline MRI or CT tumour assessment, intracranial disease control was reported in 15 (79% [95% CI 54-94]) of 19 ALK inhibitor-naive patients and in 49 (65% [54-76]) of 75 ALK inhibitor-pretreated patients. Of these 94 patients, 11 had measurable brain lesions and no previous radiotherapy to the brain, six of whom achieved a partial intracranial response. Serious adverse events were recorded in 117 (48%) of 246 patients. The most common grade 3-4 laboratory abnormalities were increased alanine aminotransferase (73 [30%] patients) and increased aspartate aminotransferase (25 [10%]). The most common grade 3-4 non-laboratory adverse events were diarrhoea and nausea, both of which occurred in 15 (6%) patients. Two on-treatment deaths during the study were deemed to be related to study drug by the investigators, one due to interstitial lung disease and one as a result of multiorgan failure that occurred in the context of infection and ischaemic hepatitis. Interpretation The durable whole-body responses reported, together with the intracranial activity, support a clinical benefit for treatment with ceritinib in patients with ALK-rearranged NSCLC who have received crizotinib, or as an alternative to crizotinib. A confi rmatory phase 2 clinical trial is ongoing to assess ceritinib activity in patients with ALK-rearranged NSCLC and brain or leptomeningeal metastases. C1 [Kim, Dong-Wan] Seoul Natl Univ Hosp, Seoul 110744, South Korea. [Mehra, Ranee] Fox Chase Canc Ctr, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Tan, Daniel S. W.] Natl Canc Ctr, Singapore, Singapore. [Felip, Enriqueta] Vall dHebron Univ, Barcelona, Spain. [Chow, Laura Q. M.] Univ Washington, Seattle, WA 98195 USA. [Camidge, D. Ross] Univ Colorado, Denver, CO 80202 USA. [Vansteenkiste, Johan] Univ Hosp KU Leuven, Leuven, Belgium. [Sharma, Sunil] Huntsman Canc Inst, Salt Lake City, UT USA. [De Pas, Tommaso] Ist Europeo Oncol, Milan, Italy. [Riely, Gregory J.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Solomon, Benjamin J.] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [Wolf, Juergen] Univ Hosp Cologne, Ctr Integrated Oncol, Cologne, Germany. [Thomas, Michael] Univ Klinikum Heidelberg, Translat Lung Res Ctr Heidelberg TLRC H, Thoraxklin, Internist Onkol Thoraxtumoren, Heidelberg, Germany. [Schuler, Martin] Univ Duisburg Essen, Univ Hosp Essen, German Canc Consortium DKTK, Partner Site Univ Hosp Essen, Essen, Germany. [Liu, Geoffrey] Princess Margaret Canc Ctr, Toronto, ON, Canada. [Santoro, Armando] IRCCS Inst Clin Humanitas, Milan, Italy. [Sutradhar, Santosh; Li, Siyu; Szczudlo, Tomasz] Novartis Pharmaceut, E Hanover, NJ USA. [Yovine, Alejandro] Novartis Pharma AG, Basel, Switzerland. [Shaw, Alice T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Shaw, AT (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM ashaw1@partners.org RI Liu, Geoffrey/N-4421-2016 FU Novartis Pharmaceuticals Corporation FX Novartis Pharmaceuticals Corporation. NR 35 TC 19 Z9 22 U1 6 U2 13 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD APR PY 2016 VL 17 IS 4 BP 452 EP 463 DI 10.1016/S1470-2045(15)00614-2 PG 12 WC Oncology SC Oncology GA DI4VN UT WOS:000373497600046 PM 26973324 ER PT J AU Garcia-Manero, G Fenaux, P Al-Kali, A Baer, MR Sekeres, MA Roboz, GJ Gaidano, G Scott, BL Greenberg, P Platzbecker, U Steensma, DP Kambhampati, S Kreuzer, KA Godley, LA Atallah, E Collins, R Kantarjian, H Jabbour, E Wilhelm, FE Azarnia, N Silverman, LR AF Garcia-Manero, Guillermo Fenaux, Pierre Al-Kali, Aref Baer, Maria R. Sekeres, Mikkael A. Roboz, Gail J. Gaidano, Gianluca Scott, Bart L. Greenberg, Peter Platzbecker, Uwe Steensma, David P. Kambhampati, Suman Kreuzer, Karl-Anton Godley, Lucy A. Atallah, Ehab Collins, Robert, Jr. Kantarjian, Hagop Jabbour, Elias Wilhelm, Francois E. Azarnia, Nozar Silverman, Lewis R. CA ONTIME Study Investigators TI Rigosertib versus best supportive care for patients with high-risk myelodysplastic syndromes after failure of hypomethylating drugs (ONTIME): a randomised, controlled, phase 3 trial SO LANCET ONCOLOGY LA English DT Article ID MANTLE CELL LYMPHOMA; CLONAL HEMATOPOIESIS; SCORING SYSTEM; CYCLIN D1; THERAPY; MDS; PROGNOSIS; 01910.NA AB Background Hypomethylating drugs are the standard treatment for patients with high-risk myelodysplastic syndromes. Survival is poor after failure of these drugs; there is no approved second-line therapy. We compared the overall survival of patients receiving rigosertib and best supportive care with that of patients receiving best supportive care only in patients with myelodysplastic syndromes with excess blasts after failure of azacitidine or decitabine treatment. Methods We did this randomised controlled trial at 74 hospitals and university medical centres in the USA and Europe. We enrolled patients with diagnosis of refractory anaemia with excess blasts (RAEB)-1, RAEB-2, RAEB-t, or chronic myelomonocytic leukaemia based on local site assessment, and treatment failure with a hypomethylating drug in the past 2 years. Patients were randomly assigned (2: 1) to receive rigosertib 1800 mg per 24 h via 72-h continuous intravenous infusion administered every other week or best supportive care with or without low-dose cytarabine. Randomisation was stratified by pretreatment bone marrow blast percentage. Neither patients nor investigators were masked to treatment assignment. The primary outcome was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT01241500. Findings From Dec 13, 2010, to Aug 15, 2013, we enrolled 299 patients: 199 assigned to rigosertib, 100 assigned to best supportive care. Median follow-up was 19.5 months (IQR 11.9-27.3). As of Feb 1, 2014, median overall survival was 8.2 months (95% CI 6.1-10.1) in the rigosertib group and 5.9 months (4.1-9.3) in the best supportive care group (hazard ratio 0.87, 95% CI 0.67-1.14; p=0.33). The most common grade 3 or higher adverse events were anaemia (34 [18%] of 184 patients in the rigosertib group vs seven [8%] of 91 patients in the best supportive care group), thrombocytopenia (35 [19%] vs six [7%]), neutropenia (31 [17%] vs seven [8%]), febrile neutropenia (22 [12%] vs ten [11%]), and pneumonia (22 [12%] vs ten [11%]). 41 (22%) of 184 patients in the rigosertib group and 30 (33%) of 91 patients in the best supportive care group died due to adverse events and three deaths were attributed to rigosertib treatment. Interpretation Rigosertib did not significantly improve overall survival compared with best supportive care. A randomised phase 3 trial of rigosertib (NCT 02562443) is underway in specific subgroups of patients deemed to be at high risk, including patients with very high risk per the Revised International Prognostic Scoring System criteria. C1 [Garcia-Manero, Guillermo; Kantarjian, Hagop; Jabbour, Elias] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, 1515 Holcombe Blvd,Unit 428, Houston, TX 77030 USA. [Fenaux, Pierre] Univ Paris 07, Hop St Louis, Paris, France. [Al-Kali, Aref] Mayo Clin, Rochester, MN USA. [Baer, Maria R.] Univ Maryland, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. [Sekeres, Mikkael A.] Cleveland Clin, Leukemia Program, Cleveland, OH 44106 USA. [Roboz, Gail J.] Weill Cornell Med Coll, New York, NY USA. [Gaidano, Gianluca] Amedeo Avogadro Univ Eastern Piedmont, Dept Translat Med, Div Hematol, Novara, Italy. [Scott, Bart L.] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Greenberg, Peter] Stanford Canc Ctr, Stanford, CA USA. [Platzbecker, Uwe] Univ Klinikum Dresden, Med Klin & Poliklin 1, Dresden, Germany. [Steensma, David P.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Kambhampati, Suman] Univ Kansas, Med Ctr, Westwood, KS USA. [Kreuzer, Karl-Anton] Univ Klinikum Koln, Klin Innere Med 1, Cologne, Nordhein Westfa, Germany. [Godley, Lucy A.] Univ Chicago, Med Ctr, Chicago, IL 60637 USA. [Atallah, Ehab] Med Coll Wisconsin, Froedtert Mem Lutheran Hosp, Milwaukee, WI 53226 USA. [Atallah, Ehab] Med Coll Wisconsin, Div Hematol & Oncol, Milwaukee, WI 53226 USA. [Collins, Robert, Jr.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Wilhelm, Francois E.; Azarnia, Nozar] Onconova Therapeut, Newtown, PA USA. [Silverman, Lewis R.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. RP Garcia-Manero, G (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Leukemia, 1515 Holcombe Blvd,Unit 428, Houston, TX 77030 USA. EM ggarciam@mdanderson.org FU Onconova Therapeutics; Leukemia & Lymphoma Society FX Onconova Therapeutics, Leukemia & Lymphoma Society. NR 33 TC 10 Z9 10 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD APR PY 2016 VL 17 IS 4 BP 496 EP 508 DI 10.1016/S1470-2045(16)00009-7 PG 13 WC Oncology SC Oncology GA DI4VN UT WOS:000373497600050 PM 26968357 ER PT J AU Temel, JS Abernethy, AP Currow, DC Friend, J Duus, EM Yan, Y Fearon, KC AF Temel, Jennifer S. Abernethy, Amy P. Currow, David C. Friend, John Duus, Elizabeth M. Yan, Ying Fearon, Kenneth C. TI Anamorelin in patients with non-small-cell lung cancer and cachexia (ROMANA 1 and ROMANA 2): results from two randomised, double-blind, phase 3 trials SO LANCET ONCOLOGY LA English DT Article ID GHRELIN RECEPTOR AGONIST; WEIGHT-LOSS; FUNCTIONAL ASSESSMENT; MEGESTROL-ACETATE; BODY-COMPOSITION; MUSCLE STRENGTH; CLINICAL-TRIAL; SYNDROME CACS; OLDER-ADULTS; ANOREXIA AB Background Patients with advanced cancer frequently experience anorexia and cachexia, which are associated with reduced food intake, altered body composition, and decreased functionality. We assessed anamorelin, a novel ghrelin-receptor agonist, on cachexia in patients with advanced non-small-cell lung cancer and cachexia. Methods ROMANA 1 and ROMANA 2 were randomised, double-blind, placebo-controlled phase 3 trials done at 93 sites in 19 countries. Patients with inoperable stage III or IV non-small-cell lung cancer and cachexia (defined as >= 5% weight loss within 6 months or body-mass index < 20 kg/m(2)) were randomly assigned 2: 1 to anamorelin 100 mg orally once daily or placebo, with a computer-generated randomisation algorithm stratified by geographical region, cancer treatment status, and weight loss over the previous 6 months. Co-primary efficacy endpoints were the median change in lean body mass and handgrip strength over 12 weeks and were measured in all study participants (intention-to-treat population). Both trials are now completed and are registered with ClinicalTrials.gov, numbers NCT01387269 and NCT01387282. Findings From July 8, 2011, to Jan 28, 2014, 484 patients were enrolled in ROMANA 1 (323 to anamorelin, 161 to placebo), and from July 14, 2011, to Oct 31, 2013, 495 patients were enrolled in ROMANA 2 (330 to anamorelin, 165 to placebo). Over 12 weeks, lean body mass increased in patients assigned to anamorelin compared with those assigned to placebo in ROMANA 1 (median increase 0.99 kg [95% CI 0.61 to 1.36] vs -0.47 kg [-1.00 to 0.21], p< 0.0001) and ROMANA 2 (0.65 kg [0.38 to 0.91] vs -0.98 kg [-1.49 to -0.41], p< 0.0001). We noted no difference in handgrip strength in ROMANA 1 (-1.10 kg [-1.69 to -0.40] vs -1.58 kg [-2.99 to -1.14], p=0.15) or ROMANA 2 (-1.49 kg [-2.06 to -0.58] vs -0.95 kg [-1.56 to 0.04], p= 0.65). There were no differences in grade 3-4 treatment-related adverse events between study groups; the most common grade 3-4 adverse event was hyperglycaemia, occurring in one (< 1%) of 320 patients given anamorelin in ROMANA 1 and in four (1%) of 330 patients given anamorelin in ROMANA 2. Interpretation Anamorelin significantly increased lean body mass, but not handgrip, strength in patients with advanced non-small-cell lung cancer. Considering the unmet medical need for safe and effective treatments for cachexia, anamorelin might be a treatment option for patients with cancer anorexia and cachexia. C1 [Temel, Jennifer S.] Massachusetts Gen Hosp, Ctr Canc, Dept Med, Boston, MA 02114 USA. [Abernethy, Amy P.] Duke Univ, Sch Med, Dept Med, Durham, NC 27706 USA. [Currow, David C.] Flinders Univ S Australia, Dept Palliat & Support Care, Adelaide, SA 5001, Australia. [Friend, John; Duus, Elizabeth M.; Yan, Ying] Helsinn Therapeut US Inc, Iselin, NJ USA. [Fearon, Kenneth C.] Royal Infirm, Dept Surg, Edinburgh, Midlothian, Scotland. RP Temel, JS (reprint author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. EM jtemel@partners.org OI Currow, David/0000-0003-1988-1250 FU Helsinn Therapeutics FX Helsinn Therapeutics. NR 33 TC 25 Z9 26 U1 8 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 APR PY 2016 VL 17 IS 4 BP 519 EP 531 DI 10.1016/S1470-2045(15)00558-6 PG 13 WC Oncology SC Oncology GA DI4VN UT WOS:000373497600052 PM 26906526 ER PT J AU Shaikh, F Murray, MJ Amatruda, JF Coleman, N Nicholson, JC Hale, JP Pashankar, F Stoneham, SJ Poynter, JN Olson, TA Billmire, DF Stark, D Rodriguez-Galindo, C Frazier, AL AF Shaikh, Furqan Murray, Matthew J. Amatruda, James F. Coleman, Nicholas Nicholson, James C. Hale, Juliet P. Pashankar, Farzana Stoneham, Sara J. Poynter, Jenny N. Olson, Thomas A. Billmire, Deborah F. Stark, Daniel Rodriguez-Galindo, Carlos Frazier, A. Lindsay TI Paediatric extracranial germ-cell tumours SO LANCET ONCOLOGY LA English DT Review ID CHILDRENS ONCOLOGY GROUP; HUMAN CHORIONIC-GONADOTROPIN; MEDICAL-RESEARCH-COUNCIL; GENOME-WIDE ASSOCIATION; LONG-TERM SURVIVORS; TESTICULAR-CANCER; STAGE-I; ALPHA-FETOPROTEIN; RANDOMIZED-TRIAL; UNITED-KINGDOM AB Management of paediatric extracranial germ-cell tumours carries a unique set of challenges. Germ-cell tumours are a heterogeneous group of neoplasms that present across a wide age range and vary in site, histology, and clinical behaviour. Patients with germ-cell tumours are managed by a diverse array of specialists. Thus, staging, risk stratification, and treatment approaches for germ-cell tumours have evolved disparately along several trajectories. Paediatric germ-cell tumours differ from the adolescent and adult disease in many ways, leading to complexities in applying age-appropriate, evidence-based care. Suboptimal outcomes remain for several groups of patients, including adolescents, and patients with extragonadal tumours, high tumour markers at diagnosis, or platinum-resistant disease. Survivors have significant long-term toxicities. The challenge moving forward will be to translate new insights from molecular studies and collaborative clinical data into improved patient outcomes. Future trials will be characterised by improved risk-stratification systems, biomarkers for response and toxic effects, rational reduction of therapy for low-risk patients and novel approaches for poor-risk patients, and improved international collaboration across paediatric and adult cooperative research groups. C1 [Shaikh, Furqan] Hosp Sick Children, Div Haematol & Oncol, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. [Shaikh, Furqan] Univ Toronto, Toronto, ON M5G 1X8, Canada. [Murray, Matthew J.; Coleman, Nicholas] Univ Cambridge, Dept Pathol, Tennis Court Rd, Cambridge CB2 1QP, England. [Murray, Matthew J.; Nicholson, James C.] Addenbrookes Hosp, Dept Paediat Haematol & Oncol, Cambridge, England. [Amatruda, James F.] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dept Mol Biol, Dallas, TX 75390 USA. [Amatruda, James F.] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA. [Amatruda, James F.] Childrens Hlth, Gill Ctr Canc & Blood Disorders, Dallas, TX USA. [Coleman, Nicholas] Addenbrookes Hosp, Dept Histopathol, Hills Rd, Cambridge, England. [Hale, Juliet P.] Royal Victoria Infirm NHS Fdn Trust, Newcastle Upon Tyne, Tyne & Wear, England. [Pashankar, Farzana] Yale Univ, Sch Med, New Haven, CT USA. [Stoneham, Sara J.] Univ Coll London Hosp NHS Fdn Trust, London, England. [Poynter, Jenny N.] Univ Minnesota, Div Pediat Epidemiol & Clin Res, Minneapolis, MN USA. [Poynter, Jenny N.] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN USA. [Olson, Thomas A.] Emory Univ, Aflac Canc & Blood Disorders Ctr, Atlanta, GA 30322 USA. [Billmire, Deborah F.] Riley Hosp Children, Indianapolis, IN USA. [Stark, Daniel] Univ Leeds, Inst Canc & Pathol, Leeds LS2 9JT, W Yorkshire, England. [Rodriguez-Galindo, Carlos; Frazier, A. Lindsay] Boston Childrens Hosp, Boston, MA USA. [Rodriguez-Galindo, Carlos; Frazier, A. Lindsay] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Shaikh, F (reprint author), Hosp Sick Children, Div Haematol & Oncol, 555 Univ Ave, Toronto, ON M5G 1X8, Canada.; Shaikh, F (reprint author), Univ Toronto, Toronto, ON M5G 1X8, Canada. EM furqan.shaikh@sickkids.ca FU Teenage Cancer Trust FX DS received grants from the Teenage Cancer Trust during the conduct of the study. ALF has served on the Germ Cell Tumor Advisory Board for Seattle Genetics and has consulted for Decibel Therapeutics. All other authors declare no competing interests. NR 95 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 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD APR PY 2016 VL 17 IS 4 BP E149 EP E162 PG 14 WC Oncology SC Oncology GA DI4VN UT WOS:000373497600026 PM 27300675 ER PT J AU Abuelkasem, E Mazzeffi, MA Lu, SY Planinsic, RM Sakai, T Tanaka, KA AF Abuelkasem, Ezeldeen Mazzeffi, Michael A. Lu, Shu Yang Planinsic, Raymond M. Sakai, Tetsuro Tanaka, Kenichi A. TI Ex vivo evaluation of 4 different viscoelastic assays for detecting moderate to severe coagulopathy during liver transplantation SO LIVER TRANSPLANTATION LA English DT Article ID CONVENTIONAL COAGULATION TESTS; RANDOMIZED-CLINICAL-TRIAL; CARDIAC-SURGERY; RISK-FACTORS; TRANSFUSION; THROMBOELASTOMETRY; THROMBELASTOGRAPHY; TRAUMA; PLASMA; HYPOFIBRINOGENEMIA AB Prolonged prothrombin time (PT) and its ratio are routinely used for the assessment of candidates for liver transplantation (LT), but intraoperative coagulation management of transfusion is hindered by its long turnaround time. Abnormal reaction time (R time) on thromboelastography (TEG) or clotting time (CT) of rotational thromboelastometry (ROTEM) are presumably an alternative, but there is a paucity of clinical data on abnormal R time/CT values compared to PT during LT. After receiving institutional review board approval and informed consent, we obtained blood samples from 36 LT patients for international normalized ratio (INR), factor (F) X level, and viscoelastic tests (EXTEM/INTEM and kaolin/rapid TEG) at baseline and 30 minutes after graft reperfusion. Receiver operating characteristic (ROC) curves were calculated for INR>1.5 and viscoelastic R time/CT thresholds to assess the ability to diagnose FX deficiency at the moderate (<50%) or severe (<35%) level. The FX deficiency data were calculated using cutoff values of INR (>1.5) and abnormal R time/CT for TEG and ROTEM. Tissue factor (TF)-activated INR and EXTEM-CT performed well in diagnosing FX below 50%, but rapid TEG with combined TF and kaolin activators failed. Improved performance of INTEM-CT in diagnosing FX below 35% underlies multifactorial deficiency involving both intrinsic and common pathways. In conclusion, the differences among different viscoelastic tests and clinical situations should be carefully considered when they are used to guide transfusion during LT. C1 [Abuelkasem, Ezeldeen; Planinsic, Raymond M.; Sakai, Tetsuro] Univ Pittsburgh, Dept Anesthesiol, Pittsburgh, PA USA. [Mazzeffi, Michael A.; Tanaka, Kenichi A.] Univ Maryland, Dept Anesthesiol, 22 South Greene St,Suite S8D12, Baltimore, MD 21201 USA. [Lu, Shu Yang] Massachusetts Gen Hosp, Dept Anesthesiol, Boston, MA 02114 USA. RP Tanaka, KA (reprint author), Univ Maryland, Dept Anesthesiol, 22 South Greene St,Suite S8D12, Baltimore, MD 21201 USA. EM ktanaka@anes.umm.edu FU University of Pittsburgh Medical Center; Department of Anesthesiology (Pittsburgh, PA) FX Financial support for this work was provided solely by the University of Pittsburgh Medical Center and the Department of Anesthesiology (Pittsburgh, PA). TEM Innovations (Munich, Germany) provided 2 ROTEM devices for this study at the University of Pittsburgh Medical Center (Pittsburgh, PA). NR 27 TC 5 Z9 5 U1 3 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1527-6465 EI 1527-6473 J9 LIVER TRANSPLANT JI Liver Transplant. PD APR PY 2016 VL 22 IS 4 BP 468 EP 475 DI 10.1002/lt.24379 PG 8 WC Gastroenterology & Hepatology; Surgery; Transplantation SC Gastroenterology & Hepatology; Surgery; Transplantation GA DI5UU UT WOS:000373566800010 PM 26610182 ER PT J AU Adler, JT Hyder, JA Markmann, JF Axelrod, DA Yeh, H AF Adler, Joel T. Hyder, Joseph A. Markmann, James F. Axelrod, David A. Yeh, Heidi TI Socioeconomic gradients between locally transplanted and exported liver donors and recipients SO LIVER TRANSPLANTATION LA English DT Letter ID GEOGRAPHIC DISPARITIES; QUALITATIVE LITERATURE; ORGAN DONATION C1 [Adler, Joel T.; Markmann, James F.; Axelrod, David A.; Yeh, Heidi] Massachusetts Gen Hosp, Div Transplant Surg, 55 Fruit St,White 516, Boston, MA 02114 USA. [Hyder, Joseph A.] Mayo Clin, Dept Anesthesiol, Rochester, MN USA. [Axelrod, David A.] Dartmouth Hitchcock Med Ctr, Sect Transplant Surg, Lebanon, NH 03766 USA. RP Yeh, H (reprint author), Massachusetts Gen Hosp, Div Transplant Surg, 55 Fruit St,White 516, Boston, MA 02114 USA. EM hyeh@partners.org OI Adler, Joel/0000-0001-8190-3444 NR 10 TC 1 Z9 1 U1 5 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1527-6465 EI 1527-6473 J9 LIVER TRANSPLANT JI Liver Transplant. PD APR PY 2016 VL 22 IS 4 BP 557 EP 558 DI 10.1002/lt.24410 PG 2 WC Gastroenterology & Hepatology; Surgery; Transplantation SC Gastroenterology & Hepatology; Surgery; Transplantation GA DI5UU UT WOS:000373566800020 PM 26845498 ER PT J AU Fukumura, D Incio, J Shankaraiah, RC Jain, RK AF Fukumura, Dai Incio, Joao Shankaraiah, Ram C. Jain, Rakesh K. TI Obesity and Cancer: An Angiogenic and Inflammatory Link SO MICROCIRCULATION LA English DT Review DE obesity; immune environment; desmoplasia; metformin; hypoxia; cytokines; IL-6; IL-1; VEGFR-1 ID ANTIDIABETIC DRUG METFORMIN; ENDOTHELIAL GROWTH-FACTOR; WHITE ADIPOSE-TISSUE; HUMAN BREAST-CANCER; BODY-MASS-INDEX; SP TRANSCRIPTION-FACTORS; MAMMARY-TUMOR GROWTH; PANCREATIC-CANCER; INSULIN-RESISTANCE; ENERGY-BALANCE AB With the current epidemic of obesity, a large number of patients diagnosed with cancer are overweight or obese. Importantly, this excess body weight is associated with tumor progression and poor prognosis. The mechanisms for this worse outcome, however, remain poorly understood. We review here the epidemiological evidence for the association between obesity and cancer, and discuss potential mechanisms focusing on angiogenesis and inflammation. In particular, we will discuss how the dysfunctional angiogenesis and inflammation occurring in adipose tissue in obesity may promote tumor progression, resistance to chemotherapy, and targeted therapies such as anti-angiogenic and immune therapies. Better understanding of how obesity fuels tumor progression and therapy resistance is essential to improve the current standard of care and the clinical outcome of cancer patients. To this end, we will discuss how an anti-diabetic drug such as metformin can overcome these adverse effects of obesity on the progression and treatment resistance of tumors. C1 [Fukumura, Dai; Incio, Joao; Shankaraiah, Ram C.; Jain, Rakesh K.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol,Edwin L Steele Labs, Boston, MA USA. [Incio, Joao] Univ Porto, Inst Innovat & Res Heath, Metab Nutr & Endocrinol Grp, Dept Biochem,Fac Med,I3S, Rua Campo Alegre 823, P-4100 Oporto, Portugal. [Incio, Joao] Hosp Sao Joao, Dept Internal Med, Oporto, Portugal. [Shankaraiah, Ram C.] Univ Ferrara, Dept Morphol Surg & Expt Med, I-44100 Ferrara, Italy. [Shankaraiah, Ram C.] Univ Ferrara, Lab Technol Adv Therapies LTTA, I-44100 Ferrara, Italy. RP Fukumura, D (reprint author), Massachusetts Gen Hosp, 100 Blossom St,Cox 7, Boston, MA 02114 USA. EM dai@steele.mgh.harvard.edu FU Foundation for Science and Technology (Portugal, POPH/FSE funding program); National Institutes of Health [CA080124, CA085140, CA096915, CA115767, CA126642, CA197743]; US Department of Defense [W81XWH-10-1-0016]; Lustgarten Foundation FX The authors' work was supported by a fellowship from the Foundation for Science and Technology (http://www.fct.pt/; Portugal, POPH/FSE funding program) (JI) and funds from the National Institutes of Health (http://nih.gov/; CA080124, CA085140, CA096915, CA115767, CA126642, CA197743), the US Department of Defense (W81XWH-10-1-0016), and the Lustgarten Foundation. NR 181 TC 6 Z9 6 U1 2 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1073-9688 EI 1549-8719 J9 MICROCIRCULATION JI Microcirculation PD APR PY 2016 VL 23 IS 3 BP 191 EP 206 DI 10.1111/micc.12270 PG 16 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA DI6NY UT WOS:000373617500003 PM 26808917 ER PT J AU Katz, DA Stewart, K Paez, M Holman, J Adams, SL Vander Weg, MW Battaglia, CT Joseph, AM Titler, MG Ono, S AF Katz, David A. Stewart, Kenda Paez, Monica Holman, John Adams, Susan L. Vander Weg, Mark W. Battaglia, Catherine T. Joseph, Anne M. Titler, Marita G. Ono, Sarah TI "Let Me Get You a Nicotine Patch": Nurses' Perceptions of Implementing Smoking Cessation Guidelines for Hospitalized Veterans SO MILITARY MEDICINE LA English DT Article ID CONTROLLED-TRIAL; STANDARDIZED PATIENTS; CARE; SERVICE; INTERVENTIONS; PREVENTION; PROGRAM AB Many hospitalized smokers do not receive guideline-recommended tobacco treatment, but little is known about the perceptions of inpatient nurses with regard to tobacco treatment. We used a sequential explanatory mixed methods design to help explain the findings of an academic detailing intervention trial on the inpatient medicine units of four Veterans Affairs (VA) hospitals. We surveyed 164 nurses and conducted semistructured interviews in a purposeful sample of 33 nurses with different attitudes toward cessation counseling. Content analysis was used to inductively characterize the issues raised by participants. Emerging themes were categorized using the knowledge-attitudes-behavior framework of guideline adherence. Knowledge-related and attitudinal barriers included perceived lack of skills in cessation counseling and skepticism about the effectiveness of cessation guidelines in hospitalized veterans. Nurses also reported multiple behavioral and organizational barriers to guideline adherence: resistance from patients, insufficient time and resources, the presence of smoking areas on VA premises, and lack of coordination with primary care. VA hospitals should train inpatient staff how to negotiate behavior change, integrate cessation counseling into nurses' workflow, develop alternative referral mechanisms for post-discharge cessation counseling, and adopt hospital policies to promote inpatient abstinence. C1 [Katz, David A.; Stewart, Kenda; Paez, Monica; Holman, John; Adams, Susan L.; Vander Weg, Mark W.; Ono, Sarah] Iowa City VA Hlth Care Syst, Comprehens Access & Delivery Res & Evaluat CADRE, Iowa City, IA USA. [Katz, David A.; Vander Weg, Mark W.] Univ Iowa, Dept Med, Iowa City, IA 52242 USA. [Katz, David A.] Univ Iowa, Dept Epidemiol, Iowa City, IA USA. [Vander Weg, Mark W.] Univ Iowa, Dept Psychol, Iowa City, IA 52242 USA. [Battaglia, Catherine T.] VA Eastern Colorado Hlth Care Syst, Dept Med, Denver, CO USA. [Battaglia, Catherine T.] Denver Seattle Ctr Vet Centr Value Based Res DiSC, Denver, CO USA. Univ Minnesota, Dept Med, Box 736 UMHC, Minneapolis, MN 55455 USA. [Titler, Marita G.] Univ Michigan, Sch Nursing, Ann Arbor, MI 48109 USA. [Ono, Sarah] Portland VA Med Ctr, Ctr Improve Vet Involvement Care, Portland, OR USA. RP Katz, DA (reprint author), Iowa City VA Hlth Care Syst, Comprehens Access & Delivery Res & Evaluat CADRE, Iowa City, IA USA. FU Veterans Affairs Health Services Research and Development [IIR 07-113] FX The authors acknowledge Jonathan Thomas for assistance with transcription of in-depth interviews, George Bailey, MS and Ray Opiola for assisting with database design and data management, Bonnie Bootsmiller, PhD and Sue Kieffer for administrative support, and Jennifer Reed for assistance with manuscript preparation. This work was funded by the Veterans Affairs Health Services Research and Development (IIR 07-113). NR 41 TC 1 Z9 1 U1 4 U2 6 PU ASSOC MILITARY SURG US PI BETHESDA PA 9320 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0026-4075 EI 1930-613X J9 MIL MED JI Milit. Med. PD APR PY 2016 VL 181 IS 4 BP 373 EP 382 DI 10.7205/MILMED-D-15-00101 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA DI3NO UT WOS:000373405600015 PM 27046185 ER PT J AU van der Watt, PJ Chi, A Stelma, T Stowell, C Strydom, E Carden, S Angus, L Hadley, K Lang, D Wei, W Birrer, MJ Trent, JO Leaner, VD AF van der Watt, Pauline J. Chi, Alicia Stelma, Tamara Stowell, Catherine Strydom, Erin Carden, Sarah Angus, Liselotte Hadley, Kate Lang, Dirk Wei, Wei Birrer, Michael J. Trent, John O. Leaner, Virna D. TI Targeting the Nuclear Import Receptor Kpn beta 1 as an Anticancer Therapeutic SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID SMALL-MOLECULE INHIBITOR; TRANSCRIPTION FACTOR; CERVICAL-CANCER; CELL-LINES; RAN GTPASE; T-CELLS; BETA; TRANSPORT; EXPORT; LOCALIZATION AB Karyopherin beta 1 (Kpn beta 1) is a nuclear transport receptor that imports cargoes into the nucleus. Recently, elevated Kpnb1 expression was found in certain cancers and Kpnb1 silencing with siRNA was shown to induce cancer cell death. This study aimed to identify novel small molecule inhibitors of Kpnb1, and determine their anticancer activity. An in silico screen identified molecules that potentially bind Kpnb1 and Inhibitor of Nuclear Import-43, INI-43 (3-(1H-benzimidazol-2-yl)-1-(3-dimethylaminopropyl) pyrrolo[5,4-b] quinoxalin-2-amine) was investigated further as it interfered with the nuclear localization of Kpn beta 1 and known Kpn beta 1 cargoes NFAT, NFkB, AP-1, and NFY and inhibited the proliferation of cancer cells of different tissue origins. Minimum effect on the proliferation of noncancer cells was observed at the concentration of INI-43 that showed a significant cytotoxic effect on various cervical and esophageal cancer cell lines. A rescue experiment confirmed that INI-43 exerted its cell killing effects, in part, by targeting Kpn beta 1. INI-43 treatment elicited a G2-M cell-cycle arrest in cancer cells and induced the intrinsic apoptotic pathway. Intraperitoneal administration of INI-43 significantly inhibited the growth of subcutaneously xenografted esophageal and cervical tumor cells. We propose that Kpn beta 1 inhibitors could have therapeutic potential for the treatment of cancer. (C) 2016 AACR. C1 [van der Watt, Pauline J.; Chi, Alicia; Stelma, Tamara; Stowell, Catherine; Strydom, Erin; Carden, Sarah; Angus, Liselotte; Hadley, Kate; Leaner, Virna D.] Univ Cape Town, Inst Infect Dis & Mol Med, SAMRC UCT Gynaecol Canc Res Ctr, Div Med Biochem,Dept Integrat Biomed Sci,Fac Hlth, ZA-7925 Cape Town, South Africa. [Lang, Dirk] Univ Cape Town, Confocal & Light Microscope Imaging Facil, Dept Human Biol, Fac Hlth Sci, ZA-7925 Cape Town, South Africa. [Wei, Wei; Birrer, Michael J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc Res,Gillette Ctr Gynecol Oncol, Boston, MA USA. [Trent, John O.] Univ Louisville, Dept Med, JG Brown Canc Ctr, Louisville, KY 40292 USA. RP Leaner, VD (reprint author), Univ Cape Town, Div Med Biochem, Fac Hlth Sci, ZA-7925 Cape Town, South Africa. EM Virna.Leaner@uct.ac.za RI Lang, Dirk/I-2554-2015 OI Lang, Dirk/0000-0003-3901-2079 FU South African Medical Research Council; National Research Foundation; Cancer Association of South Africa (CANSA); University of Cape Town FX This work was supported by grants obtained by Virna D. Leaner from the South African Medical Research Council, the National Research Foundation, the Cancer Association of South Africa (CANSA), and the University of Cape Town. NR 50 TC 1 Z9 1 U1 5 U2 12 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 EI 1538-8514 J9 MOL CANCER THER JI Mol. Cancer Ther. PD APR PY 2016 VL 15 IS 4 BP 560 EP 573 DI 10.1158/1535-7163.MCT-15-0052 PG 14 WC Oncology SC Oncology GA DI6GD UT WOS:000373596300003 PM 26832790 ER PT J AU Ji, Z Song, RS Huang, HL Regev, A Struhl, K AF Ji, Zhe Song, Ruisheng Huang, Hailiang Regev, Aviv Struhl, Kevin TI Transcriptome-scale RNase-footprinting of RNA-protein complexes SO NATURE BIOTECHNOLOGY LA English DT Article ID LONG NONCODING RNAS; IN-VIVO; NUCLEOTIDE RESOLUTION; BINDING PROTEIN; ELEMENTS; SITES; TRANSLATION; SPLICEOSOME; ANNOTATION; CLIP AB Ribosome profiling is widely used to study translation in vivo, but not all sequence reads correspond to ribosome-protected RNA. Here we describe Rfoot, a computational pipeline that analyzes ribosomal profiling data and identifies native, nonribosomal RNA-protein complexes. We use Rfoot to precisely map RNase-protected regions within small nucleolar RNAs, spliceosomal RNAs, microRNAs, tRNAs, long noncoding (lnc) RNAs and 3' untranslated regions of mRNAs in human cells. We show that RNAs of the same class can show differential complex association. Although only a subset of lncRNAs show RNase footprints, many of these have multiple footprints, and the protected regions are evolutionarily conserved, suggestive of biological functions. C1 [Ji, Zhe; Song, Ruisheng; Struhl, Kevin] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Ji, Zhe; Huang, Hailiang; Regev, Aviv] Broad Inst MIT & Harvard, Cambridge, MA USA. [Huang, Hailiang] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Regev, Aviv] MIT, Dept Biol, Cambridge, MA USA. [Regev, Aviv] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Struhl, K (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA.; Regev, A (reprint author), Broad Inst MIT & Harvard, Cambridge, MA USA.; Regev, A (reprint author), MIT, Dept Biol, Cambridge, MA USA.; Regev, A (reprint author), Howard Hughes Med Inst, Chevy Chase, MD USA. EM aregev@broadinstitute.org; kevin@hms.harvard.edu FU National Institutes of Health [CA 107486] FX This work was supported by grants to K.S. from the National Institutes of Health (CA 107486). A.R. is a Howard Hughes Investigator. NR 25 TC 7 Z9 7 U1 0 U2 11 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 APR PY 2016 VL 34 IS 4 BP 410 EP + DI 10.1038/nbt.3441 PG 5 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA DI6NL UT WOS:000373616100021 PM 26900662 ER PT J AU Yu, CN Mannan, AM Yvone, GM Ross, KN Zhang, YL Marton, MA Taylor, BR Crenshaw, A Gould, JZ Tamayo, P Weir, BA Tsherniak, A Wong, B Garraway, LA Shamji, AF Palmer, MA Foley, MA Winckler, W Schreiber, SL Kung, AL Golub, TR AF Yu, Channing Mannan, Aristotle M. Yvone, Griselda Metta Ross, Kenneth N. Zhang, Yan-Ling Marton, Melissa A. Taylor, Bradley R. Crenshaw, Andrew Gould, Joshua Z. Tamayo, Pablo Weir, Barbara A. Tsherniak, Aviad Wong, Bang Garraway, Levi A. Shamji, Alykhan F. Palmer, Michelle A. Foley, Michael A. Winckler, Wendy Schreiber, Stuart L. Kung, Andrew L. Golub, Todd R. TI High-throughput identification of genotype-specific cancer vulnerabilities in mixtures of barcoded tumor cell lines SO NATURE BIOTECHNOLOGY LA English DT Article ID KINASE INHIBITOR SELECTIVITY; DRUG-SENSITIVITY; RESISTANCE; RESOURCE; EFFICACY; GENE AB Hundreds of genetically characterized cell lines are available for the discovery of genotype-specific cancer vulnerabilities. However, screening large numbers of compounds against large numbers of cell lines is currently impractical, and such experiments are often difficult to control(1-4). Here we report a method called PRISM that allows pooled screening of mixtures of cancer cell lines by labeling each cell line with 24-nucleotide barcodes. PRISM revealed the expected patterns of cell killing seen in conventional (unpooled) assays. In a screen of 102 cell lines across 8,400 compounds, PRISM led to the identification of BRD-7880 as a potent and highly specific inhibitor of aurora kinases B and C. Cell line pools also efficiently formed tumors as xenografts, and PRISM recapitulated the expected pattern of erlotinib sensitivity in vivo. C1 [Yu, Channing; Mannan, Aristotle M.; Yvone, Griselda Metta; Ross, Kenneth N.; Zhang, Yan-Ling; Marton, Melissa A.; Taylor, Bradley R.; Crenshaw, Andrew; Gould, Joshua Z.; Tamayo, Pablo; Weir, Barbara A.; Tsherniak, Aviad; Wong, Bang; Garraway, Levi A.; Shamji, Alykhan F.; Palmer, Michelle A.; Foley, Michael A.; Winckler, Wendy; Schreiber, Stuart L.; Golub, Todd R.] Broad Inst Harvard & MIT, Cambridge, MA USA. [Yu, Channing; Garraway, Levi A.; Kung, Andrew L.; Golub, Todd R.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Yu, Channing; Garraway, Levi A.; Kung, Andrew L.; Golub, Todd R.] Harvard Univ, Sch Med, Boston, MA USA. [Schreiber, Stuart L.] Harvard Univ, Cambridge, MA 02138 USA. [Schreiber, Stuart L.; Golub, Todd R.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Yvone, Griselda Metta] Univ Calif Los Angeles, Los Angeles, CA USA. [Ross, Kenneth N.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Palmer, Michelle A.] ImmunoGen, Waltham, MA USA. [Foley, Michael A.] Triinst Therapeut Discovery Inst, New York, NY USA. [Kung, Andrew L.] Columbia Univ, Med Ctr, New York, NY USA. RP Golub, TR (reprint author), Broad Inst Harvard & MIT, Cambridge, MA USA.; Golub, TR (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA.; Golub, TR (reprint author), Harvard Univ, Sch Med, Boston, MA USA.; Golub, TR (reprint author), Howard Hughes Med Inst, Chevy Chase, MD USA. EM golub@broadinstitute.org OI Kung, Andrew/0000-0002-9091-488X FU US National Institutes of Health (NIH) Genomics Based Drug Discovery consortium grants [RL1-CA133834, RL1-GM084437, UL1DE019585]; US National Cancer Institute Integrative Cancer Biology Program grant [U54CA112962]; Howard Hughes Medical Institute; Claudia Adams Barr Program in Cancer Research Innovative Basic Science Research Program Grant; American Society of Clinical Oncology Conquer Cancer Foundation Young Investigator Award; Prostate Cancer Foundation; NIH grant [RL1-HG004671] FX We thank S. Kim, G. Bonamy, J. (J.) Che, J. Thibault, T. Huynh, I. Engels and A. Shipway at Novartis for sharing data before publication; A. Christie and T. Davis for technical assistance in animal studies; C. Hartland, S. Donovan, E. Rubin and E. Winchester for technical assistance in compound assays; J. Bittker, J. McGrath and G. Wendel for assistance in compound management; S. Le Quement and J. Duvall for assistance in compound synthesis; J. Gale for technical assistance in enzyme kinetic assays; S. Howell for assistance in curation of computational data sets; A. Koehler, S. Dandapani, B. Munoz, C. Scherer, D. Gray, D. Bachovchin, S. Santaguida and J. Elkins for expert scientific guidance; J. Barretina, N. Stransky, S. Nijman, B. Julian, W. Read-Button, J. Davis and D. Peck for technical advice; and members of the Golub laboratory for critical review of the manuscript. This work was supported in part by the US National Institutes of Health (NIH) Genomics Based Drug Discovery consortium grants RL1-CA133834, RL1-GM084437 and UL1DE019585 (administratively linked to NIH grant RL1-HG004671), US National Cancer Institute Integrative Cancer Biology Program grant U54CA112962, the Howard Hughes Medical Institute, the Claudia Adams Barr Program in Cancer Research Innovative Basic Science Research Program Grant, the American Society of Clinical Oncology Conquer Cancer Foundation Young Investigator Award and the Prostate Cancer Foundation. NR 25 TC 3 Z9 3 U1 1 U2 5 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 APR PY 2016 VL 34 IS 4 BP 419 EP + DI 10.1038/nbt.3460 PG 7 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA DI6NL UT WOS:000373616100023 PM 26928769 ER PT J AU Freyermuth, F Rau, F Kokunai, Y Linke, T Sellier, C Nakamori, M Kino, Y Arandel, L Jollet, A Thibault, C Philipps, M Vicaire, S Jost, B Udd, B Day, JW Duboc, D Wahbi, K Matsumura, T Fujimura, H Mochizuki, H Deryckere, F Kimura, T Nukina, N Ishiura, S Lacroix, V Campan-Fournier, A Navratil, V Chautard, E Auboeuf, D Horie, M Imoto, K Lee, KY Swanson, MS de Munain, AL Inada, S Itoh, H Nakazawa, K Ashihara, T Wang, E Zimmer, T Furling, D Takahashi, MP Charlet-Berguerand, N AF Freyermuth, Fernande Rau, Frederique Kokunai, Yosuke Linke, Thomas Sellier, Chantal Nakamori, Masayuki Kino, Yoshihiro Arandel, Ludovic Jollet, Arnaud Thibault, Christelle Philipps, Muriel Vicaire, Serge Jost, Bernard Udd, Bjarne Day, John W. Duboc, Denis Wahbi, Karim Matsumura, Tsuyoshi Fujimura, Harutoshi Mochizuki, Hideki Deryckere, Francois Kimura, Takashi Nukina, Nobuyuki Ishiura, Shoichi Lacroix, Vincent Campan-Fournier, Amandine Navratil, Vincent Chautard, Emilie Auboeuf, Didier Horie, Minoru Imoto, Keiji Lee, Kuang-Yung Swanson, Maurice S. Lopez de Munain, Adolfo Inada, Shin Itoh, Hideki Nakazawa, Kazuo Ashihara, Takashi Wang, Eric Zimmer, Thomas Furling, Denis Takahashi, Masanori P. Charlet-Berguerand, Nicolas TI Splicing misregulation of SCN5A contributes to cardiac-conduction delay and heart arrhythmia in myotonic dystrophy SO NATURE COMMUNICATIONS LA English DT Article ID PRE-MESSENGER-RNA; BRUGADA-SYNDROME; MUSCULAR-DYSTROPHY; MUSCLEBLIND PROTEINS; STRUCTURAL INSIGHTS; CHLORIDE CHANNEL; SKELETAL-MUSCLE; MOUSE MODEL; CTG REPEAT; TYPE-1 AB Myotonic dystrophy (DM) is caused by the expression of mutant RNAs containing expanded CUG repeats that sequester muscleblind-like (MBNL) proteins, leading to alternative splicing changes. Cardiac alterations, characterized by conduction delays and arrhythmia, are the second most common cause of death in DM. Using RNA sequencing, here we identify novel splicing alterations in DM heart samples, including a switch from adult exon 6B towards fetal exon 6A in the cardiac sodium channel, SCN5A. We find that MBNL1 regulates alternative splicing of SCN5A mRNA and that the splicing variant of SCN5A produced in DM presents a reduced excitability compared with the control adult isoform. Importantly, reproducing splicing alteration of Scn5a in mice is sufficient to promote heart arrhythmia and cardiac-conduction delay, two predominant features of myotonic dystrophy. In conclusion, misregulation of the alternative splicing of SCN5A may contribute to a subset of the cardiac dysfunctions observed in myotonic dystrophy. C1 [Freyermuth, Fernande; Sellier, Chantal; Thibault, Christelle; Philipps, Muriel; Vicaire, Serge; Jost, Bernard; Charlet-Berguerand, Nicolas] Univ Strasbourg, INSERM U964, CNRS UMR7104, Dept Translat Med & Neurogenet,IGBMC, F-67400 Illkirch Graffenstaden, France. [Rau, Frederique; Arandel, Ludovic; Jollet, Arnaud; Furling, Denis] Univ Paris 06, Sorbonne Univ, INSERM, CNRS,Ctr Rech Myol,UMRS974,FRE3617,Inst Myol,GH P, F-75013 Paris, France. [Kokunai, Yosuke; Nakamori, Masayuki; Mochizuki, Hideki; Takahashi, Masanori P.] Osaka Univ, Grad Sch Med, Dept Neurol, Osaka 5650871, Japan. [Linke, Thomas; Zimmer, Thomas] Friedrich Schiller Univ Hosp, Dept Physiol, D-07743 Jena, Germany. [Kino, Yoshihiro] Meiji Pharmaceut Univ, Dept Bioinformat & Mol Neuropathol, Kiyose 2058588, Japan. [Udd, Bjarne] Tampere Univ, Neuromuscular Res Ctr, Tampere 33520, Finland. [Udd, Bjarne] Tampere Univ Hosp, Tampere 33520, Finland. [Udd, Bjarne] Univ Helsinki, Dept Med Genet, Folkhalsan Inst Genet, Helsinki 00250, Finland. [Udd, Bjarne] Vaasa Cent Hosp, Dept Neurol, Vaasa 65130, Finland. [Day, John W.] Stanford Univ, Dept Neurol, Stanford, CA 94304 USA. [Duboc, Denis; Wahbi, Karim] Univ Paris 05, Hop Cochin, AP HP, Serv Cardiol, F-75014 Paris, France. [Matsumura, Tsuyoshi; Fujimura, Harutoshi] Toneyama Natl Hosp, Dept Neurol, Toyonaka, Osaka 5608552, Japan. [Deryckere, Francois] Ecole Super Biotechnol Strasbourg, CNRS, UMR7175, F-67400 Illkirch Graffenstaden, France. [Kimura, Takashi] Hyogo Coll Med, Div Neurol, Nishinomiya, Hyogo 6638501, Japan. [Nukina, Nobuyuki] Doshisha Univ, Grad Sch Brain Sci, Lab Struct Neuropathol, Kyoto 6100394, Japan. [Ishiura, Shoichi] Univ Tokyo, Grad Sch Arts & Sci, Tokyo 1538902, Japan. [Lacroix, Vincent] Univ Lyon 1, CNRS, LBBE UMR5558, F-69622 Villeurbanne, France. [Campan-Fournier, Amandine] Hosp Civils Lyon, Lab Cytogenet Constitut, F-69500 Bron, France. [Navratil, Vincent] Univ Lyon 1, Pole Rhone Alpes Bioinformat, Batiment Gregor Mendel, F-69100 Villeurbanne, France. [Chautard, Emilie; Auboeuf, Didier] Ctr Rech Cancerol Lyon, F-69373 Lyon, France. [Horie, Minoru; Itoh, Hideki; Ashihara, Takashi] Shiga Med Univ, Dept Cardiovasc & Resp Med, Otsu, Shiga 5202192, Japan. [Imoto, Keiji] Natl Inst Nat Sci, Natl Inst Physiol Sci, Dept Informat Physiol, 38 Nishigonaka, Okazaki, Aichi 4448585, Japan. [Lee, Kuang-Yung] Chang Gung Mem Hosp, Dept Neurol, Keelung 20401, Taiwan. [Swanson, Maurice S.; Wang, Eric] Univ Florida, Coll Med, Dept Mol Genet & Microbiol, Ctr NeuroGenet, Gainesville, FL 32610 USA. [Swanson, Maurice S.; Wang, Eric] Univ Florida, Coll Med, Genet Inst, Gainesville, FL 32610 USA. [Lopez de Munain, Adolfo] Hosp Univ DONOSTIA, Inst Biodonostia CIBERNED, Neurosci Area, Dept Neurol, San Sebastian 20014, Spain. [Lopez de Munain, Adolfo] Univ Basque Country UPV EHU, San Sebastian 20014, Spain. [Inada, Shin; Nakazawa, Kazuo] Natl Cerebral & Cardiovasc Ctr, Res Inst, Lab Biomed Sci & Informat Management, Osaka 5658565, Japan. [Freyermuth, Fernande] Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Charlestown, MA 02129 USA. RP Charlet-Berguerand, N (reprint author), Univ Strasbourg, INSERM U964, CNRS UMR7104, Dept Translat Med & Neurogenet,IGBMC, F-67400 Illkirch Graffenstaden, France.; Furling, D (reprint author), Univ Paris 06, Sorbonne Univ, INSERM, CNRS,Ctr Rech Myol,UMRS974,FRE3617,Inst Myol,GH P, F-75013 Paris, France.; Takahashi, MP (reprint author), Osaka Univ, Grad Sch Med, Dept Neurol, Osaka 5650871, Japan. EM denis.furling@upmc.fr; mtakahas@neurol.med.osaka-u.ac.jp; ncharlet@igbmc.fr RI Charlet-Berguerand, Nicolas/I-6727-2016; Auboeuf, Didier/M-4610-2014; navratil, vincent/C-4193-2008 OI Charlet-Berguerand, Nicolas/0000-0002-4423-4920; FU UPMC/INSERM/CNRS/AIM; AFM [18833]; ERC-StG [310659]; MEXT [25136705]; JSPS [25713034, 15K09314]; Intramural Research Grant of NCNP [26-8]; AMED; [ANR-10-LABX-0030-INRT]; [ANR-10-IDEX-0002-02]; [ANR-12-RARE-0005-01] FX We thank Tom Cooper (Baylor College of Medicine, Houston, USA) for the gift of the DT960 and tgCUGBP1 plasmids, Christiane Branlant (CNRS, Nancy, France) for the gift of the pGEX-MBNL1 Delta101 vector, the Research Resource Network Japan and the Myobank of the Institute of Myology for providing human heart tissue samples, Feriel Azibani (UMRS974, Paris, France) and all members of the French DM Network for fruitful discussion. We also deeply thank the IGBMC Microarray and Sequencing platform, the informatics resources of the PRABI, Nathalie Mougenot from the UPMC PECMV-CEF facility, the Federation de Recherche en Imagerie Multimodalite (www.bichat.inserm.fr), the AAV platform of the Centre de Recherche en Myologie, the Penn Vector Core, Gene Therapy Program, University of Pennsylvania (Philadelphia) for providing the pAAV2/9 plasmid (p5E18-VD29), members of the France Genomique program for RNA sequencing and all IGBMC common facilities for assistance. This work was supported by UPMC/INSERM/CNRS/AIM (D.F.); ANR-12-RARE-0005-01 E-RARE 'HEART DM' (N.C.-B. and D.F.); AFM #18833, ERC-2012-StG #310659 'RNA DISEASES' and ANR-10-LABX-0030-INRT and ANR-10-IDEX-0002-02 (N.C.-B.); Research Grants for Practical Research Project for Rare / Intractable Diseases and for Comprehensive Research on Persons with Disabilities from AMED (H.M., M.P.T.); Grants-in-Aids from MEXT (25136705) (H.I.); Grants-in-Aids from JSPS (25713034 (M.N.) and 15K09314 (M.P.T.)); and Intramural Research Grant of NCNP 26-8 (M.P.T.). NR 73 TC 7 Z9 7 U1 3 U2 11 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 APR PY 2016 VL 7 AR 11067 DI 10.1038/ncomms11067 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DI9JO UT WOS:000373819100001 PM 27063795 ER PT J AU Gusev, A Shi, H Kichaev, G Pomerantz, M Li, F Long, HW Ingles, SA Kittles, RA Strom, SS Rybicki, BA Nemesure, B Isaacs, WB Zheng, W Pettaway, CA Yeboah, ED Tettey, Y Biritwum, RB Adjei, AA Tay, E Truelove, A Niwa, S Chokkalingam, AP John, EM Murphy, AB Signorello, LB Carpten, J Leske, MC Wu, SY Hennis, AJM Neslund-Dudas, C Hsing, AW Chu, L Goodman, PJ Klein, EA Witte, JS Casey, G Kaggwa, S Cook, MB Stram, DO Blot, WJ Eeles, RA Easton, D Kote-Jarai, Z Al Olama, AA Benlloch, S Muir, K Giles, GG Southey, MC Fitzgerald, LM Gronberg, H Wiklund, F Aly, M Henderson, BE Schleutker, J Wahlfors, T Tammela, TLJ Nordestgaard, BG Key, TJ Travis, RC Neal, DE Donovan, JL Hamdy, FC Pharoah, P Pashayan, N Khaw, KT Stanford, JL Thibodeau, SN McDonnell, SK Schaid, DJ Maier, C Vogel, W Luedeke, M Herkommer, K Kibel, AS Cybulski, C Wokolorczyk, D Kluzniak, W Cannon-Albright, L Teerlink, C Brenner, H Dieffenbach, AK Arndt, V Park, JY Sellers, TA Lin, HY Slavov, C Kaneva, R Mitev, V Batra, J Spurdle, A Clements, JA Teixeira, MR Pandha, H Michael, A Paulo, P Maia, S Kierzek, A Conti, DV Albanes, D Berg, C Berndt, SI Campa, D Crawford, ED Diver, WR Gapstur, SM Gaziano, JM Giovannucci, E Hoover, R Hunter, DJ Johansson, M Kraft, P Le Marchand, L Lindstrom, S Navarro, C Overvad, K Riboli, E Siddiq, A Stevens, VL Trichopoulos, D Vineis, P Yeager, M Trynka, G Raychaudhuri, S Schumacher, FR Price, AL Freedman, ML Haiman, CA Pasaniuc, B Cook, M Guy, M Govindasami, K Leongamornlert, D Sawyer, EJ Wilkinson, R Saunders, EJ Tymrakiewicz, M Dadaev, T Morgan, A Fisher, C Hazel, S Livni, N Lophatananon, A Pedersen, J Hopper, JL Adolfson, J Stattin, P Johansson, JE Cavalli-Bjoerkman, C Karlsson, A Broms, M Auvinen, A Kujala, P Maeaettaenen, L Murtola, T Taari, K Weischer, M Nielsen, SF Klarskov, P Roder, A Iversen, P Wallinder, H Gustafsson, S Cox, A Brown, P George, A Marsden, G Lane, A Davis, M Zheng, W Signorello, LB Blot, WJ Tillmans, L Riska, S Wang, L Rinckleb, A Lubiski, J Stegmaier, C Pow-Sang, J Park, H Radlein, S Rincon, M Haley, J Zachariah, B Kachakova, D Popov, E Mitkova, A Vlahova, A Dikov, T Christova, S Heathcote, P Wood, G Malone, G Saunders, P Eckert, A Yeadon, T Kerr, K Collins, A Turner, M Srinivasan, S Kedda, MA Alexander, K Omara, T Wu, HH Henrique, R Pinto, P Santos, J Barros-Silva, J AF Gusev, Alexander Shi, Huwenbo Kichaev, Gleb Pomerantz, Mark Li, Fugen Long, Henry W. Ingles, Sue A. Kittles, Rick A. Strom, Sara S. Rybicki, Benjamin A. Nemesure, Barbara Isaacs, William B. Zheng, Wei Pettaway, Curtis A. Yeboah, Edward D. Tettey, Yao Biritwum, Richard B. Adjei, Andrew A. Tay, Evelyn Truelove, Ann Niwa, Shelley Chokkalingam, Anand P. John, Esther M. Murphy, Adam B. Signorello, Lisa B. Carpten, John Leske, M. Cristina Wu, Suh-Yuh Hennis, Anslem J. M. Neslund-Dudas, Christine Hsing, Ann W. Chu, Lisa Goodman, Phyllis J. Klein, Eric A. Witte, John S. Casey, Graham Kaggwa, Sam Cook, Michael B. Stram, Daniel O. Blot, William J. Eeles, Rosalind A. Easton, Douglas Kote-Jarai, ZSofia Al Olama, Ali Amin Benlloch, Sara Muir, Kenneth Giles, Graham G. Southey, Melissa C. Fitzgerald, Liesel M. Gronberg, Henrik Wiklund, Fredrik Aly, Markus Henderson, Brian E. Schleutker, Johanna Wahlfors, Tiina Tammela, Teuvo L. J. Nordestgaard, Borge G. Key, Tim J. Travis, Ruth C. Neal, David E. Donovan, Jenny L. Hamdy, Freddie C. Pharoah, Paul Pashayan, Nora Khaw, Kay-Tee Stanford, Janet L. Thibodeau, Stephen N. McDonnell, Shannon K. Schaid, Daniel J. Maier, Christiane Vogel, Walther Luedeke, Manuel Herkommer, Kathleen Kibel, Adam S. Cybulski, Cezary Wokolorczyk, Dominika Kluzniak, Wojciech Cannon-Albright, Lisa Teerlink, Craig Brenner, Hermann Dieffenbach, Aida K. Arndt, Volker Park, Jong Y. Sellers, Thomas A. Lin, Hui-Yi Slavov, Chavdar Kaneva, Radka Mitev, Vanio Batra, Jyotsna Spurdle, Amanda Clements, Judith A. Teixeira, Manuel R. Pandha, Hardev Michael, Agnieszka Paulo, Paula Maia, Sofia Kierzek, Andrzej Conti, David V. Albanes, Demetrius Berg, Christine Berndt, Sonja I. Campa, Daniele Crawford, E. David Diver, W. Ryan Gapstur, Susan M. Gaziano, J. Michael Giovannucci, Edward Hoover, Robert Hunter, David J. Johansson, Mattias Kraft, Peter Le Marchand, Loic Lindstrom, Sara Navarro, Carmen Overvad, Kim Riboli, Elio Siddiq, Afshan Stevens, Victoria L. Trichopoulos, Dimitrios Vineis, Paolo Yeager, Meredith Trynka, Gosia Raychaudhuri, Soumya Schumacher, Frederick R. Price, Alkes L. Freedman, Matthew L. Haiman, Christopher A. Pasaniuc, Bogdan Cook, Margaret Guy, Michelle Govindasami, Koveela Leongamornlert, Daniel Sawyer, Emma J. Wilkinson, Rosemary Saunders, Edward J. Tymrakiewicz, Malgorzata Dadaev, Tokhir Morgan, Angela Fisher, Cyril Hazel, Steve Livni, Naomi Lophatananon, Artitaya Pedersen, John Hopper, John L. Adolfson, Jan Stattin, Paer Johansson, Jan-Erik Cavalli-Bjoerkman, Carin Karlsson, Ami Broms, Michael Auvinen, Anssi Kujala, Paula Maeaettaenen, Liisa Murtola, Teemu Taari, Kimmo Weischer, Maren Nielsen, Sune F. Klarskov, Peter Roder, Andreas Iversen, Peter Wallinder, Hans Gustafsson, Sven Cox, Angela Brown, Paul George, Anne Marsden, Gemma Lane, Athene Davis, Michael Zheng, Wei Signorello, Lisa B. Blot, William J. Tillmans, Lori Riska, Shaun Wang, Liang Rinckleb, Antje Lubiski, Jan Stegmaier, Christa Pow-Sang, Julio Park, Hyun Radlein, Selina Rincon, Maria Haley, James Zachariah, Babu Kachakova, Darina Popov, Elenko Mitkova, Atanaska Vlahova, Aleksandrina Dikov, Tihomir Christova, Svetlana Heathcote, Peter Wood, Glenn Malone, Greg Saunders, Pamela Eckert, Allison Yeadon, Trina Kerr, Kris Collins, Angus Turner, Megan Srinivasan, Srilakshmi Kedda, Mary-Anne Alexander, Kimberly Omara, Tracy Wu, Huihai Henrique, Rui Pinto, Pedro Santos, Joana Barros-Silva, Joao CA PRACTICAL Consortium TI Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation SO NATURE COMMUNICATIONS LA English DT Article ID GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; COMMON DISEASES; COMPLEX TRAITS; RISK; SNPS; ENHANCERS; ELEMENTS; PITFALLS; ENCODE AB Although genome-wide association studies have identified over 100 risk loci that explain similar to 33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa. C1 [Gusev, Alexander; Signorello, Lisa B.; Gaziano, J. Michael; Giovannucci, Edward; Hunter, David J.; Kraft, Peter; Lindstrom, Sara; Trichopoulos, Dimitrios] Harvard TH Chan Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA 02115 USA. [Gusev, Alexander; Raychaudhuri, Soumya; Freedman, Matthew L.] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. [Shi, Huwenbo; Kichaev, Gleb; Pasaniuc, Bogdan] Univ Calif Los Angeles, Bioinformat Interdept Program, Los Angeles, CA 90095 USA. [Pomerantz, Mark; Long, Henry W.; Freedman, Matthew L.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Pomerantz, Mark; Long, Henry W.; Freedman, Matthew L.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Li, Fugen; Long, Henry W.; Freedman, Matthew L.] Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02115 USA. [Li, Fugen] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Ingles, Sue A.; Casey, Graham; Stram, Daniel O.] Univ So Calif, Keck Sch Med, Dept Preventat Med, Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Kittles, Rick A.] Univ Arizona, Coll Med, Tucson, AZ 85721 USA. [Kittles, Rick A.] Univ Arizona, Ctr Canc, Tucson, AZ 85721 USA. [Strom, Sara S.] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Nemesure, Barbara; Leske, M. Cristina; Wu, Suh-Yuh; Hennis, Anslem J. M.] Henry Ford Hosp, Dept Publ Hlth Sci, Detroit, MI 48202 USA. [Isaacs, William B.; Price, Alkes L.] SUNY Stony Brook, Dept Prevent Med, Stony Brook, NY 11794 USA. [Isaacs, William B.; Price, Alkes L.] Johns Hopkins Univ Hosp, James Buchanan Brady Urol Inst, Baltimore, MD 21205 USA. [Isaacs, William B.; Price, Alkes L.] Inst Med, Baltimore, MD 21205 USA. [Zheng, Wei; Blot, William J.] Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, Div Epidemiol,Dept Med, Nashville, TN 37232 USA. [Pettaway, Curtis A.] Univ Texas MD Anderson Canc Ctr, Dept Urol, Houston, TX 77030 USA. [Yeboah, Edward D.; Tettey, Yao; Biritwum, Richard B.; Adjei, Andrew A.; Tay, Evelyn] Korle Bu Teaching Hosp, Accra, Ghana. [Yeboah, Edward D.; Tettey, Yao; Biritwum, Richard B.; Adjei, Andrew A.; Tay, Evelyn] Univ Ghana, Sch Med, Accra, Ghana. [Truelove, Ann; Niwa, Shelley] Westat Corp, Rockville, MD 20850 USA. [Chokkalingam, Anand P.] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. [John, Esther M.; Hsing, Ann W.; Chu, Lisa] Canc Prevent Inst Calif, Fremont, CA 94538 USA. [John, Esther M.; Hsing, Ann W.; Chu, Lisa] Stanford Univ, Sch Med, Palo Alto, CA 94305 USA. [John, Esther M.; Hsing, Ann W.; Chu, Lisa] Stanford Canc Inst, Palo Alto, CA 94305 USA. [Murphy, Adam B.] Northwestern Univ, Dept Urol, Chicago, IL 60611 USA. [Signorello, Lisa B.; Blot, William J.] Int Epidemiol Inst, Rockville, MD 20850 USA. [Carpten, John] Translat Genom Res Inst, Phoenix, AZ 85004 USA. [Hennis, Anslem J. M.] Univ W Indies, Chron Dis Res Ctr, Bridgetown, Barbados. [Hennis, Anslem J. M.] Univ W Indies, Fac Med Sci, Bridgetown, Barbados. [Goodman, Phyllis J.] Fred Hutchinson Canc Res Ctr, SWOG Stat Ctr, Seattle, WA 98109 USA. [Klein, Eric A.] Cleveland Clin, Glickman Urol & Kidney Inst, Cleveland, OH 44195 USA. [Witte, John S.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94118 USA. [Witte, John S.] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94118 USA. [Kaggwa, Sam] Makerere Univ, Dept Surg, Coll Hlth Sci, Kampala 94118, Uganda. [Cook, Michael B.; Berndt, Sonja I.; Hoover, Robert; Yeager, Meredith] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Eeles, Rosalind A.; Kote-Jarai, ZSofia; Guy, Michelle; Govindasami, Koveela; Leongamornlert, Daniel; Sawyer, Emma J.; Wilkinson, Rosemary; Saunders, Edward J.; Tymrakiewicz, Malgorzata; Dadaev, Tokhir; Morgan, Angela; Fisher, Cyril; Hazel, Steve; Livni, Naomi] Inst Canc Res, Sutton SM2 5NG, Surrey, England. [Eeles, Rosalind A.] Royal Marsden Natl Hlth Serv NHS Fdn Trust, London, England. [Eeles, Rosalind A.] Royal Marsden Natl Hlth Serv NHS Fdn Trust, Sutton, Surrey, England. [Easton, Douglas; Al Olama, Ali Amin; Benlloch, Sara; Cook, Margaret] Univ Cambridge, Strangeways Lab, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Worts Causeway, Cambridge CB1 8RN, England. [Muir, Kenneth; Lophatananon, Artitaya] Univ Manchester, Inst Populat Hlth, Manchester M13 9PL, Lancs, England. [Muir, Kenneth; Lophatananon, Artitaya] Univ Warwick, Warwick Med Sch, Coventry CV4 7AL, W Midlands, England. [Giles, Graham G.; Fitzgerald, Liesel M.] Canc Council Victoria, Canc Epidemiol Ctr, 615 St Kilda Rd, Melbourne, Vic 3004, Australia. [Giles, Graham G.; Hopper, John L.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic 3004, Australia. [Southey, Melissa C.] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Grattan St, Melbourne, Vic 3010, Australia. [Gronberg, Henrik; Wiklund, Fredrik; Aly, Markus; Adolfson, Jan; Stattin, Paer; Johansson, Jan-Erik; Cavalli-Bjoerkman, Carin; Karlsson, Ami; Broms, Michael] Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden. [Aly, Markus] Danderyd Hosp, Dept Clin Sci, S-17177 Stockholm, Sweden. [Henderson, Brian E.] Univ So Calif, Norris Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90007 USA. [Schleutker, Johanna] Univ Turku, Inst Biomed, Dept Med Biochem & Genet, Kiinamyllynkatu 10, FI-20014 Turku, Finland. [Schleutker, Johanna; Wahlfors, Tiina] Univ Tampere, BioMediTech, Tampere 33200, Finland. [Schleutker, Johanna; Wahlfors, Tiina] FimLab Labs, Tampere 33200, Finland. [Tammela, Teuvo L. J.] Univ Tampere, Dept Urol, Tampere Univ Hosp, Tampere 33200, Finland. [Tammela, Teuvo L. J.] Univ Tampere, Sch Med, Tampere 33200, Finland. [Nordestgaard, Borge G.; Weischer, Maren; Nielsen, Sune F.] Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, DK-2730 Herlev, Denmark. [Nordestgaard, Borge G.; Nielsen, Sune F.] Univ Copenhagen, Fac Hlth & Med Sci, DK-1165 Copenhagen, Denmark. [Nordestgaard, Borge G.; Nielsen, Sune F.] Univ Copenhagen, Med Sci, DK-1165 Copenhagen, Denmark. [Key, Tim J.; Travis, Ruth C.] Univ Oxford, Canc Epidemiol, Nuffield Dept Populat Hlth, Oxford OX3 7LF, England. [Neal, David E.] Univ Cambridge, Dept Oncol, Addenbrookes Hosp, Cambridge CB2 0QQ, England. [Neal, David E.] Li Ka Shing Ctr, Canc Res UK Cambridge Res Inst, Cambridge, England. [Donovan, Jenny L.; Brown, Paul; George, Anne; Marsden, Gemma; Lane, Athene; Davis, Michael] Univ Bristol, Sch Social & Community Med, Canynge Hall,39Whatley Rd, Bristol BS8 2PS, Avon, England. [Hamdy, Freddie C.] Aarhus Univ, Epidemiol Sect, Dept Publ Hlth, Aarhus OX1 3PN, Denmark. [Hamdy, Freddie C.] Univ Oxford, John Radcliffe Hosp, Fac Med Sci, Oxford OX1 3PN, England. [Pharoah, Paul; Pashayan, Nora] Univ Cambridge, Dept Oncol, Strangeways Lab, Ctr Canc Genet Epidemiol, Worts Causeway, Cambridge CB1 8RN, England. [Pashayan, Nora] UCL, Dept Appl Hlth Res, 1-19 Torrington Pl, London WC1E 7HB, England. [Khaw, Kay-Tee] Univ Cambridge, Clin Gerontol Unit, Cambridge CB1 8RN, England. [Stanford, Janet L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Stanford, Janet L.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98109 USA. [Thibodeau, Stephen N.; McDonnell, Shannon K.; Schaid, Daniel J.; Tillmans, Lori; Riska, Shaun; Wang, Liang] Mayo Clin, Rochester, MN 55905 USA. [Maier, Christiane; Vogel, Walther] Univ Hosp Ulm, Inst Human Genet, D-89081 Ulm, Germany. [Luedeke, Manuel; Rinckleb, Antje] Univ Hosp Ulm, Dept Urol, D-89081 Ulm, Germany. [Herkommer, Kathleen] Tech Univ Munich, Klinikum Rechts Isar, Dept Urol, D-81675 Munich, Germany. [Kibel, Adam S.] Brigham & Womens Hosp, Dana Farber Canc Inst, Div Urol Surg, 75 Francis St, Boston, MA 02115 USA. [Cybulski, Cezary; Wokolorczyk, Dominika; Kluzniak, Wojciech; Lubiski, Jan] Pomeranian Med Univ, Dept Genet & Pathol, Int Hereditary Canc Ctr, Szczecin, Poland. [Cannon-Albright, Lisa; Teerlink, Craig] Univ Utah, Div Genet Epidemiol, Dept Med, Sch Med, Salt Lake City, UT 84132 USA. [Cannon-Albright, Lisa; Teerlink, Craig] George E Wahlen Dept Vet Affairs, Med Ctr, Salt Lake City, UT 84132 USA. [Brenner, Hermann; Dieffenbach, Aida K.; Arndt, Volker] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, D-69120 Heidelberg, Germany. [Brenner, Hermann; Dieffenbach, Aida K.] German Canc Consortium DKTK, D-69120 Heidelberg, Germany. [Park, Jong Y.; Sellers, Thomas A.; Pow-Sang, Julio; Park, Hyun; Radlein, Selina; Rincon, Maria; Haley, James; Zachariah, Babu] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, 12902 Magnolia Dr, Tampa, FL 33612 USA. [Lin, Hui-Yi] H Lee Moffitt Canc Ctr & Res Inst, Biostat Program, 12902 Magnolia Dr, Tampa, FL 33612 USA. [Slavov, Chavdar; Popov, Elenko] Med Univ, Dept Urol, Sofia 1431, Bulgaria. [Slavov, Chavdar; Popov, Elenko] Med Univ, Alexandrovska Univ Hosp, Sofia 1431, Bulgaria. [Kaneva, Radka; Mitev, Vanio; Kachakova, Darina; Mitkova, Atanaska] Med Univ, Mol Med Ctr, Dept Med Chem & Biochem, 2 Zdrave Str, Sofia 1431, Bulgaria. [Batra, Jyotsna; Clements, Judith A.; Vlahova, Aleksandrina; Heathcote, Peter; Wood, Glenn; Malone, Greg; Saunders, Pamela; Eckert, Allison; Yeadon, Trina; Kerr, Kris; Collins, Angus; Turner, Megan; Srinivasan, Srilakshmi; Kedda, Mary-Anne; Alexander, Kimberly; Omara, Tracy] Queensland Univ Technol, Australian Prostate Canc Res Ctr Qld, Inst Hlth & Biomed Innovat, Brisbane, Qld 4000, Australia. [Batra, Jyotsna; Clements, Judith A.; Heathcote, Peter; Wood, Glenn; Malone, Greg; Saunders, Pamela; Eckert, Allison; Yeadon, Trina; Kerr, Kris; Collins, Angus; Turner, Megan; Srinivasan, Srilakshmi; Kedda, Mary-Anne; Alexander, Kimberly; Omara, Tracy] Queensland Univ Technol, Sch Biomed Sci, Brisbane, Qld 4000, Australia. [Spurdle, Amanda] Queensland Inst Med Res, Mol Canc Epidemiol Lab, Brisbane, Qld 4000, Australia. [Teixeira, Manuel R.; Paulo, Paula; Maia, Sofia; Henrique, Rui; Pinto, Pedro; Santos, Joana; Barros-Silva, Joao] Portuguese Oncol Inst, Dept Genet, P-4200 Oporto, Portugal. [Teixeira, Manuel R.] Univ Porto, Biomed Sci Inst ICBAS, P-4200 Oporto, Portugal. [Pandha, Hardev; Michael, Agnieszka; Kierzek, Andrzej; Vlahova, Aleksandrina; Dikov, Tihomir; Christova, Svetlana] Univ Surrey, Guildford GU2 7XH, Surrey, England. [Conti, David V.; Schumacher, Frederick R.; Haiman, Christopher A.] Univ So Calif, Keck Sch Med, Norris Canc Ctr, Dept Prevent Med, Los Angeles, CA 90033 USA. [Albanes, Demetrius] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Berg, Christine; Overvad, Kim] Johns Hopkins Med, Dept Radiat Oncol & Mol Radiat Sci, Baltimore, MD 21287 USA. [Campa, Daniele] German Canc Res Ctr, Genom Epidemiol Grp, D-69121 Heidelberg, Germany. [Crawford, E. David] Univ Colorado, Urol Oncol, Denver Hlth Sci Ctr, Denver, CO 80230 USA. [Diver, W. Ryan; Gapstur, Susan M.; Stevens, Victoria L.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30303 USA. [Gaziano, J. Michael] Harvard Univ, Dept Med, Sch Med, Boston, MA 02115 USA. [Gaziano, J. Michael] Brigham & Womens Hosp, Div Aging, Boston, MA 02115 USA. [Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Johansson, Mattias] Int Agcy Res Canc, F-69008 Lyon, France. [Johansson, Mattias] Umea Univ, Dept Surg & Perioperat Sci Urol & Androl, S-90736 Umea, Sweden. [Kraft, Peter; Lindstrom, Sara] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Le Marchand, Loic] Univ Hawaii, Program Epidemiol, Ctr Canc, Honolulu, HI 96813 USA. [Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London SW7 2AZ, England. [Siddiq, Afshan] Univ London Imperial Coll Sci Technol & Med, Dept Genom Common Dis, London SW7 2AZ, England. [Trichopoulos, Dimitrios] Acad Athens, Bur Epidemiol Res, Athens 10679, Greece. [Trichopoulos, Dimitrios] Hellen Hlth Fdn, Athens 10679, Greece. [Vineis, Paolo] HuGeF Fdn, I-10126 Turin, Italy. [Vineis, Paolo] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, London SW7 2AZ, England. [Trynka, Gosia; Raychaudhuri, Soumya] Brigham & Womens Hosp, Dept Med, Div Genet, 75 Francis St, Boston, MA 02115 USA. [Trynka, Gosia; Raychaudhuri, Soumya] Brigham & Womens Hosp, Dept Med, Div Rheumatol, 75 Francis St, Boston, MA 02115 USA. [Trynka, Gosia; Raychaudhuri, Soumya] Harvard Univ, Sch Med, Boston, MA USA. [Trynka, Gosia] Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Cambridge CB10 1SA, England. [Raychaudhuri, Soumya] Univ Manchester, Inst Inflammat & Repair, Manchester M13 9PT, Lancs, England. [Pasaniuc, Bogdan] Univ Calif Los Angeles, Dept Pathol, Los Angeles, CA 90024 USA. [Pasaniuc, Bogdan] Univ Calif Los Angeles, Dept Lab Med, Los Angeles, CA USA. [Pasaniuc, Bogdan] Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA 90095 USA. [Pedersen, John] Tissupath Pty Ltd, Melbourne, Vic 3122, Australia. [Auvinen, Anssi] Univ Tampere, Sch Hlth Sci, Dept Epidemiol, Tampere 33014, Finland. [Kujala, Paula] Tampere Univ Hosp, Fimlab Labs, Tampere, Finland. [Maeaettaenen, Liisa] Finnish Canc Registry, FIN-00170 Helsinki, Finland. [Murtola, Teemu] Univ Tampere, Sch Med, FIN-33101 Tampere, Finland. [Murtola, Teemu] Tampere Univ Hosp, Dept Urol, Tampere, Finland. [Taari, Kimmo] Univ Helsinki, Cent Hosp, Dept Urol, SF-00100 Helsinki, Finland. [Taari, Kimmo] Univ Helsinki, SF-00100 Helsinki, Finland. [Klarskov, Peter] Copenhagen Univ Hosp, Herlev Hosp, Dept Urol, Ringvej 75, DK-230 Herlev, Denmark. [Roder, Andreas; Iversen, Peter] Copenhagen Univ Hosp, Dept Urol, Rigshosp, Copenhagen Prostate Canc Ctr, DK-2200 Copenhagen, Denmark. [Wallinder, Hans; Gustafsson, Sven] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London SW7 2AZ, England. [Cox, Angela] Univ Sheffield, CR UK YCR Sheffield Canc Res Ctr, Sheffield S10 2TN, S Yorkshire, England. [Zheng, Wei] Vanderbilt Univ, Med Ctr, Dept Med, Div Epidemiol, 2525 West End Ave, Nashville, TN 37232 USA. [Signorello, Lisa B.] NCI, NIH, 9609 Med Ctr Dr, Bethesda, MD 20892 USA. [Signorello, Lisa B.] NCI, NIH, Rockville, MD 20850 USA. [Blot, William J.] Int Inst Epidemiol, 1555 Res Blvd,Suite 550, Rockville, MD 20850 USA. [Blot, William J.] Vanderbilt Univ, Sch Med, Div Epidemiol, Dept Med,Vanderbilt Epidemiol Ctr,Vanderbilt Ingr, Nashville, TN 37232 USA. [Stegmaier, Christa] Saarland Canc Registry, Saarbrucken, Germany. [Wu, Huihai] Univ Surrey, Guildford GU2 7XH, Surrey, England. RP Gusev, A (reprint author), Harvard TH Chan Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA 02115 USA.; Pasaniuc, B (reprint author), Univ Calif Los Angeles, Bioinformat Interdept Program, Los Angeles, CA 90095 USA. EM agusev@hsph.harvard.edu; pasaniuc@ucla.edu RI Cook, Michael/A-5641-2009; Batra, Jyotsna/B-4130-2011; Campa, Daniele/K-1617-2016; Zheng, Wei/O-3351-2013; Brenner, Hermann/B-4627-2017; OI Cook, Michael/0000-0002-0533-7302; Campa, Daniele/0000-0003-3220-9944; Zheng, Wei/0000-0003-1226-070X; Brenner, Hermann/0000-0002-6129-1572; Teerlink, Craig/0000-0002-1992-2326; albright, lisa/0000-0003-2602-3668; Taari, Kimmo/0000-0002-0077-4896; Clements, Judith/0000-0001-6026-1964 FU NIH fellowship [F32 GM106584]; NIH [R01 MH101244, R01 CA188392, U01 CA194393, R01 GM107427, R01 CA193910, CA63464, CA54281, CA098758, R01 CA092447]; Prostate Cancer Foundation Challenge Award; Wellcome Trust [076113]; European Commission's Seventh Framework Programme [223175 (HEALTH-F2-2009-223175)]; Cancer Research UK [C5047/A7357, C5047/A3354, C16913/A6135, C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A10123, C8197/A10865, C522/A8649, C490/A10124]; National Institute of Health (NIH) Cancer Post-Cancer GWAS initiative Grant [1 U19 CA 148537-01]; National Institutes of Health [CA128978]; Post-Cancer GWAS initiative [1U19 CA148537, 1U19 CA148065, 1U19 CA148112]; Department of Defense [W81XWH-10-1-0341]; Linneus Centre [70867902]; Swedish Research Council [K2010-70X-20430-04-3]; Swedish Cancer Foundation [09-0677]; US National Cancer Institute, National Institutes of Health [RO1CA056678, RO1CA082664, RO1CA092579]; US National Cancer Institute [R01CA72818, R01CA128813]; National Health and Medical Research Council, Australia [126402, 209057, 251533, 396414, 450104, 504700, 504702, 504715, 623204, 940394, 614296]; Bulgarian National Science Fund, Ministry of Education and Science [DOO-119/2009, DUNK01/2-2009, DFNI-B01/28/2012]; NIHR Health Technology Assessment Programme [96/20/06, 96/20/99]; Medical Research Council of England [G0500966, 75466]; NCRI, UK; US Dept of Defense award [W81XWH-04-1-0280]; Australia Project Grant [614296, 390130, 1009458]; Prostate Cancer Foundation of Australia; Vanderbilt-Ingram Cancer Center [P30 CA68485]; UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge; Competitive Research Funding of the Tampere University Hospital [9N069, X51003]; National Cancer Institute [P30CA042014]; [G0500966/75466] FX This work was supported by NIH fellowship F32 GM106584 (AG), NIH grants R01 MH101244(A.G.), R01 CA188392 (B.P.), U01 CA194393(B.P.), R01 GM107427 (M.L.F.), R01 CA193910 (M.L.F./M.P.) and Prostate Cancer Foundation Challenge Award (M.L.F./M.P.). This study makes use of data generated by the Wellcome Trust Case Control Consortium and the Wellcome Trust Sanger Institute. A full list of the investigators who contributed to the generation of the Wellcome Trust Case Control Consortium data is available on www.wtccc.org.uk. Funding for the Wellcome Trust Case Control Consortium project was provided by the Wellcome Trust under award 076113. This study makes use of data generated by the UK10K Consortium. A full list of the investigators who contributed to the generation of the data is available online (http://www.UK10K.org). The PRACTICAL consortium was supported by the following grants: European Commission's Seventh Framework Programme grant agreement no 223175 (HEALTH-F2-2009-223175), Cancer Research UK Grants C5047/A7357, C1287/A10118, C5047/A3354, C5047/A10692, C16913/A6135 and The National Institute of Health (NIH) Cancer Post-Cancer GWAS initiative Grant: no. 1 U19 CA 148537-01 (the GAME-ON initiative); Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007 and C5047/A10692), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112-the GAME-ON initiative), the Department of Defense (W81XWH-10-1-0341), A Linneus Centre (Contract ID 70867902), Swedish Research Council (grant no K2010-70X-20430-04-3), the Swedish Cancer Foundation (grant no 09-0677), grants RO1CA056678, RO1CA082664 and RO1CA092579 from the US National Cancer Institute, National Institutes of Health; US National Cancer Institute (R01CA72818); support from The National Health and Medical Research Council, Australia (126402, 209057, 251533, 396414, 450104, 504700, 504702, 504715, 623204, 940394 and 614296); NIH grants CA63464, CA54281 and CA098758; US National Cancer Institute (R01CA128813, PI: J.Y. Park); Bulgarian National Science Fund, Ministry of Education and Science (contract DOO-119/2009; DUNK01/2-2009; DFNI-B01/28/2012); Cancer Research UK grants [C8197/A10123] and [C8197/A10865]; grant code G0500966/75466; NIHR Health Technology Assessment Programme (projects 96/20/06 and 96/20/99); Cancer Research UK grant number C522/A8649, Medical Research Council of England grant number G0500966, ID 75466 and The NCRI, UK; The US Dept of Defense award W81XWH-04-1-0280; Australia Project Grant [390130, 1009458] and Enabling Grant [614296 to APCB]; the Prostate Cancer Foundation of Australia (Project Grant [PG7] and Research infrastructure grant [to APCB]); NIH grant R01 CA092447; Vanderbilt-Ingram Cancer Center (P30 CA68485); Cancer Research UK [C490/A10124] and supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge; Competitive Research Funding of the Tampere University Hospital (9N069 and X51003); Award Number P30CA042014 from the National Cancer Institute. NR 39 TC 4 Z9 4 U1 1 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD APR PY 2016 VL 7 AR 10979 DI 10.1038/ncomms10979 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DI9EK UT WOS:000373804700001 PM 27052111 ER PT J AU Ono, W Sakagami, N Nishimori, S Ono, N Kronenberg, HM AF Ono, Wanida Sakagami, Naoko Nishimori, Shigeki Ono, Noriaki Kronenberg, Henry M. TI Parathyroid hormone receptor signalling in osterix-expressing mesenchymal progenitors is essential for tooth root formation SO NATURE COMMUNICATIONS LA English DT Article ID OSTEOBLAST DIFFERENTIATION; PTH/PTHRP RECEPTOR; PRIMARY FAILURE; I COLLAGEN; BONE; PROTEIN; ERUPTION; HEDGEHOG; CELLS; GENE AB Dental root formation is a dynamic process in which mesenchymal cells migrate toward the site of the future root, differentiate and secrete dentin and cementum. However, the identities of dental mesenchymal progenitors are largely unknown. Here we show that cells expressing osterix are mesenchymal progenitors contributing to all relevant cell types during morphogenesis. The majority of cells expressing parathyroid hormone-related peptide (PTHrP) are in the dental follicle and on the root surface, and deletion of its receptor (PPR) in these progenitors leads to failure of eruption and significantly truncated roots lacking periodontal ligaments. The PPR-deficient progenitors exhibit accelerated cementoblast differentiation with upregulation of nuclear factor I/C (Nfic). Deletion of histone deacetylase-4 (HDAC4) partially recapitulates the PPR deletion root phenotype. These findings indicate that PPR signalling in dental mesenchymal progenitors is essential for tooth root formation, underscoring importance of the PTHrP-PPR system during root morphogenesis and tooth eruption. C1 [Ono, Wanida; Nishimori, Shigeki; Ono, Noriaki; Kronenberg, Henry M.] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Ono, Wanida; Nishimori, Shigeki; Ono, Noriaki; Kronenberg, Henry M.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Ono, Wanida; Sakagami, Naoko; Ono, Noriaki] Univ Michigan, Dept Orthodont & Pediat Dent, Ann Arbor, MI 48109 USA. RP Kronenberg, HM (reprint author), Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA.; Kronenberg, HM (reprint author), Harvard Univ, Sch Med, Boston, MA 02114 USA. EM hkronenberg@mgh.harvard.edu FU National Institutes of Health [DE022564, DK011794]; Japan Society for the Promotion of Science [21689051] FX The authors thank Eric Olson for HDAC4-null and HDAC4-floxed mice, Arthur Broadus for PTHrP-LacZ mice and David Rowe for Col2.3-GFP and Oc-GFP mice. This study was supported by National Institutes of Health Grants DE022564 to N.O. and DK011794 to H.M.K., and Japan Society for the Promotion of Science Grant-in-Aid for Young Scientists 21689051 to N.O. NR 47 TC 2 Z9 2 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD APR PY 2016 VL 7 AR 11277 DI 10.1038/ncomms11277 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DI9NW UT WOS:000373830600001 PM 27068606 ER PT J AU Vinegoni, C Swisher, CL Feruglio, PF Giedt, RJ Rousso, DL Stapleton, S Weissleder, R AF Vinegoni, C. Swisher, C. Leon Feruglio, P. Fumene Giedt, R. J. Rousso, D. L. Stapleton, S. Weissleder, R. TI Real-time high dynamic range laser scanning microscopy SO NATURE COMMUNICATIONS LA English DT Article ID SINGLE-CELL; 2-PHOTON MICROSCOPY; LIGHT-MICROSCOPY; BRAIN; NEUROSCIENCE; RECONSTRUCTION; ILLUMINATION; SENSITIVITY; IMAGES; SCALE AB In conventional confocal/multiphoton fluorescence microscopy, images are typically acquired under ideal settings and after extensive optimization of parameters for a given structure or feature, often resulting in information loss from other image attributes. To overcome the problem of selective data display, we developed a new method that extends the imaging dynamic range in optical microscopy and improves the signal-to-noise ratio. Here we demonstrate how real-time and sequential high dynamic range microscopy facilitates automated three-dimensional neural segmentation. We address reconstruction and segmentation performance on samples with different size, anatomy and complexity. Finally, in vivo real-time high dynamic range imaging is also demonstrated, making the technique particularly relevant for longitudinal imaging in the presence of physiological motion and/or for quantification of in vivo fast tracer kinetics during functional imaging. C1 [Vinegoni, C.; Swisher, C. Leon; Feruglio, P. Fumene; Giedt, R. J.; Stapleton, S.; Weissleder, R.] Massachusetts Gen Hosp, Ctr Syst Biol, 185 Cambridge St, Boston, MA 02114 USA. [Vinegoni, C.; Swisher, C. Leon; Feruglio, P. Fumene; Giedt, R. J.; Stapleton, S.; Weissleder, R.] Harvard Univ, Sch Med, Richard B Simches Res Ctr, 185 Cambridge St, Boston, MA 02114 USA. [Feruglio, P. Fumene] Univ Verona, Dept Neurol Biomed & Movement Sci, Str Le Grazie 8, I-37134 Verona, Italy. [Rousso, D. L.] Harvard Univ, Ctr Brain Sci, Dept Mol & Cell Biol, 52 Oxford St, Cambridge, MA 02138 USA. RP Vinegoni, C (reprint author), Massachusetts Gen Hosp, Ctr Syst Biol, 185 Cambridge St, Boston, MA 02114 USA.; Vinegoni, C (reprint author), Harvard Univ, Sch Med, Richard B Simches Res Ctr, 185 Cambridge St, Boston, MA 02114 USA. EM cvinegoni@mgh.harvard.edu FU Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services [HHSN26820100004xC]; NRSA postdoctoral fellowship [F32-CA192531]; Natural Sciences and Engineering Research Council of Canada (NSERC); CDMRP DOD BCRP postdoctoral fellowship [BC134081]; Institute of Biomedical Engineering [R01EB006432]; EC [622182] FX We thank Professor J.R. Sanes, Drs John Dubach, Kevin King, Nicolas De Silva, Michael Cuccarese, Aaron Aguirre and Jonathan Carlson for helpful discussions on applications of High Dynamic Range to fluorescence microscopy as well as Yoshiko Guiles for help with sample preparation and Dr Hunter Elliott for training with IMARIS. This project was funded in part by Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services (under Contract No. HHSN26820100004xC), NRSA postdoctoral fellowship F32-CA192531, the Natural Sciences and Engineering Research Council of Canada (NSERC) postdoctoral fellowship, CDMRP DOD BCRP postdoctoral fellowship BC134081 and from the Institute of Biomedical Engineering (under R01EB006432). The research leading to these results has also received funding from the EC Seventh Framework Programme under the Grant Agreement nr. 622182. NR 50 TC 3 Z9 3 U1 1 U2 10 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 APR PY 2016 VL 7 AR 11077 DI 10.1038/ncomms11077 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DI4NE UT WOS:000373475800001 PM 27032979 ER PT J AU Spring, BQ Sears, RB Zheng, LZ Mai, ZM Watanabe, R Sherwood, ME Schoenfeld, DA Pogue, BW Pereira, SP Villa, E Hasan, T AF Spring, Bryan Q. Sears, R. Bryan Zheng, Lei Zak Mai, Zhiming Watanabe, Reika Sherwood, Margaret E. Schoenfeld, David A. Pogue, Brian W. Pereira, Stephen P. Villa, Elizabeth Hasan, Tayyaba TI A photoactivable multi-inhibitor nanoliposome for tumour control and simultaneous inhibition of treatment escape pathways SO NATURE NANOTECHNOLOGY LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; ADVANCED PANCREATIC-CANCER; TARGETED DRUG-DELIVERY; NEAR-INFRARED LIGHT; PHOTODYNAMIC THERAPY; IN-VIVO; OVARIAN-CANCER; C-MET; ANTIANGIOGENIC THERAPY; METASTASIS AB Nanoscale drug delivery vehicles can facilitate multimodal therapies of cancer by promoting tumour-selective drug release. However, few are effective because cancer cells develop ways to resist and evade treatment. Here, we introduce a photoactivable multi-inhibitor nanoliposome (PMIL) that imparts light-induced cytotoxicity in synchrony with a photoinitiated and sustained release of inhibitors that suppress tumour regrowth and treatment escape signalling pathways. The PMIL consists of a nanoliposome doped with a photoactivable chromophore (benzoporphyrin derivative, BPD) in the lipid bilayer, and a nanoparticle containing cabozantinib (XL184)-a multikinase inhibitor-encapsulated inside. Near-infrared tumour irradiation, following intravenous PMIL administration, triggers photodynamic damage of tumour cells and microvessels, and simultaneously initiates release of XL184 inside the tumour. A single PMIL treatment achieves prolonged tumour reduction in two mouse models and suppresses metastatic escape in an orthotopic pancreatic tumour model. The PMIL offers new prospects for cancer therapy by enabling spatiotemporal control of drug release while reducing systemic drug exposure and associated toxicities. C1 [Spring, Bryan Q.; Sears, R. Bryan; Zheng, Lei Zak; Mai, Zhiming; Sherwood, Margaret E.; Hasan, Tayyaba] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Spring, Bryan Q.; Sears, R. Bryan; Zheng, Lei Zak; Mai, Zhiming; Sherwood, Margaret E.; Hasan, Tayyaba] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Spring, Bryan Q.] Northeastern Univ, Dept Phys, Boston, MA 02115 USA. [Sears, R. Bryan] Emmanuel Coll, Dept Chem, Boston, MA 02115 USA. [Watanabe, Reika] Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA 92093 USA. [Schoenfeld, David A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Schoenfeld, David A.] Harvard Univ, Biostat Unit, Boston, MA 02114 USA. [Pogue, Brian W.] Dartmouth Coll, Thayer Sch Engn, Hanover, NH 03755 USA. [Pereira, Stephen P.] UCL, UCL Inst Liver & Digest Hlth, Royal Free Hosp Campus, London NW3 2QG, England. [Hasan, Tayyaba] Harvard Univ, Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Hasan, Tayyaba] MIT, Cambridge, MA 02139 USA. RP Hasan, T (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA.; Hasan, T (reprint author), Harvard Univ, Sch Med, Boston, MA 02114 USA.; Hasan, T (reprint author), Harvard Univ, Div Hlth Sci & Technol, Cambridge, MA 02139 USA.; Hasan, T (reprint author), MIT, Cambridge, MA 02139 USA. EM thasan@mgh.harvard.edu RI Villa, Elizabeth/D-1811-2010 OI Villa, Elizabeth/0000-0003-4677-9809 FU National Institutes of Health Grants [R01 CA156177, R01-CA160998, P01-CA084203, F32-CA144210] FX We thank N. Watson (W.M. Kreck Microscopy Facility at the Whitehead Institute, Massachusetts Institute of Technology) for providing ionized carbon coated grids; E. Oliva (Department of Pathology at Massachusetts General Hospital) for expert histopathologic review of tissue sections; G. Orbaid for a critical reading; and, A. Villanueva for assistance in preparing a 3D render of a PMIL cryo-EM tomogram. This work was supported by National Institutes of Health Grants R01 CA156177 (to T.H.), R01-CA160998 (to T.H.), and P01-CA084203 (to B.W.P., S.P.P. and T.H.) and F32-CA144210 (to B.Q.S.). NR 50 TC 13 Z9 13 U1 25 U2 65 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1748-3387 EI 1748-3395 J9 NAT NANOTECHNOL JI Nat. Nanotechnol. PD APR PY 2016 VL 11 IS 4 BP 378 EP + DI 10.1038/NNANO.2015.311 PG 12 WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Science & Technology - Other Topics; Materials Science GA DI4FJ UT WOS:000373455500016 PM 26780659 ER PT J AU Notarangelo, LD Kim, MS Walter, JE Lee, YN AF Notarangelo, Luigi D. Kim, Min-Sung Walter, Jolan E. Lee, Yu Nee TI Human RAG mutations: biochemistry and clinical implications SO NATURE REVIEWS IMMUNOLOGY LA English DT Review ID SEVERE COMBINED IMMUNODEFICIENCY; COMBINED IMMUNE-DEFICIENCY; RECOMBINATION-ACTIVATING GENE; HYPEREOSINOPHILIA OMENNS SYNDROME; COMMON VARIABLE IMMUNODEFICIENCY; IMMUNOGLOBULIN-SECRETING CELLS; REGULATORY T-CELLS; V(D)J RECOMBINATION; B-CELLS; GRANULOMATOUS-DISEASE AB The recombination-activating gene 1 (RAG1) and RAG2 proteins initiate the V(D)J recombination process, which ultimately enables the generation of T cells and B cells with a diversified repertoire of antigen-specific receptors. Mutations of the RAG genes in humans are associated with a broad spectrum of clinical phenotypes, ranging from severe combined immunodeficiency to autoimmunity. Recently, novel insights into the phenotypic diversity of this disease have been provided by resolving the crystal structure of the RAG complex, by developing novel assays to test recombination activity of the mutant RAG proteins and by characterizing the molecular and cellular basis of immune dysregulation in patients with RAG deficiency. C1 [Notarangelo, Luigi D.; Walter, Jolan E.; Lee, Yu Nee] Harvard Univ, Sch Med, Div Immunol, Boston Childrens Hosp, Boston, MA 02115 USA. [Kim, Min-Sung] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Walter, Jolan E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pediat Allergy & Immunol, Boston, MA 02114 USA. [Walter, Jolan E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Immunol & Inflammatory Dis, Boston, MA 02114 USA. RP Notarangelo, LD (reprint author), Harvard Univ, Sch Med, Div Immunol, Boston Childrens Hosp, Boston, MA 02115 USA. EM luigi.notarangelo@childrens.harvard.edu FU NIAID NIH HHS [5K08AI103035, 5R01AI100887, K08 AI103035] NR 103 TC 9 Z9 9 U1 2 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1733 EI 1474-1741 J9 NAT REV IMMUNOL JI Nat. Rev. Immunol. PD APR PY 2016 VL 16 IS 4 BP 234 EP 246 DI 10.1038/nri.2016.28 PG 13 WC Immunology SC Immunology GA DH7MD UT WOS:000372977200009 PM 26996199 ER PT J AU Fu, ZL Liu, M Li, Z Fan, Y Zhang, JH Zhang, XC Li, Q AF Fu, Zhanli Liu, Meng Li, Ziao Fan, Yan Zhang, Jianhua Zhang, Xuchu Li, Qian TI Is the bullhead sign on bone scintigraphy really common in the patient with SAPHO syndrome? A single-center study of a 16-year experience SO NUCLEAR MEDICINE COMMUNICATIONS LA English DT Article DE bullhead sign; SAPHO syndrome; whole-body bone scintigraphy ID PUSTULOTIC ARTHROOSTEITIS; FOLLOW-UP; SPECTRUM; HYPEROSTOSIS AB ObjectiveThe aim of this study was to assess the bone lesion distribution and analyze the frequency of the bullhead sign in patients with SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome using whole-body bone scintigraphy (WBBS) in a relatively populous study population.MethodsIn this study, the Nuclear Medicine Department's records of one center were retrospectively reviewed and the patients who fulfilled the diagnostic criteria for SAPHO syndrome and underwent Tc-99m-methylene diphosphonate WBBS were identified over a 16-year period. The following data were collected from patients, including age, sex, surgically proved pathology of the bone lesions, WBBS surveillance interval, and SAPHO syndrome components. The bone lesion distribution and the frequency of bullhead sign involving the manubrium and bilateral sternoclavicular junctions were analyzed.ResultsForty-eight patients were enrolled in this study. The initial WBBS indicated bone involvement in all of the 48 (100%) patients, in whom the most commonly affected region was the anterior chest wall (ACW) (100%, 48/48). The frequency of the upper costosternal junction involvement was the highest (38/48, 79.2%), and 28.9% (11/38) patients were found to show isolated involvement of the first rib in ACW. The frequency of the bullhead sign was only 22.9% (11/48, 95% CI: 12.0-37.3). In the eight (16.7%, 8/48) patients who were followed up using WBBS with an interval that ranged from 1 to 10 years, one patient with an initially single sternoclavicular junction lesion developed a typical bullhead sign over 10 years; other patients with or without the initial typical bullhead sign showed stable appearance over 1-4 years.ConclusionThis retrospective study shows that in patients with proposed SAPHO syndrome, the bone lesions are most likely located in ACW, and the configuration of the bullhead sign is characteristic, but not entirely sensitive. The value of upper costosternal junction involvement, especially the first rib, may be underevaluated. C1 [Fu, Zhanli; Liu, Meng; Li, Ziao; Fan, Yan; Zhang, Jianhua; Zhang, Xuchu] Peking Univ, Hosp 1, Dept Nucl Med, Beijing 100871, Peoples R China. [Li, Qian] Harvard Univ, Massachusetts Gen Hosp, Dept Radiol, Sch Med, 55 Fruit St,White 270, Boston, MA 02114 USA. RP Li, Q (reprint author), Harvard Univ, Massachusetts Gen Hosp, Dept Radiol, Sch Med, 55 Fruit St,White 270, Boston, MA 02114 USA. EM qli14@mgh.harvard.edu FU Seeding Grant for Medicine and Engineering Sciences of Peking University [BMU20140398] FX This work was supported, in part, by the Seeding Grant for Medicine and Engineering Sciences of Peking University (BMU20140398). NR 20 TC 3 Z9 4 U1 0 U2 0 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 APR PY 2016 VL 37 IS 4 BP 387 EP 392 DI 10.1097/MNM.0000000000000451 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DI5GI UT WOS:000373526500008 PM 26619395 ER PT J AU Bove, RM Gerweck, AV Mancuso, SM Bredella, MA Sherman, JC Miller, KK AF Bove, Riley M. Gerweck, Anu V. Mancuso, Sarah M. Bredella, Miriam A. Sherman, Janet C. Miller, Karen K. TI Association between adiposity and cognitive function in young men: Hormonal mechanisms SO OBESITY LA English DT Article ID BODY-MASS INDEX; BINDING GLOBULIN; INSULIN SENSITIVITY; METABOLIC SYNDROME; OBESITY; TESTOSTERONE; BRAIN; WOMEN; PERFORMANCE; MEMORY AB ObjectiveTo determine the association between adiposity, hormones, and cognition in young men with abdominal obesity. MethodsIn this cross-sectional observational study, 53 nondiabetic men with abdominal obesity (mean body mass index, 37.3 kg/m(2); age, 22-45 years) and normal intelligence underwent detailed measures of body composition, hormonal profiles, and cognition. Age- and education-adjusted performance in five cognitive domains was examined. ResultsTotal fat percentage was negatively associated with visuospatial skills (P=0.002) and visual memory (P=0.012). Insulin resistance (homeostatic model assessment of insulin resistance) was also negatively associated with these domains (P=0.05 and trend, P=0.06, respectively). Total testosterone levels were negatively associated with executive function and verbal learning and memory (P=0.04 for each), but free testosterone was not. Sex hormone-binding globulin (SHBG) was also inversely associated with performance in these domains (P=0.015 and trend, P=0.09, respectively). In a stepwise regression model including percentage fat, homeostatic model assessment of insulin resistance, SHBG, and free testosterone, SHBG was the only variable selected for executive function (P=0.05) and showed a trend for verbal learning and memory (P=0.09). ConclusionsAdiposity and insulin resistance were associated with worse function in visual domains. An unexpected negative association is reported between SHBG and cognitive measures, which seemed to be independent of free testosterone levels. C1 [Bove, Riley M.] Brigham & Womens Hosp, Dept Neurol, 75 Francis St, Boston, MA 02115 USA. [Bove, Riley M.; Bredella, Miriam A.; Sherman, Janet C.; Miller, Karen K.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Gerweck, Anu V.; Miller, Karen K.] Massachusetts Gen Hosp, Dept Med, Neuroendocrine Unit, Boston, MA 02114 USA. [Mancuso, Sarah M.; Sherman, Janet C.] Massachusetts Gen Hosp, Dept Psychiat, Psychol Assessment Ctr, Boston, MA 02114 USA. [Bredella, Miriam A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Miller, KK (reprint author), Harvard Univ, Sch Med, Boston, MA 02115 USA.; Miller, KK (reprint author), Massachusetts Gen Hosp, Dept Med, Neuroendocrine Unit, Boston, MA 02114 USA. EM kkmiller@partners.org; kkmiller@partners.org FU National Institutes of Health [R01 HL-077674, K23 RR-23090, K24 HL092902-03, UL1 RR-025758]; 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 research was supported by National Institutes of Health awards: R01 HL-077674, K23 RR-23090, K24 HL092902-03, and UL1 RR-025758. This work was conducted with support from Harvard Catalyst/The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award UL1 TR001102) and financial contributions from Harvard University and its affiliated academic health care centers. NR 40 TC 2 Z9 2 U1 3 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD APR PY 2016 VL 24 IS 4 BP 954 EP 961 DI 10.1002/oby.21415 PG 8 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA DI6MM UT WOS:000373613200028 PM 26880680 ER PT J AU Hou, SS Bacskai, BJ Kumar, ATN AF Hou, Steven S. Bacskai, Brian J. Kumar, Anand T. N. TI Optimal estimator for tomographic fluorescence lifetime multiplexing SO OPTICS LETTERS LA English DT Article ID CONTRAST AB We use the model resolution matrix to analytically derive an optimal Bayesian estimator for multiparameter inverse problems that simultaneously minimizes inter-parameter cross talk and the total reconstruction error. Application of this estimator to time-domain diffuse fluorescence imaging shows that the optimal estimator for lifetime multiplexing is identical to a previously developed asymptotic time-domain (ATD) approach, except for the inclusion of a diagonal regularization term containing decay amplitude uncertainties. We show that, while the optimal estimator and ATD provide zero cross talk, the optimal estimator provides lower reconstruction error, while ATD results in superior relative quantitation. The framework presented here is generally applicable to other multiplexing problems where the simultaneous and accurate relative quantitation of multiple parameters is of interest. (C) 2016 Optical Society of America C1 [Hou, Steven S.; Kumar, Anand T. N.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol,Athinoula A Martinos Ctr Biomed Imagi, Charlestown, MA 02129 USA. [Hou, Steven S.; Bacskai, Brian J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol,Alzheimers Dis Res Unit, Charlestown, MA 02129 USA. RP Kumar, ATN (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol,Athinoula A Martinos Ctr Biomed Imagi, Charlestown, MA 02129 USA. EM ankumar@nmr.mgh.harvard.edu FU National Institute of Biomedical Imaging and Bioengineering (NIBIB) [R01 EB000768, R01 EB015325] FX National Institute of Biomedical Imaging and Bioengineering (NIBIB) (R01 EB000768, R01 EB015325). NR 13 TC 1 Z9 1 U1 2 U2 3 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 0146-9592 EI 1539-4794 J9 OPT LETT JI Opt. Lett. PD APR 1 PY 2016 VL 41 IS 7 BP 1352 EP 1355 DI 10.1364/OL.41.001352 PG 4 WC Optics SC Optics GA DI0ZI UT WOS:000373225400012 PM 27192234 ER PT J AU Crema, MD Roemer, FW Li, L Rosen, LB Dudley, A Alexander, RC Guermazi, A AF Crema, M. D. Roemer, F. W. Li, L. Rosen, L. B. Dudley, A. Alexander, R. C. Guermazi, A. TI SEMIQUANTITATIVE AND QUANTITATIVE METHODS FOR THE ASSESSMENT OF SYNOVITIS IN KNEE OSTEOARTHRITIS USING NON ENHANCED AND GADOLINIUM-ENHANCED MRI SO OSTEOARTHRITIS AND CARTILAGE LA English DT Meeting Abstract CT World Congress of the Osteoarthritis-Research-Society-International (OARSI) on Osteoarthritis CY MAR 31-APR 03, 2016 CL Amsterdam, NETHERLANDS SP Osteoarthritis Res Soc Int C1 [Crema, M. D.; Roemer, F. W.; Guermazi, A.] Boston Univ, Boston, MA 02215 USA. [Li, L.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Rosen, L. B.] Flex Pharma, Boston, MA USA. [Dudley, A.] AstraZeneca NeuroSci Innovat Med, Cambridge, MA USA. [Alexander, R. C.] Pfizer NeuroSci, Cambridge, MA USA. NR 0 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 1063-4584 EI 1522-9653 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PD APR PY 2016 VL 24 SU S MA 453 BP S269 EP S269 PG 1 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA DI5KW UT WOS:000373538800483 ER PT J AU Wink, AE Niu, J Felson, DT Nevitt, MC Lewis, CE Torner, J Brown, CA Shakoor, N Sharma, L Gross, KD AF Wink, A. E. Niu, J. Felson, D. T. Nevitt, M. C. Lewis, C. E. Torner, J. Brown, C. A. Shakoor, N. Sharma, L. Gross, K. D. TI STRUCTURAL AND SENSORIMOTOR CORRELATES OF VARUS KNEE THRUST DURING WALKING: THE MULTICENTER OSTEOARTHRITIS STUDY SO OSTEOARTHRITIS AND CARTILAGE LA English DT Meeting Abstract CT World Congress of the Osteoarthritis-Research-Society-International (OARSI) on Osteoarthritis CY MAR 31-APR 03, 2016 CL Amsterdam, NETHERLANDS SP Osteoarthritis Res Soc Int C1 [Wink, A. E.; Niu, J.; Felson, D. T.; Brown, C. A.; Gross, K. D.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Nevitt, M. C.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Lewis, C. E.] Univ Alabama Birmingham, Birmingham, AL USA. [Torner, J.] Univ Iowa, Iowa City, IA USA. [Shakoor, N.] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Sharma, L.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Gross, K. D.] Massachusetts Gen Hosp, Inst Hlth Profess, Boston, MA 02114 USA. NR 0 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 1063-4584 EI 1522-9653 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PD APR PY 2016 VL 24 SU S MA 140 BP S89 EP S90 PG 2 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA DI5KW UT WOS:000373538800170 ER PT J AU Wink, AE Gross, KD Brown, CA Niu, J Torner, J Lewis, CE Nevitt, MC Guermazi, A Roemer, FW Sharma, L Felson, DT AF Wink, A. E. Gross, K. D. Brown, C. A. Niu, J. Torner, J. Lewis, C. E. Nevitt, M. C. Guermazi, A. Roemer, F. W. Sharma, L. Felson, D. T. TI RELATION OF VARUS KNEE THRUST DURING WALKING TO RISK OF INCIDENT AND PROGRESSIVE MRI LESIONS: THE MULTICENTER OSTEOARTHRITIS STUDY SO OSTEOARTHRITIS AND CARTILAGE LA English DT Meeting Abstract CT World Congress of the Osteoarthritis-Research-Society-International (OARSI) on Osteoarthritis CY MAR 31-APR 03, 2016 CL Amsterdam, NETHERLANDS SP Osteoarthritis Res Soc Int C1 [Wink, A. E.; Gross, K. D.; Brown, C. A.; Niu, J.; Guermazi, A.; Roemer, F. W.; Felson, D. T.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Gross, K. D.] Massachusetts Gen Hosp, Inst Hlth Profess, Boston, MA 02114 USA. [Torner, J.] Univ Iowa, Iowa City, IA USA. [Lewis, C. E.] Univ Alabama Birmingham, Birmingham, AL USA. [Nevitt, M. C.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Sharma, L.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1063-4584 EI 1522-9653 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PD APR PY 2016 VL 24 SU S MA 36 BP S29 EP S29 PG 1 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA DI5KW UT WOS:000373538800066 ER PT J AU Bergroth, E Aakula, M Korppi, M Remes, S Kivisto, JE Piedra, PA Camargo, CA Jartti, T AF Bergroth, Eija Aakula, Matilda Korppi, Matti Remes, Sami Kivisto, Juho E. Piedra, Pedro A. Camargo, Carlos A., Jr. Jartti, Tuomas TI Post-bronchiolitis Use of Asthma Medication A Prospective 1-year Follow-up Study SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE bronchiolitis; long-term; respiratory syncytial virus; rhinovirus; treatment ID RESPIRATORY SYNCYTIAL VIRUS; DAY-CARE ATTENDANCE; LENGTH-OF-STAY; EARLY-LIFE; ALLERGIC SENSITIZATION; RHINOVIRUS ILLNESSES; CHILDHOOD ASTHMA; WHEEZING EPISODE; YOUNG-CHILDREN; VIRAL-ETIOLOGY AB Background: Our aim was to evaluate the association between viral findings during bronchiolitis and the use of asthma controller medication (primary outcome) and systemic corticosteroids (secondary outcome) during the first post-bronchiolitis year. Methods: We enrolled 408 children hospitalized for bronchiolitis at <24 months of age in a prospective, 3-center, 1-year follow-up study in Finland. Viruses were detected with polymerase chain reaction in nasopharyngeal aspirates. The parents underwent a structured interview during hospitalization. Twelve months later, the use of asthma medication was asked in a structured questionnaire. Multivariable logistic regression was used for statistical analysis. Results: In total, 365 (89%) children completed the 1-year follow-up. The use of long-term asthma controller medication was highest in the rhinovirus-positive group (61% vs. 15% in respiratory syncytial virus-positive group; adjusted odd ratios, 7.5; 95% confidence interval: 3.7-15.3), followed by children negative for both respiratory syncytial virus and rhinovirus (36%; adjusted odd ratios, 2.6; 95% confidence interval: 1.3-5.3). Likewise, rhinovirus etiology was associated with more courses of systemic corticosteroids during the follow-up. The main findings were similar in a subset of infants aged <12 months with first wheezing. Conclusions: Children hospitalized for rhinovirus-positive bronchiolitis used long-term asthma controller medication more often than those hospitalized for rhinovirus-negative bronchiolitis during first year after hospitalization. C1 [Bergroth, Eija; Remes, Sami] Kuopio Univ Hosp, Dept Pediat, SF-70210 Kuopio, Finland. [Bergroth, Eija] Cent Hosp Cent Finland, Dept Pediat, Keskussairaalantie 19, Jyvaskyla 40620, Finland. [Aakula, Matilda; Jartti, Tuomas] Turku Univ Hosp, Dept Pediat, FIN-20520 Turku, Finland. [Korppi, Matti; Kivisto, Juho E.] Tampere Univ, Ctr Child Hlth Res, FIN-33101 Tampere, Finland. [Korppi, Matti; Kivisto, Juho E.] Tampere Univ Hosp, Tampere, Finland. [Kivisto, Juho E.] Tampere Univ Hosp, Allergy Ctr, Tampere, Finland. [Kivisto, Juho E.] Karolinska Inst, Inst Environm Med, S-10401 Stockholm, Sweden. [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. [Camargo, Carlos A., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA USA. RP Bergroth, E (reprint author), Cent Hosp Cent Finland, Dept Pediat, Keskussairaalantie 19, Jyvaskyla 40620, Finland. EM bergroth@student.uef.fi FU Kerttu and Kalle Viik Foundation (Kuopio, Finland); EVO; Academy of Finland (Helsinki, Finland); Finnish Medical Foundation (Helsinki, Finland); Sigrid Juselius Foundation (Helsinki, Finland); Foundation for pediatric research (Helsinki, Finland) FX E.B. received funding from Kerttu and Kalle Viik Foundation (Kuopio, Finland) and received EVO funding. T.J. received funding from the Academy of Finland, the Finnish Medical Foundation, the Sigrid Juselius Foundation and the Foundation for pediatric research (all in Helsinki, Finland). The authors have no other funding or conflicts of interest to disclose. NR 46 TC 3 Z9 3 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0891-3668 EI 1532-0987 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD APR PY 2016 VL 35 IS 4 BP 363 EP 368 DI 10.1097/INF.0000000000001017 PG 6 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA DH5PL UT WOS:000372843600001 PM 26658529 ER PT J AU Eberlin, KR Kobraei, EM Upton, J AF Eberlin, Kyle R. Kobraei, Edward M. Upton, Joseph, III TI Reply: Salvage Palmar Fasciectomy following Initial Treatment with Collagenase Clostridium Histolyticum SO PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Letter C1 [Eberlin, Kyle R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Plast Surg, Boston, MA USA. [Kobraei, Edward M.; Upton, Joseph, III] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Plast Surg, Boston, MA 02215 USA. RP Eberlin, KR (reprint author), Massachusetts Gen Hosp, Div Plast & Reconstruct Surg, Wang Ambulatory Care Ctr 435,15 Parkman St, Boston, MA 02114 USA. EM keberlin@mgh.harvard.edu NR 2 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 0032-1052 EI 1529-4242 J9 PLAST RECONSTR SURG JI Plast. Reconstr. Surg. PD APR PY 2016 VL 137 IS 4 BP 761E EP 762E DI 10.1097/PRS.0000000000001997 PG 2 WC Surgery SC Surgery GA DI8XD UT WOS:000373784800001 PM 26741890 ER PT J AU Mayer, VL McDonough, K Seligman, H Mitra, N Long, JA AF Mayer, Victoria L. McDonough, Kevin Seligman, Hilary Mitra, Nandita Long, Judith A. TI Food insecurity, coping strategies and glucose control in low-income patients with diabetes SO PUBLIC HEALTH NUTRITION LA English DT Article DE Diabetes; Nutrition; Vulnerable populations; Socio-economic factors; Disease management ID NUTRITION ASSISTANCE PROGRAM; OF-THE-LITERATURE; GLYCEMIC CONTROL; DIETARY QUALITY; ADULTS; HEALTH; MANAGEMENT; OBESITY; PARTICIPANTS; SUFFICIENCY AB Objective: To examine the relationship between food insecurity and coping strategies (actions taken to manage economic stress) hypothesized to worsen glucose control in patients with diabetes. Design: Using a cross-sectional telephone survey and clinical data, we compared food-insecure and food-secure individuals in their use of coping strategies. Using logistic regression models, we then examined the association between poor glucose control (glycated Hb, HbA1c >= 8.0 %), food insecurity and coping strategies. Setting: An urban medical centre, between June and December 2013. Subjects: Four hundred and seven adults likely to be low income (receiving Medicaid or uninsured and/or residing in a zip code with >30 % of the population below the federal poverty level) with type 2 diabetes. Results: Of respondents, 40.5 % were food insecure. A significantly higher percentage of the food-insecure group reported use of most examined coping strategies, including foregone medical care, participation in the Supplemental Nutrition Assistance Program (SNAP)) and use of emergency food programmes. Food insecurity was associated with poor glucose control (OR=2.23; 95 % CI 1.22, 4.10); coping strategies that were more common among the food insecure were not associated with poor glucose control. Among the food insecure, receipt of SNAP was associated with lower risk of poor glucose control (OR=0.27; 95 % CI 0.09, 0.80). Conclusions: While food insecurity was associated with poor glucose control, most examined coping strategies did not explain this relationship. However, receipt of SNAP among food-insecure individuals was associated with better diabetes control, suggesting that such programmes may play a role in improving health. C1 [Mayer, Victoria L.] Icahn Sch Med Mt Sinai, Dept Populat Hlth Sci & Policy, 1 Gustave L Levy Pl,Box 1077, New York, NY 10029 USA. [Mayer, Victoria L.] Icahn Sch Med Mt Sinai, Dept Med, Div Gen Internal Med, New York, NY 10029 USA. [McDonough, Kevin] Univ Penn, Sch Arts & Sci, Philadelphia, PA 19104 USA. [Seligman, Hilary] Univ Calif San Francisco, Div Gen Internal Med, San Francisco, CA 94143 USA. [Mitra, Nandita] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Mitra, Nandita; Long, Judith A.] Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. [Long, Judith A.] Univ Penn, Dept Med, Perelman Sch Med, Div Gen Internal Med, Philadelphia, PA 19104 USA. [Long, Judith A.] Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. RP Mayer, VL (reprint author), Icahn Sch Med Mt Sinai, Dept Populat Hlth Sci & Policy, 1 Gustave L Levy Pl,Box 1077, New York, NY 10029 USA.; Mayer, VL (reprint author), Icahn Sch Med Mt Sinai, Dept Med, Div Gen Internal Med, New York, NY 10029 USA. EM victoria.mayer@mountsinai.org FU Division of General Internal Medicine Matt Slap Award from the Perelman School of Medicine at the University of Pennsylvania; National Institutes of Health Institutional Training Grant [5-T32-HP-100296-20-00]; Empire Clinical Research Investigator Program FX V.L.M. was supported with funding from the Division of General Internal Medicine Matt Slap Award from the Perelman School of Medicine at the University of Pennsylvania and the National Institutes of Health Institutional Training Grant 5-T32-HP-100296-20-00. She is currently supported by the Empire Clinical Research Investigator Program (Investigator Dr Carol Horowitz). The funders had no role in the design, analysis, or writing of this article.Principal NR 52 TC 0 Z9 0 U1 3 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 APR PY 2016 VL 19 IS 6 BP 1103 EP 1111 DI 10.1017/S1368980015002323 PG 9 WC Public, Environmental & Occupational Health; Nutrition & Dietetics SC Public, Environmental & Occupational Health; Nutrition & Dietetics GA DI7US UT WOS:000373708100019 PM 26328922 ER PT J AU Jensen, M Murphy, V Mattes, J Gibson, P Carmargo, C AF Jensen, M. Murphy, V Mattes, J. Gibson, P. Carmargo, Jr C. TI MATERNAL SERUM VITAMIN D LEVELS >= 75 NMOL/L DURING PREGNANCY ARE ASSOCIATED WITH FEWER ADVERSE RESPIRATORY OUTCOMES IN INFANTS AT 12 MONTHS OF AGE SO RESPIROLOGY LA English DT Meeting Abstract C1 [Jensen, M.; Murphy, V; Mattes, J.; Gibson, P.] Univ Newcastle, Ctr Asthma & Resp Dis, Callaghan, NSW 2308, Australia. [Carmargo, Jr C.] Massachusetts Gen Hosp, Emergency Med Network, Boston, MA 02114 USA. [Gibson, P.] John Hunter Hosp, Dept Resp & Sleep Med, New Lambton Hts, NSW, Australia. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1323-7799 EI 1440-1843 J9 RESPIROLOGY JI Respirology PD APR PY 2016 VL 21 SU 2 SI SI MA TO 061 BP 51 EP 51 PG 1 WC Respiratory System SC Respiratory System GA DH9FS UT WOS:000373102400103 ER PT J AU Chan, A Stewart, A Foster, J Mitchell, E Camargo, C Harrison, J AF Chan, A. Stewart, A. Foster, J. Mitchell, E. Camargo, Jr C. Harrison, J. TI ETHNICITY AND AGE AT DIAGNOSIS PREDICT PREVENTER ADHERENCE IN CHILDREN WITH ASTHMA SO RESPIROLOGY LA English DT Meeting Abstract C1 [Chan, A.; Harrison, J.] Univ Auckland, Sch Pharm, Fac Med & Hlth Sci, Auckland 1, New Zealand. [Stewart, A.] Univ Auckland, Fac Med & Hlth Sci, Sch Populat Hlth, Epidemiol & Biostat, Auckland 1, New Zealand. [Foster, J.] Univ Sydney, Woolcock Inst Med Res, Sydney, NSW 2006, Australia. [Mitchell, E.] Univ Auckland, Sch Med, Fac Med & Hlth Sci, Dept Pediat Child & Youth Hlth, Auckland, New Zealand. [Camargo, Jr C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1323-7799 EI 1440-1843 J9 RESPIROLOGY JI Respirology PD APR PY 2016 VL 21 SU 2 SI SI MA TO 140 BP 92 EP 92 PG 1 WC Respiratory System SC Respiratory System GA DH9FS UT WOS:000373102400186 ER PT J AU Stone, WS Mesholam-Gately, RI Giuliano, AJ Woodberry, KA Addington, J Bearden, CE Cadenhead, KS Cannon, TD Cornblatt, BA Mathalon, DH McGlashan, TH Perkins, DO Tsuang, MT Walker, EF Woods, SW McCarley, RW Heinssen, R Green, MF Nuechterlein, K Seidman, LJ AF Stone, William S. Mesholam-Gately, Raquelle I. Giuliano, Anthony J. Woodberry, Kristen A. Addington, Jean Bearden, Carrie E. Cadenhead, Kristin S. Cannon, Tyrone D. Cornblatt, Barbara A. Mathalon, Daniel H. McGlashan, Thomas H. Perkins, Diana O. Tsuang, Ming T. Walker, Elaine F. Woods, Scott W. McCarley, Robert W. Heinssen, Robert Green, Michael F. Nuechterlein, Keith Seidman, Larry J. TI Healthy adolescent performance on the MATRICS Consensus Cognitive Battery (MCCB): Developmental data from two samples of volunteers SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Healthy controls; Adolescents; MATRICS Consensus Cognitive Battery; Psychosis; Clinical high risk; Schizophrenia; Cognition ID IQ-ADJUSTED NORMS; ONSET SCHIZOPHRENIA; NEUROCOGNITIVE BATTERY; SPECTRUM DISORDERS; CHILDHOOD-ONSET; ADULT-ONSET; FOLLOW-UP; PSYCHOSIS; MEMORY; STANDARDIZATION AB The MATRICS Consensus Cognitive Battery (MCCB) fills a significant need for a standardized battery of cognitive tests to use in clinical trials for schizophrenia in adults aged 20-59. A need remains, however, to develop norms for younger individuals, who also show elevated risks for schizophrenia. Toward this end, we assessed performance in healthy adolescents. Baseline MCCB, reading and IQ data were obtained from healthy controls (ages 12-19) participating in two concurrent NIMH-funded studies: North American Prodromal Longitudinal Study phase 2 (NAPLS-2; n = 126) and Boston Center for Intervention Development and Applied Research (CIDAR; n = 13). All MCCB tests were administered except the Managing Emotions subtest from the Mayer-Salovey-Caruso Emotional Intelligence Test. Data were collected from 8 sites across North America. MCCB scores were presented in four 2-year age cohorts as T-scores for each test and cognitive domain, and analyzed for effects of age and sex. Due to IQ differences between age-grouped subsamples, IQ served as a covariate in analyses. Overall and sex-based raw scores for individual MCCB tests are presented for each age-based cohort. Adolescents generally showed improvement with age in most MCCB cognitive domains, with the clearest linear trends in Attention/Vigilance and Working Memory. These control data show that healthy adolescence is a dynamic period for cognitive development that is marked by substantial improvement in MCCB performance through the 12-19 age range. They also provide healthy comparison raw scores to facilitate clinical evaluations of adolescents, including those at risk for developing psychiatric disorders such as schizophrenia-related conditions. (C) 2016 Elsevier B.V. All rights reserved. C1 [Stone, William S.; Mesholam-Gately, Raquelle I.; Woodberry, Kristen A.; Seidman, Larry J.] Massachusetts Mental Hlth Ctr, 75 Fenwood Rd, Boston, MA 02115 USA. [Stone, William S.; Mesholam-Gately, Raquelle I.; Woodberry, Kristen A.; Seidman, Larry J.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA USA. [Giuliano, Anthony J.] Worcester Recovery Ctr & Hosp, Dept Psychol, Worcester, MA USA. [Addington, Jean] Univ Calgary, Hotchkiss Brain Inst, Dept Psychiat, Calgary, AB T2N 1N4, Canada. [Bearden, Carrie E.] Univ Calif Los Angeles, Dept Psychiat & Biobehavioral Sci & Psychol, Los Angeles, CA USA. [Cadenhead, Kristin S.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Cannon, Tyrone D.] Yale Univ, Dept Psychol, New Haven, CT USA. [Cannon, Tyrone D.] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. [Cornblatt, Barbara A.] Zucker Hillside Hosp, Dept Psychiat, Long Isl City, NY USA. [Mathalon, Daniel H.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [McGlashan, Thomas H.; Woods, Scott W.] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. [Perkins, Diana O.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Tsuang, Ming T.] Univ Calif San Diego, Dept Psychiat, Ctr Behav Gen, Inst Genom Med, La Jolla, CA 92093 USA. [Walker, Elaine F.] Emory Univ, Dept Psychiat & Psychol, Atlanta, GA 30322 USA. [McCarley, Robert W.] Harvard Univ, Sch Med, Brockton VA Med Ctr, Dept Psychiat, Brockton, MA 02401 USA. [Heinssen, Robert] NIMH, Div Adult Translat Res & Treatment Dev, Bethesda, MD 20892 USA. [Green, Michael F.] Univ Calif Los Angeles, Geffen Sch Med, Dept Psychiat & Biobehavioral Sci, Los Angeles, CA USA. [Green, Michael F.] VA Greater Angeles Healthcare Syst, Los Angeles, CA USA. [Nuechterlein, Keith] Univ Calif Los Angeles, David Geffen Sch Med, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90095 USA. [Seidman, Larry J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA USA. RP Stone, WS (reprint author), Massachusetts Mental Hlth Ctr, 75 Fenwood Rd, Boston, MA 02115 USA. EM wstone@bidmc.Harvard.edu FU National Institute of Mental Health [U01MH0818902, U01MH081984, P50MH066286, U01MH082022, U01MH081857, U01MH082004, U01MH081928, U01MH081988, U01MH066160, P50MH080272]; Commonwealth Research Center of the Massachusetts Department of Mental Health [SCDMH82101008006]; Harvard Catalyst; Harvard Clinical and Translational Science Center Harvard Catalyst Clinical Research Center at Beth Israel Deaconess Medical Center; Harvard University Clinical and Translational Science Center Research Unit (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health) [1UL1 TR001102-01] FX National Institute of Mental Health grants (U01MH0818902 to T.D.C., U01MH081984 to J.M.A., P50MH066286 to C.E.B., U01MH082022 to K.S.C., U01MH081857 to B.A.C., U01MH082004 to D.O.P., U01MH081928 to L.J.S., U01MH081988 to E.F.W., U01MH066160 to S.W.W., P50MH080272 to R.W.M.) and the Commonwealth Research Center of the Massachusetts Department of Mental Health (SCDMH82101008006 to L.J.S.). This work was also conducted with support from Harvard Catalyst, The Harvard Clinical and Translational Science Center Harvard Catalyst Clinical Research Center at Beth Israel Deaconess Medical Center, A Harvard University Clinical and Translational Science Center Research Unit (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award 1UL1 TR001102-01 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 60 TC 1 Z9 1 U1 4 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 EI 1573-2509 J9 SCHIZOPHR RES JI Schizophr. Res. PD APR PY 2016 VL 172 IS 1-3 BP 106 EP 113 DI 10.1016/j.schres.2016.02.003 PG 8 WC Psychiatry SC Psychiatry GA DI5GY UT WOS:000373528100017 PM 26896388 ER PT J AU Pierre, JM Gandal, M Son, M AF Pierre, Joseph M. Gandal, Michael Son, Maya TI Cannabis-induced psychosis associated with high potency "wax dabs" SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Marijuana; Tetrahydrocannabinol; Cannabis; Cannabis oil; Cannabis wax; Cannabis-induced psychosis, catatonia ID MARIJUANA; DANGERS; RISK AB With mounting evidence that the risk of cannabis-induced psychosis may be related to both dose and potency of tetrahydrocannbinol (THC), increasing reports of psychosis associated with cannabinoids containing greater amounts of THC are anticipated. We report two cases of emergent psychosis after using a concentrated THC extract known as cannabis "wax," "oil," or "dabs" raising serious concerns about its psychotic liability. Although "dabbing" with cannabis wax is becoming increasingly popular in the US for both recreational and "medicinal" intentions, our cases raise serious concerns about its psychotic liability and highlight the importance of understanding this risk by physicians recommending cannabinoids for purported medicinal purposes. Published by Elsevier B.V. C1 [Pierre, Joseph M.; Gandal, Michael] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Pierre, Joseph M.] VA Greater Los Angeles Healthcare Syst, Dept Vet Affairs, Los Angeles, CA USA. [Son, Maya] Univ Vermont, Coll Med, Burlington, VT USA. RP Pierre, JM (reprint author), 11301 Wilshire Blvd,Bldg 210 Room15, Los Angeles, CA 90073 USA. EM joseph.pierre2@va.gov NR 10 TC 2 Z9 2 U1 4 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 EI 1573-2509 J9 SCHIZOPHR RES JI Schizophr. Res. PD APR PY 2016 VL 172 IS 1-3 BP 211 EP 212 DI 10.1016/j.schres.2016.01.056 PG 2 WC Psychiatry SC Psychiatry GA DI5GY UT WOS:000373528100034 PM 26876313 ER PT J AU Jain, IH Zazzeron, L Goli, R Alexa, K Schatzman-Bone, S Dhillon, H Goldberger, O Peng, J Shalem, O Sanjana, NE Zhang, F Goessling, W Zapol, WM Mootha, VK AF Jain, Isha H. Zazzeron, Luca Goli, Rahul Alexa, Kristen Schatzman-Bone, Stephanie Dhillon, Harveen Goldberger, Olga Peng, Jun Shalem, Ophir Sanjana, Neville E. Zhang, Feng Goessling, Wolfram Zapol, Warren M. Mootha, Vamsi K. TI Hypoxia as a therapy for mitochondrial disease SO SCIENCE LA English DT Article ID TUMOR-SUPPRESSOR PROTEIN; HIPPEL-LINDAU PROTEIN; COMPLEX-I DEFICIENCY; INDUCIBLE FACTOR; OXYGEN-CONSUMPTION; LEIGH-SYNDROME; HUMAN-CELLS; INHIBITION; ADAPTATION; DISORDERS AB Defects in the mitochondrial respiratory chain (RC) underlie a spectrum of human conditions, ranging from devastating inborn errors of metabolism to aging. We performed a genome-wide Cas9-mediated screen to identify factors that are protective during RC inhibition. Our results highlight the hypoxia response, an endogenous program evolved to adapt to limited oxygen availability. Genetic or small-molecule activation of the hypoxia response is protective against mitochondrial toxicity in cultured cells and zebrafish models. Chronic hypoxia leads to a marked improvement in survival, body weight, body temperature, behavior, neuropathology, and disease biomarkers in a genetic mouse model of Leigh syndrome, the most common pediatric manifestation of mitochondrial disease. Further preclinical studies are required to assess whether hypoxic exposure can be developed into a safe and effective treatment for human diseases associated with mitochondrial dysfunction. C1 [Jain, Isha H.; Goli, Rahul; Dhillon, Harveen; Goldberger, Olga; Peng, Jun; Mootha, Vamsi K.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Jain, Isha H.; Goli, Rahul; Dhillon, Harveen; Goldberger, Olga; Peng, Jun; Mootha, Vamsi K.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. [Jain, Isha H.; Goli, Rahul; Dhillon, Harveen; Goldberger, Olga; Peng, Jun; Mootha, Vamsi K.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA USA. [Jain, Isha H.; Goli, Rahul; Dhillon, Harveen; Goldberger, Olga; Peng, Jun; Shalem, Ophir; Sanjana, Neville E.; Zhang, Feng; Goessling, Wolfram; Mootha, Vamsi K.] Broad Inst Harvard & MIT, Cambridge, MA USA. [Zazzeron, Luca; Zapol, Warren M.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Alexa, Kristen; Schatzman-Bone, Stephanie; Goessling, Wolfram] Harvard Univ, Brigham & Womens Hosp, Div Genet, Sch Med, Boston, MA 02115 USA. [Shalem, Ophir; Sanjana, Neville E.; Zhang, Feng] McGovern Inst Brain Res, Cambridge, MA USA. [Shalem, Ophir; Sanjana, Neville E.; Zhang, Feng] MIT, Dept Brain & Cognit Sci, E25-618, Cambridge, MA 02139 USA. [Shalem, Ophir; Sanjana, Neville E.; Zhang, Feng] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Goessling, Wolfram] Dana Farber Canc Inst, Gastrointestinal Canc Ctr, Boston, MA 02115 USA. [Goessling, Wolfram] Harvard Stem Cell Inst, Cambridge, MA USA. RP Mootha, VK (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA.; Mootha, VK (reprint author), Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA.; Mootha, VK (reprint author), Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA USA.; Mootha, VK (reprint author), Broad Inst Harvard & MIT, Cambridge, MA USA. EM vamsi@hms.harvard.edu OI Goessling, Wolfram/0000-0001-9972-1569 FU Department of Energy Computational Science Graduate Fellowship Program [DE-FG02-97ER25308]; National Institutes of Health (NIH) through a NHGRI [K99-HG008171]; Simons Center for the Social Brain at the Massachusetts Institute of Technology; NIH through NIMH [5DP1-MH100706, 1R01-MH110049]; NIDDK [5R01DK097768-03]; NSF; New York Stem Cell; Simons, Paul G. Allen Family Foundation; Vallee Foundation; NIH [R01DK090311, R24OD017870] FX We thank W. Kaelin Jr. and members of the Mootha lab for valuable feedback; R. Sharma, M. Ferrari, A. Rogers, and the MGH animal facility for assistance with experiments; and F. van Eeden for Tg(phd3::EGFP) zebrafish. I.H.J. is supported by the Department of Energy Computational Science Graduate Fellowship Program (grant DE-FG02-97ER25308). N.E.S. is supported by the National Institutes of Health (NIH) through a NHGRI Pathway to Independence Award (K99-HG008171) and a postdoctoral fellowship from the Simons Center for the Social Brain at the Massachusetts Institute of Technology. F. Z. is supported by NIH through NIMH (grants 5DP1-MH100706 and 1R01-MH110049) and NIDDK (grant 5R01DK097768-03); a Waterman Award from NSF; the New York Stem Cell, Simons, Paul G. Allen Family, and Vallee Foundations; and B. Metcalfe. F. Z. is a New York Stem Cell Foundation Robertson Investigator. W. G. is supported by NIH grants R01DK090311 and R24OD017870 and is a Pew Scholar in the Biomedical Sciences. This work was supported by a gift from the Marriott Mitochondrial Disorders Research Fund (V. K. M.) and a gift in memory of Daniel Garland (V. K. M.). V. K. M. is an Investigator of the Howard Hughes Medical Institute. V. K. M. is a founder of and paid scientific advisor for Raze Therapeutics. W. G. is a paid consultant for FATE Therapeutics. F. Z. is a founder of and a scientific advisor for Editas Medicine and a scientific advisor for Horizon Discovery. V. K. M., I. H. J., L. Z., and W. M. Z. are listed as inventors on a patent application filed by Massachusetts General Hospital related to technology reported in this paper on the use of hypoxia and the hypoxia response in the treatment of mitochondrial dysfunction. F.Z., O.S., and N.E.S. are listed as inventors on a patent application (PCT/US2013/074800) filed by The Broad Institute/MIT related to the genome-scale CRISPR knockout screening technology used in this study. The CRISPR knockout library is available through a Uniform Biological Materials Transfer Agreement from Addgene. The Ndufs4 KO mice were a kind gift of R. Palmiter and are available under a materials transfer agreement with the University of Washington, Seattle. NR 40 TC 18 Z9 19 U1 16 U2 45 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD APR 1 PY 2016 VL 352 IS 6281 BP 54 EP 61 DI 10.1126/science.aad9642 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH8JP UT WOS:000373039600033 PM 26917594 ER PT J AU Robinson, TM O'Donnell, PV Fuchs, EJ Luznik, L AF Robinson, Tara M. O'Donnell, Paul V. Fuchs, Ephraim J. Luznik, Leo TI Haploidentical bone marrow and stem cell transplantation: experience with post-transplantation cyclophosphamide SO SEMINARS IN HEMATOLOGY LA English DT Article DE Haploidentical; Bone marrow transplant; Post-transplant cyclophosphamide; GVHD prophylaxis ID TOTAL-BODY IRRADIATION; HLA-IDENTICAL SIBLINGS; UNRELATED DONOR TRANSPLANTATION; ACUTE MYELOID-LEUKEMIA; VERSUS-HOST-DISEASE; HEMATOLOGIC MALIGNANCIES; HIGH-RISK; PHASE-II; ALDEHYDE DEHYDROGENASE; PROGENITOR CELLS AB Allogeneic blood or bone marrow transplantation (BMT) is a potentially curative therapy for high-risk hematologic malignancies not curable by standard chemotherapy, but the procedure is limited by the availability of human leukocyte antigen-matched donors for many patients, as well as toxicities including graft-versus-host disease (GVHD). Our group has developed the use of high-dose post-transplantation cyclophosphamide (PTCy) to selectively remove alloreactive T cells without compromising engraftment. This protocol has allowed for successful transplantation of human leukocyte antigen (HLA)-haploidentical (haplo) grafts, thus expanding the donor pool for the many patients who would not otherwise be a candidate for this life-saving procedure. In this review we will summarize the data that led to the development of PTCy, then focus on the outcomes of haploBMT trials with PTCy across different transplant platforms for patients with malignant hematologic diseases, and finally we will discuss emerging evidence that suggests equivalency of haploBMT with PTCy compared with more traditional transplants. (C) 2016 Elsevier Inc. All rights reserved. C1 [Robinson, Tara M.; Fuchs, Ephraim J.; Luznik, Leo] Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Robinson, Tara M.; Fuchs, Ephraim J.; Luznik, Leo] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [O'Donnell, Paul V.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. RP Luznik, L (reprint author), 1650 Orleans St, Baltimore, MD 21287 USA. EM luznile@jhmi.edu FU NCI NIH HHS [P01 CA015396] NR 60 TC 11 Z9 11 U1 0 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 0037-1963 EI 1532-8686 J9 SEMIN HEMATOL JI Semin. Hematol. PD APR PY 2016 VL 53 IS 2 BP 90 EP 97 DI 10.1053/j.seminhematol.2016.01.005 PG 8 WC Hematology SC Hematology GA DI5QU UT WOS:000373554500007 PM 27000732 ER PT J AU Kekre, N Antin, JH AF Kekre, Natasha Antin, Joseph H. TI Cord blood versus haploidentical stem cell transplantation for hematological malignancies SO SEMINARS IN HEMATOLOGY LA English DT Article DE Umbilical cord blood; Haploidentical; Transplantation ID BONE-MARROW-TRANSPLANTATION; ACUTE MYELOID-LEUKEMIA; ALTERNATIVE DONOR TRANSPLANTATION; 1ST COMPLETE REMISSION; UNRELATED DONORS; HIGH-RISK; POSTTRANSPLANTATION CYCLOPHOSPHAMIDE; ADULTS; OUTCOMES; GRAFTS AB Umbilical cord blood (UCB) and haploidentical donor stem cell sources represent common alternative donor strategies used when a matched sibling donor (MRD) or matched unrelated donor (MUD) is not available for hematopoietic stem cell transplantation (HSCT). Both donor sources require less stringent human leukocyte antigen (HLA) matching and thereby increase the donor pool for patients without a complete HLA-matched donor. Although a randomized trial comparing these donor sources is ongoing, currently available comparisons rely on observational data and small phase II trials. In hematologic malignancies, both donor sources offer the chance of eradicating disease, albeit with different results for engraftment time, graft failure, graft-versus-host disease (GVHD), transplant-related mortality (TRM), and relapse risk. This review focuses on comparing those outcomes and providing clinicians with evidence to help guide the decision between these alternative donor sources. (C) 2016 Elsevier Inc. All rights reserved. C1 [Kekre, Natasha] Ottawa Hosp, Div Hematol, Ottawa, ON, Canada. [Antin, Joseph H.] Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA 02115 USA. RP Antin, JH (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM jantin@partners.org NR 37 TC 2 Z9 2 U1 1 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 0037-1963 EI 1532-8686 J9 SEMIN HEMATOL JI Semin. Hematol. PD APR PY 2016 VL 53 IS 2 BP 98 EP 102 DI 10.1053/j.seminhematol.2016.01.007 PG 5 WC Hematology SC Hematology GA DI5QU UT WOS:000373554500008 PM 27000733 ER PT J AU Stowkowy, J Liu, L Cadenhead, KS Cannon, TD Cornblatt, BA McGlashan, TH Perkins, DO Seidman, LJ Tsuang, MT Walker, EF Woods, SW Bearden, CE Mathalon, DH Addington, J AF Stowkowy, Jacqueline Liu, Lu Cadenhead, Kristin S. Cannon, Tyrone D. Cornblatt, Barbara A. McGlashan, Thomas H. Perkins, Diana O. Seidman, Larry J. Tsuang, Ming T. Walker, Elaine F. Woods, Scott W. Bearden, Carrie E. Mathalon, Daniel H. Addington, Jean TI Early traumatic experiences, perceived discrimination and conversion to psychosis in those at clinical high risk for psychosis SO SOCIAL PSYCHIATRY AND PSYCHIATRIC EPIDEMIOLOGY LA English DT Article DE Clinical high risk; Psychosis; Trauma; Perceived discrimination; Prodrome; Risk ID ULTRA-HIGH-RISK; CHILDHOOD TRAUMA; PRODROMAL-SYMPTOMS; CANNABIS USE; SCHIZOPHRENIA; INDIVIDUALS; HISTORY; COHORT; METAANALYSIS; NETHERLANDS AB There is evidence to suggest that both early traumatic experiences and perceived discrimination are associated with later onset of psychosis. Less is known about the impact these two factors may have on conversion to psychosis in those who are at clinical high risk (CHR) of developing psychosis. The purpose of this study was to determine if trauma and perceived discrimination were predictors of conversion to psychosis. The sample consisted of 764 individuals who were at CHR of developing psychosis and 280 healthy controls. All participants were assessed on past trauma, bullying and perceived discrimination. Individuals at CHR reported significantly more trauma, bullying and perceived discrimination than healthy controls. Only perceived discrimination was a predictor of later conversion to psychosis. Given that CHR individuals are reporting increased rates of trauma and perceived discrimination, these should be routinely assessed, with the possibility of offering interventions aimed at ameliorating the impact of past traumas as well as improving self-esteem and coping strategies in an attempt to reduce perceived discrimination. C1 [Stowkowy, Jacqueline; Liu, Lu; Addington, Jean] Univ Calgary, Mathison Ctr Mental Hlth Res & Educ, Dept Psychiat, 3280 Hosp Dr NW, Calgary, AB T2N 4Z6, Canada. [Cadenhead, Kristin S.; Tsuang, Ming T.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Cornblatt, Barbara A.] Zucker Hillside Hosp, Dept Psychiat, Long Isl City, NY USA. [Cannon, Tyrone D.; McGlashan, Thomas H.; Woods, Scott W.] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. [Perkins, Diana O.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Seidman, Larry J.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Psychiat, Boston, MA 02215 USA. [Seidman, Larry J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Walker, Elaine F.] Emory Univ, Dept Psychol, Atlanta, GA 30322 USA. [Walker, Elaine F.] Emory Univ, Dept Psychiat, Atlanta, GA 30322 USA. [Bearden, Carrie E.] Univ Calif Los Angeles, Dept Psychiat & Psychol, Los Angeles, CA USA. [Bearden, Carrie E.] Univ Calif Los Angeles, Dept Biobehav Sci, Los Angeles, CA USA. [Mathalon, Daniel H.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. RP Stowkowy, J (reprint author), Univ Calgary, Mathison Ctr Mental Hlth Res & Educ, Dept Psychiat, 3280 Hosp Dr NW, Calgary, AB T2N 4Z6, Canada. EM stowkowy@ucalgary.ca; jmadding@ucalgary.ca FU National Institute of Mental Health [U01MH081984, U01 MH081928, P50 MH080272, R01 MH60720, U01 MH082022, K24 MH76191, U01MH081902, U01MH082004-01A1, U01MH081988, U01MH082022, UO1 MH081857-05]; National Institute of Mental Health (Commonwealth of Massachusetts) [SCDMH82101008006] FX This study was supported by the National Institute of Mental Health (Grant U01MH081984 to Dr Addington; Grants U01 MH081928; P50 MH080272; Commonwealth of Massachusetts SCDMH82101008006 to Dr Seidman; Grants R01 MH60720, U01 MH082022 and K24 MH76191 to Dr Cadenhead; Grant U01MH081902 to Dr Cannon; Grant U01MH082004-01A1 to Dr Perkins; Grant U01MH081988 to Dr Walker; Grant U01MH082022 to Dr Woods; and UO1 MH081857-05 Grant to Dr Cornblatt. The NIMH had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. NR 30 TC 3 Z9 3 U1 5 U2 11 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0933-7954 EI 1433-9285 J9 SOC PSYCH PSYCH EPID JI Soc. Psychiatry Psychiatr. Epidemiol. PD APR PY 2016 VL 51 IS 4 BP 497 EP 503 DI 10.1007/s00127-016-1182-y PG 7 WC Psychiatry SC Psychiatry GA DI7UN UT WOS:000373707600003 PM 26851943 ER PT J AU Guo, LN Nagle, KF Heaton, JT AF Guo, Liana Nagle, Kathleen F. Heaton, James T. TI Generating tonal distinctions in Mandarin Chinese using an electrolarynx with preprogrammed tone patterns SO SPEECH COMMUNICATION LA English DT Article DE Electrolarynx; Mandarin Chinese; Tonal control; Speech intelligibility ID NORMAL LARYNGEAL; PERCEPTIONS; ESOPHAGEAL; SPEECH; DESIGN AB An electrolarynx (EL) is a valuable rehabilitative option for individuals who have undergone laryngectomy, but current monotone ELs do not support controlled variations in fundamental frequency for producing tonal languages. The present study examined the production and perception of Mandarin Chinese using a customized hand-held EL driven by computer software to generate tonal distinctions (tonal EL). Four native Mandarin speakers were trained to articulate their speech coincidentally with preprogrammed tonal patterns in order to produce mono and di-syllabic words with a monotone EL and tonal EL. Three native Mandarin speakers later transcribed and rated the speech samples for intelligibility and acceptability. Results indicated that words produced using the tonal EL were significantly more intelligible and acceptable than those produced using the monotone EL. (C) 2016 Elsevier B.V. All rights reserved. C1 [Guo, Liana; Heaton, James T.] Massachusetts Gen Hosp, Inst Hlth Profess, 36 1st Ave, Boston, MA 02129 USA. [Guo, Liana; Nagle, Kathleen F.; Heaton, James T.] Massachusetts Gen Hosp, Ctr Laryngeal Surg & Voice Rehabil, 1 Bowdoin Sq,11th Floor, Boston, MA 02114 USA. RP Heaton, JT (reprint author), Massachusetts Gen Hosp, Ctr Laryngeal Surg & Voice Rehabil, 1 Bowdoin Sq,11th Floor, Boston, MA 02114 USA. EM james.heaton@mgh.harvard.edu OI Nagle, Kathleen/0000-0001-8916-3639 FU Christopher Norman Education Fund at the MGH Institute of Health Professions [R42DC011212-02] FX We would like to thank Mark Robertson at Griffin Laboratories for providing the modified TruTone (R) EL used in the study. This project was supported by a grant from the Christopher Norman Education Fund at the MGH Institute of Health Professions and R42DC011212-02 to Mark Robertson and James Heaton, Multiple PI. We would also like to acknowledge Anthony Guarino, PhD of the Massachusetts General Hospital Institute of Health Professions for help with statistical analysis, and Jie (Kingsley) Yang, PhD for invaluable assistance as a native speaker of Mandarin. NR 15 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-6393 EI 1872-7182 J9 SPEECH COMMUN JI Speech Commun. PD APR PY 2016 VL 78 BP 34 EP 41 DI 10.1016/j.specom.2016.01.002 PG 8 WC Acoustics; Computer Science, Interdisciplinary Applications SC Acoustics; Computer Science GA DI3SR UT WOS:000373419300004 PM 26951783 ER PT J AU Tofler, GH Massarob, J O'Donnell, CJ Wilson, PWF Vasan, RS Sutherland, PA Meigs, JB Levy, D D'Agostino, RB AF Tofler, G. H. Massarob, J. O'Donnell, C. J. Wilson, P. W. F. Vasan, R. S. Sutherland, P. A. Meigs, J. B. Levy, D. D'Agostino, R. B., Sr. TI Plasminogen activator inhibitor and the risk of cardiovascular disease: The Framingham Heart Study SO THROMBOSIS RESEARCH LA English DT Article DE Plasminogen activator inhibitor 1; Tissue plasminogen activator; Myocardial infarction; Cardiovascular diseases ID LEFT-VENTRICULAR HYPERTROPHY; LINKED-IMMUNOSORBENT-ASSAY; CORONARY-ARTERY-DISEASE; MYOCARDIAL-INFARCTION; FIBRINOLYTIC FACTORS; PLASMA; EVENTS; PAI-1; PREDICTION; WOMEN AB Introduction: Although plasminogen activator inhibitor (PAI-1) plays a key regulatory role in fibrinolysis, it has not been clearly shown to independently predict cardiovascular disease (CVD) among individuals without prior CVD. We investigated, in the Framingham Heart Study offspring cohort, whether PAI-1 predicted CVD risk among individuals without prior CVD. Methods: Plasma PAI-1 antigen and tissue plasminogen activator (TPA) antigen were measured in 3203 subjects without prior CVD between 1991 and 1995; average follow-up of 10 years. PAI-1 was remeasured 4 years after baseline, to determine the effect of serial change on risk. Results: PAI-1 levels (mean +/- SD) were 29.1 ng/ml (19.2) versus 22.1 (16.5) for those and without incident CVD; p < 0.001, and TPA levels were 12.0 ng/ml (5.7) versus 9.0 (4.7); p < 0.001. PAI-1 and TPA antigen levels had a strong unadjusted linear relation with incident CVD (p < 0.001). After adjustment for conventional risk factors, the hazard ratios (HRs) for higher quartiles of PAI-1, compared with the lowest, were 1.9, 1.9, 2.6 (linear trend p=0.006), and 1.6, 1.6, 2.9 (p < 0.001) for TPA antigen. The adjusted HRs for increasing quartiles of serial change in PAI-1 at 4 years, compared with the lowest, were 0.9, 0.8, 1.3 (p=0.050). C statistic assessment showed that adding PAI-1 or TPA to conventional risk factors resulted in small increases in discrimination and modest reclassification of risk, which was statistically significant for TPA (net reclassification 6.8%, p = 0.037) but not PAI-1 (4.8%, p = 0.113). Conclusion: PAI-1 and TPA antigen levels are predictive of CVD events after accounting for established risk factors. A serial increase in PAI-1 is associated with a further increase in risk. These findings support the importance of fibrinolytic potential in CVD. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Tofler, G. H.] Univ Sydney, Royal N Shore Hosp, Sydney, NSW 2006, Australia. [Massarob, J.; D'Agostino, R. B., Sr.] Boston Univ, Boston, MA 02215 USA. [O'Donnell, C. J.; Vasan, R. S.; Sutherland, P. A.; Levy, D.] NHLBI, Framingham Heart Study, NIH, Bethesda, MD USA. [O'Donnell, C. J.; Sutherland, P. A.; Levy, D.] NHLBI, Populat Sci Branch, NIH, Bethesda, MD USA. [O'Donnell, C. J.; Meigs, J. B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Wilson, P. W. F.] Emory Univ, Atlanta, GA 30322 USA. RP Tofler, GH (reprint author), Royal N Shore Hosp, Dept Cardiol, St Leonards, NSW 2065, Australia. EM Geoffrey.Tofler@health.nsw.gov.au OI Ramachandran, Vasan/0000-0001-7357-5970 FU AHA [92011960]; National Institutes of Health [RO1-HL-48157]; National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195]; Ducker Bequest and Heart Research Australia FX This work was supported by an AHA Grant-in-Aid (92011960), the National Institutes of Health (RO1-HL-48157), the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195), and the Ducker Bequest and Heart Research Australia. NR 35 TC 5 Z9 5 U1 2 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0049-3848 J9 THROMB RES JI Thromb. Res. PD APR PY 2016 VL 140 BP 30 EP 35 DI 10.1016/j.thromres.2016.02.002 PG 6 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA DI8DX UT WOS:000373732600005 PM 26896607 ER PT J AU Kokoye, Y Ivanov, I Cheng, QF Matafonov, A Dickeson, SK Mason, S Sexton, DJ Renne, T McCrae, K Feener, EP Gailani, D AF Kokoye, Yasin Ivanov, Ivan Cheng, Qiufang Matafonov, Anton Dickeson, S. Kent Mason, Shauna Sexton, Daniel J. Renne, Thomas McCrae, Keith Feener, Edward P. Gailani, David TI A comparison of the effects of factor XII deficiency and prekallikrein deficiency on thrombus formation SO THROMBOSIS RESEARCH LA English DT Article DE Factor XII; Factor XIIa; Prekallikrein; alpha-Kallikrein; Thrombosis ID COAGULATION-FACTOR-XII; MOLECULAR-WEIGHT KININOGEN; HUMAN HAGEMAN-FACTOR; IN-VIVO; CONTACT ACTIVATION; BLOOD-COAGULATION; PLASMA KALLIKREIN; SELECTIVE DEPLETION; MICE; INHIBITION AB Studies with animal models implicate the plasma proteases factor XIIa (FXIIa) and alpha-kallikrein in arterial and venous thrombosis. As congenital deficiencies of factor XII ( FXII) or prekallikrein (PK), the zymogens of FXIIa and alpha-kallikrein respectively, do not cause bleeding disorders, inhibition of these enzymesmay have therapeutic benefit without compromising hemostasis. The relative contributions of FXIIa and alpha-kallikrein to thrombosis in animal models are not clear. We compared mice lacking FXII or PK to wild type mice in established models of arterial thrombosis. Wild type mice developed carotid artery occlusion when the vessel was exposed to a 3.5% solution of ferric chloride (FeCl3). FXII-deficient mice were resistant to occlusion at 5% FeCl3 and partially resistant at 10% FeCl3. PK-deficient mice were resistant at 3.5% FeCl3 and partially resistant at 5% FeCl3. Mice lacking high molecular weight kininogen, a cofactor for PK activation and activity, were also partially resistant to thrombosis at 5% FeCl3. Induction of carotid artery thrombosis with Rose Bengal was delayed in FXII-deficient mice compared to wild type or PK-deficient animals. In human plasma supplemented with silica, DNA or collagen to induce contact activation, an antibody to the FXIIa active site was more effective at preventing thrombin generation than an antibody to the alpha-kallikrein active site. Similarly, the FXIIa antibody was more effective at reducing fibrin formation in human blood flowing through collagen coated-tubes. The findings suggest that inhibitors of FXIIa will have more potent anti-thrombotic effects than inhibitors of alpha-kallikrein. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Kokoye, Yasin; Ivanov, Ivan; Cheng, Qiufang; Matafonov, Anton; Dickeson, S. Kent; Gailani, David] Vanderbilt Univ, Dept Pathol Microbiol & Immunol, 221 Kirkland Hall, Nashville, TN 37235 USA. [Matafonov, Anton] Tomsk Polytech Univ, Dept Bioengn & Organ Chem, Tomsk, Russia. [Mason, Shauna; Sexton, Daniel J.] Dyax Corp, Burlington, MA USA. [Renne, Thomas] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. [Renne, Thomas] Univ Hosp, Stockholm, Sweden. [Renne, Thomas] Univ Med Ctr Hamburg Eppendorf, Inst Clin Chem & Lab Med, Hamburg, Germany. [McCrae, Keith] Cleveland Clin, Dept Hematol & Oncol, Cleveland, OH 44106 USA. [Feener, Edward P.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. RP Gailani, D (reprint author), Vanderbilt Univ, Hematol Oncol Div, 777 Preston Res Bldg,2220 Pierce Ave, Nashville, TN USA. EM dave.gailani@vanderbilt.edu FU National Heart, Lung, and Blood Institute [HL81326, HL58837, HL089796]; National Institute of Neurological Disorders and Stroke [NS077006]; Vetenskapsradet [K2013-65X-21462-014-5]; German Research Society [SFB877, SFB841]; European Research Council [ERC-StG-2012-311575_F-12] FX The authors wish to acknowledge support from awards HL81326 and HL58837 (D. Gailani) and HL089796 to (K. McCrae) from the National Heart, Lung, and Blood Institute; award NS077006 (E.P. Feener) from the National Institute of Neurological Disorders and Stroke; and awards K2013-65X-21462-014-5 from Vetenskapsradet, SFB877, TP A11 and SFB841, TP B8 from the German Research Society, and ERC-StG-2012-311575_F-12 from the European Research Council (T. Renne). NR 42 TC 5 Z9 5 U1 1 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0049-3848 J9 THROMB RES JI Thromb. Res. PD APR PY 2016 VL 140 BP 118 EP 124 DI 10.1016/j.thromres.2016.02.020 PG 7 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA DI8DX UT WOS:000373732600019 PM 26950760 ER PT J AU Leung, AM Korevaar, TIM Peeters, RP Zoeller, RT Kohrle, J Duntas, LH Brent, GA Demeneix, BA AF Leung, Angela M. Korevaar, Tim I. M. Peeters, Robin P. Zoeller, R. Thomas Koehrle, Josef Duntas, Leonidas H. Brent, Gregory A. Demeneix, Barbara A. TI Exposure to Thyroid-Disrupting Chemicals: A Transatlantic Call for Action SO THYROID LA English DT Editorial Material C1 [Leung, Angela M.; Brent, Gregory A.] Univ Calif Los Angeles, David Geffen Sch Med, Div Endocrinol, Los Angeles, CA 90095 USA. [Leung, Angela M.; Brent, Gregory A.] VA Greater Los Angeles Healthcare Syst, Div Endocrinol, Los Angeles, CA USA. [Korevaar, Tim I. M.; Peeters, Robin P.] Erasmus MC, Generat R Study Grp, Rotterdam, Netherlands. [Korevaar, Tim I. M.; Peeters, Robin P.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Korevaar, Tim I. M.; Peeters, Robin P.] Erasmus MC, Rotterdam Thyroid Ctr, Rotterdam, Netherlands. [Zoeller, R. Thomas] Univ Massachusetts, Dept Biol, Amherst, MA 01003 USA. [Zoeller, R. Thomas] Univ Massachusetts, Program Mol & Cellular Biol, Amherst, MA 01003 USA. [Koehrle, Josef] Charite, Inst Expt Endokrinol, D-13353 Berlin, Germany. [Duntas, Leonidas H.] Univ Athens, Thyroid Unit, Evgenid Hosp, Athens, Greece. [Demeneix, Barbara A.] Museum Natl Hist Nat, Dept Regulat Dev & Diversite Mol, Evolut Regulat Endocriniennes, F-75231 Paris, France. RP Leung, AM (reprint author), VA Greater Angeles Healthcare Syst, Div Endocrinol 111D, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM amleung@mednet.ucla.edu OI Kohrle, Josef/0000-0002-9187-9078 FU NICHD NIH HHS [K23HD068552] NR 4 TC 3 Z9 3 U1 2 U2 4 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 APR 1 PY 2016 VL 26 IS 4 BP 479 EP 480 DI 10.1089/thy.2016.0077 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DI1DY UT WOS:000373237400001 PM 26906244 ER PT J AU Su, HK Wenig, BM Haser, GC Rowe, ME Asa, SL Baloch, Z Du, E Faquin, WC Fellegara, G Giordano, T Ghossein, R LiVolsi, VA Lloyd, R Mete, O Ozbek, U Rosai, J Suster, S Thompson, LD Turk, AT Urken, ML AF Su, Henry K. Wenig, Bruce M. Haser, Grace C. Rowe, Meghan E. Asa, Sylvia L. Baloch, Zubair Du, Eugenie Faquin, William C. Fellegara, Giovanni Giordano, Thomas Ghossein, Ronald LiVolsi, Virginia A. Lloyd, Ricardo Mete, Ozgur Ozbek, Umut Rosai, Juan Suster, Saul Thompson, Lester D. Turk, Andrew T. Urken, Mark L. TI Inter-Observer Variation in the Pathologic Identification of Minimal Extrathyroidal Extension in Papillary Thyroid Carcinoma SO THYROID LA English DT Article ID EXTRANODAL EXTENSION; LYMPH-NODES; WELL; CANCER AB Background: Extrathyroidal extension (ETE) is a significant prognostic factor in papillary thyroid carcinoma (PTC). Minimal extrathyroidal extension (mETE) is characterized by involvement of the sternothyroid muscle or perithyroid soft tissue, and is generally identified by light microscope examination. Patients with mETE, identified pathologically, are automatically upstaged to pT3. However, the prognostic implications of mETE have been a source of controversy in the literature. Moreover, there is also controversy surrounding the identification of mETE on pathological specimens. The objective of this study was to determine the level of agreement among expert pathologists in the identification of mETE in PTC cases. Methods: Eleven expert pathologists from the United States, Italy, and Canada were asked to perform a review of 69 scanned slides of representative permanent sections of PTC specimens. Each slide was evaluated for the presence of mETE. The pathologists were also asked to list the criteria they use to identify mETE. Results: The overall strength of agreement for identifying mETE was slight (=0.14). Inter-pathologist agreement was best for perithyroidal skeletal muscle involvement (=0.46, moderate agreement) and worst for invasion around thick-walled vascular structures (=0.02, slight agreement). In addition, there was disagreement over the constellation of histologic features that are diagnostic for mETE, which affected overall agreement for diagnosing mETE. Conclusions: Overall agreement for the identification of mETE is poor. Disagreement is a result of both variation in individual pathologists' interpretations of specimens and disagreement on the histologic criteria for mETE. Thus, the utility of mETE in staging and treatment of PTC is brought into question. The lack of concordance may explain the apparent lack of agreement regarding the prognostic significance of this pathologic feature. C1 [Su, Henry K.; Haser, Grace C.; Rowe, Meghan E.] Thyroid Head & Neck Canc THANC Fdn, Dept Otolaryngol Head & Neck Surg, New York, NY 10003 USA. [Wenig, Bruce M.] Mt Sinai Beth Israel, Dept Pathol, New York, NY USA. [Urken, Mark L.] Mt Sinai Beth Israel, Dept Otolaryngol Head & Neck Surg, New York, NY USA. [Asa, Sylvia L.; Mete, Ozgur] Toronto Gen Hosp, Dept Pathol, Lab Med Program, Toronto, ON, Canada. [Baloch, Zubair; LiVolsi, Virginia A.] Univ Penn, Dept Pathol & Lab Med, Hosp, Philadelphia, PA 19104 USA. [Du, Eugenie] Albert Einstein Coll Med, Montefiore Med Ctr, Dept Otorhinolaryngol Head & Neck Surg, Bronx, NY 10467 USA. [Faquin, William C.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Fellegara, Giovanni; Rosai, Juan] Ctr Diagnost Italiano, Ctr Consulenze Anat Patolog Oncolog, Milan, Italy. [Giordano, Thomas] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA. [Ghossein, Ronald] Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA. [Lloyd, Ricardo] Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI 53706 USA. [Ozbek, Umut] Mt Sinai Hosp, Populat Hlth Sci & Policy, New York, NY 10029 USA. [Suster, Saul] Med Coll Wisconsin, Dept Pathol, Milwaukee, WI 53226 USA. [Thompson, Lester D.] Woodland Hills Med Ctr, Dept Pathol, Woodland Hills, CA USA. [Turk, Andrew T.] New York Presbyterian Columbia, Dept Pathol, New York, NY USA. RP Haser, GC (reprint author), Thyroid Head & Neck Canc THANC Fdn, 10 Union Sq East,Suite 5B, New York, NY 10003 USA. EM ghaser@thancfoundation.org FU Mount Sinai Health System FX The authors would like to acknowledge the Mount Sinai Health System for its generous support of this research project. NR 18 TC 0 Z9 0 U1 0 U2 1 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 APR 1 PY 2016 VL 26 IS 4 BP 512 EP 517 DI 10.1089/thy.2015.0508 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DI1DY UT WOS:000373237400006 PM 26953223 ER PT J AU Greiman, A Shah, J Bhavsar, R Armeson, K Caulder, S Jones, R Keane, TE Clarke, HS Savage, SJ AF Greiman, Alyssa Shah, Jaimin Bhavsar, Robin Armeson, Kent Caulder, Susan Jones, Rabun Keane, Thomas E. Clarke, Harry S. Savage, Stephen J. TI Six Weeks of Fluoroquinolone Antibiotic Therapy for Patients With Elevated Serum Prostate-specific Antigen Is Not Clinically Beneficial: A Randomized Controlled Clinical Trial SO UROLOGY LA English DT Article ID PSA LEVELS; CANCER; BIOPSY; BENIGN; MARKER AB OBJECTIVE To evaluate asymptomatic men with elevated serum prostate-specific antigen (PSA) to determine whether a 6-week course of fluoroquinolone antibiotics lowers serum PSA and affects recommendations for prostate biopsy. MATERIALS AND METHODS A randomized, single-center prospective trial of 150 men with an initial elevated PSA was conducted. Patients were randomized to 6 weeks of ciprofloxacin or observation. Those patients with persistently elevated PSA were recommended to proceed with transrectal ultrasound-guided 12-core biopsy. Those with reduced PSA were offered transrectal ultrasound-guided biopsy but could opt to continue serial digital rectal examination/PSA. Patients were followed an average of 4.6 years to assess trends in PSA and biopsy results. RESULTS Of 136 men who completed the trial, 63 were in the treatment and 73 were in the observation group. The average PSA change from baseline was borderline statistically significant with a change of -0.68 ng/mL in the treatment arm and 0.01 ng/mL in the observation arm (P = .052). Of those who underwent biopsy, prostate cancer was diagnosed in the first biopsy in 24 (63%) of the treatment vs 27 (52%) of the observation group (P = .60) over follow-up. CONCLUSION In a cohort of asymptomatic men with elevated PSA, there was only a borderline statistically significant change in serum PSA between patients randomized to a 6-week course of fluoroquinolones vs observation, and there was no difference in positive prostate biopsy results. Our clinical recommendation is one should not treat patients with elevated serum PSA with antibiotics in the absence of clinical symptoms of prostatitis. Published by Elsevier Inc. C1 [Greiman, Alyssa; Shah, Jaimin; Bhavsar, Robin; Armeson, Kent; Caulder, Susan; Jones, Rabun; Keane, Thomas E.; Clarke, Harry S.; Savage, Stephen J.] Med Univ S Carolina, Ralph H Johnson Vet Affairs Med Ctr, Dept Urol, Urol Sect, 96 Jonathan Lucas St,CSB 644, Charleston, SC 29425 USA. RP Greiman, A (reprint author), Med Univ S Carolina, Ralph H Johnson Vet Affairs Med Ctr, Dept Urol, Urol Sect, 96 Jonathan Lucas St,CSB 644, Charleston, SC 29425 USA. EM greiman@musc.edu NR 30 TC 1 Z9 1 U1 2 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 EI 1527-9995 J9 UROLOGY JI Urology PD APR PY 2016 VL 90 BP 32 EP 37 DI 10.1016/j.urology.2015.11.046 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA DI4JT UT WOS:000373466900017 PM 26802800 ER PT J AU Vasilevskis, EE Kripalani, S Ong, MK Rosenthal, JT Longnecker, DE Harmon, B Hohmann, SF Wright, K Black, JT AF Vasilevskis, Eduard E. Kripalani, Sunil Ong, Michael K. Rosenthal, J. Thomas Longnecker, David E. Harmon, Brian Hohmann, Samuel F. Wright, Kelly Black, Jeanne T. TI Variability in Implementation of Interventions Aimed at Reducing Readmissions Among Patients With Heart SO ACADEMIC MEDICINE LA English DT Article ID HOSPITAL READMISSIONS; 30-DAY READMISSIONS; RANDOMIZED-TRIALS; TRANSITIONAL CARE; FAILURE PATIENTS; PALLIATIVE CARE; HEALTH-CARE; FOLLOW-UP; STRATEGIES; RATES AB Purpose To highlight teaching hospitals' efforts to reduce readmissions by describing interventions implemented to improve care transitions for heart failure (HF) patients and the variability in implemented HF-specific and care transition interventions. Method In 2012, the authors surveyed a network of 17 teaching hospitals to capture information about the number, type, stage of implementation, and structure of 4 HF-specific and 21 care transition (predischarge, bridging, and postdischarge) interventions implemented to reduce readmissions among patients with HF. The authors summarized data using descriptive statistics, including the mean number of interventions implemented and the frequency and stage of specific interventions, and descriptive plots of the structure of two common interventions (multidisciplinary rounds and follow-up telephone calls). Results Sixteen hospitals (94%) responded. The number and stage of implementation of the HF-specific and care transition interventions implemented varied across institutions. The mean number of interventions at an advanced stage of implementation (i.e., implemented for 75% of HF patients on the cardiology service or on all services) was 10.9 (standard deviation = 4.3). Overall, predischarge interventions were more common than bridging or postdischarge interventions. There was variability in the personnel involved in multidisciplinary rounds and in the processes/content of follow-up telephone calls. Conclusions Teaching hospitals have implemented a wide range of interventions aimed at reducing hospital readmissions, but there is substantial variability in the types, stages, and structure of their interventions. This heterogeneity highlights the need for collaborative efforts to improve understanding of intervention effectiveness. C1 [Vasilevskis, Eduard E.] Vanderbilt Univ, Dept Med, Div Gen Internal Med & Publ Hlth, Med,Sect Hosp Med, Nashville, TN 37232 USA. [Vasilevskis, Eduard E.] VA Tennessee Valley Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Nashville, TN USA. [Kripalani, Sunil] Vanderbilt Univ, Dept Med, Div Gen Internal Med & Publ Hlth, Ctr Clin Qual & Implementat Res,Sect Hosp Med, Nashville, TN 37232 USA. [Ong, Michael K.] Univ Calif Los Angeles, Dept Med, Med, Los Angeles, CA 90024 USA. [Ong, Michael K.] VA Greater Los Angeles Hlth Care Syst, Los Angeles, CA USA. [Rosenthal, J. Thomas] Univ Calif Los Angeles Hlth Syst, Los Angeles, CA USA. [Longnecker, David E.] Univ Penn, Anesthesiol, Philadelphia, PA 19104 USA. [Longnecker, David E.] Coalit Transform Adv Care, Washington, DC USA. [Harmon, Brian] Childrens Hosp & Clin Minnesota, Minneapolis, MN USA. [Hohmann, Samuel F.] Univ HealthSyst Consortium, Comparat Data & Informat Res, Chicago, IL USA. [Hohmann, Samuel F.] Rush Univ, Dept Hlth Syst Management, Chicago, IL 60612 USA. [Wright, Kelly] Vanderbilt Univ, Div Gen Internal Med & Publ Hlth, Sect Hosp Med, Dept Med, Nashville, TN 37232 USA. [Black, Jeanne T.] Cedars Sinai Hlth Syst, Hlth Policy & Program Evaluat, Los Angeles, CA USA. RP Vasilevskis, EE (reprint author), Vanderbilt Univ, Med Ctr, 1215 21st Ave S,6006 Med Ctr East NT, Nashville, TN 37232 USA. EM eduard.vasilevskis@vanderbilt.edu FU National Institutes of Health [K23 AG040157]; Tennessee Valley Geriatric Research, Education and Clinical Center (GRECC); Robert Wood Johnson Foundation [RWJF 67627] FX Funding for E.E. Vasilevskis was provided by the National Institutes of Health (K23 AG040157) and the Tennessee Valley Geriatric Research, Education and Clinical Center (GRECC). The Variations Collaborative Study Group additionally received support from the Robert Wood Johnson Foundation (RWJF 67627). NR 40 TC 2 Z9 2 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1040-2446 EI 1938-808X J9 ACAD MED JI Acad. Med. PD APR PY 2016 VL 91 IS 4 BP 522 EP 529 PG 8 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA DH6XW UT WOS:000372936400027 PM 26579793 ER PT J AU Hser, YI Evans, E Huang, D Weiss, R Saxon, A Carroll, KM Woody, G Liu, D Wakim, P Matthews, AG Hatch-Maillette, M Jelstrom, E Wiest, K McLaughlin, P Ling, W AF Hser, Yih-Ing Evans, Elizabeth Huang, David Weiss, Robert Saxon, Andrew Carroll, Kathleen M. Woody, George Liu, David Wakim, Paul Matthews, Abigail G. Hatch-Maillette, Mary Jelstrom, Eve Wiest, Katharina McLaughlin, Paul Ling, Walter TI Long-term outcomes after randomization to buprenorphine/naloxone versus methadone in a multi-site trial SO ADDICTION LA English DT Article DE Buprenorphine; methadone; opioid dependence; longitudinal; outcomes; opioid use; mortality ID MAINTENANCE THERAPY; OPIOID DEPENDENCE; RETENTION; ADDICTION; METHAMPHETAMINE; PERSPECTIVES; MEDICATION; HEALTH; ENTRY; USERS AB AimsTo compare long-term outcomes among participants randomized to buprenorphine or methadone. Design, Setting and ParticipantsFollow-up was conducted in 2011-14 of 1080 opioid-dependent participants entering seven opioid treatment programs in the United States between 2006 and 2009 and randomized (within each program) to receive open-label buprenorphine/naloxone or methadone for up to 24weeks; 795 participants completed in-person interviews (similar to 74% follow-up interview rate) covering on average 4.5years. MeasurementsOutcomes were indicated by mortality and opioid use. Covariates included demographics, site, cocaine use and treatment experiences. FindingsMortality was not different between the two randomized conditions, with 23 (3.6%) of 630 participants randomized to buprenorphine having died versus 26 (5.8%) of 450 participants randomized to methadone. Opioid use at follow-up was higher among participants randomized to buprenorphine relative to methadone [42.8 versus 31.7% positive opioid urine specimens, P<0.01, effect size (h)=0.23 (0.09, 0.38); 5.8days versus 4.4days of past 30-day heroin use, P<0.05, effect size (d)=0.14 (0.00, 0.28)]. Opioid use during the follow-up period by randomization condition was also significant (F-(7,F-39600)=3.16; P<0.001) due mainly to less treatment participation among participants randomized to buprenorphine than methadone. Less opioid use was associated with both buprenorphine and methadone treatment (relative to no treatment); no difference was found between the two treatments. Individuals who are white or used cocaine at baseline responded better to methadone than to buprenorphine. ConclusionsThere are few differences in long-term outcomes between buprenorphine and methadone treatment for opioid dependence, and treatment with each medication is associated with a strong reduction in opioid use. C1 [Hser, Yih-Ing; Evans, Elizabeth; Huang, David; Weiss, Robert; Ling, Walter] Univ Calif Los Angeles, Los Angeles, CA USA. [Saxon, Andrew] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. [Carroll, Kathleen M.] Yale Univ, Sch Med, New Haven, CT USA. [Woody, George] Univ Penn, Philadelphia, PA 19104 USA. [Liu, David; Wakim, Paul] NIDA, Bethesda, MD 20892 USA. [Matthews, Abigail G.; Jelstrom, Eve] Emmes Corp, Rockville, MD USA. [Hatch-Maillette, Mary] Univ Washington, Seattle, WA 98195 USA. [Wiest, Katharina] CODA Inc, Portland, OR USA. [McLaughlin, Paul] Hartford Dispensary, Hartford, CT USA. RP Hser, YI (reprint author), Univ Calif Los Angeles, Integrated Subst Abuse Programs, 11075 Santa Monica Blvd,Suite 200, Los Angeles, CA USA. EM yhser@ucla.edu FU National Institute on Drug Abuse (NIDA) through the Clinical Trials Network (CTN) [U10 DA01714, U10 DA 015815, U10 DA13038, U10 DA13043, U10 DA13045]; NIDA [P30DA016383] FX The corresponding author, Yih-Ing Hser, has full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Sincere appreciation to our participating networks: the Pacific Northwest Node and Evergreen Treatment Services; the Western States Node and CODA Inc. and Bi-Valley Medical Clinic; the New England Node and Connecticut Counseling Centers and Yale and Hartford Dispensary; the Delaware Valley Node and NET Steps; the Pacific Region Node and Matrix Institute; and the EMMES Corporation (CCC); the CCTN and NIDA. The main study funding was provided by the National Institute on Drug Abuse (NIDA) through the Clinical Trials Network (CTN) through a series of grants provided to each participating node: the Pacific Northwest Node (U10 DA01714); the Western States Node (U10 DA 015815); the New England Node (U10 DA13038); the Delaware Valley Node (U10 DA13043); and he Pacific Region Node (U10 DA13045). Funding was also provided by NIDA through grant number P30DA016383. NR 29 TC 2 Z9 2 U1 5 U2 14 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 APR PY 2016 VL 111 IS 4 BP 695 EP 705 DI 10.1111/add.13238 PG 11 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA DH6NM UT WOS:000372907400022 PM 26599131 ER PT J AU Kao, SY Soares, VYR Kristiansen, AG Stankovic, KM AF Kao, Shyan-Yuan Soares, Vitor Y. R. Kristiansen, Arthur G. Stankovic, Konstantina M. TI Activation of TRAIL-DR5 pathway promotes sensorineural degeneration in the inner ear SO AGING CELL LA English DT Article DE TRAIL; DR5; OPG; cochlea; hair cells; spiral ganglion neuron ID TUMOR-NECROSIS-FACTOR; NF-KAPPA-B; HEARING-LOSS; INDUCED APOPTOSIS; LIGAND TRAIL; CELL-DEATH; COCHLEAR NERVE; HAIR-CELLS; EXPRESSION; RECEPTOR AB Tumor necrosis factor (TNF) family cytokines are important mediators of inflammation. Elevated levels of serum TNF- are associated with human sensorineural hearing loss via poorly understood mechanisms. We demonstrate, for the first time, expression of TNF-related apoptosis-inducing ligand (TRAIL) and its signaling death receptor 5 (DR5) in the murine inner ear and show that exogenous TRAIL can trigger hair cell and neuronal degeneration, which can be partly prevented with DR5-blocking antibodies. C1 [Kao, Shyan-Yuan; Soares, Vitor Y. R.; Kristiansen, Arthur G.; Stankovic, Konstantina M.] Massachusetts Eye & Ear Infirm, Eaton Peabody Labs, Boston, MA 02114 USA. [Kao, Shyan-Yuan; Soares, Vitor Y. R.; Kristiansen, Arthur G.; Stankovic, Konstantina M.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. [Soares, Vitor Y. R.; Stankovic, Konstantina M.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Stankovic, Konstantina M.] Harvard Univ, Sch Med, Program Speech & Hearing Biosci & Technol, Boston, MA 02115 USA. RP Stankovic, KM (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM konstantina_stankovic@meei.harvard.edu FU Department of Defense [W81XWH-15-1-0472]; Bertarelli Foundation; Nancy Sayles Day Foundation; Lauer Tinnitus Research Center FX This study was supported by grants from the Department of Defense grant W81XWH-15-1-0472, the Bertarelli Foundation, the Nancy Sayles Day Foundation, and the Lauer Tinnitus Research Center (all to K.M.S.). NR 45 TC 2 Z9 2 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1474-9718 EI 1474-9726 J9 AGING CELL JI Aging Cell PD APR PY 2016 VL 15 IS 2 BP 301 EP 308 DI 10.1111/acel.12437 PG 8 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA DH6DF UT WOS:000372880500011 PM 26791792 ER PT J AU Magidson, JF Li, X Mimiaga, MJ Moore, AT Srithanaviboonchai, K Friedman, RK Limbada, M Hughes, JP Cummings, V Gaydos, CA Elharrar, V Celentano, D Mayer, KH Safren, SA AF Magidson, Jessica F. Li, Xin Mimiaga, Matthew J. Moore, Ayana T. Srithanaviboonchai, Kriengkrai Friedman, Ruth Khalili Limbada, Mohammad Hughes, James P. Cummings, Vanessa Gaydos, Charlotte A. Elharrar, Vanessa Celentano, David Mayer, Kenneth H. Safren, Steven A. TI Antiretroviral Medication Adherence and Amplified HIV Transmission Risk Among Sexually Active HIV-Infected Individuals in Three Diverse International Settings SO AIDS AND BEHAVIOR LA English DT Article DE Adherence; Treatment as prevention; HIV transmission; Amplified risk; Alcohol use; MSM; Biomedical prevention ID CARE; PREVALENCE; BEHAVIORS; THERAPY; SCALE; MEN AB Successful biomedical prevention/treatment-as-prevention (TasP) requires identifying individuals at greatest risk for transmitting HIV, including those with antiretroviral therapy (ART) nonadherence and/or 'amplified HIV transmission risk,' defined as condomless sex with HIV-uninfected/unknown-status partners when infectious (i.e., with detectable viremia or STI diagnosis according to Swiss criteria for infectiousness). This study recruited sexually-active, HIV-infected patients in Brazil, Thailand, and Zambia to examine correlates of ART nonadherence and 'amplified HIV transmission risk'. Lower alcohol use (OR = .71, p < .01) and higher health-related quality of life (OR = 1.10, p < .01) were associated with greater odds of ART adherence over and above region. Of those with viral load data available (in Brazil and Thailand only), 40 % met Swiss criteria for infectiousness, and 29 % had 'amplified HIV transmission risk.' MSM had almost three-fold (OR = 2.89, p < .001) increased odds of 'amplified HIV transmission risk' (vs. heterosexual men) over and above region. TasP efforts should consider psychosocial and contextual needs, particularly among MSM with detectable viremia. C1 [Magidson, Jessica F.; Mimiaga, Matthew J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat, One Bowdoin Sq,7th Floor, Boston, MA 02114 USA. [Li, Xin; Hughes, James P.] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Mimiaga, Matthew J.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Mimiaga, Matthew J.; Mayer, Kenneth H.; Safren, Steven A.] Fenway Hlth, Fenway Inst, Boston, MA USA. [Moore, Ayana T.] FHI360, Durham, NC USA. [Srithanaviboonchai, Kriengkrai] Chiang Mai Univ, Res Inst Hlth Sci, Chiang Mai 50000, Thailand. [Srithanaviboonchai, Kriengkrai] Chiang Mai Univ, Fac Med, Chiang Mai 50000, Thailand. [Friedman, Ruth Khalili] Inst Pesquisa Clin Evandro Chagas, Rio De Janeiro, Brazil. [Limbada, Mohammad] Ctr Infect Dis Res Zambia, Lusaka, Zambia. [Hughes, James P.] Univ Washington, Seattle, WA 98195 USA. [Cummings, Vanessa; Gaydos, Charlotte A.] Johns Hopkins Sch Med, Div Infect Dis, Dept Pathol & Med, Baltimore, MD USA. [Elharrar, Vanessa] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Celentano, David] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Mayer, Kenneth H.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. [Safren, Steven A.] Univ Miami, Dept Psychol, Coral Gables, FL 33124 USA. RP Magidson, JF (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat, One Bowdoin Sq,7th Floor, Boston, MA 02114 USA. EM jmagidson@mgh.harvard.edu OI Srithanaviboonchai, Kriengkrai/0000-0002-1683-4259 FU NIH [T32MH093310, K24MH094214]; Harvard University Center for AIDS Research (HU CFAR) NIH [P30AI060354]; Division of AIDS (DAIDS), National Institute of Allergy and Infectious Disease (NIAID), National Institute on Drug Abuse (NIDA); National Institute of Mental Health (NIMH) [UM1AI068619] FX HPTN 063 was funded by the Division of AIDS (DAIDS), National Institute of Allergy and Infectious Disease (NIAID), National Institute on Drug Abuse (NIDA), and the National Institute of Mental Health (NIMH) under Cooperative Agreement # UM1AI068619. 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 or The HIV Prevention Trials Network. The authors would also like to acknowledge the staff at the HPTN 063 study sites for their contributions to the study. Additionally, Dr. Magidson's work on this manuscript was supported by NIH Grant T32MH093310, and Dr. Safren was supported by NIH Grant K24MH094214. Dr. Mayer and Dr. Safren were also supported by the Harvard University Center for AIDS Research (HU CFAR) NIH P30AI060354. This manuscript was supported by consultation from other members of the HU CFAR Social and Behavioral Sciences Core. NR 20 TC 2 Z9 2 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 APR PY 2016 VL 20 IS 4 BP 699 EP 709 DI 10.1007/s10461-015-1142-7 PG 11 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA DH7HF UT WOS:000372962700001 PM 26246068 ER PT J AU Colby, DJ Oldenburg, CE Nguyen, T Closson, EF Biello, KB Mayer, KH Mimiaga, MJ AF Colby, Donn J. Oldenburg, Catherine E. Thi Nguyen Closson, Elizabeth F. Biello, Katie B. Mayer, Kenneth H. Mimiaga, Matthew J. TI HIV, Hepatitis C, and Other Sexually Transmitted Infections Among Male Sex Workers in Ho Chi Minh City, Vietnam SO AIDS AND BEHAVIOR LA English DT Article DE HIV; Hepatitis C; Prevalence; Male sex work; Vietnam ID TRANSACTIONAL SEX; RISK; STREET; MEN; ENVIRONMENT; ENGAGE; USERS; HANOI AB There is little data on the burden of HIV and other infections that affect male sex workers (MSW) in Vietnam. We conducted behavioral and biological sexual health surveys with 300 MSW in Ho Chi Minh City. Generalized estimating equation models were built to assess factors associated with HIV, hepatitis C, and other sexually transmitted infections (STI). Of 300 MSW, 19 (6.3 %) were diagnosed seropositive for HIV, 11 (3.7 %) had hepatitis C, and 26 (8.7 %) had at least one prevalent STI. In a multivariable model, opiate use was significantly associated with HIV infection (aOR 6.46, 95 % CI 1.28-32.7) and hepatitis C (aOR = 19.6, 95 % CI 2.35-163.6). Alcohol dependency was associated with increased odds of hepatitis C (aOR = 4.79, 95 % CI 1.02-22.5) and decreased odds of other STI (aOR = 0.30, 95 % CI 0.10-0.97). These findings suggest that MSW in Vietnam would benefit from regular HIV and STI testing, as well as linkage to care and substance use rehabilitation services. C1 [Colby, Donn J.] Thai Red Cross AIDS Res Ctr, SEARCH, 104 Rajdamri Rd, Bangkok 10330, Thailand. [Colby, Donn J.] Ctr Appl Res Men & Hlth, Ho Chi Minh City, Vietnam. [Oldenburg, Catherine E.; Biello, Katie B.; Mimiaga, Matthew J.] Harvard Univ, Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Oldenburg, Catherine E.; Closson, Elizabeth F.; Biello, Katie B.; Mayer, Kenneth H.; Mimiaga, Matthew J.] Fenway Community Hlth, Fenway Inst, Boston, MA USA. [Thi Nguyen] Harvard Univ, Med Sch AIDS Initiat Vietnam, Ho Chi Minh City, Vietnam. [Mayer, Kenneth H.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Mayer, Kenneth H.] Harvard Univ, Chan Sch Publ Hlth, Dept Global Hlth & Populat, Boston, MA 02115 USA. [Mimiaga, Matthew J.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP Colby, DJ (reprint author), Thai Red Cross AIDS Res Ctr, SEARCH, 104 Rajdamri Rd, Bangkok 10330, Thailand.; Colby, DJ (reprint author), Ctr Appl Res Men & Hlth, Ho Chi Minh City, Vietnam. EM doctordonn@gmail.com OI colby, donn/0000-0003-3931-5926 FU Harvard Catalyst - the Harvard Clinical and Translational Science Center; National Institute of Drug Abuse T32 NRSA Grant [T32 DA0131911]; Harvard Global Health Institute Fellowship FX This study was conducted with the support of a pilot Grant from Harvard Catalyst - the Harvard Clinical and Translational Science Center (PIs: DJC and MJM). CEO is supported by a National Institute of Drug Abuse T32 NRSA Grant (T32 DA0131911; PI: Flanigan) and by a Harvard Global Health Institute Fellowship. NR 24 TC 0 Z9 0 U1 3 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 APR PY 2016 VL 20 IS 4 BP 768 EP 775 DI 10.1007/s10461-015-1247-z PG 8 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA DH7HF UT WOS:000372962700009 PM 26563761 ER PT J AU Adams, GL Mustapha, J Gray, W Hargus, NJ Martinsen, BJ Ansel, G Jaff, MR AF Adams, George L. Mustapha, Jihad Gray, William Hargus, Nick J. Martinsen, Brad J. Ansel, Gary Jaff, Michael R. TI The LIBERTY study: Design of a prospective, observational, multicenter trial to evaluate the acute and long-term clinical and economic outcomes of real-world endovascular device interventions in treating peripheral artery disease SO AMERICAN HEART JOURNAL LA English DT Article ID CRITICAL LIMB ISCHEMIA; LOWER-EXTREMITY AMPUTATION; SUPERVISED EXERCISE; INTERMITTENT CLAUDICATION; REVASCULARIZATION; REHABILITATION; STANDARDS; THERAPY; CLEVER; TRENDS AB Background Most peripheral artery disease (PAD) clinical device trials are supported by commercial manufacturers and designed for regulatory device approval, with extensive inclusion/exclusion criteria to support homogeneous patient populations. High-risk patients with advanced disease, including critical limb ischemia (CLI), are often excluded leading to difficulty in translating trial results into real-world clinical practice. As a result, physicians have no direct guidance regarding the use of endovascular devices. There is a need for objectively assessed studies to evaluate clinical, functional, and economic outcomes in PAD patient populations. Study Design LIBERTY is a prospective, observational, multicenter study sponsored by Cardiovascular Systems Inc (St Paul, MN) to evaluate procedural and long-term clinical and economic outcomes of endovascular device interventions in patients with symptomatic lower extremity PAD. Approximately 1,200 patients will be enrolled and followed up to 5 years: 500 patients in the "Claudicant Rutherford 2-3" arm, 600 in the "CLI Rutherford 4-5" arm, and 100 in the "CLI Rutherford6" arm. The study will use 4 core laboratories for independent analysis and will evaluate the following: procedural and lesion success, rates of major adverse events, duplex ultrasound interpretations, wound status, quality of life, 6-minute walk test, and economic analysis. The LIBERTY Patient Risk Score(s) will be developed as a clinical predictor of outcomes to provide guidance for interventions in this patient population. Conclusion LIBERTY will investigate real-world PAD patients treated with endovascular revascularization with rigorous study guidelines and independent oversight of outcomes. This study will provide observational, all-comer patient clinical data to guide future endovascular therapy. C1 [Adams, George L.] Rex Healthcare, 4414 Lake Boone Trail,Suite 402, Raleigh, NC 27607 USA. [Mustapha, Jihad] Metro Hlth Hosp, Wyoming, MI USA. [Gray, William] Columbia Univ, Med Ctr, New York, NY USA. [Hargus, Nick J.; Martinsen, Brad J.] Cardiovasc Syst Inc, St Paul, MN USA. [Ansel, Gary] Riverside Methodist Hosp, Columbus, OH 43214 USA. [Jaff, Michael R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Adams, GL (reprint author), Rex Healthcare, 4414 Lake Boone Trail,Suite 402, Raleigh, NC 27607 USA. EM George.Adams@rexhealth.com FU Cardiovascular Systems Inc. FX Financial support for the study is provided by Cardiovascular Systems Inc. The authors thank Ann Behrens, BS, and Zsuzsanna Igyarto, PhD, of Cardiovascular Systems Inc, for editing and critical review of this manuscript. NR 23 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 0002-8703 EI 1097-5330 J9 AM HEART J JI Am. Heart J. PD APR PY 2016 VL 174 BP 14 EP 21 DI 10.1016/j.ahj.2015.12.013 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DH1IV UT WOS:000372538500005 PM 26995365 ER PT J AU Axon, RN Gebregziabher, M Everett, CJ Heidenreich, P Hunt, KJ AF Axon, R. Neal Gebregziabher, Mulugeta Everett, Charles J. Heidenreich, Paul Hunt, Kelly J. TI Dual health care system use is associated with higher rates of hospitalization and hospital readmission among veterans with heart failure SO AMERICAN HEART JOURNAL LA English DT Article ID GUIDELINES PROGRAM; AMBULATORY-CARE; MEDICARE; OUTCOMES; INPATIENT; MORTALITY; ADMISSION; SERVICES; REGRESSION; PATIENT AB Background Heart failure (HF) frequently causes hospital admission and readmission. Patients receiving care from multiple providers and facilities (dual users) may risk higher health care utilization and worse health outcomes. Methods To determine rates of emergency department (ED) visits, hospitalizations, and hospital readmissions relative to dual use among HF patients, we analyzed a retrospective cohort of 13,977 veterans with HF hospitalized at the Veterans Affairs (VA) or non-VA facilities from 2007 to 2011; we analyzed rates of acute health care utilization using zero-inflated negative binomial regression. Results Compared to VA-only users and dual users, individuals receiving all of their ED and hospital care outside the VA tended to be older, more likely to be non-Hispanic white and married, and less likely to have high levels of service connected disability. Compared to VA-only users, dual users had significantly higher rates of ED visits for HF as a primary diagnosis (adjusted rate ratio 1.15, 95% CI 1.04-1.27), hospitalization for HF (adjusted rate ratio 1.4, 95% CI 1.26-1.56), hospital readmission after HF hospitalization (all cause) (1.46, 95% CI 1.30-1.65), and HF-specific hospital readmission after HF hospitalization (1.46, 95% CI 1.31-1.63). With the exception of hospitalization for any primary diagnosis, non-VA-only users had significantly lower rates of ED visits, hospitalization, and readmission compared to VA-only users. Conclusions Dual use is associated with higher rates of health care utilization among patients with HF. Interventions should be devised to encourage continuity of care where possible and to improve the effectiveness and safety of dual use in instances where it is necessary or desired. C1 [Axon, R. Neal; Gebregziabher, Mulugeta; Everett, Charles J.; Hunt, Kelly J.] Ralph H Johnson VA Med Ctr, Charleston Hlth Equ & Rural Outreach Innovat Ctr, Charleston, SC USA. [Axon, R. Neal] Med Univ S Carolina, Dept Med, Div Gen Internal Med, Charleston, SC 29425 USA. [Gebregziabher, Mulugeta; Hunt, Kelly J.] Med Univ S Carolina, Dept Publ Hlth Sci, Charleston, SC 29425 USA. [Heidenreich, Paul] Stanford Univ, Med Ctr, Div Cardiol, VA Palo Alto Healthcare Syst, Palo Alto, CA 94304 USA. RP Axon, RN (reprint author), 109 Bee St,Mail Code 111, Charleston, SC 29401 USA. EM axon@musc.edu OI Gebregziabher, Mulugeta/0000-0002-4826-481X FU VA Health Services Research and Development [IIR 12-331] FX VA Health Services Research and Development (IIR 12-331, Axon-PI). NR 40 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 0002-8703 EI 1097-5330 J9 AM HEART J JI Am. Heart J. PD APR PY 2016 VL 174 BP 157 EP 163 DI 10.1016/j.ahj.2015.09.023 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DH1IV UT WOS:000372538500023 PM 26995383 ER PT J AU Alinari, L Gru, A Quinion, C Huang, Y Lozanski, A Lozanski, G Poston, J Venkataraman, G Oak, E Kreisel, F Park, SI Matthews, S Abramson, JS Lim, HI Martin, P Cohen, JB Evens, A Al-Mansour, Z Singavi, A Fenske, TS Blum, KA AF Alinari, Lapo Gru, Alejandro Quinion, Carl Huang, Ying Lozanski, Arletta Lozanski, Gerard Poston, Jacqueline Venkataraman, Girish Oak, Eunhye Kreisel, Friederike Park, Steven I. Matthews, Stephanie Abramson, Jeremy S. Lim, Hana Iris Martin, Peter Cohen, Jonathon B. Evens, Andrew Al-Mansour, Zeina Singavi, Arun Fenske, Timothy S. Blum, Kristie A. TI De novo CD5+diffuse large B-cell lymphoma: Adverse outcomes with and without stem cell transplantation in a large, multicenter, rituximab treated cohort SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article ID CHEMOTHERAPY; CHOP; THERAPY; EXPRESSION AB De novo CD5+ diffuse large B-cell lymphomas (DLBCL) are a distinct subgroup of DLBCL with poor prognosis. However the role of rituximab-containing therapy and salvage stem cell transplantation in this patients' population remain to be defined. We retrospectively reviewed clinical features and outcomes of 102 patients with de novo CD5+ DLBCL treated with rituximab-containing therapy at nine different institutions. By Hans' criteria, 64 patients had activated B-cell (ABC) subtype, 24 germinal center B-cell (GCB) subtype, and 14 were not evaluated. No patients had a myc translocation. Eighty-three patients were treated with rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP), 7 with rituximab, etoposide, cyclophosphamide, doxorubicin, vincristine, prednisone (R-EPOCH), and 6 with R-CHOP with methotrexate, 3 g/m(2). The overall response rate to front-line therapy was 85%. The 3-year progression free survival (PFS) and overall survival (OS) for all patients were 40 and 65%, respectively. The 3-year PFS for ABC- and GCB-subtypes was 34 and 45%, respectively. The 3-year OS for ABC- and GCB-subtypes was 62 and 67%, respectively. The median time to second treatment failure was 3 months and 1 month for ABC- and GCB-subtypes, respectively. Twenty of 28 (71%) transplanted patients with autologous, allogeneic, or both, relapsed. This study confirms the poor prognosis of de novo CD5+ DLBCL in a large multi-center cohort despite initial rituximab-containing chemotherapy and suggests that stem cell transplantation fails to salvage the majority of these patients. Approaches to prevent recurrence and/or novel therapies for relapsed disease are needed for this subgroup of DLBCL patients. Am. J. Hematol. 91:395-399, 2016. (c) 2016 Wiley Periodicals, Inc. C1 [Alinari, Lapo; Quinion, Carl; Huang, Ying; Lozanski, Arletta; Blum, Kristie A.] Ohio State Univ, Wexner Med Ctr, Dept Internal Med, Div Hematol, Columbus, OH 43210 USA. [Gru, Alejandro; Lozanski, Gerard] Ohio State Univ, Wexner Med Ctr, Dept Pathol, Div Hematopathol, Columbus, OH 43210 USA. [Poston, Jacqueline] Univ Chicago, Dept Internal Med, Div Hematol, Chicago, IL 60637 USA. [Venkataraman, Girish] Univ Chicago, Dept Pathol, Div Hematopathol, 5841 S Maryland Ave, Chicago, IL 60637 USA. [Oak, Eunhye] Washington Univ, Sch Med, Dept Internal Med, Div Hematol, St Louis, MO 63110 USA. [Kreisel, Friederike] Washington Univ, Sch Med, Dept Pathol, Div Hematopathol, St Louis, MO 63110 USA. [Park, Steven I.; Matthews, Stephanie] Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Internal Med, Div Hematol, Chapel Hill, NC 27599 USA. [Abramson, Jeremy S.] Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Div Hematol,Dept Internal Med,Ctr Lymphoma,Med Sc, Boston, MA 02114 USA. [Lim, Hana Iris; Martin, Peter] Weill Cornell Med Coll, Dept Internal Med, Div Hematol, New York, NY USA. [Cohen, Jonathon B.] Emory Univ, Winship Canc Ctr, Dept Internal Med, Div Hematol, Atlanta, GA 30322 USA. [Evens, Andrew] Tufts Univ, Sch Med, Tufts Med Ctr, Div Hematol,Dept Internal Med, Boston, MA 02111 USA. [Al-Mansour, Zeina] Univ Massachusetts, Sch Med, Dept Internal Med, Div Hematol, Worcester, MA USA. [Singavi, Arun; Fenske, Timothy S.] Med Coll Wisconsin, Dept Internal Med, Div Hematol, Milwaukee, WI 53226 USA. RP Alinari, L (reprint author), Ohio State Univ, Dept Internal Med, Div Hematol, Med Ctr, 320 W 10th Ave,406C-1 Starling Loving Hall, Columbus, OH 43210 USA. EM Lapo.alinari@osumc.edu FU NCI NIH HHS [K24 CA201524, U10 CA180838] NR 22 TC 2 Z9 2 U1 0 U2 6 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 APR PY 2016 VL 91 IS 4 BP 395 EP 399 DI 10.1002/ajh.24299 PG 5 WC Hematology SC Hematology GA DH8CN UT WOS:000373021200014 PM 26800311 ER PT J AU Ghobrial, IM Siegel, DS Vij, R Berdeja, JG Richardson, PG Neuwirth, R Patel, CG Zohren, F Wolf, JL AF Ghobrial, Irene M. Siegel, David S. Vij, Ravi Berdeja, Jesus G. Richardson, Paul G. Neuwirth, Rachel Patel, Chirag G. Zohren, Fabian Wolf, Jeffrey L. TI TAK-228 (formerly MLN0128), an investigational oral dual TORC1/2 inhibitor: A phase I dose escalation study in patients with relapsed or refractory multiple myeloma, non-Hodgkin lymphoma, or Waldenstrom's macroglobulinemia SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article ID MTOR KINASE INHIBITOR; ADVANCED SOLID TUMORS; MAMMALIAN TARGET; HEMATOLOGIC MALIGNANCIES; INTERNATIONAL WORKSHOP; RESPONSE CRITERIA; PI3K INHIBITOR; PATIENTS PTS; RAPAMYCIN; CANCER AB The PI3K/AKT/mTOR signaling pathways are frequently dysregulated in multiple human cancers, including multiple myeloma (MM), non-Hodgkin lymphoma (NHL), and Waldenstrom's macroglobulinemia (WM). This was the first clinical study to evaluate the safety, tolerability, maximal-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics, and preliminary clinical activity of TAK-228, an oral TORC1/2 inhibitor, in patients with MM, NHL, or WM. Thirty-nine patients received TAK-228 once daily (QD) at 2, 4, 6, or 7 mg, or QD for 3 days on and 4 days off each week (QDx3d QW) at 9 or 12 mg, in 28-day cycles. The overall median age was 61.0 years (range 46-85); 31 patients had MM, four NHL, and four WM. Cycle 1 DLTs occurred in five QD patients (stomatitis, urticaria, blood creatinine elevation, fatigue, and nausea and vomiting) and four QDx3d QW patients (erythematous rash, fatigue, asthenia, mucosal inflammation, and thrombocytopenia). The MTDs were determined to be 4 mg QD and 9 mg QDx3d QW. Thirty-six patients (92%) reported at least one drug-related toxicity; the most common grade 3 drug-related toxicities were thrombocytopenia (15%), fatigue (10%), and neutropenia (5%). TAK-228 exhibited a dose-dependent increase in plasma exposure and no appreciable accumulation with repeat dosing; mean plasma elimination half-life was 6-8 hr. Of the 33 response-evaluable patients, one MM patient had a minimal response, one WM patient achieved partial response, one WM patient had a minor response, and 18 patients (14 MM, two NHL, and two WM) had stable disease. These findings encourage further studies including combination strategies. Am. J. Hematol. 91:400-405, 2016. (c) 2016 Wiley Periodicals, Inc. C1 [Ghobrial, Irene M.; Richardson, Paul G.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Siegel, David S.] Hackensack Univ, Med Ctr, John Theurer Canc Ctr, Hackensack, NJ USA. [Vij, Ravi] Washington Univ, Sch Med, Div Hematol & Oncol, St Louis, MO USA. [Berdeja, Jesus G.] Sarah Cannon Res Inst, Nashville, TN USA. [Neuwirth, Rachel] Millennium Pharmaceut Inc, Global Biostat, Cambridge, MA USA. [Patel, Chirag G.] Millennium Pharmaceut Inc, Clin Pharmacol, Cambridge, MA USA. [Zohren, Fabian] Millennium Pharmaceut Inc, Oncol Clin Res, Cambridge, MA USA. [Wolf, Jeffrey L.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. RP Ghobrial, IM (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. EM irene_ghobrial@dfci.harvard.edu NR 47 TC 3 Z9 3 U1 0 U2 3 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 APR PY 2016 VL 91 IS 4 BP 400 EP 405 DI 10.1002/ajh.24300 PG 6 WC Hematology SC Hematology GA DH8CN UT WOS:000373021200015 PM 26800393 ER PT J AU Hill, SY Jones, BL Steinhauer, SR Zezza, N Stiffler, S AF Hill, Shirley Y. Jones, Bobby L. Steinhauer, Stuart R. Zezza, Nicholas Stiffler, Scott TI Longitudinal predictors of cannabis use and dependence in offspring from families at ultra high risk for alcohol dependence and in control families SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE CNR1; D2; cannabis use; cannabis abuse; cannabis dependence ID RECEPTOR GENE CNR1; EVENT-RELATED POTENTIALS; LINKAGE-PHYSICAL MAP; SUBSTANCE USE; P300 AMPLITUDE; MARIJUANA USE; DEVELOPMENTAL TRAJECTORIES; HAPLOTYPE RECONSTRUCTION; GENOTYPE DATA; HUMAN GENOME AB Cannabis use is common among adolescents. Identification of the factors associated with continued heavy use into young adulthood and development of cannabis abuse and dependence is of considerable importance. The role of familial risk for addiction and an associated endophenotype, P300 amplitude, has not previously been related to cannabis use and dependence. A prospective longitudinal study spanning childhood and young adulthood provided the opportunity for exploring these factors, along with genetic variation, in the cannabis use behaviors of 338 young adult offspring from high and low familial risk for alcohol dependence families (ages 19-30). P300 data were collected multiple times in childhood. The association between young adult patterns of cannabis use or cannabis abuse/dependence was tested with genetic variation in the cannabinoid gene, CNR1, the ANKK1-DRD2 gene, and childhood developmental trajectories of P300. Young adult patterns of cannabis use was characterized by three patterns: (i) no use throughout; (ii) declining use from adolescence through young adulthood; and (iii) frequent use throughout. Following the low P300 trajectory in childhood predicted cannabis abuse and dependence by young adulthood. A four SNP ANKK1-DRD2 haplotype (G-G-G-C) was found to be significantly associated with the frequency of use patterns (P=0.0008). Although CNR1 variation overall was not significantly associated with these patterns, among individuals with cannabis abuse/dependence the presence of one or both copies of the rs806368 A>G minor allele conferred a 5.4-fold increase (P=0.003) in the likelihood that they would be in the frequent and persistent use group rather than the declining use group. (c) 2016 Wiley Periodicals, Inc. C1 [Hill, Shirley Y.; Jones, Bobby L.; Zezza, Nicholas; Stiffler, Scott] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [Steinhauer, Stuart R.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. RP Hill, SY (reprint author), Univ Pittsburgh, Dept Psychiat, Med Ctr, 3811 O Hara St, Pittsburgh, PA 15213 USA. EM syh50@imap.pitt.edu FU NIAAA [AA018289, AA05909, AA08082, AA015168] FX Grant sponsor: NIAAA; Grant numbers: AA018289, AA05909, AA08082, AA015168. NR 76 TC 0 Z9 0 U1 6 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4841 EI 1552-485X J9 AM J MED GENET B JI Am. J. Med. Genet. B PD APR PY 2016 VL 171 IS 3 BP 383 EP 395 DI 10.1002/ajmg.b.32417 PG 13 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA DH8FO UT WOS:000373029100009 PM 26756393 ER PT J AU Hirsch, JA Nicola, G McGinty, G Liu, RW Barr, RM Chittle, MD Manchikanti, L AF Hirsch, J. A. Nicola, G. McGinty, G. Liu, R. W. Barr, R. M. Chittle, M. D. Manchikanti, L. TI ICD-10: History and Context SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Article ID CLASSIFICATIONS; GROWTH; FAMILY; READY AB In recent months, organized medicine has been consumed by the anticipated transition to the 10th iteration of the International Classification of Disease system. Implementation has come and gone without the disruptive effects predicted by many. Despite the fundamental role the International Classification of Disease system plays in health care delivery and payment policy, few neuroradiologists are familiar with the history of its implementation and implications beyond coding for diseases. C1 [Hirsch, J. A.; Liu, R. W.; Chittle, M. D.] Harvard Univ, Massachusetts Gen Hosp, Dept Radiol, Sch Med, 55 Fruit St,Gray Bldg 2nd Floor, Boston, MA 02114 USA. [Nicola, G.] Univ Med Ctr, Dept Radiol, Hackensack Radiol Grp, River Edge, NJ USA. [McGinty, G.] Weill Cornell Med Coll, Dept Radiol, New York, NY USA. [Barr, R. M.] Mecklenburg Radiol Associates, Charlotte, NC USA. [Manchikanti, L.] Univ Louisville, Pain Management Ctr Paducah, Dept Anesthesiol & Perioperat Med, Paducah, KY USA. RP Hirsch, JA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Dept Radiol, Sch Med, 55 Fruit St,Gray Bldg 2nd Floor, Boston, MA 02114 USA. EM jahirsch@mgh.harvard.edu OI McGinty, Geraldine/0000-0001-6111-2514 NR 21 TC 1 Z9 1 U1 1 U2 2 PU AMER SOC NEURORADIOLOGY PI DENVILLE PA PO BOX 3000, DENVILLE, NJ 07834-9349 USA SN 0195-6108 EI 1936-959X J9 AM J NEURORADIOL JI Am. J. Neuroradiol. PD APR PY 2016 VL 37 IS 4 BP 596 EP 599 DI 10.3174/ajnr.A4696 PG 4 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DI2RV UT WOS:000373346900010 PM 26822730 ER PT J AU Das, F Ghosh-Choudhury, N Mariappan, MM Kasinath, BS Choudhury, GG AF Das, Falguni Ghosh-Choudhury, Nandini Mariappan, Meenalakshmi M. Kasinath, Balakuntalam S. Choudhury, Goutam Ghosh TI Hydrophobic motif site-phosphorylated protein kinase C beta II between mTORC2 and Akt regulates high glucose-induced mesangial cell hypertrophy SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE diabetic nephropathy; signal transduction; mTOR complex; protein kinase C ID GROWTH-FACTOR-BETA; DIABETIC-NEPHROPATHY; RENAL HYPERTROPHY; IN-VIVO; PHOSPHOINOSITIDE 3-KINASE; TRANSPLANT RECIPIENTS; RAPAMYCIN COMPLEXES; DIACYLGLYCEROL MASS; ENDOTHELIAL-CELLS; BINDING PARTNER AB PKC beta II controls the pathologic features of diabetic nephropathy, including glomerular mesangial cell hypertrophy. PKC beta II contains the COOH-terminal hydrophobic motif site Ser-660. Whether this hydrophobic motif phosphorylation contributes to high glucose-induced mesangial cell hypertrophy has not been determined. Here we show that, in mesangial cells, high glucose increased phosphorylation of PKC beta II at Ser-660 in a phosphatidylinositol 3-kinase (PI3-kinase)-dependent manner. Using siRNAs to downregulate PKC beta II, dominant negative PKC beta II, and PKC beta II hydrophobic motif phosphorylation-deficient mutant, we found that PKCbII regulates activation of mechanistic target of rapamycin complex 1 (mTORC1) and mesangial cell hypertrophy by high glucose. PKCbII via its phosphorylation at Ser-660 regulated phosphorylation of Akt at both catalytic loop and hydrophobic motif sites, resulting in phosphorylation and inactivation of its substrate PRAS40. Specific inhibition of mTORC2 increased mTORC1 activity and induced mesangial cell hypertrophy. In contrast, inhibition of mTORC2 decreased the phosphorylation of PKC beta II and Akt, leading to inhibition of PRAS40 phosphorylation and mTORC1 activity and prevented mesangial cell hypertrophy in response to high glucose; expression of constitutively active Akt or mTORC1 restored mesangial cell hypertrophy. Moreover, constitutively active PKC beta II reversed the inhibition of high glucose-stimulated Akt phosphorylation and mesangial cell hypertrophy induced by suppression of mTORC2. Finally, using renal cortexes from type 1 diabetic mice, we found that increased phosphorylation of PKC beta II at Ser-660 was associated with enhanced Akt phosphorylation and mTORC1 activation. Collectively, our findings identify a signaling route connecting PI3-kinase to mTORC2 to phosphorylate PKC beta II at the hydrophobic motif site necessary for Akt phosphorylation and mTORC1 activation, leading to mesangial cell hypertrophy. C1 [Das, Falguni; Mariappan, Meenalakshmi M.; Kasinath, Balakuntalam S.; Choudhury, Goutam Ghosh] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Mail Code 7882,7703 Floyd Curl Dr, San Antonio, TX 78229 USA. [Ghosh-Choudhury, Nandini; Kasinath, Balakuntalam S.; Choudhury, Goutam Ghosh] South Texas Vet Hlth Care Syst, Vet Affairs Res, San Antonio, TX USA. [Choudhury, Goutam Ghosh] South Texas Vet Hlth Care Syst, Geriatr Res Educ & Clin Res, San Antonio, TX USA. [Ghosh-Choudhury, Nandini] Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78229 USA. RP Choudhury, GG (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Mail Code 7882,7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM choudhuryg@uthscsa.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [R01-DK-50190]; Veterans Affairs (VA) Research Service Merit Review Grant [5I01BX000926]; VA Senior Research Career Scientist Award; VA Merit Review Grants [5I01BX000150, 5I01BX001340] FX This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant R01-DK-50190 and Veterans Affairs (VA) Research Service Merit Review Grant 5I01BX000926 (to G. G. Choudhury). G. G. Choudhury is a recipient of VA Senior Research Career Scientist Award. N. Ghosh-Choudhury and B. S. Kasinath are supported by VA Merit Review Grants 5I01BX000150 and 5I01BX001340, respectively. NR 87 TC 1 Z9 1 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 EI 1522-1563 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD APR 1 PY 2016 VL 310 IS 7 BP C583 EP C596 DI 10.1152/ajpcell.00266.2015 PG 14 WC Cell Biology; Physiology SC Cell Biology; Physiology GA DI1RR UT WOS:000373273900009 PM 26739493 ER PT J AU Wang, J Han, L Sinnett-Smith, J Han, LL Stevens, JV Rozengurt, N Young, SH Rozengurt, E AF Wang, Jia Han, Liang Sinnett-Smith, James Han, Li-Li Stevens, Jan V. Rozengurt, Nora Young, Steven H. Rozengurt, Enrique TI Positive cross talk between protein kinase D and beta-catenin in intestinal epithelial cells: impact on beta-catenin nuclear localization and phosphorylation at Ser552 SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE G protein-coupled receptors; angiotensin II; IEC-18 cells; PKA; PKD family inhibitors; CRT006610; kb NB 142-70; PKD1 transgenic mice ID ACTIVATION LOOP SER(744); STEM-CELLS; IN-VIVO; ANG-II; G(Q)-COUPLED RECEPTORS; SIGNALING PATHWAYS; COUPLED RECEPTOR; ANGIOTENSIN-II; DNA-SYNTHESIS; LYSOPHOSPHATIDIC ACID AB Given the fundamental role of beta-catenin signaling in intestinal epithelial cell proliferation and the growth-promoting function of protein kinase D1 (PKD1) in these cells, we hypothesized that PKDs mediate cross talk with beta-catenin signaling. The results presented here provide several lines of evidence supporting this hypothesis. We found that stimulation of intestinal epithelial IEC-18 cells with the G protein-coupled receptor (GPCR) agonist angiotensin II (ANG II), a potent inducer of PKD activation, promoted endogenous beta-catenin nuclear localization in a time-dependent manner. A significant increase was evident within 1 h of ANG II stimulation (P < 0.01), peaked at 4 h (P < 0.001), and declined afterwards. GPCR stimulation also induced a marked increase in beta-catenin-regulated genes and phosphorylation at Ser(552) in intestinal epithelial cells. Exposure to preferential inhibitors of the PKD family (CRT006610 or kb NB 142-70) or knockdown of the isoforms of the PKD family prevented the increase in beta-catenin nuclear localization and phosphorylation at Ser(552) in response to ANG II. GPCR stimulation also induced the formation of a complex between PKD1 and beta-catenin, as shown by coimmuno-precipitation that depended on PKD1 catalytic activation, as it was abrogated by cell treatment with PKD family inhibitors. Using transgenic mice that express elevated PKD1 protein in the intestinal epithelium, we detected a marked increase in the localization of beta-catenin in the nucleus of crypt epithelial cells in the ileum of PKD1 transgenic mice, compared with nontransgenic littermates. Collectively, our results identify a novel cross talk between PKD and beta-catenin in intestinal epithelial cells, both in vitro and in vivo. C1 [Wang, Jia; Han, Liang; Sinnett-Smith, James; Han, Li-Li; Stevens, Jan V.; Young, Steven H.; Rozengurt, Enrique] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Digest Dis, Los Angeles, CA 90095 USA. [Sinnett-Smith, James; Rozengurt, Nora; Rozengurt, Enrique] Digest Dis Res Ctr, CURE, Los Angeles, CA USA. [Rozengurt, Enrique] Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA. [Sinnett-Smith, James; Young, Steven H.; Rozengurt, Enrique] Vet Affairs Greater Los Angeles Hlth Care Syst, Los Angeles, CA USA. RP Rozengurt, E (reprint author), Univ Calif Los Angeles, Sch Med, Dept Med, Warren Hall Rm 11-124,900 Vet Ave, Los Angeles, CA 90095 USA. EM erozengurt@mednet.ucla.edu FU National Institutes of Health [R01-DK-100405, P30-DK-41301, P01-CA-163200]; Department of Veterans Affair Grant [1I01BX001473]; Chinese Scholarship Council FX This work was supported by National Institutes of Health Grants R01-DK-100405, P30-DK-41301, and P01-CA-163200 and by Department of Veterans Affair Grant 1I01BX001473 (to E. Rozengurt). L. Han and L.-L. Han were both supported by a scholarship from the Chinese Scholarship Council. NR 85 TC 0 Z9 0 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 EI 1522-1563 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD APR 1 PY 2016 VL 310 IS 7 BP C542 EP C557 DI 10.1152/ajpcell.00302.2015 PG 16 WC Cell Biology; Physiology SC Cell Biology; Physiology GA DI1RR UT WOS:000373273900005 PM 26739494 ER PT J AU Patterson, RE Kalavalapalli, S Williams, CM Nautiyal, M Mathew, JT Martinez, J Reinhard, MK McDougall, DJ Rocca, JR Yost, RA Cusi, K Garrett, TJ Sunny, NE AF Patterson, Rainey E. Kalavalapalli, Srilaxmi Williams, Caroline M. Nautiyal, Manisha Mathew, Justin T. Martinez, Janie Reinhard, Mary K. McDougall, Danielle J. Rocca, James R. Yost, Richard A. Cusi, Kenneth Garrett, Timothy J. Sunny, Nishanth E. TI Lipotoxicity in steatohepatitis occurs despite an increase in tricarboxylic acid cycle activity SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE steatosis; hepatic insulin resistance; mitochondria; nonalcoholic steatohepatitis ID NONALCOHOLIC FATTY LIVER; HEPATIC INSULIN-RESISTANCE; TCA CYCLE; MITOCHONDRIAL DYSFUNCTION; GLUCOSE-PRODUCTION; AMINO-ACIDS; DISEASE; METABOLISM; MODEL; GLUCONEOGENESIS AB The hepatic tricarboxylic acid (TCA) cycle is central to integrating macro-nutrient metabolism and is closely coupled to cellular respiration, free radical generation, and inflammation. Oxidative flux through the TCA cycle is induced during hepatic insulin resistance, in mice and humans with simple steatosis, reflecting early compensatory remodeling of mitochondrial energetics. We hypothesized that progressive severity of hepatic insulin resistance and the onset of nonalcoholic steatohepatitis (NASH) would impair oxidative flux through the hepatic TCA cycle. Mice (C57/BL6) were fed a high-trans-fat high-fructose diet (TFD) for 8 wk to induce simple steatosis and NASH by 24 wk. In vivo fasting hepatic mitochondrial fluxes were determined by C-13-nuclear magnetic resonance (NMR)-based isotopomer analysis. Hepatic metabolic intermediates were quantified using mass spectrometry- based targeted metabolomics. Hepatic triglyceride accumulation and insulin resistance preceded alterations in mitochondrial metabolism, since TCA cycle fluxes remained normal during simple steatosis. However, mice with NASH had a twofold induction (P < 0.05) of mitochondrial fluxes (mu mol/min) through the TCA cycle (2.6 +/- 0.5 vs. 5.4 +/- 0.6), anaplerosis (9.1 +/- 1.2 vs. 16.9 +/- 2.2), and pyruvate cycling (4.9 +/- 1.0 vs. 11.1 +/- 1.9) compared with their age-matched controls. Induction of the TCA cycle activity during NASH was concurrent with blunted ketogenesis and accumulation of hepatic diacylglycerols (DAGs), ceramides (Cer), and long-chain acylcar-nitines, suggesting inefficient oxidation and disposal of excess free fatty acids (FFA). Sustained induction of mitochondrial TCA cycle failed to prevent accretion of "lipotoxic" metabolites in the liver and could hasten inflammation and the metabolic transition to NASH. C1 [Patterson, Rainey E.; McDougall, Danielle J.; Yost, Richard A.] Univ Florida, Dept Chem, Gainesville, FL 32610 USA. [Kalavalapalli, Srilaxmi; Nautiyal, Manisha; Mathew, Justin T.; Martinez, Janie; Cusi, Kenneth; Sunny, Nishanth E.] Univ Florida, Dept Med, Div Endocrinol Diabet & Metab, 1600 SW Archer Rd, Gainesville, FL 32610 USA. [Williams, Caroline M.] Univ Calif Berkeley, Dept Integrat Biol, Berkeley, CA 94720 USA. [Reinhard, Mary K.] Univ Florida, Anim Care Serv, Gainesville, FL 32610 USA. [Rocca, James R.] Univ Florida, McKnight Brain Inst, Adv Magnet Resonance Imaging & Spect Facil, Gainesville, FL 32610 USA. [Cusi, Kenneth] Malcom Randall Vet Adm Med Ctr, Div Endocrinol Diabet & Metab, Gainesville, FL USA. [Cusi, Kenneth] Univ Texas Hlth Sci Ctr San Antonio, Div Diabet, San Antonio, TX 78229 USA. [Cusi, Kenneth] Audie L Murphy Vet Adm Med Ctr, Div Diabet, San Antonio, TX USA. [Yost, Richard A.; Garrett, Timothy J.] Univ Florida, Dept Pathol, Gainesville, FL 32610 USA. RP Sunny, NE (reprint author), Univ Florida, Dept Med, Div Endocrinol Diabet & Metab, 1600 SW Archer Rd, Gainesville, FL 32610 USA. EM nishanth.sunny@medicine.ufl.edu FU University of Florida [00089467]; Southeast Center for Integrated Metabolomics National Institute of Diabetes and Digestive and Kidney Diseases Grant [U24-DK-097209]; National Center for Research Resources Clinical and Translational Science Award [UL1-TR-00064]; National Institutes of Health FX This work was supported by a University of Florida Research Opportunity Seed Fund Award (00089467; to N. E. Sunny), a Southeast Center for Integrated Metabolomics National Institute of Diabetes and Digestive and Kidney Diseases Grant (U24-DK-097209), and a National Institutes of Health and National Center for Research Resources Clinical and Translational Science Award to the University of Florida (UL1-TR-00064). NR 45 TC 4 Z9 4 U1 2 U2 8 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 EI 1522-1555 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD APR 1 PY 2016 VL 310 IS 7 BP E484 EP E494 DI 10.1152/ajpendo.00492.2015 PG 11 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA DI1RJ UT WOS:000373272900002 PM 26814015 ER PT J AU Blevins, JE Thompson, BW Anekonda, VT Ho, JM Graham, JL Roberts, ZS Hwang, BH Ogimoto, K Wolden-Hanson, T Nelson, J Kaiyala, KJ Havel, PJ Bales, KL Morton, GJ Schwartz, MW Baskin, DG AF Blevins, James E. Thompson, Benjamin W. Anekonda, Vishwanath T. Ho, Jacqueline M. Graham, James L. Roberts, Zachary S. Hwang, Bang H. Ogimoto, Kayoko Wolden-Hanson, Tami Nelson, Jarrell Kaiyala, Karl J. Havel, Peter J. Bales, Karen L. Morton, Gregory J. Schwartz, Michael W. Baskin, Denis G. TI Chronic CNS oxytocin signaling preferentially induces fat loss in high-fat diet-fed rats by enhancing satiety responses and increasing lipid utilization SO AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY LA English DT Article DE obesity; food intake; energy expenditure; oxytocin ID BROWN ADIPOSE-TISSUE; TYPE-2 DIABETIC-PATIENTS; CAUSES WEIGHT-LOSS; NERVOUS-SYSTEM OUTFLOW; INDUCED OBESE RATS; FOOD-INTAKE; ENERGY-EXPENDITURE; PARAVENTRICULAR NUCLEUS; METABOLIC SYNDROME; BODY-WEIGHT AB Based largely on a number of short-term administration studies, growing evidence suggests that central oxytocin is important in the regulation of energy balance. The goal of the current work is to determine whether long-term third ventricular (3V) infusion of oxytocin into the central nervous system (CNS) is effective for obesity prevention and/or treatment in rat models. We found that chronic 3V oxytocin infusion between 21 and 26 days by osmotic minipumps both reduced weight gain associated with the progression of high-fat diet (HFD)-induced obesity and elicited a sustained reduction of fat mass with no decrease of lean mass in rats with established diet-induced obesity. We further demonstrated that these chronic oxytocin effects result from 1) maintenance of energy expenditure at preintervention levels despite ongoing weight loss, 2) a reduction in respiratory quotient, consistent with increased fat oxidation, and 3) an enhanced satiety response to cholecystokinin-8 and associated decrease of meal size. These weight-reducing effects persisted for approximately 10 days after termination of 3V oxytocin administration and occurred independently of whether sucrose was added to the HFD. We conclude that long-term 3V administration C1 [Blevins, James E.; Thompson, Benjamin W.; Anekonda, Vishwanath T.; Ho, Jacqueline M.; Roberts, Zachary S.; Hwang, Bang H.; Wolden-Hanson, Tami; Baskin, Denis G.] Vet Affairs Puget Sound Hlth Care Syst, Off Res & Dev Med Res Serv, Dept Vet Affairs Med Ctr, Seattle, WA 98108 USA. [Blevins, James E.; Ho, Jacqueline M.; Morton, Gregory J.; Schwartz, Michael W.; Baskin, Denis G.] Univ Washington, Sch Med, Dept Med, Div Metab Endocrinol & Nutr, Seattle, WA 98195 USA. [Ogimoto, Kayoko; Nelson, Jarrell; Morton, Gregory J.; Schwartz, Michael W.] Univ Washington, Sch Med, Diabet & Obes Ctr Excellence, Seattle, WA USA. [Kaiyala, Karl J.] Univ Washington, Sch Dent, Dept Oral Hlth Sci, Seattle, WA 98195 USA. [Graham, James L.; Havel, Peter J.] Univ Calif Davis, Sch Vet Med, Dept Nutr, Davis, CA 95616 USA. [Graham, James L.; Havel, Peter J.] Univ Calif Davis, Sch Vet Med, Dept Mol Biosci, Davis, CA 95616 USA. [Bales, Karen L.] Univ Calif Davis, Dept Psychol, Davis, CA 95616 USA. RP Blevins, JE (reprint author), VA Puget Sound Hlth Care Syst, Res 151, 1660 South Columbian Way, Seattle, WA 98108 USA. EM jeblevin@u.washington.edu FU Office of Research and Development, Medical Research Service, Department of Veterans Affairs (VA); VA Puget Sound Health Care System Rodent Metabolic and Behavioral Phenotyping Core; Cellular and Molecular Imaging Core of the Diabetes Research Center at the University of Washington; National Institutes of Health (NIH) [P30DK017047, P30 DK035816, P30DK017047-31689, 2T32DK007247]; Energy Balance and Glucose Metabolism Core of the Nutrition Obesity Research Center at the University of Washington; Department of Veterans Affairs Biomedical Laboratory R&D Merit Review Program; NIH [DK-095980, HL-091333, HL-107256]; University of California Office of the President; VA Senior Research Career Scientist award FX This material is based upon work supported by the Office of Research and Development, Medical Research Service, Department of Veterans Affairs (VA), the VA Puget Sound Health Care System Rodent Metabolic and Behavioral Phenotyping Core, and the Cellular and Molecular Imaging Core of the Diabetes Research Center at the University of Washington. This study was supported by National Institutes of Health (NIH) Grant P30DK017047. This work is also supported by the Energy Balance and Glucose Metabolism Core of the Nutrition Obesity Research Center at the University of Washington and supported by National Institutes of Health (NIH) Grant P30 DK035816. The research in our laboratory has been supported by the Department of Veterans Affairs Biomedical Laboratory R&D Merit Review Program as well as National Institutes of Health Grants P30DK017047-31689 and the Diabetes, Obesity, and Metabolism Training Grant 2T32DK007247. P. J. Havel's research program also receives research support from NIH Grants DK-095980, HL-091333, HL-107256, HL-107256 and a Multi-campus grant from the University of California Office of the President. D. G. Baskin is the recipient of a VA Senior Research Career Scientist award. NR 105 TC 6 Z9 6 U1 1 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6119 EI 1522-1490 J9 AM J PHYSIOL-REG I JI Am. J. Physiol.-Regul. Integr. Comp. Physiol. PD APR 1 PY 2016 VL 310 IS 7 BP R640 EP R658 DI 10.1152/ajpregu.00220.2015 PG 19 WC Physiology SC Physiology GA DI1PU UT WOS:000373268800012 PM 26791828 ER PT J AU Stites, M Pianykh, OS AF Stites, Mark Pianykh, Oleg S. TI How Secure Is Your Radiology Department? Mapping Digital Radiology Adoption and Security Worldwide SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE DICOM; firewall; networking; PACS; security ID MEDICAL IMAGES; WATERMARKING AB OBJECTIVE. Despite the long history of digital radiology, one of its most critical aspects-information security-still remains extremely underdeveloped and poorly standardized. To study the current state of radiology security, we explored the worldwide security of medical image archives. MATERIALS AND METHODS. Using the DICOM data-transmitting standard, we implemented a highly parallel application to scan the entire World Wide Web of networked computers and devices, locating open and unprotected radiology servers. We used only legal and radiology-compliant tools. Our security-probing application initiated a standard DICOM handshake to remote computer or device addresses, and then assessed their security posture on the basis of handshake replies. RESULTS. The scan discovered a total of 2774 unprotected radiology or DICOM servers worldwide. Of those, 719 were fully open to patient data communications. Geolocation was used to analyze and rank our findings according to country utilization. As a result, we built maps and world ranking of clinical security, suggesting that even the most radiology-advanced countries have hospitals with serious security gaps. CONCLUSION. Despite more than two decades of active development and implementation, our radiology data still remains insecure. The results provided should be applied to raise awareness and begin an earnest dialogue toward elimination of the problem. The application we designed and the novel scanning approach we developed can be used to identify security breaches and to eliminate them before they are compromised. C1 [Stites, Mark] Harvard Univ, Sch Med, Harvard Extens Sch, Grad Div, Boston, MA 02114 USA. [Pianykh, Oleg S.] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, 25 New Chardon St,Off 470, Boston, MA 02114 USA. [Pianykh, Oleg S.] Natl Res Univ Higher Sch Econ, Sch Data Anal & Artificial Intelligence, Moscow, Russia. RP Pianykh, OS (reprint author), Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, 25 New Chardon St,Off 470, Boston, MA 02114 USA.; Pianykh, OS (reprint author), Natl Res Univ Higher Sch Econ, Sch Data Anal & Artificial Intelligence, Moscow, Russia. EM opiany@gmail.com NR 12 TC 1 Z9 1 U1 3 U2 5 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 APR PY 2016 VL 206 IS 4 BP 797 EP 804 DI 10.2214/AJR.15.15283 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DH5BJ UT WOS:000372799700025 PM 26934387 ER PT J AU Morgan, TA Chandran, S Burger, IM Zhang, CA Goldstein, RB AF Morgan, T. A. Chandran, S. Burger, I. M. Zhang, C. A. Goldstein, R. B. TI Complications of Ultrasound-Guided Renal Transplant Biopsies SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article ID KIDNEY BIOPSY; CORE BIOPSY; SAFETY; NEEDLE; GUN; ALLOGRAFTS; ADEQUACY; EFFICACY; YIELD; TRIAL AB Renal transplant biopsies to diagnose transplant pathology are routinely performed using ultrasound guidance. Few large studies have assessed the rate and risk factors of major biopsy complications. This study is a single-center 5-year retrospective cohort analysis of 2514 biopsies. Major complications occurred in 47 of 2514 patients (1.9%) and included hospitalization, transfusion of blood products, operative exploration and interventional radiology procedures. The complication rate among cause biopsies was significantly higher than in protocol biopsies (2.7% vs. 0.33%, p < 0.001). Complications presented on postbiopsy days 0-14, with the majority diagnosed on the same day as the biopsy and manifested by hematocrit drop, although the presence of such delayed presentation of complications occurring >24 h after the biopsy on days 2-14 is previously unreported. Specific patient characteristics associated with increased risk of a complication were increased age and blood urea nitrogen, decreased platelet count, history of prior renal transplant, deceased donor transplant type and use of anticoagulant medications but not aspirin. The authors review the incidence of major complications associated with ultrasound-guided renal transplant biopsies, including timing, presentation, and association with clinical factors, including patient demographics and prebiopsy laboratory values. C1 [Morgan, T. A.; Zhang, C. A.; Goldstein, R. B.] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [Chandran, S.] Univ Calif San Francisco, Dept Med, Kidney Transplant Serv, Div Nephrol, San Francisco, CA USA. [Burger, I. M.] Kaiser Permanente Los Angeles, VA Greater Angeles Healthcare Syst, Dept Radiol, Los Angeles, CA USA. RP Morgan, TA (reprint author), Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. EM tara.morgan@ucsf.edu NR 25 TC 2 Z9 2 U1 0 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 APR PY 2016 VL 16 IS 4 BP 1298 EP 1305 DI 10.1111/ajt.13622 PG 8 WC Surgery; Transplantation SC Surgery; Transplantation GA DH8VQ UT WOS:000373075400031 PM 26601796 ER PT J AU Pejo, E Liu, JF Lin, XJ Raines, DE AF Pejo, Ervin Liu, Jifeng Lin, Xiangjie Raines, Douglas E. TI Distinct Hypnotic Recoveries After Infusions of Methoxycarbonyl Etomidate and Cyclopropyl Methoxycarbonyl Metomidate: The Role of the Metabolite SO ANESTHESIA AND ANALGESIA LA English DT Article ID RETROMETABOLIC DRUG DESIGN; IN-VITRO; ENZYMATIC-HYDROLYSIS; ACID METABOLITE; RENAL-FAILURE; PHARMACOKINETICS; PHARMACODYNAMICS; REMIFENTANIL; ESMOLOL; ANALOG AB BACKGROUND: Methoxycarbonyl etomidate (MOC-etomidate) and cyclopropyl methoxycarbonyl metomidate (CPMM) are rapidly metabolized soft etomidate analogs. CPMM's duration of hypnotic effect is context insensitive, whereas MOC-etomidate's is not. In this study, we tested the hypothesis that CPMM's effect is context insensitive because, unlike MOC-etomidate, its metabolite fails to reach physiologically important concentrations in vivo even with prolonged continuous infusion. METHODS: We compared the potencies with which MOC-etomidate and CPMM activate (1)(L264T)(32) -aminobutyric acid type A receptors and induce loss-of-righting reflexes (i.e., produce hypnosis) in tadpoles with those of their metabolites (MOC-etomidate's carboxylic acid metabolite [MOC-ECA] and CPMM's carboxylic acid metabolite [CPMM-CA], respectively). We measured metabolite concentrations in the blood and cerebrospinal fluid of Sprague-Dawley rats on CPMM infusion and compared them with those achieved with MOC-etomidate infusion. We measured the rates with which brain tissue from Sprague-Dawley rats metabolize MOC-etomidate and CPMM. RESULTS: Both analogs and their metabolites enhanced -aminobutyric acid type A receptor function and induced loss-of-righting reflexes in a concentration-dependent manner. However, in these 2 assays, CPMM-CA's potency relative to its parent hypnotic was approximately 1:4900 and 1:1900, respectively, whereas MOC-ECA's was only approximately 1:415 and 1:390, respectively. With 2-hour CPMM infusions, CPMM-CA reached respective concentrations in the blood and cerebrospinal fluid that were 2 and >3 orders of magnitude lower than that which produced hypnosis. CPMM was metabolized by the brain tissue at a rate that is approximately 1/15th that of MOC-etomidate. CONCLUSIONS: Hypnotic recovery after CPMM administration is context insensitive because its metabolite does not accumulate to hypnotic levels in the central nervous system. This reflects the very large potency ratio between CPMM and CPMM-CA and the resistance of CPMM to metabolism by esterases present in the brain. C1 [Pejo, Ervin; Raines, Douglas E.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA. [Liu, Jifeng; Lin, Xiangjie] Aberjona Labs, Woburn, MA USA. RP Raines, DE (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA. EM draines@partners.org FU Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts; [R01-GM087316] FX This research was supported by grant R01-GM087316 to DER and by the Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts. NR 27 TC 1 Z9 1 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD APR PY 2016 VL 122 IS 4 BP 1008 EP 1014 DI 10.1213/ANE.0000000000001146 PG 7 WC Anesthesiology SC Anesthesiology GA DG8OQ UT WOS:000372343900001 PM 26991617 ER PT J AU Yuan, J Cui, GY Li, WL Zhang, XL Wang, XY Zheng, H Zhang, J Xiang, SL Xie, ZC AF Yuan, Jing Cui, Guiyun Li, Wenlu Zhang, Xiaoli Wang, Xiaoying Zheng, Hui Zhang, Jian Xiang, Shuanglin Xie, Zhongcong TI Propofol Enhances Hemoglobin-Induced Cytotoxicity in Neurons SO ANESTHESIA AND ANALGESIA LA English DT Article ID PERMEABILITY TRANSITION PORE; CEREBRAL-ISCHEMIA; CORTICAL-NEURONS; IN-VITRO; NEUROPROTECTION; ACTIVATION; INJURY; BRAIN; NEUROTOXICITY; APOPTOSIS AB BACKGROUND: It has been increasingly suggested that propofol protects against hypoxic-/ischemic-induced neuronal injury. As evidenced by hemorrhage-induced stroke, hemorrhage into the brain may also cause brain damage. Whether propofol protects against hemorrhage-induced brain damage remains unknown. Therefore, in this study, we investigated the effects of propofol on hemoglobin-induced cytotoxicity in cultured mouse cortical neurons. METHODS: Neurons were prepared from the cortex of embryonic 15-day-old mice. Hemoglobin was used to induce cytotoxicity in the neurons. The neurons were then treated with propofol for 4 hours. Cytotoxicity was determined by lactate dehydrogenase release assay. Caspase-3 activation was examined by Western blot analysis. Finally, the free radical scavenger U83836E was used to examine the potential involvement of oxidative stress in propofol's effects on hemoglobin-induced cytotoxicity. RESULTS: We found that treatment with hemoglobin induced cytotoxicity in the neurons. Propofol enhanced hemoglobin-induced cytotoxicity. Specifically, there was a significant difference in the amount of lactate dehydrogenase release between hemoglobin plus saline (19.84% +/- 5.38%) and hemoglobin plus propofol (35.79% +/- 4.41%) in mouse cortical neurons (P = 0.00058, Wilcoxon Mann-Whitney U test, n = 8 in the control group or the treatment group). U83836E did not attenuate the enhancing effects of propofol on hemoglobin-induced cytotoxicity in the neurons, and propofol did not significantly affect caspase-3 activation induced by hemoglobin. These data suggested that caspase-3 activation and oxidative stress might not be the underlying mechanisms by which propofol enhanced hemoglobin-induced cytotoxicity. Moreover, these data suggested that the neuroprotective effects of propofol would be dependent on the condition of the brain injury, which will need to be confirmed in future studies. CONCLUSIONS: These results from our current proof-of-concept study should promote more research in vitro and in vivo to develop better anesthesia care for patients with hemorrhagic stroke. C1 [Yuan, Jing; Zhang, Jian; Xiang, Shuanglin] Hunan Normal Univ, Key Lab Prot Biochem & Dev Biol, State Educ Minist, Coll Life Sci, Changsha 410081, Hunan, Peoples R China. [Yuan, Jing; Li, Wenlu; Zhang, Xiaoli; Wang, Xiaoying] Massachusetts Gen Hosp, Neuroprotect Res Lab, Charlestown, MA USA. [Yuan, Jing; Li, Wenlu; Zhang, Xiaoli; Wang, Xiaoying] Massachusetts Gen Hosp, Dept Radiol, Charlestown, MA USA. [Yuan, Jing; Li, Wenlu; Zhang, Xiaoli; Wang, Xiaoying] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA USA. [Yuan, Jing; Li, Wenlu; Zhang, Xiaoli; Wang, Xiaoying] Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02129 USA. [Cui, Guiyun] Xuzhou Med Coll, Affiliated Hosp, Dept Neurol, Xuzhou, Jiangsu, Peoples R China. [Cui, Guiyun; Xie, Zhongcong] Harvard Univ, Geriatr Anesthesia Res Unit, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med,Sch Med, 149,13th St,Room 4310, Charlestown, MA 02129 USA. [Zheng, Hui] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Biostat, Charlestown, MA 02129 USA. RP Xie, ZC (reprint author), Harvard Univ, Geriatr Anesthesia Res Unit, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med,Sch Med, 149,13th St,Room 4310, Charlestown, MA 02129 USA.; Xiang, SL (reprint author), Hunan Normal Univ, Coll Life Sci, State Educ Minist, Key Lab Prot Chem & Dev Biol, Changsha 410081, Hunan, Peoples R China. EM xshlin@hunnu.edu.cn; zxie@mgh.harvard.edu FU National Institutes of Health, Bethesda, MD [R01 GM088801, R01 AG041274]; Alzheimer's Association, Chicago, IL; Cure Alzheimer's Fund, Wellesley, MA FX This research was supported by R01 GM088801 and R01 AG041274 from the National Institutes of Health, Bethesda, MD; the Investigator-initiated research grant from Alzheimer's Association, Chicago, IL; and Cure Alzheimer's Fund, Wellesley, MA (to ZX). NR 26 TC 2 Z9 2 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD APR PY 2016 VL 122 IS 4 BP 1024 EP 1030 DI 10.1213/ANE.0000000000001123 PG 7 WC Anesthesiology SC Anesthesiology GA DG8OQ UT WOS:000372343900003 PM 26771264 ER PT J AU Aplin, AC Nicosia, RF AF Aplin, Alfred C. Nicosia, Roberto F. TI Hypoxia paradoxically inhibits the angiogenic response of isolated vessel explants while inducing overexpression of vascular endothelial growth factor SO ANGIOGENESIS LA English DT Article DE Endothelial cells; Pericytes; Neovessels; Vascular endothelial growth factor; Aorta; Vein; Collagen; Neovascularization ID AORTIC RING MODEL; SOLUBLE VEGF RECEPTOR-1; RAT AORTA; IN-VITRO; OXYGEN; CELLS; PERMEABILITY; EXPRESSION; SYSTEM; PHOSPHORYLATION AB This study was designed to investigate how changes in O-2 levels affected angiogenesis in vascular organ culture. Although hypoxia is a potent inducer of angiogenesis, aortic rings cultured in collagen paradoxically failed to produce an angiogenic response in 1-4 % O-2. Additionally, aortic neovessels preformed in atmospheric O-2 lost pericytes and regressed at a faster rate than control when exposed to hypoxia. Aortic explants remained viable in hypoxia and produced an angiogenic response when returned to atmospheric O-2. Hypoxic aortic rings were unresponsive to VEGF, while increased oxygenation of the system dose-dependently enhanced VEGF-induced angiogenesis. Hypoxia-induced refractoriness to angiogenic stimulation was not restricted to the aorta because similar results were obtained with vena cava explants or isolated endothelial cells. Unlike endothelial cells, aorta-derived mural cells were unaffected by hypoxia. Hypoxia downregulated expression in aortic explants of key signaling molecules including VEGFR2, NRP1 and Prkc-beta while upregulating expression of VEGFR1. Medium conditioned by hypoxic cultures exhibited angiostatic and anti-VEGF activities likely mediated by sVEGFr1. Hypoxia reduced expression of VEGFR1 and VEGFR2 in endothelial cells while upregulating VEGFR1 in macrophages and VEGF in both macrophages and mural cells. Thus, changes in O-2 levels profoundly affect the endothelial response to angiogenic stimuli. These results suggest that hypoxia-induced angiogenesis is fine-tuned by complex regulatory mechanisms involving not only production of angiogenic factors including VEGF but also differential regulation of VEGFR expression in different cell types and production of inhibitors of VEGF function such as sVEGFR1. C1 [Aplin, Alfred C.; Nicosia, Roberto F.] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [Nicosia, Roberto F.] VA Puget Sound Hlth Care Syst, Pathol & Lab Med Serv S Lab 113, Seattle, WA USA. RP Nicosia, RF (reprint author), Univ Washington, Dept Pathol, Seattle, WA 98195 USA.; Nicosia, RF (reprint author), VA Puget Sound Hlth Care Syst, Pathol & Lab Med Serv S Lab 113, Seattle, WA USA. EM Roberto.Nicosia@va.gov FU United States (U.S.) Department of Veterans Affairs Biomedical Laboratory Research and Development Service; American Heart Association FX This work was supported in part by a Merit Review Award from the United States (U.S.) Department of Veterans Affairs Biomedical Laboratory Research and Development Service. The contents do not represent the views of the U.S. Department of Veteran Affairs or the United States Government. In addition, we gratefully acknowledge the support of a grant-in-aid from the American Heart Association. NR 55 TC 2 Z9 2 U1 1 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0969-6970 EI 1573-7209 J9 ANGIOGENESIS JI Angiogenesis PD APR PY 2016 VL 19 IS 2 BP 133 EP 146 DI 10.1007/s10456-015-9493-2 PG 14 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DI0IK UT WOS:000373178900003 PM 26748649 ER PT J AU Wang, RC Rodriguez, RM Moghadassi, M Noble, V Bailitz, J Mallin, M Corbo, J Kang, TL Chu, P Shiboski, S Smith-Bindman, R AF Wang, Ralph C. Rodriguez, Robert M. Moghadassi, Michelle Noble, Vicki Bailitz, John Mallin, Mike Corbo, Jill Kang, Tarina L. Chu, Phillip Shiboski, Steve Smith-Bindman, Rebecca TI External Validation of the STONE Score, a Clinical Prediction Rule for Ureteral Stone: An Observational Multi-institutional Study SO ANNALS OF EMERGENCY MEDICINE LA English DT Article ID ACUTE FLANK PAIN; UNENHANCED HELICAL CT; COMPUTED-TOMOGRAPHY; DECISION RULES; METHODOLOGIC STANDARDS; EMERGENCY-MEDICINE; CALCULI; US; ULTRASONOGRAPHY; NEPHROLITHIASIS AB Study objective: The STONE score is a clinical decision rule that classifies patients with suspected nephrolithiasis into low-, moderate-, and high-score groups, with corresponding probabilities of ureteral stone. We evaluate the STONE score in a multi-institutional cohort compared with physician gestalt and hypothesize that it has a sufficiently high specificity to allow clinicians to defer computed tomography (CT) scan in patients with suspected nephrolithiasis. Methods: We assessed the STONE score with data from a randomized trial for participants with suspected nephrolithiasis who enrolled at 9 emergency departments between October 2011 and February 2013. In accordance with STONE predictors, we categorized participants into low-, moderate-, or high-score groups. We determined the performance of the STONE score and physician gestalt for ureteral stone. Results: Eight hundred forty-five participants were included for analysis; 331 (39%) had a ureteral stone. The global performance of the STONE score was superior to physician gestalt (area under the receiver operating characteristic curve=0.78 [95% confidence interval (CI) 0.74 to 0.81] versus 0.68 [95% CI 0.64 to 0.71]). The prevalence of ureteral stone on CTscan ranged from 14% (95% CI 9% to 19%) to 73% (95% CI 67% to 78%) in the low-, moderate-, and high-score groups. The sensitivity and specificity of a high score were 53% (95% CI 48% to 59%) and 87% (95% CI 84% to 90%), respectively. Conclusion: The STONE score can successfully aggregate patients into low-, medium-, and high-risk groups and predicts ureteral stone with a higher specificity than physician gestalt. However, in its present form, the STONE score lacks sufficient accuracy to allow clinicians to defer CTscan for suspected ureteral stone. C1 [Wang, Ralph C.; Rodriguez, Robert M.] Univ Calif San Francisco, Dept Emergency Med, San Francisco, CA 94143 USA. [Moghadassi, Michelle; Chu, Phillip; Smith-Bindman, Rebecca] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [Shiboski, Steve; Smith-Bindman, Rebecca] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Noble, Vicki] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Bailitz, John] John H Stroger Jr Hosp Cook Cty, Dept Emergency Med, Chicago, IL USA. [Mallin, Mike] Univ Utah, Div Emergency Med, Salt Lake City, UT USA. [Corbo, Jill] Albert Einstein Coll Med, Dept Emergency Med, Jacobi Med Ctr, New York, NY USA. [Kang, Tarina L.] Univ So Calif, Dept Emergency Med, Los Angeles, CA USA. RP Wang, RC (reprint author), Univ Calif San Francisco, Dept Emergency Med, San Francisco, CA 94143 USA. EM ralph.wang@ucsf.edu FU Agency for Healthcare Research and Quality (AHRQ) [K08 HS02181]; National Center for Advancing Translational Sciences (NCATS) [8 KL2 TR000143-08]; American Recovery and Reinvestment Act through AHRQ grant [R01HS019312]; K24 award [NIH K24 CA125036] 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: This study was supported by funding from Agency for Healthcare Research and Quality (AHRQ) grant K08 HS02181 and National Center for Advancing Translational Sciences (NCATS) grant 8 KL2 TR000143-08. The Study of Ultrasonography Versus Computed Tomography for Suspected Nephrolithiasis was supported by the American Recovery and Reinvestment Act of 2009 through AHRQ grant R01HS019312. Rebecca Smith-Bindman received a K24 award (NIH K24 CA125036). NR 30 TC 8 Z9 8 U1 1 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 APR PY 2016 VL 67 IS 4 BP 423 EP 432 DI 10.1016/j.annemergmed.2015.08.019 PG 10 WC Emergency Medicine SC Emergency Medicine GA DI1FK UT WOS:000373241800003 PM 26440490 ER PT J AU Domsic, RT Nihtyanova, SI Wisniewski, SR Fine, MJ Lucas, M Kwoh, CK Denton, CP Medsger, TA AF Domsic, Robyn T. Nihtyanova, Svetlana I. Wisniewski, Stephen R. Fine, Michael J. Lucas, Mary Kwoh, C. Kent Denton, Christopher P. Medsger, Thomas A., Jr. TI Derivation and External Validation of a Prediction Rule for Five-Year Mortality in Patients With Early Diffuse Cutaneous Systemic Sclerosis SO ARTHRITIS & RHEUMATOLOGY LA English DT Article ID CLINICAL-PREDICTION; EUSTAR DATABASE; SCLERODERMA; SURVIVAL; FEATURES; DEATH; EMPHASIS; DISEASE; COHORT; MODEL AB ObjectiveAlthough diffuse cutaneous systemic sclerosis (dcSSc) is associated with a reduction in life expectancy, there are no validated prognostic models for determining 5-year mortality in patients with dcSSc. The objective of this study was to derive and validate a rule for predicting 5-year mortality in patients with early dcSSc. MethodsWe studied an inception cohort of 388 US Caucasian patients with early dcSSc (<2 years from the appearance of the first symptom). Predefined baseline variables were analyzed in a stepwise logistic regression model in order to identify factors independently associated with 5-year all-cause mortality. We rounded the beta weights to the nearest integer and summed the points assigned to each variable in order to stratify patients into low-risk (<0 points), moderate-risk (1-2 points), and high-risk (3 points) groups. We then applied this rule to an external validation cohort of 144 Caucasian patients with early dcSSc from the Royal Free Hospital cohort and compared stratum-specific 5-year mortality. ResultsSix independent predictors (rounded beta weight) comprised the model: age at first visit (points allotted: -1, 0, or 1), male sex (points allotted: 0 or 1), tendon friction rubs (points allotted: 0 or 1), gastrointestinal involvement (points allotted: 0 or 1), RNA polymerase III antibodies (points allotted: 0 or 1), and anemia (points allotted: 0 or 1). The 3-level risk stratification model performed well, with no significant differences between the US derivation cohort and the UK validation cohort. ConclusionWe derived and externally validated, in US and UK cohorts, an easy-to-use 6-variable prediction rule that assigns low-risk, moderate-risk, and high-risk categories for 5-year mortality in patients with early dcSSc. Only history, physical examination, and basic laboratory assessments are required. C1 [Domsic, Robyn T.; Wisniewski, Stephen R.; Lucas, Mary; Medsger, Thomas A., Jr.] Univ Pittsburgh, Pittsburgh, PA USA. [Nihtyanova, Svetlana I.; Denton, Christopher P.] UCL, Sch Med, Royal Free Hosp, Mortimer St, London W1N 8AA, England. [Fine, Michael J.] Univ Pittsburgh, Pittsburgh, PA USA. [Fine, Michael J.] Vet Affairs Pittsburgh Healthcare, Vet Affairs Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. [Kwoh, C. Kent] Univ Arizona, Arthrit Ctr, Tucson, AZ USA. RP Domsic, RT (reprint author), Univ Pittsburgh, S724 Biomed Sci Tower,3500 Terrace St, Pittsburgh, PA 15261 USA. EM rtd4@pitt.edu OI Wisniewski, Stephen/0000-0002-3877-9860 FU NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases) [K23-AR-057845] FX Dr. Domsic's work was supported by the NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases grant K23-AR-057845). NR 40 TC 2 Z9 2 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2326-5191 EI 2326-5205 J9 ARTHRITIS RHEUMATOL JI Arthritis Rheumatol. PD APR PY 2016 VL 68 IS 4 BP 993 EP 1003 DI 10.1002/art.39490 PG 11 WC Rheumatology SC Rheumatology GA DH9QH UT WOS:000373130300026 PM 26554637 ER PT J AU Williams, KM Cheng, GS Pusic, I Jagasia, M Burns, L Ho, VT Pidala, J Palmer, J Johnston, L Mayer, S Chien, JW Jacobsohn, DA Pavletic, SZ Martin, PJ Storer, BE Inamoto, Y Chai, XY Flowers, MED Lee, SJ AF Williams, Kirsten M. Cheng, Guang-Shing Pusic, Iskra Jagasia, Madan Burns, Linda Ho, Vincent T. Pidala, Joseph Palmer, Jeanne Johnston, Laura Mayer, Sebastian Chien, Jason W. Jacobsohn, David A. Pavletic, Steven Z. Martin, Paul J. Storer, Barry E. Inamoto, Yoshihiro Chai, Xiaoyu Flowers, Mary E. D. Lee, Stephanie J. TI Fluticasone, Azithromycin, and Montelukast Treatment for New-Onset Bronchiolitis Obliterans Syndrome after Hematopoietic Cell Transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Bronchiolitis obliterans syndrome; Fluticasone; Azithromycin; Montelukast; Hematopoietic cell transplantation; Lung chronic graft-versus-host disease; Leukotrienes ID VERSUS-HOST-DISEASE; BONE-MARROW-TRANSPLANTATION; CONSENSUS DEVELOPMENT PROJECT; AIR-FLOW OBSTRUCTION; WORKING GROUP-REPORT; MEASURING THERAPEUTIC RESPONSE; RECEPTOR ENBREL ETANERCEPT; PLACEBO-CONTROLLED TRIAL; LONG-TERM SURVIVORS; LUNG TRANSPLANTATION AB Bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic cell transplantation (HCT) is associated with high mortality. We hypothesized that inhaled fluticasone, azithromycin, and montelukast (FAM) with a brief steroid pulse could avert progression of new-onset BOS. We tested this in a phase II, single-arm, open-label, multicenter study (NCT01307462). Thirty-six patients were enrolled within 6 months of BOS diagnosis. The primary endpoint was treatment failure, defined as 10% or greater forced expiratory volume in 1 second decline at 3 months. At 3 months, 6% (2 of 36, 95% confidence interval, 1% to 19%) had treatment failure (versus 40% in historical controls, P < .001). FAM was well tolerated. Steroid dose was reduced by 50% or more at 3 months in 48% of patients who could be evaluated (n = 27). Patient-reported outcomes at 3 months were statistically significantly improved for Short-Form 36 social functioning score and mental component score, Functional Assessment of Cancer Therapies emotional well-being, and Lee symptom scores in lung, skin, mouth, and the overall summary score compared to enrollment (n = 24). At 6 months, 36% had treatment failure (95% confidence interval, 21% to 54%, n = 13 of 36, with 6 documented failures, 7 missing pulmonary function tests). Overall survival was 97% (95% confidence interval, 84% to 100%) at 6 months. These data suggest that FAM was well tolerated and that treatment with FAM and steroid pulse may halt pulmonary decline in new-onset BUS in the majority of patients and permit reductions in systemic steroid exposure, which collectively may improve quality of life. However, additional treatments are needed for progressive BUS despite FAM. (C) 2016 American Society for Blood and Marrow Transplantation. C1 [Williams, Kirsten M.; Jacobsohn, David A.] Childrens Natl Hlth Syst, Childrens Res Inst, Div Blood & Marrow Transplantat, Washington, DC USA. [Williams, Kirsten M.; Pavletic, Steven Z.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Cheng, Guang-Shing; Martin, Paul J.; Storer, Barry E.; Chai, Xiaoyu; Flowers, Mary E. D.; Lee, Stephanie J.] Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA. [Pusic, Iskra] Washington Univ, Div Med & Oncol, St Louis, MO USA. [Jagasia, Madan] Vandebilt Univ, Div Hematol Oncol, Nashville, TN USA. [Burns, Linda] Univ Minnesota, Div Hematol Oncol & Transplantat, Minneapolis, MN USA. [Ho, Vincent T.] Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA 02115 USA. [Pidala, Joseph] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Blood & Marrow Transplantat, Tampa, FL 33682 USA. [Palmer, Jeanne] Mayo Clin, Div Hematol Oncol, Scottsdale, AZ USA. [Johnston, Laura] Stanford Univ, Div Blood & Marrow Transplantat, Stanford, CA 94305 USA. [Mayer, Sebastian] Weill Cornell Med Coll, Dept Med, New York, NY USA. [Chien, Jason W.] Gilead Sci Inc, Seattle, WA USA. [Inamoto, Yoshihiro] Natl Canc Ctr, Div Hematopoiet Stem Cell Transplantat, 1-1 Tsukiji 5 chome, Tokyo, Japan. RP Williams, KM (reprint author), George Washington Univ, Med Ctr, Childrens Natl Med Ctr, Div Blood & Marrow Transplantat,Ctr Canc & Blood, 111 Michigan Ave NW, Washington, DC 20010 USA. EM kmwillia@cnmc.org FU NCATS; National Cancer Institute; GlaxoSmithKline [113611] FX The Chronic GVHD Consortium (U54 CA163438) is part of the NCATS Rare Diseases Clinical Research Network (RDCRN). RDCRN is an initiative of the Office of Rare Disease Research NCATS, funded through a collaboration between NCATS and the National Cancer Institute. GlaxoSmithKline provided fluticasone propionate under grant number 113611, and Merck provided montelukast. NR 50 TC 9 Z9 9 U1 1 U2 3 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 APR PY 2016 VL 22 IS 4 BP 710 EP 716 DI 10.1016/j.bbmt.2015.10.009 PG 7 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DH9CH UT WOS:000373093500017 PM 26475726 ER PT J AU Yu, EW Carmody, JS Brooks, DJ LaJoie, S Kaplan, LM Bouxsein, ML AF Yu, Elaine W. Carmody, Jill S. Brooks, Daniel J. LaJoie, Scott Kaplan, Lee M. Bouxsein, Mary L. TI Cortical and trabecular deterioration in mouse models of Roux-en-Y gastric bypass SO BONE LA English DT Article DE Bariatric surgery; Gastric bypass; Weight loss; Obesity; Bone loss; Bone microarchitecture; Mouse models ID BONE-MINERAL DENSITY; VERTICAL SLEEVE GASTRECTOMY; WEIGHT-LOSS; BARIATRIC SURGERY; METABOLIC-ACIDOSIS; MORBID-OBESITY; ANIMAL-MODELS; RATS; RESTRICTION; TURNOVER AB Roux-en-Y gastric bypass (RYGB) is a profoundly effective treatment for severe obesity, but results in significant bone loss in patients. Developing a murine model that recapitulates this skeletal phenotype will provide a robust tool with which to study the physiologic mechanisms of this bone loss. We studied adult male C57BL/6J mice who underwent either RYGB or sham operation. Twelve weeks after surgery, we characterized biochemical bone markers (parathyroid hormone, PTH; C-telopeptide, CTX; and type 1 procollagen, P1NP) and bone microarchitectural parameters as measured by microcomputed tomography. RYGB-treated mice had significant trabecular and cortical bone deficits compared with sham-operated controls. Although adjustment for final body weight eliminated observed cortical differences, the trabecular bone volume fraction remained significantly lower in RYGB mice even after weight adjustment. PTH levels were similar between groups, but RYGB mice had significantly higher indices of bone turnover than sham controls. These data demonstrate that murine models of RYGB recapitulate patterns of bone loss and turnover that have been observed in human clinical studies. Future studies that exploit this murine model will help delineate the alterations in bone metabolism and mechanisms of bone loss after RYGB. (C) 2016 Elsevier Inc. All rights reserved. C1 [Yu, Elaine W.; Brooks, Daniel J.; Bouxsein, Mary L.] Massachusetts Gen Hosp, Endocrine Unit, 50 Blossom St,Thier 1041, Boston, MA 02114 USA. [Carmody, Jill S.; LaJoie, Scott; Kaplan, Lee M.] Massachusetts Gen Hosp, Obes Metab & Nutr Inst, Boston, MA 02114 USA. [Carmody, Jill S.; LaJoie, Scott; Kaplan, Lee M.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Brooks, Daniel J.; Bouxsein, Mary L.] Beth Israel Deaconess Med Ctr, Ctr Adv Orthoped Studies, Boston, MA USA. RP Yu, EW (reprint author), Massachusetts Gen Hosp, Endocrine Unit, 50 Blossom St,Thier 1041, Boston, MA 02114 USA. FU NIH [DK093713, DK088661]; Ethicon, Inc. FX This work was supported by NIH grants DK093713 (E.W.Y.), DK088661 (L.M.K.) and a research grant from Ethicon, Inc. NR 40 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 EI 1873-2763 J9 BONE JI Bone PD APR PY 2016 VL 85 BP 23 EP 28 DI 10.1016/j.bone.2016.01.017 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DH4QJ UT WOS:000372770200004 PM 26806052 ER PT J AU Paluch-Shimon, S Pagani, O Partridge, AH Bar-Meir, E Fallowfield, L Fenlon, D Friedman, E Gelmon, K Gentilini, O Geraghty, J Harbeck, N Higgins, S Loibl, S Moser, E Peccatori, F Raanani, H Kaufman, B Cardoso, F AF Paluch-Shimon, Shani Pagani, Olivia Partridge, Ann H. Bar-Meir, Eran Fallowfield, Lesley Fenlon, Deborah Friedman, Eitan Gelmon, Karen Gentilini, Oreste Geraghty, James Harbeck, Nadia Higgins, Stephen Loibl, Sibylle Moser, Elizabeth Peccatori, Fedro Raanani, Hila Kaufman, Bella Cardoso, Fatima TI Second international consensus guidelines for breast cancer in young women (BCY2) SO BREAST LA English DT Article DE Breast cancer; Young women; Guidelines; Consensus ID ADJUVANT ENDOCRINE THERAPY; BRCA MUTATION CARRIERS; OVARIAN-FUNCTION SUPPRESSION; NIPPLE-SPARING MASTECTOMY; BONE-MINERAL DENSITY; QUALITY-OF-LIFE; PREMENOPAUSAL WOMEN; RANDOMIZED-TRIAL; ZOLEDRONIC ACID; HOT FLASHES AB The 2nd International Consensus Conference for Breast Cancer in Young Women (BCY2) took place in November 2014, in Dublin, Ireland organized by the European School of Oncology (ESO). Consensus recommendations for the management of breast cancer in young women (BCYW) were updated from BCY1 with incorporation of new evidence to inform the guidelines, and areas of research priorities were identified. This manuscript summarizes these international consensus recommendations, which are also endorsed by the European Society of Breast Specialists (EUSOMA). (C) 2015 Elsevier Ltd. All rights reserved. C1 [Paluch-Shimon, Shani; Friedman, Eitan; Raanani, Hila; Kaufman, Bella] Sheba Med Ctr, Ramat Gan, Israel. [Pagani, Olivia] Oncol Inst Southern Switzerland, Bellinzona, Switzerland. [Pagani, Olivia] Breast Unit Southern Switzerland, Bellinzona, Switzerland. [Partridge, Ann H.] Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. [Bar-Meir, Eran] Bar Ilan Univ, Fac Med, IL-52100 Ramat Gan, Israel. [Fallowfield, Lesley] Univ Sussex, Brighton & Sussex Med Sch, SHORE C, Falmer, England. [Fenlon, Deborah] Univ Southampton, Southampton, Hants, England. [Gelmon, Karen] British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. [Gentilini, Oreste] Hosp San Raffaele, Breast Surg Unit, I-20132 Milan, Italy. [Geraghty, James] St Vincent Hosp, Dublin, Ireland. [Harbeck, Nadia] Univ Munich LMU, Dept OB&GYN, Breast Ctr, Munich, Germany. [Higgins, Stephen] Tallaght Hosp, Dublin, Ireland. [Higgins, Stephen] Our Ladys Hosp Sick Children, Dublin, Ireland. [Loibl, Sibylle] German Breast Grp, Neu Isenburg, Germany. [Loibl, Sibylle] Sana Klinikum Offenbach, Sana, Germany. [Moser, Elizabeth; Cardoso, Fatima] Champalimaud Canc Ctr, Breast Unit, Av Brasilia S-N, P-1400038 Lisbon, Portugal. [Peccatori, Fedro] European Inst Oncol, Milan, Italy. [Cardoso, Fatima] European Sch Oncol, Rome, Italy. RP Cardoso, F (reprint author), Champalimaud Canc Ctr, Breast Unit, Av Brasilia S-N, P-1400038 Lisbon, Portugal. EM fatimacardoso@fundacaochampalimaud.pt OI Cardoso, Fatima/0000-0002-6692-2249; Fenlon, Deborah/0000-0001-7347-8919 NR 142 TC 8 Z9 8 U1 3 U2 7 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 APR PY 2016 VL 26 BP 87 EP 99 DI 10.1016/j.breast.2015.12.010 PG 13 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA DH9JO UT WOS:000373112600012 PM 27017247 ER PT J AU Chapman, JAW Shepherd, LE Ingle, JN Muss, HB Pritchard, KI Gelmon, KA Whelan, TJ Elliott, C Goss, PE AF Chapman, Judith-Anne W. Shepherd, Lois E. Ingle, James N. Muss, Hyman B. Pritchard, Kathleen I. Gelmon, Karen A. Whelan, Timothy J. Elliott, Catherine Goss, Paul E. TI Competing risks of death in women treated with adjuvant aromatase inhibitors for early breast cancer on NCIC CTG MA.27 SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Competing risks; Breast cancer death; Cardiovascular death; Elderly ID THERAPY; TRIAL AB Baseline patient and tumor characteristics differentially affected type of death in the MA.17 placebo-controlled letrozole trial where cardiovascular death was not separately identified. The MA.27 trial allowed competing risks analysis of breast cancer (BC), cardiovascular, and other type (OT) of death. MA.27 was a phase III adjuvant breast cancer trial of exemestane versus anastrozole. Effects of baseline patient and tumor characteristics were tested for whether factors were associated with (1) all cause mortality and (2) cause-specific mortality. We also fit step-wise forward cause-specific-adjusted models. 7576 women (median age 64 years; 5417 (72 %) < 70 years and 2159 (28 %) a parts per thousand yen 70 years) were enrolled and followed for median 4.1 years. The 432 deaths comprised 187 (43 %) BC, 66 (15 %) cardiovascular, and 179 (41 %) OT. Five baseline factors were differentially associated with type of death. Older patients had greater BC (p = 0.03), cardiovascular (p < 0.001), and other types (p < 0.001) of mortality. Patients with pre-existing cardiovascular history had worse cardiovascular mortality (p < 0.001); those with worse ECOG performance status had worse OT mortality (p < 0.001). Patients with T1 tumors (p < 0.001) and progesterone receptor positive had less BC mortality (p < 0.001). Fewer BC deaths occurred with node-negative disease (p < 0.001), estrogen receptor-positive tumors (p = 0.001), and without adjuvant chemotherapy (p = 0.005); worse cardiovascular mortality (p = 0.01), with trastuzumab; worse OT mortality, for non-whites (p = 0.03) and without adjuvant radiotherapy (p = 0.003). Overall, 57 % of deaths in MA.27 AI-treated patients were non-breast cancer related. Baseline patient and tumor characteristics differentially affected type of death with women 70 or older experiencing more non-breast cancer death. C1 [Chapman, Judith-Anne W.; Shepherd, Lois E.; Elliott, Catherine] Queens Univ, Canadian Canc Trials Grp, NCIC Clin Trials Grp, Kingston, ON, Canada. [Ingle, James N.] Mayo Clin, Rochester, MN USA. [Muss, Hyman B.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Pritchard, Kathleen I.] Univ Toronto, Sunnybrook Odette Canc Ctr, Toronto, ON, Canada. [Gelmon, Karen A.] British Columbia Canc Agcy, Vancouver Ctr, Vancouver, BC V5Z 4E6, Canada. [Whelan, Timothy J.] McMaster Univ, Juravinski Canc Ctr Hamilton Hlth Sci, Hamilton, ON, Canada. [Goss, Paul E.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. RP Chapman, JAW (reprint author), Queens Univ, Canadian Canc Trials Grp, NCIC Clin Trials Grp, Kingston, ON, Canada. EM jachapma@aol.com; Lshepherd@ctg.queensu.ca; ingle.james@mayo.edu; hyman_muss@med.unc.edu; kathy.pritchard@sunnybrook.ca; kgelmon@bccancer.bc.ca; twhelan@hhsc.ca; CElliott@ctg.queensu.ca; pgoss@mgh.harvard.edu RI Whelan, Timothy/D-3185-2017 FU Canadian Cancer Society Research Institute [015761, 015764]; United States National Cancer Institute at the National Institutes of Health [CA77202]; Pfizer (New York, Canada); Avon Foundation FX This work was supported by the Canadian Cancer Society Research Institute [grant numbers 015761,015764]; the United States National Cancer Institute at the National Institutes of Health [grant number CA77202]; and Pfizer (New York, Canada). Dr. Goss is supported by the Avon Foundation. NR 10 TC 1 Z9 1 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 EI 1573-7217 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD APR PY 2016 VL 156 IS 2 BP 343 EP 349 DI 10.1007/s10549-016-3761-8 PG 7 WC Oncology SC Oncology GA DI0DI UT WOS:000373164800013 PM 27006189 ER PT J AU Abuelkasem, E Lu, S Tanaka, K Planinsic, R Sakai, T AF Abuelkasem, E. Lu, S. Tanaka, K. Planinsic, R. Sakai, T. TI Comparison between thrombelastography and thromboelastometry in hyperfibrinolysis detection during adult liver transplantation SO BRITISH JOURNAL OF ANAESTHESIA LA English DT Article DE clinical laboratory techniques; fibrinolysis; liver transplantation; thrombelastography ID PLASMINOGEN-ACTIVATOR; CLOT RETRACTION; FACTOR-XIII; FIBRINOLYSIS; BLOOD; DISEASE; LYSIS; ACID AB Background: Hyperfibrinolysis is one of the main causes of non-surgical bleeding during liver transplantation (LT). Viscoelastic haemostatic assays, including thromboelastometry (ROTEM (R)) and thrombelastography (TEG (R)), can detect hyperfibrinolysis at the bedside. No study has yet demonstrated which device or assay is more suitable for detecting hyperfibrinolysis. Methods: This prospective observational study compared ROTEM (R) and TEG (R) in isolated adult LT. ROTEM (R) (EXTEM (R) [tissue factor activation], FIBTEM (R) [tissue factor activation with platelet inhibition], and APTEM (R) [tissue factor activation with tranexamic acid/aprotinin]) and TEG (R) (kaolin-TEG (R)) were simultaneously performed using arterial blood samples at eight time-points during LT: induction of general anaesthesia, 60 min after skin incision, 10 and 45 min after portal vein clamp, 15 min before graft reperfusion, and five, 30, and 90 min after graft reperfusion. Hyperfibrinolysis was identified per the manufacturers' definitions (maximum lysis >15% in ROTEM (R) or Lysis30>8% in TEG (R)) and confirmed with APTEM (R); incidence was compared between assays McNemar's test. Results: Among 296 possible measurement points from 376 consecutive LT recipients, 250 underwent final analysis: 46 measurement points were excluded because of missing assays or flat line. Hyperfibrinolysis was confirmed at 89 (36%) of 250 measurement points: FIBTEM (R), EXTEM (R), and kaolin-TEG (R) detected 84 (94%), 41 (46%), and 21 (24%) hyperfibrinolysis, respectively. These hyperfibrinolysis detection rates significantly differed from each other (P<0.001). Conclusions: Tissue factor-triggered ROTEM (R) tests were more sensitive than contact-activated k-TEG (R) in identifying hyperfibrinolysis in LT patients. Inhibition of platelet-fibrin interaction in FIBTEM (R) enhanced sensitivity to hyperfibrinolysis detection compared with EXTEM (R). C1 [Abuelkasem, E.; Planinsic, R.; Sakai, T.] Univ Pittsburgh, Dept Anesthesiol, Med Ctr, 200 Lothrop St, Pittsburgh, PA 15213 USA. [Lu, S.] Harvard Univ, Massachusetts Gen Hosp, Dept Anesthesiol, Sch Med, Boston, MA 02114 USA. [Tanaka, K.] Univ Maryland, Dept Anesthesiol, Med Ctr, Baltimore, MD 21201 USA. [Sakai, T.] Univ Pittsburgh, Clin & Translat Sci Inst, Atwood & Sennott St, Pittsburgh, PA 15260 USA. RP Sakai, T (reprint author), Univ Pittsburgh, Dept Anesthesiol, Med Ctr, 200 Lothrop St, Pittsburgh, PA 15213 USA.; Sakai, T (reprint author), Univ Pittsburgh, Clin & Translat Sci Inst, Atwood & Sennott St, Pittsburgh, PA 15260 USA. EM sakait@upmc.edu FU Tem International FX K.A.T. is currently participating in a clinical study sponsored by Tem International. The other authors declare no conflicts of interest. NR 22 TC 3 Z9 3 U1 1 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0007-0912 EI 1471-6771 J9 BRIT J ANAESTH JI Br. J. Anaesth. PD APR PY 2016 VL 116 IS 4 BP 507 EP 512 DI 10.1093/bja/aew023 PG 6 WC Anesthesiology SC Anesthesiology GA DH2BB UT WOS:000372588000012 PM 26934942 ER PT J AU Ballen, KK Lazarus, H AF Ballen, Karen K. Lazarus, Hillard TI Cord blood transplant for acute myeloid leukaemia SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Review DE umbilical cord blood; allogeneic haematopoietic cell transplantation ID STEM-CELL TRANSPLANTATION; MYELOABLATIVE CONDITIONING REGIMEN; ALTERNATIVE DONOR TRANSPLANTATION; ACUTE MYELOGENOUS LEUKEMIA; ANTI-HLA ANTIBODIES; HEMATOLOGIC MALIGNANCIES; UNRELATED DONOR; BONE-MARROW; ADULT PATIENTS; PROSPECTIVE MULTICENTER AB Umbilical cord blood is a haematopoietic progenitor cell source for patients with acute myeloid leukaemia (AML), other haematological malignancies and metabolic diseases who can be cured by allogeneic haematopoietic cell transplantation, but who do not have a human leucocyte antigen compatible related or unrelated donor. Although the first cord blood transplants were done in children, there are currently more cord blood transplants performed in adults. In this review, we explore the history of umbilical cord blood transplantation, paediatric and adult outcome results, and novel trends to improve engraftment and reduce infection. Umbilical cord blood transplantation cures approximately 30-40% of adults and 60-70% of children with AML. Controversial issues, including the use of double versus single cord blood units for transplantation, optimal cord blood unit selection, infection prophylaxis, conditioning regimens and graft versus host disease prophylaxis, will be reviewed. Finally, comparison to other graft sources, cost, access to care, and the ideal graft source are discussed. C1 [Ballen, Karen K.] Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02114 USA. [Lazarus, Hillard] Case Western Reserve Univ, Seidman Canc Ctr, Cleveland, OH 44106 USA. RP Ballen, KK (reprint author), Massachusetts Gen Hosp, Ctr Canc, Div Hematol Oncol, Zero Emerson,Suite 118, Boston, MA 02114 USA. EM kballen@partners.org NR 86 TC 0 Z9 0 U1 3 U2 7 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 APR PY 2016 VL 173 IS 1 BP 25 EP 36 DI 10.1111/bjh.13926 PG 12 WC Hematology SC Hematology GA DH9TL UT WOS:000373138700002 PM 26766286 ER PT J AU Ting, KR Brady, JJ Hameed, A Le, G Meiller, J Verburgh, E Bayers, C Benjamin, D Anderson, KC Richardson, PG Dowling, P Clynes, M Fitzgibbon, MC O'Gorman, P AF Ting, Kay R. Brady, Jennifer J. Hameed, Abdul Le, Giao Meiller, Justine Verburgh, Estelle Bayers, Christopher Benjamin, Dalia Anderson, Kenneth C. Richardson, Paul G. Dowling, Paul Clynes, Martin Fitzgibbon, Maria C. O'Gorman, Peter TI Clinical utility of C-terminal telopeptide of type 1 collagen in multiple myeloma SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE multiple myeloma; CTX-1; myeloma bone disease; bone markers; bone resorption ID GROUP CONSENSUS STATEMENT; BONE-DISEASE; BIOCHEMICAL MARKERS; WORKING GROUP; PATHOLOGICAL FRACTURES; IMAGING TECHNIQUES; MANAGEMENT; RESORPTION; CHEMISTRY; DIAGNOSIS AB Myeloma bone disease (MBD) is a major cause of morbidity in multiple myeloma (MM). We investigated bone turnover markers (BTM) as relapse predictors and biomarkers for monitoring MBD. We measured C-terminal telopeptide of type I collagen (CTX-1), and Procollagen type 1N Propeptide (P1NP) in 86 MM patients and 26 controls. CTX-1 was higher in newly diagnosed patients compared to control, remission and relapse (P<005), and decreased following treatment. In the setting of relapse, a CTX-1 rise greater than the calculated least significant change (LSC) was observed in 26% of patients 3-6months prior to relapse (P=0007), and in 608% up to 3months before relapse (P=0015). Statistically significant changes in CTX-1 levels were also observed in patients who were with and without bisphosphonate therapy at the time of relapse. In patients with normal renal function, mean CTX-1 level was highest in the newly diagnosed group (0771 +/- 0400g/l), and lowest in the remission group (0099 +/- 0070g/l) (P<00001). P1NP levels were not statistically different across the patient groups. We conclude that CTX-1, measured on an automated hospital laboratory platform, has a role in routine treatment monitoring and predicting relapse of MBD, even in patients on bisphosphonates. C1 [Ting, Kay R.; Hameed, Abdul; Le, Giao; Verburgh, Estelle; Bayers, Christopher; Benjamin, Dalia; O'Gorman, Peter] Mater Misericordiae Univ Hosp, Dept Haematol, Dublin 7, Ireland. [Ting, Kay R.; Hameed, Abdul; Le, Giao; Meiller, Justine; Dowling, Paul; Clynes, Martin; O'Gorman, Peter] Dublin City Univ, Natl Inst Cellular Biotechnol, Dublin 9, Ireland. [Brady, Jennifer J.; Fitzgibbon, Maria C.] Mater Misericordiae Univ Hosp, Dept Clin Chem & Diagnost Endocrinol, Dublin 7, Ireland. [Anderson, Kenneth C.; Richardson, Paul G.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Anderson, Kenneth C.; Richardson, Paul G.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Dowling, Paul] Maynooth Univ, Dept Biol, Maynooth, Kildare, Ireland. [O'Gorman, Peter] Univ Coll Dublin, Sch Med & Med Sci, Dublin 4, Ireland. RP O'Gorman, P (reprint author), 8 Berkeley Rd, Dublin 7, Ireland. EM pogorman@mater.ie OI Dowling, Paul/0000-0002-9290-9267 NR 30 TC 0 Z9 1 U1 1 U2 4 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 APR PY 2016 VL 173 IS 1 BP 82 EP 88 DI 10.1111/bjh.13928 PG 7 WC Hematology SC Hematology GA DH9TL UT WOS:000373138700007 PM 26787413 ER PT J AU Armand, P Redd, R Bsat, J Mayuram, S Giardino, A Fisher, DC LaCasce, AS Jacobson, C Davids, MS Brown, JR Weng, L Wilkins, J Faham, M Freedman, AS Joyce, R Jacobsen, ED AF Armand, Philippe Redd, Robert Bsat, Jad Mayuram, Sangeetha Giardino, Angela Fisher, David C. LaCasce, Ann S. Jacobson, Caron Davids, Matthew S. Brown, Jennifer R. Weng, Li Wilkins, Jennifer Faham, Malek Freedman, Arnold S. Joyce, Robin Jacobsen, Eric D. TI A phase 2 study of Rituximab-Bendamustine and Rituximab-Cytarabine for transplant-eligible patients with mantle cell lymphoma SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE malignant lymphomas; clinical trials; chemotherapy ID NON-HODGKIN-LYMPHOMA; PROSPECTIVE RANDOMIZED-TRIAL; ACUTE LYMPHOBLASTIC-LEUKEMIA; RESIDUAL DISEASE DETECTION; PROGRESSION-FREE SURVIVAL; CIRCULATING TUMOR DNA; SEQUENCING APPROACH; FOLLOW-UP; IMMUNOCHEMOTHERAPY; REMISSION AB Chemoimmunotherapy followed by autologous stem cell transplantation (ASCT) is a standard therapy for transplant-eligible patients with newly diagnosed mantle cell lymphoma (MCL). The achievement of complete remission (CR) and minimal residual disease (MRD) negativity are associated with better outcomes. We tested an induction regimen of rituximab/bendamustine followed by rituximab/high-dose cytarabine (RB/RC). This phase 2 study (NCT01661881) enrolled 23 transplant-eligible patients aged 42-69, of whom 70% were MCL international prognostic index low-risk. Patients received three cycles of RB followed by three cycles of RC. The primary endpoint of the trial was the rate of CR after six cycles of therapy, with a rate of 75% considered promising. 96% of patients achieved a CR/unconfirmed CR after treatment, meeting the primary objective. One patient progressed on study, one declined ASCT in CR, and the remaining 21 underwent successful stem cell collection and ASCT. After a median follow-up of 13months, the progression-free survival rate was 96%. Among 15 MRD-evaluable patients who completed treatment, 93% achieved MRD negativity after RB/RC. In conclusion, RB/RC achieves very high CR and MRD negativity rates in transplant-eligible patients, with a favourable safety profile. RB/RC warrants further comparative studies, and may become a useful alternative to RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone)-based induction regimens in this patient population. C1 [Armand, Philippe; Bsat, Jad; Mayuram, Sangeetha; Fisher, David C.; LaCasce, Ann S.; Jacobson, Caron; Davids, Matthew S.; Brown, Jennifer R.; Freedman, Arnold S.; Jacobsen, Eric D.] Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. [Redd, Robert] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Giardino, Angela] Dana Farber Canc Inst, Dept Radiol, Boston, MA 02115 USA. [Weng, Li; Wilkins, Jennifer; Faham, Malek] Sequenta Inc, San Francisco, CA USA. [Joyce, Robin] Beth Israel Deaconess Med Ctr, Dept Med Oncol, Boston, MA 02215 USA. RP Armand, P (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM parmand@partners.org FU ASH Scholar Award; ASCO Career Development Award; ASBMT/Genentech Young Investigator Award; Dunkin Donuts Rising Star award FX P.A. was supported by an ASH Scholar Award, an ASCO Career Development Award, an ASBMT/Genentech Young Investigator Award, and a Dunkin Donuts Rising Star award. We are also indebted to the nursing and research staff who were involved in this study, and to all of the participants and their families. NR 28 TC 5 Z9 5 U1 1 U2 4 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 APR PY 2016 VL 173 IS 1 BP 89 EP 95 DI 10.1111/bjh.13929 PG 7 WC Hematology SC Hematology GA DH9TL UT WOS:000373138700008 PM 26729345 ER PT J AU Armand, P Kim, HT Sainvil, MM Lange, PB Giardino, AA Bachanova, V Devine, SM Waller, EK Jagirdar, N Herrera, AF Cutler, C Ho, VT Koreth, J Alyea, EP McAfee, SL Soiffer, RJ Chen, YB Antin, JH AF Armand, Philippe Kim, Haesook T. Sainvil, Marie-Michele Lange, Paulina B. Giardino, Angela A. Bachanova, Veronika Devine, Steven M. Waller, Edmund K. Jagirdar, Neera Herrera, Alex F. Cutler, Corey Ho, Vincent T. Koreth, John Alyea, Edwin P. McAfee, Steven L. Soiffer, Robert J. Chen, Yi-Bin Antin, Joseph H. TI The addition of sirolimus to the graft-versus-host disease prophylaxis regimen in reduced intensity allogeneic stem cell transplantation for lymphoma: a multicentre randomized trial SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE clinical trials; lymphomas; stem cell transplantation; GVHD ID PHASE-II TRIAL; LOW-DOSE METHOTREXATE; UNRELATED DONOR TRANSPLANTATION; SINGLE-AGENT TEMSIROLIMUS; GVHD PROPHYLAXIS; CLINICAL-TRIALS; TACROLIMUS; COMBINATION; BLOOD; EVEROLIMUS AB Inhibition of the mechanistic target of rapamycin (mTOR) pathway has clinical activity in lymphoma. The mTOR inhibitor sirolimus has been used in the prevention and treatment of graft-versus-host disease (GVHD) after allogeneic haematopoietic stem cell transplantation (HSCT). A retrospective study suggested that patients with lymphoma undergoing reduced intensity conditioning (RIC) HSCT who received sirolimus as part of their GVHD prophylaxis regimen had a lower rate of relapse. We therefore performed a multicentre randomized trial comparing tacrolimus, sirolimus and methotrexate to standard regimens in adult patients undergoing RIC HSCT for lymphoma in order to assess the possible benefit of sirolimus on HSCT outcome. 139 patients were randomized. There was no difference overall in 2-year overall survival, progression-free survival, relapse, non-relapse mortality or chronic GVHD. However, the sirolimus-containing arm had a significantly lower incidence of grade II-IV acute GVHD (9% vs. 25%, P=0015), which was more marked for unrelated donor grafts. In conclusion, the addition of sirolimus for GVHD prophylaxis in RIC HSCT is associated with no increased overall toxicity and a lower risk of acute GVHD, although it does not improve survival; this regimen is an acceptable option for GVHD prevention in RIC HSCT. This trial is registered at clinicaltrials.gov (NCT00928018). C1 [Armand, Philippe; Sainvil, Marie-Michele; Lange, Paulina B.; Cutler, Corey; Ho, Vincent T.; Koreth, John; Alyea, Edwin P.; Soiffer, Robert J.; Antin, Joseph H.] Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. [Kim, Haesook T.] Dana Farber Canc Inst, Biostat & Computat Biol, Boston, MA 02115 USA. [Giardino, Angela A.] Brigham & Womens Hosp, Dept Radiol, 75 Francis St, Boston, MA 02115 USA. [Bachanova, Veronika] Univ Minnesota, Dept Med Oncol, Minneapolis, MN USA. [Devine, Steven M.] Ohio State Univ, Ctr Comprehens Canc, Dept Med, Columbus, OH 43210 USA. [Waller, Edmund K.; Jagirdar, Neera] Emory Univ, Winship Canc Inst, Dept Hematol Oncol, Atlanta, GA 30322 USA. [Herrera, Alex F.] City Hope Canc Ctr, Duarte, CA USA. [McAfee, Steven L.; Chen, Yi-Bin] Massachusetts Gen Hosp, Div Hematol Oncol, Bone Marrow Transplant Unit, Boston, MA 02114 USA. RP Armand, P (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM parmand@partners.org FU ASH Scholar Award; ASCO Career Development Award; ASBMT/Genentech Young Investigator Award; Dunkin Donuts Rising Star award; NIAID [U19 AI 29530]; NCI [P01 CA142106]; Jock and Bunny Adams Research and Education Endowment FX P.A. was supported by an ASH Scholar Award, an ASCO Career Development Award, an ASBMT/Genentech Young Investigator Award, and a Dunkin Donuts Rising Star award for this work. This work was also supported by NIAID U19 AI 29530, NCI P01 CA142106, and the Jock and Bunny Adams Research and Education Endowment. We are also indebted to the nursing and research staff who were involved in this study, and to all of the participants and their families. NR 35 TC 8 Z9 8 U1 0 U2 1 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 APR PY 2016 VL 173 IS 1 BP 96 EP 104 DI 10.1111/bjh.13931 PG 9 WC Hematology SC Hematology GA DH9TL UT WOS:000373138700009 PM 26729448 ER PT J AU Van Dyke, DL Werner, L Rassenti, LZ Neuberg, D Ghia, E Heerema, NA Dal Cin, P Dell Aquila, M Sreekantaiah, C Greaves, AW Kipps, TJ Kay, NE AF Van Dyke, Daniel L. Werner, Lillian Rassenti, Laura Z. Neuberg, Donna Ghia, Emanuella Heerema, Nyla A. Dal Cin, Paola Dell Aquila, Marie Sreekantaiah, Chandrika Greaves, Andrew W. Kipps, Thomas J. Kay, Neil E. TI The Dohner fluorescence insitu hybridization prognostic classification of chronic lymphocytic leukaemia (CLL): the CLL Research Consortium experience SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE chronic lymphocytic leukaemia; cytogenetics; leukaemia; fluorescence insitu hybridization ID GENOMIC ABERRATIONS; DISEASE PROGRESSION; CLONAL EVOLUTION; FOLLOW-UP; HETEROGENEITY; MUTATIONS; REVEALS; ZAP-70; IMPACT; COHORT AB This study revisited the Dohner prognostic hierarchy in a cohort of 1585 well-documented patients with chronic lymphocytic leukaemia. The duration of both time to first treatment (TTFT) and overall survival (OS) were significantly longer than observed previously, and this is at least partly due to improved therapeutic options. Deletion 13q remains the most favourable prognostic group with median TTFT and OS from fluorescence insitu hybridization (FISH) testing of 72months and >12years, respectively. Deletion 11q had the poorest median TTFT (22months) and 17p deletion the poorest median OS (5years). The percentages of abnormal nuclei were significantly associated with differential TTFT for the trisomy 12, 13q and 17p deletion cohorts but not for the 11q deletion cohort. From the date of the first FISH study, patients with >85% 13q deletion nuclei had a notably shorter TTFT (24months). Patients with 20% 17p deletion nuclei had longer median TTFT and OS from the date of the first FISH study (44months and 11years), and were more likely to be IGHV mutated. C1 [Van Dyke, Daniel L.; Kay, Neil E.] Mayo Clin, Dept Lab Med & Pathol, 200 First St SW, Rochester, MN 55902 USA. [Van Dyke, Daniel L.; Kay, Neil E.] Mayo Clin, Dept Internal Med, Rochester, MN USA. [Werner, Lillian; Neuberg, Donna] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Rassenti, Laura Z.; Ghia, Emanuella; Dell Aquila, Marie; Greaves, Andrew W.; Kipps, Thomas J.] Moores Univ Calif San Diego, Ctr Canc, La Jolla, CA 92093 USA. [Heerema, Nyla A.] Ohio State Univ, Dept Pathol, Columbus, OH 43210 USA. [Dal Cin, Paola] Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA 02115 USA. [Sreekantaiah, Chandrika] North Shore LIJ Hlth Syst, Long Isl City, NY USA. RP Van Dyke, DL (reprint author), Mayo Clin, Dept Lab Med & Pathol, 200 First St SW, Rochester, MN 55902 USA. EM vandyke.daniel@mayo.edu FU National Institutes of Health [PO1-CA81534] FX 'This work was supported by a grant (PO1-CA81534) from the National Institutes of Health to T. J. Kipps for the CLL Research Consortium'. We appreciate the technical support and cytogenetic data from C Sreekantaiah and SA Smoley. NR 25 TC 6 Z9 7 U1 0 U2 1 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 APR PY 2016 VL 173 IS 1 BP 105 EP 113 DI 10.1111/bjh.13933 PG 9 WC Hematology SC Hematology GA DH9TL UT WOS:000373138700010 PM 26848054 ER PT J AU Fisher, MB Belkin, NS Milby, AH Henning, EA Soegaard, N Kim, M Pfeifer, C Saxena, V Dodge, GR Burdick, JA Schaer, TP Steinberg, DR Mauck, RL AF Fisher, Matthew B. Belkin, Nicole S. Milby, Andrew H. Henning, Elizabeth A. Soeegaard, Nicole Kim, Minwook Pfeifer, Christian Saxena, Vishal Dodge, George R. Burdick, Jason A. Schaer, Thomas P. Steinberg, David R. Mauck, Robert L. TI Effects of Mesenchymal Stem Cell and Growth Factor Delivery on Cartilage Repair in a Mini-Pig Model SO CARTILAGE LA English DT Article DE cartilage; repair; mesenchymal stem cells; TGF-3; animal models ID HYALURONIC-ACID HYDROGELS; AUTOLOGOUS CHONDROCYTE IMPLANTATION; ENGINEERED CARTILAGE; IN-VIVO; OSTEOCHONDRAL DEFECTS; ARTICULAR-CARTILAGE; CHONDROGENIC DIFFERENTIATION; ALGINATE MICROSPHERES; STROMAL CELLS; MATRIX AB Objective We have recently shown that mesenchymal stem cells (MSCs) embedded in a hyaluronic acid (HA) hydrogel and exposed to chondrogenic factors (transforming growth factor-3 [TGF-3]) produce a cartilage-like tissue in vitro. The current objective was to determine if these same factors could be combined immediately prior to implantation to induce a superior healing response in vivo relative to the hydrogel alone. Design Trochlear chondral defects were created in Yucatan mini-pigs (6 months old). Treatment groups included an HA hydrogel alone and hydrogels containing allogeneic MSCs, TGF-3, or both. Six weeks after surgery, micro-computed tomography was used to quantitatively assess defect fill and subchondral bone remodeling. The quality of cartilage repair was assessed using the ICRS-II histological scoring system and immunohistochemistry for type II collagen. Results Treatment with TGF-3 led to a marked increase in positive staining for collagen type II within defects (P < 0.05), while delivery of MSCs did not (P > 0.05). Neither condition had an impact on other histological semiquantitative scores (P > 0.05), and inclusion of MSCs led to significantly less defect fill (P < 0.05). For all measurements, no synergistic interaction was found between TGF-3 and MSC treatment when they were delivered together (P > 0.05). Conclusions At this early healing time point, treatment with TGF-3 promoted the formation of collagen type II within the defect, while allogeneic MSCs had little benefit. Combination of TGF-3 and MSCs at the time of surgery did not produce a synergistic effect. An in vitro precultured construct made of these components may be required to enhance in vivo repair in this model system. C1 [Fisher, Matthew B.; Belkin, Nicole S.; Milby, Andrew H.; Henning, Elizabeth A.; Soeegaard, Nicole; Kim, Minwook; Pfeifer, Christian; Saxena, Vishal; Dodge, George R.; Steinberg, David R.; Mauck, Robert L.] Univ Penn, Perelman Sch Med, Dept Orthopaed Surg, McKay Orthopaed Res Lab, Philadelphia, PA 19104 USA. [Fisher, Matthew B.; Belkin, Nicole S.; Milby, Andrew H.; Henning, Elizabeth A.; Soeegaard, Nicole; Kim, Minwook; Pfeifer, Christian; Saxena, Vishal; Dodge, George R.; Burdick, Jason A.; Steinberg, David R.; Mauck, Robert L.] Philadelphia VA Med Ctr, Translat Musculoskeletal Res Ctr, Philadelphia, PA USA. [Fisher, Matthew B.] Univ N Carolina, Dept Biomed Engn, Chapel Hill, NC USA. [Fisher, Matthew B.] N Carolina State Univ, Raleigh, NC 27695 USA. [Pfeifer, Christian] Univ Regensburg, Med Ctr, Dept Trauma Surg, D-93053 Regensburg, Germany. [Burdick, Jason A.; Mauck, Robert L.] Univ Penn, Dept Bioengn, Philadelphia, PA 19104 USA. [Schaer, Thomas P.] Univ Penn, Sch Vet Med, Comparat Orthopaed Res Lab, Philadelphia, PA 19104 USA. RP Mauck, RL (reprint author), Univ Penn, Perelman Sch Med, Dept Orthopaed Surg, 424 Stemmler Hall,36th St & Hamilton Walk, Philadelphia, PA 19104 USA.; Mauck, RL (reprint author), Univ Penn, Perelman Sch Med, Dept Bioengn, 424 Stemmler Hall,36th St & Hamilton Walk, Philadelphia, PA 19104 USA. EM lemauck@mail.med.upenn.edu FU National Institutes of Health [R01 EB008722, F32 AR062971]; Department of Veterans Affairs [I01 RX000700]; AO Foundation; Orthopaedic Research and Education Foundation FX The authors thank Liming Bian, Megan Farrell, Tristan Driscoll, Sylvia Qu, and Marc Bostrom for their technical assistance. This work was supported by the National Institutes of Health (R01 EB008722 and F32 AR062971), the Department of Veterans Affairs (I01 RX000700), the AO Foundation, and the Orthopaedic Research and Education Foundation (Resident Clinician Scientist Training Grant). NR 52 TC 1 Z9 1 U1 7 U2 18 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1947-6035 EI 1947-6043 J9 CARTILAGE JI Cartilage PD APR PY 2016 VL 7 IS 2 BP 174 EP 184 DI 10.1177/1947603515623030 PG 11 WC Orthopedics SC Orthopedics GA DH6LG UT WOS:000372901500006 PM 27047640 ER PT J AU Cormier, AC Drapek, L Fahey, J Rowen, B Burns-Britton, BA Lavadinho-Lemos, M Hultman, T AF Cormier, Aurelie C. Drapek, Lorraine Fahey, Jean Rowen, Brenna Burns-Britton, Betty Ann Lavadinho-Lemos, Maria Hultman, Todd TI When the Patient Seeks Cure: Challenging Chemotherapy and Radiation Side Effects Requiring Creative Solutions SO CLINICAL JOURNAL OF ONCOLOGY NURSING LA English DT Editorial Material DE rectal cancer; concomitant chemoradiotherapy; radiation dermatitis; pain AB When undergoing concomitant chemotherapy and radiation therapy for anal cancer, patients often experience significant side effects, including grade 1 or 2 radiation dermatitis, pain, exudate, and diarrhea. This case study presents a grade 3 reaction complicated by complex medical conditions. In addition to an evidence-based skin care treatment and side effect management plan that support patients during this intense period, this article offers creative strategies to provide a cost-effective healing option. C1 [Cormier, Aurelie C.; Fahey, Jean; Rowen, Brenna; Burns-Britton, Betty Ann; Lavadinho-Lemos, Maria] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Drapek, Lorraine] Massachusetts Gen Hosp, Gastrointestinal Radiat Oncol, Boston, MA 02114 USA. [Hultman, Todd] HealthONE, Denver, CO USA. RP Cormier, AC (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM acormier@partners.org NR 7 TC 0 Z9 0 U1 1 U2 3 PU ONCOLOGY NURSING SOC PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 1092-1095 EI 1538-067X J9 CLIN J ONCOL NURS JI Clin. J. Oncol. Nurs. PD APR PY 2016 VL 20 IS 2 BP 117 EP 120 DI 10.1188/16.CJON.117-120 PG 4 WC Oncology; Nursing SC Oncology; Nursing GA DH8ID UT WOS:000373035800002 PM 26991702 ER PT J AU Sullivan, CM Dalby, C Gross, AH Chesnulevich, K Lilienfeld, CW Hooper, C Rizzo, P Kochanek, T AF Sullivan, Clare M. Dalby, Carole Gross, Anne H. Chesnulevich, Kaitlin Lilienfeld, Christine W. Hooper, Catherine Rizzo, Patricia Kochanek, Thomas TI Oral Chemotherapy Education: Using Innovation to Ensure Broad Access SO CLINICAL JOURNAL OF ONCOLOGY NURSING LA English DT Editorial Material DE oral chemotherapy; audiovisual education; social media AB The purpose of this article is to share one institution's intervention to improve oral chemotherapy patient education. The overall aim was to provide clinicians with a single source of educational materials that would meet a diverse group of patients' educational needs and be consistent with published guidelines. C1 [Sullivan, Clare M.] Dana Farber Canc Inst, Patient Educ, Boston, MA 02115 USA. [Sullivan, Clare M.] Dana Farber Canc Inst, Patient Educ, Boston, MA 02115 USA. [Dalby, Carole] Dana Farber Canc Inst, Clin Qual Improvement, Boston, MA 02115 USA. [Gross, Anne H.] Dana Farber Canc Inst, Adult Nursing & Clin Serv, Boston, MA 02115 USA. [Chesnulevich, Kaitlin; Hooper, Catherine] Dana Farber Canc Inst, Boston, MA 02115 USA. [Lilienfeld, Christine W.; Rizzo, Patricia] Dana Farber Canc Inst, Ctr Gastrointestinal Canc, Boston, MA 02115 USA. [Kochanek, Thomas] Rhode Isl Coll, Feinstein Sch Educ & Human Dev, Providence, RI 02908 USA. RP Sullivan, CM (reprint author), Dana Farber Canc Inst, Patient Educ, Boston, MA 02115 USA.; Sullivan, CM (reprint author), Dana Farber Canc Inst, Patient Educ, Boston, MA 02115 USA. EM clare_sullivan@dfci.harvard.edu NR 7 TC 0 Z9 0 U1 1 U2 4 PU ONCOLOGY NURSING SOC PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 1092-1095 EI 1538-067X J9 CLIN J ONCOL NURS JI Clin. J. Oncol. Nurs. PD APR PY 2016 VL 20 IS 2 BP 126 EP 128 DI 10.1188/16.CJON.126-128 PG 3 WC Oncology; Nursing SC Oncology; Nursing GA DH8ID UT WOS:000373035800003 PM 26991703 ER PT J AU Post, RM Leverich, GS Kupka, R Keck, PE McElroy, SL Altshuler, LL Frye, MA Rowe, M Grunze, H Suppes, T Nolen, WA AF Post, Robert M. Leverich, Gabriele S. Kupka, Ralph Keck, Paul E., Jr. McElroy, Susan L. Altshuler, Lori L. Frye, Mark A. Rowe, Michael Grunze, Heinz Suppes, Trisha Nolen, Willem A. TI Clinical correlates of sustained response to individual drugs used in naturalistic treatment of patients with bipolar disorder SO COMPREHENSIVE PSYCHIATRY LA English DT Article ID LIFE-CHART METHOD; I DISORDER; ANTIDEPRESSANT TREATMENT; CONTROLLED-TRIAL; DOUBLE-BLIND; EARLY-ONSET; STEP-BD; LITHIUM; OUTPATIENTS; DEPRESSION AB Objective: To report use and treatment success rates of medications for bipolar disorder as a function of patients' clinical characteristics. Method: Outpatients with bipolar illness diagnosed by SCID were rated by research assistants on the NIMH-LCM and those who had an good response for at least 6 months (much or very much improved on the CGI-BP) were considered responders (treatment "success"). Clinical characteristics associated with treatment response in the literature were examined for how often a drug was in a successful regimen when a given characteristic was either present or absent. Results: Lithium was less successful in those with histories of rapid cycling, substance abuse, or (surprisingly) a positive parental history of mood disorders. Valproate was less successful in those with >= 20 prior episodes. Lamotrigine (LTG) was less successful in those with a parental history of mood disorders or in BP-I compared to BP-II disorder. Antidepressants (ADs) had low success rates, especially in those with a history of anxiety disorders. Benzodiazepines had low success rates in those with child abuse, substance use, or >= 20 episodes. Atypical antipsychotics were less successful in the presence of rapid cycling, >= 20 prior episodes, or a greater number of poor prognosis factors. Conclusion: Success rates reflect medications used in combination with an average of two other drugs during naturalistic treatment and thus should be considered exploratory. However, the low long-term success rates of drugs (even when used in combination with others) that occurred in the presence of many very common clinical characteristics of bipolar illness speak to the need for the development of alternative treatment strategies. (C) 2016 Elsevier Inc. All rights reserved. C1 [Post, Robert M.; Leverich, Gabriele S.; Rowe, Michael] Bipolar Collaborat Network, Bethesda, MD USA. [Post, Robert M.] George Washington Univ, Dept Psychiat & Behav Sci, Washington, DC USA. [Kupka, Ralph] Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, Amsterdam, Netherlands. [Keck, Paul E., Jr.] Univ Cincinnati, Coll Med, Dept Psychiat & Behav Neurosci, Cincinnati, OH USA. [Keck, Paul E., Jr.; McElroy, Susan L.] Lindner Ctr HOPE, Mason, OH USA. [McElroy, Susan L.] Univ Cincinnati, Coll Med, Biol Psychiat Program, Cincinnati, OH USA. [Altshuler, Lori L.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Altshuler, Lori L.] West Los Angeles Healthcare Ctr, VA Greater Los Angeles Healthcare Syst, Dept Psychiat, Los Angeles, CA USA. [Frye, Mark A.] Mayo Clin, Dept Psychiat, Rochester, MI USA. [Grunze, Heinz] Newcastle Univ, Acad Psychiat, Inst Neurosci, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Suppes, Trisha] Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Palo Alto, CA 94304 USA. [Suppes, Trisha] VA Palo Alto Hlth Care Syst, Palo Alto, CA USA. [Nolen, Willem A.] Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands. RP Post, RM (reprint author), Bipolar Collaborat Network, 5415 West Cedar Lane,Suite 201-B, Bethesda, MD 20814 USA. EM robert.post@speakeasy.net OI Grunze, Heinz/0000-0003-4712-8979 NR 43 TC 2 Z9 2 U1 2 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 0010-440X EI 1532-8384 J9 COMPR PSYCHIAT JI Compr. Psychiat. PD APR PY 2016 VL 66 BP 146 EP 156 DI 10.1016/j.comppsych.2016.01.009 PG 11 WC Psychiatry SC Psychiatry GA DH4ML UT WOS:000372760000020 PM 26995248 ER PT J AU Lynch, CP Williams, JS Voronca, D Walker, RJ Egede, LE AF Lynch, Cheryl P. Williams, Joni Strom Voronca, Delia Walker, Rebekah J. Egede, Leonard E. TI Meaning of Illness and Cardiovascular Risk Factors in Patients With Type 2 Diabetes SO DIABETES EDUCATOR LA English DT Article ID SELF-MANAGEMENT; DEPRESSION; MELLITUS; ADULTS; HEALTH; QUESTIONNAIRE; RELIABILITY; ASSOCIATION; DISTRESS; VALIDITY AB Purpose The purpose of this study was to examine the relationship between meaning of illness and cardiovascular disease risk factors in patients with type 2 diabetes. Methods The sample population was recruited from primary care clinics in the southeastern United States. The meaning of illness was assessed by a validated questionnaire with 5 subscales. The primary outcomes were cardiovascular disease (CVD) risk factors, assessed by A1C, systolic and diastolic blood pressure (SBP and DBP, respectively), and low-density lipoprotein cholesterol (LDL-C). Multivariate linear regression models investigated associations between the clinical outcomes and the 5 MIQ factors, controlling for possible confounders. Results The sample comprised 302 black and white participants of whom more than half were elderly (65+ years) and the vast majority were male (98%). Systolic blood pressure was positively associated with non-anticipated vulnerability. Diastolic blood pressure was negatively associated with degree of stress/change in commitments and positively associated with challenge/motivation/hope and non-anticipated vulnerability. Low-density lipoprotein cholesterol was significantly and negatively associated with degree of stress/change in commitments. Conclusions Meaning of illness had a significant effect on measured outcomes of CVD risk. The specific factor included in the overarching concept of meaning of illness differed in its influence, with more positive views of stress/commitments associated with lower blood pressure and LDL but more positive views of the challenge/hope/motivation and negative views of non-anticipated vulnerability associated with diabetes associated with higher systolic and diastolic blood pressure. C1 [Lynch, Cheryl P.; Walker, Rebekah J.; Egede, Leonard E.] Ralph H Johnson Vet Affairs Med Ctr, HEROIC, Charleston, SC USA. [Lynch, Cheryl P.; Williams, Joni Strom; Voronca, Delia; Walker, Rebekah J.; Egede, Leonard E.] Med Univ S Carolina, Dept Med, Ctr Hlth Dispar Res, Charleston, SC 29425 USA. [Lynch, Cheryl P.; Williams, Joni Strom; Voronca, Delia; Egede, Leonard E.] Med Univ S Carolina, Dept Med, Div Gen Internal Med & Geriatr, Charleston, SC 29425 USA. RP Egede, LE (reprint author), Med Univ S Carolina, Ctr Hlth Dispar Res, Hlth Equ & Rural Outreach Innovat Ctr, 135 Rutledge Ave,Room 280G,POB 250593, Charleston, SC 29425 USA. EM egedel@musc.edu FU VHA Health Services Research and Development (HSRD) program [TRP 04-038] FX This study was supported by grant No. TRP 04-038 funded by the VHA Health Services Research and Development (HSR&D) program. The funding agency did not participate in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript. The manuscript represents the views of the authors and not those of the VA or HSR&D. NR 29 TC 0 Z9 0 U1 0 U2 4 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0145-7217 EI 1554-6063 J9 DIABETES EDUCATOR JI Diabetes Educ. PD APR PY 2016 VL 42 IS 2 BP 220 EP 227 DI 10.1177/0145721716631430 PG 8 WC Endocrinology & Metabolism; Public, Environmental & Occupational Health SC Endocrinology & Metabolism; Public, Environmental & Occupational Health GA DH6DV UT WOS:000372882100007 PM 26879460 ER PT J AU Iezzoni, LI Wint, AJ Kuhlthau, KA Boudreau, AA AF Iezzoni, Lisa I. Wint, Amy J. Kuhlthau, Karen A. Boudreau, Alexy Arauz TI Adults' recollections and perceptions of childhood caregiving to a parent with significant physical disability SO DISABILITY AND HEALTH JOURNAL LA English DT Article DE Disability; Caregiving; Child; Parent ID YOUNG CARERS; MULTIPLE-SCLEROSIS; FAMILY-MEMBERS; CHILDREN; IMPACT AB Background: Caregiving roles of children < 18 years of age living with parents with health conditions or disability have been studied extensively abroad, but little U.S. research has examined the caregiving activities and perceptions of children with parents with significant physical disability. Objective: To examine children's caregiving activities for their disabled parent, childhood perceptions of these activities, and adult views of this caregiving. Methods: We conducted 1-h, semi-structured, open-ended interviews with 20 persons age >= 21 years who as children (age < 18 years) had a parent with significant mobility disability. We used conventional content analysis to identify themes. Results: Interviewees' mean (standard deviation) age was 36.7 (13.8) years; 4 were male. As children, most interviewees assisted their disabled parent with activities of daily living (ADLs) and instrumental ADLs; some children provided more medical supports. Several parents, especially of older interviewees, did not seek their children's care. Interviewees reported both positive and negative childhood attitudes about caregiving. Roughly half recalled as children feeling proud, special, or otherwise positively toward caregiving activities, while about one-third viewed caregiving as just part of their daily reality (i.e., simply needing to be done). Approximately half remembered also feeling resentful, primarily from time demands, insufficient appreciation, and being different from their peers. Interviewees reported gender and cultural factors affecting their caregiving roles and perceptions. Conclusions: Children can provide significant care to parents with physical disability. Understanding better their roles and perceptions could suggest ways to improve these experiences for both child and parent. (C) 2016 Elsevier Inc. All rights reserved. C1 [Iezzoni, Lisa I.; Wint, Amy J.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, 50 Staniford St,Room 901B, Boston, MA 02114 USA. [Kuhlthau, Karen A.; Boudreau, Alexy Arauz] Massachusetts Gen Hosp Children, Dept Pediat, Boston, MA USA. [Iezzoni, Lisa I.] Harvard Univ, Sch Med, Dept Med, Cambridge, MA 02138 USA. [Kuhlthau, Karen A.; Boudreau, Alexy Arauz] Harvard Univ, Sch Med, Dept Pediat, Cambridge, MA 02138 USA. RP Iezzoni, LI (reprint author), Massachusetts Gen Hosp, Mongan Inst Hlth Policy, 50 Staniford St,Room 901B, Boston, MA 02114 USA. EM liezzoni@mgh.harvard.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [R21HD073553-01A2] FX The Eunice Kennedy Shriver National Institute of Child Health and Human Development funded this study (Grant No. R21HD073553-01A2). The authors have no financial conflicts of interest. NR 36 TC 0 Z9 0 U1 2 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-6574 EI 1876-7583 J9 DISABIL HEALTH J JI Disabil. Health J. PD APR PY 2016 VL 9 IS 2 BP 208 EP 217 DI 10.1016/j.dhjo.2015.10.009 PG 10 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health; Rehabilitation SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Rehabilitation GA DH3WT UT WOS:000372718200007 PM 26712460 ER PT J AU Tritos, NA AF Tritos, Nicholas A. TI Skeletal health in adult growth hormone deficiency SO ENDOCRINE LA English DT Editorial Material ID BONE-MINERAL DENSITY; GH DEFICIENCY; REPLACEMENT THERAPY; PREVALENCE C1 [Tritos, Nicholas A.] Massachusetts Gen Hosp, Neuroendocrine Unit, Zero Emerson Pl 112, Boston, MA 02114 USA. [Tritos, Nicholas A.] Harvard Univ, Sch Med, Zero Emerson Pl 112, Boston, MA 02114 USA. RP Tritos, NA (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, Zero Emerson Pl 112, Boston, MA 02114 USA.; Tritos, NA (reprint author), Harvard Univ, Sch Med, Zero Emerson Pl 112, Boston, MA 02114 USA. EM ntritos@partners.org NR 10 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-008X EI 1559-0100 J9 ENDOCRINE JI Endocrine PD APR PY 2016 VL 52 IS 1 BP 1 EP 2 DI 10.1007/s12020-016-0859-z PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DH9XA UT WOS:000373148100001 PM 26767651 ER PT J AU Svensson, E Farkas, DK Gradus, JL Lash, TL Sorensen, HT AF Svensson, E. Farkas, D. K. Gradus, J. L. Lash, T. L. Sorensen, H. T. TI Adjustment disorder and risk of Parkinson's disease SO EUROPEAN JOURNAL OF NEUROLOGY LA English DT Article DE adjustment disorder; Parkinson's disease; psychological stress ID SEVERE STRESS; REGISTER; DEPRESSION; EPIDEMIOLOGY; DIAGNOSES; SYMPTOMS; SMOKING; COHORT; SYSTEM AB Background and purposeIt has been postulated that stress is part of the etiological process of Parkinson's disease (PD). The risk of PD was examined in a cohort of patients with adjustment disorders, a diagnosis made in the presence of a severe response to a stressful life event. MethodsUsing Danish medical registries, PD occurrence was examined in a nationwide population-based cohort of patients with adjustment disorder diagnosed between 1995 and 2011. The standardized incidence ratio of PD was calculated as the ratio of observed to expected cases, stratified by time and potential risk factors, including depression and anxiety. ResultsOur adjustment disorder cohort (67 786 patients) was followed for a median of 8 years (interquartile range 4, 12.6 years). During follow-up, 119 patients developed PD, versus 64 expected, corresponding to a standardized incidence ratio of 1.84 (95% confidence interval 1.53, 2.20). Consistent results were observed after stratification on potential risk factors, including depression and anxiety. ConclusionAdjustment disorder, a diagnosis made in the presence of severe response to stressful life events, was associated with an increased risk of PD. C1 [Svensson, E.; Farkas, D. K.; Gradus, J. L.; Lash, T. L.; Sorensen, H. T.] Aarhus Univ Hosp, Dept Clin Epidemiol, Olof Palmes Alle 43-45, DK-8000 Aarhus N, Denmark. [Gradus, J. L.] VA Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA USA. [Gradus, J. L.] Boston Univ, Dept Psychiat, Boston, MA 02215 USA. [Gradus, J. L.] Boston Univ, Dept Epidemiol, Boston, MA 02215 USA. [Lash, T. L.] Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. RP Svensson, E (reprint author), Aarhus Univ Hosp, Dept Clin Epidemiol, Olof Palmes Alle 43-45, DK-8000 Aarhus N, Denmark. EM Elisabeth.svensson@clin.au.dk FU National Institute of Mental Health [1R21MH094551-01A1]; Program for Clinical Research Infrastructure FX This work was supported by a National Institute of Mental Health grant 'Constructing a Danish Reaction to Severe Stress Cohort' (1R21MH094551-01A1), Jaimie Gradus, Principal Investigator, the Program for Clinical Research Infrastructure established by Lundbeck and Novo Nordisk Foundations, Aarhus University Research Foundation. NR 30 TC 0 Z9 0 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1351-5101 EI 1468-1331 J9 EUR J NEUROL JI Eur. J. Neurol. PD APR PY 2016 VL 23 IS 4 BP 751 EP 756 DI 10.1111/ene.12933 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DH7KK UT WOS:000372972300017 PM 26756302 ER PT J AU Robles, AI Traverso, G Zhang, M Roberts, NJ Khan, MA Joseph, C Lauwers, GY Selaru, FM Popoli, M Pittman, ME Ke, XQ Hruban, RH Meltzer, SJ Kinzler, KW Vogelstein, B Harris, CC Papadopoulos, N AF Robles, Ana I. Traverso, Giovanni Zhang, Ming Roberts, Nicholas J. Khan, Mohammed A. Joseph, Christine Lauwers, Gregory Y. Selaru, Florin M. Popoli, Maria Pittman, Meredith E. Ke, Xiquan Hruban, Ralph H. Meltzer, Stephen J. Kinzler, Kenneth W. Vogelstein, Bert Harris, Curtis C. Papadopoulos, Nickolas TI Whole-Exome Sequencing Analyses of Inflammatory Bowel Disease-Associated Colorectal Cancers SO GASTROENTEROLOGY LA English DT Article DE Exome; Sequencing; Ulcerative Colitis; Crohn's Disease ID C-KI-RAS; COLITIS-ASSOCIATED NEOPLASMS; SPORADIC COLON-CARCINOMA; ULCERATIVE-COLITIS; MICROSATELLITE INSTABILITY; GENE-MUTATIONS; GASTRIC-CANCER; NITRIC-OXIDE; ESOPHAGEAL ADENOCARCINOMA; ABERRANT METHYLATION AB BACKGROUND & AIMS: A long duration of inflammatory bowel disease (IBD) increases the risk for colorectal cancer. Mutation analysis of limited numbers of genes has indicated that colorectal tumors that develop in patients with IBD differ from those of patients without IBD. We performed whole-exome sequencing analyses to characterize the genetic landscape of these tumors. METHODS: We collected colorectal tumor and non-neoplastic tissues from 31 patients with IBD and colorectal cancer (15 with ulcerative colitis, 14 with Crohn's disease, and 2 with indeterminate colitis) and performed whole-exome sequencing analyses of the micro-dissected tumor and matched nontumor tissues. We identified somatic alterations by comparing matched specimens. The prevalence of mutations in sporadic colorectal tumors was obtained from previously published exome-sequencing studies. RESULTS: Two specimens had somatic mutations in the DNA proofreading or mismatch repair genes POLE, MLH1, and MSH6 and the tumor cells had a hypermutable phenotype. The remaining tumors had, on average, 71 alterations per sample. TP53 was the most commonly mutated gene, with prevalence similar to that of sporadic colorectal tumors (63% of cases). However, tumors from the patients with IBD had a different mutation spectrum. APC and KRAS were mutated at significantly lower rates in tumors from patients with IBD than in sporadic colorectal tumors (13% and 20% of cases, respectively). Several genes were mutated more frequently or uniquely in tumors from patients with IBD, including SOX9 and EP300 (which encode proteins in the WNT pathway), NRG1 (which encodes an ERBB ligand), and IL16 (which encodes a cytokine). Our study also revealed recurrent mutations in components of the Rho and Rac GTPase network, indicating a role for noncanonical WNT signaling in development of colorectal tumors in patients with IBD. CONCLUSIONS: Colorectal tumors that develop in patients with IBD have distinct genetic features from sporadic colorectal tumors. These findings could be used to develop disease-specific markers for diagnosis and treatment of patients with IBD and colorectal cancer. C1 [Robles, Ana I.; Khan, Mohammed A.; Harris, Curtis C.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, 37 Convent Dr,Room 3068A,MSC 4258, Bethesda, MD 20892 USA. [Traverso, Giovanni] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Gastroenterol, Boston, MA USA. [Traverso, Giovanni] MIT, Dept Chem Engn, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Zhang, Ming; Roberts, Nicholas J.; Joseph, Christine; Popoli, Maria; Kinzler, Kenneth W.; Vogelstein, Bert; Papadopoulos, Nickolas] Ludwig Ctr Johns Hopkins, Baltimore, MD 21287 USA. [Roberts, Nicholas J.; Pittman, Meredith E.; Hruban, Ralph H.] Johns Hopkins Univ, Sch Med, Dept Pathol, Sol Goldman Pancreat Canc Res Ctr, Baltimore, MD 21205 USA. [Lauwers, Gregory Y.] Harvard Univ, Sch Med, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Selaru, Florin M.; Ke, Xiquan; Meltzer, Stephen J.] Johns Hopkins Univ, Sch Med, Div Gastroenterol, Baltimore, MD USA. [Vogelstein, Bert] Howard Hughes Med Inst, Chevy Chase, MD USA. [Kinzler, Kenneth W.; Vogelstein, Bert; Papadopoulos, Nickolas] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. RP Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, 37 Convent Dr,Room 3068A,MSC 4258, Bethesda, MD 20892 USA.; Vogelstein, B; Papadopoulos, N (reprint author), Ludwig Ctr Johns Hopkins, Dept Oncol, 1650 Orleans St,CRB1 Room 585, Baltimore, MD 21287 USA. EM bertvog@gmail.com; harrisc@mail.nih.gov; npapado1@jhmi.edu FU Intramural NIH HHS; NCI NIH HHS [R01 CA133012, CA057345, CA133012, CA152753, CA190040, CA43460, CA62924, P50 CA062924, R01 CA057345, R01 CA190040, R37 CA043460, R37 CA057345, U01 CA152753]; NIDDK NIH HHS [P30 DK089502, T32 DK007191, T32-DK007191-38-S1] NR 98 TC 14 Z9 14 U1 6 U2 12 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 APR PY 2016 VL 150 IS 4 BP 931 EP 943 DI 10.1053/j.gastro.2015.12.036 PG 13 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DH4BH UT WOS:000372730000032 PM 26764183 ER PT J AU Francis, FF Kulich, SM Hashash, JG AF Francis, Fadi F. Kulich, Scott M. Hashash, Jana G. TI Diarrhea, Ascites, and Eosinophilia Image 3: Hypereosinophilic Syndrome SO GASTROENTEROLOGY LA English DT Editorial Material C1 [Francis, Fadi F.] VA Pittsburgh Hlth Care Syst, Div Gastroenterol Hepatol & Nutr, Pittsburgh, PA USA. [Francis, Fadi F.; Hashash, Jana G.] Univ Pittsburgh, Div Gastroenterol Hepatol & Nutr, Pittsburgh, PA USA. [Kulich, Scott M.] VA Pittsburgh Hlth Care Syst, Dept Pathol, Pittsburgh, PA USA. [Kulich, Scott M.] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA USA. RP Francis, FF (reprint author), VA Pittsburgh Hlth Care Syst, Div Gastroenterol Hepatol & Nutr, Pittsburgh, PA USA.; Francis, FF (reprint author), Univ Pittsburgh, Div Gastroenterol Hepatol & Nutr, Pittsburgh, PA USA. NR 3 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 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD APR PY 2016 VL 150 IS 4 BP E6 EP E8 DI 10.1053/j.gastro.2015.10.019 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DH4BH UT WOS:000372730000003 PM 26930018 ER PT J AU Coleman, RL Matulonis, UA AF Coleman, Robert L. Matulonis, Ursula A. TI Precision medicine SO GYNECOLOGIC ONCOLOGY LA English DT Editorial Material C1 [Coleman, Robert L.] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol & Reprod Med, Houston, TX 77030 USA. [Matulonis, Ursula A.] Dana Farber Canc Inst, Gynecol Oncol Program, Dept Med Oncol, Boston, MA 02215 USA. RP Matulonis, UA (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM Ursula_Matulonis@dfci.harvard.edu NR 0 TC 0 Z9 0 U1 1 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD APR PY 2016 VL 141 IS 1 SI SI BP 1 EP 1 DI 10.1016/j.ygyno.2016.03.017 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA DI1HG UT WOS:000373246600001 PM 27016221 ER PT J AU Myers, AP Filiaci, VL Zhang, YP Pearl, M Behbakht, K Makker, V Hanjani, P Zweizig, S Burke, JJ Downey, G Leslie, KK Van Hummelen, P Birrer, MJ Fleming, GF AF Myers, Andrea P. Filiaci, Virginia L. Zhang, Yuping Pearl, Michael Behbakht, Kian Makker, Vicky Hanjani, Parviz Zweizig, Susan Burke, James J., II Downey, Gordon Leslie, Kimberly K. Van Hummelen, Paul Birrer, Michael J. Fleming, Gini F. TI Tumor mutational analysis of GOG248, a phase II study of temsirolimus or temsirolimus and alternating megestrol acetate and tamoxifen for advanced endometrial cancer (EC): An NRG Oncology/Gynecologic Oncology Group study SO GYNECOLOGIC ONCOLOGY LA English DT Article ID TUBEROUS SCLEROSIS COMPLEX; MAMMALIAN TARGET; RAPAMYCIN INHIBITION; CARCINOMA; EVEROLIMUS; RECURRENT; TRIAL; RIDAFOROLIMUS; WOMEN; PTEN AB Objective. Rapamycin analogs have reproducible but modest efficacy in endometrial cancer (EC). Identification of molecular biomarkers that predict benefit could guide clinical development. Methods. Fixed primary tissue and whole blood were collected prospectively from patients enrolled on GOG 248. DNA was isolated from macro-dissected tumors and blood; next-generation sequence analysis was performed on a panel of cancer related genes. Associations between clinical outcomes [response rate (RR) 20%; progression-free survival (PFS) median 4.9 months] and mutations (PTEN, PIK3CA, PIK3R1, KRAS, CTNNB1, AKT1, TSC1, TSC2, NF1, FBXW7) were explored. Results. Sequencing data was obtained from tumors of 55 of the 73 enrolled pts. Mutation rates were consistent with published reports: mutations in PTEN (45%), PIK3CA (29%), PIK3R1 (24%), K-RAS (16%), CTNNB1 (18%) were common and mutations in AKT1 (4%), TSC1 (2%), TSC2 (2%), NF1 (9%) and FBXW7 (4%) were less common. Increased PFS (HR 0.16; 95% CI 0.01-0.78) and RR (response difference 0.83; 95% CI 0.03-0.99) were noted for AKT1 mutation. An increase in PFS (HR 0.46; 95% CI 0.20-0.97) but not RR (response difference 0.00, 95% CI-0.34-0.34) was identified for CTNNB1 mutation. Both patients with TSC mutations had an objective response. There were no statistically significant associations between mutations in PIK3CA, PTEN, PIK3R1, or KRAS and PFS or RR. Conclusions. Mutations in AKT1, TSC1 and TSC2 are rare, but may predict clinical benefit from temsirolimus. CTNNB1 mutations were associated with longer PFS on temsirolimus. (C) 2016 Published by Elsevier Inc. C1 [Myers, Andrea P.; Van Hummelen, Paul] Dana Farber Canc Inst, Boston, MA 02115 USA. [Filiaci, Virginia L.] NRG Oncol Stat & Data Management Ctr, Buffalo, NY USA. [Zhang, Yuping; Leslie, Kimberly K.] Univ Iowa Hosp & Clin, Iowa City, IA 52242 USA. [Pearl, Michael] SUNY Stony Brook, Stony Brook, NY 11794 USA. [Behbakht, Kian] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Makker, Vicky] Mem Sloan Kettering Canc Ctr, Weill Cornell Med Coll, 1275 York Ave, New York, NY 10021 USA. [Hanjani, Parviz] Abington Mem Hosp, Gladwyne, PA USA. [Zweizig, Susan] Univ Massachusetts Mem Hlth Care, Worcester, MA USA. [Burke, James J., II] Mercer Univ, Sch Med, Savannah, GA USA. [Downey, Gordon] Gynecol Oncol West Michigan, Grand Rapids, MI USA. [Birrer, Michael J.] Massachusetts Gen Hosp, Dana Farber Canc Ctr, Boston, MA 02114 USA. [Fleming, Gini F.] Univ Chicago, Med Ctr, Chicago, IL 60637 USA. RP Myers, AP (reprint author), Novartis Inst BioMed Res, 220 Massachusetts Ave, Cambridge, MA 02139 USA. EM andrea.myers@novartis.com FU NCI grants [CA 27469]; GOG Statistical and Data Center [CA 37517]; NRG Oncology [1 U10CA180822]; Susan Smith Executive Council FX NCI grants to the GOG Administrative Office (CA 27469), the GOG Statistical and Data Center (CA 37517), and the NRG Oncology 1 U10CA180822. Molecular analysis was funded by a Susan Smith Executive Council Grant to A. M. NR 38 TC 1 Z9 1 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD APR PY 2016 VL 141 IS 1 SI SI BP 43 EP 48 DI 10.1016/j.ygyno.2016.02.025 PG 6 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA DI1HG UT WOS:000373246600008 PM 27016228 ER PT J AU Liu, J Westin, SN AF Liu, Joyce Westin, Shannon N. TI Rational selection of biomarker driven therapies for gynecologic cancers: The more we know, the more we know we don't know SO GYNECOLOGIC ONCOLOGY LA English DT Article DE Gynecologic cancer; Biomarkers; Personalized medicine; Targeted therapy; Precision medicine ID RECURRENT EPITHELIAL OVARIAN; PHASE-II TRIAL; METASTATIC ENDOMETRIAL CANCER; OLAPARIB MAINTENANCE THERAPY; PRIMARY PERITONEAL CANCER; GRADE SEROUS CARCINOMA; FALLOPIAN-TUBE CANCER; CELL LUNG-CANCER; ONCOLOGY-GROUP; BRAF MUTATION AB Precision medicine is a rapidly evolving area in the treatment of gynecologic malignancies. Advances in sequencing technology have resulted in an increasing wealth of data regarding the genomic characteristics of ovarian, endometrial, and cervical cancers. These vast new datasets of information have led to novel insights into potential vulnerabilities and therapeutic targets for these cancers. However, unraveling the complex molecular changes within cancer cells to determine how best to attack these targets and to identify effective biomarkers of response remains a significant challenge. In this article, we review the current status of biomarker-driven targeted therapy in gynecologic malignancies. (C) 2016 Elsevier Inc. All rights reserved. C1 [Liu, Joyce] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Westin, Shannon N.] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol & Reprod Med, Houston, TX 77030 USA. RP Westin, SN (reprint author), Univ Texas MD Anderson Canc Ctr, 1155 Herman Pressler Blvd,Unit 1362, Houston, TX 77030 USA. EM swestin@mdanderson.org OI Westin, Shannon/0000-0002-1922-0156 FU Calabresi Scholar Award [K12 CA088084 K12]; NIH SPORE in Uterine Cancer [2P50 CA098258-06]; NIH SPORE in Ovarian Cancer [2P50CA083639] FX K12 CA088084 K12 Calabresi Scholar Award (SW).; NIH 2P50 CA098258-06 SPORE in Uterine Cancer (SW).; NIH 2P50CA083639 SPORE in Ovarian Cancer (SW). NR 97 TC 2 Z9 2 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD APR PY 2016 VL 141 IS 1 SI SI BP 65 EP 71 DI 10.1016/j.ygyno.2016.01.003 PG 7 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA DI1HG UT WOS:000373246600011 PM 27016231 ER PT J AU Penson, RT Sales, E Sullivan, L Borger, DR Krasner, CN Goodman, AK del Carmen, MG Growdon, WB Schorge, JO Boruta, DM Castro, CM Dizon, DS Birrer, MJ AF Penson, R. T. Sales, E. Sullivan, L. Borger, D. R. Krasner, C. N. Goodman, A. K. del Carmen, M. G. Growdon, W. B. Schorge, J. O. Boruta, D. M. Castro, C. M. Dizon, D. S. Birrer, M. J. TI A SNaPshot of potentially personalized care: Molecular diagnostics in gynecologic cancer SO GYNECOLOGIC ONCOLOGY LA English DT Article DE Personalized targeted therapy genotyping ID MUTATIONS; CARCINOMA; INHIBITORS; MEDICINE; BREAST AB Background. Genetic abnormalities underlie the development and progression of cancer, and represent potential opportunities for personalized cancer therapy in Gyn malignancies. Methods. We identified Gyn oncology patients at the MGH Cancer Center with tumors genotyped for a panel of mutations by SNaPshot, a CLIA approved assay, validated in lung cancer, that uses SNP genotyping in degraded DNA from FFPE tissue to identify 160 described mutations across 15 cancer genes (AKT1, APC, BRAF, CTNNB1, EGFR, ERBB2, IDH1, KIT, KRAS, MAP2KI, NOTCH1, NRAS, PIK3CA, PTEN, TP53). Results. Between 5/17/10 and 8/8/13, 249 pts consented to SNaPshot analysis. Median age 60 (29-84) yrs. Tumors were ovarian 123 (49%), uterine 74(30%), cervical 14(6%), fallopian 9(4%), primary peritoneal 13(5%), or rare 16(6%) with the incidence of testing high grade serous ovarian cancer (HGSOC) halving over time. SNaPshot was positive in 75 (30%), with 18 of these (24%) having 2 or 3 (n = 5) mutations identified. TP53 mutations are most common in high-grade serous cancers yet a low detection rate (17%) was likely related to the assay. However, 4 of the 7 purely endometrioid ovarian tumors (57%) harbored a p53 mutation. Of the 38 endometrioid uterine tumors, 18 mutations (47%) in the PI3Kinase pathway were identified. Only 9 of 122 purely serous (7%) tumors across all tumor types harbored a 'drugable' mutation, compared with 20 of 45 (44%) of endometrioid tumors (p < 0.0001). 17 pts subsequently enrolled on a clinical trial; all but 4 of whom had PIK3CA pathway mutations. Eight of 14 (47%) cervical tumors harbored a 'drugable' mutation. Conclusion. Although SNaPshot can identify potentially important therapeutic targets, the incidence of 'drugable' targets in ovarian cancer is low. In this cohort, only 7% of subjects eventually were treated on a relevant clinical trial. Geneotyping should be used judiciously and reflect histologic subtype and available platform. (C) 2016 Elsevier Inc. All rights reserved. C1 [Penson, R. T.; Sales, E.; Sullivan, L.; Borger, D. R.; Krasner, C. N.; Goodman, A. K.; del Carmen, M. G.; Growdon, W. B.; Schorge, J. O.; Boruta, D. M.; Castro, C. M.; Dizon, D. S.; Birrer, M. J.] Massachusetts Gen Hosp, Div Hematol Oncol, Yawkey 9-064,32 Fruit St, Boston, MA 02114 USA. RP Penson, RT (reprint author), Massachusetts Gen Hosp, Div Hematol Oncol, Yawkey 9-064,32 Fruit St, Boston, MA 02114 USA. EM rpenson@partners.org NR 19 TC 0 Z9 0 U1 1 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD APR PY 2016 VL 141 IS 1 SI SI BP 108 EP 112 DI 10.1016/j.ygyno.2016.02.032 PG 5 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA DI1HG UT WOS:000373246600017 PM 27016236 ER PT J AU Nunes, MCP Nascimento, BR Lodi-Junqueira, L Tan, TC Athayde, GRS Hung, J AF Nunes, Maria Carmo P. Nascimento, Bruno Ramos Lodi-Junqueira, Lucas Tan, Timothy C. Sant'Anna Athayde, Guilherme Rafael Hung, Judy TI Update on percutaneous mitral commissurotomy SO HEART LA English DT Review ID RHEUMATIC HEART-DISEASE; TERM-FOLLOW-UP; BALLOON VALVOTOMY; TRICUSPID REGURGITATION; ATRIAL-FIBRILLATION; ECHOCARDIOGRAPHIC ASSESSMENT; VALVE CALCIFICATION; INOUE-BALLOON; VALVULOPLASTY; STENOSIS AB Percutaneous mitral commissurotomy (PMC) is the first-line therapy for managing rheumatic mitral stenosis. Over the past two decades, the indications of the procedure have expanded to include patients with unfavourable valve anatomy as a consequence of epidemiological changes in patient population. The procedure is increasingly being performed in patients with increased age, more deformed valves and associated comorbidities. Echocardiography plays a crucial role in patient selection and to guide a more efficient procedure. The main echocardiographic predictors of immediate results after PMC are mitral valve area, subvalvular thickening and valve calcification, especially at the commissural level. However, procedural success rate is not only dependent on valve anatomy, but a number of other factors including patient characteristics, interventional management strategies and operator expertise. Severe mitral regurgitation continues to be the most common immediate procedural complication with unchanged incidence rates over time. The long-term outcome after PMC is mainly determined by the immediate procedural results. Postprocedural parameters associated with late adverse events include mitral valve area, mitral regurgitation severity, mean gradient and pulmonary artery pressure. Mitral restenosis is an important predictor of event-free survival rates after successful PMC, and repeat procedure can be considered in cases with commissural refusion. PMC can be performed in special situations, which include high-risk patients, during pregnancy and in the presence of left atrial thrombus, especially in centres with specialised expertise. Therefore, procedural decision-making should take into account the several determinant factors of PMC outcomes. This paper provides an overview and update of PMC techniques, complications, immediate and long-term results over time, and assessment of suitability for the procedure. C1 [Nunes, Maria Carmo P.; Nascimento, Bruno Ramos; Lodi-Junqueira, Lucas; Sant'Anna Athayde, Guilherme Rafael] Univ Fed Minas Gerais, Sch Med, Hosp Clin, Ave Prof Alfredo Balena,190,Room 246, BR-30130100 Belo Horizonte, MG, Brazil. [Tan, Timothy C.] Univ Western Sydney, Blacktown Hosp, Dept Cardiol, Sydney, NSW, Australia. [Hung, Judy] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac Ultrasound Lab, Boston, MA 02115 USA. RP Nunes, MCP (reprint author), Univ Fed Minas Gerais, Sch Med, Hosp Clin, Ave Prof Alfredo Balena,190,Room 246, BR-30130100 Belo Horizonte, MG, Brazil. EM mcarmo@waymail.com.br OI Nascimento, Bruno/0000-0002-5586-774X NR 63 TC 0 Z9 0 U1 0 U2 2 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1355-6037 EI 1468-201X J9 HEART JI Heart PD APR 1 PY 2016 VL 102 IS 7 BP 500 EP 507 DI 10.1136/heartjnl-2015-308091 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DI2EM UT WOS:000373308500005 PM 26743926 ER PT J AU Baker, MA Huang, SS Letourneau, AR Kaganov, RE Peeples, JR Drees, M Platt, R Yokoe, DS AF Baker, Meghan A. Huang, Susan S. Letourneau, Alyssa R. Kaganov, Rebecca E. Peeples, Jennifer R. Drees, Marci Platt, Richard Yokoe, Deborah S. CA Ctr Dis Control Prevention Epictr TI Lack of Comprehensive Outbreak Detection in Hospitals SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Article ID CARE-ASSOCIATED INFECTIONS; STAPHYLOCOCCUS-AUREUS; PREVENTION AB Timely identification of outbreaks of hospital-associated infections is needed to implement control measures and minimize impact. Survey results from 33 hospitals indicated that most hospitals lacked a formal cluster definition and all targeted a very limited group of prespecified pathogens. Standardized, statistically based outbreak detection could greatly improve current practice. C1 [Baker, Meghan A.; Kaganov, Rebecca E.; Platt, Richard] Harvard Univ, Sch Med, Dept Populat Med, Boston, MA USA. [Baker, Meghan A.; Kaganov, Rebecca E.; Platt, Richard] Harvard Pilgrim Hlth Care Inst, Boston, MA 02215 USA. [Baker, Meghan A.; Yokoe, Deborah S.] Brigham & Womens Hosp, Dept Med, Div Infect Dis, 75 Francis St, Boston, MA 02115 USA. [Huang, Susan S.] Univ Calif Irvine, Sch Med, Div Infect Dis, Dept Med, Orange, CA 92668 USA. [Letourneau, Alyssa R.] Massachusetts Gen Hosp, Div Infect Dis, Dept Med, Boston, MA 02114 USA. [Peeples, Jennifer R.] Premier, Charlotte, NC USA. [Drees, Marci] Christiana Care Hlth Syst, Div Infect Dis, Dept Med, Newark, DE USA. RP Baker, MA (reprint author), Harvard Pilgrim Hlth Care Inst, Dept Populat Med, 133 Brookline Ave,6th Fl, Boston, MA 02215 USA. EM meghan_baker@harvardpilgrim.org FU Centers for Disease Control and Prevention Epicenters Program [1U54 CK000172-01] FX Centers for Disease Control and Prevention Epicenters Program (grant 1U54 CK000172-01). NR 12 TC 1 Z9 1 U1 1 U2 2 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0899-823X EI 1559-6834 J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD APR PY 2016 VL 37 IS 4 BP 466 EP 468 DI 10.1017/ice.2015.325 PG 3 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA DH5AD UT WOS:000372796200014 PM 26996060 ER PT J AU Charidimou, A Shams, S AF Charidimou, Andreas Shams, Sara TI Introducing @microbleeds: A pilot Twitter space for cerebral microbleeds research SO INTERNATIONAL JOURNAL OF STROKE LA English DT Letter C1 [Charidimou, Andreas] Harvard Univ, Massachusetts Gen Hosp, Dept Neurol, Hemorrhag Stroke Res Program,Stroke Res Ctr, Boston, MA 02115 USA. [Shams, Sara] Karolinska Inst, Div Med Imaging & Technol, Dept Clin Sci Intervent & Technol, Stockholm, Sweden. [Shams, Sara] Karolinska Univ Hosp, Dept Radiol, Stockholm, Sweden. RP Charidimou, A (reprint author), Massachusetts Gen Hosp, Dept Neurol, Hemorrhag Stroke Res Program, 175 Cambridge St,Suite 300, Boston, MA 02114 USA. EM andreas.charidimou.09@ucl.ac.uk NR 2 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 1747-4930 EI 1747-4949 J9 INT J STROKE JI Int. J. Stroke PD APR PY 2016 VL 11 IS 3 BP NP40 EP NP41 DI 10.1177/1747493016632251 PG 2 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DH5FL UT WOS:000372811200006 PM 26865156 ER PT J AU Helenius, IT Nair, A Bittar, HET Sznajder, JI Sporn, PHS Beitel, GJ AF Helenius, Iiro Taneli Nair, Aisha Bittar, Humberto E. Trejo Sznajder, Jacob I. Sporn, Peter H. S. Beitel, Greg J. TI Focused Screening Identifies Evoxine as a Small Molecule That Counteracts CO2-Induced Immune Suppression SO JOURNAL OF BIOMOLECULAR SCREENING LA English DT Article DE anti-infective drugs; cell-based assays; immune system diseases; reporter gene assays ID DROSOPHILA-MELANOGASTER; FUROQUINOLINE ALKALOIDS; ACUTE EXACERBATION; HUMAN-DISEASE; CO2; CELLS; EXPRESSION; PROTEIN; MACROPHAGES; MORTALITY AB Patients with severe lung disease may develop hypercapnia, elevation of the levels of CO2 in the lungs and blood, which is associated with increased risk of death, often from infection. To identify compounds that ameliorate the adverse effects of hypercapnia, we performed a focused screen of 8832 compounds using a CO2-responsive luciferase reporter in Drosophila S2* cells. We found that evoxine, a plant alkaloid, counteracts the CO2-induced transcriptional suppression of antimicrobial peptides in S2* cells. Strikingly, evoxine also inhibits hypercapnic suppression of interleukin-6 and the chemokine CCL2 expression in human THP-1 macrophages. Evoxine's effects are selective, since it does not prevent hypercapnic inhibition of phagocytosis by THP-1 cells or CO2-induced activation of AMPK in rat ATII pulmonary epithelial cells. The results suggest that hypercapnia suppresses innate immune gene expression by definable pathways that are evolutionarily conserved and demonstrate for the first time that specific CO2 effects can be targeted pharmacologically. C1 [Helenius, Iiro Taneli; Beitel, Greg J.] Northwestern Univ, Dept Mol Biosci, Evanston, IL USA. [Nair, Aisha; Bittar, Humberto E. Trejo; Sznajder, Jacob I.; Sporn, Peter H. S.] Northwestern Univ, Feinberg Sch Med, Div Pulm & Crit Care Med, Evanston, IL USA. [Sporn, Peter H. S.] Jesse Brown Vet Affairs Med Ctr, Chicago, IL USA. [Helenius, Iiro Taneli] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. RP Beitel, GJ (reprint author), Northwestern Univ, Hogan Hall,Rm 2-100,22015 Tech Dr, Evanston, IL 60208 USA. EM beitel@northwestern.edu FU NIH [NHLBI/R01-HL107629, NHLBI/R01-HL-85534, NERCE/NSRB U54-AI057159, NIGMS/R01-GM067761]; American Heart Association [0855686G, 0715562Z]; Chicago Biomedical Consortium; Searle Funds at The Chicago Community Trust; Northwestern University Robert H. Lurie Comprehensive Cancer Center 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 grants from the NIH to GJB and PHSS (NHLBI/R01-HL107629), to JIS (NHLBI/R01-HL-85534), to ICCB-Longwood (NERCE/NSRB U54-AI057159), and to DRSC (NIGMS/R01-GM067761); from the American Heart Association to GJB (grant-in-aid award, 0855686G) and to ITH (predoctoral fellowship, 0715562Z); from the Chicago Biomedical Consortium with support from The Searle Funds at The Chicago Community Trust to NU CMIDD; and from the Northwestern University Robert H. Lurie Comprehensive Cancer Center to the NU HTA core facility. NR 30 TC 1 Z9 1 U1 3 U2 4 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1087-0571 EI 1552-454X J9 J BIOMOL SCREEN JI J. Biomol. Screen PD APR PY 2016 VL 21 IS 4 BP 363 EP 371 DI 10.1177/1087057115624091 PG 9 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Chemistry GA DH6EG UT WOS:000372883200005 PM 26701099 ER PT J AU Hayakawa, K Pham, LDD Seo, JH Miyamoto, N Maki, T Terasaki, Y Sakadzic, S Boas, D van Leyen, K Waeber, C Kim, KW Arai, K Lo, EH AF Hayakawa, Kazuhide Pham, Loc-Duyen D. Seo, Ji Hae Miyamoto, Nobukazu Maki, Takakuni Terasaki, Yasukazu Sakadzic, Sava Boas, David van Leyen, Klaus Waeber, Christian Kim, Kyu-Won Arai, Ken Lo, Eng H. TI CD200 restrains macrophage attack on oligodendrocyte precursors via toll-like receptor 4 downregulation SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE CD200; macrophage; phagocytosis; oligodendrocyte precursors; white matter injury ID SPINAL-CORD-INJURY; MICROGLIA/MACROPHAGE POLARIZATION DYNAMICS; WHITE-MATTER INJURY; ISCHEMIC-STROKE; BRAIN; CELLS; MECHANISMS; PHAGOCYTOSIS; ACTIVATION; DISEASE AB There are numerous barriers to white matter repair after central nervous system injury and the underlying mechanisms remain to be fully understood. In this study, we propose the hypothesis that inflammatory macrophages in damaged white matter attack oligodendrocyte precursor cells via toll-like receptor 4 signaling thus interfering with this endogenous progenitor recovery mechanism. Primary cell culture experiments demonstrate that peritoneal macrophages can attack and digest oligodendrocyte precursor cells via toll-like receptor 4 signaling, and this phagocytosis of oligodendrocyte precursor cells can be inhibited by using CD200-Fc to downregulate toll-like receptor 4. In an in vivo model of white matter ischemia induced by endothelin-1, treatment with CD200-Fc suppressed toll-like receptor 4 expression in peripherally circulating macrophages, thus restraining macrophage phagocytosis of oligodendrocyte precursor cells and leading to improved myelination. Taken together, these findings suggest that deleterious macrophage effects may occur after white matter ischemia, whereby macrophages attack oligodendrocyte precursor cells and interfere with endogenous recovery responses. Targeting this pathway with CD200 may offer a novel therapeutic approach to amplify endogenous oligodendrocyte precursor cell-mediated repair of white matter damage in mammalian brain. C1 [Hayakawa, Kazuhide; Pham, Loc-Duyen D.; Seo, Ji Hae; Miyamoto, Nobukazu; Maki, Takakuni; Terasaki, Yasukazu; van Leyen, Klaus; Arai, Ken; Lo, Eng H.] Massachusetts Gen Hosp, Neuroprotect Res Lab, Dept Radiol, Charlestown, MA USA. [Hayakawa, Kazuhide; Pham, Loc-Duyen D.; Seo, Ji Hae; Miyamoto, Nobukazu; Maki, Takakuni; Terasaki, Yasukazu; van Leyen, Klaus; Arai, Ken; Lo, Eng H.] Massachusetts Gen Hosp, Neuroprotect Res Lab, Dept Neurol, Charlestown, MA USA. [Hayakawa, Kazuhide; Pham, Loc-Duyen D.; Seo, Ji Hae; Miyamoto, Nobukazu; Maki, Takakuni; Terasaki, Yasukazu; Sakadzic, Sava; Boas, David; van Leyen, Klaus; Arai, Ken; Lo, Eng H.] Harvard Univ, Sch Med, Charlestown, MA USA. [Seo, Ji Hae; Kim, Kyu-Won] Seoul Natl Univ, NeuroVasc Protect Res Ctr, Coll Pharm, Seoul, South Korea. [Seo, Ji Hae; Kim, Kyu-Won] Seoul Natl Univ, Pharmaceut Sci Res Inst, Seoul, South Korea. [Sakadzic, Sava; Boas, David] Massachusetts Gen Hosp, Opt Div, MHG MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Charlestown, MA USA. [Waeber, Christian] Natl Univ Ireland Univ Coll Cork, Sch Pharm, Dept Pharmacol & Therapeut, Cork, Ireland. [Kim, Kyu-Won] Seoul Natl Univ, Dept Mol Med & Biopharmaceut Sci, Grad Sch Convergence Sci & Technol, Seoul, South Korea. [Kim, Kyu-Won] Seoul Natl Univ, Coll Med, Seoul, South Korea. [Kim, Kyu-Won] Seoul Natl Univ, Coll Pharm, Seoul, South Korea. RP Hayakawa, K; Lo, EH (reprint author), Neuroprotect Res Lab, MGH East 149-2401, Charlestown, MA 02129 USA. EM Khayakawa1@mgh.harvard.edu; Lo@helix.mgh.harvard.edu FU National Institutes of Health; National Research Foundation of Korea; World Class University Program; Global Research Laboratory Program FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study is supported in part by National Institutes of Health, National Research Foundation of Korea, the World Class University Program, and the Global Research Laboratory Program. NR 48 TC 1 Z9 1 U1 1 U2 2 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 APR PY 2016 VL 36 IS 4 BP 781 EP 793 DI 10.1177/0271678X15606148 PG 13 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA DI2VA UT WOS:000373355900012 PM 26661156 ER PT J AU McGrath, LM Braaten, EB Doty, ND Willoughby, BL Wilson, HK O'Donnell, EH Colvin, MK Ditmars, HL Blais, JE Hill, EN Metzger, A Perlis, RH Willcutt, EG Smoller, JW Waldman, ID Faraone, SV Seidman, LJ Doyle, AE AF McGrath, Lauren M. Braaten, Ellen B. Doty, Nathan D. Willoughby, Brian L. Wilson, H. Kent O'Donnell, Ellen H. Colvin, Mary K. Ditmars, Hillary L. Blais, Jessica E. Hill, Erin N. Metzger, Aaron Perlis, Roy H. Willcutt, Erik G. Smoller, Jordan W. Waldman, Irwin D. Faraone, Stephen V. Seidman, Larry J. Doyle, Alysa E. TI Extending the "cross-disorder' relevance of executive functions to dimensional neuropsychiatric traits in youth SO JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY LA English DT Article DE Executive functions; mania; psychosis; social responsiveness; cross-disorder; dimensional traits ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; INDIVIDUAL-DIFFERENCES; PSYCHIATRIC-DISORDERS; BIPOLAR DISORDER; COGNITIVE DEFICITS; SCHIZOPHRENIA; METAANALYSIS; AUTISM; PSYCHOPATHOLOGY; INTELLIGENCE AB BackgroundEvidence that different neuropsychiatric conditions share genetic liability has increased interest in phenotypes with cross-disorder' relevance, as they may contribute to revised models of psychopathology. Cognition is a promising construct for study; yet, evidence that the same cognitive functions are impaired across different forms of psychopathology comes primarily from separate studies of individual categorical diagnoses versus controls. Given growing support for dimensional models that cut across traditional diagnostic boundaries, we aimed to determine, within a single cohort, whether performance on measures of executive functions (EFs) predicted dimensions of different psychopathological conditions known to share genetic liability. MethodsData are from 393 participants, ages 8-17, consecutively enrolled in the Longitudinal Study of Genetic Influences on Cognition (LOGIC). This project is conducting deep phenotyping and genomic analyses in youth referred for neuropsychiatric evaluation. Using structural equation modeling, we examined whether EFs predicted variation in core dimensions of the autism spectrum disorder, bipolar illness, and schizophrenia (including social responsiveness, mania/emotion regulation, and positive symptoms of psychosis, respectively). ResultsWe modeled three cognitive factors (working memory, shifting, and executive processing speed) that loaded on a second-order EF factor. The EF factor predicted variation in our three target traits, but not in a negative control (somatization). Moreover, this EF factor was primarily associated with the overlapping (rather than unique) variance across the three outcome measures, suggesting that it related to a general increase in psychopathology symptoms across those dimensions. ConclusionsFindings extend support for the relevance of cognition to neuropsychiatric conditions that share underlying genetic risk. They suggest that higher-order cognition, including EFs, relates to the dimensional spectrum of each of these disorders and not just the clinical diagnoses. Moreover, results have implications for bottom-up models linking genes, cognition, and a general psychopathology liability. C1 [McGrath, Lauren M.] Amer Univ, Sch Educ, Washington, DC 20016 USA. [Braaten, Ellen B.; Doty, Nathan D.; Willoughby, Brian L.; Wilson, H. Kent; O'Donnell, Ellen H.; Colvin, Mary K.; Perlis, Roy H.; Smoller, Jordan W.; Seidman, Larry J.; Doyle, Alysa E.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02115 USA. [Ditmars, Hillary L.; Blais, Jessica E.; Hill, Erin N.; Perlis, Roy H.; Smoller, Jordan W.; Doyle, Alysa E.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Metzger, Aaron] W Virginia Univ, Dept Psychol, Morgantown, WV 26506 USA. [Perlis, Roy H.; Smoller, Jordan W.; Doyle, Alysa E.] Broad Inst Harvard & MIT, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Willcutt, Erik G.] Univ Colorado, Dept Psychol & Neurosci, Boulder, CO 80309 USA. [Waldman, Irwin D.] Emory Univ, Dept Psychol, Atlanta, GA 30322 USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY 13210 USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Neurosci & Physiol, Syracuse, NY 13210 USA. [Seidman, Larry J.] Harvard Univ, Sch Med, Commonwealth Res Ctr, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. RP Doyle, AE (reprint author), MGH Ctr Human Genet Res, 185 Cambridge St,CPZN 6240, Boston, MA 02114 USA. EM doylea@helix.mgh.harvard.edu FU Stanley Center for Psychiatric Research; American University faculty research support grant; David Judah Foundation; Akili Interactive Labs; Alcobra; VAYA Pharma; SynapDx; National Institutes of Health (NIH); Shire; Otsuka; McNeil; Janssen; Novartis; Pfizer; Eli Lilly; K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway; European Union's Seventh Framework Programme [602805]; NIMH [R13MH059126, R01MH094469]; NIMH; Massachusetts Department of Mental Health; Sidney R. Baer, Jr. Foundation; [R03 MH106862] FX This research was supported in part by the Stanley Center for Psychiatric Research and R03 MH106862 (to A. E. D.), an American University faculty research support grant (to L. M. M.), and the David Judah Foundation (to A. E. D. and E. B. B.). The authors wish to thank Pieter Vuijk for his comments on this manuscript. Author R.P. consults to or serves on scientific advisory boards for Genomind, Healthrageous, Pamlab, Perfect Health, Pfizer, Proteus Biomedical, Psybrain, and RIDVentures. The author receives royalties from UBC, a Medco subsidiary. In the past year, author S.F. received consulting income, travel expenses, and/or research support from Akili Interactive Labs, Alcobra, VAYA Pharma, and SynapDx and research support from the National Institutes of Health (NIH). The author's institution is seeking a patent for the use of sodium-hydrogen exchange inhibitors in the treatment of ADHD. In previous years, the author received consulting fees or was on Advisory Boards or participated in continuing medical education programs sponsored by Shire, Alcobra, Otsuka, McNeil, Janssen, Novartis, Pfizer and Eli Lilly. The author receives royalties from books published by Guilford Press: Straight Talk about Your Child's Mental Health and Oxford University Press: Schizophrenia: The Facts. He is supported by the K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway, the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no 602805 and NIMH grants R13MH059126 and R01MH094469. Author J.S. serves on the scientific advisory board of PsyBrain. Author L.S. reports no competing interests. The author receives support from NIMH, the Massachusetts Department of Mental Health, and the Sidney R. Baer, Jr. Foundation. All other authors declare that they have no competing or potential conflicts of interests. NR 48 TC 2 Z9 2 U1 5 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9630 EI 1469-7610 J9 J CHILD PSYCHOL PSYC JI J. Child Psychol. Psychiatry PD APR PY 2016 VL 57 IS 4 BP 462 EP 471 DI 10.1111/jcpp.12463 PG 10 WC Psychology, Developmental; Psychiatry; Psychology SC Psychology; Psychiatry GA DH9JU UT WOS:000373113200004 PM 26411927 ER PT J AU Michalska, KJ Zeffiro, TA Decety, J AF Michalska, Kalina J. Zeffiro, Thomas A. Decety, Jean TI Brain response to viewing others being harmed in children with conduct disorder symptoms SO JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY LA English DT Article DE Conduct disorder; callousness; affective arousal; emotional empathy; insula; anterior cingulate cortex ID CALLOUS-UNEMOTIONAL TRAITS; ANTISOCIAL-BEHAVIOR; NEURAL RESPONSES; PSYCHOPATHIC TENDENCIES; OPPOSITIONAL DEFIANT; PROACTIVE AGGRESSION; AMYGDALA RESPONSE; COMMUNITY SAMPLE; EARLY-ONSET; EMPATHY AB BackgroundDeficient empathic processing is thought to foster conduct disorder (CD). It is important to determine the extent to which neural response associated with perceiving harm to others predicts CD symptoms and callous disregard for others. MethodsA total of 107 9- to 11-year-old children (52 female) were recruited from pediatric and mental health clinics, representing a wide range of CD symptoms. Children were scanned with functional magnetic resonance imaging while viewing brief video clips of persons being harmed intentionally or accidentally. ResultsPerceiving harm evoked increased hemodynamic response in the anterior insula (aINS), anterior cingulate cortex (ACC), amygdala, periaqueductal gray (PAG), caudate, and inferior parietal lobe (IPL) across all participants. Intentionally caused, relative to unintentional harm was associated with greater activity in the aINS, amygdala, and temporal pole. There was an inverse association of number of CD symptoms with right posterior insula in both the Harm>No Harm and the Intentional>Unintentional Harm contrasts. Furthermore, an inverse association between callousness and posterior insula activation was found in the Harm>No Harm contrast, with the opposite pattern for reactive aggression scores. An interaction revealed a stronger association in girls between CD symptoms and the right posterior superior temporal sulcus (pSTS) in the Intentional Harm versus Unintentional Harm contrast. ConclusionsChildren with greater CD and callousness exhibit dampened hemodynamic response to viewing others being harmed in the insula, a region which plays a key role in empathy and emotional awareness. Sex differences in the neural correlates of CD were observed. C1 [Michalska, Kalina J.; Decety, Jean] Univ Chicago, Dept Psychol, 5848 S Univ Ave, Chicago, IL 60637 USA. [Michalska, Kalina J.] NIMH, Bethesda, MD 20892 USA. [Michalska, Kalina J.] Univ Maryland, Dept Human Dev, College Pk, MD 20742 USA. [Zeffiro, Thomas A.] Massachusetts Gen Hosp, Neural Syst Grp, Charlestown, MA USA. [Decety, Jean] Univ Chicago Med, Dept Psychiat & Behav Neurosci, Chicago, IL USA. RP Decety, J (reprint author), Univ Chicago, Child Neurosuite, 5848 S Univ Ave, Chicago, IL 60637 USA. EM decety@uchicago.edu FU NIMH [R01-MH084934] FX This study was supported by NIMH grant R01-MH084934 to J.D. The authors are grateful to Jason M. Cowell for helpful suggestions and to Carrie Swetlik and Talia Reiter for their help with data collection and entry. The authors have declared that they have no competing or potential conflicts of interests. NR 49 TC 6 Z9 6 U1 18 U2 20 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9630 EI 1469-7610 J9 J CHILD PSYCHOL PSYC JI J. Child Psychol. Psychiatry PD APR PY 2016 VL 57 IS 4 BP 510 EP 519 DI 10.1111/jcpp.12474 PG 10 WC Psychology, Developmental; Psychiatry; Psychology SC Psychology; Psychiatry GA DH9JU UT WOS:000373113200009 PM 26472591 ER PT J AU Qian, QF Urman, G Cederroth, T Najarian, R Kirby, JE AF Qian, Qinfang Urman, Grigoriy Cederroth, Terra Najarian, Robert Kirby, James E. TI A Man with Fever and Cough SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Editorial Material ID PULMONARY BLASTOMYCOSIS C1 [Qian, Qinfang] Beth Israel Deaconess Med Ctr, Dept Pathol, 330 Brookline Ave, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA USA. [Qian, Qinfang] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Qian, QF (reprint author), Beth Israel Deaconess Med Ctr, Dept Pathol, 330 Brookline Ave, Boston, MA 02215 USA.; Qian, QF (reprint author), Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. EM qqian@mgh.harvard.edu NR 8 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 0095-1137 EI 1098-660X J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD APR PY 2016 VL 54 IS 4 BP 825 EP + DI 10.1128/JCM.00852-14 PG 2 WC Microbiology SC Microbiology GA DI2OX UT WOS:000373337100001 PM 27016589 ER PT J AU White, PL Wiederhold, NP Loeffler, J Najvar, LK Melchers, W Herrera, M Bretagne, S Wickes, B Kirkpatrick, WR Barnes, RA Donnelly, JP Patterson, TF AF White, P. Lewis Wiederhold, Nathan P. Loeffler, Juergen Najvar, Laura K. Melchers, Willem Herrera, Monica Bretagne, Stephane Wickes, Brian Kirkpatrick, William R. Barnes, Rosemary A. Donnelly, J. Peter Patterson, Thomas F. TI Comparison of Nonculture Blood-Based Tests for Diagnosing Invasive Aspergillosis in an Animal Model SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID HIGH-RISK HEMATOLOGY; RANDOMIZED CONTROLLED-TRIAL; GUINEA-PIG MODEL; REAL-TIME PCR; FUNGAL DISEASE; PULMONARY ASPERGILLOSIS; AMPHOTERICIN-B; FUMIGATUS DNA; GALACTOMANNAN; SERUM AB The European Aspergillus PCR Initiative (EAPCRI) has provided recommendations for the PCR testing of whole blood (WB) and serum/plasma. It is important to test these recommended protocols on nonsimulated "in vivo" specimens before full clinical evaluation. The testing of an animal model of invasive aspergillosis (IA) overcomes the low incidence of disease and provides experimental design and control that is not possible in the clinical setting. Inadequate performance of the recommended protocols at this stage would require reassessment of methods before clinical trials are performed and utility assessed. The manuscript describes the performance of EAPCRI protocols in an animal model of invasive aspergillosis. Blood samples taken from a guinea pig model of IA were used for WB and serum PCR. Galactomannan and beta-D-glucan detection were evaluated, with particular focus on the timing of positivity and on the interpretation of combination testing. The overall sensitivities for WB PCR, serum PCR, galactomannan, and beta-D-glucan were 73%, 65%, 68%, and 46%, respectively. The corresponding specificities were 92%, 79%, 80%, and 100%, respectively. PCR provided the earliest indicator of IA, and increasing galactomannan and beta-D-glucan values were indicators of disease progression. The combination of WB PCR with galactomannan and beta-D-glucan proved optimal (area under the curve [AUC], 0.95), and IA was confidently diagnosed or excluded. The EAPRCI-recommended PCR protocols provide performance comparable to commercial antigen tests, and clinical trials are warranted. By combining multiple tests, IA can be excluded or confirmed, highlighting the need for a combined diagnostic strategy. However, this approach must be balanced against the practicality and cost of using multiple tests. C1 [White, P. Lewis] PHW Microbiol, Cardiff, S Glam, Wales. [Wiederhold, Nathan P.; Najvar, Laura K.; Herrera, Monica; Wickes, Brian; Kirkpatrick, William R.; Patterson, Thomas F.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio Ctr Med Mycol, San Antonio, TX 78229 USA. [Loeffler, Juergen] Univ Wurzburg, D-97070 Wurzburg, Germany. [Melchers, Willem; Donnelly, J. Peter] Radboud Univ Nijmegen, Med Ctr, NL-6525 ED Nijmegen, Netherlands. [Bretagne, Stephane] Hop St Louis, Paris, France. [Barnes, Rosemary A.] Cardiff Univ, UHW, Cardiff CF10 3AX, S Glam, Wales. [Patterson, Thomas F.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. RP White, PL (reprint author), PHW Microbiol, Cardiff, S Glam, Wales. EM lewis.white@wales.nhs.uk OI Bretagne, Stephane/0000-0001-6870-3800; Wiederhold, Nathan/0000-0002-2225-5122; Donnelly, J Peter/0000-0002-8521-335X FU HHS\ NIH\ National Institute of Allergy and Infectious Diseases (NIAID) [N01-AI-30041] FX HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) provided funding to Nathan P. Wiederhold, Laura K. Najvar, Monica L. Herrera, Brian L. Wickes, William R. Kirkpatrick, and Thomas F. Patterson under grant number N01-AI-30041. NR 30 TC 2 Z9 2 U1 1 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 EI 1098-660X J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD APR PY 2016 VL 54 IS 4 BP 960 EP 966 DI 10.1128/JCM.03233-15 PG 7 WC Microbiology SC Microbiology GA DI2OX UT WOS:000373337100015 PM 26791366 ER PT J AU Jelden, KC Iwen, PC Herstein, JJ Biddinger, PD Kraft, CS Saiman, L Smith, PW Hewlett, AL Gibbs, SG Lowe, JJ AF Jelden, Katelyn C. Iwen, Peter C. Herstein, Jocelyn J. Biddinger, Paul D. Kraft, Colleen S. Saiman, Lisa Smith, Philip W. Hewlett, Angela L. Gibbs, Shawn G. Lowe, John J. TI US Ebola Treatment Center Clinical Laboratory Support SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID UNITED-STATES; VIRUS AB Fifty-five hospitals in the United States have been designated Ebola treatment centers (ETCs) by their state and local health authorities. Designated ETCs must have appropriate plans to manage a patient with confirmed Ebola virus disease (EVD) for the full duration of illness and must have these plans assessed through a CDC site visit conducted by an interdisciplinary team of subject matter experts. This study determined the clinical laboratory capabilities of these ETCs. ETCs were electronically surveyed on clinical laboratory characteristics. Survey responses were returned from 47 ETCs (85%). Forty-one (87%) of the ETCs planned to provide some laboratory support (e.g., point-of-care [POC] testing) within the room of the isolated patient. Forty-four (94%) ETCs indicated that their hospital would also provide clinical laboratory support for patient care. Twenty-two (50%) of these ETC clinical laboratories had biosafety level 3 (BSL-3) containment. Of all respondents, 34 (72%) were supported by their jurisdictional public health laboratory (PHL), all of which had available BSL-3 laboratories. Overall, 40 of 44 (91%) ETCs reported BSL-3 laboratory support via their clinical laboratory and/or PHL. This survey provided a snapshot of the laboratory support for designated U.S. ETCs. ETCs have approached high-level isolation critical care with laboratory support in close proximity to the patient room and by distributing laboratory support among laboratory resources. Experts might review safety considerations for these laboratory testing/diagnostic activities that are novel in the context of biocontainment care. C1 [Jelden, Katelyn C.; Herstein, Jocelyn J.; Gibbs, Shawn G.; Lowe, John J.] Univ Nebraska Med Ctr, Dept Environm Agr & Occupat Hlth, Omaha, NE USA. [Iwen, Peter C.] Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Coll Med, Omaha, NE USA. [Iwen, Peter C.] Nebraska Publ Hlth Lab, Omaha, NE USA. [Biddinger, Paul D.] Massachusetts Gen Hosp, Dept Emergency Med, Div Emergency Preparedness, Boston, MA 02114 USA. [Biddinger, Paul D.] Harvard Univ, Sch Med, Dept Emergency Med, Boston, MA USA. [Kraft, Colleen S.] Emory Univ, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. [Kraft, Colleen S.] Emory Univ, Dept Med, Div Infect Dis, Atlanta, GA 30322 USA. [Saiman, Lisa] Columbia Univ, Dept Pediat, Med Ctr, New York, NY 10027 USA. [Saiman, Lisa] New York Presbyterian Hosp, Dept Infect Prevent & Control, New York, NY USA. [Smith, Philip W.; Hewlett, Angela L.] Univ Nebraska Med Ctr, Dept Internal Med, Div Infect Dis, Omaha, NE USA. [Gibbs, Shawn G.] Indiana Univ, Sch Publ Hlth, Dept Environm Hlth, Bloomington, IN USA. RP Lowe, JJ (reprint author), Univ Nebraska Med Ctr, Dept Environm Agr & Occupat Hlth, Omaha, NE USA. EM jjlowe@unmc.edu NR 17 TC 1 Z9 1 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 EI 1098-660X J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD APR PY 2016 VL 54 IS 4 BP 1031 EP 1035 DI 10.1128/JCM.02905-15 PG 5 WC Microbiology SC Microbiology GA DI2OX UT WOS:000373337100025 PM 26842705 ER PT J AU Moldovan, M Calin, A Kumaraswamy, VM Braver, D Simon, MV AF Moldovan, Mihai Calin, Alexandru Kumaraswamy, Vishakhadatta M. Braver, Diana Simon, Mirela V. TI Burst-Suppression Ratio on Electrocorticography Depends on Interelectrode Distance SO JOURNAL OF CLINICAL NEUROPHYSIOLOGY LA English DT Article DE asynchrony; distance; EEG burst-suppression ID BISPECTRAL INDEX; ANESTHESIA; PROPOFOL; EEG; ISOFLURANE; BRAIN; ELECTROENCEPHALOGRAM; PROTECTION; MODEL; COMA AB Introduction: With deepening of anesthesia-induced comatose states, the EEG becomes fragmented by increasing periods of suppression. When measured from conventional EEG recordings, the binary burst-suppression signal (BS) appears similar across the scalp. As such, the BS ratio (BSR), quantifying the fraction of time spent in suppression, is clinically considered a global index of brain function in sedation monitoring. Recent studies indicate that BS may be considerably asynchronous when measured with higher spatial resolution such as on electrocorticography. The authors investigated the magnitude of BSR changes with cortical recording interelectrode distance. Methods: The authors selected fronto-parietal electrocorticography recordings showing propofol-induced BS recorded via 8-electrode strips (1-cm interelectrode distance) during cortical motor mapping in 31 patients. For 1-minute epochs, bipolar recordings were computed between each electrode pair. The median BSR, burst duration (BD), and bursting frequency were derived for each interelectrode distance. Results: At 1-cm interelectrode distance, with increasing BSR, BD decreased exponentially. For a BSR between 50% and 80%, BD reached a plateau of 2.1 seconds while the bursting frequency decreased from 14 to 6 bursts per minute. With increasing interelectrode distance, BD increased at a rate of 0.2 seconds per cm. This correlated with a decrease in BSR with distance that reached the rate of -4.4 percentage per centimeters during deepest anesthesia. Conclusions: With increasing cortical interelectrode recording distance, burst summation leads to an increasing BD associated with a reduction in BSR. Standardization of interelectrode distance is important for cortical BSR measurements. C1 [Moldovan, Mihai; Calin, Alexandru] Carol Davila Univ Med & Pharm, Dept Funct Sci, Div Physiol & Neurosci, Bucharest, Romania. [Moldovan, Mihai] Univ Copenhagen, Dept Neurosci & Pharmacol, Copenhagen, Denmark. [Calin, Alexandru; Kumaraswamy, Vishakhadatta M.; Braver, Diana; Simon, Mirela V.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Intraoperat Neurophysiol Unit,Dept Neurol, Boston, MA USA. [Calin, Alexandru] Univ Oxford, Dept Pharmacol, S Parks Rd, Oxford OX1 3QT, England. [Kumaraswamy, Vishakhadatta M.] Univ Hosp Case Med Ctr, Dept Neurol, Cleveland, OH USA. RP Simon, MV (reprint author), Massachusetts Gen Hosp, WACC 739G,55 Fruit St, Boston, MA 02114 USA. EM mvsimon@mgh.harvard.edu RI Moldovan, Mihai/C-4215-2011 OI Moldovan, Mihai/0000-0003-2512-3499 FU Romanian National Authority for Scientific Research, CNCS-UEFISCDI [PN-II-ID-PCE-2011-3-0847, PN-II-PT-PCCA-2011-3.2-1290] FX This study was supported by grants of the Romanian National Authority for Scientific Research, CNCS-UEFISCDI, project number PN-II-ID-PCE-2011-3-0847, and PN-II-PT-PCCA-2011-3.2-1290 to M.M. NR 31 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 0736-0258 EI 1537-1603 J9 J CLIN NEUROPHYSIOL JI J. Clin. Neurophysiol. PD APR PY 2016 VL 33 IS 2 BP 127 EP 132 DI 10.1097/WNP.0000000000000248 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DI0YP UT WOS:000373223500008 PM 26690549 ER PT J AU Lee, JW LaRoche, S Choi, H Ruiz, AAR Fertig, E Politsky, JM Herman, ST Loddenkemper, T Sansevere, AJ Korb, PJ Abend, NS Goldstein, JL Sinha, SR Dombrowski, KE Ritzl, EK Westover, MB Gavvala, JR Gerard, EE Schmitt, SE Szaflarski, JP Ding, K Haas, KF Buchsbaum, R Hirsch, LJ Wusthoff, CJ Hopp, JL Hahn, CD AF Lee, Jong Woo LaRoche, Suzette Choi, Hyunmi Ruiz, Andres A. Rodriguez Fertig, Evan Politsky, Jeffrey M. Herman, Susan T. Loddenkemper, Tobias Sansevere, Arnold J. Korb, Pearce J. Abend, Nicholas S. Goldstein, Joshua L. Sinha, Saurabh R. Dombrowski, Keith E. Ritzl, Eva K. Westover, Michael B. Gavvala, Jay R. Gerard, Elizabeth E. Schmitt, Sarah E. Szaflarski, Jerzy P. Ding, Kan Haas, Kevin F. Buchsbaum, Richard Hirsch, Lawrence J. Wusthoff, Courtney J. Hopp, Jennifer L. Hahn, Cecil D. CA Critical Care EEG Monitoring Res C TI Development and Feasibility Testing of a Critical Care EEG Monitoring Database for Standardized Clinical Reporting and Multicenter Collaborative Research SO JOURNAL OF CLINICAL NEUROPHYSIOLOGY LA English DT Article DE Clinical reporting tool; Research database; Continuous EEG monitoring ID NONCONVULSIVE STATUS EPILEPTICUS; REFRACTORY STATUS EPILEPTICUS; CONSENSUS STATEMENT; ILL ADULTS; TERMINOLOGY; SEIZURES; DISCHARGES; PATTERNS; EPILEPSY; CHILDREN AB Purpose: The rapid expansion of the use of continuous critical care electroencephalogram (cEEG) monitoring and resulting multicenter research studies through the Critical Care EEG Monitoring Research Consortium has created the need for a collaborative data sharing mechanism and repository. The authors describe the development of a research database incorporating the American Clinical Neurophysiology Society standardized terminology for critical care EEG monitoring. The database includes flexible report generation tools that allow for daily clinical use. Methods: Key clinical and research variables were incorporated into a Microsoft Access database. To assess its utility for multicenter research data collection, the authors performed a 21-center feasibility study in which each center entered data from 12 consecutive intensive care unit monitoring patients. To assess its utility as a clinical report generating tool, three large volume centers used it to generate daily clinical critical care EEG reports. Results: A total of 280 subjects were enrolled in the multicenter feasibility study. The duration of recording (median, 25.5 hours) varied significantly between the centers. The incidence of seizure (17.6%), periodic/rhythmic discharges (35.7%), and interictal epileptiform discharges (11.8%) was similar to previous studies. The database was used as a clinical reporting tool by 3 centers that entered a total of 3,144 unique patients covering 6,665 recording days. Conclusions: The Critical Care EEG Monitoring Research Consortium database has been successfully developed and implemented with a dual role as a collaborative research platform and a clinical reporting tool. It is now available for public download to be used as a clinical data repository and report generating tool. C1 [Lee, Jong Woo] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [LaRoche, Suzette; Ruiz, Andres A. Rodriguez] Emory Univ Hosp, Dept Neurol, 1364 Clifton Rd NE, Atlanta, GA 30322 USA. [Choi, Hyunmi] Columbia Univ, Dept Neurol, New York, NY USA. [Fertig, Evan; Politsky, Jeffrey M.] Atlantic Hlth Systems Northeast Reg Epilepsy Grp, Hackensack, NJ USA. [Herman, Susan T.] Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA USA. [Loddenkemper, Tobias; Sansevere, Arnold J.] Childrens Hosp, 300 Longwood Ave, Boston, MA 02115 USA. [Korb, Pearce J.] Univ Colorado, Sch Med, Dept Neurol, Aurora, CO USA. [Abend, Nicholas S.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Goldstein, Joshua L.] Northwestern Univ, Dept Pediat, Sect Pediat Neurocrit Care, Chicago, IL 60611 USA. [Sinha, Saurabh R.; Dombrowski, Keith E.] Duke Univ, Med Ctr, Dept Neurol, Durham, NC USA. [Ritzl, Eva K.] Johns Hopkins Univ, Baltimore, MD USA. [Westover, Michael B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Gavvala, Jay R.; Gerard, Elizabeth E.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Schmitt, Sarah E.] Hosp Univ Penn, 3400 Spruce St, Philadelphia, PA 19104 USA. [Szaflarski, Jerzy P.] Univ Alabama Birmingham, Birmingham, AL USA. [Ding, Kan] UT Southwestern Med Ctr, Dallas, TX USA. [Haas, Kevin F.] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Buchsbaum, Richard] Columbia Univ, Dept Biostat, New York, NY USA. [Hirsch, Lawrence J.] Yale Med Ctr, New Haven, CT USA. [Wusthoff, Courtney J.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Hopp, Jennifer L.] Univ Maryland, Sch Med, Dept Neurol, Baltimore, MD 21201 USA. [Hahn, Cecil D.] Univ Toronto, Hosp Sick Children, Div Neurol, Toronto, ON M5G 1X8, Canada. RP Hahn, CD (reprint author), Hosp Sick Children, Div Neurol, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. EM cecil.hahn@sickkids.ca RI Hahn, Cecil/J-3372-2016; OI Hahn, Cecil/0000-0002-0887-8761; Gavvala, Jay/0000-0002-9392-6608 FU UCB-Pharma; Upsher-Smith; Lundbeck; Eisai; Sunovion; Neuropace; GSK; Sage Therapeutics; UCB; Acorda Therapeutics Inc; Marinus Pharmaceuticals; NINDS; Canadian Institutes of Health Research; Physicians' Services Incorporated Foundation; Hospital for Sick Children Foundation; UCB Pharma; Lundbeck, Inc; National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS); Fidelity Biosciences Research Initiative; Epilepsy Therapy Development Project; T. Loddenkemper American Epilepsy Society; Epilepsy Foundation of America; Epilepsy Therapy Project; PCORI; Pediatric Epilepsy Research Foundation; CURE; Danny-Did Foundation; HHV-6 Foundation; Biogen; Cyberonics Inc; NIH; Shor Foundation for Epilepsy Research; AES; EFA; FDA; State of AL General Funds; DoD; Epilepsy Study Consortium (HEP); UAB; American Brain Foundation; NIH-NINDS [1K23NS090900]; Rappaport Foundation FX L. J. Hirsch: Research support to Yale for investigator initiated studies from UCB-Pharma, Upsher-Smith, Lundbeck, Eisai and Sunovion, consultation fees for advising from Lundbeck, Upsher-Smith, Neuropace, and GSK, honoraria for speaking from Neuropace (last 12/2014), royalties for authoring chapters for UpToDate-Neurology, chapters for Medlink-Neurology, and from Wiley for coauthoring the book "Atlas of EEG in Critical Care," by Hirsch and Brenner, 2010; Dr. Hirsch spends about 25% of his clinically billable time implementing and interpreting critical care EEG studies.; N. S. Abend: NINDS (NIH NS076550); H. Choi: UCB-Pharma, Lundbeck, Sunovion, and Eisai (research support); K. E. Dombrowski: Sage Therapeutics (salary support); E. Fertig: UCB (research funding), Acorda Therapeutics Inc (research funding), and Marinus Pharmaceuticals (research funding); Gerard: NINDS (research funding), SAGE pharmaceuticals (site-PI), and UCB/Duke (research consultant work); C. D. Hahn: Canadian Institutes of Health Research, the Physicians' Services Incorporated Foundation, and The Hospital for Sick Children Foundation (research support); S. Herman: Biotie, Inc (consultant), UCB Pharma, Lundbeck, Inc, National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS), Fidelity Biosciences Research Initiative, and Epilepsy Therapy Development Project (research support); L. J. Hirsch: Research support to Yale for investigator-initiated studies from UCB-Pharma, Upsher-Smith, Lundbeck, Eisai and Sunovion, consultation fees for advising from Lundbeck, Upsher-Smith, Neuropace, and GSK, honoraria for speaking from Natus (last 1/2014) and Neuropace (last 12/2014), royalties for authoring chapters for UpToDate-Neurology, chapters for Medlink-Neurology, and from Wiley for coauthoring the book "Atlas of EEG in Critical Care," by Hirsch and Brenner, 2010, spends about 25% of his clinically billable time implementing and interpreting critical care EEG studies; J. L. Hopp: NETT study member, UpToDate (royalties); S. LaRoche: Demos Publishing (royalties); J. W. Lee: NINDS (research funding), Advance Medical and SleepMed/DigiTrace (consultant/contract work), UCB (research funding), and Sunovion (research funding); T. Loddenkemper: T. Loddenkemper American Epilepsy Society, Epilepsy Foundation of America, Epilepsy Therapy Project, PCORI, Pediatric Epilepsy Research Foundation, CURE, Danny-Did Foundation, HHV-6 Foundation, Lundbeck, Eisai, and Upsher-Smith (research support); S.R. Sinha: UCB (research funding), Acorda Therapeutics Inc (research funding), Biogen (research funding), Sage Therapeutics (research funding), and Cyberonics Inc (research funding, speakers bureau); J. P. Szaflarski: Funding: NIH, Shor Foundation for Epilepsy Research, AES, EFA, FDA, State of AL General Funds, DoD, Epilepsy Study Consortium (HEP), UAB; Editorial Boards: Associate Editor, Journal of Epileptology; Associate Editor: Restorative Neurology and Neuroscience; Editorial Board Member: Folia Medica Copernicana, Journal of Medical Science; Epilepsy and Behavior; Consultant: Sage Pharmaceuticals; Biomedical Systems, Inc, Medico-legal expert; and M. B. Westover: American Brain Foundation, NIH-NINDS (1K23NS090900), and the Rappaport Foundation (research support). NR 23 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 0736-0258 EI 1537-1603 J9 J CLIN NEUROPHYSIOL JI J. Clin. Neurophysiol. PD APR PY 2016 VL 33 IS 2 BP 133 EP 140 DI 10.1097/WNP.0000000000000230 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DI0YP UT WOS:000373223500009 PM 26943901 ER PT J AU Bankoff, SM Marks, AK Swenson, LP Pantalone, DW AF Bankoff, Sarah M. Marks, Amy K. Swenson, Lance P. Pantalone, David W. TI Examining Associations of Sexual Attraction and Attitudes on Women's Disordered Eating Behavior SO JOURNAL OF CLINICAL PSYCHOLOGY LA English DT Article DE disordered eating; sexual attractions; women; implicit attitudes; heterosexism ID INTERNALIZED HETEROSEXISM; ORIENTATION; SYMPTOMS; PATTERNS; WEIGHT; SCALE; RISK; QUESTIONNAIRE; PREVALENCE; VALIDATION AB ObjectiveWe aimed to expand the scant research on disordered eating in women identifying same-sex sexual attractions. MethodWe used multiple linear regressions to explore potential mechanisms driving disordered eatingboth explicit and implicit weight bias and heterosexismin a cross-sectional, online-recruited community sample of women (N = 437). Participants endorsed a range of sexual attractions from exclusively opposite-sex (21.1%) to exclusively same-sex (19.5%) attraction. ResultsFindings revealed no associations between sexual attraction and disordered eating. Awareness of sociocultural norms valuing thinness accounted for disordered eating for all women, regardless of sexual attraction, and was influenced by attitudes regarding weight. Among women endorsing same-sex attractions, self-reported internalized heterosexism influenced disordered eating. DiscussionFindings contradict long-held beliefs that same-sex attracted women are protected from disordered eating. They emphasize a universal risk, for all women, of sociocultural norms valuing thinness, as well as the risk of internalized heterosexism among same-sex attracted women. C1 [Bankoff, Sarah M.] VA Boston Healthcare Syst, Boston, MA 02130 USA. [Marks, Amy K.; Swenson, Lance P.] Suffolk Univ, Boston, MA USA. [Pantalone, David W.] Univ Massachusetts Boston, Boston, MA USA. [Pantalone, David W.] Fenway Hlth, Fenway Inst, Boston, MA USA. RP Bankoff, SM (reprint author), VA Boston Healthcare Syst, Primary Care Serv, 11PC,150 South Huntington Ave, Boston, MA 02130 USA. EM sarah.bankoff@va.gov NR 50 TC 0 Z9 0 U1 3 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9762 EI 1097-4679 J9 J CLIN PSYCHOL JI J. Clin. Psychol. PD APR PY 2016 VL 72 IS 4 BP 350 EP 364 DI 10.1002/jclp.22244 PG 15 WC Psychology, Clinical SC Psychology GA DH7KX UT WOS:000372973800004 PM 26613200 ER PT J AU Wahbeh, H Goodrich, E Goy, E Oken, BS AF Wahbeh, Helane Goodrich, Elena Goy, Elizabeth Oken, Barry S. TI Mechanistic Pathways of Mindfulness Meditation in Combat Veterans With Posttraumatic Stress Disorder SO JOURNAL OF CLINICAL PSYCHOLOGY LA English DT Article DE meditation; mindfulness; veteran; combat; posttraumatic stress disorder ID AUTONOMIC NERVOUS-SYSTEM; HEART-RATE-VARIABILITY; PSYCHOMETRIC PROPERTIES; CLINICAL-TRIAL; WAR VETERANS; METAANALYSIS; PTSD; SYMPTOMS; EEG; QUESTIONNAIRE AB ObjectiveThis study's objective was to evaluate the effect of two common components of meditation (mindfulness and slow breathing) on potential mechanistic pathways. MethodsA total of 102 combat veterans with posttraumatic stress disorder (PTSD) were randomized to (a) the body scan mindfulness meditation (MM), (b) slow breathing (SB) with a biofeedback device, (c) mindful awareness of the breath with an intention to slow the breath (MM+SB), or (d) sitting quietly (SQ). Participants had 6 weekly one-on-one sessions with 20 minutes of daily home practice. The mechanistic pathways and measures were as follows: (a) autonomic nervous system (hyperarousal symptoms, heart rate [HR], and heart rate variability [HRV]); (b) frontal cortex activity (attentional network task [ANT] conflict effect and event-related negativity and intrusive thoughts); and (c) hypothalamic-pituitary-adrenal axis (awakening cortisol). PTSD measures were also evaluated. ResultsMeditation participants had significant but modest within-group improvement in PTSD and related symptoms, although there were no effects between groups. Perceived impression of PTSD symptom improvement was greater in the meditation arms compared with controls. Resting respiration decreased in the meditation arms compared with SQ. For the mechanistic pathways, (a) subjective hyperarousal symptoms improved within-group (but not between groups) for MM, MM+SB, and SQ, while HR and HRV did not; (b) intrusive thoughts decreased in MM compared with MM+SB and SB, while the ANT measures did not change; and (c) MM had lower awakening cortisol within-group (but not between groups). ConclusionTreatment effects were mostly specific to self-report rather than physiological measures. Continued research is needed to further evaluate mindfulness meditation's mechanism in people with PTSD. C1 [Wahbeh, Helane; Goodrich, Elena; Oken, Barry S.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Wahbeh, Helane] Natl Coll Nat Med, Portland, OR USA. [Goy, Elizabeth] Portland VA Med Ctr, Portland, OR USA. RP Wahbeh, H (reprint author), 3181 SW Sam Jackson Pk Rd CR120, Portland, OR 97239 USA. EM wahbehh@ohsu.edu FU National Center for Advancing Translational Sciences of the National Institutes of Health [UL1TR000128]; National Center for Complementary and Alternative Medicine of the National Institutes of Health [T32AT002688, K01AT004951, K24AT005121] FX Research reported in this publication was supported by National Center for Advancing Translational Sciences of the National Institutes of Health under award number UL1TR000128 and the National Center for Complementary and Alternative Medicine of the National Institutes of Health [grant numbers T32AT002688, K01AT004951, K24AT005121]. NR 81 TC 0 Z9 0 U1 13 U2 22 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9762 EI 1097-4679 J9 J CLIN PSYCHOL JI J. Clin. Psychol. PD APR PY 2016 VL 72 IS 4 BP 365 EP 383 DI 10.1002/jclp.22255 PG 19 WC Psychology, Clinical SC Psychology GA DH7KX UT WOS:000372973800005 PM 26797725 ER PT J AU Nasser, AF Henderson, DC Fava, M Fudala, PJ Twumasi-Ankrah, P Kouassi, A Heidbreder, C AF Nasser, Azmi F. Henderson, David C. Fava, Maurizio Fudala, Paul J. Twumasi-Ankrah, Philip Kouassi, Alex Heidbreder, Christian TI Efficacy, Safety, and Tolerability of RBP-7000 Once-Monthly Risperidone for the Treatment of Acute Schizophrenia An 8-Week, Randomized, Double-Blind, Placebo-Controlled, Multicenter Phase 3 Study SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Article DE RBP-7000; schizophrenia; ATRIGEL; long-acting risperidone ID ACTING INJECTABLE RISPERIDONE; POPULATION PHARMACOKINETICS; FORMULATION; DISORDERS; RELAPSE; TRIAL; OCCUPANCY; PROLACTIN; INJECTION; MORTALITY AB RBP-7000 is a sustained-release formulation of risperidone for the treatment of schizophrenia, designed to be administered by once-monthly subcutaneous injection using the ATRIGEL delivery system. This study assessed the efficacy, safety, and tolerability of RBP-7000 compared with placebo in subjects with acute exacerbation of schizophrenia. Inpatients were randomly assigned to 8 weeks of double-blind treatment with subcutaneous 90 or 120 mg of RBP-7000 or placebo. Efficacy was evaluated using a mixed-model repeated-measures analysis of the change from baseline (the last nonmissing value before the first dose of RBP-7000 or placebo on day 1) to end of the study in Positive and Negative Syndrome Scale (PANSS) total score (primary efficacy measure) and Clinical Global Impression-Severity score (secondary efficacy measure). The least-squares means from the repeated-measures analysis for the change from baseline in the PANSS total scores for placebo was -9.219 (SE, 1.2162). RBP-7000 produced statistically and clinically significant differences in mean reductions from baseline in PANSS total scores (90-mg RBP-7000 compared with placebo, -6.148 [-9.982 to -2.314], P = 0.0004; 120-mg RBP-7000 compared with placebo, -7.237 [-11.045 to -3.429], P < 0.0001) and significantly improved Clinical Global Impression-Severity scores (90-mg RBP-7000 compared with placebo, -0.350 [-0.557 to -0.143], P = 0.0002; 120-mg RBP-7000 compared with placebo, -0.396 [-0.602 to -0.190], P < 0.0001). Both RBP-7000 dosages were generally well tolerated. The most frequently reported treatment-emergent adverse events in RBP-7000 groups compared with placebo were somnolence, weight gain, and akathisia. The overall incidence of extrapyramidal syndrome-related effects was low and similar across groups. RBP-7000 may provide a new, long-acting alternative treatment for use in adults with acute schizophrenia. C1 [Nasser, Azmi F.; Fudala, Paul J.; Twumasi-Ankrah, Philip; Kouassi, Alex; Heidbreder, Christian] Indivior Inc, Global Res & Dev, Richmond, VA 23235 USA. [Henderson, David C.] Massachusetts Gen Hosp, Schizophrenia Clin & Res Program, Chester M Pierce MD Div Global Psychiat, Boston, MA 02114 USA. [Henderson, David C.] Harvard Univ, Sch Med, Dept Psychiat, Harvard Sch Publ Hlth, Boston, MA 02115 USA. [Fava, Maurizio] Massachusetts Gen Hosp, Dept Psychiat, Div Clin Res, Clin Trials Network & Inst, Boston, MA 02114 USA. [Fava, Maurizio] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. RP Heidbreder, C (reprint author), Indivior Inc, 10710 Midlothian Turnpike,Suite 430, Richmond, VA 23235 USA. EM christian.heidbreder@indivior.com FU Indivior, Inc. FX This study was sponsored and supported by Indivior, Inc. At the time, this manuscript was submitted for publication, A.F. Nasser, P.J. Fudala, P. Twumasi-Ankrah, A. Kouassi, and C. Heidbreder were full-time employees of Indivior, Inc. D.C. Henderson and M. Fava were full-time employees of the Massachusetts General Hospital, Harvard Medical School, and were paid consultants for Indivior, Inc. NR 43 TC 1 Z9 1 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0271-0749 EI 1533-712X J9 J CLIN PSYCHOPHARM JI J. Clin. Psychopharmacol. PD APR PY 2016 VL 36 IS 2 BP 130 EP 140 DI 10.1097/JCP.0000000000000479 PG 11 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA DG5FG UT WOS:000372100800006 PM 26862829 ER PT J AU Gurrera, RJ Parlee, AC Perry, NL AF Gurrera, Ronald J. Parlee, Anne C. Perry, Nicole L. TI Aspiration Pneumonia An Underappreciated Risk of Clozapine Treatment SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Letter ID ANTIPSYCHOTIC-DRUG USE; SALIVARY FLOW-RATE; ESOPHAGEAL DYSFUNCTION; SCHIZOPHRENIA; SIALORRHEA; SMOKING; REASONS C1 [Gurrera, Ronald J.; Perry, Nicole L.] VA Boston Healthcare Syst, Boston, MA USA. [Gurrera, Ronald J.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Parlee, Anne C.] Boston Med Ctr, Boston, MA USA. RP Gurrera, RJ (reprint author), VA Boston Healthcare Syst, Boston, MA USA.; Gurrera, RJ (reprint author), Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. EM ronald.gurrera@va.gov NR 25 TC 1 Z9 1 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0271-0749 EI 1533-712X J9 J CLIN PSYCHOPHARM JI J. Clin. Psychopharmacol. PD APR PY 2016 VL 36 IS 2 BP 174 EP 176 DI 10.1097/JCP.0000000000000458 PG 3 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA DG5FG UT WOS:000372100800014 PM 26848787 ER PT J AU Turner, AP Hartoonian, N Sloan, AP Benich, M Kivlahan, DR Hughes, C Hughes, AJ Haselkorn, JK AF Turner, Aaron P. Hartoonian, Narineh Sloan, Alicia P. Benich, Marisa Kivlahan, Daniel R. Hughes, Christina Hughes, Abbey J. Haselkorn, Jodie K. TI Improving Fatigue and Depression in Individuals With Multiple Sclerosis Using Telephone-Administered Physical Activity Counseling SO JOURNAL OF CONSULTING AND CLINICAL PSYCHOLOGY LA English DT Article DE fatigue; depression; physical activity; motivational interviewing; self-management ID QUALITY-OF-LIFE; RANDOMIZED CONTROLLED-TRIAL; DISABILITY STATUS SCALE; SELF-REPORT; MAJOR DEPRESSION; CLINICAL-TRIALS; MENTAL-HEALTH; PRIMARY-CARE; MS PATIENTS; EXERCISE AB Objective: To evaluate the impact of a physical activity intervention consisting of telephone counseling with home-based monitoring to improve fatigue and depression in individuals with multiple sclerosis (MS). Method: Single-blind randomized controlled trial. Sixty-four individuals with MS received either telephone counseling (N = 31), or self-directed physical activity education (N = 33). The education condition (EC) consisted of advice to increase physical activity and a DVD with examples of in-home exercises for multiple physical ability levels. The telephone counseling condition (TC) included EC as well as mailed graphic feedback, 6 telephone counseling sessions using principles of motivational interviewing, and telehealth home monitoring to track progress on physical activity goals. Booster sessions were provided when participants indicated they did not meet their goals. Assessment was conducted at baseline, 3-month, and 6-month follow-up. Results: TC participants reported significantly reduced fatigue (d = -.70), reduced depression (d = -.72) and increased physical activity (d =.92) relative to EC participants. Of individuals receiving TC, 33.3% experienced clinically significant improvement in fatigue (vs. 18.2% in EC) and 53.3% experienced clinically significant improvement in depression (vs. 9.1% in EC). Improvements in physical activity mediated improvements in fatigue with a similar trend for depression. TC was highly feasible (participants completed 99.5% of schedule telephone sessions) and well tolerated (100% rated it highly successful). Conclusion: Telephone-based counseling with home monitoring is a promising modality to improve physical activity and treat fatigue and depression. C1 [Turner, Aaron P.; Benich, Marisa; Hughes, Abbey J.] VA Puget Sound Hlth Care Syst, VA Multiple Sclerosis Ctr Excellence, Seattle, WA USA. [Turner, Aaron P.; Hughes, Abbey J.] Univ Washington, Dept Rehabil Med, Seattle, WA 98195 USA. [Hartoonian, Narineh; Sloan, Alicia P.; Haselkorn, Jodie K.] VA Multiple Sclerosis Ctr Excellence West, Seattle, WA USA. [Kivlahan, Daniel R.] Vet Hlth Adm, Mental Hlth Serv, Washington, DC USA. [Kivlahan, Daniel R.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Haselkorn, Jodie K.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. RP Turner, AP (reprint author), VA Puget Sound Hlth Care Syst, Rehabil Care Serv, S-117 RCS,1660 South Columbian Way, Seattle, WA 98108 USA. EM Aaron.Turner@med.va.gov OI Turner, Aaron/0000-0001-6897-8003 FU Department of Veterans Affairs Rehabilitation Research and Development Service Career Development Award [B4927W]; VA Multiple Sclerosis Center of Excellence West; VA Center of Excellence for Limb Loss Prevention and Prosthetic Engineering; VA Center of Excellence in Substance Abuse Treatment and Education FX This research was supported by Department of Veterans Affairs Rehabilitation Research and Development Service Career Development Award B4927W to Aaron P. Turner. Additional support was provided by the VA Multiple Sclerosis Center of Excellence West, the VA Center of Excellence for Limb Loss Prevention and Prosthetic Engineering, and the VA Center of Excellence in Substance Abuse Treatment and Education. Trial Registration clinicaltrials.gov Identifier: NCT01198977. Special thanks to Charles Bombardier who provided mentorship and consultation on this project. NR 75 TC 1 Z9 1 U1 10 U2 17 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0022-006X EI 1939-2117 J9 J CONSULT CLIN PSYCH JI J. Consult. Clin. Psychol. PD APR PY 2016 VL 84 IS 4 BP 297 EP 309 DI 10.1037/ccp0000086 PG 13 WC Psychology, Clinical SC Psychology GA DH8PP UT WOS:000373057100002 PM 26913621 ER PT J AU Jarrett, RB Minhajuddin, A Vittengl, JR Clark, LA Thase, ME AF Jarrett, Robin B. Minhajuddin, Abu Vittengl, Jeffrey R. Clark, Lee Anna Thase, Michael E. TI Quantifying and Qualifying the Preventive Effects of Acute-Phase Cognitive Therapy: Pathways to Personalizing Care SO JOURNAL OF CONSULTING AND CLINICAL PSYCHOLOGY LA English DT Article DE depression; cognitive therapy; relapse; recurrence; predictors of outcomes ID MAJOR DEPRESSIVE DISORDER; ATTRIBUTIONAL STYLE QUESTIONNAIRE; RECURRENT DEPRESSION; CONTINUATION PHASE; FOLLOW-UP; SOCIAL-ADJUSTMENT; RANDOMIZED-TRIAL; PILL PLACEBO; SELF-CONTROL; RELAPSE AB Objective: To determine the extent to which prospectively identified responders to cognitive therapy (CT) for recurrent major depressive disorder (MDD) hypothesized to be lower risk show significantly less relapse or recurrence than treated higher risk counterparts across 32 months. Method: Outpatients (N = 523), aged 18-70, with recurrent MDD received 12-14 weeks of CT. The last 7 consecutive scores from the Hamilton Rating Scale for Depression (HRSD-17) were used to stratify or define responders (n = 290) into lower (7 HRSD-17 scores of less than or equal to 6; n = 49; 17%) and higher risk (n = 241; 83%). The lower risk patients entered the 32-month follow-up. Higher risk patients were randomized to 8 months of continuation-phase CT or clinical management plus double-blind fluoxetine or pill placebo, with a 24-month follow-up. Results: Lower risk patients were significantly less likely to relapse over the first 8 months compared to higher risk patients (Kaplan-Meier [KM] estimates; i.e., 4.9% = lower risk; 22.1% = higher risk; log-rank chi(2) = 6.83, p = .009). This increased risk was attenuated, but not completely neutralized, by active continuation-phase therapy. Over the subsequent 24 months, the lower and higher risk groups did not differ in relapse or recurrence risk. Conclusions: Rapid and sustained acute-phase CT remission identifies responders who do not require continuation-phase treatment to prevent relapse (i.e., return of an index episode). To prevent recurrence (i.e., new episodes), however, strategic allocation and more frequent "dosing" of CT and/or targeted maintenance-phase treatments may be required. Longitudinal follow-up is recommended. C1 [Jarrett, Robin B.] Univ Texas SW Med Ctr Dallas, Dept Psychiat, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. [Minhajuddin, Abu] Univ Texas SW Med Ctr Dallas, Dept Clin Sci, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. [Vittengl, Jeffrey R.] Truman State Univ, Dept Psychol, Kirksville, MO USA. [Clark, Lee Anna] Univ Notre Dame, Dept Psychol, Notre Dame, IN 46556 USA. [Thase, Michael E.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Thase, Michael E.] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. RP Jarrett, RB (reprint author), Univ Texas SW Med Ctr Dallas, Dept Psychiat, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM robin.jarrett@utsouthwestern.edu FU Alkermes; Assurerx; AstraZeneca; Avenir; Eli Lilly and Company; Forest Laboratories; Janssen/Johnson Johnson; Otsuka; Roche; Agency for Healthcare Research and Quality; National Institute of Mental Health (NIMH); NIMH [K24 MH001571, R01 MH058397, R01 MH069619, R01 MH058356, R01 MH069618] FX During the past 3 years, Michael E. Thase has consulted with and/or served on advisory boards for Advir, Alkermes, Allergan, AstraZeneca, Avenir, Bristol-Myers Squibb Company, Cerecor, Cerenex, Eli Lilly and Company, Forest Laboratories, Janssen Pharmaceutica, Johnson & Johnson, Lundbeck, MedAvante, Merck, Moksha8, Naurex, Neuronetics, Novartis, Otsuka, Nestle (formerly Pamlab), Pfizer Pharmaceuticals, Roche, Shire, Sunovion, Takeda, and Teva. During this time, he has received grant support from Alkermes, Assurerx, AstraZeneca, Avenir, Eli Lilly and Company, Forest Laboratories, Janssen/Johnson & Johnson, Otsuka, and Roche, as well as funding from the Agency for Healthcare Research and Quality and the National Institute of Mental Health (NIMH). He has equity holdings for MedAvante, Inc., and has received royalties from American Psychiatric Publishing, Inc. (APPI), Guilford Publications, Herald House, and W. W. Norton & Company, Inc. Two books currently promoted by the APPI specifically pertain to cognitive therapy. Michael E. Thase also discloses that his spouse is an employee of Peloton Advantage, which does business with several pharmaceutical companies that market medications used to treat depression. Robin B. Jarrett's medical center collects the payments from the cognitive therapy she provides to patients. Jarrett is a paid consultant to the NIMH and the National Institutes of Health (NIH). Robin B. Jarrett and Jeffrey R. Vittengl are paid reviewers for UpToDate.; This report was supported by Grants K24 MH001571, R01 MH058397, and R01 MH069619 (to Robin B. Jarrett) and R01 MH058356 and R01 MH069618 (to Michael E. Thase) from the NIMH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIMH or the NIH. We also wish to acknowledge the unrestricted support of Eli Lilly and Company, which provided fluoxetine and matched pill placebo for the first 6 years of the study. Thereafter, study materials were purchased and prepared to appear identical for both sites by the pharmacy at The University of Texas Southwestern Medical Center. We are grateful to our patients, research teams, and colleagues at The University of Texas Southwestern Medical Center, the University of Pittsburgh, and the University of Pennsylvania who made this trial possible. We appreciate the assistance of Lauren Singer, M. S. and Joanne Sanders, M. S. for their research support. NR 47 TC 1 Z9 1 U1 8 U2 11 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0022-006X EI 1939-2117 J9 J CONSULT CLIN PSYCH JI J. Consult. Clin. Psychol. PD APR PY 2016 VL 84 IS 4 BP 365 EP 376 DI 10.1037/ccp0000069 PG 12 WC Psychology, Clinical SC Psychology GA DH8PP UT WOS:000373057100008 PM 26654211 ER PT J AU Lopez, L Tan-McGrory, A Horner, G Betancourt, JR AF Lopez, Lenny Tan-McGrory, Aswita Horner, Gabrielle Betancourt, Joseph R. TI Eliminating disparities among Latinos with type 2 diabetes: Effective eHealth strategies SO JOURNAL OF DIABETES AND ITS COMPLICATIONS LA English DT Review DE Disparities; Diabetes; eHealth; Interventions; Latino ID RANDOMIZED CONTROLLED-TRIALS; SELF-MANAGEMENT EDUCATION; BEHAVIOR-CHANGE INTERVENTIONS; ETHNIC-MINORITY GROUPS; PHYSICAL-ACTIVITY; HEALTH-EDUCATION; DIVERSE BACKGROUNDS; MEXICAN-AMERICANS; AFRICAN-AMERICAN; GLYCEMIC CONTROL AB Latinos are at increased risk for obesity and type 2 diabetes (T2D). Well-designed information technology (IT) interventions have been shown to be generally efficacious in improving diabetes self-management. However, there are very few published IT intervention studies focused on Latinos. With the documented close of the digital divide, Latinos stand to benefit from such advances. There are limited studies on how best to address the unique socio-cultural-linguistic characteristics that would optimize adoption, use and benefit among Latinos. Successful e-health programs involve frequent communication, bidirectionality including feedback, and multimodal delivery of the intervention. The use of community health workers (CHWs) has been shown consistently to improve T2D outcomes in Latinos. Incorporating CHWs into eHealth interventions is likely to address barriers with technology literacy and improve patient activation, satisfaction and adherence. Additionally, tailored interventions are more successful in improving patient activation. It is important to note that tailoring is more than linguistic translation; tailoring interventions to the Latino population will need to address educational, language, literacy and acculturation levels, along with unique illness beliefs and attitudes about T2D found among Latinos. Interventions will need to go beyond the lone participant and include shared decision making models that incorporate family members and friends. (C) 2016 Elsevier Inc. All rights reserved. C1 [Lopez, Lenny; Tan-McGrory, Aswita; Betancourt, Joseph R.] Massachusetts Gen Hosp, Dispar Solut Ctr, Boston, MA 02114 USA. [Lopez, Lenny; Tan-McGrory, Aswita; Horner, Gabrielle; Betancourt, Joseph R.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, 50 Staniford St,Ninth Floor, Boston, MA 02114 USA. [Lopez, Lenny] Massachusetts Gen Hosp, Dept Gen Internal Med, Boston, MA 02114 USA. [Lopez, Lenny] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. RP Lopez, L (reprint author), Massachusetts Gen Hosp, Mongan Inst Hlth Policy, 50 Staniford St,Ninth Floor, Boston, MA 02114 USA.; Lopez, L (reprint author), Massachusetts Gen Hosp, Dept Gen Internal Med, Boston, MA 02114 USA. EM lopezlenny77@gmail.com FU Robert Wood Johnson Foundation Harold Amos Medical Faculty Development Program; [NIDDK1K23DK098280-01] FX Dr. Lenny Lopez acknowledges the support of the Robert Wood Johnson Foundation Harold Amos Medical Faculty Development Program and NIDDK1K23DK098280-01. This funding body was not involved in the design, data collection, analysis, interpretation or the preparation of the manuscript. NR 70 TC 0 Z9 0 U1 7 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1056-8727 EI 1873-460X J9 J DIABETES COMPLICAT JI J. Diabetes Complications PD APR PY 2016 VL 30 IS 3 BP 554 EP 560 DI 10.1016/j.jdiacomp.2015.12.003 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DH6ZJ UT WOS:000372940300028 PM 26774790 ER PT J AU Gomes, CBF Treisten, NS Millen, B Armand, P Friedland, B AF Ferreira Gomes, Camilla Borges Treisten, Nathaniel Simon Millen, Brian Armand, Philippe Friedland, Bernard TI Pulp Obliteration in a Patient with Sclerodermatous Chronic Graft-versus-Host Disease SO JOURNAL OF ENDODONTICS LA English DT Article DE Allogeneic hematopoietic cell transplantation; dental pulp obliteration; oral chronic graft-versus-host disease; pulp calcification ID SYSTEMIC-SCLEROSIS; CALCIFICATIONS; PATHOGENESIS; PREVALENCE; DIAGNOSIS; THERAPY; STONES AB Dental pulp calcification is a common finding associated with localized dental trauma, genetic disorders, and systemic inflammatory diseases. Chronic graft-versus-host disease (cGVHD) is a frequent complication after allogeneic hematopoietic cell transplantation (allo-HCT) characterized by immune-mediated injury to the skin, mouth, eyes, liver, and other tissues, resulting in significant disability and reduced quality of life. We report a patient with sclerodermatous cGVHD who presented with general pulp calcification in all teeth 5 years after allo-HCT. A review of full mouth dental radiographs obtained just before allo-HCT revealed normal-appearing pulp chambers. Based on prior reports of generalized pulp calcification associated with progressive systemic sclerosis, we hypothesized that the etiology was likely related to the presence of cGVHD with associated vascular and fibrotic tissue changes within the pulp vasculature. Clinicians should consider cGVHD in the differential diagnosis of generalized pulp calcification. C1 [Ferreira Gomes, Camilla Borges] Univ Estadual Campinas, Sch Dent, Dept Oral Diag, Sao Paulo, Brazil. [Ferreira Gomes, Camilla Borges; Treisten, Nathaniel Simon] Brigham & Womens Hosp, Div Oral Med & Dent, 75 Francis St, Boston, MA 02115 USA. [Ferreira Gomes, Camilla Borges; Treisten, Nathaniel Simon] Dana Farber Canc Inst, Boston, MA 02115 USA. [Treisten, Nathaniel Simon; Armand, Philippe] Dana Farber Canc Inst, Dept Med Oncol Hematol Malignancies, Boston, MA 02115 USA. [Millen, Brian] Miller Lung Dent Grp, South Attleboro, MA USA. [Friedland, Bernard] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, 188 Longwood Ave, Boston, MA 02115 USA. RP Gomes, CBF (reprint author), Univ Estadual Campinas, Sch Dent, Dept Oral Diag, Av Limeira 901, BR-13414018 Piracicaba, SP, Brazil. EM camillabfgomes@hotmail.com NR 23 TC 0 Z9 0 U1 3 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0099-2399 EI 1878-3554 J9 J ENDODONT JI J. Endod. PD APR PY 2016 VL 42 IS 4 BP 678 EP 680 DI 10.1016/j.joen.2016.01.009 PG 3 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA DI1FL UT WOS:000373241900029 PM 26906241 ER PT J AU Lightner, AL Shannon, E Gibbons, MM Russell, MM AF Lightner, Amy L. Shannon, Evan Gibbons, Melinda Maggard Russell, Marcia M. TI Primary Gastrointestinal Non-Hodgkin's Lymphoma of the Small and Large Intestines: a Systematic Review SO JOURNAL OF GASTROINTESTINAL SURGERY LA English DT Review DE Lymphoma; Small intestine; Large intestine; Surgery; Outcomes ID B-CELL LYMPHOMA; PRIMARY COLONIC LYMPHOMA; FOLLICULAR LYMPHOMA; CLINICAL-FEATURES; CLINICOPATHOLOGICAL ANALYSIS; MALT LYMPHOMA; POPULATION; MANAGEMENT; RITUXIMAB; TRACT AB Primary gastrointestinal non-Hodgkin's lymphoma (PGINHL) of small and large intestines is a group of heterogeneous, rare malignancies. Optimal treatment practices remain undefined. A systematic review (2003-2015) was performed to assess tumor characteristics, treatment practices, and treatment outcomes of PGINHL of small and large intestines. Twenty-eight studies (1658 patients) were included; five focused on follicular lymphoma subtype. Of the non-follicular patients, 59.3 % presented with abdominal pain, 37.2 % were located in ileocecum, and 53.6 % were diffuse large B cell lymphoma subtype. The majority of patients (60.7 %) were treated with a combination of surgery and chemotherapy. Forty-three percent of studies concluded an overall survival benefit with surgery; none reported increased postoperative morbidity or mortality. Survival outcomes were not typically stratified by emergent versus elective surgery. Multivariate analysis within individual studies associated B cell lymphoma and ileocecum location with higher survival, while advanced stage and B symptoms were associated with poorer survival. Patients with asymptomatic follicular lymphoma had no progression with a watchful waiting approach. The majority of patients with non-follicular small and large intestinal PGINHLs are treated with both chemotherapy and surgery. Although surgery appears to be an important part of the treatment algorithm, definitive statements regarding its survival benefit remain limited due to lack of patient stratification based on timing and indication for surgery. C1 [Lightner, Amy L.; Gibbons, Melinda Maggard; Russell, Marcia M.] Univ Calif Los Angeles, Dept Surg, David Geffen Sch Med, 200 1st St SW Rochester, Los Angeles, MN 55905 USA. [Shannon, Evan] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Russell, Marcia M.] VA Greater Angeles Healthcare Syst, Los Angeles, CA USA. RP Lightner, AL (reprint author), Univ Calif Los Angeles, Dept Surg, David Geffen Sch Med, 200 1st St SW Rochester, Los Angeles, MN 55905 USA. EM Lightner.amy@mayo.edu NR 57 TC 2 Z9 2 U1 2 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1091-255X EI 1873-4626 J9 J GASTROINTEST SURG JI J. Gastrointest. Surg. PD APR PY 2016 VL 20 IS 4 BP 827 EP 839 DI 10.1007/s11605-015-3052-4 PG 13 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA DI0BB UT WOS:000373158700021 PM 26676930 ER PT J AU Alvino, DML Chang, DC Fong, ZV AF Alvino, Donna Marie L. Chang, David C. Fong, Zhi Ven TI How Does Outcomes Research Help Advance Our Knowledge of Patient Outcomes in Hepatopancreaticobiliary Surgery? SO JOURNAL OF GASTROINTESTINAL SURGERY LA English DT Editorial Material DE Health services research; Outcomes; Pancreas; Hepatopancreaticobiliary surgery ID INSTRUMENTAL-VARIABLE-ANALYSIS; PANCREATIC FISTULA; PANCREATICODUODENECTOMY; CANCER; MORTALITY; TRENDS AB Randomized controlled trials have historically been regarded as the gold standard of modern clinical research tools, allowing us to elucidate the efficacy of novel therapeutics in an unparalleled manner. However, when attempting to generalize trial results to broader populations, it becomes apparent that the unexplained outcome variability exists among treatment recipients, suggesting that randomized controlled trials harbor inherent limitations. Herein, we explore the benefits of health services (outcomes) research utilization in addressing variation in patient outcomes following surgical intervention in the non-randomized setting, with a specific focus on hepatopancreaticobiliary surgery outcomes. To achieve this, we have constructed a framework that outlines the complex interactions existing between therapeutic, patient, and provider factors that subsequently lead to variation in outcomes. By exploring examples in the current literature, we have highlighted the areas where the knowledge is currently lacking and can be further strengthened through the application of outcomes research. Furthermore, we have attempted to demonstrate the utility of alternative study designs in the investigation of novel clinical questions currently unanswered in the field of hepatopancreaticobiliary surgery. C1 [Alvino, Donna Marie L.; Chang, David C.; Fong, Zhi Ven] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg,Codman Ctr Clin Effectiveness Surg, 165 Cambridge St, Boston, MA 02114 USA. RP Fong, ZV (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg,Codman Ctr Clin Effectiveness Surg, 165 Cambridge St, Boston, MA 02114 USA. EM zfong@partners.org NR 25 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1091-255X EI 1873-4626 J9 J GASTROINTEST SURG JI J. Gastrointest. Surg. PD APR PY 2016 VL 20 IS 4 BP 871 EP 877 DI 10.1007/s11605-015-3072-0 PG 7 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA DI0BB UT WOS:000373158700027 PM 26861969 ER PT J AU Harris, AHS Chen, C Rubinsky, AD Hoggatt, KJ Neuman, M Vanneman, ME AF Harris, Alex H. S. Chen, Cheng Rubinsky, Anna D. Hoggatt, Katherine J. Neuman, Matthew Vanneman, Megan E. TI Are Improvements in Measured Performance Driven by Better Treatment or "Denominator Management"? SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE quality measurement; measurement reactivity; performance contracts ID PREVENTING UNINTENDED CONSEQUENCES; QUALITY MEASUREMENT; REPORT CARDS; INFORMATION AB Process measures of healthcare quality are usually formulated as the number of patients who receive evidence-based treatment (numerator) divided by the number of patients in the target population (denominator). When the systems being evaluated can influence which patients are included in the denominator, it is reasonable to wonder if improvements in measured quality are driven by expanding numerators or contracting denominators. In 2003, the US Department of Veteran Affairs (VA) based executive compensation in part on performance on a substance use disorder (SUD) continuity-of-care quality measure. The first goal of this study was to evaluate if implementing the measure in this way resulted in expected improvements in measured performance. The second goal was to examine if the proportion of patients with SUD who qualified for the denominator contracted after the quality measure was implemented, and to describe the facility-level variation in and correlates of denominator contraction or expansion. Using 40 quarters of data straddling the implementation of the performance measure, an interrupted time series design was used to evaluate changes in two outcomes. All veterans with an SUD diagnosis in all VA facilities from fiscal year 2000 to 2009. The two outcomes were 1) measured performance-patients retained/patients qualified and 2) denominator prevalence-patients qualified/patients with SUD program contact. Measured performance improved over time (P < 0.001). Notably, the proportion of patients with SUD program contact who qualified for the denominator decreased more rapidly after the measure was implemented (p = 0.02). Facilities with higher pre-implementation denominator prevalence had steeper declines in denominator prevalence after implementation (p < 0.001). These results should motivate the development of measures that are less vulnerable to denominator management, and also the exploration of "shadow measures" to monitor and reduce undesirable denominator management. C1 [Harris, Alex H. S.; Chen, Cheng; Rubinsky, Anna D.; Neuman, Matthew; Vanneman, Megan E.] VA Palo Alto Hlth Care Syst, Ctr Innovat Implementat, 795 Willow Rd, Menlo Pk, CA 94025 USA. [Hoggatt, Katherine J.] VA Greater Los Angeles Hlth Care Syst, Los Angeles, CA USA. [Hoggatt, Katherine J.] Univ Calif Los Angeles, Los Angeles, CA USA. [Vanneman, Megan E.] Stanford Univ, Ctr Hlth Policy Primary Care & Outcomes Res, Sch Med, Stanford, CA 94305 USA. RP Harris, AHS (reprint author), VA Palo Alto Hlth Care Syst, Ctr Innovat Implementat, 795 Willow Rd, Menlo Pk, CA 94025 USA. EM Alexander.Harris2@va.gov FU VA Health Services Research and Development (HSRD) Service [IIR 10-370-2]; VA Substance Use Disorder Quality Enhancement Research Initiative (SUD QUERI) [SUDQ-LIP-1208, SUDQ-LIP-1314]; VA HSR&D/QUERI Career Development Award; VA HSR&D Postdoctoral Fellowship; VA HSR&D Research Career Scientist Award [RCS-14-232] FX This study was funded by the VA Health Services Research and Development (HSR&D) Service (IIR 10-370-2), VA Substance Use Disorder Quality Enhancement Research Initiative (SUD QUERI; SUDQ-LIP-1208; SUDQ-LIP-1314), a VA HSR&D/QUERI Career Development Award to Dr. Hoggatt, a VA HSR&D Postdoctoral Fellowship to Dr. Vanneman, and a VA HSR&D Research Career Scientist Award (RCS-14-232) to Dr. Harris. The views expressed herein are not necessarily those of the Department of Veterans Affairs. NR 21 TC 2 Z9 2 U1 3 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD APR PY 2016 VL 31 SU 1 BP 21 EP 27 DI 10.1007/s11606-015-3558-1 PG 7 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA DI0BN UT WOS:000373159900006 PM 26951270 ER PT J AU Farmer, MM Rubenstein, LV Sherbourne, CD Huynh, A Chu, K Lam, CA Fickel, JJ Lee, ML Metzger, ME Verchinina, L Post, EP Chaney, EF AF Farmer, Melissa M. Rubenstein, Lisa V. Sherbourne, Cathy D. Huynh, Alexis Chu, Karen Lam, Christine A. Fickel, Jacqueline J. Lee, Martin L. Metzger, Maureen E. Verchinina, Lilia Post, Edward P. Chaney, Edmund F. TI Depression Quality of Care: Measuring Quality over Time Using VA Electronic Medical Record Data SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE performance measurement; depression; Veterans; measurement; quality assessment ID RANDOMIZED CONTROLLED-TRIAL; COLLABORATIVE CARE; PERFORMANCE-MEASURES; CHRONIC DISEASE; MENTAL-HEALTH; IMPROVEMENT; OUTCOMES; IMPACT AB The Veterans Health Administration (VA) has invested substantially in evidence-based mental health care. Yet no electronic performance measures for assessing the level at which the population of Veterans with depression receive appropriate care have proven robust enough to support rigorous evaluation of the VA's depression initiatives. Our objectives were to develop prototype longitudinal electronic population-based measures of depression care quality, validate the measures using expert panel judgment by VA and non-VA experts, and examine detection, follow-up and treatment rates over a decade (2000-2010). We describe our development methodology and the challenges to creating measures that capture the longitudinal course of clinical care from detection to treatment. Data come from the National Patient Care Database and Pharmacy Benefits Management Database for primary care patients from 1999 to 2011, from nine Veteran Integrated Service Networks. We developed four population-based quality metrics for depression care that incorporate a 6-month look back and 1-year follow-up: detection of a new episode of depression, 84 and 180 day follow-up, and minimum appropriate treatment 1-year post detection. Expert panel techniques were used to evaluate the measure development methodology and results. Key challenges to creating valid longitudinal measures are discussed. Over the decade, the rates for detection of new episodes of depression remained stable at 7-8 %. Follow-up at 84 and 180 days were 37 % and 45 % in 2000 and increased to 56 % and 63 % by 2010. Minimum appropriate treatment remained relatively stable over the decade (82-84 %). The development of valid longitudinal, population-based quality measures for depression care is a complex process with numerous challenges. If the full spectrum of care from detection to follow-up and treatment is not captured, performance measures could actually mask the clinical areas in need of quality improvement efforts. C1 [Farmer, Melissa M.; Rubenstein, Lisa V.; Huynh, Alexis; Chu, Karen; Lam, Christine A.; Fickel, Jacqueline J.; Lee, Martin L.] VA Greater Los Angeles Healthcare Syst, VA HSR&D Ctr Study Healthcare Innovat Implementat, 16111 Plummer St 152, Sepulveda, CA 91343 USA. [Rubenstein, Lisa V.; Sherbourne, Cathy D.] RAND Corp, Santa Monica, CA USA. [Rubenstein, Lisa V.; Lee, Martin L.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Rubenstein, Lisa V.; Lee, Martin L.] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Los Angeles, CA 90095 USA. [Metzger, Maureen E.; Verchinina, Lilia; Post, Edward P.] HSR&D Ctr Clin Management Res, VA Ann Arbor, Ann Arbor, MI USA. [Post, Edward P.] Univ Michigan, Sch Med, Ann Arbor, MI 48109 USA. [Chaney, Edmund F.] Univ Washington, Sch Med, Seattle, WA 98195 USA. RP Farmer, MM (reprint author), VA Greater Los Angeles Healthcare Syst, VA HSR&D Ctr Study Healthcare Innovat Implementat, 16111 Plummer St 152, Sepulveda, CA 91343 USA. EM Melissa.Farmer@va.gov FU VA Health Services Research Development [IIR 11-326] FX Funding for this research was supported by a grant from VA Health Services Research & Development (Project #IIR 11-326; PI: Farmer). We would like to acknowledge the expert panelists for their contribution as well as Britney Chow, MPH and Ismelda Canelo, MPA for administrative support. NR 33 TC 3 Z9 3 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD APR PY 2016 VL 31 SU 1 BP 36 EP 45 DI 10.1007/s11606-015-3563-4 PG 10 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA DI0BN UT WOS:000373159900008 PM 26951274 ER PT J AU Saini, SD Powell, AA Dominitz, JA Fisher, DA Francis, J Kinsinger, L Pittman, KS Schoenfeld, P Moser, SE Vijan, S Kerr, EA AF Saini, Sameer D. Powell, Adam A. Dominitz, Jason A. Fisher, Deborah A. Francis, Joseph Kinsinger, Linda Pittman, Kathleen S. Schoenfeld, Philip Moser, Stephanie E. Vijan, Sandeep Kerr, Eve A. TI Developing and Testing an Electronic Measure of Screening Colonoscopy Overuse in a Large Integrated Healthcare System SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE performance measurement; colorectal cancer; screening; health services research ID SOCIETY TASK-FORCE; COLORECTAL-CANCER; MEDICARE POPULATION; QUALITY MEASURES; GUIDELINES AB Most existing performance measures focus on underuse of care, but there is growing interest in identifying and reducing overuse. We aimed to develop a valid and reliable electronic performance measure of overuse of screening colonoscopy in the Veterans Affairs Health Care System (VA), and to quantify overuse in VA. This was a cross-sectional study with multiple cross-sections. U.S. Veterans who underwent screening colonoscopy between 2011 and 2013. Overuse of screening colonoscopy, using a validated electronic measure developed by an expert workgroup. Compared to results obtained from manual record review, the electronic measure was highly specific (97 %) for overuse, but not sensitive (20 %). After exclusion of diagnostic and high-risk screening or surveillance procedures, the validated electronic measure identified 88,754 average-risk screening colonoscopies performed in VA during 2013. Of these, 20,530 (23 %) met the definition for probable (17 %) or possible (6 %) overuse. Substantial variation in colonoscopy overuse was noted between Veterans Integrated Care Networks (VISNs) and between facilities, with a nearly twofold difference between the maximum and minimum rates of overuse at the VISN level and a nearly eightfold difference at the facility level. Overuse at the VISN and facility level was relatively stable over time. Overuse of screening colonoscopy can be measured reliably and with high specificity using electronic data, and is common in a large integrated healthcare system. Overuse measures, such as those we have specified through a consensus workgroup process, could be combined with underuse measures to improve the appropriateness of colorectal cancer screening. C1 [Saini, Sameer D.; Schoenfeld, Philip; Moser, Stephanie E.; Vijan, Sandeep; Kerr, Eve A.] Vet Affairs Ctr Clin Management Res CCMR, 2215 Fuller Rd,111D, Ann Arbor, MI 48105 USA. [Saini, Sameer D.; Schoenfeld, Philip; Vijan, Sandeep; Kerr, Eve A.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Saini, Sameer D.; Schoenfeld, Philip; Vijan, Sandeep; Kerr, Eve A.] Univ Michigan, Inst Healthcare Policy & Innovat, Ann Arbor, MI 48109 USA. [Powell, Adam A.] Minneapolis VA HealthCare Syst, CCDOR, Minneapolis, MN USA. [Powell, Adam A.] Anthem Inc, Minneapolis, MN USA. [Dominitz, Jason A.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Fisher, Deborah A.] Durham Vet Affairs Med Ctr, Durham, NC USA. [Fisher, Deborah A.] Duke Univ, Dept Med, Durham, NC USA. [Francis, Joseph] VHA Off Analyt & Business Intelligence, Washington, DC USA. [Kinsinger, Linda; Pittman, Kathleen S.] VHA Natl Ctr Hlth Promot & Dis Prevent, Durham, NC USA. [Vijan, Sandeep] Univ Michigan, Dept Anesthesiol, Ann Arbor, MI 48109 USA. RP Saini, SD (reprint author), Vet Affairs Ctr Clin Management Res CCMR, 2215 Fuller Rd,111D, Ann Arbor, MI 48105 USA. EM sdsaini@umich.edu FU VA Health Services Research and Development [CDA 09-213-2, RRP 12-184]; Veterans Health Administration (VHA) Office of Informatics and Analytics (OIA) FX This work was funded by VA Health Services Research and Development (CDA 09-213-2 and RRP 12-184). Partial funding for this work was provided by the Veterans Health Administration (VHA) Office of Informatics and Analytics (OIA). These funding agencies had no role in the design and conduct of the study. VHA OIA reviewed the manuscript prior to submission. The opinions expressed in this paper are of the authors and do not necessarily reflect those of the Department of Veterans Affairs. NR 22 TC 2 Z9 2 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD APR PY 2016 VL 31 SU 1 BP 53 EP 60 DI 10.1007/s11606-015-3569-y PG 8 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA DI0BN UT WOS:000373159900010 PM 26951277 ER PT J AU Kondo, KK Damberg, CL Mendelson, A Motu'apuaka, M Freeman, M O'Neil, M Relevo, R Low, A Kansagara, D AF Kondo, Karli K. Damberg, Cheryl L. Mendelson, Aaron Motu'apuaka, Makalapua Freeman, Michele O'Neil, Maya Relevo, Rose Low, Allison Kansagara, Devan TI Implementation Processes and Pay for Performance in Healthcare: A Systematic Review SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Review DE pay for performance; financial incentives; implementation; performance metrics; systematic review ID FOR-PERFORMANCE; OUTCOMES-FRAMEWORK; GENERAL PRACTICES; DIABETES CARE; PRACTICE SIZE; QUALITY; PROGRAM; INCENTIVES; IMPACT; CONTRACT AB Over the last decade, various pay-for-performance (P4P) programs have been implemented to improve quality in health systems, including the VHA. P4P programs are complex, and their effects may vary by design, context, and other implementation processes. We conducted a systematic review and key informant (KI) interviews to better understand the implementation factors that modify the effectiveness of P4P. We searched PubMed, PsycINFO, and CINAHL through April 2014, and reviewed reference lists. We included trials and observational studies of P4P implementation. Two investigators abstracted data and assessed study quality. We interviewed P4P researchers to gain further insight. Among 1363 titles and abstracts, we selected 509 for full-text review, and included 41 primary studies. Of these 41 studies, 33 examined P4P programs in ambulatory settings, 7 targeted hospitals, and 1 study applied to nursing homes. Related to implementation, 13 studies examined program design, 8 examined implementation processes, 6 the outer setting, 18 the inner setting, and 5 provider characteristics. Results suggest the importance of considering underlying payment models and using statistically stringent methods of composite measure development, and ensuring that high-quality care will be maintained after incentive removal. We found no conclusive evidence that provider or practice characteristics relate to P4P effectiveness. Interviews with 14 KIs supported limited evidence that effective P4P program measures should be aligned with organizational goals, that incentive structures should be carefully considered, and that factors such as a strong infrastructure and public reporting may have a large influence. There is limited evidence from which to draw firm conclusions related to P4P implementation. Findings from studies and KI interviews suggest that P4P programs should undergo regular evaluation and should target areas of poor performance. Additionally, measures and incentives should align with organizational priorities, and programs should allow for changes over time in response to data and provider input. C1 [Kondo, Karli K.; Motu'apuaka, Makalapua; Freeman, Michele; O'Neil, Maya; Relevo, Rose; Low, Allison; Kansagara, Devan] Evidence Based Synth Program, Portland Vet Affairs Med Ctr, Mailcode RD71,3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. [Damberg, Cheryl L.] RAND Corp, Santa Monica, CA USA. [Kondo, Karli K.; Mendelson, Aaron; O'Neil, Maya; Kansagara, Devan] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. RP Kondo, KK (reprint author), Evidence Based Synth Program, Portland Vet Affairs Med Ctr, Mailcode RD71,3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM karli.kondo@va.gov RI haron, suhaila/E-9360-2017; OI Low, Allison/0000-0003-2088-2429 FU U.S. Department of Veterans Affairs, Veterans Health Administration (VHA) ESP [05-225] FX This project was funded by the U.S. Department of Veterans Affairs, Veterans Health Administration (VHA) ESP Project #05-225. NR 49 TC 4 Z9 4 U1 9 U2 19 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 APR PY 2016 VL 31 SU 1 BP 61 EP 69 DI 10.1007/s11606-015-3567-0 PG 9 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA DI0BN UT WOS:000373159900011 PM 26951276 ER PT J AU Prentice, JC Frakt, AB Pizer, SD AF Prentice, Julia C. Frakt, Austin B. Pizer, Steven D. TI Metrics That Matter SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE metric validation; metric implementation; access to care metrics; mental health metrics; veterans ID HEALTH-CARE; QUALITY MEASURES; ACCESS; CONSEQUENCES; MEDICARE; OUTCOMES AB Increasingly, performance metrics are seen as key components for accurately measuring and improving health care value. Disappointment in the ability of chosen metrics to meet these goals is exemplified in a recent Institute of Medicine report that argues for a consensus-building process to determine a simplified set of reliable metrics. Overall health care goals should be defined and then metrics to measure these goals should be considered. If appropriate data for the identified goals are not available, they should be developed. We use examples from our work in the Veterans Health Administration (VHA) on validating waiting time and mental health metrics to highlight other key issues for metric selection and implementation. First, we focus on the need for specification and predictive validation of metrics. Second, we discuss strategies to maintain the fidelity of the data used in performance metrics over time. These strategies include using appropriate incentives and data sources, using composite metrics, and ongoing monitoring. Finally, we discuss the VA's leadership in developing performance metrics through a planned upgrade in its electronic medical record system to collect more comprehensive VHA and non-VHA data, increasing the ability to comprehensively measure outcomes. C1 [Prentice, Julia C.; Frakt, Austin B.; Pizer, Steven D.] VA Boston Healthcare Syst, Hlth Care Financing & Econ, 150 S Huntington Ave,Mailstop 152H, Boston, MA 02130 USA. [Prentice, Julia C.; Frakt, Austin B.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Prentice, Julia C.; Frakt, Austin B.] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Frakt, Austin B.] Harvard Univ, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Pizer, Steven D.] Northeastern Univ, Boston, MA 02115 USA. RP Prentice, JC (reprint author), VA Boston Healthcare Syst, Hlth Care Financing & Econ, 150 S Huntington Ave,Mailstop 152H, Boston, MA 02130 USA. EM Julia.Prentice@va.gov FU VHA Access & Clinic Administration Program; Health Services Research and Development Service, Department of Veterans Affairs [CREATE 12023] FX Funding for this research was provided by the VHA Access & Clinic Administration Program and CREATE 12023 from the Health Services Research and Development Service, Department of Veterans Affairs. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs, Boston University, Havard University or Northeastern University. NR 31 TC 1 Z9 1 U1 5 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 APR PY 2016 VL 31 SU 1 BP 70 EP 73 DI 10.1007/s11606-015-3559-0 PG 4 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA DI0BN UT WOS:000373159900012 PM 26951272 ER PT J AU Wagner, TH Burstin, H Frakt, AB Krein, SL Lorenz, K Maciejewski, ML Pizer, SD Weiner, M Yoon, J Zulman, DM Asch, SM AF Wagner, Todd H. Burstin, Helen Frakt, Austin B. Krein, Sarah L. Lorenz, Karl Maciejewski, Matthew L. Pizer, Steven D. Weiner, Michael Yoon, Jean Zulman, Donna M. Asch, Steven M. TI Opportunities to Enhance Value-Related Research in the US Department of Veterans Affairs SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article ID COST-EFFECTIVENESS ANALYSIS; HEALTH-CARE; QUALITY IMPROVEMENT; TECHNOLOGY; TRIAL; ORGANIZATIONS; INTERVENTIONS; PERSPECTIVES; CHALLENGES; SURGERY C1 [Wagner, Todd H.; Yoon, Jean] Hlth Econ Resource Ctr, Menlo Pk, CA USA. [Wagner, Todd H.; Lorenz, Karl; Yoon, Jean; Zulman, Donna M.; Asch, Steven M.] Ctr Innovat Implementat, Menlo Pk, CA USA. [Wagner, Todd H.] Stanford Univ, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Burstin, Helen] Natl Qual Forum, Washington, DC USA. [Burstin, Helen] George Washington Univ, Washington, DC USA. [Frakt, Austin B.; Pizer, Steven D.] VA Boston Hlth Care Syst, Hlth Care Financing & Econ, Boston, MA USA. [Frakt, Austin B.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Frakt, Austin B.] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Krein, Sarah L.] VA Ann Arbor Ctr Clin Management Res, Ann Arbor, MI USA. [Krein, Sarah L.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Lorenz, Karl] VA Palliat Care Qual Improvement Resource Ctr QuI, Menlo Pk, CA USA. [Lorenz, Karl; Zulman, Donna M.; Asch, Steven M.] Stanford Univ, Div Gen Med Disciplines, Stanford, CA 94305 USA. [Maciejewski, Matthew L.] Durham VA Med Ctr, Ctr Innovat, Durham, NC USA. [Maciejewski, Matthew L.] Duke Univ, Dept Med, Div Gen Internal Med, Durham, NC USA. [Pizer, Steven D.] Northeastern Univ, Dept Pharm Practice, Boston, MA 02115 USA. [Pizer, Steven D.] Northeastern Univ, Dept Econ, Boston, MA 02115 USA. [Weiner, Michael] VA Ctr Hlth Informat & Commun, Indianapolis, IN USA. [Weiner, Michael] Regenstrief Inst Inc, Indianapolis, IN USA. [Weiner, Michael] Indiana Univ, Ctr Hlth Serv & Outcomes Res, Indianapolis, IN 46204 USA. RP Wagner, TH (reprint author), VA Palo Alto, Hlth Econ Resource Ctr, 795 Willow Rd,152-MPD, Menlo Pk, CA 94025 USA. EM todd.wagner@va.gov FU VA Health Services Research and Development Service FX The VA State of the Art Conference was funded by the VA Health Services Research and Development Service. All commentary and conclusions are our own and do not represent the opinions of the Health Services Research and Development Service or the Department of Veterans Affairs. The committee presented its findings at the Performance Measurement SOTA Plenary on May 6, 2015. NR 47 TC 1 Z9 1 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD APR PY 2016 VL 31 SU 1 BP 78 EP 83 DI 10.1007/s11606-015-3538-5 PG 6 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA DI0BN UT WOS:000373159900014 PM 26951279 ER PT J AU Tosteson, ANA Beaber, EF Tiro, J Kim, J McCarthy, AM Quinn, VP Doria-Rose, VP Wheeler, CM Barlow, WE Bronson, M Garcia, M Corley, DA Haas, JS Halm, EA Kamineni, A Rutter, CM Tosteson, TD Trentham-Dietz, A Weaver, DL AF Tosteson, Anna N. A. Beaber, Elisabeth F. Tiro, Jasmin Kim, Jane McCarthy, Anne Marie Quinn, Virginia P. Doria-Rose, V. Paul Wheeler, Cosette M. Barlow, William E. Bronson, Mackenzie Garcia, Michael Corley, Douglas A. Haas, Jennifer S. Halm, Ethan A. Kamineni, Aruna Rutter, Carolyn M. Tosteson, Tor D. Trentham-Dietz, Amy Weaver, Donald L. CA PROSPR Consortium TI Variation in Screening Abnormality Rates and Follow-Up of Breast, Cervical and Colorectal Cancer Screening within the PROSPR Consortium SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE breast cancer screening; colorectal cancer screening; cervical cancer screening; practice variation ID FORCE RECOMMENDATION STATEMENT; EARLY-DETECTION PROGRAM; PERSONALIZED REGIMENS; CONCEPTUAL-MODEL; NATIONAL BREAST; UNITED-STATES; PRIMARY-CARE; TIMELINESS; WOMEN; MAMMOGRAPHY AB Primary care providers and health systems have prominent roles in guiding effective cancer screening. To characterize variation in screening abnormality rates and timely initial follow-up for common cancer screening tests. Population-based cohort undergoing screening in 2011, 2012, or 2013 at seven research centers comprising the National Cancer Institute-sponsored Population-based Research Optimizing Screening through Personalized Regimens (PROSPR) consortium. Adults undergoing mammography with or without digital breast tomosynthesis (n = 97,683 ages 40-75 years), fecal occult blood or fecal immunochemical tests (n = 759,553 ages 50-75 years), or Papanicolaou with or without human papillomavirus tests (n = 167,330 ages 21-65 years). Breast, colorectal, or cervical cancer screening. Abnormality rates per 1000 screens; percentage with timely initial follow-up (within 90 days, except 9-month window for BI-RADS 3). Primary care clinic-level variation in percentage with screening abnormality and percentage with timely initial follow-up. There were 10,248/97,683 (104.9 per 1000) abnormal breast cancer screens, 35,847/759,553 (47.2 per 1000) FOBT/FIT-positive colorectal cancer screens, and 13,266/167,330 (79.3 per 1000) abnormal cervical cancer screens. The percentage with timely follow-up was 93.2 to 96.7 % for breast centers, 46.8 to 68.7 % for colorectal centers, and 46.6 % for the cervical cancer screening center (low-grade squamous intraepithelial lesions or higher). The primary care clinic variation (25th to 75th percentile) was smaller for the percentage with an abnormal screen (breast, 8.5-10.3 %; colorectal, 3.0-4.8 %; cervical, 6.3-9.9 %) than for the percentage with follow-up within 90 days (breast, 90.2-95.8 %; colorectal, 43.4-52.0 %; cervical, 29.6-61.4 %). Variation in both the rate of screening abnormalities and their initial follow-up was evident across organ sites and primary care clinics. This highlights an opportunity for improving the delivery of cancer screening through focused study of patient, provider, clinic, and health system characteristics associated with timely follow-up of screening abnormalities. C1 [Tosteson, Anna N. A.; Bronson, Mackenzie; Tosteson, Tor D.] Geisel Sch Med Dartmouth, Lebanon, NH USA. [Tosteson, Anna N. A.; Tosteson, Tor D.] Norris Cotton Canc Ctr, Lebanon, NH USA. [Beaber, Elisabeth F.; Garcia, Michael] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Tiro, Jasmin] Univ Texas Southwestern, Dallas, TX USA. [Kim, Jane] Harvard Univ, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [McCarthy, Anne Marie] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Quinn, Virginia P.] Kaiser Permanente So Calif, Pasadena, CA 91101 USA. [Doria-Rose, V. Paul] NCI, Bethesda, MD 20892 USA. [Wheeler, Cosette M.] Univ New Mexico, Albuquerque, NM 87131 USA. [Barlow, William E.] Canc Res & Biostat, Seattle, WA USA. [Corley, Douglas A.] Kaiser Permanente No Calif, Oakland, CA USA. [Haas, Jennifer S.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Halm, Ethan A.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Kamineni, Aruna] Grp Hlth, Seattle, WA USA. [Rutter, Carolyn M.] RAND Corp, Santa Monica, CA USA. [Trentham-Dietz, Amy] Univ Wisconsin, Madison, WI USA. [Weaver, Donald L.] Univ Vermont, Burlington, VT USA. RP Tosteson, ANA (reprint author), Geisel Sch Med Dartmouth, Lebanon, NH USA. EM Anna.Tosteson@Dartmouth.edu OI Doria-Rose, Vincent/0000-0002-8802-5143 FU National Cancer Institute (NCI) [U01CA163304, U54CA163303, U54CA163307, U54CA163313, U54CA163308, U54CA163308-04S1, U54CA163261, U54CA163261-04S1, U54CA163262, U54CA163262-04S1, U54CA164336] FX This work was supported by the National Cancer Institute (NCI)-funded Population-based Research Optimizing Screening through Personalized Regimens (PROSPR) consortium (grant numbers U01CA163304 to M.T., W.B.; U54CA163303 to D.L.W., B.S.; U54CA163307 to A.N.A.T., T.O., J.H.; U54CA163313 to K.A., M.S.; U54CA163308 to C.S.S., E.H.; U54CA163308-04S1 to C.S.S., J.A.T.; U54CA163261 to C.R.; U54CA163261-04S1 to J.C., A.K.; U54CA163262 to A.G.Z., D.C., C.D., T.L.; U54CA163262-04S1 to D.C., M.S.; and U54CA164336 to C.W.). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the Department of Veterans Affairs or the United States government. NR 41 TC 5 Z9 5 U1 3 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD APR PY 2016 VL 31 IS 4 BP 372 EP 379 DI 10.1007/s11606-015-3552-7 PG 8 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA DI0BR UT WOS:000373160300005 PM 26658934 ER PT J AU Linsky, A AF Linsky, Amy TI Capsule Commentary on Genoff et al., Navigating Language Barriers: A Systematic Review of Patient Navigators' Impact on Cancer Screening for Limited English Proficient Patients SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Editorial Material ID CONCORDANCE C1 [Linsky, Amy] VA Boston Healthcare Syst, Gen Internal Med Sect, Boston, MA 02130 USA. [Linsky, Amy] Boston Univ, Sch Med, Gen Internal Med, Boston, MA 02215 USA. RP Linsky, A (reprint author), VA Boston Healthcare Syst, Gen Internal Med Sect, Boston, MA 02130 USA. EM amy.linsky@va.gov NR 5 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD APR PY 2016 VL 31 IS 4 BP 415 EP 415 DI 10.1007/s11606-016-3602-9 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA DI0BR UT WOS:000373160300014 PM 26857729 ER PT J AU Oslin, DW Lynch, KG Maisto, SA Lantinga, LJ Mckay, JR Possemato, K Ingram, E Wierzbicki, M AF Oslin, David W. Lynch, Kevin G. Maisto, Stephen A. Lantinga, Larry J. McKay, James R. Possemato, Kyle Ingram, Erin Wierzbicki, Michael TI A Randomized Clinical Trial of Alcohol Care Management Delivered in Department of Veterans Affairs Primary Care Clinics Versus Specialty Addiction Treatment (vol 29, pg 162, 2014) SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Correction C1 [Oslin, David W.; McKay, James R.; Ingram, Erin] Univ Penn, Philadelphia VA Med Ctr, Mental Illness Res Educ & Clin Ctr, Philadelphia, PA 19104 USA. [Oslin, David W.; Lynch, Kevin G.; McKay, James R.] Univ Penn, Perelman Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. [Maisto, Stephen A.; Lantinga, Larry J.; Possemato, Kyle] Syracuse Univ, Dept Psychol, Syracuse, NY USA. [Maisto, Stephen A.; Lantinga, Larry J.; Possemato, Kyle] VISN2, Dept Vet Affairs, Ctr Integrated Healthcare, Syracuse, NY USA. [Wierzbicki, Michael] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. RP Oslin, DW (reprint author), Univ Penn, Philadelphia VA Med Ctr, Mental Illness Res Educ & Clin Ctr, Philadelphia, PA 19104 USA.; Oslin, DW (reprint author), Univ Penn, Perelman Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD APR PY 2016 VL 31 IS 4 BP 449 EP 449 DI 10.1007/s11606-015-3419-y PG 1 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA DI0BR UT WOS:000373160300023 PM 26055225 ER PT J AU Ghosh, A Leahy, KP Singhal, S Einhorn, E Howlett, P Cohen, NA Mirza, N AF Ghosh, A. Leahy, K. P. Singhal, S. Einhorn, E. Howlett, P. Cohen, N. A. Mirza, N. TI A murine model of subglottic granulation SO JOURNAL OF LARYNGOLOGY AND OTOLOGY LA English DT Article DE Subglottic Stenosis, Acquired; Airway Obstruction; Granulation Tissue; Animal Model ID RABBIT MODEL; STENOSIS; INJURY AB Objective: This study aimed to develop a functional model of subglottic stenosis by inducing direct airway irritation in transplanted mouse laryngotracheal complexes. Methods: Laryngotracheal complexes from C57BL/6 mice were harvested and divided into three groups: uninjured, mechanically injured and chemically injured. Donor laryngotracheal complexes from each group were placed in dorsal subcutaneous pockets of recipient mice. Each week, the transplanted laryngotracheal complexes were harvested, and tissues were fixed, sectioned, and stained with haematoxylin and eosin. Representative slides were reviewed by a blinded pathologist, to determine the formation of granulation tissue, and graded as to the degree of granulation formation. Results: Direct airway irritation induced granulation tissue formation under the disrupted epithelium of airway mucosa; this was seen as early as two weeks after chemical injury. Conclusion: Results indicate that granulation tissue formation in a murine model may be an efficient tool for investigating the development and treatment of subglottic stenosis. C1 [Ghosh, A.; Leahy, K. P.; Cohen, N. A.; Mirza, N.] Univ Penn, Dept Otorhinolaryngol Head & Neck Surg, 3400 Spruce St,5 Ravdin, Philadelphia, PA 19104 USA. [Singhal, S.] Univ Penn, Dept Thorac Surg, 3400 Spruce St,5 Ravdin, Philadelphia, PA 19104 USA. [Einhorn, E.; Howlett, P.] Philadelphia Vet Affairs Med Ctr, Dept Pathol, Philadelphia, PA USA. RP Ghosh, A (reprint author), Univ Penn, Dept Otorhinolaryngol Head & Neck Surg, 3400 Spruce St,5 Ravdin, Philadelphia, PA 19104 USA. EM ankona.ghosh@uphs.upenn.edu OI Cohen, Noam/0000-0002-9462-3932 NR 9 TC 0 Z9 0 U1 1 U2 1 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 0022-2151 EI 1748-5460 J9 J LARYNGOL OTOL JI J. Laryngol. Otol. PD APR PY 2016 VL 130 IS 4 BP 380 EP 387 DI 10.1017/S0022215116000049 PG 8 WC Otorhinolaryngology SC Otorhinolaryngology GA DH9PJ UT WOS:000373127800013 PM 26991876 ER PT J AU Panych, LP Chiou, YG Qin, L Kimbrell, VL Bussolari, L Mulkern, RV AF Panych, Lawrence P. Chiou, Jr-Yuan George Qin, Lei Kimbrell, Vera L. Bussolari, Lisa Mulkern, Robert V. TI On replacing the manual measurement of ACR phantom images performed by MRI technologists with an automated measurement approach SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article DE ACR phantom imaging; quality control; quality assurance; accreditation ID QUALITY-ASSURANCE; MULTICENTER; VALIDATION AB PurposeTo assess whether measurements on American College of Radiology (ACR) phantom images performed by magnetic resonance imaging (MRI) technologists as part of a weekly quality control (QC) program could be performed exclusively using an automated system without compromising the integrity of the QC program. Materials and MethodsACR phantom images are acquired on 15 MRI scanners at a number of ACR-accredited sites to fulfill requirements of a weekly QC program. MRI technologists routinely perform several measurements on these images. Software routines are also used to perform the measurements. A set of geometry measurements made by technologists over a five week period and those made using software routines were compared to reference-standard measurements made by two MRI physicists. ResultsThe geometry measurements performed by software routines had a very high positive correlation (0.92) with the reference-standard measurements. Technologist measurements also had a high positive correlation (0.63), although the correlation was less than for the automated measurements. Bland-Altman analysis revealed overall good agreement between the automated and reference-standard measurements, with the 95% limits of agreement being within 0.62mm. Agreement between the technologist and the reference-standard measurements was demonstratively poorer, with 95% limits of agreement being +/- 1.46mm. Some of the technologist measurements differed from the reference standard by as much as 2mm. ConclusionThe technologists' geometry measurements may be able to be replaced by automated measurement without compromising the weekly QC program required by the ACR. J. Magn. Reson. Imaging 2016;43:843-852 C1 [Panych, Lawrence P.; Chiou, Jr-Yuan George; Kimbrell, Vera L.; Bussolari, Lisa; Mulkern, Robert V.] Brigham & Womens Hosp, Dept Radiol, 75 Francis St, Boston, MA 02115 USA. [Panych, Lawrence P.; Chiou, Jr-Yuan George; Qin, Lei; Mulkern, Robert V.] Harvard Univ, Sch Med, Boston, MA USA. [Qin, Lei] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Imaging, 44 Binney St, Boston, MA 02115 USA. [Mulkern, Robert V.] Childrens Hosp Boston, Dept Radiol, Boston, MA USA. RP Panych, LP (reprint author), 75 Francis St, Boston, MA 02115 USA. EM panych@bwh.harvard.edu NR 16 TC 0 Z9 0 U1 2 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-1807 EI 1522-2586 J9 J MAGN RESON IMAGING JI J. Magn. Reson. Imaging PD APR PY 2016 VL 43 IS 4 BP 843 EP 852 DI 10.1002/jmri.25052 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DH7UY UT WOS:000373000500007 PM 26395366 ER PT J AU Mansouri, M Aran, S Harvey, HB Shaqdan, KW Abujudeh, HH AF Mansouri, Mohammad Aran, Shima Harvey, Harlan B. Shaqdan, Khalid W. Abujudeh, Hani H. TI Rates of safety incident reporting in MRI in a large academic medical center SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article DE patient safety; incident report; safety report; MRI safety; quality and safety; safety incident reporting system ID ADVERSE EVENTS; INTENSIVE-CARE; ERRORS; FALLS; EXPERIENCE; INJECTIONS; HOSPITALS; RADIOLOGY; SYSTEMS; CONSEQUENCES AB PurposeTo describe our multiyear experience in incident reporting related to magnetic resonance imaging (MRI) in a large academic medical center. Materials and MethodsThis was an Institutional Review Board (IRB)-approved, Health Insurance Portability and Accountability Act (HIPAA)-compliant study. Incident report data were collected during the study period from April 2006 to September 2012. The incident reports filed during the study period were searched for all reports related to MRI. Incident reports were classified with regard to the patient type (inpatient vs. outpatient), primary reason for the incident report, and the severity of patient harm resulting from the incident. ResultsA total of 362,090 MRI exams were performed during the study period, resulting in 1290 MRI-related incident reports. The rate of incident reporting was 0.35% (1290/362,090). MRI-related incident reporting was significantly higher in inpatients compared to outpatients (0.74% [369/49,801] vs. 0.29% [921/312,288], P < 0.001). The most common reason for incident reporting was diagnostic test orders (31.5%, 406/1290), followed by adverse drug reactions (19.1%, 247/1290) and medication/IV safety (14.3%, 185/1290). Approximately 39.6% (509/1290) of reports were associated with no patient harm and did not affect the patient, followed by no patient harm but did affect the patient (35.8%, 460/1290), temporary or minor patient harm (23.9%, 307/1290), permanent or major patient harm (0.6%, 8/1290) and patient death (0.2%, 2/1290). ConclusionMRI-related incident reports are relatively infrequent, occur at significantly higher rates in inpatients, and usually do not result in patient harm. Diagnostic test orders, adverse drug reactions, and medication/IV safety were the most frequent safety incidents. J. Magn. Reson. Imaging 2016;43:998-1007 C1 [Mansouri, Mohammad; Aran, Shima; Harvey, Harlan B.; Shaqdan, Khalid W.; Abujudeh, Hani H.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St,Founders Bldg,Room 210, Boston, MA 02114 USA. RP Abujudeh, HH (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St,Founders Bldg,Room 210, Boston, MA 02114 USA. EM Habujudeh@partners.org RI Mansouri, Mohammad/M-4774-2016 OI Mansouri, Mohammad/0000-0002-7472-1287 NR 37 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-1807 EI 1522-2586 J9 J MAGN RESON IMAGING JI J. Magn. Reson. Imaging PD APR PY 2016 VL 43 IS 4 BP 998 EP 1007 DI 10.1002/jmri.25055 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DH7UY UT WOS:000373000500025 PM 26483127 ER PT J AU Manchikanti, L Atluri, S Kaye, AD Hirsch, JA AF Manchikanti, Laxmaiah Atluri, Sairam Kaye, Alan David Hirsch, Joshua A. TI A report of spinal subdural abscess provides incomplete and inaccurate information SO JOURNAL OF NEUROSURGERY-SPINE LA English DT Letter ID LONG-TERM RELIEF; 2-YEAR FOLLOW-UP; EPIDURAL INJECTIONS; RANDOMIZED-TRIAL; DOUBLE-BLIND; STENOSIS; PAIN C1 [Manchikanti, Laxmaiah] Univ Louisville, Louisville, KY 40292 USA. [Manchikanti, Laxmaiah] Pain Management Ctr Paducah, Murray, KY 42071 USA. [Atluri, Sairam] Tri State Spine Care Inst, Cincinnati, OH USA. [Kaye, Alan David] LSU Sch Med, New Orleans, LA USA. [Hirsch, Joshua A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Manchikanti, L (reprint author), Univ Louisville, Louisville, KY 40292 USA.; Manchikanti, L (reprint author), Pain Management Ctr Paducah, Murray, KY 42071 USA. NR 18 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 1547-5654 EI 1547-5646 J9 J NEUROSURG-SPINE JI J. Neurosurg.-Spine PD APR PY 2016 VL 24 IS 4 BP 675 EP 676 DI 10.3171/2015.7.SPINE15846 PG 2 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA DH3DZ UT WOS:000372669000026 PM 26722958 ER PT J AU Schreibeis-Baum, HC Xenakis, LE Chen, EK Hanson, M Ahluwalia, S Ryan, G Lorenz, KA AF Schreibeis-Baum, Hannah C. Xenakis, Lea E. Chen, Emily K. Hanson, Mark Ahluwalia, Sangeeta Ryan, Gery Lorenz, Karl A. TI A Qualitative Inquiry on Palliative and End-of-Life Care Policy Reform SO JOURNAL OF PALLIATIVE MEDICINE LA English DT Article ID TOBACCO CONTROL; HEALTH; OPPORTUNITIES; SMOKING AB Background: There is increasing recognition of the role of palliative care (PC) in health care delivery, but priorities for state and federal policy to support PC are unclear and have sometimes engendered controversy. We canvassed experts to shed light on general recommendations for improving PC. Objective: The study objective was to identify challenges to and potential solutions for promoting, adopting, and implementing policies that would support or expand high-quality PC. Methods: Semistructured telephone interviews were used to solicit challenges to and potential solutions for promoting, adopting, and implementing policies that would support or expand high-quality PC. Interviews were analyzed using qualitative methods. The subjects were a purposive sample of 22 professional state and federal-level advocates who work in the field of aging and/or PC. Results: Respondents identified four central challenges to advancing PC policies: (1) knowledge about PC in the health care setting, (2) cultural beliefs about PC, (3) payment/reimbursement for PC services, and (4) public understanding of PC. Of the wide range of solutions proposed by respondents, we present the eight most frequently discussed solutions to these challenges targeted towards policymakers, health care professionals, research, and the general public. Respondents' understanding of the relationships between problems and solutions revealed many dependencies and interconnectedness. Conclusions: A qualitative approach of querying experts identified multiple significant challenges to improving and expanding PC, most of which are acknowledged in existing consensus statements. Proposed solutions were more numerous and diffuse than descriptions of the problems, signaling the need for further consensus building around actionable policy, and better understanding of how to advance a PC policy agenda. C1 [Schreibeis-Baum, Hannah C.] VA Greater Angeles, Ctr Healthcare Innovat Implementat & Policy, Hlth Serv Res & Dev, Los Angeles, CA USA. [Xenakis, Lea E.; Chen, Emily K.; Hanson, Mark; Ahluwalia, Sangeeta; Ryan, Gery; Lorenz, Karl A.] RAND Corp, RAND Hlth, Santa Monica, CA USA. [Lorenz, Karl A.] VA Palo Alto, Ctr Innovat Implementat Ci2i, Palo Alto, CA USA. [Lorenz, Karl A.] Stanford Univ, Sch Med, Sect Palliat Med, Stanford, CA 94305 USA. RP Lorenz, KA (reprint author), Stanford Univ, Sch Med, Div Gen Med Disciplines, Sch Med, Off Bldg,1265 Welch Rd,Room X3c46,MC 5411, Stanford, CA 94305 USA. EM kalorenz@stanford.edu FU National Institute of Nursing Research [NINR R01NR013372]; California Healthcare Foundation [CHCF 17173] FX The Trajectories and Palliation Study (TAPS) was funded by a grant from the National Institute of Nursing Research (NINR R01NR013372), and the TAPS Policy Project was funded by the California Healthcare Foundation (CHCF 17173). NR 22 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1096-6218 EI 1557-7740 J9 J PALLIAT MED JI J. Palliat. Med. PD APR 1 PY 2016 VL 19 IS 4 BP 400 EP 407 DI 10.1089/jpm.2015.0296 PG 8 WC Health Care Sciences & Services SC Health Care Sciences & Services GA DI1DZ UT WOS:000373237500013 PM 27035522 ER PT J AU Sadeghi, B Walling, AM Romano, PS Ahluwalia, SC Ong, MK AF Sadeghi, Bahman Walling, Anne M. Romano, Patrick S. Ahluwalia, Sangeeta C. Ong, Michael K. TI A Hospital-Based Advance Care Planning Intervention for Patients with Heart Failure: A Feasibility Study SO JOURNAL OF PALLIATIVE MEDICINE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; LIFE-SUSTAINING TREATMENT; DECISION-MAKING; PREFERENCES; ADULTS AB Background: Early discussions about advance care planning (ACP) have been associated with improved patient and caregiver outcomes for patients with serious illness. Many patients with heart failure (HF) may benefit from more timely ACP, in part due to the unpredictable trajectory of the disease. Objectives: The purpose of this study was to evaluate the feasibility of implementing a multiple-component hospital-based intervention on completion of ACP forms among HF patients. Methods: A brief hospital-based ACP intervention was led by a nonclinician health educator that included (1) an educational video about shared decision making and (2) a protocol to engage HF providers in patients' ACP decision making after the hospitalization. We surveyed patients regarding attitudes toward the ACP intervention and studied completion rates of advance directives (ADs) or physician orders for life sustaining treatment (POLST) forms six months following discharge. Results: The educational video component of this intervention was considered helpful by 92% of participants, and 70% said they were more likely to talk with their physician about their end-of-life preferences after watching the video and interacting with the health educator. Of 37 participants, 49% had evidence of completion of an AD or POLST in their medical records six months after the index hospitalization compared to 32% before the intervention. The number of patients having a signed scanned POLST form increased from 10 (27%) before the intervention to 16 (43%) six months after the intervention (p = 0.03). Conclusions: A hospital-based ACP intervention using nonclinician health educators is feasible to implement and has the potential to facilitate the ACP process. C1 [Sadeghi, Bahman; Walling, Anne M.; Ong, Michael K.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Gen Internal Med & Hlth Serv Res, 10940 Wilshire Blvd, Los Angeles, CA 90024 USA. [Walling, Anne M.; Ong, Michael K.] Vet Affairs Greater Los Angeles Healthcare Syst, Dept Med, Los Angeles, CA USA. [Romano, Patrick S.] Univ Calif Davis, Dept Internal Med, Davis, CA 95616 USA. [Romano, Patrick S.] Univ Calif Davis, Dept Pediat, Davis, CA 95616 USA. [Ahluwalia, Sangeeta C.] RAND Corp, Santa Monica, CA USA. [Ahluwalia, Sangeeta C.] Univ Calif Los Angeles, UCLA Fielding Sch Publ Hlth, Dept Hlth Policy & Management, Los Angeles, CA 90024 USA. RP Ong, MK (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Gen Internal Med & Hlth Serv Res, 10940 Wilshire Blvd, Los Angeles, CA 90024 USA. EM mong@mednet.ucla.edu FU California Healthcare Foundation [15666]; Agency for Healthcare Research and Quality [R01 HS019311]; NIH National Center for Advancing Translational Science UCLA Clinical and Translational Science Institute (CTSI) [UL1TR000124]; NIH Loan Repayment Program; Foundation for Informed Medical Decision Making FX This study was supported by a grant from the California Healthcare Foundation (#15666). The authors would like to acknowledge the work of Kymberly Aoki, Jennifer Matsui, Wern Ong, and Matt Tiacharoen at the UCLA Medical Center and Mauricio Rodriguez and Meghan Soulsby at the UCD Medical Center. We acknowledge the support we received for the patient screening process from the BEAT-HF study funded by a grant from the Agency for Healthcare Research and Quality (#R01 HS019311). Dr. Walling was also supported by the NIH National Center for Advancing Translational Science UCLA Clinical and Translational Science Institute (CTSI) (#UL1TR000124) and the NIH Loan Repayment Program. We appreciate the support from the Foundation for Informed Medical Decision Making with regards to the videos used in this study. NR 15 TC 1 Z9 1 U1 3 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 APR 1 PY 2016 VL 19 IS 4 BP 451 EP 455 DI 10.1089/jpm.2015.0269 PG 5 WC Health Care Sciences & Services SC Health Care Sciences & Services GA DI1DZ UT WOS:000373237500019 PM 26862682 ER PT J AU Bekelman, DB Rabin, BA Nowels, CT Sahay, A Heidenreich, PA Fischer, SM Main, DS AF Bekelman, David B. Rabin, Borsika A. Nowels, Carolyn T. Sahay, Anju Heidenreich, Paul A. Fischer, Stacy M. Main, Deborah S. TI Barriers and Facilitators to Scaling Up Outpatient Palliative Care SO JOURNAL OF PALLIATIVE MEDICINE LA English DT Article ID CHRONIC HEART-FAILURE; RANDOMIZED CONTROLLED-TRIAL; QUALITY-OF-LIFE; IMPLEMENTATION SCIENCE; INTERVENTION; CONSULTATION; PROGRAMS; OUTCOMES; FRAMEWORK; ADOPTION AB Background: The Institute of Medicine recommends people with serious advanced illness have access to skilled palliative care. However, the predominant delivery model of nonhospice palliative care is inpatient, consultative care focused on the end of life, with a small specialist palliative care workforce. Objective: The study objective was to understand organizational factors that could influence the adoption and scale-up of outpatient palliative care in chronic advanced illness, using the example of heart failure. Methods: This was a cross-sectional qualitative study. Participants were 17 health care providers and local, regional, and national health system leaders from the Veterans Health Administration (VHA) who were considering whether and how to adopt and sustain outpatient palliative care. Individual interviews using semistructured questions assessed domains of the Consolidated Framework for Implementation Science. Results: Most providers and leaders perceived outpatient palliative care as high priority in the VHA given its patient-centeredness and potential to decrease health care use and costs associated with conditions like heart failure. They also supported a collaborative care team model of outpatient palliative care delivery where a palliative care specialist collaborates with medical nurses and social workers. They reported lack of performance measures/incentives for patient-centered care processes and outcomes as a potential barrier to implementation. Features of outpatient palliative care viewed as important for successful adoption and scale-up included coordination and communication with other providers, ease of integration into existing programs, and evidence of improving quality of care while not substantially increasing overall health care costs. Conclusion: Incentives such as performance measures and collaboration with local VHA providers and leaders could improve adoption and scale-up of outpatient palliative care. C1 [Bekelman, David B.] Eastern Colorado Hlth Care Syst, Dept Vet Affairs, Denver, CO USA. [Bekelman, David B.; Nowels, Carolyn T.; Fischer, Stacy M.] Univ Colorado, Sch Med, Dept Med, Anschutz Med Campus, Aurora, CO USA. [Rabin, Borsika A.] Univ Colorado, Sch Med, Dept Family Med, Anschutz Med Campus, Aurora, CO USA. [Rabin, Borsika A.] Univ Colorado, Sch Med, Colorado Hlth Outcomes Program, Anschutz Med Campus, Aurora, CO USA. [Sahay, Anju; Heidenreich, Paul A.] VA Palo Alto Hlth Care Syst, Palo Alto, CA USA. [Main, Deborah S.] Univ Colorado, Dept Hlth & Behav Sci, Denver, CO 80202 USA. RP Bekelman, DB (reprint author), Denver VA Med Ctr, 1055 Clermont St,Res 151, Denver, CO 80220 USA. EM david.bekelman@va.gov FU VA HSR&D Quality Enhancement Research Initiative (QUERI) Rapid Response Project [11-239] FX This study was funded by VA HSR&D Quality Enhancement Research Initiative (QUERI) Rapid Response Project #11-239. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States government. NR 28 TC 1 Z9 1 U1 5 U2 9 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 APR 1 PY 2016 VL 19 IS 4 BP 456 EP 459 DI 10.1089/jpm.2015.0280 PG 4 WC Health Care Sciences & Services SC Health Care Sciences & Services GA DI1DZ UT WOS:000373237500020 PM 26974489 ER PT J AU Yoshida, N Miyoshi, H Kato, T Sakata-Yanagimoto, M Niino, D Taniguchi, H Moriuchi, Y Miyahara, M Kurita, D Sasaki, Y Shimono, J Kawamoto, K Utsunomiya, A Imaizumi, Y Seto, M Ohshima, K AF Yoshida, Noriaki Miyoshi, Hiroaki Kato, Takeharu Sakata-Yanagimoto, Mamiko Niino, Daisuke Taniguchi, Hiroaki Moriuchi, Yukiyoshi Miyahara, Masaharu Kurita, Daisuke Sasaki, Yuya Shimono, Joji Kawamoto, Keisuke Utsunomiya, Atae Imaizumi, Yoshitaka Seto, Masao Ohshima, Koichi TI CCR4 frameshift mutation identifies a distinct group of adult T cell leukaemia/lymphoma with poor prognosis SO JOURNAL OF PATHOLOGY LA English DT Article DE adult T cell leukaemia/lymphoma; CCR4 mutation; clinicopathological analyses; prognostic impact; tissue array ID WALDENSTROM MACROGLOBULINEMIA; LEUKEMIA/LYMPHOMA; LYMPHOMA; EXPRESSION; SURVIVAL; LEUKEMIA; CXCR4 AB Adult T cell leukaemia/lymphoma (ATLL) is an intractable T cell neoplasm caused by human T cell leukaemia virus type 1. Next-generation sequencing-based comprehensive mutation studies have revealed recurrent somatic CCR4 mutations in ATLL, although clinicopathological findings associated with CCR4 mutations remain to be delineated. In the current study, 184 cases of peripheral T cell lymphoma, including 113 cases of ATLL, were subjected to CCR4 mutation analysis. This sequence analysis identified mutations in 27% (30/113) of cases of ATLL and 9% (4/44) of cases of peripheral T cell lymphoma not otherwise specified. Identified mutations included nonsense (NS) and frameshift (FS) mutations. No significant differences in clinicopathological findings were observed between ATLL cases stratified by presence of CCR4 mutation. All ATLL cases with CCR4 mutations exhibited cell-surface CCR4 positivity. Semi-quantitative CCR4 protein analysis of immunohistochemical sections revealed higher CCR4 expression in cases with NS mutations of CCR4 than in cases with wild-type (WT) CCR4. Furthermore, among ATLL cases, FS mutation was significantly associated with a poor prognosis, compared with NS mutation and WTCCR4. These results suggest that CCR4 mutation is an important determinant of the clinical course in ATLL cases, and that NS and FS mutations of CCR4 behave differently with respect to ATLL pathophysiology. Copyright (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. C1 [Yoshida, Noriaki; Miyoshi, Hiroaki; Kato, Takeharu; Niino, Daisuke; Kurita, Daisuke; Sasaki, Yuya; Shimono, Joji; Kawamoto, Keisuke; Seto, Masao; Ohshima, Koichi] Kururne Univ, Dept Pathol, Sch Med, 67 Asahi Machi, Kurume, Fukuoka 8300011, Japan. [Kato, Takeharu; Imaizumi, Yoshitaka] Nagasaki Univ, Atom Bomb Dis Inst, Dept Haematol, Atom Bomb Dis & Hibakusha Med Unit, Nagasaki, Japan. [Sakata-Yanagimoto, Mamiko] Univ Tsukuba, Fac Med, Dept Haematol, Tsukuba, Ibaraki 305, Japan. [Taniguchi, Hiroaki; Moriuchi, Yukiyoshi] Sasebo City Gen Hosp, Dept Haematol, Sasebo, Japan. [Miyahara, Masaharu] Karatsu Red Cross Hosp, Dept Internal Med, Fukushima, Japan. [Utsunomiya, Atae] Imamura Bun In Hosp, Dept Haematol, Kagoshima, Japan. [Yoshida, Noriaki] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. [Niino, Daisuke] Nagasaki Univ, Grad Sch Biomed Sci, Dept Pathol, Nagasaki 852, Japan. RP Ohshima, K (reprint author), Kururne Univ, Dept Pathol, Sch Med, 67 Asahi Machi, Kurume, Fukuoka 8300011, Japan. EM ohshima_kouichi@med.kurume-u.ac.jp OI Yoshida, Noriaki/0000-0001-7001-0106 NR 20 TC 2 Z9 2 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3417 EI 1096-9896 J9 J PATHOL JI J. Pathol. PD APR PY 2016 VL 238 IS 5 BP 621 EP 626 DI 10.1002/path.4699 PG 6 WC Oncology; Pathology SC Oncology; Pathology GA DH7QE UT WOS:000372988100004 PM 26847489 ER PT J AU Scharf, JM AF Scharf, Jeremiah M. TI Parity in Tourette Syndrome: Reproducible Risk Factors for an Underrecognized Neurodevelopmental Disorder SO JOURNAL OF PEDIATRICS LA English DT Editorial Material ID AUTISM SPECTRUM DISORDER; POPULATION-BASED COHORT; TIC DISORDERS; PREVALENCE; AGE; METAANALYSIS C1 [Scharf, Jeremiah M.] Brigham & Womens Hosp, Psychiat & Neurodev Genet Unit, Ctr Human Genet Res,Div Cognit & Behav Neurol, Div Movement Disorders,Dept Neurol,Massachusetts, 75 Francis St, Boston, MA 02115 USA. [Scharf, Jeremiah M.] Brigham & Womens Hosp, Psychiat & Neurodev Genet Unit, Ctr Human Genet Res,Div Cognit & Behav Neurol,Dep, Div Movement Disorders,Dept Neurol,Massachusetts, 75 Francis St, Boston, MA 02115 USA. RP Scharf, JM (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat Neurodev Genet Unit, 185 Cambridge St,6th Floor, Boston, MA 02114 USA. EM jscharf@partners.org FU NIMH NIH HHS [R01 MH096767]; NINDS NIH HHS [K02 NS085048] NR 22 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 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD APR PY 2016 VL 171 BP 17 EP 19 DI 10.1016/j.jpeds.2015.12.048 PG 4 WC Pediatrics SC Pediatrics GA DH4KC UT WOS:000372753600008 PM 26778098 ER PT J AU Wu, XM Hu, XQ Hamblin, MR AF Wu, Ximing Hu, Xiaoqing Hamblin, Michael R. TI Ultraviolet blood irradiation: Is it time to remember "the cure that time forgot"? SO JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY LA English DT Review DE Ultraviolet irradiation of blood; Systemic infections; DNA repair; Blood cells; Phagocytes; Lymphocytes; Extracorporeal photopheresis; Bone marrow; Cytokines ID T-CELL LYMPHOMA; ANTIGEN-PRESENTING CELLS; UV-C IRRADIATION; EXTRACORPOREAL PHOTOCHEMOTHERAPY; DRUG DEVELOPMENT; CONTROLLED TRIAL; B IRRADIATION; DNA-REPAIR; IN-VITRO; LYMPHOCYTES AB Ultraviolet blood irradiation (UBI) was extensively used in the 1940s and 1950s to treat many diseases including septicemia, pneumonia, tuberculosis, arthritis, asthma, and even poliomyelitis. The early studies were carried out by several physicians in USA and published in the American Journal of Surgery. However, with the development of antibiotics, the use of UBI declined and it has now been called "the cure that time forgot." Later studies were mostly performed by Russian workers, and in other Eastern countries, and the modern view in Western countries is that UBI remains highly controversial. This review discusses the potential of UBI as an alternative approach to current methods used to treat infections, as an immune-modulating therapy and as a method for normalizing blood parameters. Low and mild doses of UV kill microorganisms by damaging the DNA, while any DNA damage in host cells can be rapidly repaired by DNA repair enzymes. However, the use of UBI to treat septicemia cannot be solely due to UV-mediated killing of bacteria in the bloodstream, as only 5-7% of blood volume needs to be treated with UV to produce the optimum benefit, and higher doses can be damaging. There may be some similarities to extracorporeal photopheresis (ECP) using psoralens and UVA irradiation. However, there are differences between UBI and ECP in that UBI tends to stimulate the immune system, while ECP tends to be immunosuppressive. With the recent emergence of bacteria that are resistant to all known antibiotics, UBI should be more investigated as an alternative approach to infections, and as an immune-modulating therapy. (C) 2016 Elsevier B.V. All rights reserved. C1 [Wu, Ximing] Guangxi Med Univ, Dept Emergency, Affiliated Coll & Hosp 1, Nanning 530021, Peoples R China. [Wu, Ximing; Hu, Xiaoqing; Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Wu, Ximing; Hu, Xiaoqing; Hamblin, Michael R.] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Hu, Xiaoqing] Jiangnan Univ, State Key Lab Food Sci & Technol, Wuxi 214122, Peoples R China. [Hamblin, Michael R.] Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Hamblin, MR (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. EM Hamblin@helix.mgh.harvard.edu FU US NIH [R01AI050875] FX Research in the Hamblin laboratory is supported by US NIH grant R01AI050875. NR 92 TC 0 Z9 0 U1 3 U2 8 PU ELSEVIER SCIENCE SA PI LAUSANNE PA PO BOX 564, 1001 LAUSANNE, SWITZERLAND SN 1011-1344 J9 J PHOTOCH PHOTOBIO B JI J. Photochem. Photobiol. B-Biol. PD APR PY 2016 VL 157 BP 89 EP 96 DI 10.1016/j.jphotobiol.2016.02.007 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA DH3KV UT WOS:000372686800009 PM 26894849 ER PT J AU Sapkota, BR Hopkins, R Bjonnes, A Ralhan, S Wander, GS Mehra, NK Singh, JR Blackett, PR Saxena, R Sanghera, DK AF Sapkota, Bishwa R. Hopkins, Ruth Bjonnes, Andrew Ralhan, Sarju Wander, Gurpreet S. Mehra, Narinder K. Singh, Jai Rup Blackett, Piers R. Saxena, Richa Sanghera, Dharambir K. TI Genome-wide association study of 25(OH) Vitamin D concentrations in Punjabi Sikhs: Results of the Asian Indian diabetic heart study SO JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article DE Vitamin D deficiency; 25(OH)D levels (ELISA); Type 2 diabetes; Genome-wide association study; Punjabi Sikhs ID PARATHYROID-HORMONE; ENERGY-METABOLISM; GENE; POLYMORPHISMS; METAANALYSIS; OSTEOBLASTS; VARIANTS; RISK; EXPRESSION; CAUCASIANS AB Vitamin D deficiency is implicated in multiple disease conditions and accumulating evidence supports that the variation in serum vitamin D (25(OH)D) levels, including deficiency, is under strong genetic control. However, the underlying genetic mechanism associated with vitamin 25(OH)D concentrations is poorly understood. We earlier reported a very high prevalence of vitamin D deficiency associated with an increased risk for type 2 diabetes and obesity in a Punjabi Sikh diabetic cohort as part of the Asian Indian diabetic heart study (AIDHS). Here we have performed the first genome-wide association study (GWAS) of serum 25(OH)D on 3538 individuals from this Punjabi Sikh population. Our discovery GWAS comprised of 1387 subjects followed by validation of 24 putative SNPs (P < 10(-4)) using an independent replication sample (n = 2151) from the same population by direct genotyping. A novel locus at chromosome 20p11.21 represented by rs2207173 with minor allele frequency (MAF) 0.29, [beta = -0.13, p = 4.47 x 10(-9)] between FOXA2 and SSTR4 was identified to be associated with 25(OH)D levels. Another suggestive association signal at rs11586313 (MAF 0.54) [beta = 0.90; p = 1.36 x 10(-6)] was found within the regulatory region of the IVL gene on chromosome 1q21.3. Additionally, our study replicated 3 of 5 known GWAS genes associated with 25(OH)D concentrations including GC (p = 0.007) and CYP2R1 (p = 0.019) reported in Europeans and the DAB1 (p = 0.003), reported in Hispanics. Identification of novel association signals in biologically plausible regions with 25(OH)D metabolism will provide new molecular insights on genetic drivers of vitamin D status and its implications in health disparities. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Sapkota, Bishwa R.; Hopkins, Ruth; Sanghera, Dharambir K.] Univ Oklahoma, Hlth Sci Ctr, Coll Med, Dept Pediat,Sect Genet, Oklahoma City, OK 73104 USA. [Blackett, Piers R.] Univ Oklahoma, Hlth Sci Ctr, Coll Med, Dept Pediat,Sect Endocrinol, Oklahoma City, OK 73104 USA. [Sanghera, Dharambir K.] Univ Oklahoma, Hlth Sci Ctr, Coll Pharm, Dept Pharmaceut Sci, Oklahoma City, OK 73104 USA. [Sanghera, Dharambir K.] Univ Oklahoma, Hlth Sci Ctr, Oklahoma Ctr Neurosci, Oklahoma City, OK 73104 USA. [Ralhan, Sarju; Wander, Gurpreet S.] Hero DMC Heart Inst, Ludhiana, Punjab, India. [Mehra, Narinder K.] All India Inst Med Sci & Res, New Delhi, India. [Singh, Jai Rup] Cent Univ Punjab, Bathinda, Punjab, India. [Bjonnes, Andrew; Saxena, Richa] Broad Inst Massachusetts Inst Technol & Harvard, Massachusetts Gen Hosp, Cambridge, MA USA. RP Sanghera, DK (reprint author), Univ Oklahoma, Hlth Sci Ctr, Coll Med, Dept Pediat, 940 Stanton L Young Blvd,Rm 317 BMSB, Oklahoma City, OK 73104 USA. EM Dharambir-sanghera@ouhsc.edu FU NIH - National Institute of Health (NIDDK) [-R01DK082766]; NHGRI [NOT-HG-11-009]; VPR Bridge Grant from University of Oklahoma Health Sciences Center FX This work was supported by NIH grants -R01DK082766 funded by the National Institute of Health (NIDDK) and NOT-HG-11-009 funded by NHGRI, and a VPR Bridge Grant from University of Oklahoma Health Sciences Center. Technical support provided by Timothy Braun and Praveen Natt is duly acknowledged. Authors thank all the participants of AIDHS/SDS and PhenX RISING consortium (NHGRI), and are grateful for their contribution in this study. NR 44 TC 0 Z9 0 U1 4 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-0760 J9 J STEROID BIOCHEM JI J. Steroid Biochem. Mol. Biol. PD APR PY 2016 VL 158 BP 149 EP 156 DI 10.1016/j.jsbmb.2015.12.014 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA DH3MD UT WOS:000372690200016 PM 26704534 ER PT J AU Kougias, P Tiwari, V Berger, DH AF Kougias, Panos Tiwari, Vikram Berger, David H. TI Use of simulation to assess a statistically driven surgical scheduling system SO JOURNAL OF SURGICAL RESEARCH LA English DT Article DE Simulation; Statistical modeling; Effectiveness ID OPERATING-ROOM EFFICIENCY; TIMES; EXPENDITURES; VARIABILITY; PREDICTION; SURGERY; THEATER; LENGTH; MODEL AB Background: To maximize operating room (OR) utilization, better estimates of case duration lengths are needed. We used computerized simulation to determine whether scheduling OR cases using a statistically driven system that incorporates patient and surgery-specific factors in the process of case duration prediction improves OR throughput and utilization. Methods: We modeled surgical and anesthetic length of vascular surgical procedures as a function of patient and operative characteristics using a multivariate linear regression approach (Predictive Modeling System [PMS]). Mean historical operative time per surgeon (HMS) and mean anesthetic time were also calculated for each procedure type. A computerized simulation of scheduling in a single OR performing vascular operations was then created using either the PMS or the HMS. Results: Compared to HMS, scheduling the operating room using the PMS increased throughput by a minimum of 15% (99.8% cumulative probability, P < 0.001). The PMS was slightly more likely to lead to overtime (mean 13% versus 11% of operative days during a calendar year, P < 0.001). However, the overtime lasted longer in the HMS group (mean 140 versus 95 min per day of overtime, P < 0.001). PMS was associated with lower OR underutilization rate (mean 23% versus 34% of operative days, P < 0.001) and less lengthy OR underutilization (mean 120 versus 193 min per day of underutilization, P < 0.001). Conclusions: This computerized simulation demonstrates that using the PMS for scheduling in a single operating room increases throughput and other measures of surgical efficiency. Published by Elsevier Inc. C1 [Kougias, Panos; Berger, David H.] Michael E DeBakey VA Med Ctr, Houston, TX USA. [Kougias, Panos] Baylor Coll Med, Div Vasc Surg, Houston, TX 77030 USA. [Kougias, Panos; Berger, David H.] Ctr Innovat Qual Effectiveness & Safety, Houston, TX USA. [Tiwari, Vikram] Vanderbilt Univ, Dept Anesthesiol, 221 Kirkland Hall, Nashville, TN 37235 USA. [Berger, David H.] Baylor Coll Med, Dept Surg, Houston, TX 77030 USA. RP Kougias, P (reprint author), Houston VAMC, Michael E DeBakey Dept Surg, 2002 Holcombe Blvd OCL 112, Houston, TX 77030 USA. EM pkougias@bcm.edu NR 17 TC 2 Z9 2 U1 4 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0022-4804 EI 1095-8673 J9 J SURG RES JI J. Surg. Res. PD APR PY 2016 VL 201 IS 2 BP 306 EP 312 DI 10.1016/j.jss.2015.10.043 PG 7 WC Surgery SC Surgery GA DH8VS UT WOS:000373075600010 PM 27020812 ER PT J AU Urban, LE Weber, JL Heyman, MB Schichtl, RL Verstraete, S Lowery, NS Das, SK Schleicher, MM Rogers, G Economos, C Masters, WA Roberts, SB AF Urban, Lorien E. Weber, Judith L. Heyman, Melvin B. Schichtl, Rachel L. Verstraete, Sofia Lowery, Nina S. Das, Sai Krupa Schleicher, Molly M. Rogers, Gail Economos, Christina Masters, William A. Roberts, Susan B. TI Energy Contents of Frequently Ordered Restaurant Meals and Comparison with Human Energy Requirements and US Department of Agriculture Database Information: A Multisite Randomized Study SO JOURNAL OF THE ACADEMY OF NUTRITION AND DIETETICS LA English DT Article DE Dietary energy; Restaurants; Obesity; Fast food; Weight gain ID FAST-FOOD RESTAURANTS; UNITED-STATES; PORTION SIZES; TEMPORAL TRENDS; DIETARY-INTAKE; OBESITY; MENU; CONSUMPTION; SODIUM; ADULTS AB Background Excess energy intake from meals consumed away from home is implicated as a major contributor to obesity, and similar to 50% of US restaurants are individual or small-chain (non-chain) establishments that do not provide nutrition information. Objective To measure the energy content of frequently ordered meals in non-chain restaurants in three US locations, and compare with the energy content of meals from large-chain restaurants, energy requirements, and food database information. Design A multisite random-sampling protocol was used to measure the energy contents of the most frequently ordered meals from the most popular cuisines in non-chain restaurants, together with equivalent meals from large-chain restaurants. Setting Meals were obtained from restaurants in San Francisco, CA; Boston, MA; and Little Rock, AR, between 2011 and 2014. Main outcome measures Meal energy content determined by bomb calorimetry. Statistical analysis performed Regional and cuisine differences were assessed using a mixed model with restaurant nested within region x cuisine as the random factor. Paired t tests were used to evaluate differences between non-chain and chain meals, human energy requirements, and food database values. Results Meals from non-chain restaurants contained 1,205 +/- 465 kcal/meal, amounts that were not significantly different from equivalent meals from large-chain restaurants (+5.1%; P=0.41). There was a significant effect of cuisine on non-chain meal energy, and three of the four most popular cuisines (American, Italian, and Chinese) had the highest mean energy (1,495 kcal/meal). Ninety-two percent of meals exceeded typical energy requirements for a single eating occasion. Conclusions Non-chain restaurants lacking nutrition information serve amounts of energy that are typically far in excess of human energy requirements for single eating occasions, and are equivalent to amounts served by the large-chain restaurants that have previously been criticized for providing excess energy. Restaurants in general, rather than specific categories of restaurant, expose patrons to excessive portions that induce overeating through established biological mechanisms. C1 [Urban, Lorien E.] Gelesis Inc, Boston, MA USA. [Urban, Lorien E.; Lowery, Nina S.; Das, Sai Krupa; Schleicher, Molly M.; Roberts, Susan B.] Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Energy Metab Lab, 711 Washington St, Boston, MA 02111 USA. [Weber, Judith L.] Univ Arkansas Med Sci, Coll Med, Dept Pediat, Pediat, Little Rock, AR 72205 USA. [Schichtl, Rachel L.] Univ Arkansas Med Sci, Coll Med, Dept Pediat, Little Rock, AR 72205 USA. [Heyman, Melvin B.] Univ Calif San Francisco, Dept Pediat, Pediat Clin, San Francisco, CA USA. [Verstraete, Sofia] Univ Calif San Francisco, Dept Pediat, San Francisco, CA USA. [Lowery, Nina S.] Massachusetts Gen Hosp, Phys Assistant Program, Boston, MA 02114 USA. [Rogers, Gail] Tufts Univ, Jean Mayer US Dept Agr Human Nutr Res Ctr Aging, Nutr Epidemiol Program, Boston, MA 02111 USA. [Economos, Christina; Masters, William A.] Tufts Univ, Friedman Sch Nutr Sci & Policy, Boston, MA 02111 USA. [Schleicher, Molly M.] Broad Inst, Off Res Subject Protect, Cambridge, MA USA. RP Roberts, SB (reprint author), Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Energy Metab Lab, 711 Washington St, Boston, MA 02111 USA. EM susan.roberts@tufts.edu RI Masters, William/A-4796-2017 OI Masters, William/0000-0002-4546-7291 FU USDA [58-1950-0-0014, 1950-51000-072-02S]; Tufts University; Arkansas Children's Hospital Research Institute; National Institutes of Health [DK00776] FX Supported by the USDA under agreement nos. 58-1950-0-0014 and 1950-51000-072-02S with Tufts University. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the views of the USDA. This research was supported, in part, with funding from the Arkansas Children's Hospital Research Institute and in part by National Institutes of Health grant no. DK00776. NR 46 TC 0 Z9 0 U1 4 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2212-2672 EI 2212-2680 J9 J ACAD NUTR DIET JI J. Acad. Nutr. Diet. PD APR PY 2016 VL 116 IS 4 BP 590 EP + DI 10.1016/j.jand.2015.11.009 PG 15 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DH4KJ UT WOS:000372754500006 PM 26803805 ER PT J AU Friedlander, AH Chang, TI Aghazadehsanai, N Graves, LL AF Friedlander, Arthur H. Chang, Tina I. Aghazadehsanai, Nona Graves, Lindsay L. TI COST-EFFECTIVENESS OF ANTIBIOTIC PROPHYLAXIS SO JOURNAL OF THE AMERICAN DENTAL ASSOCIATION LA English DT Letter C1 [Friedlander, Arthur H.] Vet Affairs Greater Los Angeles Healthcare Syst, Grad Med Educ, Los Angeles, CA USA. [Friedlander, Arthur H.] Ronald Reagan UCLA Med Ctr, Hosp Dent Serv, Qual Assurance, Los Angeles, CA USA. [Friedlander, Arthur H.; Chang, Tina I.] Univ Calif Los Angeles, Sch Dent, Dept Oral & Maxillofacial Surg, Los Angeles, CA 90024 USA. [Chang, Tina I.] Vet Affairs Greater Los Angeles Healthcare Syst, Inpatient Oral & Maxillofacial Surg, Los Angeles, CA USA. [Aghazadehsanai, Nona; Graves, Lindsay L.] Vet Affairs Greater Los Angeles Healthcare Syst, Oral & Maxillofacial Surg Sect, Dent Serv, Los Angeles, CA USA. RP Friedlander, AH (reprint author), Vet Affairs Greater Los Angeles Healthcare Syst, Grad Med Educ, Los Angeles, CA USA.; Friedlander, AH (reprint author), Ronald Reagan UCLA Med Ctr, Hosp Dent Serv, Qual Assurance, Los Angeles, CA USA.; Friedlander, AH (reprint author), Univ Calif Los Angeles, Sch Dent, Dept Oral & Maxillofacial Surg, Los Angeles, CA 90024 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER DENTAL ASSOC PI CHICAGO PA 211 E CHICAGO AVE, CHICAGO, IL 60611 USA SN 0002-8177 EI 1943-4723 J9 J AM DENT ASSOC JI J. Am. Dent. Assoc. PD APR PY 2016 VL 147 IS 4 BP 229 EP 230 DI 10.1016/j.adaj.2016.02.004 PG 3 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA DH9LD UT WOS:000373116700003 PM 27017589 ER PT J AU Wrocklage, KM Schweinsburg, BC Krystal, JH Trejo, M Roy, A Weisser, V Moore, TM Southwick, SM Scott, JC AF Wrocklage, Kristen M. Schweinsburg, Brian C. Krystal, John H. Trejo, Marcia Roy, Alicia Weisser, Valerie Moore, Tyler M. Southwick, Steven M. Scott, J. Cobb TI Neuropsychological Functioning in Veterans with Posttraumatic Stress Disorder: Associations with Performance Validity, Comorbidities, and Functional Outcomes SO JOURNAL OF THE INTERNATIONAL NEUROPSYCHOLOGICAL SOCIETY LA English DT Article DE Posttraumatic stress disorder; Neuropsychology; Cognitive abilities; Memory; Executive functions; Quality of life; Occupational functioning ID TRAUMATIC BRAIN-INJURY; TERM BENZODIAZEPINE USE; MEMORY PERFORMANCE; COMBAT EXPOSURE; VERBAL MEMORY; ARMY SOLDIERS; WAR VETERANS; FOLLOW-UP; PTSD; HEALTH AB Objectives: Numerous studies have shown that individuals with posttraumatic stress disorder (PTSD) display reduced performances on neuropsychological tests, although most prior research has not adequately accounted for comorbidities or performance validity concerns that are common in this population and could partially account for the observed neurocognitive findings. Moreover, few studies have examined the functional implications of neuropsychological results in PTSD. Methods: We examined neuropsychological functioning in 44 veterans with PTSD and 40 veteran trauma comparison (TC) participants with combat exposure and no PTSD. Results: After excluding four veterans with PTSD for performance validity concerns, multivariate analyses of variance by neurocognitive domain revealed significantly worse performance by the PTSD group in the domains of speed of information processing (p = .035) and executive functions (p = .017), but no group differences in attention/working memory, verbal/language functioning, visuoconstruction, or episodic memory. Group differences by PTSD status were still present after covarying for depression, a history of head injuries, and substance use disorders. Executive functioning performance was associated with poorer self-reported occupational functioning and physical health-related quality of life, while speed of information processing performance was associated with poorer physical health-related quality of life. Discussion: These results are generally consistent with a fronto-limbic conceptualization of PTSD-associated neuropsychological dysfunction and show that cognitive functioning may be associated with critical functional outcomes. Taken together, results suggest that consideration of neurocognitive functioning may enhance the clinical management of individuals with PTSD. C1 [Wrocklage, Kristen M.; Schweinsburg, Brian C.; Krystal, John H.; Trejo, Marcia; Roy, Alicia; Weisser, Valerie; Southwick, Steven M.] Natl Ctr PTSD, Clin Neurosci Div, West Haven, CT USA. [Wrocklage, Kristen M.; Schweinsburg, Brian C.; Krystal, John H.; Trejo, Marcia; Roy, Alicia; Weisser, Valerie; Southwick, Steven M.] VA Connecticut Healthcare Syst, West Haven, CT USA. [Schweinsburg, Brian C.; Krystal, John H.; Roy, Alicia; Southwick, Steven M.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Krystal, John H.] Yale Univ, Sch Med, Dept Neurobiol, New Haven, CT USA. [Krystal, John H.] Yale New Haven Med Ctr, Psychiat Serv, 20 York St, New Haven, CT 06504 USA. [Moore, Tyler M.; Scott, J. Cobb] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Scott, J. Cobb] Philadelphia VA Med Ctr, Mental Illness Res Educ & Clin Ctr VISN4, Philadelphia, PA 19104 USA. RP Scott, JC (reprint author), Philadelphia VA Med Ctr, MIRECC 116, 3900 Woodland Ave, Philadelphia, PA 19104 USA. EM scott1@upenn.edu FU Department of Veterans Affairs Career Development Award [IK2CX000772]; National Center for PTSD (NCPTSD); National Center for Advancing Translational Science [1UH2TR000960-01]; Department of Veterans Affairs (NCPTSD); National Institute on Alcohol Abuse and Alcoholism [P50AA12870, M01RR00125]; Yale Center for Clinical Investigation [UL1 RR024139] FX This work was supported by a Department of Veterans Affairs Career Development Award (IK2CX000772) to Dr. Scott, as well as the National Center for PTSD (NCPTSD). Dr. Krystal's participation was supported by the National Center for Advancing Translational Science (1UH2TR000960-01), the Department of Veterans Affairs (NCPTSD), the National Institute on Alcohol Abuse and Alcoholism (P50AA12870, M01RR00125), and the Yale Center for Clinical Investigation (UL1 RR024139). Portions of this research were presented at the 2014 Annual Meeting of the American Psychological Association (APA). 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. The authors declare no conflicts of interest. NR 92 TC 5 Z9 5 U1 6 U2 12 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1355-6177 EI 1469-7661 J9 J INT NEUROPSYCH SOC JI J. Int. Neuropsychol. Soc. PD APR PY 2016 VL 22 IS 4 BP 399 EP 411 DI 10.1017/S1355617716000059 PG 13 WC Clinical Neurology; Neurosciences; Psychiatry; Psychology SC Neurosciences & Neurology; Psychiatry; Psychology GA DI1ZK UT WOS:000373295300003 PM 26892753 ER PT J AU Streiff, MB Agnelli, G Connors, JM Crowther, M Eichinger, S Lopes, RD McBane, RD Moll, S Ansell, J AF Streiff, Michael B. Agnelli, Giancarlo Connors, Jean M. Crowther, Mark Eichinger, Sabine Lopes, Renato D. McBane, Robert D. Moll, Stephan Ansell, Jack TI Guidance for the treatment of deep vein thrombosis and pulmonary embolism (vol 41, pg 32, 2016) SO JOURNAL OF THROMBOSIS AND THROMBOLYSIS LA English DT Correction C1 [Streiff, Michael B.] Johns Hopkins Univ, Sch Med, Dept Pathol & Med, Div Hematol, Baltimore, MD USA. [Agnelli, Giancarlo] Univ Perugia, Dept Internal Med, Stroke Unit, I-06100 Perugia, Italy. [Connors, Jean M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Hematol Div,Brigham & Womens Hosp, 44 Binney St, Boston, MA 02115 USA. [Crowther, Mark] McMaster Univ, Dept Med, Hamilton, ON, Canada. [Crowther, Mark] McMaster Univ, Dept Pathol, Hamilton, ON, Canada. [Crowther, Mark] McMaster Univ, Dept Mol Med, Hamilton, ON, Canada. [Eichinger, Sabine] Med Univ Vienna, Dept Med, Vienna, Austria. [Lopes, Renato D.] Duke Univ, Med Ctr, Dept Med, Div Cardiol, Durham, NC 27710 USA. [McBane, Robert D.] Mayo Clin, Dept Med, Cardiovasc Div, Rochester, MN USA. [Moll, Stephan] Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC USA. [Ansell, Jack] Hofstra North Shore LIJ Sch Med, Dept Med, Hempstead, NY USA. RP Streiff, MB (reprint author), Johns Hopkins Univ, Sch Med, Dept Pathol & Med, Div Hematol, Baltimore, MD USA. EM mstreif@jhmi.edu NR 1 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0929-5305 EI 1573-742X J9 J THROMB THROMBOLYS JI J. Thromb. Thrombolysis PD APR PY 2016 VL 41 IS 3 BP 548 EP 548 DI 10.1007/s11239-016-1345-4 PG 1 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA DH8CF UT WOS:000373020400026 PM 26945859 ER PT J AU Sammon, JD Dalela, D Abdollah, F Choueiri, TK Han, PK Hansen, M Nguyen, PL Sood, A Menon, M Trinh, QD AF Sammon, Jesse D. Dalela, Deepansh Abdollah, Firas Choueiri, Toni K. Han, Paul K. Hansen, Moritz Nguyen, Paul L. Sood, Akshay Menon, Mani Trinh, Quoc-Dien TI Determinants of Prostate Specific Antigen Screening among Black Men in the United States in the Contemporary Era SO JOURNAL OF UROLOGY LA English DT Article DE prostate; prostate specific antigen; mass screening; African American; education ID AFRICAN-AMERICAN MEN; DECISION-MAKING; FOLLOW-UP; US MEN; CANCER; TRENDS; MORTALITY; RISK AB Purpose: Although black men represent a high risk population for prostate specific antigen screening for prostate cancer, recommendations in black men are unclear. To our knowledge the resultant effect of conflicting recommendations and disparities in access to care on prostate specific antigen screening in black men is unknown. Materials and Methods: We compared the rate of self-reported prostate specific antigen screening in black men relative to that in nonHispanic white men. The BRFSS (Behavioral Risk Factor Surveillance System) 2012 data set was used to identify asymptomatic men 40 to 99 years old who reported undergoing prostate specific antigen screening in the last 12 months. Age, education, income, residence location, marital status, health insurance, regular access to a health care provider and a health care provider recommendation to undergo screening were extracted. Subgroup analyses by race and age were performed using complex samples logistic regression models to assess the odds of undergoing prostate specific antigen screening. Results: In 2012 there were 122,309 survey respondents (weighted estimate 54.5 million) in the study population, of whom 29% of black and 32% of nonHispanic white men reported undergoing prostate specific antigen screening. Younger black males had higher rates and odds of screening than nonHispanic white men of a similar age (ages 45 to 49, 50 to 54 and 55 to 59 years OR 1.66, 1.58 and 1.36, respectively). Among black men only a higher education level (graduates vs nongraduates OR 2.12), regular access to a health care provider (OR 2.05) and a health care provider recommendation for screening (OR 8.43) were independently associated with prostate specific antigen screening. Conclusions: Despite long-standing disparities in health care access black males 45 to 60 years old have a higher rate and probability of prostate specific antigen screening than nonHispanic white men. Among black men educational attainment had a more pronounced association. In contrast the association with health care provider recommendations was less pronounced relative to that in nonHispanic white men. Future research may shed more light on the gamut of factors that influence the decision making process for prostate specific antigen testing. C1 [Sammon, Jesse D.; Trinh, Quoc-Dien] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Surg & Publ Hlth, Boston, MA 02115 USA. [Sammon, Jesse D.; Han, Paul K.; Hansen, Moritz] Tufts Univ, Sch Med, Medford, MA USA. [Choueiri, Toni K.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. [Nguyen, Paul L.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, 44 Binney St, Boston, MA 02115 USA. [Sammon, Jesse D.; Han, Paul K.; Hansen, Moritz] Maine Med Ctr, Res Inst, Portland, ME 04102 USA. [Sammon, Jesse D.; Dalela, Deepansh; Abdollah, Firas; Sood, Akshay; Menon, Mani; Trinh, Quoc-Dien] Henry Ford Hlth Syst, Vattikuti Urol Inst, Ctr Outcomes Res Analyt & Evaluat, Detroit, MI USA. RP Sammon, JD (reprint author), Brigham & Womens Hosp, Ctr Surg & Publ Hlth, 45 Francis St,ASB 2-3, Boston, MA 02115 USA. EM jsammon79@gmail.com OI Han, Paul/0000-0003-0165-1940 FU Vattikuti Urology Institute FX Supported by the Professor Walter MorrisHale Distinguished Chair in Urologic Oncology at Brigham and Women's Hospital and an unrestricted educational grant from the Vattikuti Urology Institute (QDT). NR 29 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 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD APR PY 2016 VL 195 IS 4 BP 913 EP 918 DI 10.1016/j.juro.2015.11.023 PN 1 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA DI3LW UT WOS:000373401200030 PM 26598427 ER PT J AU Sorensen, MD AF Sorensen, Mathew D. TI A Prospective Randomized Controlled Trial of the Efficacy of External Physical Vibration Lithecbole after Extracorporeal Shock Wave Lithotripsy for a Lower Pole Renal Stone Less Than 2 cm EDITORIAL COMMENT SO JOURNAL OF UROLOGY LA English DT Editorial Material C1 [Sorensen, Mathew D.] Univ Washington, Dept Urol, VA Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. RP Sorensen, MD (reprint author), Univ Washington, Dept Urol, VA Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD APR PY 2016 VL 195 IS 4 BP 970 EP 970 PN 1 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA DI3LW UT WOS:000373401200048 PM 26812396 ER PT J AU Lo, RC Buck, DB Herrmann, J Hamdan, AD Wyers, M Patel, VI Fillinger, M Schermerhorn, ML AF Lo, Ruby C. Buck, Dominique B. Herrmann, Jeremy Hamdan, Allen D. Wyers, Mark Patel, Virendra I. Fillinger, Mark Schermerhorn, Marc L. CA Vasc Study Grp New England TI Risk factors and consequences of persistent type II endoleaks SO JOURNAL OF VASCULAR SURGERY LA English DT Article; Proceedings Paper CT 41st Annual Symposium of the Society-for-Clinical-Vascular-Surgery CY MAR 12-16, 2013 CL Miami Beach, FL SP Soc Clin Vasc Surg ID ABDOMINAL AORTIC-ANEURYSM; ENDOVASCULAR REPAIR; SELECTIVE INTERVENTION; RANDOMIZED-TRIAL; OUTCOMES; EMBOLIZATION; SAFE AB Objective: Type II endoleaks are common after endovascular aneurysm repair (EVAR), but their clinical significance remains undefined and their management controversial. We determined risk factors for type II endoleaks and associations with adverse outcomes. Methods: We identified all EVAR patients in the Vascular Study Group of New England abdominal aortic aneurysm database. Patients were subdivided into two groups: (1) those with no endoleak or transient type II endoleak and (2) persistent type II endoleak or new type II endoleak (no endoleak at completion of case). Patients with other endoleak types and follow-up shorter than 6 months were excluded. Multivariable analysis was used to evaluate predictors of persistent or new type II endoleaks. Kaplan-Meier and Cox regression analysis were used to evaluate predictors of reintervention and survival. Results: Two thousand three hundred sixty-seven EVAR patients had information on endoleaks: 1977 (84%) were in group 1, of which 79% had no endoleaks at all, and 21% had transient endoleaks that resolved at follow-up. The other 390 (16%) were in group 2, of which 31% had a persistent leak, and 69% had a new leak at follow-up that was not seen at the time of surgery. Group 2 was older (mean age, 75 vs 73 years; P < .001) and less likely to have chronic obstructive pulmonary disease (COPD; 24% vs 34%; P < .001) or elevated creatinine levels (2.6% vs 5.3%; P = .027). Coil embolization of one or both hypogastric arteries was associated with a higher rate of persistent type II endoleaks (12 vs 8%; P = .024), as was distal graft extension (12% vs 8%; P = .008). In multivariable analysis, COPD (odds ratio [OR], 0.7; 95% confidence interval [CI], 0.5-0.9; P = .017) was protective against persistent type II endoleak, while hypogastric artery coil embolization (OR, 1.5; 95% CI, 1.0-2.2; P = .044), distal graft extension (OR, 1.6; 95% CI, 1.1-2.3; P = .025), and age >= 80 (OR, 2.7; 95% CI, 1.4-5.3; P = .004) were predictive. Graft type was also associated with endoleak development. Persistent type II endoleaks were predictive of postdischarge reintervention (OR, 15.3; 95% CI, 9.7-24.3; P < .001); however, they were not predictive of long-term survival (OR, 1.1; 95% CI, 0.9-1.6; P = .477). Conclusions: Persistent type II endoleak is associated with hypogastric artery coil embolization, distal graft extension, older age, the absence of COPD, and graft type, but not with aneurysm size. Persistent type II endoleaks are associated with an increased risk of reinterventions, but not rupture or survival. This reinforces the need for continued surveillance of patients with persistent type II endoleaks and the importance of follow-up to detect new type II endoleaks over time. C1 [Lo, Ruby C.; Buck, Dominique B.; Herrmann, Jeremy; Hamdan, Allen D.; Wyers, Mark; Schermerhorn, Marc L.] Beth Israel Deaconess Med Ctr, Div Vasc & Endovasc Surg, Boston, MA 02215 USA. [Patel, Virendra I.] Massachusetts Gen Hosp, Div Vasc & Endovasc Surg, Boston, MA 02114 USA. [Fillinger, Mark] Dartmouth Hitchcock Med Ctr, Vasc Surg Sect, Lebanon, NH 03766 USA. RP Schermerhorn, ML (reprint author), 110 Francis St,Ste 5B, Boston, MA USA. EM mscherme@bidmc.harvard.edu FU NHLBI NIH HHS [R01 HL105453, 5R01HL105453-03, T32 HL007734] NR 25 TC 2 Z9 2 U1 1 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD APR PY 2016 VL 63 IS 4 BP 895 EP 901 DI 10.1016/j.jvs.2015.10.088 PG 7 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA DH7FR UT WOS:000372958200008 PM 26796291 ER PT J AU Daniel, VT Gupta, N Raffetto, JD McPhee, JT AF Daniel, Vijaya T. Gupta, Naren Raffetto, Joseph D. McPhee, James T. TI Impact of coexisting aneurysms on open revascularization for aortoiliac occlusive disease SO JOURNAL OF VASCULAR SURGERY LA English DT Article; Proceedings Paper CT 43rd Annual Symposium of the Society-for-Clinical-Vascular-Surgery on Vascular Surgery CY MAR 29-APR 02, 2015 CL Miami, FL SP Soc Clin Vasc Surg ID ABDOMINAL AORTIC-ANEURYSM; PREDICTING 1-YEAR MORTALITY; RISK-FACTORS; REPAIR AB Objective: National data evaluating outcomes for occlusive abdominal aortic reconstructions are well described. The relative effect of operative indication as well as the presence of concomitant abdominal aortic aneurysm (AAA) on in-hospital mortality is not well defined. Methods: The Nationwide Inpatient Sample was queried to identify patients who underwent open aortic surgery (2003-2010). Indication for surgery was classified by International Classification of Diseases, Ninth Revision diagnostic codes to identify isolated occlusive indications as well as combined occlusive disease and AAA. Primary outcome was in-hospital mortality. Secondary outcomes were complications and discharge disposition. Results: Overall, 56,374 underwent aortic reconstruction, 48,591 for occlusive disease (86.2%) and 7783 for combined occlusive disease with AAA (13.8%). Intermittent claudication was the most common indication for intervention (60.9%), whereas 39.7% underwent intervention for critical limb ischemia (22.2% rest pain, 17.6% gangrene). Patients with intermittent claudication had more concomitant AAAs (17.3%) than did patients with critical limb ischemia (8.4%). The baseline characteristics for those with occlusive disease and combined occlusive with AAA disease were similar in terms of obesity (4.8% vs 4.2%; P=.27) and congestive heart failure (6.6% vs 6.3%; P = .65) but differed by age (62.2 years vs 68.4 years; P < .0001) and hypertension (65.4% vs 69.1%; P = .005). Patients with combined occlusive and AAA disease had higher mortality than those with occlusive disease alone (3.9% vs 2.7%; P = .01). On multivariable regression, factors associated with in-hospital mortality included gangrene with AAA compared with gangrene alone (odds ratio [OR], 2.8; 95% confidence interval [CI], 1.6-4.7; P < .0002), age > 65 years age (OR, 3.1; 95% CI, 2.4-4.1; P <.0001), renal failure (OR, 2.7; 95% CI, 1.9-3.8; P < .0001), and concurrent lower extremity revascularization (OR, 1.3; 95% CI, 1.1-1.7; P < .02). Conclusions: Intermittent claudication or critical limb ischemia with concomitant AAA carries a higher mortality than intermittent claudication or critical limb ischemia alone, especially in older patients with gangrene requiring revascularization and renal insufficiency. Preoperative risk stratification strategies should focus on the indication for surgery as well as the presence of concomitant C1 [Daniel, Vijaya T.] Univ Massachusetts, Sch Med, Dept Surg, Worcester, MA USA. [Gupta, Naren; Raffetto, Joseph D.; McPhee, James T.] VA Boston Healthcare Syst, Div Vasc Surg, West Roxbury, MA USA. [Gupta, Naren; Raffetto, Joseph D.] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Gupta, Naren; Raffetto, Joseph D.] Brigham & Womens Hosp, Div Vasc & Endovasc Surg, 75 Francis St, Boston, MA 02115 USA. [McPhee, James T.] Boston Univ, Sch Med, Dept Surg, Boston, MA 02118 USA. RP Daniel, VT (reprint author), Univ Massachusetts, Dept Surg, 55 N Lake Ave, Worcester, MA 01655 USA. EM v.m.thomas@gmail.com NR 18 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 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD APR PY 2016 VL 63 IS 4 BP 944 EP 948 DI 10.1016/j.jvs.2015.10.062 PG 5 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA DH7FR UT WOS:000372958200016 PM 26843353 ER PT J AU Corey, MR Ergul, EA Cambria, RP English, SJ Patel, VI Lancaster, RT Kwolek, CJ Conrad, MF AF Corey, Michael R. Ergul, Emel A. Cambria, Richard P. English, Sean J. Patel, Virendra I. Lancaster, R. Todd Kwolek, Christopher J. Conrad, Mark F. TI The natural history of splanchnic artery aneurysms and outcomes after operative intervention SO JOURNAL OF VASCULAR SURGERY LA English DT Article; Proceedings Paper CT Vascular Annual Meeting of the Society-for-Vascular-Surgery CY JUN 17-20, 2015 CL Chicago, IL SP Soc Vasc Surg ID ABDOMINAL AORTIC-ANEURYSMS; CELIAC ARTERY; PANCREATICODUODENAL ARTERIES; CLINICAL IMPORTANCE; CURRENT MANAGEMENT; EXPERIENCE; PSEUDOANEURYSMS; RUPTURE AB Objective: Splanchnic artery aneurysms (SAAs) are uncommon, and standards for surveillance and intervention are lacking. The goal of this study was to review our 20-year experience with managing SAAs. Methods: The Research Patient Data Registry at the Massachusetts General Hospital was queried, and all patients with SAAs identified by axial imaging from 1994 to 2014 were included. Aneurysms were stratified into two cohorts: those that underwent early intervention (<6 months after lesion discovery) and those that received surveillance. Primary study end points included aneurysm growth or rupture during surveillance and patient 30-day morbidity or mortality after aneurysm repair. Results: There were 264 SAAs identified in 250 patients. In 166 patients, 176 SAAs (66.6%) were placed into the surveillance cohort; 38 SAAs (21.6%) did not have subsequent axial imaging and were considered lost to follow-up. Mean aneurysm size in the surveillance cohort at first imaging study was 16.28 mm (8-41 mm), and mean surveillance time was 36.1 months (2-155 months); 126 SAAs (91.3%) remained stable in size over time, and 8 SAAs (5.8%) required intervention for aneurysm growth after a mean of 24 months. There were no ruptures in the surveillance cohort. There were 88 SAAs (33.3%) repaired early. Mean size of SAAs that were repaired early was 31.1 mm (10-140 mm). For intact SAAs, 30-day morbidity and mortality rates after repair were 13% and 3%, respectively. In the early repair cohort, 13 SAAs (14.7%) were ruptured at presentation. The 30-day morbidity and mortality rates after rupture were 54% and 8%, respectively. Five ruptured SAAs (38%) were anatomically located in the pancreaticoduodenal arcade. On univariate analysis, pancreaticoduodenal aneurysms were strongly associated with rupture (P = .0002). Conclusions: Small SAAs (<= 25 mm) are not prone to significant expansion and do not require frequent surveillance imaging. Imaging every 3 years for small SAAs is adequate. Aneurysms of the pancreaticoduodenal arcade and gastroduodenal aneurysms are more likely to rupture and therefore warrant a more aggressive interventional approach. C1 [Corey, Michael R.; Ergul, Emel A.; Cambria, Richard P.; English, Sean J.; Patel, Virendra I.; Lancaster, R. Todd; Kwolek, Christopher J.; Conrad, Mark F.] Massachusetts Gen Hosp, Dept Vasc & Endovasc Surg, Boston, MA 02114 USA. RP Conrad, MF (reprint author), 15 Parkman St,WACC 440, Boston, MA 02114 USA. EM mconrad@partners.org NR 31 TC 3 Z9 3 U1 2 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD APR PY 2016 VL 63 IS 4 BP 949 EP 957 DI 10.1016/j.jvs.2015.10.066 PG 9 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA DH7FR UT WOS:000372958200017 PM 26792545 ER PT J AU Kikuchi, S Kenagy, RD Gao, L Wight, TN Azuma, N Sobel, M Clowes, AW AF Kikuchi, Shinsuke Kenagy, Richard D. Gao, Lu Wight, Thomas N. Azuma, Nobuyoshi Sobel, Michael Clowes, Alexander W. TI Surgical marking pen dye inhibits saphenous vein cell proliferation and migration in saphenous vein graft tissue SO JOURNAL OF VASCULAR SURGERY LA English DT Article ID LOWER-EXTREMITY BYPASS; SMOOTH-MUSCLE; INTIMAL HYPERPLASIA; RANDOMIZED-TRIAL; PROGENITOR CELLS; METHYLENE-BLUE; NEOINTIMA; INSITU; MYOFIBROBLASTS; APOPTOSIS AB Objective: Markers containing dyes such as crystal violet (CAS 548-62-9) are routinely used on the adventitia of vein bypass grafts to avoid twisting during placement. Because little is known about how these dyes affect vein graft healing and function, we determined the effect of crystal violet on cell migration and proliferation, which are responses to injury after grafting. Methods: Fresh human saphenous veins were obtained as residual specimens from leg bypass surgeries. Portions of the vein that had been surgically marked with crystal violet were analyzed separately from those that had no dye marking. In the laboratory, they were split into easily dissected inner and outer layers after removal of endothelium. This cleavage plane was within the circular muscle layer of the media. Cell migration from explants was measured daily as either (1) percentage of migration-positive explants, which exclusively measures migration, or (2) number of cells on the plastic surrounding each explant, which measures migration plus proliferation. Cell proliferation and apoptosis (Ki67 and TUNEL staining, respectively) were determined in dye-marked and unmarked areas of cultured vein rings. The dose-dependent effects of crystal violet were measured for cell migration from explants as well as for proliferation, migration, and death of cultured outer layer cells. Dye was extracted from explants with ethanol and quantified by spectrophotometry. Results: There was significantly less cell migration from visibly blue compared with unstained outer layer explants by both methods. There was no significant difference in migration from inner layer explants adjacent to blue-stained or unstained sections of vein because dye did not penetrate to the inner layer. Ki67 staining of vein in organ culture, which is a measure of proliferation, progressively increased up to 6 days in nonblue outer layer and was abolished in the blue outer layer. Evidence of apoptosis (TUNEL staining) was present throughout the wall and not different in blue-stained and unstained vein wall segments. Blue outer layer explants had 65.9 +/- 8.0 ng dye/explant compared with 2.1 +/- 1.3 for nonblue outer layer explants. Dye applied in vitro to either outer or inner layer explants dose dependently inhibited migration (IC50 similar to 10 ng/explant). The IC(50)s of crystal violet for outer layer cell proliferation and migration were 0.1 and 1.2 mg/mL, whereas the EC50 for death was between 1 and 10 mg/mL. Conclusions: Crystal violet inhibits venous cell migration and proliferation, indicating that alternative methods should be considered for marking vein grafts. C1 [Kikuchi, Shinsuke; Kenagy, Richard D.; Gao, Lu; Sobel, Michael; Clowes, Alexander W.] Univ Washington, Dept Surg, Seattle, WA 98195 USA. [Kikuchi, Shinsuke; Azuma, Nobuyoshi] Asahikawa Med Univ, Dept Vasc Surg, Asahikawa, Hokkaido, Japan. [Wight, Thomas N.] Virginia Mason, Benaroya Res Inst, Matrix Biol Program, Seattle, WA USA. [Sobel, Michael] VA Puget Sound Hlth Care Syst, Div Vasc Surg, Seattle, WA USA. [Sobel, Michael] Univ Washington, Seattle, WA 98195 USA. RP Kenagy, RD (reprint author), Univ Washington, Ctr Cardiovasc Biol, POB 358050,850 Republican St, Seattle, WA 98109 USA. EM rkenagy@u.washington.edu FU CSRD VA [I01 CX000712]; NHLBI NIH HHS [R41 HL106967, R01 HL030946, R01 HL30946] NR 34 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD APR PY 2016 VL 63 IS 4 BP 1044 EP 1050 DI 10.1016/j.jvs.2014.10.017 PG 7 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA DH7FR UT WOS:000372958200031 PM 25935273 ER PT J AU Rosales, IA Colvin, RB AF Rosales, Ivy A. Colvin, Robert B. TI Glomerular disease with idiopathic linear immunoglobulin deposition: a rose by any other name would be atypical SO KIDNEY INTERNATIONAL LA English DT Editorial Material ID ANTI-GBM DISEASE; BASEMENT-MEMBRANE; AUTOANTIBODIES; GLOMERULONEPHRITIS AB Nasr et al. (2016) report 20 cases of "atypical anti-GBM disease," characterized by bright, linear glomerular basement membrane (GBM) immunoglobulin deposition in patients who lacked anti-GBM antibodies by conventional testing and who had a relatively benign course. Half had light chain restriction. The term " idiopathic linear immunoglobulin deposition" may be preferable until anti-GBM activity is demonstrable, since there are alternative mechanisms of linear deposition in the GBM, including physicochemical affinity for GBM components and alterations of the GBM itself. (C) 2016 International Society of Nephrology C1 [Rosales, Ivy A.; Colvin, Robert B.] Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St, Boston, MA 02114 USA. RP Colvin, RB (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St, Boston, MA 02114 USA. EM colvin@helix.mgh.harvard.edu NR 9 TC 1 Z9 1 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 EI 1523-1755 J9 KIDNEY INT JI Kidney Int. PD APR PY 2016 VL 89 IS 4 BP 750 EP 752 DI 10.1016/j.kint.2016.01.018 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA DH1CD UT WOS:000372521100007 PM 26994573 ER PT J AU Nasr, SH Collins, AB Alexander, MP Schraith, DF Hernandez, LH Fidler, ME Sethi, S Leung, N Fervenza, FC Cornell, LD AF Nasr, Samih H. Collins, A. Bernard Alexander, Mariam Priya Schraith, Daniel F. Hernandez, Loren Herrera Fidler, Mary E. Sethi, Sanjeev Leung, Nelson Fervenza, Fernando C. Cornell, Lynn D. TI The clinicopathologic characteristics and outcome of atypical anti-glomerular basement membrane nephritis SO KIDNEY INTERNATIONAL LA English DT Article DE anti-GBM disease; glomerulonephritis; kidney biopsy; nephrotic syndrome; renal pathology ID NORMAL RENAL-FUNCTION; IMMUNOGLOBULIN DEPOSITION DISEASE; LINKED IMMUNOSORBENT ASSAYS; ANTIBODY-MEDIATED DISEASE; GOODPASTURES-SYNDROME; GLOMERULONEPHRITIS; AUTOANTIBODIES; AUTOANTIGEN; IGG; NEPHROPATHY AB Classic anti-glomerular basement membrane (GBM) disease presents with rapidly progressive glomerulonephritis (GN) with or without pulmonary hemorrhage. On biopsy typical disease displays bright polytypic linear GBM staining for IgG by immunofluorescence and diffuse crescentic/necrotizing GN on light microscopy. Here, we studied 20 patients with atypical anti-GBM nephritis typified by bright linear GBM staining for immunoglobulins but without a diffuse crescentic phenotype. Patients had hematuria, proteinuria, and mild renal insufficiency, without pulmonary hemorrhage. Light microscopy showed endocapillary proliferative GN in 9 patients, mesangial proliferative GN in 6, membranoproliferative GN in 3, and focal segmental glomerulosclerosis with mesangial hypercellularity in 2. Eight of the 20 showed features of microangiopathy. Crescents/necrosis were absent in 12 and were focal in 8 patients. Bright linear GBM staining for IgG was seen in 17 patients, IgM in 2, and IgA in 1 patient, which was polytypic in 10 patients and monotypic in 10 patients. No circulating alpha 3NC1 antibodies were detected by commercial ELISA. The 1-year patient and renal survival rates were 93% and 85%, respectively. Thus, atypical anti-GBM nephritis is a rare variant of anti-GBM disease characterized clinically by an indolent course, no pulmonary involvement, and undetectable circulating a3NC1 antibodies. Further studies are needed to characterize the molecular architecture of GBM autoantigens in these patients and establish optimal therapy. C1 [Nasr, Samih H.; Alexander, Mariam Priya; Hernandez, Loren Herrera; Fidler, Mary E.; Sethi, Sanjeev; Cornell, Lynn D.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA. [Collins, A. Bernard] Massachusetts Gen Hosp, Pathol Serv, Boston, MA 02114 USA. [Schraith, Daniel F.] Gundersen Hlth Syst, Dept Pathol & Lab Med, La Crosse, WI USA. [Leung, Nelson; Fervenza, Fernando C.] Mayo Clin, Div Nephrol & Hypertens, Rochester, MN 55905 USA. RP Cornell, LD (reprint author), Mayo Clin, Div Anat Pathol, 200 First St SW, Rochester, MN 55905 USA. EM cornell.lynn@mayo.edu NR 46 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 0085-2538 EI 1523-1755 J9 KIDNEY INT JI Kidney Int. PD APR PY 2016 VL 89 IS 4 BP 897 EP 908 DI 10.1016/j.kint.2016.02.001 PG 12 WC Urology & Nephrology SC Urology & Nephrology GA DH1CD UT WOS:000372521100020 PM 26994577 ER PT J AU Healy, DY Chhabra, N Metson, R Holbrook, EH Gray, ST AF Healy, David Y., Jr. Chhabra, Nipun Metson, Ralph Holbrook, Eric H. Gray, Stacey T. TI Surgical risk factors for recurrence of inverted papilloma SO LARYNGOSCOPE LA English DT Article DE Inverted papilloma; Schneiderian papilloma; paranasal sinus tumor; endoscopic sinus surgery; risk factors ID STAGING SYSTEM; MANAGEMENT AB Objectives/HypothesisTo identify variations in surgical technique that impact the recurrence of inverted papilloma following endoscopic excision. Study DesignRetrospective cohort. MethodsData from 127 consecutive patients who underwent endoscopic excision of inverted papilloma and oncocytic papilloma at a tertiary care medical center from 1998 to 2011 were reviewed. Patient demographics, comorbidities, tumor stage, and intraoperative details, including tumor location and management of the base, were evaluated to identify factors associated with tumor recurrence. ResultsRecurrence of papilloma occurred in 16 patients (12.6%). Mean time to recurrence was 31.0 months (range, 5.2-110.0 months). Mucosal stripping alone was associated with a recurrence rate of 52.2% (12/23 patients), compared to 4.9% (3/61 patients) when the tumor base was drilled, 4.7% (1/21 patients) when it was cauterized, and 0.0% (0/22 patients) when it was completely excised (P = .001). Increased recurrence rate was associated with tumors located in the maxillary sinus (P = .03), as well as the performance of endoscopic medial maxillectomy (P = .001) and external frontal approaches (P = .02). ConclusionsDrilling, cauterizing, or completely excising the bone underlying the tumor base during endoscopic resection reduces the recurrence rate of inverted and oncocytic papilloma, when compared to mucosal stripping alone. Surgeons who perform endoscopic resection of these tumors should consider utilization of these techniques when possible. Level of Evidence4 Laryngoscope, 126:796-801, 2016 C1 [Healy, David Y., Jr.] Naval Med Ctr Portsmouth, Dept Otolaryngol, 620 John Paul Jones Circle, Portsmouth, VA 23708 USA. [Chhabra, Nipun] Univ Illinois, Coll Med, Dept Surg, St Anthony Med Ctr, Rockford, IL 61107 USA. [Metson, Ralph; Holbrook, Eric H.; Gray, Stacey T.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. [Metson, Ralph; Holbrook, Eric H.; Gray, Stacey T.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. RP Healy, DY (reprint author), Naval Med Ctr Portsmouth, Dept Otolaryngol, 620 John Paul Jones Circle, Portsmouth, VA 23708 USA. EM dyhealy@hotmail.com NR 14 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X EI 1531-4995 J9 LARYNGOSCOPE JI Laryngoscope PD APR PY 2016 VL 126 IS 4 BP 796 EP 801 DI 10.1002/lary.25663 PG 6 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA DI3EV UT WOS:000373382100010 PM 26372045 ER PT J AU Lu, IC Wu, CW Chang, PY Chen, HY Tseng, KY Randolph, GW Cheng, KI Chiang, FY AF Lu, I-Cheng Wu, Che-Wei Chang, Pi-Ying Chen, Hsiu-Ya Tseng, Kuang-Yi Randolph, Gregory W. Cheng, Kuang-I Chiang, Feng-Yu TI Reversal of rocuronium-induced neuromuscular blockade by sugammadex allows for optimization of neural monitoring of the recurrent laryngeal nerve SO LARYNGOSCOPE LA English DT Article DE Intraoperative neuromonitoring; neuromuscular blocking agent; sugammadex; recurrent laryngeal nerve; thyroid surgery; anesthesia ID PROSPECTIVE PORCINE MODEL; RELAXANT BINDING-AGENT; THYROID-SURGERY; ENDOTRACHEAL-TUBE; INJURY; IDENTIFICATION; VECURONIUM; SUCCINYLCHOLINE; STIMULATION; RLN AB Objectives/HypothesisThe use of neuromuscular blocking agent may effect intraoperative neuromonitoring (IONM) during thyroid surgery. An enhanced neuromuscular-blockade (NMB) recovery protocol was investigated in a porcine model and subsequently clinically applied during human thyroid neural monitoring surgery. Study DesignProspective animal and retrospective clinical study. MethodsIn the animal experiment, 12 piglets were injected with rocuronium 0.6 mg/kg and randomly allocated to receive normal saline, sugammadex 2 mg/kg, or sugammadex 4mg/kg to compare the recovery of laryngeal electromyography (EMG). In a subsequent clinical application study, 50 patients who underwent thyroidectomy with IONM followed an enhanced NMB recovery protocolrocuronium 0.6 mg/kg at anesthesia induction and sugammadex 2 mg/kg at the operation start. The train-of-four (TOF) ratio was used for continuous quantitative monitoring of neuromuscular transmission. ResultsIn our porcine model, it took 49 15, 13.2 5.6, and 4.2 +/- 1.5 minutes for the 80% recovery of laryngeal EMG after injection of saline, sugammadex 2 mg/kg, and sugammadex 4 mg/kg, respectively. In subsequent clinical human application, the TOF ratio recovered from 0 to >0.9 within 5 minutes after administration of sugammadex 2 mg/kg at the operation start. All patients had positive and high EMG amplitude at the early stage of the operation, and intubation was without difficulty in 96% of patients. ConclusionsBoth porcine modeling and clinical human application demonstrated that sugammadex 2 mg/kg allows effective and rapid restoration of neuromuscular function suppressed by rocuronium. Implementation of this enhanced NMB recovery protocol assures optimal conditions for tracheal intubation as well as IONM in thyroid surgery. Level of EvidenceNA Laryngoscope, 126:1014-1019, 2016 C1 [Lu, I-Cheng; Wu, Che-Wei; Cheng, Kuang-I; Chiang, Feng-Yu] Kaohsiung Med Univ, Coll Med, Grad Inst Med, 100 TzYou First Rd, Kaohsiung 807, Taiwan. [Lu, I-Cheng; Wu, Che-Wei; Cheng, Kuang-I; Chiang, Feng-Yu] Kaohsiung Med Univ, Coll Med, Fac Med, 100 TzYou First Rd, Kaohsiung 807, Taiwan. [Lu, I-Cheng] Kaohsiung Med Univ, Kaohsiung Municipal Hsiao Kang Hosp, Dept Anesthesiol, 100 TzYou First Rd, Kaohsiung 807, Taiwan. [Chang, Pi-Ying; Chen, Hsiu-Ya; Tseng, Kuang-Yi; Cheng, Kuang-I] Kaohsiung Med Univ, Kaohsiung Med Univ Hosp, Dept Anesthesiol, 100 TzYou First Rd, Kaohsiung 807, Taiwan. [Wu, Che-Wei; Chiang, Feng-Yu] Kaohsiung Med Univ, Kaohsiung Med Univ Hosp, Dept Otolaryngol Head & Neck Surg, 100 TzYou First Rd, Kaohsiung 807, Taiwan. [Randolph, Gregory W.] Harvard Univ, Massachusetts Gen Hosp, Sch Med,Div Thyroid & Parathyroid Surg, Massachusetts Eye & Ear Infirm,Dept Laryn & Otol, Boston, MA USA. [Randolph, Gregory W.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg,Div Surg Oncol, Boston, MA USA. RP Cheng, KI (reprint author), Kaohsiung Med Univ, Coll Med, 100 TzYou First Rd, Kaohsiung 807, Taiwan. EM fychiang@kmu.edu.tw OI Wu, Che-Wei/0000-0003-1052-5348 FU Kaohsiung Medical University Hospital (KMUH) [103-3T07, 103-3R36]; Ministry of Science and Technology, Taiwan (MOST) [103-2314-B-037-037-MY2] FX This study was supported by grants from the Kaohsiung Medical University Hospital (KMUH 103-3T07, 103-3R36) and the Ministry of Science and Technology, Taiwan (MOST 103-2314-B-037-037-MY2). NR 33 TC 4 Z9 4 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X EI 1531-4995 J9 LARYNGOSCOPE JI Laryngoscope PD APR PY 2016 VL 126 IS 4 BP 1014 EP 1019 DI 10.1002/lary.25577 PG 6 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA DI3EV UT WOS:000373382100048 PM 26748952 ER PT J AU Salari, B Ren, Y Kamani, D Randolph, GW AF Salari, Behzad Ren, Yin Kamani, Dipti Randolph, Gregory W. TI Revision neural monitored surgery for recurrent thyroid cancer: Safety and thyroglobulin response SO LARYNGOSCOPE LA English DT Article DE Revision thyroid surgery; thyroglobulin; Tg; safety; complications ID CENTRAL COMPARTMENT DISSECTION; LYMPH-NODE DISSECTION; NECK DISSECTION; PAPILLARY; CARCINOMA; EFFICACY; REOPERATION; OUTCOMES; ULTRASOUND; MORBIDITY AB Objectives/HypothesisTo evaluate the quantitative biochemical response, recurrence rate, and rate of surgical complications for thyroid cancer revision surgery. Study DesignRetrospective review. MethodsThis is a single institution analysis of a prospective database of 181 patients undergoing reoperation for local recurrent thyroid cancer by the same surgeon from 2004 to 2013 with intraoperative neural monitoring. Main outcome measures included pathologic findings, surgical complications, effect of reoperation on thyroglobulin (Tg) levels, and recurrence rate. We defined biochemical complete remission as postoperative stimulated Tg of 0.2 ng/mL or less. ResultsFourteen percent of the patients presented with permanent vocal cord palsy (VCP), and 20% of the patients presented with hypocalcemia prior to surgery. Among them, 70% of the patients underwent first revision surgery; whereas in 30% the surgery represented second or higher revision surgery, with 8% being a third or higher revision. None developed temporary or permanent VCP. Temporary hypocalcemia occurred in 9% of the patients, and permanent hypocalcemia occurred in 4.2%. The rate of cervical node recurrence was 5% at a median follow-up of 3.4 years. There were no disease-specific deaths. Mean preoperative basal Tg was 22.3 ng/mL and mean postoperative Tg was 5.7 ng/mL, a decline of 74% (P = 0.023, paired t test). Biochemical complete remission was achieved in 58% of all revision cases. ConclusionReoperative neural monitored surgery for recurrent thyroid cancer is a safe and effective procedure with limited morbidity in experienced hands, even in the setting of multiple prior revision surgeries and existing comorbidities such as VCP and hypocalcemia. Level of Evidence4. Laryngoscope, 126:1020-1025, 2016 C1 [Salari, Behzad; Ren, Yin; Kamani, Dipti; Randolph, Gregory W.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Otolaryngol,Div Thyroid & Parathyroid Surg, Boston, MA USA. [Randolph, Gregory W.] Massachusetts Gen Hosp, Dept Surg, Div Surg Oncol, Boston, MA 02114 USA. [Randolph, Gregory W.] Harvard Univ, Sch Med, Boston, MA USA. RP Randolph, GW (reprint author), Dept Otolaryngol, Thyroid & Parathyroid Endocrine Surg Div, 243 Charles St, Boston, MA 02114 USA. EM gregory_randolph@meei.harvard.edu FU John and Claire Bertucci Thyroid Research FX The authors thank The John and Claire Bertucci Thyroid Research fund for supporting this research. NR 34 TC 2 Z9 2 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X EI 1531-4995 J9 LARYNGOSCOPE JI Laryngoscope PD APR PY 2016 VL 126 IS 4 BP 1020 EP 1025 DI 10.1002/lary.25796 PG 6 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA DI3EV UT WOS:000373382100049 PM 26608969 ER PT J AU Torrado-Carvajal, A Herraiz, JL Hernandez-Tamames, JA Jose-Estepar, RS Eryaman, Y Rozenholc, Y Adalsteinsson, E Wald, LL Malpica, N AF Torrado-Carvajal, Angel Herraiz, Joaquin L. Hernandez-Tamames, Juan A. Jose-Estepar, Raul San Eryaman, Yigitcan Rozenholc, Yves Adalsteinsson, Elfar Wald, Lawrence L. Malpica, Norberto TI Multi-Atlas and Label Fusion Approach for Patient-Specific MRI Based Skull Estimation SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE atlas-based; label fusion; MRI; skull segmentation; tissue models ID MULTIMODALITY IMAGE REGISTRATION; ATTENUATION CORRECTION; MUTUAL-INFORMATION; HUMAN-BODY; SEGMENTATION; PERFORMANCE; MODELS; MAXIMIZATION AB Purpose: MRI-based skull segmentation is a useful procedure for many imaging applications. This study describes a methodology for automatic segmentation of the complete skull from a single T1-weighted volume. Methods: The skull is estimated using a multi-atlas segmentation approach. Using a whole head computed tomography (CT) scan database, the skull in a new MRI volume is detected by nonrigid image registration of the volume to every CT, and combination of the individual segmentations by label-fusion. We have compared Majority Voting, Simultaneous Truth and Performance Level Estimation (STAPLE), Shape Based Averaging (SBA), and the Selective and Iterative Method for Performance Level Estimation (SIMPLE) algorithms. Results: The pipeline has been evaluated quantitatively using images from the Retrospective Image Registration Evaluation database (reaching an overlap of 72.46 +/- 6.99%), a clinical CT-MR dataset (maximum overlap of 78.31 +/- 6.97%), and a whole head CT-MRI pair (maximum overlap 78.68%). A qualitative evaluation has also been performed on MRI acquisition of volunteers. Conclusion: It is possible to automatically segment the complete skull from MRI data using a multi-atlas and label fusion approach. This will allow the creation of complete MRI-based tissue models that can be used in electromagnetic dosimetry applications and attenuation correction in PET/MR. (C) 2015 Wiley Periodicals, Inc. C1 [Torrado-Carvajal, Angel; Hernandez-Tamames, Juan A.; Malpica, Norberto] Univ Rey Juan Carlos, Med Image Anal & Biometry Lab, Madrid, Spain. [Torrado-Carvajal, Angel; Herraiz, Joaquin L.; Hernandez-Tamames, Juan A.; Jose-Estepar, Raul San; Eryaman, Yigitcan; Adalsteinsson, Elfar; Malpica, Norberto] Madrid MIT M Vis Consortium, Madrid, Spain. [Herraiz, Joaquin L.; Eryaman, Yigitcan] MIT, Elect Res Lab, Inst Technol, Cambridge, MA 02139 USA. [Jose-Estepar, Raul San] Brigham & Womens Hosp, Dept Radiol, 75 Francis St, Boston, MA 02115 USA. [Eryaman, Yigitcan; Wald, Lawrence L.] Massachusetts Gen Hosp, Dept Radiol, AA Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Rozenholc, Yves] Univ Paris 05, CNRS, MAP5, UMR 8145, Paris, France. [Rozenholc, Yves] INRIA Saclay Ile de France SELECT, Paris, France. [Adalsteinsson, Elfar] MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA. [Adalsteinsson, Elfar; Wald, Lawrence L.] MIT, Harvard MIT Hlth Sci & Technol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Adalsteinsson, Elfar] MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA. RP Torrado-Carvajal, A (reprint author), Univ Rey Juan Carlos, Med Image Anal & Biometry Lab, Biomed Engn, Madrid, Spain. EM angel.torrado@urjc.es RI Wald, Lawrence/D-4151-2009; Hernandez-Tamames, Juan /N-5319-2014; LOPEZ HERRAIZ, JOAQUIN/E-9234-2010; Malpica, Norberto/I-2090-2015 OI Hernandez-Tamames, Juan /0000-0003-0027-9518; LOPEZ HERRAIZ, JOAQUIN/0000-0001-7208-8863; Malpica, Norberto/0000-0003-4618-7459 FU Comunidad de Madrid; Madrid-MIT M+Vision Consortium FX Grant sponsor: Comunidad de Madrid; Grant sponsor: Madrid-MIT M+Vision Consortium. NR 36 TC 2 Z9 2 U1 3 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD APR PY 2016 VL 75 IS 4 BP 1797 EP 1807 DI 10.1002/mrm.25737 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DH6OR UT WOS:000372910900042 PM 25981161 ER PT J AU Di Stefano, B Collombet, S Jakobsen, JS Wierer, M Sardina, JL Lackner, A Stadhouders, R Segura-Morales, C Francesconi, M Limone, F Mann, M Porse, B Thieffry, D Graf, T AF Di Stefano, Bruno Collombet, Samuel Jakobsen, Janus Schou Wierer, Michael Luis Sardina, Jose Lackner, Andreas Stadhouders, Ralph Segura-Morales, Carolina Francesconi, Mirko Limone, Francesco Mann, Matthias Porse, Bo Thieffry, Denis Graf, Thomas TI C/EBP alpha creates elite cells for iPSC reprogramming by upregulating Klf4 and increasing the levels of Lsd1 and Brd4 SO NATURE CELL BIOLOGY LA English DT Article ID PLURIPOTENT STEM-CELLS; ACUTE MYELOID-LEUKEMIA; MLL-REARRANGED AML; TRANSCRIPTION FACTORS; SUPER-ENHANCERS; HEMATOPOIETIC DIFFERENTIATION; SELECTIVE-INHIBITION; SIGNALING PATHWAYS; HIGHLY EFFICIENT; SOMATIC-CELLS AB Reprogramming somatic cells into induced pluripotent stem cells (iPSCs) is typically inefficient and has been explained by elite-cell and stochastic models. We recently reported that B cells exposed to a pulse of C/EBP alpha (B alpha' cells) behave as elite cells, in that they can be rapidly and efficiently reprogrammed into iPSCs by the Yamanaka factors OSKM. Here we show that C/EBP alpha post-transcriptionally increases the abundance of several hundred proteins, including Lsd1, Hdac1, Brd4, Med1 and Cdk9, components of chromatin-modifying complexes present at super-enhancers. Lsd1 was found to be required for B cell gene silencing and Brd4 for the activation of the pluripotency program. C/EBP alpha also promotes chromatin accessibility in pluripotent cells and upregulates Klf4 by binding to two haematopoietic enhancers. B alpha' cells share many properties with granulocyte/macrophage progenitors, naturally occurring elite cells that are obligate targets for leukaemic transformation, whose formation strictly requires C/EBP alpha. C1 [Di Stefano, Bruno; Luis Sardina, Jose; Lackner, Andreas; Stadhouders, Ralph; Segura-Morales, Carolina; Francesconi, Mirko; Limone, Francesco; Graf, Thomas] Barcelona Inst Sci & Technol, Ctr Genom Regulat CRG, Dr Aiguader 88, Barcelona 08003, Spain. [Di Stefano, Bruno; Luis Sardina, Jose; Lackner, Andreas; Stadhouders, Ralph; Segura-Morales, Carolina; Francesconi, Mirko; Limone, Francesco; Graf, Thomas] Univ Pompeu Fabra, Barcelona 08003, Spain. [Collombet, Samuel; Thieffry, Denis] PSL Res Univ, Ecole Normale Super, IBENS, CNRS,INSERM,U1024,UMR8197, F-75005 Paris, France. [Jakobsen, Janus Schou; Porse, Bo] Univ Copenhagen, Fac Hlth Sci, Rigshosp, Finsen Lab, Ole Maaloes Vej 5, DK-2200 Copenhagen, Denmark. [Jakobsen, Janus Schou; Porse, Bo] Univ Copenhagen, BRIC, Ole Maaloes Vej 5, DK-2200 Copenhagen, Denmark. [Jakobsen, Janus Schou; Porse, Bo] Univ Copenhagen, Fac Hlth Sci, Danish Stem Cell Ctr DanStem, 3B Blegdamsvej, DK-2200 Copenhagen, Denmark. [Wierer, Michael; Mann, Matthias] Max Planck Inst Biochem, D-82152 Munich, Germany. [Di Stefano, Bruno] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Di Stefano, Bruno] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Lackner, Andreas] Univ Vienna, Max F Perutz Labs, Vienna Bioctr VBC, Dr Bohr Gasse 9-3, A-1030 Vienna, Austria. RP Di Stefano, B; Graf, T (reprint author), Barcelona Inst Sci & Technol, Ctr Genom Regulat CRG, Dr Aiguader 88, Barcelona 08003, Spain.; Di Stefano, B; Graf, T (reprint author), Univ Pompeu Fabra, Barcelona 08003, Spain.; Di Stefano, B (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA.; Di Stefano, B (reprint author), Harvard Univ, Sch Med, Boston, MA 02114 USA. EM distefano@molbio.mgh.harvard.edu; thomas.graf@crg.eu RI francesconi, mirko/O-8080-2015; OI francesconi, mirko/0000-0002-8702-0877; Di Stefano, Bruno/0000-0003-2532-3087 FU Ministerio de Educacion y Ciencia [SAF.2012-37167]; Fundacio La Marato [TV3 120410]; AGAUR [SGR 1136]; European Research Council Synergy Grant (4D-Genome); EMBO Long-term Fellowship (ALTF) [1201-2014]; Marie Curie Individual Fellowship (H2020-MSCA-IF); MINECO [IJCI-2014-21872]; NovoNordisk Foundation (Section for Stem Cell Biology in Human Disease) [R179-A1513] FX We thank J. E. Bradner (Dana Farber Cancer Institute, Harvard Medical School, USA) for the JQ1 compound, J. Zuber (Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Austria) for the Brd4 shRNA construct, R. Levine (Memorial Sloan Kettering Cancer Center, USA) for the Tet2 shRNA construct, L. de Andres for help with GMP isolations, L. Batlle for help with the chimaeric mice, the Genomics Facility and the Biomolecular Screening & Protein Technologies Facility of the CRG for technical assistance and members of the Graf laboratory for discussions. This work was supported by Ministerio de Educacion y Ciencia, SAF.2012-37167, Fundacio La Marato TV3 120410, AGAUR SGR 1136 and European Research Council Synergy Grant (4D-Genome). R.S. was supported by an EMBO Long-term Fellowship (ALTF 1201-2014) and a Marie Curie Individual Fellowship (H2020-MSCA-IF-2014). J.L.S. was supported by MINECO (IJCI-2014-21872). Work in the Porse laboratory was supported through a Centre grant from the NovoNordisk Foundation (Section for Stem Cell Biology in Human Disease and R179-A1513). NR 69 TC 7 Z9 7 U1 8 U2 23 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 APR PY 2016 VL 18 IS 4 BP 371 EP + DI 10.1038/ncb3326 PG 25 WC Cell Biology SC Cell Biology GA DH7LX UT WOS:000372976600005 PM 26974661 ER PT J AU Boettger, LM Salem, RM Handsaker, RE Peloso, GM Kathiresan, S Hirschhorn, JN McCarroll, SA AF Boettger, Linda M. Salem, Rany M. Handsaker, Robert E. Peloso, Gina M. Kathiresan, Sekar Hirschhorn, Joel N. McCarroll, Steven A. TI Recurring exon deletions in the HP (haptoglobin) gene contribute to lower blood cholesterol levels SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; APOLIPOPROTEIN-E; COPY NUMBER; GENOTYPE IMPUTATION; NATURAL-SELECTION; POPULATION; HEMOGLOBIN; PROTEINS; BINDING; HUMANS AB One of the first protein polymorphisms identified in humans involves the abundant blood protein haptoglobin. Two exons of the HP gene (encoding haptoglobin) exhibit copy number variation that affects HP protein structure and multimerization. The evolutionary origins and medical relevance of this polymorphism have been uncertain. Here we show that this variation has likely arisen from many recurring deletions, more specifically, reversions of an ancient hominin-specific duplication of these exons. Although this polymorphism has been largely invisible to genome-wide genetic studies thus far, we describe a way to analyze it by imputation from SNP haplotypes and find among 22,288 individuals that these HP exonic deletions associate with reduced LDL and total cholesterol levels. We further show that these deletions, and a SNP that affects HP expression, appear to drive the strong association of cholesterol levels with SNPs near HP. Recurring exonic deletions in HP likely enhance human health by lowering cholesterol levels in the blood. C1 [Boettger, Linda M.; Salem, Rany M.; Handsaker, Robert E.; Hirschhorn, Joel N.; McCarroll, Steven A.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Boettger, Linda M.; Salem, Rany M.; Handsaker, Robert E.; Peloso, Gina M.; Kathiresan, Sekar; Hirschhorn, Joel N.; McCarroll, Steven A.] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA. [Salem, Rany M.; Hirschhorn, Joel N.] Boston Childrens Hosp, Div Endocrinol, Boston, MA USA. [Salem, Rany M.; Hirschhorn, Joel N.] Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA USA. [Peloso, Gina M.; Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. RP McCarroll, SA (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA USA.; McCarroll, SA (reprint author), Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA. EM mccarroll@genetics.med.harvard.edu FU National Human Genome Research Institute [R01HG006855]; Yerkes Center [P51OD011132]; US National Institutes of Health/National Heart, Lung, and Blood Institute K99 award [1K99HL122515-01A1]; Juvenile Diabetes Research Foundation [JDRF 3-APF-2014-111-A-N]; National Heart, Lung, and Blood Institute of the US National Institutes of Health [K01HL125751] FX We thank C. Usher for comments on the manuscript and work on the figures. This work was supported by a grant from the National Human Genome Research Institute (R01HG006855 to S.A.M.). The Yerkes Center (grant P51OD011132) provided primate DNA samples. R.M.S. was supported by a US National Institutes of Health/National Heart, Lung, and Blood Institute K99 award (1K99HL122515-01A1) and an advanced postdoctoral fellowship award from the Juvenile Diabetes Research Foundation (JDRF 3-APF-2014-111-A-N). G.M.P. was supported by the National Heart, Lung, and Blood Institute of the US National Institutes of Health under award K01HL125751. NR 50 TC 3 Z9 3 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD APR PY 2016 VL 48 IS 4 BP 359 EP + DI 10.1038/ng.3510 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA DH6NZ UT WOS:000372908800007 PM 26901066 ER PT J AU Dunning, AM Michailidou, K Kuchenbaecker, KB Thompson, D French, JD Beesley, J Healey, CS Kar, S Pooley, KA Lopez-Knowles, E Dicks, E Barrowdale, D Sinnott-Armstrong, NA Sallari, RC Hillman, KM Kaufmann, S Sivakumaran, H Marjaneh, MM Lee, JS Hills, M Jarosz, M Drury, S Canisius, S Bolla, MK Dennis, J Wang, Q Hopper, JL Southey, MC Broeks, A Schmidt, MK Lophatananon, A Muir, K Beckmann, MW Fasching, PA dos-Santos-Silva, I Peto, J Sawyer, EJ Tomlinson, I Burwinkel, B Marme, F Guenel, P Truong, T Bojesen, SE Flyger, H Gonzalez-Neira, A Perez, JIA Anton-Culver, H Eunjung, L Arndt, V Brenner, H Meindl, A Schmutzler, RK Brauch, H Hamann, U Aittomaki, K Blomqvist, C Ito, H Matsuo, K Bogdanova, N Dork, T Lindblom, A Margolin, S Kosma, VM Mannermaa, A Tseng, CC Wu, AH Lambrechts, D Wildiers, H Chang-Claude, J Rudolph, A Peterlongo, P Radice, P Olson, JE Giles, GG Milne, RL Haiman, CA Henderson, BE Goldberg, MS Teo, SH Yip, CH Nord, S Borresen-Dale, AL Kristensen, V Long, J Zheng, W Pylkas, K Winqvist, R Andrulis, IL Knight, JA Devilee, P Seynaeve, C Figueroa, J Sherman, ME Czene, K Darabi, H Hollestelle, A van den Ouweland, AMW Humphreys, K Gao, YT Shu, XO Cox, A Cross, SS Blot, W Cai, Q Ghoussaini, M Perkins, BJ Shah, M Choi, JY Kang, D Lee, SC Hartman, M Kabisch, M Torres, D Jakubowska, A Lubinski, J Brennan, P Sangrajrang, S Ambrosone, CB Toland, AE Shen, CY Wu, PE Orr, N Swerdlow, A McGuffog, L Healey, S Lee, A Kapuscinski, M John, EM Terry, MB Daly, MB Goldgar, DE Buys, SS Janavicius, R Tihomirova, L Tung, N Dorfling, CM van Rensburg, EJ Neuhausen, SL Ejlertsen, B Hansen, TVO Osorio, A Benitez, J Rando, R Weitzel, JN Bonanni, B Peissel, B Manoukian, S Papi, L Ottini, L Konstantopoulou, I Apostolou, P Garber, J Rashid, MU Frost, D Izatt, L Ellis, S Godwin, AK Arnold, N Niederacher, D Rhiem, K Bogdanova-Markov, N Sagne, C Stoppa-Lyonnet, D Damiola, F Sinilnikova, OM Mazoyer, S Isaacs, C Claes, KBM De Leeneer, K De la Hoya, M Caldes, T Nevanlinna, H Khan, S Mensenkamp, AR Hooning, MJ Rookus, MA Kwong, A Olah, E Diez, O Brunet, J Pujana, MA Gronwald, J Huzarski, T Barkardottir, RB Laframboise, R Soucy, P Montagna, M Agata, S Teixeira, MR Park, SK Lindor, N Couch, FJ Tischkowitz, M Foretova, L Vijai, J Offit, K Singer, CF Rappaport, C Phelan, CM Greene, MH Mai, PL Rennert, G Imyanitov, EN Hulick, PJ Phillips, KA Piedmonte, M Mulligan, AM Glendon, G Bojesen, A Thomassen, M Caligo, MA Yoon, SY Friedman, E Laitman, Y Borg, A Von Wachenfeldt, A Ehrencrona, H Rantala, J Olopade, OI Ganz, PA Nussbaum, RL Gayther, SA Nathanson, KL Domchek, SM Arun, BK Mitchell, G Karlan, BY Lester, J Maskarinec, G Woolcott, C Scott, C Stone, J Apicella, C Tamimi, R Luben, R Khaw, KT Helland, A Haakensen, V Dowsett, M Pharoah, PDP Simard, J Hall, P Garcia-Closas, M Vachon, C Chenevix-Trench, G Antoniou, AC Easton, DF Edwards, SL AF Dunning, Alison M. Michailidou, Kyriaki Kuchenbaecker, Karoline B. Thompson, Deborah French, Juliet D. Beesley, Jonathan Healey, Catherine S. Kar, Siddhartha Pooley, Karen A. Lopez-Knowles, Elena Dicks, Ed Barrowdale, Daniel Sinnott-Armstrong, Nicholas A. Sallari, Richard C. Hillman, Kristine M. Kaufmann, Susanne Sivakumaran, Haran Marjaneh, Mahdi Moradi Lee, Jason S. Hills, Margaret Jarosz, Monika Drury, Suzie Canisius, Sander Bolla, Manjeet K. Dennis, Joe Wang, Qin Hopper, John L. Southey, Melissa C. Broeks, Annegien Schmidt, Marjanka K. Lophatananon, Artitaya Muir, Kenneth Beckmann, Matthias W. Fasching, Peter A. dos-Santos-Silva, Isabel Peto, Julian Sawyer, Elinor J. Tomlinson, Ian Burwinkel, Barbara Marme, Frederik Guenel, Pascal Truong, Therese Bojesen, Stig E. Flyger, Henrik Gonzalez-Neira, Anna Perez, Jose I. A. Anton-Culver, Hoda Eunjung, Lee Arndt, Volker Brenner, Hermann Meindl, Alfons Schmutzler, Rita K. Brauch, Hiltrud Hamann, Ute Aittomaki, Kristiina Blomqvist, Carl Ito, Hidemi Matsuo, Keitaro Bogdanova, Natasha Dork, Thilo Lindblom, Annika Margolin, Sara Kosma, Veli-Matti Mannermaa, Arto Tseng, Chiu-chen Wu, Anna H. Lambrechts, Diether Wildiers, Hans Chang-Claude, Jenny Rudolph, Anja Peterlongo, Paolo Radice, Paolo Olson, Janet E. Giles, Graham G. Milne, Roger L. Haiman, Christopher A. Henderson, Brian E. Goldberg, Mark S. Teo, Soo H. Yip, Cheng Har Nord, Silje Borresen-Dale, Anne-Lise Kristensen, Vessela Long, Jirong Zheng, Wei Pylkas, Katri Winqvist, Robert Andrulis, Irene L. Knight, Julia A. Devilee, Peter Seynaeve, Caroline Figueroa, Jonine Sherman, Mark E. Czene, Kamila Darabi, Hatef Hollestelle, Antoinette van den Ouweland, Ans M. W. Humphreys, Keith Gao, Yu-Tang Shu, Xiao-Ou Cox, Angela Cross, Simon S. Blot, William Cai, Qiuyin Ghoussaini, Maya Perkins, Barbara J. Shah, Mitul Choi, Ji-Yeob Kang, Daehee Lee, Soo Chin Hartman, Mikael Kabisch, Maria Torres, Diana Jakubowska, Anna Lubinski, Jan Brennan, Paul Sangrajrang, Suleeporn Ambrosone, Christine B. Toland, Amanda E. Shen, Chen-Yang Wu, Pei-Ei Orr, Nick Swerdlow, Anthony McGuffog, Lesley Healey, Sue Lee, Andrew Kapuscinski, Miroslav John, Esther M. Terry, Mary Beth Daly, Mary B. Goldgar, David E. Buys, Saundra S. Janavicius, Ramunas Tihomirova, Laima Tung, Nadine Dorfling, Cecilia M. van Rensburg, Elizabeth J. Neuhausen, Susan L. Ejlertsen, Bent Hansen, Thomas V. O. Osorio, Ana Benitez, Javier Rando, Rachel Weitzel, Jeffrey N. Bonanni, Bernardo Peissel, Bernard Manoukian, Siranoush Papi, Laura Ottini, Laura Konstantopoulou, Irene Apostolou, Paraskevi Garber, Judy Rashid, Muhammad Usman Frost, Debra Izatt, Louise Ellis, Steve Godwin, Andrew K. Arnold, Norbert Niederacher, Dieter Rhiem, Kerstin Bogdanova-Markov, Nadja Sagne, Charlotte Stoppa-Lyonnet, Dominique Damiola, Francesca Sinilnikova, Olga M. Mazoyer, Sylvie Isaacs, Claudine Claes, Kathleen B. M. De Leeneer, Kim De la Hoya, Miguel Caldes, Trinidad Nevanlinna, Heli Khan, Sofia Mensenkamp, Arjen R. Hooning, Maartje J. Rookus, Matti A. Kwong, Ava Olah, Edith Diez, Orland Brunet, Joan Pujana, Miquel Angel Gronwald, Jacek Huzarski, Tomasz Barkardottir, Rosa B. Laframboise, Rachel Soucy, Penny Montagna, Marco Agata, Simona Teixeira, Manuel R. Park, Sue Kyung Lindor, Noralane Couch, Fergus J. Tischkowitz, Marc Foretova, Lenka Vijai, Joseph Offit, Kenneth Singer, Christian F. Rappaport, Christine Phelan, Catherine M. Greene, Mark H. Mai, Phuong L. Rennert, Gad Imyanitov, Evgeny N. Hulick, Peter J. Phillips, Kelly-Anne Piedmonte, Marion Mulligan, Anna Marie Glendon, Gord Bojesen, Anders Thomassen, Mads Caligo, Maria A. Yoon, Sook-Yee Friedman, Eitan Laitman, Yael Borg, Ake Von Wachenfeldt, Anna Ehrencrona, Hans Rantala, Johanna Olopade, Olufunmilayo I. Ganz, Patricia A. Nussbaum, Robert L. Gayther, Simon A. Nathanson, Katherine L. Domchek, Susan M. Arun, Banu K. Mitchell, Gillian Karlan, Beth Y. Lester, Jenny Maskarinec, Gertraud Woolcott, Christy Scott, Christopher Stone, Jennifer Apicella, Carmel Tamimi, Rulla Luben, Robert Khaw, Kay-Tee Helland, Aslaug Haakensen, Vilde Dowsett, Mitch Pharoah, Paul D. P. Simard, Jacques Hall, Per Garcia-Closas, Montserrat Vachon, Celine Chenevix-Trench, Georgia Antoniou, Antonis C. Easton, Douglas F. Edwards, Stacey L. CA EMBRACE GEMO Study Collaborators HEBON KConFab Investigators TI Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170 SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; BRCA2 MUTATION CARRIERS; BONE-MINERAL DENSITY; MAMMOGRAPHIC DENSITY; SUSCEPTIBILITY LOCUS; METAANALYSIS; EXPRESSION; MODIFIERS; REVEALS; DISEASE AB We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor a) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER+ or ER-) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER-tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression. C1 [Dunning, Alison M.; Healey, Catherine S.; Kar, Siddhartha; Dicks, Ed; Ghoussaini, Maya; Perkins, Barbara J.; Shah, Mitul; Pharoah, Paul D. P.; Easton, Douglas F.] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England. [Michailidou, Kyriaki; Kuchenbaecker, Karoline B.; Thompson, Deborah; Pooley, Karen A.; Barrowdale, Daniel; Bolla, Manjeet K.; Dennis, Joe; Wang, Qin; McGuffog, Lesley; Lee, Andrew; Frost, Debra; Ellis, Steve; Pharoah, Paul D. P.; Antoniou, Antonis C.; Easton, Douglas F.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [French, Juliet D.; Beesley, Jonathan; Hillman, Kristine M.; Kaufmann, Susanne; Sivakumaran, Haran; Marjaneh, Mahdi Moradi; Lee, Jason S.; Healey, Sue; Chenevix-Trench, Georgia; Edwards, Stacey L.] QIMR Berghofer Med Res Inst, Canc Div, Brisbane, Qld, Australia. [Lopez-Knowles, Elena; Jarosz, Monika; Drury, Suzie; Dowsett, Mitch] Breakthrough Breast Canc Res Ctr, Breast Canc Res, London, England. [Lopez-Knowles, Elena; Hills, Margaret; Jarosz, Monika; Drury, Suzie; Dowsett, Mitch] Royal Marsden Hosp, Acad Biochem, London SW3 6JJ, England. [Sinnott-Armstrong, Nicholas A.] Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA. [Sallari, Richard C.] MIT, Comp Sci & Artificial Intelligence Lab, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Canisius, Sander; Broeks, Annegien; Schmidt, Marjanka K.] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands. 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[Osorio, Ana; Benitez, Javier] Biomed Network Rare Dis CIBERER, Madrid, Spain. [Benitez, Javier] Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Program, Human Genotyping CEGEN Unit, Madrid, Spain. [Rando, Rachel] City Hope Clin Canc Genom Community Res Network, Duarte, CA USA. [Weitzel, Jeffrey N.] City Hope Natl Med Ctr, Clin Canc Genet, Duarte, CA USA. [Bonanni, Bernardo] Ist Europeo Oncol, Div Canc Prevent & Genet, Milan, Italy. [Peissel, Bernard; Manoukian, Siranoush] Ist Nazl Tumori, Fdn Ist Ricovero & Cura Carattere Sci, Dept Prevent & Predict Med, Unit Med Genet, Via Venezian 1, I-20133 Milan, Italy. [Papi, Laura] Univ Florence, Dept Biomed Expt & Clin Sci, Unit Med Genet, Florence, Italy. [Ottini, Laura] Univ Roma La Sapienza, Dept Mol Med, Piazzale Aldo Moro 5, I-00185 Rome, Italy. [Konstantopoulou, Irene; Apostolou, Paraskevi] Aghia Paraskevi Attikis, Natl Ctr Sci Res Demokritos, INRASTES Inst Nucl & Radiol Sci & Technol, Mol Diagnost Lab, Athens, Greece. [Garber, Judy] Dana Farber Canc Inst, Canc Risk & Prevent Clin, Boston, MA 02115 USA. [Rashid, Muhammad Usman] Shaukat Khanum Mem Canc Hosp & Res Ctr, Dept Basic Sci, Lahore, Pakistan. [Izatt, Louise] Guys & St Thomas Natl Hlth Serv NHS Fdn Trust, Clin Genet, London, England. [Godwin, Andrew K.] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66103 USA. [Arnold, Norbert] Univ Kiel, Univ Hosp Schleswig Holstein, Dept Gynaecol & Obstet, Campus Kiel, Kiel, Germany. [Niederacher, Dieter] Univ Dusseldorf, Dusseldorf, Germany. [Rhiem, Kerstin] Univ Hosp Cologne, Ctr Mol Med Cologne, Dept Obstet & Gynaecol, Ctr Familial Breast & Ovarian Canc, Cologne, Germany. [Rhiem, Kerstin] Univ Hosp Cologne, Ctr Mol Med Cologne, Ctr Integrated Oncol, Cologne, Germany. [Bogdanova-Markov, Nadja] Univ Munster, Inst Human Genet, D-48149 Munster, Germany. [Sagne, Charlotte; Damiola, Francesca; Sinilnikova, Olga M.; Mazoyer, Sylvie] Univ Lyon 1, CNRS UMR 5286, INSERM U1052, Ctr Rech Cancerol Lyon, F-69365 Lyon, France. [Stoppa-Lyonnet, Dominique] Inst Curie, Dept Tumour Biol, Paris, France. [Stoppa-Lyonnet, Dominique] Univ Paris 05, Sorbonne Paris Cite, Paris, France. [Sinilnikova, Olga M.] Hosp Civils Lyon, Ctr Leon Berard, Unite Mixte Genet Constitutionnelle Canc Frequent, Lyon, France. [Isaacs, Claudine] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA. [Claes, Kathleen B. M.; De Leeneer, Kim] Univ Ghent, Ctr Med Genet, B-9000 Ghent, Belgium. [De la Hoya, Miguel; Caldes, Trinidad] Hosp Clin San Carlos, IdISSC, Mol Oncol Lab, Madrid, Spain. [Nevanlinna, Heli; Khan, Sofia] Univ Helsinki, Dept Obstet & Gynecol, Helsinki, Finland. [Nevanlinna, Heli; Khan, Sofia] Univ Helsinki, Cent Hosp, Helsinki, Finland. [Mensenkamp, Arjen R.] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands. [Hooning, Maartje J.] Erasmus Univ, Med Ctr, Family Canc Clin, Dept Med Oncol, Rotterdam, Netherlands. [Rookus, Matti A.] Netherlands Canc Inst, Dept Epidemiol, Amsterdam, Netherlands. [Kwong, Ava] Hong Kong Sanat & Hosp, Canc Genet Ctr, Hong Kong Hereditary Breast Canc Family Registry, Hong Kong, Hong Kong, Peoples R China. [Kwong, Ava] Univ Hong Kong, Dept Surg, Hong Kong, Hong Kong, Peoples R China. [Olah, Edith] Natl Inst Oncol, Dept Mol Genet, Budapest, Hungary. [Diez, Orland] Vall dHebron Univ Hosp, VHIO, Oncogenet Lab, Barcelona, Spain. [Brunet, Joan] Catalan Inst Oncol, IDIBGI, Hereditary Canc Program, Genet Counseling Unit, Girona, Spain. [Pujana, Miquel Angel] Catalan Inst Oncol, IDIBELL Bellvitge Biomed Res Inst, Breast Canc & Syst Biol Unit, Barcelona, Spain. [Barkardottir, Rosa B.] Univ Iceland, Fac Med, Landspitali Univ Hosp, Dept Pathol, Reykjavik, Iceland. [Barkardottir, Rosa B.] Univ Iceland, Fac Med, Biomed Ctr BMC, Reykjavik, Iceland. [Laframboise, Rachel] Ctr Hosp Univ Quebec, Div Med Genet, Quebec City, PQ, Canada. [Laframboise, Rachel; Soucy, Penny; Simard, Jacques] Univ Laval, Quebec City, PQ, Canada. [Soucy, Penny; Simard, Jacques] Ctr Hosp Univ Quebec, Quebec City, PQ, Canada. [Montagna, Marco; Agata, Simona] IRCCS, IOV, Immunol & Mol Oncol Unit, Padua, Italy. [Teixeira, Manuel R.] Portuguese Oncol Inst, Dept Genet, Oporto, Portugal. [Teixeira, Manuel R.] Univ Porto, Biomed Sci Inst ICBAS, Rua Campo Alegre 823, P-4100 Oporto, Portugal. [Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Tischkowitz, Marc] McGill Univ, Program Canc Genet, Montreal, PQ, Canada. [Foretova, Lenka] Masaryk Univ, Masaryk Mem Canc Inst, Brno, Czech Republic. [Foretova, Lenka] Masaryk Univ, Fac Med, Brno, Czech Republic. [Vijai, Joseph; Offit, Kenneth] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA. [Singer, Christian F.; Rappaport, Christine] Med Univ Vienna, Ctr Comprehens Canc, Dept Obstet & Gynecol, Vienna, Austria. [Phelan, Catherine M.] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Canc Epidemiol, Tampa, FL 33682 USA. [Greene, Mark H.; Mai, Phuong L.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, US NIH, Rockville, MD USA. [Rennert, Gad] Carmel Hosp, Dept Community Med & Epidemiol, Haifa, Israel. [Rennert, Gad] Technion Israel Inst Technol, Bruce Rappaport Fac Med, POB 9649, IL-31096 Haifa, Israel. [Rennert, Gad] Clalit Natl Israeli Canc Control Ctr, Haifa, Israel. [Imyanitov, Evgeny N.] NN Petrov Oncol Res Inst, St Petersburg, Russia. [Hulick, Peter J.] NorthShore Univ Hlth Syst, Ctr Med Genet, Evanston, IL USA. [Phillips, Kelly-Anne] Peter MacCallum Canc Ctr, Div Canc Med, East Melbourne, Vic, Australia. [Piedmonte, Marion] Roswell Pk Canc Inst, Stat & Data Management Ctr, NRG Oncol, Buffalo, NY 14263 USA. [Mulligan, Anna Marie] Univ Hlth Network, Lab Med Program, Toronto, ON, Canada. [Mulligan, Anna Marie] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada. [Bojesen, Anders] Vejle Hosp, Dept Clin Genet, Vejle, Denmark. [Thomassen, Mads] Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense, Denmark. [Caligo, Maria A.] Univ Pisa, Dept Lab Med, Sect Genet Oncol, Pisa, Italy. [Caligo, Maria A.] Univ Hosp Pisa, Pisa, Italy. [Yoon, Sook-Yee] Univ Malaya, Univ Malaya Med Ctr, Fac Med, Univ Malaya Canc Res Inst, Kuala Lumpur, Malaysia. [Friedman, Eitan; Laitman, Yael] Chaim Sheba Med Ctr, Susanne Levy Gertner Oncogenet Unit, IL-52621 Tel Hashomer, Israel. [Borg, Ake] Lund Univ, Dept Oncol, Lund, Sweden. [Ehrencrona, Hans] Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden. [Ehrencrona, Hans] Univ Lund Hosp, Dept Clin Genet, S-22185 Lund, Sweden. [Rantala, Johanna] Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden. [Olopade, Olufunmilayo I.] Univ Chicago, Med Ctr, Ctr Clin Canc Genet & Global Hlth, Chicago, IL 60637 USA. [Ganz, Patricia A.] Univ Calif Los Angeles, Sch Med, Johnsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, Los Angeles, CA USA. [Ganz, Patricia A.] Univ Calif Los Angeles, Sch Publ Hlth, Johnsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, Los Angeles, CA USA. [Nussbaum, Robert L.] Univ Calif San Francisco, Dept Med & Genet, San Francisco, CA 94143 USA. [Nathanson, Katherine L.; Domchek, Susan M.] Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA. [Arun, Banu K.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Mitchell, Gillian] Peter MacCallum Canc Ctr, Familial Canc Ctr, Melbourne, Vic, Australia. [Mitchell, Gillian] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Melbourne, Vic, Australia. [Karlan, Beth Y.; Lester, Jenny] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Los Angeles, CA 90048 USA. [Maskarinec, Gertraud] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. [Woolcott, Christy] Dalhousie Univ, Dept Obstet Gynaecol & Pediat, Halifax, NS, Canada. [Stone, Jennifer] Univ Western Australia, Ctr Genet Origins Hlth & Dis, Perth, WA 6009, Australia. [Tamimi, Rulla] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Tamimi, Rulla] Harvard Univ, Sch Med, Boston, MA USA. [Tamimi, Rulla] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Tamimi, Rulla] Harvard Univ, Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, 665 Huntington Ave, Boston, MA 02115 USA. [Luben, Robert; Khaw, Kay-Tee] Univ Cambridge, Dept Publ Hlth & Primary Care, Clin Gerontol, Cambridge, England. RP Dunning, AM; Easton, DF; Edwards, SL (reprint author), Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England.; Easton, DF (reprint author), Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England.; Edwards, SL (reprint author), QIMR Berghofer Med Res Inst, Canc Div, Brisbane, Qld, Australia. EM amd24@medschl.cam.ac.uk; dfe20@medschl.cam.ac.uk; stacey.edwards@qimrberghofer.edu.au RI Gronwald, Jacek/A-4576-2017; Brenner, Hermann/B-4627-2017; manoukian, siranoush/E-7132-2017; Peissel, Bernard/E-8187-2017; montagna, marco/E-2225-2012; Zheng, Wei/O-3351-2013; Nord, Silje/R-5212-2016; Helland, Aslaug/H-3910-2015; Andrulis, Irene/E-7267-2013; Edwards, Stacey/A-4980-2011; Arnold, Norbert/E-3012-2010; Jansen van Rensburg, Elizabeth (Lizette)/B-9104-2011; Osorio, Ana/I-4324-2014; Lee, Jason/M-7522-2016; Dork, Thilo/J-8620-2012; Yip, Cheng-Har/B-1909-2010; Teo, Soo-hwang/H-2353-2014; Knight, Julia/A-6843-2012 OI Dunning, Alison Margaret/0000-0001-6651-7166; Matsuo, Keitaro/0000-0003-1761-6314; Evans, Gareth/0000-0002-8482-5784; Gronwald, Jacek/0000-0002-3643-2871; Brenner, Hermann/0000-0002-6129-1572; manoukian, siranoush/0000-0002-6034-7562; Peissel, Bernard/0000-0001-9233-3571; montagna, marco/0000-0002-4929-2150; Ehrencrona, Hans/0000-0002-5589-3622; Phillips, Kelly-Anne/0000-0002-0475-1771; Barrowdale, Daniel/0000-0003-1661-3939; Khan, Sofia/0000-0003-4185-8882; Brunet, Joan/0000-0003-1945-3512; Sivakumaran, Haran/0000-0002-4691-4989; Dowsett, Mitch/0000-0003-4122-744X; Zheng, Wei/0000-0003-1226-070X; Nord, Silje/0000-0002-3271-5356; Helland, Aslaug/0000-0002-5520-0275; Arnold, Norbert/0000-0003-4523-8808; Osorio, Ana/0000-0001-8124-3984; Lee, Jason/0000-0003-0879-934X; FU National Institute for Health Research (NIHR); European Community [223175 (HEALTH-F2-2009-223175)]; Cancer Research UK [C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565]; US National Institutes of Health (NIH) [CA128978, CA192393, CA116167, CA176785]; US National Institutes of Health (NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer) [CA116201]; Post-Cancer GWAS initiative [1U19 CA148537, 1U19 CA148065, 1U19 CA148112]; Post-Cancer GWAS initiative (GAME-ON initiative); US Department of Defense [W81XWH-10-1-0341]; Canadian Institutes of Health Research (CIHR); Komen Foundation for the Cure; Breast Cancer Research Foundation; Ovarian Cancer Research Fund FX We thank all the individuals who took part in these studies and all the researchers, clinicians, technicians and administrative staff who have enabled this work to be carried out. This study would not have been possible without the contributions of the following: A. Berchuck (OCAC), R.A. Eeles, A. A. Al Olama, Z. Kote-Jarai and S. Benlloch (PRACTICAL), C. Luccarini and the staff of the Centre for Genetic Epidemiology Laboratory, the staff of the CNIO genotyping unit, D.C. Tessier, F. Bacot, D. Vincent, S. LaBoissiere, F. Robidoux and the staff of the McGill University and Genome Quebec Innovation Centre, S. F. Nielsen, B.G. Nordestgaard and the staff of the Copenhagen DNA laboratory, and J.M. Cunningham, S. A. Windebank, C. A. Hilker, J. Meyer and the staff of the Mayo Clinic Genotyping Core Facility. Normal human tissues from the Susan G. Komen for the Cure Tissue Bank at the Indiana University Simon Cancer Center (Indianapolis) were used in this study. We thank the contributors, including Indiana University who collected samples used in this study, as well as the donors and their families, whose help and participation made this work possible. We also acknowledge National Institute for Health Research (NIHR) support to the Royal Marsden Biomedical Research Centre. Funding for the iCOGS infrastructure came from the European Community's Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692 and C8197/A16565), the US National Institutes of Health (NIH; CA128978, CA192393, CA116167, CA176785 and an NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201)) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112, the GAME-ON initiative), the US Department of Defense (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, the Komen Foundation for the Cure, the Breast Cancer Research Foundation and the Ovarian Cancer Research Fund. Full acknowledgments are given in the Supplementary Note. NR 46 TC 7 Z9 7 U1 6 U2 27 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD APR PY 2016 VL 48 IS 4 BP 374 EP + DI 10.1038/ng.3521 PG 16 WC Genetics & Heredity SC Genetics & Heredity GA DH6NZ UT WOS:000372908800009 PM 26928228 ER PT J AU Jang, C Oh, SF Wada, S Rowe, GC Liu, L Chan, MC Rhee, J Hoshino, A Kim, B Ibrahim, A Baca, LG Kim, E Ghosh, CC Parikh, SM Jiang, AH Chu, QW Forman, DE Lecker, SH Krishnaiah, S Rabinowitz, JD Weljie, AM Baur, JA Kasper, DL Arany, Z AF Jang, Cholsoon Oh, Sungwhan F. Wada, Shogo Rowe, Glenn C. Liu, Laura Chan, Mun Chun Rhee, James Hoshino, Atsushi Kim, Boa Ibrahim, Ayon Baca, Luisa G. Kim, Esl Ghosh, Chandra C. Parikh, Samir M. Jiang, Aihua Chu, Qingwei Forman, Daniel E. Lecker, Stewart H. Krishnaiah, Saikumari Rabinowitz, Joshua D. Weljie, Aalim M. Baur, Joseph A. Kasper, Dennis L. Arany, Zoltan TI A branched-chain amino acid metabolite drives vascular fatty acid transport and causes insulin resistance SO NATURE MEDICINE LA English DT Article ID TRANSCRIPTIONAL COACTIVATOR PGC-1-ALPHA; SKELETAL-MUSCLE; IN-VIVO; EXPRESSION; CAPACITY; DISEASE; FIBERS; PLASMA; RISK AB Epidemiological and experimental data implicate branched-chain amino acids (BCAAs) in the development of insulin resistance, but the mechanisms that underlie this link remain unclear(1-3). Insulin resistance in skeletal muscle stems from the excess accumulation of lipid species(4), a process that requires blood-borne lipids to initially traverse the blood vessel wall. How this trans-endothelial transport occurs and how it is regulated are not well understood. Here we leveraged PPARGC1a (also known as PGC-1 alpha; encoded by Ppargc1a), a transcriptional coactivator that regulates broad programs of fatty acid consumption, to identify 3-hydroxyisobutyrate (3-HIB), a catabolic intermediate of the BCAA valine, as a new paracrine regulator of trans-endothelial fatty acid transport. We found that 3-HIB is secreted from muscle cells, activates endothelial fatty acid transport, stimulates muscle fatty acid uptake in vivo and promotes lipid accumulation in muscle, leading to insulin resistance in mice. Conversely, inhibiting the synthesis of 3-HIB in muscle cells blocks the ability of PGC-1 alpha to promote endothelial fatty acid uptake. 3-HIB levels are elevated in muscle from db/db mice with diabetes and from human subjects with diabetes, as compared to those without diabetes. These data unveil a mechanism in which the metabolite 3-HIB, by regulating the trans-endothelial flux of fatty acids, links the regulation of fatty acid flux to BCAA catabolism, providing a mechanistic explanation for how increased BCAA catabolic flux can cause diabetes. C1 [Jang, Cholsoon; Wada, Shogo; Hoshino, Atsushi; Kim, Boa; Ibrahim, Ayon; Chu, Qingwei; Krishnaiah, Saikumari; Weljie, Aalim M.; Baur, Joseph A.; Arany, Zoltan] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Jang, Cholsoon; Rowe, Glenn C.; Liu, Laura; Chan, Mun Chun; Rhee, James; Baca, Luisa G.; Kim, Esl; Ghosh, Chandra C.; Parikh, Samir M.; Jiang, Aihua; Lecker, Stewart H.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Oh, Sungwhan F.; Kasper, Dennis L.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA USA. [Rhee, James] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Forman, Daniel E.] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. [Rabinowitz, Joshua D.] Princeton Univ, Lewis Sigler Inst Integrat Genom, Princeton, NJ 08544 USA. [Rowe, Glenn C.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. RP Arany, Z (reprint author), Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. EM zarany@mail.med.upenn.edu RI Krishnaiah, Saikumari/I-7140-2016; OI Rowe, Glenn/0000-0002-8195-9605 FU Lotte Scholarship; American Heart Association (AHA); Crohn's and Colitis Foundation of America (Research Fellowship Award); Toyobo Biotechnology Foundation; US National Institute of Arthritis and Musculoskeletal and Skin Diseases [AR062128]; US National Institutes of Health [5 T32 GM7592-35]; US National Heart, Lung, and Blood Institute (NHLBI) [HL093234, HL125275]; US National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [DK095072]; NIDDK [DK098656, DK049210]; NHLBI [HL094499]; AHA; Geis Realty Group Emerging Initiatives Fund FX Human endothelial colony forming cells (ECFCs) were kindly provided by J. Bischoff (Boston Children's Hospital). Fatp4-/- and Cd36-/- mice were kindly provided by J. Miner (Washington University School of Medicine) and J. Lawler (Harvard Medical School), respectively. Flt1flox/flox and Kdrflox/flox mice were kindly provided by Genentech. C.J. is supported by the Lotte Scholarship and American Heart Association (AHA). S.F.O. is supported by the Crohn's and Colitis Foundation of America (Research Fellowship Award). S.W. is supported by the Toyobo Biotechnology Foundation. G.C.R. is supported by the US National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR062128). J.R. is supported by the US National Institutes of Health (5 T32 GM7592-35). S.M.P. is supported by the US National Heart, Lung, and Blood Institute (NHLBI) (HL093234; HL125275) and the US National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (DK095072). Q.C. and J.A.B. are supported by the NIDDK (DK098656; DK049210). Z.A. is supported by the NHLBI (HL094499), the AHA and the Geis Realty Group Emerging Initiatives Fund and Dean and Ann Geis. NR 25 TC 17 Z9 17 U1 15 U2 32 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD APR PY 2016 VL 22 IS 4 BP 421 EP + DI 10.1038/nm.4057 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA DI4GF UT WOS:000373457700018 PM 26950361 ER PT J AU Baumann, M Krause, M Overgaard, J Debus, J Bentzen, SM Daartz, J Richter, C Zips, D Bortfeld, T AF Baumann, Michael Krause, Mechthild Overgaard, Jens Debus, Juergen Bentzen, Soren M. Daartz, Juliane Richter, Christian Zips, Daniel Bortfeld, Thomas TI Radiation oncology in the era of precision medicine SO NATURE REVIEWS CANCER LA English DT Review ID SQUAMOUS-CELL CARCINOMA; RELATIVE BIOLOGICAL EFFECTIVENESS; INTENSITY-MODULATED RADIOTHERAPY; RANDOMIZED CONTROLLED-TRIAL; GENOME-WIDE ASSOCIATION; GROWTH-FACTOR RECEPTOR; DOUBLE-STRAND BREAKS; NECK-CANCER PATIENTS; LOCAL TUMOR-CONTROL; 3-DIMENSIONAL CONFORMAL RADIOTHERAPY AB Technological advances and clinical research over the past few decades have given radiation oncologists the capability to personalize treatments for accurate delivery of radiation dose based on clinical parameters and anatomical information. Eradication of gross and microscopic tumours with preservation of health-related quality of life can be achieved in many patients. Two major strategies, acting synergistically, will enable further widening of the therapeutic window of radiation oncology in the era of precision medicine: technology-driven improvement of treatment conformity, including advanced image guidance and particle therapy, and novel biological concepts for personalized treatment, including biomarker-guided prescription, combined treatment modalities and adaptation of treatment during its course. C1 [Baumann, Michael; Krause, Mechthild; Richter, Christian] Tech Univ Dresden, Fac Med, Dept Radiat Oncol, D-01307 Dresden, Germany. [Baumann, Michael; Krause, Mechthild; Richter, Christian] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Fetscherstr 74, D-01307 Dresden, Germany. [Baumann, Michael; Krause, Mechthild; Richter, Christian] Tech Univ Dresden, Fac Med, Natl Ctr Radiat Res Oncol NCRO, OncoRay, Fetscherstr 74, D-01307 Dresden, Germany. [Baumann, Michael; Krause, Mechthild; Richter, Christian] Helmholtz Zentrum Dresden Rossendorf, Fetscherstr 74, D-01307 Dresden, Germany. [Baumann, Michael; Krause, Mechthild; Richter, Christian] Natl Ctr Tumor Dis NCT, Fetscherstr 74, D-01307 Dresden, Germany. [Baumann, Michael; Krause, Mechthild; Richter, Christian] German Canc Consortium DKTK, Dresden, Germany. [Baumann, Michael; Krause, Mechthild; Debus, Juergen; Richter, Christian; Zips, Daniel] German Canc Res Ctr, Neuenheimer Feld 280, D-69120 Heidelberg, Germany. [Baumann, Michael; Krause, Mechthild] Helmholtz Zentrum Dresden Rossendorf, Inst Radiat Oncol, Bautzner Landstr 400, D-01328 Dresden, Germany. [Overgaard, Jens] Aarhus Univ Hosp, Dept Expt Clin Oncol, Norrebrogade 44, DK-8000 Aarhus C, Denmark. [Debus, Juergen] Heidelberg Univ, Sch Med, Natl Ctr Radiat Res Oncol NCRO, HIRO, Neuenheimer Feld 280, D-69120 Heidelberg, Germany. [Debus, Juergen] Natl Ctr Tumor Dis NCT, Neuenheimer Feld 460, D-69120 Heidelberg, Germany. [Debus, Juergen] Heidelberg Univ, Sch Med, Dept Radiat Oncol, Heidelberg Ion Therapy Ctr HIT, Neuenheimer Feld 400, D-69120 Heidelberg, Germany. [Debus, Juergen] German Canc Consortium DKTK, Heidelberg, Germany. [Bentzen, Soren M.] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, 22 S Greene St S9a03, Baltimore, MD 21201 USA. [Bentzen, Soren M.] Univ Maryland, Sch Med, Greenebaum Canc Ctr, 22 S Greene St S9a03, Baltimore, MD 21201 USA. [Daartz, Juliane; Bortfeld, Thomas] Massachusetts Gen Hosp, Dept Radiat Oncol, Div Phys, 1000 Blossom St Cox 362, Boston, MA 02114 USA. [Daartz, Juliane; Bortfeld, Thomas] Harvard Univ, Sch Med, 1000 Blossom St Cox 362, Boston, MA 02114 USA. [Zips, Daniel] German Canc Consortium Tubingen, Postfach 2669, D-72016 Tubingen, Germany. [Zips, Daniel] Univ Tubingen, Fac Med, Dept Radiat Oncol, Hoppe Seyler Str 3, D-72016 Tubingen, Germany. [Zips, Daniel] Univ Tubingen, Univ Hosp Tubingen, Hoppe Seyler Str 3, D-72016 Tubingen, Germany. RP Baumann, M (reprint author), Tech Univ Dresden, Fac Med, Dept Radiat Oncol, D-01307 Dresden, Germany.; Baumann, M (reprint author), Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Fetscherstr 74, D-01307 Dresden, Germany.; Baumann, M (reprint author), Tech Univ Dresden, Fac Med, Natl Ctr Radiat Res Oncol NCRO, OncoRay, Fetscherstr 74, D-01307 Dresden, Germany.; Baumann, M (reprint author), Helmholtz Zentrum Dresden Rossendorf, Fetscherstr 74, D-01307 Dresden, Germany.; Baumann, M (reprint author), Natl Ctr Tumor Dis NCT, Fetscherstr 74, D-01307 Dresden, Germany.; Baumann, M (reprint author), German Canc Consortium DKTK, Dresden, Germany.; Baumann, M (reprint author), German Canc Res Ctr, Neuenheimer Feld 280, D-69120 Heidelberg, Germany.; Baumann, M (reprint author), Helmholtz Zentrum Dresden Rossendorf, Inst Radiat Oncol, Bautzner Landstr 400, D-01328 Dresden, Germany. EM michael.baumann@uniklinikum-dresden.de RI Bentzen, Soren/E-3997-2012 OI Bentzen, Soren/0000-0002-7444-7564 NR 227 TC 15 Z9 15 U1 6 U2 32 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-175X EI 1474-1768 J9 NAT REV CANCER JI Nat. Rev. Cancer PD APR PY 2016 VL 16 IS 4 BP 234 EP 249 DI 10.1038/nrc.2016.18 PG 16 WC Oncology SC Oncology GA DH5AI UT WOS:000372796700006 PM 27009394 ER PT J AU Bates, SE Fojo, T AF Bates, Susan E. Fojo, Tito TI New drug for pancreatic cancer highlights the dual effect of regulatory approvals SO NATURE REVIEWS CLINICAL ONCOLOGY LA English DT Editorial Material ID PACLITAXEL PLUS GEMCITABINE; FOLFIRINOX; TRIALS AB The recent FDA approval of MM-398 as a second-line treatment of metastatic pancreatic cancer, based on a 1.9-month overall survival benefit observed in the NAPOLI-1 trial, adds a new therapeutic option for this notoriously difficult-to-treat disease; however, by discouraging clinical trial enrolment, this approval might have negative consequences for the development of novel agents, which remain an essential unmet need. C1 [Bates, Susan E.; Fojo, Tito] Columbia Univ, Med Ctr, Dept Med, Div Hematol Oncol, Herbert Irving Pavil,9th Floor, New York, NY 10032 USA. [Bates, Susan E.; Fojo, Tito] James J Peters VA Med Ctr, 130 West Kingsbridge Rd, Bronx, NY 10468 USA. RP Bates, SE (reprint author), Columbia Univ, Med Ctr, Dept Med, Div Hematol Oncol, Herbert Irving Pavil,9th Floor, New York, NY 10032 USA.; Bates, SE (reprint author), James J Peters VA Med Ctr, 130 West Kingsbridge Rd, Bronx, NY 10468 USA. EM seb2227@cumc.columbia.edu NR 9 TC 0 Z9 0 U1 7 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4774 EI 1759-4782 J9 NAT REV CLIN ONCOL JI Nat. Rev. Clin. Oncol. PD APR PY 2016 VL 13 IS 4 BP 205 EP 206 DI 10.1038/nrclinonc.2016.22 PG 2 WC Oncology SC Oncology GA DH4DF UT WOS:000372735000002 PM 26902963 ER PT J AU Banks, WA AF Banks, William A. TI From blood-brain barrier to blood-brain interface: new opportunities for CNS drug delivery SO NATURE REVIEWS DRUG DISCOVERY LA English DT Review ID AMYLOID-BETA-PROTEIN; CENTRAL-NERVOUS-SYSTEM; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; MICROVASCULAR ENDOTHELIAL-CELLS; RECEPTOR-RELATED PROTEIN-1; CEREBRAL-ARTERY OCCLUSION; NECROSIS-FACTOR-ALPHA; SPINAL-CORD BARRIER; ALZHEIMERS-DISEASE AB One of the biggest challenges in the development of therapeutics for central nervous system (CNS) disorders is achieving sufficient blood-brain barrier (BBB) penetration. Research in the past few decades has revealed that the BBB is not only a substantial barrier for drug delivery to the CNS but also a complex, dynamic interface that adapts to the needs of the CNS, responds to physiological changes, and is affected by and can even promote disease. This complexity confounds simple strategies for drug delivery to the CNS, but provides a wealth of opportunities and approaches for drug development. Here, I review some of the most important areas that have recently redefined the BBB and discuss how they can be applied to the development of CNS therapeutics. C1 [Banks, William A.] Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, 1660 S Columbian Way, Seattle, WA 98108 USA. [Banks, William A.] Univ Washington, Sch Med, Dept Med, Div Gerontol & Geriatr Med, 1660 S Columbian Way, Seattle, WA 98108 USA. RP Banks, WA (reprint author), Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, 1660 S Columbian Way, Seattle, WA 98108 USA.; Banks, WA (reprint author), Univ Washington, Sch Med, Dept Med, Div Gerontol & Geriatr Med, 1660 S Columbian Way, Seattle, WA 98108 USA. EM wabanks1@uw.edu FU US Department of Veterans Affairs; US National Institute on Aging [R01 AG046619] FX The author is supported by the US Department of Veterans Affairs and a grant from the US National Institute on Aging (grant R01 AG046619). NR 174 TC 18 Z9 18 U1 15 U2 46 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1776 EI 1474-1784 J9 NAT REV DRUG DISCOV JI Nat. Rev. Drug Discov. PD APR PY 2016 VL 15 IS 4 BP 275 EP + DI 10.1038/nrd.2015.21 PG 18 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA DI0ZM UT WOS:000373225800017 PM 26794270 ER PT J AU McCarthy, MS Warren, M Roberts, PR AF McCarthy, Mary S. Warren, Malissa Roberts, Pamela R. TI Recent Critical Care Nutrition Trials and the Revised Guidelines: Do They Reconcile? SO NUTRITION IN CLINICAL PRACTICE LA English DT Editorial Material ID SUPPLEMENTAL PARENTERAL-NUTRITION; IMMUNE-MODULATING NUTRIENTS; OIL LIPID EMULSIONS; ILL PATIENT SOCIETY; ACUTE LUNG INJURY; CLINICAL-TRIAL; GASTROINTESTINAL SURGERY; ENTERAL NUTRITION; RANDOMIZED-TRIAL; NOSOCOMIAL INFECTIONS C1 [McCarthy, Mary S.] Madigan Army Med Ctr, Ctr Nursing Sci & Clin Inquiry, 9040 Jackson Ave, Tacoma, WA 98431 USA. [Warren, Malissa] Portland VA Med Ctr, Portland, OR USA. [Roberts, Pamela R.] Univ Oklahoma, Coll Med, Dept Anesthesiol, Oklahoma City, OK 73190 USA. RP McCarthy, MS (reprint author), Madigan Army Med Ctr, Ctr Nursing Sci & Clin Inquiry, 9040 Jackson Ave, Tacoma, WA 98431 USA. EM Mary.s.mccarthy1.civ@mail.mil NR 34 TC 1 Z9 1 U1 2 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0884-5336 EI 1941-2452 J9 NUTR CLIN PRACT JI Nutr. Clin. Pract. PD APR PY 2016 VL 31 IS 2 BP 150 EP 154 DI 10.1177/0884533616630301 PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DH6LS UT WOS:000372902700002 PM 26915509 ER PT J AU Curtis, CS Busch, RA Crass, RL Webb, AP Kudsk, KA AF Curtis, Caitlin S. Busch, Rebecca A. Crass, Ryan L. Webb, Aaron P. Kudsk, Kenneth A. TI Use of Premixed Parenteral Nutrition During a Phosphate Shortage in a Non-Critically Ill Population SO NUTRITION IN CLINICAL PRACTICE LA English DT Article DE parenteral nutrition; nutritional support; dietary phosphorus; phosphates ID DRUG SHORTAGES; IMPACT AB Background: Drug shortages pose prescribing problems to clinicians. During fiscal year (FY) 2014, an acute shortage of intravenous potassium phosphate (K-Phos IV), a common supplement in parenteral nutrition (PN), prompted the use of premixed instead of individualized PN to conserve K-Phos IV. Here we quantify the K-Phos IV conserved by using premixed PN and the associated cost differences. Materials and Methods: Costs of preparing premixed PN vs individualized PN of equivalent composition were calculated for FY 2014 at a single-center tertiary care facility. Quantity and cost of K-Phos IV saved were calculated based on the number of premixed PN prescriptions. Costs for FY 2015 were projected based on drug costs from July 2014. Results: During FY 2014, prescribing premixed in lieu of individualized PN conserved 16,440 mmol K-Phos IV but increased the cost of PN by $4080.45. However, increases in K-Phos IV cost at the end of FY 2014 resulted in premixed PN as a relatively less expensive therapy than individualized PN for our institution. Cost savings of $7092.20 due to use of premixed PN is projected for FY 2015. Conclusions: Prescribing premixed PN conserves K-Phos IV during shortages, but it increased direct drug spending in non-critically ill patients at our institution during FY 2014. Persistent shortages can drive market costs of K-Phos IV, however, necessitating frequent reconsideration of resource utilization. C1 [Kudsk, Kenneth A.] William S Middleton Mem Vet Adm Med Ctr, Veteran Adm Surg Serv, Madison, WI USA. [Curtis, Caitlin S.; Webb, Aaron P.] Univ Wisconsin Hosp & Clin, Dept Pharm, Madison, WI 53792 USA. [Busch, Rebecca A.; Kudsk, Kenneth A.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Surg, Madison, WI USA. [Crass, Ryan L.] Univ Wisconsin, Sch Pharm, 425 N Charter St, Madison, WI 53706 USA. RP Kudsk, KA (reprint author), G5 341 Clin Sci Ctr, 600 Highland Ave, Madison, WI 53792 USA. EM kudsk@surgery.wisc.edu FU Surgical Oncology Research Training Program [T32 CA090217]; William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin FX This material is the result of work supported with the resources and use of facilities at the William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin. The contents of this article do not represent the views of the Department of Veterans Affairs or the United States government. The project described was supported in part by the Surgical Oncology Research Training Program T32 CA090217. NR 9 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0884-5336 EI 1941-2452 J9 NUTR CLIN PRACT JI Nutr. Clin. Pract. PD APR PY 2016 VL 31 IS 2 BP 218 EP 222 DI 10.1177/0884533615583093 PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DH6LS UT WOS:000372902700012 PM 25896971 ER PT J AU Holland, CL Rubio, D Rodriguez, KL Kraemer, KL Day, N Arnold, RM Tarr, JA Chang, JC AF Holland, Cynthia L. Rubio, Doris Rodriguez, Keri L. Kraemer, Kevin L. Day, Nancy Arnold, Robert M. Tarr, Jill A. Chang, Judy C. TI Obstetric Health Care Providers' Counseling Responses to Pregnant Patient Disclosures of Marijuana Use SO OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT International Conference on Communication in Healthcare CY OCT 25-28, 2015 CL New Orleans, LA ID EXPOSURE; ATTENTION; BEHAVIOR; ALCOHOL; ABUSE; DRUG; AGE AB OBJECTIVE: To describe obstetric health care providers' responses and counseling approaches to patients' disclosures of marijuana use during first prenatal visits. METHODS: We performed a content analysis of audio-recorded patient-health care provider first prenatal visits for obstetrics health care providers' responses to patients' disclosure of marijuana use. The study was conducted at five urban outpatient clinics located in Pittsburgh, Pennsylvania. RESULTS: Among 468 audio-recorded first obstetric encounters, 90 patients (19%) disclosed marijuana use to 47 health care providers; mean number of recoded encounters containing marijuana disclosures for participating health providers was 1.8 +/- 1.4. In 48% of these 90 visits, obstetric health care providers did not respond to marijuana use disclosures or offer counseling. When counseling was offered, it consisted of general statements without specific information on the risks or outcomes related to marijuana use in pregnancy, discussions regarding the need for urine toxicology testing, and warnings that use detected at the time of delivery would initiate child protective services involvement. CONCLUSION: Obstetric health care provider responses to disclosure of marijuana use occurred in approximately half of patient encounters when marijuana use was disclosed and focused on legal and procedural consequences with less focus on health or medical implications. Our results suggest a need for health care provider training on potential consequences of perinatal marijuana use and communication skills for counseling patients about perinatal marijuana. C1 Magee Womens Res Inst, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA. Univ Pittsburgh, Dept Internal Med, Ctr Res Hlth Care, Div Gen Internal Med,Clin & Translat Sci Inst, Pittsburgh, PA USA. Vet Affairs Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. Ctr Res Hlth Care, Inst Enhance Palliat Care, Sect Palliat Care & Med Eth, Inst Doctor Patient Commun, Pittsburgh, PA USA. RP Chang, JC (reprint author), 300 Halket St, Pittsburgh, PA 15213 USA. EM jchang@mail.magee.edu RI Day, Nancy/H-3171-2016 FU NCATS NIH HHS [UL1 TR000005, UL1TR000005]; NIDA NIH HHS [1R01DA026410-01A1, R01 DA026410] NR 24 TC 2 Z9 2 U1 2 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD APR PY 2016 VL 127 IS 4 BP 681 EP 687 DI 10.1097/AOG.0000000000001343 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DH4YF UT WOS:000372791000009 PM 26959210 ER PT J AU Tracy, EE Bortoletto, P AF Tracy, Erin E. Bortoletto, Pietro TI The Role of Social Networks, Medical-Legal Climate, and Patient Advocacy on Surgical Options A New Era SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID ESSURE; STERILIZATION; MESH AB The dissemination of information online and resultant public discourse through social media and other online channels has influenced the practice of medicine in dramatic ways. Physicians have historically worked to develop new techniques and devices for the benefit of their patients. It is only a more recent phenomenon, however, that these tools are either removed or their use is curtailed largely driven by anecdotal reports; passionate, vocal, often media-savvy advocates; and plaintiff attorneys. The use of power morcellation, hysteroscopic tubal sterilization, and mesh in urogynecologic procedures all have been victims of these societal pressures. It is important for health care professionals to be involved in the debate to ensure that public outcry does not unduly influence what we, as clinicians, are able to safely offer our patients. By being better advocates for our field, our instruments, and our patients, we can ensure medical decision-making is driven by good science and not public fervor. C1 [Tracy, Erin E.; Bortoletto, Pietro] Massachusetts Gen Hosp, Vincent Obstet & Gynecol, 55 Fruit St,406 Founders House, Boston, MA 02114 USA. RP Bortoletto, P (reprint author), Massachusetts Gen Hosp, Vincent Obstet & Gynecol, 55 Fruit St,406 Founders House, Boston, MA 02114 USA. EM pbortoletto@partners.org NR 23 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 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD APR PY 2016 VL 127 IS 4 BP 758 EP 762 DI 10.1097/AOG.0000000000001335 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DH4YU UT WOS:000372792600003 PM 26959205 ER PT J AU Schorge, JO AF Schorge, John O. TI What Is New in Prevention of Ovarian Cancer? Best Articles From the Past Year SO OBSTETRICS AND GYNECOLOGY LA English DT Editorial Material AB This month we focus on current research in preventing ovarian cancer. Dr. Schorge discusses four recent publications, which are concluded with a bottom line that is the take-home message. The complete reference for each can be found in Box 1 on this page, along with direct links to the abstracts. C1 [Schorge, John O.] Massachusetts Gen Hosp, Dept OB GYN Gynecol Oncol, Boston, MA 02114 USA. RP Schorge, JO (reprint author), Massachusetts Gen Hosp, Dept OB GYN Gynecol Oncol, Boston, MA 02114 USA. EM jschorge@partners.org NR 2 TC 1 Z9 1 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD APR PY 2016 VL 127 IS 4 BP 795 EP 796 DI 10.1097/AOG.0000000000001380 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DH4ZC UT WOS:000372793500004 PM 26959218 ER PT J AU McCarrier, KP Deal, LS Abraham, L Blum, SI Bush, EN Martin, ML Thase, ME Coons, SJ AF McCarrier, Kelly P. Deal, Linda S. Abraham, Lucy Blum, Steven I. Bush, Elizabeth Nicole Martin, Mona L. Thase, Michael E. Coons, Stephen Joel CA PRO Consortium's Depression Workin TI Patient-Centered Research to Support the Development of the Symptoms of Major Depressive Disorder Scale (SMDDS): Initial Qualitative Research SO PATIENT-PATIENT CENTERED OUTCOMES RESEARCH LA English DT Article ID OUTCOMES PRO INSTRUMENTS; INTERRATER RELIABILITY; RATING-SCALE; SELF-REPORT; MELANCHOLIA; VALIDATION; SEVERITY AB Content valid, patient-reported outcome (PRO) measures of major depressive disorder (MDD) symptoms are needed to assess MDD treatment benefit. While a range of questionnaires are currently available to evaluate aspects of depression from the patient's perspective, their comprehensiveness and qualitative development histories are unclear. The objective of this study was to describe the process and results of the preliminary qualitative development of a new symptom-based PRO measure intended to assess treatment benefit in MDD clinical trials. Qualitative interviews were conducted with adult MDD patients in the USA who recently experienced a major depressive episode. Experienced interviewers conducted concept elicitation (CE) and cognitive interviews using semi-structured interview guides. The CE interview guide was used to elicit spontaneous reports of symptom experiences along with probing to further explore and confirm concepts. The cognitive interview guide was developed to evaluate concept relevance, understandability, and structure of the draft items, and to facilitate further instrument refinement. Forty patients participated in the CE interviews. A total of 3022 symptom codes, representing 84 different concepts were derived from the transcripts. Data from the CE interviews were considered alongside existing literature and clinical expert opinion during an item-generation process, leading to development of a preliminary version of the Symptoms of Major Depressive Disorder Scale (SMDDS). Fifteen patients participated in three waves of cognitive interviews, during which the SMDDS was further refined. The SMDDS is a 35-item PRO measure intended for use as an endpoint in MDD clinical trials to support medical product labeling. The SMDDS uses a 7-day recall period and verbal rating scales. It was developed in accordance with the US Food and Drug Administration (FDA)'s PRO Guidance and best practices. Qualitative interviews have provided evidence for content validity. Future quantitative studies will confirm the SMDDS's measurement properties and support FDA qualification. C1 [McCarrier, Kelly P.; Martin, Mona L.] Hlth Res Associates Inc, 6505 216th St SW Suite 105, Mountlake Terrace, WA 98043 USA. [Deal, Linda S.] Shire, Clin Outcomes Assessment, Wayne, PA USA. [Abraham, Lucy] Pfizer Ltd, Outcomes & Evidence, Tadworth, Surrey, England. [Blum, Steven I.] GlaxoSmithKline, Patient Reported Outcomes, King Of Prussia, PA USA. [Bush, Elizabeth Nicole] Eli Lilly & Co, PRO Ctr Expertise, Indianapolis, IN 46285 USA. [Thase, Michael E.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Thase, Michael E.] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. [Coons, Stephen Joel] Crit Path Inst, Patient Reported Outcome Consortium, Tucson, AZ USA. RP McCarrier, KP (reprint author), Hlth Res Associates Inc, 6505 216th St SW Suite 105, Mountlake Terrace, WA 98043 USA. EM mccarrier@hrainc.net FU AbbVie; Bristol-Myers Squibb; Eli Lilly and Company; Forest Research Institute; Janssen; Pfizer; Roche Products Limited; Shire; Sunovion; Takeda; United States Food and Drug Administration [U01FD003865] FX This research was funded by the following members of the PRO Consortium: AbbVie, Bristol-Myers Squibb, Eli Lilly and Company, Forest Research Institute, Janssen, Pfizer, Roche Products Limited, Shire, Sunovion, and Takeda. The PRO Consortium receives support through Grant U01FD003865 from the United States Food and Drug Administration to the Critical Path Institute. NR 28 TC 1 Z9 1 U1 0 U2 1 PU ADIS INT LTD PI NORTHCOTE PA 5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND SN 1178-1653 EI 1178-1661 J9 PATIENT JI Patient PD APR PY 2016 VL 9 IS 2 BP 117 EP 134 DI 10.1007/s40271-015-0132-1 PG 18 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA DH6EL UT WOS:000372883700003 PM 26113249 ER PT J AU Rowan, CM Gertz, SJ McArthur, J Fitzgerald, JC Nitu, ME Loomis, A Hsing, DD Duncan, CN Mahadeo, KM Smith, LS Moffet, J Hall, MW Pinos, EL Cheifetz, IM Tamburro, RF AF Rowan, Courtney M. Gertz, Shira J. McArthur, Jennifer Fitzgerald, Julie C. Nitu, Mara E. Loomis, Ashley Hsing, Deyin D. Duncan, Christine N. Mahadeo, Kris M. Smith, Lincoln S. Moffet, Jerelyn Hall, Mark W. Pinos, Emily L. Cheifetz, Ira M. Tamburro, Robert F. CA Investigators Pediat Acute Lung In TI Invasive Mechanical Ventilation and Mortality in Pediatric Hematopoietic Stem Cell Transplantation: A Multicenter Study* SO PEDIATRIC CRITICAL CARE MEDICINE LA English DT Article DE critical care; hematopoietic stem cell transplantation; respiratory insufficiency; artificial respiration; mortality ID RESPIRATORY-DISTRESS-SYNDROME; BONE-MARROW-TRANSPLANTATION; ACUTE LUNG INJURY; FREQUENCY OSCILLATORY VENTILATION; RENAL REPLACEMENT THERAPY; REQUIRING INTENSIVE-CARE; CRITICALLY-ILL CHILDREN; INHALED NITRIC-OXIDE; PERMISSIVE HYPOXEMIA; FLUID OVERLOAD AB Objective: To establish the current respiratory practice patterns in pediatric hematopoietic stem cell transplant patients and investigate their associations with mortality across multiple centers. Design: Retrospective cohort between 2009 and 2014. Setting: Twelve children's hospitals in the United States. Patients: Two hundred twenty-two pediatric allogeneic hematopoietic stem cell transplant recipients with acute respiratory failure using invasive mechanical ventilation. Interventions: None. Measurements and Main Results: PICU mortality of our cohort was 60.4%. Mortality at 180 days post PICU discharge was 74%. Length of PICU stay prior to initiation of invasive mechanical ventilation was significantly lower in survivors, and the odds of mortality increased for longer length of PICU stay prior to intubation. A total of 91 patients (41%) received noninvasive ventilation at some point during their PICU stay prior to intubation. Noninvasive ventilation use preintubation was associated with increased mortality (odds ratio, 2.1; 95% CI, 1.2-3.6; p = 0.010). Patients ventilated longer than 15 days had higher odds of death (odds ratio, 2.4; 95% CI, 1.3-4.2; p = 0.004). Almost 40% of patients (n = 85) were placed on high-frequency oscillatory ventilation with a mortality of 76.5% (odds ratio, 3.3; 95% CI, 1.7-6.5; p = 0.0004). Of the 20 patients who survived high-frequency oscillatory ventilation, 18 were placed on high-frequency oscillatory ventilation no later than the third day of invasive mechanical ventilation. In this subset of 85 patients, transition to high-frequency oscillatory ventilation within 2 days of the start of invasive mechanical ventilation resulted in a 76% decrease in the odds of death compared with those who transitioned to high-frequency oscillatory ventilation later in the invasive mechanical ventilation course. Conclusions: This study suggests that perhaps earlier more aggressive critical care interventions in the pediatric hematopoietic stem cell transplant patient with respiratory failure requiring invasive mechanical ventilation may offer an opportunity to improve outcomes. C1 [Rowan, Courtney M.; Nitu, Mara E.] Indiana Univ Sch Med, Riley Hosp Children, Dept Pediat, Indianapolis, IN 46202 USA. [Gertz, Shira J.] Hackensack Univ, Med Ctr, Joseph M Sanzari Childrens Hosp, Dept Pediat, Hackensack, NJ USA. [McArthur, Jennifer] Med Coll Wisconsin, Childrens Hosp Wisconsin, Dept Pediat, Milwaukee, WI 53226 USA. [Fitzgerald, Julie C.] Univ Penn, Childrens Hosp Philadelphia, Perelman Sch Med, Dept Anesthesia, Philadelphia, PA 19104 USA. [Loomis, Ashley] Univ Minnesota, Masonic Childrens Hosp, Dept Pediat, Minneapolis, MN USA. [Hsing, Deyin D.] New York Presbyterian Hosp, Weill Cornell Med Coll, Dept Pediat, New York, NY USA. [Duncan, Christine N.] Dana Farber Canc Inst, Dept Pediat, Boston, MA 02115 USA. [Mahadeo, Kris M.] Childrens Hosp Montefiore, Albert Einstein Coll Med, Dept Pediat, Bronx, NY USA. [Smith, Lincoln S.] Univ Washington, Dept Pediat, Seattle, WA 98195 USA. [Smith, Lincoln S.] Seattle Childrens Hosp, Seattle, WA USA. [Moffet, Jerelyn; Cheifetz, Ira M.] Duke Childrens Hosp, Dept Pediat, Durham, NC USA. [Hall, Mark W.] Nationwide Childrens Hosp, Dept Pediat, Columbus, OH USA. [Pinos, Emily L.; Tamburro, Robert F.] Penn State Univ, Coll Med, Penn State Hershey Childrens Hosp, Dept Pediat, Hershey, PA USA. [Tamburro, Robert F.] Penn State Univ, Coll Med, Penn State Hershey Childrens Hosp, Dept Publ Hlth, Hershey, PA USA. RP Rowan, CM (reprint author), Indiana Univ Sch Med, Riley Hosp Children, Dept Pediat, Indianapolis, IN 46202 USA. EM coujohns@iu.edu FU Riley Children's Foundation; NIH; Philips; CareFusion; Covidien; Teleflex; Ikaria; U.S. FDA Office of Orphan Product Development FX Dr. Rowan received grant support from the Riley Children's Foundation. Dr. Gertz is employed by Hackensack University Medical Center. Her institution received support for travel from Baxter Pharmaceuticals (investigator start up meeting for ongoing clinical trial). Dr. Moffet is employed by Duke University. Dr. Hall's institution received grant support from the NIH (Dr. Hall is NIH-funded for work unrelated to this project). Dr. Cheifetz consulted for Philips and Hill-Rom (Medical Advisor) and provided expert testimony for various entities. His institution received grant support from Philips, CareFusion, Covidien, Teleflex, and Ikaria. Dr. Tamburro received royalties from Verlag-Springer (textbook and study guide that he helped prepare as an associate editor). His institution received grant support (Dr. Tamburro received a grant from the U.S. FDA Office of Orphan Product Development to study the use of exogenous surfactant [calfactant] in pediatric hematopoietic stem cell transplant patients with acute lung injury. The medication for the trial was donated by the manufacturer [Ony, LLC]). The remaining authors have disclosed that they do not have any potential conflicts of interest. NR 39 TC 5 Z9 5 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1529-7535 EI 1947-3893 J9 PEDIATR CRIT CARE ME JI Pediatr. Crit. Care Med. PD APR PY 2016 VL 17 IS 4 BP 294 EP 302 DI 10.1097/PCC.0000000000000673 PG 9 WC Critical Care Medicine; Pediatrics SC General & Internal Medicine; Pediatrics GA DI0UA UT WOS:000373211600003 PM 26910477 ER PT J AU Berg, AT Baca, CB Rychlik, K Vickrey, BG Caplan, R Testa, FM Levy, SR AF Berg, Anne T. Baca, Christine B. Rychlik, Karen Vickrey, Barbara G. Caplan, Rochelle Testa, Francine M. Levy, Susan R. TI Determinants of Social Outcomes in Adults With Childhood-onset Epilepsy SO PEDIATRICS LA English DT Article ID LONG-TERM PROGNOSIS; ABSENCE EPILEPSY; 2 DECADES; CHILDREN; SEIZURES; DIAGNOSIS; BEHAVIOR; DUTCH; LIFE AB BACKGROUND: Adults with childhood-onset epilepsy experience poorer adult social outcomes than their peers. The relative roles of seizures over time versus learning and psychiatric problems are unclear. METHODS: We examined independent influences of psychiatric and learning disorders and of seizure course in 241 young adults (22-35 years old) with uncomplicated epilepsy in a longitudinal community-based cohort study. Social outcomes were ascertained throughout the study. A history of psychiatric and learning problems was ascertained similar to 9 years after study entry. Seizure course was: "Excellent," no seizures after the first year, in complete remission at last contact (N = 95, 39%); " Good, " seizures occurred 1 to 5 years after diagnosis, in complete remission at last contact (N = 56, 23%); " Fluctuating, " more complicated trajectories, but never pharmacoresistant (N = 70, 29%); " Pharmacoresistant, " long-term pharmacoresistant (N = 20, 8%). Multiple logistic regression was used to identify contributors to each social outcome. RESULTS: Better seizure course predicted college completion, being either employed or pursuing a degree, and driving, but was not substantially associated with other social outcomes. Poorer seizure course was associated with a greater likelihood of having offspring, particularly in women without partners. Learning problems, psychiatric disorders, or both negatively influenced all but 2 of the social outcomes. CONCLUSIONS: In young adults with uncomplicated epilepsy, the course of seizures contributed primarily to education, employment, and driving. A history of learning problems and psychiatric disorders adversely influenced most adult outcomes. These findings identify potential reasons for vocational and social difficulties encountered by young adults with childhood epilepsy and areas to target for counseling and transition planning. C1 [Berg, Anne T.] Ann & Robert H Lurie Childrens Hosp Chicago, Epilepsy Ctr, Box 29,225 East Chicago Ave, Chicago, IL 60611 USA. [Rychlik, Karen] Ann & Robert H Lurie Childrens Hosp Chicago, Stanley Manne Childrens Res Inst, Biostat Res Core, Chicago, IL 60611 USA. [Berg, Anne T.] Northwestern Feinberg Sch Med, Dept Pediat, Chicago, IL USA. [Baca, Christine B.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Dept Neurol, Los Angeles, CA 90024 USA. [Caplan, Rochelle] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, David Geffen Sch Med, Los Angeles, CA 90024 USA. [Baca, Christine B.] VA Greater Los Angeles Hlth Care Syst, Dept Neurol, Los Angeles, CA USA. [Vickrey, Barbara G.] Icahn Sch Med Mt Sinai, Dept Neurol, New York, NY 10029 USA. [Testa, Francine M.; Levy, Susan R.] Yale Univ, Sch Med, Dept Neurol, New Haven, CT 06510 USA. [Testa, Francine M.; Levy, Susan R.] Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06510 USA. RP Berg, AT (reprint author), Ann & Robert H Lurie Childrens Hosp Chicago, Epilepsy Ctr, Box 29,225 East Chicago Ave, Chicago, IL 60611 USA. EM atberg@luriechildrens.org FU National Institute of Neurologic Disorders and Stroke [R37-NS31146]; National Institutes of Health (NIH) FX This study was funded by grant R37-NS31146 from the National Institute of Neurologic Disorders and Stroke. Funded by the National Institutes of Health (NIH). NR 37 TC 1 Z9 1 U1 1 U2 4 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD APR PY 2016 VL 137 IS 4 AR e20153944 DI 10.1542/peds.2015-3944 PG 10 WC Pediatrics SC Pediatrics GA DI0OU UT WOS:000373197500049 ER PT J AU Treister, NS London, WB Guo, DJ Malsch, M Verrill, K Brewer, J Margossian, S Duncan, C AF Treister, Nathaniel S. London, Wendy B. Guo, Dongjing Malsch, Maggie Verrill, Kelly Brewer, Jennifer Margossian, Steven Duncan, Christine TI A Feasibility Study Evaluating Extraoral Photobiomodulation Therapy for Prevention of Mucositis in Pediatric Hematopoietic Cell Transplantation SO PHOTOMEDICINE AND LASER SURGERY LA English DT Article ID LEVEL LASER THERAPY; ORAL MUCOSITIS; CANCER; LLLT; METAANALYSIS; SCT AB Objective: The objective of this study was to determine the feasibility, safety, and tolerability of providing extraoral photobiomodulation therapy (PBT) for prevention of oral mucositis (OM) in pediatric hematopoietic cell transplantation (HCT). Background data: OM is a frequent complication in pediatric HCT. Methods: Patients 4-21 years of age scheduled for myeloablative HCT were eligible to participate. PBT was delivered using a THOR Model LX2M with a 69 Diode LED Cluster Probe (34 x 660 nm 10 mW, 35 x 850 nm 30 mW; 1390 mW total power output) at an irradiance of 50 mW/cm(2). Daily treatment exposed six sites (right, left, and midline face and neck) for 60 sec each, for a total dose of 3.0 J/cm(2). Treatment was initiated on the 1st day of conditioning, through day +20. OM assessments were completed at baseline then daily, from day -1 through day +20. Feasibility assessment included both qualitative and quantitative measures and outcomes from patients and providers. Results: Thirteen patients with a median age of 15 years (range, 4.8-21.6) were consented and enrolled, and completed the protocol. The incidence of severe OM [World Health Organization (WHO) Grade >= 3] was 77%, with a median duration of 4 days (range, 1-14). Of 355 attempted PBT administrations, there were six refusals, and the mean proportion of days with data submitted was 96.2% [95% confidence interval (CI): 78.5-97.2%]. The 10 trained nurses all reported that the device was accessible, maneuverable, and lightweight, and that training was effective. There was no reported toxicity attributed to the PBT. Conclusions: Daily delivery of external PBT and completion of OM evaluations is feasible in children undergoing HCT. C1 [Treister, Nathaniel S.; Brewer, Jennifer] Brigham & Womens Hosp, Div Oral Med & Dent, 1620 Tremont St,3rd Floor, Boston, MA 02120 USA. [Treister, Nathaniel S.] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, 188 Longwood Ave, Boston, MA 02115 USA. [London, Wendy B.; Guo, Dongjing; Margossian, Steven; Duncan, Christine] Boston Childrens Hosp, Dana Farber Canc Inst, Div Pediat Hematol Oncol, Boston, MA USA. [London, Wendy B.; Margossian, Steven; Duncan, Christine] Harvard Univ, Sch Med, Boston, MA USA. [Malsch, Maggie; Verrill, Kelly] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA USA. RP Treister, NS (reprint author), Brigham & Womens Hosp, Div Oral Med & Dent, 1620 Tremont St,3rd Floor, Boston, MA 02120 USA. EM ntreister@partners.org NR 13 TC 0 Z9 0 U1 1 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1549-5418 EI 1557-8550 J9 PHOTOMED LASER SURG JI Photomed. Laser Surg. PD APR 1 PY 2016 VL 34 IS 4 BP 178 EP 184 DI 10.1089/pho.2015.4021 PG 7 WC Surgery SC Surgery GA DI1TD UT WOS:000373277800007 PM 26982624 ER PT J AU Fleseriu, M Pivonello, R Young, J Hamrahian, AH Molitch, ME Shimizu, C Tanaka, T Shimatsu, A White, T Hilliard, A Tian, C Sauter, N Biller, BMK Bertagna, X AF Fleseriu, Maria Pivonello, Rosario Young, Jacques Hamrahian, Amir H. Molitch, Mark E. Shimizu, Chikara Tanaka, Tomoaki Shimatsu, Akira White, Tracy Hilliard, Annie Tian, Chuan Sauter, Nicholas Biller, Beverly M. K. Bertagna, Xavier TI Osilodrostat, a potent oral 11 beta-hydroxylase inhibitor: 22-week, prospective, Phase II study in Cushing's disease SO PITUITARY LA English DT Article DE LCI699; Osilodrostat; 11 beta-hydroxylase; Cushing's; Cortisol ID GLUCOCORTICOID-RECEPTOR ANTAGONIST; PROSPECTIVE MULTICENTER; MEDICAL-MANAGEMENT; MIFEPRISTONE; PEGVISOMANT; THERAPY AB In a 10-week proof-of-concept study (LINC 1), the potent oral 11 beta-hydroxylase inhibitor osilodrostat (LCI699) normalized urinary free cortisol (UFC) in 11/12 patients with Cushing's disease. The current 22-week study (LINC 2; NCT01331239) further evaluated osilodrostat in patients with Cushing's disease. Phase II, open-label, prospective study of two patient cohorts. Follow-up cohort: 4/12 patients previously enrolled in LINC 1, offered re-enrollment if baseline mean UFC was above ULN. Expansion cohort: 15 newly enrolled patients with baseline UFC > 1.5 x ULN. In the follow-up cohort, patients initiated osilodrostat twice daily at the penultimate efficacious/tolerable dose in LINC 1; dose was adjusted as needed. In the expansion cohort, osilodrostat was initiated at 4 mg/day (10 mg/day if baseline UFC > 3 x ULN), with dose escalated every 2 weeks to 10, 20, 40, and 60 mg/day until UFC a parts per thousand currency sign ULN. Main efficacy endpoint was the proportion of responders (UFC a parts per thousand currency sign ULN or a parts per thousand yen50 % decrease from baseline) at weeks 10 and 22. Overall response rate was 89.5 % (n/N = 17/19) at 10 weeks and 78.9 % (n/N = 15/19) at 22 weeks; at week 22, all responding patients had UFC a parts per thousand currency sign ULN. The most common AEs observed during osilodrostat treatment were nausea, diarrhea, asthenia, and adrenal insufficiency (n = 6 for each). New or worsening hirsutism (n = 2) and/or acne (n = 3) were reported among four female patients, all of whom had increased testosterone levels. Osilodrostat treatment reduced UFC in all patients; 78.9 % (n/N = 15/19) had normal UFC at week 22. Treatment with osilodrostat was generally well tolerated. C1 [Fleseriu, Maria] Oregon Hlth & Sci Univ, Dept Med, Northwest Pituitary Ctr, Portland, OR 97201 USA. [Fleseriu, Maria] Oregon Hlth & Sci Univ, Dept Neurol Surg, Northwest Pituitary Ctr, Portland, OR 97201 USA. [Pivonello, Rosario] Univ Naples Federico II, Dipartimento Med Clin & Chirurg, Sez Endocrinol, Naples, Italy. [Young, Jacques] Univ Paris 11, Hop Bicetre, AP HP, Dept Endocrinol, Paris, France. [Hamrahian, Amir H.] Cleveland Clin Fdn, Dept Diabet Endocrinol & Metab, 9500 Euclid Ave, Cleveland, OH 44195 USA. [Molitch, Mark E.] Northwestern Univ, Div Endocrinol Metab & Mol Med, Chicago, IL 60611 USA. [Shimizu, Chikara] Hokkaido Univ Hosp, Div Lab & Transfus Med, Sapporo, Hokkaido 060, Japan. [Tanaka, Tomoaki] Chiba Univ Hosp, Div Endocrinol & Metab, Chiba, Japan. [Shimatsu, Akira] Natl Hosp Org, Kyoto Med Ctr, Clin Res Inst, Kyoto, Japan. [White, Tracy; Hilliard, Annie; Tian, Chuan; Sauter, Nicholas] Novartis Pharmaceut, E Hanover, NJ USA. [Biller, Beverly M. K.] Massachusetts Gen Hosp, Neuroendocrine Clin Ctr, Boston, MA 02114 USA. [Bertagna, Xavier] Univ Paris 05, Hop Cochin, Ctr Reference Malad Rares Surrenale, Dept Endocrinol,Fac Med Paris Descartes, Paris, France. RP Fleseriu, M (reprint author), Oregon Hlth & Sci Univ, Dept Med, Northwest Pituitary Ctr, Portland, OR 97201 USA.; Fleseriu, M (reprint author), Oregon Hlth & Sci Univ, Dept Neurol Surg, Northwest Pituitary Ctr, Portland, OR 97201 USA. EM fleseriu@ohsu.edu FU Novartis Pharma AG; Novartis Pharmaceuticals Corporation FX This study was funded by Novartis Pharma AG. Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation. We thank Peter Unge, Albert Kandra, and Michael Roughton for their support with the development of this manuscript. We thank Andrew Jones PhD for medical editorial assistance with this manuscript. We thank the sub-investigators and the study coordinators/nurses involved in this study, and give special thanks to the patients who made this study possible. NR 25 TC 4 Z9 4 U1 0 U2 2 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 APR PY 2016 VL 19 IS 2 BP 138 EP 148 DI 10.1007/s11102-015-0692-z PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DH6WI UT WOS:000372932400004 PM 26542280 ER PT J AU Green, JD Jakupcak, M AF Green, Jonathan D. Jakupcak, Matthew TI Masculinity and Men's Self-Harm Behaviors: Implications for Non-Suicidal Self-Injury Disorder SO PSYCHOLOGY OF MEN & MASCULINITY LA English DT Article DE gender; masculinity; nonsuicidal self-injury disorder; self-harm; self-injury ID BORDERLINE PERSONALITY-DISORDER; COLLEGE POPULATION; SEX-DIFFERENCES; MUTILATION; PSYCHOPATHOLOGY; ADOLESCENTS; AGGRESSION; INVENTORY; THOUGHTS; FEATURES AB A composite of clinical cases treated by the authors is presented to illustrate the complexity of understanding nonsuicidal self-harm as it occurs in men, particularly in the context of Non-Suicidal Self-Injury (NSSI) disorder, a condition for further study in the fifth edition of Diagnostic and Statistical Manual of Mental Disorders. As a function of adherence to masculine norms, intentionality, social acceptability, and functions of self-harm behaviors common among men do not appear to be in line with diagnostic criteria for NSSI disorder, despite these behaviors resulting in serious tissue damage worthy of clinical and research attention. Suggestions for novel approaches to the assessment and treatment of self-harm, particularly in light of men's difficulty identifying and discussing intentionality of self-harm behaviors, are presented along with specific recommendations clinical practice. C1 [Green, Jonathan D.] VA Boston Healthcare Syst, 116B-4,150 South Huntington Ave, Boston, MA 02130 USA. [Green, Jonathan D.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02215 USA. [Jakupcak, Matthew] VA Puget Sound Healthcare Syst, Northwest Mental Illness Res Educ & Clin Ctr MIRE, Seattle, WA USA. [Jakupcak, Matthew] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. RP Green, JD (reprint author), VA Boston Healthcare Syst, 116B-4,150 South Huntington Ave, Boston, MA 02130 USA. EM Green.JonathanD@gmail.com NR 61 TC 1 Z9 1 U1 4 U2 8 PU EDUCATIONAL PUBLISHING FOUNDATION-AMERICAN PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST, NE, WASHINGTON, DC 20002-4242 USA SN 1524-9220 EI 1939-151X J9 PSYCHOL MEN MASCULIN JI Psychol. Men Masculinity PD APR PY 2016 VL 17 IS 2 BP 147 EP 155 DI 10.1037/a0039691 PG 9 WC Psychology, Social SC Psychology GA DI0RJ UT WOS:000373204400004 ER PT J AU Commissariat, PV Kenowitz, JR Trast, J Heptulla, RA Gonzalez, JS AF Commissariat, Persis V. Kenowitz, Joslyn R. Trast, Jeniece Heptulla, Rubina A. Gonzalez, Jeffrey S. TI Developing a Personal and Social Identity With Type 1 Diabetes During Adolescence: A Hypothesis Generative Study SO QUALITATIVE HEALTH RESEARCH LA English DT Article DE diabetes; adolescents; youth; young adults; lived experience; health; self; stigma; qualitative; thematic analysis; USA ID SELF-CARE; METABOLIC-CONTROL; MELLITUS; ILLNESS; GENDER; ASSOCIATION; SUPPORT; HEALTH; YOUTH; LIFE AB This study explored the incorporation of type 1 diabetes mellitus (T1DM) into self-identity among adolescents. Guided interviews explored 40 adolescents' views of T1DM in relation to their sense of self and relationships with others. Responses were analyzed using thematic analysis. Results revealed that the entire sample described T1DM as a significant burden; many described how T1DM made them feel less normal. Adolescents described both positive and negative aspects of self-management in social relationships, though most reported benefits in sharing T1DM with friends. Females were more likely to share information about T1DM and to describe positive changes in self-perception as a result of T1DM. The psychosocial processes related to integration of T1DM into self-identity described in these qualitative data provide hypothesis-generating findings that can guide future quantitative research examining incorporation of T1DM into adolescent self-identity in relation to measures of self-esteem, peer orientation, self-management, and glycemic control. C1 [Commissariat, Persis V.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Kenowitz, Joslyn R.; Gonzalez, Jeffrey S.] Yeshiva Univ, Ferkauf Grad Sch Psychol, Bronx, NY USA. [Heptulla, Rubina A.] Yeshiva Univ, Albert Einstein Coll Med, Pediat & Med, Bronx, NY USA. [Trast, Jeniece; Heptulla, Rubina A.; Gonzalez, Jeffrey S.] Montefiore Med Ctr, 111 E 210th St, Bronx, NY 10467 USA. [Gonzalez, Jeffrey S.] Yeshiva Univ, Albert Einstein Coll Med, Diabet Res Ctr, 1300 Morris Pk Ave,Rousso Bldg, Bronx, NY 10461 USA. RP Gonzalez, JS (reprint author), Yeshiva Univ, Albert Einstein Coll Med, Diabet Res Ctr, 1300 Morris Pk Ave,Rousso Bldg, Bronx, NY 10461 USA. EM jeffrey.gonzalez@einstein.yu.edu FU National Institutes of Health [P60 DK020541, R18 DK098742] FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Dr. Gonzalez's time and effort were partially supported by Grants P60 DK020541 and R18 DK098742 from the National Institutes of Health. NR 50 TC 0 Z9 0 U1 4 U2 8 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 APR PY 2016 VL 26 IS 5 SI SI BP 672 EP 684 DI 10.1177/1049732316628835 PG 13 WC Information Science & Library Science; Social Sciences, Interdisciplinary; Social Sciences, Biomedical SC Information Science & Library Science; Social Sciences - Other Topics; Biomedical Social Sciences GA DH5KE UT WOS:000372825900008 PM 26893304 ER PT J AU Hong, JX Zhong, TL Li, HL Xu, JM Ye, XF Mu, Z Lu, Y Mashaghi, A Zhou, Y Tan, MX Li, QY Sun, XH Liu, ZG Xu, JJ AF Hong, Jiaxu Zhong, Taoling Li, Huili Xu, Jianming Ye, Xiaofang Mu, Zhe Lu, Yi Mashaghi, Alireza Zhou, Ying Tan, Mengxi Li, Qiyuan Sun, Xinghuai Liu, Zuguo Xu, Jianjiang TI Ambient air pollution, weather changes, and outpatient visits for allergic conjunctivitis: A retrospective registry study SO SCIENTIFIC REPORTS LA English DT Article ID CLIMATE-CHANGE; PARTICULATE MATTER; ARMA MODEL; HEALTH; CHINA; SYMPTOMS; CHILDREN; ASTHMA; PREVALENCE; EPITHELIUM AB Allergic conjunctivitis is a common problem that significantly impairs patients' quality of life. Whether air pollution serves as a risk factor for the development of allergic conjunctivitis remains elusive. In this paper, we assess the relationship between air pollutants and weather conditions with outpatient visits for allergic conjunctivitis. By using a time-series analysis based on the largest dataset ever assembled to date, we found that the number of outpatient visits for allergic conjunctivitis was significantly correlated with the levels of NO2, O-3, and temperature, while its association with humidity was statistically marginal. No associations between PM10, PM2.5, SO2, or wind velocity and outpatient visits were seen. Subgroup analyses showed that sex seemed to modify the effects of humidity on outpatient visits for allergic conjunctivitis, but not for NO2, O-3, or temperature. People younger than 40 were found to be susceptible to changes of all four parameters, while those older than 40 were only consistently affected by NO2 levels. Our findings revealed that higher levels of ambient NO2, O-3, and temperature increase the chances of outpatient visits for allergic conjunctivitis. Ambient air pollution and weather changes may contribute to the worsening of allergic conjunctivitis. C1 [Hong, Jiaxu; Lu, Yi; Sun, Xinghuai; Xu, Jianjiang] Fudan Univ, Shanghai Med Coll, Dept Ophthalmol & Visual Sci, Eye & ENT Hosp, 83 Rd Fenyang, Shanghai 200433, Peoples R China. [Hong, Jiaxu; Zhong, Taoling; Li, Huili; Zhou, Ying; Li, Qiyuan; Liu, Zuguo] Xiamen Univ, Inst Eye, Rd Xiangan Nan, Xiamen, Peoples R China. [Xu, Jianming; Ye, Xiaofang; Mu, Zhe] Shanghai Key Lab Meteorol & Hlth, 951 Rd Jinxiu, Shanghai, Peoples R China. [Hong, Jiaxu; Mashaghi, Alireza] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA 02114 USA. [Sun, Xinghuai] Fudan Univ, Inst Brain Sci, State Key Lab Med Neurobiol, Shanghai 200433, Peoples R China. [Sun, Xinghuai] Minist Hlth China, Myopia Key Lab, Shanghai, Peoples R China. [Tan, Mengxi] Westminster Coll, Dept Environm Sci, Fulton, MO 65251 USA. RP Xu, JJ (reprint author), Fudan Univ, Shanghai Med Coll, Dept Ophthalmol & Visual Sci, Eye & ENT Hosp, 83 Rd Fenyang, Shanghai 200433, Peoples R China.; Liu, ZG (reprint author), Xiamen Univ, Inst Eye, Rd Xiangan Nan, Xiamen, Peoples R China. EM zuguoliu@126.com; jianjiangxu@126.com FU Key Clinic Medicine Research Program, the Ministry of Health, China [201302015]; National Science and Technology Research Program, the Ministry of Science and Technology, China [2012BAI08B01]; National Natural Science Foundation of China [81170817, 81200658, 81300735, 81270978, U1205025, 81330022]; Scientific Research Program, Science and Technology Commission of Shanghai Municipality, Shanghai [13441900900, 13430720400]; Chinese Postdoctoral Fund [XMU135890]; New Technology Joint Research Project in Shanghai Hospitals [SHDC12014114] FX The authors thank Prof. Reza Dana and Prof. David A. Sullivan from Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, for their constructive critique and suggestions. The authors were supported by grants from the Key Clinic Medicine Research Program, the Ministry of Health, China (201302015); the National Science and Technology Research Program, the Ministry of Science and Technology, China (2012BAI08B01); the National Natural Science Foundation of China (81170817, 81200658, 81300735, 81270978, U1205025, and 81330022); the Scientific Research Program, Science and Technology Commission of Shanghai Municipality, Shanghai (13441900900, 13430720400); the Chinese Postdoctoral Fund (XMU135890); and the New Technology Joint Research Project in Shanghai Hospitals (SHDC12014114). The sponsor or funding organization had no role in the design or conduct of this research. NR 32 TC 0 Z9 0 U1 7 U2 22 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 APR 1 PY 2016 VL 6 AR 23858 DI 10.1038/srep23858 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DI0RG UT WOS:000373204100001 PM 27033635 ER PT J AU Munn, LL Jain, RK AF Munn, Lance L. Jain, Rakesh K. TI The Forces of Cancer SO SCIENTIST LA English DT Article ID TUMOR-GROWTH; PRESSURE; CELLS; MICROENVIRONMENT; INVASION; THERAPY; VESSELS; FLOW C1 [Munn, Lance L.] Harvard Univ, Med Sch, Radiat Oncol, Cambridge, MA 02138 USA. [Jain, Rakesh K.] Harvard Univ, Med Sch, Tumor Biol Radiat Oncol, Cambridge, MA 02138 USA. [Jain, Rakesh K.] Massachusetts Gen Hosp, EL Steele Labs Tumor Biol, Boston, MA 02114 USA. RP Munn, LL (reprint author), Harvard Univ, Med Sch, Radiat Oncol, Cambridge, MA 02138 USA. RI Munn, Lance/L-3950-2016 OI Munn, Lance/0000-0003-0698-7232 NR 17 TC 0 Z9 0 U1 2 U2 7 PU LABX MEDIA GROUP PI MIDLAND PA PO BOX 216, 478 BAY ST, MIDLAND, ONTARIO L4R 1K9, CANADA SN 0890-3670 EI 1547-0806 J9 SCIENTIST JI Scientist PD APR PY 2016 VL 30 IS 4 BP 52 EP 57 PG 6 WC Information Science & Library Science; Multidisciplinary Sciences SC Information Science & Library Science; Science & Technology - Other Topics GA DH7BS UT WOS:000372946800014 ER PT J AU Gremmel, T Frelinger, AL Michelson, AD AF Gremmel, Thomas Frelinger, Andrew L., III Michelson, Alan D. TI Platelet Physiology SO SEMINARS IN THROMBOSIS AND HEMOSTASIS LA English DT Article DE platelet function; platelet structure; platelet granules; platelet surface glycoproteins; platelet activation pathways; platelet physiology; review ID ACUTE CORONARY SYNDROMES; GLYCOPROTEIN-IIB-IIIA; IB-IX-V; OPEN CANALICULAR SYSTEM; LYSOSOME-RELATED ORGANELLES; ELECTRON MICROSCOPIC OBSERVATIONS; PROTEASE-ACTIVATED RECEPTORS; HERMANSKY-PUDLAK-SYNDROME; STORAGE POOL-DEFICIENCY; HUMAN-BLOOD PLATELETS AB Platelets are the smallest blood cells, numbering 150 to 350 x 10(9)/L in healthy individuals. The ability of activated platelets to adhere to an injured vessel wall and form aggregates was first described in the 19th century. Besides their long-established roles in thrombosis and hemostasis, platelets are increasingly recognized as pivotal players in numerous other pathophysiological processes including inflammation and atherogenesis, antimicrobial host defense, and tumor growth and metastasis. Consequently, profound knowledge of platelet structure and function is becoming more important in research and in many fields of modern medicine. This review provides an overview of platelet physiology focusing particularly on the structure, granules, surface glycoproteins, and activation pathways of platelets. C1 [Gremmel, Thomas; Frelinger, Andrew L., III; Michelson, Alan D.] Dana Farber Canc Inst, Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Gremmel, Thomas] Med Univ Vienna, Dept Internal Med 2, Vienna, Austria. RP Gremmel, T (reprint author), Boston Childrens Hosp, Div Hematol Oncol, Ctr Platelet Res Studies, 300 Longwood Ave, Boston, MA USA. EM thomas.gremmel@childrens.harvard.edu OI Gremmel, Thomas/0000-0001-9554-7292 NR 226 TC 8 Z9 8 U1 5 U2 11 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0094-6176 EI 1098-9064 J9 SEMIN THROMB HEMOST JI Semin. Thromb. Hemost. PD APR PY 2016 VL 42 IS 3 BP 191 EP 204 DI 10.1055/s-0035-1564835 PG 14 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA DH9TR UT WOS:000373139300003 PM 26926581 ER PT J AU Shindo, A Maki, T Mandeville, ET Liang, AC Egawa, N Itoh, K Itoh, N Borlongan, M Holder, JC Chuang, TT McNeish, JD Tomimoto, H Lok, J Lo, EH Arai, K AF Shindo, Akihiro Maki, Takakuni Mandeville, Emiri T. Liang, Anna C. Egawa, Naohiro Itoh, Kanako Itoh, Naoki Borlongan, Mia Holder, Julie C. Chuang, Tsu Tshen McNeish, John D. Tomimoto, Hidekazu Lok, Josephine Lo, Eng H. Arai, Ken TI Astrocyte-Derived Pentraxin 3 Supports Blood-Brain Barrier Integrity Under Acute Phase of Stroke SO STROKE LA English DT Article DE astrocyte; blood-brain barrier; cell-cell interaction; endothelium; stroke ID ACUTE MYOCARDIAL-INFARCTION; LONG PENTRAXIN; ENDOTHELIAL-CELLS; PTX3; INJURY; ANGIOGENESIS; EXPRESSION; PROTEIN; GROWTH; DISRUPTION AB Background and Purpose Pentraxin 3 (PTX3) is released on inflammatory responses in many organs. However, roles of PTX3 in brain are still mostly unknown. Here we asked whether and how PTX3 contributes to blood-brain barrier dysfunction during the acute phase of ischemic stroke. Methods In vivo, spontaneously hypertensive rats were subjected to focal cerebral ischemia by transient middle cerebral artery occlusion. At day 3, brains were analyzed to evaluate the cellular origin of PTX3 expression. Correlations with blood-brain barrier breakdown were assessed by IgG staining. In vitro, rat primary astrocytes and rat brain endothelial RBE.4 cells were cultured to study the role of astrocyte-derived PTX3 on vascular endothelial growth factor-mediated endothelial permeability. Results During the acute phase of stroke, reactive astrocytes in the peri-infarct area expressed PTX3. There was negative correlation between gradients of IgG leakage and PTX3-positive astrocytes. Cell culture experiments showed that astrocyte-conditioned media increased levels of tight junction proteins and reduced endothelial permeability under normal conditions. Removing PTX3 from astrocyte-conditioned media by immunoprecipitation increased endothelial permeability. PTX3 strongly bound vascular endothelial growth factor in vitro and was able to decrease vascular endothelial growth factor-induced endothelial permeability. Conclusions Astrocytes in peri-infarct areas upregulate PTX3, which may support blood-brain barrier integrity by regulating vascular endothelial growth factor-related mechanisms. This response in astrocytes may comprise a compensatory mechanism for maintaining blood-brain barrier function after ischemic stroke. C1 [Shindo, Akihiro; Maki, Takakuni; Mandeville, Emiri T.; Liang, Anna C.; Egawa, Naohiro; Itoh, Kanako; Itoh, Naoki; Borlongan, Mia; Lok, Josephine; Lo, Eng H.; Arai, Ken] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neuroprotect Res Lab,Dept Radiol, Charlestown, MA USA. [Shindo, Akihiro; Maki, Takakuni; Mandeville, Emiri T.; Liang, Anna C.; Egawa, Naohiro; Itoh, Kanako; Itoh, Naoki; Borlongan, Mia; Lok, Josephine; Lo, Eng H.; Arai, Ken] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neuroprotect Res Lab,Dept Neurol, Charlestown, MA USA. [Lok, Josephine] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pediat, Charlestown, MA USA. [Holder, Julie C.; Chuang, Tsu Tshen; McNeish, John D.] GlaxoSmithKline, Dept Vasc Biol, Harlow, Essex, England. [Shindo, Akihiro; Tomimoto, Hidekazu] Mie Univ, Grad Sch Med, Dept Neurol, Tsu, Mie, Japan. RP Arai, K (reprint author), Neuroprotect Res Lab, MGH East 149-2401, Charlestown, MA 02129 USA. EM karai@partners.org FU National Institutes of Health [P01-NS55104, R01-NS065089]; Glaxo-Smith-Kline-Harvard-Stem-Cell-Institute consortium FX This study was supported, in part, by grants from National Institutes of Health (P01-NS55104 and R01-NS065089) and the Glaxo-Smith-Kline-Harvard-Stem-Cell-Institute consortium. NR 34 TC 5 Z9 5 U1 5 U2 10 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 APR PY 2016 VL 47 IS 4 BP 1094 EP 1100 DI 10.1161/STROKEAHA.115.012133 PG 7 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA DH5SX UT WOS:000372853200028 PM 26965847 ER PT J AU Raffeld, MR Debette, S Woo, D AF Raffeld, Miriam R. Debette, Stephanie Woo, Daniel TI International Stroke Genetics Consortium Update SO STROKE LA English DT Article DE epidemiology; genetics; stroke ID SPONTANEOUS INTRACEREBRAL HEMORRHAGE; AMERICAN-HEART-ASSOCIATION C1 [Raffeld, Miriam R.] Massachusetts Gen Hosp, Dept Neurol, Ctr Human Genet Res, Boston, MA 02114 USA. [Debette, Stephanie] Univ Paris 07, DHU Neurovasc Sorbonne Paris Cite, Dept Neurol, Lariboisiere Hosp, Paris, France. [Debette, Stephanie] Bordeaux Univ, Inserm U897, Talence, France. [Woo, Daniel] Univ Cincinnati, Med Ctr, Dept Neurol, 222 Piedmont Ave,3200, Cincinnati, OH 45219 USA. RP Woo, D (reprint author), Univ Cincinnati, Med Ctr, Dept Neurol, 222 Piedmont Ave,3200, Cincinnati, OH 45219 USA. EM daniel.woo@Uc.edu FU Wellcome Trust; National Institute of Neurological Diseases and Stroke; National Institutes of Health FX This work was funded by Wellcome Trust awards, The National Institute of Neurological Diseases and Stroke awards, and The National Institutes of Health. NR 4 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 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD APR PY 2016 VL 47 IS 4 BP 1144 EP 1145 DI 10.1161/STROKEAHA.116.012682 PG 2 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA DH5SX UT WOS:000372853200038 PM 26906919 ER PT J AU Gurol, ME AF Gurol, M. Edip TI Molecular Neuroimaging in Vascular Cognitive Impairment SO STROKE LA English DT Review DE cerebral amyloid angiopathy; cerebral small vessel disease; leukoaraiosis; magnetic resonance imaging; magnetic resonance spectroscopy; Pittsburgh Compound B; positron emission tomography ID CEREBRAL AMYLOID ANGIOPATHY; PITTSBURGH COMPOUND-B; SMALL VESSEL DISEASE; ALZHEIMERS-DISEASE; WHITE-MATTER; INTRACEREBRAL HEMORRHAGE; LOBAR MICROBLEEDS; MR SPECTROSCOPY; IMAGING AGENTS; POTENTIAL USE C1 [Gurol, M. Edip] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Gurol, ME (reprint author), MGH Stroke Res, 175 Cambridge St 300, Boston, MA 02114 USA. EM edip@mail.harvard.edu RI Gurol, Edip/J-2279-2014 OI Gurol, Edip/0000-0002-2169-4457 FU National Institutes of Health [K23 NS 083711] FX This work was made possible through research grant support from National Institutes of Health (K23 NS 083711). NR 48 TC 3 Z9 3 U1 0 U2 3 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 APR PY 2016 VL 47 IS 4 BP 1146 EP 1152 DI 10.1161/STROKEAHA.115.007958 PG 7 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA DH5SX UT WOS:000372853200039 PM 26883497 ER PT J AU Wise, SS Holmes, AL Liou, L Adam, RM Wise, JP AF Wise, Sandra S. Holmes, Arnie L. Liou, Louis Adam, Rosalyn M. Wise, John Pierce, Sr. TI Hexavalent chromium induces chromosome instability in human urothelial cells SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Chromium; Chromate; Urothelial; Bladder cancer; Aneuploidy; Genotoxicity ID HUMAN LUNG-CELLS; HUMAN BRONCHIAL CELLS; TOTAL HIP REPLACEMENTS; DOUBLE-STRAND BREAKS; LOWER URINARY-TRACT; CHRONIC EXPOSURE; INDUCED CYTOTOXICITY; GENOTOXICITY; PARTICULATE; CANCER AB Numerous metals are well-known human bladder carcinogens. Despite the significant occupational and public health concern of metals and bladder cancer, the carcinogenic mechanisms remain largely unknown. Chromium, in particular, is a metal of concern as incidences of bladder cancer have been found elevated in chromate workers, and there is an increasing concern for patients with metal hip implants. However, the impact of hexavalent chromium (Cr(VI)) on bladder cells has not been studied. We compared chromate toxicity in two bladder cell lines; primary human urothelial cells and hTERT-immortalized human urothelial cells. Cr(VI) induced a concentration and time-dependent increase in chromosome damage in both cell lines, with the hTERT-immortalized cells exhibiting more chromosome damage than the primary cells. Chronic exposure to Cr(VI) also induced a concentration-dependent increase in aneuploid metaphases in both cell lines which was not observed after a 24 h exposure. Aneuploidy induction was higher in the hTERT-immortalized cells. When we correct for uptake, Cr(VI) induces a similar amount of chromosome damage and aneuploidy suggesting that the differences in Cr(VI) sensitivity between the two cells lines were due to differences in uptake. The increase in chromosome instability after chronic chromate treatment suggests this may be a mechanism for chromate-induced bladder cancer, specifically, and may be a mechanism for metal-induced bladder cancer, in general. (C) 2016 Published by Elsevier Inc. C1 [Wise, Sandra S.; Holmes, Arnie L.; Wise, John Pierce, Sr.] Univ So Maine, Wise Lab Environm & Genet Toxicol, Maine Ctr Toxicol & Environm Hlth, Dept Appl Sci Med, Sci Bldg,96 Falmouth St, Portland, ME 04103 USA. [Holmes, Arnie L.] Dana Farber Canc Inst, Dept Radiat Oncol, 450 Brookline Ave, Boston, MA 02215 USA. [Liou, Louis] Boston Univ, Dept Pathol, Sch Med, 670 Albany St, Boston, MA 02118 USA. [Adam, Rosalyn M.] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Wise, Sandra S.] Univ Louisville, Wise Lab Environm & Genet Toxicol, Dept Pharmacol & Toxicol, 505 S Prescott St, Louisville, KY 40292 USA. RP Wise, JP (reprint author), Univ Louisville, Wise Lab Environm & Genet Toxicol, Dept Pharmacol & Toxicol, 505 S Prescott St, Louisville, KY 40292 USA. EM john.wise@louisville.edu FU National Institute of Environmental Health Sciences (NIEHS) [ES016893]; Army Research Office (ARO) Grant [W911NF-09-1-0296]; Maine Center for Toxicology and Environmental Health FX The authors would like to thank Melanie Hebert and Christy Gianios, Jr for the technical assistance. This work was supported by the National Institute of Environmental Health Sciences (NIEHS) grant ES016893 (J.P.W.), Army Research Office (ARO) Grant #W911NF-09-1-0296 (J.P.W.), and the Maine Center for Toxicology and Environmental Health. NR 37 TC 0 Z9 0 U1 2 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X EI 1096-0333 J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD APR 1 PY 2016 VL 296 BP 54 EP 60 DI 10.1016/j.taap.2016.02.015 PG 7 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA DH3IV UT WOS:000372681600006 PM 26908176 ER PT J AU Rago, AP Sharma, U Duggan, M King, DR AF Rago, Adam P. Sharma, Upma Duggan, Michael King, David R. TI Percutaneous damage control with self-expanding foam: pre-hospital rescue from abdominal exsanguination SO TRAUMA-ENGLAND LA English DT Review DE Non-compressible hemorrhage; bleeding; foam; pre-hospital; abdominal ID ENDOVASCULAR BALLOON OCCLUSION; SMALL-BOWEL INJURIES; PRIMARY REPAIR; PRIMARY ANASTOMOSIS; HEMORRHAGE CONTROL; IMPROVES SURVIVAL; CLOSED-ABDOMEN; COLON INJURIES; OUTCOMES; TRAUMA AB Non-compressible intra-abdominal hemorrhage results in significant morbidity and mortality in contemporary trauma medicine. Regrettably, many deaths from non-compressible hemorrhage are attributable to potentially survivable injuries. A self-expanding polyurethane foam has been developed for rapid, percutaneous damage control of exsanguinating abdominal hemorrhage, for patients not expected to survive to definitive surgical care. Foam intervention creates a temporary, commensal, hemostatic environment within the abdominal cavity. This tropism away from exsanguination physiology creates a hemostatic bridge such that the patient may reach definitive surgical intervention. This review article summarizes the existing literature characterizing the safety and efficacy of this intervention, along with a study in recently deceased patients that enables dose translation from animal models to human beings. C1 [Rago, Adam P.; Sharma, Upma] Arsenal Med Inc, Watertown, MA USA. [Duggan, Michael; King, David R.] Massachusetts Gen Hosp, Div Trauma Emergency Surg & Surg Crit Care, 165 Cambridge St,Suite 810, Boston, MA 02114 USA. RP King, DR (reprint author), Massachusetts Gen Hosp, Div Trauma Emergency Surg & Surg Crit Care, 165 Cambridge St,Suite 810, Boston, MA 02114 USA. EM dking3@mgh.harvard.edu NR 30 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 1460-4086 EI 1477-0350 J9 TRAUMA JI Trauma PD APR PY 2016 VL 18 IS 2 BP 85 EP 91 DI 10.1177/1460408615617790 PG 7 WC Emergency Medicine SC Emergency Medicine GA DH5KC UT WOS:000372825600002 ER PT J AU Henderson, MX Wirak, GS Zhang, YQ Dai, F Ginsberg, SD Dolzhanskaya, N Staropoli, JF Nijssen, PCG Lam, TT Roth, AF Davis, NG Dawson, G Velinov, M Chandra, SS AF Henderson, Michael X. Wirak, Gregory S. Zhang, Yong-quan Dai, Feng Ginsberg, Stephen D. Dolzhanskaya, Natalia Staropoli, John F. Nijssen, Peter C. G. Lam, TuKiet T. Roth, Amy F. Davis, Nicholas G. Dawson, Glyn Velinov, Milen Chandra, Sreeganga S. TI Neuronal ceroid lipofuscinosis with DNAJC5/CSP alpha mutation has PPT1 pathology and exhibit aberrant protein palmitoylation SO ACTA NEUROPATHOLOGICA LA English DT Article DE Neuronal ceroid lipofuscinosis (NCL); Cysteine-string protein alpha (CSP alpha); Palmitoyl-protein thioesterase 1 (PPT1); Palmitoylation; Neurodegeneration ID CYSTEINE-STRING PROTEIN; HUMAN NEUROBLASTOMA-CELLS; AUTOSOMAL-DOMINANT; CSP-ALPHA; THIOESTERASE-1 DEFICIENCY; SYNAPTIC VESICLES; CLN3 PROTEIN; KUFS-DISEASE; REVEALS; MICE AB Neuronal ceroid lipofuscinoses (NCL) are a group of inherited neurodegenerative disorders with lysosomal pathology (CLN1-14). Recently, mutations in the DNAJC5/CLN4 gene, which encodes the presynaptic co-chaperone CSP alpha were shown to cause autosomal-dominant NCL. Although 14 NCL genes have been identified, it is unknown if they act in common disease pathways. Here we show that two disease-associated proteins, CSP alpha and the depalmitoylating enzyme palmitoyl-protein thioesterase 1 (PPT1/CLN1) are biochemically linked. We find that in DNAJC5/CLN4 patient brains, PPT1 is massively increased and mis-localized. Surprisingly, the specific enzymatic activity of PPT1 is dramatically reduced. Notably, we demonstrate that CSP alpha is depalmitoylated by PPT1 and hence its substrate. To determine the consequences of PPT1 accumulation, we compared the palmitomes from control and DNAJC5/CLN4 patient brains by quantitative proteomics. We discovered global changes in protein palmitoylation, mainly involving lysosomal and synaptic proteins. Our findings establish a functional link between two forms of NCL and serve as a springboard for investigations of NCL disease pathways. C1 [Henderson, Michael X.; Wirak, Gregory S.; Zhang, Yong-quan; Chandra, Sreeganga S.] Yale Univ, Program Cellular Neurosci Neurodegenerat & Regene, New Haven, CT USA. [Henderson, Michael X.; Wirak, Gregory S.; Zhang, Yong-quan; Chandra, Sreeganga S.] Yale Univ, Dept Neurol, New Haven, CT USA. [Henderson, Michael X.; Chandra, Sreeganga S.] Yale Univ, Interdept Neurosci Program, New Haven, CT USA. [Dai, Feng] Yale Ctr Analyt Serv, New Haven, CT USA. [Ginsberg, Stephen D.] Nathan S Kline Inst Psychiat Res, Orangeburg, NY USA. [Ginsberg, Stephen D.] NYU, Langone Med Ctr, Dept Psychiat, New York, NY USA. [Ginsberg, Stephen D.] NYU, Langone Med Ctr, Dept Neurosci & Physiol, New York, NY USA. [Staropoli, John F.] Massachusetts Gen Hosp, Ctr Human Genet Res, Dept Neurol, Boston, MA 02114 USA. [Staropoli, John F.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Nijssen, Peter C. G.] St Elizabeth Hosp, Dept Neurol, NL-5022 GC Tilburg, Netherlands. [Lam, TuKiet T.] Yale Univ, Dept Mol Biophys & Biochem, New Haven, CT USA. [Roth, Amy F.; Davis, Nicholas G.] Wayne State Univ, Dept Pharmacol, Detroit, MI 48201 USA. [Dawson, Glyn] Univ Chicago, Dept Pediat, Chicago, IL 60637 USA. [Velinov, Milen] Albert Einstein Coll Med, Dept Pediat, New York, NY USA. [Velinov, Milen] New York State Inst Basic Res Dev Disabil, Dept Human Genet, 1050 Forest Hill Rd, Staten Isl, NY 10314 USA. [Chandra, Sreeganga S.] Yale Univ, Dept Mol Cell & Dev Biol, New Haven, CT USA. [Staropoli, John F.] Biogen Idec Inc, Cambridge, MA 02142 USA. RP Chandra, SS (reprint author), Yale Univ, Program Cellular Neurosci Neurodegenerat & Regene, New Haven, CT USA.; Chandra, SS (reprint author), Yale Univ, Dept Neurol, New Haven, CT USA.; Chandra, SS (reprint author), Yale Univ, Interdept Neurosci Program, New Haven, CT USA.; Chandra, SS (reprint author), Yale Univ, Dept Mol Cell & Dev Biol, New Haven, CT USA. EM sreeganga.chandra@yale.edu RI di Ronza, Alberto/H-7674-2016; OI di Ronza, Alberto/0000-0002-9813-5143; Henderson, Michael/0000-0001-9710-0726; Ginsberg, Stephen/0000-0002-1797-4288 FU Battens Disease Research and Support Association; NIH [R01NS083846, R01NS064963]; NIDA Neuroproteomic Center [5 P30 DA018343-07]; NRSA [NS078861-02]; CTSA Grant from the National Center for Research Resources (NCRR) [UL1 RR024139]; National Center for Advancing Translational Science (NCATS) FX We thank Dr. Katherine Sims for contributing pathologic material from the Massachusetts General Hospital NCL Biorepository. We also thank Ted Voss, Jean Kanyo, and Kathrin Wilczak for assistance with sample prep, data collection, and LFQ analysis, respectively. We would like to thank Art Horwich, Shawn Ferguson, Pietro De Camilli, Thomas Biederer, and members of our laboratories for critical discussions related to this paper. We would also like to thank Zack Gomez for data analysis. This work was supported by the Battens Disease Research and Support Association Grant, NIH R01NS083846, R01NS064963 (to S.S.C.), NIDA Neuroproteomic Center Grant (5 P30 DA018343-07) and by a NRSA NS078861-02 (to M.X.H) as well as CTSA Grant UL1 RR024139 from the National Center for Research Resources (NCRR) and the National Center for Advancing Translational Science (NCATS). NR 42 TC 3 Z9 3 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-6322 EI 1432-0533 J9 ACTA NEUROPATHOL JI Acta Neuropathol. PD APR PY 2016 VL 131 IS 4 BP 621 EP 637 DI 10.1007/s00401-015-1512-2 PG 17 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA DG7XR UT WOS:000372297500009 PM 26659577 ER PT J AU Kittiskulnam, P Chertow, GM Kaysen, GA Delgado, C Dalrymple, LS Johansen, KL AF Kittiskulnam, Piyawan Chertow, Glenn M. Kaysen, George A. Delgado, Cynthia Dalrymple, Lorien S. Johansen, Kirsten L. TI Misclassification of Obesity by Body Mass Index Among Patients Receiving Hemodialysis SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Letter ID WAIST CIRCUMFERENCE; DIAGNOSING OBESITY; POPULATION; MORTALITY; DISEASE C1 [Kittiskulnam, Piyawan; Delgado, Cynthia; Johansen, Kirsten L.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Kittiskulnam, Piyawan; Delgado, Cynthia; Johansen, Kirsten L.] San Francisco VA Med Ctr, San Francisco, CA USA. [Kittiskulnam, Piyawan] Chulalongkorn Univ, Bangkok, Thailand. [Kittiskulnam, Piyawan] King Chulalongkorn Mem Hosp, Thai Red Cross Soc, Bangkok, Thailand. [Chertow, Glenn M.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Kaysen, George A.; Dalrymple, Lorien S.] Univ Calif Davis, Sacramento, CA 95817 USA. [Johansen, Kirsten L.] Univ Calif San Francisco, US Renal Data Syst Nutr Special Studies Ctr, San Francisco, CA 94143 USA. RP Johansen, KL (reprint author), Univ Calif San Francisco, San Francisco, CA 94143 USA.; Johansen, KL (reprint author), San Francisco VA Med Ctr, San Francisco, CA USA.; Johansen, KL (reprint author), Univ Calif San Francisco, US Renal Data Syst Nutr Special Studies Ctr, San Francisco, CA 94143 USA. EM kirsten.johansen@ucsf.edu FU CSRD VA [IK2 CX000527]; NIDDK NIH HHS [K24DK085153, N01-DK-7-0005, K23DK093584]; PHS HHS [KD-7-5004] NR 10 TC 1 Z9 1 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 EI 1523-6838 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD APR PY 2016 VL 67 IS 4 BP 709 EP 711 DI 10.1053/j.ajkd.2015.09.028 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA DH3XO UT WOS:000372720300027 PM 26612278 ER PT J AU Boudreaux, ED Camargo, CA Arias, SA Sullivan, AF Allen, MH Goldstein, AB Manton, AP Espinola, JA Miller, IW AF Boudreaux, Edwin D. Camargo, Carlos A., Jr. Arias, Sarah A. Sullivan, Ashley F. Allen, Michael H. Goldstein, Amy B. Manton, Anne P. Espinola, Janice A. Miller, Ivan W. TI Improving Suicide Risk Screening and Detection in the Emergency Department SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID FOLLOW-UP; IDEATION; MULTICENTER; PREVENTION; VISITS; TRENDS AB Introduction: The Emergency Department Safety Assessment and Follow-up Evaluation Screening Outcome Evaluation examined whether universal suicide risk screening is feasible and effective at improving suicide risk detection in the emergency department (ED). Methods: A three-phase interrupted time series design was used: Treatment as Usual (Phase 1), Universal Screening (Phase 2), and Universal Screening + Intervention (Phase 3). Eight EDs from seven states participated from 2009 through 2014. Data collection spanned peak hours and 7 days of the week. Chart reviews established if screening for intentional self-harm ideation/behavior (screening) was documented in the medical record and whether the individual endorsed intentional self-harm ideation/behavior (detection). Patient interviews determined if the documented intentional self-harm was suicidal. In Phase 2, universal suicide risk screening was implemented during routine care. In Phase 3, improvements were made to increase screening rates and fidelity. Chi-square tests and generalized estimating equations were calculated. Data were analyzed in 2014. Results: Across the three phases (N=236,791 ED visit records), documented screenings rose from 26% (Phase 1) to 84% (Phase 3) (chi(2) [2, n=236,789]=71,000, p < 0.001). Detection rose from 2.9% to 5.7% (chi(2) [2, n=236,789]=902, p < 0.001). The majority of detected intentional self-harm was confirmed as recent suicidal ideation or behavior by patient interview. Conclusions: Universal suicide risk screening in the ED was feasible and led to a nearly twofold increase in risk detection. If these findings remain true when scaled, the public health impact could be tremendous, because identification of risk is the first and necessary step for preventing suicide. (C) 2016 American Journal of Preventive Medicine C1 [Boudreaux, Edwin D.] Univ Massachusetts, Sch Med, Dept Emergency Med, Worcester, MA 01655 USA. [Boudreaux, Edwin D.] Univ Massachusetts, Sch Med, Dept Psychiat, Worcester, MA 01655 USA. [Boudreaux, Edwin D.] Univ Massachusetts, Sch Med, Dept Quantitat Hlth Sci, Worcester, MA 01655 USA. [Camargo, Carlos A., Jr.; Sullivan, Ashley F.; Espinola, Janice A.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Arias, Sarah A.; Miller, Ivan W.] Brown Univ, Dept Psychiat & Human Behav, Butler Hosp, Providence, RI 02912 USA. [Arias, Sarah A.; Miller, Ivan W.] Brown Univ, Warren Alpert Med Sch, Providence, RI 02912 USA. [Allen, Michael H.] Univ Colorado, Depress Ctr, Aurora, CO USA. [Allen, Michael H.] Rocky Mt Crisis Partners, Aurora, CO USA. [Goldstein, Amy B.] NIMH, Div Serv & Intervent Res, NIH, Bethesda, MD 20892 USA. [Manton, Anne P.] Cape Cod Hosp, Ctr Behav Hlth, Cape Cod, MA USA. RP Boudreaux, ED (reprint author), Univ Massachusetts, Sch Med, Emergency Med, LA-189,55 Lake Ave North, Worcester, MA 01655 USA. EM edwin.boudreaux@umassmed.edu RI Allen, Michael/A-8776-2011 FU NIMH [U01MH088278]; NIMH FX The project described was supported by Award Number U01MH088278 from NIMH. This grant was funded as a cooperative award by NIMH. NIMH was represented on the Emergency Department Safety Assessment and Follow-up Evaluation (ED-SAFE) Steering Committee by Amy Goldstein, PhD. She collaborated with the other committee members and investigators to oversee the conduct of the study, data collection, analysis, and interpretation. NIMH provided Data and Safety Monitoring Board (DSMB) oversight of the study. The NIMH DSMB liaison was Adam Haim, PhD. NR 25 TC 5 Z9 5 U1 1 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD APR PY 2016 VL 50 IS 4 BP 445 EP 453 DI 10.1016/j.amepre.2015.09.029 PG 9 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA DH1RP UT WOS:000372562900003 PM 26654691 ER PT J AU Havens, JM Do, WS Kaafarani, H Mesar, T Reznor, G Cooper, Z Askari, R Kelly, E Columbus, AB Gates, JD Haider, AH Salim, A AF Havens, Joaquim M. Do, Woo S. Kaafarani, Haytham Mesar, Tomaz Reznor, Gally Cooper, Zara Askari, Reza Kelly, Edward Columbus, Alexandra B. Gates, Jonathan D. Haider, Adil H. Salim, Ali TI Explaining the excess morbidity of emergency general surgery: packed red blood cell and fresh frozen plasma transfusion practices are associated with major complications in nonmassively transfused patients SO AMERICAN JOURNAL OF SURGERY LA English DT Article DE Emergency general surgery; Transfusion; Surgical outcomes ID IMPROVEMENT PROGRAM ANALYSIS; CLINICAL DECISION-SUPPORT; I TRAUMA CENTER; LAST 60 YEARS; APGAR SCORE; MULTIPLE IMPUTATION; RISK-FACTORS; MORTALITY; HANDWRITTEN; PERFORMANCE AB BACKGROUND: Intraoperative blood product transfusions carry risk but are often necessary in emergency general surgery (EGS). METHODS: We queried the American College of Surgery-National Surgical Quality Improvement Program database for EGS patients (2008 to 2012) at 2 tertiary academic hospitals. Outcomes included rates of high packed red blood cell (pRBC) use (estimated blood loss: pRBC, 350: 1) and high fresh frozen plasma (FFP) use (FFP: pRBC >1:1.5). Patients were then stratified by exposure to high blood product use. Stepwise logistic regression was performed. RESULTS: Of 992 patients, 33% underwent EGS. Estimated blood loss was similar between EGS and non-EGS (282 vs 250 cc, P = .288). EGS patients were more often exposed to high pRBC use (adjusted odds ratio [OR] = 2.01, 95% confidence interval [CI] = 1.11 to 3.66) and high-FFP use (OR = 2.75, 95% CI: = 1.10 to 6.84). High blood product use was independently associated with major nonbleeding complications (high pRBC: OR = 1.73, 95% CI = 1.04 to 2.91; high FFP: OR = 2.15, 95% CI = 1.15 to 4.02). CONCLUSIONS: Despite similar blood loss, EGS patients received higher rates of intraoperative blood product transfusion, which was independently associated with major complication. (C) 2016 Elsevier Inc. All rights reserved. C1 [Havens, Joaquim M.; Do, Woo S.; Cooper, Zara; Askari, Reza; Kelly, Edward; Columbus, Alexandra B.; Gates, Jonathan D.; Salim, Ali] Brigham & Womens Hosp, Div Trauma Burns & Surg Crit Care, 75 Francis St, Boston, MA 02115 USA. [Havens, Joaquim M.; Reznor, Gally; Cooper, Zara; Haider, Adil H.; Salim, Ali] Brigham & Womens Hosp, Ctr Surg & Publ Hlth, Dept Surg, 75 Francis St, Boston, MA 02115 USA. [Kaafarani, Haytham; Mesar, Tomaz] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Do, WS (reprint author), Brigham & Womens Hosp, Div Trauma Burns & Surg Crit Care, 75 Francis St, Boston, MA 02115 USA. EM wdo@post.harvard.edu NR 34 TC 1 Z9 1 U1 1 U2 2 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9610 EI 1879-1883 J9 AM J SURG JI Am. J. Surg. PD APR PY 2016 VL 211 IS 4 BP 656 EP U219 DI 10.1016/j.amjsurg.2015.11.031 PG 12 WC Surgery SC Surgery GA DG9WH UT WOS:000372434000003 PM 26860622 ER PT J AU Pace, MM Sharma, B Anderson-Dam, J Fleischmann, K Warren, L Stefanovich, P AF Pace, Meredith M. Sharma, Balram Anderson-Dam, John Fleischmann, Katherine Warren, Lisa Stefanovich, Peter TI Ultrasound-Guided Thoracic Paravertebral Blockade: A Retrospective Study of the Incidence of Complications SO ANESTHESIA AND ANALGESIA LA English DT Article ID BREAST SURGERY; NERVE BLOCK; INTERCOSTAL APPROACH; CHRONIC PAIN; SPREAD; BUPIVACAINE; METAANALYSIS; ANESTHESIA; INJECTION AB BACKGROUND: The benefits of thoracic paravertebral block (TPVB) have been demonstrated for patients undergoing surgery for breast cancer. However, pleural puncture resulting in pneumothorax is a serious complication associated with traditional approaches using guidance from anatomic landmarks and nerve stimulation and may contribute to the low utilization of this block. An ultrasound-guided technique has the potential to reduce complications by providing direct visualization of the paravertebral space during needle manipulation. We evaluated the complications using a single-injection, transverse, in-plane ultrasound-guided technique for paravertebral blockade in patients undergoing mastectomy with immediate reconstruction for breast cancer treatment or prophylaxis. METHODS: Data from all patients who underwent TPVB between January 1, 2010, and December 3, 2013, at Massachusetts General Hospital was prospectively recorded in a computerized database. All blocks were placed for postoperative analgesia after unilateral or bilateral mastectomy with immediate breast reconstruction. Medical records were retrospectively reviewed for any patient who developed complications including accidental pleural puncture, symptomatic pneumothorax, hypotension, or bradycardia, as well as signs and symptoms of toxicity or effects of local anesthetic outside of the paravertebral space. RESULTS: Eight hundred fifty-six patients underwent a total of 1427 thoracic paravertebral injections (285 unilateral and 571 bilateral TPVB). There were 6 complications (0.70%; 99.2% confidence interval, 0.17%-1.86%) including symptomatic bradycardia and hypotension (n = 3), vasovagal episode (n = 1), and evidence of possible local anesthetic toxicity (n = 2). There was no incidence of suspected accidental pleural puncture or symptomatic pneumothorax identified in our study population. CONCLUSIONS: The routine use of a single-injection, transverse, in-plane ultrasound-guided technique for TPVB in patients undergoing mastectomy with immediate breast reconstruction is associated with very few complications. C1 [Pace, Meredith M.; Sharma, Balram; Anderson-Dam, John; Fleischmann, Katherine; Warren, Lisa; Stefanovich, Peter] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St,Gray Bigelow 444, Boston, MA 02114 USA. RP Stefanovich, P (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St,Gray Bigelow 444, Boston, MA 02114 USA. EM pstefanovich@mgh.harvard.edu NR 25 TC 6 Z9 6 U1 4 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD APR PY 2016 VL 122 IS 4 BP 1186 EP 1191 DI 10.1213/ANE.0000000000001117 PG 6 WC Anesthesiology SC Anesthesiology GA DG8PA UT WOS:000372344900008 PM 26756911 ER PT J AU Meyer, MJ Hyder, JA Cole, DJ Kamdar, NV AF Meyer, Matthew J. Hyder, Joseph A. Cole, Daniel J. Kamdar, Nirav V. TI The Mandate to Measure Patient Experience: How Can Patients "Value" Anesthesia Care? SO ANESTHESIA AND ANALGESIA LA English DT Editorial Material ID PERIOPERATIVE SURGICAL HOME; HEALTH-CARE; SATISFACTION; OUTCOMES C1 [Meyer, Matthew J.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA. [Hyder, Joseph A.] Mayo Clin, Ctr Sci Hlth Care Delivery, Dept Anesthesiol, Rochester, MN USA. [Cole, Daniel J.; Kamdar, Nirav V.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Anesthesiol & Perioperat Med, Los Angeles, CA 90095 USA. RP Meyer, MJ (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA. EM mjmeyer@mgh.harvard.edu NR 36 TC 1 Z9 1 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD APR PY 2016 VL 122 IS 4 BP 1211 EP 1215 DI 10.1213/ANE.0000000000001198 PG 5 WC Anesthesiology SC Anesthesiology GA DG8PA UT WOS:000372344900011 PM 26991623 ER PT J AU Xie, ZC Wang, H AF Xie, Zhongcong Wang, Hui TI Regarding "2-Deoxy-D-Glucose Enhances Anesthetic Effects in Mice" Response SO ANESTHESIA AND ANALGESIA LA English DT Letter ID P-31 MAGNETIC-RESONANCE; SPECTROSCOPY; BRAIN C1 [Xie, Zhongcong] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Charlestown, MA USA. [Xie, Zhongcong] Harvard Univ, Sch Med, Charlestown, MA USA. [Wang, Hui] Capital Med Univ, Dept Anesthesia, Beijing Chaoyang Hosp, Beijing, Peoples R China. RP Xie, ZC (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Charlestown, MA USA. EM zxie@mgh.harvard.edu NR 6 TC 1 Z9 1 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD APR PY 2016 VL 122 IS 4 BP 1225 EP 1225 DI 10.1213/ANE.0000000000001177 PG 1 WC Anesthesiology SC Anesthesiology GA DG8PA UT WOS:000372344900018 PM 26991630 ER PT J AU Thomas, KM Wright, AGC Lukowitsky, MR Donnellan, MB Hopwood, CJ AF Thomas, Katherine M. Wright, Aidan G. C. Lukowitsky, Mark R. Donnellan, M. Brent Hopwood, Christopher J. TI Correction to "Evidence for the Criterion Validity and Clinical Utility of the Pathological Narcissism Inventory" SO ASSESSMENT LA English DT Article DE correction; narcissism; validity; clinical utility AB In our article Evidence for the Criterion Validity and Clinical Utility of the Pathological Narcissism Inventory (2012), we provided incorrect values for the r(contrast-cv) coefficients we presented in Table 1. In the current report, we provide correct r(contrast-cv) values in Table 1 and discuss the implications of our updated results, particularly with respect to how these results differ from our initial report. C1 [Thomas, Katherine M.; Hopwood, Christopher J.] Michigan State Univ, E Lansing, MI 48824 USA. [Thomas, Katherine M.] San Francisco VA Med Ctr, Bldg 8 Behav Hlth, San Francisco, CA 94118 USA. [Wright, Aidan G. C.] Univ Pittsburgh, Pittsburgh, PA USA. [Lukowitsky, Mark R.] Albany Med Ctr, Albany, NY USA. [Donnellan, M. Brent] Texas A&M Univ, College Stn, TX USA. RP Thomas, KM (reprint author), San Francisco VA Med Ctr, Bldg 8 Behav Hlth, San Francisco, CA 94118 USA. EM thomas.kate.m@gmail.com NR 5 TC 1 Z9 1 U1 0 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1073-1911 EI 1552-3489 J9 ASSESSMENT JI Assessment PD APR PY 2016 VL 23 IS 2 BP 262 EP 263 DI 10.1177/1073191115584971 PG 2 WC Psychology, Clinical SC Psychology GA DG8CO UT WOS:000372310200011 PM 26019298 ER PT J AU Kammerdiener, LL Speiser, JL Aquavella, JV Harissi-Dagher, M Dohlman, CH Chodosh, J Ciolino, JB AF Kammerdiener, Leah L. Speiser, Jaime Lynn Aquavella, James V. Harissi-Dagher, Mona Dohlman, Claes H. Chodosh, James Ciolino, Joseph B. TI Protective effect of soft contact lenses after Boston keratoprosthesis SO BRITISH JOURNAL OF OPHTHALMOLOGY LA English DT Article AB Purpose To evaluate associations between preoperative diagnosis, soft contact lens (SCL) retention and complications. Methods A retrospective chart review was conducted of 92 adult patients (103 eyes) who received a Boston keratoprosthesis type I at the Massachusetts's Eye and Ear Infirmary or the Flaum Eye Institute. Records were reviewed for preoperative diagnosis, SCL retention and subsequent complications. Preoperative categories included 16 autoimmune (Stevens-Johnson syndrome, ocular cicatricial pemphigoid, rheumatoid arthritis and uveitis), 9 chemical injury and 67 'other' (aniridia, postoperative infection, dystrophies, keratopathies) patients. Results 50% of the lenses had been lost the first time after about a year. A subset (n= 17) experienced more than 2 SCL losses per year; this group is comprised of 1 patient with autoimmune diseases, 2 patients with chemical injuries and 14 patients with 'other' diseases. The preoperative diagnosis was not predictive of contact lens retention. However, multivariate analysis demonstrated that the absence of a contact lens was an independent risk factor for postoperative complications, such as corneal melts with or without aqueous humour leak/extrusion and infections. Conclusions Presence of a contact lens after Boston keratoprosthesis implantation decreases the risk of postoperative complications; this has been clinically experienced by ophthalmologists, but never before has the benefit of contact lens use in this patient population been statistically documented. C1 [Kammerdiener, Leah L.; Aquavella, James V.] Univ Rochester, Dept Ophthalmol, Flaum Eye Inst, Rochester, NY USA. [Kammerdiener, Leah L.] Med Univ S Carolina, Storm Eye Inst, Dept Ophthalmol, Charleston, SC 29425 USA. [Speiser, Jaime Lynn] Med Univ S Carolina, Dept Publ Hlth Sci, Charleston, SC 29425 USA. [Harissi-Dagher, Mona] Univ Montreal, Dept Ophthalmol, Montreal, PQ, Canada. [Dohlman, Claes H.; Chodosh, James; Ciolino, Joseph B.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA USA. RP Kammerdiener, LL (reprint author), Med Univ S Carolina, Storm Eye Inst, Dept Ophthalmol, Charleston, SC 29425 USA. EM lkammerdiener@gmail.com FU Research to Prevent Blindness, New York, New York, USA FX Supported in part by an unrestricted grant to the Department of Ophthalmology-Harvard Medical School from Research to Prevent Blindness, New York, New York, USA. NR 9 TC 3 Z9 3 U1 4 U2 8 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0007-1161 EI 1468-2079 J9 BRIT J OPHTHALMOL JI Br. J. Ophthalmol. PD APR PY 2016 VL 100 IS 4 BP 549 EP 552 DI 10.1136/bjophthalmol-2014-306396 PG 4 WC Ophthalmology SC Ophthalmology GA DH0JA UT WOS:000372469300021 PM 26276169 ER PT J AU Kim, AE Lundgreen, A Wolff, RK Fejerman, L John, EM Torres-Mejia, G Ingles, SA Boone, SD Connor, AE Hines, LM Baumgartner, KB Giuliano, A Joshi, AD Slattery, ML Stern, MC AF Kim, Andre E. Lundgreen, Abbie Wolff, Roger K. Fejerman, Laura John, Esther M. Torres-Mejia, Gabriela Ingles, Sue A. Boone, Stephanie D. Connor, Avonne E. Hines, Lisa M. Baumgartner, Kathy B. Giuliano, Anna Joshi, Amit D. Slattery, Martha L. Stern, Mariana C. TI Red meat, poultry, and fish intake and breast cancer risk among Hispanic and Non-Hispanic white women: The Breast Cancer Health Disparities Study SO CANCER CAUSES & CONTROL LA English DT Article DE Breast cancer; Meat; Hispanics; Processed meat ID POLYUNSATURATED FATTY-ACIDS; MULTIETHNIC POPULATION; POSTMENOPAUSAL WOMEN; PROSPECTIVE COHORT; SOUTHERN FRANCE; US LATINAS; CONSUMPTION; METAANALYSIS; FOOD; ASSOCIATION AB There is suggestive but limited evidence for a relationship between meat intake and breast cancer (BC) risk. Few studies included Hispanic women. We investigated the association between meats and fish intake and BC risk among Hispanic and NHW women. The study included NHW (1,982 cases and 2,218 controls) and the US Hispanics (1,777 cases and 2,218 controls) from two population-based case-control studies. Analyses considered menopausal status and percent Native American ancestry. We estimated pooled ORs combining harmonized data from both studies, and study- and race-/ethnicity-specific ORs that were combined using fixed or random effects models, depending on heterogeneity levels. When comparing highest versus lowest tertile of intake, among NHW we observed an association between tuna intake and BC risk (pooled OR 1.25; 95 % CI 1.05-1.50; trend p = 0.006). Among Hispanics, we observed an association between BC risk and processed meat intake (pooled OR 1.42; 95 % CI 1.18-1.71; trend p < 0.001), and between white meat (OR 0.80; 95 % CI 0.67-0.95; trend p = 0.01) and BC risk, driven by poultry. All these findings were supported by meta-analysis using fixed or random effect models and were restricted to estrogen receptor-positive tumors. Processed meats and poultry were not associated with BC risk among NHW women; red meat and fish were not associated with BC risk in either race/ethnic groups. Our results suggest the presence of ethnic differences in associations between meat and BC risk that may contribute to BC disparities. C1 [Kim, Andre E.; Ingles, Sue A.; Stern, Mariana C.] Univ So Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Dept Prevent Med, 1441 Eastlake Ave,Room 5421A, Los Angeles, CA 90089 USA. [Lundgreen, Abbie; Wolff, Roger K.; Slattery, Martha L.] Univ Utah, Dept Internal Med, Hlth Sci Ctr, Salt Lake City, UT 84112 USA. [Fejerman, Laura] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA. [Fejerman, Laura] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [John, Esther M.] Canc Prevent Inst Calif, Epidemiol, Fremont, CA USA. [John, Esther M.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Div Epidemiol, Stanford, CA 94305 USA. [John, Esther M.] Stanford Univ, Sch Med, Stanford Canc Inst, Stanford, CA 94305 USA. [Torres-Mejia, Gabriela] Ctr Invest Salud Poblac, Inst Nacl Salud Publ, Cuernavaca, Morelos, Mexico. [Boone, Stephanie D.; Baumgartner, Kathy B.] Univ Louisville, Sch Publ Hlth & Informat Sci, Dept Epidemiol & Populat Hlth, Louisville, KY 40292 USA. [Connor, Avonne E.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Connor, Avonne E.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Oncol, Baltimore, MD USA. [Connor, Avonne E.] Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Hines, Lisa M.] Univ Colorado, Dept Biol, Colorado Springs, CO 80907 USA. [Giuliano, Anna] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Immunol, Tampa, FL 33612 USA. [Joshi, Amit D.] Massachusetts Gen Hosp, Dept Gastroenterol, Boston, MA 02114 USA. RP Stern, MC (reprint author), Univ So Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Dept Prevent Med, 1441 Eastlake Ave,Room 5421A, Los Angeles, CA 90089 USA. EM marianas@usc.edu OI Fejerman, Laura/0000-0003-3179-1151 FU National Cancer Institute [CA14002, CA63446, CA77305, CA078682, CA078762, CA078552, CA078802, P30CA014089]; US Department of Defense [DAMD17-96-1-6071]; California Breast Cancer Research Program [7PB-0068]; National Cancer Institute's Surveillance, Epidemiology and End Results Program [HHSN261201000036C]; Centers for Disease Control and Prevention's National Program of Cancer Registries [1U58 DP000807-01]; Utah Cancer Registry from the National Cancer Institute [N01-PC-67000]; State of Utah Department of Health; New Mexico Tumor Registry; Arizona and Colorado cancer registries; Centers for Disease Control and Prevention National Program of Cancer Registries; Consejo Nacional de Ciencia y Tecnologia (CONACyT) [SALUD-2002-C01-7462]; American Cancer Society [RSF-09-020-01-CNE]; National Institute of Environmental Health Sciences [5P30 ES07048, 5T32 ES013678] FX The Breast Cancer Health Disparities Study was funded by Grant CA14002 from the National Cancer Institute to Dr. Slattery. The San Francisco Bay Area Breast Cancer Study was supported by Grants CA63446 and CA77305 from the National Cancer Institute, Grant DAMD17-96-1-6071 from the US Department of Defense, and Grant 7PB-0068 from the California Breast Cancer Research Program. The collection of cancer incidence data used in this study was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885; the National Cancer Institute's Surveillance, Epidemiology and End Results Program under contract HHSN261201000036C awarded to the Cancer Prevention Institute of California; and the Centers for Disease Control and Prevention's National Program of Cancer Registries, under agreement #1U58 DP000807-01 awarded to the Public Health Institute. The 4-Corners Breast Cancer Study was funded by Grants CA078682, CA078762, CA078552, and CA078802 from the National Cancer Institute. The research also was supported by the Utah Cancer Registry, which is funded by contract N01-PC-67000 from the National Cancer Institute, with additional support from the State of Utah Department of Health, the New Mexico Tumor Registry, and the Arizona and Colorado cancer registries, funded by the Centers for Disease Control and Prevention National Program of Cancer Registries and additional state support. The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official view of the National Cancer Institute or endorsement by the State of California Department of Public Health, the National Cancer Institute, and the Centers for Disease Control and Prevention or their Contractors and Subcontractors. The Mexico Breast Cancer Study was funded by Consejo Nacional de Ciencia y Tecnologia (CONACyT) (SALUD-2002-C01-7462). Mariana C. Stern received support from Grant RSF-09-020-01-CNE from the American Cancer Society, from award number 5P30 ES07048 from the National Institute of Environmental Health Sciences and award number P30CA014089 from the National Cancer Institute. Andre E. Kim received support from Grant 5T32 ES013678 from the National Institute of Environmental Health Sciences. NR 68 TC 2 Z9 2 U1 7 U2 16 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 APR PY 2016 VL 27 IS 4 BP 527 EP 543 DI 10.1007/s10552-016-0727-4 PG 17 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DH1OM UT WOS:000372554500007 PM 26898200 ER PT J AU Bove, RM White, CC Geriveck, AV Mancuso, SM Bredella, MA Sherman, JC Miller, KK AF Bove, Riley M. White, Charles C. Geriveck, Anu V. Mancuso, Sarah M. Bredella, Miriam A. Sherman, Janet C. Miller, Karen K. TI Effect of growth hormone on cognitive function in young women with abdominal obesity SO CLINICAL ENDOCRINOLOGY LA English DT Letter ID CONTROLLED-TRIAL C1 [Bove, Riley M.; Bredella, Miriam A.; Sherman, Janet C.; Miller, Karen K.] Harvard Univ, Sch Med, Boston, MA USA. [Bove, Riley M.; White, Charles C.] Brigham & Womens Hosp, Ann Romney Ctr Neurol Dis, 75 Francis St, Boston, MA 02115 USA. [White, Charles C.] Brigham & Womens Hosp, Program Translat NeuroPsychiat Genom, Dept Neurol, Inst Neurosci, 75 Francis St, Boston, MA 02115 USA. [White, Charles C.] Brigham & Womens Hosp, Inst Neurosci, Dept Psychiat, 75 Francis St, Boston, MA 02115 USA. [White, Charles C.] Broad Inst, Program Med & Populat Genet, Cambridge, England. [Geriveck, Anu V.; Miller, Karen K.] Massachusetts Gen Hosp, Neuroendocrine Unit, Dept Med, Boston, MA 02114 USA. [Mancuso, Sarah M.; Sherman, Janet C.] Massachusetts Gen Hosp, Psychol Assessment Ctr, Boston, MA 02114 USA. [Bredella, Miriam A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. RP Miller, KK (reprint author), Harvard Univ, Sch Med, Boston, MA USA. EM kkmiller@partners.org FU NCRR NIH HHS [M01 RR001066, UL1 RR025758, K23 RR023090, K23 RR-23090, UL1 RR-025758]; NHLBI NIH HHS [K24 HL092902-03, K24 HL092902, R01 HL077674, R01-HL077674]; NICHD NIH HHS [K12 HD051959] NR 4 TC 0 Z9 0 U1 2 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0300-0664 EI 1365-2265 J9 CLIN ENDOCRINOL JI Clin. Endocrinol. PD APR PY 2016 VL 84 IS 4 BP 635 EP 637 DI 10.1111/cen.12996 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DH0WR UT WOS:000372505300024 PM 26663235 ER PT J AU Lazar, AA Bonetti, M Cole, BF Yip, WK Gelber, RD AF Lazar, Ann A. Bonetti, Marco Cole, Bernard F. Yip, Wai-ki Gelber, Richard D. TI Identifying treatment effect heterogeneity in clinical trials using subpopulations of events: STEPP SO CLINICAL TRIALS LA English DT Article DE Biomarker; breast cancer; competing risk; interaction; permutation-based inference; personalized medicine; precision medicine; survival analysis; overview ID TREATMENT-COVARIATE INTERACTIONS; BREAST-CANCER; SUBGROUP ANALYSES; POSTMENOPAUSAL WOMEN; LETROZOLE; REGRESSION; TAMOXIFEN; SUBSETS; MODEL; INDEX AB Background: Investigators conducting randomized clinical trials often explore treatment effect heterogeneity to assess whether treatment efficacy varies according to patient characteristics. Identifying heterogeneity is central to making informed personalized healthcare decisions. Treatment effect heterogeneity can be investigated using subpopulation treatment effect pattern plot (STEPP), a non-parametric graphical approach that constructs overlapping patient subpopulations with varying values of a characteristic. Procedures for statistical testing using subpopulation treatment effect pattern plot when the endpoint of interest is survival remain an area of active investigation. Methods: A STEPP analysis was used to explore patterns of absolute and relative treatment effects for varying levels of a breast cancer biomarker, Ki-67, in the phase III Breast International Group 1-98 randomized clinical trial, comparing letrozole to tamoxifen as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer. Absolute treatment effects were measured by differences in 4-year cumulative incidence of breast cancer recurrence, while relative effects were measured by the subdistribution hazard ratio in the presence of competing risks using O-E (observed-minus-expected) methodology, an intuitive non-parametric method. While estimation of hazard ratio values based on O-E methodology has been shown, a similar development for the subdistribution hazard ratio has not. Furthermore, we observed that the subpopulation treatment effect pattern plot analysis may not produce results, even with 100 patients within each subpopulation. After further investigation through simulation studies, we observed inflation of the type I error rate of the traditional test statistic and sometimes singular variance-covariance matrix estimates that may lead to results not being produced. This is due to the lack of sufficient number of events within the subpopulations, which we refer to as instability of the subpopulation treatment effect pattern plot analysis. We introduce methodology designed to improve stability of the subpopulation treatment effect pattern plot analysis and generalize O-E methodology to the competing risks setting. Simulation studies were designed to assess the type I error rate of the tests for a variety of treatment effect measures, including subdistribution hazard ratio based on O-E estimation. This subpopulation treatment effect pattern plot methodology and standard regression modeling were used to evaluate heterogeneity of Ki-67 in the Breast International Group 1-98 randomized clinical trial. Results: We introduce methodology that generalizes O-E methodology to the competing risks setting and that improves stability of the STEPP analysis by pre-specifying the number of events across subpopulations while controlling the type I error rate. The subpopulation treatment effect pattern plot analysis of the Breast International Group 1-98 randomized clinical trial showed that patients with high Ki-67 percentages may benefit most from letrozole, while heterogeneity was not detected using standard regression modeling. Conclusion: The STEPP methodology can be used to study complex patterns of treatment effect heterogeneity, as illustrated in the Breast International Group 1-98 randomized clinical trial. For the subpopulation treatment effect pattern plot analysis, we recommend a minimum of 20 events within each subpopulation. C1 [Lazar, Ann A.] Univ Calif San Francisco, Dept Prevent & Restorat Dent Sci, Div Oral Epidemiol, 3333 Calif St,Ste 495, San Francisco, CA 94143 USA. [Lazar, Ann A.] Univ Calif San Francisco, Dept Epidemiol & Biostat, Div Biostat, San Francisco, CA 94143 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. [Yip, Wai-ki; Gelber, Richard D.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Yip, Wai-ki; Gelber, Richard D.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. RP Lazar, AA (reprint author), Univ Calif San Francisco, Dept Prevent & Restorat Dent Sci, Div Oral Epidemiol, 3333 Calif St,Ste 495, San Francisco, CA 94143 USA. EM ann.lazar@ucsf.edu FU US National Institutes of Health [T32 CA-09337, CA-23318, P30-DE-020752, CA-75362]; Hellman Family Foundation; Italian Ministry of Education, University and Research [2007AYHZWC] FX This work was supported by the US National Institutes of Health (No. T32 CA-09337, CA-23318, P30-DE-020752, and CA-75362); Hellman Family Foundation; and The Italian Ministry of Education, University and Research Protocol 2007AYHZWC. NR 28 TC 3 Z9 3 U1 0 U2 1 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 APR PY 2016 VL 13 IS 2 BP 169 EP 179 DI 10.1177/1740774515609106 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DG8AY UT WOS:000372306000007 PM 26493094 ER PT J AU Walders-Abramson, N Anderson, B Larkin, ME Chang, N Venditti, E Bzdick, S Tryggestad, JB Tan, K Geffner, ME Hirst, K AF Walders-Abramson, Natalie Anderson, Barbara Larkin, Mary E. Chang, Nancy Venditti, Elizabeth Bzdick, Suzan Tryggestad, Jeanie B. Tan, Kenny Geffner, Mitchell E. Hirst, Kathryn TI Benefits and barriers to participating in longitudinal research of youth-onset type 2 diabetes: Results from the TODAY retention survey SO CLINICAL TRIALS LA English DT Article DE Retention; type 2 diabetes; adolescents; underserved minorities; longitudinal follow-up ID ADOLESCENTS AB Background/Aims: Conducting longitudinal research related to chronic illness in adolescents is inherently challenging due to developmental changes and psychosocial stressors. Participants in the Treatment Options for type 2 Diabetes in Adolescents and Youth clinical trial were socioeconomically disadvantaged as well. This study assessed attitudes and beliefs about retention in Treatment Options for type 2 Diabetes in Adolescents and Youth to shed light on the factors that potentially promote and detract from the likelihood of sustained participation. Methods: After an average 7.3years of follow-up (range 4.9-9.5), Treatment Options for type 2 Diabetes in Adolescents and Youth participants completed a survey examining their perceptions of the benefits and barriers to sustained involvement in the protocol. Results: The most common reasons for staying in Treatment Options for type 2 Diabetes in Adolescents and Youth included having a strong relationship with the medical team, getting study-provided diabetes care, access to free diabetes medicine and supplies, and being part of a large study to learn more about how to care for youth-onset type 2 diabetes. The most commonly endorsed challenges included scheduling conflicts, possibly disappointing others, difficulties getting to study visits, and the occurrence of other medical issues. Conclusions: Similar to other published reports, a supportive relationship with study staff was commonly endorsed as a benefit of engagement in the longitudinal study, suggesting that rapport, staff consistency, and relationship quality are important components of optimal retention. Moreover, our findings suggest the value of trying to remove logistical barriers, such as transportation and scheduling challenges, in order to promote long-term participation in research. Further research is recommended to evaluate factors that contribute to attrition versus retention in an a priori manner within longitudinal studies, especially protocols involving cohorts that are more vulnerable to attrition due to developmental transitions and/or socioeconomic challenges. Additional efforts to optimize quantitative and qualitative measurement of barriers would also help to expand our understanding of how to optimally retain participants in longitudinal protocols. C1 [Walders-Abramson, Natalie] Univ Colorado Denver, Dept Pediat, Aurora, CO USA. [Walders-Abramson, Natalie] Childrens Hosp Colorado, Aurora, CO USA. [Anderson, Barbara] Texas Childrens Hosp, Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Larkin, Mary E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Diabet, Boston, MA USA. [Chang, Nancy] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Venditti, Elizabeth] Univ Pittsburgh, Sch Med, Western Psychiat Inst & Clin, Pittsburgh, PA USA. [Bzdick, Suzan] SUNY Upstate Med Univ, Syracuse, NY 13210 USA. [Tryggestad, Jeanie B.] Univ Oklahoma, Hlth Sci Ctr, Dept Pediat, Sect Pediat Diabet & Endocrinol, Oklahoma City, OK 73190 USA. [Tan, Kenny; Hirst, Kathryn] George Washington Univ, Ctr Biostat, 6110 Execut Blvd,Suite 750, Rockville, MD 20852 USA. [Geffner, Mitchell E.] Univ So Calif, Keck Sch Med, Childrens Hosp Los Angeles, Saban Res Inst, Los Angeles, CA 90033 USA. RP Tan, K (reprint author), George Washington Univ, Ctr Biostat, 6110 Execut Blvd,Suite 750, Rockville, MD 20852 USA. EM ktan@bsc.gwu.edu FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Institutes of Health (NIH) Office of the Director (OD) [U01-DK61212, U01-DK61230, U01-DK61239, U01-DK61242, U01-DK61254]; National Center for Research Resources (NCRR) General Clinical Research Centers Program [M01-RR00036, M01-RR00043-45, M01-RR00069, M01-RR00084, M01-RR01066, M01-RR00125, M01-RR14467]; NCRR Clinical and Translational Science Awards [UL1-RR024134, UL1-RR024139, UL1-RR024153, UL1-RR024989, UL1-RR024992, UL1-RR025758, UL1-RR025780] FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was completed with funding from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Institutes of Health (NIH) Office of the Director (OD) through grants U01-DK61212, U01-DK61230, U01-DK61239, U01-DK61242, and U01-DK61254; from the National Center for Research Resources (NCRR) General Clinical Research Centers Program grant numbers M01-RR00036 (Washington University School of Medicine), M01-RR00043-45 (Children's Hospital Los Angeles), M01-RR00069 (University of Colorado Denver), M01-RR00084 (Children's Hospital of Pittsburgh), M01-RR01066 (Massachusetts General Hospital), M01-RR00125 (Yale University), and M01-RR14467 (University of Oklahoma Health Sciences Center); and from the NCRR Clinical and Translational Science Awards grant numbers UL1-RR024134 (Children's Hospital of Philadelphia), UL1-RR024139 (Yale University), UL1-RR024153 (Children's Hospital of Pittsburgh), UL1-RR024989 (Case Western Reserve University), UL1-RR024992 (Washington University in St Louis), UL1-RR025758 (Massachusetts General Hospital), and UL1-RR025780 (University of Colorado Denver). NR 8 TC 0 Z9 0 U1 0 U2 3 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 APR PY 2016 VL 13 IS 2 BP 240 EP 243 DI 10.1177/1740774515613949 PG 4 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DG8AY UT WOS:000372306000015 PM 26531295 ER PT J AU Sales, CS Terry, MA Veldman, PB Mayko, ZM Straiko, MD AF Sales, Christopher S. Terry, Mark A. Veldman, Peter B. Mayko, Zachary M. Straiko, Michael D. TI Relationship Between Tissue Unscrolling Time and Endothelial Cell Loss SO CORNEA LA English DT Article DE DMEK; endothelial cell loss ID TRYPAN BLUE; CORNEAL ENDOTHELIUM; CATARACT-EXTRACTION; KERATOPLASTY; GRAFT; DMEK; REJECTION; SURGERY AB Purpose: To assess the relationship between intraoperative unscrolling time of the donor Descemet membrane endothelial keratoplasty (DMEK) tissue and 6-month postoperative endothelial cell loss (ECL), and to determine whether donor age, scroll tightness, and the presence of an S stamp are related to unscrolling time. Methods: Ninety-three consecutive uncomplicated DMEK surgeries performed on eyes with Fuchs endothelial dystrophy using our standardized technique (ie, prestripped tissue with or without a premarked S stamp from our eye bank, overstripping the recipient, Straiko glass injector, no-touch tap technique, and bubble of 20% SF6 gas) were evaluated. Intraoperative unscrolling times and 6-month endothelial cell densities were measured and analyzed. Results: Sixty-nine cases comprised the study cohort. The median unscrolling time was 4 minutes (range: 0.8-17.5 minutes), and the median ECL was 26.9% (range: -4.3% to 80.0%). There was no relationship between unscrolling time and ECL at 6 months by the Pearson correlation coefficient (r = -0.02, P = 0.89). Younger donor age, tighter scrolls, and absence of an S stamp had no correlation with longer unscrolling times (all P > 0.05). Only 2 of 4 cases of iatrogenic primary graft failure had unscrolling times available for analysis; in this limited sample, there was no association between iatrogenic primary graft failure and unscrolling time. Conclusions: Once the DMEK tissue is safely in the anterior chamber, surgeons need not rush the "DMEK dance" because longer unscrolling times may not endanger the endothelium. C1 [Sales, Christopher S.] Ophthalm Consultants Boston, 50 Staniford St,Suite 600, Boston, MA 02114 USA. [Terry, Mark A.; Straiko, Michael D.] Devers Eye Inst, Portland, OR USA. [Veldman, Peter B.] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Mayko, Zachary M.] Lions VisionGift, Portland, OR USA. RP Sales, CS (reprint author), Ophthalm Consultants Boston, 50 Staniford St,Suite 600, Boston, MA 02114 USA. EM Christopher.Sales@gmail.com NR 28 TC 2 Z9 2 U1 2 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0277-3740 EI 1536-4798 J9 CORNEA JI Cornea PD APR PY 2016 VL 35 IS 4 BP 471 EP 476 DI 10.1097/ICO.0000000000000771 PG 6 WC Ophthalmology SC Ophthalmology GA DG8QZ UT WOS:000372350000008 PM 26845314 ER PT J AU Naseripour, M Aghaei, H Sedaghat, A Kheirkhah, A Jaberi, R Azma, Z AF Naseripour, Masood Aghaei, Hossein Sedaghat, Ahad Kheirkhah, Ahmad Jaberi, Ramin Azma, Zohreh TI Corneal Patch Graft: A New Approach for Scleral Necrosis Secondary to Plaque Radiotherapy SO CORNEA LA English DT Article DE plaque radiotherapy; corneal patch graft; scleral necrosis; uveal melanoma ID UVEAL MELANOMA; HISTOPATHOLOGIC FINDINGS; AUTOGENOUS PERIOSTEUM; OCULAR COMPLICATIONS; CONSECUTIVE PATIENTS; RADIATION-THERAPY; MANAGEMENT; BRACHYTHERAPY; IRRADIATION; REPAIR AB Purpose: To evaluate the anatomical outcomes of corneal patch grafts in patients with progressive scleral necrosis secondary to plaque radiotherapy used for uveal malignant melanoma management. Methods: In this case series, 4 patients with progressive scleral necrosis after Ru-106 plaque radiotherapy underwent corneal patch grafts with the anterior corneal button from Descemet stripping automated endothelial keratoplasty donor tissue to strengthen the sclera and to improve appearance of the eye. Results: Ciliary body involvement was evident in all cases. All 4 patients had received radiation doses of 400 Gy or more to the tumor base. The mean time interval between plaque radiotherapy and scleral necrosis was 24.5 +/- 7.5 months (range, 18-34 months). Successful results were achieved in all patients with tectonic graft. No patients experienced graft thinning, rejection, infection, or tumor recurrence in a mean follow-up of 28.5 +/- 7.9 months (range, 20-39 months). Conclusions: Corneal patch graft by anterior corneal button from Descemet stripping automated endothelial keratoplasty donor tissue results in successful restoration of globe integrity and satisfactory cosmetic appearance in patients with scleral necrosis secondary to plaque radiotherapy. C1 [Naseripour, Masood; Aghaei, Hossein; Sedaghat, Ahad] Iran Univ Med Sci, Rassoul Akram Hosp, Eye Res Ctr, Tehran, Iran. [Kheirkhah, Ahmad] Harvard Univ, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Cornea & Refract Surg Serv,Med Sch, Boston, MA USA. [Jaberi, Ramin] Univ Tehran Med Sci, Inst Canc, Imam Khomeini Hosp, Tehran, Iran. [Azma, Zohreh] Shahid Beheshti Univ, Dept Radiat Med, Tehran, Iran. [Naseripour, Masood] Noor Eye Hosp, Noor Eye Res Ctr, Tehran, Iran. RP Sedaghat, A (reprint author), Rassoul Akram Hosp, Eye Res Ctr, Sattarkhan Niayesh St, Tehran 1445613131, Iran. EM ahad_s2000@yahoo.com NR 25 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0277-3740 EI 1536-4798 J9 CORNEA JI Cornea PD APR PY 2016 VL 35 IS 4 BP 565 EP 568 DI 10.1097/ICO.0000000000000716 PG 4 WC Ophthalmology SC Ophthalmology GA DG8QZ UT WOS:000372350000025 PM 26863496 ER PT J AU Han, K Viswanathan, AN AF Han, Kathy Viswanathan, Akila N. TI Brachytherapy in Gynecologic Cancers: Why Is It Underused? SO CURRENT ONCOLOGY REPORTS LA English DT Review DE Brachytherapy; Gynecologic cancer; Cervical cancer; Vaginal cancer; Utilization; Intensity-modulated radiotherapy ID SQUAMOUS-CELL CARCINOMA; INTACT CERVICAL-CANCER; ATOMIC-ENERGY AGENCY; RADIATION-THERAPY; VAGINAL-CANCER; ENDOMETRIAL CANCER; UNITED-STATES; STAGE-III; RADIOTHERAPY; PATTERNS AB Despite its established efficacy, brachytherapy is underused in the management of cervical and vaginal cancers in some parts of the world. Possible reasons for the underutilization of brachytherapy include the adoption of less invasive techniques, such as intensity-modulated radiotherapy; reimbursement policies favoring these techniques over brachytherapy; poor physician or patient access to brachytherapy; inadequate maintenance of brachytherapy skills among practicing radiation oncologists; transitioning to high-dose-rate (HDR) brachytherapy with increased time requirements; and insufficient training of radiation oncology residents. C1 [Han, Kathy] Univ Toronto, Dept Radiat Oncol, Princess Margaret Canc Ctr, Toronto, ON, Canada. [Viswanathan, Akila N.] Dana Farber Canc Inst, Dept Radiat Oncol, 75 Francis St,ASB1 L2, Boston, MA 02115 USA. [Viswanathan, Akila N.] Brigham & Womens Hosp, 75 Francis St,ASB1 L2, Boston, MA 02115 USA. RP Viswanathan, AN (reprint author), Dana Farber Canc Inst, Dept Radiat Oncol, 75 Francis St,ASB1 L2, Boston, MA 02115 USA.; Viswanathan, AN (reprint author), Brigham & Womens Hosp, 75 Francis St,ASB1 L2, Boston, MA 02115 USA. EM akila@post.harvard.edu FU PHS HHS [R21 167800] NR 34 TC 1 Z9 1 U1 0 U2 1 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 APR PY 2016 VL 18 IS 4 AR 26 DI 10.1007/s11912-016-0508-y PG 5 WC Oncology SC Oncology GA DG6XO UT WOS:000372229600004 PM 26940059 ER PT J AU Shahid, H Singh, JA AF Shahid, Hania Singh, Jasvinder A. TI Racial/Ethnic Disparity in Rates and Outcomes of Total Joint Arthroplasty SO CURRENT RHEUMATOLOGY REPORTS LA English DT Article DE Total joint arthroplasty (TJA); Race; Ethnicity; Disparity; Total joint replacement (TJR); Total knee arthroplasty (TKA); Total hip arthroplasty (THA); Total ankle arthroplasty (TAA); Total elbow arthroplasty (TEA); Total shoulder arthroplasty (TSA); Osteoarthritis (OA); Rheumatoid arthritis (RA); White; Caucasian; African American (AA); Black; Hispanic ID TOTAL KNEE REPLACEMENT; TOTAL HIP-REPLACEMENT; STATES MEDICARE POPULATION; CLINICAL DECISION-MAKING; QUALITY-OF-LIFE; RACIAL DISPARITIES; UNITED-STATES; AFRICAN-AMERICANS; SHOULDER ARTHROPLASTY; PATIENT EXPECTATIONS AB Racial/ethnic disparity in total joint arthroplasty (TJA) has grown over the last two decades as studies have documented the widening gap between Blacks and Whites in TJA utilization rates despite the known benefits of TJA. Factors contributing to this disparity have been explored and include demographics, socioeconomic status, patient knowledge, patient preference, willingness to undergo TJA, patient expectation of post-arthroplasty outcome, religion/spirituality, and physician-patient interaction. Improvement in patient knowledge by effective physician-patient communication and other methods can possibly influence patient's perception of the procedure. Such interventions can provide patient-relevant data on benefits/risks and dispel myths related to benefits/risks of arthroplasty and possibly reduce this disparity. This review will summarize the literature on racial/ethnic disparity on TJA utilization and outcomes and the factors underlying this disparity. C1 [Shahid, Hania] Rawalpindi Med Coll, Dept Med, Rawalpindi, Pakistan. [Shahid, Hania; Singh, Jasvinder A.] UAB, Sch Med, Dept Med, Birmingham, AL USA. [Singh, Jasvinder A.] UAB, Sch Publ Hlth, Div Epidemiol, 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 Singh, JA (reprint author), UAB, Sch Med, Dept Med, Birmingham, AL USA.; Singh, JA (reprint author), UAB, Sch Publ Hlth, Div Epidemiol, Birmingham, AL USA.; Singh, JA (reprint author), Birmingham VA Med Ctr, Med Serv, Birmingham, AL USA.; Singh, JA (reprint author), Mayo Clin, Coll Med, Dept Orthoped Surg, Rochester, MN USA. EM Jasvinder.md@gmail.com FU UAB Division of Rheumatology FX This material is the result of work supported by research funds from UAB Division of Rheumatology and the resources and use of facilities at the Birmingham VA Medical Center. NR 90 TC 0 Z9 0 U1 4 U2 5 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 APR PY 2016 VL 18 IS 4 AR 20 DI 10.1007/s11926-016-0570-3 PG 13 WC Rheumatology SC Rheumatology GA DH2DO UT WOS:000372594600003 PM 26984804 ER PT J AU Ejaz, A Martinez-Guino, L Goldfine, AB Ribas-Aulinas, F De Nigris, V Ribo, S Gonzalez-Franquesa, A Garcia-Roves, PM Li, E Dreyfuss, JM Gall, W Kim, JK Bottiglieri, T Villarroya, F Gerszten, RE Patti, ME Lerin, C AF Ejaz, Asma Martinez-Guino, Laura Goldfine, Allison B. Ribas-Aulinas, Francesc De Nigris, Valeria Ribo, Silvia Gonzalez-Franquesa, Alba Garcia-Roves, Pablo M. Li, Elizabeth Dreyfuss, Jonathan M. Gall, Walt Kim, Jason K. Bottiglieri, Teodoro Villarroya, Francesc Gerszten, Robert E. Patti, Mary-Elizabeth Lerin, Carles TI Dietary Betaine Supplementation Increases Fgf21 Levels to Improve Glucose Homeostasis and Reduce Hepatic Lipid Accumulation in Mice SO DIABETES LA English DT Article ID GROWTH-FACTOR 21; NONALCOHOLIC FATTY LIVER; PLASMA HOMOCYSTEINE CONCENTRATIONS; WHITE ADIPOSE-TISSUE; ENERGY-EXPENDITURE; INSULIN-RESISTANCE; ELDERLY-MEN; OBESE MICE; PPAR-ALPHA; METABOLISM AB Identifying markers of human insulin resistance may permit development of new approaches for treatment and prevention of type 2 diabetes. To this end, we analyzed the fasting plasma metabolome in metabolically characterized human volunteers across a spectrum of insulin resistance. We demonstrate that plasma betaine levels are reduced in insulin-resistant humans and correlate closely with insulin sensitivity. Moreover, betaine administration to mice with diet-induced obesity prevents the development of impaired glucose homeostasis, reduces hepatic lipid accumulation, increases white adipose oxidative capacity, and enhances whole-body energy expenditure. In parallel with these beneficial metabolic effects, betaine supplementation robustly increased hepatic and circulating fibroblast growth factor (Fgf)21 levels. Betaine administration failed to improve glucose homeostasis and liver fat content in Fgf21(-/-) mice, demonstrating that Fgf21 is necessary for betaine's beneficial effects. Together, these data indicate that dietary betaine increases Fgf21 levels to improve metabolic health in mice and suggest that betaine supplementation merits further investigation as a supplement for treatment or prevention of type 2 diabetes in humans. C1 [Ejaz, Asma; Goldfine, Allison B.; Li, Elizabeth; Dreyfuss, Jonathan M.; Patti, Mary-Elizabeth] Joslin Diabet Ctr, Div Res, 1 Joslin Pl, Boston, MA 02215 USA. [Ejaz, Asma; Goldfine, Allison B.; Li, Elizabeth; Dreyfuss, Jonathan M.; Gerszten, Robert E.; Patti, Mary-Elizabeth] Harvard Univ, Sch Med, Boston, MA USA. [Martinez-Guino, Laura; Ribo, Silvia; Lerin, Carles] Hosp St Joan de Deu, Endocrinol Sect, Barcelona, Spain. [Ribas-Aulinas, Francesc; Villarroya, Francesc] Univ Barcelona, Inst Biomed, Dept Biochem & Mol Biol, Barcelona, Spain. [Ribas-Aulinas, Francesc; Villarroya, Francesc] CIBER Fisiopatol Obesidad & Nutr, Barcelona, Spain. [De Nigris, Valeria; Gonzalez-Franquesa, Alba; Garcia-Roves, Pablo M.] Inst Invest Biomed August Pi Sunyer, Diabet & Obes Lab, Barcelona, Spain. [Garcia-Roves, Pablo M.] CIBERDEM, Barcelona, Spain. [Garcia-Roves, Pablo M.] Univ Barcelona, Dept Physiol Sci 2, Barcelona, Spain. [Dreyfuss, Jonathan M.] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. [Gall, Walt] Metabolon Inc, Durham, NC USA. [Kim, Jason K.] Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA USA. [Bottiglieri, Teodoro] Baylor Res Inst, Inst Metab Dis, Dallas, TX USA. [Gerszten, Robert E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Patti, ME (reprint author), Joslin Diabet Ctr, Div Res, 1 Joslin Pl, Boston, MA 02215 USA.; Patti, ME (reprint author), Harvard Univ, Sch Med, Boston, MA USA.; Lerin, C (reprint author), Hosp St Joan de Deu, Endocrinol Sect, Barcelona, Spain. EM mary.elizabeth.patti@joslin.harvard.edu; clerin@fsjd.org OI Gonzalez-Franquesa, Alba/0000-0001-9081-753X; Villarroya, Francesc/0000-0003-1266-9142 FU Ajinomoto, Inc.; American Diabetes Association [7-12-MN-66, 7-13-CE-17]; Spanish Government (Ministerio de Economia y Competitividad) [RYC2010-06789, SAF2011-28502]; European Foundation for the Study of Diabetes/Lilly Diabetes grants; Ministerio de Economia y Competitividad [RYC-2009-05158, BFU2011-24679]; Seventh Framework Programme FP7-BetaBat project; National Institutes of Health (NIH) [DK-081572]; NIH [DK-036836, U24-DK-093000] FX A.E. and M.-E.P. were supported by an unrestricted 3ARP grant from Ajinomoto, Inc., and a mentor-based grant from the American Diabetes Association (7-12-MN-66). A.B.G. was supported by a grant from the American Diabetes Association (7-13-CE-17). This work was supported by Seventh Framework Programme Marie Curie FP7-PEOPLE-2011-CIG, grants from the Spanish Government (Ministerio de Economia y Competitividad) (RYC2010-06789 and SAF2011-28502), and European Foundation for the Study of Diabetes/Lilly Diabetes grants (to C.L.); Ministerio de Economia y Competitividad grants RYC-2009-05158 and BFU2011-24679 (to P.M.G.-R.); and the Seventh Framework Programme FP7-BetaBat project (to F.V.). R.E.G. was supported by National Institutes of Health (NIH) grant DK-081572. A.E., A.G.-F., J.M.D., and M.-E.P. were also supported by NIH grant DK-036836. The National Mouse Metabolic Phenotyping Center at the University of Massachusetts was supported by NIH grant U24-DK-093000. No other potential conflicts of interest were reported. NR 56 TC 5 Z9 5 U1 5 U2 12 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD APR PY 2016 VL 65 IS 4 BP 902 EP 912 DI 10.2337/db15-1094 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DH5VC UT WOS:000372859200010 PM 26858359 ER PT J AU Pesenacker, AM Wang, AY Singh, A Gillies, J Kim, Y Piccirillo, CA Nguyen, D Haining, WN Tebbutt, SJ Panagiotopoulos, C Levings, MK AF Pesenacker, Anne M. Wang, Adele Y. Singh, Amrit Gillies, Jana Kim, Youngwoong Piccirillo, Ciriaco A. Duc Nguyen Haining, W. Nicholas Tebbutt, Scott J. Panagiotopoulos, Constadina Levings, Megan K. TI A Regulatory T-Cell Gene Signature Is a Specific and Sensitive Biomarker to Identify Children With New-Onset Type 1 Diabetes SO DIABETES LA English DT Article ID EXPRESSION; GARP; RECEPTOR; LOCUS AB Type 1 diabetes (T1D) is caused by immune-mediated destruction of insulin-producing beta-cells. Insufficient control of autoreactive T cells by regulatory T cells (Tregs) is believed to contribute to disease pathogenesis, but changes in Treg function are difficult to quantify because of the lack of Treg-exclusive markers in humans and the complexity of functional experiments. We established a new way to track Tregs by using a gene signature that discriminates between Tregs and conventional T cells regardless of their activation states. The resulting 31-gene panel was validated with the NanoString nCounter platform and then measured in sorted CD4(+)CD25(hi)CD127(lo) Tregs from children with T1D and age-matched control subjects. By using biomarker discovery analysis, we found that expression of a combination of six genes, including TNFRSF1B (CD120b) and FOXP3, was significantly different between Tregs from subjects with new-onset T1D and control subjects, resulting in a sensitive (mean SD 0.86 +/- 0.14) and specific (0.78 +/- 0.18) biomarker algorithm. Thus, although the proportion of Tregs in peripheral blood is similar between children with T1D and control subjects, significant changes in gene expression can be detected early in disease process. These findings provide new insight into the mechanisms underlying the failure to control autoimmunity in T1D and might lead to a biomarker test to monitor Tregs throughout disease progression. C1 [Pesenacker, Anne M.; Wang, Adele Y.; Gillies, Jana; Levings, Megan K.] Univ British Columbia, Dept Surg, Vancouver, BC V6T 1W5, Canada. [Pesenacker, Anne M.; Wang, Adele Y.; Gillies, Jana; Duc Nguyen; Panagiotopoulos, Constadina; Levings, Megan K.] Child & Family Res Inst, Vancouver, BC, Canada. [Singh, Amrit; Kim, Youngwoong; Tebbutt, Scott J.] Univ British Columbia, Dept Med, Vancouver, BC, Canada. [Singh, Amrit; Kim, Youngwoong; Tebbutt, Scott J.] Univ British Columbia, Ctr Heart Lung Innovat, Vancouver, BC, Canada. [Singh, Amrit; Kim, Youngwoong; Tebbutt, Scott J.] St Pauls Hosp, Prevent Organ Failure PROOF Ctr Excellence, Vancouver, BC V6Z 1Y6, Canada. [Piccirillo, Ciriaco A.] McGill Univ, Dept Microbiol & Immunol, Montreal, PQ, Canada. [Duc Nguyen; Panagiotopoulos, Constadina] Univ British Columbia, Dept Pediat, Vancouver, BC V6T 1W5, Canada. [Haining, W. Nicholas] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol,Broad Inst, 44 Binney St, Boston, MA 02115 USA. RP Levings, MK (reprint author), Univ British Columbia, Dept Surg, Vancouver, BC V6T 1W5, Canada.; Levings, MK (reprint author), Child & Family Res Inst, Vancouver, BC, Canada. EM megan.levings@ubc.ca OI Pesenacker, Anne/0000-0002-7968-0277 FU Canadian Institutes of Health Research (CIHR) [MOP-115199]; Canucks for Kids Fund; Genome British Columbia; Genome Quebec; STEMCELL Technologies Inc.; CIHR Strategic Training Initiative in Health Research Program in Transplantation; 4 What Matters Foundation; JDRF postdoctoral fellowship; CFRI Research Methodology Training Grant; CIHR; CFRI FX This study was supported by grants from the Canadian Institutes of Health Research (CIHR) (MOP-115199), the Canucks for Kids Fund, Genome British Columbia, Genome Quebec, and STEMCELL Technologies Inc. A.M.P. holds fellowships from the CIHR Strategic Training Initiative in Health Research Program in Transplantation and the 4 What Matters Foundation and a JDRF postdoctoral fellowship. A.Y.W. was funded by a CFRI Research Methodology Training Grant. A.S. is supported by a CIHR Banting and Best Doctoral Award. M.K.L. receives a Scientist Salary Award from CFRI. NR 35 TC 2 Z9 2 U1 3 U2 4 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD APR PY 2016 VL 65 IS 4 BP 1031 EP 1039 DI 10.2337/db15-0572 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DH5VC UT WOS:000372859200021 PM 26786322 ER PT J AU Pugliese, A Boulware, D Yu, LP Babu, S Steck, AK Becker, D Rodriguez, H DiMeglio, L Evans-Molina, C Harrison, LC Schatz, D Palmer, JP Greenbaum, C Eisenbarth, GS Sosenko, JM AF Pugliese, Alberto Boulware, David Yu, Liping Babu, Sunanda Steck, Andrea K. Becker, Dorothy Rodriguez, Henry DiMeglio, Linda Evans-Molina, Carmella Harrison, Leonard C. Schatz, Desmond Palmer, Jerry P. Greenbaum, Carla Eisenbarth, George S. Sosenko, Jay M. CA Type 1 Diabet TrialNet Study Grp TI HLA-DRB1*15:01-DQA1*01:02-DQB1*06:02 Haplotype Protects Autoantibody-Positive Relatives From Type 1 Diabetes Throughout the Stages of Disease Progression SO DIABETES LA English DT Article ID CLASS-II MOLECULES; GLUTAMIC-ACID DECARBOXYLASE; TRIALNET NATURAL-HISTORY; 1ST DEGREE RELATIVES; DOMINANT PROTECTION; IMPROVE PREDICTION; ISLET AUTOIMMUNITY; HLA; MELLITUS; INSULIN AB The HLA-DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype is linked to protection from the development of type 1 diabetes (T1D). However, it is not known at which stages in the natural history of T1D development this haplotype affords protection. We examined a cohort of 3,358 auto antibody -positive relatives of T1D patients in the Pathway to Prevention (PTP) Study of the Type 1 Diabetes Trial Net. The PTP study examines risk factors for T1D and disease progression in relatives. HLA typing revealed that 155 relatives carried this protective haplotype. A comparison with 60 autoantibody-negative relatives suggested protection from autoantibody development. Moreover, the relatives with DRB1*15:01-D0A1*01:02-DQB1*06:02 less frequently expressed autoantibodies associated with higher T1D risk, were less likely to have multiple autoantibodies at baseline, and rarely converted from single to multiple autoantibody positivity on follow-up. These relatives also had lower frequencies of metabolic abnormalities at baseline and exhibited no overall metabolic worsening on follow-up. Ultimately, they had a very low 5-year cumulative incidence of T1D. In conclusion, the protective influence of DRB1*15:01-DQA1*01:02-DQB1*06:02 spans from autoantibody development through all stages of progression, and relatives with this allele only rarely develop T1D. C1 [Pugliese, Alberto; Sosenko, Jay M.] Univ Miami, Diabet Res Inst, Miller Sch Med, Miami, FL USA. [Pugliese, Alberto] Univ Miami, Miller Sch Med, Dept Microbiol & Immunol, Miami, FL USA. [Boulware, David] Univ Miami, Div Endocrinol Metab & Diabet, Dept Med, Miller Sch Med, Miami, FL USA. [Yu, Liping; Babu, Sunanda; Steck, Andrea K.; Eisenbarth, George S.] Univ S Florida, Div Bioinformat & Biostat, Tampa, FL USA. [Becker, Dorothy] Univ Colorado, Barbara Davis Ctr Childhood Diabet, Anschutz Med Campus, Aurora, CO USA. [Rodriguez, Henry] Univ Pittsburgh, Med Ctr, Dept Pediat, Childrens Hosp Pittsburgh, Pittsburgh, PA USA. [DiMeglio, Linda] Univ S Florida, Dept Pediat, Morsani Coll Med, Tampa, FL USA. [Evans-Molina, Carmella] Indiana Univ Hlth, Riley Hosp Children, Dept Pediat Endocrinol, Indianapolis, IN USA. [Harrison, Leonard C.] Indiana Univ Sch Med, Dept Med, Indianapolis, IN 46202 USA. [Harrison, Leonard C.] Richard L Roudebush VA Med Ctr, Indianapolis, IN USA. [Schatz, Desmond] Univ Melbourne, Dept Med Biol, Walter & Eliza Hall Inst Med Res, Parkville, Vic 3052, Australia. [Palmer, Jerry P.] Univ Florida, Dept Pediat, Gainesville, FL USA. [Greenbaum, Carla] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Greenbaum, Carla] Univ Washington, Seattle, WA 98195 USA. [Sosenko, Jay M.] Benaroya Res Inst, Seattle, WA USA. RP Pugliese, A (reprint author), Univ Miami, Diabet Res Inst, Miller Sch Med, Miami, FL USA.; Pugliese, A (reprint author), Univ Miami, Miller Sch Med, Dept Microbiol & Immunol, Miami, FL USA. EM apuglies@med.miami.edu FU National Institutes of Health_(NIH) through the National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Allergy and Infectious Diseases; Eunice Kennedy Shriver National Institute of Child Health and Human Development [U01 DK061010, U01 DK061034, U01 DK061042, U01 DK061058, U01 DK085465, U01 DK085453, U01 DK085461, U01 DK085463, U01 DK085466, U01 DK085499, U01 DK085504, U01 DK085505, U01 DK085509, U01 DK103180, U01 DK103153, U01 DK085476, U01 DK103266]; JDRF FX The sponsor of the trial was the Type 1 Diabetes TrialNet Pathway to Prevention Study Group. Type 1 Diabetes TrialNet Pathway to Prevention Study Group is a clinical trials network funded by the National Institutes of Health_(NIH) through the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development through the cooperative agreements U01 DK061010, U01 DK061034, U01 DK061042, U01 DK061058, U01 DK085465, U01 DK085453, U01 DK085461, U01 DK085463, U01 DK085466, U01 DK085499, U01 DK085504, U01 DK085505, U01 DK085509, U01 DK103180, U01 DK103153, U01 DK085476, and U01 DK103266. The study group is also funded by JDRF. NR 48 TC 0 Z9 0 U1 1 U2 3 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD APR PY 2016 VL 65 IS 4 BP 1109 EP 1119 DI 10.2337/db15-1105 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DH5VC UT WOS:000372859200028 PM 26822082 ER PT J AU Vindigni, SM Kaz, AM AF Vindigni, Stephen M. Kaz, Andrew M. TI Universal Screening of Colorectal Cancers for Lynch Syndrome: Challenges and Opportunities SO DIGESTIVE DISEASES AND SCIENCES LA English DT Review DE Lynch syndrome; Hereditary non-polyposis colorectal cancer; HNPCC; Universal screening; Universal testing; Colorectal cancer screening; Genetic testing ID REVISED BETHESDA GUIDELINES; COST-EFFECTIVENESS ANALYSIS; GENETIC TESTING STRATEGIES; MSH6 GERMLINE MUTATIONS; MICROSATELLITE-INSTABILITY; COLON-CANCER; FOLLOW-UP; IDENTIFICATION; IMMUNOHISTOCHEMISTRY; INDIVIDUALS AB Lynch syndrome (LS) is the most common heritable colorectal cancer (CRC) syndrome, accounting for approximately 3 % of CRC cases in the USA each year. LS results from a genetic mutation in one of the four mismatch repair genes, and clinically LS is associated with CRC and other gastrointestinal and extra-gastrointestinal malignancies. In this review, we describe the various clinical criteria utilized for the identification of LS patients and the inherent flaws with these criteria. We discuss the concept of universal testing for LS in all cases of newly diagnosed CRC, along with the potential benefits and challenges of universal testing. Several studies have shown that universal tumor testing is cost-effective and identifies cases of LS that are missed using traditional clinical criteria, which may result in reduced cancer mortality for probands and their families. Yet the full benefits of universal tumor testing may be limited by the availability and patient acceptance of genetic testing, and by logistical obstacles affecting the implementation of universal testing programs. Lastly, we comment on developing technologies such as massively parallel next-generation sequencing, which permits simultaneous sequencing of multiple genes involved in LS and other inherited colon cancer syndromes. C1 [Vindigni, Stephen M.; Kaz, Andrew M.] Univ Washington, Div Gastroenterol, Sch Med, 1959 NE Pacific St,Box 356424, Seattle, WA 98105 USA. [Kaz, Andrew M.] VA Puget Sound Hlth Care Syst, 1660 S Columbian Way,S 111 Gastro, Seattle, WA 98108 USA. RP Kaz, AM (reprint author), Univ Washington, Div Gastroenterol, Sch Med, 1959 NE Pacific St,Box 356424, Seattle, WA 98105 USA.; Kaz, AM (reprint author), VA Puget Sound Hlth Care Syst, 1660 S Columbian Way,S 111 Gastro, Seattle, WA 98108 USA. EM vindigni@uw.edu; Andrew.kaz@va.gov NR 52 TC 1 Z9 1 U1 0 U2 4 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 APR PY 2016 VL 61 IS 4 BP 969 EP 976 DI 10.1007/s10620-015-3964-6 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DG7ZJ UT WOS:000372301900008 PM 26602911 ER PT J AU Kiess, AP Agrawal, N Brierley, JD Duvvuri, U Ferris, RL Genden, E Wong, RJ Tuttle, RM Lee, NY Randolph, GW AF Kiess, Ana P. Agrawal, Nishant Brierley, James D. Duvvuri, Umamaheswar Ferris, Robert L. Genden, Eric Wong, Richard J. Tuttle, R. Michael Lee, Nancy Y. Randolph, Gregory W. TI External-beam radiotherapy for differentiated thyroid cancer locoregional control: A statement of the American Head and Neck Society SO HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK LA English DT Article DE radiotherapy; radiation; thyroid cancer; papillary; follicular ID PERCUTANEOUS ETHANOL INJECTION; 2ND PRIMARY MALIGNANCIES; RADIOACTIVE IODINE; PROGNOSTIC-FACTORS; RADIATION-THERAPY; RADIOFREQUENCY ABLATION; EXTRATHYROID EXTENSION; RADIOIODINE THERAPY; REMNANT ABLATION; PAPILLARY AB The use of external-beam radiotherapy (EBRT) in differentiated thyroid cancer (DTC) is debated because of a lack of prospective clinical data, but recent retrospective studies have reported benefits in selected patients. The Endocrine Surgery Committee of the American Head and Neck Society provides 4 recommendations regarding EBRT for locoregional control in DTC, based on review of literature and expert opinion of the authors. (1) EBRT is recommended for patients with gross residual or unresectable locoregional disease, except for patients <45 years old with limited gross disease that is radioactive iodine (RAI)-avid. (2) EBRT should not be routinely used as adjuvant therapy after complete resection of gross disease. (3) After complete resection, EBRT may be considered in select patients >45 years old with high likelihood of microscopic residual disease and low likelihood of responding to RAI. (4) Cervical lymph node involvement alone should not be an indication for adjuvant EBRT. (C) 2015 Wiley Periodicals, Inc. C1 [Kiess, Ana P.] Johns Hopkins Med Inst, Dept Radiat Oncol, Baltimore, MD 21205 USA. [Agrawal, Nishant] Johns Hopkins Med Inst, Dept Otolaryngol Head & Neck Surg, Baltimore, MD 21205 USA. [Brierley, James D.] Univ Toronto, Dept Radiat Oncol, Toronto, ON, Canada. [Duvvuri, Umamaheswar; Ferris, Robert L.] Univ Pittsburgh, Dept Otolaryngol, Pittsburgh, PA 15260 USA. [Duvvuri, Umamaheswar] VA Pittsburgh Hlth Syst, Pittsburgh, PA USA. [Genden, Eric] Mt Sinai Hosp, Dept Otolaryngol, New York, NY 10029 USA. [Wong, Richard J.] Mem Sloan Kettering Canc Ctr, Dept Surg, Head & Neck Serv, 1275 York Ave, New York, NY 10021 USA. [Tuttle, R. Michael] Mem Sloan Kettering Canc Ctr, Dept Med, Serv Endocrinol, 1275 York Ave, New York, NY 10021 USA. [Lee, Nancy Y.; Randolph, Gregory W.] Mem Sloan Kettering Canc Ctr, Dept Radiat Oncol, 1275 York Ave, New York, NY 10021 USA. [Randolph, Gregory W.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Otolaryngol, Boston, MA USA. RP Kiess, AP (reprint author), Johns Hopkins Univ, Dept Radiat Oncol & Mol Radiat Sci, 401 North Broadway,Suite 1440, Baltimore, MD 21231 USA. EM akiess1@jhmi.edu FU Department of Veterans Affairs BLSRD FX Contract grant sponsor: This work was supported in part by funds from the Department of Veterans Affairs BLSR&D (U.D.). This work does not represent the views of the U.S. Government or the Department of Veterans Affairs. NR 60 TC 4 Z9 4 U1 3 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 APR PY 2016 VL 38 IS 4 BP 493 EP 498 DI 10.1002/hed.24357 PG 6 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA DH3YO UT WOS:000372722900007 PM 26716601 ER PT J AU Eising, E Huisman, SMH Mahfouz, A Vijfhuizen, LS Anttila, V Winsvold, BS Kurth, T Ikram, MA Freilinger, T Kaprio, J Boomsma, DI van Duijn, CM Jarvelin, MRR Zwart, JA Quaye, L Strachan, DP Kubisch, C Dichgans, M Smith, GD Stefansson, K Palotie, A Chasman, DI Ferrari, MD Terwindt, GM de Vries, B Nyholt, DR Lelieveldt, BPF van den Maagdenberg, AMJM Reinders, MJT AF Eising, Else Huisman, Sjoerd M. H. Mahfouz, Ahmed Vijfhuizen, Lisanne S. Anttila, Verneri Winsvold, Bendik S. Kurth, Tobias Ikram, M. Arfan Freilinger, Tobias Kaprio, Jaakko Boomsma, Dorret I. van Duijn, Cornelia M. Jarvelin, Marjo-Riitta R. Zwart, John-Anker Quaye, Lydia Strachan, David P. Kubisch, Christian Dichgans, Martin Smith, George Davey Stefansson, Kari Palotie, Aarno Chasman, Daniel I. Ferrari, Michel D. Terwindt, Gisela M. de Vries, Boukje Nyholt, Dale R. Lelieveldt, Boudewijn P. F. van den Maagdenberg, Arn M. J. M. Reinders, Marcel J. T. TI Gene co-expression analysis identifies brain regions and cell types involved in migraine pathophysiology: a GWAS-based study using the Allen Human Brain Atlas SO HUMAN GENETICS LA English DT Article ID FAMILIAL HEMIPLEGIC MIGRAINE; GENOME-WIDE ASSOCIATION; CORTICAL SPREADING DEPRESSION; RANDOMIZED CONTROLLED-TRIAL; ADULT HUMAN BRAIN; SUSCEPTIBILITY LOCI; AURA; TRANSCRIPTOME; ABNORMALITIES; NETWORK AB Migraine is a common disabling neurovascular brain disorder typically characterised by attacks of severe headache and associated with autonomic and neurological symptoms. Migraine is caused by an interplay of genetic and environmental factors. Genome-wide association studies (GWAS) have identified over a dozen genetic loci associated with migraine. Here, we integrated migraine GWAS data with high-resolution spatial gene expression data of normal adult brains from the Allen Human Brain Atlas to identify specific brain regions and molecular pathways that are possibly involved in migraine pathophysiology. To this end, we used two complementary methods. In GWAS data from 23,285 migraine cases and 95,425 controls, we first studied modules of co-expressed genes that were calculated based on human brain expression data for enrichment of genes that showed association with migraine. Enrichment of a migraine GWAS signal was found for five modules that suggest involvement in migraine pathophysiology of: (i) neurotransmission, protein catabolism and mitochondria in the cortex; (ii) transcription regulation in the cortex and cerebellum; and (iii) oligodendrocytes and mitochondria in subcortical areas. Second, we used the high-confidence genes from the migraine GWAS as a basis to construct local migraine-related co-expression gene networks. Signatures of all brain regions and pathways that were prominent in the first method also surfaced in the second method, thus providing support that these brain regions and pathways are indeed involved in migraine pathophysiology. C1 [Eising, Else; Vijfhuizen, Lisanne S.; de Vries, Boukje; van den Maagdenberg, Arn M. J. M.] Leiden Univ, Dept Human Genet, Med Ctr, NL-2333 ZC Leiden, Netherlands. [Huisman, Sjoerd M. H.; Mahfouz, Ahmed; Lelieveldt, Boudewijn P. F.; Reinders, Marcel J. T.] Delft Univ Technol, Dept Intelligent Syst, Delft Bioinformat Lab, NL-2628 CD Delft, Netherlands. [Huisman, Sjoerd M. H.; Mahfouz, Ahmed; Lelieveldt, Boudewijn P. F.] Leiden Univ, Med Ctr, Dept Radiol, Div Image Proc, NL-2333 ZA Leiden, Netherlands. [Anttila, Verneri; Palotie, Aarno] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Anttila, Verneri; Palotie, Aarno] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Anttila, Verneri; Palotie, Aarno] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Anttila, Verneri; Palotie, Aarno] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA. [Winsvold, Bendik S.; Zwart, John-Anker] Oslo Univ Hosp, FORMI, N-0424 Oslo, Norway. [Winsvold, Bendik S.; Zwart, John-Anker] Oslo Univ Hosp, Dept Neurol, N-0424 Oslo, Norway. [Winsvold, Bendik S.; Zwart, John-Anker] Univ Oslo, N-0424 Oslo, Norway. [Kurth, Tobias] Charite, Inst Publ Hlth, D-10117 Berlin, Germany. [Kurth, Tobias; Chasman, Daniel I.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med,Div Prevent, Boston, MA 02215 USA. [Ikram, M. Arfan; van Duijn, Cornelia M.] Erasmus Univ, Med Ctr, Dept Epidemiol, NL-3015 CE Rotterdam, Netherlands. [Ikram, M. Arfan] Erasmus Univ, Med Ctr, Dept Radiol, NL-3015 CE Rotterdam, Netherlands. [Ikram, M. Arfan] Erasmus Univ, Med Ctr, Dept Neurol, NL-3015 CE Rotterdam, Netherlands. [Freilinger, Tobias] Univ Tubingen, Dept Neurol & Epileptol, D-72076 Tubingen, Germany. [Freilinger, Tobias] Univ Tubingen, Hertie Inst Clin Brain Res, D-72076 Tubingen, Germany. [Freilinger, Tobias; Dichgans, Martin] Univ Munich, Klinikum Univ mUNCHEN, Inst Stroke & Dementia Res, Marchioninistr 15, D-81377 Munich, Germany. [Kaprio, Jaakko] Univ Helsinki, Dept Publ Hlth, Helsinki 00014, Finland. [Boomsma, Dorret I.] Vrije Univ Amsterdam, Dept Biol Psychol, NL-1081 HV Amsterdam, Netherlands. [Jarvelin, Marjo-Riitta R.] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, MRC PHE Ctr Environm & Hlth, Dept Epidemiol & Biostat, London W2 1PG, England. [Jarvelin, Marjo-Riitta R.] Univ Oulu, Ctr Life Course Hlth Res, Fac Med, POB 5000, Oulu 90014, Finland. [Jarvelin, Marjo-Riitta R.] Univ Oulu, Fac Med, Northern Finland Cohort Ctr, POB 5000, Oulu 90014, Finland. [Jarvelin, Marjo-Riitta R.] Univ Oulu, Bioctr Oulu, Aapistie 5A,POB 5000, Oulu 90014, Finland. [Dichgans, Martin] Oulu Univ Hosp, Unit Primary Care, Kajaanintie 50,90029 OYS,POB 20, Oulu 90220, Finland. [Quaye, Lydia] Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England. [Strachan, David P.] Univ London, Populat Hlth Res Inst, London SW17 0RE, England. [Kubisch, Christian] Univ Med Ctr Hamburg Eppendorf, Inst Human Genet, D-20246 Hamburg, Germany. [Dichgans, Martin] Munich Cluster Syst Neurol SyNergy, D-81377 Munich, Germany. [Smith, George Davey] Univ Bristol, Sch Social & Commun Med, Med Res Council Integrat Epidemiol Unit IEU, Bristol BS8 2PS, Avon, England. [Stefansson, Kari] deCODE Genet, IS-101 Reykjavik, Iceland. [Stefansson, Kari] Univ Iceland, Sch Med, IS-101 Reykjavik, Iceland. [Kaprio, Jaakko; Palotie, Aarno] Univ Helsinki, Inst Mol Med Finland FIMM, FIN-00290 Helsinki, Finland. [Ferrari, Michel D.; Terwindt, Gisela M.; van den Maagdenberg, Arn M. J. M.] Leiden Univ, Med Ctr, Dept Neurol, NL-2333 ZA Leiden, Netherlands. [Nyholt, Dale R.] Queensland Univ Technol, Inst Hlth & Biomed Innovat, Brisbane, Qld 4059, Australia. [Nyholt, Dale R.] Queensland Inst Med Res, Berghofer Med Res Inst, Brisbane, Qld 4006, Australia. RP van den Maagdenberg, AMJM (reprint author), Leiden Univ, Dept Human Genet, Med Ctr, NL-2333 ZC Leiden, Netherlands.; Reinders, MJT (reprint author), Delft Univ Technol, Dept Intelligent Syst, Delft Bioinformat Lab, NL-2628 CD Delft, Netherlands.; van den Maagdenberg, AMJM (reprint author), Leiden Univ, Med Ctr, Dept Neurol, NL-2333 ZA Leiden, Netherlands. EM A.M.J.M.van_den_Maagdenberg@lumc.nl; m.j.t.reinders@tudelft.nl RI Kubisch, Christian/F-1893-2011; Lelieveldt, Boudewijn/B-6501-2008; Kurth, Tobias/A-9243-2012; Davey Smith, George/A-7407-2013; OI Kubisch, Christian/0000-0003-4220-0978; Lelieveldt, Boudewijn/0000-0001-8269-7603; Kurth, Tobias/0000-0001-7169-2620; Davey Smith, George/0000-0002-1407-8314; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Winsvold, Bendik Slagsvold/0000-0003-4171-8919; Huisman, Sjoerd/0000-0002-4322-8289 FU Dutch Technology Foundation STW, as part of the STW Project "Genes in Space" under the IMAGENE perspective program [12721]; Spinoza; European Union [602633, 604102]; Center for Medical Systems Biology (CMSB) [050-060-409]; Orion Farmos Research Foundation FX This research was supported by the Dutch Technology Foundation STW, as part of the STW Project 12721: "Genes in Space" under the IMAGENE perspective program; the Spinoza (2009) Grant to M.D.F.; European Union Seventh Framework Programme Projects EUROHEADPAIN Project [Grant Number 602633] & Human Brain Project [Grant Number 604102]; the Center for Medical Systems Biology (CMSB) established in the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research (NGI/NWO) [Project Nr. 050-060-409]; and the Orion Farmos Research Foundation (to V.A.). The authors gratefully acknowledge the Allen Institute for Brain Science. NR 64 TC 3 Z9 3 U1 2 U2 13 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 EI 1432-1203 J9 HUM GENET JI Hum. Genet. PD APR PY 2016 VL 135 IS 4 BP 425 EP 439 DI 10.1007/s00439-016-1638-x PG 15 WC Genetics & Heredity SC Genetics & Heredity GA DH2JA UT WOS:000372610000006 PM 26899160 ER PT J AU Mehta, DD Van Stan, JH Hillman, RE AF Mehta, Daryush D. Van Stan, Jarrad H. Hillman, Robert E. TI Relationships Between Vocal Function Measures Derived from an Acoustic Microphone and a Subglottal Neck-Surface Accelerometer SO IEEE-ACM TRANSACTIONS ON AUDIO SPEECH AND LANGUAGE PROCESSING LA English DT Article DE Ambulatory voice monitoring; cepstral peak prominence; harmonics-to-noise ratio; neck-surface accelerometer; vocal function analysis; vocal perturbation ID VOICE SIGNALS; FUNDAMENTAL-FREQUENCY; SPEECH; HYPERFUNCTION; RESONANCES; VIBRATION; SENSORS; FEMALE AB Monitoring subglottal neck-surface acceleration has received renewed attention due to the ability of low-profile accelerometers to confidentially and noninvasively track properties related to normal and disordered voice characteristics and behavior. This study investigated the ability of subglottal neck-surface acceleration to yield vocal function measures traditionally derived from the acoustic voice signal and help guide the development of clinically functional accelerometer-based measures from a physiological perspective. Results are reported for 82 adult speakers with voice disorders and 52 adult speakers with normal voices who produced the sustained vowels /a/, /i/, and /u/ at a comfortable pitch and loudness during the simultaneous recording of radiated acoustic pressure and subglottal neck-surface acceleration. As expected, timing-related measures of jitter exhibited the strongest correlation between acoustic and neck-surface acceleration waveforms (r <= 0.99), whereas amplitude-based measures of shimmer correlated less strongly (r <= 0.74). Additionally, weaker correlations were exhibited by spectral measures of harmonics-to-noise ratio (r <= 0.69) and tilt (r <= 0.57), whereas the cepstral peak prominence correlated more strongly (r <= 0.90). These empirical relationships provide evidence to support the use of accelerometers as effective complements to acoustic recordings in the assessment and monitoring of vocal function in the laboratory, clinic, and during an individual's daily activities. C1 [Mehta, Daryush D.; Van Stan, Jarrad H.; Hillman, Robert E.] Massachusetts Gen Hosp, Ctr Laryngeal Surg & Voice Rehabil, Boston, MA 02114 USA. [Mehta, Daryush D.; Van Stan, Jarrad H.; Hillman, Robert E.] Massachusetts Gen Hosp, Inst Hlth Profess, Boston, MA 02114 USA. [Mehta, Daryush D.] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Hillman, Robert E.] Harvard Univ, Sch Med, Surg & Hlth Sci & Technol, Boston, MA 02115 USA. RP Mehta, DD; Van Stan, JH; Hillman, RE (reprint author), Massachusetts Gen Hosp, Ctr Laryngeal Surg & Voice Rehabil, Boston, MA 02114 USA.; Mehta, DD; Van Stan, JH; Hillman, RE (reprint author), Massachusetts Gen Hosp, Inst Hlth Profess, Boston, MA 02114 USA.; Mehta, DD (reprint author), Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA.; Hillman, RE (reprint author), Harvard Univ, Sch Med, Surg & Hlth Sci & Technol, Boston, MA 02115 USA. EM daryush@mgh.harvard.edu; jvanstan@mghihp.edu; hillman.robert@mgh.harvard.edu FU NIH National Institute on Deafness and Other Communication Disorders [R33 DC011588]; Voice Health Institute FX This work was supported in part by the NIH National Institute on Deafness and Other Communication Disorders under Grant R33 DC011588 and in part by the Voice Health Institute. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. The associate editor coordinating the review of this manuscript and approving it for publication was Dr. Wai-Yip Geoffrey Chan. NR 49 TC 1 Z9 1 U1 0 U2 0 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 2329-9290 J9 IEEE-ACM T AUDIO SPE JI IEEE-ACM Trans. Audio Speech Lang. PD APR PY 2016 VL 24 IS 4 BP 659 EP 668 DI 10.1109/TASLP.2016.2516647 PG 10 WC Acoustics; Engineering, Electrical & Electronic SC Acoustics; Engineering GA DH0FR UT WOS:000372458400005 PM 27066520 ER PT J AU Lam, KO Lee, AWM Choi, CW Sze, HCK Zietman, AL Hopkins, KI Rosenblatt, E AF Lam, Ka-On Lee, Anne W. M. Choi, Cheuk-Wai Sze, Henry C. K. Zietman, Anthony L. Hopkins, Kirsten I. Rosenblatt, Eduardo TI Global Pattern of Nasopharyngeal Cancer: Correlation of Outcome With Access to Radiation Therapy SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID RADIOTHERAPY; CARCINOMA; SURVIVAL; INFRASTRUCTURE; SURVEILLANCE; ERA AB Purpose: This study aimed to estimate the treatment outcome of nasopharyngeal cancer (NPC) across the world and its correlation with access to radiation therapy (RT). Methods and Materials: The age-standardized mortality (ASM) and age-standardized incidence (ASI) rates of NPC from GLOBOCAN (2012) were summarized, and [1 -(ASM/ASI)] was computed to give the proxy relative survival (RS). Data from the International Atomic Energy Agency (IAEA) and the World Bank were used to assess the availability of RT in surrogate terms: the number of RT equipment units and radiation oncologists per million population. Results: A total of 112 countries with complete valid data were analyzed, and the proxy RS varied widely from 0% to 83% (median, 50%). Countries were categorized into Good, Median, and Poor outcome groups on the basis of their proxy RS (<45%, 45%-55%, and >55%). Eighty percent of new cases occurred in the Poor outcome group. Univariable linear regression showed a significant correlation between outcome and the availability of RT: proxy RS increased at 3.4% (P<.001) and 1.5% (P=.001) per unit increase in RT equipment and oncologist per million population, respectively. The median number of RT equipment units per million population increased significantly from 0.5 in the Poor, to 1.5 in the Median, to 4.6 in the Good outcome groups, and the corresponding number of oncologists increased from 1.1 to 3.3 to 7.1 (P<.001). Conclusions: Nasopharyngeal cancer is a highly treatable disease, but the outcome varies widely across the world. The current study shows a significant correlation between survival and access to RT based on available surrogate indicators. However, the possible reasons for poor outcome are likely to be multifactorial and complex. Concerted international efforts are needed not only to address the fundamental requirement for adequate RT access but also to obtain more comprehensive and accurate data for research to improve cancer outcome. (C) 2016 Elsevier Inc. All rights reserved. C1 [Lam, Ka-On; Lee, Anne W. M.; Sze, Henry C. K.] Univ Hong Kong, Shenzhen Hosp, Clin Oncol Ctr, 1 Haiyuan First Rd, Shenzhen 518053, Guangdong, Peoples R China. [Choi, Cheuk-Wai] City Univ Hong Kong, Dept Syst Engn & Engn Management, Hong Kong, Hong Kong, Peoples R China. [Zietman, Anthony L.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Hopkins, Kirsten I.; Rosenblatt, Eduardo] IAEA, A-1400 Vienna, Austria. RP Lee, AWM (reprint author), Univ Hong Kong, Shenzhen Hosp, Clin Oncol Ctr, 1 Haiyuan First Rd, Shenzhen 518053, Guangdong, Peoples R China. EM annelee@hku-szh.org NR 14 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 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD APR 1 PY 2016 VL 94 IS 5 BP 1106 EP 1112 DI 10.1016/j.ijrobp.2015.11.047 PG 7 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DH1SI UT WOS:000372564800016 PM 27026314 ER PT J AU Muehe, AM Feng, D Eyben, R Luna-Fineman, S Link, MP Muthig, T Huddleston, AE Neuwelt, EA Daldrup-Link, HE AF Muehe, Anne M. Feng, Dan von Eyben, Rie Luna-Fineman, Sandra Link, Michael P. Muthig, Travis Huddleston, Amy E. Neuwelt, Edward A. Daldrup-Link, Heike E. TI Safety Report of Ferumoxytol for Magnetic Resonance Imaging in Children and Young Adults SO INVESTIGATIVE RADIOLOGY LA English DT Article DE pediatric; ferric compounds; ferumoxytol; adverse events/adverse effects; safety; toxicity; contrast media ID IRON-OXIDE NANOPARTICLES; HEMODIALYSIS-PATIENTS; DEFICIENCY ANEMIA; ADVERSE-REACTIONS; KIDNEY-DISEASE; CONTRAST AGENT; LIFE-SUPPORT; MRI; THERAPY; MANAGEMENT AB Objective The aim of this study was to assess the safety profile of ferumoxytol as an intravenous magnetic resonance imaging contrast agent in children. Materials and Methods We prospectively evaluated the safety of ferumoxytol administrations as an "off-label" contrast agent for magnetic resonance imaging in nonrandomized phase 4 clinical trials at 2 centers. From September 2009 to February 2015, 49 pediatric patients (21 female and 28 male, 5-18 years) and 19 young adults (8 female and 11 male, 18-25 years) were reported under an investigator-initiated investigational new drug investigation with institutional review board approval, in health insurance portability and accountability act compliance, and after written informed consent of the child's legal representative or the competent adult patient was obtained. Patients received either a single dose (5 mg Fe/kg) or up to 4 doses of ferumoxytol (0.7-4 mg Fe/kg) intravenously, which were approximately equivalent to one third of the dose for anemia treatment. We monitored vital signs and adverse events directly for up to 1 hour after injection. In addition, we examined weekly vitals, hematologic, renal, and liver serum panels for 1 month after injection in over 20 pediatric patients. At fixed time points before and after ferumoxytol injection, data were evaluated for significant differences by a repeated measures linear mixed model. Results Four mild adverse events, thought to be related to ferumoxytol, were observed within 1 hour of 85 ferumoxytol injections: 2 episodes of mild hypotension and 1 case of nausea in 65 injections in pediatric patients without related clinical symptoms. One young adult patient developed warmness and erythema at the injection site. All adverse events were self-resolving. No spontaneous serious adverse events were reported. At a dose of 5 mg Fe/kg or lower, intravenous ferumoxytol injection had no clinical relevance or statistically significant effect (P > 0.05) on vital signs, hematological parameters, kidney function, or liver enzymes within 1 month of the injection. Conclusions Ferumoxytol was overall well tolerated among 49 pediatric and 19 young adult patients experiencing various tumors or kidney transplants without major adverse events or signs of hematologic and kidney impairment or liver toxicity. Larger studies are needed to determine the incidence of anaphylactic reactions. C1 [Muehe, Anne M.; Feng, Dan; Daldrup-Link, Heike E.] Stanford Univ, Mol Imaging Program Stanford, Dept Radiol, Stanford, CA 94305 USA. [Muehe, Anne M.; Feng, Dan; Daldrup-Link, Heike E.] Stanford Univ, Lucile Packard Childrens Hosp, Stanford, CA 94305 USA. [von Eyben, Rie] Stanford Univ, Dept Radiat Oncol, Stanford, CA 94305 USA. [Luna-Fineman, Sandra; Link, Michael P.] Stanford Univ, Sect Pediat Hematol & Oncol, Dept Pediat, Stanford, CA 94305 USA. [Muthig, Travis] Univ S Carolina, Sch Med, Columbia, SC USA. [Huddleston, Amy E.; Neuwelt, Edward A.] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA. [Neuwelt, Edward A.] Oregon Hlth & Sci Univ, Dept Neurosurg, Portland, OR 97201 USA. [Neuwelt, Edward A.] Portland VA Med Ctr, Portland, OR USA. RP Daldrup-Link, HE (reprint author), Stanford Sch Med, Dept Radiol, 725 Welch Rd, Stanford, CA 94305 USA. EM H.E.Daldrup-Link@stanford.edu RI Daldrup-Link, Heike/D-9829-2012 OI Daldrup-Link, Heike/0000-0002-4929-819X FU National Institute of Child Health and Human Development [R01 HD081123A]; Translational Research and Applied Medicine Program at Stanford University; National Institute of Health [CA137488]; Walter S. and Lucienne Driskill Foundation; Stanford Medical Scholars Fellowship Program FX Supported by R01 HD081123A from the National Institute of Child Health and Human Development, a grant from the Translational Research and Applied Medicine Program at Stanford University (H.E.D.L. and D.F.), by National Institute of Health grant CA137488, and by the Walter S. and Lucienne Driskill Foundation to Oregon Health & Science University (E.A.N.). D.F. was supported by a stipend from the Stanford Medical Scholars Fellowship Program. NR 41 TC 7 Z9 7 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0020-9996 EI 1536-0210 J9 INVEST RADIOL JI Invest. Radiol. PD APR PY 2016 VL 51 IS 4 BP 221 EP 227 DI 10.1097/RLI.0000000000000230 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DH0CX UT WOS:000372451200002 PM 26656202 ER PT J AU Walsh, EA Kirkpatrick, JB Rutherford, SD Smith, DC Sogin, M D'Hondt, S AF Walsh, Emily A. Kirkpatrick, John B. Rutherford, Scott D. Smith, David C. Sogin, Mitchell D'Hondt, Steven TI Bacterial diversity and community composition from seasurface to subseafloor SO ISME JOURNAL LA English DT Article ID OXYGEN MINIMUM ZONE; SOUTH-PACIFIC GYRE; DEEP-SEA; MARINE-SEDIMENTS; THERMOPHILIC BACTERIA; SURFACE SEDIMENTS; BIOGEOGRAPHY; OCEAN; ASSEMBLAGES; PATTERNS AB We investigated compositional relationships between bacterial communities in the water column and those in deep-sea sediment at three environmentally distinct Pacific sites (two in the Equatorial Pacific and one in the North Pacific Gyre). Through pyrosequencing of the v4-v6 hypervariable regions of the 16S ribosomal RNA gene, we characterized 450 104 pyrotags representing 29 814 operational taxonomic units (OTUs, 97% similarity). Hierarchical clustering and non-metric multidimensional scaling partition the samples into four broad groups, regardless of geographic location: a photic-zone community, a subphotic community, a shallow sedimentary community and a subseafloor sedimentary community (>= 1.5 meters below seafloor). Abundance-weighted community compositions of water-column samples exhibit a similar trend with depth at all sites, with successive epipelagic, mesopelagic, bathypelagic and abyssopelagic communities. Taxonomic richness is generally highest in the water-column O-2 minimum zone and lowest in the subseafloor sediment. OTUs represented by abundant tags in the subseafloor sediment are often present but represented by few tags in the water column, and represented by moderately abundant tags in the shallow sediment. In contrast, OTUs represented by abundant tags in the water are generally absent from the subseafloor sediment. These results are consistent with (i) dispersal of marine sedimentary bacteria via the ocean, and (ii) selection of the subseafloor sedimentary community from within the community present in shallow sediment. C1 [Walsh, Emily A.] Forsyth Inst, Dept Microbiol, Cambridge, MA USA. [Walsh, Emily A.] Harvard Univ, Sch Dent Med, 188 Longwood Ave, Boston, MA 02115 USA. [Kirkpatrick, John B.; Smith, David C.; D'Hondt, Steven] Univ Rhode Isl, Grad Sch Oceanog, Narragansett Bay Campus, Narragansett, RI 02882 USA. [Rutherford, Scott D.] Roger Williams Univ, Dept Environm Sci, Bristol, RI 02809 USA. [Sogin, Mitchell] Marine Biol Lab, Josephine Bay Paul Ctr Comparat Mol Biol & Evolut, Woods Hole, MA 02543 USA. RP Walsh, EA (reprint author), Forsyth Inst, 245 First St, Cambridge, MA 02145 USA. EM ewalsh@forsyth.org OI Kirkpatrick, John/0000-0002-5741-7005 FU Biological Oceanography Program of the US National Science Foundation [OCE-0752336]; NSF [NSF-OCE-0939564] FX We thank Captain Kent Sheasley, and the crew and scientific party of R/V Knorr Expedition 195-3 for our samples. We also thank Robert Pockalny for mapping and helping to select the Expedition 195-3 sampling sites. This study was funded by the Biological Oceanography Program of the US National Science Foundation (grant OCE-0752336) and by the NSF-funded Center for Dark Energy Biosphere Investigations (grant NSF-OCE-0939564). This is C-DEBI publication 269. NR 45 TC 8 Z9 8 U1 12 U2 43 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1751-7362 EI 1751-7370 J9 ISME J JI ISME J. PD APR PY 2016 VL 10 IS 4 BP 979 EP 989 DI 10.1038/ismej.2015.175 PG 11 WC Ecology; Microbiology SC Environmental Sciences & Ecology; Microbiology GA DG8WJ UT WOS:000372364000017 PM 26430855 ER PT J AU Parthasarathy, A Lai, J Bartlett, EL AF Parthasarathy, Aravindakshan Lai, Jesyin Bartlett, Edward L. TI Age-Related Changes in Processing Simultaneous Amplitude Modulated Sounds Assessed Using Envelope Following Responses SO JARO-JOURNAL OF THE ASSOCIATION FOR RESEARCH IN OTOLARYNGOLOGY LA English DT Article DE colliculus; ASSR; auditory nerve; FFR; EFR; cochlear neuropathy; synaptopathy ID AUDITORY-EVOKED POTENTIALS; STEADY-STATE RESPONSES; DETECTION INTERFERENCE; INFERIOR COLLICULUS; HEARING-LOSS; SPEECH RECOGNITION; PHENOMENOLOGICAL MODEL; NERVE FIBERS; BRAIN-STEM; FREQUENCY AB Listening conditions in the real world involve segregating the stimuli of interest from competing auditory stimuli that differ in their sound level and spectral content. It is in these conditions of complex spectro-temporal processing that listeners with age-related hearing loss experience the most difficulties. Envelope following responses (EFRs) provide objective neurophysiological measures of auditory processing. EFRs were obtained to two simultaneous sinusoidally amplitude modulated (sAM) tones from young and aged Fischer-344 rats. One was held at a fixed suprathreshold sound level (sAM1(FL)) while the second varied in sound level (sAM2(VL)) and carrier frequency. EFR amplitudes to sAM1(FL) in the young decreased with signal-to-noise ratio (SNR), and this reduction was more pronounced when the sAM2(VL) carrier frequency was spectrally separated from sAM1(FL). Aged animals showed similar trends, while having decreased overall response amplitudes compared to the young. These results were replicated using an established computational model of the auditory nerve. The trends observed in the EFRs were shown to be due to the contributions of the low-frequency tails of high-frequency neurons, rather than neurons tuned to the sAM1(FL) carrier frequency. Modeling changes in threshold and neural loss reproduced some of the changes seen with age, but accuracy improved when combined with an additional decrease representing synaptic loss of auditory nerve neurons. Sound segregation in this case derives primarily from peripheral processing, regardless of age. Contributions by more central neural mechanisms are likely to occur only at low SNRs. C1 [Parthasarathy, Aravindakshan; Lai, Jesyin; Bartlett, Edward L.] Purdue Univ, Interdisciplinary Life Sci Program, Dept Biol Sci, W Lafayette, IN 47907 USA. [Parthasarathy, Aravindakshan; Lai, Jesyin; Bartlett, Edward L.] Purdue Univ, Weldon Sch Biomed Engn, W Lafayette, IN 47907 USA. [Parthasarathy, Aravindakshan] Harvard Univ, Eaton Peabody Lab, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA 02114 USA. RP Bartlett, EL (reprint author), Purdue Univ, Interdisciplinary Life Sci Program, Dept Biol Sci, W Lafayette, IN 47907 USA.; Bartlett, EL (reprint author), Purdue Univ, Weldon Sch Biomed Engn, W Lafayette, IN 47907 USA. EM ebartle@purdue.edu FU National Institutes of Health (NIDCD) [R01DC011580] FX This study was supported by a grant from the National Institutes of Health (NIDCD R01DC011580) to ELB. NR 59 TC 1 Z9 1 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1525-3961 EI 1438-7573 J9 JARO-J ASSOC RES OTO JI JARO PD APR PY 2016 VL 17 IS 2 BP 119 EP 132 DI 10.1007/s10162-016-0554-z PG 14 WC Neurosciences; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA DH1JJ UT WOS:000372539900004 PM 26905273 ER PT J AU Huz, I Nyer, M Dickson, C Farabaugh, A Alpert, J Fava, M Baer, L AF Huz, Ilana Nyer, Maren Dickson, Claire Farabaugh, Amy Alpert, Jonathan Fava, Maurizio Baer, Lee TI Obsessive-Compulsive Symptoms as a Risk Factor for Suicidality in US College Students SO JOURNAL OF ADOLESCENT HEALTH LA English DT Article DE Suicidality; Obsessive-compulsive symptoms; College students; Mental health screening ID BECK DEPRESSION INVENTORY; QUESTIONNAIRE; VALIDATION; POPULATION; DISORDER AB Purpose: The purpose of this study was to assess the association of obsessive-compulsive symptoms (OCS) with suicide risk among college students. Methods: Subjects were 474 college students who attended mental health screenings at two private universities and completed multiple self-report questionnaires. Results: Presence of one or more OCS was associated with an increased odds ratio of suicide risk of approximately 2.4, although this was no longer a significant risk factor when controlling for depressive symptoms. Of the OCS assessed, only obsessions about speaking or acting violently remained an independent risk factor for suicidality over and above depression. Conclusions: Although our study was cross-sectional in nature and thus cannot determine causality, increased burden of particular OCS symptom clusters, such as violent or aggressive obsessions, may increase risk among college students, for suicidal ideation. (C) 2016 Society for Adolescent Health and Medicine. All rights reserved. C1 [Huz, Ilana; Nyer, Maren; Dickson, Claire; Farabaugh, Amy; Alpert, Jonathan; Fava, Maurizio; Baer, Lee] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Nyer, Maren; Farabaugh, Amy; Alpert, Jonathan; Fava, Maurizio; Baer, Lee] Harvard Univ, Sch Med, Boston, MA USA. RP Huz, I (reprint author), Massachusetts Gen Hosp, Depress Clin & Res Program, 1 Bowdoin Sq,6th Floor, Boston, MA 02114 USA. EM IlanaHuz@gmail.com OI Alpert, Jonathan/0000-0002-4332-908X FU Chirag Foundation FX Funding provided by the Chirag Foundation. NR 10 TC 1 Z9 1 U1 1 U2 5 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 APR PY 2016 VL 58 IS 4 BP 481 EP 484 DI 10.1016/j.jadohealth.2015.11.011 PG 4 WC Psychology, Developmental; Public, Environmental & Occupational Health; Pediatrics SC Psychology; Public, Environmental & Occupational Health; Pediatrics GA DH3WM UT WOS:000372717500016 PM 26803200 ER PT J AU Banerji, A Busse, P Riedl, M Lumry, W Davis-Lorton, M Wedner, HJ Jacobs, J Baker, J Bernstein, JA Lockey, R Li, H Craig, T Cicardi, M Al-Ghazawi, A Soo, C Iarrobino, R Sexton, D TenHoor, C Faucette, R Biedenkapp, J Chyung, Y Adelman, B AF Banerji, Aleena Busse, Paula Riedl, Marc Lumry, William Davis-Lorton, Mark Wedner, H. James Jacobs, Joshua Baker, James Bernstein, Jonathan A. Lockey, Richard Li, Henry Craig, Timothy Cicardi, Marco Al-Ghazawi, Ahmad Soo, Carolyn Iarrobino, Ryan Sexton, Dan TenHoor, Chris Faucette, Ryan Biedenkapp, Joseph Chyung, Yung Adelman, Burt TI DX-2930 IN PATIENTS WITH HEREDITARY ANGIOEDEMA-FINAL RESULTS OF A PHASE 1b STUDY SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [Banerji, Aleena] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Busse, Paula] Mt Sinai Med Ctr, Miami Beach, FL USA. [Riedl, Marc] Univ Calif San Diego, La Jolla, CA 92093 USA. [Lumry, William] AARA Res Ctr, New York, NY USA. [Davis-Lorton, Mark] Winthrop Univ Hosp, Mineola, NY USA. [Wedner, H. James] Washington Univ, Sch Med, St Louis, MO 63130 USA. [Jacobs, Joshua] Allergy & Asthma Clin Res, Skillman, NJ USA. [Baker, James] Baker Allergy Asthma & Dermatol, Wilsonville, OR USA. [Bernstein, Jonathan A.] Univ Cincinnati, Coll Med, Div Immunol Allergy & Rheumatol, Cincinnati, OH USA. [Lockey, Richard] Univ S Florida, Tampa, FL 33620 USA. [Li, Henry] Inst Allergy & Asthma, Silver Spring, MD USA. [Craig, Timothy] Penn State Hershey Med Ctr, Hershey, PA USA. [Cicardi, Marco] Univ Milan, I-20122 Milan, Italy. [Al-Ghazawi, Ahmad] Triumpharma, Al Yarout, Jordan. [Soo, Carolyn; Iarrobino, Ryan; Sexton, Dan; TenHoor, Chris; Faucette, Ryan; Biedenkapp, Joseph; Chyung, Yung; Adelman, Burt] Dyax, Tehran, Iran. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 EI 1573-2592 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD APR PY 2016 VL 36 IS 3 MA 4289 BP 240 EP 240 PG 1 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300021 ER PT J AU Felgentreff, K Baxi, SN Lee, YN Dobbs, K Henderson, LA Csomos, K Tsitsikov, EN Armanios, MY Walter, JE Notarangelo, LD AF Felgentreff, Kerstin Baxi, Sachin N. Lee, Yu Nee Dobbs, Kerry Henderson, Lauren A. Csomos, Krisztian Tsitsikov, Erdyni N. Armanios, Mary Y. Walter, Jolan E. Notarangelo, Luigi D. TI SIGNIFICANT IMMUNE ABNORMALITIES IN ASYMPTOMATIC LIG4 MUTATION CARRIERS SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [Felgentreff, Kerstin] Univ Ulm, Dept Pediat & Adolescent Med, Univ Med Ctr Ulm, D-89069 Ulm, Germany. [Felgentreff, Kerstin; Baxi, Sachin N.; Lee, Yu Nee; Dobbs, Kerry; Henderson, Lauren A.; Walter, Jolan E.; Notarangelo, Luigi D.] Harvard Univ, Sch Med, Boston Childrens Hosp, Div Immunol, Boston, MA USA. [Csomos, Krisztian] Massachusetts Gen Hosp Children, Div Pediat Allergy Immunol, Boston, MA USA. [Tsitsikov, Erdyni N.] Boston Childrens Hosp, Dept Lab Med, Boston, MA USA. [Armanios, Mary Y.] Johns Hopkins Univ, Sch Med, Dept Oncol, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA. [Armanios, Mary Y.] Johns Hopkins Univ, Sch Med, Dept Pathol, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA. [Walter, Jolan E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Immunol & Inflammatory Dis, Boston, MA USA. [Notarangelo, Luigi D.] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 EI 1573-2592 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD APR PY 2016 VL 36 IS 3 MA 4302 BP 241 EP 242 PG 2 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300024 ER PT J AU Farmer, J Yonker, LM Suez, D Sullivan, K Cunningham-Rundles, C Walter, J AF Farmer, Jocelyn Yonker, Lael M. Suez, Daniel Sullivan, Kathleen Cunningham-Rundles, Charlotte Walter, Jolan TI TERTIARY CARE PATIENTS WITH COMMON VARIABLE IMMUNE DEFICIENCY (CVID) ARE AT SIMILAR RISK FOR NONINFECTIOUS COMPLICATIONS: A COMPARATIVE COHORT ANALYSIS BETWEEN PARTNERS-AFFILIATED HOSPITALS IN BOSTON, MA AND THE USIDNET NATIONAL REGISTRY. SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [Farmer, Jocelyn] Massachusetts Gen Hosp, Dept Allergy & Immunol, Boston, MA 02114 USA. [Yonker, Lael M.] Massachusetts Gen Hosp, Pediat Pulm, Boston, MA 02114 USA. [Suez, Daniel] Univ Texas SW Med Ctr Dallas, Div Allergy & Immunol, Dallas, TX 75390 USA. [Sullivan, Kathleen] Childrens Hosp Philadelphia, Div Allergy & Immunol, Philadelphia, PA 19104 USA. [Cunningham-Rundles, Charlotte] Icahn Sch Med Mt Sinai, Dept Med, Div Clin Immunol, New York, NY 10029 USA. [Walter, Jolan] Massachusetts Gen Hosp, Dept Pediat, Div Allergy & Immunol, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 EI 1573-2592 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD APR PY 2016 VL 36 IS 3 MA 4443 BP 266 EP 266 PG 1 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300085 ER PT J AU Barmettler, S Farmer, J Choi, H Walter, J AF Barmettler, Sara Farmer, Jocelyn Choi, Hyon Walter, Jolan TI RITUXIMAB AND HYPOGAMMAGLOBULINEMIA-COMPARATIVE OUTCOMES AT MASSACHUSETTS GENERAL HOSPITAL SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [Barmettler, Sara; Farmer, Jocelyn] Massachusetts Gen Hosp, Dept Allergy & Immunol, Boston, MA 02114 USA. [Choi, Hyon] Massachusetts Gen Hosp, Dept Rheumatol, Boston, MA 02114 USA. [Walter, Jolan] Massachusetts Gen Hosp, Dept Pediat, Div Allergy & Immunol, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 EI 1573-2592 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD APR PY 2016 VL 36 IS 3 MA 4464 BP 273 EP 273 PG 1 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300103 ER PT J AU Dobbs, K Tabellini, G Martinez, MP Al-Herz, W Bleesing, JJ Booth, C Cancrini, C Chou, J Cowan, M de la Morena, MT Geha, RS Gennery, A Giliani, S Holland, SM Kanariou, M King, A Kuijpers, T Lougaris, V Meyts, I Moratto, D Plebani, A Walter, JE Parolini, S Notarangelo, LD AF Dobbs, Kerry Tabellini, G. Martinez, Maria Paula Al-Herz, Waleed Bleesing, Jack J. Booth, Claire Cancrini, Caterina Chou, Janet Cowan, Morton de la Morena, M. Teresa Geha, Raif S. Gennery, Andrew Giliani, Silvia Holland, Steve M. Kanariou, Maria King, Alejandra Kuijpers, Taco Lougaris, Vassilios Meyts, Isabelle Moratto, Daniele Plebani, Alessandro Walter, Jolan E. Parolini, Silvia Notarangelo, Luigi D. TI NK CELLS FROM PATIENTS WITH RAG AND ARTEMIS DEFICIENCY HAVE AN IMMATURE PHENOTYPE AND DISPLAY INCREASED DEGRANULATION CAPACITY-IMPLICATIONS FOR HEMATOPOIETIC CELL TRANSPLANTATION SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [Dobbs, Kerry; Martinez, Maria Paula] Boston Childrens Hosp, Div Immunol, Boston, MA USA. [Al-Herz, Waleed] Kuwait Univ, Fac Med, Dept Pediat, Kuwait, Kuwait. [Bleesing, Jack J.] Cincinnati Childrens Hosp Med Ctr, Div Bone Marrow Transplantat & Immune Deficiency, Cincinnati, OH 45229 USA. [Booth, Claire] Great Ormond St Hosp Sick Children, Dept Paediat Immunol, London, England. [Booth, Claire] Great Ormond St Hosp Sick Children, Dept Paediat Immunol, London, North Ireland. [Cancrini, Caterina] Childrens Hosp Bambino Gesu, Dept Pediat, Rome, Italy. [Cancrini, Caterina] Univ Roma Tor Vergata, Sch Med, Rome, Italy. [Chou, Janet; Geha, Raif S.] Harvard Univ, Sch Med, Dept Pediat, Immunol Div,Boston Childrens Hosp, Boston, MA 02115 USA. [Cowan, Morton] Univ Calif San Francisco, San Francisco, CA 94143 USA. [de la Morena, M. Teresa] UT Southwestern Med Ctr, Childrens Med Ctr Dallas, Dept Pediat, Dallas, TX USA. [Gennery, Andrew] Newcastle Upon Tyne Hosp, Dept Pediat Immunol, Newcastle Upon Tyne, Tyne & Wear, England. [Gennery, Andrew] Newcastle Upon Tyne Hosp, Inst Cellular Med, Newcastle Upon Tyne, Tyne & Wear, England. [Gennery, Andrew] Newcastle Upon Tyne Hosp, Dept Pediat Immunol, Newcastle Upon Tyne, North Ireland. [Gennery, Andrew] Newcastle Upon Tyne Hosp, Inst Cellular Med, Newcastle Upon Tyne, North Ireland. [Giliani, Silvia] Univ Brescia, Dept Pathol, Dept Mol & Traslat Med, A Nocivelli Inst Mol Med, I-25121 Brescia, Italy. [Holland, Steve M.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Kanariou, Maria] Aghia Sophia Childrens Hosp, Dept Immunol Histocompatibil, Specialized Ctr, Athens, Greece. [Kanariou, Maria] Aghia Sophia Childrens Hosp, Referral Ctr Primary Immunodeficiencies Pediat Im, Athens, Greece. [King, Alejandra] Hosp Ninos Luis Calvo Mackenna, Div Pediat Immunol, Santiago, Chile. [Kuijpers, Taco] Univ Amsterdam, Acad Med Ctr, Emma Childrens Hosp, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. [Lougaris, Vassilios; Plebani, Alessandro] Univ Brescia, Spedali Civili, Pediat Clin, Brescia, Italy. [Lougaris, Vassilios; Plebani, Alessandro] Univ Brescia, Spedali Civili, Dept Clin & Expt Sci, Inst Mol Med A Nocivelli, Brescia, Italy. [Meyts, Isabelle] Univ Hosp Leuven, Childhood Immunol, Leuven, Belgium. [Moratto, Daniele] Univ Brescia, A Nocivelli Inst Mol Med, Dept Pathol, Brescia, Italy. [Walter, Jolan E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Immunol & Inflammatory Dis, Boston, MA USA. [Parolini, Silvia] Univ Brescia, Dipartimento Med Mol & Traslaz, Brescia, Italy. [Notarangelo, Luigi D.] Harvard Univ, Sch Med, Boston Childrens Hosp, Div Immunol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 EI 1573-2592 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD APR PY 2016 VL 36 IS 3 MA 4514 BP 283 EP 284 PG 2 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300127 ER PT J AU Foldvari, Z Ujhazi, B Abolhassani, H Abraham, R Adeli, M Aghamohammadi, A Al-Herz, W Assaf-Casals, A Bertaina, A Bleesing, JJ Booth, C Buchbinder, D Cancrini, C Chen, K Chou, J Costa-Carvalho, BT Dbaibo, G DeRavin, SS Dilley, MA Dutmer, CM Eibl, MM Ferguson, PJ Geier, CB Geha, RS Gelfand, EW Hanna-Wakim, R Holland, SM Joshi, AY Kanariou, M Locatelli, F Lykopoulou, E Massaad, MJ Nicholas, SK Palma, P Patiroglu, T Puck, JM Reiff, A Schuetz, C Sleasman, J Unal, E Wolff, H Notarangelo, LD Walter, JE AF Foldvari, Zsofia Ujhazi, Boglarka Abolhassani, Hassan Abraham, Roshini Adeli, Mehdi Aghamohammadi, Asghar Al-Herz, Waleed Assaf-Casals, Aia Bertaina, Alice Bleesing, Jack J. Booth, Claire Buchbinder, David Cancrini, Caterina Chen, Karin Chou, Janet Costa-Carvalho, Beatriz Tavares Dbaibo, Ghassan DeRavin, Suk See Dilley, Meredith A. Dutmer, Cullen M. Eibl, Martha M. Ferguson, Polly J. Geier, Christoph B. Geha, Raif S. Gelfand, Erwin W. Hanna-Wakim, Rima Holland, Steven M. Joshi, Avni Y. Kanariou, Maria Locatelli, Franco Lykopoulou, E. Massaad, Michel J. Nicholas, Sarah Kogan Palma, Paolo Patiroglu, Turkan Puck, Jennifer M. Reiff, Andreas Schuetz, Catharina Sleasman, John Unal, Ekrem Wolff, Hermann Notarangelo, Luigi D. Walter, Jolan E. TI CLINICAL SPECTRUM AND OUTCOME OF TREATMENT FOR AUTOIMMUNE CYTOPENIAS IN RAG DEFICIENCY SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [Foldvari, Zsofia] Univ Debrecen, Fac Med, Dept Immunol, Debrecen, Hungary. [Foldvari, Zsofia] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pediat Allergy & Immunol, Boston, MA USA. [Foldvari, Zsofia; Ujhazi, Boglarka; Walter, Jolan E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Immunol & Inflammatory Dis, Boston, MA USA. [Ujhazi, Boglarka; Walter, Jolan E.] Massachusetts Gen Hosp Children, Div Pediat Allergy Immunol, Boston, MA USA. [Abolhassani, Hassan; Aghamohammadi, Asghar] Univ Tehran Med Sci, Childrens Med Ctr, Pediat Ctr Excellence, Res Ctr Immunodeficiencies, Tehran, Iran. [Abraham, Roshini] Mayo Clin, Lab Med & Pathol, Rochester, MN USA. [Adeli, Mehdi] Weill Cornell Med Coll Qatar, Pediat, Doha, Qatar. [Adeli, Mehdi] Sidra Med & Res Ctr, Allergy & Immunol, Doha, Qatar. [Adeli, Mehdi] Hamad Med Corp, Doha, Qatar. [Al-Herz, Waleed] Kuwait Univ, Fac Med, Dept Pediat, Safat 13060, Kuwait. [Assaf-Casals, Aia; Dbaibo, Ghassan; Hanna-Wakim, Rima] Amer Univ Beirut, Ctr Infect Dis Res, Dept Pediat & Adolescent Med, Beirut, Lebanon. [Bertaina, Alice] Bambino Gesu Pediat Hosp, Dept Oncohematol, Stem Cell Transplant Unit, Rome, Italy. [Bleesing, Jack J.] Cincinnati Childrens Hosp Med Ctr, Div Bone Marrow Transplantat & Immune Deficiency, Cincinnati, OH 45229 USA. [Bleesing, Jack J.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Booth, Claire] Great Ormond St Hosp Sick Children, Dept Paediat Immunol, London, England. [Booth, Claire] Great Ormond St Hosp Sick Children, Dept Paediat Immunol, London, North Ireland. [Buchbinder, David] UC Irvine, CHOC Childrens Hosp, Pediat Hematol, Orange, CA USA. [Cancrini, Caterina; Palma, Paolo] Childrens Hosp Bambino Gesu, Dept Pediat, Rome, Italy. [Cancrini, Caterina; Palma, Paolo] Univ Roma Tor Vergata, Sch Med, Rome, Italy. [Chen, Karin] Univ Utah, Dept Pediat, Div Allergy Immunol & Rheumatol, Salt Lake City, UT USA. [Chou, Janet; Geha, Raif S.; Massaad, Michel J.] Harvard Univ, Sch Med, Dept Pediat, Immunol Div,Boston Childrens Hosp, Boston, MA 02115 USA. [Costa-Carvalho, Beatriz Tavares] Univ Fed Sao Paulo, Dept Allergy Clin Immunol & Rheumatol, Sao Paulo, Brazil. [DeRavin, Suk See] NIAID, Host Def Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Dilley, Meredith A.] Boston Childrens Hosp, Dept Immunol, Boston, MA USA. [Dilley, Meredith A.] Harvard Univ, Sch Med, Boston, MA USA. [Dutmer, Cullen M.] Univ Colorado, Sch Med, Childrens Hosp Colorado, Div Allergy & Immunol, Boulder, CO 80309 USA. [Eibl, Martha M.; Geier, Christoph B.; Wolff, Hermann] Immunol Outpatient Clin, Vienna, Austria. [Ferguson, Polly J.] Univ Iowa, Dept Pediat, Carver Coll Med, Iowa City, IA 52242 USA. [Gelfand, Erwin W.] Natl Jewish Hlth, Dept Pediat, Div Pediat Allergy & Clin Immunol, Denver, CO USA. [Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Joshi, Avni Y.] Mayo Clin, Div Pediat Allergy Immunol, Rochester, MN USA. [Kanariou, Maria] Aghia Sophia Childrens Hosp, Specialized Ctr, Dept Immunol Histocompatibil, Athens, Greece. [Kanariou, Maria] Aghia Sophia Childrens Hosp, Referral Ctr Primary Immunodeficiencies Pediat Im, Athens, Greece. [Locatelli, Franco] Osped Pediat Bambino Gesu, Dept Pediat Hematol & Oncol, Rome, Italy. [Lykopoulou, E.] IRCCS Bambino Gesu Childrens Hosp, Dept Pediat Hematol & Oncol, Rome, Italy. [Nicholas, Sarah Kogan] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Nicholas, Sarah Kogan] Texas Childrens Hosp, Sect Allergy & Immunol, Houston, TX 77030 USA. [Patiroglu, Turkan; Unal, Ekrem] Erciyes Univ, Sch Med, Dept Pediat Hematol & Oncol, Kayseri, Turkey. [Patiroglu, Turkan] Erciyes Univ, Sch Med, Dept Pediat Immunol, Kayseri, Turkey. [Puck, Jennifer M.] Univ Calif San Fransisco, Pediat Immunol & Bone Marrow Transplantat, San Francisco, CA USA. [Reiff, Andreas] Childrens Hosp Los Angeles, USC Keck Sch Med, Los Angeles, CA 90027 USA. [Schuetz, Catharina] Univ Hosp Ulm, Dept Pediat & Adolescent Med, Ulm, Germany. [Sleasman, John] Duke Univ, Sch Med, Div Allergy & Immunol, Durham, NC USA. [Notarangelo, Luigi D.; Walter, Jolan E.] Harvard Univ, Sch Med, Boston Childrens Hosp, Div Immunol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 2 U2 3 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 EI 1573-2592 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD APR PY 2016 VL 36 IS 3 MA 4585 BP 301 EP 303 PG 3 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300167 ER PT J AU Williams, KA Shorser-Gentile, L Sarvode, S Pasternack, MS Geller, DA Walter, J AF Williams, Kyle A. Shorser-Gentile, Leah Sarvode, Suraj Pasternack, Mark S. Geller, Daniel A. Walter, Jolan TI IgA DEFICIENCY IS ASSOCIATED WITH PEDIATRIC OBSESSIVE COMPULSIVE DISORDER SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [Williams, Kyle A.; Geller, Daniel A.] Massachusetts Gen Hosp, Psychiat Child Psychiat, Boston, MA 02114 USA. [Shorser-Gentile, Leah; Sarvode, Suraj] Massachusetts Gen Hosp, Psychiat, Boston, MA 02114 USA. [Pasternack, Mark S.] Massachusetts Gen Hosp, Pediat Infect Dis, Boston, MA 02114 USA. [Walter, Jolan] Massachusetts Gen Hosp, Dept Pediat, Div Allergy & Immunol, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 EI 1573-2592 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD APR PY 2016 VL 36 IS 3 MA 4584 BP 301 EP 301 PG 1 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300166 ER PT J AU Ujhazi, B Csomos, K Sturgeon, C Beca, F Silver, JN Gilbert, JA Sangwan, N Wesemann, D Fasano, A Notarangelo, LD Walter, JE AF Ujhazi, Boglarka Csomos, Krisztian Sturgeon, Craig Beca, Francisco Silver, Jared Nathan Gilbert, Jack A. Sangwan, Naseer Wesemann, Duane Fasano, Alessio Notarangelo, Luigi D. Walter, Jolan E. TI FEATURES AND MECHANISMS OF MUCOSAL IMMUNE DYSREGULATION IN A MOUSE MODEL OF LEAKY SCID DUE TO HYPOMORPHIC RAG MUTATIONS SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [Ujhazi, Boglarka; Csomos, Krisztian; Walter, Jolan E.] Massachusetts Gen Hosp Children, Div Pediat Allergy Immunol, Boston, MA USA. [Ujhazi, Boglarka; Csomos, Krisztian; Walter, Jolan E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Immunol & Inflammatory Dis, Boston, MA USA. [Sturgeon, Craig; Fasano, Alessio] Massachusetts Gen Hosp, Ctr Celiac Res, Mucosal Immunol & Biol Res Ctr, Boston, MA 02114 USA. [Sturgeon, Craig; Fasano, Alessio] Massachusetts Gen Hosp Children, Div Pediat Gastroenterol & Nutr, Boston, MA USA. [Beca, Francisco] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. [Silver, Jared Nathan; Wesemann, Duane] Brigham & Womens Hosp, Dept Med, Div Rheumatol Immunol & Allergy, 75 Francis St, Boston, MA 02115 USA. [Silver, Jared Nathan; Wesemann, Duane] Harvard Univ, Sch Med, Boston, MA USA. [Gilbert, Jack A.; Sangwan, Naseer] Univ Chicago, Dept Surg, Argonne Natl Lab, Biosci Div, 5841 S Maryland Ave, Chicago, IL 60637 USA. [Notarangelo, Luigi D.; Walter, Jolan E.] Harvard Univ, Sch Med, Div Immunol, Boston Childrens Hosp, Boston, MA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 EI 1573-2592 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD APR PY 2016 VL 36 IS 3 MA 4597 BP 306 EP 306 PG 1 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300176 ER PT J AU Csomos, K Ujhazi, B Yu, SH Causton, B Medoff, B Umetsu, DT Notarangelo, LD Walter, JE AF Csomos, Krisztian Ujhazi, Boglarka Yu, Sanhong Causton, Benjamin Medoff, Benjamin Umetsu, Dale T. Notarangelo, Luigi D. Walter, Jolan E. TI EMERGING ROLE OF TYPE-2 INNATE LYMPHOCYTES (ILC2) IN TH2 SKEWING OF LEAKY SCID/OMENN SYNDROME SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [Csomos, Krisztian; Ujhazi, Boglarka; Walter, Jolan E.] Massachusetts Gen Hosp Children, Div Pediat Allergy Immunol, Boston, MA USA. [Csomos, Krisztian; Ujhazi, Boglarka; Causton, Benjamin; Medoff, Benjamin; Walter, Jolan E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Immunol & Inflammatory Dis, Boston, MA USA. [Yu, Sanhong] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Yu, Sanhong] Harvard Univ, Sch Med, Boston, MA USA. Harvard Univ, Sch Med, Boston Childrens Hosp, Div Immunol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 EI 1573-2592 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD APR PY 2016 VL 36 IS 3 MA 4630 BP 315 EP 316 PG 2 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300197 ER PT J AU Farmer, J Barmettler, S Oza, A Schickel, JN Sng, J Subtelny, A Kharal, GA Srikanth, M Channick, R Rodriguez-Lopez, J Nazarian, RM Meffre, E Stone, JH Al-Herz, W Walter, J AF Farmer, Jocelyn Barmettler, Sara Oza, Amar Schickel, Jean-Nicolas Sng, Joel Subtelny, Alex Kharal, Ghulam Abbas Srikanth, Maya Channick, Richard Rodriguez-Lopez, Josanna Nazarian, Rosalynn M. Meffre, Eric Stone, John H. Al-Herz, Waleed Walter, Jolan TI UNDERSTANDING AUTOIMMUNE PATHOLOGY IN ACTIVATION-INDUCED CYTIDINE DEAMINASE (AID) DEFICIENCY, A CASE REPORT OF SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) WITH EVIDENCE OF PATHOGENIC AUTOREACTIVE IgM. SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [Farmer, Jocelyn; Barmettler, Sara] Massachusetts Gen Hosp, Dept Allergy & Immunol, Boston, MA 02114 USA. [Oza, Amar; Stone, John H.] Massachusetts Gen Hosp, Dept Rheumatol, Boston, MA 02114 USA. [Schickel, Jean-Nicolas; Sng, Joel; Meffre, Eric] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT USA. [Subtelny, Alex] Harvard Univ, Sch Med, Boston, MA USA. [Kharal, Ghulam Abbas; Srikanth, Maya] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Rodriguez-Lopez, Josanna] Massachusetts Gen Hosp, Dept Pulm & Crit Care Med, Boston, MA 02114 USA. [Nazarian, Rosalynn M.] Massachusetts Gen Hosp, Dermatopathol Unit, Pathol Serv, Boston, MA 02114 USA. [Al-Herz, Waleed] Kuwait Univ, Fac Med, Dept Pediat, Kuwait, Kuwait. [Walter, Jolan] Massachusetts Gen Hosp, Dept Pediat, Div Allergy & Immunol, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 EI 1573-2592 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD APR PY 2016 VL 36 IS 3 MA 4633 BP 317 EP 317 PG 1 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300200 ER PT J AU Otani, IM Barmettler, S Ballas, ZK Bonilla, F Ochs, H Walter, JE AF Otani, Iris M. Barmettler, Sara Ballas, Zuhair K. Bonilla, Francisco Ochs, Hans Walter, Jolan E. TI INFLAMMATORY BOWEL DISEASE IN X-LINKED AGAMMAGLOBULINEMIA SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [Otani, Iris M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Barmettler, Sara] Massachusetts Gen Hosp, Dept Allergy & Immunol, Boston, MA 02114 USA. [Ballas, Zuhair K.] Univ Iowa Hosp & Clin, Allergy & Immunol, Iowa City, IA 52242 USA. [Bonilla, Francisco] Childrens Hosp Boston, Boston, MA USA. [Ochs, Hans] Seattle Childrens Res Inst, Ctr Immun & Immunotherapies, Seattle, WA USA. [Walter, Jolan E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Immunol & Inflammatory Dis, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 EI 1573-2592 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD APR PY 2016 VL 36 IS 3 MA 4638 BP 318 EP 318 PG 1 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300202 ER PT J AU Csomos, K Ujhazi, B Kis-Toth, K Szanto, A Volpi, S Alt, F Recher, M Notarangelo, LD Walter, JE AF Csomos, Krisztian Ujhazi, Boglarka Kis-Toth, Katalin Szanto, Attila Volpi, Stefano Alt, Frederick Recher, Mike Notarangelo, Luigi D. Walter, Jolan E. TI FATAL HYPERINFLAMMATION IN MURINE MODEL OF LEAKY SCID/OMENN SYNDROME: INNATE OVERACTIVATION LOCALIZED IN SMALL AND LARGE INTESTINES SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [Csomos, Krisztian; Ujhazi, Boglarka; Walter, Jolan E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Immunol & Inflammatory Dis, Boston, MA USA. [Csomos, Krisztian; Ujhazi, Boglarka; Walter, Jolan E.] Massachusetts Gen Hosp Children, Div Pediat Allergy Immunol, Boston, MA USA. [Kis-Toth, Katalin] Beth Israel Deaconess Med Ctr, Div Rheumatol, Boston, MA 02215 USA. [Szanto, Attila] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Volpi, Stefano; Notarangelo, Luigi D.; Walter, Jolan E.] Harvard Univ, Sch Med, Boston Childrens Hosp, Div Immunol, Boston, MA USA. [Alt, Frederick] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA USA. [Recher, Mike] Univ Basel Hosp, Med Outpatient Unit, Clin Primary Immunodeficiency, CH-4031 Basel, Switzerland. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 EI 1573-2592 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD APR PY 2016 VL 36 IS 3 MA 4642 BP 319 EP 320 PG 2 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300206 ER PT J AU Yee, C Lo, M Tsitsikov, E Avagyan, S Cantor, A Lane, A AF Yee, Christina Lo, Mindy Tsitsikov, Erdyni Avagyan, Serine Cantor, Alan Lane, Andrew TI CHILDHOOD ONSET LYMPHOCYTIC VARIANT HYPEREOSINOPHILIC SYNDROME WITH TENOSYNOVITIS, ABNORMALT CELL PROLIFERATION, AND CLONAL CD3-CD4+T CELLS SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Meeting Abstract CT CIS Annual Meeting on Immune Deficiency and Dysregulation North American Conference CY APR 14-17, 2016 CL Boston, MA SP Clin Immunol Soc C1 [Yee, Christina; Lo, Mindy; Tsitsikov, Erdyni; Avagyan, Serine; Cantor, Alan] Boston Childrens Hosp, Boston, MA USA. [Avagyan, Serine; Cantor, Alan; Lane, Andrew] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 EI 1573-2592 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD APR PY 2016 VL 36 IS 3 MA 4641 BP 319 EP 319 PG 1 WC Immunology SC Immunology GA DG6AT UT WOS:000372165300205 ER PT J AU Noiret, L Rose, CF AF Noiret, Lorette Rose, Christopher F. TI Mathematical models and hepatology; oil and vinegar? SO JOURNAL OF HEPATOLOGY LA English DT Editorial Material C1 [Noiret, Lorette] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol,Syst Biol, Boston, MA USA. [Rose, Christopher F.] Univ Montreal, CRCHUM, Hepatoneuro Lab, Montreal, PQ, Canada. RP Rose, CF (reprint author), Univ Montreal, CRCHUM, Hepatoneuro Lab, Montreal, PQ, Canada. EM christopher.rose@umontreal.ca RI Rose, Christopher/F-1105-2010 OI Rose, Christopher/0000-0001-9854-6834 NR 8 TC 0 Z9 0 U1 0 U2 6 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 APR PY 2016 VL 64 IS 4 BP 768 EP 769 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DH3IY UT WOS:000372681900004 PM 26812072 ER PT J AU Derbinski, J Schulte, A Kyewski, B Klein, L AF Derbinski, Jens Schulte, Antje Kyewski, Bruno Klein, Ludger TI Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MYELIN BASIC-PROTEIN; AMYLOID P-COMPONENT; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; ANTIGEN-PRESENTING CELLS; REGULATORY T-CELLS; STROMAL CELLS; LYMPHOID ORGANS; DENDRITIC CELLS; MESSENGER-RNA; IN-VIVO AB Expression of peripheral antigens in the thymus has been implicated in T cell tolerance and autoimmunity. Here we identified medullary thymic epithelial cells as being a unique cell type that expresses a diverse range of tissue-specific antigens. We found that this promiscuous gene expression was a cell-autonomous property of medullary epithelial cells and was maintained during the entire period of thymic T cell output. It may facilitate tolerance induction to self-antigens that would otherwise be temporally or spatially secluded from the immune system. However, the array of promiscuously expressed self-antigens appeared random rather than selected and was not confined to secluded self-antigens. C1 [Derbinski, Jens; Schulte, Antje; Kyewski, Bruno] German Canc Res Ctr, Div Cellular Immunol, Tumor Immunol Program, INF 280, D-69120 Heidelberg, Germany. [Klein, Ludger] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, 1 Jimmy Fund Way, Boston, MA 02115 USA. RP Kyewski, B (reprint author), German Canc Res Ctr, Div Cellular Immunol, Tumor Immunol Program, INF 280, D-69120 Heidelberg, Germany. EM b.kyewski@dkfz.de FU Deutsche Forschungsgemeinschaft [Ky7/6-1, SFB 405, LK1228/1-1]; German Cancer Research Center FX We thank J. Gotter, J. Trotter, and W. van Ewijk for helpful suggestions; M. B. Pepys (Royal Free and University College Medical School, London) for providing purified mouse SAP and SAP-deficient mice; B. Arnold, T. Boehm, R. Ganss, J. Trotter, T. Schlake and B. van den Eynde for reagents and mice; and S. Hoeflinger, S. Fuchs and K. Hexel for assistance. Supported by the Deutsche Forschungsgemeinschaft (grants Ky7/6-1 and the SFB 405 to B. K. and LK1228/1-1 to L. K.) and the German Cancer Research Center. NR 63 TC 1 Z9 1 U1 4 U2 6 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 APR 1 PY 2016 VL 196 IS 7 BP 2915 EP 2922 PG 8 WC Immunology SC Immunology GA DG8MU UT WOS:000372339100002 PM 26994303 ER PT J AU Riou, C Strickland, N Soares, AP Corleis, B Kwon, DS Wherry, EJ Wilkinson, RJ Burgers, WA AF Riou, Catherine Strickland, Natalie Soares, Andreia P. Corleis, Bjorn Kwon, Douglas S. Wherry, E. John Wilkinson, Robert J. Burgers, Wendy A. TI HIV Skews the Lineage-Defining Transcriptional Profile of Mycobacterium tuberculosis-Specific CD4(+) T Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID PATHOGENIC T(H)17 CELLS; TH17 CELLS; INFECTION; DIFFERENTIATION; HELPER; COMMITMENT; PLASTICITY; EFFECTOR; MEMORY; GAMMA AB HIV-infected persons are at greater risk of developing tuberculosis (TB) even before profound CD4 loss occurs, suggesting that HIV alters CD4(+) T cell functions capable of containing bacterial replication. An effective immune response to Mycobacterium tuberculosis most likely relies on the development of a balanced CD4 response, in which distinct CD4(+) Th subsets act in synergy to control the infection. To define the diversity of M. tuberculosis-specific CD4(+) Th subsets and determine whether HIV infection impacts such responses, the expression of lineage-defining transcription factors T-bet, Gata3, ROR gamma t, and Foxp3 was measured in M. tuberculosis-specific CD4(+) T cells in HIV-uninfected (n = 20) and HIV-infected individuals (n = 20) with latent TB infection. Our results show that, upon 5-d restimulation in vitro, M. tuberculosis-specific CD4(+) T cells from healthy individuals have the ability to exhibit a broad spectrum of Th subsets, defined by specific patterns of transcription factor coexpression. These transcription factor profiles were skewed in HIV-infected individuals where the proportion of T-bet(high) Foxp3(+) M. tuberculosis-specific CD4(+) T cells was significantly decreased (p = 0.002) compared with HIV-uninfected individuals, a change that correlated inversely with HIV viral load (p = 0.0007) and plasma TNF-alpha (p = 0.027). Our data demonstrate an important balance in Th subset diversity defined by lineage-defining transcription factor coexpression profiles that is disrupted by HIV infection and suggest a role for HIV in impairing TB immunity by altering the equilibrium of M. tuberculosis-specific CD4(+) Th subsets. C1 [Riou, Catherine; Strickland, Natalie; Soares, Andreia P.; Burgers, Wendy A.] Univ Cape Town, Fac Hlth Sci, Dept Pathol, Div Med Virol, ZA-7925 Cape Town, South Africa. [Riou, Catherine; Strickland, Natalie; Soares, Andreia P.; Wilkinson, Robert J.; Burgers, Wendy A.] Univ Cape Town, Inst Infect Dis & Mol Med, ZA-7925 Cape Town, South Africa. [Corleis, Bjorn; Kwon, Douglas S.] Ragon Inst MGH MIT & Harvard, Cambridge, MA 02139 USA. [Corleis, Bjorn; Kwon, Douglas S.] Massachusetts Gen Hosp, Div Infect Dis, Cambridge, MA 02139 USA. [Wherry, E. John] Univ Penn, Perelman Sch Med, Dept Microbiol, Inst Immunol, Philadelphia, PA 19104 USA. [Wilkinson, Robert J.] Univ London Imperial Coll Sci Technol & Med, Dept Med, London W21 PG, England. [Wilkinson, Robert J.] Francis Crick Inst Mill Hill Lab, London NW7 1AA, England. [Wilkinson, Robert J.] Univ Cape Town, Clin Infect Dis Res Initiat, ZA-7925 Cape Town, South Africa. RP Riou, C (reprint author), Univ Cape Town, Div Med Virol, Inst Infect Dis & Mol Med, Falmouth Bldg,1 Anzio Rd, ZA-7925 Cape Town, South Africa. EM c.riou@uct.ac.za OI Wilkinson, Robert/0000-0002-2753-1800 FU National Research Foundation of South Africa [92558, 96841]; Poliomyelitis Research Foundation [14/20]; National Institutes of Health, Office of the Director [R21AI115977]; European and Developing Countries Clinical Trials Partnership [TA_08_40200_020]; Wellcome Trust [104803]; Medical Research Council [U1175.02.002.00014.01]; European Union [FP7-Health-F3-2012-305578, FP7-PEOPLE-2011-IRSES] FX This work was supported by the National Research Foundation of South Africa (Grant 92558 to C.R.), the Poliomyelitis Research Foundation (Grant 14/20 to C.R.), the National Institutes of Health, Office of the Director (R21AI115977 to C.R. and E.J.W.), and the European and Developing Countries Clinical Trials Partnership (TA_08_40200_020 to W.A.B.). R.J.W. is supported by the Wellcome Trust (104803), the Medical Research Council (U1175.02.002.00014.01), the European Union (FP7-Health-F3-2012-305578 and FP7-PEOPLE-2011-IRSES), and the National Research Foundation of South Africa (Grant 96841). W.A.B. is a Wellcome Trust Intermediate Fellow in Public Health and Tropical Medicine (089832/Z/09/Z). NR 55 TC 1 Z9 1 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD APR 1 PY 2016 VL 196 IS 7 BP 3006 EP 3018 DI 10.4049/jimmunol.1502094 PG 13 WC Immunology SC Immunology GA DG8MU UT WOS:000372339100012 PM 26927799 ER PT J AU Kleffel, S Lee, N Lezcano, C Wilson, BJ Sobolewski, K Saab, KR Mueller, H Zhan, Q Posch, C Elco, CP DoRosario, A Garcia, SS Thakuria, M Wang, YYE Wang, LDC Murphy, GF Frank, MH Schatton, T AF Kleffel, Sonja Lee, Nayoung Lezcano, Cecilia Wilson, Brian J. Sobolewski, Kristine Saab, Karim R. Mueller, Hansgeorg Zhan, Qian Posch, Christian Elco, Christopher P. DoRosario, Andrew Garcia, Sarah S. Thakuria, Manisha Wang, Yaoyu E. Wang, Linda C. Murphy, George F. Frank, Markus H. Schatton, Tobias TI ABCB5-Targeted Chemoresistance Reversal Inhibits Merkel Cell Carcinoma Growth SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID MELANOMA-INITIATING CELLS; MALIGNANT-MELANOMA; ABCB5; POLYOMAVIRUS; SKIN; IDENTIFICATION; ESTABLISHMENT; TRANSPORTER; XENOGRAFTS; LINE AB Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine skin cancer with profound but poorly understood resistance to chemotherapy, which poses a significant barrier to clinical MCC treatment. Here we show that ATP-binding cassette member B5 (ABCB5) confers resistance to standard-of-care MCC chemotherapeutic agents and provide proof-of-principle that ABCB5 blockade can inhibit human MCC tumor growth through sensitization to drug-induced cell cytotoxicity. ABCB5 expression was detected in both established MCC lines and clinical MCC specimens at levels significantly higher than those in normal skin. Carboplatinand etoposide-resistant MCC cell lines exhibited increased expression of ABCB5, along with enhanced ABCB1 and ABCC3 transcript expression. ABCB5-expressing MCC cells in heterogeneous cancers preferentially survived treatment with carboplatin and etoposide in vitro and in human MCC xenograft-bearing mice in vivo. Moreover, patients with MCC also exhibited enhanced ABCB5 positivity after carboplatin-and etoposide-based chemotherapy, pointing to clinical significance of this chemoresistance mechanism. Importantly, ABCB5 blockade reversed MCC drug resistance and impaired tumor growth in xenotransplantation models in vivo. Our results establish ABCB5 as a chemoresistance mechanism in MCC and suggest utility of this molecular target for improved MCC therapy. C1 [Kleffel, Sonja; Lee, Nayoung; Sobolewski, Kristine; Mueller, Hansgeorg; Posch, Christian; Elco, Christopher P.; Garcia, Sarah S.; Thakuria, Manisha; Wang, Linda C.; Frank, Markus H.; Schatton, Tobias] Harvard Univ, Sch Med, Dept Dermatol, Harvard Skin Dis Res Ctr,Brigham & Womens Hosp, Boston, MA 02115 USA. [Lezcano, Cecilia; Zhan, Qian; Elco, Christopher P.; Murphy, George F.] Harvard Univ, Sch Med, Dept Pathol, Brigham & Womens Hosp, Boston, MA 02115 USA. [Wilson, Brian J.; Saab, Karim R.; Frank, Markus H.; Schatton, Tobias] Harvard Univ, Sch Med, Dept Med, Boston Childrens Hosp, Boston, MA USA. [DoRosario, Andrew; Garcia, Sarah S.; Thakuria, Manisha; Wang, Linda C.] Harvard Univ, Sch Med, Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Wang, Yaoyu E.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Canc Computat Biol, 44 Binney St, Boston, MA 02115 USA. [Frank, Markus H.] Edith Cowan Univ Joondalup, Sch Med Sci, Joondalup, WA, Australia. RP Schatton, T (reprint author), Brigham & Womens Hosp, Harvard Inst Med, Dept Dermatol, Rm 673C,77 Ave Louis Pasteur, Boston, MA 02115 USA.; Frank, MH (reprint author), Boston Childrens Hosp, Enders Res Bldg,Rm 507,300 Longwood Ave, Boston, MA 02115 USA. EM markus.frank@childrens.harvard.edu; tschatton@bwh.harvard.edu FU Brigham and Women's Hospital, Department of Dermatology; Brigham Research Institute; NIH/NCI [1R01CA113796, 1R01CA138231, 1R01CA158467]; Dermatology Foundation; American Skin Association FX The authors thank Dr. James DeCaprio for providing Merkel cell carcinoma cell lines for our study. This work was supported by Brigham and Women's Hospital, Department of Dermatology funding for new investigators and a Fund to Sustain Research Excellence from the Brigham Research Institute (to TS), NIH/NCI grants 1R01CA113796 and 1R01CA138231 (to MHF), and 1R01CA158467 (to MHF and GFM). TS is the recipient of a Research Career Development award from the Dermatology Foundation. NL is the recipient of a Medical Student Grant from the American Skin Association. NR 27 TC 0 Z9 0 U1 2 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD APR PY 2016 VL 136 IS 4 BP 838 EP 846 DI 10.1016/j.jid.2015.12.038 PG 9 WC Dermatology SC Dermatology GA DH0QK UT WOS:000372488500025 PM 26827764 ER PT J AU Einstein, AJ Lloyd, SG Chaudhry, FA AlJaroudi, WA Hage, FG AF Einstein, Andrew J. Lloyd, Steven G. Chaudhry, Farooq A. AlJaroudi, Wael A. Hage, Fadi G. TI Multi-modality Imaging: Bird's eye view from the 2015 American Heart Association Scientific Sessions SO JOURNAL OF NUCLEAR CARDIOLOGY LA English DT Article DE AHA; cardiac computed tomography; CMRI ID CORONARY FLOW RESERVE AB Multiple novel studies were presented at the 2015 American Heart Association Scientific Sessions which was considered a successful conference at many levels. In this review, we will summarize key studies in nuclear cardiology, cardiac magnetic resonance, echocardiography, and cardiac computed tomography that were presented at the Sessions. We hope that this bird's eye view will keep readers updated on the newest imaging studies presented at the meeting whether or not they were able to attend the meeting. C1 [Einstein, Andrew J.] Columbia Univ, New York Presbyterian Hosp, Med Ctr, New York, NY USA. [Lloyd, Steven G.; Hage, Fadi G.] Univ Alabama Birmingham, Lyons Harrison Res Bldg 314,1900 Univ BLVD, Birmingham, AL 35294 USA. [Lloyd, Steven G.; Hage, Fadi G.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [Chaudhry, Farooq A.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [AlJaroudi, Wael A.] Clemenceau Med Ctr, Beirut, Lebanon. RP Hage, FG (reprint author), Univ Alabama Birmingham, Lyons Harrison Res Bldg 314,1900 Univ BLVD, Birmingham, AL 35294 USA. EM fadihage@uab.edu OI Hage, Fadi/0000-0002-1397-4942 FU Astellas Pharma FX Dr Hage reports grant support from Astellas Pharma. 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 1071-3581 EI 1532-6551 J9 J NUCL CARDIOL JI J. Nucl. Cardiol. PD APR PY 2016 VL 23 IS 2 BP 235 EP 243 DI 10.1007/s12350-016-0404-8 PG 9 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA DG7UR UT WOS:000372289700008 PM 26818142 ER PT J AU Harmon, JL Wills, LP McOmish, CE Demireva, EY Gingrich, JA Beeson, CC Schnellmann, RG AF Harmon, Jennifer L. Wills, Lauren P. McOmish, Caitlin E. Demireva, Elena Y. Gingrich, Jay A. Beeson, Craig C. Schnellmann, Rick G. TI 5-HT2 Receptor Regulation of Mitochondrial Genes: Unexpected Pharmacological Effects of Agonists and Antagonists SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID ACUTE KIDNEY INJURY; PROXIMAL TUBULES; OXIDATIVE STRESS; CHOROID-PLEXUS; ANIMAL-MODELS; SB 242084; BIOGENESIS; DYSFUNCTION; PGC-1-ALPHA; CELLS AB In acute organ injuries, mitochondria are often dysfunctional, and recent research has revealed that recovery of mitochondrial and renal functions is accelerated by induction of mitochondrial biogenesis (MB). We previously reported that the nonselective 5-HT2 receptor agonist DOI [1-(4-iodo-2,5-dimethoxyphenyl) propan-2-amine] induced MB in renal proximal tubular cells (RPTCs). The goal of this study was to determine the role of 5-HT2 receptors in the regulation of mitochondrial genes and oxidative metabolism in the kidney. The 5-HT2C receptor agonist CP-809,101 [2-[(3-chlorophenyl)methoxy]-6-(1-piperazinyl)pyrazine] and antagonist SB-242,084 [6-chloro-2,3-dihydro-5-methyl-N-[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]-1H-indole-1-carboxyamide dihydrochloride] were used to examine the induction of renal mitochondrial genes and oxidative metabolism in RPTCs and in mouse kidneys in the presence and absence of the 5-HT2C receptor. Unexpectedly, both CP-809,101 and SB-242,084 increased RPTC respiration and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha) mRNA expression in RPTCs at 1-10 nM. In addition, CP-809,101 and SB-242,084 increased mRNA expression of PGC-1 alpha and the mitochondrial proteins NADH dehydrogenase subunit 1 and NADH dehydrogenase (ubiquinone) beta subcomplex 8 in mice. These compounds increased mitochondrial genes in RPTCs in which the 5-HT2C receptor was downregulated with small interfering RNA and in the renal cortex of mice lacking the 5-HT2C receptor. By contrast, the ability of these compounds to increase PGC-1 alpha mRNA and respiration was blocked in RPTCs treated with 5-HT2A receptor small interfering RNA or the 5-HT2A receptor antagonist eplivanserin. In addition, the 5-HT2A receptor agonist NBOH-2C-CN [4-[2-[[(2-hydroxyphenyl)methyl]amino]ethyl]-2,5-dimethoxybenzonitrile] increased RPTC respiration at 1-100 nM. These results suggest that agonism of the 5-HT2A receptor induces MB and that the classic 5-HT2C receptor agonist CP-809,101 and antagonist SB-242,084 increase mitochondrial genes and oxidative metabolism through the 5-HT2A receptor. To our knowledge, this is the first report that links 5-HT2A receptor agonism to mitochondrial function. C1 [Harmon, Jennifer L.; Wills, Lauren P.; Beeson, Craig C.; Schnellmann, Rick G.] Med Univ S Carolina, Dept Drug Discovery & Biomed Sci, 280 Calhoun St,MSC140, Charleston, SC 29425 USA. [McOmish, Caitlin E.; Demireva, Elena Y.; Gingrich, Jay A.] Columbia Univ, Dept Psychiat, Sackler Inst Dev Psychobiol, New York, NY USA. [McOmish, Caitlin E.] Univ Melbourne, Div Mol Psychiat, Florey Inst Neurosci & Mental Hlth, Melbourne Brain Ctr, Parkville, Vic 3052, Australia. [Demireva, Elena Y.; Gingrich, Jay A.] New York State Psychiat Inst & Hosp, Div Dev Neurosci, New York, NY 10032 USA. [Schnellmann, Rick G.] Ralph H Johnson Vet Adm Med Ctr, Charleston, SC USA. RP Schnellmann, RG (reprint author), Med Univ S Carolina, Dept Drug Discovery & Biomed Sci, 280 Calhoun St,MSC140, Charleston, SC 29425 USA. EM schnell@musc.edu FU National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [F30DK091107, T32DK083262]; National Health and Medical Research Council; Brain and Behavior Research Foundation; National Institutes of Health National Institute of Mental Health [R21MH099458, R01MH080116]; National Institutes of Health National Institute of General Medical Sciences [R01GM084147, P20GM103542-02]; National Institutes of Health National Center for Research Resources [UL1RR029882, C06RR015455]; Biomedical Laboratory Research and Development Program of the U.S. Department of Veterans Affairs [5I01 BX-000851]; South Carolina Clinical and Translational Research Institute at the Medical University of South Carolina FX This research was supported in part by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grants F30DK091107 and T32DK083262 (to J.L.H.)]; the National Health and Medical Research Council [C.J. Martin Overseas Biomedical Fellowship (to C.E.M.)]; the Brain and Behavior Research Foundation [Young Investigator Award (to C.E.M.)]; the National Institutes of Health National Institute of Mental Health [Grants R21MH099458 and R01MH080116 (to J.A.G.)]; the National Institutes of Health National Institute of General Medical Sciences [Grants R01GM084147 (to R.G.S) and P20GM103542-02 (to South Carolina COBRE in Oxidants, Redox Balance, and Stress Signaling)]; the National Institutes of Health National Center for Research Resources [Grant UL1RR029882]; the Biomedical Laboratory Research and Development Program of the U.S. Department of Veterans Affairs [Grant 5I01 BX-000851 (to R.G.S.)]; and the South Carolina Clinical and Translational Research Institute at the Medical University of South Carolina. Animal facilities were funded by the National Institutes of Health National Center for Research Resources [Grant C06RR015455]. NR 44 TC 1 Z9 1 U1 1 U2 3 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 EI 1521-0103 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD APR PY 2016 VL 357 IS 1 BP 1 EP 9 DI 10.1124/jpet.115.228395 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DG5TX UT WOS:000372142800001 PM 26787771 ER PT J AU Kachooei, AR Talaei-Khoei, M Faghfouri, A Ring, D AF Kachooei, Amir Reza Talaei-Khoei, Mojtaba Faghfouri, Aram Ring, David TI Factors associated with operative treatment of enthesopathy of the extensor carpi radialis brevis origin SO JOURNAL OF SHOULDER AND ELBOW SURGERY LA English DT Article DE Extensor carpi radialis brevis; enthesopathy; lateral epicondylitis; tennis elbow; variation; corticosteroid injections ID LOCAL INJECTION TREATMENT; TENNIS ELBOW; LATERAL EPICONDYLITIS; CORTICOSTEROID INJECTION; TRIAL; HYDROCORTISONE; MANAGEMENT; PAIN AB Background: This study investigated the factors associated with variation in the rate of surgery for enthesopathy of the extensor carpi radialis brevis (eECRB). Methods: We used a large database from 3 academic hospitals including 5964 patients with the diagnosis of eECRB from 2001 to 2007. Of those, 244 patients (4%) had surgery for eECRB. We used the date of the first encounter as the date of diagnosis. We also recorded the date of the first cortisone injection and surgery for eECRB. We used Cox multivariable regression analysis to find factors associated with surgery. We considered the following explanatory factors: age, sex, race, diabetes, a diagnosis of major depression, a diagnosis of an anxiety disorder, hospital, provider (surgeon vs. nonsurgeon), corticosteroid injection, and the time from diagnosis to the first cortisone injection. Results: The hazard ratio of having surgery was 12-times greater if the initial provider was an orthopedic surgeon rather a nonsurgeon and 1.7-times greater at 1 of the 2 hospitals. The rate of surgery varied substantially, ranging from 0% to 22%. Corticosteroid injection delayed the time to surgery but was ultimately associated with a higher rate of surgery. The majority (86%) of surgeries were done within 1 year of the first documented office visit. Conclusions: It seems likely that an emphasis on the preferences and values of the patient rather than the surgeon would decrease the variation in surgery rates for eECRB observed in this study. Methods for optimizing the influence of patient preferences and values on decision making (eg, decision aids) merit additional study. (C) 2016 Journal of Shoulder and Elbow Surgery Board of Trustees. C1 [Kachooei, Amir Reza; Talaei-Khoei, Mojtaba; Faghfouri, Aram; Ring, David] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Orthoped Hand & Upper Extrem Dept, Boston, MA 02114 USA. [Kachooei, Amir Reza] Mashhad Univ Med Sci, Orthoped Res Ctr, Mashhad, Iran. [Ring, David] Univ Texas Austin, Comprehens Care Dell Med Sch, Austin, TX 78712 USA. RP Ring, D (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Yawkey Ctr, 55 Fruit St,Ste 2100, Boston, MA 02114 USA. EM david.ring@austin.utexas.edu OI Kachooei, Amir Reza/0000-0001-7795-1830; Ring, David/0000-0002-6506-4879 NR 22 TC 1 Z9 1 U1 1 U2 2 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 APR PY 2016 VL 25 IS 4 BP 666 EP 670 DI 10.1016/j.jse.2015.12.019 PG 5 WC Orthopedics; Sport Sciences; Surgery SC Orthopedics; Sport Sciences; Surgery GA DG9VK UT WOS:000372431700025 PM 26995457 ER PT J AU Svensson, LG Gillinov, AM Weisel, RD Keshavjee, S Bacha, EA Moon, MR Cameron, DE Sugarbaker, DJ Adams, DH Gaynor, JW Coselli, JS Del Nido, PJ Jones, D Sundt, TM Cohn, LH Pomar, JL Lytle, BW Schaff, HV AF Svensson, Lars G. Gillinov, A. Marc Weisel, Richard D. Keshavjee, Shaf Bacha, Emile A. Moon, Marc R. Cameron, Duke E. Sugarbaker, David J. Adams, David H. Gaynor, J. William Coselli, Joseph S. Del Nido, Pedro J. Jones, David Sundt, Thoralf M. Cohn, Lawrence H. Pomar, Jose L. Lytle, Bruce W. Schaff, Hartzell V. TI The American Association for Thoracic Surgery Consensus Guidelines: Reasons and purpose SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Editorial Material DE guidelines ID CLINICAL-PRACTICE GUIDELINES; SYSTEMATIC REVIEWS; PRISMA STATEMENT; TASK-FORCE; METAANALYSES; ELABORATION; EXPLANATION; EVOLUTION; COLLEGE AB The time interval for the doubling of medical knowledge continues to decline. Physicians, patients, administrators, government officials, and payors are struggling to keep up to date with the waves of new information and to integrate the knowledge into new patient treatment protocols, processes, and metrics. Guidelines, Consensus Guidelines, and Consensus Statements, moderated by seasoned content experts, offer one method to rapidly distribute new information in a timely manner and also guide minimal standards of treatment of clinical care pathways as they are developed as part of bundled care programs. These proposed Consensus Guidelines advance The American Association for Thoracic Surgery's mission of leading in cardiothoracic health care, education, innovation, and modeling excellence. C1 [Svensson, Lars G.; Gillinov, A. Marc] Cleveland Clin, Dept Thorac & Cardiovasc Surg, Cleveland, OH 44915 USA. [Weisel, Richard D.] Toronto Gen Hosp, Div Cardiac Surg, Toronto, ON, Canada. [Keshavjee, Shaf] Toronto Gen Hosp, Div Thorac Surg, Toronto, ON, Canada. [Bacha, Emile A.] Columbia Univ, Morgan Stanley Childrens Hosp New York, Div Cardiac Thorac & Vasc Surg, New York, NY 10027 USA. [Moon, Marc R.] Washington Univ, Sch Med, Div Cardiothorac Surg, St Louis, MO 63110 USA. [Cameron, Duke E.] Johns Hopkins Univ Hosp, Div Cardiac Surg, Baltimore, MD 21287 USA. [Sugarbaker, David J.] Baylor Coll Med, Div Gen Thorac Surg, Houston, TX 77030 USA. [Adams, David H.] Icahn Sch Med Mt Sinai, Dept Cardiovasc Surg, New York, NY 10029 USA. [Gaynor, J. William] Childrens Hosp Philadelphia, Div Cardiothorac Surg, Philadelphia, PA 19104 USA. [Coselli, Joseph S.] Baylor Coll Med, Texas Heart Inst, Div Cardiothorac Surg, Houston, TX 77030 USA. [Del Nido, Pedro J.] Childrens Hosp Boston, Dept Cardiac Surg, Boston, MA USA. [Jones, David] Mem Sloan Kettering Canc Ctr, Dept Surg, 1275 York Ave, New York, NY 10021 USA. [Sundt, Thoralf M.] Massachusetts Gen Hosp, Div Cardiac Surg, Boston, MA 02114 USA. [Cohn, Lawrence H.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiac Surg, Boston, MA 02115 USA. [Pomar, Jose L.] Hosp Cinco Barcelona, Dept Cardiovasc Surg, Barcelona, Spain. [Lytle, Bruce W.] Heart Hosp Baylor Plano, Dept Cardiac & Thorac Surg, Plano, TX USA. [Schaff, Hartzell V.] Mayo Clin, Div Cardiac Surg, Rochester, MN USA. RP Svensson, LG (reprint author), Cleveland Clin, Inst Heart & Vasc, 9500 Euclid Ave Desk J4-1, Cleveland, OH 44915 USA. EM svenssl@ccf.org NR 20 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 0022-5223 EI 1097-685X J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD APR PY 2016 VL 151 IS 4 BP 935 EP 939 DI 10.1016/j.jtcvs.2015.09.138 PG 5 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA DG9XK UT WOS:000372436900023 PM 26892077 ER PT J AU Kron, IL Acker, MA Adams, DH Ailawadi, G Bolling, SF Hung, JW Lim, DS LaPar, DJ Mack, MJ O'Gara, PT Parides, MK Puskas, JD AF Kron, Irving L. Acker, Michael A. Adams, David H. Ailawadi, Gorav Bolling, Steven F. Hung, Judy W. Lim, D. Scott LaPar, Damien J. Mack, Michael J. O'Gara, Patrick T. Parides, Michael K. Puskas, John D. TI 2015 The American Association for Thoracic Surgery Consensus Guidelines: Ischemic mitral valve regurgitation SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Editorial Material ID TIME 3-DIMENSIONAL ECHOCARDIOGRAPHY; VENTRICULAR SYSTOLIC DYSFUNCTION; VALVULAR HEART-DISEASE; VENA CONTRACTA AREA; FLOW CONVERGENCE REGION; DILATED CARDIOMYOPATHY; CARDIAC RESYNCHRONIZATION; RESTRICTIVE ANNULOPLASTY; DOPPLER-ECHOCARDIOGRAPHY; QUANTITATIVE ASSESSMENT C1 [Kron, Irving L.; Ailawadi, Gorav; Lim, D. Scott; LaPar, Damien J.] Univ Virginia, Charlottesville, VA 22908 USA. [Acker, Michael A.] Univ Penn, Philadelphia, PA 19104 USA. [Adams, David H.; Parides, Michael K.; Puskas, John D.] Mt Sinai Med Ctr, New York, NY 10029 USA. [Bolling, Steven F.] Univ Michigan, Ann Arbor, MI 48109 USA. [Hung, Judy W.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Mack, Michael J.] Baylor Hlth Syst, Plano, TX USA. [O'Gara, Patrick T.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. RP Kron, IL (reprint author), Univ Virginia, Sch Med, Dept Surg, Div Thorac & Cardiovasc Surg, POB 800679, Charlottesville, VA 22908 USA. EM ilk@virginia.edu NR 87 TC 5 Z9 6 U1 3 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5223 EI 1097-685X J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD APR PY 2016 VL 151 IS 4 BP 940 EP 956 DI 10.1016/j.jtcvs.2015.08.127 PG 17 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA DG9XK UT WOS:000372436900024 ER PT J AU Konheim, JA Kon, ZN Pasrija, C Luo, QY Sanchez, PG Garcia, JP Griffith, BP Jeudy, J AF Konheim, Jeremy A. Kon, Zachary N. Pasrija, Chetan Luo, Qingyang Sanchez, Pablo G. Garcia, Jose P. Griffith, Bartley P. Jeudy, Jean TI Predictive equations for lung volumes from computed tomography for size matching in pulmonary transplantation SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Article DE computed tomography; lung; organ donor management; regression analysis; lung transplantation ID HEALTHY NONSMOKING ADULTS; FUNCTION TESTS; CT; CAPACITY; VALUES; DONOR; REGRESSION; SELECTION; CHILDREN; SINGLE AB Objective: Size matching for lung transplantation is widely accomplished using height comparisons between donors and recipients. This gross approximation allows for wide variation in lung size and, potentially, size mismatch. Three-dimensional computed tomography (3D-CT) volumetry comparisons could offer more accurate size matching. Although recipient CT scans are universally available, donor CT scans are rarely performed. Therefore, predicted donor lung volumes could be used for comparison to measured recipient lung volumes, but no such predictive equations exist. We aimed to use 3D-CT volumetry measurements from a normal patient population to generate equations for predicted total lung volume (pTLV), predicted right lung volume (pRLV), and predicted left lung volume (pLLV), for size-matching purposes. Methods: Chest CT scans of 400 normal patients were retrospectively evaluated. 3D-CT volumetry was performed to measure total lung volume, right lung volume, and left lung volume of each patient, and predictive equations were generated. The fitted model was tested in a separate group of 100 patients. The model was externally validated by comparison of total lung volume with total lung capacity from pulmonary function tests in a subset of those patients. Results: Age, gender, height, and race were independent predictors of lung volume. In the test group, there were strong linear correlations between predicted and actual lung volumes measured by 3D-CT volumetry for pTLV (r = 0.72), pRLV (r = 0.72), and pLLV (r = 0.69). A strong linear correlation was also observed when comparing pTLV and total lung capacity (r = 0.82). Conclusions: We successfully created a predictive model for pTLV, pRLV, and pLLV. These may serve as reference standards and predict donor lung volume for size matching in lung transplantation. C1 [Konheim, Jeremy A.; Kon, Zachary N.; Pasrija, Chetan; Sanchez, Pablo G.; Griffith, Bartley P.] Univ Maryland, Sch Med, Div Cardiac Surg, Baltimore, MD 21201 USA. [Jeudy, Jean] Univ Maryland, Sch Med, Div Thorac Radiol, Baltimore, MD 21201 USA. [Luo, Qingyang] Ochsner Clin Fdn, Div Appl Hlth Serv Res, New Orleans, LA USA. [Garcia, Jose P.] Massachusetts Gen Hosp, Div Cardiac Surg, Boston, MA 02114 USA. RP Pasrija, C (reprint author), Univ Maryland, Div Cardiac Surg, 22 S Greene St, Baltimore, MD 21201 USA. EM cpasrija@smail.umaryland.edu NR 27 TC 1 Z9 1 U1 1 U2 5 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5223 EI 1097-685X J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD APR PY 2016 VL 151 IS 4 BP 1163 EP + DI 10.1016/j.jtcvs.2015.10.051 PG 8 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA DG9XK UT WOS:000372436900074 PM 26725712 ER PT J AU Brachtel, EF Johnson, NB Huck, AE Rice-Stitt, TL Vangel, MG Smith, BL Tearney, GJ Kang, D AF Brachtel, Elena F. Johnson, Nicole B. Huck, Amelia E. Rice-Stitt, Travis L. Vangel, Mark G. Smith, Barbara L. Tearney, Guillermo J. Kang, Dongkyun TI Spectrally encoded confocal microscopy for diagnosing breast cancer in excision and margin specimens SO LABORATORY INVESTIGATION LA English DT Article ID OPTICAL COHERENCE TOMOGRAPHY; REFLECTANCE SPECTROSCOPY; CONSERVATION SURGERY; PATHOLOGIES; MASTECTOMY; LUMPECTOMY; TISSUES; IMPACT; RATES; FIELD AB A large percentage of breast cancer patients treated with breast conserving surgery need to undergo multiple surgeries due to positive margins found during post-operative margin assessment. Carcinomas could be removed completely during the initial surgery and additional surgery avoided if positive margins can be determined intraoperatively. Spectrally encoded confocal microscopy (SECM) is a high-speed reflectance confocal microscopy technology that has a potential to rapidly image the entire surgical margin at subcellular resolution and accurately determine margin status intraoperatively. In this study, in order to test the feasibility of using SECM for intraoperative margin assessment, we have evaluated the diagnostic accuracy of SECM for detecting various types of breast cancers. Forty-six surgically removed breast specimens were imaged with an SECM system. Side-by-side comparison between SECM and histologic images showed that SECM images can visualize key histomorphologic patterns of normal/benign and malignant breast tissues. Small (500 mu m x 500 mu m) spatially registered SECM and histologic images (n = 124 for each) were diagnosed independently by three pathologists with expertise in breast pathology. Diagnostic accuracy of SECM for determining malignant tissues was high, average sensitivity of 0.91, specificity of 0.93, positive predictive value of 0.95, and negative predictive value of 0.87. Intra-observer agreement and inter-observer agreement for SECM were also high, 0.87 and 0.84, respectively. Results from this study suggest that SECM may be developed into an intraoperative margin assessment tool for guiding breast cancer excisions. C1 [Brachtel, Elena F.; Huck, Amelia E.; Rice-Stitt, Travis L.; Tearney, Guillermo J.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Johnson, Nicole B.] Beth Israel Deaconess Med Ctr, Dept Pathol, 330 Brookline Ave, Boston, MA 02215 USA. [Vangel, Mark G.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Vangel, Mark G.] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Smith, Barbara L.] Massachusetts Gen Hosp, Gillette Ctr Womens Canc, Boston, MA 02114 USA. [Smith, Barbara L.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Tearney, Guillermo J.; Kang, Dongkyun] Massachusetts Gen Hosp, Wellman Ctr Photomed, 55 Fruit St, Boston, MA 02114 USA. [Tearney, Guillermo J.] Harvard Mit Div Hlth Sci & Technol, Boston, MA USA. RP Kang, D (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, 55 Fruit St, Boston, MA 02114 USA. EM dkang@mgh.harvard.edu FU Center for Integration of Medicine and Innovative Technology (CIMIT) under US Army Medical Research Acquisition Activity Cooperative Agreement [W81XWH-09-2-0001]; Harvard Catalyst \ The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health) [UL1 TR001102]; Harvard University and its affiliated academic healthcare centers FX We thank Jeonghyun Lee for his help on digitizing histology slides. We also thank the MGH surgical pathology unit for their help on procuring surgical breast tissues. This work was supported by Center for Integration of Medicine and Innovative Technology (CIMIT) under US Army Medical Research Acquisition Activity Cooperative Agreement (W81XWH-09-2-0001). This work was conducted with support from Harvard Catalyst vertical bar The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award UL1 TR001102) and financial contributions from Harvard University and its affiliated academic healthcare centers.The information contained herein does not necessarily reflect the position or policy of the Government, and no official endorsement should be inferred. 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 31 TC 2 Z9 2 U1 1 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD APR PY 2016 VL 96 IS 4 BP 459 EP 467 DI 10.1038/labinvest.2015.158 PG 9 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA DH4QD UT WOS:000372769600008 PM 26779830 ER PT J AU Byrne, EH Anahtar, MN Cohen, KE Moodley, A Padavattan, N Ismail, N Bowman, BA Olson, GS Mabhula, A Leslie, A Ndung'u, T Walker, BD Ghebremichael, MS Dong, KL Kwon, DS AF Byrne, Elizabeth H. Anahtar, Melis N. Cohen, Kathleen E. Moodley, Amber Padavattan, Nikita Ismail, Nasreen Bowman, Brittany A. Olson, Gregory S. Mabhula, Amanda Leslie, Alasdair Ndung'u, Thumbi Walker, Bruce D. Ghebremichael, Musie S. Dong, Krista L. Kwon, Douglas S. TI Association between injectable progestin-only contraceptives and HIV acquisition and HIV target cell frequency in the female genital tract in South African women: a prospective cohort study SO LANCET INFECTIOUS DISEASES LA English DT Article ID DEPOT MEDROXYPROGESTERONE ACETATE; HORMONAL CONTRACEPTION; T-CELLS; MENSTRUAL-CYCLE; CCR5 EXPRESSION; RISK; INFECTION; SIV; NORETHISTERONE; TRANSMISSION AB Background The use of injectable progestin-only contraceptives has been associated with increased risk of HIV acquisition in observational studies, but the biological mechanisms of this risk remain poorly understood. We aimed to assess the effects of progestins on HIV acquisition risk and the immune environment in the female genital tract. Methods In this prospective cohort, we enrolled HIV-negative South African women aged 18-23 years who were not pregnant and were living in Umlazi, South Africa from the Females Rising through Education, Support, and Health (FRESH) study. We tested for HIV-1 twice per week to monitor incident infection. Every 3 months, we collected demographic and behavioural data in addition to blood and cervical samples. The study objective was to characterise host immune determinants of HIV acquisition risk, including those associated with injectable progestin-only contraceptive use. Hazard ratios (HRs) were estimated using Cox proportional hazards methods. Findings Between Nov 19, 2012, and May 31, 2015, we characterised 432 HIV-uninfected South African women from the FRESH study. In this cohort, 152 women used injectable progestin-only contraceptives, 43 used other forms of contraception, and 222 women used no method of long-term contraception. Women using injectable progestin-only contraceptives were at substantially higher risk of acquiring HIV (12.06 per 100 person-years, 95% CI 6.41-20.63) than women using no long-term contraception (3.71 per 100 person-years, 1.36-8.07; adjusted hazard ratio [aHR] 2.93, 95% CI 1.09-7.868, p=0.0326). HIV-negative injectable progestin-only contraceptive users had 3.92 times the frequency of cervical HIV target cells (CCR5+ CD4 T cells) compared with women using no long-term contraceptive (p=0.0241). Women using no long-term contraceptive in the luteal phase of the menstrual cycle also had a 3.25 times higher frequency of cervical target cells compared with those in the follicular phase (p=0.0488), suggesting that a naturally high progestin state had similar immunological effects to injectable progestin-only contraceptives. Interpretation Injectable progestin-only contraceptive use and high endogenous progesterone are both associated with increased frequency of activated HIV targets cells at the cervix, the site of initial HIV entry in most women, providing a possible biological mechanism underlying increased HIV acquisition in women with high progestin exposure. C1 [Byrne, Elizabeth H.; Anahtar, Melis N.; Cohen, Kathleen E.; Bowman, Brittany A.; Olson, Gregory S.; Ndung'u, Thumbi; Walker, Bruce D.; Ghebremichael, Musie S.; Kwon, Douglas S.] Ragon Inst MGH MIT & Harvard, Cambridge, MA 02139 USA. [Walker, Bruce D.; Kwon, Douglas S.] Massachusetts Gen Hosp, Div Infect Dis, Cambridge, MA USA. [Moodley, Amber; Dong, Krista L.] Females Rising Educ Support & Hlth, Durban, Kwazulu Natal, South Africa. [Padavattan, Nikita; Ismail, Nasreen; Ndung'u, Thumbi] Univ KwaZulu Natal, HIV Pathogenesis Programme, Nelson R Mandela Sch Med, Durban, South Africa. [Mabhula, Amanda; Leslie, Alasdair; Ndung'u, Thumbi] Univ KwaZulu Natal, KwaZulu Natal Res Inst TB & HIV, Nelson R Mandela Sch Med, Durban, South Africa. [Ndung'u, Thumbi] Max Planck Inst Infect Biol, Charitepl, Berlin, Germany. [Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Kwon, DS (reprint author), Ragon Inst MGH MIT & Harvard, Cambridge, MA 02139 USA. EM dkwon@mgh.harvard.edu FU Bill and Melinda Gates Foundation; National Institute of Allergy and Infectious Diseases FX The Bill and Melinda Gates Foundation and the National Institute of Allergy and Infectious Diseases. NR 26 TC 5 Z9 5 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1473-3099 EI 1474-4457 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD APR PY 2016 VL 16 IS 4 BP 441 EP 448 DI 10.1016/S1473-3099(15)00429-6 PG 8 WC Infectious Diseases SC Infectious Diseases GA DH0CH UT WOS:000372449600037 PM 26723758 ER PT J AU Winblad, B Amouyel, P Andrieu, S Ballard, C Brayne, C Brodaty, H Cedazo-Minguez, A Dubois, B Edvardsson, D Feldman, H Fratiglioni, L Frisoni, GB Gauthier, S Georges, J Graff, C Iqbal, K Jessen, F Johansson, G Jonsson, L Kivipelto, M Knapp, M Mangialasche, F Melis, R Nordberg, A Rikkert, MO Qiu, CX Sakmar, TP Scheltens, P Schneider, LS Sperling, R Tjernberg, LO Waldemar, G Wimo, A Zetterberg, H AF Winblad, Bengt Amouyel, Philippe Andrieu, Sandrine Ballard, Clive Brayne, Carol Brodaty, Henry Cedazo-Minguez, Angel Dubois, Bruno Edvardsson, David Feldman, Howard Fratiglioni, Laura Frisoni, Giovanni B. Gauthier, Serge Georges, Jean Graff, Caroline Iqbal, Khalid Jessen, Frank Johansson, Gunilla Jonsson, Linus Kivipelto, Miia Knapp, Martin Mangialasche, Francesca Melis, Rene Nordberg, Agneta Rikkert, Marcel Olde Qiu, Chengxuan Sakmar, Thomas P. Scheltens, Philip Schneider, Lon S. Sperling, Reisa Tjernberg, Lars O. Waldemar, Gunhild Wimo, Anders Zetterberg, Henrik TI Defeating Alzheimer's disease and other dementias: a priority for European science and society SO LANCET NEUROLOGY LA English DT Article ID MILD COGNITIVE IMPAIRMENT; RANDOMIZED CONTROLLED-TRIAL; TRAUMATIC BRAIN-INJURY; QUALITY-OF-LIFE; AMYLOID PRECURSOR PROTEIN; NURSING-HOME RESIDENTS; GENOME-WIDE ASSOCIATION; VASCULAR RISK-FACTORS; COMPREHENSIVE GERIATRIC ASSESSMENT; SUBJECTIVE MEMORY IMPAIRMENT C1 [Winblad, Bengt; Cedazo-Minguez, Angel; Graff, Caroline; Johansson, Gunilla; Jonsson, Linus; Kivipelto, Miia; Sakmar, Thomas P.; Tjernberg, Lars O.; Wimo, Anders] Karolinska Inst, Ctr Alzheimer Res, Dept Neurobiol Care Sci & Soc, Div Neurogeriatr, SE-14157 Huddinge, Sweden. [Nordberg, Agneta] Karolinska Inst, Ctr Alzheimer Res, Dept Neurobiol Care Sci & Soc, Div Translat Alzheimer Biol, SE-14157 Huddinge, Sweden. [Winblad, Bengt; Graff, Caroline; Kivipelto, Miia; Nordberg, Agneta] Karolinska Univ Hosp, Dept Geriatr Med, Huddinge, Sweden. [Amouyel, Philippe] Ctr Hosp Reg & Univ Lille, Inst Pasteur Lille, INSERM RID AGE U1167, Unite Epidemiol & Sante Publ,Labex DISTALZ, Pl Verdun, F-59037 Lille, France. [Andrieu, Sandrine] Toulouse Univ Hosp, Fac Med, Dept Epidemiol & Publ Hlth, Toulouse, France. [Ballard, Clive] Kings Coll London, Wolfson Ctr Age Related Dis, London WC2R 2LS, England. [Brayne, Carol] Univ Cambridge, Cambridge Inst Publ Hlth, Cambridge, England. [Brodaty, Henry] Univ New S Wales, Ctr Hlth Brain Ageing, Sydney, NSW, Australia. [Brodaty, Henry] Univ New S Wales, Dementia Collaborat Res Ctr, Sydney, NSW, Australia. [Dubois, Bruno] Univ Paris 06, Grp Hosp Pitie Salpetriere, Inst Cerveau & Moelle Epiniere, IM2A,INSERM,UMR S975, Paris, France. [Edvardsson, David] La Trobe Univ, Sch Nursing & Midwifery, Melbourne, Vic, Australia. [Edvardsson, David] Umea Univ, Dept Nursing, Umea, Sweden. [Feldman, Howard] Univ British Columbia, Fac Med, Div Neurol, Vancouver, BC, Canada. [Fratiglioni, Laura; Kivipelto, Miia; Mangialasche, Francesca; Qiu, Chengxuan] Karolinska Inst, Ctr Alzheimer Res, Dept Neurobiol Care Sci & Soc, Aging Res Ctr, Stockholm, Sweden. [Frisoni, Giovanni B.] Univ Hosp Geneva, Geneva, Switzerland. [Frisoni, Giovanni B.] Univ Geneva, Geneva, Switzerland. [Frisoni, Giovanni B.] IRCCS Ctr San Giovanni Dio Fatebenefratelli, Brescia, Italy. [Gauthier, Serge] McGill Ctr Studies Aging, Alzheimers Dis Res Unit, Montreal, PQ, Canada. [Gauthier, Serge] Douglas Mental Hlth Univ Inst, Montreal, PQ, Canada. [Georges, Jean] Alzheimer Europe, Luxembourg, Luxembourg. [Iqbal, Khalid] New York State Inst Basic Res, Dept Neurochem, Staten Isl, NY USA. [Jessen, Frank] Univ Cologne, Dept Psychiat, D-50931 Cologne, Germany. [Jessen, Frank] German Ctr Neurodegenerat Dis DZNE, Bonn, Germany. [Knapp, Martin] Univ London London Sch Econ & Polit Sci, Personal Social Serv Res Unit, Houghton St, London WC2A 2AE, England. [Melis, Rene; Rikkert, Marcel Olde] Radboud Univ Nijmegen, Med Ctr, Radboudumc Alzheimer Ctr, NL-6525 ED Nijmegen, Netherlands. [Melis, Rene; Rikkert, Marcel Olde] Radboud Univ Nijmegen, Med Ctr, Dept Geriatr Med, NL-6525 ED Nijmegen, Netherlands. [Sakmar, Thomas P.] Rockefeller Univ, Lab Chem Biol & Signal Transduct, 1230 York Ave, New York, NY 10021 USA. [Scheltens, Philip] Vrije Univ Amsterdam, Med Ctr, Dept Neurol, Amsterdam, Netherlands. [Scheltens, Philip] Vrije Univ Amsterdam, Med Ctr, Alzheimer Ctr, Amsterdam, Netherlands. [Schneider, Lon S.] Univ So Calif, Keck Sch Med, Leonard Davis Sch Gerontol, Dept Psychiat & Behav Sci, Los Angeles, CA 90033 USA. [Schneider, Lon S.] Univ So Calif, Keck Sch Med, Leonard Davis Sch Gerontol, Dept Neurol, Los Angeles, CA 90033 USA. [Sperling, Reisa] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Alzheimer Res & Treatment,Dept Neurol, Boston, MA 02115 USA. [Sperling, Reisa] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Waldemar, Gunhild] Univ Copenhagen, Rigshosp, Dept Neurol, Danish Dementia Res Ctr, DK-2100 Copenhagen, Denmark. [Zetterberg, Henrik] Univ Gothenburg, Sahlgrenska Acad, Dept Neurosci & Physiol, Clin Neurochem Lab, Molndal, Sweden. [Zetterberg, Henrik] UCL Inst Neurol, London, England. RP Winblad, B (reprint author), Karolinska Inst, Ctr Alzheimer Res, Dept Neurobiol Care Sci & Soc, Div Neurogeriatr, SE-14157 Huddinge, Sweden. EM bengt-winblad-swedishbrainpower@ki.se RI Olde Rikkert, M.G.M./H-8078-2014; Frisoni, Giovanni B/K-1360-2016; Melis, Rene/J-5943-2012; Sakmar, Thomas/D-1833-2015; Cedazo-Minguez, Angel/C-6707-2012; OI Olde Rikkert, M.G.M./0000-0003-1397-1677; Frisoni, Giovanni B/0000-0002-6419-1753; Melis, Rene/0000-0002-7863-4738; Sakmar, Thomas/0000-0002-2836-8953; Cedazo-Minguez, Angel/0000-0003-4626-4864; Feldman, Howard/0000-0002-9258-4538 FU AlzProtect; Genoscreen; Hoffmann-La Roche; Servier; Takeda; Acadia; Lundbeck; GlaxoSmithKline; Heptares; Lilly; Orion; Otusaka; Roche; Tau Therapeutics; Nutricia; Eli Lilly; Brain Canada Multi-Investigator Research Initiative; Canadian Institutes of Health Research; US National Institutes of Health; Pacific Alzheimer Research Foundation; TauRx Therapeutics; Alzheimer Society of Canada; Arena Pharmaceuticals; Biogen; General Electric; Hakko Kyowa Kirin Pharmaceuticals; Isis Pharmaceuticals; Swedish Alzheimer Foundation; Gun and Bertil Stohne Foundation; Karolinska Institutet; King Gustaf V and Queen Victoria's Foundation of Freemasons; Swedish Brain Power; Swedish Research Council; Novartis; Piramal; Schwabe; Pfizer Centers for Therapeutic Innovation; GE Healthcare; Stichting VUMC Fonds; Janssen Research Foundation; Takeda Pharmaceuticals; Baxter; Forum; Merck; US National Institute on Aging; University of Southern California; AC Immune; vTv Therapeutics; Boehringer Ingelheim; Sanofi; Brain Biomarker Solutions; GU-Venture-based platform company at the University of Gothenburg, Sweden FX No funding was provided specifically for this Commission paper. PA has received personal fees from AlzProtect, Genoscreen, Hoffmann-La Roche, Servier, Takeda, and Total. CBa has received grants from Acadia and Lundbeck, and personal fees from Acadia, GlaxoSmithKline, Heptares, Lilly, Lundbeck, Orion, Otusaka, and Roche. HB has received grants from Servier and Tau Therapeutics, and fees for advisory board activities from Nutricia. BD has received personal fees from Eli Lilly. HF has received grants and research funds from the Brain Canada Multi-Investigator Research Initiative, the Canadian Institutes of Health Research, Hoffmann-La Roche, Lilly, the US National Institutes of Health, the Pacific Alzheimer Research Foundation, and TauRx Therapeutics; expenses for research policy committee activities from the Alzheimer Society of Canada; consulting fees (paid to the University of British Columbia [UBC]) from Arena Pharmaceuticals, Biogen, General Electric, Hakko Kyowa Kirin Pharmaceuticals, Isis Pharmaceuticals, and Lilly; fees for diagnostic outcome monitoring board activities (paid to UBC) from the Banner Alzheimer's Institute and Genentech; fees for safety monitoring board activities (paid to UBC) from Eisai; travel expenses and consultancy fees for health outcomes research advisory board activities (paid to UBC) from Merck; and personal fees from the Bluefield Project to Cure Frontotemporal Dementia, Danone Nutricia, and the Rainwater Foundation Tau Consortium. HF is the recipient of the Ralph Fisher Family and Alzheimer Society of British Columbia Endowed Professorship in Alzheimer's Disease Research. He has a patent issued: detecting and treating dementia (application number US 12/302691; US patent PCT/US2007/070008). GBF has received grants from the Alzheimer's Association, Avid/Lilly, General Electric, Lilly, Lundbeck, Piramal, Roche, and Wyeth; personal fees from AstraZeneca, Bayer, Baxter, BMS, Elan, General Electric, Lilly, Lundbeck, Piramal, Pfizer, TauRx, and Wyeth; and non -financial support from Avid/Lilly, General Electric, Lilly, and Piramal. CG has received grants and research funding from the Swedish Alzheimer Foundation, the Gun and Bertil Stohne Foundation, the Karolinska Institutet, the King Gustaf V and Queen Victoria's Foundation of Freemasons, Swedish Brain Power, and the Swedish Research Council. KI has six patents issued (US patents 7256003, 8338378, 8349577, 8592374, 8796214, and 8796215) and six patents pending on the treatment of AD and related conditions; he is chairman of the scientific advisory committee of Axon Neuroscience. FJ has received personal fees from AstraZeneca, Boehringer Ingelheim, Lilly, Novartis, Nutricia, Piramal, and Schwabe. H has received personal fees from Lundbeck. MKn has received grants from Lundbeck, and personal fees from Lundbeck and Takeda. TPS has received grants through the Pfizer Centers for Therapeutic Innovation; he has a patent issued: nucleobindin I variant protein compositions and methods of use (US patent 8703707). PS has received grants from Alzheimer Nederland, GE Healthcare, Merck, Piramal, Stichting Dioraphte, and Stichting VUMC Fonds; and consultancy fees (paid to his institution) from AbbVie, Avraham Pharmaceuticals, EIP Pharma, the Janssen Research Foundation, MD Start, Nutricia, Probiodrug AG, and Takeda Pharmaceuticals.; LSS has received grants and other research support from Baxter, Eli Lilly, Forum, Lundbeck, Merck, the US National Institute on Aging, Novartis, Roche/Genentech, the state of California, TauRx, and the University of Southern California, and personal fees from AC Immune, Accera, Avraham, Boehringer Ingelheim, Cerespir, Cognition, Forum, Merck, Neurim, Roche, Stemedica, Takeda, TauRx, Toyama/FujiFilm, Transition, and vTv Therapeutics. RS has received grants from Eli Lilly, Janssen, and the US National Institute on Aging; and personal fees from Boehringer Ingelheim, Biogen, Bracket, Genentech, Isis Pharmaceuticals, Lundbeck, Roche, and Sanofi. GW is a board member of the Lundbeck Foundation. HZ is cofounder of Brain Biomarker Solutions, a GU-Venture-based platform company at the University of Gothenburg, Sweden. BW, SA, CBr, AC-M, DE, LF, SG, JG, GJ, MKi, FM, RM, AN, MOR, CQ, LOT, and AW declare no competing interests. NR 554 TC 49 Z9 50 U1 21 U2 52 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1474-4422 EI 1474-4465 J9 LANCET NEUROL JI Lancet Neurol. PD APR PY 2016 VL 15 IS 5 BP 455 EP 532 PG 78 WC Clinical Neurology SC Neurosciences & Neurology GA DG8IU UT WOS:000372328100003 PM 26987701 ER PT J AU Leritz, EC McGlinchey, RE Salat, DH Milberg, WP AF Leritz, Elizabeth C. McGlinchey, Regina E. Salat, David H. Milberg, William P. TI Elevated levels of serum cholesterol are associated with better performance on tasks of episodic memory SO METABOLIC BRAIN DISEASE LA English DT Article DE Cerebrovascular health; Cerebrovascular risk; Cholesterol; Cognition ID DENSITY-LIPOPROTEIN CHOLESTEROL; ALZHEIMERS-DISEASE; COGNITIVE PERFORMANCE; BLOOD-PRESSURE; VASCULAR RISK; OLDER-ADULTS; INTERINDIVIDUAL VARIATION; APOLIPOPROTEIN E4; ELDERLY ADULTS; PLASMA-LIPIDS AB We examined how serum cholesterol, an established risk factor for cerebrovascular disease (CVD), relates to cognitive function in healthy middle-older aged individuals with no neurologic or CVD history. A complete lipid panel was obtained from a cohort of one hundred twenty individuals, ages 43-85, who also underwent a comprehensive neuropsychological examination. In order to reduce the number of variables and empirically identify broad cognitive domains, scores from neuropsychological tests were submitted into a factor analysis. This analysis revealed three explainable factors: Memory, Executive Function and Memory/Language. Three separate hierarchical multiple regression analyses were conducted using individual cholesterol metrics (total cholesterol, low density lipoprotein; LDL, high density lipoprotein; HDL, and triglycerides), as well as age, education, medication status (lipid lowering agents), ApoE status, and additional risk factors for CVD to predict neuropsychological function. The Memory Factor was predicted by a combination of age, LDL, and triglyceride levels; both age and triglycerides were negatively associated with factor score, while LDL levels revealed a positive relationship. Both the Executive and Memory/Language factor were only explained by education, whereby more years were associated with better performance. These results provide evidence that individual cholesterol lipoproteins and triglycerides may differentially impact cognitive function, over and above other common CVD risk factors and ApoE status. Our findings demonstrate the importance of consideration of vascular risk factors, such as cholesterol, in studies of cognitive aging. C1 [Leritz, Elizabeth C.; McGlinchey, Regina E.; Salat, David H.; Milberg, William P.] VA Boston Healthcare Syst, GRECC, Boston, MA USA. [Leritz, Elizabeth C.; McGlinchey, Regina E.; Salat, David H.; Milberg, William P.] VA Boston Healthcare Syst, Neuroimaging Res Vet Ctr NERVE, Boston, MA USA. [Leritz, Elizabeth C.; McGlinchey, Regina E.; Salat, David H.; Milberg, William P.] Harvard Univ, Sch Med, Boston, MA USA. [Salat, David H.] Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. RP Leritz, EC (reprint author), VA Boston Healthcare Syst, GRECC, Boston, MA USA.; Leritz, EC (reprint author), VA Boston Healthcare Syst, Neuroimaging Res Vet Ctr NERVE, Boston, MA USA.; Leritz, EC (reprint author), Harvard Univ, Sch Med, Boston, MA USA. EM elizabeth_leritz@hms.harvard.edu RI McGlinchey, Regina/R-1971-2016 FU National Institute of Neurologic Disorders and Stroke [K23NS062148, R01NS086882]; National Institute of Nursing Research [R01NR010827]; National Institute on Aging; Medical Research Service VA Merit Review Awards FX This work was supported by the National Institute of Neurologic Disorders and Stroke (K23NS062148 & R01NS086882), the National Institute of Nursing Research (R01NR010827), the National Institute on Aging, and by Medical Research Service VA Merit Review Awards. NR 54 TC 5 Z9 5 U1 2 U2 5 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0885-7490 EI 1573-7365 J9 METAB BRAIN DIS JI Metab. Brain Dis. PD APR PY 2016 VL 31 IS 2 BP 465 EP 473 DI 10.1007/s11011-016-9797-y PG 9 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA DG8GI UT WOS:000372320600027 PM 26873100 ER PT J AU Mishra, S Whetstine, JR AF Mishra, Sweta Whetstine, Johnathan R. TI Different Facets of Copy Number Changes: Permanent, Transient, and Adaptive SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Review ID DOUBLE-MINUTE CHROMOSOMES; HOMOGENEOUSLY STAINING REGIONS; DIHYDROFOLATE-REDUCTASE GENES; IN-SITU HYBRIDIZATION; COMPARATIVE GENOMIC HYBRIDIZATION; RECENT SEGMENTAL DUPLICATIONS; NEUROBLASTOMA-CELL-LINES; TUMOR-SUPPRESSOR GENE; OVARIAN-CANCER CELLS; FOLIC-ACID REDUCTASE AB Chromosomal copy number changes are frequently associated with harmful consequences and are thought of as an underlying mechanism for the development of diseases. However, changes in copy number are observed during development and occur during normal biological processes. In this review, we highlight the causes and consequences of copy number changes in normal physiologic processes as well as cover their associations with cancer and acquired drug resistance. We discuss the permanent and transient nature of copy number gains and relate these observations to a new mechanism driving transient site-specific copy gains (TSSGs). Finally, we discuss implications of TSSGs in generating intratumoral heterogeneity and tumor evolution and how TSSGs can influence the therapeutic response in cancer. C1 [Whetstine, Johnathan R.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA USA. Harvard Univ, Sch Med, Dept Med, Charlestown, MA USA. RP Whetstine, JR (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA USA. EM jwhetstine@hms.harvard.edu FU HHS \ National Institutes of Health (NIH) [GM097360, CA059267]; American Cancer Society (ACS) [RSG-13-115-01-CCG]; American Lung Association; Alex Lemonade Stand Foundation; Leukemia and Lymphoma Society FX HHS vertical bar National Institutes of Health (NIH) provided funding to Johnathan R. Whetstine under grant numbers GM097360 and CA059267. American Cancer Society (ACS) provided funding to Johnathan R. Whetstine under grant number RSG-13-115-01-CCG.; Additional support to Johnathan R. Whetstine and Sweeta Mishra was provided by the American Lung Association, the Alex Lemonade Stand Foundation, and the Leukemia and Lymphoma Society. NR 191 TC 2 Z9 2 U1 2 U2 4 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 APR PY 2016 VL 36 IS 7 BP 1050 EP 1063 DI 10.1128/MCB.00652-15 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DG8JZ UT WOS:000372331400001 PM 26755558 ER PT J AU van Erp, TGM Hibar, DP Rasmussen, JM Glahn, DC Pearlson, GD Andreassen, OA Agartz, I Westlye, LT Haukvik, UK Dale, AM Melle, I Hartberg, CB Gruber, O Kraemer, B Zilles, D Donohoe, G Kelly, S McDonald, C Morris, DW Cannon, DM Corvin, A Machielsen, MWJ Koenders, L de Haan, L Veltman, DJ Satterthwaite, TD Wolf, DH Gur, RC Gur, RE Potkin, SG Mathalon, DH Mueller, BA Preda, A Macciardi, F Ehrlich, S Walton, E Hass, J Calhoun, VD Bockholt, HJ Sponheim, SR Shoemaker, JM van Haren, NEM Pol, HEH Ophoff, RA Kahn, RS Roiz-Santianez, R Crespo-Facorro, B Wang, L Alpert, KI Jonsson, EG Dimitrova, R Bois, C Whalley, HC McIntosh, AM Lawrie, SM Hashimoto, R Thompson, PM Turner, JA AF van Erp, T. G. M. Hibar, D. P. Rasmussen, J. M. Glahn, D. C. Pearlson, G. D. Andreassen, O. A. Agartz, I. Westlye, L. T. Haukvik, U. K. Dale, A. M. Melle, I. Hartberg, C. B. Gruber, O. Kraemer, B. Zilles, D. Donohoe, G. Kelly, S. McDonald, C. Morris, D. W. Cannon, D. M. Corvin, A. Machielsen, M. W. J. Koenders, L. de Haan, L. Veltman, D. J. Satterthwaite, T. D. Wolf, D. H. Gur, R. C. Gur, R. E. Potkin, S. G. Mathalon, D. H. Mueller, B. A. Preda, A. Macciardi, F. Ehrlich, S. Walton, E. Hass, J. Calhoun, V. D. Bockholt, H. J. Sponheim, S. R. Shoemaker, J. M. van Haren, N. E. M. Pol, H. E. H. Ophoff, R. A. Kahn, R. S. Roiz-Santianez, R. Crespo-Facorro, B. Wang, L. Alpert, K. I. Jonsson, E. G. Dimitrova, R. Bois, C. Whalley, H. C. McIntosh, A. M. Lawrie, S. M. Hashimoto, R. Thompson, P. M. Turner, J. A. CA ENIGMA Schizophrenia Working Grp TI Subcortical brain volume abnormalities in 2028 individuals with schizophrenia and 2540 healthy controls via the ENIGMA consortium SO MOLECULAR PSYCHIATRY LA English DT Article ID VOXEL-BASED MORPHOMETRY; HIPPOCAMPAL VOLUME; 1ST-EPISODE SCHIZOPHRENIA; ANTIPSYCHOTIC TREATMENT; BIPOLAR DISORDER; GRAY-MATTER; METAANALYSIS; RISK; DEHYDRATION; REDUCTION AB The profile of brain structural abnormalities in schizophrenia is still not fully understood, despite decades of research using brain scans. To validate a prospective meta-analysis approach to analyzing multicenter neuroimaging data, we analyzed brain MRI scans from 2028 schizophrenia patients and 2540 healthy controls, assessed with standardized methods at 15 centers worldwide. We identified subcortical brain volumes that differentiated patients from controls, and ranked them according to their effect sizes. Compared with healthy controls, patients with schizophrenia had smaller hippocampus (Cohen's d = -0.46), amygdala (d = -0.31), thalamus (d = -0.31), accumbens (d = -0.25) and intracranial volumes (d = -0.12), as well as larger pallidum (d = 0.21) and lateral ventricle volumes (d = 0.37). Putamen and pallidum volume augmentations were positively associated with duration of illness and hippocampal deficits scaled with the proportion of unmedicated patients. Worldwide cooperative analyses of brain imaging data support a profile of subcortical abnormalities in schizophrenia, which is consistent with that based on traditional meta-analytic approaches. This first ENIGMA Schizophrenia Working Group study validates that collaborative data analyses can readily be used across brain phenotypes and disorders and encourages analysis and data sharing efforts to further our understanding of severe mental illness. C1 [van Erp, T. G. M.; Rasmussen, J. M.; Potkin, S. G.; Preda, A.; Macciardi, F.] Univ Calif Irvine, Dept Psychiat & Human Behav, Irvine, CA 92717 USA. [Hibar, D. P.; Kelly, S.; Thompson, P. M.] Univ So Calif, Imaging Genet Ctr, Los Angeles, CA USA. [Glahn, D. C.; Pearlson, G. D.] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. [Glahn, D. C.; Pearlson, G. D.] Inst Living, Olin Neuropsychiat Res Ctr, Hartford, CT USA. [Andreassen, O. A.; Agartz, I.; Westlye, L. T.; Haukvik, U. K.; Melle, I.; Hartberg, C. B.; Jonsson, E. G.] Oslo Univ Hosp, KG Jebsen Ctr Psychosis Res, Norwegian Ctr Mental Disorders Res NORMENT, Div Mental Hlth & Addict, Oslo, Norway. [Agartz, I.; Hartberg, C. B.] Diakonhjemmet Hosp, Dept Psychiat Res, Oslo, Norway. [Agartz, I.; Jonsson, E. G.] Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden. [Westlye, L. T.] Univ Oslo, Dept Psychol, Oslo, Norway. [Dale, A. M.] Univ Calif San Diego, Dept Radiol, MMIL, San Diego, CA 92103 USA. [Dale, A. M.] Univ Calif San Diego, Dept Cognit Sci Neurosci & Psychiat, San Diego, CA 92103 USA. [Gruber, O.; Kraemer, B.; Zilles, D.] Univ Med Ctr Gottingen, Dept Psychiat, Gottingen, Germany. [Zilles, D.] Natl Univ Ireland, Ctr Translat Res Syst Psychol, Galway, Ireland. [Donohoe, G.; Kelly, S.; Morris, D. W.; Corvin, A.] Trinity Coll Dublin, Dept Psychiat, Neuropsychiat Genet Res Grp, Dublin, Ireland. [Donohoe, G.; Kelly, S.; Morris, D. W.; Corvin, A.] Trinity Coll Dublin, Inst Psychiat, Dublin, Ireland. [McDonald, C.; Cannon, D. M.] Natl Univ Ireland, Coll Med Nursing & Hlth Sci, Clin Neuroimaging Lab, Galway, Ireland. [Machielsen, M. W. J.; Koenders, L.; de Haan, L.] Univ Amsterdam, Acad Med Ctr, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. [Veltman, D. J.] Vrije Univ Amsterdam, Univ Med Ctr, Amsterdam, Netherlands. [Satterthwaite, T. D.; Wolf, D. H.; Gur, R. C.; Gur, R. E.] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Mathalon, D. H.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Mathalon, D. H.] San Francisco VA Med Ctr, San Francisco, CA USA. [Mueller, B. A.] Univ Minnesota, Dept Psychiat, Minneapolis, MN 55455 USA. [Ehrlich, S.; Walton, E.; Hass, J.] Tech Univ Dresden, Dept Child & Adolescent Psychiat, Translat Dev Neurosci Sect, D-01062 Dresden, Germany. [Ehrlich, S.] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Ehrlich, S.] Massachusetts Gen Hosp, MGH MIT HMS Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Calhoun, V. D.; Bockholt, H. J.; Shoemaker, J. M.; Turner, J. A.] Mind Res Network, Albuquerque, NM USA. [Calhoun, V. D.] Univ New Mexico, Dept Elect & Comp Engn, Albuquerque, NM 87131 USA. [Bockholt, H. J.] Adv Biomed Informat Grp LLC, Iowa City, IA USA. [Bockholt, H. J.] Univ Iowa, Iowa City, IA USA. [Sponheim, S. R.] Univ Minnesota, Minneapolis VA Healthcare Syst, St Paul, MN USA. [Sponheim, S. R.] Univ Minnesota, Dept Psychiat, St Paul, MN USA. [van Haren, N. E. M.; Pol, H. E. H.; Ophoff, R. A.; Kahn, R. S.] Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Utrecht, Netherlands. [Ophoff, R. A.] Univ Calif Los Angeles, Ctr Neurobehav Genet, Los Angeles, CA USA. [Roiz-Santianez, R.; Crespo-Facorro, B.] Univ Cantabria, IDIVAL, Univ Hosp Marques de Valdecilla, Dept Psychiat, E-39005 Santander, Spain. [Roiz-Santianez, R.; Crespo-Facorro, B.] Ctr Invest Biomed Red Salud Mental, CIBERSAM, Madrid, Spain. [Wang, L.; Alpert, K. I.] Northwestern Univ, Feinberg Sch Med, Dept Psychiat & Behav Sci, Evanston, IL USA. [Wang, L.] Northwestern Univ, Feinberg Sch Med, Dept Radiol, Evanston, IL USA. [Dimitrova, R.; Bois, C.; Whalley, H. C.; McIntosh, A. M.; Lawrie, S. M.] Univ Edinburgh, Sch Med, Div Psychiat, Edinburgh, Midlothian, Scotland. [Hashimoto, R.] Osaka Univ, United Grad Sch Child Dev, Mol Res Ctr Childrens Mental Dev, Osaka, Japan. [Turner, J. A.] Georgia State Univ, Dept Psychol, 758 Urban Life, Atlanta, GA 30302 USA. [Turner, J. A.] Georgia State Univ, Dept Neurosci, 758 Urban Life, Atlanta, GA 30302 USA. RP Turner, JA (reprint author), Georgia State Univ, Dept Psychol, 758 Urban Life, Atlanta, GA 30302 USA.; Turner, JA (reprint author), Georgia State Univ, Dept Neurosci, 758 Urban Life, Atlanta, GA 30302 USA. EM jturner63@gsu.edu RI Macciardi, Fabio/N-3768-2014; Roiz-Santianez, Roberto/H-6462-2015; Melle, Ingrid /B-4858-2011; McDonald, Colm/C-1430-2009; OI Macciardi, Fabio/0000-0003-0537-4266; Corvin, Aiden/0000-0001-6717-4089; Walton, Esther/0000-0002-0935-2200; Roiz-Santianez, Roberto/0000-0002-5176-2983; Preda, Adrian /0000-0003-3373-2438; Jonsson, Erik/0000-0001-8368-6332; Donohoe, Gary/0000-0003-3037-7426; McIntosh, Andrew/0000-0002-0198-4588; Melle, Ingrid /0000-0002-9783-548X; Agartz, Ingrid/0000-0002-9839-5391 FU Medical Research Council [MR/K026992/1]; NCATS NIH HHS [UL1 TR001414]; NCRR NIH HHS [U24 RR021992]; NIBIB NIH HHS [P41 EB015922, R01 EB005846, U54 EB020403]; NIGMS NIH HHS [P20 GM103472]; NIMH NIH HHS [K23 MH085096, R01 MH094524, R01 MH101111, U01 MH097435]; Wellcome Trust [104036] NR 58 TC 34 Z9 34 U1 9 U2 14 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 APR PY 2016 VL 21 IS 4 BP 547 EP 553 DI 10.1038/mp.2015.63 PG 7 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA DG9RM UT WOS:000372421500014 PM 26033243 ER PT J AU Hatzios, SK Abel, S Martell, J Hubbard, T Sasabe, J Munera, D Clark, L Bachovchin, DA Qadri, F Ryan, ET Davis, BM Weerapana, E Waldor, MK AF Hatzios, Stavroula K. Abel, Soeren Martell, Julianne Hubbard, Troy Sasabe, Jumpei Munera, Diana Clark, Lars Bachovchin, Daniel A. Qadri, Firdausi Ryan, Edward T. Davis, Brigid M. Weerapana, Eranthie Waldor, Matthew K. TI Chemoproteomic profiling of host and pathogen enzymes active in cholera SO NATURE CHEMICAL BIOLOGY LA English DT Article ID SERINE HYDROLASE ACTIVITIES; LINEAR MIXED MODELS; VIBRIO-CHOLERAE; PROTEOMIC ANALYSIS; COMPLEX PROTEOMES; PROTEIN; IDENTIFICATION; INTELECTIN-1; MECHANISMS; EXPRESSION AB Activity-based protein profiling (ABPP) is a chemoproteomic tool for detecting active enzymes in complex biological systems. We used ABPP to identify secreted bacterial and host serine hydrolases that are active in animals infected with the cholera pathogen Vibrio cholerae. Four V. cholerae proteases were consistently active in infected rabbits, and one, VC0157 (renamed IvaP), was also active in human choleric stool. Inactivation of IvaP influenced the activity of other secreted V. cholerae and rabbit enzymes in vivo, and genetic disruption of all four proteases increased the abundance of intelectin, an intestinal lectin, and its binding to V. cholerae in infected rabbits. Intelectin also bound to other enteric bacterial pathogens, suggesting that it may constitute a previously unrecognized mechanism of bacterial surveillance in the intestine that is inhibited by pathogen-secreted proteases. Our work demonstrates the power of activity-based proteomics to reveal host-pathogen enzymatic dialog in an animal model of infection. C1 [Hatzios, Stavroula K.; Abel, Soeren; Hubbard, Troy; Sasabe, Jumpei; Munera, Diana; Clark, Lars; Davis, Brigid M.; Waldor, Matthew K.] Brigham & Womens Hosp, Div Infect Dis, 75 Francis St, Boston, MA 02115 USA. [Hatzios, Stavroula K.; Abel, Soeren; Hubbard, Troy; Sasabe, Jumpei; Munera, Diana; Clark, Lars; Davis, Brigid M.; Waldor, Matthew K.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA USA. [Hatzios, Stavroula K.; Hubbard, Troy; Sasabe, Jumpei; Munera, Diana; Clark, Lars; Davis, Brigid M.; Waldor, Matthew K.] Howard Hughes Med Inst, Boston, MA 02115 USA. [Abel, Soeren] Arctic Univ Norway, Univ Tromso UiT, Dept Pharm, Tromso, Norway. [Martell, Julianne; Weerapana, Eranthie] Boston Coll, Dept Chem, Chestnut Hill, MA 02167 USA. [Bachovchin, Daniel A.] Eli & Edythe L Broad Inst, Cambridge, MA USA. [Qadri, Firdausi] Icddr B, Dhaka, Bangladesh. [Ryan, Edward T.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Ryan, Edward T.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Waldor, MK (reprint author), Brigham & Womens Hosp, Div Infect Dis, 75 Francis St, Boston, MA 02115 USA.; Waldor, MK (reprint author), Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA USA.; Waldor, MK (reprint author), Howard Hughes Med Inst, Boston, MA 02115 USA.; Weerapana, E (reprint author), Boston Coll, Dept Chem, Chestnut Hill, MA 02167 USA. EM eranthie@bc.edu; mwaldor@research.bwh.harvard.edu FU National Institutes of Health [R37 AI-042347, F31 AI-120665, R01 AI-106878, U01 AI-058935, T32 DK 7477-30]; Howard Hughes Medical Institute; Charles A. King Trust Postdoctoral Fellowship Program; Bank of America; Damon Runyon Cancer Research Foundation [DRR-18-12]; Smith Family Foundation; Swiss National Science Foundation [P300P3_155287/1] FX We gratefully acknowledge R. LaRocque, Y. Millet and J. Lee for reagents and technical assistance, and members of M.K.W.'s lab for helpful discussions. We also thank V. Carey for the statistical analysis of MS data and D. Bak for help formatting MS data sets. This work was supported by the National Institutes of Health (R37 AI-042347 to M.K.W., F31 AI-120665 to T.H., R01 AI-106878 and U01 AI-058935 to E.T.R., Institutional Training Grant T32 DK 7477-30 to S.K.H.), the Howard Hughes Medical Institute (M.K.W.), the Charles A. King Trust Postdoctoral Fellowship Program, Bank of America, N.A., Co-Trustee (S.K.H.), the Damon Runyon Cancer Research Foundation (DRR-18-12 to E.W.), the Smith Family Foundation (E.W.) and the Swiss National Science Foundation (P300P3_155287/1 to S.A.). NR 59 TC 4 Z9 4 U1 4 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1552-4450 EI 1552-4469 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD APR PY 2016 VL 12 IS 4 BP 268 EP + DI 10.1038/NCHEMBIO.2025 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DH2DA UT WOS:000372593200014 PM 26900865 ER PT J AU Chan, P Han, X Zheng, BH Deran, M Yu, JZ Jarugumilli, GK Deng, H Pan, DJ Luo, XL Wu, X AF Chan, PuiYee Han, Xiao Zheng, Baohui DeRan, Michael Yu, Jianzhong Jarugumilli, Gopala K. Deng, Hua Pan, Duojia Luo, Xuelian Wu, Xu TI Autopalmitoylation of TEAD proteins regulates transcriptional output of the Hippo pathway SO NATURE CHEMICAL BIOLOGY LA English DT Article ID STRUCTURAL BASIS; C-ABL; PALMITOYLATION; YAP; CANCER; COMPLEX; GROWTH; TAZ; ACYLTRANSFERASES; DIFFERENTIATION AB TEA domain (TEAD) transcription factors bind to the coactivators YAP and TAZ and regulate the transcriptional output of the Hippo pathway, playing critical roles in organ size control and tumorigenesis. Protein S-palmitoylation attaches a fatty acid, palmitate, to cysteine residues and regulates protein trafficking, membrane localization and signaling activities. Using activity-based chemical probes, we discovered that human TEADs possess intrinsic palmitoylating enzyme-like activities and undergo autopalmitoylation at evolutionarily conserved cysteine residues under physiological conditions. We determined the crystal structures of lipid-bound TEADs and found that the lipid chain of palmitate inserts into a conserved deep hydrophobic pocket. Strikingly, palmitoylation did not alter TEAD's localization, but it was required for TEAD's binding to YAP and TAZ and was dispensable for its binding to the Vgll4 tumor suppressor. Moreover, palmitoylation-deficient TEAD mutants impaired TAZ-mediated muscle differentiation in vitro and tissue overgrowth mediated by the Drosophila YAP homolog Yorkie in vivo. Our study directly links autopalmitoylation to the transcriptional regulation of the Hippo pathway. C1 [Chan, PuiYee; Zheng, Baohui; DeRan, Michael; Jarugumilli, Gopala K.; Wu, Xu] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA USA. [Han, Xiao] Jilin Univ, Sch Life Sci, Minist Educ, Key Lab Mol Enzymol & Engn, Changchun 130023, Peoples R China. [Han, Xiao; Luo, Xuelian] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA. [Han, Xiao; Luo, Xuelian] Univ Texas SW Med Ctr Dallas, Dept Biophys, Dallas, TX 75390 USA. [Yu, Jianzhong; Deng, Hua; Pan, Duojia] Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21205 USA. [Yu, Jianzhong; Deng, Hua; Pan, Duojia] Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA. RP Wu, X (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA USA.; Luo, XL (reprint author), Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA.; Luo, XL (reprint author), Univ Texas SW Med Ctr Dallas, Dept Biophys, Dallas, TX 75390 USA. EM xuelian.luo@utsouthwestern.edu; xwu@cbrc2.mgh.harvard.edu RI Deng, Hua/D-6393-2016 FU Stewart Rahr-MRA (Melanoma Research Alliance) Young Investigator Award; Department of Defense (DoD) Career Development Award [W81XWH-13-1-0203]; American Cancer Society [124929-RSG-13-291-01-TBE]; US National Institutes of Health/National Cancer Institute [R01CA181537]; National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases [R01DK107651-01]; National Institutes of Health/National Institute of General Medical Sciences [R01GM107415]; National Institute of Health/National Eye Institute [R01EY015708]; Howard Hughes Medical Institute; US Department of Energy (DOE) [DE-AC02-06CH11357] FX This work was supported by a Stewart Rahr-MRA (Melanoma Research Alliance) Young Investigator Award, a Department of Defense (DoD) Career Development Award (W81XWH-13-1-0203), and grants from the American Cancer Society (124929-RSG-13-291-01-TBE), US National Institutes of Health/National Cancer Institute (R01CA181537) (to X.W.), National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (R01DK107651-01) (to X.W. and X.L.), National Institutes of Health/National Institute of General Medical Sciences (R01GM107415) (to X.L.) and National Institute of Health/National Eye Institute (R01EY015708) (to D.P.); D.P. is supported by the Howard Hughes Medical Institute. We thank N. Bardeesy, M. Fukata, K.-L. Guan and K. White for constructs and cell lines; J.-R.J. Yeh, H. Yu and N. Gray for discussion and critical comments on the manuscript; and the Taplin Mass Spec Core facility at Harvard Medical School and the Proteomics Core at UTSW for proteomic studies. Use of the Argonne National Laboratory Structural Biology Center beamlines at the Advanced Photon Source was supported by the US Department of Energy (DOE) under contract DE-AC02-06CH11357. NR 48 TC 5 Z9 6 U1 6 U2 15 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1552-4450 EI 1552-4469 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD APR PY 2016 VL 12 IS 4 BP 282 EP + DI 10.1038/NCHEMBIO.2036 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DH2DA UT WOS:000372593200017 PM 26900866 ER PT J AU Butowski, N Colman, H De Groot, JF Omuro, AM Nayak, L Wen, PY Cloughesy, TF Marimuthu, A Haidar, S Perry, A Huse, J Phillips, J West, BL Nolop, KB Hsu, HH Ligon, KL Molinaro, AM Prados, M AF Butowski, Nicholas Colman, Howard De Groot, John F. Omuro, Antonio M. Nayak, Lakshmi Wen, Patrick Y. Cloughesy, Timothy F. Marimuthu, Adhirai Haidar, Sam Perry, Arie Huse, Jason Phillips, Joanna West, Brian L. Nolop, Keith B. Hsu, Henry H. Ligon, Keith L. Molinaro, Annette M. Prados, Michael TI Orally administered colony stimulating factor 1 receptor inhibitor PLX3397 in recurrent glioblastoma: an Ivy Foundation Early Phase Clinical Trials Consortium phase II study SO NEURO-ONCOLOGY LA English DT Article DE CSF1R; glioblastoma; glioma; microglia; PLX3397 ID PROGRESSION-FREE SURVIVAL; HIGH-GRADE GLIOMAS; RADIOTHERAPY; TEMOZOLOMIDE; PDGFRA; GROWTH; IDH1; EGFR; CELL AB Background. The colony stimulating factor 1 receptor (CSF1R) ligands, CSF1 and interleukin-34, and the KIT ligand, stem cell factor, are expressed in glioblastoma (GB). Microglia, macrophages, blood vessels, and tumor cells also express CSF1R, and depletion of the microglia reduces tumor burden and invasive capacity. PLX3397 is an oral, small molecule that selectively inhibits CSF1R and KIT, penetrates the blood-brain barrier in model systems, and represents a novel approach for clinical development. Methods. We conducted a phase II study in patients with recurrent GB. The primary endpoint was 6-month progression-free survival (PFS6). Secondary endpoints included overall survival response rate, safety, and plasma/tumor tissue pharmacokinetics. Exploratory endpoints included pharmacodynamic measures of drug effect in blood and tumor tissue. Results. A total of 37 patients were enrolled, with 13 treated prior to a planned surgical resection (Cohort 1) and 24 treated without surgery (Cohort 2). PLX3397 was given at an oral dose of 1000 mg daily and was well tolerated. The primary efficacy endpoint of PFS6 was only 8.6%, with no objective responses. Pharmacokinetic endpoints revealed a median maximal concentration (C-max) of 8090 ng/mL, with a time to attain C-max of 2 hour in plasma. Tumor tissue obtained after 7 days of drug exposure revealed a median drug level of 5500 ng/g. Pharmacodynamic changes included an increase in colony stimulating factor 1 and reduced CD14(dim)/CD16+ monocytes in plasma compared with pretreatment baseline values. Conclusion. PLX3397 was well tolerated and readily crossed the blood-tumor barrier but showed no efficacy. Additional studies are ongoing, testing combination strategies and potential biomarkers to identify patients with greater likelihood of response. C1 [Butowski, Nicholas; Perry, Arie; Phillips, Joanna; Molinaro, Annette M.; Prados, Michael] Univ Calif San Francisco, 505 Parnassus Ave,M-779, San Francisco, CA 94117 USA. [Colman, Howard] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA. [De Groot, John F.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Omuro, Antonio M.] Mem Sloan Kettering Canc Hosp, Dept Neurol, New York, NY USA. [Nayak, Lakshmi; Wen, Patrick Y.; Haidar, Sam; Ligon, Keith L.] Dana Farber Brigham & Womens Canc Ctr, Ctr Neurooncol, Boston, MA USA. [Cloughesy, Timothy F.] Univ Calif Los Angeles, Med Ctr, Los Angeles, CA 90024 USA. [Marimuthu, Adhirai; West, Brian L.; Nolop, Keith B.; Hsu, Henry H.] Plexxikon Inc, Berkeley, CA USA. [Ligon, Keith L.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Huse, Jason] Mem Sloan Kettering Canc Hosp, Dept Pathol, New York, NY USA. RP Butowski, N (reprint author), Univ Calif San Francisco, Dept Neurol Surg, 505 Parnassus Ave,M-779, San Francisco, CA 94117 USA. EM butowski@neurosurg.ucsf.edu FU Plexxikon; Ivy Foundation Early Phase Clinical Trials Consortium FX This work was supported by Plexxikon and conducted with support from the Ivy Foundation Early Phase Clinical Trials Consortium. NR 20 TC 14 Z9 15 U1 4 U2 7 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD APR PY 2016 VL 18 IS 4 BP 557 EP 564 DI 10.1093/neuonc/nov245 PG 8 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA DH0VV UT WOS:000372503100012 PM 26449250 ER PT J AU Radhakrishnan, R Cornelius, R Cunnane, MB Golnik, K Morales, H AF Radhakrishnan, Rupa Cornelius, Rebecca Cunnane, Mary Beth Golnik, Karl Morales, Humberto TI MR imaging findings of endophthalmitis SO NEURORADIOLOGY JOURNAL LA English DT Review DE Endophthalmitis; magnetic resonance imaging; computed tomography; globe infection; ocular infection; diffusion-weighted images ID ENDOGENOUS BACTERIAL ENDOPHTHALMITIS; CT; RETINOBLASTOMA; EPIDEMIOLOGY; EXPERIENCE; INFECTION; ABSCESS; GLOBE AB Endophthalmitis is a sight-threatening ophthalmologic emergency. The clinical diagnosis is often challenging, and delayed diagnosis may exacerbate the poor visual prognosis. B-scan ultrasonography or spectral domain optical coherence tomography are imaging aids at the clinician's office. Cross-sectional imaging such as CT and particularly MRI can also help in the assessment of disease extent or complications. MR imaging findings are rarely described in the literature. Here, we discuss the spectrum of imaging findings of endophthalmitis and correlate them with key anatomic and pathophysiologic details of the globe. Early disease is often subtle on MR imaging with thick uveal enhancement, while advanced disease demonstrates retinal/choroidal detachment, vitreal exudates and peribulbar inflammation. Other noninfectious inflammatory diseases of the globe can show similar findings; however, MR diffusion-weighted images help identify infectious exudates and evaluate response to therapy. Knowledge of the spectrum of imaging findings of this disease is important for radiologists and help in the management decision process. C1 [Radhakrishnan, Rupa] Cincinnati Childrens Hosp Med Ctr, Dept Radiol, Cincinnati, OH 45229 USA. [Cornelius, Rebecca; Morales, Humberto] Univ Cincinnati, Med Ctr, Dept Radiol, Cincinnati, OH 45221 USA. [Cunnane, Mary Beth] Massachusetts Eye & Ear Infirm, Dept Radiol, Boston, MA USA. [Golnik, Karl] Univ Cincinnati, Med Ctr, Dept Ophthalmol, Cincinnati, OH 45221 USA. RP Morales, H (reprint author), Univ Cincinnati, Dept Radiol, 234 Goodman St, Cincinnati, OH 45219 USA. EM moralehc@ucmail.uc.edu FU NCATS NIH HHS [UL1 TR001425] NR 25 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1971-4009 EI 2385-1996 J9 NEURORADIOL J JI Neuradiology J. PD APR PY 2016 VL 29 IS 2 BP 122 EP 129 DI 10.1177/1971400916633480 PG 8 WC Neuroimaging SC Neurosciences & Neurology GA DH1MO UT WOS:000372548800005 PM 26915896 ER PT J AU Tawk, RG Grewal, SS Heckman, MG Rawal, B Miller, DA Edmonston, D Ferguson, JL Navarro, R Ng, L Brown, BL Meschia, JF Freeman, WD AF Tawk, Rabih G. Grewal, Sanjeet S. Heckman, Michael G. Rawal, Bhupendra Miller, David A. Edmonston, Drucilla Ferguson, Jennifer L. Navarro, Ramon Ng, Lauren Brown, Benjamin L. Meschia, James F. Freeman, William D. TI The Relationship Between Serum Neuron-Specific Enolase Levels and Severity of Bleeding and Functional Outcomes in Patients With Nontraumatic Subarachnoid Hemorrhage SO NEUROSURGERY LA English DT Article DE Glasgow Coma Scale; Neuron-specific enolase; Subarachnoid hemorrhage; Hunt and Hess; WFNS Scale; Fisher grade; Modified Rankin Scale ID CEREBROSPINAL-FLUID; BRAIN-INJURY; PROTEIN; NSE; VASOSPASM; MARKERS; TRAUMA; STROKE AB BACKGROUND: The value of neuron-specific enolase (NSE) in predicting clinical outcomes has been investigated in a variety of neurological disorders. OBJECTIVE: To investigate the associations of serum NSE with severity of bleeding and functional outcomes in patients with subarachnoid hemorrhage (SAH). METHODS: We retrospectively reviewed the records of patients with SAH from June 2008 to June 2012. The severity of SAH bleeding at admission was measured radiographically with the Fisher scale and clinically with the Glasgow Coma Scale, Hunt and Hess grade, and World Federation of Neurologic Surgeons scale. Outcomes were assessed with the modified Rankin Scale at discharge. RESULTS: We identified 309 patients with nontraumatic SAH, and 71 had NSE testing. Median age was 54 years (range, 23-87 years), and 44% were male. In multivariable analysis, increased NSE was associated with a poorer Hunt and Hess grade (P = .003), World Federation of Neurologic Surgeons scale score (P < .001), and Glasgow Coma Scale score (P = .003) and worse outcomes (modified Rankin Scale at discharge; P = .001). There was no significant association between NSE level and Fisher grade (P = .81) in multivariable analysis. CONCLUSION: We found a significant association between higher NSE levels and poorer clinical presentations and worse outcomes. Although it is still early for any relevant clinical conclusions, our results suggest that NSE holds promise as a tool for screening patients at increased risk of poor outcomes after SAH. ABBREVIATIONS: BMI, body mass index GCS, Glasgow Coma Scale mRS, modified Rankin Scale NSE, neuron-specific enolase SAH, subarachnoid hemorrhage WFNS, World Federation of Neurologic Surgeons C1 [Tawk, Rabih G.; Grewal, Sanjeet S.; Miller, David A.; Navarro, Ramon; Brown, Benjamin L.; Freeman, William D.] Mayo Clin, Mayo Sch Hlth Sci, Coll Med, Dept Neurosurg, Jacksonville, FL 32224 USA. [Heckman, Michael G.; Rawal, Bhupendra] Mayo Clin, Mayo Sch Hlth Sci, Coll Med, Div Biomed Stat & Informat, Jacksonville, FL 32224 USA. [Edmonston, Drucilla; Ferguson, Jennifer L.] Mayo Clin, Mayo Sch Hlth Sci, Coll Med, Dept Neurol, Jacksonville, FL 32224 USA. [Ng, Lauren; Freeman, William D.] Mayo Clin, Dept Crit Care, Jacksonville, FL 32224 USA. [Meschia, James F.; Freeman, William D.] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. [Rawal, Bhupendra] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Edmonston, Drucilla] Florida State Univ, Coll Med, Tallahassee, FL 32306 USA. [Navarro, Ramon] Cleveland Clin, Neurol Inst, Abu Dhabi, U Arab Emirates. RP Tawk, RG (reprint author), Mayo Clin, Dept Neurosurg, 4500 San Pablo Rd, Jacksonville, FL 32224 USA. EM tawk.rabih@mayo.edu NR 23 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 0148-396X J9 NEUROSURGERY JI Neurosurgery PD APR PY 2016 VL 78 IS 4 BP 487 EP 491 DI 10.1227/NEU.0000000000001140 PG 5 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA DG8PG UT WOS:000372345500003 PM 26606669 ER PT J AU Wang, YE Kakigi, C Barbosa, D Porco, T Chen, R Wang, S Li, YJ Singh, K Pasquale, LR Lin, SC AF Wang, Ye Elaine Kakigi, Caitlin Barbosa, Diego Porco, Travis Chen, Rebecca Wang, Sophia Li, Yingjie Singh, Kuldev Pasquale, Louis R. Lin, Shan C. TI Oral Contraceptive Use and Prevalence of Self-Reported Glaucoma or Ocular Hypertension in the United States SO OPHTHALMOLOGY LA English DT Article ID OPEN-ANGLE GLAUCOMA; HORMONE REPLACEMENT THERAPY; FEMALE REPRODUCTIVE FACTORS; EARLY BILATERAL OOPHORECTOMY; INTRAOCULAR-PRESSURE; ESTROGEN-RECEPTOR; NURSES HEALTH; WOMEN; EYE; MENOPAUSE AB Purpose: To investigate the association between oral contraceptive (OC) use and glaucoma prevalence in the United States. Design: Cross-sectional study. Participants: A total of 3406 female participants, aged 40 years or older, from the 2005 to 2008 National Health and Nutrition Examination Survey, who reported a presence or absence of glaucoma or ocular hypertension completed both the vision and the reproductive health questionnaires and underwent eye examinations. Methods: Multivariate regression analysis was used to assess the correlation between OC use and self-reported glaucoma or ocular hypertension (n = 231 cases), controlling for potential confounders, including age, ethnicity, systemic comorbidities such as hypertension and stroke, ocular diseases such as cataract and diabetic retinopathy, and reproductive health factors, including age at menopause, age at menarche, history of hormone replacement therapy, and gynecological surgical history. Main Outcome Measures: The outcome variable was self-reported glaucoma or ocular hypertension. Results: After adjusting for confounders, those with >= 3 years of OC use had greater odds (odds ratio, 1.94; 95% confidence interval, 1.22-3.07) of self-reported glaucoma or ocular hypertension. Other factors associated with higher glaucoma or ocular hypertension prevalence included older age, African American race, and later age at menarche. Conclusions: Oral contraceptive use may be associated with increased risk of self-reported glaucoma or ocular hypertension. (C) 2016 by the American Academy of Ophthalmology. C1 [Wang, Ye Elaine; Kakigi, Caitlin; Barbosa, Diego; Porco, Travis; Chen, Rebecca; Wang, Sophia; Li, Yingjie; Lin, Shan C.] Univ Calif San Francisco, Dept Ophthalmol, 10 Koret Way,K301, San Francisco, CA 94143 USA. [Wang, Ye Elaine] Univ Calif Los Angeles, Jules Stein Eye Inst, Harbor UCLA Med Ctr, Dept Ophthalmol, Los Angeles, CA 90024 USA. [Chen, Rebecca] Case Western Reserve Univ, Sch Med, Cleveland, OH USA. [Wang, Sophia] Univ Michigan, Kellogg Eye Inst, Ann Arbor, MI 48109 USA. [Li, Yingjie] Nanchang Univ, Sch Med, Hosp 3, Nanchang, Jiangxi, Peoples R China. [Singh, Kuldev] Stanford Univ, Sch Med, Dept Ophthalmol, Stanford, CA 94305 USA. [Pasquale, Louis R.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Glaucoma Serv, Boston, MA USA. [Pasquale, Louis R.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Div Network Med, Boston, MA 02115 USA. RP Lin, SC (reprint author), Univ Calif San Francisco, Dept Ophthalmol, 10 Koret Way,K301, San Francisco, CA 94143 USA. EM lins@vision.ucsf.edu OI Barbosa, Diego/0000-0002-9105-5263; Chen, Rebecca/0000-0003-4581-8204 FU Glaucoma Foundation; Harvard Medical School Distinguished Ophthalmology Scholar Award; National Eye Institute Grant [R01 EY EY015473]; Aerie Pharmaceuticals; Glaukos FX The author(s) have made the following disclosure(s): L.R.P.: Speaker - Allergan; Consultant - Novartis, Bausch & Lomb; Travel support - Exfoliation Glaucoma Think Tank Meeting in New York sponsored by the Glaucoma Foundation; Aerie Pharmaceuticals and Glaukos provided support to travel to the Nantucket Glaucoma Meeting in August 2015; Supported by a Harvard Medical School Distinguished Ophthalmology Scholar Award and a National Eye Institute Grant (R01 EY EY015473). NR 35 TC 1 Z9 1 U1 2 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD APR PY 2016 VL 123 IS 4 BP 729 EP 736 DI 10.1016/j.ophtha.2015.11.029 PG 8 WC Ophthalmology SC Ophthalmology GA DH3WU UT WOS:000372718300016 PM 26948305 ER PT J AU Belsky, JB Klausner, HA Karson, J Dunne, RB AF Belsky, Justin B. Klausner, Howard A. Karson, Jeffrey Dunne, Robert B. TI Survey of Emergency Department Chemical Hazard Preparedness in Michigan, USA: A Seven Year Comparison SO PREHOSPITAL AND DISASTER MEDICINE LA English DT Article DE disaster; disaster planning; hazardous substances ID HOSPITAL PREPAREDNESS; INCIDENTS; VICTIMS AB Objective: To compare the state of chemical hazard preparedness in emergency departments (EDs) in Michigan, USA between 2005 and 2012. Methods: This was a longitudinal study involving a 30 question survey sent to ED directors at each hospital listed in the Michigan College of Emergency Physician (MCEP) Directory in 2005 and in 2012. The surveys contained questions relating to chemical, biological, radiological, nuclear, and explosive events with a focus on hazardous material capabilities. Results: One hundred twelve of 139 EDs responded to the 2005 survey compared to 99/136 in 2012. Ten of 27 responses were statistically significant, all favoring an enhancement in disaster preparedness in 2012 when compared to 2005. Questions with improvement included: EDs with employees participating in the Michigan voluntary registry; EDs with decontamination rooms; MARK 1 and cyanide kits available; those planning to use dry decontamination, powered air purifiers, surgical masks, chemical gloves, and surgical gowns; and those wishing for better coordination with local and regional resources. Forty-two percent of EDs in 2012 had greater than one-half of their staff trained in decontamination and 81% of respondents wished for more training opportunities in disaster preparedness. Eighty-four percent of respondents believed that they were more prepared in disaster preparedness in 2012 versus seven years prior. Conclusions: Emergency departments in Michigan have made significant advances in chemical hazard preparedness between 2005 and 2012 based on survey responses. Despite these improvements, staff training in decontamination and hazardous material events remains a weakness among EDs in the state of Michigan. C1 [Belsky, Justin B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA USA. [Klausner, Howard A.; Karson, Jeffrey] Henry Ford Hosp, Dept Emergency Med, Detroit, MI 48202 USA. [Dunne, Robert B.] St Johns Hosp, Dept Emergency Med, Detroit, MI USA. RP Belsky, JB (reprint author), 55 Fruit St,Zero Emerson Pl,Suite 3B, Boston, MA 02114 USA. EM jbelsky@partners.org NR 6 TC 0 Z9 0 U1 1 U2 2 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1049-023X EI 1945-1938 J9 PREHOSPITAL DISASTER JI Prehospital Disaster Med. PD APR PY 2016 VL 31 IS 2 BP 224 EP 227 DI 10.1017/S1049023X16000108 PG 4 WC Emergency Medicine SC Emergency Medicine GA DG8RX UT WOS:000372352400018 PM 26831281 ER PT J AU Meyer, CP Allard, CB Sammon, JD Hanske, J McNabb-Baltar, J Goldberg, JE Reznor, G Lipsitz, SR Choueiri, TK Nguyen, PL Weissman, JS Trinh, QD AF Meyer, Christian P. Allard, Christopher B. Sammon, Jesse D. Hanske, Julian McNabb-Baltar, Julia Goldberg, Joel E. Reznor, Gally Lipsitz, Stuart R. Choueiri, Toni K. Nguyen, Paul L. Weissman, Joel S. Quoc-Dien Trinh TI The impact of Medicare eligibility on cancer screening behaviors SO PREVENTIVE MEDICINE LA English DT Article DE Preventive services; Medicare; Cancer screening; USPSTF; Colorectal cancer; Prostate cancer; Cervical cancer; Breast cancer ID SERVICES TASK-FORCE; PREVENTIVE SERVICES; HEALTH-CARE; UNITED-STATES; RECOMMENDATION STATEMENT; UNINSURED ADULTS; DISPARITIES; COVERAGE; TRENDS; BREAST AB Introduction. Lack of health insurance limits access to preventive services, including cancer screening. We examined the effects of Medicare eligibility on the appropriate use of cancer screening services in the United States. Methods. We performed a cross-sectional analysis of the 2012 Behavioral Risk Factor and Surveillance System (analyzed in 2014). Univariable and logistic regression analyses were performed for participants aged 60-64 and 66-70 to examine the effects of Medicare eligibility on prevalence of self-reported screening for colorectal, breast, and prostate cancers. Sub-analyses were performed among low-income (.$25,000 annual/household) individuals. Results. Medicare-eligible individuals were significantly more likely to undergo all examined preventive services (colorectal cancer OR: 1.90; 95% CI 1.79-2.04; prostate cancer OR: 1.29; 95% CI 1.17-1.43; breast cancer OR: 1.23; 95% Cl 1.10-1.37) and the effect was most pronounced among low-income individuals (colorectal cancer OR: 2.04; 95% Cl 1.8-2.32; prostate cancer OR: 1.39; 95% Cl 1.12-1.72; breast cancer OR: 1.42, 95% Cl 1.201.67). Access to a healthcare provider was the strongest independent predictor of undergoing appropriate screening, ranging from OR 2.73 (95% Cl 2.20-3.39) for colorectal cancer screening in the low-income population to 0R4.79 (95% Cl 3.95-5.81) for breast cancer screening in the overall cohort. The difference in screening prevalence was most pronounced when comparing Medicare -eligible participants to uninsured Medicare -ineligible participants (-33.2%). Conclusions. Medicare eligibility impacts the prevalence of cancer screening, likely as a result of increased access to primary care. Low-income individuals benefit most from Medicare eligibility. Expanded public insurance coverage to these individuals may improve access to preventive services. (C) 2015 Elsevier Inc. All rights reserved. C1 [Meyer, Christian P.; Sammon, Jesse D.; Hanske, Julian; Reznor, Gally; Lipsitz, Stuart R.; Weissman, Joel S.; Quoc-Dien Trinh] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Surg & Publ Hlth, Boston, MA 02115 USA. [Allard, Christopher B.; Quoc-Dien Trinh] Brigham & Womens Hosp, Div Urol Surg, Boston, NM USA. [McNabb-Baltar, Julia] Brigham & Womens Hosp, Dept Med, Gastroenterol, 75 Francis St, Boston, MA 02115 USA. [Goldberg, Joel E.] Brigham & Womens Hosp, Dept Surg Gastrointestinal & Gen Surg, 75 Francis St, Boston, MA 02115 USA. [Choueiri, Toni K.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dana Farber Canc Inst,Dept Med Oncol, Boston, MA 02115 USA. [Nguyen, Paul L.] Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. RP Trinh, QD (reprint author), Harvard Univ, Sch Med, Ctr Surg & Publ Hlth, 45 Francis St, Boston, MA 02115 USA.; Trinh, QD (reprint author), Harvard Univ, Brigham & Womens Hosp, Div Urol Surg, 45 Francis St, Boston, MA 02115 USA. EM trinh.qd@gmail.com FU Vattikuti Urology Institute; Brigham and Women's Hospital FX Quoc-Dien Trinh is supported by an unrestricted educational grant from the Vattikuti Urology Institute and the Professor Walter Morris Hale Distinguished Chair in Urologic Oncology at Brigham and Women's Hospital. NR 35 TC 2 Z9 2 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 EI 1096-0260 J9 PREV MED JI Prev. Med. PD APR PY 2016 VL 85 BP 47 EP 52 DI 10.1016/j.ypmed.2015.12.019 PG 6 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA DH1NS UT WOS:000372552300008 PM 26763164 ER PT J AU Robinson, AI Carnes, F Oreskovic, NM AF Robinson, Alyssa I. Carnes, Fei Oreskovic, Nicolas M. TI Spatial analysis of crime incidence and adolescent physical activity SO PREVENTIVE MEDICINE LA English DT Article DE Crime; Youth; Adolescents; Physical activity; GIS ID BUILT ENVIRONMENT; NEIGHBORHOOD SAFETY; CHILDREN; WALKING AB Objectives. Adolescents do not achieve recommended levels of physical activity. Crime is believed to be a barrier to physical activity among youth, but findings arc inconsistent. This study compares the spatial distribution of crime incidences and moderate-to-vigorous physical activity (MVPA) among adolescents in Massachusetts between 2011 and 2012, and examines the correlation between crime and MVPA. Methods. Eighty adolescents provided objective physical activity (accelerometer) and location (Global Positioning Systems) data Crime report data were obtained from the city police department. Data were mapped using geographic information systems, and crime and MVPA densities were calculated using kernel density estimations. Spearman's correlation tested for associations between crime and MVPA. Results. Overall, 1694 reported crimes and 16,702 minof MVPA were included in analyses. A strong positive correlation was present between crime and adolescent MVPA (p = 0.72, p = 0.0001). Crime remained positively associated with MVPA in locations falling within the lowest quartile (p = 0.43, p = 0.0001) and highest quartile 032, p < 0.0001) of crime density. Conclusions. This study found a strong positive association between crime and adolescent MVPA, despite research suggesting the opposite relationship. This counterintuitive finding may be explained by the logic of a common destination: neighborhood spaces which are desirable destinations and promote physical activity may likewise attract crime. (C) 2016 Elsevier Inc. All rights reserved. C1 [Robinson, Alyssa I.; Oreskovic, Nicolas M.] Massachusetts Gen Hosp, Gen Acad Pediat, Boston, MA 02114 USA. [Carnes, Fei] Harvard Univ, Ctr Geog Anal, Cambridge, MA 02138 USA. [Oreskovic, Nicolas M.] Massachusetts Gen Hosp, Dept Internal Med, Boston, MA 02114 USA. [Oreskovic, Nicolas M.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Oreskovic, Nicolas M.] Harvard Univ, Sch Med, Boston, MA USA. RP Oreskovic, NM (reprint author), Massachusetts Gen Hosp, Gen Acad Pediat, Boston, MA 02114 USA. EM arobinson13@mgh.harvard.edu; fmeng@cga.harvard.edu; noreskovic@mgh.harvard.edu FU National Heart, Lung, and Blood Institute [K23HL103841] FX The authors wish to thank Christine Giraud for her assistance in conceptualizing this study. This research was supported by the National Heart, Lung, and Blood Institute (grant K23HL103841). NR 16 TC 0 Z9 0 U1 7 U2 18 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 EI 1096-0260 J9 PREV MED JI Prev. Med. PD APR PY 2016 VL 85 BP 74 EP 77 DI 10.1016/j.ypmed.2016.01.012 PG 4 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA DH1NS UT WOS:000372552300012 PM 26820115 ER PT J AU Song, Y Hernandez, N Shoag, J Goldfarb, DS Eisner, BH AF Song, Yan Hernandez, Natalia Shoag, Jonathan Goldfarb, David S. Eisner, Brian H. TI Potassium citrate decreases urine calcium excretion in patients with hypocitraturic calcium oxalate nephrolithiasis SO UROLITHIASIS LA English DT Article DE Kidney stone; Potassium citrate; Urine calcium ID STONE-FORMERS; PATHOPHYSIOLOGY; MANAGEMENT AB Two previous studies (< 10 patients each) have demonstrated that alkali therapy may reduce urine calcium excretion in patients with calcium oxalate nephrolithiasis. The hypothesized mechanisms are (1) a decrease in bone turnover due to systemic alkalinization by the medications; (2) binding of calcium by citrate in the gastrointestinal tract; (3) direct effects on TRPV5 activity in the distal tubule. We performed a retrospective review of patients on potassium citrate therapy to evaluate the effects of this medication on urinary calcium excretion. A retrospective review was performed of a metabolic stone database at a tertiary care academic hospital. Patients were identified with a history of calcium oxalate nephrolithiasis and hypocitraturia who were on potassium citrate therapy for a minimum of 3 months. 24-h urine composition was assessed prior to the initiation of potassium citrate therapy and after 3 months of therapy. Patients received 30-60 mEq potassium citrate by mouth daily. Inclusion criterion was a change in urine potassium of 20 mEq/day or greater, which suggests compliance with potassium citrate therapy. Paired t test was used to compare therapeutic effect. Twenty-two patients were evaluated. Mean age was 58.8 years (SD 14.0), mean BMI was 29.6 kg/m(2) (SD 5.9), and gender prevalence was 36.4 % female:63.6 % male. Mean pre-treatment 24-h urine values were as follows: citrate 280.0 mg/day, potassium 58.7 mEq/day, calcium 216.0 mg/day, pH 5.87. Potassium citrate therapy was associated with statistically significant changes in each of these parameters-citrate increased to 548.4 mg/day (p < 0.0001), potassium increased to 94.1 mEq/day (p < 0.0001), calcium decreased to 156.5 mg/day (p = 0.04), pH increased to 6.47 (p = 0.001). Urine sodium excretion was not different pre- and post-therapy (175 mEq/day pre-therapy versus 201 mEq/day post-therapy, p = NS). Urinary calcium excretion decreased by a mean of 60 mg/day on potassium citrate therapy-a nearly 30 % decrease in urine calcium excretion. These data lend support to the hypothesis that alkali therapy reduces urine calcium excretion. C1 [Song, Yan] Med Univ, ShengJing Hosp China, Dept Urol, Shenyang 110004, Liaoning, Peoples R China. [Hernandez, Natalia; Eisner, Brian H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Urol, 55 Fruit St,GRB 1102, Boston, MA 02114 USA. [Shoag, Jonathan] New York Presbyterian Hosp, Weill Cornell Med Coll, Dept Urol, New York, NY USA. [Goldfarb, David S.] NYU, Langone Med Ctr, Nephrol Sect, New York Harbor Vet Affairs Healthcare Syst, New York, NY USA. RP Eisner, BH (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Urol, 55 Fruit St,GRB 1102, Boston, MA 02114 USA. EM beisner@partners.org OI Goldfarb, David/0000-0002-9215-1273 FU NIDDK FX Brian Eisner is a consultant for Boston Scientific, Bard, Olympus, and Retrophin and owner of the Ravine Group. David Goldfarb is a consultant for Hospira, Takeda, Amgen, Keryx, and Quntiles, Owner of Ravine group, and receives funding from NIDDK. Other authors have no disclosures. NR 18 TC 0 Z9 0 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 2194-7228 EI 2194-7236 J9 UROLITHIASIS JI Urolithiasis PD APR PY 2016 VL 44 IS 2 BP 145 EP 148 DI 10.1007/s00240-015-0819-8 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA DH4JE UT WOS:000372750900006 PM 26582172 ER PT J AU Sanchez, A Rodriguez, D Allard, CB Bechis, SK Sullivan, RJ Boeke, CE Kuppermann, D Cheng, JS Barrisford, GW Preston, MA Feldman, AS AF Sanchez, Alejandro Rodriguez, Dayron Allard, Christopher B. Bechis, Seth K. Sullivan, Ryan J. Boeke, Caroline E. Kuppermann, David Cheng, Jed -Sian Barrisford, Glen W. Preston, Mark A. Feldman, Adam S. TI Primary genitourinary melanoma: Epidemiology and disease-specific survival in a large population-based cohort SO UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS LA English DT Article DE Genitourinary neoplasms; Melanoma; Outcomes; Prognostic factors; SEER ID MUCOSAL MELANOMA; URETHRA; VULVAR; EXPERIENCE; PENIS AB Background: Primary genitourinary (GU) melanoma is a rare disease, which is poorly characterized. Objective: To examine clinical characteristics and survival outcomes of primary GU melanoma among men and women. Design, setting, and participants: Retrospective study using the Surveillance, Epidemiology, and End Results database (1973 2010) was used to identify primary GU melanoma cases by tumor site and histology codes. We examined associations of GU melanoma with demographic, clinical, and pathologic characteristics, as well as disease-specific survival (DSS). Outcome measurements and statistical analysis: DSS was calculated using the Kaplan-Meier method. Cox-proportional hazard models were used to calculate hazard ratios and 95% CI for factors associated with worse DSS. Results and limitations: A total of 1,586 histologically confirmed cases of primary GU melanoma were identified with a median age of 66.1 years (IQR: 55-80). Incidence of primary GU melanoma was 0.2 cases/million among men and 1.80 cases/million among women. Overall, 60.1% of patients had localized disease at presentation and 90.5% of patients had cancer-directed surgery. Patients with urothelial melanoma had the worst 5- and 10-year DSS (39% and 29%, respectively). Women with vulvar/vaginal melanoma had worse 5- and 10-year DSS compared to men with penile/scrotal melanoma. In multivariate analysis, decreased survival was associated with increasing age, distant stage, and lymph node involvement. Results are limited by the lack of standardized staging for primary GU melanoma and the retrospective design of our study. Conclusions: Patients with primary GU melanoma present with advanced stage and have a poor prognosis. Women have worse DSS compared to men. DSS is negatively associated with advanced age at diagnosis, higher stage, and lymph node involvement. Patient summary: Clinicians and patients must be aware of the poor disease-specific outcomes associated with primary GU melanoma. Most importantly, women fare worse than men and mucosal melanomas have worse outcomes compared to cutaneous melanomas. (C) 2016 Elsevier Inc. All rights reserved. C1 [Sanchez, Alejandro; Rodriguez, Dayron; Allard, Christopher B.; Bechis, Seth K.; Kuppermann, David; Feldman, Adam S.] Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. [Sullivan, Ryan J.] Massachusetts Gen Hosp, Dept Med Oncol, Boston, MA 02114 USA. [Boeke, Caroline E.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Boeke, Caroline E.] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Cheng, Jed -Sian] Cooper Univ Hosp, Cooper Med Sch, Camden, NJ USA. [Barrisford, Glen W.] Santa Rosa Med Ctr, Dept Urol, Kaiser Permanente, Santa Rosa, CA 95403 USA. [Preston, Mark A.] Brigham & Womens Hosp, Div Urol, 75 Francis St, Boston, MA 02115 USA. RP Feldman, AS (reprint author), Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. EM afeldman@partners.org OI Kuppermann, David/0000-0003-1191-0870 NR 19 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 1078-1439 EI 1873-2496 J9 UROL ONCOL-SEMIN ORI JI Urol. Oncol.-Semin. Orig. Investig. PD APR PY 2016 VL 34 IS 4 DI 10.1016/j.urolonc.2015.11.009 PG 8 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA DH3UQ UT WOS:000372712700006 ER PT J AU Therkelsen, KE Pedley, A Hoffmann, U Fox, CS Murabito, JM AF Therkelsen, Kate E. Pedley, Alison Hoffmann, Udo Fox, Caroline S. Murabito, Joanne M. TI Intramuscular fat and physical performance at the Framingham Heart Study SO AGE LA English DT Article DE Epidemiology; Muscle; Adipose tissue; Physical function ID TRUNK MUSCLE COMPOSITION; METABOLIC RISK-FACTORS; HUMAN SKELETAL-MUSCLE; GAIT-SPEED DECLINE; OLDER-ADULTS; BODY-COMPOSITION; MOBILITY LIMITATION; BACK-PAIN; HEALTH; STRENGTH AB Intramuscular fat may mediate associations between obesity and physical disability. We examined the associations between muscle attenuation, a proxy for intramuscular fat, and physical function. Paraspinous muscle computed tomography attenuation was obtained on a Framingham Heart Study subgroup (n = 1152, 56% women, mean age 66 years). Regressions modeled cross-sectional associations between muscle attenuation and mobility disability, grip strength, and walking speed with standard covariates; models additionally adjusted for body mass index (BMI) and visceral adipose tissue (VAT). Separate models investigated associations between VAT and subcutaneous adipose tissue (SAT) and physical function. Per 1 standard deviation decrement in muscle attenuation (i.e., more muscle fat), we observed 1.29 (95 % CI=1.11, 1.50; p = 0.0009) increased odds of walking speed <= 1 m/s in women and men. This persisted after separate BMI and VAT adjustments (p < 0.02). In men, there was a 1.29 kg (95 % CI= 0.57, 2.01; p = 0.0005) decrement in grip strength, which persisted after BMI and VAT adjustments (p <= 0.0004). For VAT and SAT, similar associations were not observed. Intramuscular fat is associated with increased odds of walking speed <= 1 m/s in both sexes and lower grip strength in men. There were no similar associations for VAT and SAT, highlighting the specificity of intramuscular fat in association with physical function. C1 [Therkelsen, Kate E.; Pedley, Alison; Fox, Caroline S.; Murabito, Joanne M.] Natl Heart Lung & Blood Inst Framingham Heart Stu, 73 Mt Wayte Ave Suite 2, Framingham, MA 01702 USA. [Therkelsen, Kate E.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Hoffmann, Udo] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Fox, Caroline S.] NHLBI, Div Intra Mural Res, Framingham, MA USA. [Fox, Caroline S.] Ctr Populat Studies, Framingham, MA USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol & Metab, 75 Francis St, Boston, MA 02115 USA. [Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Murabito, Joanne M.] Boston Univ, Sch Med, Gen Internal Med Sect, Boston, MA 02118 USA. RP Murabito, JM (reprint author), Natl Heart Lung & Blood Inst Framingham Heart Stu, 73 Mt Wayte Ave Suite 2, Framingham, MA 01702 USA. EM murabito@bu.edu FU [N01-HC-25195]; [HHSN268201500001I]; [R0129451] FX The Framingham Heart Study of the National Heart, Lung and Blood Institute is supported by contract N01-HC-25195 and HHSN268201500001I. Dr Joanne Murabito is supported by R0129451. NR 46 TC 2 Z9 2 U1 1 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0161-9152 EI 1574-4647 J9 AGE JI Age PD APR PY 2016 VL 38 IS 2 AR 31 DI 10.1007/s11357-016-9893-2 PG 12 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA DG7GM UT WOS:000372252800003 PM 26899132 ER PT J AU Foust-Wright, CE Wakamatsu, M Johnson, A Weinstein, M Pulliam, SJ AF Foust-Wright, C. E. Wakamatsu, M. Johnson, A. Weinstein, M. Pulliam, S. J. TI Decreasing length of stay for vaginal hysterectomy through quality improvement cycle SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 42nd Annual Scientific Meeting of the Society-of-Gynecologic-Surgeons CY APR 10-13, 2016 CL Palm Springs, CA SP Soc Gynecol Surg C1 [Foust-Wright, C. E.; Wakamatsu, M.; Johnson, A.; Weinstein, M.; Pulliam, S. J.] Massachusetts Gen Hosp, Obstet & Gynecol, Framingham, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD APR PY 2016 VL 214 IS 4 SU S MA 9 BP S471 EP S471 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DG4ZA UT WOS:000372080500030 ER PT J AU Penn, C Morgan, DM Rauh-Hain, J Rice, LW Uppal, S AF Penn, C. Morgan, D. M. Rauh-Hain, J. Rice, L. W. Uppal, S. TI Reasons for unplanned 30-day readmission after hysterectomy for benign disease SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 42nd Annual Scientific Meeting of the Society-of-Gynecologic-Surgeons CY APR 10-13, 2016 CL Palm Springs, CA SP Soc Gynecol Surg C1 [Penn, C.; Morgan, D. M.; Uppal, S.] Univ Michigan, Ann Arbor, MI 48109 USA. [Rauh-Hain, J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Rice, L. W.] Univ Wisconsin, Madison, WI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD APR PY 2016 VL 214 IS 4 SU S MA 1 BP S455 EP S455 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DG4ZA UT WOS:000372080500002 ER PT J AU Vargas, MV Moawad, G Sievers, C Opoku-Anane, J Marfori, C Robinson, J AF Vargas, M. V. Moawad, G. Sievers, C. Opoku-Anane, J. Marfori, C. Robinson, J. TI Feasibility, safety, and prediction of complications for complex minimally invasive myomectomy SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 42nd Annual Scientific Meeting of the Society-of-Gynecologic-Surgeons CY APR 10-13, 2016 CL Palm Springs, CA SP Soc Gynecol Surg C1 [Vargas, M. V.; Moawad, G.; Marfori, C.] George Washington Univ, Med Ctr, Div Gynecol, Washington, DC 20037 USA. [Opoku-Anane, J.] Univ San Francisco, Obstet & Gynecol, San Francisco, CA 94117 USA. [Sievers, C.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Sievers, C.] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA. [Sievers, C.] Broad Inst Massachusetts Inst Technol & Harvard, Cambridge, MA USA. [Robinson, J.] MedStar Washington Hosp Ctr, Minimally Invas Surg, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD APR PY 2016 VL 214 IS 4 SU S MA 58 BP S497 EP S498 PG 4 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DG4ZA UT WOS:000372080500079 ER PT J AU Liao, J Seggio, JA Ahmad, ST AF Liao, Jennifer Seggio, Joseph A. Ahmad, S. Tariq TI Mutations in the circadian gene period alter behavioral and biochemical responses to ethanol in Drosophila SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE Alcoholism; Circadian rhythm; Drosophila; Ethanol period ID ALCOHOL-CONSUMPTION; ACTIVITY RHYTHMS; EXPOSURE ALTERS; LOCOMOTOR-ACTIVITY; CLOCK GENES; MELANOGASTER; TOLERANCE; EXPRESSION; SENSITIVITY; SYSTEM AB Clock genes, such as period, which maintain an organism's circadian rhythm, can have profound effects on metabolic activity, including ethanol metabolism. In turn, ethanol exposure has been shown in Drosophila and mammals to cause disruptions of the circadian rhythm. Previous studies from our labs have shown that larval ethanol exposure disrupted the free-running period and period expression of Drosophila. In addition, a recent study has shown that arrhythmic flies show no tolerance to ethanol exposure. As such, Drosophila period mutants, which have either a shorter than wild-type free-running period (perS) or a longer one (perL), may also exhibit altered responses to ethanol due to their intrinsic circadian differences. In this study, we tested the initial sensitivity and tolerance of ethanol exposure on Canton-S, perS, and perL, and then measured their Alcohol Dehydrogenase (ADH) and body ethanol levels. We showed that perL flies had slower sedation rate, longer recovery from ethanol sedation, and generated higher tolerance for sedation upon repeated ethanol exposure compared to Canton-S wild-type flies. Furthermore, perL flies had lower ADH activity and had a slower ethanol clearance compared to wild-type flies. The findings of this study suggest that period mutations influence ethanol induced behavior and ethanol metabolism in Drosophila and that flies with longer circadian periods are more sensitive to ethanol exposure. (C) 2016 Elsevier B.V. All rights reserved. C1 [Liao, Jennifer; Ahmad, S. Tariq] Colby Coll, Dept Biol, 5720 Mayflower Hill Dr, Waterville, ME 04901 USA. [Seggio, Joseph A.] Bridgewater State Univ, Dept Biol Sci, 24 Pk Ave, Bridgewater, MA 02325 USA. [Liao, Jennifer] Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. RP Ahmad, ST (reprint author), 5720 Mayflower Hill Dr, Waterville, ME 04901 USA. EM Jennifer_liao@dfci.harvard.edu; joseph.seggio@bridgew.edu; stahmad@colby.edu FU National Institute of General Medical Sciences of the National Institutes of Health [P20GM0103423]; Natural Science Division Grant, Colby College (STA); ATP; CARS; Daniel Smith Awards, Bridgewater State University FX This work was supported by an investigator grant of Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20GM0103423 to STA, Natural Science Division Grant, Colby College (STA) and ATP, CARS, and Daniel Smith Awards, Bridgewater State University to JAS. We would like to acknowledge Joshua Kavaler and Ahmad lab members for suggestions on the manuscript. NR 39 TC 1 Z9 1 U1 5 U2 18 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 EI 1872-7549 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD APR 1 PY 2016 VL 302 BP 213 EP 219 DI 10.1016/j.bbr.2016.01.041 PG 7 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA DG3DU UT WOS:000371950500025 PM 26802726 ER PT J AU Ramos-Kuri, M Rapti, K Mehel, H Zhang, SH Dhandapany, PS Liang, LF Garcia-Carranca, A Bobe, R Fischmeister, R Adnot, S Lebeche, D Hajjar, RJ Lipskaia, L Chemaly, ER AF Ramos-Kuri, Manuel Rapti, Kleopatra Mehel, Hind Zhang, Shihong Dhandapany, Perundurai S. Liang, Lifan Garcia-Carranca, Alejandro Bobe, Regis Fischmeister, Rodolphe Adnot, Serge Lebeche, Djamel Hajjar, Roger J. Lipskaia, Larissa Chemaly, Elie R. TI Dominant negative Ras attenuates pathological ventricular remodeling in pressure overload cardiac hypertrophy (vol 1853, pg 2870, 2015) SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH LA English DT Correction C1 [Ramos-Kuri, Manuel; Rapti, Kleopatra; Zhang, Shihong; Liang, Lifan; Lebeche, Djamel; Hajjar, Roger J.; Lipskaia, Larissa; Chemaly, Elie R.] Icahn Sch Med Mt Sinai, Cardiovasc Res Ctr, New York, NY 10029 USA. [Dhandapany, Perundurai S.] Icahn Sch Med Mt Sinai, Dept Pediat, One Gustave L Levy Pl, New York, NY 10029 USA. [Ramos-Kuri, Manuel] Ctr Invest Social Avanzada, Ave Fray Luis de Leon 1000, Queretaro 76190, Mexico. [Ramos-Kuri, Manuel; Liang, Lifan; Lebeche, Djamel; Hajjar, Roger J.; Chemaly, Elie R.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. [Ramos-Kuri, Manuel] Univ Panamer, Lab Biol Mol, Mexico City, DF, Mexico. [Ramos-Kuri, Manuel; Garcia-Carranca, Alejandro] Univ Nacl Autonoma Mexico, Inst Invest Biomed, Mexico City 04510, DF, Mexico. [Adnot, Serge; Lipskaia, Larissa] UPEC, INSERM, U955, F-94010 Creteil, France. [Adnot, Serge; Lipskaia, Larissa] UPEC, Hop Henri Mondor, AP HP, Dept Physiol, F-94010 Creteil, France. [Bobe, Regis] Univ Paris 11, INSERM, U770, Le Kremlin Bicetre, France. [Mehel, Hind; Fischmeister, Rodolphe] INSERM, UMR S 1180, LabEx LERMIT DHU TORINO, Chatenay Malabry, France. [Mehel, Hind; Fischmeister, Rodolphe] Univ Paris 11, Fac Pharm, F-92290 Chatenay Malabry, France. RP Ramos-Kuri, M (reprint author), Ctr Invest Social Avanzada, Ave Fray Luis de Leon 1000, Queretaro 76190, Mexico. EM manuel.ramos@cisav.org NR 1 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4889 EI 0006-3002 J9 BBA-MOL CELL RES JI Biochim. Biophys. Acta-Mol. Cell Res. PD APR PY 2016 VL 1863 IS 4 BP 785 EP 785 DI 10.1016/j.bbamcr.2015.12.006 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DG2ZY UT WOS:000371940500025 ER PT J AU Mallis, RJ Reinherz, EL Wagner, G Arthanari, H AF Mallis, Robert J. Reinherz, Ellis L. Wagner, Gerhard Arthanari, Haribabu TI Backbone resonance assignment of N15, N30 and D10 T cell receptor beta subunits SO BIOMOLECULAR NMR ASSIGNMENTS LA English DT Article DE T-cell receptor; TCR; MHC; Immunology; Protein refolding ID TCR AB The alpha beta T Cell receptor (TCR) governs T cell immunity through its interaction with peptide bound to major histocompatibility complex molecules (pMHC). Previously, soluble ectodomain constructs have been used to elucidate the binding mode of the TCR for the MHC. However, the full heterodimeric alpha beta TCR has proven difficult to produce reproducibly in recombinant systems to the extent seen in the routine production of novel antibodies. Particularly, the route of production in E. coli, which is most convenient for isotopic labeling of proteins, is challenging for a wide range of alpha beta TCR, including N15 alpha beta, N30 alpha beta, but not D10 alpha beta. With the aim of understanding the TCR-pMHC interaction through the use of dynamic binding measurements, we set out to produce TCR beta subunits with which we could investigate binding with pMHC. The TCR beta constructs are more readily produced and refolded than their alpha beta counterparts and have proven to be an effective model of preTCR in pMHC binding studies. As a first step towards characterizing potential interactions with protein ligands, we have assigned the backbone resonances of three TCR beta subunits, N15 beta, N30 beta and D10 beta. C1 [Mallis, Robert J.; Wagner, Gerhard; Arthanari, Haribabu] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Reinherz, Ellis L.] Dana Farber Canc Inst, Dept Med Oncol, Immunobiol Lab, Boston, MA 02115 USA. [Reinherz, Ellis L.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Arthanari, H (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. EM hari_arthanari@hms.harvard.edu FU National Institutes of Health [P01GM04746, R01AI37581, P41-EB002026, R01AI19807, R01AI100643] FX This work was supported by National Institutes of Health Grants P01GM04746, R01AI37581, and P41-EB002026 (GW) and R01AI19807 and R01AI100643 (ELR). NR 16 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1874-2718 EI 1874-270X J9 BIOMOL NMR ASSIGN JI Biomol. NMR Assign. PD APR PY 2016 VL 10 IS 1 BP 35 EP 39 DI 10.1007/s12104-015-9632-0 PG 5 WC Biophysics; Spectroscopy SC Biophysics; Spectroscopy GA DG6WX UT WOS:000372227900006 PM 26275917 ER PT J AU Semler, MW Wheeler, AP Thompson, BT Bernard, GR Wiedemann, HP Rice, TW AF Semler, Matthew W. Wheeler, Arthur P. Thompson, B. Taylor Bernard, Gordon R. Wiedemann, Herbert P. Rice, Todd W. CA Natl Inst Hlth Natl Heart Lung & B TI Impact of Initial Central Venous Pressure on Outcomes of Conservative Versus Liberal Fluid Management in Acute Respiratory Distress Syndrome SO CRITICAL CARE MEDICINE LA English DT Article DE acute lung injury; diuresis; fluid therapy; respiratory distress syndrome; adult; sepsis; shock ID ACUTE LUNG INJURY; CRITICALLY ILL PATIENTS; GOAL-DIRECTED THERAPY; PULMONARY-ARTERY; SEVERE SEPSIS; WEDGE PRESSURE; SEPTIC SHOCK; BALANCE; METAANALYSIS; VOLUME AB Objectives: In acute respiratory distress syndrome, conservative fluid management increases ventilator-free days without affecting mortality. Response to fluid management may differ based on patients' initial central venous pressure. We hypothesized that initial central venous pressure would modify the effect of fluid management on outcomes. Design: Retrospective analysis of the Fluid and Catheter Treatment Trial, a multicenter randomized trial comparing conservative with liberal fluid management in acute respiratory distress syndrome. We examined the relationship between initial central venous pressure, fluid strategy, and 60-day mortality in univariate and multivariable analysis. Setting: Twenty acute care hospitals. Patients: Nine hundred thirty-four ventilated acute respiratory distress syndrome patients with a central venous pressure available at enrollment, 609 without baseline shock (for whom fluid balance was managed by the study protocol). Interventions: None. Measurements and Main Results: Among patients without baseline shock, those with initial central venous pressure greater than 8 mm Hg experienced similar mortality with conservative and liberal fluid management (18% vs 18%; p = 0.928), whereas those with central venous pressure of 8 mm Hg or less experienced lower mortality with a conservative strategy (17% vs 36%; p = 0.005). Multivariable analysis demonstrated an interaction between initial central venous pressure and the effect of fluid strategy on mortality (p = 0.031). At higher initial central venous pressures, the difference in treatment between arms was predominantly furosemide administration, which was not associated with mortality (p = 0.122). At lower initial central venous pressures, the difference between arms was predominantly fluid administration, with additional fluid associated with increased mortality (p = 0.013). Conclusions: Conservative fluid management decreases mortality for acute respiratory distress syndrome patients with a low initial central venous pressure. In this population, the administration of IV fluids seems to increase mortality. C1 [Semler, Matthew W.; Wheeler, Arthur P.; Bernard, Gordon R.; Rice, Todd W.] Vanderbilt Univ, Sch Med, Div Allergy Pulm & Crit Care Med, Nashville, TN 37212 USA. [Thompson, B. Taylor] Massachusetts Gen Hosp, Div Pulm & Crit Care Med, Boston, MA 02114 USA. [Wiedemann, Herbert P.] Cleveland Clin Fdn, Div Pulm & Crit Care Med, 9500 Euclid Ave, Cleveland, OH 44195 USA. RP Semler, MW (reprint author), 1161 21st Ave S,T-2220 MCN, Nashville, TN 37232 USA. EM matthew.w.semler@vanderbilt.edu FU National Heart, Lung, and Blood Institute, National Institutes of Health [NO1-HR-46046-64, NO1-HR-16146-54]; National Heart, Lung, and Blood Institute [HL087738 09]; National Institutes of Health (NIH); National Heart, Lung, and Blood Institute (NHLBI); NHLBI [NO1-HR-46046-64, NO1-HR-16146-54]; NIH; NHLBI; NIH [NO1-HR-46046-64, NO1-HR-16146-54]; AstraZeneca FX Supported, in part, by contracts (NO1-HR-46046-64 and NO1-HR-16146-54) with the National Heart, Lung, and Blood Institute, National Institutes of Health. Investigators conducting the current study were supported by a National Heart, Lung, and Blood Institute T32 award (HL087738 09). The funding institutions had no role in conception, design, or conduct of the study; collection, management, analysis, interpretation, or presentation of the data; or preparation, review, or approval of the article.; Dr. Semler received support for this research from the National Institutes of Health (NIH) and National Heart, Lung, and Blood Institute (NHLBI). His institution received grant support and support for travel from the NHLBI (contracts, NO1-HR-46046-64 and NO1-HR-16146-54). Dr. Wheeler consulted for Siemens, lectured for various CME presentations at academic medical centers, has stock in Cumberland pharmaceuticals (compensation for consulting work), and received support for this research from the NIH and NHLBI. Dr. Thompson received support for this research from the NIH and the NHLBI. His institution received grant support from the NHLBI and NIH (contracts, NO1-HR-46046-64 and NO1-HR-16146-54). Dr. Bernard received support for this research from the NIH and the NHLBI. His institution received grant support and support for travel from AstraZeneca (for an investigator-initiated randomized clinical trial in ICU pneumonia). Dr. Wiedemann received support for this research from the NIH and the NHBLI. His institution received grant support and support for travel from the NHBLI and NIH (contracts, NO1-HR-46046-64 and NO1-HR-16146-54). Dr. Rice consulted for GlaxoSmithKline, LLC (Data and Safety Monitoring Board for a study of gastrointestinal motility), Avisa, LLC (consultant for a tuberculosis and ventilator associated pneumonia detection device), and Metagenics (consultant for immunonutrition). He received support for this article research from the NIH and NHBLI. NR 34 TC 1 Z9 1 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0090-3493 EI 1530-0293 J9 CRIT CARE MED JI Crit. Care Med. PD APR PY 2016 VL 44 IS 4 BP 782 EP 789 DI 10.1097/CCM.0000000000001555 PG 8 WC Critical Care Medicine SC General & Internal Medicine GA DG1NU UT WOS:000371835600016 PM 26741580 ER PT J AU Urday, S Beslow, LA Dai, F Zhang, F Battey, TWK Vashkevich, A Ayres, AM Leasure, AC Selim, MH Simard, JM Rosand, J Kimberly, WT Sheth, KN AF Urday, Sebastian Beslow, Lauren A. Dai, Feng Zhang, Fan Battey, Thomas W. K. Vashkevich, Anastasia Ayres, Alison M. Leasure, Audrey C. Selim, Magdy H. Simard, J. Marc Rosand, Jonathan Kimberly, W. Taylor Sheth, Kevin N. TI Rate of Perihematomal Edema Expansion Predicts Outcome After Intracerebral Hemorrhage SO CRITICAL CARE MEDICINE LA English DT Article DE brain edema; cerebral hemorrhage; outcome ID PERIHAEMATOMAL EDEMA; BRAIN-INJURY; VOLUME; MECHANISMS; SYSTEM; LEVEL; MODEL; TRIAL; MASS AB Objectives: Intracerebral hemorrhage is a devastating disorder with no current treatment. Whether perihematomal edema is an independent predictor of neurologic outcome is controversial. We sought to determine whether perihematomal edema expansion rate predicts outcome after intracerebral hemorrhage. Design: Retrospective cohort study. Setting: Tertiary medical center. Patients: One hundred thirty-nine consecutive supratentorial spontaneous intracerebral hemorrhage patients 18 years or older admitted between 2000 and 2013. Interventions: None. Measurements and Main Results: Intracerebral hemorrhage, intraventricular hemorrhage, and perihematomal edema volumes were measured from CT scans obtained at presentation, 24-hours, and 72-hours postintracerebral hemorrhage. Perihematomal edema expansion rate was the difference between initial and follow-up perihematomal edema volumes divided by the time interval. Logistic regression was performed to evaluate the relationship between 1) perihematomal edema expansion rate at 24 hours and 90-day mortality and 2) perihematomal edema expansion rate at 24 hours and 90-day modified Rankin Scale score. Perihematomal edema expansion rate between admission and 24-hours postintracerebral hemorrhage was a significant predictor of 90-day mortality (odds ratio, 2.97; 95% CI, 1.48-5.99; p = 0.002). This association persisted after adjusting for all components of the intracerebral hemorrhage score (odds ratio, 2.21; 95% CI, 1.05-4.64; p = 0.04). Similarly, higher 24-hour perihematomal edema expansion rate was associated with poorer modified Rankin Scale score in an ordinal shift analysis (odds ratio, 2.40; 95% CI, 1.37-4.21; p = 0.002). The association persisted after adjustment for all intracerebral hemorrhage score components (odds ratio, 2.07; 95% CI, 1.12-3.83; p = 0.02). Conclusions: Faster perihematomal edema expansion rate 24-hours postintracerebral hemorrhage is associated with worse outcome. Perihematomal edema may represent an attractive translational target for secondary injury after intracerebral hemorrhage. C1 [Urday, Sebastian; Beslow, Lauren A.; Dai, Feng; Zhang, Fan; Leasure, Audrey C.; Sheth, Kevin N.] Yale Univ, Sch Med, Dept Neurol, New Haven, CT 06510 USA. [Battey, Thomas W. K.; Vashkevich, Anastasia; Ayres, Alison M.; Rosand, Jonathan; Kimberly, W. Taylor] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Selim, Magdy H.] Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA 02215 USA. [Simard, J. Marc] Univ Maryland, Sch Med, Dept Neurosurg, Baltimore, MD 21201 USA. RP Urday, S (reprint author), Yale Univ, Sch Med, Dept Neurol, New Haven, CT 06510 USA. EM sebastian.urday@yale.edu FU American Heart Association Stroke Council; National Institute of Neurological Disorders and Stroke (NINDS) [K12-NS049453]; Department of Veterans Affairs (Baltimore) [BX001629]; NINDS [NS060801, NS061808, K23-NS076597]; National Heart, Lung and Blood Institute [HL082517]; NIH; American Heart Association; Remedy Pharmaceutics; Novartis; Leon Rosenberg, MD Medical Student Research Fund in Genetics (Yale University School of Medicine) FX Dr. Urday received support for article research from Leon Rosenberg, MD Medical Student Research Fund in Genetics (Yale University School of Medicine), and a 2014 Student Scholarship in Cerebrovascular Disease and Stroke (American Heart Association Stroke Council). He disclosed that Drs. Beslow, Kimberly, and Sheth are investigators in Glyburide Advantage in Malignant Edema and Stroke-Remedy Pharmaceuticals, a phase II study of an investigational compound aimed at preventing swelling after large stroke. Dr. Beslow is supported by the National Institute of Neurological Disorders and Stroke (NINDS; K12-NS049453). Dr. Simard is supported by grants from the Department of Veterans Affairs (Baltimore; BX001629), the NINDS (NS060801, NS061808), and the National Heart, Lung and Blood Institute (HL082517). Dr. Kimberly is supported by NINDS K23-NS076597. Dr. Sheth receive funding from the NIH, the American Heart Association, Remedy Pharmaceutics and Novartis for research related to cerebral edema. The remaining authors have disclosed that they do not have any potential conflicts of interest. NR 32 TC 2 Z9 2 U1 3 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0090-3493 EI 1530-0293 J9 CRIT CARE MED JI Crit. Care Med. PD APR PY 2016 VL 44 IS 4 BP 790 EP 797 DI 10.1097/CCM.0000000000001553 PG 8 WC Critical Care Medicine SC General & Internal Medicine GA DG1NU UT WOS:000371835600017 PM 26757167 ER PT J AU Pirrone, M Pinciroli, R Berra, L AF Pirrone, Massimiliano Pinciroli, Riccardo Berra, Lorenzo TI Microbiome, biofilms, and pneumonia in the ICU SO CURRENT OPINION IN INFECTIOUS DISEASES LA English DT Review DE biofilms; chronic obstructive pulmonary disease; cystic fibrosis; microbiome; pneumonia ID VENTILATOR-ASSOCIATED-PNEUMONIA; COATED ENDOTRACHEAL-TUBES; OBSTRUCTIVE PULMONARY-DISEASE; SUBGLOTTIC SECRETION DRAINAGE; CRITICALLY-ILL PATIENTS; CUFF PRESSURE; MECHANICAL VENTILATION; BACTERIAL-COLONIZATION; MUCUS SHAVER; RANDOMIZED-TRIAL AB Purpose of reviewLower respiratory tract infections remain one of the leading causes of death in the world. Recently, the introduction of molecular methods based on DNA sequencing and microarrays for the identification of nonculturable microorganisms and subspecies variations has challenged the previous one bug - one disease' paradigm, providing us with a broader view on human microbial communities and their role in the development of infectious diseases. The purpose of this review is to describe recent understanding of the role of microbiome and bacterial biofilm in the development of lung infections, and, at the same time, to present new areas of research opportunities.Recent findingsThe review describes recent literature in cystic fibrosis patients, chronic obstructive pulmonary disease patients, and literature in mechanically ventilated patients that helped to elucidate the role of microbiome and biofilm formation in the development of pneumonia.SummaryThe characterization of the human microbiome and biofilms has changed our understanding of lower respiratory tract infections. More comprehensive, sensitive, and fast methods for bacterial, fungal, and viral detection are warranted to establish the colonization of the lower respiratory tract in healthy individuals and sick patients. Future research might explore the global bacterial, fungal, and viral pulmonary ecosystems and their interdependence to target novel preventive approaches and therapeutic strategies in chronic and acute lung infections. C1 [Pirrone, Massimiliano] Univ Milan, Dipartimento Anestesiol Terapia Intens & Sci Derm, Milan, Italy. [Pinciroli, Riccardo] Osped Niguarda Ca Granda, Dipartimento Anestesia & Rianimaz, Milan, Italy. [Berra, Lorenzo] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA. RP Berra, L (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA. EM lberra@mgh.harvard.edu FU Department of Anaesthesiology, Massachusetts General Hospital, Boston, USA FX The work was supported by the Department of Anaesthesiology, Massachusetts General Hospital, Boston, USA. NR 64 TC 1 Z9 1 U1 5 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0951-7375 EI 1473-6527 J9 CURR OPIN INFECT DIS JI Curr. Opin. Infect. Dis. PD APR PY 2016 VL 29 IS 2 BP 160 EP 166 DI 10.1097/QCO.0000000000000255 PG 7 WC Infectious Diseases SC Infectious Diseases GA DG1KK UT WOS:000371826400009 PM 26855081 ER PT J AU Brastianos, PK Santagata, S AF Brastianos, Priscilla K. Santagata, Sandro TI BRAF V600E mutations in papillary craniopharyngioma SO EUROPEAN JOURNAL OF ENDOCRINOLOGY LA English DT Review ID HAIRY-CELL LEUKEMIA; LOW-DOSE VEMURAFENIB; LONG-TERM OUTCOMES; METASTATIC MELANOMA; BETA-CATENIN; ADAMANTINOMATOUS CRANIOPHARYNGIOMA; RAPID RESPONSE; GENE-MUTATIONS; SELLAR REGION; VE1 ANTIBODY AB Papillary craniopharyngioma (PCP) is an intracranial tumor that results in high levels of morbidity. We recently demonstrated that the vast majority of these tumors harbor the oncogenic BRAF V600E mutation. The pathologic diagnosis of PCP can now be confirmed using mutation specific immunohistochemistry and targeted genetic testing. Treatment with targeted agents is now also a possibility in select situations. We recently reported a patient with a multiply recurrent PCP in whom targeting both BRAF and MEK resulted in a dramatic therapeutic response with a marked anti-tumor immune response. This work shows that activation of the MAPK pathway is the likely principal oncogenic driver of these tumors. We will now investigate the efficacy of this approach in a multicenter phase II clinical trial. Post-treatment resection samples will be monitored for the emergence of resistance mechanisms. Further advances in the non-invasive diagnosis of PCP by radiologic criteria and by cell-free DNA testing could someday allow neo-adjuvant therapy for this disease in select patient populations. C1 [Brastianos, Priscilla K.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Neurooncol, Boston, MA 02114 USA. [Santagata, Sandro] Harvard Univ, Dana Farber Canc Inst, Sch Med, Dept Canc Biol, Boston, MA 02215 USA. [Santagata, Sandro] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, 77 Ave Louis Pasteur, Boston, MA 02215 USA. [Santagata, Sandro] Harvard Univ, Sch Med, Boston Childrens Hosp, Dept Pathol, Boston, MA 02215 USA. RP Santagata, S (reprint author), Harvard Univ, Dana Farber Canc Inst, Sch Med, Dept Canc Biol, Boston, MA 02215 USA.; Santagata, S (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, 77 Ave Louis Pasteur, Boston, MA 02215 USA.; Santagata, S (reprint author), Harvard Univ, Sch Med, Boston Childrens Hosp, Dept Pathol, Boston, MA 02215 USA. EM ssantagata@bics.bwh.harvard.edu FU National Institutes of Health [K08 NS064168, K12 CA090354-11]; Brain Science Foundation; Conquer Cancer Foundation; American Brain Tumor Association; Jared Branfman Sunflowers for Life Fund for Pediatric Brain, and Spinal Cancer Research; Kid's Brain Tumor Cure Foundation; Pedals for Pediatrics; Clark Family; Stahl Family Charitable Foundation; Stop & Shop Pediatric Brain Tumor Program; Pediatric Brain Tumor Clinical and Research Fund FX This work was supported by the National Institutes of Health (K08 NS064168 and K12 CA090354-11), the Brain Science Foundation, the Conquer Cancer Foundation, the American Brain Tumor Association, the Jared Branfman Sunflowers for Life Fund for Pediatric Brain, and Spinal Cancer Research, A Kid's Brain Tumor Cure Foundation, Pedals for Pediatrics and the Clark Family, the Stahl Family Charitable Foundation, the Stop & Shop Pediatric Brain Tumor Program, and the Pediatric Brain Tumor Clinical and Research Fund. NR 58 TC 4 Z9 4 U1 3 U2 7 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0804-4643 EI 1479-683X J9 EUR J ENDOCRINOL JI Eur. J. Endocrinol. PD APR PY 2016 VL 174 IS 4 BP R139 EP R144 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DG4VX UT WOS:000372072300004 PM 26563980 ER PT J AU Yeh, JM Hur, C Ward, Z Schrag, D Goldie, SJ AF Yeh, Jennifer M. Hur, Chin Ward, Zachary Schrag, Deborah Goldie, Sue J. TI Gastric adenocarcinoma screening and prevention in the era of new biomarker and endoscopic technologies: a cost-effectiveness analysis SO GUT LA English DT Article ID HELICOBACTER-PYLORI INFECTION; SERUM PEPSINOGEN TEST; INTESTINAL METAPLASIA; UNITED-STATES; ATROPHIC GASTRITIS; LUNG-CANCER; FOLLOW-UP; PRENEOPLASTIC LESIONS; CLINICAL-IMPLICATIONS; PRECANCEROUS LESIONS AB Objective To estimate the cost-effectiveness of noncardia gastric adenocarcinoma (NCGA) screening strategies based on new biomarker and endoscopic technologies. Design Using an intestinal-type NCGA microsimulation model, we evaluated the following one-time screening strategies for US men: (1) serum pepsinogen to detect gastric atrophy (with endoscopic follow-up of positive screen results), (2) endoscopic screening to detect dysplasia and asymptomatic cancer (with endoscopic mucosal resection (EMR) treatment for detected lesions) and (3) Helicobacter pylori screening and treatment. Screening performance, treatment effectiveness, cancer and cost data were based on published literature and databases. Subgroups included current, former and never smokers. Outcomes included lifetime cancer risk and incremental cost-effectiveness ratios (ICERs), expressed as cost per quality-adjusted-life-year (QALY) gained. Results Screening the general population at age 50 years reduced the lifetime intestinal-type NCGA risk (0.24%) by 26.4% with serum pepsinogen screening, 21.2% with endoscopy and EMR and 0.2% with H. pylori screening/treatment. Targeting current smokers reduced the lifetime risk (0.35%) by 30.8%, 25.5%, and 0.1%, respectively. For all subgroups, serum pepsinogen screening was more effective and more cost-effective than all other strategies, although its ICER varied from $76 000/QALY (current smokers) to $ 105 400/QALY (general population). Results were sensitive to H. pylori prevalence, screen age and serum pepsinogen test sensitivity. Probabilistic sensitivity analysis found that at a $ 100 000/QALY willingness-to-pay threshold, the probability that serum pepsinogen screening was preferred was 0.97 for current smokers. Conclusions Although not warranted for the general population, targeting high-risk smokers for serum pepsinogen screening may be a cost-effective strategy to reduce intestinal-type NCGA mortality. C1 [Yeh, Jennifer M.; Ward, Zachary; Goldie, Sue J.] Harvard TH Chan Sch Publ Hlth, Ctr Hlth Decis Sci, 718 Huntington Ave, Boston, MA 02115 USA. [Hur, Chin] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [Schrag, Deborah] Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. RP Yeh, JM (reprint author), Harvard TH Chan Sch Publ Hlth, Ctr Hlth Decis Sci, 718 Huntington Ave, Boston, MA 02115 USA. EM jyeh@hsph.harvard.edu OI Hur, Chin/0000-0002-2819-7576 FU National Cancer Institute [K07CA143044] FX JMY was supported by the National Cancer Institute grant K07CA143044. NR 86 TC 8 Z9 8 U1 4 U2 19 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 APR PY 2016 VL 65 IS 4 BP 563 EP 574 DI 10.1136/gutjnl-2014-308588 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DG6CZ UT WOS:000372171100006 PM 25779597 ER PT J AU Tabansky, I Messina, MD Bangeranye, C Goldstein, J Blitz-Shabbir, KM Machado, S Jeganathan, V Wright, P Najjar, S Cao, YH Sands, W Keskin, DB Stern, JNH AF Tabansky, Inna Messina, Mark D. Bangeranye, Catherine Goldstein, Jeffrey Blitz-Shabbir, Karen M. Machado, Suly Jeganathan, Venkatesh Wright, Paul Najjar, Souhel Cao, Yonghao Sands, Warren Keskin, Derin B. Stern, Joel N. H. TI Advancing drug delivery systems for the treatment of multiple sclerosis (vol 63, pg 58, 2015) SO IMMUNOLOGIC RESEARCH LA English DT Correction C1 [Tabansky, Inna; Stern, Joel N. H.] Rockefeller Univ, Dept Neurobiol & Behav, 1230 York Ave, New York, NY 10021 USA. [Messina, Mark D.; Goldstein, Jeffrey; Blitz-Shabbir, Karen M.; Machado, Suly; Wright, Paul; Najjar, Souhel; Stern, Joel N. H.] Hofstra North Shore LIJ Sch Med, Dept Neurol, Hempstead, NY USA. [Messina, Mark D.; Bangeranye, Catherine; Goldstein, Jeffrey; Machado, Suly; Stern, Joel N. H.] Hofstra North Shore LIJ Sch Med, Dept Sci Educ, Hempstead, NY USA. [Jeganathan, Venkatesh; Cao, Yonghao; Stern, Joel N. H.] North Shore LIJ Hlth Syst, Feinstein Inst Med Res, Dept Autoimmun, Manhasset, NY USA. [Sands, Warren] Harvard Univ, Sch Engn & Appl Sci, Cambridge, MA 02138 USA. [Sands, Warren] Univ Pittsburgh, Med Ctr, Dept Med, Pittsburgh, PA USA. [Keskin, Derin B.] Dana Farber Harvard Canc Inst, Dept Canc Immunol & AIDS, Boston, MA USA. RP Stern, JNH (reprint author), Rockefeller Univ, Dept Neurobiol & Behav, 1230 York Ave, New York, NY 10021 USA.; Stern, JNH (reprint author), Hofstra North Shore LIJ Sch Med, Dept Neurol, Hempstead, NY USA.; Stern, JNH (reprint author), Hofstra North Shore LIJ Sch Med, Dept Sci Educ, Hempstead, NY USA.; Stern, JNH (reprint author), North Shore LIJ Hlth Syst, Feinstein Inst Med Res, Dept Autoimmun, Manhasset, NY USA. EM jstern01@rockefeller.edu NR 2 TC 0 Z9 0 U1 2 U2 3 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0257-277X EI 1559-0755 J9 IMMUNOL RES JI Immunol. Res. PD APR PY 2016 VL 64 IS 2 BP 640 EP 640 DI 10.1007/s12026-016-8791-0 PG 1 WC Immunology SC Immunology GA DG6YH UT WOS:000372231500036 PM 26895430 ER PT J AU Loucks, EB Britton, WB Howe, CJ Gutman, R Gilman, SE Brewer, J Eaton, CB Buka, SL AF Loucks, Eric B. Britton, Willoughby B. Howe, Chanelle J. Gutman, Roee Gilman, Stephen E. Brewer, Judson Eaton, Charles B. Buka, Stephen L. TI Associations of Dispositional Mindfulness with Obesity and Central Adiposity: the New England Family Study SO INTERNATIONAL JOURNAL OF BEHAVIORAL MEDICINE LA English DT Article DE Mindfulness; Obesity; Adiposity; Epidemiology; Prevention ID PHYSICAL-ACTIVITY QUESTIONNAIRE; RANDOMIZED CONTROLLED-TRIAL; WEIGHT-LOSS; SHORT-FORM; INTERVENTION; PREVALENCE; MEDITATION; SEPARATE; VALIDITY; DIETARY AB To evaluate whether dispositional mindfulness (defined as the ability to attend nonjudgmentally to one's own physical and mental processes) is associated with obesity and central adiposity. Study participants (n = 394) were from the New England Family Study, a prospective birth cohort, with median age 47 years. Dispositional mindfulness was assessed using the Mindful Attention Awareness Scale (MAAS). Central adiposity was assessed using dual-energy X-ray absorptiometry (DXA) scans with primary outcomes android fat mass and android/gynoid ratio. Obesity was defined as body mass index a parts per thousand yen30 kg/m(2). Multivariable-adjusted regression analyses demonstrated that participants with low vs. high MAAS scores were more likely to be obese (prevalence ratio for obesity = 1.34 (95 % confidence limit (CL): 1.02, 1.77)), adjusted for age, gender, race/ethnicity, birth weight, childhood socioeconomic status, and childhood intelligence. Furthermore, participants with low vs. high MAAS level had a 448 (95 % CL 39, 857) g higher android fat mass and a 0.056 (95 % CL 0.003, 0.110) greater android/gynoid fat mass ratio. Prospective analyses demonstrated that participants who were not obese in childhood and became obese in adulthood (n = 154) had -0.21 (95 % CL -0.41, -0.01; p = 0.04) lower MAAS scores than participants who were not obese in childhood or adulthood (n = 203). Dispositional mindfulness may be inversely associated with obesity and adiposity. Replication studies are needed to adequately establish whether low dispositional mindfulness is a risk factor for obesity and adiposity. C1 [Loucks, Eric B.; Howe, Chanelle J.; Eaton, Charles B.; Buka, Stephen L.] Brown Univ, Dept Epidemiol, Sch Publ Hlth, 121 South Main St, Providence, RI 02912 USA. [Britton, Willoughby B.] Brown Univ, Dept Behav & Social Sci, Sch Publ Hlth, Providence, RI 02912 USA. [Britton, Willoughby B.] Brown Univ, Dept Psychiat & Human Behav, Warren Alpert Med Sch, Providence, RI 02912 USA. [Gutman, Roee] Brown Univ, Dept Biostat, Sch Publ Hlth, Providence, RI 02912 USA. [Gilman, Stephen E.] Harvard Univ, Sch Publ Hlth, Dept Social & Behav Sci, 665 Huntington Ave, Boston, MA 02115 USA. [Gilman, Stephen E.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Gilman, Stephen E.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Brewer, Judson] Univ Massachusetts, Sch Med, Ctr Mindfulness Med Hlth Care & Soc, Worcester, MA USA. [Eaton, Charles B.] Brown Univ, Dept Family Med, Warren Alpert Med Sch, Providence, RI 02912 USA. RP Loucks, EB (reprint author), Brown Univ, Dept Epidemiol, Sch Publ Hlth, 121 South Main St, Providence, RI 02912 USA. EM eric.loucks@brown.edu OI Gilman, Stephen/0000-0002-8331-6419 FU NIH/NIA [1RC2AG036666]; NIH/NCCIH/OBBSR [UH2AT009145] FX Funding for this study was provided by NIH/NIA grant 1RC2AG036666 and NIH/NCCIH/OBBSR grant UH2AT009145. NR 52 TC 0 Z9 0 U1 2 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1070-5503 EI 1532-7558 J9 INT J BEHAV MED JI Int. J. Behav. Med. PD APR PY 2016 VL 23 IS 2 BP 224 EP 233 DI 10.1007/s12529-015-9513-z PG 10 WC Psychology, Clinical SC Psychology GA DG7HV UT WOS:000372256300012 PM 26481650 ER PT J AU Kohler, J Schuler, M Gauler, TC Nopel-Dunnebacke, S Ahrens, M Hoffmann, AC Kasper, S Nensa, F Gomez, B Hahnemann, M Breitenbuecher, F Cheufou, D Ozkan, F Darwiche, K Hoiczyk, M Reis, H Welter, S Eberhardt, WEE Eisenacher, M Teschler, H Stamatis, G Schmiegel, W Hahn, SA Baraniskin, A AF Koehler, Jens Schuler, Martin Gauler, Thomas Christoph Noepel-Duennebacke, Stefanie Ahrens, Maike Hoffmann, Andreas-Claudius Kasper, Stefan Nensa, Felix Gomez, Benedikt Hahnemann, Maria Breitenbuecher, Frank Cheufou, Danjouma Oezkan, Filiz Darwiche, Kaid Hoiczyk, Mathias Reis, Henning Welter, Stefan Eberhardt, Wilfried Ernst Erich Eisenacher, Martin Teschler, Helmut Stamatis, Georgios Schmiegel, Wolff Hahn, Stephan Albrecht Baraniskin, Alexander TI Circulating U2 small nuclear RNA fragments as a diagnostic and prognostic biomarker in lung cancer patients SO JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY LA English DT Article DE Lung cancer; RNU2-1f; Serum biomarker; Diagnostic; Prognostic; Treatment monitoring ID STANDARDIZED UPTAKE VALUE; PRIMARY TUMOR; FOLLOW-UP; MICRORNA; SURVIVAL; ADENOCARCINOMA; TOMOGRAPHY; SIGNATURE; MORTALITY; DISEASE AB Lung cancer accounts for one in five cancer deaths. Broad screening strategies for high-risk populations are unavailable, and the validation of biomarkers for early cancer detection remains a prime interest. Therefore, we investigated the value of circulating U2 small nuclear RNA fragments (RNU2-1f) as a biomarker for diagnosis, prognosis estimation and treatment monitoring in a large lung cancer cohort. We determined RNU2-1f abundance in sera of patients with treatment-naive lung cancer (n = 211, 25.6 % early stage), chronic lung disease (n = 56) and healthy controls (n = 58) by reverse transcription quantitative PCR. Initial levels and changes after one chemotherapy cycle were correlated with treatment outcomes in patient subsets. Relative serum RNU2-1f expression levels (REL) were elevated in lung cancer patients compared with patients with chronic lung disease and healthy controls (p < 0.0001). The area under the receiver operating characteristic curve for the complete data set (lung cancer vs. healthy) was 0.91 (95 % CI 0.87-0.95). By applying a REL of -4.505 as diagnostic cutoff (Youden's criterion), sensitivity and specificity reached 0.86 and 0.81, respectively. To determine the generalization error, in a subsampling study, sensitivity and specificity were estimated as 0.82 and 0.77 for the application to future, independent samples. High initial RNU2-1f REL were associated with shorter median survival in stage IIIB/IV disease (RNU2-1f(high) = 228 days/RNU2-1f(low) = 484 days; p = 0.009, log-rank test, HR1.43 95 % CI 1.23-1.66). Multivariate analysis confirmed RNU2-1f as an independent prognostic factor. Patients with subsequent RNU2-1f reduction had a trend toward better treatment outcome. Serum RNU2-1f may serve as a biomarker for lung cancer detection, prognosis prediction and treatment monitoring. C1 [Koehler, Jens; Schuler, Martin; Gauler, Thomas Christoph; Hoffmann, Andreas-Claudius; Kasper, Stefan; Breitenbuecher, Frank; Hoiczyk, Mathias; Eberhardt, Wilfried Ernst Erich] Univ Duisburg Essen, Univ Hosp Essen, West German Canc Ctr, Div Thorac Oncol,Dept Med Oncol, Hufelandstr 55, D-45122 Essen, Germany. [Schuler, Martin; Kasper, Stefan; Breitenbuecher, Frank] German Canc Consortium DKTK, D-69120 Heidelberg, Germany. [Noepel-Duennebacke, Stefanie; Hahn, Stephan Albrecht; Baraniskin, Alexander] Ruhr Univ Bochum, Dept Mol Gastrointestinal Oncol, Univ Str 150, Bochum, Germany. [Ahrens, Maike; Eisenacher, Martin] Ruhr Univ Bochum, Med Proteom Ctr, Bioinformat Biostat, Univ Str 150, Bochum, Germany. [Nensa, Felix; Hahnemann, Maria] Univ Duisburg Essen, Univ Hosp Essen, Dept Diagnost & Intervent Radiol & Neuroradiol, Essen, Germany. [Gomez, Benedikt] Univ Duisburg Essen, Univ Hosp Essen, Dept Nucl Med, Essen, Germany. [Cheufou, Danjouma; Welter, Stefan; Stamatis, Georgios] Univ Duisburg Essen, Univ Hosp Essen, Ruhrlandklin, Dept Thorac Surg, Essen, Germany. [Oezkan, Filiz; Darwiche, Kaid] Univ Duisburg Essen, Univ Hosp Essen, Ruhrlandklin, Dept Intervent Pneumonol,West German Lung Ctr, Essen, Germany. [Reis, Henning] Univ Duisburg Essen, Univ Hosp Essen, Inst Pathol, Essen, Germany. [Teschler, Helmut] Univ Duisburg Essen, Univ Hosp Essen, Ruhrlandklin, Dept Pneumonol, Essen, Germany. [Schmiegel, Wolff; Baraniskin, Alexander] Ruhr Univ Bochum, Knappschaftskrankenhaus, Dept Internal Med, Univ Str 150, Bochum, Germany. [Koehler, Jens] Harvard Univ, Sch Med, Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, 44 Binney St, Boston, MA 02115 USA. RP Kohler, J (reprint author), Univ Duisburg Essen, Univ Hosp Essen, West German Canc Ctr, Div Thorac Oncol,Dept Med Oncol, Hufelandstr 55, D-45122 Essen, Germany.; Kohler, J (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, 44 Binney St, Boston, MA 02115 USA. EM jens.koehler@uk-essen.de RI Eisenacher, Martin/J-8044-2014; OI Eisenacher, Martin/0000-0003-2687-7444; Nensa, Felix/0000-0002-5811-7100 FU Ministry of Science of North Rhine-Westphalia, Germany [PURE] FX This study was supported by the Ministry of Science of North Rhine-Westphalia, Germany (Grant number: PURE). NR 37 TC 3 Z9 4 U1 4 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0171-5216 EI 1432-1335 J9 J CANCER RES CLIN JI J. Cancer Res. Clin. Oncol. PD APR PY 2016 VL 142 IS 4 BP 795 EP 805 DI 10.1007/s00432-015-2095-y PG 11 WC Oncology SC Oncology GA DG7WS UT WOS:000372295000010 PM 26687686 ER PT J AU Sima, C Cheng, Q Rautava, J Levesque, C Sherman, P Glogauer, M AF Sima, C. Cheng, Q. Rautava, J. Levesque, C. Sherman, P. Glogauer, M. TI Identification of quantitative trait loci influencing inflammation-mediated alveolar bone loss: insights into polygenic inheritance of host-biofilm disequilibria in periodontitis SO JOURNAL OF PERIODONTAL RESEARCH LA English DT Article DE alveolar bone loss; heritability; oral dysbiosis; periodontitis; Quantitative trait locus ID GINGIVAL CREVICULAR FLUID; TRANSCRIPTION FACTOR SP3; GENOME-WIDE ASSOCIATION; PORPHYROMONAS-GINGIVALIS; CYTOKINE PROFILE; DISEASE; TISSUE; MICROBIOTA; SUSCEPTIBILITY; INFORMATION AB Background and ObjectiveThe relative contribution of genetic and environmental factors to the onset and progression of periodontitis is inconclusive. Despite the high prevalence, phenotypic heterogeneity and significant local and systemic implications of this disease, early detection and individualized therapy are problematic. Using a murine model of periodontitis in a panel of 17 recombinant inbred mice, the current study addressed the heritability of, and oral dysbiosis associated with, inflammation-mediated alveolar bone loss (iABL), the hallmark of periodontitis. Material and MethodsQuantitative trait locus (QTL) genomics and quantitative PCR for over 99% of known murine oral microbiota were used. ResultsIt was found that iABL is a polygenic trait with 32.7% heritability. One suggestive QTL, nicknamed inflammation-mediated alveolar bone loss locus (iABLL), was identified on chromosome 2. Eleven genes involved in innate immune responses and bone metabolism, particularly related to macrophage and osteoblast function, namely Etl4, Pdss1, Cobll1, 9330158F14Rik, Xirp2, Stk39, Mettl5, Metapl1, Itga6, Pdk1 and Sp3, were found in the iABLL using cis expression QTL and nonsynonymous single nucleotide polymorphism analyses. Specific oral microbiome shifts in saliva and tongue mucosa are associated with disease in this model. ConclusionOur results indicate that complex host-biofilm interactions generate pathogenic states that extend beyond subgingival biofilms and periodontal tissues. Although no temporal relationship between the onset of iABL and microbiome changes were established, our findings suggest that host factors may be responsible for pathogenic shifts in subgingival biofilms when persistent and undisturbed. C1 [Sima, C.] Forsyth Inst, Dept Appl Oral Sci, Cambridge, MA USA. [Sima, C.] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, 188 Longwood Ave, Boston, MA 02115 USA. [Sima, C.; Cheng, Q.; Glogauer, M.] Univ Toronto, Fac Dent, Matrix Dynam Grp, Toronto, ON M5S 3E2, Canada. [Rautava, J.] Univ Turku, Inst Dent, Dept Oral Pathol & Oral Radiol, Turku, Finland. [Rautava, J.; Sherman, P.] Univ Toronto, Res Inst, Hosp Sick Children, Cell Biol Program, Toronto, ON M5S 3E2, Canada. [Levesque, C.] Univ Toronto, Dept Oral Microbiol, Fac Dent, Toronto, ON M5S 3E2, Canada. RP Glogauer, M (reprint author), Univ Toronto, Fac Dent, Room 221,Fitzgerald Bldg,150 Coll St, Toronto, ON M5S 3E2, Canada. EM michael.glogauer@utoronto.ca OI Sherman, Philip/0000-0002-4733-6690; Sima, Corneliu/0000-0003-3526-4850 FU Canadian Institutes of Health Research [TBO-122068] FX Funded by Canadian Institutes of Health Research grant TBO-122068 (M.G.). NR 55 TC 0 Z9 1 U1 0 U2 5 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 APR PY 2016 VL 51 IS 2 BP 237 EP 249 DI 10.1111/jre.12303 PG 13 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA DG4JH UT WOS:000372038000011 PM 26126603 ER PT J AU Paydas, S Acikalin, A Ergin, M Celik, H Yavuz, B Tanriverdi, K AF Paydas, Semra Acikalin, Arbil Ergin, Melek Celik, Hikmet Yavuz, Basak Tanriverdi, Kahraman TI Micro-RNA (miRNA) profile in Hodgkin lymphoma: association between clinical and pathological variables SO MEDICAL ONCOLOGY LA English DT Article DE Hodgkin lymphoma; Subtype; miRNA; Prognosis; Clinicopathological correlation; Survival; qPCR; B symptom ID CIRCULATING MICRORNAS; CANCER; EXPRESSION; BIOMARKERS AB miRNAs are small RNAs and control the expression of protein-encoding genes. The aim of this study was to determine the association between miRNA profile and clinical variables including age, stage, B symptom, histopathologic subtype, response to treatment, disease-free survival (DFS) and overall survival (OS) in classical Hodgkin lymphoma (cHL). A total of 377 miRNAs were studied by qPCR in 32 cases with cHL, and results were compared with 60 samples taken from cases with reactive lymphadenopathy. Biogazelle qbasePLUS 2.0 software was used to analyze the results. miR-582-3p, miR-525-3p, miR-448, miR-512-3p, miR-642a-5p, miR-876-5p, miR-532-3p, miR-654-5p, miR128, miR-145-5p, miR-15b-5p, miR-328 and miR-660-5p were found to be decreased in cHLcompared with controls. In contrast, miR-34a-5p (2.626-fold), miR-146a-5p (4.32-fold), miR-93-5p (2.347-fold), miR-20a-5p (4.930-fold), miR-3393p (4.948-fold), miR-324-3p (4.98-fold), miR-372 (7.038fold), miR-127-3p (8.234-fold), miR-155-5p (4.947-fold), miR-320a (17.502-fold) and miR-370 (21.479-fold) (p< 0.05) were found to be increased in cHL. There was no difference in miRNA profile according to the age, sex, stage, response to treatment, DFS and OS. However, miR-889 was found to be increased in patients with B symptom and miR-127-3p was found to be increased in nodular sclerosing subtype. Some miRNAs increase and some decrease in cHL. However, there was no clinical association between clinical variables and with the majority of the miRNA profile studied in this study. miR-889 and miR-127-3p were related to B symptom and nodular sclerosis subtype, respectively. We need more studies evaluating miRNA profile and clinical outcome in Hodgkin Lymphoma. C1 [Paydas, Semra] Cukurova Univ, Fac Med, Dept Med Oncol, Adana, Turkey. [Acikalin, Arbil; Ergin, Melek] Cukurova Univ, Dept Pathol, Fac Med, Adana, Turkey. [Celik, Hikmet; Yavuz, Basak] Mersin Univ, TorosGen Biotechnol, Technoscope, Mersin, Turkey. [Tanriverdi, Kahraman] Massachusetts Gen Hosp, Dept Biochem, Boston, MA 02114 USA. RP Paydas, S (reprint author), Cukurova Univ, Fac Med, Dept Med Oncol, Adana, Turkey. EM sepay@cu.edu.tr RI Celik, Hikmet/P-1796-2016 OI Celik, Hikmet/0000-0001-7995-5712 FU Turkish Society of Hematology FX This study has been supported by Turkish Society of Hematology. NR 15 TC 1 Z9 1 U1 1 U2 4 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1357-0560 EI 1559-131X J9 MED ONCOL JI Med. Oncol. PD APR PY 2016 VL 33 IS 4 AR 34 DI 10.1007/s12032-016-0749-5 PG 5 WC Oncology SC Oncology GA DG7KK UT WOS:000372263000005 PM 26951445 ER PT J AU Keating, JJ Okusanya, OT De Jesus, E Judy, R Jiang, J Deshpande, C Nie, S Low, P Singhal, S AF Keating, Jane J. Okusanya, Olugbenga T. De Jesus, Elizabeth Judy, Ryan Jiang, Jack Deshpande, Charuhas Nie, Shuming Low, Philip Singhal, Sunil TI Intraoperative Molecular Imaging of Lung Adenocarcinoma Can Identify Residual Tumor Cells at the Surgical Margins SO MOLECULAR IMAGING AND BIOLOGY LA English DT Article DE Surgical oncology; Molecular imaging; Lung cancer; Thoracic surgery; Folate receptor alpha ID FOLATE RECEPTOR-ALPHA; FLUORESCENCE-GUIDED SURGERY; TARGETED IMMUNOTHERAPY; INFLAMMATORY DISEASES; PANCREATIC-CANCER; MOUSE MODELS; RESECTION; THERAPY; CHEMOTHERAPY; ANTIBODY AB Purpose: During lung surgery, identification of surgical margins is challenging. We hypothesized that molecular imaging with a fluorescent probe to pulmonary adenocarcinomas could enhance residual tumor during resection. Procedures: Mice with flank tumors received a contrast agent targeting folate receptor alpha. Optimal dose and time of injection was established. Margin detection was compared using traditional methods versus molecular imaging. A pilot study was then performed in three humans with lung adenocarcinoma. Results: The peak tumor-to-background ratio (TBR) of murine tumors was 3.9. Fluorescence peaked at 2 h and was not improved beyond 0.1 mg/kg. Traditional inspection identified 30 % of mice with positive margins. Molecular imaging identified an additional 50 % of residual tumor deposits (p < 0.05). The fluorescent probe visually enhanced all human tumors with a mean TBR of 3.5. Conclusions: Molecular imaging is an important adjunct to traditional inspection to identify surgical margins after tumor resection. C1 [Keating, Jane J.; Okusanya, Olugbenga T.; De Jesus, Elizabeth; Judy, Ryan; Jiang, Jack; Singhal, Sunil] Univ Penn, Dept Surg, Div Thorac Surg, Philadelphia, PA 19104 USA. [Keating, Jane J.; Okusanya, Olugbenga T.; De Jesus, Elizabeth; Judy, Ryan; Jiang, Jack; Singhal, Sunil] Philadelphia VA Med Ctr, Philadelphia, PA USA. [Deshpande, Charuhas] Univ Penn, Perelman Sch Med, Dept Pathol, Philadelphia, PA 19104 USA. [Nie, Shuming] Emory Univ, Dept Biomed Engn, Atlanta, GA 30322 USA. [Nie, Shuming] Emory Univ, Dept Chem, Atlanta, GA 30322 USA. [Low, Philip] Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. [Singhal, Sunil] Univ Penn, Sch Med, Div Thorac Surg, 6 White Bldg,3400 Spruce St, Philadelphia, PA 19104 USA. RP Singhal, S (reprint author), Univ Penn, Dept Surg, Div Thorac Surg, Philadelphia, PA 19104 USA.; Singhal, S (reprint author), Philadelphia VA Med Ctr, Philadelphia, PA USA.; Singhal, S (reprint author), Univ Penn, Sch Med, Div Thorac Surg, 6 White Bldg,3400 Spruce St, Philadelphia, PA 19104 USA. EM sunil.singhal@uphs.upenn.edu OI Low, Philip/0000-0001-9042-5528 FU National Institutes of Health [RO1CA163256] FX This work was supported by the National Institutes of Health RO1CA163256. NR 30 TC 6 Z9 6 U1 2 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1536-1632 EI 1860-2002 J9 MOL IMAGING BIOL JI Mol. Imaging. Biol. PD APR PY 2016 VL 18 IS 2 BP 209 EP 218 DI 10.1007/s11307-015-0878-9 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DG7JP UT WOS:000372260900007 PM 26228697 ER PT J AU Maye, JE Betensky, RA Gidicsin, CM Locascio, J Becker, JA Pepin, L Carmasin, J Rentz, DM Marshall, GA Blacker, D Sperling, RA Johnson, KA AF Maye, Jacqueline E. Betensky, Rebecca A. Gidicsin, Christopher M. Locascio, Joseph Becker, J. Alex Pepin, Lesley Carmasin, Jeremy Rentz, Dorene M. Marshall, Gad A. Blacker, Deborah Sperling, Reisa A. Johnson, Keith A. TI Maternal dementia age at onset in relation to amyloid burden in non-demented elderly offspring SO NEUROBIOLOGY OF AGING LA English DT Article DE PET; Family history; PiB; Amyloid-beta ID MITOCHONDRIAL CASCADE HYPOTHESIS; SPORADIC ALZHEIMERS-DISEASE; FAMILY-HISTORY; NORMAL ADULTS; NORMAL INDIVIDUALS; GENETIC RISK; BETA BURDEN; CHILDREN; PARENTS; ATROPHY AB Family history (FH) of dementia is a major risk factor for Alzheimer's disease, particularly when the FH is maternal and when the age of dementia onset (AO) is younger. This study tested whether brain amyloid-beta deposition, measured in vivo with C-11-Pittsburgh compound B (PiB), was associated with parental dementia and/or younger parental AO. Detailed FH and positron emission tomography (PiB) data were acquired in 147 nondemented aging individuals (mean age 75 +/- 8). No participant had both positive maternal and paternal FH. A series of analyses revealed that those with maternal, but not paternal, FH had greater levels of PiB retention in a global cortical region than those without FH. PiB retention in maternal FH was not significantly greater than paternal FH. Younger maternal dementia AO was related to greater PiB retention in offspring, whereas younger paternal dementia AO was not. Overall, results suggest that not only is amyloid-beta burden greater in individuals with maternal FH, but also that the burden is greater in association with younger maternal AO. (C) 2016 Elsevier Inc. All rights reserved. C1 [Maye, Jacqueline E.; Gidicsin, Christopher M.; Becker, J. Alex; Pepin, Lesley; Carmasin, Jeremy; Johnson, Keith A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA USA. [Maye, Jacqueline E.] Univ Florida, Dept Clin & Hlth Psychol, Gainesville, FL USA. [Betensky, Rebecca A.] Harvard Univ, Dept Biostat, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Locascio, Joseph; Rentz, Dorene M.; Marshall, Gad A.; Sperling, Reisa A.; Johnson, Keith A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA USA. [Carmasin, Jeremy] Univ Louisville, Dept Psychol & Brain Sci, Louisville, KY 40292 USA. [Rentz, Dorene M.; Marshall, Gad A.; Sperling, Reisa A.; Johnson, Keith A.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Blacker, Deborah] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA USA. [Blacker, Deborah] Harvard Univ, Dept Epidemiol, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. RP Johnson, KA (reprint author), Massachusetts Gen Hosp, Div Nucl Med & Mol Imaging, 55 Fruit St White 427, Boston, MA 02114 USA. EM kajohnson@pet.mgh.harvard.edu FU National Institute on Aging (NIA) [P01 AG036694, R01 AG034556, R01 AG037497, K01 AG040197]; Alzheimer's Association Zenith Award FX This research was supported by grants from the National Institute on Aging (NIA): P01 AG036694, R01 AG034556, R01 AG037497, and K01 AG040197, and the Alzheimer's Association Zenith Award. NR 55 TC 1 Z9 1 U1 3 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD APR PY 2016 VL 40 BP 61 EP 67 DI 10.1016/j.neurobiolaging.2015.12.013 PG 7 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA DG2OZ UT WOS:000371908400006 PM 26973104 ER PT J AU Yuan, A Chai, X Martins, F Arai, S Arora, M Correa, ME Pidala, J Cutler, CS Lee, SJ Treister, NS AF Yuan, A. Chai, X. Martins, F. Arai, S. Arora, M. Correa, M. E. Pidala, J. Cutler, C. S. Lee, S. J. Treister, N. S. TI Oral chronic GVHD outcomes and resource utilization: a subanalysis from the chronic GVHD consortium SO ORAL DISEASES LA English DT Article DE oral cavity; chronic graft-versus-host disease; hematopoietic cell transplantation; ancillary therapy; consensus; guidelines ID VERSUS-HOST-DISEASE; CONSENSUS DEVELOPMENT PROJECT; WORKING GROUP-REPORT; CLINICAL-TRIALS; SUPPORTIVE CARE; CRITERIA; TRANSPLANTATION; VALIDATION; MORTALITY; DIAGNOSIS AB ObjectivesThis study evaluated the extent to which oral chronic graft-versus-host disease (cGVHD) consensus assessments are predictive of management across institutions with and without oral medicine (OM) centers, and whether ancillary care guidelines are followed within clinical practice. MethodsLongitudinal oral cGVHD data were abstracted from the cGVHD Consortium, and additional mouth-specific management data were analyzed across five transplant centers. ResultsSeventy-nine patients with 656 visits were observed for a median of 7.1months with one visit per follow-up month. Ancillary therapies for oral cGVHD were prescribed for 67% of patients for a median of 0.46months (per follow-up month) at OM centers and 0.78months at non-OM centers. Patients treated with ancillary therapy were more likely to have an National Institutes of Health (NIH) mouth score of 1 (P<0.001, odds ratio: 5.1) and mouth pain (P=0.01, odds ratio: 2.6). The odds ratios of receiving ancillary therapy from OM experts were higher than transplant physicians (53%; P=0.03). ConclusionsOral cGVHD consensus assessments corresponding with ancillary therapy use were mouth pain and NIH mouth score, with higher odds ratios of receiving therapy from OM experts. Ancillary care guidelines for oral cGVHD are reflected in academic clinical practice with respect to utilization of recommended prescriptions. C1 [Yuan, A.; Treister, N. S.] Brigham & Womens Hosp, Div Oral Med, 75 Francis St, Boston, MA 02115 USA. [Yuan, A.; Treister, N. S.] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, 188 Longwood Ave, Boston, MA 02115 USA. [Chai, X.; Correa, M. E.; Lee, S. J.] Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA. [Martins, F.] Univ Sao Paulo, Sch Dent, Dept Oral Pathol & Oral Diag, Sao Paulo, Brazil. [Arai, S.] Stanford Univ, Med Ctr, Div Blood & Marrow Transplantat, Stanford, CA 94305 USA. [Arora, M.] Univ Minnesota, Dept Med, Boston, MA USA. [Correa, M. E.] State Univ Campinas UNICAMP, Hematol & Blood Transfus Ctr, Oral Med Ambulatory, Bone Marrow Transplantat Unit, Campinas, SP, Brazil. [Pidala, J.] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Blood & Marrow Transplantat, Tampa, FL 33682 USA. [Cutler, C. S.] Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA 02115 USA. RP Yuan, A (reprint author), Brigham & Womens Hosp, Div Oral Med, 75 Francis St, Boston, MA 02115 USA. EM annayuan@post.harvard.edu RI Pizzigatti Correa, Maria Elvira/J-4389-2012 OI Pizzigatti Correa, Maria Elvira/0000-0001-5714-4089 NR 29 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1354-523X EI 1601-0825 J9 ORAL DIS JI Oral Dis. PD APR PY 2016 VL 22 IS 3 BP 235 EP 240 DI 10.1111/odi.12429 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA DG8SR UT WOS:000372354400012 PM 26708609 ER PT J AU Friedlander, AH Giaconi, JA Tsui, I Aghazadehsanai, N Chang, TI Garrett, NR AF Friedlander, Arthur H. Giaconi, JoAnn A. Tsui, Irena Aghazadehsanai, Nona Chang, Tina I. Garrett, Neal R. TI Meaningful correlation between asymptomatic retinal arteriole emboli and calcified carotid plaque found on panoramic dental imaging of males with diabetes SO ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL RADIOLOGY LA English DT Article ID BEAVER DAM EYE; CHOLESTEROL EMBOLI; RADIOGRAPHY; DISEASE; ATHEROMA; STROKE; RISK; CALCIFICATIONS; DUPLEX; AID AB Objective. There is ongoing controversy with regard to the stability of calcified carotid artery plaques (CCAPs) seen in the bifurcation area on panoramic images (PIs). Therefore, we sought to evaluate the possibility of these plaques shedding emboli by observing their relationship with ipsilateral retinal emboli. Study Design. The study group included 50 neurologically and visually asymptomatic males with diabetes, with PIs that incidentally demonstrated CCAPs (CCAP+) and contemporaneous digital retinal images that had been obtained for evaluation of diabetic retinopathy. The control group consisted of 50 males with diabetes who were matched for age and body mass index and had undergone both imaging studies and whose PIs were devoid of carotid plaques (CCAP-). The presence of retinal emboli was determined by two ophthalmologists blinded to the patients' medical histories, and the prevalence rates for the two groups were calculated. Results. The presence of asymptomatic retinal arteriolar emboli was found in the eye ipsilateral to the radiographically observed carotid atheroma in 10 of 50 (20%) of the patients in the CCAP+ group, compared with 2 of 50 (4%) in the CCAP- group, and this difference was statistically significant (Fisher's exact P <.03). Conclusions. Some male patients with diabetes mellitus type II having calcified carotid artery atheromas in the bifurcation area, as visualized on PIs, may have significant sequelae as evidenced by retinal artery emboli. C1 [Friedlander, Arthur H.] Univ Calif Los Angeles, Vet Affairs Greater Los Angeles Healthcare Syst, Grad Med Educ, Los Angeles, CA USA. [Friedlander, Arthur H.] Univ Calif Los Angeles, Ronald Reagan UCLA Med Ctr, Hosp Dent Serv, Qual Assurance, Los Angeles, CA USA. [Friedlander, Arthur H.] Univ Calif Los Angeles, Sch Dent, Oral & Maxillofacial Surg, Los Angeles, CA 90024 USA. [Giaconi, JoAnn A.] Vet Affairs Greater Los Angeles Healthcare Syst, Ophthalmol, Los Angeles, CA USA. [Giaconi, JoAnn A.; Tsui, Irena] Univ Calif Los Angeles, Jules Stein Eye Inst, Los Angeles, CA USA. [Tsui, Irena] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Aghazadehsanai, Nona] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Chang, Tina I.] Univ Calif Los Angeles, Sch Dent, Vet Affairs Greater Los Angeles Healthcare Syst, Res Fellowship & Inpatient Oral & Maxillofacial S, Los Angeles, CA 90024 USA. [Chang, Tina I.] Univ Calif Los Angeles, Sch Dent, Oral & Maxillofacial Surg, Los Angeles, CA 90024 USA. [Garrett, Neal R.] Univ Calif Los Angeles, Sch Dent, Los Angeles, CA 90024 USA. RP Friedlander, AH (reprint author), VA Greater Los Angeles Healthcare Syst, Grad Med Educ, 11301 Wilshire Blvd 14, Los Angeles, CA 90073 USA. EM Arthur.friedlander@va.gov NR 29 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 2212-4403 EI 1528-395X J9 OR SURG OR MED OR PA JI Oral Surg. Oral Med. Oral Pathol. Oral Radiol. PD APR PY 2016 VL 121 IS 4 BP 434 EP 440 DI 10.1016/j.oooo.2015.12.005 PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA DG3UU UT WOS:000371996800018 PM 26972542 ER PT J AU Arvold, ND Heidari, P Kunawudhi, A Sequist, LV Mahmood, U AF Arvold, Nils D. Heidari, Pedram Kunawudhi, Anchisa Sequist, Lecia V. Mahmood, Umar TI Tumor Hypoxia Response After Targeted Therapy in EGFR-Mutant Non-Small Cell Lung Cancer: Proof of Concept for FMISO-PET SO TECHNOLOGY IN CANCER RESEARCH & TREATMENT LA English DT Article DE FMISO; PET; hypoxia; EGFR; lung cancer; erlotinib ID GROWTH-FACTOR RECEPTOR; POSITRON-EMISSION-TOMOGRAPHY; TYROSINE KINASE; F-18 FLUOROMISONIDAZOLE; SOLID TUMORS; NECK-CANCER; GEFITINIB; MUTATIONS; INHIBITION; F-18-FLUOROMISONIDAZOLE AB Hypoxia is associated with resistance to radiotherapy and chemotherapy. Functional imaging of hypoxia in non-small cell lung cancer (NSCLC) could allow early assessment of tumor response and guide subsequent therapies. Epidermal growth factor receptor (EGFR) inhibition with erlotinib reduces hypoxia in vivo. [18F]-Fluoromisonidazole (FMISO) is a radiolabeled tracer that selectively accumulates in hypoxic cells. We sought to determine whether FMISO positron emission tomography (FMISO-PET) could detect changes in hypoxia in vivo in response to EGFR-targeted therapy. In a preclinical investigation, nude mice with human EGFR-mutant lung adenocarcinoma xenografts underwent FMISO-PET scans before and 5 days after erlotinib or empty vehicle initiation. Descriptive statistics and analysis of variance (ANOVA) tests were used to analyze changes in standardized uptake value (SUV), with pooled analyses for the mice in each group (baseline, postvehicle, and posterlotinib). In a small correlative pilot human study, patients with EGFR-mutant metastatic NSCLC underwent FMISO-PET scans before and 10 to 12 days after erlotinib initiation. Changes in SUV were compared to standard chest computed tomography (CT) scans performed 6 weeks after erlotinib initiation. The mean (+/- standard error of the mean; SUVmean) of the xenografts was 0.17 +/- 0.014, 0.14 +/- 0.008, and 0.06 +/- 0.004 for baseline, postvehicle, and posterlotinib groups, respectively, with lower SUVmean among the posterlotinib group compared to other groups (P < .05). Changes on preclinical PET imaging were striking, with near-complete disappearance of FMISO uptake after erlotinib initiation. Two patients were enrolled on the pilot study. In the first patient, SUVmean increased by 21% after erlotinib, with progression on 6-week chest CT followed by death after 4.8 months. In the second patient, SUVmean decreased by 7% after erlotinib, with regression on 6-week chest CT accompanied by clinical improvement; the patient had stable disease at 14.5 months. In conclusion, we observed that FMISO-PET can detect changes in hypoxia levels after EGFR-directed therapy in EGFR-mutant NSCLC. Further study is warranted to determine its utility as an imaging biomarker of early response to EGFR-directed therapy. C1 [Arvold, Nils D.] Dana Farber Brigham & Womens Canc Ctr, Dept Radiat Oncol, 75 Francis St,ASBI L2, Boston, MA 02115 USA. [Heidari, Pedram; Kunawudhi, Anchisa; Mahmood, Umar] Massachusetts Gen Hosp, Dept Radiol, Div Nucl Med & Mol Imaging, Boston, MA USA. [Sequist, Lecia V.] Massachusetts Gen Hosp, Dept Med, Div Hematol & Oncol, Boston, MA 02114 USA. RP Arvold, ND (reprint author), Dana Farber Brigham & Womens Canc Ctr, Dept Radiat Oncol, 75 Francis St,ASBI L2, Boston, MA 02115 USA. EM narvold@partners.org FU Radiological Society of North America [RR1040] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by Radiological Society of North America grant RR1040 to N.D.A. NR 32 TC 2 Z9 2 U1 1 U2 7 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1533-0346 EI 1533-0338 J9 TECHNOL CANCER RES T JI Technol. Cancer Res. Treat. PD APR PY 2016 VL 15 IS 2 BP 234 EP 242 DI 10.1177/1533034615574386 PG 9 WC Oncology SC Oncology GA DG5YR UT WOS:000372158600003 PM 25759424 ER PT J AU Park, YK Sharp, GC AF Park, Yang-Kyun Sharp, Gregory C. TI Gain Correction for an X-ray Imaging System With a Movable Flat Panel Detector and Intrinsic Localization Crosshair SO TECHNOLOGY IN CANCER RESEARCH & TREATMENT LA English DT Article DE gain correction; moving panel; heel effect; intrinsic obstacle ID FIELD NONUNIFORMITY; QUANTUM EFFICIENCY; ELIMINATION; RADIOGRAPHY; IMAGES AB Gain calibration for X-ray imaging systems with a movable flat panel detector and an intrinsic crosshair is a challenge due to the geometry-dependent heel effect and crosshair artifact. This study aims to develop a gain correction method for such systems by implementing the Multi-Acquisition Gain Image Correction technique. Flood field images containing crosshair and heel effect were acquired in 4 different flat panel detector positions at fixed exposure parameters. The crosshair region was automatically detected using common image processing algorithms and removed by a simple interpolation procedure, resulting in a crosshair-removed image. A large kernel-based correction was then used to remove the heel effect. Mask filters corresponding to each crosshair region were applied to the resultant heel effect-removed images to invalidate the pixels of the original crosshair region. Finally, a seamless gain map was composed with corresponding valid pixels from the processed images either by the sequential replacement or by the selective averaging techniques developed in this study. Quantitative evaluation was performed based on normalized noise power spectrum and detective quantum efficiency improvement factor for the flood field images corrected by the Multi-Acquisition Gain Image Correction-based gain maps. For comparison purposes, a single crosshair-removed gain map was also tested. As a result, it was demonstrated that the Multi-Acquisition Gain Image Correction technique achieved better image quality than the crosshair-removed technique, showing lower normalized noise power spectrum values over most of spatial frequencies. The improvement was more obvious at the priori-crosshair region of the gain map. The mean detective quantum efficiency improvement factor was 1.09 +/- 0.06, 2.46 +/- 0.32, and 3.34 +/- 0.36 in the priori-crosshair region and 2.35 +/- 0.31, 2.33 +/- 0.31, and 3.09 +/- 0.34 in the normal region, for crosshair-removed, Multi-Acquisition Gain Image Correction-sequential replacement, and Multi-Acquisition Gain Image Correction-selective averaging techniques, respectively. Therefore, this study indicates that the introduced Multi-Acquisition Gain Image Correction technique is an appropriate method for gain calibration of an imaging system associated with a moving flat panel detector and an intrinsic crosshair. C1 [Park, Yang-Kyun; Sharp, Gregory C.] Massachusetts Gen Hosp, Dept Radiat Oncol, 55 Fruit St, Boston, MA 02114 USA. RP Park, YK (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, 55 Fruit St, Boston, MA 02114 USA. EM theday79@gmail.com FU NIH [P01-CA021239-29A1]; NIH/MGH Federal Share [C06CA059267] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported in part by NIH P01-CA021239-29A1 and NIH/MGH Federal Share C06CA059267. NR 12 TC 1 Z9 1 U1 1 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1533-0346 EI 1533-0338 J9 TECHNOL CANCER RES T JI Technol. Cancer Res. Treat. PD APR PY 2016 VL 15 IS 2 BP 387 EP 395 DI 10.1177/1533034615576829 PG 9 WC Oncology SC Oncology GA DG5YR UT WOS:000372158600019 PM 25795048 ER PT J AU Heyman, SN Leibowitz, D Levi, IMY Liberman, A Eisenkraft, A Alcalai, R Khamaisi, M Rosenberger, C AF Heyman, S. N. Leibowitz, D. Levi, I. Mor-Yosef Liberman, A. Eisenkraft, A. Alcalai, R. Khamaisi, M. Rosenberger, C. TI Adaptive response to hypoxia and remote ischaemia pre-conditioning: a new hypoxia-inducible factors era in clinical medicine SO ACTA PHYSIOLOGICA LA English DT Review DE heart; hypoxia; hypoxia-inducible factors; kidney; pre-conditioning; prolyl hydroxylase ID RANDOMIZED-CONTROLLED-TRIAL; ACUTE KIDNEY INJURY; AORTIC-ANEURYSM REPAIR; BYPASS GRAFT-SURGERY; MYOCARDIAL-INFARCTION; INDUCED CARDIOPROTECTION; PROLYL 4-HYDROXYLASES; CEREBRAL-ISCHEMIA; ELDERLY-PATIENTS; CARDIAC-SURGERY AB Transient ischaemia leads to tolerance to subsequent protracted ischaemia. This ischaemia pre-conditioning' results from the induction of numerous protective genes, involved in cell metabolism, proliferation and survival, in antioxidant capacity, angiogenesis, vascular tone and erythropoiesis. Hypoxia-inducible factors (HIF) play a pivotal role in this transcriptional adaptive response. HIF prolyl hydroxylases (PHDs), serving as oxygen sensors, control HIF degradation. HIF-mediated ischaemic pre-conditioning can be achieved with the administration of PHD inhibitors, with the attenuation of organ injury under various hypoxic and toxic insults. Clinical trials are currently under way, evaluating PHD inhibitors as inducers of erythropoietin. Once their safety is established, their potential use might be further tested in clinical trials in various forms of acute ischaemic and toxic organ damage. Repeated transient limb ischaemia was also found to attenuate ischaemic injury in remote organs. This remote ischaemic pre-conditioning' phenomenon (RIP) has been extensively studied recently in small clinical trials, preceding, or in parallel with an abrupt insult, such as myocardial infarction, cardiac surgery or radiocontrast administration. Initial results are promising, suggesting organ protection. Large-scale multi-centre studies are currently under way, evaluating the protective potential of RIP in cardiac surgery, in the management of myocardial infarction and in organ transplantation. The mechanisms of organ protection provided by RIP are poorly understood, but HIF seemingly play a role as well. Thus, Inhibition of HIF degradation with PHD inhibitors, as well as RIP (in part through HIF), might develop into novel clinical interventions in organ protection in the near future. C1 [Heyman, S. N.; Leibowitz, D.; Alcalai, R.] Hadassah Hebrew Univ Hosp, Dept Med, Jerusalem, Israel. [Leibowitz, D.; Alcalai, R.] Hadassah Hebrew Univ Hosp, Dept Cardiol, Jerusalem, Israel. [Levi, I. Mor-Yosef] Hadassah Hebrew Univ Hosp, Dept Nephrol, Jerusalem, Israel. [Liberman, A.] Hadassah Hebrew Univ Hosp, Dept Neurol, Jerusalem, Israel. [Eisenkraft, A.] Hebrew Univ Jerusalem, Sch Med, Res Inst Mil Med, IL-91010 Jerusalem, Israel. [Eisenkraft, A.] Israeli Def Force Med Corps, Jerusalem, Israel. [Khamaisi, M.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Rosenberger, C.] Charite, Dept Nephrol, D-13353 Berlin, Germany. RP Heyman, SN (reprint author), Hadassah Hebrew Univ Hosp, Dept Med, POB 24035, IL-91240 Jerusalem, Israel. EM heyman@cc.huji.ac.il FU Akebia; FibroGen FX CR participates in clinical studies by Astellas and Astra-Zeneca and has received consulting fees from Akebia. SNH conducted laboratory studies funded by FibroGen. NR 71 TC 7 Z9 7 U1 5 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1748-1708 EI 1748-1716 J9 ACTA PHYSIOL JI Acta Physiol. PD APR PY 2016 VL 216 IS 4 BP 395 EP 406 DI 10.1111/apha.12613 PG 12 WC Physiology SC Physiology GA DF8TL UT WOS:000371632100005 PM 26449466 ER PT J AU Sun, M Trinh, QD AF Sun, Maxine Quoc-Dien Trinh TI A Surveillance, Epidemiology and End Results (SEER) database malfunction: perceptions, pitfalls and verities SO BJU INTERNATIONAL LA English DT Editorial Material ID RADICAL PROSTATECTOMY; RADIOTHERAPY; CANCER C1 [Sun, Maxine; Quoc-Dien Trinh] Harvard Univ, Sch Med,Ctr Surg & Publ Hlth, Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Trinh, QD (reprint author), Brigham & Womens Hosp, Urol ASB 2 3, 45 Francis St, Boston, MA 02115 USA. EM qtrinh@partners.org NR 6 TC 3 Z9 3 U1 1 U2 1 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 APR PY 2016 VL 117 IS 4 BP 551 EP 552 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA DG3FT UT WOS:000371955600012 PM 26190064 ER PT J AU Park, JM Storch, EA Pinto, A Lewin, AB AF Park, Jennifer M. Storch, Eric A. Pinto, Anthony Lewin, Adam B. TI Obsessive-Compulsive Personality Traits in Youth with Obsessive-Compulsive Disorder SO CHILD PSYCHIATRY & HUMAN DEVELOPMENT LA English DT Article DE Obsessive compulsive personality disorder; Obsessive compulsive disorder; Perfectionism; Youth ID MULTIDIMENSIONAL ANXIETY SCALE; PSYCHOMETRIC PROPERTIES; CHILD VERSION; PERFECTIONISM; RELIABILITY; ADOLESCENTS; IMPAIRMENT; PREVALENCE; INVENTORY; VALIDITY AB While interest in the relationship between obsessive-compulsive disorder (OCD) and obsessive compulsive personality disorder has increased, there are currently no studies that have examined the presence of obsessive compulsive personality traits (OCPTs) in youth. The current study sought to determine the latent factors and psychometric properties of a modified version of the Childhood Retrospective Perfectionism Questionnaire (CHIRP) and examine the correlates of specific OCPTs (e.g., rigidity, perfectionism) in youth with OCD. Participants included 96 treatment-seeking youth diagnosed with primary OCD (and a parent). Parents and youth completed measures of OCPTs, OCD severity, depression, and disability. A confirmatory factor analysis of the modified CHIRP resulted in a two-factor model: perfectionism and preoccupation with details. The CHIRP and its subscales demonstrated acceptable internal consistency and preliminary evidence for convergent and divergent validity. Obsessive compulsive traits in youth were also found to be associated with the checking, symmetry and contamination symptom dimensions. C1 [Park, Jennifer M.] Massachusetts Gen Hosp, Child CBT Program, 151 Merrimac St,3rd Floor, Boston, MA 02114 USA. [Storch, Eric A.; Lewin, Adam B.] Univ S Florida, Dept Psychol, Tampa, FL 33620 USA. [Storch, Eric A.; Lewin, Adam B.] Univ S Florida, Dept Pediat, Tampa, FL 33620 USA. [Storch, Eric A.; Lewin, Adam B.] Univ S Florida, Dept Psychiat & Behav Neurosci, Tampa, FL USA. [Pinto, Anthony] North Shore LIJ Hlth Syst, Zucker Hillside Hosp, Div Psychiat Res, Glen Oaks, NY USA. [Pinto, Anthony] Hofstra North Shore LIJ Sch Med, Dept Psychiat, Hempstead, NY USA. RP Park, JM (reprint author), Massachusetts Gen Hosp, Child CBT Program, 151 Merrimac St,3rd Floor, Boston, MA 02114 USA. EM jpark12@mgh.harvard.edu RI Pinto, Anthony/D-2718-2017 OI Pinto, Anthony/0000-0002-6078-7242 NR 43 TC 1 Z9 1 U1 5 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-398X EI 1573-3327 J9 CHILD PSYCHIAT HUM D JI Child Psychiat. Hum. Dev. PD APR PY 2016 VL 47 IS 2 BP 281 EP 290 DI 10.1007/s10578-015-0565-8 PG 10 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA DF8KN UT WOS:000371606700011 PM 26160348 ER PT J AU Wen, JC Jiang, FG Yeh, CK Sun, YY AF Wen, Jianchuan Jiang, Fuguang Yeh, Chih-Ko Sun, Yuyu TI Controlling fungal biofilms with functional drug delivery denture biomaterials SO COLLOIDS AND SURFACES B-BIOINTERFACES LA English DT Article DE Denture; Grafting; Drug delivery; Fungal; Biofilm-controlling ID IN-VITRO; BIOMEDICAL APPLICATIONS; SILVER NANOPARTICLES; SURFACE MODIFICATION; ANTIFUNGAL ACTIVITY; MICONAZOLE-NITRATE; CANDIDA-ALBICANS; STOMATITIS; PLASMA; ETIOLOGY AB Candida-associated denture stomatitis (CADS), caused by colonization and biofilm-formation of Candida species on denture surfaces, is a significant clinical concern. We show here that modification of conventional denture materials with functional groups can significantly increase drug binding capacity and control drug release rate of the resulting denture materials for potentially managing CADS. In our approach, poly(methyl methacrylate) (PMMA)-based denture resins were surface grafted with three kinds of polymers, poly(1-vinyl-2-pyrrolidinone) (PNVP), poly(methacrylic acid) (PMAA), and poly(2-hydroxyethyl methacrylate) (PHEMA), through plasma-initiated grafting polymerization. With a grafting yield as low as 2 wt%, the three classes of new functionalized denture materials showed significantly higher drug binding capacities toward miconazole, a widely used antifungal drug, than the original PMMA denture resin control, leading to sustained drug release and potent biofilm-controlling effects against Candida. Among the three classes of functionalized denture materials, PNVP-grafted resin provided the highest miconazole binding capability and the most powerful antifungal and biofilm-controlling activities. Drug binding mechanisms were studied. These results demonstrated the importance of specific interactions between drug molecules and functional groups on biomaterials, shedding lights on future design of CADS-managing denture materials and other related devices for controlled drug delivery. (C) 2015 Elsevier B.V. All rights reserved. C1 [Wen, Jianchuan; Jiang, Fuguang; Sun, Yuyu] Univ Massachusetts, Dept Chem, Lowell, MA 01854 USA. [Yeh, Chih-Ko] South Texas Vet Hlth Care Syst, Audie L Murphy Div, Geriatr Res Educ & Clin Ctr, San Antonio, TX 78229 USA. [Yeh, Chih-Ko] Univ Texas Hlth Sci Ctr San Antonio, Dept Comprehens Dent, San Antonio, TX 78229 USA. RP Sun, YY (reprint author), Univ Massachusetts, Dept Chem, Lowell, MA 01854 USA. EM yuyu_sun@uml.edu FU NIDCR, NIH [R01 DE021084]; VA Merit Review [1I01BX001103] FX This study was supported by NIDCR, NIH (R01 DE021084) and VA Merit Review (1I01BX001103). NR 51 TC 3 Z9 3 U1 8 U2 26 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0927-7765 EI 1873-4367 J9 COLLOID SURFACE B JI Colloid Surf. B-Biointerfaces PD APR 1 PY 2016 VL 140 BP 19 EP 27 DI 10.1016/j.colsurfb.2015.12.028 PG 9 WC Biophysics; Chemistry, Physical; Materials Science, Biomaterials SC Biophysics; Chemistry; Materials Science GA DF6DG UT WOS:000371445500003 PM 26731194 ER PT J AU Li, YP Gao, X Winkelman, J Cespedes, E Jackson, C Walters, A Schernhammer, E Redline, S Hu, FB AF Li, Yanping Gao, Xiang Winkelman, John W. Cespedes, Elizabeth M. Jackson, Chandra L. Walters, Arthur S. Schernhammer, Eva Redline, Susan Hu, Frank B. TI Association between sleeping difficulty and type 2 diabetes in women SO DIABETOLOGIA LA English DT Article DE Diabetes; Pathways; Sleeping difficulty ID PHYSICAL-ACTIVITY; POPULATION; MELLITUS; RISK; MEN; INSOMNIA; DURATION; DISTURBANCES; METAANALYSIS; DISRUPTION AB Aims/hypothesis Sleeping difficulty has been associated with type 2 diabetes in some prior studies. Whether the observed associations are independent of health behaviours, other cardiovascular risk factors or other sleep disorders is unclear. Methods We analysed data from 133,353 women without diabetes, cardiovascular disease and cancer at baseline in the Nurses' Health Study (NHS, 2000-2010) and the NHSII (2001-2011). Sleeping difficulty was assessed as having difficulty falling or staying asleep 'all of the time' or 'most of the time' at baseline (2000 in NHS and 2001 in NHSII). Results We documented 6,407 incident cases of type 2 diabetes during up to 10 years of follow-up. After adjustment for lifestyle factors at baseline, comparing women with and without sleeping difficulty, the multivariate-adjusted HR (95% CI) for type 2 diabetes was 1.45 (95% CI 1.33, 1.58), which changed to 1.22 (95% CI 1.12, 1.34) after further adjustment for hypertension, depression and BMI based on the updated repeated measurements. Women who reported all four sleep conditions (sleeping difficulty, frequent snoring, sleep duration <= 6 h and sleep apnoea in NHS or rotating shift work in NHSII) had more than a fourfold increased likelihood of type 2 diabetes (HR 4.17, 95% CI 2.93, 5.91). Conclusions/interpretation Sleeping difficulty was significantly associated with type 2 diabetes. This association was partially explained by associations with hypertension, BMI and depression symptoms, and was particularly strong when combined with other sleep disorders. Our findings highlight the importance of sleep disturbance in the development and prevention of type 2 diabetes. C1 [Li, Yanping; Cespedes, Elizabeth M.; Hu, Frank B.] Harvard Univ, Dept Nutr, TH Chan Sch Publ Hlth, 665 Huntington Ave, Boston, MA 02115 USA. [Gao, Xiang] Penn State Univ, Dept Nutr Sci, University Pk, PA 16802 USA. [Winkelman, John W.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Winkelman, John W.] Massachusetts Gen Hosp, Sleep Disorders Clin Res Program, Dept Psychiat & Neurol, Boston, MA 02114 USA. [Cespedes, Elizabeth M.; Jackson, Chandra L.; Schernhammer, Eva; Redline, Susan; Hu, Frank B.] Harvard Univ, Dept Epidemiol, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Cespedes, Elizabeth M.] Kaiser Permanente Calif, Div Res, Oakland, CA USA. [Jackson, Chandra L.] Harvard Catalyst Clin & Translat Sci Ctr, Boston, MA USA. [Walters, Arthur S.] Vanderbilt Univ, Med Ctr, Sch Med, Nashville, TN 37232 USA. [Redline, Susan] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Redline, Susan] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02115 USA. [Hu, Frank B.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Hu, Frank B.] Harvard Univ, Sch Med, Boston, MA USA. RP Hu, FB (reprint author), Harvard Univ, Dept Nutr, TH Chan Sch Publ Hlth, 665 Huntington Ave, Boston, MA 02115 USA.; Hu, FB (reprint author), Harvard Univ, Dept Epidemiol, TH Chan Sch Publ Hlth, Boston, MA 02115 USA.; Hu, FB (reprint author), Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA.; Hu, FB (reprint author), Harvard Univ, Sch Med, Boston, MA USA. EM nhbfh@channing.harvard.edu RI Jackson, Chandra/A-6291-2017; OI Jackson, Chandra/0000-0002-0915-8272; Cespedes Feliciano, Elizabeth/0000-0003-1192-4017 FU NIH [UM1 CA186107, UM1 CA176726] FX The Study was supported by NIH grants UM1 CA186107 and UM1 CA176726. NR 35 TC 3 Z9 3 U1 0 U2 7 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 APR PY 2016 VL 59 IS 4 BP 719 EP 727 DI 10.1007/s00125-015-3860-9 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DG1CK UT WOS:000371802700010 PM 26818148 ER PT J AU Oto, J Su, ZB Duggan, M Wang, JW King, DR Kacmarek, RM Jiang, YD AF Oto, Jun Su, Zhenbo Duggan, Michael Wang, Jingwen King, David R. Kacmarek, Robert M. Jiang, Yandong TI Efficacy of coaxial ventilation with a novel endotracheal catheter equipped with a functional cuff A swine model study SO EUROPEAN JOURNAL OF ANAESTHESIOLOGY LA English DT Article ID AIRWAY EXCHANGE CATHETER; FREQUENCY JET VENTILATION; SURGERY; TUBE; COMPLICATIONS; PNEUMOTHORAX; PRESSURE AB BACKGROUND We have developed an endotracheal catheter with a functional cuff (ECFC) that inflates during inspiration and deflates during expiration. This catheter, together with a regular ICU ventilator, can provide coaxial ventilation. OBJECTIVE The aim of this study was to determine the efficacy of ventilation in adult human-sized swine using an ECFC and a regular ICU ventilator. DESIGN A prospective animal study. SETTING Experimental, Trauma Transplant Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA. ANIMALS Eight adult Yorkshire swine, weighing 45 to 50 kg, were studied. INTERVENTIONS To create the ECFC, a 5 cm long latex cuff was placed over the distal side ports of either a 14 or 19-Fr gauge endotracheal catheter and a 1 cm long piece of plastic tube was inserted into the tip of the endotracheal catheter to create an internal resistance. The ECFC was placed into the trachea and the proximal end of the ECFC was connected to an ICU ventilator in pressure-control mode, with peak pressures set at either 25, 50 or 70 cmH(2)O. MAIN OUTCOME MEASURES Tidal volume was calculated using plethysmography. RESULTS During pressure control ventilation with the 14-Fr gauge ECFC at set inspiratory pressures of 25, 50 and 75 cmH(2)O, the tidal volumes generated were 209 +/- 36, 309 +/- 61 and 367 +/- 85 ml, respectively, and with the 19-Fr gauge ECFC these were 277 +/- 51, 442 +/- 91 and 538 +/- 123 ml, respectively. No complications were observed. CONCLUSION An ECFC combined with a regular pressure-controlled ICU ventilator can produce adequate tidal volumes in adult human-sized swine. Our results establish the feasibility of ventilation with this new alternative technique. The safety and advantages of such a technique remain to be determined in humans. C1 [Oto, Jun] Tokushima Univ Hosp, Emergency & Crit Care Med, Tokushima, Japan. [Su, Zhenbo; Wang, Jingwen] Massachusetts Gen Hosp, Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Duggan, Michael; King, David R.] Massachusetts Gen Hosp, Trauma Transplant Surg, Boston, MA 02114 USA. [Kacmarek, Robert M.] Massachusetts Gen Hosp, Resp Care Serv, Boston, MA 02114 USA. [Jiang, Yandong] Vanderbilt Univ, Anesthesiol Clin, 1211 Med Ctr Dr, Nashville, TN 37232 USA. RP Jiang, YD (reprint author), Vanderbilt Univ, Anesthesiol Clin, 1211 Med Ctr Dr, Nashville, TN 37232 USA. EM yandong.jiang@vanderbilt.edu FU Covidien; Venner Medical FX RMK is a consultant for Covidien and has been in receipt of a research grant from both Covidien and Venner Medical. NR 21 TC 0 Z9 0 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0265-0215 EI 1365-2346 J9 EUR J ANAESTH JI Eur. J. Anaesth. PD APR PY 2016 VL 33 IS 4 BP 250 EP 256 DI 10.1097/EJA.0000000000000359 PG 7 WC Anesthesiology SC Anesthesiology GA DF8TV UT WOS:000371633400006 PM 26479512 ER PT J AU Pereira, FR Macri, F Jackowski, MP Kostis, WJ Gris, JC Beregi, JP Mekkaoui, C AF Pereira, Fabricio R. Macri, Francesco Jackowski, Marcel P. Kostis, William J. Gris, Jean-Christophe Beregi, Jean-Paul Mekkaoui, Choukri TI Diffusion tensor imaging in patients with obstetric antiphospholipid syndrome without neuropsychiatric symptoms SO EUROPEAN RADIOLOGY LA English DT Article DE Diffusion tensor imaging; Magnetic resonance imaging; White matter; Antiphospholipid syndrome; Pregnancy ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; NEUROLOGICAL MANIFESTATIONS; SPATIAL STATISTICS; MOUSE MODEL; ANTIBODIES; BRAIN; ASSOCIATION; IMAGES; BINDING; CHOREA AB Objectives To evaluate white matter (WM) integrity in neurologically asymptomatic antiphospholipid syndrome (APS) using diffusion tensor imaging (DTI) in women with no thrombotic history but with pregnancy loss. Methods Imaging was performed with a 3 T scanner using structural MRI (T1-weighted, fluid attenuation inversion recovery [FLAIR]) and DTI sequences in 66 women with APS and a control group of 17 women. Women with APS were further categorized as positive for lupus anticoagulant (LA) and/or a beta 2GPI-G antibodies (LA/a beta 2GPI-G-positive, N = 29) or negative (LA/a beta 2GPI-G-negative, N = 37) for both. Tract-based spatial statistics of standard DTI-based indices were compared among groups. Results Women with APS had significantly lower fractional anisotropy (p < 0.05) associated with higher mean diffusivity and radial diffusivity compared to the control group. There was a stronger association of abnormal DTI features among women positive for LA and/or a beta 2GPI-IgG antibodies than those who were negative. Conclusions DTI appears sensitive to subtle WM changes in women with APS with no thrombotic history but with pregnancy loss, compatible with alterations in axonal structure and in the myelin sheath. The preferential association of abnormal DTI features with the two most pathogenic aPLAbs reinforces the pathophysiological relevance of our findings. C1 [Pereira, Fabricio R.; Macri, Francesco; Beregi, Jean-Paul; Mekkaoui, Choukri] Univ Hosp Ctr Nimes, Dept Radiol, Nimes, France. [Pereira, Fabricio R.; Macri, Francesco; Beregi, Jean-Paul; Mekkaoui, Choukri] Res Team EA 2415, Nimes, France. [Macri, Francesco; Gris, Jean-Christophe; Beregi, Jean-Paul; Mekkaoui, Choukri] Univ Montpellier, Fac Med, F-34059 Montpellier, France. [Jackowski, Marcel P.] Univ Sao Paulo, Inst Math & Stat, Dept Comp Sci, Sao Paulo, Brazil. [Kostis, William J.; Mekkaoui, Choukri] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Kostis, William J.; Mekkaoui, Choukri] Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Gris, Jean-Christophe] Univ Hosp Ctr Nimes, Dept & Lab Hematol, Nimes, France. RP Mekkaoui, C (reprint author), Univ Hosp Ctr Nimes, Dept Radiol, Nimes, France.; Mekkaoui, C (reprint author), Res Team EA 2415, Nimes, France.; Mekkaoui, C (reprint author), Univ Montpellier, Fac Med, F-34059 Montpellier, France.; Mekkaoui, C (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA.; Mekkaoui, C (reprint author), Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. EM mekkaoui@nmr.mgh.harvard.edu NR 37 TC 0 Z9 0 U1 2 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0938-7994 EI 1432-1084 J9 EUR RADIOL JI Eur. Radiol. PD APR PY 2016 VL 26 IS 4 BP 959 EP 968 DI 10.1007/s00330-015-3922-x PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DF8RE UT WOS:000371625100005 PM 26201292 ER PT J AU Kaz, AM Anwar, A O'Neill, DR Dominitz, JA AF Kaz, Andrew M. Anwar, Asma O'Neill, Darby Robinson Dominitz, Jason A. TI Use of a novel polyp "ruler snare" improves estimation of colon polyp size SO GASTROINTESTINAL ENDOSCOPY LA English DT Article ID SOCIETY-TASK-FORCE; COLORECTAL-CANCER; COLONOSCOPY SURVEILLANCE; POLYPECTOMY; ACCURATE; GUIDELINE AB Background and Aims: Prior studies have demonstrated that endoscopists' estimates of polyp size are imprecise. The aim of this study was to determine whether a modified polypectomy "ruler snare" improves the accuracy of assessment of polyp size in real time without the use of additional devices. Methods: Ten artificial polyps of predetermined sizes (4 to 25 mm) were affixed to the inside of a colon model. A standard polypectomy snare was modified by adding 5-mm graduated markings to the distal end of the plastic sheath. Study participants estimated the sizes of the artificial polyps during simulated colonoscopies, first using a standard snare and then with the modified ruler snare. Results: Thirty-four private practice and academic gastroenterologists participated in the study. Endoscopists' ability to accurately classify polyps by size (diminutive, small, or large) improved from 48.5% to 60.3% with the ruler snare (P = .002). The greatest improvement in precision was seen among the large polyps, where accuracy increased from 35.9% to 58.2% with use of the ruler snare (P < .0001). Participants underestimated polyp size by a mean of 3.6 mm (interquartile range, -5 to -2 mm) with the standard snare and 1.8 mm (interquartile range, -3 to 0 mm) with the ruler snare, which corresponded to a 44.2% improvement in accuracy with the ruler snare (P < .05). Conclusions: The modified ruler snare improved polyp size assessment compared with a standard snare, particularly with large polyps. Overall, although size estimation continues to be imprecise, the addition of calibrated markings to a polypectomy snare is a simple and likely low-cost means to improve neoplasia surveillance recommendations. C1 [Kaz, Andrew M.; Dominitz, Jason A.] VA Puget Sound Hlth Care Syst, Gastroenterol Sect, Seattle, WA USA. [Kaz, Andrew M.; Anwar, Asma; Dominitz, Jason A.] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. [O'Neill, Darby Robinson] Everett Clin, Gastroenterol & Liver Dis, Everett, WA USA. RP Dominitz, JA (reprint author), VA Puget Sound Hlth Care Syst, 1660 S Columbian Way,S-111 Gastro, Seattle, WA 98108 USA. OI Dominitz, Jason/0000-0002-8070-7086 NR 16 TC 1 Z9 1 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0016-5107 EI 1097-6779 J9 GASTROINTEST ENDOSC JI Gastrointest. Endosc. PD APR PY 2016 VL 83 IS 4 BP 812 EP 816 DI 10.1016/j.gie.2015.08.082 PG 5 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DG2JX UT WOS:000371894300023 PM 26382052 ER PT J AU Kreitchmann, R Coelho, DF Kakehasi, FM Hofer, CB Read, JS Losso, M Haberer, JE Siberry, GK Harris, DR Yu, QL AF Kreitchmann, Regis Coelho, Debora Fernandes Kakehasi, Fabiana Maria Hofer, Cristina Barroso Read, Jennifer S. Losso, Marcelo Haberer, Jessica E. Siberry, George K. Harris, D. Robert Yu, Qilu TI Long-term postpartum adherence to antiretroviral drugs among women in Latin America SO INTERNATIONAL JOURNAL OF STD & AIDS LA English DT Article DE HIV; AIDS; treatment; women; antiretroviral; adherence; postpartum; mother-to-child transmission ID HUMAN-IMMUNODEFICIENCY-VIRUS; SELF-REPORTED ADHERENCE; TO-CHILD TRANSMISSION; HIV-INFECTED PATIENTS; MEDICATION ADHERENCE; THERAPY ADHERENCE; INTERAGENCY HIV; PREGNANT-WOMEN; UNITED-STATES; METAANALYSIS AB Antiretroviral adherence in the postpartum period is crucial for maternal health and decreasing the risk of mother-to-child HIV transmission and transmission to sexual partners. Self-reported antiretroviral adherence was examined between 6- to 12-weeks and 30 months postpartum among 270 HIV-infected women enrolled in a prospective cohort study from 2008 to 2010 at multiple sites in Latin America. Adherence data were collected at each study visit to quantify the proportion of prescribed antiretrovirals taken during the previous three days, assess the timing of the last missed dose, and identify predictors of adherence. Mean adherence rates were 89.5% at 6-12 weeks and 92.4% at 30 months; the proportions with perfect adherence were 80.3% and 83.6%, respectively. The overall trend for perfect adherence was not significant (p=0.71). In adjusted regression modelling, younger age was associated with an increased probability of non-perfect adherence at 18 and 24 months postpartum. Other factors associated with increased probability of non-perfect adherence were higher parity, current use of alcohol and tobacco, and more advanced HIV disease. Women with perfect adherence had lower viral loads. Interventions for alcohol and tobacco use cessation, and support for young women and those with advanced HIV disease should be considered to improve postpartum adherence. C1 [Kreitchmann, Regis; Coelho, Debora Fernandes] Irmandade Santa Casa Misericordia Porto Alegre, Prof Annes Dias 285, BR-90020090 Porto Alegre, RS, Brazil. [Kreitchmann, Regis; Coelho, Debora Fernandes] Univ Fed Ciencias Saude Porto Alegre, Porto Alegre, RS, Brazil. [Kakehasi, Fabiana Maria] Univ Fed Minas Gerais, Belo Horizonte, MG, Brazil. [Hofer, Cristina Barroso] Univ Fed Rio de Janeiro, Inst Puericultura & Pediat Martagao Gesteira, Rio De Janeiro, Brazil. [Hofer, Cristina Barroso] Univ Fed Rio de Janeiro, Dept Prevent Med, Rio De Janeiro, Brazil. [Read, Jennifer S.; Siberry, George K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal & Pediat Infect Dis Branch, Bethesda, MD USA. [Read, Jennifer S.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Losso, Marcelo] Hosp Gen Agudos Jose Maria Ramos Mejia, Buenos Aires, DF, Argentina. [Haberer, Jessica E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Harris, D. Robert; Yu, Qilu] WESTAT Corp, Rockville, MD 20850 USA. RP Kreitchmann, R (reprint author), Irmandade Santa Casa Misericordia Porto Alegre, Prof Annes Dias 285, BR-90020090 Porto Alegre, RS, Brazil. EM regis.kr@terra.com.br OI Harris, Donald/0000-0002-8262-3716 FU NICHD [N01-HD-3-3345, HHSN267200800001C, HHSN275201300003C] 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 NICHD Contracts N01-HD-3-3345 (2002-2007), HHSN267200800001C (2007-2012), and HHSN275201300003C (2012-2017). NR 34 TC 1 Z9 1 U1 2 U2 6 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 APR PY 2016 VL 27 IS 5 BP 377 EP 386 DI 10.1177/0956462415584483 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DF8SO UT WOS:000371629200006 PM 25931238 ER PT J AU Fusco, MR Stapleton, CJ Griessenauer, CJ Thomas, AJ Ogilvy, CS AF Fusco, Matthew R. Stapleton, Christopher J. Griessenauer, Christoph J. Thomas, Ajith J. Ogilvy, Christopher S. TI Endovascular treatment of intracranial infectious aneurysms in eloquent cortex with super-selective provocative testing: Case series and literature review SO INTERVENTIONAL NEURORADIOLOGY LA English DT Review DE Aneurysm; aneurysm embolization; awake brain surgery; eloquent cortex; infectious endocarditis; intracranial infectious embolism; Wada testing ID CEREBRAL MYCOTIC-ANEURYSMS; ARTERIOVENOUS-MALFORMATIONS; EMBOLIZATION; ENDOCARDITIS; MANAGEMENT; LIDOCAINE; ARTERY AB Intracranial infectious aneurysms (IIAs) are a rare subgroup of intracranial aneurysms. Often erroneously termed mycotic aneurysms, these lesions most often result from infectious endocarditis and involve the distal anterior cortical circulation. Diagnosis typically follows headaches or septic infarcts, although increasing numbers of lesions are found incidentally, during screening protocols for infectious endocarditis. Open surgical treatment was previously the mainstay of treatment; however, these IIAs are often fusiform and quite fragile, making open surgical obliteration difficult and typically requiring lesion trapping. Current treatment techniques more commonly involve endovascular coil embolization or parent vessel occlusion. Many of these lesions occur distally, in or around the eloquent cortex, making embolization potentially dangerous. We present cases that highlight the use of super-selective provocative testing with sodium amobarbital and lidocaine, to help clarify and predict the risk of parent vessel occlusion in IIAs located in the eloquent cortex. C1 [Fusco, Matthew R.] Vanderbilt Univ, Dept Neurosurg, 221 Kirkland Hall, Nashville, TN 37235 USA. [Fusco, Matthew R.; Griessenauer, Christoph J.; Thomas, Ajith J.; Ogilvy, Christopher S.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Neurosurg, Boston, MA 02215 USA. [Stapleton, Christopher J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurosurg, Boston, MA USA. RP Griessenauer, CJ (reprint author), 110 Francis St,Suite 3B, Boston, MA 02215 USA. EM christoph.griessenauer@gmail.com NR 15 TC 0 Z9 0 U1 0 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 APR PY 2016 VL 22 IS 2 BP 148 EP 152 DI 10.1177/1591019915617326 PG 5 WC Clinical Neurology; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DF8QU UT WOS:000371624000004 PM 26672110 ER PT J AU Matthews, LT Ribaudo, HB Kaida, A Bennett, K Musinguzi, N Siedner, MJ Kabakyenga, J Hunt, PW Martin, JN Boum, Y Haberer, JE Bangsberg, DR AF Matthews, Lynn T. Ribaudo, Heather B. Kaida, Angela Bennett, Kara Musinguzi, Nicholas Siedner, Mark J. Kabakyenga, Jerome Hunt, Peter W. Martin, Jeffrey N. Boum, Yap Haberer, Jessica E. Bangsberg, David R. TI HIV-Infected Ugandan Women on Antiretroviral Therapy Maintain HIV-1 RNA Suppression Across Periconception, Pregnancy, and Postpartum Periods SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE periconception; antiretroviral adherence; HIV-1; Uganda; pregnancy; postpartum ID TO-CHILD-TRANSMISSION; OPTION B PLUS; DAR-ES-SALAAM; MITRA PLUS; LOW-INCOME; PREVENTION; ADHERENCE; RETENTION; TANZANIA; MALAWI AB Background: HIV-infected women risk sexual and perinatal HIV transmission during conception, pregnancy, childbirth, and breastfeeding. We compared HIV-1 RNA suppression and medication adherence across periconception, pregnancy, and postpartum periods, among women on antiretroviral therapy (ART) in Uganda. Methods: We analyzed data from women in a prospective cohort study, aged 18-49 years, enrolled at ART initiation and with >= 1 pregnancy between 2005 and 2011. Participants were seen quarterly. The primary exposure of interest was pregnancy period, including periconception (3 quarters before pregnancy), pregnancy, postpartum (6 months after pregnancy outcome), or nonpregnancy related. Regression models using generalized estimating equations compared the likelihood of HIV-1 RNA <= 400 copies per milliliter, <80% average adherence based on electronic pill caps (medication event monitoring system), and likelihood of 72-hour medication gaps across each period. Results: One hundred eleven women contributed 486 person-years of follow-up. Viral suppression was present at 89% of nonpregnancy, 97% of periconception, 93% of pregnancy, and 89% of postpartum visits, and was more likely during periconception (adjusted odds ratio, 2.15) compared with nonpregnant periods. Average ART adherence was 90% [interquartile range (IQR), 70%-98%], 93% (IQR, 82%-98%), 92% (IQR, 72%-98%), and 88% (IQR, 63%-97%) during nonpregnant, periconception, pregnant, and postpartum periods, respectively. Average adherence <80% was less likely during periconception (adjusted odds ratio, 0.68), and 72-hour gaps per 90 days were less frequent during periconception (adjusted relative risk, 0.72) and more frequent during postpartum (adjusted relative risk, 1.40). Conclusions: Women with pregnancy were virologically suppressed at most visits, with an increased likelihood of suppression and high adherence during periconception follow-up. Increased frequency of 72-hour gaps suggests a need for increased adherence support during postpartum periods. C1 [Matthews, Lynn T.; Siedner, Mark J.; Bangsberg, David R.] Massachusetts Gen Hosp, Ctr Global Hlth, Div Infect Dis, 15th Floor,100 Cambridge St, Boston, MA 02114 USA. [Ribaudo, Heather B.] Harvard Univ, TH Chan Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Kaida, Angela] Simon Fraser Univ, Fac Hlth Sci, Burnaby, BC V5A 1S6, Canada. [Bennett, Kara] Bennett Stat Consulting, Ballston Lake, NY USA. [Musinguzi, Nicholas; Kabakyenga, Jerome] Mbarara Univ Sci & Technol, Mbarara, Uganda. [Hunt, Peter W.; Martin, Jeffrey N.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Martin, Jeffrey N.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Boum, Yap] Epictr Mbarara, Mbarara, Uganda. [Haberer, Jessica E.] Massachusetts Gen Hosp, Ctr Global Hlth, Dept Gen Med, Boston, MA 02114 USA. RP Matthews, LT (reprint author), Massachusetts Gen Hosp, Ctr Global Hlth, Div Infect Dis, 15th Floor,100 Cambridge St, Boston, MA 02114 USA. EM ltmatthews@partners.org FU US National Institutes of Health [R21HD069194, K23 MH095655, R01MH054907, P30AI027763, U01CA066529, K24 MH87227, K23 MH099916, R01MH087328]; Sullivan Family Foundation FX Supported by US National Institutes of Health, R21HD069194, K23 MH095655, R01MH054907, P30AI027763, U01CA066529, K24 MH87227, K23 MH099916, and R01MH087328, and the Sullivan Family Foundation. NR 32 TC 4 Z9 4 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD APR 1 PY 2016 VL 71 IS 4 BP 399 EP 406 DI 10.1097/QAI.0000000000000874 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DG0II UT WOS:000371748100007 PM 26495883 ER PT J AU Zash, R Souda, S Chen, JY Binda, K Dryden-Peterson, S Lockman, S Mmalane, M Makhema, J Essex, M Shapiro, R AF Zash, Rebecca Souda, Sajini Chen, Jennifer Y. Binda, Kelebogile Dryden-Peterson, Scott Lockman, Shahin Mmalane, Mompati Makhema, Joseph Essex, Max Shapiro, Roger TI Reassuring Birth Outcomes With Tenofovir/Emtricitabine/Efavirenz Used for Prevention of Mother-to-Child Transmission of HIV in Botswana SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE stillbirth; preterm delivery; HIV; antiretroviral therapy; small for gestational age; PMTCT ID TENOFOVIR DISOPROXIL FUMARATE; INTRAUTERINE GROWTH-RETARDATION; ACTIVE ANTIRETROVIRAL THERAPY; INFECTED WOMEN; PREMATURE DELIVERY; PRETERM DELIVERY; PREGNANT-WOMEN; INCREASED RISK; SAFETY; EMTRICITABINE AB Background: Before introduction of tenofovir/emtricitabine/efavirenz (TDF/FTC/EFV), 3-drug antiretroviral therapy (ART) was associated with increased adverse birth outcomes when used for prevention of mother-to-child HIV transmission (PMTCT) in Botswana. Methods: We extracted obstetric records from all women at the 2 largest maternities in Botswana from 2009-2011 when Botswana National Guidelines recommended zidovudine (ZDV) from 28 weeks gestational age (GA) for CD4 >= 350 and ART for CD4 <350, and again in 2013-2014 after implementation of TDF/FTC/EFV for prevention of mother-to-child HIV transmission regardless of CD4 or GA. We compared the use of TDF/FTC/EFV in pregnancy with other 3-drug ART regimens, and with initiation of ZDV, among women with similar CD4 cell counts. Outcomes included small for gestational age (SGA), preterm delivery (PTD) (<37 weeks GA), and stillbirths (SB). Results: Among 9445 HIV-infected women delivering during the study period, 170 were on TDF/FTC/EFV at conception and 1468 initiated TDF/FTC/EFV during pregnancy. Adverse birth outcomes were high overall (3% SB, 21% PTD, and 18% SGA) and among women receiving TDF/FTC/EFV (3% SB, 22% PTD, and 12% SGA). There was no difference in PTD or SB among women initiating TDF/FTC/EFV compared with ZDV or other 3-drug ART, but initiating TDF/FTC/EFV was associated with fewer SGA infants than other 3-drug ART (adjusted odds ratio: 0.4, 95% confidence interval: 0.2 to 0.7). Conclusions: Adverse birth outcomes remain high among HIV-infected women. TDF/FTC/EFV was at least as safe as other ART and associated with fewer SGA infants when initiated during pregnancy. Larger studies are needed to evaluate birth outcomes and congenital abnormalities among women on TDF/FTC/EFV at conception. C1 [Zash, Rebecca] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Zash, Rebecca; Binda, Kelebogile; Dryden-Peterson, Scott; Lockman, Shahin; Mmalane, Mompati; Makhema, Joseph; Essex, Max; Shapiro, Roger] Botswana Harvard AIDS Inst Partnership, Gaborone, Botswana. [Zash, Rebecca; Dryden-Peterson, Scott; Lockman, Shahin; Essex, Max; Shapiro, Roger] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Souda, Sajini] Univ Botswana, Fac Hlth Sci, Gaborone, Botswana. [Chen, Jennifer Y.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Dryden-Peterson, Scott; Lockman, Shahin] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. RP Zash, R (reprint author), Beth Israel Deaconess Med Ctr, Div Infect Dis, 110 Francis St,Lowry Med Off Bldg, Boston, MA 02215 USA. EM rzash@bidmc.harvard.edu FU Centers for Disease Control [U2GPS000941]; NIH/NIAID [T32 5T32AI007433-21] FX This work was funded by Centers for Disease Control (U2GPS000941) and NIH/NIAID (T32 5T32AI007433-21). NR 40 TC 10 Z9 10 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD APR 1 PY 2016 VL 71 IS 4 BP 428 EP 436 DI 10.1097/QAI.0000000000000847 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DG0II UT WOS:000371748100011 PM 26379069 ER PT J AU Ashack, KA Burton, KA Johnson, TR Currie, DW Comstock, RD Dellavalle, RP AF Ashack, Kurt A. Burton, Kyle A. Johnson, Teresa R. Currie, Dustin W. Comstock, R. Dawn Dellavalle, Robert P. TI Skin infections among US high school athletes: A national survey SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article DE athletes; competition; high school; injury; prevention; skin infections; sports ID HERPES GLADIATORUM; COMPETITIVE SPORTS; DISEASE OUTBREAKS; INJURIES AB Background: Skin infections have long been a reported problem among high school athletes, particularly wrestlers. There has yet to be a national study describing the epidemiology of skin infections across multiple high school sports. Objective: We sought to report the epidemiology of skin infections among US high school athletes. Methods: High school sports-related skin infections resulting in time loss were reported by a convenience sample of US high schools from 2009/2010 through 2013/2014 via High School Reporting Information Online. Results: During the study, 474 skin infections were reported among 20,858,781 athlete exposures, a rate of 2.27 per 100,000 athlete exposures. The largest number of skin infections occurred in wrestling (73.6%) followed by football (17.9%). The most common infections were bacterial (60.6%) and tinea (28.4%) infections. Body parts most often affected were the head/face (25.3%) followed by the forearm (12.7%). Limitations: The study included only high schools with National Athletic Trainers' Associationeaffiliated athletic trainers, which may limit generalizability. However, using athletic trainers as data reporters improved data quality. Conclusions: Skin infections are an important subset of high school sports-related adverse events. An understanding of the epidemiology of sports-related skin infections should promote awareness and drive evidence-based prevention efforts. C1 [Ashack, Kurt A.] Michigan State Univ, Coll Human Med, Grand Rapids, MI USA. [Johnson, Teresa R.] Univ Cent Florida, Coll Med, Dept Med Educ, Orlando, FL 32816 USA. [Burton, Kyle A.] Univ Cent Florida, Coll Med, Orlando, FL 32816 USA. [Currie, Dustin W.; Comstock, R. Dawn; Dellavalle, Robert P.] Univ Colorado, Colorado Sch Publ Hlth, Dept Epidemiol, Anschutz Med Campus, Aurora, CO USA. [Comstock, R. Dawn] Univ Colorado, Dept Pediat Emergency Med, Anschutz Med Campus, Aurora, CO USA. [Dellavalle, Robert P.] Univ Colorado, Dept Dermatol, Anschutz Med Campus, Aurora, CO USA. [Dellavalle, Robert P.] US Dept Vet Affairs, Dermatol Serv, Eastern Colorado Hlth Care Syst, Denver, CO USA. RP Dellavalle, RP (reprint author), US Dept Vet Affairs, Dermatol Serv, 1055 Clermont St,Box 165, Denver, CO 80220 USA. EM robert.dellavalle@ucdenver.edu FU Centers for Disease Control and Prevention [R49/CE000674-01, R49/CE001172-01]; National Federation of State High School Associations; National Operating Committee on Standards for Athletic Equipment; DonJoy Orthotics; EyeBlack FX The content of this report representing data collection by the National High School Sports-Related Injury Surveillance Study (High School Reporting Information Online) was funded in part by the Centers for Disease Control and Prevention grants R49/CE000674-01 and R49/CE001172-01. We also acknowledge the generous research funding contributions of the National Federation of State High School Associations, the National Operating Committee on Standards for Athletic Equipment, DonJoy Orthotics, and EyeBlack. The content of this report is solely the responsibility of the authors and does not necessarily represent the official views of the Centers for Disease Control and Prevention or any of the other institutions that provided financial support for this research. NR 21 TC 0 Z9 0 U1 3 U2 6 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 APR PY 2016 VL 74 IS 4 BP 679 EP U156 DI 10.1016/j.jaad.2015.10.042 PG 7 WC Dermatology SC Dermatology GA DG0ZM UT WOS:000371794800021 PM 26850656 ER PT J AU Zhang, XM Chen, YLE Lim, R Huang, C Chebib, IA El Fakhri, G AF Zhang, Xiaomeng Chen, Yen-Lin E. Lim, Ruth Huang, Chuan Chebib, Ivan A. El Fakhri, Georges TI Synergistic role of simultaneous PET/MRI-MRS in soft tissue sarcoma metabolism imaging SO MAGNETIC RESONANCE IMAGING LA English DT Article DE Simultaneous PET/MR; PET guided MR spectroscopy; Soft tissue sarcoma ID RADIATION-THERAPY; EXTREMITY; EDEMA AB The primary objective of this study was to develop and validate simultaneous PET/MRI-MRS as a novel biological image-guided approach to neoadjuvant radiotherapy (RT) and/or chemoradiation (chemoRT) in soft tissue sarcomas (STS). A patient with sarcoma of the right thigh underwent PET/MRI scan before and after neoadjuvant (preoperative) radiotherapy. The magnetic resonance imaging (MRI) and 2-deoxy-2-[-fluorine-18]-fluoro-D-glucose-Positron Emission Tomography (F-18-FDG-PET) scans were performed simultaneously. In the post-radiation scan, magnetic resonance spectroscopy (MRS) was subsequently acquired with volume of interest positioned in a residual hyper-metabolic region detected by PET. Post-radiation PET/MRI showed a residual T2-hyperintense mass with significantly reduced F-18-FDG-uptake, compatible with near complete response to radiotherapy. However, a small region of residual high F-18-FDG uptake was detected at the tumor margin. MRS of this region had similar metabolite profile as normal tissue, and was thus considered false positive on PET scan. Pathology results were obtained after surgery for confirmation of imaging findings. (C) 2015 Elsevier Inc. All rights reserved. C1 [Zhang, Xiaomeng; Chen, Yen-Lin E.; Lim, Ruth; Huang, Chuan; El Fakhri, Georges] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gordon Ctr Med Imaging,Radiol Dept, Boston, MA 02114 USA. [Chen, Yen-Lin E.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Huang, Chuan] Stony Brook Med, Dept Radiol & Psychiat, Stony Brook, NY 11794 USA. [Chebib, Ivan A.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP El Fakhri, G (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gordon Ctr Med Imaging,Radiol Dept, Boston, MA 02114 USA. EM zhang@pet.mgh.harvard.edu; elfakhri@pet.mgh.harvard.edu FU NIH [R01CA165221, T32 5T32EB013180-04] FX Financial support: NIH R01CA165221; NIH T32 5T32EB013180-04. NR 11 TC 1 Z9 1 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0730-725X EI 1873-5894 J9 MAGN RESON IMAGING JI Magn. Reson. Imaging PD APR PY 2016 VL 34 IS 3 BP 276 EP 279 DI 10.1016/j.mri.2015.10.027 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DF8ZL UT WOS:000371649900006 PM 26523656 ER PT J AU Jahn, B Rochau, U Kurzthaler, C Paulden, M Kluibenschadl, M Arvandi, M Kuhne, F Goehler, A Krahn, MD Siebert, U AF Jahn, Beate Rochau, Ursula Kurzthaler, Christina Paulden, Mike Kluibenschaedl, Martina Arvandi, Marjan Kuehne, Felicitas Goehler, Alexander Krahn, Murray D. Siebert, Uwe TI Lessons Learned from a Cross-Model Validation between a Discrete Event Simulation Model and a Cohort State-Transition Model for Personalized Breast Cancer Treatment SO MEDICAL DECISION MAKING LA English DT Article DE cross-model validation; decision analysis; discrete event simulation; Markov models; state-transition model; cost-effectiveness analysis ID RECURRENCE SCORE ASSAY; RT-PCR ASSAY; ADJUVANT CHEMOTHERAPY; COST-EFFECTIVENESS; 21-GENE ASSAY; TASK-FORCE; ECONOMIC-ANALYSIS; GENE-EXPRESSION; FOLLOW-UP; NODE AB Objectives. Breast cancer is the most common malignancy among women in developed countries. We developed a model (the Oncotyrol breast cancer outcomes model) to evaluate the cost-effectiveness of a 21-gene assay when used in combination with Adjuvant! Online to support personalized decisions about the use of adjuvant chemotherapy. The goal of this study was to perform a cross-model validation. Methods. The Oncotyrol model evaluates the 21-gene assay by simulating a hypothetical cohort of 50-year-old women over a lifetime horizon using discrete event simulation. Primary model outcomes were life-years, quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratios (ICERs). We followed the International Society for Pharmacoeconomics and Outcomes Research-Society for Medical Decision Making (ISPOR-SMDM) best practice recommendations for validation and compared modeling results of the Oncotyrol model with the state-transition model developed by the Toronto Health Economics and Technology Assessment (THETA) Collaborative. Both models were populated with Canadian THETA model parameters, and outputs were compared. Results. The differences between the models varied among the different validation end points. The smallest relative differences were in costs, and the greatest were in QALYs. All relative differences were less than 1.2%. The cost-effectiveness plane showed that small differences in the model structure can lead to different sets of nondominated test-treatment strategies with different efficiency frontiers. We faced several challenges: distinguishing between differences in outcomes due to different modeling techniques and initial coding errors, defining meaningful differences, and selecting measures and statistics for comparison (means, distributions, multivariate outcomes). Conclusions. Cross-model validation was crucial to identify and correct coding errors and to explain differences in model outcomes. In our comparison, small differences in either QALYs or costs led to changes in ICERs because of changes in the set of dominated and nondominated strategies. C1 [Jahn, Beate; Rochau, Ursula; Kurzthaler, Christina; Kluibenschaedl, Martina; Arvandi, Marjan; Kuehne, Felicitas; Goehler, Alexander; Siebert, Uwe] UMIT Univ Hlth Sci Med Informat & Technol, Dept Publ Hlth & Hlth Technol Assessment, Inst Publ Hlth Med Decis Making & Hlth Technol As, Hall I-T, Innsbruck, Austria. [Jahn, Beate; Rochau, Ursula; Kurzthaler, Christina; Kluibenschaedl, Martina; Kuehne, Felicitas; Siebert, Uwe] ONCOTYROL Ctr Personalized Canc Med, Div Publ Hlth Decis Modelling Hlth Technol Assess, Innsbruck, Austria. [Paulden, Mike; Kluibenschaedl, Martina] Univ Toronto, Toronto Hlth Econ & Technol Assessment THETA Co, Toronto, ON M5S 1A1, Canada. [Paulden, Mike] Univ Alberta, Dept Emergency Med, Edmonton, AB, Canada. [Goehler, Alexander] Yale Univ, Dept Radiol, New Haven, CT USA. [Goehler, Alexander] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA USA. [Goehler, Alexander] Univ Duisburg Essen, Inst Hlth Syst Management, Alfried Krupp Bohlen & Halbach Fdn, Essen, Germany. [Siebert, Uwe] Harvard Univ, Sch Med, Dept Hlth Policy & Management, Ctr Hlth Decis Sci, Boston, MA 02115 USA. [Siebert, Uwe] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02115 USA. [Siebert, Uwe] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02115 USA. RP Jahn, B (reprint author), UMIT Univ Hlth Sci Med Informat & Technol, Inst Publ Hlth Med Decis Making & HTA, Eduard Wallnoefer Ctr 1, Hall I-T, A-6060 Innsbruck, Austria. EM Beate.Jahn@umit.at RI Paulden, Michael/E-2061-2016 FU COMET Center ONCOTYROL - Austrian Federal Ministries BMVIT/BMWFJ (via FFG); Tiroler Zukunftsstiftung/Standortagentur Tirol (SAT) FX Financial support for this study was provided in part by the COMET Center ONCOTYROL, which is funded by the Austrian Federal Ministries BMVIT/BMWFJ (via FFG) and the Tiroler Zukunftsstiftung/Standortagentur Tirol (SAT). The funding agreement ensured the authors' independence in designing the study, interpreting the data, writing, and publishing the report. The following authors are or have been employed by the sponsor: B. Jahn, U. Rochau, C. Kurzthaler, M. Kluibenschadl, M. Arvandi, F. Kuhne, and U. Siebert. Revision accepted for publication 13 July 2015. NR 44 TC 0 Z9 0 U1 1 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0272-989X EI 1552-681X J9 MED DECIS MAKING JI Med. Decis. Mak. PD APR PY 2016 VL 36 IS 3 BP 375 EP 390 DI 10.1177/0272989X15604158 PG 16 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA DF9QV UT WOS:000371697100010 PM 26476865 ER PT J AU McAllister, TW Zafonte, R Jain, S Flashman, LA George, MS Grant, GA He, F Lohr, JB Andaluz, N Summerall, L Paulus, MP Raman, R Stein, MB AF McAllister, Thomas W. Zafonte, Ross Jain, Sonia Flashman, Laura A. George, Mark S. Grant, Gerald A. He, Feng Lohr, James B. Andaluz, Norberto Summerall, Lanier Paulus, Martin P. Raman, Rema Stein, Murray B. TI Randomized Placebo-Controlled Trial of Methylphenidate or Galantamine for Persistent Emotional and Cognitive Symptoms Associated with PTSD and/or Traumatic Brain Injury SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; DEPLOYED MILITARY PERSONNEL; POSTCONCUSSIVE SYMPTOMS; PSYCHIATRIC-DISORDERS; SUICIDE RISK; DEPRESSION; IRAQ; SYMPTOMATOLOGY; AFGHANISTAN; VETERANS AB We report findings from a 12-week randomized double-blinded placebo-controlled trial of methylphenidate or galantamine to treat emotional and cognitive complaints in individuals (n=32) with a history of PTSD, TBI, or both conditions. In this small pilot study, methylphenidate treatment was associated with clinically meaningful and statistically significant improvement compared with placebo on the primary outcome, a measure of cognitive complaints (Ruff Neurobehavioral Inventory-Postmorbid Cognitive Scale), as well as on the secondary outcomes reflecting post-concussive (Rivermead Post Concussive Symptom Questionnaire) and post-traumatic stress symptoms (Posttraumatic Stress Disorder Checklist). Treatment was well tolerated. These results suggest the need for a larger RCT to replicate and confirm these findings. Design considerations for such a trial should include the need for multiple sites to facilitate adequate recruitment and extension of the treatment and follow-up periods. C1 [McAllister, Thomas W.] Indiana Univ Sch Med, Dept Psychiat, 355W,16th St,Suite 4800, Indianapolis, IN 46202 USA. [Zafonte, Ross] Brigham & Womens Hosp, Massachusetts Gen Hosp, Spaulding Rehabil Hosp, Dept Phys Med & Rehabil, 75 Francis St, Boston, MA 02115 USA. [Zafonte, Ross] Harvard Univ, Sch Med, Boston, MA USA. [Jain, Sonia; He, Feng; Raman, Rema] Univ Calif San Diego, Biostat Res Ctr, Dept Family Med & Publ Hlth, San Diego, CA 92103 USA. [Flashman, Laura A.] Dartmouth Hitchcock Med Ctr, Geisel Sch Med Dartmouth, Dept Psychiat, Neuropsychol Program, Lebanon, NH 03766 USA. [George, Mark S.] Med Univ S Carolina, Dept Psychiat, Charleston, SC 29425 USA. [Grant, Gerald A.] Stanford Univ, Lucile Packard Childrens Hosp, Dept Neurosurg, Stanford, CA 94305 USA. [Lohr, James B.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Andaluz, Norberto] Univ Cincinnati, Mayfield Clin, Neurosci Inst, Dept Neurosurg,Coll Med, Cincinnati, OH USA. [Summerall, Lanier] Ralph H Johnson VA Med Ctr, Dept Psychiat, Charleston, SC USA. [Paulus, Martin P.] Laureate Inst Brain Res, Tulsa, OK USA. [Stein, Murray B.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Stein, Murray B.] Univ Calif San Diego, Dept Family Med & Publ Hlth, San Diego, CA 92103 USA. RP McAllister, TW (reprint author), Indiana Univ Sch Med, Dept Psychiat, 355W,16th St,Suite 4800, Indianapolis, IN 46202 USA. EM twmcalli@iupui.edu FU United States Department of Defense grant [W81XWH08-2-0159]; Janssen Pharmaceutica; Pfizer; Tonix Pharmaceuticals; Biological Psychiatry; UpToDate FX This study was funded by the United States Department of Defense grant W81XWH08-2-0159. MBS reports consulting income in the past 3 years from Janssen Pharmaceutica, Pfizer, and Tonix Pharmaceuticals; and income for editorial work for Biological Psychiatry and UpToDate. RZ has received compensation from Demos Medical Publishing, as well as Oakstone Institute for educational products. The remaining authors declare no conflict of interest. NR 43 TC 2 Z9 2 U1 4 U2 11 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 APR PY 2016 VL 41 IS 5 BP 1191 EP 1198 DI 10.1038/npp.2015.282 PG 8 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DG1BW UT WOS:000371801200002 PM 26361060 ER PT J AU Minzenberg, MJ Yoon, JH Cheng, YA Carter, CS AF Minzenberg, Michael J. Yoon, Jong H. Cheng, Yaoan Carter, Cameron S. TI Sustained Modafinil Treatment Effects on Control-Related Gamma Oscillatory Power in Schizophrenia SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID INDEPENDENT COMPONENT ANALYSIS; COGNITIVE CONTROL; PREFRONTAL CORTEX; LOCUS-COERULEUS; RULE SELECTION; WORKING-MEMORY; IN-VITRO; MODULATION; DOPAMINE; NOREPINEPHRINE AB Control-related cognitive processes such as rule selection and maintenance are associated with cortical oscillations in the gamma range, and modulated by catecholamine neurotransmission. Control-related gamma power is impaired in schizophrenia, and an understudied treatment target. It remains unknown whether pro-catecholamine pharmacological agents augment control-related gamma oscillations in schizophrenia. We tested the effects of 4-week fixed-dose daily adjunctive modafinil (MOD) 200 mg, in a randomized double-blind, placebo-controlled, parallel-groups design. Twenty-seven stable schizophrenia patients performed a cognitive control task during EEG, at baseline and after 4 weeks of treatment. EEG data underwent time-frequency decomposition with Morlet wavelets to determine power of 4-80 Hz oscillations. The modafinil group (n = 14), relative to placebo group (n = 13), exhibited enhanced oscillatory power associated with high-control rule selection in the gamma range after treatment, with additional effects during rule maintenance in gamma and sub-gamma ranges. MOD-treated patients who exhibited improved task performance with treatment also showed greater treatment-related delay period gamma compared with MOD-treated patients without improved performance. This is the first evidence in schizophrenia of augmentation of cognition-related gamma oscillations by an FDA-approved agent with therapeutic potential. Gamma oscillations represent a novel treatment target in this disorder, and modulation of catecholamine signaling may represent a viable strategy at this target. C1 [Minzenberg, Michael J.; Cheng, Yaoan] Univ Calif San Francisco, Sch Med, Dept Psychiat, San Francisco, CA 94143 USA. [Minzenberg, Michael J.; Cheng, Yaoan] San Francisco VA Med Ctr, San Francisco, CA USA. [Yoon, Jong H.] Stanford Univ, Sch Med, Dept Psychiat, Palo Alto, CA 94304 USA. [Yoon, Jong H.] Palo Alto Vet Affairs Med Ctr, Palo Alto, CA USA. [Carter, Cameron S.] Univ Calif Davis, Sch Med, Dept Psychiat, Sacramento, CA 95817 USA. [Carter, Cameron S.] Univ Calif Davis, Ctr Neurosci, Program Neurosci, Davis, CA 95616 USA. RP Minzenberg, MJ (reprint author), UCSF, Psychiat, Outpatient Mental Hlth Serv, San Francisco Vet Affairs Ctr, 116C,4150 Clement St, San Francisco, CA 94121 USA. EM Michael.minzenberg@ucsf.edu OI Cheng, Yaoan/0000-0001-5858-6161 FU Clinical Scientist Development Award from the Doris Duke Charitable Foundation; Young Investigator award from NARSAD (Brain and Behavior Foundation) FX This work was supported by Clinical Scientist Development Award from the Doris Duke Charitable Foundation, and a Young Investigator award from NARSAD (Brain and Behavior Foundation), to MJM. The authors declare no conflict of interest. NR 60 TC 1 Z9 1 U1 1 U2 12 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 APR PY 2016 VL 41 IS 5 BP 1231 EP 1240 DI 10.1038/npp.2015.271 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DG1BW UT WOS:000371801200006 PM 26329382 ER PT J AU Sander, CY Hooker, JM Catana, C Rosen, BR Mandeville, JB AF Sander, Christin Y. Hooker, Jacob M. Catana, Ciprian Rosen, Bruce R. Mandeville, Joseph B. TI Imaging Agonist-Induced D2/D3 Receptor Desensitization and Internalization In Vivo with PET/fMRI SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; DOPAMINE-RECEPTORS; D2 RECEPTORS; HUMAN-BRAIN; FUNCTIONAL POTENCIES; ENDOGENOUS DOPAMINE; PHARMACOLOGICAL MRI; H-3 RACLOPRIDE; RAT-BRAIN; BINDING AB This study investigated the dynamics of dopamine receptor desensitization and internalization, thereby proposing a new technique for noninvasive, in vivo measurements of receptor adaptations. The D2/D3 agonist quinpirole, which induces receptor internalization in vitro, was administered at graded doses in non-human primates while imaging with simultaneous positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). A pronounced temporal divergence between receptor occupancy and fMRI signal was observed: occupancy remained elevated while fMRI responded transiently. Analogous experiments with an antagonist (prochlorperazine) and a lower-affinity agonist (ropinirole) exhibited reduced temporal dissociation between occupancy and function, consistent with a mechanism of desensitization and internalization that depends upon drug efficacy and affinity. We postulated a model that incorporates internalization into a neurovascular-coupling relationship. This model yielded in vivo desensitization/internalization rates (0.2/min for quinpirole) consistent with published in vitro measurements. Overall, these results suggest that simultaneous PET/fMRI enables characterization of dynamic neuroreceptor adaptations in vivo, and may offer a first non-invasive method for assessing receptor desensitization and internalization. C1 [Sander, Christin Y.; Hooker, Jacob M.; Catana, Ciprian; Rosen, Bruce R.; Mandeville, Joseph B.] Massachusetts Gen Hosp, Dept Radiol, AA Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Sander, Christin Y.; Hooker, Jacob M.; Catana, Ciprian; Rosen, Bruce R.; Mandeville, Joseph B.] Harvard Univ, Sch Med, Boston, MA USA. [Rosen, Bruce R.] Harvard MIT, Hlth Sci & Technol, Cambridge, MA USA. RP Sander, CY (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging,Dept Radiol, 149 Thirteenth St,Room 2301, Charlestown, MA 02129 USA. EM csander@mgh.harvard.edu FU National Institutes of Health [R90DA023427, P41EB015896, S10RR026666, S10RR022976, S10RR019933, S10RR017 208] FX This research was supported by grants from the National Institutes of Health: R90DA023427, P41EB015896, S10RR026666, S10RR022976, S10RR019933 and S10RR017 208. The authors declare no conflict of interest. NR 59 TC 2 Z9 2 U1 4 U2 12 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 APR PY 2016 VL 41 IS 5 BP 1427 EP 1436 DI 10.1038/npp.2015.296 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DG1BW UT WOS:000371801200025 PM 26388148 ER PT J AU Crossley, NA Fox, PT Bullmore, ET AF Crossley, N. A. Fox, P. T. Bullmore, E. T. TI Meta-connectomics: human brain network and connectivity meta-analyses SO PSYCHOLOGICAL MEDICINE LA English DT Review DE Connectome; cytoarchitectonics; gene expression; graph theory; neuroimaging ID RICH-CLUB ORGANIZATION; FUNCTIONAL CONNECTIVITY; CEREBRAL-CORTEX; COACTIVATION PATTERNS; PREFRONTAL CORTEX; SCHIZOPHRENIA; FMRI; DISORDERS; MODEL; HETEROGENEITY AB Abnormal brain connectivity or network dysfunction has been suggested as a paradigm to understand several psychiatric disorders. We here review the use of novel meta-analytic approaches in neuroscience that go beyond a summary description of existing results by applying network analysis methods to previously published studies and/or publicly accessible databases. We define this strategy of combining connectivity with other brain characteristics as meta-connectomics'. For example, we show how network analysis of task-based neuroimaging studies has been used to infer functional co-activation from primary data on regional activations. This approach has been able to relate cognition to functional network topology, demonstrating that the brain is composed of cognitively specialized functional subnetworks or modules, linked by a rich club of cognitively generalized regions that mediate many inter-modular connections. Another major application of meta-connectomics has been efforts to link meta-analytic maps of disorder-related abnormalities or MRI lesions' to the complex topology of the normative connectome. This work has highlighted the general importance of network hubs as hotspots for concentration of cortical grey-matter deficits in schizophrenia, Alzheimer's disease and other disorders. Finally, we show how by incorporating cellular and transcriptional data on individual nodes with network models of the connectome, studies have begun to elucidate the microscopic mechanisms underpinning the macroscopic organization of whole-brain networks. We argue that meta-connectomics is an exciting field, providing robust and integrative insights into brain organization that will likely play an important future role in consolidating network models of psychiatric disorders. C1 [Crossley, N. A.] Kings Coll London, Inst Psychiat Psychol & Neurosci, Dept Psychosis Studies, London WC2R 2LS, England. [Crossley, N. A.] P Catholic Univ Chile, Inst Biol & Med Engn, Sch Med, Santiago, Chile. [Crossley, N. A.] P Catholic Univ Chile, Sch Biol Sci & Engn, Santiago, Chile. [Crossley, N. A.] P Catholic Univ Chile, Sch Med, Dept Psychiat, Santiago, Chile. [Fox, P. T.] Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, San Antonio, TX 78229 USA. [Fox, P. T.] Univ Texas Hlth Sci Ctr San Antonio, Dept Radiol, San Antonio, TX 78229 USA. [Fox, P. T.] South Texas Vet Hlth Care Syst, Res Serv, San Antonio, TX USA. [Bullmore, E. T.] Univ Cambridge, Dept Psychiat, Behav & Clin Neurosci Inst, Cambridge, England. [Bullmore, E. T.] Cambridgeshire & Peterborough NHS Fdn Trust, Cambridge, England. [Bullmore, E. T.] GlaxoSmithKline, ImmunoPsychiat Alternat Discovery & Dev, Cambridge, England. RP Crossley, NA (reprint author), Kings Coll London, Inst Psychiat Psychol & Neurosci, Dept Psychosis Studies, London WC2R 2LS, England. EM nicolas.crossley@kcl.ac.uk OI Bullmore, Edward/0000-0002-8955-8283; Crossley, Nicolas/0000-0002-3060-656X FU National Institute of Health (NIH) [R01MH074457] FX PTF is supported by a National Institute of Health (NIH) award (R01MH074457). NR 70 TC 4 Z9 4 U1 5 U2 24 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0033-2917 EI 1469-8978 J9 PSYCHOL MED JI Psychol. Med. PD APR PY 2016 VL 46 IS 5 BP 897 EP 907 DI 10.1017/S0033291715002895 PG 11 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA DF8PQ UT WOS:000371620700001 PM 26809184 ER PT J AU Williams, A Nakagawa, A Sado, M Fujisawa, D Mischoulon, D Smith, F Mimura, M Sato, Y AF Williams, Aya Nakagawa, Atsuo Sado, Mitsuhiro Fujisawa, Daisuke Mischoulon, David Smith, Felicia Mimura, Masaru Sato, Yuji TI Comparison of Initial Psychological Treatment Selections by US and Japanese Early-Career Psychiatrists for Patients with Major Depression: A Case Vignette Study SO ACADEMIC PSYCHIATRY LA English DT Article DE Major depressive disorder; Psychotherapy; Treatment selection; Residency; Culture ID MODEL AB Objective The authors compared early-career psychiatrists' selection of psychological treatments for patients with mild to moderate major depressive disorder (MDD) in the US and Japan. Methods A total of 120 early-career psychiatrists from two residency programs in the US and Japan participated in web-based surveys. The psychiatrists selected first-and secondline psychological treatments in response to two case vignettes of patients with mild and moderate MDD. Results Eighty-one psychiatrists (68 %) returned the surveys, of whom 39 (48 %) were American and 42 (52 %) Japanese. In response to the mild MDD case, more US psychiatrists selected high-intensity psychological treatments (P<0.001), whereas more Japanese psychiatrists selected low-intensity psychological treatments (P<0.001). In both countries, more psychiatrists selected psychological treatment than medication. In response to the moderate MDD case, one third of the US psychiatrists selected high-intensity psychological treatments (P<0.001), whereas half of the Japanese psychiatrists selected low-intensity psychological treatments (P=0.010). Conclusions Residency training, availability of psychological treatments, and cultural beliefs may shape differences in treatment selections, which in turn may impact the dissemination and implementation of psychological treatment in clinical practice across cultures. C1 [Williams, Aya] Univ Calif Berkeley, Berkeley, CA 94720 USA. [Nakagawa, Atsuo; Sado, Mitsuhiro; Fujisawa, Daisuke; Mimura, Masaru; Sato, Yuji] Keio Univ, Sch Med, Tokyo, Japan. [Mischoulon, David; Smith, Felicia] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Williams, A (reprint author), Univ Calif Berkeley, Berkeley, CA 94720 USA. EM aiwilliams@berkeley.edu FU Health Labor Sciences Research Grant from the Japanese Ministry of Health, Labour, and Welfare [H25-Seishin-Shitei-011, H26-Seishin-Shitei-001] FX This study was made possible by a Health Labor Sciences Research Grant (H25-Seishin-Shitei-011, H26-Seishin-Shitei-001) from the Japanese Ministry of Health, Labour, and Welfare. The authors also thank Dr. Nhi-Ha Trinh and Dr. Justin Chen from the MGH Depression Clinical and Research Program for their contributions to the study design and recruitment. NR 26 TC 0 Z9 0 U1 2 U2 6 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 APR PY 2016 VL 40 IS 2 BP 235 EP 241 DI 10.1007/s40596-015-0398-6 PG 7 WC Education & Educational Research; Psychiatry SC Education & Educational Research; Psychiatry GA DF5WH UT WOS:000371422800007 PM 26268880 ER PT J AU Matura, LA McDonough, A Carroll, DL AF Matura, Lea Ann McDonough, Annette Carroll, Diane L. TI Symptom Prevalence, Symptom Severity, and Health-Related Quality of Life Among Young, Middle, and Older Adults With Pulmonary Arterial Hypertension SO AMERICAN JOURNAL OF HOSPICE & PALLIATIVE MEDICINE LA English DT Article DE symptoms; quality of life; pulmonary; hypertension; aging; severity ID HEART-FAILURE; EMERGENCY-DEPARTMENT; END-POINTS; CARE; ELDERS; PREDICTORS; DIAGNOSIS; THERAPY; STATES; SF-36 AB Pulmonary arterial hypertension (PAH) is a chronic, life threatening illness that affects primarily women. The purpose of this study was to describe the prevalence of PAH symptoms and to determine whether there are differences in symptom severity and HRQOL in PAH symptoms among young, middle, and older adults with PAH. A cross sectional design was utilized. For all the age groups, shortness of breath (SOB) on exertion and fatigue were the two most prevalent symptoms. SOB on exertion had the highest symptom severity scores followed by fatigue for all groups. Symptom severity was significantly different among the groups for palpitations, abdominal swelling and nausea. For components of HRQOL, physical functioning worsened with age. All groups had diminished general health, role physical and vitality levels. There are some differences in symptom prevalence, symptom severity and HRQOL among young, middle and older adults. Awareness of these differences is important for healthcare providers to know and assess overtime. Palliative care should be an integral part of caring for patients with PAH. C1 [Matura, Lea Ann] Univ Penn, Sch Nursing, Claire M Fagin Hall,418 Curie Blvd,Room 322, Philadelphia, PA 19104 USA. [McDonough, Annette] Univ Massachusetts, Massachusetts Gen Hosp, Lowell, MA USA. [Carroll, Diane L.] Inst Patient Care, Munn Ctr Nursing Res, Boston, MA USA. RP Matura, LA (reprint author), Univ Penn, Sch Nursing, Claire M Fagin Hall,418 Curie Blvd,Room 322, Philadelphia, PA 19104 USA. EM matura@nursing.upenn.edu FU Bouve College of Health Sciences, Northeastern University; Sigma Theta Tau International Gamma Epsilon grant FX This work was partially supported by a Bouve College of Health Sciences, Northeastern University intramural grant and Sigma Theta Tau International Gamma Epsilon grant. NR 44 TC 1 Z9 1 U1 4 U2 10 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 APR PY 2016 VL 33 IS 3 BP 214 EP 221 DI 10.1177/1049909114554079 PG 8 WC Health Care Sciences & Services SC Health Care Sciences & Services GA DF4LF UT WOS:000371319000002 PM 25294227 ER PT J AU Mallory, MA Losk, K Camuso, K Caterson, S Nimbkar, S Golshan, M AF Mallory, Melissa Anne Losk, Katya Camuso, Kristen Caterson, Stephanie Nimbkar, Suniti Golshan, Mehra TI Does "Two is Better Than One" Apply to Surgeons? Comparing Single-Surgeon Versus Co-surgeon Bilateral Mastectomies SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID STAGE BREAST-CANCER; VENOUS THROMBOEMBOLISM; 2-SURGEON TECHNIQUE; RECONSTRUCTION; SATISFACTION; OUTCOMES; TRENDS; TIME AB Bilateral mastectomies (BM) are traditionally performed by single surgeons (SS); a co-surgeon (CS) technique, where each surgeon concurrently performs a unilateral mastectomy, offers an alternative approach. We examined differences in general surgery time (GST), overall surgery time (OST), and patient complications for BM performed by CS and SS. Patients undergoing BM with tissue expander reconstruction (BMTR) between January 2010 and May 2014 at our center were identified through operative case logs. GST (incision to end of BM procedure), reconstruction duration (RST) (plastic surgery start to end of reconstruction) and OST (OST = GST + RST) was calculated. Patient age, presence/stage of cancer, breast weight, axillary procedure performed, and 30-day postoperative complications were extracted from medical records. Differences in GST and OST between CS and SS cases were assessed with a t test. A multivariate linear regression was fit to identify factors associated with GST. A total of 116 BMTR cases were performed [CS, n = 67 (57.8 %); SS, n = 49 (42.2 %)]. Demographic characteristics did not differ between groups. GST and OST were significantly shorter for CS cases, 75.8 versus 116.8 min, p < .0001, and 255.2 versus 278.3 min, p = .005, respectively. Presence of a CS significantly reduces BMTR time (beta = -38.82, p < .0001). Breast weight (beta = 0.0093, p = .03) and axillary dissection (beta = 28.69, p = .0003) also impacted GST. The CS approach to BMTR reduced both GST and OST; however, the degree of time savings (35.1 and 8.3 %, respectively) was less than hypothesized. A larger study is warranted to better characterize time, cost, and outcomes of the CS-approach for BM. C1 [Mallory, Melissa Anne; Nimbkar, Suniti; Golshan, Mehra] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Surg, Boston, MA 02115 USA. [Mallory, Melissa Anne; Golshan, Mehra] Dana Farber Canc Inst, Dept Surg, Boston, MA 02115 USA. [Losk, Katya; Camuso, Kristen] Dana Farber Canc Inst, Dept Qual & Patient Safety, Boston, MA 02115 USA. [Caterson, Stephanie] Brigham & Womens Hosp, Div Plast Surg, 75 Francis St, Boston, MA 02115 USA. RP Golshan, M (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Surg, Boston, MA 02115 USA.; Golshan, M (reprint author), Dana Farber Canc Inst, Dept Surg, Boston, MA 02115 USA. EM MGolshan@partners.org FU NCI NIH HHS [R25 CA089017] NR 25 TC 0 Z9 0 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD APR PY 2016 VL 23 IS 4 BP 1111 EP 1116 DI 10.1245/s10434-015-4956-7 PG 6 WC Oncology; Surgery SC Oncology; Surgery GA DF4QA UT WOS:000371333200009 PM 26514122 ER PT J AU Amri, R Bordeianou, LG Berger, DL AF Amri, Ramzi Bordeianou, Liliana G. Berger, David L. TI Effect of High-Grade Disease on Outcomes of Surgically Treated Colon Cancer SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID LARGE BOWEL-CANCER; COLORECTAL-CANCER; MULTIVARIATE-ANALYSIS; PROGNOSTIC-FACTORS; RECTAL-CANCER; SURVIVAL; CARCINOMA AB Tumor grade is one of the cardinal pathological characteristics of colon cancer. Despite a large body of evidence on disease grade in general, the exact impact of high-grade disease in the context of the simplified high/low-grade dichotomy that is based on glandular formation rate has yet to be quantified. Patients with sporadic colon cancer treated surgically at our center (2004-2011) were included in an institutional review board-approved database. We measured the rates of distant and nodal disease spread in baseline pathology and the multivariable hazard radio (mHR) of recurrence and overall- and disease-specific mortality. Among 922 patients with specified tumor grade in baseline surgical pathology, 175 (19.0 %) had high-grade disease. These patients were at far higher risk of lymph node metastasis (63.8 vs. 39.6 %; P < 0.001) and metastatic presentation (31.4 vs. 15.8 %; P < 0.001). These baseline differences also led to significantly worse outcomes, including disease recurrence (17.1 vs. 10.6 %; mHR = 1.83; P = 0.026), overall mortality (57.7 vs. 33.3 %; mHR = 1.65; P < 0.001), and colon cancer-specific mortality (39.4 vs. 16.9 %; mHR = 1.57; P = 0.004). Most significantly, in stage II patients (n = 294), those with high-grade disease (16.0 %) had an mHR of 2.84 (P < 0.001) for mortality. High-grade disease on baseline surgical pathology is associated with a considerably higher rate of nodal and distant metastasis in colon cancer. As a result, the colon cancer-related mortality doubles for patients with high-grade disease. These findings were independent of baseline staging and confirm that the high-/low-grade tumor dichotomy is an important prognostic factor greatly influencing colon cancer outcomes across stages. C1 [Amri, Ramzi; Bordeianou, Liliana G.; Berger, David L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Gen Surg & Gastrointestinal Surg, Boston, MA USA. RP Berger, DL (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Gen Surg & Gastrointestinal Surg, Boston, MA USA. EM dberger@mgh.harvard.edu OI Amri, Ramzi/0000-0001-7416-6650 NR 20 TC 1 Z9 1 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD APR PY 2016 VL 23 IS 4 BP 1157 EP 1163 DI 10.1245/s10434-015-4983-4 PG 7 WC Oncology; Surgery SC Oncology; Surgery GA DF4QA UT WOS:000371333200016 PM 26589501 ER PT J AU Shen, T Bao, XD Alfille, PH AF Shen, Tao Bao, Xiaodong Alfille, Paul H. TI Perioperative complications in adults with a posterior mediastinal mass: a retrospective observational cohort study SO CANADIAN JOURNAL OF ANESTHESIA-JOURNAL CANADIEN D ANESTHESIE LA English DT Article ID MANAGEMENT; PATIENT AB We studied the incidence of perioperative complications in patients presenting with a posterior mediastinal mass and the possible predictors of complications in these patients. We conducted a review of the perioperative records of patients aged over 18 years with a posterior mediastinal mass confirmed by computed tomography (CT) who were admitted for surgical procedures relating to the mass during 2004-2014. Perioperative complications were defined as 1) hypoxemia (pulse oximetry < 90% at a fraction of inspired oxygen of 1.0), 2) difficult ventilation (peak pressure > 40 cm H2O or respiratory acidosis with PaCO2 > 60 mmHg), and 3) hemodynamic instability (systolic pressure < 70 mmHg, pulse rate < 40 beats center dot min(-1) and/or > 120 beats center dot min(-1) for over five minutes). The review also extended to the first 24 hr postoperatively for cardiovascular and respiratory instability. Forty-three patients underwent 44 procedures, and the surgery entailed resection of the mediastinal mass in all but one patient. All patients received general anesthesia following intravenous induction. In 43 of 44 cases, intubation was achieved uneventfully with direct laryngoscopy after neuromuscular blockade. The incidence of perioperative cardiopulmonary complications was seven of 44 (16%) procedures. Four of these involved severe hypoxemia, two concerned hemodynamic instability, and two led to postoperative respiratory distress. No cardiovascular collapse or complete airway occlusion occurred. All occurrences of intraoperative complications transpired mid-surgery - six of the seven with the patient in the lateral position. Patients who developed complications were more likely to have a mass with a larger diameter and evidence of airway compression on the preoperative CT scan. The incidence of perioperative complications in patients with a posterior mediastinal mass is not insignificant; however, no catastrophic airway or cardiopulmonary event was encountered in this study. C1 [Shen, Tao; Bao, Xiaodong; Alfille, Paul H.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Gray Bigelow 444,55 Fruit St, Boston, MA 02114 USA. [Shen, Tao; Bao, Xiaodong; Alfille, Paul H.] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Shen, T (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Gray Bigelow 444,55 Fruit St, Boston, MA 02114 USA. EM tshen2@partners.org NR 12 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0832-610X EI 1496-8975 J9 CAN J ANESTH JI Can. J. Anesth. PD APR PY 2016 VL 63 IS 4 BP 454 EP 460 DI 10.1007/s12630-015-0516-7 PG 7 WC Anesthesiology SC Anesthesiology GA DF7HR UT WOS:000371529200008 PM 26497724 ER PT J AU Janssen, SJ Molleman, J Guitton, TG Ring, D AF Janssen, Stein J. Molleman, Jeroen Guitton, Thierry G. Ring, David CA Sci Variation Grp TI What Middle Phalanx Base Fracture Characteristics are Most Reliable and Useful for Surgical Decision-making? (vol 473, pg 3943, 2015) SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Correction C1 [Janssen, Stein J.; Molleman, Jeroen; Ring, David] Massachusetts Gen Hosp, Yawkey Ctr, Dept Orthopaed Surg, Hand & Upper Extrem Serv, Suite 2100,55 Fruit St, Boston, MA 02114 USA. [Guitton, Thierry G.] Univ Amsterdam, Acad Med Ctr, Dept Orthopaed Surg, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. RP Ring, D (reprint author), Massachusetts Gen Hosp, Yawkey Ctr, Dept Orthopaed Surg, Hand & Upper Extrem Serv, Suite 2100,55 Fruit St, Boston, MA 02114 USA. EM dring@partners.org NR 1 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-921X EI 1528-1132 J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD APR PY 2016 VL 474 IS 4 BP 1080 EP 1081 DI 10.1007/s11999-016-4728-0 PG 2 WC Orthopedics; Surgery SC Orthopedics; Surgery GA DF5JA UT WOS:000371386600035 PM 26842233 ER PT J AU Jeff, JM Peloso, GM Do, R AF Jeff, Janina M. Peloso, Gina M. Do, Ron TI What can we learn about lipoprotein metabolism and coronary heart disease from studying rare variants? SO CURRENT OPINION IN LIPIDOLOGY LA English DT Review DE exome sequencing; rare variant association studies; coronary heart disease; lipoprotein metabolism ID FAMILIAL COMBINED HYPOLIPIDEMIA; SEQUENCING IDENTIFIES RARE; GENOME-WIDE ASSOCIATION; ARTERY-DISEASE; LOW-FREQUENCY; COMMON VARIANTS; COMPLEX DISEASE; LIPID-LEVELS; MUTATIONS; CHOLESTEROL AB Purpose of review Rare variant association studies (RVAS) target the class of genetic variation with frequencies less than 1%. Recently, investigators have used exome sequencing in RVAS to identify rare alleles responsible for Mendelian diseases but have experienced greater difficulty discovering such alleles for complex diseases. In this review, we describe what we have learned about lipoprotein metabolism and coronary heart disease through the conduct of RVAS. Recent findings Rare protein-altering genetic variation can provide important insights that are not as easily attainable from common variant association studies. First, RVAS can facilitate gene discovery by identifying novel rare protein-altering variants in specific genes that are associated with disease. Second, rare variant associations can provide supportive evidence for putative drug targets for novel therapies. Finally, rare variants can uncover new pathways and reveal new biologic mechanisms. The field of human genetics has already made tremendous progress in understanding lipoprotein metabolism and the causes of coronary heart disease in the context of rare variants. As next generation sequencing becomes more cost-effective, RVAS with larger sample sizes will be conducted. This will lead to more novel rare variant discoveries and the translation of genomic data into biological knowledge and clinical insights for cardiovascular disease. C1 [Jeff, Janina M.; Do, Ron] Icahn Sch Med Mt Sinai, Charles F Bronfman Inst Personalized Med, New York, NY 10029 USA. [Peloso, Gina M.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Do, Ron] Icahn Sch Med Mt Sinai, Charles F Bronfman Inst Personalized Med, Ctr Stat Genet, New York, NY 10029 USA. [Do, Ron] Icahn Sch Med Mt Sinai, Charles F Bronfman Inst Personalized Med, Zena & Michael A Weiner Cardiovasc Inst, New York, NY 10029 USA. [Do, Ron] Icahn Sch Med Mt Sinai, Charles F Bronfman Inst Personalized Med, Dept Genet & Genom Sci, One Gustave L Levy Pl,Box 1003, New York, NY 10029 USA. RP Do, R (reprint author), Icahn Sch Med Mt Sinai, Charles F Bronfman Inst Personalized Med, Dept Genet & Genom Sci, One Gustave L Levy Pl,Box 1003, New York, NY 10029 USA. EM ron.do@mssm.edu FU National Heart, Lung, and Blood Institute of the National Institutes of Health [K01HL125751] FX G.M.P. is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number K01HL125751. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 46 TC 0 Z9 0 U1 1 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0957-9672 EI 1473-6535 J9 CURR OPIN LIPIDOL JI Curr. Opin. Lipidology PD APR PY 2016 VL 27 IS 2 BP 99 EP 104 DI 10.1097/MOL.0000000000000277 PG 6 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Peripheral Vascular Disease SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Cardiovascular System & Cardiology GA DF8UK UT WOS:000371635100001 PM 26844526 ER PT J AU Lindner, O Pascual, TNB Mercuri, M Acampa, W Burchert, W Flotats, A Kaufmann, PA Kitsiou, A Knuuti, J Underwood, SR Vitola, JV Mahmarian, JJ Karthikeyan, G Better, N Rehani, MM Kashyap, R Dondi, M Paez, D Einstein, AJ AF Lindner, Oliver Pascual, Thomas N. B. Mercuri, Mathew Acampa, Wanda Burchert, Wolfgang Flotats, Albert Kaufmann, Philipp A. Kitsiou, Anastasia Knuuti, Juhani Underwood, S. Richard Vitola, Joao V. Mahmarian, John J. Karthikeyan, Ganesan Better, Nathan Rehani, Madan M. Kashyap, Ravi Dondi, Maurizio Paez, Diana Einstein, Andrew J. CA INCAPS Investigators Grp TI Nuclear cardiology practice and associated radiation doses in Europe: results of the IAEA Nuclear Cardiology Protocols Study (INCAPS) for the 27 European countries SO EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING LA English DT Article DE Nuclear cardiology; Myocardial perfusion scintigraphy; SPECT; PET; Radiation dose; Best practices; Quality of care; Europe ID POSITRON-EMISSION-TOMOGRAPHY; CORONARY-ARTERY-DISEASE; MYOCARDIAL-PERFUSION SCINTIGRAPHY; COMPUTED-TOMOGRAPHY; PROGNOSTIC VALUE; MEDICAL THERAPY; EXPOSURE; METAANALYSIS; REVASCULARIZATION; MORTALITY AB Purpose Nuclear cardiology is widely used to diagnose coronary artery disease and to guide patient management, but data on current practices, radiation dose-related best practices, and radiation doses are scarce. To address these issues, the IAEA conducted a worldwide study of nuclear cardiology practice. We present the European subanalysis. Methods In March 2013, the IAEA invited laboratories across the world to document all SPECT and PET studies performed in one week. The data included age, gender, weight, radiopharmaceuticals, injected activities, camera type, positioning, hardware and software. Radiation effective dose was calculated for each patient. A quality score was defined for each laboratory as the number followed of eight predefined best practices with a bearing on radiation exposure (range of quality score 0 - 8). The participating European countries were assigned to regions (North, East, South, and West). Comparisons were performed between the four European regions and between Europe and the rest-of-the-world (RoW). Results Data on 2,381 European patients undergoing nuclear cardiology procedures in 102 laboratories in 27 countries were collected. A cardiac SPECT study was performed in 97.9 % of the patients, and a PET study in 2.1 %. The average effective dose of SPECT was 8.0 +/- 3.4 mSv (RoW 11.4 +/- 4.3 mSv; P < 0.001) and of PET was 2.6 +/- 1.5 mSv (RoW 3.8 +/- 2.5 mSv; P < 0.001). The mean effective doses of SPECT and PET differed between European regions (P < 0.001 and P = 0.002, respectively). The mean quality score was 6.2 +/- 1.2, which was higher than the RoW score (5.0 +/- 1.1; P < 0.001). Adherence to best practices did not differ significantly among the European regions (range 6 to 6.4; P = 0.73). Of the best practices, stress-only imaging and weight-adjusted dosing were the least commonly used. Conclusion In Europe, the mean effective dose from nuclear cardiology is lower and the average quality score is higher than in the RoW. There is regional variation in effective dose in relation to the best practice quality score. A possible reason for the differences between Europe and the RoW could be the safety culture fostered by actions under the Euratom directives and the implementation of diagnostic reference levels. Stress-only imaging and weight-adjusted activity might be targets for optimization of European nuclear cardiology practice. C1 [Lindner, Oliver; Burchert, Wolfgang] Ruhr Univ, Inst Radiol Nucl Med & Mol Imaging, Heart & Diabet Ctr North Rhine Westphalia Bochum, Univ Hosp, Georgstr 11, D-32545 Bad Oeynhausen, Germany. [Pascual, Thomas N. B.; Kashyap, Ravi; Dondi, Maurizio; Paez, Diana] IAEA, Sect Nucl Med & Diagnost, Div Human Hlth, A-1400 Vienna, Austria. [Mercuri, Mathew; Einstein, Andrew J.] Columbia Univ, Dept Med, Div Cardiol, Med Ctr, New York, NY USA. [Mercuri, Mathew; Einstein, Andrew J.] New York Presbyterian Hosp, New York, NY USA. [Acampa, Wanda] CNR, Inst Biostruct & Bioimaging, Naples, Italy. [Flotats, Albert] Univ Autonoma Barcelona, Hosp Santa Creu & Sant Pau, Dept Nucl Med, E-08193 Barcelona, Spain. [Kaufmann, Philipp A.] Univ Zurich Hosp, Dept Nucl Med & Cardiac Imaging, CH-8091 Zurich, Switzerland. [Kitsiou, Anastasia] Sismanoglio Hosp, Dept Cardiol, Athens, Greece. [Knuuti, Juhani] Univ Turku, Turku PET Ctr, Turku, Finland. [Knuuti, Juhani] Turku Univ Hosp, FIN-20520 Turku, Finland. [Underwood, S. Richard] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England. [Underwood, S. Richard] Royal Brompton & Harefield Hosp, Dept Nucl Med, London, England. [Vitola, Joao V.] Quanta Diagnost & Terapia, Curitiba, Parana, Brazil. [Mahmarian, John J.] Houston Methodist DeBakey Heart & Vasc Ctr, Dept Cardiol, Houston, TX USA. [Karthikeyan, Ganesan] All India Inst Med Sci, Dept Cardiol, New Delhi, India. [Better, Nathan] Royal Melbourne Hosp, Dept Nucl Med, Melbourne, Vic, Australia. [Better, Nathan] Univ Melbourne, Melbourne, Vic, Australia. [Rehani, Madan M.] IAEA, Radiat Protect Patients Unit, A-1400 Vienna, Austria. [Rehani, Madan M.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Rehani, Madan M.] Harvard Univ, Sch Med, Boston, MA USA. [Einstein, Andrew J.] Columbia Univ, Med Ctr, Dept Radiol, New York, NY USA. RP Lindner, O (reprint author), Ruhr Univ, Inst Radiol Nucl Med & Mol Imaging, Heart & Diabet Ctr North Rhine Westphalia Bochum, Univ Hosp, Georgstr 11, D-32545 Bad Oeynhausen, Germany. EM olindner@hdz-nrw.de RI Lahoutte, Tony/O-6381-2016; Maffioli, Lorenzo Stefano/Q-4985-2016; OI Al-Mallah, Mouaz/0000-0003-2348-0484; Maffioli, Lorenzo Stefano/0000-0002-8867-2447; Knuuti, Juhani/0000-0003-3156-9593 FU IAEA; Margaret Q. Landenberger Research Foundation; Irving Scholars Program FX Funding was obtained from the IAEA, the Margaret Q. Landenberger Research Foundation, and the Irving Scholars Program. NR 28 TC 1 Z9 1 U1 4 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1619-7070 EI 1619-7089 J9 EUR J NUCL MED MOL I JI Eur. J. Nucl. Med. Mol. Imaging PD APR PY 2016 VL 43 IS 4 BP 718 EP 728 DI 10.1007/s00259-015-3270-8 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DF1BT UT WOS:000371074100014 PM 26686336 ER PT J AU Badri, H Pitter, K Holland, EC Michor, F Leder, K AF Badri, H. Pitter, K. Holland, E. C. Michor, F. Leder, K. TI Optimization of radiation dosing schedules for proneural glioblastoma SO JOURNAL OF MATHEMATICAL BIOLOGY LA English DT Article DE Brain tumors; Radiotherapy; Nonlinear programming; Linear-quadratic model ID LINEAR-QUADRATIC MODEL; CANCER STEM-CELLS; DOSE DISTRIBUTION; SIMULATION-MODEL; TUMOR RESPONSE; IN-VIVO; FRACTIONATION; RADIOTHERAPY; GLIOMA; SUBCLASSES AB Glioblastomas are the most aggressive primary brain tumor. Despite treatment with surgery, radiation and chemotherapy, these tumors remain uncurable and few significant increases in survival have been observed over the last half-century. We recently employed a combined theoretical and experimental approach to predict the effectiveness of radiation administration schedules, identifying two schedules that led to superior survival in a mouse model of the disease (Leder et al., Cell 156(3):603-616, 2014). Here we extended this approach to consider fractionated schedules to best minimize toxicity arising in early- and late-responding tissues. To this end, we decomposed the problem into two separate solvable optimization tasks: (i) optimization of the amount of radiation per dose, and (ii) optimization of the amount of time that passes between radiation doses. To ensure clinical applicability, we then considered the impact of clinical operating hours by incorporating time constraints consistent with operational schedules of the radiology clinic. We found that there was no significant loss incurred by restricting dosage to an 8:00 a.m. to 5:00 p.m. window. Our flexible approach is also applicable to other tumor types treated with radiotherapy. C1 [Badri, H.; Leder, K.] Univ Minnesota, Dept Ind & Syst Engn, Minneapolis, MN 55455 USA. [Pitter, K.] Weill Cornell Med Coll, New York, NY 10065 USA. [Holland, E. C.] Fred Hutchinson Canc Res Ctr, Div Human Biol, Seattle, WA 98195 USA. [Michor, F.] Dana Farber Canc Inst, Dept Computat Biol, Boston, MA 02215 USA. [Michor, F.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. RP Leder, K (reprint author), Univ Minnesota, Dept Ind & Syst Engn, Minneapolis, MN 55455 USA. EM badri019@umn.edu; kep2008@med.cornell.edu; eholland@fhcrc.org; michor@jimmy.harvard.edu; lede0024@umn.edu FU NSF [CMMI-1362236, DMS-1224362]; NIH [U54CA143798, U54 CA143798, U54CA163167-01] FX HB is partially supported by NSF Grants CMMI-1362236. KL is partially supported by NSF Grants DMS-1224362 and CMMI-1362236. FM is partially supported by the Grant NIH U54CA143798. E.H is supported by NIH grants U54 CA143798 and U54CA163167-01. We would like to thank an anonymous referee for their helpful comments. NR 29 TC 6 Z9 6 U1 0 U2 9 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0303-6812 EI 1432-1416 J9 J MATH BIOL JI J. Math. Biol. PD APR PY 2016 VL 72 IS 5 BP 1301 EP 1336 DI 10.1007/s00285-015-0908-x PG 36 WC Biology; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology GA DF4CH UT WOS:000371294400007 PM 26094055 ER PT J AU Valenza, G Orsolini, S Diciotti, S Citi, L Scilingo, EP Guerrisi, M Danti, S Lucetti, C Tessa, C Barbieri, R Toschi, N AF Valenza, Gaetano Orsolini, Stefano Diciotti, Stefano Citi, Luca Scilingo, Enzo Pasquale Guerrisi, Maria Danti, Sabrina Lucetti, Claudio Tessa, Carlo Barbieri, Riccardo Toschi, Nicola TI Assessment of spontaneous cardiovascular oscillations in Parkinson's disease SO BIOMEDICAL SIGNAL PROCESSING AND CONTROL LA English DT Article DE Parkinson's disease; Heart rate variability; Autonomic nervous system; Point process; Laguerre expansion; Bispectrum Lyapunov exponents; Support vector machine; Autonomic dysfunction ID HEART-RATE-VARIABILITY; MULTISCALE ENTROPY ANALYSIS; MULTIPLE SYSTEM ATROPHY; AUTONOMIC DYSFUNCTION; ORTHOSTATIC HYPOTENSION; FAILURE; PATHOPHYSIOLOGY; DIFFERENTIATION; PATHOGENESIS; PREVALENCE AB Parkinson's disease (PD) has been reported to involve postganglionic sympathetic failure and a wide spectrum of autonomic dysfunctions including cardiovascular, sexual, bladder, gastrointestinal and sudomotor abnormalities. While these symptoms may have a significant impact on daily activities, as well as quality of life, the evaluation of autonomic nervous system (ANS) dysfunctions relies on a large and expensive battery of autonomic tests only accessible in highly specialized laboratories. In this paper we aim to devise a comprehensive computational assessment of disease-related heartbeat dynamics based on instantaneous, time-varying estimates of spontaneous (resting state) cardiovascular oscillations in PD. To this end, we combine standard ANS-related heart rate variability (HRV) metrics with measures of instantaneous complexity (dominant Lyapunov exponent and entropy) and higher-order statistics (bispectra). Such measures are computed over 600-s recordings acquired at rest in 29 healthy subjects and 30 PD patients. The only significant group-wise differences were found in the variability of the dominant Lyapunov exponent. Also, the best PD vs. healthy controls classification performance (balanced accuracy: 73.47%) was achieved only when retaining the time-varying, non-stationary structure of the dynamical features, whereas classification performance dropped significantly (balanced accuracy: 61.91%) when excluding variability-related features. Additionally, both linear and nonlinear model features correlated with both clinical and neuropsychological assessments of the considered patient population. Our results demonstrate the added value and potential of instantaneous measures of heartbeat dynamics and its variability in characterizing PD-related disabilities in motor and cognitive domains. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Valenza, Gaetano; Barbieri, Riccardo] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Citi, Luca] Univ Essex, Sch Comp Sci & Elect Engn, Colchester CO4 3SQ, Essex, England. [Valenza, Gaetano; Scilingo, Enzo Pasquale] Univ Pisa, Dept Informat Engn, Largo Lucio Lazzarino 1, I-56122 Pisa, Italy. [Valenza, Gaetano; Scilingo, Enzo Pasquale] Univ Pisa, Res Ctr E Piaggio, Largo Lucio Lazzarino 1, I-56122 Pisa, Italy. [Guerrisi, Maria; Toschi, Nicola] Univ Roma Tor Vergata, Dept Biomed & Prevent, Rome, Italy. [Orsolini, Stefano; Diciotti, Stefano] Univ Bologna, Dept Elect Elect & Informat Engn Guglielmo Marcon, Cesena, Italy. [Danti, Sabrina; Lucetti, Claudio; Tessa, Carlo] Versilia Hosp, Viareggio, Italy. [Barbieri, Riccardo] Politecn Milan, Dept Elect Informat & Bioengn, I-20133 Milan, Italy. [Toschi, Nicola] AA Martinos Ctr Biomed Imaging MGH, Athens, GA USA. [Toschi, Nicola] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Valenza, G (reprint author), Univ Pisa, Dept Informat Engn, Largo Lucio Lazzarino 1, I-56122 Pisa, Italy.; Valenza, G (reprint author), Univ Pisa, Res Ctr E Piaggio, Largo Lucio Lazzarino 1, I-56122 Pisa, Italy. EM g.valenza@ieee.org RI Diciotti, Stefano/C-4167-2008; Toschi, Nicola/J-2555-2012 OI Diciotti, Stefano/0000-0001-8778-7819; Toschi, Nicola/0000-0003-1929-5833 FU Department of Anesthesia, Critical Care & Pain Medicine, Massachusetts General Hospital; Harvard Medical School, Boston, MA, USA; European Union Seventh Framework Programme of project "WEARHAP" [601165] FX The research leading to these results has received partial funding from the Department of Anesthesia, Critical Care & Pain Medicine, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA, and European Union Seventh Framework Programme FP7/2007-2013 under Grant No. 601165 of the project "WEARHAP". NR 48 TC 5 Z9 5 U1 5 U2 12 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1746-8094 EI 1746-8108 J9 BIOMED SIGNAL PROCES JI Biomed. Signal Process. Control PD APR PY 2016 VL 26 BP 80 EP 89 DI 10.1016/j.bspc.2015.12.001 PG 10 WC Engineering, Biomedical; Medical Laboratory Technology SC Engineering; Medical Laboratory Technology GA DE8QA UT WOS:000370900200010 ER PT J AU Schaller, SJ Stauble, CG Suemasa, M Heim, M Duarte, IM Mensch, O Bogdanski, R Lewald, H Eikermann, M Blobner, M AF Schaller, Stefan J. Staeuble, Christiane G. Suemasa, Mika Heim, Markus Duarte, Ingrid Moreno Mensch, Oliver Bogdanski, Ralph Lewald, Heidrun Eikermann, Matthias Blobner, Manfred TI The German Validation Study of the Surgical Intensive Care Unit Optimal Mobility Score SO JOURNAL OF CRITICAL CARE LA English DT Article DE Muscle wasting; Intensive care unit-acquired weakness (ICUAW); Early mobilization; Scoring system; SOMS ID CRITICALLY-ILL PATIENTS; ACUTE RESPIRATORY-FAILURE; LENGTH-OF-STAY; SUBARACHNOID HEMORRHAGE; PREDICTS MORTALITY; EARLY MOBILIZATION; BRAIN-INJURY; HYPERNATREMIA; IMPROVEMENT; SURGERY AB Purpose: Immobilization of critically ill patients leads to muscle weakness, which translates to increased costs of care and long-term functional disability. We tested the validity of a German Surgical Intensive Care Unit (ICU) Optimal Mobilization Score (SOMS) in 2 different cohorts (neurocritical and nonneurocritical care patients). Materials and Methods: Physical therapists estimated the patients' mobilization capacity by using the German version of the SOMS the morning after admission. We tested the prognostic value of the prediction for ICU and hospital length of stay (LOS) as well as for mortality, and built a model to account for other known predictors of these outcomes in the 2 cohorts. Results: A total of 128 patients were included in the analysis, 48 of these were neurocritical care patients. The SOMS predicted mortality and ICU and hospital LOS. Neurocritical care patients stayed significantly longer in the ICU (median 12 vs 4 days, P<.001) and in the hospital (25 vs 17 days, P = .02). The SOMS predicted ICU and hospital LOS. It predicted mortality only in nonneurocritical patients. Conclusions: The German SOMS assessed by physical therapists on the day after ICU admission predicts ICU and hospital LOS, and mortality. Our data suggest that the association between early mobilization and mortality is more complex in neurocritical care patients. (C) 2015 Elsevier Inc. All rights reserved. C1 [Schaller, Stefan J.; Staeuble, Christiane G.; Suemasa, Mika; Heim, Markus; Mensch, Oliver; Bogdanski, Ralph; Lewald, Heidrun; Blobner, Manfred] Tech Univ Munich, Klinikum Rechts Isar, Klin Anaesthesiol, Ismaningerstr 22, D-81675 Munich, Germany. [Duarte, Ingrid Moreno; Eikermann, Matthias] Massachusetts Gen Hosp, Dept Anesthesia, Crit Care, Pain Med, Boston, MA 02114 USA. RP Schaller, SJ (reprint author), Tech Univ Munich, Klinikum Rechts Isar, Klin Anaesthesiol, Ismaningerstr 22, D-81675 Munich, Germany. EM stefan.schaller@tum.de OI Lewald, Heidrun/0000-0002-5192-425X; Schaller, Stefan/0000-0002-6683-9584 FU MSD Sharpe Dohme; Essex; Baxter; Care Fusion; GE Healthcare; MERCK; ResMed Foundation; GlaxoSmithKline FX Dr Stefan Schaller holds stocks of the following companies in the health care sector in small amounts: Bayer AG, Siemens AG, GE, Merck & CO INC, Rhoen-Klinikum AG, and Fresenius SE. However, these holdings do not influence any decisions regarding the study. Dr Christiane G. Stauble has received honoraria and a travel grant from MSD Sharpe & Dohme. However, these did not influence any decisions regarding the study. M. Suemasa, M. Heim, I. Muerno Duarte, R. Bogdanski, and O. Mensch have no conflict of interest declared. Dr Heidrun Lewald has received honoraria and travel grants from the following companies: MSD Sharp & Dohme, Essex, Baxter, Care Fusion, and GE Healthcare. However, these did not influence any decisions regarding the study. M. Eikermann has received research funding from MERCK and the ResMed Foundation. Prof Manfred Blobner received honoraria and travel grants from MSD Sharp & Dohme and GlaxoSmithKline. K.U. However, these did not influence any decisions regarding the study. NR 31 TC 3 Z9 3 U1 2 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 0883-9441 EI 1557-8615 J9 J CRIT CARE JI J. Crit. Care PD APR PY 2016 VL 32 BP 201 EP 206 DI 10.1016/j.jcrc.2015.12.020 PG 6 WC Critical Care Medicine SC General & Internal Medicine GA DE8DV UT WOS:000370866900035 PM 26857328 ER PT J AU Dasari, M Borrero, S Akers, AY Sucato, GS Dick, R Hicks, A Miller, E AF Dasari, Mohini Borrero, Sonya Akers, Aletha Y. Sucato, Gina S. Dick, Rebecca Hicks, Angela Miller, Elizabeth TI Barriers to Long-Acting Reversible Contraceptive Uptake Among Homeless Young Women SO JOURNAL OF PEDIATRIC AND ADOLESCENT GYNECOLOGY LA English DT Article DE Contraception; LARC; IUD; Implant; Homelessness; Mixed-methods ID ADOLESCENT; ATTITUDES; PERSPECTIVES; YOUTH; LARC AB Study Objective: To identify barriers to long-acting reversible contraception (LARC) uptake among homeless young women. Design: In this mixed methods study surveys and guided interviews were used to explore women's contraceptive and reproductive experiences, interactions with the health care system, and their histories of homelessness. Setting: All surveys and interviews were conducted at a homeless drop-in center or shelter. Participants: Fifteen women between 18 and 24 years of age with a past year history of homelessness. Interventions: None. Main Outcome Measures: Perceived barriers to contraceptive use, including knowledge and access barriers and interactions with the health care system around reproductive health. Results: Confusion about the possibility of early termination of LARC, and the perception that providers deliberately withhold selective information about contraceptive options to bias contraceptive decision-making, were 2 key new findings. Women also reported interest in visual aids accompanying verbal contraceptive counseling. Pregnancy attitudes and history of reproductive and sexual coercion also influenced contraceptive decision-making and reported interest in LARC methods. Conclusion: Comprehensive counseling about all contraceptive options, including LARC, are important for targeting the perceived gaps in contraceptive education and care among homeless young women. C1 [Dasari, Mohini] Univ Pittsburgh, Sch Med, M240 Scaife Hall,3550 Terrace St, Pittsburgh, PA 15261 USA. [Borrero, Sonya] Univ Pittsburgh, Sch Med, Div Gen Internal Med, Pittsburgh, PA 15261 USA. [Borrero, Sonya] VA Pittsburgh Healthcare Syst, CHERP, Pittsburgh, PA USA. [Akers, Aletha Y.] Childrens Hosp Philadelphia, Craig Dalsimer Div Adolescent Med, Philadelphia, PA 19104 USA. [Sucato, Gina S.] Seattle Childrens Hosp, Adolescent Hlth, Grp Hlth Cooperat, Seattle, WA USA. [Dick, Rebecca; Hicks, Angela; Miller, Elizabeth] Univ Pittsburgh, Med Ctr, Childrens Hosp Pittsburgh, Div Adolescent & Young Adult Med, Pittsburgh, PA 15261 USA. [Miller, Elizabeth] Univ Pittsburgh, Sch Med, Dept Pediat, Pittsburgh, PA 15261 USA. RP Dasari, M (reprint author), Univ Pittsburgh, Sch Med, M240 Scaife Hall,3550 Terrace St, Pittsburgh, PA 15261 USA. EM mod13@pitt.edu NR 26 TC 0 Z9 0 U1 5 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-3188 EI 1873-4332 J9 J PEDIATR ADOL GYNEC JI J. Pediatr Adolesc. Gynecol. PD APR PY 2016 VL 29 IS 2 BP 104 EP 110 DI 10.1016/j.jpag.2015.07.003 PG 7 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA DF2SA UT WOS:000371192900006 PM 26210293 ER PT J AU Labonte, AJ Benzer, JK Burgess, JF Cramer, IE Meterko, M Pogoda, TK Charns, MP AF Labonte, Alan J. Benzer, Justin K. Burgess, James F., Jr. Cramer, Irene E. Meterko, Mark Pogoda, Terri K. Charns, Martin P. TI The Effects of Organization Design and Patient Perceptions of Care on Switching Behavior and Reliance on a Health Care System Across Time SO MEDICAL CARE RESEARCH AND REVIEW LA English DT Article DE service quality; reliance; health care system; switching behavior; organization design ID PARKINSONS-DISEASE; CHRONIC ILLNESS; VETERANS; SATISFACTION; AFFAIRS; VALIDATION; EDUCATION; SERVICES; QUALITY; MODEL AB Sustaining ongoing relationships with patients is a strategic, clinically relevant goal of health care systems. This study develops and tests a conceptual model that aims to account for the influence of organization design, perceptions of quality of patient care, and other patient-level factors on the extent to which patients sustain reliance on a health care system. We use a longitudinal survey design and structural equation modeling to predict increases or decreases in patient reliance on the Department of Veterans Affairs health care system across a 4-year period for Veterans with Parkinson's Disease. Our findings show that specialized and integrated clinical practices have a positive association with the quality of patient care. Health care systems may be able to foster long-term relations with patients and improve service quality by allocating resources to form integrated, specialized, disease-specific centers of care designed for patients with chronic illnesses. C1 [Labonte, Alan J.; Benzer, Justin K.; Burgess, James F., Jr.; Cramer, Irene E.; Meterko, Mark; Pogoda, Terri K.; Charns, Martin P.] VA Ctr Healthcare Org & Implementat Res, Boston, MA USA. [Benzer, Justin K.] VISN 17 Ctr Excellence Res Returning War Vet, Waco, TX USA. [Labonte, Alan J.; Benzer, Justin K.; Burgess, James F., Jr.; Meterko, Mark; Pogoda, Terri K.; Charns, Martin P.] Boston Univ, Sch Publ Hlth, Hlth Policy & Management Dept, Boston, MA 02215 USA. RP Labonte, AJ (reprint author), VA Boston Healthcare Syst, Ctr Healthcare Org & Implementat Res, 150 South Huntington Ave 152M, Boston, MA 02130 USA. EM marian@bu.edu OI Benzer, Justin/0000-0001-5151-2127 FU Health Services Research and Development Service, Office of Research and Development, United States Department of Veterans Affairs [SDR 02-215] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Health Services Research and Development Service, Office of Research and Development, United States Department of Veterans Affairs (Project Number SDR 02-215). NR 37 TC 0 Z9 0 U1 2 U2 5 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 APR PY 2016 VL 73 IS 2 BP 182 EP 204 DI 10.1177/1077558715601543 PG 23 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA DF1IV UT WOS:000371094000002 PM 26311255 ER PT J AU El Khoury, NB Gratuze, M Petry, F Papon, MA Julien, C Marcouiller, F Morin, F Nicholls, SB Calon, F Hebert, SS Marette, A Planel, E AF El Khoury, Noura B. Gratuze, Maud Petry, Franck Papon, Marie-Amelie Julien, Carl Marcouiller, Francois Morin, Francoise Nicholls, Samantha B. Calon, Frederic Hebert, Sebastien S. Marette, Andre Planel, Emmanuel TI Hypothermia mediates age-dependent increase of tau phosphorylation in db/db mice SO NEUROBIOLOGY OF DISEASE LA English DT Article DE Alzheimer's disease; Diabetes mellitus; db/db mice; Tau hyperphosphorylation; Hippocampus; Kinase; Phosphatase; Hypothermia; Temperature; Thermoregulation ID PROTEIN PHOSPHATASE 2A; ALZHEIMERS-DISEASE; DIABETES-MELLITUS; O-GLCNACYLATION; NEUROFIBRILLARY TANGLES; CASPASE-CLEAVAGE; IN-VIVO; HYPERPHOSPHORYLATION; INSULIN; MOUSE AB Accumulating evidence from epidemiological studies suggest that type 2 diabetes is linked to an increased risk of Alzheimer's disease (AD). However, the consequences of type 2 diabetes on AD pathologies, such as tau hyperphosphorylation, are not well understood. Here, we evaluated the impact of type 2 diabetes on tau phosphorylation in db/db diabetic mice aged 4 and 26 weeks. We found increased tau phosphorylation at the CP13 epitope correlating with a deregulation of c-Jun. N-terminal kinase (JNK) and Protein Phosphatase 2A (PP2A) in 4-week-old db/db mice. 26-week-old db/db mice displayed tau hyperphosphorylation at multiple epitopes (CP13, AT8, PHF-1), but no obvious change in kinases or phosphatases, no cleavage of tau, and no deregulation of central insulin signaling pathways. In contrast to younger animals, 26-week-old db/db mice were hypothermic and restoration of normothermia rescued phosphorylation at most epitopes. Our results suggest that, at early stages of type 2 diabetes, changes in tau phosphorylation may be due to deregulation of JNK and PP2A, while at later stages hyperphosphorylation is mostly a consequence of hypothermia. These results provide a novel link between diabetes and tau pathology, and underlie the importance of recording body temperature to better understand the relationship between diabetes and AD. (C) 2016 Elsevier Inc. All rights reserved. C1 [El Khoury, Noura B.; Gratuze, Maud; Petry, Franck; Marcouiller, Francois; Hebert, Sebastien S.; Planel, Emmanuel] Univ Laval, Fac Med, Dept Psychiat & Neurosci, Quebec City, PQ G1K 7P4, Canada. [El Khoury, Noura B.; Gratuze, Maud; Petry, Franck; Papon, Marie-Amelie; Julien, Carl; Marcouiller, Francois; Morin, Francoise; Calon, Frederic; Hebert, Sebastien S.; Planel, Emmanuel] Univ Laval, Ctr Rech Ctr Hosp, Axe Neurosci, Quebec City, PQ, Canada. [Nicholls, Samantha B.] Harvard Univ, Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Dept Neurol,Alzheimers Dis Res Lab,Med Sch, Charlestown, MA USA. [Calon, Frederic] Univ Laval, Fac Pharm, Quebec City, PQ G1K 7P4, Canada. [Marette, Andre] Inst Univ Cardiol & Pneumol Quebec, Ctr Rech, Quebec City, PQ, Canada. RP Planel, E (reprint author), CHUL, CRCHU Quebec, P-9800,2705 Blvd Laurier, Quebec City, PQ G1V 4G2, Canada. EM emmanuel@planel.org FU Alzheimer Society of Canada; Alzheimer Society of Saskatchewan; Canadian Institute of Health Research [MOP-106423, PCN-102993]; Fonds de Recherche en Sante du Quebec [16205, 20048]; Natural Sciences and Engineering Research Council of Canada [354722]; CIHR FX We thank Dr. Peter Davies (Albert Einstein University, New York, NY, USA) for the generous gift of antibodies. This work was supported by Biomedical Doctoral Awards from the Alzheimer Society of Canada (to N.E.K. and M.G.), Postdoctoral Awards from the Alzheimer Society of Canada and the Alzheimer Society of Saskatchewan (to C.J.) and grants to E.P. from the Canadian Institute of Health Research (MOP-106423, PCN-102993), Fonds de Recherche en Sante du Quebec (16205, 20048) and the Natural Sciences and Engineering Research Council of Canada (354722). A.M. holds a CIHR/Pfizer research Chair on the pathogenesis of insulin resistance and cardiovascular diseases. A.M., F.C. and S.S.H. were funded by grants from the CIHR The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 58 TC 3 Z9 3 U1 2 U2 7 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 APR PY 2016 VL 88 BP 55 EP 65 DI 10.1016/j.nbd.2016.01.005 PG 11 WC Neurosciences SC Neurosciences & Neurology GA DE8TH UT WOS:000370909100005 PM 26777665 ER PT J AU Sonpavde, G Bellmunt, J AF Sonpavde, Guru Bellmunt, Joaquim TI Docetaxel for Castration-sensitive Prostate Cancer: Wrapping up Unfinished Business? SO EUROPEAN UROLOGY LA English DT Editorial Material ID ESTRAMUSTINE; MITOXANTRONE; PREDNISONE; THERAPY C1 [Sonpavde, Guru] Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL 35294 USA. [Bellmunt, Joaquim] Dana Farber Canc Inst, Boston, MA 02115 USA. [Bellmunt, Joaquim] Harvard Univ, Sch Med, Boston, MA USA. [Bellmunt, Joaquim] Univ Hosp del Mar IMIM, Barcelona, Spain. RP Bellmunt, J (reprint author), Dana Farber Brigham & Womens Canc Ctr, Bladder Canc Ctr, 450 Brookline Ave, Boston, MA 02215 USA. EM joaquim_bellmunt@dfci.harvard.edu NR 11 TC 0 Z9 0 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 APR PY 2016 VL 69 IS 4 BP 574 EP 575 DI 10.1016/j.eururo.2015.10.022 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA DE1AG UT WOS:000370357200012 PM 26497920 ER PT J AU Giannatempo, P Pond, GR Sonpavde, G Raggi, D Naik, G Galsky, MD Bellmunt, J Necchi, A AF Giannatempo, Patrizia Pond, Gregory R. Sonpavde, Guru Raggi, Daniele Naik, Gurudatta Galsky, Matthew D. Bellmunt, Joaquim Necchi, Andrea TI The Impact of Adding Taxanes to Gemcitabine and Platinum Chemotherapy for the First-Line Therapy of Advanced or Metastatic Urothelial Cancer: A Systematic Review and Meta-analysis SO EUROPEAN UROLOGY LA English DT Review DE First-line therapy; Meta-analysis; Systemic therapy; Taxanes; Urothelial carcinoma ID TRANSITIONAL-CELL CARCINOMA; PHASE-II TRIAL; CISPLATIN-BASED CHEMOTHERAPY; COOPERATIVE-ONCOLOGY-GROUP; IMPAIRED RENAL-FUNCTION; ADVANCED BLADDER-CANCER; PLUS CISPLATIN; ELDERLY-PATIENTS; URINARY-TRACT; OPEN-LABEL AB Context: Gemcitabine/platinum chemotherapy is the most widely used first-line regimen for metastatic urothelial carcinoma, and the potential improvement of adding taxanes needs to be clarified. Objective: To study the survival impact of taxane plus gemcitabine/platinum compared with gemcitabine/platinum alone as upfront therapy. Evidence acquisition: Literature was searched for studies including gemcitabine/platinum +/- taxanes (paclitaxel or docetaxel only). We pooled trial level data including the median, proportions, and confidence intervals on response-rate, progression-free survival, overall survival (OS), and side effects. Univariable and multivariable regression models evaluated the prognostic role of addition of taxanes after adjusting for platinum type, performance status 2, and the presence of visceral metastases. Data were weighted by the logarithm of the trial sample size. Evidence synthesis: Thirty-five arms of trials including 2,365 patients were selected (seven with taxanes [n = 617], and 28 arms without taxanes [n = 1,748]). Median OS was univariably significantly different (p = 0.019) between trials with and without taxanes. Across trials, the median 'median OS' amongst trials containing taxanes was 15.5mo, compared with 12.5mo in trials which did not. Multivariably, visceral disease and performance status were significantly associated with OS, and the addition of taxanes trended toward significantly better OS (p = 0.056) and increase in grade >= 3 neurotoxicity (p = 0.051), regardless of specific platinum agent used. Conclusions: In this meta-analysis, adding taxanes to gemcitabine and platinum showed a trend for improved OS and higher grade >= 3 neurotoxicity. Improvements in patient selection and the evaluation of a more potent and tolerable tubulin inhibitor in combination with gemcitabine/platinum in a well-powered trial are the critical next steps. Patient summary: In this report, a trend for improved overall survival and worse neurotoxicity was observed for adding a taxane to first-line gemcitabine/platinum chemotherapy for metastatic urothelial carcinoma. More effective taxanes should be investigated further in urothelial carcinoma in combination with gemcitabine/platinum. (C) 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved. C1 [Giannatempo, Patrizia; Raggi, Daniele; Necchi, Andrea] Fdn IRCCS Ist Nazl Tumori, I-20133 Milan, Italy. [Pond, Gregory R.] McMaster Univ, Hamilton, ON, Canada. [Sonpavde, Guru; Naik, Gurudatta] UAB Comprehens Canc Ctr, Birmingham, AL USA. [Galsky, Matthew D.] Tisch Canc Inst, Mt Sinai Sch Med, New York, NY USA. [Bellmunt, Joaquim] Dana Farber Canc Inst, Boston, MA 02115 USA. [Bellmunt, Joaquim] Harvard Univ, Sch Med, Boston, MA USA. RP Necchi, A (reprint author), Fdn IRCCS Ist Nazl Tumori, Dept Med Oncol, Via Giacomo Venezian 1, I-20133 Milan, Italy. EM andea.necchi@istitutotumori.mi.it OI Necchi, Andrea/0000-0002-3007-2756 NR 50 TC 3 Z9 3 U1 2 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 EI 1873-7560 J9 EUR UROL JI Eur. Urol. PD APR PY 2016 VL 69 IS 4 BP 624 EP 633 DI 10.1016/j.eururo.2015.09.051 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA DE1AG UT WOS:000370357200023 PM 26497923 ER PT J AU Sonpavde, G Pond, GR Choueiri, TK Mullane, S Niegisch, G Albers, P Necchi, A Di Lorenzo, G Buonerba, C Rozzi, A Matsumoto, K Lee, JL Kitamura, H Kume, H Bellmunt, J AF Sonpavde, Guru Pond, Gregory R. Choueiri, Toni K. Mullane, Stephanie Niegisch, Guenter Albers, Peter Necchi, Andrea Di Lorenzo, Giuseppe Buonerba, Carlo Rozzi, Antonio Matsumoto, Kazumasa Lee, Jae-Lyun Kitamura, Hiroshi Kume, Haruki Bellmunt, Joaquim TI Single-agent Taxane Versus Taxane-containing Combination Chemotherapy as Salvage Therapy for Advanced Urothelial Carcinoma SO EUROPEAN UROLOGY LA English DT Article DE Advanced urothelial carcinoma; Salvage; chemotherapy; Combination; Survival ID TRANSITIONAL-CELL CARCINOMA; PHASE-II TRIAL; BLADDER-CANCER; RANDOMIZED-TRIAL; PACLITAXEL; CISPLATIN; PLATINUM; GEMCITABINE; TRACT; IFOSFAMIDE AB Background: Single-agent taxanes are commonly used as salvage systemic therapy for patients with advanced urothelial carcinoma (UC). Objective: To study the impact of combination chemotherapy delivering a taxane plus other chemotherapeutic agents compared with single-agent taxane as salvage therapy. Design, setting, and participants: Individual patient-level data from phase 2 trials of salvage systemic therapy were used. Interventions: Trials evaluating either single agents (paclitaxel or docetaxel) or combination chemotherapy (taxane plus one other chemotherapeutic agent or more) following prior platinum-based therapy were used. Outcome measurements and statistical analysis: Information regarding the known major baseline prognostic factors was required: time from prior chemotherapy, hemoglobin, performance status, albumin, and liver metastasis status. Cox proportional hazards regression was used to evaluate the association of prognostic factors and combination versus single-agent chemotherapy with overall survival (OS). Results and limitations: Data were available from eight trials including 370 patients; two trials (n = 109) evaluated single-agent chemotherapy with docetaxel (n = 72) and cremophor-free paclitaxel (n = 37), and six trials (n = 261) evaluated combination chemotherapy with gemcitabine-paclitaxel (two trials, with n = 99 and n = 24), paclitaxel-cyclophosphamide (n = 32), paclitaxel-ifosfamide-nedaplatin (n = 45), docetaxelifosfamide-cisplatin (n = 26), and paclitaxel-epirubicin (n = 35). On multivariable analysis after adjustment for baseline prognostic factors, combination chemotherapy was independently and significantly associated with improved OS (hazard ratio: 0.60; 95% confidence interval, 0.45-0.82; p = 0.001). The retrospective design of this analysis and the trial-eligible population were inherent limitations. Conclusions: Patients enrolled in trials of combination chemotherapy exhibited improved OS compared with patients enrolled in trials of single-agent chemotherapy as salvage therapy for advanced UC. Prospective randomized trials are required to validate a potential role for rational and tolerable combination chemotherapeutic regimens for the salvage therapy of advanced UC. Patient summary: This retrospective study suggests that a combination of chemotherapy agents may extend survival compared with single-agent chemotherapy in selected patients with metastatic urothelial cancer progressing after prior chemotherapy. (C) 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved. C1 [Sonpavde, Guru] UAB Comprehens Canc Ctr, Birmingham, AL USA. [Pond, Gregory R.] McMaster Univ, Hamilton, ON L8S 4L8, Canada. [Choueiri, Toni K.; Mullane, Stephanie; Bellmunt, Joaquim] Dana Farber Canc Inst, Boston, MA 02115 USA. [Choueiri, Toni K.; Mullane, Stephanie; Bellmunt, Joaquim] Harvard Univ, Sch Med, Boston, MA USA. [Niegisch, Guenter; Albers, Peter] Univ Dusseldorf, Dusseldorf, Germany. [Necchi, Andrea] Fdn IRCCS Ist Nazl Tumori, Milan, Italy. [Di Lorenzo, Giuseppe] Univ Naples Federico II, Naples, Italy. [Buonerba, Carlo] Ctr Riferimento Oncol Basilicata IRCCS, Rionero In Vulture, Italy. [Rozzi, Antonio] Ist Neurotraumatol Italiano, Grottaferrata, Italy. [Matsumoto, Kazumasa] Kitasato Univ, Sch Med, Sagamihara, Kanagawa 228, Japan. [Lee, Jae-Lyun] Asan Med Ctr, Seoul, South Korea. [Kitamura, Hiroshi] Sapporo Med Univ, Sch Med, Sapporo, Hokkaido, Japan. [Kume, Haruki] Tokyo Univ Hosp, Tokyo 113, Japan. RP Sonpavde, G (reprint author), Univ Alabama Birmingham, Birmingham Comprehens Canc Ctr, 1720 2nd Ave S,NP2540B, Birmingham, AL 35294 USA. EM gsonpavde@uabmc.edu OI Necchi, Andrea/0000-0002-3007-2756 NR 27 TC 12 Z9 12 U1 4 U2 15 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 EI 1873-7560 J9 EUR UROL JI Eur. Urol. PD APR PY 2016 VL 69 IS 4 BP 634 EP 641 DI 10.1016/j.eururo.2015.08.039 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA DE1AG UT WOS:000370357200024 PM 26264159 ER PT J AU Sonpavde, G Pond, GR Bellmunt, J AF Sonpavde, Guru Pond, Gregory R. Bellmunt, Joaquim TI Reply from Authors re: Tracy L. Rose, Matthew I. Milowsky. A Small Step Toward Improving Salvage Treatment for Metastatic Bladder Cancer - At What Cost? Eur Urol 2016;69:642-44 Combination Chemotherapy as a Viable Salvage Therapy Strategy for Advanced Urothelial Carcinoma SO EUROPEAN UROLOGY LA English DT Editorial Material ID GERM-CELL TUMORS; DOUBLE-BLIND; OXALIPLATIN; BEVACIZUMAB; CARCINOMA; PLACEBO; TRIAL C1 [Sonpavde, Guru] Univ Alabama Birmingham, Ctr Comprehens Canc, 1720 2nd Ave South,NP2540B, Birmingham, AL 35294 USA. [Pond, Gregory R.] McMaster Univ, Hamilton, ON L8S 4L8, Canada. [Bellmunt, Joaquim] Dana Farber Canc Inst, Boston, MA 02115 USA. [Bellmunt, Joaquim] Harvard Univ, Sch Med, Boston, MA USA. RP Sonpavde, G (reprint author), Univ Alabama Birmingham, Ctr Comprehens Canc, 1720 2nd Ave South,NP2540B, Birmingham, AL 35294 USA. EM gsonpavde@uabmc.edu NR 10 TC 0 Z9 0 U1 0 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 APR PY 2016 VL 69 IS 4 BP 644 EP 645 DI 10.1016/j.eururo.2015.09.015 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA DE1AG UT WOS:000370357200026 PM 26415779 ER PT J AU Gray, PJ Efstathiou, JA Shipley, WU AF Gray, Phillip J. Efstathiou, Jason A. Shipley, William U. TI Re: Radical Cystectomy vs. Chemoradiation in T2-4aN0M0 Bladder Cancer: A Case-control Study SO EUROPEAN UROLOGY LA English DT Editorial Material ID COMBINED-MODALITY THERAPY; LONG-TERM OUTCOMES; PRESERVATION C1 [Gray, Phillip J.; Efstathiou, Jason A.; Shipley, William U.] Massachusetts Gen Hosp, Dept Radiat Oncol, 100 Blossom St,Cox 3, Boston, MA 02114 USA. RP Gray, PJ (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, 100 Blossom St,Cox 3, Boston, MA 02114 USA. EM pjgray@partners.org NR 6 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 EI 1873-7560 J9 EUR UROL JI Eur. Urol. PD APR PY 2016 VL 69 IS 4 BP 757 EP 758 DI 10.1016/j.eururo.2016.01.022 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA DE1AG UT WOS:000370357200048 PM 26972501 ER PT J AU Rosenberg, AR Bona, K Wharton, CM Bradford, M Shaffer, ML Wolfe, J Baker, KS AF Rosenberg, Abby R. Bona, Kira Wharton, Claire M. Bradford, Miranda Shaffer, Michele L. Wolfe, Joanne Baker, Kevin Scott TI Adolescent and Young Adult Patient Engagement and Participation in Survey-Based Research: A Report From the "Resilience in Adolescents and Young Adults With Cancer" Study SO PEDIATRIC BLOOD & CANCER LA English DT Article DE Adolescent and Young Adult Oncology (AYA); health-services research; patient-reported outcomes; pediatric cancer ID QUALITY-OF-LIFE; OUTCOMES; DISTRESS; CHILDREN; TRIALS; CARE AB Conducting patient-reported outcomes research with adolescents and young adults (AYAs) is difficult due to low participation rates and high attrition. Forty-seven AYAs with newly diagnosed cancer at two large hospitals were prospectively surveyed at the time of diagnosis and 3-6 and 12-18 months later. A subset participated in 1:1 semistructured interviews. Attrition prompted early study closure at one site. The majority of patients preferred paper-pencil to online surveys. Interview participants were more likely to complete surveys (e.g., 93% vs. 58% completion of 3-6 month surveys, P = 0.02). Engaging patients through qualitative methodologies and using patient-preferred instruments may optimize future research success. C1 [Rosenberg, Abby R.; Wharton, Claire M.; Baker, Kevin Scott] Seattle Childrens Hosp, Canc & Blood Disorders Ctr, 4800 Sand PointWay NE,MS MB 8-501,POB 5371, Seattle, WA 98145 USA. [Rosenberg, Abby R.; Wharton, Claire M.; Bradford, Miranda; Shaffer, Michele L.; Baker, Kevin Scott] 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.; Shaffer, Michele L.; Baker, Kevin Scott] Univ Washington, Dept Pediat, Seattle, WA 98195 USA. [Bona, Kira; Wolfe, Joanne] Boston Childrens Hosp, Dept Med, Boston, MA USA. [Bona, Kira] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Bona, Kira; Wolfe, Joanne] Harvard Univ, Sch Med, Dept Pediat Hematol Oncol, Boston, MA USA. [Wolfe, Joanne] Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, Seattle, WA USA. [Baker, Kevin Scott] Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA. RP Rosenberg, AR (reprint author), Seattle Childrens Hosp, Canc & Blood Disorders Ctr, 4800 Sand PointWay NE,MS MB 8-501,POB 5371, Seattle, WA 98145 USA. EM abby.rosenberg@seattlechildrens.org FU St. Baldrick's Fellow award; Young Investigator award from CureSearch for Children's Cancer; Clinical Research Scholar Award from Seattle Children's Hospital's Center for Clinical and Translational Research; National Center for Advancing Translational Sciences of the National Institutes of Health [KL2TR000421] FX Grant sponsors: St. Baldrick's Fellow award; Grant sponsor: Young Investigator award from CureSearch for Children's Cancer; Grant sponsor: Clinical Research Scholar Award from Seattle Children's Hospital's Center for Clinical and Translational Research; Grant sponsor: National Center for Advancing Translational Sciences of the National Institutes of Health; Grant number: KL2TR000421. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding organizations. NR 13 TC 7 Z9 7 U1 3 U2 8 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 APR PY 2016 VL 63 IS 4 BP 734 EP 736 DI 10.1002/pbc.25843 PG 3 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA DE2ZR UT WOS:000370497100031 PM 26681427 ER PT J AU Huang, SS Chen, CL Huang, FW Johnson, FE Huang, JS AF Huang, Shuan Shian Chen, Chun-Lin Huang, Franklin W. Johnson, Frank E. Huang, Jung San TI Ethanol Enhances TGF-beta Activity by Recruiting TGF-beta Receptors From Intracellular Vesicles/Lipid Rafts/Caveolae to Non-Lipid Raft Microdomains SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Article DE TGF-beta ENHANCER; CANONICAL TGF-beta SIGNALING; TGF-beta RECEPTORS; NON-LIPID RAFT MICRODOMAINS ID GROWTH-FACTOR-BETA; C-REACTIVE PROTEIN; DI-LEUCINE FAMILY; LIPID RAFTS; ALCOHOL-CONSUMPTION; CONSTITUTIVE ENDOCYTOSIS; DEPENDENT ENDOCYTOSIS; MEDIATED ENDOCYTOSIS; PLASMA-CONCENTRATION; SIGNAL-TRANSDUCTION AB Regular consumption of moderate amounts of ethanol has important health benefits on atherosclerotic cardiovascular disease (ASCVD). Overindulgence can cause many diseases, particularly alcoholic liver disease (ALD). The mechanisms by which ethanol causes both beneficial and harmful effects on human health are poorly understood. Here we demonstrate that ethanol enhances TGF-stimulated luciferase activity with a maximum of 0.5-1% (v/v) in Mv1Lu cells stably expressing a luciferase reporter gene containing Smad2-dependent elements. In Mv1Lu cells, 0.5% ethanol increases the level of P-Smad2, a canonical TGF- signaling sensor, by approximate to 2-3-fold. Ethanol (0.5%) increases cell-surface expression of the type II TGF- receptor (TR-II) by approximate to 2-3-fold from its intracellular pool, as determined by I-125-TGF--cross-linking/Western blot analysis. Sucrose density gradient ultracentrifugation and indirect immunofluorescence staining analyses reveal that ethanol (0.5% and 1%) also displaces cell-surface TR-I and TR-II from lipid rafts/caveolae and facilitates translocation of these receptors to non-lipid raft microdomains where canonical signaling occurs. These results suggest that ethanol enhances canonical TGF- signaling by increasing non-lipid raft microdomain localization of the TGF- receptors. Since TGF- plays a protective role in ASCVD but can also cause ALD, the TGF- enhancer activity of ethanol at low and high doses appears to be responsible for both beneficial and harmful effects. Ethanol also disrupts the location of lipid raft/caveolae of other membrane proteins (e.g., neurotransmitter, growth factor/cytokine, and G protein-coupled receptors) which utilize lipid rafts/caveolae as signaling platforms. Displacement of these membrane proteins induced by ethanol may result in a variety of pathologies in nerve, heart and other tissues. J. Cell. Biochem. 117: 860-871, 2016. (c) 2015 Wiley Periodicals, Inc. C1 [Huang, Shuan Shian] Auxagen Inc, St Louis, MO 63132 USA. [Chen, Chun-Lin] Natl Sun Yat Sen Univ, Dept Biol Sci, Kaohsiung 804, Taiwan. [Chen, Chun-Lin] Natl Sun Yat Sen Univ, Doctoral Degree Program Marine Biotechnol, Kaohsiung 804, Taiwan. [Chen, Chun-Lin] Acad Sinica, Kaohsiung 804, Taiwan. [Huang, Franklin W.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Huang, Franklin W.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Johnson, Frank E.] St Louis Univ, Sch Med, Dept Surg, St Louis, MO 63104 USA. [Huang, Jung San] St Louis Univ, Dept Biochem & Mol Biol, Sch Med, Doisy Res Ctr, Room 413,1100 S Grand Blvd, St Louis, MO 63104 USA. RP Huang, JS (reprint author), St Louis Univ, Dept Biochem & Mol Biol, Sch Med, Doisy Res Ctr, Room 413,1100 S Grand Blvd, St Louis, MO 63104 USA. EM huangjs@slu.edu FU NIH [HL 095261, AR 052578]; University President's Research Fund, Saint Louis University; NSYSU-KMU Joint Research Project, National Sun Yat-sen University [NSYSUKMU104-I004] FX Grant sponsor: NIH; Grant numbers: HL 095261, AR 052578; Grant sponsor: University President's Research Fund, Saint Louis University (J.S.H.); Grant sponsor: NSYSU-KMU Joint Research Project (NSYSUKMU104-I004), National Sun Yat-sen University (C.L.C). NR 69 TC 3 Z9 3 U1 1 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0730-2312 EI 1097-4644 J9 J CELL BIOCHEM JI J. Cell. Biochem. PD APR PY 2016 VL 117 IS 4 BP 860 EP 871 DI 10.1002/jcb.25389 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DD8FD UT WOS:000370159900006 PM 26419316 ER PT J AU Fraile, LM Herraiz, JL Udias, JM Cal-Gonzalez, J Corzo, PMG Espana, S Herranz, E Perez-Liva, M Picado, E Vicente, E Munoz-Martin, A Vaquero, JJ AF Fraile, L. M. Herraiz, J. L. Udias, J. M. Cal-Gonzalez, J. Corzo, P. M. G. Espana, S. Herranz, E. Perez-Liva, M. Picado, E. Vicente, E. Munoz-Martin, A. Vaquero, J. J. TI Experimental validation of gallium production and isotope-dependent positron range correction in PET SO NUCLEAR INSTRUMENTS & METHODS IN PHYSICS RESEARCH SECTION A-ACCELERATORS SPECTROMETERS DETECTORS AND ASSOCIATED EQUIPMENT LA English DT Article DE Radioisotope production; Positron emission tomography; Positron range; Ga-66; Ga-68 ID TOMOGRAPHY; NANOPARTICLES; PERFORMANCE; RESOLUTION; PENELOPET; THERAPY AB Positron range (PR) is one of the important factors that limit the spatial resolution of positron emission tomography (PET) preclinical images. Its blurring effect can be corrected to a large extent if the appropriate method is used during the image reconstruction. Nevertheless, this correction requires an accurate modelling of the PR for the particular radionuclide and materials in the sample under study. In this work we investigate PET imaging with Ga-68 and Ga-66 radioisotopes, which have a large PR and are being used in many preclinical and clinical PET studies. We produced a Ga-68 and Ga-66 phantom on a natural zinc target through (p,n) reactions using the 9-MeV proton beam delivered by the 5-MV CMAM tandetron accelerator. The phantom was imaged in an ARGUS small animal PET/CT scanner and reconstructed with a fully 3D iterative algorithm, with and without PR corrections. The reconstructed images at different time frames show significant improvement in spatial resolution when the appropriate PR is applied for each frame, by taking into account the relative amount of each isotope in the sample. With these results we validate our previously proposed PR correction method for isotopes with large PR. Additionally, we explore the feasibility of PET imaging with Ga-68 and Ga-66 radioisotopes in proton therapy. (C) 2016 Elsevier B.V. All rights reserved. C1 [Fraile, L. M.; Herraiz, J. L.; Udias, J. M.; Cal-Gonzalez, J.; Corzo, P. M. G.; Espana, S.; Herranz, E.; Perez-Liva, M.; Picado, E.; Vicente, E.] Univ Complutense Madrid, Dept Fis Atom Mol & Nucl, Grp Fis Nucl, E-28040 Madrid, Spain. [Munoz-Martin, A.] Univ Autonoma Madrid, Ctr Microanal Mat, E-28049 Madrid, Spain. [Vaquero, J. J.] Univ Carlos III Madrid, Dept Bioingn & Ingn Aeroespacial, E-28903 Getafe, Spain. [Cal-Gonzalez, J.] Med Univ Vienna, Vienna, Austria. [Corzo, P. M. G.] Blue Telecom Consulting, Madrid 28037, Spain. [Espana, S.] Ctr Nacl Invest Cardiovasc, Madrid 28029, Spain. [Herranz, E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Herranz, E.] Harvard Univ, Sch Med, Boston, MA USA. [Picado, E.] Univ Nacl, Heredia 863000, Costa Rica. [Vicente, E.] Johns Hopkins Univ, Baltimore, MD USA. RP Fraile, LM (reprint author), Univ Complutense Madrid, Dept Fis Atom Mol & Nucl, Grp Fis Nucl, E-28040 Madrid, Spain. EM lmfraile@ucm.es RI Udias, Jose/A-7523-2010; Espana, Samuel/E-9240-2010; Vaquero, Juan Jose/D-3033-2009; LOPEZ HERRAIZ, JOAQUIN/E-9234-2010; Fraile, Luis/B-8668-2011; Picado, Esteban/I-3009-2015; OI Udias, Jose/0000-0003-3714-764X; Espana, Samuel/0000-0001-9092-4597; Vaquero, Juan Jose/0000-0001-9200-361X; LOPEZ HERRAIZ, JOAQUIN/0000-0001-7208-8863; Fraile, Luis/0000-0002-6281-3635; Picado, Esteban/0000-0002-2691-9520; Perez Liva, Mailyn/0000-0002-4985-247X FU Spanish MINECO [FPA2010-17142, FPA2013-41267-P, CSD-2007-00042, RTC-2015-3772-1]; Comunidad de Madrid via the TOPUS project [S2013/MIT-3024] FX We acknowledge support from the Spanish MINECO through projects FPA2010-17142, FPA2013-41267-P, CSD-2007-00042 (CPAN), and the RTC-2015-3772-1 Grant. We also acknowledge support from Comunidad de Madrid via the TOPUS S2013/MIT-3024 project. NR 25 TC 0 Z9 0 U1 2 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-9002 EI 1872-9576 J9 NUCL INSTRUM METH A JI Nucl. Instrum. Methods Phys. Res. Sect. A-Accel. Spectrom. Dect. Assoc. Equip. PD APR 1 PY 2016 VL 814 BP 110 EP 116 DI 10.1016/j.nima.2016.01.013 PG 7 WC Instruments & Instrumentation; Nuclear Science & Technology; Physics, Nuclear; Physics, Particles & Fields SC Instruments & Instrumentation; Nuclear Science & Technology; Physics GA DD1OW UT WOS:000369692000015 ER PT J AU Contractor, AA Presseau, C Capone, C Reddy, MK Shea, MT AF Contractor, Ateka A. Presseau, Candice Capone, Christy Reddy, Madhavi K. Shea, M. Tracie TI The moderating role of dysphoria in the relationship between intrusions and alcohol use SO ADDICTIVE BEHAVIORS LA English DT Article DE PTSD symptoms; Intrusions; Dysphoria; Alcohol use; Veterans ID POSTTRAUMATIC-STRESS-DISORDER; SUBSTANCE USE DISORDERS; RANDOMIZED CONTROLLED-TRIAL; ADMINISTERED PTSD SCALE; PRIMARY-CARE; SYMPTOM DIMENSIONS; MAJOR DEPRESSION; SELF-MEDICATION; GULF-WAR; ABUSE AB Posttraumatic Stress Disorder (PTSD) is frequently comorbid with alcohol use disorders (AUD; Calabrese et al., 2011; McFall, Mackay, & Donovan, 1992). Among several explanations for this comorbidity, the most empirically supported is the self-medication theory which postulates that substances are used to medicate PTSD-related distress (Keane & Wolfe, 1990; Khantzian, 1985; Stewart, 1996). The current study examines the effects of trauma-related distress on alcohol use (total drinking days, drinks per drinking day, heavy drinking days) in a sample of 127 trauma-exposed Veterans following deployment to Iraq or Afghanistan. The dysphoria symptoms of PTSD were used as an indicator of distress, and examined as a moderator in the relationship between intrusion symptoms of PTSD and alcohol use. The proposed moderation model was tested using cross-sectional data from the first month following return from deployment, and at 6 months and at 12 months post-deployment. Results showed that dysphoria symptoms significantly moderated relations between intrusions and total drinking days and heavy drinking days at one month post-deployment; however, a significant pattern was not demonstrated at 6 months and 12 months. Further, dysphoria did not moderate the relation between intrusion symptoms and drinks per drinking day at the three time points. Theoretical and clinical implications are subsequently discussed. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Contractor, Ateka A.] Univ Toledo, Dept Psychol, 2801 W Bancroft St, Toledo, OH 43606 USA. [Contractor, Ateka A.; Capone, Christy; Reddy, Madhavi K.; Shea, M. Tracie] Brown Univ, Dept Psychiat & Human Behav, Warren Alpert Med Sch, Box Box G-BH, Providence, RI 02912 USA. [Presseau, Candice; Capone, Christy; Shea, M. Tracie] Providence VA Med Ctr, Dept Vet Affairs, 830 Chalkstone Ave, Providence, RI 02908 USA. [Presseau, Candice] Lehigh Univ, Dept Educ & Human Serv, Coll Educ, 111 Res Dr, Bethlehem, PA 18015 USA. [Reddy, Madhavi K.] Univ Texas Hlth Sci Ctr Houston, Dept Psychiat & Behav Sci, 1941 East Rd, Houston, TX 77054 USA. RP Contractor, AA (reprint author), VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr, 150 South Huntington Ave, Jamaica Plain, MA 02130 USA. EM ateka.c@gmail.com FU U.S. Army Medical Research and Materiel Command [W81XWH-06-1-0573] FX This research was supported by grant W81XWH-06-1-0573, from the U.S. Army Medical Research and Materiel Command. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. NR 68 TC 0 Z9 0 U1 2 U2 18 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4603 EI 1873-6327 J9 ADDICT BEHAV JI Addict. Behav. PD APR PY 2016 VL 55 BP 5 EP 14 DI 10.1016/j.addbeh.2015.12.010 PG 10 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA DC8EU UT WOS:000369453500002 PM 26735913 ER PT J AU Buckner, JD Langdon, KJ Jeffries, ER Zvolensky, MJ AF Buckner, Julia D. Langdon, Kirsten J. Jeffries, Emily R. Zvolensky, Michael J. TI Socially anxious smokers experience greater negative affect and withdrawal during self-quit attempts SO ADDICTIVE BEHAVIORS LA English DT Article DE Social anxiety; Self-quit; Smoking cessation; Nicotine withdrawal; Negative affect; Ecological momentary assessment ID ECOLOGICAL MOMENTARY ASSESSMENT; POSTTRAUMATIC-STRESS-DISORDER; EARLY SMOKING LAPSE; ANXIETY DISORDER; DEPENDENCE; CESSATION; RELAPSE; VALIDATION; SYMPTOMS; MOTIVES AB Despite evidence of a strong and consistent relation between smoking and elevated social anxiety, strikingly little empirical work has identified mechanisms underlying the smoldng-social anxiety link. Persons with elevated social anxiety may rely on smoking to cope with more severe nicotine withdrawal and post-quit negative mood states; yet, no known studies have investigated the relation of social anxiety to withdrawal severity. The current study examined the relation of social anxiety to post-quit nicotine withdrawal severity among 51 (333% female, M-age = 34.6) community-recruited smokers during the first two weeks following an unaided (i.e., no treatment) cessation attempt. Ecological momentary assessment was used to collect multiple daily ratings of withdrawal and negative mood states. Baseline social anxiety was related to increases in negative affect during the monitoring period and remained significantly related to post-quit withdrawal after controlling for negative affect, gender, lapses, and substance use. Persons with elevated social anxiety experience more severe post-quit withdrawal symptoms and increases in negative affect during a cessation attempt and may therefore benefit from intervention and treatment strategies geared toward helping them learn to cope with withdrawal and negative affect to improve cessation rates among these vulnerable smokers. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Buckner, Julia D.; Jeffries, Emily R.] Louisiana State Univ, Dept Psychol, 236 Audubon Hall, Baton Rouge, LA 70803 USA. [Langdon, Kirsten J.] VA Boston Healthcare Syst, Natl Ctr PTSD, Womens Hlth Sci Div, 150 South Huntington St, Boston, MA 02130 USA. [Langdon, Kirsten J.] Boston Univ, Sch Med, 72 East Concord St, Boston, MA 02118 USA. [Zvolensky, Michael J.] Univ Houston, Dept Psychol, Heyne Bldg, Houston, TX 77204 USA. [Zvolensky, Michael J.] Univ Texas MD Anderson Canc Ctr, 1515 Holcombe Blvd, Houston, TX 77030 USA. RP Buckner, JD (reprint author), Louisiana State Univ, Dept Psychol, 236 Audubon Hall, Baton Rouge, LA 70803 USA. EM jbuckner@lsu.edu; kirstenjlangdon@gmail.com; emily.jeffries.7@gmail.com; mjzvolen@central.uh.edu FU National Institute of Drug Abuse [1R34DA031937, F31DA026634] FX The authors would like to note that funding for this study was provided in part by grants from the National Institute of Drug Abuse (1R34DA031937, F31DA026634). NIDA had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication. NR 33 TC 1 Z9 1 U1 5 U2 15 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4603 EI 1873-6327 J9 ADDICT BEHAV JI Addict. Behav. PD APR PY 2016 VL 55 BP 46 EP 49 DI 10.1016/j.addbeh.2016.01.004 PG 4 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA DC8EU UT WOS:000369453500008 PM 26790139 ER PT J AU Pope, CA Escobar-Gomez, M Davis, BH Roberts, JR O'Brien, ES Hinton, E Darden, PM AF Pope, C. A. Escobar-Gomez, M. Davis, B. H. Roberts, J. R. O'Brien, E. S. Hinton, E. Darden, P. M. TI The challenge of tetradic relationships in medically interpreted pediatric primary care visits: A descriptive study of communication practices SO PATIENT EDUCATION AND COUNSELING LA English DT Article DE Adolescent; Primary care; Healthcare disparities; Communication barriers; Linguistics; Hispanic Americans ID LIMITED ENGLISH PROFICIENCY; OF-THE-LITERATURE; LANGUAGE SERVICES; HEALTH-CARE; CONSULTATIONS; FAMILIES AB Objective: To examine spoken interactions between pediatricians and community-based interpreters speaking with adolescents and parents with Limited English proficiency (LEP) in primary care to identify the challenges of interpreting in a four-person or tetradic visit, its sources of co-constructed errors, and specific practices for educational intervention. Methods: As part of a larger study of vaccine decision-making at six clinical sites in two states, this descriptive study used discourse analysis to examine 20 routine primary care visits in a Latino Clinic in interactions between adolescents, parents, community-based interpreters, and pediatricians. Specific patterns of communication practices were identified that contributed to inaccuracies in medical interpretation Results: Practices needing improvement were tallied for simple frequencies and included: omissions; false fluency; substitutions; editorializing; added clarification, information, or questions; medical terminology; extra explanation to mother; and, cultural additions. Of these speaking practices, omissions were the most common (123 out of 292 total) and the most affected by pediatricians. Conclusion: The dynamics of both pediatricians and interpreters contributed to identification of areas for improvement, with more adolescent participation in bilingual than monolingual visits. Practice implications: These observations provide opportunities for mapping a communication skills training intervention based on observations for future testing of an evidence-based curriculum. Published by Elsevier Ireland Ltd. C1 [Pope, C. A.] Med Univ S Carolina, Coll Nursing, 99 Jonathan Lucas St SN511,MSC 160, Charleston, SC 29425 USA. [Pope, C. A.] Ralph H Johnson Vet Affairs VA Med Ctr, Charleston, SC 29401 USA. [Davis, B. H.] Univ N Carolina, Dept English, Charlotte, NC 28223 USA. [Roberts, J. R.; O'Brien, E. S.; Hinton, E.] Med Univ S Carolina, Coll Med, Dept Pediat, Charleston, SC 29425 USA. [Darden, P. M.] Univ Oklahoma, Hlth Sci Ctr, Gen & Community Pediat, Oklahoma City, OK 73104 USA. [Escobar-Gomez, M.] Bilingo LLC, Goose Creek, SC USA. RP Pope, CA (reprint author), Med Univ S Carolina, Coll Nursing, 99 Jonathan Lucas St SN511,MSC 160, Charleston, SC 29425 USA. EM popec@musc.edu; eskobarm@gmail.com; bdavis@uncc.edu; robertsj@musc.edu; obriene@musc.edu; HintonE@musc.edu; paul-darden@ouhsc.edu FU South Carolina Pediatric Practice Research Network; Oklahoma Child Health Research Network; Department of Health and Human Services, Health Resources and Services Administration, Maternal and Child Health Research Program [R40 MC 21522] FX This research was supported by funding from the R40 MC 21522 through the Department of Health and Human Services, Health Resources and Services Administration, Maternal and Child Health Research Program, Principal Investigator, Dr. Paul Darden. We are grateful to the adolescents, parents, and pediatric practices that allowed us to record and learn from their encounters and the support of the South Carolina Pediatric Practice Research Network and the Oklahoma Child Health Research Network. NR 31 TC 0 Z9 0 U1 4 U2 8 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0738-3991 J9 PATIENT EDUC COUNS JI Patient Educ. Couns. PD APR PY 2016 VL 99 IS 4 BP 542 EP 548 DI 10.1016/j.pec.2015.10.032 PG 7 WC Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary SC Public, Environmental & Occupational Health; Social Sciences - Other Topics GA DH7IE UT WOS:000372965900008 PM 26796067 ER PT J AU Skotko, BG Levine, SP Macklin, EA Goldstein, RD AF Skotko, Brian G. Levine, Susan P. Macklin, Eric A. Goldstein, Richard D. TI Family perspectives about Down syndrome SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE trisomy 21; prenatal tests; noninvasive prenatal screens; abortion; family attitudes; quality of life AB National medical organizations recommend that during prenatal counseling sessions, healthcare providers discuss how having a child with Down syndrome (DS) might impact the family unit. Few studies, to date, have surveyed families about their life experiences. For this investigation, we examined 41 family attitudes, which were obtained from mailed questionnaires completed by 1,961 parents/guardians, 761 brothers/sisters, and 283 people with DS who were members of six DS non-profit organizations, chosen for their size, ethnic/racial diversities, and geographic distribution throughout the United States. About 83% of families reported to all being proud of the family member with DS, and 87% reported to all feeling love for the member with DS. Younger siblings (ages 9-11) were more likely to feel embarrassed by their sibling with DS if their parents/guardians also did. If one or more parents/guardians felt that their children without DS did have a good relationship with their child with DS, siblings were more likely to report that they loved and liked their brother/sister with DS. Overall, our data demonstrate that positive themes tend to dominate within modern-day families who have members with DS, although challenges were not insignificant for some. (c) 2015 Wiley Periodicals, Inc. C1 [Skotko, Brian G.] Massachusetts Gen Hosp, Dept Pediat, Div Med Genet, Boston, MA 02114 USA. [Skotko, Brian G.; Macklin, Eric A.; Goldstein, Richard D.] Harvard Univ, Sch Med, Boston, MA USA. [Levine, Susan P.] Family Resource Associates Inc, Shrewsbury, NJ USA. [Macklin, Eric A.] Massachusetts Gen Hosp, Biostat Ctr, Boston, MA 02114 USA. [Goldstein, Richard D.] Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, Boston, MA 02115 USA. RP Skotko, BG (reprint author), Massachusetts Gen Hosp, 185 Cambridge St,Room 2222, Boston, MA 02114 USA. EM bskotko@mgh.harvard.edu OI Macklin, Eric/0000-0003-1618-3502 FU Tim White Foundation; Fred Lovejoy House-staff Research and Education Fund; Joel and Barbara Alpert Endowment for the Children of the City; Harvard NeuroDiscovery Center FX Grant sponsor: Tim White Foundation; Grant sponsor: Fred Lovejoy House-staff Research and Education Fund; Grant sponsor: Joel and Barbara Alpert Endowment for the Children of the City; Grant sponsor: Harvard NeuroDiscovery Center. NR 17 TC 2 Z9 2 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 APR PY 2016 VL 170 IS 4 BP 930 EP 941 DI 10.1002/ajmg.a.37520 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA DH9EN UT WOS:000373099300015 PM 26692378 ER PT J AU Richardson, PG Riches, ML Kernan, NA Brochstein, JA Mineishi, S Termuhlen, AM Arai, S Grupp, SA Guinan, EC Martin, PL Steinbach, G Krishnan, A Nemecek, ER Giralt, S Rodriguez, T Duerst, R Doyle, J Antin, JH Smith, A Lehmann, L Champlin, R Gillio, A Bajwa, R D'Agostino, RB Massaro, J Warren, D Miloslavsky, M Hume, RL Iacobelli, M Nejadnik, B Hannah, AL Soiffer, RJ AF Richardson, Paul G. Riches, Marcie L. Kernan, Nancy A. Brochstein, Joel A. Mineishi, Shin Termuhlen, Amanda M. Arai, Sally Grupp, Stephan A. Guinan, Eva C. Martin, Paul L. Steinbach, Gideon Krishnan, Amrita Nemecek, Eneida R. Giralt, Sergio Rodriguez, Tulio Duerst, Reggie Doyle, John Antin, Joseph H. Smith, Angela Lehmann, Leslie Champlin, Richard Gillio, Alfred Bajwa, Rajinder D'Agostino, Ralph B., Sr. Massaro, Joseph Warren, Diane Miloslavsky, Maja Hume, Robin L. Iacobelli, Massimo Nejadnik, Bijan Hannah, Alison L. Soiffer, Robert J. TI Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure SO BLOOD LA English DT Article ID STEM-CELL TRANSPLANTATION; SINUSOIDAL OBSTRUCTION SYNDROME; HIGH-RISK POPULATION; MARROW-TRANSPLANTATION; SIGNIFICANT TOXICITY; COMPASSIONATE-USE; CHILDREN; LIVER; MECHANISM; VOD AB Hepatic veno-occlusive disease (VOD), also called sinusoidal obstruction syndrome (SOS), is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). Untreated hepatic VOD/SOS with multi-organ failure (MOF) is associated with >80% mortality. Defibrotide has shown promising efficacy treating hepatic VOD/SOS with MOF in phase 2 studies. This phase 3 study investigated safety and efficacy of defibrotide in patients with established hepatic VOD/SOS and advanced MOF. Patients (n = 102) given defibrotide 25 mg/kg per day were compared with 32 historical controls identified out of 6867 medical charts of HSCT patients by blinded independent reviewers. Baseline characteristics between groups were well balanced. The primary endpoint was survival at day 1100 post-HSCT; observed rates equaled 38.2% in the defibrotide group and 25% in the controls (23% estimated difference; 95.1% confidence interval [CI], 5.2-40.8; P = .0109, using a propensity-adjusted analysis). Observed day 1100 complete response (CR) rates equaled 25.5% for defibrotide and 12.5% for controls (19% difference using similar methodology; 95.1% CI, 3.5-34.6; P = .0160). Defibrotide was generally well tolerated with manageable toxicity. Related adverse events (AEs) included hemorrhage or hypotension; incidence of common hemorrhagic AEs (including pulmonary alveolar [11.8% and 15.6%] and gastrointestinal bleeding [7.8% and 9.4%]) was similar between the defibrotide and control groups, respectively. Defibrotide was associated with significant improvement in day 1100 survival and CR rate. The historical-control methodology offers a novel, meaningful approach for phase 3 evaluation of orphan diseases associated with high mortality. This trial was registered at www.clinicaltrials.gov as #NCT00358501. C1 [Richardson, Paul G.; Guinan, Eva C.; Antin, Joseph H.; Lehmann, Leslie; Warren, Diane; Soiffer, Robert J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Riches, Marcie L.] Univ N Carolina, Canc Hosp, Bone Marrow & Stem Cell Transplant Clin, Div Hematol Oncol,Univ North Carolina Hosp, Chapel Hill, NC USA. [Kernan, Nancy A.] Mem Sloan Kettering Canc Ctr, Pediat Bone Marrow Transplant Serv, 1275 York Ave, New York, NY 10021 USA. [Brochstein, Joel A.] Cohen Childrens Med Ctr, Stem Cell Transplant Program, Dept Pediat, New Hyde Pk, NY USA. [Mineishi, Shin] Univ Alabama Birmingham, Div Hematol & Oncol, Birmingham, AL USA. [Termuhlen, Amanda M.] Childrens Hosp Los Angeles, Div Pediat Hematol Oncol Blood & Marrow Transplan, Los Angeles, CA 90027 USA. [Arai, Sally] Stanford Univ, Med Ctr, Blood & Marrow Transplantat, Stanford, CA 94305 USA. [Grupp, Stephan A.] Childrens Hosp Philadelphia, Pediat Oncol, Philadelphia, PA 19104 USA. [Guinan, Eva C.; Lehmann, Leslie] Childrens Hosp, Dept Hematol Oncol, 300 Longwood Ave, Boston, MA 02115 USA. [Martin, Paul L.] Duke Univ, Med Ctr, Div Pediat Blood & Marrow Transplant, Durham, NC USA. [Steinbach, Gideon] Univ Washington, Sch Med, Div Gastroenterol, Seattle, WA 98195 USA. [Steinbach, Gideon] Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA. [Krishnan, Amrita] City Hope Natl Med Ctr, Dept Hematol & Hematopoiet Cell Transplantat, Duarte, CA USA. [Nemecek, Eneida R.] Oregon Hlth & Sci Univ, Pediat Bone Marrow Transplant Program, Portland, OR 97201 USA. [Giralt, Sergio] Mem Sloan Kettering Canc Ctr, Adult Bone Marrow Transplant Serv, 1275 York Ave, New York, NY 10021 USA. [Rodriguez, Tulio] Loyola Univ, Med Ctr, Hematol Oncol, Chicago, IL 60611 USA. [Duerst, Reggie] Ann & Robert H Lurie Childrens Hosp Chicago, Stem Cell Transplant Program, Chicago, IL 60611 USA. [Doyle, John] CancerCare Manitoba, Pediat Hematol Oncol, Winnipeg, MB, Canada. [Doyle, John] Univ Manitoba, Winnipeg, MB, Canada. [Smith, Angela] Univ Minnesota, Div Blood & Marrow Transplantat, Minneapolis, MN USA. [Champlin, Richard] Univ Texas Houston, MD Anderson Canc Ctr, Dept Stem Cell Transplantat & Cellular Therapy, 1515 Holcombe Blvd, Houston, TX 77030 USA. [Gillio, Alfred] Hackensack Univ, Med Ctr, Dept Pediat, Hackensack, NJ USA. [Bajwa, Rajinder] Ohio State Univ, Nationwide Childrens Hosp, Dept Hematol Oncol BMT, Columbus, OH 43210 USA. [D'Agostino, Ralph B., Sr.; Massaro, Joseph] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Miloslavsky, Maja] Jazz Pharmaceut, Biostat, Palo Alto, CA USA. [Hume, Robin L.] Jazz Pharmaceut, Regulatory Affairs, Palo Alto, CA USA. [Iacobelli, Massimo] Techitra Srl, Life Sci, Milan, Italy. [Nejadnik, Bijan] Galena Biopharma, Res & Clin Dev, San Ramon, CA USA. [Hannah, Alison L.] Jazz Pharmaceut, Clin Operat, Palo Alto, CA USA. RP Richardson, PG (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM paul_richardson@dfci.harvard.edu FU Jazz Pharmaceuticals; National Cancer Institute of the National Institutes of Health [P30 CA008748] FX The authors gratefully acknowledge the members of the independent MRC, specifically Professors Selim Corbacioglu and Ernst Holler, for their essential role in identifying the historical controls and comprehensive chart review; all data and study monitoring members, study staff, nursing teams, and medical personnel; and in particular all participating patients and their families. Medical writing and editorial assistance for the development of this manuscript was provided by Dr Jonathan Viney (apothecom scopemedical) and The Curry Rockefeller Group, LLC, funded by Jazz Pharmaceuticals.; This study was funded by Gentium SpA, now Jazz Pharmaceuticals. N.A.K.'s research was supported by the National Cancer Institute of the National Institutes of Health (P30 CA008748). The content is solely the responsibility of the author and does not necessarily represent the official views of the National Institutes of Health. NR 32 TC 12 Z9 12 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD MAR 31 PY 2016 VL 127 IS 13 BP 1656 EP 1665 DI 10.1182/blood-2015-10-676924 PG 10 WC Hematology SC Hematology GA DI4ZI UT WOS:000373507500011 PM 26825712 ER PT J AU Kuzuya, A Zoltowska, KM Post, KL Arimon, M Li, XJ Svirsky, S Maesako, M Muzikansky, A Gautam, V Kovacs, D Hyman, BT Berezovska, O AF Kuzuya, Akira Zoltowska, Katarzyna M. Post, Kathryn L. Arimon, Muriel Li, Xuejing Svirsky, Sarah Maesako, Masato Muzikansky, Alona Gautam, Vivek Kovacs, Dora Hyman, Bradley T. Berezovska, Oksana TI Identification of the novel activity-driven interaction between synaptotagmin 1 and presenilin 1 links calcium, synapse, and amyloid beta SO BMC BIOLOGY LA English DT Article DE Synaptotagmin 1; Presenilin 1; Alzheimer's disease; Beta amyloid ID FAMILIAL ALZHEIMERS-DISEASE; PRECURSOR PROTEIN APP; GAMMA-SECRETASE; IN-VIVO; COGNITIVE IMPAIRMENT; NEURONAL-ACTIVITY; SENILE PLAQUES; RELEASE; CONFORMATION; CLEAVAGE AB Background: Synaptic loss strongly correlates with memory deterioration. Local accumulation of amyloid beta (A beta) peptide, and neurotoxic A beta 42 in particular, due to abnormal neuronal activity may underlie synaptic dysfunction, neurodegeneration, and memory impairments. To gain an insight into molecular events underlying neuronal activity-regulated A beta production at the synapse, we explored functional outcomes of the newly discovered calcium-dependent interaction between Alzheimer's disease-associated presenilin 1 (PS1)/gamma-secretase and synaptic vesicle proteins. Results: Mass spectrometry screen of mouse brain lysates identified synaptotagmin 1 (Syt1) as a novel synapse-specific PS1-binding partner that shows Ca2+-dependent PS1 binding profiles in vitro and in vivo. We found that A beta level, and more critically, conformation of the PS1 and the A beta(42/40) ratio, are affected by Syt1 overexpression or knockdown, indicating that Syt1 and its interaction with PS1 might regulate A beta production at the synapse. Moreover, beta-secretase 1 (BACE1) stability, beta- and gamma-secretase activity, as well as intracellular compartmentalization of PS1 and BACE1, but not of amyloid precursor protein (APP), nicastrin (Nct), presenilin enhancer 2 (Pen-2), or synaptophysin (Syp) were altered in the absence of Syt1, suggesting a selective effect of Syt1 on PS1 and BACE1 trafficking. Conclusions: Our findings identify Syt1 as a novel Ca2+-sensitive PS1 modulator that could regulate synaptic A beta, opening avenues for novel and selective synapse targeting therapeutic strategies. C1 [Kuzuya, Akira; Zoltowska, Katarzyna M.; Post, Kathryn L.; Arimon, Muriel; Li, Xuejing; Svirsky, Sarah; Maesako, Masato; Gautam, Vivek; Kovacs, Dora; Hyman, Bradley T.; Berezovska, Oksana] Harvard Univ, Massachusetts Gen Hosp, Sch Med, MassGen Inst Neurodegenerat Dis,Dept Neurol, Charlestown, MA 02129 USA. [Muzikansky, Alona] Massachusetts Gen Hosp, MGH Biostat Ctr, Boston, MA 02114 USA. RP Berezovska, O (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, MassGen Inst Neurodegenerat Dis,Dept Neurol, Charlestown, MA 02129 USA. EM oberezovska@mgh.harvard.edu FU NIH [AG15379, AG044486]; Kyoto University Foundation FX We thank Zhanyun Fan (MGH, Boston) for help with generating Syt1 calcium mutant constructs and Dr. A.B. Harkins (St. Louis University School of Medicine) for PC12 parental and Syt1 KD cell lines. This work was supported by NIH grants AG15379 and AG044486 (OB) and 'The Kyoto University Foundation' (AK). NR 58 TC 6 Z9 6 U1 1 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7007 J9 BMC BIOL JI BMC Biol. PD MAR 31 PY 2016 VL 14 AR 25 DI 10.1186/s12915-016-0248-3 PG 24 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DH8UW UT WOS:000373073400002 PM 27036734 ER PT J AU Killian, NJ Vernekar, VN Potter, SM Vukasinovic, J AF Killian, Nathaniel J. Vernekar, Varadraj N. Potter, Steve M. Vukasinovic, Jelena TI A Device for Long-Term Perfusion, Imaging, and Electrical Interfacing of Brain Tissue In vitro SO FRONTIERS IN NEUROSCIENCE LA English DT Article DE perforated microelectrode array; neurons; brain slice; three-dimensional culture; MEA ID ORGANOTYPIC SLICE CULTURES; MICROELECTRODE ARRAYS; MULTIELECTRODE ARRAYS; EXTRACELLULAR-SPACE; NERVOUS-TISSUE; SYSTEM; VIVO; ELECTROPHYSIOLOGY; STIMULATION; RECORDINGS AB Distributed microelectrode array (MEA) recordings from consistent, viable, >500 mu m thick tissue preparations over time periods from days to weeks may aid in studying a wide range of problems in neurobiology that require in vivo-like organotypic morphology. Existing tools for electrically interfacing with organotypic slices do not address necrosis that inevitably occurs within thick slices with limited diffusion of nutrients and gas, and limited removal of waste. We developed an integrated device that enables long-term maintenance of thick, functionally active, brain tissue models using interstitial perfusion and distributed recordings from thick sections of explanted tissue on a perforated multi-electrode array. This novel device allows for automated culturing, in situ imaging, and extracellular multi-electrode interfacing with brain slices, 3-D cell cultures, and potentially other tissue culture models. The device is economical, easy to assemble, and integrable with standard electrophysiology tools. We found that convective perfusion through the culture thickness provided a functional benefit to the preparations as firing rates were generally higher in perfused cultures compared to their respective unperfused controls. This work is a step toward the development of integrated tools for days-long experiments with more consistent, healthier, thicker, and functionally more active tissue cultures with built-in distributed electrophysiological recording and stimulation functionality. The results may be useful for the study of normal processes, pathological conditions, and drug screening strategies currently hindered by the limitations of acute (a few hours long) brain slice preparations. C1 [Killian, Nathaniel J.; Potter, Steve M.] Georgia Tech, Wallace H Coulter Dept Biomed Engn, Lab NeuroEngn, Atlanta, GA USA. [Killian, Nathaniel J.; Potter, Steve M.] Emory Univ, Georgia Inst Technol, Atlanta, GA 30322 USA. [Vernekar, Varadraj N.; Vukasinovic, Jelena] Lena Biosci Inc, ATDC, Atlanta, GA USA. [Killian, Nathaniel J.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. RP Vukasinovic, J (reprint author), Lena Biosci Inc, ATDC, Atlanta, GA USA. EM jvukasinovic@lenabio.com OI Killian, Nathaniel/0000-0002-4546-0516 FU National Institutes of Health SBIR awards [1 R43 NS065543, 5 R43 NS065543, 5 R01 NS079757] FX This work was supported by the National Institutes of Health SBIR awards to Lena Biosciences, Inc. 1 R43 NS065543 and 5 R43 NS065543 and 5 R01 NS079757 to Georgia Tech. We thank Multi Channel Systems MCS GmbH for graciously providing pMEAs for this work. We thank Michelle LaPlaca, Ph.D. and James Shoemaker for sharing cell culture equipment and brain tissue; Michelle Kuykendal for sharing fluorescent dyes and reagents; and Alex Calhoun, Ming-fai Fong, Jon Newman, and Riley Zeller Townson for technical advice. NR 56 TC 2 Z9 2 U1 1 U2 5 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-453X J9 FRONT NEUROSCI-SWITZ JI Front. Neurosci. PD MAR 31 PY 2016 VL 10 AR 135 DI 10.3389/fnins.2016.00135 PG 14 WC Neurosciences SC Neurosciences & Neurology GA DH8IS UT WOS:000373037300002 PM 27065793 ER PT J AU Craddock, RC Margulies, DS Bellec, P Nichols, BN Alcauter, S Barrios, FA Burnod, Y Cannistraci, CJ Cohen-Adad, J De Leener, B Dery, S Downar, J Dunlop, K Franco, AR Froehlich, CS Gerber, AJ Ghosh, SS Grabowski, TJ Hill, S Heinsfeld, AS Hutchison, RM Kundu, P Laird, AR Liew, SL Lurie, DJ McLaren, DG Meneguzzi, F Mennes, M Mesmoudi, S O'Connor, D Pasaye, EH Peltier, S Poline, JB Prasad, G Pereira, RF Quirion, PO Rokem, A Saad, ZS Shi, YG Strother, SC Toro, R Uddin, LQ Van Horn, JD Van Meter, JW Welsh, RC Xu, T AF Craddock, R. Cameron Margulies, Daniel S. Bellec, Pierre Nichols, B. Nolan Alcauter, Sarael Barrios, Fernando A. Burnod, Yves Cannistraci, Christopher J. Cohen-Adad, Julien De Leener, Benjamin Dery, Sebastien Downar, Jonathan Dunlop, Katharine Franco, Alexandre R. Froehlich, Caroline Seligman Gerber, Andrew J. Ghosh, Satrajit S. Grabowski, Thomas J. Hill, Sean Heinsfeld, Anibal Solon Hutchison, R. Matthew Kundu, Prantik Laird, Angela R. Liew, Sook-Lei Lurie, Daniel J. McLaren, Donald G. Meneguzzi, Felipe Mennes, Maarten Mesmoudi, Salma O'Connor, David Pasaye, Erick H. Peltier, Scott Poline, Jean-Baptiste Prasad, Gautam Pereira, Ramon Fraga Quirion, Pierre-Olivier Rokem, Ariel Saad, Ziad S. Shi, Yonggang Strother, Stephen C. Toro, Roberto Uddin, Lucina Q. Van Horn, John D. Van Meter, John W. Welsh, Robert C. Xu, Ting TI Brainhack: a collaborative workshop for the open neuroscience community SO GIGASCIENCE LA English DT Review DE Hackathon; Unconference; Open science; Neuroscience; Data sharing; Collaboration; Networking ID THICKNESS; MRI AB Brainhack events offer a novel workshop format with participant-generated content that caters to the rapidly growing open neuroscience community. Including components from hackathons and unconferences, as well as parallel educational sessions, Brainhack fosters novel collaborations around the interests of its attendees. Here we provide an overview of its structure, past events, and example projects. Additionally, we outline current innovations such as regional events and post-conference publications. Through introducing Brainhack to the wider neuroscience community, we hope to provide a unique conference format that promotes the features of collaborative, open science. C1 [Craddock, R. Cameron; Margulies, Daniel S.; Bellec, Pierre; Nichols, B. Nolan; Franco, Alexandre R.; Froehlich, Caroline Seligman; Ghosh, Satrajit S.; Hutchison, R. Matthew; Kundu, Prantik; Liew, Sook-Lei; McLaren, Donald G.; Mennes, Maarten; Toro, Roberto; Uddin, Lucina Q.] Neuro Bur, D-04317 Leipzig, Germany. [Craddock, R. Cameron; Froehlich, Caroline Seligman] Nathan S Kline Inst Psychiat Res, Ctr Biomed Imaging & Neuromodulat, Computat Neuroimaging Lab, Orangeburg, NY 10962 USA. [Craddock, R. Cameron; O'Connor, David; Xu, Ting] Child Mind Inst, Ctr Dev Brain, New York, NY 10022 USA. [Margulies, Daniel S.] Max Planck Inst Human Cognit & Brain Sci, Max Planck Res Grp Neuroanat & Connect, D-04103 Leipzig, Germany. [Bellec, Pierre] Univ Montreal, Dept Informat & Rech Operat, Montreal, PQ H3W 1W5, Canada. [Bellec, Pierre; Cohen-Adad, Julien; Quirion, Pierre-Olivier] Inst Univ Geriatrie Montreal, Ctr Rech, Funct Neuroimaging Unit, Montreal, PQ H3W 1W5, Canada. [Nichols, B. Nolan] SRI Int, Ctr Hlth Sci, Menlo Pk, CA 94025 USA. [Nichols, B. Nolan] Stanford Univ, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. [Alcauter, Sarael; Barrios, Fernando A.; Pasaye, Erick H.] Univ Nacl Autonoma Mexico, Inst Neurobiol, Queretaro 76203, Mexico. [Burnod, Yves] Univ Paris 06, Univ Sorbonne, Lab Imagerie Biomed, F-75005 Paris, France. [Burnod, Yves; Mesmoudi, Salma] Inst Syst Complexes Paris Ile de France, F-75013 Paris, France. [Cannistraci, Christopher J.; Kundu, Prantik] Icahn Sch Med Mt Sinai, Translat & Mol Imaging Inst, New York, NY 10029 USA. [Cohen-Adad, Julien; De Leener, Benjamin] Ecole Polytech, Inst Biomed Engn, Montreal, PQ H3T 1J4, Canada. [Dery, Sebastien] McGill Univ, Montreal Neurol Inst, McConnell Brain Imaging Ctr, 3801 Univ St, Montreal, PQ H3A 2B4, Canada. [Downar, Jonathan; Dunlop, Katharine] Univ Hlth Network, MRI Guided rTMS Clin, Toronto, ON M5T 2S8, Canada. [Downar, Jonathan] Univ Toronto, Univ Hlth Network, Dept Psychiat, Toronto, ON M5T 2S8, Canada. [Downar, Jonathan; Dunlop, Katharine; Strother, Stephen C.] Univ Toronto, Inst Med Sci, 100 Coll St, Toronto, ON M5S 1A8, Canada. [Franco, Alexandre R.] Pontificia Univ Catolica Rio Grande do Sul, Fac Engn, BR-90619 Porto Alegre, RS, Brazil. [Franco, Alexandre R.] Pontificia Univ Catolica Rio Grande do Sul, Inst Cerebro Rio Grande do Sul, BR-90610 Porto Alegre, RS, Brazil. [Franco, Alexandre R.] Pontificia Univ Catolica Rio Grande do Sul, Fac Med, BR-90619 Porto Alegre, RS, Brazil. [Gerber, Andrew J.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Gerber, Andrew J.] Columbia Univ, Dept Psychiat, Div Child & Adolescent Psychiat, New York, NY 10032 USA. [Ghosh, Satrajit S.] MIT, McGovern Inst Brain Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Ghosh, Satrajit S.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Grabowski, Thomas J.] Univ Washington, Dept Radiol, Seattle, WA 98105 USA. [Grabowski, Thomas J.] Univ Washington, Dept Neurol, Seattle, WA 98105 USA. [Hill, Sean] Int Neuroinformat Coordinating Facil, S-17177 Stockholm, Sweden. [Hill, Sean] Karolinska Inst, S-17177 Stockholm, Sweden. [Heinsfeld, Anibal Solon; Meneguzzi, Felipe; Pereira, Ramon Fraga] Pontificia Univ Catolica Rio Grande do Sul, Fac Informat, BR-90619 Porto Alegre, RS, Brazil. [Hutchison, R. Matthew] Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA. [Laird, Angela R.] Florida Int Univ, Dept Phys, Miami, FL 33199 USA. [Liew, Sook-Lei] Univ So Calif, Dept Neurol, Div Phys Therapy & Biokinesiol, Chan Div Occupat Sci & Occupat Therapy, Los Angeles, CA 90033 USA. [Liew, Sook-Lei; Van Horn, John D.] Univ So Calif, USC Mark & Mary Stevens Neuroimaging & Informat I, Los Angeles, CA 90033 USA. [Lurie, Daniel J.] Univ Calif Berkeley, Dept Psychol, Berkeley, CA 94720 USA. [McLaren, Donald G.] Biospective Inc, Montreal, PQ H4P 1K6, Canada. [McLaren, Donald G.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Mennes, Maarten] Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Ctr Cognit Neuroimaging, NL-6525 EN Nijmegen, Netherlands. [Mesmoudi, Salma] Univ Paris 01, Sorbonne Univ, Equipement Excellence MATRICE, F-75005 Paris, France. [Peltier, Scott] Univ Michigan, Funct MRI Lab, Ann Arbor, MI 48109 USA. [Poline, Jean-Baptiste] Univ Calif Berkeley, Helen Wills Neurosci Inst, Berkeley, CA 94720 USA. [Poline, Jean-Baptiste] Univ Calif Berkeley, Henry H Wheeler Jr Brain Imaging Ctr, Berkeley, CA 94709 USA. [Prasad, Gautam; Shi, Yonggang] Univ So Calif, Keck Sch Med, Stevens Neuroimaging & Informat Inst, Lab Neuro Imaging, Los Angeles, CA 90033 USA. [Rokem, Ariel] Univ Washington, ESci Inst, Seattle, WA 98195 USA. [Saad, Ziad S.] NIMH, Sci & Stat Comp Core, Bethesda, MD 20892 USA. [Strother, Stephen C.] Baycrest Hosp, Rotman Res Inst, Toronto, ON M6A 2E1, Canada. [Strother, Stephen C.] Univ Toronto, Dept Med Biophys, Toronto, ON M5G 1L7, Canada. [Toro, Roberto] Inst Pasteur, Human Genet & Cognit Funct Unit, F-75015 Paris, France. [Toro, Roberto] Inst Pasteur, CNRS, Genes Synapses & Cognit, UMR 3571, F-75015 Paris, France. [Uddin, Lucina Q.] Univ Miami, Dept Psychol, Coral Gables, FL 33124 USA. [Uddin, Lucina Q.] Univ Miami, Neurosci Program, Miller Sch Med, Miami, FL 33136 USA. [Van Meter, John W.] Georgetown Univ, Med Ctr, Ctr Funct & Mol Imaging, Washington, DC 20007 USA. [Welsh, Robert C.] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. [Welsh, Robert C.] Univ Michigan, Dept Radiol, Ann Arbor, MI 48109 USA. RP Craddock, RC (reprint author), Neuro Bur, D-04317 Leipzig, Germany. EM cameron.craddock@gmail.com RI Margulies, Daniel/L-4719-2016; OI Margulies, Daniel/0000-0002-8880-9204; Craddock, Cameron/0000-0002-4950-1303; Nichols, Nolan/0000-0003-1099-3328 FU Allen Institute for Brain Science (OHBM); Amazon Web Services (OHBM); Amazon Web Services (Boston); Amazon Web Services (Brainhack AMX); Athinoula A. Martinos Center for Biomedical Imaging (Boston); Child Mind Institute, Inc. (NYC); Child Mind Institute, Inc. (MX); FIU Division of Research (Miami); Frontiers (OHBM); Frontiers in Neuroscience (OHBM); International Neuroinformatics Coordinating Facility (OHBM); International Neuroinformatics Coordinating Facility (MX); MATRICE (Paris); Max Planck Institute for Cognitive and Brain Sciences (Leipzig); Microsoft Azure (OHBM); NIH BD2K Center [1U54EB020406-01]; Big Data for Discovery Science (USC, PI: Toga, LA); Enigma Center for Worldwide Medicine, Imaging, and Genomics (USC, PI: Thompson, LA); NIH BD2K [3U01AA021697-04S1, 5U01AA021697-04]; Organization for Human Brain Mapping (OHBM); Ontario Brain Institute (Toronto); Quebec Bio-Imaging Network (MTL); Siemens (Paris); University of Miami Flipse Funds (Miami) FX The authors would like to thank prior organizers and attendees of Brainhacks over the past four years. We would also like to thank our sponsors, whose funds have been used to enrich the educational experience at Brainhack and have provided travel support for attendees. These include (in alphabetical order): Allen Institute for Brain Science (OHBM 2013), Amazon Web Services (OHBM 2013, OHBM 2014, Boston 2014, Brainhack AMX 2015), Athinoula A. Martinos Center for Biomedical Imaging (Boston 2014), Child Mind Institute, Inc. (NYC 2014, NYC 2015, MX 2015), FIU Division of Research (Miami 2014), Frontiers (OHBM 2014), Frontiers in Neuroscience (OHBM 2013), International Neuroinformatics Coordinating Facility (OHBM 2013, OHBM 2014, OHBM 2015, MX 2015), MATRICE (Paris 2013), Max Planck Institute for Cognitive and Brain Sciences (Leipzig 2012), Microsoft Azure (OHBM 2015), NIH BD2K Center (1U54EB020406-01) Big Data for Discovery Science (USC, PI: Toga, LA 2015), NIH BD2K Center (1U54EB020403-01) Enigma Center for Worldwide Medicine, Imaging, and Genomics (USC, PI: Thompson, LA 2015), NIH BD2K Supplement for NCANDA (3U01AA021697-04S1) and NCANDA: Data Analysis Component (5U01AA021697-04) (SRI International, PI: Pohl, OHBM2015, MX 2015), Organization for Human Brain Mapping (OHBM 2013, OHBM 2014, OHBM 2015), Ontario Brain Institute (Toronto 2014), Quebec Bio-Imaging Network (MTL 2014, MTL 2015), Siemens (Paris 2013), and University of Miami Flipse Funds (Miami 2015). NR 13 TC 2 Z9 2 U1 4 U2 11 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2047-217X J9 GIGASCIENCE JI GigaScience PD MAR 31 PY 2016 VL 5 AR 16 DI 10.1186/s13742-016-0121-x PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DI1LR UT WOS:000373258100001 ER PT J AU Lee, JD Friedmann, PD Kinlock, TW Nunes, EV Boney, TY Hoskinson, RA Wilson, D McDonald, R Rotrosen, J Gourevitch, MN Gordon, M Fishman, M Chen, DT Bonnie, RJ Cornish, JW Murphy, SM O'Brien, CP AF Lee, Joshua D. Friedmann, Peter D. Kinlock, Timothy W. Nunes, Edward V. Boney, Tamara Y. Hoskinson, Randall A., Jr. Wilson, Donna McDonald, Ryan Rotrosen, John Gourevitch, Marc N. Gordon, Michael Fishman, Marc Chen, Donna T. Bonnie, Richard J. Cornish, James W. Murphy, Sean M. O'Brien, Charles P. TI Extended-Release Naltrexone to Prevent Opioid Relapse in Criminal Justice Offenders SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID RANDOMIZED CLINICAL-TRIAL; METHADONE-MAINTENANCE; BUPRENORPHINE; DEPENDENCE; TIME; PROBATIONERS; POSTRELEASE; ADDICTION; SEVERITY; PAROLEES AB BACKGROUND Extended-release naltrexone, a sustained-release monthly injectable formulation of the full mu-opioid receptor antagonist, is effective for the prevention of relapse to opioid dependence. Data supporting its effectiveness in U.S. criminal justice populations are limited. METHODS In this five-site, open-label, randomized trial, we compared a 24-week course of extended-release naltrexone (Vivitrol) with usual treatment, consisting of brief counseling and referrals for community treatment programs, for the prevention of opioid relapse among adult criminal justice offenders (i.e., persons involved in the U.S. criminal justice system) who had a history of opioid dependence and a preference for opioid-free rather than opioid maintenance treatments and who were abstinent from opioids at the time of randomization. The primary outcome was the time to an opioid-relapse event, which was defined as 10 or more days of opioid use in a 28-day period as assessed by self-report or by testing of urine samples obtained every 2 weeks; a positive or missing sample was computed as 5 days of opioid use. Post-treatment follow-up occurred at weeks 27, 52, and 78. RESULTS A total of 153 participants were assigned to extended-release naltrexone and 155 to usual treatment. During the 24-week treatment phase, participants assigned to extended-release naltrexone had a longer median time to relapse than did those assigned to usual treatment (10.5 vs. 5.0 weeks, P<0.001; hazard ratio, 0.49; 95% confidence interval [CI], 0.36 to 0.68), a lower rate of relapse (43% vs. 64% of participants, P<0.001; odds ratio, 0.43; 95% CI, 0.28 to 0.65), and a higher rate of opioid-negative urine samples (74% vs. 56%, P<0.001; odds ratio, 2.30; 95% CI, 1.48 to 3.54). At week 78 (approximately 1 year after the end of the treatment phase), rates of opioid-negative urine samples were equal (46% in each group, P = 0.91). The rates of other prespecified secondary outcome measures - self-reported cocaine, alcohol, and intravenous drug use, unsafe sex, and reincarceration - were not significantly lower with extended-release naltrexone than with usual treatment. Over the total 78 weeks observed, there were no overdose events in the extended-release naltrexone group and seven in the usual-treatment group (P = 0.02). CONCLUSIONS In this trial involving criminal justice offenders, extended-release naltrexone was associated with a rate of opioid relapse that was lower than that with usual treatment. Opioid-use prevention effects waned after treatment discontinuation. C1 [Lee, Joshua D.; McDonald, Ryan; Gourevitch, Marc N.] NYU, Dept Populat Hlth, 227 E 30th St, New York, NY 10016 USA. [Lee, Joshua D.] NYU, Dept Med, Div Gen Internal Med & Clin Innovat, New York, NY USA. [Rotrosen, John] NYU, Dept Psychiat, New York, NY USA. [Nunes, Edward V.] Columbia Univ, Coll Phys & Surg, New York State Psychiat Inst, New York, NY USA. [Friedmann, Peter D.; Hoskinson, Randall A., Jr.; Wilson, Donna] Rhode Isl Hosp, Div Gen Internal Med, Dept Med, Providence, RI USA. [Friedmann, Peter D.; Hoskinson, Randall A., Jr.; Wilson, Donna] Brown Univ, Alpert Med Sch, Providence, RI 02912 USA. [Kinlock, Timothy W.; Gordon, Michael; Fishman, Marc] Univ Baltimore, Sch Criminal Justice, Friends Res Inst, Baltimore, MD 21201 USA. [Fishman, Marc] Maryland Treatment Ctr, Baltimore, MD USA. [Boney, Tamara Y.; Cornish, James W.; O'Brien, Charles P.] Univ Penn, Philadelphia, PA 19104 USA. [Cornish, James W.] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. [Chen, Donna T.] Univ Virginia, Ctr Biomed Eth & Humanities, Sch Med, Charlottesville, VA USA. [Bonnie, Richard J.] Univ Virginia, Sch Law, Charlottesville, VA USA. [Murphy, Sean M.] Washington State Univ, Spokane, WA USA. RP Lee, JD (reprint author), NYU, Dept Populat Hlth, 227 E 30th St, New York, NY 10016 USA. EM joshua.lee@nyumc.org OI Gourevitch, Marc/0000-0001-6865-2126 FU National Institute on Drug Abuse FX Funded by the National Institute on Drug Abuse NR 24 TC 13 Z9 13 U1 5 U2 10 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 31 PY 2016 VL 374 IS 13 BP 1232 EP 1242 DI 10.1056/NEJMoa1505409 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA DH8ZM UT WOS:000373085500006 PM 27028913 ER PT J AU Coughlin, B Schnabolk, G Joseph, K Raikwar, H Kunchithapautham, K Johnson, K Moore, K Wang, Y Rohrer, B AF Coughlin, Beth Schnabolk, Gloriane Joseph, Kusumam Raikwar, Himanshu Kunchithapautham, Kannan Johnson, Krista Moore, Kristi Wang, Yi Rohrer, Baerbel TI Connecting the innate and adaptive immune responses in mouse choroidal neovascularization via the anaphylatoxin C5a and gamma delta T-cells SO SCIENTIFIC REPORTS LA English DT Article ID RETINAL-PIGMENT EPITHELIUM; COMPLEMENT-MEDIATED INJURY; FACTOR-H POLYMORPHISM; MACULAR DEGENERATION; OXIDATIVE STRESS; RISK-FACTORS; MONOCLONAL-ANTIBODY; FACTOR-B; ACTIVATION; DRUSEN AB Neovascular age-related macular degeneration (AMD) is characterized by choroidal neovascularization (CNV). An overactive complement system is associated with AMD pathogenesis, and serum proinflammatory cytokines, including IL-17, are elevated in AMD patients. IL-17 is produced by complement C5a-receptor-expressing T-cells. In murine CNV, infiltrating gamma delta T-rather than Th17-cells produce the IL-17 measurable in lesioned eyes. Here we asked whether C5a generated locally in response to CNV recruits IL-17-producing T-cells to the eye. CNV lesions were generated using laser photocoagulation and quantified by imaging; T-lymphocytes were characterized by QRT-PCR. CNV resulted in an increase in splenic IL-17-producing gamma delta T- and Th17-cells; yet in the CNV eye, only elevated levels of gamma delta T-cells were observed. Systemic administration of anti-C5- or anti-C5a-blocking antibodies blunted the CNV-induced production of splenic Th17- and gamma delta T-cells, reduced CNV size and eliminated ocular gamma delta T-cell infiltration. In ARPE-19 cell monolayers, IL-17 triggered a pro-inflammatory state; and splenocyte proliferation was elevated in response to ocular proteins. Thus, we demonstrated that CNV lesions trigger a systemic immune response, augmenting local ocular inflammation via the infiltration of IL-17-producing gamma delta T-cells, which are presumably recruited to the eye in a C5a-dependent manner. Understanding the complexity of complement-mediated pathological mechanisms will aid in the development of an AMD treatment. C1 [Coughlin, Beth; Joseph, Kusumam; Raikwar, Himanshu; Kunchithapautham, Kannan; Rohrer, Baerbel] Med Univ S Carolina, Dept Ophthalmol, 171 Ashley Ave, Charleston, SC 29425 USA. [Schnabolk, Gloriane; Rohrer, Baerbel] Ralph H Johnson VA Med Ctr, Res Serv, Charleston, SC 29401 USA. [Johnson, Krista; Moore, Kristi; Wang, Yi] Alex Pharmaceut, 352 Knotter Dr, Cheshire, CT 06410 USA. [Raikwar, Himanshu] Pandit Bhagwat Dayal Sharma Post Grad Inst Med Sc, Rohtak, Haryana, India. RP Rohrer, B (reprint author), Med Univ S Carolina, Dept Ophthalmol, 171 Ashley Ave, Charleston, SC 29425 USA.; Rohrer, B (reprint author), Ralph H Johnson VA Med Ctr, Res Serv, Charleston, SC 29401 USA. EM rohrer@musc.edu FU National Institutes of Health (NIH) [R01EY019320, C06 RR015455]; Department of Veterans Affairs [I01 RX000444]; Foundation Fighting Blindness; Alexion Therapeutics; Research to Prevent Blindness (RPB), Inc., New York, NY FX Supported in part by the National Institutes of Health (NIH) (R01EY019320), Department of Veterans Affairs (I01 RX000444), Foundation Fighting Blindness, an unrestricted grant to MUSC from Research to Prevent Blindness (RPB), Inc., New York, NY and a sponsored research agreement by Alexion Therapeutics to BR. Animal studies were conducted in a facility constructed with support from the NIH (C06 RR015455). NR 84 TC 2 Z9 2 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAR 31 PY 2016 VL 6 AR 23794 DI 10.1038/srep23794 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DI0ET UT WOS:000373168600001 PM 27029558 ER PT J AU Kwok, SJJ Choi, M Bhayana, B Zhang, XL Ran, CZ Yun, SH AF Kwok, Sheldon J. J. Choi, Myunghwan Bhayana, Brijesh Zhang, Xueli Ran, Chongzhao Yun, Seok-Hyun TI Two-photon excited photoconversion of cyanine-based dyes SO SCIENTIFIC REPORTS LA English DT Article ID IN-VIVO; FLUORESCENT PROTEINS; LIVING CELLS; SUPERRESOLUTION MICROSCOPY; CROSS-SECTIONS; ONE-PHOTON; SINGLE; PROBES; FLUOROPHORES; TRACKING AB The advent of phototransformable fluorescent proteins has led to significant advances in optical imaging, including the unambiguous tracking of cells over large spatiotemporal scales. However, these proteins typically require activating light in the UV-blue spectrum, which limits their in vivo applicability due to poor light penetration and associated phototoxicity on cells and tissue. We report that cyanine-based, organic dyes can be efficiently photoconverted by nonlinear excitation at the near infrared (NIR) window. Photoconversion likely involves singlet-oxygen mediated photochemical cleavage, yielding blue-shifted fluorescent products. Using SYTO62, a biocompatible and cell-permeable dye, we demonstrate photoconversion in a variety of cell lines, including depth-resolved labeling of cells in 3D culture. Two-photon photoconversion of cyanine-based dyes offer several advantages over existing photoconvertible proteins, including use of minimally toxic NIR light, labeling without need for genetic intervention, rapid kinetics, remote subsurface targeting, and long persistence of photoconverted signal. These findings are expected to be useful for applications involving rapid labeling of cells deep in tissue. C1 [Kwok, Sheldon J. J.; Choi, Myunghwan; Bhayana, Brijesh; Yun, Seok-Hyun] Harvard Univ, Sch Med, 50 Blossom St, Boston, MA 02114 USA. [Kwok, Sheldon J. J.; Choi, Myunghwan; Bhayana, Brijesh; Yun, Seok-Hyun] Massachusetts Gen Hosp, Wellman Ctr Photomed, 50 Blossom St, Boston, MA 02114 USA. [Kwok, Sheldon J. J.; Yun, Seok-Hyun] MIT, Harvard Mit Hlth Sci & Technol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Choi, Myunghwan] Sungkyunkwan Univ, Dept Biomed Engn, 2066 Seobu Ro, Suwon, Gyeong Gi Do, South Korea. [Choi, Myunghwan] Inst Basic Sci, Ctr Neurosci & Imaging Res, 2066 Seobu Ro, Suwon, Gyeong Gi Do, South Korea. [Zhang, Xueli; Ran, Chongzhao] MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Mol Imaging Lab, Bldg 149,13th St, Charlestown, MA 02129 USA. [Zhang, Xueli] Southeast Univ, Zhongda Hosp, Dept Pharm, Nanjing 210009, Peoples R China. RP Yun, SH (reprint author), Harvard Univ, Sch Med, 50 Blossom St, Boston, MA 02114 USA.; Yun, SH (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, 50 Blossom St, Boston, MA 02114 USA.; Yun, SH (reprint author), MIT, Harvard Mit Hlth Sci & Technol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM syun@hms.harvard.edu OI Choi, Myunghwan/0000-0002-4235-7003 FU National Institutes of Health [P01HL120839, P41EB015903, R01CA192878] FX We thank Eunha Kim for helping with the chemical analysis. We thank Shannon Bromley for providing leukocytes isolated from mice spleens. We thank Giuliano Scarcelli, Heebeom Koo, Ki Su Kim, Kyung Bok Lee, Sang Yeon Cho and Matjaz Humar for useful discussions. This research was funded by grants (P01HL120839, P41EB015903, R01CA192878) from National Institutes of Health. NR 51 TC 0 Z9 0 U1 13 U2 36 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAR 31 PY 2016 VL 6 AR 23866 DI 10.1038/srep23866 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DI0FL UT WOS:000373170400001 PM 27029524 ER PT J AU Cavadini, S Fischer, ES Bunker, RD Potenza, A Lingaraju, GM Goldie, KN Mohamed, WI Faty, M Petzold, G Beckwith, REJ Tichkule, RB Hassiepen, U Abdulrahman, W Pantelic, RS Matsumoto, S Sugasawa, K Stahlberg, H Thoma, NH AF Cavadini, Simone Fischer, Eric S. Bunker, Richard D. Potenza, Alessandro Lingaraju, Gondichatnahalli M. Goldie, Kenneth N. Mohamed, Weaam I. Faty, Mahamadou Petzold, Georg Beckwith, Rohan E. J. Tichkule, Ritesh B. Hassiepen, Ulrich Abdulrahman, Wassim Pantelic, Radosav S. Matsumoto, Syota Sugasawa, Kaoru Stahlberg, Henning Thomae, Nicolas H. TI Cullin-RING ubiquitin E3 ligase regulation by the COP9 signalosome SO NATURE LA English DT Article ID PIGMENTOSUM GROUP-E; GROWTH-FACTOR RECEPTOR; DNA-BINDING PROTEIN; DAMAGED DNA; C-CBL; STRUCTURAL BASIS; COMPLEX; SCF; LENALIDOMIDE; ARCHITECTURE AB The cullin-RING ubiquitin E3 ligase (CRL) family comprises over 200 members in humans. The COP9 signalosome complex (CSN) regulates CRLs by removing their ubiquitin-like activator NEDD8. The CUL4A-RBX1-DDB1-DDB2 complex (CRL4A(DDB2)) monitors the genome for ultraviolet-light-induced DNA damage. CRL4A(DBB2) is inactive in the absence of damaged DNA and requires CSN to regulate the repair process. The structural basis of CSN binding to CRL4A(DDB2) and the principles of CSN activation are poorly understood. Here we present cryo-electron microscopy structures for CSN in complex with neddylated CRL4A ligases to 6.4 angstrom resolution. The CSN conformers defined by cryo-electron microscopy and a novel apo-CSN crystal structure indicate an induced-fit mechanism that drives CSN activation by neddylated CRLs. We find that CSN and a substrate cannot bind simultaneously to CRL4A, favouring a deneddylated, inactive state for substrate-free CRL4 complexes. These architectural and regulatory principles appear conserved across CRL families, allowing global regulation by CSN. C1 [Cavadini, Simone; Fischer, Eric S.; Bunker, Richard D.; Potenza, Alessandro; Lingaraju, Gondichatnahalli M.; Mohamed, Weaam I.; Faty, Mahamadou; Petzold, Georg; Abdulrahman, Wassim; Thomae, Nicolas H.] Friedrich Miescher Inst Biomed Res, Maulbeerstr 66, CH-4058 Basel, Switzerland. [Cavadini, Simone; Fischer, Eric S.; Bunker, Richard D.; Potenza, Alessandro; Lingaraju, Gondichatnahalli M.; Mohamed, Weaam I.; Faty, Mahamadou; Petzold, Georg; Abdulrahman, Wassim; Thomae, Nicolas H.] Univ Basel, Peterspl 10, CH-4003 Basel, Switzerland. [Fischer, Eric S.] Dana Farber Canc Inst, Dept Canc Biol, LC-4312,360 Longwood Ave, Boston, MA 02215 USA. [Fischer, Eric S.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02215 USA. [Goldie, Kenneth N.; Pantelic, Radosav S.; Stahlberg, Henning] Univ Basel, Ctr Cellular Imaging & NanoAnalyt, Biozentrum, CH-4058 Basel, Switzerland. [Beckwith, Rohan E. J.; Tichkule, Ritesh B.] Novartis Inst Biomed Res, 250 Massachusetts Ave, Cambridge, MA 02139 USA. [Hassiepen, Ulrich] Novartis Pharma AG, Inst Biomed Res, Novartis Campus, CH-4056 Basel, Switzerland. [Pantelic, Radosav S.] Gatan R&D, 5974 W Las Positas Blvd, Pleasanton, CA 94588 USA. [Matsumoto, Syota; Sugasawa, Kaoru] Kobe Univ, Org Adv Sci & Technol, Biosignal Res Ctr, Kobe, Hyogo 6578501, Japan. [Matsumoto, Syota; Sugasawa, Kaoru] Kobe Univ, Grad Sch Sci, Kobe, Hyogo 6578501, Japan. RP Thoma, NH (reprint author), Friedrich Miescher Inst Biomed Res, Maulbeerstr 66, CH-4058 Basel, Switzerland.; Thoma, NH (reprint author), Univ Basel, Peterspl 10, CH-4003 Basel, Switzerland. EM nicolas.thoma@fmi.ch RI Stahlberg, Henning/H-1868-2011 OI Stahlberg, Henning/0000-0002-1185-4592 FU Novartis Research Foundation; European Research Council [ERC-2014-ADG 666068 CSNCRL]; Swiss initiative for Systems Biology (SystemsX.ch grant 'C-CINA'); European Molecular Biology Organization (EMBO) [ALTF-1350-2013]; Human Frontier Science Program (HFSP) [LT000210/2014]; Boehringer Ingelheim Fonds FX We thank K. Bohm for technical assistance in protein expression and purification, D. Hess and J. Seebacher for mass spectrometry analysis, and M. Jones, B. Martoglio, R. Assenberg, C. Logel, I. Bechtold and M. Renatus for help developing the TR-FRET and PT22 CSN assays. We thank B. Anderson and A. Fecteau-Lefebvre ('C-CINA') for technical support and TEM maintenance. We are grateful to T. Walz and D. Barford for help and discussions. Part of this work was performed at beamline X10SA of the Swiss Light Source. This work was supported by the Novartis Research Foundation and grants to N.H.T. from the European Research Council (ERC-2014-ADG 666068 CSNCRL) and to H.S. from the Swiss initiative for Systems Biology (SystemsX.ch grant 'C-CINA'). G.P. was supported by long-term fellowships of the European Molecular Biology Organization (EMBO; ALTF-1350-2013) and the Human Frontier Science Program (HFSP; LT000210/2014). W.I.M. was supported by the Boehringer Ingelheim Fonds. NR 47 TC 7 Z9 7 U1 8 U2 20 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD MAR 31 PY 2016 VL 531 IS 7596 BP 598 EP + DI 10.1038/nature17416 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH8EX UT WOS:000373027400030 PM 27029275 ER PT J AU Lee, MH Appleton, KM Strungs, EG Kwon, JY Morinelli, TA Peterson, YK Laporte, SA Luttrell, LM AF Lee, Mi-Hye Appleton, Kathryn M. Strungs, Erik G. Kwon, Joshua Y. Morinelli, Thomas A. Peterson, Yuri K. Laporte, Stephane A. Luttrell, Louis M. TI The conformational signature of beta-arrestin2 predicts its trafficking and signalling functions SO NATURE LA English DT Article ID COUPLED RECEPTOR ACTIVATION; BETA-ARRESTIN; G-PROTEIN; CRYSTAL-STRUCTURE; CLATHRIN ADAPTER; BIASED AGONISM; LIVING CELLS; ENDOCYTOSIS; MECHANISM; PHOSPHORYLATION AB Arrestins are cytosolic proteins that regulate G-protein-coupled receptor (GPCR) desensitization, internalization, trafficking and signalling(1,2). Arrestin recruitment uncouples GPCRs from heterotrimeric G proteins, and targets the proteins for internalization via clathrin-coated pits(3,4). Arrestins also function as ligand-regulated scaffolds that recruit multiple non-G-protein effectors into GPCR-based 'signalsomes'(5,6). Although the dominant function(s) of arrestins vary between receptors, the mechanism whereby different GPCRs specify these divergent functions is unclear. Using a panel of intramolecular fluorescein arsenical hairpin (FlAsH) bioluminescence resonance energy transfer (BRET) reporters(7) to monitor conformational changes in beta-arrestin2, here we show that GPCRs impose distinctive arrestin 'conformational signatures' that reflect the stability of the receptor-arrestin complex and role of a-arrestin2 in activating or dampening downstream signalling events. The predictive value of these signatures extends to structurally distinct ligands activating the same GPCR, such that the innate properties of the ligand are reflected as changes in beta-arrestin2 conformation. Our findings demonstrate that information about ligand-receptor conformation is encoded within the population average a-arrestin2 conformation, and provide insight into how different GPCRs can use a common effector for different purposes. This approach may have application in the characterization and development of functionally selective GPCR ligands(8,9) and in identifying factors that dictate arrestin conformation and function. C1 [Lee, Mi-Hye; Appleton, Kathryn M.; Strungs, Erik G.; Kwon, Joshua Y.; Morinelli, Thomas A.; Luttrell, Louis M.] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. [Peterson, Yuri K.] Med Univ S Carolina, Coll Pharm, Dept Pharmaceut & Biomed Sci, Charleston, SC 29425 USA. [Laporte, Stephane A.] McGill Univ, Res Inst, Ctr Hlth, Dept Med, Quebec City, PQ H4A 3J1, Canada. [Laporte, Stephane A.] McGill Univ, Pharmacol & Therapeut, Montreal, PQ H3G 1Y6, Canada. [Laporte, Stephane A.] McGill Univ, Anat & Cell Biol, Quebec City, PQ H3A 0C7, Canada. [Luttrell, Louis M.] Ralph H Johnson Vet Affairs Med Ctr, Res Serv, Charleston, SC 29401 USA. RP Luttrell, LM (reprint author), Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA.; Luttrell, LM (reprint author), Ralph H Johnson Vet Affairs Med Ctr, Res Serv, Charleston, SC 29401 USA. EM luttrell@musc.edu FU National Institutes of Health [DK055524, GM095497, RR027777]; Dialysis Clinics, Inc.; Research Service of the Charleston, SC Veterans Affairs Medical Center; Canadian Institutes of Health [MOP-74603] FX This work was supported by National Institutes of Health grants DK055524 (L.M.L.) and GM095497 (L.M.L.), funds provided by Dialysis Clinics, Inc. (T.A.M), and the Research Service of the Charleston, SC Veterans Affairs Medical Center (L.M.L.). Supported by Canadian Institutes of Health Research operating grant MOP-74603 (S.A.L.). National Institutes of Health grant RR027777 (L.M.L.) supported the FLIPRTETRA facility. The contents of this article do not represent the views of the Department of Veterans Affairs or the United States Government. NR 33 TC 17 Z9 17 U1 10 U2 21 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD MAR 31 PY 2016 VL 531 IS 7596 BP 665 EP + DI 10.1038/nature17154 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH8EX UT WOS:000373027400044 PM 27007854 ER PT J AU Li, L Lelyveld, VS Prywes, N Szostak, JW AF Li, Li Lelyveld, Victor S. Prywes, Noam Szostak, Jack W. TI Experimental and Computational Evidence for a Loose Transition State in Phosphoroimidazolide Hydrolysis SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID PHOSPHORYL-TRANSFER REACTIONS; TEMPLATE-DIRECTED SYNTHESIS; MONOESTER HYDROLYSIS; PHOSPHATE-ESTERS; ISOTOPE; MODELS; DEPROTONATION; GEOMETRIES; MECHANISM; EXCHANGE AB Phosphoroimidazolides play a critical role in several enzymatic phosphoryl transfer reactions and have been studied extensively as activated monomers for nonenzymatic nucleic acid replication, but the detailed mechanisms of these phosphoryl transfer reactions remain elusive. Some aspects of the mechanism can be deduced by studying the hydrolysis reaction, a simpler system that is amenable to a thorough mechanistic treatment. Here we characterize the transition state of phosphoroimidazolide hydrolysis by kinetic isotope effect (KIE) and linear free energy relationship (LFER) measurements, and theoretical calculations. The KIE and LFER observations are best explained by calculated loose transition structures with extensive scissile bond cleavage. These three-dimensional models of the transition state provide the basis for future mechanistic investigations of phosphoroimidazolide reactions. C1 [Szostak, Jack W.] Massachusetts Gen Hosp, Dept Mol Biol, Howard Hughes Med Inst, Boston, MA 02114 USA. Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. RP Szostak, JW (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Howard Hughes Med Inst, Boston, MA 02114 USA. EM szostak@molbio.mgh.harvard.edu FU Simons Foundation [290363]; FAS Division of Science, Research Computing Group at Harvard University FX J.W.S. is an Investigator of the Howard Hughes Medical Institute. L.L. is a Life Sciences Research Foundation Fellow. This work was supported in part by a grant (290363) from the Simons Foundation to J.W.S. The authors thank Szostak lab members Dr. A. C. Fahrenbach, Dr. N. P. Kamat, Dr. A. Pal, J. Tam, and T. Walton for assistance with the synthesis and Dr. Eugene Kwan (Harvard University) for helpful discussions. Computations were run on the Odyssey cluster supported by the FAS Division of Science, Research Computing Group, at Harvard University. NR 29 TC 3 Z9 3 U1 7 U2 15 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 MAR 30 PY 2016 VL 138 IS 12 BP 3986 EP 3989 DI 10.1021/jacs.6b00784 PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA DI5DJ UT WOS:000373518800013 PM 26974265 ER PT J AU Wu, WM Parmar, C Grossmann, P Quackenbush, J Lambin, P Bussink, J Mak, R Aerts, HJWL AF Wu, Weimiao Parmar, Chintan Grossmann, Patrick Quackenbush, John Lambin, Philippe Bussink, Johan Mak, Raymond Aerts, Hugo J. W. L. TI Exploratory Study to Identify Radiomics Classifiers for Lung Cancer Histology SO FRONTIERS IN ONCOLOGY LA English DT Article DE quantitative imaging; radiomics; lung cancer histology; computational science; feature selection ID SQUAMOUS-CELL CARCINOMA; TEXTURE ANALYSIS; GLUCOSE-METABOLISM; ADENOCARCINOMA; EXPRESSION; IMAGES; CLASSIFICATION; VARIABILITY; SURVIVAL; FEATURES AB Background: Radiomics can quantify tumor phenotypic characteristics non-invasively by applying feature algorithms to medical imaging data. In this study of lung cancer patients, we investigated the association between radiomic features and the tumor histologic subtypes (adenocarcinoma and squamous cell carcinoma). Furthermore, in order to predict histologic subtypes, we employed machine-learning methods and independently evaluated their prediction performance. Methods: Two independent radiomic cohorts with a combined size of 350 patients were included in our analysis. A total of 440 radiomic features were extracted from the segmented tumor volumes of pretreatment CT images. These radiomic features quantify tumor phenotypic characteristics on medical images using tumor shape and size, intensity statistics, and texture. Univariate analysis was performed to assess each feature's association with the histological subtypes. In our multivariate analysis, we investigated 24 feature selection methods and 3 classification methods for histology prediction. Multivariate models were trained on the training cohort and their performance was evaluated on the independent validation cohort using the area under ROC curve (AUC). Histology was determined from surgical specimen. Results: In our univariate analysis, we observed that fifty-three radiomic features were significantly associated with tumor histology. In multivariate analysis, feature selection methods ReliefF and its variants showed higher prediction accuracy as compared to other methods. We found that Naive Baye's classifier outperforms other classifiers and achieved the highest AUC (0.72; p-value = 2.3 x 10(-7)) with five features: Stats_min, Wavelet_HLL_rIgl_lowGrayLevelRunEmphasis, Wavelet_HHL_stats_median, Wavelet_HLL_stats_skewness, and Wavelet_HLH_glcm_clusShade. Conclusion: Histological subtypes can influence the choice of a treatment/therapy for lung cancer patients. We observed that radiomic features show significant association with the lung tumor histology. Moreover, radiomics-based multivariate classifiers were independently validated for the prediction of histological subtypes. Despite achieving lower than optimal prediction accuracy (AUC 0.72), our analysis highlights the impressive potential of non-invasive and cost-effective radiomics for precision medicine. Further research in this direction could lead us to optimal performance and therefore to clinical applicability, which could enhance the efficiency and efficacy of cancer care. C1 [Wu, Weimiao; Parmar, Chintan; Grossmann, Patrick; Mak, Raymond; Aerts, Hugo J. W. L.] Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol,Med Sch, Boston, MA 02115 USA. [Wu, Weimiao; Quackenbush, John] Harvard Univ, TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Parmar, Chintan; Grossmann, Patrick; Aerts, Hugo J. W. L.] Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiol,Med Sch, Boston, MA 02115 USA. [Parmar, Chintan; Lambin, Philippe] Maastricht Univ, Res Inst GROW, NL-6200 MD Maastricht, Netherlands. [Grossmann, Patrick; Quackenbush, John; Aerts, Hugo J. W. L.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Bussink, Johan] Radboud Univ Nijmegen, Med Ctr, Dept Radiat Oncol, NL-6525 ED Nijmegen, Netherlands. RP Wu, WM; Aerts, HJWL (reprint author), Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol,Med Sch, Boston, MA 02115 USA.; Wu, WM (reprint author), Harvard Univ, TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA.; Aerts, HJWL (reprint author), Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiol,Med Sch, Boston, MA 02115 USA.; Aerts, HJWL (reprint author), Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. EM weimiao.wu@mail.harvard.edu; hugo@jimmy.harvard.edu RI Aerts, Hugo/P-6350-2015 OI Aerts, Hugo/0000-0002-2122-2003 FU NCI NIH HHS [U01 CA190234, U24 CA194354] NR 63 TC 2 Z9 3 U1 7 U2 21 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 2234-943X J9 FRONT ONCOL JI Front. Oncol. PD MAR 30 PY 2016 VL 6 AR 71 DI 10.3389/fonc.2016.00071 PG 11 WC Oncology SC Oncology GA DI0PN UT WOS:000373199400001 PM 27064691 ER PT J AU Mehraei, G Hickox, AE Bharadwaj, HM Goldberg, H Verhulst, S Liberman, MC Shinn-Cunningham, BG AF Mehraei, Golbarg Hickox, Ann E. Bharadwaj, Hari M. Goldberg, Hannah Verhulst, Sarah Liberman, M. Charles Shinn-Cunningham, Barbara G. TI Auditory Brainstem Response Latency in Noise as a Marker of Cochlear Synaptopathy SO JOURNAL OF NEUROSCIENCE LA English DT Article DE auditory brainstem response; auditory nerve loss; cochlear synaptopathy; hidden hearing loss; temporal coding ID OTOACOUSTIC EMISSIONS; NERVE FIBERS; TRANSPOSED STIMULI; EVOKED-RESPONSE; NORMAL-HEARING; AGE; NEUROPATHY; AUDIOGRAM; DEGENERATION; THRESHOLDS AB Evidence from animal and human studies suggests that moderate acoustic exposure, causing only transient threshold elevation, can nonetheless cause "hidden hearing loss" that interferes with coding of suprathreshold sound. Such noise exposure destroys synaptic connections between cochlear hair cells and auditory nerve fibers; however, there is no clinical test of this synaptopathy in humans. In animals, synaptopathy reduces the amplitude of auditory brainstem response (ABR) wave-I. Unfortunately, ABR wave-I is difficult to measure in humans, limiting its clinical use. Here, using analogous measurements in humans and mice, we show that the effect of masking noise on the latency of the more robust ABR wave-V mirrors changes in ABR wave-I amplitude. Furthermore, in our human cohort, the effect of noise on wave-V latency predicts perceptual temporal sensitivity. Our results suggest that measures of the effects of noise on ABR wave-V latency can be used to diagnose cochlear synaptopathy in humans. C1 [Mehraei, Golbarg; Hickox, Ann E.; Goldberg, Hannah; Liberman, M. Charles] Harvard Univ, MIT, Program Speech & Hearing Biosci & Technol, Cambridge, MA 02139 USA. [Mehraei, Golbarg; Bharadwaj, Hari M.; Verhulst, Sarah; Shinn-Cunningham, Barbara G.] Boston Univ, Ctr Computat Neurosci & Neural Technol, Boston, MA 02215 USA. [Shinn-Cunningham, Barbara G.] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. [Hickox, Ann E.; Liberman, M. Charles] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Liberman, M. Charles] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02114 USA. [Verhulst, Sarah] Carl von Ossietzky Univ Oldenburg, Dept Med Phys & Acoust, Cluster Excellence Hearing4All & Med Phys, D-26129 Oldenburg, Germany. [Bharadwaj, Hari M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Martinos Ctr Biomed Imaging,Dept Neurol, Charlestown, MA 02129 USA. RP Mehraei, G (reprint author), 677 Beacon St, Boston, MA 02215 USA. EM gmehraei@mit.edu OI Bharadwaj, Hari/0000-0001-8685-9630; Mehraei, Golbarg/0000-0002-0389-8632; Shinn-Cunningham, Barbara/0000-0002-5096-5914; Hickox, Ann E./0000-0003-1033-9887 FU Office of Assistant Secretary of Defense for Research and Engineering; National Institute on Deafness and Other Communication Disorders Grant [T32 DC-00038, R01 DC-00188, P30 DC-05029]; Amelia Peabody Charitable Fund FX This work was supported by a fellowship from the Office of Assistant Secretary of Defense for Research and Engineering (B.G.S.-C.), National Institute on Deafness and Other Communication Disorders Grant T32 DC-00038 (G.M., A.E.H.), National Institute on Deafness and Other Communication Disorders Grants R01 DC-00188 (M.C.L.) and P30 DC-05029 (M.C.L.), and the Amelia Peabody Charitable Fund (A.E.H.). We thank K. Hancock for assistance in implementing mouse-specific masking noise and L. D. Liberman for expert assistance in cochlear histological processing. NR 49 TC 12 Z9 13 U1 5 U2 13 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 MAR 30 PY 2016 VL 36 IS 13 BP 3755 EP 3764 DI 10.1523/JNEUROSCI.4460-15.2016 PG 10 WC Neurosciences SC Neurosciences & Neurology GA DH7NI UT WOS:000372980300011 PM 27030760 ER PT J AU Sakae, N Liu, CC Shinohara, M Frisch-Daiello, J Ma, L Yamazaki, Y Tachibana, M Younkin, L Kurti, A Carrasquillo, MM Zou, FG Sevlever, D Bisceglio, G Gan, M Fol, R Knight, P Wang, M Han, XL Fryer, JD Fitzgerald, ML Ohyagi, Y Younkin, SG Bu, GJ Kanekiyo, T AF Sakae, Nobutaka Liu, Chia-Chen Shinohara, Mitsuru Frisch-Daiello, Jessica Ma, Li Yamazaki, Yu Tachibana, Masaya Younkin, Linda Kurti, Aishe Carrasquillo, Minerva M. Zou, Fanggeng Sevlever, Daniel Bisceglio, Gina Gan, Ming Fol, Romain Knight, Patrick Wang, Miao Han, Xianlin Fryer, John D. Fitzgerald, Michael L. Ohyagi, Yasumasa Younkin, Steven G. Bu, Guojun Kanekiyo, Takahisa TI ABCA7 Deficiency Accelerates Amyloid-beta Generation and Alzheimer's Neuronal Pathology SO JOURNAL OF NEUROSCIENCE LA English DT Article DE ABCA7; APP; BACE1; cognitive function; lipid homeostasis; neuron ID CASSETTE TRANSPORTER A7; ENDOPLASMIC-RETICULUM; CHOLESTEROL EFFLUX; SHOTGUN LIPIDOMICS; BACE1 EXPRESSION; COMMON VARIANTS; MOUSE MODEL; IN-VIVO; DISEASE; PHAGOCYTOSIS AB In Alzheimer's disease (AD), the accumulation and deposition of amyloid-beta (A beta) peptides in the brain is a central event. A beta is cleaved from amyloid precursor protein (APP) by beta-secretase and gamma-secretase mainly in neurons. Although mutations in APP, PS1, or PS2 cause early-onset familial AD, ABCA7 encoding ATP-binding cassette transporter A7 is one of the susceptibility genes for late-onset AD (LOAD), in which its loss-of-function variants increase the disease risk. ABCA7 is homologous to a major lipid transporter ABCA1 and is highly expressed in neurons and microglia in the brain. Here, we show that ABCA7 deficiency altered brain lipid profile and impaired memory in ABCA7 knock-out (Abca7(-/-)) mice. When bred to amyloid model APP/PS1 mice, plaque burden was exacerbated by ABCA7 deficit. In vivo microdialysis studies indicated that the clearance rate of A beta was unaltered. Interestingly, ABCA7 deletion facilitated the processing of APP to A beta by increasing the levels of beta-site APP cleaving enzyme 1 (BACE1) and sterol regulatory element-binding protein 2 (SREBP2) in primary neurons and mouse brains. Knock-down of ABCA7 expression in neurons caused endoplasmic reticulum stress highlighted by increased level of protein kinase R-like endoplasmic reticulum kinase (PERK) and increased phosphorylation of eukaryotic initiation factor 2 alpha (eIF2 alpha). In the brains of APP/PS1; Abca7(-/-) mice, the level of phosphorylated extracellular regulated kinase (ERK) was also significantly elevated. Together, our results reveal novel pathways underlying the association of ABCA7 dysfunction and LOAD pathogenesis. C1 [Sakae, Nobutaka; Liu, Chia-Chen; Shinohara, Mitsuru; Ma, Li; Yamazaki, Yu; Tachibana, Masaya; Younkin, Linda; Kurti, Aishe; Carrasquillo, Minerva M.; Zou, Fanggeng; Sevlever, Daniel; Bisceglio, Gina; Gan, Ming; Fol, Romain; Knight, Patrick; Fryer, John D.; Younkin, Steven G.; Bu, Guojun; Kanekiyo, Takahisa] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA. [Frisch-Daiello, Jessica; Wang, Miao; Han, Xianlin] Sanford Burnham Prebys Med Discovery Inst, Orlando, FL 32827 USA. [Fitzgerald, Michael L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Lipid Metab Unit, Boston, MA 02114 USA. [Fitzgerald, Michael L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Ohyagi, Yasumasa] Ehime Univ, Dept Geriatr Med & Neurol, Grad Sch Med, Toon, Ehime 7910295, Japan. RP Bu, GJ; Kanekiyo, T (reprint author), Mayo Clin, 4500 San Pablo Rd, Jacksonville, FL 32224 USA. EM bu.guojun@mayo.edu; kanekiyo.takahisa@mayo.edu OI Knight, Patrick/0000-0003-0813-8760 FU Robert and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program; National Institutes of Health [R01AG18023, R01AG035355, R01AG027924, R01AG046205, RF1AG051504 01, P01NS074969, P50AG016574, R01HL074136, R01HL101274]; Alzheimer's Association; Cure Alzheimer's Fund FX This work was supported by the Robert and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program (S.G.Y.), the National Institutes of Health (Grants R01AG18023 to S.G.Y.; Grants R01AG035355, R01AG027924, R01AG046205, RF1AG051504 01, P01NS074969, and P50AG016574 to G.B.; and Grants R01HL074136 and R01HL101274 to M.L.F.), the Alzheimer's Association (T.K.), and the Cure Alzheimer's Fund (G.B. and T.K.). We thank Sumiko Abe-Dohmae at Nagoya City University for the gift of human and mouse ABCA7 antibodies; Kazumitsu Ueda at Kyoto University for the gift of human ABCA7 plasmid constructs; Dennis W. Dickson, Melissa E. Murray, Monica Castanedes Casey, and Linda Rousseau at Mayo Clinic Jacksonville for histology and immunohistochemical analyses; Tynickwa Mims and Tammee M. Parson in the Younkin laboratory for animal care; Mary D. Davis for careful reading of this manuscript; and Christopher Janus at the University of Florida and Michelle Mielke at Mayo Clinic Rochester for critical comments. NR 57 TC 7 Z9 7 U1 4 U2 10 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 MAR 30 PY 2016 VL 36 IS 13 BP 3848 EP 3859 DI 10.1523/JNEUROSCI.3757-15.2016 PG 12 WC Neurosciences SC Neurosciences & Neurology GA DH7NI UT WOS:000372980300020 PM 27030769 ER PT J AU Lord, A Ehrlich, S Borchardt, V Geisler, D Seidel, M Huber, S Murr, J Walter, M AF Lord, Anton Ehrlich, Stefan Borchardt, Viola Geisler, Daniel Seidel, Maria Huber, Stefanie Murr, Julia Walter, Martin TI Brain parcellation choice affects disease-related topology differences increasingly from global to local network levels SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE Anorexia nervosa; Resting state; Graph metrics; fMRI ID STATE FUNCTIONAL CONNECTIVITY; SMALL-WORLD NETWORKS; ANOREXIA-NERVOSA; INSULA ACTIVATION; CINGULATE CORTEX; ANTERIOR INSULA; BULIMIA-NERVOSA; MRI; STIMULI; WOMEN AB Network-based analyses of deviant brain function have become extremely popular in psychiatric neuroimaging. Underpinning brain network analyses is the selection of appropriate regions of interest (ROls). Although ROI selection is fundamental in network analysis, its impact on detecting disease effects remains unclear. We investigated the impact of parcellation choice when comparing results from different studies. We investigated the effects of anatomical (AAL) and literature-based (Dosenbach) parcellation schemes on comparability of group differences in 35 female patients with anorexia nervosa and 35 age and sex-matched healthy controls. Global and local network properties, including network-based statistics (NBS), were assessed on resting state functional magnetic resonance imaging data obtained at 3 T. Parcellation schemes were comparably consistent on global network properties, while NBS and local metrics differed in location, but not metric type. Location of local metric alterations varied for AAL (parietal and cingulate cortices) versus Dosenbach (insula, thalamus) parcellation approaches. However, consistency was observed for the occipital cortex. Patient-specific global network properties can be robustly observed using different parcellation schemes, while graph metrics characterizing impairments of individual nodes vary considerably. Therefore, the impact of parcellation choice on specific group differences varies depending on the level of network organization. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Lord, Anton; Borchardt, Viola; Walter, Martin] Leibniz Inst Neurobiol, Magdeburg, Saxony Anhalt, Germany. [Lord, Anton; Borchardt, Viola; Walter, Martin] Clin Affect Neuroimaging Lab, Magdeburg, Saxony Anhalt, Germany. [Ehrlich, Stefan; Geisler, Daniel; Seidel, Maria; Huber, Stefanie] Tech Univ Dresden, Fac Med, Eating Disorder Res & Treatment Ctr, Dept Child & Adolescent Psychiat, D-01062 Dresden, Germany. [Ehrlich, Stefan] Massachusetts Gen Hosp, MGH MIT HMS Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Ehrlich, Stefan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA USA. [Ehrlich, Stefan; Geisler, Daniel; Seidel, Maria; Huber, Stefanie; Murr, Julia; Walter, Martin] Tech Univ Dresden, Univ Hosp CG Carus, Dept Psychosomat Med & Psychotherapy, Fac Med, D-01062 Dresden, Germany. [Murr, Julia; Walter, Martin] Otto Von Guericke Univ, Dept Psychiat & Psychotherapy, Magdeburg, Germany. [Walter, Martin] CBBS, Magdeburg, Saxony Anhalt, Germany. RP Walter, M (reprint author), Univ Magdeburg, Leibniz Inst Neurobiol, Dept Psychiat, Clin Affect Neuroimaging Lab, Zenit Bldg 65 Leipziger Str 44, D-39120 Magdeburg, Germany.; Walter, M (reprint author), Univ Magdeburg, Leibniz Inst Neurobiol, Dept Neurol, Clin Affect Neuroimaging Lab, Zenit Bldg 65 Leipziger Str 44, D-39120 Magdeburg, Germany. EM martin.walter@med.ovgu.de NR 61 TC 2 Z9 2 U1 2 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0925-4927 EI 1872-7506 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD MAR 30 PY 2016 VL 249 BP 12 EP 19 DI 10.1016/j.pscychresns.2016.02.001 PG 8 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DH1EG UT WOS:000372526600002 PM 27000302 ER PT J AU Corbo, V Salat, DH Powell, MA Milberg, WP McGlinchey, RE AF Corbo, Vincent Salat, David H. Powell, Margaret A. Milberg, William P. McGlinchey, Regina E. TI Combat exposure is associated with cortical thickness in Veterans with a history of chronic pain SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE Combat exposure; Pain; Cortical thickness; PTSD; Trauma; Veterans ID POSTTRAUMATIC-STRESS-DISORDER; TRAUMATIC BRAIN-INJURY; GRAY-MATTER LOSS; ANTERIOR CINGULATE CORTEX; SURFACE-BASED ANALYSIS; COMORBID CHRONIC PAIN; CHRONIC BACK-PAIN; RESPONSE-INHIBITION; COORDINATE SYSTEM; CEREBRAL-CORTEX AB Chronic Pain (CP) has been associated with changes in gray matter integrity in the cingulate and insular cortex. However, these changes have not been studied in Veterans, despite high prevalence rates of CP and interactions with combat-derived disorders. In the current study, 54 Veterans with a history of CP and 103 Veterans without CP were recruited from the Translational Research Center for Traumatic Brain Injury and Stress Disorders (TRACTS). Cortical thickness from structural MRI scans was determined using the FreeSurfer software package. Results showed that Veterans with CP showed a negative association between cortical thickness and levels of combat exposure in the left inferior frontal gyrus and superior parietal cortex, as well as the right rostral middle frontal gyrus, precentral and postcentral gyri and the superior temporal cortex. These findings suggest that CP may alter the relationship between cortical thickness and exposure to the stress of combat. Published by Elsevier Ireland Ltd. C1 [Corbo, Vincent; Salat, David H.; Milberg, William P.; McGlinchey, Regina E.] VA Boston Healthcare Syst, GRECC, Translat Res Ctr TBI & Stress Disorders TRACTS, Boston, MA USA. [Corbo, Vincent] Boston Univ, Sch Med, Boston, MA 02118 USA. [Salat, David H.] Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Milberg, William P.; McGlinchey, Regina E.] Harvard Univ, Sch Med, Dept Psychiat, Cambridge, MA 02138 USA. [Powell, Margaret A.] Boston Coll, Sch Social Work, Boston, MA USA. RP Corbo, V (reprint author), TRACTS, C-11-36,150 South Huntington Ave, Boston, MA 02130 USA. EM Vincent.corbo@va.gov RI McGlinchey, Regina/R-1971-2016 FU Translational Research Center for TBI and Stress Disorders (TRACTS), a VA Rehabilitation Research and Development Traumatic Brain Injury Center of Excellence by the United States (U.S.) Department of Veterans Affairs [B6796-C]; NIH [R01NR10827] FX This research was support by the Translational Research Center for TBI and Stress Disorders (TRACTS), a VA Rehabilitation Research and Development Traumatic Brain Injury Center of Excellence (B6796-C) provided by the United States (U.S.) Department of Veterans Affairs, as well as NIH grant #R01NR10827 (Dr. David Salat). The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government. NR 87 TC 0 Z9 0 U1 3 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0925-4927 EI 1872-7506 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD MAR 30 PY 2016 VL 249 BP 38 EP 44 DI 10.1016/j.pscychresns.2016.02.003 PG 7 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DH1EG UT WOS:000372526600005 PM 27000305 ER PT J AU Bakhshaie, J Ditre, JW Langdon, KJ Asmundson, GJG Paulus, DJ Zvolensky, MJ AF Bakhshaie, Jafar Ditre, Joseph W. Langdon, Kirsten J. Asmundson, Gordon J. G. Paulus, Daniel J. Zvolensky, Michael J. TI Pain intensity and smoking behavior among treatment seeking smokers SO PSYCHIATRY RESEARCH LA English DT Article DE Tobacco smoking; Nicotine dependence; Addiction; Pain intensity; Behavior; Emotion ID FAGERSTROM TOLERANCE QUESTIONNAIRE; NICOTINE DEPENDENCE; CIGARETTE-SMOKING; RHEUMATOID-ARTHRITIS; REPRESENTATIVE SAMPLE; BACK DISORDERS; CESSATION; ADULTS; INDEX; RELIABILITY AB Empirical evidence supporting the interplay between pain intensity and tobacco smoking has been growing. The current investigation advances this work in three important ways: (1) controlling for negative affectivity and gender; (2) examining pain intensity in smokers from a community sample, rather than specialized pain treatment centers; and, (3) studying smokers who are highly motivated to quit. Participants were adult smokers (N=112; 35% female; M-age=41.4, SD=13.1) participating in a larger study examining barriers to cessation during a self-guided quit attempt. At baseline, participants completed self-report measures on pain intensity and smoking severity outcomes. As hypothesized, more intense pain was significantly associated with all four smoking severity variables: years as a daily smoker, current cigarettes per day, cigarettes per day during the heaviest lifetime smoking period, and current level of nicotine dependence. These associations remained when taking into account the variance accounted for by gender and negative affectivity. These data provide evidence that more intense pain is related to more severe smoking behavior and nicotine dependence. Pain reduction could be an important target in regard to smokers with chronic pain. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Bakhshaie, Jafar; Paulus, Daniel J.; Zvolensky, Michael J.] Univ Houston, Dept Psychol, Houston, TX USA. [Ditre, Joseph W.] Syracuse Univ, Dept Psychol, New York, NY USA. [Langdon, Kirsten J.] VA Boston Healthcare Syst, Womens Hlth Sci Div, Natl Ctr PTSD, Boston, MA USA. [Langdon, Kirsten J.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Asmundson, Gordon J. G.] Univ Regina, Dept Psychol, Regina, SK S4S 0A2, Canada. [Zvolensky, Michael J.] Univ Texas MD Anderson Canc Ctr, Dept Behav Sci, Houston, TX 77030 USA. RP Bakhshaie, J (reprint author), Univ Houston, Anxiety & Hlth Res Lab, 126 Heyne Bldg, Houston, TX 77024 USA.; Bakhshaie, J (reprint author), Univ Houston, Subst Use Treatment Clin AHRL SUTC, 126 Heyne Bldg, Houston, TX 77024 USA. EM jbakhshaie@uh.edu OI Paulus, Daniel/0000-0002-8799-4372 NR 50 TC 1 Z9 1 U1 1 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD MAR 30 PY 2016 VL 237 BP 67 EP 71 DI 10.1016/j.psychres.2016.01.073 PG 5 WC Psychiatry SC Psychiatry GA DG2ZM UT WOS:000371939300011 PM 26921054 ER PT J AU Chouinard, VA Pingali, SM Chouinard, G Henderson, DC Mallya, SG Cypess, AM Cohen, BM Ongur, D AF Chouinard, Virginie-Anne Pingali, Samira M. Chouinard, Guy Henderson, David C. Mallya, Sonal G. Cypess, Aaron M. Cohen, Bruce M. Oenguer, Dost TI Factors associated with overweight and obesity in schizophrenia, schizoaffective and bipolar disorders SO PSYCHIATRY RESEARCH LA English DT Article DE Schizophrenia; Bipolar; Affective; Overweight; Obesity; BMI ID BODY-MASS INDEX; QUALITY-OF-LIFE; SELF-REPORTED WEIGHT; DRUG-NAIVE PATIENTS; METABOLIC SYNDROME; I-DISORDER; CARDIOVASCULAR MORTALITY; DIABETES-MELLITUS; 1ST-EPISODE MANIA; SPECTRUM PATIENTS AB Evidence suggests abnormal bioenergetic status throughout the body in psychotic disorders. The present study examined predictors of elevated body mass index (BMI) across diagnostic categories of schizophrenia, schizoaffective and bipolar disorders. In a cross-sectional study, we studied demographic and clinical risk factors for overweight and obesity in a well-characterized sample of 262 inpatients and outpatients with schizophrenia (n=59), schizoaffective disorder (n=81) and bipolar I disorder (n=122). Across the three diagnostic categories, the prevalence of overweight (29.4%) and obesity (33.2%) combined was 62.6% (164/262). Logistic regression analyses, adjusted for age, sex and ethnicity, showed that schizoaffective disorder, lifetime major depressive episode, presence of prior suicide attempt, and more than 5 lifetime hospitalizations were significantly associated with BMI >= 25. Patients with schizophrenia had significantly lower risk for overweight and obesity. Overall, we found that affective components of illness were associated with elevated BMI in our cross-diagnostic sample. Our results show that patients with schizoaffective disorder have a greater risk for obesity. Identifying predictors of elevated BMI in patients with psychotic and mood disorders will help prevent obesity and related cardiovascular and cerebral complications. Future studies are needed to elucidate the mechanistic nature of the relationship between obesity and psychiatric illness. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Chouinard, Virginie-Anne; Pingali, Samira M.; Mallya, Sonal G.; Cohen, Bruce M.; Oenguer, Dost] McLean Hosp, Psychot Disorders Div, 115 Mill St,Mailstop 108, Belmont, MA 02478 USA. [Chouinard, Virginie-Anne; Henderson, David C.; Cohen, Bruce M.; Oenguer, Dost] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Chouinard, Guy] McGill Univ, Clin Pharmacol & Toxicol Program, Montreal, PQ, Canada. [Chouinard, Guy] Montreal Fernand Seguin Res Ctr, Mental Hlth Inst, Montreal, PQ, Canada. [Henderson, David C.] Massachusetts Gen Hosp, Schizophrenia Clin & Res Program, Boston, MA 02114 USA. [Henderson, David C.] Harvard Univ, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Cypess, Aaron M.] NIDDK, Translat Physiol Sect, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. RP Chouinard, VA (reprint author), McLean Hosp, Psychot Disorders Div, 115 Mill St,Mailstop 108, Belmont, MA 02478 USA. EM vchouinard@mclean.harvard.edu FU Shervert Frazier Research Institute; National Institute of Mental Health [K23MH079982]; Harvard Catalyst I The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health) [UL1 TR001102]; Harvard University FX The authors would like to gratefully acknowledge patients who participated in this study. Funding for this study was provided from the Shervert Frazier Research Institute to Bruce M. Cohen and National Institute of Mental Health (K23MH079982) to Dost Ongur. This work was conducted with statistical support from Harvard Catalyst I 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 funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. NR 74 TC 4 Z9 4 U1 7 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD MAR 30 PY 2016 VL 237 BP 304 EP 310 DI 10.1016/j.psychres.2016.01.024 PG 7 WC Psychiatry SC Psychiatry GA DG2ZM UT WOS:000371939300047 PM 26805561 ER PT J AU Luz, PM Girouard, MP Grinsztejn, B Freedberg, KA Veloso, VG Losina, E Struchiner, CJ MacLean, RL Parker, RA Paltiel, AD Walensky, RP AF Luz, Paula M. Girouard, Michael P. Grinsztejn, Beatriz Freedberg, Kenneth A. Veloso, Valdilea G. Losina, Elena Struchiner, Claudio J. MacLean, Rachel L. Parker, Robert A. Paltiel, A. David Walensky, Rochelle P. TI Survival benefits of antiretroviral therapy in Brazil: a model-based analysis SO JOURNAL OF THE INTERNATIONAL AIDS SOCIETY LA English DT Article DE HIV; Brazil; highly active antiretroviral therapy; survival; modelling; Latin America ID RIO-DE-JANEIRO; HIV-INFECTED PATIENTS; TWICE-DAILY LOPINAVIR/RITONAVIR; ONCE-DAILY ATAZANAVIR/RITONAVIR; TENOFOVIR DISOPROXIL FUMARATE; COST-EFFECTIVENESS; AIDS PATIENTS; SAO-PAULO; HIV-1-INFECTED PATIENTS; CONTROLLED-TRIAL AB Objective: In Brazil, universal provision of antiretroviral therapy (ART) has been guaranteed free of charge to eligible HIV-positive patients since December 1996. We sought to quantify the survival benefits of ART attributable to this programme. Methods: We used a previously published microsimulation model of HIV disease and treatment (CEPAC-International) and data from Brazil to estimate life expectancy increase for HIV-positive patients initiating ART in Brazil. We divided the period of 1997 to 2014 into six eras reflecting increased drug regimen efficacy, regimen availability and era-specific mean CD4 count at ART initiation. Patients were simulated first without ART and then with ART. The 2014-censored and lifetime survival benefits attributable to ART in each era were calculated as the product of the number of patients initiating ART in a given era and the increase in life expectancy attributable to ART in that era. Results: In total, we estimated that 598,741 individuals initiated ART. Projected life expectancy increased from 2.7, 3.3, 4.1, 4.9, 5.5 and 7.1 years without ART to 11.0, 17.5, 20.7, 23.0, 25.3, and 27.0 years with ART in Eras 1 through 6, respectively. Of the total projected lifetime survival benefit of 9.3 million life-years, 16% (or 1.5 million life-years) has been realized as of December 2014. Conclusions: Provision of ART through a national programme has led to dramatic survival benefits in Brazil, the majority of which are still to be realized. Improvements in initial and subsequent ART regimens and higher CD4 counts at ART initiation have contributed to these increasing benefits. C1 [Luz, Paula M.; Grinsztejn, Beatriz; Veloso, Valdilea G.; Struchiner, Claudio J.] Fundacao Oswaldo Cruz, Inst Nacl Infectol Evandro Chagas, Ave Brasil 4365, BR-21040360 Rio De Janeiro, Brazil. [Girouard, Michael P.; Freedberg, Kenneth A.; Losina, Elena; MacLean, Rachel L.; Parker, Robert A.; Walensky, Rochelle P.] Massachusetts Gen Hosp, Med Practice Evaluat Ctr, Boston, MA 02114 USA. [Girouard, Michael P.; Freedberg, Kenneth A.; MacLean, Rachel L.; Walensky, Rochelle P.] Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. [Freedberg, Kenneth A.; Walensky, Rochelle P.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Freedberg, Kenneth A.; Losina, Elena; Parker, Robert A.; Walensky, Rochelle P.] Harvard Univ, Sch Med, Ctr AIDS Res, Boston, MA USA. [Freedberg, Kenneth A.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Freedberg, Kenneth A.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Losina, Elena] Brigham & Womens Hosp, Dept Orthoped Surg, 75 Francis St, Boston, MA 02115 USA. [Losina, Elena] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Parker, Robert A.] Massachusetts Gen Hosp, Biostat Ctr, Boston, MA 02114 USA. [Paltiel, A. David] Yale Univ, Sch Publ Hlth, Dept Hlth Policy & Management, New Haven, CT USA. [Walensky, Rochelle P.] Brigham & Womens Hosp, Div Infect Dis, 75 Francis St, Boston, MA 02115 USA. RP Luz, PM (reprint author), Fundacao Oswaldo Cruz, Inst Nacl Infectol Evandro Chagas, Ave Brasil 4365, BR-21040360 Rio De Janeiro, Brazil. EM paula.luz@ipec.fiocruz.br FU National Institute of Allergy and Infectious Diseases [R01 AI058736] FX This work was supported by the National Institute of Allergy and Infectious Diseases (R01 AI058736). NR 48 TC 1 Z9 1 U1 0 U2 4 PU INT AIDS SOCIETY PI GENEVA PA AVENUE DE FRANCE 23, GENEVA, 1202, SWITZERLAND SN 1758-2652 J9 J INT AIDS SOC JI J. Int. AIDS Soc. PD MAR 29 PY 2016 VL 19 AR 20623 DI 10.7448/IAS.19.1.20623 PG 11 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DM2JV UT WOS:000376173800001 PM 27029828 ER PT J AU Yuan, GD Zhang, BX Yang, SZ Jin, L Datta, A Bae, S Chen, XP Datta, PK AF Yuan, Guandou Zhang, Bixiang Yang, Shanzhong Jin, Lin Datta, Arunima Bae, Sejong Chen, Xiaoping Datta, Pran K. TI Novel role of STRAP in progression and metastasis of colorectal cancer through Wnt/beta-catenin signaling SO ONCOTARGET LA English DT Article DE STRAP; beta-catenin; CRC; metastasis; tissue microarray ID RECEPTOR-ASSOCIATED PROTEIN; BETA-CATENIN; DESTRUCTION COMPLEX; KINASE; EXPRESSION; INHIBITION; APC; IDENTIFICATION; ACTIVATION; GSK3-BETA AB Serine-Threonine Kinase Receptor-Associated Protein (STRAP) interacts with a variety of proteins and influences a wide range of cellular processes. Aberrant activation of Wnt/beta-catenin signaling has been implicated in the development of colorectal cancer (CRC). Here, we show the molecular mechanism by which STRAP induces CRC metastasis by promoting beta-catenin signaling through its stabilization. We have genetically engineered a series of murine and human CRC and lung cancer cell lines to investigate the effects of STRAP on cell migration and invasion in vitro, and on tumorigenicity and metastasis in vivo. Downregulation of STRAP inhibits invasion, tumorigenicity, and metastasis of CRC cells. Mechanistically, STRAP binds with GSK-3 beta and reduces the phosphorylation, ubiquitylation, and degradation of beta-catenin through preventing its binding to the destruction complex. This leads to an inhibition of Wnt/beta-catenin signaling and reduction in the expression of downstream targets, such as Cyclin D1, matrix metalloproteinases 2 and 9, and beta-TrCP. In human CRC specimens, higher STRAP expression correlates significantly with beta-catenin expression with increased nuclear levels (R = 0.696, p < .0001, n = 128). Together, these results suggest that STRAP increases invasion and metastasis of CRC partly through inhibiting ubiquitin-dependent degradation of beta-catenin and promoting Wnt/beta-catenin signaling. C1 [Yuan, Guandou; Yang, Shanzhong; Jin, Lin; Datta, Arunima; Datta, Pran K.] Univ Alabama Birmingham, Dept Med, UAB Comprehens Canc Ctr, Div Hematol & Oncol, Birmingham, AL 35294 USA. [Datta, Pran K.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [Yuan, Guandou; Zhang, Bixiang; Chen, Xiaoping] Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Hepat Surg Ctr, Wuhan 430074, Peoples R China. [Bae, Sejong] Univ Alabama Birmingham, Div Prevent Med, Birmingham, AL USA. RP Datta, PK (reprint author), Univ Alabama Birmingham, Dept Med, UAB Comprehens Canc Ctr, Div Hematol & Oncol, Birmingham, AL 35294 USA.; Datta, PK (reprint author), Birmingham Vet Affairs Med Ctr, Birmingham, AL USA.; Chen, XP (reprint author), Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Hepat Surg Ctr, Wuhan 430074, Peoples R China. EM chenxpchenxp@163.com; prandatta@uabmc.edu FU National Cancer Institute [R01 CA95195]; Veterans Affairs Merit Review Award; UAB Comprehensive Cancer Center [P30 CA013148] FX This study was supported by National Cancer Institute R01 CA95195, Veterans Affairs Merit Review Award, and a Faculty Development Award from UAB Comprehensive Cancer Center, P30 CA013148 (to PK Datta). NR 46 TC 3 Z9 3 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 MAR 29 PY 2016 VL 7 IS 13 BP 16023 EP 16037 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DL5QW UT WOS:000375692900057 PM 26910283 ER PT J AU Nakayama, R Zhang, YX Czaplinski, JT Anatone, AJ Sicinska, ET Fletcher, JA Demetri, GD Wagner, AJ AF Nakayama, Robert Zhang, Yi-Xiang Czaplinski, Jeffrey T. Anatone, Alex J. Sicinska, Ewa T. Fletcher, Jonathan A. Demetri, George D. Wagner, Andrew J. TI Preclinical activity of selinexor, an inhibitor of XPO1, in sarcoma SO ONCOTARGET LA English DT Article DE sarcoma; gastrointestinal stromal tumor; liposarcoma; selinexor; preclinical study ID GASTROINTESTINAL STROMAL TUMORS; CHRONIC LYMPHOCYTIC-LEUKEMIA; ACUTE MYELOID-LEUKEMIA; NUCLEAR EXPORT SIGNAL; SOFT PART SARCOMA; LEPTOMYCIN-B; INDUCED PHOSPHORYLATION; KPT-330 INHIBITOR; GENE-EXPRESSION; P53 PATHWAY AB Selinexor is an orally bioavailable selective inhibitor of nuclear export that has been demonstrated to have preclinical activity in various cancer types and that is currently in Phase I and II clinical trials for advanced cancers. In this study, we evaluated the effects of selinexor in several preclinical models of various sarcoma subtypes. The efficacy of selinexor was investigated in vitro and in vivo using 17 cell lines and 9 sarcoma xenograft models including gastrointestinal stromal tumor (GIST), liposarcoma (LPS), leiomyosarcoma, rhabdomyosarcoma, undifferentiated sarcomas, and alveolar soft part sarcoma (ASPS). Most sarcoma cell lines were sensitive to selinexor with IC50s ranging from 28.8 nM to 218.2 nM (median: 66.1 nM). Selinexor suppressed sarcoma tumor xenograft growth, including models of ASPS that were resistant in vitro. In GIST cells with KIT mutations, selinexor induced G1-arrest without attenuation of phosphorylation of KIT, AKT, or MAPK, in contrast to imatinib. In LPS cell lines with MDM2 and CDK4 amplification, selinexor induced G1-arrest and apoptosis irrespective of p53 expression or mutation and irrespective of RB expression. Selinexor increased p53 and p21 expression at the protein but not RNA level, indicating a post-transcriptional effect. These results indicate that selinexor has potent in vitro and in vivo activity against a wide variety of sarcoma models by inducing G1-arrest independent of known molecular mechanisms in GIST and LPS. These studies further justify the exploration of selinexor in clinical trials targeting various sarcoma subtypes. C1 [Nakayama, Robert; Zhang, Yi-Xiang; Demetri, George D.; Wagner, Andrew J.] Harvard Univ, Sch Med, Ludwig Ctr Dana Farber Harvard, Boston, MA USA. [Nakayama, Robert; Zhang, Yi-Xiang; Demetri, George D.; Wagner, Andrew J.] Harvard Univ, Sch Med, Ctr Sarcoma & Bone Oncol, Dept Med Oncol, Boston, MA USA. [Nakayama, Robert] Keio Univ, Sch Med, Dept Orthopaed Surg, Tokyo, Japan. [Czaplinski, Jeffrey T.; Anatone, Alex J.; Sicinska, Ewa T.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. [Czaplinski, Jeffrey T.; Anatone, Alex J.; Sicinska, Ewa T.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Mol Oncol Pathol, 44 Binney St, Boston, MA 02115 USA. [Fletcher, Jonathan A.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Wagner, AJ (reprint author), Harvard Univ, Sch Med, Ludwig Ctr Dana Farber Harvard, Boston, MA USA.; Wagner, AJ (reprint author), Harvard Univ, Sch Med, Ctr Sarcoma & Bone Oncol, Dept Med Oncol, Boston, MA USA. EM Andrew_wagner@dfci.harvard.edu FU WWWW Foundation (QuadW); Uehara Memorial Foundation; NIH/NCI [1P50CA127003, 1P50CA168512]; Ludwig Center at Harvard; Fasseas Family Liposarcoma Research Fund FX The WWWW Foundation (QuadW) (RN), The Uehara Memorial Foundation (RN), NIH/NCI 1P50CA127003 (JAF and GDD), NIH/NCI 1P50CA168512 (JAF and GDD), the Ludwig Center at Harvard (GDD and AJW), and the Fasseas Family Liposarcoma Research Fund (AJW and GDD). NR 51 TC 4 Z9 4 U1 1 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 MAR 29 PY 2016 VL 7 IS 13 BP 16581 EP 16592 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DL5QW UT WOS:000375692900098 PM 26918731 ER PT J AU Bijnsdorp, IV Hodzic, J Lagerweij, T Westerman, B Krijgsman, O Broeke, J Verweij, F Nilsson, RJA Rozendaal, L van Beusechem, VW van Moorselaar, JA Wurdinger, T Geldof, AA AF Bijnsdorp, Irene V. Hodzic, Jasmina Lagerweij, Tonny Westerman, Bart Krijgsman, Oscar Broeke, Jurjen Verweij, Frederik Nilsson, R. Jonas A. Rozendaal, Lawrence van Beusechem, Victor W. van Moorselaar, Jeroen A. Wurdinger, Thomas Geldof, Albert A. TI miR-129-3p controls centrosome number in metastatic prostate cancer cells by repressing CP110 SO ONCOTARGET LA English DT Article DE prostate cancer; centrosome; CP110; miR-129-3p; metastasis ID EPITHELIAL-MESENCHYMAL TRANSITION; AMPLIFICATION; EXPRESSION; THERAPY; BIOGENESIS; CARCINOMA; MECHANISM; MEMBRANE; INVASION; DYNAMICS AB The centrosome plays a key role in cancer invasion and metastasis. However, it is unclear how abnormal centrosome numbers are regulated when prostate cancer (PCa) cells become metastatic. CP110 was previously described for its contribution of centrosome amplification (CA) and early development of aggressive cell behaviour. However its regulation in metastatic cells remains unclear. Here we identified miR-129-3p as a novel metastatic microRNA. CP110 was identified as its target protein. In PCa cells that have metastatic capacity, CP110 expression was repressed by miR-129-3p. High miR-129-3p expression levels increased cell invasion, while increasing CP110 levels decreased cell invasion. Overexpression of CP110 in metastatic PCa cells resulted in a decrease in the number of metastasis. In tissues of PCa patients, low CP110 and high miR-129-3p expression levels correlated with metastasis, but not with the expression of genes related to EMT. Furthermore, overexpression of CP110 in metastatic PCa cells resulted in excessive-CA (E-CA), and a change in F-actin distribution which is in agreement with their reduced metastatic capacity. Our data demonstrate that miR-129-3p functions as a CA gatekeeper in metastatic PCa cells by maintaining pro-metastatic centrosome amplification (CA) and preventing anti-metastatic E-CA. C1 [Bijnsdorp, Irene V.; van Moorselaar, Jeroen A.; Geldof, Albert A.] Vrije Univ Amsterdam Med Ctr, Dept Urol, Amsterdam, Netherlands. [Hodzic, Jasmina; van Beusechem, Victor W.] Vrije Univ Amsterdam Med Ctr, Dept Med Oncol, Amsterdam, Netherlands. [Lagerweij, Tonny; Westerman, Bart; Nilsson, R. Jonas A.; Wurdinger, Thomas] Vrije Univ Amsterdam Med Ctr, Dept Neurosurg, Amsterdam, Netherlands. [Krijgsman, Oscar; Verweij, Frederik; Rozendaal, Lawrence] Vrije Univ Amsterdam Med Ctr, Dept Pathol, Amsterdam, Netherlands. [Krijgsman, Oscar] Netherlands Canc Inst, Dept Mol Oncol, Amsterdam, Netherlands. [Broeke, Jurjen] Vrije Univ Amsterdam, Ctr Neurogen & Cognit Res, Amsterdam, Netherlands. [Nilsson, R. Jonas A.] Umea Univ, Dept Radiat Sci, Umea, Sweden. [Wurdinger, Thomas] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Bijnsdorp, IV (reprint author), Vrije Univ Amsterdam Med Ctr, Dept Urol, Amsterdam, Netherlands. EM iv.bijnsdorp@vumc.nl FU Stichting VUmc CCA; Stichting Pon; Worldwide Cancer Research Foundation (AICR) [15-1005] FX Stichting Pon, Stichting VUmc CCA and the Worldwide Cancer Research Foundation (AICR #15-1005) are kindly acknowledged for financially supporting the present study. NR 51 TC 1 Z9 1 U1 1 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 MAR 29 PY 2016 VL 7 IS 13 BP 16676 EP 16687 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DL5QW UT WOS:000375692900105 PM 26918338 ER PT J AU Brauner, E Gunda, V Vanden Borre, P Zurakowski, D Kim, YS Dennett, KV Amin, S Freeman, GJ Parangi, S AF Brauner, Eran Gunda, Viswanath Vanden Borre, Pierre Zurakowski, David Kim, Yon Seon Dennett, Kate Virginia Amin, Salma Freeman, Gordon James Parangi, Sareh TI Combining BRAF inhibitor and anti PD-L1 antibody dramatically improves tumor regression and anti tumor immunity in an immunocompetent murine model of anaplastic thyroid cancer SO ONCOTARGET LA English DT Article DE anaplastic thyroid cancer; programmed cell death-1; programmed cell death-ligand 1; BRAF inhibitor; MEK inhibitor ID T-CELL-ACTIVATION; DEATH-LIGAND 1; METASTATIC MELANOMA; PROGRAMMED DEATH-1; CHECKPOINT BLOCKADE; ANTITUMOR IMMUNITY; VIRAL-INFECTION; MOUSE MODEL; EXPRESSION; IMMUNOTHERAPY AB The interaction of programmed cell death-1 and its ligand is widely studied in cancer. Monoclonal antibodies blocking these molecules have had great success but little is known about them in thyroid cancer. We investigated the role of PD-L1 in thyroid cancer with respect to BRAF mutation and MAP kinase pathway activity and the effect of anti PD-L1 antibody therapy on tumor regression and intra-tumoral immune response alone or in combination with BRAF inhibitor (BRAFi). BRAF(V600E) cells showed significantly higher baseline expression of PD-L1 at mRNA and protein levels compared to BRAF(WT) cells. MEK inhibitor treatment resulted in a decrease of PD-L1 expression across all cell lines. BRAFi treatment decreased PD-L1 expression in BRAF(V600E) cells, but paradoxically increased its expression in BRAF(WT) cells. BRAF(V600E) mutated patients samples had a higher level of PD-L1 mRNA compared to BRAF(WT) (p=0.015). Immunocompetent mice (B6129SF1/J) implanted with syngeneic 3747 BRAF(V600E/WT) P53(-/-) murine tumor cells were randomized to control, PLX4720, anti PD-L1 antibody and their combination. In this model of aggressive thyroid cancer, control tumor volume reached 782.3 +/- 174.6mm(3) at two weeks. The combination dramatically reduced tumor volume to 147.3 +/- 60.8, compared to PLX4720 (439.3 +/- 188.4 mm(3), P=0.023) or PD-L1 antibody (716.7 +/- 62.1, P<0.001) alone. Immunohistochemistry analysis revealed intense CD8(+) CTL infiltration and cytotoxicity and favorable CD8(+): Treg ratio compared to each individual treatment. Our results show anti PD-L1 treatment potentiates the effect of BRAFi on tumor regression and intensifies anti tumor immune response in an immunocompetent model of ATC. Clinical trials of this therapeutic combination may be of benefit in patients with ATC. C1 [Brauner, Eran; Gunda, Viswanath; Vanden Borre, Pierre; Kim, Yon Seon; Dennett, Kate Virginia; Amin, Salma; Parangi, Sareh] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Zurakowski, David] Harvard Univ, Sch Med, Dept Surg, Boston Childrens Hosp, Boston, MA 02115 USA. [Zurakowski, David] Harvard Univ, Sch Med, Dept Anesthesia, Boston Childrens Hosp, Boston, MA 02115 USA. [Kim, Yon Seon] Univ Ulsan, Coll Med, Ulsan Univ Hosp, Dept Surg, Ulsan 680749, South Korea. [Freeman, Gordon James] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. RP Parangi, S (reprint author), Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02115 USA. EM sparangi@partners.org FU National Institution of Health [R01 1R01CA149738-01A1]; ENDOCRINE TISSUE BANK Ruane Fund; NCI [P50CA101942]; NIH [P01AI054456]; Clair and Emanuel G. Rosenblatt Fund; American Healthcare Professionals and Friends for Medicine in Israel FX This work was supported by the National Institution of Health Grant R01 1R01CA149738-01A1 and the ENDOCRINE TISSUE BANK Ruane Fund (SP). NCI P50CA101942 and NIH P01AI054456 (GJF). The Clair and Emanuel G. Rosenblatt Fund and American Healthcare Professionals and Friends for Medicine in Israel (EB). NR 59 TC 1 Z9 1 U1 2 U2 7 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAR 29 PY 2016 VL 7 IS 13 BP 17194 EP 17211 PG 18 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DL5QW UT WOS:000375692900142 PM 26943572 ER PT J AU Cappi, C Brentani, H Lima, L Sanders, SJ Zai, G Diniz, BJ Reis, VNS Hounie, AG do Rosario, MC Mariani, D Requena, GL Puga, R Souza-Duran, FL Shavitt, RG Pauls, DL Miguel, EC Fernandez, TV AF Cappi, C. Brentani, H. Lima, L. Sanders, S. J. Zai, G. Diniz, B. J. Reis, V. N. S. Hounie, A. G. Conceicao do Rosario, M. Mariani, D. Requena, G. L. Puga, R. Souza-Duran, F. L. Shavitt, R. G. Pauls, D. L. Miguel, E. C. Fernandez, T. V. TI Whole-exome sequencing in obsessive-compulsive disorder identifies rare mutations in immunological and neurodevelopmental pathways SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID DE-NOVO MUTATIONS; AUTISM SPECTRUM DISORDERS; COPY NUMBER VARIATION; INTELLECTUAL DISABILITY; MISSING HERITABILITY; TOURETTE SYNDROME; HUMAN-DISEASE; PROTEIN; GENE; NETWORK AB Studies of rare genetic variation have identified molecular pathways conferring risk for developmental neuropsychiatric disorders. To date, no published whole-exome sequencing studies have been reported in obsessive-compulsive disorder (OCD). We sequenced all the genome coding regions in 20 sporadic OCD cases and their unaffected parents to identify rare de novo (DN) single-nucleotide variants (SNVs). The primary aim of this pilot study was to determine whether DN variation contributes to OCD risk. To this aim, we evaluated whether there is an elevated rate of DN mutations in OCD, which would justify this approach toward gene discovery in larger studies of the disorder. Furthermore, to explore functional molecular correlations among genes with nonsynonymous DN SNVs in OCD probands, a protein-protein interaction (PPI) network was generated based on databases of direct molecular interactions. We applied Degree-Aware Disease Gene Prioritization (DADA) to rank the PPI network genes based on their relatedness to a set of OCD candidate genes from two OCD genome-wide association studies (Stewart et al., 2013; Mattheisen et al., 2014). In addition, we performed a pathway analysis with genes from the PPI network. The rate of DN SNVs in OCD was 2.51 x 10(-8) per base per generation, significantly higher than a previous estimated rate in unaffected subjects using the same sequencing platform and analytic pipeline. Several genes harboring DN SNVs in OCD were highly interconnected in the PPI network and ranked high in the DADA analysis. Nearly all the DN SNVs in this study are in genes expressed in the human brain, and a pathway analysis revealed enrichment in immunological and central nervous system functioning and development. The results of this pilot study indicate that further investigation of DN variation in larger OCD cohorts is warranted to identify specific risk genes and to confirm our preliminary finding with regard to PPI network enrichment for particular biological pathways and functions. C1 [Cappi, C.; Brentani, H.; Lima, L.; Diniz, B. J.; Reis, V. N. S.; Hounie, A. G.; Mariani, D.; Requena, G. L.; Puga, R.; Souza-Duran, F. L.; Shavitt, R. G.; Miguel, E. C.] Univ Sao Paulo, Sch Med, Dept Psychiat, Sao Paulo, Brazil. [Sanders, S. J.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Zai, G.] Univ Toronto, Inst Med Sci, Neurogenet Sect, Ctr Addict & Mental Hlth, Toronto, ON, Canada. [Zai, G.] Univ Toronto, Dept Psychiat, Toronto, ON, Canada. [Hounie, A. G.; Conceicao do Rosario, M.] Fed Univ Sao Paulo UPIA UNIFESP, Sao Paulo, Brazil. [Pauls, D. L.] Harvard Univ, Sch Med, Dept Psychiat,Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit,Ctr Human Genet Re, Boston, MA 02115 USA. [Fernandez, T. V.] Yale Univ, Sch Med, Ctr Child Study, New Haven, CT 06510 USA. [Fernandez, T. V.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. RP Fernandez, TV (reprint author), Yale Child Study Ctr, 230 South Frontage Rd, New Haven, CT 06520 USA. EM thomas.fernandez@yale.edu RI Brentani, Helena/G-6839-2011; Duran, Fabio/L-1371-2013; Fernandez, Thomas/D-4295-2009; Reis, Viviane/J-3996-2014 OI Brentani, Helena/0000-0001-5192-4682; Duran, Fabio/0000-0002-7603-6152; Fernandez, Thomas/0000-0003-0830-022X; Reis, Viviane/0000-0002-4959-2954 FU Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP); Sao Paulo Research Foundation [2008/11537-7, 2011/14658-2]; Brazilian Instituto Nacional de Psiquiatria do Desenvolvimento para Infancia e Adolescencia (INPD); National Institute of Developmental Psychiatry for Children and Adolescents FX We thank Dr Marcelo Batistuzzo, Dr Daniel L Costa and Dr Michael Bloch for their helpful comments on the manuscript. We also thank the families and patients who participated in this research. This work was supported by grants from the Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP, Sao Paulo Research Foundation-process: 2008/11537-7; and process: 2011/14658-2); the Brazilian Instituto Nacional de Psiquiatria do Desenvolvimento para Infancia e Adolescencia (INPD, National Institute of Developmental Psychiatry for Children and Adolescents). NR 66 TC 2 Z9 2 U1 8 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD MAR 29 PY 2016 VL 6 AR e764 DI 10.1038/tp.2016.30 PG 9 WC Psychiatry SC Psychiatry GA DJ0QR UT WOS:000373909900001 PM 27023170 ER PT J AU Stringer, S Minica, CC Verweij, KJH Mbarek, H Bernard, M Derringer, J van Eijk, KR Isen, JD Loukola, A Maciejewski, DF Mihailov, E van der Most, PJ Sanchez-Mora, C Roos, L Sherva, R Walters, R Ware, JJ Abdellaoui, A Bigdeli, TB Branje, SJT Brown, SA Bruinenberg, M Casas, M Esko, T Garcia-Martinez, I Gordon, SD Harris, JM Hartman, CA Henders, AK Heath, AC Hickie, IB Hickman, M Hopfer, CJ Hottenga, JJ Huizink, AC Irons, DE Kahn, RS Korhonen, T Kranzler, HR Krauter, K van Lier, PAC Lubke, GH Madden, PAF Magi, R McGue, MK Medland, SE Meeus, WHJ Miller, MB Montgomery, GW Nivard, MG Nolte, IM Oldehinkel, AJ Pausova, Z Qaiser, B Quaye, L Ramos-Quiroga, JA Richarte, V Rose, RJ Shin, J Stallings, MC Stiby, AI Wall, TL Wright, MJ Koot, HM Paus, T Hewitt, JK Ribases, M Kaprio, J Boks, MP Snieder, H Spector, T Munafo, MR Metspalu, A Gelernter, J Boomsma, DI Iacono, WG Martin, NG Gillespie, NA Derks, EM Vink, JM AF Stringer, S. Minica, C. C. Verweij, K. J. H. Mbarek, H. Bernard, M. Derringer, J. van Eijk, K. R. Isen, J. D. Loukola, A. Maciejewski, D. F. Mihailov, E. van der Most, P. J. Sanchez-Mora, C. Roos, L. Sherva, R. Walters, R. Ware, J. J. Abdellaoui, A. Bigdeli, T. B. Branje, S. J. T. Brown, S. A. Bruinenberg, M. Casas, M. Esko, T. Garcia-Martinez, I. Gordon, S. D. Harris, J. M. Hartman, C. A. Henders, A. K. Heath, A. C. Hickie, I. B. Hickman, M. Hopfer, C. J. Hottenga, J. J. Huizink, A. C. Irons, D. E. Kahn, R. S. Korhonen, T. Kranzler, H. R. Krauter, K. van Lier, P. A. C. Lubke, G. H. Madden, P. A. F. Magi, R. McGue, M. K. Medland, S. E. Meeus, W. H. J. Miller, M. B. Montgomery, G. W. Nivard, M. G. Nolte, I. M. Oldehinkel, A. J. Pausova, Z. Qaiser, B. Quaye, L. Ramos-Quiroga, J. A. Richarte, V. Rose, R. J. Shin, J. Stallings, M. C. Stiby, A. I. Wall, T. L. Wright, M. J. Koot, H. M. Paus, T. Hewitt, J. K. Ribases, M. Kaprio, J. Boks, M. P. Snieder, H. Spector, T. Munafo, M. R. Metspalu, A. Gelernter, J. Boomsma, D. I. Iacono, W. G. Martin, N. G. Gillespie, N. A. Derks, E. M. Vink, J. M. TI Genome-wide association study of lifetime cannabis use based on a large meta-analytic sample of 32330 subjects from the International Cannabis Consortium SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID ILLICIT DRUG-USE; NICOTINE DEPENDENCE; CANDIDATE GENES; SMOKING-BEHAVIOR; USE INITIATION; ENVIRONMENTAL-INFLUENCES; HAPLOTYPIC VARIANTS; ALCOHOL DEPENDENCE; LINKAGE ANALYSES; USE DISORDERS AB Cannabis is the most widely produced and consumed illicit psychoactive substance worldwide. Occasional cannabis use can progress to frequent use, abuse and dependence with all known adverse physical, psychological and social consequences. Individual differences in cannabis initiation are heritable (40-48%). The International Cannabis Consortium was established with the aim to identify genetic risk variants of cannabis use. We conducted a meta-analysis of genome-wide association data of 13 cohorts (N = 32 330) and four replication samples (N = 5627). In addition, we performed a gene-based test of association, estimated single-nucleotide polymorphism (SNP)-based heritability and explored the genetic correlation between lifetime cannabis use and cigarette use using LD score regression. No individual SNPs reached genome-wide significance. Nonetheless, gene-based tests identified four genes significantly associated with lifetime cannabis use: NCAM1, CADM2, SCOC and KCNT2. Previous studies reported associations of NCAM1 with cigarette smoking and other substance use, and those of CADM2 with body mass index, processing speed and autism disorders, which are phenotypes previously reported to be associated with cannabis use. C1 [Stringer, S.] Vrije Univ Amsterdam, Ctr Neurogen & Cognit Res, Dept Complex Trait Genet, Amsterdam, Netherlands. [Stringer, S.; Derks, E. M.] Univ Amsterdam, Acad Med Ctr, Dept Psychiat, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. [Minica, C. C.; Verweij, K. J. H.; Mbarek, H.; Abdellaoui, A.; Hottenga, J. J.; Lubke, G. H.; Nivard, M. G.; Boomsma, D. I.; Vink, J. M.] Vrije Univ Amsterdam, Netherlands Twin Register, Dept Biol Psychol, Amsterdam, Netherlands. [Verweij, K. J. H.; Boomsma, D. I.] Neurosci Campus Amsterdam, Amsterdam, Netherlands. [Verweij, K. J. H.; Maciejewski, D. F.; Huizink, A. C.; van Lier, P. A. C.; Koot, H. M.] Vrije Univ Amsterdam, Dept Dev Psychol, Amsterdam, Netherlands. [Verweij, K. J. H.; Maciejewski, D. F.; Huizink, A. C.; van Lier, P. A. C.; Koot, H. M.] Vrije Univ Amsterdam, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands. [Bernard, M.; Pausova, Z.; Shin, J.] Hosp Sick Children, Res Inst, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. [Derringer, J.] Univ Illinois, Dept Psychol, Champaign, IL USA. [van Eijk, K. R.; Kahn, R. S.; Boks, M. P.] Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Dept Human Neurogenet, Utrecht, Netherlands. [Isen, J. D.; Irons, D. E.; McGue, M. K.; Miller, M. B.; Iacono, W. G.] Univ Minnesota, Dept Psychol, Minneapolis, MN USA. [Loukola, A.; Korhonen, T.; Qaiser, B.; Kaprio, J.] Univ Helsinki, Dept Publ Hlth, Hjelt Inst, Helsinki, Finland. [Mihailov, E.; Esko, T.; Magi, R.; Metspalu, A.] Univ Tartu, Estonian Genome Ctr, Ulikooli 18, EE-50090 Tartu, Estonia. [van der Most, P. J.; Nolte, I. M.; Snieder, H.] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands. [Sanchez-Mora, C.; Garcia-Martinez, I.; Ribases, M.] Univ Autonoma Barcelona, VHIR, Psychiat Genet Unit, E-08193 Barcelona, Spain. [Sanchez-Mora, C.; Casas, M.; Garcia-Martinez, I.; Ramos-Quiroga, J. A.; Richarte, V.; Ribases, M.] Hosp Univ Vall Hebron, Dept Psychiat, Barcelona, Spain. [Sanchez-Mora, C.; Casas, M.; Ramos-Quiroga, J. A.; Ribases, M.] Biomed Network Res Ctr Mental Hlth CIBERSAM, Barcelona, Spain. [Roos, L.; Harris, J. M.; Quaye, L.; Spector, T.] Kings Coll London, Twin Res & Genet Epidemiol, London WC2R 2LS, England. [Sherva, R.] Boston Univ, Sch Med, Biomed Genet Dept, Boston, MA 02118 USA. [Walters, R.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Walters, R.] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Walters, R.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Ware, J. J.; Hickman, M.; Stiby, A. I.; Munafo, M. R.] Univ Bristol, Sch Social & Community Med, Bristol, Avon, England. [Ware, J. J.] Univ Bristol, MRC Integrat Epidemiol Unit IEU, Bristol, Avon, England. [Bigdeli, T. B.; Gillespie, N. A.] Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Dept Psychiat, Richmond, VA USA. [Branje, S. J. T.; Meeus, W. H. J.] Univ Utrecht, Res Ctr Adolescent Dev, Utrecht, Netherlands. [Brown, S. A.] Univ Calif San Diego, Dept Psychol & Psychiat, La Jolla, CA 92093 USA. [Bruinenberg, M.] Univ Groningen, Univ Med Ctr Groningen, LifeLines Cohort Study, Groningen, Netherlands. [Casas, M.; Ramos-Quiroga, J. A.] Univ Autonoma Barcelona, Dept Psychiat & Legal Med, E-08193 Barcelona, Spain. [Gordon, S. D.; Henders, A. K.; Medland, S. E.; Montgomery, G. W.; Wright, M. J.; Martin, N. G.; Gillespie, N. A.] QIMR Berghofer Med Res Inst, Genet Epidemiol Mol Epidemiol & Neurogenet Labs, Brisbane, Qld, Australia. [Hartman, C. A.] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands. [Heath, A. C.; Madden, P. A. F.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. [Hickie, I. B.] Univ Sydney, Brain & Mind Res Inst, Sydney, NSW 2006, Australia. [Hopfer, C. J.] Univ Colorado Denver, Dept Psychiat, Aurora, CO USA. [Korhonen, T.] Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Kuopio, Finland. [Korhonen, T.; Kaprio, J.] Natl Inst Hlth & Welf, Dept Mental Hlth & Subst Abuse Serv, Helsinki, Finland. [Kranzler, H. R.] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Krauter, K.] Univ Colorado, Dept Mol Cellular & Dev Biol, Boulder, CO 80309 USA. [Lubke, G. H.] Univ Notre Dame, Dept Psychol, Notre Dame, IN 46556 USA. [Meeus, W. H. J.] Tilburg Univ, Dev Psychol, NL-5000 LE Tilburg, Netherlands. [Oldehinkel, A. J.] Univ Groningen, Univ Med Ctr Groningen, Interdisciplinary Ctr Pathol & Emot Regulat, Groningen, Netherlands. [Pausova, Z.] Univ Toronto, Dept Physiol & Nutr Sci, Toronto, ON, Canada. [Rose, R. J.] Indiana Univ, Dept Psychol & Brain Sci, Bloomington, IN USA. [Stallings, M. C.; Hewitt, J. K.] Univ Colorado, Inst Behav Genet, Dept Psychol & Neurosci, Boulder, CO 80309 USA. [Wall, T. L.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Paus, T.] Rotman Res Inst, Toronto, ON, Canada. [Paus, T.] Univ Toronto, Dept Psychol & Psychiat, Toronto, ON, Canada. [Paus, T.] Child Mind Inst, Ctr Developing Brain, New York, NY USA. [Kaprio, J.] Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland. [Munafo, M. R.] Univ Bristol, UK Ctr Tobacco & Alcohol Studies, Bristol, Avon, England. [Munafo, M. R.] Univ Bristol, Sch Expt Psychol, Bristol, Avon, England. [Gelernter, J.] Yale Univ, Sch Med, Dept Psychiat Genet & Neurobiol, West Haven, CT 06516 USA. [Gelernter, J.] VA CT, West Haven, CT USA. [Vink, J. M.] Radboud Univ Nijmegen, Behav Sci Inst, Montessorilaan 3, NL-6525 HR Nijmegen, Netherlands. RP Vink, JM (reprint author), Radboud Univ Nijmegen, Behav Sci Inst, Montessorilaan 3, NL-6525 HR Nijmegen, Netherlands. EM j.vink@bsi.ru.nl RI Derks, Eske/A-1652-2017; Branje, Susan/A-7813-2010; OI Derks, Eske/0000-0002-6292-6883; Branje, Susan/0000-0002-9999-5313; Loukola, Anu-Maria/0000-0003-0542-5967; Roos, Leonie/0000-0001-7885-2105; Korhonen, Tellervo/0000-0003-2838-3085; Kaprio, Jaakko/0000-0002-3716-2455; Hickman, Matthew/0000-0001-9864-459X FU European Research Council (Beyond the Genetics of Addiction) [ERC-284167]; Foundation Volksbond Rotterdam; Netherlands Organization for Health Research and Development (ZonMW) [31160212]; NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation; US National Institutes of Health, National Institute on Drug Abuse [R00DA023549]; NIDA [R37 DA-018673]; NSF [BCS-1229450]; NIH [U01 MH094432]; Netherlands Organization for Scientific Research (NWO) [480-05-003]; Dutch Brain Foundation; VU University Amsterdam; UK Medical Research Council; Wellcome Trust [102215/2/13/2, WT083431MA]; University of Bristol; 23andMe; Oak Foundation; UK Medical Research Council [MC_UU_12013/6]; British Heart Foundation; Cancer Research UK; Economic and Social Research Council; Medical Research Council and the National Institute for Health Research; UK Clinical Research; United States National Institute on Drug Abuse [R00DA023549]; Australian Research Council [DP0343921, DP0664638, DP1093900, A7960034, A79906588, A79801419, DP0770096, DP0212016]; Australian National Health and Medical Research Council Australia Fellowships [464914, 619667]; ARC future fellowship [FT110100548]; National Institute on Drug Abuse [P60 DA011015, R01 DA012845, R01 DA021913, R01 DA021905, R01 DA035804, DA05147, DA13240, DA024417]; FP7 [278913, 306031, 313010]; Center of Excellence in Genomics (EXCEGEN); University of Tartu (SP1GVARENG); Academy of Finland Center of Excellence in Complex Disease Genetics [213506, 129680]; Academy of Finland [100499, 205585, 118555, 141054, 265240, 263278, 264146]; National Institute of Alcohol Abuse and Alcoholism [AA-12502, AA-00145, AA-09203, AA15416, K02AA018755]; Sigrid Juselius Foundation; Welcome Trust Sanger Institute, UK; 'Instituto de Salud Carlos III-FIS' [PI11/00571, PI11/01629, PI12/01139]; 'Plan Nacional Sobre Drogas' (PNSD) [20110080]; 'Agencia de Gestio d'Ajuts Universitaris i de Recerca-AGAUR, Generalitat de Catalunya' [2014SGR1357]; 'Departament de Salut', Government of Catalonia, Spain; 'Instituto de Salud Carlos III, Ministerio de Ciencia e Innovacion', Spain; National Institute on Alcohol Abuse and Alcoholism [AA09367, AA11886]; National Institute on Mental Health [MH066140]; Netherlands Organization for Scientific Research [ZonMW Addiction 31160008, ZonMW 940-37-024, NWO/SPI 56-464-14192, NWO-400-05-717, NWO-MW 904-61-19, NWO-MagW 480-04-004, NWO-Veni 016-115-035]; European Research Council [ERC-284167, ERC-230374]; Centre for Medical Systems Biology (NWO Genomics); Netherlands Bioinformatics [Center/BioAssist/RK/2008.024]; EMGO+ Institute for Health and Care Research; Neuroscience Campus Amsterdam, BBMRI-NL (Biobanking and Biomolecular Resources Research Infrastructure) [184.021.007]; Avera Institute, Sioux Falls, South Dakota (USA); National Institutes of Health [4R37DA018673-06, RC2 MH089951, NIH R01 HD042157-01A1, MH081802, 1RC2 MH089951, 1RC2 MH089995]; Rutgers University Cell and DNA Repository cooperative agreement (National Institute of Mental Health) [U24 MH068457-06]; Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health; Netherlands Scientific Organization (NWO) [480-05-003]; Department of Psychology and Education of the VU University Amsterdam; National Institutes of Health Grants [AA07535, AA0758O, AA07728, AA10249, AA13320, AA13321, AA14041, AA11998, AA17688, DA012854, DA018267, DA018660, DA23668, DA019951]; Australian National Health and Medical Research Council [241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 552485, 552498, 628911]; 5th Framework Programme (FP-5) GenomEUtwin Project [QLG2-CT-2002-01254]; Centre for Research Excellence on Suicide Prevention (CRESP-Australia); Netherlands Organisation for Scientific Research (Brain and Cognition) [056-21-010]; Netherlands Organisation for Scientific Research (GB-MAGW) [480-03-005]; Stichting Achmea Slachtoffer en Samenleving (SASS); Netherlands Organisation for Scientific Research; Utrecht University; Netherlands Organization for Health Research and Development; ZonMW [31160212]; Canadian Institutes of Health Research; Heart and Stroke Foundation of Canada; Netherlands Organization for Scientific Research NWO (Medical Research Council program) [GB-MW 940-38-011]; Netherlands Organization for Scientific Research NWO (ZonMW Brainpower) [100-001-004]; Netherlands Organization for Scientific Research NWO (ZonMw Risk Behavior and Dependence) [60-60600-97-118]; Netherlands Organization for Scientific Research NWO (ZonMw Culture and Health) [261-98-710]; Netherlands Organization for Scientific Research NWO (Social Sciences Council medium-sized investment) [GBMaGW 480-01-006, GB-MaGW 480-07-001]; Netherlands Organization for Scientific Research NWO (Social Sciences Council) [GB-MaGW 452-04-314, GB-MaGW 452-06-004]; Netherlands Organization for Scientific Research NWO (NWO large-sized investment) [175.010.2003.005]; Netherlands Organization for Scientific Research NWO (NWO Longitudinal Survey and Panel Funding) [481-08-013]; Dutch Ministry of Justice (WODC); European Science Foundation (EuroSTRESS) [FP-006]; Biobanking and Biomolecular Resources Research Infrastructure BBMRI-NL [CP 32]; Accare Center for Child and Adolescent Psychiatry; Wellcome Trust; European Community's Seventh Framework Programme (FP7); National Institute for Health Research (NIHR); Clinical Research Facility and Biomedical Research Centre based at Guy's; St Thomas' NHS Foundation Trust; King's College London; NWO (Netherlands Organization for Scientific Research) [91207039]; National Institutes of Health to The Johns Hopkins University [N01-HG-65403]; National Institutes of Health grant [RC2 DA028909, R01 DA12690, R01 DA12849, R01 DA18432, R01 AA11330, R01 AA017535]; VA Connecticut; Philadelphia VA MIRECCs FX JMV, CCM and HM are supported by the European Research Council (Beyond the Genetics of Addiction ERC-284167, PI JMV). SS and EMD are supported by the Foundation Volksbond Rotterdam. KJHV is supported in part by the Netherlands Organization for Health Research and Development (ZonMW 31160212) and in part by a 2014 NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation. NAG is supported by US National Institutes of Health, National Institute on Drug Abuse R00DA023549. GHL is supported by NIDA R37 DA-018673 and NSF BCS-1229450. RW is supported by NIH U01 MH094432 and NSF BCS-1229450. Statistical analyses were carried out on the Genetic Cluster Computer (http://www.geneticcluster.org) hosted by SURFsara and financially supported by the Netherlands Organization for Scientific Research (NWO 480-05-003 PI: Posthuma) along with a supplement from the Dutch Brain Foundation and the VU University Amsterdam. The study site acknowledgments are as follows: ALSPAC-We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The UK Medical Research Council and the Wellcome Trust (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. GWAS data were generated by Sample Logistics and Genotyping Facilities at the Wellcome Trust Sanger Institute and LabCorp (Laboratory Corportation of America) using support from 23andMe. AIS is supported by a Wellcome Trust 4-year PhD studentship in molecular, genetic and lifecourse epidemiology (WT083431MA). JJW is supported by a Postdoctoral Research Fellowship from the Oak Foundation. JJW and MRM are members of the MRC Integrative Epidemiology Unit at the University of Bristol, funded by the UK Medical Research Council (MC_UU_12013/6) and the University of Bristol. JJW and MRM are also members of the UK Centre for Tobacco and Alcohol Studies, a UKCRC Public Health Research: Centre of Excellence. Funding from British Heart Foundation, Cancer Research UK, Economic and Social Research Council, Medical Research Council and the National Institute for Health Research, under the auspices of the UK Clinical Research Collaboration is gratefully acknowledged. BLTS-The BLTS was supported by grants from the United States National Institute on Drug Abuse (R00DA023549) awarded to NAG, by the Australian Research Council to MJW (Nos. DP0343921, DP0664638 and DP1093900) and by Australian National Health and Medical Research Council Australia Fellowships awarded to Ian Hickie (No. 464914) and GWM (No. 619667). We acknowledge and thank the following project staff: AKH, Leanne Wallace and Lisa Bowdler for the laboratory processing, genotyping and QC; Soad Hancock as Project Coordinator; Lenore Sullivan as Research Editor; our research interviewers Pieta-Marie Shertock and Jill Wood; and David Smyth for IT. We also thank the twins and their siblings for their willing cooperation. SEM was supported by an ARC future fellowship FT110100548. CADD-The Center on Antisocial Drug Dependence (CADD) data reported here were funded by grants from the National Institute on Drug Abuse (P60 DA011015, R01 DA012845, R01 DA021913, R01 DA021905, R01 DA035804). EGCUT received financing by FP7 grants (278913, 306031, 313010), Center of Excellence in Genomics (EXCEGEN) and University of Tartu (SP1GVARENG).; r We acknowledge EGCUT technical personnel, especially Mr V Soo and S Smit. Data analyses were carried out in part in the High Performance Computing Center of University of Tartu. FinnTwin-We warmly thank the participating twin pairs and their family members for their contribution. We express our appreciation to the skilled study interviewers A-M Livonen, K Karhu, H-M Kuha, U Kulmala-Grahn, M Mantere, K Saanakorpi, M Saarinen, R Sipila, L Viljanen and E Voipio. Anja Happola and Kauko Heikkila are acknowledged for their valuable contribution in recruitment, data collection and data management. Phenotyping and genotyping of the Finnish twin cohorts has been supported by the Academy of Finland Center of Excellence in Complex Disease Genetics (grants 213506, 129680), the Academy of Finland (grants 100499, 205585, 118555, 141054, 265240, 263278 and 264146 to JK), National Institute of Alcohol Abuse and Alcoholism (grants AA-12502, AA-00145, and AA-09203 to RJR and AA15416 and K02AA018755 to DM Dick), Sigrid Juselius Foundation (to JK), and the Welcome Trust Sanger Institute, UK. Antti-Pekka Sarin and Samuli Ripatti are acknowledged for genotype data quality controls and imputation. GWAS analyses were run at the ELIXIR Finland node hosted at CSC-IT Center for Science for ICT resources. HUVH-Financial support was received from 'Instituto de Salud Carlos III-FIS' (PI11/00571, PI11/01629, PI12/01139), 'Plan Nacional Sobre Drogas' (PNSD# 20110080), 'Agencia de Gestio d'Ajuts Universitaris i de Recerca-AGAUR, Generalitat de Catalunya' (2014SGR1357) and 'Departament de Salut', Government of Catalonia, Spain. MR is a recipient of a Miguel de Servet contract from the 'Instituto de Salud Carlos III, Ministerio de Ciencia e Innovacion', Spain. MCTFR-This research was supported in part by USPHS Grants from the National Institute on Alcohol Abuse and Alcoholism (AA09367 and AA11886), the National Institute on Drug Abuse (DA05147, DA13240 and DA024417) and the National Institute on Mental Health (MH066140). NTR-We thank the Netherlands Twin Register participants whose data we analyzed in this study. This work was supported by grants from the Netherlands Organization for Scientific Research (ZonMW Addiction 31160008; ZonMW 940-37-024; NWO/SPI 56-464-14192; NWO-400-05-717; NWO-MW 904-61-19; NWO-MagW 480-04-004; NWO-Veni 016-115-035), the European Research Council (Beyond the Genetics of Addiction ERC-284167; Genetics of Mental Illness: ERC-230374), the Centre for Medical Systems Biology (NWO Genomics), Netherlands Bioinformatics Center/BioAssist/RK/2008.024. We acknowledge the EMGO+ Institute for Health and Care Research, the Neuroscience Campus Amsterdam, BBMRI-NL (184.021.007: Biobanking and Biomolecular Resources Research Infrastructure), the Avera Institute, Sioux Falls, South Dakota (USA) for support. Genotyping was funded in part by grants from the National Institutes of Health (4R37DA018673-06, RC2 MH089951), Rutgers University Cell and DNA Repository cooperative agreement (National Institute of Mental Health U24 MH068457-06), and the National Institutes of Health (NIH R01 HD042157-01A1, MH081802, Grand Opportunity grants 1RC2 MH089951 and 1RC2 MH089995) and the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health. The statistical analyses were carried out on the Genetic Cluster Computer (http://www.geneticcluster.; org) which is supported by the Netherlands Scientific Organization (NWO 480-05-003), the Dutch Brain Foundation and the Department of Psychology and Education of the VU University Amsterdam.r QIMRThis is supported by National Institutes of Health Grants AA07535, AA0758O, AA07728, AA10249, AA13320, AA13321, AA14041, AA11998, AA17688, DA012854, DA018267, DA018660, DA23668 and DA019951; by Grants from the Australian National Health and Medical Research Council (241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 552485, 552498 and 628911); by Grants from the Australian Research Council (A7960034, A79906588, A79801419, DP0770096, DP0212016 and DP0343921); and by the 5th Framework Programme (FP-5) GenomEUtwin Project (QLG2-CT-2002-01254). This research was further supported by the Centre for Research Excellence on Suicide Prevention (CRESP-Australia). We thank AKH, Richard Parker, Soad Hancock, Judith Moir, Sally Rodda, Pieta-Maree Shertock, Heather Park, Jill Wood, Pam Barton, Fran Husband, Adele Somerville, Ann Eldridge, Marlene Grace, Kerrie McAloney, Lisa Bowdler, Alexandre Todorov, Steven Crooks, David Smyth, Harry Beeby and Daniel Park. Last, we thank the twins and their families for their participation. RADAR-We thank all the adolescents and their families and friends for their participation. Moreover, we thank the various assistants that helped in recruiting participants as well as collecting and cleaning the data. The research was funded partly by the Netherlands Organisation for Scientific Research (Brain and Cognition, 056-21-010). Data of the RADAR study were used. RADAR has been financially supported by main grants from the Netherlands Organisation for Scientific Research (GB-MAGW 480-03-005), and Stichting Achmea Slachtoffer en Samenleving (SASS) and various other grants from the Netherlands Organisation for Scientific Research, the VU University Amsterdam and Utrecht University. ACH is supported by the Netherlands Organization for Health Research and Development, ZonMW 31160212. Saguenay Youth Study-The Canadian Institutes of Health Research and the Heart and Stroke Foundation of Canada fund the SYS (TP, ZP). TP is the Tanenbaum Chair in Population Neuroscience (University of Toronto) and the Dr John and Consuela Phelan Scholar (Child Mind Institute). TRAILS-TRAILS (TRacking Adolescents' Individual Lives Survey) is a collaborative project involving various departments of the University Medical Center and University of Groningen, the Erasmus University Medical Center Rotterdam, the University of Utrecht, the Radboud Medical Center Nijmegen and the Parnassia Bavo group, all in the Netherlands. TRAILS has been financially supported by grants from the Netherlands Organization for Scientific Research NWO (Medical Research Council program grant GB-MW 940-38-011; ZonMW Brainpower grant 100-001-004; ZonMw Risk Behavior and Dependence grant 60-60600-97-118; ZonMw Culture and Health grant 261-98-710; Social Sciences Council medium-sized investment grants GBMaGW 480-01-006 and GB-MaGW 480-07-001; Social Sciences Council project grants GB-MaGW 452-04-314 and GB-MaGW 452-06-004; NWO large-sized investment grant 175.010.2003.005; NWO Longitudinal Survey and Panel Funding 481-08-013); the Dutch Ministry of Justice (WODC), the European Science Foundation (EuroSTRESS project FP-006), Biobanking and Biomolecular Resources Research Infrastructure BBMRI-NL (CP 32), the participating universities and Accare Center for Child and Adolescent Psychiatry.; We are grateful to all the adolescents, their parents and teachers who participated in this research and to everyone who worked on this project and made it possible. Statistical analyses were carried out on the Genetic Cluster Computer (http://www.r geneticcluster.org), which is financially supported by the Netherlands Scientific Organization (NWO 480-05-003) along with a supplement from the Dutch Brain Foundation. TwinsUK-The study was funded by the Wellcome Trust; European Community's Seventh Framework Programme (FP7/2007-2013). The study also receives support from the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London. SNP Genotyping was performed by The Wellcome Trust Sanger Institute and National Eye Institute via NIH/C. Utrecht-We are grateful to Chris Schubart and Willemijn van Gastel and numerous students for their work in the study. Foremost, we thank our study participants. This study was financially supported by a grant of the NWO (Netherlands Organization for Scientific Research), grant no. 91207039. The study was performed at the University Medical Centre Utrecht, The Netherlands. Yale Penn-Genotyping services for a part of our GWAS study were provided by the Center for Inherited Disease Research (CIDR) and Yale University (Center for Genome Analysis). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University (contract number N01-HG-65403). This study was supported by the National Institutes of Health grants RC2 DA028909, R01 DA12690, R01 DA12849, R01 DA18432, R01 AA11330, R01 AA017535, and the VA Connecticut and Philadelphia VA MIRECCs. NR 71 TC 5 Z9 5 U1 5 U2 17 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD MAR 29 PY 2016 VL 6 AR e769 DI 10.1038/tp.2016.36 PG 9 WC Psychiatry SC Psychiatry GA DJ0QR UT WOS:000373909900006 PM 27023175 ER PT J AU Maron, BA Hess, E Maddox, TM Opotowsky, AR Tedford, RJ Lahm, T Joynt, KE Kass, DJ Stephens, T Stanislawski, MA Swenson, ER Goldstein, RH Leopold, JA Zamanian, RT Elwing, JM Plomondon, ME Grunwald, GK Baron, AE Rumsfeld, JS Choudhary, G AF Maron, Bradley A. Hess, Edward Maddox, Thomas M. Opotowsky, Alexander R. Tedford, Ryan J. Lahm, Tim Joynt, Karen E. Kass, Daniel J. Stephens, Thomas Stanislawski, Maggie A. Swenson, Erik R. Goldstein, Ronald H. Leopold, Jane A. Zamanian, Roham T. Elwing, Jean M. Plomondon, Mary E. Grunwald, Gary K. Baron, Anna E. Rumsfeld, John S. Choudhary, Gaurav TI Association of Borderline Pulmonary Hypertension With Mortality and Hospitalization in a Large Patient Cohort: Insights From the Veterans Affairs Clinical Assessment, Reporting, and Tracking Program SO CIRCULATION LA English DT Article DE pulmonary hypertension; pulmonary heart disease; outcome assessment ID REDUCED EJECTION FRACTION; ARTERY SYSTOLIC PRESSURE; HEART-FAILURE; AFRICAN-AMERICANS; DIAGNOSIS; CLASSIFICATION AB Background- Pulmonary hypertension (PH) is associated with increased morbidity across the cardiopulmonary disease spectrum. Based primarily on expert consensus opinion, PH is defined by a mean pulmonary artery pressure (mPAP) >= 25 mm Hg. Although mPAP levels below this threshold are common among populations at risk for PH, the relevance of mPAP < 25 mm Hg to clinical outcome is unknown. Methods and Results- We analyzed retrospectively all US veterans undergoing right heart catheterization (2007-2012) in the Veterans Affairs healthcare system (n=21 727; 908-day median follow-up). Cox proportional hazards models were used to evaluate the association between mPAP and outcomes of all-cause mortality and hospitalization, adjusted for clinical covariates. When treating mPAP as a continuous variable, the mortality hazard increased beginning at 19 mm Hg (hazard ratio [HR]=1.183; 95% confidence interval [CI], 1.004-1.393) relative to 10 mm Hg. Therefore, patients were stratified into 3 groups: (1) referent (<= 18 mm Hg; n=4 207); (2) borderline PH (19-24 mm Hg; n=5 030); and (3) PH (>= 25 mm Hg; n=12 490). The adjusted mortality hazard was increased for borderline PH (HR=1.23; 95% CI, 1.12-1.36; P < 0.0001) and PH (HR=2.16; 95% CI, 1.96-2.38; P < 0.0001) compared with the referent group. The adjusted hazard for hospitalization was also increased in borderline PH (HR=1.07; 95% CI, 1.01-1.12; P=0.0149) and PH (HR=1.15; 95% CI, 1.09-1.22; P < 0.0001). The borderline PH cohort remained at increased risk for mortality after excluding the following high-risk subgroups: (1) patients with pulmonary artery wedge pressure > 15 mm Hg; (2) pulmonary vascular resistance >= 3.0 Wood units; or (3) inpatient status at the time of right heart catheterization. Conclusions- These data illustrate a continuum of risk according to mPAP level and that borderline PH is associated with increased mortality and hospitalization. Future investigations are needed to test the generalizability of our findings to other populations and study the effect of treatment on outcome in borderline PH. C1 [Maron, Bradley A.; Goldstein, Ronald H.] Vet Affairs Boston Healthcare Syst, West Roxbury, MA 02132 USA. [Maron, Bradley A.; Opotowsky, Alexander R.; Stephens, Thomas; Leopold, Jane A.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Maron, Bradley A.; Opotowsky, Alexander R.; Stephens, Thomas; Leopold, Jane A.] Harvard Univ, Sch Med, Boston, MA USA. [Hess, Edward; Maddox, Thomas M.; Stanislawski, Maggie A.; Plomondon, Mary E.; Grunwald, Gary K.; Baron, Anna E.; Rumsfeld, John S.] Vet Affairs Eastern Colorado Hlth Care Syst, Denver, CO USA. [Maddox, Thomas M.] Univ Colorado, Sch Med, Boulder, CO 80309 USA. [Opotowsky, Alexander R.] Boston Childrens Hosp, Boston, MA USA. [Tedford, Ryan J.] Johns Hopkins Sch Med, Div Cardiol, Dept Med, Baltimore, MD USA. [Lahm, Tim] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Lahm, Tim] Richard L Roudebush Vet Affairs Med Ctr, 1481 W 10th St, Indianapolis, IN 46202 USA. [Joynt, Karen E.] US Dept HHS, Off Assistant Secretary Planning & Evaluat, Washington, DC 20201 USA. [Kass, Daniel J.] Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Swenson, Erik R.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Swenson, Erik R.] Univ Washington, Seattle, WA 98195 USA. [Zamanian, Roham T.] Stanford Univ, Sch Med, Vera Moulton Wall Ctr Pulm Vasc Dis, Stanford, CA 94305 USA. [Elwing, Jean M.] Cincinnati Vet Affairs Med Ctr, Cincinnati, OH USA. [Elwing, Jean M.] Univ Cincinnati, Cincinnati, OH 45221 USA. [Choudhary, Gaurav] Brown Univ, Providence Vet Affairs Med Ctr, Providence, RI 02912 USA. [Choudhary, Gaurav] Brown Univ, Alpert Med Sch, Providence, RI 02912 USA. RP Maron, BA (reprint author), Vet Affairs Boston Healthcare Syst, Div Cardiol, Dept Med, 1400 VFW Pkwy, West Roxbury, MA 02132 USA. EM Bradley.Maron@va.gov FU National Institutes of Health (NIH) [1K08HL11207-01A1]; American Heart Association [15GRNT25080016]; Pulmonary Hypertension Association; Cardiovascular Medical Research and Education Fund; Klarman Foundation at Brigham and Women's Hospital; Gilead Young Scholars Foundation (Gilead Sciences); Veterans Affairs Health Services Research and Development Career Development Award [CDA 08-021]; Dunlevie Family Fund; Office of Research and Development: Biomedical Laboratory Research and Development Service (MERIT Review Award) [1I01BX002042-01A2, IBX000711A]; Department of Veterans Affairs, Veterans Health Administration; Catherine and Lowe Berger and Pauline L. Ford Scholarship in Pulmonary Medicine; Department of Medicine, Indiana University; VA Merit Award from the Department of Veterans Affairs, Veterans Health Administration; Office of Research and Development: Clinical Science Research and Development Service; NIH/National Heart, Lung, and Blood Institute (NHLBI) [1U01HL125215-01]; Junior Faculty Endowment by Vera Moulton Wall Center for Pulmonary Vascular Disease; NIH/NHLBI/National Institute of Allergy and Infectious Diseases [PO1 HL108797, UO1 HL107393, R24 HL123767, N01 HV00242, ASCO1]; Department of Medicine, Alpert Medical School FX Dr Maron was supported by National Institutes of Health (NIH) Grant 1K08HL11207-01A1, American Heart Association Grant 15GRNT25080016, the Pulmonary Hypertension Association, the Cardiovascular Medical Research and Education Fund, the Klarman Foundation at Brigham and Women's Hospital, and Gilead Young Scholars Foundation (Gilead Sciences). Dr Maddox was supported by Veterans Affairs Health Services Research and Development Career Development Award CDA 08-021. Dr Opotowsky was supported by the Dunlevie Family Fund. Dr Lahm was supported by Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development: Biomedical Laboratory Research and Development Service (MERIT Review Award 1I01BX002042-01A2), and Catherine and Lowe Berger and Pauline L. Ford Scholarship in Pulmonary Medicine, Department of Medicine, Indiana University. Dr Goldstein was supported by VA Merit Award from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development: Clinical Science Research and Development Service. Dr Leopold was supported by NIH/National Heart, Lung, and Blood Institute (NHLBI) Grant 1U01HL125215-01. Dr Zamanian was supported by Junior Faculty Endowment by Vera Moulton Wall Center for Pulmonary Vascular Disease and NIH/NHLBI/National Institute of Allergy and Infectious Diseases Grants PO1 HL108797, UO1 HL107393, R24 HL123767, N01 HV00242, and ASCO1. Dr Choudhary was supported by Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development: Biomedical Laboratory Research and Development Service (MERIT Review Award IBX000711A) and the Department of Medicine, Alpert Medical School. NR 30 TC 10 Z9 10 U1 2 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 MAR 29 PY 2016 VL 133 IS 13 BP 1240 EP 1248 DI 10.1161/CIRCULATIONAHA.115.020207 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DH5ST UT WOS:000372852800004 PM 26873944 ER PT J AU Bohula, EA Giugliano, RP Cannon, CP Zhou, J Murphy, SA White, J Tershakovec, AM Blazing, MA Braunwald, E AF Bohula, Erin A. Giugliano, Robert P. Cannon, Christopher P. Zhou, Jing Murphy, Sabina A. White, Jennifer Tershakovec, Andrew M. Blazing, Michael A. Braunwald, Eugene TI Response to Letter Regarding Article, "Achievement of Dual Low-Density Lipoprotein Cholesterol and High-Sensitivity C-Reactive Protein Targets More Frequent With the Addition of Ezetimibe to Simvastatin and Associated With Better Outcomes in IMPROVE-IT" SO CIRCULATION LA English DT Letter ID TRIALS C1 [Bohula, Erin A.; Giugliano, Robert P.; Cannon, Christopher P.; Zhou, Jing; Murphy, Sabina A.; Braunwald, Eugene] Harvard Univ, Brigham & Womens Hosp, Sch Med, TIMI Study Grp,Cardiovasc Div,Dept Med, Boston, MA 02115 USA. [White, Jennifer; Blazing, Michael A.] Duke Clin Res Inst, Durham, NC USA. [Tershakovec, Andrew M.] Merck, Kenilworth, NJ USA. RP Bohula, EA (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, TIMI Study Grp,Cardiovasc Div,Dept Med, Boston, MA 02115 USA. NR 4 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 29 PY 2016 VL 133 IS 13 BP E463 EP E463 DI 10.1161/CIRCULATIONAHA.116.020947 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DH5SU UT WOS:000372852900007 PM 27022050 ER PT J AU Herisson, F Godard, S Volteau, C Le Blanc, E Guillon, B Gaudron, M AF Herisson, Fanny Godard, Sophie Volteau, Christelle Le Blanc, Emilie Guillon, Benoit Gaudron, Marie CA SEVEL Study Grp TI Early Sitting in Ischemic Stroke Patients (SEVEL): A Randomized Controlled Trial SO PLOS ONE LA English DT Article ID EARLY MOBILIZATION; MEDICAL COMPLICATIONS; EARLY REHABILITATION; MORTALITY; SAFETY; LENGTH; AVERT; STAY; UNIT AB Background Extended immobility has been associated with medical complications during hospitalization. However no clear recommendations are available for mobilization of ischemic stroke patients. Objective As early mobilization has been shown to be feasible and safe, we tested the hypothesis that early sitting could be beneficial to stroke patient outcome. Methods This prospective multicenter study tested two sitting procedures at the acute phase of ischemic stroke, in a randomized controlled fashion (clinicaltrials.org registration number NCT01573299). Patients were eligible if they were above 18 years of age and showed no sign of massive infarction or any contra-indication for sitting. In the early-sitting group, patients were seated out of bed at the earliest possible time but no later than one calendar day after stroke onset, whereas the progressively-sitting group was first seated out of bed on the third calendar day after stroke onset. Primary outcome measure was the proportion of patients with a modified Rankin score [0-2] at 3 months post stroke. Secondary outcome measures were a.) prevalence of medical complications, b.) length of hospital stay, and c.) tolerance to the procedure. Results One hundred sixty seven patients were included in the study, of which 29 were excluded after randomization. Data from 138 patients, 63 in the early-sitting group and 75 in the progressively-sitting group were analyzed. There was no difference regarding outcome of people with stroke, with a proportion of Rankin [0-2] score at 3 months of 76.2% and 77.3% of patients in the early-and progressive-sitting groups, respectively (p = 0.52). There was also no difference between groups for secondary outcome measures, and the procedure was well tolerated in both arms. Conclusion Due to a slow enrollment, fewer patients than anticipated were available for analysis. As a result, we can only detect beneficial/detrimental effects of +/- 15% of the early sitting procedure on stroke outcome with a realized 37% power. However, enrollment was sufficient to rule out effect sizes greater than 25% with 80% power, indicating that early sitting is unlikely to have an extreme effect in either direction on stroke outcome. Additionally, we were not able to provide a blinded assessment of the primary outcome. Taking these limitations into account, our results may help guide the development of more effective acute stroke rehabilitation strategies, and the design of future acute stroke trials involving out of bed activities and other mobilization regimens. C1 [Herisson, Fanny; Guillon, Benoit] Nantes Univ Hosp, Dept Neurol, Nantes, France. [Herisson, Fanny; Guillon, Benoit] Nantes Univ Hosp, Stroke Unit, Nantes, France. [Godard, Sophie] Angers Univ Hosp, Dept Neurol, Angers, France. [Godard, Sophie] Angers Univ Hosp, Stroke Unit, Angers, France. [Volteau, Christelle; Le Blanc, Emilie] Nantes Univ Hosp, Clin Res Unit, Nantes, France. [Gaudron, Marie] Tours Univ Hosp, Dept Neurol, Tours, France. [Gaudron, Marie] Tours Univ Hosp, Stroke Unit, Tours, France. [Herisson, Fanny] Massachusetts Gen Hosp, Stroke & Neurovasc Regulat Lab, CNY 149 13th St, Charlestown, MA USA. RP Herisson, F (reprint author), Nantes Univ Hosp, Dept Neurol, Nantes, France.; Herisson, F (reprint author), Nantes Univ Hosp, Stroke Unit, Nantes, France.; Herisson, F (reprint author), Massachusetts Gen Hosp, Stroke & Neurovasc Regulat Lab, CNY 149 13th St, Charlestown, MA USA. EM fherisson@partners.org NR 17 TC 1 Z9 2 U1 2 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 29 PY 2016 VL 11 IS 3 AR e0149466 DI 10.1371/journal.pone.0149466 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH9KB UT WOS:000373113900005 PM 27023901 ER PT J AU Sawen, P Lang, S Mandal, P Rossi, DJ Soneji, S Bryder, D AF Sawen, Petter Lang, Stefan Mandal, Pankaj Rossi, Derrick J. Soneji, Shamit Bryder, David TI Mitotic History Reveals Distinct Stem Cell Populations and Their Contributions to Hematopoiesis SO CELL REPORTS LA English DT Article ID GENE-EXPRESSION ANALYSIS; SLAM FAMILY RECEPTORS; ADULT BONE-MARROW; FETAL LIVER; SELF-RENEWAL; IN-VIVO; MULTIPOTENT PROGENITORS; CYCLE TRANSIT; PROLIFERATION; KINETICS AB Homeostasis of short-lived blood cells is dependent on rapid proliferation of immature precursors. Using a conditional histone 2B-mCherry-labeling mouse model, we characterize hematopoietic stem cell (HSC) and progenitor proliferation dynamics in steady state and following several types of induced stress. HSC proliferation following HSC transplantation into lethally irradiated mice is fundamentally different not only from native hematopoiesis but also from other stress contexts. Whereas transplantation promoted sustained, long-term proliferation of HSCs, both cytokine-induced mobilization and acute depletion of selected blood cell lineages elicited very limited recruitment of HSCs to the proliferative pool. By coupling mCherry-based analysis of proliferation history with multiplex gene expression analyses on single cells, we have found that HSCs can be stratified into four distinct subtypes. These subtypes have distinct molecular signatures and differ significantly in their reconstitution potentials, showcasing the power of tracking proliferation history when resolving functional heterogeneity of HSCs. C1 [Sawen, Petter; Lang, Stefan; Soneji, Shamit; Bryder, David] Lund Univ, Dept Lab Med, Div Mol Hematol, Fac Med, Klinikgatan 26,BMC B12, S-22184 Lund, Sweden. [Mandal, Pankaj; Rossi, Derrick J.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Bryder, David] Lund Univ, Hematolinne, S-22184 Lund, Sweden. [Lang, Stefan; Soneji, Shamit; Bryder, David] Lund Univ, StemTherapy, S-22184 Lund, Sweden. [Lang, Stefan; Soneji, Shamit; Bryder, David] Lund Univ, Lund Stem Cell Ctr, S-22184 Lund, Sweden. [Mandal, Pankaj; Rossi, Derrick J.] Boston Childrens Hosp, Div Hematol Oncol, Program Cellular & Mol Med, Boston, MA 02116 USA. RP Bryder, D (reprint author), Lund Univ, Dept Lab Med, Div Mol Hematol, Fac Med, Klinikgatan 26,BMC B12, S-22184 Lund, Sweden.; Bryder, D (reprint author), Lund Univ, Hematolinne, S-22184 Lund, Sweden.; Bryder, D (reprint author), Lund Univ, StemTherapy, S-22184 Lund, Sweden.; Bryder, D (reprint author), Lund Univ, Lund Stem Cell Ctr, S-22184 Lund, Sweden. EM david.bryder@med.lu.se FU Swedish Cancer Society; Swedish Medical Research Council; ERC [615068] FX We thank Gerd Sten and Eva Erlandsson for expert technical support. This work was supported by grants from the Swedish Cancer Society, the Swedish Medical Research Council, and ERC Consolidator grant 615068 to D.B. NR 44 TC 7 Z9 7 U1 1 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD MAR 29 PY 2016 VL 14 IS 12 BP 2809 EP 2818 DI 10.1016/j.celrep.2016.02.073 PG 10 WC Cell Biology SC Cell Biology GA DH5YX UT WOS:000372869300005 PM 26997272 ER PT J AU Yip, SSF Coroller, TP Sanford, NN Mamon, H Aerts, HJWL Berbeco, RI AF Yip, Stephen S. F. Coroller, Thibaud P. Sanford, Nina N. Mamon, Harvey Aerts, Hugo J. W. L. Berbeco, Ross I. TI Relationship between the Temporal Changes in Positron-Emission Tomography-Imaging-Based Textural Features and Pathologic Response and Survival in Esophageal Cancer Patients SO FRONTIERS IN ONCOLOGY LA English DT Article DE pathologic response; PET imaging; texture analysis; esophageal cancer; neoadjuvant therapy ID SQUAMOUS-CELL CARCINOMA; PHASE-III TRIAL; NEOADJUVANT CHEMORADIATION; TUMOR HETEROGENEITY; FDG-PET; PREOPERATIVE CHEMORADIATION; ESOPHAGOGASTRIC JUNCTION; PREDICTIVE-VALUE; THERAPY; CHEMORADIOTHERAPY AB Purpose: Although change in standardized uptake value (SUV) measures and PET-based textural features during treatment have shown promise in tumor response prediction, it is unclear which quantitative measure is the most predictive. We compared the relationship between PET-based features and pathologic response and overall survival with the SUV measures in esophageal cancer. Methods: Fifty-four esophageal cancer patients received PET/CT scans before and after chemoradiotherapy. Of these, 45 patients underwent surgery and were classified into complete, partial, and non responders to the preoperative chemoradiation. SUVmax and SUVmean, two cooccurrence matrix (Entropy and Homogeneity), two run-length matrix (RLM) (high-gray-run emphasis and Short-run high-gray-run emphasis), and two size-zone matrix (high-gray-zone emphasis and short zone high-gray emphasis) textures were computed. The relationship between the relative difference of each measure at different treatment time points and the pathologic response and overall survival was assessed using the area under the receiver-operating-characteristic curve (AUC) and Kaplan-Meier statistics, respectively. Results: All Textures, except Homogeneity, were better related to pathologic response than SUVmax and SUVmean Entropy was found to significantly distinguish non-responders from the complete (AUG = 0.79, p = 1.7 x 10(-4)) and partial (AUC = 0.71, p = 0.01) responders. Non responders can also be significantly differentiated from partial and complete responders by the change in the run-length and size-zone matrix textures (AUC = 0.71-0.76, p <= 0.02). Homogeneity, SUVmax and SUVmean, failed to differentiate between any of the responders (AUG = 0.50-0.57, p >= 0.46). However, none of the measures were found to significantly distinguish between complete and partial responders with AUC <0.60 (p = 0.37). Median Entropy and RLM textures significantly discriminated patients with good and poor survival (log-rank p < 0.02), while all other textures and survival were poorly related (log-rank p > 0.25). Conclusion: For the patients studied, temporal changes in Entropy and all RLM were better correlated with pathological response and survival than the SUV measures. The hypothesis that these metrics can be used as clinical predictors of better patient outcomes will be tested in a larger patient dataset in the future. C1 [Yip, Stephen S. F.; Coroller, Thibaud P.; Sanford, Nina N.; Mamon, Harvey; Aerts, Hugo J. W. L.; Berbeco, Ross I.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol,Brigham & Womens Hosp, 44 Binney St, Boston, MA 02115 USA. [Aerts, Hugo J. W. L.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiol, 44 Binney St, Boston, MA 02115 USA. RP Yip, SSF (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol,Brigham & Womens Hosp, 44 Binney St, Boston, MA 02115 USA. EM syip@lroc.harvard.edu RI Aerts, Hugo/P-6350-2015; OI Aerts, Hugo/0000-0002-2122-2003; Coroller, Thibaud/0000-0001-7662-8724 NR 64 TC 4 Z9 4 U1 2 U2 3 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 2234-943X J9 FRONT ONCOL JI Front. Oncol. PD MAR 29 PY 2016 VL 6 AR 72 DI 10.3389/fonc.2016.00072 PG 10 WC Oncology SC Oncology GA DI0PK UT WOS:000373199100001 PM 27066454 ER PT J AU Malik, R Traylor, M Pulit, SL Bevan, S Hopewell, JC Holliday, EG Zhao, W Abrantes, P Amouyel, P Attia, JR Battey, TWK Berger, K Boncoraglio, GB Chauhan, G Cheng, YC Chen, WM Clarke, R Cotlarciuc, I Debette, S Falcone, GJ Ferro, JM Gamble, DM Ilinca, A Kittner, SJ Kourkoulis, CE Lemmens, R Levi, CR Lichtner, P Lindgren, A Liu, JM Meschia, JF Mitchell, BD Oliveira, SA Pera, J Reiner, AP Rothwell, PM Sharma, P Slowik, A Sudlow, CLM Tatlisumak, T Thijs, V Vicente, AM Woo, D Seshadri, S Saleheen, D Rosand, J Markus, HS Worrall, BB Dichgans, M AF Malik, Rainer Traylor, Matthew Pulit, Sara L. Bevan, Steve Hopewell, Jemma C. Holliday, Elizabeth G. Zhao, Wei Abrantes, Patricia Amouyel, Philippe Attia, John R. Battey, Thomas W. K. Berger, Klaus Boncoraglio, Giorgio B. Chauhan, Ganesh Cheng, Yu-Ching Chen, Wei-Min Clarke, Robert Cotlarciuc, Ioana Debette, Stephanie Falcone, Guido J. Ferro, Jose M. Gamble, Dale M. Ilinca, Andreea Kittner, Steven J. Kourkoulis, Christina E. Lemmens, Robin Levi, Christopher R. Lichtner, Peter Lindgren, Arne Liu, Jingmin Meschia, James F. Mitchell, Braxton D. Oliveira, Sofia A. Pera, Joana Reiner, Alex P. Rothwell, Peter M. Sharma, Pankaj Slowik, Agnieszka Sudlow, Cathie L. M. Tatlisumak, Turgut Thijs, Vincent Vicente, Astrid M. Woo, Daniel Seshadri, Sudha Saleheen, Danish Rosand, Jonathan Markus, Hugh S. Worrall, Bradford B. Dichgans, Martin CA ISGC Anal Grp METASTROKE Collaboration Wellcome Trust Case Control Consor NINDS Stroke Genetics Network SiGN TI Low-frequency and common genetic variation in ischemic stroke The METASTROKE collaboration SO NEUROLOGY LA English DT Article ID GENOME-WIDE ASSOCIATION; NONVALVULAR ATRIAL-FIBRILLATION; SOLUBLE CD40 LIGAND; NITRIC-OXIDE; RISK-FACTORS; ATHEROSCLEROTIC STROKE; MYOCARDIAL-INFARCTION; METAANALYSIS; VARIANTS; SEQUENCE AB Objective: To investigate the influence of common and low-frequency genetic variants on the risk of ischemic stroke (all IS) and etiologic stroke subtypes. Methods: We meta-analyzed 12 individual genome-wide association studies comprising 10,307 cases and 19,326 controls imputed to the 1000 Genomes (1 KG) phase I reference panel. We selected variants showing the highest degree of association (p < 1E-5) in the discovery phase for replication in Caucasian (13,435 cases and 29,269 controls) and South Asian (2,385 cases and 5,193 controls) samples followed by a transethnic meta-analysis. We further investigated the p value distribution for different bins of allele frequencies for all IS and stroke subtypes. Results: We showed genome-wide significance for 4 loci: ABO for all IS, HDAC9 for large vessel disease (LVD), and both PITX2 and ZFHX3 for cardioembolic stroke (CE). We further refined the association peaks for ABO and PITX2. Analyzing different allele frequency bins, we showed significant enrichment in low-frequency variants (allele frequency <5%) for both LVD and small vessel disease, and an enrichment of higher frequency variants (allele frequency 10% and 30%) for CE (all p < 1E-5). Conclusions: Our findings suggest that the missing heritability in IS subtypes can in part be attributed to low-frequency and rare variants. Larger sample sizes are needed to identify the variants associated with all IS and stroke subtypes. C1 [Malik, Rainer; Dichgans, Martin] Univ Munich, Klinikum Univ Munchen, Inst Stroke & Dementia Res, Marchioninistr 15, D-80539 Munich, Germany. [Traylor, Matthew; Bevan, Steve; Markus, Hugh S.] Univ Cambridge, Dept Clin Neurosci, Cambridge CB2 1TN, England. [Pulit, Sara L.] Univ Med Ctr Utrecht, Dept Med Genet, Ctr Mol Med, Utrecht, Netherlands. [Hopewell, Jemma C.; Clarke, Robert] Univ Oxford, Nuffield Dept Populat Hlth, CTSU, Oxford OX1 2JD, England. [Holliday, Elizabeth G.; Attia, John R.] Hunter Med Res Inst, Publ Hlth Res Program, Newcastle, NSW, Australia. [Zhao, Wei; Saleheen, Danish] Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA. [Abrantes, Patricia; Oliveira, Sofia A.] Univ Lisbon, Inst Mol Med, Fac Med, P-1699 Lisbon, Portugal. [Abrantes, Patricia; Oliveira, Sofia A.; Vicente, Astrid M.] Inst Gulbenkian Ciencias, Oeiras, Portugal. [Amouyel, Philippe] Pasteur Inst Lille, INSERM, U1167, Lille, France. [Amouyel, Philippe] Univ Lille Nord France, Dept Publ Hlth, Lille Univ Hosp, Lille, France. [Battey, Thomas W. K.; Falcone, Guido J.; Kourkoulis, Christina E.; Rosand, Jonathan] Massachusetts Gen Hosp, Div Neurocrit Care & Emergency Neurol, Boston, MA 02114 USA. [Battey, Thomas W. K.; Falcone, Guido J.; Kourkoulis, Christina E.; Rosand, Jonathan] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Battey, Thomas W. K.; Falcone, Guido J.; Kourkoulis, Christina E.; Rosand, Jonathan] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Falcone, Guido J.] Massachusetts Gen Hosp, J Philip Kistler Stroke Res Ctr, Boston, MA 02114 USA. [Berger, Klaus] Univ Munster, Inst Epidemiol & Social Med, Munster, Germany. [Boncoraglio, Giorgio B.] Fdn IRCCS Ist Neurolog Carlo Besta, Dept Cardiovasc Dis, Milan, Italy. [Chauhan, Ganesh; Debette, Stephanie] INSERM, Res Ctr Epidemiol & Biostat, Team Neuroepidemiol, U897, Bordeaux, France. [Chauhan, Ganesh; Debette, Stephanie] Univ Bordeaux, Bordeaux, France. [Kittner, Steven J.] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Chen, Wei-Min; Worrall, Bradford B.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. [Chen, Wei-Min; Worrall, Bradford B.] Univ Virginia, Cardiovasc Res Ctr, Charlottesville, VA USA. [Cotlarciuc, Ioana; Sharma, Pankaj] Univ London, ICR2UL, Inst Cardiovasc Res Royal Holloway, London WC1E 7HU, England. [Falcone, Guido J.; Kourkoulis, Christina E.; Rosand, Jonathan] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Meschia, James F.] Hosp Santa Maria, Dept Neurosci, Neurol, Lisbon, Portugal. [Gamble, Dale M.; Meschia, James F.] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. [Ilinca, Andreea; Lindgren, Arne] Lund Univ, Neurol, Dept Clin Sci Lund, S-22100 Lund, Sweden. [Kittner, Steven J.] Vet Adm Med Ctr, Dept Neurol, Baltimore, MD 21218 USA. [Lemmens, Robin; Thijs, Vincent] Univ Leuven, KU Leuven, Dept Neurosci, Expt Neurol, Louvain, Belgium. [Lemmens, Robin; Thijs, Vincent] Univ Leuven, KU Leuven, Leuven Res Inst Neurosc & Dis LIND, Louvain, Belgium. [Lemmens, Robin; Thijs, Vincent] Vesalius Res Ctr, VIB, Neurobiol Lab, Leuven, Belgium. [Levi, Christopher R.] Hunter Med Res Inst, Brain & Mental Hlth Program, Newcastle, NSW, Australia. [Lichtner, Peter] Helmholtz Zentrum Munchen, Munich, Germany. [Lichtner, Peter] Tech Univ Munich, D-80290 Munich, Germany. [Liu, Jingmin; Reiner, Alex P.] Inst Human Genet & Anthropol, Munich, Germany. [Liu, Jingmin; Reiner, Alex P.] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Pera, Joana; Slowik, Agnieszka] Jagiellonian Univ, Coll Med, Dept Neurol, Krakow, Poland. [Rothwell, Peter M.] Univ Oxford, Nuffield Dept Clin Neurosci, Stroke Prevent Res Unit, Oxford OX1 2JD, England. [Sharma, Pankaj] Ashford & St Peters NHS Fdn Trust, Surrey, England. [Sudlow, Cathie L. M.] Univ Edinburgh, Div Clin Neurosci, Edinburgh EH8 9YL, Midlothian, Scotland. [Thijs, Vincent] Austin Hlth, Dept Neurol, Heidelberg, Vic, Australia. [Thijs, Vincent] Univ Melbourne, Florey Inst Neurosci & Mental Hlth, Heidelberg, Vic, Australia. [Tatlisumak, Turgut] Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Gothenburg, Sweden. [Tatlisumak, Turgut] Sahlgrens Univ Hosp, Dept Neurol, Gothenburg, Sweden. [Vicente, Astrid M.] Inst Nacl Saude Dr Ricardo Jorge INSA, Dept Promocao Saude Doencas Cron DPSDC, Lisbon, Portugal. [Vicente, Astrid M.] Ctr Biodivers Funct & Integrat Genom BIOFIG, Lisbon, Portugal. [Woo, Daniel] Univ Cincinnati, Coll Med, Dept Neurol & Rehabil, Cincinnati, OH 45221 USA. [Seshadri, Sudha] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Worrall, Bradford B.] Univ Virginia Hlth Syst, Dept Neurol, Charlottesville, VA USA. [Worrall, Bradford B.] Univ Virginia Hlth Syst, Dept Publ Hlth Sci, Charlottesville, VA USA. [Dichgans, Martin] Munich Cluster Syst Neurol SyNergy, Munich, Germany. RP Dichgans, M (reprint author), Univ Munich, Klinikum Univ Munchen, Inst Stroke & Dementia Res, Marchioninistr 15, D-80539 Munich, Germany. EM martin.dichgans@med.uni-muenchen.de RI Falcone, Guido/L-2287-2016; Boncoraglio, Giorgio/B-8647-2011; Thijs, Vincent/C-3647-2009; OI Falcone, Guido/0000-0002-6407-0302; Thijs, Vincent/0000-0002-6614-8417; Traylor, Matthew/0000-0001-6624-8621 FU Australian National and Medical Health Research Council (NHMRC) [569257]; Australian National Heart Foundation (NHF) [G 04S 1623]; University of Newcastle; Gladys M. Brawn Fellowship scheme; Vincent Fairfax Family Foundation in Australia; National Stroke Foundation of Australia [100071]; Senior Fellowship from the Department of Health (UK); UK-India Education Research Institutive (UKIERI) from the British Council; NIH Genes; Environment and Health Initiative (GEI) [U01 HG004436]; GENEVA consortium under GEI; Mid-Atlantic Nutrition and Obesity Research Center [P30 DK072488]; Office of Research and Development, Medical Research Service; Baltimore Geriatrics Research, Education, and Clinical Center of the Department of Veterans Affairs; Johns Hopkins University Center for Inherited Disease Research (CIDR); NIH [HHSN268200782096C]; GENEVA Coordinating Center [U01 HG 004446]; Division of Adult and Community Health; Centers for Disease Control and Prevention; NINDS; NIH Office of Research on Women's Health [R01 NS45012, U01 NS06920801]; Heart Protection Study (HPS) [ISRCTN48489393]; UK Medical Research Council (MRC); British Heart Foundation, Merck and Co.; Roche Vitamins Ltd; Merck and Co; British Heart Foundation [FS/14/55/30806]; NIH-NINDS Human Genetics Resource Center DNA and Cell Line Repository; Intramural Research Program of the NIA, NIH [Z01 AG-000015-50, Z01 AG-000954-06]; NIH-NINDS grant [R01 NS-42733, R01 NS39987]; NINDS [U01 NS069208]; American Heart Association/Bugher Foundation Centers for Stroke Prevention Research [0775010N]; NIH and NHLBI's STAMPEED genomics research program [R01 HL087676]; National Center for Research Resources; National Center for Research resources [U54 RR020278]; Italian Ministry of Health [RC 2007/LR6, RC 2008/LR6, RC 2009/LR8, RC 2010/LR8, FP6 LSHM-CT2007- 037273]; Wellcome Trust; Wellcome Trust Case Control Consortium 2 project [085475/B/08/Z, 085475/Z/08/Z, WT084724MA]; MRC; Dunhill Medical Trust; National Institute of Health Research (NIHR); NIHR Biomedical Research Centre, Oxford; Binks Trust; Scottish Funding Council Brain Imaging Research Centre; Division of Clinical Neurosciences; University of Edinburgh; Wellcome Trust Clinical Research Facility; SINAPSE (Scottish Imaging Network-A Platform for Scientific Excellence); Scottish Funding Council and the Chief Scientist Office; Vascular Dementia Research Foundation; BHF Centre of Research Excellence in Oxford; Wellcome Trust core award [090532/Z/09/Z]; Department of Neurology; University Hospital Leuven; Fundamental Clinical Investigatorships from FWO; Swedish Research Council [K2007-61X-20378-01-3, K2010-61X-20378-04-3]; Swedish Heart and Lung Foundation; Skane University Hospital, Region Skane; Freemasons Lodge of Instruction EOS in Lund, King Gustaf V and Queen Victoria's Foundation; Lund University; Swedish Stroke Association; German Federal Ministry of Education and Research [01GI9909/3]; Institute of Epidemiology and Social Medicine University of Muenster; German Migraine and Headache Society (DMKG); Almirall; Astra Zeneca; Berlin Chemie; Boehringer; Boots Health Care; Glaxo-Smith-Kline; Janssen Cilag; McNeil Pharma; MSD Sharp Dohme; Jagiellonian University, Krakow, Poland [K/ZDS/002848]; United States National Human Genome Research Institute (NHGRI) [U01 HG005160]; NIHU [01 HG005157]; investigator-initiated research [NS34447]; United States Public Health Service; Bethesda; Maryland; United States National Center for Biotechnology Information; US National Library of Medicine; WHI-GARNET through NHGRI GARNET [U01 HG005152]; GARNET Coordinating Center [U01 HG005157]; NIH Genes, Environment, and Health Initiative [GEI; U01 HG004424]; National Institute of Neurological Disorders and Stroke (NINDS) [U01 NS069208]; Johns Hopkins University [HHSN268200782096C]; German Federal Ministry of Education and Research (BMBF); FP7 European Union project; DFG as part of the CRC [1123 (B3)]; Corona Foundation; Fondation Leducq (Transatlantic Network of Excellence on the Pathogenesis of Small Vessel Disease of the Brain); Stroke Association; [PTDC/SAU-GMG/64426/2006] FX This research was funded by grants from the Australian National and Medical Health Research Council (NHMRC project grant ID: 569257), the Australian National Heart Foundation (NHF project grant ID: G 04S 1623), the University of Newcastle, the Gladys M. Brawn Fellowship scheme, and the Vincent Fairfax Family Foundation in Australia. Elizabeth G. Holliday was supported by a Fellowship from the National Heart Foundation and National Stroke Foundation of Australia (ID: 100071). Bio-Repository of DNA in Stroke (BRAINS) is partly funded by a Senior Fellowship from the Department of Health (UK) to P. Sharma, the Henry Smith Charity, and the UK-India Education Research Institutive (UKIERI) from the British Council. Genetics of Early Onset Stroke (GEOS) Study, Baltimore, Maryland, USA, was supported by the NIH Genes, Environment and Health Initiative (GEI) grant U01 HG004436, as part of the GENEVA consortium under GEI, with additional support provided by the Mid-Atlantic Nutrition and Obesity Research Center (P30 DK072488), the Office of Research and Development, Medical Research Service, and the Baltimore Geriatrics Research, Education, and Clinical Center of the Department of Veterans Affairs. Genotyping services were provided by the Johns Hopkins University Center for Inherited Disease Research (CIDR), which is fully funded through a federal contract from the NIH to the Johns Hopkins University (contract number HHSN268200782096C). Assistance with data cleaning was provided by the GENEVA Coordinating Center (U01 HG 004446; PI Bruce S. Weir). Study recruitment and assembly of datasets were supported by a cooperative agreement with the Division of Adult and Community Health, Centers for Disease Control and Prevention, and by grants from NINDS and the NIH Office of Research on Women's Health (R01 NS45012, U01 NS06920801). Heart Protection Study (HPS) (ISRCTN48489393) was supported by the UK Medical Research Council (MRC), British Heart Foundation, Merck and Co. (manufacturers of simvastatin), and Roche Vitamins Ltd. (manufacturers of vitamins). Genotyping was supported by a grant to Oxford University and CNG from Merck and Co. Jemma C. Hopewell acknowledges support from the British Heart Foundation (FS/14/55/30806). Ischemic Stroke Genetics Study (ISGS)/Siblings With Ischemic Stroke Study (SWISS) was supported in part by the Intramural Research Program of the NIA, NIH project Z01 AG-000954-06. ISGS/SWISS used samples and clinical data from the NIH-NINDS Human Genetics Resource Center DNA and Cell Line Repository (http://ccr.coriell.org/ninds), human subjects protocol numbers 2003-081 and 2004-147. ISGS/SWISS used stroke-free participants from the Baltimore Longitudinal Study of Aging (BLSA) as controls. The inclusion of BLSA samples was supported in part by the Intramural Research Program of the NIA, NIH project Z01 AG-000015-50, human subjects protocol number 2003-078. The ISGS study was funded by NIH-NINDS grant R01 NS-42733 (J.F. Meschia). The SWISS study was funded by NIH-NINDS grant R01 NS39987 (J.F. Meschia). This study used the high-performance computational capabilities of the Biowulf Linux cluster at the NIH (http://hpc.nih.gov). MGH Genes Affecting Stroke Risk and Outcome Study (MGH-GASROS) was supported by NINDS (U01 NS069208), the American Heart Association/Bugher Foundation Centers for Stroke Prevention Research 0775010N, the NIH and NHLBI's STAMPEED genomics research program (R01 HL087676), and a grant from the National Center for Research Resources.; The Broad Institute Center for Genotyping and Analysis is supported by grant U54 RR020278 from the National Center for Research resources. Milano-Besta Stroke Register Collection and genotyping of the Milan cases within CEDIR were supported by annual research funding of the Italian Ministry of Health (grant numbers: RC 2007/LR6, RC 2008/LR6, RC 2009/LR8, RC 2010/LR8), and FP6 LSHM-CT2007- 037273 for the PROCARDIS control samples. Wellcome Trust Case-Control Consortium 2 (WTCCC2) was principally funded by the Wellcome Trust, as part of the Wellcome Trust Case Control Consortium 2 project (085475/B/08/Z and 085475/Z/08/Z and WT084724MA). The Stroke Association provided additional support for collection of some of the St George's, London cases. The Oxford cases were collected as part of the Oxford Vascular Study, which is funded by the MRC, Stroke Association, Dunhill Medical Trust, National Institute of Health Research (NIHR), and the NIHR Biomedical Research Centre, Oxford. The Edinburgh Stroke Study was supported by the Wellcome Trust (clinician scientist award to C. Sudlow) and the Binks Trust. Sample processing occurred in the Genetics Core Laboratory of the Wellcome Trust Clinical Research Facility, Western General Hospital, Edinburgh. Much of the neuroimaging occurred in the Scottish Funding Council Brain Imaging Research Centre (www.sbirc.ed.ac.uk), Division of Clinical Neurosciences, University of Edinburgh, a core area of the Wellcome Trust Clinical Research Facility and part of the SINAPSE (Scottish Imaging Network-A Platform for Scientific Excellence) collaboration (www.sinapse.ac.uk), funded by the Scottish Funding Council and the Chief Scientist Office. Collection of the Munich cases and data analysis was supported by the Vascular Dementia Research Foundation. M. Farrall and A. Helgadottir acknowledge support from the BHF Centre of Research Excellence in Oxford and the Wellcome Trust core award (090532/Z/09/Z). Leuven Stroke Study is funded by personal research funds from the Department of Neurology, University Hospital Leuven, Belgium. V. Thijs and R. Lemmens are supported by Fundamental Clinical Investigatorships from FWO. Flanders Lund Stroke Register (LSR) was supported by the Swedish Research Council (K2007-61X-20378-01-3, K2010-61X-20378-04-3), the Swedish Heart and Lung Foundation, Skane University Hospital, Region Skane, the Freemasons Lodge of Instruction EOS in Lund, King Gustaf V and Queen Victoria's Foundation, Lund University, and the Swedish Stroke Association. DNA extraction and preparation for LSR was performed by the SWEGENE Resource Center for Profiling Polygenic Disease, Skane University Hospital, Malmo, Sweden. Biobank services were provided by Region Skane Competence Centre (RSKC Malmo), Skane University Hospital, Malmo, Sweden, and Biobank, Labmedicin, Skane University and Regional Laboratories Region Skane, Sweden. Munster (Westphalian Stroke Cases and Controls from the Dortmund Health Study, Germany): Case ascertainment in the Westphalian Stroke Register was part of the German Competence Net Stroke, supported by the German Federal Ministry of Education and Research (01GI9909/3). Blood collection in the Dortmund Health Study was done through funds from the Institute of Epidemiology and Social Medicine University of Muenster.; The collection of sociodemographic and clinical data in the Dortmund Health Study was supported by the German Migraine and Headache Society (DMKG) and by unrestricted grants of equal share from Almirall, Astra Zeneca, Berlin Chemie, Boehringer, Boots Health Care, Glaxo-Smith-Kline, Janssen Cilag, McNeil Pharma, MSD Sharp & Dohme, and Pfizer to the University of Muenster. Portugal: S.A.O., J.M.F., and A.M.V. thank the Portuguese study participants, the genotyping unit at the Instituto Gulbenkian de Ciencia, and the Portuguese study neurologists and nurses for their contributions. This work was supported by the PTDC/SAU-GMG/64426/2006 grant, a Cilencia 2008 contract (S.A.O.), doctoral fellowships, and an Investigator-FCT contract (S.A.O.) from the Portuguese Fundacaao para a Ciencia e a Tecnologia to the Johns Hopkins University. Assistance with data cleaning was provided by the GARNET Coordinating Center. Poland: The study was supported by a grant from the Jagiellonian University, Krakow, Poland: K/ZDS/002848. VISP: The GWAS component of the VISP study was supported by the United States National Human Genome Research Institute (NHGRI), grant U01 HG005160 (PI Michele Sale and Bradford Worrall), as part of the Genomics and Randomized Trials Network (GARNET). Genotyping services were provided by the Johns Hopkins University Center for Inherited Disease Research (CIDR), which is fully funded through a federal contract from the NIH (U01 HG005157; PI Bruce S. Weir). Study recruitment and collection of datasets for the VISP clinical trial were supported by an investigator-initiated research grant (R01 NS34447; PI James Toole) from the United States Public Health Service, NINDS, Bethesda, Maryland. Control data were obtained through the database of genotypes and phenotypes (dbGAP) maintained and supported by the United States National Center for Biotechnology Information, US National Library of Medicine. WHI Funding support for WHI-GARNET was provided through the NHGRI GARNET (grant number U01 HG005152). Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GARNET Coordinating Center (U01 HG005157). Funding support for genotyping, which was performed at the Broad Institute of MIT and Harvard, was provided by the NIH Genes, Environment, and Health Initiative (GEI; U01 HG004424). The Stroke Genetics Network (SiGN) study was funded by a cooperative agreement grant from the National Institute of Neurological Disorders and Stroke (NINDS) U01 NS069208. Genotyping services were provided by the Johns Hopkins University Center for Inherited Disease Research (CIDR), which is fully funded through a federal contract from the NIH to the Johns Hopkins University (contract no. HHSN268200782096C). The Biostatistics Department Genetics Coordinating Center at the University of Washington, Seattle, provided more extensive quality control of the genotype data through a subcontract with CIDR. Additional support to the Administrative Core of SiGN was provided by the Dean's Office, University of Maryland School of Medicine. This work was supported by grants received from the German Federal Ministry of Education and Research (BMBF) in the context of the e: Med program (e:AtheroSysMed), the FP7 European Union project CVgenes@target (261123), the DFG as part of the CRC 1123 (B3), the Corona Foundation, and the Fondation Leducq (Transatlantic Network of Excellence on the Pathogenesis of Small Vessel Disease of the Brain). NR 40 TC 8 Z9 8 U1 3 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD MAR 29 PY 2016 VL 86 IS 13 BP 1217 EP 1226 DI 10.1212/WNL.0000000000002528 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA DH5SV UT WOS:000372853000008 PM 26935894 ER PT J AU Yien, YY Paw, BH AF Yien, Yvette Y. Paw, Barry H. TI A role for iron deficiency in dopaminergic neurodegeneration SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID LACKING TRANSFERRIN RECEPTOR; NEURODEVELOPMENT; ASSIMILATION; ACCUMULATION; HOMEOSTASIS; HIPPOCAMPUS; METABOLISM; EXPORTER; MEMORY C1 [Yien, Yvette Y.; Paw, Barry H.] Brigham & Womens Hosp, Dept Med, Div Hematol, 75 Francis St, Boston, MA 02115 USA. [Yien, Yvette Y.; Paw, Barry H.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Yien, Yvette Y.; Paw, Barry H.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Paw, Barry H.] Boston Childrens Hosp, Dept Med, Div Hematol Oncol, Boston, MA 02115 USA. [Paw, Barry H.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. RP Paw, BH (reprint author), Brigham & Womens Hosp, Dept Med, Div Hematol, 75 Francis St, Boston, MA 02115 USA.; Paw, BH (reprint author), Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA.; Paw, BH (reprint author), Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA.; Paw, BH (reprint author), Boston Childrens Hosp, Dept Med, Div Hematol Oncol, Boston, MA 02115 USA.; Paw, BH (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. EM bpaw@rics.bwh.harvard.edu FU NHLBI NIH HHS [P01 HL032262]; NIDDK NIH HHS [F32 DK098866, K01 DK106156, R01 DK070838] NR 27 TC 0 Z9 0 U1 1 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 29 PY 2016 VL 113 IS 13 BP 3417 EP 3418 DI 10.1073/pnas.1601976113 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH6BQ UT WOS:000372876400029 PM 26984501 ER PT J AU Arsalan, M Szerlip, M Vemulapalli, S Holper, EM Arnold, SV Li, ZK DiMaio, MJ Rumsfeld, JS Brown, DL Mack, MJ AF Arsalan, Mani Szerlip, Molly Vemulapalli, Sreekanth Holper, Elizabeth M. Arnold, Suzanne V. Li, Zhuokai DiMaio, Michael J. Rumsfeld, John S. Brown, David L. Mack, Michael J. TI Should Transcatheter Aortic Valve Replacement Be Performed in Nonagenarians? Insights From the STS/ACC TVT Registry SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE centenarians; elderly; quality of life; TAVI; TAVR; transcatheter aortic valve implantation ID CITY CARDIOMYOPATHY QUESTIONNAIRE; END-POINT DEFINITIONS; CARDIAC-SURGERY; IMPLANTATION; STENOSIS; OUTCOMES; MANAGEMENT; VERSION; RISK; SAFE AB BACKGROUND Data demonstrating the outcome of transcatheter aortic valve replacement (TAVR) in the very elderly patients are limited, as they often represent only a small proportion of the trial populations. OBJECTIVES The purpose of this study was to compare the outcomes of nonagenarians to younger patients undergoing TAVR in current practice. METHODS We analyzed data from the Society of Thoracic Surgeons/American College of Cardiology TVT (Transcatheter Valve Therapy) Registry. Outcomes at 30 days and 1 year were compared between patients >= 90 years versus <90 years of age using cumulative incidence curves. Quality of life was assessed with the 12-item Kansas City Cardiomyopathy Questionnaire. RESULTS Between November 2011 and September 2014, 24,025 patients underwent TAVR in 329 participating hospitals, of which 3,773 (15.7%) were age >= 90 years. The 30-day and 1-year mortality rates were significantly higher among nonagenarians (age >= 90 years vs. <90 years: 30-day: 8.8% vs. 5.9%; p < 0.001; 1 year: 24.8% vs. 22.0%; p < 0.001, absolute risk: 2.8%, relative risk: 12.7%). However, nonagenarians had a higher mean Society of Thoracic Surgeons Predicted Risk of Operative Mortality score (10.9% vs. 8.1%; p < 0.001) and, therefore, had similar ratios of observed to expected rates of 30-day death (age >= 90 years vs. <90 years: 0.81, 95% confidence interval: 0.70 to 0.92 vs. 0.72, 95% confidence interval: 0.67 to 0.78). There were no differences in the rates of stroke, aortic valve reintervention, or myocardial infarction at 30 days or 1 year. Nonagenarians had lower (worse) median Kansas City Cardiomyopathy Questionnaire scores at 30 days; however, there was no significant difference at 1 year. CONCLUSIONS In current U.S. clinical practice, approximately 16% of patients undergoing TAVR are >= 90 years of age. Although 30-day and 1-year mortality rates were statistically higher compared with younger patients undergoing TAVR, the absolute and relative differences were clinically modest. TAVR also improves quality of life to the same degree in nonagenarians as in younger patients. These data support safety and efficacy of TAVR in select very elderly patients. (C) 2016 by the American College of Cardiology Foundation. C1 [Arsalan, Mani; Szerlip, Molly; Holper, Elizabeth M.; DiMaio, Michael J.; Brown, David L.; Mack, Michael J.] Heart Hosp Baylor Plano, 1100 Allied Dr, Plano, TX 75093 USA. [Arsalan, Mani] Kerckhoff Heart Ctr, Bad Nauheim, Germany. [Vemulapalli, Sreekanth; Li, Zhuokai] Duke Clin Res Inst, Durham, NC USA. [Arnold, Suzanne V.] St Lukes Mid Amer Heart Inst, Kansas City, MO USA. [Rumsfeld, John S.] Denver VA Med Ctr, Denver, CO USA. RP Mack, MJ (reprint author), Heart Hosp Baylor Plano, 1100 Allied Dr, Plano, TX 75093 USA. EM MichaeMa@baylorhealth.edu RI Li, Zhuokai/F-4681-2017 FU American College of Cardiology's National Cardiovascular Data Registry (NCDR); Abbott Vascular; Boston Scientific; American College of Cardiology FX The Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy (STS/ACC TVT) Registry is an initiative of the Society of Thoracic Surgeons and the American College of Cardiology. This research was supported by the American College of Cardiology's National Cardiovascular Data Registry (NCDR). The views expressed in this paper represent those of the author(s) and do not necessarily represent the official views of the NCDR or its associated professional societies identified at CVQuality.ACC.org/NCDR. Dr. Szerlip has served as a speaker for Edwards Lifesciences. Dr. Vemulapalli has received research grants from Abbott Vascular, Boston Scientific, and the American College of Cardiology. Dr. Holper has been a consultant to Boston Scientific and Asahi Intecc. Dr. Rumsfeld is Chief Science Officer of the NCDR. Dr. Mack is an uncompensated member of the executive committee of the PARTNER (Placement of Aortic Transcatheter Valve) trial of Edwards Lifesciences. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 25 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 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 29 PY 2016 VL 67 IS 12 BP 1387 EP 1395 DI 10.1016/j.jacc.2016.01.055 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DG9NA UT WOS:000372408500001 PM 27012397 ER PT J AU Teerlink, JR Felker, GM McMurray, JJV Ponikowski, P Metra, M Filippatos, GS Ezekowitz, JA Dickstein, K Cleland, JGF Kim, JB Lei, L Knusel, B Wolff, AA Malik, FI Wasserman, SM AF Teerlink, John R. Felker, G. Michael McMurray, John J. V. Ponikowski, Piotr Metra, Marco Filippatos, Gerasimos S. Ezekowitz, Justin A. Dickstein, Kenneth Cleland, John G. F. Kim, Jae B. Lei, Lei Knusel, Beat Wolff, Andrew A. Malik, Fady I. Wasserman, Scott M. CA ATOMIC-AHF Investigators TI Acute Treatment With Omecamtiv Mecarbil to Increase Contractility in Acute Heart Failure The ATOMIC-AHF Study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE arrhythmia; cardiac myosin activator; dyspnea; inotrope ID CARDIAC MYOSIN ACTIVATOR; MYOCARDIAL OXYGEN-CONSUMPTION; TASK-FORCE; CONTROLLED TRIAL; ATPASE ACTIVITY; RELAX-AHF; ASCEND-HF; ASSOCIATION; OUTCOMES; HOSPITALIZATION AB BACKGROUND Omecamtiv mecarbil (OM) is a selective cardiac myosin activator that increases myocardial function in healthy volunteers and in patients with chronic heart failure. OBJECTIVES This study evaluated the pharmacokinetics, pharmacodynamics, tolerability, safety, and efficacy of OM in patients with acute heart failure (AHF). METHODS Patients admitted for AHF with left ventricular ejection fraction <= 40%, dyspnea, and elevated plasma concentrations of natriuretic peptides were randomized to receive a double-blind, 48-h intravenous infusion of placebo or OM in 3 sequential, escalating-dose cohorts. RESULTS In 606 patients, OM did not improve the primary endpoint of dyspnea relief (3 OM dose groups and pooled placebo: placebo, 41%; OM cohort 1, 42%; cohort 2, 47%; cohort 3, 51%; p = 0.33) or any of the secondary outcomes studied. In supplemental, pre-specified analyses, OM resulted in greater dyspnea relief at 48 h (placebo, 37% vs. OM, 51%; p = 0.034) and through 5 days (p = 0.038) in the high-dose cohort. OM exerted plasma concentration-related increases in left ventricular systolic ejection time (p < 0.0001) and decreases in end-systolic dimension (p < 0.05). The adverse event profile and tolerability of OM were similar to those of placebo, without increases in ventricular or supraventricular tachyarrhythmias. Plasma troponin concentrations were higher in OM-treated patients compared with placebo (median difference at 48 h, 0.004 ng/ml), but with no obvious relationship with OM concentration (p = 0.95). CONCLUSIONS In patients with AHF, intravenous OM did not meet the primary endpoint of dyspnea improvement, but it was generally well tolerated, it increased systolic ejection time, and it may have improved dyspnea in the high-dose group. (Acute Treatment with Omecamtiv Mecarbil to Increase Contractility in Acute Heart Failure [ATOMIC-AHF]; NCT01300013) (C) 2016 by the American College of Cardiology Foundation. C1 [Teerlink, John R.] Univ Calif San Francisco, Sch Med, San Francisco, CA USA. [Teerlink, John R.] San Francisco VA Med Ctr, Sect Cardiol, San Francisco, CA 94121 USA. [Felker, G. Michael] Duke Univ, Sch Med, Div Cardiol, Durham, NC USA. [McMurray, John J. V.] Univ Glasgow, British Heart Fdn Cardiovasc Res Ctr, Glasgow, Lanark, Scotland. [Ponikowski, Piotr] Med Univ, Clin Mil Hosp, Dept Heart Dis, Wroclaw, Poland. [Metra, Marco] Univ Brescia, Div Cardiol, Dept Med & Surg Specialties Radiol Sci & Publ Hlt, Brescia, Italy. [Filippatos, Gerasimos S.] Univ Athens, Hosp Attikon, Dept Cardiol, Athens, Greece. [Ezekowitz, Justin A.] Univ Alberta, Canadian VIGOUR Ctr, Edmonton, AB, Canada. [Dickstein, Kenneth] Univ Bergen, Cardiol Div, Bergen, Norway. [Dickstein, Kenneth] Stavanger Univ Hosp, Cardiol Div, Stavanger, Norway. [Cleland, John G. F.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Royal Brompton Hosp, London, England. [Cleland, John G. F.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Harefield Hosp, London, England. [Kim, Jae B.; Lei, Lei; Knusel, Beat; Wasserman, Scott M.] Amgen Inc, Thousand Oaks, CA 91320 USA. [Wolff, Andrew A.; Malik, Fady I.] Cytokinetics Inc, San Francisco, CA USA. RP Teerlink, JR (reprint author), San Francisco VA Med Ctr, Cardiol, 111C,4150 Clement St, San Francisco, CA 94121 USA. EM john.teerlink@ucsf.edu RI Ponikowski, Piotr/O-6454-2015; OI Ponikowski, Piotr/0000-0002-3391-7064; mcmurray, john/0000-0002-6317-3975 FU Amgen, Inc.; Cytokinetics, Inc.; Amgen; Cytokinetics; Mast Therapeutics; Novartis; Sorbent; Trevena; Roche Diagnostics; Otsuka; National Heart, Lung, and Blood Institute; Singulex; Bayer; Servier; Cardiorentis; Vifor; European Union; Abbott; AstraZeneca; Biotronik; Boston Scientific; Johnson Johnson; Medtronic; Merck; Pfizer; Sanofi; Sorin; St. Jude Medical; University of Bergen; Alere; Philips; StealthPeptides FX The ATOMIC-AHF study was funded by Amgen, Inc. in collaboration with Cytokinetics, Inc. The design of the study protocols was the responsibility of the authors, Amgen, Inc., and Cytokinetics, Inc. All statistical analyses were performed by Amgen, Inc. Dr. Teerlink received research grants from Amgen, Cytokinetics, Mast Therapeutics, Novartis, Sorbent, and Trevena; and has served as a consultant to Amgen, Cytokinetics, Mast Therapeutics, Novartis, and Trevena. Dr. Felker has received research grants from Amgen, Roche Diagnostics, Novartis, Otsuka, and the National Heart, Lung, and Blood Institute; and has served as a consultant for Amgen, Novartis, Roche Diagnostics, Singulex, Trevena, Celladon, Bristol-Myers Squibb, Merck, and Medtronic. Dr. McMurray's employer, Glasgow University, has been paid by Cytokinetics and Amgen for his time spent working on the clinical trial program with omecamtiv mecarbil. Dr. McMurray has had travel and accommodation costs paid by Cytokinetics and Amgen in relation to advisory board and clinical trial meetings about omecamtiv mecarbil. Dr. Ponikowski has received consultancy and speaker honoraria from Amgen, Bayer, Cardiorentis, Johnson & Johnson, Novartis, and Servier; and has received an institutional research grant from Singulex. Dr. Metra has received consulting fees from Amgen, Bayer, Mast Therapeutics, Novartis, Servier, and Trevena. Dr. Filippatos has received research grants or consulting fees, or both, from Bayer, Novartis, Cardiorentis, Vifor, and the European Union. Dr. Ezekowitz has received research grants or honoraria from Amgen, Novartis, Trevena, and Cardiorentis. Dr. Dickstein has received honoraria and research support from Abbott, Amgen, AstraZeneca, Bayer, Biotronik, Boston Scientific, Johnson & Johnson, Medtronic, Merck, Novartis, Pfizer, Sanofi, Servier, Sorin, and St. Jude Medical; and has received a research grant from the University of Bergen. Dr. Cleland has received research grants from Alere, Amgen, Roche Diagnostics, Novartis, Philips, Servier, and StealthPeptides; has served as a consultant for Amgen, Novartis, Philips, Roche Diagnostics, Merck, Medtronic, Servier, and Zoll; and has received speaker honoraria from Bayer and Novartis. Dr. Kim is a former employee of and shareholder in Amgen; and is current employee of and shareholder in MyoKardia. Drs. Wolff and Malik are employees of and shareholders in Cytokinetics. Drs. Lei, Knusel, and Wasserman are employees of and shareholders in Amgen. NR 29 TC 13 Z9 13 U1 5 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 29 PY 2016 VL 67 IS 12 BP 1444 EP 1455 DI 10.1016/j.jacc.2016.01.031 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DG9NA UT WOS:000372408500009 PM 27012405 ER PT J AU Kedersha, N Panas, MD Achorn, CA Lyons, S Tisdale, S Hickman, T Thomas, M Lieberman, J McInerney, GM Ivanov, P Anderson, P AF Kedersha, Nancy Panas, Marc D. Achorn, Christopher A. Lyons, Shawn Tisdale, Sarah Hickman, Tyler Thomas, Marshall Lieberman, Judy McInerney, Gerald M. Ivanov, Pavel Anderson, Paul TI G3BP-Caprin 1-USP10 complexes mediate stress granule condensation and associate with 40S subunits SO JOURNAL OF CELL BIOLOGY LA English DT Article ID RNA-BINDING PROTEINS; VIRUS-INFECTED CELLS; MESSENGER-RNA; EUKARYOTIC TRANSLATION; PROCESSING BODIES; PHASE-TRANSITION; LIQUID DROPLETS; P-BODIES; PHOSPHORYLATION; G3BP AB Mammalian stress granules (SGs) contain stalled translation preinitiation complexes that are assembled into discrete granules by specific RNA-binding proteins such as G3BP. We now show that cells lacking both G3BP1 and G3BP2 cannot form SGs in response to eukaryotic initiation factor 2a phosphorylation or eIF4A inhibition, but are still SG-competent when challenged with severe heat or osmotic stress. Rescue experiments using G3BP1 mutants show that phosphomimetic G3BP1-5149E fails to rescue SG formation, whereas G3BP1-F33W, a mutant unable to bind G3BP partner proteins Caprinl or USP10, rescues SG formation. Caprin1/USP10 binding to G3BP is mutually exclusive: Caprin binding promotes, but USP10 binding inhibits, SG formation. G3BP interacts with 405 ribosomal subunits through its RGG motif, which is also required for G3BP-mediated SG formation. We propose that G3BP mediates the condensation of SGs by shifting between two different states that are controlled by the phosphorylation of S149 and by binding to Caprinl or USP10. C1 [Kedersha, Nancy; Panas, Marc D.; Achorn, Christopher A.; Lyons, Shawn; Tisdale, Sarah; Hickman, Tyler; Ivanov, Pavel; Anderson, Paul] Harvard Univ, Sch Med, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. [Kedersha, Nancy; Panas, Marc D.; Achorn, Christopher A.; Lyons, Shawn; Tisdale, Sarah; Hickman, Tyler; Ivanov, Pavel; Anderson, Paul] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Thomas, Marshall; Lieberman, Judy] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [McInerney, Gerald M.] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, SE-17177 Stockholm, Sweden. [Ivanov, Pavel] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. [Tisdale, Sarah] Columbia Univ, Dept Pathol & Cell Biol, New York, NY 10032 USA. [Hickman, Tyler] Harvard Univ, Sch Med, Dept Otolaryngol, Boston, MA 02111 USA. [Thomas, Marshall] Harvard Univ, Med Sch External Educ, Boston, MA 02115 USA. RP Kedersha, N (reprint author), Harvard Univ, Sch Med, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA.; Kedersha, N (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM nkedersha@rics.bwh.harvard.edu OI McInerney, Gerald/0000-0003-2257-7241; Ivanov, Pavel/0000-0002-7986-7760 FU National Institutes of Health [AI0655858, CA168872, NS094918]; Amyotrophic Lateral Sclerosis Association [N7W220]; Swedish Cancer Society [CAN 2012/789]; Vetenskapsradet [621-2014-4718] FX This work was supported by National Institutes of Health (AI0655858 and CA168872) to P. Anderson, National Institutes of Health (NS094918) and Amyotrophic Lateral Sclerosis Association (N7W220) to P. Ivanov, and Swedish Cancer Society (CAN 2012/789) and Vetenskapsradet (621-2014-4718) to G.M. McInerney. NR 66 TC 15 Z9 15 U1 2 U2 8 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 MAR 28 PY 2016 VL 212 IS 7 BP 845 EP 860 DI 10.1083/jcb.201508028 PG 16 WC Cell Biology SC Cell Biology GA DI5FB UT WOS:000373523200014 PM 27022092 ER PT J AU Hannan, EL Samadashvili, Z Stamato, NJ Lahey, SJ Wechsler, A Jordan, D Sundt, TM Gold, JP Ruiz, CE Ashraf, MH Smith, CR AF Hannan, Edward L. Samadashvili, Zaza Stamato, Nicholas J. Lahey, Stephen J. Wechsler, Andrew Jordan, Desmond Sundt, Thoralf M., III Gold, Jeffrey P. Ruiz, Carlos E. Ashraf, Mohammed H. Smith, Craig R. TI Utilization and 1-Year Mortality for Transcatheter Aortic Valve Replacement and Surgical Aortic Valve Replacement in New York Patients With Aortic Stenosis 2011 to 2012 SO JACC-CARDIOVASCULAR INTERVENTIONS LA English DT Article DE mortality; surgical aortic valve replacement; transcatheter aortic valve implantation ID HIGH-RISK PATIENTS; PROPENSITY SCORE; CLINICAL-OUTCOMES; 2-YEAR OUTCOMES; EDWARDS SAPIEN; IMPLANTATION; REGISTRY; TRIAL; COREVALVE; SURGERY AB OBJECTIVES The purpose of this study was to investigate changes in the use of transcatheter aortic valve replacement (TAVR) relative to surgical aortic valve replacement (SAVR) and to examine relative 1-year TAVR and SAVR outcomes in 2011 to 2012 in a population-based setting. BACKGROUND TAVR has become a popular option for patients with severe aortic stenosis, particularly for higher-risk patients. METHODS New York's Cardiac Surgery Reporting System was used to identify TAVR and SAVR volumes and to propensity match TAVR and SAVR patients using numerous patient risk factors contained in the registry to compare 1-year mortality rates. Mortality rates were also compared for different levels of patient risk. RESULTS The total number of aortic valve replacement patients increased from 2,291 in 2011 to 2,899 in 2012, an increase of 27%. The volume of SAVR patients increased by 7.1% from 1,994 to 2,135 and the volume of TAVR patients increased 157% from 297 to 764. The percentage of SAVR patients that were at higher risk (>= 3% New York State [NYS] score, equivalent to a Society of Thoracic Surgeons score of about 8%) decreased from 27% to 23%, and the percentage of TAVR patients that were at higher risk decreased from 83% to 76%. There was no significant difference in 1-year mortality between TAVR and SAVR patients (15.6% vs. 13.1%; hazard ratio [HR]: 1.30 [95% confidence interval (CI): 0.89 to 1.92]). There were no differences among patients with NYS score <3% (12.5% vs. 10.2%; HR: 1.42 [ 95% CI: 0.68 to 2.97]) or among patients with NYS score >= 3% (17.1% vs. 14.5%; HR: 1.27 [ 95% CI: 0.81 to 1.98]). CONCLUSIONS TAVR has assumed a much larger share of all aortic valve replacements for severe aortic stenosis, and the average level of pre-procedural risk has decreased substantially. There are no differences between 1-year mortality rates for TAVR and SAVR patients. (J Am Coll Cardiol Intv 2016;9:578-85) (C) 2016 by the American College of Cardiology Foundation. C1 [Hannan, Edward L.; Samadashvili, Zaza] SUNY Albany, Sch Publ Hlth, Albany, NY 12222 USA. [Stamato, Nicholas J.] Campbell Cty Mem Hosp, Dept Cardiol, Gillette, WY USA. [Lahey, Stephen J.] Univ Connecticut, Div Cardiothorac Surg, Storrs, CT USA. [Wechsler, Andrew] Drexel Univ, Coll Med, Dept Cardiothorac Surg, Philadelphia, PA 19104 USA. [Jordan, Desmond; Smith, Craig R.] Columbia Presbyterian Med Ctr, Dept Surg, New York, NY 10032 USA. [Sundt, Thoralf M., III] Massachusetts Gen Hosp, Cardiac Surg Div, Boston, MA 02114 USA. [Gold, Jeffrey P.] Univ Nebraska Med Ctr, Omaha, NE USA. [Ruiz, Carlos E.] Lenox Hill Hosp, Div Struct & Congenital Heart Dis, New York, NY 10021 USA. [Ashraf, Mohammed H.] Kaleida Hlth, Dept Cardiothorac Surg, Buffalo, NY USA. RP Hannan, EL (reprint author), SUNY Albany, Sch Publ Hlth, One Univ Pl, Rensselaer, NY 12144 USA. EM elh03@health.state.ny.us FU St. Jude Medical Center; Edwards Lifesciences FX Dr. Ruiz has received a grant and speaker honoraria from St. Jude Medical Center. Dr. Smith is the surgical principal investigator of the PARTNER trial, for which he receives reimbursement from the sponsor (Edwards Lifesciences) for travel and customary expenses related to trial management. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 42 TC 5 Z9 5 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-8798 EI 1876-7605 J9 JACC-CARDIOVASC INTE JI JACC-Cardiovasc. Interv. PD MAR 28 PY 2016 VL 9 IS 6 BP 578 EP 585 DI 10.1016/j.jcin.2015.12.022 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DH3WQ UT WOS:000372717900015 PM 27013157 ER PT J AU Boyce, RM Reyes, R Matte, M Ntaro, M Mulogo, E Lin, FC Siedner, MJ AF Boyce, Ross M. Reyes, Raquel Matte, Michael Ntaro, Moses Mulogo, Edgar Lin, Feng-Chang Siedner, Mark J. TI Practical Implications of the Non-Linear Relationship between the Test Positivity Rate and Malaria Incidence SO PLOS ONE LA English DT Article AB Background The test positivity rate (TPR), defined as the number of laboratory-confirmed malaria tests per 100 suspected cases examined, is widely used by malaria surveillance programs as one of several key indicators of temporal trends in malaria incidence. However, there have been few studies using empiric data to examine the quantitative nature of this relationship. Methods To characterize the relationship between the test positivity rate and the incidence of malaria, we fit regression models using the confirmed malaria case rate as the outcome of interest and TPR as the predictor of interest. We varied the relationship between the two by alternating linear and polynomial terms for TPR, and compared the goodness of fit of each model. Results A total of 7,668 encounters for malaria diagnostic testing were recorded over the study period within a catchment area of 25,617 persons. The semi-annual TPR ranged from 4.5% to 59% and the case rates ranged from 0.5 to 560 per 1,000 persons. The best fitting model was an exponential growth model (R-2 = 0.80, AIC = 637). At low transmission levels (TPR<10%), the correlation between TPR and CMCR was poor, with large reductions in the TPR, for example from 10% to 1%, was associated with a minimal change in the CMCR (3.9 to 1.7 cases per 1,000 persons). At higher transmission levels, the exponential relationship made relatively small changes in TPR suggestive of sizeable change in estimated malaria incidence, suggesting that TPR remains a valuable surveillance indicator in such settings. Conclusions The TPR and the confirmed malaria case rate have a non-linear relationship, which is likely to have important implications for malaria surveillance programs, especially at the extremes of transmission. C1 [Boyce, Ross M.] Univ N Carolina, Div Infect Dis, Chapel Hill, NC USA. [Reyes, Raquel] Univ N Carolina, Div Gen Med, Chapel Hill, NC USA. [Matte, Michael; Ntaro, Moses; Mulogo, Edgar] Mbarara Univ Sci & Technol, Dept Community Hlth, Mbarara, Uganda. [Lin, Feng-Chang] Univ N Carolina, Dept Biostat, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Siedner, Mark J.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Siedner, Mark J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Boyce, RM (reprint author), Univ N Carolina, Div Infect Dis, Chapel Hill, NC USA. EM ross.boyce@unchealth.unc.edu OI Boyce, Ross/0000-0002-9489-6324 FU Harvard Global Health Institute; Thrasher Research Fund; National Institutes of Health [K23MH099916] FX RMB receives support from the Harvard Global Health Institute (http://globalhealth.harvard.edu/) and Thrasher Research Fund (https://www.thrasherresearch.org/default.aspx). MJS receives support from the National Institutes of Health (K23MH099916). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 20 TC 1 Z9 1 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 28 PY 2016 VL 11 IS 3 AR e0152410 DI 10.1371/journal.pone.0152410 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH5EH UT WOS:000372807800052 PM 27018990 ER PT J AU Bilen, O Kamal, A Virani, SS AF Bilen, Ozlem Kamal, Ayeesha Virani, Salim S. TI Lipoprotein abnormalities in South Asians and its association with cardiovascular disease: Current state and future directions SO WORLD JOURNAL OF CARDIOLOGY LA English DT Review DE Dyslipidemia; South Asians; Asian Indians; Cardiovascular disease ID CORONARY-HEART-DISEASE; LOW-DENSITY-LIPOPROTEIN; INTIMA-MEDIA THICKNESS; APOLIPOPROTEIN-A-I; RISK-FACTORS; ARTERY-DISEASE; MYOCARDIAL-INFARCTION; ELEVATED LIPOPROTEIN(A); INDIAN SUBCONTINENT; CHOLESTEROL EFFLUX AB South Asians have a high prevalence of coronary heart disease (CHD) and suffer from early-onset CHD compared to other ethnic groups. Conventional risk factors may not fully explain this increased CHD risk in this population. Indeed, South Asians have a unique lipid profile which may predispose them to premature CHD. Dyslipidemia in this patient population seems to be an important contributor to the high incidence of coronary atherosclerosis. The dyslipidemia in South Asians is characterized by elevated levels of triglycerides, low levels of high-density lipoprotein (HDL) cholesterol, elevated lipoprotein(a) levels, and a higher atherogenic particle burden despite comparable low-density lipoprotein cholesterol levels compared with other ethnic subgroups. HDL particles also appear to be smaller, dysfunctional, and proatherogenic in South Asians. Despite the rapid expansion of the current literature with better understanding of the specific lipid abnormalities in this patient population, studies with adequate sample sizes are needed to assess the significance and contribution of a given lipid parameter on overall cardiovascular risk in this population. Specific management goals and treatment thresholds do not exist for South Asians because of paucity of data. Current treatment recommendations are mostly extrapolated from Western guidelines. Lastly, large, prospective studies with outcomes data are needed to assess cardiovascular benefit associated with various lipid-lowering therapies (including combination therapy) in this patient population. C1 [Bilen, Ozlem; Virani, Salim S.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Kamal, Ayeesha] Aga Khan Univ Hosp, Dept Med, Neurol Sect, Karachi 3500, Pakistan. RP Virani, SS (reprint author), Baylor Coll Med, Dept Med, Michael E DeBakey Vet Affairs Med Ctr, Hlth Serv Res & Dev 152, 2002 Holcombe Blvd, Houston, TX 77030 USA. EM virani@bcm.edu OI Virani, Salim/0000-0001-9541-6954 NR 92 TC 2 Z9 2 U1 0 U2 1 PU BAISHIDENG PUBLISHING GROUP INC PI PLEASANTON PA 8226 REGENCY DR, PLEASANTON, CA 94588 USA SN 1949-8462 J9 WORLD J CARDIOL JI World J. Cardiol. PD MAR 26 PY 2016 VL 8 IS 3 BP 247 EP 257 DI 10.4330/wjc.v8.i3.247 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA DH4LF UT WOS:000372756800001 PM 27022456 ER PT J AU Dhakal, BP Lewis, GD AF Dhakal, Bishnu P. Lewis, Gregory D. TI Exercise oscillatory ventilation: Mechanisms and prognostic significance SO WORLD JOURNAL OF CARDIOLOGY LA English DT Review DE Exercise; Oscillatory ventilation; Heart failure ID CHRONIC HEART-FAILURE; CHEYNE-STOKES RESPIRATION; IDIOPATHIC DILATED CARDIOMYOPATHY; OBSTRUCTIVE SLEEP-APNEA; PERIPHERAL CHEMORECEPTORS; CARDIAC TRANSPLANTATION; CARDIOVASCULAR-DISEASE; CLINICAL-IMPLICATIONS; WEDGE PRESSURE; REFLEX CONTROL AB Alteration in breathing patterns characterized by cyclic variation of ventilation during rest and during exercise has been recognized in patients with advanced heart failure (HF) for nearly two centuries. Periodic breathing (PB) during exercise is known as exercise oscillatory ventilation (EOV) and is characterized by the periods of hyperpnea and hypopnea without interposed apnea. EOV is a non-invasive parameter detected during submaximal cardiopulmonary exercise testing. Presence of EOV during exercise in HF patients indicates significant impairment in resting and exercise hemodynamic parameters. EOV is also an independent risk factor for poor prognosis in HF patients both with reduced and preserved ejection fraction irrespective of other gas exchange variables. Circulatory delay, increased chemosensitivity, pulmonary congestion and increased ergoreflex signaling have been proposed as the mechanisms underlying the generation of EOV in HF patients. There is no proven treatment of EOV but its reversal has been noted with phosphodiesterase inhibitors, exercise training and acetazolamide in relatively small studies. In this review, we discuss the mechanistic basis of PB during exercise and the clinical implications of recognizing PB patterns in patients with HF. C1 [Dhakal, Bishnu P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA 02114 USA. [Lewis, Gregory D.] Massachusetts Gen Hosp, Heart Failure & Cardiac Transplantat Unit, Bigelow 800,55 Fruit St, Boston, MA 02114 USA. RP Lewis, GD (reprint author), Massachusetts Gen Hosp, Heart Failure & Cardiac Transplantat Unit, Bigelow 800,55 Fruit St, Boston, MA 02114 USA. EM glewis@partners.org NR 79 TC 1 Z9 1 U1 2 U2 3 PU BAISHIDENG PUBLISHING GROUP INC PI PLEASANTON PA 8226 REGENCY DR, PLEASANTON, CA 94588 USA SN 1949-8462 J9 WORLD J CARDIOL JI World J. Cardiol. PD MAR 26 PY 2016 VL 8 IS 3 BP 258 EP 266 DI 10.4330/wjc.v8.i3.258 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA DH4LF UT WOS:000372756800002 PM 27022457 ER PT J AU Hu, KJ Feng, DH AF Hu, Kejia Feng, Dehong TI Barriers in palliative care in China SO LANCET LA English DT Letter C1 [Hu, Kejia] Fudan Univ, Huashan Hosp, Shanghai 200040, Peoples R China. [Hu, Kejia] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurosurg, Boston, MA USA. [Feng, Dehong] Nanjing Med Univ, Wuxi Peoples Hosp, Wuxi, Jiangsu, Peoples R China. RP Hu, KJ (reprint author), Fudan Univ, Huashan Hosp, Shanghai 200040, Peoples R China.; Hu, KJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurosurg, Boston, MA USA. EM Kjhu14@fudan.edu.cn NR 4 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 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD MAR 26 PY 2016 VL 387 IS 10025 BP 1272 EP 1272 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA DH3OY UT WOS:000372697500018 PM 27025427 ER PT J AU Zhao, LL Bi, YY Kou, JJ Shi, JL Piao, DX AF Zhao, Liangliang Bi, Yayan Kou, Junjie Shi, Jialan Piao, Daxun TI Phosphatidylserine exposing-platelets and microparticles promote procoagulant activity in colon cancer patients SO JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH LA English DT Article DE Colon cancer; Phosphatidylserine; Platelets and microparticles; Procoagulant activity ID FIBRIN-RELATED MARKERS; COLORECTAL-CANCER; TISSUE FACTOR; COAGULATION ACTIVATION; VENOUS THROMBOEMBOLISM; BLOOD-COAGULATION; ASPIRIN USE; IN-VIVO; EXPOSURE; EXPRESSION AB Background: Colon cancer is invariably accompanied by altered coagulation activity; however, the precise role of phosphatidylserine (PS) in the hypercoagulable state of colon cancer patients remains unclear. We explored the exposure of PS on platelets and microparticles (MPs), and evaluate its role in procoagulant activity in colon cancer patients. Methods: PS-positive platelets and MPs, mainly from platelets and endothelial cells, were detected by flow cytometry and confocal microscopy, and their procoagulant activity was assessed with purified coagulation complex assays, clotting time, and fibrin turbidity. Results: Plasma levels of PS-positive platelets increased gradually from stage I to IV and were higher in all stages of the patients than in the healthy control, while PS-positive platelet-derived MPs only increased significantly in stage III/IV patients. Meanwhile, PS-positive MPs and endothelial-derived MPs in stage II/III/IV patients were markedly higher than ones in controls but no difference with stage I. Tissue factor positive MPs were higher in all 4 stages of colon cancer patients than in the healthy control. Platelets and MPs from the patients demonstrated significantly enhanced intrinsic/extrinsic FXa and thrombin generation, greatly shortened coagulation time, and increased fibrin formation. Combined treatment with PS antagonist lactadherin, strongly prolonged the coagulation time and reduced fibrin formation by inhibiting factor tenase and prothrombinase complex activity. In contrast, pretreatment with anti tissue factor antibody played a lesser role in suppression of procoagulant activity. Conclusion: Our results suggest that PS-positive platelets and MPs contribute to hypercoagulability and represent a potential therapeutic target to prevent coagulation in patients with colon cancer. C1 [Zhao, Liangliang; Piao, Daxun] Harbin Med Univ, Affiliated Hosp 1, Dept Colorectal Surg, 23 Youzheng St, Harbin 150001, Heilongjiang Pr, Peoples R China. [Bi, Yayan; Shi, Jialan] Harbin Med Univ, Affiliated Hosp 1, Dept Med, 23 Youzheng St, Harbin 150001, Heilongjiang Pr, Peoples R China. [Kou, Junjie] Harbin Med Univ, Affiliated Hosp 2, Dept Cardiol, 246 Xuefu Rd, Harbin 150086, Heilongjiang Pr, Peoples R China. [Shi, Jialan] Harvard Univ, Sch Med, VA Boston Healthcare Syst, Dept Surg,Brigham & Womens Hosp, Boston, MA 02132 USA. [Shi, Jialan] Harbin Med Univ, Affiliated Hosp 1, Dept Hematol, 23 Youzheng St, Harbin 150001, Heilongjiang Pr, Peoples R China. RP Piao, DX (reprint author), Harbin Med Univ, Affiliated Hosp 1, Dept Colorectal Surg, 23 Youzheng St, Harbin 150001, Heilongjiang Pr, Peoples R China.; Shi, JL (reprint author), Harbin Med Univ, Affiliated Hosp 1, Dept Med, 23 Youzheng St, Harbin 150001, Heilongjiang Pr, Peoples R China. EM jialan_shi@hms.harvard.edu; piaodaxun2015@163.com FU National Science Foundation of China [81270588, 81470301]; Natural Science Foundation of Heilongjiang province (China) [ZD201317] FX We thank Yuekun Zhu, Zhiwei Zhao and Chundi Qin for the excellent technical assistance. This work was supported by grants (81270588, 81470301) from the National Science Foundation of China and the Natural Science Foundation of Heilongjiang province (China) (ZD201317). NR 56 TC 0 Z9 0 U1 1 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-9966 J9 J EXP CLIN CANC RES JI J. Exp. Clin. Cancer Res. PD MAR 25 PY 2016 VL 35 AR 54 DI 10.1186/s13046-016-0328-9 PG 12 WC Oncology SC Oncology GA DH5XO UT WOS:000372865800002 PM 27015840 ER PT J AU Wala, J Beroukhim, R AF Wala, Jeremiah Beroukhim, Rameen TI CANCER The oncogene makes its escape SO SCIENCE LA English DT Editorial Material ID TERT PROMOTER MUTATIONS; MELANOMA; GENOME C1 [Beroukhim, Rameen] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. Broad Inst, Cambridge, MA 02142 USA. RP Beroukhim, R (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM rameen_beroukhim@dfci.edu FU NHGRI NIH HHS [T32 HG002295] NR 13 TC 1 Z9 1 U1 0 U2 10 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD MAR 25 PY 2016 VL 351 IS 6280 BP 1398 EP 1399 DI 10.1126/science.aaf5542 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH4KZ UT WOS:000372756200023 PM 27013717 ER PT J AU Barrera, LA Vedenko, A Kurland, JV Rogers, JM Gisselbrecht, SS Rossin, EJ Woodard, J Mariani, L Kock, KH Inukai, S Siggers, T Shokri, L Gordan, R Sahni, N Cotsapas, C Hao, T Yi, S Kellis, M Daly, MJ Vidal, M Hill, DE Bulyk, ML AF Barrera, Luis A. Vedenko, Anastasia Kurland, Jesse V. Rogers, Julia M. Gisselbrecht, Stephen S. Rossin, Elizabeth J. Woodard, Jaie Mariani, Luca Kock, Kian Hong Inukai, Sachi Siggers, Trevor Shokri, Leila Gordan, Raluca Sahni, Nidhi Cotsapas, Chris Hao, Tong Yi, Song Kellis, Manolis Daly, Mark J. Vidal, Marc Hill, David E. Bulyk, Martha L. TI Survey of variation in human transcription factors reveals prevalent DNA binding changes SO SCIENCE LA English DT Article ID CONE-ROD DYSTROPHY; HOMEOBOX GENE; MUTATIONS; PHOTORECEPTOR; DISEASE; IDENTIFICATION; ASSOCIATIONS; EXPRESSION; EVOLUTION; VARIANTS AB Sequencing of exomes and genomes has revealed abundant genetic variation affecting the coding sequences of human transcription factors (TFs), but the consequences of such variation remain largely unexplored. We developed a computational, structure-based approach to evaluate TF variants for their impact on DNA binding activity and used universal protein-binding microarrays to assay sequence-specific DNA binding activity across 41 reference and 117 variant alleles found in individuals of diverse ancestries and families with Mendelian diseases. We found 77 variants in 28 genes that affect DNA binding affinity or specificity and identified thousands of rare alleles likely to alter the DNA binding activity of human sequence-specific TFs. Our results suggest that most individuals have unique repertoires of TF DNA binding activities, which may contribute to phenotypic variation. C1 [Barrera, Luis A.; Vedenko, Anastasia; Kurland, Jesse V.; Rogers, Julia M.; Gisselbrecht, Stephen S.; Woodard, Jaie; Mariani, Luca; Kock, Kian Hong; Inukai, Sachi; Siggers, Trevor; Shokri, Leila; Gordan, Raluca; Bulyk, Martha L.] Brigham & Womens Hosp, Dept Med, Div Genet, 75 Francis St, Boston, MA 02115 USA. [Barrera, Luis A.; Vedenko, Anastasia; Kurland, Jesse V.; Rogers, Julia M.; Gisselbrecht, Stephen S.; Woodard, Jaie; Mariani, Luca; Kock, Kian Hong; Inukai, Sachi; Siggers, Trevor; Shokri, Leila; Gordan, Raluca; Bulyk, Martha L.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Barrera, Luis A.; Rogers, Julia M.; Woodard, Jaie; Bulyk, Martha L.] Harvard Univ, Comm Higher Degrees Biophys, Cambridge, MA 02138 USA. [Barrera, Luis A.; Rossin, Elizabeth J.; Bulyk, Martha L.] Harvard Univ, Sch Med, Harvard Mit Div Hlth Sci & Technol, Boston, MA 02115 USA. [Barrera, Luis A.; Kellis, Manolis] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. [Rossin, Elizabeth J.; Cotsapas, Chris; Daly, Mark J.] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Rossin, Elizabeth J.; Cotsapas, Chris; Daly, Mark J.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Rossin, Elizabeth J.; Cotsapas, Chris; Kellis, Manolis; Bulyk, Martha L.] Broad Inst Harvard & MIT, Cambridge, MA 02139 USA. [Kock, Kian Hong; Bulyk, Martha L.] Harvard Univ, Program Biol & Biomed Sci, Cambridge, MA 02138 USA. [Sahni, Nidhi; Hao, Tong; Yi, Song; Vidal, Marc; Hill, David E.; Bulyk, Martha L.] Dana Farber Canc Inst, CCSB, Boston, MA 02215 USA. [Sahni, Nidhi; Hao, Tong; Yi, Song; Vidal, Marc; Hill, David E.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Sahni, Nidhi; Hao, Tong; Yi, Song; Vidal, Marc; Hill, David E.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Daly, Mark J.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Daly, Mark J.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Bulyk, Martha L.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. RP Bulyk, ML (reprint author), Brigham & Womens Hosp, Dept Med, Div Genet, 75 Francis St, Boston, MA 02115 USA.; Bulyk, ML (reprint author), Harvard Univ, Sch Med, Boston, MA 02115 USA.; Bulyk, ML (reprint author), Harvard Univ, Comm Higher Degrees Biophys, Cambridge, MA 02138 USA.; Bulyk, ML (reprint author), Harvard Univ, Sch Med, Harvard Mit Div Hlth Sci & Technol, Boston, MA 02115 USA.; Bulyk, ML (reprint author), Broad Inst Harvard & MIT, Cambridge, MA 02139 USA.; Bulyk, ML (reprint author), Harvard Univ, Program Biol & Biomed Sci, Cambridge, MA 02138 USA.; Bulyk, ML (reprint author), Dana Farber Canc Inst, CCSB, Boston, MA 02215 USA.; Bulyk, ML (reprint author), Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. EM mlbulyk@receptor.med.harvard.edu OI Gisselbrecht, Stephen/0000-0001-8723-902X FU National Institutes of Health [NHGRI R01 HG003985, P50 HG004233]; A*STAR National Science Scholarship; National Science Foundation FX We thank M. Hume, Y.-H. Hsu, Y. Shen, and D. Balcha for technical assistance and A. Gimelbrant for helpful discussions. We are grateful to the Exome Aggregation Consortium for making its data publicly available prior to publication. This work was supported by the National Institutes of Health (grants NHGRI R01 HG003985 to M.L.B. and T.H. and P50 HG004233 to M.V. and D.E.H.), an A*STAR National Science Scholarship to K.H.K., and National Science Foundation Graduate Research Fellowships to L.A.B. and J.M.R. TF PBM data have been deposited into UniPROBE (publication data set accession BAR15A). GST negative control PBM 8-mer data are provided in table S7. M.L.B. is a coinventor on U.S. patents no. 6,548,021 and no. 8,530,638 on PBM technology and corresponding universal sequence designs, respectively. Universal PBM array designs used in this study are available via a materials transfer agreement with The Brigham and Women's Hospital. A.V., J.V.K., J.M.R., N.S., T.H., and S.Y. performed experiments; L.A.B., J.V.K., J.M.R., S.S.G., E.J.R., J.W., L.M., K.H.K., S.I., T.S., L.S., R.G., and C.C. performed data analysis; M.K., M.J.D., M.V., D.E.H., and M.L.B. supervised research; L.A.B., L.M., K.H.K., D.E.H., and M.L.B. designed the study and wrote the manuscript; and L.A.B., J.V.K., J.M.R., S.S.G., L.M., K.H.K., S.I., and M.L.B. prepared figures and tables. NR 22 TC 7 Z9 8 U1 11 U2 21 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD MAR 25 PY 2016 VL 351 IS 6280 BP 1450 EP 1454 DI 10.1126/science.aad2257 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH4KZ UT WOS:000372756200049 PM 27013732 ER PT J AU McGranahan, N Furness, AJS Rosenthal, R Ramskov, S Lyngaa, R Saini, SK Jamal-Hanjani, M Wilson, GA Birkbak, NJ Hiley, CT Watkins, TBK Shafi, S Murugaesu, N Mitter, R Akarca, AU Linares, J Marafioti, T Henry, JY Van Allen, EM Miao, DN Schilling, B Schadendorf, D Garraway, LA Makarov, V Rizvi, NA Snyder, A Hellmann, MD Merghoub, T Wolchok, JD Shukla, SA Wu, CJ Peggs, KS Chan, TA Hadrup, SR Quezada, SA Swanton, C AF McGranahan, Nicholas Furness, Andrew J. S. Rosenthal, Rachel Ramskov, Sofie Lyngaa, Rikke Saini, Sunil Kumar Jamal-Hanjani, Mariam Wilson, Gareth A. Birkbak, Nicolai J. Hiley, Crispin T. Watkins, Thomas B. K. Shafi, Seema Murugaesu, Nirupa Mitter, Richard Akarca, Ayse U. Linares, Joseph Marafioti, Teresa Henry, Jake Y. Van Allen, Eliezer M. Miao, Diana Schilling, Bastian Schadendorf, Dirk Garraway, Levi A. Makarov, Vladimir Rizvi, Naiyer A. Snyder, Alexandra Hellmann, Matthew D. Merghoub, Taha Wolchok, Jedd D. Shukla, Sachet A. Wu, Catherine J. Peggs, Karl S. Chan, Timothy A. Hadrup, Sine R. Quezada, Sergio A. Swanton, Charles TI Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade SO SCIENCE LA English DT Article ID ANALYSIS REVEALS; CTLA-4 BLOCKADE; LUNG-CANCER; EVOLUTION; MELANOMA; GENES AB As tumors grow, they acquire mutations, some of which create neoantigens that influence the response of patients to immune checkpoint inhibitors. We explored the impact of neoantigen intratumor heterogeneity (ITH) on antitumor immunity. Through integrated analysis of ITH and neoantigen burden, we demonstrate a relationship between clonal neoantigen burden and overall survival in primary lung adenocarcinomas. CD8+ tumor-infiltrating lymphocytes reactive to clonal neoantigens were identified in early-stage non-small cell lung cancer and expressed high levels of PD-1. Sensitivity to PD-1 and CTLA-4 blockade in patients with advanced NSCLC and melanoma was enhanced in tumors enriched for clonal neoantigens. T cells recognizing clonal neoantigens were detectable in patients with durable clinical benefit. Cytotoxic chemotherapy-induced subclonal neoantigens, contributing to an increased mutational load, were enriched in certain poor responders. These data suggest that neoantigen heterogeneity may influence immune surveillance and support therapeutic developments targeting clonal neoantigens. C1 [McGranahan, Nicholas; Wilson, Gareth A.; Birkbak, Nicolai J.; Hiley, Crispin T.; Watkins, Thomas B. K.; Mitter, Richard; Swanton, Charles] Francis Crick Inst, London WC2A 3LY, England. [McGranahan, Nicholas] UCL, Ctr Math & Phys Life Sci & Expt Biol CoMPLEX, Mortimer St, London WC1E 6BT, England. [McGranahan, Nicholas; Furness, Andrew J. S.; Rosenthal, Rachel; Jamal-Hanjani, Mariam; Wilson, Gareth A.; Birkbak, Nicolai J.; Hiley, Crispin T.; Watkins, Thomas B. K.; Shafi, Seema; Murugaesu, Nirupa; Henry, Jake Y.; Peggs, Karl S.; Quezada, Sergio A.; Swanton, Charles] UCL Canc Inst, Canc Res UK Lung Canc Ctr Excellence, London WC1E 6BT, England. [Furness, Andrew J. S.; Akarca, Ayse U.; Linares, Joseph; Marafioti, Teresa; Henry, Jake Y.; Peggs, Karl S.; Quezada, Sergio A.] UCL, UCL Canc Inst, Canc Immunol Unit, Mortimer St, London WC1E 6BT, England. [Ramskov, Sofie; Lyngaa, Rikke; Saini, Sunil Kumar; Hadrup, Sine R.] Tech Univ Denmark, Natl Vet Inst, Sect Immunol & Vaccinol, DK-1970 Frederiksberg C, Denmark. [Akarca, Ayse U.; Linares, Joseph; Marafioti, Teresa] UCL, Dept Cellular Pathol, Mortimer St, London WC1E 6BT, England. [Van Allen, Eliezer M.; Miao, Diana; Garraway, Levi A.; Shukla, Sachet A.; Wu, Catherine J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Van Allen, Eliezer M.; Miao, Diana; Garraway, Levi A.; Shukla, Sachet A.; Wu, Catherine J.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Van Allen, Eliezer M.; Garraway, Levi A.] Dana Farber Canc Inst, Ctr Canc Precis Med, Boston, MA 02215 USA. [Schilling, Bastian; Schadendorf, Dirk] Univ Duisburg Essen, Univ Hosp, Dept Dermatol, D-45147 Essen, Germany. [Schilling, Bastian; Schadendorf, Dirk] German Canc Consortium DKTK, D-69121 Heidelberg, Germany. [Makarov, Vladimir; Chan, Timothy A.] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA. [Rizvi, Naiyer A.] Columbia Univ, Hematol Oncol Div, 177 Ft Washington Ave, New York, NY 10032 USA. [Snyder, Alexandra; Hellmann, Matthew D.; Merghoub, Taha; Wolchok, Jedd D.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA. [Snyder, Alexandra; Hellmann, Matthew D.; Wolchok, Jedd D.] Weill Cornell Med Coll, New York, NY 10065 USA. [Merghoub, Taha; Wolchok, Jedd D.] Mem Sloan Kettering Canc Ctr, Ludwig Collaborat Lab, New York, NY 10065 USA. [Wu, Catherine J.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Wu, Catherine J.] Brigham & Womens Hosp, Dept Internal Med, 75 Francis St, Boston, MA 02115 USA. RP Swanton, C (reprint author), Francis Crick Inst, London WC2A 3LY, England.; Quezada, SA; Swanton, C (reprint author), UCL Canc Inst, Canc Res UK Lung Canc Ctr Excellence, London WC1E 6BT, England.; Quezada, SA (reprint author), UCL, UCL Canc Inst, Canc Immunol Unit, Mortimer St, London WC1E 6BT, England. EM s.quezada@ucl.ac.uk; charles.swanton@crick.ac.uk FU CRUK (TRACERx); CRUK Lung Cancer Centre of Excellence; Stand Up 2 Cancer Laura Ziskin prize (SU2C); Rosetrees Trust; NovoNordisk Foundation [16584]; Prostate Cancer Foundation; Breast Cancer Research Foundation; European Research Council (THESEUS); EU FP7 (PREDICT); CRUK Career Development Fellowship; CRUK Biotherapeutic Programme Grant; World Wide Cancer Research; Cancer Research Institute; Sam Keen Foundation; TRACERx CRUK grant; FP7-People-ITN [(2013)607722 - PloidyNet]; Blavatnik Family Foundation; NIH/National Heart, Lung, and Blood Institute [1R01CA155010-02]; NIH/National Cancer Institute [1R01CA182461-01, 1R01CA184922-01]; Cancer Research UK-UCL Centre; CRUK-UCL Centre Clinical Research Fellowship; Cancer Research UK-UCL Centre Cancer Immuno-Therapy Accelerator Award; National Institute for Health Research; University College London Hospitals Biomedical Research Centre; Cancer Research UK University College London Experimental Cancer Medicine Centre; Janssen; Boerhinger Ingelheim; Ventana; Novartis; Roche; Sequenom; Natera; Grail; Apogen Biotechnologies; Epic Biosciences; Sarah Cannon Research Institute; Bristol-Myers Squibb; Merck; Amgen; Geneocea; OncoSpire; Cancer Genetics; Syapse; Roche Ventana; Takeda; Third Rock Ventures; Genentech; AstraZeneca; Neon; Boehringer Ingelheim; Foundation Medicine; Warp Drive Bio FX C.S. is a senior Cancer Research UK (CRUK) clinical research fellow and is funded by CRUK (TRACERx), the CRUK Lung Cancer Centre of Excellence, Stand Up 2 Cancer Laura Ziskin prize (SU2C), the Rosetrees Trust, NovoNordisk Foundation (ID 16584), the Prostate Cancer Foundation, the Breast Cancer Research Foundation, the European Research Council (THESEUS), and EU FP7 (PREDICT). S.A.Q is funded by a CRUK Career Development Fellowship, CRUK Biotherapeutic Programme Grant, World Wide Cancer Research, and a Cancer Research Institute Investigator Award. A.J.S.F receives support from the Sam Keen Foundation. R.R., N.M., N.J.B., and G.A.W. are funded by the TRACERx CRUK grant. T.B.K.W. is funded by the FP7-People-2013-ITN [grant (2013)607722 - PloidyNet]. C.T.H. is funded by the Rosetrees Trust. C.J.W. is a Scholar of the Leukemia and Lymphoma Society and acknowledges support from the Blavatnik Family Foundation, NIH/National Heart, Lung, and Blood Institute (grant 1R01CA155010-02) and NIH/National Cancer Institute (grants 1R01CA182461-01 and 1R01CA184922-01). S.S. is funded by the Cancer Research UK-UCL Centre, and M.J.H. is funded by a CRUK-UCL Centre Clinical Research Fellowship. A.A. is funded by the Cancer Research UK-UCL Centre Cancer Immuno-Therapy Accelerator Award. We thank N. Hacohen and S. Turajlic for helpful advice on the manuscript. This research is supported by the National Institute for Health Research, the University College London Hospitals Biomedical Research Centre, and the Cancer Research UK University College London Experimental Cancer Medicine Centre. Certain data were received under a material transfer agreement with Memorial Sloan Kettering Cancer Center. Data from multiregion sequenced NSCLC are available at the European Bioinformatics Institute (accession no. EGAS00001000809). Data from the Rizvi cohort (2) are available at the database of Genotypes and Phenotypes (dbGAP) (accession no. phs000980.v1.p1). Data from the Snyder cohort (4) are available at dbGAP (accession no. phs001041.v1.p1). Data from the Van Allen cohort (17) are available at dbGAP (accession no. phs000452.v2.p1). The results published here are in part based on data generated by a TCGA pilot project established by the National Cancer Institute and National Human Genome Research Institute. The data were retrieved through dbGaP authorization (accession no. phs000178.v9.p8). Information about TCGA and the investigators and institutions that constitute the TCGA research network can be found at http://cancergenome.nih.gov. C.S. is a paid advisor for Janssen, Boerhinger Ingelheim, Ventana, Novartis, Roche, Sequenom, Natera, Grail, Apogen Biotechnologies, Epic Biosciences, and the Sarah Cannon Research Institute. D.S. is a paid advisor for Bristol-Myers Squibb, Roche, Novartis, Merck, and Amgen. B.S. is a paid advisor for Bristol-Myers Squibb. T.A.C. is a cofounder of and holds equity in Gritstone Oncology; is a paid advisor for Geneocea, OncoSpire, and Cancer Genetics; and receives funding from Bristol-Myers Squibb for research on the genomics of immune response. N.A.R. is a cofounder of and holds equity in Gritstone Oncology. E.M.V.A. is a paid advisor for Syapse, Roche Ventana, Takeda, and Third Rock Ventures. M.D.H is a paid advisor for Bristol-Myers Squibb, Merck, Genentech, AstraZeneca, and Neon. J.D.W is a paid advisor for Bristol-Myers Squibb. L.A.G. is a paid scientific advisor for Novartis, Boehringer Ingelheim, Foundation Medicine, and Warp Drive Bio. C.S., N.M., R.R., S.A.Q., and K.S.P. are co-inventors on UK patent applications (1516047.; 6, 1601098.5, 1601098.5, and 1601099.3) filed by Cancer Research Technology relating to methods for identifying and targeting neoantigens, methods of predicting prognosis of cancer patients, and/or identifying cancer patients who will benefit from treatment that involves determining the number of neoantigens. NR 20 TC 143 Z9 145 U1 29 U2 75 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD MAR 25 PY 2016 VL 351 IS 6280 BP 1463 EP 1469 DI 10.1126/science.aaf1490 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH4KZ UT WOS:000372756200052 PM 26940869 ER PT J AU Segal, RA AF Segal, Rosalind A. TI Lessons from a bridge generation SO SCIENCE LA English DT Editorial Material C1 [Segal, Rosalind A.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Segal, Rosalind A.] Dana Farber Canc Inst, Canc Biol, Boston, MA 02115 USA. RP Segal, RA (reprint author), Harvard Univ, Sch Med, Cambridge, MA 02138 USA.; Segal, RA (reprint author), Dana Farber Canc Inst, Canc Biol, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD MAR 25 PY 2016 VL 351 IS 6280 BP 1494 EP 1494 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH4KZ UT WOS:000372756200055 PM 27013735 ER PT J AU Rosenfield, K Ghoshhajra, BB Dudzinski, DM Stone, JR AF Rosenfield, Kenneth Ghoshhajra, Brian B. Dudzinski, David M. Stone, James R. TI Case 9-2016: A 29-Year-Old Man with Dyspnea and Chest Pain SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ACUTE PULMONARY-EMBOLISM; CLOT LOAD SCORES; MANAGEMENT; ECHOCARDIOGRAPHY; SYNCOPE C1 [Rosenfield, Kenneth; Dudzinski, David M.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Ghoshhajra, Brian B.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Stone, James R.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Rosenfield, Kenneth; Dudzinski, David M.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Ghoshhajra, Brian B.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Stone, James R.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Rosenfield, K (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA.; Rosenfield, K (reprint author), Harvard Univ, Sch Med, Dept Med, Boston, MA USA. NR 18 TC 0 Z9 0 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 24 PY 2016 VL 374 IS 12 BP 1178 EP 1188 DI 10.1056/NEJMcpc1512452 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA DH2AA UT WOS:000372585100012 PM 27007962 ER PT J AU Luskin, MR Lee, JW Fernandez, HF Abdel-Wahab, O Bennett, JM Ketterling, RP Lazarus, HM Levine, RL Litzow, MR Paietta, EM Patel, JP Racevskis, J Rowe, JM Tallman, MS Sun, ZX Luger, SM AF Luskin, Marlise R. Lee, Ju-Whei Fernandez, Hugo F. Abdel-Wahab, Omar Bennett, John M. Ketterling, Rhett P. Lazarus, Hillard M. Levine, Ross L. Litzow, Mark R. Paietta, Elisabeth M. Patel, Jay P. Racevskis, Janis Rowe, Jacob M. Tallman, Martin S. Sun, Zhuoxin Luger, Selina M. TI Benefit of high-dose daunorubicin in AML induction extends across cytogenetic and molecular groups SO BLOOD LA English DT Article ID ACUTE MYELOID-LEUKEMIA; ACUTE NONLYMPHOCYTIC LEUKEMIA; ACUTE MYELOGENOUS LEUKEMIA; CYTOSINE-ARABINOSIDE; ADULT PATIENTS; GROUP-B; INTENSIFIED INDUCTION; GEMTUZUMAB OZOGAMICIN; REMISSION INDUCTION; TANDEM DUPLICATION AB The initial report of the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Research Group trial E1900 (#NCT00049517) showed that induction therapy with high-dose (HD) daunorubicin (90 mg/m(2)) improved overall survival in adults <60 years old with acute myeloid leukemia (AML); however, at initial analysis, the benefit was restricted to younger patients (<50 years) and patients without unfavorable cytogenetics or a FLT3-ITD mutation. Here, we update the results of E1900 after longer follow-up (median, 80.1 months among survivors), focusing on the benefit of HD daunorubicin on common genetic subgroups. Compared with standard-dose daunorubicin (45 mg/m(2)), HD daunorubicin is associated with a hazard ratio (HR) for death of 0.74 (P = .001). Younger patients (<50 years) benefited from HD daunorubicin (HR, 0.66; P = .002), as did patients with favorable and intermediate cytogenetics (HR, 0.51; P = .03 and HR, 0.68; P = .01, respectively). Patients with unfavorable cytogenetics were shown to benefit from HD daunorubicin on multivariable analysis (adjusted HR, 0.66; P = .04). Patients with FLT3-ITD (24%), DNMT3A (24%), and NPM1 (26%) mutant AML all benefited from HD daunorubicin (HR, 0.61, P = .009; HR, 0.62, P = .02; and HR, 0.50, P = .002; respectively). HD benefit was seen in the subgroup of older patients (50-60 years) with the FLT3-ITD or NPM1 mutation. Additionally, the presence of an NPM1 mutation confers a favorable prognosis only for patients receiving anthracycline dose intensification during induction. C1 [Luskin, Marlise R.; Luger, Selina M.] Univ Penn, Abramson Canc Ctr, Div Hematol & Oncol, Philadelphia, PA 19104 USA. [Lee, Ju-Whei; Sun, Zhuoxin] Dana Farber Canc Inst, Imaging Network Biostat Ctr, Amer Coll Radiol, Eastern Cooperat Oncol Grp, Boston, MA 02115 USA. [Fernandez, Hugo F.] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Blood & Marrow Transplantat, Tampa, FL 33682 USA. [Abdel-Wahab, Omar; Levine, Ross L.; Patel, Jay P.] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10021 USA. [Abdel-Wahab, Omar; Levine, Ross L.; Tallman, Martin S.] Mem Sloan Kettering Canc Ctr, Dept Med, Leukemia Serv, 1275 York Ave, New York, NY 10021 USA. [Bennett, John M.] Univ Rochester, Dept Pathol, Rochester, NY 14627 USA. [Ketterling, Rhett P.] Mayo Clin, Dept Lab Med & Pathol, Div Hematopathol, Rochester, MN USA. [Lazarus, Hillard M.] Case Western Reserve Univ, Seidman Canc Ctr, Cleveland, OH 44106 USA. [Litzow, Mark R.] Mayo Clin, Dept Hematol, Rochester, MN USA. [Paietta, Elisabeth M.; Racevskis, Janis] Montefiore Med Ctr, Dept Oncol, 111 E 210Th St, Bronx, NY 10467 USA. [Rowe, Jacob M.] Rambam Med Ctr, Haifa, Israel. RP Luger, SM (reprint author), Univ Penn, Perelman Sch Med, Abramson Canc Ctr, Div Hematol & Oncol, 3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM selina.luger@uphs.upenn.edu FU Public Health Service Grants [CA180820, CA180794, CA180867, CA180791, CA180790, CA180583, CA189859]; National Cancer Institute, National Institutes of Health and the Department of Health and Human Services FX This study was conducted by the ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD, and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported in part by Public Health Service Grants CA180820, CA180794, CA180867, CA180791, CA180790, CA180583, and CA189859, the National Cancer Institute, National Institutes of Health, and the Department of Health and Human Services. NR 31 TC 12 Z9 13 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD MAR 24 PY 2016 VL 127 IS 12 BP 1551 EP 1558 DI 10.1182/blood-2015-07-657403 PG 8 WC Hematology SC Hematology GA DI4YP UT WOS:000373505600010 PM 26755712 ER PT J AU Jeselsohn, R Brown, M AF Jeselsohn, Rinath Brown, Myles TI BREAST CANCER How drug resistance takes shape SO ELIFE LA English DT Editorial Material ID ESTROGEN-RECEPTOR-ALPHA; MUTATIONS C1 [Jeselsohn, Rinath; Brown, Myles] Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02115 USA. [Jeselsohn, Rinath; Brown, Myles] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Jeselsohn, Rinath; Brown, Myles] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Brown, M (reprint author), Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02115 USA.; Brown, M (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA.; Brown, M (reprint author), Harvard Univ, Sch Med, Dept Med, Boston, MA USA. EM myles_brown@dfci.harvard.edu NR 6 TC 0 Z9 0 U1 0 U2 0 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD MAR 24 PY 2016 VL 5 AR e14973 DI 10.7554/eLife.14973 PG 3 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DJ0MP UT WOS:000373898300001 ER PT J AU Basu, R Whitlock, BM Husson, J Le Floc'h, A Jin, WY Oyler-Yaniv, A Dotiwala, F Giannone, G Hivroz, C Biais, N Lieberman, J Kam, LC Huse, M AF Basu, Roshni Whitlock, Benjamin M. Husson, Julien Le Floc'h, Audrey Jin, Weiyang Oyler-Yaniv, Alon Dotiwala, Farokh Giannone, Gregory Hivroz, Claire Biais, Nicolas Lieberman, Judy Kam, Lance C. Huse, Morgan TI Cytotoxic T Cells Use Mechanical Force to Potentiate Target Cell Killing SO CELL LA English DT Article ID IMMUNOLOGICAL SYNAPSE; MEMBRANE TENSION; PLASMA-MEMBRANE; CENTROSOME POLARIZATION; ACTIN POLYMERIZATION; GRANULE SECRETION; RETROGRADE FLOW; MYOSIN-II; ACTIVATION; MECHANOTRANSDUCTION AB The immunological synapse formed between a cytotoxic T lymphocyte (CTL) and an infected or transformed target cell is a physically active structure capable of exerting mechanical force. Here, we investigated whether synaptic forces promote the destruction of target cells. CTLs kill by secreting toxic proteases and the pore forming protein perforin into the synapse. Biophysical experiments revealed a striking correlation between the magnitude of force exertion across the synapse and the speed of perforin pore formation on the target cell, implying that force potentiates cytotoxicity by enhancing perforin activity. Consistent with this interpretation, we found that increasing target cell tension augmented pore formation by perforin and killing by CTLs. Our data also indicate that CTLs coordinate perforin release and force exertion in space and time. These results reveal an unappreciated physical dimension to lymphocyte function and demonstrate that cells use mechanical forces to control the activity of outgoing chemical signals. C1 [Basu, Roshni; Le Floc'h, Audrey; Huse, Morgan] Mem Sloan Kettering Canc Ctr, Program Immunol, New York, NY 10065 USA. [Whitlock, Benjamin M.] Weill Cornell Med Coll, Biochem & Mol Biol Grad Program, New York, NY 10065 USA. [Husson, Julien] Ecole Polytech, Hydrodynam Lab LadHyX, Dept Mech, F-91128 Palaiseau, France. [Jin, Weiyang; Kam, Lance C.] Columbia Univ, Dept Biomed Engn, New York, NY 10027 USA. [Oyler-Yaniv, Alon] Mem Sloan Kettering Canc Ctr, Computat Biol Program, New York, NY 10065 USA. [Dotiwala, Farokh; Lieberman, Judy] Harvard Univ, Program Cellular & Mol Med, Sch Med, Boston, MA 02115 USA. [Giannone, Gregory] Univ Bordeaux, Interdisciplinary Inst Neurosci, UMR 5297, CNRS, F-33000 Bordeaux, France. [Hivroz, Claire] PSL Res Univ, INSERM, U932, Inst Curie, F-75005 Paris, France. [Biais, Nicolas] CUNY Brooklyn Coll, Dept Biol, New York, NY 11201 USA. RP Huse, M (reprint author), Mem Sloan Kettering Canc Ctr, Program Immunol, New York, NY 10065 USA. EM husem@mskcc.org RI Hivroz, Claire/H-2711-2014 FU NIH [R01-AI087644, R01-AI088377, PN2-EY016586, P30-CA008748]; AXA-Ecole Polytechnique Chair; Labex LaSIPS MECALEUCO; French National Research Agency [ANR-13-BSV2-0018]; French Foundation for Medical Research [FRM DEQ20140329513]; Geoffrey Beene Cancer Research Center; Starr Cancer Consortium; Leukemia and Lymphoma Society FX We thank N. Bantilan and M. Kaissar for technical support; U. Bandyopadhyay and M. Overholtzer for assistance with nitrogen cavitation; A. Gondarenko for assistance with micropillar fabrication; the Molecular Cytology Core Facility for help with imaging; the Antibody and Bioresource Core Facility for fluorescently conjugated Fab fragments; S. Budhu and J. Wolchok for providing B16 cells; E. Mace and J. Orange for pHluorin-Lamp1; S. Rudensky and K. Pham for critical reading of the manuscript; and members of the M.H., L.C.K., M.O. Li, and G. Altan-Bonnet labs for advice. This work was supported in part by the NIH (R01-AI087644 to M.H., R01-AI088377 to L.C.K., PN2-EY016586 to L.C.K., and P30-CA008748 to Memorial Sloan-Kettering Cancer Center), the AXA-Ecole Polytechnique Chair (J.H.), Labex LaSIPS MECALEUCO (J.H.), the French National Research Agency (ANR-13-BSV2-0018 to C.H.), the French Foundation for Medical Research (FRM DEQ20140329513 to C.H.), the Geoffrey Beene Cancer Research Center (M.H.), the Starr Cancer Consortium (M.H.), and the Leukemia and Lymphoma Society (M.H.). NR 56 TC 5 Z9 5 U1 9 U2 26 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD MAR 24 PY 2016 VL 165 IS 1 BP 100 EP 110 DI 10.1016/j.cell.2016.01.021 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DH4WF UT WOS:000372785600013 PM 26924577 ER PT J AU Gudnadottir, TA Bateman, BT Hernadez-Diaz, S Luque-Fernandez, MA Valdimarsdottir, U Zoega, H AF Gudnadottir, Thuridur A. Bateman, Brian T. Hernadez-Diaz, Sonia Luque-Fernandez, Miguel Angel Valdimarsdottir, Unnur Zoega, Helga TI Body Mass Index, Smoking and Hypertensive Disorders during Pregnancy: A Population Based Case-Control Study SO PLOS ONE LA English DT Article ID NHLBI WORKING GROUP; RISK-FACTORS; GESTATIONAL HYPERTENSION; CIGARETTE-SMOKING; NULLIPAROUS WOMEN; PREECLAMPSIA; STATES; OBESITY AB While obesity is an indicated risk factor for hypertensive disorders of pregnancy, smoking during pregnancy has been shown to be inversely associated with the development of pre-eclampsia and gestational hypertension. The purpose of this study was to investigate the combined effects of high body mass index and smoking on hypertensive disorders during pregnancy. This was a case-control study based on national registers, nested within all pregnancies in Iceland 1989-2004, resulting in birth at the Landspitali University Hospital. Cases (n = 500) were matched 1:2 with women without a hypertensive diagnosis who gave birth in the same year. Body mass index (kg/m(2)) was based on height and weight at 10-15 weeks of pregnancy. We used logistic regression models to calculate odds ratios and corresponding 95% confidence intervals as measures of association, adjusting for potential con-founders and tested for additive and multiplicative interactions of body mass index and smoking. Women's body mass index during early pregnancy was positively associated with each hypertensive outcome. Compared with normal weight women, the multivariable adjusted odds ratio for any hypertensive disorder was 1.8 (95% confidence interval, 1.32.3) for overweight women and 3.1 (95% confidence interval, 2.2-4.3) for obese women. The odds ratio for any hypertensive disorder with obesity was 3.9 (95% confidence interval 1.8-8.6) among smokers and 3.0 (95% confidence interval 2.1-4.3) among non-smokers. The effect estimates for hypertensive disorders with high body mass index appeared more pronounced among smokers than non-smokers, although the observed difference was not statistically significant. Our findings may help elucidate the complicated interplay of these lifestyle-related factors with the hypertensive disorders during pregnancy. C1 [Gudnadottir, Thuridur A.; Valdimarsdottir, Unnur; Zoega, Helga] Univ Iceland, Fac Med, Ctr Publ Hlth Sci, Reykjavik, Iceland. [Bateman, Brian T.] Harvard Univ, Sch Med, Dept Anesthesia Crit Care & Pain Med, Massachusetts Gen Hosp, Boston, MA USA. [Bateman, Brian T.] Harvard Univ, Brigham & Womens Hosp, Div Pharmacoepidemiol & Pharmacoecon, Dept Med,Med Sch, Boston, MA 02115 USA. [Hernadez-Diaz, Sonia; Luque-Fernandez, Miguel Angel; Valdimarsdottir, Unnur] Harvard Univ, Dept Epidemiol, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. RP Zoega, H (reprint author), Univ Iceland, Fac Med, Ctr Publ Hlth Sci, Reykjavik, Iceland. EM helgaz@hi.is RI LUQUE FERNANDEZ, MIGUEL ANGEL/L-4053-2015 OI LUQUE FERNANDEZ, MIGUEL ANGEL/0000-0001-6683-5164 FU Icelandic Centre for Research; START - Reintegration fellowship [130814-051]; Eunice Kennedy Shriver National Institute of Child Health & Human Development of National Institutes of Health (Bethesda, Maryland, United States) [K08HD075831]; US National Institute of Mental Health [R01MH100216] FX HZ and TAG received financial support for this study from the Icelandic Centre for Research, START - Reintegration fellowship (#130814-051), http://www.rannis.is/. BTB was supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health (Bethesda, Maryland, United States) under award number K08HD075831, https://www.nichd.nih.gov/Pages/index.aspx. SHD was supported by grant R01MH100216 from the US National Institute of Mental Health, https://www.nimh.nih.gov/index.shtml. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript. The authors did not receive financial support from any other organization for the submitted work. NR 34 TC 1 Z9 1 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 24 PY 2016 VL 11 IS 3 AR e0152187 DI 10.1371/journal.pone.0152187 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH3SV UT WOS:000372708000105 PM 27010734 ER PT J AU Su, Y Blazey, TM Owen, CJ Christensen, JJ Friedrichsen, K Joseph-Mathurin, N Wang, Q Hornbeck, RC Ances, BM Snyder, AZ Cash, LA Koeppe, RA Klunk, WE Galasko, D Brickman, AM McDade, E Ringman, JM Thompson, PM Saykin, AJ Ghetti, B Sperling, RA Johnson, KA Salloway, SP Schofield, PR Masters, CL Villemagne, VL Fox, NC Forster, S Chen, KW Reiman, EM Xiong, CJ Marcus, DS Weiner, MW Morris, JC Bateman, RJ Benzinger, TLS AF Su, Yi Blazey, Tyler M. Owen, Christopher J. Christensen, Jon J. Friedrichsen, Karl Joseph-Mathurin, Nelly Wang, Qing Hornbeck, Russ C. Ances, Beau M. Snyder, Abraham Z. Cash, Lisa A. Koeppe, Robert A. Klunk, William E. Galasko, Douglas Brickman, Adam M. McDade, Eric Ringman, John M. Thompson, Paul M. Saykin, Andrew J. Ghetti, Bernardino Sperling, Reisa A. Johnson, Keith A. Salloway, Stephen P. Schofield, Peter R. Masters, Colin L. Villemagne, Victor L. Fox, Nick C. Foerster, Stefan Chen, Kewei Reiman, Eric M. Xiong, Chengjie Marcus, Daniel S. Weiner, Michael W. Morris, John C. Bateman, Randall J. Benzinger, Tammie L. S. CA Dominantly Inherited Alzheimer Net TI Quantitative Amyloid Imaging in Autosomal Dominant Alzheimer's Disease: Results from the DIAN Study Group SO PLOS ONE LA English DT Article ID PARTIAL-VOLUME CORRECTION; WHITE-MATTER REFERENCE; GRAPHICAL ANALYSIS; PET; GENE; QUANTIFICATION; IMPLEMENTATION; VARIABILITY; MUTATION; RECEPTOR AB Amyloid imaging plays an important role in the research and diagnosis of dementing disorders. Substantial variation in quantitative methods to measure brain amyloid burden exists in the field. The aim of this work is to investigate the impact of methodological variations to the quantification of amyloid burden using data from the Dominantly Inherited Alzheimer's Network (DIAN), an autosomal dominant Alzheimer's disease population. Cross-sectional and longitudinal [C-11]-Pittsburgh Compound B (PiB) PET imaging data from the DIAN study were analyzed. Four candidate reference regions were investigated for estimation of brain amyloid burden. A regional spread function based technique was also investigated for the correction of partial volume effects. Cerebellar cortex, brain-stem, and white matter regions all had stable tracer retention during the course of disease. Partial volume correction consistently improves sensitivity to group differences and longitudinal changes over time. White matter referencing improved statistical power in the detecting longitudinal changes in relative tracer retention; however, the reason for this improvement is unclear and requires further investigation. Full dynamic acquisition and kinetic modeling improved statistical power although it may add cost and time. Several technical variations to amyloid burden quantification were examined in this study. Partial volume correction emerged as the strategy that most consistently improved statistical power for the detection of both longitudinal changes and across-group differences. For the autosomal dominant Alzheimer's disease population with PiB imaging, utilizing brainstem as a reference region with partial volume correction may be optimal for current interventional trials. Further investigation of technical issues in quantitative amyloid imaging in different study populations using different amyloid imaging tracers is warranted. C1 [Su, Yi; Blazey, Tyler M.; Owen, Christopher J.; Christensen, Jon J.; Friedrichsen, Karl; Joseph-Mathurin, Nelly; Wang, Qing; Hornbeck, Russ C.; Cash, Lisa A.; Marcus, Daniel S.; Benzinger, Tammie L. S.] Washington Univ, Sch Med, Dept Radiol, St Louis, MO 63110 USA. [Ances, Beau M.; Snyder, Abraham Z.; McDade, Eric; Morris, John C.; Bateman, Randall J.] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. [Koeppe, Robert A.] Univ Michigan, Dept Radiol, Ann Arbor, MI 48109 USA. [Klunk, William E.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Galasko, Douglas] Univ Calif San Diego, La Jolla, CA 92093 USA. [Brickman, Adam M.] Columbia Univ, New York, NY USA. [Ringman, John M.] Univ So Calif, Keck Sch Med, Dept Neurol, Los Angeles, CA 90033 USA. [Thompson, Paul M.] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Saykin, Andrew J.; Ghetti, Bernardino] Indiana Univ, Dept Radiol, Indianapolis, IN 46204 USA. [Sperling, Reisa A.; Johnson, Keith A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Salloway, Stephen P.] Butler Hosp, Providence, RI 02906 USA. [Salloway, Stephen P.] Brown Univ, Providence, RI 02912 USA. [Schofield, Peter R.] Univ New S Wales, Neurosci Res Australia, Sydney, NSW, Australia. [Schofield, Peter R.] Univ New S Wales, Sch Med Sci, Sydney, NSW, Australia. [Masters, Colin L.; Villemagne, Victor L.] Florey Inst, Parkville, Vic, Australia. [Masters, Colin L.; Villemagne, Victor L.] Univ Melbourne, Parkville, Vic 3052, Australia. [Fox, Nick C.] Inst Neurol, Dememtia Res Ctr, Queen Sq, London WC1N 3BG, England. [Foerster, Stefan] Tech Univ Munich, Deutsch Zentrum Neurodegenerat Erkrankungen DZNE, D-80290 Munich, Germany. [Foerster, Stefan] Tech Univ Munich, Dept Nucl Med, D-80290 Munich, Germany. [Chen, Kewei; Reiman, Eric M.] Banner Hlth, Banner Alzheimers Inst, 901 E Willetta St, Phoenix, AZ USA. [Xiong, Chengjie] Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA. [Weiner, Michael W.] Univ Calif San Francisco, Dept Radiol, San Francisco, CA USA. RP Su, Y (reprint author), Washington Univ, Sch Med, Dept Radiol, St Louis, MO 63110 USA. EM suy@mir.wustl.edu RI Fox, Nick/B-1319-2009 OI Fox, Nick/0000-0002-6660-657X FU Knight Alzheimer's Disease Research Center; Washington University Institute of Clinical and Translational Sciences; National Institute of Health [UL1TR000448]; National Institute of Neurological Disorders and Stroke [P30NS048056]; National Institute of Ageing [P01AG026276, U19AG032438, P50AG005681, P01AG003991]; NIHR Queen Square Dementia Biomedical Research Unit FX YS received funds from the Knight Alzheimer's Disease Research Center (http://knightadrc.wustl.edu/) pilot award, Washington University Institute of Clinical and Translational Sciences (http://icts.wustl.edu/) Pilot Grant supported by the Clinical and Translational Science Award (CTSA) program (https://www.ctsacentral.org/) of National Institute of Health (http://www.nih.gov/): UL1TR000448. AZS and DSM received funds from National Institute of Neurological Disorders and Stroke (http://www.ninds.nih.gov/): P30NS048056; JCM and TLSB received funds from National Institute of Ageing (http://www.nia.nih.gov/): P01AG026276, U19AG032438, P50AG005681, P01AG003991. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; We acknowledge the altruism of the DIAN participants and their families and contributions of the DIAN research. We acknowledge the DIAN genetics core for APOE genotype and mutation status; the DIAN clinical core for providing CDR status; and the DIAN biostatistics, informatics, neuropathology, and biomarker cores for their assistance in the DIAN project. We acknowledge each of the participating sites (list follows in alphabetical order) and their staff for their contributions to this study (see DIAN website (www.DIAN-info.org) for a list of DIAN sites and other DIAN related information). We also acknowledge Alzheimer's Disease Cooperative Study (ADCS) for coordination of clinical and neuropsychological evaluations and monitoring of the acquisition of imaging studies and collection of biological fluids; Mayo Clinic Rochester for MRI site training and standardization; University of Michigan for PET site training and standardization; and San Francisco Veteran's Administration Medical Center and Alzheimer's Disease Neuroimaging Initiative (ADNI) for the assistance in the conduct of project research. Support was also provided by the NIHR Queen Square Dementia Biomedical Research Unit. NR 41 TC 6 Z9 7 U1 3 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 MAR 24 PY 2016 VL 11 IS 3 AR e0152082 DI 10.1371/journal.pone.0152082 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH3SV UT WOS:000372708000083 PM 27010959 ER PT J AU Weber, K Lau, EF Stillerman, B Kuperberg, GR AF Weber, Kirsten Lau, Ellen F. Stillerman, Benjamin Kuperberg, Gina R. TI The Yin and the Yang of Prediction: An fMRI Study of Semantic Predictive Processing SO PLOS ONE LA English DT Article ID EVENT-RELATED FMRI; PERISYLVIAN LANGUAGE NETWORKS; PRIME-GENERATED EXPECTANCIES; INFERIOR PREFRONTAL CORTEX; ANTERIOR CINGULATE CORTEX; BRAIN POTENTIAL ANALYSIS; SENTENCE COMPREHENSION; LEXICAL-DECISION; PSYCHOPHYSIOLOGICAL INTERACTIONS; EFFECTIVE CONNECTIVITY AB Probabilistic prediction plays a crucial role in language comprehension. When predictions are fulfilled, the resulting facilitation allows for fast, efficient processing of ambiguous, rapidly-unfolding input; when predictions are not fulfilled, the resulting error signal allows us to adapt to broader statistical changes in this input. We used functional Magnetic Resonance Imaging to examine the neuroanatomical networks engaged in semantic predictive processing and adaptation. We used a relatedness proportion semantic priming paradigm, in which we manipulated the probability of predictions while holding local semantic context constant. Under conditions of higher (versus lower) predictive validity, we replicate previous observations of reduced activity to semantically predictable words in the left anterior superior/middle temporal cortex, reflecting facilitated processing of targets that are consistent with prior semantic predictions. In addition, under conditions of higher (versus lower) predictive validity we observed significant differences in the effects of semantic relatedness within the left inferior frontal gyrus and the posterior portion of the left superior/middle temporal gyrus. We suggest that together these two regions mediated the suppression of unfulfilled semantic predictions and lexico-semantic processing of unrelated targets that were inconsistent with these predictions. Moreover, under conditions of higher (versus lower) predictive validity, a functional connectivity analysis showed that the left inferior frontal and left posterior superior/middle temporal gyrus were more tightly interconnected with one another, as well as with the left anterior cingulate cortex. The left anterior cingulate cortex was, in turn, more tightly connected to superior lateral frontal cortices and subcortical regions-a network that mediates rapid learning and adaptation and that may have played a role in switching to a more predictive mode of processing in response to the statistical structure of the wider environmental context. Together, these findings highlight close links between the networks mediating semantic prediction, executive function and learning, giving new insights into how our brains are able to flexibly adapt to our environment. C1 [Weber, Kirsten; Lau, Ellen F.; Stillerman, Benjamin; Kuperberg, Gina R.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA USA. [Weber, Kirsten; Lau, Ellen F.; Stillerman, Benjamin; Kuperberg, Gina R.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Weber, Kirsten; Lau, Ellen F.; Stillerman, Benjamin; Kuperberg, Gina R.] Tufts Univ, Dept Psychol, Medford, MA 02155 USA. [Weber, Kirsten; Lau, Ellen F.; Stillerman, Benjamin; Kuperberg, Gina R.] Tufts Univ, Ctr Cognit Sci, Medford, MA 02155 USA. [Weber, Kirsten] Max Planck Inst Psycholinguist, Nijmegen, Netherlands. [Lau, Ellen F.] Univ Maryland, Dept Linguist, College Pk, MD 20742 USA. RP Weber, K (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA USA.; Weber, K (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA.; Weber, K (reprint author), Tufts Univ, Dept Psychol, Medford, MA 02155 USA.; Weber, K (reprint author), Tufts Univ, Ctr Cognit Sci, Medford, MA 02155 USA.; Weber, K (reprint author), Max Planck Inst Psycholinguist, Nijmegen, Netherlands. EM kirsten.weber@mpi.nl FU National Institutes of Health [R01MH071635, F32HD063221] FX This work was supported by the National Institutes of Health (grants R01MH071635 to GK and F32HD063221 to EL). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 118 TC 2 Z9 2 U1 6 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 24 PY 2016 VL 11 IS 3 AR e0148637 DI 10.1371/journal.pone.0148637 PG 25 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH3SV UT WOS:000372708000017 PM 27010386 ER PT J AU Tran, MT Zsengeller, ZK Berg, AH Khankin, EV Bhasin, MK Kim, W Clish, CB Stillman, IE Karumanchi, SA Rhee, EP Parikh, SM AF Tran, Mei T. Zsengeller, Zsuzsanna K. Berg, Anders H. Khankin, Eliyahu V. Bhasin, Manoj K. Kim, Wondong Clish, Clary B. Stillman, Isaac E. Karumanchi, S. Ananth Rhee, Eugene P. Parikh, Samir M. TI PGC1 alpha drives NAD biosynthesis linking oxidative metabolism to renal protection SO NATURE LA English DT Article ID ISCHEMIA-REPERFUSION INJURY; ACUTE KIDNEY INJURY; NICOTINAMIDE PHOSPHORIBOSYLTRANSFERASE; MITOCHONDRIAL INJURY; MICE; PGC-1-ALPHA; FAILURE; COACTIVATOR; PROMOTES; PATHWAY AB The energetic burden of continuously concentrating solutes against gradients along the tubule may render the kidney especially vulnerable to ischaemia. Acute kidney injury (AKI) affects 3% of all hospitalized patients(1,2). Here we show that the mitochondrial biogenesis regulator, PGC1 alpha(3,4), is a pivotal determinant of renal recovery from injury by regulating nicotinamide adenine dinucleotide (NAD) biosynthesis. Following renal ischaemia, PGC1 alpha(-/-) (also known as Ppargc1a(-/-)) mice develop local deficiency of the NAD precursor niacinamide (NAM, also known as nicotinamide), marked fat accumulation, and failure to reestablish normal function. Notably, exogenous NAM improves local NAD levels, fat accumulation, and renal function in post-ischaemic PGC1 alpha(-/-) mice. Inducible tubular transgenic mice (iNephPGC1 alpha) recapitulate the effects of NAM supplementation, including more local NAD and less fat accumulation with better renal function after ischaemia. PGC1 alpha coordinately upregulates the enzymes that synthesize NAD de novo from amino acids whereas PGC1 alpha deficiency or AKI attenuates the de novo pathway. NAM enhances NAD via the enzyme NAMPT and augments production of the fat breakdown product beta-hydroxybutyrate, leading to increased production of prostaglandin PGE(2) (ref. 5), a secreted autacoid that maintains renal function. NAM treatment reverses established ischaemic AKI and also prevented AKI in an unrelated toxic model. Inhibition of beta-hydroxybutyrate signalling or prostaglandin production similarly abolishes PGC1 alpha-dependent renoprotection. Given the importance of mitochondrial health in ageing and the function of metabolically active organs, the results implicate NAM and NAD as key effectors for achieving PGC1 alpha-dependent stress resistance. C1 [Tran, Mei T.; Zsengeller, Zsuzsanna K.; Khankin, Eliyahu V.; Karumanchi, S. Ananth; Parikh, Samir M.] Beth Israel Deaconess Med Ctr, Div Nephrol, Boston, MA 02215 USA. [Tran, Mei T.; Zsengeller, Zsuzsanna K.; Khankin, Eliyahu V.; Karumanchi, S. Ananth; Parikh, Samir M.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Tran, Mei T.; Zsengeller, Zsuzsanna K.; Berg, Anders H.; Khankin, Eliyahu V.; Bhasin, Manoj K.; Stillman, Isaac E.; Karumanchi, S. Ananth; Parikh, Samir M.] Harvard Univ, Sch Med, Boston, MA 02215 USA. [Tran, Mei T.; Zsengeller, Zsuzsanna K.; Khankin, Eliyahu V.; Bhasin, Manoj K.; Karumanchi, S. Ananth; Parikh, Samir M.] Beth Israel Deaconess Med Ctr, Ctr Vasc Biol Res, Boston, MA 02215 USA. [Zsengeller, Zsuzsanna K.; Berg, Anders H.] Beth Israel Deaconess Med Ctr, Div Clin Chem, Boston, MA 02215 USA. [Berg, Anders H.; Stillman, Isaac E.] Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA. [Bhasin, Manoj K.] Beth Israel Deaconess Med Ctr, Bioinformat & Syst Biol Core, Boston, MA 02215 USA. [Kim, Wondong; Rhee, Eugene P.] Massachusetts Gen Hosp, Nephrol Div, Boston, MA 02114 USA. [Kim, Wondong; Rhee, Eugene P.] Massachusetts Gen Hosp, Div Endocrine, Boston, MA 02114 USA. [Kim, Wondong; Rhee, Eugene P.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Clish, Clary B.; Rhee, Eugene P.] Broad Inst MIT & Harvard, Cambridge, MA 02139 USA. [Karumanchi, S. Ananth] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Parikh, SM (reprint author), Beth Israel Deaconess Med Ctr, Div Nephrol, Boston, MA 02215 USA.; Parikh, SM (reprint author), Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA.; Parikh, SM (reprint author), Harvard Univ, Sch Med, Boston, MA 02215 USA.; Parikh, SM (reprint author), Beth Israel Deaconess Med Ctr, Ctr Vasc Biol Res, Boston, MA 02215 USA. EM sparikh1@bidmc.harvard.edu FU Satellite Healthcare; [R01-DK095072]; [K08-DK090142]; [K08-DK101560] FX The authors thank B. Spiegelman (Harvard Medical School, Dana Farber Cancer Institute) for support from this project's inception; M. Zeidel (Harvard Medical School, BIDMC) for advice; Z. Arany (University of Pennsylvania) for the VE-cadherin-tTA x TRE-PGC1 alpha mice; A. Agarwal (University of Alabama, NIH P30-DK079337) for LC-MS measurements of serum creatinine; A. Kurmann and A. Hollenberg (Harvard Medical School, BIDMC) for thyroxine measurements; and P. Pacher (NIH) for cisplatin-treated kidneys for microscopy. This work was supported by R01-DK095072 and philanthropic funds to S.M.P.; K08-DK090142 and a grant from Satellite Healthcare to E.P.R.; and K08-DK101560 to E.V.K. NR 41 TC 12 Z9 12 U1 11 U2 23 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD MAR 24 PY 2016 VL 531 IS 7595 BP 528 EP + DI 10.1038/nature17184 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH3QK UT WOS:000372701300046 PM 26982719 ER PT J AU Iezzoni, LI Dorner, SC Ajayi, T AF Iezzoni, Lisa I. Dorner, Stephen C. Ajayi, Toyin TI Community Paramedicine - Addressing Questions as Programs Expand SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Iezzoni, Lisa I.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. [Iezzoni, Lisa I.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Dorner, Stephen C.] Harvard Univ, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Ajayi, Toyin] Commonwealth Care Alliance, Boston, MA USA. [Dorner, Stephen C.] Vanderbilt Univ, Sch Med, 221 Kirkland Hall, Nashville, TN 37235 USA. RP Iezzoni, LI (reprint author), Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA.; Iezzoni, LI (reprint author), Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. NR 5 TC 2 Z9 2 U1 1 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 24 PY 2016 VL 374 IS 12 BP 1107 EP 1109 DI 10.1056/NEJMp1516100 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA DH2AA UT WOS:000372585100003 PM 27007957 ER PT J AU Stitziel, NO Stirrups, KE Masca, NGD Erdmann, J Ferrario, PG Konig, IR Weeke, PE Webb, TR Auer, PL Schick, UM Lu, YC Zhang, H Dube, MP Goel, A Farrall, M Peloso, GM Won, HH Do, R van Iperen, E Kanoni, S Kruppa, J Mahajan, A Scott, RA Willenborg, C Braund, PS van Capelleveen, JC Doney, ASF Donnelly, LA Asselta, R Merlini, PA Duga, S Marziliano, N Denny, JC Shaffer, CM El-Mokhtari, NE Franke, A Gottesman, O Heilmann, S Hengstenberg, C Hoffmann, P Holmen, OL Hveem, K Jansson, JH Jockel, KH Kessler, T Kriebel, J Laugwitz, KL Marouli, E Martinelli, N McCarthy, MI Van Zuydam, NR Meisinger, C Esko, T Mihailov, E Escher, SA Alver, M Moebus, S Morris, AD Muller-Nurasyid, M Nikpay, M Olivieri, O Perreault, LPL AlQarawi, A Robertson, NR Akinsanya, KO Reilly, DF Vogt, TF Yin, W Asselbergs, FW Kooperberg, C Jackson, RD Stahl, E Strauch, K Varga, TV Waldenberger, M Zeng, LY Kraja, AT Liu, CY Ehret, GB Newton-Cheh, C Chasman, DI Chowdhury, R Ferrario, M Ford, I Jukema, JW Kee, F Kuulasmaa, K Nordestgaard, BG Perola, M Saleheen, D Sattar, N Surendran, P Tregouet, D Young, R Howson, JMM Butterworth, AS Danesh, J Ardissino, D Bottinger, EP Erbel, R Franks, PW Girelli, D Hall, AS Hovingh, GK Kastrati, A Lieb, W Meitinger, T Kraus, WE Shah, SH McPherson, R Orho-Melander, M Melander, O Metspalu, A Palmer, CNA Peters, A Rader, DJ Reilly, MP Loos, RJF Reiner, AP Roden, DM Tardif, JC Thompson, JR Wareham, NJ Watkins, H Willer, CJ Kathiresan, S Deloukas, P Samani, NJ Schunkert, H AF Stitziel, Nathan O. Stirrups, Kathleen E. Masca, Nicholas G. D. Erdmann, Jeanette Ferrario, Paola G. Koenig, Inke R. Weeke, Peter E. Webb, Thomas R. Auer, Paul L. Schick, Ursula M. Lu, Yingchang Zhang, He Dube, Marie-Pierre Goel, Anuj Farrall, Martin Peloso, Gina M. Won, Hong-Hee Do, Ron van Iperen, Erik Kanoni, Stavroula Kruppa, Jochen Mahajan, Anubha Scott, Robert A. Willenborg, Christina Braund, Peter S. van Capelleveen, Julian C. Doney, Alex S. F. Donnelly, Louise A. Asselta, Rosanna Merlini, Piera A. Duga, Stefano Marziliano, Nicola Denny, Josh C. Shaffer, Christian M. El-Mokhtari, Nour Eddine Franke, Andre Gottesman, Omri Heilmann, Stefanie Hengstenberg, Christian Hoffmann, Per Holmen, Oddgeir L. Hveem, Kristian Jansson, Jan-Hakan Joeckel, Karl-Heinz Kessler, Thorsten Kriebel, Jennifer Laugwitz, Karl L. Marouli, Eirini Martinelli, Nicola McCarthy, Mark I. Van Zuydam, Natalie R. Meisinger, Christa Esko, Tonu Mihailov, Evelin Escher, Stefan A. Alver, Maris Moebus, Susanne Morris, Andrew D. Mueller-Nurasyid, Martina Nikpay, Majid Olivieri, Oliviero Perreault, Louis-Philippe Lemieux AlQarawi, Alaa Robertson, Neil R. Akinsanya, Karen O. Reilly, Dermot F. Vogt, Thomas F. Yin, Wu Asselbergs, Folkert W. Kooperberg, Charles Jackson, Rebecca D. Stahl, Eli Strauch, Konstantin Varga, Tibor V. Waldenberger, Melanie Zeng, Lingyao Kraja, Aldi T. Liu, Chunyu Ehret, Georg B. Newton-Cheh, Christopher Chasman, Daniel I. Chowdhury, Rajiv Ferrario, Marco Ford, Ian Jukema, J. Wouter Kee, Frank Kuulasmaa, Kari Nordestgaard, Borge G. Perola, Markus Saleheen, Danish Sattar, Naveed Surendran, Praveen Tregouet, David Young, Robin Howson, Joanna M. M. Butterworth, Adam S. Danesh, John Ardissino, Diego Bottinger, Erwin P. Erbel, Raimund Franks, Paul W. Girelli, Domenico Hall, Alistair S. Hovingh, G. Kees Kastrati, Adnan Lieb, Wolfgang Meitinger, Thomas Kraus, William E. Shah, Svati H. McPherson, Ruth Orho-Melander, Marju Melander, Olle Metspalu, Andres Palmer, Colin N. A. Peters, Annette Rader, Daniel J. Reilly, Muredach P. Loos, Ruth J. F. Reiner, Alex P. Roden, Dan M. Tardif, Jean-Claude Thompson, John R. Wareham, Nicholas J. Watkins, Hugh Willer, Cristen J. Kathiresan, Sekar Deloukas, Panos Samani, Nilesh J. Schunkert, Heribert TI Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID OF-FUNCTION MUTATIONS; LIPOPROTEIN-LIPASE; ARTERY-DISEASE; HEART-DISEASE; PCSK9; TRIGLYCERIDES; INHIBITION; VARIANT; APOC3; HDL AB BACKGROUND The discovery of low-frequency coding variants affecting the risk of coronary artery disease has facilitated the identification of therapeutic targets. METHODS Through DNA genotyping, we tested 54,003 coding-sequence variants covering 13,715 human genes in up to 72,868 patients with coronary artery disease and 120,770 controls who did not have coronary artery disease. Through DNA sequencing, we studied the effects of loss-of-function mutations in selected genes. RESULTS We confirmed previously observed significant associations between coronary artery disease and low-frequency missense variants in the genes LPA and PCSK9. We also found significant associations between coronary artery disease and low-frequency missense variants in the genes SVEP1 (p.D2702G; minor-allele frequency, 3.60%; odds ratio for disease, 1.14; P = 4.2x10(-10)) and ANGPTL4 (p.E40K; minor-allele frequency, 2.01%; odds ratio, 0.86; P = 4.0x10(-8)), which encodes angiopoietin-like 4. Through sequencing of ANGPTL4, we identified 9 carriers of loss-of-function mutations among 6924 patients with myocardial infarction, as compared with 19 carriers among 6834 controls (odds ratio, 0.47; P = 0.04); carriers of ANGPTL4 loss-of-function alleles had triglyceride levels that were 35% lower than the levels among persons who did not carry a loss-of-function allele (P = 0.003). ANGPTL4 inhibits lipoprotein lipase; we therefore searched for mutations in LPL and identified a loss-of-function variant that was associated with an increased risk of coronary artery disease (p.D36N; minor-allele frequency, 1.9%; odds ratio, 1.13; P = 2.0x10(-4)) and a gain-of-function variant that was associated with protection from coronary artery disease (p.S447*; minor-allele frequency, 9.9%; odds ratio, 0.94; P = 2.5x10(-7)). CONCLUSIONS We found that carriers of loss-of-function mutations in ANGPTL4 had triglyceride levels that were lower than those among noncarriers; these mutations were also associated with protection from coronary artery disease. C1 [Stitziel, Nathan O.] Washington Univ, Sch Med, Div Cardiovasc, Dept Med, St Louis, MO 63130 USA. [Stitziel, Nathan O.] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63130 USA. [Stitziel, Nathan O.] Washington Univ, Sch Med, McDonnell Genome Inst, St Louis, MO 63130 USA. [Kraja, Aldi T.] Washington Univ, Sch Med, Div Stat Genom, Dept Genet, St Louis, MO 63130 USA. [Kraja, Aldi T.] Washington Univ, Sch Med, Ctr Genome Sci & Syst Biol, St Louis, MO 63130 USA. [Stirrups, Kathleen E.; Kanoni, Stavroula; Marouli, Eirini; Deloukas, Panos] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England. [Asselbergs, Folkert W.] UCL, Inst Cardiovasc Sci, Fac Populat Hlth Sci, London, England. [Stirrups, Kathleen E.] Univ Cambridge, Dept Haematol, Cambridge, England. [Braund, Peter S.; Chowdhury, Rajiv; Young, Robin; Howson, Joanna M. M.; Butterworth, Adam S.; Danesh, John] Univ Cambridge, Cardiovasc Epidemiol Unit, Dept Publ Hlth & Primary Care, Cambridge, England. [Danesh, John] Univ Cambridge, Natl Inst Hlth Res Blood & Transplant Res Unit Do, Cambridge, England. [Scott, Robert A.; Wareham, Nicholas J.] Addenbrookes Hosp, MRC, Epidemiol Unit, Inst Metab Sci, Cambridge, England. 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[El-Mokhtari, Nour Eddine] Kreiskrankenhaus Rendsburg, Innere Med Klin, Rendsburg, Germany. [Franke, Andre] Univ Kiel, Inst Clin Mol Biol, Kiel, Germany. [Lieb, Wolfgang] Univ Kiel, Inst Epidemiol & Biobank Popgen, Kiel, Germany. [Heilmann, Stefanie; Hoffmann, Per] Univ Bonn, Inst Human Genet, Bonn, Germany. [Heilmann, Stefanie; Hoffmann, Per] Univ Bonn, Dept Genom, Life & Brain Ctr, Bonn, Germany. [Hengstenberg, Christian; Kessler, Thorsten; Zeng, Lingyao; Kastrati, Adnan; Schunkert, Heribert] Tech Univ Munich, Deutsch Herzzentrum Munchen, D-80290 Munich, Germany. [Meitinger, Thomas] Tech Univ Munich, Inst Human Genet, D-80290 Munich, Germany. [Hengstenberg, Christian; Laugwitz, Karl L.; Mueller-Nurasyid, Martina; Meitinger, Thomas; Peters, Annette; Schunkert, Heribert] DZHK Partner Site Munich Heart Alliance, Munich, Germany. [Laugwitz, Karl L.] Tech Univ Munich, Klinikum Rechts Isar, Med Klin & Poliklin 1, D-80290 Munich, Germany. [Mueller-Nurasyid, Martina] Univ Munich, Dept Med 1, Munich, Germany. [Strauch, Konstantin] Univ Munich, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Joeckel, Karl-Heinz; Moebus, Susanne; Erbel, Raimund] Univ Hosp Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany. [Kriebel, Jennifer; Waldenberger, Melanie] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Neuherberg, Germany. [Kriebel, Jennifer; Meisinger, Christa; Waldenberger, Melanie; Peters, Annette] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, Neuherberg, Germany. [Mueller-Nurasyid, Martina; Strauch, Konstantin] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Genet Epidemiol, Neuherberg, Germany. [Meitinger, Thomas] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Human Genet, Neuherberg, Germany. [Kriebel, Jennifer] German Ctr Diabet Res, Neuherberg, Germany. [Weeke, Peter E.; Denny, Josh C.; Shaffer, Christian M.; Roden, Dan M.] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA. [Denny, Josh C.] Vanderbilt Univ, Med Ctr, Dept Biomed Informat, Nashville, TN USA. [Roden, Dan M.] Vanderbilt Univ, Med Ctr, Dept Pharmacol, Nashville, TN 37232 USA. [Weeke, Peter E.] Copenhagen Univ Hosp, Rigshosp, Mol Cardiol Lab, Dept Cardiol, Copenhagen, Denmark. [Nordestgaard, Borge G.] Copenhagen Univ Hosp, Copenhagen, Denmark. [Nordestgaard, Borge G.] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark. [Auer, Paul L.] Univ Wisconsin, Sch Publ Heath, Milwaukee, WI 53201 USA. [Schick, Ursula M.; Kooperberg, Charles; Reiner, Alex P.] Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle, WA 98195 USA. [Reiner, Alex P.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Lu, Yingchang; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA. 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[Chasman, Daniel I.] Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA. [Franks, Paul W.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Peloso, Gina M.; Won, Hong-Hee; Newton-Cheh, Christopher; Kathiresan, Sekar] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Esko, Tonu] Broad Inst Massachusetts Inst Technol & Harvard, Cambridge, MA USA. [Liu, Chunyu] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Won, Hong-Hee] Sungkyunkwan Univ, Samsung Med Ctr, SAIHST, Seoul, South Korea. [van Iperen, Erik] Univ Amsterdam, Acad Med Ctr, Dept Biostat, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. [van Capelleveen, Julian C.; Hovingh, G. Kees] Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. [Asselbergs, Folkert W.] UMC Utrecht, Div Heart & Lungs, Dept Cardiol, Utrecht, Netherlands. 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[Ehret, Georg B.] Univ Hosp Geneva, Dept Med, Div Cardiol, Geneva, Switzerland. [Holmen, Oddgeir L.; Hveem, Kristian] Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, HUNT Res Ctr, Levanger, Norway. [Hveem, Kristian] Nord Trondelag Hlth Trust Norway, Levanger Hosp, Dept Med, Levanger, Norway. [Holmen, Oddgeir L.] Univ Trondheim Hosp, St Olav Hosp, Trondheim, Norway. [Jansson, Jan-Hakan] Umea Univ, Res Unit Skelleftea, Dept Publ Hlth & Clin Med, Umea, Sweden. [Franks, Paul W.] Umea Univ Hosp, Dept Publ Hlth & Clin Med, S-90185 Umea, Sweden. [Escher, Stefan A.; Varga, Tibor V.; Franks, Paul W.] Lund Univ, Ctr Diabet, Dept Clin Sci, Genet & Mol Epidemiol Unit, Malmo, Sweden. [Orho-Melander, Marju; Melander, Olle] Lund Univ, Ctr Diabet, Clin Res Ctr, Skane Univ Hosp,Dept Clin Sci Malmo, Malmo, Sweden. [Esko, Tonu; Mihailov, Evelin; Alver, Maris; Metspalu, Andres] Univ Tartu, Estonian Genome Ctr, Ulikooli 18, EE-50090 Tartu, Estonia. [Alver, Maris; Metspalu, Andres] Inst Mol & Cell Biol, Tartu, Estonia. [AlQarawi, Alaa; Deloukas, Panos] King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah 21413, Saudi Arabia. [Akinsanya, Karen O.; Reilly, Dermot F.; Vogt, Thomas F.; Yin, Wu] Merck Sharp & Dohme Ltd, Pob 2000, Rahway, NJ 07065 USA. [Jackson, Rebecca D.] Ohio State Univ, Dept Med, Div Endocrinol Diabet & Metab, Columbus, OH USA. [Liu, Chunyu] NHLBI, Populat Sci Branch, Bldg 10, Bethesda, MD 20892 USA. [Ehret, Georg B.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Ctr Complex Dis Genom, Baltimore, MD USA. [Kee, Frank] Queens Univ Belfast, Belfast, Antrim, North Ireland. [Kuulasmaa, Kari; Perola, Markus] Natl Inst Hlth & Welf, Helsinki, Finland. [Saleheen, Danish] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Rader, Daniel J.] Univ Penn, Perelman Sch Med, Dept Genet, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Reilly, Muredach P.] Univ Penn, Perelman Sch Med, Dept Genet, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA. [Saleheen, Danish] Ctr Noncommunicable Dis, Karachi, Pakistan. [Tregouet, David] Univ Paris 06, Sorbonne Univ, ICAN Inst Cardiometab & Nutr, Paris, France. [Kraus, William E.; Shah, Svati H.] Duke Univ, Duke Mol Physiol Inst, Durham, NC USA. [Kraus, William E.; Shah, Svati H.] Duke Univ, Dept Med, Div Cardiol, Durham, NC USA. RP Stitziel, NO (reprint author), Washington Univ, Sch Med, Div Cardiovasc, Dept Med, St Louis, MO 63130 USA.; Stitziel, NO (reprint author), Washington Univ, Sch Med, Dept Genet, St Louis, MO 63130 USA.; Stitziel, NO (reprint author), Washington Univ, Sch Med, McDonnell Genome Inst, St Louis, MO 63130 USA.; Deloukas, P (reprint author), Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England.; Samani, NJ (reprint author), Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England.; Samani, NJ (reprint author), Glenfield Hosp, NIHR Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England.; Schunkert, H (reprint author), Tech Univ Munich, Deutsch Herzzentrum Munchen, D-80290 Munich, Germany.; Schunkert, H (reprint author), DZHK Partner Site Munich Heart Alliance, Munich, Germany.; Kathiresan, S (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.; Kathiresan, S (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA.; Kathiresan, S (reprint author), Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA.; Kathiresan, S (reprint author), Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA.; Kathiresan, S (reprint author), Broad Inst, Program Med & Populat Genet, Cambridge, MA USA.; Deloukas, P (reprint author), King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah 21413, Saudi Arabia. EM nstitziel@wustl.edu; skathiresan@partners.org; p.deloukas@qmul.ac.uk; njs@le.ac.uk; schunkert@dhm.mhn.de RI Erdmann, Jeanette/P-7513-2014; Martinelli, Nicola/J-5622-2016; Palmer, Colin/C-7053-2008; Study, GoDARTS/K-9448-2016; Tregouet, David-Alexandre/E-3961-2016; Webb, Tom/C-6237-2011; Waldenberger, Melanie/B-5355-2014; Peters, Annette/A-6117-2011; Deloukas, Panos/B-2922-2013; Dube, Marie-Pierre/B-9364-2008; Konig, Inke/A-4544-2009; Franke, Andre/B-2151-2010; Lieb, Wolfgang/C-1990-2012 OI Erdmann, Jeanette/0000-0002-4486-6231; Stitziel, Nathan/0000-0002-4963-8211; Meisinger, Christa/0000-0002-9026-6544; Kuulasmaa, Kari/0000-0003-2165-1411; Heilmann-Heimbach, Stefanie/0000-0003-1057-465X; Watkins, Hugh/0000-0002-5287-9016; Varga, Tibor/0000-0002-2383-699X; Peters, Annette/0000-0001-6645-0985; Martinelli, Nicola/0000-0001-6465-5119; Ferrario, Marco M/0000-0003-2741-7124; Palmer, Colin/0000-0002-6415-6560; Waldenberger, Melanie/0000-0003-0583-5093; Deloukas, Panos/0000-0001-9251-070X; Dube, Marie-Pierre/0000-0001-8442-4393; Franke, Andre/0000-0003-1530-5811; FU National Heart, Lung, and Blood Institute, National Institutes of Health (NIH) [K08HL114642]; Foundation for Barnes Jewish Hospital; National Heart, Lung, and Blood Institute of the NIH [K01HL125751]; Massachusetts General Hospital; Donovan Family Foundation; NIH [R01HL107816, R01HL127564]; Fondation Leducq; Merck; Italian Ministry of Health [RFPS-2007-3-644382]; Regione Emilia Romagna Area; Wellcome Trust [090532/Z/09/Z, 098381]; British Heart Foundation (BHF) Centre of Research Excellence; National Cancer Institute [R25CA094880]; EU FP7 AMP; Wellcome Trust Institutional; National Institute for Health Research (NIHR); British Heart Foundation; NIHR Leicester Cardiovascular Biomedical Research Unit (BRU); BRU; American Heart Association [15POST23280019]; European Union [261123]; Fondation Leducq (CADgenomics) [12CVD02]; German Federal Ministry of Education and Research e:Med program (e:AtheroSysMed and sysINFLAME); Deutsche Forschungsgemeinschaft cluster of excellence "Inflammation at Interfaces"; SFB [1123]; DZHK; BHF [RG/14/5/30893] FX Supported by a career development award from the National Heart, Lung, and Blood Institute, National Institutes of Health (NIH) (K08HL114642 to Dr. Stitziel) and by the Foundation for Barnes Jewish Hospital. Dr. Peloso is supported by the National Heart, Lung, and Blood Institute of the NIH (award number K01HL125751). Dr. Kathiresan is supported by a Research Scholar award from the Massachusetts General Hospital, the Donovan Family Foundation, grants from the NIH (R01HL107816 and R01HL127564), a grant from Fondation Leducq, and an investigator-initiated grant from Merck. Dr. Merlini was supported by a grant from the Italian Ministry of Health (RFPS-2007-3-644382). Drs. Ardissino and Marziliano were supported by Regione Emilia Romagna Area 1 Grants. Drs. Farrall and Watkins acknowledge the support of the Wellcome Trust core award (090532/Z/09/Z), the British Heart Foundation (BHF) Centre of Research Excellence. Dr. Schick is supported in part by a grant from the National Cancer Institute (R25CA094880). Dr. Goel acknowledges EU FP7 & Wellcome Trust Institutional strategic support fund. Dr. Deloukas's work forms part of the research themes contributing to the translational research portfolio of Barts Cardiovascular Biomedical Research Unit, which is supported and funded by the National Institute for Health Research (NIHR). Drs. Webb and Samani are funded by the British Heart Foundation, and Dr. Samani is an NIHR Senior Investigator. Dr. Masca was supported by the NIHR Leicester Cardiovascular Biomedical Research Unit (BRU), and this work forms part of the portfolio of research supported by the BRU. Dr. Won was supported by a postdoctoral award from the American Heart Association (15POST23280019). Dr. McCarthy is a Wellcome Trust Senior Investigator (098381) and an NIHR Senior Investigator. Dr. Danesh is a British Heart Foundation Professor, European Research Council Senior Investigator, and NIHR Senior Investigator. Drs. Erdmann, Webb, Samani, and Schunkert are supported by the FP7 European Union project CVgenes@target (261123) and the Fondation Leducq (CADgenomics, 12CVD02). Drs. Erdmann and Schunkert are also supported by the German Federal Ministry of Education and Research e:Med program (e:AtheroSysMed and sysINFLAME), and Deutsche Forschungsgemeinschaft cluster of excellence "Inflammation at Interfaces" and SFB 1123. Dr. Kessler received a DZHK Rotation Grant. The analysis was funded, in part, by a Programme Grant from the BHF (RG/14/5/30893 to Dr. Deloukas). Additional funding is listed in the Supplementary Appendix. NR 23 TC 21 Z9 21 U1 7 U2 21 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 24 PY 2016 VL 374 IS 12 BP 1134 EP 1144 DI 10.1056/NEJMoa1507652 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA DH2AA UT WOS:000372585100006 ER PT J AU Farzan, F Pascual-Leone, A Schmahmann, JD Halko, M AF Farzan, Faranak Pascual-Leone, Alvaro Schmahmann, Jeremy D. Halko, Mark TI Enhancing the Temporal Complexity of Distributed Brain Networks with Patterned Cerebellar Stimulation SO SCIENTIFIC REPORTS LA English DT Article ID THETA-BURST STIMULATION; TRANSCRANIAL MAGNETIC STIMULATION; DEFICIT HYPERACTIVITY DISORDER; RESTING-STATE NETWORKS; HUMAN MOTOR CORTEX; FUNCTIONAL CONNECTIVITY; OLIVOCEREBELLAR SYSTEM; MULTISCALE ENTROPY; LATERAL CEREBELLUM; DEFAULT MODE AB Growing evidence suggests that sensory, motor, cognitive and affective processes map onto specific, distributed neural networks. Cerebellar subregions are part of these networks, but how the cerebellum is involved in this wide range of brain functions remains poorly understood. It is postulated that the cerebellum contributes a basic role in brain functions, helping to shape the complexity of brain temporal dynamics. We therefore hypothesized that stimulating cerebellar nodes integrated in different networks should have the same impact on the temporal complexity of cortical signals. In healthy humans, we applied intermittent theta burst stimulation (iTBS) to the vermis lobule VII or right lateral cerebellar Crus I/II, subregions that prominently couple to the dorsal-attention/fronto-parietal and default-mode networks, respectively. Cerebellar iTBS increased the complexity of brain signals across multiple time scales in a network-specific manner identified through electroencephalography (EEG). We also demonstrated a region-specific shift in power of cortical oscillations towards higher frequencies consistent with the natural frequencies of targeted cortical areas. Our findings provide a novel mechanism and evidence by which the cerebellum contributes to multiple brain functions: specific cerebellar subregions control the temporal dynamics of the networks they are engaged in. C1 [Farzan, Faranak] Univ Toronto, Temerty Ctr Therapeut Brain Intervent, Ctr Addict & Mental Hlth, Toronto, ON M6J 1H4, Canada. [Pascual-Leone, Alvaro; Halko, Mark] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Berenson Allen Ctr Noninvas Brain Stimulat, Boston, MA 02215 USA. [Pascual-Leone, Alvaro; Halko, Mark] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Cognit Neurol,Dept Neurol, Boston, MA 02215 USA. [Schmahmann, Jeremy D.] Harvard Univ, Massachusetts Gen Hosp, Cognit Behav Neurol Unit,Dept Neurol,Med Sch, Lab Neuroanat & Cerebellar Neurobiol,Ataxia Unit, Boston, MA 02114 USA. RP Farzan, F (reprint author), Univ Toronto, Temerty Ctr Therapeut Brain Intervent, Ctr Addict & Mental Hlth, Toronto, ON M6J 1H4, Canada.; Halko, M (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Berenson Allen Ctr Noninvas Brain Stimulat, Boston, MA 02215 USA.; Halko, M (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Cognit Neurol,Dept Neurol, Boston, MA 02215 USA. EM faranak.farzan@utoronto.ca; mhalko@bidmc.harvard.edu RI Halko, Mark/G-8633-2016 OI Halko, Mark/0000-0002-7427-0789 FU Canadian Institute of Health Research (CIHR) [201102MFE-246635-181538]; Natural Sciences and Engineering Research Council of Canada (NSERC); Sidney R. Baer Jr. 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, National Institutes of Health) [KL2 TR001100]; National Ataxia Foundation; Ataxia Telangiectasia Children's Project; Birmingham Foundation; MINDlink Foundation; NIH [R01HD069776, R01NS073601, R21 MH099196, R21 NS085491, R21 HD07616]; Harvard Catalyst \ The Harvard Clinical and Translational Science Center (NCRR); Harvard Catalyst \ The Harvard Clinical and Translational Science Center (NCATS NIH) [UL1 RR025758] FX This study was primarily funded by the Sidney R. Baer Jr. Foundation. Dr. Farzan has received funding from Canadian Institute of Health Research (CIHR 201102MFE-246635-181538), and Natural Sciences and Engineering Research Council of Canada (NSERC). Dr. Halko was supported by a Sidney R. Baer Jr. Foundation Fellowship and the KL2/Catalyst Medical Research Investigator Training award (an appointed KL2 award) from Harvard Catalyst vertical bar The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award KL2 TR001100). Dr. Schmahmann was also supported by the National Ataxia Foundation, the Ataxia Telangiectasia Children's Project, and the Birmingham and MINDlink Foundations. Dr. Pascual-Leone was also supported in part by the NIH (R01HD069776, R01NS073601, R21 MH099196, R21 NS085491, R21 HD07616), and Harvard Catalyst vertical bar The Harvard Clinical and Translational Science Center (NCRR and the NCATS NIH, UL1 RR025758). 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 Institutes of Health, or the Sidney R. Baer Jr. Foundation. NR 59 TC 4 Z9 4 U1 6 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAR 24 PY 2016 VL 6 AR 23599 DI 10.1038/srep23599 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH3PN UT WOS:000372699000001 PM 27009405 ER PT J AU Zhou, C York, SR Chen, JY Pondick, JV Motola, DL Chung, RT Mullen, AC AF Zhou, Chan York, Samuel R. Chen, Jennifer Y. Pondick, Joshua V. Motola, Daniel L. Chung, Raymond T. Mullen, Alan C. TI Long noncoding RNAs expressed in human hepatic stellate cells form networks with extracellular matrix proteins SO GENOME MEDICINE LA English DT Article ID SMOOTH-MUSCLE ACTIN; HEPATOCELLULAR-CARCINOMA PATIENTS; MASTER TRANSCRIPTION FACTORS; FIBROTIC HUMAN-LIVER; ACTIVATION IN-VIVO; TRANSGENIC MICE; GENE-EXPRESSION; COEXPRESSION NETWORK; SUPER-ENHANCERS; X-CHROMOSOME AB Background: Hepatic fibrosis is the underlying cause of cirrhosis and liver failure in nearly every form of chronic liver disease, and hepatic stellate cells (HSCs) are the primary cell type responsible for fibrosis. Long noncoding RNAs (lncRNAs) are increasingly recognized as regulators of development and disease; however, little is known about their expression in human HSCs and their function in hepatic fibrosis. Methods: We performed RNA sequencing and ab initio assembly of RNA transcripts to define the lncRNAs expressed in human HSC myofibroblasts. We analyzed chromatin immunoprecipitation data and expression data to identify lncRNAs that were regulated by transforming growth factor beta (TGF-beta) signaling, associated with super-enhancers and restricted in expression to HSCs compared with 43 human tissues and cell types. Co-expression network analyses were performed to discover functional modules of lncRNAs, and principle component analysis and K-mean clustering were used to compare lncRNA expression in HSCs with other myofibroblast cell types. Results: We identified over 3600 lncRNAs that are expressed in human HSC myofibroblasts. Many are regulated by TGF-beta, a major fibrotic signal, and form networks with genes encoding key components of the extracellular matrix (ECM), which is the substrate of the fibrotic scar. The lncRNAs directly regulated by TGF-beta signaling are also enriched at super-enhancers. More than 400 of the lncRNAs identified in HSCs are uniquely expressed in HSCs compared with 43 other human tissues and cell types and HSC myofibroblasts demonstrate different patterns of lncRNA expression compared with myofibroblasts originating from other tissues. Co-expression analyses identified a subset of lncRNAs that are tightly linked to collagen genes and numerous proteins that regulate the ECM during formation of the fibrotic scar. Finally, we identified lncRNAs that are induced during progression of human liver disease. Conclusions: lncRNAs are likely key contributors to the formation and progression of fibrosis in human liver disease. C1 [Zhou, Chan; York, Samuel R.; Chen, Jennifer Y.; Pondick, Joshua V.; Motola, Daniel L.; Chung, Raymond T.; Mullen, Alan C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit,Dept Med, 55 Fruit St, Boston, MA 02114 USA. [Mullen, Alan C.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Mullen, AC (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit,Dept Med, 55 Fruit St, Boston, MA 02114 USA.; Mullen, AC (reprint author), Harvard Stem Cell Inst, Cambridge, MA 02138 USA. EM acmullen@mgh.harvard.edu RI ZHOU, Chan/A-7110-2009 OI ZHOU, Chan/0000-0002-0351-6235 FU NIDDK [DK078772, DK098079]; American Gastroenterological Association Elsevier Pilot Award; Massachusetts General Hospital Department of Medicine Transformative Scholar Award FX We thank Kaveh Daneshvar for helpful discussions and assistance with image processing and Scott Friedman for helpful discussions and review of the manuscript. We also thank Igor Ulitsky for advice on determining protein-coding potential. We thank Massachusetts General Hospital (MGH) Next Generation Sequencing Core for sequencing and the MGH Program in Membrane Biology microscopy core. This project was supported by NIDDK DK078772 and DK098079 (RTC) and the American Gastroenterological Association Elsevier Pilot Award and Massachusetts General Hospital Department of Medicine Transformative Scholar Award (ACM). NR 115 TC 3 Z9 3 U1 0 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-994X J9 GENOME MED JI Genome Med. PD MAR 23 PY 2016 VL 8 AR 31 DI 10.1186/s13073-016-0285-0 PG 20 WC Genetics & Heredity SC Genetics & Heredity GA DH4VS UT WOS:000372784300001 PM 27007663 ER PT J AU Strickland, KC Howitt, BE Shukla, SA Rodig, S Ritterhouse, LL Liu, JF Garber, JE Chowdhury, D Wu, CJ D'Andrea, AD Matulonis, UA Konstantinopoulos, PA AF Strickland, Kyle C. Howitt, Brooke E. Shukla, Sachet A. Rodig, Scott Ritterhouse, Lauren L. Liu, Joyce F. Garber, Judy E. Chowdhury, Dipanjan Wu, Catherine J. D'Andrea, Alan D. Matulonis, Ursula A. Konstantinopoulos, Panagiotis A. TI Association and prognostic significance of BRCA1/2-mutation status with neoantigen load, number of tumor-infiltrating lymphocytes and expression of PD-1/PD-L1 in high grade serous ovarian cancer SO ONCOTARGET LA English DT Article DE high grade serous ovarian cancer; BRCA1 and BRCA2 mutations; homologous recombination DNA repair; immunogenicity; PD-1 and PD-L1 ID ANTI-PD-L1 ANTIBODY; T-CELLS; RECOMBINATION; MUTATIONS; SURVIVAL; BRCA1; DEFICIENCY; CARCINOMAS; BLOCKADE; SAFETY AB Immune checkpoint inhibitors (e.g., anti-PD-1 and anti-PD-L1 antibodies) have demonstrated remarkable efficacy against hypermutated cancers such as melanomas and lung carcinomas. One explanation for this effect is that hypermutated lesions harbor more tumor-specific neoantigens that stimulate recruitment of an increased number of tumor-infiltrating lymphocytes (TILs), which is counterbalanced by overexpression of immune checkpoints such as PD-1 or PD-L1. Given that BRCA1/2-mutated high grade serous ovarian cancers (HGSOCs) exhibit a higher mutational load and a unique mutational signature with an elevated number of larger indels up to 50 bp, we hypothesized that they may also harbor more tumor-specific neoantigens, and, therefore, exhibit increased TILs and PD-1/PD-L1 expression. Here, we report significantly higher predicted neoantigens in BRCA1/2-mutated tumors compared to tumors without alterations in homologous recombination (HR) genes (HR-proficient tumors). Tumors with higher neoantigen load were associated with improved overall survival and higher expression of immune genes associated with tumor cytotoxicity such as genes of the TCR, the IFN-gamma and the TNFR pathways. Furthermore, immunohistochemistry studies demonstrated that BRCA1/2-mutated tumors exhibited significantly increased CD3+ and CD8+ TILs, as well as elevated expression of PD-1 and PD-L1 in tumor-associated immune cells compared to HR-proficient tumors. Survival analysis showed that both BRCA1/2-mutation status and number of TILs were independently associated with outcome. Of note, two distinct groups of HGSOCs, one with very poor prognosis (HR proficient with low number of TILs) and one with very good prognosis (BRCA1/2-mutated tumors with high number of TILs) were defined. These findings support a link between BRCA1/2-mutation status, immunogenicity and survival, and suggesting that BRCA1/2-mutated HGSOCs may be more sensitive to PD-1/PD-L1 inhibitors compared to HR-proficient HGSOCs. C1 [Strickland, Kyle C.; Howitt, Brooke E.; Rodig, Scott; Ritterhouse, Lauren L.] Harvard Univ, Sch Med, Dept Pathol, Brigham & Womens Hosp, Boston, MA 02115 USA. [Shukla, Sachet A.; Wu, Catherine J.] Broad Inst Harvard & MIT, Cambridge, MA USA. [Liu, Joyce F.; Matulonis, Ursula A.; Konstantinopoulos, Panagiotis A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Med Gynecol Oncol Program, 44 Binney St, Boston, MA 02115 USA. [Shukla, Sachet A.; Garber, Judy E.; Wu, Catherine J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. [Chowdhury, Dipanjan; D'Andrea, Alan D.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Genom Stabil & DNA Repair, 44 Binney St, Boston, MA 02115 USA. RP Konstantinopoulos, PA (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Med Gynecol Oncol Program, 44 Binney St, Boston, MA 02115 USA. EM panagiotis_konstantinopoulos@dfci.harvard.edu FU Blavatnik Family Foundation; NIH/NCI [1R01CA155010-04]; Scholar of the Leukemia and Lymphoma Society; DOD Ovarian Cancer Academy Award [W81XWH-10-1-0585]; Susan Smith Center for Women's Cancers; Stand Up To Cancer-Ovarian Cancer Research Fund-Ovarian Cancer National Alliance-National Ovarian Cancer Coalition Dream Team Translational Research Grant [SU2C-AACR-DT16-15]; Bristol-Myers Squibb; Roche-Ventana FX CJW acknowledges support from the Blavatnik Family Foundation and NIH/NCI (1R01CA155010-04), and is a Scholar of the Leukemia and Lymphoma Society. PAK acknowledges support from the DOD Ovarian Cancer Academy Award W81XWH-10-1-0585 and the Susan Smith Center for Women's Cancers. ADA and PAK acknowledge support from Stand Up To Cancer-Ovarian Cancer Research Fund-Ovarian Cancer National Alliance-National Ovarian Cancer Coalition Dream Team Translational Research Grant (grant number: SU2C-AACR-DT16-15).; SR has received research funding from Bristol-Myers Squibb and Roche-Ventana. All other authors have no conflicts of interests or financial disclosures to declare. NR 33 TC 22 Z9 22 U1 2 U2 4 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAR 22 PY 2016 VL 7 IS 12 BP 13587 EP 13598 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DL5OT UT WOS:000375687200024 PM 26871470 ER PT J AU Batth, I Yun, HY Hussain, S Meng, P Osumulski, P Huang, THM Bedolla, R Profit, A Reddick, R Kumar, A AF Batth, Izhar Yun, Huiyoung Hussain, Suleman Meng, Peng Osumulski, Powel Huang, Tim Hui-Ming Bedolla, Roble Profit, Amanda Reddick, Robert Kumar, Addanki TI Crosstalk between RON and androgen receptor signaling in the development of castration resistant prostate cancer SO ONCOTARGET LA English DT Article DE castrate resistant prostate cancer; apoptosis; FLIP; RON; MSTIR ID EPITHELIAL-MESENCHYMAL TRANSITION; TYROSINE KINASE; PANCREATIC-CANCER; DEPRIVATION THERAPY; ALTERED EXPRESSION; TUMOR PROGRESSION; BREAST-CANCER; C-MET; CELLS; GROWTH AB Castrate-resistant prostate cancer (CRPC) is the fatal form of prostate cancer. Although reactivation of androgen receptor (AR) occurs following androgen deprivation, the precise mechanism involved is unclear. Here we show that the receptor tyrosine kinase, RON alters mechanical properties of cells to influence epithelial to mesenchymal transition and functions as a transcription factor to differentially regulate AR signaling. RON inhibits AR activation and subset of AR-regulated transcripts in androgen responsive LNCaP cells. However in C4-2B, a castrate-resistant sub-line of LNCaP and AR-negative androgen independent DU145 cells, RON activates subset of AR-regulated transcripts. Expression of AR in PC-3 cells leads to activation of RON under androgen deprivation but not under androgen proficient conditions implicating a role for RON in androgen independence. Consistently, RON expression is significantly elevated in castrate resistant prostate tumors. Taken together our results suggest that RON activation could aid in promoting androgen independence and that inhibition of RON in combination with AR antagonist(s) merits serious consideration as a therapeutic option during hormone deprivation therapy. C1 [Batth, Izhar; Meng, Peng; Bedolla, Roble; Kumar, Addanki] Dept Urol, San Antonio, TX USA. [Yun, Huiyoung; Hussain, Suleman; Kumar, Addanki] Univ Texas San Antonio, Hlth Sci Ctr, Dept Pharmacol, 7703 Floyd Curl Dr, San Antonio, TX 78284 USA. [Osumulski, Powel; Huang, Tim Hui-Ming; Kumar, Addanki] Dept Mol Med, San Antonio, TX USA. [Profit, Amanda; Reddick, Robert] Univ Texas San Antonio, Hlth Sci Ctr, Dept Pathol, San Antonio, TX 78284 USA. [Huang, Tim Hui-Ming; Kumar, Addanki] Dept Canc Therapy & Res Ctr, San Antonio, TX USA. [Kumar, Addanki] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Kumar, Addanki] South Texas Vet Hlth Care Syst, San Antonio, TX USA. [Meng, Peng] Lawrence Berkeley Natl Lab, Div Life Sci, Berkeley, CA USA. [Batth, Izhar] Univ Texas MD Anderson Canc Ctr, Dept Pediat, Houston, TX 77030 USA. RP Kumar, A (reprint author), Dept Urol, San Antonio, TX USA.; Kumar, A (reprint author), Univ Texas San Antonio, Hlth Sci Ctr, Dept Pharmacol, 7703 Floyd Curl Dr, San Antonio, TX 78284 USA.; Kumar, A (reprint author), Dept Mol Med, San Antonio, TX USA.; Kumar, A (reprint author), Dept Canc Therapy & Res Ctr, San Antonio, TX USA.; Kumar, A (reprint author), Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA.; Kumar, A (reprint author), South Texas Vet Hlth Care Syst, San Antonio, TX USA. EM kumara3@uthscsa.edu FU Veterans Affairs-Merit Award [I01 BX 000766-01, 1R01CA135451, 1R01AT007448]; CTRC at UT Health Science Center San Antonio (UTHSCSA) through the National Cancer Institute [2P30 CA 054174-17]; CTRC 40th Anniversary Distinguished Professor of Oncology Endowment FX This work was supported in part by funds from Veterans Affairs-Merit Award I01 BX 000766-01, 1R01CA135451 and 1R01AT007448 (APK). We acknowledge support provided by CTRC at UT Health Science Center San Antonio (UTHSCSA) through the National Cancer Institute support grant #2P30 CA 054174-17. We acknowledge support provided by the CTRC 40th Anniversary Distinguished Professor of Oncology Endowment to APK. We thank Dr. JW Freeman, (UTHSCSA) for the RON-reporter; Dr. A. Lowey, (UC-San Diego) for the RON expression plasmid; Dr. D. Tindall, (Mayo Clinic Rochester) for pGL3-PSAARE constructs; and Dr. R. Vadlamudi (UTHSCSA) for providing PC-3AR cells. We sincerely thank Dr. R. Ghosh, (UTHSCSA) for critically reading the manuscript. NR 56 TC 1 Z9 1 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 MAR 22 PY 2016 VL 7 IS 12 BP 14048 EP 14063 PG 16 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DL5OT UT WOS:000375687200058 PM 26872377 ER PT J AU Kadoch, C Copeland, RA Keilhack, H AF Kadoch, Cigall Copeland, Robert A. Keilhack, Heike TI PRC2 and SWI/SNF Chromatin Remodeling Complexes in Health and Disease SO BIOCHEMISTRY LA English DT Article ID EMBRYONIC STEM-CELLS; HISTONE METHYLTRANSFERASE ACTIVITY; EZH2 SUPPRESSES METHYLATION; LYSINE 27 METHYLATION; DNA TRANSLOCATION; SYNOVIAL SARCOMA; RHABDOID TUMORS; GENE-EXPRESSION; SELF-RENEWAL; PROTEIN METHYLTRANSFERASES AB The dynamic structure of histones and DNA, also known as chromatin, is regulated by two classes of enzymes.: those that mediate covalent modifications on either histone proteins or DNA and those that use the energy generated by ATP hydrolysis to mechanically alter chromatic structure. Both classes of enzymes are often found in large protein complexes. In this review, we describe two such complexes: polycomb repressive complex 2 (PRC2), with the protein methyltransferase EZH2 as its catalytic subunit, and the ATP-dependent chromatin remodeler switch/sucrose non-fermentable (SWI/SNF). EZH2 catalyzes the methylation of lysine 27 on histone H3, a covalent chromatin modification that is associated with repressed heterochromatin. The catalytic activity of SWI/SNF, in contrast, leads to a state of open chromatin associated with active transcription. In this review, we discuss the biochemical properties of both complexes, outline the principles of their regulation, and describe their opposing roles in normal development, which can be perturbed in disease settings such as cancer. C1 [Kadoch, Cigall] Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. [Kadoch, Cigall] Harvard Univ, Sch Med, 450 Brookline Ave, Boston, MA 02215 USA. [Copeland, Robert A.; Keilhack, Heike] Epizyme Inc, 400 Technol Sq,4th Floor, Cambridge, MA 02139 USA. [Keilhack, Heike] Ribon Therapeut, 99 Hayden Ave,Bldg D,Suite 100, Lexington, MA 02421 USA. RP Keilhack, H (reprint author), Epizyme Inc, 400 Technol Sq,4th Floor, Cambridge, MA 02139 USA.; Keilhack, H (reprint author), Ribon Therapeut, 99 Hayden Ave,Bldg D,Suite 100, Lexington, MA 02421 USA. EM hkeilhack@ribontx.com NR 151 TC 4 Z9 4 U1 6 U2 14 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAR 22 PY 2016 VL 55 IS 11 BP 1600 EP 1614 DI 10.1021/acs.biochem.5b01191 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DH5UB UT WOS:000372856400005 PM 26836503 ER PT J AU Lacroix, M Battista, MC Doyon, M Moreau, J Patenaude, J Guillemette, L Menard, J Ardilouze, JL Perron, P Hivert, MF AF Lacroix, Marilyn Battista, Marie-Claude Doyon, Myriam Moreau, Julie Patenaude, Julie Guillemette, Laetitia Menard, Julie Ardilouze, Jean-Luc Perron, Patrice Hivert, Marie-France TI Higher maternal leptin levels at second trimester are associated with subsequent greater gestational weight gain in late pregnancy SO BMC PREGNANCY AND CHILDBIRTH LA English DT Article DE Leptin; Pregnancy; Weight gain; Body mass index ID INSULIN SENSITIVITY; GLUCOSE-TOLERANCE; DIABETES-MELLITUS; BODY-WEIGHT; HIGHER RISK; OBESITY; WOMEN; HYPOTHALAMUS; SUPPRESSION; DEFICIENCY AB Background: Excessive gestational weight gain (GWG) is associated with adverse pregnancy outcomes. In non-pregnant populations, low leptin levels stimulate positive energy balance. In pregnancy, both the placenta and adipose tissue contribute to circulating leptin levels. We tested whether maternal leptin levels are associated with subsequent GWG and whether this association varies depending on stage of pregnancy and on maternal body mass index (BMI). Methods: This prospective cohort study included 675 pregnant women followed from 1st trimester until delivery. We collected anthropometric measurements, blood samples at 1st and 2nd trimester, and clinical data until delivery. Maternal leptin was measured by ELISA (Luminex technology). We classified women by BMI measured at 1st trimester: BMI < 25 kg/m(2) = normal weight; 25 <= BMI < 30 kg/m(2) = overweight; and BMI >= 30 kg/m(2) = obese. Results: Women gained a mean of 6.7 +/- 3.0 kg between 1st and 2nd trimester (mid pregnancy GWG) and 5.6 +/- 2.5 kg between 2nd and the end of 3rd trimester (late pregnancy GWG). Higher 1st trimester leptin levels were associated with lower mid pregnancy GWG, but the association was no longer significant after adjusting for % body fat (% BF; beta = 0.38 kg per log-leptin; SE = 0.52; P = 0.46). Higher 2nd trimester leptin levels were associated with greater late pregnancy GWG and this association remained significant after adjustment for BMI (beta = 2.35; SE = 0.41; P < 0.0001) or % BF (beta = 2.01; SE = 0.42; P < 0.0001). In BMI stratified analyses, higher 2nd trimester leptin levels were associated with greater late pregnancy GWG in normal weight women (beta = 1.33; SE = 0.42; P = 0.002), and this association was stronger in overweight women (beta = 2.85; SE= 0.94; P = 0.003 - P for interaction = 0.05). Conclusions: Our results suggest that leptin may regulate weight gain differentially at 1st versus 2nd trimester of pregnancy: at 2nd trimester, higher leptin levels were associated with greater subsequent weight gain -the opposite of its physiologic regulation in non-pregnancy -and this association was stronger in overweight women. We suspect the existence of a feed-forward signal from leptin in second half of pregnancy, stimulating a positive energy balance and leading to greater weight gain. C1 [Lacroix, Marilyn; Battista, Marie-Claude; Patenaude, Julie; Guillemette, Laetitia; Ardilouze, Jean-Luc; Perron, Patrice; Hivert, Marie-France] Univ Sherbrooke, Dept Med, 3001 12th Ave North, Sherbrooke, PQ J1K 2R1, Canada. [Doyon, Myriam; Moreau, Julie; Menard, Julie; Ardilouze, Jean-Luc; Perron, Patrice; Hivert, Marie-France] Ctr Hosp Univ Sherbrooke, Ctr Rech, 3001 12th Ave North,Wing 9,Door 6, Sherbrooke, PQ J1K 2R1, Canada. [Hivert, Marie-France] Massachusetts Gen Hosp, Diabet Ctr, 50 Staniford St, Boston, MA 02114 USA. [Hivert, Marie-France] Harvard Univ, Sch Med, Harvard Pilgrim Hlth Care Inst, Dept Populat Med, 401 Pk Dr,Suite 401, Boston, MA USA. RP Hivert, MF (reprint author), Univ Sherbrooke, Dept Med, 3001 12th Ave North, Sherbrooke, PQ J1K 2R1, Canada.; Hivert, MF (reprint author), Ctr Hosp Univ Sherbrooke, Ctr Rech, 3001 12th Ave North,Wing 9,Door 6, Sherbrooke, PQ J1K 2R1, Canada.; Hivert, MF (reprint author), Massachusetts Gen Hosp, Diabet Ctr, 50 Staniford St, Boston, MA 02114 USA.; Hivert, MF (reprint author), Harvard Univ, Sch Med, Harvard Pilgrim Hlth Care Inst, Dept Populat Med, 401 Pk Dr,Suite 401, Boston, MA USA. EM marie-france_hivert@harvardpilgrim.org FU Fonds de Recherche du Quebec - Sante (FRQ-S); Diabete Quebec; Canadian Diabetes Association; Canadian Diabetes Association (CDA); Maud Menten Award from Institute of Genetics (IG) - Canadian Institute of Health Research (CIHR); ADA [1-15-ACE-26]; FRQ-S; Centre de recherche Mere-Enfant of Sherbrooke's University; Foundation of Stars FX The study was supported by a Fonds de Recherche du Quebec - Sante (FRQ-S) Operating Grant (MF Hivert), Diabete Quebec (P Perron) and a Canadian Diabetes Association Operating Grant (JL Ardilouze). MF Hivert was a FRQ-S research scholar and the recipient of a Clinical Scientist Award from the Canadian Diabetes Association (CDA) and the Maud Menten Award from the Institute of Genetics (IG) - Canadian Institute of Health Research (CIHR); MF Hivert is now the recipient of an ADA Accelerator Award #1-15-ACE-26. JL Ardilouze is a FRQ-S Junior 2 scholar. M Lacroix was supported by the FRQ-S, Diabete Quebec, the Centre de recherche Mere-Enfant of Sherbrooke's University, and the Foundation of Stars. NR 36 TC 2 Z9 2 U1 2 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2393 J9 BMC PREGNANCY CHILDB JI BMC Pregnancy Childbirth PD MAR 22 PY 2016 VL 16 AR 62 DI 10.1186/s12884-016-0842-y PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DH4TY UT WOS:000372779500002 PM 27004421 ER PT J AU Vijayvargia, R Epand, R Leitner, A Jung, TY Shin, B Jung, R Lloret, A Atwal, RS Lee, H Lee, JM Aebersold, R Hebert, H Song, JJ Seong, IS AF Vijayvargia, Ravi Epand, Raquel Leitner, Alexander Jung, Tae-Yang Shin, Baehyun Jung, Roy Lloret, Alejandro Atwal, Randy Singh Lee, Hyeongseok Lee, Jong-Min Aebersold, Ruedi Hebert, Hans Song, Ji-Joon Seong, Ihn Sik TI Huntingtin's spherical solenoid structure enables polyglutamine tract-dependent modulation of its structure and function SO ELIFE LA English DT Article ID DISEASE GENE ALLELES; MASS-SPECTROMETRY; CAG REPEAT; IN-VIVO; TOXICITY; PROTEIN; PHOSPHORYLATION; EXPRESSION; COMPLEX; DOMAIN AB The polyglutamine expansion in huntingtin protein causes Huntington's disease. Here, we investigated structural and biochemical properties of huntingtin and the effect of the polyglutamine expansion using various biophysical experiments including circular dichroism, single particle electron microscopy and cross-linking mass spectrometry. Huntingtin is likely composed of five distinct domains and adopts a spherical alpha-helical solenoid where the amino-terminal and carboxyl-terminal regions fold to contain a circumscribed central cavity. Interestingly, we showed that the polyglutamine expansion increases alpha-helical properties of huntingtin and affects the intramolecular interactions among the domains. Our work delineates the structural characteristics of full-length huntingtin, which are affected by the polyglutamine expansion, and provides an elegant solution to the apparent conundrum of how the extreme amino-terminal polyglutamine tract confers a novel property on huntingtin, causing the disease. C1 [Vijayvargia, Ravi; Shin, Baehyun; Jung, Roy; Lloret, Alejandro; Atwal, Randy Singh; Lee, Jong-Min; Seong, Ihn Sik] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Vijayvargia, Ravi; Shin, Baehyun; Jung, Roy; Lloret, Alejandro; Atwal, Randy Singh; Lee, Jong-Min; Seong, Ihn Sik] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Epand, Raquel] McMaster Univ, Biochem & Biomed Sci, Hamilton, ON, Canada. [Leitner, Alexander; Aebersold, Ruedi] ETH, Inst Mol Syst Biol, Dept Biol, Zurich, Switzerland. [Jung, Tae-Yang; Lee, Hyeongseok; Song, Ji-Joon] Korea Adv Inst Sci & Technol, KAIST Inst BioCentury, Dept Biol Sci, Canc Metastasis Control Ctr, Daejeon, South Korea. [Jung, Tae-Yang; Hebert, Hans] Karolinska Inst, Dept Biosci & Nutr, Solna, Sweden. [Jung, Tae-Yang; Hebert, Hans] KTH Royal Inst Technol, Novum, Sch Technol & Hlth, Stockholm, Sweden. [Aebersold, Ruedi] Univ Zurich, Fac Sci, Zurich, Switzerland. [Vijayvargia, Ravi] Maharaja Sayajirao Univ Baroda, Dept Biochem, Vadodara, India. [Lloret, Alejandro] Univ Autonoma Queretaro, Fac Med, Santiago De Queretaro, Mexico. RP Seong, IS (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.; Seong, IS (reprint author), Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA.; Song, JJ (reprint author), Korea Adv Inst Sci & Technol, KAIST Inst BioCentury, Dept Biol Sci, Canc Metastasis Control Ctr, Daejeon, South Korea. EM songj@kaist.ac.kr; iseong@mgh.harvard.edu RI Song, Ji-Joon/C-1721-2011 FU CHDI Foundation Inc; National Institutes of Health/National Institute of Neurological Disorders and Stroke [R01 NS079651]; Natural Sciences and Engineering Research Council of Canada [9848]; European Research Council [Proteomics v. 3.0, ERC Advanced Grant ] [233226]; National Research Foundation of Korea [NRF-2013R1A1A2055605, NRF-2014K2A3A1000137, 2011-0020334, 2011-0031955]; KIB [CMCC] [N10150028]; Brain Pool program by Korean Federation of Science and Technology Society (KOFST) - Korea Ministry of Science, ICT and Future Planning [152S-4-3-1328]; Jonasson donation FX We thank the members of the MacDonald, Lee, Song and Seong laboratories and Drs. S Kwak, R Lee, and D Lavery for suggestions and discussions. We are grateful to Jayalakshmi Mysore and Tammy Gillis (MGH NextGen Sequencing Core) for excellent technical support. This work was supported by CHDI Foundation Inc (JML and ISS); and National Institutes of Health/National Institute of Neurological Disorders and Stroke [R01 NS079651 to ISS]; Natural Sciences and Engineering Research Council of Canada [Grant 9848 to RE]; the European Research Council [Proteomics v. 3.0, ERC Advanced Grant 233226 to RA]; National Research Foundation of Korea [NRF-2013R1A1A2055605, NRF-2014K2A3A1000137, 2011-0020334, 2011-0031955 to JS]; and KIB [CMCC, N10150028 to JS]. ISS and JS were supported by Brain Pool program (152S-4-3-1328) by the Korean Federation of Science and Technology Society (KOFST) funded by the Korea Ministry of Science, ICT and Future Planning. T-YJ is supported by the Jonasson donation. NR 40 TC 2 Z9 2 U1 2 U2 6 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD MAR 22 PY 2016 VL 5 AR e11184 DI 10.7554/eLife.11184 PG 16 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DI2MW UT WOS:000373331100001 PM 27003594 ER PT J AU Breuer-Weil, A Almasoud, NN Abbasi, B Yetisen, AK Yun, SH Butt, H AF Breuer-Weil, Aaron Almasoud, Naif Nasser Abbasi, Badaruddin Yetisen, Ali K. Yun, Seok-Hyun Butt, Haider TI Parametric Simulations of Slanted 1D Photonic Crystal Sensors SO NANOSCALE RESEARCH LETTERS LA English DT Article ID CARBON NANOTUBE ARRAYS; HOLOGRAPHIC SENSORS; NANOSENSOR AB Photonic crystals and band gap materials act as manipulators of light and have a plethora of applications. They are made up of stacks of alternating dielectric constants. This article shows the simulations of an inclined, one dimensional and tuneble photonic crystal, using numerical finite element methods. The photonic crystal was made up of silver nanoparticles embedded in a hydrogel matrix and it has the ability to change and recover its periodicity. A series of factors concerning the geometry of the lattice were tested in order to analyze the efficiency, performance and optimize the properties of the optical sensor. These factors range from the size of the nanoparticles and their density within the stacks, to observing the effect of diffraction angle in readouts. C1 [Breuer-Weil, Aaron; Butt, Haider] Univ Birmingham, Sch Engn, Nanotechnol Lab, Birmingham B15 2TT, W Midlands, England. [Almasoud, Naif Nasser] Univ Dammam, Coll Dent, Dammam, Saudi Arabia. [Abbasi, Badaruddin] Univ Dammam, Deanship Sci Res, Dammam, Saudi Arabia. [Yetisen, Ali K.; Yun, Seok-Hyun] Harvard Univ, Sch Med, 65 Landsdowne St, Cambridge, MA 02139 USA. [Yetisen, Ali K.; Yun, Seok-Hyun] Massachusetts Gen Hosp, Wellman Ctr Photomed, 65 Landsdowne St, Cambridge, MA 02139 USA. [Yetisen, Ali K.; Yun, Seok-Hyun] MIT, Harvard MIT Div Hlth Sci & Technol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. RP Butt, H (reprint author), Univ Birmingham, Sch Engn, Nanotechnol Lab, Birmingham B15 2TT, W Midlands, England. EM h.butt@bham.ac.uk OI Butt, Haider/0000-0003-2434-9525 FU Leverhulme Trust FX HB thanks the Leverhulme Trust for research funding. NR 30 TC 1 Z9 1 U1 9 U2 143 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1556-276X J9 NANOSCALE RES LETT JI Nanoscale Res. Lett. PD MAR 22 PY 2016 VL 11 AR 157 DI 10.1186/s11671-016-1321-0 PG 10 WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied SC Science & Technology - Other Topics; Materials Science; Physics GA DH9AX UT WOS:000373089300005 PM 27000025 ER PT J AU Behrens, AJ Vasiljevic, S Pritchard, LK Harvey, DJ Andev, RS Krumm, SA Struwe, WB Cupo, A Kumar, A Zitzmann, N Seabright, GE Kramer, HB Spencer, DIR Royle, L Lee, JH Klasse, PJ Burton, DR Wilson, IA Ward, AB Sanders, RW Moore, JP Doores, KJ Crispin, M AF Behrens, Anna-Janina Vasiljevic, Snezana Pritchard, Laura K. Harvey, David J. Andev, Rajinder S. Krumm, Stefanie A. Struwe, Weston B. Cupo, Albert Kumar, Abhinav Zitzmann, Nicole Seabright, Gemma E. Kramer, Holger B. Spencer, Daniel I. R. Royle, Louise Lee, Jeong Hyun Klasse, Per J. Burton, Dennis R. Wilson, Ian A. Ward, Andrew B. Sanders, Rogier W. Moore, John P. Doores, Katie J. Crispin, Max TI Composition and Antigenic Effects of Individual Glycan Sites of a Trimeric HIV-1 Envelope Glycoprotein SO CELL REPORTS LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; BROADLY NEUTRALIZING ANTIBODIES; GLYCOSYLATION PROFILES; GP41-GP120 INTERFACE; DEPENDENT EPITOPE; CRYSTAL-STRUCTURE; VACCINE DESIGN; MANNOSE PATCH; ENV TRIMER; POTENT AB The HIV-1 envelope glycoprotein trimer is covered by an array of N-linked glycans that shield it from immune surveillance. The high density of glycans on the trimer surface imposes steric constraints limiting the actions of glycan-processing enzymes, so that multiple under-processed structures remain on specific areas. These oligomannose glycans are recognized by broadly neutralizing antibodies (bNAbs) that are not thwarted by the glycan shield but, paradoxically, target it. Our site-specific glycosylation analysis of a soluble, recombinant trimer (BG505 SOSIP.664) maps the extremes of simplicity and diversity of glycan processing at individual sites and reveals a mosaic of dense clusters of oligomannose glycans on the outer domain. Although individual sites usually minimally affect the global integrity of the glycan shield, we identify examples of how deleting some glycans can subtly influence neutralization by bNAbs that bind at distant sites. The network of bNAb-targeted glycans should be preserved on vaccine antigens. C1 [Behrens, Anna-Janina; Vasiljevic, Snezana; Pritchard, Laura K.; Harvey, David J.; Struwe, Weston B.; Kumar, Abhinav; Zitzmann, Nicole; Seabright, Gemma E.; Crispin, Max] Univ Oxford, Oxford Glycobiol Inst, S Parks Rd, Oxford OX1 3QU, England. [Behrens, Anna-Janina; Vasiljevic, Snezana; Pritchard, Laura K.; Harvey, David J.; Struwe, Weston B.; Kumar, Abhinav; Zitzmann, Nicole; Seabright, Gemma E.; Crispin, Max] Univ Oxford, Dept Biochem, S Parks Rd, Oxford OX1 3QU, England. [Andev, Rajinder S.; Krumm, Stefanie A.; Doores, Katie J.] Guys Hosp, Kings Coll London, Fac Life Sci & Med, Dept Infect Dis, London SE1 9RT, England. [Cupo, Albert; Klasse, Per J.; Sanders, Rogier W.; Moore, John P.] Weill Cornell Med Coll, Dept Microbiol & Immunol, New York, NY 10021 USA. [Kramer, Holger B.] Univ Oxford, Dept Physiol Anat & Genet, S Parks Rd, Oxford OX1 3QX, England. [Spencer, Daniel I. R.; Royle, Louise] Ludger Ltd, Culham Sci Ctr, Abingdon OX14 3EB, Oxon, England. [Lee, Jeong Hyun; Wilson, Ian A.; Ward, Andrew B.] Scripps Res Inst, Neutralizing Antibody Ctr, Int AIDS Vaccine Initiat, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA. [Lee, Jeong Hyun; Burton, Dennis R.; Wilson, Ian A.; Ward, Andrew B.] Scripps Res Inst, Ctr HIV AIDS Vaccine Immunol & Immunogen Discover, CAVD, La Jolla, CA 92037 USA. [Burton, Dennis R.] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Burton, Dennis R.] Ragon Inst Massachusetts Gen Hosp Massachusetts I, Cambridge, MA 02142 USA. [Wilson, Ian A.] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA. [Sanders, Rogier W.] Univ Amsterdam, Acad Med Ctr, Ctr Infect & Immun Amsterdam CINIMA, Lab Expt Virol,Dept Med Microbiol, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. RP Crispin, M (reprint author), Univ Oxford, Oxford Glycobiol Inst, S Parks Rd, Oxford OX1 3QU, England.; Crispin, M (reprint author), Univ Oxford, Dept Biochem, S Parks Rd, Oxford OX1 3QU, England.; Doores, KJ (reprint author), Guys Hosp, Kings Coll London, Fac Life Sci & Med, Dept Infect Dis, London SE1 9RT, England. EM katie.doores@kcl.ac.uk; max.crispin@bioch.ox.ac.uk RI Ward, Andrew/F-9203-2014; OI Ward, Andrew/0000-0001-7153-3769; Struwe, Weston/0000-0003-0594-226X; Doores, Katie/0000-0002-5507-1725 FU Chris Scanlan Memorial Scholarship from Corpus Christi College; University of Oxford; NIH [P01 AI110657, R37 AI36082]; International AIDS Vaccine Initiative Neutralizing Antibody Center CAVD grant; Scripps CHAVI-ID [1UM1AI100663]; Medical Research Council [MR/K024426/1]; Vidi grant from the Netherlands Organization for Scientific Research (NWO); Starting Investigator Grant from the European Research Council [ERC-StG-2011-280829-SHEV] FX We thank Professor Raymond A. Dwek, FRS, for insightful discussions. A.-J.B. is a recipient of a Chris Scanlan Memorial Scholarship from Corpus Christi College, University of Oxford. L.K.P. was supported by a scholarship from the Department of Biochemistry, University of Oxford. M.C. is a Fellow of Oriel College, University of Oxford. This work was supported by NIH grants P01 AI110657 (HIVRAD) and R37 AI36082, an International AIDS Vaccine Initiative Neutralizing Antibody Center CAVD grant (Glycan characterization and Outer Domain glycoform design), the Scripps CHAVI-ID (1UM1AI100663), and the Medical Research Council MR/K024426/1. R.W.S. is a recipient of a Vidi grant from the Netherlands Organization for Scientific Research (NWO) and a Starting Investigator Grant from the European Research Council (ERC-StG-2011-280829-SHEV). We are grateful to Anila Yasmeen for expert technical assistance with surface plasmon resonance analysis and Florian Klein for providing the 3BNC117 Fab plasmid. D.I.R.S. and L.R. are employees of Ludger, Ltd. NR 66 TC 27 Z9 27 U1 3 U2 14 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 MAR 22 PY 2016 VL 14 IS 11 BP 2695 EP 2706 DI 10.1016/j.celrep.2016.02.058 PG 12 WC Cell Biology SC Cell Biology GA DH0UG UT WOS:000372499000018 PM 26972002 ER PT J AU Natarajan, P O'Donnell, CJ AF Natarajan, Pradeep O'Donnell, Christopher J. TI Reducing Cardiovascular Risk Using Genomic Information in the Era of Precision Medicine SO CIRCULATION LA English DT Editorial Material DE lipoproteins; predictive genetic tests; genetic association studies; genetic notification; coronary artery disease; Editorials ID CORONARY-HEART-DISEASE; GENETIC RISK; CYSTIC-FIBROSIS; PREDICTION; EVENTS; SCORE; METAANALYSIS; ASSOCIATION; MUTATION; RECEPTOR C1 [Natarajan, Pradeep] Broad Inst, Cambridge, MA USA. [Natarajan, Pradeep] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Natarajan, Pradeep; O'Donnell, Christopher J.] Harvard Univ, Sch Med, Boston, MA USA. [O'Donnell, Christopher J.] Brigham & Womens Hosp, Div Cardiovasc, 75 Francis St, Boston, MA 02115 USA. [O'Donnell, Christopher J.] Boston Vet Adm Healthcare Syst, Cardiol Sect, 1400 Vet Foreign Wars Pkwy, Boston, MA 02132 USA. RP O'Donnell, CJ (reprint author), Boston Vet Adm Healthcare Syst, Cardiol Sect, 1400 Vet Foreign Wars Pkwy, Boston, MA 02132 USA. EM odonnellc@nhlbi.nih.gov FU Intramural NIH HHS [Z01 HL006002-02] NR 25 TC 1 Z9 1 U1 0 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 MAR 22 PY 2016 VL 133 IS 12 BP 1155 EP 1159 DI 10.1161/CIRCULATIONAHA.116.021765 PG 5 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DG9MC UT WOS:000372406100002 PM 26915631 ER PT J AU Charidimou, A Merwick, A AF Charidimou, Andreas Merwick, Aine TI Statin therapy in acute ischemic stroke Time for large randomized trials? SO NEUROLOGY LA English DT Editorial Material ID INFLAMMATION; RECURRENCE AB Despite improvements in stroke mortality coupled with therapeutic advances, stroke patients often face the prospect of substantial disability. Novel strategies are clearly needed to further improve stroke outcomes. These might include new indications for previously licensed drugs proven effective and safe in related disease processes,(1) such as statins. Unlike strong evidence supporting statin use in cardiovascular risk reduction and acute myocardial ischemia, their effects on cerebral tissue and potential benefits on stroke outcomes remain poorly understood and understudied. The only current stroke-specific indication for statin use is atorvastatin for secondary stroke prevention.(2) Recent meta-analyses found an association between prestroke statin use and good functional outcome (pooled odds ratio [OR]: 1.50; 95% confidence interval [CI]: 1.29-1.75; p < 0.001),(3) and lower mortality (pooled OR: 0.42; 95% CI: 0.21-0.82; p = 0.0108),(3-5) even in acute stroke patients treated with IV thrombolysis.(3) However, these estimates derive from relatively small observational cohorts at risk of bias. C1 [Charidimou, Andreas] Harvard Univ, Massachusetts Gen Hosp, Ctr Stroke Res,Med Sch, J Philip Kistler Stroke Res Ctr,Dept Neurol, Boston, MA USA. [Charidimou, Andreas] UCL Inst Neurol, Queen Sq, London, England. [Merwick, Aine] Chelsea & Westminster NHS Fdn Trust, London, England. RP Charidimou, A (reprint author), Harvard Univ, Massachusetts Gen Hosp, Ctr Stroke Res,Med Sch, J Philip Kistler Stroke Res Ctr,Dept Neurol, Boston, MA USA.; Charidimou, A (reprint author), UCL Inst Neurol, Queen Sq, London, England. EM andreas.charidimou.09@ucl.ac.uk NR 10 TC 2 Z9 2 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD MAR 22 PY 2016 VL 86 IS 12 BP 1082 EP 1083 DI 10.1212/WNL.0000000000002501 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA DG9KX UT WOS:000372403000002 PM 26911635 ER PT J AU Cong, LL Muir, ER Chen, C Qian, YS Liu, JW Biju, KC Clark, RA Li, SL Duong, TQ AF Cong, Linlin Muir, Eric R. Chen, Cang Qian, Yusheng Liu, Jingwei Biju, K. C. Clark, Robert A. Li, Senlin Duong, Timothy Q. TI Multimodal MRI Evaluation of the MitoPark Mouse Model of Parkinson's Disease SO PLOS ONE LA English DT Article ID CEREBRAL-BLOOD-FLOW; DEFICIENT DOPAMINE NEURONS; IRON-DEPOSITION; COGNITIVE IMPAIRMENT; SUBSTANTIA-NIGRA; ANIMAL-MODELS; BRAIN-TISSUE; IN-VIVO; DIFFUSION; MICE AB The MitoPark mouse, a relatively new genetic model of Parkinson's disease (PD), has a dopaminergic neuron-specific knock-out that inactivates the mitochondrial transcription factor A (Tfam), a protein essential for mitochondrial DNA expression and maintenance. This study used multimodal MRI to characterize the neuroanatomical correlates of PD-related deficits in MitoPark mice, along with functional behavioral tests. Compared with age-matched wild-type animals, MitoPark mice at 30 weeks showed: i) reduced whole-brain volume and increased ventricular volume, indicative of brain atrophy, ii) reduced transverse relaxation time (T-2*) of the substantia nigra and striatum, suggestive of abnormal iron accumulation, iii) reduced apparent diffusion coefficient in the substantia nigra, suggestive of neuronal loss, iv) reduced fractional anisotropy in the corpus callosum and substantia nigra, indicative of white-matter damages, v) cerebral blood flow was not significantly affected, and vi) reduced motor activity in open-field tests, reduced memory in novel object recognition tests, as well as decreased mobility in tail suspension tests, an indication of depression. In sum, MitoPark mice recapitulate changes in many MRI parameters reported in PD patients. Multimodal MRI may prove useful for evaluating neuroanatomical correlates of PD pathophysiology in MitoPark mice, and for longitudinally monitoring disease progression and therapeutic interventions for PD. C1 [Cong, Linlin; Muir, Eric R.; Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, San Antonio, TX 78229 USA. [Cong, Linlin] Univ Texas San Antonio, Grad Sch Biomed Sci, San Antonio, TX USA. [Muir, Eric R.; Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Dept Ophthalmol, San Antonio, TX 78229 USA. [Chen, Cang; Qian, Yusheng; Liu, Jingwei; Biju, K. C.; Clark, Robert A.; Li, Senlin] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Clark, Robert A.; Li, Senlin; Duong, Timothy Q.] South Texas Vet Hlth Care Syst, Dept Vet Affairs, San Antonio, TX USA. RP Muir, ER; Duong, TQ (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, San Antonio, TX 78229 USA.; Muir, ER; Duong, TQ (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Ophthalmol, San Antonio, TX 78229 USA.; Duong, TQ (reprint author), South Texas Vet Hlth Care Syst, Dept Vet Affairs, San Antonio, TX USA. EM muire@uthscsa.edu; duongt@uthscsa.edu FU United States (U.S.) Department of Veterans Biomedical Laboratory Research and Development Service [I01BX000737]; William and Ella Owens Medical Research Foundation FX work was supported by Merit Review Award #I01BX000737 from the United States (U.S.) Department of Veterans Biomedical Laboratory Research and Development Service and by a grant from the William and Ella Owens Medical Research Foundation awarded to S.L. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 0 Z9 0 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 22 PY 2016 VL 11 IS 3 AR e0151884 DI 10.1371/journal.pone.0151884 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH3OX UT WOS:000372697400053 PM 27003179 ER PT J AU Breckwoldt, MO Armoundas, AA Aon, MA Bendszus, M O'Rourke, B Schwarzlander, M Dick, TP Kurz, FT AF Breckwoldt, Michael O. Armoundas, Antonis A. Aon, Miguel A. Bendszus, Martin O'Rourke, Brian Schwarzlaender, Markus Dick, Tobias P. Kurz, Felix T. TI Mitochondrial redox and pH signaling occurs in axonal and synaptic organelle clusters SO SCIENTIFIC REPORTS LA English DT Article ID CARDIAC MYOCYTES; IN-VIVO; INDIVIDUAL MITOCHONDRIA; NEUROMUSCULAR-JUNCTIONS; SUPEROXIDE FLASHES; OSCILLATIONS; HEART; WAVES; ARABIDOPSIS; METABOLISM C1 [Breckwoldt, Michael O.; Bendszus, Martin; Kurz, Felix T.] Heidelberg Univ, Dept Neuroradiol, Neuenheimer Feld 400, D-69120 Heidelberg, Germany. [Armoundas, Antonis A.; Kurz, Felix T.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. [Aon, Miguel A.; O'Rourke, Brian] Johns Hopkins Univ, Dept Med, Div Cardiol, Baltimore, MD USA. [Aon, Miguel A.] NIA, Lab Cardiovasc Sci, Baltimore, MD 21224 USA. [Schwarzlaender, Markus] Univ Bonn, Inst Crop Sci & Resource Conservat INRES, Friedrich Ebert Allee 144, D-53113 Bonn, Germany. [Dick, Tobias P.] DKFZ ZMBH Alliance, Div Redox Regulat, German Canc Res Ctr DKFZ, Neuenheimer Feld 280, D-69120 Heidelberg, Germany. RP Breckwoldt, MO; Kurz, FT (reprint author), Heidelberg Univ, Dept Neuroradiol, Neuenheimer Feld 400, D-69120 Heidelberg, Germany.; Kurz, FT (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. EM michael.breckwoldt@med.uni-heidelberg.de; felix.kurz@med.uni-heidelberg.de RI Aon, Miguel/A-6564-2008 OI Aon, Miguel/0000-0002-4355-5431 FU physician-scientist fellowship of the Medical Faculty, University of Heidelberg; Hoffmann-Klose Foundation (University of Heidelberg); DFG through the Emmy Noether-Program [SCHW1719/1-1]; DFG Priority Program "Dynamics of thiol-based redox switches in cellular physiology" [SPP1710] FX We thank T. Misgeld (TU Munich) and M. Kerschensteiner (LMU Munich) for the support of this research and the critical discussion of the manuscript. We acknowledge experimental help by F. Bareyre, P. Bradley, A. Schmalz (LMU Munich) and L. Godinho and F. Pfister (TU Munich). We thank M. Murphy (University of Cambridge) for the kind gift of MitoQ and N. Demaurex (University of Geneva) for providing the SypHer construct. M.O.B. and F.T.K. were supported by a physician-scientist fellowship of the Medical Faculty, University of Heidelberg and by the Hoffmann-Klose Foundation (University of Heidelberg). M.O.B. was supported by a Neurowind e.V. prize for experimental neurology. M.S. is grateful for funding by the DFG through the Emmy Noether-Program (SCHW1719/1-1). M.S. and T.P.D. are supported by the DFG Priority Program "Dynamics of thiol-based redox switches in cellular physiology" (SPP1710). NR 48 TC 2 Z9 2 U1 3 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 MAR 22 PY 2016 VL 6 AR 23251 DI 10.1038/srep23251 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH0UM UT WOS:000372499600001 PM 27000952 ER PT J AU Lynch, CP Williams, JS Ruggiero, KJ Knapp, RG Egede, LE AF Lynch, Cheryl P. Williams, Joni S. Ruggiero, Kenneth J. Knapp, Rebecca G. Egede, Leonard E. TI Tablet-Aided BehavioraL intervention EffecT on Self-management skills (TABLETS) for Diabetes SO TRIALS LA English DT Article ID AMERICAN-HEART-ASSOCIATION; DISEASE RISK-FACTORS; CARDIOVASCULAR-DISEASE; PHYSICAL-ACTIVITY; RANDOMIZED-TRIAL; ETHNIC-DIFFERENCES; EMPOWERMENT SCALE; GLYCEMIC CONTROL; HEALTH LITERACY; PEER SUPPORT AB Background: Multiple randomized controlled trials (RCTs) show that behavioral lifestyle interventions are effective in improving diabetes management and that comprehensive risk factor management improves cardiovascular disease (CVD) outcomes. The role of technology has been gaining strong support as evidence builds of its potential to improve diabetes management; however, evaluation of its impact in minority populations is limited. This study intends to provide early evidence of a theory-driven intervention, Tablet-Aided BehavioraL intervention EffecT on Self-management skills (TABLETS), using real-time videoconferencing for education and skills training. We examine the potential for TABLETS to improve health risk behaviors and reduce CVD risk outcomes among a low-income African American (AA) population with poorly controlled type 2 diabetes. Methods: The study is a two-arm, pilot controlled trial that randomizes 30 participants to the TABLETS intervention and 30 participants to a usual care group. Blinded outcome assessments will be completed at baseline, 2.5 months (immediate post-intervention), and 6.5 months (follow-up). The TABLETS intervention consists of culturally tailored telephone-delivered diabetes education and skills training delivered via videoconferencing on tablet devices, with two booster sessions delivered via tablet-based videoconferencing at 3 months and 5 months to stimulate ongoing use of the tablet device with access to intervention materials via videoconferencing slides and a manual of supplementary materials. The primary outcomes are physical activity, diet, medication adherence, and self-monitoring behavior, whereas the secondary outcomes are HbA1c, low-density lipoprotein cholesterol (LDL-C), BP, CVD risk, and quality of life. Discussion: This study provides a unique opportunity to assess the feasibility and efficacy of a theory-driven, tablet-aided behavioral intervention that utilizes real-time videoconferencing technology for education and skills training on self-management behaviors and quality of life among a high-risk, low-income AA population with an uncontrolled dyad or triad of CVD risk factors (diabetes with or without hypertension or hyperlipidemia). The intervention leverages the use of novel technology for education and skill-building to foster improved diabetes self-management. The findings of this study will inform the process of disseminating the intervention to a broader and larger sample of people and can potentially be refined to align with clinical workflows that target a subsample of patients with poor diabetes self-management. C1 [Lynch, Cheryl P.; Williams, Joni S.; Egede, Leonard E.] Med Univ S Carolina, Div Gen Internal Med & Geriatr, Ctr Hlth Dispar Res, 135 Rutledge Ave,MSC 593, Charleston, SC 29425 USA. [Lynch, Cheryl P.; Ruggiero, Kenneth J.; Knapp, Rebecca G.; Egede, Leonard E.] Ralph H Johnson VAMC, Hlth Equity & Rural Outreach Innovat Ctr, 109 Bee St, Charleston, SC 29401 USA. [Ruggiero, Kenneth J.] Med Univ S Carolina, Coll Nursing, 19 Hagood Ave,Suite 1002,MSC 160, Charleston, SC 29425 USA. [Ruggiero, Kenneth J.] Med Univ S Carolina, Dept Psychiat & Behav Sci, 19 Hagood Ave,Suite 1002,MSC 160, Charleston, SC 29425 USA. [Knapp, Rebecca G.] Med Univ S Carolina, Dept Publ Hlth Sci, 135 Cannon St,MSC 835, Charleston, SC 29425 USA. RP Lynch, CP (reprint author), Med Univ S Carolina, Div Gen Internal Med & Geriatr, Ctr Hlth Dispar Res, 135 Rutledge Ave,MSC 593, Charleston, SC 29425 USA.; Lynch, CP (reprint author), Ralph H Johnson VAMC, Hlth Equity & Rural Outreach Innovat Ctr, 109 Bee St, Charleston, SC 29401 USA. EM lynchcp@musc.edu FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH) [R03DK098489] FX The study is funded by grant number R03DK098489 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH). NR 72 TC 0 Z9 0 U1 5 U2 8 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 MAR 22 PY 2016 VL 17 AR 157 DI 10.1186/s13063-016-1243-2 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DH2HC UT WOS:000372604300006 PM 27005766 ER PT J AU Ahmed, R Rifat, AA Yetisen, AK Dai, Q Yun, SH Butt, H AF Ahmed, Rajib Rifat, Ahmmed A. Yetisen, Ali K. Dai, Qing Yun, Seok Hyun Butt, Haider TI Multiwall carbon nanotube microcavity arrays SO JOURNAL OF APPLIED PHYSICS LA English DT Article ID OPTICAL-PROPERTIES; WAVE-GUIDE; FIBER; SENSOR; CORE AB Periodic highly dense multi-wall carbon nanotube (MWCNT) arrays can act as photonic materials exhibiting band gaps in the visible regime and beyond terahertz range. MWCNT arrays in square arrangement for nanoscale lattice constants can be configured as a microcavity with predictable resonance frequencies. Here, computational analyses of compact square microcavities (approximate to 0.8 x 0.8 mu m(2)) in MWCNT arrays were demonstrated to obtain enhanced quality factors (approximate to 170-180) and narrow-band resonance peaks. Cavity resonances were rationally designed and optimized (nanotube geometry and cavity size) with finite element method. Series (1 x 2 and 1 x 3) and parallel (2 x 1 and 3 x 1) combinations of microcavities were modeled and resonance modes were analyzed. Higher order MWCNT microcavities showed enhanced resonance modes, which were red shifted with increasing Q-factors. Parallel microcavity geometries were also optimized to obtain narrow-band tunable filtering in low-loss communication windows (810, 1336, and 1558 nm). Compact series and parallel MWCNT microcavity arrays may have applications in optical filters and miniaturized optical communication devices. (C) 2016 AIP Publishing LLC. C1 [Ahmed, Rajib; Butt, Haider] Univ Birmingham, Sch Mech Engn, Nanotechnol Lab, Birmingham B15 2TT, W Midlands, England. [Rifat, Ahmmed A.] Univ Malaya, Fac Engn, Dept Elect Engn, Integrated Lightwave Res Grp, Kuala Lumpur 50603, Malaysia. [Yetisen, Ali K.; Yun, Seok Hyun] Harvard Univ, Sch Med, 65 Landsdowne St, Cambridge, MA 02139 USA. [Yetisen, Ali K.; Yun, Seok Hyun] Massachusetts Gen Hosp, Wellman Ctr Photomed, 65 Landsdowne St, Cambridge, MA 02139 USA. [Yetisen, Ali K.; Yun, Seok Hyun] MIT, Harvard MIT Div Hlth Sci & Technol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Dai, Qing] Natl Ctr Nanosci & Technol, Beijing 100190, Peoples R China. RP Butt, H (reprint author), Univ Birmingham, Sch Mech Engn, Nanotechnol Lab, Birmingham B15 2TT, W Midlands, England. EM h.butt@bham.ac.uk RI engineering, @UM-2016/I-9329-2016; OI Butt, Haider/0000-0003-2434-9525 NR 32 TC 7 Z9 7 U1 6 U2 14 PU AMER INST PHYSICS PI MELVILLE PA 1305 WALT WHITMAN RD, STE 300, MELVILLE, NY 11747-4501 USA SN 0021-8979 EI 1089-7550 J9 J APPL PHYS JI J. Appl. Phys. PD MAR 21 PY 2016 VL 119 IS 11 AR 113105 DI 10.1063/1.4944318 PG 7 WC Physics, Applied SC Physics GA DI3FG UT WOS:000373383300005 ER PT J AU Henderson, TO Moskowitz, CS Chou, JF Bradbury, AR Neglia, JP Dang, CT Onel, K Friedman, DN Bhatia, S Strong, LC Stovall, M Kenney, LB Barnea, D Lorenzi, E Hammond, S Leisenring, WM Robison, LL Armstrong, GT Diller, LR Oeffinger, KC AF Henderson, Tara O. Moskowitz, Chaya S. Chou, Joanne F. Bradbury, Angela R. Neglia, Joseph Phillip Dang, Chau T. Onel, Kenan Friedman, Danielle Novetsky Bhatia, Smita Strong, Louise C. Stovall, Marilyn Kenney, Lisa B. Barnea, Dana Lorenzi, Elena Hammond, Sue Leisenring, Wendy M. Robison, Leslie L. Armstrong, Gregory T. Diller, Lisa R. Oeffinger, Kevin C. TI Breast Cancer Risk in Childhood Cancer Survivors Without a History of Chest Radiotherapy: A Report From the Childhood Cancer Survivor Study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ALKYLATING AGENT EXPOSURE; YOUNG-ADULT CANCER; HODGKINS LYMPHOMA; 5-YEAR SURVIVORS; SUBSEQUENT NEOPLASMS; SECONDARY SARCOMAS; FEMALE SURVIVORS; LATE MORTALITY; BONE SARCOMAS; RADIATION AB Purpose Little is known about the breast cancer risk among childhood cancer survivors who did not receive chest radiotherapy. We sought to determine the magnitude of risk and associated risk factors for breast cancer among these women. Patients and Methods We evaluated cumulative breast cancer risk in 3,768 female childhood cancer survivors without a history of chest radiotherapy who were participants in the Childhood Cancer Survivor Study. Results With median follow up of 25.5 years (range, 8 to 39 years), 47 women developed breast cancer at a median age of 38.0 years (range, 22 to 47 years) and median of 24.0 years (range, 10 to 34 years) from primary cancer to breast cancer. A four-fold increased breast cancer risk (standardized incidence ratio [SIR] = 4.0; 95% CI, 3.0 to 5.3) was observed when compared with the general population. Risk was highest among sarcoma and leukemia survivors (SIR = 5.3; 95% CI, 3.6 to 7.8 and SIR = 4.1; 95% CI, 2.4 to 6.9, respectively). By the age of 45 years, the cumulative incidence of breast cancer in sarcoma and leukemia survivors was 5.8% (95% CI, 3.7 to 8.4) and 6.3% (95% CI, 3.0 to 11.3), respectively. No other primary cancer diagnosis was associated with an elevated risk. Alkylators and anthracyclines were associated with an increased breast cancer risk in a dose-dependent manner (P values from test for trend were both,. 01). Conclusions Women not exposed to chest radiotherapy who survive childhood sarcoma or leukemia have an increased risk of breast cancer at a young age. The data suggest high-dose alkylator and anthracycline chemotherapy increase the risk of breast cancer. This may suggest a possible underlying gene-environment interaction that warrants further study. C1 [Henderson, Tara O.; Onel, Kenan] Univ Chicago, Chicago, IL 60637 USA. [Moskowitz, Chaya S.; Chou, Joanne F.; Dang, Chau T.; Friedman, Danielle Novetsky; Barnea, Dana; Lorenzi, Elena; Oeffinger, Kevin C.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Bradbury, Angela R.] Univ Penn, Philadelphia, PA 19104 USA. [Neglia, Joseph Phillip] Univ Minnesota, Minneapolis, MN USA. [Bhatia, Smita] Univ Alabama Birmingham, Birmingham, AL USA. [Strong, Louise C.; Stovall, Marilyn] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Kenney, Lisa B.; Diller, Lisa R.] Childrens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. [Lorenzi, Elena] Humanitas Clin & Res Ctr, Milan, Italy. [Hammond, Sue] Nationwide Childrens Hosp, Columbus, OH USA. [Leisenring, Wendy M.] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Robison, Leslie L.; Armstrong, Gregory T.] St Jude Childrens Res Hosp, 332 N Lauderdale St, Memphis, TN 38105 USA. RP Henderson, TO (reprint author), Univ Chicago, Comer Childrens Hosp, 5841 S Maryland Ave,MC 4060, Chicago, IL 60637 USA. EM thenderson@peds.bsd.uchicago.edu OI Friedman, Danielle Novetsky/0000-0003-4668-9176 FU National Cancer Institute [U24CA55727, K07CA134935, R01CA136783, K05CA160724, R01CA134722]; Meg Berte Owen Foundation; American Lebanese-Syrian Associated Charities; [P30 CA008748] FX Supported by grants from the National Cancer Institute (U24CA55727 [G.T.A.], K07CA134935 [T.O.H.], R01CA136783 [C.S.M.], K05CA160724, and R01CA134722 [K.C.O.]) and the Meg Berte Owen Foundation. Support to St Jude Children's Research Hospital was also provided by the American Lebanese-Syrian Associated Charities. Support to Memorial Sloan Kettering was provided by the core grant P30 CA008748. NR 54 TC 2 Z9 2 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 20 PY 2016 VL 34 IS 9 BP 910 EP + DI 10.1200/JCO.2015.62.3314 PG 10 WC Oncology SC Oncology GA DJ6OZ UT WOS:000374334100009 PM 26700127 ER PT J AU Vora, A Andreano, A Pui, CH Hunger, SP Schrappe, M Moericke, A Biondi, A Escherich, G Silverman, LB Goulden, N Taskinen, M Pieters, R Horibe, K Devidas, M Locatelli, F Valsecchi, MG AF Vora, Ajay Andreano, Anita Pui, Ching-Hon Hunger, Stephen P. Schrappe, Martin Moericke, Anja Biondi, Andrea Escherich, Gabriele Silverman, Lewis B. Goulden, Nicholas Taskinen, Mervi Pieters, Rob Horibe, Keizo Devidas, Meenakshi Locatelli, Franco Valsecchi, Maria Grazia TI Influence of Cranial Radiotherapy on Outcome in Children With Acute Lymphoblastic Leukemia Treated With Contemporary Therapy SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID MINIMAL RESIDUAL DISEASE; FARBER CANCER INSTITUTE; CHILDHOOD T-CELL; MRC UKALL XI; ONCOLOGY GROUP; PROGNOSTIC-FACTORS; COMPETING RISKS; AIEOP-BFM; TRIAL; METAANALYSIS AB Purpose We sought to determine whether cranial radiotherapy (CRT) is necessary to prevent relapse in any subgroup of children with acute lymphoblastic leukemia (ALL). Patients and Methods We obtained aggregate data on relapse and survival outcomes for 16,623 patients age 1 to 18 years old with newly diagnosed ALL treated between 1996 and 2007 by 10 cooperative study groups from around the world. The proportion of patients eligible for prophylactic CRT varied from 0% to 33% by trial and was not related to the proportion eligible for allogeneic stem-cell transplantation in first complete remission. Using a random effects model, with CRT as a dichotomous covariate, we performed a single-arm meta-analysis to compare event-free survival and cumulative incidence of isolated or any CNS relapse and isolated bone marrow relapse in high-risk subgroups of patients who either did or did not receive CRT. Results Although there was significant heterogeneity in all outcome end points according to trial, CRT was associated with a reduced risk of relapse only in the small subgroup of patients with overt CNS disease at diagnosis, who had a significantly lower risk of isolated CNS relapse (4% with CRT v 17% without CRT; P =.02) and a trend toward lower risk of any CNS relapse (7% with CRT v 17% without CRT; P =.09). However, this group had a relatively high rate of events regardless of whether or not they received CRT (32% [95% CI, 26% to 39%] v 34% [95% CI, 19% to 54%]; P =.8). Conclusion CRT does not have an impact on the risk of relapse in children with ALL treated on contemporary protocols. C1 [Vora, Ajay] Sheffield Childrens Hosp, Sheffield, S Yorkshire, England. [Vora, Ajay] Univ Sheffield, Sheffield, S Yorkshire, England. [Goulden, Nicholas] Great Ormond St Hosp Sick Children, London, England. [Andreano, Anita; Valsecchi, Maria Grazia] Univ Milano Bicocca, Sch Med & Surg, Milan, Italy. [Biondi, Andrea] Univ Milano Bicocca, Monza, Italy. [Locatelli, Franco] Bambino Gesu Pediat Hosp, Rome, Italy. [Locatelli, Franco] Univ Pavia, Via Palestro 3, I-27100 Pavia, Italy. [Pui, Ching-Hon] St Jude Childrens Res Hosp, 332 N Lauderdale St, Memphis, TN 38105 USA. [Pui, Ching-Hon] Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. [Hunger, Stephen P.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Hunger, Stephen P.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Silverman, Lewis B.] Dana Faber Canc Inst, Boston, MA USA. [Silverman, Lewis B.] Boston Childrens Hosp, Boston, MA USA. [Devidas, Meenakshi] Stat & Data Ctr, Childrens Oncol Grp, Gainesville, FL USA. [Devidas, Meenakshi] Univ Florida, Gainesville, FL USA. [Schrappe, Martin; Moericke, Anja] Univ Med Ctr, Kiel, Germany. [Schrappe, Martin; Moericke, Anja] Univ Kiel, Kiel, Germany. [Escherich, Gabriele] Univ Med Ctr Hamburg Eppendorf, Hamburg, Germany. [Taskinen, Mervi] Helsinki Univ Hosp, Helsinki, Finland. [Pieters, Rob] Princess Maxima Ctr Pediat Oncol, Utrecht, Netherlands. [Pieters, Rob] Dutch Childhood Oncol Grp, The Hague, Netherlands. [Horibe, Keizo] Natl Hosp Org Nagoya Med Ctr, Nagoya, Aichi, Japan. RP Vora, A (reprint author), Sheffield Childrens Hosp, Dept Pediat Hematol, Sheffield S10 2TH, S Yorkshire, England. EM ajay.vora@sch.nhs.uk OI Andreano, Anita/0000-0002-9667-7010 FU National Institutes of Health [U10 CA98543, U10 CA98413, CA21765, CA36401, U01 GM92666]; American Lebanese Syrian Associated Charities; United Kingdom Medical Research Council; Leukaemia and Lymphoma Research; Ministry of Health, Labour and Welfare of Japan; European Network of Cancer Research in Children and Adolescents from the European Commission for Statistical Analysis [FP7-HEALTH-F2-2011 261474] FX Supported in part by Grants No. U10 CA98543, U10 CA98413, CA21765, CA36401, and U01 GM92666 from the National Institutes of Health, American Lebanese Syrian Associated Charities, the United Kingdom Medical Research Council, and Leukaemia and Lymphoma Research; grants for Clinical Cancer Research from the Ministry of Health, Labour and Welfare of Japan; and European Network of Cancer Research in Children and Adolescents Grant No. FP7-HEALTH-F2-2011 261474 from the European Commission for Statistical Analysis. NR 31 TC 5 Z9 5 U1 2 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 20 PY 2016 VL 34 IS 9 BP 919 EP + DI 10.1200/JCO.2015.64.2850 PG 9 WC Oncology SC Oncology GA DJ6OZ UT WOS:000374334100010 PM 26755523 ER PT J AU Colleoni, M Sun, Z Price, KN Karlsson, P Forbes, JF Thulimann, B Gianni, L Castiglione, M Gelber, RD Coates, AS Goldhirsch, A AF Colleoni, Marco Sun, Zhuoxin Price, Karen N. Karlsson, Per Forbes, John F. Thurlimann, Beat Gianni, Lorenzo Castiglione, Monica Gelber, Richard D. Coates, Alan S. Goldhirsch, Aron TI Annual Hazard Rates of Recurrence for Breast Cancer During 24 Years of Follow-Up: Results From the International Breast Cancer Study Group Trials I to V SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID AGE 50 YEARS; RANDOMIZED-TRIALS; ADJUVANT CHEMOTHERAPY; NATURAL-HISTORY; PRIMARY THERAPY; TUMOR DORMANCY; COMPETING RISK; WOMEN; SURVIVAL; SURGERY AB Purpose Predicting the pattern of recurrence can aid in the development of targeted surveillance and treatment strategies. We identified patient populations that remain at risk for an event at a median follow-up of 24 years from the diagnosis of operable breast cancer. Patients and Methods International Breast Cancer Study Group clinical trials I to V randomly assigned 4,105 patients between 1978 and 1985. Annualized hazards were estimated for breast cancer-free interval (primary end point), disease-free survival, and overall survival. Results For the entire group, the annualized hazard of recurrence was highest during the first 5 years (10.4%), with a peak between years 1 and 2 (15.2%). During the first 5 years, patients with estrogen receptor (ER) - positive disease had a lower annualized hazard compared with those with ER-negative disease (9.9% v 11.5%; P =.01). However, beyond 5 years, patients with ER-positive disease had higher hazards (5 to 10 years: 5.4% v 3.3%; 10 to 15 years: 2.9% v 1.3%; 15 to 20 years: 2.8% v 1.2%; and 20 to 25 years: 1.3% v 1.4%; P<. 001). Among patients with ER-positive disease, annualized hazards of recurrence remained elevated and fairly stable beyond 10 years, even for those with no axillary involvement (2.0%, 2.1%, and 1.1% for years 10 to 15, 15 to 20, and 20 to 25, respectively) and for those with one to three positive nodes (3.0%, 3.5%, and 1.5%, respectively). Conclusion Patients with ER-positive breast cancer maintain a significant recurrence rate during extended follow up. Strategies for follow up and treatments to prevent recurrences may be most efficiently applied and studied in patients with ER-positive disease followed for a long period of time. C1 [Colleoni, Marco; Goldhirsch, Aron] European Inst Oncol, Milan, Italy. [Colleoni, Marco; Goldhirsch, Aron] Int Breast Canc Study Grp, Milan, Italy. [Gianni, Lorenzo] Osped Infermi, Rimini, Italy. [Gianni, Lorenzo] Ist Sci Romagnolo Studio & Cura Tumori, Rimini, Italy. [Sun, Zhuoxin; Price, Karen N.; Gelber, Richard D.] Int Breast Canc Study Grp, Ctr Stat, Bern, Switzerland. [Sun, Zhuoxin; Price, Karen N.; Gelber, Richard D.] Frontier Sci & Technol Res Fdn Inc, Madison, WI USA. [Sun, Zhuoxin; Gelber, Richard D.] Harvard Univ, TH Chan Sch Publ Hlth, Cambridge, MA 02138 USA. [Gelber, Richard D.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Gelber, Richard D.] Harvard Univ, Sch Med, Boston, MA USA. [Karlsson, Per] Sahlgrens Univ Hosp, Sahlgrenska Acad, Inst Selected Clin Sci, Gothenburg, Sweden. [Forbes, John F.] Univ Newcastle, Australia & New Zealand Breast Canc Trials Grp, Newcastle Mater Hosp, Newcastle, NSW 2300, Australia. [Coates, Alan S.] Int Breast Canc Study Grp, Sydney, NSW, Australia. [Coates, Alan S.] Univ Sydney, Sydney, NSW 2006, Australia. [Thurlimann, Beat] Kantonsspital, Breast Ctr, St Gallen, Switzerland. [Thurlimann, Beat] Swiss Grp Clin Canc Res, Bern, Switzerland. [Castiglione, Monica] Int Breast Canc Study Grp, Bern, Switzerland. RP Colleoni, M (reprint author), European Inst Oncol, Div Med Senol, Via Ripamonti 435, I-20141 Milan, Italy. EM marco.colleoni@ieo.it FU Ludwig Institute for Cancer Research; Cancer League of Ticino; US National Cancer Institute [CA-75362] FX Supported initially by the Ludwig Institute for Cancer Research and the Cancer League of Ticino; supported currently in central coordination, data management, and statistics by the Swedish Cancer League, Cancer Council Australia, Australian New Zealand Breast Cancer Trials Group, Frontier Science and Technology Research Foundation, Swiss Group for Clinical Cancer Research, Swiss Cancer League, and US National Cancer Institute (Grant No. CA-75362); by the Cancer Association of South Africa for Cape Town participants; and by the Foundation for Clinical Cancer Research of Eastern Switzerland for St Gallen participants. NR 35 TC 5 Z9 5 U1 11 U2 13 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 20 PY 2016 VL 34 IS 9 BP 927 EP + DI 10.1200/JCO.2015.62.3504 PG 11 WC Oncology SC Oncology GA DJ6OZ UT WOS:000374334100011 PM 26786933 ER PT J AU Freedman, RA Gelman, RS Wefel, JS Melisko, ME Hess, KR Connolly, RM Van Poznak, CH Niravath, PA Puhalla, SL Ibrahim, N Blackwell, KL Moy, B Herold, C Liu, MC Lowe, A Agar, NYR Ryabin, N Farooq, S Lawler, E Rimawi, MF Krop, IE Wolff, AC Winer, EP Lin, NU AF Freedman, Rachel A. Gelman, Rebecca S. Wefel, Jeffrey S. Melisko, Michelle E. Hess, Kenneth R. Connolly, Roisin M. Van Poznak, Catherine H. Niravath, Polly A. Puhalla, Shannon L. Ibrahim, Nuhad Blackwell, Kimberly L. Moy, Beverly Herold, Christina Liu, Minetta C. Lowe, Alarice Agar, Nathalie Y. R. Ryabin, Nicole Farooq, Sarah Lawler, Elizabeth Rimawi, Mothaffar F. Krop, Ian E. Wolff, Antonio C. Winer, Eric P. Lin, Nancy U. TI Translational Breast Cancer Research Consortium (TBCRC) 022: A Phase II Trial of Neratinib for Patients With Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer and Brain Metastases SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CIRCULATING TUMOR-CELLS; LAPATINIB PLUS CAPECITABINE; NERVOUS-SYSTEM METASTASES; TYROSINE KINASE INHIBITOR; NEUROCOGNITIVE FUNCTION; PERIPHERAL-BLOOD; NORMATIVE DATA; SOLID TUMORS; TRASTUZUMAB; SURVIVAL AB Purpose Evidence-based treatments for metastatic, human epidermal growth factor receptor 2 (HER2)-positive breast cancer in the CNS are limited. Neratinib is an irreversible inhibitor of erbB1, HER2, and erbB4, with promising activity in HER2-positive breast cancer; however, its activity in the CNS is unknown. We evaluated the efficacy of treatment with neratinib in patients with HER2-positive breast cancer brain metastases in a multicenter, phase II open-label trial. Patients and Methods Eligible patients were those with HER2-positive brain metastases (>= 1 cm in longest dimension) who experienced progression in the CNS after one or more line of CNS-directed therapy, such as whole-brain radiotherapy, stereotactic radiosurgery, and/or surgical resection. Patients received neratinib 240 mg orally once per day, and tumors were assessed every two cycles. The primary endpoint was composite CNS objective response rate (ORR), requiring all of the following: >= 50% reduction in volumetric sum of target CNS lesions and no progression of non-target lesions, new lesions, escalating corticosteroids, progressive neurologic signs/symptoms, or non-CNS progression-the threshold for success was five of 40 responders. Results Forty patients were enrolled between February 2012 and June 2013; 78% of patients had previous whole-brain radiotherapy. Three women achieved a partial response (CNS objective response rate, 8%; 95% CI, 2% to 22%). The median number of cycles received was two (range, one to seven cycles), with a median progression-free survival of 1.9 months. Five women received six or more cycles. The most common grade >= 3 event was diarrhea (occurring in 21% of patients taking prespecified loperamide prophylaxis and 28% of those without prophylaxis). Patients in the study experienced a decreased quality of life over time. Conclusion Although neratinib had low activity and did not meet our threshold for success, 12.5% of patients received six or more cycles. Studies combining neratinib with chemotherapy in patients with CNS disease are ongoing. C1 [Freedman, Rachel A.; Gelman, Rebecca S.; Herold, Christina; Ryabin, Nicole; Farooq, Sarah; Lawler, Elizabeth; Krop, Ian E.; Winer, Eric P.; Lin, Nancy U.] Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. [Moy, Beverly] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Lowe, Alarice; Agar, Nathalie Y. R.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Wefel, Jeffrey S.; Hess, Kenneth R.; Ibrahim, Nuhad] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Niravath, Polly A.; Rimawi, Mothaffar F.] Baylor Coll Med, Houston, TX 77030 USA. [Melisko, Michelle E.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Connolly, Roisin M.; Wolff, Antonio C.] Johns Hopkins Univ, Baltimore, MD USA. [Van Poznak, Catherine H.] Univ Michigan, Ann Arbor, MI 48109 USA. [Puhalla, Shannon L.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Puhalla, Shannon L.] Magee Womens Hosp, Pittsburgh, PA USA. [Blackwell, Kimberly L.] Duke Univ, Med Ctr, Durham, NC USA. [Liu, Minetta C.] Mayo Clin, Rochester, MN USA. RP Freedman, RA (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM rafreedman@partners.org FU AVON Foundation; Breast Cancer Research Foundation; Susan G. Komen for the Cure; Dana-Farber Women's Cancer Program Executive Council; Dana-Farber/Harvard Cancer Center [P30 CA006516]; Puma Biotechnology FX Support provided to the Translational Breast Cancer Research Consortium by the AVON Foundation, the Breast Cancer Research Foundation, and Susan G. Komen for the Cure. Additional funding support provided by the Breast Cancer Research Foundation (N.U.L.), the Dana-Farber Women's Cancer Program Executive Council Personalized Medicine Award (N.U.L.), Dana-Farber/Harvard Cancer Center P30 CA006516 (R.S.G.), and Puma Biotechnology. NR 46 TC 10 Z9 10 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 20 PY 2016 VL 34 IS 9 BP 945 EP + DI 10.1200/JCO.2015.63.0343 PG 10 WC Oncology SC Oncology GA DJ6OZ UT WOS:000374334100013 PM 26834058 ER PT J AU Dizon, DS Krilov, L Cohen, E Gangadhar, T Ganz, PA Hensing, TA Hunger, S Krishnamurthi, SS Lassman, AB Markham, MJ Mayer, E Neuss, M Pal, SK Richardson, LC Schilsky, R Schwartz, GK Spriggs, DR Villalona-Calero, MA Villani, G Masters, G AF Dizon, Don S. Krilov, Lada Cohen, Ezra Gangadhar, Tara Ganz, Patricia A. Hensing, Thomas A. Hunger, Stephen Krishnamurthi, Smitha S. Lassman, Andrew B. Markham, Merry Jennifer Mayer, Erica Neuss, Michael Pal, Sumanta Kumar Richardson, Lisa C. Schilsky, Richard Schwartz, Gary K. Spriggs, David R. Villalona-Calero, Miguel Angel Villani, Gina Masters, Gregory TI Clinical Cancer Advances 2016: Annual Report on Progress Against Cancer From the American Society of Clinical Oncology SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CELL LUNG-CANCER; ACUTE LYMPHOBLASTIC-LEUKEMIA; RANDOMIZED CONTROLLED-TRIAL; CHIMERIC ANTIGEN RECEPTOR; SENSITIVE OVARIAN-CANCER; ADVANCED BREAST-CANCER; UNITED-STATES; UNTREATED MELANOMA; PALLIATIVE CARE; PD-1 BLOCKADE C1 [Dizon, Don S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Mayer, Erica] Dana Farber Canc Inst, Boston, MA 02115 USA. [Krilov, Lada; Schilsky, Richard] Amer Soc Clin Oncol, 2318 Mill Rd,Suite 800, Alexandria, VA 22314 USA. [Cohen, Ezra] Univ Calif San Diego, San Diego, CA 92103 USA. [Ganz, Patricia A.] Univ Calif Los Angeles, Los Angeles, CA USA. [Pal, Sumanta Kumar] City Hope Comprehens Canc Ctr, Duarte, CA USA. [Gangadhar, Tara] Univ Penn, Philadelphia, PA 19104 USA. [Hunger, Stephen] Childrens Hosp Ctr Philadelphia, Philadelphia, PA USA. [Hensing, Thomas A.] Univ Chicago, Evanston, IL USA. [Krishnamurthi, Smitha S.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Lassman, Andrew B.; Schwartz, Gary K.] Columbia Univ, New York, NY USA. [Spriggs, David R.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Villani, Gina] Ralph Lauren Ctr Canc Care & Prevent, New York, NY USA. [Markham, Merry Jennifer] Univ Florida, Gainesville, FL USA. [Villalona-Calero, Miguel Angel] Miami Canc Inst, Miami, FL USA. [Neuss, Michael] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Richardson, Lisa C.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Masters, Gregory] Helen F Graham Canc Ctr & Res Inst, Newark, DE USA. RP Krilov, L (reprint author), Amer Soc Clin Oncol, 2318 Mill Rd,Suite 800, Alexandria, VA 22314 USA. EM lada.krilov@asco.org OI Markham, Merry/0000-0003-3567-3494 FU Intramural CDC HHS [CC999999]; NCATS NIH HHS [UL1 TR001427] NR 86 TC 20 Z9 23 U1 1 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 20 PY 2016 VL 34 IS 9 BP 987 EP + DI 10.1200/JCO.2015.65.8427 PG 27 WC Oncology SC Oncology GA DJ6OZ UT WOS:000374334100018 PM 26846975 ER PT J AU Wright, AA Cronin, A O'Malley, DM AF Wright, Alexi A. Cronin, Angel O'Malley, David M. TI Potential Simpson's Paradox in Multicenter Study of Intraperitoneal Chemotherapy for Ovarian Cancer Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID CISPLATIN; PACLITAXEL C1 [Wright, Alexi A.; Cronin, Angel] Dana Farber Canc Inst, Boston, MA 02115 USA. [Wright, Alexi A.; Cronin, Angel] Brigham & Womens Canc Ctr, Boston, MA USA. [O'Malley, David M.] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. RP Wright, AA (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA.; Wright, AA (reprint author), Brigham & Womens Canc Ctr, Boston, MA USA. FU NCI NIH HHS [K07 CA166210] NR 5 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 20 PY 2016 VL 34 IS 9 DI 10.1200/JCO.2015.65.3782 PG 3 WC Oncology SC Oncology GA DJ6OZ UT WOS:000374334100024 PM 26755516 ER PT J AU Cui, DM Han, DM Nicolas, B Hu, CL Wu, J Su, MM AF Cui, Dan-Mo Han, De-Min Nicolas, Busaba Hu, Chang-Long Wu, Jun Su, Min-Min TI Three-dimensional Evaluation of Nasal Surgery in Patients with Obstructive Sleep Apnea SO CHINESE MEDICAL JOURNAL LA English DT Article DE Nasal Surgery; Obstructive Sleep Apnea; Postoperative Outcome; Three-dimensional Computed Tomography Scan ID BEAM COMPUTED-TOMOGRAPHY; AIRWAY; RESPIRATION; ACCURACY AB Background: Obstructive sleep apnea (OSA) is a common sleep disorder and is characterized by airway collapse at multiple levels of upper airway. The effectiveness of nasal surgery has been discussed in several studies and shows a promising growing interest. In this study, we intended to evaluate the effects of nasal surgery on the upper airway dimensions in patients with OSA using three-dimensional (3D) reconstruction of cone-beam computed tomography (CT). Methods: Twelve patients with moderate to severe OSA who underwent nasal surgery were included in this study. All patients were diagnosed with OSA using polysomnography (PSG) in multi sleep health centers associated with Massachusetts General Hospital, Massachusetts Eye and Ear Infirmary and the Partners Health Care from May 31, 2011 to December 14, 2013. The effect of nasal surgery was evaluated by the examination of PSG, subjective complains, and 3D reconstructed CT scan. Cross-sectional area was measured in eleven coronal levels, and nasal cavity volume was evaluated from anterior nasal spine to posterior nasal spine. The thickness of soft tissue in oral pharynx region was also measured. Results: Five out of the 12 patients were successfully treated by nasal surgery, with more than 50% drop of apnea-hypopnea index. All the 12 patients showed significant increase of cross-sectional area and volume postoperatively. The thickness of soft tissue in oral pharynx region revealed significant decrease postoperatively, which decreased from 19.14 +/- 2.40 cm(2) and 6.11 +/- 1.76 cm(2) to 17.13 +/- 1.91 cm(2) and 5.22 +/- 1.20 cm(2) . Conclusions: Nasal surgery improved OSA severity as measured by PSG, subjective complaints, and 3D reconstructed CT scan. 3D assessment of upper airway can play an important role in the evaluation of treatment outcome. C1 [Cui, Dan-Mo; Han, De-Min; Hu, Chang-Long; Wu, Jun; Su, Min-Min] Capital Med Univ, Beijing Tongren Hosp, Dept Otolaryngol Head & Neck Surg, Beijing 100730, Peoples R China. [Cui, Dan-Mo; Nicolas, Busaba] Harvard Univ, Dept Otolaryngol Head & Neck Surg, Massachusetts Eye & Ear Infirm, Cambridge, MA 02138 USA. [Han, De-Min] Beijing Inst Otorhinolaryngol, Key Lab Otorhinolaryngol Head & Neck Surg, Minist Educ, Beijing 100005, Peoples R China. RP Han, DM (reprint author), Capital Med Univ, Beijing Tongren Hosp, Dept Otolaryngol Head & Neck Surg, Beijing 100730, Peoples R China.; Han, DM (reprint author), Beijing Inst Otorhinolaryngol, Key Lab Otorhinolaryngol Head & Neck Surg, Minist Educ, Beijing 100005, Peoples R China. EM enthandm@126.com NR 28 TC 1 Z9 1 U1 2 U2 4 PU MEDKNOW PUBLICATIONS & MEDIA PVT LTD PI MUMBAI PA B-9, KANARA BUSINESS CENTRE, OFF LINK RD, GHAKTOPAR-E, MUMBAI, 400075, INDIA SN 0366-6999 J9 CHINESE MED J-PEKING JI Chin. Med. J. PD MAR 20 PY 2016 VL 129 IS 6 BP 651 EP 656 DI 10.4103/0366-6999.177971 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA DG5XG UT WOS:000372153300004 PM 26960367 ER PT J AU Cesar, C Koethe, JR Giganti, MJ Rebeiro, P Althoff, KN Napravnik, S Mayor, A Grinsztejn, B Wolff, M Padgett, D Sierra-Madero, J Gotuzzo, E Sterling, TR Willig, J Levison, J Kitahata, M Rodriguez-Barradas, MC Moore, RD McGowan, C Shepherd, BE Cahn, P AF Cesar, Carina Koethe, John R. Giganti, Mark J. Rebeiro, Peter Althoff, Keri N. Napravnik, Sonia Mayor, Angel Grinsztejn, Beatriz Wolff, Marcelo Padgett, Denis Sierra-Madero, Juan Gotuzzo, Eduardo Sterling, Timothy R. Willig, James Levison, Julie Kitahata, Mari Rodriguez-Barradas, Maria C. Moore, Richard D. McGowan, Catherine Shepherd, Bryan E. Cahn, Pedro CA Caribbean Cent South Amer Network North Amer AIDS Cohort TI Health outcomes among HIV-positive Latinos initiating antiretroviral therapy in North America versus Central and South America SO JOURNAL OF THE INTERNATIONAL AIDS SOCIETY LA English DT Article DE HIV; antiretroviral therapy; highly active; mortality; Latin America; North America; cohort studies ID LONG-TERM OUTCOMES; UNITED-STATES; HIV-1-INFECTED PATIENTS; INFECTED PATIENTS; INCOME COUNTRIES; COHORT PROFILE; AIDS COHORT; HAART ERA; 1ST YEAR; MORTALITY AB Introduction: Latinos living with HIV in the Americas share a common ethnic and cultural heritage. In North America, Latinos have a relatively high rate of new HIV infections but lower rates of engagement at all stages of the care continuum, whereas in Latin America antiretroviral therapy (ART) services continue to expand to meet treatment needs. In this analysis, we compare HIV treatment outcomes between Latinos receiving ART in North America versus Latin America. Methods: HIV-positive adults initiating ART at Caribbean, Central and South America Network for HIV (CCASAnet) sites were compared to Latino patients (based on country of origin or ethnic identity) starting treatment at North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) sites in the United States and Canada between 2000 and 2011. Cox proportional hazards models compared mortality, treatment interruption, antiretroviral regimen change, virologic failure and loss to follow-up between cohorts. Results: The study included 8400 CCASAnet and 2786 NA-ACCORD patients initiating ART. CCASAnet patients were younger (median 35 vs. 37 years), more likely to be female (27% vs. 20%) and had lower nadir CD4 count (median 148 vs. 195 cells/mu L, p<0.001 for all). In multivariable analyses, CCASAnet patients had a higher risk of mortality after ART initiation (adjusted hazard ratio (AHR) 1.61; 95% confidence interval (CI): 1.32 to 1.96), particularly during the first year, but a lower hazard of treatment interruption (AHR: 0.46; 95% CI: 0.42 to 0.50), change to second-line ART (AHR: 0.56; 95% CI: 0.51 to 0.62) and virologic failure (AHR: 0.52; 95% CI: 0.48 to 0.57). Conclusions: HIV-positive Latinos initiating ART in Latin America have greater continuity of treatment but are at higher risk of death than Latinos in North America. Factors underlying these differences, such as HIV testing, linkage and access to care, warrant further investigation. C1 [Cesar, Carina; Cahn, Pedro] Fdn Huesped, Invest Clin, Buenos Aires, DF, Argentina. [Koethe, John R.; Rebeiro, Peter; Sterling, Timothy R.; McGowan, Catherine] Vanderbilt Univ, Sch Med, Div Infect Dis, Nashville, TN 37212 USA. [Giganti, Mark J.; Shepherd, Bryan E.] Vanderbilt Univ, Sch Med, Dept Biostat, Nashville, TN 37212 USA. [Althoff, Keri N.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Napravnik, Sonia] Univ N Carolina, Dept Med, Chapel Hill, NC USA. [Mayor, Angel] Univ Cent Caribe, Dept Internal Med, Bayamon, PR USA. [Grinsztejn, Beatriz] Fundacao Oswaldo Cruz, Inst Pesquisa Clin Evandro Chagas, Rio De Janeiro, Brazil. [Wolff, Marcelo] Fdn Arriaran, Santiago, Chile. [Wolff, Marcelo] Univ Chile, Fac Med, Santiago 7, Chile. [Padgett, Denis] Inst Hondureno Seguridad Social, Tegucigalpa, Honduras. [Padgett, Denis] Hosp Escuela Univ, Tegucigalpa, Honduras. [Sierra-Madero, Juan] Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Mexico City, DF, Mexico. [Gotuzzo, Eduardo] Inst Med Trop Alexander von Humboldt, Lima, Peru. [Willig, James] Univ Alabama Birmingham, Div Infect Dis, Birmingham, AL USA. [Levison, Julie] Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. [Levison, Julie] Harvard Univ, Sch Med, Boston, MA USA. [Kitahata, Mari] Univ Washington, Div Infect Dis, Seattle, WA 98195 USA. [Rodriguez-Barradas, Maria C.] Baylor Coll Med, Infect Dis Sect, Michael E De Bakey VAMC, Houston, TX 77030 USA. [Moore, Richard D.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. RP Cesar, C (reprint author), Peluffo 3932,C1202ABB, Buenos Aires, DF, Argentina. EM carina.cesar@huesped.org.ar OI Mayor, Angel M./0000-0002-7705-837X; Rebeiro, Peter/0000-0003-1951-9104; Justice, Amy/0000-0003-0139-5502 FU National Institutes of Health, USA [U01-AI069918, U01-AA013566, U24-AA020794, U01-AA020790, U01-AI31834, U01-AI34989, U01-AI34993, U01-AI34994, U01-AI35004, U01-AI35039]; Disease Control and Prevention, USA [CDC200-2006-18797]; Agency for Healthcare Research and Quality, USA [90047713]; Health Resources and Services Administration, USA [90051652]; National Institute of Mental Health of the National Institutes of Health [K23MH100978]; Canadian Institutes of Health Research, Canada [TGF-96118, HCP-97105, CBR-86906, CBR-94036]; Canadian Institutes of Health Research New Investigator Award; Ontario Ministry of Health and Long Term Care; Government of Alberta, Canada; Intramural Research Program of the National Cancer Institute, National Institutes of Health; [P30-AI027763]; [P30-AI094189]; [P30-AI27757]; [P30-AI27767]; [P30-AI036219]; [P30-AI50410]; [P30-AI54999]; [P30-MH62246]; [P30 AI110527]; [R01-AA16893]; [R01-CA165937]; [R01-DA04334]; [R01-DA11602]; [R01-DA12568]; [R24-AI067039]; [R56-AI102622]; [F31-DA037788]; [Z01-CP010214]; [Z01-CP010176]; [U01-AI35040]; [U01-AI35041]; [U01-AI35042]; [U01-AI37613]; [U01-AI37984]; [U01-AI38855]; [U01-AI38858]; [U01-AI42590]; [U01-AI68634]; [U01-AI68636]; [U01-AI69432]; [U01-AI69434]; [U01-DA036935]; [U01-HD32632]; [U10-EY08052]; [U10-EY08057]; [U10-EY08067]; [U54-MD007587]; [UL1-RR024131]; [UL1-TR000083]; [UM1-AI35043]; [G12-MD007583]; [K01-AI071754]; [K01-AI093197]; [K23-EY013707]; [K24-DA00432]; [K24-AI065298]; [KL2-TR000421]; [MO1-RR-00052]; [N02-CP55504] FX NA-ACCORD: This work was supported by the National Institutes of Health, USA (grants U01-AI069918, U01-AA013566, U24-AA020794, U01-AA020790, U01-AI31834, U01-AI34989, U01-AI34993, U01-AI34994, U01-AI35004, U01-AI35039, U01-AI35040, U01-AI35041, U01-AI35042, U01-AI37613, U01-AI37984, U01-AI38855, U01-AI38858, U01-AI42590, U01-AI68634, U01-AI68636, U01-AI69432, U01-AI69434, U01-DA036935, U01-HD32632, U10-EY08052, U10-EY08057, U10-EY08067, U54-MD007587, UL1-RR024131, UL1-TR000083, UM1-AI35043, G12-MD007583, K01-AI071754, K01-AI093197, K23-EY013707, K24-DA00432, K24-AI065298, KL2-TR000421, MO1-RR-00052, N02-CP55504, P30-AI027763, P30-AI094189, P30-AI27757, P30-AI27767, P30-AI036219, P30-AI50410, P30-AI54999, P30-MH62246, P30 AI110527, R01-AA16893, R01-CA165937, R01-DA04334, R01-DA11602, R01-DA12568, R24-AI067039, R56-AI102622, F31-DA037788, Z01-CP010214, and Z01-CP010176); Disease Control and Prevention, USA (contract CDC200-2006-18797); the Agency for Healthcare Research and Quality, USA (contract 90047713); the Health Resources and Services Administration, USA (contract 90051652); National Institute of Mental Health of the National Institutes of Health (grant K23MH100978); the Canadian Institutes of Health Research, Canada (grants TGF-96118, HCP-97105, CBR-86906, CBR-94036); Canadian Institutes of Health Research New Investigator Award (A. Burchell); Ontario Ministry of Health and Long Term Care; and the Government of Alberta, Canada. Additional support was provided by the Intramural Research Program of the National Cancer Institute, National Institutes of Health.; CCASAnet: This work was supported by the National Institutes of Health, USA (grant 2-U01-AI069923). NR 38 TC 1 Z9 1 U1 2 U2 5 PU INT AIDS SOCIETY PI GENEVA PA AVENUE DE FRANCE 23, GENEVA, 1202, SWITZERLAND SN 1758-2652 J9 J INT AIDS SOC JI J. Int. AIDS Soc. PD MAR 18 PY 2016 VL 19 AR 20684 DI 10.7448/IAS.19.1.20684 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DM2JL UT WOS:000376172800001 PM 26996992 ER PT J AU Fu, WM Sun, J Huang, GC Liu, JC Kaufman, A Ryan, RJH Ramanathan, SY Venkatesh, T Singh, B AF Fu, Weimin Sun, Joanne Huang, Guochang Liu, Jeffrey C. Kaufman, Andrew Ryan, Russell J. H. Ramanathan, Suresh Y. Venkatesh, Tadmiri Singh, Bhuvanesh TI Squamous Cell Carcinoma-related Oncogene (SCCRO) Family Members Regulate Cell Growth and Proliferation through Their Cooperative and Antagonistic Effects on Cullin Neddylation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE head and neck cancer; lung cancer; oncogene; tumor suppressor gene; ubiquitylation (ubiquitination) ID DROSOPHILA-MELANOGASTER; E3 LIGASE; UBIQUITIN-LIGASE; PROTEIN NEDD8; COMPETITION; MECHANISMS; STABILITY; LIGATION; GENE; CUL1 AB SCCRO (squamous cell carcinoma-related oncogene; also known as DCUN1D1) is a highly conserved gene that functions as an E3 in neddylation. Although inactivation of SCCRO in yeast results in lethality, SCCRO-/- mice are viable. The exclusive presence of highly conserved paralogues in higher organisms led us to assess whether compensation by SCCRO paralogues rescues lethality in SCCRO-/- mice. Using murine and Drosophila models, we assessed the in vivo activities of SCCRO and its paralogues in cullin neddylation. We found that SCCRO family members have overlapping and antagonistic activity that regulates neddylation and cell proliferation activities in vivo. In flies, both dSCCRO and dSCCRO3 promote neddylation and cell proliferation, whereas dSCCRO4 negatively regulates these processes. Analysis of somatic clones showed that the effects that these paralogues have on proliferation serve to promote cell competition, leading to apoptosis in clones with a net decrease in neddylation activity. We found that dSCCRO and, to a lesser extent, dSCCRO3 rescue the neddylation and proliferation defects promoted by expression of SCCRO4. dSCCRO and dSCCRO3 functioned cooperatively, with their coexpression resulting in an increase in both the neddylated cullin fraction and proliferation activity. In contrast, human SCCRO and SCCRO4 promote, and human SCCRO3 inhibits, neddylation and proliferation when expressed in flies. Our findings provide the first insights into the mechanisms through which SCCRO family members cooperatively regulate neddylation and cell proliferation. C1 [Fu, Weimin; Sun, Joanne; Huang, Guochang; Liu, Jeffrey C.; Kaufman, Andrew; Ryan, Russell J. H.; Ramanathan, Suresh Y.; Singh, Bhuvanesh] Mem Sloan Kettering Canc Ctr, Lab Epithelial Canc Biol, Dept Surg, New York, NY 10065 USA. [Venkatesh, Tadmiri] CUNY City Coll, Dept Biol, New York, NY 10031 USA. [Liu, Jeffrey C.] Temple Univ, Div Head & Neck Oncol Surg, Philadelphia, PA 19140 USA. [Kaufman, Andrew; Ramanathan, Suresh Y.] Mt Sinai Med Ctr, Dept Thorac Surg, New York, NY 10029 USA. [Ryan, Russell J. H.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Ryan, Russell J. H.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Ryan, Russell J. H.] Broad Inst Harvard Univ & MIT, Cambridge, MA 02142 USA. RP Singh, B (reprint author), Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10065 USA. EM singhb@mskcc.org FU NCI, National Institutes of Health [P30 CA008748, U54CA137788/U54CA132378]; Hackers for Hope FX This work was supported by NCI, National Institutes of Health Grant P30 CA008748, NCI, National Institutes of Health Grant U54CA137788/U54CA132378 (to B. S. and T. V.), and a grant from Hackers for Hope (to B. S.). The authors declare they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 44 TC 1 Z9 1 U1 2 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 18 PY 2016 VL 291 IS 12 BP 6200 EP 6217 DI 10.1074/jbc.M115.692756 PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DH6IM UT WOS:000372894200013 PM 26792857 ER PT J AU Lal, D Reinthaler, EM Dejanovici, B May, P Thiele, H Lehesjoki, AE Schwarz, G Riesch, E Ikram, MA van Duijn, CM Uitterlinden, AG Hofman, A Steinbock, H Gruber-Sedlmayr, U Neophytou, B Zara, F Hahn, A Gormley, P Becker, F Weber, YG Cilio, MR Kunz, WS Krause, R Zimprich, F Lemke, JR Nurnberg, P Sander, T Lerche, H Neubauer, BA AF Lal, Dennis Reinthaler, Eva M. Dejanovici, Borislav May, Patrick Thiele, Holger Lehesjoki, Anna-Elina Schwarz, Gunter Riesch, Erik Ikram, M. Arfan van Duijn, Cornelia M. Uitterlinden, Andre G. Hofman, Albert Steinboeck, Hannelore Gruber-Sedlmayr, Ursula Neophytou, Birgit Zara, Federico Hahn, Andreas Gormley, Padhraig Becker, Felicitas Weber, Yvonne G. Cilio, Maria Roberta Kunz, Wolfram S. Krause, Roland Zimprich, Fritz Lemke, Johannes R. Nuernberg, Peter Sander, Thomas Lerche, Holger Neubauer, Bernd A. CA Genetic Comm Italian League Agains EuroEPINOMICS CoGIE Consortium TI Evaluation of Presumably Disease Causing SCN1A Variants in a Cohort of Common Epilepsy Syndromes SO PLOS ONE LA English DT Article ID FEBRILE SEIZURES PLUS; NEURONAL SODIUM-CHANNEL; SEVERE MYOCLONIC EPILEPSY; GENERALIZED EPILEPSY; DRAVET SYNDROME; HEMIPLEGIC MIGRAINE; ITALIAN PATIENTS; MUTATION; GENE; PREVALENCE AB Objective The SCN1A gene, coding for the voltage-gated Na+ channel alpha subunit NaV1.1, is the clinically most relevant epilepsy gene. With the advent of high-throughput next-generation sequencing, clinical laboratories are generating an ever-increasing catalogue of SCN1A variants. Variants are more likely to be classified as pathogenic if they have already been identified previously in a patient with epilepsy. Here, we critically re-evaluate the pathogenicity of this class of variants in a cohort of patients with common epilepsy syndromes and subsequently ask whether a significant fraction of benign variants have been misclassified as pathogenic. Methods We screened a discovery cohort of 448 patients with a broad range of common genetic epilepsies and 734 controls for previously reported SCN1A mutations that were assumed to be disease causing. We re-evaluated the evidence for pathogenicity of the identified variants using in silico predictions, segregation, original reports, available functional data and assessment of allele frequencies in healthy individuals as well as in a follow up cohort of 777 patients. Results and Interpretation We identified 8 known missense mutations, previously reported as pathogenic, in a total of 17 unrelated epilepsy patients (17/448; 3.80%). Our re-evaluation indicates that 7 out of these 8 variants (p.R27T; p.R28C; p.R542Q; p.R604H; p.T1250M; p.E1308D; p.R1928G; NP_001159435.1) are not pathogenic. Only the p. T1174S mutation may be considered as a genetic risk factor for epilepsy of small effect size based on the enrichment in patients (P = 6.60 x 10(-4); OR = 0.32, fishers exact test), previous functional studies but incomplete penetrance. Thus, incorporation of previous studies in genetic counseling of SCN1A sequencing results is challenging and may produce incorrect conclusions. C1 [Lal, Dennis; Thiele, Holger; Nuernberg, Peter; Sander, Thomas] Univ Cologne, Cologne Ctr GenoM, D-50931 Cologne, Germany. [Lal, Dennis; Gormley, Padhraig] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Lal, Dennis; Gormley, Padhraig] Harvard Univ, Sch Med, Boston, MA USA. [Lal, Dennis; Gormley, Padhraig] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA. [Lal, Dennis; Gormley, Padhraig; Nuernberg, Peter] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Reinthaler, Eva M.; Zimprich, Fritz] Med Univ Vienna, Dept Neurol, Vienna, Austria. [Dejanovici, Borislav; Schwarz, Gunter] Univ Cologne, Dept Chem, Inst Biochem, D-50931 Cologne, Germany. [May, Patrick; Krause, Roland] Univ Luxembourg, LCSB, Esch Sur Alzette, Luxembourg. [Lehesjoki, Anna-Elina] Folkhalsan Inst Genet, Helsinki, Finland. [Lehesjoki, Anna-Elina] Univ Helsinki, Ctr Neurosci, Helsinki, Finland. [Lehesjoki, Anna-Elina] Univ Helsinki, Mol Neurol, Res Programs Unit, Helsinki, Finland. [Riesch, Erik] CeGaT GmbH Ctr Genom & Transcript, Tubingen, Germany. [Ikram, M. Arfan; van Duijn, Cornelia M.] Erasmus MC, Dept Epidemiol, Neurol, Radiol, Rotterdam, Netherlands. [Uitterlinden, Andre G.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Hofman, Albert] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Gruber-Sedlmayr, Ursula] Med Univ Graz, Dept Pediat, Graz, Austria. [Neophytou, Birgit] St Anna Childrens Hosp, Dept Neuropediat, A-1090 Vienna, Austria. [Zara, Federico] Inst G Gaslini, Lab Neurogenet & Neurosci, Genoa, Italy. [Hahn, Andreas; Neubauer, Bernd A.] Univ Med Ctr Giessen & Marburg, Dept Neuropediat, Giessen, Germany. [Becker, Felicitas; Weber, Yvonne G.; Lerche, Holger] Univ Tubingen, Hertie Inst Clin Brain Res, Dept Neurol & Epileptol, Tubingen, Germany. [Cilio, Maria Roberta] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Cilio, Maria Roberta] Univ Calif San Francisco, Dept Pediat, San Francisco, CA USA. [Kunz, Wolfram S.] Univ Bonn, Dept Epileptol, Bonn, Germany. [Lemke, Johannes R.] Univ Leipzig, Inst Human Genet, D-04109 Leipzig, Germany. [Nuernberg, Peter] Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, D-50931 Cologne, Germany. RP Lal, D (reprint author), Univ Cologne, Cologne Ctr GenoM, D-50931 Cologne, Germany.; Lal, D (reprint author), Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA.; Lal, D (reprint author), Harvard Univ, Sch Med, Boston, MA USA.; Lal, D (reprint author), Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA. EM Dennis.Lal@uni-koeln.de RI baulac, stephanie/O-2099-2016; Caglayan, Hande/A-2368-2016; OI Caglayan, Hande/0000-0001-6402-3306; Gormley, Padhraig/0000-0002-8908-6968; May, Patrick/0000-0001-8698-3770 FU EuroEPINOMICS programme (DFG grant) within the EUROCORES framework of the European Science Foundation (ESF) [LE1030/11-1, BN416/5-1, NU50/8-1, SA434/5-1]; EuroEPINOMICS programme (FWF grant) within the EUROCORES framework of the European Science Foundation (ESF) [1643-B09]; Netherlands Organization of Scientific Research NOW Investments [175.010.2005.011, 911-03-012]; Netherlands Genomics Initiative (NGI)/NOW project (Netherlands Consortium for Healthy Ageing; NCHA) [050-060-810]; Erasmus Medical Center and Erasmus University, Rotterdam; Netherlands Organization for the Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly (RIDE); Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; European Commission (DG XII); Municipality of Rotterdam FX HL BN PN TS F. Zimprich received grants by the EuroEPINOMICS programme (DFG grant numbers: HL: LE1030/11-1, BN: BN416/5-1, PN: NU50/8-1, TS: SA434/5-1, FWF grant number: F. Zimprich: 1643-B09) within the EUROCORES framework of the European Science Foundation (ESF). The generation and management of genomics data for the Rotterdam Study are supported by the Netherlands Organization of Scientific Research NOW Investments (nr. 175.010.2005.011, 911-03-012) and the Netherlands Genomics Initiative (NGI)/NOW project nr. 050-060-810 (Netherlands Consortium for Healthy Ageing; NCHA). The authors thank the members of the Genomics Lab and the ERGO support team for their help in sampling the data and in creating the database, the study participants, the staff of the Rotterdam Study and the participating general practitioners and pharmacists. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; We thank all participants and their families for participating in this study. The authors would like to thank the Exome Aggregation Consortium and the groups that provided exome variant data for comparison. A full list of contributing groups can be found at (http://exac. broadinstitute.org/). H.L., B.N., P.N., T.S. and F.Z. received grants by the EuroEPINOMICS programme (DFG grant numbers: HL: LE1030/11-1, BN: BN416/5-1, PN: NU50/8-1, TS: SA434/5-1, FWF grant number: FZ: 1643-B09) within the EUROCORES framework of the European Science Foundation (ESF). The generation and management of genomics data for the Rotterdam Study are supported by the Netherlands Organization of Scientific Research NOW Investments (nr. 175.010.2005.011, 911-03-012) and the Netherlands Genomics Initiative (NGI)/NOW project nr. 050-060-810 (Netherlands Consortium for Healthy Ageing; NCHA). We thank the members of the Genomics Lab and the ERGO support team for their help in sampling the data and in creating the database, the study participants, the staff of the Rotterdam Study and the participating general practitioners and pharmacists. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 0 Z9 0 U1 4 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 18 PY 2016 VL 11 IS 3 AR e0150426 DI 10.1371/journal.pone.0150426 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH1ZE UT WOS:000372582800030 PM 26990884 ER PT J AU Leventhal, JS Ni, J Osmond, M Lee, K Gusella, GL Salem, F Ross, MJ AF Leventhal, Jeremy S. Ni, Jie Osmond, Morgan Lee, Kyung Gusella, G. Luca Salem, Fadi Ross, Michael J. TI Autophagy Limits Endotoxemic Acute Kidney Injury and Alters Renal Tubular Epithelial Cell Cytokine Expression SO PLOS ONE LA English DT Article ID SEPSIS; MICE; PROTECTS; DISEASE; INACTIVATION; APOPTOSIS; PREVENTS; FAILURE; PLAYS; GENE AB Sepsis related acute kidney injury (AKI) is a common in-hospital complication with a dismal prognosis. Our incomplete understanding of disease pathogenesis has prevented the identification of hypothesis-driven preventive or therapeutic interventions. Increasing evidence in ischemia-reperfusion and nephrotoxic mouse models of AKI support the theory that autophagy protects renal tubular epithelial cells (RTEC) from injury. However, the role of RTEC autophagy in septic AKI remains unclear. We observed that lipopolysaccharide (LPS), a mediator of gram-negative bacterial sepsis, induces RTEC autophagy in vivo and in vitro through TLR4-initiated signaling. We modeled septic AKI through intraperitoneal LPS injection in mice in which autophagy-related protein 7 was specifically knocked out in the renal proximal tubules (ATG7KO). Compared to control littermates, ATG7KO mice developed more severe renal dysfunction (24hr BUN 100.1mg/dl +/- 14.8 vs 54.6mg/dl +/- 11.3) and parenchymal injury. After injection with LPS, analysis of kidney lysates identified higher IL-6 expression and increased STAT3 activation in kidney lysates from ATG7KO mice compared to controls. In vitro experiments confirmed an altered response to LPS in RTEC with genetic or pharmacological impairment of autophagy. In conclusion, RTEC autophagy protects against endotoxin induced injury and regulates downstream effects of RTEC TLR4 signaling. C1 [Leventhal, Jeremy S.; Ni, Jie; Osmond, Morgan; Lee, Kyung; Gusella, G. Luca; Ross, Michael J.] Icahn Sch Med Mt Sinai, Dept Med, Div Nephrol, New York, NY 10029 USA. [Leventhal, Jeremy S.; Ross, Michael J.] James J Peters Bronx VA Med Ctr, Div Renal, Bronx, NY USA. [Salem, Fadi] Icahn Sch Med Mt Sinai, Dept Pathol, New York, NY 10029 USA. RP Leventhal, JS (reprint author), Icahn Sch Med Mt Sinai, Dept Med, Div Nephrol, New York, NY 10029 USA.; Leventhal, JS (reprint author), James J Peters Bronx VA Med Ctr, Div Renal, Bronx, NY USA. EM jeremy.leventhal@mssm.edu FU NIH/NIDDK grant [R01 DK101338, DK108346, K08 DK090217] FX This research was supported by the NIH/NIDDK grant R01 DK101338 and DK108346 (MR) and an NIH/NIDDK K08 DK090217 grant (JSL).; This research was supported by the NIH/NIDDK grant R01 DK101338 and DK108346 (M.R.) and an NIH/NIDDK K08 DK090217 (J.S.L). Microscopy was performed at the Microscopy CORE at the Icahn School of Medicine at Mount Sinai. NR 32 TC 1 Z9 2 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 18 PY 2016 VL 11 IS 3 AR e0150001 DI 10.1371/journal.pone.0150001 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH1ZE UT WOS:000372582800023 PM 26990086 ER PT J AU Sweadner, KJ Toro, C Whitlow, CT Snively, BM Cook, JF Ozelius, LJ Markello, TC Brashear, A AF Sweadner, Kathleen J. Toro, Camilo Whitlow, Christopher T. Snively, Beverly M. Cook, Jared F. Ozelius, Laurie J. Markello, Thomas C. Brashear, Allison TI ATP1A3 Mutation in Adult Rapid-Onset Ataxia SO PLOS ONE LA English DT Article ID ALTERNATING HEMIPLEGIA; DYSTONIA-PARKINSONISM; CEREBELLAR-ATAXIA; CRYSTAL-STRUCTURE; CAPOS SYNDROME; CHILDHOOD; PROTEIN; DISORDERS; CHILDREN; SPECTRUM AB A 21-year old male presented with ataxia and dysarthria that had appeared over a period of months. Exome sequencing identified a de novo missense variant in ATP1A3, the gene encoding the alpha 3 subunit of Na,K-ATPase. Several lines of evidence suggest that the variant is causative. ATP1A3 mutations can cause rapid-onset dystonia-parkinsonism (RDP) with a similar age and speed of onset, as well as severe diseases of infancy. The patient's ATP1A3 p.Gly316Ser mutation was validated in the laboratory by the impaired ability of the expressed protein to support the growth of cultured cells. In a crystal structure of Na,K-ATPase, the mutated amino acid was directly apposed to a different amino acid mutated in RDP. Clinical evaluation showed that the patient had many characteristics of RDP, however he had minimal fixed dystonia, a defining symptom of RDP. Successive magnetic resonance imaging (MRI) revealed progressive cerebellar atrophy, explaining the ataxia. The absence of dystonia in the presence of other RDP symptoms corroborates other evidence that the cerebellum contributes importantly to dystonia pathophysiology. We discuss the possibility that a second de novo variant, in ubiquilin 4 (UBQLN4), a ubiquitin pathway component, contributed to the cerebellar neurodegenerative phenotype and differentiated the disease from other manifestations of ATP1A3 mutations. We also show that a homozygous variant in GPRIN1 (G protein-regulated inducer of neurite outgrowth 1) deletes a motif with multiple copies and is unlikely to be causative. C1 [Sweadner, Kathleen J.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Sweadner, Kathleen J.] Harvard Univ, Sch Med, Boston, MA USA. [Toro, Camilo] NHGRI, NIH Undiagnosed Dis Program Common Fund, Off Director, NIH, Bethesda, MD 20892 USA. [Toro, Camilo] NHGRI, Off Clin Director, Bethesda, MD 20892 USA. [Whitlow, Christopher T.] Wake Forest Sch Med, Dept Radiol, Winston Salem, NC USA. [Whitlow, Christopher T.] Wake Forest Sch Med, Dept Biomed Engn, Winston Salem, NC USA. [Snively, Beverly M.] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC USA. [Cook, Jared F.; Brashear, Allison] Wake Forest Sch Med, Dept Neurol, Winston Salem, NC USA. [Ozelius, Laurie J.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Markello, Thomas C.] NHGRI, NIH Undiagnosed Dis Program, Common Fund, Off Director,NIH, Bethesda, MD 20892 USA. [Markello, Thomas C.] NHGRI, Human Biochem Genet Sect, Med Genet Branch, Bethesda, MD 20892 USA. RP Sweadner, KJ (reprint author), Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA.; Sweadner, KJ (reprint author), Harvard Univ, Sch Med, Boston, MA USA. EM sweadner@helix.mgh.harvard.edu FU Common Fund of the National Institutes of Health; National Institutes of Health (NIH) [5R01 NS058949]; National Institutes of Health (NIH) Undiagnosed Diseases Program [HSSN30221300096P, HSSN268201300238P] FX The Undiagnosed Diseases Program is funded by the Common Fund of the National Institutes of Health. This study was supported by National Institutes of Health (NIH) grant 5R01 NS058949 to AB, and by the National Institutes of Health (NIH) Undiagnosed Diseases Program HSSN30221300096P to AB and HSSN268201300238P to KJS. NR 49 TC 5 Z9 5 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 18 PY 2016 VL 11 IS 3 AR e0151429 DI 10.1371/journal.pone.0151429 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH1ZE UT WOS:000372582800063 PM 26990090 ER PT J AU Tapela, NM Mpunga, T Hedt-Gauthier, B Moore, M Mpanumusingo, E Xu, MJ Nzayisenga, I Hategekimana, V Umuhizi, DG Pace, LE Bigirimana, JB Wang, JJ Driscoll, C Uwizeye, FR Drobac, PC Ngoga, G Shyirambere, C Muhayimana, C Lehmann, L Shulman, LN AF Tapela, Neo M. Mpunga, Tharcisse Hedt-Gauthier, Bethany Moore, Molly Mpanumusingo, Egide Xu, Mary Jue Nzayisenga, Ignace Hategekimana, Vedaste Umuhizi, Denis Gilbert Pace, Lydia E. Bigirimana, Jean Bosco Wang, JingJing Driscoll, Caitlin Uwizeye, Frank R. Drobac, Peter C. Ngoga, Gedeon Shyirambere, Cyprien Muhayimana, Clemence Lehmann, Leslie Shulman, Lawrence N. TI Pursuing equity in cancer care: implementation, challenges and preliminary findings of a public cancer referral center in rural Rwanda SO BMC CANCER LA English DT Article DE Cancer; Implementation; Rwanda; Resource-limited setting; Capacity building; Twinning; Task-shifting ID COUNTRIES; PROGRAMS; OUTCOMES; AFRICA AB Background: Cancer services are inaccessible in many low-income countries, and few published examples describe oncology programs within the public sector. In 2011, the Rwanda Ministry of Health (RMOH) established Butaro Cancer Center of Excellence (BCCOE) to expand cancer services nationally. In hopes of informing cancer care delivery in similar settings, we describe program-level experience implementing BCCOE, patient characteristics, and challenges encountered. Methods: Butaro Cancer Center of Excellence was founded on diverse partnerships that emphasize capacity building. Services available include pathology-based diagnosis, basic imaging, chemotherapy, surgery, referral for radiotherapy, palliative care and socioeconomic access supports. Retrospective review of electronic medical records (EMR) of patients enrolled between July 1, 2012 and June 30, 2014 was conducted, supplemented by manual review of paper charts and programmatic records. Results: In the program's first 2 years, 2326 patients presented for cancer-related care. Of these, 70.5 % were female, 4.3 % children, and 74.3 % on public health insurance. In the first year, 66.3 % (n = 1144) were diagnosed with cancer. Leading adult diagnoses were breast, cervical, and skin cancer. Among children, nephroblastoma, acute lymphoblastic leukemia, and Hodgkin lymphoma were predominant. As of June 30, 2013, 95 cancer patients had died. Challenges encountered include documentation gaps and staff shortages. Conclusion: Butaro Cancer Center of Excellence demonstrates that complex cancer care can be delivered in the most resource-constrained settings, accessible to vulnerable patients. Key attributes that have made BCCOE possible are: meaningful North-south partnerships, innovative task-and infrastructure-shifting, RMOH leadership, and an equity-driven agenda. Going forward, we will apply our experiences and lessons learned to further strengthen BCCOE, and employ the developed EMR system as a valuable platform to assess long-term clinical outcomes and improve care. C1 [Tapela, Neo M.] Botswana Minist Hlth, Gaborone, Botswana. [Hedt-Gauthier, Bethany; Nzayisenga, Ignace; Bigirimana, Jean Bosco; Wang, JingJing; Uwizeye, Frank R.; Drobac, Peter C.; Ngoga, Gedeon; Shyirambere, Cyprien; Lehmann, Leslie; Shulman, Lawrence N.] Partners Hlth Inshuti Mu Buzima, Kigali, Rwanda. [Tapela, Neo M.; Hedt-Gauthier, Bethany; Drobac, Peter C.; Lehmann, Leslie; Shulman, Lawrence N.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Tapela, Neo M.; Hedt-Gauthier, Bethany; Xu, Mary Jue; Pace, Lydia E.; Drobac, Peter C.; Lehmann, Leslie] Harvard Univ, Sch Med, Boston, MA USA. [Mpunga, Tharcisse; Mpanumusingo, Egide; Hategekimana, Vedaste; Umuhizi, Denis Gilbert; Muhayimana, Clemence] Rwanda Minist Hlth, Kigali, Rwanda. [Lehmann, Leslie] Boston Childrens Hosp, Boston, MA USA. [Moore, Molly] Univ Vermont, Coll Med, Burlington, VT 05405 USA. [Driscoll, Caitlin] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Shulman, Lawrence N.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Tapela, Neo M.] Brigham & Womens Hosp, Div Global Hlth Equ, 75 Francis St, Boston, MA 02115 USA. RP Tapela, NM (reprint author), Botswana Minist Hlth, Gaborone, Botswana.; Tapela, NM (reprint author), Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA.; Tapela, NM (reprint author), Harvard Univ, Sch Med, Boston, MA USA.; Tapela, NM (reprint author), Brigham & Womens Hosp, Div Global Hlth Equ, 75 Francis St, Boston, MA 02115 USA. EM ntapela@gmail.com FU Dana Farber/Brigham and Women's Cancer Center; Brigham and Women's Hospital Division of Global Health Equity; Boston Children's Hospital; Harvard Medical School Department of Global Health and Social Medicine Research Core; Non-Communicable Diseases Writing Group; Rwanda Ministry of Health leadership; National University of Rwanda; Jeff Gordon Children's Foundation; Livestrong Foundation; GlaxoSmithKline; Breast Cancer Research Foundation; Max Foundation; Partners In Health; Rwanda Ministry of Health; Rwanda Biomedical Center FX The authors would like to thank the oncology clinical and EMR teams at Butaro Cancer Center of Excellence for their dedicated work, the Dana Farber/Brigham and Women's Cancer Center, Brigham and Women's Hospital Division of Global Health Equity, Boston Children's Hospital, Harvard Medical School Department of Global Health and Social Medicine Research Core, Non-Communicable Diseases Writing Group, Rwanda Ministry of Health leadership, National University of Rwanda for scholarship and mentorship, Lori Buswell, Temidayo Fadelu, Fidel Rubagumya, Cheryl Amoroso, Sara Stulac, Gaspard Muvugabigwi, Gene Bukhman, Irenee Nshimiyimana, Shekinah Elmore and Aimee Muhimpundu. We are also grateful to Jeff Gordon Children's Foundation, Livestrong Foundation, GlaxoSmithKline, Breast Cancer Research Foundation, Max Foundation, Dana Farber/Brigham and Women's Cancer Center, Partners In Health, Rwanda Ministry of Health and Rwanda Biomedical Center for funding and other supports for patient care that have made this work possible. NR 21 TC 1 Z9 1 U1 1 U2 3 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 MAR 18 PY 2016 VL 16 AR 237 DI 10.1186/s12885-016-2256-7 PG 9 WC Oncology SC Oncology GA DH1ST UT WOS:000372565900001 PM 26992690 ER PT J AU Khullar, D Jena, A AF Khullar, Dhruv Jena, Anupam TI Reducing prognostic errors: a new imperative in quality healthcare SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Editorial Material ID CLINICAL DECISION-MAKING; DIAGNOSTIC ERRORS; COHORT; CANCER C1 [Khullar, Dhruv; Jena, Anupam] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Jena, Anupam] Harvard Univ, Sch Med, Dept Hlth Care Policy, 180 Longwood Ave, Boston, MA 02115 USA. [Jena, Anupam] Natl Bur Econ Res, Cambridge, MA 02138 USA. RP Jena, A (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA.; Jena, A (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, 180 Longwood Ave, Boston, MA 02115 USA.; Jena, A (reprint author), Natl Bur Econ Res, Cambridge, MA 02138 USA. EM jena@hcp.med.harvard.edu FU NIH HHS [DP5 OD017897, 1DP5OD017897-01] NR 17 TC 1 Z9 1 U1 4 U2 5 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1756-1833 J9 BMJ-BRIT MED J JI BMJ-British Medical Journal PD MAR 18 PY 2016 VL 352 AR i1417 DI 10.1136/bmj.i1417 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA DH2AI UT WOS:000372586000001 PM 26993146 ER PT J AU Baenninger, A Hernandez, LD Rieger, K Ford, JM Kottlow, M Koenig, T AF Baenninger, Anja Hernandez, Laura Diaz Rieger, Kathryn Ford, Judith M. Kottlow, Mara Koenig, Thomas TI Inefficient Preparatory fMRI-BOLD Network Activations Predict Working Memory Dysfunctions in Patients with Schizophrenia SO FRONTIERS IN PSYCHIATRY LA English DT Article DE schizophrenia; working memory; temporally coherent networks; state-dependent information processing; simultaneous EEG-fMRI; covariance mapping ID DEFAULT MODE NETWORK; DORSOLATERAL PREFRONTAL CORTEX; CORTICAL OSCILLATORY ACTIVITY; RESTING-STATE; FUNCTIONAL CONNECTIVITY; BRAIN NETWORKS; EXECUTIVE NETWORKS; SUBSEQUENT-MEMORY; EEG ABNORMALITIES; HEALTHY CONTROLS AB Patients with schizophrenia show abnormal dynamics and structure of temporally coherent networks (TCNs) assessed using fMRI, which undergo adaptive shifts in preparation for a cognitively demanding task. During working memory (WM) tasks, patients with schizophrenia show persistent deficits in TCNs as well as EEG indices of WM. Studying their temporal relationship during WM tasks might provide novel insights into WM performance deficits seen in schizophrenia. Simultaneous EEG-fMRI data were acquired during the performance of a verbal Sternberg WM task with two load levels (load 2 and load 5) in 17 patients with schizophrenia and 17 matched healthy controls. Using covariance mapping, we investigated the relationship of the activity in the TCNs before the memoranda were encoded and EEG spectral power during the retention interval. We assessed four TCNs- default mode network (DMN), dorsal attention network (dAN), left and right working memory networks (WMNs)- and three EEG bands- theta, alpha, and beta. In healthy controls, there was a load-dependent inverse relation between DMN and frontal midline theta power and an anti-correlation between DMN and dAN. Both effects were not significantly detectable in patients. In addition, healthy controls showed a left-lateralized load dependent recruitment of the WMNs. Activation of the WMNs was bilateral in patients, suggesting more resources were recruited for successful performance on the WM task. Our findings support the notion of schizophrenia patients showing deviations in their neurophysiological responses before the retention of relevant information in a verbal WM task. Thus, treatment strategies as neurofeedback targeting prestates could be beneficial as task performance relies on the preparatory state of the brain. C1 [Baenninger, Anja; Hernandez, Laura Diaz; Kottlow, Mara; Koenig, Thomas] Univ Bern, Univ Hosp Psychiat & Psychotherapy, Translat Res Ctr, Bern, Switzerland. [Baenninger, Anja; Ford, Judith M.] San Francisco VA Med Ctr, San Francisco, CA USA. [Hernandez, Laura Diaz; Rieger, Kathryn; Kottlow, Mara; Koenig, Thomas] Univ Bern, Ctr Cognit Learning & Memory, Bern, Switzerland. [Ford, Judith M.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. RP Baenninger, A (reprint author), Univ Bern, Univ Hosp Psychiat & Psychotherapy, Translat Res Ctr, Bern, Switzerland.; Baenninger, A (reprint author), San Francisco VA Med Ctr, San Francisco, CA USA. EM anja.baenninger@puk.unibe.ch RI Koenig, Thomas/F-6454-2010; OI Koenig, Thomas/0000-0002-1472-4638; Baenninger, Anja/0000-0001-8921-5216; Diaz Hernandez, Laura/0000-0003-3452-8797 NR 87 TC 1 Z9 1 U1 2 U2 10 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 MAR 18 PY 2016 VL 7 AR 29 DI 10.3389/fpsyt.2016.00029 PG 15 WC Psychiatry SC Psychiatry GA DG8XY UT WOS:000372368100002 PM 27047395 ER PT J AU Downey, JE Weiss, JM Muelling, K Venkatraman, A Valois, JS Hebert, M Bagnell, JA Schwartz, AB Collinger, JL AF Downey, John E. Weiss, Jeffrey M. Muelling, Katharina Venkatraman, Arun Valois, Jean-Sebastien Hebert, Martial Bagnell, J. Andrew Schwartz, Andrew B. Collinger, Jennifer L. TI Blending of brain-machine interface and vision-guided autonomous robotics improves neuroprosthetic arm performance during grasping SO JOURNAL OF NEUROENGINEERING AND REHABILITATION LA English DT Article DE Brain-machine interface; Brain-computer interface; Neuroprosthetic; Shared mode control; Assistive technology ID SPINAL-CORD-INJURY; COMPUTER INTERFACE; PRIORITIES; USERS AB Background: Recent studies have shown that brain-machine interfaces (BMIs) offer great potential for restoring upper limb function. However, grasping objects is a complicated task and the signals extracted from the brain may not always be capable of driving these movements reliably. Vision-guided robotic assistance is one possible way to improve BMI performance. We describe a method of shared control where the user controls a prosthetic arm using a BMI and receives assistance with positioning the hand when it approaches an object. Methods: Two human subjects with tetraplegia used a robotic arm to complete object transport tasks with and without shared control. The shared control system was designed to provide a balance between BMI-derived intention and computer assistance. An autonomous robotic grasping system identified and tracked objects and defined stable grasp positions for these objects. The system identified when the user intended to interact with an object based on the BMI-controlled movements of the robotic arm. Using shared control, BMI controlled movements and autonomous grasping commands were blended to ensure secure grasps. Results: Both subjects were more successful on object transfer tasks when using shared control compared to BMI control alone. Movements made using shared control were more accurate, more efficient, and less difficult. One participant attempted a task with multiple objects and successfully lifted one of two closely spaced objects in 92 % of trials, demonstrating the potential for users to accurately execute their intention while using shared control. Conclusions: Integration of BMI control with vision-guided robotic assistance led to improved performance on object transfer tasks. Providing assistance while maintaining generalizability will make BMI systems more attractive to potential users. C1 [Downey, John E.; Weiss, Jeffrey M.; Schwartz, Andrew B.; Collinger, Jennifer L.] Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA 15213 USA. [Downey, John E.; Schwartz, Andrew B.; Collinger, Jennifer L.] Ctr Neural Basis Cognit, Pittsburgh, PA USA. [Weiss, Jeffrey M.; Collinger, Jennifer L.] Univ Pittsburgh, Dept Phys Med & Rehabil, Pittsburgh, PA 15213 USA. [Muelling, Katharina; Venkatraman, Arun; Valois, Jean-Sebastien; Hebert, Martial; Bagnell, J. Andrew] Carnegie Mellon Univ, Inst Robot, Pittsburgh, PA 15213 USA. [Schwartz, Andrew B.] Univ Pittsburgh, Dept Neurobiol, Pittsburgh, PA 15213 USA. [Collinger, Jennifer L.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Collinger, Jennifer L.] Univ Pittsburgh, 3520 5th Ave,Suite 300, Pittsburgh, PA 15213 USA. RP Collinger, JL (reprint author), Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA 15213 USA.; Collinger, JL (reprint author), Ctr Neural Basis Cognit, Pittsburgh, PA USA. EM collinger@pitt.edu OI Downey, John/0000-0002-2992-2848 FU US Food and Drug Administration [NCT01364480, NCT01894802]; Defense Advanced Research Projects Agency's (DARPA, Arlington, VA, USA) Revolutionizing Prosthetics program [N66001-10-C-4056]; Autonomous Robotic Manipulation Software Track (ARM-S) program; National Science Foundation's NRI Purposeful Prediction program [1227495]; GRF program [DGE-1252522] FX This study was done under investigational device exemptions granted by the US Food and Drug Administration (NCT01364480 and NCT01894802). We thank Jan Scheuermann and Nathan Copeland for their extraordinary commitment and effort in relation to this study and insightful discussions with the study team; Karina Palko for her participation as an honorary research team member and support of the study; Debbie Harrington (Physical Medicine and Rehabilitation) for regulatory management of the study; the University of Pittsburgh Clinical and Translational Science Institute and the Office of Investigator-Sponsored Investigational New Drugs and Investigational Device Exemption support for assistance with protocol development and regulatory reporting and compliance; the volunteer members of the DSMB for their continued monitoring of this study; and Blackrock Microsystems (Salt Lake City, UT, USA) for technical support in relation to this project. This research was developed with funding from the Defense Advanced Research Projects Agency's (DARPA, Arlington, VA, USA) Revolutionizing Prosthetics program (contract number N66001-10-C-4056), and the Autonomous Robotic Manipulation Software Track (ARM-S) program. National Science Foundation's NRI Purposeful Prediction program (award no. 1227495) and GRF program (award no. DGE-1252522). The views, opinions, and/or findings contained in this article are those of the authors and should not be interpreted as representing the official views or policies of the Department of Veterans Affairs, Department of Defense, or US Government. NR 23 TC 0 Z9 0 U1 4 U2 21 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1743-0003 J9 J NEUROENG REHABIL JI J. NeuroEng. Rehabil. PD MAR 18 PY 2016 VL 13 AR 28 DI 10.1186/s12984-016-0134-9 PG 12 WC Engineering, Biomedical; Neurosciences; Rehabilitation SC Engineering; Neurosciences & Neurology; Rehabilitation GA DH2DW UT WOS:000372595400001 PM 26987662 ER PT J AU Howitt, MR Lavoie, S Michaud, M Blum, AM Tran, SV Weinstock, JV Gallini, CA Redding, K Margolskee, RF Osborne, LC Artis, D Garrett, WS AF Howitt, Michael R. Lavoie, Sydney Michaud, Monia Blum, Arthur M. Tran, Sara V. Weinstock, Joel V. Gallini, Carey Ann Redding, Kevin Margolskee, Robert F. Osborne, Lisa C. Artis, David Garrett, Wendy S. TI Tuft cells, taste-chemosensory cells, orchestrate parasite type 2 immunity in the gut SO SCIENCE LA English DT Article ID INTESTINAL EPITHELIAL-CELLS; CHAIN FATTY-ACIDS; HELMINTH INFECTIONS; RECEPTOR-CELLS; BRUSH CELLS; SWEET TASTE; STEM-CELLS; IN-VITRO; INNATE; BITTER AB The intestinal epithelium forms an essential barrier between a host and its microbiota. Protozoa and helminths are members of the gut microbiota of mammals, including humans, yet the many ways that gut epithelial cells orchestrate responses to these eukaryotes remain unclear. Here we show that tuft cells, which are taste-chemosensory epithelial cells, accumulate during parasite colonization and infection. Disruption of chemosensory signaling through the loss of TRMP5 abrogates the expansion of tuft cells, goblet cells, eosinophils, and type 2 innate lymphoid cells during parasite colonization. Tuft cells are the primary source of the parasite-induced cytokine interleukin-25, which indirectly induces tuft cell expansion by promoting interleukin-13 production by innate lymphoid cells. Our results identify intestinal tuft cells as critical sentinels in the gut epithelium that promote type 2 immunity in response to intestinal parasites. C1 [Howitt, Michael R.; Lavoie, Sydney; Michaud, Monia; Gallini, Carey Ann; Garrett, Wendy S.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Howitt, Michael R.; Lavoie, Sydney; Michaud, Monia; Gallini, Carey Ann; Garrett, Wendy S.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Genet & Complex Dis, Boston, MA 02115 USA. [Blum, Arthur M.; Weinstock, Joel V.] Tufts Med Ctr, Div Gastroenterol, Boston, MA 02111 USA. [Tran, Sara V.; Redding, Kevin; Margolskee, Robert F.] Monell Chem Senses Ctr, 3500 Market St, Philadelphia, PA 19104 USA. [Osborne, Lisa C.; Artis, David] Cornell Univ, Jill Roberts Inst Res Inflammatory Bowel Dis, Weill Cornell Med Coll, New York, NY 10021 USA. [Garrett, Wendy S.] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA 02142 USA. [Garrett, Wendy S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Osborne, Lisa C.] Univ British Columbia, Dept Microbiol & Immunol, Vancouver, BC V6T 1Z3, Canada. RP Garrett, WS (reprint author), Harvard Univ, TH Chan Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA.; Garrett, WS (reprint author), Harvard Univ, TH Chan Sch Publ Hlth, Dept Genet & Complex Dis, Boston, MA 02115 USA.; Garrett, WS (reprint author), Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA 02142 USA.; Garrett, WS (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. EM wgarrett@hsph.harvard.edu FU NUN National Research Service Award (NRSA) [F32DK098826]; NIH NRSA [F31DK105653]; NIH [R01 CA154426, R01 GM099531]; Burroughs Wellcome Career in Medical Sciences Award; Searle Scholars Award FX We thank members of the Garret Lab for helpful discussion, T. Stappenbeck for supplying L-WRN cells, R. Montgomery for help with organoid imaging, and W. Fowle for help with SEM. The data from this study are tabulated in the main paper and in the supplementary materials. Trpm5eGFP), Trpm5-/- and gustducin-/- mice are available from Monell Chemical Senses Center under a material transfer agreement. This work was supported by NUN National Research Service Award (NRSA) F32DK098826 to M.R.H.; NIH NRSA F31DK105653 to S.L.; and NIH grants R01 CA154426 and R01 GM099531, a Burroughs Wellcome Career in Medical Sciences Award, and a Searle Scholars Award to W.S.G. The authors declare no competing financial interests. NR 47 TC 42 Z9 43 U1 15 U2 28 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD MAR 18 PY 2016 VL 351 IS 6279 BP 1329 EP 1333 DI 10.1126/science.aaf1648 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DG9JD UT WOS:000372397700045 PM 26847546 ER PT J AU Kempfle, JS Turban, JL Edge, ASB AF Kempfle, Judith S. Turban, Jack L. Edge, Albert S. B. TI Sox2 in the differentiation of cochlear progenitor cells SO SCIENTIFIC REPORTS LA English DT Article ID EMBRYONIC STEM-CELLS; MAMMALIAN INNER-EAR; DEVELOPING NERVOUS-SYSTEM; HAIR-CELLS; EXPRESSION; FATE; MICE; REGENERATION; ORGAN; MATH1 AB HMG domain transcription factor, Sox2, is a critical gene for the development of cochlear hair cells, the receptor cells for hearing, but this has been ascribed to expansion of the progenitors that become hair cells. Here, we show that Sox2 activated Atoh1, a transcription factor important for hair cell differentiation, through an interaction with the 3' enhancer of Atoh1. Binding to consensus sequences in the Atoh1 enhancer was dependent on the level of Sox2, and the extent of enhancer binding correlated to the extent of activation. Atoh1 activation by Sox2 was required for embryonic hair cell development: deletion of Sox2 in an inducible mutant, even after progenitor cells were fully established, halted development of hair cells, and silencing also inhibited postnatal differentiation of hair cells induced by inhibition of gamma-secretase. Sox2 is thus required in the cochlea to both expand the progenitor cells and initiate their differentiation to hair cells. C1 [Kempfle, Judith S.; Turban, Jack L.; Edge, Albert S. B.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Kempfle, Judith S.; Turban, Jack L.; Edge, Albert S. B.] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Edge, Albert S. B.] Harvard & MIT, Program Speech & Hearing Biosci & Technol, Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Edge, ASB (reprint author), Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA.; Edge, ASB (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA.; Edge, ASB (reprint author), Harvard & MIT, Program Speech & Hearing Biosci & Technol, Div Hlth Sci & Technol, Cambridge, MA 02139 USA. EM albert_edge@meei.harvard.edu FU National Institute on Deafness and other Communicative Disorders [RO1 DC007174, P30 DC05209]; Deafness Research Foundation; European Commission (FP7 Health Innovation); Shulsky Foundation FX This work was supported by grants from the National Institute on Deafness and other Communicative Disorders, RO1 DC007174 and P30 DC05209, by a grant from the Deafness Research Foundation, a cooperative grant from the European Commission (FP7 Health 2013 Innovation), by the Shulsky Foundation, David H. Koch, and Robert Boucai. NR 50 TC 4 Z9 4 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAR 18 PY 2016 VL 6 AR 23293 DI 10.1038/srep23293 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH0JF UT WOS:000372469800001 PM 26988140 ER PT J AU Ruan, YF Jiang, J Guo, L Li, Y Huang, HL Shen, L Luan, MQ Li, M Du, HH Ma, C He, L Zhang, XQ Qin, SY AF Ruan, Yunfeng Jiang, Jie Guo, Liang Li, Yan Huang, Hailiang Shen, Lu Luan, Mengqi Li, Mo Du, Huihui Ma, Cheng He, Lin Zhang, Xiaoqing Qin, Shengying TI Genetic Association of Curative and Adverse Reactions to Tyrosine Kinase Inhibitors in Chinese advanced Non-Small Cell Lung Cancer patients SO SCIENTIFIC REPORTS LA English DT Article ID GROWTH-FACTOR RECEPTOR; 1ST-LINE TREATMENT; OPEN-LABEL; AKT1 GENE; EGFR; POLYMORPHISMS; GEFITINIB; ERLOTINIB; RISK; PHARMACOGENETICS AB Epidermal growth factor receptor (EGFR) Tyrosine kinase inhibitor (TKI) is an effective targeted therapy for advanced non-small cell lung cancer (NSCLC) but also causes adverse drug reactions (ADRs) e.g., skin rash and diarrhea. SNPs in the EGFR signal pathway, drug metabolism/transport pathways and miRNA might contribute to the interpersonal difference in ADRs but biomarkers for therapeutic responses and ADRs to TKIs in Chinese population are yet to be fully investigated. We recruited 226 Chinese advanced NSCLC patients who received TKIs erlotinib, gefitinib and icotinib hydrochloride and systematically studied the genetic factors associated with therapeutic responses and ADRs. Rs884225 (T > C) in EGFR 3'UTR was significantly associated with lower risk of ADRs to erlotinib (p value = 0.0010, adjusted p value = 0.042). A multivariant interaction four-SNP model (rs884225 in EGFR 3'UTR, rs7787082 in ABCB1 intron, rs38845 in MET intron and rs3803300 in AKT1 5'UTR) was associated with ADRs in general and the more specific drug induced skin injury. The SNPs associated with both therapeutic responses and ADRs indicates they might share a common genetic basis. Our study provided potential biomarkers and clues for further research of biomarkers for therapeutic responses and ADRs in Chinese NSCLC patients. C1 [Ruan, Yunfeng; Jiang, Jie; Shen, Lu; Luan, Mengqi; Li, Mo; Du, Huihui; Ma, Cheng; He, Lin; Qin, Shengying] Shanghai Jiao Tong Univ, BioX Inst, Key Lab Genet Dev & Neuropsychiat Disorders, Minist Educ, Shanghai 200030, Peoples R China. [Guo, Liang] Fourth Hosp Jinan City, Taishan Med Coll, Jinan, Peoples R China. [Li, Yan] Univ Hong Kong, Ctr Genom Sci, Hong Kong, Hong Kong, Peoples R China. [Huang, Hailiang] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Huang, Hailiang] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Huang, Hailiang] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. [Zhang, Xiaoqing] Tongji Univ, Sch Med, Shanghai Pulm Hosp, Dept Pharm, Shanghai 200092, Peoples R China. [Qin, Shengying] Shanghai Jiao Tong Univ, Sch Med, Shanghai Mental Hlth Ctr, Shanghai Key Lab Psychot Disorders, Shanghai 200030, Peoples R China. RP Qin, SY (reprint author), Shanghai Jiao Tong Univ, BioX Inst, Key Lab Genet Dev & Neuropsychiat Disorders, Minist Educ, Shanghai 200030, Peoples R China.; Zhang, XQ (reprint author), Tongji Univ, Sch Med, Shanghai Pulm Hosp, Dept Pharm, Shanghai 200092, Peoples R China.; Qin, SY (reprint author), Shanghai Jiao Tong Univ, Sch Med, Shanghai Mental Hlth Ctr, Shanghai Key Lab Psychot Disorders, Shanghai 200030, Peoples R China. EM zxqkitten@163.com; 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]; Shanghai Municipal Commission of Science and Technology Program [11DZ1950300, 09DJ1400601]; Public Health Key Disciplines in Shanghai-Health Microbiology [12GWZX0801]; Public Science and Technology Research Funds [201210056]; Shanghai Jiao Tong University Interdisciplinary Research fund; Shanghai Leading Academic Discipline Project [B205] FX We sincerely thank all the patients who agreed to participate in the study and all the staff who helped with sample collection and lab work. We also sincerely thank our colleagues in King's College London for their great help and inspiration during the manuscript preparation. 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), Shanghai Municipal Commission of Science and Technology Program (11DZ1950300, 09DJ1400601), the Public Health Key Disciplines in Shanghai-Health Microbiology (12GWZX0801), Public Science and Technology Research Funds (201210056), the Shanghai Jiao Tong University Interdisciplinary Research fund, and the Shanghai Leading Academic Discipline Project (B205). NR 37 TC 0 Z9 0 U1 3 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 MAR 18 PY 2016 VL 6 AR 23368 DI 10.1038/srep23368 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH0LB UT WOS:000372474600001 PM 26988277 ER PT J AU Saito, K He, YL Yang, YJ Zhu, LR Wang, CM Xu, PW Hinton, AO Yan, XF Zhao, J Fukuda, M Tong, QC Clegg, DJ Xu, Y AF Saito, Kenji He, Yanlin Yang, Yongjie Zhu, Liangru Wang, Chunmei Xu, Pingwen Hinton, Antentor Othrell Yan, Xiaofeng Zhao, Jean Fukuda, Makoto Tong, Qingchun Clegg, Deborah J. Xu, Yong TI PI3K in the ventromedial hypothalamic nucleus mediates estrogenic actions on energy expenditure in female mice SO SCIENTIFIC REPORTS LA English DT Article ID HORMONE REPLACEMENT THERAPY; RECEPTOR-ALPHA; BODY-WEIGHT; OVARIECTOMIZED RATS; METABOLIC SYNDROME; ADIPOSE-TISSUE; FOOD-INTAKE; NEURONS; HOMEOSTASIS; LEPTIN AB Estrogens act in the ventromedial hypothalamic nucleus (VMH) to regulate body weight homeostasis. However, the molecular mechanisms underlying these estrogenic effects are unknown. We show that activation of estrogen receptor-alpha (ER alpha) stimulates neural firing of VMH neurons expressing ERa, and these effects are blocked with intracellular application of a pharmacological inhibitor of the phosphatidyl inositol 3-kinase (PI3K). Further, we demonstrated that mice with genetic inhibition of PI3K activity in VMH neurons showed a sexual dimorphic obese phenotype, with only female mutants being affected. In addition, inhibition of VMH PI3K activity blocked effects of 17 beta-estradiol to stimulate energy expenditure, but did not affect estrogen-induced anorexia. Collectively, our results indicate that PI3K activity in VMH neurons plays a physiologically relevant role in mediating estrogenic actions on energy expenditure in females. C1 [Saito, Kenji; He, Yanlin; Yang, Yongjie; Zhu, Liangru; Wang, Chunmei; Xu, Pingwen; Hinton, Antentor Othrell; Yan, Xiaofeng; Fukuda, Makoto; Xu, Yong] Baylor Coll Med, Dept Pediat, Childrens Nutr Res Ctr, Houston, TX 77030 USA. [Zhu, Liangru] Huazhong Univ Sci & Technol, Union Hosp, Dept Gastroenterol, Tongji Med Coll, Wuhan 430022, Peoples R China. [Zhao, Jean] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Zhao, Jean] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Tong, Qingchun] Univ Texas Hlth Sci Ctr Houston, Brown Fdn Inst Mol Med, Houston, TX 77030 USA. [Clegg, Deborah J.] Cedars Sinai Med Ctr, Diabet & Obes Res Inst, Dept Biomed Res, Los Angeles, CA 90048 USA. [Xu, Yong] Baylor Coll Med, Dept Mol & Cellular Biol, One Baylor Plaza, Houston, TX 77030 USA. RP Xu, Y (reprint author), Baylor Coll Med, Dept Pediat, Childrens Nutr Res Ctr, Houston, TX 77030 USA.; Xu, Y (reprint author), Baylor Coll Med, Dept Mol & Cellular Biol, One Baylor Plaza, Houston, TX 77030 USA. EM yongx@bcm.edu RI Fukuda, Makoto/I-7915-2014; OI Fukuda, Makoto/0000-0003-0112-9925; He, Yanlin/0000-0002-5471-9016 FU NIH [Baylor College of Medicine] [R01DK093587, R01DK101379, R00DK085330]; USDA ARS/CRIS Award [6250-51000- 055]; American Diabetes Association; American Heart Association postdoctoral fellowship; American Heart Association National Scientist Development Grant; National Natural Science Foundation of China Award (Baylor College of Medicine) [81200623]; USDA ARS; NIH [Cedars-Sinai Medical Center] [F31 HL128054, P01 DK088761]; NIH [University of Texas Health Science Center at Houston] [R01DK092605] FX This work was supported by grants from the NIH (R01DK093587, R01DK101379, and R00DK085330 to Y.Xu. [Baylor College of Medicine]; F31 HL128054 to A.H. Jr.; P01 DK088761 to D.J.C. [Cedars-Sinai Medical Center]; R01DK092605 to Q.T. [University of Texas Health Science Center at Houston]); USDA ARS/CRIS Award 6250-51000- 055 (Y.Xu.), American Diabetes Association (Y.Xu.), American Heart Association postdoctoral fellowship (P.X. and C.W. [Baylor College of Medicine]), American Heart Association National Scientist Development Grant (Q.T.), and National Natural Science Foundation of China Award 81200623 to L.Z. (Baylor College of Medicine). Measurements of body composition, food intake, energy expenditure and energy expenditure were performed in the Mouse Metabolic Research Unit (MMRU) at the USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, which is supported by funds from the USDA ARS (www.bcm.edu/cnrc/mmru). The authors acknowledge the expert assistance of Mr. Firoz Vohra and the MMRU Core Director, Dr. Marta Fiorotto. NR 36 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAR 18 PY 2016 VL 6 AR 23459 DI 10.1038/srep23459 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DH0ON UT WOS:000372483600001 PM 26988598 ER PT J AU Yang, D Ward, A Halvorsen, K Wong, WP AF Yang, Darren Ward, Andrew Halvorsen, Ken Wong, Wesley P. TI Multiplexed single-molecule force spectroscopy using a centrifuge SO NATURE COMMUNICATIONS LA English DT Article ID DNA NANOSWITCHES; MANIPULATION; TEMPERATURE; MECHANICS; TWEEZERS; MOTION AB We present a miniature centrifuge force microscope (CFM) that repurposes a benchtop centrifuge for high-throughput single-molecule experiments with high-resolution particle tracking, a large force range, temperature control and simple push-button operation. Incorporating DNA nanoswitches to enable repeated interrogation by force of single molecular pairs, we demonstrate increased throughput, reliability and the ability to characterize population heterogeneity. We perform spatiotemporally multiplexed experiments to collect 1,863 bond rupture statistics from 538 traceable molecular pairs in a single experiment, and show that 2 populations of DNA zippers can be distinguished using per-molecule statistics to reduce noise. C1 [Yang, Darren] Harvard Univ, Sch Engn & Appl Sci, Cambridge, MA 02138 USA. [Ward, Andrew; Halvorsen, Ken; Wong, Wesley P.] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Ward, Andrew; Halvorsen, Ken; Wong, Wesley P.] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Halvorsen, Ken] Univ Albany, RNA Inst, Albany, NY 12222 USA. [Wong, Wesley P.] Harvard Univ Boston, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA. RP Halvorsen, K; Wong, WP (reprint author), Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA.; Halvorsen, K; Wong, WP (reprint author), Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA.; Halvorsen, K (reprint author), Univ Albany, RNA Inst, Albany, NY 12222 USA.; Wong, WP (reprint author), Harvard Univ Boston, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA. EM khalvorsen@albany.edu; wesley.wong@childrens.harvard.edu OI Halvorsen, Ken/0000-0002-2578-1339 FU Arnold and Mabel Beckman Foundation through the Beckman Young Investigator Award; US National Institutes of Health [R21 RGM107907A]; Wyss Institute at Harvard University; Boston Children's Hospital startup funds; National Science Foundation Graduate Research Fellowship [DGE-1144152] FX We thank Andreas Karl and Thermo Fisher Scientific for providing materials and support for centrifuge automation, Chris Stokes for technical assistance with early prototypes, Marco Catipovic for assistance with experimental protocols and preparations. W.P.W. acknowledges support from the Arnold and Mabel Beckman Foundation through the Beckman Young Investigator Award, US National Institutes of Health R21 RGM107907A, the Wyss Institute at Harvard University and Boston Children's Hospital startup funds. D.Y. was supported by the National Science Foundation Graduate Research Fellowship DGE-1144152. NR 34 TC 3 Z9 3 U1 4 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD MAR 17 PY 2016 VL 7 AR 11026 DI 10.1038/ncomms11026 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EH6BF UT WOS:000391856600001 PM 26984516 ER PT J AU Kuznetsova, A Yu, Y Hollister-Lock, J Opare-Addo, L Rozzo, A Sadagurski, M Norquay, L Reed, JE El Khattabi, I Bonner-Weir, S Weir, GC Sharma, A White, MF AF Kuznetsova, Alexandra Yu, Yue Hollister-Lock, Jennifer Opare-Addo, Lynn Rozzo, Aldo Sadagurski, Marianna Norquay, Lisa Reed, Jessica E. El Khattabi, Ilham Bonner-Weir, Susan Weir, Gordon C. Sharma, Arun White, Morris F. TI Trimeprazine increases IRS2 in human islets and promotes pancreatic beta cell growth and function in mice SO JCI INSIGHT LA English DT Article ID INSULIN-RECEPTOR SUBSTRATE-2; ANTI-CD3 MONOCLONAL-ANTIBODY; PROTEIN-COUPLED RECEPTORS; TYPE-2 DIABETES-MELLITUS; PLURIPOTENT CELLS; SELF-RENEWAL; NOD MICE; ROAD MAP; EXPRESSION; GLUCOSE AB The capacity of pancreatic beta cells to maintain glucose homeostasis during chronic physiologic and immunologic stress is important for cellular and metabolic homeostasis. Insulin receptor substrate 2 (IRS2) is a regulated adapter protein that links the insulin and IGF1 receptors to downstream signaling cascades. Since strategies to maintain or increase IRS2 expression can promote beta cell growth, function, and survival, we conducted a screen to find small molecules that can increase IRS2 mRNA in isolated human pancreatic islets. We identified 77 compounds, including 15 that contained a tricyclic core. To establish the efficacy of our approach, one of the tricyclic compounds, trimeprazine tartrate, was investigated in isolated human islets and in mouse models. Trimeprazine is a first-generation antihistamine that acts as a partial agonist against the histamine H1 receptor (H1R) and other GPCRs, some of which are expressed on human islets. Trimeprazine promoted CREB phosphorylation and increased the concentration of IRS2 in islets. IRS2 was required for trimeprazine to increase nuclear Pdx1, islet mass, beta cell replication and function, and glucose tolerance in mice. Moreover, trimeprazine synergized with anti-CD3 Abs to reduce the progression of diabetes in NOD mice. Finally, it increased the function of human islet transplants in streptozotocin-induced (STZ-induced) diabetic mice. Thus, trimeprazine, its analogs, or possibly other compounds that increase IRS2 in islets and beta cells without adverse systemic effects might provide mechanism-based strategies to prevent the progression of diabetes. C1 [Kuznetsova, Alexandra; Yu, Yue; Opare-Addo, Lynn; Rozzo, Aldo; Sadagurski, Marianna; Norquay, Lisa; White, Morris F.] Harvard Med Sch, Boston Childrens Hosp, Dept Med, Div Endocrinol, Boston, MA USA. [Hollister-Lock, Jennifer; El Khattabi, Ilham; Bonner-Weir, Susan; Weir, Gordon C.; Sharma, Arun] Harvard Med Sch, Joslin Diabet Ctr, Dept Med, Sect Islet Cell & Regenerat Biol, Boston, MA USA. [Reed, Jessica E.] Housey Pharmaceut Res Labs, Southfield, MI USA. [Kuznetsova, Alexandra] Felicitex Therapeut, Watertown, MA USA. [Sadagurski, Marianna] Univ Michigan, Ann Arbor, MI 48109 USA. [Norquay, Lisa] Janssen Pharmaceut Inc, Titusville, NJ USA. [Sharma, Arun] MedImmune LLC, Gaithersburg, MD USA. RP White, MF (reprint author), Harvard Med Sch, Boston Childrens Hosp, Div Endocrinol, CLS, Rm 16020,3 Blackfan Circle, Boston, MA 02115 USA. EM morris.white@childrens.harvard.edu NR 70 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 2379-3708 J9 JCI INSIGHT JI JCI Insight PD MAR 17 PY 2016 VL 1 IS 3 AR e80749 DI 10.1172/jci.insight.80749 PG 20 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EB1IR UT WOS:000387104000002 ER PT J AU Scully, EP Lockhart, A Garcia-Beltran, W Palmer, CD Musante, C Rosenberg, E Allen, TM Chang, JJ Bosch, RJ Altfeld, M AF Scully, Eileen P. Lockhart, Ainsley Garcia-Beltran, Wilfredo Palmer, Christine D. Musante, Chelsey Rosenberg, Eric Allen, Todd M. Chang, J. Judy Bosch, Ronald J. Altfeld, Marcus TI Innate immune reconstitution with suppression of HIV-1 SO JCI INSIGHT LA English DT Article ID IMMUNODEFICIENCY-VIRUS-INFECTION; SINGLE-STRANDED RNA; ANTIRETROVIRAL THERAPY; DENDRITIC CELLS; IN-VIVO; INFLAMMATORY SYNDROME; HUMAN MACROPHAGES; MONOCYTE SUBSET; HOST-DEFENSE; TLR LIGANDS AB Progressive HIV-1 infection leads to both profound immune suppression and pathologic inflammation in the majority of infected individuals. While adaptive immune dysfunction, as evidenced by CD4(+) T cell depletion and exhaustion, has been extensively studied, less is known about the functional capacity of innate immune cell populations in the context of HIV-1 infection. Given the broad susceptibility to opportunistic infections and the dysregulated inflammation observed in progressive disease, we hypothesized that there would be significant changes in the innate cellular responses. Using a cohort of patients with multiple samplings before and after antiretroviral therapy (ART) initiation, we demonstrated increased responses to innate immune stimuli following viral suppression, as measured by the production of inflammatory cytokines. Plasma viral load itself had the strongest association with this change in innate functional capacity. We further identified epigenetic modifications in the TNFA promoter locus in monocytes that are associated with viremia, suggesting a molecular mechanism for the observed changes in innate immune function following initiation of ART. These data indicate that suppression of HIV-1 viremia is associated with changes in innate cellular function that may in part determine the restoration of protective immune responses. C1 [Scully, Eileen P.; Lockhart, Ainsley; Garcia-Beltran, Wilfredo; Palmer, Christine D.; Musante, Chelsey; Allen, Todd M.; Chang, J. Judy; Altfeld, Marcus] Ragon Inst Massachusetts Gen Hosp Massachusetts I, 400 Technol Sq, Cambridge, MA 20139 USA. [Scully, Eileen P.] Brigham & Womens Hosp, Div Infect Dis, 75 Francis St, Boston, MA 02115 USA. [Rosenberg, Eric] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Bosch, Ronald J.] Harvard Sch Publ Hlth, Boston, MA USA. [Altfeld, Marcus] Heinrich Pette Inst, Martinistrase52, Hamburg, Germany. [Chang, J. Judy] Univ Melbourne, Doherty Inst Infect & Immun, Melbourne, Vic, Australia. RP Scully, EP; Altfeld, M (reprint author), Ragon Inst Massachusetts Gen Hosp Massachusetts I, 400 Technol Sq, Cambridge, MA 20139 USA.; Altfeld, M (reprint author), Heinrich Pette Inst, Martinistrase52, Hamburg, Germany. EM escully@partners.org; marcus.altfeld@hpi.uni-hamburg.de RI Allen, Todd/F-5473-2011 FU NIAID NIH HHS [F31 AI116366, P01 AI074415, R01 AI078784, T32 AI007387]; NIGMS NIH HHS [T32 GM007753] NR 70 TC 1 Z9 1 U1 1 U2 1 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 2379-3708 J9 JCI INSIGHT JI JCI Insight PD MAR 17 PY 2016 VL 1 IS 3 AR e85433 DI 10.1172/jci.insight.85433 PG 14 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EB1IR UT WOS:000387104000005 PM 27158667 ER PT J AU Morena, D Maestro, N Bersani, F Forni, PE Lingua, MF Foglizzo, V Scepanovic, P Miretti, S Morotti, A Shern, JF Khan, J Ala, U Provero, P Sala, V Crepaldi, T Gasparini, P Casanova, M Ferrari, A Sozzi, G Chiarle, R Ponzetto, C Taulli, R AF Morena, Deborah Maestro, Nicola Bersani, Francesca Forni, Paolo Emanuele Lingua, Marcello Francesco Foglizzo, Valentina Scepanovic, Peter Miretti, Silvia Morotti, Alessandro Shern, Jack F. Khan, Javed Ala, Ugo Provero, Paolo Sala, Valentian Crepaldi, Tiziana Gasparini, Patrizia Casanova, Michela Ferrari, Andrea Sozzi, Gabriella Chiarle, Roberto Ponzetto, Carola Taulli, Riccardo TI Hepatocyte Growth Factor-mediated satellite cells niche perturbation promotes development of distinct sarcoma subtypes SO ELIFE LA English DT Article ID SOFT-TISSUE SARCOMAS; UNDIFFERENTIATED PLEOMORPHIC SARCOMA; CHILDRENS ONCOLOGY GROUP; ADULT SKELETAL-MUSCLE; EMBRYONAL RHABDOMYOSARCOMA; ALVEOLAR RHABDOMYOSARCOMA; INTRATUMOR HETEROGENEITY; FIBROUS HISTIOCYTOMA; LARGE SERIES; STEM-CELLS AB Embryonal Rhabdomyosarcoma (ERMS) and Undifferentiated Pleomorphic Sarcoma (UPS) are distinct sarcoma subtypes. Here we investigate the relevance of the satellite cell (SC) niche in sarcoma development by using Hepatocyte Growth Factor (HGF) to perturb the niche microenvironment. In a Pax7 wild type background, HGF stimulation mainly causes ERMS that originate from satellite cells following a process of multistep progression. Conversely, in a Pax7 null genotype ERMS incidence drops, while UPS becomes the most frequent subtype. Murine EfRMS display genetic heterogeneity similar to their human counterpart. Altogether, our data demonstrate that selective perturbation of the SC niche results in distinct sarcoma subtypes in a Pax7 lineage-dependent manner, and define a critical role for the Met axis in sarcoma initiation. Finally, our results provide a rationale for the use of combination therapy, tailored on specific amplifications and activated signaling pathways, to minimize resistance emerging from sarcomas heterogeneity. C1 [Morena, Deborah; Maestro, Nicola; Bersani, Francesca; Forni, Paolo Emanuele; Lingua, Marcello Francesco; Foglizzo, Valentina; Scepanovic, Peter; Sala, Valentian; Crepaldi, Tiziana; Ponzetto, Carola; Taulli, Riccardo] Univ Turin, Dept Oncol, Turin, Italy. [Morena, Deborah; Maestro, Nicola; Bersani, Francesca; Forni, Paolo Emanuele; Lingua, Marcello Francesco; Foglizzo, Valentina; Scepanovic, Peter; Chiarle, Roberto; Ponzetto, Carola; Taulli, Riccardo] Ctr Expt Res & Med Studies, CeRMS, Turin, Italy. [Miretti, Silvia] Univ Turin, Dept Vet Sci, Grugliasco, Italy. [Morotti, Alessandro] Univ Turin, Dept Clin & Biol Sci, Orbassano, Italy. [Shern, Jack F.; Khan, Javed] NIH, Pediat Oncol Branch, Oncogen Sect, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. [Ala, Ugo; Provero, Paolo; Chiarle, Roberto] Univ Turin, Dept Mol Biotechnol & Hlth Sci, Turin, Italy. [Gasparini, Patrizia; Casanova, Michela; Ferrari, Andrea; Sozzi, Gabriella] Fdn IRCCS Ist Nazl Tumori, Dept Expt Oncol, Milan, Italy. [Chiarle, Roberto] Boston Childrens Hosp, Dept Pathol, Boston, MA USA. [Chiarle, Roberto] Harvard Univ, Sch Med, Boston, MA USA. [Maestro, Nicola] UCL, Samantha Dickson Canc Unit, Canc Inst, London, England. [Bersani, Francesca] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Canc Ctr, Charlestown, MA USA. [Forni, Paolo Emanuele] SUNY Albany, Dept Biol Sci, Albany, NY 12222 USA. [Forni, Paolo Emanuele] SUNY Albany, Ctr Neurosci Res, Albany, NY 12222 USA. [Foglizzo, Valentina] Francis Crick Inst, Mill Hill Lab, London, England. [Scepanovic, Peter] Ecole Polytech Fed Lausanne, Sch Life Sci, CH-1015 Lausanne, Switzerland. [Scepanovic, Peter] Swiss Inst Bioinformat, Lausanne, Switzerland. RP Taulli, R (reprint author), Univ Turin, Dept Oncol, Turin, Italy.; Taulli, R (reprint author), Ctr Expt Res & Med Studies, CeRMS, Turin, Italy. EM riccardo.taulli@unito.it RI Ala, Ugo/K-2029-2016; sozzi, gabriella/G-8259-2011; Casanova, Michela/K-8436-2016; Khan, Javed/P-9157-2014; Gasparini, Patrizia/Q-7626-2016; OI Ala, Ugo/0000-0001-5408-6397; sozzi, gabriella/0000-0001-9360-6914; Casanova, Michela/0000-0003-0368-7883; Khan, Javed/0000-0002-5858-0488; Gasparini, Patrizia/0000-0002-9548-3724; Morotti, Alessandro/0000-0002-8407-2903; Ferrari, Andrea/0000-0002-4724-0517 FU Italian Association for Cancer Research [IG12089, 15405]; Regione Piemonte; Associazione Bianca Garavaglia [A/15/01N] FX Italian Association for Cancer Research AIRC Project number, IG12089 Carola Ponzetto; Regione Piemonte IMMONC Project Carola Ponzetto; Italian Association for Cancer Research AIRC Start-Up, Project number 15405 Riccardo Taulli; Associazione Bianca Garavaglia A/15/01N Gabriella Sozzi NR 68 TC 1 Z9 1 U1 1 U2 2 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD MAR 17 PY 2016 VL 5 AR e12116 DI 10.7554/eLife.12116 PG 24 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DJ0ML UT WOS:000373897900001 ER PT J AU Labonne, JDJ Shen, YP Kong, IK Diamond, MP Layman, LC Kim, HG AF Labonne, Jonathan D. J. Shen, Yiping Kong, Il-Keun Diamond, Michael P. Layman, Lawrence C. Kim, Hyung-Goo TI Comparative deletion mapping at 1p31.3p32.2 implies NFIA responsible for intellectual disability coupled with macrocephaly and the presence of several other genes for syndromic intellectual disability SO MOLECULAR CYTOGENETICS LA English DT Article DE 1p microdeletion; Intellectual disability; Delayed psychomotor development; Craniofacial anomalies; DAB1; HOOK1; NFIA; DOCK7; DNAJC6; PDE4B ID NEURONAL CEROID-LIPOFUSCINOSES; DENOVO INTERSTITIAL DELETION; HYPOPLASTIC CORPUS-CALLOSUM; URINARY-TRACT DEFECTS; CLINICAL PHENOTYPE; BATTEN-DISEASE; PATIENT; MICRODELETION; 1P; FEATURES AB Background: While chromosome 1 is the largest chromosome in the human genome, less than two dozen cases of interstitial microdeletions in the short arm have been documented. More than half of the 1p microdeletion cases were reported in the pre-microarray era and as a result, the proximal and distal boundaries containing the exact number of genes involved in the microdeletions have not been clearly defined. Results: We revisited a previous case of a 10-year old female patient with a 1p32.1p32.3 microdeletion displaying syndromic intellectual disability. We performed microarray analysis as well as qPCR to define the proximal and distal deletion breakpoints and revised the karyotype from 1p32.1p32.3 to 1p31.3p32.2. The deleted chromosomal region contains at least 35 genes including NFIA. Comparative deletion mapping shows that this region can be dissected into five chromosomal segments containing at least six candidate genes (DAB1, HOOK1, NFIA, DOCK7, DNAJC6, and PDE4B) most likely responsible for syndromic intellectual disability, which was corroborated by their reduced transcript levels in RT-qPCR. Importantly, one patient with an intragenic microdeletion within NFIA and an additional patient with a balanced translocation disrupting NFIA display intellectual disability coupled with macrocephaly. Conclusion: We propose NFIA is responsible for intellectual disability coupled with macrocephaly, and microdeletions at 1p31.3p32.2 constitute a contiguous gene syndrome with several genes contributing to syndromic intellectual disability. C1 [Labonne, Jonathan D. J.; Diamond, Michael P.; Layman, Lawrence C.; Kim, Hyung-Goo] Augusta Univ, Dept Obstet & Gynecol, 1120 15th St, Augusta, GA 30912 USA. [Labonne, Jonathan D. J.; Layman, Lawrence C.; Kim, Hyung-Goo] Augusta Univ, Dept Neurosci & Regenerat Med, Med Coll Georgia, 1120 15th St, Augusta, GA 30912 USA. [Shen, Yiping] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA 02114 USA. [Kong, Il-Keun] Gyeongsang Natl Univ, Inst Agr & Life Sci, Div Appl Life Sci BK21Plus, Dept Anim Sci, Jinju, Gyeongsangnam D, South Korea. [Layman, Lawrence C.] Augusta Univ, Med Coll Georgia, Neurosci Program, Augusta, GA 30912 USA. RP Kim, HG (reprint author), Augusta Univ, Dept Obstet & Gynecol, 1120 15th St, Augusta, GA 30912 USA.; Kim, HG (reprint author), Augusta Univ, Dept Neurosci & Regenerat Med, Med Coll Georgia, 1120 15th St, Augusta, GA 30912 USA. EM hkim@gru.edu FU Wellcome Trust FX We would like to thank the patient who kindly consented to participate in our study. We wish to thank Lynn Chorich and Megan Sullivan. We also extend our thanks to Paul Browne. The present study makes use of data generated by the DECIPHER community. A full list of centres who contributed to the generation of the data is available from http://decipher.sanger.ac.uk and via email from decipher@sanger.ac.uk. Funding for the DECIPHER project was provided by the Wellcome Trust. This study was undertaken following the guidelines established by the Institutional Review Board at AU. NR 38 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 1755-8166 J9 MOL CYTOGENET JI Mol. Cytogenet. PD MAR 17 PY 2016 VL 9 AR 24 DI 10.1186/s13039-016-0234-z PG 12 WC Genetics & Heredity SC Genetics & Heredity GA DH2FF UT WOS:000372598900001 PM 26997977 ER EF