FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Kozin, ED Remenschneider, AK Cheng, S Nakajima, HH Lee, DJ AF Kozin, Elliott D. Remenschneider, Aaron K. Cheng, Song Nakajima, Hideko Heidi Lee, Daniel J. TI Three-Dimensional Printed Prosthesis for Repair of Superior Canal Dehiscence SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Article DE superior semicircular canal dehiscence; superior semicircular canal dehiscence syndrome; 3-dimensional printing ID SURGICAL-MANAGEMENT; POROUS TITANIUM AB Outcomes following repair of superior canal dehiscence (SCD) are variable, and surgery carries a risk of persistent or recurrent SCD symptoms, as well as a risk of hearing loss and vestibulopathy. Poor outcomes may occur from inadequate repair of the SCD or mechanical insult to the membranous labyrinth. Repair of SCD using a customized, fixed-length prosthesis may address current operative limitations and improve surgical outcomes. We aim to 3-dimensionally print customized prostheses to resurface or occlude bony SCD defects. Dehiscences were created along the arcuate eminence of superior semicircular canals in cadaveric temporal bones. Prostheses were designed and created using computed tomography and a 3-dimensional printer. The prostheses occupied the superior semicircular canal defect, reflected in postrepair computed tomography scans. This novel approach to SCD repair could have advantages over current techniques. Refinement of prosthesis design and materials will be important if this approach is translated into clinical use. C1 [Kozin, Elliott D.; Remenschneider, Aaron K.; Cheng, Song; Nakajima, Hideko Heidi; Lee, Daniel J.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Kozin, Elliott D.; Remenschneider, Aaron K.; Cheng, Song; Nakajima, Hideko Heidi; Lee, Daniel J.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol Head & Neck Surg, Boston, MA 02114 USA. RP Remenschneider, AK (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM Aaron_Remenschneider@meei.harvard.edu NR 15 TC 0 Z9 0 U1 3 U2 4 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0194-5998 EI 1097-6817 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD OCT PY 2015 VL 153 IS 4 BP 616 EP 619 DI 10.1177/0194599815592602 PG 4 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA CS9XD UT WOS:000362445800025 PM 26150379 ER PT J AU Singal, G Upadhyay, GA Borgquist, R Friedman, DJ Chatterjee, NA Kandala, J Park, MY Orencole, M Dec, GW Picard, MH Singh, JP Mela, T AF Singal, Gaurav Upadhyay, Gaurav A. Borgquist, Rasmus Friedman, Daniel J. Chatterjee, Neal A. Kandala, Jagdesh Park, Mi Young Orencole, Mary Dec, George W. Picard, Michael H. Singh, Jagmeet P. Mela, Theofanie TI Renal Response in Patients with Chronic Kidney Disease Predicts Outcome Following Cardiac Resynchronization Therapy SO PACE-PACING AND CLINICAL ELECTROPHYSIOLOGY LA English DT Article DE heart failure; cardiorenal syndrome; chronic kidney disease; cardiac resynchronization therapy; pacemakers ID GLOMERULAR-FILTRATION-RATE; CHRONIC HEART-FAILURE; CARDIORENAL SYNDROME; INSUFFICIENCY; DYSFUNCTION; MORTALITY; TRIAL; ASSOCIATIONS; COHORT; DEATH AB BackgroundChronic kidney disease (CKD) severity is associated with increased morbidity and mortality in congestive heart failure. There is a paucity of data regarding renal improvement after cardiac resynchronization therapy (CRT) and its potential impact on clinical outcomes, especially in patients with severe CKD. MethodThis was a retrospective analysis of a prospectively collected cohort of 260 patients with CKD undergoing CRT at a single center. Renal function was compared before and after CRT. The primary end point was a composite of death, heart transplant, and left ventricular assist device (LVAD), assessed at 5 years. ResultsPatients with more severe CKD demonstrated increased risk of death, transplant, or LVAD following CRT (P = 0.015). Renal response (estimated glomerular filtration rate improvement 10 mL/min/1.73 m(2)) was observed in 14% of all patients and 28% of patients with stage IV CKD. Independent predictors of renal response included left ventricular ejection fraction improvement (odds ratio [OR] 1.06, confidence interval [CI] 1.01-1.10), angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use (OR 4.31, CI 1.08-17.23), and advanced CKD stage (OR 2.19, CI 1.14-4.23). Renal response independently decreased hazard of the primary outcome (HR 0.24, CI 0.08-0.73, P = 0.01). Renal responders with stage IV CKD had 80% 5-year event-free survival, compared to 0% for nonrenal responders in stage IV (P = 0.03). ConclusionAlthough severity of CKD is associated with poorer outcome after CRT, improvement in renal function can occur in patients across all CKD stages. Renal responders, including those with stage IV CKD, demonstrate favorable 5-year outcomes. Assessment of renal response may help better prognostic outcomes following CRT. C1 [Singal, Gaurav; Friedman, Daniel J.; Chatterjee, Neal A.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Upadhyay, Gaurav A.; Borgquist, Rasmus; Kandala, Jagdesh; Orencole, Mary; Singh, Jagmeet P.; Mela, Theofanie] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Upadhyay, Gaurav A.; Kandala, Jagdesh; Park, Mi Young; Orencole, Mary; Dec, George W.; Picard, Michael H.; Singh, Jagmeet P.; Mela, Theofanie] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Borgquist, Rasmus] Lund Univ, Skane Univ Hosp, Arrhythmia Clin, Lund, Sweden. RP Mela, T (reprint author), Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Gray 109,75 Fruit St, Boston, MA 02114 USA. EM tmela@partners.org OI Picard, Michael/0000-0002-9264-3243; Friedman, Daniel /0000-0001-5791-1954 FU Swedish Heart and Lung Foundation; Swedish National Health Service FX Dr. Borgquist was supported by grants from the Swedish Heart and Lung Foundation and by governmental funding of clinical research within the Swedish National Health Service. NR 31 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0147-8389 EI 1540-8159 J9 PACE JI PACE-Pacing Clin. Electrophysiol. PD OCT PY 2015 VL 38 IS 10 BP 1192 EP 1200 DI 10.1111/pace.12685 PG 9 WC Cardiac & Cardiovascular Systems; Engineering, Biomedical SC Cardiovascular System & Cardiology; Engineering GA CT1MZ UT WOS:000362563900008 PM 26179289 ER PT J AU Huber, RJ O'Day, DH AF Huber, Robert J. O'Day, Danton H. TI Proteomic profiling of the extracellular matrix (slime sheath) of Dictyostelium discoideum SO PROTEOMICS LA English DT Article DE Cell biology; Development; Dictyostelium discoideum; Extracellular matrix; Model system ID EGF-LIKE PEPTIDE; CELL-MIGRATION; MATRICELLULAR PROTEIN; MEDIATED CHEMOTAXIS; MASS-SPECTROMETRY; STATISTICAL-MODEL; MOTILITY; DATABASE; SLUG; CHEMOATTRACTANT AB Dictyostelium discoideum has historically served as a model system for cell and developmental biology, but recently it has gained increasing attention as a model for the study of human diseases. The extracellular matrix (ECM) of this eukaryotic microbe serves multiple essential functions during development. It not only provides structural integrity to the moving multicellular pseudoplasmodium, or slug, it also provides components that regulate cell motility and differentiation. An LC/MS/MS analysis of slug ECM revealed the presence of a large number of proteins in two wild-type strains, NC4 and WS380B. GO annotation identified a large number of proteins involved in some form of binding (e.g. protein, polysaccharide, cellulose, carbohydrate, ATP, cAMP, ion, lipid, vitamin), as well as proteins that modulate metabolic processes, cell movement, and multicellular development. In addition, this proteomic analysis identified numerous expected (e.g. EcmA, EcmD, discoidin I, discoidin II), as well as unexpected (e.g. ribosomal and nuclear proteins) components. These topics are discussed in terms of the structure and function of the ECM during the development of this model amoebozoan and their relevance to ongoing biomedical research. C1 [Huber, Robert J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Ctr Human Genet Res, Boston, MA USA. [O'Day, Danton H.] Univ Toronto, Dept Cell & Syst Biol, Toronto, ON, Canada. [O'Day, Danton H.] Univ Toronto, Dept Biol, Mississauga, ON L5L 1C6, Canada. RP Huber, RJ (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, 185 Cambridge St, Boston, MA 02114 USA. EM rhuber@mgh.harvard.edu FU CIHR [MFE127336]; NSERC DG [A6807] FX CIHR Fellowship (MFE127336 to R.J.H.); NSERC DG (A6807 to D.H.O'D.). NR 38 TC 3 Z9 3 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1615-9853 EI 1615-9861 J9 PROTEOMICS JI Proteomics PD OCT PY 2015 VL 15 IS 19 BP 3315 EP 3319 DI 10.1002/pmic.201500143 PG 5 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CT0RP UT WOS:000362504300005 PM 26152465 ER PT J AU Kasckow, J Gao, SS Hanusa, B Rotondi, A Chinman, M Zickmund, S Gurklis, J Fox, L Cornelius, J Richmond, I Haas, GL AF Kasckow, John Gao, Shasha Hanusa, Barbara Rotondi, Armando Chinman, Matthew Zickmund, Susan Gurklis, John Fox, Lauren Cornelius, Jack Richmond, Ira Haas, Gretchen L. TI Telehealth Monitoring of Patients with Schizophrenia and Suicidal Ideation SO SUICIDE AND LIFE-THREATENING BEHAVIOR LA English DT Article ID DEPRESSION RATING-SCALE; VETERANS; RISK; SYMPTOMS; MORTALITY; DISORDER; OUTCOMES; MINI AB A telehealth system was developed to monitor risk following hospitalization for suicidal ideation. We hypothesized that 3months of telehealth monitoring will result in a greater reduction in suicidal ideation. Veterans with schizophrenia admitted with recent suicidal ideation and/or a suicidal attempt were recruited into a discharge program of VA Usual Care with daily Health Buddy (c) monitoring (HB) or Usual Care (UC) alone. Fifteen of 25 were randomized to HB and 10 received UC. Daily adherence in the use of the HB system during months 1-3 was, respectively, 86.9%, 86.3%, and 84.1%. There were significant improvements in Beck Scale for Suicide Ideation scores in HB participants. There were no changes in depressive symptoms. Telehealth monitoring for this population of patients appears to be feasible. C1 [Kasckow, John] VA Pittsburgh MIRECC, CHERP & Behav Hlth, Pittsburgh, PA USA. [Kasckow, John; Cornelius, Jack; Haas, Gretchen L.] UPMC Western Psychiat Inst & Clin, Pittsburgh, PA USA. [Gao, Shasha; Zickmund, Susan] VA Pittsburgh CHERP, Pittsburgh, PA USA. [Hanusa, Barbara; Rotondi, Armando; Chinman, Matthew; Fox, Lauren; Cornelius, Jack] VA Pittsburgh MIRECC, Pittsburgh, PA USA. [Rotondi, Armando] UPMC Crit Care, Pittsburgh, PA USA. [Chinman, Matthew] CHERP, Pittsburgh, PA USA. [Zickmund, Susan] UPMC Dept Med, Pittsburgh, PA USA. [Gurklis, John] VA Pittsburgh Behav Hlth, Pittsburgh, PA USA. [Richmond, Ira] VA Pittsburgh Patient Care Serv, Pittsburgh, PA USA. [Haas, Gretchen L.] VA Pittsburgh MIRECC & Behav Hlth, Pittsburgh, PA USA. RP Kasckow, J (reprint author), VA Pittsburgh Hlth Care Syst, Behav Hlth 116A, Univ Dr C, Pittsburgh, PA 15240 USA. EM kasckowjw@upmc.edu FU VISN 4 MIRECC; HSRD PPO [10-249-2] FX Funded by the VISN 4 MIRECC and HSRD PPO 10-249-2 (JWK). The views do not represent the views of the U.S. Department of veterans Affairs or that of the U.S. government. NR 33 TC 2 Z9 2 U1 2 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0363-0234 EI 1943-278X J9 SUICIDE LIFE-THREAT JI Suicide Life-Threat. Behav. PD OCT PY 2015 VL 45 IS 5 BP 600 EP 611 DI 10.1111/sltb.12154 PG 12 WC Psychiatry; Psychology, Multidisciplinary SC Psychiatry; Psychology GA CT3FR UT WOS:000362693100007 ER PT J AU Venne, VL Scheuner, MT AF Venne, Vickie L. Scheuner, Maren T. TI Securing and Documenting Cancer Family History in the Age of the Electronic Medical Record SO SURGICAL ONCOLOGY CLINICS OF NORTH AMERICA LA English DT Article DE Family health history; Pedigree; Genetic risk assessment; Electronic medical records ID GENETIC RISK-ASSESSMENT; PRIMARY-CARE; BREAST-CANCER; DECISION-SUPPORT; HEREDITARY BREAST; OVARIAN-CANCER; TOOL; TELEPHONE; IMPACT; WOMEN AB Family health history is one of the least expensive, most useful, and most underused methods available to conduct assessments of the genetic aspect of a condition or to target the need for a genetic evaluation. This article introduces to the surgical oncologist the reason and process of collecting family history information. As medical records shift from paper to electronic formats, pedigree drawings are not readily available within the electronic health records. International efforts are underway to develop searchable, updatable, and interoperable formats that can collect family history information to inform clinical decision support for genetic risk assessment. C1 [Venne, Vickie L.] SLC VA Med Ctr, Genom Med Serv, Salt Lake City, UT 84148 USA. [Scheuner, Maren T.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Scheuner, Maren T.] VA Greater Los Angeles Healthcare Syst, Med Genet, Los Angeles, CA 90073 USA. RP Venne, VL (reprint author), SLC VA Med Ctr, Genom Med Serv, 500 Foothill Dr, Salt Lake City, UT 84148 USA. EM vickie.venne@va.gov NR 44 TC 1 Z9 1 U1 2 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 1055-3207 EI 1558-5042 J9 SURG ONCOL CLIN N AM JI Surg. Oncol. Clin. N. Am. PD OCT PY 2015 VL 24 IS 4 BP 639 EP + DI 10.1016/j.soc.2015.06.001 PG 15 WC Oncology; Surgery SC Oncology; Surgery GA CT3GA UT WOS:000362694000004 PM 26363534 ER PT J AU Yeh, DD Ghoshhajra, B Inglessis-Azuaje, I MacGillivray, T Liberthson, R Bhatt, AB AF Yeh, Doreen DeFaria Ghoshhajra, Brian Inglessis-Azuaje, Ignacio MacGillivray, Thomas Liberthson, Richard Bhatt, Ami B. TI Massive Pulmonary Artery Aneurysm Causing Left Main Coronary Artery Compression in the Absence of Pulmonary Hypertension SO TEXAS HEART INSTITUTE JOURNAL LA English DT Article DE Angina pectoris/etiology; coronary vessel anomalies/complications; heart defects; congenital/complications/diagnosis/radiography; heart valves/abnormalities; pulmonary artery/abnormalities/pathology/surgery; treatment outcome ID TETRALOGY; FALLOT AB We report the case of a 62-year-old woman who presented with classic symptoms of stable angina. Cardiac images and catheterization results revealed absent pulmonary valve syndrome and compression of the left main coronary artery by a massively dilated pulmonary artery aneurysm. The patient's anginal symptoms were relieved after pulmonary arterioplasty. Others have described proximal left main coronary artery compression in the presence of a dilated and hypertensive pulmonary artery To our knowledge, this is the first case in which a pulmonary artery aneurysm caused left main coronary insufficiency in the absence of pulmonary hypertension a clinically important complication of congenital pulmonary valve-related pulmonary arteriopathy. C1 [Yeh, Doreen DeFaria; Inglessis-Azuaje, Ignacio; Bhatt, Ami B.] Massachusetts Gen Hosp, Div Cardiol, Dept Med, Boston, MA 02114 USA. [Ghoshhajra, Brian] Massachusetts Gen Hosp, Dept Radiol, Cardiac Radiol Sect, Boston, MA 02114 USA. [MacGillivray, Thomas] Massachusetts Gen Hosp, Cardiothorac Surg Sect, Dept Surg, Boston, MA 02114 USA. [Liberthson, Richard] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Liberthson, Richard] Massachusetts Gen Hosp, Dept Pediat, Div Cardiol, Boston, MA 02114 USA. RP Yeh, DD (reprint author), Massachusetts Gen Hosp, Div Cardiol, Yawkey 5B,55 Fruit St, Boston, MA 02114 USA. EM ddefariayeh@partners.org NR 8 TC 0 Z9 0 U1 0 U2 1 PU TEXAS HEART INST PI HOUSTON PA PO BOX 20345, HOUSTON, TX 77225-0345 USA SN 0730-2347 EI 1526-6702 J9 TEX HEART I J JI Tex. Heart Inst. J. PD OCT PY 2015 VL 42 IS 5 BP 465 EP 467 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CS9SD UT WOS:000362430900013 PM 26504443 ER PT J AU Al-Alusi, MA Du, L Li, N Yeh, MW He, XM Braverman, LE Leung, AM AF Al-Alusi, Mostafa A. Du, Lin Li, Ning Yeh, Michael W. He, Xuemei Braverman, Lewis E. Leung, Angela M. TI Metformin Does Not Suppress Serum Thyrotropin by Increasing Levothyroxine Absorption SO THYROID LA English DT Article ID DIABETIC-PATIENTS; RESPIRATORY-CHAIN; HYPOTHYROIDISM; WOMEN; TSH; EXPRESSION; THERAPY; KINASE; OBESE; CREB AB Background: Levothyroxine (LT4) absorption is affected by concomitant ingestion of certain minerals, medications, and foods. It has been hypothesized that metformin may suppress serum thyrotropin (TSH) concentrations by enhancing LT4 absorption or by directly affecting the hypothalamic-pituitary axis. This study examined the effect of metformin ingestion on LT4 absorption, as assessed by serum total thyroxine (TT4) concentrations. Methods: A modified Food and Drug Administration LT4 bioequivalence protocol was applied to healthy, metformin-naive, euthyroid adult volunteers. Following an overnight fast, 600g LT4 was administered orally. Serum TT4 concentrations were measured at baseline and at 0.5, 1, 1.5, 2, 4, and 6h following LT4 administration. Measurements were performed before and after one week of metformin ingestion (850mg three times daily). Peak serum TT4 concentrations, time to peak TT4 concentrations, and area under the concentration-time curve (AUC) were calculated. Results: Twenty-six subjects (54% men, 27% white, age 3310 years) were studied. There were no significant differences in peak serum TT4 concentrations (p=0.13) and time to peak TT4 concentrations (p=0.19) before and after one week of metformin use. A trend toward reduced TT4 AUC was observed after metformin ingestion (pre-metformin 3893 +/- 568g/dL-min, post-metformin 3765 +/- 588g/dL-min, p=0.09). Conclusions: LT4 absorption is unchanged by concomitant metformin ingestion. Mechanisms other than increased LT4 absorption may be responsible for the suppressed TSH concentrations observed in patients ingesting both drugs. C1 [Al-Alusi, Mostafa A.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90073 USA. [Du, Lin] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Dept Biostat, Los Angeles, CA 90073 USA. [Li, Ning] Univ Calif Los Angeles, David Geffen Sch Med, Dept Biomath, Los Angeles, CA 90073 USA. [Yeh, Michael W.] Univ Calif Los Angeles, David Geffen Sch Med, Sect Endocrine Surg, Los Angeles, CA 90073 USA. [Leung, Angela M.] Univ Calif Los Angeles, David Geffen Sch Med, Div Endocrinol, Los Angeles, CA 90073 USA. [He, Xuemei; Braverman, Lewis E.] Boston Univ, Sch Med, Sect Endocrinol Diabet & Nutr, Boston, MA 02118 USA. [Leung, Angela M.] VA Greater Los Angeles Healthcare Syst, Div Endocrinol, Los Angeles, CA USA. RP Leung, AM (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Div Endocrinol 111D, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM amleung@mednet.ucla.edu FU NIH [K23HD068552]; NIH/National Center for Advancing Translational Science (NCATS) UCLA CTSI [UL1TR000124] FX This work was funded by NIH K23HD068552 (A.M.L.) and NIH/National Center for Advancing Translational Science (NCATS) UCLA CTSI UL1TR000124. This work was presented as an abstract at the 2015 Annual Meeting of the Endocrine Society under the title "The Effect of Metformin on Levothyroxine Absorption." NR 30 TC 1 Z9 1 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 OCT 1 PY 2015 VL 25 IS 10 BP 1080 EP 1084 DI 10.1089/thy.2015.0211 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CS7LY UT WOS:000362266300002 PM 26191653 ER PT J AU McLeod, DSA Jonklaas, J Brierley, JD Ain, KB Cooper, DS Fein, HG Haugen, BR Ladenson, PW Magner, J Ross, DS Skarulis, MC Steward, DL Xing, MZ Litofsky, DR Maxon, HR Sherman, SI AF McLeod, Donald S. A. Jonklaas, Jacqueline Brierley, James D. Ain, Kenneth B. Cooper, David S. Fein, Henry G. Haugen, Bryan R. Ladenson, Paul W. Magner, James Ross, Douglas S. Skarulis, Monica C. Steward, David L. Xing, Mingzhao Litofsky, Danielle R. Maxon, Harry R. Sherman, Steven I. TI Reassessing the NTCTCS Staging Systems for Differentiated Thyroid Cancer, Including Age at Diagnosis SO THYROID LA English DT Article ID TALL-CELL VARIANT; CARCINOMA; PAPILLARY; PROGNOSIS; SURVIVAL; THERAPY; THYROTROPIN; REGISTRY; RISK AB Background: Thyroid cancer is unique for having age as a staging variable. Recently, the commonly used age cut-point of 45 years has been questioned. Objective: This study assessed alternate staging systems on the outcome of overall survival, and compared these with current National Thyroid Cancer Treatment Cooperative Study (NTCTCS) staging systems for papillary and follicular thyroid cancer. Methods: A total of 4721 patients with differentiated thyroid cancer were assessed. Five potential alternate staging systems were generated at age cut-points in five-year increments from 35 to 70 years, and tested for model discrimination (Harrell's C-statistic) and calibration (R-2). The best five models for papillary and follicular cancer were further tested with bootstrap resampling and significance testing for discrimination. Results: The best five alternate papillary cancer systems had age cut-points of 45-50 years, with the highest scoring model using 50 years. No significant difference in C-statistic was found between the best alternate and current NTCTCS systems (p=0.200). The best five alternate follicular cancer systems had age cut-points of 50-55 years, with the highest scoring model using 50 years. All five best alternate staging systems performed better compared with the current system (p=0.003-0.035). There was no significant difference in discrimination between the best alternate system (cut-point age 50 years) and the best system of cut-point age 45 years (p=0.197). Conclusions: No alternate papillary cancer systems assessed were significantly better than the current system. New alternate staging systems for follicular cancer appear to be better than the current NTCTCS system, although they require external validation. C1 [McLeod, Donald S. A.] Royal Brisbane & Womens Hosp, Dept Endocrinol & Diabet, Herston, Qld, Australia. [McLeod, Donald S. A.] QIMR Berghofer Med Res Inst, Populat Hlth Dept, Herston, Qld, Australia. [McLeod, Donald S. A.] Univ Queensland, Sch Med, Herston, Qld, Australia. [Jonklaas, Jacqueline] Georgetown Univ, Med Ctr, Dept Med, Div Endocrinol, Washington, DC 20007 USA. [Brierley, James D.] Princess Margaret Hosp, Dept Radiat Oncol, Toronto, ON M4X 1K9, Canada. [Ain, Kenneth B.] Vet Affairs Med Ctr, Dept Internal Med, Lexington, KY USA. [Ain, Kenneth B.] Univ Kentucky, Lexington, KY USA. [Cooper, David S.; Ladenson, Paul W.; Xing, Mingzhao] Johns Hopkins Univ, Sch Med, Div Endocrinol Diabet & Metab, Baltimore, MD USA. [Fein, Henry G.] Sinai Hosp, Div Endocrinol & Metab, Baltimore, MD 21215 USA. [Haugen, Bryan R.] Univ Colorado, Sch Med, Div Endocrinol Metab & Diabet, Aurora, CO USA. [Magner, James] Genzyme, Cambridge, MA USA. [Ross, Douglas S.] Massachusetts Gen Hosp, Thyroid Unit, Boston, MA 02114 USA. [Skarulis, Monica C.] NIH, Diabet, Endocrinol, Obes Branch, Bethesda, MD 20892 USA. [Steward, David L.] Univ Cincinnati, Med Ctr, Dept Head & Neck Surg, Cincinnati, OH 45267 USA. [Maxon, Harry R.] Univ Cincinnati, Med Ctr, Dept Nucl Med, Cincinnati, OH 45267 USA. [Litofsky, Danielle R.; Sherman, Steven I.] Univ Texas MD Anderson Canc Ctr, Dept Endocrine Neoplasia & Hormonal Disorders, Houston, TX 77030 USA. RP Sherman, SI (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Endocrine Neoplasia & Hormonal Disorders, 1400 Pressler,Unit 1461, Houston, TX 77030 USA. EM sisherma@mdanderson.org RI McLeod, Donald/C-4242-2014; OI McLeod, Donald/0000-0003-1131-020X; Sherman, Steven/0000-0002-3079-5153 FU Genzyme; Sanofi Company; Pfizer; University of Texas M.D. Anderson Cancer Center Support Grant (NCI) [P30 CA016672]; Cancer Council Queensland; National Health and Medical Research Council of Australia [APP1092153] FX The NTCTCS has been supported in part by research grants from Genzyme, a Sanofi Company, and Pfizer, and by the University of Texas M.D. Anderson Cancer Center Support Grant (NCI Grant P30 CA016672). The Cancer Council Queensland (PhD Scholarship) and the National Health and Medical Research Council of Australia (APP1092153) supported D.M. NR 35 TC 4 Z9 4 U1 0 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1050-7256 EI 1557-9077 J9 THYROID JI Thyroid PD OCT 1 PY 2015 VL 25 IS 10 BP 1097 EP 1105 DI 10.1089/thy.2015.0148 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CS7LY UT WOS:000362266300005 PM 26203804 ER PT J AU Lee, RA Ray, M Kasuga, DT Kumar, V Witherspoon, CD Baddley, JW AF Lee, R. A. Ray, M. Kasuga, D. T. Kumar, V. Witherspoon, C. D. Baddley, J. W. TI Ocular bartonellosis in transplant recipients: two case reports and review of the literature SO TRANSPLANT INFECTIOUS DISEASE LA English DT Article DE Bartonella henselae; cat scratch disease; transplant; bartonellosis; chorioretinitis ID CAT-SCRATCH DISEASE; SOLID-ORGAN; COMPLICATIONS AB Cat scratch disease is caused by Bartonella henselae and usually manifests as localized lymphadenopathy and fever in immunocompetent patients. Immunocompromised patients are at risk for developing disseminated disease affecting the liver, spleen, eyes, central nervous system, and other organs. Bartonellosis is infrequently reported in solid organ transplant recipients, and published case reports usually discuss disseminated infection. Localized ocular disease with B.henselae, while well documented in immunocompetent hosts, is uncommon in immunocompromised patients. Herein, we present 2 cases of ocular bartonellosis in renal transplant patients, 1 with disseminated infection, and 1 without. C1 [Lee, R. A.; Ray, M.; Baddley, J. W.] Univ Alabama Birmingham, Div Infect Dis, Dept Med, Birmingham, AL 35294 USA. [Kasuga, D. T.; Witherspoon, C. D.] Univ Alabama Birmingham, Dept Ophthalmol, Birmingham, AL 35294 USA. [Kumar, V.] Univ Alabama Birmingham, Dept Med, Div Nephrol, Birmingham, AL 35294 USA. [Baddley, J. W.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. RP Lee, RA (reprint author), Univ Alabama Birmingham, Infect Dis, 1900 Univ Blvd,THT 229, Birmingham, AL 35294 USA. EM ralee@uabmc.edu OI Witherspoon, Clark/0000-0003-4456-9437 NR 15 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1398-2273 EI 1399-3062 J9 TRANSPL INFECT DIS JI Transpl. Infect. Dis. PD OCT PY 2015 VL 17 IS 5 BP 723 EP 727 DI 10.1111/tid.12418 PG 5 WC Immunology; Infectious Diseases; Transplantation SC Immunology; Infectious Diseases; Transplantation GA CT1YB UT WOS:000362597900014 PM 26146758 ER PT J AU Ahmad, S Hur, S AF Ahmad, Sadeem Hur, Sun TI Helicases in Antiviral Immunity: Dual Properties as Sensors and Effectors SO TRENDS IN BIOCHEMICAL SCIENCES LA English DT Review ID DOUBLE-STRANDED-RNA; RECEPTOR RIG-I; INNATE IMMUNITY; C-ELEGANS; CAENORHABDITIS-ELEGANS; STRUCTURAL BASIS; PATTERN-RECOGNITION; SIGNAL-TRANSDUCTION; DSRNA RECOGNITION; MAMMALIAN-CELLS AB Many helicases have a unique ability to couple cognate RNA binding to ATP hydrolysis, which can induce a large conformational change that affects its interaction with RNA, position along RNA, or oligomeric state. A growing number of these helicases contribute to the innate immune system, either as sensors that detect foreign nucleic acids and/or as effectors that directly participate in the clearance of such foreign species. In this review, we discuss a few examples, including retinoic acid-inducible gene-I (RIG-I), melanoma differentiation-associated gene 5 (MDA5), and Dicer, focusing on their dual functions as both sensors and effectors. We will also discuss the closely related, but less understood, helicases, laboratory of genetics and physiology 2 (LGP2) and Dicerrelated helicase-1 and -3 (DRH-1 and -3). C1 [Ahmad, Sadeem; Hur, Sun] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Ahmad, Sadeem; Hur, Sun] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA USA. RP Hur, S (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. EM Sun.Hur@childrens.harvard.edu FU [AI106912]; [AI111784] FX We apologize in advance to those whose work was not discussed owing to space limitations. This work was supported by R01 grants AI106912 (S.H.) and AI111784 (S.H.). NR 91 TC 5 Z9 5 U1 2 U2 6 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0968-0004 J9 TRENDS BIOCHEM SCI JI Trends Biochem.Sci. PD OCT PY 2015 VL 40 IS 10 BP 576 EP 585 DI 10.1016/j.tibs.2015.08.001 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CT2DJ UT WOS:000362611900006 PM 26410598 ER PT J AU Grazioli, S Matute-Bello, G AF Grazioli, Serge Matute-Bello, Gustavo TI Ccn1, a molecular switch that imposes a self-limiting control on inflammation and wound healing in a multitude of organs? Reply SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Letter ID MYOFIBROBLASTS C1 [Grazioli, Serge] Univ Hosp Geneva, Pediat Crit Care Unit, Geneva, Switzerland. [Grazioli, Serge; Matute-Bello, Gustavo] Univ Washington, Div Pulm & Crit Med, Dept Med, Ctr Lung Biol, Seattle, WA 98109 USA. [Matute-Bello, Gustavo] VA Puget Sound Healthcare Syst, Seattle, WA USA. RP Matute-Bello, G (reprint author), Univ Washington, 850 Republican St, Seattle, WA 98109 USA. EM matuteb@u.washington.edu RI Grazioli, Serge/A-1457-2016 NR 5 TC 0 Z9 0 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1040-0605 EI 1522-1504 J9 AM J PHYSIOL-LUNG C JI Am. J. Physiol.-Lung Cell. Mol. Physiol. PD OCT 1 PY 2015 VL 309 IS 7 BP L749 EP L749 DI 10.1152/ajplung.00265.2015 PG 1 WC Physiology; Respiratory System SC Physiology; Respiratory System GA CS7BN UT WOS:000362238600012 PM 26429904 ER PT J AU Perlis, RH AF Perlis, Roy H. TI Getting Past Proof of Concept For New Treatments SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Editorial Material C1 [Perlis, Roy H.] Massachusetts Gen Hosp, Dept Psychiat, Ctr Expt Drugs & Diagnost, Boston, MA 02114 USA. [Perlis, Roy H.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. RP Perlis, RH (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Ctr Expt Drugs & Diagnost, Boston, MA 02114 USA. NR 3 TC 0 Z9 0 U1 1 U2 1 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X EI 1535-7228 J9 AM J PSYCHIAT JI Am. J. Psychiat. PD OCT PY 2015 VL 172 IS 10 BP 937 EP 938 DI 10.1176/appi.ajp.2015.15070906 PG 2 WC Psychiatry SC Psychiatry GA CS5XH UT WOS:000362151100004 PM 26423476 ER PT J AU Keraliya, AR Rosenthal, MH Krajewski, KM Jagannathan, JP Shinagare, AB Tirumani, SH Ramaiya, NH AF Keraliya, Abhishek R. Rosenthal, Michael H. Krajewski, Katherine M. Jagannathan, Jyothi P. Shinagare, Atul B. Tirumani, Sree Harsha Ramaiya, Nikhil H. TI Imaging of Fluid in Cancer Patients Treated With Systemic Therapy: Chemotherapy, Molecular Targeted Therapy, and Hematopoietic Stem Cell Transplantation SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Review DE fluid; hematopoietic stem cell transplantation; molecular targeted therapy ID HEPATIC VENOOCCLUSIVE DISEASE; CHRONIC MYELOID-LEUKEMIA; BREAST-CANCER; LIVER METASTASES; CARDIOTOXICITY; MANAGEMENT; CHILDREN; CT; COMPLICATIONS; TRASTUZUMAB AB OBJECTIVE. The purpose of this article is to provide a comprehensive review of the imaging features of various systemic treatment-related causes of fluid accumulation in cancer patients. CONCLUSION. Systemic treatment-related fluid accumulation can occur with chemotherapy, molecular targeted therapy, or hematopoietic stem cell transplantation. Imaging findings such as new ascites, pleural and pericardial effusions, and subcutaneous edema should be interpreted with caution on restaging studies. C1 [Keraliya, Abhishek R.; Rosenthal, Michael H.; Krajewski, Katherine M.; Jagannathan, Jyothi P.; Shinagare, Atul B.; Tirumani, Sree Harsha; Ramaiya, Nikhil H.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Imaging, Boston, MA 02215 USA. [Keraliya, Abhishek R.; Rosenthal, Michael H.; Krajewski, Katherine M.; Jagannathan, Jyothi P.; Shinagare, Atul B.; Tirumani, Sree Harsha; Ramaiya, Nikhil H.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Radiol, Boston, MA 02215 USA. RP Keraliya, AR (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Imaging, 450 Brookline Ave, Boston, MA 02215 USA. EM akeraliya@partners.org FU Radiological Society of North America FX A. B. Shinagare received a research grant from the Radiological Society of North America (start date: July 2014). NR 65 TC 0 Z9 1 U1 1 U2 3 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 OCT PY 2015 VL 205 IS 4 BP 709 EP 719 DI 10.2214/AJR.15.14459 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CS1SF UT WOS:000361847300019 PM 26397319 ER PT J AU Zurkiya, O Walker, TG AF Zurkiya, Omar Walker, T. Gregory TI Angiographic Evaluation and Management of Nonvariceal Gastrointestinal Hemorrhage SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Review DE angiography; gastrointestinal hemorrhage; provocative angiography; therapeutic embolization ID METHYLENE-BLUE INJECTION; ARTERIOVENOUS-MALFORMATION; BOWEL; CT AB OBJECTIVE. The purpose of this article is to review the roles of angiography, embolization, and various ancillary techniques in evaluating and managing gastrointestinal hemorrhage. CONCLUSION. Nonvariceal gastrointestinal hemorrhage typically resolves spontaneously or responds to medical or endoscopic management. Refractory hemorrhage may require angiography and transcatheter intervention. Noninvasive imaging evaluation may be useful for characterizing the bleeding source and confirming the presence of active hemorrhage before angiography. If a bleeding source is angiographically identified, superselective catheterization with embolization is typically effective in controlling hemorrhage while minimizing complications. C1 [Zurkiya, Omar; Walker, T. Gregory] Massachusetts Gen Hosp, Div Intervent Radiol, Boston, MA 02114 USA. RP Walker, TG (reprint author), Massachusetts Gen Hosp, Div Intervent Radiol, 55 Fruit St,GRB 298, Boston, MA 02114 USA. EM Tgwalker@mgh.harvard.edu NR 19 TC 1 Z9 1 U1 0 U2 0 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X EI 1546-3141 J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD OCT PY 2015 VL 205 IS 4 BP 753 EP 763 DI 10.2214/AJR.15.14803 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CS1SF UT WOS:000361847300024 PM 26397323 ER PT J AU Petranovic, M Gilman, MD Muniappan, A Hasserjian, RP Digumarthy, SR Muse, VV Sharma, A Shepard, JAO Wu, CC AF Petranovic, Milena Gilman, Matthew D. Muniappan, Ashok Hasserjian, Robert P. Digumarthy, Subba R. Muse, Victorine V. Sharma, Amita Shepard, Jo-Anne O. Wu, Carol C. TI Diagnostic Yield of CT-Guided Percutaneous Transthoracic Needle Biopsy for Diagnosis of Anterior Mediastinal Masses SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE anterior mediastinal masses; CT-guided biopsy ID ON-SITE EVALUATION; FINE-NEEDLE; ASPIRATION BIOPSY; ACCURACY; LYMPHOMA; TUMORS AB OBJECTIVE. The purpose of this study was to evaluate the diagnostic yield and accuracy of CT-guided percutaneous biopsy of anterior mediastinal masses and assess prebiopsy characteristics that may help to select patients with the highest diagnostic yield. MATERIALS AND METHODS. Retrospective review of all CT-guided percutaneous biopsies of the anterior mediastinum conducted at our institution from January 2003 through December 2012 was performed to collect data regarding patient demographics, imaging characteristics of biopsied masses, presence of complications, and subsequent surgical intervention or medical treatment (or both). Cytology, core biopsy pathology, and surgical pathology results were recorded. A per-patient analysis was performed using two-tailed t test, Fisher's exact test, and Pearson chi-square test. RESULTS. The study cohort included 52 patients (32 men, 20 women; mean age, 49 years) with mean diameter of mediastinal mass of 6.9 cm. Diagnostic yield of CT-guided percutaneous biopsy was 77% (40/52), highest for thymic neoplasms (100% [11/11]). Non-diagnostic results were seen in 12 of 52 patients (23%), primarily in patients with lymphoma (75% [9/12]). Fine-needle aspiration yielded the correct diagnosis in 31 of 52 patients (60%), and core biopsy had a diagnostic rate of 77% (36/47). None of the core biopsies were discordant with surgical pathology. There was no statistically significant difference between the diagnostic and the nondiagnostic groups in patient age, lesion size, and presence of necrosis. The complication rate was 3.8% (2/52), all small self-resolving pneumothoraces. CONCLUSION. CT-guided percutaneous biopsy is a safe diagnostic procedure with high diagnostic yield (77%) for anterior mediastinal lesions, highest for thymic neoplasms (100%), and can potentially obviate more invasive procedures. C1 [Petranovic, Milena; Gilman, Matthew D.; Digumarthy, Subba R.; Muse, Victorine V.; Sharma, Amita; Shepard, Jo-Anne O.; Wu, Carol C.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Muniappan, Ashok] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Hasserjian, Robert P.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Petranovic, M (reprint author), Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St,FND 202, Boston, MA 02114 USA. EM mpetranovic@mgh.harvard.edu NR 22 TC 4 Z9 5 U1 0 U2 0 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X EI 1546-3141 J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD OCT PY 2015 VL 205 IS 4 BP 774 EP 779 DI 10.2214/AJR.15.14442 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CS1SF UT WOS:000361847300026 PM 26397325 ER PT J AU Zucker, EJ Newman, B Larson, DB Rubesova, E Barth, RA AF Zucker, Evan J. Newman, Beverley Larson, David B. Rubesova, Erika Barth, Richard A. TI Added Value of Radiologist Consultation for Pediatric Ultrasound: Implementation and Survey Assessment SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE anxiety; pediatric; radiologist consultation; satisfaction; survey; ultrasound ID PATIENT COMMUNICATION; PATIENTS PREFERENCES; IMAGING FINDINGS; DOCTOR; DISCLOSURE; ATTITUDES; TIME AB OBJECTIVE. The purpose of this study was to determine whether radiologist-parent (guardian) consultation sessions for pediatric ultrasound with immediate disclosure of examination results if desired increases visit satisfaction, decreases anxiety, and increases understanding of the radiologist's role. SUBJECTS AND METHODS. Parents chaperoning any outpatient pediatric ultrasound were eligible and completed surveys before and after ultrasound examinations. Before the second survey, parents met with a pediatric radiologist on a randomized basis but could opt out and request or decline the consultation. Differences in anxiety and understanding of the radiologist's role before and after the examination were compared, and overall visit satisfaction measures were tabulated. RESULTS. Seventy-seven subjects participated, 71 (92%) of whom spoke to a radiologist, mostly on request. In the consultation group, the mean score (1, lowest; 4, highest) for overall experience was 3.8 +/- 0.4 (SD), consultation benefit was 3.7 +/- 0.6, and radiologist interaction was 3.7 +/- 0.6. Demographics were not predictive of satisfaction with statistical significance in a multivariate model. Forty-six of 68 (68%) respondents correctly described the radiologist's role before consultation. The number increased to 60 (88%) after consultation, and the difference was statistically significant (p < 0.001). There was also a statistically significant decrease in mean anxiety score from 2.0 +/- 1.0 to 1.5 +/- 0.8 after consultation (p < 0.001). Sixty-four of 70 (91%) respondents indicated that they would prefer to speak with a radiologist during every visit. CONCLUSION. Radiologist consultation is well received among parents and associated with decreased anxiety and increased understanding of the radiologist's role. The results of this study support the value of routine radiologist-parent interaction for pediatric ultrasound. C1 [Zucker, Evan J.; Newman, Beverley; Larson, David B.; Rubesova, Erika; Barth, Richard A.] Stanford Univ, Sch Med, Lucile Packard Childrens Hosp, Dept Radiol, Stanford, CA 94305 USA. RP Zucker, EJ (reprint author), Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St, Boston, MA 02114 USA. EM zucker@post.harvard.edu NR 27 TC 1 Z9 1 U1 0 U2 0 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X EI 1546-3141 J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD OCT PY 2015 VL 205 IS 4 BP 822 EP 826 DI 10.2214/AJR.15.14542 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CS1SF UT WOS:000361847300033 PM 26397331 ER PT J AU Zhu, QL Faquin, WC Samir, AE AF Zhu, Qing-Li Faquin, William C. Samir, Anthony E. TI Relationship Between Sonographic Characteristics and Afirma Gene Expression Classifier Results in Thyroid Nodules With Indeterminate Fine-Needle Aspiration Cytopathology SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE Afirma; fine-needle aspiration; indeterminate; thyroid nodules; ultrasound ID UNDETERMINED SIGNIFICANCE; FOLLICULAR LESION; BETHESDA SYSTEM; SCIENCE CONFERENCE; MALIGNANCY RATE; ATYPIA; MANAGEMENT; CYTOLOGY; RECOMMENDATIONS; DIAGNOSIS AB OBJECTIVE. The purpose of this article is to investigate whether specific clinical and sonographic characteristics are predictive of a benign Afirma test result. MATERIALS AND METHODS. We conducted a retrospective study of Afirma gene expression classifier analysis performed in 44 patients with 45 indeterminate thyroid fine-needle aspiration (FNA) cytologic results between March 2013 and April 2014. Of these, 33 of 45 nodules (73.3%) were repeat atypia of undetermined significance (AUS) and follicular lesions of undetermined significance (FLUS), or follicular neoplasm (FN) and suspicious for a follicular neoplasm (SFN) before Afirma testing. RESULTS. Of the 45 nodules, 21 (46.7%) were cytologically diagnosed as FLUS, 16 (35.6%) were diagnosed as AUS, and eight (17.8%) were diagnosed as FN or SFN. By Afirma testing, 23 of the 45 nodules (51.1%) were benign, 21 (46.7%) were suspicious, and one (2.2%) had nondiagnostic results. The mean (+/- SD) nodule size was smaller in the Afirma-benign group than in the Afirma-suspicious group (1.8 +/- 0.8 cm [95% CI, 1.4-2.1] vs 2.2 +/- 0.8 cm [ 95% CI, 1.8-2.6]; p < 0.035). No sonographic feature was statistically significantly different between the Afirma-benign and -suspicious groups, including nodule solidity (p = 0.225), echogenicity (p = 0.543), calcification (p = 0.542), and hypervascularity (p = 0.976). All nodules were ovoid shaped and had circumscribed margins in both Afirma groups. CONCLUSION. Smaller nodule size was the only characteristic associated with a benign diagnosis on Afirma testing. Sonographic characteristics are not helpful in cases that had a repeat indeterminate FNA finding before Afirma testing. C1 [Zhu, Qing-Li] Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Ultrasound, Beijing 100730, Peoples R China. [Zhu, Qing-Li; Samir, Anthony E.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol Abdominal Imaging & Intervent, Boston, MA 02114 USA. [Faquin, William C.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Samir, AE (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol Abdominal Imaging & Intervent, White 270,55 Fruit St, Boston, MA 02114 USA. EM asamir@mgh.harvard.edu NR 22 TC 2 Z9 2 U1 1 U2 1 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X EI 1546-3141 J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD OCT PY 2015 VL 205 IS 4 BP 861 EP 865 DI 10.2214/AJR.14.13984 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CS1SF UT WOS:000361847300039 PM 26397337 ER PT J AU Drubach, LA Jenkins, KJ Stamoulis, C Palmer, EL Lee, EY AF Drubach, Laura A. Jenkins, Kathy J. Stamoulis, Catherine Palmer, Edwin L., III Lee, Edward Y. TI Evaluation of Primary Pulmonary Vein Stenosis in Children: Comparison of Radionuclide Perfusion Lung Scan and Angiography SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE angiography; pediatric; primary pulmonary vein stenosis; radionuclide perfusion lung scan ID PEDIATRIC-PATIENTS; CHEST; SCINTIGRAPHY; FLOW AB OBJECTIVE. The purpose of this study was to evaluate the utility of radionuclide perfusion lung scanning in the evaluation of primary pulmonary vein stenosis (PVS) in pediatric patients by comparing it with angiography. MATERIALS AND METHODS. We retrospectively identified pediatric patients with primary PVS who underwent both lung scanning and angiography. A cohort of 34 patients was evaluated. The presence of PVS in the right upper, right lower, left upper, and left lower pulmonary veins on angiograms was recorded. Two nuclear medicine physicians evaluated the lung scans for perfusion defects. Agreement between lung scan and angiographic findings was assessed with contingency tables. Sensitivity and specificity of lung scanning for accurate detection of PVS with angiographic findings as the reference standard were assessed by ROC analysis. RESULTS. Angiography depicted PVS in 90 of the total 136 pulmonary veins (66%). Lung scans correctly depicted 65 (72%) of the cases of PVS diagnosed with angiography. The sensitivity and specificity of lung scans were 76.0% and 88.9% for the right upper pulmonary vein, 70.6% and 94.1% for the right lower pulmonary vein, 77.3% and 58.3% for the left upper pulmonary vein, and 65.4% and 87.5% for the left lower pulmonary vein. CONCLUSION. Lung scan findings correlate with angiographic findings in the detection of primary PVS in pediatric patients. Perfusion lung scanning may have a role in angiographically diagnosed PVS by noninvasively showing relative perfusion at the tissue level. C1 [Drubach, Laura A.; Stamoulis, Catherine; Lee, Edward Y.] Boston Childrens Hosp, Dept Radiol, Boston, MA 02466 USA. [Drubach, Laura A.; Jenkins, Kathy J.; Stamoulis, Catherine; Palmer, Edwin L., III; Lee, Edward Y.] Harvard Univ, Sch Med, Boston, MA 02466 USA. [Jenkins, Kathy J.] Boston Childrens Hosp, Dept Cardiol, Boston, MA 02466 USA. [Palmer, Edwin L., III] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Drubach, LA (reprint author), Boston Childrens Hosp, Dept Radiol, 300 Longwood Ave, Boston, MA 02466 USA. EM Laura.drubach@childrens.harvard.edu NR 20 TC 1 Z9 1 U1 0 U2 1 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X EI 1546-3141 J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD OCT PY 2015 VL 205 IS 4 BP 873 EP 877 DI 10.2214/AJR.14.13581 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CS1SF UT WOS:000361847300041 PM 26397339 ER PT J AU Shriki, JE Seyal, AR Dighe, MK Yeh, MM Jalikis, FG Andeen, NK Lall, C Bhargava, P AF Shriki, Jabi E. Seyal, Adeel R. Dighe, Manjiri K. Yeh, Matthew M. Jalikis, Florencia G. Andeen, Nicole K. Lall, Chandana Bhargava, Puneet TI CT of Atypical and Uncommon Presentations of Hepatocellular Carcinoma SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Review DE CT; hepatocellular carcinoma; imaging ID TRANSCATHETER ARTERIAL CHEMOEMBOLIZATION; MR-IMAGING DIAGNOSIS; OF-THE-LITERATURE; HEPATITIS-C; LIVER-TRANSPLANTATION; UNITED-STATES; US POPULATION; RISK-FACTORS; CIRRHOSIS; DISEASE AB OBJECTIVE. The purpose of this article is to familiarize radiologists with uncommon presentations of hepatocellular carcinoma (HCC) with an emphasis on the CT spectrum of atypical appearances. CONCLUSION. HCC is the fifth most common neoplasm worldwide and the second most common cause of cancer-related death. In many cases, HCC can be confidently diagnosed with noninvasive imaging. However, there are numerous unusual appearances of HCC with which the radiologist must be familiar. C1 [Shriki, Jabi E.; Dighe, Manjiri K.; Bhargava, Puneet] Univ Washington, Sch Med, Dept Radiol, Seattle, WA 98195 USA. [Shriki, Jabi E.; Bhargava, Puneet] VA Puget Sound Hlth Care Syst, Dept Radiol, Seattle, WA 98108 USA. [Seyal, Adeel R.] Northwestern Univ, Dept Radiol, Chicago, IL 60611 USA. [Yeh, Matthew M.; Jalikis, Florencia G.; Andeen, Nicole K.] Univ Washington, Sch Med, Dept Pathol, Seattle, WA 98195 USA. [Lall, Chandana] Univ Calif Irvine, Dept Radiol, Orange, CA 92668 USA. RP Bhargava, P (reprint author), Univ Washington, Sch Med, Dept Radiol, Seattle, WA 98195 USA. EM bhargp@uw.edu NR 82 TC 0 Z9 0 U1 1 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 OCT PY 2015 VL 205 IS 4 BP W411 EP W423 DI 10.2214/AJR.14.14000 PG 13 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CS1SF UT WOS:000361847300004 PM 26397348 ER PT J AU Howitt, BE Emori, MM Drapkin, R Gaspar, C Barletta, JA Nucci, MR McCluggage, WG Oliva, E Hirsch, MS AF Howitt, Brooke E. Emori, Megan M. Drapkin, Ronny Gaspar, Cynthia Barletta, Justine A. Nucci, Marisa R. McCluggage, W. Glenn Oliva, Esther Hirsch, Michelle S. TI GATA3 Is a Sensitive and Specific Marker of Benign and Malignant Mesonephric Lesions in the Lower Female Genital Tract SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE mesonephric; cervix; GATA3; endocervical; endometrial; FATWO; immunohistochemistry; Mullerian; Wolffian ID PLACENTAL S100 S100P; BINDING-PROTEIN 3; OF-THE-LITERATURE; UTERINE CERVIX; UROTHELIAL CARCINOMA; HUMAN-PAPILLOMAVIRUS; GLANDULAR LESIONS; PAX8 EXPRESSION; IMMUNOHISTOCHEMICAL EVALUATION; ENDOCERVICAL ADENOCARCINOMAS AB GATA3 is a transcription factor critical for embryogenesis, development, and cell differentiation. Recent studies have suggested that GATA3 is a sensitive and relatively specific biomarker for urothelial and breast carcinomas, with most Mullerian carcinomas being negative. We investigated GATA3 expression in mesonephric/Wolffian remnants and tumors in the female genital tract. A western blot was performed to assess specificity for the GATA3 antibody. GATA3 immunohistochemistry was performed on 59 formalin-fixed paraffin-embedded mesonephric samples, including 17 mesonephric remnants (MR; 11 cervical and 6 fallopian tube), 15 mesonephric hyperplasias, 21 mesonephric carcinomas, and 6 female adnexal tumors of probable Wolffian origin. Thirty conventional endocervical adenocarcinomas (ENDO-CA), 9 gastric-type cervical adenocarcinomas, and 165 endometrial adenocarcinomas (EM-CA) were also evaluated. GATA3 nuclear intensity and extent of staining was evaluated. The western blot revealed GATA3 expression in seminal vesicle and cell lines derived from breast and urothelial carcinomas, but not in other cell lines including ovarian, cervical, and endometrial cancers. All cervical MRs and mesonephric hyperplasias, 5/6 (83%) fallopian tube MRs, and 20/21 (95%) mesonephric carcinomas were GATA3 positive, although with great variability in both intensity (weak to strong) and extent (1+ to 3+) of staining. Only 1/6 (17%) female adnexal tumors of probable Wolffian origin showed weak multifocal staining. One of 30 (3%) usual-type ENDO-CAs and 3/165 EM-CAs exhibited weak-moderate GATA3 immunoreactivity; all gastric-type cervical adenocarcinomas were negative. GATA3 is a highly sensitive and specific marker for mesonephric lesions in the lower genital tract; however, its utility in the upper genital tract may be more limited. In addition, GATA3 can aid in distinguishing lower genital mesonephric lesions from usual-type and gastric-type ENDO-CAs and uterine EM-CAs. C1 [Howitt, Brooke E.; Drapkin, Ronny; Gaspar, Cynthia; Barletta, Justine A.; Nucci, Marisa R.; Hirsch, Michelle S.] Brigham & Womens Hosp, Dept Pathol, Div Womens & Perinatal Pathol, Boston, MA 02115 USA. [Howitt, Brooke E.; Drapkin, Ronny; Barletta, Justine A.; Nucci, Marisa R.; Oliva, Esther; Hirsch, Michelle S.] Harvard Univ, Sch Med, Boston, MA USA. [Emori, Megan M.; Drapkin, Ronny] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Oliva, Esther] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [McCluggage, W. Glenn] Belfast Hlth & Social Care Trust, Dept Pathol, Belfast, Antrim, North Ireland. RP Hirsch, MS (reprint author), Brigham & Womens Hosp, Dept Pathol, 75 Francis St,Amory 3, Boston, MA 02115 USA. EM mhirsch1@partners.org RI Drapkin, Ronny/E-9944-2016 OI Drapkin, Ronny/0000-0002-6912-6977 FU Debra and Robert First Fund; Honorable Tina Brozman Foundation FX The authors wish to acknowledge administrative and laboratory assistance from the Brigham and Women's Hospital histology and IHC laboratories, especially Marc Buchanan, Mei Zheng, Tatiana Zolotarev, Derek Bernay, and Wanjiang Wei, and the Dana Farber/Harvard Cancer Center tissue microarray core facility. Research support was provided by the Debra and Robert First Fund (R.D.) and the Honorable Tina Brozman Foundation (R.D.). NR 70 TC 7 Z9 8 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0147-5185 EI 1532-0979 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD OCT PY 2015 VL 39 IS 10 BP 1411 EP 1419 DI 10.1097/PAS.0000000000000471 PG 9 WC Pathology; Surgery SC Pathology; Surgery GA CS5IU UT WOS:000362112400015 PM 26135559 ER PT J AU Irving, JA Lee, CH Yip, S Oliva, E McCluggage, WG Young, RH AF Irving, Julie A. Lee, Cheng-Han Yip, Stephen Oliva, Esther McCluggage, W. Glenn Young, Robert H. TI Microcystic Stromal Tumor A Distinctive Ovarian Sex Cord-Stromal Neoplasm Characterized by FOXL2, SF-1, WT-1, Cyclin D1, and beta-catenin Nuclear Expression and CTNNB1 Mutations SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE microcystic stromal tumor; ovary; immunohistochemistry; -catenin; FOXL2 ID SOLID PSEUDOPAPILLARY NEOPLASM; GRANULOSA-CELL TUMORS; OF-THE-LITERATURE; BETA-CATENIN; E-CADHERIN; NUCLEAR-LOCALIZATION; OVARIAN NEOPLASM; PANCREAS; FOXL2; EXPRESSION AB Since our first description of the microcystic stromal tumor (MST) of the ovary, a rare and distinctive neoplasm with a definitional, usually striking microcystic pattern and a CD10(+)/vimentin(+)/inhibin(-)/calretinin(-) immunophenotype, 3 examples with -catenin nuclear localization, and CTNNB1 mutation have been reported. We undertook a detailed immunohistochemical study and molecular analysis of CTNNB1 and FOXL2 of 15 cases of MST to further characterize this neoplasm and establish its histogenesis. Diffuse nuclear staining for FOXL2, WT-1, cyclin D1, and -catenin was present in all tumors tested, and 12/15 were positive for steroidogenic factor-1 (SF-1). Heterozygous missense point mutations in exon 3 of CTNNB1 were detected in 8 of 14 cases, resulting in amino acid changes at codons 32, 34, 35, and 37. There was no correlation between CTNNB1 exon 3 mutation status and tumor immunophenotype. All 14 cases tested showed wild-type FOXL2. Our study establishes that MST of the ovary exhibits a characteristic FOXL2/SF-1/WT-1/cyclin D1/nuclear -catenin-positive immunohistochemical profile, which may be useful in diagnosis and in the exclusion of histologic mimics. The presence of diffuse nuclear FOXL2 and WT-1 immunostaining in all cases and SF-1 in most supports the classification of MST within the sex cord-stromal category. Aberrant nuclear -catenin expression, detected in all MSTs, appears to be the result of stabilizing CTNNB1 mutations in 57% of cases, providing further evidence that dysregulation of the Wnt/B-catenin pathway is involved in the tumorigenesis of MST and may involve activation of -catenin with upregulation of cyclin D1. C1 [Irving, Julie A.] Royal Jubilee Hosp, Dept Lab Med Pathol & Med Genet, Victoria, BC V8R 1J8, Canada. [Irving, Julie A.] Univ British Columbia, Dept Pathol, Vancouver, BC, Canada. [Yip, Stephen] Vancouver Gen Hosp, Dept Pathol & Lab Med, Vancouver, BC, Canada. [Lee, Cheng-Han] Univ Alberta, Dept Lab Med & Pathol, Edmonton, AB, Canada. [Lee, Cheng-Han] Royal Alexandra Hosp, Edmonton, AB, Canada. [Oliva, Esther; Young, Robert H.] Massachusetts Gen Hosp, James Homer Wright Pathol Labs, Boston, MA 02114 USA. [Oliva, Esther; Young, Robert H.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [McCluggage, W. Glenn] Belfast Hlth & Social Care Trust, Dept Pathol, Belfast, Antrim, North Ireland. RP Irving, JA (reprint author), Royal Jubilee Hosp, Dept Lab Med Pathol & Med Genet, 1952 Bay St, Victoria, BC V8R 1J8, Canada. EM julie.irving@viha.ca NR 30 TC 10 Z9 12 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0147-5185 EI 1532-0979 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD OCT PY 2015 VL 39 IS 10 BP 1420 EP 1426 DI 10.1097/PAS.0000000000000482 PG 7 WC Pathology; Surgery SC Pathology; Surgery GA CS5IU UT WOS:000362112400016 PM 26200099 ER PT J AU Rivera, CM Copeland, LA McNeal, CJ Mortensen, EM Pugh, MJ MacCarthy, DJ AF Rivera, Cathleen M. Copeland, Laurel A. McNeal, Catherine J. Mortensen, Eric M. Pugh, Mary J. MacCarthy, Daniel J. TI Use of Health Care System-Supplied Aspirin by Veterans With Postoperative Heart Attack or Unstable Angina SO AMERICAN JOURNAL OF THE MEDICAL SCIENCES LA English DT Article DE Aspirin; Epidemiology; Preventive Medicine; Primary Care; Veterans ID SECONDARY PREVENTION; CARDIOVASCULAR-DISEASE; MYOCARDIAL-INFARCTION; STATIN THERAPY; NUTRITION EXAMINATION; ATHEROSCLEROSIS RISK; MEDICATION ADHERENCE; NATIONAL-HEALTH; METAANALYSIS; CORONARY AB Evidence-based guidelines for the use of aspirin in secondary prevention of cardiovascular disease events are well established. Despite this, the prevalence of aspirin use for secondary prevention is suboptimal. The study aimed to determine the prevalence of aspirin use for secondary prevention of cardiovascular disease events when it is dispensed as a prescription, as is performed in the Veterans Affairs (VA) managed care system. VA patients who had undergone major surgery and experienced a postoperative myocardial infarction (MI) or unstable angina between the years 2005 and 2009 were identified from administrative databases. VA pharmacy records were used to determine whether a prescription for aspirin was filled after the postoperative MI or unstable angina. Multivariable logistic regression models estimated odd ratios of filling aspirin prescriptions for the predictors of interest. Of the 321,131 men and women veterans who underwent major surgery, 7,700 experienced a postoperative MI or unstable angina. Among those 7,700, 47% filled an aspirin prescription. Only 59% of veterans with no co-pay filled an aspirin prescription. Aspirin fills were more common in younger veterans, Blacks, Hispanics, males, hypertensive veterans, mentally ill patients, those with no co-pay and those prescribed antiplatelets/anticoagulants in addition to aspirin postoperatively. These findings suggest that the impact of dispensing aspirin as a prescription may not be significant in increasing the appropriate use of aspirin for secondary prevention. C1 [Rivera, Cathleen M.; Copeland, Laurel A.; McNeal, Catherine J.] Baylor Scott & White Hlth, Cent Texas Vet Hlth Care Syst, Ctr Appl Hlth Res, Dept Med, Temple, TX 76502 USA. [Mortensen, Eric M.] Univ Texas Southwestern Med Ctr, Dept Internal Med, Dallas, TX 75390 USA. [Mortensen, Eric M.] Univ Texas Southwestern Med Ctr, Dept Clin Sci, Dallas, TX 75390 USA. [Pugh, Mary J.] South Texas Vet Hlth Care Syst, Res Serv, San Antonio, TX USA. [MacCarthy, Daniel J.] Univ Texas Hlth Sci Ctr San Antonio, Dept Epidemiol & Biostat, San Antonio, TX USA. RP Copeland, LA (reprint author), Baylor Scott & White Hlth, Cent Texas Vet Hlth Care Syst, Temple, TX 76502 USA. EM laurelacopeland@gmail.com OI Mortensen, Eric/0000-0002-3880-5563; Copeland, Laurel/0000-0002-9478-0209 NR 34 TC 0 Z9 0 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0002-9629 EI 1538-2990 J9 AM J MED SCI JI Am. J. Med. Sci. PD OCT PY 2015 VL 350 IS 4 BP 263 EP 267 DI 10.1097/MAJ.0000000000000560 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA CS6UM UT WOS:000362218400005 PM 26351774 ER PT J AU Makris, UE Pugh, MJ Alvarez, CA Berlowitz, DR Turner, BJ Aung, K Mortensen, EM AF Makris, Una E. Pugh, Mary Jo Alvarez, Carlos A. Berlowitz, Dan R. Turner, Barbara J. Aung, KoKo Mortensen, Eric M. TI Exposure to High-Risk Medications is Associated With Worse Outcomes in Older Veterans With Chronic Pain SO AMERICAN JOURNAL OF THE MEDICAL SCIENCES LA English DT Article DE Pharmacoepidemiology; Adverse drug outcomes; Chronic pain; Aging ID LOW-BACK-PAIN; RECEIVING PRIMARY-CARE; ADVERSE DRUG EVENTS; PERSISTENT PAIN; PREVALENCE; HEALTH; ADULTS; MANAGEMENT; TRENDS; METAANALYSIS AB Background:Chronic pain is common, costly and leads to significant morbidity in older adults, yet there are limited data on medication safety. The authors sought to evaluate the association of incident high-risk medication in the elderly (HRME) with mortality, emergency department (ED) or hospital care among older adults with chronic pain.Methods:A retrospective Veterans Health Administration cohort study was conducted examining older veterans with chronic pain diagnoses and use of incident HRME (opioids, skeletal muscle relaxants, antihistamines and psychotropics). Outcomes evaluated included all-cause mortality, ED visits or inpatient hospital care. Descriptive statistics summarized variables for the overall cohort, the chronic pain cohort and those with and without HRME. Separate generalized linear mixed-effect regression models were used to examine the association of incident HRME on each outcome, controlling for potential confounders.Results:Among 1,807,404 veterans who received Department of Veterans Affairs care in 2005 to 2006, 584,066 (32.3%) had chronic pain; 45,945 veterans with chronic pain (7.9%) had incident HRME exposure. The strongest significant associations of incident HRME were for high-risk opioids with all-cause hospitalizations (odds ratio [OR] 2.08, 95% confidence interval [CI] 1.95-2.23), skeletal muscle relaxants with all-cause ED visits (OR 2.62, 95% CI 2.52-2.73) and mortality (OR 0.80, 95% CI 0.74-0.86), antihistamines with all-cause ED visits (OR 2.82 95% CI 2.72-2.95) and psychotropics with all-cause hospitalizations (OR 2.15, 95% CI 1.96-2.35).Conclusions:Our data indicate that incident HRME is associated with clinically important adverse outcomes in older veterans with chronic pain and highlight the importance of being judicious with prescribing certain classes of drugs in this vulnerable population. C1 [Makris, Una E.; Alvarez, Carlos A.; Mortensen, Eric M.] VA North Texas Hlth Care Syst, Dallas, TX USA. [Makris, Una E.; Alvarez, Carlos A.; Mortensen, Eric M.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Pugh, Mary Jo] South Texas Vet Hlth Care Syst, San Antonio, TX USA. [Alvarez, Carlos A.] Texas Tech Univ, Hlth Sci Ctr, Dallas, TX USA. [Pugh, Mary Jo; Turner, Barbara J.; Aung, KoKo] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Berlowitz, Dan R.] Ctr Healthcare Org & Implementat Res, Edith Nourse Rogers Mem Vet Hosp, Bedford, MA USA. RP Mortensen, EM (reprint author), Dallas VA Med Ctr, Gen Internal Med 111E,4500 South Lancaster, Dallas, TX 75216 USA. EM Eric.Mortensen@UTSouthwestern.edu OI Mortensen, Eric/0000-0002-3880-5563 FU Rheumatology Research Foundation/ASP Junior Career Development Award in Geriatric Medicine; NIA GEMSSTAR [R03AG040653]; Center for Translational Medicine, NIH/NCATS [KL2TR001103, UL1TR001105] FX U.E.M. was supported by the Rheumatology Research Foundation/ASP Junior Career Development Award in Geriatric Medicine, an NIA GEMSSTAR (R03AG040653) and the Center for Translational Medicine, NIH/NCATS Grants (KL2TR001103 and UL1TR001105). The content is solely the responsibility of the authors and does not necessarily represent the official views of the Center for Translational Medicine, UT Southwestern Medical Center and its affiliated academic and health care centers, the National Center for Advancing Translational Sciences, or the National Institutes of Health. NR 37 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 0002-9629 EI 1538-2990 J9 AM J MED SCI JI Am. J. Med. Sci. PD OCT PY 2015 VL 350 IS 4 BP 279 EP 285 DI 10.1097/MAJ.0000000000000552 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA CS6UM UT WOS:000362218400008 PM 26418380 ER PT J AU Kamen, DL Oates, JC AF Kamen, Diane L. Oates, Jim C. TI A Pilot Study to Determine if Vitamin D Repletion Improves Endothelial Function in Lupus Patients SO AMERICAN JOURNAL OF THE MEDICAL SCIENCES LA English DT Article DE Systemic lupus erythematosus; Endothelial function; Nitric oxide; Vitamin D; Flow-mediated dilation ID NF-KAPPA-B; NITRIC-OXIDE SYNTHASE; C-REACTIVE PROTEIN; 25-HYDROXYVITAMIN D; D DEFICIENCY; ARTERIAL STIFFNESS; DISEASE-ACTIVITY; CONTROLLED-TRIAL; S-NITROSYLATION; BRACHIAL-ARTERY AB Background:The endothelium is important not only in regulating vascular tone but also in modulating inflammation. Patients with systemic lupus erythematosus (SLE) have deficits in these endothelial functions. Vitamin D is a nuclear hormone that regulates vascular endothelial nitric oxide synthase activity and expression. Many SLE patients have insufficient levels of vitamin D. The effect of this hormone on vascular endothelial function in SLE patients is not known. This study was designed to determine the effect size of repleting vitamin D levels on endothelial function in patients with SLE and vitamin D deficiency.Methods:SLE patients with 25(OH) vitamin D (25(OH)D) levels <20 ng/mL were randomized to oral vitamin D3 (D3) doses that did or did not raise 25(OH)D levels to 32 ng/mL. Endothelial function was measured with flow-mediated dilation (FMD) before and after 16 weeks of vitamin D3 supplementation.Results:Half of those who achieved 25(OH)D levels of 32 ng/mL experienced increases in FMD, whereas none of those with continued low 25(OH)D levels did. Those with increases in FMD had significantly higher final 25(OH)D levels. Using the effect size from this study, future studies designed to test the effect of repleting 25(OH)D on FMD in vitamin D-deficient SLE patients will require 35 patients in each group.Conclusions:These results suggest a potential role for vitamin D in SLE-related endothelial dysfunction and that an adaptive, multi-arm, treat-to-target, serum-level trial design may increase the efficiency and likelihood of success of such a study. C1 [Kamen, Diane L.; Oates, Jim C.] Med Univ S Carolina, Div Rheumatol & Immunol, Dept Med, Charleston, SC 29425 USA. [Oates, Jim C.] Ralph H Johnson VA Med Ctr, Med Serv, Rheumatol Sect, Charleston, SC USA. RP Oates, JC (reprint author), Med Univ S Carolina, Div Rheumatol & Immunol, Dept Med, 96 Jonathan Lucas St,Suite 912,MSC 637, Charleston, SC 29425 USA. EM oatesjc@musc.edu FU Arthritis Foundation; NIH/NCRR MUSC-SCTR [UL1 RR029882]; NIH/NIAMS [K23 AR052364]; MUSC General and Clinical Research Center [M01RR001070] FX Supported by a grant from the Arthritis Foundation. This material is the result of work supported with resources and the use of facilities at the Ralph H. Johnson VA Medical Center, NIH/NCRR MUSC-SCTR Grant number UL1 RR029882, NIH/NIAMS Grant number K23 AR052364 and the MUSC General and Clinical Research Center (M01RR001070). NR 49 TC 4 Z9 4 U1 2 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0002-9629 EI 1538-2990 J9 AM J MED SCI JI Am. J. Med. Sci. PD OCT PY 2015 VL 350 IS 4 BP 302 EP 307 DI 10.1097/MAJ.0000000000000556 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA CS6UM UT WOS:000362218400012 PM 26351776 ER PT J AU Mathison, DJ AF Mathison, Douglas J. TI Introducing Policy Perspectives SO ANNALS OF THORACIC SURGERY LA English DT Editorial Material C1 Massachusetts Gen Hosp, Div Thorac Surg, Boston, MA 02114 USA. RP Mathison, DJ (reprint author), Massachusetts Gen Hosp, Div Thorac Surg, Blake 1570,55 Fruit St, Boston, MA 02114 USA. EM dmathisen@partners.org NR 1 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-4975 EI 1552-6259 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD OCT PY 2015 VL 100 IS 4 BP 1142 EP 1142 DI 10.1016/j.athoracsur.2015.08.026 PG 1 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA CS7TE UT WOS:000362288000010 PM 26434422 ER PT J AU Kobrin, DM McCarthy, FH Herrmann, HC Anwaruddin, S Kobrin, S Szeto, WY Bavaria, JE Groeneveld, PW Desai, ND AF Kobrin, Dale M. McCarthy, Fenton H. Herrmann, Howard C. Anwaruddin, Saif Kobrin, Sidney Szeto, Wilson Y. Bavaria, Joseph E. Groeneveld, Peter W. Desai, Nimesh D. TI Transcatheter and Surgical Aortic Valve Replacement in Dialysis Patients: A Propensity-Matched Comparison SO ANNALS OF THORACIC SURGERY LA English DT Article ID CHRONIC KIDNEY-DISEASE; LONG-TERM SURVIVAL; HIGH-RISK PATIENTS; CLINICAL-OUTCOMES; CARDIAC-SURGERY; STENOSIS; IMPLANTATION; MORTALITY; HEMODIALYSIS; IMPACT AB Background. Transcatheter aortic valve replacement (TAVR) clinical trials in North America excluded patients on dialysis and, consequently, the outcomes of TAVR in dialysis-dependent patients remain unknown. Methods. All Medicare fee-for-service patients undergoing TAVR (n=5,005) or surgical aortic valve replacement (SAVR) (n=32,634) between January 1, 2011, and November 30, 2012, were identified using procedural codes collected by the Centers for Medicare & Medicaid Services. Dialysis status and comorbidities were identified using diagnosis codes present on arrival for TAVR hospitalization. Patients supported on dialysis who underwent TAVR (n=224) were compared with non-dialysis patients who underwent TAVR as well as a propensity-matched group of contemporaneous dialysis patients who underwent SAVR (n=194 pairs). Results. The TAVR patients on dialysis were younger than non-dialysis TAVR patients (79.2 years vs 84.1 years; p < 0.01) but had higher prevalence of comorbidities. Dialysis TAVR patients had increased mortality at 30 days (13% vs 6%, p < 0.01) and significantly worse survival by Kaplan-Meier analysis. Multivariable regression found dialysis to be independently associated with worse survival (hazard ratio, 1.73; 95% confidence interval, 1.33% to 2.25%, p < 0.01) in TAVR patients. Propensity-matched dialysis SAVR and dialysis TAVR patients had no significant differences in demographic or risk factors. Matched dialysis TAVR patients had shorter length of stay (6 interquartile range, 4 to 10] vs 10 [IQR 7 to 18] days; p < 0.01) and comparable survival. Conclusions. TAVR in dialysis patients is associated with decreased survival compared with non-dialysis patients; however, it is comparable with SAVR in high risk dialysis patients based on a propensity-matched comparison. (C) 2015 by The Society of Thoracic Surgeons C1 [Desai, Nimesh D.] Univ Penn, Perelman Sch Med, Div Cardiovasc Surg, Philadelphia, PA 19104 USA. Univ Penn, Perelman Sch Med, Div Cardiovasc Med, Philadelphia, PA 19104 USA. Univ Penn, Perelman Sch Med, Renal Elect & Hypertens Div, Philadelphia, PA 19104 USA. Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA. Leonard Davis Inst Hlth Econ, Philadelphia, PA USA. Philadephia Vet Affairs Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. RP Desai, ND (reprint author), Univ Penn, Perelman Sch Med, Div Cardiovasc Surg, 3400 Spruce St,6 Silverstein, Philadelphia, PA 19104 USA. EM nimesh.desai@uphd.upenn.edu NR 26 TC 4 Z9 4 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-4975 EI 1552-6259 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD OCT PY 2015 VL 100 IS 4 BP 1230 EP 1237 DI 10.1016/j.athoracsur.2015.05.039 PG 8 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA CS7TE UT WOS:000362288000027 PM 26271581 ER PT J AU Stephens, EH Odell, D Stein, W La Par, DJ DeNino, WF Aftab, M Berfield, K Eilers, AL Groth, S Lazar, JF Robich, MP Shah, AA Smith, DA Stock, C Tchantchaleishvili, V Mery, CM Turek, JW Salazar, J Nguyen, TC AF Stephens, Elizabeth H. Odell, David Stein, William La Par, Damien J. DeNino, Walter F. Aftab, Muhammad Berfield, Kathleen Eilers, Amanda L. Groth, Shawn Lazar, John F. Robich, Michael P. Shah, Asad A. Smith, Danielle A. Stock, Cameron Tchantchaleishvili, Vakhtang Mery, Carlos M. Turek, Joseph W. Salazar, Jorge Nguyen, Tom C. TI A Decade of Change: Training and Career Paths of Cardiothoracic Surgery Residents 2003 to 2014 SO ANNALS OF THORACIC SURGERY LA English DT Article ID THORACIC SURGICAL EDUCATION; FUTURE; APPLICANTS; BRIGHTEST; PROGRAM AB Background. During the past decade, cardiothoracic surgery (CTS) education has undergone tremendous change with the advent of new technologies and the implementation of integrated programs, to name a few. The goal of this study was to assess how residents' career paths, training, and perceptions changed during this period. Methods. The 2006 to 2014 surveys accompanying the Thoracic Surgery Residents Association/Thoracic Surgery Directors' Association in-training examination taken by CTS residents were analyzed, along with a 2003 survey of graduating CTS residents. Of 2,563 residents surveyed, 2,434 (95%) responded. Results. During the decade, fewer residents were interested in mixed adult cardiac/thoracic practice (20% in 2014 vs 52% in 2003, p=0.004), more planned on additional training (10% in 2003 vs 41% to 47% from 2011 to 2014), and the frequent use of simulation increased from 1% in 2009 to 24% in 2012 (p < 0.001). More residents recommended CTS to potential trainees (79% in 2014 vs 65% in 2010, p=0.007). Job offers increased from a low of 12% in 2008 with three or more offers to 34% in 2014. Debt increased from 0% with more than $ 200,000 in 2003 to 40% in 2013 (p < 0.001). Compared with residents in traditional programs, more integrated residents in 2014 were interested in adult cardiac surgery (53% vs 31%) and congenital surgery (22% vs 7%), fewer were interested in general thoracic surgery (5% vs 31%, p < 0.001), and more planned on additional training (66% vs 36%, p < 0.001). Conclusions. With the evolution in CTS over the last decade, residents' training and career paths have changed substantially, with increased specialization and simulation accompanied by increased resident satisfaction and an improved job market. (C) 2015 by The Society of Thoracic Surgeons C1 Columbia Univ, Dept Cardiac Thorac & Vasc Surg, New York, NY USA. Univ Pittsburgh, Dept Cardiothorac Surg, Pittsburgh, PA USA. Emory Univ, Div Cardiothorac Surg, Atlanta, GA 30322 USA. Univ Virginia, Div Thorac & Cardiovasc Surg, Charlottesville, VA USA. Med Univ S Carolina, Div Cardiothorac Surg, Charleston, SC 29425 USA. Cleveland Clin, Dept Thorac & Cardiovasc Surg, Cleveland, OH 44106 USA. Univ Washington, Div Cardiothorac Surg, Seattle, WA 98195 USA. Univ Texas Hlth Sci Ctr San Antonio, Dept Cardiothorac Surg, San Antonio, TX 78229 USA. Baylor Coll Med, Div Gen Thorac Surg, Houston, TX 77030 USA. Pinnacle Hlth CardioVasc Inst, Harrisburg, PA USA. Duke Univ, Dept Surg, Durham, NC USA. Northwestern Univ, Div Cardiac Surg, Chicago, IL 60611 USA. Massachusetts Gen Hosp, Div Thorac Surg, Boston, MA 02114 USA. Univ Rochester, Med Ctr, Div Cardiothorac Surg, Rochester, NY 14642 USA. Texas Childrens Hosp, Congenital Heart Surg, Dept Surg, Houston, TX 77030 USA. Univ Iowa, Dept Cardiothorac Surg, Iowa City, IA USA. Univ Mississippi, Div Cardiothorac Surg, Oxford, MS USA. Univ Texas Mem Hermann Texas Med Ctr, Dept Cardiothorac & Vasc Surg, Houston, TX USA. RP Nguyen, TC (reprint author), 6400 Fannin St,Ste 2850, Houston, TX 77030 USA. EM tom.c.nguyen@gmail.com NR 17 TC 6 Z9 6 U1 0 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 OCT PY 2015 VL 100 IS 4 BP 1305 EP 1314 DI 10.1016/j.athoracsur.2015.04.026 PG 10 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA CS7TE UT WOS:000362288000037 PM 26169046 ER PT J AU Shahian, DM He, X Jacobs, JP Kurlansky, PA Badhwar, V Cleveland, JC Fazzalari, FL Filardo, G Normand, SLT Furnary, AP Magee, MJ Rankin, JS Welke, KF Han, J O'Brien, SM AF Shahian, David M. He, Xia Jacobs, Jeffrey P. Kurlansky, Paul A. Badhwar, Vinay Cleveland, Joseph C., Jr. Fazzalari, Frank L. Filardo, Giovanni Normand, Sharon-Lise T. Furnary, Anthony P. Magee, Mitchell J. Rankin, J. Scott Welke, Karl F. Han, Jane O'Brien, Sean M. TI The Society of Thoracic Surgeons Composite Measure of Individual Surgeon Performance for Adult Cardiac Surgery: A Report of The Society of Thoracic Surgeons Quality Measurement Task Force SO ANNALS OF THORACIC SURGERY LA English DT Article ID BYPASS-GRAFTING SURGERY; NEW-YORK-STATE; MORTALITY-RATES; HOSPITAL OUTCOMES; SURGICAL QUALITY; LIMITATIONS; CARE; CLUSTER; ISSUES; VOLUME AB Background. Previous composite performance measures of The Society of Thoracic Surgeons (STS) were estimated at the STS participant level, typically a hospital or group practice. The STS Quality Measurement Task Force has now developed a multiprocedural, multidimensional composite measure suitable for estimating the performance of individual surgeons. Methods. The development sample from the STS National Database included 621,489 isolated coronary artery bypass grafting procedures, isolated aortic valve replacement, aortic valve replacement plus coronary artery bypass grafting, mitral, or mitral plus coronary artery bypass grafting procedures performed by 2,286 surgeons between July 1, 2011, and June 30, 2014. Each surgeon's composite score combined their aggregate risk-adjusted mortality and major morbidity rates (each weighted inversely by their standard deviations) and reflected the proportion of case types they performed. Model parameters were estimated in a Bayesian framework. Composite star ratings were examined using 90%, 95%, or 98% Bayesian credible intervals. Measure reliability was estimated using various 3-year case thresholds. Results. The final composite measure was defined as 0.81 x (1 minus risk-standardized mortality rate) + 0.19 x (1 minus risk-standardized complication rate). Riskadjusted mortality (median, 2.3%; interquartile range, 1.7% to 3.0%), morbidity (median, 13.7%; interquartile range, 10.8% to 17.1%), and composite scores (median, 95.4%; interquartile range, 94.4% to 96.3%) varied substantially across surgeons. Using 98% Bayesian credible intervals, there were 207 1-star (lower performance) surgeons (9.1%), 1,701 2-star (as-expected performance) surgeons (74.4%), and 378 3-star (higher performance) surgeons (16.5%). With an eligibility threshold of 100 cases over 3 years, measure reliability was 0.81. Conclusions. The STS has developed a multiprocedural composite measure suitable for evaluating performance at the individual surgeon level. (C) 2015 by The Society of Thoracic Surgeons C1 [Shahian, David M.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Shahian, David M.] Massachusetts Gen Hosp, Ctr Qual & Safety, Boston, MA 02114 USA. [Shahian, David M.] Harvard Univ, Sch Med, Boston, MA USA. [He, Xia; O'Brien, Sean M.] Clin Res Inst, Durham, NC USA. [Jacobs, Jeffrey P.] Johns Hopkins All Childrens Heart Inst, St Petersburg, FL USA. [Kurlansky, Paul A.] Columbia Univ Coll Phys & Surg, Columbia HeartSource, New York, NY 10032 USA. [Badhwar, Vinay] Univ Pittsburgh, Med Ctr, Dept Cardiothorac Surg, Pittsburgh, PA USA. [Cleveland, Joseph C., Jr.] Univ Colorado, Sch Med, Div Cardiothorac Surg, Aurora, CO USA. [Fazzalari, Frank L.] Univ Michigan Hlth Syst, Dept Cardiac Surg, Ann Arbor, MI USA. [Filardo, Giovanni] Baylor Hlth Care Syst, Inst Hlth Care Res & Improvement, Dallas, TX USA. [Normand, Sharon-Lise T.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Normand, Sharon-Lise T.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Furnary, Anthony P.] Starr Wood Cardiac Grp, Portland, OR USA. [Magee, Mitchell J.] HCA North Texas Div, Dallas, TX USA. [Rankin, J. Scott] Cardiothorac Surg Associates, Nashville, TN USA. [Welke, Karl F.] Childrens Hosp Illinois, Peoria, IL USA. [Welke, Karl F.] Univ Illinois, Coll Med, Peoria, IL 61656 USA. [Han, Jane] Soc Thorac Surg, Chicago, IL USA. RP Shahian, DM (reprint author), Massachusetts Gen Hosp, 55 Fruit St,Bulfinch 284, Boston, MA 02114 USA. EM dshahian@partners.org NR 37 TC 11 Z9 11 U1 1 U2 4 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 OCT PY 2015 VL 100 IS 4 BP 1315 EP 1325 DI 10.1016/j.athoracsur.2015.06.122 PG 11 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA CS7TE UT WOS:000362288000038 PM 26330012 ER PT J AU Velasquez, JF Ramirez, MF Ai, D Lewis, V Cata, JP AF Velasquez, Jose F. Ramirez, Maria F. Ai, Di Lewis, Valerae Cata, Juan P. TI Impaired Immune Function in Patients Undergoing Surgery for Bone Cancer SO ANTICANCER RESEARCH LA English DT Article DE Bone cancer; surgery; immune function; inflammatory response ID NATURAL-KILLER-CELLS; PROGNOSTIC-FACTOR; COLORECTAL-CANCER; SURGICAL STRESS; MURINE MODEL; LUNG-CANCER; TUMOR-CELLS; NK CELLS; CARCINOMA; INTERLEUKIN-6 AB Background: Natural killer (NK) cells undergo quantitative and functional changes after oncological surgery. Patients and Methods: After Institutional Review Board approval, the count and function of NK cells from patients with malignant bone tumors were assessed only days 1, 3, 5 and during first postoperative visit, and compared with preoperative values. The serum concentrations of interleukins (IL)-2, -4 and -6 were also measured before and after surgery. Results: Complete clinical and laboratory data were analyzed from 17 patients with different bone malignancies. The number of NK cells significantly decreased postoperatively as well as their function. The maximum deterioration in their function occurred 5 days postoperatively. The serum concentrations of IL-2 and IL-4 did not change perioperatively. In contrast, a significant increase in the concentrations of IL-6 was observed on day 1, 3 and 5 postoperatively. Conclusion: A significant inflammatory response and innate immune suppression occurred after surgery for malignant bone tumors. C1 [Velasquez, Jose F.; Cata, Juan P.] Univ Texas MD Anderson Canc Ctr, Dept Anesthesiol & Perioperat Med, Houston, TX 77030 USA. [Lewis, Valerae] Univ Texas MD Anderson Canc Ctr, Dept Orthoped Oncol, Houston, TX 77030 USA. [Ramirez, Maria F.] Massachusetts Gen Hosp, Dept Anesthesiol, Boston, MA 02114 USA. [Cata, Juan P.] Anesthesia & Surg Oncol Res Grp, Houston, TX USA. [Ai, Di] Baylor Scott & White Mem Hosp, Texas A&M Canc Ctr, Dept Pathol, Temple, TX USA. RP Cata, JP (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Anesthesiol & Perioperat Med, Unit 409,1515 Holcombe Blvd, Houston, TX 77030 USA. EM jcata@mdanderson.org FU Triumph Over Kid Cancer foundation FX This work was funded by a grant award to JPC from the Triumph Over Kid Cancer foundation. NR 32 TC 0 Z9 0 U1 0 U2 1 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDRITIOU-KALAMOU RD KAPANDRITI, PO BOX 22, ATHENS 19014, GREECE SN 0250-7005 EI 1791-7530 J9 ANTICANCER RES JI Anticancer Res. PD OCT PY 2015 VL 35 IS 10 BP 5461 EP 5466 PG 6 WC Oncology SC Oncology GA CS1KM UT WOS:000361823200037 PM 26408709 ER PT J AU Kohan, R Mole, SE Cotman, SL AF Kohan, Romina Mole, Sara E. Cotman, Susan L. TI Special issue: Molecular basis of NCL Preface SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE LA English DT Editorial Material C1 [Kohan, Romina] Univ Nacl Cordoba, Fac Odontol, Fac Ciencias Med, Ctr Estudio Metabolopatias Congenitas CEMECO, RA-5000 Cordoba, Argentina. [Mole, Sara E.] UCL, MRC Lab Mol Cell Biol, London WC1E 6BT, England. [Mole, Sara E.] UCL, Dept Genet Evolut & Environm, London WC1E 6BT, England. [Mole, Sara E.] UCL Inst Child Hlth, Genet & Genom Med Programme, Genet & Epigenet Hlth & Dis, London WC1N 1EH, England. [Cotman, Susan L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA 02114 USA. [Cotman, Susan L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA 02114 USA. RP Mole, SE (reprint author), UCL, MRC Lab Mol Cell Biol, Gower St, London WC1E 6BT, England. EM kohanromina@gmail.com; s.mole@ucl.ac.uk; cotman@helix.mgh.harvard.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4439 EI 0006-3002 J9 BBA-MOL BASIS DIS JI Biochim. Biophys. Acta-Mol. Basis Dis. PD OCT PY 2015 VL 1852 IS 10 SI SI BP 2235 EP 2236 DI 10.1016/j.bbadis.2015.06.023 PN B PG 2 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA CS2TM UT WOS:000361924900001 PM 26122823 ER PT J AU Mole, SE Connan, SL AF Mole, Sara E. Connan, Susan L. TI Genetics of the neuronal ceroid lipofuscinoses (Batten disease) SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE LA English DT Review DE Batten; CLN; Neuronal ceroid lipofuscinosis; NCL, genetics, mutation ID CATHEPSIN-D DEFICIENCY; TRANSMEMBRANE PROTEIN; MISSENSE MUTATION; KUFS-DISEASE; MUTANT MICE; ONSET; VARIANT; KCTD7; CLN8; PROGRANULIN AB The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative disorders that affect children and adults and are grouped together by similar clinical features and the accumulation of autofluorescent storage material. More than a dozen genes containing over 430 mutations underlying human NCLs have been identified. These genes encode lysosomal enzymes (CLN1, CLN2, CLN10, CLN13), a soluble lysosomai protein (CLN5), a protein in the secretory pathway (CLN11), two cytoplasmic proteins that also peripherally associate with membranes (CLN4, CLN14), and many transmembrane proteins with different subcellular locations (CLN3, CLN6, CLN7, CLN8, CLN12). For most NCLs, the function of the causative gene has not been fully defined. Most of the mutations in these genes are associated with a typical disease phenotype, but some result in variable disease onset, severity, and progression, including distinct clinical phenotypes. There remain disease subgroups with unknown molecular genetic backgrounds. This article is part of a Special Issue entitled: "Current Research on the Neuronal Ceroid Lipofiiscinoses (Batten Disease)." (C) 2015 Elsevier B.V. All rights reserved. C1 [Mole, Sara E.] UCL, MRC Lab Mol Cell Biol, London WC1E 6BT, England. [Mole, Sara E.] UCL, UCL Inst Child Hlth, London WC1E 6BT, England. [Mole, Sara E.] UCL, Dept Genet Evolut & Environm, London WC1E 6BT, England. [Connan, Susan L.] Massachusetts Gen Hosp, Dept Neurol, Ctr Human Genet Res, Boston, MA 02114 USA. RP Mole, SE (reprint author), UCL, MRC Lab Mol Cell Biol, Gower St, London WC1E 6BT, England. EM s.mole@ucl.ac.uk OI Mole, Sara/0000-0003-4385-4957 FU UK Batten Disease Family Association; USA Batten Disease Support and Research Association in the maintenance of this database; National Institutes of Health: National Institute of Neurological Disorders Stroke [R01NS073813] FX The authors thank clinicians, scientists, and families who continue to report or directly submit new changes in NCL genes and more recently cases to the NCL Mutation Database. We acknowledge financial support from the UK Batten Disease Family Association and the USA Batten Disease Support and Research Association in the maintenance of this database. SLC receives research support from by the National Institutes of Health: National Institute of Neurological Disorders & Stroke (R01NS073813). NR 39 TC 19 Z9 19 U1 1 U2 17 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4439 EI 0006-3002 J9 BBA-MOL BASIS DIS JI Biochim. Biophys. Acta-Mol. Basis Dis. PD OCT PY 2015 VL 1852 IS 10 SI SI BP 2237 EP 2241 DI 10.1016/j.bbadis.2015.05.011 PN B PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA CS2TM UT WOS:000361924900002 PM 26026925 ER PT J AU Kohan, R Pesaola, F Guelbert, N Pons, P Oller-Ramirez, AM Rautenberg, G Becerra, A Sims, K Xin, WN Cismondi, IA de Halac, IN AF Kohan, Romina Pesaola, Favio Guelbert, Norberto Pons, Patricia Maria Oller-Ramirez, Ana Rautenberg, Gisela Becerra, Adriana Sims, Katherine Xin, Winnie Adriana Cismondi, Ines Noher de Halac, Ines TI The neuronal ceroid lipofuscinoses program: A translational research experience in Argentina SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE LA English DT Review DE Neuronal ceroid lipofuscinoses; Algorithm; Morphology; Enzymes; DNA variants ID PALMITOYL-PROTEIN THIOESTERASE; TRIPEPTIDYL-PEPTIDASE-I; GRANULAR OSMIOPHILIC DEPOSITS; CATHEPSIN-D DEFICIENCY; B KUFS-DISEASE; BATTEN-DISEASE; MUTATIONS; GENE; DIAGNOSIS; ONSET AB Background: The Argentinean program was initiated more than a decade ago as the first experience of systematic translational research focused on NCL in Latin America. The aim was to overcome misdiagnoses and underdiagnoses in the region. Subjects: 216 NCL suspected individuals from 8 different countries and their direct family members. Methods: Clinical assessment, enzyme testing, electron microscopy, and DNA screening. Results and discussion: 1) The study confirmed NCL disease in 122 subjects. Phenotypic studies comprised epileptic seizures and movement disorders, ophthalmology, neurophysiology, image analysis, rating scales, enzyme testing, and electron microscopy, carried out under a consensus algorithm; 2) DNA screening and validation of mutations in genes PPT1 (CLN1), TPP1 (CLN2), CLN3, CLN5, CLN6, MFSD8 (CLN7), and CLN8: characterization of variant types, novel/known mutations and polymorphisms; 3) Progress of the epidemiological picture in Latin America; and 4) NCL-like pathology studies in progress. The Translational Research Program was highly efficient in addressing the misdiagnosis/underdiagnosis in the NCL disorders. The study of "orphan diseases" in a public administrated hospital should be adopted by the health systems, as it positively impacts upon the family's quality of life, the collection of epidemiological data, and triggers research advances. This article is part of a Special Issue entitled: "Current Research on the Neuronal Ceroid Lipofuscinoses (Batten Disease)". (C) 2015 Elsevier B.V. All rights reserved. C1 [Kohan, Romina; Pesaola, Favio; Guelbert, Norberto; Maria Oller-Ramirez, Ana; Rautenberg, Gisela; Becerra, Adriana; Adriana Cismondi, Ines; Noher de Halac, Ines] Univ Nacl Cordoba, Fac Ciencias Med, Ctr Estudio Metabolopatias Congenitas CEMECO, RA-5014 Cordoba, Argentina. [Kohan, Romina; Adriana Cismondi, Ines; Noher de Halac, Ines] Univ Nacl Cordoba, Fac Odontol, RA-5000 Cordoba, Argentina. [Pesaola, Favio; Noher de Halac, Ines] Consejo Nacl Invest Cient & Tecn, RA-1033 Buenos Aires, DF, Argentina. [Pons, Patricia] Univ Nacl Cordoba, Fac Ciencias Med, Ctr Microscopia Elect, RA-5000 Cordoba, Argentina. [Sims, Katherine; Xin, Winnie] Massachusetts Gen Hosp, Dept Neurol, Ctr Genet Res CHGR, Boston, MA 02114 USA. RP de Halac, IN (reprint author), Univ Nacl Cordoba, Fac Ciencias Med, CEMECO, Ferroviarios 1250, RA-5014 Cordoba, Argentina. EM kohanromina@gmail.com; favio.pesaola@gmail.com; nguelbert@arnet.com.ar; ppons@cmefcm.uncor.edu; ramirezoller@gmail.com; giselarautenberg@hotmail.com; dra.adrianabecerra@hotmail.com; sims@helix.mgh.harvard.edu; xin@helix.mgh.harvard.edu; ines.adriana.cismondi@unc.edu.ar; nclcemeco1789@gmail.com FU Argentinean National Research Council (CONICET-RA) [PIP 6185-2005, PIP 112-2011]; Secretary of Science and Technology of the National University Cordoba (SECyT-UNC) [05/J155, 05/H295, 05/J079]; Ministry of Science and Technology from the Province of Cordoba (MINCYT: PID); NIH (Fogarty Program "Brain Disorders in the Developing World") [1R21TW008433-01]; Batten Disease Support and Research Association (BDSRA-US) FX We kindly acknowledge the NCL families from Latin America, the personnel of the Centro de Estudio de las Metabolopatias Congenitas (CEMECO) at the Children's Hospital, Cordoba Argentina, and the National University Cordoba. We thank the Science and Technology Organizations that provided grant support to our research: Argentinean National Research Council (CONICET-RA: PIP 6185-2005, PIP 112-2011), Secretary of Science and Technology of the National University Cordoba (SECyT-UNC: 05/J155, 05/H295, 05/J079), Ministry of Science and Technology from the Province of Cordoba (MINCYT: PID 2009), NIH (Fogarty Program "Brain Disorders in the Developing World": 1R21TW008433-01), and Batten Disease Support and Research Association (BDSRA-US: years 2001-2002-2003-2005-2006). We thank Michael Fietz from Australia for the comments on his SCAR7 patient, Ana Lia Taratuto from Argentina for her contribution with EM photographs, and all the colleagues that derived patients and samples for study, from Chile (Monica Troncoso, Sacarlett Witting, Gloria Duran), Brazil (Roberto Giugliani, Marta Regina Clivati), Mexico (Sandra Nieto-Martinez, Matilde Ruiz-Garcia), Uruguay (Roberto Quadrelli), Colombia (Lisseth Cabarcas Castro), Argentina (Raquel Dodelson de Kremer, Maria del Rosario Aldao, Liliana Czornyj, Alejandra Visich, Ana Maria Guercio, Mercedes Villanueva, Santiago Sfaello, Hugo Arroyo, Rosana Ocampo, Gabriel Vazquez, Soledad Monges, Ines Denzler, Laura Cassar, Silvia Tenembaun, Marcela Pereyra, Griselda Ray, Femanda Garro, Ricardo Fauze, and other neuropediatricians and clinical geneticians, residents and fellows of our country). NR 94 TC 2 Z9 2 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4439 EI 0006-3002 J9 BBA-MOL BASIS DIS JI Biochim. Biophys. Acta-Mol. Basis Dis. PD OCT PY 2015 VL 1852 IS 10 SI SI BP 2301 EP 2311 DI 10.1016/j.bbadis.2015.05.003 PN B PG 11 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA CS2TM UT WOS:000361924900010 PM 25976102 ER PT J AU Cotman, SL Mole, SE Kohan, R AF Cotman, Susan L. Mole, Sara E. Kohan, Romina TI Future perspectives: Moving towards NCL treatments SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE LA English DT Review DE Neuronal Ceroid Lipofuscinosis (NCL); Batten disease ID NEURONAL CEROID-LIPOFUSCINOSIS; ENZYME REPLACEMENT; BATTEN-DISEASE; METABOLOMICS; MUTATION; BRAIN; PATHOLOGY; MODEL; TPP1; CLN3 AB Clinicians, basic researchers, representatives from pharma and families from around the world met in Cordoba, Argentina in October, 2014 to discuss recent research progress at the 14th International Congress on Neuronal Ceroid Lipofuscinoses (NCLs; Batten disease), a group of clinically overlapping fatal, inherited lysosomal disorders with primarily neurodegenerative symptoms. This brief review article will provide perspectives on the anticipated future directions of NCL basic and clinical research as we move towards improved diagnosis, care and treatment of NCL patients. This article is part of a Special Issue entitled: Current Research on the Neuronal Ceroid Lipofuscinoses (Batten Disease). (C) 2015 Elsevier B.V. All rights reserved. C1 [Cotman, Susan L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA 02114 USA. [Cotman, Susan L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA 02114 USA. [Mole, Sara E.] UCL, UCL Inst Child Hlth, Dept Genet Evolut & Environm, MRC Lab Cell Biol, London WC1E 6BT, England. [Kohan, Romina] Univ Nacl Cordoba, Fac Ciencias Med, Ctr Estudio Metabolopatias Congenitas CEMECO, RA-5014 Cordoba, Argentina. RP Cotman, SL (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, 185 Cambridge St, Boston, MA 02114 USA. EM cotman@helix.mgh.harvard.edu OI Mole, Sara/0000-0003-4385-4957 FU NINDS NIH HHS [R01 NS073813] NR 20 TC 0 Z9 0 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4439 EI 0006-3002 J9 BBA-MOL BASIS DIS JI Biochim. Biophys. Acta-Mol. Basis Dis. PD OCT PY 2015 VL 1852 IS 10 SI SI BP 2336 EP 2338 DI 10.1016/j.bbadis.2015.04.001 PN B PG 3 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA CS2TM UT WOS:000361924900015 PM 25857620 ER PT J AU Kressin, NR Lin, MY AF Kressin, Nancy R. Lin, Meng-Yun TI Race/ethnicity, and Americans' perceptions and experiences of over- and under-use of care: a cross-sectional study SO BMC HEALTH SERVICES RESEARCH LA English DT Article DE Patient preferences; Disparities; Survey research ID HEALTH; PHYSICIANS; LITERACY AB Background: Despite widespread documentation of racial/ethnic disparities in care (predominantly under-use of needed care), differences in population-wide attitudes or experiences about under-or overuse (care where harms may outweigh potential benefits) of care are not well understood. We examined whether race/ethnicity is associated with perceptions or experiences of overuse or underuse. Methods: We conducted secondary analysis of a cross-sectional national telephone survey of nationally representative sample of 1238 American adults; 57.9 % female, 75.4 % Non-Hispanic White, 11.8 % Non-Hispanic Black, 10.1 % Hispanic. The main outcome measures are general perceptions and personal experiences of overuse and underuse, including cost-related dimensions of each. Results: Bivariate results indicated that respondents of minority race/ethnicity generally viewed both overuse and underuse as bigger problems than did Whites, and reported more personal experiences of each. After adjustment, Hispanics were less likely than Whites to report personal experiences of overuse (odds ratio [OR] [95 % CI], 0.44 [0.23 to 0.86]), while Blacks and Others were more likely to report cost-related overuse (ORs [95 % CIs], 4.16 [2.30 to 7.51]; 3.55 [1.52 to 8.28], respectively). Non-Hispanic Others more often reported doctors' protection from overuse (OR [95 % CI], 3.69 [1.75 to 7.78]). General concerns with underuse were more frequent among Blacks and Hispanics (ORs [95 % CIs], 3.07 [1.72 to 5.54]; 2.12 [1.24 to 3.61] respectively), while Others reported significantly fewer concerns (OR [95 % CI], 0.43 [0.23 to 0.80]). Conclusions: Over-and underuse of medical care are important problems for many Americans, and experiences vary by race/ethnicity. Clinician communication and educational campaigns about appropriateness of care may need tailoring for varying population groups. C1 [Kressin, Nancy R.; Lin, Meng-Yun] Boston Univ, Sch Med, Sect Gen Internal Med, Crosstown Ctr, Boston, MA 02118 USA. [Kressin, Nancy R.] VA Boston Healthcare Syst, Boston, MA 02130 USA. [Lin, Meng-Yun] Boston Univ, Sch Publ Hlth, Hlth Policy & Management Dept, Boston, MA 02118 USA. RP Kressin, NR (reprint author), Boston Univ, Sch Med, Sect Gen Internal Med, Crosstown Ctr, 801 Massachusetts Ave, Boston, MA 02118 USA. EM nkressin@bu.edu FU Department of Veterans Affairs, Health Services Research & Development Service [RCS 02-066-1] FX Dr. Kressin is supported in part by a Research Career Scientist award from the Department of Veterans Affairs, Health Services Research & Development Service (RCS 02-066-1). NR 22 TC 0 Z9 0 U1 1 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6963 J9 BMC HEALTH SERV RES JI BMC Health Serv. Res. PD OCT 1 PY 2015 VL 15 AR 443 DI 10.1186/s12913-015-1106-7 PG 9 WC Health Care Sciences & Services SC Health Care Sciences & Services GA CS6DY UT WOS:000362169000001 PM 26428620 ER PT J AU Peppercorn, J Houck, K Beri, N Villagra, V Wogu, AF Lyman, GH Wheeler, SB AF Peppercorn, Jeffrey Houck, Kevin Beri, Nina Villagra, Victor Wogu, Adane F. Lyman, Gary H. Wheeler, Stephanie B. TI Breast cancer screening utilization and understanding of current guidelines among rural US women with private insurance SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Breast cancer screening; Rural; Health disparities; Survey; Guidelines ID SERVICES TASK-FORCE; CARCINOMA MORTALITY; MAMMOGRAPHY; IMPACT; DIAGNOSIS; THERAPY; TRIAL; RECOMMENDATIONS; POPULATION; PROGRAM AB Women living in rural areas of the U.S. face disparities in screening mammography and breast cancer outcomes. We sought to evaluate utilization of mammography, awareness of screening guidelines, and attitudes towards screening among rural insured U.S. women. We conducted a cross-sectional self-administered anonymous survey among 2000 women aged 40-64 insured by the National Rural Electric Cooperative Association, a non-profit insurer for electrical utility workers in predominantly rural areas across the U.S. Outcomes included mammographic screening in the past year, screening interval, awareness of guidelines, and perceived barriers to screening. 1588 women responded to the survey (response rate 79.4 %). 74 % of respondents lived in a rural area. Among women aged 40-49, 66.5 % reported mammographic screening in the past year. 46 % received annual screening, 32 % biennial screening, and 22 % rare/no screening. Among women aged 50-64, 77.1 % reported screening in the past year. 63 % received annual screening, 25 % biennial screening, and 12 % rare/no screening. The majority of women (98 %) believed that the mammography can find breast cancer early and save lives. Less than 1 % of younger women, and only 14 % of women over age 50 identified the recommendations of the U.S. Preventative Services Screening Task Force as the current expert recommendations for screening. Screening practices tended to follow perceived guideline recommendations. When rural U.S. women over age 40 have insurance, most receive breast cancer screening. The screening guidelines of cancer advocacy groups and specialty societies appear more influential and widely recognized than those of the U.S. preventative services taskforce. C1 [Peppercorn, Jeffrey] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Houck, Kevin; Beri, Nina] Duke Univ, Med Ctr, Durham, NC USA. [Villagra, Victor] Univ Connecticut, Ctr Hlth, Farmington, CT USA. [Wogu, Adane F.; Wheeler, Stephanie B.] Univ N Carolina, Sch Global Publ Hlth, Chapel Hill, NC USA. [Lyman, Gary H.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. RP Peppercorn, J (reprint author), Massachusetts Gen Hosp, Ctr Canc, 55 Fruit St, Boston, MA 02114 USA. EM jpeppercorn@mgh.harvard.edu FU American Cancer Society FX This study was supported by a Research Scholar grant from the American Cancer Society (JP). NR 30 TC 2 Z9 2 U1 1 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 OCT PY 2015 VL 153 IS 3 BP 659 EP 667 DI 10.1007/s10549-015-3566-1 PG 9 WC Oncology SC Oncology GA CS3PS UT WOS:000361987300019 PM 26386956 ER PT J AU Chan, CHF Coopey, SB Freer, PE Hughes, KS AF Chan, Carlos H. F. Coopey, Suzanne B. Freer, Phoebe E. Hughes, Kevin S. TI False-negative rate of combined mammography and ultrasound for women with palpable breast masses SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Breast ultrasound; Mammography; Palpable breast mass ID FINE-NEEDLE ASPIRATION; COMBINED PHYSICAL-EXAMINATION; TRIPLE-TEST; SYMPTOMATIC POPULATION; CLINICAL EXAMINATION; CANCER; DIAGNOSIS; BENIGN; BIOPSY; ACCURACY AB Mammography and ultrasound are often used concurrently for patients with palpable breast masses. While mammography has a false-negative rate of approximately 15 %, the addition of breast ultrasound decreases this rate among patients with palpable breast masses. There are no recent outcome data regarding the use of combined reporting of ultrasound and mammography (CRUM) for palpable breast masses. In this study, female patients presenting with a palpable breast mass were retrospectively reviewed in a prospectively entered database at a single institution from June 2010 to July 2013. All cancer cases and false-negative cases using CRUM were identified. Cancer rates, false-negative rates, and negative predictive values were calculated based on CRUM breast imaging-reporting and data system (BI-RADS) categories. One thousand two hundreds and twelve female patients presenting with a palpable breast mass were identified; 77 % of patients had CRUM and 73 % (682/932) were BI-RADS 1-2. Despite negative or benign BI-RADS, 9.5 % of patients with BI-RADS 1-2 (65/682) underwent biopsy, compared to 96 % of patients with a BI-RADS 4-5 designation. Eighty-one patients were found to have cancers; 2 had BI-RADS 1-2 imaging. The false-negative rate of CRUM was 2.4 % (2/81). Since 69 % (428/617) of BI-RADS 1-2 patients without tissue diagnosis had follow-up imaging and/or clinical exam (median: 27 months, range: 2-62 months) and none developed cancers, the cancer rate and negative predictive value of a palpable breast mass of BI-RADS 1-2 were estimated to be 0.3 % (2/682) and 99.7 %, respectively. In the modern era of combined imaging for breast masses, a patient with a low suspicion exam can be reassured with a negative CRUM report. C1 [Chan, Carlos H. F.; Coopey, Suzanne B.; Hughes, Kevin S.] Massachusetts Gen Hosp, Div Surg Oncol, Boston, MA 02114 USA. [Freer, Phoebe E.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Hughes, KS (reprint author), Massachusetts Gen Hosp, Div Surg Oncol, 55 Fruit St, Boston, MA 02114 USA. EM carloshfchan@gmail.com; kshughes@partners.org OI Freer, Phoebe/0000-0001-6886-7100 NR 21 TC 1 Z9 1 U1 1 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 OCT PY 2015 VL 153 IS 3 BP 699 EP 702 DI 10.1007/s10549-015-3557-2 PG 4 WC Oncology SC Oncology GA CS3PS UT WOS:000361987300023 PM 26341750 ER PT J AU Frazer, JK Li, KJ Galardy, P Perkins, SL Auperin, A Anderson, JR Pinkerton, R Buxton, A Gross, TG Weinstein, H Harrison, L Shiramizu, B Barth, M Goldman, S Patte, C Cairo, MS AF Frazer, J. Kimble Li, Kevin J. Galardy, Paul Perkins, Sherrie L. Auperin, Anne Anderson, James R. Pinkerton, Ross Buxton, Allen Gross, Thomas G. Weinstein, Howard Harrison, Lauren Shiramizu, Bruce Barth, Matthew Goldman, Stanton Patte, Catherine Cairo, Mitchell S. TI Excellent outcomes in children and adolescents with central nervous system-positive (CNS+) Burkitt lymphoma/leukemia (BL) or other mature B-NHL using intrathecal and systemic chemotherapy without CNS irradiation: results from FAB/LMB96 and ANHL01P1 studies SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Meeting Abstract CT 5th International Symposium on Childhood, Adolescent and Young Adult Non-Hodgkin Lymphoma CY OCT 22, 2015 CL Varese, ITALY C1 [Frazer, J. Kimble; Li, Kevin J.] Univ Oklahoma, Hlth Sci Ctr, Pediat Hematol Oncol, Oklahoma City, OK USA. [Galardy, Paul] Mayo Clin, Pediat Hematol Oncol, Rochester, MN USA. [Perkins, Sherrie L.] Univ Utah, Pathol Labs, Salt Lake City, UT USA. [Perkins, Sherrie L.] Univ Utah, ARUP Labs, Salt Lake City, UT USA. [Auperin, Anne; Patte, Catherine] CLCC Inst Cancerol Gustave Roussy, Dept Cancerol Enfant & Adolescent, Villejuif, France. [Anderson, James R.] Frontier Sci & Technol Res Fdn Inc, Madison, WI USA. [Pinkerton, Ross] Univ Queensland, Brisbane, Qld, Australia. [Buxton, Allen] Childrens Oncol Grp, Monrovia, CA USA. [Gross, Thomas G.] NCI, Ctr Global Hlth, NIH, Rockville, MD USA. [Weinstein, Howard] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pediat Hematol Oncol, Boston, MA USA. [Harrison, Lauren; Cairo, Mitchell S.] New York Med Coll, Pediat, Valhalla, NY 10595 USA. [Shiramizu, Bruce] Univ Hawaii, Pediat Hematol Oncol, Honolulu, HI 96822 USA. [Barth, Matthew] Roswell Pk Canc Inst, Pediat, Buffalo, NY 14263 USA. [Goldman, Stanton] Med City Childrens Hosp, Pediat Hematol Oncol, Dallas, TX USA. [Cairo, Mitchell S.] New York Med Coll, Med Pathol Microbiol & Immunol, Valhalla, NY 10595 USA. [Cairo, Mitchell S.] New York Med Coll, Cell Biol & Anat, Valhalla, NY 10595 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1048 EI 1365-2141 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD OCT PY 2015 VL 171 SU 1 SI SI MA 10 BP 6 EP 7 PG 2 WC Hematology SC Hematology GA CS9QG UT WOS:000362425300009 ER PT J AU Chen, HY Liu, X Clayman, ES Shao, FY Xiao, MS Tian, XY Fu, WY Zhang, CY Ruan, BB Zhou, PJ Liu, Z Wang, YF Rui, W AF Chen, Hongyuan Liu, Xiao Clayman, Eric S. Shao, Fangyuan Xiao, Manshan Tian, Xuyan Fu, Wuyu Zhang, Caiyun Ruan, Bibo Zhou, Pengjun Liu, Zhong Wang, Yifei Rui, Wen TI Synthesis and Evaluation of a CBZ-AAN-Dox Prodrug and its in vitro Effects on SiHa Cervical Cancer Cells Under Hypoxic Conditions SO CHEMICAL BIOLOGY & DRUG DESIGN LA English DT Article DE asparagine endopeptidase; doxorubicin; hypoxia; legumain; N-benzyloxycarbonyl-Ala-Ala-Asn-Doxorubicin; prodrug; SiHa cells ID BREAST-CANCER; LEGUMAIN EXPRESSION; TUMOR MICROENVIRONMENT; DOXORUBICIN UPTAKE; PROGNOSTIC-FACTOR; TARGET; ASSOCIATION; THERAPY; GROWTH; GENE AB Although doxorubicin (Dox) is widely used in clinical treatment for solid tumors, it causes many side-effects such as heart and kidney damage, bone marrow suppression, and drug resistance. Legumain is a lysosomal protease that is elevated and associated with an invasive and metastatic phenotype in a number of solid tumors. In this study, we designed and synthesized a Dox prodrug, N-benzyloxycarbonyl-Ala-Ala-Asn-Doxorubicin (CBZ-AAN-Dox), with 94% purity. Single substrate kinetic assays demonstrated hLegumain-specific enzymatic cleavage and activation of the prodrug in vitro, and this enzymatic cleavage of the prodrug substrate was more sensitive in acidic conditions, releasing more than 70% of Dox after 24h. Treatment of tumor cells with our prodrug demonstrated a much higher IC50 value, significantly enhanced uptake of the prodrug, and considerably less cellular toxicity compared to Dox treatment alone. Our study presents a novel prodrug, CBZ-AAN-Dox, to potentially increase both the safety and efficacy of clinical treatment of tumors by exploiting the tumor's innate expression of legumain. C1 [Chen, Hongyuan; Liu, Xiao; Shao, Fangyuan; Xiao, Manshan; Tian, Xuyan; Fu, Wuyu; Zhang, Caiyun; Ruan, Bibo; Zhou, Pengjun] Guangdong Pharmaceut Univ, Sch Basic Course, Dept Pathogen Biol & Immunol, Guangzhou 510060, Guangdong, Peoples R China. [Chen, Hongyuan] Guangdong Pharmaceut Univ, Guangdong Key Lab Pharmaceut Bioact Subst, Guangzhou 510006, Guangdong, Peoples R China. [Clayman, Eric S.] Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02129 USA. [Clayman, Eric S.] Harvard Univ, Sch Med, Boston, MA 02129 USA. [Liu, Zhong; Wang, Yifei] Jinan Univ, Natl Engn Res Ctr Genet Med, Guangdong Prov Key Lab Bioengn Med, Biomed Res & Dev Ctr, Guangzhou 510632, Guangdong, Peoples R China. [Rui, Wen] Guangdong Pharmaceut Univ, Ctr Lab, Guangzhou 510006, Guangdong, Peoples R China. RP Rui, W (reprint author), Guangdong Pharmaceut Univ, Ctr Lab, Guangzhou 510006, Guangdong, Peoples R China. EM r_wing@163.com RI Liu, Zhong/B-6323-2016 OI Liu, Zhong/0000-0002-5132-7463 FU China Postdoctoral Science Foundation [2013M542234]; Science and Technology Planning Project of Guangdong Province [2013B021800085]; Science and Technology Project Guangzhou City Grant [2014J4100058] FX This research were supported by China Postdoctoral Science Foundation (No. 2013M542234), 2013 Science and Technology Planning Project of Guangdong Province (No. 2013B021800085), and Science and Technology Project Guangzhou City Grant (No. 2014J4100058). NR 32 TC 3 Z9 3 U1 2 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1747-0277 EI 1747-0285 J9 CHEM BIOL DRUG DES JI Chem. Biol. Drug Des. PD OCT PY 2015 VL 86 IS 4 BP 589 EP 598 DI 10.1111/cbdd.12525 PG 10 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA CS6BZ UT WOS:000362163500021 PM 25619622 ER PT J AU Asplund, KM Kair, LR Arain, YH Cervantes, M Oreskovic, NM Zuckerman, KE AF Asplund, Karin M. Kair, Laura R. Arain, Yassar H. Cervantes, Marlene Oreskovic, Nicolas M. Zuckerman, Katharine E. TI Early Childhood Screen Time and Parental Attitudes Toward Child Television Viewing in a Low-Income Latino Population Attending the Special Supplemental Nutrition Program for Women, Infants, and Children SO CHILDHOOD OBESITY LA English DT Article ID YOUNG-CHILDREN; MEDIA USE; ADOLESCENTS; OVERWEIGHT; ENVIRONMENT; OBESITY; RISK AB Background: Early childhood media exposure is associated with obesity and multiple adverse health conditions. The aims of this study were to assess parental attitudes toward childhood television (TV) viewing in a low-income population and examine the extent to which child BMI, child/parent demographics, and household media environment are associated with adherence to American Academy of Pediatrics (AAP) guidelines for screen time. Methods: This was a cross-sectional survey study of 314 parents of children ages 0-5 years surveyed in English or Spanish by self-administered questionnaire at a Special Supplemental Nutrition Program for Women, Infants and Children (WIC) clinic in Oregon. Results: In this majority Latino sample (73%), half (53%) of the children met AAP guidelines on screen time limits, 56% met AAP guidelines for no TV in the child's bedroom, and 29% met both. Children were more likely to meet AAP guidelines when there were <2 TVs in the home, there was no TV during dinner, or their parents spent less time viewing electronic media. Parents who spent less time viewing electronic media were more likely to report believing that TV provides little value or usefulness. Conclusions: In this low-income, predominantly Latino population attending WIC, parent media-viewing and household media environment are strongly associated with child screen time. Programs aimed at reducing child screen time may benefit from interventions that address parental viewing habits. C1 [Asplund, Karin M.] Oregon Hlth & Sci Univ, Sch Med, Portland, OR 97239 USA. [Kair, Laura R.] Univ Iowa, Carver Coll Med, Stead Family Dept Pediat, Iowa City, IA USA. [Arain, Yassar H.] Lucile Packard Childrens Hosp Stanford, Dept Pediat, Stanford, CA USA. [Cervantes, Marlene; Zuckerman, Katharine E.] Oregon Hlth & Sci Univ, Div Gen Pediat, Doernbecher Childrens Hosp, Portland, OR 97239 USA. [Oreskovic, Nicolas M.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Oreskovic, Nicolas M.] Massachusetts Gen Hosp, Dept Internal Med, Boston, MA 02114 USA. [Oreskovic, Nicolas M.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. RP Asplund, KM (reprint author), Oregon Hlth & Sci Univ, Sch Med, Mail Code L102,3181 Southwest Sam Jackson Pk Rd, Portland, OR 97239 USA. EM asplund@ohsu.edu FU National Institute of Mental Health [1K23MH095828]; National Heart, Lung, and Blood Institute [K23HL103841] FX Dr. Zuckerman's effort was funded by grant 1K23MH095828 from the National Institute of Mental Health. Dr. Oreskovic's effort was funded by grant K23HL103841 from the National Heart, Lung, and Blood Institute. The funding sources 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 38 TC 0 Z9 0 U1 3 U2 16 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 2153-2168 EI 2153-2176 J9 CHILD OBES JI Child Obes. PD OCT 1 PY 2015 VL 11 IS 5 BP 590 EP 599 DI 10.1089/chi.2015.0001 PG 10 WC Pediatrics SC Pediatrics GA CS7NE UT WOS:000362269500014 PM 26390321 ER PT J AU Tsai, TY Li, JS Dimitriou, D Kwon, YM AF Tsai, Tsung-Yuan Li, Jing-Sheng Dimitriou, Dimitris Kwon, Young-Min TI Does component alignment affect gait symmetry in unilateral total hip arthroplasty patients? SO CLINICAL BIOMECHANICS LA English DT Article DE Total hip arthroplasty; Gait; Component alignment; Kinematics; Fluoroscope ID REPLACEMENT PATIENTS; SURGICAL APPROACH; IN-VITRO; MOTION; RANGE; KINEMATICS; WALKING; IMPINGEMENT; ORIENTATION; OFFSET AB Background: Component malposition in total hip arthroplasty patients has been associated with adverse clinical outcomes. However, whether the component alignment influences hip dynamic performance following total hip arthroplasty remains unclear. The purpose of this study was to investigate the relationship between the component alignment and in vivo hip kinematics during gait. Methods: Nineteen unilateral total hip arthroplasty patients received CT scan for creation of 3D hip models. The component alignment between the non-implanted and implanted hips were measured and compared. Three-dimensional hip kinematics for both hips of the total hip arthroplasty patients during gait was quantified using a dual fluoroscopic imaging technique. The differences between the implanted and non-implanted hip kinematics during gait were calculated. A forward stepwise multiple linear regression was performed to evaluate the relationships between the changes in implanted hip kinematics and the differences in component alignment with respect to the non-implanted hips. Findings: An average 5.1 degrees (SD 6.5 degrees; range -11.1 degrees to 18.3 degrees) increase in internal rotation was observed in the implanted hip than the contralateral non-implanted hip and significantly correlated with a linear combination of the increase of cup anteversion, cup medial translation and leg lengthening (R = 0.81). Interpretation: Results suggested that the total hip arthroplasty patients compensated the changes in hip geometry by altering the dynamic movement during gait. Restoration of the native hip geometry, including acetabular cup anteversion, position and leg length could be one of the factors that influence the hip kinematics symmetry in total hip arthroplasty patients during gait. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Tsai, Tsung-Yuan; Li, Jing-Sheng; Dimitriou, Dimitris; Kwon, Young-Min] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthopaed Surg, Boston, MA 02114 USA. RP Kwon, YM (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthopaed Surg, Boston, MA 02114 USA. EM ymkwon@mgh.harvard.edu OI Tsai, Tsung-Yuan/0000-0003-1522-2987; Dimitriou, Dimitris/0000-0002-9558-7080 FU MAKO Surgical Corp./Stryker Medical [2011P000444] FX Technical guidance of Dr. Guoan Li and Dr. Harry E. Rubash is greatly appreciated. Thanks for financial support from MAKO Surgical Corp./Stryker Medical (2011P000444). NR 42 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0268-0033 EI 1879-1271 J9 CLIN BIOMECH JI Clin. Biomech. PD OCT PY 2015 VL 30 IS 8 BP 802 EP 807 DI 10.1016/j.clinbiomech.2015.06.010 PG 6 WC Engineering, Biomedical; Orthopedics; Sport Sciences SC Engineering; Orthopedics; Sport Sciences GA CS5VH UT WOS:000362145900006 PM 26117163 ER PT J AU Pianta, A Drouin, EE Crowley, JT Arvikar, S Strle, K Costello, CE Steere, AC AF Pianta, Annalisa Drouin, Elise E. Crowley, Jameson T. Arvikar, Sheila Strle, Klemen Costello, Catherine E. Steere, Allen C. TI Annexin A2 is a target of autoimmune T and B cell responses associated with synovial fibroblast proliferation in patients with antibiotic-refractory Lyme arthritis SO CLINICAL IMMUNOLOGY LA English DT Article DE Annexin A2; Autoantigen; Lyme arthritis; Lyme disease; Borrelia burgdorferi ID RHEUMATOID-ARTHRITIS; ANTIPHOSPHOLIPID-SYNDROME; BORRELIA-BURGDORFERI; GROWTH-FACTOR; DISEASE; AUTOANTIBODIES; AUTOANTIGEN; RECEPTOR; PLASMINOGEN; ANTIBODIES AB In this study, autoantibody responses to annexin A2 were found in 11-15% of 278 patients with Lyme disease, including in those with erythema migrans (EM), an early sign of the illness, and in those with antibiotic-responsive or antibiotic-refractory Lyme arthritis (IA), a late disease manifestation. In contrast, robust T cell reactivity to annexin A2 peptides was found only in patients with responsive or refractory LA. In LA patients, annexin A2 protein levels, which were higher in the refractory group, correlated with annexin A2 antibody levels in sera and synovial fluid. In addition, in patients with antibiotic-refractory LA who had anti-annexin A2 antibodies, synovial tissue had intense staining for annexin A2 protein, greater synovial fibroblast proliferation and more tissue fibrosis. Thus, a subset of LA patients had T and B cell responses to annexin A2, and in the refractory group, annexin A2 autoantibodies were associated with specific pathologic findings. (C) 2015 Elsevier Inc. All rights reserved. C1 [Pianta, Annalisa; Drouin, Elise E.; Crowley, Jameson T.; Arvikar, Sheila; Strle, Klemen; Steere, Allen C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Immunol & Inflammatory Dis, Boston, MA USA. [Costello, Catherine E.] Boston Univ, Sch Med, Ctr Biomed Mass Spectrometry, Boston, MA 02118 USA. RP Pianta, A (reprint author), Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, CNY 149-8301,55 Fruit St, Boston, MA 02114 USA. EM apianta@mgh.harvard.edu FU NIH [RO1 AI-101175, AR-007258, K01-AR-062098]; English, Bonter, Mitchell Foundation; Ounsworth-Fitzgerald Foundation; Eshe Fund; Lyme Disease and Arthritis Research Fund at Massachusetts General Hospital FX This work was supported by a NIH grant (RO1 AI-101175), the English, Bonter, Mitchell Foundation, the Ounsworth-Fitzgerald Foundation, the Eshe Fund, and the Lyme Disease and Arthritis Research Fund at Massachusetts General Hospital. Dr. Arvikar was supported by the NIH (training grant AR-007258), and Dr. Strle was supported by the NIH (grant K01-AR-062098). NR 38 TC 7 Z9 8 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 1521-6616 EI 1521-7035 J9 CLIN IMMUNOL JI Clin. Immunol. PD OCT PY 2015 VL 160 IS 2 BP 336 EP 341 DI 10.1016/j.clim.2015.07.005 PG 6 WC Immunology SC Immunology GA CS5XL UT WOS:000362151500024 PM 26187145 ER PT J AU Rinaldi, L Vecchi, T Fantino, M Merabet, LB Cattaneo, Z AF Rinaldi, Luca Vecchi, Tomas Fantino, Micaela Merabet, Lotfi B. Cattaneo, Zaira TI The effect of hand movements on numerical bisection judgments in early blind and sighted individuals SO CORTEX LA English DT Article DE Number bisection; Blindness; Pseudoneglect; Number line; Hand movements; Lateralization ID MENTAL NUMBER LINE; VISUAL EXPERIENCE; SPATIAL REPRESENTATION; MINDS EYE; SPACE; NEGLECT; BIASES; ACTIVATION; ATTENTION; MAGNITUDE AB Recent evidence suggests that in representing numbers blind individuals might be affected differently by proprioceptive cues (e.g., hand positions, head turns) than are sighted individuals. In this study, we asked a group of early blind and sighted individuals to perform a numerical bisection task while executing hand movements in left or right peripersonal space and with either hand. We found that in bisecting ascending numerical intervals, the hemi-space in which the hand was moved (but not the moved hand itself) influenced the bisection bias similarly in both early blind and sighted participants. However, when numerical intervals were presented in descending order, the moved hand (and not the hemispace in which it was moved) affected the bisection bias in all participants. Overall, our data show that the operation to be performed on the mental number line affects the activated spatial reference frame, regardless of participants' previous visual experience. In particular, both sighted and early blind individuals representation of numerical magnitude is mainly rooted in world-centered coordinates when numerical information is given in canonical orientation (i.e., from small to large), whereas hand-centered coordinates become more relevant when the scanning of the mental number line proceeds in noncanonical direction. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Rinaldi, Luca; Cattaneo, Zaira] Univ Milano Bicocca, Dept Psychol, Milan, Italy. [Vecchi, Tomas; Cattaneo, Zaira] C Mondino Natl Neurol Inst, Brain Connect Ctr, Pavia, Italy. [Vecchi, Tomas; Fantino, Micaela] Univ Pavia, Dept Brain & Behav Sci, I-27100 Pavia, Italy. [Merabet, Lotfi B.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Lab Visual Neuroplast,Dept Ophthalmol, Boston, MA USA. RP Cattaneo, Z (reprint author), Univ Milano Bicocca, Dept Psychol, Milan, Italy. EM zaira.cattaneo@unimib.it NR 57 TC 2 Z9 2 U1 2 U2 7 PU ELSEVIER MASSON PI MILANO PA VIA PALEOCAPA 7, 20121 MILANO, ITALY SN 0010-9452 EI 1973-8102 J9 CORTEX JI Cortex PD OCT PY 2015 VL 71 BP 76 EP 84 DI 10.1016/j.cortex.2015.06.005 PG 9 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA CS5PV UT WOS:000362131300008 PM 26184675 ER PT J AU Ohtani, T Bouix, S Lyall, AE Hosokawa, T Saito, Y Melonakos, E Westin, CF Seidman, LJ Goldstein, J Mesholam-Gately, R Petryshen, T Wojcik, J Kubicki, M AF Ohtani, Toshiyuki Bouix, Sylvain Lyall, Amanda E. Hosokawa, Taiga Saito, Yukiko Melonakos, Eric Westin, Carl-Fredrik Seidman, Larry J. Goldstein, Jill Mesholam-Gately, Raquelle Petryshen, Tracey Wojcik, Joanne Kubicki, Marek TI Abnormal white matter connections between medial frontal regions predict symptoms in patients with first episode schizophrenia SO CORTEX LA English DT Article DE White matter; Fractional anisotropy; Orbitofrontal cortex; Anterior cingulate cortex; First episode schizophrenia ID ANTERIOR CINGULATE CORTEX; RECENT-ONSET SCHIZOPHRENIA; DIFFUSION TENSOR; 1ST-EPISODE SCHIZOPHRENIA; ORBITOFRONTAL CORTEX; CORPUS-CALLOSUM; AUDITORY HALLUCINATIONS; FUNCTIONAL NEUROANATOMY; NONVERBAL TASK; PSYCHOSIS AB Introduction: The medial orbitofrontal cortex (mOFC) and rostral part of anterior cingulate cortex (rACC) have been suggested to be involved in the neural network of salience and emotional processing, and associated with specific clinical symptoms in schizophrenia. Considering the schizophrenia dysconnectivity hypothesis, the connectivity abnormalities between mOFC and rACC might be associated with clinical characteristics in first episode schizophrenia patients (FESZ). Methods: After parcellating mOFC into the anterior and posterior part, diffusion properties of the mOFC-rACC white matter connections for 21 patients with FESZ and 21 healthy controls (HCs) were examined using stochastic tractography, one of the most effective Diffusion Tensor Imaging (DTI) methods for examining tracts between adjacent gray matter (GM) regions. Results: Fractional anisotropy (FA) reductions were observed in bilateral posterior, but not anterior mOFC-rACC connections (left: p < .0001; right: p < .0001) in FESZ compared to HCs. In addition, reduced FA in the left posterior mOFC-rACC connection was associated with more severe anhedonia-asociality (rho = -.633, p = .006) and total score (rho = -.520, p = .032) in the Scale for the Assessment of Negative Symptoms (SANS); reduced FA in the right posterior mOFC-rACC connection was associated with more severe affective flattening (rho = -.644, p = .005), total score (rho = -.535, p = .027) in SANS, hallucinations (rho = -.551, p = .018), delusions (rho = -.632, p = .005) and total score (rho = -.721, p = .001) in the Scale for the Assessment of Positive Symptoms (SAPS) in FESZ. Conclusions: The observed white matter abnormalities within the connections between mOFC and rACC might be associated with the psychopathology of the early stage of schizophrenia. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Ohtani, Toshiyuki; Bouix, Sylvain; Lyall, Amanda E.; Hosokawa, Taiga; Saito, Yukiko; Melonakos, Eric; Kubicki, Marek] Harvard Univ, Brigham & Womens Hosp, Sch Med, Psychiat Neuroimaging Lab,Dept Psychiat, Boston, MA 02115 USA. [Ohtani, Toshiyuki; Hosokawa, Taiga; Kubicki, Marek] VA Boston Healthcare Syst, Boston, MA USA. [Seidman, Larry J.; Mesholam-Gately, Raquelle] Harvard Univ, Beth Israel Deaconess Med Ctr, Massachusetts Mental Hlth Ctr, Publ Psychiat Div,Dept Psychiat,Sch Med, Boston, MA 02215 USA. [Seidman, Larry J.; Goldstein, Jill; Wojcik, Joanne] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Petryshen, Tracey] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Boston, MA USA. [Petryshen, Tracey] Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Westin, Carl-Fredrik] Harvard Univ, Brigham & Womens Hosp, Sch Med, Surg Planning Lab,MRI Div,Dept Radiol, Boston, MA 02115 USA. [Ohtani, Toshiyuki] Chiba Univ, Safety & Hlth Org, Chiba, Chiba, Japan. [Hosokawa, Taiga] Tsuchida Hosp, Tokyo, Japan. [Saito, Yukiko] Kansai Med Univ, Dept Neuropsychiat, Moriguchi, Osaka 570, Japan. RP Kubicki, M (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Psychiat Neuroimaging Lab,Dept Psychiat, Boston, MA 02115 USA. EM kubicld@bwh.harvard.edu OI Melonakos, Eric D./0000-0002-3643-9838 FU National Institute of Health [K05 MH070047, R01AG042512, R01MH102377, R01 MH 50740, R01 MH 40799, R01 MH 082918, R01MH 074794, P50MH 080272, 1P50MH080272-01]; VA Schizophrenia Center Grant; National Alliance for Medical Image Computing (NAMIC); National Institutes of Health through the NIH Roadmap for Medical Research [U54 EB005149]; NIH [P41 RR013218]; Center for Integration of Medicine and Innovative Technology Soldier in Medicine Award FX We gratefully acknowledge the support of the National Institute of Health (K05 MH070047, R01AG042512, R01MH102377, R01 MH 50740, R01 MH 40799, R01 MH 082918, R01MH 074794, P50MH 080272, 1P50MH080272-01, the VA Schizophrenia Center Grant. This work is also part of the National Alliance for Medical Image Computing (NAMIC), funded by the National Institutes of Health through the NIH Roadmap for Medical Research, Grant U54 EB005149, and is also supported by NIH Grant P41 RR013218 to the Neuroimage Analysis Center. In addition, the work has been supported by the Center for Integration of Medicine and Innovative Technology Soldier in Medicine Award. NR 82 TC 4 Z9 5 U1 2 U2 12 PU ELSEVIER MASSON PI MILANO PA VIA PALEOCAPA 7, 20121 MILANO, ITALY SN 0010-9452 EI 1973-8102 J9 CORTEX JI Cortex PD OCT PY 2015 VL 71 BP 264 EP 276 DI 10.1016/j.cortex.2015.05.028 PG 13 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA CS5PV UT WOS:000362131300024 PM 26277547 ER PT J AU Mannel, C Meyer, L Wilcke, A Boltze, J Kirsten, H Friederici, AD AF Maennel, Claudia Meyer, Lars Wilcke, Arndt Boltze, Johannes Kirsten, Holger Friederici, Angela D. TI Working-memory endophenotype and dyslexia-associated genetic variant predict dyslexia phenotype SO CORTEX LA English DT Article DE Developmental dyslexia; Genetic risk; Gray matter; Posterior temporal cortex; Working memory ID VOXEL-BASED MORPHOMETRY; TUMOR-NECROSIS-FACTOR; VISUAL WORD RECOGNITION; SHORT-TERM-MEMORY; WHITE-MATTER STRUCTURE; PREDATE READING ONSET; DEVELOPMENTAL DYSLEXIA; FUNCTIONAL NEUROANATOMY; SPEECH-PERCEPTION; CONNECTIONIST MODELS AB Developmental dyslexia, a severe impairment of literacy acquisition, is known to have a neurological basis and a strong genetic background. However, effects of individual genetic variations on dyslexia-associated deficits are only moderate and call for the assessment of the genotype's impact on mediating neuro-endophenotypes by the imaging genetics approach. Using voxel-based morphometry (VBM) in German participants with and without dyslexia, we investigated gray matter changes and their association with impaired phonological processing, such as reduced verbal working memory. These endophenotypical alterations were, together with dyslexia-associated genetic variations, examined on their suitability as potential predictors of dyslexia. We identified two gray matter clusters in the left posterior temporal cortex related to verbal working memory capacity. Regional cluster differences correlated with genetic risk variants in TNFRSF1B. High-genetic-risk participants exhibit a structural predominance of auditory-association areas relative to auditory-sensory areas, which may partly compensate for deficient early auditory-sensory processing stages of verbal working memory. The reverse regional predominance observed in low-genetic-risk participants may in turn reflect reliance on these early auditorysensory processing stages. Logistic regression analysis further supported that regional gray matter differences and genetic risk interact in the prediction of individuals' diagnostic status: With increasing genetic risk, the working-memory related structural predominance of auditory-association areas relative to auditory-sensory areas classifies participants with dyslexia versus control participants. Focusing on phonological deficits in dyslexia, our findings suggest endophenotypical changes in the left posterior temporal cortex could comprise novel pathomechanisms for verbal working memory-related processes translating TNFRSF1B genotype into the dyslexia phenotype. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Maennel, Claudia; Meyer, Lars; Friederici, Angela D.] Max Planck Inst Human Cognit & Brain Sci, Dept Neuropsychol, D-04103 Leipzig, Germany. [Wilcke, Arndt; Boltze, Johannes; Kirsten, Holger] Fraunhofer Inst Cell Therapy & Immunol, Leipzig, Germany. [Wilcke, Arndt; Boltze, Johannes; Kirsten, Holger] Univ Leipzig, Translat Ctr Regenerat Med, D-04109 Leipzig, Germany. [Boltze, Johannes] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Boltze, Johannes] Harvard Univ, Sch Med, Boston, MA USA. [Kirsten, Holger] Univ Leipzig, IMISE, D-04109 Leipzig, Germany. RP Mannel, C (reprint author), Max Planck Inst Human Cognit & Brain Sci, Dept Neuropsychol, Stephanstr 1a, D-04103 Leipzig, Germany. EM maennel@cbs.mpg.de OI Mannel, Claudia/0000-0003-0678-4697; Meyer, Lars/0000-0002-7487-5518 FU Max Planck Society; German Federal Ministry of Education and Research [PtJ-Bio 0315883] FX We thank Anke Kummer, Mandy Jochemko, and Domenica Wilfing for imaging data acquisition, and Elfi Quente for technical assistance. This work was supported by the Max Planck Society (C. M., L. M., and A. F.) and the German Federal Ministry of Education and Research (H. K. and A. W., grant number PtJ-Bio 0315883). NR 172 TC 3 Z9 3 U1 4 U2 22 PU ELSEVIER MASSON PI MILANO PA VIA PALEOCAPA 7, 20121 MILANO, ITALY SN 0010-9452 EI 1973-8102 J9 CORTEX JI Cortex PD OCT PY 2015 VL 71 BP 291 EP 305 DI 10.1016/j.cortex.2015.06.029 PG 15 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA CS5PV UT WOS:000362131300026 PM 26283516 ER PT J AU Izamis, ML Perk, S Calhoun, C Uygun, K Yarmush, ML Berthiaume, F AF Izamis, Maria-Louisa Perk, Sinem Calhoun, Candice Uygun, Korkut Yarmush, Martin L. Berthiaume, Francois TI Machine perfusion enhances hepatocyte isolation yields from ischemic livers SO CRYOBIOLOGY LA English DT Article DE Perfusion; UW; Williams E; Vasosol; Lifor; Hepatocytes; Viscosity; Temperature; Isolation ID MONITORING BATCH PROCESSES; NORMOTHERMIC EXTRACORPOREAL PERFUSION; SATURATED LIFOR SOLUTION; PIG ISOLATED HEARTS; CELL TRANSPLANTATION; ORGAN PRESERVATION; DONOR LIVER; LOW-FLOW; VIVO; 26-DEGREES-C AB Background: High-quality human hepatocytes form the basis of drug safety and efficacy tests, cell-based therapies, and bridge-to-transplantation devices. Presently the only supply of cells derives from an inadequate pool of suboptimal disqualified donor livers. Here we evaluated whether machine perfusion could ameliorate ischemic injury that many of these livers experience prior to hepatocyte isolation. Methods: Non-heparinized female Lewis rat livers were exposed to an hour of warm ischemia (34 degrees C) and then perfused for 3 h. Five different perfusion conditions that utilized the cell isolation apparatus were investigated, namely: (1) modified Williams Medium E and (2) Lifor, both with active oxygenation (95%O-2/5%CO2), as well as (3) Lifor passively oxygenated with ambient air (21%O-2/0.04%CO2), all at ambient temperatures (20 +/- 2 degrees C). At hypothermic temperatures, (5 +/- 1 degrees C) and under passive oxygenation were (4) University of Wisconsin solution (MN) and (5) Vasosol. Negative and positive control groups comprised livers that had ischemia (WI) and livers that did not (Fresh) prior to cell isolation, respectively. Results: Fresh livers yielded 32 +/- 9 million cells/g liver while an hour of ischemia reduced the cell yield to 1.6 +/- 0.6 million cells/g liver. Oxygenated Williams Medium E and Lifor recovered yields of 39 +/- 11 and 31 +/- 2.3 million cells/g liver, respectively. The passively oxygenated groups produced 15 +/- 7 (Lifor), 13 +/- 7 (Vasosol), and 10 +/- 6 (UW) million cells/g liver. Oxygenated Williams Medium E was most effective at sustaining pH values, avoiding the accumulation of lactate, minimizing edematous weight gain and producing bile during perfusion. Conclusions: Machine perfusion results in a dramatic increase in cell yields from livers that have had up to an hour of warm ischemia, but perfusate choice significantly impacts the extent of recovery. Oxygenated Williams Medium E at room temperature is superior to Lifor, UW and Vasosol, largely facilitated by its high oxygen content and low viscosity. (C) 2015 Elsevier Inc. All rights reserved. C1 [Izamis, Maria-Louisa; Perk, Sinem; Calhoun, Candice; Uygun, Korkut; Yarmush, Martin L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn Med Surg Serv, Boston, MA 02114 USA. [Yarmush, Martin L.; Berthiaume, Francois] Rutgers State Univ, Dept Biomed Engn, Piscataway, NJ 08854 USA. RP Yarmush, ML (reprint author), Rutgers State Univ, Dept Biomed Engn, 599 Taylor Rd, Piscataway, NJ 08854 USA. EM mizamis@mgh.harvard.edu; perksin@gmail.com; Calhoun.ck@gmail.com; uygun.korkut@mgh.harvard.edu; ireis@sbi.org; fberthia@rci.rutgers.edu FU US National Institutes of Health [R01DK59766, R01 DK096075, R00DK08896]; Shriners Hospitals for Children; Lifeblood Medical Inc. FX Funding from the US National Institutes of Health (R01DK59766, R01 DK096075, R00DK088962), the Shriners Hospitals for Children, and Lifeblood Medical Inc. is gratefully acknowledged. NR 55 TC 0 Z9 1 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0011-2240 EI 1090-2392 J9 CRYOBIOLOGY JI Cryobiology PD OCT PY 2015 VL 71 IS 2 BP 244 EP 255 DI 10.1016/j.cryobiol.2015.07.006 PG 12 WC Biology; Physiology SC Life Sciences & Biomedicine - Other Topics; Physiology GA CS8BU UT WOS:000362311500007 PM 26188080 ER PT J AU Cheung, EJ Chuang, GS Grassi, AM AF Cheung, Evelyn J. Chuang, Gary S. Grassi, Anita M. TI Cutaneous and Mucosal Manifestations of Hereditary Hemorrhagic Telangiectasia Treated With Pulsed Dye Laser SO DERMATOLOGIC SURGERY LA English DT Letter C1 [Cheung, Evelyn J.; Chuang, Gary S.; Grassi, Anita M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dermatol Laser & Cosmet Ctr, Boston, MA 02138 USA. [Chuang, Gary S.] Tufts Med Ctr, Dept Dermatol, Boston, MA USA. RP Cheung, EJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dermatol Laser & Cosmet Ctr, Boston, MA 02138 USA. NR 5 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 1076-0512 EI 1524-4725 J9 DERMATOL SURG JI Dermatol. Surg. PD OCT PY 2015 VL 41 IS 10 BP 1186 EP 1188 DI 10.1097/DSS.0000000000000445 PG 3 WC Dermatology; Surgery SC Dermatology; Surgery GA CS5LS UT WOS:000362120200016 PM 26336056 ER PT J AU Fisichella, PM Ramirez, M Patti, MG AF Fisichella, P. Marco Ramirez, Mauricio Patti, Marco G. TI An underappreciated cause of intermittent chest pain, asthma, and iron deficiency anaemia SO DIGESTIVE AND LIVER DISEASE LA English DT Editorial Material C1 [Fisichella, P. Marco] Brigham & Womens Hosp, Dept Surg, Boston VA Hlth Care Syst, Boston, MA 02115 USA. [Ramirez, Mauricio; Patti, Marco G.] Univ Chicago, Pritzker Sch Med, Dept Surg, Chicago, IL 60637 USA. [Ramirez, Mauricio; Patti, Marco G.] Univ Chicago, Pritzker Sch Med, Ctr Esophageal Dis, Chicago, IL 60637 USA. RP Fisichella, PM (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Surg,Boston VA Healthcare Syst, 1400 VFW Pkwy, West Roxbury, MA 02132 USA. EM piero.fisichella@va.gov OI Fisichella, P. Marco/0000-0002-7697-7884 NR 1 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 1590-8658 EI 1878-3562 J9 DIGEST LIVER DIS JI Dig. Liver Dis. PD OCT PY 2015 VL 47 IS 10 BP 897 EP 897 DI 10.1016/j.dld.2015.05.015 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CS1RZ UT WOS:000361846700015 PM 26089035 ER PT J AU Nomoto, H Kondo, T Miyoshi, H Nakamura, A Hida, Y Yamashita, K Sharma, AJ Atsumi, T AF Nomoto, Hiroshi Kondo, Takuma Miyoshi, Hideaki Nakamura, Akinobu Hida, Yoko Yamashita, Ken-ichiro Sharma, Arun J. Atsumi, Tatsuya TI Inhibition of Small Maf Function in Pancreatic beta-Cells Improves Glucose Tolerance Through the Enhancement of Insulin Gene Transcription and Insulin Secretion SO ENDOCRINOLOGY LA English DT Article ID MOLECULE GLUCOKINASE ACTIVATOR; CHRONIC EXPOSURE; TRANSGENIC MICE; EXPRESSION; PROTEINS; RIPE3B1; BINDING; DIFFERENTIATION; PROLIFERATION; HETERODIMER AB The large-Maf transcription factor v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA) has been found to be crucial for insulin transcription and synthesis and for pancreatic beta-cell function and maturation. However, insights about the effects of small Maf factors on beta-cells are limited. Our goal was to elucidate the function of small-Maf factors on beta-cells using an animal model of endogenous small-Maf dysfunction. Transgenic (Tg) mice with beta-cell-specific expression of dominant-negative MafK (DN-MafK) experiments, which can suppress the function of all endogenous small-Mafs, were fed a high-fat diet, and their in vivo phenotypes were evaluated. Phenotypic analysis, glucose tolerance tests, morphologic examination of beta-cells, and islet experiments were performed. DN-MafK-expressed MIN6 cells were also used for in vitro analysis. The results showed that DN-MafK expression inhibited endogenous small-Maf binding to insulin promoter while increasing MafA binding. DN-MafK Tg mice under high-fat diet conditions showed improved glucose metabolism compared with control mice via incremental insulin secretion, without causing changes in insulin sensitivity or MafA expression. Moreover, up-regulation of insulin and glucokinase gene expression was observed both in vivo and in vitro under DN-MafK expression. We concluded that endogenous small-Maf factors negatively regulates beta-cell function by competing for MafA binding, and thus, the inhibition of small-Maf activity can improve beta-cell function. C1 [Nomoto, Hiroshi; Kondo, Takuma; Miyoshi, Hideaki; Nakamura, Akinobu; Hida, Yoko; Atsumi, Tatsuya] Hokkaido Univ, Grad Sch Med, Div Rheumatol Endocrinol & Nephrol, Sapporo, Hokkaido 0608638, Japan. [Yamashita, Ken-ichiro] Hokkaido Univ, Grad Sch Med, Dept Transplant Surg, Sapporo, Hokkaido 0608638, Japan. [Sharma, Arun J.] Joslin Diabet Ctr, Sect Islet Transplantat & Cell Biol, Boston, MA 02215 USA. [Sharma, Arun J.] MedImmune LLC, Gaithersburg, MD 20878 USA. RP Kondo, T (reprint author), Hokkaido Univ, Grad Sch Med, Div Rheumatol Endocrinol & Nephrol, Kita Ku, North 15,West 7, Sapporo, Hokkaido 0608638, Japan. EM takkondo@med.hokudai.ac.jp FU Japanese Ministry of Education, Culture, Sports, Science, Technology Foundation; Suzuken Memorial Foundation; National Institutes of Health [RO1 DK60127] FX This work was supported by grants from the Japanese Ministry of Education, Culture, Sports, Science, Technology Foundation and the Suzuken Memorial Foundation (H.M.) and by the National Institutes of Health Grant RO1 DK60127 (to A.J.S.). NR 33 TC 2 Z9 2 U1 0 U2 3 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD OCT PY 2015 VL 156 IS 10 BP 3570 EP 3580 DI 10.1210/en.2014-1906 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CS7AG UT WOS:000362235300025 PM 25763640 ER PT J AU Ni, JQ Wood, K Wang, X Li, GA AF Ni, Jianqiang Wood, Kirkham B. Wang, Xin Li, Guoan TI Letter to the Editor concerning "ALIF and total disc replacement versus 2-level circumferential fusion with TLIF: a prospective, randomized, clinical and radiological trial" by Hoff EK, Strube P, Pumberger M et al. (2015). Eur Spine J. Mar 7. [Epub ahead of print] SO EUROPEAN SPINE JOURNAL LA English DT Letter ID GUIDELINE C1 [Ni, Jianqiang; Wang, Xin] Qingdao Univ, Yuhungding Hosp, Dept Orthoped, Qingdao, Shandong, Peoples R China. [Ni, Jianqiang; Wood, Kirkham B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthoped, Boston, MA 02114 USA. [Li, Guoan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthopaed Surg,Bioengn Lab, Boston, MA 02114 USA. RP Ni, JQ (reprint author), Qingdao Univ, Yuhungding Hosp, Dept Orthoped, Qingdao, Shandong, Peoples R China. EM njqspine@163.com NR 5 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0940-6719 EI 1432-0932 J9 EUR SPINE J JI Eur. Spine J. PD OCT PY 2015 VL 24 IS 10 BP 2345 EP 2346 DI 10.1007/s00586-015-3967-1 PG 2 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA CS8FC UT WOS:000362320200038 PM 25900298 ER PT J AU Li, YR van Setten, J Verma, SS Lu, YT Holmes, MV Gao, H Lek, M Nair, N Chandrupatla, H Chang, BL Karczewski, KJ Wong, C Mohebnasab, M Mukhtar, E Phillips, R Tragante, V Hou, CP Steel, L Lee, T Garifallou, J Guettouche, T Cao, HZ Guan, WH Himes, A van Houten, J Pasquier, A Yu, RN Carrigan, E Miller, MB Schladt, D Akdere, A Gonzalez, A Llyod, KM McGinn, D Gangasani, A Michaud, Z Colasacco, A Snyder, J Thomas, K Wang, TC Wu, BL Alzahrani, AJ Al-Ali, AK Al-Muhanna, FA Al-Rubaish, AM Al-Mueilo, S Monos, DS Murphy, B Olthoff, KM Wijmenga, C Webster, T Kamoun, M Balasubramanian, S Lanktree, MB Oetting, WS Garcia-Pavia, P MacArthur, DG de Bakker, PIW Hakonarson, H Birdwell, KA Jacobson, PA Ritchie, MD Asselbergs, FW Israni, AK Shaked, A Keating, BJ AF Li, Yun R. van Setten, Jessica Verma, Shefali S. Lu, Yontao Holmes, Michael V. Gao, Hui Lek, Monkol Nair, Nikhil Chandrupatla, Hareesh Chang, Baoli Karczewski, Konrad J. Wong, Chanel Mohebnasab, Maede Mukhtar, Eyas Phillips, Randy Tragante, Vinicius Hou, Cuiping Steel, Laura Lee, Takesha Garifallou, James Guettouche, Toumy Cao, Hongzhi Guan, Weihua Himes, Aubree van Houten, Jacob Pasquier, Andrew Yu, Reina Carrigan, Elena Miller, Michael B. Schladt, David Akdere, Abdullah Gonzalez, Ana Llyod, Kelsey M. McGinn, Daniel Gangasani, Abhinav Michaud, Zach Colasacco, Abigail Snyder, James Thomas, Kelly Wang, Tiancheng Wu, Baolin Alzahrani, Alhusain J. Al-Ali, Amein K. Al-Muhanna, Fahad A. Al-Rubaish, Abdullah M. Al-Mueilo, Samir Monos, Dimitri S. Murphy, Barbara Olthoff, Kim M. Wijmenga, Cisca Webster, Teresa Kamoun, Malek Balasubramanian, Suganthi Lanktree, Matthew B. Oetting, William S. Garcia-Pavia, Pablo MacArthur, Daniel G. de Bakker, Paul I. W. Hakonarson, Hakon Birdwell, Kelly A. Jacobson, Pamala A. Ritchie, Marylyn D. Asselbergs, Folkert W. Israni, Ajay K. Shaked, Abraham Keating, Brendan J. TI Concept and design of a genome-wide association genotyping array tailored for transplantation-specific studies SO GENOME MEDICINE LA English DT Article ID KIDNEY-TRANSPLANTATION; SNP ARRAY; GENE; POLYMORPHISMS; RECIPIENTS; POPULATION; MISMATCH; MANAGEMENT; IMPUTATION; REJECTION AB Background: In addition to HLA genetic incompatibility, non-HLA difference between donor and recipients of transplantation leading to allograft rejection are now becoming evident. We aimed to create a unique genome-wide platform to facilitate genomic research studies in transplant-related studies. We designed a genome-wide genotyping tool based on the most recent human genomic reference datasets, and included customization for known and potentially relevant metabolic and pharmacological loci relevant to transplantation. Methods: We describe here the design and implementation of a customized genome-wide genotyping array, the 'TxArray', comprising approximately 782,000 markers with tailored content for deeper capture of variants across HLA, KIR, pharmacogenomic, and metabolic loci important in transplantation. To test concordance and genotyping quality, we genotyped 85 HapMap samples on the array, including eight trios. Results: We show low Mendelian error rates and high concordance rates for HapMap samples (average parent-parent-child heritability of 0.997, and concordance of 0.996). We performed genotype imputation across autosomal regions, masking directly genotyped SNPs to assess imputation accuracy and report an accuracy of >0.962 for directly genotyped SNPs. We demonstrate much higher capture of the natural killer cell immunoglobulin-like receptor (KIR) region versus comparable platforms. Overall, we show that the genotyping quality and coverage of the TxArray is very high when compared to reference samples and to other genome-wide genotyping platforms. Conclusions: We have designed a comprehensive genome-wide genotyping tool which enables accurate association testing and imputation of ungenotyped SNPs, facilitating powerful and cost-effective large-scale genotyping of transplant-related studies. C1 [Li, Yun R.; Akdere, Abdullah; Gonzalez, Ana; Llyod, Kelsey M.; McGinn, Daniel; Gangasani, Abhinav; Michaud, Zach; Colasacco, Abigail] Univ Penn, Perelman Sch Med, Med Scientist Training Program, Philadelphia, PA 19104 USA. [Li, Yun R.; Gao, Hui; Nair, Nikhil; Chandrupatla, Hareesh; Chang, Baoli; Wong, Chanel; Mohebnasab, Maede; Mukhtar, Eyas; Phillips, Randy; Hou, Cuiping; Steel, Laura; Lee, Takesha; Garifallou, James; Guettouche, Toumy; Himes, Aubree; van Houten, Jacob; Pasquier, Andrew; Yu, Reina; Carrigan, Elena; Snyder, James; Thomas, Kelly; Wang, Tiancheng; Monos, Dimitri S.; Hakonarson, Hakon; Keating, Brendan J.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [van Setten, Jessica; Tragante, Vinicius; Asselbergs, Folkert W.] Univ Med Ctr Utrecht, Div Heart & Lungs, Dept Cardiol, Utrecht, Netherlands. [Lu, Yontao; Webster, Teresa] Affymetrix Inc, Santa Clara, CA USA. [Holmes, Michael V.; Gao, Hui; Nair, Nikhil; Chandrupatla, Hareesh; Chang, Baoli; Wong, Chanel; Mukhtar, Eyas; Phillips, Randy; Steel, Laura; Lee, Takesha; Himes, Aubree; Olthoff, Kim M.; Lanktree, Matthew B.; Shaked, Abraham; Keating, Brendan J.] Hosp Univ Penn, Penn Transplant Inst, Philadelphia, PA 19104 USA. [Verma, Shefali S.; Ritchie, Marylyn D.] Penn State Univ, Ctr Syst Genom, University Pk, PA 16802 USA. [Lek, Monkol; Karczewski, Konrad J.; MacArthur, Daniel G.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Lek, Monkol; Karczewski, Konrad J.; MacArthur, Daniel G.] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Ctr Mol Med, Dept Med Genet, Utrecht, Netherlands. [de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Dept Epidemiol, Utrecht, Netherlands. [Cao, Hongzhi] BGI Shenzhen, Shenzhen, Peoples R China. [Cao, Hongzhi] Univ Copenhagen, Dept Biol, Copenhagen, Denmark. [Guan, Weihua; Wu, Baolin] Univ Minnesota, Div Biostat, Minneapolis, MN USA. [Miller, Michael B.] Univ Minnesota, Dept Psychol, Minneapolis, MN 55455 USA. [Al-Ali, Amein K.; Al-Muhanna, Fahad A.; Al-Rubaish, Abdullah M.; Al-Mueilo, Samir] Univ Dammam, Coll Med, Dammam, Saudi Arabia. [Monos, Dimitri S.; Kamoun, Malek] Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Monos, Dimitri S.; Kamoun, Malek] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Murphy, Barbara] Icahn Sch Med Mt Sinai, Div Nephrol, New York, NY 10029 USA. [Murphy, Barbara] Icahn Sch Med Mt Sinai, Dept Med, New York, NY 10029 USA. [Wijmenga, Cisca] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9713 AV Groningen, Netherlands. [Balasubramanian, Suganthi] Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT USA. [Balasubramanian, Suganthi] Yale Univ, Dept Biochem & Mol Biophys, New Haven, CT USA. [Oetting, William S.] Univ Minnesota, Expt & Clin Pharmacol, Minneapolis, MN USA. [Garcia-Pavia, Pablo] Hosp Univ Puerta de Hierro Majadahonda, Dept Cardiol, Heart Failure & Inherited Cardiac Dis Unit, Madrid, Spain. [Birdwell, Kelly A.] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Jacobson, Pamala A.] Univ Minnesota, Coll Pharm, Minneapolis, MN 55455 USA. [Asselbergs, Folkert W.] ICIN Netherlands Heart Inst, Durrer Ctr Cardiogenet Res, Utrecht, Netherlands. [Asselbergs, Folkert W.] UCL, Fac Populat Hlth Sci, Inst Cardiovasc Sci, London, England. [Alzahrani, Alhusain J.] King Saud Univ, Coll Appl Med Sci, Dept Clin Labs Sci, Riyadh, Saudi Arabia. [Schladt, David] Hennepin Cty Med Ctr, Minneapolis Med Res Fd, Minneapolis, MN 55415 USA. [Israni, Ajay K.] Univ Minnesota, Hennepin Cty Med Ctr, Minneapolis, MN 55415 USA. [Keating, Brendan J.] Univ Penn, Dept Pediat, Philadelphia, PA 19104 USA. [Keating, Brendan J.] Hosp Univ Penn, Div Transplantat, Philadelphia, PA 19104 USA. RP Keating, BJ (reprint author), Hosp Univ Penn, Penn Transplant Inst, 3400 Spruce St, Philadelphia, PA 19104 USA. EM bkeating@mail.med.upenn.edu RI Wijmenga, Cisca/D-2173-2009; OI Birdwell, Kelly/0000-0002-7996-3947; Karczewski, Konrad/0000-0003-2878-4671 FU Fundacion Mutua Madrilena, Spain - Dutch PLN Foundation; UCL Hospitals NIHR Biomedical Research Centre; Dekker scholarship - Netherlands Heart Foundation [2014T001]; Deanship of Scientific Research at King Saud University, Riyadh; NIH [U01 HG006830, U01-DK062494, UM1AI109565, U01-AI63589, U19-AI070119] FX We would like to thank the patients and their families for their participation in the genotyping studies. We are also very thankful for the contributions of the all of the study coordinators and clinicians from the respective studies that made collection of these DNA samples and phenotyping possible. This project was funded in part by Fundacion Mutua Madrilena, Spain. Part of this work is also supported by the Dutch PLN Foundation (www.stichtingpln.nl). Folkert W. Asselbergs is supported by UCL Hospitals NIHR Biomedical Research Centre and by a Dekker scholarship-Junior Staff Member 2014T001 - Netherlands Heart Foundation. Partial funding was also provided by the Deanship of Scientific Research at King Saud University, Riyadh. We also acknowledge funding from the following NIH grants: U01 HG006830; U01-DK062494; UM1AI109565; U01-AI63589 and U19-AI070119. NR 50 TC 3 Z9 3 U1 1 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-994X J9 GENOME MED JI Genome Med. PD OCT 1 PY 2015 VL 7 AR 90 DI 10.1186/s13073-015-0211-x PG 13 WC Genetics & Heredity SC Genetics & Heredity GA CS4VW UT WOS:000362075200001 PM 26423053 ER PT J AU Hoybye, C Cohen, P Hoffman, AR Ross, R Biller, BMK Christiansen, JS AF Hoybye, Charlotte Cohen, Pinchas Hoffman, Andrew R. Ross, Richard Biller, Beverly M. K. Christiansen, Jens Sandahl CA Growth Hormone Res Soc TI Status of long-acting-growth hormone preparations-2015 SO GROWTH HORMONE & IGF RESEARCH LA English DT Review DE Growth hormone; Growth hormone deficiency; Growth hormone treatment; Long-acting growth hormone preparations ID GH-DEFICIENT ADULTS; PREPARATION NUTROPIN DEPOT; WEEKLY TREATMENT PROFILE; PHARMACODYNAMIC CHARACTERISTICS; DOUBLE-BLIND; HALF-LIFE; WEEKLY IM; CHILDREN; RELEASE; INJECTIONS AB Growth hormone (GH) treatment has been an established therapy for GH deficiency (GHD) in children and adults for more than three decades. Numerous studies have shown that GH treatment improves height, body composition, bone density, cardiovascular risk factors, physical fitness and quality of life and that the treatment has few side effects. Initially GH was given as intramuscular injections three times per week, but daily subcutaneous injections were shown to be more effective and less inconvenient and the daily administration has been used since its introduction in the 1980s. However, despite ongoing improvements in injection device design, daily subcutaneous injections remain inconvenient, painful and distressing for many patients, leading to noncompliance, reduced efficacy and increased health care costs. To address these issues a variety of long-acting formulations of GH have been developed. In this review we present the current status of long-acting GH preparations and discuss the specific issues related to their development. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Hoybye, Charlotte] Karolinska Univ Hosp, Dept Endocrinol Metab & Diabetol, S-17176 Stockholm, Sweden. [Hoybye, Charlotte] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. [Cohen, Pinchas] Univ So Calif, Leonard Davis Sch Gerontol, Los Angeles, CA 90089 USA. [Hoffman, Andrew R.] VA Palo Alto Hlth Care Syst, Dept Med, Palo Alto, CA USA. [Hoffman, Andrew R.] Stanford Univ, Palo Alto, CA 94304 USA. [Ross, Richard] Univ Sheffield, Dept Human Metab, Sheffield S10 2TN, S Yorkshire, England. [Biller, Beverly M. K.] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Christiansen, Jens Sandahl] Aarhus Univ Hosp, Dept Endocrinol, MEA, NBG, DK-8000 Aarhus, Denmark. RP Hoybye, C (reprint author), Karolinska Univ Hosp, Dept Endocrinol Metab & Diabetol, S-17176 Stockholm, Sweden. EM charlotte.hoybye@karolinska.se OI Cohen, Pinchas/0000-0002-0035-8366 FU OPKO; Novartis; Novo Nordisk FX Beverly MK Biller is an investigator on research grants to Massachusetts General Hospital from OPKO, Novartis and Novo Nordisk and has received occasional consulting honoraria from Novartis, Novo Nordisk, Pfizer and Versartis. NR 56 TC 10 Z9 10 U1 3 U2 9 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1096-6374 EI 1532-2238 J9 GROWTH HORM IGF RES JI Growth Horm. IGF Res. PD OCT PY 2015 VL 25 IS 5 BP 201 EP 206 DI 10.1016/j.ghir.2015.07.004 PG 6 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA CS5SS UT WOS:000362139000001 PM 26187188 ER PT J AU Ravicz, ME Chien, WW Rosowski, JJ AF Ravicz, Michael E. Chien, Wade W. Rosowski, John J. TI Restoration of middle-ear input in fluid-filled middle ears by controlled introduction of air or a novel air-filled implant SO HEARING RESEARCH LA English DT Article DE Middle ear; Otitis media; Effusion; Implant; Aeration ID ACUTE OTITIS-MEDIA; GERBIL MERIONES-UNGUICULATUS; SOUND-POWER COLLECTION; HEXA FLUORIDE SF6; TYMPANIC MEMBRANE; HEARING-LOSS; AUDITORY PERIPHERY; GUINEA-PIGS; MODEL; MECHANICS AB The effect of small amounts of air on sound-induced umbo velocity in an otherwise saline-filled middle ear (ME) was investigated to examine the efficacy of a novel balloon-like air-filled ME implant suitable for patients with chronically non-aerated MEs. In this study, air bubbles or air-filled implants were introduced into saline-filled human cadaveric MEs. Umbo velocity, a convenient measure of ME response, served as an indicator of hearing sensitivity. Filling the ME with saline reduced umbo velocity by 25-30 dB at low frequencies and more at high frequencies, consistent with earlier work (Ravicz et al., Hear. Res. 195: 103-130 (2004)). Small amounts of air (similar to 30 mu l) in the otherwise saline-filled ME increased umbo velocity substantially, to levels only 10-15 dB lower than in the dry ME, in a frequency- and location-dependent manner: air in contact with the tympanic membrane (TM) increased umbo velocity at all frequencies, while air located away from the TM increased umbo velocity only below about 500 Hz. The air-filled implant also affected umbo velocity in a manner Similar to an air bubble of equivalent compliance. Inserting additional implants into the ME had the same effect as increasing air volume. These results suggest these middle-ear implants would significantly reduce conductive hearing loss in patients with chronically fluid-filled MEs. (C) 2015 Elsevier B.V. All rights reserved. C1 [Ravicz, Michael E.; Chien, Wade W.; Rosowski, John J.] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Ravicz, Michael E.; Chien, Wade W.; Rosowski, John J.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. RP Ravicz, ME (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, 243 Charles St, Boston, MA 02114 USA. EM Mike_Ravicz@meei.harvard.edu FU NIDCD [R01 DC004798]; MEEI Foundation FX We dedicate this manuscript to our late and beloved colleague Saumil Merchant, who was the driving force behind this project and who was taken from us suddenly and much too soon. We thank Diane Jones of the Otopathology Laboratory, Heidi Nakajima, and the staff of the Eaton-Peabody Laboratory for technical support. Supported by NIDCD R01 DC004798 and the MEEI Foundation. NR 65 TC 1 Z9 1 U1 2 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5955 EI 1878-5891 J9 HEARING RES JI Hear. Res. PD OCT PY 2015 VL 328 BP 8 EP 23 DI 10.1016/j.heares.2015.06.012 PG 16 WC Audiology & Speech-Language Pathology; Neurosciences; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Neurosciences & Neurology; Otorhinolaryngology GA CS5XQ UT WOS:000362152000002 PM 26121946 ER PT J AU Fowler, CG Chiasson, KB Colman, RJ Kemnitz, JW Beasley, TM Weindruch, RH AF Fowler, Cynthia G. Chiasson, Kirstin Beach Colman, Ricki J. Kemnitz, Joseph W. Beasley, T. Mark Weindruch, Richard H. TI Hyperinsulinemia/diabetes, hearing, and aging in the University of Wisconsin calorie restriction monkeys SO HEARING RESEARCH LA English DT Article DE Age-related hearing loss; Auditory evoked potentials; Caloric restriction; Distortion product otoacoustic emissions; Hearing; Rhesus macaque; Hyperinsulinemia; Type 2 diabetes ID PRODUCT OTOACOUSTIC EMISSIONS; DEPENDENT DIABETES-MELLITUS; RHESUS-MONKEYS; AUDITORY FUNCTION; DIETARY RESTRICTION; MACACA-MULATTA; AGE; HUMANS; ASSOCIATION; POPULATION AB The purpose of this study was to determine the effects of hyperinsulinemia/Type 2 diabetes mellitus (HI-T2DM) on hearing impairment using rhesus monkeys to obtain control over diet and lifestyle factors that confound human studies. The study is a retrospective evaluation of rhesus monkeys from the Wisconsin National Primate Research Center (WNPRC) study on caloric restriction and aging. The research questions were the following: 1. Is HI-T2DM related to hearing impairment? 2. If so, what is the site of lesion in the auditory system? and 3. What physiological factors affect the risk of hearing loss in HI-T2DM? Three groups of eight monkeys each were matched by sex and age; the caloric restricted (CR) monkeys had a reduced risk of diabetes, the normal control (NL) group had a normal risk, and the hyperinsulinemia/diabetes (HI-D) group had already developed HI-T2DM. Auditory testing included distortion product otoacoustic emissions (DPOAEs) with 12 frequencies from 2211 to 8837 Hz and auditory brainstem responses (ABRs) obtained with clicks and tone bursts (8, 16, and 32 kHz). DPOAEs had signal-to-noise ratios 8-17 dB larger in the NL group than in the HI-D and CR groups, signifying that cochlear function was best in the NL group. ABR thresholds were 5-8 dB better in the NL group than in the HI-D group, although no significant differences across the groups were evident for the thresholds, latencies, inter-wave intervals, or amplitudes. Correlations were significant for quadratic relations between body mass index (BMI) and DPOAE, with largest DPOAEs for animals in the middle of the BMI range. ABR thresholds elicited with 16 and 32 kHz signals were significantly correlated, positively with BMI and HbA1c, and negatively with K-G (glucose tolerance), S-I (insulin sensitivity index) and DI (disposition index). These findings suggest that the hearing loss associated with HI-T2DM is predominantly cochlear, and auditory structures underlying the higher frequencies are at risk with HI-T2DM. Loss of auditory function begins in the hyperinsulinemia, pre-diabetic state. (C) 2015 Elsevier B.V. All rights reserved. C1 [Fowler, Cynthia G.] Univ Wisconsin, Dept Commun Sci & Disorders, Madison, WI 53706 USA. [Chiasson, Kirstin Beach] Cascade Ear Nose Throat & Facial Plast Surg, Klamath Falls, OR USA. [Colman, Ricki J.; Kemnitz, Joseph W.] Univ Wisconsin, Wisconsin Natl Primate Res Ctr, Madison, WI 53715 USA. [Kemnitz, Joseph W.] Univ Wisconsin, Dept Cell & Regenerat Biol, Madison, WI 53715 USA. [Beasley, T. Mark] Univ Alabama Birmingham, Sch Publ Hlth, Dept Biostat, Birmingham, AL 35294 USA. [Weindruch, Richard H.] Univ Wisconsin, Dept Med, William S Middleton Mem Vet Hosp, Madison, WI 53705 USA. RP Fowler, CG (reprint author), Univ Wisconsin, Dept Commun Sci & Disorders, 1975 Willow Dr Madison, Madison, WI 53706 USA. EM cgfowler@wisc.edu; rcolman@primate.wisc.edu; kemnitz@primate.wisc.edu; mbeasley@ms.soph.uab.edu; rhweindr@wisc.edu OI Kemnitz, Joseph/0000-0001-6511-404X FU National Institutes of Health (NIH) [P01 AG 11915, P51 RR000167, RO1AG040178]; Research Facilities Improvement Program [RR15459-01, RR020141-01] FX This publication was made possible by grants P01 AG 11915, P51 RR000167, and RO1AG040178 from the National Institutes of Health (NIH). This research was conducted at a facility constructed with support from Research Facilities Improvement Program grant numbers RR15459-01 and RR020141-01. NR 37 TC 1 Z9 1 U1 2 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5955 EI 1878-5891 J9 HEARING RES JI Hear. Res. PD OCT PY 2015 VL 328 BP 78 EP 86 DI 10.1016/j.heares.2015.07.001 PG 9 WC Audiology & Speech-Language Pathology; Neurosciences; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Neurosciences & Neurology; Otorhinolaryngology GA CS5XQ UT WOS:000362152000008 PM 26163094 ER PT J AU Verrier, RL AF Verrier, Richard L. TI What can mechanics teach electricians about arrhythmias in heart failure? SO HEART RHYTHM LA English DT Editorial Material C1 [Verrier, Richard L.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. RP Verrier, RL (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Med,Div Cardiovasc Med,Harvard Thorndike Electrop, 99 Brookline Ave,RN-301, Boston, MA 02215 USA. EM rverrier@bidmc.harvard.edu NR 8 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 1547-5271 EI 1556-3871 J9 HEART RHYTHM JI Heart Rhythm PD OCT PY 2015 VL 12 IS 10 BP 2184 EP 2185 DI 10.1016/j.hrthm.2015.06.006 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CS1RK UT WOS:000361845200022 PM 26051532 ER PT J AU Cornejo, KM Dong, F Zhou, AG Wu, CL Young, RH Braaten, K Sadow, PM Nielsen, GP Oliva, E AF Cornejo, Kristine M. Dong, Fei Zhou, Amy G. Wu, Chin-Lee Young, Robert H. Braaten, Kristina Sadow, Peter M. Nielsen, G. P. Oliva, Esther TI Papillary renal cell carcinoma: correlation of tumor grade and histologic characteristics with clinical outcome SO HUMAN PATHOLOGY LA English DT Article DE Papillary renal cell carcinoma; Fuhnnan grade; International Society of Urological Pathology nucleolar grade; Prognosis; PRCC; ISUP ID PATHOLOGICAL PROGNOSTIC PARAMETERS; HISTOMORPHOLOGIC CHARACTERISTICS; MULTIVARIATE-ANALYSIS; ONCOCYTIC CELLS; SURVIVAL; FEATURES; CLASSIFICATION; UTILITY; SYSTEM; SERIES AB Histologic prognostic parameters in papillary renal cell carcinoma (PRCC) are unclear. The aims were to review the clinicopathological features of PRCC, including Fuhrman grade and International Society of Urological Pathology (ISUP) nucleolar grade, and to identify parameters that may be independent prognostic indicators. PRCCs in patients treated by nephrectomy were retrieved from the pathology files from 1984 to 2010. Parameters studied included tumor multifocality, size, PRCC type (1 or 2), Fuhrman grade, ISUP nucleolar grade, presence of necrosis, lymphovascular invasion, and stage at presentation. Cancer-specific survival (CSS) and overall survival (OS) were used as prognostic measures. Of 154 PRCCs, 112 (73%) were type 1, and 42 (27%), type 2. A total of 125 patients were male, and 29, female, with ages from 26 to 86 (mean, 62.7) years Fuhnnan grade was 1 in 8 (5%), 2 in 95 (62%), 3 in 49 (32%), and 4 in 2 (1%) tumors, respectively. ISUP nucleolar grade was 1 in 47 (31%), 2 in 56 (36%), 3 in 49 (32%), and 4 in 2 (1%) tumors, respectively. Mean follow-up interval was 73.9 months (0.13-222 months). ISUP nucleolar grade was a significant predictor of both CSS and OS in univariate (CSS, P = .001; OS, P = .004) and multivariate (CSS, P = .04; OS, P = .008) analyses, whereas Fuhrman grade was only predictive of CSS in univariate (P = .001) and multivariate (P = .04) analyses. Only ISUP nucleolar grade and lymphovascular invasion were independently prognostic for CSS and OS in univariate and multivariate analyses. Therefore, the ISUP nucleolar grade appears to be superior in predicting survival in patients with PRCC. (C) 2015 Elsevier Inc. All rights reserved. C1 [Cornejo, Kristine M.; Dong, Fei; Wu, Chin-Lee; Young, Robert H.; Braaten, Kristina; Sadow, Peter M.; Nielsen, G. P.; Oliva, Esther] Massachusetts Gen Hosp, James Homer Wright Pathol Labs, Boston, MA 02114 USA. [Cornejo, Kristine M.; Dong, Fei; Wu, Chin-Lee; Young, Robert H.; Braaten, Kristina; Sadow, Peter M.; Nielsen, G. P.; Oliva, Esther] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02114 USA. [Zhou, Amy G.] Univ Massachusetts, Sch Med, Dept Pathol, Worcester, MA 01605 USA. RP Cornejo, KM (reprint author), UMass Mem Healthcare, Dept Pathol, One Innovat Dr,Biotech 3, Worcester, MA 01605 USA. EM Kristine.Cornejo@umassmemorial.org NR 35 TC 2 Z9 2 U1 2 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0046-8177 EI 1532-8392 J9 HUM PATHOL JI Hum. Pathol. PD OCT PY 2015 VL 46 IS 10 BP 1411 EP 1417 DI 10.1016/j.humpath.2015.07.001 PG 7 WC Pathology SC Pathology GA CS4QQ UT WOS:000362061400001 PM 26297250 ER PT J AU Komatsu, Y Doi, T Sawaki, A Kanda, T Yamada, Y Kuss, I Demetri, GD Nishida, T AF Komatsu, Yoshito Doi, Toshihiko Sawaki, Akira Kanda, Tatsuo Yamada, Yasuhide Kuss, Iris Demetri, George D. Nishida, Toshirou TI Regorafenib for advanced gastrointestinal stromal tumors following imatinib and sunitinib treatment: a subgroup analysis evaluating Japanese patients in the phase III GRID trial SO INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY LA English DT Article DE Regorafenib; Japanese; Gastrointestinal stromal tumor; Hand-foot syndrome; Hypertension ID RENAL-CELL CARCINOMA; EFFICACY; SAFETY; GIST; THERAPY AB The randomized, double-blind, placebo-controlled GRID trial tested the oral multikinase inhibitor regorafenib in 199 patients with advanced gastrointestinal stromal tumors (GIST) following failure of at least imatinib and sunitinib, and showed a significant improvement in progression-free survival (PFS) versus placebo [hazard ratio (HR) 0.27; 95 % confidence interval (CI) 0.19-0.39; p < 0.0001]. A subgroup analysis of Japanese patients in the GRID study was performed to compare the efficacy and safety of oral regorafenib 160 mg once daily with matching placebo, in combination with best supportive care. The primary study endpoint was progression-free survival (PFS); safety was evaluated through the incidence of adverse events (AEs). Seventeen Japanese patients were randomized to regorafenib (n = 12) or placebo (n = 5). Patient demographics were consistent with those of the overall study population. PFS was significantly longer with regorafenib than placebo (HR 0.08; 95 % CI 0.02-0.45; p = 0.000164). Centrally assessed disease control rates were 58 % and 20 % in the regorafenib and placebo groups, respectively (p = 0.080796). Treatment-related adverse events (AEs) were reported in all regorafenib-treated patients and 60 % of placebo recipients; the most frequent AE was hand-foot skin reaction (HFSR) (92 % versus 20 %, respectively). Regorafenib showed efficacy and a manageable safety profile in Japanese patients with advanced GIST, consistent with the overall GRID study population. AEs, such as HFSR and maculopapular rash, were observed more frequently in Japanese patients. Although dose modification was frequently reported, only one patient with hepatic failure discontinued regorafenib because of AEs. C1 [Komatsu, Yoshito] Hokkaido Univ Hosp, Ctr Canc, Kita Ku, Sapporo, Hokkaido 0608648, Japan. [Doi, Toshihiko] Natl Canc Ctr, Hosp East, Kashiwa, Chiba, Japan. [Sawaki, Akira] Nagoya Second Red Cross Hosp, Dept Oncol & Gastroenterol, Nagoya, Aichi, Japan. [Kanda, Tatsuo] Niigata Univ, Div Digest & Gen Surg, Sch Med & Dent Sci, Niigata, Japan. [Yamada, Yasuhide] Natl Canc Ctr, Gastrointestinal Oncol Div, Tokyo, Japan. [Kuss, Iris] Bayer Pharma AG, Global Clin Dev Oncol Ophthalmol & Neurol, Berlin, Germany. [Demetri, George D.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Ludwig Canc Ctr, Boston, MA 02115 USA. [Nishida, Toshirou] Natl Canc Ctr, Hosp East, Dept Surg, Kashiwa, Chiba, Japan. RP Komatsu, Y (reprint author), Hokkaido Univ Hosp, Ctr Canc, Kita Ku, Kita 14 Nishi 5, Sapporo, Hokkaido 0608648, Japan. EM ykomatsu@ac.cyberhome.ne.jp FU Bayer Health Care Pharmaceuticals FX We thank the participating patients and staff at each of the study centers. Editorial assistance in the preparation of this manuscript was provided by Succinct Medical Communications, with financial support from Bayer Health Care Pharmaceuticals; the authors retained editorial control over the content. NR 19 TC 4 Z9 5 U1 0 U2 2 PU SPRINGER JAPAN KK PI TOKYO PA CHIYODA FIRST BLDG EAST, 3-8-1 NISHI-KANDA, CHIYODA-KU, TOKYO, 101-0065, JAPAN SN 1341-9625 EI 1437-7772 J9 INT J CLIN ONCOL JI Int. J. Clin. Oncol. PD OCT PY 2015 VL 20 IS 5 BP 905 EP 912 DI 10.1007/s10147-015-0790-y PG 8 WC Oncology SC Oncology GA CS3VC UT WOS:000362002200009 PM 25655899 ER PT J AU Rosenbaum, BL Bui, E Marin, MF Holt, DJ Lasko, NB Pitman, RK Orr, SP Milad, MR AF Rosenbaum, Blake L. Bui, Eric Marin, Marie-France Holt, Daphne J. Lasko, Natasha B. Pitman, Roger K. Orr, Scott P. Milad, Mohammed R. TI Demographic factors predict magnitude of conditioned fear SO INTERNATIONAL JOURNAL OF PSYCHOPHYSIOLOGY LA English DT Article DE Fear conditioning; Demographics; Classical conditioning; Education; Extinction; Skin conductance ID POSTTRAUMATIC-STRESS-DISORDER; OBSESSIVE-COMPULSIVE DISORDER; EXTINCTION RETENTION; SEX-DIFFERENCES; HUMANS; PTSD; NEUROSCIENCE; AWARENESS; RESPONSES; VETERANS AB There is substantial variability across individuals in the magnitudes of their skin conductance (SC) responses during the acquisition and extinction of conditioned fear. To manage this variability, subjects may be matched for demographic variables, such as age, gender and education. However, limited data exist addressing how much variability in conditioned SC responses is actually explained by these variables. The present study assessed the influence of age, gender and education on the SC responses of 222 subjects who underwent the same differential conditioning paradigm. The demographic variables were found to predict a small but significant amount of variability in conditioned responding during fear acquisition, but not fear extinction learning or extinction recall. A larger differential change in SC during acquisition was associated with more education. Older participants and women showed smaller differential SC during acquisition. Our findings support the need to consider age, gender and education when studying fear acquisition but not necessarily when examining fear extinction learning and recall. Variability in demographic factors across studies may partially explain the difficulty in reproducing some SC findings. (C) 2015 Published by Elsevier B.V. C1 [Rosenbaum, Blake L.; Bui, Eric; Marin, Marie-France; Holt, Daphne J.; Lasko, Natasha B.; Pitman, Roger K.; Orr, Scott P.; Milad, Mohammed R.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Bui, Eric; Marin, Marie-France; Holt, Daphne J.; Lasko, Natasha B.; Pitman, Roger K.; Orr, Scott P.; Milad, Mohammed R.] Harvard Univ, Sch Med, Boston, MA USA. [Holt, Daphne J.; Milad, Mohammed R.] HST MIT Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. RP Milad, MR (reprint author), Massachusetts Gen Hosp, Dept Psychiat, 149 13th St,CNY 2614, Charlestown, MA 02129 USA. EM milad@nmr.mgh.harvard.edu RI Bui, Eric/J-8347-2015 OI Bui, Eric/0000-0002-1413-6473 FU National Institute of Mental Health [1R01MH097964]; Department of Psychiatry at MGH FX This work was supported by the National Institute of Mental Health grant 1R01MH097964 and institutional funds from the Department of Psychiatry at MGH to MRM. The authors would like to thank the Translation Neuroscience team for their help preparing this manuscript. NR 42 TC 0 Z9 0 U1 2 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-8760 EI 1872-7697 J9 INT J PSYCHOPHYSIOL JI Int. J. Psychophysiol. PD OCT PY 2015 VL 98 IS 1 BP 59 EP 64 DI 10.1016/j.ijpsycho.2015.06.010 PG 6 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA CS5QT UT WOS:000362133700008 PM 26151498 ER PT J AU Wagner, C Abramson, LY Alloy, LB AF Wagner, Clara Abramson, Lyn Y. Alloy, Lauren B. TI Brief report: Executive functions in adolescent offspring of mothers with a history of depression SO JOURNAL OF ADOLESCENCE LA English DT Article DE Executive functions; Depression; Adolescents; Maternal depression ID EVERYDAY-ATTENTION; CHILDREN; RISK; PSYCHOPATHOLOGY; PERFORMANCE; DISORDERS AB Deficits in executive functions (EFs) have been documented among individuals with unipolar depression, but controversy exists as to whether such deficits are state-dependent or are trait markers that precede disorder onset. The present study examined whether maternal history of unipolar depression was associated with deficits in EFs in early adolescent offspring, a finding that would support a trait marker conceptualization of EF deficits. Participants were a diverse sample (N = 493) of adolescents and their mothers recruited through local schools. Measures included semi-structured diagnostic interviews of mother and adolescent, mother-report forms assessing demographic information, and tests of executive function. Hierarchical linear regression analyses were conducted to examine the association between maternal depression diagnosis and adolescent offspring performance on tests of EF. Maternal lifetime history of depression was not associated with offspring EF task performance. Findings are not consistent with the conceptualization of impaired executive functions as trait markers of unipolar depression. Published by Elsevier Ltd on behalf of The Foundation for Professionals in Services for Adolescents. C1 [Wagner, Clara] Philadelphia VA Med Ctr, VA Ctr Hlth Equity Res & Promot, Philadelphia, PA 19104 USA. [Abramson, Lyn Y.] Univ Wisconsin, Dept Psychol, Philadelphia, PA 19104 USA. [Alloy, Lauren B.] Temple Univ, Dept Psychol, Philadelphia, PA 19122 USA. RP Wagner, C (reprint author), Philadelphia VA Med Ctr, VA Ctr Hlth Equity Res & Promot, 3900 Woodland Ave,Bldg 4100 Annex, Philadelphia, PA 19104 USA. EM Clara.Wagner@va.gov FU National Institute of Mental Health [MH79369, MH101168] FX This research was supported by National Institute of Mental Health grants MH79369 and MH101168 to Lauren B. Alloy. 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 19 TC 1 Z9 1 U1 5 U2 12 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0140-1971 EI 1095-9254 J9 J ADOLESCENCE JI J. Adolesc. PD OCT PY 2015 VL 44 BP 32 EP 36 DI 10.1016/j.adolescence.2015.06.005 PG 5 WC Psychology, Developmental SC Psychology GA CS5PP UT WOS:000362130600004 PM 26208078 ER PT J AU Rusanescu, G Mao, JR AF Rusanescu, Gabriel Mao, Jianren TI Immature spinal cord neurons are dynamic regulators of adult nociceptive sensitivity SO JOURNAL OF CELLULAR AND MOLECULAR MEDICINE LA English DT Article DE neuronal differentiation; chronic pain; neurotrophins; peripheral nerve injury; adult neurogenesis; nociception; BDNF; 7; 8-dihydroxyflavone ID PERIPHERAL-NERVE INJURY; NEURAL STEM-CELL; NEUROPATHIC PAIN; DORSAL-HORN; PROGENITOR CELLS; RECEPTOR DESENSITIZATION; GABAERGIC INHIBITION; OLFACTORY-BULB; MESSENGER-RNA; DNA-SYNTHESIS AB Chronic pain is a debilitating condition with unknown mechanism. Nociceptive sensitivity may be regulated by genetic factors, some of which have been separately linked to neuronal progenitor cells and neuronal differentiation. This suggests that genetic factors that interfere with neuronal differentiation may contribute to a chronic increase in nociceptive sensitivity, by extending the immature, hyperexcitable stage of spinal cord neurons. Although adult rodent spinal cord neurogenesis was previously demonstrated, the fate of these progenitor cells is unknown. Here, we show that peripheral nerve injury in adult rats induces extensive spinal cord neurogenesis and a long-term increase in the number of spinal cord laminae I-II neurons ipsilateral to injury. The production and maturation of these new neurons correlates with the time course and modulation of nociceptive behaviour, and transiently mimics the cellular and behavioural conditions present in genetically modified animal models of chronic pain. This suggests that the number of immature neurons present at any time in the spinal cord dorsal horns contributes to the regulation of nociceptive sensitivity. The continuous turnover of these neurons, which can fluctuate between normal and injured states, is a dynamic regulator of nociceptive sensitivity. In support of this hypothesis, we find that promoters of neuronal differentiation inhibit, while promoters of neurogenesis increase long-term nociception. TrkB agonists, well-known promoters of nociception in the short-term, significantly inhibit long-term nociception by promoting the differentiation of newly produced immature neurons. These findings suggest that promoters of neuronal differentiation may be used to alleviate chronic pain. C1 [Rusanescu, Gabriel; Mao, Jianren] Harvard Univ, Massachusetts Gen Hosp, MGH Ctr Translat Pain Res, Dept Anesthesia Crit Care & Pain Med,Sch Med, Boston, MA 02115 USA. RP Rusanescu, G (reprint author), Harvard Univ, Massachusetts Gen Hosp, MGH Ctr Translat Pain Res, Dept Anesthesia Crit Care & Pain Med,Sch Med, Boston, MA 02115 USA. EM grusanes@gmail.com OI Rusanescu, Gabriel/0000-0002-2811-905X FU NIDCR NIH HHS [R01 DE022901] NR 79 TC 1 Z9 1 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1582-4934 J9 J CELL MOL MED JI J. Cell. Mol. Med. PD OCT PY 2015 VL 19 IS 10 BP 2352 EP 2364 DI 10.1111/jcmm.12648 PG 13 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA CS6WB UT WOS:000362222800005 PM 26223362 ER PT J AU Srinivasan, VJ Yu, E Radhakrishnan, H Can, A Climov, M Leahy, C Ayata, C Eikermann-Haerter, K AF Srinivasan, Vivek J. Yu, Esther Radhakrishnan, Harsha Can, Anil Climov, Mihail Leahy, Conor Ayata, Cenk Eikermann-Haerter, Katharina TI Micro-heterogeneity of flow in a mouse model of chronic cerebral hypoperfusion revealed by longitudinal Doppler optical coherence tomography and angiography SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE angiography; capillary recruitment; Doppler optical coherence tomography; hypoperfusion; vascular dementia ID BLOOD-FLOW; ALZHEIMERS-DISEASE; VASCULAR DEMENTIA; CORTEX; BRAIN; MICROSCOPY; PERFUSION; ISCHEMIA; RAT; DYSFUNCTION AB Although microvascular dysfunction accompanies cognitive decline in aging, vascular dementia, and Alzheimer's disease, tools to study microvasculature longitudinally in vivo are lacking. Here, we use Doppler optical coherence tomography (OCT) and angiography for noninvasive, longitudinal imaging of mice with chronic cerebral hypoperfusion for up to 1 month. In particular, we optimized the OCT angiography method to selectively image red blood cell (RBC)-perfused capillaries, leading to a novel way of assessing capillary supply heterogeneity in vivo. After bilateral common carotid artery stenosis (BCAS), cortical blood flow measured by Doppler OCT dropped to half of baseline throughout the imaged tissue acutely. Microscopic imaging of the capillary bed with OCT angiography further revealed local heterogeneities in cortical flow supply during hypoperfusion. The number of RBC-perfused capillaries decreased, leading to increased oxygen diffusion distances in the days immediately after BCAS. Linear regression showed that RBC-perfused capillary density declined by 0.3% for a drop in flow of 1 mL/100 g per minute, and decreases in RBC-perfused capillary density as high as 25% were observed. Taken together, these results demonstrate the existence of local supply heterogeneity at the capillary level even at nonischemic global flow levels, and demonstrate a novel imaging method to assess this heterogeneity. C1 [Srinivasan, Vivek J.; Radhakrishnan, Harsha; Leahy, Conor] Univ Calif Davis, Dept Biomed Engn, Davis, CA 95616 USA. [Yu, Esther; Can, Anil; Climov, Mihail; Ayata, Cenk; Eikermann-Haerter, Katharina] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Neurovasc Res Lab,Dept Radiol, Charlestown, MA USA. [Ayata, Cenk] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Stroke Serv, Boston, MA USA. [Ayata, Cenk] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neurosci Intens Care Unit,Dept Neurol, Boston, MA USA. RP Srinivasan, VJ (reprint author), Univ Calif Davis, Dept Biomed Engn, 451 E Hlth Sci Dr,GBSF 2521, Davis, CA 95616 USA. EM vjsriniv@ucdavis.edu OI Climov, Mihail/0000-0001-9150-8608 FU National Institutes of Health [NS067050, NS061505, NS055104]; American Heart Association [IRG5440002, 10SDG2610275]; Glaucoma Research Foundation Catalyst for a Cure; Massachusetts General Hospital Claflin Distinguished Award; Fondation Leducq; Heitman Foundation; Ellison Foundation FX We thank Maria Angela Franceschini, Michael Moskowitz, and Bruce Rosen for general support. We thank Yahya Atalay and Andrea Negro for assistance with data analysis. We acknowledge support from the National Institutes of Health (VJS: NS067050; CA: NS061505, NS055104), the American Heart Association (VJS: IRG5440002; KE-H: 10SDG2610275), the Glaucoma Research Foundation Catalyst for a Cure (VJS), The Massachusetts General Hospital Claflin Distinguished Award, and Fondation Leducq (CA), The Heitman Foundation (CA), and The Ellison Foundation (CA). NR 34 TC 3 Z9 3 U1 1 U2 4 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 OCT PY 2015 VL 35 IS 10 BP 1552 EP 1560 DI 10.1038/jcbfm.2015.175 PG 9 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA CS4KS UT WOS:000362045300002 PM 26243708 ER PT J AU Kim, JI Turka, LA AF Kim, James I. Turka, Laurence A. TI Transplant tolerance: a new role for IL-34 SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Editorial Material ID REGULATORY T-CELLS; LANGERHANS CELLS; MACROPHAGES; DIFFERENTIATION; MECHANISMS; FREQUENCY; INDUCTION; CYTOKINE; RECEPTOR AB Immune-suppressive cell populations, including Tregs and suppressor monocytes, have been implicated in long-term survival of allografts in both human transplant recipients and animal models. The factors that drive differentiation and function of these cell populations are not completely understood. In this issue, Bezie and colleagues identify IL-34 as an important mediator of allograft tolerance in a rat model of heart transplantation. Their data support a model in which IL-34 production by Tregs promotes a population of suppressive macrophages that in turn promote Treg differentiation. The results of this study support further exploration of the immunosuppressive properties of IL-34. C1 Massachusetts Gen Hosp, Dept Surg, Ctr Transplantat Sci, Boston, MA 02129 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Turka, LA (reprint author), Massachusetts Gen Hosp, Ctr Transplantat Sci, MGH East, Bldg 149-9019,13th St, Boston, MA 02129 USA. EM lturka@partners.org FU NIAID NIH HHS [R01 AI037691] NR 19 TC 0 Z9 1 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 OCT PY 2015 VL 125 IS 10 BP 3751 EP 3753 DI 10.1172/JCI84010 PG 3 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CS8BW UT WOS:000362311700007 PM 26389671 ER PT J AU Koh, SH Lo, EH AF Koh, Seong-Ho Lo, Eng H. TI The Role of the PI3K Pathway in the Regeneration of the Damaged Brain by Neural Stem Cells after Cerebral Infarction SO JOURNAL OF CLINICAL NEUROLOGY LA English DT Review DE neural stem cells; stroke; phosphatidylinositol-3-kinases; regeneration ID EXTRACELLULAR-REGULATED KINASES; EPIDERMAL-GROWTH-FACTOR; ADULT-RAT BRAIN; PROGENITOR CELLS; SIGNALING PATHWAY; PHOSPHATIDYLINOSITOL 3-KINASE; NEUROTROPHIC FACTOR; DIFFERENTIAL REGULATION; HIPPOCAMPAL-NEURONS; ISCHEMIC-STROKE AB Neurologic deficits resulting from stroke remain largely intractable, which has prompted thousands of studies aimed at developing methods for treating these neurologic sequelae. Endogenous neurogenesis is also known to occur after brain damage, including that due to cerebral infarction. Focusing on this process may provide a solution for treating neurologic deficits caused by cerebral infarction. The phosphatidylinositol-3-kinase (PI3K) pathway is known to play important roles in cell survival, and many studies have focused on use of the PI3K pathway to treat brain injury after stroke. Furthermore, since the PI3K pathway may also play key roles in the physiology of neural stem cells (NSCs), eliciting the appropriate activation of the PI3K pathway in NSCs may help to improve the sequelae of cerebral infarction. This review describes the PI3K pathway, its roles in the brain and NSCs after cerebral infarction, and the therapeutic possibility of activating the pathway to improve neurologic deficits after cerebral infarction. C1 [Koh, Seong-Ho; Lo, Eng H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neuroprotect Res Lab, Boston, MA USA. [Koh, Seong-Ho] Hanyang Univ, Coll Med, Dept Neurol, Seoul, South Korea. RP Koh, SH (reprint author), Hanyang Univ, Coll Med, Dept Neurol, 153 Gyeongchun Ro, Guri 11923, South Korea. EM ksh213@hanyang.ac.kr FU Korea Research Foundation [2012R1A1B3000473]; NanoBio R&D Program of the Korea Science and Engineering Foundation - Ministry of Education, Science and Technology [2007-04717] FX This work was supported by a grant from the Korea Research Foundation (no. 2012R1A1B3000473), and a grant from the NanoBio R&D Program of the Korea Science and Engineering Foundation, funded by the Ministry of Education, Science and Technology (no. 2007-04717). NR 71 TC 7 Z9 10 U1 2 U2 8 PU KOREAN NEUROLOGICAL ASSOC PI SEOUL PA 1111 DAEIL BLD, 43 INSA-DONG, JONGNO-GU, SEOUL, 110-741, SOUTH KOREA SN 1738-6586 EI 2005-5013 J9 J CLIN NEUROL JI J. Clin. Neurol. PD OCT PY 2015 VL 11 IS 4 BP 297 EP 304 DI 10.3988/jcn.2015.11.4.297 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA CS2UE UT WOS:000361926700001 PM 26320845 ER PT J AU Blakeley, JO Grossman, SA Mikkelsen, T Rosenfeld, MR Peereboom, D Nabors, LB Chi, AS Emmons, G Ribas, IG Supko, JG Desideri, S Ye, XB AF Blakeley, Jaishri O. Grossman, Stuart A. Mikkelsen, Tom Rosenfeld, Myrna R. Peereboom, David Nabors, L. Burt Chi, Andrew S. Emmons, Gary Ribas, Ignacio Garcia Supko, Jeffrey G. Desideri, Serena Ye, Xiaobu TI Phase I study of iniparib concurrent with monthly or continuous temozolomide dosing schedules in patients with newly diagnosed malignant gliomas SO JOURNAL OF NEURO-ONCOLOGY LA English DT Article DE Malignant glioma; Newly diagnosed; Dose finding; Cytotoxic; Combination therapy ID GLIOBLASTOMA-MULTIFORME; TUMOR-CELLS; RELAPSE; TRIAL AB Iniparib is a prodrug that converts to highly reactive cytotoxic metabolites intracellularly with activity in preclinical glioma models. We investigated the maximum tolerated dose (MTD) of iniparib with monthly (m) and continuous (c) temozolomide (TMZ) dosing schedules in patients with malignant gliomas (MG). Adults with newly diagnosed MG who had successfully completed a parts per thousand yen80 % of radiation (RT) and TMZ without toxicity received mTMZ dosing (150-200 mg/m(2) days 1-5/28 days) or cTMZ dosing (75 mg/m(2)/days x 6 weeks) in conjunction with iniparib (i.v. 2 days/week) in the adjuvant setting. Iniparib was dose escalated using a modified continual reassessment method (mCRM). 43 patients (32 male; 34 GBM, 8 AA, 1 gliosarcoma; median age 54 years; median KPS 90) were enrolled across 4 dose levels. In the mTMZ group, 2/4 patients had dose limiting toxicities (DLT) at 19 mg/kg/week (rash/hypersensitivity). At 17.2 mg/kg/week, 1/9 patients had a DLT (grade 3 fatigue). Additional grade 3 toxicities were neutropenia, lymphopenia, and nausea. In the cTMZ group, one DLT (thromboembolic event) occurred at 10.2 mg/kg/week. Dose escalation stopped at 16 mg/kg/week based on mCRM. The mean maximum plasma concentration of iniparib increased with dose. Concentration of the two major circulating metabolites, 4-iodo-3-aminobenzamide and 4-iodo-3-aminobenzoic acid, was a parts per thousand currency sign5 % of the corresponding iniparib concentration. Iniparib is well tolerated, at doses higher than previously investigated, in combination with TMZ after completion of RT + TMZ in patients with MG. Recommended phase 2 dosing of iniparib based on mCRM is 17.2 mg/kg/week with mTMZ and 16 mg/kg/week with cTMZ. An efficacy study of TMZ/RT + iniparib followed by TMZ + iniparib in newly diagnosed GBM using these doses has completed enrollment. Survival assessment is ongoing. C1 [Blakeley, Jaishri O.; Grossman, Stuart A.; Desideri, Serena; Ye, Xiaobu] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD 21287 USA. [Mikkelsen, Tom] Henry Ford Hosp, Detroit, MI 48202 USA. [Rosenfeld, Myrna R.] Univ Penn, Philadelphia, PA 19104 USA. [Peereboom, David] Cleveland Clin, Cleveland, OH 44106 USA. [Chi, Andrew S.; Supko, Jeffrey G.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Nabors, L. Burt] Univ Alabama Birmingham, Birmingham, AL USA. [Emmons, Gary; Ribas, Ignacio Garcia] Sanofi, Cambridge, MA USA. RP Blakeley, JO (reprint author), Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, 1550 Orleans St,Suite 1 M-16, Baltimore, MD 21287 USA. EM jblakel3@jhmi.edu OI Rosenfeld, Myrna/0000-0001-5095-2534 FU National Institutes of Health [U01 CA-62475, U01 CA-137443]; Sanofi Pharmaceuticals, Inc. FX National Institutes of Health (U01 CA-62475 to S.G., U01 CA-137443 to S.G.); Sanofi Pharmaceuticals, Inc. NR 22 TC 1 Z9 1 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X EI 1573-7373 J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD OCT PY 2015 VL 125 IS 1 BP 123 EP 131 DI 10.1007/s11060-015-1876-0 PG 9 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA CS8JY UT WOS:000362334800013 PM 26285766 ER PT J AU Balboni, MJ Bandini, J Mitchell, C Epstein-Peterson, ZD Amobi, A Cahill, J Enzinger, AC Peteet, J Balboni, T AF Balboni, Michael J. Bandini, Julia Mitchell, Christine Epstein-Peterson, Zachary D. Amobi, Ada Cahill, Jonathan Enzinger, Andrea C. Peteet, John Balboni, Tracy TI Religion, Spirituality, and the Hidden Curriculum: Medical Student and Faculty Reflections SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Article DE Professionalism; hidden curriculum; religion; spirituality; medical education ID PHYSICIAN BURNOUT; SUICIDAL IDEATION; NATIONAL-SURVEY; PROFESSIONALISM; EDUCATION; SCHOOL; HEALTH; US; MULTICENTER; DEPRESSION AB Context. Religion and spirituality play an important role in physicians' medical practice, but little research has examined their influence within the socialization of medical trainees and the hidden curriculum. Objectives. The objective is to explore the role of religion and spirituality as they intersect with aspects of medicine's hidden curriculum. Methods. Semiscripted, one-on-one interviews and focus groups (n = 33 respondents) were conducted to assess Harvard Medical School student and faculty experiences of religion/spirituality and the professionalization process during medical training. Using grounded theory, theme extraction was performed with interdisciplinary input (medicine, sociology, and theology), yielding a high inter-rater reliability score (kappa = 0.75). Results. Three domains emerged where religion and spirituality appear as a factor in medical training. First, religion/spirituality may present unique challenges and benefits in relation to the hidden curriculum. Religious/spiritual respondents more often reported to struggle with issues of personal identity, increased self-doubt, and perceived medical knowledge inadequacy. However, religious/spiritual participants less often described relationship conflicts within the medical team, work-life imbalance, and emotional stress arising from patient suffering. Second, religion/spirituality may influence coping strategies during encounters with patient suffering. Religious/spiritual trainees described using prayer, faith, and compassion as means for coping whereas nonreligious/nonspiritual trainees discussed compartmentalization and emotional repression. Third, levels of religion/spirituality appear to fluctuate in relation to medical training, with many trainees experiencing an increase in religiousness/spirituality during training. Conclusion. Religion/spirituality has a largely unstudied but possibly influential role in medical student socialization. Future study is needed to characterize its function within the hidden curriculum. (C) 2015 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved. C1 [Balboni, Michael J.; Peteet, John] Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, Boston, MA 02115 USA. [Enzinger, Andrea C.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Balboni, Tracy] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Balboni, Michael J.; Amobi, Ada; Enzinger, Andrea C.; Peteet, John; Balboni, Tracy] Harvard Univ, Sch Med, Boston, MA USA. [Bandini, Julia] Brandeis Univ, Dept Sociol, Waltham, MA USA. [Mitchell, Christine] Harvard Univ, Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02115 USA. [Epstein-Peterson, Zachary D.] Univ Washington, Dept Med, Seattle, WA USA. [Cahill, Jonathan] Boston Coll, Dept Theol, Chestnut Hill, MA 02167 USA. RP Balboni, MJ (reprint author), Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, Dana 1101,450 Brookline Ave, Boston, MA 02115 USA. EM Michael_Balboni@dfci.harvard.edu FU Templeton Foundation Award; University of Chicago Program in Religion and Medicine Faculty Scholars Award FX This research was supported in part by a Templeton Foundation Award and a University of Chicago Program in Religion and Medicine Faculty Scholars Award. None of the authors have relationships with any entities having a financial interest in this topic. NR 42 TC 4 Z9 4 U1 3 U2 18 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0885-3924 EI 1873-6513 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD OCT PY 2015 VL 50 IS 4 BP 507 EP 515 DI 10.1016/j.jpainsymman.2015.04.020 PG 9 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA CS5CN UT WOS:000362093800012 PM 26025271 ER PT J AU Ahluwalia, SC Tisnado, DM Walling, AM Dy, SM Asch, SM Ettner, SL Kim, B Pantoja, P Schreibeis-Baum, HC Lorenz, KA AF Ahluwalia, Sangeeta C. Tisnado, Diana M. Walling, Anne M. Dy, Sydney M. Asch, Steven M. Ettner, Susan L. Kim, Benjamin Pantoja, Philip Schreibeis-Baum, Hannah C. Lorenz, Karl A. TI Association of Early Patient-Physician Care Planning Discussions and End-of-Life Care Intensity in Advanced Cancer SO JOURNAL OF PALLIATIVE MEDICINE LA English DT Article ID EARLY PALLIATIVE CARE; RANDOMIZED CONTROLLED-TRIAL; VETERANS-AFFAIRS; PRIVATE-SECTOR; OLDER PATIENTS; NEAR-DEATH; QUALITY; HEALTH; AGGRESSIVENESS; INDICATORS AB Background: Early patient-physician care planning discussions may influence the intensity of end-of-life (EOL) care received by veterans with advanced cancer. Objective: The study objective was to evaluate the association between medical record documentation of patient-physician care planning discussions and intensity of EOL care among veterans with advanced cancer. Methods: This was a retrospective cohort study. Subjects were 665 veteran decedents diagnosed with stage IV colorectal, lung, or pancreatic cancer in 2008, and followed till death or the end of the study period in 2011. We estimated the effect of patient-physician care planning discussions documented within one month of metastatic diagnosis on the intensity of EOL care measured by receipt of acute care, intensive interventions, chemotherapy, and hospice care, using multivariate logistic regression models. Results: Veterans in our study were predominantly male (97.1%), white (74.7%), with an average age at diagnosis of 66.4 years. Approximately 31% received some acute care, 9.3% received some intensive intervention, and 6.5% had a new chemotherapy regimen initiated in the last month of life. Approximately 41% of decedents received no hospice or were admitted within three days of death. Almost half (46.8%) had documentation of a care planning discussion within the first month after diagnosis and those who did were significantly less likely to receive acute care at EOL (OR: 0.67; p=0.025). Documented discussions were not significantly associated with intensive interventions, chemotherapy, or hospice care. Conclusion: Early care planning discussions are associated with lower rates of acute care use at the EOL in a system with already low rates of intensive EOL care. C1 [Ahluwalia, Sangeeta C.] RAND Corp, Santa Monica, CA 90401 USA. [Walling, Anne M.; Pantoja, Philip; Schreibeis-Baum, Hannah C.; Lorenz, Karl A.] VA Greater Los Angeles Med Ctr, Los Angeles, CA USA. [Walling, Anne M.; Lorenz, Karl A.] UCLA Sch Med, Los Angeles, CA USA. [Dy, Sydney M.] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Asch, Steven M.] VA Palo Alto Healthcare Syst, Palo Alto, CA USA. [Asch, Steven M.] Stanford Univ Sch Med, Palo Alto, CA USA. [Ettner, Susan L.] UCLA Fielding Sch Publ Hlth, Los Angeles, CA USA. [Kim, Benjamin] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Tisnado, Diana M.] Calif State Univ Fullerton, Dept Hlth Sci, Fullerton, CA 92634 USA. RP Ahluwalia, SC (reprint author), RAND Corp, 1776 Main St, Santa Monica, CA 90401 USA. EM sahluwal@rand.org FU U.S. Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research & Development Service [IIR 09-097]; National Palliative Care Research Center Career Development Award; VA/NIMH Implementation Research Fellowship [R25 MH080916-01A2]; UCLA CTSI [UL1TR000124]; NIH Loan Repayment Program FX This work was supported by the U.S. Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research & Development Service (IIR 09-097). The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the U.S. government. Dr. Ahluwalia was supported by a National Palliative Care Research Center Career Development Award and a VA/NIMH Implementation Research Fellowship (R25 MH080916-01A2). Dr. Walling was supported by UCLA CTSI grant number UL1TR000124 and the NIH Loan Repayment Program. NR 25 TC 1 Z9 1 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1096-6218 EI 1557-7740 J9 J PALLIAT MED JI J. Palliat. Med. PD OCT 1 PY 2015 VL 18 IS 10 BP 834 EP 841 DI 10.1089/jpm.2014.0431 PG 8 WC Health Care Sciences & Services SC Health Care Sciences & Services GA CS7MY UT WOS:000362268900009 PM 26186553 ER PT J AU Higgins, PC Garrido, MM Prigerson, HG AF Higgins, Philip C. Garrido, Melissa M. Prigerson, Holly G. TI Factors Predicting Bereaved Caregiver Perception of Quality of Care in the Final Week of Life: Implications for Health Care Providers SO JOURNAL OF PALLIATIVE MEDICINE LA English DT Article ID FAMILY-MEMBERS; CANCER-PATIENTS; MENTAL-HEALTH; MEDICAL-CARE; PALLIATIVE CARE; PSYCHIATRIC-DISORDERS; POSTTRAUMATIC STRESS; HOSPICE ENROLLMENT; INITIAL VALIDATION; TERMINAL ILLNESS AB Background: Cancer caregivers are key stakeholders in the final weeks of life and in bereavement. Research has highlighted end-of-life (EOL) factors important to caregivers, as well as factors contributing to caregiver mental health and bereavement outcomes. There has been limited data on factors predicting caregiver perceptions of quality of EOL care. Objective: This study's purpose was to identify modifiable predictors of caregivers' Caregiver Evaluation of Quality of End of Life Care (CEQUEL) scores, with the broader aim of informing clinical interventions to improve caregiver impressions of care and subsequent bereavement adjustment. Methods: Study data came from Coping with Cancer I (CwC1). CwC1 investigators interviewed advanced cancer patients and caregivers prior to the patient's death (Wave 1) and reinterviewed caregivers following the death (Wave 2) (N=275 dyads). The authors identified potential Wave 1 predictors of CEQUEL scores and performed a series of linear regression analyses to identify a parsimonious predictive model using corrected Akaike's Information Criterion (AICc) values. Results: In adjusted analyses, caregivers rated quality of care as poorer when patients died in a hospital (B=-1.40, SE=0.40, p=0.001) (B, unstandardized regression coefficient; SE, standard error) or had less than one week of inpatient hospice care (B=-1.98, SE=-0.70, p=0.006). Whole-person physician care and caregiver religiosity were associated with perceived higher quality of care in unadjusted, but not adjusted, analyses. Conclusions: Findings suggest that place of death and hospice length of stay best predict bereaved caregiver evaluations of quality of EOL care. These findings equip health care providers with modifiable targets to improve caregivers' experience of EOL care and subsequent bereavement. C1 [Higgins, Philip C.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Higgins, Philip C.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Garrido, Melissa M.] James J Peters Vet Affairs Med Ctr, Bronx, NY USA. [Garrido, Melissa M.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Prigerson, Holly G.] Weill Cornell Med Coll, Ctr Res End Of Life Care, New York, NY 10065 USA. RP Prigerson, HG (reprint author), Weill Cornell Med Coll, Ctr Res End Of Life Care, 525 East 68th St,Box 39,1404 Baker Pavil, New York, NY 10065 USA. EM hgp2001@med.cornell.edu FU American Cancer Society [DSW1009403SW]; Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research and Development Service [CDA 11-201/CDP 12-255]; National Institute of Mental Health [MH63892]; National Cancer Institute [CA106370, CA156732] FX This research was supported in part by the following grants and other funding sources: Dr. Higgins is supported by DSW1009403SW from the American Cancer Society. Dr. Garrido is supported by CDA 11-201/CDP 12-255 from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research and Development Service. Dr. Prigerson was supported by MH63892 from the National Institute of Mental Health and CA106370 and CA156732 from the National Cancer Institute. These grants paid for the Coping with Cancer study on which these analyses are based. NR 64 TC 2 Z9 2 U1 2 U2 12 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 OCT 1 PY 2015 VL 18 IS 10 BP 849 EP 857 DI 10.1089/jpm.2015.29001.hp PG 9 WC Health Care Sciences & Services SC Health Care Sciences & Services GA CS7MY UT WOS:000362268900011 PM 26186021 ER PT J AU Smith, D Kuzla, N Thorpe, J Scott, L Ersek, M AF Smith, Dawn Kuzla, Natalie Thorpe, Joshua Scott, Laura Ersek, Mary TI Exploring Nonresponse Bias in the Department of Veterans Affairs' Bereaved Family Survey SO JOURNAL OF PALLIATIVE MEDICINE LA English DT Article ID PATIENT SATISFACTION SURVEYS; LIFE CARE; QUALITY MEASURE; HOSPITAL SURVEY; RESPONSE BIAS; END; HEALTH; NATIONWIDE; IMPACT; MODEL AB Background: Patients' and families' evaluations of health care, including palliative care, are widely used as performance measures. Survey scores may be affected by nonresponse bias, resulting in inaccurate performance evaluation. Objectives: Our aim was to examine nonresponse bias for the mailed version of the Department of Veterans Affairs (VA) Bereaved Family Survey Performance Measure (BFS-PM) and evaluate the effect of nonresponse bias on facilities' BFS-PM scores. Methods: A cross-sectional analysis of a national sample was conducted. The sample consisted of 20,540 veterans who died in one of 146 VA Medical Centers (VAMCs) between October 2012 and September 2013. Next of kin (NOK) were asked to complete and return the survey. The BFS-PM is defined as the proportion of NOK who rated overall care for the veteran during the last month of life as excellent. After creating a model to predict the likelihood of response based on patient and clinical characteristics, we applied inverse probability weights to examine their effect on facilities' scores. We also evaluated facility performance before and after weighting for nonresponse vis-a-vis varying benchmarks. Results: We received 8912 surveys (45% response rate). The mean change in facility BFS-PM scores after weighting was -2%, (range: -10% to+11%). The scores of 31% of facilities changed more than2%. The number of facilities meeting hypothetical benchmarks of 60%, 70%, and 80% also changed as a result of weighting for nonresponse. Conclusion: Our results underscore the importance of appropriately addressing nonresponse in the use of quality-of-care metrics based on Bereaved Family Survey (BFS) data. C1 [Smith, Dawn; Kuzla, Natalie; Thorpe, Joshua; Scott, Laura; Ersek, Mary] Philadelphia Vet Affairs Med Ctr, PROMISE Ctr, Philadelphia, PA 19104 USA. [Thorpe, Joshua] Dept Vet Affairs Med Ctr, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. [Thorpe, Joshua] Univ Pittsburgh, Sch Pharm, Dept Pharm & Therapeut, Pittsburgh, PA 15261 USA. [Smith, Dawn; Kuzla, Natalie; Ersek, Mary] Univ Penn, Sch Nursing, Philadelphia, PA 19104 USA. RP Ersek, M (reprint author), Philadelphia Vet Affairs Med Ctr, 3900 Woodland Ave,Annex Suite 203, Philadelphia, PA 19104 USA. EM Mary.ersek@va.gov FU Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development FX This material is based upon work supported by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, which had no role in the design, methods, participant recruitment, data collection, analysis, or preparation of manuscript or in the decision to submit the manuscript for publication. All authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the U.S. Government. NR 35 TC 1 Z9 1 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1096-6218 EI 1557-7740 J9 J PALLIAT MED JI J. Palliat. Med. PD OCT 1 PY 2015 VL 18 IS 10 BP 858 EP 864 DI 10.1089/jpm.2015.0050 PG 7 WC Health Care Sciences & Services SC Health Care Sciences & Services GA CS7MY UT WOS:000362268900012 PM 26172910 ER PT J AU Steffens, JP Wang, XS Starr, JR Spolidorio, LC Van Dyke, TE Kantarci, A AF Steffens, Joao Paulo Wang, Xiaoshan Starr, Jacqueline R. Spolidorio, Luis Carlos Van Dyke, Thomas E. Kantarci, Alpdogan TI Associations Between Sex Hormone Levels and Periodontitis in Men: Results From NHANES III SO JOURNAL OF PERIODONTOLOGY LA English DT Article DE Androgens; cross-sectional studies; gonadal steroid hormones; inflammation; periodontitis; testosterone ID MIDDLE-AGED MEN; BODY-MASS INDEX; 3RD NATIONAL-HEALTH; WAIST-HIP RATIO; CIGARETTE-SMOKING; TESTOSTERONE LEVELS; HYPERGONADOTROPIC HYPOGONADISM; MULTIPLE-IMPUTATION; SERUM TESTOSTERONE; BINDING GLOBULIN AB Background: Sex hormones are linked to inflammation and bone turnover. The goal of this study is to explore the association between sex hormone levels and periodontitis in men using data from the third National Health and Nutrition Examination Survey (NHANES III). Methods: Data from 755 men (aged >= 30 years), including serum levels of testosterone, estradiol, sex hormone binding globulin, and androstenediol glucuronide, were analyzed. Calculated bioavailable testosterone (CBT) and estradiol-to-testosterone ratio were calculated. Periodontitis was defined using the latest classification of extent and severity of periodontitis for NHANES data (>= 2 interproximal sites with >= 3 mm attachment loss, >= 2 interproximal sites with probing depth [PD] >= 4 mm not on the same tooth, or one site with PD >= 5 mm). Sex hormones were evaluated as categorized and continuous variables. Correlations between the presence and severity of periodontitis and levels of sex hormones were determined and expressed as odds ratios (ORs). Results: When adjusted for confounding factors, high total testosterone (TT) and CBT levels correlated with both the prevalence (OR [95% confidence interval (CI)], 2.1 [1 to 4.5] and 3.9 [1 to 14.8], respectively) and severity (OR [95% CI], 2.1 [1 to 4.3] and 3.4 [1.2 to 9.8]) of periodontitis. When continuous variables were used, the ORs (95% CIs) for presence and severity of periodontitis were 1.4 (0.6 to 3.3) and 1.5 (0.6 to 3.6) for TT and 1.3 (0.9 to 1.9) and 1.3 (0.9 to 1.8) for CBT, respectively. Conclusions: These findings are consistent with the existence of an association of periodontitis with sex hormone levels, especially testosterone, in men. C1 [Steffens, Joao Paulo; Wang, Xiaoshan; Starr, Jacqueline R.; Van Dyke, Thomas E.; Kantarci, Alpdogan] Forsyth Inst, Ctr Periodontol, Dept Appl Oral Sci, Cambridge, MA USA. [Steffens, Joao Paulo; Spolidorio, Luis Carlos] Univ Estadual Paulista, Sch Dent Araraquara, Dept Physiol & Pathol, Araraquara, SP, Brazil. [Starr, Jacqueline R.] Harvard Univ, Sch Dent Med, Dept Oral Hlth Policy & Epidemiol, Boston, MA 02115 USA. [Starr, Jacqueline R.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. RP Kantarci, A (reprint author), 245 First St, Cambridge, MA 02142 USA. EM akantarci@forsyth.org FU Sao Paulo State Research Foundation (FAPESP), Sao Paulo, SP, Brazil [2010/09658-0, 2010/12021-4]; Coordination for the Improvement of Higher Education Personnel (CAPES), Brasilia, DF, Brazil [5258-11-1]; National Council for Scientific and Technological Development (CNPq), Brasilia, DF, Brazil [470870/2011-7]; National Institutes of Health/National Institute of Dental and Craniofacial Research [DE015566, DE020906] FX JPS is a Post-Doctoral Fellow at UNESP, Araraquara, SP, Brazil, and was the recipient of a scholarship from the Sao Paulo State Research Foundation (FAPESP), Sao Paulo, SP, Brazil (#2010/09658-0) and from the Coordination for the Improvement of Higher Education Personnel (CAPES), Brasilia, DF, Brazil (#5258-11-1). JPS and LCS held research support grants from FAPESP (#2010/12021-4) and from the National Council for Scientific and Technological Development (CNPq), Brasilia, DF, Brazil (#470870/2011-7). LCS holds a Productivity Scholarship from CNPq. Supported by National Institutes of Health/National Institute of Dental and Craniofacial Research grants DE015566 and DE020906 to AK and TVD. The authors report no conflicts of interest related to this study. NR 54 TC 1 Z9 1 U1 0 U2 3 PU AMER ACAD PERIODONTOLOGY PI CHICAGO PA 737 NORTH MICHIGAN AVENUE, SUITE 800, CHICAGO, IL 60611-2690 USA SN 0022-3492 EI 1943-3670 J9 J PERIODONTOL JI J. Periodont. PD OCT PY 2015 VL 86 IS 10 BP 1116 EP 1125 DI 10.1902/jop.2015.140530 PG 10 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA CS4KR UT WOS:000362045200003 PM 26062840 ER PT J AU Grubbs, V Vittinghoff, E Beck, JD Kshirsagar, AV Wang, W Griswold, ME Powe, NR Correa, A Young, B AF Grubbs, Vanessa Vittinghoff, Eric Beck, James D. Kshirsagar, Abhijit V. Wang, Wei Griswold, Michael E. Powe, Neil R. Correa, Adolfo Young, Bessie TI Association Between Periodontal Disease and Kidney Function Decline in African Americans: The Jackson Heart Study SO JOURNAL OF PERIODONTOLOGY LA English DT Article DE African Americans; disease progression; health status disparities; periodontal disease; renal insufficiency; chronic; risk factors ID STAGE RENAL-DISEASE; ATHEROSCLEROSIS RISK; SERUM CREATININE; COMMUNITIES; POPULATION; PREVALENCE; ADULTS; CKD AB Background: Chronic kidney disease (CKD) remains a prevalent public health problem that disproportionately affects African Americans, despite intense efforts targeting traditional risk factors. Periodontal disease, a chronic bacterial infection of the oral cavity, is both common and modifiable and has been implicated as a novel potential CKD risk factor. The authors seek to examine to what extent periodontal disease is associated with kidney function decline. Methods: This retrospective cohort study examines 699 African American participants with preserved kidney function (defined by estimated glomerular filtration rate (eGFR) >60 mL/minute/1.73m(2) at baseline) who underwent complete dental examinations as part of the Dental-Atherosclerosis Risk in Communities study (1996 to 1998) and subsequently enrolled in the Jackson Heart Study (2000 to 2004). Using multivariable Poisson regression, the authors examined the association of periodontal disease (severe versus non-severe) with incident CKD, defined as incident eGFR <60 mL/minute/1.73m(2) and rapid (5% annualized) eGFR decline at follow-up among those with preserved eGFR at baseline. Results: Mean (+/- SD) age at baseline was 65.4 (+/- 5.2) years, and 16.3% (n = 114) had severe periodontal disease. There were 21 cases (3.0%) of incident CKD after a mean follow-up of 4.8 (+/- 0.6) years. Compared with participants with non-severe periodontal disease, those with severe periodontal disease had a four-fold greater rate of incident CKD (adjusted incidence rate ratio 4.18 [95% confidence interval 1.68 to 10.39], P = 0.002). Conclusions: Severe periodontal disease is prevalent among a population at high risk for CKD and is associated with clinically significant kidney function decline. Further research is needed to determine if periodontal disease treatment alters the trajectory of renal deterioration. C1 [Grubbs, Vanessa] Univ Calif San Francisco, Div Nephrol, San Francisco, CA 94143 USA. [Grubbs, Vanessa] San Francisco Gen Hosp, Div Nephrol, San Francisco, CA 94110 USA. [Vittinghoff, Eric] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Beck, James D.] Univ N Carolina, Sch Dent, Chapel Hill, NC USA. [Kshirsagar, Abhijit V.] Univ N Carolina, Div Nephrol & Hypertens, Chapel Hill, NC USA. [Wang, Wei; Griswold, Michael E.] Univ Mississippi, Med Ctr, Ctr Biostat & Bioinformat, Jackson, MS 39216 USA. [Powe, Neil R.] San Francisco Gen Hosp, Dept Med, San Francisco, CA 94110 USA. [Correa, Adolfo] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Young, Bessie] Univ Washington, Kidney Res Inst, Div Nephrol, Vet Affairs Puget Sound, Seattle, WA 98195 USA. RP Grubbs, V (reprint author), 1001 Potrero Ave,Bldg 100,Room 342, San Francisco, CA 94110 USA. EM vanessa.grubbs@ucsf.edu FU National Institute of Diabetes and Digestive and Kidney Disease (NIDDK), Bethesda, Maryland [1K23DK093710-01A1, 1R01DK102134-01]; Harold Amos Medical Faculty Development Program of Robert Wood Johnson Foundation, Princeton, New Jersey; National Heart, Lung, and Blood Institute [HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C]; National Institute on Minority Health and Health Disparities, Bethesda, Maryland; Valeant Pharmaceuticals, Bridgewater, New Jersey; Amgen (Thousand Oaks, California) FX The authors thank the participants and staff of the Dental-Atherosclerosis Risk in Communities and Jackson Heart Studies. VG was supported by grant 1K23DK093710-01A1 from the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK), Bethesda, Maryland, and by the Harold Amos Medical Faculty Development Program of the Robert Wood Johnson Foundation, Princeton, New Jersey. BY was supported by grant 1R01DK102134-01 from the NIDDK. The Jackson Heart Study is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, and HHSN268201300050C from the National Heart, Lung, and Blood Institute and the National Institute on Minority Health and Health Disparities, Bethesda, Maryland. VG received investigator-initiated research funding from Valeant Pharmaceuticals, Bridgewater, New Jersey. AVK received investigator-initiated research funding from Amgen (Thousand Oaks, California) and has served on an advisory board for Fresenius (Waltham, Massachusetts). No other co-authors have any potential conflicts of interests to disclose. NR 23 TC 1 Z9 1 U1 0 U2 1 PU AMER ACAD PERIODONTOLOGY PI CHICAGO PA 737 NORTH MICHIGAN AVENUE, SUITE 800, CHICAGO, IL 60611-2690 USA SN 0022-3492 EI 1943-3670 J9 J PERIODONTOL JI J. Periodont. PD OCT PY 2015 VL 86 IS 10 BP 1126 EP 1132 DI 10.1902/jop.2015.150195 PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA CS4KR UT WOS:000362045200004 PM 26110451 ER PT J AU Pinheiro, LR Scarfe, WC Sales, MAD Gaia, BF Cortes, ARG Cavalcanti, MG AF Pinheiro, Lucas Rodrigues Scarfe, William C. de Oliveira Sales, Marcelo Augusto Gaia, Bruno Felipe Gonzalez Cortes, Arthur Rodriguez Cavalcanti, Marcelo Gusmao TI Effect of Cone-Beam Computed Tomography Field of View and Acquisition Frame on the Detection of Chemically Simulated Peri-Implant Bone Loss In Vitro SO JOURNAL OF PERIODONTOLOGY LA English DT Article DE Animal; bone and bones; cone-beam computed tomography; dental implants; diagnosis; peri-implantitis ID INDUCED PERIAPICAL LESIONS; HORIZONTAL ROOT FRACTURE; ANGULAR MEASUREMENTS; CONVENTIONAL FILM; DENTAL IMPLANTS; DEFECTS; RADIOGRAPHY; ACCURACY; MULTISLICE; IMPACT AB Background: The aim of this study is to determine the influence of field of view (FOV) and number of acquisition projection images (frames) on the detection of chemically simulated peri-implant defects by cone-beam computed tomography (CBCT) using an in vitro bovine rib bone model. Methods: Eighty implants were placed in bovine ribs in which small and large bone defects were created using 70% perchloric acid. CBCT images were acquired at three acquisition protocols: protocol 1 (FOV 4 x 4 cm, 0.08-mm voxel size, 1,009 frames [high fidelity]; protocol 2 (same as protocol 1 except 512 frames [standard]); and protocol 3 (FOV 14 x 5 cm, 0.25-mm voxel size; high fidelity). Two oral and maxillofacial radiologists (OMRs) and two oral and maxillofacial surgeons (OMSs) rated the presence or absence of bone defects on a five-point scale. k and area under the curve (AUC) were calculated and compared using analysis of variance with post hoc Tukey test at P <= 0.05. Results: Intra- and interobserver agreement for OMRs ranged from moderate to good and from slight to moderate for OMSs. For the detection of small lesions, protocol 1 (AUC 0.813 +/- 0.045) provided higher detection rates than protocol 2 (AUC 0.703 +/- 0.02) and protocol 3 (AUC 0.773 +/- 0.55) [F(2,9) = 1.6377]. For larger defects, the trends were similar, with protocol 1 (AUC 0.852 +/- 0.108) providing higher detection rates than protocol 2 (AUC 0.730 +/- 0.045) and protocol 3 (AUC 0.783 +/- 0.058) [F(2,9) = 1.9576]. Conclusion: Within the limits of this study, optimal detection of chemically simulated pericircumferential implant crestal bone defects is achieved at the least radiation detriment using the smallest FOV, the highest number of acquisition frames, and the smallest voxel. C1 [Pinheiro, Lucas Rodrigues; Scarfe, William C.] Univ Louisville, Sch Dent, Dept Surg & Hosp Dent, Louisville, KY 40292 USA. [de Oliveira Sales, Marcelo Augusto; Gaia, Bruno Felipe; Cavalcanti, Marcelo Gusmao] Univ Sao Paulo, Sch Dent, Dept Stomatol, Sao Paulo, Brazil. [Gonzalez Cortes, Arthur Rodriguez] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Pinheiro, LR (reprint author), Ave Prof Lineu Prestes 2227, BR-05508000 Sao Paulo, Brazil. EM lrp@usp.br RI Cortes, Arthur/C-8738-2013 OI Cortes, Arthur/0000-0001-6591-7256 FU National Council for Research (CNPq), Brasilia, Brazil; Universal Research Project [472895/2009-5]; Research Productivity Scholarship [303847/2009-3]; FAPESP (Foundation of Research of Sao Paulo State, Sao Paulo, Brazil) [2011/20179-0]; Coordination of Advancement of Higher Education (CAPES), Brasilia; [2011/20304-9] FX This study was funded by National Council for Research (CNPq), Brasilia, Brazil, Universal Research Project (grant 472895/2009-5), Research Productivity Scholarship (grant 303847/2009-3), and FAPESP (Foundation of Research of Sao Paulo State, Sao Paulo, Brazil; grant 2011/20179-0) to MC. The authors thank Coordination of the Advancement of Higher Education (CAPES), Brasilia, for its financial support provided through grants to BG and FAPESP for its grant to LP (2011/20304-9). The authors also thank Implancil De Bortoli, Sao Paulo, for providing the implants. The authors report no conflicts of interest related to this study. NR 28 TC 0 Z9 0 U1 0 U2 2 PU AMER ACAD PERIODONTOLOGY PI CHICAGO PA 737 NORTH MICHIGAN AVENUE, SUITE 800, CHICAGO, IL 60611-2690 USA SN 0022-3492 EI 1943-3670 J9 J PERIODONTOL JI J. Periodont. PD OCT PY 2015 VL 86 IS 10 BP 1159 EP 1165 DI 10.1902/jop.2015.150223 PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA CS4KR UT WOS:000362045200008 PM 26156676 ER PT J AU Rubinsky, AD Chen, C Batki, SL Williams, EC Harris, AHS AF Rubinsky, Anna D. Chen, Cheng Batki, Steven L. Williams, Emily C. Harris, Alex H. S. TI Comparative utilization of pharmacotherapy for alcohol use disorder and other psychiatric disorders among US Veterans Health Administration patients with dual diagnoses SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Alcohol use disorder; Pharmacotherapy; Medication; Dual diagnosis; Psychiatric disorders ID NATIONAL EPIDEMIOLOGIC SURVEY; DSM-IV ALCOHOL; SUBSTANCE USE; MENTAL-DISORDERS; UNITED-STATES; SMOKING-CESSATION; TOBACCO USE; DEPENDENCE; CARE; METAANALYSIS AB Patients with alcohol use disorder (AUD) and another co-occurring psychiatric disorder are a vulnerable population with high symptom severity. Such patients may benefit from a full arsenal of treatment options including pharmacotherapy. Receipt of AUD pharmacotherapy is generally very low despite recommendations that it be made available to every patient with AUD, including those with co-occurring disorders. Little is known about pharmacotherapy rates for AUD compared to other psychiatric disorders among patients with dual diagnoses. This study compared rates of pharmacotherapy for AUD to those for non-substance use psychiatric disorders and tobacco use disorder among patients with dual diagnoses in the U.S. Veterans Affairs (VA) healthcare system. VA data were used to identify patients with AUD and another psychiatric disorder in fiscal year 2012, and to estimate the proportion receiving pharmacotherapy for AUD and for each comorbid condition. Among subsets of patients with AUD and co-occurring schizophrenic, bipolar, posttraumatic stress or major depressive disorder, receipt of medications for AUD ranged from 7% to 11%, whereas receipt of medications for the comorbid disorder ranged from 69% to 82%. Among patients with AUD and co-occurring tobacco use disorder, 6% received medication for their AUD and 34% for their tobacco use disorder. Among patients with dual diagnoses, rates of pharmacotherapy for AUD were far lower than those for the comorbid disorders and contrary to evidence that medications for AUD are effective. Additional system-wide implementation efforts to identify and address patient- and provider-level barriers are needed to increase AUD pharmacotherapy in this highneed population. Published by Elsevier Ltd. C1 [Rubinsky, Anna D.; Harris, Alex H. S.] VA Palo Alto Hlth Care Syst, Vet Affairs VA Substance Use Disorder Qual Enhanc, Menlo Pk, CA 94025 USA. [Rubinsky, Anna D.; Chen, Cheng; Harris, Alex H. S.] VA Palo Alto Hlth Care Syst, Ctr Innovat Implementat Ci2i, Hlth Serv Res & Dev, Menlo Pk, CA 94025 USA. [Batki, Steven L.] San Francisco VA Med Ctr, Addict Psychiat Res Program, San Francisco, CA 94121 USA. [Batki, Steven L.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Williams, Emily C.] VA Puget Sound Hlth Care Syst, Seattle Ctr Innovat Veteran Ctr & Value Driven Ca, Hlth Serv Res & Dev S152, Seattle, WA 98108 USA. [Williams, Emily C.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. RP Rubinsky, AD (reprint author), VA Palo Alto Hlth Care Syst, Vet Affairs VA Substance Use Disorder Qual Enhanc, 795 Willow Rd MPD 152, Menlo Pk, CA 94025 USA. EM Anna.Rubinsky@va.gov FU United States Department of Veterans Affairs (VA) Health Services Research & Development (HSRD) Program; VA HSR&D Substance Use Disorders Quality Enhancement Research Initiative (SUD QUERI); VA HSRD [CDA 12-276]; National Institute of Mental Health [R25 MH080916-01A2]; VA HSRD QUERI FX This work was supported by the United States Department of Veterans Affairs (VA) Health Services Research & Development (HSR&D) Program and VA HSR&D Substance Use Disorders Quality Enhancement Research Initiative (SUD QUERI). Dr. Williams is supported by a Career Development Award from VA HSR&D (CDA 12-276) and is an investigator with the Implementation Research Institute (IRI) at the George Warren Brown School of Social Work at Washington University in St. Louis. IRI is supported through an award from the National Institute of Mental Health (R25 MH080916-01A2) and the VA HSR&D QUERI. NR 73 TC 5 Z9 5 U1 3 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 EI 1879-1379 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD OCT PY 2015 VL 69 BP 150 EP 157 DI 10.1016/j.jpsychires.2015.07.016 PG 8 WC Psychiatry SC Psychiatry GA CS2UP UT WOS:000361927800022 PM 26343607 ER PT J AU Isakova, T Ix, JH Sprague, SM Raphael, KL Fried, L Gassman, JJ Raj, D Cheung, AK Kusek, JW Flessner, MF Wolf, M Block, GA AF Isakova, Tamara Ix, Joachim H. Sprague, Stuart M. Raphael, Kalani L. Fried, Linda Gassman, Jennifer J. Raj, Dominic Cheung, Alfred K. Kusek, John W. Flessner, Michael F. Wolf, Myles Block, Geoffrey A. TI Rationale and Approaches to Phosphate and Fibroblast Growth Factor 23 Reduction in CKD SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Review ID CHRONIC KIDNEY-DISEASE; STAGE RENAL-DISEASE; DIETARY PHOSPHORUS RESTRICTION; RANDOMIZED CLINICAL-TRIAL; PLACEBO-CONTROLLED TRIAL; LEFT-VENTRICULAR MASS; VITAMIN-D METABOLISM; HEMODIALYSIS-PATIENTS; PARATHYROID-HORMONE; CARDIOVASCULAR EVENTS AB Patients with CKD often progress to ESRD and develop cardiovascular disease (CVD), yet available therapies only modestly improve clinical outcomes. Observational studies report independent associations between elevated serum phosphate and fibroblast growth factor 23 (FGF23) levels and risks of ESRD, CVD, and death. Phosphate excess induces arterial calcification, and although elevated FGF23 helps maintain serum phosphate levels in the normal range in CKD, it may contribute mechanistically to left ventricular hypertrophy (LVH). Consistent epidemiologic and experimental findings suggest the need to test therapeutic approaches that lower phosphate and FGF23 in CKD. Dietary phosphate absorption is one modifiable determinant of serum phosphate and FGF23 levels. Limited data from pilot studies in patients with CKD stages 3-4 suggest that phosphate binders, low phosphate diets, or vitamin B3 derivatives, such as niacin or nicotinamide, may reduce dietary phosphate absorption and serum phosphate and FGF23 levels. This review summarizes current knowledge regarding the deleterious systemic effects of phosphate and FGF23 excess, identifies questions that must be addressed before advancing to a full-scale clinical outcomes trial, and presents a novel therapeutic approach to lower serum phosphate and FGF23 levels that will be tested in the COMBINE Study: The CKD Optimal Management With Binders and NicotinannidE study. C1 [Isakova, Tamara; Wolf, Myles] Northwestern Univ, Feinberg Sch Med, Div Nephrol & Hypertens, Dept Med, Chicago, IL 60611 USA. [Isakova, Tamara; Wolf, Myles] Northwestern Univ, Feinberg Sch Med, Ctr Translat Metab & Hlth, Inst Publ Hlth & Med, Chicago, IL 60611 USA. [Ix, Joachim H.] Univ Calif San Diego, Nephrol Sect, Vet Affairs San Diego Healthcare Syst, San Diego, CA 92103 USA. [Ix, Joachim H.] Univ Calif San Diego, Div Nephrol & Prevent Med, San Diego, CA 92103 USA. [Sprague, Stuart M.] Univ Chicago, Pritzker Sch Med, NprthShore Univ Hlth Syst, Evanston, IL USA. [Raphael, Kalani L.; Cheung, Alfred K.] Univ Utah, Salt Lake City Vet Affairs Healthcare Syst, Salt Lake City, UT USA. [Raphael, Kalani L.; Cheung, Alfred K.] Univ Utah, Div Nephrol & Hypertens, Salt Lake City, UT USA. [Fried, Linda] Univ Pittsburgh, Sch Med, VA Pittsburgh Healthcare Syst, Renal Sect, Pittsburgh, PA USA. [Gassman, Jennifer J.] Cleveland Clin Fdn, Dept Biostat & Epidemiol, Cleveland, OH 44195 USA. [Raj, Dominic] George Washington Univ, Div Renal Dis & Hypertens, Washington, DC USA. [Kusek, John W.; Flessner, Michael F.] NIDDK, Bethesda, MD USA. [Block, Geoffrey A.] Denver Nephrol, Denver, CO USA. RP Isakova, T (reprint author), 633 N St Clair St,Suite 18-083, Chicago, IL 60611 USA. EM tamara.isakova@northwestern.edu OI Raphael, Kalani/0000-0002-1378-2609 FU National Institute of Diabetes and Digestive and Kidney Diseases [K23-DK081673, R01-DK102438, U01-DK099877, U01-DK097093, U01-DK099930, U01-DK099933, U01-DK099924]; Carl W. Gottschalk Research Scholar Grant from the American Society of Nephrology Foundation for Kidney Research; VA Career Development Award [IK2CX000537]; Harold Amos Medical Faculty Development Award from the Robert Wood Johnson Foundation FX T.I. is supported by grants K23-DK081673 and R01-DK102438 from the National Institute of Diabetes and Digestive and Kidney Diseases and by the Carl W. Gottschalk Research Scholar Grant from the American Society of Nephrology Foundation for Kidney Research.; K.L.R. is supported by the VA Career Development Award (IK2CX000537) and the Harold Amos Medical Faculty Development Award from the Robert Wood Johnson Foundation.; The COMBINE study is supported by grants U01-DK099877, U01-DK097093, U01-DK099930, U01-DK099933, U01-DK099924, and R01-DK102438 from the National Institute of Diabetes and Digestive and Kidney Diseases. NR 102 TC 20 Z9 22 U1 0 U2 11 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD OCT PY 2015 VL 26 IS 10 BP 2328 EP 2339 DI 10.1681/ASN.2015020117 PG 12 WC Urology & Nephrology SC Urology & Nephrology GA CS5ZL UT WOS:000362156700007 PM 25967123 ER PT J AU Safa, K Ohori, S Borges, TJ Uehara, M Batal, I Shimizu, T Magee, CN Belizaire, R Abdi, R Wu, C Chandraker, A Riella, LV AF Safa, Kassem Ohori, Shunsuke Borges, Thiago J. Uehara, Mayuko Batal, Ibrahim Shimizu, Tetsunosuke Magee, Ciara N. Belizaire, Roger Abdi, Reza Wu, Chuan Chandraker, Anil Riella, Leonardo V. TI Salt Accelerates Allograft Rejection through Serum- and Glucocorticoid-Regulated Kinase-1-Dependent Inhibition of Regulatory T Cells SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID RENAL-TRANSPLANT RECIPIENTS; PATHOGENIC T(H)17 CELLS; BLOOD-PRESSURE; PROTEIN-KINASE; FOXP3 EXPRESSION; SGK; DIFFERENTIATION; INDUCTION; FOXO3A; MODEL AB A high-salt diet (HSD) in humans is linked to a number of complications, including hypertension and cardiovascular events. Whether a HSD affects the immune response in transplantation is unknown. Using a murine transplantation model, we investigated the effect of NaCl on the alloimmune response in vitro and in vivo. Incremental NaCl concentrations in vitro augmented T cell proliferation in the settings of both polyclonal and allospecific stimulation. Feeding a HSD to C57BL/6 wild-type recipients of bm12 allografts led to accelerated cardiac allograft rejection, despite similar mean BP and serum sodium levels in HSD and normal salt diet (NSD) groups. The accelerated rejection was associated with a reduction in the proportion of CD4(+)Foxp3(+) regulatory T cells (Tregs) and a significant decrease in Treg proliferation, leading to an increased ratio of antigen-experienced CDC+ T cells to Tregs in mice recipients of a HSD compared with mice recipients of a NSD. Because serum- and glucocorticoid-regulated kinase-1 (SGK1) has been proposed as a potential target of salt in immune cells, we fed a HSD to CD4(Cre)SGK1(fl/fl) B6-transplanted recipients and observed abrogation of the deleterious effect of a HSD in the absence of SGK1 on CD4(+) cells. In summary, we show that NaCl negatively affects the regulatory balance of T cells in transplantation and precipitates rejection in an SGK1-dependent manner. C1 [Safa, Kassem; Ohori, Shunsuke; Borges, Thiago J.; Uehara, Mayuko; Shimizu, Tetsunosuke; Magee, Ciara N.; Abdi, Reza; Chandraker, Anil; Riella, Leonardo V.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Schuster Family Transplantat Res Ctr,Div Renal, Boston, MA USA. [Safa, Kassem] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplant Ctr, Boston, MA USA. [Safa, Kassem] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Nephrol, Boston, MA USA. [Borges, Thiago J.] Pontificia Univ Catolica Rio Grande do Sul, Sch Biosci, Porto Alegre, RS, Brazil. [Borges, Thiago J.] Pontificia Univ Catolica Rio Grande do Sul, Biomed Res Inst, Porto Alegre, RS, Brazil. [Batal, Ibrahim; Belizaire, Roger] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Magee, Ciara N.] Natl Hlth Serv Fdn Trust, Royal Free London, Dept Renal Med & Transplantat, London, England. [Wu, Chuan] Harvard Univ, Sch Med, Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA USA. RP Riella, LV (reprint author), 221 Longwood Ave, Boston, MA 02115 USA. EM lriella@rics.bwh.harvard.edu OI Borges, Thiago J/0000-0002-6554-0169 FU NIAID NIH HHS [K99 AI110649] NR 27 TC 8 Z9 8 U1 0 U2 8 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD OCT PY 2015 VL 26 IS 10 BP 2341 EP 2347 DI 10.1681/ASN.2014090914 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA CS5ZL UT WOS:000362156700008 PM 25833841 ER PT J AU Ix, JH Biggs, ML Mukamal, K Djousse, L Siscovick, D Tracy, R Katz, R Delaney, JA Chaves, P Rifkin, DE Hughes-Austin, JM Garimella, PS Sarnak, MJ Shlipak, MG Kizer, JR AF Ix, Joachim H. Biggs, Mary L. Mukamal, Kenneth Djousse, Luc Siscovick, David Tracy, Russell Katz, Ronit Delaney, Joseph A. Chaves, Paulo Rifkin, Dena E. Hughes-Austin, Jan M. Garimella, Pranav S. Sarnak, Mark J. Shlipak, Michael G. Kizer, Jorge R. TI Urine Collagen Fragments and CKD Progression-The Cardiovascular Health Study SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID AMINO-TERMINAL PROPEPTIDE; CREATININE EXCRETION RATE; INJURY MOLECULE-1 KIM-1; KIDNEY-FUNCTION DECLINE; CASE-COHORT DESIGNS; CYSTATIN-C; SERUM BICARBONATE; III PROCOLLAGEN; ATHEROSCLEROSIS MESA; LIPOCALIN NGAL AB Tubulointerstitial fibrosis is common with ageing and strongly prognostic for ESRD but is poorly captured by eGFR or urine albumin to creatinine ratio (ACR). Higher urine levels of procollagen type III N-terminal propeptide (PIIINP) mark the severity of tubulointerstitial fibrosis in biopsy studies, but the association of urine PIIINP with CKD progression is unknown. Among community-living persons aged >= 65 years, we measured PIIINP in spot urine specimens from the 1996 to 1997 Cardiovascular Health Study visit among individuals with CKD progression (30% decline in eGFR over 9 years, n=192) or incident ESRD (n=54) during follow-up, and in 958 randomly selected participants. We evaluated associations of urine PIIINP with CKD progression and incident ESRD. Associations of urine PIIINP with cardiovascular disease, heart failure, and death were evaluated as secondary end points. At baseline, mean age (+/- SD) was 78 +/- 5 years, mean eGFR was 63 +/- 18 ml/min per 1.73 m(2), and median urine PIIINP was 2.6 (interquartile range, 1.4-4.2) mu g/L. In a case-control study (192 participants, 231 controls), each doubling of urine PIIINP associated with 22% higher odds of CKD progression (adjusted odds ratio, 1.22; 95% confidence interval, 1.00 to 1.49). Higher urine PIIINP level was also associated with incident ESRD, but results were not significant in fully adjusted models. In a prospective study among the 958 randomly selected participants, higher urine PIIINP was significantly associated with death, but not with incident cardiovascular disease or heart failure. These data suggest higher urine PIIINP levels associate with CKD progression independently of eGFR and ACR in older individuals. C1 [Ix, Joachim H.; Rifkin, Dena E.] Univ Calif San Diego & Vet Affairs San Diego Heal, Div Nephrol Hypertens, San Diego, CA USA. [Biggs, Mary L.] Univ Washington, Sch Publ Hlth & Community Med, Dept Biostat, Seattle, WA 98195 USA. [Mukamal, Kenneth] Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care, Boston, MA 02215 USA. [Djousse, Luc] Brigham & Womens Hosp & Boston Vet Affairs Hlth S, Div Aging, Boston, MA USA. [Siscovick, David] New York Acad Med, New York, NY USA. [Tracy, Russell] Univ Vermont, Dept Pathol, Burlington, VT 05405 USA. [Katz, Ronit] Univ Washington, Div Nephrol, Seattle, WA 98195 USA. [Delaney, Joseph A.] Univ Washington, Sch Publ Hlth & Community Med, Dept Epidemiol, Seattle, WA 98195 USA. [Chaves, Paulo] Florida Int Univ, Dept Med, Miami, FL 33199 USA. [Hughes-Austin, Jan M.] Univ Calif San Diego, Dept Family & Prevent Med, San Diego, CA 92103 USA. [Garimella, Pranav S.; Sarnak, Mark J.] Tufts Med Ctr, Div Nephrol, Boston, MA USA. [Shlipak, Michael G.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Shlipak, Michael G.] San Francisco VA Med Ctr, San Francisco, CA USA. [Kizer, Jorge R.] Albert Einstein Coll Med, Dept Med, Bronx, NY 10467 USA. [Kizer, Jorge R.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. RP Ix, JH (reprint author), Univ Calif San Diego, Div Nephrol Hypertens, 3350 La Jolla Village Dr,Mail Code 9111-H, San Diego, CA 92161 USA. EM joeix@ucsd.edu RI Djousse, Luc/F-5033-2017 OI Djousse, Luc/0000-0002-9902-3047 FU National Institute of Diabetes Digestive and Kidney Diseases [R01-DK098234]; National Heart, Lung, and Blood Institute [R01-HL094555, U01-HL080295]; American Heart Association Established Investigator Award [14EIA18560026]; National Institute on Aging [R01-AG027002, R01-AG023629]; [HHSN268201200036C]; [HHSN268200800007C]; [N01-HC55222]; [N01-HC85079]; [N01-HC85080]; [N01-HC85081]; [N01-HC85082]; [N01-HC85083]; [N01-HC85086] FX Supported by grants from the National Institute of Diabetes Digestive and Kidney Diseases (grant no. R01-DK098234) (to Drs. Ix and Shlipak); National Heart, Lung, and Blood Institute (grant no. R01-HL094555) (to Drs. Ix, Mukamal, Djousse, and Kizer); American Heart Association Established Investigator Award (award no. 14EIA18560026) (to Dr. Ix); and National Institute on Aging (grant nos. R01-AG027002) (Dr Sarnak). The CHS was supported by contracts HHSN268201200036C, HHSN268200800007C, N01-HC55222, N01-HC85079, N01-HC85080, N01-HC85081, N01-HC85082, N01-HC85083, N01-HC85086, and grant U01-HL080295 from the National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke and from grant R01-AG023629 from the National Institute on Aging. This material is the result of work supported with resources of the VA San Diego Healthcare System. NR 38 TC 7 Z9 7 U1 1 U2 1 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD OCT PY 2015 VL 26 IS 10 BP 2494 EP 2503 DI 10.1681/ASN.2014070696 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA CS5ZL UT WOS:000362156700021 PM 25655067 ER PT J AU King, DR Butler, F Kragh, JF AF King, David R. Butler, Frank Kragh, John F. TI Re: Tourniquet use at the Boston Marathon bombing SO JOURNAL OF TRAUMA AND ACUTE CARE SURGERY LA English DT Letter C1 [King, David R.] Harvard Univ, Sch Med, Knight Surg Res Lab, Div Trauma Acute Care Surg & Surg Crit Care, Boston, MA 02115 USA. [King, David R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Butler, Frank] Dept Def Comm Tact Combat Casualty Care, Prehosp Care Branch, Dept Def Joint Trauma Syst, Def Hlth Board,Trauma & Injury Subcomm, Washington, DC USA. [Kragh, John F.] USUHS Sch Med, US Army Inst Surg Res, Damage Control Resuscitat, San Antonio, TX USA. RP King, DR (reprint author), Harvard Univ, Sch Med, Knight Surg Res Lab, Div Trauma Acute Care Surg & Surg Crit Care, Boston, MA 02115 USA. OI King, David/0000-0003-1028-1478 NR 5 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 2163-0755 EI 2163-0763 J9 J TRAUMA ACUTE CARE JI J. Trauma Acute Care Surg. PD OCT PY 2015 VL 79 IS 4 BP 702 EP 703 DI 10.1097/TA.0000000000000803 PG 2 WC Critical Care Medicine; Surgery SC General & Internal Medicine; Surgery GA CS5IZ UT WOS:000362112900028 PM 26402551 ER PT J AU Grob, JJ Amonkar, MM Karaszewska, B Schachter, J Dummer, R Mackiewicz, A Stroyakovskiy, D Drucis, K Grange, F Chiarion-Sileni, V Rutkowski, P Lichinitser, M Levchenko, E Wolter, P Hauschild, A Long, GV Nathan, P Ribas, A Flaherty, K Sun, P Legos, JJ McDowell, DO Mookerjee, B Schadendorf, D Robert, C AF Grob, Jean Jacques Amonkar, Mayur M. Karaszewska, Boguslawa Schachter, Jacob Dummer, Reinhard Mackiewicz, Andrzej Stroyakovskiy, Daniil Drucis, Kamil Grange, Florent Chiarion-Sileni, Vanna Rutkowski, Piotr Lichinitser, Mikhail Levchenko, Evgeny Wolter, Pascal Hauschild, Axel Long, Georgina V. Nathan, Paul Ribas, Antoni Flaherty, Keith Sun, Peng Legos, Jeffrey J. McDowell, Diane Opatt Mookerjee, Bijoyesh Schadendorf, Dirk Robert, Caroline TI Comparison of dabrafenib and trametinib combination therapy with vemurafenib monotherapy on health-related quality of life in patients with unresectable or metastatic cutaneous BRAF Val600-mutation-positive melanoma (COMBI-v): results of a phase 3, open-label, randomised trial SO LANCET ONCOLOGY LA English DT Article ID QUESTIONNAIRE QLQ-C30; EUROPEAN-ORGANIZATION; CANCER; RELIABILITY; VALIDITY; SURVIVAL; SCORES; EQ-5D AB Background In the COMBI-v trial, patients with previously untreated BRAF Val600Glu or Val600Lys mutant unresectable or metastatic melanoma who were treated with the combination of dabrafenib and trametinib had significantly longer overall and progression-free survival than those treated with vemurafenib alone. Here, we present the effects of treatments on health-related quality of life (HRQoL), an exploratory endpoint in the COMBI-v study. Methods COMBI-v was an open-label, randomised phase 3 study in which 704 patients with metastatic melanoma with a BRAF Val600 mutation were randomly assigned (1: 1) by an interactive voice response system to receive either a combination of dabrafenib (150 mg twice-daily) and trametinib (2 mg once-daily) or vemurafenib monotherapy (960 mg twice-daily) orally as first-line therapy. The primary endpoint was overall survival. In this pre-specified exploratory analysis, we prospectively assessed HRQoL in the intention-to-treat population with the European Organisation for Research and Treatment of Cancer quality of life (EORTC QLQ-C30), EuroQoL-5D (EQ-5D), and Melanoma Subscale of the Functional Assessment of Cancer Therapy-Melanoma (FACT-M), completed at baseline, during study treatment, at disease progression, and after progression. We used a mixed-model, repeated measures ANCOVA to assess differences in mean scores between groups with baseline score as covariate; all p-values are descriptive. The COMBI-v trial is registered with ClinicalTrials.gov, number NCT01597908, and is ongoing for the primary endpoint, but is not recruiting patients. Findings From June 4, 2012, to Oct 7, 2013, 1645 patients at 193 centres worldwide were screened for eligibility, and 704 patients were randomly assigned to dabrafenib plus trametinib (n=352) or vemurafenib (n=352). Questionnaire completion rates for both groups were high (>95% at baseline, >80% at follow-up assessments, and >70% at disease progression) with similar HRQoL and symptom scores reported at baseline in both treatment groups for all questionnaires. Differences in mean scores between treatment groups were signifi cant and clinically meaningful in favour of the combination compared with vemurafenib monotherapy for most domains across all three questionnaires during study treatment and at disease progression, including EORTC QLQ-C30 global health (7.92, 7.62, 6.86, 7.47, 5.16, 7.56, and 7.57 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; p<0.001 for all assessments except p=0.005 at week 40), EORTC QLQ-C30 pain (-13.20, -8.05, -8.82, -12.69, -12.46, -11.41, and -10.57 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; all p< 0.001), EQ-5D thermometer scores (7.96, 8.05, 6.83, 11.53, 7.41, 9.08, and 10.51 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; p< 0.001 for all assessments except p=0.006 at week 32), and FACT-M Melanoma Subscale score (3.62, 2.93, 2.45, 3.39, 2.85, 3.00, and 3.68 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; all p< 0.001). Interpretation From the patient's perspective, which integrates not only survival advantage but also disease-associated and adverse-event-associated symptoms, treatment with the combination of a BRAF inhibitor plus a MEK inhibitor (dabrafenib plus trametinib) adds a clear benefit over monotherapy with the BRAF inhibitor vemurafenib and supports the combination therapy as standard of care in this population. C1 [Grob, Jean Jacques] Aix Marseille Univ, Serv Dermatol, Marseille, France. [Grob, Jean Jacques] Univ Hosp Timone, APHM, Marseille, France. [Amonkar, Mayur M.; Sun, Peng; Legos, Jeffrey J.; McDowell, Diane Opatt; Mookerjee, Bijoyesh] GlaxoSmithKline Oncol Res & Dev, Collegeville, PA USA. [Karaszewska, Boguslawa] Przychodnia Lekarska Komed, Konin, Poland. [Schachter, Jacob] Chaim Sheba Med Ctr, Ramat Gan, Ramat, Israel. [Dummer, Reinhard] Univ Zurich, Dept Dermatol, Zurich, Switzerland. [Mackiewicz, Andrzej] Poznan Univ Med Sci, Med Polonia, Div Oncol, Poznan, Poland. [Stroyakovskiy, Daniil] Moscow City Oncol Hosp 62, Moscow, Russia. [Drucis, Kamil] Swissmed Ctr Zdrowia, Gdansk, Poland. [Drucis, Kamil] Gdansk Med Univ, Gdansk, Poland. [Grange, Florent] Hop Robert Debre, Ctr Hosp Univ Reims, Reims, France. [Chiarion-Sileni, Vanna] Ist Ricovero & Cura Carattere Sci, Ist Oncol Veneto, Padua, Italy. [Rutkowski, Piotr] Maria Sklodowska Curie Mem Canc Ctr, Warsaw, Poland. [Rutkowski, Piotr] Inst Oncol, Warsaw, Poland. [Lichinitser, Mikhail] NN Blokhin Russian Canc Res Ctr, Moscow, Russia. [Levchenko, Evgeny] NN Petrov Oncol Res Inst, St Petersburg, Russia. [Wolter, Pascal] Univ Hosp Leuven, Leuven Canc Inst, Leuven, Belgium. [Hauschild, Axel] UKSH, Dept Dermatol, Kiel, Germany. [Long, Georgina V.] Univ Sydney, Melanoma Inst Australia, Sydney, NSW 2006, Australia. [Long, Georgina V.] Mater Hosp, Sydney, NSW, Australia. [Nathan, Paul] Mt Vernon Canc Ctr, Northwood, Middx, England. [Ribas, Antoni] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90024 USA. [Flaherty, Keith] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Schadendorf, Dirk] Univ Hosp Essen, Dept Dermatol, Essen, Germany. [Robert, Caroline] Gustave Roussy, Dept Med Oncol, Serv Dermatol, Villejuif, France. [Robert, Caroline] Univ Paris 11, Fac Med, Villejuif, France. RP Grob, JJ (reprint author), Aix Marseille Univ, Serv Dermatol, 264 Rue St Pierre, Marseille, France. EM jean-jacques.grob@ap-hm.fr FU GlaxoSmithKline FX Medical writing assistance in the form of collating author comments, copyediting, and editorial assistance was provided by Beverley Swain (SciMentum, UK), and funded by GlaxoSmithKline. NR 25 TC 21 Z9 22 U1 3 U2 10 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 OCT PY 2015 VL 16 IS 13 BP 1389 EP 1398 PG 10 WC Oncology SC Oncology GA CS3BO UT WOS:000361946300045 PM 26433819 ER PT J AU Grob, JJ Long, GV Schadendorf, D Flaherty, K AF Grob, Jean Jacques Long, Georgina V. Schadendorf, Dirk Flaherty, Keith TI Disease kinetics for decision-making in advanced melanoma: a call for scenario-driven strategy trials SO LANCET ONCOLOGY LA English DT Article ID METASTATIC MELANOMA; CUTANEOUS MELANOMA; BRAF; SURVIVAL; IPILIMUMAB; VEMURAFENIB; DABRAFENIB; NIVOLUMAB AB In the past 5 years, the treatment of metastatic melanoma has changed from almost no effective treatment to the use of targeted and immune therapies with proven improvements in survival. The time has now come to define the optimal drug combinations, sequence of treatment, and drug regimens (intermittent vs continuous dosing) in the treatment of patients with metastatic melanoma. In view of the prevalence of advanced melanoma, finite resources, and the heterogeneity of disease characteristics, not all possibilities can be tested in therapeutic trials starting from an unselected population of patients with metastatic melanoma. In practice, clinicians rely on a few clinically derived signals, especially dynamic signals, to categorise patients into scenarios, from fast disease kinetics to slow disease kinetics, which drive clinicians' therapeutic decision making. The realistic goals of therapy are different in each scenario. We recommend that these scenarios are incorporated into clinical trials as either patient inclusion criteria or stratification factors. This approach is not only feasible but is also the only way to generate evidence for more effective and individualised treatment strategies for patients with metastatic melanoma. C1 [Grob, Jean Jacques] Aix Marseille Univ, F-13885 Marseille, France. [Grob, Jean Jacques] APHM Hosp CHU Timone, F-13885 Marseille, France. [Long, Georgina V.] Univ Sydney, Melanoma Inst Australia, Sydney, NSW 2006, Australia. [Long, Georgina V.] Mater Hosp, Sydney, NSW, Australia. [Schadendorf, Dirk] Univ Hosp Essen, Essen, Germany. [Schadendorf, Dirk] German Canc Consortium, Essen, Germany. [Flaherty, Keith] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. RP Grob, JJ (reprint author), Aix Marseille Univ, F-13885 Marseille, France. EM jean-jacques.grob@ap-hm.fr FU Roche; GlaxoSmithKline; Bristol-Myers Squibb; Merck; Novartis; Amgen; Electra FX JJG has received research grants to his institution from Roche, personal fees for lectures from Roche and GlaxoSmithKline, and personal fees for advisory boards from Roche, GlaxoSmithKline, Bristol-Myers Squibb, Merck, Novartis, Amgen, and Electra. GVL has acted as a consultant advisor for Amgen, Bristol-Myers Squibb, Merck, Novartis, Provectus Biopharmaceuticals, and Roche. DS has received honoraria for consultancy, speaker's bureau, and advisory boards from Bristol-Myers Squibb, Merck, Novartis, Roche, Boehringer Ingelheim, Pfizer, Merck Serono, and GlaxoSmithKline. KF has acted as a consultant advisor for GSK, Novartis, Roche, and Merck. NR 19 TC 5 Z9 5 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD OCT PY 2015 VL 16 IS 13 BP E522 EP E526 PG 5 WC Oncology SC Oncology GA CS3BO UT WOS:000361946300020 PM 26433825 ER PT J AU Saxon, AJ AF Saxon, Andrew J. TI Comparative safety of methadone and buprenorphine SO LANCET PSYCHIATRY LA English DT Editorial Material ID PHARMACOKINETICS; DEPENDENCE; INDUCTION; HUMANS C1 Univ Washington, Dept Psychiat & Behav Sci, CESATE, VA Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. RP Saxon, AJ (reprint author), Univ Washington, Dept Psychiat & Behav Sci, CESATE, VA Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. EM asaxon@uw.edu FU Alkermes FX I have received an honoraria for lectures from ReckittBenckiser, scientific advisory board fees from Alkermes, and royalties from UpToDate. NR 11 TC 0 Z9 0 U1 0 U2 8 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2215-0374 J9 LANCET PSYCHIAT JI Lancet Psychiatry PD OCT PY 2015 VL 2 IS 10 BP 855 EP 856 DI 10.1016/S2215-0366(15)00413-7 PG 2 WC Psychiatry SC Psychiatry GA CS5GU UT WOS:000362106500005 PM 26384620 ER PT J AU Bril, F Cusi, K AF Bril, Fernando Cusi, Kenneth TI Response to do ultrasonographic semiquantitative indices predict histological changes in NASH irrespective of steatosis extent? SO LIVER INTERNATIONAL LA English DT Letter ID FATTY LIVER C1 [Bril, Fernando; Cusi, Kenneth] Univ Florida, Div Endocrinol Diabet & Metab, Gainesville, FL 32611 USA. [Bril, Fernando; Cusi, Kenneth] Malcom Randall Vet Adm Med Ctr, 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, San Antonio, TX USA. RP Bril, F (reprint author), Univ Florida, Div Endocrinol Diabet & Metab, Gainesville, FL 32611 USA. NR 5 TC 1 Z9 1 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1478-3223 EI 1478-3231 J9 LIVER INT JI Liver Int. PD OCT PY 2015 VL 35 IS 10 BP 2341 EP 2342 DI 10.1111/liv.12869 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CS6PC UT WOS:000362201800021 PM 25964992 ER PT J AU Molina, Y Silva, A Rauscher, GH AF Molina, Yamile Silva, Abigail Rauscher, Garth H. TI Racial/Ethnic Disparities in Time to a Breast Cancer Diagnosis The Mediating Effects of Health Care Facility Factors SO MEDICAL CARE LA English DT Article DE breast cancer; disparities; between-facility effects; accreditation; multisite care ID FOLLOW-UP; WOMEN; MAMMOGRAPHY; PREDICTORS; SURVIVAL; DELAY; STAGE; RACE/ETHNICITY; INSURANCE; HOSPITALS AB Background:Racial/ethnic disparities exist along the breast cancer continuum, including time to a diagnosis. Previous research has largely focused on patient-level factors, and less is known about the role that health care facilities may play in delayed breast cancer care.Objectives:We examined racial/ethnic disparities in delayed diagnosis for breast cancer in the Breast Cancer Care in Chicago Study and estimated the potential mediating effects of facility factors.Research Design and Subjects:Breast cancer patients (N=606) contributed interview and medical record data as part of a population-based study.Measures:Race/ethnicity was self-reported at interview. Diagnostic delay was defined as an excess of 60 days between medical presentation and a definitive diagnosis. Facility factors included the facility of medical presentation with respect to: (1) accreditation through the National Consortium of Breast Centers; (2) certification as a Breast Imaging Center of Excellence through the American College of Radiology; and (3) status as a disproportionate share hospital through the state of Illinois as well as the number of facilities used between presentation and diagnosis.Results:Relative to non-Hispanic whites, minorities were more likely to experience a diagnostic delay, present at a nonaccredited facility and at a disproportionate share hospital, and involve multiple facilities in their diagnosis. Together, facility factors accounted for 43% of the disparity in diagnostic delay (P<0.0001).Conclusions:Initial presentation of breast cancer at higher resourced facilities can reduce diagnostic delays. Disparities in delay are partly due to a disproportionate presentation at lower resourced facilities by minorities. C1 [Molina, Yamile; Rauscher, Garth H.] Univ Illinois, Sch Publ Hlth, Chicago, IL USA. [Molina, Yamile] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Silva, Abigail] US Dept Vet Affairs, Vet Affairs Edward Hines Jr Hosp, Ctr Innovat Complex Chron Healthcare, Hines, IL 60141 USA. RP Molina, Y (reprint author), 1603 West Taylor,6th Floor, Chicago, IL 60612 USA. EM ymolin2@uic.edu OI Silva, Abigail/0000-0002-1112-1209; Rauscher, Garth/0000-0003-0374-944X FU National Institutes of Health [P50CA106743, P50CA148143, R25CA92408]; University of Illinois-Chicago Center for Research on Women and Gender; University of Illinois Cancer Center; Office of Academic Affiliations, Department of Veterans Affairs [TPP 42-013] FX Supported by multiple National Institutes of Health grants (P50CA106743, P50CA148143, R25CA92408). Dr Molina was supported by the University of Illinois-Chicago Center for Research on Women and Gender and the University of Illinois Cancer Center. Dr Silva's work was supported by the Office of Academic Affiliations (TPP 42-013), Department of Veterans Affairs. The conclusions, opinions, and recommendations expressed in this article are not necessarily that of the Department of Veterans Affairs nor National Institutes of Health. NR 46 TC 2 Z9 2 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0025-7079 EI 1537-1948 J9 MED CARE JI Med. Care PD OCT PY 2015 VL 53 IS 10 BP 872 EP 878 DI 10.1097/MLR.0000000000000417 PG 7 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA CS5IL UT WOS:000362111500006 PM 26366519 ER PT J AU Urech, TH Woodard, LD Virani, SS Dudley, RA Lutschg, MZ Petersen, LA AF Urech, Tracy H. Woodard, LeChauncy D. Virani, Salim S. Dudley, R. Adams Lutschg, Meghan Z. Petersen, Laura A. TI Calculations of Financial Incentives for Providers in a Pay-for-Performance Program Manual Review Versus Data From Structured Fields in Electronic Health Records SO MEDICAL CARE LA English DT Article DE payment system design; performance measurement; incentives ID QUALITY MEASURES; MEASURING-AGREEMENT; HYPERTENSION CARE; KAPPA; TRIAL AB Background:Hospital report cards and financial incentives linked to performance require clinical data that are reliable, appropriate, timely, and cost-effective to process. Pay-for-performance plans are transitioning to automated electronic health record (EHR) data as an efficient method to generate data needed for these programs.Objective:To determine how well data from automated processing of structured fields in the electronic health record (AP-EHR) reflect data from manual chart review and the impact of these data on performance rewards.Research Design:Cross-sectional analysis of performance measures used in a cluster randomized trial assessing the impact of financial incentives on guideline-recommended care for hypertension.Subjects:A total of 2840 patients with hypertension assigned to participating physicians at 12 Veterans Affairs hospital-based outpatient clinics. Fifty-two physicians and 33 primary care personnel received incentive payments.Measures:Overall, positive and negative agreement indices and Cohen's kappa were calculated for assessments of guideline-recommended antihypertensive medication use, blood pressure (BP) control, and appropriate response to uncontrolled BP. Pearson's correlation coefficient was used to assess how similar participants' calculated earnings were between the data sources.Results:By manual chart review data, 72.3% of patients were considered to have received guideline-recommended antihypertensive medications compared with 65.0% by AP-EHR review (=0.51). Manual review indicated 69.5% of patients had controlled BP compared with 66.8% by AP-EHR review (=0.87). Compared with 52.2% of patients per the manual review, 39.8% received an appropriate response by AP-EHR review (=0.28). Participants' incentive payments calculated using the 2 methods were highly correlated (r0.98). Using the AP-EHR data to calculate earnings, participants' payment changes ranged from a decrease of $91.00 (-30.3%) to an increase of $18.20 (+7.4%) for medication use (interquartile range, -14.4% to 0%) and a decrease of $100.10 (-31.4%) to an increase of $36.40 (+15.4%) for BP control or appropriate response to uncontrolled BP (interquartile range, -11.9% to -6.1%).Conclusions:Pay-for-performance plans that use only EHR data should carefully consider the measures and the structure of the EHR before data collection and financial incentive disbursement. For this study, we feel that a 10% difference in the total amount of incentive earnings disbursed based on AP-EHR data compared with manual review is acceptable given the time and resources required to abstract data from medical records. C1 [Urech, Tracy H.; Woodard, LeChauncy D.; Virani, Salim S.; Lutschg, Meghan Z.; Petersen, Laura A.] Baylor Coll Med, Hlth Policy Qual & Informat Program, Michael E DeBakey VA HSR&D Ctr Innovat Qual Effec, Houston, TX 77030 USA. [Urech, Tracy H.; Woodard, LeChauncy D.; Virani, Salim S.; Lutschg, Meghan Z.; Petersen, Laura A.] Baylor Coll Med, Dept Med, Sect Hlth Serv Res, Houston, TX 77030 USA. [Dudley, R. Adams] Univ Calif San Francisco, Dept Med, Philip R Lee Inst Hlth Policy Studies, San Francisco, CA USA. [Dudley, R. Adams] Univ Calif San Francisco, Hlth Serv Informat, San Francisco, CA USA. RP Petersen, LA (reprint author), Michael E De Bakey Vet Affairs Med Ctr, HSR&D 152,2002 Holcombe Blvd, Houston, TX 77030 USA. EM laura.petersen@va.gov OI Virani, Salim/0000-0001-9541-6954 FU US Department of Veterans Affairs, Veterans Health Administration, Health Services Research & Development (HSR&D) Investigator-Initiated Research (IIR) [04-349]; National Institutes of Health (NIH) [RO1 HL079173-01]; American Heart Association Established Investigator Award [0540043N] FX Supported in part by the US Department of Veterans Affairs, Veterans Health Administration, Health Services Research & Development (HSR&D) Investigator-Initiated Research (IIR) 04-349 (L.A.P.) and the National Institutes of Health (NIH) RO1 HL079173-01 (L.A.P.).; L.A.P. is the Director at the Center for Innovations in Quality, Effectiveness and Safety (CIN 13-413), Michael E. DeBakey VA Medical Center, Houston, TX. L.A.P. was a recipient of the American Heart Association Established Investigator Award (Grant number 0540043N). R.A.D. is a Robert Wood Johnson Investigator Awardee in Health Policy. The remaining authors declare no conflict of interest. NR 26 TC 0 Z9 0 U1 4 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0025-7079 EI 1537-1948 J9 MED CARE JI Med. Care PD OCT PY 2015 VL 53 IS 10 BP 901 EP 907 DI 10.1097/MLR.0000000000000418 PG 7 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA CS5IL UT WOS:000362111500010 PM 26340661 ER PT J AU Haley, L Tseng, LH Zheng, G Dudley, J Anderson, DA Azad, NS Gocke, CD Eshleman, JR Lin, MT AF Haley, Lisa Tseng, Li-Hui Zheng, Gang Dudley, Jonathan Anderson, Derek A. Azad, Nilofer S. Gocke, Christopher D. Eshleman, James R. Lin, Ming-Tseh TI Performance characteristics of next-generation sequencing in clinical mutation detection of colorectal cancers SO MODERN PATHOLOGY LA English DT Article ID RAS MUTATIONS; ACQUIRED-RESISTANCE; MOLECULAR-FEATURES; KRAS MUTATIONS; BRAF MUTATIONS; PHASE-III; CHALLENGES; CETUXIMAB; MELANOMA; TRIAL AB Activating mutations in downstream genes of the epidermal growth factor receptor (EGFR) pathway may cause anti-EGFR resistance in patients with colorectal cancers. We present performance characteristics of a next-generation sequencing assay designed to detect such mutations. In this retrospective quality assessment study, we analyzed mutation detected in the KRAS, NRAS, BRAF, and PIK3CA genes by a clinically validated next-generation sequencing assay in 310 colorectal cancer specimens. Tumor cellularity and mutant allele frequency were analyzed to identify tumor heterogeneity and mutant allele-specific imbalance. Next-generation sequencing showed precise measurement of mutant allele frequencies and detected 23% of mutations with 2-20% mutant allele frequencies. Of the KRAS mutations detected, 17% were outside of codons 12 and 13. Among PIK3CA mutations, 48% were outside of codons 542, 545, and 1047. The percentage of tumors with predicted resistance to anti-EGFR therapy increased from 40% when testing for only mutations in KRAS exon 2 to 47% when testing for KRAS exons 2-4, 48% when testing for KRAS and NRAS exons 2-4, 58% when including BRAF codon 600 mutations, and 59% when adding PIK3CA exon 20 mutations. Right-sided colorectal cancers carried a higher risk of predicted anti-EGFR resistance. A concomitant KRAS mutation was detected in 51% of PIK3CA, 23% of NRAS, and 33% of kinase-impaired BRAF-mutated tumors. Lower than expected mutant allele frequency indicated tumor heterogeneity, while higher than expected mutant allele frequency indicated mutant allele-specific imbalance. Two paired neuroendocrine carcinomas and adjacent adenomas showed identical KRAS mutations, but only PIK3CA mutations in neuroendocrine carcinomas. Next-generation sequencing is a robust tool for mutation detection in clinical laboratories. It demonstrates high analytic sensitivity and broad reportable range, and it provides simultaneous detection of concomitant mutations and a quantitative measurement of mutant allele frequencies to predict tumor heterogeneity and mutant allele-specific imbalance. C1 [Haley, Lisa; Tseng, Li-Hui; Zheng, Gang; Dudley, Jonathan; Anderson, Derek A.; Gocke, Christopher D.; Eshleman, James R.; Lin, Ming-Tseh] Johns Hopkins Univ, Sch Med, Dept Pathol, Johns Hopkins Hosp, Baltimore, MD 21287 USA. [Tseng, Li-Hui] Natl Taiwan Univ Hosp, Dept Med Genet, Taipei, Taiwan. [Dudley, Jonathan] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Azad, Nilofer S.; Gocke, Christopher D.; Eshleman, James R.] Johns Hopkins Univ, Sch Med, Johns Hopkins Hosp, Dept Oncol, Baltimore, MD 21287 USA. RP Lin, MT (reprint author), Johns Hopkins Univ, Sch Med, Dept Pathol, Pk SB202,600 North Wolfe St, Baltimore, MD 21287 USA. EM mlin36@jhmi.edu FU National Cancer Institute of USA [1UM1CA186691-01] FX Supported by 1UM1CA186691-01 from the National Cancer Institute of USA. NR 41 TC 11 Z9 11 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD OCT PY 2015 VL 28 IS 10 BP 1390 EP 1399 DI 10.1038/modpathol.2015.86 PG 10 WC Pathology SC Pathology GA CS6NH UT WOS:000362195900010 PM 26226847 ER PT J AU Westin, SN Ju, ZL Broaddus, RR Krakstad, C Li, J Pal, N Lu, KH Coleman, RL Hennessy, BT Klempner, SJ Werner, HMJ Salvesen, HB Cantley, LC Mills, GB Myers, AP AF Westin, Shannon N. Ju, Zhenlin Broaddus, Russell R. Krakstad, Camilla Li, Jane Pal, Navdeep Lu, Karen H. Coleman, Robert L. Hennessy, Bryan T. Klempner, Samuel J. Werner, Henrica M. J. Salvesen, Helga B. Cantley, Lewis C. Mills, Gordon B. Myers, Andrea P. TI PTEN loss is a context-dependent outcome determinant in obese and non-obese endometrioid endometrial cancer patients SO MOLECULAR ONCOLOGY LA English DT Article DE Endometrial cancer; PTEN loss; Obesity; Survival; PI3K/AKT pathway ID BODY-MASS INDEX; CLINICAL-TRIALS GROUP; PROTEIN EXPRESSION; GYNECOLOGICAL MALIGNANCIES; PROMOTER METHYLATION; AKT PHOSPHORYLATION; PIK3CA MUTATIONS; PROGNOSTIC VALUE; HIGH-FREQUENCY; BETA-CATENIN AB Endometrial cancer incidence is increasing, due in part to a strong association with obesity. Mutations in the phosphatidylinositol 3-kinase (PI3K) pathway, the central relay pathway of insulin signals, occur in the majority of endometrioid adenocarcinomas, the most common form of endometrial cancer. We sought to determine the impact of PI3K pathway alterations on progression free survival in a cohort of endometrioid endometrial cancers. Prognostic utility of PIK3CA, PIK3R1, and PTEN mutations, as well as PTEN protein loss by immunohistochemistry, was explored in the context of patient body mass index. Reverse-phase protein arrays were utilized to assess protein expression based on PTEN status. Among 187 endometrioid endometrial cancers, there were no statistically significant associations between PFS and PIK3CA, PIK3R1, PTEN mutation or loss. When stratified by body mass index, PTEN loss was associated with improved progression free survival (P < 0.006) in obese (body mass index >= 30) patients. PTEN loss resulted in distinct protein changes: Canonical PI3K pathway activation was observed only in the non-obese population while decreased expression of beta-CATENIN and phosphorylated FOXO3A was observed in obese patients. These data suggest the impact of PTEN loss on tumor biology and clinical outcomes must be interpreted in the context of body mass index, and provide a potential explanation for discrepant reports on the effect of PTEN status and obesity on prognosis in endometrial cancer. This reveals a clinically important interaction between metabolic state and tumor genetics that may unveil the biologic underpinning of obesity-related cancers and impact ongoing clinical trials with PI3K pathway inhibitors. (C) 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. C1 [Westin, Shannon N.; Pal, Navdeep; Lu, Karen H.; Coleman, Robert L.] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol & Reprod Med, Houston, TX 77030 USA. [Ju, Zhenlin] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA. [Broaddus, Russell R.] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Krakstad, Camilla; Werner, Henrica M. J.; Salvesen, Helga B.] Haukeland Hosp, Dept Obstet & Gynecol, N-5021 Bergen, Norway. [Krakstad, Camilla; Werner, Henrica M. J.; Salvesen, Helga B.] Univ Bergen, Dept Clin Sci, Bergen, Norway. [Li, Jane; Mills, Gordon B.] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA. [Hennessy, Bryan T.] Beaumont Hosp, Dublin 9, Ireland. [Hennessy, Bryan T.] Royal Coll Surgeons Ireland, Dublin 2, Ireland. [Klempner, Samuel J.; Cantley, Lewis C.; Myers, Andrea P.] Beth Israel Deaconess Med Ctr, Hematol Oncol, Boston, MA 02215 USA. [Cantley, Lewis C.] Weill Cornell Med Coll, Dept Med, New York, NY USA. [Myers, Andrea P.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Westin, SN (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol & Reprod Med, Unit 1362, 1155 Herman Pressler Blvd, Houston, TX 77030 USA. EM swestin@mdanderson.org RI Cantley, Lewis/D-1800-2014; salvesen, Helga/C-1187-2017; OI Cantley, Lewis/0000-0002-1298-7653; salvesen, Helga/0000-0002-4438-8831; Krakstad, Camilla/0000-0002-0174-8139 FU NIH [K12 CA088084]; NCI SPORE in Uterine Cancer [2P50 CA098258-06]; NCI Cancer Center [P30 CA016672]; Program of the Entertainment Industry Foundation [SU2C-AACR-DT0209]; Helse Vest; Research Council of Norway; Norwegian Cancer Society FX NIH K12 Calabresi Scholar Award (K12 CA088084) to SNW, NCI SPORE in Uterine Cancer (2P50 CA098258-06) to SNW, RRB, KHL, GBM. NCI Cancer Center Support Grant (P30 CA016672) to MD Anderson Cancer Center Stand Up to Cancer Dream Team Translational Research Grant, a Program of the Entertainment Industry Foundation (SU2C-AACR-DT0209) to SNW, RRB, RLC, KHL, LCC, GBM, APM, Helse Vest, Research Council of Norway and The Norwegian Cancer Society, Harald Andersens legat to HBS. NR 52 TC 8 Z9 8 U1 0 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1574-7891 EI 1878-0261 J9 MOL ONCOL JI Mol. Oncol. PD OCT PY 2015 VL 9 IS 8 BP 1694 EP 1703 DI 10.1016/j.molonc.2015.04.014 PG 10 WC Oncology SC Oncology GA CS8AQ UT WOS:000362308500015 PM 26045339 ER PT J AU Govindan, JA Jayamani, E Zhang, XR Breen, P Larkins-Ford, J Mylonakis, E Ruvkun, G AF Govindan, J. Amaranath Jayamani, Elamparithi Zhang, Xinrui Breen, Peter Larkins-Ford, Jonah Mylonakis, Eleftherios Ruvkun, Gary TI Lipid signalling couples translational surveillance to systemic detoxification in Caenorhabditis elegans SO NATURE CELL BIOLOGY LA English DT Article ID C. ELEGANS; MAPK PHOSPHATASE; BACTERIA; PROLIFERATION; ASSOCIATION; INFECTIONS; RESISTANCE; INHIBITION; IMMUNITY; PATHWAYS AB Translation in eukaryotes is followed to detect toxins and virulence factors and coupled to the induction of defence pathways. Caenorhabditis elegans germline-specific mutations in translation components are detected by this system to induce detoxification and immune responses in distinct somatic cells. An RNA interference screen revealed gene inactivations that act at multiple steps in lipid biosynthetic and kinase pathways upstream of MAP kinase to mediate the systemic communication of translation defects to induce detoxification genes. Mammalian bile acids can rescue the defect in detoxification gene induction caused by C. elegans lipid biosynthetic gene inactivations. Extracts prepared from C. elegans with translation deficits but not from the wild type can also rescue detoxification gene induction in lipid-biosynthesis-defective strains. These eukaryotic antibacterial countermeasures are not ignored by bacteria: particular bacterial species suppress normal C. elegans detoxification responses to mutations in translation factors. C1 [Govindan, J. Amaranath; Jayamani, Elamparithi; Zhang, Xinrui; Breen, Peter; Larkins-Ford, Jonah; Ruvkun, Gary] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Govindan, J. Amaranath; Ruvkun, Gary] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Jayamani, Elamparithi; Mylonakis, Eleftherios] Brown Univ, Rhode Isl Hosp, Alpert Med Sch, Div Infect Dis, Providence, RI 02903 USA. RP Ruvkun, G (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. EM ruvkun@molbio.mgh.harvard.edu FU NIH Office at Research Infrastructure Programs [P40 OD010440]; Japanese National Bioresources Project; National Institutes it Health [AG043184-16A] FX Strains were provided by the Caenorhabditis Genetics Center (CGC), which is funded by the NIH Office at Research Infrastructure Programs (P40 OD010440), and S. Mitani of the Japanese National Bioresources Project. This work was supported in part by the National Institutes it Health Grant AG043184-16A (to G.R). Thanks to D. Coil and J. Eisen tor providing Kocuria species. NR 37 TC 5 Z9 5 U1 1 U2 11 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 OCT PY 2015 VL 17 IS 10 BP 1294 EP + DI 10.1038/ncb3229 PG 24 WC Cell Biology SC Cell Biology GA CS6SZ UT WOS:000362213500009 PM 26322678 ER PT J AU Kottakis, F Bardeesy, N AF Kottakis, Filippos Bardeesy, Nabeel TI Gene signatures from pancreatic cancer tumor and stromal cells predict disease outcome SO NATURE GENETICS LA English DT Editorial Material ID DUCTAL ADENOCARCINOMA AB Pancreatic cancers consist of a heterogeneous amalgam of assorted cell types, making it challenging to develop a classification system that groups these tumors according to common molecular features. A new study tackles this important issue using bioinformatics approaches to decipher gene expression signatures derived specifically from either tumor cells or nonmalignant stromal cells that predict patient outcome and may inform personalized treatments. C1 [Kottakis, Filippos; Bardeesy, Nabeel] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA. [Kottakis, Filippos; Bardeesy, Nabeel] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Kottakis, Filippos; Bardeesy, Nabeel] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Kottakis, F (reprint author), Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA. EM bardeesy.nabeel@mgh.harvard.edu NR 15 TC 1 Z9 1 U1 1 U2 7 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 OCT PY 2015 VL 47 IS 10 BP 1102 EP 1103 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA CS3JR UT WOS:000361969900002 PM 26417858 ER PT J AU Nikpay, M Goel, A Won, HH Hall, LM Willenborg, C Kanoni, S Saleheen, D Kyriakou, T Nelson, CP Hopewell, JC Webb, TR Zeng, L Dehghan, A Alver, M Armasu, SM Auro, K Bjonnes, A Chasman, DI Chen, SF Ford, I Franceschini, N Gieger, C Grace, C Gustafsson, S Huang, J Hwang, SJ Kim, YK Kleber, ME Lau, KW Lu, XF Lu, YC Lyytikainen, LP Mihailov, E Morrison, AC Pervjakova, N Qu, LM Rose, LM Salfati, E Saxena, R Scholz, M Smith, AV Tikkanen, E Uitterlinden, A Yang, XL Zhang, WH Zhao, W de Andrade, M de Vries, PS van Zuydam, NR Anand, SS Bertram, L Beutner, F Dedoussis, G Frossard, P Gauguier, D Goodall, AH Gottesman, O Haber, M Han, BG Huang, J Jalilzadeh, S Kessler, T Konig, IR Lannfelt, L Lieb, W Lind, L Lindgren, CM Lokki, ML Magnusson, PK Mallick, NH Mehra, N Meitinger, T Memon, FUR Morris, AP Nieminen, MS Pedersen, NL Peters, A Rallidis, LS Rasheed, A Samuel, M Shah, SH Sinisalo, J Stirrups, KE Trompet, S Wang, LY Zaman, KS Ardissino, D Boerwinkle, E Borecki, IB Bottinger, EP Buring, JE Chambers, JC Collins, R Cupples, LA Danesh, J Demuth, I Elosua, R Epstein, SE Esko, T Feitosa, MF Franco, OH Franzosi, MG Granger, CB Gu, DF Gudnason, V Hall, AS Hamsten, A Harris, TB Hazen, SL Hengstenberg, C Hofman, A Ingelsson, E Iribarren, C Jukema, JW Karhunen, PJ Kim, BJ Kooner, JS Kullo, IJ Lehtimaki, T Loos, RJF Melander, O Metspalu, A Marz, W Palmer, CN Perola, M Quertermous, T Rader, DJ Ridker, PM Ripatti, S Roberts, R Salomaa, V Sanghera, DK Schwartz, SM Seedorf, U Stewart, AF Stott, DJ Thiery, J Zalloua, PA O'Donnell, CJ Reilly, MP Assimes, TL Thompson, JR Erdmann, J Clarke, R Watkins, H Kathiresan, S McPherson, R Deloukas, P Schunkert, H Samani, NJ Farrall, M AF Nikpay, Majid Goel, Anuj Won, Hong-Hee Hall, Leanne M. Willenborg, Christina Kanoni, Stavroula Saleheen, Danish Kyriakou, Theodosios Nelson, Christopher P. Hopewell, Jemma C. Webb, Thomas R. Zeng, Lingyao Dehghan, Abbas Alver, Maris Armasu, Sebastian M. Auro, Kirsi Bjonnes, Andrew Chasman, Daniel I. Chen, Shufeng Ford, Ian Franceschini, Nora Gieger, Christian Grace, Christopher Gustafsson, Stefan Huang, Jie Hwang, Shih-Jen Kim, Yun Kyoung Kleber, Marcus E. Lau, King Wai Lu, Xiangfeng Lu, Yingchang Lyytikainen, Leo-Pekka Mihailov, Evelin Morrison, Alanna C. Pervjakova, Natalia Qu, Liming Rose, Lynda M. Salfati, Elias Saxena, Richa Scholz, Markus Smith, Albert V. Tikkanen, Emmi Uitterlinden, Andre Yang, Xueli Zhang, Weihua Zhao, Wei de Andrade, Mariza de Vries, Paul S. van Zuydam, Natalie R. Anand, Sonia S. Bertram, Lars Beutner, Frank Dedoussis, George Frossard, Philippe Gauguier, Dominique Goodall, Alison H. Gottesman, Omri Haber, Marc Han, Bok-Ghee Huang, Jianfeng Jalilzadeh, Shapour Kessler, Thorsten Koenig, Inke R. Lannfelt, Lars Lieb, Wolfgang Lind, Lars Lindgren, Cecilia M. Lokki, Marja-Liisa Magnusson, Patrik K. Mallick, Nadeem H. Mehra, Narinder Meitinger, Thomas Memon, Fazal-ur-Rehman Morris, Andrew P. Nieminen, Markku S. Pedersen, Nancy L. Peters, Annette Rallidis, Loukianos S. Rasheed, Asif Samuel, Maria Shah, Svati H. Sinisalo, Juha Stirrups, Kathleen E. Trompet, Stella Wang, Laiyuan Zaman, Khan S. Ardissino, Diego Boerwinkle, Eric Borecki, Ingrid B. Bottinger, Erwin P. Buring, Julie E. Chambers, John C. Collins, Rory Cupples, L. Adrienne Danesh, John Demuth, Ilja Elosua, Roberto Epstein, Stephen E. Esko, Tonu Feitosa, Mary F. Franco, Oscar H. Franzosi, Maria Grazia Granger, Christopher B. Gu, Dongfeng Gudnason, Vilmundur Hall, Alistair S. Hamsten, Anders Harris, Tamara B. Hazen, Stanley L. Hengstenberg, Christian Hofman, Albert Ingelsson, Erik Iribarren, Carlos Jukema, J. Wouter Karhunen, Pekka J. Kim, Bong-Jo Kooner, Jaspal S. Kullo, Iftikhar J. Lehtimaki, Terho Loos, Ruth J. F. Melander, Olle Metspalu, Andres Maerz, Winfried Palmer, Colin N. Perola, Markus Quertermous, Thomas Rader, Daniel J. Ridker, Paul M. Ripatti, Samuli Roberts, Robert Salomaa, Veikko Sanghera, Dharambir K. Schwartz, Stephen M. Seedorf, Udo Stewart, Alexandre F. Stott, David J. Thiery, Joachim Zalloua, Pierre A. O'Donnell, Christopher J. Reilly, Muredach P. Assimes, Themistocles L. Thompson, John R. Erdmann, Jeanette Clarke, Robert Watkins, Hugh Kathiresan, Sekar McPherson, Ruth Deloukas, Panos Schunkert, Heribert Samani, Nilesh J. Farrall, Martin CA CARDIoGRAMplusC4D Consortium TI A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease SO NATURE GENETICS LA English DT Article ID HEART-DISEASE; CARDIOVASCULAR-DISEASE; MYOCARDIAL-INFARCTION; SUSCEPTIBILITY LOCUS; GENETIC-VARIANTS; CELL-MIGRATION; IDENTIFIES 13; MICE LACKING; EXPRESSION; RISK AB Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of similar to 185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size. C1 [Nikpay, Majid; Stewart, Alexandre F.; McPherson, Ruth] Univ Ottawa, Inst Heart, Ruddy Canadian Cardiovasc Genet Ctr, Ottawa, ON, Canada. [Goel, Anuj; Kyriakou, Theodosios; Grace, Christopher; Jalilzadeh, Shapour; Watkins, Hugh; Farrall, Martin] Univ Oxford, Div Cardiovasc Med, Radcliffe Dept Med, Oxford, England. [Goel, Anuj; Kyriakou, Theodosios; Grace, Christopher; van Zuydam, Natalie R.; Jalilzadeh, Shapour; Lindgren, Cecilia M.; Morris, Andrew P.; Ingelsson, Erik; Watkins, Hugh; Farrall, Martin] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Won, Hong-Hee; Bjonnes, Andrew; Saxena, Richa; Lindgren, Cecilia M.; Esko, Tonu; Kathiresan, Sekar] Broad Inst MIT & Harvard Univ, Cambridge, MA USA. [Won, Hong-Hee; Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Won, Hong-Hee; Bjonnes, Andrew; Saxena, Richa; Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Won, Hong-Hee; Kathiresan, Sekar] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Hall, Leanne M.; Nelson, Christopher P.; Webb, Thomas R.; Samani, Nilesh J.] Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England. [Willenborg, Christina; Erdmann, Jeanette] Univ Lubeck, Inst Integrat & Expt Genom, Lubeck, Germany. [Willenborg, Christina; Koenig, Inke R.; Erdmann, Jeanette] DZHK German Res Ctr Cardiovasc Res, Lubeck, Germany. [Kanoni, Stavroula; Stirrups, Kathleen E.; Deloukas, Panos] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England. [Saleheen, Danish; Zhao, Wei] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Saleheen, Danish; Frossard, Philippe; Rasheed, Asif; Samuel, Maria] Ctr Noncommunicable Dis, Karachi, Pakistan. [Nelson, Christopher P.; Webb, Thomas R.; Goodall, Alison H.; Samani, Nilesh J.] Glenfield Hosp, NIHR, Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England. [Hopewell, Jemma C.; Lau, King Wai; Collins, Rory; Clarke, Robert] Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Oxford, England. [Hopewell, Jemma C.; Lau, King Wai; Collins, Rory; Clarke, Robert] Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit CTSU, Oxford, England. [Zeng, Lingyao; Kessler, Thorsten; Hengstenberg, Christian; Schunkert, Heribert] Tech Univ Munich, Deutsches Herzzentrum Munchen, D-80290 Munich, Germany. [Zeng, Lingyao; Gieger, Christian; Meitinger, Thomas; Peters, Annette; Hengstenberg, Christian; Schunkert, Heribert] DZHK German Ctr Cardiovasc Res, Munich, Germany. [Dehghan, Abbas; Uitterlinden, Andre; de Vries, Paul S.; Franco, Oscar H.; Hofman, Albert] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [Alver, Maris; Mihailov, Evelin; Pervjakova, Natalia; Esko, Tonu; Metspalu, Andres; Perola, Markus] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia. [Alver, Maris; Metspalu, Andres] Univ Tartu, Inst Mol & Cell Biol, EE-50090 Tartu, Estonia. [Armasu, Sebastian M.; de Andrade, Mariza] Mayo Clin, Dept Hlth Sci Res, Div Biomed Stat & Informat, Rochester, MN USA. [Auro, Kirsi; Pervjakova, Natalia; Perola, Markus] Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland. [Auro, Kirsi; Pervjakova, Natalia; Tikkanen, Emmi; Perola, Markus; Ripatti, Samuli] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland. [Auro, Kirsi; Pervjakova, Natalia; Perola, Markus] Univ Helsinki, Diabet & Obes Res Program, Helsinki, Finland. [Chasman, Daniel I.; Rose, Lynda M.; Buring, Julie E.; Ridker, Paul M.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Chasman, Daniel I.; Ridker, Paul M.] Harvard Univ, Sch Med, Boston, MA USA. [Chen, Shufeng; Lu, Xiangfeng; Yang, Xueli; Wang, Laiyuan; Gu, Dongfeng] Chinese Acad Med Sci, Natl Ctr Cardiovasc Dis, Fuwai Hosp, State Key Lab Cardiovasc Dis, Beijing 100730, Peoples R China. [Chen, Shufeng; Lu, Xiangfeng; Yang, Xueli; Huang, Jianfeng; Wang, Laiyuan; Gu, Dongfeng] Peking Union Med Coll, Beijing 100021, Peoples R China. [Ford, Ian] Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland. [Franceschini, Nora] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. 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[Kleber, Marcus E.; Maerz, Winfried] Heidelberg Univ, Med Fac Mannheim, Vth Dept Med Nephrol Hypertensiol Endocrinol Diab, Mannheim, Germany. [Lu, Yingchang; Gottesman, Omri; Bottinger, Erwin P.; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA. [Lu, Yingchang; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA. [Lyytikainen, Leo-Pekka; Karhunen, Pekka J.; Lehtimaki, Terho] Fimlab Labs, Dept Clin Chem, Tampere, Finland. [Lyytikainen, Leo-Pekka; Lehtimaki, Terho] Univ Tampere, Sch Med, Dept Clin Chem, FIN-33101 Tampere, Finland. [Morrison, Alanna C.; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Sch Publ Hlth, Houston, TX 77030 USA. [Qu, Liming] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Salfati, Elias; Ingelsson, Erik; Quertermous, Thomas; Assimes, Themistocles L.] Stanford Univ, Dept Med, Div Cardiovasc Med, Stanford, CA 94305 USA. [Saxena, Richa] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA USA. [Scholz, Markus] Univ Leipzig, Fac Med, Inst Med Informat Stat & Epidemiol, D-04109 Leipzig, Germany. [Scholz, Markus; Beutner, Frank; Thiery, Joachim] LIFE Res Ctr Civilizat Dis, Leipzig, Germany. [Smith, Albert V.; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Smith, Albert V.; Gudnason, Vilmundur] Univ Iceland, Fac Med, Reykjavik, Iceland. [Tikkanen, Emmi; Ripatti, Samuli] Univ Helsinki, Dept Publ Hlth, Helsinki, Finland. [Zhang, Weihua; Chambers, John C.] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London, England. [Zhang, Weihua; Chambers, John C.; Kooner, Jaspal S.] Ealing Hosp Natl Hlth Serv NHS Trust, Dept Cardiol, Southall, Middx, England. [van Zuydam, Natalie R.; Palmer, Colin N.] Univ Dundee, Med Res Inst, Dundee, Scotland. [Anand, Sonia S.] McMaster Univ, Dept Med, Populat Hlth Res Inst, Hamilton Hlth Sci, Hamilton, ON, Canada. [Bertram, Lars] Univ Lubeck, Inst Neurogenet & Integrat, Platform Genome Analyt, Lubeck, Germany. [Bertram, Lars] Univ Lubeck, Inst Expt Gen, Platform Genome Analyt, Lubeck, Germany. [Bertram, Lars] Univ London Imperial Coll Sci Technol & Med, Fac Med, Sch Publ Hlth, Neuroepidemiol & Ageing Res Unit, London, England. [Beutner, Frank] Univ Leipzig, Heart Ctr Leipzig, Cardiol, D-04109 Leipzig, Germany. [Dedoussis, George] Harokopio Univ, Dept Dietet Nutr, Athens, Greece. [Gauguier, Dominique] INSERM, Ctr Rech Cordeliers, UMRS 1138, Paris, France. [Goodall, Alison H.] Univ Leicester, Glenfield Hosp, Dept Cardiovasc Sci, Leicester, Leics, England. [Haber, Marc; Zalloua, Pierre A.] Lebanese Amer Univ, Sch Med, Beirut, Lebanon. [Huang, Jianfeng] Chinese Acad Med Sci, Natl Ctr Cardiovasc Dis, Fuwai Hosp, Hypertens Div, Beijing 100730, Peoples R China. [Kessler, Thorsten] Klinikum Rechts Der Isar, Munich, Germany. [Koenig, Inke R.] Univ Lubeck, Inst Med Biometrie & Stat, Lubeck, Germany. [Lannfelt, Lars] Uppsala Univ, Dept Publ Hlth & Caring Sci, Geriatr, Uppsala, Sweden. [Lieb, Wolfgang] Univ Kiel, Inst Epidemiol, Kiel, Germany. [Lind, Lars] Uppsala Univ, Dept Med Sci, Cardiovasc Epidemiol, Uppsala, Sweden. [Lokki, Marja-Liisa] Univ Helsinki, Haartman Inst, Transplantat Lab, Helsinki, Finland. [Magnusson, Patrik K.; Pedersen, Nancy L.] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Mallick, Nadeem H.] Punjab Inst Cardiol, Lahore, Pakistan. [Mehra, Narinder] All India Inst Med Sci, New Delhi, India. [Meitinger, Thomas] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Humangenet, Neuherberg, Germany. [Meitinger, Thomas] Tech Univ Munich, Inst Human Genet, D-80290 Munich, Germany. [Memon, Fazal-ur-Rehman; Rasheed, Asif] Red Crescent Inst Cardiol, Hyderabad, Andhra Pradesh, Pakistan. [Morris, Andrew P.] Univ Liverpool, Dept Biostat, Liverpool L69 3BX, Merseyside, England. [Nieminen, Markku S.; Sinisalo, Juha] Univ Helsinki, Cent Hosp, Dept Med, Dept Cardiol, Helsinki, Finland. [Rallidis, Loukianos S.] Univ Athens, Sch Med, Attikon Hosp, Dept Cardiol 2, GR-11527 Athens, Greece. [Shah, Svati H.; Granger, Christopher B.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Stirrups, Kathleen E.] Univ Cambridge, Dept Haematol, Cambridge, England. [Trompet, Stella; Jukema, J. Wouter] Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands. [Trompet, Stella] Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, Leiden, Netherlands. [Wang, Laiyuan] Natl Human Genome Ctr Beijing, Beijing, Peoples R China. [Zaman, Khan S.] Natl Inst Cardiovasc Dis, Karachi, Pakistan. [Ardissino, Diego] Univ Parma, Azienda Osped, Div Cardiol, I-43100 Parma, Italy. [Ardissino, Diego] Assoc Studio Trombosi Cardiol, Pavia, Italy. [Boerwinkle, Eric] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Borecki, Ingrid B.; Feitosa, Mary F.] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. [Chambers, John C.; Kooner, Jaspal S.] Imperial Coll Healthcare NHS Trust, London, England. [Danesh, John] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Demuth, Ilja] Berlin Aging Study 2, Berlin, Germany. [Demuth, Ilja] Charite, Res Grp Geriatr, D-13353 Berlin, Germany. [Demuth, Ilja] Charite, Inst Med & Human Genet, D-13353 Berlin, Germany. [Elosua, Roberto] Inst Hosp Mar Invest Med IMIM, Grp Epidemiol & Genet Cardiovasc, Barcelona, Spain. [Epstein, Stephen E.] MedStar Washington Hosp Ctr, MedStar Heart & Vasc Inst, Washington, DC USA. [Esko, Tonu] Boston Childrens Hosp, Div Endocrinol & Basic & Translat Obes Res, Boston, MA USA. [Esko, Tonu] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Franzosi, Maria Grazia] IRCCS Ist Ric Farmacol Mario Negri, Dept Cardiovasc Res, Milan, Italy. [Hall, Alistair S.] Univ Leeds, Leeds Inst Genet Hlth & Therapeut, Leeds, W Yorkshire, England. [Hamsten, Anders] Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Cardiovasc Genet & Genom Grp, Stockholm, Sweden. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Hazen, Stanley L.] Cleveland Clin, Dept Cellular & Mol Med, Cleveland, OH 44106 USA. [Iribarren, Carlos] Kaiser Permanente Div Res, Oakland, CA USA. [Jukema, J. Wouter] Durrer Ctr Cardiogenet Res, Amsterdam, Netherlands. [Jukema, J. Wouter] Interunivers Cardiol Inst Netherlands, Utrecht, Netherlands. [Karhunen, Pekka J.] Univ Tampere, Sch Med, Dept Forens Med, FIN-33101 Tampere, Finland. [Kooner, Jaspal S.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Cardiovasc Sci, London, England. [Kullo, Iftikhar J.] Mayo Clin, Dept Med, Cardiovasc Dis, Rochester, MN USA. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA. [Melander, Olle] Lund Univ, Univ Hosp Malmo, Dept Clin Sci Hypertens & Cardiovasc Dis, Malmo, Sweden. [Maerz, Winfried] Synlab Acad, Synlab Serv, Mannheim, Germany. [Maerz, Winfried] Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, Graz, Austria. [Quertermous, Thomas; Assimes, Themistocles L.] Stanford Univ, Stanford Cardiovasc Inst, Stanford, CA 94305 USA. [Rader, Daniel J.] Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA. [Rader, Daniel J.] Univ Penn, Perelman Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Roberts, Robert] Univ Ottawa, Inst Heart, Ottawa, ON, Canada. [Salomaa, Veikko] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Sanghera, Dharambir K.] Univ Oklahoma, Hlth Sci Ctr, Dept Pediat, Coll Med, Oklahoma City, OK 73190 USA. [Sanghera, Dharambir K.] Univ Oklahoma, Hlth Sci Ctr, Coll Pharm, Dept Pharmaceut Sci, Oklahoma City, OK 73190 USA. [Sanghera, Dharambir K.] Oklahoma Ctr Neurosci, Oklahoma City, OK USA. [Schwartz, Stephen M.] Fred Hutchinson Canc Res Ctr, Publ Hlth Sci Div, Seattle, WA 98104 USA. [Schwartz, Stephen M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Seedorf, Udo] Univ Med Ctr Hamburg Eppendorf, Ctr Dent & Oral Med, Dept Prosthet Dent, Hamburg, Germany. [Stott, David J.] Univ Glasgow, Fac Med, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland. [Thiery, Joachim] Univ Hosp Leipzig, Fac Med, Inst Lab Med Clin Chem & Mol Diagnost, Leipzig, Germany. [Zalloua, Pierre A.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Bethesda, MD 20892 USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Cardiol Div, Boston, MA 02114 USA. [Thompson, John R.] Univ Leicester, Dept Hlth Sci, Leicester, Leics, England. [Deloukas, Panos] King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah 21413, Saudi Arabia. RP Watkins, H (reprint author), Univ Oxford, Div Cardiovasc Med, Radcliffe Dept Med, Oxford, England. EM hugh.watkins@rdm.ox.ac.uk; sekar@broadinstitute.org; rmcpherson@ottawaheart.ca; martin.farrall@well.ox.ac.uk RI Konig, Inke/A-4544-2009; Magnusson, Patrik/C-4458-2017; Lieb, Wolfgang/C-1990-2012; Feitosa, Mary/K-8044-2012; Meitinger, Thomas/O-1318-2015; Kessler, Thorsten/O-7426-2015; Webb, Tom/C-6237-2011; Peters, Annette/A-6117-2011; Lyytikainen, Leo-Pekka/C-8544-2016; Bertram, Lars/K-3889-2015; Smith, Albert/K-5150-2015; Deloukas, Panos/B-2922-2013; Study, GoDARTS/K-9448-2016; Gudnason, Vilmundur/K-6885-2015; Erdmann, Jeanette/P-7513-2014; OI Feitosa, Mary/0000-0002-0933-2410; Lyytikainen, Leo-Pekka/0000-0002-7200-5455; Bertram, Lars/0000-0002-0108-124X; Smith, Albert/0000-0003-1942-5845; Deloukas, Panos/0000-0001-9251-070X; Won, Hong-Hee/0000-0001-5719-0552; Gudnason, Vilmundur/0000-0001-5696-0084; ELOSUA, ROBERTO/0000-0001-8235-0095; Palmer, Colin/0000-0002-6415-6560; Stewart, Alexandre/0000-0003-2673-9164; Gieger, Christian/0000-0001-6986-9554; Erdmann, Jeanette/0000-0002-4486-6231; Zhao, Wei/0000-0002-8301-9297; zalloua, pierre/0000-0002-8494-5081; Watkins, Hugh/0000-0002-5287-9016; Assimes, Themistocles/0000-0003-2349-0009; Sinisalo, Juha/0000-0002-0169-5137; Kleber, Marcus/0000-0003-0663-7275; Dehghan, Abbas/0000-0001-6403-016X; Peters, Annette/0000-0001-6645-0985 FU British Heart Foundation [RG/08/014/24067, FS/14/55/30806, RE/13/1/30181, RG/14/5/30893]; Medical Research Council [MR/L003120/1, MR/L01629X/1]; NCI NIH HHS [UM1 CA182913]; NHLBI NIH HHS [R01 HL117078, R01 HL127564, R33 HL120757]; NIDDK NIH HHS [R01 DK089256] NR 83 TC 110 Z9 111 U1 11 U2 38 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 OCT PY 2015 VL 47 IS 10 BP 1121 EP + DI 10.1038/ng.3396 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA CS3JR UT WOS:000361969900007 PM 26343387 ER PT J AU Dina, C Bouatia-Naji, N Tucker, N Delling, FN Toomer, K Durst, R Perrocheau, M Fernandez-Friera, L Solis, J Le Tourneau, T Chen, MH Probst, V Bosse, Y Pibarot, P Zelenika, D Lathrop, M Hercberg, S Roussel, R Benjamin, EJ Bonnet, F Lo, SH Dolmatova, E Simonet, F Lecointe, S Kyndt, F Redon, R Le Marec, H Froguel, P Ellinor, PT Vasan, RS Bruneval, P Markwald, RR Norris, RA Milan, DJ Slaugenhaupt, SA Levine, RA Schott, JJ Hagege, AA Jeunemaitre, X AF Dina, Christian Bouatia-Naji, Nabila Tucker, Nathan Delling, Francesca N. Toomer, Katelynn Durst, Ronen Perrocheau, Maelle Fernandez-Friera, Leticia Solis, Jorge Le Tourneau, Thierry Chen, Ming-Huei Probst, Vincent Bosse, Yohan Pibarot, Philippe Zelenika, Diana Lathrop, Mark Hercberg, Serge Roussel, Ronan Benjamin, Emelia J. Bonnet, Fabrice Lo, Su Hao Dolmatova, Elena Simonet, Floriane Lecointe, Simon Kyndt, Florence Redon, Richard Le Marec, Herve Froguel, Philippe Ellinor, Patrick T. Vasan, Ramachandran S. Bruneval, Patrick Markwald, Roger R. Norris, Russell A. Milan, David J. Slaugenhaupt, Susan A. Levine, Robert A. Schott, Jean-Jacques Hagege, Albert A. Jeunemaitre, Xavier CA PROMESA Investigators MVP-France Leducq Transatlantic MITRAL Networ TI Genetic association analyses highlight biological pathways underlying mitral valve prolapse SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; CARDIAC VALVULAR DYSTROPHY; FILAMIN-A; NATURAL-HISTORY; MARFAN-SYNDROME; CELL-MIGRATION; EXPRESSION; LOCUS; PATHOGENESIS; METAANALYSIS AB Nonsyndromic mitral valve prolapse (MVP) is a common degenerative cardiac valvulopathy of unknown etiology that predisposes to mitral regurgitation, heart failure and sudden death(1). Previous family and pathophysiological studies suggest a complex pattern of inheritance(2-5). We performed a meta-analysis of 2 genome-wide association studies in 1,412 MVP cases and 2,439 controls. We identified 6 loci, which we replicated in 1,422 cases and 6,779 controls, and provide functional evidence for candidate genes. We highlight LMCD1 (LIM and cysteine-rich domains 1), which encodes a transcription factor(6) and for which morpholino knockdown of the ortholog in zebrafish resulted in atrioventricular valve regurgitation. A similar zebrafish phenotype was obtained with knockdown of the ortholog of TNS1, which encodes tensin 1, a focal adhesion protein involved in cytoskeleton organization. We also showed expression of tensin 1 during valve morphogenesis and describe enlarged posterior mitral leaflets in Tns(1-/-) mice. This study identifies the first risk loci for MVP and suggests new mechanisms involved in mitral valve regurgitation, the most common indication for mitral valve repair(7). C1 [Dina, Christian; Le Tourneau, Thierry; Probst, Vincent; Simonet, Floriane; Lecointe, Simon; Kyndt, Florence; Redon, Richard; Le Marec, Herve; Schott, Jean-Jacques] CNRS, INSERM, Inst Thorax, UMR 1087,UMR 6291, Nantes, France. [Dina, Christian; Le Tourneau, Thierry; Probst, Vincent; Lecointe, Simon; Kyndt, Florence; Redon, Richard; Le Marec, Herve; Schott, Jean-Jacques] Univ Nantes, CHU Nantes, Nantes, France. [Bouatia-Naji, Nabila; Perrocheau, Maelle; Bruneval, Patrick; Hagege, Albert A.; Jeunemaitre, Xavier] Paris Cardiovasc Res Ctr, INSERM, UMR 970, Paris, France. [Bouatia-Naji, Nabila; Perrocheau, Maelle; Hercberg, Serge; Bruneval, Patrick; Jeunemaitre, Xavier] Paris Descartes Univ, Paris Sorbonne Cite, Paris, France. [Tucker, Nathan; Dolmatova, Elena; Ellinor, Patrick T.; Milan, David J.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. [Delling, Francesca N.; Chen, Ming-Huei; Benjamin, Emelia J.; Vasan, Ramachandran S.] NHLBI, Framingham Heart Study, Populat Sci Branch, Div Intramural Res,US Natl Inst Hlth, Framingham, MA USA. [Delling, Francesca N.; Benjamin, Emelia J.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Med,Cardiovasc Div, Boston, MA 02215 USA. [Toomer, Katelynn; Markwald, Roger R.; Norris, Russell A.] Med Univ S Carolina, Childrens Res Inst, Cardiovasc Dev Biol Ctr, Dept Regenerat Med & Cell Biol, Charleston, SC 29425 USA. [Durst, Ronen] Hadassah Hebrew Univ Med Ctr, Dept Cardiol, Jerusalem, Israel. [Fernandez-Friera, Leticia; Solis, Jorge] Univ Ctr Estudios Univ CEU, Hosp Univ Monteprincipe, Madrid, Spain. [Fernandez-Friera, Leticia; Solis, Jorge; Leducq Transatlantic MITRAL Networ] Carlos III CNIC, Ctr Nacl Invest Cardiovasc, Madrid, Spain. [Chen, Ming-Huei] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Bosse, Yohan; Pibarot, Philippe] Univ Laval, Inst Univ Cardiol & Pneumol Quebec, Quebec City, PQ, Canada. [Zelenika, Diana; Lathrop, Mark] Ctr Natl Genotypage, Evry, France. [Lathrop, Mark] Genome Quebec, Montreal, PQ, Canada. [Hercberg, Serge] Univ Paris 13, Sorbonne Paris Cite, Bobigny, France. [Hercberg, Serge] INRA, INSERM, U1153, U1125,Nutr Epidemiol Res Unit,Epidemiol & Biostat, Bobigny, France. [Hercberg, Serge] Avicenne Hosp, AP HP, Dept Publ Hlth, Bobigny, France. [Hercberg, Serge; Roussel, Ronan] Paris Diderot Univ, Paris, France. [Roussel, Ronan] Ctr Rech Cordeliers, INSERM, UMRS 1138, Paris, France. [Roussel, Ronan] Hop Xavier Bichat, AP HP, Fibrosis Inflammat Remodeling Cardiovasc Resp & R, Dept Endocrinol Diabet & Nutr, Paris, France. [Bonnet, Fabrice] Univ Hosp Pontchaillou, INSERM, CIC 0203, Rennes, France. [Bonnet, Fabrice] Univ Hosp, Dept Endocrinol, Rennes, France. [Lo, Su Hao] Univ Calif Davis, Sch Med, Dept Biochem & Mol Med, Davis, CA 95616 USA. [Froguel, Philippe] Univ Lille 2, CNRS, Lille Pasteur Inst, UMR 8199,EGID, Lille, France. [Froguel, Philippe] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Genom Common Dis, London, England. [Ellinor, Patrick T.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Bruneval, Patrick] Hop Europeen Georges Pompidou, AP HP, Dept Pathol, Paris, France. [Slaugenhaupt, Susan A.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Slaugenhaupt, Susan A.; Levine, Robert A.] Harvard Univ, Sch Med, Boston, MA USA. [Levine, Robert A.] Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Boston, MA 02114 USA. [Hagege, Albert A.] Hop Europeen Georges Pompidou, AP HP, Dept Cardiol, Paris, France. [Jeunemaitre, Xavier] Hop Europeen Georges Pompidou, AP HP, Dept Genet, Paris, France. RP Dina, C (reprint author), CNRS, INSERM, Inst Thorax, UMR 1087,UMR 6291, Nantes, France. EM christian.dina@univ-nantes.fr; nabila.bouatia-naji@inserm.fr; xavier.jeunemaitre@inserm.fr RI probst, vincent/D-4996-2015; BOUATIA-NAJI, NABILA/D-5863-2013; Redon, Richard/F-3303-2014; OI Benjamin, Emelia/0000-0003-4076-2336; Redon, Richard/0000-0001-7751-2280; Bouatia-Naji, Nabila/0000-0001-5424-2134 FU Nantes Hospital (CHU Nantes); US National Institutes of Health (NIH) [K24 HL67434, R01 HL72265, HL109506]; French young investigator fund [ANR-13-ISV1-0006-0]; Hassenfeld Scholar Program; NIH [HL092577, HL104156, K24HL105780, HL065962]; American Heart Association [13EIA14220013, 15GRNT25080052]; Fondation Leducq [14CVD01]; Canadian Institutes of Health Research (CIHR) [MOP-102737, MOP-114997, MOP-126072]; Fonds de recherche Quebec-Sante (FRQS); CIHR [MOP-102481, MOP-137058]; Spanish Society of Cardiology; fund for medical discovery of the Massachusetts General Hospital; European Commission; US National Institutes of Health [C06 RR018823]; Extramural Research Facilities Program of the Heart, Lung, and Blood Institute [R01-HL33756, COBRE 1P30 GM103342, 8P20 GM103444-07, R01-HL127692]; INSERM; French Society of Cardiology FX We acknowledge the major contribution of the Leducq Foundation, Paris for supporting a transatlantic consortium investigating the physiopathology of mitral valve disease, for which this genome-wide association study was a major project (coordinators: R.A.L. and A.A.H.). We thank J. Leyton-Mange, X.-X. Nguyen and M. McLellan for help with the zebrafish experiments and P. Mathieu as one of the main investigators of the PROGRAM (Determinants of the Progression and Outcomes of Organic Mitral Regurgitation) study, from which was ascertained the Canadian MVP case control study. C.D., T.L.T. and J.-J.S. acknowledge a translational research grant on genetics of mitral valve funded by the Nantes Hospital (CHU Nantes). R.A.L. acknowledges grant support from the US National Institutes of Health (NIH; grants K24 HL67434, R01 HL72265 and HL109506). N.B.-N. is recipient of a French young investigator fund (ANR-13-ISV1-0006-0). D.J.M. acknowledges the support of the Hassenfeld Scholar Program and a gift from Michael Zak. P.T.E. is supported by grants from the NIH (HL092577, HL104156, K24HL105780, HL065962), an Established Investigator Award from the American Heart Association (13EIA14220013) and support from the Fondation Leducq (14CVD01). P.P. holds the Canada Research Chair in Valvular Heart Diseases and is supported by grants from the Canadian Institutes of Health Research (CIHR; grants MOP-102737, MOP-114997 and MOP-126072). Y.B. is the recipient of a Junior 2 Research Scholar award from the Fonds de recherche Quebec-Sante (FRQS) and is supported by the CIHR (MOP-102481 and MOP-137058). L.F.-F. and J.S. received financial support from the Spanish Society of Cardiology. R.D. was supported by fellowships from the fund for medical discovery of the Massachusetts General Hospital and by a Marie Curie reintegration award from the European Commission R.R.M. and R.A.N. performed their work in a facility constructed with support from the US National Institutes of Health, grant C06 RR018823, from the Extramural Research Facilities Program of the Heart, Lung, and Blood Institute: R01-HL33756 (R.R.M.), COBRE 1P30 GM103342 (R.R.M. and R.A.N.), 8P20 GM103444-07 (R.R.M. and R.A.N.), R01-HL127692 (D.J.M., S.A.S. and R.A.N.) and American Heart Association 15GRNT25080052 (R.A.N.). A.A.H., N.B.-N. and X.J. acknowledge funds from INSERM and the French Society of Cardiology. NR 38 TC 11 Z9 11 U1 4 U2 23 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 OCT PY 2015 VL 47 IS 10 BP 1206 EP + DI 10.1038/ng.3383 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA CS3JR UT WOS:000361969900017 PM 26301497 ER PT J AU Janiszewska, M Liu, L Almendro, V Kuang, Y Paweletz, C Sakr, RA Weigelt, B Hanker, AB Chandarlapaty, S King, TA Reis, JS Arteaga, CL Park, SY Michor, F Polyak, K AF Janiszewska, Michalina Liu, Lin Almendro, Vanessa Kuang, Yanan Paweletz, Cloud Sakr, Rita A. Weigelt, Britta Hanker, Ariella B. Chandarlapaty, Sarat King, Tari A. Reis-Filho, Jorge S. Arteaga, Carlos L. Park, So Yeon Michor, Franziska Polyak, Kornelia TI In situ single-cell analysis identifies heterogeneity for PIK3CA mutation and HER2 amplification in HER2-positive breast cancer SO NATURE GENETICS LA English DT Article ID PRACTICE GUIDELINE UPDATE; PI3K PATHWAY ACTIVATION; INTRATUMORAL HETEROGENEITY; CLINICAL ONCOLOGY/COLLEGE; GENE AMPLIFICATION; AMERICAN SOCIETY; TRASTUZUMAB RESISTANCE; PCR-AMPLIFICATION; TUMOR EVOLUTION; DIGITAL PCR AB Detection of minor, genetically distinct subpopulations within tumors is a key challenge in cancer genomics. Here we report STAR-FISH (specific-to-allele PCR-FISH), a novel method for the combined detection of single-nucleotide and copy number alterations in single cells in intact archived tissues. Using this method, we assessed the clinical impact of changes in the frequency and topology of PIK3CA mutation and HER2 (ERBB2) amplification within HER2-positive breast cancer during neoadjuvant therapy. We found that these two genetic events are not always present in the same cells. Chemotherapy selects for PIK3CA-mutant cells, a minor subpopulation in nearly all treatment-naive samples, and modulates genetic diversity within tumors. Treatment-associated changes in the spatial distribution of cellular genetic diversity correlated with poor long-term outcome following adjuvant therapy with trastuzumab. Our findings support the use of in situ single cell-based methods in cancer genomics and imply that chemotherapy before HER2-targeted therapy may promote treatment resistance. C1 [Janiszewska, Michalina; Almendro, Vanessa; Kuang, Yanan; Paweletz, Cloud; Polyak, Kornelia] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Janiszewska, Michalina; Almendro, Vanessa; Polyak, Kornelia] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Janiszewska, Michalina; Almendro, Vanessa; Polyak, Kornelia] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Liu, Lin; Michor, Franziska] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Liu, Lin; Michor, Franziska] Harvard Univ, TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Kuang, Yanan; Paweletz, Cloud] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA USA. [Sakr, Rita A.; King, Tari A.] Mem Sloan Kettering Canc Ctr, Dept Surg, Breast Serv, New York, NY 10021 USA. [Weigelt, Britta; Reis-Filho, Jorge S.] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. [Hanker, Ariella B.; Arteaga, Carlos L.] Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Dept Canc Biol, Nashville, TN 37235 USA. [Chandarlapaty, Sarat; Reis-Filho, Jorge S.] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10021 USA. [Arteaga, Carlos L.] Vanderbilt Univ, Dept Med, Breast Canc Res Program, Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Park, So Yeon] Seoul Natl Univ, Coll Med, Dept Pathol, Seoul 151, South Korea. [Polyak, Kornelia] Broad Inst, Cambridge, MA USA. [Polyak, Kornelia] Harvard Stem Cell Inst, Cambridge, MA USA. RP Polyak, K (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM michor@jimmy.harvard.edu; kornelia_polyak@dfci.harvard.edu OI Hanker, Ariella/0000-0002-8655-8341 FU Dana-Farber Cancer Institute Physical Sciences-Oncology Center [U54CA143798]; European Molecular Biology Organization (EMBO); Swiss National Science Foundation; American Cancer Society [CRP-07-234-06-COUN]; Breast Cancer Research Foundation FX We thank E. Winer, I. Krop, B. Vogelstein and members of the Polyak and Michor laboratories for their critical reading of the manuscript and useful discussions. We thank A. Marusyk and D. Tabassum for their help with the xenograft assays, R. Witwicki for help with data processing, L. Cameron in the Dana-Farber Cancer Institute Confocal Microscopy center for her technical support, A. Richardson (Dana-Farber Cancer Institute) for providing slides from a human breast tumor with known status for the PIK3CA mutation encoding p.His1047Arg, and H. Russness and I. Rye (Oslo University Hospital) for providing the BAC probe for HER2. This work was supported by the Dana-Farber Cancer Institute Physical Sciences-Oncology Center (U54CA143798 to F.M.), the European Molecular Biology Organization (EMBO; M.J.), the Swiss National Science Foundation (M.J.), the American Cancer Society (CRP-07-234-06-COUN to C.L.A.) and the Breast Cancer Research Foundation (K.P.). NR 55 TC 27 Z9 27 U1 3 U2 16 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 OCT PY 2015 VL 47 IS 10 BP 1212 EP + DI 10.1038/ng.3391 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA CS3JR UT WOS:000361969900018 PM 26301495 ER PT J AU Hernandez, SF Vahidi, NA Park, S Weitzel, RP Tisdale, J Rueda, BR Wolff, EF AF Hernandez, Silvia F. Vahidi, Nima A. Park, Solji Weitzel, R. Patrick Tisdale, John Rueda, Bo R. Wolff, Erin F. TI Characterization of extracellular DDX4-or Ddx4-positive ovarian cells SO NATURE MEDICINE LA English DT Letter ID ACTIVE GERM-CELLS; LINE; MOUSE C1 [Hernandez, Silvia F.; Rueda, Bo R.] Massachusetts Gen Hosp, Dept Obstet & Gynecol, Vincent Ctr Reprod Biol, Boston, MA 02114 USA. [Hernandez, Silvia F.; Rueda, Bo R.] Harvard Univ, Sch Med, Boston, MA USA. [Rueda, Bo R.] Massachusetts Gen Hosp, Dept Obstet & Gynecol, Div Gynecol Oncol, Boston, MA 02114 USA. [Vahidi, Nima A.; Park, Solji; Wolff, Erin F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Weitzel, R. Patrick; Tisdale, John; Wolff, Erin F.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Wolff, EF (reprint author), Massachusetts Gen Hosp, Dept Obstet & Gynecol, Vincent Ctr Reprod Biol, Boston, MA 02114 USA. EM erin.wolff@nih.gov FU Intramural NIH HHS NR 6 TC 8 Z9 8 U1 2 U2 6 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 OCT PY 2015 VL 21 IS 10 BP 1114 EP 1116 DI 10.1038/nm.3966 PG 3 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA CS8RG UT WOS:000362355400006 PM 26444630 ER PT J AU Gilja, V Pandarinath, C Blabe, CH Nuyujukian, P Simeral, JD Sarma, AA Sorice, BL Perge, JA Jarosiewicz, B Hochberg, LR Shenoy, KV Henderson, JM AF Gilja, Vikash Pandarinath, Chethan Blabe, Christine H. Nuyujukian, Paul Simeral, John D. Sarma, Anish A. Sorice, Brittany L. Perge, Janos A. Jarosiewicz, Beata Hochberg, Leigh R. Shenoy, Krishna V. Henderson, Jaimie M. TI Clinical translation of a high-performance neural prosthesis SO NATURE MEDICINE LA English DT Article ID POSTERIOR PARIETAL CORTEX; CORTICAL CONTROL; MOVEMENT SIGNAL; TETRAPLEGIA; INTERFACE; HUMANS; FEEDBACK; DEVICES; ARM AB Neural prostheses have the potential to improve the quality of life of individuals with paralysis by directly mapping neural activity to limb- and computer-control signals. We translated a neural prosthetic system previously developed in animal model studies for use by two individuals with amyotrophic lateral sclerosis who had intracortical microelectrode arrays placed in motor cortex. Measured more than 1 year after implant, the neural cursor-control system showed the highest published performance achieved by a person to date, more than double that of previous pilot clinical trial participants. C1 [Gilja, Vikash; Pandarinath, Chethan; Blabe, Christine H.; Nuyujukian, Paul; Henderson, Jaimie M.] Stanford Univ, Dept Neurosurg, Stanford, CA 94305 USA. [Gilja, Vikash; Pandarinath, Chethan; Nuyujukian, Paul; Shenoy, Krishna V.] Stanford Univ, Dept Elect Engn, Stanford, CA 94305 USA. [Gilja, Vikash; Simeral, John D.; Sarma, Anish A.; Perge, Janos A.; Hochberg, Leigh R.] Brown Univ, Sch Engn, Providence, RI 02912 USA. [Gilja, Vikash] Univ Calif San Diego, Dept Elect & Comp Engn, La Jolla, CA 92093 USA. [Pandarinath, Chethan; Nuyujukian, Paul; Shenoy, Krishna V.; Henderson, Jaimie M.] Stanford Univ, Stanford Neurosci Inst, Stanford, CA 94305 USA. [Simeral, John D.; Sarma, Anish A.; Perge, Janos A.; Jarosiewicz, Beata; Hochberg, Leigh R.] Dept Vet Affairs Med Ctr, Rehabil R&D Serv, Ctr Neurorestorat & Neurotechnol, Providence, RI USA. [Simeral, John D.; Sarma, Anish A.; Perge, Janos A.; Jarosiewicz, Beata; Hochberg, Leigh R.] Brown Univ, Brown Inst Brain Sci, Providence, RI 02912 USA. [Simeral, John D.; Sarma, Anish A.; Sorice, Brittany L.; Hochberg, Leigh R.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Jarosiewicz, Beata] Brown Univ, Dept Neurosci, Providence, RI 02912 USA. [Hochberg, Leigh R.] Harvard Univ, Sch Med, Neurol, Boston, MA USA. [Shenoy, Krishna V.] Stanford Univ, Dept Neurobiol, Stanford, CA 94305 USA. [Shenoy, Krishna V.] Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA. [Shenoy, Krishna V.] Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA. RP Henderson, JM (reprint author), Stanford Univ, Dept Neurosurg, Stanford, CA 94305 USA. EM henderj@stanford.edu OI Pandarinath, Chethan/0000-0003-1241-1432; Blabe, Christine/0000-0003-4623-4251 FU Stanford Institute for Neuro-Innovation and Translational Neuroscience; Stanford BioX-NeuroVentures; Stanford Office of Postdoctoral Affairs; Garlick Foundation; Craig H. Neilsen Foundation; US National Institutes of Health: the National Institute on Deafness and Other Communication Disorders (NIDCD) [R01DC009899, R01DC014034]; US National Institutes of Health: National Institute of Neurological Disorders and Stroke (NINDS) [RO1NS066311-S1]; US National Institutes of Health: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)-National Center for Medical Rehabilitation Research (NCMRR) [N01HD53403, N01HD10018]; Rehabilitation Research and Development Service, Department of Veterans Affairs [B6453R, B6310N]; Massachusetts General Hospital (MGH)-Deane Institute for Integrated Research on Atrial Fibrillation and Stroke FX The authors would like to thank participants T6, T7, S3 and their families; E.N. Eskandar for participant T7's implantation surgery; B. Davis, B. Pedrick, M. Coburn, B. Travers and D. Rosler for administrative support; S.I. Ryu for surgical assistance; L. Barefoot, P. Gigante, A. Sachs, S. Cash, J. Menon and S. Mernoff for clinical assistance; K. Newell for data collection assistance; J. Saab and N. Schmansky for technical assistance; and J.P. Donoghue for helpful scientific discussions. This work was supported by the Stanford Institute for Neuro-Innovation and Translational Neuroscience; Stanford BioX-NeuroVentures; the Stanford Office of Postdoctoral Affairs; the Garlick Foundation; the Craig H. Neilsen Foundation; The US National Institutes of Health: the National Institute on Deafness and Other Communication Disorders (NIDCD) (R01DC009899, principal investigator (PI): L.R.H.; R01DC014034, PI: J.M.H.), the National Institute of Neurological Disorders and Stroke (NINDS) (RO1NS066311-S1, PI: K.V.S.), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)-National Center for Medical Rehabilitation Research (NCMRR) (N01HD53403 and N01HD10018, Sub-award PI: L.R.H.); the Rehabilitation Research and Development Service, Department of Veterans Affairs (B6453R and B6310N, PI: L.R.H.); and the Massachusetts General Hospital (MGH)-Deane Institute for Integrated Research on Atrial Fibrillation and Stroke. The content of this paper is solely the responsibility of the authors and does not necessarily represent the official views of the US National Institutes of Health, the Department of Veterans Affairs or the United States Government. NR 31 TC 23 Z9 24 U1 3 U2 18 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 OCT PY 2015 VL 21 IS 10 BP 1142 EP + DI 10.1038/nm.3953 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA CS8RG UT WOS:000362355400015 PM 26413781 ER PT J AU Mazur, PK Herner, A Mello, SS Wirth, M Hausmann, S Sanchez-Rivera, FJ Lofgren, SM Kuschma, T Hahn, SA Vangala, D Trajkovic-Arsic, M Gupta, A Heid, I Noel, PB Braren, R Erkan, M Kleeff, J Sipos, B Sayles, LC Heikenwalder, M Hessmann, E Ellenrieder, V Esposito, I Jacks, T Bradner, JE Khatri, P Sweet-Cordero, EA Attardi, LD Schmid, RM Schneider, G Sage, J Siveke, JT AF Mazur, Pawel K. Herner, Alexander Mello, Stephano S. Wirth, Matthias Hausmann, Simone Sanchez-Rivera, Francisco J. Lofgren, Shane M. Kuschma, Timo Hahn, Stephan A. Vangala, Deepak Trajkovic-Arsic, Marija Gupta, Aayush Heid, Irina Noel, Peter B. Braren, Rickmer Erkan, Mert Kleeff, Joerg Sipos, Bence Sayles, Leanne C. Heikenwalder, Mathias Hessmann, Elisabeth Ellenrieder, Volker Esposito, Irene Jacks, Tyler Bradner, James E. Khatri, Purvesh Sweet-Cordero, E. Alejandro Attardi, Laura D. Schmid, Roland M. Schneider, Guenter Sage, Julien Siveke, Jens T. TI Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma SO NATURE MEDICINE LA English DT Article ID ENGINEERED MOUSE MODELS; LUNG-CANCER; C-MYC; INTRAEPITHELIAL NEOPLASIA; BROMODOMAIN INHIBITION; SELECTIVE-INHIBITION; DRUG-COMBINATION; IN-VIVO; PROGRESSION; KRAS AB Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers and shows resistance to any therapeutic strategy used. Here we tested small-molecule inhibitors targeting chromatin regulators as possible therapeutic agents in PDAC. We show that JQ1, an inhibitor of the bromodomain and extraterminal (BET) family of proteins, suppresses PDAC development in mice by inhibiting both MYC activity and inflammatory signals. The histone deacetylase (HDAC) inhibitor SAHA synergizes with JQ1 to augment cell death and more potently suppress advanced PDAC. Finally, using a CRISPR-Cas9-based method for gene editing directly in the mouse adult pancreas, we show that de-repression of p57 (also known as KIP2 or CDKN1C) upon combined BET and HDAC inhibition is required for the induction of combination therapy-induced cell death in PDAC. SAHA is approved for human use, and molecules similar to JQ1 are being tested in clinical trials. Thus, these studies identify a promising epigenetic-based therapeutic strategy that may be rapidly implemented in fatal human tumors. C1 [Mazur, Pawel K.; Kuschma, Timo; Sayles, Leanne C.; Sweet-Cordero, E. Alejandro; Sage, Julien] Stanford Univ, Sch Med, Dept Pediat, Stanford, CA 94305 USA. [Mazur, Pawel K.; Mello, Stephano S.; Kuschma, Timo; Attardi, Laura D.; Sage, Julien] Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA. [Herner, Alexander; Wirth, Matthias; Trajkovic-Arsic, Marija; Gupta, Aayush; Schmid, Roland M.; Schneider, Guenter; Siveke, Jens T.] Tech Univ Munich, Klinikum Rechts Isar, Dept Internal Med 2, D-80290 Munich, Germany. [Mello, Stephano S.; Attardi, Laura D.] Stanford Univ, Sch Med, Dept Radiat Oncol, Stanford, CA 94305 USA. [Hausmann, Simone; Erkan, Mert; Kleeff, Joerg] Tech Univ Munich, Klinikum Rechts Isar, Dept Surg, D-80290 Munich, Germany. [Sanchez-Rivera, Francisco J.; Jacks, Tyler] MIT, Dept Biol, David H Koch Inst Integrat Canc Res, Cambridge, MA USA. [Sanchez-Rivera, Francisco J.; Jacks, Tyler] MIT, Howard Hughes Med Inst, Cambridge, MA USA. [Lofgren, Shane M.; Khatri, Purvesh] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. [Lofgren, Shane M.; Khatri, Purvesh] Stanford Univ, Sch Med, Inst Immun Transplantat & Infect, Stanford, CA 94305 USA. [Hahn, Stephan A.] Ruhr Univ Bochum, Dept Mol Gastrointestinal Oncol, Bochum, Germany. [Vangala, Deepak] Ruhr Univ Bochum, Med Clin, Knappschaftskrankenhaus, Bochum, Germany. [Heid, Irina; Noel, Peter B.; Braren, Rickmer] Tech Univ Munich, Klinikum Rechts Isar, Inst Radiol, D-80290 Munich, Germany. [Sipos, Bence] Univ Tubingen, Inst Pathol, Tubingen, Germany. [Heikenwalder, Mathias] Tech Univ Munich, Klinikum Rechts Isar, Inst Virol, D-80290 Munich, Germany. [Heikenwalder, Mathias] German Canc Res Ctr, Div Chron Inflammat & Canc, Heidelberg, Germany. [Hessmann, Elisabeth; Ellenrieder, Volker] Univ Med Ctr Gottingen, Dept Gastroenterol & Gastrointestinal Oncol, Gottingen, Germany. [Esposito, Irene] Tech Univ Munich, Klinikum Rechts Isar, Inst Pathol, D-80290 Munich, Germany. [Bradner, James E.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Schmid, Roland M.; Siveke, Jens T.] German Canc Consortium DKTK, Heidelberg, Germany. [Schmid, Roland M.; Siveke, Jens T.] German Canc Res Ctr, Heidelberg, Germany. RP Mazur, PK (reprint author), Stanford Univ, Sch Med, Dept Pediat, Stanford, CA 94305 USA. EM pmazur@stanford.edu; julsage@stanford.edu; j.siveke@dkfz.de RI Hahn, Stephan/E-3880-2010; Kleeff, Jorg/B-2124-2009; OI Kleeff, Jorg/0000-0003-3432-6669; Mazur, Pawel/0000-0002-5820-8344; Noel, Peter/0000-0002-9671-6171 FU German Research Foundation [SFB824/C4]; European Union [602783]; German Cancer Consortium (DKTK); Lustgarten Foundation; Tobacco-Related Disease Research Program; Stanford University; Child Health Research Institute; Lucile Packard Foundation for Children's Health at Stanford; Boehringer Ingelheim Fonds MD Fellowship FX P.K.M. and A.H. significantly contributed to the work and are listed as co-first authors based on a previous agreement. We thank C. Vakoc (Cold Spring Harbor Laboratory) for sharing shRNA plasmids, M. Winslow (Stanford University) for the R26CAG-tdTomato reporter mice and I. Moreno de Alboran (Spanish National Biotechnology Centre) for MycloxP mice. This work was supported by the German Research Foundation (SFB824/C4 to J.T.S.), the European Union's Seventh Framework Program for research, technological development and demonstration (FP7/CAM-PaC) under grant agreement 602783, the German Cancer Consortium (DKTK) (to R.M.S. and J.T.S.), and the Lustgarten Foundation (J.S.). P.K.M. was supported by the Tobacco-Related Disease Research Program, a Dean's Fellowship from Stanford University, and the Child Health Research Institute and Lucile Packard Foundation for Children's Health at Stanford. J.S. is the Harriet and Mary Zelencik Scientist in Children's Cancer and Blood Diseases. T.K. was supported by a Boehringer Ingelheim Fonds MD Fellowship. NR 79 TC 42 Z9 42 U1 5 U2 36 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 OCT PY 2015 VL 21 IS 10 BP 1163 EP + DI 10.1038/nm.3952 PG 13 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA CS8RG UT WOS:000362355400018 PM 26390243 ER PT J AU Sinatra, R Deville, P Szell, M Wang, DS Barabsi, AL AF Sinatra, Roberta Deville, Pierre Szell, Michael Wang, Dashun Barabsi, Albert-Laszlo TI A century of physics SO NATURE PHYSICS LA English DT Article ID SCIENTIFIC IMPACT; EVOLUTION C1 [Sinatra, Roberta; Deville, Pierre; Szell, Michael; Barabsi, Albert-Laszlo] Northeastern Univ, Ctr Complex Network Res, Boston, MA 02115 USA. [Sinatra, Roberta; Deville, Pierre; Szell, Michael; Barabsi, Albert-Laszlo] Northwestern Univ, Dept Phys, Boston, MA 02115 USA. [Wang, Dashun] Penn State Univ, Coll Informat Sci & Technol, University Pk, PA 16801 USA. [Wang, Dashun] Catholic Univ Louvain, Dept Appl Math, B-1348 Louvain La Neuve, Belgium. [Barabsi, Albert-Laszlo] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA. [Barabsi, Albert-Laszlo] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. [Barabsi, Albert-Laszlo] Cent European Univ, Ctr Network Sci, H-1051 Budapest, Hungary. RP Sinatra, R (reprint author), Northeastern Univ, Ctr Complex Network Res, Boston, MA 02115 USA. EM r.sinatra@neu.edu; alb@neu.edu OI Sinatra, Roberta/0000-0002-7558-1028 FU AFOSR [FA9550-15-1-0077, FA9550-15-1-0162]; National Foundation for Scientific Research (FNRS); Research Department of the Communaute Francaise de Belgique (Large Graph Concerted Research Action); James S. McDonnell Foundation; Future and Emerging Technologies Project - European Commission [317 532] FX R.S., M.S. and A.L.B. are supported by the AFOSR grant FA9550-15-1-0077. P.D. is supported by the National Foundation for Scientific Research (FNRS) and by the Research Department of the Communaute Francaise de Belgique (Large Graph Concerted Research Action). D.W. is supported by the AFOSR, grant FA9550-15-1-0162. R.S. is also supported by the James S. McDonnell Foundation. A.L.B. is also supported by the Future and Emerging Technologies Project 317 532 'Multiplex' financed by the European Commission. We wish to thank I. Georgescu for many fruitful discussions and ideas throughout this project and J. De Nicolo for support with handling the WoS data. NR 24 TC 17 Z9 17 U1 7 U2 23 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1745-2473 EI 1745-2481 J9 NAT PHYS JI Nat. Phys. PD OCT PY 2015 VL 11 IS 10 BP 791 EP 796 PG 6 WC Physics, Multidisciplinary SC Physics GA CS6KX UT WOS:000362188600003 ER PT J AU Angulo, MT Liu, YY Slotine, JJ AF Angulo, Marco Tulio Liu, Yang-Yu Slotine, Jean-Jacques TI Network motifs emerge from interconnections that favour stability SO NATURE PHYSICS LA English DT Article ID PARADOXICAL COMPONENTS; SYSTEMS; ORGANIZATION; MODULARITY; EVOLUTION; CIRCUITS; DESIGN AB The microscopic principles organizing dynamic units in complex networks-from proteins to power generators-can be understood in terms of network 'motifs': small interconnection patterns that appear much more frequently in real networks than expected in random networks(1,2). When considered as small subgraphs isolated from a large network, these motifs are more robust to parameter variations, easier to synchronize than other possible subgraphs, and can provide specific functionalities(3-15). But one can isolate these subgraphs only by assuming, for example, a significant separation of timescales, and the origin of network motifs and their functionalities when embedded in larger networks remain unclear. Here we show that most motifs emerge from interconnection patterns that best exploit the intrinsic stability characteristics at different scales of interconnection, from simple nodes to whole modules. This functionality suggests an efficient mechanism to stably build complex systems by recursively interconnecting nodes and modules as motifs. We present direct evidence of this mechanism in several biological networks. C1 [Angulo, Marco Tulio] Northeastern Univ, Ctr Complex Networks Res, Boston, MA 02115 USA. [Angulo, Marco Tulio; Liu, Yang-Yu] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Angulo, Marco Tulio; Liu, Yang-Yu] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Liu, Yang-Yu] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA. [Slotine, Jean-Jacques] MIT, Nonlinear Syst Lab, Cambridge, MA 02139 USA. [Slotine, Jean-Jacques] MIT, Dept Mech Engn, Cambridge, MA 02139 USA. [Slotine, Jean-Jacques] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. RP Liu, YY (reprint author), Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. EM yyl@channing.harvard.edu; jjs@mit.edu RI Liu, Yang-Yu/G-8885-2011 OI Liu, Yang-Yu/0000-0003-2728-4907 FU CONACyT postdoctoral grant [207609]; ARL NS-CTA grant [W911NF-09-2-0053]; DARPA grant [W911NF-12-C-002]; John Templeton Foundation [51977] FX We thank A.-L. Barabasi for valuable discussions. M.T.A. was supported by the CONACyT postdoctoral grant 207609, the ARL NS-CTA grant (W911NF-09-2-0053), and the DARPA grant (W911NF-12-C-002). Y.-Y.L. was supported in part by the John Templeton Foundation (award number 51977). NR 30 TC 1 Z9 1 U1 3 U2 17 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1745-2473 EI 1745-2481 J9 NAT PHYS JI Nat. Phys. PD OCT PY 2015 VL 11 IS 10 BP 848 EP 852 DI 10.1038/NPHYS3402 PG 5 WC Physics, Multidisciplinary SC Physics GA CS6KX UT WOS:000362188600021 ER PT J AU MacRae, CA Peterson, RT AF MacRae, Calum A. Peterson, Randall T. TI Zebrafish as tools for drug discovery SO NATURE REVIEWS DRUG DISCOVERY LA English DT Review ID CHEMICAL GENETIC SCREEN; WNT/BETA-CATENIN PATHWAY; BLOOD-BRAIN-BARRIER; SMALL MOLECULES; ANTIANGIOGENIC COMPOUNDS; TRANSGENIC ZEBRAFISH; NEURAL CREST; STEM-CELLS; INHIBITION; SYSTEM AB The zebrafish has become a prominent vertebrate model for disease and has already contributed to several examples of successful phenotype-based drug discovery. For the zebrafish to become useful in drug development more broadly, key hurdles must be overcome, including a more comprehensive elucidation of the similarities and differences between human and zebrafish biology. Recent studies have begun to establish the capabilities and limitations of zebrafish for disease modelling, drug screening, target identification, pharmacology, and toxicology. As our understanding increases and as the technologies for manipulating zebrafish improve, it is hoped that the zebrafish will have a key role in accelerating the emergence of precision medicine. C1 [MacRae, Calum A.] Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02115 USA. [MacRae, Calum A.] Brigham & Womens Hosp, Network Med Div, Boston, MA 02115 USA. [MacRae, Calum A.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [MacRae, Calum A.; Peterson, Randall T.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [MacRae, Calum A.; Peterson, Randall T.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Peterson, Randall T.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. [Peterson, Randall T.] Harvard Univ, Dept Syst Biol, Sch Med, Boston, MA 02115 USA. RP MacRae, CA (reprint author), Brigham & Womens Hosp, Div Cardiovasc Med, 75 Francis St, Boston, MA 02115 USA. EM camacrae@bics.bwh.harvard.edu; peterson@cvrc.mgh.harvard.edu FU Innovation in Regulatory Science Award from the Burroughs Wellcome Fund FX The authors thank A. Rennekamp for his help compiling Table 1. R.T.P acknowledges support from The toxicology work of C.A.M. has been funded by an Innovation in Regulatory Science Award from the Burroughs Wellcome Fund. NR 106 TC 44 Z9 45 U1 13 U2 48 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 OCT PY 2015 VL 14 IS 10 BP 721 EP 731 DI 10.1038/nrd4627 PG 11 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA CS6LT UT WOS:000362191100015 PM 26361349 ER PT J AU Braga, RM Leech, R AF Braga, Rodrigo M. Leech, Robert TI Echoes of the Brain: Local-Scale Representation of Whole-Brain Functional Networks within Transmodal Cortex SO NEUROSCIENTIST LA English DT Review DE transmodal cortex; multimodal; association; integration; networks; hubs; intrinsic connectivity networks; neural dynamics ID POSTERIOR CINGULATE CORTEX; DEFAULT MODE NETWORK; RICH-CLUB ORGANIZATION; HUMAN CEREBRAL-CORTEX; RESTING HUMAN BRAIN; CONNECTIVITY NETWORKS; COGNITIVE CONTROL; ARCHITECTURE; TASK; FMRI AB Transmodal (nonsensory-specific) regions sit at the confluence of different information streams, and play an important role in cognition. These regions are thought to receive and integrate information from multiple functional networks. However, little is known about (1) how transmodal cortices are functionally organized and (2) how this organization might facilitate information processing. In this article, we discuss recent findings that transmodal cortices contain a detailed local functional architecture of adjacent and partially overlapping subregions. These subregions show relative specializations, and contain traces or echoes of the activity of different large-scale intrinsic connectivity networks. We propose that this finer-grained organization can (1) explain how the same transmodal region can play a role in multiple tasks and cognitive disorders, (2) provide a mechanism by which different types of signals can be simultaneously segregated and integrated within transmodal regions, and (3) enhance current network- and node-level models of brain function, by showing that non-stationary functional connectivity patterns may be a result of dynamic shifts in subnodal signals. Finally, we propose that LFA may have an important role in regulating neural dynamics and facilitating balanced activity across the cortex to enable efficient and flexible high-level cognition. C1 [Braga, Rodrigo M.; Leech, Robert] Univ London Imperial Coll Sci Technol & Med, Computat Cognit & Clin Neuroimaging Lab, Div Brain Sci, London W12 0NN, England. [Braga, Rodrigo M.] Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA. [Braga, Rodrigo M.] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Braga, Rodrigo M.] Harvard Univ, Sch Med, Charlestown, MA USA. RP Leech, R (reprint author), Univ London Imperial Coll Sci Technol & Med, Imaging Neurosci Computat Cognit & Clin Neuroimag, Div Brain Sci, Hammersmith Hosp Campus,Du Cane Rd, London W12 0NN, England. EM r.leech@imperial.ac.uk FU Wellcome Trust FX RMB is supported by the Wellcome Trust. NR 92 TC 3 Z9 3 U1 1 U2 7 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1073-8584 EI 1089-4098 J9 NEUROSCIENTIST JI Neuroscientist PD OCT PY 2015 VL 21 IS 5 BP 540 EP 551 DI 10.1177/1073858415585730 PG 12 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CS7TU UT WOS:000362290000013 ER PT J AU Takahashi, H Jin, C Rajabi, H Pitroda, S Alam, M Ahmad, R Raina, D Hasegawa, M Suzuki, Y Tagde, A Bronson, RT Weichselbaum, R Kufe, D AF Takahashi, H. Jin, C. Rajabi, H. Pitroda, S. Alam, M. Ahmad, R. Raina, D. Hasegawa, M. Suzuki, Y. Tagde, A. Bronson, R. T. Weichselbaum, R. Kufe, D. TI MUC1-C activates the TAK1 inflammatory pathway in colon cancer SO ONCOGENE LA English DT Article ID COLITIS-ASSOCIATED CANCER; COLORECTAL-CANCER; BOWEL-DISEASE; LUNG-CANCER; TRANSCRIPTION FACTOR; MONOCLONAL-ANTIBODY; MOUSE MODEL; ONCOPROTEIN; KINASE; CELLS AB The mucin 1 (MUC1) oncoprotein has been linked to the inflammatory response by promoting cytokine-mediated activation of the NF-kappa B pathway. The TGF-beta-activated kinase 1 (TAK1) is an essential effector of proinflammatory NF-kappa B signaling that also regulates cancer cell survival. The present studies demonstrate that the MUC1-C transmembrane subunit induces TAK1 expression in colon cancer cells. MUC1 also induces TAK1 in a MUC1(+/-)/IL-10(-/-) mouse model of colitis and colon tumorigenesis. We show that MUC1C promotes NF-kappa B-mediated activation of TAK1 transcription and, in a positive regulatory loop, MUC1-C contributes to TAK1-induced NF-kappa B signaling. In this way, MUC1-C binds directly to TAK1 and confers the association of TAK1 with TRAF6, which is necessary for TAK1-mediated activation of NF-kappa B. Targeting MUC1-C thus suppresses the TAK1 -> NF-kappa B pathway, downregulates BCL-XL and in turn sensitizes colon cancer cells to MEK inhibition. Analysis of colon cancer databases further indicates that MUC1, TAK1 and TRAF6 are upregulated in tumors associated with decreased survival and that MUC1-C-induced gene expression patterns predict poor outcomes in patients. These results support a model in which MUC1-C-induced TAK1 -> NF-kappa B signaling contributes to intestinal inflammation and colon cancer progression. C1 [Takahashi, H.; Rajabi, H.; Alam, M.; Ahmad, R.; Hasegawa, M.; Suzuki, Y.; Tagde, A.; Kufe, D.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02215 USA. [Jin, C.; Raina, D.] Genus Oncol, Boston, MA USA. [Pitroda, S.; Weichselbaum, R.] Univ Chicago, Dept Radiat & Cellular Oncol, Ludwig Ctr Metastasis Res, Chicago, IL 60637 USA. [Bronson, R. T.] Harvard Univ, Sch Med, Div Immunol, Dept Microbiol & Immunobiol, Boston, MA 02215 USA. RP Kufe, D (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 450 Brookline Ave,Dana 830, Boston, MA 02215 USA. EM donald_kufe@dfci.harvard.edu RI Tagde, Ashujit/M-9497-2014 OI Tagde, Ashujit/0000-0002-0770-097X FU Department of Defense; National Cancer Institute of the National Institutes of Health [CA97098, CA166480]; CDMRP [CA110495] FX Research reported in this publication was supported by Grant CDMRP CA110495 awarded by the Department of Defense and by the National Cancer Institute of the National Institutes of Health under award numbers CA97098 and CA166480. NR 50 TC 15 Z9 16 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD OCT 1 PY 2015 VL 34 IS 40 BP 5187 EP 5197 DI 10.1038/onc.2014.442 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA CS6ZP UT WOS:000362233400008 PM 25659581 ER PT J AU Jampel, JD Safren, SA Blashill, AJ AF Jampel, Jonathan D. Safren, Steven A. Blashill, Aaron J. TI Muscularity Disturbance and Methamphetamine Use Among HIV-Infected Men Who Have Sex With Men SO PSYCHOLOGY OF MEN & MASCULINITY LA English DT Article DE HIV/AIDS; gay and bisexual men; body image; methamphetamine use; muscularity concerns ID ANABOLIC-ANDROGENIC STEROIDS; QUALITY-OF-LIFE; BODY-IMAGE; ADOLESCENT BOYS; BISEXUAL MEN; ADULT MEN; DRUG-USE; HEALTH; RISK; BEHAVIORS AB Previous research has established a link between methamphetamine use and body dissatisfaction among HIV-infected men who have sex with men (MSM). However, to date, no study has examined the specific role that muscularity disturbance, a key component of body dissatisfaction among men, has in this relationship. Thus, the current study aimed to examine links between muscularity disturbance and methamphetamine use among HIV-infected MSM. Participants were 97 HIV-infected MSM, who completed a number of self-report measures of muscularity disturbance, depressive symptoms, and substance use. Results indicated that after controlling for depression and polysubstance use, elevated muscularity disturbance was associated with increased methamphetamine use. Future interventions may benefit from integrating body image dissatisfaction and methamphetamine use in an approach that encompasses the intertwined psychosocial stressors that HIV-infected MSM face. C1 [Jampel, Jonathan D.; Safren, Steven A.; Blashill, Aaron J.] Fenway Hlth, Fenway Inst, Boston, MA USA. [Safren, Steven A.; Blashill, Aaron J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat, Cambridge, MA 02138 USA. RP Blashill, AJ (reprint author), Massachusetts Gen Hosp, Dept Psychiat, 1 Bowdoin Sq,7th Floor, Boston, MA 02114 USA. EM ablashill@mgh.harvard.edu FU National Institute of Mental Health of the National Institutes of Health [K23MH096647]; Harvard University Center for AIDS Research/National Institutes of Health [5P30 AI060354-08, K24MH094214] FX Research reported in this publication was supported by the National Institute of Mental Health of the National Institutes of Health (K23MH096647) and awards from the Harvard University Center for AIDS Research/National Institutes of Health to Aaron J. Blashill (5P30 AI060354-08) and Steven A. Safren (K24MH094214). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 51 TC 2 Z9 2 U1 5 U2 7 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 OCT PY 2015 VL 16 IS 4 BP 474 EP 479 DI 10.1037/a0038461 PG 6 WC Psychology, Social SC Psychology GA CS2NB UT WOS:000361906800016 ER PT J AU Dueck, AC Mitchell, SA Rogak, LJ Ginos, B Sargent, DJ Shi, Q Farma, JM Eng, C Crane, C Kennecke, H O'Mara, AM Minasian, LM Schrag, D Basch, E AF Dueck, Amylou C. Mitchell, Sandra A. Rogak, Lauren J. Ginos, Brenda Sargent, Daniel J. Shi, Qian Farma, Jeffrey M. Eng, Cathy Crane, Christopher Kennecke, Hagen O'Mara, Ann M. Minasian, Lori M. Schrag, Deborah Basch, Ethan TI A cluster-randomized study of clinician-patient shared vs standard reporting of symptomatic adverse events using PRO-CTCAE nested in a multicenter trial of multimodal therapy for rectal cancer (Alliance N1048 PROSPECT) SO QUALITY OF LIFE RESEARCH LA English DT Meeting Abstract C1 [Dueck, Amylou C.; Ginos, Brenda] Mayo Clin, Scottsdale, AZ USA. [Mitchell, Sandra A.; O'Mara, Ann M.; Minasian, Lori M.] NCI, Rockville, MD USA. [Rogak, Lauren J.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Sargent, Daniel J.; Shi, Qian] Mayo Clin, Rochester, MN USA. [Farma, Jeffrey M.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Eng, Cathy; Crane, Christopher] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Kennecke, Hagen] British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. [Schrag, Deborah] Dana Farber Canc Inst, Boston, MA 02115 USA. [Basch, Ethan] Univ N Carolina, Chapel Hill, NC USA. NR 0 TC 1 Z9 1 U1 1 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 EI 1573-2649 J9 QUAL LIFE RES JI Qual. Life Res. PD OCT PY 2015 VL 24 SU 1 MA 2 BP 1 EP 2 PG 2 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA CS3RA UT WOS:000361991100003 ER PT J AU Basch, E Deal, A Dueck, A Bennett, A Atkinson, TM Rogak, LJ Sloan, JA Schrag, D AF Basch, Ethan Deal, Allison Dueck, Amylou Bennett, Antonia Atkinson, Thomas M. Rogak, Lauren J. Sloan, Jeff A. Schrag, Deborah TI Effect of electronic patient reporting of symptoms during cancer treatment: a randomized controlled trial SO QUALITY OF LIFE RESEARCH LA English DT Meeting Abstract C1 [Basch, Ethan; Deal, Allison; Bennett, Antonia] Univ N Carolina, Chapel Hill, NC USA. [Dueck, Amylou] Mato Clin, Scottsdale, AZ USA. [Atkinson, Thomas M.; Rogak, Lauren J.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Sloan, Jeff A.] Mayo Clin, Rochester, MN USA. [Schrag, Deborah] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 EI 1573-2649 J9 QUAL LIFE RES JI Qual. Life Res. PD OCT PY 2015 VL 24 SU 1 MA 104.1 BP 19 EP 19 PG 1 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA CS3RA UT WOS:000361991100050 ER PT J AU Reeve, BB McFatrich, M Baker, JN Freyer, DR Gagne, J Gattuso, JS Gibson, D Kohler, RE Levine, A Lollar, S Lukshis, J Mack, JW Martens, C Mowbray, C Palma, D Pinheiro, LC Sung, LL Taddei, SC Tomlinson, D Waldron, M Weaver, M Wind, J Withycombe, J Hinds, PS AF Reeve, Bryce B. McFatrich, Molly Baker, Justin N. Freyer, David R. Gagne, Joshua Gattuso, Jami S. Gibson, Deborah Kohler, Racquel E. Levine, Alyssa Lollar, Selena Lukshis, Jane Mack, Jennifer W. Martens, Christa Mowbray, Catriona Palma, Diana Pinheiro, Laura C. Sung, Lillian Taddei, Sarah C. Tomlinson, Deborah Waldron, Mia Weaver, Meaghann Wind, Jennifer Withycombe, Janice Hinds, Pamela S. TI Integrating the child's voice in adverse event reporting in oncology trials: cognitive interview findings from the multisite pediatric PRO-CTCAE initiative SO QUALITY OF LIFE RESEARCH LA English DT Meeting Abstract C1 [Reeve, Bryce B.; McFatrich, Molly; Kohler, Racquel E.; Martens, Christa; Pinheiro, Laura C.] Univ N Carolina, Chapel Hill, NC USA. [Baker, Justin N.; Gattuso, Jami S.; Gibson, Deborah] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Freyer, David R.; Palma, Diana] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Gagne, Joshua; Levine, Alyssa; Mack, Jennifer W.; Taddei, Sarah C.; Wind, Jennifer] Boston Childrens Hosp, Dana Farber Canc Inst, Boston, MA USA. [Lollar, Selena; Lukshis, Jane; Withycombe, Janice] Palmetto Hlth Childrens Hosp, Columbia, SC USA. [Mowbray, Catriona; Waldron, Mia; Hinds, Pamela S.] Childrens Natl Hlth Syst, Washington, DC USA. [Sung, Lillian; Tomlinson, Deborah] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Weaver, Meaghann] St Jude Childrens Res Hosp, Childrens Natl Hlth Syst, Memphis, TN 38105 USA. NR 0 TC 0 Z9 0 U1 4 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 EI 1573-2649 J9 QUAL LIFE RES JI Qual. Life Res. PD OCT PY 2015 VL 24 SU 1 MA 3033 BP 161 EP 162 PG 2 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA CS3RA UT WOS:000361991100360 ER PT J AU Rahimy, E Kuehlewein, L Sadda, SR Sarraf, D AF Rahimy, Ehsan Kuehlewein, Laura Sadda, Srinivas R. Sarraf, David TI Paracentral Acute Middle Maculopathy What We Knew Then and What We Know Now SO RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES LA English DT Editorial Material ID ACUTE MACULAR NEURORETINOPATHY; DEEP CAPILLARY ISCHEMIA; COHERENCE TOMOGRAPHY ANGIOGRAPHY; RETINAL ARTERY-OCCLUSION; FLUORESCEIN ANGIOGRAPHY; OXYGEN DISTRIBUTION; VASCULATURE; SPECTRUM; OCT C1 [Rahimy, Ehsan] Wills Eye Hosp & Res Inst, Retina Serv, Philadelphia, PA USA. [Kuehlewein, Laura; Sadda, Srinivas R.] Doheny Eye Inst, Los Angeles, CA 90033 USA. [Sarraf, David] Univ Calif Los Angeles, Jules Stein Eye Inst, Los Angeles, CA 90024 USA. [Sarraf, David] Greater Los Angeles VA Healthcare Ctr, Los Angeles, CA USA. RP Sarraf, D (reprint author), Univ Calif Los Angeles, Jules Stein Eye Inst, Los Angeles, CA 90024 USA. NR 31 TC 7 Z9 8 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0275-004X EI 1539-2864 J9 RETINA-J RET VIT DIS JI Retin.-J. Retin. Vitr. Dis. PD OCT PY 2015 VL 35 IS 10 BP 1921 EP 1930 DI 10.1097/IAE.0000000000000785 PG 10 WC Ophthalmology SC Ophthalmology GA CS6US UT WOS:000362219000001 PM 26360227 ER PT J AU Manschreck, TC Chun, J Merrill, AM Maher, BA Boshes, RA Glatt, SJ Faraone, SV Tsuang, MT Seidman, LJ AF Manschreck, T. C. Chun, J. Merrill, A. M. Maher, B. A. Boshes, R. A. Glatt, S. J. Faraone, S. V. Tsuang, M. T. Seidman, L. J. TI Impaired motor performance in adolescents at familial high-risk for schizophrenia SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Schizophrenia; Familial high-risk; Motor performance; Genetics; Lateralization ID NEUROLEPTIC-NAIVE; WORKING-MEMORY; GENETIC RISK; YOUNG-ADULTS; CHILDREN; PSYCHOSIS; SYMPTOMS; METAANALYSIS; INDIVIDUALS; IMPAIRMENTS AB Background: The Harvard Adolescent Family High Risk (FHR) Study examined multiple domains of function in young relatives of individuals diagnosed with schizophrenia to identify precursors of the illness. One such area is motor performance, which is deviant in people with schizophrenia and in children at risk for schizophrenia, usually offspring. The present study assessed accuracy of motor performance and degree of lateralization in FHR adolescents and young adults. Methods: Subjects were 33 non-psychotic, first-degree relatives of individuals diagnosed with schizophrenia, and 30 non-psychotic comparison subjects (NpC), ranging in age from 13 to 25 who were compared using a line-drawing task. Results: FHR individuals exhibited less precise and coordinated line drawing but greater degree of lateralization than controls. Performance on the linedrawing task was correlated with degree of genetic loading, a possible predictor of higher risk for schizophrenia in the pedigree. Conclusions: The observation of increased motor deviance and increased lateralization in FHR can be utilized in identification and initiation of the treatment in those at high risk in order to prevent or delay the full manifestation of this devastating condition. The use of a rigorously quantified measure is likely to add to the sensitivity of measuring motor performance, especially when impairments may be subtle. (C) 2015 Elsevier B.V. All rights reserved. C1 [Manschreck, T. C.; Chun, J.; Merrill, A. M.; Boshes, R. A.; Seidman, L. J.] Harvard Univ, Commonwealth Res Ctr, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02115 USA. [Manschreck, T. C.; Chun, J.; Merrill, A. M.; Maher, B. A.; Boshes, R. A.] Harvard Univ, Lab Clin & Expt Psychopathol, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02115 USA. [Manschreck, T. C.; Chun, J.; Merrill, A. M.; Maher, B. A.; Boshes, R. A.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Glatt, S. J.] Med Genet Res Ctr, Psychiat Genet Epidemiol & Neurobiol Lab PsychGEN, Syracuse, NY USA. [Glatt, S. J.; Faraone, S. V.] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY 13210 USA. [Glatt, S. J.; Faraone, S. V.] SUNY Upstate Med Univ, Dept Neurosci & Physiol, Syracuse, NY 13210 USA. [Tsuang, M. T.] Univ Calif San Diego, Ctr Behav Genom, Dept Psychiat, Inst Genom Med, San Diego, CA 92103 USA. [Seidman, L. J.] Harvard Univ, Beth Israel Deaconess Med Ctr, Massachusetts Mental Hlth Ctr,Div Publ Psychiat, Dept Psychiat,Sch Med, Boston, MA 02115 USA. [Seidman, L. J.] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Manschreck, TC (reprint author), Lab Clin & Expt Psychopathol, 49 Hillside St, Fall River, MA USA. EM theo.manschreck@state.ma.us OI Glatt, Stephen/0000-0002-0360-7567; Faraone, Stephen/0000-0002-9217-3982 FU Stanley Medical Research Institute; National Association for Research on Schizophrenia and Depression (NARSAD); Mental Illness and Neuroscience Discovery (MIND) Institute [MH-43518, MH-46318]; Commonwealth Research Center of the Massachusetts Department of Mental Health [SCDMH82101008006] FX This study was funded by the following: Stanley Medical Research Institute (LJS); National Association for Research on Schizophrenia and Depression (NARSAD; LJS, MTT); Mental Illness and Neuroscience Discovery (MIND) Institute (LJS); MH-43518 (MTT, LJS); MH-46318 (MTT); and The Commonwealth Research Center of the Massachusetts Department of Mental Health, SCDMH82101008006 (LJS, TCM). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies. NR 58 TC 3 Z9 3 U1 1 U2 2 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 OCT PY 2015 VL 168 IS 1-2 BP 44 EP 49 DI 10.1016/j.schres.2015.06.013 PG 6 WC Psychiatry SC Psychiatry GA CS1LK UT WOS:000361826400007 PM 26165939 ER PT J AU Kranz, TM Goetz, RR Walsh-Messinger, J Goetz, D Antonius, D Dolgalev, I Heguy, A Seandel, M Malaspina, D Chao, MV AF Kranz, Thorsten M. Goetz, Ray R. Walsh-Messinger, Julie Goetz, Deborah Antonius, Daniel Dolgalev, Igor Heguy, Adriana Seandel, Marco Malaspina, Dolores Chao, Moses V. TI Rare variants in the neurotrophin signaling pathway implicated in schizophrenia risk SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Schizophrenia; Sporadic; De novo; ARMS; Kidins220; Rare variant; Neurotrophin; Exome sequencing ID DENDRITIC SPINE PATHOLOGY; MEMBRANE-SPANNING PROTEIN; NEGATIVE SYNDROME SCALE; NERVE GROWTH-FACTOR; DE-NOVO MUTATIONS; ALZHEIMERS-DISEASE; DEVELOPMENTAL DELAY; BIPOLAR DISORDER; MOOD DISORDERS; MESSENGER-RNA AB Multiple lines of evidence corroborate impaired signaling pathways as relevant to the underpinnings of schizophrenia. There has been an interest in neurotrophins, since they are crucial mediators of neurodevelopment and in synaptic connectivity in the adult brain. Neurotrophins and their receptors demonstrate aberrant expression patterns in cortical areas for schizophrenia cases in comparison to control subjects. There is little known about the contribution of neurotrophin genes in psychiatric disorders. To begin to address this issue, we conducted high-coverage targeted exome capture in a subset of neurotrophin genes in 48 comprehensively characterized cases with schizophrenia-related psychosis. We herein report rare missense polymorphisms and novel missense mutations in neurotrophin receptor signaling pathway genes. Furthermore, we observed that several genes have a higher propensity to harbor missense coding variants than others. Based on this initial analysis we suggest that rare variants and missense mutations in neurotrophin genes might represent genetic contributions involved across psychiatric disorders. (C) 2015 Elsevier B.V. All rights reserved. C1 [Kranz, Thorsten M.; Chao, Moses V.] NYU, Skirball Inst Biomol Med, Dept Cell Biol, New York, NY 10016 USA. [Kranz, Thorsten M.; Chao, Moses V.] NYU, Skirball Inst Biomol Med, Dept Physiol & Neurosci, New York, NY 10016 USA. [Kranz, Thorsten M.; Chao, Moses V.] NYU, Skirball Inst Biomol Med, Dept Psychiat, New York, NY 10016 USA. [Goetz, Ray R.] New York State Psychiat Inst & Hosp, Div Clin Phenomenol, New York, NY 10032 USA. [Goetz, Ray R.] Columbia Univ, Dept Psychiat, New York, NY 10032 USA. [Walsh-Messinger, Julie] James J Peters VA Med Ctr, MIRECC, Bronx, NY 10468 USA. [Walsh-Messinger, Julie] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Goetz, Deborah; Antonius, Daniel; Malaspina, Dolores] NYU, Dept Psychiat Social & Psychiat Initiat, New York, NY 10016 USA. [Antonius, Daniel] SUNY Buffalo, Dept Psychiat, Buffalo, NY 14215 USA. [Dolgalev, Igor; Heguy, Adriana] NYU, Genome Technol Ctr, Langone Med Ctr, New York, NY 10016 USA. [Seandel, Marco] Weill Cornell Med Coll, Dept Surg, New York, NY 10065 USA. RP Kranz, TM (reprint author), NYU, Sch Med, Skirball Inst Biomol Med, 540 First Ave,Rm 5-15, New York, NY 10016 USA. EM Thorsten.Kranz@nyumc.org OI Dolgalev, Igor/0000-0003-4451-126X; Chao, Moses/0000-0002-6969-3744 FU National Institutes of Health [NS21072, MH086651, RC1-MH088843, 5K24MH001699]; NYU CTSI [UL1TR000038] FX This work was supported in part by the National Institutes of Health Grants NS21072 (MVC), MH086651 (MVC), RC1-MH088843 (DM), 5K24MH001699 (DM) and NYU CTSI UL1TR000038 (DM). NR 67 TC 6 Z9 6 U1 2 U2 6 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 OCT PY 2015 VL 168 IS 1-2 BP 421 EP 428 DI 10.1016/j.schres.2015.07.002 PG 8 WC Psychiatry SC Psychiatry GA CS1LK UT WOS:000361826400060 PM 26215504 ER PT J AU Tabak, NT Horan, WP Green, MF AF Tabak, Naomi T. Horan, William P. Green, Michael F. TI Mindfulness in schizophrenia: Associations with self-reported motivation, emotion regulation, dysfunctional attitudes, and negative symptoms SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Mindfulness; Motivation; Emotion regulation; Cognitive reappraisal; Dysfunctional attitudes; Defeatist beliefs ID RANDOMIZED CONTROLLED-TRIAL; COMMITMENT THERAPY; BEHAVIORAL ACTIVATION; INHIBITION SYSTEMS; COGNITIVE THERAPY; MEDITATION; ACCEPTANCE; PSYCHOSIS; ASYMMETRY; DYSREGULATION AB Mindfulness-based interventions are gaining empirical support as alternative or adjunctive treatments for a variety of mental health conditions, including anxiety, depression, and substance use disorders. Emerging evidence now suggests that mindfulness-based treatments may also improve clinical features of schizophrenia, including negative symptoms. However, no research has examined the construct of mindfulness and its correlates in schizophrenia. In this study, we examined self-reported mindfulness in patients (n = 35) and controls (n = 25) using the Five-Facet Mindfulness Questionnaire. We examined correlations among mindfulness, negative symptoms, and psychological constructs associated with negative symptoms and adaptive functioning, including motivation, emotion regulation, and dysfunctional attitudes. As hypothesized, patients endorsed lower levels of mindfulness than controls. In patients, mindfulness was unrelated to negative symptoms, but it was associated with more adaptive emotion regulation (greater reappraisal) and beliefs (lower dysfunctional attitudes). Some facets of mindfulness were also associated with self-reported motivation (behavioral activation and inhibition). These patterns of correlations were similar in patients and controls. Findings from this initial study suggest that schizophrenia patients may benefit from mindfulness-based interventions because they (a) have lower self-reported mindfulness than controls and (b) demonstrate strong relationships between mindfulness and psychological constructs related to adaptive functioning. (C) 2015 Elsevier B.V. All rights reserved. C1 [Tabak, Naomi T.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90024 USA. [Tabak, Naomi T.; Horan, William P.; Green, Michael F.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Horan, William P.; Green, Michael F.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90024 USA. RP Tabak, NT (reprint author), Univ Calif Los Angeles, MIRECC 210A,Bldg 210,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM ntabak@ucla.edu FU Veterans Affairs Merit grant; NIMH [MH095878]; NIMH training grant in Cognitive and Affective Dysfunctions in the Psychoses at the University of California, Los Angeles [T32MH09668] FX Funding for the current study was provided by a Veterans Affairs Merit grant (Dr. Horan) and NIMH grant MH095878 (Dr. Green). A postdoctoral fellowship for Dr. Tabak was supported by an NIMH training grant in Cognitive and Affective Dysfunctions in the Psychoses at the University of California, Los Angeles (T32MH09668). NR 48 TC 3 Z9 3 U1 5 U2 37 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 OCT PY 2015 VL 168 IS 1-2 BP 537 EP 542 DI 10.1016/j.schres.2015.07.030 PG 6 WC Psychiatry SC Psychiatry GA CS1LK UT WOS:000361826400076 PM 26232242 ER PT J AU Becker, MA Fitz-Patrick, D Choi, HK Dalbeth, N Storgard, C Cravets, M Baumgartner, S AF Becker, Michael A. Fitz-Patrick, David Choi, Hyon K. Dalbeth, Nicola Storgard, Chris Cravets, Matt Baumgartner, Scott TI An open-label, 6-month study of allopurinol safety in gout: The LASSO study SO SEMINARS IN ARTHRITIS AND RHEUMATISM LA English DT Review DE Allopurinol; Dose titration; Gout; Hyperuricemia; Open-label study; Serum uric acid ID URATE-LOWERING THERAPIES; SERUM URATE; RENAL-FUNCTION; DOSE ASPIRIN; HYPERURICEMIA; FEBUXOSTAT; MANAGEMENT; ADHERENCE; ARTHRITIS; EPIDEMIOLOGY AB Objectives: Allopurinol is the most widely prescribed serum uric acid-lowering therapy (ULT) in gout. To achieve serum uric acid (sUA) concentrations associated with clinical benefit, allopurinol is serially uptitrated with sUA monitoring. Suboptimal dosing is a key contributor to poor clinical outcomes, but few data are available on the safety and efficacy of dose-titrated allopurinol, particularly at doses >300 mg/d. The objective of this open-label study was to investigate the safety and efficacy of allopurinol under conditions where investigators were encouraged to titrate to optimal, medically appropriate doses. Methods: Long-term Allopurinol Safety Study Evaluating Outcomes in Gout Patients (LASSO) was a large, 6-month, multicenter study of allopurinol (NCT01391325). Adults meeting American Rheumatism Association Criteria for Classification of Acute Arthritis of Primary Gout and >= 2 gout flares in the previous year were eligible. Investigators were encouraged (but not required) to titrate allopurinol doses to achieve target sUA < 6.0 mg/dl.. The primary objective was evaluation of the safety of dose-titrated allopurinol by clinical and laboratory examinations at monthly visits. Secondary objectives included sUA-lowering efficacy and gout flare frequency. Results: Of 1735 patients enrolled, 1732 received >= 1 allopurinol doses. The maximal daily allopurinol dose during study was < 300 mg in 14.4%, 300 mg in 65.4%, and > 300 mg in 20.2% of patients; dosing duration was 115.5, 152.0, and 159.7 days, respectively. Overall, baseline demographic characteristics and comorbidity rates were similar across these three categories, but patients receiving > 300-mg maximal dose had more severe gout. Treatment-emergent adverse events possibly related to allopurinol occurred in 15.2%, 9.5%, and 11.4% of patients in the <300-, 300-, and >300-mg categories, respectively. Rash incidence was low (1.5%) and allopurinol hypersensitivity syndrome was not reported. No clinically meaningful changes occurred in laboratory values. sUA < 6.0 mg/cIL at month 6 was achieved by 35.9% of patients overall: 22.4%, 35.0%, and 483% in dosing categories <300, 300, and >300 mg, respectively. Conclusions: This large multicenter study found that the allopurinol dose-titration strategy was well tolerated, without new safety signals emerging over 6 months. However, despite encouragement to treat to target, significant proportions of patients did not achieve target sUA. 0 2015 The Authors. Published by Elsevier HS Journals, Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.orgflicenses/by-nc-nd/4.0/). C1 [Becker, Michael A.] Univ Chicago Med, Dept Med, Chicago, IL 60637 USA. [Fitz-Patrick, David] East West Med Res Inst, Honolulu, HI USA. [Choi, Hyon K.] Harvard Univ, Sch Med, Boston, MA USA. [Choi, Hyon K.] Massachusetts Gen Hosp, Gout & Crystal Arthropathy Ctr, Boston, MA 02114 USA. [Dalbeth, Nicola] Univ Auckland, Dept Med, Auckland, New Zealand. [Storgard, Chris] Ardea Biosci Inc, Clin Res & Dev, San Diego, CA USA. [Cravets, Matt] Ardea Biosci Inc, Biostat, San Diego, CA USA. [Baumgartner, Scott] Ardea Biosci Inc, Med Affairs, San Diego, CA USA. RP Becker, MA (reprint author), Univ Chicago Med, Dept Med, MC0930,5841 S Maryland Ave, Chicago, IL 60637 USA. EM mbecker@medicine.bsd.uchicago.edu FU Ardea Biosciences, Inc., a member of the AstraZeneca Group; AstraZeneca FX This clinical study was funded by Ardea Biosciences, Inc., a member of the AstraZeneca Group. The study sponsor had a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and review and approval of the article. Editorial support for this article was provided by Bill Wolvey of PAREXEL, which was funded by AstraZeneca. NR 31 TC 8 Z9 8 U1 2 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 0049-0172 EI 1532-866X J9 SEMIN ARTHRITIS RHEU JI Semin. Arthritis Rheum. PD OCT PY 2015 VL 45 IS 2 BP 174 EP 183 DI 10.1016/j.semarthrit.2015.05.005 PG 10 WC Rheumatology SC Rheumatology GA CS5ZA UT WOS:000362155600008 PM 26190562 ER PT J AU Avina-Zubieta, JA Vostretsova, K De Vera, MA Sayre, EC Choi, HK AF Avina-Zubieta, J. Antonio Vostretsova, Kateryna De Vera, Mary A. Sayre, Eric C. Choi, Hyon K. TI The risk of pulmonary embolism and deep venous thrombosis in systemic lupus erythematosus: A general population-based study SO SEMINARS IN ARTHRITIS AND RHEUMATISM LA English DT Review DE Cardiovascular disease; Systemic lupus erythematosus; Deep venous thrombosis; Pulmonary embolism; Risk ID ACUTE MYOCARDIAL-INFARCTION; RHEUMATOID-ARTHRITIS; ANTIPHOSPHOLIPID ANTIBODIES; ADMINISTRATIVE DATA; VEIN THROMBOSIS; THROMBOEMBOLISM; COHORT; DISEASE; GLUCOCORTICOIDS; SENSITIVITY AB Objective: To estimate the future risk and time trends of newly diagnosed venous thromboembolism (VTE) in individuals with incident systemic lupus erythematosus (SLE) in the general population. Methods: Using a population-based database that includes all residents of British Columbia, Canada we conducted a study cohort of all patients with incident SLE and up to 10 age-, sex-, and entry-time-matched individuals from the general population. We compared incidence rates of pulmonary embolism (PE), deep venous thrombosis (DVT), and VTE between the two groups according to SLE disease duration. We calculated hazards ratios (FIR), adjusting for confounders. Results: Among 4863 individuals with SLE (86% female; mean age, 48.9 years), the incidence rates (IRS) of PE, DVT, and VTE were 2.58, 3.33, and 5.32 per 1000 person-years, respectively, whereas the corresponding rates in the comparison cohort were 0.67, 0.57, and 1.11 per 1000 person-years. Compared with non-SLE individuals, the multivariable HRs among SLE patients were 3.04 (95% CI: 2.08-4.45), 4.46 (95% Cl: 3.11-6.41), and 3.55 (95% CI: 2.69-4.69), respectively. The age-, sex-, and entry-time-matched HRs for PE, DVT, and VTE were highest during the first year after SLE diagnosis [13.57 (95% CI: 7.66-24.02), 11.13 (95% CI: 6.55-18.90), and 12.89 (95% Cl: 8.56-19.41), respectively]. Conclusion: These findings provide population-based evidence that patients with SLE have a substantially increased risk of VTE, especially in the first year after SLE diagnosis. Awareness and increased vigilance of this potentially fatal, but preventable, complication is recommended. (C) 2015 Elsevier Inc. All rights reserved. C1 [Avina-Zubieta, J. Antonio; De Vera, Mary A.; Sayre, Eric C.; Choi, Hyon K.] Univ British Columbia, Arthrit Res Canada, Dept Med, Div Rheumatol, Richmond, BC, Canada. [Avina-Zubieta, J. Antonio] Univ British Columbia, Dept Med, Div Rheumatol, Vancouver, BC, Canada. [Vostretsova, Kateryna] Univ British Columbia, Fac Med, Vancouver, BC, Canada. [De Vera, Mary A.] Univ British Columbia, Fac Pharmaceut Sci, Vancouver, BC, Canada. [Choi, Hyon K.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Rheumatol Allergy & Immunol, Boston, MA USA. RP Avina-Zubieta, JA (reprint author), Arthrit Res Canada, 5591 3 Rd, Richmond, BC V6X 2C7, Canada. EM azubieta@arthritisresearch.ca FU Canadian Arthritis Network, Toronto, ON, Canada [10-SRP-IJD-01]; British Columbia Lupus Society, Vancouver, BC, Canada [10-SRP-IJD-01]; Canadian Institutes for Health Research, Ottawa, ON, Canada [MOP 125960, THC 135235] FX This study was funded by the Canadian Arthritis Network (Grant 10-SRP-IJD-01, Toronto, ON, Canada) and the British Columbia Lupus Society (Grant: 10-SRP-IJD-01, Vancouver, BC, Canada) and the Canadian Institutes for Health Research (Grants: MOP 125960 and THC 135235, Ottawa, ON, Canada), Dr. Avina-Zubieta is the British Columbia Lupus Society Research Scholar and a Michael Smith Foundation for Health Research Scholar. NR 47 TC 4 Z9 4 U1 0 U2 11 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0049-0172 EI 1532-866X J9 SEMIN ARTHRITIS RHEU JI Semin. Arthritis Rheum. PD OCT PY 2015 VL 45 IS 2 BP 195 EP 201 DI 10.1016/j.semarthrit.2015.05.008 PG 7 WC Rheumatology SC Rheumatology GA CS5ZA UT WOS:000362155600011 PM 26364556 ER PT J AU Aritake, S Blackwell, T Peters, KW Rueschman, M Mobley, D Morrical, MG Platt, SF Dam, TTL Redline, S Winkelman, JW AF Aritake, Sayaka Blackwell, Terri Peters, Katherine W. Rueschman, Michael Mobley, Daniel Morrical, Michael G. Platt, Samuel F. Dam, Thuy-Tien L. Redline, Susan Winkelman, John W. CA Osteoporotic Fractures Men MrOS TI Prevalence and associations of respiratory-related leg movements: the MrOS sleep study SO SLEEP MEDICINE LA English DT Article DE Leg movement; Obstructive sleep apnea; Respiratory-related events; Cardiovascular disease; Hypertension ID PERIODIC LIMB MOVEMENTS; TO-NIGHT VARIABILITY; OSTEOPOROTIC FRACTURES; BLOOD-PRESSURE; OLDER MEN; APNEA; SCALE; HYPERTENSION; HYPOXEMIA; AROUSALS AB Objectives: Obstructive respiratory events often terminate with an associated respiratory-related leg movement (RRLM). Such leg movements are not scored as periodic leg movements (periodic limb movements during sleep, PLMS), although the criteria for distinguishing RRLM from PLMS differ between the American Academy of Sleep Medicine (AASM) and the World Association of Sleep Medicine (WASM)/International Restless Legs Syndrome Study Group (IRLSSG) scoring manuals. Such LMs may be clinically significant in patients with obstructive sleep apnea (OSA). The prevalence and correlation of RRLM in men with OSA were examined. Methods: A case-control sample of 575 men was selected from all men with an apnea-hypopnea index (AHI, >= 3% desaturation criteria) >= 10 and good data from piezoelectric leg movement sensors at the first in-home sleep study in the MrOS cohort (mean age = 76.8 years). Sleep studies were rescored for RRLMs using five different RRLM definitions varying in both latency of leg movement onset from respiratory event termination and duration of the leg movement. The quartile of RRLM% (the number of RRLM/the number of hypopneas + apneas) was derived. Results: The nonparametric densities of RRLM% were most influenced by alterations in the latency rather than the duration of the LM. The most liberal RRLM definition (latency 0-5 s, duration 0.5-10 s) led to a median RRLM% of 23.4 (interquartile range 12.41, 37.12) in this sample. The average AHI and arousal index increased as the quartile of RRLM% increased, as well as the prevalence of chronic obstructive pulmonary disease (COPD). The prevalence of those with a history of hypertension decreased as RRLM% increased. The non-Caucasian race was associated with lower RRLM%. Conclusion: Within an elderly sample with moderate to severe OSA, piezoelectric-defined RRLM% is associated with a number of sleep-related and demographic factors. Further study of the optimal definition, predictors, and consequences of RRLM is warranted. (C) 2015 Elsevier B.V. All rights reserved. C1 [Aritake, Sayaka; Winkelman, John W.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Sleep Med,Dept Med, Boston, MA 02115 USA. [Aritake, Sayaka] Japan Soc Promot Sci, Tokyo, Japan. [Blackwell, Terri; Peters, Katherine W.] San Francisco Coordinating Ctr, Calif Pacific Med Ctr Res Inst, San Francisco, CA USA. [Rueschman, Michael; Mobley, Daniel; Morrical, Michael G.; Platt, Samuel F.] Brigham & Womens Hosp, Div Sleep Med, Boston, MA 02115 USA. [Dam, Thuy-Tien L.] Columbia Univ, Dept Med, Div Geriatr Med & Aging, New York, NY USA. [Redline, Susan] Brigham & Womens Hosp, Dept Med, Div Sleep Med, Boston, MA 02115 USA. [Redline, Susan] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. RP Winkelman, JW (reprint author), Massachusetts Gen Hosp, Dept Psychiat, 1 Bowdoin Sq, Boston, MA 02114 USA. EM jwwinkelman@partners.org FU National Institutes of Health; National Institute on Aging (NIA); National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); National Center for Advancing Translational Sciences (NCATS); NIH Roadmap for Medical Research [U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, UL1 TR000128]; National Heart, Lung, and Blood Institute (NHLBI) [R01 HL071194, R01 HL070848, R01 HL070847, R01 HL070842, R01 HL070841, R01 HL070837, R01 HL070838, R01 HL070839] FX The Osteoporotic Fractures in Men (MrOS) Study is supported by National Institutes of Health funding. The following institutes provide support: the National Institute on Aging (NIA), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Center for Advancing Translational Sciences (NCATS), and NIH Roadmap for Medical Research under the following grant numbers: U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, and UL1 TR000128. The National Heart, Lung, and Blood Institute (NHLBI) provides funding for the MrOS Sleep ancillary study "Outcomes of Sleep Disorders in Older Men" under the following grant numbers: R01 HL071194, R01 HL070848, R01 HL070847, R01 HL070842, R01 HL070841, R01 HL070837, R01 HL070838, and R01 HL070839. NR 43 TC 3 Z9 3 U1 3 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1389-9457 EI 1878-5506 J9 SLEEP MED JI Sleep Med. PD OCT PY 2015 VL 16 IS 10 BP 1236 EP 1244 DI 10.1016/j.sleep.2015.06.012 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA CS5BQ UT WOS:000362091100011 PM 26429752 ER PT J AU Gelaye, B Kajeepeta, S Zhong, QY Borba, CPC Rondon, MB Sanchez, SE Henderson, DC Williams, MA AF Gelaye, Bizu Kajeepeta, Sandhya Zhong, Qiu-Yue Borba, Christina P. C. Rondon, Marta B. Sanchez, Sixto E. Henderson, David C. Williams, Michelle A. TI Childhood abuse is associated with stress-related sleep disturbance and poor sleep quality in pregnancy SO SLEEP MEDICINE LA English DT Article DE Childhood abuse; Sleep disturbance; Pregnancy; Stress; Life course ID PATIENT HEALTH QUESTIONNAIRE; INTIMATE PARTNER VIOLENCE; SEXUAL-ABUSE; PRIMARY INSOMNIA; PERUVIAN WOMEN; EXPERIENCES; DEPRESSION; SEVERITY; VALIDITY; ADULTS AB Objectives: Childhood abuse is associated with increased risks of adult psychiatric disorders and physical health conditions. Mounting evidence documents associations of childhood abuse with sleep disturbances in adulthood. However, to date, no study has evaluated associations of childhood abuse and sleep disturbances among pregnant women. Methods: This cross-sectional study included 634 pregnant Peruvian women. To collect information regarding socio-demographic characteristics, history of childhood abuse, and complaints of sleep disturbances, face-to-face interviews were conducted with women in early pregnancy. Ford Insomnia Response to Stress Test (FIRST-S) and the Pittsburgh Sleep Quality Index (PSQI-S), translated from English to Spanish, were used to assess stress-related sleep disturbance and sleep quality, respectively. Logistic regression was used to estimate adjusted odds ratios (aOR) and 95% confidence intervals (95% CIs). Results: Women who experienced any childhood abuse had a 1.65-fold increased odds of stress-related sleep disturbance (aOR = 1.65; 95% CI: 1.15-2.38) and 2.11-fold increased odds of poor sleep quality during early pregnancy (aOR = 2.11; 95% CI: 1.35-3.30) as compared with women who reported no abuse. Women who reported both physical and sexual abuse during childhood were more than twice as likely to suffer from stress-related sleep disturbance (aOR = 2.26; 95% CI: 1.44-3.53) and poor sleep quality (aOR = 2.43; 95% CI: 1.45-4.09) in comparison to women who reported no childhood abuse. Conclusions: A history of childhood abuse is associated with increased odds of stress-related sleep disturbance and poor sleep quality during pregnancy. These findings, if replicated, should be used to inform the development of trauma-informed care for such sleep disturbances induced by childhood trauma. (C) 2015 Elsevier B.V. All rights reserved. C1 [Gelaye, Bizu; Kajeepeta, Sandhya; Zhong, Qiu-Yue; Henderson, David C.; Williams, Michelle A.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Borba, Christina P. C.; Henderson, David C.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Borba, Christina P. C.; Henderson, David C.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Rondon, Marta B.] Cayetano Heredia Peruvian Univ, Dept Med, Lima, Peru. [Sanchez, Sixto E.] Univ Peruana Ciencias Aplicadas, Lima, Peru. [Sanchez, Sixto E.] Asociac Civil PROESA, Lima, Peru. RP Gelaye, B (reprint author), Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave,K505F, Boston, MA 02115 USA. EM bgelaye@hsph.harvard.edu OI Gelaye, Bizu/0000-0001-7934-548X FU National Institutes of Health (NIH) [R01-HD-059835, T37-MD000149, K01MH100428] FX This study was supported by awards from the National Institutes of Health (NIH; R01-HD-059835, T37-MD000149 and K01MH100428). The NIH 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. The authors wish to thank the dedicated staff members of Asociacion Civil Proyectos en Salud (PROESA), Peru, and Instituto Materno Perinatal, Peru, for their expert technical assistance with this study. NR 50 TC 3 Z9 3 U1 2 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1389-9457 EI 1878-5506 J9 SLEEP MED JI Sleep Med. PD OCT PY 2015 VL 16 IS 10 BP 1274 EP 1280 DI 10.1016/j.sleep.2015.07.004 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA CS5BQ UT WOS:000362091100016 PM 26429757 ER PT J AU Tsai, AC Venkataramani, AS AF Tsai, Alexander C. Venkataramani, Atheendar S. TI The causal effect of education on HIV stigma in Uganda: Evidence from a natural experiment SO SOCIAL SCIENCE & MEDICINE LA English DT Article DE AIDS/HIV; Behavioral interventions; Developing countries; International health; Social determinants ID UNIVERSAL PRIMARY-EDUCATION; SUB-SAHARAN AFRICA; ANTIDEPRESSANT MEDICATION TREATMENT; REGRESSION DISCONTINUITY DESIGNS; AIDS-RELATED STIGMA; SOUTH-AFRICA; RURAL UGANDA; CAPE-TOWN; ANTIRETROVIRAL THERAPY; RANDOMIZED EXPERIMENTS AB Rationale: HIV is highly stigmatized in sub-Saharan Africa. This is an important public health problem because HIV stigma has many adverse effects that threaten to undermine efforts to control the HIV epidemic. Objective: The implementation of a universal primary education policy in Uganda in 1997 provided us with a natural experiment to test the hypothesis that education is causally related to HIV stigma. Methods: For this analysis, we pooled publicly available, population-based data from the 2011 Uganda Demographic and Health Survey and the 2011 Uganda AIDS Indicator Survey. The primary outcomes of interest were negative attitudes toward persons with HIV, elicited using four questions about anticipated stigma and social distance. Results: Standard least squares estimates suggested a statistically significant, negative association between years of schooling and HIV stigma (each P < 0.001, with t-statistics ranging from 4.9 to 14.7). We then used a natural experiment design, exploiting differences in birth cohort exposure to universal primary education as an instrumental variable. Participants who were <13 years old at the time of the policy change had 1.36 additional years of schooling compared to those who were >13 years old. Adjusting for linear age trends before and after the discontinuity, two-stage least squares estimates suggested no statistically significant causal effect of education on HIV stigma (P-values ranged from 0.21 to 0.69). Three of the four estimated regression coefficients were positive, and in all cases the lower confidence limits convincingly excluded the possibility of large negative effect sizes. These instrumental variables estimates have a causal interpretation and were not overturned by several robustness checks. Conclusion: We conclude that, for young adults in Uganda, additional years of education in the formal schooling system driven by a universal primary school intervention have not had a causal effect on reducing negative attitudes toward persons with HIV. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Tsai, Alexander C.; Venkataramani, Atheendar S.] Massachusetts Gen Hosp, MGH Global Hlth, Boston, MA 02114 USA. [Tsai, Alexander C.; Venkataramani, Atheendar S.] Harvard Ctr Populat & Dev Studies, Cambridge, MA 02138 USA. [Tsai, Alexander C.] Mbarara Univ Sci & Technol, Mbarara, Uganda. [Venkataramani, Atheendar S.] Massachusetts Gen Hosp, Dept Med, Div Gen Internal Med, Boston, MA 02114 USA. RP Tsai, AC (reprint author), Massachusetts Gen Hosp, MGH Global Hlth, 125 Nashua St,Suite 722, Boston, MA 02114 USA. EM actsai@partners.org OI Tsai, Alexander/0000-0001-6397-7917 FU U.S. National Institutes of Health [K23 MH096620]; Robert Wood Johnson Health and Society Scholars Program FX No specific funding was received for this study. ACT acknowledges salary support from U.S. National Institutes of Health K23 MH096620 and the Robert Wood Johnson Health and Society Scholars Program. No funders had any role in the collection, analysis, or interpretation of data; in the writing of the article; or in the decision to submit it for publication. NR 106 TC 4 Z9 4 U1 3 U2 12 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0277-9536 J9 SOC SCI MED JI Soc. Sci. Med. PD OCT PY 2015 VL 142 BP 37 EP 46 DI 10.1016/j.socscimed.2015.08.009 PG 10 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA CS4QL UT WOS:000362060900005 PM 26282707 ER PT J AU Hoerster, KD Millstein, RA Hall, KS Gray, KE Reiber, GE Nelson, KM Saelens, BE AF Hoerster, Katherine D. Millstein, Rachel A. Hall, Katherine S. Gray, Kristen E. Reiber, Gayle E. Nelson, Karin M. Saelens, Brian E. TI Individual and contextual correlates of physical activity among a clinical sample of United States Veterans SO SOCIAL SCIENCE & MEDICINE LA English DT Article DE Veterans; Physical activity; Neighborhood; Social support ID OLDER-ADULTS; MULTIPLE IMPUTATION; NATIONAL SAMPLE; HEALTH-CARE; ODDS RATIO; EXERCISE; OBESITY; ASSOCIATIONS; DISABILITY; LIFE AB Rationale: Veterans, especially those using U.S. Department of Veterans Affairs (VA) healthcare, have poorer health than the general population. In addition, Veterans using VA services are more likely than non-VA users to be physically inactive. Little is known about physical activity correlates among Veterans. To identify targets for health promotion interventions, understanding barriers to and facilitators of physical activity in this population is critical. Methods: This study examined individual-, social-, and perceived neighborhood-level associations of meeting weekly physical activity recommendations (150 min/week of combined leisure and transportation activity) based on the International Physical Activity Questionnaire (IPAQ) among N = 717 patients from VA Puget Sound, Seattle Division using a mailed survey sent 2012-2013 (response rate = 40%). Independent associations were identified with direct estimation of relative risks using generalized linear models (dichotomous outcome), and linear regression (continuous outcome), including variables associated in bivariate tests (p < .05). Results: Most participants were male, Caucasian, and unemployed, and had an annual income <=$40,000. Over two-thirds (69.9%) reported meeting physical activity recommendations. Fewer days of limitations due to physical or mental health (Relative Risk (RR) = 0.99 per day; 95% Confidence Interval (CI) = 0.98, 0.99; p = .01), others doing physical activity with the Veteran (RR = 1.18; 95% Cl = 1.04, 133; p = .01), receiving ideas from others regarding physical activity (RR = 1.14; 95% Cl = 1.01, 1.29; p = .03) and better perceived neighborhood aesthetics (RR = 1.14; 95% Cl = 1.06, 1.24; p = .001) were associated with meeting physical activity recommendations. Findings were comparable for total weekly physical activity, but lower depression symptom severity was also associated with increased physical activity. Conclusion: This study identified individual and contextual correlates of physical activity among VA-using Veterans. Targeting these factors will be important in promoting physical activity in order to address the disproportionate disease burden facing U.S. Veterans. Existing VA interventions targeting physical activity may need to be adapted to account for the influence of contextual factors. Published by Elsevier Ltd. C1 [Hoerster, Katherine D.; Millstein, Rachel A.] VA Puget Sound Healthcare Syst, Seattle Div, Mental Hlth Serv, Seattle, WA 98108 USA. [Hoerster, Katherine D.; Saelens, Brian E.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Millstein, Rachel A.] San Diego State Univ, Univ Calif San Diego, Joint Doctoral Program Clin Psychol, San Diego, CA 92182 USA. [Hall, Katherine S.] Durham Vet Affairs Med Ctr, Geriatr Res Educ & Clin Ctr, Durham, NC USA. [Hall, Katherine S.] Duke Univ, Dept Med, Durham, NC 27706 USA. [Gray, Kristen E.; Reiber, Gayle E.; Nelson, Karin M.] VA Puget Sound Healthcare Syst, Seattle Div, Hlth Serv Res & Dev, Seattle, WA 98108 USA. [Gray, Kristen E.; Reiber, Gayle E.] Univ Washington, Sch Publ Hlth, Dept Hlth Serv, Seattle, WA 98195 USA. [Reiber, Gayle E.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Nelson, Karin M.] VA Puget Sound Healthcare Syst, Gen Internal Med Serv, Seattle, WA 98108 USA. [Nelson, Karin M.] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Saelens, Brian E.] Seattle Childrens Res Inst, Seattle, WA USA. RP Hoerster, KD (reprint author), VA Puget Sound Healthcare Syst, Seattle Div, Mental Hlth Serv, 1660 S Columbian Way S-116, Seattle, WA 98108 USA. EM Katherine.Hoerster@va.gov FU VA Puget Sound, Seattle Division Mental Illness Research Education and Clinical Center; VA Puget Sound, Seattle Division Health Services Research and Development Center of Excellence; VA Career Development Awards [RRD 1IK2RX001316, HSRD CDA 12-263]; VA HSR&D Senior Research Career Scientist Award [RCS 98-353] FX We would like to thank Linda Guerrero, David Tice, and Marie Lutton for their work on managing the survey mailing, Carol Malte for extracting VA administrative data, and Jeff Rodenbaugh for his assistance with running analyses. This material is the result of work supported by resources from VA Puget Sound Healthcare System. Funding for the study was provided by the VA Puget Sound, Seattle Division Mental Illness Research Education and Clinical Center and the VA Puget Sound, Seattle Division Health Services Research and Development Center of Excellence. Drs. Hall and Hoerster are supported by VA Career Development Awards (RRD 1IK2RX001316 and HSR&D CDA 12-263, respectively). Dr. Reiber is funded through a VA HSR&D Senior Research Career Scientist Award (RCS 98-353). The funding sources had no involvement in study design; in the collection, analysis and interpretation of data; in the writing of the article; and in the decision to submit it for publication. The abstract for this paper was presented at the 2015 Society of Behavioral Medicine Annual Meeting. 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 66 TC 3 Z9 3 U1 3 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0277-9536 J9 SOC SCI MED JI Soc. Sci. Med. PD OCT PY 2015 VL 142 BP 100 EP 108 DI 10.1016/j.socscimed.2015.07.034 PG 9 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA CS4QL UT WOS:000362060900011 PM 26298646 ER PT J AU Gupta, MK Teo, AKK Rao, TN Bhatt, S Kleinridders, A Shirakawa, J Takatani, T Hu, J De Jesus, DF Windmueller, R Wagers, AJ Kulkarni, RN AF Gupta, Manoj K. Teo, Adrian Kee Keong Rao, Tata Nageswara Bhatt, Shweta Kleinridders, Andre Shirakawa, Jun Takatani, Tomozumi Hu, Jiang De Jesus, Dario F. Windmueller, Rebecca Wagers, Amy J. Kulkarni, Rohit N. TI Excessive Cellular Proliferation Negatively Impacts Reprogramming Efficiency of Human Fibroblasts SO STEM CELLS TRANSLATIONAL MEDICINE LA English DT Article DE Reprogramming; Insulin signaling; Cell proliferation; Human pluripotency ID PLURIPOTENT STEM-CELLS; SMALL-MOLECULE COMPOUNDS; SOMATIC-CELLS; DEFINED FACTORS; INDUCTION; INHIBITORS; OCT4; PKM2 AB The impact of somatic cell proliferation rate on induction of pluripotent stem cells remains controversial. Herein, we report that rapid proliferation of human somatic fibroblasts is detrimental to reprogramming efficiency when reprogrammed using a lentiviral vector expressing OCT4, SOX2, KLF4, and cMYC in insulin-rich defined medium. Human fibroblasts grown in this medium showed higher proliferation, enhanced expression of insulin signaling and cell cycle genes, and a switch from glycolytic to oxidative phosphorylation metabolism, but they displayed poor reprogramming efficiency compared with cells grown in normal medium. Thus, in contrast to previous studies, our work reveals an inverse correlation between the proliferation rate of somatic cells and reprogramming efficiency, and also suggests that upregulation of proteins in the growth factor signaling pathway limits the ability to induce pluripotency in human somatic fibroblasts. STEM CELLS TRANSLATIONAL MEDICINE 2015;4:1101-1108 C1 [Gupta, Manoj K.; Teo, Adrian Kee Keong; Rao, Tata Nageswara; Bhatt, Shweta; Shirakawa, Jun; Takatani, Tomozumi; Hu, Jiang; De Jesus, Dario F.; Windmueller, Rebecca; Wagers, Amy J.; Kulkarni, Rohit N.] Harvard Univ, Sch Med, Sect Islet Cell & Regenerat Biol, Boston, MA 02215 USA. [Kleinridders, Andre] Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Integrat Physiol & Metab, Boston, MA 02215 USA. [Gupta, Manoj K.; Teo, Adrian Kee Keong; Bhatt, Shweta; Kleinridders, Andre; Shirakawa, Jun; Takatani, Tomozumi; Hu, Jiang; De Jesus, Dario F.; Windmueller, Rebecca; Kulkarni, Rohit N.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02215 USA. [Rao, Tata Nageswara; Wagers, Amy J.] Harvard Univ, Howard Hughes Med Inst, Harvard Stem Cell Inst, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. RP Kulkarni, RN (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Islet Cell & Regenerat Biol, Boston, MA 02215 USA. EM rohit.kulkarni@joslin.harvard.edu RI Teo, Adrian/A-4009-2013; OI Teo, Adrian/0000-0001-5901-7075; Shirakawa, Jun/0000-0002-0822-8750 FU NIH [5 P30 DK036836-27, R01 DK67536]; Juvenile Diabetes Research Foundation Postdoctoral Fellowship; Deutsche Forschungsgemeinschaft [KL2399/1-1, KL2399/3-1]; AstraZeneca FX We thank Dr. G. Mostoslavsky (Boston University) for the kind gift of lentiviral plasmids and R. Martinez for technical assistance. We thank Dr. C.R. Kahn (Joslin Diabetes Center) for allowing access to the Seahorse instrument. The Joslin DRC iPS Core is supported by NIH Grant 5 P30 DK036836-27. A.K.K.T. is supported by a Juvenile Diabetes Research Foundation Postdoctoral Fellowship. A.K. was supported by Deutsche Forschungsgemeinschaft projects KL2399/1-1 and KL2399/3-1. R.N.K. is supported by NIH Grant R01 DK67536 and a grant from AstraZeneca. NR 31 TC 2 Z9 2 U1 1 U2 4 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 2157-6564 EI 2157-6580 J9 STEM CELL TRANSL MED JI Stem Cells Transl. Med. PD OCT PY 2015 VL 4 IS 10 BP 1101 EP 1108 DI 10.5966/sctm.2014-0217 PG 8 WC Cell & Tissue Engineering SC Cell Biology GA CS5XO UT WOS:000362151800005 PM 26253715 ER PT J AU Zhang, WT Liu, J Hu, XM Li, PY Leak, RK Gao, YQ Chen, J AF Zhang, Wenting Liu, Jia Hu, Xiaoming Li, Peiying Leak, Rehana K. Gao, Yanqin Chen, Jun TI n-3 Polyunsaturated Fatty Acids Reduce Neonatal Hypoxic/Ischemic Brain Injury by Promoting Phosphatidylserine Formation and Akt Signaling SO STROKE LA English DT Article DE docosahexaenoic acids; eicosapentaenoic acid; neurons; omega-3 fatty acids; phosphatidylserine synthase ID FOCAL CEREBRAL-ISCHEMIA; DOCOSAHEXAENOIC ACID; NEURONAL APOPTOSIS; CELL-SURVIVAL; ACTIVATION; OMEGA-3-FATTY-ACIDS; NEUROPROTECTION; STROKE; DEATH; PHOSPHORYLATION AB Background and Purpose Omega-3 polyunsaturated fatty acids (n-3 PUFAs) attenuate neonatal hypoxic/ischemic (H/I) brain damage, but the underlying mechanisms are not fully understood. This study tested the hypothesis that n-3 PUFAs enhance Akt-dependent prosurvival signaling by promoting the biosynthesis of phosphatidylserine in neuronal cell membranes. Methods Dietary n-3 PUFA supplementation was initiated on the second day of pregnancy in dams. H/I was induced in 7-day-old rat pups by ipsilateral common carotid artery occlusion followed by hypoxia (8% oxygen for 2.5 hours). Neurological outcomes, brain tissue loss, cell death, and the activation of signaling events were assessed after H/I. The effects of n-3 PUFAs (docosahexaenoic acid and eicosapentaenoic acid) on oxygen-glucose deprivation-induced cell death and the underlying mechanism of protection were also examined in primary cortical neuron cultures. Resultsn-3 PUFAs reduced brain tissue loss at 7 days after H/I and improved neurological outcomes, whereas inhibition of PI3K/Akt signaling by LY294002 partially abrogated this neuroprotective effect. Docosahexaenoic acid/eicosapentaenoic acid also prevented ischemic neuronal death through the Akt prosurvival pathway in vitro. Furthermore, docosahexaenoic acid/eicosapentaenoic acid increased the production of phosphatidylserine, the major membrane-bound phospholipids, after ischemia both in vitro and in vivo. A reduction in membrane phosphatidylserine by shRNA-mediated knockdown of phosphatidylserine synthetase-1 attenuated Akt activation and neuronal survival after docosahexaenoic acid/eicosapentaenoic acid treatment in the oxygen-glucose deprivation model. Conclusionsn-3 PUFAs robustly protect against H/I-induced brain damage in neonates by activating Akt prosurvival pathway in compromised neurons. In addition, n-3 PUFAs promote the formation of membrane phosphatidylserine, thereby promoting Akt activity and improving cellular survival. C1 [Zhang, Wenting; Liu, Jia; Hu, Xiaoming; Li, Peiying; Gao, Yanqin; Chen, Jun] Fudan Univ, Inst Brain Sci, State Key Lab Med Neurobiol, Shanghai 200433, Peoples R China. [Zhang, Wenting; Liu, Jia; Hu, Xiaoming; Li, Peiying; Gao, Yanqin; Chen, Jun] Fudan Univ, Collaborat Innovat Ctr Brain Sci, Shanghai 200433, Peoples R China. [Hu, Xiaoming; Chen, Jun] Univ Pittsburgh, Sch Med, Dept Neurol, Ctr Cerebrovasc Dis Res, Pittsburgh, PA 15213 USA. [Leak, Rehana K.] Duquesne Univ, Div Pharmaceut Sci, Pittsburgh, PA 15219 USA. [Hu, Xiaoming; Chen, Jun] Vet Affairs Pittsburgh Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA USA. RP Chen, J (reprint author), Univ Pittsburgh, Sch Med, Dept Neurol, S-507,Biomed Sci Tower, Pittsburgh, PA 15213 USA. EM wtzhang@fudan.edu.cn; chenj2@upmc.edu RI Gao, Yanqin/I-6790-2016 OI Gao, Yanqin/0000-0002-4915-9819 FU US National Institutes of Health [NS095671, NS36736, NS089534, NS45048, NS092618]; US Department of Veterans Affairs [I01RX000420]; Chinese Natural Science Foundation [81020108021, 81171149, 81371306, 81571285, 81228008, 81529002]; Shanghai Committee of Science and Technology Support Program [14431907002]; American Heart Association [13SDG14570025]; China Postdoctoral Science Foundation [20110490665]; Shanghai Postdoctoral Sustentation Fund [11R21410500]; Fudan University [20520131150]; National Natural Science Foundation [81100978, 81471332, 81400956]; Science and Technology Commission of Shanghai Municipality [13ZR1452200] FX This project was supported by the US National Institutes of Health grants NS095671, NS36736, NS089534, and NS45048 (to Dr Chen) and NS092618 (to Dr Hu); the US Department of Veterans Affairs Research Career Scientist Award and RR & D Merit Review I01RX000420 (to Dr Chen); the Chinese Natural Science Foundation grants 81020108021, 81171149, 81371306, 81571285 (to Dr Gao), and 81228008, 81529002 (to Dr Chen); the Shanghai Committee of Science and Technology Support Program 14431907002 (to Dr Gao); and the American Heart Association Scientist Development grant 13SDG14570025 (to Dr Hu). Dr Zhang was supported by the China Postdoctoral Science Foundation grants (No. 20110490665), the Shanghai Postdoctoral Sustentation Fund (No. 11R21410500), the Young Teacher Program of Fudan University (No. 20520131150), and National Natural Science Foundation grants (No. 81100978 and No. 81471332). Dr Li is supported by the Science and Technology Commission of Shanghai Municipality (13ZR1452200) and National Natural Science Foundation grant (No. 81400956). NR 42 TC 3 Z9 4 U1 1 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 OCT PY 2015 VL 46 IS 10 BP 2943 EP 2950 DI 10.1161/STROKEAHA.115.010815 PG 8 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA CS3TT UT WOS:000361998600034 PM 26374481 ER PT J AU Fagenholz, PJ Fuentes, E Kaafarani, H Cropano, C King, D de Moya, M Butler, K Velmahos, G Chang, YC Yeh, DD AF Fagenholz, Peter J. Fuentes, Eva Kaafarani, Haytham Cropano, Catrina King, David de Moya, Marc Butler, Kathryn Velmahos, George Chang, Yuchiao Yeh, D. Dante TI Computed Tomography Is More Sensitive than Ultrasound for the Diagnosis of Acute Cholecystitis SO SURGICAL INFECTIONS LA English DT Article ID CT EVALUATION; ACCURACY; DISEASE; PAIN AB Background: Ultrasound (US) is the first-line diagnostic study for evaluating gallstone disease and is considered the test of choice for diagnosing acute cholecystitis (AC). However, computed tomography (CT) is used widely for the evaluation of abdominal pain and is often obtained as a first abdominal imaging test, particularly in cases in which typical clinical signs of AC are absent or other possible diagnoses are being considered. We hypothesized that CT is more sensitive than US for diagnosing AC. Methods: A prospective registry of all urgent cholecystectomies performed by our acute care surgery service between June 2008 and January 2014 was searched for cases of AC. The final diagnosis was based on operative findings and pathology. Patients were classified into two groups according to pre-operative radiographic work-up: US only or CT and US. The US group was compared with the CT and US group with respect to clinical and demographic characteristics. For patients undergoing both tests the sensitivity of the two tests was compared. Results: One hundred one patients with AC underwent both US and CT. Computed tomography was more sensitive than US for the diagnosis of AC (92% versus 79%, p=0.015). Ultrasound was more sensitive than CT for identification of cholelithiasis (87% versus 60%, p<0.01). Patients undergoing both tests prior to surgery were more likely to be older, male, have medical comorbidities, and lack typical clinical signs of AC. Conclusions: Computed tomography is more sensitive than US for the diagnosis of AC and is most often used in patients without typical clinical signs of AC. C1 [Fagenholz, Peter J.] Massachusetts Gen Hosp, Div Trauma Emergency Surg & Crit Care, Dept Surg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Fagenholz, PJ (reprint author), Massachusetts Gen Hosp, Div Trauma Emergency Surg & Crit Care, Dept Surg, 165 Cambridge St,St 810, Boston, MA 02114 USA. EM pfagenholz@mgh.harvard.edu OI King, David/0000-0003-1028-1478 NR 12 TC 2 Z9 2 U1 1 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1096-2964 EI 1557-8674 J9 SURG INFECT JI Surg. Infect. PD OCT 1 PY 2015 VL 16 IS 5 BP 509 EP 512 DI 10.1089/sur.2015.102 PG 4 WC Infectious Diseases; Surgery SC Infectious Diseases; Surgery GA CS6VT UT WOS:000362221800005 PM 26375322 ER PT J AU Landow, SM Oh, DH Weinstock, MA AF Landow, Shoshana M. Oh, Dennis H. Weinstock, Martin A. TI Teledermatology Within the Veterans Health Administration, 2002-2014 SO TELEMEDICINE AND E-HEALTH LA English DT Article DE telehealth; telemedicine; teledermatology; teleconsultation AB Background:In order to increase veterans' access to dermatologic care, the Veterans Health Administration (VHA) has developed one of the largest teledermatology programs in the United States. This article describes the recent expansion of the VHA's teledermatology program after local and national initiatives and resource allocation.Materials and Methods:This report describes routinely collected VHA data.Results:For the first half of fiscal year 2014, the VHA recorded 31,926 teledermatology encounters, which represents 14% of all recorded teledermatology visits. Although every region in the VHA used teledermatology in the past year, four regions created 51% of the encounters. The use of store-and-forward telehealth (SFT), in which physicians view patient images after the patients were photographed, is increasing, whereas live video use is decreasing. Starting in 2012, encounters for patients in urban areas exceeded those in rural areas. The majority of patients were male veterans 60-79 years of age. Seventy-one percent of SFT consultations for the first half of 2014 were completed within 1 week.Conclusions:Although errors in and the evolution of coding encounters may distort results, the data show rapid growth of a telemedicine system that increases access to dermatology services for veterans. Most likely this growth reflects institutional commitment to telehealth via policy and resources. C1 [Landow, Shoshana M.; Weinstock, Martin A.] Providence VA Med Ctr, Providence, RI 02908 USA. [Landow, Shoshana M.; Weinstock, Martin A.] Brown Univ, Providence, RI 02912 USA. [Oh, Dennis H.] San Francisco VA Med Ctr, San Francisco, CA USA. [Oh, Dennis H.] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Landow, SM (reprint author), Providence VA Med Ctr, 830 Chalkstone Ave, Providence, RI 02908 USA. EM Shoshana.Landow@va.gov NR 6 TC 6 Z9 6 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1530-5627 EI 1556-3669 J9 TELEMED E-HEALTH JI Telemed. e-Health PD OCT 1 PY 2015 VL 21 IS 10 BP 769 EP 773 DI 10.1089/tmj.2014.0225 PG 5 WC Health Care Sciences & Services SC Health Care Sciences & Services GA CS6LZ UT WOS:000362191800002 PM 26083585 ER PT J AU Pang, YG Tsigkou, O Spencer, JA Lin, CP Neville, C Grottkau, B AF Pang, Yonggang Tsigkou, Olga Spencer, Joel A. Lin, Charles P. Neville, Craig Grottkau, Brian TI Analyzing Structure and Function of Vascularization in Engineered Bone Tissue by Video-Rate Intravital Microscopy and 3D Image Processing SO TISSUE ENGINEERING PART C-METHODS LA English DT Article ID MESENCHYMAL STEM-CELLS; IN-VIVO; OPTICAL MICROSCOPY; ANGIOGENESIS; SCAFFOLDS; TRACKING; DELIVERY; MARROW AB Vascularization is a key challenge in tissue engineering. Three-dimensional structure and microcirculation are two fundamental parameters for evaluating vascularization. Microscopic techniques with cellular level resolution, fast continuous observation, and robust 3D postimage processing are essential for evaluation, but have not been applied previously because of technical difficulties. In this study, we report novel video-rate confocal microscopy and 3D postimage processing techniques to accomplish this goal. In an immune-deficient mouse model, vascularized bone tissue was successfully engineered using human bone marrow mesenchymal stem cells (hMSCs) and human umbilical vein endothelial cells (HUVECs) in a poly (d,l-lactide-co-glycolide) (PLGA) scaffold. Video-rate (30 FPS) intravital confocal microscopy was applied in vitro and in vivo to visualize the vascular structure in the engineered bone and the microcirculation of the blood cells. Postimage processing was applied to perform 3D image reconstruction, by analyzing microvascular networks and calculating blood cell viscosity. The 3D volume reconstructed images show that the hMSCs served as pericytes stabilizing the microvascular network formed by HUVECs. Using orthogonal imaging reconstruction and transparency adjustment, both the vessel structure and blood cells within the vessel lumen were visualized. Network length, network intersections, and intersection densities were successfully computed using our custom-developed software. Viscosity analysis of the blood cells provided functional evaluation of the microcirculation. These results show that by 8 weeks, the blood vessels in peripheral areas function quite similarly to the host vessels. However, the viscosity drops about fourfold where it is only 0.8mm away from the host. In summary, we developed novel techniques combining intravital microscopy and 3D image processing to analyze the vascularization in engineered bone. These techniques have broad applicability for evaluating vascularization in other engineered tissues as well. C1 [Pang, Yonggang; Neville, Craig; Grottkau, Brian] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. [Tsigkou, Olga] Univ Manchester, Sch Mat, Manchester, Lancs, England. [Spencer, Joel A.; Lin, Charles P.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. RP Grottkau, B (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Orthopaed Surg, 55 Fruit St, Boston, MA 02114 USA. EM bgrottkau@partners.org OI Tsigkou, Olga/0000-0002-5250-8610 NR 30 TC 1 Z9 1 U1 3 U2 10 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3384 EI 1937-3392 J9 TISSUE ENG PART C-ME JI Tissue Eng. Part C-Methods PD OCT 1 PY 2015 VL 21 IS 10 BP 1025 EP 1031 DI 10.1089/ten.tec.2015.0091 PG 7 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA CS5AI UT WOS:000362087300004 PM 25962617 ER PT J AU Desai, NR Sabatine, MS AF Desai, Nihar R. Sabatine, Marc S. TI PCSK9 inhibition in patients with hypercholesterolemia SO TRENDS IN CARDIOVASCULAR MEDICINE LA English DT Article ID SUBTILISIN/KEXIN TYPE 9; DENSITY-LIPOPROTEIN CHOLESTEROL; HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA; PLACEBO-CONTROLLED TRIAL; EVOLOCUMAB AMG 145; MONOCLONAL-ANTIBODY; LDL CHOLESTEROL; DOUBLE-BLIND; RANDOMIZED-TRIAL; HEALTHY-VOLUNTEERS AB Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that plays an important role in modulating low-density lipoprotein cholesterol (LDL-C) levels by targeting LDL-C receptors for lysosomal degradation. Genetic association studies have demonstrated that loss-of-function mutations in PCSK9 are associated with low plasma LDL-C levels and a reduction in the incidence of adverse cardiovascular events. Monoclonal antibodies directed against PCSK9 have been developed and have been shown in phase 1, 2, and 3 trials to dramatically reduce LDL-C regardless of background lipid-lowering therapy, including in clinically challenging populations such as patients intolerant to statin therapy and those with familial hypercholesterolemia. To date, the clinical trials have not raised any significant safety concerns, with no appreciable excess of myalgias, elevation in aminotransferases, or other adverse events. Large, cardiovascular outcomes trials are underway to assess definitively the efficacy and safety of 3 monoclonal antibodies (evolocumab, alirocumab, and bococizumab), while additional non-monoclonal antibody approaches to inhibit PCSK9 continue in the early-phase development. (C) 2015 Elsevier Inc. All rights reserved. C1 [Desai, Nihar R.] Yale Univ, Yale New Haven Hosp, Ctr Outcomes Res & Evaluat, Sect Cardiovasc Med,Sch Med, New Haven, CT USA. [Sabatine, Marc S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiovasc Med,TIMI Study Grp, Boston, MA 02115 USA. RP Sabatine, MS (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiovasc Med,TIMI Study Grp, Boston, MA 02115 USA. EM msabatine@partners.org NR 55 TC 12 Z9 12 U1 0 U2 14 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1050-1738 J9 TRENDS CARDIOVAS MED JI Trends Cardiovasc. Med. PD OCT PY 2015 VL 25 IS 7 BP 567 EP 574 DI 10.1016/j.tcm.2015.01.009 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CS4NY UT WOS:000362053700001 PM 25771732 ER PT J AU Huffman, JC Celano, CM AF Huffman, Jeff C. Celano, Christopher M. TI Depression in cardiovascular disease: From awareness to action SO TRENDS IN CARDIOVASCULAR MEDICINE LA English DT Editorial Material ID AMERICAN-HEART-ASSOCIATION; COLLABORATIVE CARE; TREATING DEPRESSION; CARDIOLOGY; RECOMMENDATIONS; OUTCOMES; TRIAL C1 [Huffman, Jeff C.; Celano, Christopher M.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Huffman, Jeff C.; Celano, Christopher M.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. RP Huffman, JC (reprint author), Massachusetts Gen Hosp, Dept Psychiat, 55 Fruit St Blake 11, Boston, MA 02114 USA. EM jhuffman@partners.org FU NHLBI NIH HHS [R01HL113272, R01 HL113272] NR 17 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1050-1738 J9 TRENDS CARDIOVAS MED JI Trends Cardiovasc. Med. PD OCT PY 2015 VL 25 IS 7 BP 623 EP 624 DI 10.1016/j.tcm.2015.02.007 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CS4NY UT WOS:000362053700010 PM 25910599 ER PT J AU Weinberg, I Gu, XK Giri, J Kim, SE Bacharach, MJ Gray, BH Katzen, BT Matsumoto, AH Chi, YW Rogers, KR Froehlich, J Olin, JW Gornik, HL Jaff, MR AF Weinberg, Ido Gu, Xiaokui Giri, Jay Kim, Soo E. Bacharach, Michael J. Gray, Bruce H. Katzen, Barry T. Matsumoto, Alan H. Chi, Yung-Wei Rogers, Kevin R. Froehlich, James Olin, Jeffrey W. Gornik, Heather L. Jaff, Michael R. TI Anti-platelet and anti-hypertension medication use in patients with fibromuscular dysplasia: Results from the United States Registry for Fibromuscular Dysplasia SO VASCULAR MEDICINE LA English DT Article DE anti-platelet; fibromuscular dysplasia; FMD; hypertension; medication ID CLINICAL-PRACTICE GUIDELINES; ED AMERICAN-COLLEGE; ANTITHROMBOTIC THERAPY; PREVENTION; THROMBOSIS AB Fibromuscular dysplasia (FMD), a non-inflammatory arterial disease, may lead to renovascular hypertension (HTN) and cerebrovascular disease. Little is known about medication use in FMD. Clinical features and medication use were reviewed in a national FMD registry (12 US sites). Medication usage was assessed in raw and adjusted analyses. Covariates included demographic characteristics, co-morbid conditions and vascular bed involvement. A total of 874 subjects (93.6% female) were included in the analysis. Mean age was 55.6 +/- 13.1 years, 74.5% had HTN, 25.4% had a history of transient ischemic attack or stroke, and 7.5% had a history of coronary artery disease (CAD). Renal and cerebrovascular arteries were affected in 70.4% and 74.7%, respectively. Anti-platelet agents were administered to 72.9% of patients. In multivariate analyses, factors associated with a greater likelihood of anti-platelet agent use were older age (OR=1.02 per year, p=0.005), CAD (OR=3.76, p=0.015), cerebrovascular artery FMD involvement in isolation (OR=2.31, p<0.0001) or a history of previous intervention for FMD (OR=1.52, p=0.036). A greater number of anti-HTN medications was evident in isolated renal versus isolated cerebrovascular FMD patients. Factors associated with a greater number of anti-HTN medications were older age (OR=1.03 per year, p<0.0001), history of HTN (OR=24.04, p<0.0001), history of CAD (OR=2.71, p=0.0008) and a history of a previous therapeutic procedure (OR=1.72, p=0.001). In conclusion, in FMD, medication use varies based on vascular bed involvement. Isolated renal FMD patients receive more anti-HTN agents and there is greater anti-platelet agent use among patients with cerebrovascular FMD. Further studies correlating medication use in FMD with clinically meaningful patient outcomes are necessary. C1 [Weinberg, Ido; Jaff, Michael R.] Massachusetts Gen Hosp, Fireman Vasc Ctr, Boston, MA 02114 USA. [Gu, Xiaokui] Univ Michigan, Ctr Cardiovasc, Ann Arbor, MI 48109 USA. [Giri, Jay] Univ Penn, Div Cardiovasc Med, Philadelphia, PA 19104 USA. [Kim, Soo E.; Gornik, Heather L.] Case Western Reserve Univ, Cleveland Clin, Inst Heart & Vasc, Cleveland, OH 44106 USA. [Kim, Soo E.; Gornik, Heather L.] Case Western Reserve Univ, Cleveland Clin, Lerner Coll Med, Cleveland, OH 44106 USA. [Bacharach, Michael J.] North Cent Heart Inst, Soux Falls, SD USA. [Gray, Bruce H.] Sch Med, Sch Medicine, Greenville, SC USA. [Katzen, Barry T.] Baptist Cardiac & Vasc Inst, Miami, FL USA. [Matsumoto, Alan H.] Univ Virginia Hlth Syst, Div Vasc Intervent Radiol, Dept Radiol, Charlottesville, VA USA. [Chi, Yung-Wei] Univ Calif Davis, Davis Med Ctr, Div Cardiovasc Med, Sacramento, CA 95817 USA. [Rogers, Kevin R.] Univ Colorado, Div Cardiol, Denver, CO 80202 USA. [Froehlich, James] Univ Michigan, Ctr Cardiovasc, Ann Arbor, MI 48109 USA. [Olin, Jeffrey W.] Mt Sinai Sch Med, Zena & Michael Wiener Cardiovasc Inst, New York, NY USA. [Olin, Jeffrey W.] Mt Sinai Sch Med, Marie Jose & Henry R Kravis Ctr Cardiovasc Hlth, New York, NY USA. RP Weinberg, I (reprint author), Massachusetts Gen Hosp, Fireman Vasc Ctr, 55 Fruit St,GB 800, Boston, MA 02114 USA. EM iweinberg@partners.org FU FMD Society of America FX The United States Registry for FMD is funded by the FMD Society of America. NR 16 TC 2 Z9 2 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1358-863X EI 1477-0377 J9 VASC MED JI Vasc. Med. PD OCT PY 2015 VL 20 IS 5 BP 447 EP 453 DI 10.1177/1358863X15584982 PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA CS8PT UT WOS:000362351000007 PM 25964292 ER PT J AU Jaff, MR White, CJ Hiatt, WR Fowkes, GR Dormandy, J Razavi, M Reekers, J Norgren, L AF Jaff, Michael R. White, Christopher J. Hiatt, William R. Fowkes, Gerry R. Dormandy, John Razavi, Mahmood Reekers, Jim Norgren, Lars CA TASC Steering Comm TI An Update on Methods for Revascularization and Expansion of the TASC Lesion Classification to Include Below-the-Knee Arteries: A Supplement to the Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II) SO VASCULAR MEDICINE LA English DT Article DE angioplasty; arteries; claudication; critical limb ischemia; occlusion; peripheral artery disease; revascularization; stenosis; stents; surgery ID CRITICAL LIMB ISCHEMIA; AORTOILIAC OCCLUSIVE DISEASE; SUPERFICIAL FEMORAL-ARTERY; PERCUTANEOUS TRANSLUMINAL ANGIOPLASTY; RANDOMIZED CONTROLLED-TRIAL; NITINOL STENT IMPLANTATION; DRUG-ELUTING STENTS; BARE-METAL STENTS; EXTREMITY BYPASS-SURGERY; VEIN GRAFT FAILURE AB The Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC) guidelines were last updated in 2007 (TASC II) and represented the collaboration of international vascular specialties involved in the management of patients with peripheral arterial disease (PAD). Since the publication of TASC II, there have been innovations in endovascular revascularization strategies for patients with PAD. The intent of this publication is to provide a complete anatomic lower limb TASC lesion classification, including the infrapopliteal segment, and an updated literature review of new endovascular techniques and practice patterns employed by vascular specialists today. C1 [Jaff, Michael R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [White, Christopher J.] Univ Queensland, Ochsner Clin Sch, Ochsner Clin Fdn, New Orleans, LA USA. [Hiatt, William R.] Univ Colorado, Sch Med, Div Cardiol, Aurora, CO USA. [Hiatt, William R.] CPC Clin Res, Aurora, CO USA. [Fowkes, Gerry R.] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh EH8 9YL, Midlothian, Scotland. [Dormandy, John] St George Hosp, London, England. [Razavi, Mahmood] St Joseph Hosp, Orange, CA USA. [Reekers, Jim] Univ Hosp Amsterdam, Acad Med Ctr, Amsterdam, Netherlands. [Norgren, Lars] Orebro Univ, Fac Med & Hlth, Dept Surg, Orebro, Sweden. RP Norgren, L (reprint author), Orebro Univ Hosp, Dept Surg, Surg, SE-70185 Orebro, Sweden. EM lars.norgren@regionorebrolan.se FU VIVA Physicians; Aastrom Biosciences; Abbott Vascular; AnGes MG Inc; Bayer Schering Pharma; Biomedix; Cook; ev3; Medtronic; Mitsubishi Tanabe; Otsuka Pharmaceutical Co; Sanofi-Aventis; Toray Industries FX The author(s) report receiving the following financial support for the research, authorship, and/or publication of this article: VIVA Physicians [a 501(c)(3) education and research multispecialty organization] provided an unrestricted grant to the TASC organization. The development of this TASC II Supplement was supported by unrestricted educational grants awarded to Discovery London from (in alphabetical order): Aastrom Biosciences, Abbott Vascular, AnGes MG Inc, Bayer Schering Pharma, Biomedix, Cook, ev3, Medtronic, Mitsubishi Tanabe, Otsuka Pharmaceutical Co, Sanofi-Aventis, and Toray Industries. The companies did not participate in the discussions or in the preparation, review, or approval of the document. NR 91 TC 2 Z9 2 U1 3 U2 6 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1358-863X EI 1477-0377 J9 VASC MED JI Vasc. Med. PD OCT PY 2015 VL 20 IS 5 BP 465 EP 478 DI 10.1177/1358863X15597877 PG 14 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA CS8PT UT WOS:000362351000010 ER PT J AU Prabhakar, HB Kraeft, JJ Schorge, JO Scott, JA Lee, SI AF Prabhakar, Hima B. Kraeft, Jessica J. Schorge, John O. Scott, James A. Lee, Susanna I. TI FDG PET-CT of gynecologic cancers: pearls and pitfalls SO ABDOMINAL IMAGING LA English DT Article DE PET-CT; PET image quality; Gynecologic cancer; Female pelvic imaging ID POSITRON-EMISSION-TOMOGRAPHY; STAGE CERVICAL-CANCER; CORPUS LUTEAL CYST; ENDOMETRIAL CANCER; F-18-FDG PET/CT; OVARIAN-CANCER; RADICAL HYSTERECTOMY; RADIATION-THERAPY; NODE METASTASES; CONTRAST AGENTS AB FDG PET-CT plays an important role in treatment planning and in prognosis assessment of gynecologic cancer patients. Detection of hypermetabolic tissue with FDG PET, when combined with the high spatial resolution of CT, results in improved cancer detection and localization not afforded by either modality independently. This article is a primer for a radiologist performing PET-CT on gynecologic cancer patients and includes the imaging protocol, normal pattern of FDG distribution in the female pelvis and the lymph node drainage pathways from the gynecologic organs. Clinically relevant imaging findings that should be included in the report are discussed. Case examples illustrate how potential errors in exam interpretation can be avoided by concurrently performing a high-quality diagnostic CT with the FDG PET scan and by analyzing both the stand-alone and the fusion images. C1 [Prabhakar, Hima B.] Univ Penn, Univ Penn Hlth Syst, Penn Hosp, Dept Radiol, Philadelphia, PA 19104 USA. [Kraeft, Jessica J.; Scott, James A.; Lee, Susanna I.] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Scott, James A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gillette Ctr Gynecol Oncol, Boston, MA USA. [Kraeft, Jessica J.] Tufts Univ, Sch Med, Tufts Med Ctr, Dept Radiol, Boston, MA 02111 USA. RP Prabhakar, HB (reprint author), Univ Penn, Univ Penn Hlth Syst, Penn Hosp, Dept Radiol, 800 Spruce St, Philadelphia, PA 19104 USA. EM himaprab@gmail.com NR 50 TC 2 Z9 2 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0942-8925 EI 1432-0509 J9 ABDOM IMAGING JI Abdom. Imaging PD OCT PY 2015 VL 40 IS 7 BP 2472 EP 2485 DI 10.1007/s00261-015-0362-7 PG 14 WC Gastroenterology & Hepatology; Radiology, Nuclear Medicine & Medical Imaging SC Gastroenterology & Hepatology; Radiology, Nuclear Medicine & Medical Imaging GA CS1OJ UT WOS:000361835700042 PM 25680500 ER PT J AU Pedrelli, P Nyer, M Yeung, A Zulauf, C Wilens, T AF Pedrelli, Paola Nyer, Maren Yeung, Albert Zulauf, Courtney Wilens, Timothy TI College Students: Mental Health Problems and Treatment Considerations SO ACADEMIC PSYCHIATRY LA English DT Article DE College; Mental health; Treatment considerations ID AGE-OF-ONSET; COMORBIDITY SURVEY REPLICATION; OBSESSIVE-COMPULSIVE DISORDER; MAJOR DEPRESSIVE DISORDER; ADOLESCENT MARIJUANA USE; SUBSTANCE USE DISORDERS; BIPOLAR-I DISORDER; BINGE-DRINKING; PSYCHIATRIC-DISORDERS; SUICIDAL-BEHAVIOR AB Attending college can be a stressful time for many students. In addition to coping with academic pressure, some students have to deal with the stressful tasks of separation and individuation from their family of origin while some may have to attend to numerous work and family responsibilities. In this context, many college students experience the first onset of mental health and substance use problems or an exacerbation of their symptoms. Given the uniqueness of college students, there is a need to outline critical issues to consider when working with this population. In this commentary, first, the prevalence of psychiatric and substance use problems in college students and the significance of assessing age of onset of current psychopathology are described. Then, the concerning persistent nature of mental health problems among college students and its implications are summarized. Finally, important aspects of treatment to consider when treating college students with mental health problems are outlined, such as the importance of including parents in the treatment, communicating with other providers, and employing of technology to increase adherence. It is concluded that, by becoming familiar with the unique problems characteristic of the developmental stage and environment college students are in, practitioners will be able to better serve them. C1 [Pedrelli, Paola; Nyer, Maren; Yeung, Albert; Zulauf, Courtney; Wilens, Timothy] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Pedrelli, P (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM ppedrelli@partners.org FU NIH [K24 DA016264]; NIAAA [K23AA020064-012]; National Institute on Drug Abuse (NIDA); Euthymics; Shire; Theravance; TRIS FX This research was supported by NIH K24 DA016264 to Timothy Wilens and in part by NIAAA K23AA020064-012 to Paola Pedrelli. Timothy Wilens receives/d research support from or is/has been on the advisory board for the following Pharmaceutical Companies: National Institute on Drug Abuse (NIDA), Euthymics, Shire, Theravance, and TRIS. Dr. Timothy Wilens is or has been a consultant for Euthymics, Major League Baseball, Minor League Baseball, the National Football League, and Shire. Dr. Timothy Wilens has a published book with Guilford Press: Straight Talk About Psychiatric Medications for Kids. Drs. Pedrelli, Nyer, and Yeung as well as Ms. Zulauf have no conflicts of interest to report. NR 114 TC 3 Z9 3 U1 7 U2 29 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 OCT PY 2015 VL 39 IS 5 BP 503 EP 511 DI 10.1007/s40596-014-0205-9 PG 9 WC Education & Educational Research; Psychiatry SC Education & Educational Research; Psychiatry GA CR8JA UT WOS:000361596100003 PM 25142250 ER PT J AU Geller, BJ Giugliano, RP Braunwald, E Murphy, SA Hanyok, JJ Jin, JQ Mercuri, M Antman, EM Ruff, CT AF Geller, Bram J. Giugliano, Robert P. Braunwald, Eugene Murphy, Sabina A. Hanyok, James J. Jin, Jianqing Mercuri, Michele Antman, Elliott M. Ruff, Christian T. TI Systemic, noncerebral, arterial embolism in 21,105 patients with atrial fibrillation randomized to edoxaban or warfarin: Results from the Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction Study 48 trial SO AMERICAN HEART JOURNAL LA English DT Article ID STROKE PREVENTION; RISK-FACTORS; METAANALYSIS; THROMBOEMBOLISM; XIMELAGATRAN; PREVALENCE; MANAGEMENT; EVENTS AB Background Atrial fibrillation (AF) is a major risk factor for stroke and systemic embolism. Trials comparing warfarin with non-vitamin K oral anticoagulants (NOACs) have demonstrated that, when compared with warfarin, the NOACs are at least as effective in preventing stroke, although detailed analyses characterizing systemic embolic events (SEEs) are lacking. Methods and results We performed a prespecified analysis in 21,105 patients with AF enrolled in the ENGAGE AF-TIMI 48 trial, which compared 2 once-daily regimens of edoxaban with warfarin for the prevention of stroke and SEE. Of 1,016 patients who met the primary end point, 67 (6.6%) experienced an SEE of which 13% were fatal. Of 73 total SEEs (including recurrent events), 85% involved the extremities, and 41% required a surgical or percutaneous intervention. There were 23 (0.12%/year) SEEs with warfarin versus 15 with higher dose edoxaban (0.08%/year; hazard ratio vs warfarin 0.65; 95% CI 0.34-1.24; P = .19) and 29 with lower dose edoxaban (0.15%/year; hazard ratio vs warfarin 1.24; 95% CI 0.72-2.15; P = .43). In a meta-analysis of 4 warfarin-controlled phase 3 AF trials, NOACs significantly reduced the risk of SEE by 37% (relative risk 0.63; 95% CI 0.43-0.91; P = .01). Conclusion Although considerably less frequent than stroke, systemic embolism is associated with significant morbidity and mortality in patients with AF. Although the overall number of events was too small to show a significant difference in the risk of SEE between edoxaban and warfarin, a meta-analysis of all the NOAC trials demonstrates that NOACs significantly reduce the risk of SEE compared with warfarin. C1 [Geller, Bram J.] Univ Penn Hlth Syst, Philadelphia, PA USA. [Giugliano, Robert P.; Braunwald, Eugene; Murphy, Sabina A.; Antman, Elliott M.; Ruff, Christian T.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Giugliano, Robert P.; Braunwald, Eugene; Murphy, Sabina A.; Antman, Elliott M.; Ruff, Christian T.] Harvard Univ, Sch Med, Boston, MA USA. [Hanyok, James J.; Jin, Jianqing; Mercuri, Michele] Daiichi Sankyo Pharma Dev, Edison, NJ USA. RP Ruff, CT (reprint author), Brigham & Womens Hosp, TIMI Study Grp, 350 Longwood Ave,First Floor, Boston, MA 02115 USA. EM cruff@partners.org FU Abbott; Amgen; AstraZeneca; Bayer Healthcare; Beckman Coulter; BG Medicine; BRAHMS; Bristol-Myers Squibb; Buhlmann; Critical Diagnostics; CV Therapeutics; Eli Lilly and Co; GlaxoSmithKline; Johnson Johnson; Merck and Co; Nanosphere; Novartis Pharmaceuticals; Ortho-Clinical Diagnostics; Pfizer; Randox; Roche Diagnostics; Sanofi-Aventis; Siemens; Singulex; Janssen; Daiichi Sankyo; Merck; Portola; Sanofi; Medicines Company; Menarini; Medscape; Bayer; Boehringer Ingelheim; Eisai; Intarcia FX In addition to study support provided by Daiichi Sankyo Pharma Division for conducting the ENGAGE AF-TIMI 48 trial, the TIMI Study Group has received research grant support from Abbott, Amgen, AstraZeneca, Bayer Healthcare, Beckman Coulter, BG Medicine, BRAHMS, Bristol-Myers Squibb, Buhlmann, Critical Diagnostics, CV Therapeutics, Eli Lilly and Co, GlaxoSmithKline, Johnson & Johnson, Merck and Co, Nanosphere, Novartis Pharmaceuticals, Ortho-Clinical Diagnostics, Pfizer, Randox, Roche Diagnostics, Sanofi-Aventis, Siemens, and Singulex. Dr Geller, none to report. Dr Giugliano, reports receiving consulting fees from Bristol-Myers Squibb, Janssen, Daiichi Sankyo, Merck, Pfizer, Portola, and Sanofi; and grant support to his institution from Daiichi Sankyo, Merck, Johnson & Johnson, Sanofi, and AstraZeneca. Dr Braunwald, reports receiving consulting fees from The Medicines Company; lecture fees from Menarini and Medscape; and grant support through his institution from Daiichi Sankyo, AstraZeneca, Merck & Co, and GlaxoSmithKline. He also reports serving as an unpaid consultant for Merck and Novartis and providing uncompensated lectures for Merck & Co. Ms Murphy, reports receiving grant support through her institution from Daiichi Sankyo. Dr Hanyok, employed at Daiichi Sankyo. Dr Jin, employed at Daiichi Sankyo. Dr Mercuri, employed at Daiichi Sankyo. Dr Antman, reports receiving grant support through his institution from Daiichi Sankyo. Dr Ruff, reports receiving consulting fees from Bayer, Daiichi Sankyo, Portola, and Boehringer Ingelheim and grant support through his institution from Daiichi Sankyo, Astra Zeneca, Eisai, and Intarcia. Submitted April 3, 2015; accepted June 21, 2015. NR 25 TC 5 Z9 5 U1 1 U2 6 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 OCT PY 2015 VL 170 IS 4 BP 669 EP 674 DI 10.1016/j.ahj.2015.06.020 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CR8BD UT WOS:000361575200008 PM 26386790 ER PT J AU Bansilal, S Bloomgarden, Z Halperin, JL Hellkamp, AS Lokhnygina, Y Patel, MR Becker, RC Breithardt, G Hacke, W Hankey, GJ Nessel, CC Singer, DE Berkowitz, SD Piccini, JP Mahaffey, KW Fox, KAA AF Bansilal, Sameer Bloomgarden, Zachary Halperin, Jonathan L. Hellkamp, Anne S. Lokhnygina, Yuliya Patel, Manesh R. Becker, Richard C. Breithardt, Guenter Hacke, Werner Hankey, Graeme J. Nessel, Christopher C. Singer, Daniel E. Berkowitz, Scott D. Piccini, Jonathan P. Mahaffey, Kenneth W. Fox, Keith A. A. CA ROCKET AF Steering Committee TI Efficacy and safety of rivaroxaban in patients with diabetes and nonvalvular atrial fibrillation: The Rivaroxaban Once-daily, Oral, Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF Trial) SO AMERICAN HEART JOURNAL LA English DT Article ID RISK-FACTORS; MELLITUS; THERAPY; PREDICTORS; WARFARIN AB Background The prevalence of both atrial fibrillation (AF) and diabetes mellitus (DM) are rising, and these conditions often occur together. Also, DM is an independent risk factor for stroke in patients with AF. We aimed to examine the safety and efficacy of rivaroxaban vs warfarin in patients with nonvalvular AF and DM in a prespecified secondary analysis of the ROCKET AF trial. Methods We stratified the ROCKET AF population by DM status, assessed associations with risk of outcomes by DM status and randomized treatment using Cox proportional hazards models, and tested for interactions between randomized treatments. For efficacy, primary outcomes were stroke (ischemic or hemorrhagic) or non-central nervous system embolism. For safety, the primary outcome was major or nonmajor clinically relevant bleeding. Results The 5,695 patients with DM (40%) in ROCKET AF were younger, were more obese, and had more persistent AF, but fewer had previous stroke (the CHADS(2) score includes DM and stroke). The relative efficacy of rivaroxaban and warfarin for prevention of stroke and systemic embolism was similar in patients with (1.74 vs 2.14/100 patient-years, hazard ratio [HR] 0.82) and without (2.12 vs 2.32/100 patient-years, HR 0.92) DM (interaction P = .53). The safety of rivaroxaban vs warfarin regarding major bleeding (HRs 1.00 and 1.12 for patients with and without DM, respectively; interaction P = .43), major or nonmajor clinically relevant bleeding (HRs 0.98 and 1.09; interaction P = .17), and intracerebral hemorrhage (HRs 0.62 and 0.72; interaction P = .67) was independent of DM status. Adjusted exploratory analyses suggested 1.3-, 1.5-, and 1.9-fold higher 2-year rates of stroke, vascular mortality, and myocardial infarction in DM patients. Conclusions and Relevance The relative efficacy and safety of rivaroxaban vs warfarin was similar in patients with and without DM, supporting use of rivaroxaban as an alternative to warfarin in diabetic patients with AF. C1 [Bansilal, Sameer; Bloomgarden, Zachary; Halperin, Jonathan L.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Hellkamp, Anne S.; Lokhnygina, Yuliya; Patel, Manesh R.; Piccini, Jonathan P.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. [Becker, Richard C.] Univ Cincinnati, Coll Med, Cincinnati, OH USA. [Breithardt, Guenter] Univ Hosp Munster, Div Electrophysiol, Dept Cardiovasc Med, Munster, Germany. [Hacke, Werner] Heidelberg Univ, Heidelberg, Germany. [Hankey, Graeme J.] Univ Western Australia, Sch Med & Pharmacol, Crawley, Australia. [Nessel, Christopher C.] Janssen Res & Dev, Raritan, NJ USA. [Singer, Daniel E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Singer, Daniel E.] Harvard Univ, Sch Med, Boston, MA USA. [Berkowitz, Scott D.] Bayer HealthCare Pharmaceut, Whippany, NJ USA. [Mahaffey, Kenneth W.] Stanford Univ, Dept Med, Stanford, CA 94305 USA. [Fox, Keith A. A.] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Fox, Keith A. A.] Royal Infirm Edinburgh NHS Trust, Edinburgh, Midlothian, Scotland. RP Halperin, JL (reprint author), Mt Sinai Med Ctr, Icahn Sch Med Mt Sinai, Cardiovasc Inst, Box 1030,Fifth Ave & 100th St, New York, NY 10029 USA. EM jonathan.halperin@mssm.edu RI Hankey, Graeme /H-4968-2014 OI Hankey, Graeme /0000-0002-6044-7328 FU AstraZeneca; Astra Zeneca; Janssen; NovoNordisk; Merck; Amgen; Novartis; Bayer AG HealthCare; Biotronik; Boehringer Ingelheim; Boston Scientific; Daiichi Sankyo; Johnson Johnson; Medtronic; Ortho-McNeil-Janssen Pharmaceuticals; Pfizer; Sanofi Aventis; Portola; Bayer; Medscape; ARCA Biopharma; GE Healthcare; Janssen Scientific; ResMed; Sanofi-Aventis; Johnson Johnson/Bayer; Eli Lilly FX Bansilal: consulting fees from AstraZeneca; institutional research grants from AstraZeneca. Bloomgarden: consulting fees from Astra Zeneca, Janssen, NovoNordisk, Merck, Amgen, and Novartis; speaker's bureau for Astra Zeneca, Janssen, NovoNordisk, and Merck; and ownership interest in Baxter International, CVS Caremark, Roche Holdings, St Jude Medical, and Novartis. Halperin: consulting fees from AstraZeneca, Bayer AG HealthCare, Biotronik, Boehringer Ingelheim, Boston Scientific, Daiichi Sankyo, Janssen, Johnson & Johnson, Medtronic, Ortho-McNeil-Janssen Pharmaceuticals, Pfizer, and Sanofi Aventis. Hellkamp and Lokhnygina: nothing to report. Patel: consultant/advisory board for Bayer, Janssen, AstraZeneca, and Genzyme; institutional research grant for Johnson & Johnson and AstraZeneca. Becker: consulting fees/honoraria from Portola, Daiichi-Sankyo, Bristol-Myers Squibb, and Boehringer Ingelheim; research grants from AstraZeneca and Johnson & Johnson. Breithardt: honoraria from Bayer HealthCare and BMS/Pfizer; consultant/advisory board for Bayer HealthCare, BMS/Pfizer, and Sanofi Aventis. Hacke: consulting fees from Boehringer Ingelheim, Bayer HealthCare, and Daiichi Sankyo; research grants from Boehringer Ingelheim. Hankey: honoraria/consulting fees from Bayer and Medscape (theheart.org). Nessel: employee of Janssen Research & Development. Singer: consulting/advisory board for Bayer HealthCare, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Johnson & Johnson, Merck, and Pfizer; research grants from Bristol-Myers Squibb and Johnson & Johnson. Berkowitz: employee of Bayer HealthCare Pharmaceuticals. Piccini: research grants from ARCA Biopharma, Boston Scientific, GE Healthcare, Janssen Scientific, Johnson & Johnson, and ResMed; consultant/advisory boards for ChanRx, Johnson & Johnson, and Spectranetics. Mahaffey: full disclosures prior to August 1, 2013, available at www.dcri.org;disclosures after August 1, 2013, available at http://med.stanford.edu/profiles/kenneth_mahaffey. Fox: consulting fees/honoraria from Boehringer Ingelheim, Sanofi-Aventis, Astra Zeneca, Johnson & Johnson/Bayer, and Janssen; research grants from Eli Lilly. NR 16 TC 5 Z9 6 U1 2 U2 6 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 OCT PY 2015 VL 170 IS 4 BP 675 EP + DI 10.1016/j.ahj.2015.07.006 PG 16 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CR8BD UT WOS:000361575200009 PM 26386791 ER PT J AU Wang, TY Henry, TD Mccoy, LA Berger, PB Cohen, DJ Effron, MB Zettler, M Baker, BA Messenger, JC Peterson, ED AF Wang, Tracy Y. Henry, Timothy D. Mccoy, Lisa A. Berger, Peter B. Cohen, David J. Effron, Mark B. Zettler, Marjorie Baker, Brian A. Messenger, John C. Peterson, Eric D. TI Contemporary use of platelet function and pharmacogenomic testingamongpatients with acute myocardial infarction undergoing percutaneous coronary intervention in the United States SO AMERICAN HEART JOURNAL LA English DT Article ID ASSOCIATION TASK-FORCE; RANDOMIZED-TRIAL; CARDIOVASCULAR-ANGIOGRAPHY; PRACTICE GUIDELINES; CLOPIDOGREL; REACTIVITY; MANAGEMENT; PRASUGREL; THERAPY; SOCIETY AB Background Although platelet function and pharmacogenomic testing have been studied in clinical trials, their adoption into contemporary practice is unknown. Methods We studied patterns of platelet function and pharmacogenomic testing among 10,048 patients with acute myocardial infarction treated with percutaneous coronary intervention at 226 US hospitals in the TRANSLATE-ACS observational study between April 2010 and October 2012, excluding those receiving research protocol-mandated testing. Inverse probability-weighted propensity adjustment was used to compare 1-year bleeding and major adverse cardiac event risks between patients with and without testing. Results Overall, 337 (3.4%) patients underwent predischarge platelet function testing, whereas 85 (0.9%) underwent pharmacogenomic testing; 82% and 93% of hospitals never performed any platelet function or pharmacogenomic testing, respectively. Patients undergoing testing were more likely to be on an adenosine diphosphate receptor inhibitor preadmission or to have percutaneous coronary intervention of a previously treated lesion. Tested patients were more likely than nontested patients to be switched from clopidogrel to prasugrel/ticagrelor (25.7% vs 9.7%, P < .001) and were more likely to be on prasugrel/ticagrelor 6 months postdischarge (33.8% vs 25.1%, P < .001). No significant differences in 1-year bleeding and major adverse cardiac event risks were observed between tested and nontested patients (adjusted hazard ratios 1.06 [95% CI 0.68-1.65] and 1.21 [95% CI 0.94-1.54], respectively). Conclusions Platelet function and pharmacogenomic testing are rarely performed in contemporary myocardial infarction patients in the United States. When tested, patients were more likely to be treated with higher-potency adenosine diphosphate receptor inhibitors, yet no significant differences in longitudinal outcomes were observed. C1 [Wang, Tracy Y.; Mccoy, Lisa A.; Berger, Peter B.; Peterson, Eric D.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. [Henry, Timothy D.] Abbott NW Hosp, Minneapolis Heart Inst Fdn, Minneapolis, MN 55407 USA. [Cohen, David J.] St Lukes Mid Amer Heart Inst, Kansas City, MO USA. [Effron, Mark B.; Zettler, Marjorie] Lilly USA LLC, Indianapolis, IN USA. [Baker, Brian A.] Daiichi Sankyo Inc, Parsippany, NJ USA. [Messenger, John C.] Denver Vet Affairs Med Ctr, Denver, CO USA. RP Wang, TY (reprint author), Duke Clin Res Inst, Durham, NC 27705 USA. EM tracy.wang@duke.edu RI Effron, Mark/P-9300-2015 FU Daiichi Sankyo, Inc; Lilly USA FX The TRANSLATE-ACS study (NCT01088503) is sponsored by Daiichi Sankyo, Inc, and Lilly USA. The Duke Clinical Research Institute is the coordinating center for this study, which represents a collaborative effort with the American College of Cardiology. NR 18 TC 2 Z9 2 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 OCT PY 2015 VL 170 IS 4 BP 706 EP 714 DI 10.1016/j.ahj.2015.06.021 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CR8BD UT WOS:000361575200012 PM 26386794 ER PT J AU Lee, YH Armstrong, EJ Kim, G Oh, J Kang, SM Lee, BW Ahn, CW Cha, BS Lee, HC Mantzoros, CS Kang, ES AF Lee, Yong-ho Armstrong, Ehrin J. Kim, Gyuri Oh, Jaewon Kang, Seok-Min Lee, Byung-Wan Ahn, Chul Woo Cha, Bong Soo Lee, Hyun Chul Mantzoros, Christos S. Kang, Eun Seok TI Undiagnosed diabetes is prevalent in younger adults and associated with a higher risk cardiometabolic profile compared to diagnosed diabetes SO AMERICAN HEART JOURNAL LA English DT Article ID PERCUTANEOUS CORONARY INTERVENTION; ACUTE MYOCARDIAL-INFARCTION; FASTING GLUCOSE; UNITED-STATES; US ADULTS; CARDIOVASCULAR-DISEASE; NATIONAL-HEALTH; POST-CHALLENGE; ARTERY-DISEASE; MELLITUS AB Background A substantial percentage of patients have undiagnosed diabetes. We investigated the demographic characteristics and cardiometabolic profiles of subjects with undiagnosed diabetes. Methods A cross-sectional study with nationally representative samples of 25490 subjects aged >= 20 years from the KHNANES 2008 to 2011, which applied a complex, multistage, probability proportional to size sampling design. Subjects were categorized as having normal glucose (n = 16880), impaired fasting glucose (n = 5771), undiagnosed diabetes (n = 713), or diagnosed diabetes (n = 2126). Hyper low-density lipoprotein cholesterolemia was individually evaluated by the 2004 Adult Treatment Panel III guidelines and predicted risk of cardiovascular disease was estimated from the Framingham model. Results Among overall subjects with diabetes, the prevalence of undiagnosed diabetes was markedly increased in younger adults compared to older adults (49% in diabetic subjects <50 years vs 23% in diabetic subjects >= 50 years, P < .001), suggesting significant discrepancies in age-based screening. Patients with undiagnosed diabetes were also more likely to have undiagnosed or uncontrolled hypertension and hyper-low-density lipoprotein cholesterolemia. Individuals with undiagnosed diabetes had a significantly higher predicted 10-year Framingham cardiovascular disease risk than those with diagnosed diabetes (11% vs 8% in <50 years, 33% vs 30% in >= 50 years; both P < .001). Patients with undiagnosed diabetes were also more likely to have multiple cardiovascular risk factors including obesity, smoking and uncontrolled hypertension. Conclusions People with undiagnosed diabetes have a higher predicted risk for cardiovascular disease compared to those with diagnosed diabetes. Intensive screening for diabetes in younger adults should be stressed in public healthcare to reduce the burden of modifiable cardiometabolic risk among individuals with undiagnosed diabetes. C1 [Lee, Yong-ho; Kim, Gyuri; Lee, Byung-Wan; Ahn, Chul Woo; Cha, Bong Soo; Lee, Hyun Chul; Kang, Eun Seok] Yonsei Univ, Coll Med, Dept Internal Med, Div Endocrinol & Metab, Seoul 120752, South Korea. [Armstrong, Ehrin J.] Univ Colorado, Sch Med, Div Cardiol, Denver, CO USA. [Oh, Jaewon; Kang, Seok-Min] Yonsei Univ, Coll Med, Severance Cardiovasc Hosp, Div Cardiol, Seoul 120752, South Korea. [Oh, Jaewon; Kang, Seok-Min] Yonsei Univ, Coll Med, Cardiovasc Res Inst, Seoul 120752, South Korea. [Lee, Byung-Wan; Ahn, Chul Woo; Cha, Bong Soo; Lee, Hyun Chul; Kang, Eun Seok] Yonsei Univ, Coll Med, Inst Endocrine Res, Seoul 120752, South Korea. [Mantzoros, Christos S.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Endocrinol Diabet & Metab, Boston, MA 02215 USA. [Mantzoros, Christos S.] Harvard Univ, Sch Med, Boston VA Healthcare Syst, Sect Endocrinol, Boston, MA USA. RP Kang, ES (reprint author), Yonsei Univ, Coll Med, Dept Internal Med, Div Endocrinol & Metab, 50-1 Yonsei Ro, Seoul 120752, South Korea. EM edgo@yuhs.ac NR 39 TC 2 Z9 2 U1 0 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 OCT PY 2015 VL 170 IS 4 BP 760 EP + DI 10.1016/j.ahj.2015.07.024 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CR8BD UT WOS:000361575200018 PM 26386800 ER PT J AU Alonso, A Bahnson, JL Gaussoin, SA Bertoni, AG Johnson, KC Lewis, CE Vetter, M Mantzoros, CS Jeffery, RW Soliman, EZ AF Alonso, Alvaro Bahnson, Judy L. Gaussoin, Sarah A. Bertoni, Alain G. Johnson, Karen C. Lewis, Cora E. Vetter, Marion Mantzoros, Christos S. Jeffery, Robert W. Soliman, Elsayed Z. CA Look AHEAD Res Grp TI Effect of an intensive lifestyle intervention on atrial fibrillation risk in individuals with type 2 diabetes: The Look AHEAD randomized trial SO AMERICAN HEART JOURNAL LA English DT Article ID BODY-MASS INDEX; ATHEROSCLEROSIS RISK; CARDIORESPIRATORY FITNESS; PHYSICAL-ACTIVITY; CLINICAL-TRIAL; FOLLOW-UP; COMMUNITIES; OBESITY; HEALTH; EPIDEMIOLOGY AB Background Obesity is associated with higher risk of atrial fibrillation (AF), but the impact of behavioral weight loss interventions on atrial fibrillation (AF) risk in persons with diabetes is unknown. We addressed this question in the Look AHEAD randomized trial. Methods and results A total of 5,067 overweight or obese individuals 45 to 76 years old with type 2 diabetes without prevalent AF were randomized to either an intensive lifestyle intervention (ILI) designed to achieve and maintain weight loss through caloric reduction and increased physical activity or a diabetes support and education usual care group. Atrial fibrillation was ascertained from electrocardiograms at study examinations and hospitalization discharge summaries. Multivariable Cox models were used to estimate the intention-to-treat effect of the intervention adjusting for baseline covariates. During a mean follow-up of 9.0 years, 294 incident AF cases were identified. Rates of AF were comparable in the ILI and diabetes support and education groups (6.1 and 6.7 cases per 1,000 person-years, respectively, P = .42). The intervention did not affect AF incidence (multivariable hazard ratio [HR] 0.99, 95% CI 0.77-1.28). Similarly, neither weight loss nor improvement in physical fitness during the first year of the intervention was significantly associated with AF incidence: multivariable hazard ratio (95% CI) comparing top versus bottom quartile was 0.70 (0.41-1.18) for weight loss and 0.88 (0.55-1.43) for physical fitness improvement. Conclusion In a large randomized trial of overweight and obese individuals with type 2 diabetes, an ILI that induced modest weight loss did not reduce the risk of developing AF. C1 [Alonso, Alvaro; Jeffery, Robert W.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN 55454 USA. [Bahnson, Judy L.; Gaussoin, Sarah A.] Wake Forest Sch Med, Div Publ Hlth Sci, Dept Biostat Sci, Winston Salem, NC USA. [Bertoni, Alain G.; Soliman, Elsayed Z.] Wake Forest Sch Med, Div Publ Hlth Sci, Dept Epidemiol & Prevent, Winston Salem, NC USA. Univ Tennessee, Hlth Sci Ctr, Dept Prevent Med, Memphis, TN USA. [Lewis, Cora E.] Univ Alabama Birmingham, Dept Med, Div Prevent Med, Birmingham, AL 35294 USA. [Vetter, Marion] Univ Penn, Dept Psychiat, Perelman Sch Med, Ctr Weight & Eating Disorders, Philadelphia, PA 19104 USA. [Vetter, Marion] Bristol Myers Squib Inc, Philadelphia, PA USA. [Mantzoros, Christos S.] Harvard Univ, Sch Med, Boston VA Healthcare Syst, Sect Endocrinol, Boston, MA USA. RP Alonso, A (reprint author), Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, 1300 S 2nd St,Suite 300, Minneapolis, MN 55454 USA. EM alonso@umn.edu RI Alonso, Alvaro/A-4917-2010 OI Alonso, Alvaro/0000-0002-2225-8323 FU National Institute of Diabetes and Digestive and Kidney Diseases FX The primary sponsor, the National Institute of Diabetes and Digestive and Kidney Diseases, was represented on the Steering Committee and played a part in design and management of the Look AHEAD trial. The statistician (S.G.) had access to the raw data. Alvaro Alonso had full access to all results. All authors shared the final responsibility to submit for publication. NR 33 TC 7 Z9 7 U1 0 U2 4 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 OCT PY 2015 VL 170 IS 4 BP 770 EP + DI 10.1016/j.ahj.2015.07.026 PG 13 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CR8BD UT WOS:000361575200019 PM 26386801 ER PT J AU Kini, V McCarthy, FH Rajaei, S Epstein, AJ Heidenreich, PA Groeneveld, PW AF Kini, Vinay McCarthy, Fenton H. Rajaei, Sheeva Epstein, Andrew J. Heidenreich, Paul A. Groeneveld, Peter W. TI Variation in use of echocardiography among veterans who use the Veterans Health Administration vs Medicare SO AMERICAN HEART JOURNAL LA English DT Article ID LIFE TREATMENT INTENSITY; APPROPRIATE USE CRITERIA; QUALITY-OF-CARE; GEOGRAPHIC-VARIATION; UNITED-STATES; MYOCARDIAL-INFARCTION; REGIONAL-VARIATIONS; HEART-FAILURE; RISK; BENEFICIARIES AB Background Rapid growth in the provision of cardiac imaging tests has led to concerns about overuse. Little is known about the degree to which health care delivery system characteristics influence use and variation in echocardiography. Methods We analyzed administrative claims of veterans with heart failure older than 65 years from 2007 to 2010 across 34 metropolitan service areas (MSAs). We compared overall rates and geographic variation in use of transthoracic echocardiography (TTE) between veterans who used the Veterans Health Administration (VA) and propensity-matched veterans who used Medicare. "Dual users" were excluded. Results There were no significant differences in clinical characteristics ormortality between the propensity-matched cohorts (overall n = 30,404 veterans, mean age 76 years, mortality rate 52%). The Medicare cohort had a significantly higher overall rate of TTE use compared with the VA cohort (1.25 vs 0.38 TTEs per person-year, incidence rate ratio 2.89 [95% CI 2.80-3.00], both P < .001), but a similar coefficient of variation across MSAs (0.36 [95% CI 0.27-0.45] vs 0.48 [95% CI 0.37-0.59]). There was a moderate to strong correlation in variation at the MSA level between cohorts (Spearman r = 0.58, P < .001). Conclusion Overall rates of TTE use were significantly higher in a Medicare cohort compared with a propensity scorematched VA cohort of veterans with heart failure living in urban areas, with similar relative degrees of geographic variation and moderate to strong regional correlation. Rates of TTE use may be strongly influenced by health care system characteristics, but local practice styles influence echocardiography rates irrespective of health system. C1 [Kini, Vinay] Hosp Univ Penn, Div Cardiovasc Med, Philadelphia, PA 19104 USA. [Kini, Vinay; McCarthy, Fenton H.; Epstein, Andrew J.; Groeneveld, Peter W.] Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. [McCarthy, Fenton H.] Hosp Univ Penn, Div Cardiovasc Surg, Philadelphia, PA 19104 USA. [Rajaei, Sheeva; Heidenreich, Paul A.] Stanford Univ, Sch Med, Div Cardiovasc Med, Stanford, CA 94305 USA. [Epstein, Andrew J.; Groeneveld, Peter W.] Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equ & Res Promot, Dept Vet Affairs, Philadelphia, PA USA. [Epstein, Andrew J.; Groeneveld, Peter W.] Univ Penn, Perelman Sch Med, Div Gen Internal Med, Philadelphia, PA 19104 USA. [Heidenreich, Paul A.] VA Palo Alto Hlth Care Syst, Palo Alto, CA USA. RP Kini, V (reprint author), Hosp Univ Penn, Cardiovasc Med, 3400 Spruce St,9021 Gates, Philadelphia, PA 19104 USA. EM vinay.kini@uphs.upenn.edu FU NHLBI NIH HHS [T32 HL007843] NR 40 TC 1 Z9 1 U1 2 U2 3 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 OCT PY 2015 VL 170 IS 4 BP 805 EP 811 DI 10.1016/j.ahj.2015.07.016 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CR8BD UT WOS:000361575200023 PM 26386805 ER PT J AU Patorno, E Wang, SV Schneeweiss, S Liu, J Bateman, BT AF Patorno, Elisabetta Wang, Shirley V. Schneeweiss, Sebastian Liu, Jun Bateman, Brian T. TI Patterns of beta-blocker initiation in patients undergoing intermediate to high-risk noncardiac surgery SO AMERICAN HEART JOURNAL LA English DT Article ID RANDOMIZED-CONTROLLED-TRIAL; ASSOCIATION TASK-FORCE; PERIOPERATIVE CARDIOVASCULAR EVALUATION; PRACTICE GUIDELINES; AMERICAN-COLLEGE; MYOCARDIAL-INFARCTION; MULTICENTER TRIAL; VASCULAR-SURGERY; ARTERY-DISEASE; CARDIAC RISK AB Background Based on 2 small randomized controlled trials (RCTs) from the 1990s, beta-blockers were promoted to prevent perioperative cardiac events in patients undergoing noncardiac surgery. In 2008, a large RCT (POISE trial) showed an increased mortality risk associated with perioperative beta-blockade, raising concerns about an extensive beta-Blocker use. Objectives The objective of the study is to examine patterns of beta-Blocker initiation among patients undergoing noncardiac elective surgery in the US. Methods From a large, nationwide US health care insurer, we identified patients >= 18 years old who underwent moderate-to high-risk noncardiac elective surgery between 2003 and 2012 and initiated a beta-Blocker within 30 days before surgery. We evaluated temporal trends and assessed the impact of the POISE trial on perioperative beta-Blocker initiation. We also evaluated patient characteristics and examined the effect of temporal proximity to surgery on the likelihood of beta-Blocker initiation. Results Of 499,752 patients undergoing surgery, 9,014 (18 per 1,000 patients) initiated a beta-Blocker. beta-Blocker initiation increased from 12 per 1,000 patients in 2003 to 23 before POISE, after which it decreased to 14 by December 2012 (P = .0001). beta-Blocker initiation remained relatively high among patients undergoing vascular surgery or with Revised Cardiac Risk Index score >= 2. Proximity to surgery was highly predictive of beta-Blocker initiation (odds ratio 3.34, 95% CI 3.17-3.51). Conclusions After a period of a rapidly increasing trend, perioperative beta-Blocker initiation decreased sharply in the second half of 2008 and continued to decrease afterwards. beta-Blocker initiation remained relatively high in patients with Revised Cardiac Risk Index score >= 2 and in those undergoing major vascular surgery. C1 [Patorno, Elisabetta; Wang, Shirley V.; Schneeweiss, Sebastian; Liu, Jun; Bateman, Brian T.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Pharmacoepidemiol & Pharmacoecon,Dept Med, Boston, MA 02120 USA. [Bateman, Brian T.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Patorno, E (reprint author), Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, 1620 Tremont St,Suite 3030, Boston, MA 02120 USA. EM epatorno@partners.org RI Schneeweiss, Sebastian/C-2125-2013 FU Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham; Women's Hospital, Harvard Medical School, Boston, MA FX This study was funded by the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA. NR 32 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 0002-8703 EI 1097-5330 J9 AM HEART J JI Am. Heart J. PD OCT PY 2015 VL 170 IS 4 BP 812 EP + DI 10.1016/j.ahj.2015.06.028 PG 15 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CR8BD UT WOS:000361575200024 PM 26386806 ER PT J AU Carter, J Tseng, LH Zheng, G Dudley, J Illei, P Gocke, CD Eshleman, JR Lin, MT AF Carter, Jamal Tseng, Li-Hui Zheng, Gang Dudley, Jonathan Illei, Peter Gocke, Christopher D. Eshleman, James R. Lin, Ming-Tseh TI Non-p.V600E BRAF Mutations Are Common Using a More Sensitive and Broad Detection Tool SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE BRAF; Lung cancer; Colorectal cancer; Melanoma; Next-generation sequencing ID CELL LUNG-CANCER; METASTATIC MELANOMA; COLORECTAL-CANCER; V600E MUTATION; INHIBITOR VEMURAFENIB; CLINICAL VALIDATION; MALIGNANT-MELANOMA; TUMOR CELLULARITY; IMPROVED SURVIVAL; OPEN-LABEL AB Objectives: To assess the performance of a next-generation sequencing (NGS) platform for the clinical detection of BRAF mutations. Methods: In this retrospective quality assessment of an NGS assay, we analyzed BRAF mutations within parts of exons 11 and 15 in 835 neoplastic tissues submitted to our molecular diagnostics laboratory. Results: The NGS assays detected a BRAF mutation in 5.9% of lung adenocarcinomas, 13% of colorectal cancers, and 44% of melanomas. Mutant allele frequencies were less than 20% in 28% of 88 BRAF-mutated specimens. Two lymph node specimens with subcapsular or infiltrative metastasis showed 1% to 2% mutant alleles. There were 26 unique BRAF mutations in exons 11 and 15, including three novel mutations. Mutations were located outside codon 600 in 39% of BRAF-mutated tumors. Lung adenocarcinomas showed significantly higher non-p. V600E mutations (86%) than did colorectal cancers (23%) and melanomas (34%). The three most common BRAF mutations in lung cancers accounted for only 41% of the observed BRAF mutations (p.D594G [18%], p.V600E [14%], and p.G469A [9%]). Conclusions: The NGS assay demonstrated a high analytic sensitivity and a broad reportable range for clinical detection of BRAF mutations. Elucidating the spectrum of non-p. V600E BRAF mutations in different malignancies is a first step toward understanding their clinical significance. C1 [Carter, Jamal; Tseng, Li-Hui; Zheng, Gang; Dudley, Jonathan; Illei, Peter; Gocke, Christopher D.; Eshleman, James R.; Lin, Ming-Tseh] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21287 USA. [Gocke, Christopher D.; Eshleman, James R.] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21287 USA. [Tseng, Li-Hui] Natl Taiwan Univ Hosp, Dept Med Genet, Taipei, Taiwan. [Dudley, Jonathan] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Lin, MT (reprint author), Johns Hopkins Univ, Sch Med, Dept Pathol, Pk SB202,600 North Wolfe St, Baltimore, MD 21287 USA. EM mlin36@jhmi.edu NR 54 TC 9 Z9 9 U1 0 U2 4 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 EI 1943-7722 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD OCT PY 2015 VL 144 IS 4 BP 620 EP 628 DI 10.1309/AJCP85ATMJOZOUDJ PG 9 WC Pathology SC Pathology GA CR7XJ UT WOS:000361565000011 PM 26386083 ER PT J AU Hagiwara, Y Watase, H Okamoto, H Goto, T Hasegawa, K AF Hagiwara, Yusuke Watase, Hiroko Okamoto, Hiroshi Goto, Tadahiro Hasegawa, Kohei CA Japanese Emergency Med Network TI Prospective validation of the modified LEMON criteria to predict difficult intubation in the ED SO AMERICAN JOURNAL OF EMERGENCY MEDICINE LA English DT Article ID TRACHEAL INTUBATION; ENDOTRACHEAL INTUBATION; AIRWAY MANAGEMENT; SCORE; GUIDELINES; OUTCOMES AB Background: Evidence to predict difficult intubation remains scarce in the emergency department (ED) setting. A previously defined clinical decision rule, the modified LEMON criteria, may provide a reliable and reproducible means of identifying difficult intubations. We aimed to prospectively evaluate the external validity of the modified LEMON criteria in the EDs. Methods: We conducted a 13-center prospective observational study, the second Japanese Emergency Airway Network study. We prospectively collected data on all patients undergoing intubations in the ED from February 2012 through September 2014. The primary outcomes were sensitivity, specificity, and predictive values of the modified LEMON criteria for predicting difficult intubation (>= 2 attempts by emergency attending physicians or anesthesiologists). Results: The database recorded a total of 4034 encounters (capture rate, 96%) in the EDs. Of these, 3313 patients (84%) underwent the intubation attempt with a direct laryngoscope and 610 patients (16%) with a video laryngoscope. The proportion of difficult intubation was 5.4% (95% confidence interval [CI], 4.7%-6.2%) in the direct laryngoscope group and 7.4% (95% CI, 5.6%-9.7%) in the video laryngoscope group. The sensitivity was 85.7% (95% CI, 79.3%-90.4%) with direct laryngoscope and 94.9% (95% CI, 83.5%-98.6%) with video laryngoscope. The specificity was 47.6% (95% CI, 47.2%-47.9%) and 40.3% (95% CI, 39.4%-40.6%), respectively. The negative predictive value was 98.2% (95% CI, 97.5%-98.8%) and 99.0% (95% CI, 96.6%-99.7%), respectively. Conclusions: In this multicenter prospective study, we found a high sensitivity and a negative predictive value of the modified LEMON criteria for predicting difficult intubation. The modified LEMON might assist ED providers in better identifying difficult intubations. (C) 2015 Elsevier Inc. All rights reserved. C1 [Hagiwara, Yusuke] Tokyo Metropolitan Childrens Med Ctr, Dept Pediat Emergency & Crit Care Med, Fuchu, Tokyo 1838561, Japan. [Watase, Hiroko] Univ Washington, Dept Radiol, Seattle, WA 98195 USA. [Okamoto, Hiroshi] Kurashiki Cent Hosp, Dept Emergency Med, Kurashiki, Okayama, Japan. [Goto, Tadahiro; Hasegawa, Kohei] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA USA. RP Hagiwara, Y (reprint author), Tokyo Metropolitan Childrens Med Ctr, Dept Pediat Emergency & Crit Care Med, 2-8-29 Musashidai, Fuchu, Tokyo 1838561, Japan. EM yusukehagiwara-tky@umin.ac.jp; hiroko7@uw.edu; hiroshi.okamota.1121@gmail.com; tadahirogoto@gmail.com; khasegawa@partners.org FU St Luke's Life Science Institute FX This study was supported by a grant from St Luke's Life Science Institute. The study sponsors have no involvement in the study design; in the collection, analysis, and interpretation of data; in the writing of the manuscript; and in the decision to submit the manuscript for publication. NR 21 TC 2 Z9 3 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0735-6757 EI 1532-8171 J9 AM J EMERG MED JI Am. J. Emerg. Med. PD OCT PY 2015 VL 33 IS 10 BP 1492 EP 1496 DI 10.1016/j.ajem.2015.06.038 PG 5 WC Emergency Medicine SC Emergency Medicine GA CS1PM UT WOS:000361839300032 PM 26166379 ER PT J AU Fourman, LT Fogelman, AG AF Fourman, Lindsay T. Fogelman, Amy G. TI Lost in the Woods: Granulomatosis with Polyangiitis SO AMERICAN JOURNAL OF MEDICINE LA English DT Editorial Material ID WEGENERS-GRANULOMATOSIS; DIAGNOSIS C1 [Fourman, Lindsay T.; Fogelman, Amy G.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Fourman, LT (reprint author), Massachusetts Gen Hosp, Dept Med, 55 Fruit St, Boston, MA 02114 USA. EM LindsayFourman@gmail.com NR 9 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 OCT PY 2015 VL 128 IS 10 BP 1080 EP 1082 DI 10.1016/j.amjmed.2015.06.019 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA CR9DE UT WOS:000361652600042 PM 26164563 ER PT J AU Melton, BL Zillich, AJ Russell, SA Weiner, M McManus, MS Spina, JR Russ, AL AF Melton, Brittany L. Zillich, Alan J. Russell, Scott A. Weiner, Michael McManus, M. Sue Spina, Jeffrey R. Russ, Alissa L. TI Reducing Prescribing Errors Through Creatinine Clearance Alert Redesign SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE Electronic health records; Evaluation; Health information technology; Patient safety; Renal disease ID CLINICAL DECISION-SUPPORT; HUMAN-FACTORS PRINCIPLES; DRUG INTERACTION ALERTS; PHYSICIAN ORDER ENTRY; RENAL-INSUFFICIENCY; SAFETY ALERTS; SYSTEMS; DESIGN; EFFICIENCY; USABILITY AB BACKGROUND: Literature has shown that computerized creatinine clearance alerts reduce errors during prescribing, and applying human factors principles may further reduce errors. Our objective was to apply human factors principles to creatinine clearance alert design and assess whether the redesigned alerts increase usability and reduce prescribing errors compared with the original alerts. METHODS: Twenty Veterans Affairs (VA) outpatient providers (14 physicians, 2 nurse practitioners, and 4 clinical pharmacists) completed 2 usability sessions in a counterbalanced study to evaluate original and redesigned alerts. Each session consisted of fictional patient scenarios with 3 medications that warranted prescribing changes because of renal impairment, each associated with creatinine clearance alerts. Quantitative and qualitative data were collected to assess alert usability and the occurrence of prescribing errors. RESULTS: There were 43% fewer prescribing errors with the redesigned alerts compared with the original alerts (P = .001). Compared with the original alerts, redesigned alerts significantly reduced prescribing errors for allopurinol and ibuprofen (85% vs 40% and 65% vs 25%, P = .012 and P = .008, respectively), but not for spironolactone (85% vs 65%). Nine providers (45%) voiced confusion about why the alert was appearing when they encountered the original alert design. When laboratory links were presented on the redesigned alert, laboratory information was accessed 3.5 times more frequently. CONCLUSIONS: Although prescribing errors were high with both alert designs, the redesigned alerts significantly improved prescribing outcomes. This investigation provides some of the first evidence on how alerts may be designed to support safer prescribing for patients with renal impairment. (C) 2015 Elsevier Inc. All rights reserved. C1 [Melton, Brittany L.] Univ Kansas, Sch Pharm, Lawrence, KS 66045 USA. [Zillich, Alan J.; Russell, Scott A.; Weiner, Michael; Russ, Alissa L.] Hlth Serv Res & Dev Serv CIN 13 416, Ctr Hlth Informat & Commun, Dept Vet Affairs, Vet Hlth Adm, Indianapolis, IN USA. [Zillich, Alan J.; Weiner, Michael; Russ, Alissa L.] Regenstrief Inst Inc, Indianapolis, IN USA. [Zillich, Alan J.; Weiner, Michael; Russ, Alissa L.] Indiana Univ, Ctr Hlth Serv & Outcomes Res, Indianapolis, IN 46204 USA. [Zillich, Alan J.; Russ, Alissa L.] Purdue Univ, Coll Pharm, W Lafayette, IN 47907 USA. [McManus, M. Sue] Nephrol Serv Cent Texas, Dept Vet Affairs, Temple, TX USA. [Spina, Jeffrey R.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Spina, Jeffrey R.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. RP Melton, BL (reprint author), 3901 Rainbow Blvd,Wescoe 6012,Mailstop 4047, Kansas City, KS 66160 USA. EM bmelton2@kumc.edu FU VA Health Services Research & Development Grant [PPO 09-298]; VA Health Services Research & Development Research Career Development Awards [CDA 11-214, RCD 06-304-1] FX This work was supported by VA Health Services Research & Development Grant PPO 09-298 (Principal Investigator, ALR). AJZ and ALR were supported by VA Health Services Research & Development Research Career Development Awards (CDA 11-214, and RCD 06-304-1, respectively). The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs or the US government. NR 42 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 OCT PY 2015 VL 128 IS 10 BP 1117 EP 1125 DI 10.1016/j.amjmed.2015.05.033 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA CR9DE UT WOS:000361652600048 PM 26087048 ER PT J AU Brondfield, S Reid, M Patel, K Ten, R Dhaliwal, G AF Brondfield, Sam Reid, Michael Patel, Kiran Ten, Rosa Dhaliwal, Gurpreet TI Disseminated Mycobacterial Infection and Scabies Infestation SO AMERICAN JOURNAL OF MEDICINE LA English DT Letter C1 [Brondfield, Sam] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Reid, Michael] Univ Calif San Francisco, Dept Med, Div Infect Dis, San Francisco, CA 94143 USA. [Patel, Kiran] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. [Ten, Rosa] Univ Calif San Francisco, Dept Med, Div Pulm Allergy & Immunol, San Francisco, CA 94143 USA. [Dhaliwal, Gurpreet] Univ Calif San Francisco, Dept Med, San Francisco VA Med Ctr, San Francisco, CA 94143 USA. RP Brondfield, S (reprint author), Univ Calif San Francisco, Dept Med, 505 Parnassus Ave,Rm 987, San Francisco, CA 94143 USA. EM sam.brondfield@ucsf.edu NR 5 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 0002-9343 EI 1555-7162 J9 AM J MED JI Am. J. Med. PD OCT PY 2015 VL 128 IS 10 BP E41 EP E42 DI 10.1016/j.amjmed.2015.06.008 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA CR9DE UT WOS:000361652600015 PM 26149672 ER PT J AU O'Malley, DP Louissaint, A Vasef, MA Auerbach, A Miranda, R Brynes, RK Fedoriw, Y Hudnall, SD AF O'Malley, Dennis P. Louissaint, Abner, Jr. Vasef, Mohammad A. Auerbach, Aaron Miranda, Roberto Brynes, Russell K. Fedoriw, Yuri Hudnall, S. David CA Int Spleen Consortium TI Recommendations for gross examination and sampling of surgical specimens of the spleen SO ANNALS OF DIAGNOSTIC PATHOLOGY LA English DT Article DE spleen; gross examination; sampling histology; pathology ID T-CELL LYMPHOMA; SPLENIC-GONADAL FUSION; INFLAMMATORY PSEUDOTUMOR; SPONTANEOUS RUPTURE; GAMMA-DELTA; INFECTIOUS-MONONUCLEOSIS; DIAGNOSIS; SPLENOSIS; LEUKEMIA; FEATURES AB This review examines handling and processing of spleen biopsies and splenectomy specimens with the aim of providing the pathologist with guidance in optimizing examination and diagnosis of splenic disorders. It also offers recommendations as to relevant reporting factors in gross examination, which may guide diagnostic workup. The role of splenic needle biopsies is discussed. The International Spleen Consortium is a group dedicated to promoting education and research on the anatomy, physiology, and pathology of the spleen. In keeping with these goals, we have undertaken to provide guidelines for gross examination, sectioning, and sampling of spleen tissue to optimize diagnosis (Burke Ill). The pathology of the spleen may be complicated in routine practice due to a number of factors. Among these are lack of familiarity with lesions, complex histopathology, mimicry within several types of lesions, and overall rarity. To optimize diagnosis, appropriate handling and processing of splenic tissue are crucial. The importance of complete and accurate clinical history cannot be overstated. In many cases, significant clinical history such as previous lymphoproliferative disorders, hematologic disorders, trauma, etc, can provide important information to guide the evaluation of spleen specimens. Clinical information helps plan for appropriate processing of the spleen specimen. The pathologist should encourage surgical colleagues, who typically provide the specimens, to include as much clinical information as possible. (C) 2015 Elsevier Inc. All rights reserved. C1 [O'Malley, Dennis P.] Clarient Diagnost Serv, Aliso Viejo, CA 92656 USA. [Louissaint, Abner, Jr.] Massachusetts Gen Hosp, Pathol Serv, Boston, MA 02114 USA. [Vasef, Mohammad A.] TriCore Reference Labs, Albuquerque, NM 87102 USA. [Auerbach, Aaron] Joint Pathol Ctr, Silver Spring, MD 20910 USA. [Miranda, Roberto] Univ Texas Houston, MD Anderson Canc Ctr, Houston, TX 77030 USA. [Brynes, Russell K.] Univ So Calif, Keck Sch Med, Dept Pathol, Los Angeles, CA 90033 USA. [Fedoriw, Yuri] Univ N Carolina, Sch Med, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA. [Hudnall, S. David] Yale Univ, Dept Pathol, New Haven, CT 06520 USA. RP O'Malley, DP (reprint author), Clarient Diagnost Serv, 31 Columbia, Aliso Viejo, CA 92656 USA. EM domalley@clarientinc.com; alouissaint@partners.org; mvasef@salud.unm.edu; aaron.auerbach.civ@mail.mil; Roberto.miranda@mdanderson.org; brynes@usc.edu; Gfedoriw@unch.unc.edu; david.hudnall@yale.edu OI Bhagat, Govind/0000-0001-6250-048X NR 61 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 1092-9134 EI 1532-8198 J9 ANN DIAGN PATHOL JI Ann. Diagn. Pathol. PD OCT PY 2015 VL 19 IS 5 BP 288 EP 295 DI 10.1016/j.anndiagpath.2015.06.004 PG 8 WC Pathology SC Pathology GA CR8ZI UT WOS:000361642600003 PM 26143481 ER PT J AU Blasi, F Oliveira, BL Rietz, TA Rotile, NJ Naha, PC Cormode, DP Izquierdo-Garcia, D Catana, C Caravan, P AF Blasi, Francesco Oliveira, Bruno L. Rietz, Tyson A. Rotile, Nicholas J. Naha, Pratap C. Cormode, David P. Izquierdo-Garcia, David Catana, Ciprian Caravan, Peter TI Multisite Thrombus Imaging and Fibrin Content Estimation With a Single Whole-Body PET Scan in Rats SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE diagnostic techniques; cardiovascular; fibrin; magnetic resonance imaging; molecular imaging; positron-emission tomography; thrombosis; whole body imaging ID DEEP-VEIN THROMBOSIS; CONTRAST AGENT; PULMONARY-EMBOLISM; CORONARY THROMBUS; THROMBOLYSIS; MODEL; STROKE; SUSCEPTIBILITY; FEASIBILITY; VALIDATION AB Objective Thrombosis is a leading cause of morbidity and mortality worldwide. Current diagnostic strategies rely on imaging modalities that are specific for distinct vascular territories, but a thrombus-specific whole-body imaging approach is still missing. Moreover, imaging techniques to assess thrombus composition are underdeveloped, although therapeutic strategies may benefit from such technology. Therefore, our goal was to test whether positron emission tomography (PET) with the fibrin-binding probe Cu-64-FBP8 allows multisite thrombus detection and fibrin content estimation. Approach and Results Thrombosis was induced in Sprague-Dawley rats (n=32) by ferric chloride application on both carotid artery and femoral vein. Cu-64-FBP8-PET/CT imaging was performed 1, 3, or 7 days after thrombosis to detect thrombus location and to evaluate age-dependent changes in target uptake. Ex vivo biodistribution, autoradiography, and histopathology were performed to validate imaging results. Arterial and venous thrombi were localized on fused PET/CT images with high accuracy (97.6%; 95% confidence interval, 92-100). A single whole-body PET/MR imaging session was sufficient to reveal the location of both arterial and venous thrombi after Cu-64-FBP8 administration. PET imaging showed that probe uptake was greater in younger clots than in older ones for both arterial and venous thrombosis (P<0.0001). Quantitative histopathology revealed an age-dependent reduction of thrombus fibrin content (P<0.001), consistent with PET results. Biodistribution and autoradiography further confirmed the imaging findings. Conclusions We demonstrated that Cu-64-FBP8-PET is a feasible approach for whole-body thrombus detection and that molecular imaging of fibrin can provide, noninvasively, insight into clot composition. C1 [Blasi, Francesco; Oliveira, Bruno L.; Rietz, Tyson A.; Rotile, Nicholas J.; Izquierdo-Garcia, David; Catana, Ciprian; Caravan, Peter] Harvard Univ, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol,Med Sch, Charlestown, MA USA. [Naha, Pratap C.; Cormode, David P.] Univ Penn, Dept Radiol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Caravan, Peter] Massachusetts Gen Hosp, Inst Innovat Imaging, Boston, MA 02114 USA. RP Caravan, P (reprint author), Bldg 149,Room 2301,13th St, Charlestown, MA 02129 USA. EM caravan@nmr.mgh.harvard.edu RI Blasi, Francesco/G-1055-2015; OI Blasi, Francesco/0000-0002-6616-8418; Cormode, David/0000-0002-8391-9500; Oliveira, Bruno/0000-0002-7687-4746 FU National Heart, Lung, and Blood Institute [HL109448]; National Center for Research Resources [RR029495]; Office of the Director at NIH [OD010650] FX This work was supported by HL109448 from the National Heart, Lung, and Blood Institute. The National Center for Research Resources (RR029495) and the Office of the Director (OD010650) at NIH are acknowledged for funding instrumentation used. NR 37 TC 6 Z9 6 U1 2 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1079-5642 EI 1524-4636 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD OCT PY 2015 VL 35 IS 10 BP 2114 EP 2121 DI 10.1161/ATVBAHA.115.306055 PG 8 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA CR8NL UT WOS:000361610700008 PM 26272938 ER PT J AU Cavusoglu, E Marmur, JD Yanamadala, S Chopra, V Hegde, S Nazli, A Singh, KP Zhang, M Eng, C AF Cavusoglu, Erdal Marmur, Jonathan D. Yanamadala, Sunitha Chopra, Vineet Hegde, Sudhanva Nazli, Anila Singh, Kamal Preet Zhang, Ming Eng, Calvin TI Elevated baseline plasma IL-8 levels are an independent predictor of long-term all-cause mortality in patients with acute coronary syndrome SO ATHEROSCLEROSIS LA English DT Article DE IL-8; Biomarkers; Acute coronary syndrome; Prognosis; Mortality ID HUMAN-ENDOTHELIAL-CELLS; SMOOTH-MUSCLE-CELLS; NATRIURETIC PEPTIDE; INTERLEUKIN-8; MACROPHAGES; EXPRESSION; PROTEIN; TISSUE; CHEMOATTRACTANT; POPULATION AB Objectives: To investigate the long-term prognostic significance of baseline plasma IL-8 levels in a group of well-characterized male patients presenting with acute coronary syndrome. Background: IL-8 is a cytokine that has been implicated in the pathogenesis of atherosclerosis and acute coronary syndrome. Elevated plasma levels have been reported in patients with acute coronary syndrome. Methods: Baseline plasma IL-8 levels were measured in 180 male patients with acute coronary syndrome who were referred for coronary angiography and followed prospectively for the development of all-cause mortality for 5 years. Results: In a multivariate model that included a wide variety of baseline clinical, laboratory and angiographic parameters in the selection process, baseline plasma IL-8 levels (analyzed as a continuous variable) emerged as a significant predictor of all-cause mortality at 5 years (HR, 1.43; 95% CI, 1.08-1.88; p = 0.0123). Furthermore, in 3 additional multivariate models that also included in the selection process a number of contemporary biomarkers with established prognostic efficacy in ACS (i.e., NT-proBNP, hs-CRP, hemoglobin and RDW), IL-8 remained an independent predictor of all-cause mortality at 5 years. Conclusion: Elevated baseline plasma levels of IL-8 are associated with an increased risk of long-term all-cause mortality in patients with acute coronary syndrome. Furthermore, this association is independent of a variety of clinical, laboratory and angiographic variables, including contemporary biomarkers with established prognostic efficacy in acute coronary syndrome. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Cavusoglu, Erdal; Chopra, Vineet; Eng, Calvin] Bronx Vet Affairs Med Ctr, Div Cardiol, Dept Med, Bronx, NY USA. [Cavusoglu, Erdal; Marmur, Jonathan D.; Yanamadala, Sunitha; Hegde, Sudhanva; Nazli, Anila; Singh, Kamal Preet] Suny Downstate Med Ctr, Div Cardiol, Dept Med, Brooklyn, NY 11203 USA. [Zhang, Ming] Suny Downstate Med Ctr, Dept Cell Biol, Brooklyn, NY 11203 USA. [Zhang, Ming] Suny Downstate Med Ctr, Dept Anesthesiol, Brooklyn, NY 11203 USA. RP Cavusoglu, E (reprint author), Suny Downstate Med Ctr, 450 Clarkson Ave,Box 1199, Brooklyn, NY 11203 USA. EM ECavusoglu@aol.com NR 27 TC 1 Z9 1 U1 1 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 EI 1879-1484 J9 ATHEROSCLEROSIS JI Atherosclerosis PD OCT PY 2015 VL 242 IS 2 BP 589 EP 594 DI 10.1016/j.atherosclerosis.2015.08.022 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA CR7DV UT WOS:000361509000030 PM 26318109 ER PT J AU Nicolaidis, C Raymaker, DM Ashkenazy, E McDonald, KE Dern, S Baggs, AEV Kapp, SK Weiner, M Boisclair, WC AF Nicolaidis, Christina Raymaker, Dora M. Ashkenazy, Elesia McDonald, Katherine E. Dern, Sebastian Baggs, Amelia E. V. Kapp, Steven K. Weiner, Michael Boisclair, W. Cody TI "Respect the way I need to communicate with you": Healthcare experiences of adults on the autism spectrum SO AUTISM LA English DT Article DE adults; autism spectrum disorders; community-based participatory research; health services; qualitative research ID DISORDER; PARTNERSHIP; DISPARITIES; SERVICES; AQ AB Our objective was to obtain an in-depth understanding of autistic adults' experiences with healthcare and their recommendations for improving care. Our academic-community partnership used a community-based participatory research approach to conduct semi-structured, open-ended interviews with 39 autistic adults and 16 people who had experience supporting autistic adults in healthcare settings. Participants identified patient-level, autism-related factors that impact healthcare interactions, including verbal communication skills, sensory sensitivities, challenges with body awareness, slow processing speed, atypical non-verbal communication, and challenges with organization. However, the success of healthcare interactions largely depended on the interplay between patient- and provider-level factors, as well as the larger context in which patients were receiving care. Provider-level factors included providers' knowledge about autism in adults, incorrect assumptions about individual patients, willingness to allow written communication, use of accessible language, openness to providing other accommodations, and skill in appropriately incorporating supporters. System-level factors included the availability of supporters, complexity of the healthcare system, accessibility of healthcare facilities, and stigma about autism. Further efforts are needed to empower patients, adequately train providers, increase the accessibility of the healthcare system, and decrease discrimination. C1 [Nicolaidis, Christina; Raymaker, Dora M.] Portland State Univ, Portland, OR 97201 USA. [Nicolaidis, Christina] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Nicolaidis, Christina; Raymaker, Dora M.; Ashkenazy, Elesia; McDonald, Katherine E.; Dern, Sebastian; Baggs, Amelia E. V.; Kapp, Steven K.; Weiner, Michael; Boisclair, W. Cody] Acad Autist Spectrum Partnership Res & Educ, Washington, DC USA. [McDonald, Katherine E.] Syracuse Univ, Syracuse, NY 13244 USA. [Weiner, Michael] Indiana Univ, Ctr Hlth Serv & Outcomes Res, Bloomington, IN 47405 USA. [Weiner, Michael] Regenstrief Inst Inc, Indianapolis, IN USA. [Weiner, Michael] US Dept Vet Affairs, Washington, DC USA. RP Nicolaidis, C (reprint author), Portland State Univ, Reg Res Inst, Sch Social Work, 1600 SW 4th Ave,Suite 900, Portland, OR 97201 USA. EM Nicol22@pdx.edu FU National Institute of Mental Health [R34MH092503]; Oregon Clinical and Translational Research Institute (OCTRI) from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) [UL1 RR024140]; NIH Roadmap for Medical Research FX This study was funded by the National Institute of Mental Health [R34MH092503] and the Oregon Clinical and Translational Research Institute (OCTRI), grant number UL1 RR024140 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. NR 20 TC 6 Z9 6 U1 3 U2 22 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1362-3613 EI 1461-7005 J9 AUTISM JI Autism PD OCT PY 2015 VL 19 IS 7 SI SI BP 824 EP 831 DI 10.1177/1362361315576221 PG 8 WC Psychology, Developmental SC Psychology GA CS0RK UT WOS:000361769700007 PM 25882392 ER PT J AU Williams, DL Minshew, NJ Goldstein, G AF Williams, Diane L. Minshew, Nancy J. Goldstein, Gerald TI Further understanding of complex information processing in verbal adolescents and adults with autism spectrum disorders SO AUTISM LA English DT Article DE adults; autism spectrum disorders; conceptual reasoning; information processing; language ID HIGH-FUNCTIONING AUTISM; DIAGNOSTIC OBSERVATION SCHEDULE; UNDERCONNECTIVITY; INDIVIDUALS; CHILDREN; SYNCHRONIZATION; COMPREHENSION; ACTIVATION; INTERVIEW; LANGUAGE AB More than 20years ago, Minshew and colleagues proposed the Complex Information Processing model of autism in which the impairment is characterized as a generalized deficit involving multiple modalities and cognitive domains that depend on distributed cortical systems responsible for higher order abilities. Subsequent behavioral work revealed a related dissociation between concept formation and concept identification in autism suggesting the lack of an underlying organizational structure to manage increases in processing loads. The results of a recent study supported the impact of this relative weakness in conceptual reasoning on adaptive functioning in children and adults with autism. In this study, we provide further evidence of the difficulty relatively able older adolescents and adults with autism have with conceptual reasoning and provide evidence that this characterizes their difference from age- and ability-matched controls with typical development better than their differences in language. For verbal adults with autism, language may serve as a bootstrap or compensatory mechanism for learning but cannot overcome an inherent weakness in concept formation that makes information processing challenging as task demands increase. C1 [Williams, Diane L.] Duquesne Univ, Pittsburgh, PA USA. [Minshew, Nancy J.] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Goldstein, Gerald] VA Pittsburgh Healthcare Syst, Pittsburgh, PA 15240 USA. RP Goldstein, G (reprint author), VA Pittsburgh Healthcare Syst, Univ Dr 151R, Pittsburgh, PA 15240 USA. EM ggold@nb.net RI Williams, Diane/B-4128-2017 FU National Institute of Neurological Disorders and Stroke (NINDS) [NS3335]; National Institute of Child Health and Human Development (NICHD) Collaborative Program of Excellence in Autism (CPEA) [HD35469]; Medical Research Service, Department of Veterans Affairs FX This work was supported by the National Institute of Neurological Disorders and Stroke (NINDS) [grant NS3335]; by the National Institute of Child Health and Human Development (NICHD) Collaborative Program of Excellence in Autism (CPEA) [grant HD35469]; and the Medical Research Service, Department of Veterans Affairs. NR 49 TC 4 Z9 4 U1 3 U2 16 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1362-3613 EI 1461-7005 J9 AUTISM JI Autism PD OCT PY 2015 VL 19 IS 7 SI SI BP 859 EP 867 DI 10.1177/1362361315586171 PG 9 WC Psychology, Developmental SC Psychology GA CS0RK UT WOS:000361769700011 PM 26019307 ER PT J AU Matar, AJ Patil, AR Al-Musa, A Hanekamp, I Sachs, DH Huang, CA Duran-Struuck, R AF Matar, Abraham J. Patil, Aarti R. Al-Musa, Ahmad Hanekamp, Isabel Sachs, David H. Huang, Christene A. Duran-Struuck, Raimon TI Effect of Irradiation on Incidence of Post-Transplant Lymphoproliferative Disorder after Hematopoietic Cell Transplantation in Miniature Swine SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Hematopoietic cell transplantation; Post-transplant lymphoproliferative disease ID EPSTEIN-BARR-VIRUS; LARGE-ANIMAL-MODEL; PREPARATIVE REGIMEN; MIXED CHIMERISM; CD3 IMMUNOTOXIN; BONE-MARROW; SCID MICE; IN-VIVO; DISEASE AB Post-transplant lymphoproliferative disease (PTLD) is a major complication of clinical organ and cell transplantation. Conditioning and immunosuppressive regimens that significantly impair T cell immunity, including depleting antibodies and calcineurin inhibitors, increase the risk of PTLD after transplantation. Swine PTLD has been shown to closely resemble human PTLD in morphology, histology, and viral-driven reactivation of B cells. Previously, we reported high incidences of PTLD after hematopoietic cell transplantation (HCT) in miniature swine recipients conditioned with thymic irradiation (TI) in addition to T cell depletion and cyclosporine A monotherapy after transplantation. Replacement of TI with 100 cGy of total body irradiation resulted in similar numbers of B cells early post-transplantation, greater numbers of T cells at day 0, and markedly decreased incidence of PTLD, suggesting that a threshold number of T cells may be necessary to prevent subsequent B cell proliferation and development of overt PTLD. Results from this large cohort of animals provide insight into the important effect of irradiation and T cell immunity on the incidence of PTLD after HCT and reinforce the pig model as a valuable tool for the study of PTLD and HCT. (C) 2015 American Society for Blood and Marrow Transplantation. C1 [Matar, Abraham J.; Patil, Aarti R.; Al-Musa, Ahmad; Hanekamp, Isabel; Sachs, David H.; Huang, Christene A.; Duran-Struuck, Raimon] Massachusetts Gen Hosp, Dept Surg, Transplantat Biol Res Ctr, Boston, MA 02114 USA. [Matar, Abraham J.] Univ Cent Florida, Coll Med, Orlando, FL 32816 USA. [Duran-Struuck, Raimon] Columbia Univ, Columbia Ctr Translat Immunol, New York, NY USA. RP Duran-Struuck, R (reprint author), Univ Penn, Dept Pathobiol, 3800 Spruce St, Philadelphia, PA 19104 USA. EM rduranst@gmail.com OI Al-musa, Ahmad/0000-0002-4192-0140; Hanekamp, Isabel/0000-0002-6218-3979 FU National Cancer Institute [P01CA111519]; National Institute of Allergy and Infectious Disease of the National Institutes of Health [R01A184657]; NCRR [1K01RR024466] FX Financial disclosure: Supported in part by grants from the National Cancer Institute (P01CA111519; D.H.S.) and the National Institute of Allergy and Infectious Disease (R01A184657; C.A.H.) of the National Institutes of Health. Also supported by NCRR (1K01RR024466; R.D.-S.). We acknowledge C06RR020135-01 for construction of the facility used for production and maintenance of miniature swine and Novartis for the generous gift of cyclosporine A. NR 20 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 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD OCT PY 2015 VL 21 IS 10 BP 1732 EP 1738 DI 10.1016/j.bbmt.2015.07.017 PG 7 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CS0VU UT WOS:000361781100007 PM 26210443 ER PT J AU Urbano-Ispizua, A Pavletic, SZ Flowers, ME Klein, JP Zhang, MJ Carreras, J Montoto, S Perales, MA Aljurf, MD Akpek, G Bredeson, CN Costa, LJ Dandoy, C Freytes, CO Fung, HC Gale, RP Gibson, J Hamadani, M Hayashi, RJ Inamoto, Y Inwards, DJ Lazarus, HM Maloney, DG Martino, R Munker, R Nishihori, T Olsson, RF Rizzieri, DA Reshef, R Saad, A Savani, BN Schouten, HC Smith, SM Socie, G Wirk, B Yu, LC Saber, W AF Urbano-Ispizua, Alvaro Pavletic, Steven Z. Flowers, Mary E. Klein, John P. Zhang, Mei-Jie Carreras, Jeanette Montoto, Silvia Perales, Miguel-Angel Aljurf, Mahmoud D. Akpek, Goerguen Bredeson, Christopher N. Costa, Luciano J. Dandoy, Christopher Freytes, Cesar O. Fung, Henry C. Gale, Robert Peter Gibson, John Hamadani, Mehdi Hayashi, Robert J. Inamoto, Yoshihiro Inwards, David J. Lazarus, Hillard M. Maloney, David G. Martino, Rodrigo Munker, Reinhold Nishihori, Taiga Olsson, Richard F. Rizzieri, David A. Reshef, Ran Saad, Ayman Savani, Bipin N. Schouten, Harry C. Smith, Sonali M. Socie, Gerard Wirk, Baldeep Yu, Lolie C. Saber, Wael TI The Impact of Graft-versus-Host Disease on the Relapse Rate in Patients with Lymphoma Depends on the Histological Subtype and the Intensity of the Conditioning Regimen SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Graft-versus-host disease; Lymphoma ID STEM-CELL TRANSPLANTATION; BONE-MARROW TRANSPLANT; NON-HODGKIN-LYMPHOMA; ALLOGENEIC TRANSPLANTATION; FOLLICULAR LYMPHOMA; AUTOLOGOUS TRANSPLANTATION; EUROPEAN GROUP; BLOOD; INFUSIONS; REMISSIONS AB The purpose of this study was to analyze the impact of graft-versus-host disease (GVHD) on the relapse rate of different lymphoma subtypes after allogeneic hematopoietic cell transplantation (allo-HCT). Adult patients with a diagnosis of Hodgkin lymphoma, diffuse large B cell lymphoma, follicular lymphoma (FL), peripheral T cell lymphoma, or mantle cell lymphoma (MCL) undergoing HLA-identical sibling or unrelated donor hematopoietic cell transplantation between 1997 and 2009 were included. Two thousand six hundred eleven cases were included. A reduced-intensity conditioning (RIC) regimen was used in 62.8% of the transplantations. In a multivariate analysis of myeloablative cases (n = 970), neither acute (aGVHD) nor chronic GVHD (cGVHD) were significantly associated with a lower incidence of relapse/progression in any lymphoma subtype. In contrast, the analysis of RIC cases (n = 1641) showed that cGVHD was associated with a lower incidence of relapse/progression in FL (risk ratio [RR],.51; P = 3.049) and in MCL (RR,.41; P = .019). Patients with FL or MCL developing both aGVHD and cGVHD had the lowest risk of relapse (RR,.14; P = .007; and RR,.15; P = .0019, respectively). Of interest, the effect of GVHD on decreasing relapse was similar in patients with sensitive disease and chemoresistant disease. Unfortunately, both aGVHD and cGVHD had a deleterious effect on treatment-related mortality and overall survival (OS) in FL cases but did not affect treatment-related mortality, OS or PFS in MCL. This study reinforces the use of RIC allo-HCT as a platform for immunotherapy in FL and MCL patients. (C) 2015 American Society for Blood and Marrow Transplantation. C1 [Urbano-Ispizua, Alvaro] Univ Barcelona, Hosp Clin, IDIBAPS, Dept Hematol, Barcelona, Spain. [Urbano-Ispizua, Alvaro] Inst Res Josep Carreras, Barcelona, Spain. [Pavletic, Steven Z.] NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Flowers, Mary E.; Inamoto, Yoshihiro; Maloney, David G.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. [Klein, John P.; Zhang, Mei-Jie; Carreras, Jeanette; Hamadani, Mehdi; Saber, Wael] Med Coll Wisconsin, Dept Med, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Klein, John P.; Zhang, Mei-Jie] Med Coll Wisconsin, Inst Hlth & Soc, Div Biostat, Milwaukee, WI 53226 USA. [Montoto, Silvia] Barts Hlth NHS Trust, St Bartholomews Hosp, Dept Haematooncol, London, England. [Perales, Miguel-Angel] Mem Sloan Kettering Canc Ctr, Dept Med, Bone Marrow Transplant Serv, New York, NY 10021 USA. [Aljurf, Mahmoud D.] King Faisal Specialist Hosp Ctr & Res, Dept Oncol, Riyadh, Saudi Arabia. [Akpek, Goerguen] Banner MD Anderson Canc Ctr, Hematol Oncol Sect, Gilbert, AZ USA. [Bredeson, Christopher N.] Ottawa Hosp, Blood & Marrow Transplant Program, Ottawa, ON, Canada. [Bredeson, Christopher N.] Ottawa Hosp, Res Inst, Ottawa, ON, Canada. [Costa, Luciano J.; Saad, Ayman] Univ Alabama Birmingham, Dept Med, Div Hematol Oncol, Birmingham, AL 35294 USA. [Dandoy, Christopher] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Freytes, Cesar O.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. [Freytes, Cesar O.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Fung, Henry C.] Temple Hlth, Fox Chase Canc Ctr, Dept Med Oncol, Philadelphia, PA USA. [Gale, Robert Peter] Univ London Imperial Coll Sci Technol & Med, Dept Med, Div Expt Med, Hematol Res Ctr, London, England. [Gibson, John] Royal Prince Alfred Hosp, Inst Haematol, Camperdown, NSW 2050, Australia. [Hayashi, Robert J.] Washington Univ, Sch Med, Dept Pediat, Div Pediat Hematol Oncol, St Louis, MO 63110 USA. [Inwards, David J.] Mayo Clin, Div Hematol, Rochester, MN USA. [Lazarus, Hillard M.] Univ Hosp Case Med Ctr, Seidman Canc Ctr, Cleveland, OH USA. [Martino, Rodrigo] Hosp Santa Creu & Sant Pau, Div Hematol, Barcelona, Spain. [Munker, Reinhold] Louisiana State Univ Hlth, Dept Internal Med, Div Hematol Oncol, Shreveport, LA USA. [Nishihori, Taiga] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Med Oncol, Tampa, FL 33612 USA. [Olsson, Richard F.] Karolinska Inst, Dept Lab Med, Div Therapeut Immunol, Stockholm, Sweden. [Olsson, Richard F.] Uppsala Univ, Ctr Clin Res Sormland, Uppsala, Sweden. [Rizzieri, David A.] Duke Univ, Div Hematol Malignancies & Cellular Therapy, Durham, NC USA. [Reshef, Ran] Univ Penn, Dept Med, Abramson Canc Ctr, Med Ctr, Philadelphia, PA 19104 USA. [Savani, Bipin N.] Vanderbilt Univ, Med Ctr, Dept Med, Div Hematol Oncol, Nashville, TN USA. [Schouten, Harry C.] Acad Ziekenhuis, Dept Hematol, Maastricht, Netherlands. [Smith, Sonali M.] Univ Chicago, Hematol Oncol Sect, Chicago, IL 60637 USA. [Socie, Gerard] Hop St Louis, Dept Hematol, Paris, France. [Wirk, Baldeep] SUNY Stony Brook, Med Ctr, Dept Internal Med, Stony Brook, NY 11794 USA. [Yu, Lolie C.] Louisiana State Univ, Med Ctr, Childrens Hosp, Div Hematol Oncol,Ctr Canc & Blood Disorders, New Orleans, LA USA. RP Urbano-Ispizua, A (reprint author), Hosp Clin Barcelona, Dept Hematol, Villarroel 170, E-08036 Barcelona, Spain. EM aurbano@clinic.ub.es OI Saad, Ayman /0000-0003-0003-0130 FU National Cancer Institute [U24-CA076518]; National Heart, Lung, and Blood Institute [5U10HL069294]; National Institute of Allergy and Infectious Diseases; Health Resources and Services Administration [HHSH250201200016C]; Office of Naval Research [N00014-12-1-0142, N00014-13-1-0039]; Actinium Pharmaceuticals; Allos Therapeutics, Inc.; Amgen FX The CIBMTR is supported by Public Health Service grant/cooperative agreement U24-CA076518 from the National Cancer Institute, the National Heart, Lung, and Blood Institute, and the National Institute of Allergy and Infectious Diseases; grant/cooperative agreement 5U10HL069294 from the National Heart, Lung, and Blood Institute and National Cancer Institute; contract HHSH250201200016C with Health Resources and Services Administration; 2 grants from the Office of Naval Research (N00014-12-1-0142 and N00014-13-1-0039); and grants from *Actinium Pharmaceuticals; Allos Therapeutics, Inc.; *Amgen; an anonymous donation to the Medical College of Wisconsin; Ariad; Be The Match Foundation; *Blue Cross and Blue Shield Association; *Celgene Corporation; Chimerix, Inc.; Fred Hutchinson Cancer Research Center; Fresenius-Biotech North America, Inc.; *Gamida Cell Teva Joint Venture Ltd.; Genentech, Inc.; *Gentium SpA; Genzyme Corporation; GlaxoSmithKline; Health Research, Inc.; Roswell Park Cancer Institute; Histo-Genetics; Incyte Corporation; Jeff Gordon Children's Foundation; Kiadis Pharma; The Leukemia & Lymphoma Society; Medac GmbH; The Medical College of Wisconsin; Merck & Co., Inc.; Millennium: The Takeda Oncology Co.; *Milliman USA, Inc.; *Miltenyi Biotec; National Marrow Donor Program; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Osiris Therapeutics; Otsuka America Pharmaceutical, Inc.; Perkin Elmer, Inc.; *Remedy Informatics; 'Sanofi US; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; St. Baldrick's Foundation; StemCyte, A Global Cord Blood Therapeutics Co.; Stemsoft Software, Inc.; Swedish Orphan Biovitrum; *Tarix Pharmaceuticals; *Terumo BCT; *Teva Neuroscience, Inc.; *Therakos; University of Minnesota; University of Utah; and *WellPoint. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, Health Resources and Services Administration, or any other agency of the US Government. NR 27 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 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD OCT PY 2015 VL 21 IS 10 BP 1746 EP 1753 DI 10.1016/j.bbmt.2015.05.010 PG 8 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CS0VU UT WOS:000361781100009 PM 25981509 ER PT J AU Inamoto, Y Flowers, MED Wang, T Urbano-Ispizua, A Hemmer, MT Cutler, CS Couriel, DR Alousi, AM Antin, JH Gale, RP Gupta, V Hamilton, BK Kharfan-Dabaja, MA Marks, DI Ringden, OTH Socie, G Solh, MM Akpek, G Cairo, MS Chao, NJ Hayashi, RJ Nishihori, T Reshef, R Saad, A Shah, A Teshima, T Tallman, MS Wirk, B Spellman, SR Arora, M Martin, PJ AF Inamoto, Yoshihiro Flowers, Mary E. D. Wang, Tao Urbano-Ispizua, Alvaro Hemmer, Michael T. Cutler, Corey S. Couriel, Daniel R. Alousi, Amin M. Antin, Joseph H. Gale, Robert Peter Gupta, Vikas Hamilton, Betty K. Kharfan-Dabaja, Mohamed A. Marks, David I. Ringden, Olle T. H. Socie, Gerard Solh, Melhem M. Akpek, Goerguen Cairo, Mitchell S. Chao, Nelson J. Hayashi, Robert J. Nishihori, Taiga Reshef, Ran Saad, Ayman Shah, Ami Teshima, Takanori Tallman, Martin S. Wirk, Baldeep Spellman, Stephen R. Arora, Mukta Martin, Paul J. TI Tacrolimus versus Cyclosporine after Hematopoietic Cell Transplantation for Acquired Aplastic Anemia SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Aplastic anemia; Hematopoietic cell transplantation; Graft-versus-host disease; Immunosuppression; Cyclosporine; Tacrolimus ID BONE-MARROW-TRANSPLANTATION; VERSUS-HOST-DISEASE; UNRELATED DONOR TRANSPLANTATION; PERIPHERAL-BLOOD; COMPARING METHOTREXATE; SIBLING DONORS; ACUTE GVHD; PHASE-III; GRAFT; PROPHYLAXIS AB Combinations of cyclosporine (CSP) with methotrexate (MTX) have been widely used for immunosuppression after allogeneic transplantation for acquired aplastic anemia. We compared outcomes with tacrolimus (TAC)+MTX versus CSP+MTX after transplantation from HLA-identical siblings (SIB) or unrelated donors (URD) in a retrospective cohort of 949 patients with severe aplastic anemia. Study endpoints included hematopoietic recovery, graft failure, acute graft-versus-host disease (GVHD), chronic GVHD, and mortality. TAC+MTX was used more frequently in older patients and, in recent years, in both SIB and URD groups. In multivariate analysis, TAC+MTX was associated with a lower risk of mortality in URD recipients and with slightly earlier absolute neutrophil count recovery in SIB recipients. Other outcomes did not differ statistically between the 2 regimens. No firm conclusions were reached regarding the relative merits of TAC+MTX versus CSP+MTX after hematopoietic cell transplantation for acquired aplastic anemia, Prospective studies would be needed to determine whether the use of TAC+MTX is associated with lower risk of mortality in URD recipients with acquired aplastic anemia. (C) 2015 American Society for Blood and Marrow Transplantation. C1 [Inamoto, Yoshihiro] Natl Canc Ctr, Div Hematopoiet Stem Cell Transplantat, Tokyo 1040045, Japan. [Flowers, Mary E. D.; Martin, Paul J.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. [Wang, Tao; Hemmer, Michael T.] Med Coll Wisconsin, Dept Med, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Wang, Tao] Med Coll Wisconsin, Div Biostat, Inst Hlth & Soc, Milwaukee, WI 53226 USA. [Urbano-Ispizua, Alvaro] Univ Barcelona, Dept Hematol, Hosp Clin, IDIBAPS, Barcelona, Spain. [Urbano-Ispizua, Alvaro] Inst Res Josep Carreras, Barcelona, Spain. [Cutler, Corey S.; Antin, Joseph H.] Dana Farber Canc Inst, Dept Med Oncol, Ctr Hematol Oncol, Boston, MA 02115 USA. [Couriel, Daniel R.] Univ Michigan, Dept Med, Ann Arbor, MI 48109 USA. [Alousi, Amin M.] Univ Texas MD Anderson Canc Ctr, Dept Stem Cell Transplantat, Div Canc Med, Houston, TX 77030 USA. [Gale, Robert Peter] Univ London Imperial Coll Sci Technol & Med, Hematol Res Ctr, Dept Med, Div Expt Med, London, England. [Gupta, Vikas] Univ Hlth Network, Princess Margaret Canc Ctr, Blood & Marrow Transplant Program, Toronto, ON, Canada. [Hamilton, Betty K.] Cleveland Clin, Taussig Canc Inst, Blood & Marrow Transplant Program, Cleveland, OH 44106 USA. [Kharfan-Dabaja, Mohamed A.; Nishihori, Taiga] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Blood & Marrow Transplantat, Tampa, FL 33612 USA. [Marks, David I.] Univ Hosp Bristol NHS Trust, Pediat Bone Marrow Transplant, Bristol, Avon, England. [Ringden, Olle T. H.] Karolinska Inst, Dept Lab Med, Div Therapeut Immunol, Stockholm, Sweden. [Ringden, Olle T. H.] Ctr Allogene Stem Cell Transplantat, Stockholm, Sweden. [Socie, Gerard] Hosp St Louis, Dept Hematol, Paris, France. [Solh, Melhem M.] Florida Hosp, Med Grp, Blood & Marrow Transplant Ctr, Orlando, FL USA. [Akpek, Goerguen] Banner MD Anderson Canc Ctr, Stem Cell Transplantat & Cellular Therapy Program, Gilbert, AZ USA. [Cairo, Mitchell S.] New York Med Coll, Dept Pediat, Valhalla, NY 10595 USA. [Chao, Nelson J.] Duke Univ, Med Ctr, Dept Med, Div Cell Therapy & Hematol, Durham, NC 27710 USA. [Hayashi, Robert J.] Washington Univ, Dept Pediat, Sch Med St Louis, Div Pediat Hematol Oncol, St Louis, MO 63130 USA. [Reshef, Ran] Univ Penn, Med Ctr, Abramson Canc Ctr, Dept Med, Philadelphia, PA 19104 USA. [Saad, Ayman] Univ Alabama Birmingham, Dept Med, Div Hematol Oncol, Birmingham, AL 35294 USA. [Shah, Ami] Univ Calif Los Angeles, Dept Pediat, Mattel Childrens Hosp, Div Hematol Oncol, Los Angeles, CA 90024 USA. [Teshima, Takanori] Hokkaido Univ, Grad Sch Med, Dept Hematol, Sapporo, Hokkaido, Japan. [Tallman, Martin S.] Mem Sloan Kettering Canc Ctr, Dept Med, Leukemia Serv, New York, NY 10021 USA. [Wirk, Baldeep] Seattle Canc Care Alliance, Div Bone Marrow Transplant, Seattle, WA USA. [Spellman, Stephen R.] Ctr Int Blood & Marrow Transplant Res, Natl Marrow Donor Program, Be Match, Minneapolis, MN USA. [Arora, Mukta] Univ Minnesota, Med Ctr, Dept Med, Div Hematol,Oncol,Transplantat, Minneapolis, MN 55455 USA. RP Inamoto, Y (reprint author), Natl Canc Ctr, Chuo Ku, 5-1-1 Tsukiji, Tokyo 1040045, Japan. EM yinamoto@ncc.go.jp OI Saad, Ayman /0000-0003-0003-0130 FU National Cancer Institute [U24-CA076518]; National Heart, Lung, and Blood Institute; National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute [5U10HL069294]; Health Resources and Services Administration (HRSA/DHHS) [HHSH250201200016C]; Office of Naval Research [N00014-13-1-0039, N00014-14-1-0028]; Actinium Pharmaceuticals; Allos Therapeutics, Inc.; Amgen FX The CIBMTR is supported by Public Health Service grant/cooperative agreement U24-CA076518 from the National Cancer Institute, the National Heart, Lung, and Blood Institute, and the National Institute of Allergy and Infectious Diseases; a grant/cooperative agreement 5U10HL069294 from National Heart, Lung, and Blood Institute and National Cancer Institute; a contract HHSH250201200016C with Health Resources and Services Administration (HRSA/DHHS); 2 grants N00014-13-1-0039 and N00014-14-1-0028 from the Office of Naval Research; and grants from *Actinium Pharmaceuticals; Allos Therapeutics, Inc.; *Amgen; an anonymous donation to the Medical College of Wisconsin; Ariad; Be The Match Foundation; *Blue Cross and Blue Shield Association; *Celgene Corporation; Chimerix, Inc.; Fred Hutchinson Cancer Research Center; Fresenius-Biotech North America, Inc.; *Gamida Cell Teva Joint Venture Ltd.; Genentech, Inc.; *Gentium SpA; Genzyme Corporation; GlaxoSmithKline; Health Research, Inc.; Roswell Park Cancer Institute; HistoGenetics; Incyte Corporation; Jeff Gordon Children's Foundation; Kiadis Pharma; The Leukemia & Lymphoma Society; Medac GmbH; The Medical College of Wisconsin; Merck & Co., Inc.; Millennium: The Takeda Oncology Co.; *Milliman USA, Inc.; *Miltenyi Biotec; National Marrow Donor Program; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Osiris Therapeutics; Otsuka America Pharmaceutical, Inc.; Perkin Elmer, Inc.; *Remedy Informatics; *Sanofi US; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; St. Baldrick's Foundation; StemCyte, A Global Cord Blood Therapeutics Co.; Stemsoft Software, Inc.; Swedish Orphan Biovitrum; *Tarix Pharmaceuticals; *Terumo BCT; *Teva Neuroscience, Inc.; *Therakos; University of Minnesota; University of Utah; and *WellPoint The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, Health Resources and Services Administration or any other agency of the US Government. NR 25 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD OCT PY 2015 VL 21 IS 10 BP 1776 EP 1782 DI 10.1016/j.bbmt.2015.05.023 PG 7 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CS0VU UT WOS:000361781100013 PM 26033280 ER PT J AU Verneris, MR Lee, SJ Ahn, KW Wang, HL Battiwalla, M Inamoto, Y Fernandez-Vina, MA Gajewski, J Pidala, J Munker, R Aljurf, M Saber, W Spellman, S Koreth, J AF Verneris, Michael R. Lee, Stephanie J. Ahn, Kwang Woo Wang, Hai-Lin Battiwalla, Minoo Inamoto, Yoshihiro Fernandez-Vina, Marcelo A. Gajewski, James Pidala, Joseph Munker, Reinhold Aljurf, Mahmoud Saber, Wael Spellman, Stephen Koreth, John TI HLA Mismatch Is Associated with Worse Outcomes after Unrelated Donor Reduced-Intensity Conditioning Hematopoietic Cell Transplantation: An Analysis from the Center for International Blood and Marrow Transplant Research SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Bone marrow transplantation; Leukemia; Hematologic malignancies; Pediatric oncology ID CLASS-I; CLINICAL-SIGNIFICANCE; HLA-DPB1; GRAFT; SURVIVAL; RECIPIENTS; LEUKEMIA; REGISTRY; IMPACT AB Over the past 2 decades, reduced-intensity conditioning allogeneic hematopoietic cell transplantation (RIC HCT) has increased substantially. Many patients do not have fully HLA-matched donors, and the impact of HLA mismatch on RIC HCT has not been examined in large cohorts. We analyzed 2588 recipients of 8/8 HLA-high resolution matched (n = 2025) or single-locus mismatched (n = 563) unrelated donor (URD) RIC HCT from 1999 to 2011. Overall survival (OS) was the primary outcome. Secondary endpoints included treatment-related mortality (TRM), relapse, disease-free survival (DFS), and acute/chronic graft-versus-host disease (GVHD). Adjusted 1- and 3-year OS was better in 8/8- versus 7/8-matched recipients (54.7% versus 48.8%, P = .01, and 37.4% versus 30.9%, P = .005, respectively). In multivariate models 7/8 URD RIC HCT recipients had more grades II to IV acute GVHD (RR = 1.29, P = .0034), higher TRM (RR = 1.52, P < .0001), and lower DFS (RR = 1.12, P = .0015) and OS (RR = 1.25, P = .0001), with no difference in relapse or chronic GVHD. In subgroup analysis, inferior transplant outcomes were noted regardless of the HLA allele mismatched. Previously reported permissive mismatches at HLA-C (C*03:03/C*03:04) and HLA-DPI (based on T cell epitope matching) were not associated with better outcomes. Although feasible, single-locus mismatch in RIC URD HCT is associated with inferior outcomes. (C) 2015 American Society for Blood and Marrow Transplantation. C1 [Verneris, Michael R.] Univ Minnesota, Dept Pediat BMT, Minneapolis, MN 55455 USA. [Lee, Stephanie J.; Inamoto, Yoshihiro] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. [Ahn, Kwang Woo] Med Coll Wisconsin, Div Biostat, Milwaukee, WI 53226 USA. [Wang, Hai-Lin; Saber, Wael] Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Battiwalla, Minoo] NHLBI, Hematol Branch, Bethesda, MD 20892 USA. [Fernandez-Vina, Marcelo A.] Stanford Univ, Dept Pathol, Palo Alto, CA 94304 USA. [Gajewski, James] Oregon Hlth & Sci Univ, Dept Hematol, Portland, OR 97201 USA. [Pidala, Joseph] Univ S Florida, Dept Blood & Marrow Transplantat, Tampa, FL USA. [Munker, Reinhold] Louisiana State Univ, Hlth Sci Ctr, Dept Hematol Oncol, Shreveport, LA 71105 USA. [Aljurf, Mahmoud] King Faisal Specialist Hosp & Res Ctr, Pediat HSCT, Adult HSCT, Riyadh 11211, Saudi Arabia. [Spellman, Stephen] Ctr Int Blood & Marrow Transplant Res, Minneapolis, MN USA. [Koreth, John] Dana Farber Canc Inst, Dept Hematol Oncol, Boston, MA 02115 USA. RP Verneris, MR (reprint author), Univ Minnesota, Dept Pediat BMT, 425 E River Rd,CCRB 654, Minneapolis, MN 55455 USA. EM verneris@umn.edu OI Verneris, Michael/0000-0002-7097-5917 FU NCI NIH HHS [U24 CA076518]; NHLBI NIH HHS [U01 HL069294] NR 26 TC 10 Z9 11 U1 4 U2 5 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 OCT PY 2015 VL 21 IS 10 BP 1783 EP 1789 DI 10.1016/j.bbmt.2015.05.028 PG 7 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CS0VU UT WOS:000361781100014 PM 26055300 ER PT J AU Khera, N Majhail, NS Brazauskas, R Wang, ZW He, NY Aljurf, MD Akpek, G Atsuta, Y Beattie, S Bredeson, CN Burns, LJ Dalal, JD Freytes, CO Gupta, V Inamoto, Y Lazarus, HM LeMaistre, CF Steinberg, A Szwajcer, D Wingard, JR Wirk, B Wood, WA Joffe, S Hahn, TE Loberiza, FR Anasetti, C Horowitz, MM Lee, SJ AF Khera, Nandita Majhail, Navneet S. Brazauskas, Ruta Wang, Zhiwei He, Naya Aljurf, Mahmoud D. Akpek, Goerguen Atsuta, Yoshiko Beattie, Sara Bredeson, Christopher N. Burns, Linda J. Dalal, Jignesh D. Freytes, Cesar O. Gupta, Vikas Inamoto, Yoshihiro Lazarus, Hillard M. LeMaistre, Charles F. Steinberg, Amir Szwajcer, David Wingard, John R. Wirk, Baldeep Wood, William A. Joffe, Steven Hahn, Theresa E. Loberiza, Fausto R. Anasetti, Claudio Horowitz, Mary M. Lee, Stephanie J. TI Comparison of Characteristics and Outcomes of Trial Participants and Nonparticipants: Example of Blood and Marrow Transplant Clinical Trials Network 0201 Trial SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Trial participation; Hematopoietic cell transplantation ID VERSUS-HOST-DISEASE; UNRELATED DONORS; MYOCARDIAL-INFARCTION; EXTERNAL VALIDITY; IMPROVED SURVIVAL; CANCER; POPULATION; GENERALIZABILITY; LEUKEMIA; REGISTRY AB Controversy surrounds the question of whether clinical trial participants have better outcomes than comparable patients who are not treated on a trial. We explored this question using a recent large, randomized, multicenter study comparing peripheral blood (PB) with bone marrow transplantation from unrelated donors, conducted by the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). We compared characteristics and outcomes of study participants (n = 494) and nonparticipants (n = 1384) who appeared eligible and received similar treatment without enrolling on the BMT CTN trial at participating centers during the study time period. Data were obtained from the Center for International Blood and Marrow Transplant Research. Outcomes were compared between the 2 groups using Cox proportional hazards regression models. No significant differences in age, sex, disease distribution, race/ethnicity, HLA matching, comorbidities, and interval from diagnosis to hematopoietic cell transplantation were seen between the participants and non-participants. Nonparticipants were more likely to have lower performance status, lower risk disease, and older donors, and to receive myeloablative conditioning and antithymocyte globulin. Nonparticipants were also more likely to receive PB grafts, the intervention tested in the trial (66% versus 50%, P < .001). Overall survival, transplantation-related mortality, and incidences of acute or chronic graft-versus-host disease were comparable between the 2 groups though relapse was higher (hazard ratio, 1.22; 95% confidence interval, 1.02 to 1.46; P = .028) in nonparticipants. Despite differences in certain baseline characteristics, survival was comparable between study participants and nonparticipants. The results of the BMT CTN trial appear generalizable to the population of trial-eligible patients. (C) 2015 American Society for Blood and Marrow Transplantation. C1 [Khera, Nandita] Mayo Clin, Dept Hematol Oncol, Phoenix, AZ 85054 USA. [Majhail, Navneet S.] Cleveland Clin, Taussig Canc Inst, Blood & Marrow Transplant Program, Cleveland, OH 44106 USA. [Brazauskas, Ruta; Wang, Zhiwei; He, Naya; Horowitz, Mary M.] Med Coll Wisconsin, Dept Med, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Brazauskas, Ruta] Med Coll Wisconsin, Inst Hlth & Soc, Div Biostat, Milwaukee, WI 53226 USA. [Aljurf, Mahmoud D.] King Faisal Specialist Hosp Ctr & Res, Dept Oncol, Riyadh, Saudi Arabia. [Akpek, Goerguen] Banner MD Anderson Canc Ctr, Hematol Oncol Sect, Gilbert, AZ USA. [Atsuta, Yoshiko] Japanese Data Ctr Hematopoiet Cell Transplantat, Nagoya, Aichi, Japan. [Atsuta, Yoshiko] Nagoya Univ, Grad Sch Med, Nagoya, Aichi 4648601, Japan. [Beattie, Sara] Univ Ottawa, Sch Psychol, Ottawa, ON K1N 6N5, Canada. [Bredeson, Christopher N.] Ottawa Hosp, Blood & Marrow Transplant Program, Ottawa, ON, Canada. [Bredeson, Christopher N.] Ottawa Hosp, Res Inst, Ottawa, ON, Canada. [Burns, Linda J.] Be Match, Natl Marrow Donor Program, Hlth Serv Res, Minneapolis, MN USA. [Dalal, Jignesh D.] Childrens Mercy Hosp & Clin, Bone Marrow Transplantat, Pediat Hematol Oncol, Kansas City, MO USA. [Freytes, Cesar O.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. [Freytes, Cesar O.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Gupta, Vikas] Univ Hlth Network, Blood & Marrow Transplant Program, Princess Margaret Canc Ctr, Toronto, ON, Canada. [Inamoto, Yoshihiro] Natl Canc Ctr, Div Hematopoiet Stem Cell Transplantat, Tokyo, Japan. [Lazarus, Hillard M.] Univ Hosp Cleveland, Case Med Ctr, Seidman Canc Ctr, Cleveland, OH 44106 USA. [LeMaistre, Charles F.] Sarah Cannon, Hematol & Bone Marrow Transplant, Nashville, TN USA. [Steinberg, Amir] Mt Sinai Hosp, Dept Hematol Oncol, New York, NY 10029 USA. [Szwajcer, David] Univ Manitoba, Dept Hematol, CancerCare Manitoba, Winnipeg, MB, Canada. [Wingard, John R.] Univ Florida, Div Hematol & Oncol, Dept Med, Gainesville, FL USA. [Wirk, Baldeep] SUNY Stony Brook, Dept Internal Med, Stony Brook, NY 11794 USA. [Wood, William A.] Univ N Carolina, Dept Med, Div Hematol Oncol, Chapel Hill, NC USA. [Joffe, Steven] Univ Penn, Perelman Sch Med, Dept Med Eth & Hlth Policy, Philadelphia, PA 19104 USA. [Hahn, Theresa E.] Roswell Pk Canc Inst, Dept Med, Buffalo, NY 14263 USA. [Loberiza, Fausto R.] Nebraska Med Ctr, Dept Internal Med, Omaha, NE USA. [Anasetti, Claudio] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Bone Marrow Transplant Program, Tampa, FL 33612 USA. [Lee, Stephanie J.] Fred Hutchinson Canc Res Ctr, Clin Transplant Res, Seattle, WA 98104 USA. RP Khera, N (reprint author), Mayo Clin, Coll Med, Med, 5777 E Mayo Blvd, Phoenix, AZ 85054 USA. EM khera.nandita@mayo.edu OI Joffe, Steven/0000-0002-0667-7384 FU NCI [U24-CA076518]; NHLBI; National Institute of Allergy and Infectious Diseases; NHLBI [5U10HL069294]; NCI; Health Resources and Services Administration (HRSA/DHHS) [HHSH250201200016C]; Office of Naval Research [N00014-12-1-0142, N00014-13-1-0039]; Actinium Pharmaceuticals; Allos Therapeutics, Inc.; Amgen FX The CIBMTR is supported by Public Health Service grant/cooperative agreement U24-CA076518 from the NCI, the NHLBI, and the National Institute of Allergy and Infectious Diseases; a grant/cooperative agreement 5U10HL069294 from NHLBI and NCI; a contract HHSH250201200016C with Health Resources and Services Administration (HRSA/DHHS); 2 Grants N00014-12-1-0142 and N00014-13-1-0039 from the Office of Naval Research; and grants from *Actinium Pharmaceuticals; Allos Therapeutics, Inc.; *Amgen; anonymous donation to the Medical College of Wisconsin; Ariad; Be The Match Foundation; *Blue Cross and Blue Shield Association; *Celgene Corporation; Chimerix, Inc.; Fred Hutchinson Cancer Research Center; Fresenius-Biotech North America, Inc.; *Gamida Cell Teva Joint Venture Ltd.; Genentech, Inc.; *Gentium SpA; Genzyme Corporation; GlaxoSmithKline; Health Research, Inc.; Roswell Park Cancer Institute; HistoGenetics; Incyte Corporation; Jeff Gordon Children's Foundation; Kiadis Pharma; The Leukemia & Lymphoma Society; Medac GmbH; The Medical College of Wisconsin; Merck & Co., Inc.; Millennium: The Takeda Oncology Co.; *Milliman USA, Inc.; *Miltenyi Biotec; National Marrow Donor Program; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Osiris Therapeutics; Otsuka America Pharmaceutical, Inc.; Perkin Elmer, Inc.; *Remedy Informatics; *Sanofi US; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; St. Baldrick's Foundation; StemCyte, A Global Cord Blood Therapeutics Co.; Stemsoft Software, Inc.; Swedish Orphan Biovitrum; *Tarix Pharmaceuticals; *Terumo BCT; *Teva Neuroscience, Inc.; *Therakos; University of Minnesota; University of Utah; and *WellPoint. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, Health Resources and Services Administration or any other agency of the US Government. NR 24 TC 2 Z9 2 U1 0 U2 7 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 OCT PY 2015 VL 21 IS 10 BP 1815 EP 1822 DI 10.1016/j.bbmt.2015.06.004 PG 8 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CS0VU UT WOS:000361781100019 PM 26071866 ER PT J AU Ustun, C Stone, R Weisdorf, D AF Ustun, Celalettin Stone, Richard Weisdorf, Daniel TI New Models of Therapy: When Acute Leukemia Becomes Chronic SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Letter ID ACUTE MYELOID-LEUKEMIA; STEM-CELL TRANSPLANTATION; ACUTE LYMPHOBLASTIC-LEUKEMIA; INTERNAL TANDEM DUPLICATION; MOLECULAR REMISSION; SORAFENIB; CHEMOTHERAPY; IMATINIB; DASATINIB; TRIAL C1 [Ustun, Celalettin] Univ Minnesota, Dept Med, Div Hematol Oncol & Transplantat, Minneapolis, MN 55455 USA. [Stone, Richard; Weisdorf, Daniel] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Ustun, C (reprint author), Univ Minnesota, Dept Med, Div Hematol Oncol & Transplantat, 14-142 PWB,516 Delaware St SE, Minneapolis, MN 55455 USA. EM custun@umn.edu NR 16 TC 0 Z9 0 U1 0 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 OCT PY 2015 VL 21 IS 10 BP 1856 EP 1857 DI 10.1016/j.bbmt.2015.07.011 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA CS0VU UT WOS:000361781100024 PM 26183079 ER PT J AU Hofer, AM AF Hofer, Aldebaran M. TI Ca2+ signaling at membrane contact sites SO CELL CALCIUM LA English DT Editorial Material C1 [Hofer, Aldebaran M.] Harvard Univ, Sch Med, Boston, MA 02132 USA. [Hofer, Aldebaran M.] VA Boston Healthcare Syst, Boston, MA 02132 USA. RP Hofer, AM (reprint author), Harvard Univ, Sch Med, Boston, MA 02132 USA. EM Aldebaran_Hofer@hms.harvard.edu NR 10 TC 0 Z9 0 U1 3 U2 11 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0143-4160 EI 1532-1991 J9 CELL CALCIUM JI Cell Calcium PD OCT PY 2015 VL 58 IS 4 SI SI BP 331 EP 332 DI 10.1016/j.ceca.2015.07.002 PG 2 WC Cell Biology SC Cell Biology GA CS1TD UT WOS:000361849700001 PM 26248790 ER PT J AU Chhatwal, J Chen, QS Kanwal, F AF Chhatwal, Jagpreet Chen, Qiushi Kanwal, Fasiha TI Why We Should Be Willing to Pay for Hepatitis C Treatment SO CLINICAL GASTROENTEROLOGY AND HEPATOLOGY LA English DT Editorial Material ID GENOTYPE 1 INFECTION; COST-EFFECTIVENESS; UNITED-STATES; VIRUS; REGIMENS; BOCEPREVIR; SOFOSBUVIR; THERAPY; BURDEN C1 [Chhatwal, Jagpreet] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Inst Technol Assessment, Boston, MA 02114 USA. [Chen, Qiushi] Georgia Inst Technol, H Milton Stewart Sch Ind & Syst Engn, Atlanta, GA 30332 USA. [Kanwal, Fasiha] Michael E DeBakey VA Med Ctr, Ctr Excellence, Hlth Serv Res & Dev, Houston Vet Affairs, Houston, TX USA. [Kanwal, Fasiha] Baylor Coll Med, Dept Med Gastroenterol & Hepatol, Houston, TX 77030 USA. RP Chhatwal, J (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Inst Technol Assessment, Boston, MA 02114 USA. FU NCATS NIH HHS [KL2 TR000146] NR 21 TC 3 Z9 3 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1542-3565 EI 1542-7714 J9 CLIN GASTROENTEROL H JI Clin. Gastroenterol. Hepatol. PD OCT PY 2015 VL 13 IS 10 BP 1711 EP 1713 DI 10.1016/j.cgh.2015.06.005 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CR8AW UT WOS:000361574500006 PM 26091736 ER PT J AU Sahora, K Ferrone, CR Brugge, WR Morales-Oyarvide, V Warshaw, AL Lillemoe, KD Fernandez-del Castillo, C AF Sahora, Klaus Ferrone, Cristina R. Brugge, William R. Morales-Oyarvide, Vicente Warshaw, Andrew L. Lillemoe, Keith D. Fernandez-del Castillo, Carlos TI Effects of Comorbidities on Outcomes of Patients With Intraductal Papillary Mucinous Neoplasms SO CLINICAL GASTROENTEROLOGY AND HEPATOLOGY LA English DT Article DE Pancreas; Management; Treatment; Cancer Risk ID PANCREATIC-CANCER; NONOPERATIVE MANAGEMENT; SURGERY; VALIDATION; MORTALITY; INDEX; RISK AB BACKGROUND & AIMS: Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas occur mostly in older individuals. Individual life expectancy and risk of death from other factors must be carefully considered in analyzing the risks that IPMNs pose. We investigated whether there is a subset of patients with IPMNs and a high risk of dying from other causes who would not benefit from pancreatic surgery. METHODS: We collected data from 725 patients at Massachusetts General Hospital who underwent resection or have been under observation for IPMNs from 1992 through 2012. Comorbidities were classified according to the age-adjusted Charlson comorbidity index (CACI). Causes of death were recorded, and survival data were analyzed by the Kaplan-Meier method. RESULTS: The patients' median CACI score was 3; 10% of patients had CACI of 7 or more. Of the entire cohort, 55% underwent resection, and the remaining 45% have been under observation. After a median follow-up period of 5 years, 177 patients died (24%, 55% of deaths within 5 years of diagnosis); 78% of deaths were not related to IPMNs. The median survival time for all patients with CACI score of 7 or more was 43 months. Multivariate regression analysis revealed that the chance of non-IPMN-related death within 3 years of diagnosis is 11-fold higher for patients with CACI score of 7 or more than for patients with lower scores. CONCLUSIONS: The CACI can be used to identify patients with a high risk of death from factors other than IPMNs within a few years after diagnosis. These patients are therefore not likely to benefit from further IPMN observation or pancreatic resection. C1 [Sahora, Klaus; Ferrone, Cristina R.; Morales-Oyarvide, Vicente; Warshaw, Andrew L.; Lillemoe, Keith D.; Fernandez-del Castillo, Carlos] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Brugge, William R.] Massachusetts Gen Hosp, Dept Gastroenterol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Fernandez-del Castillo, C (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg,Wang Ambulatory Care Ctr 460, 15 Parkman St, Boston, MA 02114 USA. EM CFERNANDEZ@mgh.harvard.edu NR 22 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 1542-3565 EI 1542-7714 J9 CLIN GASTROENTEROL H JI Clin. Gastroenterol. Hepatol. PD OCT PY 2015 VL 13 IS 10 BP 1816 EP 1823 DI 10.1016/j.cgh.2015.04.177 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CR8AW UT WOS:000361574500023 PM 25956837 ER PT J AU Westover, MB Ching, SN Kumaraswamy, VM Akeju, O Pierce, E Cash, SS Kilbride, R Brown, EN Purdon, PL AF Westover, M. Brandon Ching, ShiNung Kumaraswamy, Vishakhadatta M. Akeju, Oluwaseun Pierce, Eric Cash, Sydney S. Kilbride, Ronan Brown, Emery N. Purdon, Patrick L. TI The human burst suppression electroencephalogram of deep hypothermia SO CLINICAL NEUROPHYSIOLOGY LA English DT Article DE Burst suppression; Electroencephalogram; Hypothermia ID CIRCULATORY ARREST; MODERATE HYPOTHERMIA; CEREBRAL METABOLISM; EVOKED-POTENTIALS; CARDIAC-ARREST; BRAIN-INJURY; EEG; ANESTHESIA; COMA; NEUROPHYSIOLOGY AB Objective: Deep hypothermia induces 'burst suppression' (BS), an electroencephalogram pattern with low-voltage 'suppressions' alternating with high-voltage 'bursts'. Current understanding of BS comes mainly from anesthesia studies, while hypothermia-induced BS has received little study. We set out to investigate the electroencephalogram changes induced by cooling the human brain through increasing depths of BS through isoelectricity. Methods: We recorded scalp electroencephalograms from eleven patients undergoing deep hypothermia during cardiac surgery with complete circulatory arrest, and analyzed these using methods of spectral analysis. Results: Within patients, the depth of BS systematically depends on the depth of hypothermia, though responses vary between patients except at temperature extremes. With decreasing temperature, burst lengths increase, and burst amplitudes and lengths decrease, while the spectral content of bursts remains constant. Conclusions: These findings support an existing theoretical model in which the common mechanism of burst suppression across diverse etiologies is the cyclical diffuse depletion of metabolic resources, and suggest the new hypothesis of local micro-network dropout to explain decreasing burst amplitudes at lower temperatures. Significance: These results pave the way for accurate noninvasive tracking of brain metabolic state during surgical procedures under deep hypothermia, and suggest new testable predictions about the network mechanisms underlying burst suppression. (C) 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. C1 [Westover, M. Brandon; Kumaraswamy, Vishakhadatta M.; Cash, Sydney S.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02113 USA. [Westover, M. Brandon; Cash, Sydney S.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Ching, ShiNung] Washington Univ, Elect & Syst Engn, St Louis, MO 63130 USA. [Akeju, Oluwaseun; Pierce, Eric; Brown, Emery N.; Purdon, Patrick L.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02113 USA. [Pierce, Eric; Brown, Emery N.; Purdon, Patrick L.] Harvard Univ, Sch Med, Dept Anaesthesiol, Boston, MA USA. [Kilbride, Ronan] Beaumont Hosp, Dept Neurol, Dublin 9, Ireland. [Brown, Emery N.; Purdon, Patrick L.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. RP Westover, MB (reprint author), Massachusetts Gen Hosp, Dept Neurol, 55 Fruit St,WACC 735, Boston, MA 02113 USA. EM mwestover@mgh.harvard.edu; patrickp@nmr.mgh.harvard.edu FU National Institutes of Health, Bethesda, Maryland [DP2-OD006454, DP1-OD003646, TR01-GM104948, T32GM007592]; FAER; MGH MAO/ECOR Faculty Development award; Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts; Burroughs-Wellcome Fund FX American Brain Foundation (MBW); DP2-OD006454 (to PLP), DP1-OD003646 and TR01-GM104948 (to ENB), and T32GM007592 (to OA) from the National Institutes of Health, Bethesda, Maryland; FAER and MGH MAO/ECOR Faculty Development award to (OA); Funds from the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts. SC Holds a Career Award at the Scientific Interface from the Burroughs-Wellcome Fund. NR 49 TC 4 Z9 4 U1 0 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1388-2457 EI 1872-8952 J9 CLIN NEUROPHYSIOL JI Clin. Neurophysiol. PD OCT PY 2015 VL 126 IS 10 BP 1901 EP 1914 DI 10.1016/j.clinph.2014.12.022 PG 14 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CS0HR UT WOS:000361739500008 ER PT J AU Grob, SR Jakobiec, FA Stagner, AM Colby, KA AF Grob, Seanna R. Jakobiec, Frederick A. Stagner, Anna M. Colby, Kathryn A. TI Diffuse Epibulbar Complex Lacrimal-Cartilaginous Choristoma: Diagnostic Clues and Management SO CORNEA LA English DT Article DE complex choristoma; lacrimal; ocular surface reconstruction; pediatric ocular surface neoplasms ID AMNIOTIC MEMBRANE TRANSPLANTATION; RECONSTRUCTION AB Purpose:To describe the clinical and histopathologic features distinguishing an extensive complex choristoma of the epibulbar surface and to address the management of such lesions.Methods:Clinical history, diagnostic imaging studies, and histopathologic sections stained with hematoxylin and eosin were reviewed from a 2-year-old girl with a congenital conjunctival lesion of the right eye that was surgically excised.Results:The patient clinically displayed an extensive, vascularized amelanotic conjunctival lesion located superotemporally with extension onto the cornea. Her visual acuity was reduced to 20/670. The clinical diagnosis was a large lacrimal gland choristoma with corneal involvement and resulting deprivation amblyopia. The patient underwent an excision of the lesion including the corneal portion, and the ocular surface was reconstructed with amniotic membrane. Histopathologic evaluation disclosed lobules of lacrimal tissue and cartilage plaques, smooth muscle, and nerves consistent with a complex choristoma. Six weeks postoperatively, the visual acuity had improved to 20/180. The patient returned to her local ophthalmologist for amblyopia management.Conclusions:We emphasize the importance of recognizing lesion-induced amblyopia and the timely performance of appropriate surgery for complex epibulbar choristomas. A differential diagnosis of other congenital epibulbar lesions is provided. C1 [Grob, Seanna R.; Jakobiec, Frederick A.; Stagner, Anna M.; Colby, Kathryn A.] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Jakobiec, Frederick A.; Stagner, Anna M.] Massachusetts Eye & Ear Infirm, David G Cogan Lab Ophthalm Pathol, Boston, MA 02114 USA. [Colby, Kathryn A.] Massachusetts Eye & Ear Infirm, Cornea & Refract Surg, Boston, MA 02114 USA. [Colby, Kathryn A.] Boston Childrens Hosp, Pediat Cornea Serv, Boston, MA USA. RP Jakobiec, FA (reprint author), Massachusetts Eye & Ear Infirm, David G Cogan Ophthalm Pathol Lab, Suite 328,243 Charles St, Boston, MA 02114 USA. EM fred_jakobiec@meei.harvard.edu NR 13 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 0277-3740 EI 1536-4798 J9 CORNEA JI Cornea PD OCT PY 2015 VL 34 IS 10 BP 1321 EP 1323 DI 10.1097/ICO.0000000000000517 PG 3 WC Ophthalmology SC Ophthalmology GA CR7MF UT WOS:000361533500024 PM 26147834 ER PT J AU Ozieh, MN Bishu, KG Dismuke, CE Egede, LE AF Ozieh, Mukoso N. Bishu, Kinfe G. Dismuke, Clara E. Egede, Leonard E. TI Trends in Health Care Expenditure in US Adults With Diabetes: 2002-2011 SO DIABETES CARE LA English DT Article ID MEDICARE PART D; UNITED-STATES; DRUG COVERAGE; COSTS; HYPERTENSION; PROJECTIONS; DIAGNOSIS; MELLITUS; RECEIPT; BURDEN AB OBJECTIVEDirect medical cost of diabetes in the U.S. has been estimated to be 2.3 times higher relative to individuals without diabetes. This study examines trends in health care expenditures by expenditure category in U.S. adults with diabetes between 2002 and 2011.RESEARCH DESIGN AND METHODSWe analyzed 10 years of data representing a weighted population of 189,013,514 U.S. adults aged 18 years from the Medical Expenditure Panel Survey. We used a novel two-part model to estimate adjusted mean and incremental medical expenditures by diabetes status, while adjusting for demographics, comorbidities, and time.RESULTSRelative to individuals without diabetes ($5,058 [95% CI 4,949-5,166]), individuals with diabetes ($12,180 [11,775-12,586]) had more than double the unadjusted mean direct expenditures over the 10-year period. After adjustment for confounders, individuals with diabetes had $2,558 (2,266-2,849) significantly higher direct incremental expenditures compared with those without diabetes. For individuals with diabetes, inpatient expenditures rose initially from $4,014 in 2002/2003 to $4,183 in 2004/2005 and then decreased continuously to $3,443 in 2010/2011, while rising steadily for individuals without diabetes. The estimated unadjusted total direct expenditures for individuals with diabetes were $218.6 billion/year and adjusted total incremental expenditures were approximately $46 billion/year.CONCLUSIONSOur findings show that compared with individuals without diabetes, individuals with diabetes had significantly higher health expenditures from 2002 to 2011 and the bulk of the expenditures came from hospital inpatient and prescription expenditures. C1 [Ozieh, Mukoso N.; Bishu, Kinfe G.; Egede, Leonard E.] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. [Ozieh, Mukoso N.; Bishu, Kinfe G.; Dismuke, Clara E.; Egede, Leonard E.] Med Univ S Carolina, Ctr Hlth Dispar Res, Charleston, SC 29425 USA. [Dismuke, Clara E.; Egede, Leonard E.] Ralph H Johnson VA Med Ctr, Hlth Equ & Rural Outreach Innovat Ctr, Charleston, SC USA. RP Egede, LE (reprint author), Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. EM egedel@musc.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [K24DK093699] FX This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (grant K24DK093699, principal investigator L.E.E.). NR 36 TC 7 Z9 7 U1 2 U2 9 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD OCT PY 2015 VL 38 IS 10 BP 1844 EP 1851 DI 10.2337/dc15-0369 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CS1PW UT WOS:000361840500019 PM 26203060 ER PT J AU Jacobson, AM Braffett, BH Cleary, PA Dunn, RL Larkin, ME Wessells, H Sarma, AV AF Jacobson, Alan M. Braffett, Barbara H. Cleary, Patricia A. Dunn, Rodney L. Larkin, Mary E. Wessells, Hunter Sarma, Aruna V. CA DCCT-EDIC Res Grp TI Relationship of Urologic Complications With Health-Related Quality of Life and Perceived Value of Health in Men and Women With Type 1 Diabetes: The Diabetes Control and Complications Trial/Epidemiology of Interventions and Complications (DCCT/EDIC) Cohort SO DIABETES CARE LA English DT Article ID URINARY-TRACT SYMPTOMS; SEXUAL DYSFUNCTION; ERECTILE DYSFUNCTION; SURVEY SF-36; FOLLOW-UP; INDEX; IMPACT; TESTS; TRIAL; ADULTS AB OBJECTIVELimited information exists about the influence of urologic complications on health-related quality of life (HRQOL) in patients with type 1 diabetes.RESEARCH DESIGN AND METHODSWe studied 664 men and 580 women from the Diabetes Control and Complications Trial/Epidemiology of Interventions and Complications Study: mean ages were 51.6 6.6 and 50.6 7.2 years and duration of diabetes was 29.5 +/- 4.8 and 29.8 +/- 5.1 years, respectively. We assessed associations of sexual dysfunction, lower urinary tract symptoms (LUTS), and, in women, urinary incontinence (UI) with general quality of life (SF-36), perceived value of health (EuroQol-5), diabetes-related quality of life (Diabetes Quality of Life Scale [DQOL]), and psychiatric symptoms (Symptom Checklist 90-R).RESULTSIn both men and women, urologic complications adversely affected HRQOL and psychiatric symptoms, even after accounting for history of depression leading to treatment. Multivariable analyses accounting for the presence of diabetic retinopathy, neuropathy, and nephropathy also revealed substantial independent effects. In men, for example, the odds (95% CI) of a low DQOL score (25th percentile) were 3.01 (1.90-4.75) times greater with erectile dysfunction and 2.65 (1.68-4.18) times greater with LUTS and in women, 2.04 (1.25-3.35) times greater with sexual dysfunction and 2.71 (1.72-4.27) times greater with UI/LUTS combined compared with men and women without such complications. Similar effects were observed for the other measures.CONCLUSIONSSexual dysfunction and urinary complications with type 1 diabetes are associated with decreased quality of life and perceived value of health and with higher levels of psychiatric symptoms, even after accounting for other diabetes complications and depression treatment. C1 [Jacobson, Alan M.] Winthrop Univ Hosp, Res Inst, Mineola, NY 11501 USA. [Braffett, Barbara H.; Cleary, Patricia A.] George Washington Univ, Ctr Biostat, Rockville, MD USA. [Dunn, Rodney L.; Sarma, Aruna V.] Univ Michigan, Dept Urol, Ann Arbor, MI 48109 USA. [Larkin, Mary E.] Massachusetts Gen Hosp, Diabet Res Ctr, Boston, MA 02114 USA. [Wessells, Hunter] Univ Washington, Dept Urol, Seattle, WA 98195 USA. RP Jacobson, AM (reprint author), Winthrop Univ Hosp, Res Inst, Mineola, NY 11501 USA. EM amjacobson@winthrop.org FU Division of Diabetes Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases [U01 DK094176, U01 DK094157, R01 DK083927]; National Eye Institute, the National Institute of Neurological Disorders and Stroke, the General Clinical Research Center Program; Clinical and Translational Science Center Program, Bethesda, MD FX The DCCT/EDIC has been supported by cooperative agreement grants (1982-1993, 2012-2017) and contracts (1982-2012) with the Division of Diabetes Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases (current grant numbers U01 DK094176 and U01 DK094157 and additional support by grant R01 DK083927) and by the National Eye Institute, the National Institute of Neurological Disorders and Stroke, the General Clinical Research Center Program (1993-2007), and the Clinical and Translational Science Center Program (2000-present), Bethesda, MD. NR 31 TC 3 Z9 3 U1 1 U2 6 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD OCT PY 2015 VL 38 IS 10 BP 1904 EP 1912 DI 10.2337/dc15-0286 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CS1PW UT WOS:000361840500027 PM 26203062 ER PT J AU Lo, CS Shi, YX Chang, SY Abdo, S Chenier, I Filep, JG Ingelfinger, JR Zhang, SL Chan, JSD AF Lo, Chao-Sheng Shi, Yixuan Chang, Shiao-Ying Abdo, Shaaban Chenier, Isabelle Filep, Janos G. Ingelfinger, Julie R. Zhang, Shao-Ling Chan, John S. D. TI Overexpression of heterogeneous nuclear ribonucleoprotein F stimulates renal Ace-2 gene expression and prevents TGF-beta 1-induced kidney injury in a mouse model of diabetes SO DIABETOLOGIA LA English DT Article DE ACE-2; Akita mice; Angiotensinogen; Diabetes; Heterogeneous nuclear ribonucleoprotein F; Hypertension; Renal fibrosis; TGF-beta 1 ID PROXIMAL TUBULAR CELLS; GROWTH-FACTOR-BETA; ANGIOTENSIN-CONVERTING ENZYME-2; TRANSGENIC MICE; TUBULOINTERSTITIAL FIBROSIS; BINDING PROTEIN; TGF-BETA; RAT; NEPHROPATHY; HYPERTENSION AB Aims/hypothesis We investigated whether heterogeneous nuclear ribonucleoprotein F (hnRNP F) stimulates renal ACE-2 expression and prevents TGF-beta 1 signalling, TGF-beta 1 inhibition of Ace-2 gene expression and induction of tubulo-fibrosis in an Akita mouse model of type 1 diabetes. Methods Adult male Akita transgenic (Tg) mice overexpressing specifically hnRNP F in their renal proximal tubular cells (RPTCs) were studied. Non-Akita littermates and Akita mice served as controls. Immortalised rat RPTCs stably transfected with plasmid containing either rat Hnrnpf cDNA or rat Ace-2 gene promoter were also studied. Results Overexpression of hnRNP F attenuated systemic hypertension, glomerular filtration rate, albumin/creatinine ratio, urinary angiotensinogen (AGT) and angiotensin (Ang) II levels, renal fibrosis and profibrotic gene (Agt, Tgf-beta 1, TGF-beta receptor II [Tgf-beta rII]) expression, stimulated anti-profibrotic gene (Ace-2 and Ang 1-7 receptor [MasR]) expression, and normalised urinary Ang 1-7 level in Akita Hnrnpf-Tg mice as compared with Akita mice. In vitro, hnRNP F overexpression stimulated Ace-2 gene promoter activity, mRNA and protein expression, and attenuated Agt, Tgf-beta 1 and Tgf-beta rII gene expression. Furthermore, hnRNP F overexpression prevented TGF-beta 1 signalling and TGF-beta 1 inhibition of Ace-2 gene expression. Conclusions/interpretation These data demonstrate that hnRNP F stimulates Ace-2 gene transcription, prevents TGF-beta 1 inhibition of Ace-2 gene transcription and induction of kidney injury in diabetes. HnRNP F may be a potential target for treating hypertension and renal fibrosis in diabetes. C1 [Lo, Chao-Sheng; Shi, Yixuan; Chang, Shiao-Ying; Abdo, Shaaban; Chenier, Isabelle; Zhang, Shao-Ling; Chan, John S. D.] Univ Montreal, Ctr Rech, Ctr Hosp Univ Montreal CRCHUM, Montreal, PQ H2X 0A9, Canada. [Filep, Janos G.] Univ Montreal, Res Ctr, Maisonneuve Rosemont Hosp, Montreal, PQ H2X 0A9, Canada. [Ingelfinger, Julie R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pediat Nephrol Unit, Boston, MA USA. RP Zhang, SL (reprint author), Univ Montreal, Ctr Rech, Ctr Hosp Univ Montreal CRCHUM, Tour Viger Pavillon R,900 St Denis St, Montreal, PQ H2X 0A9, Canada. EM shao.ling.zhang@umontreal.ca; john.chan@umontreal.ca FU Canadian Institutes of Health Research [MOP 84363, MOP 106688, MOP-86450, MOP-97742]; Kidney Foundation of Canada [KFOC120008]; Canadian Diabetes Association [NOD_OG-3-14-4472-JC]; National Institutes of Health (NIH) of USA [HL-48455]; Montreal Diabetes Research Centre of the CRCHUM FX This work was supported by grants from the Canadian Institutes of Health Research (MOP 84363 and MOP 106688 to JSDC, MOP-86450 to SLZ and MOP-97742 to JGF), the Kidney Foundation of Canada (KFOC120008 to JSDC), the Canadian Diabetes Association (NOD_OG-3-14-4472-JC to JSDC), and the National Institutes of Health (NIH) of USA (HL-48455 to JRI). CSL is the recipient of a fellowship from the Montreal Diabetes Research Centre of the CRCHUM. Editorial assistance was provided by the CRCHUM Research Support Office. NR 51 TC 0 Z9 0 U1 0 U2 0 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 OCT PY 2015 VL 58 IS 10 BP 2443 EP 2454 DI 10.1007/s00125-015-3700-y PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CR7NY UT WOS:000361538600028 PM 26232095 ER PT J AU Markland, AD Burgio, KL Whitehead, WE Richter, HE Wilcox, CM Redden, DT Beasley, TM Goode, PS AF Markland, Alayne D. Burgio, Kathryn L. Whitehead, William E. Richter, Holly E. Wilcox, C. Mel Redden, David T. Beasley, Timothy M. Goode, Patricia S. TI Loperamide Versus Psyllium Fiber for Treatment of Fecal Incontinence: The Fecal Incontinence Prescription (Rx) Management (FIRM) Randomized Clinical Trial SO DISEASES OF THE COLON & RECTUM LA English DT Article DE Accidental bowel leakage; Comparative effectiveness; Crossover design; Fecal incontinence; Functional bowel disorders; Quality of life; Randomized controlled trial ID QUALITY-OF-LIFE; RISK-FACTORS; CROSSOVER TRIALS; ANORECTAL DISORDERS; NICE GUIDANCE; ADULTS; PREVALENCE; HEALTH; OLDER; SUPPLEMENTATION AB BACKGROUND: Fecal incontinence is a devastating condition with few US Food and Drug Administration-approved pharmacologic treatment options. Loperamide and psyllium, both first-line treatments, have different mechanisms of action without any comparative data. OBJECTIVE: The purpose of this study was to examine the effectiveness and tolerability of loperamide compared with psyllium for reducing fecal incontinence. We hypothesized that psyllium fiber supplementation would be more effective than loperamide for reducing fecal incontinence episodes and have fewer adverse effects. DESIGN: We conducted a randomized, double-blind, placebo-controlled crossover trial comparing loperamide (followed by psyllium) with psyllium (followed by loperamide). SETTINGS: Our sites included outpatient clinics within a Veterans Affairs medical center and university affiliate. PATIENTS: Participants included community-dwelling adults (n = 80) with at least 1 fecal incontinent episode on a 7-day bowel diary. INTERVENTION: Participants received either daily loperamide (plus placebo psyllium powder) or psyllium powder (plus loperamide placebo) for 4 weeks. After a 2-week washout, participants crossed over to 4 weeks of alternate treatment. MAIN OUTCOME MEASURES: The primary outcome was the number of fecal incontinence episodes from 7-day bowel diaries. Secondary outcomes included symptom severity, quality of life, and tolerability. RESULTS: Mean age was 60.7 10.1 years; 68% were men. After determining nonsignificant carryover effects, combined analyses showed no differences between the loperamide and psyllium groups for reducing fecal incontinent episodes, symptom severity, or quality of life. Within each group, both loperamide and psyllium reduced fecal incontinent episodes and improved symptom severity and quality of life. Constipation occurred in 29% of participants for loperamide vs 10% for psyllium. LIMITATIONS: Limitations include the washout period length and dropout rate after crossing over to the second intervention. CONCLUSIONS: Both loperamide and psyllium improve fecal incontinence. Loperamide was associated with more adverse effects, especially constipation. C1 [Markland, Alayne D.; Burgio, Kathryn L.; Goode, Patricia S.] Birmingham Dept Vet Affairs Med Ctr, Birmingham Atlanta Geriatr Res Educ & Clin Ctr, Birmingham, AL USA. [Markland, Alayne D.; Burgio, Kathryn L.; Goode, Patricia S.] Univ Alabama Birmingham, Dept Med, Div Gerontol Geriatr & Palliat Care, Birmingham, AL 35233 USA. [Whitehead, William E.] Univ N Carolina, Dept Med, Div Gastroenterol, Chapel Hill, NC USA. [Richter, Holly E.] Univ Alabama Birmingham, Dept Obstet & Gynecol, Div Urogynecol & Pelv Reconstruct Surg, Birmingham, AL 35233 USA. [Wilcox, C. Mel] Univ Alabama Birmingham, Dept Med, Div Gastroenterol, Birmingham, AL 35233 USA. [Redden, David T.; Beasley, Timothy M.] Univ Alabama Birmingham, Sch Publ Hlth, Birmingham, AL 35233 USA. RP Markland, AD (reprint author), Univ Alabama Birmingham, Dept Med, Div Gerontol Geriatr & Palliat Care, Birmingham Vet Affairs Med Ctr, GRECC 11-G,900 South 18th St, Birmingham, AL 35233 USA. EM markland@uab.edu OI Markland, Alayne/0000-0002-6567-6744 FU Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Rehabilitation Research and Development Service Career Development Awards [CDA-2, B6126W]; John A. Hartford Foundation through the Southeast Center of Excellence in Geriatric Medicine FX This study was supported by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Rehabilitation Research and Development Service Career Development Awards (CDA-2) to Dr Markland (B6126W) and a grant from the John A. Hartford Foundation through the Southeast Center of Excellence in Geriatric Medicine. NR 36 TC 5 Z9 5 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0012-3706 EI 1530-0358 J9 DIS COLON RECTUM JI Dis. Colon Rectum PD OCT PY 2015 VL 58 IS 10 BP 983 EP 993 DI 10.1097/DCR.0000000000000442 PG 11 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA CR6JJ UT WOS:000361452300010 PM 26347971 ER PT J AU Goto, T Watase, H Morita, H Nagai, H Brown, CA Brown, DFM Hasegawa, K AF Goto, Tadahiro Watase, Hiroko Morita, Hiroshi Nagai, Hideya Brown, Calvin A., III Brown, David F. M. Hasegawa, Kohei CA Japanese Emergency Med Network Inv TI Repeated attempts at tracheal intubation by a single intubator associated with decreased success rates in emergency departments: an analysis of a multicentre prospective observational study SO EMERGENCY MEDICINE JOURNAL LA English DT Article ID AIRWAY MANAGEMENT; ENDOTRACHEAL INTUBATION; LARYNGOSCOPY AB Objective To determine whether the success rate of repeated attempts at tracheal intubation by a single intubator was lower than those by alternate intubators in the emergency department (ED). Methods An analysis of data from a multicentre prospective registry (Japanese Emergency Airway Network Registry) of 13 academic and community EDs in Japan between April 2010 and August 2012. We included all adult and paediatric patients who underwent repeated attempts at tracheal intubation in the ED. We compared the intubation success rates at the second and third attempts between attempts at intubation by a single intubator who performed the previous attempts, and the attempts by alternate intubators. Results We recorded 4094 patients (capture rate, 96%); 1289 patients with repeated attempts at tracheal intubation were eligible for this study. Among these, 871 patients (68%) had a second attempt at intubation by single intubators. At the second attempt, tracheal intubation by a single intubator was associated with a decreased success rate (adjusted odds ratio or AOR, 0.50; 95% CI 0.36 to 0.71), compared with alternate intubators. At the third attempt, intubation by a single intubator was also associated with a decreased success rate (58% vs 70%; unadjusted OR, 0.58; 95% CI 0.38 to 0.89). However, after adjustment for potential confounders, the association lost statistical significance (AOR, 0.89; 95% CI 0.52 to 1.56). Conclusions In this large multicentre study of ED patients undergoing tracheal intubation, second attempts at intubation by a single intubator, compared with those by alternate intubators, were independently associated with a decreased success rate. C1 [Goto, Tadahiro; Morita, Hiroshi] Univ Fukui Hosp, Dept Emergency Med, Fukui 9101193, Japan. [Goto, Tadahiro] Osaka Saiseikai Senri Hosp, Senri Crit Care Med Ctr, Suita, Osaka, Japan. [Watase, Hiroko] Japanese Emergency Med Network, Seattle, WA USA. [Nagai, Hideya] Fukui Prefectural Hosp, Dept Emergency Med, Fukui, Japan. [Brown, Calvin A., III] Brigham & Womens Hosp, Dept Emergency Med, Boston, MA 02115 USA. [Brown, David F. M.; Hasegawa, Kohei] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. RP Goto, T (reprint author), Univ Fukui Hosp, Dept Emergency Med, 23-3 Shimoaiduki, Fukui 9101193, Japan. EM qq_gto@yahoo.co.jp FU St Luke's Life Science Institute; Massachusetts General Hospital; Brigham and Women's Hospital FX This study was supported by a grant from St Luke's Life Science Institute, and a grant from Massachusetts General Hospital and Brigham and Women's Hospital. The study sponsors have no involvement in the study design, in the collection, analysis and interpretation of data; in the writing of the manuscript; and in the decision to submit the manuscript for publication. NR 15 TC 1 Z9 1 U1 0 U2 2 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1472-0205 EI 1472-0213 J9 EMERG MED J JI Emerg. Med. J. PD OCT PY 2015 VL 32 IS 10 BP 781 EP 786 DI 10.1136/emermed-2013-203473 PG 6 WC Emergency Medicine SC Emergency Medicine GA CS0IQ UT WOS:000361743100007 PM 25552546 ER PT J AU Fan, BJ Pasquale, LR Kang, JH Levkovitch-Verbin, H Haines, JL Wiggs, JL AF Fan, Bao J. Pasquale, Louis R. Kang, Jae H. Levkovitch-Verbin, Hani Haines, Jonathan L. Wiggs, Janey L. TI Association of clusterin (CLU) variants and exfoliation syndrome: An analysis in two Caucasian studies and a meta-analysis SO EXPERIMENTAL EYE RESEARCH LA English DT Article DE Exfoliation syndrome; Glaucoma; Clusterin; Genetic variants; Meta-analysis ID PSEUDOEXFOLIATION SYNDROME; LOXL1 GENE; SEQUENCE VARIANTS; UNITED-STATES; RISK ALLELE; GLAUCOMA; POPULATION; SUSCEPTIBILITY; POLYMORPHISMS; PATHOGENESIS AB Exfoliation syndrome (XFS) is an important risk factor for glaucoma (XFG) worldwide. LOXL1 variants are highly associated with XFS in most populations; however, the high frequency of risk alleles in normal individuals and the reversal of risk alleles in different ethnic populations suggest that other factors contribute to XFS pathogenesis. Clusterin (CLU) is an extracellular matrix chaperone that prevents protein aggregation and is highly expressed in ocular tissues affected by XFS. Studies examining common CLU variants for association with XFS have been inconsistent. The purpose of this study was to evaluate CLU variants for association with XFS in two independent datasets from the United States (222 cases and 344 controls) and Israel (92 cases and 102 controls). Seven tag SNPs that captured >95% of alleles at r(2) greater than 0.8 across the CLU genomic region were genotyped using TaqMan assays. Genotypes for an additional SNP, rs2279590, were imputed using phased haplotypes of HapMap reference CEU samples. Of the 8 CLU SNPs selected for the study, none were significantly associated with XFS in either case control group (age and sex adjusted P> 0.14 and 0.36, respectively, in the US and Israeli datasets), or when they were meta-analyzed together (age and sex adjusted P> 0.13). Haplotype analysis using all 8 SNPs or only the promoter region SNPs also did not show significant associations of CLU with XFS in the combined US and Israeli dataset (P> 0.28). Meta-analysis of the data from this study and previous studies in Caucasian populations (1184 cases and 978 controls) resulted in statistically significant association of rs2279590 with XFS (summary OR = 1.18, 95% CI: 1.03-1.33, P = 0.01). Significant association between rs2279590 and XFS was also found in Indian populations (summary OR = 0.76, 95% CI: 0.61-0.96; P = 0.02); however, significant heterogeneity between the Caucasian and Indian populations possibly due to reversal of the risk allele precluded an overall meta-analysis for rs2279590 (Q = 0.001, I-2 = 91%). No significant association was identified for rs3087554 in either Caucasian populations (summary OR = 0.90, 95% CI: 0.77-1.05, P = 0.17) or Indian populations (summary OR = 0.89, 95% Cl: 0.72-1.10, P = 0.28), or in both populations combined (1705 cases and 3713 controls; summary OR = 0.90, 95% CI: 0.79-1.01, P = 0.08). Significant heterogeneity precluded the addition of the Japanese data to the meta-analysis for rs3087554 (Q = 0.006, I-2 = 87%). Our results suggest that common CLU variants may contribute to modest XFS risk but even larger datasets are required to confirm these findings. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Fan, Bao J.; Pasquale, Louis R.; Wiggs, Janey L.] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. [Pasquale, Louis R.; Kang, Jae H.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Channing Div Network Med,Dept Med, Boston, MA 02114 USA. [Levkovitch-Verbin, Hani] Tel Aviv Univ, Goldschleger Eye Inst, Chaim Sheba Med Ctr, Tel Hashomer, Israel. [Haines, Jonathan L.] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. RP Wiggs, JL (reprint author), Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM janey_wiggs@meei.harvard.edu OI Fan, Baojian/0000-0002-6851-2737 FU National Eye Institute [R01 EY020928, R01 EY015872, P30 EY014104]; Research to Prevent Blindness; Arthur Ashley Foundation; Massachusetts Lions Eye Research Fund FX This work was supported in part by National Eye Institute Grants R01 EY020928, R01 EY015872 and P30 EY014104, Research to Prevent Blindness, the Arthur Ashley Foundation and The Massachusetts Lions Eye Research Fund. A Harvard Medical School Ophthalmology Distinguished Scholar Award supports Dr. Pasquale. NR 31 TC 2 Z9 2 U1 0 U2 3 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0014-4835 EI 1096-0007 J9 EXP EYE RES JI Exp. Eye Res. PD OCT PY 2015 VL 139 BP 115 EP 122 DI 10.1016/j.exer.2015.08.004 PG 8 WC Ophthalmology SC Ophthalmology GA CS0VW UT WOS:000361781300012 PM 26272660 ER PT J AU Wolfsen, HC Sharma, P Wallace, MB Leggett, C Tearney, G Wang, KK AF Wolfsen, Herbert C. Sharma, Prateek Wallace, Michael B. Leggett, Cadman Tearney, Guillermo Wang, Kenneth K. TI Safety and feasibility of volumetric laser endomicroscopy in patients with Barrett's esophagus (with videos) SO GASTROINTESTINAL ENDOSCOPY LA English DT Article ID OPTICAL COHERENCE TOMOGRAPHY; HIGH-GRADE DYSPLASIA; RANDOMIZED CONTROLLED-TRIAL; IN-VIVO; INTRAMUCOSAL CARCINOMA; INTESTINAL METAPLASIA; CONFOCAL MICROSCOPY; CLINICAL UTILITY; HIGH-SPEED; REAL-TIME AB Background: Volumetric laser endomicroscopy (VLE) produces high-resolution, cross-sectional surface, and subsurface images for detecting neoplasia, targeting biopsies, and guiding real-time treatment. Objective: To evaluate the safety and feasibility of the Nvision VLE system. Design: Prospective, multicenter study. Setting: Tertiary-care medical centers. Patients: One hundred patients with suspected Barrett's esophagus, including 52 patients with prior endotherapy. Interventions: The first-generation Nvision VLE Imaging System, a balloon-centered, rotating optical probe provided images of the mucosa and submucosa through a 6-cm segment length and 360 degrees scan of the distal esophagus. Main Outcome Measurements: Acquisition of a complete, 6-cm scan from the distal esophagus, demographic and procedural data, and final histologic diagnosis. Results: VLE imaging was successfully performed in 87 cases. After VLE imaging, biopsy specimens were obtained in 77 patients and mucosal resection was performed in 20 patients. The final pathologic diagnoses of the patients studied were adenocarcinoma (4 patients), high-grade dysplasia (10 patients), low-grade dysplasia (11 patients), indefinite (5 patients), intestinal metaplasia (29 patients), and normal squamous cells (18 patients). VLE was not completed in 13 of 100 (13%) because of optical probe and console issues. There were 2 minor adverse events (mucosal lacerations not requiring therapy). Limitations: This was a feasibility study with a first-generation device. There was no direct histopathologic correlation with the VLE images or any comparative analysis with white-light endoscopy or narrow-band imaging findings. Conclusion: VLE is a safe procedure for patients with suspected or confirmed Barrett's esophagus. Real-time VLE images enabled visualization of the mucosa and submucosa in 87% of cases. Further studies are needed to evaluate the in vivo diagnostic accuracy and clinical utility of VLE. C1 [Wolfsen, Herbert C.; Wallace, Michael B.] Mayo Clin, Dept Gastroenterol, Jacksonville, FL 32224 USA. [Sharma, Prateek] Kansas City Vet Adm Med Ctr, Gastroenterol Hepatol & Motil, Kansas City, MO USA. [Leggett, Cadman; Wang, Kenneth K.] Mayo Clin Rochester, Dept Gastroenterol, Rochester, MN USA. [Tearney, Guillermo] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Wolfsen, HC (reprint author), Mayo Clin Florida, Div Gastroenterol, Med, 4500 San Pablo Rd South, Jacksonville, FL 32224 USA. FU NinePoint Medical (Cambridge, Mass); Olympus Inc; Cook Medical; CDx Laboratories; NinePoint Medical; Olympus Inc.; iLumen Medical; Olympus; Boston Scientific; CSA Medical; Fujinon; CDx Diagnostics; Covidien (Barrx) FX Study funding, including volumetric laser endomicroscopy imaging consoles and optical probes, was provided by NinePoint Medical (Cambridge, Mass). H. Wolfsen receives research support from Olympus Inc and NinePoint Medical. He is a consultant for CSA Medical, Mauna Kea Technologies, Covidien, and Fuji Film. P. Sharma receives grant funding from Cook Medical, CDx Laboratories, NinePoint Medical, and Olympus Inc. G. Tearney receives research support from iLumen Medical and NinePoint Medical. He is a consultant for NinePoint Medical and Samsung. Massachusetts General Hospital has a licensing arrangement with NinePoint Medical. G. Tearney has the rights to receive royalties from this licensing arrangement. M. Wallace receives research funding from Olympus, Boston Scientific, and NinePoint Medical. K. Wang receives research support from NinePoint Medical, CSA Medical, Fujinon, and CDx Diagnostics and is on the advisory boards for NinePoint Medical and CDx Diagnostics. K. Wang received research support from Covidien (Barrx) completed within the past 12 months. Mayo Clinic does not endorse any specific products, advertisers, or services included in this material. NR 39 TC 10 Z9 10 U1 2 U2 4 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 OCT PY 2015 VL 82 IS 4 BP 631 EP 640 DI 10.1016/j.gie.2015.03.1968 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CR8BB UT WOS:000361575000007 PM 25956472 ER PT J AU Rodriguez, HP Meredith, LS Hamilton, AB Yano, EM Rubenstein, LV AF Rodriguez, Hector P. Meredith, Lisa S. Hamilton, Alison B. Yano, Elizabeth M. Rubenstein, Lisa V. TI Huddle up!: The adoption and use of structured team communication for VA medical home implementation SO HEALTH CARE MANAGEMENT REVIEW LA English DT Article DE huddles; organizational change; practice redesign; team communication; teamwork ID TRANSACTIVE MEMORY-SYSTEMS; PRIMARY-CARE; LEARNING ORGANIZATION; SITUATION AWARENESS; READINESS; FRAMEWORK; BURNOUT AB Background: Daily clinical team meetings (i.e., huddles) may be helpful in implementing new roles and responsibilities for patient care because they provide a regular opportunity for member learning and feedback. Purposes: We examined how huddles were implemented in the context of the VA patient-centered medical home (PCMH) transformation, including assessing barriers and facilitators to regular huddling among small teams (teamlets). We assessed the extent to which teamlet members that huddled had higher self-efficacy for PCMH changes, reported better teamwork experiences, and perceived more supportive practice environments. Methodology/Approach: We used a convergent mixed-methods approach to analyze 79 teamlet member interviews from six VA primary care practices and 418 clinician and staff PCMH survey responses from the six interviewed practices and 13 additional practices in the same region. Findings: Most members reported participating in teamlet huddles when asked in surveys (85%). A minority of interview participants, however, described routine huddling focused on previsit planning that included all members. When members reported routine teamlet huddling, activities included (a) previsit planning, (b) strategizing treatment plans for patients with special or complex needs, (c) addressing daily workflow and communication issues through collective problem solving, and (d) ensuring awareness of what team members do and what actions are happening on the teamlet and in the practice. Primary care providers (PCPs) were least likely to report routine huddling. PCP huddlers reported greater self-efficacy for implementing PCMH changes. All huddlers, irrespective of role, reported better teamwork and more supportive practice climates. The most common barriers to teamlet huddling were limited time and operational constraints. Practice Implications: In order to improve the impact of huddles on patient care, practice leaders should clearly communicate the goals, requirements, and benefits of huddling and provide adequate time and resources to ensure that frontline teams use huddle time to improve patient care. C1 [Rodriguez, Hector P.] Univ Calif Berkeley, Sch Publ Hlth, Ctr Healthcare Org & Innovat Res, Hlth Policy & Management, Berkeley, CA 94720 USA. [Rodriguez, Hector P.] Univ Calif Berkeley, Sch Publ Hlth, Ctr Healthcare Org & Innovat Res, Berkeley, CA 94720 USA. [Meredith, Lisa S.] RAND Corp, Behav & Policy Sci Res Dept, Santa Monica, CA USA. [Hamilton, Alison B.; Yano, Elizabeth M.] VA Greater Los Angeles Hlth Care Syst, HSR&D Ctr Study Healthcare Innovat Implementat &, North Hills, CA USA. [Hamilton, Alison B.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Yano, Elizabeth M.] Univ Calif Los Angeles, Fielding Sch Publ, Hlth Policy & Management, Los Angeles, CA 90024 USA. [Rubenstein, Lisa V.] Ctr Implementat Practice & Res Support, North Hills, CA USA. [Rubenstein, Lisa V.] Univ Calif Los Angeles, David Geffen Sch Med, Med, Los Angeles, CA 90095 USA. [Rubenstein, Lisa V.] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Med, Los Angeles, CA 90024 USA. RP Rodriguez, HP (reprint author), Univ Calif Berkeley, Sch Publ Hlth, Ctr Healthcare Org & Innovat Res, Hlth Policy & Management, Berkeley, CA 94720 USA. EM hrod@berkeley.edu FU Veterans Health Administration's PACT Demonstration Laboratory initiative; VA Office of Patient Care Services; VA HSR&D Service Senior Research Career Scientist award [05-195] FX This work was undertaken as part of the Veterans Health Administration's PACT Demonstration Laboratory initiative, supporting and evaluating VA's transition to a patient-centered medical home. Funding for the PACT Demonstration Laboratory initiative is provided by the VA Office of Patient Care Services. Dr. Yano's effort was funded by a VA HSR&D Service Senior Research Career Scientist award (Project #05-195). The views expressed within are solely those of the authors and do not necessarily represent the views of the Department of Veterans Affairs or the United States government. NR 32 TC 5 Z9 5 U1 3 U2 17 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0361-6274 EI 1550-5030 J9 HEALTH CARE MANAGE R JI Health Care Manage. Rev. PD OCT-DEC PY 2015 VL 40 IS 4 BP 286 EP 299 DI 10.1097/HMR.0000000000000036 PG 14 WC Health Policy & Services SC Health Care Sciences & Services GA CR8LU UT WOS:000361604800003 PM 25029511 ER PT J AU Singer, SJ Hayes, JE Gray, GC Kiang, MV AF Singer, Sara J. Hayes, Jennifer E. Gray, Garry C. Kiang, Mathew V. TI Making time for learning-oriented leadership in multidisciplinary hospital management groups SO HEALTH CARE MANAGEMENT REVIEW LA English DT Article DE collective learning; leadership; learning-oriented leadership; mixed methods; safety ID HEALTH-CARE; TECHNOLOGY IMPLEMENTATION; PSYCHOLOGICAL SAFETY; TEAMS; PERSPECTIVE; PERFORMANCE; BEHAVIOR; IMPROVEMENT; DYNAMICS; PROGRAM AB Background: Although the clinical requirements of health care delivery imply the need for interdisciplinary management teams to work together to promote frontline learning, such interdisciplinary, learning-oriented leadership is atypical. Purpose: We designed this study to identify behaviors enabling groups of diverse managers to perform as learning-oriented leadership teams on behalf of quality and safety. Approach: We randomly selected 12 of 24 intact groups of hospital managers from one hospital to participate in a Safety Leadership Team Training program. We collected primary data from March 2008 to February 2010 including pre- and post-staff surveys, multiple interviews, observations, and archival data from management groups. We examined the level and trend in frontline perceptions of managers' learning-oriented leadership following the intervention and ability of management groups to achieve objectives on targeted improvement projects. Among the 12 intervention groups, we identified higher- and lower-performing intervention groups and behaviors that enabled higher performers to work together more successfully. Findings: Management groups that achieved more of their performance goals and whose staff perceived more and greater improvement in their learning-oriented leadership after participation in Safety Leadership Team Training invested in structures that created learning capacity and conscientiously practiced prescribed learning-oriented management and problem-solving behaviors. They made the time to do these things because they envisioned the benefits of learning, valued the opportunity to learn, and maintained an environment of mutual respect and psychological safety within their group. Practice Implications: Learning in management groups requires vision of what learning can accomplish; will to explore, practice, and build learning capacity; and mutual respect that sustains a learning environment. C1 [Singer, Sara J.] Harvard Univ, Sch Publ Hlth, Sch Med, Hlth Care Management & Policy, Boston, MA 02115 USA. [Hayes, Jennifer E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hayes, Jennifer E.] VA Boston Healthcare Syst, Ctr Org Leadership & Management Res, Boston, MA USA. [Gray, Garry C.] Univ Victoria, Sociol, Victoria, BC V8W 2Y2, Canada. [Gray, Garry C.] Harvard Univ, Edmond J Safra Ctr Eth, Cambridge, MA 02138 USA. [Kiang, Mathew V.] Harvard Univ, Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02115 USA. RP Singer, SJ (reprint author), Harvard Univ, Sch Publ Hlth, Sch Med, Hlth Care Management & Policy, 665 Huntington Ave, Boston, MA 02115 USA. EM ssinger@hsph.harvard.edu FU Donaghue Foundation of Hartford CT [DF07-212]; Massachusetts General Hospital, Boston MA FX The authors wish to thank participants in the Healthcare Adventures Safety Leadership Team Training Program for their insightful contributions to this program, to the faculty and staff of the Center for Medical Simulation, Cambridge, MA, for creating and conducting the simulations, and to the editor and reviewers for their insightful suggestions for improving an earlier version of this manuscript. We gratefully acknowledge financial support for this research from the Donaghue Foundation of Hartford CT (#DF07-212) and from the Massachusetts General Hospital, Boston MA. The research described herein was approved by the institutional review board at participating institutions. NR 40 TC 3 Z9 3 U1 5 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0361-6274 EI 1550-5030 J9 HEALTH CARE MANAGE R JI Health Care Manage. Rev. PD OCT-DEC PY 2015 VL 40 IS 4 BP 300 EP 312 DI 10.1097/HMR.0000000000000037 PG 13 WC Health Policy & Services SC Health Care Sciences & Services GA CR8LU UT WOS:000361604800004 PM 25029508 ER PT J AU Lambiase, MJ Kubzansky, LD Thurston, RC AF Lambiase, Maya J. Kubzansky, Laura D. Thurston, Rebecca C. TI Positive Psychological Health and Stroke Risk: The Benefits of Emotional Vitality SO HEALTH PSYCHOLOGY LA English DT Article DE psychological health; emotions; stroke; cardiovascular disease; prospective ID CARDIOVASCULAR HEALTH; ASSOCIATION AB Objective: Stroke is a leading cause of death and disability. Various forms of positive psychological health (e.g., emotional vitality) are associated with lower risk for heart disease. However, it is unclear whether positive psychological health may also be beneficial for stroke risk. The purpose of the present study was to examine prospectively the association between emotional vitality and incident stroke in a nationally representative sample of 6,019 participants in the first National Health and Nutrition Examination Survey Epidemiologic Follow-up Study. Methods: Emotional vitality was assessed via self-report at study baseline in 1971-1975. Stroke cases were identified from hospital/nursing home discharge reports and death certificates. Multivariate Cox proportional hazards regression models were used to estimate hazard ratios and 95% confidence intervals of incident stroke associated with a 1 SD increase in emotional vitality scores. Models were adjusted for traditional cardiovascular disease risk factors and subsequently for psychological distress. Results: Higher emotional vitality was associated with lower risk of incident stroke over a mean of 16.29 (SD = 4.75) years of follow -up (hazard ratio = 0.89; 95% confidence interval: 0.81, 0.99). Findings persisted when controlling for traditional cardiovascular disease risk factors and psychological distress. Conclusions: Higher levels of emotional vitality were prospectively associated with lower stroke risk in a representative sample of the U.S. population. Associations were independent of psychological distress. Results point to the potential importance of positive psychological functioning for cardiovascular health and for stroke prevention. C1 [Lambiase, Maya J.] VA Pittsburgh Healthcare Syst, Dept Vet Affairs, Pittsburgh, PA 15240 USA. [Lambiase, Maya J.; Thurston, Rebecca C.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15260 USA. [Kubzansky, Laura D.] Harvard Univ, Sch Publ Hlth, Dept Social & Behav Sci, Cambridge, MA 02138 USA. RP Lambiase, MJ (reprint author), VA Pittsburgh Healthcare Syst, Res Off Bldg 151R,Univ Dr C, Pittsburgh, PA 15240 USA. EM Maya.Lambiase@va.gov FU Department of Veterans Affairs Advanced Fellowship in Women's Health, VA Pittsburgh Healthcare System; National Institute of Mental Health [MH092707-01]; Robert Wood Johnson Foundation Health and Society Scholars Implementation [045821]; Robert Wood Johnson Foundation FX This work is supported by resources and funding from the Department of Veterans Affairs Advanced Fellowship in Women's Health, VA Pittsburgh Healthcare System. This work was also supported by the National Institute of Mental Health (MH092707-01), the Robert Wood Johnson Foundation Health and Society Scholars Implementation Grant 045821, and the Robert Wood Johnson Foundation grant, "Exploring the Concept of Positive Health." The contents do not represent the views of the Department of Veterans Affairs, Department of Defense, or the United States Government. NR 13 TC 2 Z9 2 U1 6 U2 12 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0278-6133 EI 1930-7810 J9 HEALTH PSYCHOL JI Health Psychol. PD OCT PY 2015 VL 34 IS 10 BP 1043 EP 1046 DI 10.1037/hea0000228 PG 4 WC Psychology, Clinical; Psychology SC Psychology GA CR8XC UT WOS:000361636600009 PM 25867031 ER PT J AU Wang, ZJ Zhou, YJ Galper, BZ Gao, F Yeh, RW Mauri, L AF Wang, Zhi Jian Zhou, Yu Jie Galper, Benjamin Z. Gao, Fei Yeh, Robert W. Mauri, Laura TI Association of body mass index with mortality and cardiovascular events for patients with coronary artery disease: a systematic review and meta-analysis SO HEART LA English DT Article ID OBESITY PARADOX; HEART-DISEASE; MYOCARDIAL-INFARCTION; US ADULTS; IMPACT; INTERVENTION; PREVALENCE; FITNESS; WEIGHT; COHORT AB Objectives The association between obesity and prognosis in patients with coronary artery disease (CAD) remains uncertain. We undertook a meta-analysis for the effects of body mass index (BMI) on mortality and cardiovascular events in these patients. Methods We identified studies that provided risk estimates for mortality or cardiovascular events on the basis of BMI in patients with CAD. Summary estimates of relative risks were obtained for five BMI groups: underweight, normal-weight, overweight, obese and grade II/III obese. Mortality was analysed separately as short-term (<6 months) and long-term (>= 6 months). Results Data from 89 studies with 1 300 794 patients were included. Mean follow-up of long-term estimates was 3.2 years. Using normal-weight as the reference, underweight was associated with higher risk of short-term mortality (2.24 (1.85 to 2.72)) and long-term mortality (1.70 (1.56 to 1.86)), overweight and obesity were both associated with lower risk of short-term mortality (0.69 (0.64 to 0.75); 0.68 (0.61 to 0.75)) and long-term mortality (0.78 (0.74 to 0.82); 0.79 (0.73 to 0.85)), but the long-term benefit of obesity disappeared after 5 years of follow-up (0.99 (0.91 to 1.08)). Grade II/III obesity was associated with lower risk of mortality in the short term (0.76 (0.62 to 0.91)) but higher risk after 5 years of follow-up (1.25 (1.14 to 1.38)). The similar J-shaped pattern was also seen for cardiovascular mortality and across different treatment strategies. Meta-regression found an attenuation of the inverse association between BMI and risk of mortality over longer follow-up. Conclusions Our data support a J-shaped relationship between mortality and BMI in patients with CAD. The limitation of current literature warrants better design of future studies. C1 [Wang, Zhi Jian; Zhou, Yu Jie; Gao, Fei] Capital Med Univ, Beijing Anzhen Hosp, Beijing Inst Heart Lung & Blood Vessel Dis, Beijing 100029, Peoples R China. [Wang, Zhi Jian; Galper, Benjamin Z.; Mauri, Laura] Brigham & Womens Hosp, Boston, MA 02115 USA. [Wang, Zhi Jian; Galper, Benjamin Z.; Yeh, Robert W.; Mauri, Laura] Harvard Univ, Sch Med, Boston, MA USA. [Yeh, Robert W.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Yeh, Robert W.; Mauri, Laura] Harvard Clin Res Inst, Boston, MA USA. RP Zhou, YJ (reprint author), Capital Med Univ, Beijing Anzhen Hosp, Dept Cardiol, Anzhen Ave 2, Beijing 100029, Peoples R China. EM azzyj12@163.com NR 28 TC 20 Z9 20 U1 1 U2 8 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 OCT PY 2015 VL 101 IS 20 BP 1631 EP 1638 DI 10.1136/heartjnl-2014-307119 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CS1KT UT WOS:000361824200008 PM 26025084 ER PT J AU Faghih, RT Dahleh, MA Adler, GK Klerman, EB Brown, EN AF Faghih, Rose T. Dahleh, Munther A. Adler, Gail K. Klerman, Elizabeth B. Brown, Emery N. TI Quantifying Pituitary-Adrenal Dynamics and Deconvolution of Concurrent Cortisol and Adrenocorticotropic Hormone Data by Compressed Sensing SO IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING LA English DT Article DE Algorithms; biological system modeling; biomedical signal processing; compressed sensing; parameter estimation ID MODEL; ALGORITHM; PROFILES; FEEDBACK; FOCUSS; WOMEN; ACTH AB Pulsatile release of cortisol from the adrenal glands is governed by pulsatile release of adrenocorticotropic hormone (ACTH) from the anterior pituitary. In return, cortisol has a negative feedback effect on ACTH release. Simultaneous recording of ACTH and cortisol is not typical, and determining the number, timing, and amplitudes of pulsatile events from simultaneously recorded data is challenging because of several factors: 1) stimulator ACTH pulse activity, 2) kinematics of ACTH and cortisol, 3) the sampling interval, and 4) the measurement error. We model ACTH and cortisol secretion simultaneously using a linear differential equations model with Gaussian errors and sparse pulsatile events as inputs to the model. We propose a novel framework for recovering pulses and parameters underlying the interactions between ACTH and cortisol. We recover the timing and amplitudes of pulses using compressed sensing and employ generalized cross validation for determining the number of pulses. We analyze serum ACTH and cortisol levels sampled at 10-min intervals over 24 h from ten healthy women. We recover physiologically plausible timing and amplitudes for these pulses and model the feedback effect of cortisol. We recover 15 to 18 pulses over 24 h, which is highly consistent with the results of another cortisol data analysis approach. Modeling the interactions between ACTH and cortisol allows for accurate quantification of pulsatile events, and normal and pathological states. This could lay the basis for a more physiologically-based approach for administering cortisol therapeutically. The proposed approach can be adapted to deconvolve other pairs of hormones with similar interactions. C1 [Faghih, Rose T.; Dahleh, Munther A.] MIT, Cambridge, MA 02139 USA. [Faghih, Rose T.] Massachusetts Gen Hosp, MIT Harvard Neurosci Stat Res Lab, Boston, MA 02114 USA. [Adler, Gail K.; Klerman, Elizabeth B.; Brown, Emery N.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Adler, Gail K.; Klerman, Elizabeth B.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Brown, Emery N.] MIT, Massachusetts Gen Hosp, Cambridge, MA 02139 USA. [Faghih, Rose T.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Faghih, Rose T.] MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA. [Faghih, Rose T.] MIT, Lab Informat & Decis Syst, Cambridge, MA 02139 USA. [Dahleh, Munther A.] MIT, Dept Elect Engn & Comp Sci EECS, EECS, Cambridge, MA 02139 USA. [Adler, Gail K.] Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, Med, Boston, MA 02115 USA. [Adler, Gail K.] Brigham & Womens Hosp, Harvard Catalyst Clin Res Ctr, Boston, MA 02115 USA. [Klerman, Elizabeth B.] Brigham & Womens Hosp, Div Sleep & Circadian Disorders, Analyt & Modeling Unit, Med & Neurol, Boston, MA 02115 USA. [Brown, Emery N.] MIT, Inst Med Engn & Sci, Med Engn, Cambridge, MA 02139 USA. [Brown, Emery N.] MIT, Dept Brain & Cognit Sci, Computat Neurosci, Cambridge, MA 02139 USA. [Brown, Emery N.] Harvard Univ, Sch Med, Anaesthesia, Cambridge, MA 02138 USA. RP Faghih, RT (reprint author), MIT, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM rfaghih@mit.edu FU NIH [R01AR43130, M01RR20635, K01AG00661, R01GM 53559, K24 HL103845, DP1 OD003646]; NASA [NCC9-58]; NSBRI; NSF Graduate Research Fellowship; National Space Biomedical Research Institute through NASA [NIH P01-AG09975, K24-HL105664, RC2-HL101340, R01-HL-11408, R01-64105018, HFP01603, HFP02802, NCC 9-58]; NSF [0836720]; [EFRI-0735956] FX The original data collection was supported under Grant NIH R01AR43130 (GKA), Grant M01RR20635 (BWH GCRC), Grant K01AG00661 (EBK), Grant R01GM 53559 (ENB), and Grant NASA NCC9-58 with the NSBRI. The work of R. T. Faghih was supported in part by the NSF Graduate Research Fellowship. The work of M. A. Dahleh was supported in part under Grant EFRI-0735956. The work of G. K. Adler was supported in part under Grant NIH K24 HL103845. The work of E. B. Klerman was supported in part under Grant NIH P01-AG09975, Grant K24-HL105664, Grant RC2-HL101340, Grant R01-HL-11408, Grant R01-64105018, and Grant HFP01603 and Grant HFP02802 from the National Space Biomedical Research Institute through NASA NCC 9-58. The work of E. N. Brown was supported in part by NIH under Grant DP1 OD003646 and by NSF under Grant 0836720. A preliminary version of this work was presented in R. T. Faghih's Ph.D. dissertation [4]. Asterisk indicates corresponding author.. NR 28 TC 1 Z9 1 U1 0 U2 8 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0018-9294 EI 1558-2531 J9 IEEE T BIO-MED ENG JI IEEE Trans. Biomed. Eng. PD OCT PY 2015 VL 62 IS 10 BP 2379 EP 2388 DI 10.1109/TBME.2015.2427745 PG 10 WC Engineering, Biomedical SC Engineering GA CR9TZ UT WOS:000361701300006 PM 25935025 ER PT J AU Ghassemi, M Van Stan, JH Mehta, DD Zanartu, M Cheyne, HA Hillman, RE Guttag, JV AF Ghassemi, Marzyeh Van Stan, Jarrad H. Mehta, Daryush D. Zanartu, Matias Cheyne, Harold A., II Hillman, Robert E. Guttag, John V. TI Learning to Detect Vocal Hyperfunction From Ambulatory Neck-Surface Acceleration Features: Initial Results For Vocal Fold Nodules (vol 61, pg 1668, 2014) SO IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING LA English DT Correction C1 [Ghassemi, Marzyeh; Guttag, John V.] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. [Van Stan, Jarrad H.] Massachusetts Gen Hosp, Ctr Laryngeal Surg & Voice Rehabil, Boston, MA 02114 USA. [Van Stan, Jarrad H.; Hillman, Robert E.] Massachusetts Gen Hosp, Inst Hlth Profess, Boston, MA 02114 USA. [Mehta, Daryush D.; Hillman, Robert E.] Massachusetts Gen Hosp, Ctr Laryngeal Surg & Voice Rehabil, Boston, MA 02114 USA. [Mehta, Daryush D.; Hillman, Robert E.] Harvard Univ, Sch Med, Dept Surg, Cambridge, MA 02138 USA. [Zanartu, Matias] Univ Tecn Federico Santa Maria, Dept Elect Engn, Valparaiso, Chile. [Cheyne, Harold A., II] Cornell Univ, Ornithol Lab, Bioacoust Res Program, Ithaca, NY 14853 USA. RP Ghassemi, M (reprint author), MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. EM mghassem@mit.edu NR 1 TC 0 Z9 0 U1 2 U2 4 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0018-9294 EI 1558-2531 J9 IEEE T BIO-MED ENG JI IEEE Trans. Biomed. Eng. PD OCT PY 2015 VL 62 IS 10 BP 2544 EP 2544 DI 10.1109/TBME.2015.2465051 PG 1 WC Engineering, Biomedical SC Engineering GA CR9TZ UT WOS:000361701300021 PM 26389645 ER PT J AU Pringle, PL Stewart, KO Peloquin, JM Sturgeon, HC Nguyen, D Sauk, J Garber, JJ Yajnik, V Ananthakrishnan, AN Chan, AT Xavier, RJ Khalili, H AF Pringle, Patricia L. Stewart, Kathleen O. Peloquin, Joanna M. Sturgeon, Holly C. Deanna Nguyen Sauk, Jenny Garber, John J. Yajnik, Vijay Ananthakrishnan, Ashwin N. Chan, Andrew T. Xavier, Ramnik J. Khalili, Hamed TI Body Mass Index, Genetic Susceptibility, and Risk of Complications Among Individuals with Crohn's Disease SO INFLAMMATORY BOWEL DISEASES LA English DT Article DE obesity; Crohn's disease complications; genetic predisposition ID INFLAMMATORY-BOWEL-DISEASE; MESENTERIC ADIPOSE-TISSUE; NECROSIS-FACTOR-ALPHA; CLINICAL-COURSE; INSULIN-RESISTANCE; ADIPONECTIN; OBESITY; PROTEIN; IMPACT; COHORT AB Background:Obesity is associated with systemic and intestine-specific inflammation and alterations in gut microbiota, which in turn impact mucosal immunity. Nonetheless, a specific role of obesity and its interaction with genetics in the progression of Crohn's disease (CD) is unclear.Methods:We conducted a cross-sectional study of patients with CD enrolled in Prospective Registry in Inflammatory Bowel Disease Study at Massachusetts General Hospital (PRISM). Information on diagnosis of CD and its complications were collected and confirmed through review of medical records. A genetic risk score was calculated using previously reported single-nucleotide polymorphisms-associated genome-wide with CD susceptibility. We used logistic regression to estimate the effect of body mass index (BMI) and its interaction with genetic risk on risk of CD complications.Results:Among 846 patients with CD, 350 required surgery, 242 with penetrating disease, 182 with stricturing disease, and 226 with perianal disease. There were no associations between obesity (BMI 30 kg/m(2)) and risk of perianal disease, stricturing disease, or surgery. Compared with normal-weight individuals with BMI < 25 kg/m(2), obesity was associated with lower risk of penetrating disease (odds ratio [OR = 0.56; 95% confidence interval [CI], 0.31-0.99). This association persists among a subgroup of participants with available BMI before development of penetrating disease (OR = 0.40; 95% CI, 0.16-0.88). There were no interactions between BMI and genetic risk score on risk of CD complications (all P-interaction > 0.28).Conclusions:Our data suggest that obesity does not negatively impact long-term progression of CD, even after accounting for genetic predisposition. C1 [Pringle, Patricia L.; Stewart, Kathleen O.; Peloquin, Joanna M.; Sturgeon, Holly C.; Deanna Nguyen; Sauk, Jenny; Garber, John J.; Yajnik, Vijay; Ananthakrishnan, Ashwin N.; Chan, Andrew T.; Xavier, Ramnik J.; Khalili, Hamed] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Gastroenterol, Boston, MA USA. [Chan, Andrew T.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Div Network Med, Boston, MA 02115 USA. [Xavier, Ramnik J.] Broad Inst, Cambridge, MA USA. [Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. RP Khalili, H (reprint author), Massachusetts Gen Hosp, Digest Healthcare Ctr, Crohns & Colitis Ctr, 165 Cambridge St,9th Floor, Boston, MA 02114 USA. EM hkhalili@mgh.harvard.edu FU Crohn's and Colitis Foundation of America (CCFA); American Gastroenterological Association (AGA); National Institute of Diabetes and Digestive and Kidney Diseases [K23 DK099681]; [K24 DK098311] FX A. T. Chan is supported by a senior investigator grant from the Crohn's and Colitis Foundation of America (CCFA) and K24 DK098311. H. Khalili is supported by a career development award from the American Gastroenterological Association (AGA) and by National Institute of Diabetes and Digestive and Kidney Diseases (K23 DK099681). A. N. Ananthakrishnan is a member of the scientific advisory board for Prometheus Inc, and Janssen, Inc. A. T. Chan has served as a consultant for Bayer Healthcare, Millennium Pharmaceuticals, Pfizer Inc., and Pozen Inc. R. J. Xavier has served as a consultant for Novartis. V. Yajnik has served as a consultant for Biogen, UCB, NPS, Jansen, AbbVie, and Takeda. The remaining authors have no conflict of interest to disclose. NR 31 TC 4 Z9 4 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1078-0998 EI 1536-4844 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD OCT PY 2015 VL 21 IS 10 BP 2304 EP 2310 DI 10.1097/MIB.0000000000000498 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CR6WW UT WOS:000361489900009 PM 26181430 ER PT J AU Ananthakrishnan, AN Khalili, H Song, MY Higuchi, LM Richter, JM Nimptsch, K Wu, K Chan, AT AF Ananthakrishnan, Ashwin N. Khalili, Hamed Song, Mingyang Higuchi, Leslie M. Richter, James M. Nimptsch, Katharina Wu, Kana Chan, Andrew T. TI High School Diet and Risk of Crohn's Disease and Ulcerative Colitis SO INFLAMMATORY BOWEL DISEASES LA English DT Article DE Crohn's disease; ulcerative colitis; diet; iron; fiber ID INFLAMMATORY-BOWEL-DISEASE; FOOD FREQUENCY QUESTIONNAIRE; MIDDLE-AGED WOMEN; LONG-TERM INTAKE; FATTY-ACIDS; IRON SUPPLEMENTATION; PROSPECTIVE COHORT; ADOLESCENT DIET; OLMSTED COUNTY; NURSES HEALTH AB Background:Diet may play an important role in the pathogenesis of Crohn's disease (CD) and ulcerative colitis (UC); yet, there are few prospective studies of dietary factors. None have examined the association between adolescent diet and risk of inflammatory bowel diseases (CD and UC).Methods:This study included women enrolled in Nurses' Health Study II who completed a validated high school dietary questionnaire in 1998. We examined the effect of dietary patterns (prudent or Western diet) and individual components of each patterns. We documented incident cases of CD and UC through 2011 based on physician review of medical records and used Cox proportional hazards models adjusting for confounders to estimate hazard ratios and confidence intervals for CD and UC.Results:Over 763,229 person-years of follow-up, we identified 70 incident cases of CD and 103 cases of UC. Compared with women in the lowest quartile of a prudent diet score (characterized by greater intake of fruits, vegetables, and fish), women in the highest quartile had a 53% lower risk of CD (hazard ratio, 0.47; 95% confidence interval, 0.23-0.98; P-trend = 0.04). Specifically, greater intake of fish (P-trend = 0.01) and fiber (P-trend = 0.06) were associated with lower risk of CD. In contrast, Western diet score was not associated with risk of CD. Neither dietary patterns nor individual food or nutrient groups was associated with UC.Conclusions:Adolescent diet is associated with risk of CD, but not UC, offering insights into disease pathogenesis. C1 [Ananthakrishnan, Ashwin N.; Khalili, Hamed; Richter, James M.; Chan, Andrew T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Gastroenterol, Boston, MA USA. [Song, Mingyang; Nimptsch, Katharina; Wu, Kana] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA. [Song, Mingyang; Nimptsch, Katharina; Wu, Kana] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Higuchi, Leslie M.] Harvard Univ, Sch Med, Childrens Hosp Boston, Div Gastroenterol & Nutr, Boston, MA USA. [Nimptsch, Katharina] Max Delbruck Ctr Mol Med MDC, Mol Epidemiol Res Grp, Berlin, Germany. [Chan, Andrew T.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Div Network Med,Dept Med, Boston, MA 02115 USA. RP Ananthakrishnan, AN (reprint author), Massachusetts Gen Hosp, Crohns & Colitis Ctr, 165 Cambridge St,9th Floor, Boston, MA 02114 USA. EM aananthakrishnan@mgh.harvard.edu RI Song, Mingyang/M-6701-2013; OI Song, Mingyang/0000-0002-1324-0316; Nimptsch, Katharina/0000-0001-7877-205X FU Crohn's and Colitis Foundation of America; National Institutes of Health [K24 DK098311, P01 CA87969, P30 DK043351, K08 DK064256, K23 DK091742, K23 DK099681, UM1 CA176276] FX Supported by a Senior Investigator Award from the Crohn's and Colitis Foundation of America (to A.T.C.) and the National Institutes of Health (K24 DK098311, P01 CA87969, P30 DK043351, K08 DK064256, K23 DK091742, K23 DK099681, and UM1 CA176276). A. N. Ananthakrishnan: Scientific advisory board for Cubist and Abbvie. J. M. Richter: Consultant for Policy Analysis, Inc.; A. T. Chan: Consultant for Bayer HealthCare, Millennium Pharmaceuticals, Pfizer Inc., Pozen Inc. The remaining authors have no conflict of interest to disclose. NR 61 TC 5 Z9 5 U1 3 U2 10 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 OCT PY 2015 VL 21 IS 10 BP 2311 EP 2319 DI 10.1097/MIB.0000000000000501 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CR6WW UT WOS:000361489900010 PM 26236952 ER PT J AU Bengali, R Vazquez, R AF Bengali, Raheel Vazquez, Rafael TI Inferior Vena Cava Filter Embolus to the Right Ventricle: Anesthesia and High-Risk Percutaneous Procedures SO JOURNAL OF CARDIOTHORACIC AND VASCULAR ANESTHESIA LA English DT Article DE inferior vena cava filter; interventional radiology; IVC filter; embolization; retrieval; anesthesia for percutaneous procedures ID EMBOLIZATION; ASSOCIATION; TAMPONADE; PLACEMENT; FRACTURE C1 [Bengali, Raheel; Vazquez, Rafael] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Bengali, R (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St,Jackson 422, Boston, MA 02114 USA. EM rbengali@partners.org NR 12 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 1053-0770 EI 1532-8422 J9 J CARDIOTHOR VASC AN JI J. Cardiothorac. Vasc. Anesth. PD OCT PY 2015 VL 29 IS 5 BP 1322 EP 1327 DI 10.1053/j.jvca.2014.05.021 PG 6 WC Anesthesiology; Cardiac & Cardiovascular Systems; Respiratory System; Peripheral Vascular Disease SC Anesthesiology; Cardiovascular System & Cardiology; Respiratory System GA CS0WM UT WOS:000361782900035 PM 25304888 ER PT J AU Lo, WK Mashimo, H AF Lo, Wai-Kit Mashimo, Hiroshi TI Critical Assessment of Endoscopic Techniques for Gastroesophageal Reflux Disease SO JOURNAL OF CLINICAL GASTROENTEROLOGY LA English DT Review DE gastroesophageal reflux disease; advanced endoscopic techniques; radiofrequency; endoscopic placation; injectable bulking agents ID TRANSORAL INCISIONLESS FUNDOPLICATION; RADIOFREQUENCY ENERGY DELIVERY; LOWER ESOPHAGEAL SPHINCTER; FULL-THICKNESS PLICATION; LAPAROSCOPIC ANTIREFLUX SURGERY; SHAM-CONTROLLED TRIAL; RANDOMIZED CLINICAL-TRIAL; PUMP INHIBITOR THERAPY; LONG-TERM FAILURE; STRETTA RADIOFREQUENCY AB Over the past 2 decades, a number of new endoscopic techniques have been developed for management of gastroesophageal (GE) reflux disease symptoms as alternatives to medical management and surgical fundoplication. These devices include application of radiofrequency treatment (Stretta), endoscopic plication (EndoCinch, Plicator, Esophyx, MUSE), and injection of bulking agents (Enteryx, Gatekeeper, Plexiglas, Duragel). Their goal was symptom relief through reduction of tissue compliance and enhancement of anatomic resistance at the GE junction. In this review, we critically assess the research behind the efficacy, safety, and durability of these treatments to better understand their roles in contemporary GE reflux disease management. C1 [Lo, Wai-Kit; Mashimo, Hiroshi] VA Boston Healthcare Syst, Dept Gastroenterol, West Roxbury, MA 02132 USA. [Lo, Wai-Kit] Brigham & Womens Hosp, Div Gastroenterol Hepatol & Endoscopy, Boston, MA 02115 USA. [Lo, Wai-Kit; Mashimo, Hiroshi] Harvard Univ, Sch Med, Boston, MA USA. RP Mashimo, H (reprint author), VA Boston Healthcare Syst, Dept Gastroenterol, 1400 VFW Pkwy, West Roxbury, MA 02132 USA. EM hmashimo@hms.harvard.edu OI Lo, Wai-Kit/0000-0002-1526-352X NR 52 TC 3 Z9 4 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0192-0790 EI 1539-2031 J9 J CLIN GASTROENTEROL JI J. Clin. Gastroenterol. PD OCT PY 2015 VL 49 IS 9 BP 720 EP 724 DI 10.1097/MCG.0000000000000389 PG 5 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CR6SR UT WOS:000361478200002 PM 26241152 ER PT J AU Korsten, MA Spungen, AM Radulovic, M Rosman, AS Hunt, K Galea, MD Kornfeld, SD Lyons, BL Yen, C Bauman, WA AF Korsten, Mark A. Spungen, Ann M. Radulovic, Miroslav Rosman, Alan S. Hunt, Kristel Galea, Marinella D. Kornfeld, Stephen D. Lyons, Brian L. Yen, Christina Bauman, William A. TI Neostigmine Administered With MoviPrep Improves Bowel Preparation for Elective Colonoscopy in Patients With Spinal Cord Injury A Randomized Study SO JOURNAL OF CLINICAL GASTROENTEROLOGY LA English DT Article DE neostigmine; MoviPrep; paraplegia; tetraplegia; colonoscopy ID ORAL SODIUM-PHOSPHATE; POLYETHYLENE-GLYCOL SOLUTION; MAGNESIUM CITRATE; CONTROLLED-TRIAL; LAVAGE SOLUTION; GLYCOPYRROLATE; EVACUATION; REGIMENS; EFFICACY; SAFETY AB Background:Poor preparation for elective colonoscopy is exceedingly common in persons with spinal cord injury (SCI). This unsatisfactory outcome is likely due to long-standing difficulty with evacuation and decreased colonic motility, which may result in inadequate responses to conventional bowel preparation regimens. We determined whether the addition of neostigmine to MoviPrep before elective colonoscopy produced a higher percentage of acceptable bowel preparations in patients with SCI.Methods:Twenty-seven SCI subjects were prospectively randomized to 1 of 2 arms: low-volume polyethylene glycol-electrolyte lavage with ascorbic acid (MoviPrep) or MoviPrep plus neostigmine methylsulfate and glycopyrrolate (MoviPrep+NG); 28 able-bodied subjects received MoviPrep alone. The quality of the cleansing preparation for colonoscopy was determined by gastroenterologists calibrated to use the Ottawa Scoring System, with an acceptable Ottawa Score (OS) considered to be 3.Results:The administration of MoviPrep alone resulted in suboptimal bowel cleansing in the SCI group compared with the able-bodied group (50% vs. 89% of subjects had an acceptable OS; (2)=7.94, P=0.05). However, when NG was added to MoviPrep in the SCI group, it markedly improved the quality of the bowel preparation, with 85% of patients then having an acceptable OS. The use of NG resulted in minimal bloating and distention before bowel evacuation (P=0.0005), and eye and muscle twitching; these were resolved within 1 hour after NG administration. No significant differences were noted among the preparation groups for adenoma detection rate (P=0.41).Conclusions:The combination of MoviPrep+NG was safe, well tolerated, and an effective approach to prepare the bowel for elective colonoscopy in patients with SCI. The side effects of this preparation were significant compared with the other treatment groups but were considered mild and anticipated. C1 [Korsten, Mark A.; Spungen, Ann M.; Radulovic, Miroslav; Galea, Marinella D.; Kornfeld, Stephen D.; Lyons, Brian L.; Yen, Christina; Bauman, William A.] James J Peters VA Med Ctr, Natl Ctr Excellence Med Consequences SCI, Bronx, NY 10468 USA. [Korsten, Mark A.; Radulovic, Miroslav; Rosman, Alan S.; Hunt, Kristel; Bauman, William A.] James J Peters VA Med Ctr, Med Serv, Bronx, NY 10468 USA. [Korsten, Mark A.; Galea, Marinella D.; Kornfeld, Stephen D.; Bauman, William A.] James J Peters VA Med Ctr, Spinal Cord Injury Serv, Bronx, NY 10468 USA. [Korsten, Mark A.; Spungen, Ann M.; Radulovic, Miroslav; Rosman, Alan S.; Hunt, Kristel; Bauman, William A.] Icahn Sch Med Mt Sinai, Dept Med, New York, NY 10029 USA. [Spungen, Ann M.; Galea, Marinella D.; Kornfeld, Stephen D.; Bauman, William A.] Icahn Sch Med Mt Sinai, Dept Rehabil Med, New York, NY 10029 USA. RP Korsten, MA (reprint author), James J Peters VA Med Ctr, Natl Ctr Excellence Med Consequences SCI, Rm 7 A-13 K,130 West Kingsbridge Rd, Bronx, NY 10468 USA. EM mark.korsten@va.gov FU Department of Veterans Affairs Rehabilitation Research and Development Service [A6428R, B2468-C, B4162-C]; James J. Peters VA Medical Center FX Supported by the Department of Veterans Affairs Rehabilitation Research and Development Service (#A6428R, #B2468-C, #B4162-C) and the James J. Peters VA Medical Center. None of the authors have financial interests with Salix, the manufacturer of MoviPrep. NR 20 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0192-0790 EI 1539-2031 J9 J CLIN GASTROENTEROL JI J. Clin. Gastroenterol. PD OCT PY 2015 VL 49 IS 9 BP 751 EP 756 DI 10.1097/MCG.0000000000000284 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CR6SR UT WOS:000361478200006 PM 25599220 ER PT J AU Alvarez-Breckenridge, CA Attiah, MA Zachariah, M Gummadavelli, A Yang, J Codd, PJ AF Alvarez-Breckenridge, Christopher A. Attiah, Mark A. Zachariah, Marcus Gummadavelli, Abhijeet Yang, Jimmy Codd, Patrick J. TI Ventriculoperitoneal shunt placement for POEMS syndrome SO JOURNAL OF CLINICAL NEUROSCIENCE LA English DT Article DE Cerebrospinal fluid diversion; Intracranial pressure; Papilledema; POEMS syndrome; Vascular endothelial growth factor ID POLYNEUROPATHY AB We report a 41-year-old woman with a history of an uncomplicated spinal hemangioma resection, who developed acute onset sensory-motor polyneuropathy following influenza vaccine administration. With extensive workup she was diagnosed with POEMS syndrome with progressive headaches, visual loss with papilledema, and repeated elevated lumbar puncture opening pressures despite treatment with acetazolamide and immunosuppressive therapy. Her symptoms dramatically improved following ventriculoperitoneal shunt placement. POEMS syndrome is a paraneoplastic disorder involving a constellation of clinical symptoms including polyneuropathy, organomegaly, endocrinopathy, monoclonal protein elevation, and skin changes. The progression of the disease involves a number of neurovascular sequelae, including symmetric sensory-motor polyneuropathy resembling chronic inflammatory demyelinating polyneuropathy, cerebrovascular accidents, and papilledema associated with increased intracranial pressure. Despite the association of POEMS with papilledema, treatment for this finding typically includes acetazolamide and therapeutic large volume lumbar punctures. To our knowledge, this is the first report of cerebrospinal fluid shunting for the symptomatic management of hydrocephalus associated with POEMS syndrome. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Alvarez-Breckenridge, Christopher A.; Zachariah, Marcus; Yang, Jimmy; Codd, Patrick J.] Harvard Univ, Sch Med, Dept Neurosurg, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Attiah, Mark A.] Univ Penn, Dept Neurosurg, Perelman Sch Med, Philadelphia, PA 19104 USA. [Gummadavelli, Abhijeet] Yale Univ, Sch Med, Dept Neurosurg, New Haven, CT USA. RP Alvarez-Breckenridge, CA (reprint author), Harvard Univ, Sch Med, Dept Neurosurg, Massachusetts Gen Hosp, 15 Parkman St Wang 021, Boston, MA 02114 USA. EM calvarez-breckenridge@partners.org NR 11 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0967-5868 EI 1532-2653 J9 J CLIN NEUROSCI JI J. Clin. Neurosci. PD OCT PY 2015 VL 22 IS 10 BP 1672 EP 1674 DI 10.1016/j.jocn.2015.03.042 PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CS0SS UT WOS:000361773100024 PM 26077937 ER PT J AU Vohringer, PA Ostacher, MJ El-Mallakh, RS Holtzman, NS Thommi, SB Whitham, EA Sullivan, MC Baldassano, CF Goodwin, FK Baldessarini, RJ Ghaemi, SN AF Voehringer, Paul A. Ostacher, Michael J. El-Mallakh, Rif S. Holtzman, Niki S. Thommi, Sairah B. Whitham, Elizabeth A. Sullivan, Matthew C. Baldassano, Claudia F. Goodwin, Fredrick K. Baldessarini, Ross J. Ghaemi, S. Nassir TI Antidepressants in Type II Versus Type I Bipolar Depression A Randomized Discontinuation Trial SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Article DE bipolar disorder; antidepressants; maintenance treatment ID TREATMENT ENHANCEMENT PROGRAM; DISORDER STEP-BD; LITHIUM MONOTHERAPY; SAFETY; VENLAFAXINE; PLACEBO; DESIGN AB Background We sought to test the hypothesis that antidepressants (ADs) may show preferential efficacy and safety among patients with type II bipolar disorder (BD, BD-II) more than patients with type I BD (BD-I). Methods Patients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, BD-I (n = 21) and BD-II (n = 49) in acute major depressive episodes were treated with ADs plus mood stabilizers to euthymia sustained for 2 months and then randomized openly to continue or discontinue ADs for up to 3 years. Outcomes were episode recurrences and changes in standardized symptom ratings. Results In follow-up averaging 1.64 years, both subgroups showed improvement in depressive episode frequency with AD continuation, but contrary to the hypothesis, more improvement was seen in BD-I than in BD-II (for type II, mean [standard deviation] decrease in depressive episodes per year, 0.21 [0.26]; for type I, mean (SD) decrease, 0.35 [0.15]). Subjects with BD-II who continued on ADs had slightly more depressive, but fewer manic/hypomanic, episodes than subjects with BD-I. No notable differences were seen in either group in time to a recurrence of mood episodes or total time-in-remission. Conclusions The findings do not confirm the hypothesis that long-term AD treatment in patients with BP-II has better outcomes than in patients with BD-I, except somewhat lower risk of manic/hypomanic episodes. C1 [Voehringer, Paul A.; Holtzman, Niki S.; Thommi, Sairah B.; Whitham, Elizabeth A.; Sullivan, Matthew C.; Ghaemi, S. Nassir] Tufts Univ, Med Ctr, Dept Psychiat, Mood Disorders Program, Boston, MA 02111 USA. [Voehringer, Paul A.] Univ Chile, Fac Med, Hosp Clin Univ Chile, Dept Psychiat, Santiago 7, Chile. [Ostacher, Michael J.] Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. [El-Mallakh, Rif S.] Univ Kentucky, Coll Med, Dept Psychiat, Louisville, KY USA. [Baldassano, Claudia F.] Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. [Goodwin, Fredrick K.] George Washington Univ, Sch Med, Ctr Neurosci Med Progress & Soc, Washington, DC USA. [Baldessarini, Ross J.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Baldessarini, Ross J.] Massachusetts Gen Hosp, Int Consortium Bipolar Disorder Res, McLean Div, Belmont, MA USA. [Ghaemi, S. Nassir] Tufts Univ, Sch Med, Boston, MA 02111 USA. RP Ghaemi, SN (reprint author), Tufts Med Ctr, 800 Washington St,Box 1007, Boston, MA 02111 USA. EM nghaemi@tuftsmedicalcenter.org RI Vohringer, Paul/B-5860-2013; OI Vohringer, Paul/0000-0002-2460-4680; Ostacher, Michael/0000-0003-0353-7535 FU National Institute of Mental Health Grant [MH-64189]; Bruce J. Anderson Foundation; McLean Private Donors Research Fund; Takeda FX Dr Ghaemi received support from National Institute of Mental Health Grant MH-64189 and Dr Baldessarini received, in part, grant support from the Bruce J. Anderson Foundation and the McLean Private Donors Research Fund.; In the past 36 months, Dr Ghaemi has had a research grant with Takeda and provided research consultation to Sunovion. All other authors declare no personal or immediate family business interests that might seem to represent conflicts of interest. NR 16 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 0271-0749 EI 1533-712X J9 J CLIN PSYCHOPHARM JI J. Clin. Psychopharmacol. PD OCT PY 2015 VL 35 IS 5 BP 605 EP 608 DI 10.1097/JCP.0000000000000384 PG 4 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA CR0TM UT WOS:000361036100019 PM 26267418 ER PT J AU Jaff, MR White, CJ Hiatt, WR Fowkes, GR Dormandy, J Razavi, M Reekers, J Norgren, L AF Jaff, Michael R. White, Christopher J. Hiatt, William R. Fowkes, Gerry R. Dormandy, John Razavi, Mahmood Reekers, Jim Norgren, Lars TI An Update on Methods for Revascularization and Expansion of the TASC Lesion Classification to Include Below-the-Knee Arteries: A Supplement to the Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II) SO JOURNAL OF ENDOVASCULAR THERAPY LA English DT Article DE angioplasty; arteries; claudication; critical limb ischemia; occlusion; peripheral artery disease; revascularization; stenosis; stents; surgery ID CRITICAL LIMB ISCHEMIA; AORTOILIAC OCCLUSIVE DISEASE; SUPERFICIAL FEMORAL-ARTERY; PERCUTANEOUS TRANSLUMINAL ANGIOPLASTY; RANDOMIZED CONTROLLED-TRIAL; NITINOL STENT IMPLANTATION; DRUG-ELUTING STENTS; BARE-METAL STENTS; EXTREMITY BYPASS-SURGERY; VEIN GRAFT FAILURE AB The Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC) guidelines were last updated in 2007 (TASC II) and represented the collaboration of international vascular specialties involved in the management of patients with peripheral arterial disease (PAD). Since the publication of TASC II, there have been innovations in endovascular revascularization strategies for patients with PAD. The intent of this publication is to provide a complete anatomic lower limb TASC lesion classification, including the infrapopliteal segment, and an updated literature review of new endovascular techniques and practice patterns employed by vascular specialists today. C1 [Jaff, Michael R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [White, Christopher J.] Ochsner Clin Fdn, Ochsner Clin School Univ Queensland, New Orleans, LA USA. [Hiatt, William R.] Univ Colorado, Sch Med, Div Cardiol, Aurora, CO USA. [Hiatt, William R.] CPC Clin Res, Aurora, CO USA. [Fowkes, Gerry R.] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh EH8 9YL, Midlothian, Scotland. [Dormandy, John] St George Hosp, London, England. [Razavi, Mahmood] St Josephs Hosp, Orange, CA USA. [Reekers, Jim] Univ Hosp, Academ Med Ctr, Amsterdam, Netherlands. [Norgren, Lars] Univ Orebro, Fac Med & Hlth, Dept Surg, SE-70182 Orebro, Sweden. RP Norgren, L (reprint author), Orebro Univ Hosp, Dept Surg, Surg, SE-70185 Orebro, Sweden. EM lars.norgren@regionorebrolan.se FU Aastrom Biosciences; Abbott Vascular; AnGes MG Inc; Bayer Schering Pharma; Biomedix; Cook; ev3; Mitsubishi Tanabe; Otsuka Pharmaceutical Co; Sanofi-Aventis; Toray Industries; Medtronic FX The author(s) report receiving the following financial support for the research, authorship, and/or publication of this article: VIVA Physicians [a 501(c)(3) education and research multispecialty organization] provided an unrestricted grant to the TASC organization. The development of this TASC II Supplement was supported by unrestricted educational grants awarded to Discovery London from (in alphabetical order): Aastrom Biosciences, Abbott Vascular, AnGes MG Inc, Bayer Schering Pharma, Biomedix, Cook, ev3, Medtronic, Mitsubishi Tanabe, Otsuka Pharmaceutical Co, Sanofi-Aventis, and Toray Industries. The companies did not participate in the discussions or in the preparation, review, or approval of the document. NR 90 TC 19 Z9 19 U1 4 U2 7 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1526-6028 EI 1545-1550 J9 J ENDOVASC THER JI J. Endovascular Ther. PD OCT PY 2015 VL 22 IS 5 BP 663 EP 677 DI 10.1177/1526602815592206 PG 15 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA CS1LQ UT WOS:000361827200001 ER PT J AU Garcia, LA Jaff, MR Rocha-Singh, KJ Zeller, T Bosarge, C Kamat, S McKinsey, JF AF Garcia, Lawrence A. Jaff, Michael R. Rocha-Singh, Krishna J. Zeller, Thomas Bosarge, Christopher Kamat, Suraj McKinsey, James F. TI A Comparison of Clinical Outcomes for Diabetic and Nondiabetic Patients Following Directional Atherectomy in the DEFINITIVE LE Claudicant Cohort SO JOURNAL OF ENDOVASCULAR THERAPY LA English DT Article DE atherectomy; claudication; diabetes mellitus; directional atherectomy; infrapopliteal arteries; patency; peripheral artery disease; popliteal artery; superficial femoral artery; target lesion revascularization ID PERIPHERAL ARTERIAL-DISEASE; LOWER-EXTREMITY ISCHEMIA; RANDOMIZED-TRIAL; FEMOROPOPLITEAL ARTERIES; ELUTING BALLOON; PRIMARY PATENCY; PREVALENCE; RESTENOSIS; LESIONS AB Purpose: To report a subset analysis that evaluated the hypothesis that directional atherectomy for peripheral artery disease in diabetic claudicants has noninferior primary patency at 12 months compared with nondiabetic claudicants. Methods: DEFINITIVE LE, a US/European multicenter study, assessed the effectiveness of directional atherectomy using SilverHawk/TurboHawk systems for treatment of peripheral artery disease in the superficial femoral, popliteal, and infrapopliteal arteries. Of the 800 patients enrolled in the study, only the 598 claudicant patients (mean age 69.5 +/- 10.4 years; 336 men) who were classified at baseline as Rutherford category 1-3 were eligible for this subset analysis. Of these, 46.8% (280/598) had diabetes. Follow-up to 12 months included duplex ultrasound examination, functional assessments, and adverse event evaluations. Independent angiographic and duplex ultrasound core laboratories assessed primary patency and secondary endpoints; a clinical events committee adjudicated adverse events. Results: Although diabetics had significantly more baseline comorbidities, 12-month primary patency (77.0%) was no different than for nondiabetics (77.9%; superiority p=0.98; noninferiority p<0.001) across all anatomic territories treated. Freedom from clinically driven target lesion revascularization was no different between diabetics (83.8%) and nondiabetics (87.5%) overall (p=0.19) or by lesion locations. Secondary clinical outcomes (Rutherford category, ankle-brachial index, and walking impairment) improved at 12 months for both diabetics and nondiabetics. Conclusion: Noninferior 12-month patency rates demonstrate that directional atherectomy is an effective treatment in diabetic as well as nondiabetic claudicants. Directional atherectomy remains an attractive treatment option, improving luminal diameters without stents, which preserves future treatment options for both diabetic and nondiabetic patients with progressive, diffuse vascular disease. C1 [Garcia, Lawrence A.] Tufts Univ, St Elizabeths Med Ctr, Sch Med, Sect Intervent Cardiol, Boston, MA 02111 USA. [Garcia, Lawrence A.] Tufts Univ, St Elizabeths Med Ctr, Sch Med, Sect Vasc Med, Boston, MA 02111 USA. [Jaff, Michael R.] Massachusetts Gen Hosp, Inst Heart Vasc & Stroke Care, Boston, MA 02114 USA. [Rocha-Singh, Krishna J.] St Johns Hosp, Prairie Heart Inst, Springfield, IL USA. [Zeller, Thomas] Univ Herzzentrum Freiburg, Bad Krozingen, Germany. [Bosarge, Christopher] Coastal Vasc & Intervent, Pensacola, FL USA. [Kamat, Suraj] Christus Spohn Hosp Alice, Alice, TX USA. [McKinsey, James F.] Univ Hosp Columbia & Cornell, New York Presbyterian Hosp, Div Vasc Surg, New York, NY USA. RP Garcia, LA (reprint author), St Elizabeths Med Ctr, Sect Intervent Cardiol, 736 Cambridge St, Boston, MA 02135 USA. EM Lawrence.garcia@steward.org FU Covidien, Mansfield, MA, USA FX The author(s) report receiving the following financial support for the research, authorship, and/or publication of this article: Research funded by Covidien, Mansfield, MA, USA. NR 33 TC 3 Z9 3 U1 5 U2 8 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1526-6028 EI 1545-1550 J9 J ENDOVASC THER JI J. Endovascular Ther. PD OCT PY 2015 VL 22 IS 5 BP 701 EP 711 DI 10.1177/1526602815599550 PG 11 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA CS1LQ UT WOS:000361827200006 PM 26250748 ER PT J AU Alavi, K Chan, S Wise, P Kaiser, AM Sudan, R Bordeianou, L AF Alavi, Karim Chan, Sook Wise, Paul Kaiser, Andreas M. Sudan, Ranjan Bordeianou, Liliana TI Fecal Incontinence: Etiology, Diagnosis, and Management SO JOURNAL OF GASTROINTESTINAL SURGERY LA English DT Article DE Fecal incontinence; Sacral nerve stimulation; Sphincteroplasty; Artificial sphincter; Graciloplasty ID ANTEGRADE CONTINENCE ENEMA; SACRAL NERVE-STIMULATION; QUALITY-OF-LIFE; RANDOMIZED CONTROLLED-TRIAL; ARTIFICIAL BOWEL SPHINCTER; ANAL ENDOSONOGRAPHY; SEVERITY INDEX; FOLLOW-UP; BIOFEEDBACK; ADULTS AB We sought to review the etiology, diagnosis, and treatment of fecal incontinence based on current literature. Additionally, newer treatment methods such as Solesta will be evaluated. There are many diagnostic modalities available to assess the degree and severity of the patient's incontinence; however, a thorough history and physical exam is critical. Initial attempts at treatment focus on medical management primarily through stool texture modification with the aid of bulking agents. Failure of medical therapy is often followed by a graded increase in the complexity and invasiveness of the available treatment options. The selection of the most appropriate surgical option, such as overlapping sphincteroplasty and neuromodulation, is multifactorial involving both surgeon and patient-related factors. Neuromodulation has received increased attention in the last decade due to its documented therapeutic success, and newer office-based procedures, such as the Solesta injection, are showing promising results in properly selected patients. Finally, diversion remains an option for select patients who have failed all other therapies. The etiology of fecal incontinence is multifactorial, involving a complex interplay between stool consistency and anatomic integrity. The diagnosis and treatment of fecal incontinence continue to evolve and are showing promising results. C1 [Alavi, Karim; Chan, Sook] Univ Massachusetts, Div Colon & Rectal Surg, Mem Med Ctr, Worcester, MA 01605 USA. [Wise, Paul] Washington Univ, Div Colon & Rectal Surg, Sch Med, St Louis, MO USA. [Kaiser, Andreas M.] Univ So Calif, Keck Sch Med, Div Colon & Rectal Surg, Los Angeles, CA 90033 USA. [Sudan, Ranjan] Duke Univ, Dept Surg, Sch Med, Durham, NC USA. [Bordeianou, Liliana] Harvard Univ, Div Colon & Rectal Surg, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Alavi, K (reprint author), Univ Massachusetts, Div Colon & Rectal Surg, Mem Med Ctr, 67 Belmont St, Worcester, MA 01605 USA. EM karim.alavi@umassmemorial.org NR 55 TC 1 Z9 1 U1 1 U2 9 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 OCT PY 2015 VL 19 IS 10 BP 1910 EP 1921 DI 10.1007/s11605-015-2905-1 PG 12 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA CS0MP UT WOS:000361754800022 PM 26268955 ER PT J AU Ibrahim, SA AF Ibrahim, S. A. TI Equity in Lung Cancer Care and Outcomes SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Editorial Material ID SURVIVAL; COMORBIDITY; SMOKING; RACE C1 [Ibrahim, S. A.] Univ Penn, Perelman Sch Med, Div Gen Internal Med, Philadelphia, PA 19104 USA. [Ibrahim, S. A.] Philadelphia VA Med Ctr ANNEX, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. RP Ibrahim, SA (reprint author), Univ Penn, Perelman Sch Med, Div Gen Internal Med, Philadelphia, PA 19104 USA. EM Said.Ibrahim2@va.gov FU NIAMS NIH HHS [K24AR055259, K24 AR055259] NR 8 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 OCT PY 2015 VL 30 IS 10 BP 1385 EP 1386 DI 10.1007/s11606-015-3346-y PG 2 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA CS0MR UT WOS:000361755000002 PM 25903994 ER PT J AU Hwang, AS Atlas, SJ Cronin, P Ashburner, JM Shah, SJ He, W Hong, CS AF Hwang, Andrew S. Atlas, Steven J. Cronin, Patrick Ashburner, Jeffrey M. Shah, Sachin J. He, Wei Hong, Clemens S. TI Appointment "no-shows" are an independent predictor of subsequent quality of care and resource utilization outcomes SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE No-show; Identification of high-risk patients; Health disparities; Psychosocial issues in healthcare ID PATIENT COMPLEXITY; CO-MORBIDITY; COMORBIDITY; DISPARITIES; VALIDATION; MANAGEMENT; VISITS; MODEL AB Identifying individuals at high risk for suboptimal outcomes is an important goal of healthcare delivery systems. Appointment no-shows may be an important risk predictor. To test the hypothesis that patients with a high propensity to "no-show" for appointments will have worse clinical and acute care utilization outcomes compared to patients with a lower propensity. We calculated the no-show propensity factor (NSPF) for patients of a large academic primary care network using 5 years of outpatient appointment data. NSPF corrects for patients with fewer appointments to avoid over-weighting of no-show visits in such patients. We divided patients into three NSPF risk groups and evaluated the association between NSPF and clinical and acute care utilization outcomes after adjusting for baseline patient characteristics. A total of 140,947 patients who visited a network practice from January 1, 2007, through December 31, 2009, and were either connected to a primary care physician or to a primary care practice, based on a previously validated algorithm. Outcomes of interest were incomplete colorectal, cervical, and breast cancer screening, and above-goal hemoglobin A1c (HbA1c) and low-density lipoprotein (LDL) levels at 1-year follow-up, and hospitalizations and emergency department visits in the subsequent 3 years. Compared to patients in the low NSPF group, patients in the high NSPF group (n=14,081) were significantly more likely to have incomplete preventive cancer screening (aOR 2.41 [2.19-.66] for colorectal, aOR 1.85 [1.65-.08] for cervical, aOR 2.93 [2.62-3.28] for breast cancer), above-goal chronic disease control measures (aOR 2.64 [2.22-3.14] for HbA1c, aOR 1.39 [1.15-1.67] for LDL], and increased rates of acute care utilization (aRR 1.37 [1.31-1.44] for hospitalization, aRR 1.39 [1.35-1.43] for emergency department visits). NSPF is an independent predictor of suboptimal primary care outcomes and acute care utilization. NSPF may play an important role in helping healthcare systems identify high-risk patients. C1 [Hwang, Andrew S.] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Atlas, Steven J.; Ashburner, Jeffrey M.; Shah, Sachin J.; He, Wei; Hong, Clemens S.] Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. [Cronin, Patrick] Massachusetts Gen Hosp, Comp Sci Lab, Boston, MA 02114 USA. RP Hwang, AS (reprint author), Tufts Univ, Sch Med, Boston, MA 02111 USA. EM andrew.hwang@tufts.edu NR 29 TC 4 Z9 4 U1 2 U2 9 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 OCT PY 2015 VL 30 IS 10 BP 1426 EP 1433 DI 10.1007/s11606-015-3252-3 PG 8 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA CS0MR UT WOS:000361755000016 PM 25776581 ER PT J AU Glover, M Khalilzadeh, O Choy, G Prabhakar, AM Pandharipande, PV Gazelle, GS AF Glover, McKinley Khalilzadeh, Omid Choy, Garry Prabhakar, Anand M. Pandharipande, Pari V. Gazelle, G. Scott TI Hospital Evaluations by Social Media: A Comparative Analysis of Facebook Ratings among Performance Outliers SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE Performance measurement; Patient satisfaction; Consumer health informatics ID QUALITY-OF-CARE; HEALTH-CARE; PATIENT EXPERIENCE; ASSOCIATIONS; LIMITATIONS AB An increasing number of hospitals and health systems utilize social media to allow users to provide feedback and ratings. The correlation between ratings on social media and more conventional hospital quality metrics remains largely unclear, raising concern that healthcare consumers may make decisions on inaccurate or inappropriate information regarding quality. The purpose of this study was to examine the extent to which hospitals utilize social media and whether user-generated metrics on Facebook(A (R)) correlate with a Hospital Compare(A (R)) metric, specifically 30-day all cause unplanned hospital readmission rates. This was a retrospective cross-sectional study conducted among all U.S. hospitals performing outside the confidence interval for the national average on 30-day hospital readmission rates as reported on Hospital Compare. Participants were 315 hospitals performing better than U.S. national rate on 30-day readmissions and 364 hospitals performing worse than the U.S. national rate. The study analyzed ratings of hospitals on Facebook's five-star rating scale, 30-day readmission rates, and hospital characteristics including beds, teaching status, urban vs. rural location, and ownership type. Hospitals performing better than the national average on 30-day readmissions were more likely to use Facebook than lower-performing hospitals (93.3 % vs. 83.5 %; p < 0.01). The average rating for hospitals with low readmission rates (4.15 +/- 0.31) was higher than that for hospitals with higher readmission rates (4.05 +/- 0.41, p < 0.01). Major teaching hospitals were 14.3 times more likely to be in the high readmission rate group. A one-star increase in Facebook rating was associated with increased odds of the hospital belonging to the low readmission rate group by a factor of 5.0 (CI: 2.6-10.3, p < 0.01), when controlling for hospital characteristics and Facebook-related variables. Hospitals with lower rates of 30-day hospital-wide unplanned readmissions have higher ratings on Facebook than hospitals with higher readmission rates. These findings add strength to the concept that aggregate measures of patient satisfaction on social media correlate with more traditionally accepted measures of hospital quality. C1 [Glover, McKinley; Khalilzadeh, Omid; Choy, Garry; Pandharipande, Pari V.; Gazelle, G. Scott] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA 02138 USA. [Prabhakar, Anand M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiovasc Imaging, Boston, MA USA. [Pandharipande, Pari V.; Gazelle, G. Scott] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Inst Technol Assessment, Boston, MA USA. RP Glover, M (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA 02138 USA. EM mckinley.glover@mgh.harvard.edu NR 39 TC 6 Z9 6 U1 2 U2 21 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 OCT PY 2015 VL 30 IS 10 BP 1440 EP 1446 DI 10.1007/s11606-015-3236-3 PG 7 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA CS0MR UT WOS:000361755000018 PM 25749881 ER PT J AU Aysola, J Werner, RM Keddem, S SoRelle, R Shea, JA AF Aysola, Jaya Werner, Rachel M. Keddem, Shimrit SoRelle, Richard Shea, Judy A. TI Asking the Patient About Patient-Centered Medical Homes: A Qualitative Analysis SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE Patient-centered care; Primary care redesign; Health care delivery; Health services research; Health policy ID PRIMARY-CARE; ETHNIC-DIFFERENCES AB What patients perceive and experience within a patient-centered medical home (PCMH) is an understudied area, and to date, the patient perspective has not been an integral component of existing PCMH measurement standards. However, upcoming guidelines necessitate the use of patient-reported experiences and satisfaction in evaluations of practice and provider performance. To characterize patients' experiences with care after PCMH adoption and their understanding and perceptions of the PCMH model and its key components, and to compare responses by degree of practice-level PCMH adoption and patient race/ethnicity. Qualitative study. Adult patients with diabetes and/or hypertension (n = 48). We surveyed and ranked all PCMH adult primary care practices affiliated with one academic medical center with at least three providers (n = 23), using an instrument quantifying the degree of PCMH adoption. We purposively sampled minority and non-minority patients from the four highest-ranked and four lowest-ranked PCMH-adopting practices to determine whether responses varied by degree of PCMH adoption or patient race/ethnicity. We conducted semi-structured telephone interviews with patients about their experiences with care and their perceptions and understanding of key PCMH domains. Interviews were recorded, transcribed, and imported into NVivo 10 for coding and analysis, using a modified grounded theory approach. We found that patients uniformly lacked awareness of the PCMH concept, and the vast majority perceived no PCMH-related structural changes, regardless of the degree of practice-reported PCMH adoption or the patient's race/ethnicity. Despite this lack of awareness, patients overwhelmingly reported positive relationships with their provider and positive overall experiences. As we continue to redesign primary care delivery with an emphasis on patient experience measures as performance metrics, we need to better understand what, if any, aspects of practice structure relate to patient experience and satisfaction with care. C1 [Aysola, Jaya; Werner, Rachel M.; Shea, Judy A.] Univ Penn, Dept Med, Div Gen Internal Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Aysola, Jaya; Werner, Rachel M.] Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. [Werner, Rachel M.] Philadelphia VA Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Keddem, Shimrit; SoRelle, Richard] Univ Penn, Dept Family Med & Community Hlth, Mixed Methods Res Lab, Philadelphia, PA 19104 USA. RP Aysola, J (reprint author), Univ Penn, Dept Med, Div Gen Internal Med, Perelman Sch Med, Philadelphia, PA 19104 USA. EM jaysola@upenn.edu FU AHRQ PCOR [K12 HS021706-01] FX Jaya Aysola was funded by an AHRQ PCOR Institutional Award (K12 HS021706-01) for the duration of this study. NR 30 TC 4 Z9 4 U1 3 U2 17 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD OCT PY 2015 VL 30 IS 10 BP 1461 EP 1467 DI 10.1007/s11606-015-3312-8 PG 7 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA CS0MR UT WOS:000361755000021 PM 25876739 ER PT J AU Silverman, J Krieger, J Kiefer, M Hebert, P Robinson, J Nelson, K AF Silverman, Julie Krieger, James Kiefer, Meghan Hebert, Paul Robinson, June Nelson, Karin TI The Relationship Between Food Insecurity and Depression, Diabetes Distress and Medication Adherence Among Low-Income Patients with Poorly-Controlled Diabetes SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE food insecurity; diabetes; glycemic control ID GLYCEMIC CONTROL; SELF-MANAGEMENT; SHORT-FORM; HEALTH; SCALE; INTERVENTION; HYPOGLYCEMIA; VALIDITY; COSTS AB Food insecurity- lack of dependable access to adequate food-may play a role in poor diabetes control. We aimed to determine the relationship between food security status and depression, diabetes distress, medication adherence and glycemic control. Secondary analysis of baseline data from Peer Support for Achieving Independence in Diabetes, a randomized controlled trial that enrolled patients from November 2011 to October 2013. Participants had poorly controlled type 2 diabetes (A1c a parts per thousand yen 8.0 % on eligibility screen), household income < 250 % of the federal poverty level, were 30-70 years old, and were recruited from a large public hospital, a VA medical center and a community-health center in King County, Washington. We measured food insecurity determined by the Department of Agriculture's 6-Item Food Security Module. Depression, diabetes distress and medication adherence measured by PHQ-8, Diabetes Distress Scale and Morisky Medication Adherence Scale, respectively. Diet was assessed through Summary of Diabetes Self-Care Activities and Starting the Conversation tool. Incidence of hypoglycemic episodes was by patient report. Glycemic control was assessed with glycosylated hemoglobin (A1c) values from fingerstick blood sample. The prevalence of food insecurity was 47.4 %. Chi-square tests revealed participants with food insecurity were more likely to be depressed (40.7 % vs. 15.4 %, p < 0.001), report diabetes distress (55.2 % vs. 33.8 %, p < 0.001) and have low medication adherence (52.9 % vs. 37.2 %, p = 0.02). Based on linear regression modeling, those with food insecurity had significantly higher mean A1c levels (beta = 0.51; p = 0.02) after adjusting for sex, age, race/ethnicity, language, education, marital status, BMI, insulin use, depression, diabetes distress and low medication adherence. Almost half of participants had food insecurity. Food insecurity was associated with depression, diabetes distress, low medication adherence and worse glycemic control. Even with adjustment, people with food insecurity had higher mean A1c levels than their food-secure counterparts, suggesting there may be other mediating factors, such as diet, that explain the relationship between food security status and diabetes control. C1 [Silverman, Julie; Hebert, Paul; Nelson, Karin] Northwest HSR&D Ctr Excellence, VA Puget Sound Healthcare Syst, Seattle, WA USA. [Silverman, Julie; Nelson, Karin] Gen Internal Med Serv, VA Puget Sound Healthcare Syst, Seattle, WA USA. [Silverman, Julie; Krieger, James; Kiefer, Meghan; Nelson, Karin] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. [Krieger, James; Hebert, Paul; Nelson, Karin] Univ Washington, Sch Publ Hlth, Seattle, WA 98195 USA. [Krieger, James; Robinson, June] Publ Hlth Seattle & King Cty, Seattle, WA USA. RP Silverman, J (reprint author), Northwest HSR&D Ctr Excellence, VA Puget Sound Healthcare Syst, Seattle, WA USA. EM Julie.Silverman@va.gov FU NIH/NIDDK [5R18DK088072]; Veterans Health Administration (VHA) Diabetes Quality Enhancement Research Initiative (QUERI) FX This study was supported by the NIH/NIDDK grant 5R18DK088072 to Drs. Nelson and Krieger (co-PIs). The sponsor had no role in designing the study; collecting, analyzing, or interpreting data; writing this manuscript; or in the decision to submit this manuscript for publication. Additional funding was provided by the Veterans Health Administration (VHA) Diabetes Quality Enhancement Research Initiative (QUERI) to support Veteran recruitment efforts. The views expressed in this article are those of the authors and do not necessarily reflect the views of the Department of Veterans Affairs. NR 32 TC 6 Z9 6 U1 4 U2 38 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 OCT PY 2015 VL 30 IS 10 BP 1476 EP 1480 DI 10.1007/s11606-015-3351-1 PG 5 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA CS0MR UT WOS:000361755000023 PM 25917659 ER PT J AU Perissinotto, CM Walter, LC AF Perissinotto, Carla Maria Walter, Louise C. TI Capsule Commentary on Wolff, et al., A Look at Person- and Family-Centered Care Among Older Adults: Results from a National Survey SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Editorial Material C1 [Perissinotto, Carla Maria; Walter, Louise C.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Walter, Louise C.] San Francisco VA Med Ctr, San Francisco, CA USA. RP Perissinotto, CM (reprint author), Univ Calif San Francisco, 3333 Calif St Suite 380, San Francisco, CA 94143 USA. EM Carla.Perissinotto@ucsf.edu NR 3 TC 0 Z9 0 U1 2 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 OCT PY 2015 VL 30 IS 10 BP 1536 EP 1536 DI 10.1007/s11606-015-3408-1 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA CS0MR UT WOS:000361755000036 PM 26001544 ER PT J AU Fraser, T Hillmann, W Lederer, PA Kasmar, A Rencic, J AF Fraser, Traci Hillmann, William Lederer, Philip A. Kasmar, Anne Rencic, Joseph TI Solving Summer Fever in Early Pregnancy SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Editorial Material DE clinical reasoning; infectious diseases; obstetrics ID BABESIOSIS C1 [Fraser, Traci; Hillmann, William; Lederer, Philip A.; Kasmar, Anne] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA 02114 USA. [Lederer, Philip A.; Kasmar, Anne] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Infect Dis, Boston, MA 02114 USA. [Rencic, Joseph] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Rencic, Joseph] Tufts Med Ctr, Boston, MA USA. RP Fraser, T (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, GRB 740,55 Fruit St, Boston, MA 02114 USA. EM tnfraser@partners.org NR 13 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 OCT PY 2015 VL 30 IS 10 BP 1561 EP 1565 DI 10.1007/s11606-015-3361-z PG 5 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA CS0MR UT WOS:000361755000041 PM 25917661 ER PT J AU Chen, HY Clayman, ES Ma, WF AF Chen, Hong-Yuan Clayman, Eric S. Ma, Wei-Feng TI Phenotypic Knockout of CXCR4 Expression by a Novel Intrakine Mutant hSDF-1 alpha/54/KDEL Inhibits Breast Cancer Metastasis SO JOURNAL OF INTERFERON AND CYTOKINE RESEARCH LA English DT Article ID CHEMOKINE RECEPTOR CXCR4; TERMINAL ALPHA-HELIX; TUMOR-GROWTH; CARCINOMA-CELLS; COLON-CARCINOMA; DOWN-REGULATION; OVARIAN-CANCER; MOUSE MODEL; KDEL; CHEMOTAXIS AB Many malignant tumors express high levels of the chemokine receptor CXCR4, and the interaction between CXCR4 and its ligand, SDF-1, promotes migration, invasion, and metastasis of breast cancer cells. Therefore, blocking the interaction between CXCR4 and SDF-1 could alter the tumor's metastatic phenotype and control the development and progression of cancers. We used a cellular phenotypic knockout strategy and developed a novel recombinant gene, AdSDF-1/54/KDEL, which contains an adenovirus vector, a mutant form of SDF-1 that lacks a C-terminal -helix, and a KDEL tetrapeptide sequence that promotes retention at the endoplasmic reticulum (ER). We hypothesized that SDF-1/54/KDEL could efficiently block metastasis of breast cancer cells with less inflammatory side effects than SDF-1/KDEL. Using the MCF-7 cell line, which expresses a stable, high level of CXCR4, we found that SDF-1/54/KDEL efficiently becomes localized at the ER of tumor cells, where it specifically binds to newly synthesized CXCR4 and prevents it from reaching the cell surface. Chemotaxis and invasion assays revealed that the cells treated with SDF-1/54/KDEL failed to migrate toward SDF-1. We also found that SDF-1/54/KDEL impaired lung metastasis of metastatic breast cancer by decreasing CXCR4 on the cell surface. The novel recombinant gene, SDF-1/54/KDEL, played an instrumental role in blocking SDF-1/CXCR4-mediated cell migration, and we found that this gene-based strategy for targeting the SDF-1/CXCR4 axis offers a very effective alternative method for preventing metastasis of breast cancer and other cancers expressing high levels of CXCR4. C1 [Chen, Hong-Yuan] GuangDong Pharmaceut Univ, Sch Basic Courses, Dept Pathogen Biol & Immunol, Guangzhou 510006, Guangdong, Peoples R China. [Clayman, Eric S.] Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02114 USA. [Clayman, Eric S.] Harvard Univ, Sch Med, Boston, MA USA. [Ma, Wei-Feng] Southern Med Univ, Sch Publ Hlth & Trop Med, Dept Microbiol, Guangzhou, Guangdong, Peoples R China. RP Chen, HY (reprint author), GuangDong Pharmaceut Univ, Dept Pathogen Biol & Immunol, Guangzhou Higher Educ Mega Ctr, 280 Waihuan East Rd, Guangzhou 510006, Guangdong, Peoples R China. EM hychen1208@126.com FU 54th China Postdoctoral Science Foundation [2013M542234]; Science and Technology Project of Guangdong Province, China [2013B021800085]; Science and Technology Project Guangzhou City Grant [2014J4100058] FX This research was prompted and supported by the 54th China Postdoctoral Science Foundation No. 2013M542234, the Science and Technology Project of Guangdong Province, China (No. 2013B021800085), and the Science and Technology Project Guangzhou City Grant (No. 2014J4100058). We would also like to thank Professors Jun Du and Shao-Hui Cai for their excellent recommendations and edits with this manuscript. NR 35 TC 1 Z9 2 U1 0 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1079-9907 EI 1557-7465 J9 J INTERF CYTOK RES JI J. Interferon Cytokine Res. PD OCT 1 PY 2015 VL 35 IS 10 BP 771 EP 778 DI 10.1089/jir.2014.0141 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA CS2HK UT WOS:000361889600002 PM 25978539 ER PT J AU Varadarajan, KM Zumbrunn, T Rubash, HE Malchau, H Muratoglu, OK Li, GA AF Varadarajan, Kartik Mangudi Zumbrunn, Thomas Rubash, Harry E. Malchau, Henrik Muratoglu, Orhun K. Li, Guoan TI Reverse Engineering Nature to Design Biomimetic Total Knee Implants SO JOURNAL OF KNEE SURGERY LA English DT Article DE total knee arthroplasty; implant design; biomimetic implant; knee kinematics; normal knee ID MOTION CHARACTERISTICS; HIGH FLEXION; KINEMATICS; ARTHROPLASTY; REPLACEMENT; JOINT; ORIENTATION; ROTATION; TKA; STABILITY AB While contemporary total knee arthroplasty (TKA) provides tremendous clinical benefits, the normal feel and function of the knee is not fully restored. To address this, a novel design process was developed to reverse engineer biomimetic articular surfaces that are compatible with normal soft-tissue envelope and kinematics of the knee. The biomimetic articular surface is created by moving the TKA femoral component along in vivo kinematics of normal knees and carving out the tibial articular surface from a rectangular tibial block. Here, we describe the biomimetic design process. In addition, we utilize geometric comparisons and kinematic simulations to show that; (1) tibial articular surfaces of conventional implants are fundamentally incompatible with normal knee motion, and (2) the anatomic geometry of the biomimetic surface contributes directly to restoration of normal knee kinematics. Such biomimetic implants may enable us to achieve the long sought after goal of a normal knee post-TKA surgery. C1 [Varadarajan, Kartik Mangudi; Zumbrunn, Thomas; Rubash, Harry E.; Malchau, Henrik; Muratoglu, Orhun K.; Li, Guoan] Massachusetts Gen Hosp, Dept Orthoped Surg, Boston, MA 02114 USA. RP Varadarajan, KM (reprint author), Massachusetts Gen Hosp, Dept Orthoped Surg, 55 Fruit St,GRJ-1223, Boston, MA 02114 USA. EM kmangudivaradarajan@partners.org NR 45 TC 2 Z9 2 U1 1 U2 4 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 1538-8506 EI 1938-2480 J9 J KNEE SURG JI J. Knee Surg. PD OCT PY 2015 VL 28 IS 5 BP 363 EP 369 DI 10.1055/s-0035-1551834 PG 7 WC Orthopedics SC Orthopedics GA CS1KK UT WOS:000361822900004 PM 26166428 ER PT J AU Kim, J Won, HH Kim, Y Choi, JR Yu, N Lee, KA AF Kim, Juwon Won, Hong-Hee Kim, Yoonjung Choi, Jong Rak Yu, Nae Lee, Kyung-A TI Breakpoint mapping by whole genome sequencing identifies PTH2R gene disruption in a patient with midline craniosynostosis and a de novo balanced chromosomal rearrangement SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID ENDOCHONDRAL BONE-DEVELOPMENT; HORMONE TYPE-2 RECEPTOR; EXPRESSION AB Background Craniosynostosis (CRS) is a premature closure of calvarial sutures caused by gene mutation or environmental factors or interaction between the two. Only a small proportion of non-syndromic CRS (NSC) patients have a known genetic cause, and thus, it would be meaningful to search for a causative gene disruption for the development NSC. We applied a whole genome sequencing approach on a 15-month-old boy with sagittal and metopic synostosis to identify a gene responsible for the development of the disease. Methods and results Conventional chromosome study revealed a complex paracentric inversion involving 2q14.3 and 2q34. Array comparative genomic hybridisation did not show any copy number variation. Multicolour banding analysis was carried out and the breakpoints were refined to 2q14 and 2q34. An intronic break of the PTH2R gene was detected by whole genome sequencing and fluorescence in situ hybridisation analysis confirmed disruption of PTH2R. Conclusions We report PTH2R as a gene that is disrupted in NSC. The disruption of the PTH2R gene may cause uncontrolled proliferation and differentiation of chondrocytes, which in turn results in premature closure of sutures. This addition of PTH2R to the list of genes associated with NSC expands our understanding of the development of NSC. C1 [Kim, Juwon; Kim, Yoonjung] Yonsei Univ, Wonju Coll Med, Dept Lab Med, Wonju, South Korea. [Won, Hong-Hee] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Won, Hong-Hee] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Won, Hong-Hee] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02139 USA. [Choi, Jong Rak; Yu, Nae; Lee, Kyung-A] Yonsei Univ, Coll Med, Dept Lab Med, Seoul 135720, South Korea. RP Lee, KA (reprint author), Yonsei Univ, Coll Med, Dept Lab Med, 211 Eonju Ro, Seoul 135720, South Korea. EM kal1119@yuhs.ac FU Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea [A120030] FX This study was supported by a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A120030). NR 18 TC 1 Z9 1 U1 1 U2 14 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 EI 1468-6244 J9 J MED GENET JI J. Med. Genet. PD OCT PY 2015 VL 52 IS 10 BP 706 EP 709 DI 10.1136/jmedgenet-2015-103001 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA CS0PC UT WOS:000361763100008 PM 26044810 ER PT J AU Hirsch, JA AF Hirsch, Joshua A. TI Our changing neurointerventional world SO JOURNAL OF NEUROINTERVENTIONAL SURGERY LA English DT Editorial Material DE Political ID HEALTH-CARE; PRIMER C1 Massachusetts Gen Hosp, NeuroEndovasc Program, Boston, MA 02114 USA. RP Hirsch, JA (reprint author), Massachusetts Gen Hosp, NeuroEndovasc Program, Boston, MA 02114 USA. EM hirsch@snisonline.org NR 14 TC 0 Z9 0 U1 1 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1759-8478 EI 1759-8486 J9 J NEUROINTERV SURG JI J. NeuroInterventional Surg. PD OCT PY 2015 VL 7 IS 10 BP 703 EP 704 DI 10.1136/neurintsurg-2015-012009 PG 2 WC Neuroimaging; Surgery SC Neurosciences & Neurology; Surgery GA CS0MZ UT WOS:000361756100005 PM 26369730 ER PT J AU Jernigan, SC Stone, SSD Aronson, JP Putman, M Proctor, MR AF Jernigan, Sarah C. Stone, Scellig S. D. Aronson, Joshua P. Putman, Melissa Proctor, Mark R. TI Episodic ventriculomegaly due to hypernatremia mimicking shunt malfunction: case report SO JOURNAL OF NEUROSURGERY-PEDIATRICS LA English DT Article DE hypernatremia; ventriculomegaly; hydrocephalus; shunt ID LOW-PRESSURE HYDROCEPHALUS; BRAIN AB Patients with shunted hydrocephalus presenting with altered mental status and ventriculomegaly are generally considered to be in shunt failure requiring surgical treatment. The authors describe a case of shunted hydrocephalus secondary to a disseminated neuroectodermal tumor in a pediatric patient in whom rapid fluctuations in sodium levels due to diabetes insipidus repeatedly led to significant changes in ventricle size, with invasively confirmed normal shunt function and low intracranial pressure. This clinical picture exactly mimics shunt malfunction, requires urgent nonsurgical therapy, and underscores the importance of considering serum osmolar abnormalities in the differential diagnosis for ventriculomegaly. C1 [Jernigan, Sarah C.; Stone, Scellig S. D.; Proctor, Mark R.] Boston Childrens Hosp, Dept Neurosurg, Boston, MA 02115 USA. [Putman, Melissa] Boston Childrens Hosp, Dept Med, Div Endocrinol, Boston, MA 02115 USA. [Aronson, Joshua P.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. RP Proctor, MR (reprint author), Boston Childrens Hosp, Dept Neurosurg, Hunnewell 2,300 Longwood Ave, Boston, MA 02115 USA. EM mark.proctor@childrens.harvard.edu NR 16 TC 0 Z9 0 U1 0 U2 2 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 1933-0707 EI 1933-0715 J9 J NEUROSURG-PEDIATR JI J. Neurosurg.-Pediatr. PD OCT PY 2015 VL 16 IS 4 BP 406 EP 409 DI 10.3171/2015.3.PEDS1526 PG 4 WC Clinical Neurology; Pediatrics; Surgery SC Neurosciences & Neurology; Pediatrics; Surgery GA CS1XS UT WOS:000361862800008 PM 26186358 ER PT J AU Shin, SS Dixon, CE AF Shin, Samuel S. Dixon, C. Edward TI Alterations in Cholinergic Pathways and Therapeutic Strategies Targeting Cholinergic System after Traumatic Brain Injury SO JOURNAL OF NEUROTRAUMA LA English DT Review DE acetylcholine; cholinergic; nicotinic; traumatic brain injury ID NICOTINIC ACETYLCHOLINE-RECEPTOR; POSITIVE ALLOSTERIC MODULATOR; FLUID-PERCUSSION INJURY; CLOSED-HEAD INJURY; SHORT-TERM-MEMORY; IMPROVES COGNITIVE PERFORMANCE; PROMOTE FUNCTIONAL RECOVERY; RANDOMIZED CONTROLLED-TRIAL; CONTROLLED CORTICAL IMPACT; REDUCED EVOKED RELEASE AB Traumatic brain injury (TBI) results in varying degrees of disability in a significant number of persons annually. The mechanisms of cognitive dysfunction after TBI have been explored in both animal models and human clinical studies for decades. Dopaminergic, serotonergic, and noradrenergic dysfunction has been described in many previous reports. In addition, cholinergic dysfunction has also been a familiar topic among TBI researchers for many years. Although pharmacological agents that modulate cholinergic neurotransmission have been used with varying degrees of success in previous studies, improving their function and maximizing cognitive recovery is an ongoing process. In this article, we review the previous findings on the biological mechanism of cholinergic dysfunction after TBI. In addition, we describe studies that use both older agents and newly developed agents as candidates for targeting cholinergic neurotransmission in future studies. C1 [Shin, Samuel S.; Dixon, C. Edward] Univ Pittsburgh, Brain Trauma Res Ctr, Pittsburgh, PA 15260 USA. [Shin, Samuel S.; Dixon, C. Edward] Univ Pittsburgh, Dept Neurol Surg, Pittsburgh, PA 15260 USA. [Shin, Samuel S.; Dixon, C. Edward] Univ Pittsburgh, Safar Ctr Resuscitat Res, Pittsburgh, PA 15260 USA. [Dixon, C. Edward] Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA USA. RP Dixon, CE (reprint author), Univ Pittsburgh, Dept Neurol Surg, 201 Hill Bldg,3434 Fifth Ave, Pittsburgh, PA 15260 USA. EM dixonec@upmc.edu FU Pittsburgh Foundation Walter Copeland Fund FX The authors thank The Pittsburgh Foundation Walter Copeland Fund for their support of our TBI research. No competing financial interests exist. NR 147 TC 5 Z9 5 U1 2 U2 3 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD OCT 1 PY 2015 VL 32 IS 19 BP 1429 EP 1440 DI 10.1089/neu.2014.3445 PG 12 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA CR8NC UT WOS:000361609500001 PM 25646580 ER PT J AU Hage, FG AF Hage, Fadi G. TI Training in nuclear cardiology: What's new? SO JOURNAL OF NUCLEAR CARDIOLOGY LA English DT Editorial Material C1 [Hage, Fadi G.] Univ Alabama Birmingham, Div Cardiovasc Dis, Birmingham, AL 35294 USA. [Hage, Fadi G.] Birmingham Vet Affairs Med Ctr, Cardiol Sect, Birmingham, AL USA. RP Hage, FG (reprint author), Univ Alabama Birmingham, Div Cardiovasc Dis, Lyons Harrison Res Bldg 306,1720 2nd AVE S, Birmingham, AL 35294 USA. EM fadihage@uab.edu OI Hage, Fadi/0000-0002-1397-4942 NR 2 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1071-3581 EI 1532-6551 J9 J NUCL CARDIOL JI J. Nucl. Cardiol. PD OCT PY 2015 VL 22 IS 5 BP 861 EP 862 DI 10.1007/s12350-015-0259-4 PG 2 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA CR8RU UT WOS:000361622400001 PM 26268827 ER PT J AU Hage, F AlJaroudi, W AF Hage, Fadi G. AlJaroudi, Wael TI Review of cardiovascular literature SO JOURNAL OF NUCLEAR CARDIOLOGY LA English DT Review C1 [Hage, Fadi G.] Univ Alabama Birmingham, Dept Med, Div Cardiovasc Dis, Birmingham, AL 35294 USA. [Hage, Fadi G.] Birmingham Vet Affairs Med Ctr, Cardiol Sect, Birmingham, AL USA. [AlJaroudi, Wael] Clemenceau Med Ctr, Beirut, Lebanon. RP AlJaroudi, W (reprint author), Clemenceau Med Ctr, Beirut, Lebanon. EM Wael.jaroudi@cmc.com.lb OI Hage, Fadi/0000-0002-1397-4942 NR 0 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1071-3581 EI 1532-6551 J9 J NUCL CARDIOL JI J. Nucl. Cardiol. PD OCT PY 2015 VL 22 IS 5 BP 874 EP 876 DI 10.1007/s12350-015-0220-6 PG 3 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA CR8RU UT WOS:000361622400004 PM 26134887 ER PT J AU Ring, D Horst, TA AF Ring, David Horst, Taylor A. TI Coronoid Fractures SO JOURNAL OF ORTHOPAEDIC TRAUMA LA English DT Article DE elbow fracture; coronoid process; dislocation; open reduction and internal fixation ID TERRIBLE TRIAD INJURIES; ANTEROMEDIAL FACET; ELBOW TRAUMA; RADIAL HEAD; ULNA; DISLOCATIONS; STABILITY; POSTERIOR; FIXATION; PATTERNS AB Fractures of the coronoid process of the ulna are usually part of a more complex injury. The type of coronoid fracture corresponds with a specific pattern of injury with known pitfalls and recommended treatments. Tip fractures usually correspond with dislocation of the elbow and fracture of the radial head (the so-called terrible triad of the elbow because it is prone to redislocation, subluxation, and arthrosis) and are best repaired with a suture passed through drill holes along with repair or replacement of the fractured radial head and reattachment of the lateral collateral ligament to the lateral epicondyle. Anteromedial fractures are usually part of a subluxation injury and are best addressed with a medial buttress plate and reattachment of the lateral collateral ligament. Large basilar coronoid fractures are usually part of an olecranon fracture-dislocation and are usually repaired with 1 or 2 plates and screws. Tenuous fixation is protected with temporary external fixation or cross-pinning of the joint because healing of the coronoid with concentric elbow alignment is critical.Level of Evidence:Therapeutic Level V. See Instructions for Authors for a complete description of levels of evidence. C1 [Ring, David; Horst, Taylor A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthopaed Surg, Boston, MA USA. RP Ring, D (reprint author), Massachusetts Gen Hosp, Yawkey 2100,55 Fruit St, Boston, MA 02114 USA. EM dring@mgh.harvard.edu FU Skeletal Dynamics FX D. Ring has received honoraria from various universities, AO North America, and AO International; is currently receiving a grant from Skeletal Dynamics; and is a consultant for Acumed and Biomet. T. A. Horst reports no conflict of interest. NR 25 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 0890-5339 EI 1531-2291 J9 J ORTHOP TRAUMA JI J. Orthop. Trauma PD OCT PY 2015 VL 29 IS 10 BP 437 EP 440 DI 10.1097/BOT.0000000000000326 PG 4 WC Orthopedics; Sport Sciences SC Orthopedics; Sport Sciences GA CR8LD UT WOS:000361602400001 PM 25785359 ER PT J AU Teunis, T Bot, AGJ Thornton, ER Ring, D AF Teunis, Teun Bot, Arjan G. J. Thornton, Emily R. Ring, David TI Catastrophic Thinking Is Associated With Finger Stiffness After Distal Radius Fracture Surgery SO JOURNAL OF ORTHOPAEDIC TRAUMA LA English DT Article DE catastrophic thinking; distal radius; finger stiffness; fracture; predictors; trauma ID SYNDROME TYPE-I; LOW-BACK-PAIN; PSYCHOLOGICAL-FACTORS; ALGODYSTROPHY; DISABILITY; VALIDITY; TRAUMA; SCALE AB Objectives:To identify demographic, injury-related, or psychologic factors associated with finger stiffness at suture removal and 6 weeks after distal radius fracture surgery. We hypothesize that there are no factors associated with distance to palmar crease at suture removal.Design:Prospective cohort study.Setting:Level I Academic Urban Trauma Center.Patients:One hundred sixteen adult patients underwent open reduction and internal fixation of their distal radius fractures; 96 of whom were also available 6 weeks after surgery.Intervention:None.Main Outcome Measurements:At suture removal, we recorded patients' demographics, AO fracture type, carpal tunnel release at the time of surgery, pain catastrophizing scale, Whiteley Index, Patient Health Questionnaire-9, and disabilities of the arm, shoulder, and hand questionnaire, 11-point ordinal measure of pain intensity, distance to palmar crease, and active flexion of the thumb through the small finger. At 6 weeks after surgery, we measured motion, disabilities of the arm, shoulder, and hand, and pain intensity. Prereduction and postsurgery radiographic fracture characteristics were assessed.Results:Female sex, being married, specific surgeons, carpal tunnel release, AO type C fractures, and greater catastrophic thinking were associated with increased distance to palmar crease at suture removal. At 6 weeks, greater catastrophic thinking was the only factor associated with increased distance to palmar crease.Conclusions:Catastrophic thinking was a consistent and major determinant of finger stiffness at suture removal and 6 weeks after injury. Future research should assess if treatments that ameliorate catastrophic thinking can facilitate recovery of finger motion after operative treatment of a distal radius fracture.Level of Evidence:Prognostic Level I. See Instructions for Authors for a complete description of levels of evidence. C1 [Teunis, Teun; Thornton, Emily R.; Ring, David] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Orthopaed Hand & Upper Extrem Serv, Boston, MA 02114 USA. [Bot, Arjan G. J.] Univ Amsterdam, Acad Med Ctr, Dept Orthopaed Surg, NL-1105 AZ Amsterdam, Netherlands. RP Ring, D (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Orthopaed Hand & Upper Extrem Serv, 55 Fruit St, Boston, MA 02114 USA. EM dring@mgh.harvard.edu FU Wright Medical (US) (Memphis, TN); Skeletal Dynamics (US) (Miami, FL); Biomet (US) (Warsaw, IN); AO North America (US) (Paoli, PA); AO International (US) (Dubendorf, Switzerland) FX D. Ring certifies that he, or a member of his immediate family, has or may receive payments or benefits, during the study period from Wright Medical (US $ < 10,000) (Memphis, TN); Skeletal Dynamics (US $ < 10,000) (Miami, FL); Biomet (US $ < 10,000) (Warsaw, IN); AO North America (US $ < 10,000) (Paoli, PA); and AO International (US $ < 10,000) (Dubendorf, Switzerland). The remaining authors report no conflict of interest. NR 27 TC 3 Z9 3 U1 2 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0890-5339 EI 1531-2291 J9 J ORTHOP TRAUMA JI J. Orthop. Trauma PD OCT PY 2015 VL 29 IS 10 BP e414 EP e420 DI 10.1097/BOT.0000000000000342 PG 7 WC Orthopedics; Sport Sciences SC Orthopedics; Sport Sciences GA CR8LB UT WOS:000361602200013 PM 25866942 ER PT J AU Mallo, GC Burton, L Coats-Thomas, M Daniels, SD Sinz, NJ Warner, JJP AF Mallo, Gregory C. Burton, Lauren Coats-Thomas, Margaret Daniels, S. David Sinz, Nathan J. Warner, Jon J. P. TI Assessment of painful total shoulder arthroplasty using computed tomography arthrography SO JOURNAL OF SHOULDER AND ELBOW SURGERY LA English DT Article DE Shoulder; CT arthrography; arthroplasty; total shoulder arthroplasty; glenoid loosening; component loosening ID REPLACEMENT; ARTHROSCOPY; REMOVAL AB Background: This study assessed the accuracy of computed tomography (CT) arthrography when evaluating glenoid component stability in the setting of postarthroplasty shoulder pain. Methods: We retrospectively reviewed all patients presenting to the clinic during a 5.5-year period to identify those with a painful shoulder arthroplasty more than 1 year after the index procedure. We excluded reverse and hemiarthroplasty procedures, patients with a clearly identifiable cause for pain, such as rotator cuff insufficiency or gross component loosening as seen on plain radiographs, and those with culture-positive aspiration. There were 14 patients with suspected glenoid component loosening but inconclusive plain radiographs. Each of the 14 patients underwent a CT arthrogram that was evaluated by the senior author (J.J.P.W.) for the presence or absence of contrast material underneath the polyethylene component. Operative reports and surgical videos from subsequent arthroscopy were reviewed to assess glenoid component stability as determined by direct arthroscopic visualization. Results: CT arthrography suggested glenoid component loosening in 8 of 14 patients (57.1%), and arthroscopic inspection identified loosening in 10 of 14 patients (71.4%). In 3 of 10 patients (30%), CTA suggested a well-fixed glenoid component, but gross loosening was identified during arthroscopy. In this study, CTA yielded a sensitivity of 70%, a specificity of 75%, a positive predictive value of 87.5%, and a negative predictive value of 50.0%. Conclusion: CTA had a low negative predictive value (50%), and therefore, the prediction of component stability based on the absence of contrast between the glenoid component and the bone-cement interface does not always reflect true stability. (C) 2015 Journal of Shoulder and Elbow Surgery Board of Trustees. C1 [Mallo, Gregory C.; Burton, Lauren; Coats-Thomas, Margaret; Warner, Jon J. P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston Shoulder Inst, Boston, MA USA. [Daniels, S. David; Sinz, Nathan J.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston Shoulder Inst, Boston, MA 02115 USA. RP Mallo, GC (reprint author), Massachusetts Gen Hosp, Boston Shoulder Inst, 55 Fruit St,Ste 3200,3G, Boston, MA 02114 USA. EM gregorymallo@gmail.com NR 13 TC 2 Z9 2 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 1058-2746 J9 J SHOULDER ELB SURG JI J. Shoulder Elbow Surg. PD OCT PY 2015 VL 24 IS 10 BP 1507 EP 1511 DI 10.1016/j.jse.2015.06.027 PG 5 WC Orthopedics; Sport Sciences; Surgery SC Orthopedics; Sport Sciences; Surgery GA CR7ZT UT WOS:000361571600006 PM 26234665 ER PT J AU Menendez, ME Baker, DK Fryberger, CT Ponce, BA AF Menendez, Mariano E. Baker, Dustin K. Fryberger, Charles T. Ponce, Brent A. TI Predictors of extended length of stay after elective shoulder arthroplasty SO JOURNAL OF SHOULDER AND ELBOW SURGERY LA English DT Article DE Shoulder arthroplasty; Nationwide Inpatient Sample; length of stay; reverse total shoulder; anatomic total shoulder; NIS ID UNITED-STATES; ORTHOPEDIC-SURGERY; INPATIENT SAMPLE; HOSPITAL STAY; RISK-FACTOR; FOLLOW-UP; OUTCOMES; COMPLICATIONS; TRENDS; COST AB Background: With policymakers and hospitals increasingly looking to cut costs, length of stay after surgery has come into focus as an area for improvement. Despite the increasing popularity of total shoulder arthroplasty, there is limited research about the factors contributing to prolonged hospital stay. We sought to identify preoperative and postoperative predictors of prolonged hospital stay in patients undergoing anatomic total shoulder arthroplasty (ATSA) and reverse total shoulder arthroplasty (RTSA). Methods: Using the 2011 Nationwide Inpatient Sample, we identified an estimated 40,869 patients who underwent elective total shoulder arthroplasty (62.5% ATSA; 37.5% RTSA) and separated them into those with normal length of stay (<75th percentile) and prolonged length of stay (>75th percentile). Multivariate logistic regression modeling was performed to identify factors associated with prolonged length of stay. Results: Patient-level factors associated with prolonged length of stay common to patients undergoing ATSA or RTSA included increasing age, female sex, congestive heart failure, renal failure, chronic pulmonary disease, and preoperative anemia. Provider-related factors were lower volume and location in the South or Northeast. Postoperative complications showed a significant influence as well. Conclusion: Our data can be used to promptly identify patients at higher risk of prolonged hospitalization after elective shoulder arthroplasty and to ultimately improve quality of care and cost containment. (C) 2015 Journal of Shoulder and Elbow Surgery Board of Trustees. C1 [Menendez, Mariano E.] Massachusetts Gen Hosp, Orthopaed Hand & Upper Extrem Serv, Boston, MA 02114 USA. [Baker, Dustin K.; Fryberger, Charles T.; Ponce, Brent A.] Univ Alabama Birmingham, Div Orthopaed Surg, Birmingham, AL 35205 USA. [Baker, Dustin K.] Med Univ S Carolina, Coll Med, Charleston, SC 29425 USA. RP Ponce, BA (reprint author), Univ Alabama Birmingham, Div Orthopaed Surg, 1313 13th St S,Ste 203, Birmingham, AL 35205 USA. EM bponce@uabmc.edu NR 42 TC 6 Z9 6 U1 3 U2 3 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 OCT PY 2015 VL 24 IS 10 BP 1527 EP 1533 DI 10.1016/j.jse.2015.02.014 PG 7 WC Orthopedics; Sport Sciences; Surgery SC Orthopedics; Sport Sciences; Surgery GA CR7ZT UT WOS:000361571600009 PM 25865089 ER PT J AU Claessen, FMAP van den Ende, KIM Doornberg, JN Guitton, TG Eygendaal, D van den Bekerom, MPJ AF Claessen, Femke M. A. P. van den Ende, Kimberly I. M. Doornberg, Job N. Guitton, Thierry G. Eygendaal, Denise van den Bekerom, Michel P. J. CA Shoulder Elbow Platform Sci Variat TI Osteochondritis dissecans of the humeral capitellum: reliability of four classification systems using radiographs and computed tomography SO JOURNAL OF SHOULDER AND ELBOW SURGERY LA English DT Article DE Osteochondritis dissecans; humeral capitellum; classification; interobserver study; arthroscopy; sport traumatology ID INTEROBSERVER RELIABILITY; PATIENT PREFERENCES; SURGICAL-TREATMENT; PEDIATRIC ATHLETE; 3-DIMENSIONAL CT; DECISION-MAKING; ELBOW INJURIES; TALUS; FRACTURES; LESIONS AB Background: The radiographic appearance of osteochondritis dissecans (OCD) of the humeral capitellum varies according to the stage of the lesion. It is important to evaluate the stage of OCD lesion carefully to guide treatment. We compared the interobserver reliability of currently used classification systems for OCD of the humeral capitellum to identify the most reliable classification system. Methods: Thirty-two musculoskeletal radiologists and orthopaedic surgeons specialized in elbow surgery from several countries evaluated anteroposterior and lateral radiographs and corresponding computed tomography (CT) scans of 22 patients to classify the stage of OCD of the humeral capitellum according to the classification systems developed by (1) Minami, (2) Berndt and Harty, (3) Ferkel and Sgaglione, and (4) Anderson on a Web-based study platform including a Digital Imaging and Communications in Medicine viewer. Magnetic resonance imaging was not evaluated as part of this study. We measured agreement among observers using the Siegel and Castellan multirater kappa. Results: All OCD classification systems, except for Berndt and Harty, which had poor agreement among observers (kappa = 0.20), had fair interobserver agreement: k was 0.27 for the Minami, 0.23 for Anderson, and 0.22 for Ferkel and Sgaglione classifications. The Minami Classification was significantly more reliable than the other classifications (P < .001). Conclusions: The Minami Classification was the most reliable for classifying different stages of OCD of the humeral capitellum. However, it is unclear whether radiographic evidence of OCD of the humeral capitellum, as categorized by the Minami Classification, guides treatment in clinical practice as a result of this fair agreement. (C) 2015 Journal of Shoulder and Elbow Surgery Board of Trustees. C1 [Claessen, Femke M. A. P.; Doornberg, Job N.; Guitton, Thierry G.] Univ Amsterdam, Orthotrauma Res Ctr Amsterdam, Amsterdam, Netherlands. [Claessen, Femke M. A. P.] Massachusetts Gen Hosp, Hand & Upper Extrem Serv, Boston, MA 02114 USA. [van den Ende, Kimberly I. M.] Erasmus MC, Dept Orthopaed Surg, Rotterdam, Netherlands. [Eygendaal, Denise] Amphia Hosp, Dept Orthoped Surg, Upper Limb Unit, Breda, Netherlands. [van den Bekerom, Michel P. J.] Onze Lieve Vrouw Hosp, Shoulder & Elbow Unit, Amsterdam, Netherlands. RP Claessen, FMAP (reprint author), Massachusetts Gen Hosp, Orthopaed Hand & Upper Extrem Serv, Yawkey Ctr, 55 Fruit St, Boston, MA 02114 USA. EM fclaessen@mgh.harvard.edu OI Van Tongel, Alexander/0000-0003-3590-6614 FU Prins Bernhard Cultuur Foundation; Trust Foundation; VSB Foundation; Van Beek-Donner Foundation FX Femke M.A.P. Claessen has received a research grant from the Prins Bernhard Cultuur Foundation, the Trust Foundation, the VSB Foundation, and the Van Beek-Donner Foundation. NR 46 TC 0 Z9 0 U1 3 U2 10 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 OCT PY 2015 VL 24 IS 10 BP 1613 EP 1618 DI 10.1016/j.jse.2015.03.029 PG 6 WC Orthopedics; Sport Sciences; Surgery SC Orthopedics; Sport Sciences; Surgery GA CR7ZT UT WOS:000361571600021 PM 25953486 ER PT J AU Colman, MW Hornicek, FJ Schwab, JH AF Colman, Matthew W. Hornicek, Francis J. Schwab, Joseph H. TI Spinal Cord Blood Supply and Its Surgical Implications SO JOURNAL OF THE AMERICAN ACADEMY OF ORTHOPAEDIC SURGEONS LA English DT Review ID BILATERAL SEGMENTAL ARTERIES; THORACOABDOMINAL ANEURYSM REPAIR; SOMATOSENSORY-EVOKED-POTENTIALS; AORTIC-ANEURYSMS; VESSEL LIGATION; TEMPORARY OCCLUSION; NEUROLOGIC FUNCTION; FLUID DRAINAGE; DOG-MODEL; PARAPLEGIA AB The blood supply to the spine is based on a predictable segmental vascular structure at each spinal level, but true radiculomedullary arteries, which feed the dominant cord supply vessel, the anterior spinal artery, are relatively few and their locations variable. Under pathologic conditions, such as aortic stent grafting, spinal deformity surgery, or spinal tumor resection, sacrifice of a dominant radiculomedullary vessel may or may not lead to spinal cord ischemia, depending on dynamic autoregulatory or collateral mechanisms to compensate for its loss. Elucidation of the exact mechanisms for this compensation requires further study but will be aided by preoperative, intraoperative, and postoperative comparative angiography. Protocols in place at our center and others minimize the risk of spinal cord ischemia during planned radiculomedullary vessel sacrifice. C1 [Colman, Matthew W.; Hornicek, Francis J.; Schwab, Joseph H.] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. RP Colman, MW (reprint author), Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. FU Stryker; Biom'up FX Dr. Hornicek or an immediate family member has received research or institutional support from Stryker; has received nonincome support (such as equipment or services), commercially derived honoraria, or other non-research-related funding (such as paid travel) from Biomet; and serves as a board member, owner, officer, or committee member of the American Association of Tissue Banks and the International Society of Limb Salvage. Dr. Schwab or an immediate family member is a member of a speakers' bureau or has made paid presentations on behalf of Synthes and Stryker Spine; serves as a paid consultant to and serves as a board member, owner, officer, or committee member of Biom'up; and has received nonincome support (such as equipment or services), commercially derived honoraria, or other non-research-related funding (such as paid travel) from Globus Medical and Stryker. Neither Dr. Colman nor any immediate family member has received anything of value from or has stock or stock options held in a commercial company or institution related directly or indirectly to the subject of this article. NR 53 TC 1 Z9 2 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1067-151X EI 1940-5480 J9 J AM ACAD ORTHOP SUR JI J. Am. Acad. Orthop. Surg. PD OCT PY 2015 VL 23 IS 10 BP 581 EP 591 DI 10.5435/JAAOS-D-14-00219 PG 11 WC Orthopedics; Surgery SC Orthopedics; Surgery GA CS0ON UT WOS:000361761300001 PM 26377671 ER PT J AU Marx, A Chan, JKC Coindre, JM Detterbeck, F Girard, N Harris, NL Jaffe, ES Kurrer, MO Marom, EM Moreira, AL Mukai, K Orazi, A Strobel, P AF Marx, Alexander Chan, John K. C. Coindre, Jean-Michel Detterbeck, Frank Girard, Nicolas Harris, Nancy L. Jaffe, Elaine S. Kurrer, Michael O. Marom, Edith M. Moreira, Andre L. Mukai, Kiyoshi Orazi, Attilio Stroebel, Philipp TI The 2015 World Health Organization Classification of Tumors of the Thymus Continuity and Changes SO JOURNAL OF THORACIC ONCOLOGY LA English DT Review DE Classification; Thymus; Thymoma; Atypical type A thymoma; Thymic carcinoma; Adenocarcinoma; NUT carcinoma; Carcinoid; Neuroendocrine; Combined large-cell neuroendocrine carcinoma; Combined thymic carcinoma; Mediastinal; Mediastinum; Germ cell tumor; Lymphoma; Primary mediastinal large B-cell lymphoma; Grey zone lymphoma; Hodgkin lymphoma; Dendritic cell tumor; Sarcoma; Neuroblastoma; Metastasis; Ectopic tumor; Positron emission tomography; Computed tomography; Cytology; Histology; Pathology; Immunohistochemistry; Immunohistology; Staging; Genetic; GTF2I; International Thymic Malignancy Interest Group; World Health Organization ID B-CELL LYMPHOMA; FORTHCOMING 8TH EDITION; NUT MIDLINE CARCINOMA; CLASSICAL HODGKINS LYMPHOMA; STAGING PROJECT PROPOSALS; MALIGNANCY INTEREST GROUP; GRAY ZONE LYMPHOMA; EPITHELIAL TUMORS; MUCOEPIDERMOID CARCINOMA; TNM CLASSIFICATION AB This overview of the 4th edition of the World Health Organization (WHO) Classification of thymic tumors has two aims. First, to comprehensively list the established and new tumor entities and variants that are described in the new WHO Classification of thymic epithelial tumors, germ cell tumors, lymphomas, dendritic cell and myeloid neoplasms, and soft-tissue tumors of the thymus and mediastinum; second, to highlight major differences in the new WHO Classification that result from the progress that has been made since the 3rd edition in 2004 at immunohistochemical, genetic and conceptual levels. Refined diagnostic criteria for type A, AB, B1-B3 thymomas and thymic squamous cell carcinoma are given, and it is hoped that these criteria will improve the reproducibility of the classification and its clinical relevance. The clinical perspective of the classification has been strengthened by involving experts from radiology, thoracic surgery, and oncology; by incorporating state-of-the-art positron emission tomography/computed tomography images; and by depicting prototypic cytological specimens. This makes the thymus section of the new WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart a valuable tool for pathologists, cytologists, and clinicians alike. The impact of the new WHO Classification on therapeutic decisions is exemplified in this overview for thymic epithelial tumors and mediastinal lymphomas, and future perspectives and challenges are discussed. C1 [Marx, Alexander] Heidelberg Univ, Univ Med Ctr Mannheim, Inst Pathol, D-68167 Mannheim, Germany. [Chan, John K. C.] Queen Elizabeth Hosp, Dept Pathol, Hong Kong, Hong Kong, Peoples R China. [Coindre, Jean-Michel] Inst Bergonie, Dept Pathol, Bordeaux, France. [Detterbeck, Frank] Yale Univ, Sch Med, Dept Thorac Surg, New Haven, CT USA. [Girard, Nicolas] Hosp Civils Lyon, Louis Pradel Hosp, Dept Resp Med, Lyon, France. [Harris, Nancy L.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Jaffe, Elaine S.] NCI, Hematopathol Sect, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Kurrer, Michael O.] Gemeinschaftspraxis Pathol, Zurich, Switzerland. [Marom, Edith M.] Chaim Sheba Med Ctr, Dept Diagnost Imaging, IL-52621 Tel Hashomer, Israel. [Moreira, Andre L.] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. [Mukai, Kiyoshi] Saiseikai Cent Hosp, Dept Diagnost Pathol, Tokyo, Japan. [Orazi, Attilio] New York Presbyterian Hosp, Weill Cornell Med Ctr, Dept Pathol & Lab Med, New York, NY USA. [Stroebel, Philipp] Univ Gottingen, Dept Pathol, Univ Med Ctr Gottingen, Inst Pathol, Gottingen, Germany. RP Marx, A (reprint author), Heidelberg Univ, Univ Med Ctr Mannheim, Inst Pathol, Theodor Kutzer Ufer 1-3, D-68167 Mannheim, Germany. EM alexander.marx@umm.de FU Intramural NIH HHS [Z01 BC011070-01] NR 91 TC 21 Z9 21 U1 3 U2 15 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1556-0864 EI 1556-1380 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD OCT PY 2015 VL 10 IS 10 BP 1383 EP 1395 DI 10.1097/JTO.0000000000000654 PG 13 WC Oncology; Respiratory System SC Oncology; Respiratory System GA CS0AP UT WOS:000361719200001 PM 26295375 ER PT J AU Poghosyan, H Stock, S Sheldon, LK Cromwell, J Cooley, ME Nerenz, DR AF Poghosyan, Hermine Stock, Shannon Sheldon, Lisa Kennedy Cromwell, Jerry Cooley, Mary E. Nerenz, David R. TI Racial Disparities in Health-Related Quality of Life After Lung Cancer Surgery Findings From the Cancer Care Outcomes Research and Surveillance Consortium SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article DE Non-small-cell lung cancer; Surgery; Racial disparities; Health-related quality of life ID NONSMALL CELL; AFRICAN-AMERICANS; PSYCHOSOCIAL CARE; INSURANCE STATUS; WHITE PATIENTS; EARLY-STAGE; SURVIVAL; RACE; COMORBIDITY; DEPRESSION AB Introduction: This study investigated racial disparities in postsurgical health-related quality of life (HRQOL) among patients with non-small-cell lung cancer (NSCLC). Methods: Data were collected by the Cancer Care Outcomes Research and Surveillance Consortium. Inclusion criteria were greater than or equal to 21 years of age, NSCLC, and receipt of surgery. HRQOL data were available from patients' surveys, and complete medical record abstraction was performed to obtain clinical data. HRQOL was assessed by the physical/mental component summary scores (PCS/MCS) of the 12-item Short-Form Health Survey at two time points. Mean time between surgery and the initial assessment (time 1) after surgery was 4.1 (SD 2.2) months and between surgery and second assessment (time 2) was 12.7 (SD 3.8) months. Multivariable linear regression models were used to examine associations between race and HRQOL. Results: Of 650 patients, 80.5% were White, 8.8% Black, and 10.7% other races. At second assessment, Blacks reported lower MCS than Whites (47.4 versus 52.6, p = 0.002). In multivariable analysis, Blacks had lower MCS compared with Whites. No difference was found between Whites and Blacks on PCS. Those with less than high school education reported lower MCSs. Older age and receipt of adjuvant chemotherapy after surgery were associated with gain in MCS. Male, less than college education, and comorbidities were associated with impaired PCS. Older age was associated with improved PCS. Conclusion: Racial disparities exist in postoperative mental HRQOL. Results highlight the need for interventions after lung cancer surgery to improve mental health in Black and younger patients. C1 [Poghosyan, Hermine; Sheldon, Lisa Kennedy] Univ Massachusetts, Coll Nursing & Hlth Sci, Boston, MA 02125 USA. [Stock, Shannon] Coll Holy Cross, Dept Math & Comp Sci, Worcester, MA 01610 USA. [Cromwell, Jerry] RTI Int, Waltham, MA USA. [Cooley, Mary E.] Dana Farber Canc Inst, Phyllis F Cantor Ctr Res Nursing & Patient Care S, Boston, MA 02115 USA. [Nerenz, David R.] Henry Ford Hlth Syst, Detroit, MI USA. RP Poghosyan, H (reprint author), Northeastern Univ, Bouve Coll Hlth Sci, Sch Nursing, 408 Robinson Hall, Boston, MA 02115 USA. EM h.poghosyan@neu.edu OI Sheldon, Lisa Kennedy/0000-0002-5958-8529 FU National Cancer Institute (NCI) [U01 CA093344]; NCI [U01 CA093332, U01 CA093324, U01 CA093348, U01 CA093329, U01 CA093339, U01 CA 093326]; Department of Veteran's Affairs [VA HSRD CRS-02-164] FX The work of the CanCORS consortium was supported by grants from the National Cancer Institute (NCI) to the Statistical Coordinating Center (U01 CA093344) and the NCI supported Primary Data Collection and Research Centers (Dana-Farber Cancer Institute/Cancer Research Network U01 CA093332, Harvard Medical School/Northern California Cancer Center U01 CA093324, RAND/UCLA U01 CA093348, University of Alabama at Birmingham U01 CA093329, University of Iowa U01 CA093339, University of North Carolina U01 CA 093326) and by a Department of Veteran's Affairs grant to the Durham VA Medical Center VA HSRD CRS-02-164). NR 50 TC 2 Z9 2 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1556-0864 EI 1556-1380 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD OCT PY 2015 VL 10 IS 10 BP 1404 EP 1412 DI 10.1097/JTO.0000000000000629 PG 9 WC Oncology; Respiratory System SC Oncology; Respiratory System GA CS0AP UT WOS:000361719200003 PM 26200452 ER PT J AU Durham, CA Aranson, NJ Ergul, EA Wang, LJ Patel, VI Cambria, RP Conrad, MF AF Durham, Christopher A. Aranson, Nathan J. Ergul, Emel A. Wang, Linda J. Patel, Virendra I. Cambria, Richard P. Conrad, Mark F. TI Aneurysmal degeneration of the thoracoabdominal aorta after medical management of type B aortic dissections SO JOURNAL OF VASCULAR SURGERY LA English DT Article; Proceedings Paper CT 41st Joint Annual Meeting of the New-England-Society-for-Vascular-Surgery (NESVS) and Eastern-Vascular-Society (EVS) CY SEP 11-14, 2014 CL Boston, MA SP New England Soc Vasc Surg, Eastern Vasc Soc ID PATENT FALSE LUMEN; INTERNATIONAL REGISTRY; FOLLOW-UP; RUPTURE; PREDICTORS; RISK; SIZE; MULTICENTER; DILATATION; SURVIVAL AB Background: Patients with uncomplicated type B aortic dissections who are managed medically are at risk of aortic aneurysmal degeneration over time. However, the effect of improvement in antihypertensive medications and stricter blood pressure control is unknown. The goal of this study was to determine the rate of aneurysmal degeneration in a contemporary cohort of patients with medically treated type B dissection. Methods: Included were all patients with acute uncomplicated type B aortic dissection who were initially managed medically between March 1999 and March 2011 and had follow-up axial imaging studies. Maximum aortic growth was calculated by comparing the initial imaging study to the most current scan or imaging obtained just before any aortic-related intervention. An increase of >= 5 mm was the threshold considered as aortic growth. Predictors of aortic aneurysmal degeneration were determined using Cox proportional hazards models. Results: We identified 200 patients (61% men) with medically managed acute type B dissections receiving multiple imaging studies. Patients were an average age of 63.4 years, and 75.5% had a history of hypertension. Mean follow-up was 5.3 years (range, 0.1-14.7 years). Mean time between the initial and final imaging studies was 3.2 years (range, 0.1-12.9 years). At 5 years, only 51% were free from aortic growth. Fifty-six patients (28%) required operative intervention (50 open, 6 endovascular repair) for aneurysmal degeneration, and the actuarial 5-year freedom from intervention was 76%. After excluding five patients (2.5%) with early rapid degeneration requiring intervention within the first 2 weeks, the mean rate of aortic growth was 12.3 mm/y for the total aortic diameter, 3.8 mm/y for the true lumen diameter, and 8.6 mm/y for the false lumen diameter. Only aortic diameter at index presentation >3.5 cm was a risk factor for future growth (odds ratio, 2.54; 95% confidence interval, 1.34-4.81; P < .01). Complete thrombosis of the false lumen was protective against growth (odds ratio, 0.19; 95% confidence interval, 0.11-0.42; P < .01). Conclusions: Although medical management of uncomplicated acute, type B aortic dissections has been the standard of care, at 5 years, a significant number of patients will require operative intervention for aneurysmal degeneration. Further studies of early intervention (eg, thoracic endovascular aortic repair) for type B aortic dissection to prevent late aneurysm formation are needed. C1 [Durham, Christopher A.; Aranson, Nathan J.; Ergul, Emel A.; Wang, Linda J.; Patel, Virendra I.; Cambria, Richard P.; Conrad, Mark F.] Massachusetts Gen Hosp, Dept Vasc & Endovasc Surg, Boston, MA 02114 USA. RP Conrad, MF (reprint author), Massachusetts Gen Hosp, 15 Parkman St,WAC 440, Boston, MA 02114 USA. EM mconrad@partners.org OI Aranson, Nathan/0000-0001-8833-4643 NR 33 TC 6 Z9 6 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD OCT PY 2015 VL 62 IS 4 BP 900 EP 906 DI 10.1016/j.jvs.2015.04.423 PG 7 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA CS2GC UT WOS:000361885800011 PM 26071613 ER PT J AU Brothers, TE Ricotta, JJ Gillespie, DL Geraghty, PJ Kenwood, CT Siami, FS Ricotta, JJ White, RA AF Brothers, Thomas E. Ricotta, Joseph J., II Gillespie, David L. Geraghty, Patrick J. Kenwood, Christopher T. Siami, Flora S. Ricotta, John J. White, Rodney A. TI Contemporary results of carotid endarterectomy in "normal-risk" patients from the Society for Vascular Surgery Vascular Registry 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 ARTERY STENOSIS; OCCLUSION; MEDICARE; TRIAL; AGE AB Objective: Acceptable complication rates after carotid endarterectomy (CEA) are drawn from decades-old data. The recent Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) demonstrated improved stroke and mortality outcomes after CEA compared with carotid artery stenting, with 30-day periprocedural CEA stroke rates of 3.2% and 1.4% for symptomatic (SX) and asymptomatic (ASX) patients, respectively. It is unclear whether these target rates can be attained in "normal-risk" (NR) patients experienced outside of the trial. This study was done to determine the contemporary results of CEA from a broader selection of NR patients. Methods: The Society for Vascular Surgery (SVS) Vascular Registry was examined to determine in-hospital and 30-day event rates for NR, SX, and ASX patients undergoing CEA. NR was defined as patients without anatomic or physiologic risk factors as defined by SVS Carotid Practice Guidelines. Raw data and risk-adjusted rates of death, stroke, and myocardial infarction (MI) were compared between the ASX and SX cohorts. Results: There were 3977 patients (1456 SX, 2521 ASX) available for comparison. The SX group consisted of more men (61.7% vs 57.0%; P = .0045) but reflected a lower proportion of white patients (91.3% vs 94.4%; P = .0002), with lower prevalence of coronary artery disease (P < .0001), prior MI (P < .0001), peripheral vascular disease (P = .0017), and hypertension (P = .029), although New York Heart Association grade >3 congestive heart failure was equally present in both groups (P = .30). Baseline stenosis >80% on duplex imaging was less prevalent among SX patients (54.2% vs 67.8%; P < .0001). Perioperative stroke rates were higher for SX patients in the hospital (2.8% vs 0.8%; P < .0001) and at 30 days (3.4% vs 1.0%; P < .0001), which contributed to the higher composite death, stroke, andMI rates in the hospital (3.6% vs 1.8; P = .0003) and at 30 days (4.5% vs 2.2%; P < .0001) observed in SX patients. After risk adjustment, the rate of stroke/death was greater among SX patients in the hospital (odds ratio, 2.05; 95% confidence interval, 1.18-3.58) although not at 30 days (odds ratio, 1.36; 95% confidence interval, 0.85-2.17). No in-hospital or 30-day differences were observed for death or MI by symptom status. Conclusions: The SVS Vascular Registry results for CEA in NR patients are similar by symptom status to those reported for CREST and may serve as a benchmark for comparing results of alternative therapies for treatment of carotid stenosis in NR patients outside of monitored clinical trials. The contemporary perioperative risk of stroke after CEA in NR patients continues to be higher for SX than for ASX patients. C1 [Brothers, Thomas E.] Med Univ S Carolina, Surg Sect, Ralph H Johnson Dept Vet Affairs Med Ctr, Charleston, SC 29425 USA. [Brothers, Thomas E.] Med Univ S Carolina, Div Vasc Surg, Charleston, SC 29425 USA. [Ricotta, Joseph J., II] Northside Vasc Surg, Dept Vasc Surg & Endovasc Therapy, Atlanta, GA USA. [Gillespie, David L.] Southcoast Hlth Syst, Dept Vasc & Endovasc Surg, Fall River, MA USA. [Geraghty, Patrick J.] Washington Univ, Div Gen Surg, Vasc Surg Sect, St Louis, MO USA. [Kenwood, Christopher T.; Siami, Flora S.] New England Res Inst Inc, Inst Clin Trials & Registries, Watertown, MA 02472 USA. [Ricotta, John J.] Washington Hosp Ctr, Dept Vasc Surg, Washington, DC 20010 USA. [White, Rodney A.] Harbor UCLA, Div Vasc Surg, Los Angeles, CA USA. RP Siami, FS (reprint author), New England Res Inst Inc, 480 Pleasant St,Ste A100, Watertown, MA 02472 USA. EM ssiami@neriscience.com NR 20 TC 2 Z9 2 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD OCT PY 2015 VL 62 IS 4 BP 923 EP 928 DI 10.1016/j.jvs.2015.05.003 PG 6 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA CS2GC UT WOS:000361885800014 PM 26194815 ER PT J AU Aranson, NJ Patel, VI Durham, CA Conrad, MF Lancaster, RT MacGillivray, TE Isselbacher, E Cambria, RP AF Aranson, Nathan J. Patel, Virendra I. Durham, Christopher A. Conrad, Mark F. Lancaster, R. Todd MacGillivray, Thomas E. Isselbacher, Eric Cambria, Richard P. TI Presentation, Surgical Intervention, and Long-Term Survival in Patients With Marfan Syndrome SO JOURNAL OF VASCULAR SURGERY LA English DT Meeting Abstract CT 42nd New-England-Society for Vascular Surgery Annual Meeting CY OCT 02-04, 2015 CL Newport, RI SP New England Soc C1 [Aranson, Nathan J.; Patel, Virendra I.; Durham, Christopher A.; Conrad, Mark F.; Lancaster, R. Todd; MacGillivray, Thomas E.; Isselbacher, Eric; Cambria, Richard P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. OI Aranson, Nathan/0000-0001-8833-4643 NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD OCT PY 2015 VL 62 IS 4 BP 1094 EP 1094 PG 1 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA CS2GC UT WOS:000361885800046 ER PT J AU Conrad, MF Tuchek, J Feezor, R Bavaria, J Fairman, R White, R AF Conrad, Mark F. Tuchek, James Feezor, Robert Bavaria, Joseph Fairman, Ronald White, Rodney TI Five-Year Results of the Valor II Trial of the Medtronic Valiant Thoracic Stent Graft SO JOURNAL OF VASCULAR SURGERY LA English DT Meeting Abstract CT 42nd New-England-Society for Vascular Surgery Annual Meeting CY OCT 02-04, 2015 CL Newport, RI SP New England Soc C1 [Conrad, Mark F.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Tuchek, James] Loyola Univ, Maywood, IL 60153 USA. [Feezor, Robert] Univ Florida, Gainesville, FL USA. [Bavaria, Joseph; Fairman, Ronald] Univ Penn, Philadelphia, PA 19104 USA. [White, Rodney] Univ Calif Los Angeles, Torrance, CA 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 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD OCT PY 2015 VL 62 IS 4 BP 1094 EP 1094 PG 1 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA CS2GC UT WOS:000361885800045 ER PT J AU Clouse, WD Ergul, EA Cambria, RP Brewster, DC Kwolek, CJ Watkins, MT LaMuraglia, GM Patel, VI Conrad, MF AF Clouse, W. Darrin Ergul, Emel A. Cambria, Richard P. Brewster, David C. Kwolek, Christopher J. Watkins, Michael T. LaMuraglia, Glenn M. Patel, Virendra I. Conrad, Mark F. TI Carotid Endarterectomy with Retrograde Proximal Stenting: Not a Simple Solution SO JOURNAL OF VASCULAR SURGERY LA English DT Meeting Abstract CT 42nd New-England-Society for Vascular Surgery Annual Meeting CY OCT 02-04, 2015 CL Newport, RI SP New England Soc C1 [Clouse, W. Darrin; Ergul, Emel A.; Cambria, Richard P.; Brewster, David C.; Kwolek, Christopher J.; Watkins, Michael T.; LaMuraglia, Glenn M.; Patel, Virendra I.; Conrad, Mark F.] Massachusetts Gen Hosp, Boston, MA 02114 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 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD OCT PY 2015 VL 62 IS 4 BP 1096 EP 1096 PG 1 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA CS2GC UT WOS:000361885800051 ER PT J AU Klarin, D Lancaster, R Ergul, E Bertges, D Goodney, P Conrad, M Cambria, RP Patel, V AF Klarin, Derek Lancaster, Robert Ergul, Emel Bertges, Daniel Goodney, Phillip Conrad, Mark Cambria, Richard P. Patel, Virendra TI Perioperative and Long-Term Impact of Chronic Kidney Disease on Carotid Artery Interventions SO JOURNAL OF VASCULAR SURGERY LA English DT Meeting Abstract CT 42nd New-England-Society for Vascular Surgery Annual Meeting CY OCT 02-04, 2015 CL Newport, RI SP New England Soc C1 [Klarin, Derek; Lancaster, Robert; Ergul, Emel; Conrad, Mark; Cambria, Richard P.; Patel, Virendra] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Bertges, Daniel] Univ Vermont, Med Ctr, Burlington, VT USA. [Goodney, Phillip] Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 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 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD OCT PY 2015 VL 62 IS 4 BP 1099 EP 1099 PG 1 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA CS2GC UT WOS:000361885800057 ER PT J AU Corey, M Ergul, E Patel, V Lancaster, RT Kwolek, C Cambria, R Conrad, M AF Corey, Michael Ergul, Emel Patel, Virendra Lancaster, R. Todd Kwolek, Christopher Cambria, Richard Conrad, Mark TI The Presentation and Management of Gastroduodenal and Pancreaticoduodenal Artery Aneurysms SO JOURNAL OF VASCULAR SURGERY LA English DT Meeting Abstract CT 42nd New-England-Society for Vascular Surgery Annual Meeting CY OCT 02-04, 2015 CL Newport, RI SP New England Soc C1 [Corey, Michael; Ergul, Emel; Patel, Virendra; Lancaster, R. Todd; Kwolek, Christopher; Cambria, Richard; Conrad, Mark] Massachusetts Gen Hosp, Boston, MA 02114 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 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD OCT PY 2015 VL 62 IS 4 BP 1100 EP 1101 PG 4 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA CS2GC UT WOS:000361885800060 ER PT J AU Lancaster, RT Ergul, EA Buck, DB Schermerhorn, ML Schanzer, A Conrad, MF Cambria, RP Patel, VI AF Lancaster, Robert T. Ergul, Emel A. Buck, Dominique B. Schermerhorn, Marc L. Schanzer, Andres Conrad, Mark F. Cambria, Richard P. Patel, Virendra I. TI Similar Outcomes of Open and Endovascular Repair for Complex Aortic Aneurysms SO JOURNAL OF VASCULAR SURGERY LA English DT Meeting Abstract CT 42nd New-England-Society for Vascular Surgery Annual Meeting CY OCT 02-04, 2015 CL Newport, RI SP New England Soc C1 [Lancaster, Robert T.; Ergul, Emel A.; Conrad, Mark F.; Cambria, Richard P.; Patel, Virendra I.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Buck, Dominique B.; Schermerhorn, Marc L.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Schanzer, Andres] UMass Mem Med Ctr, Worcester, 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 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD OCT PY 2015 VL 62 IS 4 BP 1101 EP 1102 PG 5 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA CS2GC UT WOS:000361885800062 ER PT J AU Hosseini, A Qi, W Tsai, TY Liu, YJ Rubash, H Li, GA AF Hosseini, Ali Qi, Wei Tsai, Tsung-Yuan Liu, Yujie Rubash, Harry Li, Guoan TI In vivo length change patterns of the medial and lateral collateral ligaments along the flexion path of the knee SO KNEE SURGERY SPORTS TRAUMATOLOGY ARTHROSCOPY LA English DT Article DE In vivo length change pattern; Medial collateral ligament; Lateral collateral ligament; Lunge ID ANTERIOR CRUCIATE LIGAMENT; ARTHROPLASTY; JOINT; KINEMATICS; PROSTHESES; ELONGATION; BUNDLES; MOTION; RANGE; MODEL AB The knowledge of the function of the collateral ligaments-i.e., superficial medial collateral ligament (sMCL), deep medial collateral ligament (dMCL) and lateral collateral ligament (LCL)-in the entire range of knee flexion is important for soft tissue balance during total knee arthroplasty (TKA). The objective of this study was to investigate the length changes of different portions (anterior, middle and posterior) of the sMCL, dMCL and LCL during in vivo weightbearing flexion from full extension to maximal knee flexion. Using a dual fluoroscopic imaging system, eight healthy knees were imaged while performing a lunge from full extension to maximal flexion. The length changes of each portion of the collateral ligaments were measured along the flexion path of the knee. All anterior portions of the collateral ligaments were shown to have increasing length with flexion except that of the sMCL, which showed a reduction in length at high flexion. The middle portions showed minimal change in lengths except that of the sMCL, which showed a consistent reduction in length with flexion. All posterior portions showed reduction in lengths with flexion. These data indicated that every portion of the ligaments may play important roles in knee stability at different knee flexion range. The soft tissue releasing during TKA may need to consider the function of the ligament portions along the entire flexion path including maximum flexion. III. C1 [Hosseini, Ali; Qi, Wei; Tsai, Tsung-Yuan; Rubash, Harry; Li, Guoan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Bioengn Lab,Dept Orthopaed Surg, Boston, MA 02114 USA. [Qi, Wei; Liu, Yujie] Chinese Peoples Liberat Army Gen Hosp, Dept Orthopaed Surg, Beijing 100853, Peoples R China. RP Li, GA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Bioengn Lab,Dept Orthopaed Surg, 55 Fruit St,GRJ 1215, Boston, MA 02114 USA. EM gli1@partners.org OI Tsai, Tsung-Yuan/0000-0003-1522-2987 FU National Institutes of Health [R01 AR055612]; Chinese PLA General Hospital FX The authors gratefully acknowledge the support of the National Institutes of Health (R01 AR055612) and the scholarship provided by the Chinese PLA General Hospital. NR 34 TC 0 Z9 0 U1 1 U2 3 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 OCT PY 2015 VL 23 IS 10 BP 3055 EP 3061 DI 10.1007/s00167-014-3306-9 PG 7 WC Orthopedics; Sport Sciences; Surgery SC Orthopedics; Sport Sciences; Surgery GA CS0EB UT WOS:000361729400039 PM 25239504 ER PT J AU Park, ER Psaros, C Traeger, L Stagg, A Jacquart, J Willett, J Alert, MD LaRoche, KL Ecker, JL AF Park, E. R. Psaros, C. Traeger, L. Stagg, A. Jacquart, J. Willett, J. Alert, M. D. LaRoche, K. L. Ecker, J. L. TI Development of a Postpartum Stressor Measure SO MATERNAL AND CHILD HEALTH JOURNAL LA English DT Article DE Stress perception; Stress measure; Postpartum stressors ID POSTNATAL DEPRESSION SCALE; SOCIAL SUPPORT; PERCEIVED STRESS; MATERNAL STRESS; WOMENS HEALTH; PREGNANCY; SMOKING; CHILDBIRTH; SYMPTOMS; DISTRESS AB To develop a brief self-report assessment of the type and magnitude of stressors during the postpartum period. A cross-sectional study of a convenience sample of 138 women at Massachusetts General Hospital in Boston, MA completed a measure of postpartum stressors at their 6-week postpartum visit. Item analyses were conducted; items were eliminated based on low relevance, low endorsement, and cross-loadings, resulting in a 9-item measure. Items were summed to create a total postpartum stressors score. To establish concurrent validity with perceived stress, the total postpartum stressors score was correlated with the 4-item Perceived Stress Scale (PSS-4). The stressors score was tested for bivariate associations with depression (Patient Health Questionnaire-2) and with social support (three items adapted from the MOS Social Support Scale). The 9-item measure, which was comprised of three factors (baby care, well-being, and work) demonstrated good reliability (Cronbach's alpha = .74) and concurrent validity with the PSS-4 (r = .53; p < .001) in the current sample. The stressors total score was negatively associated with social support (p < .001) and was positively associated with depression symptoms (p < .001). The early psychometric results on this measure are promising and associated with postpartum social support and depressive symptoms. With additional research to enhance external validity, this measure could be used and tested in an intervention study at the 6-week postpartum visit to identify women at risk for distress. C1 [Park, E. R.; Psaros, C.; Traeger, L.; Jacquart, J.; Willett, J.; Alert, M. D.; LaRoche, K. L.] Harvard Univ, Sch Med, MGH, Benson Henry Inst Mind Body Med, Boston, MA USA. [Park, E. R.; Psaros, C.; Traeger, L.] Harvard Univ, Sch Med, Dept Psychiat, MGH, Boston, MA 02115 USA. [Park, E. R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Stagg, A.] Harvard Univ, Sch Med, MGH, Dept Gen Med, Boston, MA USA. [Stagg, A.; Ecker, J. L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Ecker, J. L.] MGH, Vincent Dept Obstet & Gynecol, Boston, MA USA. RP Park, ER (reprint author), Massachusetts Gen Hosp, 50 Staniford St,Suite 901, Boston, MA 02114 USA. EM epark@mgh.harvard.edu; CPSAROS@mgh.harvard.edu; 02114LTRAEGER@mgh.harvard.edu; ASTAGG1@mgh.harvard.edu; jolene.jacquart@gmail.com; jessica.willett21@gmail.com; marissa1787@gmail.com; KLAROCHE@mgh.harvard.edu; JECKER@PARTNERS.ORG FU CDC [R01DP000339] FX Research was supported by the CDC Grant R01DP000339. NR 42 TC 1 Z9 1 U1 0 U2 4 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1092-7875 EI 1573-6628 J9 MATERN CHILD HLTH J JI Matern. Child Health J. PD OCT PY 2015 VL 19 IS 10 BP 2094 EP 2101 DI 10.1007/s10995-015-1731-0 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CR8SV UT WOS:000361625100002 PM 25682113 ER PT J AU Derrington, TM Bernstein, J Belanoff, C Cabral, HJ Babakhanlou-Chase, H Diop, H Evans, SR Kotelchuck, M AF Derrington, Taletha Mae Bernstein, Judith Belanoff, Candice Cabral, Howard J. Babakhanlou-Chase, Hermik Diop, Hafsatou Evans, Stephen R. Kotelchuck, Milton TI Refining Measurement of Substance Use Disorders Among Women of Child-Bearing Age Using Hospital Records: The Development of the Explicit-Mention Substance Abuse Need for Treatment in Women (EMSANT-W) Algorithm SO MATERNAL AND CHILD HEALTH JOURNAL LA English DT Article DE Diagnosis code grouper; Hospital discharge data; Prevalence; Substance abuse; Women ID ILLICIT-DRUG; ALCOHOL-USE; PREGNANCY; MASSACHUSETTS; LINKAGE; CARE AB Substance use disorder (SUD) in women of reproductive age is associated with adverse health consequences for both women and their offspring. US states need a feasible population-based, case-identification tool to generate better approximations of SUD prevalence, treatment use, and treatment outcomes among women. This article presents the development of the Explicit Mention Substance Abuse Need for Treatment in Women (EMSANT-W), a gender-tailored tool based upon existing International Classification of Diseases, 9th Edition, Clinical Modification diagnostic code-based groupers that can be applied to hospital administrative data. Gender-tailoring entailed the addition of codes related to infants, pregnancy, and prescription drug abuse, as well as the creation of inclusion/exclusion rules based on other conditions present in the diagnostic record. Among 1,728,027 women and associated infants who accessed hospital care from January 1, 2002 to December 31, 2008 in Massachusetts, EMSANT-W identified 103,059 women with probable SUD. EMSANT-W identified 4,116 women who were not identified by the widely used Clinical Classifications Software for Mental Health and Substance Abuse (CCS-MHSA) and did not capture 853 women identified by CCS-MHSA. Content and approach innovations in EMSANT-W address potential limitations of the Clinical Classifications Software, and create a methodologically sound, gender-tailored and feasible population-based tool for identifying women of reproductive age in need of further evaluation for SUD treatment. Rapid changes in health care service infrastructure, delivery systems and policies require tools such as the EMSANT-W that provide more precise identification methods for sub-populations and can serve as the foundation for analyses of treatment use and outcomes. C1 [Derrington, Taletha Mae] SRI Int, Ctr Educ & Human Serv, Educ Div, Menlo Pk, CA 94025 USA. [Derrington, Taletha Mae; Bernstein, Judith; Belanoff, Candice; Evans, Stephen R.] Boston Univ, Sch Publ Hlth, Dept Community Hlth Sci, Boston, MA USA. [Cabral, Howard J.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Babakhanlou-Chase, Hermik] Massachusetts Dept Publ Hlth, Bur Subst Abuse Serv, Boston, MA USA. [Diop, Hafsatou] Massachusetts Dept Publ Hlth, Bur Family Hlth & Nutr, Off Data Translat, Boston, MA USA. [Kotelchuck, Milton] Harvard Univ, Sch Med, MassGen Hosp Children, Boston, MA USA. RP Derrington, TM (reprint author), SRI Int, Ctr Educ & Human Serv, Educ Div, 333 Ravenswood Ave,BS179, Menlo Pk, CA 94025 USA. EM taletha.derrington@sri.com FU National Institute on Alcohol Abuse and Alcoholism [R21 AA018395]; National Institute on Drug Abuse of the National Institutes of Health [R21 DA027181]; Massachusetts Department of Public Health; CDC (PELL Data System Expansion and Associated Analyses) [200-2009-31671] FX This work was supported by two R21 grants from National Institute on Alcohol Abuse and Alcoholism (grant R21 AA018395) and the National Institute on Drug Abuse (grant R21 DA027181) of the National Institutes of Health. PELL is currently administered and funded by the Massachusetts Department of Public Health. From its inception in 2001 to 2012, it was a university-government partnership between the Boston University School of Public Health, the Massachusetts Department of Public Health, and the Centers for Disease Control and Prevention (CDC) and was funded by the CDC (PELL Data System Expansion and Associated Analyses Contract No. 200-2009-31671). The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the National Institutes of Health or the Massachusetts Department of Public Health. Dr. William McAuliffe provided many hours of invaluable assistance to the study team, explaining the rationale behind the inclusion and exclusion criteria used in the SNI, and challenging investigators to examine assumptions and support them with evidence. While his index was designed with another purpose in mind, it forms the foundation that made it possible to undertake this work. NR 38 TC 2 Z9 2 U1 0 U2 6 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1092-7875 EI 1573-6628 J9 MATERN CHILD HLTH J JI Matern. Child Health J. PD OCT PY 2015 VL 19 IS 10 BP 2168 EP 2178 DI 10.1007/s10995-015-1730-1 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CR8SV UT WOS:000361625100010 PM 25680703 ER PT J AU England, L Kotelchuck, M Wilson, HG Diop, H Oppedisano, P Kim, SY Cui, XH Shapiro-Mendoza, CK AF England, Lucinda Kotelchuck, Milton Wilson, Hoyt G. Diop, Hafsatou Oppedisano, Paul Kim, Shin Y. Cui, Xiaohui Shapiro-Mendoza, Carrie K. TI Estimating the Recurrence Rate of Gestational Diabetes Mellitus (GDM) in Massachusetts 1998-2007: Methods and Findings SO MATERNAL AND CHILD HEALTH JOURNAL LA English DT Article DE Diabetes; Gestational diabetes mellitus; Diabetes recurrence; Sequential pregnancies; Pregnancy ID LIFE-STYLE INTERVENTION; PREPREGNANCY OBESITY; PREGNANT-WOMEN; HIGH-RISK; TRENDS; PREVALENCE; OUTCOMES; PRESERVATION; POPULATION; PROGRAM AB Women with gestational diabetes mellitus (GDM) may be able to reduce their risk of recurrent GDM and progression to type 2 diabetes mellitus through lifestyle change; however, there is limited population-based information on GDM recurrence rates. We used data from a population of women delivering two sequential live singleton infants in Massachusetts (1998-2007) to estimate the prevalence of chronic diabetes mellitus (CDM) and GDM in parity one pregnancies and recurrence of GDM and progression from GDM to CDM in parity two pregnancies. We examined four diabetes classification approaches; birth certificate (BC) data alone, hospital discharge (HD) data alone, both sources hierarchically combined with a diagnosis of CDM from either source taking priority over a diagnosis of GDM, and both sources combined including only pregnancies with full agreement in diagnosis. Descriptive statistics were used to describe population characteristics, prevalence of CDM and GDM, and recurrence of diabetes in successive pregnancies. Diabetes classification agreement was assessed using the Kappa statistic. Associated maternal characteristics were examined through adjusted model-based t tests and Chi square tests. A total of 134,670 women with two sequential deliveries of parities one and two were identified. While there was only slight agreement on GDM classification across HD and BC records, estimates of GDM recurrence were fairly consistent; nearly half of women with GDM in their parity one pregnancy developed GDM in their subsequent pregnancy. While estimates of progression from GDM to CDM across sequential pregnancies were more variable, all approaches yielded estimates of a parts per thousand currency sign5 %. The development of either GDM or CDM following a parity one pregnancy with no diagnosis of diabetes was < 3 % across approaches. Women with recurrent GDM were disproportionately older and foreign born. Recurrent GDM is a serious life course public health issue; the inter-pregnancy interval provides an important window for diabetes prevention. C1 [England, Lucinda; Kim, Shin Y.] Ctr Dis Control & Prevent, Atlanta, GA 30341 USA. [Kotelchuck, Milton] Harvard Univ, MassGen Hosp Children, MGH Ctr Child & Adolescent Hlth Res & Policy, Sch Med, Boston, MA 02115 USA. [Wilson, Hoyt G.] DB Consulting Grp Inc, Silver Spring, MD 20910 USA. [Diop, Hafsatou; Cui, Xiaohui] Massachusetts Dept Publ Hlth, Bur Family Hlth & Nutr, Boston, MA 02108 USA. [Oppedisano, Paul] Massachusetts Dept Publ Hlth, Boston, MA 02108 USA. [Shapiro-Mendoza, Carrie K.] Ctr Dis Control & Prevent, Div Reprod Hlth, Atlanta, GA 30341 USA. RP Kotelchuck, M (reprint author), Harvard Univ, MassGen Hosp Children, MGH Ctr Child & Adolescent Hlth Res & Policy, Sch Med, 100 Cambridge St,Room 15-1545, Boston, MA 02115 USA. EM lbe@cdc.gov; mkotelchuck@partners.org; hgw0@att.net; hafsatou.diop@state.ma.us; paul.oppedisano@state.ma.us; skim1@cdc.gov; xiaohui.cui@state.ma.usa; ayn9@cdc.gov FU Intramural CDC HHS [CC999999] NR 35 TC 3 Z9 3 U1 0 U2 3 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1092-7875 EI 1573-6628 J9 MATERN CHILD HLTH J JI Matern. Child Health J. PD OCT PY 2015 VL 19 IS 10 BP 2303 EP 2313 DI 10.1007/s10995-015-1750-x PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA CR8SV UT WOS:000361625100024 PM 26045058 ER PT J AU Agarwal, I Glazer, NL Barasch, E Djousse, L Gottdiener, JS Ix, JH Kizer, JR Rimm, EB Siscovick, DS King, GL Mukamal, KJ AF Agarwal, Isha Glazer, Nicole L. Barasch, Eddy Djousse, Luc Gottdiener, John S. Ix, Joachim H. Kizer, Jorge R. Rimm, Eric B. Siscovick, David S. King, George L. Mukamal, Ken J. TI Associations between metabolic dysregulation and circulating biomarkers of fibrosis: the Cardiovascular Health Study SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Article DE Fibrosis; Growth factors; Hyperglycemia; Insulin resistance ID GROWTH-FACTOR-BETA; GENE-EXPRESSION; TGF-BETA; INSULIN-RESISTANCE; TRANSFORMING GROWTH-FACTOR-BETA-1; COLLAGEN TURNOVER; OLDER-ADULTS; HIGH GLUCOSE; ACTIVATION; COMPLICATIONS AB Aim. Fibrosis is one postulated pathway by which diabetes produces cardiac and other systemic complications. Our aim was to determine which metabolic parameters are associated with circulating fibrosis-related biomarkers transforming growth factor-beta (TGF-beta) and procollagen type III N-terminal propeptide (PIIINP). Methods. We used linear regression to determine the cross-sectional associations of diverse metabolic parameters, including fasting glucose, fasting insulin, body mass index, fatty acid binding protein 4, and non-estelified fatty acids, with circulating levels of TGF-beta (n = 1559) and PIIINP (n = 3024) among community-living older adults in the Cardiovascular Health Study. Results. Among the main metabolic parameters we examined, only fasting glucose was associated with TGF-beta (P = 0.03). In contrast, multiple metabolic parameters were associated with PIIINP, including fasting insulin, body mass index, and non-esterified fatty acids (P<0.001, P<0.001, P=0.001, respectively). These associations remained statistically significant after mutual adjustment, except the association between BMI and PIIINP. Conclusions. Isolated hyperglycemia is associated with higher serum concentrations of TGF-beta, while a broader phenotype of insulin resistance is associated with higher serum PIIINP. Whether simultaneous pharmacologic targeting of these two metabolic phenotypes can synergistically reduce the risk of cardiac and other manifestations of fibrosis remains to be determined. (C) 2015 Elsevier Inc. All rights reserved. C1 [Agarwal, Isha; Rimm, Eric B.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Agarwal, Isha; Rimm, Eric B.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Glazer, Nicole L.] Boston Univ, Dept Med, Boston, MA 02215 USA. [Barasch, Eddy] St Francis Hosp, Ctr Heart, Dept Res & Educ, Roslyn, NY USA. [Barasch, Eddy] SUNY Stony Brook, Stony Brook, NY 11794 USA. [Djousse, Luc] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Gottdiener, John S.] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Ix, Joachim H.] Univ Calif San Diego, Dept Med, San Diego, CA 92103 USA. [Ix, Joachim H.] Vet Affairs San Diego Healthcare Syst, San Diego, CA USA. [Kizer, Jorge R.] Albert Einstein Coll Med, Dept Med, Bronx, NY 10467 USA. [Kizer, Jorge R.] Albert Einstein Coll Med, Dept Epidemiol, Bronx, NY 10467 USA. [Kizer, Jorge R.] Albert Einstein Coll Med, Dept Populat Hlth, Bronx, NY 10467 USA. [Rimm, Eric B.] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Siscovick, David S.] New York Acad Med, New York, NY USA. [Siscovick, David S.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Siscovick, David S.] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [King, George L.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. [King, George L.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Mukamal, Ken J.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. RP Agarwal, I (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave, Boston, MA 02115 USA. EM Isha_Agarwal@hms.harvard.edu RI Djousse, Luc/F-5033-2017 OI Djousse, Luc/0000-0002-9902-3047 FU National Heart, Lung, and Blood Institute (NHLBI) [HL118775, HL094555, HHSN268201200036C, HHSN268200800007C, N01 HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, HL080295]; National Institute on Aging (NIA) [AG023629] FX This research was supported by contracts HL118775, HL094555, HHSN268201200036C, HHSN268200800007C, N01 HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and grant HL080295 from the National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. NR 32 TC 2 Z9 2 U1 1 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0026-0495 EI 1532-8600 J9 METABOLISM JI Metab.-Clin. Exp. PD OCT PY 2015 VL 64 IS 10 BP 1316 EP 1323 DI 10.1016/j.metabol.2015.07.013 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CR8ZG UT WOS:000361642400015 PM 26282733 ER PT J AU Papakostas, GI Ionescu, DF AF Papakostas, G. I. Ionescu, D. F. TI Towards new mechanisms: an update on therapeutics for treatment-resistant major depressive disorder SO MOLECULAR PSYCHIATRY LA English DT Review ID TRANSCRANIAL MAGNETIC STIMULATION; RANDOMIZED CONTROLLED-TRIAL; PLACEBO-CONTROLLED TRIAL; SEROTONIN REUPTAKE INHIBITOR; D-ASPARTATE ANTAGONIST; FUNCTIONAL PARTIAL AGONIST; DOUBLE-BLIND; ANTIDEPRESSANT TREATMENT; CLINICAL-TRIAL; TESTOSTERONE GEL AB Depression is a devastating disorder that places a significant burden on both the individual and society. As such, the discovery of novel therapeutics and innovative treatments-especially for treatment-resistant depression (TRD)-are essential. Research into antidepressant therapies for TRD has evolved from explorations of antidepressants with primary mechanisms of action on the monoaminergic neurotransmitter system to augmentation agents with primary mechanisms both within and outside of the serotonin/norepinephrine system. Now the field of antidepressant research has changed trajectories yet again; this time, compounds with primary mechanisms of action on the glutamatergic, cholinergic and opioid systems are in the forefront of antidepressant exploration. In this review, we will discuss the most recent research surrounding these novel compounds. In addition, we will discuss novel device-based therapeutics, with a particular focus on transcranial magnetic stimulation. In many cases of antidepressant drug discovery, the role of serendipity coupled with meticulous clinical observation in drug development in medicine was crucial. Moving forward, we must look toward the combination of innovation plus improvements on the remarkable discoveries thus far to advance the field of antidepressant research. C1 [Papakostas, G. I.; Ionescu, D. F.] Massachusetts Gen Hosp, Clin Trials Network & Inst, Boston, MA 02114 USA. RP Papakostas, GI (reprint author), Massachusetts Gen Hosp, Clin Trials Network & Inst, 1 Bowdoin Sq,6th Floor, Boston, MA 02114 USA. EM gpapakostas@partners.org RI Ionescu, Dawn/K-5675-2015 FU AstraZeneca; Bristol-Myers Squibb Company; Forest Pharmaceuticals; National Institute of Mental Health; PAMLAB; Pfizer; Ridge Diagnostics; Sunovion Pharmaceuticals; Theracos FX Dr Papakostas has served as a consultant for Abbott Laboratories, AstraZeneca, Avanir Pharmaceuticals, Brainsway, Bristol-Myers Squibb Company, Cephalon, Dey Pharma, Eli Lilly, GlaxoSmithKline, Evotec AG, H. Lundbeck A/S, Inflabloc Pharmaceuticals, Jazz Pharmaceuticals, Novartis Pharma AG, Otsuka Pharmaceuticals, PAMLAB, Pfizer, Pierre Fabre Laboratories, Ridge Diagnostics (formerly known as Precision Human Biolaboratories), Shire Pharmaceuticals, Sunovion Pharmaceuticals, Takeda Pharmaceutical Company, Theracos and Wyeth. Dr Papakostas has received honoraria from Abbott Laboratories, Astra Zeneca, Avanir Pharmaceuticals, Bristol-Myers Squibb Company, Brainsway, Cephalon, Dey Pharma, Eli Lilly, Evotec AG, GlaxoSmithKline, Inflabloc Pharmaceuticals, Jazz Pharmaceuticals, H. Lundbeck A/S, Novartis Pharma AG, Otsuka Pharmaceuticals, PAMLAB, Pfizer, Pierre Fabre Laboratories, Ridge Diagnostics, Shire Pharmaceuticals, Sunovion Pharmaceuticals, Takeda Pharmaceutical Company, Theracos, Titan Pharmaceuticals and Wyeth. Dr Papakostas has received research support from AstraZeneca, Bristol-Myers Squibb Company, Forest Pharmaceuticals, the National Institute of Mental Health, PAMLAB, Pfizer, Ridge Diagnostics (formerly known as Precision Human Biolaboratories), Sunovion Pharmaceuticals and Theracos. Dr Papakostas has served (not currently) on the speaker's bureau for Bristol-Myers Squibb and Pfizer. Dr Ionescu has no conflict of interest to disclose, financial or otherwise. NR 107 TC 9 Z9 9 U1 6 U2 20 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 OCT PY 2015 VL 20 IS 10 BP 1142 EP 1150 DI 10.1038/mp.2015.92 PG 9 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA CS2OE UT WOS:000361909800001 PM 26148812 ER PT J AU Gottlieb, DJ Hek, K Chen, TH Watson, NF Eiriksdottir, G Byrne, EM Cornelis, M Warby, SC Bandinelli, S Cherkas, L Evans, DS Grabe, HJ Lahti, J Li, M Lehtimaki, T Lumley, T Marciante, KD Perusse, L Psaty, BM Robbins, J Tranah, GJ Vink, JM Wilk, JB Stafford, JM Bellis, C Biffar, R Bouchard, C Cade, B Curhan, GC Eriksson, JG Ewert, R Ferrucci, L Fulop, T Gehrman, PR Goodloe, R Harris, TB Heath, AC Hernandez, D Hofman, A Hottenga, JJ Hunter, DJ Jensen, MK Johnson, AD Kahonen, M Kao, L Kraft, P Larkin, EK Lauderdale, DS Luik, AI Medici, M Montgomery, GW Palotie, A Patel, SR Pistis, G Porcu, E Quaye, L Raitakari, O Redline, S Rimm, EB Rotter, JI Smith, AV Spector, TD Teumer, A Uitterlinden, AG Vohl, MC Widen, E Willemsen, G Young, T Zhang, X Liu, Y Blangero, J Boomsma, DI Gudnason, V Hu, F Mangino, M Martin, NG O'Connor, GT Stone, KL Tanaka, T Viikari, J Gharib, SA Punjabi, NM Raikkonen, K Volzke, H Mignot, E Tiemeier, H AF Gottlieb, D. J. Hek, K. Chen, T-h Watson, N. F. Eiriksdottir, G. Byrne, E. M. Cornelis, M. Warby, S. C. Bandinelli, S. Cherkas, L. Evans, D. S. Grabe, H. J. Lahti, J. Li, M. Lehtimaki, T. Lumley, T. Marciante, K. D. Perusse, L. Psaty, B. M. Robbins, J. Tranah, G. J. Vink, J. M. Wilk, J. B. Stafford, J. M. Bellis, C. Biffar, R. Bouchard, C. Cade, B. Curhan, G. C. Eriksson, J. G. Ewert, R. Ferrucci, L. Fulop, T. Gehrman, P. R. Goodloe, R. Harris, T. B. Heath, A. C. Hernandez, D. Hofman, A. Hottenga, J-J Hunter, D. J. Jensen, M. K. Johnson, A. D. Kahonen, M. Kao, L. Kraft, P. Larkin, E. K. Lauderdale, D. S. Luik, A. I. Medici, M. Montgomery, G. W. Palotie, A. Patel, S. R. Pistis, G. Porcu, E. Quaye, L. Raitakari, O. Redline, S. Rimm, E. B. Rotter, J. I. Smith, A. V. Spector, T. D. Teumer, A. Uitterlinden, A. G. Vohl, M-C Widen, E. Willemsen, G. Young, T. Zhang, X. Liu, Y. Blangero, J. Boomsma, D. I. Gudnason, V. Hu, F. Mangino, M. Martin, N. G. O'Connor, G. T. Stone, K. L. Tanaka, T. Viikari, J. Gharib, S. A. Punjabi, N. M. Raikkonen, K. Volzke, H. Mignot, E. Tiemeier, H. TI Novel loci associated with usual sleep duration: the CHARGE Consortium Genome-Wide Association Study SO MOLECULAR PSYCHIATRY LA English DT Article ID BODY-MASS INDEX; OSTEOPOROTIC FRACTURES; HYPOTHYROID PATIENTS; COHORT PROFILE; PHASE SYNDROME; DESIGN; RISK; VARIANTS; WOMEN; GENE AB Usual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality, although little is known about the genetic variants influencing this trait. A genome-wide association study (GWAS) of usual sleep duration was conducted using 18 population-based cohorts totaling 47 180 individuals of European ancestry. Genome-wide significant association was identified at two loci. The strongest is located on chromosome 2, in an intergenic region 35- to 80-kb upstream from the thyroid-specific transcription factor PAX8 (lowest P = 1.1 x 10(-9)). This finding was replicated in an African-American sample of 4771 individuals (lowest P = 9.3 x 10(-4)). The strongest combined association was at rs1823125 (P = 1.5 x 10(-10), minor allele frequency 0.26 in the discovery sample, 0.12 in the replication sample), with each copy of the minor allele associated with a sleep duration 3.1 min longer per night. The alleles associated with longer sleep duration were associated in previous GWAS with a more favorable metabolic profile and a lower risk of attention deficit hyperactivity disorder. Understanding the mechanisms underlying these associations may help elucidate biological mechanisms influencing sleep duration and its association with psychiatric, metabolic and cardiovascular disease. C1 [Gottlieb, D. J.; Chen, T-h] VA Boston Healthcare Syst, West Roxbury, MA 02132 USA. [Gottlieb, D. J.; Cade, B.; Patel, S. R.; Redline, S.] Brigham & Womens Hosp, Dept Med, Div Sleep & Circadian Disorders, Boston, MA 02115 USA. [Gottlieb, D. J.; Chen, T-h; O'Connor, G. T.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Gottlieb, D. J.; O'Connor, G. T.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Hek, K.; Tiemeier, H.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Hek, K.; Hofman, A.; Luik, A. I.; Uitterlinden, A. G.; Tiemeier, H.] Erasmus MC, Dept Psychiat, Epidemiol & Social Psychiat Res Inst, Rotterdam, Netherlands. [Watson, N. F.] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. [Watson, N. F.; Gharib, S. A.] Univ Washington, UW Med Sleep Ctr, Seattle, WA 98195 USA. [Eiriksdottir, G.; Smith, A. V.; Gudnason, V.] Icelandic Heart Assoc, Kopavogur, Iceland. [Byrne, E. M.] Univ Queensland, Queensland Brain Inst, St Lucia, Qld, Australia. [Byrne, E. M.; Montgomery, G. W.; Martin, N. G.] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Cornelis, M.; Jensen, M. K.; Rimm, E. B.; Hu, F.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Cornelis, M.; Curhan, G. C.; Rimm, E. B.; Hu, F.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Div Network Med, Boston, MA 02115 USA. [Warby, S. C.; Mignot, E.] Stanford Univ, Ctr Sleep Sci & Med, Palo Alto, CA 94304 USA. [Bandinelli, S.] Azienda Sanitaria Firenze, Geriatr Unit, Florence, Italy. [Cherkas, L.; Quaye, L.; Spector, T. D.; Mangino, M.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England. [Evans, D. S.; Tranah, G. J.; Stone, K. L.] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. [Grabe, H. J.] Univ Med Greifswald, HELIOS Hosp Stralsund, Dept Psychiat & Psychotherapy, Greifswald, Germany. [Lahti, J.; Raikkonen, K.] Univ Helsinki, Dept Behav Sci, Helsinki, Finland. [Lahti, J.; Eriksson, J. G.] Folkhalsan Res Ctr, Helsinki, Finland. [Li, M.; Kao, L.; Punjabi, N. M.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Lehtimaki, T.] Univ Tampere, Dept Clin Chem, Fimlab Labs, FIN-33101 Tampere, Finland. [Lehtimaki, T.] Univ Tampere, Sch Med, FIN-33101 Tampere, Finland. [Lumley, T.] Univ Auckland, Dept Stat, Auckland 1, New Zealand. [Marciante, K. D.; Psaty, B. M.; Gharib, S. A.] Univ Washington, Dept Med, Seattle, WA USA. [Marciante, K. D.; Psaty, B. M.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Perusse, L.] Univ Laval, Dept Kinesiol, Quebec City, PQ, Canada. [Perusse, L.; Vohl, M-C] Univ Laval, Inst Nutr & Funct Foods, Quebec City, PQ, Canada. [Psaty, B. M.] Univ Washington, Dept Epidemiol & Hlth Serv, Seattle, WA USA. [Psaty, B. M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Robbins, J.] Univ Calif Davis, Dept Internal Med, Sacramento, CA 95817 USA. [Vink, J. M.; Hottenga, J-J; Willemsen, G.; Boomsma, D. I.] Vrije Univ Amsterdam, Netherlands Twin Register, Dept Biol Psychol, Amsterdam, Netherlands. [Wilk, J. B.] Precis Med, Cambridge, MA USA. [Stafford, J. M.; Liu, Y.] Wake Forest Sch Med, Div Publ Hlth Sci, Winston Salem, NC USA. [Bellis, C.; Blangero, J.] Texas Biomed Res Inst, San Antonio, TX USA. [Biffar, R.] Univ Med Greifswald, Ctr Oral Hlth, Dept Prosthodont Gerodontol & Dent Mat, Greifswald, Germany. [Bouchard, C.] Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. [Curhan, G. C.; Hunter, D. J.; Kraft, P.; Rimm, E. B.; Hu, F.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Eriksson, J. G.] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland. [Eriksson, J. G.] Univ Helsinki, Cent Hosp, Helsinki, Finland. [Eriksson, J. G.] Natl Inst Hlth & Welf, Helsinki, Finland. Vasa Cent Hosp, Vaasa, Finland. [Ewert, R.] Univ Med Greifswald, Dept Internal Med B, Cardiol Pulm Med Infect Dis & Intens Care Med, Greifswald, Germany. [Ferrucci, L.; Tanaka, T.] NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA. [Fulop, T.] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Gehrman, P. R.] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Goodloe, R.] Vanderbilt Univ, Med Ctr, Ctr Human Genet Res, Nashville, TN USA. [Harris, T. B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Heath, A. C.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. [Hernandez, D.] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. [Hunter, D. J.; Kraft, P.] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. [Johnson, A. D.; Zhang, X.] NHLBI, Cardiovasc Epidemiol & Human Genom Branch, Framingham Heart Study, Framingham, MA USA. [Kahonen, M.] Univ Tampere, Tampere Univ Hosp, Dept Clin Physiol, FIN-33101 Tampere, Finland. [Kahonen, M.] Univ Tampere, Tampere Univ Hosp, Sch Med, FIN-33101 Tampere, Finland. [Larkin, E. K.] Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37212 USA. [Lauderdale, D. S.] Univ Chicago, Dept Hlth Studies, Chicago, IL USA. [Medici, M.; Uitterlinden, A. G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Palotie, A.; Widen, E.] Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland. [Palotie, A.] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA. [Palotie, A.] Broad Inst MIT & Harvard, Genet Anal Platform, Cambridge, MA USA. [Palotie, A.] Wellcome Trust Sanger Inst, Cambridge, England. [Pistis, G.] San Raffaele Res Inst, Div Genet & Cell Biol, Milan, Italy. [Pistis, G.] Univ Trieste, Trieste, Italy. [Pistis, G.; Porcu, E.] CNR, IRGB, Cagliari, Italy. [Pistis, G.; Porcu, E.] Univ Sassari, Dipartimento Sci Biomed, I-07100 Sassari, Italy. [Raitakari, O.] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland. [Raitakari, O.] Turku Univ Hosp, Dept Clin Physiol & Nucl Med, FIN-20520 Turku, Finland. [Rotter, J. I.] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA. [Rotter, J. I.] Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90509 USA. [Smith, A. V.; Gudnason, V.] Univ Iceland, Reykjavik, Iceland. [Teumer, A.] Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany. [Teumer, A.; Volzke, H.] Univ Med Greifswald, Inst Community Med, Greifswald, Germany. [Uitterlinden, A. G.] Netherlands Consortium Healthy Aging, Netherlands Genom Initiat, Leiden, Netherlands. [Vohl, M-C] Univ Laval, Dept Food Sci & Nutr, Quebec City, PQ, Canada. [Young, T.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Populat Hlth Sci, Madison, WI USA. [Viikari, J.] Turku Univ Hosp, Dept Med, FIN-20520 Turku, Finland. [Viikari, J.] Univ Turku, Turku, Finland. [Punjabi, N. M.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Tiemeier, H.] Erasmus MC, Dept Child & Adolescent Psychiat, Rotterdam, Netherlands. RP Gottlieb, DJ (reprint author), VA Boston Healthcare Syst, 1400 VFW Pkwy 111PI, West Roxbury, MA 02132 USA. EM djgottlieb@partners.org RI Johnson, Andrew/G-6520-2013; Montgomery, Grant/B-7148-2008; Bouchard, Claude/A-7637-2009; Smith, Albert/K-5150-2015; mangino, massimo/F-5134-2011 OI Tiemeier, Henning/0000-0002-4395-1397; Patel, Sanjay/0000-0002-9142-5172; Lahti, Jari/0000-0002-4310-5297; Martin, Nicholas/0000-0003-4069-8020; Montgomery, Grant/0000-0002-4140-8139; Smith, Albert/0000-0003-1942-5845; mangino, massimo/0000-0002-2167-7470 FU National Heart, Lung and Blood Institute [N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01HL087641, R01HL59367, R01HL086694]; National Human Genome Research Institute [U01HG004402]; National Institutes of Health [HHSN268200625226C, UL1RR025005, HHSN268200782096C, , ]; NIH Roadmap for Medical Research [, U01 AR45580, U01 AR45614, U01 AR45632, U01 AR45647, U01 AR45654, U01 AR45583, U01 AG18197, U01-AG027810, UL1 RR024140]; NHLBI [, HHSN268201200036C, N01-HC-85239, N01-HC-55222, N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85086, HL080295, HL087652, HL105756]; National Institute on Aging (NIA) [, AG023629, R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, R01 AG027576, R01 AG026720]; National Center for Advancing Translational Sciences CTSI grant [, UL1TR000124]; National Institute of Diabetes and Digestive and Kidney Disease [, DK063491]; National Heart, Lung and Blood Institute's Framingham Heart Study [, N01-HC-25195]; Affymetrix, Inc [, N02-HL-6-4278]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine; Boston Medical Center; NIA [N01-AG-62101, N01-AG-62103, N01-AG-62106, 1R01AG032098-01A1, 1R01AG030474-01A1]; NIH, NIA; Academy of Finland [134309, 126925, 121584, 124282, 129378, 117787, 41071]; Finnish Diabetes Research Society; Folkhalsan Research Foundation; Novo Nordisk Foundation; Finska Lakaresallskapet; Signe and Ane Gyllenberg Foundation; University of Helsinki; Ministry of Education; Ahokas Foundation; Emil Aaltonen Foundation; Juho Vainio Foundation; Wellcome Trust [WT089062]; National Institutes of Health [NCI] [CA40356, CA087969, CA055075, CA98233]; National Institutes of Health [NIDDK] [DK058845, DK070756]; National Institutes of Health [NHGRI] [HG004399]; National Institutes of Health [NHLBI] [HL35464]; Merck/Rosetta Research Laboratories, North Wales, PA; Italian Ministry of Health [ICS110.1/RF97.71]; U.S. National Institute on Aging [263 MD 9164, 263 MD 821336]; National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) [RC2ARO58973]; National Center for Research Resources (NCRR); National Heart, Lung, and Blood Institute (NHLBI) [R01 HL071194, R01 HL070848, R01 HL070847, R01 HL070842, R01 HL070841, R01 HL070837, R01 HL070838, R01 HL070839]; NIAMS [RC2ARO58973]; Medical Research Council of Canada; Canadian Institutes for Health Research [FRN-CCT-83028]; Australian National Health and Medical Research Council [241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 552485, 552498]; Australian Research Council [A7960034, A79906588, A79801419, DP0770096, DP0212016, DP0343921]; FP-5 GenomEUtwin Project [QLG2-CT-2002-01254]; US National Institutes of Health (NIH) [AA07535, AA10249, AA11998, AA13320, AA13321, AA13326, AA14041, MH66206]; Netherlands Scientific Organization [NWO 480-05-003]; NHMRC grant [613608]; Netherlands Organisation of Scientific Research NWO Investments [175.010.2005.011, 911-03-012]; Research Institute for Diseases in the Elderly (RIDE2) [014-93-015]; Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) [050-060-810]; Erasmus MC; Erasmus MC, Rotterdam; Erasmus University, Rotterdam; Netherlands Organization for the Health Research and Development (ZonMw); Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; European Commission; Municipality of Rotterdam; VIDI grant of ZonMw [2009-017.106.370]; BavoEuropoort; Netherlands Organization for Scientific Research (NWO: MagW/ZonMW) [904-61-090, 985-10-002, 904-61-193, 480-04-004, 400-05-717, Addiction-31160008, Middelgroot-911-09-032, Spinozapremie 56-464-14192]; Center for Medical Systems Biology (CSMB, NWO Genomics) [NBIC/BioAssist/RK(2008.024)]; Biobanking and Biomolecular Resources Research Infrastructure (BBMRI -NL) [184.021.007]; VU University's Institute for Health and Care Research (EMGO+ ); Neuroscience Campus Amsterdam (NCA); European Science Foundation (ESF) [EU/QLRT-2001-01254]; European Community [HEALTH-F4-2007-201413]; ENGAGE [HEALTH-F4-2007-201413]; European Science Council [ERC 230374]; Rutgers University Cell and DNA Repository [NIMH U24 MH068457-06]; Avera Institute, Sioux Falls, South Dakota (USA); National Institutes of Health (NIH) [R01D0042157-01A, 1RC2MH089951-01, 1RC2 MH089995-01]; Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health; Federal Ministry of Education and Research [01ZZ9603, 01ZZ0103, 01ZZ0403, 03ZIK012]; Ministry of Cultural Affairs; Social Ministry of the Federal State of Mecklenburg-West Pomerania; Siemens Healthcare, Erlangen, Germany; Federal State of Mecklenburg-West Pomerania; Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award; King's College London; National Eye Institute via an NIH/CIDR genotyping project; National Heart, Lung, and Blood Institute [R01HL62252]; National Center for Research Resources [1UL1RR025011]; Social Insurance Institution of Finland, Kuopio, Tampere; Turku University Hospital Medical Funds [9M048 for 9N035]; Paavo Nurmi Foundation; Finnish Foundation of Cardiovascular Research; Tampere Tuberculosis Foundation; Finnish Cultural Foundation; [NS23724] FX The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. The Cardiovascular Health Study was supported by NHLBI contracts HHSN268201200036C, N01-HC-85239, N01-HC-55222, N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85086; and NHLBI grants HL080295, HL087652, HL105756 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through AG023629 from the National Institute on Aging (NIA). DNA handling and genotyping was supported in part by the National Center for Research Resources grant UL1RR033176, now at the National Center for Advancing Translational Sciences CTSI grant UL1TR000124; the National Institute of Diabetes and Digestive and Kidney Disease grant DK063491 to the Southern California Diabetes Endocrinology Research Center. This research was conducted in part using data and resources from the Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine. The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. This work was partially supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (contract no. N01-HC-25195) and its contract with Affymetrix, Inc for genotyping services (contract no. N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. The Health, Aging and Body Composition Study supported by NIA contracts N01-AG-62101, N01-AG-62103 and N01-AG-62106 and NIA grants 1R01AG032098-01A1 and 1R01AG030474-01A1. Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. This research was supported in part by the Intramural Research Program of the NIH, NIA. The Helsinki Birth Cohort Study has been supported by grants from the Academy of Finland, the Finnish Diabetes Research Society, Folkhalsan Research Foundation, Novo Nordisk Foundation, Finska Lakaresallskapet, Signe and Ane Gyllenberg Foundation, University of Helsinki, Ministry of Education, Ahokas Foundation, Emil Aaltonen Foundation, Juho Vainio Foundation, and Wellcome Trust (grant number WT089062). The Nurses Health Study and Health Professional Follow-Up Study GWAS were supported by grants from the National Institutes of Health [NCI (CA40356, CA087969, CA055075, CA98233), NIDDK (DK058845, DK070756), NHGRI (HG004399), NHLBI (HL35464)] with additional support from Merck/Rosetta Research Laboratories, North Wales, PA. The Invecchiare in CHIANTI study baseline (1998 2000) was supported as a 'targeted project' (ICS110.1/RF97.; 71) by the Italian Ministry of Health and in part by the U.S. National Institute on Aging (Contracts: 263 MD 9164 and 263 MD 821336). The Osteoporotic Fractures in Men (MrOS) Study is supported by National Institutes of Health funding. The following institutes provide support: the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Institute on Aging (NIA), the National Center for Research Resources (NCRR), and NIH Roadmap for Medical Research under the following grant numbers: U01 AR45580, U01 AR45614, U01 AR45632, U01 AR45647, U01 AR45654, U01 AR45583, U01 AG18197, U01-AG027810, and UL1 RR024140. The National Heart, Lung, and Blood Institute (NHLBI) provides funding for the MrOS Sleep ancillary study 'Outcomes of Sleep Disorders in Older Men' under the following grant numbers: R01 HL071194, R01 HL070848, R01 HL070847, R01 HL070842, R01 HL070841, R01 HL070837, R01 HL070838, and R01 HL070839'. The NIAMS provides funding for the MrOS ancillary study 'GWAS in MrOS and SOF' under the grant number RC2ARO58973. The Quebec Family Study was funded by multiple grants from the Medical Research Council of Canada and the Canadian Institutes for Health Research. This work was supported by a team grant from the Canadian Institutes for Health Research (FRN-CCT-83028). Funding for the Queensland Institute of Medical Research Twin Study was provided by the Australian National Health and Medical Research Council (241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 552485, 552498), the Australian Research Council (A7960034, A79906588, A79801419, DP0770096, DP0212016, DP0343921), the FP-5 GenomEUtwin Project (QLG2-CT-2002-01254) and the US National Institutes of Health (NIH grants AA07535, AA10249, AA11998, AA13320, AA13321, AA13326, AA14041, MH66206). A portion of the genotyping on which this study was based (Illumina 370K scans) was carried out at the Center for Inherited Disease Research, Baltimore (CIDR), through an access award to our late colleague Dr Richard Todd (Psychiatry, Washington University School of Medicine, St Louis). Statistical analyses were carried out on the Genetic Cluster Computer, which is financially supported by the Netherlands Scientific Organization (NWO 480-05-003). EMB is supported by NHMRC grant 613608. The generation and management of GWAS genotype data for the Rotterdam Study are supported by the Netherlands Organisation of Scientific Research NWO Investments (no. 175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) project nr. 050-060-810. The Rotterdam Study is funded by Erasmus MC and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. Henning Tiemeier was supported by the VIDI grant of ZonMw (2009-017.106.370). Karin Hek was supported by a grant from BavoEuropoort. Netherlands Twin Registry funding was obtained from the Netherlands Organization for Scientific Research (NWO: MagW/ZonMW grants 904-61-090, 985-10-002, 904-61-193,480-04-004, 400-05-717, Addiction-31160008, Middelgroot-911-09-032, Spinozapremie 56-464-14192), Center for Medical Systems Biology (CSMB, NWO Genomics), NBIC/BioAssist/RK(2008.; 024), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI -NL, 184.021.007), VU University's Institute for Health and Care Research (EMGO+ ) and Neuroscience Campus Amsterdam (NCA), European Science Foundation (ESF, EU/QLRT-2001-01254), the European Community's Seventh Framework Program (FP7/2007-2013), ENGAGE (HEALTH-F4-2007-201413); European Science Council (ERC 230374), Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06), the Avera Institute, Sioux Falls, South Dakota (USA), and the National Institutes of Health (NIH, R01D0042157-01A, Grand Opportunity grants 1RC2MH089951-01 and 1RC2 MH089995-01). Part of the genotyping and analyses were funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health. The Study of Health in Pomerania is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103 and 01ZZ0403), the Ministry of Cultural Affairs and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. The University of Greifswald is a member of the 'Center of Knowledge Interchange' program of the Siemens AG and the Cache Campus program of the InterSystems GmbH. The Study of Osteoporotic Fractures is supported by National Institutes of Health funding. The National Institute on Aging (NIA) provides support under the following grant numbers: R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, R01 AG027576, and R01 AG026720. The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) provides funding for the ancillary study 'GWAS in MrOS and SOF' under the grant number RC2ARO58973. TwinsUK was funded by the Wellcome Trust; European Community's Seventh Framework Programme (FP7/2007-2013), ENGAGE project grant agreement (HEALTH-F4-2007-201413). The study also receives support from the Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy's & St Thomas' NHS Foundation Trust in partnership with King's College London. Genotyping was performed by the Wellcome Trust Sanger Institute, support of the National Eye Institute via an NIH/CIDR genotyping project. This research was supported for the Wisconsin Sleep Cohort Study by the National Heart, Lung, and Blood Institute (R01HL62252) and National Center for Research Resources (1UL1RR025011) and by NS23724. The Young Finns Study has been financially supported by the Academy of Finland: grants 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), and 41071 (Skidi), the Social Insurance Institution of Finland, Kuopio, Tampere and Turku University Hospital Medical Funds (grant 9M048 for 9N035 for TeLeht), Juho Vainio Foundation, Paavo Nurmi Foundation, Finnish Foundation of Cardiovascular Research and Finnish Cultural Foundation, Tampere Tuberculosis Foundation and Emil Aaltonen Foundation. NR 61 TC 14 Z9 14 U1 3 U2 10 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 OCT PY 2015 VL 20 IS 10 BP 1232 EP 1239 DI 10.1038/mp.2014.133 PG 8 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA CS2OE UT WOS:000361909800011 PM 25469926 ER PT J AU Zhang, SY Bellinger, AM Glettig, DL Barman, R Lee, YAL Zhu, JH Cleveland, C Montgomery, VA Gu, L Nash, LD Maitland, DJ Langer, R Traverso, G AF Zhang, Shiyi Bellinger, Andrew M. Glettig, Dean L. Barman, Ross Lee, Young-Ah Lucy Zhu, Jiahua Cleveland, Cody Montgomery, Veronica A. Gu, Li Nash, Landon D. Maitland, Duncan J. Langer, Robert Traverso, Giovanni TI A pH-responsive supramolecular polymer gel as an enteric elastomer for use in gastric devices SO NATURE MATERIALS LA English DT Article ID DRUG-DELIVERY SYSTEMS; BIOENTERICS INTRAGASTRIC BALLOON; RELEASE COATINGS; DOSAGE FORMS; RESIDENCE; RETENTION; DOGS; BOND AB Devices resident in the stomach-used for a variety of clinical applications including nutritional modulation for bariatrics, ingestible electronics for diagnosis and monitoring, and gastric-retentive dosage forms for prolonged drug delivery-typically incorporate elastic polymers to compress the devices during delivery through the oesophagus and other narrow orifices in the digestive system. However, in the event of accidental device fracture or migration, the non-degradable nature of these materials risks intestinal obstruction. Here, we show that an elastic, pH-responsive supramolecular gel remains stable and elastic in the acidic environment of the stomach but can be dissolved in the neutral-pH environment of the small and large intestines. In a large animal model, prototype devices with these materials as the key component demonstrated prolonged gastric retention and safe passage. These enteric elastomers should increase the safety profile for a wide range of gastric-retentive devices. C1 [Zhang, Shiyi; Bellinger, Andrew M.; Glettig, Dean L.; Barman, Ross; Lee, Young-Ah Lucy; Cleveland, Cody; Montgomery, Veronica A.; Gu, Li; Langer, Robert; Traverso, Giovanni] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Zhang, Shiyi; Bellinger, Andrew M.; Glettig, Dean L.; Barman, Ross; Lee, Young-Ah Lucy; Cleveland, Cody; Montgomery, Veronica A.; Gu, Li; Langer, Robert; Traverso, Giovanni] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Bellinger, Andrew M.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Cardiovasc Div,Dept Med, Boston, MA 02115 USA. [Barman, Ross; Traverso, Giovanni] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Zhu, Jiahua] Oak Ridge Natl Lab, Ctr Nanophase Mat Sci, Oak Ridge, TN 37831 USA. [Nash, Landon D.; Maitland, Duncan J.] Texas A&M Univ, Biomed Device Lab, Dept Biomed Engn, College Stn, TX 77843 USA. [Langer, Robert] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Langer, R (reprint author), MIT, Dept Chem Engn, Cambridge, MA 02139 USA. EM rlanger@mit.edu; ctraverso@partners.org RI Zhu, Jiahua/F-3204-2012 OI Zhu, Jiahua/0000-0003-2889-3421 FU Bill and Melinda Gates Foundation [OPP1096734]; NIH [EB000244, T32 5T32HL007604-29]; Alexander von Humboldt Foundation under the Max Planck Research Award; Federal Ministry of Education and Research; Laboratory Directed Research and Development program at Oak Ridge National Laboratory; Scientific User Facilities Division, Office of Basic Energy Sciences, US Department of Energy; US DOE [DE-AC02-06CH11357] FX This work was funded in part by the Bill and Melinda Gates Foundation Grant OPP1096734 (to R.L.) and the NIH Grant EB000244 (to R.L.). The paper was partly sponsored by the Alexander von Humboldt Foundation under the auspices of the Max Planck Research Award to R.L. funded by the Federal Ministry of Education and Research. A.M.B. was supported in part by NIH T32 5T32HL007604-29. J.Z. was supported by the Laboratory Directed Research and Development program at Oak Ridge National Laboratory, which is sponsored by the Scientific User Facilities Division, Office of Basic Energy Sciences, US Department of Energy. Use of the Advanced Photon Source, an Office of Science User Facility operated for the US Department of Energy (DOE) Office of Science by Argonne National Laboratory, was supported by the US DOE under Contract No. DE-AC02-06CH11357. We would like to thank J. Haupt and M. Jamiel for expert veterinary support. We are indebted to L. Wood, P. Eckhoff, D. Hartman, S. Kern, S. Hershenson and B. Nikolic for fruitful discussions that stimulated the development of this material. The findings and conclusions reported in this paper are those of the authors and do not necessarily reflect positions or policies of the Bill and Melinda Gates Foundation. NR 44 TC 31 Z9 33 U1 39 U2 180 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1476-1122 EI 1476-4660 J9 NAT MATER JI Nat. Mater. PD OCT PY 2015 VL 14 IS 10 BP 1065 EP + DI 10.1038/NMAT4355 PG 9 WC Chemistry, Physical; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Materials Science; Physics GA CS0SF UT WOS:000361771800028 PM 26213897 ER PT J AU Jeselsohn, R Buchwalter, G De Angelis, C Brown, M Schiff, R AF Jeselsohn, Rinath Buchwalter, Gilles De Angelis, Carmine Brown, Myles Schiff, Rachel TI ESR1 mutations-a mechanism for acquired endocrine resistance in breast cancer SO NATURE REVIEWS CLINICAL ONCOLOGY LA English DT Article ID ESTROGEN-RECEPTOR-ALPHA; DEPENDENT PROBE AMPLIFICATION; CIRCULATING TUMOR DNA; KINASE 4/6 INHIBITOR; HIGH-DOSE TAMOXIFEN; POSTMENOPAUSAL WOMEN; GENETIC-HETEROGENEITY; MOLECULAR PORTRAITS; CLONAL EVOLUTION; K303R MUTATION AB Approximately 70% of breast cancers are oestrogen receptor a (ER) positive, and are, therefore, treated with endocrine therapies. However, about 25% of patients with primary disease and almost all patients with metastases will present with or eventually develop endocrine resistance. Despite the magnitude of this clinical challenge, the mechanisms underlying the development of resistance remain largely unknown. In the past 2 years, several studies unveiled gain-of-function mutations in ESR1, the gene encoding the ER, in approximately 20% of patients with metastatic ER-positive disease who received endocrine therapies, such as tamoxifen and aromatase inhibitors. These mutations are clustered in a 'hotspot' within the ligand-binding domain (LBD) of the ER and lead to ligand-independent ER activity that promotes tumour growth, partial resistance to endocrine therapy, and potentially enhanced metastatic capacity; thus, ER LBD mutations might account for a mechanism of acquired endocrine resistance in a substantial fraction of patients with metastatic disease. In general, the absence of detectable ESR1 mutations in patients with treatment-naive disease, and the correlation between the frequency of patients with tumours harbouring these mutations and the number of endocrine treatments received suggest that, under selective treatment pressure, clonal expansion of rare mutant clones occurs, leading to resistance. Preclinical and clinical development of rationale-based novel therapeutic strategies that inhibit these ER mutants has the potential to substantially improve treatment outcomes. We discuss the contribution of ESR1 mutations to the development of acquired resistance to endocrine therapy, and evaluate how mutated ER can be detected and targeted to overcome resistance and improve patient outcomes. C1 [Jeselsohn, Rinath; Brown, Myles] Harvard Univ, Breast Oncol Ctr, Sch Med, Boston, MA 02215 USA. [Buchwalter, Gilles] Harvard Univ, Ctr Funct Canc Epigenet, Dana Farber Canc Inst, Boston, MA 02215 USA. [De Angelis, Carmine; Schiff, Rachel] Baylor Coll Med, Dept Med, Lester & Sue Smith Breast Ctr, Houston, TX 77030 USA. [De Angelis, Carmine; Schiff, Rachel] Baylor Coll Med, Dept Med, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. [De Angelis, Carmine; Schiff, Rachel] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. RP Schiff, R (reprint author), Baylor Coll Med, Dept Med, Lester & Sue Smith Breast Ctr, One Baylor Plaza,BCM 600, Houston, TX 77030 USA. EM rschiff@bcm.edu OI Brown, Myles/0000-0002-8213-1658 FU NCI [P50 CA58183, P50 CA186784-01, P30 CA125123, P50 CA168508]; Susan G. Komen for the Cure Promise [PG12221410]; Breast Cancer Research Foundation; Cancer Prevention and Research Institute of Texas (CPRIT) [RP140102]; Baylor College of Medicine; Claudia Adams Barr Award FX R.S. has been funded in part by NCI grants P50 CA58183 and P50 CA186784-01 (SPORE) and P30 CA125123, as well as by the Susan G. Komen for the Cure Promise Grant PG12221410, and the Breast Cancer Research Foundation. C.D.A. has been funded by the Cancer Prevention and Research Institute of Texas (CPRIT) programme RP140102 and the Baylor College of Medicine Comprehensive Cancer Training Program. R.J. has been funded in part by the Claudia Adams Barr Award and by the NCI grant P50 CA168508 (SPORE) Career Development Award. NR 108 TC 35 Z9 36 U1 2 U2 16 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 OCT PY 2015 VL 12 IS 10 BP 573 EP 583 DI 10.1038/nrclinonc.2015.117 PG 11 WC Oncology SC Oncology GA CS0SG UT WOS:000361771900005 PM 26122181 ER PT J AU Green, MF Horan, WP Lee, J AF Green, Michael F. Horan, William P. Lee, Junghee TI Social cognition in schizophrenia SO NATURE REVIEWS NEUROSCIENCE LA English DT Review ID EVENT-RELATED POTENTIALS; EMOTION REGULATION; BIPOLAR DISORDER; EMPATHIC ACCURACY; NEURAL RESPONSE; HUMAN BRAIN; NEUROCOGNITIVE DEFICITS; NEUROIMAGING LITERATURE; 1ST-EPISODE PSYCHOSIS; SENSORY CONTRIBUTIONS AB Individuals with schizophrenia exhibit impaired social cognition, which manifests as difficulties in identifying emotions, feeing connected to others, inferring people's thoughts and reacting emotionally to others. These social cognitive impairments interfere with social connections and are strong determinants of the degree of impaired daily functioning in such individuals. Here, we review recent findings from the fields of social cognition and social neuroscience and identify the social processes that are impaired in schizophrenia. We also consider empathy as an example of a complex social cognitive function that integrates several social processes and is impaired in schizophrenia. This information may guide interventions to improve social cognition in patients with this disorder. C1 [Green, Michael F.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90024 USA. US Dept Vet Affairs, Desert Pacific Mental Illness Res Educ & Clin Ctr, Los Angeles, CA 90073 USA. RP Green, MF (reprint author), Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Semel Inst Neurosci & Human Behav, 760 Westwood Plaza,Room 27-462, Los Angeles, CA 90024 USA. EM mgreen@ucla.edu RI Lee, Junghee/C-5226-2014 OI Lee, Junghee/0000-0001-9567-8700 NR 200 TC 52 Z9 53 U1 20 U2 63 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-003X EI 1471-0048 J9 NAT REV NEUROSCI JI Nat. Rev. Neurosci. PD OCT PY 2015 VL 16 IS 10 BP 620 EP 631 DI 10.1038/nrn4005 PG 12 WC Neurosciences SC Neurosciences & Neurology GA CR9QP UT WOS:000361691900009 PM 26373471 ER PT J AU Shang, LS Cho, MT Retterer, K Folk, L Humberson, J Rohena, L Sidhu, A Saliganan, S Iglesias, A Vitazka, P Juusola, J O'Donnell-Luria, AH Shen, YF Chung, WK AF Shang, Linshan Cho, Megan T. Retterer, Kyle Folk, Leandra Humberson, Jennifer Rohena, Luis Sidhu, Alpa Saliganan, Sheila Iglesias, Alejandro Vitazka, Patrik Juusola, Jane O'Donnell-Luria, Anne H. Shen, Yufeng Chung, Wendy K. TI Mutations in ARID2 are associated with intellectual disabilities SO NEUROGENETICS LA English DT Article DE ARID2; Intellectual disabilities; Whole exome sequencing; De novo mutations; SWI/SNF chromatin modifier ID CHROMATIN-REMODELING COMPLEX; COFFIN-SIRIS SYNDROME; GENE-EXPRESSION; NEURAL DEVELOPMENT; SWI/SNF COMPLEXES; FAMILY PROTEINS; CHARGE-SYNDROME; PHENOTYPE; SUBUNIT; PBAF AB The etiology of intellectual disabilities (ID) remains unknown for the majority of patients. Due to reduced reproductive fitness in many individuals with ID, de novo mutations account for a significant portion of severe ID. The ATP-dependent SWI/SNF chromatin modifier has been linked with neurodevelopmental disorders including ID and autism. ARID2 is an intrinsic component of polybromo-associated BAF (PBAF), the SWI/SNF subcomplex. In this study, we used clinical whole exome sequencing (WES) in proband-parent-trios to identify the etiology of ID. We identified four independent, novel, loss of function variants in ARID2 gene in four patients, three of which were confirmed to be de novo. The patients all have ID and share other clinical characteristics including attention deficit hyperactivity disorder, short stature, dysmorphic facial features, and Wormian bones. All four novel variants are predicted to lead to a premature termination with the loss of the two conservative zinc finger motifs. This is the first report of mutations in ARID2 associated with developmental delay and ID. C1 [Shang, Linshan; Iglesias, Alejandro] Columbia Univ, Med Ctr, Dept Pediat, New York, NY 10032 USA. [Cho, Megan T.; Retterer, Kyle; Folk, Leandra; Vitazka, Patrik; Juusola, Jane] GeneDx, Gaithersburg, MD USA. [Humberson, Jennifer] Univ Virginia, Dept Pediat, Div Genet & Metab, Charlottesville, VA USA. [Rohena, Luis] San Antonio Mil Med Ctr, Div Genet, Dept Pediat, San Antonio, TX USA. [Sidhu, Alpa; Saliganan, Sheila] Michigan State Univ, Dept Pediat & Human Dev, E Lansing, MI 48824 USA. [O'Donnell-Luria, Anne H.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [O'Donnell-Luria, Anne H.] Broad Inst MIT & Harvard, Cambridge, MA USA. [O'Donnell-Luria, Anne H.] Boston Childrens Hosp, Div Genet & Genom, Boston, MA USA. [Shen, Yufeng] Columbia Univ, Med Ctr, Dept Syst Biol & Biomed Informat, New York, NY USA. [Chung, Wendy K.] Columbia Univ, Dept Med, Med Ctr, New York, NY USA. RP Chung, WK (reprint author), Columbia Univ, Med Ctr, Dept Pediat, 1150 St Nicholas Ave, New York, NY 10032 USA. EM wkc15@columbia.edu OI O'Donnell-Luria, Anne/0000-0001-6418-9592 FU Simons Foundation FX We thank the families for their generous contributions. We thank the data review support from ExAC consortium. This work was supported in part by a grant from the Simons Foundation. NR 54 TC 7 Z9 7 U1 1 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1364-6745 EI 1364-6753 J9 NEUROGENETICS JI Neurogenetics PD OCT PY 2015 VL 16 IS 4 BP 307 EP 314 DI 10.1007/s10048-015-0454-0 PG 8 WC Genetics & Heredity; Clinical Neurology SC Genetics & Heredity; Neurosciences & Neurology GA CR7VG UT WOS:000361559100006 PM 26238514 ER PT J AU Cohen, RG Gurfinkel, VS Kwak, E Warden, AC Horak, FB AF Cohen, Rajal G. Gurfinkel, Victor S. Kwak, Elizabeth Warden, Amelia C. Horak, Fay B. TI Lighten Up: Specific Postural Instructions Affect Axial Rigidity and Step Initiation in Patients With Parkinson's Disease SO NEUROREHABILITATION AND NEURAL REPAIR LA English DT Article DE Parkinson's disease; postural sway; postural alignment; rigidity; gait initiation; Alexander Technique; mindfulness ID RANDOMIZED CONTROLLED-TRIAL; ALEXANDER TECHNIQUE LESSONS; LOW-BACK-PAIN; GAIT INITIATION; OLDER-ADULTS; TAI-CHI; INSTABILITY; MOVEMENT; ADJUSTMENTS; IMPROVEMENT AB Background. Parkinson's disease (PD) is associated with stooped postural alignment, increased postural sway, and reduced mobility. The Alexander Technique (AT) is a mindfulness-based approach to improving posture and mobility by reducing muscular interference while maintaining upward intentions. Evidence suggests that AT can reduce disability associated with PD, but a mechanism for this effect has not yet been established. Objective. We investigated whether AT-based instructions reduce axial rigidity and increase upright postural alignment, and whether these instructions have different effects on postural alignment, axial rigidity, postural sway, and mobility than effort-based instructions regarding posture. Method. Twenty subjects with PD practiced 2 sets of instructions and then attempted to implement both approaches (as well as a relaxed control condition) during quiet standing and step initiation. The Lighten Up instructions relied on AT principles of reducing excess tension while encouraging length. The Pull Up instructions relied on popular concepts of effortful posture correction. We measured kinematics, resistance to axial rotation, and ground reaction forces. Results. Both sets of experimental instructions led to increases in upright postural alignment relative to the control condition. Only the Lighten Up instructions led to reduced postural sway, reduced axial postural tone, greater modifiability of tone, and a smoother center of pressure trajectory during step initiation, possibly indicating greater movement efficiency. Conclusion. Mindful movement approaches such as AT may benefit balance and mobility in subjects with PD by acutely facilitating increased upright postural alignment while decreasing rigidity. C1 [Cohen, Rajal G.; Warden, Amelia C.] Univ Idaho, Moscow, ID 83844 USA. [Gurfinkel, Victor S.; Horak, Fay B.] Oregon Hlth & Sci Univ, Beaverton, OR USA. [Kwak, Elizabeth] Macalester Coll, St Paul, MN 55105 USA. [Horak, Fay B.] Portland VA Med Ctr, Portland, OR USA. RP Cohen, RG (reprint author), Univ Idaho, Dept Psychol & Commun Studies, 875 Perimeter Dr MS 3043, Moscow, ID 83844 USA. EM rcohen@uidaho.edu FU National Institutes of Health [AG-006457, T32-NS045553, T32-AT002688]; Medical Research Foundation of Oregon; University of Idaho College of Letters, Arts, and Social Sciences 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 National Institutes of Health (grants AG-006457, T32-NS045553, and T32-AT002688); Medical Research Foundation of Oregon; and University of Idaho College of Letters, Arts, and Social Sciences. NR 51 TC 5 Z9 5 U1 2 U2 13 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1545-9683 EI 1552-6844 J9 NEUROREHAB NEURAL RE JI Neurorehabil. Neural Repair PD OCT PY 2015 VL 29 IS 9 BP 878 EP 888 DI 10.1177/1545968315570323 PG 11 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA CS2JW UT WOS:000361897800008 PM 25665828 ER PT J AU Lebwohl, M Strober, B Menter, A Gordon, K Weglowska, J Puig, L Papp, K Spelman, L Toth, D Kerdel, F Armstrong, AW Stingl, G Kimball, AB Bachelez, H Wu, JJ Crowley, J Langley, RG Blicharski, T Paul, C Lacour, JP Tyring, S Kircik, L Chimenti, S Duffin, KC Bagel, J Koo, J Aras, G Li, J Song, W Milmont, CE Shi, Y Erondu, N Klekotka, P Kotzin, B Nirula, A AF Lebwohl, M. Strober, B. Menter, A. Gordon, K. Weglowska, J. Puig, L. Papp, K. Spelman, L. Toth, D. Kerdel, F. Armstrong, A. W. Stingl, G. Kimball, A. B. Bachelez, H. Wu, J. J. Crowley, J. Langley, R. G. Blicharski, T. Paul, C. Lacour, J. -P. Tyring, S. Kircik, L. Chimenti, S. Duffin, K. C. Bagel, J. Koo, J. Aras, G. Li, J. Song, W. Milmont, C. E. Shi, Y. Erondu, N. Klekotka, P. Kotzin, B. Nirula, A. TI Phase 3 Studies Comparing Brodalumab with Ustekinumab in Psoriasis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID GENOME-WIDE ASSOCIATION; QUALITY-OF-LIFE; CLINICAL-RESPONSE; PLAQUE PSORIASIS; MODERATE; SKIN; INTERLEUKIN-17; ANTIBODY; CELLS; CANDIDIASIS AB BACKGROUND Early clinical studies suggested that the anti-interleukin-17 receptor A monoclonal antibody brodalumab has efficacy in the treatment of psoriasis. METHODS In two phase 3 studies (AMAGINE-2 and AMAGINE-3), patients with moderate-to-severe psoriasis were randomly assigned to receive brodalumab (210 mg or 140 mg every 2 weeks), ustekinumab (45 mg for patients with a body weight <= 100 kg and 90 mg for patients >100 kg), or placebo. At week 12, patients receiving brodalumab were randomly assigned again to receive a brodalumab maintenance dose of 210 mg every 2 weeks or 140 mg every 2 weeks, every 4 weeks, or every 8 weeks; patients receiving ustekinumab continued to receive ustekinumab every 12 weeks, and patients receiving placebo received 210 mg of brodalumab every 2 weeks. The primary aims were to evaluate the superiority of brodalumab over placebo at week 12 with respect to at least a 75% reduction in the psoriasis area-and-severity index score (PASI 75) and a static physician's global assessment (sPGA) score of 0 or 1 (clear or almost clear skin), as well as the superiority of brodalumab over ustekinumab at week 12 with respect to a 100% reduction in PASI score (PASI 100). RESULTS At week 12, the PASI 75 response rates were higher with brodalumab at the 210-mg and 140-mg doses than with placebo (86% and 67%, respectively, vs. 8% [AMAGINE-2] and 85% and 69%, respectively, vs. 6% [AMAGINE-3]; P<0.001); the rates of sPGA scores of 0 or 1 were also higher with brodalumab (P<0.001). The week 12 PASI 100 response rates were significantly higher with 210 mg of brodalumab than with ustekinumab (44% vs. 22% [AMAGINE-2] and 37% vs. 19% [AMAGINE-3], P<0.001). The PASI 100 response rates with 140 mg of brodalumab were 26% in AMAGINE-2 (P = 0.08 for the comparison with ustekinumab) and 27% in AMAGINE-3 (P = 0.007). Rates of neutropenia were higher with brodalumab and with ustekinumab than with placebo. Mild or moderate candida infections were more frequent with brodalumab than with ustekinumab or placebo. Through week 52, the rates of serious infectious episodes were 1.0 (AMAGINE-2) and 1.3 (AMAGINE-3) per 100 patient-years of exposure to brodalumab. CONCLUSIONS Brodalumab treatment resulted in significant clinical improvements in patients with moderate-to-severe psoriasis. C1 [Lebwohl, M.; Kircik, L.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Strober, B.] Univ Connecticut, Sch Med, Farmington, CT USA. [Strober, B.; Spelman, L.; Toth, D.] Prob Med Res, Windsor, ON, Canada. [Toth, D.] XLR8 Med Res, Windsor, ON, Canada. [Papp, K.] K Papp Med Res, Waterloo, ON, Canada. [Langley, R. G.] Dalhousie Univ, Halifax, NS, Canada. [Menter, A.] Baylor Univ, Med Ctr, Dallas, TX USA. [Gordon, K.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Weglowska, J.] Niepubl Zaklad Opieki Zdrowotnej MultiMed, Wroclaw, Poland. [Blicharski, T.] Lubelskie Ctr Diagnost, Swidnik, Poland. [Puig, L.] Hosp Santa Creu & Sant Pau, Barcelona, Spain. [Spelman, L.] Verac Clin Res, Woolloongabba, Qld, Australia. [Kerdel, F.] Florida Acad Dermatol Ctr, Miami, FL USA. [Armstrong, A. W.] Univ Colorado, Denver, CO 80202 USA. [Stingl, G.] Med Univ Wien, Vienna, Austria. [Kimball, A. B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Kimball, A. B.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Bachelez, H.] Univ Paris Diderot, Sorbonne Paris Cite, AP HP, Hop St Louis, Paris, France. [Paul, C.] Univ Toulouse 3, F-31062 Toulouse, France. [Lacour, J. -P.] Univ Hosp Nice, Nice, France. [Wu, J. J.] Kaiser Permanente Los Angeles Med Ctr, Los Angeles, CA USA. [Crowley, J.] Bakersfield Dermatol & Skin Canc Med Grp, Bakersfield, CA USA. [Koo, J.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Aras, G.; Li, J.; Song, W.; Milmont, C. E.; Shi, Y.; Erondu, N.; Klekotka, P.; Kotzin, B.; Nirula, A.] Amgen Inc, Thousand Oaks, CA USA. [Tyring, S.] Univ Texas Houston, Hlth Sci Ctr, Houston, TX USA. [Kircik, L.] DermResearch, Louisville, KY USA. [Chimenti, S.] Univ Roma Tor Vergata, Rome, Italy. [Duffin, K. C.] Univ Utah, Med Ctr, Salt Lake City, UT USA. [Bagel, J.] Psoriasis Treatment Ctr Cent New Jersey, East Windsor, NJ USA. RP Lebwohl, M (reprint author), Icahn Med Inst, 2nd Fl,1425 Madison Ave, New York, NY 10029 USA. EM mark.lebwohl@mountsinai.org OI Lacour, Jean-Philippe/0000-0001-7663-2053 FU Amgen FX Funded by Amgen; AMAGINE-2 and AMAGINE-3 ClinicalTrials.gov numbers, NCT01708603 and NCT01708629. NR 24 TC 66 Z9 70 U1 4 U2 15 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 1 PY 2015 VL 373 IS 14 BP 1318 EP 1328 DI 10.1056/NEJMoa1503824 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA CS3CI UT WOS:000361948600006 PM 26422722 ER PT J AU Lennerz, JK Ramamurthy, L AF Lennerz, Jochen K. Ramamurthy, Lakshman TI ClinGen and Genetic Testing SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID FDA C1 [Lennerz, Jochen K.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Ramamurthy, Lakshman] Avalere Hlth, Washington, DC USA. RP Lennerz, JK (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM jlennerz@partners.org NR 5 TC 0 Z9 0 U1 1 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 1 PY 2015 VL 373 IS 14 BP 1377 EP 1378 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA CS3CI UT WOS:000361948600025 PM 26422740 ER PT J AU Warshaw, AL AF Warshaw, Andrew L. TI Appropriate Health Care: A Surgeon's View of the Patient With Pancreatic Disease The Paul Webster Clinical State of the Art Lecture American Pancreatic Association, November 2014 SO PANCREAS LA English DT Article C1 [Warshaw, Andrew L.] Harvard Univ, Sch Med, Boston, MA USA. [Warshaw, Andrew L.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Warshaw, AL (reprint author), Massachusetts Gen Hosp, Bulf 370C,55 Fruit St, Boston, MA 02114 USA. EM awarshaw@partners.org NR 3 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 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD OCT PY 2015 VL 44 IS 7 BP 1003 EP 1005 DI 10.1097/MPA.0000000000000387 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CR8LW UT WOS:000361605100001 PM 26355543 ER PT J AU Ruben, MA van Osch, M Blanch-Hartigan, D AF Ruben, Mollie A. van Osch, Mara Blanch-Hartigan, Danielle TI Healthcare providers' accuracy in assessing patients' pain: A systematic review SO PATIENT EDUCATION AND COUNSELING LA English DT Article; Proceedings Paper CT Conference of the European-Association-for-Communication-in-Healthcare (EACH) CY SEP 28-OCT 01, 2014 CL Amsterdam, NETHERLANDS DE Pain assessment; Provider accuracy; Clinical experience; Chronic pain; Acute pain ID QUALITY-OF-LIFE; ADVANCED CANCER-PATIENTS; LOW-BACK-PAIN; FAMILY CAREGIVERS; SELF-REPORT; HOSPITALIZED-PATIENTS; EMERGENCY-DEPARTMENT; PERCEPTION ACCURACY; FACIAL EXPRESSION; REPORTED SYMPTOMS AB Objective: Healthcare providers satisfy an important role in providing appropriate care in the prevention and management of acute and chronic pain, highlighting the importance of providers' abilities to accurately assess patients' pain. We systematically reviewed the literature on healthcare providers' pain assessment accuracy. Methods: A systematic literature search was conducted in PubMed and PsycINFO to identify studies addressing providers' pain assessment accuracy, or studies that compared patients' self-report of pain with providers' assessment of pain. Results: 60 studies met the inclusion criteria. Healthcare providers had moderate to good pain assessment accuracy. Physicians and nurses showed similar pain assessment accuracy. Differences in pain assessment accuracy were found according to providers' clinical experience, the timing of the pain assessment, vulnerable patient populations and patients' pain intensity. Conclusion: Education and training aimed at improving providers with poor pain assessment accuracy is discussed especially in relation to those with limited clinical experience (<4 years) or a great deal of clinical experience (>10 years) and those providing care for vulnerable patient populations. Practice implications: More research on characteristics that influence providers' pain assessment accuracy and trainings to improve pain assessment accuracy in medical and continuing education may improve pain treatment for patients. Published by Elsevier Ireland Ltd. C1 [Ruben, Mollie A.] US Dept Vet Affairs, Ctr Healthcare Org & Implementat Res, Boston, MA 02130 USA. [van Osch, Mara] NIVEL Netherlands Inst Hlth Serv Res, Utrecht, Netherlands. [Blanch-Hartigan, Danielle] Bentley Univ, Dept Nat & Appl Sci, Waltham, MA USA. RP Ruben, MA (reprint author), US Dept Vet Affairs, Ctr Healthcare Org & Implementat Res, 150 S Huntington Ave,Bldg 9, Boston, MA 02130 USA. EM Mollie.Ruben@va.gov OI Ruben, Mollie/0000-0001-8918-8932 NR 122 TC 2 Z9 2 U1 1 U2 7 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 OCT PY 2015 VL 98 IS 10 SI SI BP 1197 EP 1206 DI 10.1016/j.pec.2015.07.009 PG 10 WC Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary SC Public, Environmental & Occupational Health; Social Sciences - Other Topics GA CS1XR UT WOS:000361862700005 PM 26223850 ER PT J AU Wittenberg, E Bharel, M Saada, A Santiago, E Bridges, JFP Weinreb, L AF Wittenberg, Eve Bharel, Monica Saada, Adrianna Santiago, Emely Bridges, John F. P. Weinreb, Linda TI Measuring the Preferences of Homeless Women for Cervical Cancer Screening Interventions: Development of a Best-Worst Scaling Survey SO PATIENT-PATIENT CENTERED OUTCOMES RESEARCH LA English DT Article ID CONJOINT-ANALYSIS APPLICATIONS; DISCRETE-CHOICE EXPERIMENTS; HEALTH-CARE; DISPARITIES; BEHAVIORS; ACCESS; ADULTS AB Despite having multiple risk factors, women experiencing homelessness are screened for cervical cancer at a lower rate than women in the general US population. We report on the design of a stated preference study to assess homeless women's preferences for cervical cancer screening interventions, to inform efforts to overcome this disparity. We conducted focus groups with homeless women (n = 8) on cervical cancer screening decisions and analyzed the data using thematic analysis. We applied inclusion criteria to select factors for a stated preference survey: importance to women, relevance to providers, feasibility, and consistency with clinical experience. We conducted pretests (n = 35) to assess survey procedures (functionality, recruitment, administration) and content (understanding, comprehension, wording/language, length). We chose best-worst scaling (BWS)-also known as object scaling-to identify decision-relevant screening intervention factors. We chose an experimental design with 11 "objects" (i.e., factors relevant to women's screening decision) presented in 11 subsets of five objects each. Of 25 objects initially identified, we selected 11 for the BWS instrument: provider-related factors: attitude, familiarity, and gender; setting-related factors: acceptance and cost; procedure-related factors: explanation during visit and timing/convenience of visit; personal fears and barriers: concerns about hygiene, addiction, and delivery/fear of results; and a general factor of feeling overwhelmed. Good practices for the development of stated preference surveys include considered assessment of the experimental design that is used and the preference factors that are included, and pretesting of the presentation format. We demonstrate the development of a BWS study of homeless women's cervical cancer screening intervention preferences. Subsequent research will identify screening priorities to inform intervention design. C1 [Wittenberg, Eve; Saada, Adrianna] Harvard Univ, Sch Publ Hlth, Ctr Hlth Decis Sci, Boston, MA 02115 USA. [Bharel, Monica; Santiago, Emely] Boston Hlth Care Homeless Program, Boston, MA USA. [Bharel, Monica] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Bharel, Monica] Boston Med Ctr, Dept Med, Boston, MA USA. [Bridges, John F. P.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD USA. [Wittenberg, Eve] Univ Massachusetts, Sch Med, Dept Family Med & Community Hlth, Worcester, MA USA. RP Wittenberg, E (reprint author), Harvard Univ, Sch Publ Hlth, Ctr Hlth Decis Sci, 718 Huntington Ave,2nd Floor, Boston, MA 02115 USA. EM ewittenb@hsph.harvard.edu FU National Cancer Institute of the National Institutes of Health [R21CA164712] FX The research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health, under Award Number R21CA164712. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funding agreement guaranteed the authors' independence in the research. NR 29 TC 4 Z9 4 U1 4 U2 6 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 OCT PY 2015 VL 8 IS 5 BP 455 EP 467 DI 10.1007/s40271-014-0110-z PG 13 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA CR8UR UT WOS:000361630100008 PM 25586646 ER PT J AU Frigerio, A Heaton, JT Cavallari, P Knox, C Hohman, MH Hadlock, TA AF Frigerio, Alice Heaton, James T. Cavallari, Paolo Knox, Chris Hohman, Marc H. Hadlock, Tessa A. TI Electrical Stimulation of Eye Blink in Individuals with Acute Facial Palsy: Progress toward a Bionic Blink SO PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Article ID ORBICULARIS OCULI; ARTIFICIAL MUSCLE; PARALYSIS; RESTORATION; ELECTROMYOGRAPHY; ASYMMETRY; SYSTEM AB Background: Elicitation of eye closure and other movements via electrical stimulation may provide effective treatment for facial paralysis. The authors performed a human feasibility study to determine whether transcutaneous neural stimulation can elicit a blink in individuals with acute facial palsy and to obtain feedback from participants regarding the tolerability of surface electrical stimulation for daily blink restoration. Methods: Forty individuals with acute unilateral facial paralysis, HB grades 4 through 6, were prospectively studied between 6 and 60 days of onset. Unilateral stimulation of zygomatic facial nerve branches to elicit eye blink was achieved with brief bipolar, charge-balanced pulse trains, delivered transcutaneously by adhesive electrode placement; results were recorded on a high-speed video camera. The relationship between stimulation parameters and cutaneous sensation was analyzed using the Wong-Baker Faces Pain Rating Scale. Results: Complete eye closure was achieved in 55 percent of participants using stimulation parameters reported as tolerable. In those individuals, initial eye twitch was observed at an average current of 4.6 mA (1.7; average pulse width of 0.7 ms, 100 to 150 Hz), with complete closure requiring a mean of 7.2 mA (2.6). Conclusions: Transcutaneous facial nerve stimulation may artificially elicit eye blink in a majority of patients with acute facial paralysis. Although individuals varied widely in their reported degrees of discomfort from blink-eliciting stimulation, most of them indicated that such stimulation would be tolerable if it could restore eye closure. These patients would therefore benefit from a biomimetic device to facilitate eye closure until the recovery process is complete. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. C1 Univ Milan, Human Physiol Sect, Dept Pathophysiol & Transplantat, I-20122 Milan, Italy. Harvard Univ, Carolyn & Peter Lynch Ctr Laser & Reconstruct Sur, Div Facial Plast & Reconstruct Surg,Sch Med, Facial Nerve Ctr,Dept Otol & Laryngol,Massachuset, Cambridge, MA 02138 USA. Harvard Univ, Med School, Dept Surg, Massachusetts Gen Hosp, Cambridge, MA 02138 USA. RP Frigerio, A (reprint author), Massachusetts Eye & Ear Infirm, Carolyn & Peter Lynch Ctr Laser & Reconstruct Sur, 243 Charles St, Boston, MA 02114 USA. EM alice_frigerio@meei.harvard.edu NR 23 TC 3 Z9 3 U1 3 U2 10 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 OCT PY 2015 VL 136 IS 4 BP 515E EP 523E DI 10.1097/PRS.0000000000001639 PG 9 WC Surgery SC Surgery GA CS0IT UT WOS:000361743400001 PM 26397271 ER PT J AU Fairbairn, NG Ng-Glazier, J Meppelink, AM Randolph, MA Valerio, IL Fleming, ME Winograd, JM Redmond, RW AF Fairbairn, Neil G. Ng-Glazier, Joanna Meppelink, Amanda M. Randolph, Mark A. Valerio, Ian L. Fleming, Mark E. Winograd, Jonathan M. Redmond, Robert W. TI Light-Activated Sealing of Nerve Graft Coaptation Sites Improves Outcome following Large Gap Peripheral Nerve Injury SO PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Article ID RAT SCIATIC-NERVE; CROSS-LINKED COLLAGEN; FIBRIN GLUE; FACIAL-NERVE; HUMAN AMNION; CLINICAL-APPLICATIONS; MECHANICAL-PROPERTIES; AXONAL REGENERATION; SINGLET OXYGEN; IN-VIVO AB Background: Nerve repair using photochemically bonded human amnion nerve wraps can result in superior outcomes in comparison with standard suture. When applied to nerve grafts, efficacy has been limited by proteolytic degradation of bonded amnion during extended periods of recovery. Chemical cross-linking of amnion before bonding may improve wrap durability and efficacy. Methods: Three nerve wraps (amnion, cross-linked amnion, and cross-linked swine intestinal submucosa) and three fixation methods (suture, fibrin glue, and photochemical bonding) were investigated. One hundred ten Lewis rats had 15-mm left sciatic nerve gaps repaired with isografts. Nine groups (n = 10) had isografts secured by one of the aforementioned wrap/fixation combinations. Positive and negative control groups (n = 10) were repaired with graft and suture and no repair, respectively. Outcomes were assessed using sciatic function index, muscle mass retention, and histomorphometry. Statistical analysis was performed using analysis of variance and the post hoc Bonferroni test (p < 0.05). Results: Cross-linking improved amnion durability. Photochemically bonded cross-linked amnion recovered the greatest sciatic function index, although this was not significant in comparison with graft and suture. Photochemically bonded cross-linked amnion recovered significantly greater muscle mass (67.3 4.4 percent versus 60.0 +/- 5.2 percent; p = 0.02), fiber diameter, axon diameter, and myelin thickness (6.87 +/- 2.23 m versus 5.47 +/- 1.70 m; 4.51 +/- 1.83 m versus 3.50 +/- 1.44 m; and 2.35 +/- 0.64 m versus 1.96 +/- 0.47 m, respectively) in comparison with graft and suture. Conclusion: Light-activated sealing of cross-linked human amnion results in superior outcomes when compared with conventional suture. C1 Massachusetts Gen Hosp, Div Plast Surg, Boston, MA 02114 USA. Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. Walter Reed Natl Mil Med Ctr, Plast Surg Serv, Bethesda, MD USA. Walter Reed Natl Mil Med Ctr, Dept Orthoped, Bethesda, MD USA. RP Fairbairn, NG (reprint author), Massachusetts Gen Hosp, Dept Plast Surg, 55 Fruit St, Boston, MA 02114 USA. EM ngf174@hotmail.com FU Department of Defense [USMRAA W81XWH-12-1-0511] FX This article was funded by the Department of Defense (USMRAA W81XWH-12-1-0511). The content of this article does not necessarily reflect the position or the policy of the U.S. government, and no official endorsement should be inferred. NR 53 TC 4 Z9 4 U1 0 U2 4 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 OCT PY 2015 VL 136 IS 4 BP 739 EP 750 DI 10.1097/PRS.0000000000001617 PG 12 WC Surgery SC Surgery GA CS0GA UT WOS:000361735100001 PM 26397251 ER PT J AU Williams, ED Stebbins, MJ Cavanagh, PR Haynor, DR Chu, BC Fassbind, MJ Isvilanonda, V Ledoux, WR AF Williams, Evan D. Stebbins, Michael J. Cavanagh, Peter R. Haynor, David R. Chu, Baocheng Fassbind, Michael J. Isvilanonda, Vara Ledoux, William R. TI The design and validation of a magnetic resonance imaging-compatible device for obtaining mechanical properties of plantar soft tissue via gated acquisition SO PROCEEDINGS OF THE INSTITUTION OF MECHANICAL ENGINEERS PART H-JOURNAL OF ENGINEERING IN MEDICINE LA English DT Article DE Heel pad; diabetes; magnetic resonance imaging-compatible; mechanical properties ID HEEL-PAD COMPRESSIBILITY; DIABETIC FOOT; THICKNESS; GAIT; MRI AB Changes in the mechanical properties of the plantar soft tissue in people with diabetes may contribute to the formation of plantar ulcers. Such ulcers have been shown to be in the causal pathway for lower extremity amputation. The hydraulic plantar soft tissue reducer (HyPSTER) was designed to measure in vivo, rate-dependent plantar soft tissue compressive force and three-dimensional deformations to help understand, predict, and prevent ulcer formation. These patient-specific values can then be used in an inverse finite element analysis to determine tissue moduli, and subsequently used in a foot model to show regions of high stress under a wide variety of loading conditions. The HyPSTER uses an actuator to drive a magnetic resonance imaging-compatible hydraulic loading platform. Pressure and actuator position were synchronized with gated magnetic resonance imaging acquisition. Achievable loading rates were slower than those found in normal walking because of a water-hammer effect (pressure wave ringing) in the hydraulic system when the actuator direction was changed rapidly. The subsequent verification tests were, therefore, performed at 0.2Hz. The unloaded displacement accuracy of the system was within 0.31%. Compliance, presumably in the system's plastic components, caused a displacement loss of 5.7mm during a 20-mm actuator test at 1354N. This was accounted for with a target to actual calibration curve. The positional accuracy of the HyPSTER during loaded displacement verification tests from 3 to 9mm against a silicone backstop was 95.9% with a precision of 98.7%. The HyPSTER generated minimal artifact in the magnetic resonance imaging scanner. Careful analysis of the synchronization of the HyPSTER and the magnetic resonance imaging scanner was performed. With some limitations, the HyPSTER provided key functionality in measuring dynamic, patient-specific plantar soft tissue mechanical properties. C1 [Williams, Evan D.; Stebbins, Michael J.; Fassbind, Michael J.; Isvilanonda, Vara; Ledoux, William R.] VA Puget Sound Hlth Care Syst, RR&D Ctr Excellence Limb Loss Prevent & Prosthet, Seattle, WA 98108 USA. [Williams, Evan D.; Stebbins, Michael J.; Cavanagh, Peter R.; Isvilanonda, Vara; Ledoux, William R.] Univ Washington, Dept Mech Engn, Seattle, WA 98195 USA. [Cavanagh, Peter R.; Ledoux, William R.] Univ Washington, Dept Orthopaed & Sports Med, Seattle, WA 98195 USA. [Haynor, David R.; Chu, Baocheng] Univ Washington, Dept Radiol, Seattle, WA 98195 USA. RP Ledoux, WR (reprint author), VA Puget Sound Hlth Care Syst, RR&D Ctr Excellence Limb Loss Prevent & Prosthet, VA Puget Sound, Ms 151,1660 S Columbian Way, Seattle, WA 98108 USA. EM wrledoux@uw.edu FU United States (U.S.) Department of Veterans Affairs Rehabilitation Research and Development Service [A6973R] FX This work was supported by Merit Review Award A6973R from the United States (U.S.) Department of Veterans Affairs Rehabilitation Research and Development Service. NR 24 TC 1 Z9 1 U1 3 U2 10 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0954-4119 EI 2041-3033 J9 P I MECH ENG H JI Proc. Inst. Mech. Eng. Part H-J. Eng. Med. PD OCT PY 2015 VL 229 IS 10 BP 732 EP 742 DI 10.1177/0954411915606150 PG 11 WC Engineering, Biomedical SC Engineering GA CS2KH UT WOS:000361899000005 PM 26405098 ER PT J AU Willers, H Gheorghiu, L Liu, Q Efstathiou, JA Wirth, LJ Krause, M von Neubeck, C AF Willers, Henning Gheorghiu, Liliana Liu, Qi Efstathiou, Jason A. Wirth, Lori J. Krause, Mechthild von Neubeck, Claere TI DNA Damage Response Assessments in Human Tumor Samples Provide Functional Biomarkers of Radiosensitivity SO SEMINARS IN RADIATION ONCOLOGY LA English DT Article ID DOUBLE-STRAND BREAKS; HISTONE H2AX PHOSPHORYLATION; COLLAPSED REPLICATION FORKS; ORGANOTYPIC SLICE CULTURES; GAMMA-H2AX FOCI FORMATION; PROSTATE-CANCER PATIENTS; PARP INHIBITOR ABT-888; EX-VIVO ASSAY; IN-VIVO; HOMOLOGOUS RECOMBINATION AB Predictive biomarkers are urgently needed for individualization of radiation therapy and treatment with radiosensitizing anticancer agents. Genomic profiling of human cancers provides us with unprecedented insight into the mutational landscape of genes directly or indirectly involved in the response to radiation-induced DNA damage. However, to what extent this wealth of structural information about the cancer genome produces biomarkers of sensitivity to radiation remains to be seen. Investigators are increasingly studying the subnuclear accumulation (ie, foci) of proteins in the DNA damage response (DDR), such as gamma-H2AX, 53BP1, or RAD51, as a surrogate of treatment sensitivity. Recent findings from preclinical studies have demonstrated the predictive potential of DDR foci by correlating foci with clinically relevant end points such as tumor control probability. Therefore, preclinical investigations of DDR foci responses are increasingly moving into cells and tissues from patients, which is the major focus of this review. The advantage of using DDR foci as functional biomarkers is that they can detect alterations in DNA repair due to various mechanisms. Moreover, they provide a global measurement of DDR network function without needing to know the identities of all the components, many of which remain unknown. Foci assays are thus expected to yield functional insight that may complement or supersede genomic information, thereby giving radiation oncologists unique opportunities to individualize cancer treatments in the near future. Semin Radiat Oncol 25:237-250 (C) 2015 Elsevier Inc. All rights reserved. C1 [Willers, Henning; Gheorghiu, Liliana; Liu, Qi; Efstathiou, Jason A.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Wirth, Lori J.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Krause, Mechthild] German Canc Consortium DKTK Dresden, Heidelberg, Germany. [Krause, Mechthild] German Canc Res Ctr, Heidelberg, Germany. [Krause, Mechthild] Fac Med, Dept Radiat Oncol, Dresden, Germany. [Krause, Mechthild; von Neubeck, Claere] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Dresden, Germany. [Krause, Mechthild; von Neubeck, Claere] Fac Med, OncoRay Natl Ctr Radiat Res Oncol, Dresden, Germany. [Krause, Mechthild] Helmholtz Zentrum Dresden Rossendorf, Inst Radiooncol, Dresden, Germany. RP Willers, H (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, 55 Fruit St, Boston, MA 02114 USA. EM hwillers@mgh.harvard.edu FU Dana-Farber/Harvard Cancer Center SPORE in Lung Cancer; NCI [P50 CA090578]; American Cancer Society, USA [123420RSG-12-224-01-DMC]; U.S. Department of Defense, USA [W81XWH-06-1-0309]; Susan G. Komen for the Cure of Breast Cancer [BCTR0504040]; Federal Share of program income earned by Massachusetts General Hospital, USA [C06 CA059267]; Proton Therapy Research and Treatment Center FX In part supported by Dana-Farber/Harvard Cancer Center SPORE in Lung Cancer, NCI P50 CA090578 (H.W.), American Cancer Society, USA 123420RSG-12-224-01-DMC (H. W.), U.S. Department of Defense, USA W81XWH-06-1-0309 (H.W.), Susan G. Komen for the Cure of Breast Cancer BCTR0504040 (H.W.), Federal Share of program income earned by Massachusetts General Hospital, USA on C06 CA059267, Proton Therapy Research and Treatment Center (J.A.E., H.W.). L.J.W. and H.W. wish to thank Tay Morgan for his support. NR 129 TC 6 Z9 6 U1 1 U2 11 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1053-4296 EI 1532-9461 J9 SEMIN RADIAT ONCOL JI Semin. Radiat. Oncol. PD OCT PY 2015 VL 25 IS 4 BP 237 EP 250 DI 10.1016/j.semradonc.2015.05.007 PG 14 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA CS1YM UT WOS:000361864800003 PM 26384272 ER PT J AU Whitley, MJ Weissleder, R Kirsch, DG AF Whitley, Melodi J. Weissleder, Ralph Kirsch, David G. TI Tailoring Adjuvant Radiation Therapy by Intraoperative Imaging to Detect Residual Cancer SO SEMINARS IN RADIATION ONCOLOGY LA English DT Article ID SOFT-TISSUE SARCOMA; BREAST-CANCER; 5-AMINOLEVULINIC ACID; OVARIAN-CANCER; REAL-TIME; CYSTEINE CATHEPSINS; RAMAN-SPECTROSCOPY; FLUORESCENT-PROBE; LOCAL RECURRENCE; RANDOMIZED-TRIAL AB For many solid cancers, radiation therapy is offered as an adjuvant to surgical resection to lower rates of local recurrence and improve survival. However, a subset of patients treated with surgery alone will not have a local recurrence. Currently, there is no way to accurately determine which patients have microscopic residual disease in the tumor bed after surgery and therefore are most likely to benefit from adjuvant radiation therapy. To address this problem, a number of technologies have been developed to try to improve margin assessment of resected tissue and to detect residual cancer in the tumor bed. Moreover, some of these approaches have been translated from the preclinical arena into clinical trials. Here, we review different types of intraoperative molecular imaging systems for cancer. Optical imaging techniques like epi-illumination, fluorescence molecular tomography and optoacoustic imaging can be coupled with exogenous fluorescent imaging probes that accumulate in tumors passively via the enhanced permeability and retention effect or are targeted to tumor tissues based on affinity or enzyme activity. In these approaches, detection of fluorescence in the tumor bed may indicate residual disease. Protease activated probes have generated great interest because of their potential for leading to high tumor to normal contrast. Recently, the first Phase I clinical trial to assess the safety and activation of a protease activated probe was conducted. Spectroscopic methods like radiofrequency spectroscopy and Raman spectroscopy, which are based on energy absorption and scattering, respectively, have also been tested in humans and are able to distinguish between normal and tumors tissues intraoperatively. Most recently, multimodal contrast agents have been developed that target tumors and contain both fluorescent dyes and magnetic resonance imaging contrast agents, allowing for preoperative planning and intraoperative margin assessment with a single contrast agent. Further clinical testing of these various intraoperative imaging approaches may lead to more accurate methods for margin assessment and the intraoperative detection of microscopic residual disease, which could guide further resection and the use of adjuvant radiation therapy. Semin Radiat Oncol 25:313-321 (C) 2015 Elsevier Inc. All rights reserved. C1 [Whitley, Melodi J.; Kirsch, David G.] Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA. [Weissleder, Ralph] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Weissleder, Ralph] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA USA. [Kirsch, David G.] Duke Univ, Med Ctr, Dept Radiat Oncol, Durham, NC USA. RP Kirsch, DG (reprint author), Duke Univ, Med Ctr, Radiat Oncol, Durham, NC 27710 USA. EM david.kirsch@duke.edu FU NIGMS NIH HHS [T32 GM007171] NR 66 TC 3 Z9 3 U1 1 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 1053-4296 EI 1532-9461 J9 SEMIN RADIAT ONCOL JI Semin. Radiat. Oncol. PD OCT PY 2015 VL 25 IS 4 BP 313 EP 321 DI 10.1016/j.semradonc.2015.05.005 PG 9 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA CS1YM UT WOS:000361864800010 PM 26384279 ER PT J AU Wiederhold, NP Patterson, TF AF Wiederhold, Nathan P. Patterson, Thomas F. TI Emergence of Azole Resistance in Aspergillus SO SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Review DE Aspergillus fumigatus; azole resistance; aspergillosis; voriconazole; itraconazole; posaconazole; CYP51A ID INVASIVE PULMONARY ASPERGILLOSIS; ANTIFUNGAL DRUG-RESISTANCE; AMPHOTERICIN-B; CYP51A GENE; NEOSARTORYA-PSEUDOFISCHERI; ITRACONAZOLE RESISTANCE; ISAVUCONAZOLE BAL4815; FUMIGATUS; VORICONAZOLE; POSACONAZOLE AB Resistance to the azole antifungals itraconazole, voriconazole, and posaconazole in Aspergillus species is a growing concern. This is especially alarming for A. fumigatus, where acquired resistance has been documented in patients with invasive disease caused by this species that were exposed to these agents, as well as in azole-naive individuals. The primary mechanisms of resistance that have been described in clinical strains include different point mutations in the CYP51A gene, which encodes the enzyme responsible for converting lanosterol to ergosterol via demethylation. Some resistant isolates also contain a tandem repeat in the promoter region of this gene that causes increased expression. These mutations, including TR34/L98H and TR46/Y121F/T289A have also been found in the environment in several areas of the world and have been demonstrated to cause resistance to azole fungicides used in agriculture, thus raising the concern of environmental spread of resistance. Treatment options are limited in patients with infections caused by azole-resistant isolates and include amphotericin B formulations or combination therapy involving an echinocandin. However, there are few clinical data available to help guide therapy, and infections caused by resistant A. fumigatus isolates have been reported to have high mortality rates. C1 [Wiederhold, Nathan P.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, Fungus Testing Lab, San Antonio, TX 78229 USA. [Wiederhold, Nathan P.; Patterson, Thomas F.] UTHSCSA, Dept Med, Div Infect Dis, San Antonio, TX 78229 USA. [Patterson, Thomas F.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. RP Patterson, TF (reprint author), UTHSCSA, Dept Med, Div Infect Dis, 7703 Floyd Curl Dr,MC 7750, San Antonio, TX 78229 USA. EM patterson@uthscsa.edu OI Patterson, Thomas /0000-0002-9513-7127; Wiederhold, Nathan/0000-0002-2225-5122 NR 75 TC 3 Z9 3 U1 3 U2 9 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 1069-3424 EI 1098-9048 J9 SEMIN RESP CRIT CARE JI Semin. Respir. Crit. Care Med. PD OCT PY 2015 VL 36 IS 5 BP 673 EP 680 DI 10.1055/s-0035-1562894 PG 8 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA CR8ZL UT WOS:000361642900005 PM 26398534 ER PT J AU Balboni, MJ AF Balboni, Michael J. TI Everyday Religion in Hospitals SO SOCIETY LA English DT Article ID QUALITY-OF-LIFE; ADVANCED CANCER; SPIRITUAL CARE; NEAR-DEATH; PHYSICIANS; END; ASSOCIATIONS; PROVISION; MEDICINE; NURSES C1 Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, Boston, MA 02215 USA. RP Balboni, MJ (reprint author), Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, Boston, MA 02215 USA. EM michael_balboni@dfci.harvard.edu NR 24 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0147-2011 EI 1936-4725 J9 SOCIETY JI Society PD OCT PY 2015 VL 52 IS 5 BP 413 EP 417 DI 10.1007/s12115-015-9923-1 PG 5 WC Social Sciences, Interdisciplinary; Sociology SC Social Sciences - Other Topics; Sociology GA CS0IR UT WOS:000361743200003 ER PT J AU Pagano, TB Wojcik, S Costagliola, A De Biase, D Iovino, S Iovane, V Russo, V Papparella, S Paciello, O AF Pagano, Teresa B. Wojcik, Slawomir Costagliola, Alessandro De Biase, Davide Iovino, Salvatore Iovane, Valentina Russo, Valeria Papparella, Serenella Paciello, Orlando TI Age related skeletal muscle atrophy and upregulation of autophagy in dogs SO VETERINARY JOURNAL LA English DT Article DE Autophagy; Sarcopenia; Muscle atrophy; Ageing; Canine ID IN-VIVO; SARCOPENIA; DEGRADATION; PATHWAYS; DISEASE; CELLS AB Sarcopenia, the age related loss of muscle mass and strength, is a multifactorial condition that occurs in a variety of species and represents a major healthcare concern for older adults in human medicine. In veterinary medicine, skeletal muscle atrophy is often observed in dogs as they reach old age, but the process is not well understood. Autophagy is a mechanism for degradation and recycling of cellular constituents and is potentially involved in sarcopenia. The aim of the present study was to evaluate the expression of three markers of autophagy, Beclin 1, LC3 and p62, in muscle wasting of geriatric dogs, to establish whether the levels of autophagy change with increasing age. Muscle biopsies from 25 geriatric dogs were examined and compared with those from five healthy young dogs. Samples from older dogs, assessed by routine histology, histoenzymatic staining and immunohistochemistry, showed evidence of muscle atrophy, sarcoplasmic vacuolisation and mitochondrial alterations. Furthermore, in 80% of the muscle samples from the older dogs, marked intracytoplasmic staining for Beclin 1 and LC3 was observed, Significantly greater expression of LC3 II and Beclin 1, but lower expression of p62, was found by Western blotting, comparing muscle samples from old vs. young dogs. The results of the study suggest that enhanced autophagy might be one of the factors underlying muscle atrophy in dogs as they age. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Pagano, Teresa B.; Costagliola, Alessandro; De Biase, Davide; Iovane, Valentina; Russo, Valeria; Papparella, Serenella; Paciello, Orlando] Univ Naples Federico II, Lab Comparat Neuromuscular Dis, Dept Vet Med & Anim Prod, I-80137 Naples, Italy. [Wojcik, Slawomir] Med Univ Gdansk, Dept Anat & Neurobiol, PL-80211 Gdansk, Poland. [Iovino, Salvatore] Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Integrat Physiol & Metab, Boston, MA 02215 USA. RP Paciello, O (reprint author), Univ Naples Federico II, Lab Comparat Neuromuscular Dis, Dept Vet Med & Anim Prod, Via Delpino 1, I-80137 Naples, Italy. EM paciello@unina.it FU University of Naples Federico II FX This study was supported, in part, by The University of Naples Federico II. The authors thank Raffaele Ilsami for his valuable technical assistance. NR 30 TC 3 Z9 3 U1 3 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1090-0233 EI 1532-2971 J9 VET J JI Vet. J. PD OCT PY 2015 VL 206 IS 1 BP 54 EP 60 DI 10.1016/j.tvjl.2015.07.005 PG 7 WC Veterinary Sciences SC Veterinary Sciences GA CS1ZV UT WOS:000361868500009 PM 26257260 ER PT J AU Pery, E Sheehy, A Nebane, NM Misra, V Mankowski, MK Rasmussen, L White, EL Ptak, RG Gabuzda, D AF Pery, Erez Sheehy, Ann Nebane, N. Miranda Misra, Vikas Mankowski, Marie K. Rasmussen, Lynn White, E. Lucile Ptak, Roger G. Gabuzda, Dana TI Redoxal, an inhibitor of de novo pyrimidine biosynthesis, augments APOBEC3G antiviral activity against human immunodeficiency virus type 1 SO VIROLOGY LA English DT Article DE HIV-1; Vif; APOBEC3G; Antiviral; Redoxal; Pyrimidine synthesis ID ANTIRETROVIRAL DRUG-RESISTANCE; SMALL-MOLECULE INHIBITION; VIRAL LOAD STANDARDS; AMINO-ACID-RESIDUES; GROUP M SUBTYPES; HIV-1 INFECTION; VIF PROTEIN; REVERSE TRANSCRIPTION; CBF-BETA; DIHYDROOROTATE DEHYDROGENASE AB APOBEC3G (A3G) is a cytidine deaminase that restricts HIV-1 replication by inducing G-to-A hypermutation in viral DNA; deamination-independent mechanisms are also implicated. HIV-1 Vif protein counteracts A3G by inducing its proteasomal degradation. Thus, the Vif-A3G axis is a potential therapeutic target. To identify compounds that inhibit Vif:A3G interaction, a 307,520 compound library was tested in a TR-FRET screen. Two identified compounds, redoxal and lomofungin, inhibited HIV-1 replication in peripheral blood mononuclear cells. Lomofungin activity was linked to A3G, but not pursued further due to cytotoxicity. Redoxal displayed A3G-dependent restriction, inhibiting viral replication by stabilizing A3G protein levels and increasing A3G in virions. A3G-independent activity was also detected. Treatment with uridine or orotate, intermediates of pyrimidine synthesis, diminished redoxal-induced stabilization of A3G and antiviral activity. These results identify redoxal as an inhibitor of HIV-1 replication and suggest its ability to inhibit pyrimidine biosynthesis suppresses viral replication by augmenting MG antiviral activity. (C) 2015 Elsevier Inc. All rights reserved. C1 [Pery, Erez; Misra, Vikas; Gabuzda, Dana] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02215 USA. [Pery, Erez] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Gabuzda, Dana] Harvard Univ, Sch Med, Dept Neurol Microbiol, Boston, MA 02115 USA. [Sheehy, Ann] Coll Holy Cross, Dept Biol, Worcester, MA 01610 USA. [Nebane, N. Miranda; Rasmussen, Lynn; White, E. Lucile] Southern Res Inst High Throughput Screening Ctr, Birmingham, AL 35205 USA. [Mankowski, Marie K.; Ptak, Roger G.] So Res Inst, Dept Infect Dis Res, Frederick, MD 21701 USA. RP Gabuzda, D (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, CLS 1010,450 Brookline Ave, Boston, MA 02215 USA. EM dana_gabuzda@dfci.harvard.edu FU National Institutes of Health [AI67032, AI87458]; Division of AIDS (DAIDS), National Institute of Allergy and Infectious Diseases, National Institutes of Health [HHSN272200700041C, HHSN272200700042C]; Harvard Center for AIDS Research Grant [P30 AI060354]; Dana-Farber Cancer Institute/Harvard Cancer Center Research Grant [P30 CA06516] FX We thank Dr. Caroline Shamu and staff at the Institute of Chemistry and Cell Biology Longwood Screening Facility, Harvard Medical School, Boston, MA, for helpful discussions and advice during performance of the HIS and Dr. Marintha Heil, Southern Research Institute Department of Infectious Disease Research and Dr. Sara Burhlage, Dana-Farber Cancer Institute, for helpful discussions and advice. The complete results of the HIS can be found at Pubchem under AID 1117320 (https://pubchem.ncbi.nlm.nih.gov/assay/assay.cgi?aid=1117320). This work was supported by the National Institutes of Health Grants AI67032 and AI87458 to D.G. and was also conducted in part by Southern Research Institute using federal funds from the Division of AIDS (DAIDS), National Institute of Allergy and Infectious Diseases, National Institutes of Health under contracts HHSN272200700041C and HHSN272200700042C entitled "In Vitro Testing Resources for AIDS Therapeutic Development, PART A: Confirmatory In Vitro Evaluations of HIV Therapeutics and PART B: Specialized In Vitro Virological Assays for HIV Therapeutics and Topical Microbicides" under the direction of Dr. Roger Miller (DHHS, NIH, NIAID, DAIDS, BSP; contract Part B) and Dr. Steven Turk (DHHS, NIH, NIAID, DAIDS, TRP, DDCSB; contract Part A). Core facilities received support from the Harvard Center for AIDS Research Grant (P30 AI060354) and Dana-Farber Cancer Institute/Harvard Cancer Center Research Grant (P30 CA06516). NR 87 TC 0 Z9 0 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD OCT PY 2015 VL 484 BP 276 EP 287 DI 10.1016/j.virol.2015.06.014 PG 12 WC Virology SC Virology GA CR8CG UT WOS:000361578100030 PM 26141568 ER PT J AU Ben Nasr, M Vergani, A Avruch, J Liu, LY Kefaloyianni, E D'Addio, F Tezza, S Corradi, D Bassi, R Valderrama-Vasquez, A Usuelli, V Kim, J Azzi, J El Essawy, B Markmann, J Abdi, R Fiorina, P AF Ben Nasr, Moufida Vergani, Andrea Avruch, James Liu, Liye Kefaloyianni, Eirini D'Addio, Francesca Tezza, Sara Corradi, Domenico Bassi, Roberto Valderrama-Vasquez, Alessandro Usuelli, Vera Kim, James Azzi, Jamil El Essawy, Basset Markmann, James Abdi, Reza Fiorina, Paolo TI Co-transplantation of autologous MSCs delays islet allograft rejection and generates a local immunoprivileged site SO ACTA DIABETOLOGICA LA English DT Article DE Islet transplantation; Mesenchymal stem cells; Immunoprivileged site; Immunoregulation ID MESENCHYMAL STEM-CELLS; BONE-MARROW; CARDIOVASCULAR-DISEASE; DIABETIC-PATIENTS; STROMAL CELLS; NOD MICE; AUTOIMMUNE; SURVIVAL; FEATURES; THERAPY AB Aims Mesenchymal stem cells (MSCs) are multipotent cells with immunomodulatory properties. We tested the ability of MSCs to delay islet allograft rejection. Methods Mesenchymal stem cells were generated in vitro from C57BL/6 and BALB/c mice bone marrow, and their immunomodulatory properties were tested in vitro. We then tested the effect of a local or systemic administration of heterologous and autologous MSCs on graft survival in a fully allogeneic model of islet transplantation (BALB/c islets into C57BL/6 mice). Results In vitro, autologous, but not heterologous, MSCs abrogated immune cell proliferation in response to alloantigens and skewed the immune response toward a Th2 profile. A single dose of autologous MSCs co-transplanted under the kidney capsule with allogeneic islets delayed islet rejection, reduced graft infiltration, and induced long-term graft function in 30 % of recipients. Based on ex vivo analysis of recipient splenocytes, the use of autologous MSCs did not appear to have any systemic effect on the immune response toward graft alloantigens. The systemic injection of autologous MSCs or the local injection of heterologous MSCs failed to delay islet graft rejection. Conclusion Autologous, but not heterologous, MSCs showed multiple immunoregulatory properties in vitro and delayed allograft rejection in vivo when co-transplanted with islets; however, they failed to prevent rejection when injected systemically. Autologous MSCs thus appear to produce a local immunoprivileged site, which promotes graft survival. C1 [Ben Nasr, Moufida; Vergani, Andrea; D'Addio, Francesca; Tezza, Sara; Bassi, Roberto; Fiorina, Paolo] Harvard Univ, Sch Med, Boston Childrens Hosp, Div Nephrol, Boston, MA 02138 USA. [Ben Nasr, Moufida; Vergani, Andrea; D'Addio, Francesca; Valderrama-Vasquez, Alessandro; Usuelli, Vera; Fiorina, Paolo] Univ Milan, Osped San Raffaele, Transplant Med, I-20127 Milan, Italy. [Avruch, James; Liu, Liye; Kim, James; Markmann, James] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Transplantat Unit,Dept Surg, Boston, MA 02114 USA. [Kefaloyianni, Eirini] Harvard Univ, Sch Med, Brigham & Womens Hosp, Harvard Inst Med,HIM510,Div Renal, Boston, MA 02115 USA. [Corradi, Domenico] Univ Parma, Pathol & Lab Med, I-43100 Parma, Italy. [Azzi, Jamil; Abdi, Reza] Harvard Univ, Sch Med, Brigham & Womens Hosp, Transplantat Res Ctr,Div Nephrol, Boston, MA USA. [El Essawy, Basset] Al Azhar Univ, Dept Med, Cairo, Egypt. RP Fiorina, P (reprint author), Harvard Univ, Sch Med, Boston Childrens Hosp, Div Nephrol, Enders Bldg 5th Floor Room EN511,300 Longwood Ave, Boston, MA 02138 USA. EM paolo.fiorina@childrens.harvard.edu RI Corradi, Domenico/O-1666-2015; D'Addio, Francesca/F-3417-2017 OI Corradi, Domenico/0000-0002-8836-4778; D'Addio, Francesca/0000-0002-0345-0694 FU JDRF Career Development Award; ASN Career Development Award; ADA Mentor-based Fellowship Grant; Translational Research Program (TRP) from Boston Children's Hospital; Harvard Stem Cell Institute Grant ("Diabetes Program'') [DP-0123-12-00]; Italian Ministry of Health [RF- 2010-2303119, RF- FSR-2008-1213704]; AMD-SID Pasquale di Coste Scolarship; Italian Scientists and Scholars of North America Foundation (ISSNAF)-Fondazione Marche Fellowship; AST Genentech Clinical Science Fellowship Grant FX Paolo Fiorina is the recipient of a JDRF Career Development Award, an ASN Career Development Award, and an ADA Mentor-based Fellowship Grant. P.F. is also supported by a Translational Research Program (TRP) Grant from Boston Children's Hospital; Harvard Stem Cell Institute Grant ("Diabetes Program'' DP-0123-12-00); Italian Ministry of Health Grant RF- 2010-2303119. P. F. and Andrea Vergani are supported of an Italian Ministry of Health Grant: ("Staminali'' RF- FSR-2008-1213704). A. V. is supported by the "AMD-SID Pasquale di Coste Scolarship''. Francesca D'Addio is a recipient of Italian Scientists and Scholars of North America Foundation (ISSNAF)-Fondazione Marche Fellowship. Roberto Bassi is supported by an ADA Mentor-based Fellowship Grant to P. F and by an AST Genentech Clinical Science Fellowship Grant. A. V. conducted this study as partial fulfillment of his PhD in Molecular Medicine, San Raffaele University, Milan, Italy. NR 52 TC 13 Z9 14 U1 0 U2 2 PU SPRINGER-VERLAG ITALIA SRL PI MILAN PA VIA DECEMBRIO, 28, MILAN, 20137, ITALY SN 0940-5429 EI 1432-5233 J9 ACTA DIABETOL JI Acta Diabetol. PD OCT PY 2015 VL 52 IS 5 BP 917 EP 927 DI 10.1007/s00592-015-0735-y PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CR4YR UT WOS:000361346500012 PM 25808641 ER PT J AU Burton, BK Berger, KI Lewis, GD Tarnopolsky, M Treadwell, M Mitchell, JJ Muschol, N Jones, SA Sutton, VR Pastores, GM Lau, H Sparkes, R Genter, F Shaywitz, AJ Harmatz, P AF Burton, Barbara K. Berger, Kenneth I. Lewis, Gregory D. Tarnopolsky, Mark Treadwell, Marsha Mitchell, John J. Muschol, Nicole Jones, Simon A. Sutton, V. Reid Pastores, Gregory M. Lau, Heather Sparkes, Rebecca Genter, Fred Shaywitz, Adam J. Harmatz, Paul TI Safety and physiological effects of two different doses of elosulfase alfa in patients with morquio a syndrome: A randomized, double-blind, pilot study SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE mucopolysaccharidosis IV; cardiopulmonary exercise test; safety; respiratory function tests; muscle strength; physical endurance; GALNS protein; human [supplementary concept]; enzyme replacement therapy ID ENZYME REPLACEMENT THERAPY; MUCOPOLYSACCHARIDOSIS TYPE IVA; 6-MINUTE WALK TEST; OPEN-LABEL; BMN 110; CHILDREN; DISEASE; ADOLESCENTS; GUIDELINES; EFFICACY AB The primary treatment outcomes of a phase 2, randomized, double-blind, pilot study evaluating safety, physiological, and pharmacological effects of elosulfase alfa in patients with Morquio A syndrome are herewith presented. Patients aged 7 years and able to walk 200m in the 6-min walk test (6MWT) were randomized to elosulfase alfa 2.0 or 4.0mg/kg/week for 27 weeks. The primary objective was to evaluate the safety of both doses. Secondary objectives were to evaluate effects on endurance (6MWT and 3-min stair climb test [3MSCT]), exercise capacity (cardio-pulmonary exercise test [CPET]), respiratory function, muscle strength, cardiac function, pain, and urine keratan sulfate (uKS) levels, and to determine pharmacokinetic parameters. Twenty-five patients were enrolled (15 randomized to 2.0mg/kg/week and 10 to 4.0mg/kg/week). No new or unexpected safety signals were observed. After 24 weeks, there were no improvements versus baseline in the 6MWT, yet numerical improvements were seen in the 3MSCT with 4.0mg/kg/week. uKS and pharmacokinetic data suggested no linear relationship over the 2.0-4.0mg/kg dose range. Overall, an abnormal exercise capacity (evaluated in 10 and 5 patients in the 2.0 and 4.0mg/kg/week groups, respectively), impaired muscle strength, and considerable pain were observed at baseline, and there were trends towards improvements in all domains after treatment. In conclusion, preliminary data of this small study in a Morquio A population with relatively good endurance confirmed the acceptable safety profile of elosulfase alfa and showed a trend of increased exercise capacity and muscle strength and decreased pain. (c) 2015 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc. C1 [Burton, Barbara K.] Ann & Robert H Lurie Childrens Hosp, Chicago, IL USA. [Burton, Barbara K.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Berger, Kenneth I.; Pastores, Gregory M.; Lau, Heather] NYU, Sch Med, New York, NY USA. [Lewis, Gregory D.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Tarnopolsky, Mark] McMaster Univ, Med Ctr, Hamilton, ON, Canada. [Treadwell, Marsha; Harmatz, Paul] UCSF Benioff Childrens Hosp Oakland, Oakland, CA 94609 USA. [Mitchell, John J.] Montreal Childrens Hosp, Montreal, PQ H3H 1P3, Canada. [Muschol, Nicole] Univ Med Ctr Hamburg Eppendorf, Hamburg, Germany. [Jones, Simon A.] Univ Manchester, St Marys Hosp, Willink Unit, CMFT,MAHSC, Manchester M13 0JH, Lancs, England. [Sutton, V. Reid] Texas Childrens Hosp, Houston, TX 77030 USA. [Sutton, V. Reid] Baylor Coll Med, Houston, TX 77030 USA. [Pastores, Gregory M.] Mater Misericordiae Univ Hosp, Dublin, Ireland. [Sparkes, Rebecca] Alberta Childrens Prov Gen Hosp, Calgary, AB, Canada. [Genter, Fred; Shaywitz, Adam J.] BioMarin Pharmaceut Inc, Novato, CA USA. RP Harmatz, P (reprint author), UCSF Benioff Childrens Hosp Oakland, 747 52nd St, Oakland, CA 94609 USA. EM pharmatz@mail.cho.org OI Berger, Kenneth/0000-0003-4879-6071 FU BioMarin Pharmaceutical Inc.; BioMarin; National Center for Advancing Translational Sciences, National Institutes of Health, through UCSF-CTSI [UL1 TR000004] FX We acknowledge the participation of study patients and their families and the expert assistance of all study site coordinators and personnel. The authors are also grateful to Ismar Healthcare NV, funded by BioMarin Pharmaceutical Inc., for support in the process of manuscript development. The authors also acknowledge the Manchester NIHR/WTCRF. This study was sponsored by BioMarin and supported, in part, by the National Center for Advancing Translational Sciences, National Institutes of Health, through UCSF-CTSI Grant Number UL1 TR000004 (Dr. Harmatz). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. NR 22 TC 5 Z9 5 U1 0 U2 4 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 OCT PY 2015 VL 167 IS 10 BP 2272 EP 2281 DI 10.1002/ajmg.a.37172 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA CR2TS UT WOS:000361184100008 PM 26069231 ER PT J AU Turalba, A Payal, AR Gonzalez-Gonzalez, LA Cakiner-Egilmez, T Chomsky, AS Vollman, DE Baze, EF Lawrence, M Daly, MK AF Turalba, Angela Payal, Abhishek R. Gonzalez-Gonzalez, Luis A. Cakiner-Egilmez, Tulay Chomsky, Amy S. Vollman, David E. Baze, Elizabeth F. Lawrence, Mary Daly, Mary K. TI Cataract Surgery Outcomes in Glaucomatous Eyes: Results From the Veterans Affairs Ophthalmic Surgery Outcomes Data Project SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID QUALITY-OF-LIFE; OPEN-ANGLE GLAUCOMA; PERFORMED PHACOEMULSIFICATION SURGERY; RISK-FACTORS; INTRAOCULAR-PRESSURE; PSEUDOEXFOLIATION SYNDROME; AQUEOUS-HUMOR; COMPLICATIONS; EXTRACTION; TRABECULECTOMY AB PURPOSE: To compare visual acuity outcomes, vision-related quality of life, and complications related to cataract surgery in eyes with and without glaucoma. DESIGN: Retrospective cohort study. METHODS: Cataract surgery outcomes in cases with and without glaucoma from the Veterans Affairs Ophthalmic Surgical Outcomes Data Project were compared. RESULTS: We identified 608 glaucoma cases and 4306 controls undergoing planned cataract surgery alone. After adjusting for age, pseudoexfoliation, small pupil, prior ocular surgery, and anterior chamber depth, we found that glaucoma cases were more likely to have posterior capsular tear with vitrectomy (odds ratio [OR] 1.8, P =.03) and sulcus intraocular lens placement (OR 1.65, P =.03) during cataract surgery. Glaucoma cases were more likely to have postoperative inflammation (OR 1.73, P <.0001), prolonged elevated intraocular pressure (OR 2.96, P =.0003), and additional surgery within 30 days (OR 1.92, P =.03). Mean best-corrected visual acuity (BCVA) and Visual Function Questionnaire (VFQ) scores significantly improved after cataract surgery in both groups (P <.0001), but there were larger improvements in BCVA (P =.01) and VFQ composite scores (P <.0001) in the nonglaucoma vs the glaucoma group. A total of 3621 nonglaucoma cases (94.1%) had postoperative BCVA 20/40 or better, compared to 466 glaucoma cases (89.6%) (P. =.0003). CONCLUSIONS: Eyes with glaucoma are at increased risk for complications and have more modest visual outcomes after cataract surgery compared to eyes without glaucoma. Despite this, glaucoma patients still experience significant improvement in vision-related outcomes after cataract extraction. Further study is needed to explore potential factors that influence cataract surgery outcomes in glaucomatous eyes. Published by Elsevier Inc. C1 [Turalba, Angela; Payal, Abhishek R.; Gonzalez-Gonzalez, Luis A.; Cakiner-Egilmez, Tulay; Daly, Mary K.] VA Boston Healthcare Syst, Dept Ophthalmol, Jamaica Plain, MA USA. [Daly, Mary K.] Boston Univ, Sch Med, Dept Ophthalmol, Boston, MA 02130 USA. [Turalba, Angela; Payal, Abhishek R.; Daly, Mary K.] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA 02130 USA. [Chomsky, Amy S.] Vet Affairs Tennessee Valley Healthcare Syst Ctr, Nashville, TN USA. [Chomsky, Amy S.] Vanderbilt Univ, Med Ctr, Vanderbilt Eye Inst, Nashville, TN USA. [Vollman, David E.] St Louis Vet Affairs Healthcare Syst, St Louis, MO USA. [Vollman, David E.] Washington Univ, Sch Med, Dept Ophthalmol & Visual Sci, St Louis, MO 63110 USA. [Baze, Elizabeth F.] Michael E DeBakey VA Med Ctr, Houston, TX USA. [Baze, Elizabeth F.] Baylor Coll Med, Cullen Eye Inst, Houston, TX 77030 USA. [Lawrence, Mary] Vet Affairs Vis Ctr Excellence, Dept Def, Bethesda, MD USA. RP Daly, MK (reprint author), VA Boston Healthcare Syst, Ophthalmol, 150 South Huntington Ave,Suite 8C-29, Boston, MA 02130 USA. EM mary.daly2@va.gov OI Payal, Abhishek/0000-0002-4484-8279 NR 38 TC 3 Z9 3 U1 1 U2 7 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 OCT PY 2015 VL 160 IS 4 BP 693 EP 701 DI 10.1016/j.ajo.2015.07.020 PG 9 WC Ophthalmology SC Ophthalmology GA CR7BR UT WOS:000361503400010 PM 26210863 ER PT J AU Kuehlewein, L Bansal, M Lenis, TL Iafe, NA Sadda, SR Bonin, MA De Carlo, TE Waheed, NK Duker, JS Sarraf, D AF Kuehlewein, Laura Bansal, Mayank Lenis, Tamara L. Iafe, Nicholas A. Sadda, Srinivas R. Bonin Filho, Marco A. De Carlo, Talisa E. Waheed, Nadia K. Duker, Jay S. Sarraf, David TI Optical Coherence Tomography Angiography of Type 1 Neovascularization in Age-Related Macular Degeneration SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID CHOROIDAL NEOVASCULARIZATION; FLUORESCEIN ANGIOGRAPHY; MOTION CORRECTION; EYES; AMD; CLASSIFICATION AB PURPOSE: To analyze type 1 neovascular membranes in age-related macular degeneration (AMD) using optical coherence tomography (OCT) angiography, to correlate morphologic characteristics with imaging and clinical criteria, and to analyze structural features of type 1 neovascularization sequentially after anti-vascular endothelial growth factor (VEGF) therapy. DESIGN: Prospective interventional Case series. METHODS: Macular OCT angiography images were acquired using the RTVue XR Avanti with AngioVue. Distinct morphologic patterns and quantifiable features of the neovascular membranes were studied on en face projection images at baseline and follow-up. RESULTS: Thirty-three eyes of 25 patients were included. In 75% of the eyes, a highly organized vascular complex could be identified. A large main central vessel trunk/feeder vessel could be seen in 72% of these eyes, with vessels radiating in a branching pattern either in all directions from the center of the lesion ("medusa" pattern), or from one side of the lesion ("seafan" pattern). Of the 18 eyes with follow-up OCT angiography, the lesion area and vessel density remained unchanged, even after anti-vascular endothelial growth factor (VEGF) therapy, indicating a more mature longstanding neovascular complex resistant to anti-VEGF therapy. CONCLUSIONS: OCT angiography provides a unique opportunity to study the morphology of occult type 1 neovascular membranes in AMP and allows precise structural and vascular assessment noninvasively. We identified a large mature neovascular complex in approximately 75% of eyes, typically consisting of a feeder vessel and large branching vessels resistant to anti-VEGF therapy. OCT angiography may better guide evaluation and treatment of neovascular AMD, and may contribute to the development of improved therapies. (C) 2015 by Elsevier Inc. All rights reserved. C1 [Kuehlewein, Laura; Sadda, Srinivas R.] Doheny Eye Inst, Los Angeles, CA 90033 USA. [Kuehlewein, Laura; Bansal, Mayank; Lenis, Tamara L.; Iafe, Nicholas A.; Sadda, Srinivas R.; Sarraf, David] Univ Calif Los Angeles, David Geffen Sch Med, Dept Ophthalmol, Los Angeles, CA 90095 USA. [Bansal, Mayank; Lenis, Tamara L.; Iafe, Nicholas A.; Sarraf, David] Jules Stein Eye Inst, Los Angeles, CA 90024 USA. [Bonin Filho, Marco A.; De Carlo, Talisa E.; Waheed, Nadia K.; Duker, Jay S.] Tufts Univ, New England Eye Ctr, Boston, MA 02111 USA. [Bonin Filho, Marco A.; De Carlo, Talisa E.; Waheed, Nadia K.; Duker, Jay S.] Tufts Univ, Tufts Med Ctr, Boston, MA 02111 USA. [Bonin Filho, Marco A.] Minist Educ Brazil, CAPES Fdn, Brasilia, DF, Brazil. [De Carlo, Talisa E.] MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA. [De Carlo, Talisa E.] MIT, Elect Res Lab, Cambridge, MA 02139 USA. [Sarraf, David] Greater Los Angeles VA Healthcare Ctr, Los Angeles, CA USA. RP Sarraf, D (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Jules Stein Eye Inst, Retinal Disorders & Ophthalm Genet Div, 100 Stein Plaza, Los Angeles, CA 90095 USA. EM dsarraf@ucla.edu FU Allergan, Irvine, California, USA; Carl Zeiss Meditec, Dublin, California, USA; Genentech, South San Francisco, California, USA; Optos, Marlborough, Massachusetts, USA; Carl Zeiss Meditec; Massachusetts Lions Club, South Attleboro, Massachusetts, USA; OptoVue, Fremont, California, USA; Research to Prevent Blindness, Columbia, Maryland, USA; Genentech; OptoVue; Regeneron, Tarrytown, New York, USA FX SriniVas R. Sadda: Research support, Allergan, Irvine, California, USA; Carl Zeiss Meditec, Dublin, California, USA; Genentech, South San Francisco, California, USA; and Optos, Marlborough, Massachusetts, USA; Nadia K. Waheed: Research support, Carl Zeiss Meditec; Jay S. Duker: Research support, Carl Zeiss Meditec; Grant, Massachusetts Lions Club, South Attleboro, Massachusetts, USA; Research support, OptoVue, Fremont, California, USA; Grant, Research to Prevent Blindness, Columbia, Maryland, USA; David Sarraf: Research grant, Genentech; OptoVue; and Regeneron, Tarrytown, New York, USA. All authors attest that they meet the current ICIvIJE requirements to qualify as authors. NR 27 TC 57 Z9 60 U1 3 U2 8 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 OCT PY 2015 VL 160 IS 4 BP 739 EP 748 DI 10.1016/j.ajo.2015.06.030 PG 10 WC Ophthalmology SC Ophthalmology GA CR7BR UT WOS:000361503400016 PM 26164826 ER PT J AU Leung, LSB Neal, JW Wakelee, HA Sequist, LV Marmor, MF AF Leung, Loh-Shan B. Neal, Joel W. Wakelee, Heather A. Sequist, Lecia V. Marmor, Michael F. TI Rapid Onset of Retinal Toxicity From High-Dose Hydroxychloroquine Given for Cancer Therapy SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID ADVANCED SOLID TUMORS; PHASE-I TRIAL; RHEUMATOID-ARTHRITIS; RETINOPATHY; TEMOZOLOMIDE; INHIBITION; AUTOPHAGY; MELANOMA AB PURPOSE: To report rapid onset of retinal toxicity in a series of patients followed on high-dose (1000 mg daily) hydroxychloroquine during an oncologic clinical trial studying hydroxychloroquine with erlotinib for non small cell lung cancer. DESIGN: Retrospective observational case series. METHODS: Ophthalmic surveillance was performed on patients in a multicenter clinical trial testing high-dose (1000 mg daily) hydroxychloroquine for advanced non small cell lung cancer. The US Food & Drug Administration recommended screening protocol included only visual acuity testing, dilated fundus examination, Amsler grid testing, and color vision testing. In patients seen at Stanford, additional sensitive screening procedures were added at the discretion of the retinal physician: high-resolution spectral-domain optical coherence tomography (OCT), fundus autofluorescence (FAF) imaging, Humphrey visual field (HVF) testing, and multifocal electroretinography (mfERG). RESULTS: Out of the 7 patients having exposure of at least 6 months, 2 developed retinal toxicity (at 11 and 17 months of exposure). Damage was identified by OCT imaging, mfERG testing, and, in 1 case, visual field testing. Fundus autofluorescence imaging remained normal. Neither patient had symptomatic visual acuity loss. CONCLUSIONS: These cases show that high doses of hydroxychloroquine can initiate the development of retinal toxicity within 1-2 years. Although synergy with erlotinib is theoretically possible, there are no prior reports of erlotinib-associated retinal toxicity despite over a decade of use in oncology. These results also suggest that sensitive retinal screening tests should be added to ongoing and future clinical trials involving high-dose hydroxychloroquine to improve safety monitoring and preservation of vision. Published by Elsevier Inc. C1 [Leung, Loh-Shan B.; Marmor, Michael F.] Stanford Univ, Byers Eye Inst, Dept Ophthalmol, Sch Med, Palo Alto, CA 94303 USA. [Neal, Joel W.; Wakelee, Heather A.] Stanford Univ, Stanford Canc Inst, Dept Med, Div Oncol, Palo Alto, CA 94303 USA. [Sequist, Lecia V.] Massachusetts Gen Hosp, Dept Med, Ctr Canc, Div Hematol Oncol, Boston, MA 02114 USA. [Sequist, Lecia V.] Harvard Univ, Sch Med, Boston, MA USA. RP Leung, LSB (reprint author), Stanford Univ, Byers Eye Inst, Dept Ophthalmol, 2405 Watson Ct, Palo Alto, CA 94303 USA. EM lbleung@stanford.edu FU Genentech/Roche (South San Francisco, California) FX Genentech/Roche (South San Francisco, California) provided funding for the trial and for ophthalmic screening examinations. All authors attest that they meet the current ICMJE requirements to qualify as authors. NR 12 TC 6 Z9 6 U1 1 U2 2 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 OCT PY 2015 VL 160 IS 4 BP 799 EP 805 DI 10.1016/j.ajo.2015.07.012 PG 7 WC Ophthalmology SC Ophthalmology GA CR7BR UT WOS:000361503400022 PM 26189086 ER PT J AU Gopalan, A Lorincz, IS Wirtalla, C Marcus, SC Long, JA AF Gopalan, Anjali Lorincz, Ilona S. Wirtalla, Christopher Marcus, Steven C. Long, Judith A. TI Awareness of Prediabetes and Engagement in Diabetes Risk-Reducing Behaviors SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID LIFE-STYLE INTERVENTION; INCIDENT CARDIOVASCULAR EVENTS; IMPAIRED GLUCOSE-TOLERANCE; PREVENTION PROGRAM; WEIGHT-LOSS; REDUCTION; COMMUNITY; EXERCISE; MELLITUS; DIET AB Introduction: Studies have demonstrated the benefit of weight loss and physical activity for diabetes prevention among those with prediabetes. Despite this evidence, only about half of people with prediabetes report engaging in these behaviors. One presumed barrier is low patient awareness of prediabetes. The purpose of this study is to examine the impact of prediabetes awareness on the odds of engagement in diabetes risk-reduction behaviors. Methods: A pooled cross-sectional analysis of adults from two cycles (2007-2008, 2009-2010) of the National Health and Nutrition Examination Survey was conducted. Those with prediabetes were identified by excluding people with self-reported diabetes and then screening for hemoglobin A1c values between 5.7% and 6.4%. This group was then divided based on self-reported prediabetes. Multivariate logistic regression was used to estimate the effect of prediabetes awareness on the odds of engagement in physical activity, weight management, and the combination of physical activity and weight management. Results: Of those meeting the defined criteria for prediabetes (n=2,694), only 11.8% (n=288) were aware of their status. Prediabetes-aware individuals had higher odds of engagement in the combination of moderate physical activity plus BMI-appropriate weight management (AOR=1.5, 95% CI=1.1, 2.0), and the combination of at least 150 minutes/week of moderate activity and 7% weight loss in the past year (AOR=2.4, 95% CI=1.1, 5.6). Conclusions: Prediabetes-aware adults have increased odds of engagement in physical activity and weight management. Increasing patients' awareness of prediabetes could result in increased performance of exercise and weight management behaviors and, most importantly, decreased risk of future diabetes. Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine C1 [Gopalan, Anjali; Long, Judith A.] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. [Gopalan, Anjali] Univ Penn, Robert Wood Johnson Clin Scholars Program, Philadelphia, PA 19104 USA. [Lorincz, Ilona S.] Univ Penn, Div Endocrinol Diabet & Metab, Philadelphia, PA 19104 USA. [Long, Judith A.] Univ Penn, Div Gen Internal Med, Philadelphia, PA 19104 USA. [Wirtalla, Christopher] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Marcus, Steven C.] Univ Penn, Sch Social Policy & Practice, Philadelphia, PA 19104 USA. [Marcus, Steven C.; Long, Judith A.] Philadelphia Vet Affairs Ctr Hlth Equ Res & Promo, Philadelphia, PA USA. RP Gopalan, A (reprint author), Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM agopalan@upenn.edu NR 23 TC 6 Z9 6 U1 3 U2 15 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 OCT PY 2015 VL 49 IS 4 BP 512 EP 519 DI 10.1016/j.amepre.2015.03.007 PG 8 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA CR5YV UT WOS:000361421200003 PM 26091928 ER PT J AU Barry, MJ Wexler, RM Brackett, CD Sepucha, KR Simmons, LH Gerstein, BS Stringfellow, VL Fowler, FJ AF Barry, Michael J. Wexler, Richard M. Brackett, Charles D. Sepucha, Karen R. Simmons, Leigh H. Gerstein, Bethany S. Stringfellow, Vickie L. Fowler, Floyd J., Jr. TI Responses to a Decision Aid on Prostate Cancer Screening in Primary Care Practices SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; RECOMMENDATION; PHYSICIANS; STATEMENT; GUIDELINE; MORTALITY AB Introduction: Prostate-specific antigen (PSA) testing remains controversial, with most guidelines recommending shared decision making. This study describes men's PSA screening preferences before and after viewing a decision aid and relates these preferences to subsequent clinician visit content. Methods: Men were recruited from two health systems in 2009-2013. Participants answered a questionnaire before and after decision aid viewing addressing PSA screening preferences and five basic knowledge questions. At one health system, participants also answered a survey after a subsequent clinician visit. Data were analyzed in 2014. Results: One thousand forty-one predominantly white, well-educated men responded to the pre- and post-viewing questionnaire (25% and 29% response rates at the two sites). After viewing, the proportion of patients leaning away from PSA screening increased significantly (p < 0.001), with 386 (38%) leaning toward PSA screening versus 436 (43%) before viewing; 174 (17%) unsure versus 319 (32%) before; and 448 (44%) leaning away versus 253 (25%) before. Higher knowledge scores were associated with being more likely to lean against screening and less likely to be unsure (p < 0.001). Among 278 men who also completed a questionnaire after a subsequent clinician visit, participants who planned to discuss PSA screening with their clinicians were significantly more likely to report such discussions than participants who did not (148/217 [68%] vs 16/46 [35%], respectively [p < 0.001]). Conclusions: A decision aid reduces men's interest in PSA screening, particularly among the initially unsure. Men who plan to discuss PSA screening with their clinician after a decision aid are more likely to do so. (C) 2015 American Journal of Preventive Medicine C1 [Barry, Michael J.; Wexler, Richard M.; Gerstein, Bethany S.; Stringfellow, Vickie L.; Fowler, Floyd J., Jr.] Informed Med Decis Fdn, Boston, MA 02114 USA. [Sepucha, Karen R.; Simmons, Leigh H.] Massachusetts Gen Hosp, Decis Sci Unit, Div Gen Med, Boston, MA 02114 USA. [Brackett, Charles D.] Dartmouth Hitchcock Med Ctr, Dartmouth Inst, Hanover, NH USA. RP Barry, MJ (reprint author), Informed Med Decis Fdn, 40 Court St,Suite 300, Boston, MA 02114 USA. EM mbarry@imdfoundation.org FU Informed Medical Decisions Foundation, Healthwise; Informed Medical Decisions Foundation FX MJB, RW, BG, VS, and FJF receive salary support from the Informed Medical Decisions Foundation, which is now a part of Healthwise, a not-for-profit foundation that develops and distributes patient education and decision support materials. The Foundation co-produced the prostate-specific antigen decision aid used in this study with Health Dialog, and had a royalty relationship with Health Dialog that ended December 31, 2013. MJB, CDB, and KS have received grant support from the Informed Medical Decisions Foundation. NR 13 TC 4 Z9 4 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD OCT PY 2015 VL 49 IS 4 BP 520 EP 525 DI 10.1016/j.amepre.2015.03.002 PG 6 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA CR5YV UT WOS:000361421200004 PM 25960395 ER PT J AU Katon, JG Lehavot, K Simpson, TL Williams, EC Barnett, SB Grossbard, JR Schure, MB Gray, KE Reiber, GE AF Katon, Jodie G. Lehavot, Keren Simpson, Tracy L. Williams, Emily C. Barnett, Sarah Beth Grossbard, Joel R. Schure, Mark B. Gray, Kristen E. Reiber, Gayle E. TI Adverse Childhood Experiences, Military Service, and Adult Health SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; TRAUMA EXPOSURE; MENTAL-HEALTH; NATIONAL SAMPLE; PHYSICAL HEALTH; WOMEN VETERANS; SEXUAL-ABUSE; LIFE; CARE; MALTREATMENT AB Introduction: Prevalence of adverse childhood experiences (ACE) and associations with adult health may vary by gender and military service. This study compares the gender-specific prevalence of ACE by military service and determines the associations of ACE with adult health risk factors and health-related quality of life (HRQOL). Methods: This 2014 analysis used data from the 2011 and 2012 CDC Behavioral Risk Factor Surveillance System. Total ACE was operationalized as the number of reported ACE. Associations of total ACE with adult health risk factors were estimated using general linear models; associations with HRQOL were estimated using negative binomial regression. All analyses adjusted for age and race/ethnicity. Results: Those with military service had more total ACE than civilians. Higher ACE was associated with poorer HRQOL among women (physical health, military service, relative risk [RR]=1.20, 95% CI=1.09, 1.33; civilians, RR=1.18, 95% CI=1.17, 1.20; mental health, military service, RR=1.21, 95% CI=1.12, 1.32; civilians, RR=1.25, 95% CI=1.23, 1.26). Among men, these associations were somewhat attenuated in those with military service relative to civilians (physical health, military service, RR=1.13, 95% CI=1.09, 1.18; civilians, RR=1.20, 95% CI=1.17, 1.24; mental health, military service, RR=1.21, 95% CI=1.16, 1.27; civilians, RR=1.30, 95% CI=1.27, 1.34). Conclusions: Relative to civilians, men and women with military service report more ACE, but associations of ACE with adult HRQOL are weaker among men with military service relative to civilians. There is a need to implement and disseminate evidence-based programs to prevent ACE and for research on the long-term health consequences of ACE in military populations. Published by Elsevier Inc. C1 [Katon, Jodie G.; Williams, Emily C.; Grossbard, Joel R.; Schure, Mark B.; Gray, Kristen E.; Reiber, Gayle E.] Vet Affairs Puget Sound Hlth Care Syst, Hlth Serv Res & Dev, Seattle, WA USA. [Lehavot, Keren; Simpson, Tracy L.] Vet Affairs Puget Sound Hlth Care Syst, Mental Illness Res Educ & Clin Ctr, Seattle, WA USA. [Simpson, Tracy L.] Vet Affairs Puget Sound Hlth Care Syst, Ctr Excellence Subst Abuse Treatment & Educ, Seattle, WA USA. [Katon, Jodie G.; Williams, Emily C.; Barnett, Sarah Beth; Schure, Mark B.; Gray, Kristen E.; Reiber, Gayle E.] Univ Washington, Sch Publ Hlth, Dept Hlth Serv, Seattle, WA 98195 USA. [Reiber, Gayle E.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Lehavot, Keren; Simpson, Tracy L.] Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Katon, Jodie G.] Dept Vet Affairs, Off Womens Hlth Serv, Vet Affairs Off Patient Care Serv, Washington, DC USA. RP Katon, JG (reprint author), 1660 South Columbian Way S-152, Seattle, WA 98108 USA. EM jodie.katon@va.gov FU Denver-Seattle Veterans Affairs (VA) Health Services Research and Development (HSR&D) Center of Innovation; VA Office Women's Health Services; VA Career Development Award from CSRD [CX000867]; VA Career Development Award from HSRD [CDA 12-276]; National Institute of Mental Health [R25 MH080916-01A2]; VA HSR&D, Quality Enhancement Research Initiative; Office of Academic Affiliations' Associated Health Postdoctoral Fellowships [TPP 61-026, TPP 61-028]; VA HSR&D Senior Career Scientist Award [RCS 98-353] FX This work was supported by the Denver-Seattle Veterans Affairs (VA) Health Services Research and Development (HSR&D) Center of Innovation and the VA Office Women's Health Services. The authors declare no conflicts of interest. Drs. Lehavot and Williams are supported by VA Career Development Awards from CSR&D (CX000867) and HSR&D (CDA 12-276), respectively. Dr. Williams is also an investigator with the Implementation Research Institute (IRI) at the George Warren Brown School of Social Work at Washington University. IRI is supported through an award from the National Institute of Mental Health (R25 MH080916-01A2) and the VA HSR&D, Quality Enhancement Research Initiative. Drs. Gray and Schure are supported by the Office of Academic Affiliations' Associated Health Postdoctoral Fellowships (TPP 61-026 and TPP 61-028, respectively), and Dr. Reiber is supported by a VA HSR&D Senior Career Scientist Award (RCS 98-353). The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the VA. NR 48 TC 5 Z9 5 U1 2 U2 10 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 OCT PY 2015 VL 49 IS 4 BP 573 EP 582 DI 10.1016/j.amepre.2015.03.020 PG 10 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA CR5YV UT WOS:000361421200010 PM 26091925 ER PT J AU Liao, GS Chou, YC Golshan, M Hsu, HM Hong, ZJ Yu, JC Zhu, JH AF Liao, Guo-Shiou Chou, Yu-Ching Golshan, Mehra Hsu, Huan-Ming Hong, Zhi-Jie Yu, Jyh-Cherng Zhu, Ji-Hong TI Prognostic value of the lymph node ratio in breast cancer subtypes SO AMERICAN JOURNAL OF SURGERY LA English DT Article DE Lymph node ratio; Traditional lymph node-positive stratification; Breast cancer subtypes; Overall survival ID MOLECULAR SUBTYPES; CLINICOPATHOLOGICAL FEATURES; SURVIVAL; IMMUNOHISTOCHEMISTRY; INVOLVEMENT; BIOMARKERS; PREDICTS; HORMONE AB BACKGROUND: Several studies indicate that lymph node (LN) ratio (LNR) is more predictive than the traditional LN-positive stratification (pNs). We assessed whether LNR can provide additional prognostic information on node-positive breast cancer patients, particularly with breast cancer subtypes (BCS). METHODS: We retrospectively reviewed the medical records of 2,049 patients with primary breast cancer treated between January 2006 and December 2011 and identified 511 subjects with positive axillary LN. Clinicopathological findings, types of treatment, and the 5-year overall survival (OS) were included. RESULTS: The results of multivariate analysis of the cohort showed that the correlations of pNs and LNR in regard to OS were P < .001 and P < .001, respectively, with adjustment for tumor characteristics and treatment factors. Moreover, our data revealed that LNR was more predictive in luminal A, luminal B, and luminal human epidermal growth factor receptor 2 in a comparison of pNs and LNR with regard to OS among BCS. CONCLUSION: LNR and pNs are important prognostic factors with regard to OS for patients with node-positive breast cancer, but LNR has a more correlated value in BCS. (C) 2015 Elsevier Inc. All rights reserved. C1 [Liao, Guo-Shiou; Hsu, Huan-Ming; Hong, Zhi-Jie; Yu, Jyh-Cherng; Zhu, Ji-Hong] Triserv Gen Hosp, Dept Surg, Div Gen Surg, Taipei, Taiwan. [Chou, Yu-Ching] Natl Def Med Ctr, Sch Publ Hlth, Taipei, Taiwan. [Golshan, Mehra] Harvard Univ, Sch Med, Dana Farber Canc Inst, Brigham & Womens Hosp, Boston, MA 02115 USA. RP Yu, JC (reprint author), Triserv Gen Hosp, Dept Surg, Div Gen Surg, Taipei, Taiwan. EM doc20106@ndmctsgh.edu.tw NR 29 TC 7 Z9 7 U1 0 U2 4 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 OCT PY 2015 VL 210 IS 4 BP 749 EP 754 DI 10.1016/j.amjsurg.2014.12.054 PG 6 WC Surgery SC Surgery GA CR7AJ UT WOS:000361499400015 PM 26130268 ER PT J AU Driver, JA Zhou, XZ Lu, KP AF Driver, Jane A. Zhou, Xiao Zhen Lu, Kun Ping TI Pin1 dysregulation helps to explain the inverse association between cancer and Alzheimer's disease SO BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS LA English DT Review DE Pin1; Phosphorylation signaling; Cancer; Alzheimer's disease ID PROLYL-ISOMERASE PIN1; AMYLOID PRECURSOR PROTEIN; PROLINE-DIRECTED PHOSPHORYLATION; TANGLE MOUSE MODEL; TAU-PROTEIN; CELL-CYCLE; NEUROFIBRILLARY TANGLES; REGULATORY MECHANISM; BREAST-CANCER; DNA-DAMAGE AB Background: Pin1 is an intracellular signaling molecule which plays a critical but opposite role in the pathogenesis of Alzheimer's disease (AD) and many human cancers. Scope of review: We review the structure and function of the Pin1 enzyme, the diverse roles it plays in cycling cells and neurons, the epidemiologic evidence for the inverse association between cancer and AD, and the potential therapeutic implications of Pin1-based therapies. Major conclusions: Pin1 is a unique enzyme that has effects on the function of target proteins by "twisting" them into different shapes. Cycling cells use Pin1 to help coordinate cell division. It is over-expressed and/or activated by multiple mechanisms in many common human cancers, and acts on multiple signal pathways to promote tumorigenesis. Inhibition of Pin1 in animal models has profound anti-tumor effects. In contrast, Pin1 is down-regulated or inactivated by multiple mechanisms in AD brains. The absence of Pin1 impairs tau function and amyloid precursor protein processing, leading to tangle-and amyloid-related pathologies and neurodegeneration in an age-dependent manner, resembling human AD. We have developed cis and trans conformation-specific antibodies to provide the first direct evidence that tau exists in distinct cis and trans conformations and that Pin1 accelerates its cis to trans conversion, thereby protecting against tangle formation in AD. General significance: Available studies on Pin1 suggest that cancer and AD may share biological pathways that are deregulated in different directions. Pin1 biology opens exciting preventive and therapeutic horizons for both cancer and neurodegeneration. This article is part of a Special Issue entitled Proline-directed Foldases: Cell Signaling Catalysts and Drug Targets. (C) 2015 Elsevier B.V. All rights reserved. C1 [Driver, Jane A.] VA Boston Healthcare Syst, Geriatr Res Educ & Clin Ctr, Boston, MA 02132 USA. [Driver, Jane A.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Aging,Dept Med, Boston, MA 02115 USA. [Zhou, Xiao Zhen; Lu, Kun Ping] Harvard Univ, Sch Med, Beth Israel Deaconess Canc Ctr, Canc Res Inst, Boston, MA USA. [Zhou, Xiao Zhen; Lu, Kun Ping] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Med, Boston, MA 02215 USA. RP Driver, JA (reprint author), VA Boston Healthcare Syst, Geriatr Res Educ & Clin Ctr, Boston, MA 02132 USA. EM jdriver@partners.org; xzhou@bidmc.harvard.edu; Idu@bidmc.harvard.edu FU CSRD VA [I01 CX000934]; NIA NIH HHS [R01 AG039405, R01 AG046319, R01 AG022082, R01 AG017870] NR 106 TC 12 Z9 13 U1 3 U2 27 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-4165 EI 1872-8006 J9 BBA-GEN SUBJECTS JI Biochim. Biophys. Acta-Gen. Subj. PD OCT PY 2015 VL 1850 IS 10 SI SI BP 2069 EP 2076 DI 10.1016/j.bbagen.2014.12.025 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA CR3WL UT WOS:000361263700012 PM 25583562 ER PT J AU Fay, AP Bellmunt, J AF Fay, Andre P. Bellmunt, Joaquim TI Is angiogenesis still an attractive target in metastatic castration-resistant prostate cancer? SO BJU INTERNATIONAL LA English DT Editorial Material ID BEVACIZUMAB C1 [Fay, Andre P.; Bellmunt, Joaquim] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Fay, Andre P.] Pontificia Univ Catolica Rio Grande do Sul, Fac Med, Porto Alegre, RS, Brazil. [Bellmunt, Joaquim] IMIM, Univ Hosp del Mar, Barcelona, Spain. RP Fay, AP (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. NR 6 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-4096 EI 1464-410X J9 BJU INT JI BJU Int. PD OCT PY 2015 VL 116 IS 4 BP 500 EP 501 DI 10.1111/bju.13070 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA CR3GA UT WOS:000361217900005 PM 26350576 ER PT J AU Phitayakorn, R Lachman, N AF Phitayakorn, Roy Lachman, Nirusha TI Getting back together after a break-up: Relationship advice for anatomists and surgeons SO CLINICAL ANATOMY LA English DT Article DE surgery education; ACGME; graduate medical education; collaboration ID TEMPORAL BONE DISSECTION; SURGICAL SKILL; UNDERGRADUATE; ACQUISITION; SIMULATION; EDUCATORS; RESIDENTS; MODELS AB The surgeon-anatomist was originally a single individual who self-pursued knowledge and understanding of anatomy as the foundation for successful surgical outcomes. However, recent advances in medical education have ironically led to the separation of anatomy and surgery. This physical and emotional divorce of anatomists and surgeons into separate individuals has created several critical educational issues for medical and surgical educators including a general lack of anatomical knowledge in medical students and misalignment of graduate medical education procedural specialty training with the Accreditation Council of Graduate Medical Education Core Competencies and now the Next Accreditation System. There are numerous opportunities for anatomists and surgeons to work together to improve educational instruction of established difficult anatomical regions, procedural training, or even develop new techniques and procedures. Similarly, anatomists with specialized training in medical education would be invaluable partners to ensure that procedural assessments align with instructional technologies for truly longitudinal curricula that starts at the medical student level, but stops at the patient outcomes of attending surgeons. This mutually beneficial relationship would be similar to multidisciplinary care teams and current surgeon and PhD/EdD partnerships. The restoration of the relationship between anatomists and surgeons would be invaluable to surgical education and remains an exciting research opportunity. Clin. Anat. 28:931-934, 2015. (c) 2015 Wiley Periodicals, Inc. C1 [Phitayakorn, Roy] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg, Boston, MA USA. [Lachman, Nirusha] Mayo Clin, Coll Med, Dept Anat, Rochester, MN USA. RP Phitayakorn, R (reprint author), Massachusetts Gen Hosp, Dept Surg, Wang ACC,Suite 460,15 Parkman St, Boston, MA 02114 USA. EM rphitayakorn@mgh.harvard.edu OI Phitayakorn, Roy/0000-0002-8327-1484 NR 41 TC 3 Z9 3 U1 3 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0897-3806 EI 1098-2353 J9 CLIN ANAT JI Clin. Anat. PD OCT PY 2015 VL 28 IS 7 BP 931 EP 934 DI 10.1002/ca.22596 PG 4 WC Anatomy & Morphology SC Anatomy & Morphology GA CR3OK UT WOS:000361242400021 PM 26174432 ER PT J AU Alabed, YZ Sakellis, C AF Alabed, Yazan Z. Sakellis, Christopher TI Umbilical Plugoma Mimics Melanoma Metastasis on FDG PET/CT SO CLINICAL NUCLEAR MEDICINE LA English DT Editorial Material ID HERNIA REPAIR; VENTRAL HERNIA; MESH; APPEARANCE; CT AB An 84-year-old man with history of left forehead melanoma was found on a restaging F-18-FDG PET/CT scan with hypermetabolic lung nodules and a mildly FDG-avid soft tissue nodule posterior to the umbilicus. Biopsy of a right lower lobe nodule revealed metastatic melanoma. Follow-up posttreatment PET/CT scan showed complete resolution of lung nodules and unchanged FDG uptake at the level of the umbilicus. Review of the patient's medical history revealed a remote history of umbilical hernia repair. We present a case of postsurgical plugoma mimicking the appearance of melanoma metastasis on FDG PET/CT. C1 [Alabed, Yazan Z.; Sakellis, Christopher] Dana Farber Canc Inst, Dept Imaging, Boston, MA 02215 USA. [Alabed, Yazan Z.; Sakellis, Christopher] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Radiol, Boston, MA 02115 USA. RP Alabed, YZ (reprint author), Dana Farber Canc Inst, Dept Imaging, 450 Brookline Ave, Boston, MA 02215 USA. EM ziyazan_alabed@dfci.harvard.edu NR 8 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 0363-9762 EI 1536-0229 J9 CLIN NUCL MED JI Clin. Nucl. Med. PD OCT PY 2015 VL 40 IS 10 BP 812 EP 813 DI 10.1097/RLU.0000000000000859 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA CR6JB UT WOS:000361451300012 PM 26164172 ER PT J AU Neto, AS Simonis, FD Barbas, CSV Biehl, M Determann, RM Elmer, J Friedman, G Gajic, O Goldstein, JN Linko, R de Oliveira, RP Sundar, S Talmor, D Wolthuis, EK de Abreu, MG Pelosi, P Schultz, MJ AF Neto, Ary Serpa Simonis, Fabienne D. Barbas, Carmen S. V. Biehl, Michelle Determann, Rogier M. Elmer, Jonathan Friedman, Gilberto Gajic, Ognjen Goldstein, Joshua N. Linko, Rita de Oliveira, Roselaine Pinheiro Sundar, Sugantha Talmor, Daniel Wolthuis, Esther K. de Abreu, Marcelo Gama Pelosi, Paolo Schultz, Marcus J. CA PROtective Ventilation Network TI Lung-Protective Ventilation With Low Tidal Volumes and the Occurrence of Pulmonary Complications in Patients Without Acute Respiratory Distress Syndrome: A Systematic Review and Individual Patient Data Analysis SO CRITICAL CARE MEDICINE LA English DT Article DE acute respiratory distress syndrome; individual patient analysis; intensive care unit and in-hospital stay; mechanical ventilation; mortality; pulmonary complications; tidal volume ID MECHANICAL VENTILATION; ABDOMINAL-SURGERY; INJURY; PREVENTION; PNEUMONIA; MORTALITY; SEDATION; STRATEGY; TRIAL AB Objective: Protective mechanical ventilation with low tidal volumes is standard of care for patients with acute respiratory distress syndrome. The aim of this individual patient data analysis was to determine the association between tidal volume and the occurrence of pulmonary complications in ICU patients without acute respiratory distress syndrome and the association between occurrence of pulmonary complications and outcome in these patients. Design: Individual patient data analysis. Patients: ICU patients not fulfilling the consensus criteria for acute respiratory distress syndrome at the onset of ventilation. Interventions: Mechanical ventilation with low tidal volume. Measurements and Main Results: The primary endpoint was development of a composite of acute respiratory distress syndrome and pneumonia during hospital stay. Based on the tertiles of tidal volume size in the first 2 days of ventilation, patients were assigned to a low tidal volume group (tidal volumes 7 mL/kg predicted body weight), an intermediate tidal volume group (> 7 and < 10 mL/kg predicted body weight), and a high tidal volume group ( 10 mL/kg predicted body weight). Seven investigations (2,184 patients) were included. Acute respiratory distress syndrome or pneumonia occurred in 23% of patients in the low tidal volume group, in 28% of patients in the intermediate tidal volume group, and in 31% of the patients in the high tidal volume group (adjusted odds ratio [low vs high tidal volume group], 0.72; 95% CI, 0.52-0.98; p = 0.042). Occurrence of pulmonary complications was associated with a lower number of ICU-free and hospital-free days and alive at day 28 (10.0 10.9 vs 13.8 +/- 11.6 d; p < 0.01 and 6.1 +/- 8.1 vs 8.9 +/- 9.4 d; p < 0.01) and an increased hospital mortality (49.5% vs 35.6%; p < 0.01). Conclusions: Ventilation with low tidal volumes is associated with a lower risk of development of pulmonary complications in patients without acute respiratory distress syndrome. C1 [Neto, Ary Serpa; Simonis, Fabienne D.; Determann, Rogier M.; Wolthuis, Esther K.; Schultz, Marcus J.] Univ Amsterdam, Acad Med Ctr, Dept Intens Care, NL-1105 AZ Amsterdam, Netherlands. [Neto, Ary Serpa] Fac Med ABC FMABC, Program Postgrad Res & Innovat, Santo Andre, Brazil. [Neto, Ary Serpa; Barbas, Carmen S. V.] Hosp Israelita Albert Einstein, Dept Crit Care Med, Sao Paulo, Brazil. [Biehl, Michelle; Gajic, Ognjen] Mayo Clin, Div Pulm & Crit Care Med, Rochester, MN USA. [Elmer, Jonathan; Goldstein, Joshua N.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Friedman, Gilberto] Univ Fed Rio Grande do Sul, Sch Med, Porto Alegre, RS, Brazil. [Linko, Rita] Peijas Hosp, Helsinki Univ Hosp, Dept Anaesthesia & Intens Care Med, Vantaa, Finland. [de Oliveira, Roselaine Pinheiro] Univ Fed Ciencias Saude Porto Alegre, Sch Med, Porto Alegre, RS, Brazil. [Sundar, Sugantha; Talmor, Daniel] Beth Israel Deaconess Med Ctr, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02215 USA. [Sundar, Sugantha; Talmor, Daniel] Harvard Univ, Sch Med, Boston, MA USA. [de Abreu, Marcelo Gama] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Dept Anesthesiol & Intens Care Med, D-01062 Dresden, Germany. [Pelosi, Paolo] Univ Genoa, IRCCS San Martino IST, Dept Surg Sci & Integrated Diagnost, Genoa, Italy. [Schultz, Marcus J.] Univ Amsterdam, Acad Med Ctr, Lab Expt Intens Care & Anesthesiol, NL-1105 AZ Amsterdam, Netherlands. RP Neto, AS (reprint author), Univ Amsterdam, Acad Med Ctr, Dept Intens Care, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. EM aryserpa@terra.com.br RI Goldstein, Joshua/H-8953-2016; Serpa Neto, Ary/D-1927-2012 OI Serpa Neto, Ary/0000-0003-1520-9387 NR 31 TC 30 Z9 32 U1 4 U2 22 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 OCT PY 2015 VL 43 IS 10 BP 2155 EP 2163 DI 10.1097/CCM.0000000000001189 PG 9 WC Critical Care Medicine SC General & Internal Medicine GA CR5DC UT WOS:000361358900014 PM 26181219 ER PT J AU Kherada, N Heimowitz, T Rosendorff, C AF Kherada, Nisharahmed Heimowitz, Todd Rosendorff, Clive TI Antihypertensive Therapies and Cognitive Function: a Review SO CURRENT HYPERTENSION REPORTS LA English DT Review DE Dementia; Cognition; Alzheimer's disease; Stroke; Antihypertensive therapies ID RENIN-ANGIOTENSIN SYSTEM; ELDERLY HYPERTENSIVE PATIENTS; CARDIOVASCULAR RISK-FACTORS; PLACEBO-CONTROLLED TRIAL; SYSTOLIC BLOOD-PRESSURE; ALZHEIMERS-DISEASE; OLDER-ADULTS; DOUBLE-BLIND; INTERVENTION TRIAL; GINKGO EVALUATION AB Increasing life expectancy has made old age-related health problems like dementia and cognitive decline more prevalent, and these are rapidly becoming important causes of disability and poor quality of life, causing significant add-ons to health-care costs worldwide. Hypertension is the most important modifiable vascular risk factor for the development and progression of both cognitive decline and dementia. In many observational and randomized studies, antihypertensive therapies have been shown to be beneficial in slowing cognitive decline. However, due to observed discrepancies by these studies, there is a lack of consensus on the best antihypertensive strategy for the prevention or slowing of cognitive decline. It is also not clear whether the beneficial effect of antihypertensive therapy is due to the use of a specific class of agents or combination therapy. Thus, we present a comprehensive review of overall antihypertensive therapies and cognition and of the individual antihypertensive therapy classes with their specific protective mechanisms and available clinical evidence behind their effect on cognitive function. C1 [Kherada, Nisharahmed; Heimowitz, Todd] Columbia Univ, Mt Sinai Med Ctr, Dept Cardiol, Miami Beach, FL 33140 USA. [Rosendorff, Clive] Icahn Sch Med Mt Sinai, James J Peters VA Med Ctr, Dept Cardiol, Bronx, NY 10468 USA. RP Kherada, N (reprint author), Columbia Univ, Mt Sinai Med Ctr, Dept Cardiol, 4300 Alton Rd,Suite 2070, Miami Beach, FL 33140 USA. EM kherada.1@gmail.com; Todd.Heimowitz@msmc.com; Clive.Rosendorff@va.gov NR 70 TC 4 Z9 4 U1 2 U2 13 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1522-6417 EI 1534-3111 J9 CURR HYPERTENS REP JI Curr. Hypertens. Rep. PD OCT PY 2015 VL 17 IS 10 AR 79 DI 10.1007/s11906-015-0592-7 PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA CR6IR UT WOS:000361450100003 PM 26298567 ER PT J AU Elder, GA AF Elder, Gregory A. TI Update on TBI and Cognitive Impairment in Military Veterans SO CURRENT NEUROLOGY AND NEUROSCIENCE REPORTS LA English DT Review DE Alzheimer's disease; Blast; Chronic traumatic encephalopathy; Dementia; Traumatic brain injury; Military veterans ID TRAUMATIC BRAIN-INJURY; POSTTRAUMATIC-STRESS-DISORDER; DEPLOYED US MILITARY; ALZHEIMERS-DISEASE; HEAD-INJURY; SERVICE MEMBERS; ACUTE CONCUSSION; OLDER VETERANS; DEMENTIA RISK; ENCEPHALOPATHY AB Traumatic brain injury (TBI) is a common cause of morbidity and mortality in military life. Interest in military TBI has increased recently due to the conflicts in Iraq and Afghanistan. Certain types of TBI are relatively unique to the military, the most prominent being blast-related TBI. Blast-related mild TBI has been of particular concern in veterans from the most recent conflicts although controversy remains concerning its separation from post-traumatic stress disorder. TBI is also a risk factor for the later development of neurodegenerative diseases in which cognitive impairment is prominent putting veterans at risk for disorders including Alzheimer's disease and chronic traumatic encephalopathy. Recent evidence associating TBI with chronic cognitive impairment is reviewed in the context of its relevance to military veterans. C1 [Elder, Gregory A.] James J Peters Dept Vet Affairs Med Ctr, Neurol Serv, Bronx, NY 10468 USA. [Elder, Gregory A.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Elder, Gregory A.] Icahn Sch Med Mt Sinai, Dept Neurol, New York, NY 10029 USA. [Elder, Gregory A.] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA. RP Elder, GA (reprint author), James J Peters Dept Vet Affairs Med Ctr, Neurol Serv, 130 West Kingsbridge Rd, Bronx, NY 10468 USA. EM gregory.elder@va.gov FU Department of Veterans Affairs, Veterans Health Administration, Rehabilitation Research and Development Service Awards [1I01RX000179-01, 1I01RX000996-01] FX The author has received research support from the Department of Veterans Affairs, Veterans Health Administration, Rehabilitation Research and Development Service Awards 1I01RX000179-01 and 1I01RX000996-01. NR 82 TC 1 Z9 1 U1 2 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1528-4042 EI 1534-6293 J9 CURR NEUROL NEUROSCI JI Curr. Neurol. Neurosci. Rep. PD OCT PY 2015 VL 15 IS 10 AR 68 DI 10.1007/s11910-015-0591-8 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CR6HO UT WOS:000361446400004 PM 26299275 ER PT J AU Seol, JY Mihich, E Berleth, ES AF Seol, Ji-Yeon Mihich, Enrico Berleth, Erica S. TI TNF Apoptosis Protection Fraction (TAPF) prevents apoptosis induced by TNF, but not by Fas or TRAIL, via NF-kappa B-induced increase in cFLIP SO CYTOKINE LA English DT Article DE TNF; Apoptosis; TRAIL; Fas; cFLIP ID TUMOR-NECROSIS-FACTOR; SIGNALING PATHWAYS; HUMAN FIBROBLASTS; PROTEIN; ALPHA; TIP-B1; SUPERFAMILY; MECHANISMS; INDUCTION; DISEASES AB Tumor Necrosis Factor alpha (TNF alpha) induces both the apoptotic pathway and anti-apoptotic factors. Incubation of human dermal fibroblasts with TAPF (TNF Apoptosis Protection Fraction) protects them from apoptosis induced by the subsequent addition of TNF and cycloheximide (CHX). TAPF does not protect against apoptosis induced by CHX in combination with either TRAIL (TNF related apoptosis inducing ligand) or an agonistic Fas antibody, or against apoptosis induced by the chemotherapeutic agent doxorubicin. Incubation with TAPF does not affect the quantity of TNF that binds to the cell. TAPF prevents TNF-induced cleavage of caspases 8, 9, 3 and 7 and the apoptotic substrate PARP (poly-ADP ribose polymerase), but has no effect when these molecules are induced by an agonistic Fas antibody. TAPF induces rapid phosphorylation of the NF-kappa B/p65 (nuclear factor-kappa B) transcription factor at serine 536 which is indicative of its activation. TAPF increases the expression of cFLIP (cellular FLICE-inhibitory protein) which is a potent inhibitor of apoptosis that acts by preventing the cleavage of caspase 8. This increase in cFLIP is coincident with protection from TNF-induced apoptosis. Decreasing cFLIP levels using shRNA (short hairpin RNA) decreases protection by TAPF. TAPF also induced the anti-apoptotic A20 protein. These data indicate that TAPF protects human dermal fibroblasts from TNF-induced apoptosis by induction of cFLIP and subsequent inhibition of caspase 8 cleavage. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Seol, Ji-Yeon; Mihich, Enrico; Berleth, Erica S.] Roswell Pk Canc Inst, Dept Pharmacol & Therapeut, Buffalo, NY 14263 USA. RP Mihich, E (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM jseol@yahoo.com; enrico_mihich@dfci.harvard.edu; erica.berleth@gmail.com FU National Cancer Institute [R01 CA093594]; Cancer Center Support Grant [P30 CA016056] FX We thank and acknowledge Dr. M.M. Ip, as well as members of her laboratory, for helpful discussion, gifts of reagents and critical review of the manuscript. We also acknowledge the Asahi Chemical Industry Co., Ltd. for the generous gift of TNF and the National Cancer Institute for funding support to E. Berleth (R01 CA093594) and the core resources provided through the Cancer Center Support Grant to Roswell Park Cancer Institute (P30 CA016056). NR 22 TC 1 Z9 1 U1 2 U2 6 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 EI 1096-0023 J9 CYTOKINE JI Cytokine PD OCT PY 2015 VL 75 IS 2 BP 321 EP 329 DI 10.1016/j.cyto.2015.05.027 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA CR3TQ UT WOS:000361256400016 PM 26198031 ER PT J AU Stucky, EC Schloss, RS Yarmush, ML Shreiber, DI AF Stucky, Elizabeth C. Schloss, Rene S. Yarmush, Martin L. Shreiber, David I. TI Alginate micro-encapsulation of mesenchymal stromal cells enhances modulation of the neuro-inflammatory response SO CYTOTHERAPY LA English DT Article DE co-culture; inflammation mediators; mesenchymal stromal cells; organ culture; traumatic brain injury ID TRAUMATIC BRAIN-INJURY; CENTRAL-NERVOUS-SYSTEM; TUMOR-NECROSIS-FACTOR; PGE(2) EP2 RECEPTOR; BONE-MARROW; STEM-CELLS; CEREBRAL-ISCHEMIA; PROSTAGLANDIN E-2; ANTIINFLAMMATORY PROPERTIES; INDUCIBLE CYCLOOXYGENASE AB Background aims. Modulation of inflammation after brain trauma is a key therapeutic goal aimed at limiting the consequences of the subsequent injury cascade. Mesenchymal stromal cells (MSCs) have been demonstrated to dynamically regulate the inflammatory environment in several tissue systems, including the central nervous system. There has been limited success, however, with the use of direct implantation of cells in the brain caused by low viability and engraftment at the injury site. To circumvent this, we encapsulated MSCs in alginate microspheres and evaluated the ability of these encapsulated MSCs to attenuate inflammation in rat organotypic hippocarnpal slice cultures (OHSC). Methods. OHSC were administered lipopolysaccharide to induce inflammation and immediately co-cultured with encapsulated or monolayer human MSCs. After 24 h, culture media was assayed for the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) produced by OHSC, as well as MSC-produced trophic mediators. Results. Encapsulated MSCs reduced TNF-alpha more effectively than did monolayer MSCs. Additionally, there was a strong correlation between increased prostaglandin E-2 (PGE(2)) and reduction of TNF-alpha. In contrast to monolayer MS Cs, inflammatory signals were not required to stimulate PGE(2) production by encapsulated MSCs. Further encapsulation-stimulated changes were revealed in a multiplex panel analyzing 27 MSC-produced cytokines and growth factors, from which additional mediators with strong correlations to TNF-alpha levels were identified. Conclusions. These results suggest that alginate encapsulation of MSCs may not only provide an improved delivery vehicle for transplantation but may also enhance MSC therapeutic benefit for treating neuro-inflammation. C1 [Stucky, Elizabeth C.; Yarmush, Martin L.] Rutgers State Univ, Dept Chem & Biochem Engn, Piscataway, NJ 08854 USA. [Schloss, Rene S.; Yarmush, Martin L.; Shreiber, David I.] Rutgers State Univ, Dept Biomed Engn, Piscataway, NJ 08854 USA. [Yarmush, Martin L.] Massachusetts Gen Hosp, Ctr Engn Med, Boston, MA 02114 USA. RP Yarmush, ML (reprint author), Rutgers State Univ, Dept Biomed Engn, 599 Taylor Rd, Piscataway, NJ 08854 USA. EM yarmush@rci.rutgers.edu; shreiber@rci.rutgers.edu OI Stucky Hunter, Elizabeth/0000-0003-0797-9453 FU New Jersey Commission on Brain Injury Research [SNJ-DHSS-CBIR-CBIE12IPG019, 10-3215-BIR-E-0]; National Institute of Health [P41EB002503]; Rutgers-UMDNJ Biotechnology Training Fellowship [T32GM00008339-21]; NSF Stem Cell IGERT Fellowship [0801620] FX We would like to acknowledge Serom Lee, PhD, and Andrea Gray for their assistance and contribution to the statistical analyses, and Mehdi Ghodbane, PhD, for assistance with multiplex assay and analysis. This research was supported by the New Jersey Commission on Brain Injury Research (SNJ-DHSS-CBIR-CBIE12IPG019 and 10-3215-BIR-E-0), National Institute of Health Grant P41EB002503, Rutgers-UMDNJ Biotechnology Training Fellowship T32GM00008339-21 and NSF Stem Cell IGERT Fellowship 0801620. These funding agencies were not involved in the conduct of the research or preparation of the article. NR 58 TC 4 Z9 4 U1 2 U2 13 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1465-3249 EI 1477-2566 J9 CYTOTHERAPY JI Cytotherapy PD OCT PY 2015 VL 17 IS 10 BP 1353 EP 1364 DI 10.1016/j.jcyt.2015.05.002 PG 12 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Hematology; Medicine, Research & Experimental SC Cell Biology; Biotechnology & Applied Microbiology; Hematology; Research & Experimental Medicine GA CR5XX UT WOS:000361418800004 PM 26210574 ER PT J AU Chacko, L Macaron, C Burke, CA AF Chacko, Lyssa Macaron, Carole Burke, Carol A. TI Clinical Practice Patterns Suggest Female Patients Prefer Female Endoscopists Reply SO DIGESTIVE DISEASES AND SCIENCES LA English DT Letter C1 [Chacko, Lyssa] Denver Vet Affairs Med Ctr, Dept Gastroenterol & Hepatol, Denver, CO USA. [Macaron, Carole] Cleveland Vet Affairs Med Ctr, Gastroenterol Sect, Cleveland, OH USA. [Burke, Carol A.] Cleveland Clin, Dept Gastroenterol & Hepatol, Cleveland, OH 44195 USA. RP Burke, CA (reprint author), Cleveland Clin, Dept Gastroenterol & Hepatol, Desk 30,9500 Euclid Ave, Cleveland, OH 44195 USA. EM Burkec1@ccf.org NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0163-2116 EI 1573-2568 J9 DIGEST DIS SCI JI Dig. Dis. Sci. PD OCT PY 2015 VL 60 IS 10 BP 3150 EP 3150 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA CR6ZU UT WOS:000361497900043 ER PT J AU Mitra, M Long-Bellil, LM Smeltzer, SC Iezzoni, LI AF Mitra, Monika Long-Bellil, Linda M. Smeltzer, Suzanne C. Iezzoni, Lisa I. TI A perinatal health framework for women with physical disabilities SO DISABILITY AND HEALTH JOURNAL LA English DT Article DE Disability; Pregnancy; Perinatal health; Framework; Women with physical disabilities ID MULTIPLE-SCLEROSIS; CURRENT PREGNANCY; MATERNITY CARE; US WOMEN; EXPERIENCES; MOTHERS; PEOPLE; ACCESS; MASSACHUSETTS; PREVALENCE AB Background: Studies suggest that women with disabilities experience health and health care disparities before, during, and after pregnancy. However, existing perinatal health and health care frameworks do not address the needs and barriers faced by women with physical disabilities around the time of pregnancy. A new framework that addresses perinatal disparities among women with physical disabilities is needed. Objective: To propose a framework for examining perinatal health and health care disparities among women with physical disabilities. Methods: We developed a perinatal health framework guided by the International Classification of Functioning, Disability and Health (ICF) and the integrated perinatal health framework by Misra et al. Results: The proposed framework uses a life span perspective in a manner that directly addresses the multiple determinants specific to women with physical disabilities around the time of pregnancy. The framework is based on longitudinal and integrated perspectives that take into account women's functional status and environment over their life course. Conclusion: The perinatal health framework for women with physical disabilities was developed to inform the way researchers and health care professionals address disparities in perinatal health and health care among women with physical disabilities. (C) 2015 Elsevier Inc. All rights reserved. C1 [Mitra, Monika; Long-Bellil, Linda M.] Univ Massachusetts, Ctr Hlth Policy & Res, Sch Med, Shrewsbury, MA 01545 USA. [Smeltzer, Suzanne C.] Villanova Univ, Ctr Nursing Res, Coll Nursing, Villanova, PA 19085 USA. [Iezzoni, Lisa I.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. RP Mitra, M (reprint author), Univ Massachusetts, Ctr Hlth Policy & Res, Sch Med, 333 South St, Shrewsbury, MA 01545 USA. EM monika.mitra@umassmed.edu FU National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health & Human Development [R01HD074581] FX This research is funded by a grant from the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health & Human Development. Award number: R01HD074581. NR 63 TC 4 Z9 4 U1 0 U2 3 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 OCT PY 2015 VL 8 IS 4 BP 499 EP 506 DI 10.1016/j.dhjo.2015.05.007 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health; Rehabilitation SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Rehabilitation GA CR3RD UT WOS:000361249900007 PM 26189010 ER PT J AU Marino, ME Meterko, M Marfeo, EE McDonough, CM Jette, AM Ni, PS Bogusz, K Rasch, EK Brandt, DE Chan, L AF Marino, Molly Elizabeth Meterko, Mark Marfeo, Elizabeth E. McDonough, Christine M. Jette, Alan M. Ni, Pengsheng Bogusz, Kara Rasch, Elizabeth K. Brandt, Diane E. Chan, Leighton TI Work-related measures of physical and behavioral health function: Test-retest reliability SO DISABILITY AND HEALTH JOURNAL LA English DT Article DE Disability evaluation; Psychometrics; United States Social Security Administration; Computer-adaptive test; Reliability ID INTRACLASS CORRELATION-COEFFICIENTS; ITEM POOL CONSTRUCTION; QUALITY-OF-LIFE; DISABILITY EVALUATION; FUNCTION INSTRUMENT; OUTCOMES; VALIDITY; SYSTEM AB Background: The Work Disability Functional Assessment Battery (WD-FAB), developed for potential use by the US Social Security Administration to assess work-related function, currently consists of five multi-item scales assessing physical function and four multi-item scales assessing behavioral health function; the WD-FAB scales are administered as Computerized Adaptive Tests (CATs). Objective: The goal of this study was to evaluate the test-retest reliability of the WD-FAB Physical Function and Behavioral Health CATs. Methods: We administered the WD-FAB scales twice, 7-10 days apart, to a sample of 376 working age adults and 316 adults with work-disability. Intraclass correlation coefficients were calculated to measure the consistency of the scores between the two administrations. Standard error of measurement (SEM) and minimal detectable change (MDC90) were also calculated to measure the scales precision and sensitivity. Results: For the Physical Function CAT scales, the ICCs ranged from 0.76 to 0.89 in the working age adult sample, and 0.77-0.86 in the sample of adults with work-disability. ICCs for the Behavioral Health CAT scales ranged from 0.66 to 0.70 in the working age adult sample, and 0.77-0.80 in the adults with work-disability. The SEM ranged from 3.25 to 4.55 for the Physical Function scales and 5.27-6.97 for the Behavioral Health function scales. For all scales in both samples, the MDC90 ranged from 7.58 to 16.27. Conclusion: Both the Physical Function and Behavioral Health CATs of the WD-FAB demonstrated good test-retest reliability in adults with work-disability and general adult samples, a critical requirement for assessing work related functioning in disability applicants and in other contexts. (C) 2015 Elsevier Inc. All rights reserved. C1 [Marino, Molly Elizabeth; Meterko, Mark; Marfeo, Elizabeth E.; McDonough, Christine M.; Jette, Alan M.; Ni, Pengsheng; Bogusz, Kara] Boston Univ, Sch Publ Hlth, Hlth & Disabil Res Inst, Boston, MA 02118 USA. [Meterko, Mark] VA Boston Healthcare Syst, Ctr Healthcare Org & Implementat Res, Boston, MA USA. [Rasch, Elizabeth K.; Brandt, Diane E.; Chan, Leighton] NIH, Dept Rehabil Med, Mark O Hatfield Clin Res Ctr, Bethesda, MD 20892 USA. RP Marino, ME (reprint author), Boston Univ, Sch Publ Hlth, Hlth & Disabil Res Inst, 715 Albany St,T5W, Boston, MA 02118 USA. EM memarino@bu.edu FU Social Security Administration-National Institutes of Health under the National Institutes of Health [HHSN269200900004C, HHSN269201000011C, HHSN269201100009I]; National Institutes of Health Intramural Research Program FX This study was supported by Social Security Administration-National Institutes of Health Interagency Agreements under the National Institutes of Health (contract nos. HHSN269200900004C, HHSN269201000011C, HHSN269201100009I), and by the National Institutes of Health Intramural Research Program. NR 25 TC 1 Z9 1 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-6574 EI 1876-7583 J9 DISABIL HEALTH J JI Disabil. Health J. PD OCT PY 2015 VL 8 IS 4 BP 652 EP 657 DI 10.1016/j.dhjo.2015.04.001 PG 6 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health; Rehabilitation SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Rehabilitation GA CR3RD UT WOS:000361249900027 PM 25991419 ER PT J AU Siddiqi, OK Smoot, KJ Dufour, AB Cho, K Young, M Gagnon, DR Ly, S Temiyasathit, S Faxon, DP Gaziano, JM Kinlay, S AF Siddiqi, Omar K. Smoot, Kyle J. Dufour, Alyssa B. Cho, Kelly Young, Melissa Gagnon, David R. Ly, Samantha Temiyasathit, Sara Faxon, David P. Gaziano, J. Michael Kinlay, Scott TI Outcomes with prolonged clopidogrel therapy after coronary stenting in patients with chronic kidney disease SO HEART LA English DT Article ID DUAL-ANTIPLATELET THERAPY; DRUG-ELUTING STENTS; MODERATE RENAL-INSUFFICIENCY; GLOMERULAR-FILTRATION-RATE; LONG-TERM OUTCOMES; BARE-METAL; MYOCARDIAL-INFARCTION; RISK-FACTORS; IMPLANTATION; TRIAL AB Objectives Patients with chronic kidney disease (CKD) are at high risk of death or myocardial infarction (MI) after percutaneous coronary interventions (PCI). We assessed whether prolonged dual antiplatelet therapy beyond the recommended 12 months may prevent adverse outcomes in patients with CKD receiving drug-eluting stents (DES) or bare-metal stents (BMS). Methods We studied all Veterans receiving PCI with BMS or first-generation DES in the Veterans Affairs (VA) Healthcare System between 2002 and 2006, classified by CKD (estimated glomerular filtration rate < 60 mL/min) or normal renal function. We used landmark analyses from 12 months after PCI with Cox proportional hazards multivariable and propensity-adjusted models to assess the effect of prolonged clopidogrel (more than 12 months) versus 12 months or less after PCI on clinical outcomes from 1 year to 4 years after PCI. Results Of 23 042 eligible subjects receiving PCI, 4880 (21%) had CKD. Compared with normal renal function, patients with CKD had higher risks of death or MI 1-4 years after DES (21% vs 12%, HR=1.75; 95% CI 1.51 to 2.04) or BMS (28% vs 15%, HR=2.10; 95% CI 1.90 to 2.32). In patients with CKD receiving DES, clopidogrel use of more than 12 months after PCI was associated with lower risks of death or MI (18% vs 24%, HR=0.74; 95% CI 0.58 to 0.95), and death (15% vs 23%, HR=0.61; 95% CI 0.47 to 0.80), but had no effect on repeat revascularisation 1-4 years after PCI. Conclusions In patients with CKD, prolonging clopidogrel beyond 12 months after PCI may decrease the risk of death or MI only in patients receiving first-generation DES. These results support a patient-tailored approach to prolonging clopidogrel after PCI. C1 [Siddiqi, Omar K.; Smoot, Kyle J.; Dufour, Alyssa B.; Cho, Kelly; Young, Melissa; Gagnon, David R.; Ly, Samantha; Temiyasathit, Sara; Faxon, David P.; Gaziano, J. Michael; Kinlay, Scott] VA Boston Healthcare Syst, Cardiovasc Div, West Roxbury, MA 02132 USA. [Siddiqi, Omar K.] Boston Med Ctr, Cardiovasc Div, Boston, MA USA. [Smoot, Kyle J.; Dufour, Alyssa B.; Cho, Kelly; Young, Melissa; Gagnon, David R.; Gaziano, J. Michael] Vet Affairs Boston Healthcare Syst, MAVERIC, Boston, MA USA. [Dufour, Alyssa B.; Cho, Kelly; Faxon, David P.; Gaziano, J. Michael; Kinlay, Scott] Harvard Univ, Sch Med, Boston, MA USA. [Dufour, Alyssa B.] Hebrew SeniorLife, Inst Aging Res, Boston, MA USA. [Gagnon, David R.] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Faxon, David P.; Gaziano, J. Michael; Kinlay, Scott] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. RP Kinlay, S (reprint author), VA Boston Healthcare Syst, Cardiovasc Div, 1400 VFW Pkwy, West Roxbury, MA 02132 USA. EM scott.kinlay@va.gov OI Dufour, Alyssa/0000-0001-8061-9599 FU CSRD VA [I01 CX000440]; Intramural VA [VA999999] NR 30 TC 9 Z9 10 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1355-6037 EI 1468-201X J9 HEART JI Heart PD OCT PY 2015 VL 101 IS 19 BP 1569 EP 1576 DI 10.1136/heartjnl-2014-307168 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CR2OB UT WOS:000361168800011 PM 26209334 ER PT J AU Cong, J Fan, TP Yang, XQ Shen, JS Cheng, GM Zhang, Z AF Cong, Juan Fan, Tingpan Yang, Xiaoqian Shen, Jacson Cheng, Guomei Zhang, Zhan TI Maternal cardiac remodeling and dysfunction in preeclampsia: a three-dimensional speckle-tracking echocardiography study SO INTERNATIONAL JOURNAL OF CARDIOVASCULAR IMAGING LA English DT Article DE Preeclampsia; Strain; Three-dimension; Speckle-tracking; Echocardiography ID LEFT-VENTRICULAR FUNCTION; CONSENSUS STATEMENT; SOCIETY; QUANTIFICATION; HYPERTENSION; PREGNANCY; DIAGNOSIS; DISEASE; STRAIN AB Aims preeclampsia (PE) is a pregnancy complication that remains a main cause of maternal morbidity and mortality. The aims of this study were to investigate left ventricle (LV) performance in PE and to compare maternal cardiac function between early-onset preeclampsia (EP) and late-onset preeclampsia (LP) by novel threedimensional (3D) speckle-tracking echocardiography (STE) parameters while considering LV loading and shape. Methods and Results Two-dimensional echocardiography and 3D STE were performed in 43 women with EP, 41 women with LP, and 81 normal pregnancies. Global longitudinal strain (GLS), global circumferential strain (GCS), global area strain (GAS), and global radial strain (GRS) were measured using 3D speckle-tracking software. There was eccentric hypertrophy and reduced LV ejection fraction (EF) in PE; meanwhile, GLS in EP and LP, GCS in LP, as well as GAS and GRS in EP significantly decreased in PE versus controls. All 3D strain indices were correlated with gestation age. Increased left atrial (LA) volume index was detected in PE. Higher LV mass index and lower 3D-derived strain value were present in women with EP compared to that in women with LP. Conclusion PE cases exhibited significant eccentric hypertrophy, ventricular dysfunction, and LA remodeling. Furthermore, myocardial deformation abnormalities preceded chamber dysfunction in this hypertensive disorder complicated pregnancy. Compared with LP, women with EP demonstrated more remarkable cardiac damage. C1 [Cong, Juan; Fan, Tingpan] Zhengzhou Univ, Affiliated Hosp 3, Dept Ultrason Diag, Zhengzhou 450052, Henan Province, Peoples R China. [Cong, Juan; Yang, Xiaoqian; Cheng, Guomei; Zhang, Zhan] Zhengzhou Univ, Affiliated Hosp 3, Dept Obstet & Gynecol, Zhengzhou 450052, Henan Province, Peoples R China. [Cong, Juan; Yang, Xiaoqian; Cheng, Guomei; Zhang, Zhan] Zhengzhou Univ, Affiliated Hosp 3, Henan Prov Engn Res Ctr Perinatal Med, Zhengzhou 450052, Henan Province, Peoples R China. [Cong, Juan; Yang, Xiaoqian; Cheng, Guomei; Zhang, Zhan] Zhengzhou Univ, Affiliated Hosp 3, Henan Translat Med Engn Lab Maternal & Childrens, Zhengzhou 450052, Henan Province, Peoples R China. [Shen, Jacson] Massachusetts Gen Hosp, Dept Orthopaed, Boston, MA 02114 USA. RP Zhang, Z (reprint author), Zhengzhou Univ, Affiliated Hosp 3, Dept Obstet & Gynecol, Zhengzhou 450052, Henan Province, Peoples R China. EM zhangzhanmd27@126.com FU Henan Provincial Health research program [ID_201203048]; Henan Province Medical Academic Technology Leaders of Overseas Training Program [ID_201201055] FX We thank Songyan Liu and Tianwei Zhao for valuable contributions. This work was supported partially by the Henan Provincial Health research program (Grant ID_201203048) and partially by Henan Province Medical Academic Technology Leaders of Overseas Training Program (Grant ID_201201055). NR 24 TC 1 Z9 1 U1 0 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1569-5794 EI 1573-0743 J9 INT J CARDIOVAS IMAG JI Int. J. Cardiovasc. Imaging PD OCT PY 2015 VL 31 IS 7 BP 1361 EP 1368 DI 10.1007/s10554-015-0694-y PG 8 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA CR6YP UT WOS:000361494800011 PM 26077816 ER PT J AU Marshall, DC Punglia, RS Fox, D Recht, A Hattangadi-Gluth, JA AF Marshall, Deborah C. Punglia, Rinaa S. Fox, Dov Recht, Abram Hattangadi-Gluth, Jona A. TI Medical Malpractice Claims in Radiation Oncology: A Population-Based Study 1985-2012 SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID CANCER; RISK; LITIGATION; SYSTEM; REFORM AB Purpose: The purpose of this study was to determine trends in radiation oncology malpractice claims and expenses during the last 28 years and to compare radiation oncology malpractice claims to those of other specialties. Methods and Materials: We performed a retrospective analysis of closed malpractice claims filed from 1985 to 2012, collected by a nationwide medical liability insurance trade association. We analyzed characteristics and trends among closed claims, indemnity payments (payments to plaintiff), and litigation expenses. We also compared radiation oncology malpractice claims to those of 21 other medical specialties. Time series dollar amounts were adjusted for inflation (2012 was the index year). Results: There were 1517 closed claims involving radiation oncology, of which 342 (22.5%) were paid. Average and median indemnity payments were $276,792 and $122,500, respectively, ranking fifth and eighth, respectively, among the 22 specialty groups. Linear regression modeling of time trends showed decreasing total numbers of claims (beta = -1.96 annually, P =. 003), increasing average litigation expenses paid (beta = +$1472 annually, P <= .001), and no significant changes in average indemnity payments (beta = -$ 681, P = . 89). Conclusions: Medical professional liability claims filed against radiation oncologists are not common and have declined in recent years. However, indemnity payments in radiation oncology are large relative to those of many other specialties. In recent years, the average indemnity payment has been stable, whereas litigation expenses have increased. (C) 2015 Elsevier Inc. All rights reserved. C1 [Marshall, Deborah C.; Hattangadi-Gluth, Jona A.] Univ Calif San Diego, Dept Radiat Med & Appl Sci, La Jolla, CA 92093 USA. [Punglia, Rinaa S.] Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Punglia, Rinaa S.; Recht, Abram] Harvard Univ, Sch Med, Boston, MA USA. [Fox, Dov] Univ San Diego, Sch Law, San Diego, CA 92110 USA. [Recht, Abram] Beth Israel Deaconess Med Ctr, Dept Radiat Oncol, Boston, MA 02215 USA. RP Hattangadi-Gluth, JA (reprint author), Univ Calif San Diego, Moores Canc Ctr, Dept Radiat Med & Appl Sci, 3960 Hlth Sci Dr,Mail Code 0865, La Jolla, CA 92093 USA. EM jhattangadi@ucsd.edu FU Joint Center for Radiation Therapy Foundation; US National Institutes of Health [TL1TR00098, KL2TR00099, UL1TR000100] FX Supported in part by the Joint Center for Radiation Therapy Foundation (J.A.H-G.), US National Institutes of Health grants TL1TR00098 (D.M.), KL2TR00099 (J.A.H-G.), and UL1TR000100 (J.A.H-G.). NR 35 TC 0 Z9 0 U1 0 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD OCT 1 PY 2015 VL 93 IS 2 BP 241 EP 250 DI 10.1016/j.ijrobp.2015.05.040 PG 10 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA CR3RF UT WOS:000361250100004 PM 26232856 ER PT J AU Rosenthal, SA Hunt, D Sartor, O Pienta, KJ Gomella, L Grignon, D Rajan, R Kerlin, KJ Jones, CU Dobelbower, M Shipley, WU Zeitzer, K Hamstra, DA Donavanik, V Rotman, M Hartford, AC Michalski, J Seider, M Kim, H Kuban, DA Moughan, J Sandler, H AF Rosenthal, Seth A. Hunt, Daniel Sartor, Oliver Pienta, Kenneth J. Gomella, Leonard Grignon, David Rajan, Raghu Kerlin, Kevin J. Jones, Christopher U. Dobelbower, Michael Shipley, William U. Zeitzer, Kenneth Hamstra, Daniel A. Donavanik, Viroon Rotman, Marvin Hartford, Alan C. Michalski, Jeffrey Seider, Michael Kim, Harold Kuban, Deborah A. Moughan, Jennifer Sandler, Howard TI A Phase 3 Trial of 2 Years of Androgen Suppression and Radiation Therapy With or Without Adjuvant Chemotherapy for High-Risk Prostate Cancer: Final Results of Radiation Therapy Oncology Group Phase 3 Randomized Trial NRG Oncology RTOG 9902 SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID GROUP PROTOCOL 92-02; ORAL ETOPOSIDE; COMPETING RISK; III TRIAL; RADIOTHERAPY; DEPRIVATION; DURATION; ESTRAMUSTINE; PACLITAXEL; CARCINOMA AB Purpose: Long-term (LT) androgen suppression (AS) with radiation therapy (RT) is a standard treatment of high-risk, localized prostate cancer (PCa). Radiation Therapy Oncology Group 9902 was a randomized trial testing the hypothesis that adjuvant combination chemotherapy (CT) with paclitaxel, estramustine, and oral etoposide plus LT AS plus RT would improve overall survival (OS). Methods and Materials: Patients with high-risk PCa (prostate-specific antigen 20100 ng/mL and Gleason score [GS] >= 7 or clinical stage >= T2 and GS >= 8) were randomized to RT and AS (AS + RT) alone or with adjuvant CT (AS + RT + CT). CT was given as four 21-day cycles, delivered beginning 28 days after 70.2 Gy of RT. AS was given as luteinizing hormone-releasing hormone for 24 months, beginning 2 months before RT plus an oral antiandrogen for 4 months before and during RT. The study was designed based on a 6% improvement in OS from 79% to 85% at 5 years, with 90% power and a 2-sided alpha of 0.05. Results: A total of 397 patients (380 eligible) were randomized. The patients had high-risk PCa, 68% with GS 8 to 10 and 34% T3 to T4 tumors, and median prostate-specific antigen of 22.6 ng/mL. The median follow-up period was 9.2 years. The trial closed early because of excess thromboembolic toxicity in the CT arm. The 10-year results for all randomized patients revealed no significant difference between the AS + RT and AS + RT + CT arms in OS (65% vs 63%; P = . 81), biochemical failure (58% vs 54%; P = . 82), local progression (11% vs 7%; P = . 09), distant metastases (16% vs 14%; P = . 42), or disease-free survival (22% vs 26%; P = . 61). Conclusions: NRG Oncology RTOG 9902 showed no significant differences in OS, biochemical failure, local progression, distant metastases, or disease-free survival with the addition of adjuvant CT to LT AS + RT. The trial results provide valuable data regarding the natural history of high-risk PCa treated with LT AS + RT and have implications for the feasibility of clinical trial accrual and tolerability using CT for PCa. (C) 2015 Elsevier Inc. All rights reserved. C1 [Rosenthal, Seth A.; Jones, Christopher U.] Sutter Canc Cent, Radiat Oncol, Roseville, CA USA. [Hunt, Daniel; Moughan, Jennifer] NRG Oncol Stat & Data Management Ctr, Philadelphia, PA USA. [Sartor, Oliver] Tulane Univ, Med Ctr, New Orleans, LA USA. [Pienta, Kenneth J.] Johns Hopkins Sch Med, Baltimore, MD USA. [Gomella, Leonard] Thomas Jefferson Univ Hosp, Philadelphia, PA USA. [Grignon, David] Indiana Univ, Bloomington, IN USA. [Rajan, Raghu] McGill Univ, Montreal, PQ, Canada. [Kerlin, Kevin J.] Southeast Canc Control Consortium Inc, Community Clin Oncol Program, Winston Salem, NC USA. [Jones, Christopher U.] Radiol Associates Sacramento, Sacramento, CA USA. [Dobelbower, Michael] Univ Alabama Birmingham, Birmingham Med Ctr, Birmingham, AL USA. [Shipley, William U.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Shipley, William U.] Harvard Univ, Sch Med, Boston, MA USA. [Zeitzer, Kenneth] Albert Einstein Med Ctr, Bronx, NY USA. [Hamstra, Daniel A.] Univ Michigan, Med Ctr, Ann Arbor, MI USA. [Donavanik, Viroon] Christiana Care Hlth Serv Inc, Wilmington, DE USA. [Rotman, Marvin] SUNY Hlth Sci Ctr, Brooklyn, NY USA. [Hartford, Alan C.] Dartmouth Hitchcock Med Ctr, Lebanon, NH USA. [Michalski, Jeffrey] Washington Univ, St Louis, MO USA. [Seider, Michael] Akron City Hosp, Akron, OH USA. [Kim, Harold] Wayne State Univ, Detroit, MI USA. [Kuban, Deborah A.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Sandler, Howard] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. RP Rosenthal, SA (reprint author), Sutter Med Grp, Roseville Radiat Oncol, 2 Med Plaza,Suite 180, Roseville, CA 95661 USA. EM rosents@sutterhealth.org FU National Cancer Institute [RTOG U10CA21661, NRG U10CA180868, NRG U10CA180822]; Bristol Myers Squibb; Pfizer FX This project was supported by grants RTOG U10CA21661, NRG U10CA180868, and NRG U10CA180822 from the National Cancer Institute, and by Bristol Myers Squibb and Pfizer. NR 23 TC 9 Z9 9 U1 0 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD OCT 1 PY 2015 VL 93 IS 2 BP 294 EP 302 DI 10.1016/j.ijrobp.2015.05.024 PG 9 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA CR3RF UT WOS:000361250100011 PM 26209502 ER PT J AU Lam, TC Uno, H Krishnan, M Lutz, S Groff, M Cheney, M Balboni, T AF Lam, Tai-Chung Uno, Hajime Krishnan, Monica Lutz, Steven Groff, Michael Cheney, Matthew Balboni, Tracy TI Adverse Outcomes After Palliative Radiation Therapy for Uncomplicated Spine Metastases: Role of Spinal Instability and Single-Fraction Radiation Therapy SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID PAINFUL BONE METASTASES; ONCOLOGY STUDY-GROUP; RANDOMIZED-TRIAL; 8 GY; MULTIPLE FRACTIONS; NEOPLASTIC SCORE; RADIOTHERAPY TRIALS; CANCER; RELIABILITY; SURVIVAL AB Purpose: Level I evidence demonstrates equivalent pain response after single-fraction (SF) or multifraction (MF) radiation therapy (RT) for bone metastases. The purpose of this study is to provide additional data to inform the incidence and predictors of adverse outcomes after RT for spine metastases. Methods and Materials: At a single institution, 299 uncomplicated spine metastases (without cord compression, prior RT, or surgery) treated with RT from 2008 to 2013 were retrospectively reviewed. The spinal instability neoplastic score (SINS) was used to assess spinal instability. The primary outcome was time to first spinal adverse event (SAE) at the site, including symptomatic vertebral fracture, hospitalization for site-related pain, salvage surgery, interventional procedure, new neurologic symptoms, or cord compression. Fine and Gray's multivariable model assessed associations of the primary outcome with SINS, SF RT, and other significant baseline factors. Propensity score matched analysis further assessed the relationship of SF RT to first SAEs. Results: The cumulative incidence of first SAE after SF RT (n=66) was 6.8% at 30 days, 16.9% at 90 days, and 23.6% at 180 days. For MF RT (n=233), the incidence was 3.5%, 6.4%, and 9.2%, respectively. In multivariable analysis, SF RT (hazard ratio [HR] Z 2.8, 95% confidence interval [CI] 1.5-5.2, P=.001) and SINS >= 11 (HRZ2.5, 95% CI 1.3-4.9, P=.007) were predictors of the incidence of first SAE. In propensity score matched analysis, first SAEs had developed in 22% of patients with SF RT versus 6% of those with MF RT cases (HRZ3.9, 95% CI 1.6-9.6, P=.003) at 90 days after RT. Conclusion: In uncomplicated spinal metastases treated with RT alone, spinal instability with SINS >= 11 and SF RT were associated with a higher rate of SAEs. (C) 2015 Elsevier Inc. All rights reserved. C1 [Lam, Tai-Chung; Krishnan, Monica; Balboni, Tracy] Dana Farber Brigham & Womens Canc Ctr, Dept Radiat Oncol, Boston, MA 02215 USA. [Uno, Hajime] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Lutz, Steven] Blanchard Valley Reg Med Ctr, Dept Radiat Oncol, Findlay, OH USA. Brigham & Womens Hosp, Dept Neurosurg, Boston, MA 02115 USA. [Cheney, Matthew] Dana Farber Canc Inst, Harvard Radiat Oncol Program, Boston, MA 02115 USA. [Balboni, Tracy] Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, Boston, MA 02115 USA. RP Lam, TC (reprint author), Dana Farber Brigham & Womens Canc Ctr, Dept Radiat Oncol, 450 Brookline Ave,DA 1101, Boston, MA 02215 USA. EM lamtaichung@gmail.com OI Cheney, Matthew/0000-0001-8367-3427 FU American Society of Clinical Oncology Conquer Cancer Foundation Career Development Award FX Supported in part by an American Society of Clinical Oncology Conquer Cancer Foundation Career Development Award to Dr T. Balboni. NR 25 TC 3 Z9 4 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD OCT 1 PY 2015 VL 93 IS 2 BP 373 EP 381 DI 10.1016/j.ijrobp.2015.06.006 PG 9 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA CR3RF UT WOS:000361250100021 PM 26279324 ER PT J AU Pulsifer, MB Sethi, RV Kuhlthau, KA MacDonald, SM Tarbell, NJ Yock, TI AF Pulsifer, Margaret B. Sethi, Roshan V. Kuhlthau, Karen A. MacDonald, Shannon M. Tarbell, Nancy J. Yock, Torunn I. TI Early Cognitive Outcomes Following Proton Radiation in Pediatric Patients With Brain and Central Nervous System Tumors SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID CRANIOSPINAL IRRADIATION; CLINICAL-OUTCOMES; NEUROCOGNITIVE CONSEQUENCES; ONCOLOGY-GROUP; GRADE GLIOMA; THERAPY; MEDULLOBLASTOMA; CHILDHOOD; SURVIVORS; RADIOTHERAPY AB Purpose: To report, from a longitudinal study, cognitive outcome in pediatric patients treated with proton radiation therapy (PRT) for central nervous system (CNS) tumors. Methods and Materials: Sixty patients receiving PRT for medulloblastoma (38.3%), gliomas (18.3%), craniopharyngioma (15.0%), ependymoma (11.7%), and other CNS tumors (16.7%) were administered age-appropriate measures of cognitive abilities at or near PRT initiation (baseline) and afterward (follow-up). Patients were aged >= 6 years at baseline to ensure consistency in neurocognitive measures. Results: Mean age was 12.3 years at baseline; mean follow-up interval was 2.5 years. Treatment included prior surgical resection (76.7%) and chemotherapy (61.7%). Proton radiation therapy included craniospinal irradiation (46.7%) and partial brain radiation (53.3%). At baseline, mean Wechsler Full Scale IQ was 104.6; means of all 4 Index scores were also in the average range. At follow-up, no significant change was observed in mean Wechsler Full Scale IQ, Verbal Comprehension, Perceptual Reasoning/Organization, or Working Memory. However, Processing Speed scores declined significantly (mean 5.2 points), with a significantly greater decline for subjects aged <12 years at baseline and those with the highest baseline scores. Cognitive outcome was not significantly related to gender, extent of radiation, radiation dose, tumor location, histology, socioeconomic status, chemotherapy, or history of surgical resection. Conclusions: Early cognitive outcomes after PRT for pediatric CNS tumors are encouraging, compared with published outcomes from photon radiation therapy. (C) 2015 Elsevier Inc. All rights reserved. C1 [Pulsifer, Margaret B.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Sethi, Roshan V.; MacDonald, Shannon M.; Tarbell, Nancy J.; Yock, Torunn I.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Kuhlthau, Karen A.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. RP Pulsifer, MB (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Psychol Assessment Ctr, One Bowdoin Sq,7th Floor, Boston, MA 02114 USA. EM mpulsifer@mgh.harvard.edu FU National Cancer Institute [P01CA021239]; Federal Share of program, Proton Therapy Research and Treatment Center [C06 CA059267] FX The project described was supported by award no. P01CA021239 from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.; The project was supported by the Federal Share of program income earned by Massachusetts General Hospital (MGH) on C06 CA059267, Proton Therapy Research and Treatment Center. NR 34 TC 10 Z9 10 U1 3 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD OCT 1 PY 2015 VL 93 IS 2 BP 400 EP 407 DI 10.1016/j.ijrobp.2015.06.012 PG 8 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA CR3RF UT WOS:000361250100024 PM 26254679 ER PT J AU Miller, PE Martin, SS Toth, PP Santos, RD Blaha, MJ Nasir, K Virani, SS Post, WS Blumenthal, RS Jones, SR AF Miller, P. Elliott Martin, Seth S. Toth, Peter P. Santos, Raul D. Blaha, Michael J. Nasir, Khurram Virani, Salim S. Post, Wendy S. Blumenthal, Roger S. Jones, Steven R. TI Screening and advanced lipid phenotyping in familial hypercholesterolemia: The Very Large Database of Lipids Study-17 (VLDL-17) SO JOURNAL OF CLINICAL LIPIDOLOGY LA English DT Article DE Familial hypercholesterolethia; Screening; Lipid phenotyping; Friedewald equation; Low-density lipoprotein cholesterol; Lipoprotein(a); Remnant lipoprotein cholesterol ID DENSITY-LIPOPROTEIN CHOLESTEROL; ASSOCIATION EXPERT PANEL; ISCHEMIC-HEART-DISEASE; REMNANT CHOLESTEROL; GENERAL-POPULATION; UNITED-STATES; DIAGNOSIS; MANAGEMENT; GUIDANCE; RISK AB BACKGROUND: Familial hypercholesterolernia (FH) is an autosomal dominant dyslipidemia characterized by defective low-density lipoprotein (LDL) clearance. The aim of this study was to compare Friedewald-estimated LDL cholesterol (LDL-C) to biologic LDL-C in individuals screening positive for FH and then further characterize FH phenotypes. METHODS: We studied 1,320,581 individuals from the Very Large Database of Lipids, referred from 2009 to 2011 for Vertical Auto Profile ultracentrifugation testing. Friedewald LDL-C was defined as the cholesterol content of LDL-C, intermediate-density lipoprotein cholesterol, and lipoprotein(a) cholesterol (Lp(a)-C), with LDL-C representing biologic LDL-C. Using Friedewald LDL-C, we phenotypically categorized patients by the National Lipid Association guideline age-based screening thresholds for FH. In those meeting criteria, we categorized patients using population percentile-equivalent biologic LDL-C cutpoints and explored Lp(a)-C and remnant lipoprotein cholesterol (RLP-C) levels. RESULTS: Overall, 3829 patients met phenotypic criteria for FH by Friedewald LDL-C screening (FH+). Of those screening FH+, 78.8% were above and 21.2% were below the population percentile-equivalent biologic LDL-C. The mean difference in Friedewald biologic LDL-C percentiles was -0.01 (standard deviation, 0.17) for those above, and 1.92 (standard deviation, 9.16) for those below, respectively. Over 1 of 3 were found to have an elevated Lp(a)-C and over 50% had RLP-C greater than 95th percentile of the entire VLDL population CONCLUSIONS: Of those who screened FH+, Friedewald and biologic LDL-C levels were closely correlated. Large proportions of the FH+ group had excess levels of Lp(a)-C and RLP-C. Future C1 [Miller, P. Elliott; Martin, Seth S.; Toth, Peter P.; Blaha, Michael J.; Post, Wendy S.; Blumenthal, Roger S.; Jones, Steven R.] Johns Hopkins Ciccarone Ctr Prevent Heart Dis, Baltimore, MD USA. [Toth, Peter P.] CGH Med Ctr, Dept Prevent Cardiol, Sterling, IL USA. [Toth, Peter P.] Univ Illinois, Coll Med, Peoria, IL 61656 USA. [Santos, Raul D.] InCor Univ Sao Paulo, Lipid Clin Heart Inst, Prevent Med Ctr, Hosp Israelita Albert Einstein,Med Sch Hosp, Sao Paulo, Brazil. [Nasir, Khurram] Ctr Prevent & Wellness Res, Baptist Hlth Med Grp, Miami, FL USA. [Virani, Salim S.] Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Sect Cardiovasc Res, Houston, TX 77030 USA. RP Miller, PE (reprint author), Johns Hopkins Univ Hosp, Dept Med, 600 N Wolfe St, Baltimore, MD 21287 USA. EM elliottmiller@jhmi.edu RI Santos, Raul/A-1170-2010; OI Santos, Raul/0000-0002-9860-6582; Virani, Salim/0000-0001-9541-6954 FU Pollin Cardiovascular Prevention Fellowship; Marie-Josee and Henry R. Kravis endowed fellowship; National Institutes of Health [T32HL07024]; US Food and Drug Administration; Department of Veterans Affairs; American Heart Association; American Diabetes Association FX S.S.M. is supported by the Pollin Cardiovascular Prevention Fellowship, Marie-Josee and Henry R. Kravis endowed fellowship, and a National Institutes of Health training grant (T32HL07024). The article has no funding.; Dr Martin and Dr Jones are listed as coinventors on a pending patent filed by Johns Hopkins University for a method of low-density lipoprotein cholesterol estimation. Dr Blaha reports pending grant funding from the National Institutes of Health and the US Food and Drug Administration and participating in a roundtable discussion with Regeneron. Dr Virani reports having received research funding from the Department of Veterans Affairs, American Heart Association, and the American Diabetes Association. Dr Toth serves on the medical advisory board for Atherotech Diagnostic Lab and has received compensation for consultancy and lecturers from Abbvie, Aegerion, Amgen, AstraZeneca, Glaxo-SmithKline, Kowa, and Merck & Co, Novartis, and Regeneron. Dr Jones serves on the medical advisory board for Atherotech Diagnostic Lab and as an advisor to Sanofi and Regeneron. Dr Santos has received honoraria for consulting and speaker activities from AstraZeneca, Amgen, Biolab, Boehringher-Ingelheim, Bristol Myers Squibb, Eli-Lilly, Jansen, Merck, Novartis, Pfizer, Praxis, Sanofi/Regeneron, Unilever. NR 36 TC 4 Z9 4 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1933-2874 EI 1876-4789 J9 J CLIN LIPIDOL JI J. Clin. Lipidol. PD OCT PY 2015 VL 9 IS 5 BP 676 EP 683 DI 10.1016/j.jacl.2015.06.015 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CR5WQ UT WOS:000361415500009 PM 26350814 ER PT J AU Forman, MS Chuang, SK August, M AF Forman, Michael S. Chuang, Sung-Kiang August, Meredith TI The Accuracy of Clinical Diagnosis of Oral Lesions and Patient-Specific Risk Factors that Affect Diagnosis SO JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Article ID DENTAL PRACTITIONERS; CARCINOMA AB Purpose: To examine the rate of discrepancy between clinical impression and histologic diagnosis of oral lesions in patients undergoing biopsy examination and to determine whether there are patient-specific variables associated with a higher rate of discrepancy. Materials and Methods: The authors designed and implemented a retrospective cohort study that consisted of patients who underwent biopsy examination of oral lesions from 2005 through 2013 by oral and maxillofacial surgeons at the Massachusetts General Hospital. Accuracy was determined by comparing the clinical impression with the final histologic diagnosis. Clinical and histologic diagnoses were categorized as premalignant or malignant (group 1) or benign (group 2). The primary outcome variable was concordance (yes vs no) between clinical impression and histopathologic diagnosis. The effect of individual predictor variables (age, gender, duration, American Society of Anesthesiology status, cancer history, radiation therapy history, medications, alcohol abuse, and tobacco history) on outcome also was evaluated through univariate and multivariate regression analyses. Results: The study sample was composed of 1,003 oral lesions (74 pathologically confirmed premalignant or malignant and 929 benign) from patients with a mean age of 44.8 years. Of the lesions evaluated, concordance between exact clinical and histologic diagnoses was found in 61% of cases. Overall, the clinical impression, reported as benign versus premalignant or malignant, was 48.6% sensitive and 98.1% specific. Clinicians accurately identified lesions as benign in 95.9% of cases. The most common of these were fibromas (positive predictive value [PPV], 99.2%), mucoceles (PPV, 98.1%), and squamous papillomas (PPV, 96.3%). Several independent risk factors were associated with discrepancy: radiation therapy history (P = .0102), male gender (P = .0381), and patient age (P = .0468). Conclusion: The results of this study suggest that the clinical impression, although highly accurate for common benign conditions, is not an acceptable alternative to definitive biopsy findings in other cases, particularly in cases of premalignancy or malignancy. In addition, patients with identified independent risk factors (age, gender, and radiation therapy) should receive timely biopsy examination. (C) 2015 American Association of Oral and Maxillofacial Surgeons C1 [Forman, Michael S.; Chuang, Sung-Kiang; August, Meredith] Harvard Univ, Sch Dent Med, Boston, MA 02115 USA. [Chuang, Sung-Kiang; August, Meredith] Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Boston, MA 02114 USA. RP August, M (reprint author), Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, 55 Fruit St, Boston, MA 02114 USA. EM maugust@partners.org FU Department of Oral and Maxillofacial Surgery, Massachusetts General Hospital; Harvard Medical School Scholars in Medicine Office; Oral and Maxillofacial Surgery Foundation FX This study was funded by the Education and Research Fund, Department of Oral and Maxillofacial Surgery, Massachusetts General Hospital and the Harvard Medical School Scholars in Medicine Office.; This investigation was supported (in part) by a Student Research Training Award from the Oral and Maxillofacial Surgery Foundation. NR 12 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 0278-2391 EI 1531-5053 J9 J ORAL MAXIL SURG JI J. Oral Maxillofac. Surg. PD OCT PY 2015 VL 73 IS 10 BP 1932 EP 1937 DI 10.1016/j.joms.2015.04.026 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA CR3MO UT WOS:000361237300016 PM 25981860 ER PT J AU Peacock, ZS Magill, JC Tricomi, BJ Murphy, BA Nikonovskiy, V Hata, N Chauvin, L Troulis, MJ AF Peacock, Zachary S. Magill, John C. Tricomi, Brad J. Murphy, Brian A. Nikonovskiy, Vladimir Hata, Nobuhiko Chauvin, Laurent Troulis, Maria J. TI Assessment of the OsteoMark-Navigation System for Oral and Maxillofacial Surgery SO JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Article ID DISTRACTION OSTEOGENESIS; MANDIBULAR DISTRACTION; ORTHOGNATHIC SURGERY; SURGICAL NAVIGATION; RECONSTRUCTION; EXPERIENCE; NEURONAVIGATION; ACCURACY; GUIDE; HEAD AB Purpose: To assess the accuracy of a novel navigation system for maxillofacial surgery using human cadavers and a live minipig model. Materials and Methods: We tested an electromagnetic tracking system (OsteoMark-Navigation) that uses simple sensors to determine the position and orientation of a hand-held pencil-like marking device. The device can translate 3-dimensional computed tomographic data intraoperatively to allow the surgeon to localize and draw a proposed osteotomy or the resection margins of a tumor on bone. The accuracy of the OsteoMark-Navigation system in locating and marking osteotomies and screw positions in human cadaver heads was assessed. In group 1 (n = 3, 6 sides), OsteoMark-Navigation marked osteotomies and screw positions were compared to virtual treatment plans. In group 2 (n = 3, 6 sides), marked osteotomies and screw positions for distraction osteogenesis devices were compared with those performed using fabricated guide stents. Three metrics were used to document the precision and accuracy. In group 3 (n = 1), the system was tested in a standard operating room environment. Results: For group 1, the mean error between the points was 0.7 mm (horizontal) and 1.7 mm (vertical). Compared with the posterior and inferior mandibular border, the mean error was 1.2 and 1.7 mm, respectively. For group 2, the mean discrepancy between the points marked using the OsteoMark-Navigation system and the surgical guideswas 1.9 mm (range 0 to 4.1). The system maintained accuracy on a live minipig in a standard operating room environment. Conclusion: Based on this research OsteoMark-Navigation is a potentially powerful tool for clinical use in maxillofacial surgery. It has accuracy and precision comparable to that of existing clinical applications. (C) 2015 American Association of Oral and Maxillofacial Surgeons C1 [Peacock, Zachary S.; Troulis, Maria J.] Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Boston, MA 02114 USA. [Magill, John C.; Murphy, Brian A.; Nikonovskiy, Vladimir] Phys Sci Inc, Andover, MA USA. [Tricomi, Brad J.] Univ Massachusetts, Boston, MA 02125 USA. [Tricomi, Brad J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hata, Nobuhiko] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Hata, Nobuhiko; Chauvin, Laurent] Brigham & Womens Hosp, Surg Nav & Robot Lab, Boston, MA 02115 USA. RP Peacock, ZS (reprint author), Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Warren Bldg 1201,55 Fruit St, Boston, MA 02114 USA. EM zpeacock@partners.org FU National Institutes of Health/National Institute of Dental and Craniofacial Research Small Business Innovation Research [5R44DE019047-03]; Massachusetts General Hospital Department of Oral and Maxillofacial Surgery Education and Research Fund; Hanson Foundation (Boston, MA) FX This work was funded by the National Institutes of Health/National Institute of Dental and Craniofacial Research Small Business Innovation Research (grant 5R44DE019047-03), the Massachusetts General Hospital Department of Oral and Maxillofacial Surgery Education and Research Fund, and the Hanson Foundation (Boston, MA). NR 28 TC 1 Z9 1 U1 1 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0278-2391 EI 1531-5053 J9 J ORAL MAXIL SURG JI J. Oral Maxillofac. Surg. PD OCT PY 2015 VL 73 IS 10 BP 2005 EP 2016 DI 10.1016/j.joms.2015.03.017 PG 12 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA CR3MO UT WOS:000361237300028 PM 25865717 ER PT J AU Susarla, SM Swanson, EW Lopez, J Peacock, ZS Dodson, TB AF Susarla, Srinivas M. Swanson, Edward W. Lopez, Joseph Peacock, Zachary S. Dodson, Thomas B. TI Does Self-Citation Influence Quantitative Measures of Research Productivity Among Academic Oral and Maxillofacial Surgeons? SO JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Article ID H-INDEX; UNITED-STATES; IMPACT FACTOR; JOURNALS; PUBLICATION; RADIOLOGY AB Purpose: Quantitative measures of research productivity depend on the citation frequency of a publication. Citation-based metrics, such as the h-index (total number of publications h that have at least h citations), can be susceptible to self-citation, resulting in an inflated measure of research productivity. The purpose of the present study was to estimate the effect of self-citation on the h-index among academic oral and maxillofacial surgeons (OMSs). Materials and Methods: The present study was a cross-sectional study of full-time academic OMSs in the United States. The predictor variable was the frequency of self-citation. The primary outcome of interest was the h-index. Other study variables included demographic factors and citation metrics. Descriptive, bivariate, and regression statistics were computed. Results: The study sample consisted of 325 full-time academic OMSs. Most surgeons were men (88.3%); approximately 40% had medical degrees. The study subjects had an average of 23.5 +/- 37.1 publications. The mean number of self-citations was 15 + 56. The sample's mean h-index was 6.6 +/- 7.6 and was associated with self-citation (r = 0.71, P < .001). Approximately 9% of subjects had a change in their h-index after removing self-citations. After adjusting for PhD degree, total number of publications, and academic rank, an increasing self-citation rate influenced the h-index (r = 0.006, P < .001). Surgeons with more than 14 self-citations were more likely to have their h-index influenced by self-citation. Conclusion: Self-citation among full-time academic OMSs does not substantially affect the h-index. Surgeons in the top quartile of self-citation rates are more likely to influence their h-index. (C) 2015 American Association of Oral and Maxillofacial Surgeons C1 [Susarla, Srinivas M.; Swanson, Edward W.; Lopez, Joseph] Johns Hopkins Univ Hosp, Dept Plast & Reconstruct Surg, Baltimore, MD 21287 USA. [Peacock, Zachary S.] Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Boston, MA 02114 USA. [Peacock, Zachary S.] Harvard Univ, Sch Dent Med, Boston, MA 02115 USA. [Dodson, Thomas B.] Univ Washington, Sch Dent, Dept Oral & Maxillofacial Surg, Seattle, WA 98195 USA. RP Susarla, SM (reprint author), Johns Hopkins Univ Hosp, Dept Plast & Reconstruct Surg, 601 North Caroline St,JHOC8, Baltimore, MD 21287 USA. EM ssusarl1@jhmi.edu OI Susarla, Srinivas/0000-0003-0155-8260 NR 25 TC 0 Z9 0 U1 3 U2 10 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0278-2391 EI 1531-5053 J9 J ORAL MAXIL SURG JI J. Oral Maxillofac. Surg. PD OCT PY 2015 VL 73 IS 10 DI 10.1016/j.joms.2015.05.018 PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA CR3MO UT WOS:000361237300024 ER PT J AU Chua, AS Egorova, S Anderson, MC Polgar-Turcsanyi, M Chitnis, T Weiner, HL Guttmann, CRG Bakshi, R Healy, BC AF Chua, Alicia S. Egorova, Svetlana Anderson, Mark C. Polgar-Turcsanyi, Mariann Chitnis, Tanuja Weiner, Howard L. Guttmann, Charles R. G. Bakshi, Rohit Healy, Brian C. TI Using multiple imputation to efficiently correct cerebral MRI whole brain lesion and atrophy data in patients with multiple sclerosis SO NEUROIMAGE LA English DT Article DE Multiple sclerosis; Multiple imputation; Magnetic resonance imaging; Brain atrophy; T2 hyperintense lesion; Missing data ID MAGNETIC-RESONANCE TECHNIQUES; QUANTITATIVE-ANALYSIS; MISSING DATA; IMPAIRMENT; DISABILITY; BURDEN; AIDS; EDSS AB Automated segmentation of brain MRI scans into tissue classes is commonly used for the assessment of multiple sclerosis (MS). However, manual correction of the resulting brain tissue label maps by an expert reader remains necessary in many cases. Since automated segmentation data awaiting manual correction are "missing", we proposed to use multiple imputation (MI) to fill-in the missing manually-corrected MRI data for measures of normalized whole brain volume (brain parenchymal fraction-BPF) and T2 hyperintense lesion volume (T2LV). Automated and manually corrected MRI measures from 1300 patients enrolled in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brighamand Women's Hospital (CLIMB) were identified. Simulation studies were conducted to assess the performance of MI with missing data both missing completely at random and missing at random. An imputation model including the concurrent automated data as well as clinical and demographic variables explained a high proportion of the variance in the manually corrected BPF (R-2 = 0.97) and T2LV (R-2 = 0.89), demonstrating the potential to accurately impute the missing data. Further, our results demonstrate that MI allows for the accurate estimation of group differences with little to no bias and with similar precision compared to an analysis with no missing data. We believe that our findings provide important insights for efficient correction of automated MRI measures to obviate the need to perform manual correction on all cases. (C) 2015 Elsevier Inc. All rights reserved. C1 [Chua, Alicia S.; Egorova, Svetlana; Anderson, Mark C.; Polgar-Turcsanyi, Mariann; Chitnis, Tanuja; Weiner, Howard L.; Guttmann, Charles R. G.; Bakshi, Rohit; Healy, Brian C.] Brigham & Womens Hosp, Partners Multiple Sclerosis Ctr, Boston, MA 02115 USA. [Egorova, Svetlana; Chitnis, Tanuja; Weiner, Howard L.; Bakshi, Rohit; Healy, Brian C.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Healy, Brian C.] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Guttmann, Charles R. G.; Bakshi, Rohit] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. RP Healy, BC (reprint author), Brigham & Womens Hosp, Partners MS Ctr, 1 Brookline Pl,Suite 602, Brookline, MA 02445 USA. EM bchealy@partners.org OI Egorova, Svetlana/0000-0002-9873-092X FU Nancy Davis Foundation; Merck Serono S.A. FX We would like to thank the reviewers for their constructive comments. The CLIMB study is funded in part by the Nancy Davis Foundation and Merck Serono S.A. NR 29 TC 0 Z9 0 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD OCT 1 PY 2015 VL 119 BP 81 EP 88 DI 10.1016/j.neuroimage.2015.06.037 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA CR2TB UT WOS:000361182400009 PM 26093330 ER PT J AU Wood, KH Wheelock, MD Shumen, JR Bowen, KH Hoef, LWV Knight, DC AF Wood, Kimberly H. Wheelock, Muriah D. Shumen, Joshua R. Bowen, Kenton H. Hoef, Lawrence W. Ver Knight, David C. TI Controllability modulates the neural response to predictable but not unpredictable threat in humans SO NEUROIMAGE LA English DT Article DE Prefrontal cortex; Hippocampus; Controllability; Predictability; Stress resilience ID POSTTRAUMATIC-STRESS-DISORDER; FEAR-POTENTIATED STARTLE; MEDIAL PREFRONTAL CORTEX; DORSAL RAPHE NUCLEUS; SKIN-CONDUCTANCE RESPONSE; INDIVIDUAL-DIFFERENCES; BRAIN ACTIVITY; PERCEIVED CONTROLLABILITY; PHYSIOLOGICAL CONDITION; CONDITIONED DIMINUTION AB Stress resilience is mediated, in part, by our ability to predict and control threats within our environment. Therefore, determining the neural mechanisms that regulate the emotional response to predictable and controllable threats may provide important new insight into the processes that mediate resilience to emotional dysfunction and guide the future development of interventions for anxiety disorders. To better understand the effect of predictability and controllability on threat-related brain activity in humans, two groups of healthy volunteers participated in a yoked Pavlovian fear conditioning study during functional magnetic resonance imaging (fMRI). Threat predictability was manipulated by presenting an aversive unconditioned stimulus (UCS) that was either preceded by a conditioned stimulus (i.e., predictable) or by presenting the UCS alone (i.e., unpredictable). Similar to animal model research that has employed yoked fear conditioning procedures, one group (controllable condition; CC), but not the other group (uncontrollable condition; UC) was able to terminate the UCS. The fMRI signal response within the dorsolateral prefrontal cortex (PFC), dorsomedial PFC, ventromedial PFC, and posterior cingulate was diminished during predictable compared to unpredictable threat (i.e., UCS). In addition, threat-related activity within the ventromedial PFC and bilateral hippocampus was diminished only to threats that were both predictable and controllable. These findings provide insight into how threat predictability and controllability affects the activity of brain regions (i.e., ventromedial PFC and hippocampus) involved in emotion regulation, and may have important implications for better understanding neural processes that mediate emotional resilience to stress. (C) 2015 Elsevier Inc. All rights reserved. C1 [Wood, Kimberly H.; Wheelock, Muriah D.; Shumen, Joshua R.; Bowen, Kenton H.; Knight, David C.] Univ Alabama Birmingham, Dept Psychol, Birmingham, AL 35294 USA. [Hoef, Lawrence W. Ver] Univ Alabama Birmingham, Dept Neurol, Birmingham, AL 35294 USA. [Hoef, Lawrence W. Ver] Birmingham VA Med Ctr, Birmingham, AL 35294 USA. RP Knight, DC (reprint author), CIRC 235H,1720 2nd Ave S, Birmingham, AL 35294 USA. EM knightdc@uab.edu FU National Institutes of Health [MH098348] FX This research was supported by National Institutes of Health grant MH098348 (DCK). NR 108 TC 3 Z9 4 U1 10 U2 19 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD OCT 1 PY 2015 VL 119 BP 371 EP 381 DI 10.1016/j.neuroimage.2015.06.086 PG 11 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA CR2TB UT WOS:000361182400036 PM 26149610 ER PT J AU Cardenas, DP Muir, ER Huang, SL Boley, A Lodge, D Duong, TQ AF Cardenas, Damon P. Muir, Eric R. Huang, Shiliang Boley, Angela Lodge, Daniel Duong, Timothy Q. TI Functional MRI during hyperbaric oxygen: Effects of oxygen on neurovascular coupling and BOLD fMRI signals SO NEUROIMAGE LA English DT Article DE Forepaw stimulation; CBF; Oxygen therapy; BOLD ID CEREBRAL-BLOOD-FLOW; BRAIN; HYPEROXIA; HYPOXIA; HYPERCAPNIA; PERFUSION; TENSION; DISEASE AB Hyperbaric oxygen (HBO) therapy is used to treat a number of ailments. Improved understanding of how HBO affects neuronal activity, cerebral blood flow (CBF) and blood-oxygenation-level dependent (BOLD) changes could shed light on the role of oxygen in neurovascular coupling and help guide HBO treatments. The goal of this study was to test two hypotheses: i) activation-induced CBF fMRI response is not dependent on hemoglobin deoxygenation, and ii) activation-induced BOLD fMRI is markedly attenuated under HBO. CBF and BOLD fMRI of forepaw stimulation in anesthetized rats under HBO at 3 atmospheres absolute (ATA) were compared with normobaric air. Robust BOLD and CBF fMRI were detected under HBO. Inflow effects and spin-density changes did not contribute significantly to the BOLD fMRI signal under HBO. Analysis of the T2*-weighted signal at normobaric air and 1, 2 and 3ATA oxygen in the tissue and the superior sagittal sinus showed a strong dependence on increasing inhaled [O-2]. Spontaneous electrophysiological activity and evoked local-field potentials were reduced under HBO. The differences between normobaric air and HBO in basal and evoked electrical activity could not fully account for the strong BOLD responses under HBO. We concluded that activation-induced CBF regulation in the brain does not operate through an oxygen-sensing mechanism and that stimulus-evoked BOLD responses and the venous T2*-weighted signals still have room to increase under 3ATA HBO. To our knowledge, this is the first fMRI study under HBO, providing insights into the effects of HBO on neural activity, neurovascular coupling, tissue oxygenation, and the BOLD signal. (C) 2015 Elsevier Inc. All rights reserved. C1 [Cardenas, Damon P.; Duong, Timothy Q.] Univ Texas San Antonio, Grad Sch Biomed Engn, San Antonio, TX USA. [Muir, Eric R.; Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Dept Ophthalmol, San Antonio, TX 78229 USA. [Muir, Eric R.; Huang, Shiliang; Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, San Antonio, TX 78229 USA. [Boley, Angela; Lodge, Daniel] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA. [Duong, Timothy Q.] South Texas Vet Hlth Care Syst, Dept Vet Affairs, San Antonio, TX USA. RP Duong, TQ (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, 8403 Floyd Curl Dr, San Antonio, TX 78229 USA. EM duongt@uthscsa.edu FU NIH/NINDS [R01 NS45879]; NIH/NIMH [R01 MH090067]; NIH [T32HL007446] FX This work was supported in part by the NIH/NINDS (R01 NS45879), NIH/NIMH (R01 MH090067) and by NIH T32HL007446. NR 17 TC 5 Z9 5 U1 1 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD OCT 1 PY 2015 VL 119 BP 382 EP 389 DI 10.1016/j.neuroimage.2015.06.082 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA CR2TB UT WOS:000361182400037 PM 26143203 ER PT J AU Lin, Y Mallen-St Clair, J Luo, J Sharma, S Dubinett, S St John, M AF Lin, Yuan Mallen-St Clair, Jon Luo, Jie Sharma, Sherven Dubinett, Steven St John, Maie TI p53 modulates NF-kappa B mediated epithelial-to-mesenchymal transition in head and neck squamous cell carcinoma SO ORAL ONCOLOGY LA English DT Article DE Head and neck cancer; Epithelial-to-mesenchymal transition; p53; NF-kappa B; p65 ID ALPHA-INDUCED APOPTOSIS; TNF-ALPHA; CANCER-CELLS; CROSS-TALK; ACTIVATION; EXPRESSION; BCL-2; PHOSPHORYLATION; TRANSCRIPTION; PROGRESSION AB Objectives: To investigate the role of p53 in NF-kappa B mediated epithelial-to-mesenchymal (EMT) in head and neck squamous cell carcinoma (HNSCC). Materials and methods: We utilized HNSCC and normal oral epithelial cell lines as our model system. We used a lentiviral shRNA system to silence the expression of p65 and p53 in these cell lines. Mutant and wild-type (WT) p53 background genotypes were analyzed. The expression of epithelial and mesenchymal markers was determined using western blotting and quantitative PCR assays. Cell morphology, growth, and invasion were determined using a 3-dimensional spheroid culture and anchorage independent growth (AIG) assays. Results: In HNSCC cells with mutant p53 we found that silencing p65 expression promoted EMT. In contrast, in the context of WT p53, ectopic p65 over-expression promoted EMT. Ablation of WT p53 in normal oral epithelial cells blocked EMT induced by p65 over-expression. We demonstrate that AIG and apoptosis induced by NF-kappa B activation is regulated by p53. Conclusion: Our data demonstrates that p53 mutational status is critical in determining the outcome of NF-kappa B activation in HNSCC. In the presence of WT p53, excess p65 signal can promote EMT. Conversely, ablation of p65 in the context of mutant p53 drives EMT. These results demonstrate that p53 mutational status alters the outcome of NF-kappa B signaling. These results, though preliminary, demonstrate the critical role of p53 mutational status in determining the outcome of NF-kappa B signaling and suggest that monitoring p53 status may inform the utility of NF-kappa B inhibitor treatment in HNSCC. (c) 2015 Elsevier Ltd. All rights reserved. C1 [Lin, Yuan; Mallen-St Clair, Jon; St John, Maie] Univ Calif Los Angeles, David Geffen Sch Med, Dept Head & Neck Surg, Los Angeles, CA 90095 USA. [Lin, Yuan; Luo, Jie; Sharma, Sherven; Dubinett, Steven] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Pulm & Crit Care Med, Los Angeles, CA 90095 USA. [Dubinett, Steven] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA. [Lin, Yuan; Sharma, Sherven; Dubinett, Steven; St John, Maie] Univ Calif Los Angeles, David Geffen Sch Med, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA. [Sharma, Sherven; Dubinett, Steven] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. RP St John, M (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Head & Neck Surg, 37-131 CHS,10833 Le Conte Ave, Los Angeles, CA 90095 USA. EM mstjohn@mednet.ucla.edu NR 41 TC 5 Z9 5 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1368-8375 EI 1879-0593 J9 ORAL ONCOL JI Oral Oncol. PD OCT PY 2015 VL 51 IS 10 BP 921 EP 928 DI 10.1016/j.oraloncology.2015.07.006 PG 8 WC Oncology; Dentistry, Oral Surgery & Medicine SC Oncology; Dentistry, Oral Surgery & Medicine GA CR3NP UT WOS:000361240200008 PM 26306422 ER PT J AU DePalo, J Chai, X Lee, SJ Cutler, CS Treister, N AF DePalo, Joseph Chai, Xiaoyu Lee, Stephanie J. Cutler, Corey S. Treister, Nathaniel TI Assessing the relationship between oral chronic graft-versus-host disease and global measures of quality of life SO ORAL ONCOLOGY LA English DT Article DE Oral chronic graft-versus-host disease; Quality of life; Stem cell transplantation ID CONSENSUS DEVELOPMENT PROJECT; WORKING GROUP-REPORT; LONG-TERM SURVIVORS; CLINICAL-TRIALS; CHRONIC GVHD; MARROW-TRANSPLANTATION; FUNCTIONAL ASSESSMENT; CELL TRANSPLANTATION; IMPACT; CRITERIA AB Objective: Chronic GVHD (cGVHD) is a frequent complication of allogeneic hematopoietic stem cell transplantation (HSCT) and affects multiple organ systems, with the oral cavity being one of the most frequently affected sites. Patients with cGVHD experience reduced quality of life (QOL), yet the specific impact of oral cGVHD on QOL is poorly understood. The objective of this study was to characterize the impact of oral cGVHD on global measures of QOL. Materials and methods: QOL data were collected using the FACT-BMT and SF-36 instruments for 569 patients enrolled in the Chronic GVHD Consortium, with a total of 1915 follow-up visits. At study enrollment, patients were categorized as isolated oral cGVHD (n = 22), oral and concomitant extra-oral cGVHD (n = 420), and only extra-oral cGVHD (n = 127). Utilizing all longitudinal data, QOL scores were compared using a multivariable linear model controlling for demographic, transplant, and cGVHD characteristics. Results: Patients with isolated oral cGVHD reported better physical well-being (P = 0.009), BMT wellbeing (P = 0.01), and decreased bodily pain (P = 0.01) compared to patients with oral and concomitant extra-oral cGVHD, but the differences in scores did not reach the defined threshold for clinical significance (6 points for FACT-BMT domains and 5 points for SF-36 domains). Conclusions: Global QOL scores are similar in patients with isolated oral cGVHD and patients with oral and concomitant extra-oral cGVHD. (c) 2015 Elsevier Ltd. All rights reserved. C1 [DePalo, Joseph] Harvard Univ, Sch Dent Med, Boston, MA 02115 USA. [Chai, Xiaoyu; Lee, Stephanie J.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA. [Cutler, Corey S.] Dana Farber Canc Inst, Hematol Malignancies, Boston, MA 02215 USA. [Treister, Nathaniel] Brigham & Womens Hosp, Div Oral Med & Dent, Boston, MA 02120 USA. RP Treister, N (reprint author), Brigham & Womens Hosp, Div Oral Med & Dent, 1620 Tremont St,Suite BC 3-028, Boston, MA 02120 USA. EM ntreister@partners.org FU NCI NIH HHS [U01 CA118953, CA118953, R01 CA118953] NR 30 TC 2 Z9 2 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1368-8375 EI 1879-0593 J9 ORAL ONCOL JI Oral Oncol. PD OCT PY 2015 VL 51 IS 10 BP 944 EP 949 DI 10.1016/j.oraloncology.2015.07.009 PG 6 WC Oncology; Dentistry, Oral Surgery & Medicine SC Oncology; Dentistry, Oral Surgery & Medicine GA CR3NP UT WOS:000361240200011 PM 26277616 ER PT J AU Phillippe, M AF Phillippe, Mark TI Cell-Free Fetal DNA, Telomeres, and the Spontaneous Onset of Parturition SO REPRODUCTIVE SCIENCES LA English DT Review DE parturition; cell-free fetal DNA; telomeres; placental DNA; apoptosis; toll-like receptor-9; interleukin-10 ID SPONTANEOUS PRETERM DELIVERY; TOLL-LIKE RECEPTORS; NONINVASIVE PRENATAL-DIAGNOSIS; MOUSE PERITONEAL-MACROPHAGES; MOLECULAR-PATTERNS DAMPS; LOW-BIRTH-WEIGHT; MATERNAL PLASMA; HUMAN FIBROBLASTS; GESTATIONAL-AGE; BACTERIAL-DNA AB Multiple previous reports have provided compelling support for the premise that spontaneous parturition is mediated by activation of inflammation-related signaling pathways leading to increased secretion of cytokines and chemokines, the influx of neutrophils and macrophages into the pregnant uterus, increased production of uterine activation proteins (eg, connexin-43, cyclo-oxygenase-2, oxytocin receptors, etc), activation of matrix metalloproteinases, and the release of uterotonins leading to cervical ripening, membrane rupture, and myometrial contractions. The missing link has been the fetal/placental signal that triggers these proinflammatory events in the absence of microbial invasion and intrauterine infection. This article reviews the biomedical literature regarding the increase in cell-free fetal DNA (cffDNA), which is released during apoptosis in the placenta and fetal membranes at term, the ability of apoptosis modified vertebrate DNA to stimulate toll-like receptor-9 (TLR9) leading to increased release of cytokines and chemokines, and the potential fail-safe role for the anti-inflammatory cytokine IL-10. This article also reviews the literature supporting the key role that telomere loss plays in regard to increasing the ability of vertebrate (including placental) DNA to stimulate TLR9, and in regard to signaling the onset of apoptosis in the placenta and fetal membranes, thereby providing a biologic clock that determines the length of gestation and the timing for the onset of parturition. In summary, this literature review provides a strong rationale for future research to test the hypothesis that telomere loss and increased cffDNA levels trigger the proinflammatory events leading to the spontaneous onset of parturition in mammals: the cffDNA/telomere hypothesis. C1 [Phillippe, Mark] Harvard Univ, Sch Med, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. RP Phillippe, M (reprint author), Massachusetts Gen Hosp, Dept Obstet & Gynecol, Vincent Ctr Reprod Biol, 55 Fruit St,Thier Bldg 911, Boston, MA 02114 USA. EM MPhillippe@MGH.Harvard.Edu FU Vincent Center for Reproductive Biology, Massachusetts General Hospital, Boston, MA FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: I received financial support for the research, authorship and publication of this article from the Vincent Center for Reproductive Biology, Massachusetts General Hospital, Boston, MA. NR 143 TC 5 Z9 5 U1 4 U2 15 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD OCT PY 2015 VL 22 IS 10 BP 1186 EP 1201 DI 10.1177/1933719115592714 PG 16 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CR7LD UT WOS:000361530300002 PM 26134037 ER PT J AU Tiourin, E Velasco, VS Rosales, MA Sullivan, PS Janzen, DM Memarzadeh, S AF Tiourin, Ekaterina Velasco, Victor S. Rosales, Miguel A. Sullivan, Peggy S. Janzen, Deanna M. Memarzadeh, Sanaz TI Tubal Ligation Induces Quiescence in the Epithelia of the Fallopian Tube Fimbria SO REPRODUCTIVE SCIENCES LA English DT Article DE fallopian epithelial progenitors; tubal ligation; fallopian tube epithelial proliferation ID SEROUS OVARIAN-CANCER; DIVERTING COLOSTOMY; IMAGE-ANALYSIS; STERILIZATION; ANASTOMOSIS; CARCINOMA; CELLS; RISK; EXPRESSION; SYSTEM AB Tubal ligation keeps the fimbriated end of the fallopian tube intact while interrupting the conduit for sperm and egg between the uterus and ovary. Tubal ligation is associated with an approximately 20% decreased risk of high-grade serous ovarian cancers, which mounting evidence suggests arise from the distal fallopian tube epithelium. We postulated that biological changes at the epithelial cellular level of the distal fallopian tube may account for the surgical procedure's observed risk reduction. We compared the histology, presence of epithelial progenitors (basally located CD44-positive cells), and degree of epithelial proliferation (Ki67-positive cells) of distal fallopian tube from 10 patients with previous tubal ligation and 10 age-matched patients with uncut fallopian tubes. A significantly reduced population of proliferating epithelial progenitors (basally located CD44/Ki67 dual-positive cells) was detected in the tubal ligated specimens (P = .0002). To functionally assess the effect of tubal ligation, a murine model was utilized to compare the growth capacity of distal fallopian tube epithelial cells isolated from either ligated or sham-operated tubal epithelia. Murine fallopian tube epithelial cells isolated after tubal ligation showed a significantly reduced capacity to grow organoids in culture compared to sham-operated controls (P = .002). The findings of this study show that tubal ligation is associated with a reduced presence and decreased proliferation of progenitor cells in the distal fallopian tube epithelium. These compositional and functional changes suggest that tubal ligation induces quiescence of distal fallopian tube epithelial cells. C1 [Tiourin, Ekaterina; Velasco, Victor S.; Rosales, Miguel A.; Janzen, Deanna M.; Memarzadeh, Sanaz] Univ Calif Los Angeles, David Geffen Sch Med, Dept Obstet & Gynecol, Los Angeles, CA 90095 USA. [Sullivan, Peggy S.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA. [Memarzadeh, Sanaz] Univ Calif Los Angeles, Eli & Edythe Broad Ctr Regenerat Med & Stem Cell, Los Angeles, CA 90095 USA. [Memarzadeh, Sanaz] VA Greater Los Angeles Hlth Care Syst, Los Angeles, CA USA. RP Memarzadeh, S (reprint author), Univ Calif Los Angeles, 555 Westwood Plaza,Level B,Box 957243, Los Angeles, CA 90095 USA. EM smemarzadeh@mednet.ucla.edu FU VA CDA-2 Award; CDU/UCLA NIH/NCI [U54-CA-143931]; Sidney Kimmel Foundation; Concern foundation; Jonsson Comprehensive Cancer Center Seed grant; NIH/National Center for Advancing Translational Science (NCATS) UCLA CTSI [UL1TR000124]; Leath L. and Marcia L. Millen Family Fund; Ovarian Cancer Circle; Gynecologic Oncology (GO) Discovery Lab Foundation FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: SM is supported by a VA CDA-2 Award, the CDU/UCLA NIH/NCI Grant #U54-CA-143931 award, a Sidney Kimmel Foundation award, the Concern foundation, The Jonsson Comprehensive Cancer Center Seed grant, the NIH/National Center for Advancing Translational Science (NCATS) UCLA CTSI Grant Number UL1TR000124, the Leath L. and Marcia L. Millen Family Fund, the Ovarian Cancer Circle Inspired by Robin Babbini, and the Gynecologic Oncology (GO) Discovery Lab Foundation. NR 43 TC 0 Z9 0 U1 0 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD OCT PY 2015 VL 22 IS 10 BP 1262 EP 1271 DI 10.1177/1933719115574345 PG 10 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA CR7LD UT WOS:000361530300010 PM 25736327 ER PT J AU Rosenberg, SM Newman, LA Partridge, AH AF Rosenberg, Shoshana M. Newman, Lisa A. Partridge, Ann H. TI Breast Cancer in Young Women Rare Disease or Public Health Problem? SO JAMA ONCOLOGY LA English DT Editorial Material C1 [Rosenberg, Shoshana M.; Partridge, Ann H.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Newman, Lisa A.] Univ Michigan, Ctr Comprehens Canc, Breast Care Ctr, Ann Arbor, MI 48109 USA. RP Partridge, AH (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM ann_partridge@dfci.harvard.edu NR 7 TC 6 Z9 6 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2374-2445 J9 JAMA ONCOL JI JAMA Oncol. PD OCT PY 2015 VL 1 IS 7 BP 877 EP 878 DI 10.1001/jamaoncol.2015.2112 PG 2 WC Oncology SC Oncology GA DW5HX UT WOS:000383675900002 PM 26204453 ER PT J AU MacConaill, LE Lindeman, NI Rollins, BJ AF MacConaill, Laura E. Lindeman, Neal I. Rollins, Barrett J. TI Brave-ish New World-What's Needed to Make Precision Oncology a Practical Reality SO JAMA ONCOLOGY LA English DT Editorial Material ID LUNG-CANCER; MUTATIONS; GEFITINIB; PARADIGM C1 [MacConaill, Laura E.; Lindeman, Neal I.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [MacConaill, Laura E.; Lindeman, Neal I.; Rollins, Barrett J.] Havard Med Sch, Boston, MA USA. [Rollins, Barrett J.] Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. RP Rollins, BJ (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM barrett_rollins@dfci.harvard.edu NR 9 TC 1 Z9 1 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2374-2445 J9 JAMA ONCOL JI JAMA Oncol. PD OCT PY 2015 VL 1 IS 7 BP 879 EP 880 DI 10.1001/jamaoncol.2015.1540 PG 2 WC Oncology SC Oncology GA DW5HX UT WOS:000383675900003 PM 26181886 ER PT J AU Gray, PJ Zietman, AL AF Gray, Phillip J. Zietman, Anthony L. TI Dose-Escalated Radiotherapy for Prostate Cancer Is the Sky the Limit? SO JAMA ONCOLOGY LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; PROTON RADIATION; THERAPY; COLLEGE C1 [Gray, Phillip J.; Zietman, Anthony L.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA USA. RP Gray, PJ (reprint author), Massachusetts Gen, Dept Radiat Oncol, 100 Blossom St,Cox 3, Boston, MA 02114 USA. EM pjgray@partners.org NR 14 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 2374-2445 J9 JAMA ONCOL JI JAMA Oncol. PD OCT PY 2015 VL 1 IS 7 BP 883 EP 884 DI 10.1001/jamaoncol.2015.2419 PG 3 WC Oncology SC Oncology GA DW5HX UT WOS:000383675900005 PM 26181340 ER PT J AU Rettig, EM Wentz, A Posner, MR Gross, ND Haddad, RI Gillison, ML Fakhry, C Quon, H Sikora, AG Stott, WJ Lorch, JH Gourin, CG Guo, YS Xiao, WH Miles, BA Richmon, JD Andersen, PE Misiukiewicz, KJ Chung, CH Gerber, JE Rajan, SD D'Souza, G AF Rettig, Eleni M. Wentz, Alicia Posner, Marshall R. Gross, Neil D. Haddad, Robert I. Gillison, Maura L. Fakhry, Carole Quon, Harry Sikora, Andrew G. Stott, William J. Lorch, Jochen H. Gourin, Christine G. Guo, Yingshi Xiao, Weihong Miles, Brett A. Richmon, Jeremy D. Andersen, Peter E. Misiukiewicz, Krzysztof J. Chung, Christine H. Gerber, Jennifer E. Rajan, Shirani D. D'Souza, Gypsyamber TI Prognostic Implication of Persistent Human Papillomavirus Type 16 DNA Detection in Oral Rinses for Human Papillomavirus-Related Oropharyngeal Carcinoma SO JAMA ONCOLOGY LA English DT Article ID SQUAMOUS-CELL CARCINOMA; HPV INFECTION; NECK-CANCER; UNITED-STATES; HEAD; SURVIVAL; RISK; RECURRENT; PROGRESSION; TRIAL AB IMPORTANCE Human papillomavirus-related oropharyngeal carcinoma (HPV-OPC) is increasing in incidence in the United States. Although HPV-OPC has favorable prognosis, 10% to 25% of HPV-OPCs recur. Detection of human papillomavirus (HPV) DNA in oral rinses is associated with HPV-OPC, but its potential as a prognostic biomarker is unclear. OBJECTIVE To determine whether HPV DNA detection in oral rinses after treatment for HPV-OPC is associated with recurrence and survival. DESIGN, SETTING, AND PARTICIPANTS Prospective cohort study of patients with incident HPV-OPC diagnosed from 2009 to 2013 at 4 academic tertiary referral cancer centers in the United States. Oral rinse samples were collected at diagnosis and after treatment (9, 12, 18, and 24 months after diagnosis), and evaluated for HPV DNA. Among an initial cohort of 157 participants with incident HPV-OPC treated with curative intent, 124 had 1 or more posttreatment oral rinses available and were included in this study. MAIN OUTCOMES AND MEASURES Disease-free survival (DFS) and overall survival (OS) were estimated by the Kaplan-Meier method, and the association of HPV DNA detection in oral rinses with survival was evaluated using Cox regression analysis. RESULTS Oral HPV type 16 (HPV16) DNA was common at diagnosis (67 of 124 participants [54%]). In contrast, oral HPV16 DNA was detected in only 6 participants after treatment (5%), including 5 with HPV16 DNA also detected at diagnosis (persistent oral HPV16 DNA). Two-year DFS and OS were 92%(95% CI, 94%-100%) and 98%(95% CI, 93%-99%). Persistent oral HPV16 DNA was associated with worse DFS (hazard ratio, 29.7 [95% CI, 9.0-98.2]) and OS (hazard ratio, 23.5 [95% CI, 4.7-116.9]). All 5 participants with persistent oral HPV16 DNA developed recurrent disease, 3 with local disease involvement. In contrast, just 9 of 119 participants (8%) without persistent oral HPV16 DNA developed recurrent disease, only 1 (11%) with local disease involvement. Median (range) time from earliest posttreatment oral HPV16 DNA detection to recurrence was 7.0 (3.7-10.9) months. CONCLUSIONS AND RELEVANCE Human papillomavirus type 16 DNA in oral rinses is common at diagnosis but rare after treatment for HPV-OPC. Our data suggest that, although infrequent, persistent HPV16 DNA in posttreatment oral rinses is associated with poor prognosis and is a potential tool for long-term tumor surveillance, perhaps more so for local recurrence. C1 [Rettig, Eleni M.; Fakhry, Carole; Gourin, Christine G.; Richmon, Jeremy D.; Chung, Christine H.] Johns Hopkins Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, Baltimore, MD 21205 USA. [Wentz, Alicia; Fakhry, Carole; D'Souza, Gypsyamber] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, 615 N Wolfe St,E6132B, Baltimore, MD 21205 USA. [Posner, Marshall R.; Misiukiewicz, Krzysztof J.] Mt Sinai Med Ctr, Icahn Sch Med, Head & Neck Oncol Ctr, Tisch Canc Inst, New York, NY 10029 USA. [Gross, Neil D.] Univ Texas MD Anderson Canc Ctr, Dept Head & Neck Surg, Div Surg, Houston, TX 77030 USA. [Haddad, Robert I.; Lorch, Jochen H.] Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. [Gillison, Maura L.; Guo, Yingshi; Xiao, Weihong] Ohio State Univ, Ctr Comprehens Canc, Viral Oncol Program, Columbus, OH 43210 USA. [Quon, Harry] Johns Hopkins Univ, Sch Med, Dept Radiat Oncol, Baltimore, MD USA. [Sikora, Andrew G.] Baylor Coll Med, Dept Otolaryngol Head & Neck Surg, Houston, TX 77030 USA. [Stott, William J.; Andersen, Peter E.] Oregon Hlth & Sci Univ, Dept Otolaryngol Head & Neck Surg, Portland, OR 97201 USA. [Miles, Brett A.] Mt Sinai Med Ctr, Icahn Sch Med, Dept Otolaryngol, New York, NY 10029 USA. [Chung, Christine H.] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Gerber, Jennifer E.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD USA. [Rajan, Shirani D.] Louisiana State Univ, Sch Med, New Orleans, LA USA. RP D'Souza, G (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, 615 N Wolfe St,E6132B, Baltimore, MD 21205 USA. EM gdsouza2@jhu.edu FU Johns Hopkins Richard Gelb Cancer Prevention Award; Oral Cancer Foundation; National Institute of Dental and Craniofacial Research and National Institutes of Health (NIH) Research Training in Otolaryngology [2T32DC000027-26] FX This research was supported financially by the Johns Hopkins Richard Gelb Cancer Prevention Award (Dr D'Souza), the Oral Cancer Foundation (Dr D'Souza), and the National Institute of Dental and Craniofacial Research and National Institutes of Health (NIH) Research Training in Otolaryngology grant 2T32DC000027-26 (Dr Rettig). NR 26 TC 12 Z9 12 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2374-2445 J9 JAMA ONCOL JI JAMA Oncol. PD OCT PY 2015 VL 1 IS 7 BP 907 EP 915 DI 10.1001/jamaoncol.2015.2524 PG 9 WC Oncology SC Oncology GA DW5HX UT WOS:000383675900008 PM 26226294 ER PT J AU Tanguturi, S Bellon, JR AF Tanguturi, ShyamK. Bellon, Jennifer R. TI Hypofractionation for Early-Stage Breast Cancer No More Excuses SO JAMA ONCOLOGY LA English DT Editorial Material ID RADIOTHERAPY HYPOFRACTIONATION; UK STANDARDIZATION; RADIATION-THERAPY; TRIALS C1 [Tanguturi, ShyamK.] Harvard Radiat Oncol Program, Boston, MA USA. [Bellon, Jennifer R.] Harvard Med Sch, Brigham & Womens Canc Ctr, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA USA. RP Bellon, JR (reprint author), Dana Farber Canc Inst, Dept Radiat Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM jbellon@lroc.harvard.edu NR 9 TC 1 Z9 1 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2374-2445 J9 JAMA ONCOL JI JAMA Oncol. PD OCT PY 2015 VL 1 IS 7 BP 941 EP 942 DI 10.1001/jamaoncol.2015.2605 PG 3 WC Oncology SC Oncology GA DW5HX UT WOS:000383675900012 PM 26247338 ER PT J AU Desmond, A Kurian, A Gabree, M Mills, MA Anderson, MJ Kobayashi, Y Horick, N Yang, S Shannon, KM Tung, N Ford, J Lincoln, SE Ellisen, L AF Desmond, Andrea Kurian, AllisonW. Gabree, Michele Mills, Meredith A. Anderson, Michael J. Kobayashi, Yuya Horick, Nora Yang, Shan Shannon, Kristen M. Tung, Nadine Ford, JamesM. Lincoln, Stephen E. Ellisen, Leifw. TI Clinical Actionability of Multigene Panel Testing for Hereditary Breast and Ovarian Cancer Risk Assessment SO JAMA ONCOLOGY LA English DT Article ID NEXT-GENERATION; GERMLINE MUTATIONS; GENES; SUSCEPTIBILITY; FAMILIES; GENETICS; RAD51C; WOMEN; PALB2; ATM AB IMPORTANCE The practice of genetic testing for hereditary breast and/or ovarian cancer (HBOC) is rapidly evolving owing to the recent introduction of multigene panels. While these tests may identify 40% to 50% more individuals with hereditary cancer gene mutations than does testing for BRCA1/2 alone, whether finding such mutations will alter clinical management is unknown. OBJECTIVE To define the potential clinical effect of multigene panel testing for HBOC in a clinically representative cohort. DESIGN, SETTING, AND PARTICIPANTS Observational study of patients seen between 2001 and 2014 in 3 large academic medical centers. We prospectively enrolled 1046 individuals who were appropriate candidates for HBOC evaluation and who lacked BRCA1/2 mutations. INTERVENTIONS We carried out multigene panel testing on all participants, then determined the clinical actionability, if any, of finding non-BRCA1/2 mutations in these and additional comparable individuals. MAIN OUTCOMES AND MEASURES We evaluated the likelihood of (1) a posttest management change and (2) an indication for additional familial testing, considering gene-specific consensus management guidelines, gene-associated cancer risks, and personal and family history. RESULTS Among 1046 study participants, 40 BRCA1/2-negative patients (3.8%; 95% CI, 2.8%-5.2%) harbored deleterious mutations, most commonly in moderate-risk breast and ovarian cancer genes (CHEK2, ATM, and PALB2) and Lynch syndrome genes. Among these and an additional 23 mutation-positive individuals enrolled from our clinics, most of the mutations (92%) were consistent with the spectrum of cancer(s) observed in the patient or family, suggesting that these results are clinically significant. Among all 63 mutation-positive patients, additional disease-specific screening and/or prevention measures beyond those based on personal and family history alone would be considered for most (33 [52%] of 63; 95% CI, 40.3%-64.2%). Furthermore, additional familial testing would be considered for those with first-degree relatives (42 [72%] of 58; 95% CI, 59.8%-82.2%) based on potential management changes for mutation-positive relatives. This clinical effect was not restricted to a few of the tested genes because most identified genes could change clinical management for some patients. CONCLUSIONS AND RELEVANCE In a clinically representative cohort, multigene panel testing for HBOC risk assessment yielded findings likely to change clinical management for substantially more patients than does BRCA1/2 testing alone. Multigene testing in this setting is likely to alter near-term cancer risk assessment and management recommendations for mutation-affected individuals across a broad spectrum of cancer predisposition genes. C1 [Desmond, Andrea; Gabree, Michele; Horick, Nora; Shannon, Kristen M.; Ellisen, Leifw.] Massachusetts Gen Hosp, Ctr Canc, 55 Fruit St,GRJ 904, Boston, MA 02114 USA. [Kurian, AllisonW.; Mills, Meredith A.; Ford, JamesM.] Stanford Univ, Sch Med, Stanford, CA USA. [Anderson, Michael J.; Kobayashi, Yuya; Yang, Shan; Lincoln, Stephen E.] Invitae Corp, San Francisco, CA USA. [Tung, Nadine] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Tung, Nadine; Ellisen, Leifw.] Harvard Med Sch, Boston, MA USA. RP Ellisen, L (reprint author), Massachusetts Gen Hosp, Ctr Canc, 55 Fruit St,GRJ 904, Boston, MA 02114 USA. EM lellisen@mgh.harvard.edu FU MGH Friends Fighting Breast Cancer; Tracey Davis Memorial Fund; Breast Cancer Research Foundation FX This study was funded by unrestricted philanthropic gifs from the MGH Friends Fighting Breast Cancer and the Tracey Davis Memorial Fund (Ms Desmond and Dr Ellisen) and by the Breast Cancer Research Foundation (Drs Kurian and Ford). NR 32 TC 29 Z9 29 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2374-2445 J9 JAMA ONCOL JI JAMA Oncol. PD OCT PY 2015 VL 1 IS 7 BP 943 EP 951 DI 10.1001/jamaoncol.2015.2690 PG 9 WC Oncology SC Oncology GA DW5HX UT WOS:000383675900013 PM 26270727 ER PT J AU Shoag, J Halpern, J Eisner, B Lee, R Mittal, S Barbieri, CE Shoag, D AF Shoag, Jonathan Halpern, Joshua Eisner, Brian Lee, Richard Mittal, Sameer Barbieri, Christopher E. Shoag, Daniel TI Efficacy of Prostate-Specific Antigen Screening: Use of Regression Discontinuity in the PLCO Cancer Screening Trial SO JAMA ONCOLOGY LA English DT Letter ID RANDOMIZED PROSTATE C1 [Shoag, Jonathan; Halpern, Joshua; Lee, Richard; Mittal, Sameer; Barbieri, Christopher E.] New York Presbyterian Hosp, Weill Cornell Med Coll, Dept Urol, 525 E 68th St,Starr 900, New York, NY 10021 USA. [Eisner, Brian] Massachusetts Gen Hosp, Dept Urol, Boston, MA USA. [Shoag, Daniel] Harvard Kennedy Sch, Dept Publ Policy, Cambridge, MA USA. RP Shoag, J (reprint author), New York Presbyterian Hosp, Weill Cornell Med Coll, Dept Urol, 525 E 68th St,Starr 900, New York, NY 10021 USA. EM Jes9171@nyp.org NR 6 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 2374-2445 J9 JAMA ONCOL JI JAMA Oncol. PD OCT PY 2015 VL 1 IS 7 BP 983 EP 986 DI 10.1001/jamaoncol.2015.2993 PG 4 WC Oncology SC Oncology GA DW5HX UT WOS:000383675900022 ER PT J AU Ruggiero, KJ Bunnell, BE Andrews, AR Davidson, TM Hanson, RF Danielson, CK Saunders, BE Soltis, K Yarian, C Chu, B Adams, ZW AF Ruggiero, Kenneth J. Bunnell, Brian E. Andrews, Arthur R., III Davidson, Tatiana M. Hanson, Rochelle F. Danielson, Carla Kmett Saunders, Benjamin E. Soltis, Kathryn Yarian, Caleb Chu, Brian Adams, Zachary W. TI Development and Pilot Evaluation of a Tablet-Based Application to Improve Quality of Care in Child Mental Health Treatment SO JMIR RESEARCH PROTOCOLS LA English DT Article DE technology; mobile health; child mental health treatment; feasibility test; fidelity; patient engagement; traumatic stress ID REPLICATION-ADOLESCENT SUPPLEMENT; POSTTRAUMATIC-STRESS-DISORDER; RANDOMIZED-CONTROLLED-TRIAL; PROVIDERS PERSPECTIVES; COMMUNITY TREATMENT; PHONE APPLICATION; TRAUMATIC EVENTS; PTSD SYMPTOMS; DEPRESSION; FIDELITY AB Background: Children need access to high quality mental health care. Effective treatments now exist for a wide range of mental health conditions. However, these interventions are delivered with variable effectiveness in traditional mental health service settings. Innovative solutions are needed to improve treatment delivery quality and effectiveness. Objective: The aim of this study was to develop a scalable, sustainable technology-based approach to improve the quality of care in child mental health treatment. Methods: A tablet-based resource was developed with input from mental health training experts, mental health providers, and patients. A series of qualitative data collection phases (ie, expert interviews, patient and provider focus groups, usability testing) guided the initial concept and design of the resource, and then its refinement. The result was an iPad-based "e-workbook" designed to improve child engagement and provider fidelity in implementation of a best-practice treatment. We are currently conducting a small scale randomized controlled trial to evaluate the feasibility of e-workbook facilitated child mental health treatment with 10 providers and 20 families recruited from 4 local community-based mental health clinics. Results: Usability and focus group testing yielded a number of strong, favorable reactions from providers and families. Recommendations for refining the e-workbook also were provided, and these guided several improvements to the resource prior to initiating the feasibility trial, which is currently underway. Conclusions: This study aimed to develop and preliminarily evaluate a tablet-based application to improve provider fidelity and child engagement in child mental health treatment. If successful, this approach may serve as a key step toward making best-practice treatment more accessible to children and families. As various technologies continue to increase in popularity worldwide and within the health care field more specifically, it is essential to rigorously test the usability, feasibility, acceptability, and effectiveness of novel health technology solutions. It is also essential to ensure that patients and providers drive decision making that supports the development of these resources to ensure that they can be seamlessly integrated into practice. C1 [Ruggiero, Kenneth J.; Bunnell, Brian E.; Davidson, Tatiana M.; Soltis, Kathryn] Med Univ South Carolina, Coll Nursing, Technol Applicat Ctr Healthful Lifestyles, 99 Jonathan Lucas St, Charleston, SC 29425 USA. [Ruggiero, Kenneth J.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. [Andrews, Arthur R., III; Davidson, Tatiana M.; Hanson, Rochelle F.; Danielson, Carla Kmett; Saunders, Benjamin E.; Soltis, Kathryn; Adams, Zachary W.] Med Univ South Carolina, Dept Psychiat & Behav Sci, Natl Crime Victims Res & Treatment Ctr, 171 Ashley Ave, Charleston, SC 29425 USA. [Yarian, Caleb] Fuzzco, Charleston, SC USA. [Chu, Brian] Rutgers State Univ, Piscataway, NJ USA. RP Ruggiero, KJ (reprint author), Med Univ South Carolina, Coll Nursing, Technol Applicat Ctr Healthful Lifestyles, 99 Jonathan Lucas St, Charleston, SC 29425 USA. EM ruggierk@musc.edu OI Andrews III, Arthur/0000-0001-9071-0089; Chu, Brian/0000-0003-0275-1599 FU National Institute of Mental Health [R34-MH096907, R01-MH81056, R34-MH104470, T32-MH18869]; National Institute on Drug Abuse [K12-DA031794, K23-DA038257, R01-DA031285]; Substance Abuse and Mental Health Services Administration [U79-SM061269] FX We thank Judy Cohen, MD, Esther Deblinger, PhD, and Anthony Mannarino, PhD, who developed TF-CBT and have provided valuable input and feedback throughout every phase of this project. We thank Ben Jacobs of Fuzzco for his significant role in the design and development process of the TF-CBT e-workbook. We thank Josh Nissenboim of Fuzzco for his leadership and partnership in support of this project and related research. We thank Joel Sherrill of NIMH for his thoughtful feedback on early conceptualizations of this project. We also thank the families and providers who participated in this study for their time and insights. This research and the authors' time and effort were supported by National Institute of Mental Health grants R34-MH096907, R01-MH81056, R34-MH104470, and T32-MH18869; National Institute on Drug Abuse grants K12-DA031794, K23-DA038257, and R01-DA031285; and Substance Abuse and Mental Health Services Administration grant U79-SM061269. None of these funding agencies were involved in the design of the study; the collection, analysis, or interpretation of data; the writing of the manuscript, or the decision to submit the manuscript for publication. NR 62 TC 0 Z9 0 U1 0 U2 0 PU JMIR PUBLICATIONS, INC PI TORONTO PA 59 WINNERS CIRCLE, TORONTO, ON M4L 3Y7, CANADA SN 1929-0748 J9 JMIR RES PROTOC JI JMIR RES. Protoc. PD OCT-DEC PY 2015 VL 4 IS 4 AR e143 DI 10.2196/resprot.4416 PG 18 WC Health Care Sciences & Services SC Health Care Sciences & Services GA EI2LT UT WOS:000392319500010 PM 26717906 ER PT J AU Lien, YAS Calabrese, CR Michener, CM Murray, EH Van Stan, JH Mehta, DD Hillman, RE Noordzij, JP Stepp, CE AF Lien, Yu-An S. Calabrese, Carolyn R. Michener, Carolyn M. Murray, Elizabeth Heller Van Stan, Jarrad H. Mehta, Daryush D. Hillman, Robert E. Noordzij, J. Pieter Stepp, Cara E. TI Voice Relative Fundamental Frequency Via Neck-Skin Acceleration in Individuals With Voice Disorders SO JOURNAL OF SPEECH LANGUAGE AND HEARING RESEARCH LA English DT Article ID VOCAL HYPERFUNCTION; SPASMODIC DYSPHONIA; OFFSET; ONSET; ACCUMULATOR; SPEAKERS; DISEASE AB Purpose: This study investigated the use of neck-skin acceleration for relative fundamental frequency (RFF) analysis. Method: Forty individuals with voice disorders associated with vocal hyperfunction and 20 age-and sex-matched control participants were recorded with a subglottal neck-surface accelerometer and a microphone while producing speech stimuli appropriate for RFF. Rater reliabilities, RFF means, and RFF standard deviations derived from the accelerometer were compared with those derived from the microphone. Results: RFF estimated from the accelerometer had slightly higher intrarater reliability and identical interrater reliability compared with values estimated with the microphone. Although sensor type and the Vocal Cycle x Sensor and Vocal Cycle x Sensor x Group interactions showed significant effects on RFF means, the typical RFF pattern could be derived from either sensor. For both sensors, the RFF of individuals with vocal hyperfunction was lower than that of the controls. Sensor type and its interactions did not have significant effects on RFF standard deviations. Conclusions: RFF can be reliably estimated using an accelerometer, but these values cannot be compared with those collected via microphone. Future studies are needed to determine the physiological basis of RFF and examine the effect of sensors on RFF in practical voice assessment and monitoring settings. C1 [Lien, Yu-An S.; Calabrese, Carolyn R.; Michener, Carolyn M.; Murray, Elizabeth Heller; Noordzij, J. Pieter; Stepp, Cara E.] Boston Univ, Boston, MA 02215 USA. [Van Stan, Jarrad H.; Mehta, Daryush D.; Hillman, Robert E.] MGH Inst Hlth Profess, Boston, MA USA. [Van Stan, Jarrad H.; Mehta, Daryush D.; Hillman, Robert E.] Massachusetts Gen Hosp, Ctr Laryngeal Surg & Voice Rehabil, Boston, MA 02114 USA. [Mehta, Daryush D.; Hillman, Robert E.] Harvard Med Sch, Cambridge, MA USA. [Noordzij, J. Pieter; Stepp, Cara E.] Boston Univ, Sch Med, Boston, MA 02118 USA. RP Stepp, CE (reprint author), Boston Univ, Boston, MA 02215 USA. EM cstepp@bu.edu FU National Institute on Deafness and Other Communication Disorders [DC012651, DC011588]; New Century Scholars Research Grant from the American Speech-Language-Hearing Foundation FX This work was supported by National Institute on Deafness and Other Communication Disorders Grants DC012651 (awarded to Cara E. Stepp) and DC011588 (awarded to Robert E. Hillman) and a New Century Scholars Research Grant from the American Speech-Language-Hearing Foundation (awarded to Cara E. Stepp). Thanks to Defne Abur, Christina Stevens, and Alexandra Martinson for assistance with data recording and to Melissa Cooke, Amanda Fryd, and Molly Bresnahan for help with recording segmentation. We disclose that author Robert E. Hillman has a financial relationship with Pentax Medical with respect to the Ambulatory Phonation Monitor. NR 31 TC 1 Z9 1 U1 0 U2 0 PU AMER SPEECH-LANGUAGE-HEARING ASSOC PI ROCKVILLE PA 2200 RESEARCH BLVD, #271, ROCKVILLE, MD 20850-3289 USA SN 1092-4388 EI 1558-9102 J9 J SPEECH LANG HEAR R JI J. Speech Lang. Hear. Res. PD OCT PY 2015 VL 58 IS 5 BP 1482 EP 1487 DI 10.1044/2015_JSLHR-S-15-0126 PG 6 WC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation SC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation GA DX6XL UT WOS:000384529200007 PM 26134171 ER PT J AU Deliyski, DD Hillman, RE Mehta, DD AF Deliyski, Dimitar D. Hillman, Robert E. Mehta, Daryush D. TI Laryngeal High-Speed Videoendoscopy: Rationale and Recommendation for Accurate and Consistent Terminology SO JOURNAL OF SPEECH LANGUAGE AND HEARING RESEARCH LA English DT Letter ID VOCAL-FOLD VIBRATIONS; HEALTHY-SUBJECTS; OPEN QUOTIENT; IMAGES; FORM; ASYMMETRY; PHONOVIBROGRAPHY; STROBOSCOPY; RECORDINGS; PHYSIOLOGY AB Purpose: The authors discuss the rationale behind the term laryngeal high-speed videoendoscopy to describe the application of high-speed endoscopic imaging techniques to the visualization of vocal fold vibration. Method: Commentary on the advantages of using accurate and consistent terminology in the field of voice research is provided. Specific justification is described for each component of the term high-speed videoendoscopy, which is compared and contrasted with alternative terminologies in the literature. Results: In addition to the ubiquitous high-speed descriptor, the term endoscopy is necessary to specify the appropriate imaging technology and distinguish among modalities such as ultrasound, magnetic resonance imaging, and nonendoscopic optical imaging. Furthermore, the term video critically indicates the electronic recording of a sequence of optical still images representing scenes in motion, in contrast to strobed images using high-speed photography and nonoptical high-speed magnetic resonance imaging. High-speed videoendoscopy thus concisely describes the technology and can be appended by the desired anatomical nomenclature such as laryngeal. Conclusions: Laryngeal high-speed videoendoscopy strikes a balance between conciseness and specificity when referring to the typical high-speed imaging method performed on human participants. Guidance for the creation of future terminology provides clarity and context for current and future experiments and the dissemination of results among researchers. C1 [Deliyski, Dimitar D.] Cincinnati Childrens Hosp Med Ctr, Commun Sci Res Ctr, Cincinnati, OH 45229 USA. [Deliyski, Dimitar D.] Univ Cincinnati, Cincinnati, OH 45221 USA. [Hillman, Robert E.; Mehta, Daryush D.] Massachusetts Gen Hosp, Ctr Laryngeal Surg & Voice Rehabil, Boston, MA 02114 USA. [Hillman, Robert E.; Mehta, Daryush D.] Harvard Med Sch, Boston, MA USA. [Hillman, Robert E.; Mehta, Daryush D.] Massachusetts Gen Hosp, Inst Hlth Profess, Charlestown, MA USA. RP Mehta, DD (reprint author), Massachusetts Gen Hosp, Ctr Laryngeal Surg & Voice Rehabil, Boston, MA 02114 USA. EM daryush.mehta@alum.mit.edu FU National Institute on Deafness and Other Communication Disorders [R01 DC007640]; Voice Health Institute FX This work was supported by a grant from the National Institute on Deafness and Other Communication Disorders (R01 DC007640), awarded to Dimitar D. Deliyski, and by the Voice Health Institute. The article's contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. NR 57 TC 1 Z9 1 U1 0 U2 0 PU AMER SPEECH-LANGUAGE-HEARING ASSOC PI ROCKVILLE PA 2200 RESEARCH BLVD, #271, ROCKVILLE, MD 20850-3289 USA SN 1092-4388 EI 1558-9102 J9 J SPEECH LANG HEAR R JI J. Speech Lang. Hear. Res. PD OCT PY 2015 VL 58 IS 5 BP 1488 EP 1492 DI 10.1044/2015_JSLHR-S-14-0253 PG 5 WC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation SC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation GA DX6XL UT WOS:000384529200008 PM 26375398 ER PT J AU Adler, JT Yeh, H Markmann, JF Nguyen, LL AF Adler, Joel T. Yeh, Heidi Markmann, James F. Nguyen, Louis L. TI The pathway to renal transplantation: obstacles and contributions to disparities SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Meeting Abstract CT 101st Annual Clinical Congress of the American-College-of-Surgeons (ACS) CY OCT 04-10, 2015 CL Chicago, IL SP Amer Coll Surg C1 [Adler, Joel T.; Yeh, Heidi; Markmann, James F.; Nguyen, Louis L.] Massachusetts Gen Hosp, Brigham & Womens Hosptial, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 EI 1879-1190 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD OCT PY 2015 VL 221 IS 4 SU 2 BP E138 EP E138 PG 1 WC Surgery SC Surgery GA EA8PP UT WOS:000386899000338 ER PT J AU De Gregorio, L Lubitz, CC Hunter, GJ Hodin, RA Gaz, RD Parangi, S Stephen, AE AF De Gregorio, Lucia Lubitz, Carrie C. Hunter, George J. Hodin, Richard A. Gaz, Randall D. Parangi, Sareh Stephen, Antonia E. TI Should 4DCT replace sestamibi as a primary localization modality in primary hyperparathyroidism? SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Meeting Abstract CT 101st Annual Clinical Congress of the American-College-of-Surgeons (ACS) CY OCT 04-10, 2015 CL Chicago, IL SP Amer Coll Surg C1 [De Gregorio, Lucia; Lubitz, Carrie C.; Hunter, George J.; Hodin, Richard A.; Gaz, Randall D.; Parangi, Sareh; Stephen, Antonia E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 EI 1879-1190 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD OCT PY 2015 VL 221 IS 4 SU 2 BP E80 EP E80 PG 1 WC Surgery SC Surgery GA EA8PP UT WOS:000386899000191 ER PT J AU Hall, DE Stone, RA Feske, U Ling, B Shasha, G Zickmund, S Zhang, SJ Arnold, R AF Hall, Daniel E. Stone, Roslyn A. Feske, Ulrike Ling, Bruce Shasha, Gao Zickmund, Susan Zhang, Sijian Arnold, Robert TI Systematic bias against expedited review procedures across institutional review boards (IRBs) in the Veterans Health Administration (VHA) SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Meeting Abstract CT 101st Annual Clinical Congress of the American-College-of-Surgeons (ACS) CY OCT 04-10, 2015 CL Chicago, IL SP Amer Coll Surg C1 VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. Univ Pittsburgh, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 EI 1879-1190 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD OCT PY 2015 VL 221 IS 4 SU 2 BP E14 EP E14 PG 1 WC Surgery SC Surgery GA EA8PP UT WOS:000386899000031 ER PT J AU Hall, DE AF Hall, Daniel E. TI Practical wisdom provides ethical justification for the negotiation and enforcement of surgical buy-in SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Meeting Abstract CT 101st Annual Clinical Congress of the American-College-of-Surgeons (ACS) CY OCT 04-10, 2015 CL Chicago, IL SP Amer Coll Surg C1 [Hall, Daniel E.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Hall, Daniel E.] Univ Pittsburgh, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 EI 1879-1190 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD OCT PY 2015 VL 221 IS 4 SU 2 BP E13 EP E14 PG 2 WC Surgery SC Surgery GA EA8PP UT WOS:000386899000030 ER PT J AU Bassett, IV Regan, S Mbonambi, H Blossom, J Bogan, S Bearnot, B Robine, M Walensky, RP Mhlongo, B Freedberg, KA Thulare, H Losina, E AF Bassett, Ingrid V. Regan, Susan Mbonambi, Hlengiwe Blossom, Jeffrey Bogan, Stacy Bearnot, Benjamin Robine, Marion Walensky, Rochelle P. Mhlongo, Bright Freedberg, Kenneth A. Thulare, Hilary Losina, Elena TI Finding HIV in Hard to Reach Populations: Mobile HIV Testing and Geospatial Mapping in Umlazi Township, Durban, South Africa SO AIDS AND BEHAVIOR LA English DT Article DE Geospatial analysis; HIV mobile testing; South Africa ID RURAL MOZAMBIQUE; CARE; HIV/AIDS; INITIATION; COMMUNITY; SERVICES; LINKAGE; SYSTEM; STIGMA; RISK AB Mobile, community-based HIV testing may help achieve universal HIV testing in South Africa. We compared the yield, geographic distribution, and demographic characteristics of populations tested by mobile- and clinic-based HIV testing programs deployed by iThembalabantu Clinic in Durban, South Africa. From July to November 2011, 4,701 subjects were tested; HIV prevalence was 35 % among IPHC testers and 10 % among mobile testers (p < 0.001). Mobile testers varied in mean age (22-37 years) and % males (26-67 %). HIV prevalence at mobile sites ranged from 0 to 26 %. Testers traveled further than the clinic closest to their home; mobile testers were more likely to test a parts per thousand yen5 km away from home. Mobile HIV testing can improve testing access and identify testing sites with high HIV prevalence. Individuals often access mobile testing sites farther from home than their nearest clinic. Geospatial techniques can help optimize deployment of mobile units to maximize yield in hard-to-reach populations. C1 [Bassett, Ingrid V.; Regan, Susan; Robine, Marion; Walensky, Rochelle P.; Freedberg, Kenneth A.; Losina, Elena] Massachusetts Gen Hosp, Med Practice Evaluat Ctr, Boston, MA 02114 USA. [Bassett, Ingrid V.; Walensky, Rochelle P.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Bassett, Ingrid V.; Walensky, Rochelle P.; Freedberg, Kenneth A.; Losina, Elena] Harvard Univ, Harvard Ctr AIDS Res, Boston, MA 02115 USA. [Bassett, Ingrid V.; Bearnot, Benjamin; Walensky, Rochelle P.; Freedberg, Kenneth A.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Mbonambi, Hlengiwe; Mhlongo, Bright; Thulare, Hilary] AIDS Healthcare Fdn, iThembalabantu Peoples Hope Clin, Durban, South Africa. [Blossom, Jeffrey; Bogan, Stacy] Harvard Ctr Geog Anal, Cambridge, MA USA. [Walensky, Rochelle P.; Freedberg, Kenneth A.] Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. [Walensky, Rochelle P.] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Losina, Elena] Brigham & Womens Hosp, Dept Orthoped Surg, Boston, MA 02115 USA. [Losina, Elena] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. RP Bassett, IV (reprint author), Massachusetts Gen Hosp, Med Practice Evaluat Ctr, 50 Staniford St,Floor 9, Boston, MA 02114 USA. EM ibassett@partners.org FU National Institute of Allergy and Infectious Diseases; National Institute of Mental Health of the National Institutes of Health [R01 MH090326, R01 AI058736, R01 MH073445]; AIDS Healthcare Foundation; Harvard Center for AIDS Research [P30 AI042851] FX We would like to acknowledge the assistance of Njabulo Mabaso and Philisiwe Luthuli and the dedication of the research team at the iThembalabantu People's Hope Clinic. Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases and National Institute of Mental Health of the National Institutes of Health under Awards R01 MH090326, R01 AI058736 and R01 MH073445. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This Project was also supported by the AIDS Healthcare Foundation and the Harvard Center for AIDS Research (P30 AI042851). NR 34 TC 4 Z9 4 U1 2 U2 7 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 OCT PY 2015 VL 19 IS 10 BP 1888 EP 1895 DI 10.1007/s10461-015-1012-3 PG 8 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA CR0HK UT WOS:000360999000016 PM 25874754 ER PT J AU Holland, CM Ritchie, ND Du Bois, SN AF Holland, Christine M. Ritchie, Natalie D. Du Bois, Steve N. TI iTunes Song-Gifting is a Low-Cost, Efficient Recruitment Tool to Engage High-Risk MSM in Internet Research SO AIDS AND BEHAVIOR LA English DT Article DE Internet research methodology; Recruitment; Incentives; Men who have sex with men; HIV/STI prevention ID MEN; SEX; PREVENTION; GAY AB This brief report describes methodology and results of a novel, efficient, and low-cost recruitment tool to engage high-risk MSM in online research. We developed an incentivization protocol using iTunes song-gifting to encourage participation of high-risk MSM in an Internet-based survey of HIV status, childhood sexual abuse, and adult behavior and functioning. Our recruitment methodology yielded 489 participants in 4.5 months at a total incentive cost of $1.43USD per participant. The sample comprised a critically high-risk group of MSM, including 71.0 % who reported recent condomless anal intercourse. We offer a "how-to" guide to aid future investigators in using iTunes song-gifting incentives. C1 [Holland, Christine M.] VA Greater Los Angeles Healthcare Syst, Dept Mental Hlth, Los Angeles, CA USA. [Ritchie, Natalie D.] Denver Hlth & Hosp Author, Denver Hlth Managed Care, Denver, CO 80204 USA. [Du Bois, Steve N.] Northwestern Univ, Family Inst, Evanston, IL USA. [Du Bois, Steve N.] Univ Illinois, Dept Psychol, Chicago, IL 60680 USA. RP Ritchie, ND (reprint author), Denver Hlth & Hosp Author, Denver Hlth Managed Care, 777 Bannock St,MC 6000, Denver, CO 80204 USA. EM natalie.ritchie@dhha.org FU University of Illinois at Chicago Chancellor's Committee on the Status of Lesbian, Gay, Bisexual, and Transgender Issues FX This work was supported by the University of Illinois at Chicago Chancellor's Committee on the Status of Lesbian, Gay, Bisexual, and Transgender Issues. NR 11 TC 1 Z9 1 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 OCT PY 2015 VL 19 IS 10 BP 1914 EP 1918 DI 10.1007/s10461-015-1130-y PG 5 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA CR0HK UT WOS:000360999000019 PM 26174208 ER PT J AU Hughes, KS Cusack, JC AF Hughes, Kevin S. Cusack, James C. TI Genetics, Genomics, and Pharmacogenomics SO ANNALS OF SURGICAL ONCOLOGY LA English DT Editorial Material ID CLINICAL DECISION-SUPPORT; BREAST-CANCER; RANDOMIZED-TRIAL; OVARIAN-CANCER; FLUOROURACIL; TAMOXIFEN; ASSOCIATION; LEUCOVORIN; THERAPY; CYP2D6 C1 [Hughes, Kevin S.] Massachusetts Gen Hosp, Avon Comprehens Breast Evaluat Ctr, Boston, MA 02114 USA. [Hughes, Kevin S.] Bermuda Canc Genet & Risk Assessment Clin, Boston, MA USA. [Cusack, James C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Hughes, KS (reprint author), Massachusetts Gen Hosp, Avon Comprehens Breast Evaluat Ctr, Boston, MA 02114 USA. EM kshughes@partners.org NR 25 TC 0 Z9 0 U1 1 U2 14 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 OCT PY 2015 VL 22 IS 11 BP 3414 EP 3417 DI 10.1245/s10434-015-4705-y PG 4 WC Oncology; Surgery SC Oncology; Surgery GA CR1EX UT WOS:000361067900003 PM 26215191 ER PT J AU Gupta, A Mutebi, M Bardia, A AF Gupta, Arjun Mutebi, Miriam Bardia, Aditya TI Gene-Expression-Based Predictors for Breast Cancer SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID 21-GENE RECURRENCE SCORE; 70-GENE PROGNOSIS-SIGNATURE; GENOMIC GRADE INDEX; LATE DISTANT RECURRENCE; SUB-SAHARAN AFRICA; CORE BIOPSY-TISSUE; ESTROGEN-RECEPTOR; ONCOTYPE DX; ADJUVANT TAMOXIFEN; RANDOMIZED-TRIALS AB An important and often complicated management decision in early stage hormone receptor (HR)-positive breast cancer relates to the use of adjuvant systemic chemotherapy. Although traditional clinicopathologic markers exist, tremendous progress has been achieved in the field of predictive biomarkers and genomics with both prognostic and predictive capabilities to identify patients who will potentially benefit from additional therapy. The use of these genomic tests in the neoadjuvant setting is also being studied and may lead to these tests providing clinical benefit even earlier in the disease course. Landmark articles published in the last few years have expanded our knowledge of breast cancer genomics to an unprecedented level, and mutational analysis via next-generation sequencing methods allows the identification of molecular targets for novel targeted therapeutic agents and clinical trials testing efficacy of targeted therapies, such as PI3K inhibitors, in addition to endocrine therapy for HR-positive breast cancer, are ongoing. We provide an in-depth review on the role of gene expression-based predictors in early stage breast cancer and an overview of future directions, including next-generation sequencing. Over the coming years, we anticipate a significant increase in utilization of genomic-based predictors for individualized selection and duration of endocrine therapy with and without genotype-driven targeted therapy, and a major decrease in the use of chemotherapy, possibly even leading to a chemotherapy-free road for early stage HR-positive breast cancer. C1 [Gupta, Arjun] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA. [Mutebi, Miriam] Groote Schuur Hosp, ZA-7925 Cape Town, South Africa. [Bardia, Aditya] Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med, Boston, MA 02114 USA. RP Gupta, A (reprint author), Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA. EM Bardia.Aditya@mgh.harvard.edu NR 84 TC 0 Z9 0 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD OCT PY 2015 VL 22 IS 11 BP 3418 EP 3432 DI 10.1245/s10434-015-4703-0 PG 15 WC Oncology; Surgery SC Oncology; Surgery GA CR1EX UT WOS:000361067900004 PM 26215189 ER PT J AU Erstad, DJ Tumusiime, G Cusack, JC AF Erstad, Derek J. Tumusiime, Gerald Cusack, James C., Jr. TI Prognostic and Predictive Biomarkers in Colorectal Cancer: Implications for the Clinical Surgeon SO ANNALS OF SURGICAL ONCOLOGY LA English DT Review ID ISLAND METHYLATOR PHENOTYPE; III COLON-CANCER; GENOME-WIDE ASSOCIATION; GENE COPY NUMBER; TUMOR MICROSATELLITE-INSTABILITY; THYMIDYLATE SYNTHASE EXPRESSION; EGFR MONOCLONAL-ANTIBODIES; LONG-TERM PROGNOSIS; POOR-PROGNOSIS; RECTAL-CANCER AB Colorectal cancer is a heterogeneous disease with a wide range of long-term outcomes and responses to treatment. Recent advances in the genetic and molecular characterization of tumors has yielded a set of prognostic and predictive biomarkers that aid the identification of patients at higher risk for disease recurrence and progression, and in some cases indicate the likelihood of response to a specific treatment. Increasingly, these biomarkers have become integral to the treatment algorithm for managing patients with colorectal cancer. Prognostic and predictive factors in colorectal cancer can broadly be categorized into treatment impact, clinicopathologic factors, and molecular markers. This review will focus primarily on molecular markers, which are foundational to the paradigmatic shift toward personalized cancer therapy. C1 [Erstad, Derek J.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Tumusiime, Gerald] Makerere Univ, Coll Hlth Sci, Dept Gen Surg, Kampala, Uganda. [Cusack, James C., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg,Div Surg Oncol, Boston, MA USA. RP Erstad, DJ (reprint author), Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. EM jcusack@mgh.harvard.edu NR 252 TC 4 Z9 4 U1 1 U2 9 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 OCT PY 2015 VL 22 IS 11 BP 3433 EP 3450 DI 10.1245/s10434-015-4706-x PG 18 WC Oncology; Surgery SC Oncology; Surgery GA CR1EX UT WOS:000361067900005 PM 26215192 ER PT J AU DePeralta, DK Boland, GM AF DePeralta, Danielle K. Boland, Genevieve M. TI Melanoma: Advances in Targeted Therapy and Molecular Markers SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID SQUAMOUS-CELL CARCINOMA; METASTATIC MELANOMA; CUTANEOUS MELANOMA; MUTANT MELANOMA; OPEN-LABEL; IMPROVED SURVIVAL; COMPLETE RESPONSE; MUCOSAL MELANOMA; MEK INHIBITION; BRAF MUTATIONS AB In recent years, there have been dramatic improvements in the diagnosis and treatment of patients with melanoma. The development of molecular markers and associated targeted therapies have given new hope to subsets of patients with advanced disease. Here we discuss the most important advances in molecular targeted therapy and how these developments are likely to affect the practice of the clinical surgeon. Germ-line and somatic mutations are common in melanoma and provide prognostic information that can now be harnessed to provide a more personalized approach to cancer treatment. BRAF mutation at the V600 position is the most commonly identified mutation in patients with melanoma. Treatment with targeted inhibitors in patients with BRAF-mutant melanoma has afforded dramatic responses in about half of selected patients. Unfortunately, disease control is not durable and recurrences are common. We predict an increasing role for the surgeon in the multidisciplinary treatment of patients with metastatic disease, as well as a role for molecular profiling in patients with high-risk early stage disease. Further, we are only beginning to understand the prognostic significance of various gene mutations in patients with melanoma. C1 [DePeralta, Danielle K.; Boland, Genevieve M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Surg Oncol, Boston, MA 02163 USA. RP DePeralta, DK (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Surg Oncol, Boston, MA 02163 USA. EM genevieveboland@gmail.com NR 68 TC 5 Z9 5 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD OCT PY 2015 VL 22 IS 11 BP 3451 EP 3458 DI 10.1245/s10434-015-4702-1 PG 8 WC Oncology; Surgery SC Oncology; Surgery GA CR1EX UT WOS:000361067900006 PM 26224403 ER PT J AU Azzoli, CG AF Azzoli, Christopher G. TI Practical Value of Molecular Pathology in Stage I-III Lung Cancer: Implications for the Clinical Surgeon SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID TYROSINE KINASE INHIBITORS; PHASE-III; CLONAL RELATIONSHIPS; ADJUVANT ERLOTINIB; MUTATION STATUS; POOLED ANALYSIS; GEFITINIB; EGFR; SURVIVAL; TUMORS AB Over a decade since the discovery of EGFR mutation, and 6 years since prospective clinical trial data proved that routine molecular pathology tests improve survival in stage IV lung cancer, there is still debate whether to test patients with earlier stages of disease (stage I-III). As discoveries of targeted drugs for stage IV patients accelerate-prompting routine testing for ALK, ROS1, RET, BRAF V600E, and HER2, among others-there is an argument that all lung cancers should be genotyped for the purpose of classification, regardless of stage of disease. The counterargument is that because targeted drugs have only been validated for use in stage IV disease, these molecular tests need only be conducted at the time of disease recurrence. This review will describe current, practical applications of molecular pathology testing in early stage lung cancer, focusing on the immediate diagnostic, prognostic, and therapeutic implications for individual patient management. Meanwhile, large-scale clinical trials are underway to test targeted drugs as adjuvant therapies in patients with early stage disease. C1 Massachusetts Gen Hosp, Ctr Canc, Thorac Oncol Program, Boston, MA 02114 USA. RP Azzoli, CG (reprint author), Massachusetts Gen Hosp, Ctr Canc, Thorac Oncol Program, Boston, MA 02114 USA. EM cazzoli@mgh.harvard.edu NR 37 TC 1 Z9 1 U1 1 U2 8 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 OCT PY 2015 VL 22 IS 11 BP 3459 EP 3465 DI 10.1245/s10434-015-4704-z PG 7 WC Oncology; Surgery SC Oncology; Surgery GA CR1EX UT WOS:000361067900007 PM 26215190 ER PT J AU Neogi, T Jansen, TLTA Dalbeth, N Fransen, J Schumacher, HR Berendsen, D Brown, M Choi, H Edwards, NL Janssens, HJEM Liote, F Naden, RP Nuki, G Ogdie, A Perez-Ruiz, F Saag, K Singh, JA Sundy, JS Tausche, AK Vaquez-Mellado, J Yarows, SA Taylor, WJ AF Neogi, Tuhina Jansen, Tim L. Th A. Dalbeth, Nicola Fransen, Jaap Schumacher, H. Ralph Berendsen, Dianne Brown, Melanie Choi, Hyon Edwards, N. Lawrence Janssens, Hein J. E. M. Liote, Frederic Naden, Raymond P. Nuki, George Ogdie, Alexis Perez-Ruiz, Fernando Saag, Kenneth Singh, Jasvinder A. Sundy, John S. Tausche, Anne-Kathrin Vaquez-Mellado, Janitzia Yarows, Steven A. Taylor, William J. TI 2015 Gout classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID SYSTEMIC-SCLEROSIS; PRIMARY-CARE; ARTHRITIS; IDENTIFICATION; UK; QUESTIONNAIRE; POPULATION; PREVALENCE; MANAGEMENT AB Objective Existing criteria for the classification of gout have suboptimal sensitivity and/or specificity, and were developed at a time when advanced imaging was not available. The current effort was undertaken to develop new classification criteria for gout. Methods An international group of investigators, supported by the American College of Rheumatology and the European League Against Rheumatism, conducted a systematic review of the literature on advanced imaging of gout, a diagnostic study in which the presence of monosodium urate monohydrate (MSU) crystals in synovial fluid or tophus was the gold standard, a ranking exercise of paper patient cases, and a multi-criterion decision analysis exercise. These data formed the basis for developing the classification criteria, which were tested in an independent data set. Results The entry criterion for the new classification criteria requires the occurrence of at least one episode of peripheral joint or bursal swelling, pain, or tenderness. The presence of MSU crystals in a symptomatic joint/bursa (ie, synovial fluid) or in a tophus is a sufficient criterion for classification of the subject as having gout, and does not require further scoring. The domains of the new classification criteria include clinical (pattern of joint/bursa involvement, characteristics and time course of symptomatic episodes), laboratory (serum urate, MSU-negative synovial fluid aspirate), and imaging (double-contour sign on ultrasound or urate on dual-energy CT, radiographic gout-related erosion). The sensitivity and specificity of the criteria are high (92% and 89%, respectively). Conclusions The new classification criteria, developed using a data-driven and decision-analytic approach, have excellent performance characteristics and incorporate current state-of-the-art evidence regarding gout. C1 [Neogi, Tuhina; Choi, Hyon] Boston Univ, Sch Med, Boston, MA 02118 USA. [Jansen, Tim L. Th A.] Viecuri Med Ctr, Venlo, Netherlands. [Jansen, Tim L. Th A.; Fransen, Jaap; Berendsen, Dianne; Janssens, Hein J. E. M.] Radboud Univ Nijmegen, Med Ctr, NL-6525 ED Nijmegen, Netherlands. [Dalbeth, Nicola] Univ Auckland, Auckland 1, New Zealand. [Schumacher, H. Ralph; Ogdie, Alexis] Univ Penn, Philadelphia, PA 19104 USA. [Brown, Melanie; Taylor, William J.] Univ Otago, Wellington, New Zealand. [Edwards, N. Lawrence] Univ Florida, Gainesville, FL USA. [Liote, Frederic] Hop Lariboisiere, AP HP, INSERM, UMR 1132, F-75475 Paris, France. [Liote, Frederic] Univ Paris Diderot, Sorbonne Paris Cite, Paris, France. [Naden, Raymond P.] McMaster Univ, Med Ctr, Hamilton, ON, Canada. [Nuki, George] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Perez-Ruiz, Fernando] Hosp Univ Cruces, Vizcaya, Spain. [Perez-Ruiz, Fernando] BioCruces Hlth Res Inst, Vizcaya, Spain. [Saag, Kenneth] Univ Alabama Birmingham, Birmingham, AL USA. [Singh, Jasvinder A.] Birmingham VA Med Ctr, Rochester, MN USA. [Singh, Jasvinder A.] Univ Alabama Birmingham, Rochester, MN USA. [Singh, Jasvinder A.] Mayo Clin, Coll Med, Rochester, MN USA. [Sundy, John S.] Duke Univ, Durham, NC USA. [Sundy, John S.] Duke Univ, Med Ctr, Durham, NC USA. [Sundy, John S.] Gilead Sci Inc, Foster City, CA 94404 USA. [Tausche, Anne-Kathrin] Univ Hosp Carl Gustav Carus, Dresden, Germany. [Vaquez-Mellado, Janitzia] Hosp Gen Mexico City, Mexico City, DF, Mexico. [Yarows, Steven A.] Univ Michigan Hlth Syst, Chelsea, MI USA. RP Neogi, T (reprint author), Boston Univ, Sch Med, X Bldg,Suite 200,650 Albany St, Boston, MA 02118 USA. EM tneogi@bu.edu RI Fransen, J./L-4310-2015; OI Ogdie, Alexis/0000-0002-4639-0775; Neogi, Tuhina/0000-0002-9515-1711; Perez-Ruiz, Fernando/0000-0002-5268-1894 FU American College of Rheumatology; European League Against Rheumatism; NIH [P60-AR-47785, K23-AR-055127]; Agency for Healthcare Research and Quality (Center for Education and Research on Therapeutics programme); NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases); NIH (National Institute on Aging); NIH (National Cancer Institute); Arthritis New Zealand FX Supported jointly by the American College of Rheumatology and the European League Against Rheumatism. TN's work was supported by the NIH (grants P60-AR-47785 and K23-AR-055127). JAS' work was supported by the NIH (grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Institute on Aging, and the National Cancer Institute) and the Agency for Healthcare Research and Quality (Center for Education and Research on Therapeutics programme). WJT's work was supported by Arthritis New Zealand. NR 35 TC 38 Z9 48 U1 4 U2 17 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD OCT PY 2015 VL 74 IS 10 BP 1789 EP 1798 DI 10.1136/annrheumdis-2015-208237 PG 10 WC Rheumatology SC Rheumatology GA CR0WC UT WOS:000361043200005 PM 26359487 ER PT J AU Neogi, T Jansen, TLTA Dalbeth, N Fransen, J Schumacher, HR Berendsen, D Brown, M Choi, H Edwards, NL Janssens, HJEM Liote, F Naden, RP Nuki, G Ogdie, A Perez-Ruiz, F Saag, K Singh, JA Sundy, JS Tausche, AK Vaquez-Mellado, J Yarows, SA Taylor, WJ AF Neogi, Tuhina Jansen, Tim L. Th. A. Dalbeth, Nicola Fransen, Jaap Schumacher, H. Ralph Berendsen, Dianne Brown, Melanie Choi, Hyon Edwards, N. Lawrence Janssens, Hein J. E. M. Liote, Frederic Naden, Raymond P. Nuki, George Ogdie, Alexis Perez-Ruiz, Fernando Saag, Kenneth Singh, Jasvinder A. Sundy, John S. Tausche, Anne-Kathrin Vaquez-Mellado, Janitzia Yarows, Steven A. Taylor, William J. TI 2015 Gout Classification Criteria An American College of Rheumatology/European League Against Rheumatism Collaborative Initiative SO ARTHRITIS & RHEUMATOLOGY LA English DT Article ID PRIMARY-CARE; ARTHRITIS; IDENTIFICATION; POPULATION; PREVALENCE; UK; MANAGEMENT AB ObjectiveExisting criteria for the classification of gout have suboptimal sensitivity and/or specificity, and were developed at a time when advanced imaging was not available. The current effort was undertaken to develop new classification criteria for gout. MethodsAn international group of investigators, supported by the American College of Rheumatology and the European League Against Rheumatism, conducted a systematic review of the literature on advanced imaging of gout, a diagnostic study in which the presence of monosodium urate monohydrate (MSU) crystals in synovial fluid or tophus was the gold standard, a ranking exercise of paper patient cases, and a multicriterion decision analysis exercise. These data formed the basis for developing the classification criteria, which were tested in an independent data set. ResultsThe entry criterion for the new classification criteria requires the occurrence of at least 1 episode of peripheral joint or bursal swelling, pain, or tenderness. The presence of MSU crystals in a symptomatic joint/bursa (i.e., synovial fluid) or in a tophus is a sufficient criterion for classification of the subject as having gout, and does not require further scoring. The domains of the new classification criteria include clinical (pattern of joint/bursa involvement, characteristics and time course of symptomatic episodes), laboratory (serum urate, MSU-negative synovial fluid aspirate), and imaging (double-contour sign on ultrasound or urate on dual-energy computed tomography, radiographic gout-related erosion). The sensitivity and specificity of the criteria are high (92% and 89%, respectively). ConclusionThe new classification criteria, developed using a data-driven and decision analytic approach, have excellent performance characteristics and incorporate current state-of-the-art evidence regarding gout. C1 [Neogi, Tuhina; Choi, Hyon] Boston Univ, Sch Med, Boston, MA 02118 USA. [Jansen, Tim L. Th. A.] Viecuri Med Ctr, Venlo, Netherlands. [Jansen, Tim L. Th. A.; Fransen, Jaap; Berendsen, Dianne; Janssens, Hein J. E. M.] Radboud Univ Nijmegen Med Ctr, Nijmegen, Netherlands. [Dalbeth, Nicola] Univ Auckland, Auckland 1, New Zealand. [Schumacher, H. Ralph; Ogdie, Alexis] Univ Penn, Philadelphia, PA 19104 USA. [Brown, Melanie; Taylor, William J.] Univ Otago, Wellington, New Zealand. [Edwards, N. Lawrence] Univ Florida, Gainesville, FL USA. [Liote, Frederic] Hop Lariboisiere, AP HP, INSERM, UMR 1132, F-75475 Paris, France. [Liote, Frederic] Univ Paris Diderot, Sorbonne Paris Cite, Paris, France. [Naden, Raymond P.] McMaster Univ, Med Ctr, Hamilton, ON, Canada. [Nuki, George] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Perez-Ruiz, Fernando] Hosp Univ Cruces, Vizcaya, Spain. [Perez-Ruiz, Fernando] BioCruces Hlth Res Inst, Vizcaya, Spain. [Saag, Kenneth; Singh, Jasvinder A.] Univ Alabama, Tuscaloosa, AL 35487 USA. [Singh, Jasvinder A.] Birmingham VA Med Ctr, Birmingham, AL USA. [Singh, Jasvinder A.] Mayo Clin, Coll Med, Rochester, MN USA. [Sundy, John S.] Duke Univ, Durham, NC USA. [Sundy, John S.] Duke Univ, Med Ctr, Durham, NC USA. [Tausche, Anne-Kathrin] Univ Hosp Carl Gustav Carus, Dresden, Germany. [Vaquez-Mellado, Janitzia] Hosp Gen Mexico City, Mexico City, DF, Mexico. [Yarows, Steven A.] Univ Michigan Hlth Syst, Chelsea, MI USA. RP Neogi, T (reprint author), Boston Univ, Sch Med, X Bldg,Suite 200,650 Albany St, Boston, MA 02118 USA. EM tneogi@bu.edu RI Fransen, J./L-4310-2015; Jansen, T.L.Th.A./L-4407-2015; OI Ogdie, Alexis/0000-0002-4639-0775; Perez-Ruiz, Fernando/0000-0002-5268-1894 FU American College of Rheumatology; European League Against Rheumatism; NIH [P60-AR-47785, K23-AR-055127]; Agency for Healthcare Research and Quality (Center for Education and Research on Therapeutics program); Arthritis New Zealand; NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases); NIH (National Institute on Aging); NIH (National Cancer Institute); AbbVie; Bristol-Myers Squibb; Roche; Janssen; Novartis; Menarini; Takeda; Teijin; Pfizer; Fonterra; AstraZeneca/Ardea; Regeneron; AstraZeneca; Metabolex; Crealta; CymaBay; Ardea; Ipsen; Savient; Mayoly-Spindler; Amgen; Allergan; Merck; Lilly; Navigant; Berlin-Chemie Menarini FX Supported jointly by the American College of Rheumatology and the European League Against Rheumatism. Dr. Neogi's work was supported by the NIH (grants P60-AR-47785 and K23-AR-055127). Dr. Singh's work was supported by the NIH (grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Institute on Aging, and the National Cancer Institute) and the Agency for Healthcare Research and Quality (Center for Education and Research on Therapeutics program). Dr. Taylor's work was supported by Arthritis New Zealand.; Dr. Jansen has received consulting fees, speaking fees, and/or honoraria from AbbVie, Bristol-Myers Squibb, Roche, Janssen, Novartis, and Menarini (less than $10,000 each). Dr. Dalbeth has received consulting fees, speaking fees, and/or honoraria from Takeda, Teijin, Menarini, Pfizer, and Fonterra (less than $10,000 each) and AstraZeneca/Ardea (more than $10,000); she holds a patent for Fonterra milk products for gout. Dr. Schumacher has received consulting fees from Novartis, Regeneron, AstraZeneca, and Metabolex (less than $10,000 each). Dr. Choi has received consulting fees, speaking fees, and/or honoraria from AstraZeneca (less than $10,000) and Takeda (more than $10,000). Dr. Edwards has received consulting fees, speaking fees, and/or honoraria from AstraZeneca, Crealta, CymaBay, and Takeda (less than $10,000 each). Dr. Liote has received consulting fees, speaking fees, and/or honoraria from Novartis, Ardea, AstraZeneca, Ipsen, Menarini, and Savient (less than $10,000 each) and unrestricted academic grants from Novartis, AstraZeneca, Ipsen, Menarini, Savient, and Mayoly-Spindler. Dr. Perez-Ruiz has received consulting fees, speaking fees, and/or honoraria from AstraZeneca, Menarini, Pfizer, and CymaBay (less than $10,000 each). Dr. Saag has received consulting fees, speaking fees, and/or honoraria from Amgen, AstraZeneca/Ardea, Crealta, and Takeda (less than $10,000 each). Dr. Singh has received consulting fees, speaking fees, and/or honoraria from Regeneron, Allergan, and Savient (less than $10,000 each) and Takeda (more than $10,000) and research grants from Savient and Takeda. Dr. Sundy has received consulting fees from Merck, Lilly, AstraZeneca, Metabolex, Novartis, and Navigant (less than $10,000 each). Dr. Tausche has received consulting fees, speaking fees, and/or honoraria from Berlin-Chemie Menarini (less than $10,000) and has served as an expert witness on behalf of Ardea Biosciences/AstraZeneca and Novartis. Dr. Taylor has received consulting fees, speaking fees, and/or honoraria from Pfizer, AstraZeneca, AbbVie, and Roche (less than $10,000 each). NR 35 TC 26 Z9 26 U1 0 U2 4 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 OCT PY 2015 VL 67 IS 10 BP 2557 EP 2568 DI 10.1002/art.39254 PG 12 WC Rheumatology SC Rheumatology GA CR3QS UT WOS:000361248600001 PM 26352873 ER PT J AU Deason, RG Hussey, EP Flannery, S Ally, BA AF Deason, Rebecca G. Hussey, Erin P. Flannery, Sean Ally, Brandon A. TI Preserved conceptual implicit memory for pictures in patients with Alzheimer's disease SO BRAIN AND COGNITION LA English DT Article DE Conceptual implicit memory; Picture superiority effect; Familiarity; Alzheimer's disease ID MILD COGNITIVE IMPAIRMENT; SEMANTIC MEMORY; RECOGNITION MEMORY; SHARED FEATURES; REMAINS INTACT; SUPERIORITY; FAMILIARITY; DEMENTIA; TASKS; IMAGERY AB The current study examined different aspects of conceptual implicit memory in patients with mild Alzheimer's disease (AD). Specifically, we were interested in whether priming of distinctive conceptual features versus general semantic information related to pictures and words would differ for the mild AD patients and healthy older adults. In this study, 14 healthy older adults and 15 patients with mild AD studied both pictures and words followed by an implicit test section, where they were asked about distinctive conceptual or general semantic information related to the items they had previously studied (or novel items). Healthy older adults and patients with mild AD showed both conceptual priming and the picture superiority effect, but the AD patients only showed these effects for the questions focused on the distinctive conceptual information. We found that patients with mild AD showed intact conceptual picture priming in a task that required generating a response (answer) from a cue (question) for cues that focused on distinctive conceptual information. This experiment has helped improve our understanding of both the picture superiority effect and conceptual implicit memory in patients with mild AD in that these findings support the notion that conceptual implicit memory might potentially help to drive familiarity-based recognition in the face of impaired recollection in patients with mild AD. (c) 2015 Published by Elsevier Inc. C1 [Deason, Rebecca G.] Texas State Univ, Dept Psychol, San Marcos, TX USA. [Hussey, Erin P.; Ally, Brandon A.] Vanderbilt Univ, Dept Neurol, Nashville, TN 37235 USA. [Ally, Brandon A.] Vanderbilt Univ, Dept Psychiat, Nashville, TN 37235 USA. [Ally, Brandon A.] Vanderbilt Univ, Dept Psychol, Nashville, TN 37240 USA. [Flannery, Sean] VA Boston Healthcare Syst, Ctr Translat Cognit Neurosci, Boston, MA USA. [Flannery, Sean] Boston Univ, Sch Med, Boston Univ Alzheimers Dis Ctr, Boston, MA 02118 USA. RP Ally, BA (reprint author), Dept Neurol, A-0118 Med Ctr North,1161 21st Ave South, Nashville, TN 37232 USA. EM brandon.ally@vanderbilt.edu FU National Institute on Aging [AG038471, AG031925]; Department of Veterans Affairs, Veterans Health Administration, VISN 1 Early Career Development Award FX This research was supported by National Institute on Aging grants AG038471 (BAA), AG031925 (BAA), and a Department of Veterans Affairs, Veterans Health Administration, VISN 1 Early Career Development Award to RGD. We would like to thank Bruno Frustace for assistance with data collection. This material is also the result of work supported with resources and the use of facilities at the Bedford VA Hospital in Bedford, MA and the VA Boston Healthcare System, Boston, MA. NR 46 TC 1 Z9 1 U1 2 U2 13 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0278-2626 EI 1090-2147 J9 BRAIN COGNITION JI Brain Cogn. PD OCT PY 2015 VL 99 BP 112 EP 117 DI 10.1016/j.bandc.2015.07.008 PG 6 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA CR2LD UT WOS:000361160200012 PM 26291521 ER PT J AU Kaji, I Akiba, Y Said, H Narimatsu, K Kaunitz, JD AF Kaji, I. Akiba, Y. Said, H. Narimatsu, K. Kaunitz, J. D. TI Luminal 5-HT stimulates colonic bicarbonate secretion in rats SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Article ID NITRIC-OXIDE; ION-TRANSPORT; CONCISE GUIDE; ELECTROLYTE TRANSPORT; ARRIVE GUIDELINES; SEROTONIN RELEASE; ANION SECRETION; G-PROTEIN; 5-HYDROXYTRYPTAMINE; RECEPTORS AB Background and PurposeThe bioactive monoamine 5-HT, implicated in the pathogenesis of functional gastrointestinal disorders, is abundantly synthesized and stored in rat proximal colonic mucosa and released to the gut lumen and subepithelial space. Despite much data regarding its expression and function, the effects of luminal 5-HT on colonic anion secretion have not been fully investigated. Experimental ApproachWe measured short-circuit current (I-sc) as an indicator of ion transport in mucosa-submucosa or mucosa-only preparations of rat proximal colon. Total CO2 output was measured in vitro and in vivo. Immunohistochemistry was performed to investigate the localization of 5-HT4, NOS1 and NOS2. Key ResultsLuminal 5-HT gradually increased the amplitude and sustained the elevation of I-sc. Luminal 5-HT-evoked I-sc was acetazolamide sensitive and HCO3- dependent, consistent with cytosolic carbonic anhydrase-dependent electrogenic HCO3- secretion, while not affected by tetrodotoxin (TTX), atropine or indomethacin. Pretreatment with the selective 5-HT4 antagonist GR113808, but not antagonists for 5-HT3, 5-HT6 or 5-HT7, inhibited luminal 5-HT-evoked I-sc. Furthermore, luminal cisapride and tegaserod increased I-sc to the same extent as did 5-HT in the presence of indomethacin and TTX. Removal of the submucosa or pretreatment with NOS inhibitors enhanced luminal 5-HT-evoked I-sc, suggesting that NO synthesized in the submucosa suppresses mucosal anion secretion. NOS1 and NOS2 were immunostained in the submucosal neurons and glial cells respectively. Luminal 5-HT-evoked HCO3- secretion was confirmed in vivo, inhibited by co-perfusion of GR113808, but not by ondansetron. Conclusions and ImplicationsA novel apical 5-HT4-mediated HCO3- secretory pathway and an NO-dependent inhibitory mechanism are present in the proximal colon. Luminal 5-HT-evoked HCO3- secretion may be important for the maintenance of mucosal integrity by regulating luminal pH. C1 [Kaji, I.; Akiba, Y.; Narimatsu, K.; Kaunitz, J. D.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. [Kaunitz, J. D.] Univ Calif Los Angeles, Dept Surg, Sch Med, Los Angeles, CA 90024 USA. [Said, H.] Univ Calif Los Angeles, Coll Letters & Sci, Los Angeles, CA USA. [Kaji, I.; Akiba, Y.; Kaunitz, J. D.] Brentwood Biomed Res Inst, Los Angeles, CA USA. [Akiba, Y.; Kaunitz, J. D.] Greater Los Angeles Vet Affairs Healthcare Syst, Los Angeles, CA USA. RP Kaunitz, JD (reprint author), West Los Angeles VA Med Ctr, Bldg 114,Suite 217,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM jake@ucla.edu FU Department of Veterans Affairs Merit Review Award; NIH-NIDDK [R01 DK54221, P30 DK0413] FX The authors thank B. Palileo for preparing the manuscript. The helpful discussion of Dr E. Engel and Dr P. H. Guth is gratefully acknowledged. This study was supported by a Department of Veterans Affairs Merit Review Award, NIH-NIDDK R01 DK54221 (J. D. K.), and the animal core of NIH-NIDDK P30 DK0413 (J. E. Rozengurt). NR 57 TC 5 Z9 5 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1188 EI 1476-5381 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD OCT PY 2015 VL 172 IS 19 BP 4655 EP 4670 DI 10.1111/bph.13216 PG 16 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CQ9FM UT WOS:000360918200005 PM 26061462 ER PT J AU Cao, Y Meyerhardt, JA Chan, AT Wu, K Fuchs, CS Giovannucci, EL AF Cao, Yin Meyerhardt, Jeffrey A. Chan, Andrew T. Wu, Kana Fuchs, Charles S. Giovannucci, Edward L. TI Television watching and colorectal cancer survival in men SO CANCER CAUSES & CONTROL LA English DT Article DE Sedentary behavior; Television watching; Colorectal cancer; Survival ID TYPE-2 DIABETES-MELLITUS; ALL-CAUSE MORTALITY; PHYSICAL-ACTIVITY; SEDENTARY BEHAVIOR; CARDIOVASCULAR-DISEASE; VIEWING TIME; RECTAL-CANCER; COLON-CANCER; AARP DIET; RISK AB To assess the association between pre- and postdiagnostic time spent sitting watching TV as well as other sedentary behaviors (other sitting at home and at work/driving) and mortality from colorectal cancer or other causes, and overall mortality. We followed stage I-III colorectal cancer patients from the Health Professionals Follow-up Study (1986-2010). Cox models were used to calculate hazard ratios (HRs) and 95 % confidence intervals (CIs). A total of 926 and 714 patients were included in the analysis of pre- and postdiagnostic TV watching, respectively, and 471 and 325 died during follow-up. Prolonged prediagnostic TV viewing was associated with increased risk of colorectal cancer-specific mortality independent of leisure-time physical activity. The HRs (95 % CIs) for 0-6, 7-13, 14-20, and a parts per thousand yen21 h/week were 1.00 (referent), 0.84 (0.56-1.25), 1.15 (0.75-1.78), and 2.13 (1.31-3.45) (p (trend) = 0.01). The association was observed primarily among overweight and obese individuals. Prediagnostic TV watching was also associated with overall mortality within 5 years of diagnosis, largely due to the association with colorectal cancer mortality. Other prediagnostic sitting at home or at work/driving was not associated with mortality. Postdiagnostic TV viewing was associated with a nonsignificantly increased risk of colorectal cancer-specific mortality (HR for a parts per thousand yen21 vs 0-6 h/week = 1.45; 95 % CI 0.73-2.87) adjusting for TV viewing before diagnosis. Prolonged prediagnostic TV watching is associated with higher colorectal cancer-specific mortality independent of leisure-time physical activity among colorectal cancer patients. C1 [Cao, Yin; Wu, Kana; Giovannucci, Edward L.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Meyerhardt, Jeffrey A.; Fuchs, Charles S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Meyerhardt, Jeffrey A.; Chan, Andrew T.; Fuchs, Charles S.; Giovannucci, Edward L.] Harvard Univ, Sch Med, Boston, MA USA. [Chan, Andrew T.; Fuchs, Charles S.; Giovannucci, Edward L.] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Giovannucci, Edward L.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Cao, Y (reprint author), Harvard Univ, TH Chan Sch Publ Hlth, Dept Nutr, 665 Huntington Ave, Boston, MA 02115 USA. EM yic576@mail.harvard.edu FU National Institute of Health [P01 CA87969, P01 CA55075, UM1 CA167552, R01 CA137178, K24 DK098311] FX This work was supported by Grants from the National Institute of Health (P01 CA87969; P01 CA55075; UM1 CA167552; R01 CA137178; K24 DK098311). Dr. Chan is a Damon Runyon Clinical Investigator. The study sponsors had no role in the design of the study: the collection, analysis, and interpretation of the data; the writing of the manuscript; and the decision to submit the manuscript for publication. NR 40 TC 1 Z9 1 U1 0 U2 11 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 OCT PY 2015 VL 26 IS 10 BP 1467 EP 1476 DI 10.1007/s10552-015-0645-x PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CR1FD UT WOS:000361068800010 PM 26293240 ER PT J AU Poole, EM Schernhammer, E Mills, L Hankinson, SE Tworoger, SS AF Poole, Elizabeth M. Schernhammer, Eva Mills, Leigha Hankinson, Susan E. Tworoger, Shelley S. TI Urinary melatonin and risk of ovarian cancer SO CANCER CAUSES & CONTROL LA English DT Article DE Melatonin; Circadian rhythm; Ovarian cancer ID BREAST-CANCER; SHIFT-WORK; CELL-LINES; CIRCADIAN DISRUPTION; NURSES HEALTH; WOMEN; NIGHT; EXPRESSION; GROWTH; LIGHT AB Melatonin has anti-carcinogenic properties, including modulation of estradiol production, cell cycle regulation, and promotion of apoptosis. Urinary melatonin has been inversely associated with breast cancer in some studies, but the association with ovarian cancer has not been investigated. We measured urinary 6-sulfatoxymelatonin (aMT6s) in nested ovarian cancer case-control studies in the Nurses' Health Study (NHS; n = 100 cases; 199 controls) and NHSII (n = 52 cases; 105 controls); samples were mainly from first morning voids. Controls were matched to cases on year of birth, menopause status, use of menopausal hormone therapy, and urine collection characteristics. We evaluated the association of tertiles of aMT6s, corrected for creatinine concentrations, with risk of ovarian cancer using conditional logistic regression. Models were adjusted for key ovarian cancer risk factors, and we additionally evaluated adjustment for usual sleep duration, snoring, and history of rotating night shift work. aMT6s was not significantly associated with risk of ovarian cancer. In multivariable models, the odds ratio comparing the highest tertile of aMT6s to the lowest was 0.79, 95 % confidence interval (CI) 0.40-1.56 in the NHS and 2.88, and 95 % CI in the NHSII 0.97-8.52. Additional adjustment for sleep habits and night shift work had little impact on the observed results. We observed no clear association between urinary melatonin and ovarian cancer risk. These results are consistent with our previous study in which we reported no association between night shift work and ovarian cancer; however, given the small sample size in our study, additional evaluation in larger studies is warranted. C1 [Poole, Elizabeth M.; Schernhammer, Eva; Hankinson, Susan E.; Tworoger, Shelley S.] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Poole, Elizabeth M.; Schernhammer, Eva; Hankinson, Susan E.; Tworoger, Shelley S.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Schernhammer, Eva; Hankinson, Susan E.; Tworoger, Shelley S.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Mills, Leigha] Dana Farber Canc Inst, Boston, MA 02115 USA. [Hankinson, Susan E.] Univ Massachusetts, Sch Publ Hlth & Hlth Sci, Div Biostat & Epidemiol, Amherst, MA 01003 USA. RP Poole, EM (reprint author), Brigham & Womens Hosp, Channing Div Network Med, 181 Longwood Ave,3rd Floor, Boston, MA 02115 USA. EM nhlip@channing.harvard.edu FU National Cancer Institute [UM1 CA186107, P01 CA87969, R01 CA49449, UM1 CA176726, R01 CA67262] FX We would like to thank the participants and staff of the Nurses' Health Studies for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, and WY. This work was supported by National Cancer Institute Grants UM1 CA186107, P01 CA87969, R01 CA49449, UM1 CA176726, and R01 CA67262. NR 28 TC 0 Z9 0 U1 6 U2 13 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 OCT PY 2015 VL 26 IS 10 BP 1501 EP 1506 DI 10.1007/s10552-015-0640-2 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA CR1FD UT WOS:000361068800014 PM 26223889 ER PT J AU Sarma, A Shyn, PB Vivian, MA Ng, JM Tuncali, K Lorch, JH Zaheer, SN Gordon, MS Silverman, SG AF Sarma, Asha Shyn, Paul B. Vivian, Mark A. Ng, Ju-Mei Tuncali, Kemal Lorch, Jorchen H. Zaheer, Sarah N. Gordon, Michael S. Silverman, Stuart G. TI Single-Session CT-Guided Percutaneous Microwave Ablation of Bilateral Adrenal Gland Hyperplasia Due to Ectopic ACTH Syndrome SO CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article DE Image-guided intervention; Adrenal hyperplasia; Cushing's syndrome; Ectopic ACTH syndrome; Microwave ablation ID RADIOFREQUENCY ABLATION; CUSHINGS-SYNDROME; CRYOABLATION; NEOPLASMS; TUMOR AB Bilateral adrenalectomy is currently the only available treatment for adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome (ectopic ACTH syndrome) that is refractory to pharmacologic therapy. We describe two patients with refractory ectopic ACTH syndrome who were treated with CT-guided percutaneous microwave ablation of both hyperplastic adrenal glands in a single session: O ne was not a surgical candidate, and the other had undergone unsuccessful surgery. Following the procedure, both patients achieved substantial decreases in serum cortisol, symptomatic improvement, and decreased anti-hypertensive medication requirements. C1 [Sarma, Asha; Shyn, Paul B.; Tuncali, Kemal; Silverman, Stuart G.] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Vivian, Mark A.] Univ Manitoba, Dept Radiol, Winnipeg, MB R3T 2N2, Canada. [Ng, Ju-Mei] Brigham & Womens Hosp, Dept Anesthesiol, Boston, MA 02115 USA. [Lorch, Jorchen H.] Dana Farber Canc Inst, Dept Med, Boston, MA 02115 USA. [Zaheer, Sarah N.; Gordon, Michael S.] Brigham & Womens Hosp, Dept Endocrinol, Boston, MA 02115 USA. RP Shyn, PB (reprint author), Brigham & Womens Hosp, Dept Radiol, 75 Francis St, Boston, MA 02115 USA. EM ashasarma@gmail.com; pshyn@partners.org FU Canon, Inc.; Novartis FX Dr. Tuncali receives grant support from Canon, Inc. for unrelated projects. Dr. Lorch receives grant support from Novartis for unrelated projects. NR 10 TC 1 Z9 1 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0174-1551 EI 1432-086X J9 CARDIOVASC INTER RAD JI Cardiovasc. Interv. Radiol. PD OCT PY 2015 VL 38 IS 5 BP 1335 EP 1338 DI 10.1007/s00270-015-1056-9 PG 4 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA CR1FH UT WOS:000361069400039 PM 25762486 ER PT J AU Kaushal, V Dye, R Pakavathkumar, P Foveau, B Flores, J Hyman, B Ghetti, B Koller, BH LeBlanc, AC AF Kaushal, V. Dye, R. Pakavathkumar, P. Foveau, B. Flores, J. Hyman, B. Ghetti, B. Koller, B. H. LeBlanc, A. C. TI Neuronal NLRP1 inflammasome activation of Caspase-1 coordinately regulates inflammatory interleukin-1-beta production and axonal degeneration-associated Caspase-6 activation SO CELL DEATH AND DIFFERENTIATION LA English DT Article ID AMYLOID PRECURSOR PROTEIN; ALZHEIMERS-DISEASE; MICROGLIAL ACTIVATION; COGNITIVE IMPAIRMENT; MOLECULAR PLATFORM; NALP3 INFLAMMASOME; BETA-PEPTIDE; EXPRESSION; APOPTOSIS; DEATH AB Neuronal active Caspase-6 (Casp6) is associated with Alzheimer disease (AD), cognitive impairment, and axonal degeneration. Caspase-1 (Casp1) can activate Casp6 but the expression and functionality of Casp1-activating inflammasomes has not been well-defined in human neurons. Here, we show that primary cultures of human CNS neurons expressed functional Nod-like receptor protein 1 (NLRP1), absent in melanoma 2, and ICE protease activating factor, but not the NLRP3, inflammasome receptor components. NLRP1 neutralizing antibodies in a cell-free system, and NLRP1 siRNAs in neurons hampered stress-induced Casp1 activation. NLRP1 and Casp1 siRNAs also abolished stress-induced Casp6 activation in neurons. The functionality of the NLRP1 inflammasome in serum-deprived neurons was also demonstrated by NLRP1 siRNA-mediated inhibition of speck formation of the apoptosis-associated speck-like protein containing a caspase recruitment domain conjugated to green fluorescent protein. These results indicated a novel stress-induced intraneuronal NLRP1/Casp1/Casp6 pathway. Lipopolysaccharide induced Casp1 and Casp6 activation in wild-type mice brain cortex, but not in that of Nlrp1(-/-) and Casp1(-/-) mice. NLRP1 immunopositive neurons were increased 25- to 30-fold in AD brains compared with non-AD brains. NLRP1 immunoreactivity in these neurons co-localized with Casp6 activity. Furthermore, the NLRP1/Casp1/Casp6 pathway increased amyloid beta peptide 42 ratio in serum-deprived neurons. Therefore, CNS human neurons express functional NLRP1 inflammasomes, which activate Casp1 and subsequently Casp6, thus revealing a fundamental mechanism linking intraneuronal inflammasome activation to Casp1-generated interleukin-1-beta-mediated neuroinflammation and Casp6-mediated axonal degeneration. C1 [Kaushal, V.; Pakavathkumar, P.; Foveau, B.; Flores, J.; LeBlanc, A. C.] Jewish Gen Hosp, Lady Davis Inst Med Res, Bloomfield Ctr Res Aging, Montreal, PQ H3T 1E2, Canada. [Kaushal, V.; Pakavathkumar, P.; Foveau, B.; Flores, J.; LeBlanc, A. C.] McGill Univ, Dept Neurol & Neurosurg, Montreal, PQ H3A 2B4, Canada. [Dye, R.; Koller, B. H.] Dept Genet, Chapel Hill, NC 27599 USA. [Hyman, B.] Massachusetts Gen Hosp, Mass Gen Inst Neurodegenerat, Charlestown, MA USA. [Ghetti, B.] Indiana Univ, Dept Pathol & Lab Med, Indianapolis, IN 46202 USA. RP LeBlanc, AC (reprint author), Sir Mortimer B Davis Jewish Hosp, Lady Davis Inst Med Res, Bloomfield Ctr Res Aging, 3755 Ch Cote Ste Catherine, Montreal, PQ H3T 1E2, Canada. EM andrea.leblanc@mcgill.ca FU Canadian Foundation of Innovation; Canadian Institutes of Health Research (CIHR) [MOP-243413-BCA-CGAG-45097]; JGH Foundation; NIH [P30 AG010133]; McGill's CIHR Neuroinflammation Training Program award; Fonds de recherche Quebec-Sante scholarship; FRSQ-Alzheimer Society of Canada doctoral award FX We thank Marc-Andre Dery for generating the ASC-GFP construct. The Canadian Foundation of Innovation, Canadian Institutes of Health Research (CIHR) MOP-243413-BCA-CGAG-45097, and the JGH Foundation (ALB), and NIH Grant P30 AG010133 (BG) supported this work. Dr. Vikas Kaushal was a recipient of McGill's CIHR Neuroinflammation Training Program award (2010-2012); Prateep Pakavathkumar is the recipient of a Fonds de recherche Quebec-Sante scholarship (2011-2013) and the FRSQ-Alzheimer Society of Canada doctoral award (2014-2016). NR 55 TC 15 Z9 15 U1 1 U2 13 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1350-9047 EI 1476-5403 J9 CELL DEATH DIFFER JI Cell Death Differ. PD OCT PY 2015 VL 22 IS 10 BP 1676 EP 1686 DI 10.1038/cdd.2015.16 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CR0DV UT WOS:000360989400010 PM 25744023 ER PT J AU Somanna, NK Yariswamy, M Garagliano, JM Siebenlist, U Mummidi, S Valente, AJ Chandrasekar, B AF Somanna, Naveen K. Yariswamy, Manjunath Garagliano, Joseph M. Siebenlist, Ulrich Mummidi, Srinivas Valente, Anthony J. Chandrasekar, Bysani TI Aldosterone-induced cardiomyocyte growth, and fibroblast migration and proliferation are mediated by TRAF3IP2 SO CELLULAR SIGNALLING LA English DT Article DE RAAS; Aldosterone; TRAF3IP2; Hypertrophy; Mitogenesis; Migration ID KAPPA-B KINASE; HEART-FAILURE; ANGIOTENSIN-II; MYOCARDIAL FIBROSIS; CARDIAC-HYPERTROPHY; MATRIX METALLOPROTEINASES; HYPERTENSIVE PATIENTS; SYSTOLIC DYSFUNCTION; PRESSURE-OVERLOAD; OXIDATIVE STRESS AB Sustained activation of the Renin-Angiotensin-Aldosterone System (RAAS) contributes to the pathogenesis of heart failure. Aldosterone (Aldo) is known to induce both myocardial hypertrophy and fibrosis through oxidative stress and proinflammatory pathways. Here we have investigated whether Aldo-mediated cardiomycocyte hypertrophy is dependent on TRAF3IP2, an upstream regulator of IKK and JNIC We also investigated whether the pro-mitogenic and pro-migratory effects of Aldo on cardiac fibroblasts are also mediated by TRAF3IP2. Aldo induced both superoxide and hydrogen peroxide in isolated adult mouse cardiomyocytes (CM), and upregulated TRAF3IP2 expression in part via the mineralocorticoid receptor and oxidative stress. Silencing TRAF3IP2 blunted Aldo-induced IKK beta, p65, JNK, and c-Jun activation, IL-18, IL-6 and CT-1 upregulation, and cardiomyocyte hypertrophy. In isolated adult mouse cardiac fibroblasts (CF), Aldo stimulated TRAF3IP2-dependent IL-18 and IL-6 production, CTGF, collagen land III expression, MMP2 activation, and proliferation and migration. These in vitro results suggest that TRAF3IP2 may play a causal role in Aldo-induced adverse cardiac remodeling in vivo, and identify TRAF3IP2 as a potential therapeutic target in hypertensive heart disease. (C) 2015 Elsevier Inc. All rights reserved. C1 [Somanna, Naveen K.] Tulane Univ, Sch Med, Dept Microbiol, New Orleans, LA 70112 USA. [Yariswamy, Manjunath; Garagliano, Joseph M.; Chandrasekar, Bysani] Tulane Univ, Sch Med, Inst Heart & Vasc, New Orleans, LA 70112 USA. [Yariswamy, Manjunath; Chandrasekar, Bysani] Southeast Louisiana Vet Hlth Care Syst, New Orleans, LA 70161 USA. [Siebenlist, Ulrich; Chandrasekar, Bysani] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Siebenlist, Ulrich; Chandrasekar, Bysani] South Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. [Mummidi, Srinivas; Valente, Anthony J.] NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Chandrasekar, B (reprint author), Tulane Univ, Sch Med, Inst Heart & Vasc, 1430 Tulane Ave,SL-48, New Orleans, LA 70112 USA. FU Department of Veterans Affairs Research Career Scientist award; U.S. Department of Veterans Affairs, Office of Research and Development-Biomedical Laboratory Research and Development (ORD-BLRD) Service Award [VA-I01 BX002255]; Usha Ramadhyani Bourgeois Medical Student Research Endowed Fund; NIH/NIAID FX BC is a recipient of the Department of Veterans Affairs Research Career Scientist award, and is supported by the U.S. Department of Veterans Affairs, Office of Research and Development-Biomedical Laboratory Research and Development (ORD-BLRD) Service Award VA-I01 BX002255. JMG is a recipient of The Warren R Bourgeois III and Usha Ramadhyani Bourgeois Medical Student Research Endowed Fund. US is supported by the Intramural Research Program of the NIH/NIAID. The contents of this report do not represent the views of the Department of Veterans Affairs or the United States government NR 44 TC 7 Z9 8 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0898-6568 EI 1873-3913 J9 CELL SIGNAL JI Cell. Signal. PD OCT PY 2015 VL 27 IS 10 BP 1928 EP 1938 DI 10.1016/j.cellsig.2015.07.001 PG 11 WC Cell Biology SC Cell Biology GA CQ7ID UT WOS:000360775300002 PM 26148936 ER PT J AU Siegler, JE Samai, A Albright, KC Boehme, AK Martin-Schild, S AF Siegler, James E. Samai, Alyana Albright, Karen C. Boehme, Amelia K. Martin-Schild, Sheryl TI Factoring in Factor VIII With Acute Ischemic Stroke SO CLINICAL AND APPLIED THROMBOSIS-HEMOSTASIS LA English DT Review DE stroke; von Willebrand factor; thrombosis; hypercoagulability; factor viii ID VON-WILLEBRAND-FACTOR; ELEVATED FACTOR-VIII; CLOTTING FACTOR-VIII; HIGH PLASMA-LEVELS; FACTOR-V-LEIDEN; RISK-FACTORS; MYOCARDIAL-INFARCTION; VENOUS THROMBOEMBOLISM; COAGULATION-FACTORS; HIGH PREVALENCE AB There is growing research interest into the etiologies of cryptogenic stroke, in particular as it relates to hypercoagulable states. An elevation in serum levels of the procoagulant factor VIII is recognized as one such culprit of occult cerebral infarctions. It is the objective of the present review to summarize the molecular role of factor VIII in thrombogenesis and its clinical use in the diagnosis and prognosis of acute ischemic stroke. We also discuss the utility of screening for serum factor VIII levels among patients at risk for, or those who have experienced, ischemic stroke. C1 [Siegler, James E.; Samai, Alyana; Martin-Schild, Sheryl] Tulane Univ Med Ctr Hosp & Clin, Tulane Stroke Res Program, Dept Neurol, New Orleans, LA USA. [Samai, Alyana] Tulane Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA USA. [Albright, Karen C.] Birmingham VA Med Ctr, GRECC, Birmingham, AL USA. [Albright, Karen C.] Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA. [Boehme, Amelia K.] Columbia Univ, Dept Neurol, Gertrude Sergievsky Ctr, New York, NY USA. RP Martin-Schild, S (reprint author), Tulane Univ, Stroke Program, Tulane Stroke Res Program, Dept Neurol, 1440 Canal St,TB-52,Suite 1000, New Orleans, LA 70112 USA. EM smartin2@tulane.edu OI Siegler, James/0000-0003-0287-3967 FU NINDS NIH [T32 NS007153-31] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Dr. Boehme is supported by NINDS NIH T32 NS007153-31. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NINDS or the NIH. NR 48 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 1076-0296 EI 1938-2723 J9 CLIN APPL THROMB-HEM JI Clin. Appl. Thromb.-Hemost. PD OCT PY 2015 VL 21 IS 7 BP 597 EP 602 DI 10.1177/1076029615571630 PG 6 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA CQ8AB UT WOS:000360827200001 PM 25669199 ER PT J AU Marshall, AL Campigotto, F Neuberg, D Rowe, B Connors, JM AF Marshall, Ariela L. Campigotto, Federico Neuberg, Donna Rowe, Betty Connors, Jean M. TI Recurrence of Venous Thromboembolism in Patients With Cancer Treated With Warfarin SO CLINICAL AND APPLIED THROMBOSIS-HEMOSTASIS LA English DT Article DE anticoagulants; venous thromboembolism; hypercoagulability ID MOLECULAR-WEIGHT HEPARIN; SECONDARY PREVENTION; VEIN THROMBOSIS; USUAL CARE; RISK; COUMARIN; DISEASE; EVENTS AB Venous thromboembolism (VTE) is a common complication in patients with cancer. Previous randomized studies have demonstrated that the rates of recurrent VTE are lower in patients treated with low-molecular-weight heparin compared to warfarin. We performed a retrospective analysis of 236 patients with cancer managed by a dedicated oncology anticoagulation management service to compare real-world rates of recurrent VTE and bleeding in patients treated with warfarin versus parenteral anticoagulants. Initial anticoagulant regimen included a parenteral agent with transition to warfarin in 132 (55.9%) patients, enoxaparin in 53 (22.5%), dalteparin in 37 (15.7%), and fondaparinux in 14 (5.9%). Taking into account the competing risk of death, cumulative incidence of VTE recurrence at 6 months was 4.0% with warfarin, 10.3% with enoxaparin, 3.0% with dalteparin, and 7.7% with fondaparinux (P = .004). Bleeding complications occurred in 10.6% of patients on warfarin, 17.0% on enoxaparin, 27.0% on dalteparin, and 14.3% on fondaparinux (P = .089). In a dedicated anticoagulation clinic, specific for patients with cancer, warfarin may be an acceptable treatment for first thrombotic events in patients with cancer. C1 [Marshall, Ariela L.; Rowe, Betty; Connors, Jean M.] Dana Farber Canc Inst, Dept Hematol & Med Oncol, Boston, MA 02115 USA. [Campigotto, Federico; Neuberg, Donna] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Rowe, Betty; Connors, Jean M.] Brigham & Womens Hosp, Div Hematol, Boston, MA 02115 USA. RP Connors, JM (reprint author), Brigham & Womens Hosp, Dept Hematol, 75 Francis St,Mid Campus 3, Boston, MA 02115 USA. EM jconnors@partners.org FU Dana-Farber/Harvard Cancer Center Core Grant [5P30 CA-006516] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Statistical analyses were supported in part by the Dana-Farber/Harvard Cancer Center Core Grant 5P30 CA-006516. NR 23 TC 1 Z9 1 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1076-0296 EI 1938-2723 J9 CLIN APPL THROMB-HEM JI Clin. Appl. Thromb.-Hemost. PD OCT PY 2015 VL 21 IS 7 BP 632 EP 638 DI 10.1177/1076029615579099 PG 7 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA CQ8AB UT WOS:000360827200006 PM 25850917 ER PT J AU Huang, JW Feldman, AS Dong, L Cornejo, K Liu, Q Dahl, DM Wu, SL Blute, ML Huang, YR Wu, CL AF Huang, Jiwei Feldman, Adam S. Dong, Liang Cornejo, Kristine Liu, Qiang Dahl, Douglas M. Wu, Shulin Blute, Michael L. Huang, Yiran Wu, Chin-Lee TI Preoperative Anemia as an Independent Prognostic Indicator of Papillary Renal Cell Carcinoma SO CLINICAL GENITOURINARY CANCER LA English DT Article DE Anemia; Kidney; Neoplasm by histologic type; Prognosis; Renal cell carcinoma ID CLEAR-CELL; TUMOR HYPOXIA; NEPHRECTOMY; SURVIVAL; FEATURES; CANCER AB The role of preoperative anemia in the prognosis of patients with localized papillary renal cell carcinoma was retrospectively evaluated in 352 patients of 2 large institutions. Patients with anemia were older and more likely to have larger tumor size and higher Fuhrman grade. Anemia was an independent prognostic factor in terms of recurrence-free survival, cancer-specific survival, and overall survival. Preoperative anemia will provide urologists additional prognostic information in patients with papillary renal cell carcinoma. Objectives: Preoperative anemia has been proposed as a prognostic factor for clear cell renal cell carcinoma. We evaluate its role in papillary renal cell carcinoma (pRCC). Methods: At 2 institutions, patients who underwent complete resection of localized (T1-3 N0/+ M0) pRCC by radical or partial nephrectomy were retrospectively reviewed in this study. Anemia was defined as hemoglobin < 13.5 g/dL in men and < 12 g/dL in women. The associations of preoperative anemia with clinical and pathologic variables were assessed using the Student t, Wilcoxon rank-sum, and chi-square tests. Univariable and multivariable analyses using the Kaplan-Meier method and the Cox regression model were performed to determine factors that were associated with recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). Results: Our final cohort included 352 patients. Compared with patients without anemia, patients with anemia were older and more likely to have larger tumor size and higher Fuhrman grade. Kaplan-Meier curves showed that patients with preoperative anemia had significantly worse RFS, CSS, and OS than patients without anemia (log-rank test, all P<.001). Multivariable analyses revealed that anemia was an independent prognostic factor in terms of RFS, CSS, and OS (all P<.001). Conclusions: Preoperative anemia is an important independent prognostic factor associated with an increased risk of recurrence and mortality in patients after surgery with a curative intent for localized pRCC. Consideration of preoperative anemia could provide urologists additional prognostic information in patients with pRCC. (C) 2015 Elsevier Inc. All rights reserved. C1 [Huang, Jiwei; Dong, Liang; Huang, Yiran] Shanghai Jiao Tong Univ, Sch Med, Renji Hosp, Dept Urol, Shanghai 200127, Peoples R China. [Feldman, Adam S.; Dahl, Douglas M.; Blute, Michael L.] Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. [Feldman, Adam S.; Cornejo, Kristine; Dahl, Douglas M.; Wu, Shulin; Blute, Michael L.; Wu, Chin-Lee] Harvard Univ, Sch Med, Boston, MA USA. [Cornejo, Kristine; Wu, Shulin; Wu, Chin-Lee] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Liu, Qiang; Wu, Chin-Lee] Shanghai Jiao Tong Univ, Sch Med, Renji Hosp, Dept Pathol, Shanghai 200127, Peoples R China. RP Wu, CL (reprint author), Massachusetts Gen Hosp, Dept Pathol, Warren Bldg 225,55 Fruit St, Boston, MA 02114 USA. EM yrhuangrenji@163.com; cwu2@partners.org FU National Natural Science Foundation of China [81402084] FX This study was supported by Award Number 81402084 from National Natural Science Foundation of China. NR 19 TC 1 Z9 1 U1 1 U2 3 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1558-7673 EI 1938-0682 J9 CLIN GENITOURIN CANC JI Clin. Genitourin. Cancer PD OCT PY 2015 VL 13 IS 5 BP E353 EP E360 DI 10.1016/j.clgc.2015.04.014 PG 8 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA CQ9EK UT WOS:000360914600003 PM 25998556 ER PT J AU Ring, D Leopold, SS AF Ring, David Leopold, Seth S. TI Editorial-Measuring Satisfaction: Can It Be Done? SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Editorial Material ID PATIENT-SATISFACTION C1 [Ring, David] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. [Ring, David; Leopold, Seth S.] Clin Orthopaed & Related Res, Philadelphia, PA 19103 USA. RP Leopold, SS (reprint author), Clin Orthopaed & Related Res, Philadelphia, PA 19103 USA. EM sleopold@clinorthop.org NR 15 TC 1 Z9 1 U1 0 U2 2 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 OCT PY 2015 VL 473 IS 10 BP 3071 EP 3073 DI 10.1007/s11999-015-4485-5 PG 3 WC Orthopedics; Surgery SC Orthopedics; Surgery GA CQ9FO UT WOS:000360918400001 PM 26228896 ER PT J AU Janssen, SJ van der Heijden, AS van Dijke, M Ready, JE Raskin, KA Ferrone, ML Hornicek, FJ Schwab, JH AF Janssen, Stein J. van der Heijden, Andrea S. van Dijke, Maarten Ready, John E. Raskin, Kevin A. Ferrone, Marco L. Hornicek, Francis J. Schwab, Joseph H. TI 2015 Marshall Urist Young Investigator Award: Prognostication in Patients With Long Bone Metastases: Does a Boosting Algorithm Improve Survival Estimates? SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID CHARLSON COMORBIDITY INDEX; EXTERNAL VALIDATION; SKELETAL METASTASIS; PREDICTION MODEL; PROSTATE-CANCER; BREAST-CANCER; PROGNOSIS; NOMOGRAM; DISEASE; SURGERY AB Survival estimation guides surgical decision-making in metastatic bone disease. Traditionally, classic scoring systems, such as the Bauer score, provide survival estimates based on a summary score of prognostic factors. Identification of new factors might improve the accuracy of these models. Additionally, the use of different algorithms-nomograms or boosting algorithms-could further improve accuracy of prognostication relative to classic scoring systems. A nomogram is an extension of a classic scoring system and generates a more-individualized survival probability based on a patient's set of characteristics using a figure. Boosting is a method that automatically trains to classify outcomes by applying classifiers (variables) in a sequential way and subsequently combines them. A boosting algorithm provides survival probabilities based on every possible combination of variables. We wished to (1) assess factors independently associated with decreased survival in patients with metastatic long bone fractures and (2) compare the accuracy of a classic scoring system, nomogram, and boosting algorithms in predicting 30-, 90-, and 365-day survival. We included all 927 patients in our retrospective study who underwent surgery for a metastatic long bone fracture at two institutions between January 1999 and December 2013. We included only the first procedure if patients underwent multiple surgical procedures or had more than one fracture. Median followup was 8 months (interquartile range, 3-25 months); 369 of 412 (90%) patients who where alive at 1 year were still in followup. Multivariable Cox regression analysis was used to identify clinical and laboratory factors independently associated with decreased survival. We created a classic scoring system, nomogram, and boosting algorithms based on identified variables. Accuracy of the algorithms was assessed using area under the curve analysis through fivefold cross validation. The following factors were associated with a decreased likelihood of survival after surgical treatment of a metastatic long bone fracture, after controlling for relevant confounding variables: older age (hazard ratio [HR], 1.0; 95% CI, 1.0-1.0; p < 0.001), additional comorbidity (HR, 1.2; 95% CI, 1.0-1.4; p = 0.034), BMI less than 18.5 kg/m(2) (HR, 2.0; 95% CI, 1.2-3.5; p = 0.011), tumor type with poor prognosis (HR, 1.8; 95% CI, 1.6-2.2; p < 0.001), multiple bone metastases (HR, 1.3; 95% CI, 1.1-1.6; p = 0.008), visceral metastases (HR, 1.6; 95% CI, 1.4-1.9; p < 0.001), and lower hemoglobin level (HR, 0.91; 95% CI, 0.87-0.96; p < 0.001). The survival estimates by the nomogram were moderately accurate for predicting 30-day (area under the curve [AUC], 0.72), 90-day (AUC, 0.75), and 365-day (AUC, 0.73) survival and remained stable after correcting for optimism through fivefold cross validation. Boosting algorithms were better predictors of survival on the training datasets, but decreased to a performance level comparable to the nomogram when applied on testing datasets for 30-day (AUC, 0.69), 90-day (AUC, 0.75), and 365-day (AUC, 0.72) survival prediction. Performance of the classic scoring system was lowest for all prediction periods. Comorbidity status and BMI are newly identified factors associated with decreased survival and should be taken into account when estimating survival. Performance of the boosting algorithms and nomogram were comparable on the testing datasets. However, the nomogram is easier to apply and therefore more useful to aid surgical decision making in clinical practice. Level III, prognostic study. C1 [Janssen, Stein J.; van der Heijden, Andrea S.; van Dijke, Maarten; Raskin, Kevin A.; Hornicek, Francis J.; Schwab, Joseph H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthopaed Surg,Orthopaed Oncol Serv, Boston, MA USA. [Ready, John E.; Ferrone, Marco L.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Orthopaed Surg,Orthopaed Oncol Serv, Boston, MA 02115 USA. [Janssen, Stein J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Janssen, SJ (reprint author), Massachusetts Gen Hosp, Room 3-946,Yawkey Bldg,55 Fruit St, Boston, MA 02114 USA. EM steinjanssen@gmail.com FU Anna Foundation (Oegstgeest, The Netherlands); De Drie Lichten Foundation (Hilversum, The Netherlands); KWF Kankerbestrijding (Amsterdam, The Netherlands); Michael van Vloten Foundation (Rotterdam, The Netherlands); Stryker (Kalamazoo, MI, USA); Biom'up (Saint-Priest, Lyon, France) FX One author (SJ) certifies that he has received, an amount less than USD 10,000, from the Anna Foundation (Oegstgeest, The Netherlands), an amount less than USD 10,000 from the De Drie Lichten Foundation (Hilversum, The Netherlands), an amount less than USD 10,000 from the KWF Kankerbestrijding (Amsterdam, The Netherlands), and an amount less than USD 10,000, from the Michael van Vloten Foundation (Rotterdam, The Netherlands). One author (JS) certifies that he or a member of his family has or may receive payments or benefits, an amount less than USD 10,000, from Stryker (Kalamazoo, MI, USA), and an amount less than USD 10,000, from Biom'up (Saint-Priest, Lyon, France). NR 38 TC 5 Z9 5 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-921X EI 1528-1132 J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD OCT PY 2015 VL 473 IS 10 BP 3112 EP 3121 DI 10.1007/s11999-015-4446-z PG 10 WC Orthopedics; Surgery SC Orthopedics; Surgery GA CQ9FO UT WOS:000360918400009 PM 26155769 ER PT J AU Shi, LL Cahill, KE Ek, ET Tompson, JD Higgins, LD Warner, JJP AF Shi, Lewis L. Cahill, Kirk E. Ek, Eugene T. Tompson, Jeffrey D. Higgins, Laurence D. Warner, Jon J. P. TI Latissimus Dorsi and Teres Major Transfer With Reverse Shoulder Arthroplasty Restores Active Motion and Reduces Pain for Posterosuperior Cuff Dysfunction SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID EXTERNAL ROTATION; TEAR ARTHROPATHY; PSEUDOPARESIS; PROSTHESIS; ELEVATION; OUTCOMES; DEFICIT AB In patients with rotator cuff dysfunction, reverse shoulder arthroplasty can restore active forward flexion, but it does not provide a solution for the lack of active external rotation because of infraspinatus and the teres minor dysfunction. A modified L'Episcopo procedure can be performed in the same setting wherein the latissimus dorsi and teres major tendons are transferred to the lateral aspect of proximal humerus in an attempt to restore active external rotation. (1) Do latissimus dorsi and teres major tendon transfers with reverse shoulder arthroplasty improve external rotation function in patients with posterosuperior rotator cuff dysfunction? (2) Do patients experience less pain and have improved outcome scores after surgery? (3) What are the complications associated with reverse shoulder arthroplasty with latissimus dorsi and teres major transfer? Between 2007 and 2010, we treated all patients undergoing shoulder arthroplasty who had a profound external rotation lag sign and advanced fatty degeneration of the posterosuperior rotator cuff (infraspinatus plus teres minor) with this approach. A total of 21 patients (mean age 66 years; range, 58-82 years) were treated this way and followed for a minimum of 2 years (range, 26-81 months); none was lost to followup, and all have been seen in the last 5 years. We compared pre- and postoperative ranges of motion, pain, and functional status; scores were drawn from chart review. We also categorized major and minor complications. Active forward flexion improved from 56A degrees +/- 36A degrees to 120A degrees +/- 38A degrees (mean difference: 64A degrees [95% confidence interval {CI}, 45A degrees-83A degrees], p < 0.001). Active external rotation with the arm adducted improved from 6A degrees +/- 16A degrees to 38A degrees +/- 14A degrees (mean difference: 30A degrees [95% CI, 21A degrees-39A degrees], p < 0.001); active external rotation with the arm abducted improved from 19A degrees +/- 25A degrees to 74A degrees +/- 22A degrees (mean difference: 44A degrees [95% CI, 22A degrees-65A degrees], p < 0.001). Pain visual analog score improved from 8.4 +/- 2.3 to 1.7 +/- 2.1 (mean difference: -6.9 [95% CI, -8.7 to -5.2], p < 0.001), and Single Assessment Numeric Evaluation score improved from 28% +/- 21% to 80% +/- 24% (mean difference: 46% [95% CI, 28%-64%], p < 0.001). There were six major complications, five of which were treated operatively. Overall, three patients' latissimus and teres major transfer failed based on persistent lack of external rotation. In patients with posterior and superior cuff deficiency, reverse shoulder arthroplasty combined with latissimus dorsi and teres major transfer through a single deltopectoral incision can reliably increase active forward flexion and external rotation. Patients experience pain relief and functional improvement but have a high rate of complications; therefore, we recommend the procedure be limited to patients indicated for reverse who have profound external rotation loss and a high grade of infraspinatus/teres minor fatty atrophy. Level IV, therapeutic study. C1 [Shi, Lewis L.; Cahill, Kirk E.] Univ Chicago Hosp, Dept Orthopaed Surg & Rehabil Med, Chicago, IL 60637 USA. [Ek, Eugene T.] Univ Melbourne, Austin Hosp, Melbourne Orthopaed Grp, Melbourne, Vic, Australia. [Ek, Eugene T.] Univ Melbourne, Austin Hosp, Dept Orthopaed Surg, Melbourne, Vic, Australia. [Tompson, Jeffrey D.; Warner, Jon J. P.] Massachusetts Gen Hosp, Harvard Shoulder Serv, Boston, MA 02114 USA. [Higgins, Laurence D.] Brigham & Womens Hosp, Sports Med & Shoulder Serv, Boston, MA 02115 USA. RP Warner, JJP (reprint author), Massachusetts Gen Hosp, Harvard Shoulder Serv, 55 Fruit St, Boston, MA 02114 USA. EM jwarner@partners.org FU NCATS NIH HHS [UL1 TR000430] NR 18 TC 1 Z9 1 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-921X EI 1528-1132 J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD OCT PY 2015 VL 473 IS 10 BP 3212 EP 3217 DI 10.1007/s11999-015-4433-4 PG 6 WC Orthopedics; Surgery SC Orthopedics; Surgery GA CQ9FO UT WOS:000360918400022 PM 26139622 ER PT J AU Graham, JR Calloway, A Roemer, L AF Graham, Jessica R. Calloway, Amber Roemer, Lizabeth TI The Buffering Effects of Emotion Regulation in the Relationship Between Experiences of Racism and Anxiety in a Black American Sample SO COGNITIVE THERAPY AND RESEARCH LA English DT Article DE African American; Racism; Anxiety; Emotion regulation ID AMBULATORY BLOOD-PRESSURE; STRESS SCALES DASS-21; DEPRESSION ANXIETY; AFRICAN-AMERICANS; REGULATION DIFFICULTIES; ETHNIC-DIFFERENCES; COLLEGE-STUDENTS; DISCRIMINATION; DISORDER; IDENTITY AB The current study explores the potential moderating effect of difficulties in emotion regulation on the relationship between racist experiences and anxiety symptomology in a Black American sample. One hundred forty participants completed a questionnaire packet containing measures of anxious arousal and stress (general anxiety) symptoms, difficulties in emotion regulation, and experiences of racist events. Results indicated that difficulties in emotion regulation moderated the relationship between past week frequency of racist events and anxious arousal as well as past year frequency of racist events and anxious arousal. Specifically, these relationships were significantly positive at high levels of difficulties in emotion regulation and not significant at low levels of difficulties in emotion regulation. Emotion regulation skills may help Black Americans cope with anxious arousal related to racist experiences. The clinical implications of these findings and future research directions are discussed. C1 [Graham, Jessica R.] Natl Ctr PTSD, Womens Hlth Sci Div, Boston, MA 02130 USA. [Calloway, Amber; Roemer, Lizabeth] Univ Massachusetts, Dept Psychol, Boston, MA 02125 USA. RP Graham, JR (reprint author), Natl Ctr PTSD, Womens Hlth Sci Div, 150 S Huntington Ave, Boston, MA 02130 USA. EM Jessica.Rose.Graham@gmail.com FU Craig R. Bollinger Dissertation Grant through the University of Massachusetts Boston FX This study was supported by the Craig R. Bollinger Dissertation Grant through the University of Massachusetts Boston. NR 62 TC 4 Z9 4 U1 4 U2 14 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0147-5916 EI 1573-2819 J9 COGNITIVE THER RES JI Cogn. Ther. Res. PD OCT PY 2015 VL 39 IS 5 BP 553 EP 563 DI 10.1007/s10608-015-9682-8 PG 11 WC Psychology, Clinical SC Psychology GA CR1BP UT WOS:000361058100001 ER PT J AU Magruder, K Yeager, D Goldberg, J Forsberg, C Litz, B Vaccarino, V Friedman, M Gleason, T Huang, G Smith, N AF Magruder, K. Yeager, D. Goldberg, J. Forsberg, C. Litz, B. Vaccarino, V. Friedman, M. Gleason, T. Huang, G. Smith, N. TI Diagnostic performance of the PTSD checklist and the Vietnam Era Twin Registry PTSD scale SO EPIDEMIOLOGY AND PSYCHIATRIC SCIENCES LA English DT Article DE Assessment; CIDI; PCL; PTSD ID POSTTRAUMATIC-STRESS-DISORDER; PRIMARY-CARE; SCREENING INSTRUMENT; TERRORIST ATTACKS; FEMALE VETERANS; COMORBIDITY; PREVALENCE; MORTALITY; INTERVIEW; CANCER AB Aims. Self-report questionnaires are frequently used in clinical and epidemiologic studies to assess post-traumatic stress disorder (PTSD). A number of studies have evaluated these scales relative to clinician administered structured interviews; however, there has been no formal evaluation of their performance relative to non-clinician administered epidemiologic assessments such as the Composite International Diagnostic Interview (CIDI). We examined the diagnostic performance of two self-report PTSD scales, the PTSD checklist (PCL) and the Vietnam Era Twin Registry (VET-R) PTSD scale, compared to the CIDI. Methods. Data were derived from a large epidemiologic follow-up study of PTSD in 5141 Vietnam Era Veterans. Measures included the PCL, VET-R PTSD scale and CIDI. For both the PCL and VET-R PTSD scale, ROC curves, areas under the curve (AUC), sensitivity, specificity, % correctly classified, likelihood ratios, predictive values and quality estimates were generated based on the CIDI PTSD diagnosis. Results. For the PCL and VET-R PTSD scale the AUCs were 89.0 and 87.7%, respectively. Optimal PCL cutpoints varied from the 31-33 range (when considering sensitivity and specificity) to the 36-56 range (when considering quality estimates). Similar variations were found for the VET-R PTSD, ranging from 31 (when considering sensitivity and specificity) to the 37-42 range (when considering quality estimates). Conclusions. The PCL and VET-R PTSD scale performed similarly using a CIDI PTSD diagnosis as the criterion. There was a range of acceptable cutpoints, depending on the metric used, but most metrics suggested a lower PCL cutpoint than in previous studies in Veteran populations. C1 [Magruder, K.; Yeager, D.] Ralph H Johnson VA Med Ctr, Mental Hlth Serv, Charleston, SC 29401 USA. [Magruder, K.; Yeager, D.] Med Univ S Carolina, Dept Psychiat, Charleston, SC 29425 USA. [Goldberg, J.; Forsberg, C.; Smith, N.] VA Puget Sound Hlth Care Syst, Seattle Epidemiol Res & Informat Ctr, Seattle, WA USA. [Goldberg, J.; Smith, N.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Litz, B.] VA Boston Healthcare Syst, Massachusetts Epidemiol Res & Informat Ctr, Boston, MA USA. [Litz, B.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Vaccarino, V.] Emory Univ, Dept Epidemiol, Atlanta, GA 30322 USA. [Vaccarino, V.] Emory Univ, Dept Med, Atlanta, GA 30322 USA. [Friedman, M.] Natl Ctr Posttraumat Stress Disorder, Dept Vet Affairs, White River Jct, VT USA. [Friedman, M.] Geisel Sch Med Dartmouth, Dept Psychiat, Hanover, NH USA. [Friedman, M.] Geisel Sch Med Dartmouth, Dept Pharmacol & Toxicol, Hanover, NH USA. [Gleason, T.; Huang, G.] VA Off Res & Dev, Cooperat Studies Program, Clin Sci Res & Dev, Washington, DC USA. RP Magruder, K (reprint author), Ralph H Johnson VA Med Ctr, Mental Hlth Serv, 109 Bee St, Charleston, SC 29401 USA. EM magrudkm@musc.edu FU Cooperative Studies Program (CSP) of the US Department of Veterans Affairs' Office of Research and Development [569]; National Institutes of Health award [K24 HL077506] FX The Cooperative Studies Program (CSP) of the US Department of Veterans Affairs' Office of Research and Development has provided financial support for Cooperative Study #569 and the development and maintenance of the Vietnam-Era Twin (VET) Registry. Dr Viola Vaccarino was supported in part by a National Institutes of Health award, K24 HL077506. NR 36 TC 2 Z9 2 U1 0 U2 1 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 2045-7960 EI 2045-7979 J9 EPIDEMIOL PSYCH SCI JI Epidemiol. Psychiatr. Sci. PD OCT PY 2015 VL 24 IS 5 BP 415 EP 422 DI 10.1017/S2045796014000365 PG 8 WC Psychiatry SC Psychiatry GA CR2DN UT WOS:000361135400010 PM 24905737 ER PT J AU Chaudhary, K Speights, K McGuire, K White, AP AF Chaudhary, Kshitij Speights, Katharine McGuire, Kevin White, Andrew P. TI Trans-cranial motor evoked potential detection of femoral nerve injury in trans-psoas lateral lumbar interbody fusion SO JOURNAL OF CLINICAL MONITORING AND COMPUTING LA English DT Article DE Motor evoked potentials; Electromyography; Trans-psoas interbody fusion; LLIF; XLIF; DLIF; Lumbar plexus ID APPROACH CLINICAL ARTICLE; SURGERY; ELECTROMYOGRAPHY; EFFICACY AB Trans-psoas lateral lumbar interbody fusion (LLIF) is frequently associated with neurological complications, limiting its value as a less invasive procedure. The routine use of EMG neuromonitoring has been inadequate to detect iatrogenic injuries; significant postoperative deficits have gone undetected by EMG. An effective way to monitor for these intraoperative neurological events is not yet well established. To our knowledge, detection of lumbar plexus injury during LLIF by trans-cranial motor evoked potentials (MEP) without corresponding change in EMG has not been reported in the literature. Three cases are presented to illustrate the potential utility of trans-cranial MEP monitoring during trans-psoas LLIF. We introduce a modified intraoperative neuro-monitoring (IONM) protocol for LLIF surgery, which includes MEP in addition to spontaneous and triggered EMG. Postoperative neurological outcome was correlated with the IONM findings. In each case, loss of quadriceps MEP signals occurred during LLIF at L4/L5, and after prolonged retraction (27, 25 and 61 min respectively). The EMG, however, did not show any abnormal activity. Two patients had post-operative quadriceps weakness, concordant with MEP data. The third patient, in whom the MEP signals returned to normal after expeditious removal of the retractor, did not exhibit quadriceps weakness, also concordant with MEP data. These cases contribute to the developing perception that stand-alone EMG nerve monitoring is not adequate for trans-psoas surgery. The addition of MEP may improve the sensitivity of IONM during trans-psoas surgery. Multimodality IONM may offer the opportunity to intervene on evolving iatrogenic nerve injuries, and may reduce the incidence of adverse postoperative findings. C1 [Chaudhary, Kshitij; McGuire, Kevin; White, Andrew P.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Orthopaed Surg, Boston, MA 02115 USA. [White, Andrew P.] BIDMC Orthopaed, Boston, MA 02215 USA. [Speights, Katharine] Safe Passage Neuromonitoring, Boston, MA USA. RP Chaudhary, K (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Orthopaed Surg, Boston, MA 02115 USA. EM chaudhary.kc@gmail.com; apwhite@bidmc.harvard.edu NR 14 TC 4 Z9 4 U1 0 U2 1 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1387-1307 EI 1573-2614 J9 J CLIN MONIT COMPUT JI J. Clin. Monitor. Comp. PD OCT PY 2015 VL 29 IS 5 BP 549 EP 554 DI 10.1007/s10877-015-9713-8 PG 6 WC Anesthesiology SC Anesthesiology GA CR1BU UT WOS:000361058600004 PM 26076805 ER PT J AU Liu, YH Pian-Smith, MCM Leffert, LR Minehart, RD Torri, A Cote, C Kacmarek, RM Jiang, YD AF Liu, Yanhong Pian-Smith, May C. M. Leffert, Lisa R. Minehart, Rebecca D. Torri, Andrea Cote, Charles Kacmarek, Robert M. Jiang, Yandong TI Continuous measurement of cardiac output with the electrical velocimetry method in patients under spinal anesthesia for cesarean delivery SO JOURNAL OF CLINICAL MONITORING AND COMPUTING LA English DT Article DE Cardiac output; Spinal anesthesia; Electrical velocimetry; Obstetric; Cesarean delivery ID IMPEDANCE CARDIOGRAPHY; MATERNAL HEMODYNAMICS; STROKE VOLUME; PHENYLEPHRINE; THERMODILUTION; PRESSURE; SURGERY; STIMULATION; OXYTOCIN; LABOR AB In this study, we aimed to continuously measure cardiac output (CO) with the electrical velocimetry (EV) method and characterize the hemodynamic profile of patients undergoing spinal anesthesia for elective cesarean delivery (CD), and to discuss the potential benefit of using real time CO monitoring to guide patient management. Forty-two patients scheduled for elective CD under spinal anesthesia were enrolled in this observational study. A non-invasive CO monitor incorporating the electrical velocimetry algorithm, ICONA (R) (Cardiotronic(A (R)), La Jolla, California, USA), was used to measure CO and stroke volume (SV) continuously. Peripheral venous pressure was measured intermittently at pre-defined time points. Systemic vascular resistance was calculated retrospectively after completion of the study. Hemodynamic changes at pre-defined time points and caused by phenylephrine administration were analyzed. Hypotension (MAP reduction more than 20 % from baseline values) occurred in 71.1 % of patients after spinal anesthesia, while the coinstantaneous CO was increased a parts per thousand yen20 % from baseline in the majority of patients (76.3 %) at the same time. Significant increase in CO took place at 3-2 min before the administration of phenylephrine bolus. Treatment of hypotension with phenylephrine was associated with significant decrease in CO. Continuous CO monitoring with EV enables clinicians to determine CO and SV changes prior to onset of hypotension and to better understand patients' hemodynamics. It is an important addition to the current monitoring. The benefit of routinely using this technique remains to be determined in term of the patient outcomes. C1 [Liu, Yanhong; Pian-Smith, May C. M.; Leffert, Lisa R.; Minehart, Rebecca D.; Torri, Andrea; Cote, Charles; Kacmarek, Robert M.; Jiang, Yandong] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Kacmarek, Robert M.] Massachusetts Gen Hosp, Dept Resp Care, Boston, MA 02114 USA. RP Jiang, YD (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St,Jackson 422, Boston, MA 02114 USA. EM yjiang@partners.org FU Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital FX Authors sincerely thank Dr. Donald P. Bernstein, Cardiovascular Engineering Sotera Wireless, Inc. San Diego, CA for his editing of this article. This project is funded by the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital. NR 30 TC 2 Z9 2 U1 1 U2 4 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1387-1307 EI 1573-2614 J9 J CLIN MONIT COMPUT JI J. Clin. Monitor. Comp. PD OCT PY 2015 VL 29 IS 5 BP 627 EP 634 DI 10.1007/s10877-014-9645-8 PG 8 WC Anesthesiology SC Anesthesiology GA CR1BU UT WOS:000361058600016 PM 25510959 ER PT J AU Pachankis, JE Hatzenbuehler, ML Rendina, HJ Safren, SA Parsons, JT AF Pachankis, John E. Hatzenbuehler, Mark L. Rendina, H. Jonathon Safren, Steven A. Parsons, Jeffrey T. TI LGB-Affirmative Cognitive-Behavioral Therapy for Young Adult Gay and Bisexual Men: A Randomized Controlled Trial of a Transdiagnostic Minority Stress Approach SO JOURNAL OF CONSULTING AND CLINICAL PSYCHOLOGY LA English DT Article DE minority stress; stigma; LGB-affirmative; intervention; cognitive-behavioral therapy (CBT) ID PSYCHOSOCIAL HEALTH-PROBLEMS; SEXUAL COMPULSIVITY SCALE; REJECTION SENSITIVITY; EMOTIONAL DISORDERS; STRUCTURAL STIGMA; UNIFIED PROTOCOL; IMPAIRMENT SCALE; HETEROSEXUAL ADOLESCENTS; SCREENING INSTRUMENT; ALCOHOL-CONSUMPTION AB Objectives: We tested the preliminary efficacy of a transdiagnostic cognitive-behavioral treatment adapted to improve depression, anxiety, and co-occurring health risks (i.e., alcohol use, sexual compulsivity, condomless sex) among young adult gay and bisexual men. Treatment adaptations focused on reducing minority stress processes that underlie sexual orientation-related mental health disparities. Method: Young gay and bisexual men (n = 63; M age = 25.94) were randomized to immediate treatment or a 3-month waitlist. At baseline, 3-month, and 6-month assessments, participants completed self-reports of mental health and minority stress and an interview of past-90-day risk behavior. Results: Compared to waitlist, treatment significantly reduced depressive symptoms (b = -2.43, 95% CI: -4.90, 0.35, p < .001), alcohol use problems (b = -3.79, 95% CI: -5.94, -1.64, p < .001), sexual compulsivity (b = -5.09, 95% CI: -8.78, -1.40, p < .001), and past-90-day condomless sex with casual partners (b = -1.09, 95% CI: -1.80, -0.37, p < .001), and improved condom use self-efficacy (b = 10.08, 95% CI: 3.86, 16.30, p < .001). The treatment yielded moderate and marginally significant greater improvements than waitlist in anxiety symptoms (b = -2.14, 95% CI: -4.61, 0.34, p = .09) and past-90-day heavy drinking (b = -0.32, 95% CI: -0.71, 0.07, p = .09). Effects were generally maintained at follow-up. Minority stress processes showed small improvements in the expected direction. Conclusion: This study demonstrated preliminary support for the first intervention adapted to address gay and bisexual men's co-occurring health problems at their source in minority stress. If found to be efficacious compared to standard evidence-based treatments, the treatment will possess substantial potential for helping clinicians translate LGB-affirmative treatment guidelines into evidence-based practice. C1 [Pachankis, John E.] Yale Univ, Yale Sch Publ Hlth, Dept Chron Dis Epidemiol, Social & Behav Sci Div, New Haven, CT 06520 USA. [Hatzenbuehler, Mark L.] Columbia Univ, Mailman Sch Publ Hlth, Dept Sociomed Sci, New York, NY 10027 USA. [Rendina, H. Jonathon; Parsons, Jeffrey T.] Ctr HIV AIDS Educ Studies & Training CHEST, New York, NY USA. [Safren, Steven A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Cambridge, MA 02138 USA. [Parsons, Jeffrey T.] CUNY Hunter Coll, Dept Psychol, New York, NY 10021 USA. RP Pachankis, JE (reprint author), Yale Univ, Yale Sch Publ Hlth, Dept Chron Dis Epidemiol, Social & Behav Sci Div,Lab Epidemiol & Publ Hlth, 60 Coll St, New Haven, CT 06520 USA. EM john.pachankis@yale.edu RI Rendina, H. Jonathon/M-9286-2016; OI Rendina, H. Jonathon/0000-0002-0148-2852; Parsons, Jeffrey/0000-0002-6875-7566 FU National Institute of Mental Health [R34-MH096607, K24 MH094214]; National Institute on Drug Abuse [K01 DA039030] FX This project was supported by a research grant from the National Institute of Mental Health (R34-MH096607; John E. Pachankis, Principal Investigator). H. Jonathon Rendina's contribution to this project was supported, in part, by a grant from the National Institute on Drug Abuse (K01 DA039030). Steven A. Safren's contribution was supported by a grant from the National Institute of Mental Health (K24 MH094214). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors would like to acknowledge the contributions of the ESTEEM research team: Evie Arroyo, Aliza Boim, Demetria Cain, Michael Castro, Chris Cruz, Sitaji Gurung, Ethan Fusaris, Ruben Jimenez, Douglas Keeler, Alexa Michl, Brett Millar, Chloe Mirzayi, Theresa Navalta, Luis Nobrega, Brian Salfas, Martez Smith, Laurie Spacek, Rachel Proujansky, Anita Viswanath, Jonathan Warren, and Thomas Whitfield. NR 85 TC 16 Z9 16 U1 3 U2 19 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 OCT PY 2015 VL 83 IS 5 BP 875 EP 889 DI 10.1037/ccp0000037 PG 15 WC Psychology, Clinical SC Psychology GA CR3IS UT WOS:000361226400004 PM 26147563 ER PT J AU Tothova, Z Berliner, N AF Tothova, Zuzana Berliner, Nancy TI Hemophagocytic Syndrome and Critical Illness: New Insights into Diagnosis and Management SO JOURNAL OF INTENSIVE CARE MEDICINE LA English DT Review DE hemophagocytic lymphohistiocytosis; ferritin; hemophagocytic syndrome; HPS ID EPSTEIN-BARR-VIRUS; STEM-CELL TRANSPLANTATION; PERFORIN GENE-MUTATIONS; CLINICAL-FEATURES; BONE-MARROW; SOLUBLE INTERLEUKIN-2-RECEPTOR; LYMPHOHISTIOCYTOSIS FHL; INTERFERON-GAMMA; CYTOKINE PATTERN; XIAP DEFICIENCY AB Hemophagocytic lymphohistiocytosis (HLH) comprises a heterogeneous group of diseases that are characterized by a hyperinflammatory state due to uncontrolled T cell, macrophage, and histiocyte activation, accompanied by excessive cytokine production. This rare condition is almost uniformly fatal unless promptly recognized and treated. Much progress has been made in the last two decades in our understanding of the mechanisms underlying familial, and to a lesser extent, acquired cases of HLH. Recurrent mutations in more than 10 different genes have now been identified, involving biological pathways converging on intracellular vesicle trafficking and cytolytic granule exocytosis. Mechanisms underlying the majority of patients with acquired HLH, however, remain elusive, hampering both diagnostic evaluation and therapeutic management of these patients. Given that the majority of intensive care unit (ICU) patients with sepsis or multiorgan failure share many features of HLH, it is especially critical for pediatric and adult intensivists to be able to recognize patients with bona fide HLH and initiate treatment without delay. In this article, we review our current understanding of the pathophysiology, clinical testing, diagnosis, and treatment of patients with HLH, especially as it pertains to the care of critically ill patients in pediatric and medical ICUs. C1 [Tothova, Zuzana; Berliner, Nancy] Brigham & Womens Hosp, Div Hematol, Boston, MA 02115 USA. [Tothova, Zuzana; Berliner, Nancy] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Berliner, N (reprint author), Brigham & Womens Hosp, Div Hematol, Mid Campus 3,75 Francis St, Boston, MA 02115 USA. EM nancy_berliner@dfci.harvard.edu FU NCI NIH HHS [T32 CA009172] NR 84 TC 7 Z9 7 U1 1 U2 14 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0885-0666 EI 1525-1489 J9 J INTENSIVE CARE MED JI J. Intensive Care Med. PD OCT PY 2015 VL 30 IS 7 BP 401 EP 412 DI 10.1177/0885066613517076 PG 12 WC Critical Care Medicine SC General & Internal Medicine GA CR2FK UT WOS:000361141400004 PM 24407034 ER PT J AU Feldman, S Kimball, AB Warren, RB Frazier, D Proulx, J Marren, A AF Feldman, Steven Kimball, Alexandra B. Warren, Richard B. Frazier, Don Proulx, James Marren, Amy TI Pregnancy outcomes in the tofacitinib psoriasis safety database up to April 2014 SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 4th World Psoriasis and Psoriatic Arthritis Conference on Psoriasis - New Insights and Innovations CY OCT, 2015 CL Stockholm, SWEDEN C1 [Feldman, Steven] Wake Forest Univ, Sch Med, Winston Salem, NC 27109 USA. [Kimball, Alexandra B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Kimball, Alexandra B.] Harvard Univ, Sch Med, Boston, MA USA. [Warren, Richard B.] Univ Manchester, Manchester, Lancs, England. [Frazier, Don; Proulx, James] Pfizer Inc, Groton, CT 06340 USA. [Marren, Amy] Pfizer Inc, Collegeville, PA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD OCT PY 2015 VL 135 SU 3 MA P036 BP S9 EP S9 PG 1 WC Dermatology SC Dermatology GA CR2LG UT WOS:000361160500037 ER PT J AU Kimball, AB Guenther, L De Jong, E Kalia, S Goyal, K Langholff, W Fakharzadeh, S Calabro, S Crow, JA Hopkins, L Shear, NH AF Kimball, A. B. Guenther, L. De Jong, E. Kalia, S. Goyal, K. Langholff, W. Fakharzadeh, S. Calabro, S. Crow, J. A. Hopkins, L. Shear, N. H. TI Pregnancy outcomes in women with moderate to severe psoriasis: The PSOLAR experience SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 4th World Psoriasis and Psoriatic Arthritis Conference on Psoriasis - New Insights and Innovations CY OCT, 2015 CL Stockholm, SWEDEN C1 [Kimball, A. B.] Harvard Univ, Sch Med, Dermatol, Boston, MA USA. [Kimball, A. B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Guenther, L.] Guenther Dermatol Res Ctr, Dermatol, London, ON, Canada. [De Jong, E.] Univ Med Ctr Nijmegen St Radboud, Dermatol, Nijmegen, Netherlands. [Kalia, S.] UBC Dermatol, Dermatol, Vancouver, BC, Canada. [Goyal, K.; Fakharzadeh, S.; Calabro, S.; Hopkins, L.] Janssen Sci Affairs LLC, Immunol, Horsham, PA USA. [Langholff, W.] Janssen Res & Dev LLC, Biostat, Spring House, PA USA. [Crow, J. A.] Janssen Sci Affairs LLC, Dermatol, Horsham, PA USA. [Shear, N. H.] Univ Toronto, Dermatol, Toronto, ON, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD OCT PY 2015 VL 135 SU 3 MA P056 BP S16 EP S16 PG 1 WC Dermatology SC Dermatology GA CR2LG UT WOS:000361160500057 ER PT J AU Kimball, AB Nikai, E Zhu, BJ Carlier, H Yosipovitch, G AF Kimball, Alexa Boer Nikai, Enkeleida Zhu, Baojin Carlier, Hilde Yosipovitch, Gil TI Ixekizumab impact on itch severity compared to etanercept and placebo: Results from UNCOVER-2, a phase 3 trial in patients with moderate-to-severe plaque psoriasis SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 4th World Psoriasis and Psoriatic Arthritis Conference on Psoriasis - New Insights and Innovations CY OCT, 2015 CL Stockholm, SWEDEN C1 [Kimball, Alexa Boer] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Kimball, Alexa Boer] Harvard Univ, Sch Med, Boston, MA USA. [Nikai, Enkeleida; Zhu, Baojin; Carlier, Hilde] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Yosipovitch, Gil] Temple Univ, Philadelphia, PA 19122 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD OCT PY 2015 VL 135 SU 3 MA P066 BP S19 EP S19 PG 1 WC Dermatology SC Dermatology GA CR2LG UT WOS:000361160500066 ER PT J AU Yeh, DD Cropano, C Quraishi, SA Fuentes, E Kaafarani, H Lee, J Velmahos, G AF Yeh, Daniel Dante Cropano, Catrina Quraishi, Sadeq A. Fuentes, Eva Kaafarani, Haytham Lee, Jarone Velmahos, George TI Periprocedural nutrition in the intensive care unit: a pilot study SO JOURNAL OF SURGICAL RESEARCH LA English DT Article DE Compensatory feedings; Perioperative nutrition; Caloric debt; Complications; Malnutrition; Tracheostomy ID ENTERAL NUTRITION; MECHANICAL VENTILATION; PRACTICE GUIDELINES; AMERICAN-SOCIETY; TUBE FEEDINGS; DELIVERY; THERAPY; PATIENT; SUPPORT AB Background: Enteral nutrition (EN) delivery in the surgical intensive care unit (ICU) is often suboptimal as it is commonly interrupted for procedures. We hypothesized that continuing perioperative nutrition or providing compensatory nutrition would improve caloric delivery without increasing morbidity. Materials and methods: We enrolled 10 adult surgical ICU patients receiving EN who were scheduled for elective bedside percutaneous tracheostomy. In these patients (fed group), either perioperative EN was maintained or compensatory nutrition was provided. We compared the amount of calories delivered, caloric deficits, and the rate of complications of these patients with those of 22 contemporary controls undergoing tracheostomy while adhering to the traditional American Society of Anesthesiology nil per os guidelines (unfed group). We defined caloric deficit as the difference between prescribed calories and actual delivered calories. Results: There was no difference in demographic characteristics between the two groups. On the day of procedure, the fed group had higher median delivered calories (1706 kcal; interquartile range [IQR], 1481-2009 versus 588 kcal; IQR, 353-943; P < 0.0001) and received a higher percentage of prescribed calories (92%; IQR, 82%-97% versus 34%; IQR, 24%-51%; P < 0.0001). Median caloric deficit on the day of the procedure was significantly lower in the fed group (175 kcal; IQR, 49-340 versus 1133 kcal; IQR, 660-1365; P < 0.0001). There were no differences in total overall ICU complications per patient, gastrointestinal complications on the day of procedure, or total infectious complications per patient between the two groups. Conclusions: In our pilot study, perioperative and compensatory nutrition resulted in higher caloric delivery and was not associated with increased morbidity. (C) 2015 Elsevier Inc. All rights reserved. C1 [Yeh, Daniel Dante; Cropano, Catrina; Quraishi, Sadeq A.; Fuentes, Eva; Kaafarani, Haytham; Lee, Jarone; Velmahos, George] Massachusetts Gen Hosp, Dept Surg, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA 02114 USA. RP Yeh, DD (reprint author), Massachusetts Gen Hosp, Dept Surg, Div Trauma Emergency Surg & Surg Crit Care, 165 Cambridge St 810, Boston, MA 02114 USA. EM dyeh2@partners.org NR 17 TC 0 Z9 0 U1 2 U2 3 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 OCT PY 2015 VL 198 IS 2 BP 346 EP 350 DI 10.1016/j.jss.2015.06.039 PG 5 WC Surgery SC Surgery GA CQ6IM UT WOS:000360708000013 PM 26187187 ER PT J AU Albadawi, H Oklu, R Milner, JD Uong, TP Yoo, HJ Austen, WG Watkins, MT AF Albadawi, Hassan Oklu, Rahmi Milner, John D. Uong, Thuy P. Yoo, Hyung-Jin Austen, William G., Jr. Watkins, Michael T. TI Effect of limb demand ischemia on autophagy and morphology in mice SO JOURNAL OF SURGICAL RESEARCH LA English DT Article DE Limb demand ischemia; Diet-induced obesity; Type-2 diabetes; Peripheral arterial disease; Autophagy; Mitochondrial biogenesis; Muscle regeneration ID PERIPHERAL ARTERIAL-DISEASE; MUSCLE SATELLITE CELLS; SKELETAL-MUSCLE; MITOCHONDRIAL FUSION; REPERFUSION INJURY; OXIDATIVE DAMAGE; EXERCISE; MYOPATHY; GASTROCNEMIUS; DEGENERATION AB Background: Obesity is a major risk factor for diabetes and peripheral arterial disease, which frequently leads to lower limb demand ischemia. Skeletal muscle autophagy and mitochondrial biogenesis are important processes for proper oxidative capacity and energy metabolism, which are compromised in diabetes. This study compares autophagy, mitochondrial biogenesis, energy metabolism, and morphology in the hind limbs of obese diabetic mice subjected to demand or sedentary ischemia. Materials and methods: Unilateral hind limb demand ischemia was created in a group of diet-induced obese mice after femoral artery ligation and 4 wk of daily exercise. A parallel group of mice underwent femoral artery ligation but remained sedentary for 4 wk. Hind limb muscles were analyzed for markers of autophagy, mitochondrial biogenesis, adenosine triphosphate, and muscle tissue morphology. Results: At the end of the 4-wk exercise period, demand ischemia increased the autophagy mediator Beclin-1, but it did not alter the autophagy indicator, LC3B-II/I ratio, or markers of mitochondrial biogenesis, optic atrophy/dynamin-related protein. In contrast, exercise significantly increased the level of mitochondrial protein-succinate dehydrogenase subunit-A and reduced adipocyte accumulation and the percentage of centrally nucleated myofibers in the demand ischemia limb. In addition, demand ischemia resulted in decreased uncoupling protein-3 levels without altering muscle adenosine triphosphate or pS473-Akt levels. Conclusions: Limb demand ischemia markedly decreased adipocyte accumulation and enhanced muscle regeneration in obese mice, but it did not appear to enhance autophagy, mitochondrial biogenesis, energy metabolism, or insulin sensitivity. Future studies aimed at evaluating novel therapies that enhance autophagy and mitochondrial biogenesis in diabetes with peripheral arterial disease are warranted. (C) 2015 Elsevier Inc. All rights reserved. C1 [Albadawi, Hassan; Milner, John D.; Uong, Thuy P.; Yoo, Hyung-Jin; Watkins, Michael T.] Massachusetts Gen Hosp, Dept Surg, Div Vasc & Endovasc Surg, Boston, MA 02114 USA. [Albadawi, Hassan; Oklu, Rahmi; Milner, John D.; Uong, Thuy P.; Yoo, Hyung-Jin; Austen, William G., Jr.; Watkins, Michael T.] Harvard Univ, Sch Med, Boston, MA USA. [Oklu, Rahmi] Massachusetts Gen Hosp, Dept Imaging, Div Vasc & Intervent Radiol, Boston, MA 02114 USA. [Austen, William G., Jr.] Massachusetts Gen Hosp, Dept Surg, Div Plast & Reconstruct Surg, Boston, MA 02114 USA. RP Albadawi, H (reprint author), Massachusetts Gen Hosp, Dept Surg, Vasc Res Lab, Div Vasc & Endovasc Surg, Edwards 301,70 Blossom St, Boston, MA 02114 USA. EM halbadawi@mgh.harvard.edu OI Albadawi, Hassan/0000-0001-5913-8571 FU NIH [RO1 (AR055843)]; Department of Surgery, Division of Vascular and Endovascular Surgery, Henry & Nod Meyer Sundry Fund FX This study was supported by NIH grant RO1 (AR055843), the Department of Surgery, Division of Vascular and Endovascular Surgery, Henry & Nod Meyer Sundry Fund. NR 41 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 0022-4804 EI 1095-8673 J9 J SURG RES JI J. Surg. Res. PD OCT PY 2015 VL 198 IS 2 BP 515 EP 524 DI 10.1016/j.jss.2015.04.008 PG 10 WC Surgery SC Surgery GA CQ6IM UT WOS:000360708000040 PM 25959834 ER PT J AU Vargas, CR Koolen, PGL Ho, OA Ricci, JA Tobias, AM Lin, SJ Lee, BT AF Vargas, Christina R. Koolen, Pieter G. L. Ho, Olivia A. Ricci, Joseph A. Tobias, Adam M. Lin, Samuel J. Lee, Bernard T. TI Tumescent mastectomy technique in autologous breast reconstruction SO JOURNAL OF SURGICAL RESEARCH LA English DT Article DE Tumescent technique; Mastectomy; Breast cancer; Breast reconstruction; Microsurgery; Autologous reconstruction; Outcomes ID IMMEDIATE RECONSTRUCTION; PERFORATOR-DISSECTION; FLAP NECROSIS; RISK; HYDRODISSECTION; ELECTROCAUTERY; ANESTHESIA; INCREASE AB Background: Use of the tumescent mastectomy technique has been reported to facilitate development of a hydrodissection plane, reduce blood loss, and provide adjunct analgesia. Previous studies suggest that tumescent dissection may contribute to adverse outcomes after immediate implant reconstruction; however, its effect on autologous microsurgical reconstruction has not been established. Methods: A retrospective review was conducted of all immediate microsurgical breast reconstruction procedures at a single academic center between January 2004 and December 2013. Records were queried for age, body mass index, mastectomy weight, diabetes, hypertension, smoking, preoperative radiation, reconstruction flap type, and autologous flap weight. Outcomes of interest were mastectomy skin necrosis, complete and partial flap loss, return to the operating room, breast hematoma, seroma, and infection. Results: There were 730 immediate autologous breast reconstructions performed during the study period; 46% with the tumescent dissection technique. Groups were similar with respect to baseline patient and procedural characteristics. Univariate analysis revealed no significant difference in the incidence of mastectomy skin necrosis, complete or partial flap loss, return to the operating room, operative time, estimated blood loss, recurrence, breast hematoma, seroma, or infection in patients undergoing tumescent mastectomy. Multivariate analysis also demonstrated no significant association between the use of tumescent technique and postoperative breast mastectomy skin necrosis (P = 0.980), hematoma (P = 0.759), or seroma (P = 0.340). Conclusions: Use of the tumescent dissection technique during mastectomy is not significantly associated with adverse outcomes after microsurgical breast reconstruction. Despite concern for its impact on implant reconstruction, our findings suggest that this method can be used safely preceding autologous procedures. (C) 2015 Elsevier Inc. All rights reserved. C1 [Vargas, Christina R.; Tobias, Adam M.; Lin, Samuel J.; Lee, Bernard T.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Surg, Boston, MA 02215 USA. [Koolen, Pieter G. L.; Ho, Olivia A.; Ricci, Joseph A.; Tobias, Adam M.; Lin, Samuel J.; Lee, Bernard T.] Harvard Univ, Beth Israel Deaconess Med Ctr, Div Plast & Reconstruct Surg, Dept Surg,Med Sch, Boston, MA 02215 USA. RP Lee, BT (reprint author), Beth Israel Deaconess Med Ctr, Dept Surg, Div Plast & Reconstruct Surg, 110 Francis St,Suite 5A, Boston, MA 02215 USA. EM btlee@bidmc.harvard.edu RI Lee, Bernard/K-1106-2016 OI Lee, Bernard/0000-0002-5533-3166 NR 19 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 0022-4804 EI 1095-8673 J9 J SURG RES JI J. Surg. Res. PD OCT PY 2015 VL 198 IS 2 BP 525 EP 529 DI 10.1016/j.jss.2015.03.050 PG 5 WC Surgery SC Surgery GA CQ6IM UT WOS:000360708000041 PM 25891675 ER PT J AU Vargas, CR Koolen, PG Anderson, KE Paul, MA Tobias, AM Lin, SJ Lee, BT AF Vargas, Christina R. Koolen, Pieter G. Anderson, Katarina E. Paul, Marek A. Tobias, Adam M. Lin, Samuel J. Lee, Bernard T. TI Mastectomy skin necrosis after microsurgical breast reconstruction SO JOURNAL OF SURGICAL RESEARCH LA English DT Article DE Mastectomy skin necrosis; Autologous breast reconstruction; Breast cancer; Microsurgical breast reconstruction ID SPARING MASTECTOMY; FLAP NECROSIS; COMPLICATIONS; METAANALYSIS; OUTCOMES; OBESITY; RISK AB Background: Mastectomy skin necrosis represents a significant clinical morbidity after immediate breast reconstruction. In addition to aesthetic deformity, necrosis of the native mastectomy skin may require debridement, additional reconstruction, or prolonged wound care and potentially delay oncologic treatment. This study aims to evaluate patient and procedural characteristics to identify predictors of mastectomy skin necrosis after microsurgical breast reconstruction. Methods: A retrospective review was performed of all immediate microsurgical breast reconstructions performed at a single academic center. Patient records were queried for age, diabetes, active smoking, previous breast surgery, preoperative radiation, preoperative chemotherapy, body mass index, mastectomy type, mastectomy weight, flap type, autologous flap type, and postoperative mastectomy skin flap necrosis. Results: There were 746 immediate autologous microsurgical flaps performed by three plastic surgeons at our institution during the study period. The incidence of mastectomy skin flap necrosis was 13.4%. Univariate analysis revealed a significantly higher incidence of mastectomy skin necrosis in patients with higher mastectomy weight (P < 0.001), higher autologous flap weight (P < 0.001), higher body mass index (0.002), and diabetes (P = 0.021). No significant association was found for age, smoking, prior breast surgery, preoperative chemotherapy or radiation, or mastectomy type. Multivariate analysis demonstrated statistically significant associations between mastectomy skin necrosis and both increasing mastectomy weight (odds ratio 1.348 per quartile increase, P = 0.009) and diabetes (odds ratio 2.356, P = 0.011). Conclusions: Increasing mastectomy weight and coexisting diabetes are significantly associated with postoperative mastectomy skin necrosis after microsurgical reconstruction. These characteristics should be considered during patient counseling, procedure selection, operative planning, and intraoperative tissue viability assessment. (C) 2015 Elsevier Inc. All rights reserved. C1 [Vargas, Christina R.; Koolen, Pieter G.; Anderson, Katarina E.; Paul, Marek A.; Tobias, Adam M.; Lin, Samuel J.; Lee, Bernard T.] Harvard Univ, Beth Israel Deaconess Med Ctr, Div Plast & Reconstruct Surg, Dept Surg,Med Sch, Boston, MA 02215 USA. RP Lee, BT (reprint author), Beth Israel Deaconess Med Ctr, Dept Surg, Div Plast & Reconstruct Surg, 110 Francis St,Suite 5A, Boston, MA 02215 USA. EM btlee@bidmc.harvard.edu RI Lee, Bernard/K-1106-2016; OI Lee, Bernard/0000-0002-5533-3166; Paul, Marek/0000-0003-3474-9063 NR 17 TC 3 Z9 3 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0022-4804 EI 1095-8673 J9 J SURG RES JI J. Surg. Res. PD OCT PY 2015 VL 198 IS 2 BP 530 EP 534 DI 10.1016/j.jss.2015.03.076 PG 5 WC Surgery SC Surgery GA CQ6IM UT WOS:000360708000042 PM 25913487 ER PT J AU Enamandram, M Rathmell, JP Kimball, AB AF Enamandram, Monica Rathmell, James P. Kimball, Alexandra B. TI Chronic pain management in dermatology A guide to assessment and nonopioid pharmacotherapy SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Review DE hidradenitis suppurativa; nonsteroidal antiinflammatory drugs; opioid analgesia; pain management; postherpetic neuralgia ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; LOW-BACK-PAIN; POSTHERPETIC NEURALGIA; HERPES-ZOSTER; RHEUMATOID-ARTHRITIS; NEUROPATHIC PAIN; PHARMACOLOGICAL MANAGEMENT; TOPICAL LIDOCAINE; CONTROLLED-TRIAL; NONCANCER PAIN AB Pain is a central component of illness and suffering, yet unfortunately it is frequently undertreated. In dermatology, many acute and chronic conditions are characterized by pain that may require therapeutic intervention in addition to medical treatment aimed at treating the primary disease. To date, however, there are limited recommendations or evidence in the published literature on pain and pain management strategies for patients with skin disease. In an effort to enable providers to more comprehensively and effectively treat chronic pain in the primary and multidisciplinary dermatologic context, these topics will be discussed in this 2-part continuing medical education article. Part I of this series will describe important mechanisms of pain and detail individualized chronic pain assessment and treatment strategies using nonopioid analgesia. C1 [Enamandram, Monica; Kimball, Alexandra B.] Harvard Univ, Sch Med, Dept Dermatol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Rathmell, James P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA USA. RP Kimball, AB (reprint author), Massachusetts Gen Hosp, Dept Dermatol, 50 Staniford St,Ste 240, Boston, MA 02114 USA. EM harvardskinstudies@partners.org NR 72 TC 2 Z9 2 U1 1 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 OCT PY 2015 VL 73 IS 4 BP 563 EP 573 DI 10.1016/j.jaad.2014.11.039 PG 11 WC Dermatology SC Dermatology GA CR2HC UT WOS:000361146700016 PM 26369840 ER PT J AU Enamandram, M Rathmell, JP Kimball, AB AF Enamandram, Monica Rathmell, James P. Kimball, Alexandra B. TI Chronic pain management in dermatology Pharmacotherapy and therapeutic monitoring with opioid analgesia SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Review DE nonsteroidal antiinflammatory drugs; opioid analgesia; pain; postherpetic neuralgia ID CHRONIC NONCANCER PAIN; COMBINATION; GABAPENTIN; GUIDELINES; MORPHINE; EFFICACY; SAFETY AB A number of chronic dermatologic conditions may necessitate long-term adjunctive pain management in addition to treatment of the primary skin disease, such as hidradenitis suppurativa, lichen planus, and other systemic diseases associated with significant pain. Adequate management of chronic pain can represent a unique challenge, but remains an integral component of clinical treatment in relevant contexts. For nociceptive pain of moderate to severe intensity, opioid analgesics can be beneficial when other pain management strategies have failed to produce adequate relief. The decision to initiate long-term opioid therapy must be carefully weighed, and individualized treatment plans are often necessary to effectively treat pain while minimizing adverse effects. Part II of this 2-part continuing medical education article will describe the appropriate settings for initiation of opioid analgesia for dermatology patients and detail therapeutic strategies and patient monitoring guidelines. C1 [Enamandram, Monica; Kimball, Alexandra B.] Harvard Univ, Sch Med, Dept Dermatol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Rathmell, James P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA USA. RP Kimball, AB (reprint author), Massachusetts Gen Hosp, Dept Dermatol, 50 Staniford St,Ste 240, Boston, MA 02114 USA. EM harvardskinstudies@partners.org NR 26 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 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD OCT PY 2015 VL 73 IS 4 BP 575 EP 582 DI 10.1016/j.jaad.2014.11.038 PG 8 WC Dermatology SC Dermatology GA CR2HC UT WOS:000361146700017 PM 26369841 ER PT J AU Tsao, H Begolka, WS AF Tsao, Hensin Begolka, Wendy Smith CA Amer Acad Dermatology Ad Hoc Task TI Reply to: "Time to move forward after the report of the AAD Task Force for the ABCDEs of Melanoma" SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Letter C1 [Tsao, Hensin] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Tsao, Hensin] Harvard Univ, Sch Med, Boston, MA USA. [Begolka, Wendy Smith] Amer Acad Dermatol, Schaumburg, IL 60173 USA. RP Begolka, WS (reprint author), Amer Acad Dermatol, 930 E Woodfield Rd, Schaumburg, IL 60173 USA. EM wsmithbegolka@aad.org NR 3 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD OCT PY 2015 VL 73 IS 4 BP E151 EP E151 DI 10.1016/j.jaad.2015.06.044 PG 1 WC Dermatology SC Dermatology GA CR2HC UT WOS:000361146700011 PM 26369859 ER PT J AU Acher, AW LeCaire, TJ Hundt, AS Greenberg, CC Carayon, P Kind, AJ Weber, SM AF Acher, Alexandra W. LeCaire, Tamara J. Hundt, Ann Schoofs Greenberg, Caprice C. Carayon, Pascale Kind, Amy J. Weber, Sharon M. TI Using Human Factors and Systems Engineering to Evaluate Readmission after Complex Surgery SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Article ID POSTOPERATIVE COGNITIVE DYSFUNCTION; 30-DAY HOSPITAL READMISSIONS; QUALITATIVE CONTENT-ANALYSIS; HEALTH-CARE PROFESSIONALS; ABDOMINAL-SURGERY; INFORMED-CONSENT; RISK-FACTORS; DELIRIUM; PATIENT; PANCREATICODUODENECTOMY AB BACKGROUND: Our objective was to use a human factors and systems engineering approach to understand contributors to surgical readmissions from a patient and provider perspective. Previous studies on readmission have neglected the patient perspective. To address this gap and to better inform intervention design, we evaluated how transitions of care relate to and influence readmission from the patient and clinician perspective using the Systems Engineering Initiative for Patient Safety (SEIPS) model. STUDY DESIGN: Patients readmitted within 30 days of discharge after complex abdominal surgery were interviewed. A focus group of inpatient clinician providers was conducted. Questions were guided by the SEIPS framework and content was analyzed. Data were collected concurrently from the medical record for a mixed-methods approach. RESULTS: Readmission occurred a median of 8 days (range 1 to 25 days) after discharge. All patients had follow-up scheduled with their surgeon, but readmission occurred before this in 72% of patients. Primary readmission diagnoses included infection, gastrointestinal complications, and dehydration. Patients (n = 18) and clinician providers (n = 6) identified a number of factors during the transition of care that may have contributed to readmission, including poor patient and caregiver understanding; inadequate discharge preparation for home care; insufficient educational process and materials, negatively affected by electronic health record design; and inadequate care team communication. CONCLUSIONS: This is the first study to use a human factors and systems engineering approach to evaluate the impact of the quality of the transition of care and its influence on readmission from the patient and clinician perspective. Important targets for future interventions include enhancing the discharge process, improving education materials, and increasing care team coordination, with the overarching theme that improved patient and caregiver understanding and engagement are essential to decrease readmission and postdischarge health care use. (C) 2015 by the American College of Surgeons C1 [Acher, Alexandra W.; LeCaire, Tamara J.; Greenberg, Caprice C.; Weber, Sharon M.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Surg, Surg Outcomes Res Program, Madison, WI 53792 USA. [Kind, Amy J.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Med, Madison, WI 53792 USA. [LeCaire, Tamara J.; Greenberg, Caprice C.; Weber, Sharon M.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Surg, Madison, WI 53792 USA. [Hundt, Ann Schoofs; Greenberg, Caprice C.; Carayon, Pascale] Univ Wisconsin, Ctr Qual & Prod Improvement, Madison, WI 53792 USA. [Greenberg, Caprice C.; Carayon, Pascale] Univ Wisconsin, Dept Ind & Syst Engn, Coll Engn, Madison, WI 53792 USA. [Acher, Alexandra W.; Kind, Amy J.; Weber, Sharon M.] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. RP Weber, SM (reprint author), Univ Wisconsin, Dept Surg, 600 Highland Ave, Madison, WI 53792 USA. EM webers@surgery.wisc.edu FU Clinical and Translational Science Award (CTSA) program through the National Institutes of Health (NIH) National Center for Advancing Translational Sciences (NCATS) [UL1TR000427]; University of Wisconsin School of Medicine and Public Health's Wisconsin Partnership Program (WPP); Agency for Healthcare Research and Quality (AHRQ) [K18 HS022446] FX This study was supported by the Clinical and Translational Science Award (CTSA) program, through the National Institutes of Health (NIH) National Center for Advancing Translational Sciences (NCATS), grant UL1TR000427; the University of Wisconsin School of Medicine and Public Health's Wisconsin Partnership Program (WPP); and by the Agency for Healthcare Research and Quality (AHRQ), grant K18 HS022446. NR 42 TC 5 Z9 5 U1 2 U2 14 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 EI 1879-1190 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD OCT PY 2015 VL 221 IS 4 BP 810 EP 820 DI 10.1016/j.jamcollsurg.2015.06.014 PG 11 WC Surgery SC Surgery GA CR1EQ UT WOS:000361067200006 PM 26228011 ER PT J AU Nurudeen, SM Kwakye, G Berry, WR Chaikof, EL Lillemoe, KD Millham, F Rubin, M Schwaitzberg, S Shamberger, RC Zinner, MJ Sato, L Lipsitz, S Gawande, AA Haynes, AB AF Nurudeen, Suliat M. Kwakye, Gifty Berry, William R. Chaikof, Elliot L. Lillemoe, Keith D. Millham, Frederick Rubin, Marc Schwaitzberg, Steven Shamberger, Robert C. Zinner, Michael J. Sato, Luke Lipsitz, Stuart Gawande, Atul A. Haynes, Alex B. TI Can 360-Degree Reviews Help Surgeons? Evaluation of Multisource Feedback for Surgeons in a Multi-Institutional Quality Improvement Project SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Review ID PERFORMANCE; PHYSICIANS; BEHAVIOR; MANAGERS; SAFETY; TRIAL AB BACKGROUND: Medical organizations have increased interest in identifying and improving behaviors that threaten team performance and patient safety. Three hundred and sixty degree evaluations of surgeons were performed at 8 academically affiliated hospitals with a common Code of Excellence. We evaluate participant perceptions and make recommendations for future use. STUDY DESIGN: Three hundred and eighty-five surgeons in a variety of specialties underwent 360-degree evaluations, with a median of 29 reviewers each (interquartile range 23 to 36). Beginning 6 months after evaluation, surgeons, department heads, and reviewers completed follow-up surveys evaluating accuracy of feedback, willingness to participate in repeat evaluations, and behavior change. RESULTS: Survey response rate was 31% for surgeons (118 of 385), 59% for department heads (10 of 17), and 36% for reviewers (1,042 of 2,928). Eighty-seven percent of surgeons (95% CI, 75%-94%) agreed that reviewers provided accurate feedback. Similarly, 80% of department heads believed the feedback accurately reflected performance of surgeons within their department. Sixty percent of surgeon respondents (95% CI, 49%-75%) reported making changes to their practice based on feedback received. Seventy percent of reviewers (95% CI, 69%-74%) believed the evaluation process was valuable, with 82% (95% CI, 79%-84%) willing to participate in future 360-degree reviews. Thirty-two percent of reviewers (95% CI, 29%-35%) reported perceiving behavior change in surgeons. CONCLUSIONS: Three hundred and sixty degree evaluations can provide a practical, systematic, and subjectively accurate assessment of surgeon performance without undue reviewer burden. The process was found to result in beneficial behavior change, according to surgeons and their coworkers. (C) 2015 by the American College of Surgeons C1 [Nurudeen, Suliat M.; Kwakye, Gifty; Berry, William R.; Lipsitz, Stuart; Gawande, Atul A.; Haynes, Alex B.] Ariadne Labs, Boston, MA USA. [Nurudeen, Suliat M.; Kwakye, Gifty; Berry, William R.; Zinner, Michael J.; Lipsitz, Stuart; Gawande, Atul A.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Nurudeen, Suliat M.; Berry, William R.; Lipsitz, Stuart; Gawande, Atul A.; Haynes, Alex B.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Chaikof, Elliot L.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Lillemoe, Keith D.; Haynes, Alex B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Shamberger, Robert C.] Boston Childrens Hosp, Boston, MA USA. [Millham, Frederick] South Shore Hosp, South Weymouth, MA USA. [Rubin, Marc] North Shore Med Ctr, Salem, MA USA. [Schwaitzberg, Steven] Cambridge Hlth Alliance, Cambridge, MA USA. [Sato, Luke] Harvard Med Inst Inc, Risk Management Fdn, Cambridge, MA USA. RP Haynes, AB (reprint author), Massachusetts Gen Hosp, 55 Fruit St,Yawkey 7B, Boston, MA 02114 USA. EM abhaynes@mgh.harvard.edu FU Risk Management Foundation of the Harvard Medical Institutions, Inc. FX This study was supported by a grant from The Risk Management Foundation of the Harvard Medical Institutions, Inc. NR 33 TC 3 Z9 3 U1 2 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 EI 1879-1190 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD OCT PY 2015 VL 221 IS 4 BP 837 EP 844 DI 10.1016/j.jamcollsurg.2015.06.017 PG 8 WC Surgery SC Surgery GA CR1EQ UT WOS:000361067200009 PM 26272014 ER PT J AU Adler, JT Chang, DC Maguire, LH AF Adler, Joel T. Chang, David C. Maguire, Lillias H. TI Seasonal Variation in Diverticulitis: Evidence from Both Hemispheres SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Meeting Abstract CT 70th Annual Sessions of the Scientific Forum and Annual Clinical Congress of the American-College-of-Surgeons CY OCT 04-08, 2015 CL Chicago, IL SP Amer Coll Surg C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 EI 1879-1190 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD OCT PY 2015 VL 221 IS 4 SU 1 BP S36 EP S37 PG 2 WC Surgery SC Surgery GA CR1XX UT WOS:000361119700055 ER PT J AU Aggarwal, A Madigan, MC Cody, E Tzeng, E AF Aggarwal, Ankur Madigan, Michael C. Cody, Ellen Tzeng, Edith TI A Role for Topical Nitrite in Diabetic Wound Healing SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Meeting Abstract CT 70th Annual Sessions of the Scientific Forum and Annual Clinical Congress of the American-College-of-Surgeons CY OCT 04-08, 2015 CL Chicago, IL SP Amer Coll Surg C1 Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA USA. Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 EI 1879-1190 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD OCT PY 2015 VL 221 IS 4 SU 1 BP S176 EP S176 PG 1 WC Surgery SC Surgery GA CR1XX UT WOS:000361119700369 ER PT J AU Bohnen, JD Chang, DC George, BC AF Bohnen, Jordan D. Chang, David C. George, Brian C. TI Changing Trends in Operating Room Times Between Teaching and Non-Teaching Cases: Less Time for Learning? SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Meeting Abstract CT 70th Annual Sessions of the Scientific Forum and Annual Clinical Congress of the American-College-of-Surgeons CY OCT 04-08, 2015 CL Chicago, IL SP Amer Coll Surg C1 [Bohnen, Jordan D.; Chang, David C.; George, Brian C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 EI 1879-1190 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD OCT PY 2015 VL 221 IS 4 SU 1 BP S49 EP S49 PG 1 WC Surgery SC Surgery GA CR1XX UT WOS:000361119700085 ER PT J AU Chang, DC Noorbakhsh, A Mullen, J AF Chang, David C. Noorbakhsh, Abraham Mullen, John TI Analysis of Early and Late Readmission after Gastrectomy to Index and Nonindex Hospitals SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Meeting Abstract CT 70th Annual Sessions of the Scientific Forum and Annual Clinical Congress of the American-College-of-Surgeons CY OCT 04-08, 2015 CL Chicago, IL SP Amer Coll Surg C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Calif San Diego, San Diego, CA 92103 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 EI 1879-1190 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD OCT PY 2015 VL 221 IS 4 SU 1 BP S122 EP S122 PG 1 WC Surgery SC Surgery GA CR1XX UT WOS:000361119700247 ER PT J AU Cheng, L Hotta, R Graham, HK Goldstein, AM AF Cheng, Lily Hotta, Ryo Graham, Hannah K. Goldstein, Allan M. TI Serotonin Receptor Agonism Promotes Growth of Postnatal Enteric Neuronal Stem Cells SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Meeting Abstract CT 70th Annual Sessions of the Scientific Forum and Annual Clinical Congress of the American-College-of-Surgeons CY OCT 04-08, 2015 CL Chicago, IL SP Amer Coll Surg C1 [Cheng, Lily; Hotta, Ryo; Graham, Hannah K.; Goldstein, Allan M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 EI 1879-1190 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD OCT PY 2015 VL 221 IS 4 SU 1 BP S107 EP S107 PG 1 WC Surgery SC Surgery GA CR1XX UT WOS:000361119700213 ER PT J AU Kinnier, CV Ju, MH Kmiecik, TE Barnard, C Halverson, T Yang, AD Caprini, JA Bilimoria, KY AF Kinnier, Christine V. Ju, Mila H. Kmiecik, Thomas E. Barnard, Cynthia Halverson, Terri Yang, Anthony D. Caprini, Joseph A. Bilimoria, Karl Y. TI Development of a Novel Composite Process Measure for Venous Thromboembolism Prophylaxis SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Meeting Abstract CT 70th Annual Sessions of the Scientific Forum and Annual Clinical Congress of the American-College-of-Surgeons CY OCT 04-08, 2015 CL Chicago, IL SP Amer Coll Surg C1 Northwestern Univ, Chicago, IL 60611 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NorthShore Univ Hlth Syst, Evanston, IL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 EI 1879-1190 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD OCT PY 2015 VL 221 IS 4 SU 1 BP S123 EP S123 PG 1 WC Surgery SC Surgery GA CR1XX UT WOS:000361119700251 ER PT J AU Li, ZM Anderson, J Romano, PS Parker, JP Young, JN Chang, DC AF Li, Zhongmin Anderson, Jamie Romano, Patrick S. Parker, Joseph P. Young, J. Nilas Chang, David C. TI Impact of Risk Adjustment for Patient Sociodemographic Status in Public Reporting of Cardiac Surgery Outcomes SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Meeting Abstract CT 70th Annual Sessions of the Scientific Forum and Annual Clinical Congress of the American-College-of-Surgeons CY OCT 04-08, 2015 CL Chicago, IL SP Amer Coll Surg C1 Univ Calif Davis, Med Ctr, Sacramento, CA 95817 USA. Calif Off Statewide Hlth Planning & Dev, Sacramento, CA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 EI 1879-1190 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD OCT PY 2015 VL 221 IS 4 SU 1 BP S128 EP S128 PG 1 WC Surgery SC Surgery GA CR1XX UT WOS:000361119700261 ER PT J AU Liu, C Riesel, JN Twesigye, D Mugyenyi, G Ngonzi, JNJ Sanyu, F Ttendo, S Musinguzi, N Mushagara, R Firth, PG AF Liu, Charles Riesel, Johanna N. Twesigye, Deus Mugyenyi, Godfrey Ngonzi, Joseph N. J. Sanyu, Frank Ttendo, Stephen Musinguzi, Nicholas Mushagara, Rhina Firth, Paul G. TI Surgical Diagnosis and Procedure Codes for Outcomes Research in a Ugandan Regional Referral Hospital: The Mbarara Experience SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Meeting Abstract CT 70th Annual Sessions of the Scientific Forum and Annual Clinical Congress of the American-College-of-Surgeons CY OCT 04-08, 2015 CL Chicago, IL SP Amer Coll Surg C1 Mbarara Reg Referral Hosp, Mbarara, Uganda. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 EI 1879-1190 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD OCT PY 2015 VL 221 IS 4 SU 1 BP S88 EP S89 PG 2 WC Surgery SC Surgery GA CR1XX UT WOS:000361119700173 ER PT J AU Loehrer, AP Song, ZR Chang, DC Hutter, MM AF Loehrer, Andrew P. Song, Zirui Chang, David C. Hutter, Matthew M. TI Health Care Reform and Equity in Bariatric Surgery: Does Increased Access to Care Mitigate Disparities? SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Meeting Abstract CT 70th Annual Sessions of the Scientific Forum and Annual Clinical Congress of the American-College-of-Surgeons CY OCT 04-08, 2015 CL Chicago, IL SP Amer Coll Surg C1 [Loehrer, Andrew P.; Song, Zirui; Chang, David C.; Hutter, Matthew M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 EI 1879-1190 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD OCT PY 2015 VL 221 IS 4 SU 1 BP S126 EP S127 PG 2 WC Surgery SC Surgery GA CR1XX UT WOS:000361119700258 ER PT J AU Molina, G Neville, BA Lipsitz, SR Berry, W Gawande, AA Haynes, AB AF Molina, George Neville, Bridget A. Lipsitz, Stuart R. Berry, William Gawande, Atul A. Haynes, Alex B. TI Patterns of Postoperative Care after Surgery in Freestanding Ambulatory Surgery Centers in South Carolina SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Meeting Abstract CT 70th Annual Sessions of the Scientific Forum and Annual Clinical Congress of the American-College-of-Surgeons CY OCT 04-08, 2015 CL Chicago, IL SP Amer Coll Surg C1 Brigham & Womens Hosp, Ariadne Labs, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 EI 1879-1190 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD OCT PY 2015 VL 221 IS 4 SU 1 BP S130 EP S131 PG 2 WC Surgery SC Surgery GA CR1XX UT WOS:000361119700267 ER PT J AU Ramly, EP Rahbani, DDR Khalifeh, J Hoballah, JJ Kaafarani, HMA AF Ramly, Elie P. Rahbani, David D. R. Khalifeh, Jawad Hoballah, Jamal J. Kaafarani, Haytham M. A. TI Systematic Evaluation of National Surgical Capacity in Lebanon in Times of Crisis and Refugees SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Meeting Abstract CT 70th Annual Sessions of the Scientific Forum and Annual Clinical Congress of the American-College-of-Surgeons CY OCT 04-08, 2015 CL Chicago, IL SP Amer Coll Surg C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Amer Univ Beirut, Med Ctr, Beirut, Lebanon. NR 0 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 EI 1879-1190 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD OCT PY 2015 VL 221 IS 4 SU 1 BP S89 EP S89 PG 1 WC Surgery SC Surgery GA CR1XX UT WOS:000361119700174 ER PT J AU Sangji, NF Silvestri, S Abayaah, E Chang, DC Hutter, MM O'Malley, C AF Sangji, Naveen F. Silvestri, Sandra Abayaah, Evelyn Chang, David C. Hutter, Matthew M. O'Malley, Catherine TI Sharps Injuries in the Operating Room Sterile Fields of an Academic Tertiary Care Center SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Meeting Abstract CT 70th Annual Sessions of the Scientific Forum and Annual Clinical Congress of the American-College-of-Surgeons CY OCT 04-08, 2015 CL Chicago, IL SP Amer Coll Surg C1 [Sangji, Naveen F.; Silvestri, Sandra; Abayaah, Evelyn; Chang, David C.; Hutter, Matthew M.; O'Malley, Catherine] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 EI 1879-1190 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD OCT PY 2015 VL 221 IS 4 SU 1 BP S132 EP S132 PG 1 WC Surgery SC Surgery GA CR1XX UT WOS:000361119700271 ER PT J AU Deshmukh, S Sternberg, K Hernandez, N Eisner, BH AF Deshmukh, Sameer Sternberg, Kevan Hernandez, Natalia Eisner, Brian H. TI Compliance with American Urological Association Guidelines for Post-Percutaneous Nephrolithotomy Antibiotics Does Not Appear to Increase Rates of Infection SO JOURNAL OF UROLOGY LA English DT Article DE kidney; nephrostomy, percutaneous; anti-bacterial agents; standards; compliance ID RISK-FACTORS; TRACT INFECTION; PROPHYLAXIS; COMPLICATIONS; SURGERY; UROSEPSIS; SEPSIS AB Purpose: We compared infection rates after percutaneous nephrolithotomy in a group of patients without a history of infection or struvite calculi who received 24 hours or less of antibiotics postoperatively (ie compliance with AUA guidelines) vs a group that received 5 to 7 days of antibiotics postoperatively. Materials and Methods: We retrospectively reviewed the records of consecutive percutaneous nephrolithotomy procedures in patients without a history of urinary tract infection. Group 1 received 24 hours or less of antibiotics postoperatively and group 2 received a mean of 6 days of antibiotics postoperatively. Results: A total of 52 patients in group 1 (24 hours or less of antibiotics) and 30 in group 2 (mean 6 days of antibiotics) met study inclusion criteria. In 5 group 1 patients (9.6%) fever developed within 72 hours of percutaneous nephrolithotomy but none demonstrated bacteriuria or bacteremia on cultures. No patient in group 1 was treated for urinary tract infection on postoperative days 3 to 14. In 4 group 2 patients (13.3%) fever developed within 72 hours of percutaneous nephrolithotomy. Asingle patient showed bacteriuria (less than 10,000 cfu mixed gram-positive bacteria) on culture while no patient demonstrated bacteremia. No patient in group 2 was treated for urinary tract infection on postoperative days 3 to 14. There was no difference in stone-free rates or the need for additional procedures between the 2 groups. Conclusions: In this pilot series compliance with AUA guidelines for antibiotic prophylaxis did not result in higher rates of infection than in a comparable group of 30 patients who received approximately 6 days of antibiotics postoperatively. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Urol, Boston, MA USA. [Sternberg, Kevan] Univ Vermont, Coll Med, Div Urol, Burlington, VT USA. RP Eisner, BH (reprint author), Dept Urol, GRB 1102,55 Fruit St, Boston, MA 02114 USA. EM beisner@partners.org NR 15 TC 9 Z9 9 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD OCT PY 2015 VL 194 IS 4 BP 992 EP 996 DI 10.1016/j.juro.2015.04.097 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA CR3LS UT WOS:000361234900039 PM 25936864 ER PT J AU Bechis, SK Otsetov, AG Ge, RB Wang, ZW Vangel, MG Wu, CL Tabatabaei, S Olumi, AF AF Bechis, Seth K. Otsetov, Alexander G. Ge, Rongbin Wang, Zongwei Vangel, Mark G. Wu, Chin-Lee Tabatabaei, Shahin Olumi, Aria F. TI Age and Obesity Promote Methylation and Suppression of 5 alpha-Reductase 2: Implications for Personalized Therapy of Benign Prostatic Hyperplasia SO JOURNAL OF UROLOGY LA English DT Article DE prostatic hyperplasia; obesity; lower urinary tract symptoms; 5-alpha reductase inhibitors; epigenomics ID URINARY-TRACT SYMPTOMS; DNA METHYLATION; GASTRIC BYPASS; ADULT PROSTATE; WEIGHT-LOSS; CANCER; RISK; FINASTERIDE; EXPRESSION; SURGERY AB Purpose: In men with symptomatic benign prostatic hyperplasia 5 alpha-reductase inhibitors are a main modality of treatment. More than 30% of men do not respond to the therapeutic effects of 5 alpha-reductase inhibitors. We have found that a third of adult prostate samples do not express 5 alpha-reductase type 2 secondary to epigenetic modifications. We evaluated whether 5 alpha-reductase type 2 expression in benign prostatic hyperplasia specimens from symptomatic men was linked to methylation of the 5 alpha-reductase type 2 gene promoter. We also identified associations with age, obesity, cardiac risk factors and prostate specific antigen. Materials and Methods: Prostate samples from men undergoing transurethral prostate resection were used. We determined 5 alpha-reductase type 2 protein expression and gene promoter methylation status by common assays. Clinical variables included age, body mass index, hypertension, hyperlipidemia, diabetes, prostate specific antigen and prostate volume. Univariate and multivariate statistical analyses were performed followed by stepwise logistic regression modeling. Results: Body mass index and age significantly correlated with methylation of the 5 alpha-reductase type 2 gene promoter (p < 0.05) whereas prostate volume, prostate specific antigen or benign prostatic hyperplasia medication did not correlate. Methylation highly correlated with 5 alpha-reductase protein expression (p < 0.0001). In a predictive model increasing age and body mass index significantly predicted methylation status and protein expression (p < 0.01). Conclusions: Increasing age and body mass index correlate with increased 5 alpha-reductase type 2 gene promoter methylation and decreased protein expression in men with symptomatic benign prostatic hyperplasia. These results highlight the interplay among age, obesity and gene regulation. Our findings suggest an individualized epigenetic signature for symptomatic benign prostatic hyperplasia, which may be important to choose appropriate personalized treatment options. C1 [Bechis, Seth K.; Otsetov, Alexander G.; Ge, Rongbin; Wang, Zongwei; Tabatabaei, Shahin; Olumi, Aria F.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Urol, Boston, MA USA. [Vangel, Mark G.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA USA. [Wu, Chin-Lee] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA USA. [Vangel, Mark G.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Biostat, Boston, MA USA. RP Olumi, AF (reprint author), Massachusetts Gen Hosp, Dept Urol, 55 Fruit St,Yawkey Bldg,Suite 7E, Boston, MA 02114 USA. EM Olumi.Aria@mgh.harvard.edu FU National Institutes of Health [R01 DK091353]; Harvard Catalyst\The Harvard Clinical and Translational Science Center (NCRR); Harvard Catalyst\The Harvard Clinical and Translational Science Center (NCATS, National Institutes of Health) [UL1 TR001102]; Harvard University, its affiliated academic health care centers FX Supported by National Institutes of Health Grant R01 DK091353, Harvard Catalyst vertical bar The Harvard Clinical and Translational Science Center (NCRR and NCATS, National Institutes of Health Award UL1 TR001102), and financial contributions from Harvard University and its affiliated academic health care centers. NR 30 TC 1 Z9 1 U1 1 U2 4 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 OCT PY 2015 VL 194 IS 4 BP 1031 EP 1037 DI 10.1016/j.juro.2015.04.079 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA CR3LS UT WOS:000361234900067 PM 25916673 ER PT J AU Nalls, MA McLean, CY Rick, J Eberly, S Hutten, SJ Gwinn, K Sutherland, M Martinez, M Heutink, P Williams, NM Hardy, J Gasser, T Brice, A Price, TR Nicolas, A Keller, MF Molony, C Gibbs, JR Chen-Plotkin, A Suh, E Letson, C Fiandaca, MS Mapstone, M Federoff, HJ Noyce, AJ Morris, H Van Deerlin, VM Weintraub, D Zabetian, C Hernandez, DG Lesage, S Mullins, M Conley, ED Northover, CAM Frasier, M Marek, K Day-Williams, AG Stone, DJ Ioannidis, JPA Singleton, AB AF Nalls, Mike A. McLean, Cory Y. Rick, Jacqueline Eberly, Shirley Hutten, Samantha J. Gwinn, Katrina Sutherland, Margaret Martinez, Maria Heutink, Peter Williams, Nigel M. Hardy, John Gasser, Thomas Brice, Alexis Price, T. Ryan Nicolas, Aude Keller, Margaux F. Molony, Cliona Gibbs, J. Raphael Chen-Plotkin, Alice Suh, Eunran Letson, Christopher Fiandaca, Massimo S. Mapstone, Mark Federoff, Howard J. Noyce, Alastair J. Morris, Huw Van Deerlin, Vivianna M. Weintraub, Daniel Zabetian, Cyrus Hernandez, Dena G. Lesage, Suzanne Mullins, Meghan Conley, Emily Drabant Northover, Carrie A. M. Frasier, Mark Marek, Ken Day-Williams, Aaron G. Stone, David J. Ioannidis, John P. A. Singleton, Andrew B. CA Parkinson's Dis Biomarkers Program TI Diagnosis of Parkinson's disease on the basis of clinical and genetic classification: a population-based modelling study SO LANCET NEUROLOGY LA English DT Article ID GENOME-WIDE ASSOCIATION; MUTATIONS; IDENTIFICATION; METAANALYSIS AB Background Accurate diagnosis and early detection of complex diseases, such as Parkinson's disease, has the potential to be of great benefit for researchers and clinical practice. We aimed to create a non-invasive, accurate classification model for the diagnosis of Parkinson's disease, which could serve as a basis for future disease prediction studies in longitudinal cohorts. Methods We developed a model for disease classification using data from the Parkinson's Progression Marker Initiative (PPMI) study for 367 patients with Parkinson's disease and phenotypically typical imaging data and 165 controls without neurological disease. Olfactory function, genetic risk, family history of Parkinson's disease, age, and gender were algorithmically selected by stepwise logistic regression as significant contributors to our classifying model. We then tested the model with data from 825 patients with Parkinson's disease and 261 controls from five independent cohorts with varying recruitment strategies and designs: the Parkinson's Disease Biomarkers Program (PDBP), the Parkinson's Associated Risk Study (PARS), 23andMe, the Longitudinal and Biomarker Study in PD (LABS-PD), and the Morris K Udall Parkinson's Disease Research Center of Excellence cohort (Penn-Udall). Additionally, we used our model to investigate patients who had imaging scans without evidence of dopaminergic deficit (SWEDD). Findings In the population from PPMI, our initial model correctly distinguished patients with Parkinson's disease from controls at an area under the curve (AUC) of 0.923 (95% CI 0.900-0.946) with high sensitivity (0.834, 95% CI 0.711-0.883) and specificity (0.903, 95% CI 0.824-0.946) at its optimum AUC threshold (0.655). All Hosmer-Lemeshow simulations suggested that when parsed into random subgroups, the subgroup data matched that of the overall cohort. External validation showed good classification of Parkinson's disease, with AUCs of 0.894 (95% CI 0.867-0.921) in the PDBP cohort, 0.998 (0.992-1.000) in PARS, 0.955 (no 95% CI available) in 23andMe, 0.929 (0.896-0.962) in LABS-PD, and 0.939 (0.891-0.986) in the Penn-Udall cohort. Four of 17 SWEDD participants who our model classified as having Parkinson's disease converted to Parkinson's disease within 1 year, whereas only one of 38 SWEDD participants who were not classified as having Parkinson's disease underwent conversion (test of proportions, p=0.003). Interpretation Our model provides a potential new approach to distinguish participants with Parkinson's disease from controls. If the model can also identify individuals with prodromal or preclinical Parkinson's disease in prospective cohorts, it could facilitate identification of biomarkers and interventions. C1 [Nalls, Mike A.; Price, T. Ryan; Nicolas, Aude; Gibbs, J. Raphael; Letson, Christopher; Hernandez, Dena G.; Singleton, Andrew B.] NIA, NIH, Neurogenet Lab, Bethesda, MD 20892 USA. [McLean, Cory Y.; Mullins, Meghan; Conley, Emily Drabant; Northover, Carrie A. M.] 23andMe, Mountain View, CA USA. [Rick, Jacqueline; Chen-Plotkin, Alice; Weintraub, Daniel] Univ Penn, Perelman Sch Med, Dept Neurol, Philadelphia, PA 19104 USA. [Eberly, Shirley] Univ Rochester, Dept Biostat & Computat Biol, Rochester, NY 14627 USA. [Hutten, Samantha J.; Frasier, Mark] Michael J Fox Fdn, Parkinsons Res, New York, NY USA. [Gwinn, Katrina; Sutherland, Margaret] NINDS, NIH, Bethesda, MD 20892 USA. [Martinez, Maria] INSERM, UMR 1043, Ctr Physiopathol Toulouse Purpan, Toulouse, France. [Martinez, Maria] Univ Toulouse 3, F-31062 Toulouse, France. [Heutink, Peter] German Ctr Neurodegenerat Dis, Genome Biol Neurodegenerat Dis, Tubingen, Germany. [Williams, Nigel M.] Cardiff Univ, MRC Ctr Neuropsychiat Genet & Gen, Inst Psychol Med & Clin Neurosci, Cardiff CF10 3AX, S Glam, Wales. [Hardy, John; Noyce, Alastair J.; Morris, Huw] UCL, Inst Neurol, Reta Lila Weston Inst, London, England. [Gasser, Thomas] Univ Tubingen, Hertie Inst Clin Brain Res, Dept Neurodegenerat Dis, Tubingen, Germany. [Brice, Alexis; Lesage, Suzanne] Sorbonne Univ, UPMC Univ Paris 06, 1127, Paris, France. [Brice, Alexis; Lesage, Suzanne] CNRS, INSERM, UMR 7225,U 1127, Inst Cerveau & Moelle Epiniere, Paris, France. [Brice, Alexis; Lesage, Suzanne] Hop La Pitie Salpetriere, AP HP, Dept Genet & Cytogenet, Paris, France. [Keller, Margaux F.; Molony, Cliona; Stone, David J.] Merck Res Labs, Genet & Pharmacogen, West Point, PA USA. [Keller, Margaux F.; Molony, Cliona; Stone, David J.] Merck Res Labs, Boston, MA USA. [Suh, Eunran; Van Deerlin, Vivianna M.] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Ctr Neurodegenerat Dis Res, Philadelphia, PA 19104 USA. [Fiandaca, Massimo S.; Federoff, Howard J.] Georgetown Univ, Med Ctr, Dept Neurol, Washington, DC 20007 USA. [Mapstone, Mark] Univ Rochester, Med Ctr, Dept Neurol, Rochester, NY 14642 USA. [Weintraub, Daniel] Univ Penn, Perelman Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. [Zabetian, Cyrus] VA Puget Sound Hlth Care Syst, Div Neurogenet, Dept Neurol, Seattle, WA USA. [Marek, Ken] Inst Neurodegenerat Disorders, New Haven, CT USA. [Day-Williams, Aaron G.] Biogen, Precis Med, Cambridge, MA USA. [Ioannidis, John P. A.] Stanford Univ, Meta Res Innovat Ctr Stanford METRICS, Stanford, CA 94305 USA. RP Nalls, MA (reprint author), NIA, NIH, Neurogenet Lab, Bethesda, MD 20892 USA. RI Singleton, Andrew/C-3010-2009; Hardy, John/C-2451-2009; Martinez, Maria/B-3111-2013; Morris, Huw/B-8527-2008; corvol, jean-christophe/I-6387-2012; OI Martinez, Maria/0000-0003-2180-4537; Morris, Huw/0000-0002-5473-3774; corvol, jean-christophe/0000-0001-7325-0199; Gwinn, Katrina/0000-0002-8277-651X FU National Institute on Aging, National Institute of Neurological Disorders and Stroke; Michael J Fox Foundation FX National Institute on Aging, National Institute of Neurological Disorders and Stroke, and the Michael J Fox Foundation. NR 20 TC 26 Z9 26 U1 1 U2 14 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 OCT PY 2015 VL 14 IS 10 BP 1002 EP 1009 DI 10.1016/S1474-4422(15)00178-7 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA CR2VI UT WOS:000361188400011 PM 26271532 ER PT J AU Gray, NE Quinn, JF AF Gray, Nora E. Quinn, Joseph F. TI Alterations in mitochondrial number and function in Alzheimer's disease fibroblasts SO METABOLIC BRAIN DISEASE LA English DT Article DE beta-amyloid; Mitochondrial dysfunction; Alzheimer's disease ID MAGNETIC-RESONANCE-SPECTROSCOPY; MILD COGNITIVE IMPAIRMENT; CULTURED SKIN FIBROBLASTS; AMYLOID-BETA; MOUSE MODEL; BRAIN; PATHOLOGY; DEMENTIA; MICE AB Mitochondrial dysfunction is observed in brains of Alzheimer's Disease patients as well as many rodent model systems including those modeling mutations in preseinilin 1 (PSEN1). The aim of our study was to characterize mitochondrial function and number in fibroblasts from AD patients with PSEN1 mutations. We used biochemical assays, metabolic profiling and fluorescent labeling to assess mitochondrial number and function in fibroblasts from three AD patients compared to fibroblasts from three controls. The mutant AD fibroblasts had increased A beta 42 relative to controls along with reduction in ATP, basal and maximal mitochondrial respiration as well as impaired spare mitochondrial respiratory capacity. Fluorescent staining and expression of genes encoding electron transport chain enzymes showed diminished mitochondrial content in the AD fibroblasts. This study demonstrates that mitochondrial dysfunction is observable in AD fibroblasts and provides evidence that this model system could be useful as a tool to screen disease-modifying compounds. C1 [Gray, Nora E.; Quinn, Joseph F.] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97239 USA. [Quinn, Joseph F.] Portland VA Med Ctr, Dept Neurol, Portland, OR 97239 USA. [Quinn, Joseph F.] Portland VA Med Ctr, Parkinsons Dis Res Educ & Clin Care Ctr PADRECC, Portland, OR 97239 USA. RP Gray, NE (reprint author), Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97239 USA. EM grayn@ohsu.edu FU Department of Veterans Affairs Merit Review grant FX This work was funded by a Department of Veterans Affairs Merit Review grant awarded to J. Quinn. NR 28 TC 0 Z9 0 U1 0 U2 4 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 OCT PY 2015 VL 30 IS 5 BP 1275 EP 1278 DI 10.1007/s11011-015-9667-z PG 4 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA CQ8TG UT WOS:000360881400019 PM 25862550 ER PT J AU Poutiainen, P Kil, KE Zhang, ZD Kuruppu, D Tannous, B Brownell, AL AF Poutiainen, Pekka Kil, Kun-Eek Zhang, Zhaoda Kuruppu, Darshini Tannous, Bakhos Brownell, Anna-Liisa TI Co-operative binding assay for the characterization of mGlu(4) allosteric modulators SO NEUROPHARMACOLOGY LA English DT Article DE Metabotropic glutamate receptor; Parkinson disease; mGlu(4); Binding affinity ID METABOTROPIC GLUTAMATE RECEPTORS; PARKINSONS-DISEASE; PET RADIOTRACER; DRUG DISCOVERY; RADIOSYNTHESIS; INSIGHTS; FAMILY; CNS AB The interest in the role of metabotropic glutamate receptor 4 (mGlu(4)) in CNS related disorders has increased the need for methods to investigate the binding of allosteric drug candidates. Our aim is to present the first fully characterized in vitro binding assay of mGlu(4) positive allosteric modulators (PAMs). Results suggest that mGlu(4) PAMs have characteristic co-operative binding with orthosteric glutamate, which offers a notable insight to the further development of mGlu(4) targeted therapies. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Poutiainen, Pekka; Kil, Kun-Eek; Zhang, Zhaoda; Brownell, Anna-Liisa] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Athinoula A Martinos Biomed Imaging Ctr, Boston, MA 02115 USA. [Kuruppu, Darshini] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Surg Oncol, Boston, MA USA. [Tannous, Bakhos] Massachusetts Gen Hosp, Dept Neurol, Ctr Neurosci, Expt Therapeut & Mol Imaging Lab, Boston, MA 02114 USA. [Tannous, Bakhos] Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02115 USA. RP Brownell, AL (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Athinoula A Martinos Biomed Imaging Ctr, Boston, MA 02115 USA. EM abrownell@partners.org FU Orion Farmos Research Foundation; Kuopio University Foundation; [NIBIB-R01EB012864]; [NIMH-R01MH091684] FX Studies were supported by the grants NIBIB-R01EB012864 and NIMH-R01MH091684 to A-LB. PP was supported by the Orion Farmos Research Foundation and Kuopio University Foundation. We would like also to thank Drs. Tanabe and Shigetada Nakanishi's laboratory (Osaka Bioscience Institute, Osaka, Japan) for providing us the vector of mGlu4 from rat as a gift. In addition, Dr. Shilpa Prabhakar and Dr. Xandra Breakefield from Molecular Neurogenetics Unit, Massachusetts General Hospital (Boston, MA, USA) are greatly acknowledged for helping with the transfection of the cell line. NR 29 TC 1 Z9 1 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 EI 1873-7064 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD OCT PY 2015 VL 97 BP 142 EP 148 DI 10.1016/j.neuropharm.2015.05.017 PG 7 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA CQ8PC UT WOS:000360869700015 PM 26025660 ER PT J AU Gomeni, R Goyal, N Bressolle, F Fava, M AF Gomeni, Roberto Goyal, Navin Bressolle, Francoise Fava, Maurizio TI A Novel Methodology to Estimate the Treatment Effect in Presence of Highly Variable Placebo Response SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID SIGNAL-DETECTION-THEORY; CLINICAL-TRIALS; ANTIDEPRESSANT DRUGS; ENRICHMENT STRATEGY; IMPROVE EFFICIENCY; MAJOR DEPRESSION; DISORDERS; ESCITALOPRAM; PERFORMANCE; SEVERITY AB One of the main reasons for the inefficiency of multicenter randomized clinical trials (RCTs) in depression is the excessively high level of placebo response. The aim of this work was to propose a novel methodology to analyze RCTs based on the assumption that centers with high placebo response are less informative than the other centers for estimating the 'true' treatment effect (TE). A linear mixed-effect modeling approach for repeated measures (MMRM) was used as a reference approach. The new method for estimating TE was based on a nonlinear longitudinal modeling of clinical scores (NLMMRM). NLMMRM estimates TE by associating a weighting factor to the data collected in each center. The weight was defined by the posterior probability of detecting a clinically relevant difference between active treatment and placebo at that center. Data from five RCTs in depression were used to compare the performance of MMRM with NLMMRM. The results of the analyses showed an average improvement of similar to 15% in the TE estimated with NLMMRM when the center effect was included in the analyses. Opposite results were observed with MMRM: TE estimate was reduced by similar to 4% when the center effect was considered as covariate in the analysis. The novel NLMMRM approach provides a tool for controlling the confounding effect of high placebo response, to increase signal detection and to provide a more reliable estimate of the 'true' TE by controlling false negative results associated with excessively high placebo response. C1 [Gomeni, Roberto; Bressolle, Francoise] Longcol, R&D Dept, Pharmacometr, La Fouillade, France. [Goyal, Navin] GlaxoSmithKline, Clin Pharmacol Modeling & Simulat Dept, King Of Prussia, PA USA. [Fava, Maurizio] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP Gomeni, R (reprint author), Lieudit Longcol, R&D Pharmacometr, F-12270 La Fouillade, France. EM roberto.gomeni@pharmacometrica.com FU Pharmacometrica France; Abbot Laboratories; Alkermes; American Cyanamid; Aspect Medical Systems; AstraZeneca; Avanir Pharmaceuticals; BioResearch; BrainCells; Bristol-Myers Squibb; CeNeRx BioPharma; Cephalon; Clintara, LLC; Covance; Covidien; Eli Lilly and Company; EnVivo Pharmaceuticals; Euthymics Bioscience; Forest Pharmaceuticals; Ganeden Biotech; GlaxoSmithKline; Harvard Clinical Research Institute; Hoffman-LaRoche; Icon Clinical Research; i3 Innovus/Ingenix; Janssen RD, LLC; Jed Foundation; Johnson & Johnson Pharmaceutical Research Development; Lichtwer Pharma GmbH; Lorex Pharmaceuticals; Lundbeck; MedAvante; Methylation Sciences; National Alliance for Research on Schizophrenia & Depression (NARSAD); National Center for Complementary and Alternative Medicine (NCCAM); National Institute of Drug Abuse (NIDA); National Institute of Mental Health (NIMH); Neuralstem, Inc.; Novartis AG; Organon Pharmaceuticals; PamLab, LLC; Pfizer; Pharmacia-Upjohn; Pharmaceutical Research Associates; Pharmavite LLC; PharmoRx Therapeutics; Photothera; Reckitt Benckiser; Roche Pharmaceuticals; RCT Logic, LLC; Sanofi-Aventis US LLC; Shire; Solvay Pharmaceuticals; Stanley Medical Research Institute (SMRI); Synthelabo; Wyeth-Ayerst Laboratories; GSK FX This study has been sponsored by Pharmacometrica France. The authors declare no conflict of interest and that they did not receive any financial support for this study. RG is a full time employee of Pharmacometrica. NG is a full time employee of GSK. He receives salary and stocks from GSK. FB is a consultant of Pharmacometrica. MF: Research Support: Abbot Laboratories; Alkermes; American Cyanamid; Aspect Medical Systems; AstraZeneca; Avanir Pharmaceuticals; BioResearch; BrainCells; Bristol-Myers Squibb; CeNeRx BioPharma; Cephalon; Clintara, LLC; Covance; Covidien; Eli Lilly and Company; EnVivo Pharmaceuticals; Euthymics Bioscience; Forest Pharmaceuticals; Ganeden Biotech; GlaxoSmithKline; Harvard Clinical Research Institute; Hoffman-LaRoche; Icon Clinical Research; i3 Innovus/Ingenix; Janssen R&D, LLC; Jed Foundation; Johnson & Johnson Pharmaceutical Research & Development; Lichtwer Pharma GmbH; Lorex Pharmaceuticals; Lundbeck; MedAvante; Methylation Sciences; National Alliance for Research on Schizophrenia & Depression (NARSAD); National Center for Complementary and Alternative Medicine (NCCAM); National Institute of Drug Abuse (NIDA); National Institute of Mental Health (NIMH); Neuralstem, Inc.; Novartis AG; Organon Pharmaceuticals; PamLab, LLC.; Pfizer; Pharmacia-Upjohn; Pharmaceutical Research Associates; Pharmavite LLC; PharmoRx Therapeutics; Photothera; Reckitt Benckiser; Roche Pharmaceuticals; RCT Logic, LLC (formerly Clinical Trials Solutions, LLC); Sanofi-Aventis US LLC; Shire; Solvay Pharmaceuticals; Stanley Medical Research Institute (SMRI); Synthelabo; Wyeth-Ayerst Laboratories. Advisory/Consulting: Abbott Laboratories; Affectis Pharmaceuticals AG; Alkermes; Amarin Pharma; Aspect Medical Systems; AstraZeneca; Auspex Pharmaceuticals; Bayer AG; Best Practice Project Management; BioMarin Pharmaceuticals; Biovail Corporation; BrainCells; Bristol-Myers Squibb; CeNeRx BioPharma; Cephalon; Cerecor; CNS Response; Compellis Pharmaceuticals; Cypress Pharmaceutical; DiagnoSearch Life Sciences (P); Dinippon Sumitomo Pharma; Dov Pharmaceuticals; Edgemont Pharmaceuticals; Eisai; Eli Lilly and Company; EnVivo Pharmaceuticals; ePharmaSolutions; EPIX Pharmaceuticals; Euthymics Bioscience; Fabre-Kramer Pharmaceuticals; Forest Pharmaceuticals; GenOmind, LLC; GlaxoSmithKline; Grunenthal GmbH; i3 Innovus/Ingenis; Janssen Pharmaceutica; Jazz Pharmaceuticals; Johnson & Johnson Pharmaceutical Research & Development, LLC; Knoll Pharmaceuticals; Labopharm; Lorex Pharmaceuticals; Lundbeck; MedAvante; Merck; MSI Methylation Sciences; Naurex; Neuralstem; Neuronetics; NextWave Pharmaceuticals; Novartis AG; Nutrition 21; Orexigen Therapeutics; Organon Pharmaceuticals; Otsuka Pharmaceuticals; Pamlab, LLC.; Pfizer; PharmaStar; Pharmavite LLC.; PharmoRx Therapeutics; Precision Human Biolaboratory; Prexa Pharmaceuticals; Puretech Ventures; PsychoGenics; Psylin Neurosciences; RCT Logic, LLC (formerly Clinical Trials Solutions, LLC); Rexahn Pharmaceuticals; Ridge Diagnostics; Roche; Sanofi-Aventis US LLC.; Sepracor; Servier Laboratories; Schering-Plough Corporation; Solvay Pharmaceuticals; Somaxon Pharmaceuticals; Somerset Pharmaceuticals; Sunovion Pharmaceuticals; Supernus Pharmaceuticals; Synthelabo; Takeda Pharmaceutical Company Limited; Tal Medical; Tetragenex Pharmaceuticals; TransForm Pharmaceuticals; Transcept Pharmaceuticals; Vanda Pharmaceuticals.; Speaking/Publishing: Adamed; Advanced Meeting Partners; American Psychiatric Association; American Society of Clinical Psychopharmacology; AstraZeneca; Belvoir Media Group; Boehringer Ingelheim GmbH; Bristol-Myers Squibb; Cephalon; CME Institute/Physicians Postgraduate Press; Eli Lilly and Company; Forest Pharmaceuticals; GlaxoSmithKline; Imedex, LLC; MGH Psychiatry Academy/Primedia; MGH Psychiatry Academy/Reed Elsevier; Novartis AG; Organon Pharmaceuticals; Pfizer; PharmaStar; United BioSource; Wyeth-Ayerst Laboratories. Equity Holdings: Compellis; PsyBrain. Royalty/patent, other income: Patent for Sequential Parallel Comparison Design (SPCD), which are licensed by MGH to Pharmaceutical Product Development, LLC (PPD); and patent application for a combination of Ketamine plus Scopolamine in Major Depressive Disorder (MDD). Copyright for the MGH Cognitive & Physical Functioning Questionnaire (CPFQ), Sexual Functioning Inventory (SFI), Antidepressant Treatment Response Questionnaire (ATRQ), Discontinuation-Emergent Signs & Symptoms (DESS), and SAFER; Lippincott, Williams & Wilkins; Wolkers Kluwer; World Scientific Publishing. NR 32 TC 0 Z9 0 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD OCT PY 2015 VL 40 IS 11 BP 2588 EP 2595 DI 10.1038/npp.2015.105 PG 8 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA CR2EM UT WOS:000361138300011 PM 25895454 ER PT J AU Booi, AN Menendez, J Norton, HJ Anderson, WE Ellis, AC AF Booi, Amy N. Menendez, Jerome Norton, H. James Anderson, William E. Ellis, Amy C. TI Validation of a Screening Tool to Identify Undernutrition in Ambulatory Patients With Liver Cirrhosis SO NUTRITION IN CLINICAL PRACTICE LA English DT Article DE liver diseases; end-stage liver disease; nutrition assessment; malnutrition; liver cirrhosis ID MALNUTRITION; NUTRITION; DISEASE; PREVALENCE; MANAGEMENT AB Background: The prevalence of chronic liver disease is increasing in the United States. Malnutrition is common as liver disease progresses. However, an accepted method to screen these patients for malnutrition is lacking. The 6-question undernutrition screening tool was developed for professionals without nutrition training to identify a decline in the nutrition status of patients with liver cirrhosis. A 3-phase validation study was completed to assess face, content, and clinical validity of the screening tool in ambulatory patients with liver cirrhosis. Methods: In phase I, face validity was determined by surveying 13 liver disease professionals. In phase II, content validity was assessed by surveying 12 registered dietitians who specialize in liver disease. In phase III, a cross-sectional investigation was completed to compare the agreement between the undernutrition screening tool and nutrition assessment by a registered dietitian (RD). Results: Twenty-two patients with a diagnosis of liver cirrhosis participated in phase III of the investigation. The RD assessment identified undernutrition in 82% of patients (95% CI, 60%-95%). The statistic indicated a fair agreement between the screening tool and RD assessment. Sensitivity and specificity of the tool were 72% and 75%, respectively, and positive predictive value was 93%. Conclusions: Feedback from phase I, II, and III indicate that the undernutrition screening tool is simple, is easy to use, and measures the constructs that have the strongest link with undernutrition in liver disease. Additional minor adjustments to the screening tool and a multicenter investigation are indicated to confirm clinical effectiveness and cross-validity of the tool. C1 [Booi, Amy N.; Menendez, Jerome; Norton, H. James; Anderson, William E.] Carolinas Healthcare Syst, Charlotte, NC USA. [Ellis, Amy C.] Univ Alabama, Dept Human Nutr, Tuscaloosa, AL USA. RP Booi, AN (reprint author), Nutr & Food Serv, US Dept Vet Affairs, Southern Nevada Healthcare Syst, North Las Vegas Med Ctr, 6900 North Pecos Rd, North Las Vegas, NV 89096 USA. EM amybooi@gmail.com NR 15 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 0884-5336 EI 1941-2452 J9 NUTR CLIN PRACT JI Nutr. Clin. Pract. PD OCT PY 2015 VL 30 IS 5 BP 683 EP 689 DI 10.1177/0884533615587537 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CQ7DQ UT WOS:000360763500009 PM 26024676 ER PT J AU Cunningham, SED Verkaik, D Gross, G Khazim, K Hirachan, P Agarwal, G Lorenzo, C Matteucci, E Bansal, S Fanti, P AF Cunningham, Sue E. D. Verkaik, Darlene Gross, Georgiana Khazim, Khalid Hirachan, Padam Agarwal, Gurav Lorenzo, Carlos Matteucci, Elena Bansal, Shweta Fanti, Paolo TI Comparison of Nutrition Profile and Diet Record Between Veteran and Nonveteran End-Stage Renal Disease Patients Receiving Hemodialysis in Veterans Affairs and Community Clinics in Metropolitan South-Central Texas SO NUTRITION IN CLINICAL PRACTICE LA English DT Article DE wasting syndrome; inflammation; diabetes mellitus; ethnic groups; healthcare disparities; socioeconomic factors ID ENERGY-INTAKE; KIDNEY-DISEASE; PROTEIN-INTAKE; MUSCLE MASS; DIALYSIS; ASSOCIATION; MORTALITY; MEMBRANES; SURVIVAL; FAILURE AB Background: U.S. military veterans have high rates of chronic disease and social disadvantage, which are risk factors for protein-energy wasting (PEW). It is not known whether this translates into high prevalence of PEW in veterans with end-stage renal disease. Methods: We compared the clinical, socioeconomic, and nutrition status and the diet of 33 veteran and 38 nonveteran clinically stable patients receiving maintenance hemodialysis (MHD) in south-central Texas. Results: The whole cohort included 82% Mexican Americans (MAs), 72% type 2 diabetics, and 73% males. The body mass index was 28.9 +/- 6.2, while energy intake was 21.5 +/- 8.2 kcal/kg/d and protein intake was 1.0 +/- 0.4 g/kg/d. Serum albumin (bromocresol purple) was 3.5 +/- 0.4 g/dL, transferrin was 171.9 +/- 27.8 mg/d, C-reactive protein was 2.9 (1.4-6.5) mg/L, interleukin-6 (IL-6) was 8.3 (4.2-17.9) pg/mL, neutrophil gelatinase-associated lipocalin was 729 (552-1256) ng/mL, and the malnutrition-inflammation score was 8.8 +/- 3.0. In group comparison that adjusted for sex and ethnicity, the veterans had better household income, less MAs (60% vs 100%), more males (94% vs 55%), more use of a renin-angiotensin-aldosterone system blockade (66% vs 33%), and lower IL-6 levels (4.4 [3.1-5.8] vs 15.4 [8.3-20.5] pg/mL; P = .01) than nonveterans. In regression analysis, the lower serum IL-6 level in veterans was independently explained by dialysis clinic, sex, and, possibly, household income (intermediate significance). Conclusion: In a relatively small cohort of clinically stable MHD patients, the veterans showed equivalent nutrition status and dietary intake and less inflammation than the nonveterans, thus not supporting the possibility that veteran MHD patients may have worse nutrition than the nonveteran counterpart. C1 [Cunningham, Sue E. D.; Khazim, Khalid; Hirachan, Padam; Agarwal, Gurav; Fanti, Paolo] Univ Texas Hlth Sci Ctr San Antonio, Div Nephrol, San Antonio, TX 78229 USA. [Cunningham, Sue E. D.; Gross, Georgiana] Univ Texas Hlth Sci Ctr San Antonio, Sch Hlth Profess, San Antonio, TX 78229 USA. [Verkaik, Darlene; Bansal, Shweta; Fanti, Paolo] Audie L Murphy Vet Mem Hosp, STVHCS, San Antonio, TX USA. [Khazim, Khalid] Western Galilee Hosp, Div Nephrol, Nahariyya, Israel. [Lorenzo, Carlos] Univ Texas Hlth Sci Ctr San Antonio, Sch Med, Clin Epidemiol, San Antonio, TX 78229 USA. [Matteucci, Elena] Univ Pisa, Div Endocrinol, I-56100 Pisa, Italy. RP Fanti, P (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Div Nephrol, 7703 Floyd Curl Dr,MC 7882, San Antonio, TX 78229 USA. EM fanti@uthscsa.edu FU NIH-NCCAM [AT004490]; Veterans Administration [1I01CX000264]; CTSA program [NIH-NCATS 1UL TR001120] FX This work was supported by grants to PF from NIH-NCCAM (AT004490) and from the Veterans Administration (Merit Review 1I01CX000264) and by the CTSA program award to UTHSCSA (NIH-NCATS 1UL TR001120). NR 51 TC 0 Z9 0 U1 0 U2 8 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 OCT PY 2015 VL 30 IS 5 BP 698 EP 708 DI 10.1177/0884533615575046 PG 11 WC Nutrition & Dietetics SC Nutrition & Dietetics GA CQ7DQ UT WOS:000360763500011 PM 25899538 ER PT J AU Yonker, LM Pazos, MA Hurley, BP AF Yonker, L. M. Pazos, M. A. Hurley, B. P. TI NEUTROPHIL-DERIVED CYTOSOLIC PHOSPHOLIPASE A2 IS AN IMPORTANT MEDIATOR OF PSEUDOMONAS-MEDIATED NEUTROPHIL TRANSEPITHELIAL MIGRATION SO PEDIATRIC PULMONOLOGY LA English DT Meeting Abstract C1 [Yonker, L. M.; Pazos, M. A.; Hurley, B. P.] Massachusetts Gen Hosp, Mucosal Immunol & Biol Res Ctr, Boston, MA 02114 USA. [Yonker, L. M.; Pazos, M. A.; Hurley, B. P.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 8755-6863 EI 1099-0496 J9 PEDIATR PULM JI Pediatr. Pulmonol. PD OCT PY 2015 VL 50 SU 41 MA 132 BP 239 EP 240 PG 2 WC Pediatrics; Respiratory System SC Pediatrics; Respiratory System GA CQ7NS UT WOS:000360791500202 ER PT J AU Birket, S Tuggle, KL Chu, KK Harris, WT Tearney, G Fanucchi, MV Sorscher, EJ Rowe, SM AF Birket, S. Tuggle, K. L. Chu, K. K. Harris, W. T. Tearney, G. Fanucchi, M., V Sorscher, E. J. Rowe, S. M. TI THE CFTR-/- RAT IS SUSCEPTIBLE TO PSEUDOMONAS AERUGINOSA INFECTION SO PEDIATRIC PULMONOLOGY LA English DT Meeting Abstract C1 [Birket, S.; Tuggle, K. L.; Sorscher, E. J.; Rowe, S. M.] Univ Alabama Birmingham, Med, Birmingham, AL USA. [Chu, K. K.; Tearney, G.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Harris, W. T.; Fanucchi, M., V] Univ Alabama Birmingham, Birmingham, AL USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 8755-6863 EI 1099-0496 J9 PEDIATR PULM JI Pediatr. Pulmonol. PD OCT PY 2015 VL 50 SU 41 MA 139 BP 242 EP 242 PG 1 WC Pediatrics; Respiratory System SC Pediatrics; Respiratory System GA CQ7NS UT WOS:000360791500209 ER PT J AU Chu, KK Ford, TN Mojahed, D Fernandez, CM Birket, S Solomon, GM Rowe, SM Tearney, GJ AF Chu, K. K. Ford, T. N. Mojahed, D. Fernandez, C. M. Birket, S. Solomon, G. M. Rowe, S. M. Tearney, G. J. TI IN SITU RHEOLOGY AND PH MEASUREMENT OF AIRWAY MUCUS WITH DUAL MODALITY mu OCT/FLUORESCENCE IMAGING SO PEDIATRIC PULMONOLOGY LA English DT Meeting Abstract C1 [Chu, K. K.; Ford, T. N.; Tearney, G. J.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Mojahed, D.] Tufts Univ, Medford, MA 02155 USA. [Fernandez, C. M.; Birket, S.; Solomon, G. M.; Rowe, S. M.] Univ Alabama Birmingham, Birmingham, AL USA. NR 0 TC 0 Z9 0 U1 3 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 8755-6863 EI 1099-0496 J9 PEDIATR PULM JI Pediatr. Pulmonol. PD OCT PY 2015 VL 50 SU 41 MA 283 BP 298 EP 298 PG 1 WC Pediatrics; Respiratory System SC Pediatrics; Respiratory System GA CQ7NS UT WOS:000360791500353 ER PT J AU Pazos, MA Yonker, LM Moskowitz, SM Hurley, BP AF Pazos, M. A. Yonker, L. M. Moskowitz, S. M. Hurley, B. P. TI TRANSEPITHELIAL MIGRATION IS IMPAIRED IN PERIPHERAL BOOD NEUTROPHILS ISOLATED FROM CYSTIC FIBROSIS PATIENTS SO PEDIATRIC PULMONOLOGY LA English DT Meeting Abstract C1 [Pazos, M. A.; Yonker, L. M.; Hurley, B. P.] Massachusetts Gen Hosp, Mucosal Immunol & Biol Res Ctr, Charlestown, MA USA. [Pazos, M. A.; Yonker, L. M.; Moskowitz, S. M.; Hurley, B. P.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Moskowitz, S. M.] Massachusetts Gen Hosp, Pediat Cyst Fibrosis Ctr, Boston, MA 02114 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 8755-6863 EI 1099-0496 J9 PEDIATR PULM JI Pediatr. Pulmonol. PD OCT PY 2015 VL 50 SU 41 MA 374 BP 332 EP 332 PG 1 WC Pediatrics; Respiratory System SC Pediatrics; Respiratory System GA CQ7NS UT WOS:000360791500444 ER PT J AU Ballok, AE Rahme, LG AF Ballok, A. E. Rahme, L. G. TI PSEUDOMONAS AERUGINOSA VIRULENCE PHENOTYPES ARE IMPACTED BY 2,4-DIHYDROXYQUINOLINE (DHQ), AN ABUNDANT PRODUCT OF THE PQS OPERON SO PEDIATRIC PULMONOLOGY LA English DT Meeting Abstract C1 [Ballok, A. E.; Rahme, L. G.] Massachusetts Gen Hosp, Surg, Boston, MA 02114 USA. [Ballok, A. E.; Rahme, L. G.] Harvard Univ, Sch Med, Microbiol & Immunobiol, Boston, MA USA. [Ballok, A. E.; Rahme, L. G.] Shriners Hosp Children, 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 8755-6863 EI 1099-0496 J9 PEDIATR PULM JI Pediatr. Pulmonol. PD OCT PY 2015 VL 50 SU 41 MA 379 BP 334 EP 334 PG 1 WC Pediatrics; Respiratory System SC Pediatrics; Respiratory System GA CQ7NS UT WOS:000360791500449 ER PT J AU Mou, H Brazauskas, K Rajagopal, J AF Mou, Hongmei Brazauskas, Karissa Rajagopal, Jayaraj TI Personalized medicine for cystic fibrosis: Establishing human model systems SO PEDIATRIC PULMONOLOGY LA English DT Review DE cystic fibrosis (CF); airway and lung cell biology; stem cells; individualized medicine; induced pluripotent stem cells; organoids ID PLURIPOTENT STEM-CELLS; TRANSMEMBRANE CONDUCTANCE REGULATOR; AIRWAY EPITHELIAL-CELLS; C VIRUS-INFECTION; MOUSE MODEL; BICARBONATE SECRETION; EFFICIENT DERIVATION; PRIMARY CULTURES; ANIMAL-MODELS; IMMUNE-SYSTEM AB With over 1,500 identifiable mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that result in distinct functional and phenotypical abnormalities, it is virtually impossible to perform randomized clinical trials to identify the best therapeutics for all patients. Therefore, a personalized medicine approach is essential. The only way to realistically accomplish this is through the development of improved in vitro human model systems. The lack of a readily available and infinite supply of human CFTR-expressing airway epithelial cells is a key bottleneck. We propose that a concerted two-pronged approach is necessary for patient-specific cystic fibrosis research to continue to prosper and realize its potential: (1) more effective culture and differentiation conditions for growing primary human airway and nasal epithelial cells and (2) the development of collective protocols for efficiently differentiating disease- and patient-specific induced pluripotent stem cells (iPSC) into pure populations of adult epithelial cells. Ultimately, we need a personalized human model system for cystic fibrosis with the capacity for uncomplicated bankability, widespread availability, and universal applicability for patient-specific disease modeling, novel pharmacotherapy investigation and screening, and readily executable genetic modification. Pediatr Pulmonol. 2015; 50:S14-S23. (c) 2015 Wiley Periodicals, Inc. C1 [Mou, Hongmei; Rajagopal, Jayaraj] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Mou, Hongmei; Rajagopal, Jayaraj] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Mou, Hongmei; Brazauskas, Karissa] Massachusetts Gen Hosp Children, Pediat Pulm Med, Boston, MA USA. [Rajagopal, Jayaraj] Massachusetts Gen Hosp, Pulm Crit Care Unit, Internal Med & Pediat, Boston, MA 02114 USA. RP Rajagopal, J (reprint author), 185 Cambridge St CPZN 4500, Boston, MA 02114 USA. EM jrajagopal@mgh.harvard.edu NR 87 TC 2 Z9 2 U1 1 U2 24 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 8755-6863 EI 1099-0496 J9 PEDIATR PULM JI Pediatr. Pulmonol. PD OCT PY 2015 VL 50 SU 40 SI SI BP S14 EP S23 DI 10.1002/ppul.23233 PG 10 WC Pediatrics; Respiratory System SC Pediatrics; Respiratory System GA CQ7NQ UT WOS:000360791300004 PM 26335952 ER PT J AU Genewsky, A Jost, I Busch, C Huber, C Stindl, J Skerka, C Zipfel, PF Rohrer, B Strauss, O AF Genewsky, Andreas Jost, Ingmar Busch, Catharina Huber, Christian Stindl, Julia Skerka, Christine Zipfel, Peter F. Rohrer, Baerbel Strauss, Olaf TI Activation of endogenously expressed ion channels by active complement in the retinal pigment epithelium SO PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY LA English DT Article DE (4-6): complement system; Retinal pigment epithelium; RPE; L-type channels; BK channels ID MEMBRANE-ATTACK-COMPLEX; HUMAN POLYMORPHONUCLEAR LEUKOCYTES; INTRACELLULAR FREE CALCIUM; MACULAR DEGENERATION; VEGF SECRETION; CA2+ CHANNELS; FACTOR-H; CELLS; FIBROBLASTS; INCREASE AB Defective regulation of the alternative pathway of the complement system is believed to contribute to damage of retinal pigment epithelial (RPE) cells in age-related macular degeneration. Thus we investigated the effect of complement activation on the RPE cell membrane by analyzing changes in membrane conductance via patch-clamp techniques and Ca2+ imaging. Exposure of human ARPE-19 cells to complement-sufficient normal human serum (NHS) (25 %) resulted in a biphasic increase in intracellular free Ca2+ ([Ca2+](i)); an initial peak followed by sustained Ca2+ increase. C5- or C7-depleted sera did not fully reproduce the signal generated by NHS. The initial peak of the Ca2+ response was reduced by sarcoplasmic Ca2+-ATPase inhibitor thapsigargin, L-type channel blockers (R)-(+)-BayK8644 and isradipine, transient-receptor-potential (TRP) channel blocker ruthenium-red and ryanodine receptor blocker dantrolene. The sustained phase was carried by Ca(V)1.3 L-type channels via tyrosine-phosphorylation. Changes in [Ca2+](I) were accompanied by an abrupt hyperpolarization, resulting from a transient increase in membrane conductance, which was absent under extracellular Ca2+- or K+-free conditions and blocked by (R)-(+)-BayK8644 or paxilline, a maxiK channel inhibitor. Single-channel recordings confirmed the contribution of maxiK channels. Primary porcine RPE cells responded to NHS in a comparable manner. Pre-incubation with NHS reduced H2O2-induced cell death. In summary, in a concerted manner, C3a, C5a and sC5b-9 increased [Ca2+](i) by ryanodine-receptor-dependent activation of L-type channels in addition to maxi-K channels and TRP channels absent from any insertion of a lytic pore. C1 [Genewsky, Andreas] Max Planck Inst Psychiat, D-80804 Munich, Germany. [Genewsky, Andreas; Jost, Ingmar; Stindl, Julia; Strauss, Olaf] Univ Med Ctr Regensburg, Eye Clin, Expt Ophthalmol, Regensburg, Germany. [Skerka, Christine; Zipfel, Peter F.] Leibniz Inst Nat Prod Res & Infect Biol, Dept Infect Biol, Jena, Germany. [Zipfel, Peter F.] Univ Jena, Jena, Germany. [Rohrer, Baerbel] Med Univ S Carolina, Dept Ophthalmol, Charleston, SC 29425 USA. [Rohrer, Baerbel] Ralph H Johnson VA Med Ctr, Res Serv, Charleston, SC 29401 USA. [Busch, Catharina; Huber, Christian; Strauss, Olaf] Charite, Dept Ophthalmol, Expt Ophthalmol, Campus Virchow Klinikum, D-13353 Berlin, Germany. RP Strauss, O (reprint author), Charite, Dept Ophthalmol, Expt Ophthalmol, Campus Virchow Klinikum, Augustenburger Pl 1, D-13353 Berlin, Germany. EM olaf.strauss@charite.de FU National Institutes of Health (NIH) [R01EY019320]; Department for Veterans Affairs [RX000444]; Research to Prevent Blindness (RPB), New York, NY; Deutsche Forschungsgemeinschaft (DFG) [SK46/2-1, SK46/2-2] FX The authors thank Andrea Dannullis, Elfriede Eckert and Renate Fockler for expert technical assistance. Financial support: OS: Novartis Professorship; BR: in part by the National Institutes of Health (NIH) (R01EY019320), a Department for Veterans Affairs merit award RX000444 and an unrestricted grant to MUSC from Research to Prevent Blindness (RPB), New York, NY; CS: Deutsche Forschungsgemeinschaft (DFG) SK46/2-1, SK46/2-2. NR 44 TC 3 Z9 3 U1 1 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0031-6768 EI 1432-2013 J9 PFLUG ARCH EUR J PHY JI Pflugers Arch. PD OCT PY 2015 VL 467 IS 10 BP 2179 EP 2191 DI 10.1007/s00424-014-1656-2 PG 13 WC Physiology SC Physiology GA CR0IB UT WOS:000361000800011 PM 25427445 ER PT J AU True, G Rigg, KK Butler, A AF True, Gala Rigg, Khary K. Butler, Anneliese TI Understanding Barriers to Mental Health Care for Recent War Veterans Through Photovoice SO QUALITATIVE HEALTH RESEARCH LA English DT Article DE health care; access to; health care; users' experiences; lived experience; mental health and illness; participatory action research; photography; photovoice; post-traumatic stress disorder; stigma; visual methods; vulnerable populations ID RETURNING COMBAT VETERANS; TREATMENT-SEEKING; AFGHANISTAN VETERANS; IRAQ; SERVICES; INTERVENTIONS; DEPLOYMENT; SOLDIERS; PTSD; PERCEPTIONS AB Despite an urgent need for mental health care among U.S. service members returning from deployments to Iraq and Afghanistan, many veterans do not receive timely or adequate treatment. We used photovoice methods to engage veterans in identifying barriers to utilizing mental health services. Veterans described how key aspects of military culture and identity, highly adaptive during deployment, can deter help-seeking behavior and hinder recovery. Veterans' photographs highlighted how mental health symptoms and self-coping strategies operated as barriers to care. Many veterans' photos and stories revealed how negative health care encounters contributed to avoidance and abandonment of treatment; some veterans described these experiences as re-traumatizing. Visual methods can be a powerful tool for engaging recent war veterans in research. In particular, community-based participatory research approaches, which have rarely been used with veterans, hold great promise for informing effective interventions to improve access and enhance provision of patient-centered care for veterans. C1 [True, Gala] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. [Butler, Anneliese] Philadelphia Vet Affairs Med Ctr, VISN Ctr Evaluat Patient Aligned Care Teams 4, Philadelphia, PA 19104 USA. [Rigg, Khary K.] Univ S Florida, Dept Mental Hlth Law & Policy, Louis de la Parte Florida Mental Hlth Inst, Tampa, FL USA. RP True, G (reprint author), Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equity Res & Promot, 3900 Woodland Ave,Bldg 4100, Philadelphia, PA 19104 USA. EM Jennifer.True2@va.gov FU VA Health Services Research Development [PPO 10-255]; VISN 4 Center for Evaluation of Patient Aligned Care Teams (CEPACT); Center for Health Equity Research and Promotion (CHERP) FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was funded by a VA Health Services Research & Development grant to Gala True (PPO 10-255), with additional support from the VISN 4 Center for Evaluation of Patient Aligned Care Teams (CEPACT) and the Center for Health Equity Research and Promotion (CHERP). NR 45 TC 4 Z9 4 U1 3 U2 13 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 OCT PY 2015 VL 25 IS 10 SI SI BP 1443 EP 1455 DI 10.1177/1049732314562894 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 CR2AP UT WOS:000361127100012 PM 25488935 ER PT J AU Moschovis, PP Addo-Yobo, EOD Banajeh, S Chisaka, N Christiani, DC Hayden, D Jeena, P MacLeod, WB Mino, G Patel, A Qazi, S Santosham, M Thea, DM Hibberd, PL AF Moschovis, Peter P. Addo-Yobo, Emmanuel O. D. Banajeh, Salem Chisaka, Noel Christiani, David C. Hayden, Douglas Jeena, Prakash MacLeod, William B. Mino, Greta Patel, Archana Qazi, Shamim Santosham, Mathuram Thea, Donald M. Hibberd, Patricia L. TI Stunting is associated with poor outcomes in childhood pneumonia SO TROPICAL MEDICINE & INTERNATIONAL HEALTH LA English DT Article DE pneumonia; malnutrition; treatment failure; global health ID LUNG-FUNCTION; ECUADORIAN CHILDREN; NUTRITIONAL-STATUS; RISK-FACTORS; MORTALITY; INFECTION; MALNUTRITION; PREDICTORS; COUNTRIES; DISEASE AB Objective Stunting affects 26.7% of children worldwide, and little is known about its effects on the outcomes of childhood pneumonia. We evaluated the effect of stunting on the outcomes of pneumonia among children enrolled in two large clinical trials. Methods We analysed data from two WHO and USAID-sponsored inpatient treatment trials, the Severe Pneumonia Evaluation Antimicrobial Research study (n=958) and the Amoxicillin Penicillin Pneumonia International Study (n=1702), which enrolled children aged 2-59months across 16 sites in LMICs. We assessed the effect of stunting (height-for-age Z score<-2) on treatment outcome and time to resolution of hypoxaemic pneumonia. Results Among 2542 (96%) children with valid data for height, 28% were stunted and 12.8% failed treatment by 5days. The failure rate among stunted patients was 16.0% vs. 11.5% among non-stunted patients [unadjusted RR=1.24 (95% CI 1.08, 1.41); adjusted RR=1.28 (95% CI 1.10, 1.48)]. An inverse relationship was observed between height and failure rates, even among non-stunted children. Among 845 patients with hypoxaemic pneumonia, stunting was associated with a lower probability of normalisation of respiratory rate [HR=0.63 (95% CI 0.52, 0.75)] and oxygen saturation [HR=0.74 (95% CI 0.61, 0.89)]. Conclusions Stunting increases the risk of treatment failure and is associated with a longer course of recovery in children with pneumonia. Strategies to decrease stunting may decrease the burden of adverse outcomes in childhood pneumonia in low-resource settings. C1 [Moschovis, Peter P.; Christiani, David C.; Hayden, Douglas; Hibberd, Patricia L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Addo-Yobo, Emmanuel O. D.] Kwame Nkrumah Univ Sci & Technol, Komfo Anokye Teaching Hosp, Kumasi, Ghana. [Banajeh, Salem] Sanaa Univ, Al Sabeen Hosp Women & Children, Sanaa, Yemen. [Chisaka, Noel] World Bank, Washington, DC 20433 USA. [Jeena, Prakash] Univ KwaZulu Natal, Durban, South Africa. [MacLeod, William B.; Thea, Donald M.] Boston Univ, Boston, MA 02215 USA. [Mino, Greta] Childrens Hosp Dr Francisco de Ycaza Bustamante, Guayaquil, Ecuador. [Patel, Archana] Lata Med Res Fdn, Indira Gandhi Govt Med Coll, Nagpur, Maharashtra, India. [Qazi, Shamim] World Hlth Org, Geneva, Switzerland. [Santosham, Mathuram] Johns Hopkins Univ, Baltimore, MD USA. RP Moschovis, PP (reprint author), Harvard Univ, Massachusetts Gen Hosp, Div Pulm, Sch Med, 125 Nashua St,Suite 840, Boston, MA 02114 USA. EM pmoschovis@mgh.harvard.edu FU Department of Child and Adolescent Health and Development, WHO; Center for International Health and Development, Boston University; Johns Hopkins Bloomberg School of Public Health, Baltimore; National Heart, Lung, and Blood Institute of the National Institutes of Health [F32HL124951]; Harvard Clinical and Translational Science Center (National Institutes of Health) [UL1 TR001102]; Harvard University; Harvard Catalyst FX The SPEAR and APPIS studies were funded by the Department of Child and Adolescent Health and Development, WHO; Center for International Health and Development, Boston University; and Johns Hopkins Bloomberg School of Public Health, Baltimore. This analysis was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under award number F32HL124951. Statistical support was provided by 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 healthcare centers. The content is solely the responsibility of the authors and does not necessarily represent the official views of the World Health Organization or National Institutes of Health. The results of this study were presented in part at the American Thoracic Society International Conference, San Diego, USA, 16-21 May 2014. NR 32 TC 1 Z9 1 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1360-2276 EI 1365-3156 J9 TROP MED INT HEALTH JI Trop. Med. Int. Health PD OCT PY 2015 VL 20 IS 10 BP 1320 EP 1328 DI 10.1111/tmi.12557 PG 9 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA CQ7DR UT WOS:000360763600009 PM 26083963 ER PT J AU Wood, PL Barnette, BL Kaye, JA Quinn, JF Woltjer, RL AF Wood, Paul L. Barnette, Brooke L. Kaye, Jeffrey A. Quinn, Joseph F. Woltjer, Randall L. TI Non-targeted lipidomics of CSF and frontal cortex grey and white matter in control, mild cognitive impairment, and Alzheimer's disease subjects SO ACTA NEUROPSYCHIATRICA LA English DT Article DE Alzheimer's disease; lipidomics; diacylglycerols; mild cognitive impairment; frontal cortex ID PLASMALOGEN DEFICIENCY; MASS-SPECTROMETRY; HUMAN BRAIN; PATHOGENESIS; INDIVIDUALS; DEMENTIA; CERAMIDE; ENZYMES; MOUSE; AGE AB Objective: We undertook a non-targeted lipidomics analysis of postmortem cerebrospinal fluid (CSF), frontal cortex grey matter, and subjacent white matter to define potential biomarkers that distinguish cognitively intact subjects from those with incipient or established dementia. Our objective was to increase our understanding of the role of brain lipids in pathophysiology of aging and age-related cognitive impairment. Methods: Levels of 650 individual lipids, across 26 lipid subclasses, were measured utilising a high-resolution mass spectrometric analysis platform. Results: Monoacylglycerols (MAG), diacylglycerols (DAG), and the very-long-chain fatty acid 26: 0 were elevated in the grey matter of the mild cognitive impairment (MCI) and old dementia (OD) cohorts. Ethanolamine plasmalogens (PlsEtn) were decreased in the grey matter of the young dementia (YD) and OD cohorts while and phosphatidylethanolamines (PtdEth) were lower in the MCI, YD and OD cohorts. In the white matter, decrements in sulphatide levels were detected in the YD group, DAG levels were elevated in the MCI group, and MAG levels were increased in the YD and OD groups. Conclusion: The parallel changes in grey matter MAGs and DAGs in the MCI and OD groups suggest that these two cohorts may have a similar underlying pathophysiology; consistent with this, MCI subjects were more similar in age to OD than to YD subjects. While PlsEtn and phosphatidylethanolamine were decreased in the YD and OD groups they were unaltered in the MCI group indicating that alterations in plasmalogen synthesis are unlikely to represent an initiating event in the transition from MCI to dementia. C1 [Wood, Paul L.; Barnette, Brooke L.] Lincoln Mem Univ, DeBusk Coll Osteopath Med, Dept Physiol & Pharmacol, Metabol Unit, Harrogate, TN 37752 USA. [Kaye, Jeffrey A.; Quinn, Joseph F.; Woltjer, Randall L.] Oregon Hlth & Sci Univ, Portland VA Med Ctr, Dept Neurol, Portland, OR USA. RP Wood, PL (reprint author), Lincoln Mem Univ, DeBusk Coll Osteopath Med, Dept Physiol & Pharmacol, Metabol Unit, 6965 Cumberland Gap Pkwy, Harrogate, TN 37752 USA. EM paul.wood@lmunet.edu FU Lincoln Memorial University, DeBusk College of Osteopathic medicine; [NIA-AG08017] FX This research was funded by Lincoln Memorial University, DeBusk College of Osteopathic medicine, and by NIA-AG08017. NR 36 TC 9 Z9 9 U1 2 U2 17 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1601-5215 J9 ACTA NEUROPSYCHIATR JI Acta Neuropsychiatr. PD OCT PY 2015 VL 27 IS 5 BP 270 EP 278 DI 10.1017/neu.2015.18 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA CQ6CM UT WOS:000360692000002 PM 25858158 ER PT J AU Safren, SA Perry, NS Blashill, AJ O'Cleirigh, C Mayer, KH AF Safren, Steven A. Perry, Nicholas S. Blashill, Aaron J. O'Cleirigh, Conall Mayer, Kenneth H. TI The Cost and Intensity of Behavioral Interventions to Promote HIV Treatment for Prevention Among HIV-Positive Men Who Have Sex with Men SO ARCHIVES OF SEXUAL BEHAVIOR LA English DT Article DE HIV; Intervention; Prevention; Cost; Syndemic; Sexual orientation ID RANDOMIZED CONTROLLED-TRIAL; ANTIRETROVIRAL THERAPY ADHERENCE; PSYCHOSOCIAL HEALTH-PROBLEMS; INJECTION-DRUG USERS; DEPRESSION CBT-AD; UNITED-STATES; ANAL INTERCOURSE; INFECTED ADULTS; RISK BEHAVIORS; BISEXUAL MEN AB Recently, behavioral prevention interventions for HIV have been criticized as being ineffective, costly, or inefficient. In this commentary, using HIV-positive men who have sex with men (MSM) as an illustrative high-risk population, we argue that the opposite is true-that behavioral interventions for HIV prevention, if implemented with the populations who need them, are affordable and critical for future prevention efforts. We base this argument on recent evidence showing that (1) adherence to antiretroviral treatment (ART) for prevention purposes is necessary to suppress HIV replication and reduce transmissibility, (2) individuals living with HIV have multiple psychosocial concerns that impact self-care and moderate the potential effectiveness of health behavior interventions, and (3) intensive interventions targeting both concerns together (psychosocial and HIV care) can show clinically significant improvement. We follow by comparing the cost of these types of interventions to the cost of standard clinical treatment for HIV with ART and demonstrate a cost-savings of potential intensive behavioral interventions for, in this case, HIV-positive MSM who have uncontrolled virus. Keeping this evidence in mind, we conclude that individual intervention must remain a mainstay of HIV prevention for certain critical populations. C1 [Safren, Steven A.; Perry, Nicholas S.; Blashill, Aaron J.; O'Cleirigh, Conall] Massachusetts Gen Hosp, Dept Psychiat, Behav Med Serv, Boston, MA 02114 USA. [Safren, Steven A.; Perry, Nicholas S.; Blashill, Aaron J.; O'Cleirigh, Conall; Mayer, Kenneth H.] Harvard Univ, Sch Med, Boston, MA USA. [Safren, Steven A.; Blashill, Aaron J.; O'Cleirigh, Conall; Mayer, Kenneth H.] Fenway Hlth, Boston, MA USA. [Safren, Steven A.] Univ Miami, Dept Psychol, Coral Gables, FL 33124 USA. [Perry, Nicholas S.] Univ Utah, Dept Psychol, Salt Lake City, UT 84112 USA. [Blashill, Aaron J.] San Diego State Univ, Dept Psychol, San Diego, CA 92182 USA. [Mayer, Kenneth H.] Beth Israel Deaconess Med Ctr, Dept Gen Med, Boston, MA 02215 USA. RP Safren, SA (reprint author), Univ Miami, Dept Psychol, 5665 Ponce Leon Blvd,POB 248185, Coral Gables, FL 33124 USA. EM ssafren@psy.miami.edu FU National Institutes of Health [K24MH094214, P30AI060354, K23MH096647] FX Support for author time on the article came from National Institutes of Health Grants K24MH094214 and P30AI060354 awarded to the first author and K23MH096647 to the third author. NR 53 TC 1 Z9 1 U1 4 U2 10 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0004-0002 EI 1573-2800 J9 ARCH SEX BEHAV JI Arch. Sex. Behav. PD OCT PY 2015 VL 44 IS 7 BP 1833 EP 1841 DI 10.1007/s10508-014-0455-3 PG 9 WC Psychology, Clinical; Social Sciences, Interdisciplinary SC Psychology; Social Sciences - Other Topics GA CQ5TF UT WOS:000360667900017 PM 26223385 ER PT J AU Mimiaga, MJ Biello, KB Robertson, AM Oldenburg, CE Rosenberger, JG O'Cleirigh, C Novak, DS Mayer, KH Safren, SA AF Mimiaga, Matthew J. Biello, Katie B. Robertson, Angela M. Oldenburg, Catherine E. Rosenberger, Joshua G. O'Cleirigh, Conall Novak, David S. Mayer, Kenneth H. Safren, Steven A. TI High Prevalence of Multiple Syndemic Conditions Associated with Sexual Risk Behavior and HIV Infection Among a Large Sample of Spanish- and Portuguese-Speaking Men Who Have Sex with Men in Latin America SO ARCHIVES OF SEXUAL BEHAVIOR LA English DT Article DE HIV; Men who have sex with men; Sexual behavior; Syndemics; Latin America; Internet; Sexual orientation ID PSYCHOSOCIAL HEALTH-PROBLEMS; MULTICENTER AIDS COHORT; BASE-LINE DATA; UNITED-STATES; SUBSTANCE USE; BISEXUAL MEN; ACTIVE MEN; DRUG-USE; GAY; ONLINE AB The HIV epidemic in Latin America is highly concentrated in men who have sex with men (MSM). In the United States, multiple co-occurring psychosocial conditions have been shown to act as intertwined epidemics to potentiate HIV transmission among MSM. To date, no study has examined the role of syndemics and condomless sex among MSM in Latin America. In 2012, an online survey was conducted among members of the largest social/sexual networking website for MSM in Latin America. Participants were asked about demographics, sexual behaviors, HIV/STI diagnoses, and psychosocial well-being, including depression, suicidal ideation, hazardous alcohol use, hard drug use during sex, history of childhood/adolescent sexual abuse, intimate partner violence, and sexual compulsivity. Multivariable logistic generalized estimation equations were used to assess the relationship of syndemic factors and (1) engagement in higher risk condomless anal sex and (2) self-report of prior HIV diagnosis. Among 24,274 survey respondents, 74.6 % of the sample had at least one syndemic factor. In an additive model, syndemics were associated with increased odds of higher risk condomless anal sex, ranging from adjusted odds ratio of 1.31 (95 % CI 1.20, 1.43) for one syndemic factor to 4.06 (95 % CI 3.25, 5.09) for 6/7 syndemic factors. Similarly, syndemics were associated with increased odds of HIV infection (p < .0001). This study provides initial evidence that intertwined syndemics increase HIV risk behavior and HIV infection among MSM in Latin America. In the Latin American context, comprehensive HIV prevention interventions for MSM should be developed and tested that simultaneously address co-occurring psychosocial conditions and HIV risk. C1 [Mimiaga, Matthew J.; O'Cleirigh, Conall; Safren, Steven A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Behav Med,Dept Psychiat, Boston, MA 02114 USA. [Mimiaga, Matthew J.; Biello, Katie B.; Robertson, Angela M.; Oldenburg, Catherine E.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Mimiaga, Matthew J.; Biello, Katie B.; Robertson, Angela M.; Oldenburg, Catherine E.; O'Cleirigh, Conall; Mayer, Kenneth H.; Safren, Steven A.] Fenway Hlth, Fenway Inst, Boston, MA USA. [Rosenberger, Joshua G.] George Mason Univ, Dept Global & Community Hlth, Fairfax, VA 22030 USA. [Novak, David S.] Online Buddies Inc, OLB Res Inst, Cambridge, MA USA. [Mayer, Kenneth H.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Infect Dis, Boston, MA 02215 USA. RP Mimiaga, MJ (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Behav Med,Dept Psychiat, 1 Bowdoin Sq,7th Floor, Boston, MA 02114 USA. EM mmimiaga@hsph.harvard.edu OI Bazzi, Angela/0000-0001-6828-1919 NR 68 TC 8 Z9 9 U1 6 U2 21 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0004-0002 EI 1573-2800 J9 ARCH SEX BEHAV JI Arch. Sex. Behav. PD OCT PY 2015 VL 44 IS 7 BP 1869 EP 1878 DI 10.1007/s10508-015-0488-2 PG 10 WC Psychology, Clinical; Social Sciences, Interdisciplinary SC Psychology; Social Sciences - Other Topics GA CQ5TF UT WOS:000360667900020 PM 26159862 ER PT J AU Boroughs, MS Valentine, SE Ironson, GH Shipherd, JC Safren, SA Taylor, SW Dale, SK Baker, JS Wilner, JG O'Cleirigh, C AF Boroughs, Michael S. Valentine, Sarah E. Ironson, Gail H. Shipherd, Jillian C. Safren, Steven A. Taylor, S. Wade Dale, Sannisha K. Baker, Joshua S. Wilner, Julianne G. O'Cleirigh, Conall TI Complexity of Childhood Sexual Abuse: Predictors of Current Post-Traumatic Stress Disorder, Mood Disorders, Substance Use, and Sexual Risk Behavior Among Adult Men Who Have Sex with Men SO ARCHIVES OF SEXUAL BEHAVIOR LA English DT Article DE Men who have sex with men (MSM); Childhood sexual abuse (CSA); PTSD; HIV; Sexual orientation ID PSYCHOSOCIAL HEALTH-PROBLEMS; HIV-RISK; BISEXUAL MEN; PHYSICAL ABUSE; GAY MEN; BAUSERMAN 1998; URBAN MEN; LIFE-SPAN; YOUNG MEN; WOMEN AB Men who have sex with men (MSM) are the group most at risk for HIV and represent the majority of new infections in the United States. Rates of childhood sexual abuse (CSA) among MSM have been estimated as high as 46 %. CSA is associated with increased risk of HIV and greater likelihood of HIV sexual risk behavior. The purpose of this study was to identify the relationships between CSA complexity indicators and mental health, substance use, sexually transmitted infections, and HIV sexual risk among MSM. MSM with CSA histories (n = 162) who were screened for an HIV prevention efficacy trial completed comprehensive psychosocial assessments. Five indicators of complex CSA experiences were created: CSA by family member, CSA with penetration, CSA with physical injury, CSA with intense fear, and first CSA in adolescence. Adjusted regression models were used to identify relationships between CSA complexity and outcomes. Participants reporting CSA by family member were at 2.6 odds of current alcohol use disorder (OR 2.64: CI 1.24-5.63), two times higher odds of substance use disorder (OR 2.1: CI 1.02-2.36), and 2.7 times higher odds of reporting an STI in the past year (OR 2.7: CI 1.04-7.1). CSA with penetration was associated with increased likelihood of current PTSD (OR 3.17: CI 1.56-6.43), recent HIV sexual risk behavior (OR 2.7: CI 1.16-6.36), and a greater number of casual sexual partners (p = 0.02). Both CSA with Physical Injury (OR 4.05: CI 1.9-8.7) and CSA with Intense Fear (OR 5.16: CI 2.5-10.7) were related to increased odds for current PTSD. First CSA in adolescence was related to increased odds of major depressive disorder. These findings suggest that CSA, with one or more complexities, creates patterns of vulnerabilities for MSM, including post-traumatic stress disorder, substance use, and sexual risk taking, and suggests the need for detailed assessment of CSA and the development of integrated HIV prevention programs that address mental health and substance use comorbidities. C1 [Boroughs, Michael S.; Valentine, Sarah E.; Safren, Steven A.; Dale, Sannisha K.; Wilner, Julianne G.; O'Cleirigh, Conall] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Boroughs, Michael S.; Valentine, Sarah E.; Safren, Steven A.; Dale, Sannisha K.; O'Cleirigh, Conall] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Ironson, Gail H.] Univ Miami, Dept Psychol, Coral Gables, FL 33124 USA. [Shipherd, Jillian C.] VA Boston Healthcare Syst, Natl Ctr PTSD Womens Hlth Sci, Boston, MA USA. [Shipherd, Jillian C.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Safren, Steven A.; Taylor, S. Wade; Baker, Joshua S.; O'Cleirigh, Conall] Fenway Inst, Fenway Hlth, Boston, MA USA. [Taylor, S. Wade] Wheelock Coll, Dept Social Work, Boston, MA USA. RP O'Cleirigh, C (reprint author), Massachusetts Gen Hosp, Dept Psychiat, One Bowdoin Sq,7th Floor, Boston, MA 02114 USA. EM cocleirigh@mgh.harvard.edu FU NIMH [R01 MH095624]; [5K24MH094214] FX This study was supported by a Grant from the NIMH (R01 MH095624) PI: O'Cleirigh; Author time (Safren) was supported, in part, by Grant 5K24MH094214. NR 81 TC 4 Z9 4 U1 8 U2 28 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0004-0002 EI 1573-2800 J9 ARCH SEX BEHAV JI Arch. Sex. Behav. PD OCT PY 2015 VL 44 IS 7 BP 1891 EP 1902 DI 10.1007/s10508-015-0546-9 PG 12 WC Psychology, Clinical; Social Sciences, Interdisciplinary SC Psychology; Social Sciences - Other Topics GA CQ5TF UT WOS:000360667900022 PM 26159863 ER PT J AU Mimiaga, MJ Closson, EF Thomas, B Mayer, KH Betancourt, T Menon, S Safren, SA AF Mimiaga, Matthew J. Closson, Elizabeth F. Thomas, Beena Mayer, Kenneth H. Betancourt, Theresa Menon, Sunil Safren, Steven A. TI Garnering an In-depth Understanding of Men Who Have Sex with Men in Chennai, India: A Qualitative Analysis of Sexual Minority Status and Psychological Distress SO ARCHIVES OF SEXUAL BEHAVIOR LA English DT Article DE HIV; Men who have sex with men; Gay men; Bisexual men; Sexual orientation; Stigma ID RISK-TAKING; HIV RISK; GENDER NONCONFORMITY; BISEXUAL YOUTHS; HEALTH; ABUSE; GAY; PREVENTION; VICTIMIZATION; ORIENTATION AB Men who have sex with men (MSM) in India are a hidden and largely understudied population, and have an HIV prevalence 17 times higher than that of the general Indian population. Experiences of social marginalization and negative psychosocial conditions occur concurrent to HIV risk among Indian MSM. To better understand the contextual variables driving HIV risk and inform intervention development, five focus groups (n = 46) and nine key informant interviews were conducted with 55 MSM in Chennai in 2010. NVivo software was used to code the transcripts, and data were analyzed using qualitative descriptive analysis methodology. Participants described sources of psychological distress and low self-worth related to gender non-conformity and sexual minority status. These included stigma from society, pressure to marry, lack of familial acceptance, childhood sexual abuse, and the imperative to keep sexual minority status a secret. Participants' personal evaluations revealed that self-acceptance may be an important resilience factor that can shield these psychosocial and HIV risk factors. In promoting health-seeking behavioral changes for Indian MSM at an individual level, our findings point to the potential strength of strategies that focus on self-acceptance of one's sexual minority identity to foster better psychosocial and overall health. C1 [Mimiaga, Matthew J.; Safren, Steven A.] Harvard Univ, Dept Psychiat, Med Sch, Massachusetts Gen Hosp,Behav Med, Boston, MA 02114 USA. [Mimiaga, Matthew J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Mimiaga, Matthew J.; Closson, Elizabeth F.; Mayer, Kenneth H.; Safren, Steven A.] Fenway Hlth, Fenway Inst, Boston, MA USA. [Thomas, Beena] Natl Inst Res TB, Chennai, Tamil Nadu, India. [Mayer, Kenneth H.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Infect Dis, Boston, MA USA. [Mayer, Kenneth H.; Betancourt, Theresa] Harvard Univ, Sch Publ Hlth, Dept Global Hlth & Populat, Boston, MA 02115 USA. [Menon, Sunil] Sahodaran, Chennai, Tamil Nadu, India. RP Mimiaga, MJ (reprint author), Harvard Univ, Dept Psychiat, Med Sch, Massachusetts Gen Hosp,Behav Med, 1 Bowdoin Sq,7th Floor, Boston, MA 02114 USA. EM mmimiaga@partners.org FU Indo-U.S. Joint Working Group on Prevention of Sexually Transmitted Diseases and HIV/AIDS through U.S. National Institute of Mental Health [R21 MH085314-01]; Indian Council of Medical Research [Indo-U.S./41/2007-ECD-II] FX This project was supported by the Indo-U.S. Joint Working Group on Prevention of Sexually Transmitted Diseases and HIV/AIDS through U.S. National Institute of Mental Health grant #R21 MH085314-01 (Steven A. Safren, PI) and Indian Council of Medical Research grant #Indo-U.S./41/2007-ECD-II (Beena Thomas, PI). NR 50 TC 3 Z9 3 U1 8 U2 19 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0004-0002 EI 1573-2800 J9 ARCH SEX BEHAV JI Arch. Sex. Behav. PD OCT PY 2015 VL 44 IS 7 BP 2077 EP 2086 DI 10.1007/s10508-014-0369-0 PG 10 WC Psychology, Clinical; Social Sciences, Interdisciplinary SC Psychology; Social Sciences - Other Topics GA CQ5TF UT WOS:000360667900037 PM 25358949 ER PT J AU Bellmunt, J Orsola, A Sonpavde, G AF Bellmunt, Joaquim Orsola, Anna Sonpavde, Guru TI Precision and Predictive Medicine in Urothelial Cancer: Are We Making Progress? SO EUROPEAN UROLOGY LA English DT Editorial Material ID BLADDER-CANCER; PHASE-I; CARCINOMA; SENSITIVITY; EVEROLIMUS; MUTATIONS C1 [Bellmunt, Joaquim; Orsola, Anna] Dana Farber Canc Inst, Boston, MA 02115 USA. [Bellmunt, Joaquim; Orsola, Anna] Harvard Univ, Sch Med, Boston, MA USA. [Sonpavde, Guru] Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL 35294 USA. 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 13 TC 2 Z9 3 U1 0 U2 4 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 OCT PY 2015 VL 68 IS 4 BP 547 EP 549 DI 10.1016/j.eururo.2015.04.025 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA CQ4KM UT WOS:000360573600008 PM 25935702 ER PT J AU Saad, F Shore, N Van Poppel, H Rathkopf, DE Smith, MR de Bono, JS Logothetis, CJ de Souza, P Fizazi, K Mulders, PFA Mainwaring, P Hainsworth, JD Beer, TM North, S Fradet, Y Griffin, TA De Porre, P Londhe, A Kheoh, T Small, EJ Scher, HI Molina, A Ryan, CJ AF Saad, Fred Shore, Neal Van Poppel, Hendrik Rathkopf, Dana E. Smith, Matthew R. de Bono, Johann S. Logothetis, Christopher J. de Souza, Paul Fizazi, Karim Mulders, Peter F. A. Mainwaring, Paul Hainsworth, John D. Beer, Tomasz M. North, Scott Fradet, Yves Griffin, Thomas A. De Porre, Peter Londhe, Anil Kheoh, Thian Small, Eric J. Scher, Howard I. Molina, Arturo Ryan, Charles J. TI Impact of Bone-targeted Therapies in Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer Patients Treated with Abiraterone Acetate: Post Hoc Analysis of Study COU-AA-302 SO EUROPEAN UROLOGY LA English DT Article DE Abiraterone acetate; Bone-targeted therapy; Chemotherapy-naive; Metastatic castration-resistant prostate cancer ID ANDROGEN-DEPRIVATION THERAPY; PLACEBO-CONTROLLED TRIAL; QUALITY-OF-LIFE; ZOLEDRONIC ACID; SKELETAL COMPLICATIONS; SURVIVAL; MEN; RECOMMENDATIONS; PREDNISONE; CARCINOMA AB Background: Metastatic castration-resistant prostate cancer (mCRPC) often involves bone, and bone-targeted therapy (BTT) has become part of the overall treatment strategy. Objective: Investigation of outcomes for concomitant BTT in a post hoc analysis of the COU-AA-302 trial, which demonstrated an overall clinical benefit of abiraterone acetate (AA) plus prednisone over placebo plus prednisone in asymptomatic or mildly symptomatic chemotherapy-naive mCRPC patients. Design, setting, and participants: This report describes the third interim analysis (prespecified at 55% overall survival [OS] events) for the COU-AA-302 trial. Intervention: Patients were grouped by concomitant BTT use or no BTT use. Outcome measurements and statistical analysis: Radiographic progression-free survival and OS were coprimary end points. This report describes the third interim analysis (prespecified at 55% OS events) and involves patients treated with or without concomitant BTT during the COU-AA-302 study. Median follow-up for OS was 27.1 mo. Median time-to-event variables with 95% confidence intervals (CIs) were estimated using the Kaplan-Meier method. Adjusted hazard ratios (HRs), 95% CIs, and p values for concomitant BTT versus no BTT were obtained via Cox models. Results and limitations: While the post hoc nature of the analysis is a limitation, superiority of AA and prednisone versus prednisone alone was demonstrated for clinical outcomes with or without BTT use. Compared with no BTT use, concomitant BTT significantly improved OS (HR 0.75; p = 0.01) and increased the time to ECOG deterioration (HR 0.75; p < 0.001) and time to opiate use for cancer-related pain (HR 0.80; p = 0.036). The safety profile of concomitant BTT with AA was similar to that reported for AA in the overall intent-to-treat population. Osteonecrosis of the jaw (all grade 1/2) with concomitant BTT use was reported in <3% of patients. Conclusions: AA with concomitant BTT was safe and well tolerated in men with chemotherapy-naive mCRPC. The benefits of AA on clinical outcomes were increased with concomitant BTT. Patient summary: Treatment of advanced prostate cancer often includes bone-targeted therapy. This post hoc analysis showed that in patients with advanced prostate cancer who were treated with abiraterone acetate and prednisone in combination with bone-targeted therapy, there was a continued trend in prolongation of life when compared with patients treated with prednisone alone. (C) 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved. C1 [Saad, Fred] Univ Montreal, Montreal, PQ H2L 4M1, Canada. [Shore, Neal] Atlantic Urol Clin, Carolina Urol Res Ctr, Myrtle Beach, SC USA. [Van Poppel, Hendrik] Katholieke Univ Leuven Hosp, Leuven, Belgium. [Rathkopf, Dana E.; Scher, Howard I.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Rathkopf, Dana E.; Scher, Howard I.] Weill Cornell Med Coll, New York, NY USA. [Smith, Matthew R.] Harvard Univ, Sch Med, Boston, MA USA. [Smith, Matthew R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [de Bono, Johann S.] Inst Canc Res, Sutton, Surrey, England. [de Bono, Johann S.] Royal Marsden Hosp, Sutton, Surrey, England. [Logothetis, Christopher J.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [de Souza, Paul] Univ Western Sydney, Sch Med, Ingham Inst, Liverpool, Australia. [Fizazi, Karim] Univ Paris 11, Inst Gustave Roussy, Villejuif, France. [Mulders, Peter F. A.] Radboud Univ Nijmegen, Med Ctr, Nijmegen, Netherlands. [Mainwaring, Paul] Hematol & Oncol Clin Australia, Brisbane, Qld, Australia. [Hainsworth, John D.] Sarah Cannon Res Inst, Nashville, TN USA. [Beer, Tomasz M.] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. [North, Scott] Cross Canc Inst, Edmonton, AB T6G 1Z2, Canada. [Fradet, Yves] Univ Laval, Quebec City, PQ, Canada. [Griffin, Thomas A.] Janssen Res & Dev, Los Angeles, CA USA. [De Porre, Peter] Janssen Res & Dev, Beerse, Belgium. [Londhe, Anil] Janssen Res & Dev, Raritan, NJ USA. [Kheoh, Thian] Janssen Res & Dev, San Diego, CA USA. [Small, Eric J.; Ryan, Charles J.] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Molina, Arturo] Janssen Res & Dev, Menlo Pk, CA USA. RP Saad, F (reprint author), Univ Montreal, Ctr Hlth, 560 Rue Sherbrooke E, Montreal, PQ H2L 4M1, Canada. EM fredsaad@videotron.ca RI Mulders, Peter/H-8076-2014; OI Rathkopf, Dana/0000-0002-4503-7582 FU Janssen Global Services, LLC.; Janssen Research Development FX This work was supported by Janssen Research & Development (formerly Ortho Biotech Oncology Research & Development, unit of Cougar Biotechnology). Writing assistance was provided by Ann P. Tighe of PAREXEL and was funded by Janssen Global Services, LLC. The sponsor played a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, and approval of the manuscript. NR 27 TC 9 Z9 9 U1 1 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 OCT PY 2015 VL 68 IS 4 BP 570 EP 577 DI 10.1016/j.eururo.2015.04.032 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA CQ4KM UT WOS:000360573600013 PM 25985882 ER PT J AU Sun, T McKay, R Lee, GSM Kantoff, P AF Sun, Tong McKay, Rana Lee, Gwo-Shu Mary Kantoff, Philip TI The Role of miRNAs in Prostate Cancer SO EUROPEAN UROLOGY LA English DT Editorial Material ID MICRORNAS C1 [Sun, Tong; McKay, Rana; Lee, Gwo-Shu Mary; Kantoff, Philip] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. RP Kantoff, P (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. EM philip_kantoff@dfci.harvard.edu FU NCI NIH HHS [T32 CA009172] NR 10 TC 1 Z9 1 U1 1 U2 3 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 OCT PY 2015 VL 68 IS 4 BP 589 EP 590 DI 10.1016/j.eururo.2014.12.037 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA CQ4KM UT WOS:000360573600016 PM 25577717 ER PT J AU Koontz, BF Bossi, A Cozzarini, C Wiegel, T D'Amico, A AF Koontz, Bridget F. Bossi, Alberto Cozzarini, Cesare Wiegel, Thomas D'Amico, Anthony TI A Systematic Review of Hypofractionation for Primary Management of Prostate Cancer SO EUROPEAN UROLOGY LA English DT Review DE Prostate cancer; Stereotactic radiation therapy; Hypofractionation; Prostate-specific antigen; Randomized trials; Genitourinary toxicity; Gastrointestinal toxicity ID BODY RADIATION-THERAPY; QUALITY-OF-LIFE; EXTERNAL-BEAM RADIOTHERAPY; INTENSITY-MODULATED RADIOTHERAPY; RANDOMIZED CONTROLLED-TRIAL; COST-EFFECTIVENESS ANALYSIS; DOSE-ESCALATION; LATE TOXICITY; REAL-TIME; RISK AB Context: Technological advances in radiation therapy delivery have permitted the use of high-dose-per-fraction radiation therapy (RT) for early-stage prostate cancer (PCa). Level 1 evidence supporting the safety and efficacy of hypofractionated RT is evolving as this modality becomes more widely utilized and refined. Objective: To perform a systematic review of the current evidence on the safety and efficacy of hypofractionated RT for early-stage PCa and to provide in-context recommendations for current application of this technology. Evidence acquisition: Embase, PubMed, and Scopus electronic databases were queried for English-language articles from January 1990 through June 2014. Prospective studies with a minimum of 50 patients were included. Separate consideration was made for studies involving moderate hypofractionation (doses of 2.5-4 Gy per fraction) and extreme hypofractionation (5-10 Gy in 4-7 fractions). Evidence synthesis: Six relatively small superiority designed randomized trials of standard fractionation versus moderate hypofractionation in predominantly low-and intermediate-risk PCa have been published with follow-up ranging from 4 to 8 yr, noting similar biochemical control (5-yr freedom from biochemical failure in modern studies is >80% for low-risk and intermediate-risk patients) and late grade >= 2 genitourinary and gastrointestinal toxicities (between 2% and 20%). Noninferiority studies are pending. In prospective phase 2 studies, extreme hypofractionation has promising 2- to 5-yr biochemical control rates of >90% for low-risk patients. Results from a randomized trial are expected in 2015. Conclusions: Moderate hypofractionation has 5-yr data to date establishing safety compared with standard fractionation, but 10-yr outcomes and longer follow-up are needed to establish noninferiority for clinical effectiveness. Extreme hypofractionation is promising but as yet requires reporting of randomized data prior to application outside of a clinical protocol. Patient summary: Hypofractionation for prostate cancer delivers relatively high doses of radiation per treatment. Prospective studies support the safety of moderate hypofractionation, while extreme fractionation may have greater toxicity. Both show promising cancer control but long-term results of noninferiority studies of both methods are required before use in routine treatment outside of clinical protocols. (C) 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved. C1 [Koontz, Bridget F.] Duke Canc Inst, Dept Radiat Oncol, Durham, NC 27707 USA. [Bossi, Alberto] Inst Gustave Roussy, Dept Radiat Oncol, Villejuif, France. [Cozzarini, Cesare] Ist Sci San Raffaele, Dept Radiotherapy, I-20132 Milan, Italy. [Wiegel, Thomas] Univ Hosp Ulm, Dept Radiat Oncol, Ulm, Germany. [D'Amico, Anthony] Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. [D'Amico, Anthony] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Koontz, BF (reprint author), Duke Canc Inst, Dept Radiat Oncol, Box 3085, Durham, NC 27707 USA. EM bridget.koontz@duke.edu NR 50 TC 24 Z9 24 U1 3 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 EI 1873-7560 J9 EUR UROL JI Eur. Urol. PD OCT PY 2015 VL 68 IS 4 BP 683 EP 691 DI 10.1016/j.eururo.2014.08.009 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA CQ4KM UT WOS:000360573600036 PM 25171903 ER PT J AU Hazlehurst, BL Kurtz, SE Masica, A Stevens, VJ McBurnie, MA Puro, JE Vijayadeva, V Au, DH Brannon, ED Sittig, DF AF Hazlehurst, Brian L. Kurtz, Stephen E. Masica, Andrew Stevens, Victor J. McBurnie, Mary Ann Puro, Jon E. Vijayadeva, Vinutha Au, David H. Brannon, Elissa D. Sittig, Dean F. TI CER Hub: An informatics platform for conducting comparative effectiveness research using multi-institutional, heterogeneous, electronic clinical data SO INTERNATIONAL JOURNAL OF MEDICAL INFORMATICS LA English DT Article DE Comparative effectiveness research; Natural language processing; Electronic health records ID MEDICAL-RECORD; RESEARCH NETWORK; SYSTEM; CARE; INFRASTRUCTURE; QUALITY; EVENTS AB Objectives: Comparative effectiveness research (CER) requires the capture and analysis of data from disparate sources, often from a variety of institutions with diverse electronic health record (EHR) implementations. In this paper we describe the CER Hub, a web-based informatics platform for developing and conducting research studies that combine comprehensive electronic clinical data from multiple health care organizations. Methods: The CER Hub platform implements a data processing pipeline that employs informatics standards for data representation and web-based tools for developing study-specific data processing applications, providing standardized access to the patient-centric electronic health record (EHR) across organizations. Results: The CER Hub is being used to conduct two CER studies utilizing data from six geographically distributed and demographically diverse health systems. These foundational studies address the effectiveness of medications for controlling asthma and the effectiveness of smoking cessation services delivered in primary care. Discussion: The CER Hub includes four key capabilities: the ability to process and analyze both free-text and coded clinical data in the EHR; a data processing environment supported by distributed data and study governance processes; a clinical data-interchange format for facilitating standardized extraction of clinical data from EHRs; and a library of shareable clinical data processing applications. Conclusion: CER requires coordinated and scalable methods for extracting, aggregating, and analyzing complex, multi-institutional clinical data. By offering a range of informatics tools integrated into a framework for conducting studies using EHR data, the CER Hub provides a solution to the challenges of multi-institutional research using electronic medical record data. (C) 2015 Published by Elsevier Ireland Ltd. C1 [Hazlehurst, Brian L.; Kurtz, Stephen E.; Stevens, Victor J.; McBurnie, Mary Ann] Kaiser Permanente Northwest, Ctr Hlth Res, Portland, OR USA. [Masica, Andrew] Baylor Scott & White Hlth, Ctr Clin Effectiveness, Dallas, TX USA. [Puro, Jon E.] OCHIN Inc, Portland, OR USA. [Vijayadeva, Vinutha] Kaiser Permanente Hawaii, Ctr Hlth Res, Honolulu, HI USA. [Au, David H.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Brannon, Elissa D.] Kaiser Permanente Southeast, Atlanta, GA USA. [Sittig, Dean F.] Univ Texas Hlth Sci Ctr Houston, Sch Biomed Informat, Houston, TX 77030 USA. RP Hazlehurst, BL (reprint author), Kaiser Permanente Northwest, Ctr Hlth Res 3800 N, Interstate Ave Portland, Hillsboro, OR 97227 USA. EM Brian.hazlehurst@kpchr.org FU Agency for Health Care Research and Quality (AHRQ), Department of Health and Human Services [R01HS019828] FX The CER Hub project (www.cerhub.org) is funded by grant R01HS019828 (Hazlehurst, PI) from the Agency for Health Care Research and Quality (AHRQ), Department of Health and Human Services. The funders had no role in protocol development, data collection, analysis, interpretation, or manuscript production. The authors of this report are solely responsible for its content. NR 42 TC 1 Z9 1 U1 2 U2 19 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1386-5056 EI 1872-8243 J9 INT J MED INFORM JI Int. J. Med. Inform. PD OCT PY 2015 VL 84 IS 10 BP 763 EP 773 DI 10.1016/j.ijmedinf.2015.06.002 PG 11 WC Computer Science, Information Systems; Health Care Sciences & Services; Medical Informatics SC Computer Science; Health Care Sciences & Services; Medical Informatics GA CQ4GI UT WOS:000360562100005 PM 26138036 ER PT J AU Donfrancesco, R Innocenzi, M Marano, A Biederman, J AF Donfrancesco, R. Innocenzi, M. Marano, A. Biederman, J. TI Deficient Emotional Self-Regulation in ADHD Assessed Using a Unique Profile of the Child Behavior Checklist (CBCL): Replication in an Italian Study SO JOURNAL OF ATTENTION DISORDERS LA English DT Article DE emotional self-regulation; ADHD; sensitivity; specificity ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; PEDIATRIC BIPOLAR DISORDER; FAMILY RISK ANALYSIS; HYPERACTIVITY DISORDER; DIAGNOSIS; SYMPTOMS; PREDICTS; YOUTH AB Objective: A unique profile of the empirically derived Child Behavior Checklist-anxious/depressed, attention, and aggression-deficient emotional self-regulation (CBCL-AAA-DESR profile: 180 and 210) may be used to identify a sizable minority of children with ADHD with associated DESR. The main aim of this study was to replicate these findings in an Italian sample. Method: The sample consisted of 358 children and teenagers aged 6 to 17 years of both sexes with (n = 190) and without a diagnosis of ADHD (n = 168). Results: In all, 40.0% of children with ADHD had a positive CBCL-DESR profile compared with 3.5% of controls. Receiver-operating characteristic analysis showed that the CBCL-DESR profile cut-off (sensitivity = 97.33, specificity = 79.66, criterion 179, 210) discriminated the two subsamples. Conclusion: The findings replicate previous results highlighting the utility of the CBCL as a means of identifying DESR in children with ADHD. C1 [Donfrancesco, R.] ASL RM B Sandro Pertini Hosp Rome, Rome, Italy. [Innocenzi, M.] ASL RM B Rome, Rome, Italy. [Marano, A.] Univ Roma La Sapienza, Cognit Psychol Psychophysiol & Personal, I-00185 Rome, Italy. [Biederman, J.] Massachusetts Gen Hosp, Clin & Res Program Pediat Psychopharmacol & Adult, Pediat Psychopharmacol Unit, Yawkey Ctr Outpatient Care, Boston, MA 02114 USA. RP Marano, A (reprint author), Univ Roma La Sapienza, Dept Dev & Social Psychol, I-00185 Rome, Italy. EM assunta.marano@uniroma1.it NR 35 TC 1 Z9 1 U1 3 U2 18 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1087-0547 EI 1557-1246 J9 J ATTEN DISORD JI J. Atten. Disord. PD OCT PY 2015 VL 19 IS 10 SI SI BP 895 EP 900 DI 10.1177/1087054712462884 PG 6 WC Psychology, Developmental; Psychiatry SC Psychology; Psychiatry GA CQ8AV UT WOS:000360829300007 PM 23212599 ER PT J AU Schulte, M Hser, Y Saxon, A Evans, E Li, L Huang, D Hillhouse, M Thomas, C Ling, W AF Schulte, M. Hser, Y. Saxon, A. Evans, E. Li, L. Huang, D. Hillhouse, M. Thomas, C. Ling, W. TI Risk Factors Associated with HCV Among Opioid-Dependent Patients in a Multisite Study SO JOURNAL OF COMMUNITY HEALTH LA English DT Article DE Hepatitis C; Injection drug use; Buprenorphine; Methadone maintenance; Injection risk behavior ID HEPATITIS-C VIRUS; INJECTION-DRUG USERS; CORE ANTIGEN; GLOBAL EPIDEMIOLOGY; UNITED-STATES; HEROIN USERS; INFECTION; PREVALENCE; COCAINE; HEALTH AB We examined risk factors associated with hepatitis C virus (HCV) infection among opioid-dependent patients enrolled into medication-assisted therapy (buprenorphine or methadone) to determine factors affecting chronic infection. Patients (N = 1039) were randomized as part of a larger, multisite clinical trial sponsored by the National Drug Abuse Treatment Clinical Trials Network assessing liver function. HCV status was first assessed with an antibody screen; if positive, then current infection was determined with an antigen screen testing for detectable virus. Patients were classified as HCV negative, HCV positive but have cleared the virus, or as having chronic HCV. Logistic regression analysis was used to examine demographic and behavioral correlates of the three groups. Thirty-four percent of patients were classified with chronic infection and 14 % had evidence of prior infection with apparent clearing of the virus. Chronic infection was associated with recent injection drug use and cocaine use. Chronic HCV infection was also associated with being older and Hispanic. Age, ethnicity, and current drug use increase the likelihood of being chronically infected with HCV. Strategies targeting high risk subgroups can aid in preventing further disease escalation. C1 [Schulte, M.; Hser, Y.; Evans, E.; Li, L.; Huang, D.; Hillhouse, M.; Thomas, C.; Ling, W.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Integrated Subst Abuse Programs, Los Angeles, CA 90025 USA. [Saxon, A.] Vet Affairs Puget Sound Hlth Care Syst, Ctr Excellence Subst Abuse Treatment & Educ, Seattle, WA 98108 USA. [Saxon, A.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. RP Schulte, M (reprint author), Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Integrated Subst Abuse Programs, 11075 Santa Monica Blvd,Suite 200, Los Angeles, CA 90025 USA. EM mtschulte@ucla.edu RI Evans, Elizabeth/C-5294-2013 OI Evans, Elizabeth/0000-0002-3478-9957 FU National Institute on Drug Abuse [U10DA013045, P30 DA016383] FX Funding has been provided by the National Institute on Drug Abuse through Grants U10DA013045 and P30 DA016383. Thanks to the participating Nodes of the Clinical Trials Network: Pacific Region Node (Matrix Institute, Los Angeles and BAART, Turk St. Clinic, San Francisco); Western States Node (Bi-Valley Medical Clinic Inc., Sacramento and CODA Research, Portland); Delaware Valley Node (NET Steps, Philadelphia); Pacific Northwest Node (Evergreen Treatment Services, Seattle); and New England Consortium (Connecticut Counseling Centers, Waterbury and Hartford Dispensary, Hartford). NIDA had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. NR 40 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0094-5145 EI 1573-3610 J9 J COMMUN HEALTH JI J. Community Health PD OCT PY 2015 VL 40 IS 5 BP 940 EP 947 DI 10.1007/s10900-015-0016-2 PG 8 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA CQ5VC UT WOS:000360672800013 PM 25814381 ER PT J AU Ambrus, DB Benjamin, EJ Bajwa, EK Hibbert, KA Walkey, AJ AF Ambrus, Daniel B. Benjamin, Emelia J. Bajwa, Ednan K. Hibbert, Kathryn A. Walkey, Allan J. TI Risk factors and outcomes associated with new-onset atrial fibrillation during acute respiratory distress syndrome SO JOURNAL OF CRITICAL CARE LA English DT Article DE Atrial fibrillation; Acute respiratory distress syndrome; Interleukins; Troponin; Epinephrine; Mortality; Mechanism ID SEPTIC SHOCK; ARRHYTHMIAS; SEPSIS; COHORT; NOREPINEPHRINE; MANAGEMENT; MORTALITY; DOPAMINE; SCORE AB Purpose: Outcomes and risk factors associated with new-onset atrial fibrillation (AF) during acute respiratory distress syndrome (ARDS) are unclear. We investigated mortality and risk factors associated with new-onset AF during ARDS. Materials and methods: We obtained data from the ARDS Network Albuterol for Treatment of Acute Lung Injury trial, which prospectively identified new-onset AF among patients with ARDS as an adverse event. We determined Acute Physiology and Chronic Health Evaluation III-adjusted associations between new-onset AF and 90-day mortality. We also examined associations between new-onset AF and markers of inflammation (interleukin 6 and interleukin 8), myocardial injury (troponin I), autonomic activation (epinephrine), and atrial stretch (central venous pressure) as well as other clinical characteristics. Measurements and main results: Of 282 patients (mean age, 51.6 years; 45% women; 77% white) enrolled in Albuterol for Treatment of Acute Lung Injury, 28 (10%) developed new-onset AF during the study. We did not identify associations between new-onset AF and baseline central venous pressure, plasma levels of troponin I, epinephrine, interleukin 6, or interleukin 8. New-onset AF during ARDS was associated with increased 90-day mortality (new-onset AF, 43% vs no new-onset AF, 19%; Acute Physiology and Chronic Health Evaluation-adjusted odds ratio, 3.09 [95% confidence interval, 1.24-7.72]; P = .02). Conclusion: New-onset AF during ARDS is associated with increased mortality; however, its mechanisms require further study. (C) 2015 Elsevier Inc. All rights reserved. C1 [Ambrus, Daniel B.] Umass Mem Med Ctr, Sect Hosp Med, Dept Internal Med, Worcester, MA 01566 USA. [Ambrus, Daniel B.] Boston Univ, Sch Med, Div Gen Internal Med, Dept Med, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Sect Cardiovasc Med & Prevent Med, Boston, MA 02118 USA. [Bajwa, Ednan K.; Hibbert, Kathryn A.] Massachusetts Gen Hosp, Dept Med, Pulm & Crit Care Unit, Boston, MA 02114 USA. [Walkey, Allan J.] Boston Univ, Sch Med, Dept Med, Sect Pulm & Crit Care,Pulm Ctr, Boston, MA 02118 USA. RP Walkey, AJ (reprint author), Boston Univ, Sch Med, 72 E Newton St,R 304, Boston, MA 02118 USA. EM alwalkey@bu.edu OI Walkey, Allan/0000-0003-4685-6894; Benjamin, Emelia/0000-0003-4076-2336 FU National Institutes of Health/National Heart Lung and Blood Institute [K01HL116768-01, 2R01HL092577] FX National Institutes of Health/National Heart Lung and Blood Institute K01HL116768-01 (Walkey) and 2R01HL092577 (Benjamin) NR 24 TC 2 Z9 2 U1 0 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 0883-9441 EI 1557-8615 J9 J CRIT CARE JI J. Crit. Care PD OCT PY 2015 VL 30 IS 5 BP 994 EP 997 DI 10.1016/j.jcrc.2015.06.003 PG 4 WC Critical Care Medicine SC General & Internal Medicine GA CQ4FA UT WOS:000360558500022 PM 26138630 ER PT J AU Caya, T Musuuza, J Yanke, E Schmitz, M Anderson, B Carayon, P Safdar, N AF Caya, Teresa Musuuza, Jackson Yanke, Eric Schmitz, Michelle Anderson, Brooke Carayon, Pascale Safdar, Nasia TI Using a Systems Engineering Initiative for Patient Safety to Evaluate a Hospital-wide Daily Chlorhexidine Bathing Intervention SO JOURNAL OF NURSING CARE QUALITY LA English DT Article DE chlorhexidine bathing; infection control; quality improvement; SEIPS; systems engineering ID BLOOD-STREAM INFECTIONS; INTENSIVE-CARE-UNIT; ACQUIRED INFECTIONS; REDUCE; IMPACT AB We undertook a systems engineering approach to evaluate housewide implementation of daily chlorhexidine bathing. We performed direct observations of the bathing process and conducted provider and patient surveys. The main outcome was compliance with bathing using a checklist. Fifty-seven percent of baths had full compliance with the chlorhexidine bathing protocol. Additional time was the main barrier. Institutions undertaking daily chlorhexidine bathing should perform a rigorous assessment of implementation to optimize the benefits of this intervention. C1 [Safdar, Nasia] Univ Wisconsin Madison, Dept Med, Madison, WI 53705 USA. [Caya, Teresa] Univ Wisconsin Madison, Sch Med & Publ Hlth, Madison, WI 53705 USA. [Musuuza, Jackson] Univ Wisconsin Madison, Inst Clin & Translat Res, Madison, WI 53705 USA. [Carayon, Pascale] Univ Wisconsin Madison, Dept Ind & Syst Engn, Madison, WI 53705 USA. [Carayon, Pascale] Univ Wisconsin Madison, Ctr Qual & Prod Improvement, Madison, WI 53705 USA. [Yanke, Eric] William S Middleton Mem Vet Adm Med Ctr, Dept Med, Madison, WI USA. [Safdar, Nasia] William S Middleton Mem Vet Adm Med Ctr, Div Infect Dis, Madison, WI USA. [Schmitz, Michelle; Anderson, Brooke] Univ Wisconsin Hosp & Clin, Dept Infect Control, Madison, WI 53792 USA. [Safdar, Nasia] Univ Wisconsin Hosp & Clin, Dept Infect Dis, Madison, WI 53792 USA. RP Safdar, N (reprint author), Univ Wisconsin Madison, Dept Med, UWMF Centennial Bldg,1685 Highland Ave, Madison, WI 53705 USA. EM ns2@medicine.wisc.edu FU Clinical and Translational Science Award (CTSA) program, through the NIH National Center for Advancing Translational Sciences (NCATS) [UL1TR000427]; United States Department of Veterans Affairs MERIT award FX The project described was supported by the Clinical and Translational Science Award (CTSA) program, through the NIH National Center for Advancing Translational Sciences (NCATS), grant UL1TR000427, and the United States Department of Veterans Affairs MERIT award. NR 17 TC 2 Z9 2 U1 3 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1057-3631 EI 1550-5065 J9 J NURS CARE QUAL JI J. Nurs. Care Qual. PD OCT-DEC PY 2015 VL 30 IS 4 BP 337 EP 344 DI 10.1097/NCQ.0000000000000129 PG 8 WC Nursing SC Nursing GA CQ5RN UT WOS:000360663300008 PM 26035708 ER PT J AU Elabdeen, HRZ Mustafa, M Hasturk, H Klepac-Ceraj, V Ali, RW Paster, BJ Van Dyke, T Bolstad, AI AF Elabdeen, H. R. Z. Mustafa, M. Hasturk, H. Klepac-Ceraj, V. Ali, R. W. Paster, B. J. Van Dyke, T. Bolstad, A. I. TI Subgingival microbial profiles of Sudanese patients with aggressive periodontitis SO JOURNAL OF PERIODONTAL RESEARCH LA English DT Article DE human oral microbe identification microarrays; PCR; plaque; saliva ID DNA-DNA HYBRIDIZATION; HUMAN ORAL MICROBIOME; LEUKOTOXIC JP2 CLONE; ACTINOBACILLUS-ACTINOMYCETEMCOMITANS; PORPHYROMONAS-GINGIVALIS; JUVENILE PERIODONTITIS; AGGREGATIBACTER-ACTINOMYCETEMCOMITANS; MICROBIOLOGICAL FEATURES; PLAQUE; IDENTIFICATION AB Background and ObjectiveAggressive periodontitis (AgP) is prevalent and shows a rapid course in African individuals. Although a strong focus has been placed on Aggregatibacteractinomycetemcomitans, new methods support the existence of a complex subgingival microflora in AgP. The purpose of the present study was to map the subgingival microbiota as well as explore the presence of A.actinomycetemcomitans and the JP2 clone in a group of Sudanese individuals with AgP, using different analytical methods. Material and MethodsA study population consisting of 19 patients with AgP was recruited from patients seeking treatment at University of Science and Technology (UST) in Khartoum. Fifteen healthy subjects were included as controls. Plaque samples were analyzed for 272 taxa using human oral microbe identification microarrays and for 26 periodontal taxa using DNA-DNA hybridization checkerboard. Conventional polymerase chain reaction (PCR) was applied for the detection of A.actinomycetemcomitans and the JP2 clone in plaque. Saliva from patients with AgP was analyzed using quantitative PCR (qPCR) for the detection of A.actinomycetemcomitans. ResultsEubacteriumyurii was detected more frequently in patients with AgP than in controls, and E.nodatum was found in patients with AgP only. A.actinomycetemcomitans was found in plaque samples of two (12%) patients by human oral microbe identification microarrays and in five (29%) patients with AgP by conventional PCR, as well as in six (32%) of the AgP saliva samples by qPCR. The JP2 clone was identified in only one patient. ConclusionThe classical periodontal pathogens were not present in high amounts in AgP in the population studied here. Species of Eubacterium, which are not typically associated with AgP, were often detected in individuals with disease. Using laboratory methods with different sensitivities and detection levels allowed identification of variances in microbial communities. The findings reported in this study provide a basis for the further understanding of AgP. C1 [Elabdeen, H. R. Z.; Mustafa, M.; Bolstad, A. I.] Univ Bergen, Dept Clin Dent, Periodont, Bergen, Norway. [Hasturk, H.; Van Dyke, T.] Forsyth Inst, Ctr Periodontol, Dept Appl Oral Sci, Cambridge, MA 02142 USA. [Klepac-Ceraj, V.; Paster, B. J.] Forsyth Inst, Dept Microbiol, Cambridge, MA 02142 USA. [Klepac-Ceraj, V.] Wellesley Coll, Dept Biol Sci, Wellesley, MA 02481 USA. [Ali, R. W.] Univ Sci & Technol, Fac Dent, Omdurman, Sudan. [Paster, B. J.] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. RP Bolstad, AI (reprint author), Univ Bergen, Fac Med & Dent, Dept Clin Dent, Periodont, Arstadveien 19, Bergen, Norway. EM anne.bolstad@iko.uib.no FU L. Meltzers hoyskolefond; University of Bergen, Bergen, Norway FX The authors would like to thank Assoc. Professor Olav Boe, University of Bergen, for helpful advice regarding the statistical analysis, Oyunn Nilsen, University of Bergen, for technical assistance, and Professor Vidar Bakken, University of Bergen, for valuable advice regarding microbiological analysis. The technical assistance from Sean Cotton at Forsyth Institute is highly acknowledged. This study was supported by L. Meltzers hoyskolefond and University of Bergen, Bergen, Norway. NR 48 TC 3 Z9 3 U1 2 U2 7 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 OCT PY 2015 VL 50 IS 5 BP 674 EP 682 DI 10.1111/jre.12250 PG 9 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA CQ8LP UT WOS:000360859600013 PM 25487558 ER PT J AU Fontana, J Jurado, KA Cheng, NQ Ly, NL Fuchs, JR Gorelick, RJ Engelman, AN Steven, AC AF Fontana, Juan Jurado, Kellie A. Cheng, Naiqian Ly, Ngoc L. Fuchs, James R. Gorelick, Robert J. Engelman, Alan N. Steven, Alasdair C. TI Distribution and Redistribution of HIV-1 Nucleocapsid Protein in Immature, Mature, and Integrase-Inhibited Virions: a Role for Integrase in Maturation SO JOURNAL OF VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; SMALL-MOLECULE INHIBITORS; RADIATION-DAMAGE; CRYOELECTRON TOMOGRAPHY; VIRAL-REPLICATION; ELECTRON CRYOTOMOGRAPHY; 3-DIMENSIONAL STRUCTURE; NUCLEAR-LOCALIZATION; STRUCTURAL-ANALYSIS; IN-VITRO AB During virion maturation, HIV-1 capsid protein assembles into a conical core containing the viral ribonucleoprotein (vRNP) complex, thought to be composed mainly of the viral RNA and nucleocapsid protein (NC). After infection, the viral RNA is reverse transcribed into double-stranded DNA, which is then incorporated into host chromosomes by integrase (IN) catalysis. Certain IN mutations (class II) and antiviral drugs (allosteric IN inhibitors [ALLINIs]) adversely affect maturation, resulting in virions that contain "eccentric condensates," electron-dense aggregates located outside seemingly empty capsids. Here we demonstrate that in addition to this mislocalization of electron density, a class II IN mutation and ALLINIs each increase the fraction of virions with malformed capsids (from similar to 12% to similar to 53%). Eccentric condensates have a high NC content, as demonstrated by "tomo-bubblegram" imaging, a novel labeling technique that exploits the susceptibility of NC to radiation damage. Tomo-bubblegrams also localized NC inside wild-type cores and lining the spherical Gag shell in immature virions. We conclude that eccentric condensates represent nonpackaged vRNPs and that either genetic or pharmacological inhibition of IN can impair vRNP incorporation into mature cores. Supplying IN in trans as part of a Vpr-IN fusion protein partially restored the formation of conical cores with internal electron density and the infectivity of a class II IN deletion mutant virus. Moreover, the ability of ALLINIs to induce eccentric condensate formation required both IN and viral RNA. Based on these observations, we propose a role for IN in initiating core morphogenesis and vRNP incorporation into the mature core during HIV-1 maturation. IMPORTANCE Maturation, a process essential for HIV-1 infectivity, involves core assembly, whereby the viral ribonucleoprotein (vRNP, composed of vRNA and nucleocapsid protein [NC]) is packaged into a conical capsid. Allosteric integrase inhibitors (ALLINIs) affect multiple viral processes. We have characterized ALLINIs and integrase mutants that have the same phenotype. First, by comparing the effects of ALLINIs on several steps of the viral cycle, we show that inhibition of maturation accounts for compound potency. Second, by using cryoelectron tomography, we find that ALLINIs impair conical capsid assembly. Third, by developing tomo-bubblegram imaging, which specifically labels NC protein, we find that ALLINIs block vRNP packaging; instead, vRNPs form "eccentric condensates" outside the core. Fourth, malformed cores, typical of integrase-deleted virus, are partially replaced by conical cores when integrase is supplied in trans. Fifth, vRNA is necessary for ALLINI-induced eccentric condensate formation. These observations suggest that integrase is involved in capsid morphogenesis and vRNP packaging. C1 [Fontana, Juan; Cheng, Naiqian; Steven, Alasdair C.] NIAMSD, Struct Biol Res Lab, NIH, Bethesda, MD 20892 USA. [Jurado, Kellie A.; Ly, Ngoc L.; Engelman, Alan N.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Fuchs, James R.] Ohio State Univ, Coll Pharm, Div Med Chem & Pharmacognosy, Columbus, OH 43210 USA. [Gorelick, Robert J.] Leidos Biomed Res Inc, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Engelman, AN (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. EM alan_engelman@dfci.harvard.edu; stevena@mail.nih.gov RI Fontana, Juan/A-9138-2009 OI Fontana, Juan/0000-0002-9084-2927 FU Intramural Research Program of NIAMS; Intramural AIDS Targeted Antiviral Program; NIH [AI070042, GM103368]; National Cancer Institute [HHSN261200800001E]; Leidos Biomedical Research, Inc. FX This work was funded in part by the Intramural Research Program of NIAMS (A.C.S.), the Intramural AIDS Targeted Antiviral Program (A.C.S.), NIH grants AI070042 (A.N.E.) and GM103368 (A.N.E. and J.R.F.), and funds of the National Cancer Institute under contract HHSN261200800001E with Leidos Biomedical Research, Inc. (R.J.G.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 74 TC 17 Z9 17 U1 0 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD OCT PY 2015 VL 89 IS 19 BP 9765 EP 9780 DI 10.1128/JVI.01522-15 PG 16 WC Virology SC Virology GA CQ6HJ UT WOS:000360704900009 PM 26178982 ER PT J AU Murphy, SA Bell, MJ Clark, ME Whalen, MJ Noviski, N AF Murphy, Sarah A. Bell, Michael J. Clark, Maureen E. Whalen, Michael J. Noviski, Natan TI Pediatric Neurocritical Care: A Short Survey of Current Perceptions and Practices SO NEUROCRITICAL CARE LA English DT Article DE Pediatrics; Neurocritical care; Pediatric neurocritical care; Sub-specialization Critical care fellowship; Practice patterns ID TRAUMATIC BRAIN-INJURY; CARDIAC CRITICAL-CARE; INTENSIVE-CARE; MANAGEMENT; NEUROLOGY; MEDICINE; CONDUCT AB Although attention to neurologic injuries and illnesses in pediatric critical care is not new, a sub-specialized field of pediatric neurocritical care has only recently been recognized. Pediatric neurocritical care is an emerging area of clinical and investigative focus. Little is known about the prevalence of specialized pediatric neurocritical care services nor about perceptions regarding how it is impacting medical practice. This survey sought to capture perceptions about an emerging area of specialized pediatric neurocritical care among practitioners in intersecting disciplines, including pediatric intensivists, pediatric neurologits and pediatric neurosurgeons. A web-based survey was distributed via email to members of relevant professional societies and groups. Survey responses were analyzed using descriptive statistics. Differences in responses between groups of respondents were analyzed using Chi-squared analysis where appropriate. Specialized clinical PNCC programs were not uncommon among the survey respondents with 20 % currently having a PNCC service at their institution. Despite familiarity with this area of sub-specialization among the survey respondents, the survey did not find consensus regarding its value. Overall, 46 % of respondents believed that a specialized clinical PNCC service improves the quality of care of critically ill children. Support for PNCC sub-specialization was more common among pediatric neurologists and pediatric neurosurgeons than pediatric intensivists. This survey found support across specialties for creating PNCC training pathways for both pediatric intensivists and pediatric neurologists with an interest in this specialized field. PNCC programs are not uncommon; however, there is not clear agreement on the optimal role or benefit of this area of practice sub-specialization. A broader dialog should be undertaken regarding the emerging practice of pediatric neurocritical care, the potential benefits and drawbacks of this partitioning of neurology and critical care medicine practice, economic and other practical factors, the organization of clinical support services, and the formalization of training and certification pathways for sub-specialization. C1 [Murphy, Sarah A.; Bell, Michael J.; Clark, Maureen E.; Whalen, Michael J.; Noviski, Natan] MassGen Hosp Children, Pediat Crit Care Off, Boston, MA 02114 USA. RP Murphy, SA (reprint author), MassGen Hosp Children, Pediat Crit Care Off, 175 Cambridge St,CPZ5,Rm 526, Boston, MA 02114 USA. EM samurphy@partners.org FU MGHfC Pediatric Critical Care Department FX Departmental funds from the MGHfC Pediatric Critical Care Department were used to pay service fees requested by professional societies to process survey distribution. NR 31 TC 0 Z9 0 U1 2 U2 2 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1541-6933 EI 1556-0961 J9 NEUROCRIT CARE JI Neurocrit. Care PD OCT PY 2015 VL 23 IS 2 BP 149 EP 158 DI 10.1007/s12028-015-0120-2 PG 10 WC Critical Care Medicine; Clinical Neurology SC General & Internal Medicine; Neurosciences & Neurology GA CQ6FU UT WOS:000360700700002 PM 25693892 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, Jr. Keck, Paul E. McElroy, Susan L. Altshuler, Lori L. Frye, Mark A. Rowe, Michael Grunze, Heinz Suppes, Trisha Nolen, Willem A. TI Increases in multiple psychiatric disorders in parents and grandparents of patients with bipolar disorder from the USA compared with The Netherlands and Germany SO PSYCHIATRIC GENETICS LA English DT Article DE alcohol abuse; depression; family history; genetics; substance abuse ID ASTERISK-D-CHILD; MENTAL-DISORDERS; UNITED-STATES; FOLLOW-UP; MATERNAL DEPRESSION; II DISORDER; EARLY-ONSET; HIGH-RISK; STEP-BD; PSYCHOPATHOLOGY AB ObjectiveWe previously found that compared with Europe more parents of the USA patients were positive for a mood disorder, and that this was associated with early onset bipolar disorder. Here we examine family history of psychiatric illness in more detail across several generations.MethodsA total of 968 outpatients (average age 41) with bipolar disorder from four sites in the USA and three in the Netherlands and Germany (abbreviated as Europe) gave informed consent and provided detailed demographic and family history information on a patient questionnaire. Family history of psychiatric illness (bipolar disorder, unipolar depression, suicide attempt, alcohol abuse, substance abuse, and other illness) was collected for each parent, four grandparents, siblings, and children.ResultsParents of the probands with bipolar disorder from the USA compared with Europe had a significantly higher incidence of both unipolar and bipolar mood disorders, as well as each of the other psychiatric conditions listed above. With a few exceptions, this burden of psychiatric disorders was also significantly greater in the grandparents, siblings, and children of the USA versus European patients.ConclusionThe increased complexity of psychiatric illness and its occurrence over several generations in the families of patients with bipolar disorder from the USA versus Europe could be contributing to the higher incidence of childhood onsets and greater virulence of illness in the USA compared with Europe. These data are convergent with others suggesting increased both genetic and environmental risk in the USA, but require replication in epidemiologically-derived populations with data based on interviews of the family members. C1 [Post, Robert M.; Leverich, Gabriele S.; Rowe, Michael] Bipolar Collaborat Network, Bethesda, MD 20814 USA. [Post, Robert M.] George Washington Univ, Dept Psychiat & Behav Sci, Washington, DC USA. [Keck, Paul E.] Univ Cincinnati, Coll Med, Dept Psychiat & Behav Neurosci, Cincinnati, OH USA. [McElroy, Susan L.] Univ Cincinnati, Coll Med, Dept Psychiat & Behav Neurosci, Biol Psychiat Program, Cincinnati, OH USA. [Keck, Paul E.; McElroy, Susan L.] Lindner Ctr HOPE, Mason, 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, Dept Psychiat, VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Suppes, Trisha] Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. [Suppes, Trisha] VA Palo Alto HealthCare Syst, Palo Alto, CA USA. [Frye, Mark A.] Mayo Clin, Dept Psychiat, Rochester, MI USA. [Kupka, Ralph, Jr.] Vrije Univ Amsterdam, Dept Psychiat, Med Ctr, Amsterdam, Netherlands. [Nolen, Willem A.] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands. [Grunze, Heinz] Paracelsus Med Univ Salzburg, Dept Psychiat & Psychotherapy, Christian Doppler Klink, Salzburg, Austria. 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 FU Stanley Foundation Bipolar Network FX The research funding for this article was provided by the Stanley Foundation Bipolar Network from 1995-2002. NR 57 TC 5 Z9 5 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0955-8829 EI 1473-5873 J9 PSYCHIAT GENET JI Psychiatr. Genet. PD OCT PY 2015 VL 25 IS 5 BP 194 EP 200 DI 10.1097/YPG.0000000000000093 PG 7 WC Genetics & Heredity; Neurosciences SC Genetics & Heredity; Neurosciences & Neurology GA CQ5PQ UT WOS:000360658100002 PM 26146875 ER PT J AU Throckmorton, A VanderWalde, L Brackett, C Dominici, L Eisenhauer, T Johnson, N Kong, A Ludwig, K O'Neill, J Pugliese, M Teller, P Sarantou, T AF Throckmorton, Alyssa VanderWalde, Lindi Brackett, Craig Dominici, Laura Eisenhauer, Thomas Johnson, Nathalie Kong, Amanda Ludwig, Kandice O'Neill, Jennifer Pugliese, Matthew Teller, Paige Sarantou, Terry TI The Ethics of Breast Surgery SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID SKIN-SPARING MASTECTOMY; MEDICAL DECISION-MAKING; CLINICAL-PRACTICE; CONSENSUS STATEMENT; ADJUVANT TREATMENT; SYSTEMIC THERAPY; INFORMED-CONSENT; CANCER; WOMEN; GUIDELINES AB Breast surgery has evolved as a subspecialty of general surgery and requires a working knowledge of benign and malignant diseases, surgical techniques, shared decision-making with patients, collaboration with a multi-disciplinary team, and a basic foundation in surgical ethics. Ethics is defined as the practice of analyzing, evaluating, and promoting best conduct based upon available standards. As new information is obtained or as cultural values change, best conduct may be re-defined. In 2014, the Ethics Committee of the ASBrS acknowledged numerous ethical issues, specific to the practice of breast surgery. This independent review of ethical concerns was created by the Ethics Committee to provide a resource for ASBrS members as well as other surgeons who perform breast surgery. In this review, the professional, clinical, research and technology considerations that breast surgeons face are reviewed with guidelines for ethical physician behavior. C1 [Throckmorton, Alyssa; VanderWalde, Lindi] Baptist Canc Ctr, Memphis, TN 38120 USA. [Throckmorton, Alyssa] Univ Tennessee, Memphis, TN USA. [Brackett, Craig] Coastal Carolina Breast Ctr, Murrells Inlet, SC USA. [Dominici, Laura] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Eisenhauer, Thomas] Univ N Carolina, Chapel Hill, NC USA. [Johnson, Nathalie] Legacy Canc Inst, Portland, OR USA. [Kong, Amanda] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Ludwig, Kandice] Indiana Univ, Indianapolis, IN 46204 USA. [O'Neill, Jennifer] Arizona Associated Surg, Phoenix, AZ USA. [Pugliese, Matthew] Univ Hosp, Augusta, GA USA. [Teller, Paige] Atirus Hlth Harvard Vanguard Med Associates, Boston, MA USA. [Sarantou, Terry] Carolinas HealthCare Syst, Levine Canc Inst, Dept Gen Surg, Charlotte, NC USA. RP Throckmorton, A (reprint author), Baptist Canc Ctr, Memphis, TN 38120 USA. EM Alyssa.Throckmorton@BMHCC.org NR 37 TC 0 Z9 0 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD OCT PY 2015 VL 22 IS 10 BP 3191 EP 3196 DI 10.1245/s10434-015-4751-5 PG 6 WC Oncology; Surgery SC Oncology; Surgery GA CQ0RF UT WOS:000360303800006 PM 26219240 ER PT J AU Bellon, JR Golshan, M Solin, LJ AF Bellon, Jennifer R. Golshan, Mehra Solin, Lawrence J. TI Controversies in Radiation Oncology for Early-Stage Breast Cancer SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID CARCINOMA IN-SITU; GENE-EXPRESSION PATTERNS; LOCAL RECURRENCE; CONSERVING THERAPY; CONSERVATION TREATMENT; ESTROGEN-RECEPTOR; FOLLOW-UP; WOMEN; RADIOTHERAPY; TAMOXIFEN AB Multiple randomized trials, as well as a meta-analysis of these studies, have confirmed the equivalence of breast-conservation and mastectomy. In addition, in unselected populations, adjuvant radiation therapy following lumpectomy has been shown to decrease in-breast recurrence and improve overall survival. However, radiation has morbidity, and is costly and inconvenient. Multiple efforts to minimize treatment have been studied, including omitting radiation in low-risk populations, as well as in those with significant competing risks. Central to these efforts has been an increased awareness of the inherent biology, allowing treatment to be more precisely tailored to the risks posed by each individual patient's disease. In addition, an improved understanding of the radio-responsiveness of both tumor and adjacent normal tissue has permitted safe use of short-course (hypofractionated) radiation. Studies are ongoing to determine the most appropriate candidates for both hypofractionated treatment and omission of radiation entirely. The optimal management of ductal carcinoma in situ is also a subject of intense study. Multiple trials have attempted to identify patients who can safely forego radiation and, more recently, molecular predictors of recurrence have been developed to further fine-tune this low-risk population. C1 [Bellon, Jennifer R.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Bellon, Jennifer R.; Golshan, Mehra] Brigham & Womens Hosp, Boston, MA 02115 USA. [Golshan, Mehra] Dana Farber Canc Inst, Dept Surg, Boston, MA 02115 USA. [Solin, Lawrence J.] Albert Einstein Healthcare Network, Dept Radiat Oncol, Philadelphia, PA USA. RP Bellon, JR (reprint author), Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. EM jbellon@lroc.harvard.edu NR 33 TC 2 Z9 2 U1 0 U2 8 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 OCT PY 2015 VL 22 IS 10 BP 3213 EP 3218 DI 10.1245/s10434-015-4713-y PG 6 WC Oncology; Surgery SC Oncology; Surgery GA CQ0RF UT WOS:000360303800010 PM 26202560 ER PT J AU Dietz, JR Partridge, AH Gemignani, ML Javid, SH Kuerer, HM AF Dietz, Jill R. Partridge, Ann H. Gemignani, Mary L. Javid, Sara H. Kuerer, Henry M. TI Breast Cancer Management Updates: Young and Older, Pregnant, or Male SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID LYMPH-NODE BIOPSY; FERTILITY PRESERVATION; AMERICAN SOCIETY; UNITED-STATES; FOLLOW-UP; WOMEN; DIAGNOSIS; AGE; BRCA2; MAMMOGRAPHY AB Every year, more and more patients fall into rare or extreme categories of breast cancer-young, elderly, pregnant, or male. Contributing factors may be improved risk assessment and screening techniques (especially of dense breast tissue), delayed childbearing, and the aging population. These patients can challenge usual medical decision making because of their unique situation. There might be a concern for the fetus, worry about future fertility, a question of local control in a man, or concern for overdiagnosis or overtreatment in an older patient. Because these populations are seldom included in the large breast cancer trials from which standard treatment recommendations are made, an update on management for young, elderly, pregnant, and male breast cancer patients may be helpful. C1 [Dietz, Jill R.] Case Western Reserve Sch Med, Cleveland, OH 44106 USA. [Partridge, Ann H.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Gemignani, Mary L.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Javid, Sara H.] Univ Washington, Seattle, WA 98195 USA. [Kuerer, Henry M.] Univ Texas Houston, MD Anderson Canc Ctr, Houston, TX 77030 USA. RP Dietz, JR (reprint author), Case Western Reserve Sch Med, Cleveland, OH 44106 USA. EM jill.dietz@uhhospitals.org NR 53 TC 1 Z9 1 U1 1 U2 7 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 OCT PY 2015 VL 22 IS 10 BP 3219 EP 3224 DI 10.1245/s10434-015-4755-1 PG 6 WC Oncology; Surgery SC Oncology; Surgery GA CQ0RF UT WOS:000360303800011 PM 26265366 ER PT J AU Wong, SM Freedman, RA Stamell, E Sagara, Y Mbbs, JEB Desantis, SD Golshan, M AF Wong, Stephanie M. Freedman, Rachel A. Stamell, Emily Sagara, Yasuaki Mbbs, Jane E. Brock Desantis, Stephen D. Golshan, Mehra TI Modern Trends in the Surgical Management of Paget's Disease SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID BREAST-CONSERVING THERAPY; LYMPH-NODE BIOPSY; PROSPECTIVE EUROPEAN-ORGANIZATION; CONSERVATIVE MANAGEMENT; CANCER; NIPPLE; RADIOTHERAPY; DISPARITIES; EXPERIENCE; RECEIPT AB Purpose. We examined the incidence and modern national trends in the management of Paget's disease (PD), including the use of breast-conserving surgery (BCS), mastectomy, axillary surgery, and receipt of radiotherapy. Methods. Using surveillance, epidemiology and end results (SEER) data, we identified 2631 patients diagnosed with PD during 2000-2011. Of these patients, 185 (7 %) had PD of the nipple only, 953 (36.2 %) had PD with ductal carcinoma in situ (PD-DCIS), and 1493 (56.7 %) had PD with invasive ductal carcinoma (PD-IDC). Trends in age-adjusted incidence, primary surgery, sentinel lymph node biopsy (SLNB), and axillary lymph node dissection were examined. Multivariable logistic regression was used to evaluate factors associated with receipt of BCS and radiotherapy. Results. A decrease in the age-adjusted incidence of PD occurred from 2000 to 2011 (-4.3 % per year, p < 0.05). The overall rates of mastectomy in the PD only, PD-DCIS, and PD-IDC groups were 47, 69, and 88.9 %, respectively. Only in the PD-IDC group did the proportion of patients undergoing BCS increase significantly, from 8.5 % in 2000 to 15.7 % in 2011 (p = 0.01). Of those who underwent axillary surgery, the proportion of patients undergoing SLNB increased from 2000 to 2011. In adjusted analyses, Paget's subgroup, older age, central tumor location, low/intermediate grade, tumor size < 2.0 cm, SEER region, and year of diagnosis after 2006 were significantly associated with receipt of BCS. Conclusions. The incidence of Paget's disease has decreased over time while modern trends in local therapy suggest that BCS, SLNB, and adjuvant radiotherapy remain underutilized. C1 [Wong, Stephanie M.; Stamell, Emily] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Wong, Stephanie M.] McGill Univ, Dept Surg, Ctr Hlth, Montreal, PQ H3A 2T5, Canada. [Freedman, Rachel A.; Stamell, Emily; Desantis, Stephen D.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Mbbs, Jane E. Brock] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Sagara, Yasuaki; Desantis, Stephen D.; Golshan, Mehra] Dana Farber Canc Inst, Dept Surg, Brigham & Womens Hosp, Boston, MA 02115 USA. RP Wong, SM (reprint author), Harvard Univ, Sch Publ Hlth, 665 Huntington Ave, Boston, MA 02115 USA. EM mgolshan@partners.org NR 28 TC 1 Z9 1 U1 0 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 OCT PY 2015 VL 22 IS 10 BP 3308 EP 3316 DI 10.1245/s10434-015-4664-3 PG 9 WC Oncology; Surgery SC Oncology; Surgery GA CQ0RF UT WOS:000360303800024 PM 26202552 ER PT J AU Tang, R Coopey, SB Colwell, AS Specht, MC Gadd, MA Kansal, K McEvoy, MP Merrill, AL Rai, U Taghian, A Austen, WG Smith, BL AF Tang, Rong Coopey, Suzanne B. Colwell, Amy S. Specht, Michelle C. Gadd, Michele A. Kansal, Kari McEvoy, Maureen P. Merrill, Andrea L. Rai, Upahvan Taghian, Alphonse Austen, William G. Smith, Barbara L. TI Nipple-Sparing Mastectomy in Irradiated Breasts: Selecting Patients to Minimize Complications SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID RADIATION-THERAPY; RECONSTRUCTION; IMPLANTS; OUTCOMES AB Background. Nipple-sparing mastectomies (NSM) are increasingly common because of their cosmetic advantage. Radiotherapy (RT) has been a relative contraindication to immediate reconstruction because of concerns about increased complications. We aimed to evaluate outcomes of NSM plus immediate reconstruction in irradiated breasts and to determine additional risk factors for complications. Methods. We retrospectively reviewed NSM with immediate reconstruction from 2007 to 2013 at our institution. Complications were broken down into several categories. Potential risk factors for complications were evaluated. Results. There were 982 NSM: 816 had no RT, 67 had prior RT, and 97 had postmastectomy radiotherapy (PMRT). Compared to breasts with no RT, both prior RT and PMRT increased overall complications (10.2 vs. 21.7 and 17.5 %, p = 0.003, 0.03, respectively) and nipple loss (0.9 vs. 4.3 and 4.1 %, p = 0.04, 0.02, respectively), while PMRT increased rate of reconstruction failure (2.2 vs. 8.2 %, p = 0.003). On multivariate regression analysis, prior RT [odds ratio (OR) 2.53, p = 0.006], PMRT (OR 2.29, p = 0.015), age > 55 years (OR 2.03, p = 0.04), breast volume >= 800 cm(3) (OR 1.96, p = 0.04), smoking (OR 2.62, p = 0.001), and periareolar incision (OR 1.74, p = 0.03) were independent risk factors for complications requiring surgical revision. In irradiated breasts, complication rates were 13.4 % without further risk factors and 17.5, 50, and 66.7 % when 1, 2, and >= 3 additional independent risk factors were present, respectively (p < 0.001). Conclusions. Although complication rates were higher in irradiated breasts, reconstruction failure and nipple/areola necrosis was infrequent. RT should not be a contraindication to NSM. Preoperative identification of risk factors and appropriate patient selection may reduce complication rates. C1 [Tang, Rong; Coopey, Suzanne B.; Specht, Michelle C.; Gadd, Michele A.; Kansal, Kari; McEvoy, Maureen P.; Merrill, Andrea L.; Rai, Upahvan; Smith, Barbara L.] Massachusetts Gen Hosp, Gillette Ctr Womens Canc, Div Surg Oncol, Boston, MA 02114 USA. [Tang, Rong] Cent S Univ, Xiangya Med Sch, Affiliated Tumor Hosp, Div Breast Surg,Hunan Canc Hosp, Changsha, Hunan, Peoples R China. [Colwell, Amy S.; Austen, William G.] Massachusetts Gen Hosp, Div Plast Surg, Boston, MA 02114 USA. [Taghian, Alphonse] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Tang, R (reprint author), Massachusetts Gen Hosp, Gillette Ctr Womens Canc, Div Surg Oncol, Boston, MA 02114 USA. EM blsmith1@partners.org NR 15 TC 12 Z9 12 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 OCT PY 2015 VL 22 IS 10 BP 3331 EP 3337 DI 10.1245/s10434-015-4669-y PG 7 WC Oncology; Surgery SC Oncology; Surgery GA CQ0RF UT WOS:000360303800027 PM 26202557 ER PT J AU McEvoy, MP Coopey, SB Mazzola, E Buckley, J Belli, A Polubriaginof, F Merrill, AL Tang, R Garber, JE Smith, BL Gadd, MA Specht, MC Guidi, AJ Roche, CA Hughes, KS AF McEvoy, Maureen P. Coopey, Suzanne B. Mazzola, Emanuele Buckley, Julliette Belli, Ahmet Polubriaginof, Fernanda Merrill, Andrea L. Tang, Rong Garber, Judy E. Smith, Barbara L. Gadd, Michele A. Specht, Michelle C. Guidi, Anthony J. Roche, Constance A. Hughes, Keven S. TI Breast Cancer Risk and Follow-up Recommendations for Young Women Diagnosed with Atypical Hyperplasia and Lobular Carcinoma In Situ (LCIS) SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID DISEASE; MAMMOGRAPHY; TAMOXIFEN; ULTRASOUND; MRI AB Background. The risk of breast cancer in young women diagnosed with atypical hyperplasia and (LCIS) is not well defined. The objectives were to evaluate outcomes and to help determine guidelines for follow-up in this population. Methods. A retrospective review of women under age 35 diagnosed with ADH, ALH, LCIS, and severe ADH from 1987 to 2010 was performed. Patient characteristics, pathology and follow-up were determined from chart review. Results. We identified 58 young women with atypical breast lesions. Median age at diagnosis was 31 years (range 19-34). 34 patients had ADH, 11 had ALH, 8 had LCIS, and 5 had severe ADH. 7 (12%) patients developed breast cancer. The median follow-up was 86 months (range 1-298). Median time to cancer diagnosis was 90 months (range 37-231). 4 cancers were on the same side, 3 were contralateral. 4 were IDC, 1 was ILC, and 2 were DCIS. Cancer was detected by screening mammogram in 4 patients, 2 by clinical exam, and 1 unknown. In the entire cohort, 26 (45%) patients had screening mammograms as part of their follow up, 12 patients had only clinical follow up, and 20 had no additional follow up. 13 patients required subsequent biopsies. Conclusion. Young women with atypical breast lesions are at a markedly increased risk for developing breast cancer and should be followed closely. Based on our findings, we recommend close clinical follow-up, MRI starting at age 25 through age 29, and screening mammograms for those over 30 in this high-risk group of patients. C1 [McEvoy, Maureen P.; Coopey, Suzanne B.; Mazzola, Emanuele; Buckley, Julliette; Belli, Ahmet; Polubriaginof, Fernanda; Merrill, Andrea L.; Tang, Rong; Garber, Judy E.; Smith, Barbara L.; Gadd, Michele A.; Specht, Michelle C.; Guidi, Anthony J.; Roche, Constance A.; Hughes, Keven S.] Massachusetts Gen Hosp, Dept Surg Oncol, Breast Surg Div, Boston, MA 02114 USA. RP McEvoy, MP (reprint author), Massachusetts Gen Hosp, Dept Surg Oncol, Breast Surg Div, Boston, MA 02114 USA. EM mcevoy.maureen@gmail.com NR 20 TC 3 Z9 3 U1 1 U2 10 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 OCT PY 2015 VL 22 IS 10 BP 3346 EP 3349 DI 10.1245/s10434-015-4747-1 PG 4 WC Oncology; Surgery SC Oncology; Surgery GA CQ0RF UT WOS:000360303800029 PM 26242364 ER PT J AU Mallory, MA Losk, K Lin, NU Sagara, Y Birdwell, RL Cutone, L Camuso, K Bunnell, C Aydogan, F Golshan, M AF Mallory, Melissa Anne Losk, Katya Lin, Nancy U. Sagara, Yasuaki Birdwell, Robyn L. Cutone, Linda Camuso, Kristen Bunnell, Craig Aydogan, Fatih Golshan, Mehra TI The Influence of Radiology Image Consultation in the Surgical Management of Breast Cancer Patients SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID DIAGNOSTIC MAMMOGRAPHY; 2ND OPINIONS; VARIABILITY; IMPACT AB Patients referred to comprehensive cancer centers arrive with clinical data requiring review. Radiology consultation for second opinions often generates additional imaging requests; however, the impact of this service on breast cancer management remains unclear. We sought to identify the incidence of additional imaging requests and the effect additional imaging has on patients' ultimate surgical management. Between November 2013 and March 2014, 153 consecutive patients with breast cancer received second opinion imaging reviews and definitive surgery at our cancer center. We identified the number of additional imaging requests, the number of fulfilled requests, the modality of additional imaging completed, the number of biopsies performed, and the number of patients whose management was altered due to additional imaging results. Of 153 patients, the mean age was 55 years; 98.9 % were female; 23.5 % (36) had in situ carcinoma (35 DCIS/1 LCIS), and 76.5 % (117) had invasive carcinoma. Additional imaging was suggested for 47.7 % (73/153) of patients. After multidisciplinary consultation, 65.8 % (48/73) of patients underwent additional imaging. Imaging review resulted in biopsy in 43.7 % (21/48) of patients and ultimately altered preliminary treatment plans in 37.5 % (18/48) of patients (Fig. 1). Changes in management included: conversion to mastectomy or breast conservation, neoadjuvant therapy, additional wire placement, and need for contralateral breast surgery. Our analysis of second opinion imaging consultation demonstrates the significant value that this service has on breast cancer management. Overall, 11.7 % (18/153) of patients who underwent breast surgery had management changes as a consequence of radiologic imaging review. C1 [Mallory, Melissa Anne; Sagara, Yasuaki; Cutone, Linda; Aydogan, Fatih; Golshan, Mehra] Dana Farber Brigham & Womens Canc Ctr, Dept Surg, Boston, MA 02115 USA. [Losk, Katya; Camuso, Kristen] Dana Farber Canc Inst, Dept Qual & Patient Safety, Boston, MA 02115 USA. [Lin, Nancy U.; Bunnell, Craig] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Birdwell, Robyn L.] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. RP Mallory, MA (reprint author), Dana Farber Brigham & Womens Canc Ctr, Dept Surg, Boston, MA 02115 USA. EM mgolshan@partners.org FU NIH [R25CA089017]; National Comprehensive Cancer Network (NCCN) FX This study was funded in part by the NIH Grant R25CA089017 and by the National Comprehensive Cancer Network (NCCN) Opportunities for Improvement grant. NR 14 TC 3 Z9 3 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD OCT PY 2015 VL 22 IS 10 BP 3383 EP 3388 DI 10.1245/s10434-015-4663-4 PG 6 WC Oncology; Surgery SC Oncology; Surgery GA CQ0RF UT WOS:000360303800035 PM 26202551 ER PT J AU Bolon-Canedo, V Ataer-Cansizoglu, E Erdogmus, D Kalpathy-Cramer, J Fontenla-Romero, O Alonso-Betanzos, A Chiang, MF AF Bolon-Canedo, V. Ataer-Cansizoglu, E. Erdogmus, D. Kalpathy-Cramer, J. Fontenla-Romero, O. Alonso-Betanzos, A. Chiang, M. F. TI Dealing with inter-expert variability in retinopathy of prematurity: A machine learning approach SO COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE LA English DT Article DE Inter-expert variability; Clinical decision-making; Feature selection; Machine learning; Classification; Retinopathy of prematurity ID PLUS DISEASE; INTRAOBSERVER VARIABILITY; FEATURE-SELECTION; DIAGNOSIS; INTEROBSERVER; AGREEMENT; CLASSIFICATION; PATHOLOGISTS AB Background and objective: Understanding the causes of disagreement among experts in clinical decision making has been a challenge for decades. In particular, a high amount of variability exists in diagnosis of retinopathy of prematurity (ROP), which is a disease affecting low birth weight infants and a major cause of childhood blindness. A possible cause of variability, that has been mostly neglected in the literature, is related to discrepancies in the sets of important features considered by different experts. In this paper we propose a methodology which makes use of machine learning techniques to understand the underlying causes of inter-expert variability. Methods: The experiments are carried out on a dataset consisting of 34 retinal images, each with diagnoses provided by 22 independent experts. Feature selection techniques are applied to discover the most important features considered by a given expert. Those features selected by each expert are then compared to the features selected by other experts by applying similarity measures. Finally, an automated diagnosis system is built in order to check if this approach can be helpful in solving the problem of understanding high inter-rater variability. Results: The experimental results reveal that some features are mostly selected by the feature selection methods regardless the considered expert. Moreover, for pairs of experts with high percentage agreement among them, the feature selection algorithms also select similar features. By using the relevant selected features, the classification performance of the automatic system was improved or maintained. Conclusions: The proposed methodology provides a handy framework to identify important features for experts and check whether the selected features reflect the pairwise agreements/disagreements. These findings may lead to improved diagnostic accuracy and standardization among clinicians, and pave the way for the application of this methodology to other problems which present inter-expert variability. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Bolon-Canedo, V.; Fontenla-Romero, O.; Alonso-Betanzos, A.] Univ A Coruna, Dept Comp Sci, La Coruna, Spain. [Ataer-Cansizoglu, E.; Erdogmus, D.] Northeastern Univ, Cognit Syst Lab, Boston, MA USA. [Kalpathy-Cramer, J.] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Chiang, M. F.] Oregon Hlth & Sci Univ, Dept Ophthalmol & Med Informat, Portland, OR 97201 USA. [Chiang, M. F.] Oregon Hlth & Sci Univ, Dept Clin Epidemiol, Portland, OR 97201 USA. RP Bolon-Canedo, V (reprint author), Univ A Coruna, Dept Comp Sci, La Coruna, Spain. EM vbolon@udc.es RI Alonso-Betanzos, Amparo/K-5057-2014; Fontenla-Romero, Oscar/A-1142-2015; Bolon-Canedo, Veronica/A-5573-2015; OI Alonso-Betanzos, Amparo/0000-0003-0950-0012; Fontenla-Romero, Oscar/0000-0003-4203-8720; Bolon-Canedo, Veronica/0000-0002-0524-6427; Kalpathy-Cramer, Jayashree/0000-0001-8906-9618 FU Secretaria de Estado de Investigacion of the Spanish Government - FEDER funds of the European Union [TIN 2012-37954]; Xunta de Galicia - FEDER funds of the European Union [GRC 2014/035]; NSF [IIS-1118061, IIS-1149570, SMA-0835976, CNS-1136027]; NLM/NIH [R00LM009889]; NIH [EY19474, 1R21EY022387-01A1]; Research to Prevent Blindness; Xunta de Galicia [POS-A/2014/164] FX This research has been financially supported in part by the Secretaria de Estado de Investigacion of the Spanish Government through the research project TIN 2012-37954, and by the Xunta de Galicia through the research project GRC 2014/035, both of them partially funded by FEDER funds of the European Union. Also supported by grants IIS-1118061, IIS-1149570, SMA-0835976, CNS-1136027 from NSF, grant R00LM009889 from the NLM/NIH; by grants EY19474 and 1R21EY022387-01A1 from the NIH, and by unrestricted departmental funding from Research to Prevent Blindness. V. Bolon-Canedo acknowledges the support of Xunta de Galicia under posdoctoral Grant code POS-A/2014/164. M.F. Chiang is an unpaid member of the Scientific Advisory Board for Clarity Medical Systems (Pleasanton, CA). NR 50 TC 4 Z9 4 U1 1 U2 11 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0169-2607 EI 1872-7565 J9 COMPUT METH PROG BIO JI Comput. Meth. Programs Biomed. PD OCT PY 2015 VL 122 IS 1 BP 1 EP 15 DI 10.1016/j.cmpb.2015.06.004 PG 15 WC Computer Science, Interdisciplinary Applications; Computer Science, Theory & Methods; Engineering, Biomedical; Medical Informatics SC Computer Science; Engineering; Medical Informatics GA CP7ZV UT WOS:000360110100001 PM 26120072 ER PT J AU Bowen, ME Ruch, A AF Bowen, Mary Elizabeth Ruch, Alexandra TI Depressive Symptoms and Disability Risk Among Older White and Latino Adults by Nativity Status SO JOURNAL OF AGING AND HEALTH LA English DT Article DE minority health; depression; activities of daily living (ADL); instrumental activities of daily living (IADL); health paradox ID MEXICAN-AMERICANS; RACIAL/ETHNIC DIFFERENCES; FUNCTIONAL LIMITATIONS; PHYSICAL-DISABILITY; HISPANIC IMMIGRANTS; HEALTH; US; COMMUNITY; ACCULTURATION; PREVALENCE AB Objective: To examine how the relationship between depressive symptoms and disability may vary by nativity status in later life. Method: This nationally representative prospective study of community-dwelling adults age 51 years and older in the Health and Retirement Study (1998-2010) used hierarchical linear modeling to examine how depressive symptoms (Center for Epidemiological Symptoms of Depression) and disability (instrumental activities of daily living [IADL]; activities of daily living [ADL]) vary by nativity status (U.S.- vs. foreign-born), accounting for changes in social support, health behaviors, and health conditions. Results: Depressive symptoms were associated with increased IADL and ADL disability among Latinos compared with Whites; foreign-born Latinos had lower than expected depressive symptom-related IADL and ADL (0.82; p .001) disability. Discussion: Given that U.S.-born Latinos had similar or poorer depressive symptom-related disability outcomes than Whites, interventions focused on early detection and treatment of depressive symptoms for this group are warranted and may improve disablement outcomes. C1 [Bowen, Mary Elizabeth] Philadelphia VA Med Ctr, Philadelphia, PA 19104 USA. [Bowen, Mary Elizabeth; Ruch, Alexandra] West Chester Univ Penn, W Chester, PA USA. RP Bowen, ME (reprint author), Philadelphia VA Med Ctr, 3900 Woodland Ave, Philadelphia, PA 19104 USA. EM Mary.Bowen3@va.gov FU Department of Veterans Affairs, Rehabilitation Research and Development [RRD CDA E7503W] FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Dr. Bowen is supported by the Department of Veterans Affairs, Rehabilitation Research and Development (RR&D CDA E7503W). NR 41 TC 1 Z9 1 U1 3 U2 6 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0898-2643 EI 1552-6887 J9 J AGING HEALTH JI J. Aging Health PD OCT PY 2015 VL 27 IS 7 BP 1286 EP 1305 DI 10.1177/0898264315580121 PG 20 WC Gerontology; Health Policy & Services SC Geriatrics & Gerontology; Health Care Sciences & Services GA CQ2CI UT WOS:000360406600008 PM 25953809 ER PT J AU Liu, WH Ren, LN Wang, X Wang, T Zhang, N Gao, Y Luo, H Navarro-Alvarez, N Tang, LJ AF Liu, Wei-hui Ren, Li-na Wang, Xing Wang, Tao Zhang, Ning Gao, Yuan Luo, Hao Navarro-Alvarez, Nalu Tang, Li-jun TI Combination of exosomes and circulating microRNAs may serve as a promising tumor marker complementary to alpha-fetoprotein for early-stage hepatocellular carcinoma diagnosis in rats SO JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY LA English DT Article DE Hepatocellular carcinoma (HCC); Alpha-fetoprotein (AFP); Circulating miRNAs; Exosomes; Molecular diagnosis ID STEM/PROGENITOR CELLS DIFFERENTIATION; EXPRESSION; HEPATITIS; BIOMARKER; HEPATOCYTES; PROGRESSION; PROGNOSIS; TISSUES; NOTCH; GENE AB Due to unsatisfying prognosis of AFP for hepatocellular carcinoma (HCC), we aim to evaluate the prognostic value of combination of exosomes and miRNAs in detecting HCC. HCC was induced with diethylnitrosamine in rats and using a scoring system based on histological examination six different stages (normal liver, degeneration, fibrosis, cirrhosis, early HCC and late HCC) were identified in the development of HCC. The expression levels of AFP, exosomes and miRNAs (miRNA-10b, miRNA-21, miRNA-122 and miRNA-200a) were detected in both tissue and blood samples from those six stages. Receiver operating characteristic (ROC) curve analysis was conducted to evaluate the power of each parameter and their different combinations in diagnosing HCC or cirrhosis. A change in the expression of both exosomes and miRNAs was observed during cirrhosis, which in contrast with AFP starts showing up until the early HCC stage. Interestingly, the expressions of exosomes and the selected four miRNAs at early HCC stage obtained more remarkably alterations than the level of AFP (P < 0.05). On correlation analysis, four selected miRNAs had a significant closer relationship with exosomes when compared with AFP. The different combinations of AFP, exosomes, serous miRNAs and exosomal miRNAs had stronger power in predicting HCC than AFP (area under the curve of ROC, 0.943 vs 0.826). To conclude, the combination of circulating miRNAs and exosomes might serve as promising biomarkers for non-virus infected HCC screening and cirrhosis discrimination. C1 [Liu, Wei-hui; Ren, Li-na; Wang, Tao; Luo, Hao; Tang, Li-jun] Chengdu Mil Gen Hosp, Gen Surg Ctr PLA, Chengdu 610083, Sichuan Provinc, Peoples R China. [Wang, Xing; Zhang, Ning; Gao, Yuan] Xijing Hosp, Gen Surg Ctr, Xian 710032, Shanxi Province, Peoples R China. [Navarro-Alvarez, Nalu] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Liu, WH (reprint author), Chengdu Mil Gen Hosp, Gen Surg Ctr PLA, Chengdu 610083, Sichuan Provinc, Peoples R China. EM audiliu12@163.com; whjtlj1251@163.com NR 41 TC 8 Z9 10 U1 0 U2 16 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 OCT PY 2015 VL 141 IS 10 BP 1767 EP 1778 DI 10.1007/s00432-015-1943-0 PG 12 WC Oncology SC Oncology GA CP7QS UT WOS:000360083600007 PM 25724413 ER PT J AU Zemer-Wassercug, N Haim, M Leshem-Lev, D Orvin, KL Vaduganathan, M Gutstein, A Kadmon, E Mager, A Kornowski, R Lev, EL AF Zemer-Wassercug, Noa Haim, Moti Leshem-Lev, Dorit Orvin, Katia L. Vaduganathan, Muthiah Gutstein, Ariel Kadmon, Ehud Mager, Aviv Kornowski, Ran Lev, Eli L. TI The effect of dabigatran and rivaroxaban on platelet reactivity and inflammatory markers SO JOURNAL OF THROMBOSIS AND THROMBOLYSIS LA English DT Article DE Anticoagulation; Atrial fibrillation; Platelet reactivity ID NONVALVULAR ATRIAL-FIBRILLATION; UNFRACTIONATED HEPARIN; STROKE PREVENTION; REPERFUSION INJURY; RISK-FACTORS; P-SELECTIN; WARFARIN; THROMBIN; BIVALIRUDIN; INHIBITION AB The new oral anticoagulants (NOACs) reduce stroke and systemic embolism in patients with non-valvular atrial fibrillation (AF), but dabigatran may increase risk of coronary ischemic events for unclear reasons. Thus, this study assessed the effects of dabigatran and rivaroxaban on platelet reactivity and inflammatory markers in patients with non-valvular AF. Patients with non-valvular AF planned to begin treatment with NOACs were included. Seventeen patients were prescribed dabigatran and ten rivaroxaban. Platelet function (as assessed by multiple-electrode aggregometry, Impact-R shear-induced platelet deposition, P-selectin expression and plasma RANTES levels) and high-sensitivity C-reactive protein (hs-CRP) were measured at enrollment (prior to initiation of NOAC treatment) and at least 7 days into treatment with either dabigratran or rivaroxaban. Seventeen patients treated with dabigatran (mean age 69 +/- A 7 years, 35 % women, mean CHADS2 score 2.6 +/- A 1.2), and ten patients treated with rivaroxaban (mean age 73 +/- A 9 years, 20 % women, mean CHADS2 score 2.7 +/- A 1.6) completed the study. In both groups, there were no significant differences in platelet reactivity between the baseline and on-anticoagulant treatment time-points, as measured by each of the platelet-specific assays. There was a trend towards increased platelet reactivity in response to arachidonic acid from baseline to on-treatment in both groups, probably as a result of aspirin discontinuation in 33 % of patients. No significant differences were noted between baseline and on-treatment in hs-CRP in both anticoagulant groups. Treatment with dabigatran and rivaroxaban does not appear to be associated with changes in markers of platelet reactivity or systemic inflammation. C1 [Zemer-Wassercug, Noa; Orvin, Katia L.; Gutstein, Ariel; Kadmon, Ehud; Mager, Aviv; Kornowski, Ran; Lev, Eli L.] Rabin Med Ctr, Dept Cardiol, Petah Tiqwa, Israel. [Zemer-Wassercug, Noa; Haim, Moti; Leshem-Lev, Dorit; Orvin, Katia L.; Gutstein, Ariel; Kadmon, Ehud; Mager, Aviv; Kornowski, Ran; Lev, Eli L.] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. [Haim, Moti] Meir Med Ctr, Dept Cardiol, Kefar Sava, Israel. [Leshem-Lev, Dorit] Rabin Med Ctr, Felsenstein Med Res Ctr, Petah Tiqwa, Israel. [Vaduganathan, Muthiah] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA USA. RP Lev, EL (reprint author), Rabin Med Ctr, Dept Cardiol, Petah Tiqwa, Israel. EM elil@clalit.org.il RI Haim, Moti/K-7381-2014 FU Rabin Medical Center FX Rabin Medical Center. NR 37 TC 6 Z9 6 U1 0 U2 6 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 OCT PY 2015 VL 40 IS 3 BP 340 EP 346 DI 10.1007/s11239-015-1245-z PG 7 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA CP9DF UT WOS:000360193200013 PM 26184605 ER PT J AU Suchomelova, L Lopez-Meraz, ML Niquet, J Kubova, H Wasterlain, CG AF Suchomelova, L. Lopez-Meraz, M. L. Niquet, J. Kubova, H. Wasterlain, C. G. TI HYPERTHERMIA AGGRAVATES STATUS EPILEPTICUS-INDUCED EPILEPTOGENESIS AND NEURONAL LOSS IN IMMATURE RATS SO NEUROSCIENCE LA English DT Article DE neuronal injury; temperature; immature brain; lithium/pilocarpine model; EEG monitoring ID TEMPORAL-LOBE EPILEPSY; PROLONGED FEBRILE SEIZURES; UNBIASED STEREOLOGICAL ESTIMATION; HYPOXIC-ISCHEMIC ENCEPHALOPATHY; LITHIUM-PILOCARPINE MODEL; ACID-INDUCED SEIZURES; NEONATAL ENCEPHALOPATHY; BRAIN-DAMAGE; LONG-TERM; HIPPOCAMPAL EXCITABILITY AB This study tightly controlled seizure duration and severity during status epilepticus (SE) in postnatal day 10 (P10) rats, in order to isolate hyperthermia as the main variable and to study its consequences. Body temperature was maintained at 39 +/- 1 degrees C in hyperthermic SE rats (HT + SE) or at 35 +/- 1 degrees C in normothermic SE animals (NT + SE) during 30 min of SE, which was induced by lithium-pilocarpine (3 mEq/kg, 60 mg/kg) and terminated by diazepam and cooling to NT. All video/EEG measures of SE severity were similar between HT + SE and NT + SE pups. At 24 h, neuronal injury was present in the amygdala in the HT + SE group only, and was far more severe in the hippocampus in HT + SE than NT + SE pups. Separate groups of animals were monitored four months later for spontaneous recurrent seizures (SRS). Only HT + SE animals developed convulsive SRS. Both HT + SE and NT + SE animals developed electrographic SRS (83% vs. 55%), but SRS frequency and severity were higher in hyperthermic animals (12.5 +/- 3.5 vs. 4.2 +/- 2.0 SRS/day). The density of hilar neurons was lower, thickness of the amygdala and perirhinal cortex was reduced, and lateral ventricles were enlarged in HT + SE over NT + SE littermates and HT/NT controls. In this model, hyperthermia greatly increased the epileptogenicity of SE and its neuropathological sequelae. (C) 2015 IBRO. Published by Elsevier Ltd. All rights reserved. C1 [Suchomelova, L.; Niquet, J.] Vet Adm Greater Los Angeles Healthcare Syst, Epilepsy Res 151, Los Angeles, CA 90073 USA. [Lopez-Meraz, M. L.] Univ Veracruzana, Ctr Invest Cerebrales, Xalapa 91190, Veracruz, Mexico. [Kubova, H.] Acad Sci Czech Republic, Inst Physiol, Dept Dev Epileptol, CR-14220 Prague, Czech Republic. [Wasterlain, C. G.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, VA Med Ctr 127, Los Angeles, CA 90073 USA. RP Suchomelova, L (reprint author), Vet Adm Greater Los Angeles Healthcare Syst, 11 301 Wilshire Blvd,Bldg 114,Room 139, Los Angeles, CA 90073 USA. EM lsuchomelova@yahoo.com RI Kubova, Hana/C-4210-2012 OI Kubova, Hana/0000-0002-2016-7428 FU VHA Research Service; National Institute of Health [NS13515, NS059704, NS074926]; Grant Agency of the Czech Republic [P302/10/0971]; Ministry of Education of the Czech Republic [ME08045, LC554]; [AV0Z50110509]; [RVO 67985823] FX This work was supported by VHA Research Service, National Institute of Health [NS13515, NS059704, NS074926 to C.W.]; Grant Agency of the Czech Republic [P302/10/0971 to H.K.]; Ministry of Education of the Czech Republic [ME08045, LC554 to H.K.], and Research Project [AV0Z50110509 and RVO 67985823 to H.K.]. NR 88 TC 2 Z9 2 U1 2 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 EI 1873-7544 J9 NEUROSCIENCE JI Neuroscience PD OCT 1 PY 2015 VL 305 BP 209 EP 224 DI 10.1016/j.neuroscience.2015.08.006 PG 16 WC Neurosciences SC Neurosciences & Neurology GA CQ4AT UT WOS:000360547100019 PM 26259902 ER PT J AU Brunetto, AL Castillo, LA Petrilli, AS Macedo, CD Boldrini, E Costa, C Almeida, MT Kirst, D Rodriguez-Galindo, C Pereira, WV Watanabe, FM Pizza, M Benites, E Morais, V Gadelha, A Nakasato, A Abujamra, AL Gregianin, LJ AF Brunetto, Algemir L. Castillo, Luis A. Petrilli, Antonio S. Macedo, Carla D. Boldrini, Erica Costa, Cecilia Almeida, Maria T. Kirst, Daniela Rodriguez-Galindo, Carlos Pereira, Waldir V. Watanabe, Flora M. Pizza, Maria Benites, Eliana Morais, Vera Gadelha, Andrea Nakasato, Antonio Abujamra, Ana L. Gregianin, Lauro J. CA Brazilian Collaborative Brazilian Collaborative Study Grp Brazilian Soc Pediat Oncol-SOBOPE TI Carboplatin in the treatment of Ewing sarcoma: Results of the first Brazilian collaborative study group for Ewing sarcoma family tumors-EWING1 SO PEDIATRIC BLOOD & CANCER LA English DT Article DE Ewing/PNET; metastatic disease; VDC/ICE ID CHILDRENS ONCOLOGY GROUP; PRIMITIVE NEUROECTODERMAL TUMOR; PROGNOSTIC-FACTORS; STANDARD CHEMOTHERAPY; HOSPITAL EXPERIENCE; SOLID TUMORS; BONE; CONTROVERSIES; IFOSFAMIDE; GUIDELINES AB BackgroundLarge cooperative group studies have shown the efficacy of risk-adapted treatment for Ewing sarcoma. However, validation and local adaptation by National cooperative groups is needed. A multicenter protocol to determine the efficacy and safety of a risk-adapted intensive regimen was developed by the Brazilian cooperative group. ProcedurePatients <30 years old with Ewing sarcoma were eligible. Induction chemotherapy consisted of two cycles of ICE (ifosfamide, carboplatin, and etoposide) followed by two cycles of VDC (vincristine, doxorubicin, and cyclophosphamide), followed by local control. Patients with low risk (LR) disease (localized resectable with normal LDH) received 10 additional alternating courses of IE with VDC. For patients with high-risk (HR) disease (unresectable, pelvic, metastatic, or high LDH), two additional cycles of ICE were given. ResultsOne-hundred seventy five patients (39% metastatic) were enrolled. Fifty-two patients (29.7%) were LR and 123 (70.3%) were HR. Overall response rate at end of induction was 27.4%. Five-year event-free survival (EFS) and overall survival (OS) estimates were 51.4% and 54.4%, respectively. Patients with localized disease had better outcomes than patients with metastases (5-year EFS 67.9% vs. 25.5%, and 5-year OS 70.3% vs. 29.1%, respectively). On multivariate analysis, the presence of metastatic disease was the only prognostic factor (P<0.01). ConclusionThe VDC/ICE protocol was feasible, and considering the high tumor burden in our population, resulted in comparable results to those reported by cooperative groups in high-income countries. Further adaptation to maximize efficacy and minimize toxicity will be required. Pediatr Blood Cancer 2015;62:1747-1753. (c) 2015 Wiley Periodicals, Inc. C1 [Brunetto, Algemir L.; Abujamra, Ana L.] Childrens Canc Inst, Porto Alegre, RS, Brazil. [Castillo, Luis A.] Hosp Pereira Rossell, Montevideo, Uruguay. [Petrilli, Antonio S.; Macedo, Carla D.] Univ Fed Sao Paulo, Dept Pediat, Pediat Oncol Inst IOP GRAACC UNIFESP, Sao Paulo, SP, Brazil. [Boldrini, Erica] Fundacao Pio XII Hosp Infantojuvenil, Barretos, SP, Brazil. [Costa, Cecilia] Hosp Canc AC Camargo, Sao Paulo, SP, Brazil. [Almeida, Maria T.] Hosp Clin Sao Paulo ITACI, Sao Paulo, SP, Brazil. [Kirst, Daniela] Hosp Crianca Santo Antonio, Porto Alegre, RS, Brazil. [Rodriguez-Galindo, Carlos] Dana Farber Canc Inst, Boston, MA 02115 USA. [Pereira, Waldir V.] Hosp Univ Santa Maria, Santa Maria, RS, Brazil. [Watanabe, Flora M.] Hosp Infantil Pequeno Principe, Curitiba, PR, Brazil. [Pizza, Maria] Santa Casa Misercordia Sao Paulo, Sao Paulo, SP, Brazil. [Benites, Eliana] Inst Clin Pediat Bolivar Risso, Jundia, SP, Brazil. [Morais, Vera] Hosp Univ Oswaldo Cruz, Recife, PE, Brazil. [Gadelha, Andrea] Hosp Napoleao Laureano, Joao Pessoa, Paraiba, Brazil. [Nakasato, Antonio] Univ Fed Rio de Janeiro, Inst Pediat, Rio de Janeiro, RJ, Brazil. [Gregianin, Lauro J.] Hosp Sao Lucas PUC RS, Porto Alegre, RS, Brazil. [Gregianin, Lauro J.] Univ Fed Rio Grande do Sul, Dept Pediat, Hosp Clin Porto Alegre, Porto Alegre, RS, Brazil. RP Gregianin, LJ (reprint author), Hosp Clin Porto Alegre, Rua Ramiro Barcelos 2350,3 Leste Pediat Oncol, Porto Alegre, RS, Brazil. EM Igregianin@hcpa.ufrgs.br FU Children's Cancer Institute FX Grant sponsor: The Children's Cancer Institute NR 29 TC 2 Z9 2 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD OCT PY 2015 VL 62 IS 10 BP 1747 EP 1753 DI 10.1002/pbc.25562 PG 7 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA CP9PY UT WOS:000360228000011 PM 25917418 ER PT J AU Meyersohn, NM Walker, TG Oliveira, GR AF Meyersohn, Nandini M. Walker, T. Gregory Oliveira, George R. TI Advances in Axial Imaging of Peripheral Vascular Disease SO CURRENT CARDIOLOGY REPORTS LA English DT Review DE Peripheral artery disease; Peripheral vascular disease; Atherosclerosis; Arterial stenosis; Computed tomography angiography; Magnetic resonance angiography; Non-contrast angiography ID COMPUTED-TOMOGRAPHY ANGIOGRAPHY; ROW CT ANGIOGRAPHY; ENHANCED MR-ANGIOGRAPHY; DIGITAL-SUBTRACTION-ANGIOGRAPHY; MAGNETIC-RESONANCE ANGIOGRAPHY; RANDOMIZED CONTROLLED-TRIAL; ARTERIAL-DISEASE; LOWER-EXTREMITY; DIAGNOSTIC PERFORMANCE; OCCLUSIVE DISEASE AB Peripheral artery disease (PAD) has become increasingly common in the US patient population and can be a highly symptomatic and significant source of morbidity. When PAD is suspected, the first-line screening study that is obtained is typically a noninvasive evaluation that includes the ankle brachial index (ABI). Following a positive screening study, invasive catheter digital subtraction angiography (DSA) has been historically used to image the peripheral artery system and still remains the gold standard. However, newer developments in axial imaging including computed tomography angiography (CTA) and magnetic resonance angiography (MRA) have in large part supplanted DSA for imaging the peripheral artery system in clinical practice. Benefits of CTA include rapid noninvasive acquisition, wide availability, high spatial resolution, and the ability to generate isotropic datasets on 64-detector row and higher CT scanners, thereby allowing for multiplanar 3D reformatting. Drawbacks of CTA include the exposure to both iodinated contrast and ionizing radiation, although the radiation dose exposure is lower than for DSA, and newer techniques such as using low tube voltage and rapid acquisition times allow for lower contrast doses. The presence of vascular calcification also limits the evaluation of small distal arteries using CTA, although the development of dual-energy CT techniques has significantly addressed this issue. Benefits of MRA include the avoidance of exposure to ionizing radiation and high diagnostic accuracy, while drawbacks include limited availability and increased cost along with the risk of nephrogenic systemic fibrosis that is associated with gadolinium-based contrast agents, although the latter can be mitigated by using newer non-contrast MR angiography techniques. Future technical advances in CT and MR hardware and software and MR pulse sequences will likely lead to the broader applicability and increased accuracy of noninvasive axial imaging in the evaluation of patients with peripheral artery disease. C1 [Meyersohn, Nandini M.; Oliveira, George R.] Massachusetts Gen Hosp, Div Cardiovasc Imaging, Boston, MA 02114 USA. [Walker, T. Gregory; Oliveira, George R.] Massachusetts Gen Hosp, Div Intervent Radiol, Boston, MA 02114 USA. RP Meyersohn, NM (reprint author), Massachusetts Gen Hosp, Div Cardiovasc Imaging, Boston, MA 02114 USA. EM nmeyersohn@mgh.harvard.edu; tgwalker@mgh.harvard.edu; groliveira@mgh.harvard.edu NR 28 TC 0 Z9 0 U1 0 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3782 EI 1534-3170 J9 CURR CARDIOL REP JI Curr. Cardiol. Rep. PD OCT PY 2015 VL 17 IS 10 AR 87 DI 10.1007/s11886-015-0644-2 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP4OV UT WOS:000359862800009 PM 26285590 ER PT J AU Takatani, R Minagawa, M Molinaro, A Reyes, M Kinoshita, K Takatani, T Kazukawa, I Nagatsuma, M Kashimada, K Sato, K Matsushita, K Nomura, F Shimojo, N Juppner, H AF Takatani, Rieko Minagawa, Masanori Molinaro, Angelo Reyes, Monica Kinoshita, Kaori Takatani, Tomozumi Kazukawa, Itsuro Nagatsuma, Misako Kashimada, Kenichi Sato, Kenichi Matsushita, Kazuyuki Nomura, Fumio Shimojo, Naoki Jueppner, Harald TI Similar frequency of paternal uniparental disomy involving chromosome 20q (patUPD20q) in Japanese and Caucasian patients affected by sporadic pseudohypoparathyroidism type Ib (sporPHP1B) SO BONE LA English DT Article DE Pseudohypoparathyroidism; Parathyroid hormone; Epigenetic; GNAS; Uniparental disomy ID BECKWITH-WIEDEMANN-SYNDROME; IMPRINTING CONTROL ELEMENT; SILVER-RUSSELL-SYNDROME; AUTOSOMAL-DOMINANT; HEREDITARY OSTEODYSTROPHY; EPIGENETIC DEFECTS; GNAS LOCUS; NEURONATIN; DELETION; GENE AB Pseudohypoparathyroidism type Ib (PHP1B) is caused by proximal tubular resistance to parathyroid hormone that occurs in most cases in the absence of Albright's Hereditary Osteodystrophy (AHO). Familial forms of PHP1B are caused by maternally inherited microdeletions within STX16, the gene encoding syntaxin 16, or within GNAS, a complex genetic locus on chromosome 20q133 encoding Gs alpha and several splice variants thereof. These deletions lead either to a loss-of-methylation affecting GNAS exon A/B alone or to epigenetic changes involving multiple differentially methylated regions (DMRs) within GNAS. Broad GNAS methylation abnormalities are also observed in most sporadic PHP1B (sporPHP1B) cases. However, with the exception of paternal uniparental disomy involving chromosome 20q (patUPD20q), the molecular mechanism leading to this disease variant remains unknown. We now investigated 23 Japanese sporPHP1B cases, who presented with hypocalcemia, hyperphosphatemia, elevated PTH levels, and occasionally with TSH elevations and mild AHO features. Age at diagnosis was 10.6 +/- 1.45 years. Calcium, phosphate, and PTH were 63 +/- 023 mg/dL, 7.7 +/- 0.33 mg/dL, and 305 +/- 34.5 pg/mL, respectively, i.e. laboratory findings that are indistinguishable from those previously observed for Caucasian sporPHP1B cases. All investigated patients showed broad GNAS methylation changes. Eleven individuals were homozygous for SNPs within exon NESP and a pentanucleotide repeat in exon A/B. Two of these patients furthermore revealed homozygosity for numerous microsatellite markers on chromosome 20q raising the possibility of patUPD20q, which was confirmed through the analysis of parental DNA. Based on this and our previous reports, paternal duplication of the chromosomal region comprising the GNAS locus appears to be a fairly common cause of sporPHP1B that is likely to occur with equal frequency in Caucasians and Asians. (C) 2015 Elsevier Inc. All rights reserved. C1 [Takatani, Rieko; Molinaro, Angelo; Reyes, Monica; Jueppner, Harald] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Takatani, Rieko; Molinaro, Angelo; Reyes, Monica; Jueppner, Harald] Harvard Univ, Sch Med, Endocrine Unit, Boston, MA USA. [Takatani, Rieko; Minagawa, Masanori; Takatani, Tomozumi; Kazukawa, Itsuro; Shimojo, Naoki] Chiba Univ, Grad Sch Med, Dept Pediat, Chiba, Japan. [Minagawa, Masanori; Kazukawa, Itsuro] Chiba Childrens Hosp, Dept Endocrinol, Chiba, Japan. [Molinaro, Angelo] Univ Pisa, Univ Hosp Pisa, Dept Clin & Expt Med, Endocrinol Unit, Pisa, Italy. [Kinoshita, Kaori] Cimitsu Chuo Hosp, Dept Pediat, Kisarazu, Japan. [Nagatsuma, Misako; Kashimada, Kenichi] Tokyo Med & Dent Univ, Dept Pediat & Dev Biol, Tokyo, Japan. [Sato, Kenichi] Int Univ Hlth & Welf, Dept Med Technol & Sci, Fukuoka, Japan. [Matsushita, Kazuyuki; Nomura, Fumio] Chiba Univ, Grad Sch Med, Dept Mol Diag, Chiba, Japan. [Matsushita, Kazuyuki; Nomura, Fumio] Chiba Univ, Grad Sch Med, Div Clin Genet & Prote, Chiba, Japan. RP Juppner, H (reprint author), Massachusetts Gen Hosp, Endocrine Unit, Thier 10,50 Blossom St, Boston, MA 02114 USA. EM hjueppner@partners.org OI Matsushita, Kazuyuki/0000-0001-6742-0761; Molinaro, Angelo/0000-0002-8539-4429; Kashimada, Kenichi/0000-0003-2505-5932 FU National Institutes of Health [R01 DK46718-22]; Ministry of Health, Labor and Welfare, Japan FX We thank Drs. Kenji Fujieda, Shoko Ikema, Tomohiro Ishii, Hiroshi Mochizuki, Fumio Morohashi, Ayuko Narita, Shinichi Niijima, Hisayuki Oda, Masaya Osaki, Akira Otake, Tatsuya Shiina, Yoshihito Takahashi, Tomoyuki Takagi, Seiki Wada, Hiroyuki Yamaoka, Kazuko Yonamine, and Masanori Yoshida for their help in obtaining blood samples and laboratory results. Furthermore, we are grateful for continuous support and interest of all families for participation in this study. This work was supported by the National Institutes of Health (R01 DK46718-22 to H.J.) This study was also supported in part by grants from Ministry of Health, Labor and Welfare, Japan. NR 44 TC 5 Z9 6 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 OCT PY 2015 VL 79 BP 15 EP 20 DI 10.1016/j.bone.2015.05.011 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA CO9QF UT WOS:000359509700003 PM 25997889 ER PT J AU Crago, AM Chmielecki, J Rosenberg, M O'Connor, R Byrne, C Wilder, FG Thorn, K Agius, P Kuk, D Socci, ND Qin, LX Meyerson, M Hameed, M Singer, S AF Crago, Aimee M. Chmielecki, Juliann Rosenberg, Mara O'Connor, Rachael Byrne, Caitlin Wilder, Fatima G. Thorn, Katherine Agius, Phaedra Kuk, Deborah Socci, Nicholas D. Qin, Li-Xuan Meyerson, Matthew Hameed, Meera Singer, Samuel TI Near universal detection of alterations in CTNNB1 and Wnt pathway regulators in desmoid-type fibromatosis by whole-exome sequencing and genomic analysis SO GENES CHROMOSOMES & CANCER LA English DT Article ID BETA-CATENIN; AGGRESSIVE FIBROMATOSES; TUMORS; MUTATIONS; CANCER; RECURRENCE; MANAGEMENT; PROTEIN; SAMPLES; SINGLE AB CTNNB1 mutations or APC abnormalities have been observed in approximate to 85% of desmoids examined by Sanger sequencing and are associated with Wnt/-catenin activation. We sought to identify molecular aberrations in wild-type tumors (those without CTNNB1 or APC alteration) and to determine their prognostic relevance. CTNNB1 was examined by Sanger sequencing in 117 desmoids; a mutation was observed in 101 (86%) and 16 were wild type. Wild-type status did not associate with tumor recurrence. Moreover, in unsupervised clustering based on U133A-derived gene expression profiles, wild-type and mutated tumors clustered together. Whole-exome sequencing of eight of the wild-type desmoids revealed that three had a CTNNB1 mutation that had been undetected by Sanger sequencing. The mutation was found in a mean 16% of reads (vs. 37% for mutations identified by Sanger). Of the other five wild-type tumors sequenced, two had APC loss, two had chromosome 6 loss, and one had mutation of BMI1. The finding of low-frequency CTNNB1 mutation or APC loss in wild-type desmoids was validated in the remaining eight wild-type desmoids; directed miSeq identified low-frequency CTNNB1 mutation in four and comparative genomic hybridization identified APC loss in one. These results demonstrate that mutations affecting CTNNB1 or APC occur more frequently in desmoids than previously recognized (111 of 117; 95%), and designation of wild-type genotype is largely determined by sensitivity of detection methods. Even true CTNNB1 wild-type tumors (determined by next-generation sequencing) may have genomic alterations associated with Wnt activation (chromosome 6 loss/BMI1 mutation), supporting Wnt/-catenin activation as the common pathway governing desmoid initiation. (c) 2015 Wiley Periodicals, Inc. C1 [Crago, Aimee M.; O'Connor, Rachael; Wilder, Fatima G.; Thorn, Katherine; Singer, Samuel] Mem Sloan Kettering Canc Ctr, Sarcoma Biol Lab, Dept Surg, New York, NY 10065 USA. [Crago, Aimee M.; O'Connor, Rachael; Wilder, Fatima G.; Thorn, Katherine; Singer, Samuel] Mem Sloan Kettering Canc Ctr, Sarcoma Dis Management Program, Dept Surg, New York, NY 10065 USA. [Crago, Aimee M.; Singer, Samuel] Weill Cornell Med Coll, Dept Surg, New York, NY USA. [Chmielecki, Juliann; Meyerson, Matthew] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Chmielecki, Juliann; Rosenberg, Mara; Meyerson, Matthew] Broad Inst Harvard & MIT, Canc Program, Cambridge, MA USA. [Byrne, Caitlin; Agius, Phaedra; Socci, Nicholas D.] Mem Sloan Kettering Canc Ctr, Bioinformat Core, New York, NY 10065 USA. [Kuk, Deborah; Qin, Li-Xuan] Mem Sloan Kettering Canc Ctr, Biostat & Epidemiol, New York, NY 10065 USA. [Meyerson, Matthew] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Hameed, Meera] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA. RP Crago, AM (reprint author), Mem Sloan Kettering Canc Ctr, Sarcoma Dis Management Program, Dept Surg, 1275 York Ave, New York, NY 10065 USA. EM cragoa@mskcc.org OI Kuk, Deborah/0000-0003-1477-3170; Crago, Aimee/0000-0002-2965-752X; O'Connor, Rachael/0000-0002-6869-7954 FU National Cancer Institute (through the SPORE in Soft Tissue Sarcoma) [P50-CA140146]; MSKCC Institutional Cancer Center Core [P30-CA008748]; American Cancer Society (Mentored Research Scholar Grant in Applied and Clinical Research) [MRSG-15-064-01-TBG]; AstraZeneca Postdoctoral Fellowship (American Cancer Society); Kristen Ann Carr Foundation; Alicia and Corey Pinkston; Cycle for Survival; Carlos Slim Foundation, Mexico FX Supported by: National Cancer Institute (through the SPORE in Soft Tissue Sarcoma), Grant number: P50-CA140146; MSKCC Institutional Cancer Center Core, Grant number: P30-CA008748; American Cancer Society (Mentored Research Scholar Grant in Applied and Clinical Research), Grant number: MRSG-15-064-01-TBG; AstraZeneca Postdoctoral Fellowship (American Cancer Society), Kristen Ann Carr Foundation, Alicia and Corey Pinkston, and Cycle for Survival and the Carlos Slim Foundation, Mexico. NR 37 TC 8 Z9 8 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1045-2257 EI 1098-2264 J9 GENE CHROMOSOME CANC JI Gene Chromosomes Cancer PD OCT PY 2015 VL 54 IS 10 BP 606 EP 615 DI 10.1002/gcc.22272 PG 10 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA CP3MH UT WOS:000359783100002 PM 26171757 ER PT J AU Yoo, I Woo, JM Lee, SH Fava, M Mischoulon, D Papakostas, GI Kim, EJ Chung, S Ha, JH Jeon, HJ AF Yoo, Ikki Woo, Jong-Min Lee, Seung-Hwan Fava, Maurizio Mischoulon, David Papakostas, George I. Kim, Eui-Joong Chung, Seockhoon Ha, Jee Hyun Jeon, Hong Jin TI Influence of anxiety symptoms on improvement of neurocognitive functions in patients with major depressive disorder: A 12-week, multicenter, randomized trial of tianeptine versus escitalopram, the CAMPION study SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Major depressive disorder; Neurocognition; Anxiety; Antidepressant trial ID OBSESSIVE-COMPULSIVE DISORDER; COGNITIVE DEFICITS; MEMORY DYSFUNCTION; PANIC DISORDER; PERFORMANCE; ADULTS; ANTIDEPRESSANT; QUESTIONNAIRE; COMPLAINTS; MORBIDITY AB Background: Previous research has reported evidence that patients with major depressive disorder (MDD) show anxiety symptoms and neurocognitive impairments. However, the influence of anxiety on neurocognitive function in MDD patients during antidepressant treatment is unclear. Method: MDD patients (n=164) completed a 12-week, multicenter, randomized trial assigned in a 1:1 ratio to either tianeptine or escitalopram. Changes of anxiety symptoms were assessed by the Hamilton Anxiety Rating Scale (HAM-A), and the Hamilton Depression Rating Scale (HAM-D), self-rated subjective cognitive impairment on memory and concentration, the Mini-Mental Status Examination (MMSE), Continuous Performance Test (CPT), Verbal Learning Test (VLT), and Raven's Progressive Matrices (RPM) were assessed every 4 weeks. Results: During 12 weeks of treatment, decrease in the HAM-A score was significantly associated with improvement of subjective cognitive impairments on memory (p < 0.001) and concentration (p < 0.001), and objective measures on delayed memory (p =0.006) ancl reasoning ability (p-0.002), after adjusting for covariates such as baseline HAM-A scores, time, sex, age, education years and assigned medication using the Mixed effects and Generalized Estimated Equation model analysis. However, the other cognitive outcome variables, immediate memory, commission error, and MMSE, which showed significant improvement through 12-week study period, showed no significant association with improvement of anxiety. Conclusion: Improvement of anxiety symptoms was significantly associated with improvement in subjective and objective neurocognitive functions such as delayed memory and reasoning ability in elderly MDD patients during antidepressant treatment, but not significantly associated with improvement of immediate memory and commission error. Trial registration: ClinicalTrials.gov identifier NC101309776 (C) 2015 Elsevier B.V. All rights reserved. C1 [Yoo, Ikki; Jeon, Hong Jin] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Psychiat,Depress Ctr, Seoul, South Korea. [Jeon, Hong Jin] SAIHST, Dept Clin Res Design, Seoul, South Korea. [Jeon, Hong Jin] SAIHST, Dept Med Device Management & Res, Seoul, South Korea. [Fava, Maurizio; Mischoulon, David; Papakostas, George I.; Jeon, Hong Jin] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Depress Clin & Res Program, Boston, MA USA. [Woo, Jong-Min] Inje Univ, Sch Med, Seoul Paik Hosp, Dept Psychiat, Seoul, South Korea. [Lee, Seung-Hwan] Inje Univ, Sch Med, Ilsan Paik Hosp, Dept Psychiat, Seoul, South Korea. [Kim, Eui-Joong] Eulji Univ, Sch Med, Eulji Gen Hosp, Dept Psychiat, Seoul, South Korea. [Chung, Seockhoon] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Psychiat, Seoul, South Korea. [Ha, Jee Hyun] Konkuk Univ, Sch Med, Dept Psychiat, Seoul, South Korea. RP Jeon, HJ (reprint author), Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Psychiat,Depress Ctr, 50 Irwon Dong, Seoul, South Korea. EM jeonhj@skku.edu OI yoo, ikki/0000-0003-4474-4522 FU Jeil Pharmaceutical Co., LTD; Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Education, Science and Technology [2011-0013064]; Samsung Medical Center Clinical Research Development Program (CRDP) [SMO1131461] FX Financial support for this research was in the form of an unrestricted grant front the Jeil Pharmaceutical Co., LTD, the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (No. 2011-0013064), and the Samsung Medical Center Clinical Research Development Program (CRDP) Grant SMO1131461. The authors thank the 164 patients for their voluntary participation and our research team. The authors thank the Biostatistics team, Samsung Biomedical Research Institute, Chief Dr. Seon-Woo Kim and MS. Sook-Young Woo for statistical analysis. NR 47 TC 1 Z9 1 U1 3 U2 18 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 EI 1573-2517 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD OCT 1 PY 2015 VL 185 BP 24 EP 30 DI 10.1016/j.jad.2015.06.038 PG 7 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA CP2RS UT WOS:000359725400005 PM 26142691 ER PT J AU Van Horn, DHA Drapkin, M Lynch, KG Rennert, L Goodman, JD Thomas, T Ivey, M McKay, JR AF Van Horn, Deborah H. A. Drapkin, Michelle Lynch, Kevin G. Rennert, Lior Goodman, Jessica D. Thomas, Tyrone Ivey, Megan McKay, James R. TI Treatment choices and subsequent attendance by substance-dependent patients who disengage from intensive outpatient treatment SO ADDICTION RESEARCH & THEORY LA English DT Article DE Adaptive treatment; intensive outpatient programmes; treatment choice; treatment disengagement ID CONTINUING CARE; ALCOHOL DEPENDENCE; COCAINE DEPENDENCE; RANDOMIZED-TRIAL; USE DISORDERS; ENGAGEMENT; RETENTION; RELAPSE; COMMITMENT; ABSTINENCE AB In an effort to increase engagement in effective treatment, we offered a choice of alternate evidence-based treatments to 137 alcohol- or cocaine-dependent adults (110 males, 27 females), who entered an intensive outpatient programme (IOP) but disengaged within the first 8 weeks. We hypothesised that disengaged patients would choose and subsequently attend alternatives to IOP when given the chance, that their choices would be consistent with their previously-stated preferences, and that demographic and clinical characteristics would be predictive of alternatives chosen. Of 96 participants reached by phone, 19% chose no treatment; 49% chose to return to IOP; 24% chose individual psychotherapy; 6% chose telephone counselling; 2% chose naltrexone with medication management. There were few relationships between participant characteristics and choices made upon disengagement. Participants who chose alternative treatments were equally likely to attend their chosen treatment as those who chose IOP. Limited interest in alternative treatments may reflect allegiance to IOP, which was initially chosen by all participants. Implications for implementation of patient-centred adaptive treatment are discussed. C1 [Van Horn, Deborah H. A.; Drapkin, Michelle; Lynch, Kevin G.; Rennert, Lior; Goodman, Jessica D.; Thomas, Tyrone; Ivey, Megan; McKay, James R.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Drapkin, Michelle; Goodman, Jessica D.] Vet Affairs Med Ctr, Philadelphia, PA USA. [McKay, James R.] Philadelphia VA Med Ctr, CESATE, Philadelphia, PA USA. RP Van Horn, DHA (reprint author), Univ Penn, Dept Psychiat, 3440 Market St, Philadelphia, PA 19104 USA. EM dvh@mail.med.upenn.edu FU NIDA [P60-DA-05186, K24 DA029062]; NIAAA [P01-AA016821]; Department of Veterans Affairs FX The authors report no conflicts of interest. This research was supported by NIDA grants P60-DA-05186 and K24 DA029062, NIAAA grant P01-AA016821, and by the Department of Veterans Affairs. There was no involvement of a pharmaceutical company in funding this research. The sponsors played no role in preparation of this article. NR 42 TC 1 Z9 1 U1 0 U2 3 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1606-6359 EI 1476-7392 J9 ADDICT RES THEORY JI Addict. Res. Theory PD OCT PY 2015 VL 23 IS 5 BP 391 EP 403 DI 10.3109/16066359.2015.1017570 PG 13 WC Substance Abuse; Social Issues SC Substance Abuse; Social Issues GA CO0EZ UT WOS:000358824200006 PM 27667970 ER PT J AU Li, W Reategui, E Park, MH Castleberry, S Deng, JZ Hsu, B Mayner, S Jensen, AE Sequist, LV Maheswaran, S Haber, DA Toner, M Stott, SL Hammond, PT AF Li, Wei Reategui, Eduardo Park, Myoung-Hwan Castleberry, Steven Deng, Jason Z. Hsu, Bryan Mayner, Sarah Jensen, Anne E. Sequist, Lecia V. Maheswaran, Shyamala Haber, Daniel A. Toner, Mehmet Stott, Shannon L. Hammond, Paula T. TI Biodegradable nano-films for capture and non-invasive release of circulating tumor cells SO BIOMATERIALS LA English DT Article DE Biodegradable; Nano-film; Alginate; Circulating tumor cells; Layer-by-layer; Surface modification ID LAYER-BY-LAYER; PROSTATE-CANCER; BLOOD; LYMPHOCYTES; FLUORESCENT; CHALLENGES; SEPARATION; MARKER; DNA AB Selective isolation and purification of circulating tumor cells (CTCs) from whole blood is an important capability for both clinical medicine and biological research. Current techniques to perform this task place the isolated cells under excessive stresses that reduce cell viability, and potentially induce phenotype change, therefore losing valuable information about the isolated cells. We present a biodegradable nano-film coating on the surface of a microfluidic chip, which can be used to effectively capture as well as non-invasively release cancer cell lines such as PC-3, LNCaP, DU 145, H1650 and H1975. We have applied layer-by-layer (LbL) assembly to create a library of ultrathin coatings using a broad range of materials through complementary interactions. By developing an LbL nano-film coating with an affinity-based cell-capture surface that is capable of selectively isolating cancer cells from whole blood, and that can be rapidly degraded on command, we are able to gently isolate cancer cells and recover them without compromising cell viability or proliferative potential. Our approach has the capability to overcome practical hurdles and provide viable cancer cells for downstream analyses, such as live cell imaging, single cell genomics, and in vitro cell culture of recovered cells. Furthermore, CTCs from cancer patients were also captured, identified, and successfully released using the LbL-modified microchips. Published by Elsevier Ltd. C1 [Li, Wei; Park, Myoung-Hwan; Castleberry, Steven; Deng, Jason Z.; Hsu, Bryan; Mayner, Sarah; Hammond, Paula T.] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Li, Wei] Texas Tech Univ, Dept Chem Engn, Lubbock, TX 79409 USA. [Reategui, Eduardo; Maheswaran, Shyamala; Toner, Mehmet] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Reategui, Eduardo; Jensen, Anne E.; Toner, Mehmet] Harvard Univ, Sch Med, Ctr Engn Med, Boston, MA USA. [Deng, Jason Z.; Hammond, Paula T.] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Sequist, Lecia V.; Maheswaran, Shyamala; Haber, Daniel A.; Stott, Shannon L.] Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med, Boston, MA 02114 USA. [Haber, Daniel A.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Sequist, Lecia V.; Haber, Daniel A.; Stott, Shannon L.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Hammond, PT (reprint author), MIT, Dept Chem Engn, Cambridge, MA 02139 USA. EM sstott@mgh.harvard.edu; hammond@mit.edu RI Li, Wei/P-3546-2016; OI Li, Wei/0000-0002-4738-1475; Park, Myoung-Hwan/0000-0003-3095-3016 FU Stand Up to Cancer, a joint program of the Entertainment Industry Foundation (EIF); American Association for Cancer Research (AACR); National Institute for Biomedical Imaging and Bioengineering (NIBIB) [EB008047]; NIH [P41 EB002503-11] FX We express our gratitude to the all patients who participated in this study and the healthy volunteers who contributed blood samples. We are also grateful to Dr. Ajay Shah for initial critical discussions. We would like to acknowledge Octavio Hurtado and Laura Libby for their expert technical support. This work was supported by a grant from Stand Up to Cancer, a joint program of the Entertainment Industry Foundation (EIF) and the American Association for Cancer Research (AACR). We acknowledge support from: National Institute for Biomedical Imaging and Bioengineering (NIBIB) EB008047 (M. T., and D.A.H.), and NIH P41 EB002503-11 (M. T.). NR 44 TC 11 Z9 11 U1 16 U2 141 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 EI 1878-5905 J9 BIOMATERIALS JI Biomaterials PD OCT PY 2015 VL 65 BP 93 EP 102 DI 10.1016/j.biomaterials.2015.06.036 PG 10 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA CN9YH UT WOS:000358806600010 PM 26142780 ER PT J AU Cao, Y Rosner, BA Ma, J Tamimi, RM Chan, AT Fuchs, CS Wu, KN Giovannucci, EL AF Cao, Yin Rosner, Bernard A. Ma, Jing Tamimi, Rulla M. Chan, Andrew T. Fuchs, Charles S. Wu, Kana Giovannucci, Edward L. TI Assessing individual risk for high-risk colorectal adenoma at first-time screening colonoscopy SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE risk prediction; colorectal adenoma; colonoscopy; screening ID PHYSICAL-ACTIVITY QUESTIONNAIRE; FOOD FREQUENCY QUESTIONNAIRE; MALE HEALTH-PROFESSIONALS; SOCIETY-TASK-FORCE; AGE 70 YEARS; CANCER-RISK; UNITED-STATES; COLON-CANCER; BREAST-CANCER; ADVANCED NEOPLASIA AB Assessing risk of colorectal adenoma at first-time colonoscopy that are of higher likelihood of developing advanced neoplasia during surveillance could help tailor first-line colorectal cancer screening. We developed prediction models for high-risk colorectal adenoma (at least one adenoma 1 cm, or with advanced histology, or 3 adenomas) among 4,881 asymptomatic white men and 17,970 women who underwent colonoscopy as their first-time screening for colorectal cancer in two prospective US studies using logistic regressions. C-statistics and Hosmer-Lemeshow tests were used to evaluate discrimination and calibration. Ten-fold cross-validation was used for internal validation. A total of 330 (6.7%) men and 678 (3.8%) women were diagnosed with high-risk adenoma at first-time screening colonoscopy. The model for men included age, family history of colorectal cancer, BMI, smoking, sitting watching TV/VCR, regular aspirin/NSAID use, physical activity, and a joint term of multivitamin and alcohol. For women, the model included age, family history of colorectal cancer, BMI, smoking, alcohol, beef/pork/lamb as main dish, regular aspirin/NSAID, calcium, and oral contraceptive use. The C-statistic of the model for men was 0.67 and 0.60 for women (0.64 and 0.57 in cross-validation). Both models calibrated well. The predicted risk of high-risk adenoma for men in the top decile was 15.4% vs. 1.8% for men in the bottom decile (Odds Ratio [OR]=9.41), and 6.6% vs. 2.1% for women (OR=3.48). In summary, we developed and internally validated an absolute risk assessment tool for high-risk colorectal adenoma among the US population that may provide guidance for first-time colorectal cancer screening. What's New? Population screening has dramatically reduced mortality rates for colorectal cancer (CRC) in the U.S. However, colonoscopy is expensive, and healthcare resources need to be more efficiently allocated. In this study, the authors developed and validated a comprehensive risk-assessment tool for high-risk colorectal adenoma. This tool, which includes a list of risk factors, may allow first-line colorectal cancer screening to identify people who are at increased risk. These people could then be encouraged to undergo colonoscopy, and to alter their behavior and lifestyle factors to lower their risk. C1 [Cao, Yin; Wu, Kana; Giovannucci, Edward L.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Cao, Yin; Ma, Jing; Tamimi, Rulla M.; Giovannucci, Edward L.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Rosner, Bernard A.; Ma, Jing; Tamimi, Rulla M.; Chan, Andrew T.; Fuchs, Charles S.; Giovannucci, Edward L.] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Rosner, Bernard A.; Ma, Jing; Tamimi, Rulla M.; Chan, Andrew T.; Fuchs, Charles S.; Giovannucci, Edward L.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Rosner, Bernard A.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Fuchs, Charles S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Giovannucci, EL (reprint author), Harvard Univ, TH Chan Sch Publ Hlth, Dept Nutr & Epidemiol, 665 Huntington Ave, Boston, MA 02115 USA. EM egiovann@hsph.harvard.edu RI Dey, Kamalesh/E-6568-2017 FU NIH [P01 CA87969, P01 CA55075, 1UM1 CA167552, R01 CA137178, K24 DK098311]; Entertainment Industry Foundation through the National Colorectal Cancer Research Alliance FX Grant sponsor: NIH; Grant number: P01 CA87969, P01 CA55075, 1UM1 CA167552, R01 CA137178, K24 DK098311; Grant sponsor: Entertainment Industry Foundation through the National Colorectal Cancer Research Alliance. A.T.C. is a Damon Runyon Clinical Investigator. NR 59 TC 3 Z9 3 U1 1 U2 18 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD OCT 1 PY 2015 VL 137 IS 7 BP 1719 EP 1728 DI 10.1002/ijc.29533 PG 10 WC Oncology SC Oncology GA CM9FK UT WOS:000358012600020 PM 25820865 ER PT J AU Salma, N Song, JS Arany, Z Fisher, DE AF Salma, Nunciada Song, Jun S. Arany, Zoltan Fisher, David E. TI Transcription Factor Tfe3 Directly Regulates Pgc-1alpha in Muscle SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Article ID ACTIVATED RECEPTOR-GAMMA; SKELETAL-MUSCLE; OXIDATIVE-METABOLISM; INSULIN SENSITIVITY; LIPID-METABOLISM; GENE-EXPRESSION; PGC-1-ALPHA; COACTIVATOR; MICROPHTHALMIA; FAMILY AB The microphthalmia (MiT) family of transcription factors is an important mediator of metabolism. Family members Mitf and Tfeb directly regulate the expression of the master regulator of metabolism, peroxisome-proliferator activated receptor gamma coactivator-1 alpha (Pgc-1alpha), in melanomas and in the liver, respectively. Pgc-1alpha is enriched in tissues with high oxidative capacity and plays an important role in the regulation of mitochondrial biogenesis and cellular metabolism. In skeletal muscle, Pgc-1alpha affects many aspects of muscle functionally such as endurance, fiber-type switching, and insulin sensitivity. Tfe3 also regulates muscle metabolic genes that enhance insulin sensitivity in skeletal muscle. Tfe3 has not yet been shown to regulate Pgc-1alpha expression. Our results reported here show that Tfe3 directly regulates Pgc-1alpha expression in myotubes. Tfe3 ectopic expression induces Pgc-1alpha, and Tfe3 silencing suppresses Pgc-1alpha expression. This regulation is direct, as shown by Tfe3's binding to E-boxes on the Pgc-1alpha proximal promoter. We conclude that Tfe3 is a critical transcription factor that regulates Pgc-1alpha gene expression in myotubes. Since Pgc-1alpha coactivates numerous biological programs in diverse tissues, the regulation of its expression by upstream transcription factors such Tfe3 implies potential opportunities for the treatment of diseases where modulation of Pgc-1alpha expression may have important clinical outcomes. (C) 2015 Wiley Periodicals, Inc. C1 [Salma, Nunciada; Fisher, David E.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, CBRC,Dept Dermatol, Boston, MA 02114 USA. [Song, Jun S.] CDMC Theme, Inst Genom Biol, Urbana, IL USA. [Song, Jun S.] Univ Illinois, Dept Bioengn, Urbana, IL 61801 USA. [Song, Jun S.] Univ Illinois, Dept Phys, Urbana, IL 61801 USA. [Arany, Zoltan] Univ Penn, Smilow Ctr Translat Res, Sch Med, Cardiovasc Inst Perelman, Philadelphia, PA 19104 USA. RP Fisher, DE (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Bartlett 6,55 Fruit St, Boston, MA 02114 USA. EM dfisher3@partners.org FU The American Heart Association Fellowship (AHA) [AHA-0726015T, R01 CA163336, RO1-AR043369, P01 CA163222, R01 HL094499]; PhRMA Foundation; National Cancer Institute; Melanoma Research Alliance; Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; National Institutes of Health; US-Israel Binational Science Foundation; Doris Duke Medical Research Foundation FX Contract grant sponsor: The American Heart Association Fellowship (AHA);; Contract grant numbers: AHA-0726015T, R01 CA163336, RO1-AR043369, P01 CA163222, R01 HL094499.; Contract grant sponsor: PhRMA Foundation.; Contract grant sponsor: National Cancer Institute.; Contract grant sponsor: Melanoma Research Alliance.; Contract grant sponsor: Dr. Miriam and Sheldon G. Adelson Medical Research Foundation.; Contract grant sponsor: National Institutes of Health.; Contract grant sponsor: US-Israel Binational Science Foundation.; Contract grant sponsor: Doris Duke Medical Research Foundation. NR 47 TC 4 Z9 5 U1 2 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9541 EI 1097-4652 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD OCT PY 2015 VL 230 IS 10 BP 2330 EP 2336 DI 10.1002/jcp.24978 PG 7 WC Cell Biology; Physiology SC Cell Biology; Physiology GA CM6RA UT WOS:000357815600006 PM 25736533 ER PT J AU Ahonkhai, AA Banigbe, B Adeola, J Onwuatuelo, I Bassett, IV Losina, E Freedberg, KA Okonkwo, P Regan, S AF Ahonkhai, Aimalohi A. Banigbe, Bolanle Adeola, Juliet Onwuatuelo, Ifeyinwa Bassett, Ingrid V. Losina, Elena Freedberg, Kenneth A. Okonkwo, Prosper Regan, Susan TI High rates of unplanned interruptions from HIV care early after antiretroviral therapy initiation in Nigeria SO BMC INFECTIOUS DISEASES LA English DT Article DE Retention; Unplanned care interruption; Gaps in care; Resource-limited setting; HIV ID SUB-SAHARAN AFRICA; SOUTH-AFRICA; FOLLOW-UP; INFECTED ADOLESCENTS; TREATMENT PROGRAMS; PATIENT RETENTION; PATIENTS LOST; PRE-ART; MORTALITY; ADHERENCE AB Background: Unplanned care interruption (UCI) challenges effective HIV treatment. We determined the frequency and risk factors for UCI in Nigeria. Methods: We conducted a retrospective-cohort study of adults initiating antiretroviral therapy (ART) between January 2009 and December 2011. At censor, patients were defined as in care, UCI, or inactive. Associations between baseline factors and UCI rates were quantified using Poisson regression. Results: Among 2,496 patients, 44 % remained in care, 35 % had >= 1 UCI, and 21 % became inactive. UCI rates were higher in the first year on ART (39/100PY), than the second (19/100PY), third (16/100PY), and fourth (14/100PY) years (p < 0.001). In multivariate analysis, baseline CD4 > 350/uL (IRR 3.21, p < 0.0001), being a student (IRR 1.95, p < 0.0001), and less education (IRR 1.58, p = 0.001) increased risk for UCI. Fifty-five percent of patients with UCI and viral load data had HIV viral load > 1,000 copies/ml upon return to care. Discussion: UCI were observed in over one-third of patients treated, and were most common in the first year on ART. High baseline CD4 count at ART initiation was the greatest predictor of subsequent UCI. Conclusions: Interventions focused on the first year on ART are needed to improve continuity of HIV care. C1 [Ahonkhai, Aimalohi A.; Bassett, Ingrid V.; Freedberg, Kenneth A.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Ahonkhai, Aimalohi A.; Bassett, Ingrid V.; Losina, Elena; Freedberg, Kenneth A.; Regan, Susan] Massachusetts Gen Hosp, Med Practice Evaluat Ctr, Boston, MA 02114 USA. [Banigbe, Bolanle; Adeola, Juliet; Onwuatuelo, Ifeyinwa; Okonkwo, Prosper] APIN, Abuja, Nigeria. [Bassett, Ingrid V.; Freedberg, Kenneth A.; Regan, Susan] Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. [Bassett, Ingrid V.; Freedberg, Kenneth A.; Regan, Susan] Harvard Univ, Ctr AIDS Res CFAR, Boston, MA 02115 USA. [Losina, Elena] Brigham & Womens Hosp, Dept Orthoped Surg, Boston, MA 02115 USA. [Losina, Elena; Freedberg, Kenneth A.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Losina, Elena; Freedberg, Kenneth A.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Freedberg, Kenneth A.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. RP Ahonkhai, AA (reprint author), Massachusetts Gen Hosp, Div Infect Dis, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM aahonkhai@mgh.harvard.edu FU National Institute of Allergy and Infectious Diseases of the National Institutes of Health [K23 AI106406-02, R01 AI058736-09S1, R01 MH090326, 2P30AI060354]; Centers for Disease Control and Prevention [5U2GPS001058] FX Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Numbers: K23 AI106406-02, R01 AI058736-09S1, R01 MH090326, 2P30AI060354. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This study was also supported in part by cooperative agreement number 5U2GPS001058 from the Centers for Disease Control and Prevention. NR 54 TC 3 Z9 3 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2334 J9 BMC INFECT DIS JI BMC Infect. Dis. PD SEP 30 PY 2015 VL 15 AR 397 DI 10.1186/s12879-015-1137-z PG 10 WC Infectious Diseases SC Infectious Diseases GA CS7GN UT WOS:000362252200006 PM 26424505 ER PT J AU Dossett, ML Mu, L Davis, RB Bell, IR Lembo, AJ Kaptchuk, TJ Yeh, GY AF Dossett, Michelle L. Mu, Lin Davis, Roger B. Bell, Iris R. Lembo, Anthony J. Kaptchuk, Ted J. Yeh, Gloria Y. TI Patient-Provider Interactions Affect Symptoms in Gastroesophageal Reflux Disease: A Pilot Randomized, Double-Blind, Placebo-Controlled Trial SO PLOS ONE LA English DT Article ID ALTERNATIVE MEDICINE; CONVENTIONAL MEDICINE; RELATIONAL EMPATHY; CARE; COMPLEMENTARY; CONSULTATION; QUALITY; RELIABILITY; SEVERITY; OUTCOMES AB Background It is unclear whether the benefits that some patients derive from complementary and integrative medicine (CIM) are related to the therapies recommended or to the consultation process as some CIM provider visits are more involved than conventional medical visits. Many patients with gastrointestinal conditions seek out CIM therapies, and prior work has demonstrated that the quality of the patient-provider interaction can improve health outcomes in irritable bowel syndrome, however, the impact of this interaction on gastroesophageal reflux disease (GERD) is unknown. We aimed to assess the safety and feasibility of conducting a 2x2 factorial design study preliminarily exploring the impact of the patient-provider interaction, and the effect of an over-the-counter homeopathic product, Acidil, on symptoms and health-related quality of life in subjects with GERD. Methods 24 subjects with GERD-related symptoms were randomized in a 2x2 factorial design to receive 1) either a standard visit based on an empathic conventional primary care evaluation or an expanded visit with questions modeled after a CIM consultation and 2) either Acidil or placebo for two weeks. Subjects completed a daily GERD symptom diary and additional measures of symptom severity and health-related quality of life. Results There was no significant difference in GERD symptom severity between the Acidil and placebo groups from baseline to follow-up (p = 0.41), however, subjects who received the expanded visit were significantly more likely to report a 50% or greater improvement in symptom severity compared to subjects who received the standard visit (p = 0.01). Total consultation length, perceived empathy, and baseline beliefs in CIM were not associated with treatment outcomes. Conclusion An expanded patient-provider visit resulted in greater GERD symptom improvement than a standard empathic medical visit. CIM consultations may have enhanced placebo effects, and further studies to assess the active components of this visit-based intervention are warranted. C1 [Dossett, Michelle L.; Mu, Lin; Davis, Roger B.; Kaptchuk, Ted J.; Yeh, Gloria Y.] Beth Israel Deaconess Med Ctr, Dept Med, Div Gen Med & Primary Care, Boston, MA 02215 USA. [Mu, Lin] Beth Israel Deaconess Med Ctr, Clin Res Ctr, Boston, MA 02215 USA. [Davis, Roger B.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Bell, Iris R.] Univ Arizona, Coll Med, Dept Family & Community Med, Tucson, AZ USA. [Lembo, Anthony J.] Beth Israel Deaconess Med Ctr, Dept Med, Div Gastroenterol, Boston, MA 02215 USA. [Kaptchuk, Ted J.] Beth Israel Deaconess Med Ctr, Program Placebo Studies, Boston, MA 02215 USA. [Kaptchuk, Ted J.] Harvard Univ, Sch Med, Boston, MA USA. RP Dossett, ML (reprint author), Massachusetts Gen Hosp, Benson Henry Inst Mind Body Med, Boston, MA 02114 USA. EM mdossett@mgh.harvard.edu FU National Center for Complementary and Integrative Health (NCCIH) at the NIH [T32 AT000051]; Division of General Medicine and Primary Care at Beth Israel Deaconess Medical Center (BIDMC); NCCIH [K24 AT004095]; BIDMC Research Pharmacy and Clinical Research Center, Harvard Catalyst; Harvard Clinical and Translational Science Center (NIH) [1UL1 TR001102-01]; Harvard University FX MLD was supported by an institutional National Research Service Award T32 AT000051 from the National Center for Complementary and Integrative Health (NCCIH) at the NIH and by the Division of General Medicine and Primary Care at Beth Israel Deaconess Medical Center (BIDMC). TJK was supported by a K24 AT004095 (NCCIH). This work was conducted with support from the BIDMC Research Pharmacy and Clinical Research Center, Harvard Catalyst, The Harvard Clinical and Translational Science Center (NIH Award 1UL1 TR001102-01 and financial contributions from Harvard University and its affiliated academic health care centers). The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic health care centers, or the National Institutes of Health. No funding or support was received from Boiron. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 35 TC 2 Z9 2 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 30 PY 2015 VL 10 IS 9 AR e0136855 DI 10.1371/journal.pone.0136855 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CS6GF UT WOS:000362175700007 PM 26422466 ER PT J AU Wang, LX Mogami, S Yakabi, S Karasawa, H Yamada, C Yakabi, K Hattori, T Tache, Y AF Wang, Lixin Mogami, Sachiko Yakabi, Seiichi Karasawa, Hiroshi Yamada, Chihiro Yakabi, Koji Hattori, Tomohisa Tache, Yvette TI Patterns of Brain Activation and Meal Reduction Induced by Abdominal Surgery in Mice and Modulation by Rikkunshito SO PLOS ONE LA English DT Article ID CORTICOTROPIN-RELEASING-FACTOR; HYPOTHALAMIC ARCUATE NUCLEUS; STRESS-RELATED ALTERATIONS; POSTOPERATIVE GASTRIC ILEUS; CISPLATIN-INDUCED ANOREXIA; GHRELIN RECEPTOR AGONIST; COLONIC MOTOR FUNCTION; CENTRAL-NERVOUS-SYSTEM; FOOD-INTAKE; PARABRACHIAL NUCLEUS AB Abdominal surgery inhibits food intake and induces c-Fos expression in the hypothalamic and medullary nuclei in rats. Rikkunshito (RKT), a Kampo medicine improves anorexia. We assessed the alterations in meal microstructure and c-Fos expression in brain nuclei induced by abdominal surgery and the modulation by RKT in mice. RKT or vehicle was gavaged daily for 1 week. On day 8 mice had no access to food for 6-7 h and were treated twice with RKT or vehicle. Abdominal surgery (laparotomy-cecum palpation) was performed 1-2 h before the dark phase. The food intake and meal structures were monitored using an automated monitoring system for mice. Brain sections were processed for c-Fos immunoreactivity (ir) 2-h after abdominal surgery. Abdominal surgery significantly reduced bouts, meal frequency, size and duration, and time spent on meals, and increased inter-meal interval and satiety ratio resulting in 92-86% suppression of food intake at 2-24 h post-surgery compared with control group (no surgery). RKT significantly increased bouts, meal duration and the cumulative 12-h food intake by 11%. Abdominal surgery increased c-Fos in the prelimbic, cingulate and insular cortexes, and autonomic nuclei, such as the bed nucleus of the stria terminalis, central amygdala, hypothalamic supraoptic (SON), paraventricular and arcuate nuclei, Edinger-Westphal nucleus (E-W), lateral periaqueduct gray (PAG), lateral parabrachial nucleus, locus coeruleus, ventrolateral medulla and nucleus tractus solitarius (NTS). RKT induced a small increase in c-Fos-ir neurons in the SON and E-W of control mice, and in mice with surgery there was an increase in the lateral PAG and a decrease in the NTS. These findings indicate that abdominal surgery inhibits food intake by increasing both satiation (meal duration) and satiety (meal interval) and activates brain circuits involved in pain, feeding behavior and stress that may underlie the alterations of meal pattern and food intake inhibition. RKT improves food consumption post-surgically that may involve modulation of pain pathway. C1 [Wang, Lixin; Yakabi, Seiichi; Karasawa, Hiroshi; Tache, Yvette] Univ Calif Los Angeles, CURE Digest Dis Ctr, Los Angeles, CA 90089 USA. [Wang, Lixin; Yakabi, Seiichi; Karasawa, Hiroshi; Tache, Yvette] Univ Calif Los Angeles, Dept Med, Ctr Neurobiol Stress, Div Digest Dis, Los Angeles, CA 90024 USA. [Wang, Lixin; Yakabi, Seiichi; Karasawa, Hiroshi; Tache, Yvette] VA Greater Los Angeles Hlth Care Syst, Los Angeles, CA USA. [Mogami, Sachiko; Yamada, Chihiro; Hattori, Tomohisa] Tsumura & Co, Kampo Sci Strategies Div, Tsumura Res Labs, Tsukuba, Ibaraki, Japan. [Yakabi, Koji] Saitama Med Univ, Saitama Med Ctr, Dept Gastroenterol & Hepatol, Saitama, Japan. RP Wang, LX (reprint author), Univ Calif Los Angeles, CURE Digest Dis Ctr, Los Angeles, CA 90089 USA. EM lixinw@ucla.edu RI Xu, Meiqu/C-5311-2016 FU Veterans Administration Research Career Scientist Award; VA Merit Award; Tsumura Co.; [NIHDDK-41303] FX The work was supported by NIHDDK-41303 (Animal core, YT, LW), Veterans Administration Research Career Scientist Award (YT), VA Merit Award (YT) and Tsumura & Co. Drs. SM, CY and TH are employees of Tsumura & Co. The funders of Tsumura & Co. had no role in study design, data collection and analysis, decision topublish, or preparation of the manuscript. NR 85 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 SEP 30 PY 2015 VL 10 IS 9 AR e0139325 DI 10.1371/journal.pone.0139325 PG 21 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CS6GF UT WOS:000362175700094 PM 26421719 ER PT J AU Ladha, K Kurth, T Eikermann, M AF Ladha, Karim Kurth, Tobias Eikermann, Matthias TI INTRAOPERATIVE PROTECTIVE MECHANICAL VENTILATION Authors' reply to Whitlock and Saied and colleagues SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Letter C1 [Ladha, Karim; Eikermann, Matthias] Massachusetts Gen Hosp, Dept Anesthesia Crit Care Pain Med, Boston, MA 02114 USA. [Kurth, Tobias] INSERM, Res Ctr Epidemiol & Biostat, U897, Team Neuroepidemiol, Bordeaux, France. RP Ladha, K (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care Pain Med, Boston, MA 02114 USA. EM meikermann@partners.org NR 6 TC 0 Z9 0 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1756-1833 J9 BMJ-BRIT MED J JI BMJ-British Medical Journal PD SEP 30 PY 2015 VL 351 AR h5143 DI 10.1136/bmj.h5143 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA CS9ZE UT WOS:000362452200014 PM 26424610 ER PT J AU Flanagan, JC Baker, NL McRae-Clark, AL Brady, KT Maria, MMMS AF Flanagan, Julianne C. Baker, Nathaniel L. McRae-Clark, Aimee L. Brady, Kathleen T. Maria, Margaret M. Moran-Santa TI Effects of adverse childhood experiences on the association between intranasal oxytocin and social stress reactivity among individuals with cocaine dependence SO PSYCHIATRY RESEARCH LA English DT Article DE Oxytocin; Drug dependence; Social stress reactivity; HPA ID SUBSTANCE USE; PSYCHOLOGICAL DISTRESS; HOUSEHOLD DYSFUNCTION; MENTAL-HEALTH; AXIS ACTIVITY; DRUG-USE; RISK; ALCOHOL; ABUSE; ADDICTION AB Background: Drug dependence and adverse childhood experiences (ACE) are commonly reflected by dysregulation of the hypothalamic-pituitary-adrenal axis (HPA). Accumulating research indicates that the neuropeptide oxytocin may regulate HPA function, resulting in reductions in neuroendocrine reactivity to social stress among individuals with drug dependence. However, emerging literature suggests that individual differences may differentially impact intranasal oxytbcin's effects on human social behaviors. Methods: This study employed a double-blind, placebo-controlled design to examine the extent to which ACE influenced the effects of intranasal oxytocin (40 IU) on neuroendocrine reactivity to a laboratory social stress paradigm in a sample of 31 cocaine-dependent individuals. Results: ACE scores modified the relationship between intranasal oxytocin and cortisol reactivity. While ACE modified the relationship between intranasal oxytocin and DHEA response in a similar direction to what was seen in cortisol, it did not reach statistical significance. Conclusions: Findings are congruent with the emerging hypothesis that intranasal oxytocin may differentially attenuate social stress reactivity among individuals with specific vulnerabilities. Future research examining the nuances of intranasal oxytocin's therapeutic potential is necessary. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Flanagan, Julianne C.; McRae-Clark, Aimee L.; Brady, Kathleen T.; Maria, Margaret M. Moran-Santa] Med Univ S Carolina, Dept Psychiat & Behav Sci, Charleston, SC 29401 USA. [Brady, Kathleen T.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29401 USA. [Baker, Nathaniel L.] Med Univ S Carolina, Dept Publ Hlth Sci, Charleston, SC 29425 USA. RP Flanagan, JC (reprint author), Med Univ S Carolina, Dept Psychiat & Behav Sci, 5 Charleston Ctr Dr,Suite 151, Charleston, SC 29401 USA. EM hellmuth@musc.edu FU National Institute on Child Health and Human Development and the Office of Research on Women's Health [K12HD055885]; National Institute on Drug Abuse [P50DA016511]; National Center for Advancing Translational Sciences [UL1TR000062] FX This manuscript is the result of work supported, in part, by resources from the National Institute on Child Health and Human Development and the Office of Research on Women's Health (K12HD055885), the National Institute on Drug Abuse (P50DA016511), and the National Center for Advancing Translational Sciences (UL1TR000062). NR 60 TC 3 Z9 3 U1 4 U2 11 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 SEP 30 PY 2015 VL 229 IS 1-2 BP 94 EP 100 DI 10.1016/j.psychres.2015.07.064 PG 7 WC Psychiatry SC Psychiatry GA CQ7HC UT WOS:000360772600013 PM 26231584 ER PT J AU Silverstein, SM Elliott, CM Feusner, JD Keane, BP Mikkilineni, D Hansen, N Hartmann, A Wilhelm, S AF Silverstein, Steven M. Elliott, Corinna M. Feusner, Jamie D. Keane, Brian P. Mikkilineni, Deepthi Hansen, Natasha Hartmann, Andrea Wilhelm, Sabine TI Comparison of visual perceptual organization in schizophrenia and body dysmorphic disorder SO PSYCHIATRY RESEARCH LA English DT Article DE Schizophrenia; Body dysmorphic disorder; Perception; Vision; Perceptual organization; Obsessive-Compulsive Disorder; RDoC ID OBSESSIVE-COMPULSIVE SCALE; FACIAL EMOTION RECOGNITION; TOP-DOWN CONTROL; 5 FACTOR MODEL; CONTOUR INTEGRATION; EBBINGHAUS ILLUSION; SPECTRUM DISORDERS; SPATIAL-FREQUENCY; FACE RECOGNITION; CONFIGURAL INFORMATION AB People with schizophrenia are impaired at organizing potentially ambiguous visual information into well-formed shape and object representations. This perceptual organization (PO) impairment has not been found in other psychiatric disorders. However, recent data on body dysmorphic disorder (BDD), suggest that BDD may also be characterized by reduced PO. Similarities between these groups could have implications for understanding the RDoC dimension of visual perception in psychopathology, and for modeling symptom formation across these two conditions. We compared patients with SCZ (n=24) to those with BDD (n=20), as well as control groups of obsessive compulsive disorder (OCD) patients (n=20) and healthy controls (n=20), on two measures of PO that have been reliably associated with schizophrenia-related performance impairment. On both the contour integration and Ebbinghaus illusion tests, only the SCZ group demonstrated abnormal performance relative to controls; the BDD group performed similarly to the OCD and CON groups. In addition, on both tasks, the SCZ group performed more abnormally than the BDD group. Overall, these data suggest that PO reductions observed in SCZ are not present in BDD. Visual processing impairments in BDD may arise instead from other perceptual disturbances or attentional biases related to emotional factors. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Silverstein, Steven M.; Keane, Brian P.; Mikkilineni, Deepthi] Rutgers State Univ, Dept Psychiat, Piscataway, NJ 08854 USA. [Silverstein, Steven M.; Keane, Brian P.; Mikkilineni, Deepthi] Rutgers State Univ, Univ Behav Hlth Care, Piscataway, NJ 08854 USA. [Elliott, Corinna M.; Hansen, Natasha; Hartmann, Andrea; Wilhelm, Sabine] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Feusner, Jamie D.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. RP Silverstein, SM (reprint author), Rutgers State Univ, Dept Psychiat, 151 Centennial Ave, Piscataway, NJ 08854 USA. EM steven.silverstein@rutgers.edu RI Feusner, Jamie/K-2312-2012 OI Feusner, Jamie/0000-0002-0391-345X FU Fonds de Recherche du Que-bec-Sante (FRQS); NIMH [R01MH093439]; NIH IRACDA Postdoctoral Training Grant [1K12GM093854-05]; Neil and Anna Rasmussen Foundation FX We would like to thank Amanda Calkins, Lillian Reuman, Yushi Wang, and Danielle Paterno for their help with recruitment and testing. This research was supported in part by fellowship support awarded to Corinna Elliott from the Fonds de Recherche du Que-bec-Sante (FRQS), by NIMH Grant R01MH093439 to the first author, by NIH IRACDA Postdoctoral Training Grant 1K12GM093854-05 to M. W. Roche, and by funding from The Neil and Anna Rasmussen Foundation to the last author. NR 110 TC 2 Z9 2 U1 3 U2 18 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 SEP 30 PY 2015 VL 229 IS 1-2 BP 426 EP 433 DI 10.1016/j.psychres.2015.05.107 PG 8 WC Psychiatry SC Psychiatry GA CQ7HC UT WOS:000360772600061 PM 26184989 ER PT J AU Caqueo-Urizar, A Boyer, L Baumstarck, K Gilman, SE AF Caqueo-Urizar, Alejandra Boyer, Laurent Baumstarck, Karine Gilman, Stephen E. TI The relationships between patients' and caregivers' beliefs about the causes of schizophrenia and clinical outcomes in Latin American countries SO PSYCHIATRY RESEARCH LA English DT Article DE Schizophrenia; Causal beliefs; Caregivers; Health outcomes; Symptoms; Attitudes towards medication ID SERIOUS MENTAL ILLNESSES; MIDDLE-INCOME COUNTRIES; NEGATIVE SYNDROME SCALE; EXPRESSED EMOTION; FAMILY-MEMBERS; HEALTH; POVERTY; RELATIVES; MODELS; HELP AB Beliefs about the causes of schizophrenia are thought to impact treatment outcomes. We investigated 3 theoretically opposing belief systems (biological, psychosocial, magical-religious) in relation to the severity of positive and negative symptoms and to attitudes towards medications. We recruited 253 patients with schizophrenia and their primary caregivers from public mental health clinics in Bolivia, Chile, and Peru. We assessed patients' and caregivers' beliefs about the causes of schizophrenia, which were used as predictors of symptom severity and medication attitudes in linear regression analyses. Patients' scores on biological, psychosocial, and magical-religious beliefs were positively correlated with one another, indicating that these domains were not, as anticipated, "opposing". Patients with higher levels of biological and psychosocial beliefs had significantly lower levels of positive and negative symptoms; in contrast, higher levels of magical-religious beliefs were associated with increased positive symptoms and less favorable attitudes towards medications. Patients' belief systems are significant predictors of symptom severity and medication attitudes. Research is needed on the extent to which psychotherapeutic treatments for schizophrenia should bolster patients' beliefs in the biological and psychosocial domains and weaken beliefs in the magical-religious domain; this research should also attend to the ethical considerations involved in intervening on belief systems cross-culturally. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Caqueo-Urizar, Alejandra] Univ Tarapaca, Arica, Chile. [Caqueo-Urizar, Alejandra; Gilman, Stephen E.] Harvard Univ, Dept Social & Behav Sci, Sch Publ Hlth, Boston, MA 02115 USA. [Boyer, Laurent; Baumstarck, Karine] Aix Marseille Univ, Chron Dis & Qual Life Res Unit, EA Publ Hlth 3279, F-13005 Marseille, France. [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. [Gilman, Stephen E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Hlth Behav Branch, Div Intramural Populat Hlth Res, Rockville, MD 20852 USA. RP Caqueo-Urizar, A (reprint author), Univ Tarapaca, Dept Filosofia & Psicol, Ave 18 Septiembre 2222, Arica, Chile. EM acaqueo@uta.cl; Laurent.BOYER@ap-hm.fr; karine.baumstarck@univ-amu.fr; stephen.gilman@nih.gov RI Gilman, Stephen/E-7632-2010; Boyer, Laurent/E-5728-2016 OI Gilman, Stephen/0000-0002-8331-6419; Boyer, Laurent/0000-0003-1229-6622 FU CONICYT; BECAS-CHILE Postdoctorado en el Extranjero [74140004]; Convenio de De-sempenio UTA-MINEDUC; Intramural Research Program of Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This research was funded in part by CONICYT and BECAS-CHILE Postdoctorado en el Extranjero (74140004), the Convenio de De-sempenio UTA-MINEDUC, and by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 54 TC 1 Z9 1 U1 6 U2 14 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 SEP 30 PY 2015 VL 229 IS 1-2 BP 440 EP 446 DI 10.1016/j.psychres.2015.06.033 PG 7 WC Psychiatry SC Psychiatry GA CQ7HC UT WOS:000360772600063 PM 26188641 ER PT J AU Thomas, JJ Eddy, KT Murray, HB Tromp, MDP Hartmann, AS Stone, MT Levendusky, PG Becker, AE AF Thomas, Jennifer J. Eddy, Kamryn T. Murray, Helen B. Tromp, Marilou D. P. Hartmann, Andrea S. Stone, Melissa T. Levendusky, Philip G. Becker, Anne E. TI The impact of revised DSM-5 criteria on the relative distribution and inter-rater reliability of eating disorder diagnoses in a residential treatment setting SO PSYCHIATRY RESEARCH LA English DT Article DE DSM-5; Eating disorder; Diagnostic reliability; Other specified feeding or eating disorder (OSFED); Eating disorder not otherwise specified (EDNOS) ID CLINICAL UTILITY; IV; ADOLESCENTS; COMMUNITY; SEVERITY; METAANALYSIS; PREVALENCE; AGREEMENT; EDNOS AB This study evaluated the relative distribution and inter-rater reliability of revised DSM-5 criteria for eating disorders in a residential treatment program. Consecutive adolescent and young adult females (N=150) admitted to a residential eating disorder treatment facility were assigned both DSM-IV and DSM-5 diagnoses by a clinician (n=14) via routine clinical interview and a research assessor (n=4) via structured interview. We compared the frequency of diagnostic assignments under each taxonomy and by type of assessor. We evaluated concordance between clinician and researcher assignment through inter-rater reliability kappa and percent agreement. Significantly fewer patients received either clinician or researcher diagnoses of a residual eating disorder under DSM-5 (clinician-12.0%; researcher-31.3%) versus DSM-IV (clinician-28.7%; researcher-59.3%), with the majority of reassigned DSM-IV residual cases reclassified as DSM-5 anorexia nervosa. Researcher and clinician diagnoses showed moderate inter-rater reliability under DSM-IV (kappa= .48) and DSM-5 (kappa= .57), though agreement for specific DSM-5 other specified feeding or eating disorder (OSFED) presentations was poor (kappa=.05). DSM-5 revisions were associated with significantly less frequent residual eating disorder diagnoses, but not with reduced inter-rater reliability. Findings support specific dimensions of clinical utility for revised DSM-5 criteria for eating disorders. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Thomas, Jennifer J.; Eddy, Kamryn T.; Murray, Helen B.; Tromp, Marilou D. P.; Becker, Anne E.] Massachusetts Gen Hosp, Eating Disorders Clin & Res Program, Boston, MA 02114 USA. [Thomas, Jennifer J.; Eddy, Kamryn T.; Stone, Melissa T.; Levendusky, Philip G.; Becker, Anne E.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Hartmann, Andrea S.] Univ Osnabruck, Inst Psychol, D-49074 Osnabruck, Germany. [Levendusky, Philip G.] McLean Hosp, Klarman Eating Disorders Ctr, Belmont, MA 02178 USA. [Becker, Anne E.] Harvard Univ, Sch Med, Dept Global Hlth & Social Med, Boston, MA USA. RP Thomas, JJ (reprint author), Massachusetts Gen Hosp, Eating Disorders Clin & Res Program, 2 Longfellow Pl,Suite 200, Boston, MA 02114 USA. EM jjthomas@mgh.harvard.edu FU Hilda and Preston Davis Foundation; Klarman Family Foundation FX Funded by Hilda and Preston Davis Foundation, Klarman Family Foundation, Mr. and Mrs. Samuel Martini. NR 32 TC 2 Z9 2 U1 3 U2 14 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 SEP 30 PY 2015 VL 229 IS 1-2 BP 517 EP 523 DI 10.1016/j.psychres.2015.06.017 PG 7 WC Psychiatry SC Psychiatry GA CQ7HC UT WOS:000360772600074 PM 26160205 ER PT J AU De Nadai, A Nagpal, PS Piacentini, J Penis, TS Geftken, GR Geller, DA Murphy, TK Storch, EA Lewin, AB AF De Nadai, Alessandro Nagpal, Prianka S. Piacentini, John Penis, Tara S. Geftken, Gary R. Geller, Daniel A. Murphy, Tanya K. Storch, Eric A. Lewin, Adam B. TI Contemporary models of pediatric obsessive-compulsive disorder: An evaluation with a large clinical sample SO PSYCHIATRY RESEARCH LA English DT Article DE Obsessive-compulsive disorder; Pediatric; Assessment ID SCALE AB We evaluated the construct validity of the Child Yale-Brofwn Obsessive-Compulsive Scale (CYBOCS) in a large clinical sample (N=730) using confirmatory factor analysis. Results found inadequate fit for a priori models, though a model accounting for overlapping item content displayed good fit. Parallel obsessions/compulsions items may provide largely redundant information on the CYBOCS. Findings suggest modifying the CYBOCS to reduce burden on researchers, patients, and clinicians, and to more accurately measure pediatric obsessive-compulsive disorder (OCD). (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [De Nadai, Alessandro; Storch, Eric A.; Lewin, Adam B.] Univ S Florida, Dept Psychol, Tampa, FL 33620 USA. [De Nadai, Alessandro; Nagpal, Prianka S.; Murphy, Tanya K.; Storch, Eric A.; Lewin, Adam B.] Univ S Florida, Coll Med, Rothman Ctr Neuropsychiat, Dept Pediat, St Petersburg, FL 33701 USA. [De Nadai, Alessandro; Nagpal, Prianka S.; Murphy, Tanya K.; Storch, Eric A.; Lewin, Adam B.] Univ S Florida, Coll Med, Rothman Ctr Neuropsychiat, Dept Psychiat, St Petersburg, FL 33701 USA. [Piacentini, John; Penis, Tara S.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Geftken, Gary R.] Univ Florida, Dept Psychiat, Gainesville, FL 32606 USA. [Geftken, Gary R.] Univ Florida, Dept Clin & Hlth Psychol, Gainesville, FL 32611 USA. [Geller, Daniel A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA 02114 USA. [Storch, Eric A.] Rogers Behav Hlth Tampa Bay, Tampa, FL 33629 USA. [Storch, Eric A.] All Childrens Hosp Johns Hopkins Med, St Petersburg, FL 33701 USA. RP De Nadai, A (reprint author), Univ S Florida, Coll Med, Rothman Ctr Neuropsychiat, 880 6th St South,Suite 460 Box 7523, St Petersburg, FL 33701 USA. EM denadai@mail.usf.edu RI Murphy, Tanya/J-7079-2013 FU National Institutes of Health under National Institute of Mental Health [F31 MH094095, R01 MH058549, K23 MH085058, R01 MH093402, R01 MH063914, R01 MH093381, R03 MH076775]; International OCD Foundation; University of South Florida Research Council FX This research was supported by the National Institutes of Health under National Institute of Mental Health Grants F31 MH094095 (De Nadai), R01 MH058549 (Piacentini), K23 MH085058 (Peris), R01 MH093402 (Geller), R01 MH063914 (Murphy), R01 MH093381 (Storch), R03 MH076775 (Storch), as well as from the International OCD Foundation (Lewin and Murphy) and the University of South Florida Research Council (Lewin). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 11 TC 1 Z9 1 U1 1 U2 6 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 SEP 30 PY 2015 VL 229 IS 1-2 BP 620 EP 622 DI 10.1016/j.psychres.2015.03.034 PG 3 WC Psychiatry SC Psychiatry GA CQ7HC UT WOS:000360772600096 PM 26003507 ER PT J AU Bohula, EA Giugliano, RP Cannon, CP Zhou, J Murphy, SA White, JA Tershakovec, AM Blazing, MA Braunwald, E AF Bohula, Erin A. Giugliano, Robert P. Cannon, Christopher P. Zhou, Jing Murphy, Sabina A. White, Jennifer A. Tershakovec, Andrew M. Blazing, Michael A. Braunwald, Eugene TI 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 Article DE acute coronary syndrome; cholesterol, LDL; C-reactive protein; ezetimibe; hydroxymethylglutaryl-CoA reductase inhibitors; secondary prevention ID ACUTE CORONARY SYNDROMES; STATIN THERAPY; HEART-DISEASE; MYOCARDIAL-INFARCTION; RANDOMIZED-TRIALS; CLINICAL-TRIALS; EFFICACY; INFLAMMATION; SAFETY; RISK AB Background-Statins lower low-density lipoprotein cholesterol (LDL-C) and high-sensitivity C-reactive protein (hs-CRP); addition of ezetimibe to statins further reduces LDL-C and hs-CRP. An analysis of the relationship between achieved LDL-C and hs-CRP targets and outcomes for simvastatin and ezetimibe/simvastatin was prespecified in Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT). Methods and Results-The IMPROVE-IT trial randomly assigned 18 144 patients stabilized after acute coronary syndrome to simvastatin or ezetimibe/simvastatin. LDL-C and hs-CRP were measured at baseline and 1 month after randomization. Outcomes were assessed in those achieving one or both of the prespecified targets of LDL-C<70 mg/dL and hs-CRP<2 mg/L versus achieving neither target, adjusting for differences in baseline characteristics. An exploratory analysis examined targets of LDL-C<50 mg/dL and hs-CRP<1 mg/L. Patients meeting both targets at baseline, with no 1-month values, or with end points before 1 month were excluded. Of 15 179 patients, 39% achieved the dual LDL-C (<70 mg/dL) and hs-CRP (<2 mg/L) targets at 1 month, 14% met neither target, 14% met only the hs-CRP target, and 33% met only the LDL-C target. Those achieving dual targets had lower primary end point rates than those meeting neither target (cardiovascular death, major coronary event, or stroke; 38.9% versus 28.0%; adjusted hazard ratio, 0.73; 0.66-0.81; P<0.001). More patients treated with ezetimibe/simvastatin met dual targets than those treated with simvastatin alone (50% versus 29%, P<0.001). The association of dual-target attainment with improved outcomes was similar irrespective of treatment assignment (P-interaction=0.65). Similar findings were observed using the exploratory targets. Conclusions-Significantly more patients treated with ezetimibe/simvastatin met prespecified and exploratory dual LDL-C and hs-CRP targets than patients treated with simvastatin alone. Reaching both LDL-C and hs-CRP targets was associated with improved outcomes after multivariable adjustment. C1 [Bohula, Erin A.; Giugliano, Robert P.; Cannon, Christopher P.; Zhou, Jing; Murphy, Sabina A.; Braunwald, Eugene] Harvard Univ, Sch Med, Brigham & Womens Hosp, TIMI Study Grp,Cardiovasc Div,Dept Med, Boston, MA 02115 USA. [White, Jennifer A.; Blazing, Michael A.] Duke Clin Res Inst, Durham, NC USA. [Tershakovec, Andrew M.] Merck, Kenilworth, NJ USA. RP Bohula, EA (reprint author), Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, 350 Longwood Ave,First Off Floor, Boston, MA 02115 USA. EM ebohula@partners.org FU Merck and Co, Inc. FX The IMPROVE-IT Trial was sponsored by Merck and Co, Inc. NR 34 TC 34 Z9 34 U1 1 U2 7 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 SEP 29 PY 2015 VL 132 IS 13 BP 1224 EP 1233 DI 10.1161/CIRCULATIONAHA.115.018381 PG 10 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DC5IP UT WOS:000369255000013 PM 26330412 ER PT J AU Shi, P Goodson, JM Hartman, ML Hasturk, H Yaskell, T Vargas, J Cugini, M Barake, R Alsmadi, O Al-Mutawa, S Ariga, J Soparkar, P Behbehani, J Behbehani, K Welty, F AF Shi, Ping Goodson, J. Max Hartman, Mor-Li Hasturk, Hatice Yaskell, Tina Vargas, Jorel Cugini, Maryann Barake, Roula Alsmadi, Osama Al-Mutawa, Sabiha Ariga, Jitendra Soparkar, Pramod Behbehani, Jawad Behbehani, Kazem Welty, Francine TI Continuous Metabolic Syndrome Scores for Children Using Salivary Biomarkers SO PLOS ONE LA English DT Article ID PHYSICAL-ACTIVITY; RISK SCORE; ADOLESCENTS; ADIPONECTIN; LEPTIN; YOUTH; ADIPOCYTOKINES; PREVALENCE; PREDICTORS; CHILDHOOD AB Background Binary definitions of the metabolic syndrome based on the presence of a particular number of individual risk factors are limited, particularly in the pediatric population. To address this limitation, we aimed at constructing composite and continuous metabolic syndrome scores (cmetS) to represent an overall measure of metabolic syndrome (MetS) in a large cohort of metabolically at-risk children, focusing on the use of the usual clinical parameters (waist circumference (WC) and systolic blood pressure (SBP), supplemented with two salivary surrogate variables (glucose and high density lipoprotein cholesterol (HDLC). Two different approaches used to create the scores were evaluated in comparison. Methods Data from 8,112 Kuwaiti children (10.00 +/- 0.67 years) were used to construct two cmetS for each subject. The first cmetS (cmetS-Z) was created by summing standardized residuals of each variable regressed on age and gender; and the second cmetS (cmetS-PCA) was defined as the first principal component from gender-specific principal component analysis based on the four variables. Results There was a graded relationship between both scores and the number of adverse risk factors. The areas under the curve using cmetS-Z and cmetS-PCA as predictors for severe metabolic syndrome (defined as the presence of >= 3 metabolic risk factors) were 0.935 and 0.912, respectively. cmetS-Z was positively associated with WC, SBP, and glucose, but inversely associated with HDLC. Except for the lack of association with glucose, cmetS-PCA was similar to cmetS-Z in boys, but had minimum loading on HDLC in girls. Analysis using quantile regression showed an inverse association of fitness level with cmetS-PCA (p = 0.001 for boys; p = 0.002 for girls), and comparison of cmetS-Z and cmetS-PCA suggested that WC and SBP were main contributory components. Significant alterations in the relationship between cmetS and salivary adipocytokines were demonstrated in overweight and obese children as compared to underweight and normal-weight children. Conclusion We have derived continuous summary scores for MetS from a large-scale pediatric study using two different approaches, incorporating salivary measures as surrogate for plasma measures. The derived scores were viable expressions of metabolic risk, and can be utilized to study the relationships of MetS with various aspects of the metabolic disease process. C1 [Shi, Ping; Goodson, J. Max; Hartman, Mor-Li; Hasturk, Hatice; Yaskell, Tina; Vargas, Jorel; Cugini, Maryann; Soparkar, Pramod] Forsyth Res Inst, Dept Appl Oral Sci, Cambridge, MA 02142 USA. [Barake, Roula; Alsmadi, Osama; Behbehani, Kazem] Dasman Diabet Inst, Kuwait, Kuwait. [Al-Mutawa, Sabiha; Ariga, Jitendra] Minist Hlth, Kuwait, Kuwait. [Behbehani, Jawad] Kuwait Univ, Fac Dent, Kuwait, Kuwait. [Welty, Francine] Beth Israel Deaconess Med Ctr, Div Cardiol, Boston, MA 02215 USA. RP Shi, P (reprint author), Forsyth Res Inst, Dept Appl Oral Sci, Cambridge, MA 02142 USA. EM pscshi@gmail.com; mgoodson@forsyth.org FU Dasman Diabetes Institute in Kuwait; [P30 DK46200] FX This project was funded by a grant from the Dasman Diabetes Institute in Kuwait. The authors also received a consultation service from Boston Nutrition and Obesity Research Center, supported by grant P30 DK46200. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 1 Z9 1 U1 0 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 SEP 29 PY 2015 VL 10 IS 9 AR e0138979 DI 10.1371/journal.pone.0138979 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CS6EV UT WOS:000362171400030 PM 26418011 ER PT J AU Anderson, TS Good, CB Gellad, WF AF Anderson, Timothy S. Good, Chester B. Gellad, Walid F. TI Prevalence and compensation of academic leaders, professors, and trustees on publicly traded US healthcare company boards of directors: cross sectional study SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Article ID CONFLICTS-OF-INTEREST; MEDICAL-CENTERS AB OBJECTIVE To identify the prevalence, characteristics, and compensation of members of the boards of directors of healthcare industry companies who hold academic appointments as leaders, professors, or trustees. DESIGN Cross sectional study. SETTING US healthcare companies publicly traded on the NASDAQ or New York Stock Exchange in 2013. PARTICIPANTS 3434 directors of pharmaceutical, biotechnology, medical equipment and supply, and healthcare provider companies. MAIN OUTCOME MEASURES Prevalence, annual compensation, and beneficial stock ownership of directors with affiliations as leaders, professors, or trustees of academic medical and research institutions. RESULTS 446 healthcare companies met the study search criteria, of which 442 (99%) had publicly accessible disclosures on boards of directors. 180 companies (41%) had one or more academically affiliated directors. Directors were affiliated with 85 geographically diverse non-profit academic institutions, including 19 of the top 20 National Institute of Health funded medical schools and all of the 17 US News honor roll hospitals. Overall, these 279 academically affiliated directors included 73 leaders, 121 professors, and 85 trustees. Leaders included 17 chief executive officers and 11 vice presidents or executive officers of health systems and hospitals; 15 university presidents, provosts, and chancellors; and eight medical school deans or presidents. The total annual compensation to academically affiliated directors for their services to companies was $54 995 786 (35 pound 836 000; (sic)49 185 900) (median individual compensation $193 000) and directors beneficially owned 59 831 477 shares of company stock (median 50 699 shares). CONCLUSIONS A substantial number and diversity of academic leaders, professors, and trustees hold directorships at US healthcare companies, with compensation often approaching or surpassing common academic clinical salaries. Dual obligations to for profit company shareholders and non-profit clinical and educational institutions pose considerable personal, financial, and institutional conflicts of interest beyond that of simple consulting relationships. These conflicts have not been fully addressed by professional societies or academic institutions and deserve additional review, regulation, and, in some cases, prohibition when conflicts cannot be reconciled. C1 [Anderson, Timothy S.] Univ Pittsburgh, Med Ctr, Dept Internal Med, Pittsburgh, PA USA. [Good, Chester B.; Gellad, Walid F.] VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA 15240 USA. [Good, Chester B.] Univ Pittsburgh, VA Ctr Medicat Safety, Dept Vet Affairs, Sch Med, Pittsburgh, PA 15260 USA. [Gellad, Walid F.] Univ Pittsburgh, Ctr Pharmaceut Policy & Prescribing, Pittsburgh, PA 15240 USA. [Gellad, Walid F.] Univ Pittsburgh, Div Gen Internal Med, Pittsburgh, PA 15240 USA. RP Gellad, WF (reprint author), VA Pittsburgh Healthcare Syst, Pittsburgh, PA 15240 USA. EM wfg3@pitt.edu FU VA Health Services Research and Development award [CDA 09-207] FX WFG was supported by a VA Health Services Research and Development award CDA 09-207. The funder had no role in the design and conduct of the study, collection, management, analysis, and interpretation of data, or preparation of the manuscript. NR 25 TC 3 Z9 3 U1 0 U2 1 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 SEP 29 PY 2015 VL 351 AR h4826 DI 10.1136/bmj.h4826 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA CS9YU UT WOS:000362450900005 PM 26420786 ER PT J AU Otipoby, KL Waisman, A Derudder, E Srinivasan, L Franklin, A Rajewsky, K AF Otipoby, Kevin L. Waisman, Ari Derudder, Emmanuel Srinivasan, Lakshmi Franklin, Andrew Rajewsky, Klaus TI The B-cell antigen receptor integrates adaptive and innate immune signals SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE BCR; B-cell proliferation; PI-3K; GSK3 beta; Foxo1 ID MOUSE IMMUNOGLOBULIN ANTIBODIES; LYMPHOCYTE DEVELOPMENT; KAPPA-B; GENE; ACTIVATION; KINASE; EXPRESSION; RESPONSES; SURVIVAL; PATHWAY AB B cells respond to antigens by engagement of their B-cell antigen receptor (BCR) and of coreceptors through which signals from helper T cells or pathogen-associated molecular patterns are delivered. We show that the proliferative response of B cells to the latter stimuli is controlled by BCR-dependent activation of phosphoinositidyl 3-kinase (PI-3K) signaling. Glycogen synthase kinase 3 beta and Foxo1 are two PI-3K-regulated targets that play important roles, but to different extents, depending on the specific mitogen. These results suggest a model for integrating signals from the innate and the adaptive immune systems in the control of the B-cell immune response. C1 [Otipoby, Kevin L.; Derudder, Emmanuel; Srinivasan, Lakshmi; Rajewsky, Klaus] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Waisman, Ari; Rajewsky, Klaus] Univ Cologne, Inst Genet, D-50674 Cologne, Germany. [Derudder, Emmanuel; Franklin, Andrew; Rajewsky, Klaus] Max Delbruck Ctr Mol Med, Lab Immune Regulat & Canc, D-13125 Berlin, Germany. RP Rajewsky, K (reprint author), Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. EM kevin.otipoby@biogen.com; Klaus.Rajewsky@mdc-berlin.de RI Waisman, Ari/C-7383-2015 OI Waisman, Ari/0000-0003-4304-8234 FU National Institutes of Health [AI057947, AI054636]; European Research Council [ERC-2010-AdG_20100317, 268921]; European Commission [H2020-MSCA-IF-2014_ST, 660883] FX We thank Stefano Casola, Marc Schmidt-Supprian, Dinis P. Calado, Jane Seagal, Sergei B. Koralov, and Michael Reth for helpful discussions. We thank Joanne L. Viney for critically reading the finished manuscript. We are grateful to Junrong Xia, Dvora Ghitza, Anthony Monti, Alex Pellerin, and Jackie Grundy for technical support. We thank Riikka Lauhkonen-Seitz for administrative assistance. This work was supported by National Institutes of Health Grants AI057947 and AI054636. K.R. is supported by an Advanced Grant from the European Research Council (ERC-2010-AdG_20100317 Grant 268921). A.F. is supported by a Marie Sklodowska-Curie Actions Individual Fellowship from the European Commission (H2020-MSCA-IF-2014_ST Grant 660883). NR 30 TC 1 Z9 1 U1 6 U2 11 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 SEP 29 PY 2015 VL 112 IS 39 BP 12145 EP 12150 DI 10.1073/pnas.1516428112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CS2ZU UT WOS:000361941600045 PM 26371314 ER PT J AU Kamat, NP Tobe, S Hill, IT Szostak, JW AF Kamat, Neha P. Tobe, Sylvia Hill, Ian T. Szostak, Jack W. TI Electrostatic Localization of RNA to Protocell Membranes by Cationic Hydrophobic Peptides SO ANGEWANDTE CHEMIE-INTERNATIONAL EDITION LA English DT Article DE origin of life; peptides; protocells; RNA; vesicles ID CELL-PENETRATING PEPTIDES; ANTIMICROBIAL PEPTIDES; PHOSPHOLIPID-BILAYERS; VESICLES; MECHANISM; COMPLEXES; KINETICS; ORIGIN AB Cooperative interactions between RNA and vesicle membranes on the prebiotic earth may have led to the emergence of primitive cells. The membrane surface offers a potential platform for the catalysis of reactions involving RNA, but this scenario relies upon the existence of a simple mechanism by which RNA could become associated with protocell membranes. Here, we show that electrostatic interactions provided by short, basic, amphipathic peptides can be harnessed to drive RNA binding to both zwitterionic phospholipid and anionic fatty acid membranes. We show that the association of cationic molecules with phospholipid vesicles can enhance the local positive charge on a membrane and attract RNA polynucleotides. This phenomenon can be reproduced with amphipathic peptides as short as three amino acids. Finally, we show that peptides can cross bilayer membranes to localize encapsulated RNA. This mechanism of polynucleotide confinement could have been important for primitive cellular evolution. C1 [Kamat, Neha P.; Tobe, Sylvia; Hill, Ian T.; Szostak, Jack W.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Dept Mol Biol, Boston, MA 02114 USA. [Kamat, Neha P.; Tobe, Sylvia; Hill, Ian T.; Szostak, Jack W.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Tobe, Sylvia] Ra Pharmaceut, Cambridge, MA 02139 USA. [Hill, Ian T.] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. [Hill, Ian T.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02129 USA. RP Szostak, JW (reprint author), Massachusetts Gen Hosp, Howard Hughes Med Inst, Dept Mol Biol, Boston, MA 02114 USA. EM szostak@molbio.mgh.harvard.edu RI Kamat, Neha/L-2799-2016 FU NASA Exobiology Program [NNX07AJ09G]; Simons Foundation [290363]; NASA Postdoctoral Program; NSF Graduate Fellowship; NASA FX This work was supported in part by grants from the NASA Exobiology Program (grnat number NNX07AJ09G) and from the Simons Foundation (grant number 290363) to J.W.S. J.W.S. is an Investigator of the Howard Hughes Medical Institute (HHMI). N.P.K. is supported by an appointment to the NASA Postdoctoral Program, administered by Oak Ridge Associated Universities through a contract with NASA. I.T.H. is supported by an NSF Graduate Fellowship. We thank Albert Fahrenbach, Victor Lelyveld, Tony Jia, and all other members of the Szostak lab for helpful comments on the manuscript. NR 26 TC 7 Z9 7 U1 9 U2 35 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1433-7851 EI 1521-3773 J9 ANGEW CHEM INT EDIT JI Angew. Chem.-Int. Edit. PD SEP 28 PY 2015 VL 54 IS 40 BP 11735 EP 11739 DI 10.1002/anie.201505742 PG 5 WC Chemistry, Multidisciplinary SC Chemistry GA CU3AF UT WOS:000363394800023 PM 26223820 ER PT J AU Maesako, M Uemura, M Tashiro, Y Sasaki, K Watanabe, K Noda, Y Ueda, K Asada-Utsugi, M Kubota, M Okawa, K Ihara, M Shimohama, S Uemura, K Kinoshita, A AF Maesako, Masato Uemura, Maiko Tashiro, Yoshitaka Sasaki, Kazuki Watanabe, Kiwamu Noda, Yasuha Ueda, Karin Asada-Utsugi, Megumi Kubota, Masakazu Okawa, Katsuya Ihara, Masafumi Shimohama, Shun Uemura, Kengo Kinoshita, Ayae TI High Fat Diet Enhances beta-Site Cleavage of Amyloid Precursor Protein (APP) via Promoting beta-Site APP Cleaving Enzyme 1/Adaptor Protein 2/Clathrin Complex Formation SO PLOS ONE LA English DT Article ID TRANSGENIC MOUSE MODEL; ALZHEIMERS-DISEASE; CELL-SURFACE; SECRETASE PROTEIN; MEMORY DEFICITS; MICE; DEMENTIA; ENDOCYTOSIS; RISK; GENERATION AB Obesity and type 2 diabetes are risk factors of Alzheimer's disease (AD). We reported that a high fat diet (HFD) promotes amyloid precursor protein (APP) cleavage by beta-site APP cleaving enzyme 1 (BACE1) without increasing BACE1 levels in APP transgenic mice. However, the detailed mechanism had remained unclear. Here we demonstrate that HFD promotes BACE1/Adaptor protein-2 (AP-2)/clathrin complex formation by increasing AP-2 levels in APP transgenic mice. In Swedish APP overexpressing Chinese hamster ovary (CHO) cells as well as in SH-SY5Y cells, overexpression of AP-2 promoted the formation of BACE1/AP2/ clathrin complex, increasing the level of the soluble form of APP beta (sAPP beta). On the other hand, mutant D495R BACE1, which inhibits formation of this trimeric complex, was shown to decrease the level of sAPP beta. Overexpression of AP-2 promoted the internalization of BACE1 from the cell surface, thus reducing the cell surface BACE1 level. As such, we concluded that HFD may induce the formation of the BACE1/AP-2/clathrin complex, which is followed by its transport of BACE1 from the cell surface to the intracellular compartments. These events might be associated with the enhancement of beta-site cleavage of APP in APP transgenic mice. Here we present evidence that HFD, by regulation of subcellular trafficking of BACE1, promotes APP cleavage. C1 [Maesako, Masato; Sasaki, Kazuki; Noda, Yasuha; Ueda, Karin; Asada-Utsugi, Megumi; Kubota, Masakazu; Kinoshita, Ayae] Kyoto Univ, Grad Sch Med, Dept Human Hlth Sci, Kyoto, Japan. [Uemura, Maiko; Watanabe, Kiwamu; Uemura, Kengo] Kyoto Univ, Grad Sch Med, Dept Neurol, Kyoto, Japan. [Tashiro, Yoshitaka] Kyoto Univ, Grad Sch Med, SK Project Med Innovat Ctr, Kyoto, Japan. [Okawa, Katsuya] Kyowa Hakko Kirin Co Ltd, Shizuoka, Japan. [Ihara, Masafumi] Natl Cerebral & Cardiovasc Ctr, Dept Neurol, Osaka, Japan. [Shimohama, Shun] Sapporo Med Univ, Dept Neurol, Sapporo, Hokkaido, Japan. [Uemura, Kengo] Ishiki Hosp, Kagoshima, Japan. RP Kinoshita, A (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis,Alzheimers Dis Re, Charlestown, MA 02129 USA. EM kinoshita.ayae.6v@kyoto-u.ac.jp FU Ministry of Education, Culture, Sports, Science and Technology, Japan [24111524, 23591243, 13J00221]; Japan Society for the Promotion of Science [820130600001]; Kyowa Hakko Kirin Co., Ltd FX AK, K. Uemura and MM are funded with Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology, Japan (AK: 24111524, K. Uemura: 23591243, MM: 13J00221, URL: http://www.mext.go.jp/a_menu/shinkou/hojyo/main5_a5.htm). MM is funded with Japan Society for the Promotion of Science research fellowship (820130600001, URL: http://www.jsps.go.jp/). Kyowa Hakko Kirin Co., Ltd provided support in the form of salary for author KO, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific role of this author is articulated in the 'author contributions' section. NR 47 TC 6 Z9 6 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 28 PY 2015 VL 10 IS 9 AR e0131199 DI 10.1371/journal.pone.0131199 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CS6EO UT WOS:000362170700001 PM 26414661 ER PT J AU Namjou, B Marsolo, K Lingren, T Ritchie, MD Verma, SS Cobb, BL Perry, C Kitchner, TE Brilliant, MH Peissig, PL Borthwick, KM Williams, MS Grafton, J Jarvik, GP Holm, IA Harley, JB AF Namjou, Bahram Marsolo, Keith Lingren, Todd Ritchie, Marylyn D. Verma, Shefali S. Cobb, Beth L. Perry, Cassandra Kitchner, Terrie E. Brilliant, Murray H. Peissig, Peggy L. Borthwick, Kenneth M. Williams, Marc S. Grafton, Jane Jarvik, Gail P. Holm, Ingrid A. Harley, John B. TI A GWAS Study on Liver Function Test Using eMERGE Network Participants SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; SERUM BILIRUBIN LEVELS; CORONARY-HEART-DISEASE; SYNDROME TYPE-II; 7-ETHYL-10-HYDROXYCAMPTOTHECIN SN-38; ALKALINE-PHOSPHATASE; ACTIVE METABOLITE; GILBERTS-SYNDROME; UGT1A1 GENE; POPULATION AB Introduction Liver enzyme levels and total serum bilirubin are under genetic control and in recent years genome-wide population-based association studies have identified different susceptibility loci for these traits. We conducted a genome-wide association study in European ancestry participants from the Electronic Medical Records and Genomics (eMERGE) Network dataset of patient medical records with available genotyping data in order to identify genetic contributors to variability in serum bilirubin levels and other liver function tests and to compare the effects between adult and pediatric populations. Methods The process of whole genome imputation of eMERGE samples with standard quality control measures have been described previously. After removing missing data and outliers based on principal components (PC) analyses, 3294 samples from European ancestry were used for the GWAS study. The association between each single nucleotide polymorphism (SNP) and total serum bilirubin and other liver function tests was tested using linear regression, adjusting for age, gender, site, platform and ancestry principal components (PC). Results Consistent with previous results, a strong association signal has been detected for UGT1A gene cluster (best SNP rs887829, beta = 0.15, p = 1.30x10(-118)) for total serum bilirubin level. Indeed, in this region more than 176 SNPs (or indels) had p<10(-8) spanning 150Kb on the long arm of chromosome 2q37.1. In addition, we found a similar level of magnitude in a pediatric group (p = 8.26x10(-47), beta = 0.17). Further imputation using sequencing data as a reference panel revealed association of other markers including known TA7 repeat indels (rs8175347) (p = 9.78x10(-117)) and rs111741722 (p = 5.41x10(-119)) which were in proxy (r2 = 0.99) with rs887829. Among rare variants, two Asian subjects homozygous for coding SNP rs4148323 (G71R) were identified. Additional known effects for total serum bilirubin were also confirmed including organic anion transporters SLCO1B1-SLCO1B3, TDRP and ZMYND8 at FDR<0.05 with no gene-gene interaction effects. Phenome-wide association studies (PheWAS) suggest a protective effect of TA7 repeat against cerebrovascular disease in an adult cohort (OR = 0.75, p = 0.0008). Among other liver function tests, we also confirmed the previous effect of the ABO blood group locus for variation in serum alkaline phosphatase (rs579459, p = 9.44x10(-15)). Conclusions Taken together, our data present interesting findings with strong confirmation of previous effects by simply using the eMERGE electronic health record phenotyping. In addition, our findings indicate that similar to the adult population, the UGT1A1 is the main locus responsible for normal variation of serum bilirubin in pediatric populations. C1 [Namjou, Bahram; Cobb, Beth L.; Harley, John B.] Cincinnati Childrens Hosp Med Ctr CCHMC, Ctr Autoimmune Genom & Etiol, Cincinnati, OH 45229 USA. [Namjou, Bahram; Marsolo, Keith; Lingren, Todd; Harley, John B.] Univ Cincinnati, Coll Med, Cincinnati, OH USA. [Marsolo, Keith; Lingren, Todd] Cincinnati Childrens Hosp Med Ctr, Div Biomed Informat, Cincinnati, OH 45229 USA. [Ritchie, Marylyn D.; Verma, Shefali S.] Penn State Univ, Ctr Syst Genom, University Pk, PA 16802 USA. [Perry, Cassandra] Boston Childrens Hosp BCH, Div Genet & Genom, Boston, MA USA. [Kitchner, Terrie E.; Brilliant, Murray H.; Peissig, Peggy L.] Marshfield Clin Fdn Med Res & Educ, Ctr Human Genet, Marshfield, WI USA. [Borthwick, Kenneth M.; Williams, Marc S.] Geisinger Hlth Syst, Genom Med Inst, Danville, PA USA. [Grafton, Jane] Grp Hlth Res Inst, Seattle, WA USA. [Jarvik, Gail P.] Univ Washington, Dept Med, Seattle, WA USA. [Jarvik, Gail P.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Holm, Ingrid A.] Boston Childrens Hosp, Div Genet & Genom, Boston, MA USA. [Holm, Ingrid A.] Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Boston, MA USA. [Holm, Ingrid A.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Harley, John B.] US Dept Vet Affairs, Med Ctr, Cincinnati, OH USA. RP Namjou, B (reprint author), Cincinnati Childrens Hosp Med Ctr CCHMC, Ctr Autoimmune Genom & Etiol, Cincinnati, OH 45229 USA. EM Bahram.namjou@cchmc.org FU National Institutes of Health [U01HG006828, U01HG006389, U01HG006382, U01HG006375, U01HG006385, U01HG004438] FX This study was supported by the National Institutes of Health (http://www.nih.gov/) grants: U01HG006828-NHGRI-Cincinnati Children's Hospital Medical Center/Boston Children's Hospital (to JBH, IAH, BN, BLC, KM, TL, CP); U01HG006389-NHGRI-Essentia Institute of Rural Health, Marshfield Clinic Research Foundation and Pennsylvania State University (to PLP, MHB, TEK, MDR, SSV); U01HG006382-NHGRI-Geisinger Clinic (to MSW, KMB); U01HG006375-NHGRI-Group Health Cooperative/University of Washington (to GPJ, JG); U01HG006385-NHGRI-Vanderbilt University Medical Center serving as the Coordinating Center and the PGRNSeq dataset (eMERGE PGx); U01HG004438-NHGRI- The Center for Inherited Disease Research (CIDR) serving as a Sequencing Center for eMERGE. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 6 Z9 6 U1 2 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 28 PY 2015 VL 10 IS 9 AR e0138677 DI 10.1371/journal.pone.0138677 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CS6EO UT WOS:000362170700020 PM 26413716 ER PT J AU Garland, A Rolfson, O Garellick, G Karrholm, J Hailer, NP AF Garland, Anne Rolfson, Ola Garellick, Goran Karrholm, Johan Hailer, Nils P. TI Early postoperative mortality after simultaneous or staged bilateral primary total hip arthroplasty: an observational register study from the Swedish Hip Arthroplasty Register (vol 16, 77, 2015) SO BMC MUSCULOSKELETAL DISORDERS LA English DT Correction C1 [Garland, Anne] Visby Hosp, Dept Orthopaed, Visby, Sweden. [Garland, Anne; Rolfson, Ola; Garellick, Goran; Karrholm, Johan; Hailer, Nils P.] Swedish Hip Arthroplasty Register, Gothenburg, Sweden. [Rolfson, Ola; Garellick, Goran; Karrholm, Johan] Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Dept Orthopaed, Gothenburg, Sweden. [Garland, Anne; Hailer, Nils P.] Univ Uppsala Hosp, Inst Surg Sci, Dept Orthopaed, Uppsala, Sweden. [Rolfson, Ola] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Harris Orthopaed Lab, Boston, MA USA. RP Garland, A (reprint author), Visby Hosp, Dept Orthopaed, Visby, Sweden. EM anne.garland@gotland.se NR 2 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2474 J9 BMC MUSCULOSKEL DIS JI BMC Musculoskelet. Disord. PD SEP 28 PY 2015 VL 16 AR 263 DI 10.1186/s12891-015-0717-9 PG 1 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA CS1BJ UT WOS:000361796700001 PM 26415948 ER PT J AU von Keudell, AG Weaver, MJ Appelton, PT Bae, DS Dyer, GSM Heng, M Jupiter, JB Vrahas, MS AF von Keudell, Arvind G. Weaver, Michael J. Appelton, Paul T. Bae, Donald S. Dyer, George S. M. Heng, Marilyn Jupiter, Jesse B. Vrahas, Mark S. TI Diagnosis and treatment of acute extremity compartment syndrome SO LANCET LA English DT Article ID NEAR-INFRARED SPECTROSCOPY; QUALITY-OF-LIFE; TIBIAL FRACTURES; LOWER LEG; TISSUE PRESSURE; LOWER-LIMB; INTRACOMPARTMENTAL PRESSURE; ISCHEMIC CONTRACTURE; MUSCLE ISCHEMIA; SKELETAL-MUSCLE AB Acute compartment syndrome of the extremities is well known, but diagnosis can be challenging. Ineffective treatment can have devastating consequences, such as permanent dysaesthesia, ischaemic contractures, muscle dysfunction, loss of limb, and even loss of life. Despite many studies, there is no consensus about the way in which acute extremity compartment syndromes should be diagnosed. Many surgeons suggest continuous monitoring of intracompartmental pressure for all patients who have high-risk extremity injuries, whereas others suggest aggressive surgical intervention if acute compartment syndrome is even suspected. Although surgical fasciotomy might reduce intracompartmental pressure, this procedure also carries the risk of long-term complications. In this paper in The Lancet Series about emergency surgery we summarise the available data on acute extremity compartment syndrome of the upper and lower extremities in adults and children, discuss the underlying pathophysiology, and propose a clinical guideline based on the available data. C1 [von Keudell, Arvind G.; Weaver, Michael J.; Appelton, Paul T.; Dyer, George S. M.; Jupiter, Jesse B.; Vrahas, Mark S.] Harvard Univ, Sch Med, Orthoped Trauma Initiat, Boston, MA 02114 USA. [Dyer, George S. M.; Heng, Marilyn; Jupiter, Jesse B.; Vrahas, Mark S.] Harvard Univ, Sch Med, Dept Orthoped Surg, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Weaver, Michael J.; Dyer, George S. M.; Vrahas, Mark S.] Harvard Univ, Sch Med, Dept Orthoped Surg, Brigham & Womens Hosp, Boston, MA 02114 USA. [Bae, Donald S.] Harvard Univ, Sch Med, Dept Orthoped Surg, Boston Childrens Hosp, Boston, MA 02114 USA. [Appelton, Paul T.] Harvard Univ, Sch Med, Dept Orthoped Surg, Beth Israel Deaconess Hosp, Boston, MA 02114 USA. RP von Keudell, AG (reprint author), Harvard Univ, Sch Med, Orthoped Trauma Initiat, Boston, MA 02114 USA. EM avonkeudell@mgh.harvard.edu NR 104 TC 4 Z9 4 U1 3 U2 15 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 SEP 26 PY 2015 VL 386 IS 10000 BP 1299 EP 1310 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA CR9TQ UT WOS:000361700100039 PM 26460664 ER PT J AU Anderson, JC Willey, CD Mehta, A Welaya, K Chen, DQ Duarte, CW Ghatalia, P Arafat, W Madan, A Sudarshan, S Naik, G Grizzle, WE Choueiri, TK Sonpavde, G AF Anderson, Joshua C. Willey, Christopher D. Mehta, Amitkumar Welaya, Karim Chen, Dongquan Duarte, Christine W. Ghatalia, Pooja Arafat, Waleed Madan, Ankit Sudarshan, Sunil Naik, Gurudatta Grizzle, William E. Choueiri, Toni K. Sonpavde, Guru TI High Throughput Kinomic Profiling of Human Clear Cell Renal Cell Carcinoma Identifies Kinase Activity Dependent Molecular Subtypes SO PLOS ONE LA English DT Article ID BIOMARKERS; EVOLUTION; TUMORS; EXOME AB Despite the widespread use of kinase-targeted agents in clear cell renal cell carcinoma (CC-RCC), comprehensive kinase activity evaluation (kinomic profiling) of these tumors is lacking. Thus, kinomic profiling of CC-RCC may assist in devising a classification system associated with clinical outcomes, and help identify potential therapeutic targets. Fresh frozen CC-RCC tumor lysates from 41 clinically annotated patients who had localized disease at diagnosis were kinomically profiled using the PamStation (R) 12 high-content phospho-peptide substrate microarray system (PamGene International). Twelve of these patients also had matched normal kidneys available that were also profiled. Unsupervised hierarchical clustering and supervised comparisons based on tumor vs. normal kidney and clinical outcome (tumor recurrence) were performed and coupled with advanced network modeling and upstream kinase prediction methods. Unsupervised clustering analysis of localized CC-RCC tumors identified 3 major kinomic groups associated with inflammation (A), translation initiation (B), and immune response and cell adhesions (C) processes. Potential driver kinases implicated include PFTAIRE (PFTK1), PKG1, and SRC, which were identified in groups A, B, and C, respectively. Of the 9 patients who had tumor recurrence, only one was found in Group B. Supervised analysis showed decreased kinase activity of CDK1 and RSK1-4 substrates in those which progressed compared to others. Twelve tumors with matching normal renal tissue implicated increased PIM's and MAPKAPK's in tumors compared to adjacent normal renal tissue. As such, comprehensive kinase profiling of CC-RCC tumors could provide a functional classification strategy for patients with localized disease and identify potential therapeutic targets. C1 [Anderson, Joshua C.; Willey, Christopher D.] Univ Alabama Birmingham, Dept Radiat Oncol, Birmingham, AL 35294 USA. [Mehta, Amitkumar; Ghatalia, Pooja; Madan, Ankit; Naik, Gurudatta; Sonpavde, Guru] Univ Alabama Birmingham, Div Hematol & Oncol, Birmingham, AL 35294 USA. [Chen, Dongquan] Univ Alabama Birmingham, Div Preventat Med, Birmingham, AL USA. [Sudarshan, Sunil] Univ Alabama Birmingham, Dept Urol, Birmingham, AL USA. [Grizzle, William E.] Univ Alabama Birmingham, Div Anat Pathol, Birmingham, AL USA. [Welaya, Karim; Arafat, Waleed] Univ Alexandria, Dept Clin Oncol, Alexandria, Egypt. [Duarte, Christine W.] MMCRI, CORE, Portland, ME USA. [Choueiri, Toni K.] Dana Farber Canc Inst, Kidney Canc Ctr, Dept Med Oncol, Boston, MA 02115 USA. [Choueiri, Toni K.] Harvard Univ, Sch Med, Boston, MA USA. RP Sonpavde, G (reprint author), Univ Alabama Birmingham, Div Hematol & Oncol, Birmingham, AL 35294 USA. EM gsonpavde@uabmc.edu OI Anderson, Joshua/0000-0002-6977-9054 FU Egyptian Partnership & Ownership Initiative Fellowship Grant; Comprehensive Cancer Center Pilot Grant Program [P30CA013148] FX Egyptian Partnership & Ownership Initiative Fellowship Grant provided the stipend support for UAB Kinome Core Fellow (KW). The UAB Comprehensive Cancer Center Pilot Grant Program (P30CA013148) provided funding for the experimental work (to GS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 8 Z9 8 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 25 PY 2015 VL 10 IS 9 AR e0139267 DI 10.1371/journal.pone.0139267 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CS1CR UT WOS:000361800700201 PM 26406598 ER PT J AU Koh, SH Liang, AC Takahashi, Y Maki, T Shindo, A Osumi, N Zhao, J Lin, H Holder, JC Chuang, TT McNeish, JD Arai, K Lo, EH AF Koh, Seong-Ho Liang, Anna C. Takahashi, Yoko Maki, Takakuni Shindo, Akihiro Osumi, Noriko Zhao, Jing Lin, Hong Holder, Julie C. Chuang, Tsu Tshen McNeish, John D. Arai, Ken Lo, Eng H. TI Differential Effects of Isoxazole-9 on Neural Stem/Progenitor Cells, Oligodendrocyte Precursor Cells, and Endothelial Progenitor Cells SO PLOS ONE LA English DT Article ID STROKE RECOVERY; SMALL-MOLECULE; STEM-CELLS; BRAIN; ANGIOGENESIS; NEUROGENESIS; PROLIFERATION; TRANSLATION; THERAPY; FATE AB Adult mammalian brain can be plastic after injury and disease. Therefore, boosting endogenous repair mechanisms would be a useful therapeutic approach for neurological disorders. Isoxazole-9 (Isx-9) has been reported to enhance neurogenesis from neural stem/progenitor cells (NSPCs). However, the effects of Isx-9 on other types of progenitor/precursor cells remain mostly unknown. In this study, we investigated the effects of Isx-9 on the three major populations of progenitor/precursor cells in brain: NSPCs, oligodendrocyte precursor cells (OPCs), and endothelial progenitor cells (EPCs). Cultured primary NSPCs, OPCs, or EPCs were treated with various concentrations of Isx-9 (6.25, 12.5, 25, 50 mu M), and their cell numbers were counted in a blinded manner. Isx-9 slightly increased the number of NSPCs and effectively induced neuronal differentiation of NSPCs. However, Isx-9 significantly decreased OPC number in a concentration-dependent manner, suggesting cytotoxicity. Isx-9 did not affect EPC cell number. But in a matrigel assay of angiogenesis, Isx-9 significantly inhibited tube formation in outgrowth endothelial cells derived from EPCs. This potential anti-tube-formation effect of Isx-9 was confirmed in a brain endothelial cell line. Taken together, our data suggest that mechanisms and targets for promoting stem/progenitor cells in the central nervous system may significantly differ between cell types. C1 [Koh, Seong-Ho; Liang, Anna C.; Takahashi, Yoko; Maki, Takakuni; Shindo, Akihiro; Arai, Ken; Lo, Eng H.] Massachusetts Gen Hosp, Dept Radiol & Neurol, Neuroprotect Res Lab, Charlestown, MA 02129 USA. [Koh, Seong-Ho; Liang, Anna C.; Takahashi, Yoko; Maki, Takakuni; Shindo, Akihiro; Arai, Ken; Lo, Eng H.] Harvard Univ, Sch Med, Charlestown, MA USA. [Koh, Seong-Ho] Hanyang Univ, Coll Med, Dept Neurol, Seoul 133791, South Korea. [Takahashi, Yoko; Osumi, Noriko] Tohoku Univ, Grad Sch Med, United Ctr Adv Res & Translat Med, Dept Dev Neurosci, Sendai, Miyagi 980, Japan. [Zhao, Jing; Lin, Hong; Holder, Julie C.; Chuang, Tsu Tshen; McNeish, John D.] GlaxoSmithKline, Regenerat Med Discovery Performance Unit, Cambridge, MA USA. RP Lo, EH (reprint author), Massachusetts Gen Hosp, Dept Radiol & Neurol, Neuroprotect Res Lab, Charlestown, MA 02129 USA. EM Lo@helix.mgh.harvard.edu FU National Institutes of Health [P01-NS55104]; Uehara Memorial Foundation; Glaxo-Smith-Kline-Harvard-Stem-Cell-Institute consortium; Glaxo-Smith-Kline FX Work was supported in part by grants from the National Institutes of Health (P01-NS55104), the Uehara Memorial Foundation, and the Glaxo-Smith-Kline-Harvard-Stem-Cell-Institute consortium. Salaries for authors with primary appointments with Glaxo-Smith-Kline (JZ, HL, JCH, TTC, and JDM) were paid by Glaxo-Smith-Kline. JZ, HL, JCH, TTC, and JDM participated in study design and data analysis. NR 25 TC 5 Z9 5 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 25 PY 2015 VL 10 IS 9 AR e0138724 DI 10.1371/journal.pone.0138724 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CS1CR UT WOS:000361800700076 PM 26407349 ER PT J AU Byun, S Lim, S Mun, JY Kim, KH Ramadhar, TR Farrand, L Shin, SH Thimmegowda, NR Lee, HJ Frank, DA Clardy, J Lee, SW Lee, KW AF Byun, Sanguine Lim, Semi Mun, Ji Young Kim, Ki Hyun Ramadhar, Timothy R. Farrand, Lee Shin, Seung Ho Thimmegowda, N. R. Lee, Hyong Joo Frank, David A. Clardy, Jon Lee, Sam W. Lee, Ki Won TI Identification of a Dual Inhibitor of Janus Kinase 2 (JAK2) and p70 Ribosomal S6 Kinase1 (S6K1) Pathways SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID OVARIAN-CANCER CELLS; ZINGIBER-OFFICINALE; NATURAL-PRODUCTS; PROSTATE-CANCER; GINGER EXTRACT; BREAST-CANCER; GROWTH-FACTOR; APOPTOSIS; EXPRESSION; ACTIVATION AB Bioactive phytochemicals can suppress the growth of malignant cells, and investigation of the mechanisms responsible can assist in the identification of novel therapeutic strategies for cancer therapy. Ginger has been reported to exhibit potent anticancer effects, although previous reports have often focused on a narrow range of specific compounds. Through a direct comparison of various ginger compounds, we determined that gingerenone A selectively kills cancer cells while exhibiting minimal toxicity toward normal cells. Kinase array screening revealed JAK2 and S6K1 as the molecular targets primarily responsible for gingerenone A-induced cancer cell death. The effect of gingerenone A was strongly associated with relative phosphorylation levels of JAK2 and S6K1, and administration of gingerenone A significantly suppressed tumor growth in vivo. More importantly, the combined inhibition of JAK2 and S6K1 by commercial inhibitors selectively induced apoptosis in cancer cells, whereas treatment with either agent alone did not. These findings provide rationale for dual targeting of JAK2 and S6K1 in cancer for a combinatorial therapeutic approach. C1 [Byun, Sanguine; Lee, Sam W.] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. [Byun, Sanguine; Lee, Sam W.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Byun, Sanguine; Lee, Ki Won] Seoul Natl Univ, Adv Inst Convergence Technol, Suwon 443270, South Korea. [Lim, Semi; Lee, Hyong Joo; Lee, Ki Won] Seoul Natl Univ, Dept Agr Biotechnol, WCU Biomodulat Major, Seoul 151742, South Korea. [Mun, Ji Young] Eulji Univ, Coll Hlth Sci, Dept Biomed Lab Sci, Songnam 461463, South Korea. [Kim, Ki Hyun; Ramadhar, Timothy R.; Clardy, Jon] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Kim, Ki Hyun] Sungkyunkwan Univ, Sch Pharm, Suwon 440746, South Korea. [Farrand, Lee] Yuhan Corp, Yuhan Res Inst, Yongin 446902, South Korea. [Shin, Seung Ho] Univ Minnesota, Program Biomed Informat & Computat Biol, Minneapolis, MN 55455 USA. [Thimmegowda, N. R.] Govt Sri Krishnarajendra Silver Jubilee Technol I, Dept Chem, Bangalore 560001, Karnataka, India. [Frank, David A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Thimmegowda, N. R.] Korea Res Inst Biosci & Biotechnol, World Class Inst, Ochang 363883, South Korea. RP Clardy, J (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, 240 Longwood Ave, Boston, MA 02115 USA. EM jon_clardy@hms.harvard.edu; swlee@mgh.harvard.edu; kiwon@snu.ac.kr RI Regan, Clinton/E-6250-2012; OI Ramadhar, Timothy/0000-0002-7063-5445 FU National Institutes of Health [1RO1CA142805, 1RO1CA149477]; National Leap Research Program through National Research Foundation of Korea - Ministry of Science, ICT, and Future Planning (MSIP) of Korea, Republic of Korea [2010-0029233]; F32 postdoctoral fellowship from the National Institutes of Health [GM108415] FX This work was supported, in whole or in part, by National Institutes of Health Grant 1RO1CA142805 and 1RO1CA149477 (NCI). This work was also supported by the National Leap Research Program (2010-0029233) through the National Research Foundation of Korea funded by the Ministry of Science, ICT, and Future Planning (MSIP) of Korea, Republic of Korea. The authors declare that they have no conflicts of interest with the contents of this article.; Supported by an F32 postdoctoral fellowship from the National Institutes of Health (GM108415). NR 60 TC 0 Z9 0 U1 0 U2 5 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 SEP 25 PY 2015 VL 290 IS 39 BP 23553 EP 23562 DI 10.1074/jbc.M115.662445 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CS1IF UT WOS:000361816500008 PM 26242912 ER PT J AU Wheeler, TM Baker, JN Chad, DA Zilinski, JL Verzosa, S Mordes, DA AF Wheeler, Thurman M. Baker, Joshua N. Chad, David A. Zilinski, Jodi L. Verzosa, Stacey Mordes, Daniel A. TI Case 30-2015: A 50-Year-Old Man with Cardiogenic Shock SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID EXTRACORPOREAL MEMBRANE-OXYGENATION; MYOTONIC-DYSTROPHY TYPE-1; EFFECTIVE ANTIMYOTONIA TREATMENT; ADULT PATIENTS; ABNORMALITIES; EXPERIENCE; MEXILETINE; EXPANSION; SUPPORT; MUSCLE C1 [Wheeler, Thurman M.; Chad, David A.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Verzosa, Stacey] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Mordes, Daniel A.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Baker, Joshua N.] Massachusetts Gen Hosp, Div Cardiac Surg, Boston, MA 02114 USA. [Zilinski, Jodi L.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Wheeler, Thurman M.; Chad, David A.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Baker, Joshua N.] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Zilinski, Jodi L.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Verzosa, Stacey] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Mordes, Daniel A.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Wheeler, TM (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. NR 23 TC 1 Z9 1 U1 1 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 24 PY 2015 VL 373 IS 13 BP 1251 EP 1261 DI 10.1056/NEJMcpc1415169 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA CR8WP UT WOS:000361635200012 PM 26398074 ER PT J AU Kassim, AA Payne, AB Rodeghier, M Macklin, EA Strunk, RC DeBaun, MR AF Kassim, Adetola A. Payne, Amanda B. Rodeghier, Mark Macklin, Eric A. Strunk, Robert C. DeBaun, Michael R. TI Low forced expiratory volume is associated with earlier death in sickle cell anemia SO BLOOD LA English DT Article ID LUNG-FUNCTION; PULMONARY-FUNCTION; CYSTIC-FIBROSIS; REFERENCE VALUES; FUNCTION TESTS; FOLLOW-UP; DISEASE; MORTALITY; RISK; ADULTS AB Pulmonary complications result in mortality in adults with sickle cell anemia (SCA). We tested the hypothesis that abnormal pulmonary function was associated with earlier death. A prospective cohort of adults with SCA, followed in the Cooperative Study for Sickle Cell Disease, was constructed using the first pulmonary function test at >21 years of age. Spirometry measures: forced expiratory volume in 1 second (FEV1), forced vital capacity, and total lung capacity were categorized based on age, gender, height, and race. Pulmonary function patterns were categorized based on the American Thoracic Society guidelines using both spirometry and lung volumes. A cohort of 430 adults with SCA, mean age 32.6 +/- 9.5 (range, 21.0-67.8) years at time of first pulmonary function test, and a median follow-up of 5.5 years, was evaluated. A total of 63 deaths occurred. At baseline, 47% had normal, 29% restrictive, 8% obstructive, 2% mixed, and 14% nonspecific lung function patterns. In the final multivariable model, lower FEV1 percent predicted was associated with increased hazard ratio of death (HRper% predicted 1.02; 95% confidence interval [CI] 1.00-1.04; P=.037), as was older age(HR 1.07; 95% CI 1.04-1.10; P<.001), male sex (HR 2.09; 95% CI 1.20-3.65; P=.010), higher lactate dehydrogenase levels (HR per mg/dL 1.002; 95% CI 1.00-1.003; P=.015), and higher acute chest syndrome incidence rate (HR per event/year 10.4; 95% CI 3.11-34.8; P < .001). Presence of obstructive (HR 1.18; 95% CI: 0.44-3.20; P=.740) and restrictive (HR 1.31; 95% CI: 0.64-2.32; P = .557) pulmonary function patterns were not associated with earlier death. Understanding the pathophysiology of a low FEV1 percent predicted in individuals with SCA is warranted, enabling early intervention for those at risk. C1 [Kassim, Adetola A.] Vanderbilt Univ, Sch Med, Dept Med, Div Hematol Oncol, Nashville, TN 37232 USA. [Kassim, Adetola A.; DeBaun, Michael R.] Vanderbilt Univ, Sch Med, Vanderbilt Meharry Ctr Excellence Sickle Cell Dis, Nashville, TN 37232 USA. [Payne, Amanda B.] Ctr Dis Control & Prevent, Natl Ctr Birth Defects & Dev Disabil, Atlanta, GA USA. [Rodeghier, Mark] Rodeghier Consultants, Chicago, IL USA. [Macklin, Eric A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Macklin, Eric A.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Strunk, Robert C.] Washington Univ, Sch Med, Dept Pediat, Div Allergy Immunol & Pulm Med, St Louis, MO 63110 USA. [DeBaun, Michael R.] Vanderbilt Univ, Sch Med, Dept Pediat & Med, Div Hematol Oncol, Nashville, TN 37232 USA. RP DeBaun, MR (reprint author), Vanderbilt Univ, Sch Med, Vanderbilt Meharry Ctr Excellence Sickle Cell Dis, Dept Pediat, 2200 Childrens Way,11206DOT, Nashville, TN 37232 USA. EM m.debaun@vanderbilt.edu OI Macklin, Eric/0000-0003-1618-3502 FU National Institutes of Health, National Heart, Lung, and Blood Institute [5R01-HL079937-07]; Burroughs Wellcome Foundation FX This work was supported in part by the National Institutes of Health, National Heart, Lung, and Blood Institute (grant 5R01-HL079937-07) (R.C.S. and M.R.D.) and the Burroughs Wellcome Foundation (M.R.D.). The funding sources provided the financial resources to conduct the research. M.R.D. confirms that he had full access to all of the data in this study and had the final responsibility for the decision to submit for publication. NR 33 TC 7 Z9 7 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 SEP 24 PY 2015 VL 126 IS 13 BP 1544 EP 1550 DI 10.1182/blood-2015-05-644435 PG 7 WC Hematology SC Hematology GA CU4EX UT WOS:000363481000008 PM 26261241 ER PT J AU Bhatt, S Matthews, J Parvin, S Sarosiek, KA Zhao, DK Jiang, XY Isik, E Letai, A Lossos, IS AF Bhatt, Shruti Matthews, Julie Parvin, Salma Sarosiek, Kristopher A. Zhao, Dekuang Jiang, Xiaoyu Isik, Elif Letai, Anthony Lossos, Izidore S. TI Direct and immune-mediated cytotoxicity of interleukin-21 contributes to antitumor effects in mantle cell lymphoma SO BLOOD LA English DT Article ID RECOMBINANT HUMAN INTERLEUKIN-21; LYMPHOCYTIC-LEUKEMIA CELLS; PROGRESSION-FREE SURVIVAL; MYC-INDUCED APOPTOSIS; C-MYC; B-CELLS; PHASE-I; METASTATIC MELANOMA; GROWTH ARREST; BCL-2 FAMILY AB Mantle cell lymphoma (MCL) is a distinct subtype of non-Hodgkin lymphoma characterized by overexpression of cyclin D1 in 95% of patients. MCL patients experience frequent relapses resulting in median survival of 3 to 5 years, requiring more efficient therapeutic regimens. Interleukin (IL)-21, a member of the IL-2 cytokine family, possesses potent antitumor activity against a variety of cancers not expressing the IL-21 receptor (IL-21R) through immune activation. Previously, we established that IL-21 exerts direct cytotoxicity on IL-21R-expressing diffuse large B-cell lymphoma cells. Herein, we demonstrate that IL-21 possesses potent cytotoxicity against MCL cell lines and primary tumors. We identify that IL-21-induced direct cytotoxicity is mediated through signal transducer and activator of transcription 3-dependent cMyc upregulation, resulting in activation of Bax and inhibition of Bcl-2 and Bcl-XL. IL-21-mediated cMyc upregulation is only observed in IL-21-sensitive cells. Further, we demonstrate that IL-21 leads to natural killer (NK)-cell-dependent lysis of MCL cell lines that were resistant to direct cytotoxicity. In vivo treatment with IL-21 results in complete FC-muMCL1 tumor regression in syngeneicmice via NK- and T-cell-dependent mechanisms. Together, these data indicate that IL-21 has potent antitumor activity against MCL cells via direct cytotoxic and indirect, immune-mediated effects. C1 [Bhatt, Shruti; Matthews, Julie; Sarosiek, Kristopher A.; Lossos, Izidore S.] Sylvester Comprehens Canc Ctr, Dept Mol & Cellular Pharmacol, Miami, FL USA. [Bhatt, Shruti; Matthews, Julie; Parvin, Salma; Sarosiek, Kristopher A.; Zhao, Dekuang; Jiang, Xiaoyu; Lossos, Izidore S.] Sylvester Comprehens Canc Ctr, Dept Med, Div Hematol Oncol, Miami, FL USA. [Parvin, Salma; Zhao, Dekuang] Univ Miami, Miller Sch Med, Sheila & David Fuente Grad Program Canc Biol, Miami, FL 33136 USA. [Isik, Elif; Letai, Anthony] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Letai, Anthony] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RP Lossos, IS (reprint author), Univ Miami, Sylvester Comprehens Canc Ctr, Div Hematol & Oncol, 1475 NW 12th Ave D8-4, Miami, FL 33136 USA. EM ilossos@med.miami.edu RI Zhao, Dekuang/H-5671-2015 OI Zhao, Dekuang/0000-0002-7251-2481 FU Lymphoma Research Foundation; National Institutes of Health National Cancer Institute [CA109335]; Dwoskin Family Foundation; Recio Family Foundation; Antony Rizzo Foundation FX This study was supported by the Lymphoma Research Foundation ( I.S.L.). I.S.L. was also supported by a grant from the National Institutes of Health National Cancer Institute (CA109335) and the Dwoskin Family, Recio Family, and Antony Rizzo Foundations. NR 50 TC 3 Z9 4 U1 0 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD SEP 24 PY 2015 VL 126 IS 13 BP 1555 EP 1564 DI 10.1182/blood-2015-01-624585 PG 10 WC Hematology SC Hematology GA CU4EX UT WOS:000363481000010 PM 26194763 ER PT J AU Sun, BH Shah, B Fiskus, W Qi, J Rajapakshe, K Coarfa, C Li, L Devaraj, SGT Sharma, S Zhang, L Wang, ML Saenz, DT Krieger, S Bradner, JE Bhalla, KN AF Sun, Baohua Shah, Bhavin Fiskus, Warren Qi, Jun Rajapakshe, Kimal Coarfa, Cristian Li, Li Devaraj, Santhana G. T. Sharma, Sunil Zhang, Liang Wang, Michael L. Saenz, Dyana T. Krieger, Stephanie Bradner, James E. Bhalla, Kapil N. TI Synergistic activity of BET protein antagonist-based combinations in mantle cell lymphoma cells sensitive or resistant to ibrutinib SO BLOOD LA English DT Article ID NF-KAPPA-B; BRUTONS TYROSINE KINASE; SELECTIVE-INHIBITION; EMERGING ROLES; P-TEFB; BRD4; CANCER; LEUKEMIA; BROMODOMAIN; MECHANISMS AB Mantle cell lymphoma (MCL) cells exhibit increased B-cell receptor and nuclear factor (NF)-kappa B activities. The bromodomain and extra-terminal (BET) protein bromodomain 4 is essential for the transcriptional activity of NF-kappa B. Here, we demonstrate that treatment with the BET protein bromodomain antagonist (BA) JQ1 attenuates MYC and cyclin-dependent kinase (CDK) 4/6, inhibits the nuclear RelA levels and the expression of NF-kappa B target genes, including Bruton tyrosine kinase (BTK) in MCL cells. Although lowering the levels of the antiapoptotic B-cell lymphoma (BCL) 2 family proteins, BA treatment induces the proapoptotic protein BIM and exerts dose-dependent lethality against cultured and primary MCL cells. Cotreatment with BA and the BTK inhibitor ibrutinib synergistically induces apoptosis of MCL cells. Compared with each agent alone, cotreatment with BA and ibrutinib markedly improved the median survival of mice engrafted with the MCL cells. BA treatment also induced apoptosis of the in vitro isolated, ibrutinib-resistant MCL cells, which overexpress CDK6, BCL2, Bcl-xL, XIAP, and AKT, but lack ibrutinib resistance-conferring BTK mutation. Cotreatment with BA and panobinostat (pan-histone deacetylase inhibitor) or palbociclib (CDK4/6 inhibitor) or ABT-199 (BCL2 antagonist) synergistically induced apoptosis of the ibrutinib-resistant MCL cells. These findings highlight and support further in vivo evaluation of the efficacy of the BA-based combinations with these agents against MCL, including ibrutinib-resistant MCL. C1 [Sun, Baohua; Fiskus, Warren; Zhang, Liang; Wang, Michael L.; Saenz, Dyana T.; Krieger, Stephanie; Bhalla, Kapil N.] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA. [Sun, Baohua; Fiskus, Warren; Zhang, Liang; Wang, Michael L.; Saenz, Dyana T.; Krieger, Stephanie; Bhalla, Kapil N.] Univ Texas MD Anderson Canc Ctr, Dept Lymphoma & Myeloma, Houston, TX 77030 USA. [Shah, Bhavin; Devaraj, Santhana G. T.] Houston Methodist Res Inst, Canc Res, Houston, TX USA. [Qi, Jun; Bradner, James E.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Rajapakshe, Kimal; Coarfa, Cristian] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. [Li, Li] Tom & Gayle Benson Canc Ctr, Lab Translat Canc Res, New Orleans, LA USA. [Sharma, Sunil] Univ Utah, Dept Internal Med, Huntsman Canc Inst, Salt Lake City, UT 84112 USA. RP Bhalla, KN (reprint author), Univ Texas Houston, MD Anderson Canc Ctr, Leukemia Dept, 1515 Holcombe Blvd,Unit 428, Houston, TX 77030 USA. EM kbhalla@mdanderson.org RI Rajapakshe, Kimal/P-1592-2015 FU National Institutes of Health, National Cancer Institute, through the MD Anderson Cancer Center Support grant [P30 CA016672]; National Institutes of Health, National Cancer Institute, through the MD Anderson Cancer Center Leukemia Specialized Program of Research Excellence grant [CA 100632] FX This research was supported in part by the National Institutes of Health, National Cancer Institute, through the MD Anderson Cancer Center Support grant (P30 CA016672), and through the MD Anderson Cancer Center Leukemia Specialized Program of Research Excellence grant (CA 100632). NR 50 TC 11 Z9 11 U1 2 U2 8 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD SEP 24 PY 2015 VL 126 IS 13 BP 1565 EP 1574 DI 10.1182/blood-2015-04-639542 PG 10 WC Hematology SC Hematology GA CU4EX UT WOS:000363481000011 PM 26254443 ER PT J AU Wang, YB Zhang, TH Kwiatkowski, N Abraham, BJ Lee, TI Xie, SZ Yuzugullu, H Von, T Li, HY Lin, Z Stover, DG Lim, E Wang, ZGC Iglehart, JD Young, RA Gray, NS Zhao, JJ AF Wang, Yubao Zhang, Tinghu Kwiatkowski, Nicholas Abraham, Brian J. Lee, Tong Ihn Xie, Shaozhen Yuzugullu, Haluk Thanh Von Li, Heyuan Lin, Ziao Stover, Daniel G. Lim, Elgene Wang, Zhigang C. Iglehart, J. Dirk Young, Richard A. Gray, Nathanael S. Zhao, Jean J. TI CDK7-Dependent Transcriptional Addiction in Triple-Negative Breast Cancer SO CELL LA English DT Article ID EPIDERMAL-GROWTH-FACTOR; RNA-POLYMERASE-II; COVALENT CDK7 INHIBITOR; THERAPEUTIC TARGET; SUPER-ENHANCERS; MOLECULAR PORTRAITS; TUMOR-SUPPRESSOR; FACTOR RECEPTOR; CELL IDENTITY; CLAUDIN-LOW AB Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer that exhibits extremely high levels of genetic complexity and yet a relatively uniform transcriptional program. We postulate that TNBC might be highly dependent on uninterrupted transcription of a key set of genes within this gene expression program and might therefore be exceptionally sensitive to inhibitors of transcription. Utilizing kinase inhibitors and CRISPR/Cas9-mediated gene editing, we show here that triple-negative but not hormone receptor-positive breast cancer cells are exceptionally dependent on CDK7, a transcriptional cyclin-dependent kinase. TNBCcells are unique in their dependence on this transcriptional CDK and suffer apoptotic cell death upon CDK7 inhibition. An "Achilles cluster'' of TNBC-specific genes is especially sensitive to CDK7 inhibition and frequently associated with super-enhancers. We conclude that CDK7 mediates transcriptional addiction to a vital cluster of genes in TNBC and CDK7 inhibition may be a useful therapy for this challenging cancer. C1 [Wang, Yubao; Zhang, Tinghu; Xie, Shaozhen; Yuzugullu, Haluk; Thanh Von; Li, Heyuan; Lin, Ziao; Wang, Zhigang C.; Iglehart, J. Dirk; Gray, Nathanael S.; Zhao, Jean J.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Wang, Yubao; Zhang, Tinghu; Xie, Shaozhen; Yuzugullu, Haluk; Thanh Von; Gray, Nathanael S.; Zhao, Jean J.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Kwiatkowski, Nicholas; Abraham, Brian J.; Lee, Tong Ihn; Young, Richard A.] Whitehead Inst Biomed Res, Cambridge Ctr 9, Cambridge, MA 02142 USA. [Stover, Daniel G.; Lim, Elgene] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Wang, Zhigang C.; Iglehart, J. Dirk] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Young, Richard A.] MIT, Dept Biol, Cambridge, MA 02139 USA. RP Gray, NS (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. EM nathanael_gray@dfci.harvard.edu; jean_zhao@dfci.harvard.edu RI Young, Richard/F-6495-2012; Wang, Yubao/L-3912-2014; OI Young, Richard/0000-0001-8855-8647; Stover, Daniel/0000-0001-9003-8165 FU NIH [R01CA179483-01]; MIT-DFCI Bridge grant; NIH/NCI [P50 CA168504] FX We thank D. Wiederschain and F. Zhang for sharing the plasmids. We thank the Nikon Imaging Center at Harvard Medical School, DFCI Flow Cytometry Core Facility, and Dana-Farber/Harvard Cancer Center Rodent Histopathology Core for technical assistance and the use of instruments. This study was supported by NIH R01CA179483-01 (N.S.G.), a MIT-DFCI Bridge grant (N.S.G. and R.A.Y.), and NIH/NCI P50 CA168504 (J.Z.). N.S.G., T.Z., and N.K. are inventors on a patent application covering THZ1 and THZ2. N.S.G. and R.A.Y. are scientific founders of Syros Pharmaceuticals, a company that has licensed THZ1 and THZ2 from the Dana-Farber Cancer Institute. NR 55 TC 22 Z9 23 U1 4 U2 42 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 SEP 24 PY 2015 VL 163 IS 1 BP 174 EP 186 DI 10.1016/j.cell.2015.08.063 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CS1RX UT WOS:000361846500030 PM 26406377 ER PT J AU Yang, BX El Farran, CA Guo, HC Yu, T Fang, HT Wang, HF Schlesinger, S Seah, YFS Goh, GYL Neo, SP Li, YH Lorincz, MC Tergaonkar, V Lim, TM Chen, LY Gunaratne, J Collins, JJ Goff, SP Daley, GQ Li, H Bard, FA Loh, YH AF Yang, Bin Xia El Farran, Chadi A. Guo, Hong Chao Yu, Tao Fang, Hai Tong Wang, Hao Fei Schlesinger, Sharon Seah, Yu Fen Samantha Goh, Germaine Yen Lin Neo, Suat Peng Li, Yinghui Lorincz, Matthew C. Tergaonkar, Vinay Lim, Tit-Meng Chen, Lingyi Gunaratne, Jayantha Collins, James J. Goff, Stephen P. Daley, George Q. Li, Hu Bard, Frederic A. Loh, Yuin-Han TI Systematic Identification of Factors for Provirus Silencing in Embryonic Stem Cells SO CELL LA English DT Article ID PRIMER-BINDING SITE; MURINE LEUKEMIA-VIRUS; CHROMATIN ASSEMBLY FACTOR-1; LONG TERMINAL REPEAT; DNA-REPLICATION; ENDOGENOUS RETROVIRUSES; DEPENDENT RESTRICTION; CARCINOMA-CELLS; HISTONE H3.3; ES CELLS AB Embryonic stem cells (ESCs) repress the expression of exogenous proviruses and endogenous retroviruses (ERVs). Here, we systematically dissected the cellular factors involved in provirus repression in embryonic carcinomas (ECs) and ESCs by a genome-wide siRNA screen. Histone chaperones (Chaf1a/b), sumoylation factors (Sumo2/Ube2i/Sae1/Uba2/Senp6), and chromatin modifiers (Trim28/Eset/At-f7ip) are key determinants that establish provirus silencing. RNA-seq analysis uncovered the roles of Chaf1a/b and sumoylation modifiers in the repression of ERVs. ChIP-seq analysis demonstrates direct recruitment of Chaf1a and Sumo2 to ERVs. Chaf1a reinforces transcriptional repression via its interaction with members of the NuRD complex (Kdm1a, Hdac1/2) and Eset, while Sumo2 orchestrates the provirus repressive function of the canonical Zfp809/Trim28/Eset machinery by sumoylation of Trim28. Our study reports a genome-wide atlas of functional nodes that mediate proviral silencing in ESCs and illuminates the comprehensive, interconnected, and multi-layered genetic and epigenetic mechanisms by which ESCs repress retroviruses within the genome. C1 [Yang, Bin Xia; El Farran, Chadi A.; Yu, Tao; Fang, Hai Tong; Wang, Hao Fei; Seah, Yu Fen Samantha; Loh, Yuin-Han] A STAR Inst Mol & Cell Biol, Epigenet & Cell Fates Lab, Singapore 138673, Singapore. [El Farran, Chadi A.; Yu, Tao; Wang, Hao Fei; Lim, Tit-Meng; Loh, Yuin-Han] Natl Univ Singapore, Dept Biol Sci, Singapore 117543, Singapore. [Guo, Hong Chao; Chen, Lingyi] Nankai Univ, Coll Life Sci, Tianjin 300071, Peoples R China. [Schlesinger, Sharon; Goff, Stephen P.] Columbia Univ, Dept Biochem & Mol Biophys, New York, NY 10032 USA. [Schlesinger, Sharon; Goff, Stephen P.] Columbia Univ, Dept Microbiol & Immunol, New York, NY 10032 USA. [Goh, Germaine Yen Lin; Bard, Frederic A.] A STAR Inst Mol & Cell Biol, Membrane Traff Lab, Singapore 138673, Singapore. [Neo, Suat Peng; Gunaratne, Jayantha] A STAR Inst Mol & Cell Biol, Quantitat Prote Grp, Singapore 138673, Singapore. [Gunaratne, Jayantha] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Anat, Singapore 117597, Singapore. [Li, Yinghui; Tergaonkar, Vinay] A STAR Inst Mol & Cell Biol, Lab NF KB Signaling, Div Canc Genet & Therapeut, Singapore 138673, Singapore. [Lorincz, Matthew C.] Univ British Columbia, Dept Med Genet, Inst Life Sci, Vancouver, BC V6T 1Z3, Canada. [Collins, James J.] MIT, Inst Med Engn & Sci, Dept Biol Engn, Synthet Biol Ctr, Cambridge, MA 02139 USA. [Collins, James J.] Broad Inst MIT & Harvard, Cambridge, MA 02139 USA. [Collins, James J.] Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA. [Collins, James J.; Daley, George Q.] Howard Hughes Med Inst, Boston, MA 02115 USA. [Goff, Stephen P.] Howard Hughes Med Inst, New York, NY 10032 USA. [Daley, George Q.] Boston Childrens Hosp, Div Pediat Hematol Oncol, Stem Cell Transplantat Program, Boston, MA 02115 USA. [Daley, George Q.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Daley, George Q.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Daley, George Q.] Harvard Stem Cell Inst, Boston, MA 02115 USA. [Daley, George Q.] Manton Ctr Orphan Dis Res, Boston, MA 02115 USA. [Li, Hu] Mayo Clin, Dept Mol Pharmacol & Expt Therapeut, Ctr Individualized Med, Rochester, MN 55905 USA. [Tergaonkar, Vinay; Bard, Frederic A.] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, Singapore 119077, Singapore. RP Loh, YH (reprint author), A STAR Inst Mol & Cell Biol, Epigenet & Cell Fates Lab, 61 Biopolis Dr Proteos, Singapore 138673, Singapore. EM yhloh@imcb.a-star.edu.sg RI ASTAR, IMCB/E-2320-2012; Schlesinger, Sharon/A-5283-2016; OI Schlesinger, Sharon/0000-0001-9549-2383; Li, Yinghui/0000-0002-9023-9466 FU Mayo Clinic Center for Individualized Medicine; NIH [R01 CA30488]; A*Star Investigatorship research award; Biomedical Research Council, Agency for Science, Technology and Research, Singapore FX We are grateful to Yang Lin for helpful discussion. We thank Wong Chee Wai for technical assistance. H.L. is supported by Mayo Clinic Center for Individualized Medicine. S.P.G. is supported by NIH grant R01 CA30488. Y.-H.L. is supported by the A*Star Investigatorship research award. We are grateful to the Biomedical Research Council, Agency for Science, Technology and Research, Singapore for research funding. NR 57 TC 17 Z9 17 U1 5 U2 21 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 SEP 24 PY 2015 VL 163 IS 1 BP 230 EP 245 DI 10.1016/j.cell.2015.08.037 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CS1RX UT WOS:000361846500034 PM 26365490 ER PT J AU Mata, IF Jang, Y Kim, CH Hanna, DS Dorschner, MO Samii, A Agarwal, P Roberts, JW Klepitskaya, O Shprecher, DR Chung, KA Factor, SA Espay, AJ Revilla, FJ Higgins, DS Litvan, I Leverenz, JB Yearout, D Inca-Martinez, M Martinez, E Thompson, TR Cholerton, BA Hu, SC Edwards, KL Kim, KS Zabetian, CP AF Mata, Ignacio F. Jang, Yongwoo Kim, Chun-Hyung Hanna, David S. Dorschner, Michael O. Samii, Ali Agarwal, Pinky Roberts, John W. Klepitskaya, Olga Shprecher, David R. Chung, Kathryn A. Factor, Stewart A. Espay, Alberto J. Revilla, Fredy J. Higgins, Donald S. Litvan, Irene Leverenz, James B. Yearout, Dora Inca-Martinez, Miguel Martinez, Erica Thompson, Tiffany R. Cholerton, Brenna A. Hu, Shu-Ching Edwards, Karen L. Kim, Kwang-Soo Zabetian, Cyrus P. TI The RAB39B p.G192R mutation causes X-linked dominant Parkinson's disease SO MOLECULAR NEURODEGENERATION LA English DT Article ID LEWY BODY; PATHOLOGY; VARIANTS; GTPASES; RISK AB Objective: To identify the causal gene in a multi-incident U.S. kindred with Parkinson's disease (PD). Methods: We characterized a family with a classical PD phenotype in which 7 individuals (5 males and 2 females) were affected with a mean age at onset of 46.1 years (range, 29-57 years). We performed whole exome sequencing on 4 affected and 1 unaffected family members. Sanger-sequencing was then used to verify and genotype all candidate variants in the remainder of the pedigree. Cultured cells transfected with wild-type or mutant constructs were used to characterize proteins of interest. Results: We identified a missense mutation (c.574G > A; p.G192R) in the RAB39B gene that closely segregated with disease and exhibited X-linked dominant inheritance with reduced penetrance in females. The mutation occurred in a highly conserved amino acid residue and was not observed among 87,725 X chromosomes in the Exome Aggregation Consortium dataset. Sequencing of the RAB39B coding region in 587 familial PD cases yielded two additional mutations (c.428C > G [p.A143G] and c.624_626delGAG [p.R209del]) that were predicted to be deleterious in silico but occurred in families that were not sufficiently informative to assess segregation with disease. Experiments in PC12 and SK-N-BE(2) C cells demonstrated that p.G192R resulted in mislocalization of the mutant protein, possibly by altering the structure of the hypervariable C-terminal domain which mediates intracellular targeting. Conclusions: Our findings implicate RAB39B, an essential regulator of vesicular-trafficking, in clinically typical PD. Further characterization of normal and aberrant RAB39B function might elucidate important mechanisms underlying neurodegeneration in PD and related disorders. C1 [Mata, Ignacio F.; Samii, Ali; Yearout, Dora; Martinez, Erica; Thompson, Tiffany R.; Cholerton, Brenna A.; Hu, Shu-Ching; Edwards, Karen L.; Zabetian, Cyrus P.] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. [Mata, Ignacio F.; Samii, Ali; Yearout, Dora; Martinez, Erica; Hu, Shu-Ching; Zabetian, Cyrus P.] Univ Washington, Sch Med, Dept Neurol, Seattle, WA USA. [Jang, Yongwoo; Kim, Chun-Hyung; Kim, Kwang-Soo] McLean Hosp, Dept Psychiat, Mol Neurobiol Lab, Belmont, MA 02178 USA. [Jang, Yongwoo; Kim, Chun-Hyung; Kim, Kwang-Soo] McLean Hosp, Program Neurosci, Belmont, MA 02178 USA. [Jang, Yongwoo; Kim, Chun-Hyung; Kim, Kwang-Soo] Harvard Univ, Sch Med, Belmont, MA 02178 USA. [Hanna, David S.; Dorschner, Michael O.; Cholerton, Brenna A.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Hanna, David S.; Dorschner, Michael O.] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [Agarwal, Pinky] Evergreen Hosp Med Ctr, Booth Gardner Parkinsons Care Ctr, Kirkland, WA USA. [Roberts, John W.] Virginia Mason Med Ctr, Seattle, WA 98101 USA. [Klepitskaya, Olga] Univ Colorado, Dept Neurol, Denver, CO 80202 USA. [Shprecher, David R.] Univ Utah, Dept Neurol, Salt Lake City, UT USA. [Chung, Kathryn A.] Portland VA Med Ctr, Parkinsons Dis Res Educ & Clin Ctr, Portland, OR USA. [Chung, Kathryn A.] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA. [Factor, Stewart A.] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA. [Espay, Alberto J.] Univ Cincinnati, Dept Neurol Rehabil Med, Cincinnati, OH USA. [Revilla, Fredy J.] Div Neurol Greenville Hlth Syst, Greenville, SC USA. [Higgins, Donald S.] Univ S Carolina, Med Sch Greenville, Greenville, SC USA. [Higgins, Donald S.] Samuel Stratton Vet Affairs Med Ctr, Albany, NY USA. [Litvan, Irene] Univ Calif San Diego, Dept Neurosci, Movement Disorder Ctr, San Diego, CA 92103 USA. [Leverenz, James B.] Cleveland Clin, Lou Ruvo Ctr Brain Hlth, Cleveland, OH 44106 USA. [Inca-Martinez, Miguel] Inst Nacl Ciencias Neurolog, Neurogenet Res Ctr, Lima, Peru. [Edwards, Karen L.] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA. RP Zabetian, CP (reprint author), Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. EM zabetian@u.washington.edu OI Litvan, Irene/0000-0002-3485-3445 FU National Institutes of Health [P50 NS062684, R01 NS065070, R01 NS084869]; Department of Veterans Affairs [1I01BX000531] FX This work was supported by grants from the National Institutes of Health (P50 NS062684, R01 NS065070, R01 NS084869) and the Department of Veterans Affairs (1I01BX000531), and by a gift from the Dolsen Foundation. We thanks all of the individuals who participated in the study and Drs. Jennifer Witt and Rosalind Chuang for assistance with patient recruitment. NR 23 TC 15 Z9 15 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-1326 J9 MOL NEURODEGENER JI Mol. Neurodegener. PD SEP 24 PY 2015 VL 10 AR 50 DI 10.1186/s13024-015-0045-4 PG 8 WC Neurosciences SC Neurosciences & Neurology GA CR8FE UT WOS:000361585700001 PM 26399558 ER PT J AU Gupta, V Kerry, VB Goosby, E Yates, R AF Gupta, Vin Kerry, Vanessa B. Goosby, Eric Yates, Robert TI Politics and Universal Health Coverage - The Post-2015 Global Health Agenda SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Gupta, Vin] Univ Cambridge, Dept Polit & Int Studies, Cambridge, England. [Yates, Robert] Royal Inst Int Affairs, London, England. [Gupta, Vin; Kerry, Vanessa B.] Brigham & Womens Hosp, Dept Pulm & Crit Care Med, Boston, MA 02115 USA. [Kerry, Vanessa B.] Harvard Univ, Sch Med, Dept Global Hlth & Social Med, Boston, MA USA. [Kerry, Vanessa B.] Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02114 USA. [Kerry, Vanessa B.] Seed Global Hlth, Boston, MA USA. [Goosby, Eric] Univ Calif San Francisco, Ctr Implementat Sci, San Francisco, CA 94143 USA. RP Gupta, V (reprint author), Univ Cambridge, Dept Polit & Int Studies, Cambridge, England. NR 5 TC 3 Z9 3 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 SEP 24 PY 2015 VL 373 IS 13 BP 1189 EP 1192 DI 10.1056/NEJMp1508807 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA CR8WP UT WOS:000361635200003 PM 26376044 ER PT J AU Lokhorst, HM Plesner, T Laubach, JP Nahi, H Gimsing, P Hansson, M Minnema, MC Lassen, U Krejcik, J Palumbo, A van de Donk, NWCJ Ahmadi, T Khan, I Uhlar, CM Wang, J Sasser, AK Losic, N Lisby, S Basse, L Brun, N Richardson, PG AF Lokhorst, H. M. Plesner, T. Laubach, J. P. Nahi, H. Gimsing, P. Hansson, M. Minnema, M. C. Lassen, U. Krejcik, J. Palumbo, A. van de Donk, N. W. C. J. Ahmadi, T. Khan, I. Uhlar, C. M. Wang, J. Sasser, A. K. Losic, N. Lisby, S. Basse, L. Brun, N. Richardson, P. G. TI Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID MONOCLONAL-ANTIBODY; ANTITUMOR-ACTIVITY; MULTICENTER; BORTEZOMIB; ELOTUZUMAB; SAR650984; THERAPIES; SURVIVAL; PROTEIN; CELLS AB BACKGROUND Multiple myeloma cells uniformly overexpress CD38. We studied daratumumab, a CD38-targeting, human IgG1 kappa monoclonal antibody, in a phase 1-2 trial involving patients with relapsed myeloma or relapsed myeloma that was refractory to two or more prior lines of therapy. METHODS In part 1, the dose-escalation phase, we administered daratumumab at doses of 0.005 to 24 mg per kilogram of body weight. In part 2, the dose-expansion phase, 30 patients received 8 mg per kilogram of daratumumab and 42 received 16 mg per kilogram, administered once weekly (8 doses), twice monthly (8 doses), and monthly for up to 24 months. End points included safety, efficacy, and pharmacokinetics. RESULTS No maximum tolerated dose was identified in part 1. In part 2, the median time since diagnosis was 5.7 years. Patients had received a median of four prior treatments; 79% of the patients had disease that was refractory to the last therapy received (64% had disease refractory to proteasome inhibitors and immunomodulatory drugs and 64% had disease refractory to bortezomib and lenalidomide), and 76% had received autologous stem-cell transplants. Infusion-related reactions in part 2 were mild (71% of patients had an event of any grade, and 1% had an event of grade 3), with no dose-dependent adverse events. The most common adverse events of grade 3 or 4 (in >= 5% of patients) were pneumonia and thrombocytopenia. The overall response rate was 36% in the cohort that received 16 mg per kilogram (15 patients had a partial response or better, including 2 with a complete response and 2 with a very good partial response) and 10% in the cohort that received 8 mg per kilogram (3 had a partial response). In the cohort that received 16 mg per kilogram, the median progression-free survival was 5.6 months (95% confidence interval [CI], 4.2 to 8.1), and 65% (95% CI, 28 to 86) of the patients who had a response did not have progression at 12 months. CONCLUSIONS Daratumumab monotherapy had a favorable safety profile and encouraging efficacy in patients with heavily pretreated and refractory myeloma. (Funded by Janssen Research and Development and Genmab; ClinicalTrials.gov number, NCT00574288.) C1 [Lokhorst, H. M.; Minnema, M. C.; van de Donk, N. W. C. J.] Univ Med Ctr Utrecht, Dept Hematol, Utrecht, Netherlands. [Lokhorst, H. M.; van de Donk, N. W. C. J.] Vrije Univ Amsterdam Med Ctr, Dept Hematol, NL-1081 HV Amsterdam, Netherlands. [Plesner, T.; Krejcik, J.] Vejle Hosp, Vejle, Denmark. [Plesner, T.; Krejcik, J.] Univ Southern Denmark, Vejle, Denmark. [Gimsing, P.; Lassen, U.] Rigshosp, DK-2100 Copenhagen, Denmark. [Gimsing, P.; Lassen, U.] Univ Copenhagen, Copenhagen, Denmark. [Losic, N.; Lisby, S.; Basse, L.; Brun, N.] Genmab, Copenhagen, Denmark. [Laubach, J. P.; Richardson, P. G.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Nahi, H.] Karolinska Univ Hosp Huddinge, Karolinska Inst, Stockholm, Sweden. [Nahi, H.] Karolinska Univ Hosp Huddinge, Dept Med, Div Hematol, Stockholm, Sweden. [Hansson, M.] Skane Univ Hosp, Lund, Sweden. [Hansson, M.] Lund Univ, Lund, Sweden. [Palumbo, A.] Univ Turin, Div Hematol, Myeloma Unit, Turin, Italy. [Ahmadi, T.; Uhlar, C. M.; Sasser, A. K.] Janssen Res & Dev, Spring House, PA USA. [Khan, I.; Wang, J.] Janssen Res & Dev, Raritan, NJ USA. RP Lokhorst, HM (reprint author), Vrije Univ Amsterdam Med Ctr, Dept Hematol, De Boelelaan 1117, NL-1081 HV Amsterdam, Netherlands. EM h.lokhorst@vumc.nl OI Lassen, Ulrik/0000-0002-3865-4574; Krejcik, Jakub/0000-0003-1833-583X; nahi, hareth/0000-0003-4711-5094 FU Janssen Research and Development; Genmab FX Funded by Janssen Research and Development and Genmab NR 24 TC 137 Z9 139 U1 7 U2 17 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 24 PY 2015 VL 373 IS 13 BP 1207 EP 1219 DI 10.1056/NEJMoa1506348 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA CR8WP UT WOS:000361635200006 PM 26308596 ER PT J AU Raje, N Longo, DL AF Raje, Noopur Longo, Dan L. TI Monoclonal Antibodies in Multiple Myeloma Come of Age SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID THERAPY C1 [Raje, Noopur] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Raje, N (reprint author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. NR 10 TC 9 Z9 10 U1 0 U2 4 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 24 PY 2015 VL 373 IS 13 BP 1264 EP 1266 DI 10.1056/NEJMe1509419 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA CR8WP UT WOS:000361635200014 PM 26308594 ER PT J AU Larkin, J Hodi, FS Wolchok, JD AF Larkin, James Hodi, F. Stephen Wolchok, Jedd D. TI Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Larkin, James] Royal Marsden Hosp, London SW3 6JJ, England. [Hodi, F. Stephen] Dana Farber Canc Inst, Boston, MA 02115 USA. [Wolchok, Jedd D.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Larkin, J (reprint author), Royal Marsden Hosp, London SW3 6JJ, England. EM wolchokj@mskcc.org NR 1 TC 34 Z9 36 U1 5 U2 17 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 24 PY 2015 VL 373 IS 13 BP 1270 EP 1271 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA CR8WP UT WOS:000361635200017 PM 26398076 ER PT J AU De Los Angeles, A Ferrari, F Xi, RB Fujiwara, Y Benvenisty, N Deng, HK Hochedlinger, K Jaenisch, R Lee, S Leitch, HG Lensch, MW Lujan, E Pei, DQ Rossant, J Wernig, M Park, PJ Daley, GQ AF De Los Angeles, Alejandro Ferrari, Francesco Xi, Ruibin Fujiwara, Yuko Benvenisty, Nissim Deng, Hongkui Hochedlinger, Konrad Jaenisch, Rudolf Lee, Soohyun Leitch, Harry G. Lensch, M. William Lujan, Ernesto Pei, Duanqing Rossant, Janet Wernig, Marius Park, Peter J. Daley, George Q. TI Hallmarks of pluripotency SO NATURE LA English DT Review ID EMBRYONIC STEM-CELLS; PRIMORDIAL GERM-CELLS; GROUND-STATE PLURIPOTENCY; X-CHROMOSOME INACTIVATION; DNA METHYLATION; TRANSCRIPTIONAL NETWORK; REGULATORY CIRCUITRY; ISOLATED BLASTOMERES; NAIVE PLURIPOTENCY; CULTURE-CONDITIONS AB Stem cells self-renew and generate specialized progeny through differentiation, but vary in the range of cells and tissues they generate, a property called developmental potency. Pluripotent stem cells produce all cells of an organism, while multipotent or unipotent stem cells regenerate only specific lineages or tissues. Defining stem-cell potency relies upon functional assays and diagnostic transcriptional, epigenetic and metabolic states. Here we describe functional and molecular hallmarks of pluripotent stem cells, propose a checklist for their evaluation, and illustrate how forensic genomics can validate their provenance. C1 [De Los Angeles, Alejandro; Fujiwara, Yuko; Lensch, M. William; Daley, George Q.] Childrens Hosp Boston, Div Pediat Hematol Oncol, Stem Cell Transplantat Program, Boston, MA 02115 USA. [De Los Angeles, Alejandro; Fujiwara, Yuko; Lensch, M. William; Daley, George Q.] Dana Farber Canc Inst, Boston, MA 02115 USA. [De Los Angeles, Alejandro; Fujiwara, Yuko; Lensch, M. William; Daley, George Q.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [De Los Angeles, Alejandro; Fujiwara, Yuko; Hochedlinger, Konrad; Lensch, M. William; Daley, George Q.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [De Los Angeles, Alejandro; Fujiwara, Yuko; Hochedlinger, Konrad; Lensch, M. William; Daley, George Q.] Howard Hughes Med Inst, Boston, MA 02115 USA. [Ferrari, Francesco; Xi, Ruibin; Hochedlinger, Konrad; Lee, Soohyun; Park, Peter J.] Harvard Univ, Sch Med, Dept Biomed Informat, Boston, MA 02115 USA. [Xi, Ruibin] Peking Univ, Sch Math Sci, Beijing 100871, Peoples R China. [Xi, Ruibin] Peking Univ, Ctr Stat Sci, Beijing 100871, Peoples R China. [Benvenisty, Nissim] Hebrew Univ Jerusalem, Inst Life Sci, Dept Genet, Stem Cell Unit, IL-91904 Jerusalem, Israel. [Deng, Hongkui] Peking Univ, Coll Life Sci, Beijing 100871, Peoples R China. [Deng, Hongkui] Peking Univ, Peking Tsinghua Ctr Life Sci, Beijing 100871, Peoples R China. [Hochedlinger, Konrad] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Hochedlinger, Konrad] Ctr Regenerat Med, Boston, MA 02114 USA. [Jaenisch, Rudolf] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Leitch, Harry G.] Univ London Imperial Coll Sci Technol & Med, MRC, Ctr Clin Sci, London W12 0NN, England. [Lujan, Ernesto; Wernig, Marius] Stanford Univ, Inst Stem Cell Biol & Regenerat Med, Stanford, CA 94305 USA. [Pei, Duanqing] Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, South China Inst Stem Cell Biol & Regenerat Med, Guangzhou 510530, Guangdong, Peoples R China. [Rossant, Janet] Hosp Sick Children, Res Inst, Toronto, ON M5G 0A4, Canada. RP Daley, GQ (reprint author), Childrens Hosp Boston, Div Pediat Hematol Oncol, Stem Cell Transplantat Program, Boston, MA 02115 USA. EM george.daley@childrens.harvard.edu RI Ferrari, Francesco/H-5007-2012; OI Ferrari, Francesco/0000-0002-9811-3753; Rossant, Janet/0000-0002-3731-5466 FU Howard Hughes Medical Institute NR 112 TC 43 Z9 43 U1 9 U2 68 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 SEP 24 PY 2015 VL 525 IS 7570 BP 469 EP 478 DI 10.1038/nature15515 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CR8KI UT WOS:000361599900041 PM 26399828 ER PT J AU De Los Angeles, A Ferrari, F Fujiwara, Y Mathieu, R Lee, S Lee, S Tu, HC Ross, S Chou, S Nguyen, M Wu, ZT Theunissen, TW Powell, BE Imsoonthornruksa, S Chen, JK Borkent, M Krupalnik, V Lujan, E Wernig, M Hanna, JH Hochedlinger, K Pei, DQ Jaenisch, R Deng, HK Orkin, SH Park, PJ Daley, GQ AF De Los Angeles, Alejandro Ferrari, Francesco Fujiwara, Yuko Mathieu, Ronald Lee, Soohyun Lee, Semin Tu, Ho-Chou Ross, Samantha Chou, Stephanie Minh Nguyen Wu, Zhaoting Theunissen, Thorold W. Powell, Benjamin E. Imsoonthornruksa, Sumeth Chen, Jiekai Borkent, Marti Krupalnik, Vladislav Lujan, Ernesto Wernig, Marius Hanna, Jacob H. Hochedlinger, Konrad Pei, Duanqing Jaenisch, Rudolf Deng, Hongkui Orkin, Stuart H. Park, Peter J. Daley, George Q. TI Failure to replicate the STAP cell phenomenon SO NATURE LA English DT Letter ID PLURIPOTENT STEM-CELLS; SEE VOL. 511; SOMATIC-CELLS; PG. 112 C1 [De Los Angeles, Alejandro; Fujiwara, Yuko; Tu, Ho-Chou; Ross, Samantha; Chou, Stephanie; Minh Nguyen; Wu, Zhaoting; Orkin, Stuart H.; Daley, George Q.] Childrens Hosp Boston, Div Pediat Hematol Oncol, Stem Cell Transplantat Program, Boston, MA 02115 USA. [De Los Angeles, Alejandro; Fujiwara, Yuko; Tu, Ho-Chou; Ross, Samantha; Chou, Stephanie; Minh Nguyen; Wu, Zhaoting; Orkin, Stuart H.; Daley, George Q.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Dana Farber Canc Inst, Boston, MA 02115 USA. [De Los Angeles, Alejandro; Fujiwara, Yuko; Tu, Ho-Chou; Ross, Samantha; Chou, Stephanie; Minh Nguyen; Wu, Zhaoting; Borkent, Marti; Hochedlinger, Konrad; Orkin, Stuart H.; Daley, George Q.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [De Los Angeles, Alejandro; Fujiwara, Yuko; Tu, Ho-Chou; Ross, Samantha; Chou, Stephanie; Minh Nguyen; Wu, Zhaoting; Borkent, Marti; Hochedlinger, Konrad; Orkin, Stuart H.; Daley, George Q.] Howard Hughes Med Inst, Boston, MA 02115 USA. [Ferrari, Francesco; Lee, Soohyun; Lee, Semin; Park, Peter J.] Harvard Univ, Sch Med, Dept Biomed Informat, Boston, MA 02115 USA. [Mathieu, Ronald] Childrens Hosp Boston, Childrens Hosp, Boston, MA 02115 USA. [Mathieu, Ronald] Childrens Hosp Boston, Harvard Stem Cell Inst Flow Cytometry Res Facil, Boston, MA 02115 USA. [Theunissen, Thorold W.; Powell, Benjamin E.; Imsoonthornruksa, Sumeth; Jaenisch, Rudolf] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Chen, Jiekai] Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, South China Inst Stem Cell Biol & Regenerat Med, Guangzhou 510530, Guangdong, Peoples R China. [Borkent, Marti; Hochedlinger, Konrad] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Borkent, Marti; Hochedlinger, Konrad] Ctr Regenerat Med, Boston, MA 02114 USA. [Borkent, Marti] Erasmus MC, Dept Dev & Reprod, NL-3015 CN Rotterdam, Netherlands. [Krupalnik, Vladislav; Hanna, Jacob H.] Weizmann Inst Sci, Dept Mol Genet, IL-76100 Rehovot, Israel. [Lujan, Ernesto; Wernig, Marius] Stanford Univ, Inst Stem Cell Biol & Regenerat Med, Stanford, CA 94305 USA. [Deng, Hongkui] Peking Univ, Coll Life Sci, Beijing 100871, Peoples R China. [Deng, Hongkui] Peking Univ, Peking Tsinghua Ctr Life Sci, Beijing 100871, Peoples R China. RP De Los Angeles, A (reprint author), Childrens Hosp Boston, Div Pediat Hematol Oncol, Stem Cell Transplantat Program, Boston, MA 02115 USA. EM peter_park@hms.harvard.edu RI Ferrari, Francesco/H-5007-2012; HANNA, JACOB/K-1339-2012; Lee, Semin/S-2629-2016 OI Ferrari, Francesco/0000-0002-9811-3753; HANNA, JACOB/0000-0003-2042-9974; Lee, Semin/0000-0002-9015-6046 FU Howard Hughes Medical Institute NR 14 TC 11 Z9 11 U1 2 U2 43 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 SEP 24 PY 2015 VL 525 IS 7570 BP E6 EP + PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CR8KI UT WOS:000361599900009 PM 26399835 ER PT J AU Mesgari, M Ghaffarian, N Ghadiri, MK Sadeghian, H Speckmann, EJ Stummer, W Gorji, A AF Mesgari, M. Ghaffarian, N. Ghadiri, M. Khaleghi Sadeghian, H. Speckmann, E. -J. Stummer, W. Gorji, A. TI ALTERED INHIBITION IN THE HIPPOCAMPAL NEURAL NETWORKS AFTER SPREADING DEPRESSION SO NEUROSCIENCE LA English DT Article DE spreading depolarization; epilepsy; migraine; stroke; hippocampus; disinhibition ID CEREBRAL-CORTEX; SYNAPTIC-TRANSMISSION; GABAERGIC NEURONS; PYRAMIDAL NEURONS; RAT NEOCORTEX; TISSUE-SLICES; IN-VITRO; GABA; CA1; GABAPENTIN AB Prolonged neuronal depression after spreading depression (SD) is followed by a late cellular and synaptic hyperexcitability. Intra-and extracellular recordings of bioelectrical activities were performed in the rodent hippocampus to investigate the role of c-aminobutyric acid (GABA)-mediated inhibition in the late hyperexcitable state of SD. The effect of KCl-induced negative DC potential shifts was investigated on extracellularly recorded paired-pulse depression (PPD) and bicuculline-induced afterdischarges as well as intracellularly recorded inhibitory post synaptic potentials (IPSPs) in the hippocampal CA1 area. The results revealed that SD decreased the degree of PPD, enhanced the number and duration of bicuculline-induced afterdischarges, and reduced the amplitude and duration of IPSPs. Application of low concentrations of bicuculline before the induction of SD enhanced the inhibitory effect of SD on IPSPs. Data indicate the contribution of GABA-mediated inhibition to SD-induced delayed hyperexcitability. Modulation of GABA function in the late hyperexcitability phase of SD may play a role in therapeutic management of SD-related neurological disorders. (C) 2015 IBRO. Published by Elsevier Ltd. All rights reserved. C1 [Mesgari, M.; Ghaffarian, N.; Speckmann, E. -J.; Gorji, A.] Univ Munster, Epilepsy Res Ctr, D-48149 Munster, Germany. [Ghadiri, M. Khaleghi; Stummer, W.] Univ Munster, Dept Neurosurg, D-48149 Munster, Germany. [Sadeghian, H.] Harvard Univ, Massachusetts Gen Hosp, Neurovasc Res Lab, Dept Radiol,Med Sch, Charlestown, MA USA. [Gorji, A.] Univ Munster, Dept Neurol, D-48149 Munster, Germany. [Gorji, A.] Univ Munster, Inst Neurophysiol, D-48149 Munster, Germany. [Gorji, A.] Khatam Alanbia Hosp, Shefa Neurosci Res Ctr, Tehran, Iran. [Gorji, A.] Razavi Hosp, Razavi Neurosci Ctr, Mashhad, Iran. RP Gorji, A (reprint author), Univ Munster, Epilepsy Res Ctr, Robert Koch Str 27a, D-48149 Munster, Germany. EM gorjial@uni-muenster.de OI Gorji, Ali/0000-0002-4557-3270 FU Iran National Science Foundation (INSF); Shefa Neuroscience Research Center [267201] FX This article was part of PhD thesis supported by Iran National Science Foundation (INSF) and the Shefa Neuroscience Research Center Grant related to Dr Thesis 267201. NR 48 TC 2 Z9 2 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 EI 1873-7544 J9 NEUROSCIENCE JI Neuroscience PD SEP 24 PY 2015 VL 304 BP 190 EP 197 DI 10.1016/j.neuroscience.2015.07.035 PG 8 WC Neurosciences SC Neurosciences & Neurology GA CP6PD UT WOS:000360008800017 PM 26210578 ER PT J AU Sanders, SJ Xin, H Willsey, AJ Ercan-Sencicek, AG Samocha, KE Cicek, AE Murtha, MT Bal, VH Bishop, SL Shan, D Goldberg, AP Cai, JL Keaney, JF Klei, L Mandell, JD Moreno-De-Luca, D Poultney, CS Robinson, EB Smith, L Solli-Nowlan, T Su, MY Teran, NA Walker, MF Werling, DM Beaudet, AL Cantor, RM Fombonne, E Geschwind, DH Grice, DE Lord, C Lowe, JK Mane, SM Martin, DM Morrow, EM Talkowski, ME Sutcliffe, JS Walsh, CA Yu, TW Ledbetter, DH Martin, CL Cook, EH Buxbaum, JD Daly, MJ Devlin, B Roeder, K State, MW AF Sanders, Stephan J. Xin He Willsey, A. Jeremy Ercan-Sencicek, A. Gulhan Samocha, Kaitlin E. Cicek, A. Ercument Murtha, Michael T. Bal, Vanessa H. Bishop, Somer L. Shan Dong Goldberg, Arthur P. Cai Jinlu Keaney, John F., III Klei, Lambertus Mandell, Jeffrey D. Moreno-De-Luca, Daniel Poultney, Christopher S. Robinson, Elise B. Smith, Louw Solli-Nowlan, Tor Su, Mack Y. Teran, Nicole A. Walker, Michael F. Werling, Donna M. Beaudet, Arthur L. Cantor, Rita M. Fombonne, Eric Geschwind, Daniel H. Grice, Dorothy E. Lord, Catherine Lowe, Jennifer K. Mane, Shrikant M. Martin, Donna M. Morrow, Eric M. Talkowski, Michael E. Sutcliffe, James S. Walsh, Christopher A. Yu, Timothy W. Ledbetter, David H. Martin, Christa Lese Cook, Edwin H. Buxbaum, Joseph D. Daly, Mark J. Devlin, Bernie Roeder, Kathryn State, Matthew W. CA Autism Sequencing Consortium TI Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci SO NEURON LA English DT Article ID COPY-NUMBER VARIATION; DE-NOVO MUTATIONS; HIDDEN-MARKOV MODEL; SNP GENOTYPING DATA; TRUNCATING MUTATIONS; STRUCTURAL VARIATION; WILLIAMS-SYNDROME; SIMPLEX AUTISM; GENE; RARE AB Analysis of de novo CNVs (dnCNVs) from the full Simons Simplex Collection (SSC) (N = 2,591 families) replicates prior findings of strong association with autism spectrum disorders (ASDs) and confirms six risk loci (1q21.1, 3q29, 7q11.23, 16p11.2, 15q11.2-13, and 22q11.2). The addition of published CNV data from the Autism Genome Project (AGP) and exome sequencing data from the SSC and the Autism Sequencing Consortium (ASC) shows that genes within small de novo deletions, but not within large dnCNVs, significantly overlap the high-effect risk genes identified by sequencing. Alternatively, large dnCNVs are found likely to contain multiple modest-effect risk genes. Overall, we find strong evidence that de novo mutations are associated with ASD apart from the risk for intellectual disability. Extending the transmission and de novo association test (TADA) to include small de novo deletions reveals 71 ASD risk loci, including 6 CNV regions (noted above) and 65 risk genes (FDR <= 0.1). C1 [Sanders, Stephan J.; Willsey, A. Jeremy; Bal, Vanessa H.; Bishop, Somer L.; Mandell, Jeffrey D.; Smith, Louw; Walker, Michael F.; Werling, Donna M.; State, Matthew W.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Xin He] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Ercan-Sencicek, A. Gulhan; Murtha, Michael T.] Yale Univ, Program Neurogenet, Sch Med, Dept Neurosurg, New Haven, CT 06520 USA. [Samocha, Kaitlin E.; Robinson, Elise B.; Daly, Mark J.] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Samocha, Kaitlin E.; Robinson, Elise B.; Daly, Mark J.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Samocha, Kaitlin E.; Robinson, Elise B.; Daly, Mark J.] Broad Inst Harvard & MIT, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA. [Samocha, Kaitlin E.; Robinson, Elise B.; Daly, Mark J.] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Samocha, Kaitlin E.] Harvard Univ, Sch Med, Program Genet & Genom, Biol & Biomed Sci, Boston, MA 02114 USA. [Cicek, A. Ercument] Carnegie Mellon Univ, Computat Biol Dept, Pittsburgh, PA 15213 USA. [Cicek, A. Ercument] Bilkent Univ, Dept Comp Engn, TR-0680 Ankara, Turkey. [Shan Dong] Peking Univ, Sch Life Sci, Ctr Bioinformat, State Key Lab Prot & Plant Gene Res, Beijing 100871, Peoples R China. [Goldberg, Arthur P.; Cai Jinlu; Poultney, Christopher S.; Buxbaum, Joseph D.] Icahn Sch Med Mt Sinai, Seaver Autism Ctr Res & Treatment, New York, NY 10029 USA. [Goldberg, Arthur P.; Cai Jinlu; Poultney, Christopher S.; Grice, Dorothy E.; Buxbaum, Joseph D.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Keaney, John F., III] Yale Univ, Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT 06520 USA. [Klei, Lambertus; Devlin, Bernie] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15213 USA. [Moreno-De-Luca, Daniel] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06520 USA. [Solli-Nowlan, Tor] TheLab Inc, Los Angeles, CA 90068 USA. [Su, Mack Y.] Harvard Univ, Program Biophys, Boston, MA 02115 USA. [Teran, Nicole A.] Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA. [Beaudet, Arthur L.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Cantor, Rita M.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA. [Cantor, Rita M.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat, Los Angeles, CA 90095 USA. [Fombonne, Eric] Oregon Hlth & Sci Univ, Dept Psychiat, Portland, OR 97239 USA. [Fombonne, Eric] Oregon Hlth & Sci Univ, Inst Dev & Disabil, Portland, OR 97239 USA. [Geschwind, Daniel H.; Lowe, Jennifer K.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Semel Inst,Neurogenet Program, Los Angeles, CA 90095 USA. [Geschwind, Daniel H.; Lowe, Jennifer K.] Univ Calif Los Angeles, David Geffen Sch Med, Ctr Autism Res & Treatment, Semel Inst, Los Angeles, CA 90095 USA. [Lord, Catherine] Weill Cornell Med Coll, Ctr Autism & Dev Brain, White Plains, NY 10605 USA. [Mane, Shrikant M.] Yale Univ, Sch Med, Yale Ctr Genom Anal, New Haven, CT 06520 USA. [Martin, Donna M.] Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA. [Martin, Donna M.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Morrow, Eric M.] Brown Univ, Dept Mol Biol Cell Biol & Biochem, Providence, RI 02912 USA. [Morrow, Eric M.] Brown Univ, Dept Psychiat & Human Behav, Providence, RI 02912 USA. [Talkowski, Michael E.] Massachusetts Gen Hosp, Ctr Human Genet Res, Dept Neurol, Boston, MA 02114 USA. [Talkowski, Michael E.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Talkowski, Michael E.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Sutcliffe, James S.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Ctr Mol Neurosci, Nashville, TN 37232 USA. [Walsh, Christopher A.; Yu, Timothy W.] Childrens Hosp Boston, Howard Hughes Med Inst, Boston, MA 02115 USA. [Walsh, Christopher A.; Yu, Timothy W.] Childrens Hosp Boston, Div Genet & Genom, Boston, MA 02115 USA. [Walsh, Christopher A.; Yu, Timothy W.] Harvard Univ, Sch Med, Ctr Life Sci, Neurol & Pediat, Boston, MA 02115 USA. [Ledbetter, David H.; Martin, Christa Lese] Geisinger Hlth Syst, Autism & Dev Med Inst, Danville, PA 17822 USA. [Cook, Edwin H.] Univ Illinois, Dept Psychiat, Inst Juvenile Res, Chicago, IL 60637 USA. [Roeder, Kathryn] Carnegie Mellon Univ, Dept Stat, Pittsburgh, PA 15213 USA. RP Sanders, SJ (reprint author), Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. EM stephan.sanders@ucsf.edu; matthew.state@ucsf.edu OI Robinson, Elise/0000-0003-2314-2792; Sutcliffe, James/0000-0001-5200-6007; Sanders, Stephan/0000-0001-9112-5148; Buxbaum, Joseph/0000-0001-8898-8313; Yu, Timothy/0000-0003-2988-7701 FU Simons Foundation (SFARI) [124827, 307705]; National Institute for Health/National Institute for Mental Health [MH100233, MH100229, MH100239, MH057881, MH100209, DC009410, MH074090, MH071584-07, MH19961-14]; Donita B. Sullivan MD Research Professorship funds; Howard Hughes Medical Institute (International Student Research Fellowship); Canadian Institutes of Health Research (Doctoral Foreign Study Award); ADOS; ADI-R from Western Psychological Services FX We are grateful to all the families participating in this research, including the Simons Foundation Autism Research Initiative (SFARI) Simplex Collection (SSC), the Autism Sequencing Consortium (ASC), and the Autism Genome Project (AGP). This work was supported by grants from the Simons Foundation (SFARI # 124827 to M.W.S. and SFARI #307705 to S.J.S.), the National Institute for Health/National Institute for Mental Health (MH100233 to J.D.B., MH100229 to M.J.D., MH100239 to M.W.S., MH057881 and MH100209 to B.D., DC009410 to D.M.M., MH074090 to D.H.L. and C.L.M., and MH071584-07 and MH19961-14 supporting D.M.M.), Donita B. Sullivan MD Research Professorship funds to D.M.M., the Howard Hughes Medical Institute (International Student Research Fellowship to S.J.S.), and the Canadian Institutes of Health Research (Doctoral Foreign Study Award to A.J.W.). C.L. receives royalties for the ADOS and ADI-R from Western Psychological Services; royalties related to this project are donated to charities. We would like to thank the SSC principal investigators (A.L. Beaudet, R. Bernier, J. Constantino, E.H. Cook, Jr, E. Fombonne, D. Geschwind, D. E. Grice, A. Klin, D.H. Ledbetter, C. Lord, C.L. Martin, D.M. Martin, R. Maxim, J. Miles, O. Ousley, B. Peterson, J. Piggot, C. Saulnier, M.W. State, W. Stone, J.S. Sutcliffe, C. A. Walsh, and E. Wijsman) and the coordinators and staff at the SSC clinical sites; the SFARI staff, in particular M. Benedetti; the Rutgers University Cell and DNA repository for accessing biomaterials; the Yale Center of Genomic Analysis for SNP genotyping data; and I. Hart and X. Sanders for their unwavering support. D.H.L. acts as a consultant to Natera, Inc. NR 65 TC 86 Z9 86 U1 8 U2 34 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD SEP 23 PY 2015 VL 87 IS 6 BP 1215 EP 1233 DI 10.1016/j.neuron.2015.09.016 PG 19 WC Neurosciences SC Neurosciences & Neurology GA CU8HJ UT WOS:000363782200012 PM 26402605 ER PT J AU Buckholtz, JW Martin, JW Treadway, MT Jan, K Zald, DH Jones, O Marois, R AF Buckholtz, Joshua W. Martin, Justin W. Treadway, Michael T. Jan, Katherine Zald, David H. Jones, Owen Marois, Rene TI From Blame to Punishment: Disrupting Prefrontal Cortex Activity Reveals Norm Enforcement Mechanisms SO NEURON LA English DT Article ID TRANSCRANIAL MAGNETIC STIMULATION; WORKING-MEMORY; MORAL JUDGMENT; ULTIMATUM GAME; 3RD-PARTY PUNISHMENT; COSTLY PUNISHMENT; HUMAN COOPERATION; NEURAL CIRCUITRY; DECISION-MAKING; SOCIAL NORMS AB The social welfare provided by cooperation depends on the enforcement of social norms. Determining blameworthiness and assigning a deserved punishment are two cognitive cornerstones of norm enforcement. Although prior work has implicated the dorsolateral prefrontal cortex (DLPFC) in norm-based judgments, the relative contribution of this region to blameworthiness and punishment decisions remains poorly understood. Here, we used repetitive transcranial magnetic stimulation (rTMS) and fMRI to determine the specific role of DLPFC function in norm-enforcement behavior. DLPFC rTMS reduced punishment for wrongful acts without affecting blameworthiness ratings, and fMRI revealed punishment-selective DLPFC recruitment, suggesting that these two facets of norm-based decision making are neurobiologically dissociable. Finally, we show that DLPFC rTMS affects punishment decision making by altering the integration of information about culpability and harm. Together, these findings reveal a selective, causal role for DLPFC in norm enforcement: representational integration of the distinct information streams used to make punishment decisions. C1 [Buckholtz, Joshua W.; Martin, Justin W.] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. [Buckholtz, Joshua W.] Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA. [Martin, Justin W.; Jan, Katherine; Zald, David H.; Marois, Rene] Vanderbilt Univ, Dept Psychol, Nashville, TN 37235 USA. [Zald, David H.; Jones, Owen; Marois, Rene] Vanderbilt Univ, Ctr Integrat & Cognit Neurosci, Nashville, TN 37235 USA. [Jones, Owen] Vanderbilt Univ, Sch Law, Nashville, TN 37235 USA. [Jones, Owen] Vanderbilt Univ, Dept Biol Sci, Nashville, TN 37235 USA. [Treadway, Michael T.] Emory Univ, Dept Psychol, Atlanta, GA 30322 USA. [Buckholtz, Joshua W.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP Buckholtz, JW (reprint author), Harvard Univ, Dept Psychol, 52 Oxford St, Cambridge, MA 02138 USA. EM joshua_buckholtz@harvard.edu; rene.marois@vanderbilt.edu FU John D. and Catherine T. MacArthur Foundation; University of California at Santa Barbara; Vanderbilt's Center for Integrative and Cognitive Neuroscience; NIMH [T32MH018921, T32MH064913]; National Institute on Drug Abuse [1R03DA034126-01]; Sloan Foundation; Brain and Behavior Research Foundation; MGH Center for Law, Brain, and Behavior FX We wish to thank Brian Essex for assistance with the rTMS localization protocol, Randolph Blake for kindly making available TMS equipment, and Ashley Schwartzman for assistance with rTMS sessions. We are grateful to Fiery Cushman, Liane Young, and Joshua Green for comments on this manuscript. This study was supported by a grant from the John D. and Catherine T. MacArthur Foundation to Vanderbilt University and the University of California at Santa Barbara and by Vanderbilt's Center for Integrative and Cognitive Neuroscience. Its contents do not necessarily represent the official views of either the John D. and Catherine T. MacArthur Foundation or the MacArthur Foundation Research Network on Law and Neuroscience (http://www.lawneuro.org). J.W.B. was supported by the NIMH (T32MH018921 and T32MH064913), the National Institute on Drug Abuse (1R03DA034126-01), the Sloan Foundation, the Brain and Behavior Research Foundation, and the MGH Center for Law, Brain, and Behavior. NR 72 TC 7 Z9 7 U1 7 U2 24 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD SEP 23 PY 2015 VL 87 IS 6 BP 1369 EP 1380 DI 10.1016/j.neuron.2015.08.023 PG 12 WC Neurosciences SC Neurosciences & Neurology GA CU8HJ UT WOS:000363782200023 PM 26386518 ER PT J AU Baca, CB Barkley, GL AF Baca, Christine B. Barkley, Gregory L. TI Can big data help us close an epilepsy care gap? SO NEUROLOGY LA English DT Editorial Material ID DISPARITIES; OUTCOMES; PEOPLE AB Epilepsy has been termed an ambulatory care sensitive condition, meaning that high-quality outpatient epilepsy care can reduce unnecessary emergency department (ED) visits and hospitalizations. Using this framework, high ED use is a marker of poor disease control or limited access to care.(1) Do all people with epilepsy (PWE) with poorly controlled disease or limited access frequent the ED? Are other factors at play? In this changing health care landscape, with accountable care organizations and a need to reduce costs, can we predict PWE who are at high risk of frequent ED use? C1 [Baca, Christine B.] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA. [Baca, Christine B.] Vet Adm Greater Los Angeles, Dept Neurol, Los Angeles, CA USA. [Barkley, Gregory L.] Henry Ford Hosp, Dept Neurol, Detroit, MI 48202 USA. [Barkley, Gregory L.] Wayne State Univ, Sch Med, Detroit, MI USA. RP Baca, CB (reprint author), Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA. EM cbower@mednet.ucla.edu NR 8 TC 0 Z9 0 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD SEP 22 PY 2015 VL 85 IS 12 BP 1014 EP 1015 DI 10.1212/WNL.0000000000001961 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA CX3CG UT WOS:000365572500002 PM 26311744 ER PT J AU Ott, PA Hodi, FS Buchbinder, EI AF Ott, Patrick A. Hodi, F. Stephen Buchbinder, Elizabeth I. TI Inhibition of immune checkpoints and vascular endothelial growth factor as combination therapy for metastatic melanoma: an overview of rationale, preclinical evidence, and initial clinical data SO FRONTIERS IN ONCOLOGY LA English DT Review DE PD-1 :PD-1L blockade; angiogenesis inhibitors; VEGF; melanoma; immunotherapy ID REGULATORY T-CELLS; STAGE IV MELANOMA; DENDRITIC CELLS; CANCER-IMMUNOTHERAPY; UNTREATED MELANOMA; ANGIOGENIC FACTORS; FACTOR RECEPTOR-1; PLUS IPILIMUMAB; FACTOR-TRAP; TUMOR AB The role of angiogenesis as a mediator of immune regulation in the tumor microenvironment has recently come into focus. Furthermore, emerging evidence indicates that immunotherapy can lead to immune-mediated vasculopathy in the tumor, suggesting that the tumor vasculature may be an important interface between the tumor-directed immune response and the cancer itself. The advent of immune checkpoint inhibition as an effective immunotherapeutic strategy for many cancers has led to a better understanding of this interface. While the inhibition of angiogenesis through targeting of vascular endothelial growth factor (VEGF) has been used successfully for the treatment of cancer for many years, the mechanisms of its anti-tumor activity remain poorly understood. Initial studies of the complex relationship between angiogenesis, VEGF signaling and the immune system suggest that the combination of immune checkpoint blockade with angiogenesis inhibition has potential. While the majority of this work has been performed in metastatic melanoma, immunotherapy is rapidly showing promise in a broad range of malignancies and efforts to enhance immunotherapy will broadly impact the future of oncology. Here, we review the preclinical rationale and clinical investigations of combined angiogenesis inhibition and immunotherapy/immune checkpoint inhibition as a potentially promising combinatorial approach for cancer treatment. C1 [Ott, Patrick A.; Hodi, F. Stephen; Buchbinder, Elizabeth I.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Melanoma Dis Ctr,Ctr Immunooncol,Dept Med Oncol, Boston, MA 02215 USA. [Ott, Patrick A.; Hodi, F. Stephen; Buchbinder, Elizabeth I.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02215 USA. RP Ott, PA (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Melanoma Dis Ctr,Ctr Immunooncol, 450 Brookline Ave, Boston, MA 02215 USA. EM patrick_ott@dfci.harvard.edu NR 55 TC 16 Z9 16 U1 1 U2 7 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 SEP 22 PY 2015 VL 5 AR 202 DI 10.3389/fonc.2015.00202 PG 7 WC Oncology SC Oncology GA CW6UL UT WOS:000365133400001 PM 26442214 ER PT J AU Yuan, KY Yong, S Xu, F Zhou, T McDonald, JM Chen, YB AF Yuan, Kaiyu Yong, Sun Xu, Fei Zhou, Tong McDonald, Jay M. Chen, Yabing TI Calmodulin antagonists promote TRA-8 therapy of resistant pancreatic cancer SO ONCOTARGET LA English DT Article DE death receptor 5; apoptosis; resistance; calmodulin antagonists; pancreatic cancer ID APOPTOSIS-INDUCING LIGAND; TUMOR-NECROSIS-FACTOR; TRAIL-INDUCED APOPTOSIS; DEATH RECEPTOR EXPRESSION; MEDIATED APOPTOSIS; MONOCLONAL-ANTIBODY; SIGNALING COMPLEX; HEPATOMA-CELLS; IN-VITRO; ACTIVATION AB Pancreatic cancer is highly malignant with limited therapy and a poor prognosis. TRAIL-activating therapy has been promising, however, clinical trials have shown resistance and limited responses of pancreatic cancers. We investigated the effects of calmodulin(CaM) antagonists, trifluoperazine(TFP) and tamoxifen(TMX), on TRA-8-induced apoptosis and tumorigenesis of TRA-8-resistant pancreatic cancer cells, and underlying mechanisms. TFP or TMX alone did not induce apoptosis of resistant PANC-1 cells, while they dose-dependently enhanced TRA-8-induced apoptosis. TMX treatment enhanced efficacy of TRA-8 therapy on tumorigenesis in vivo. Analysis of TRA-8-induced death-inducing-signaling-complex (DISC) identified recruitment of survival signals, CaM/Src, into DR5-associated DISC, which was inhibited by TMX/TFP. In contrast, TMX/TFP increased TRA-8-induced DISC recruitment/activation of caspase-8. Consistently, caspase-8 inhibition blocked the effects of TFP/TMX on TRA-8-induced apoptosis. Moreover, TFP/TMX induced DR5 expression. With a series of deletion/point mutants, we identified CaM antagonist-responsive region in the putative Sp1-binding domain between -295 to -300 base pairs of DR5 gene. Altogether, we have demonstrated that CaM antagonists enhance TRA-8-induced apoptosis of TRA-8-resistant pancreatic cancer cells by increasing DR5 expression and enhancing recruitment of apoptotic signal while decreasing survival signals in DR5-associated DISC. Our studies support the use of these readily available CaM antagonists combined with TRAIL-activating agents for pancreatic cancer therapy. C1 [Yuan, Kaiyu; Yong, Sun; Xu, Fei; McDonald, Jay M.; Chen, Yabing] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA. [Zhou, Tong] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [McDonald, Jay M.; Chen, Yabing] Birmingham Vet Affairs Med Ctr, Birmingham, AL 35294 USA. RP Chen, YB (reprint author), Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA. EM ybchen@uab.edu FU VA Merit Review Awards [BX000311, BX002296] FX This work was supported by VA Merit Review Awards BX000311 (JMM) and BX002296 (YC). NR 50 TC 0 Z9 0 U1 0 U2 3 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD SEP 22 PY 2015 VL 6 IS 28 BP 25308 EP 25319 DI 10.18632/oncotarget.4490 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CT9TS UT WOS:000363160100062 PM 26320171 ER PT J AU Boros, K Puissant, A Back, M Alexe, G Bassil, CF Sinha, P Tholouli, E Stegmaier, K Byers, RJ Rodig, SJ AF Boros, Katalin Puissant, Alexandre Back, Morgan Alexe, Gabriela Bassil, Christopher F. Sinha, Papiya Tholouli, Eleni Stegmaier, Kimberly Byers, Richard J. Rodig, Scott J. TI Increased SYK activity is associated with unfavorable outcome among patients with acute myeloid leukemia SO ONCOTARGET LA English DT Article DE SYK tyrosine kinase; AML; poor prognosis; tissue microarray; clinical trials ID ACTIVATION LOOP TYROSINES; IN-VIVO; KINASE INHIBITOR; MUTATIONS; NETWORKS AB Recent discoveries have led to the testing of novel targeted therapies for the treatment of acute myeloid leukemia (AML). To better inform the results of clinical trials, there is a need to identify and systematically assess biomarkers of response and pharmacodynamic markers of successful target engagement. Spleen tyrosine kinase (SYK) is a candidate therapeutic target in AML. Small-molecule inhibitors of SYK induce AML differentiation and impair leukemia progression in preclinical studies. However, tools to predict response to SYK inhibition and to routinely evaluate SYK activation in primary patient samples have been lacking. In this study we quantified phosphorylated SYK (P-SYK) in AML cell lines and establish that increasing levels of baseline P-SYK are correlated with an increasing sensitivity to small-molecule inhibitors targeting SYK. In addition, we found that pharmacological inhibition of SYK activity extinguishes P-SYK expression as detected by an immunohistochemical (IHC) test. Quantitative analysis of P-SYK expression by the IHC test in a series of 70 primary bone marrow biopsy specimens revealed a spectrum of P-SYK expression across AML cases and that high P-SYK expression is associated with unfavourable outcome independent of age, cytogenetics, and white blood cell count. This study thus establishes P-SYK as a critical biomarker in AML that identifies tumors sensitive to SYK inhibition, identifies an at-risk patient population, and allows for the monitoring of target inhibition during treatment. C1 [Boros, Katalin] Manchester Royal Infirm, Dept Histopathol, Manchester M13 9WL, Lancs, England. [Puissant, Alexandre; Alexe, Gabriela; Bassil, Christopher F.; Stegmaier, Kimberly] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Puissant, Alexandre; Alexe, Gabriela; Bassil, Christopher F.; Stegmaier, Kimberly] Boston Childrens Hosp, Boston, MA USA. [Puissant, Alexandre] Fac Med Nice, INSERM, U1065, C3M,Team 2, F-06034 Nice, France. [Back, Morgan] Univ Manchester, Sch Med, Manchester, Lancs, England. [Sinha, Papiya; Rodig, Scott J.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Tholouli, Eleni] Manchester Royal Infirm, Dept Haematol, Manchester M13 9WL, Lancs, England. [Byers, Richard J.] Univ Manchester, Inst Canc Sci, Manchester, Lancs, England. RP Byers, RJ (reprint author), Univ Manchester, Inst Canc Sci, Manchester, Lancs, England. EM richard.byers@cmft.nhs.uk RI PUISSANT, ALEXANDRE/O-9575-2016; OI PUISSANT, ALEXANDRE/0000-0002-3997-9282; Byers, Richard/0000-0003-0796-0365 FU National Cancer Institute [R01 CA140292]; American Cancer Society; Starr Cancer Consortium FX This research was supported with grants from the National Cancer Institute (R01 CA140292), the American Cancer Society and the Starr Cancer Consortium (KS). KS is a Leukemia and Lymphoma Society Scholar and AP is a Leukemia and Lymphoma Society Fellow. AP received the "Prix Jeune Chercheur" of the Bettencourt foundation. NR 23 TC 2 Z9 2 U1 0 U2 3 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD SEP 22 PY 2015 VL 6 IS 28 BP 25575 EP 25587 DI 10.18632/oncotarget.4669 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CT9TS UT WOS:000363160100080 PM 26315286 ER PT J AU Balasubramanian, K Maeda, A Lee, JS Mohammadyani, D Dar, HH Jiang, JF Croix, CMS Watkins, S Tyurin, VA Tyurina, YY Kloditz, K Polimova, A Kapralova, VI Xiong, ZY Ray, P Klein-Seetharaman, J Mallampalli, RK Bayir, H Fadeel, B Kagan, VE AF Balasubramanian, Krishnakumar Maeda, Akihiro Lee, Janet S. Mohammadyani, Dariush Dar, Haider Hussain Jiang, Jian Fei Croix, Claudette M. St. Watkins, Simon Tyurin, Vladimir A. Tyurina, Yulia Y. Kloeditz, Katharina Polimova, Anastassia Kapralova, Valentyna I. Xiong, Zeyu Ray, Prabir Klein-Seetharaman, Judith Mallampalli, Rama K. Bayir, Huelya Fadeel, Bengt Kagan, Valerian E. TI Dichotomous roles for externalized cardiolipin in extracellular signaling: Promotion of phagocytosis and attenuation of innate immunity SO SCIENCE SIGNALING LA English DT Article ID APOPTOTIC CELLS; BACTERIAL LIPOPOLYSACCHARIDE; MACROPHAGE ACTIVATION; SCAVENGER RECEPTORS; MEDIATED APOPTOSIS; CELLULAR MEMBRANES; MOLECULAR-PATTERNS; ESCHERICHIA-COLI; MANNOSE RECEPTOR; STRUCTURAL BASIS AB Among the distinct molecular signatures present in the mitochondrion is the tetra-acylated anionic phospholipid cardiolipin, a lipid also present in primordial, single-cell bacterial ancestors of mitochondria and multiple bacterial species today. Cardiolipin is normally localized to the inner mitochondrial membrane; however, when cardiolipin becomes externalized to the surface of dysregulated mitochondria, it promotes inflammasome activation and stimulates the elimination of damaged or nonfunctional mitochondria by mitophagy. Given the immunogenicity of mitochondrial and bacterial membranes that are released during sterile and pathogen-induced trauma, we hypothesized that cardiolipins might function as "eat me" signals for professional phagocytes. In experiments with macrophage cell lines and primary macrophages, we found that membranes with mitochondrial or bacterial cardiolipins on their surface were engulfed through phagocytosis, which depended on the scavenger receptor CD36. Distinct from this process, the copresentation of cardiolipin with the Toll-like receptor 4 (TLR4) agonist lipopolysaccharide dampened TLR4-stimulated production of cytokines. These data suggest that externalized, extracellular cardiolipins play a dual role in host-host and host-pathogen interactions by promoting phagocytosis and attenuating inflammatory immune responses. C1 [Balasubramanian, Krishnakumar; Mohammadyani, Dariush; Dar, Haider Hussain; Jiang, Jian Fei; Tyurin, Vladimir A.; Tyurina, Yulia Y.; Polimova, Anastassia; Kapralova, Valentyna I.; Bayir, Huelya; Kagan, Valerian E.] Univ Pittsburgh, Dept Environm & Occupat Hlth, Ctr Free Radical & Antioxidant Hlth, Pittsburgh, PA 15219 USA. [Maeda, Akihiro; Kloeditz, Katharina; Fadeel, Bengt] Karolinska Inst, Inst Environm Med, Div Mol Toxicol, S-17177 Stockholm, Sweden. [Lee, Janet S.; Xiong, Zeyu; Ray, Prabir] Univ Pittsburgh, Sch Med, Dept Med, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA 15213 USA. [Croix, Claudette M. St.; Watkins, Simon] Univ Pittsburgh, Ctr Biol Imaging, Pittsburgh, PA 15261 USA. [Klein-Seetharaman, Judith] Univ Warwick, Div Metab & Vasc Hlth, Coventry CV4 7AL, W Midlands, England. [Mallampalli, Rama K.] Univ Pittsburgh, Dept Internal Med, Acute Lung Injury Ctr Excellence, Pittsburgh, PA 15213 USA. [Mallampalli, Rama K.] Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA 15215 USA. [Bayir, Huelya] Univ Pittsburgh, Sch Med, Dept Crit Care Med, Pittsburgh, PA 15261 USA. RP Balasubramanian, K (reprint author), Univ Pittsburgh, Dept Environm & Occupat Hlth, Ctr Free Radical & Antioxidant Hlth, Pittsburgh, PA 15219 USA. EM kris.balasub@gmail.com; bengt.fadeel@ki.se; kagan@pitt.edu OI Tyurin, Vladimir/0000-0002-3474-1697 FU NIH [PO1 HL114453, HL086884, U19AIO68021, ES020693, NS076511, NS061817, CA165065]; Human Frontier Science Program [HFSP-RGP0013/2014]; Swedish Research Council; NIH (NIOSH) [OH008282]; [P30CA047904] FX This study was supported by grants from the NIH (PO1 HL114453, HL086884, U19AIO68021, ES020693; NS076511, NS061817, CA165065; NIOSH OH008282), the Human Frontier Science Program (HFSP-RGP0013/2014), the Swedish Research Council, and a Core grant to the UPCI Cancer Biomarkers Facility/Luminex Core Laboratory (P30CA047904). NR 81 TC 11 Z9 11 U1 0 U2 16 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1945-0877 EI 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD SEP 22 PY 2015 VL 8 IS 395 AR ra95 DI 10.1126/scisignal.aaa6179 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CU1YJ UT WOS:000363318000002 PM 26396268 ER PT J AU Cummings, JL Lyketsos, CG Peskind, ER Porsteinsson, AP Mintzer, JE Scharre, D De La Gandara, JE Agronin, M Davis, CS Nguyen, U Shin, P Tariot, PN Siffert, J AF Cummings, Jeffrey L. Lyketsos, Constantine G. Peskind, Elaine R. Porsteinsson, Anton P. Mintzer, Jacobo E. Scharre, DouglasW. De La Gandara, Jose E. Agronin, Marc Davis, Charles S. Uyen Nguyen Shin, Paul Tariot, Pierre N. Siffert, Joao TI Effect of Dextromethorphan-Quinidine on Agitation in Patients With Alzheimer Disease Dementia A Randomized Clinical Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID PSEUDOBULBAR AFFECT; NEUROPSYCHIATRIC SYMPTOMS; BEHAVIORAL SYMPTOMS; PLACEBO-RESPONSE; IN-VITRO; AGGRESSION; DESIGN; RECOMMENDATIONS; PROGRESSION; MANAGEMENT AB IMPORTANCE Agitation is common among patients with Alzheimer disease; safe, effective treatments are lacking. OBJECTIVE To assess the efficacy, safety, and tolerability of dextromethorphan hydrobromide-quinidine sulfate for Alzheimer disease-related agitation. DESIGN, SETTING, AND PARTICIPANTS Phase 2 randomized, multicenter, double-blind, placebo-controlled trial using a sequential parallel comparison design with 2 consecutive 5-week treatment stages conducted August 2012-August 2014. Patients with probable Alzheimer disease, clinically significant agitation (Clinical Global Impressions-Severity agitation score >= 4), and a Mini-Mental State Examination score of 8 to 28 participated at 42 US study sites. Stable dosages of antidepressants, antipsychotics, hypnotics, and antidementia medications were allowed. INTERVENTIONS In stage 1, 220 patients were randomized in a 3: 4 ratio to receive dextromethorphan-quinidine (n = 93) or placebo (n = 127). In stage 2, patients receiving dextromethorphan-quinidine continued; those receiving placebo were stratified by response and rerandomized in a 1: 1 ratio to dextromethorphan-quinidine (n = 59) or placebo (n = 60). MAIN OUTCOMES AND MEASURES The primary end point was change from baseline on the Neuropsychiatric Inventory (NPI) Agitation/Aggression domain (scale range, 0 [absence of symptoms] to 12 [symptoms occur daily and with marked severity]). RESULTS A total of 194 patients (88.2%) completed the study. With the sequential parallel comparison design, 152 patients received dextromethorphan-quinidine and 127 received placebo during the study. Analysis combining stages 1 (all patients) and 2 (rerandomized placebo nonresponders) showed significantly reduced NPI Agitation/Aggression scores for dextromethorphan-quinidine vs placebo( ordinaryleastsquareszstatistic,-3.95; P < .001). In stage 1, mean NPI Agitation/Aggression scores were reduced from 7.1 to 3.8 with dextromethorphan-quinidine and from 7.0 to 5.3 with placebo. Between-groupt reatment differences were significantin stage 1(leasts quaresmean, -1.5; 95% CI, -2.3 to -0.7; P <. 001). In stage 2, NPI Agitation/Aggression scores were reduced from 5.8 to 3.8 with dextromethorphan-quinidine and from 6.7 to 5.8 with placebo. Between-group treatment differences were also significant in stage 2(least squares mean,-1.6; 95% CI,-2.9 to -0.3; P=.02). Adverseevents included falls (8.6% for dextromethorphan-quinidine vs3.9% for placebo), diarrhea (5.9% vs 3.1% respectively), and urinary tract infection (5.3% vs 3.9% respectively). Serious adverse events occurred in 7.9% with dextromethorphan-quinidine vs 4.7% with placebo. Dextromethorphan-quinidinewas not associated with cognitive impairment, sedation, or clinically significant QTc prolongation. CONCLUSIONS AND RELEVANCE In this preliminary 10-week phase 2 randomized clinical trial of patients with probable Alzheimer disease, combination dextromethorphan-quinidine demonstrated clinically relevant efficacy for agitation and was generally well tolerated. C1 [Cummings, Jeffrey L.] Cleveland Clin, Lou Ruvo Ctr Brain Hlth, Las Vegas, NV 89106 USA. [Lyketsos, Constantine G.] Johns Hopkins Bayview, Johns Hopkins Memory & Alzheimers Treatment Ctr, Baltimore, MD USA. [Peskind, Elaine R.] Univ Washington, Sch Med, VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Porsteinsson, Anton P.] Univ Rochester, Sch Med & Dent, Rochester, NY USA. [Mintzer, Jacobo E.] Roper St Francis Hosp, Clin Biotechnol Res Inst, Charleston, SC USA. [Mintzer, Jacobo E.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. [Scharre, DouglasW.] Ohio State Univ, Columbus, OH 43210 USA. [De La Gandara, Jose E.] Quantum Labs Inc, W Palm Beach, FL USA. [Agronin, Marc] Miami Jewish Hlth Syst, Miami, FL USA. [Davis, Charles S.] CSD Biostat Inc, Tucson, AZ USA. [Uyen Nguyen; Shin, Paul; Siffert, Joao] Avanir Pharmaceut Inc, Aliso Viejo, CA USA. [Tariot, Pierre N.] Banner Alzheimers Inst, Phoenix, AZ USA. RP Cummings, JL (reprint author), Cleveland Clin, Lou Ruvo Ctr Brain Hlth, 888 W Bonneville Ave, Las Vegas, NV 89106 USA. EM cumminj@ccf.org FU Avanir Pharmaceuticals Inc. FX This study was funded by Avanir Pharmaceuticals Inc. NR 34 TC 16 Z9 16 U1 1 U2 14 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD SEP 22 PY 2015 VL 314 IS 12 BP 1242 EP 1254 DI 10.1001/jama.2015.10214 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA CS5IE UT WOS:000362110700013 PM 26393847 ER PT J AU D'Amico, AV Chen, MH Renshaw, A Loffredo, M Kantoff, PW AF D'Amico, Anthony V. Chen, Ming-Hui Renshaw, Andrew Loffredo, Marian Kantoff, Philip W. TI Long-term Follow-up of a Randomized Trial of Radiation With or Without Androgen Deprivation Therapy for Localized Prostate Cancer SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [D'Amico, Anthony V.; Loffredo, Marian] Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. [Chen, Ming-Hui] Univ Connecticut, Dept Stat, Storrs, CT 06269 USA. [Renshaw, Andrew] Miami Baptist Hosp, Dept Pathol, Miami, FL USA. [Kantoff, Philip W.] Dana Farber Canc Inst, Dept Med, Boston, MA 02115 USA. RP D'Amico, AV (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. EM adamico@partners.org NR 6 TC 19 Z9 19 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD SEP 22 PY 2015 VL 314 IS 12 BP 1291 EP 1293 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA CS5IE UT WOS:000362110700020 PM 26393854 ER PT J AU Huybrechts, KF Bateman, BT Hernandez-Diaz, S AF Huybrechts, Krista F. Bateman, Brian T. Hernandez-Diaz, Sonia TI Maternal Antidepressant Use and Persistent Pulmonary Hypertension of the Newborn Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Huybrechts, Krista F.] Brigham & Womens Hosp, Dept Med, Boston, MA 02120 USA. [Bateman, Brian T.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Hernandez-Diaz, Sonia] Harvard Univ, Dept Epidemiol, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. RP Huybrechts, KF (reprint author), Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, 1620 Tremont St,Ste 3030, Boston, MA 02120 USA. EM khuybrechts@partners.org NR 2 TC 3 Z9 3 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD SEP 22 PY 2015 VL 314 IS 12 BP 1294 EP 1294 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA CS5IE UT WOS:000362110700022 PM 26393857 ER PT J AU Fisichella, PM AF Fisichella, P. Marco TI Treating Hoarseness With Proton Pump Inhibitors Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID REFLUX C1 [Fisichella, P. Marco] Harvard Univ, Sch Med, Boston VA Healthcare Syst, Boston, MA USA. RP Fisichella, PM (reprint author), Harvard Med Sch, Boston VA Healthcare Syst, 1400 VFW Pkwy, West Roxbury, MA 02132 USA. EM piero.fisichella@va.gov NR 5 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD SEP 22 PY 2015 VL 314 IS 12 BP 1295 EP 1296 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA CS5IE UT WOS:000362110700024 PM 26393858 ER PT J AU Lee, S Lee, MJ Kim, BW Gilman, JM Kuster, JK Blood, AJ Kuhnen, CM Breiter, HC AF Lee, Sang Lee, Myung J. Kim, Byoung W. Gilman, Jodi M. Kuster, John K. Blood, Anne J. Kuhnen, Camelia M. Breiter, Hans C. TI The Commonality of Loss Aversion across Procedures and Stimuli SO PLOS ONE LA English DT Article ID DECISION-MAKING; PROSPECT-THEORY; RISK-AVERSION; RESPONSES; AMYGDALA; UTILITY; CHOICE; MODEL AB Individuals tend to give losses approximately 2-fold the weight that they give gains. Such approximations of loss aversion (LA) are almost always measured in the stimulus domain of money, rather than objects or pictures. Recent work on preference-based decision-making with a schedule-less keypress task (relative preference theory, RPT) has provided a mathematical formulation for LA similar to that in prospect theory (PT), but makes no parametric assumptions in the computation of LA, uses a variable tied to communication theory (i.e., the Shannon entropy or information), and works readily with non-monetary stimuli. We evaluated if these distinct frameworks described similar LA in healthy subjects, and found that LA during the anticipation phase of the PT-based task correlated significantly with LA related to the RPT-based task. Given the ease with which non-monetary stimuli can be used on the Internet, or in animal studies, these findings open an extensive range of applications for the study of loss aversion. Furthermore, the emergence of methodology that can be used to measure preference for both social stimuli and money brings a common framework to the evaluation of preference in both social psychology and behavioral economics. C1 [Lee, Sang; Lee, Myung J.; Kim, Byoung W.; Breiter, Hans C.] Northwestern Univ, Warren Wright Adolescent Ctr, Feinberg Sch Med, Chicago, IL 60611 USA. [Lee, Sang; Lee, Myung J.; Kim, Byoung W.; Gilman, Jodi M.; Kuster, John K.; Blood, Anne J.; Breiter, Hans C.] Massachusetts Gen Hosp, Dept Psychiat, Lab Neuroimaging & Genet, Boston, MA 02114 USA. [Lee, Sang; Lee, Myung J.; Kim, Byoung W.; Gilman, Jodi M.; Kuster, John K.; Blood, Anne J.; Breiter, Hans C.] Harvard Univ, Sch Med, Boston, MA USA. [Kuster, John K.; Blood, Anne J.; Breiter, Hans C.] MGH & HMS, Mood & Motor Control Lab, Boston, MA USA. [Kuhnen, Camelia M.] Univ N Carolina, Kenan Flagler Business Sch, Chapel Hill, NC USA. [Lee, Sang; Lee, Myung J.; Kim, Byoung W.; Gilman, Jodi M.; Kuster, John K.; Blood, Anne J.; Breiter, Hans C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Lee, Sang; Lee, Myung J.; Kim, Byoung W.; Gilman, Jodi M.; Kuster, John K.; Blood, Anne J.; Breiter, Hans C.] Northwestern Univ, Phenotype Genotype Project Addict & Mood Disorder, Chicago, IL 60611 USA. RP Breiter, HC (reprint author), Northwestern Univ, Warren Wright Adolescent Ctr, Feinberg Sch Med, Chicago, IL 60611 USA. EM h-breiter@northwestern.edu FU NIDA, Bethesda, MD [14118, 026002, 026104, 027804]; Office of National Drug Control Policy - Counterdrug Technology Assessment Center, Washington, D.C. [DABK39-03-0098, DABK39-03-C-0098]; Warren Wright Adolescent Center at Northwestern Memorial Hospital & Northwestern University, Chicago Il; NINDS, Washington, D.C. [052368] FX Funding: This work was supported by grants to H.C. B. (#14118, 026002, 026104, 027804) from the NIDA, Bethesda, MD, and grants (DABK39-03-0098 & DABK39-03-C-0098; The Phenotype Genotype Project in Addiction and Mood Disorder) from the Office of National Drug Control Policy - Counterdrug Technology Assessment Center, Washington, D.C. Further support was provided to H.C.B. by the Warren Wright Adolescent Center at Northwestern Memorial Hospital & Northwestern University, Chicago Il. Also, support was provided by a grant to A.J.B. (#052368) from NINDS, Washington, D.C. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 1 Z9 1 U1 1 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 22 PY 2015 VL 10 IS 9 AR e0135216 DI 10.1371/journal.pone.0135216 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CS0ZW UT WOS:000361792100004 ER PT J AU Shoda, H Yanai, R Yoshimura, T Nagai, T Kimura, K Sobrin, L Connor, KM Sakoda, Y Tamada, K Ikeda, T Sonoda, KH AF Shoda, Hiromi Yanai, Ryoji Yoshimura, Takeru Nagai, Tomohiko Kimura, Kazuhiro Sobrin, Lucia Connor, Kip M. Sakoda, Yukimi Tamada, Koji Ikeda, Tsunehiko Sonoda, Koh-Hei TI Dietary Omega-3 Fatty Acids Suppress Experimental Autoimmune Uveitis in Association with Inhibition of Th1 and Th17 Cell Function SO PLOS ONE LA English DT Article ID KOYANAGI-HARADA-DISEASE; FATTY-ACIDS; CARDIOVASCULAR-DISEASE; EICOSAPENTAENOIC ACID; N-3 PUFA; MICE; UVEORETINITIS; NEOVASCULARIZATION; INFLAMMATION; MACROPHAGES AB Omega (omega)-3 long-chain polyunsaturated fatty acids (LCPUFAs) inhibit the production of inflammatory mediators and thereby contribute to the regulation of inflammation. Experimental autoimmune uveitis (EAU) is a well-established animal model of autoimmune retinal inflammation. To investigate the potential effects of dietary intake of omega-3 LCPUFAs on uveitis, we examined the anti-inflammatory properties of these molecules in comparison with omega-6 LCPUFAs in a mouse EAU model. C57BL/6 mice were fed a diet containing omega-3 LCPU-FAs or omega-6 LCPUFAs for 2 weeks before as well as after the induction of EAU by subcutaneous injection of a fragment of human interphotoreceptor retinoid-binding protein emulsified with complete Freund's adjuvant. Both clinical and histological scores for uveitis were smaller for mice fed omega-3 LCPUFAs than for those fed omega-6 LCPUFAs. The concentrations of the T helper 1 (Th1) cytokine interferon-gamma and the Th17 cytokine interleukin-17 in intraocular fluid as well as the production of these cytokines by lymph node cells were reduced for mice fed omega-3 LCPUFAs. Furthermore, the amounts of mRNAs for the Th1- and Th17-related transcription factors T-bet and ROR gamma t, respectively, were reduced both in the retina and in lymph node cells of mice fed omega-3 LCPUFAs. Our results thus show that a diet enriched in omega-3 LCPUFAs suppressed uveitis in mice in association with inhibition of Th1 and Th17 cell function. C1 [Shoda, Hiromi; Yanai, Ryoji; Nagai, Tomohiko; Kimura, Kazuhiro; Sonoda, Koh-Hei] Yamaguchi Univ, Grad Sch Med, Dept Ophthalmol, Ube, Yamaguchi 755, Japan. [Yoshimura, Takeru; Sobrin, Lucia; Connor, Kip M.] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Angiogenesis Lab,Dept Ophthalmol, Cambridge, MA 02138 USA. [Sakoda, Yukimi; Tamada, Koji] Yamaguchi Univ, Grad Sch Med, Dept Immunol, Ube, Yamaguchi 755, Japan. [Shoda, Hiromi; Ikeda, Tsunehiko] Osaka Med Coll, Dept Ophthalmol, Osaka, Japan. RP Yanai, R (reprint author), Yamaguchi Univ, Grad Sch Med, Dept Ophthalmol, Ube, Yamaguchi 755, Japan. EM yanai@yamaguchi-u.ac.jp OI Connor, Kip/0000-0002-2048-9080 NR 43 TC 0 Z9 0 U1 0 U2 7 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 SEP 22 PY 2015 VL 10 IS 9 AR e0138241 DI 10.1371/journal.pone.0138241 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CS0ZW UT WOS:000361792100042 PM 26393358 ER PT J AU Waldo, SW Secemsky, EA O'Brien, C Kennedy, KF Pomerantsev, E Sundt, TM McNulty, EJ Scirica, BM Yeh, RW AF Waldo, Stephen W. Secemsky, Eric A. O'Brien, Cashel Kennedy, Kevin F. Pomerantsev, Eugene Sundt, Thoralf M., III McNulty, Edward J. Scirica, Benjamin M. Yeh, Robert W. TI Response to Letter Regarding Article, "Surgical Ineligibility and Mortality Among Patients With Unprotected Left Main or Multivessel Coronary Artery Disease Undergoing Percutaneous Coronary Intervention" SO CIRCULATION LA English DT Letter C1 [Waldo, Stephen W.; Secemsky, Eric A.; O'Brien, Cashel; Pomerantsev, Eugene; Yeh, Robert W.] Massachusetts Gen Hosp, Div Cardiol, Dept Med, Boston, MA 02114 USA. [Kennedy, Kevin F.] St Lukes Midamer Heart Inst, Kansas City, MO USA. [Sundt, Thoralf M., III] Massachusetts Gen Hosp, Div Cardiac Surg, Boston, MA 02114 USA. [McNulty, Edward J.] Kaiser Permanente Med Ctr, Div Cardiol, San Francisco, CA USA. [Scirica, Benjamin M.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc Med, Boston, MA 02115 USA. RP Waldo, SW (reprint author), Massachusetts Gen Hosp, Div Cardiol, Dept Med, Boston, MA 02114 USA. NR 4 TC 0 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD SEP 22 PY 2015 VL 132 IS 12 BP E156 EP E156 DI 10.1161/CIRCULATIONAHA.115.016777 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA CR6VD UT WOS:000361485100006 PM 26391303 ER PT J AU Jack, DW Asante, KP Wylie, BJ Chillrud, SN Whyatt, RM Ae-Ngibise, KA Quinn, AK Yawson, AK Boamah, EA Agyei, O Mujtaba, M Kaali, S Kinney, P Owusu-Agyei, S AF Jack, Darby W. Asante, Kwaku Poku Wylie, Blair J. Chillrud, Steve N. Whyatt, Robin M. Ae-Ngibise, Kenneth A. Quinn, Ashlinn K. Yawson, Abena Konadu Boamah, Ellen Abrafi Agyei, Oscar Mujtaba, Mohammed Kaali, Seyram Kinney, Patrick Owusu-Agyei, Seth TI Ghana randomized air pollution and health study (GRAPHS): study protocol for a randomized controlled trial SO TRIALS LA English DT Article DE Household air pollution; LPG; Cookstove; Ghana; Pneumonia; Birth weight ID COMPARATIVE RISK-ASSESSMENT; SOLID-FUEL USE; PARTICULATE MATTER; CARBON-MONOXIDE; DEVELOPING-COUNTRIES; HIGHLAND GUATEMALA; KINTAMPO HEALTH; BIOMASS FUELS; BIRTH-WEIGHT; INDOOR AB Background: Household air pollution exposure is a major health risk, but validated interventions remain elusive. Methods/Design: The Ghana Randomized Air Pollution and Health Study (GRAPHS) is a cluster-randomized trial that evaluates the efficacy of clean fuels (liquefied petroleum gas, or LPG) and efficient biomass cookstoves in the Brong-Ahafo region of central Ghana. We recruit pregnant women into LPG, efficient cookstove, and control arms and track birth weight and physician-assessed severe pneumonia incidence in the first year of life. A woman is eligible to participate if she is in the first or second trimester of pregnancy and carrying a live singleton fetus, if she is the primary cook, and if she does not smoke. We hypothesize that babies born to intervention mothers will weigh more and will have fewer cases of physician-assessed severe pneumonia in the first year of life. Additionally, an extensive personal air pollution exposure monitoring effort opens the way for exposure-response analyses, which we will present alongside intention-to-treat analyses. Major funding was provided by the National Institute of Environmental Health Sciences, The Thrasher Research Fund, and the Global Alliance for Clean Cookstoves. Discussion: Household air pollution exposure is a major health risk that requires well-tested interventions. GRAPHS will provide important new evidence on the efficacy of both efficient biomass cookstoves and LPG, and will thus help inform health and energy policies in developing countries. C1 [Jack, Darby W.; Whyatt, Robin M.; Quinn, Ashlinn K.; Kinney, Patrick] Columbia Univ, Mailman Sch Publ Hlth, New York, NY 10027 USA. [Asante, Kwaku Poku; Ae-Ngibise, Kenneth A.; Yawson, Abena Konadu; Boamah, Ellen Abrafi; Agyei, Oscar; Mujtaba, Mohammed; Kaali, Seyram; Owusu-Agyei, Seth] Kintampo Hlth Res Ctr, Ghana Hlth Serv, Kintampo, Ghana. [Chillrud, Steve N.] Columbia Univ, Lamont Doherty Earth Observ, New York, NY USA. [Wylie, Blair J.] Massachusetts Gen Hosp, Vincent Dept Obstet & Gynecol, Div Maternal Fetal Med, Boston, MA 02114 USA. [Wylie, Blair J.] Harvard Univ, Sch Med, Boston, MA USA. RP Jack, DW (reprint author), Columbia Univ, Mailman Sch Publ Hlth, New York, NY 10027 USA. EM dj2183@cumc.columbia.edu FU NIEHS NIH HHS [1R01ES019547, ES009089, K23 ES021471, P30 ES009089, R01 ES019547, T32 ES023770] NR 37 TC 3 Z9 3 U1 4 U2 12 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 SEP 22 PY 2015 VL 16 AR 420 DI 10.1186/s13063-015-0930-8 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA CR8FX UT WOS:000361587600001 PM 26395578 ER PT J AU Foldes, ST Weber, DJ Collinger, JL AF Foldes, Stephen T. Weber, Douglas J. Collinger, Jennifer L. TI MEG-based neurofeedback for hand rehabilitation SO JOURNAL OF NEUROENGINEERING AND REHABILITATION LA English DT Article DE Brain-Computer Interface; Neurofeedback; Spinal Cord Injury; Magnetoencephalography; Neuroplasticity; Rehabilitation ID BRAIN-COMPUTER INTERFACE; MIRROR NEURON SYSTEM; MOTOR IMAGERY; STROKE REHABILITATION; PLASTICITY; FEEDBACK; SUPPRESSION; MODULATION; ARTIFACTS; RECOVERY AB Background: Providing neurofeedback (NF) of motor-related brain activity in a biologically-relevant and intuitive way could maximize the utility of a brain-computer interface (BCI) for promoting therapeutic plasticity. We present a BCI capable of providing intuitive and direct control of a video-based grasp. Methods: Utilizing magnetoencephalography's (MEG) high temporal and spatial resolution, we recorded sensorimotor rhythms (SMR) that were modulated by grasp or rest intentions. SMR modulation controlled the grasp aperture of a stop motion video of a human hand. The displayed hand grasp position was driven incrementally towards a closed or opened state and subjects were required to hold the targeted position for a time that was adjusted to change the task difficulty. Results: We demonstrated that three individuals with complete hand paralysis due to spinal cord injury (SCI) were able to maintain brain-control of closing and opening a virtual hand with an average of 63 % success which was significantly above the average chance rate of 19 %. This level of performance was achieved without pre-training and less than 4 min of calibration. In addition, successful grasp targets were reached in 1.96 +/- 0.15 s. Subjects performed 200 brain-controlled trials in approximately 30 min excluding breaks. Two of the three participants showed a significant improvement in SMR indicating that they had learned to change their brain activity within a single session of NF. Conclusions: This study demonstrated the utility of a MEG-based BCI system to provide realistic, efficient, and focused NF to individuals with paralysis with the goal of using NF to induce neuroplasticity. C1 [Foldes, Stephen T.; Weber, Douglas J.; Collinger, Jennifer L.] VA Pittsburgh Healthcare Syst, Human Engn Res Labs, Pittsburgh, PA 15206 USA. [Foldes, Stephen T.; Weber, Douglas J.; Collinger, Jennifer L.] Univ Pittsburgh, Dept Phys Med & Rehabil, Pittsburgh, PA 15213 USA. [Foldes, Stephen T.; Weber, Douglas J.; Collinger, Jennifer L.] Univ Pittsburgh, Ctr Neural Basis Cognit, Carnegie Mellon Univ, Pittsburgh, PA 15213 USA. [Weber, Douglas J.; Collinger, Jennifer L.] Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA 15213 USA. RP Collinger, JL (reprint author), VA Pittsburgh Healthcare Syst, Human Engn Res Labs, Pittsburgh, PA 15206 USA. EM collingr@pitt.edu FU Department of Veterans Affairs, Office of Research and Development, Rehabilitation Research & Development Service [B7143R]; VISN 4 Competitive Pilot Project Fund FX The authors would like to express gratitude to Betsy Harchick, Debbie Harrington, and Michael Randazzo for assistance with the experiments and Emily Grattan and Juleen Rodakowski for assistance with the functional assessments. This work was supported by the Department of Veterans Affairs, Office of Research and Development, Rehabilitation Research & Development Service (Grants #B7143R) and the VISN 4 Competitive Pilot Project Fund. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of the Department of Veterans Affairs or the United States Government. NR 47 TC 3 Z9 4 U1 2 U2 16 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 SEP 22 PY 2015 VL 12 AR 85 DI 10.1186/s12984-015-0076-7 PG 9 WC Engineering, Biomedical; Neurosciences; Rehabilitation SC Engineering; Neurosciences & Neurology; Rehabilitation GA CR6AS UT WOS:000361426100001 PM 26392353 ER PT J AU Dec, GW Arbustini, E AF Dec, G. William Arbustini, Eloisa TI Utilizing the MOGE(S) Classification for Predicting Prognosis in Dilated Cardiomyopathy SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE dilated cardiomyopathy; MOGE(S) classification; prognosis ID CARDIOLOGY; ASSOCIATION; STATEMENT; SOCIETY C1 [Dec, G. William] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Arbustini, Eloisa] Policlin San Matteo, I-27100 Pavia, Italy. RP Dec, GW (reprint author), Massachusetts Gen Hosp, Div Cardiol, 55 Fruit St,Yawkey 5B, Boston, MA 02114 USA. EM gdec@partners.org NR 9 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 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD SEP 22 PY 2015 VL 66 IS 12 BP 1324 EP 1326 DI 10.1016/j.jacc.2015.06.1335 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CR6KV UT WOS:000361456600002 PM 26383717 ER PT J AU Zhu, L Zhong, MH Elder, GA Sano, M Holtzman, DM Gandy, S Cardozo, C Haroutunian, V Robakis, NK Cai, DM AF Zhu, Li Zhong, Minghao Elder, Gregory A. Sano, Mary Holtzman, David M. Gandy, Sam Cardozo, Christopher Haroutunian, Vahram Robakis, Nikolaos K. Cai, Dongming TI Phospholipid dysregulation contributes to ApoE4-associated cognitive deficits in Alzheimer's disease pathogenesis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Alzheimer's disease; apolipoprotein E4; phospholipid; dysregulation; cognitive deficits ID AMYLOID PRECURSOR PROTEIN; APOLIPOPROTEIN-E; MOUSE MODEL; EPSILON-4 HOMOZYGOTES; ENDOCYTIC TRAFFICKING; BRAIN; METABOLISM; MEMORY; PHOSPHORYLATION; PERFORMANCE AB The apolipoprotein E4 (ApoE4) allele is the strongest genetic risk factor for developing sporadic Alzheimer's disease (AD). However, the mechanisms underlying the pathogenic nature of ApoE4 are not well understood. In this study, we have found that ApoE proteins are critical determinants of brain phospholipid homeostasis and that the ApoE4 isoform is dysfunctional in this process. We have found that the levels of phosphoinositol biphosphate (PIP2) are reduced in postmortem human brain tissues of ApoE4 carriers, in the brains of ApoE4 knock-in (KI) mice, and in primary neurons expressing ApoE4 alleles compared with those levels in ApoE3 counterparts. These changes are secondary to increased expression of a PIP2-degrading enzyme, the phosphoinositol phosphatase synaptojanin 1 (synj1), in ApoE4 carriers. Genetic reduction of synj1 in ApoE4 KI mouse models restores PIP2 levels and, more important, rescues AD-related cognitive deficits in these mice. Further studies indicate that ApoE4 behaves similar to ApoE null conditions, which fails to degrade synj1 mRNA efficiently, unlike ApoE3 does. These data suggest a loss of function of ApoE4 genotype. Together, our data uncover a previously unidentified mechanism that links ApoE4-induced phospholipid changes to the pathogenic nature of ApoE4 in AD. C1 [Zhu, Li; Elder, Gregory A.; Sano, Mary; Gandy, Sam; Cai, Dongming] James J Peters VA Med Ctr, Res & Dev, Bronx, NY 10468 USA. [Zhu, Li; Sano, Mary; Gandy, Sam; Haroutunian, Vahram; Cai, Dongming] Icahn Sch Med Mt Sinai, Alzheimer Dis Res Ctr, Dept Neurol, New York, NY 10029 USA. [Zhong, Minghao] New York Med Coll, Dept Pathol, Westchester Med Ctr, Valhalla, NY 10595 USA. [Holtzman, David M.] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63100 USA. [Cardozo, Christopher] James J Peters VA Med Ctr, Natl Ctr Excellence Med Consequences SCI, Bronx, NY 10468 USA. [Cardozo, Christopher] Icahn Sch Med Mt Sinai, Dept Med, New York, NY 10029 USA. [Cardozo, Christopher] Icahn Sch Med Mt Sinai, Dept Rehabil Med, New York, NY 10029 USA. [Haroutunian, Vahram; Robakis, Nikolaos K.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. RP Cai, DM (reprint author), James J Peters VA Med Ctr, Res & Dev, Bronx, NY 10468 USA. EM dongming.cai@mssm.edu OI Cai, Dongming/0000-0002-0601-6826 FU Department of Veteran Affairs Basic Life Science Research & Development CDA; Alzheimer Association [NIRP14-304720]; Department of Veteran Affairs Rehabilitation Research & Development Small Projects in Rehabilitation Research [1I21RX001558-01A1]; NIH R01 [1R01AG048923-01, 2R01AG008200]; NIH R37 [AG017926]; NIH UO1 [AG046170]; NIH P50 [AG005138]; NIH R34 [AG049649]; NIH RO1 [NS075685]; Department of Veterans Affairs RR&D National Center for Excellence for the Medical Consequences of Spinal Cord Injury; James J. Peters VA Medical Center Research Core Facility FX We thank Dr. Pietro De Camilli (Yale School of Medicine) for providing synj1 haploinsufficiency mice. Antibody p369 was generously provided by Dr. Paul Greengard. We also thank Dr. William Netzer (The Rockefeller University) and Dr. Michaela Kiernan (Stanford University) for critical reading of the manuscript. This work was supported in whole or in part by funding from the Department of Veteran Affairs Basic Life Science Research & Development CDA (Award CAI-spring 2010); Alzheimer Association (Award NIRP14-304720); Department of Veteran Affairs Rehabilitation Research & Development Small Projects in Rehabilitation Research (Grant 1I21RX001558-01A1); and NIH R01 (Grant 1R01AG048923-01) (to D.C.), NIH R37 (Grant AG017926) and R01 (Grant 2R01AG008200) (to N.K.R.), NIH UO1 (Grant AG046170), P50 (Grant AG005138), R34 (Grant AG049649), and RO1 (Grant NS075685) (to S.G.); as well as Department of Veterans Affairs RR&D National Center for Excellence for the Medical Consequences of Spinal Cord Injury (Grant B9212C) (to C.C.). Confocal microscopy studies were supported by the James J. Peters VA Medical Center Research Core Facility. NR 47 TC 11 Z9 11 U1 2 U2 13 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 SEP 22 PY 2015 VL 112 IS 38 BP 11965 EP 11970 DI 10.1073/pnas.1510011112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CR7JH UT WOS:000361525100066 PM 26372964 ER PT J AU Prusiner, SB Woerman, AL Mordes, DA Watts, JC Rampersaud, R Berry, DB Patel, S Oehler, A Lowe, JK Kravitz, SN Geschwind, DH Glidden, DV Halliday, GM Middleton, LT Gentleman, SM Grinberg, LT Giles, K AF Prusiner, Stanley B. Woerman, Amanda L. Mordes, Daniel A. Watts, Joel C. Rampersaud, Ryan Berry, David B. Patel, Smita Oehler, Abby Lowe, Jennifer K. Kravitz, Stephanie N. Geschwind, Daniel H. Glidden, David V. Halliday, Glenda M. Middleton, Lefkos T. Gentleman, Steve M. Grinberg, Lea T. Giles, Kurt TI Evidence for alpha-synuclein prions causing multiple system atrophy in humans with parkinsonism SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE neurodegeneration; Parkinson's disease; synucleinopathies; strains ID PROGRESSIVE SUPRANUCLEAR PALSY; GLIAL CYTOPLASMIC INCLUSIONS; CREUTZFELDT-JAKOB-DISEASE; TRANSGENIC MICE; LEWY BODIES; CONSENSUS STATEMENT; TRANSMISSION; MUTATIONS; SCRAPIE; NEURODEGENERATION AB Prions are proteins that adopt alternative conformations that become self-propagating; the PrPSc prion causes the rare human disorder Creutzfeldt-Jakob disease (CJD). We report here that multiple system atrophy (MSA) is caused by a different human prion composed of the alpha-synuclein protein. MSA is a slowly evolving disorder characterized by progressive loss of autonomic nervous system function and often signs of parkinsonism; the neuropathological hallmark of MSA is glial cytoplasmic inclusions consisting of filaments of alpha-synuclein. To determine whether human alpha-synuclein forms prions, we examined 14 human brain homogenates for transmission to cultured human embryonic kidney (HEK) cells expressing full-length, mutant human alpha-synuclein fused to yellow fluorescent protein (alpha-syn140*A53T-YFP) and TgM83(+/-) mice expressing alpha-synuclein (A53T). The TgM83(+/-) mice that were hemizygous for the mutant transgene did not develop spontaneous illness; in contrast, the TgM83(+/+) mice that were homozygous developed neurological dysfunction. Brain extracts from 14 MSA cases all transmitted neurodegeneration to TgM83(+/-) mice after incubation periods of similar to 120 d, which was accompanied by deposition of alpha-synuclein within neuronal cell bodies and axons. All of the MSA extracts also induced aggregation of alpha-syn*A53T-YFP in cultured cells, whereas none of six Parkinson's disease (PD) extracts or a control sample did so. Our findings argue that MSA is caused by a unique strain of alpha-synuclein prions, which is different from the putative prions causing PD and from those causing spontaneous neurodegeneration in TgM83(+/+) mice. Remarkably, alpha-synuclein is the first new human prion to be identified, to our knowledge, since the discovery a half century ago that CJD was transmissible. C1 [Prusiner, Stanley B.; Woerman, Amanda L.; Watts, Joel C.; Rampersaud, Ryan; Berry, David B.; Patel, Smita; Giles, Kurt] Univ Calif San Francisco, Inst Neurodegenerat Dis, San Francisco, CA 94143 USA. [Prusiner, Stanley B.; Watts, Joel C.; Grinberg, Lea T.; Giles, Kurt] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Prusiner, Stanley B.] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94143 USA. [Mordes, Daniel A.] Massachusetts Gen Hosp, Dept Pathol, CS Kubik Lab Neuropathol, Boston, MA 02114 USA. [Oehler, Abby] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA. [Lowe, Jennifer K.; Kravitz, Stephanie N.; Geschwind, Daniel H.] Univ Calif Los Angeles, Ctr Neurobehav Genet, Ctr Autism Res & Treatment, Los Angeles, CA 90095 USA. [Lowe, Jennifer K.; Kravitz, Stephanie N.; Geschwind, Daniel H.] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90095 USA. [Geschwind, Daniel H.] Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA 90095 USA. [Glidden, David V.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Halliday, Glenda M.] Univ New S Wales, Fac Med, Sch Med Sci, Randwick, NSW 2031, Australia. [Middleton, Lefkos T.] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Ageing Res Unit, London SW7 2AZ, England. [Gentleman, Steve M.] Univ London Imperial Coll Sci Technol & Med, Dept Med, Ctr Neuroinflammat & Neurodegenerat, London SW7 2AZ, England. [Grinberg, Lea T.] Univ Calif San Francisco, Memory & Aging Ctr, San Francisco, CA 94143 USA. RP Prusiner, SB (reprint author), Univ Calif San Francisco, Inst Neurodegenerat Dis, San Francisco, CA 94143 USA. EM stanley@ind.ucsf.edu RI Halliday, Glenda/E-8555-2011 OI Halliday, Glenda/0000-0003-0422-8398 FU National Institutes of Health [AG021601, AG002132, AG010770, AG031220]; Sherman Fairchild Foundation; Rainwater Charitable Foundation; Mary Jane Brinton Fund; Parkinson's UK, a charity registered in England and Wales [948776]; Parkinson's UK, a charity registered in Scotland [SC037554]; Sydney Brain Bank; Neuroscience Research Australia; University of New South Wales; National Health and Medical Research Council of Australia FX This work was supported by grants from the National Institutes of Health (AG021601, AG002132, AG010770, and AG031220) as well as the Sherman Fairchild Foundation, the Rainwater Charitable Foundation, and the Mary Jane Brinton Fund. Synucleinopathy tissue samples were supplied by the neuropathology core of the Massachusetts Alzheimer's Disease Research Center (AG005134); the Parkinson's UK Brain Bank at Imperial College London, funded by Parkinson's UK, a charity registered in England and Wales (948776) and in Scotland (SC037554); and the Sydney Brain Bank, which is supported by Neuroscience Research Australia, the University of New South Wales, and the National Health and Medical Research Council of Australia. Glenda M. Halliday is a National Health and Medical Research Council of Australia Senior Principal Research Fellow (1079679). We thank Robert L. Nussbaum for his gift of the alpha-synuclein-knockout and transgenic mice, and Eric Huang for providing the control brain sample. NR 63 TC 78 Z9 80 U1 3 U2 29 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 SEP 22 PY 2015 VL 112 IS 38 BP E5308 EP E5317 DI 10.1073/pnas.1514475112 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CR7JH UT WOS:000361525100014 PM 26324905 ER PT J AU Paterson, AM Lovitch, SB Sage, PT Juneja, VR Lee, Y Trombley, JD Arancibia-Carcamo, CV Sobel, RA Rudensky, AY Kuchroo, VK Freeman, GJ Sharpe, AH AF Paterson, Alison M. Lovitch, Scott B. Sage, Peter T. Juneja, Vikram R. Lee, Youjin Trombley, Justin D. Arancibia-Carcamo, Carolina V. Sobel, Raymond A. Rudensky, Alexander Y. Kuchroo, Vijay K. Freeman, Gordon J. Sharpe, Arlene H. TI Deletion of CTLA-4 on regulatory T cells during adulthood leads to resistance to autoimmunity SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; IN-VIVO; NEGATIVE SELECTION; CUTTING EDGE; ANTIGEN 4; CD4(+)CD8(+) THYMOCYTES; PERIPHERAL HOMEOSTASIS; ACTIVATION ANTIGEN-B7; CTLA-4-DEFICIENT MICE; CD28 COSTIMULATION AB Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an essential negative regulator of T cell responses. Germline Ctla4 deficiency is lethal, making investigation of the function of CTLA-4 on mature T cells challenging. To elucidate the function of CTLA-4 on mature T cells, we have conditionally ablated Ctla4 in adult mice. We show that, in contrast to germline knockout mice, deletion of Ctla4 during adulthood does not precipitate systemic autoimmunity, but surprisingly confers protection from experimental autoimmune encephalomyelitis (EAE) and does not lead to increased resistance to MC38 tumors. Deletion of Ctla4 during adulthood was accompanied by activation and expansion of both conventional CD4(+)Foxp3(-) (T conv) and regulatory Foxp3(+) (T reg cells) T cell subsets; however, deletion of CTLA-4 on T reg cells was necessary and sufficient for protection from EAE. CTLA-4 deleted T reg cells remained functionally suppressive. Deletion of Ctla4 on T reg cells alone or on all adult T cells led to major changes in the Ctla4 sufficient T conv cell compartment, including up-regulation of immunoinhibitory molecules IL-10, LAG-3 and PD-1, thereby providing a compensatory immunosuppressive mechanism. Collectively, our findings point to a profound role for CTLA-4 on T reg cells in limiting their peripheral expansion and activation, thereby regulating the phenotype and function of T conv cells. C1 [Paterson, Alison M.; Lovitch, Scott B.; Sage, Peter T.; Juneja, Vikram R.; Trombley, Justin D.; Sharpe, Arlene H.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. [Paterson, Alison M.; Lovitch, Scott B.; Sage, Peter T.; Juneja, Vikram R.; Lee, Youjin; Trombley, Justin D.; Kuchroo, Vijay K.; Sharpe, Arlene H.] Harvard Univ, Sch Med, Evergrande Ctr Immunol Dis, Boston, MA 02115 USA. [Paterson, Alison M.; Lovitch, Scott B.; Sage, Peter T.; Juneja, Vikram R.; Lee, Youjin; Trombley, Justin D.; Sharpe, Arlene H.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Lovitch, Scott B.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Arancibia-Carcamo, Carolina V.] Univ Oxford, Nuffield Dept Clin Med, Div Expt Med, Translat Gastroenterol Unit, Oxford OX3 9DU, England. [Sobel, Raymond A.] Stanford Univ, Dept Pathol, Stanford, CA 94304 USA. [Rudensky, Alexander Y.] Mem Sloan Kettering Canc Ctr, Ludwig Ctr, Howard Hughes Med Inst, New York, NY 10065 USA. [Rudensky, Alexander Y.] Mem Sloan Kettering Canc Ctr, Ludwig Ctr, Sloan Kettering Inst Canc Res, Program Immunol, New York, NY 10065 USA. [Freeman, Gordon J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Sharpe, AH (reprint author), Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. EM arlene_sharpe@hms.harvard.edu OI Lovitch, Scott/0000-0001-9013-0105 FU National Institutes of Health [AI38310, AI40614, P01 AI39671, PO1 AI56299]; National Multiple Sclerosis Society [FG-1916-A-1] FX This work was supported by grants from the National Institutes of Health (AI38310 and AI40614 to A.H. Sharpe; P01 AI39671 to A.H. Sharpe and V.K. Kuchroo; PO1 AI56299 to A.H. Sharpe, G.J. Freeman, and V.K. Kuchroo) and the National Multiple Sclerosis Society (FG-1916-A-1 to S.B. Lovitch). NR 81 TC 18 Z9 19 U1 2 U2 10 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD SEP 21 PY 2015 VL 212 IS 10 BP 1603 EP 1621 DI 10.1084/jem.20141030 PG 19 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA CW6VB UT WOS:000365135200012 PM 26371185 ER PT J AU Hao, Y Altundal, Y Moreau, M Sajo, E Kumar, R Ngwa, W AF Hao, Yao Altundal, Yucel Moreau, Michele Sajo, Erno Kumar, Rajiv Ngwa, Wilfred TI Potential for enhancing external beam radiotherapy for lung cancer using high-Z nanoparticles administered via inhalation SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE inhalation; cisplatin nanoparticles; carboplatin nanoparticles; radiotherapy; dose Enhancement; chemoradiotherapy ID BODY RADIATION-THERAPY; GOLD NANOPARTICLES; ANTICANCER DRUGS; DOSE ENHANCEMENT; PHOTON BEAMS; CO-DELIVERY; SIRNA AB Nanoparticle-aided radiation therapy is emerging as a promising modality to enhance radiotherapy via the radiosensitizing action of high atomic number (Z) nanoparticles. However, the delivery of sufficiently potent concentrations of such nanoparticles to the tumor remain a challenge. This study investigates the dose enhancement to lung tumors due to high-Z nanoparticles (NPs) administered via inhalation during external beam radiotherapy. Here NPs investigated include: cisplatin nanoparticles (CNPs), carboplatin nanoparticles (CBNPs), and gold nanoparticles (GNPs). Using Monte Carlo-generated megavoltage energy spectra, a previously employed analytic method was used to estimate dose enhancement to lung tumors due to radiation-induced photoelectrons from the NPs administered via inhalation route (IR) in comparison to intravenous (IV) administration. Previous studies have indicated about 5% of FDA-approved cisplatin concentrations reach the lung via IV. Meanwhile recent experimental studies indicate that 3.5-14.6 times higher concentrations of NPs can reach the lung by IR compared to IV. Taking these into account, the dose enhancement factor (DEF) defined as the ratio of the radiotherapy dose with and without nanoparticles was calculated for a range of NPs concentrations and tumor sizes. The DEF for IR was then compared with that for IV. For IR with 3.5 times higher concentrations than IV, and 2 cm diameter tumor, clinically significant DEF values of up to 1.19, 1.26, and 1.51 were obtained for CNPs, CBNPs and GNPs. In comparison values of 1.06, 1.08, and 1.15 were obtained via IV administration. For IR with 14.6 times higher concentrations, even higher DEF values were obtained e.g. 1.81 for CNPs. Results also showed that the DEF increased with increasing field size or decreasing tumor volume, as expected. The results of this work indicate that IR administration of targeted high-Z CNPs/CBNPs/GNPs could enable clinically significant DEF to lung tumors compared to IV administration during external beam radiotherapy. For FDA approved concentrations of CNPs or CBNPs considered, this could allow for additional dose enhancement to tumors via photoelectric mechanism during concomitant chemoradiotherapy. C1 [Hao, Yao; Altundal, Yucel; Moreau, Michele; Sajo, Erno; Ngwa, Wilfred] Univ Massachusetts, Lowell, MA 01854 USA. [Moreau, Michele; Kumar, Rajiv; Ngwa, Wilfred] Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Moreau, Michele; Kumar, Rajiv; Ngwa, Wilfred] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Kumar, Rajiv] North Eastern Univ, Boston, MA 02115 USA. RP Hao, Y (reprint author), Univ Massachusetts, Lowell, MA 01854 USA. EM Yao_hao@uml.edu FU National Institutes of Health NationalCancer Institute [1 K01 CA172478-01] FX This study was supported by National Institutes of Health NationalCancer Institute grant 1 K01 CA172478-01. NR 24 TC 3 Z9 3 U1 4 U2 12 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 EI 1361-6560 J9 PHYS MED BIOL JI Phys. Med. Biol. PD SEP 21 PY 2015 VL 60 IS 18 BP 7035 EP 7043 DI 10.1088/0031-9155/60/18/7035 PG 9 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA CR1ZL UT WOS:000361124000002 PM 26309064 ER PT J AU Pui, CH Yang, JJ Hunger, SP Pieters, R Schrappe, M Biondi, A Vora, A Baruchel, A Silverman, LB Schmiegelow, K Escherich, G Horibe, K Benoit, YCM Izraeli, S Yeoh, AEJ Liang, DC Downing, JR Evans, WE Relling, MV Mullighan, CG AF Pui, Ching-Hon Yang, Jun J. Hunger, Stephen P. Pieters, Rob Schrappe, Martin Biondi, Andrea Vora, Ajay Baruchel, Andre Silverman, Lewis B. Schmiegelow, Kjeld Escherich, Gabriele Horibe, Keizo Benoit, Yves C. M. Izraeli, Shai Yeoh, Allen Eng Juh Liang, Der-Cherng Downing, James R. Evans, William E. Relling, Mary V. Mullighan, Charles G. TI Childhood Acute Lymphoblastic Leukemia: Progress Through Collaboration SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID MINIMAL RESIDUAL DISEASE; B-CELL PRECURSOR; CHILDRENS ONCOLOGY GROUP; KINASE INHIBITOR THERAPY; BFM STUDY-GROUP; T-CELL; TREATMENT RESPONSE; DOWN-SYNDROME; GENOME-WIDE; ASPARAGINASE ANTIBODIES AB Purpose To review the impact of collaborative studies on advances in the biology and treatment of acute lymphoblastic leukemia (ALL) in children and adolescents. Methods A review of English literature on childhood ALL focusing on collaborative studies was performed. The resulting article was reviewed and revised by the committee chairs of the major ALL study groups. Results With long-term survival rates for ALL approaching 90% and the advent of high-resolution genome-wide analyses, several international study groups or consortia were established to conduct collaborative research to further improve outcome. As a result, treatment strategies have been improved for several subtypes of ALL, such as infant, MLL-rearranged, Philadelphia chromosome-positive, and Philadelphia chromosome-like ALL. Many recurrent genetic abnormalities that respond to tyrosine kinase inhibitors and multiple genetic determinants of drug resistance and toxicities have been identified to help develop targeted therapy. Several genetic polymorphisms have been recognized that show susceptibility to developing ALL and that help explain the racial/ethnic differences in the incidence of ALL. Conclusion The information gained from collaborative studies has helped decipher the heterogeneity of ALL to help improve personalized treatment, which will further advance the current high cure rate and the quality of life for children and adolescents with ALL. (C) 2015 by American Society of Clinical Oncology C1 [Pui, Ching-Hon; Yang, Jun J.; Downing, James R.; Evans, William E.; Relling, Mary V.; Mullighan, Charles G.] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Pui, Ching-Hon; Yang, Jun J.; Downing, James R.; Evans, William E.; Relling, Mary V.; Mullighan, Charles G.] Univ Tennessee, Hlth Sci Ctr, Memphis, TN USA. [Hunger, Stephen P.] Univ Colorado, Sch Med, Aurora, CO USA. [Hunger, Stephen P.] Univ Colorado, Ctr Canc, Aurora, CO USA. [Hunger, Stephen P.] Childrens Hosp Colorado, Aurora, CO USA. [Pieters, Rob] Princess Maxima Ctr Pediat Oncol, Utrecht, Netherlands. [Schrappe, Martin] Univ Kiel, Univ Med Ctr Schleswig Holstein, Kiel, Germany. [Escherich, Gabriele] Univ Med Ctr Hamburg Eppendorf, Clin Pediat Hematol & Oncol, Hamburg, Germany. [Biondi, Andrea] Univ Milano Bicocca, Clin Pediat, Monza, Italy. [Biondi, Andrea] Univ Milano Bicocca, Ctr Ric Tettamanti, Monza, Italy. [Vora, Ajay] Univ Manchester, Manchester Acad Hlth Sci Ctr, Sch Canc, Childrens Canc Grp, Manchester, Lancs, England. [Baruchel, Andre] Hop Robert Debre, F-75019 Paris, France. [Baruchel, Andre] Univ Paris Diderot, Paris, France. [Silverman, Lewis B.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Silverman, Lewis B.] Boston Childrens Hosp, Boston, MA USA. [Schmiegelow, Kjeld] Univ Copenhagen, Inst Clin Med, Copenhagen, Denmark. [Schmiegelow, Kjeld] Univ Hosp Rigshosp, Juliane Marie Ctr, Copenhagen, Denmark. [Horibe, Keizo] Nagoya Med Ctr, Clin Res Ctr, Nagoya, Aichi, Japan. [Benoit, Yves C. M.] Univ Ghent, Ghent, Belgium. [Izraeli, Shai] Tel Aviv Univ, Chaim Sheba Med Ctr, IL-69978 Tel Aviv, Israel. [Izraeli, Shai] Tel Aviv Univ, Sackler Sch Med, IL-69978 Tel Aviv, Israel. [Yeoh, Allen Eng Juh] Natl Univ Singapore, Yong Loo Lin Sch Med, Singapore 117595, Singapore. [Yeoh, Allen Eng Juh] Natl Univ Singapore, Canc Sci Inst, Singapore 117595, Singapore. [Yeoh, Allen Eng Juh] Natl Univ Singapore Hosp, Viva Univ Childrens Canc Ctr, Singapore, Singapore. [Liang, Der-Cherng] Mackay Mem Hosp, Taipei, Taiwan. RP Pui, CH (reprint author), St Jude Childrens Res Hosp, 262 Danny Thomas Pl, Memphis, TN 38105 USA. EM ching-hon.pui@stjude.org FU National Institutes of Health [CA21765, CA36401, U01 GM92666, U10 CA98543, U10 CA98413]; United Kingdom Medical Research Council, Leukaemia and Lymphoma Research and National Cancer Research Institute (United Kingdom Childhood Acute Lymphoblastic Leukemia trials); Stand Up to Cancer Innovative Research Grant; Singapore VIVA Foundation; American Lebanese Syrian Associated Charities FX Supported in part by Grants No. CA21765, CA36401, U01 GM92666, U10 CA98543 (to the Children's Oncology Group [COG] Chair), and U10 CA98413 (to the COG Statistical Center) from the National Institutes of Health; by the United Kingdom Medical Research Council, Leukaemia and Lymphoma Research and National Cancer Research Institute (United Kingdom Childhood Acute Lymphoblastic Leukemia trials); by a Stand Up to Cancer Innovative Research Grant (C.G.M.); by the Singapore VIVA Foundation; and by the American Lebanese Syrian Associated Charities. S.P.H. is the Ergen Family Chair in Pediatric Cancer, C.G.M. is a St Baldrick's Scholar and Pew Scholar in the Biomedical Sciences, and C.-H.P. is an American Cancer Society professor. NR 101 TC 42 Z9 44 U1 3 U2 12 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 SEP 20 PY 2015 VL 33 IS 27 BP 2938 EP U24 DI 10.1200/JCO.2014.59.1636 PG 12 WC Oncology SC Oncology GA CX9IL UT WOS:000366018800002 PM 26304874 ER PT J AU Dome, JS Graf, N Geller, JI Fernandez, CV Mullen, EA Spreafico, F Van den Heuvel-Eibrink, M Pritchard-Jones, K AF Dome, Jeffrey S. Graf, Norbert Geller, James I. Fernandez, Conrad V. Mullen, Elizabeth A. Spreafico, Filippo Van den Heuvel-Eibrink, Marry Pritchard-Jones, Kathy TI Advances in Wilms Tumor Treatment and Biology: Progress Through International Collaboration SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID STEM-CELL RESCUE; CHILDRENS ONCOLOGY GROUP; P53 GENE-MUTATIONS; FAVORABLE-HISTOLOGY; POOR-PROGNOSIS; RENAL TUMORS; PEDIATRIC-HEMATOLOGY; ITALIAN-ASSOCIATION; INITIAL TREATMENT; ACTINOMYCIN-D AB Clinical trials in Wilms tumor (WT) have resulted in overall survival rates of greater than 90%. This achievement is especially remarkable because improvements in disease-specific survival have occurred concurrently with a reduction of therapy for large patient subgroups. However, the outcomes for certain patient subgroups, including those with unfavorable histologic and molecular features, bilateral disease, and recurrent disease, remain well below the benchmark survival rate of 90%. Therapy for WT has been advanced in part by an increasingly complex risk-stratification system based on patient age; tumor stage, histology, and volume; response to chemotherapy; and loss of heterozygosity at chromosomes 1p and 16q. A consequence of this system has been the apportionment of patients into such small subgroups that only collaboration between large international WT study groups will support clinical trials that are sufficiently powered to answer challenging questions that move the field forward. This article gives an overview of the Children's Oncology Group and International Society of Pediatric Oncology approaches to WT and focuses on four subgroups (stage IV, initially inoperable, bilateral, and relapsed WT) for which international collaboration is pressing. In addition, biologic insights resulting from collaborative laboratory research are discussed. A coordinated expansion of international collaboration in both clinical trials and laboratory science will provide real opportunity to improve the treatment and outcomes for children with renal tumors on a global level. (C) 2015 by American Society of Clinical Oncology C1 [Dome, Jeffrey S.] Childrens Natl Hlth Syst, Washington, DC 20010 USA. [Geller, James I.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Mullen, Elizabeth A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Graf, Norbert] Univ Saarland, Homburg, Germany. [Fernandez, Conrad V.] IWK Hlth Ctr, Halifax, NS, Canada. [Spreafico, Filippo] Ist Nazl Tumori, Fdn Ist Ricovero & Cura Carattere Sci, I-20133 Milan, Italy. [Van den Heuvel-Eibrink, Marry] Princess Maxima Ctr Pediat Oncol, Utrecht, Netherlands. [Pritchard-Jones, Kathy] UCL, Inst Child Hlth, London, England. RP Dome, JS (reprint author), Childrens Natl Hlth Syst, Div Hematol, 111 Michigan Ave NW, Washington, DC 20010 USA. EM jdome@childrensnational.org RI Spreafico, Filippo/K-7813-2016 OI Spreafico, Filippo/0000-0002-5587-3509 FU National Institutes of Health [U10CA098543]; Children's Oncology Group [U10CA098543, U10CA180886, U10CA180899, U10CA098413]; European Union [261474, 270089]; P-Medicine: From Data Sharing and Integration via VPH Models [270089]; Cancer Research United Kingdom [C1188/A4614]; Great Ormond Street Hospital Children's Charity; Children with Cancer; National Institutes of Health Research Great Ormond Street Hospital-University College London Biomedical Research Centre; German Cancer Aid for International Society of Pediatric Oncology Gesellschaft fur Padiatrische Onkologie und Hamatologie [50-2709-Gr2] FX Supported by grants from the National Institutes of Health to the National Wilms Tumor Study Group (Grant No. U10CA098543) and the Children's Oncology Group (Grants No. U10CA180886, U10CA180899, U10CA098543, and U10CA098413). K.P.-J.'s renal tumors research receives support from the following European Union Framework Programme 7 grants: European Network for Cancer Research in Children and Adolescents (Grant No. 261474) and P-Medicine: From Data Sharing and Integration via VPH Models to Personalised Medicine (Grant No. 270089); Cancer Research United Kingdom (Grant No. C1188/A4614); Great Ormond Street Hospital Children's Charity; and Children with Cancer and the National Institutes of Health Research Great Ormond Street Hospital-University College London Biomedical Research Centre. N.G.'s renal tumor research receives funding from the German Cancer Aid for International Society of Pediatric Oncology 2001/Gesellschaft fur Padiatrische Onkologie und Hamatologie (Grant No. 50-2709-Gr2) and from the European Union Framework Programme 7 P-Medicine Grant No. 270089. NR 77 TC 11 Z9 13 U1 2 U2 4 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 20 PY 2015 VL 33 IS 27 BP 2999 EP U94 DI 10.1200/JCO.2015.62.1888 PG 11 WC Oncology SC Oncology GA CX9IL UT WOS:000366018800007 PM 26304882 ER PT J AU Olson, TA Murray, MJ Rodriguez-Galindo, C Nicholson, JC Billmore, DF Krailo, MD Dang, HM Amatruda, JF Thornton, CM Arul, GS Stoneham, SJ Pashankar, F Stark, D Shaikh, F Gershenson, DM Covens, A Hurteau, J Stenning, SP Feldman, DR Grimison, PS Huddart, RA Sweeney, C Powles, T Lopes, LF Agular, SD Chinnaswamy, G Khaleel, S Abouelnaga, S Hale, JP Frazier, AL AF Olson, Thomas A. Murray, Matthew J. Rodriguez-Galindo, Carlos Nicholson, James C. Billmore, Deborah F. Krailo, Mark D. Dang, Ha M. Amatruda, James F. Thornton, Claire M. Arul, G. Suren Stoneham, Sara J. Pashankar, Farzana Stark, Daniel Shaikh, Furqan Gershenson, David M. Covens, Allan Hurteau, Jean Stenning, Sally P. Feldman, Darren R. Grimison, Peter S. Huddart, Robert A. Sweeney, Christopher Powles, Thomas Lopes, Luiz Fernando Agular, Simone dos Santos Chinnaswamy, Girish Khaleel, Sahar Abouelnaga, Sherif Hale, Juliet P. Frazier, A. Lindsay TI Pediatric and Adolescent Extracranial Germ Cell Tumors: The Road to Collaboration SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID CHILDRENS ONCOLOGY GROUP; HIGH-DOSE CHEMOTHERAPY; INTENSIVE INDUCTION CHEMOTHERAPY; COUNCIL EUROPEAN ORGANIZATION; RANDOMIZED PHASE-III; STAGE-I; TESTICULAR CANCER; UNITED-KINGDOM; COMBINATION CHEMOTHERAPY; YOUNG-ADULTS AB During the past 35 years, survival rates for children with extracranial malignant germ cell tumors (GCTs) have increased significantly. Success has been achieved primarily through the application of platinum-based chemotherapy regimens; however, clinical challenges in GCTs remain. Excellent outcomes are not distributed uniformly across the heterogeneous distribution of age, histologic features, and primary tumor site. Despite good outcomes overall, the likelihood of a cure for certain sites and histologic conditions is less than 50%. In addition, there are considerable long-term treatment-related effects for survivors. Even modest cisplatin dosing can cause significant long-term morbidities. A particular challenge in designing new therapies for GCT is that a variety of specialists use different risk stratifications, staging systems, and treatment approaches for three distinct age groups (childhood, adolescence, and young adulthood). Traditionally, pediatric cancer patients younger than 15 years have been treated by pediatric oncologists in collaboration with their surgical specialty colleagues. Adolescents and young adults with GCTs often are treated by medical oncologists, urologists, or gynecologic oncologists. The therapeutic dilemma for all is how to best define disease risk so that therapy and toxicity can be appropriately reduced for some patients and intensified for others. Further clinical and biologic insights can only be achieved through collaborations that do not set limitations by age, sex, and primary tumor site. Therefore, international collaborations, spanning different cooperative groups and disciplines, have been developed to address these challenges. (C) 2015 by American Society of Clinical Oncology C1 [Olson, Thomas A.] Emory Univ, Atlanta, GA 30322 USA. [Murray, Matthew J.; Nicholson, James C.] Cambridge Univ Hosp Natl Hlth Serv NHS Fdn Trust, Cambridge, England. [Rodriguez-Galindo, Carlos; Frazier, A. Lindsay] Boston Childrens Hosp, Boston, MA USA. [Rodriguez-Galindo, Carlos; Sweeney, Christopher; Frazier, A. Lindsay] Dana Farber Canc Inst, Boston, MA 02115 USA. [Billmore, Deborah F.] Riley Hosp Sick Children, Indianapolis, IN USA. [Krailo, Mark D.; Dang, Ha M.] Univ So Calif, Los Angeles, CA USA. [Amatruda, James F.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Amatruda, James F.] Childrens Med Ctr, Dallas, TX 75235 USA. [Gershenson, David M.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Thornton, Claire M.] Royal Victoria Hosp, Belfast BT12 6BA, Antrim, North Ireland. [Arul, G. Suren] Birmingham Childrens Hosp NHS Fdn Trust, Birmingham, W Midlands, England. [Stoneham, Sara J.] Univ Coll London Hosp NHS Fdn Trust, London, England. [Pashankar, Farzana] Yale Univ, Sch Med, New Haven, CT USA. [Stark, Daniel] Univ Leeds, Leeds, W Yorkshire, England. [Shaikh, Furqan] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Covens, Allan] Univ Toronto, Toronto, ON, Canada. [Hurteau, Jean] Univ Chicago, Pritzker Sch Med, Chicago, IL 60637 USA. [Stenning, Sally P.] MRC, London, England. [Feldman, Darren R.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Grimison, Peter S.] Sydney Canc Ctr, Sydney, NSW, Australia. [Huddart, Robert A.] Inst Canc Res, Surrey, England. [Huddart, Robert A.] Royal Marsden Hosp, Surrey, England. [Powles, Thomas] Barts Canc Inst, London, England. [Lopes, Luiz Fernando] Barretos Pediat Canc Ctr, Sao Paulo, Brazil. [Agular, Simone dos Santos] Ctr Infantil Boldrini, Campinas, SP, Brazil. [Chinnaswamy, Girish] Tata Mem Hosp, Bombay 400012, Maharashtra, India. [Khaleel, Sahar; Abouelnaga, Sherif] Childrens Canc Hosp, Cairo, Egypt. [Hale, Juliet P.] Royal Victoria Infirm NHS Fdn Trust, Newcastle Upon Tyne, Tyne & Wear, England. RP Olson, TA (reprint author), Emory Univ, Childrens Healthcare Atlanta, Aflac Canc & Blood Disorders Ctr, Div Pediat Hematol Oncol, 2015 Uppergate Dr NE, Atlanta, GA 30322 USA. EM Thomas.Olson@choa.org RI Lopes, Luiz Fernando/L-5513-2016; OI Feldman, Darren/0000-0003-2424-4635 FU Medical Research Council [MC_U122861331]; NCI NIH HHS [U10 CA180899, U10 CA098543] NR 66 TC 6 Z9 6 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 SEP 20 PY 2015 VL 33 IS 27 BP 3018 EP U119 DI 10.1200/JCO.2014.60.5337 PG 14 WC Oncology SC Oncology GA CX9IL UT WOS:000366018800009 PM 26304902 ER PT J AU Rodriguez-Galindo, C Friedrich, P Alcasabas, P Antillon, F Banavali, S Castillo, L Israels, T Jeha, S Harif, M Sullivan, MJ Quah, TC Patte, C Pui, CH Barr, R Gross, T AF Rodriguez-Galindo, Carlos Friedrich, Paola Alcasabas, Patricia Antillon, Federico Banavali, Shripad Castillo, Luis Israels, Trijn Jeha, Sima Harif, Mhammed Sullivan, Michael J. Thuan Chong Quah Patte, Catherine Pui, Ching-Hon Barr, Ronald Gross, Thomas TI Toward the Cure of All Children With Cancer Through Collaborative Efforts: Pediatric Oncology As a Global Challenge SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID ACUTE LYMPHOBLASTIC-LEUKEMIA; RESOURCE-STRATIFIED GUIDELINES; ENDEMIC BURKITT-LYMPHOMA; MIDDLE-INCOME COUNTRIES; CHILDHOOD-CANCER; CLINICAL-TRIALS; GRADUATED-INTENSITY; ESSENTIAL DRUGS; AFRICA; MANAGEMENT AB Advances in the treatment of childhood cancers have resulted in part from the development of national and international collaborative initiatives that have defined biologic determinants and generated risk-adapted therapies that maximize cure while minimizing acute and long-term effects. Currently, more than 80% of children with cancer who are treated with modern multidisciplinary treatments in developed countries are cured; however, of the approximately 160,000 children and adolescents who are diagnosed with cancer every year worldwide, 80% live in low- and middle-income countries (LMICs), where access to quality care is limited and chances of cure are low. In addition, the disease burden is not fully known because of the lack of population-based cancer registries in low-resource countries. Regional and ethnic variations in the incidence of the different childhood cancers suggest unique interactions between genetic and environmental factors that could provide opportunities for etiologic research. Regional collaborative initiatives have been developed in Central and South America and the Caribbean, Africa, the Middle East, Asia, and Oceania. These initiatives integrate regional capacity building, education of health care providers, implementation of intensity-graduated treatments, and establishment of research programs that are adjusted to local capacity and local needs. Together, the existing consortia and regional networks operating in LMICs have the potential to reach out to almost 60% of all children with cancer worldwide. In summary, childhood cancer burden has been shifted toward LMICs and, for that reason, global initiatives directed at pediatric cancer care and control are needed. Regional networks aiming to build capacity while incorporating research on epidemiology, health services, and outcomes should be supported. (C) 2015 by American Society of Clinical Oncology C1 [Rodriguez-Galindo, Carlos; Friedrich, Paola] Dana Farber Boston Childrens Canc & Blood Disorde, Boston, MA USA. [Rodriguez-Galindo, Carlos; Friedrich, Paola] Harvard Univ, Sch Med, Boston, MA USA. [Alcasabas, Patricia] Philippines Gen Hosp, Manila, Philippines. [Antillon, Federico] Unidad Nacl Oncol Pediat, Guatemala City, Guatemala. [Antillon, Federico] Francisco Marroquin Med Sch, Guatemala City, Guatemala. [Banavali, Shripad] Tata Mem Hosp, Bombay 400012, Maharashtra, India. [Castillo, Luis] Hosp Pereira Rossell, Montevideo, Uruguay. [Israels, Trijn] Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands. [Jeha, Sima; Pui, Ching-Hon] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Harif, Mhammed] Ctr Hosp Univ Mohammed VI, Marrakech, Morocco. [Sullivan, Michael J.] Royal Childrens Hosp, Melbourne, Vic, Australia. [Thuan Chong Quah] Natl Univ Hlth Syst, Singapore, Singapore. [Patte, Catherine] Inst Gustave Roussy, Villejuif, France. [Barr, Ronald] McMaster Univ, Hamilton, ON, Canada. [Barr, Ronald] McMaster Childrens Hosp, Hamilton, ON, Canada. [Gross, Thomas] NCI, Ctr Global Hlth, Bethesda, MD 20892 USA. RP Rodriguez-Galindo, C (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,D3-133, Boston, MA 02215 USA. EM carlos_rodriguez-galindo@dfci.harvard.edu NR 62 TC 16 Z9 16 U1 4 U2 10 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 SEP 20 PY 2015 VL 33 IS 27 BP 3065 EP U175 DI 10.1200/JCO.2014.60.6376 PG 12 WC Oncology SC Oncology GA CX9IL UT WOS:000366018800014 PM 26304881 ER PT J AU Leder, BZ Tsai, JN Uihlein, AV Wallace, PM Lee, H Neer, RM Burnett-Bowie, SAM AF Leder, Benjamin Z. Tsai, Joy N. Uihlein, Alexander V. Wallace, Paul M. Lee, Hang Neer, Robert M. Burnett-Bowie, Sherri-Ann M. TI Denosumab and teriparatide transitions in postmenopausal osteoporosis (the DATA-Switch study): extension of a randomised controlled trial SO LANCET LA English DT Article ID PARATHYROID-HORMONE; FRACTURE RISK; BONE MASS; WORLDWIDE PREVALENCE; HIP FRACTURE; WOMEN; ALENDRONATE; BMD; THERAPY; DENSITY AB Background Unlike most chronic diseases, osteoporosis treatments are generally limited to a single drug at a fixed dose and frequency. Nonetheless, no approved therapy is able to restore skeletal integrity in most osteoporotic patients and the long-term use of osteoporosis drugs is controversial. Thus, many patients are treated with the sequential use of two or more therapies. The DATA study showed that combined teriparatide and denosumab increased bone mineral density more than either drug alone. Discontinuing teriparatide and denosumab, however, results in rapidly declining bone mineral density. In this DATA-Switch study, we aimed to assess the changes in bone mineral density in postmenopausal osteoporotic women who transitioned between treatments. Methods This randomised controlled trial (DATA-Switch) is a preplanned extension of the denosumab and teriparatide administration study (DATA), in which 94 postmenopausal osteoporotic women were randomly assigned to receive 24 months of teriparatide (20 mg daily), denosumab (60 mg every 6 months), or both drugs. In DATA-Switch, women originally assigned to teriparatide received denosumab (teriparatide to denosumab group), those originally assigned to denosumab received teriparatide (denosumab to teriparatide group), and those originally assigned to both received an additional 24 months of denosumab alone (combination to denosumab group). Bone mineral density at the spine, hip, and wrist were measured 6 months, 12 months, 18 months, and 24 months after the drug transitions as were biochemical markers of bone turnover. The primary endpoint was the percent change in posterior-anterior spine bone mineral density over 4 years. Between-group changes were assessed by one-way analysis of variance in our modified intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00926380. Findings Between Sept 27, 2011, and Jan 28, 2013, eligible women from the DATA study were enrolled into DATA-Switch. Of 83 potential enrollees from the DATA study, 77 completed at least one post-baseline visit. After 48 months, the primary outcome of mean spine bone mineral density increased by 18.3% (95% CI 14.9-21.8) in 27 women in the teriparatide to denosumab group, 14.0% (10.9-17.2) in 27 women the denosumab to teriparatide group, and 16.0% (14.0-18.0) in 23 women in the combination to denosumab group, although this increase did not differ significantly between groups (for between-group comparisons, p=0.13 for the teriparatide to denosumab group vs the denosumab to teriparatide group, p=0.30 for the teriparatide to denosumab group vs the combination to denosumab group, and p=0.41 for the denosumab to teriparatide group vs the combination to denosumab group). For the bone mineral density secondary outcomes, total hip bone mineral density increased more in the teriparatide to denosumab group (6.6% [95% CI 5.3-7.9]) than in the denosumab to teriparatide group (2.8% [1.3-4.2], p=0.0002), but had the greatest increase in the combination to denosumab group (8.6% [7.1-10.0]; p=0.0446 vs the teriparatide to denosumab group, p<0.0001 vs the denosumab to teriparatide group). Similarly, femoral neck bone mineral density increased more in the teriparatide to denosumab group (8.3% [95% CI 6.1-10.5]) and the combination to denosumab group (9.1% [6.1-12.0]) than in the denosumab to teriparatide group (4.9% [2.2-7.5]; p=0.0447 for teriparatide to denosumab vs denosumab to teriparatide, p=0.0336 for combination to denosumab vs denosumab to teriparatide). Differences between the combination to denosumab group and the teriparatide to denosumab group did not differ significantly (p=0.67). After 48 months, radius bone mineral density was unchanged in the teriparatide to denosumab group (0.0% [95% CI -1.3 to 1.4]), whereas it decreased by -1.8% (-5.0 to 1.3) in the denosumab to teriparatide group, and increased by 2.8% (1.2-4.4) in the combination to denosumab group (p=0.0075 for the teriparatide to denosumab group vs the combination to denosumab group; p=0.0099 for the denosumab to teriparatide group vs the combination to denosumab group). One participant in the denosumab to teriparatide group had nephrolithiasis, classified as being possibly related to treatment. Interpretation In postmenopausal osteoporotic women switching from teriparatide to denosumab, bone mineral density continued to increase, whereas switching from denosumab to teriparatide results in progressive or transient bone loss. These results should be considered when choosing the initial and subsequent management of postmenopausal osteoporotic patients. C1 [Leder, Benjamin Z.; Tsai, Joy N.; Uihlein, Alexander V.; Wallace, Paul M.; Neer, Robert M.; Burnett-Bowie, Sherri-Ann M.] Massachusetts Gen Hosp, Endocrine Unit, Dept Med, Boston, MA 02114 USA. [Lee, Hang] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. RP Leder, BZ (reprint author), Massachusetts Gen Hosp, Endocrine Unit, Thier 1051, Boston, MA 02114 USA. EM bzleder@partners.org FU Amgen; Eli Lilly; National Institutes of Health; National Institutes of Health from the National Center for Research Resources [ULI RR025758] FX Funding Amgen, Eli Lilly, and National Institutes of Health.; This study was funded by investigator-initiated grants from Amgen and Eli Lilly and by National Institutes of Health Grant ULI RR025758 from the National Center for Research Resources. NR 36 TC 26 Z9 26 U1 1 U2 8 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 SEP 19 PY 2015 VL 386 IS 9999 BP 1147 EP 1155 DI 10.1016/S0140-6736(15)61120-5 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA CR5GE UT WOS:000361368000029 PM 26144908 ER PT J AU Santos, SA Lukens, AK Coelho, L Nogueira, F Wirth, DF Mazitschek, R Moreira, R Paulo, A AF Santos, Sofia A. Lukens, Amanda K. Coelho, Lis Nogueira, Fatima Wirth, Dyann F. Mazitschek, Ralph Moreira, Rui Paulo, Alexandra TI Exploring the 3-piperidin-4-yl-1H-indole scaffold as a novel antimalarial chemotype SO EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article DE Antimalarial; Drug lead; Indole; Reagent-based diversity ID ANTIPLASMODIAL ACTIVITY; PLASMODIUM-FALCIPARUM; DRUG DISCOVERY; BIS-ALKYLAMINE; MALARIA; POTENT; SPIROINDOLONES; DERIVATIVES; PROGRESS AB A series of 3-piperidin-4-yl-1H-indoles with building block diversity was synthesized based on a hit derived from an HTS whole-cell screen against Plasmodium falciparum. Thirty-eight compounds were obtained following a three-step synthetic approach and evaluated for anti-parasitic activity. The SAR shows that 3-piperidin-4-yl-1H-indole is intolerant to most N-piperidinyl modifications. Nevertheless, we were able to identify a new compound (10d) with lead-like properties (MW = 305; cLogP = 2.42), showing antimalarial activity against drug-resistant and sensitive strains (EC50 values similar to 3 mu M), selectivity for malaria parasite and no cross-resistance with chloroquine, thus representing a potential new chemotype for further optimization towards novel and affordable antimalarial drugs. (C) 2015 Elsevier Masson SAS. All rights reserved. C1 [Santos, Sofia A.; Moreira, Rui; Paulo, Alexandra] Univ Nova Lisboa, Fac Farm, Res Inst Med IMed ULisboa, P-1640003 Lisbon, Portugal. [Santos, Sofia A.; Mazitschek, Ralph] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Lukens, Amanda K.; Wirth, Dyann F.; Mazitschek, Ralph] Infect Dis Initiat, Broad Inst, Cambridge, MA 02142 USA. [Lukens, Amanda K.; Wirth, Dyann F.; Mazitschek, Ralph] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Coelho, Lis; Nogueira, Fatima] Univ Nova Lisboa, IHMT, Ctr Malaria & Doencas Trop, UEI Malaria, P-1349008 Lisbon, Portugal. RP Paulo, A (reprint author), Univ Nova Lisboa, Fac Farm, Res Inst Med IMed ULisboa, Av Prof Gama Pinto, P-1640003 Lisbon, Portugal. EM mapaulo@ff.ulisboa.pt RI Moreira, Rui/G-7485-2011; Paulo, Alexandra/M-6683-2013; PTMS, RNEM/C-1589-2014; iMed.ULisboa, iMed.ULisboa/C-6292-2014; iMed.ULisboa, MedChem /B-4834-2014 OI Moreira, Rui/0000-0003-0727-9852; Paulo, Alexandra/0000-0003-1433-5402; FU Fundacao para a Ciencia e Tecnologia (FCT) [PTDC/SAU-FAR/114864/2009, PEst-OE/SAU/UI4013/2014, SFRH/BD/80162/2011] FX This work was supported by Fundacao para a Ciencia e Tecnologia (FCT) project grants: PTDC/SAU-FAR/114864/2009 and PEst-OE/SAU/UI4013/2014. S. A. Santos thanks FCT for a PhD grant (SFRH/BD/80162/2011). R. Mazitschek thanks ChemAxon for Instant JChem 5.9.3, 2012. NR 37 TC 1 Z9 1 U1 2 U2 13 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0223-5234 EI 1768-3254 J9 EUR J MED CHEM JI Eur. J. Med. Chem. PD SEP 18 PY 2015 VL 102 BP 320 EP 333 DI 10.1016/j.ejmech.2015.07.047 PG 14 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA CS2SS UT WOS:000361922600029 PM 26295174 ER PT J AU Larsen, AT Fahrenbach, AC Sheng, J Pian, JL Szostak, JW AF Larsen, Aaron T. Fahrenbach, Albert C. Sheng, Jia Pian, Julia Szostak, Jack W. TI Thermodynamic insights into 2-thiouridine-enhanced RNA hybridization SO NUCLEIC ACIDS RESEARCH LA English DT Article ID DOT-U PAIR; BASE-PAIRS; MOLECULAR-DYNAMICS; PRIMER EXTENSION; WOBBLE POSITION; RECOGNITION; RIBOZYME; BINDING; DNA; URIDINE AB Nucleobase modifications dramatically alter nucleic acid structure and thermodynamics. 2-thiouridine (s(2)U) is a modified nucleobase found in tRNAs and known to stabilize U:A base pairs and destabilize U:G wobble pairs. The recently reported crystal structures of s(2)U-containing RNA duplexes do not entirely explain the mechanisms responsible for the stabilizing effect of s(2)U or whether this effect is entropic or enthalpic in origin. We present here thermodynamic evaluations of duplex formation using ITC and UV thermal denaturation with RNA duplexes containing internal s(2)U:A and s(2)U:U pairs and their native counterparts. These results indicate that s(2)U stabilizes both duplexes. The stabilizing effect is entropic in origin and likely results from the s(2)U-induced preorganization of the single-stranded RNA prior to hybridization. The same preorganizing effect is likely responsible for structurally resolving the s(2)U:U pair-containing duplex into a single conformation with a well-defined H-bond geometry. We also evaluate the effect of s(2)U on single strand conformation using UV- and CD-monitored thermal denaturation and on nucleoside conformation using H-1 NMR spectroscopy, MD and umbrella sampling. These results provide insights into the effects that nucleobase modification has on RNA structure and thermodynamics and inform efforts toward improving both ribozyme-catalyzed and nonenzymatic RNA copying. C1 [Larsen, Aaron T.; Fahrenbach, Albert C.; Pian, Julia; Szostak, Jack W.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Larsen, Aaron T.; Fahrenbach, Albert C.; Pian, Julia; Szostak, Jack W.] Massachusetts Gen Hosp, Dept Mol Biol, Simches Res Ctr, Boston, MA 02114 USA. [Fahrenbach, Albert C.; Szostak, Jack W.] Tokyo Inst Technol, Earth Life Sci Inst, Meguro Ku, Tokyo 1528550, Japan. [Sheng, Jia] SUNY Albany, Dept Chem, RNA Inst, Albany, NY 12222 USA. RP Szostak, JW (reprint author), Massachusetts Gen Hosp, Howard Hughes Med Inst, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. EM szostak@molbio.mgh.harvard.edu FU Fonds de recherche du Quebec-Nature et technologies; ELSI; Autonomous Province of Trento, Call 'Grandi Progetti', project 'Characterizing and improving brain mechanisms of attention-ATTEND [CHE-0809413]; Simons Foundation [290363] FX The Autonomous Province of Trento, Call 'Grandi Progetti 2012', project 'Characterizing and improving brain mechanisms of attention-ATTEND [CHE-0809413]; Simons Foundation [290363 to J.W.S.]. A.T.L. is partially supported by a fellowship from Fonds de recherche du Quebec-Nature et technologies. A.C.F. would like to thank ELSI for a postdoctoral fellowship award. J.W.S. is an Investigator of the Howard Hughes Medical Institute. Funding for open access charge: Simons Collaboration on the Origins of Life. NR 55 TC 5 Z9 6 U1 7 U2 27 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD SEP 18 PY 2015 VL 43 IS 16 BP 7675 EP 7687 DI 10.1093/nar/gkv761 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CS4WW UT WOS:000362077900009 PM 26240387 ER PT J AU Hu, YJ Belaghzal, H Hsiao, WY Qi, J Bradner, JE Guertin, DA Sif, S Imbalzano, AN AF Hu, Yu-Jie Belaghzal, Houda Hsiao, Wen-Yu Qi, Jun Bradner, James E. Guertin, David A. Sif, Said Imbalzano, Anthony N. TI Transcriptional and post-transcriptional control of adipocyte differentiation by Jumonji domain-containing protein 6 SO NUCLEIC ACIDS RESEARCH LA English DT Article ID PHOSPHATIDYLSERINE RECEPTOR; ENHANCER RNAS; PPAR-GAMMA; SELECTIVE-INHIBITION; SUPER-ENHANCERS; GENE-EXPRESSION; PAUSE RELEASE; JMJD6; BRD4; CHROMATIN AB Jumonji domain-containing protein 6 ( JMJD6) is a nuclear protein involved in histone modification, transcription and RNA processing. Although JMJD6 is crucial for tissue development, the link between its molecular functions and its roles in any given differentiation process is unknown. We report that JMJD6 is required for adipogenic gene expression and differentiation in a manner independent of Jumonji C domain catalytic activity. JMJD6 knockdown led to a reduction of C/ EBP beta and C/ EBP delta protein expression without affectingmRNA levels in the early phase of differentiation. However, ectopic expression of C/ EBP beta and C/ EBP delta did not rescue differentiation. Further analysis demonstrated that JMJD6 was associated with the Ppar.2 and Cebp alpha loci and putative enhancers. JMJD6 was previously found associated with bromodomain and extra-terminal domain ( BET) proteins, which can be targeted by the bromodomain inhibitor JQ1. JQ1 treatment prevented chromatin binding of JMJD6, Ppar.2 and Cebpa expression, and adipogenic differentiation, yet had no effect on C/ EBP beta and C/ EBP delta expression or chromatin binding. These results indicate dual roles for JMJD6 in promoting adipogenic gene expression program by post-transcriptional regulation of C/ EBP beta and C/ EBP delta and direct transcriptional activation of Ppar.2 and Cebpa during adipocyte differentiation. C1 [Hu, Yu-Jie; Belaghzal, Houda; Imbalzano, Anthony N.] Univ Massachusetts, Sch Med, Dept Cell & Dev Biol, Worcester, MA 01655 USA. [Hsiao, Wen-Yu; Guertin, David A.] Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA 01605 USA. [Qi, Jun; Bradner, James E.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Qi, Jun; Bradner, James E.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Sif, Said] Ohio State Univ, Coll Med, Dept Internal Med, Columbus, OH 43210 USA. [Sif, Said] Qatar Univ, Coll Arts & Sci, Dept Biol & Environm Sci, Doha, Qatar. RP Imbalzano, AN (reprint author), Univ Massachusetts, Sch Med, Dept Cell & Dev Biol, Worcester, MA 01655 USA. EM anthony.imbalzano@umassmed.edu FU National Institutes of Health (NIH) [DK084278, GM56244, DK32520] FX National Institutes of Health (NIH) [DK084278 to S.S. and A.N.I., GM56244 to A.N.I., DK32520 to UMass Medical School Diabetes and Endocrine Research Center]. NR 66 TC 6 Z9 6 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD SEP 18 PY 2015 VL 43 IS 16 BP 7790 EP 7804 DI 10.1093/nar/gkv645 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CS4WW UT WOS:000362077900018 PM 26117538 ER PT J AU Teshome, BF Lee, GC Reveles, KR Attridge, RT Koeller, J Wang, CP Mortensen, EM Frei, CR AF Teshome, Besu F. Lee, Grace C. Reveles, Kelly R. Attridge, Russell T. Koeller, Jim Wang, Chen-pin Mortensen, Eric M. Frei, Christopher R. TI Application of a methicillin-resistant Staphylococcus aureus risk score for community-onset pneumonia patients and outcomes with initial treatment SO BMC INFECTIOUS DISEASES LA English DT Article ID CARE-ASSOCIATED PNEUMONIA; INFECTIOUS-DISEASES-SOCIETY; ACQUIRED PNEUMONIA; NOSOCOMIAL PNEUMONIA; ANTIBIOTIC-THERAPY; INFLUENZA SEASON; PATHOGENS; ADULTS; COHORT; EPIDEMIOLOGY AB Background: Community-onset (CO) methicillin-resistant Staphylococcus aureus (MRSA) pneumonia is an evolving problem, and there is a great need for a reliable method to assess MRSA risk at hospital admission. A new MRSA prediction score classifies CO-pneumonia patients into low, medium, and high-risk groups based on objective criteria available at baseline. Our objective was to assess the effect of initial MRSA therapy on mortality in these three risk groups. Methods: We conducted a retrospective cohort study using data from the Veterans Health Administration (VHA). Patients were included if they were hospitalized with pneumonia and received antibiotics within the first 48 h of admission. They were stratified into MRSA therapy and no MRSA therapy treatment arms based on antibiotics received in the first 48 h. Multivariable logistic regression was used to adjust for potential confounders. Results: A total of 80,330 patients met inclusion criteria, of which 36 % received MRSA therapy and 64 % did not receive MRSA therapy. The majority of patients were classified as either low (51 %) or medium (47 %) risk, with only 2 % classified as high-risk. Multivariable logistic regression analysis demonstrated that initial MRSA therapy was associated with a lower 30-day mortality in the high-risk group (adjusted odds ratio 0.57; 95 % confidence interval 0.42-0.77). Initial MRSA therapy was not beneficial in the low or medium-risk groups. Conclusions: This study demonstrated improved survival with initial MRSA therapy in high-risk CO-pneumonia patients. The MRSA risk score might help spare MRSA therapy for only those patients who are likely to benefit. C1 [Teshome, Besu F.] St Louis Coll Pharm, St Louis, MO USA. [Teshome, Besu F.; Lee, Grace C.; Reveles, Kelly R.; Koeller, Jim; Frei, Christopher R.] Univ Texas Austin, Coll Pharm, Pharmacotherapy Div, Austin, TX 78712 USA. [Teshome, Besu F.; Lee, Grace C.; Reveles, Kelly R.; Koeller, Jim; Frei, Christopher R.] Univ Texas Hlth Sci Ctr San Antonio, Sch Med, Pharmacotherapy Educ & Res Ctr, San Antonio, TX 78229 USA. [Attridge, Russell T.] Univ Incarnate Word, Feik Sch Pharm, San Antonio, TX USA. [Attridge, Russell T.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. [Wang, Chen-pin] Univ Texas Hlth Sci Ctr San Antonio, Dept Epidemiol & Biostat, San Antonio, TX 78229 USA. [Mortensen, Eric M.] VA North Texas Hlth Care Syst, Dallas, TX USA. [Mortensen, Eric M.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. RP Frei, CR (reprint author), Univ Texas Austin, Coll Pharm, Pharmacotherapy Div, Austin, TX 78712 USA. EM freic@uthscsa.edu OI Mortensen, Eric/0000-0002-3880-5563 FU National Institutes of Health (NIH)/National Institute of Nursing Research [R01NR010828]; NIH Clinical Research Scholar (KL2) career development award (National Center for Research Resources) [5KL2 RR025766]; NIH Clinical Research Scholar (KL2) career development award (National Center for Advancing Translational Sciences) [8KL2 TR000118]; Agency for Healthcare Research and Quality [R24 HS022418]; University of Texas Southwestern Center for Patient-Centered Outcomes Research FX This study was supported by a grant from the National Institutes of Health (NIH)/National Institute of Nursing Research (R01NR010828). Dr. Frei was supported in part by a NIH Clinical Research Scholar (KL2) career development award (National Center for Research Resources 5KL2 RR025766 [2010-2012] and National Center for Advancing Translational Sciences 8KL2 TR000118 [2013]). Dr. Mortensen was supported in part by a grant from the Agency for Healthcare Research and Quality (R24 HS022418) and the University of Texas Southwestern Center for Patient-Centered Outcomes Research. This material is the result of work supported with resources and the use of facilities at the South Texas Veterans Health Care System. The funding sources 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 article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs or the National Institutes of Health. Finally, the co-authors would like to acknowledge the assistance of Stefan Allen and Ashley Pechal (pharmacy students at The University of Texas at Austin College of Pharmacy, who assisted the co-authors with literature searches during part of the peer review process). NR 40 TC 3 Z9 3 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2334 J9 BMC INFECT DIS JI BMC Infect. Dis. PD SEP 18 PY 2015 VL 15 AR 380 DI 10.1186/s12879-015-1119-1 PG 11 WC Infectious Diseases SC Infectious Diseases GA CR5BV UT WOS:000361355200001 PM 26385225 ER PT J AU Miyamoto, DT Zheng, Y Wittner, BS Lee, RJ Zhu, HL Broderick, KT Desai, R Fox, DB Brannigan, BW Trautwein, J Arora, KS Desai, N Dahl, DM Sequist, LV Smith, MR Kapur, R Wu, CL Shioda, T Ramaswamy, S Ting, DT Toner, M Maheswaran, S Haber, DA AF Miyamoto, David T. Zheng, Yu Wittner, Ben S. Lee, Richard J. Zhu, Huili Broderick, Katherine T. Desai, Rushil Fox, Douglas B. Brannigan, Brian W. Trautwein, Julie Arora, Kshitij S. Desai, Niyati Dahl, Douglas M. Sequist, Lecia V. Smith, Matthew R. Kapur, Ravi Wu, Chin-Lee Shioda, Toshi Ramaswamy, Sridhar Ting, David T. Toner, Mehmet Maheswaran, Shyamala Haber, Daniel A. TI RNA-Seq of single prostate CTCs implicates noncanonical Wnt signaling in antiandrogen resistance SO SCIENCE LA English DT Article ID CIRCULATING TUMOR-CELLS; CANCER; PATHWAY; ENZALUTAMIDE; METASTASIS; DATABASE AB Prostate cancer is initially responsive to androgen deprivation, but the effectiveness of androgen receptor (AR) inhibitors in recurrent disease is variable. Biopsy of bone metastases is challenging; hence, sampling circulating tumor cells (CTCs) may reveal drug-resistance mechanisms. We established single-cell RNA-sequencing (RNA-Seq) profiles of 77 intact CTCs isolated from 13 patients (mean six CTCs per patient), by using microfluidic enrichment. Single CTCs from each individual display considerable heterogeneity, including expression of AR gene mutations and splicing variants. Retrospective analysis of CTCs from patients progressing under treatment with an AR inhibitor, compared with untreated cases, indicates activation of noncanonical Wnt signaling (P = 0.0064). Ectopic expression of Wnt5a in prostate cancer cells attenuates the antiproliferative effect of AR inhibition, whereas its suppression in drug-resistant cells restores partial sensitivity, a correlation also evident in an established mouse model. Thus, single-cell analysis of prostate CTCs reveals heterogeneity in signaling pathways that could contribute to treatment failure. C1 [Miyamoto, David T.; Zheng, Yu; Wittner, Ben S.; Lee, Richard J.; Zhu, Huili; Broderick, Katherine T.; Desai, Rushil; Fox, Douglas B.; Brannigan, Brian W.; Trautwein, Julie; Arora, Kshitij S.; Desai, Niyati; Dahl, Douglas M.; Sequist, Lecia V.; Smith, Matthew R.; Wu, Chin-Lee; Shioda, Toshi; Ramaswamy, Sridhar; Ting, David T.; Maheswaran, Shyamala; Haber, Daniel A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Massachusetts Gen Canc Ctr, Charlestown, MA 02129 USA. [Miyamoto, David T.] Harvard Univ, Massachusetts Gen Hosp, Dept Radiat Oncol, Sch Med, Charlestown, MA 02129 USA. [Zheng, Yu; Haber, Daniel A.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Wittner, Ben S.; Lee, Richard J.; Sequist, Lecia V.; Smith, Matthew R.; Ramaswamy, Sridhar; Ting, David T.; Haber, Daniel A.] Harvard Univ, Massachusetts Gen Hosp, Dept Med, Sch Med, Charlestown, MA 02129 USA. [Arora, Kshitij S.; Desai, Niyati; Wu, Chin-Lee] Harvard Univ, Massachusetts Gen Hosp, Dept Pathol, Sch Med, Charlestown, MA 02129 USA. [Dahl, Douglas M.] Harvard Univ, Massachusetts Gen Hosp, Dept Urol, Sch Med, Charlestown, MA 02129 USA. [Kapur, Ravi; Toner, Mehmet] Harvard Univ, Massachusetts Gen Hosp, Ctr Bioengn Med, Sch Med, Charlestown, MA 02129 USA. [Maheswaran, Shyamala] Harvard Univ, Massachusetts Gen Hosp, Dept Surg, Sch Med, Charlestown, MA 02129 USA. RP Haber, DA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Massachusetts Gen Canc Ctr, Charlestown, MA 02129 USA. EM haber@helix.mgh.harvard.edu; smaheswaran@mgh.harvard.edu RI bebarta, vikhyat/K-3476-2015; OI Ting, David/0000-0002-3261-2322 FU Prostate Cancer Foundation; Charles Evans Foundation; Department of Defense; Stand Up to Cancer; Howard Hughes Medical Institute; National Institute of Biomedical Imaging and Bioengineering (NIBIB); NIH [EB008047]; NCI [2RO1CA129933]; National Cancer Institute, NCI; Federal Share Program and Income; Affymetrix, Inc.; Mazzone Program-Dana-Farber Harvard Cancer Center; Burroughs Wellcome Fund; Massachusetts General Hospital-Johnson & Johnson Center for Excellence in CTC Technologies; Janssen LLC. FX We thank C. Sawyers for helpful discussions; A. McGovern, E. Stadtmueller, and B. Abebe for clinical trial support; and L. Libby and L. Nieman for technical assistance. This work was supported by grants from the Prostate Cancer Foundation (D.A.H., S.M., M.T., M.R.S., and R.J.L.), Charles Evans Foundation (D.A.H.), Department of Defense (D.T.M., R.J.L., and D.T.T.), Stand Up to Cancer (D.A.H., M.T., S.M., and L.V.S.), Howard Hughes Medical Institute (D.A.H.), National Institute of Biomedical Imaging and Bioengineering (NIBIB), NIH, EB008047 (M.T.), NCI 2RO1CA129933 (D.A.H.), National Cancer Institute, NCI, Federal Share Program and Income (S.M. and D.T.M.), Affymetrix, Inc. (D.T.T., K.A., and N.D.), Mazzone Program-Dana-Farber Harvard Cancer Center (D.T.M.), Burroughs Wellcome Fund (D.T.T.), and the Massachusetts General Hospital-Johnson & Johnson Center for Excellence in CTC Technologies (D.A.H., M.T., and S.M.). D.T.T. is a paid consultant for Affymetrix, Inc.; R.J.L. is a paid consultant for Janssen LLC. The Massachusetts General Hospital has filed for patent protection for the CTC-iChip technology. RNA-sequencing data have been deposited in GEO under accession number GSE67980. NR 30 TC 78 Z9 81 U1 10 U2 60 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 SEP 18 PY 2015 VL 349 IS 6254 BP 1351 EP 1356 DI 10.1126/science.aab0917 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CR5CR UT WOS:000361357700052 PM 26383955 ER PT J AU Feske, SK Goldberg, M Dudzinski, DM Gonzalez, RG Kovach, AE AF Feske, Steven K. Goldberg, Marcia Dudzinski, David M. Gonzalez, Ramon Gilberto Kovach, Alexandra E. TI Case 29-2015: A 38-Year-Old Pregnant Woman with Headache and Visual Symptoms SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ENDOMYOCARDIAL FIBROSIS; HYPEREOSINOPHILIC SYNDROME; EPIDEMIOLOGY; MYOCARDITIS; STROKE; SYSTEM; WOMEN; PICA; RISK C1 [Feske, Steven K.] Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. [Goldberg, Marcia] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Dudzinski, David M.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Gonzalez, Ramon Gilberto] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Kovach, Alexandra E.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Feske, Steven K.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Goldberg, Marcia; Dudzinski, David M.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Gonzalez, Ramon Gilberto] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Kovach, Alexandra E.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Feske, SK (reprint author), Brigham & Womens Hosp, Dept Neurol, 75 Francis St, Boston, MA 02115 USA. NR 23 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 SEP 17 PY 2015 VL 373 IS 12 BP 1154 EP 1164 DI 10.1056/NEJMcpc1404335 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA CR7UG UT WOS:000361556400012 PM 26376139 ER PT J AU Brook, K Camargo, CA Christopher, KB Quraishi, SA AF Brook, Karolina Camargo, Carlos A. Christopher, Kenneth B. Quraishi, Sadeq A. TI Admission vitamin D status is associated with discharge destination in critically ill surgical patients SO ANNALS OF INTENSIVE CARE LA English DT Article DE Vitamin D; 25-hydroxyvitamin D; Critical illness; Discharge destination; Patient-centered outcome ID INTENSIVE-CARE-UNIT; LOCALLY WEIGHTED REGRESSION; CHRONIC CRITICAL ILLNESS; SKELETAL-MUSCLE CELLS; LENGTH-OF-STAY; D DEFICIENCY; SEVERE SEPSIS; 25-HYDROXYVITAMIN D-1-ALPHA-HYDROXYLASE; 1,25-DIHYDROXYVITAMIN-D3 RECEPTORS; HOSPITAL DISCHARGE AB Background: Discharge destination after critical illness is increasingly recognized as a valuable patient-centered outcome. Recently, vitamin D status has been shown to be associated with important outcomes such as length of stay (LOS) and mortality in intensive care unit (ICU) patients. Our goal was to investigate whether vitamin D status on ICU admission is associated with discharge destination. Methods: We performed a retrospective analysis from an ongoing prospective cohort study of vitamin D status in critical illness. Patients were recruited from two surgical ICUs at a single teaching hospital in Boston, Massachusetts. All patients had 25-hydroxyvitamin D (25OHD) levels measured within 24 h of ICU admission. Discharge destination was dichotomized as non-home or home. Locally weighted scatterplot smoothing (LOWESS) was used to graph the relationship between 25OHD levels and discharge destination. To investigate the association between 25OHD level and discharge destination, we performed logistic regression analyses, controlling for age, sex, race, body mass index, socioeconomic status, acute physiology and chronic health evaluation II score, need for emergent vs. non-emergent surgery, vitamin D supplementation status, and hospital LOS. Results: 300 patients comprised the analytic cohort. Mean 25OHD level was 19 (standard deviation 8) ng/mL and 41 % of patients had a non-home discharge destination. LOWESS analysis demonstrated a near-inverse linear relationship between vitamin D status and non-home discharge destination to 25OHD levels around 10 ng/mL, with rapid flattening of the curve between levels of 10 and 20 ng/mL. Overall, 25OHD level at the outset of critical illness was inversely associated with non-home discharge destination (adjusted OR, 0.88; 95 % CI 0.82-0.95). When vitamin D status was dichotomized, patients with 25OHD levels < 20 ng/mL had an almost 3-fold risk of a non-home discharge destination (adjusted OR, 2.74; 95 % CI 1.23-6.14) compared to patients with 25OHD levels >= 20 ng/mL. Conclusions: Our results suggest that vitamin D status may be a modifiable risk factor for non-home discharge destination in surgical ICU patients. Future randomized, controlled trials are needed to determine whether vitamin D supplementation in surgical ICU patients can improve clinical outcomes such as the successful rate of discharge to home after critical illness C1 [Brook, Karolina; Quraishi, Sadeq A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Camargo, Carlos A.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Camargo, Carlos A.; Christopher, Kenneth B.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA. [Camargo, Carlos A.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Christopher, Kenneth B.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Quraishi, Sadeq A.] Harvard Univ, Sch Med, Dept Anaesthesia, Boston, MA 02115 USA. RP Quraishi, SA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St,GRJ 402, Boston, MA 02114 USA. EM squraishi@mgh.harvard.edu FU United States National Institutes of Health [R01 AI093723, U01 AI087881, T32 GM007592, UL1 RR025758, L30 TR001257]; Harvard Medical School FX CAC received support from the United States National Institutes of Health grants R01 AI093723 and U01 AI087881. SAQ received support from the United States National Institutes of Health grants T32 GM007592, UL1 RR025758, and L30 TR001257 as well as from Harvard Medical School. NR 82 TC 0 Z9 0 U1 1 U2 9 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 2110-5820 J9 ANN INTENSIVE CARE JI Ann. Intensive Care PD SEP 17 PY 2015 VL 5 AR 23 DI 10.1186/s13613-015-0065-9 PG 9 WC Critical Care Medicine SC General & Internal Medicine GA CZ9AY UT WOS:000367391400002 PM 26380991 ER PT J AU Buisson, R Boisvert, JL Benes, CH Zou, L AF Buisson, Remi Boisvert, Jessica L. Benes, Cyril H. Zou, Lee TI Distinct but Concerted Roles of ATR, DNA-PK, and Chk1 in Countering Replication Stress during S Phase SO MOLECULAR CELL LA English DT Article ID RIBONUCLEOTIDE REDUCTASE R2; ADVANCED SOLID TUMORS; DAMAGE CHECKPOINT; CANCER-CELLS; GENOMIC INSTABILITY; FORK PROGRESSION; DOSE-ESCALATION; DEFICIENT CELLS; BETA-TRCP; ACTIVATION AB The ATR-Chk1 pathway is critical for DNA damage responses and cell-cycle progression. Chk1 inhibition is more deleterious to cycling cells than ATR inhibition, raising questions about ATR and Chk1 functions in the absence of extrinsic replication stress. Here we show that a key role of ATR in S phase is to coordinate RRM2 accumulation and origin firing. ATR inhibitor (ATRi) induces massive ssDNA accumulation and replication catastrophe in a fraction of early S-phase cells. In other S-phase cells, however, ATRi induces moderate ssDNA and triggers a DNA-PK and Chk1-mediated backup pathway to suppress origin firing. The backup pathway creates a threshold such that ATRi selectively kills cells under high replication stress, whereas Chk1 inhibitor induces cell death at a lower threshold. The levels of ATRi-induced ssDNA correlate with ATRi sensitivity in a panel of cell lines, suggesting that ATRi-induced ssDNA could be predictive of ATRi sensitivity in cancer cells. C1 [Buisson, Remi; Boisvert, Jessica L.; Benes, Cyril H.; Zou, Lee] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02129 USA. [Zou, Lee] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Zou, L (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02129 USA. EM zou.lee@mgh.harvard.edu FU NIH [GM076388]; Federal Share of the MGH Proton Program; Wellcome Trust [102696] FX We thank J. Bartek, C. Bakkenist, B. Chen, N. Dyson, M. Lopes, S. Maheswaran, M. Pagano, and W. Wei for reagents; S. Yazinski and V. Comaills for advice on DNA fiber and qRT-PCR assays; E. Hardy for technical assistance; and members of the L.Z. lab for helpful discussions. R.B. is partly supported by a Tosteson Postdoctoral Award, a Marsha Rivkin Scientific Scholar Award, and a fellowship from the Phillips Foundation. L.Z. is a Jim & Ann Orr Massachusetts General Hospital (MGH) Research Scholar. This work was supported by grants from the NIH (GM076388) and the Federal Share of the MGH Proton Program to L.Z. and a grant from the Wellcome Trust (102696) to C.H.B. NR 70 TC 19 Z9 19 U1 1 U2 13 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 EI 1097-4164 J9 MOL CELL JI Mol. Cell PD SEP 17 PY 2015 VL 59 IS 6 BP 1011 EP 1024 DI 10.1016/j.molcel.2015.07.029 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CW7GQ UT WOS:000365166500013 PM 26365377 ER PT J AU Hiraki, M Hwang, SY Cao, SG Ramadhar, TR Byun, S Yoon, KW Lee, JH Chu, K Gurkar, AU Kolev, V Zhang, JM Namba, T Murphy, ME Newman, DJ Mandinova, A Clardy, J Lee, SW AF Hiraki, Masatsugu Hwang, So-Young Cao, Shugeng Ramadhar, Timothy R. Byun, Sanguine Yoon, Kyoung Wan Lee, Jung Hyun Chu, Kiki Gurkar, Aditi U. Kolev, Vihren Zhang, Jianming Namba, Takushi Murphy, Maureen E. Newman, David J. Mandinova, Anna Clardy, Jon Lee, Sam W. TI Small-Molecule Reactivation of Mutant p53 to Wild-Type-like p53 through the p53-Hsp40 Regulatory Axis SO CHEMISTRY & BIOLOGY LA English DT Article ID TUMOR-SUPPRESSOR P53; CANCER-CELLS; BREAST-CANCER; COMPLEX; STRESS; TARGET; IDENTIFICATION; TRANSCRIPTION; INHIBITION; EXPRESSION AB TP53 is the most frequently mutated gene in human cancer, and small-molecule reactivation of mutant p53 function represents an important anticancer strategy. A cell-based, high-throughput small-molecule screen identified chetomin (CTM) as a mutant p53 R175H reactivator. CTM enabled p53 to transac-tivate target genes, restored MDM2 negative regulation, and selectively inhibited the growth of cancer cells harboring mutant p53 R175H in vitro and in vivo. We found that CTM binds to Hsp40 and increases the binding capacity of Hsp40 to the p53 R175H mutant protein, causing a potential conformational change to a wild-type-like p53. Thus, CTM acts as a specific reactivator of the p53 R175H mutant form through Hsp40. These results provide new insights into the mechanism of reactivation of this specific p53 mutant. C1 [Hiraki, Masatsugu; Hwang, So-Young; Byun, Sanguine; Yoon, Kyoung Wan; Lee, Jung Hyun; Chu, Kiki; Gurkar, Aditi U.; Kolev, Vihren; Zhang, Jianming; Namba, Takushi; Mandinova, Anna; Lee, Sam W.] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. [Hiraki, Masatsugu; Hwang, So-Young; Byun, Sanguine; Yoon, Kyoung Wan; Lee, Jung Hyun; Chu, Kiki; Gurkar, Aditi U.; Kolev, Vihren; Zhang, Jianming; Namba, Takushi; Mandinova, Anna; Lee, Sam W.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Cao, Shugeng] Univ Hawaii, Dept Pharmaceut Sci, Daniel K Inouye Coll Pharm, Hilo, HI 96720 USA. [Cao, Shugeng; Ramadhar, Timothy R.; Clardy, Jon] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Murphy, Maureen E.] Wistar Inst Anat & Biol, Program Mol & Cellular Oncogenesis, Philadelphia, PA 19104 USA. [Newman, David J.] Frederick Natl Lab Canc Res, Nat Prod Branch, Dev Therapeut Program, Div Canc Treatment & Diag, Frederick, MD 21702 USA. [Mandinova, Anna; Lee, Sam W.] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. RP Clardy, J (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. EM jon_clardy@hms.harvard.edu; swlee@mgh.harvard.edu OI Ramadhar, Timothy/0000-0002-7063-5445 FU postdoctoral fellowships for research abroad from the Japan Society for the Promotion of Science; research fellowship for research abroad from the Uehara Memorial Foundation; F32 postdoctoral fellowship from the NIH [GM108415]; NIH [CA142805, CA149477, CA80058, GM086258]; FAS Division of Science, Research Computing group at Harvard University FX We thank Z. Yuan for MEF cells, X. Chen and J. Manfredi for mutant p53 plasmids and tet-inducible cell lines, J. Manfredi for p53 binding site of PUMA promoter plasmid, M. Taipale and S. Lindquist for materials and help on some heat-shock protein activity experiments, H. Li and S. J. Lee for help on Biacore studies, and W. Gu for in vitro gel-shift experiments. M. H. and T.N. were supported by postdoctoral fellowships for research abroad from the Japan Society for the Promotion of Science. M. H. was also supported by a research fellowship for research abroad from the Uehara Memorial Foundation. T.R.R. was supported by an F32 postdoctoral fellowship from the NIH (GM108415). The research was supported by NIH grants CA142805, CA149477, CA80058, and GM086258. Quantum-chemical calculations were run on the Odyssey cluster supported by the FAS Division of Science, Research Computing group at Harvard University. NR 46 TC 7 Z9 7 U1 1 U2 14 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-5521 EI 1879-1301 J9 CHEM BIOL JI Chem. Biol. PD SEP 17 PY 2015 VL 22 IS 9 BP 1206 EP 1216 DI 10.1016/j.chembiol.2015.07.016 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA CV1JT UT WOS:000364012100006 PM 26320861 ER PT J AU Rook, AH Gelfand, JC Wysocka, M Troxel, AB Benoit, B Surber, C Elenitsas, R Buchanan, MA Leahy, DS Watanabe, R Kirsch, IR Kim, EJ Clark, RA AF Rook, Alain H. Gelfand, Joel C. Wysocka, Maria Troxel, Andrea B. Benoit, Bernice Surber, Christian Elenitsas, Rosalie Buchanan, Marie A. Leahy, Deborah S. Watanabe, Rei Kirsch, Ilan R. Kim, Ellen J. Clark, Rachael A. TI Topical resiquimod can induce disease regression and enhance T-cell effector functions in cutaneous T-cell lymphoma SO BLOOD LA English DT Article ID IMMUNE-RESPONSE MODIFIER; MYCOSIS-FUNGOIDES; DENDRITIC CELLS; SEZARY-SYNDROME; SKIN-CANCER; IMIQUIMOD; CLASSIFICATION; INTERLEUKIN-12; RESIDENT; AGONISTS AB Early-stage cutaneous T-cell lymphoma (CTCL) is a skin-limited lymphoma with no cure aside from stem cell transplantation. Twelve patients with stage IA-IIA CTCL were treated in a phase 1 trial of 0.03% and 0.06% topical resiquimod gel, a Toll-like receptor 7/8 agonist. Treated lesions significantly improved in 75% of patients and 30% had clearing of all treated lesions. Resiquimod also induced regression of untreated lesions. Ninety-two percent of patients had more than a 50% improvement in body surface area involvement by the modified Severity-Weighted Assessment Tool analysis and 2 patients experienced complete clearing of disease. Four of 5 patients with folliculotropic disease also improved significantly. Adverse effects were minor and largely skin limited. T-cell receptor sequencing and flow cytometry studies of T cells from treated lesions demonstrated decreased clonal malignant T cells in 90% of patients and complete eradication of malignant T cells in 30%. High responses were associated with recruitment and expansion of benign T-cell clones in treated skin, increased skin T-cell effector functions, and a trend toward increased natural killer cell functions. In patients with complete or near eradication of malignant T cells, residual clinical inflammation was associated with cytokine production by benign T cells. Fifty percent of patients had increased activation of circulating dendritic cells, consistent with a systemic response to therapy. In summary, topical resiquimod is safe and effective in early-stage CTCL and the first topical therapy to our knowledge that can induce clearance of untreated lesions and complete remissions in some patients. This trial was registered at www.clinicaltrials.gov as #NCT813320. C1 [Rook, Alain H.; Gelfand, Joel C.; Wysocka, Maria; Troxel, Andrea B.; Benoit, Bernice; Elenitsas, Rosalie; Buchanan, Marie A.; Leahy, Deborah S.; Kim, Ellen J.] Univ Penn, Perelman Sch Med, Dept Dermatol, Philadelphia, PA 19104 USA. [Rook, Alain H.; Gelfand, Joel C.; Wysocka, Maria; Troxel, Andrea B.; Benoit, Bernice; Elenitsas, Rosalie; Buchanan, Marie A.; Leahy, Deborah S.; Kim, Ellen J.] Univ Penn, Perelman Sch Med, Ctr Clin Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Surber, Christian] Univ Zurich Hosp, Dept Dermatol, CH-8091 Zurich, Switzerland. [Surber, Christian] Univ Basel Hosp, Dept Dermatol, CH-4031 Basel, Switzerland. [Watanabe, Rei] Univ Tokyo, Dept Dermatol, Tokyo 113, Japan. [Watanabe, Rei; Clark, Rachael A.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Kirsch, Ilan R.] Adapt Biotechnol, Seattle, WA USA. [Clark, Rachael A.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. RP Rook, AH (reprint author), Perelman Sch Med, Dept Dermatol, 3600 Spruce St, Philadelphia, PA 19104 USA. EM arook@mail.med.upenn.edu; rclark1@partners.org OI Troxel, Andrea/0000-0002-1393-3075 FU National Institutes of Health (NIH)/National Cancer Institute [R01 CA122569, R21 CA178424, FD-RO1-04092]; NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases [R01 AR056720, R01 AR063962]; NIH [R01 AI097128]; CLARIONS from the Cutaneous Lymphoma Foundation; Leukemia and Lymphoma Society; Leukemia & Lymphoma Society FX This work was supported by the National Institutes of Health (NIH)/National Cancer Institute grant R01 CA122569 (to A.H.R.), grant R21 CA178424 (to A.H.R. and M.W.), and grant FD-RO1-04092 (to A.H.R.); NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases (grants R01 AR056720 and R01 AR063962) (to R.A.C.); and NIH (R01 AI097128) (to Thomas S. Kupper and R.A.C.). This work was also supported by a CLARIONS grant from the Cutaneous Lymphoma Foundation (to R.A.C.), a Translational Research grant from the Leukemia and Lymphoma Society (to A.H.R.), and a Special Fellow grant from the Leukemia & Lymphoma Society (to R.W.). NR 24 TC 10 Z9 10 U1 1 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD SEP 17 PY 2015 VL 126 IS 12 BP 1452 EP 1461 DI 10.1182/blood-2015-02-630335 PG 10 WC Hematology SC Hematology GA CU4ET UT WOS:000363480500011 PM 26228486 ER PT J AU Black, JC Whetstine, JR AF Black, Joshua C. Whetstine, Johnathan R. TI Too little O-2 Too much gain SO CELL CYCLE LA English DT Editorial Material ID COPY GAIN; EXPRESSION; CANCER C1 [Whetstine, Johnathan R.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 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 02129 USA. EM jwhetstine@hms.harvard.edu RI Black, Joshua/Q-2484-2015 NR 6 TC 2 Z9 2 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1538-4101 EI 1551-4005 J9 CELL CYCLE JI Cell Cycle PD SEP 17 PY 2015 VL 14 IS 18 BP 2869 EP 2870 DI 10.1080/15384101.2015.1076659 PG 2 WC Cell Biology SC Cell Biology GA CR7KE UT WOS:000361527600004 PM 26221746 ER PT J AU Xiong, ML Ferder, IC Ohguchi, Y Wang, N AF Xiong, Mulin Ferder, Ianina C. Ohguchi, Yasuyo Wang, Ning TI Quantitative analysis of male germline stem cell differentiation reveals a role for the p53-mTORC1 pathway in spermatogonial maintenance SO CELL CYCLE LA English DT Article DE differentiation; germline stem cell; mTORC1; p53; spermatogonia ID SELF-RENEWAL; UNDIFFERENTIATED SPERMATOGONIA; TUMOR SUPPRESSION; GENE-EXPRESSION; RETINOIC ACID; MTOR PATHWAY; MOUSE TESTES; P53; MICE; QUIESCENCE AB p53 protects cells from DNA damage by inducing cell-cycle arrest upon encountering genomic stress. Among other pathways, p53 elicits such an effect by inhibiting mammalian target of rapamycin complex 1 (mTORC1), the master regulator of cell proliferation and growth. Although recent studies have indicated roles for both p53 and mTORC1 in stem cell maintenance, it remains unclear whether the p53-mTORC1 pathway is conserved to mediate this process under normal physiological conditions. Spermatogenesis is a classic stem cell-dependent process in which undifferentiated spermatogonia undergo self-renewal and differentiation to maintain the lifelong production of spermatozoa. To better understand this process, we have developed a novel flow cytometry (FACS)-based approach that isolates spermatogonia at consecutive differentiation stages. By using this as a tool, we show that genetic loss of p53 augments mTORC1 activity during early spermatogonial differentiation. Functionally, loss of p53 drives spermatogonia out of the undifferentiated state and causes a consistent expansion of early differentiating spermatogonia until the stage of preleptotene (premeiotic) spermatocyte. The frequency of early meiotic spermatocytes is, however, dramatically decreased. Thus, these data suggest that p53-mTORC1 pathway plays a critical role in maintaining the homeostasis of early spermatogonial differentiation. Moreover, our FACS approach could be a valuable tool in understanding spermatogonial differentiation. C1 [Xiong, Mulin; Ferder, Ianina C.; Ohguchi, Yasuyo; Wang, Ning] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vincent Ctr Reprod Biol,Vincent Dept Obstet & Gyn, Boston, MA 02138 USA. RP Wang, N (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vincent Ctr Reprod Biol,Vincent Dept Obstet & Gyn, Boston, MA 02138 USA. EM nwang3@mgh.harvard.edu FU NIA [R00-AG-039512]; Vincent Department of Obstetrics and Gynecology at Massachusetts General Hospital FX This work was supported by NIA (R00-AG-039512) and the Vincent Department of Obstetrics and Gynecology at Massachusetts General Hospital to N.W. NR 51 TC 2 Z9 2 U1 0 U2 5 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1538-4101 EI 1551-4005 J9 CELL CYCLE JI Cell Cycle PD SEP 17 PY 2015 VL 14 IS 18 BP 2905 EP 2913 DI 10.1080/15384101.2015.1069928 PG 9 WC Cell Biology SC Cell Biology GA CR7KE UT WOS:000361527600014 PM 26177380 ER PT J AU Lammers, KM Chieppa, M Liu, L Liu, S Omatsu, T Janka-Junttila, M Casolaro, V Reinecker, HC Parent, CA Fasano, A AF Lammers, Karen M. Chieppa, Marcello Liu, Lunhua Liu, Song Omatsu, Tatsushi Janka-Junttila, Mirkka Casolaro, Vincenzo Reinecker, Hans-Christian Parent, Carole A. Fasano, Alessio TI Gliadin Induces Neutrophil Migration via Engagement of the Formyl Peptide Receptor, FPR1 SO PLOS ONE LA English DT Article ID MUCOSAL GRANULOCYTE ACTIVATION; CELIAC-DISEASE; INTESTINAL PERMEABILITY; BARRIER FUNCTION; GUT PERMEABILITY; CONTROLLED-TRIAL; GENE-EXPRESSION; GLUTEN; ZONULIN; CHEMOTAXIS AB Background Gliadin, the immunogenic component within gluten and trigger of celiac disease, is known to induce the production of Interleukin-8, a potent neutrophil-activating and chemoattractant chemokine. We sought to study the involvement of neutrophils in the early immunological changes following gliadin exposure. Methods Utilizing immunofluorescence microscopy and flow cytometry, the redistribution of major tight junction protein, Zonula occludens (ZO)-1, and neutrophil recruitment were assessed in duodenal tissues of gliadin-gavaged C57BL/6 wild-type and Lys-GFP reporter mice, respectively. Intravital microscopy with Lys-GFP mice allowed monitoring of neutrophil recruitment in response to luminal gliadin exposure in real time. In vitro chemotaxis assays were used to study murine and human neutrophil chemotaxis to gliadin, synthetic alpha-gliadin peptides and the neutrophil chemoattractant, fMet-Leu-Phe, in the presence or absence of a specific inhibitor of the fMet-Leu-Phe receptor-1 (FPR1), cyclosporine H. An irrelevant protein, zein, served as a control. Results Redistribution of ZO-1 and an influx of CD11b(+)Lys6G(+) cells in the lamina propria of the small intestine were observed upon oral gavage of gliadin. In vivo intravital microscopy revealed a slowing down of GFP(+) cells within the vessels and influx in the mucosal tissue within 2 hours after challenge. In vitro chemotaxis assays showed that gliadin strongly induced neutrophil migration, similar to fMet-Leu-Phe. We identified thirteen synthetic gliadin peptide motifs that induced cell migration. Blocking of FPR1 completely abrogated the fMet-Leu-Phe-, gliadin- and synthetic peptide-induced migration. Conclusions Gliadin possesses neutrophil chemoattractant properties similar to the classical neutrophil chemoattractant, fMet-Leu-Phe, and likewise uses FPR1 in the process. C1 [Lammers, Karen M.; Fasano, Alessio] Massachusetts Gen Hosp, Dept Pediat, Mucosal Immunol & Biol Res Ctr, Charlestown, MA 02129 USA. [Chieppa, Marcello] NIAID, Lymphocyte Biol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Liu, Lunhua; Janka-Junttila, Mirkka; Parent, Carole A.] NCI, Lab Cellular & Mol Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Liu, Song; Omatsu, Tatsushi; Reinecker, Hans-Christian] Massachusetts Gen Hosp, Dept Gastroenterol, Boston, MA 02114 USA. RP Lammers, KM (reprint author), Massachusetts Gen Hosp, Dept Pediat, Mucosal Immunol & Biol Res Ctr, Charlestown, MA 02129 USA. EM klammers@mgh.harvard.edu RI Casolaro, Vincenzo/E-9144-2010; OI Casolaro, Vincenzo/0000-0001-9810-0488; Chieppa, Marcello/0000-0001-9819-0823 FU National Institutes of Health [DK-078699, DK-48373, DK068181, AI113333, DK033506, DK043351, MFAG 10684]; Center for Cancer Research, NCI, NIH; Associazione Italiana per la Ricerca sul Cancro FX This research was supported in part by the National Institutes of Health Grants DK-078699 and DK-48373 to AF, DK068181, AI113333, DK033506 and DK043351 to HCR, MFAG 10684 (AIRC) to MC, and the Intramural Research Program of the Center for Cancer Research, NCI, NIH to CAP. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 2 Z9 2 U1 1 U2 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 SEP 17 PY 2015 VL 10 IS 9 AR e0138338 DI 10.1371/journal.pone.0138338 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CS0RH UT WOS:000361769400084 PM 26378785 ER PT J AU Elsarraj, HS Hong, Y Valdez, KE Michaels, W Hook, M Smith, WP Chien, J Herschkowitz, JI Troester, MA Beck, M Inciardi, M Gatewood, J May, L Cusick, T McGinness, M Ricci, L Fan, F Tawfik, O Marks, JR Knapp, JR Yeh, HW Thomas, P Carrasco, DR Fields, TA Godwin, AK Behbod, F AF Elsarraj, Hanan S. Hong, Yan Valdez, Kelli E. Michaels, Whitney Hook, Marcus Smith, William P. Chien, Jeremy Herschkowitz, Jason I. Troester, Melissa A. Beck, Moriah Inciardi, Marc Gatewood, Jason May, Lisa Cusick, Therese McGinness, Marilee Ricci, Lawrence Fan, Fang Tawfik, Ossama Marks, Jeffrey R. Knapp, Jennifer R. Yeh, Hung-Wen Thomas, Patricia Carrasco, D. R. Fields, Timothy A. Godwin, Andrew K. Behbod, Fariba TI Expression profiling of in vivo ductal carcinoma in situ progression models identified B cell lymphoma-9 as a molecular driver of breast cancer invasion SO BREAST CANCER RESEARCH LA English DT Article ID WNT SIGNALING PATHWAY; CANDIDATE GENES; RNA-SEQ; ACTIVATION; MARKERS; COMPLEX; TARGET; COLON; NOTCH; DCIS AB Introduction: There are an estimated 60,000 new cases of ductal carcinoma in situ (DCIS) each year. A lack of understanding in DCIS pathobiology has led to overtreatment of more than half of patients. We profiled the temporal molecular changes during DCIS transition to invasive ductal carcinoma (IDC) using in vivo DCIS progression models. These studies identified B cell lymphoma-9 (BCL9) as a potential molecular driver of early invasion. BCL9 is a newly found co-activator of Wnt-stimulated beta-catenin-mediated transcription. BCL9 has been shown to promote progression of multiple myeloma and colon carcinoma. However BCL9 role in breast cancer had not been previously recognized. Methods: Microarray and RNA sequencing were utilized to characterize the sequential changes in mRNA expression during DCIS invasive transition. BCL9-shRNA knockdown was performed to assess the role of BCL9 in in vivo invasion, epithelial-mesenchymal transition (EMT) and canonical Wnt-signaling. Immunofluorescence of 28 patient samples was used to assess a correlation between the expression of BCL9 and biomarkers of high risk DCIS. The cancer genome atlas data were analyzed to assess the status of BCL9 gene alterations in breast cancers. Results: Analysis of BCL9, by RNA and protein showed BCL9 up-regulation to be associated with DCIS transition to IDC. Analysis of patient DCIS revealed a significant correlation between high nuclear BCL9 and pathologic characteristics associated with DCIS recurrence: Estrogen receptor (ER) and progesterone receptor (PR) negative, high nuclear grade, and high human epidermal growth factor receptor2 (HER2). In vivo silencing of BCL9 resulted in the inhibition of DCIS invasion and reversal of EMT. Analysis of the TCGA data showed BCL9 to be altered in 26 % of breast cancers. This is a significant alteration when compared to HER2 (ERBB2) gene (19 %) and estrogen receptor (ESR1) gene (8 %). A significantly higher proportion of basal like invasive breast cancers compared to luminal breast cancers showed BCL9 amplification. Conclusion: BCL9 is a molecular driver of DCIS invasive progression and may predispose to the development of basal like invasive breast cancers. As such, BCL9 has the potential to serve as a biomarker of high risk DCIS and as a therapeutic target for prevention of IDC. C1 [Elsarraj, Hanan S.; Hong, Yan; Valdez, Kelli E.; Fan, Fang; Tawfik, Ossama; Thomas, Patricia; Fields, Timothy A.; Godwin, Andrew K.; Behbod, Fariba] Univ Kansas, Med Ctr, Dept Pathol, Kansas City, KS 66160 USA. [Michaels, Whitney; Hook, Marcus] Univ Kansas, Med Ctr, Sch Med, Kansas City, KS 66160 USA. [Smith, William P.; Inciardi, Marc; Gatewood, Jason] Univ Kansas, Med Ctr, Dept Radiol, Kansas City, KS 66160 USA. [Chien, Jeremy] Univ Kansas, Med Ctr, Dept Canc Biol, Kansas City, KS 66160 USA. [Herschkowitz, Jason I.] SUNY Albany, Dept Biomed Sci, Rensselaer, NY 12144 USA. [Troester, Melissa A.] Univ N Carolina, Sch Publ Hlth, Chapel Hill, NC 27599 USA. [Beck, Moriah] Wichita State Univ, Dept Chem, Wichita, KS 67260 USA. [May, Lisa; Cusick, Therese] Univ Kansas, Sch Med, Wichita, KS 67214 USA. [McGinness, Marilee] Univ Kansas, Med Ctr, Dept Med, Kansas City, KS 66160 USA. [Ricci, Lawrence] Univ Missouri, Truman Med Ctr, Dept Radiol, Kansas City, MO 64108 USA. [Marks, Jeffrey R.] Duke Univ, Dept Surg, Durham, NC 27710 USA. [Yeh, Hung-Wen] Univ Kansas, Med Ctr, Dept Biostat, Kansas City, KS 66160 USA. [Knapp, Jennifer R.] Univ Kansas, Med Ctr, Kansas Intellectual & Dev Disabil Res Ctr, Kansas City, KS 66160 USA. [Carrasco, D. R.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pathol, Boston, MA 02115 USA. RP Behbod, F (reprint author), Univ Kansas, Med Ctr, Dept Pathol, 3901 Rainbow Blvd,Mail Stop 3003, Kansas City, KS 66160 USA. EM fbehbod@kumc.edu OI Knapp, Jennifer R./0000-0003-4342-5378; Chien, Jeremy/0000-0003-4744-8374 FU Breast Cancer Research Foundation-AACR; NIH/NCI [1R21CA185460-01]; Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health [P20 GM103418]; NCI Early Detection Research Network [U01 CA084955, U01CA113916]; Komen Foundation [BCTR0603000]; University of Kansas Cancer Center [P30 CA168524]; Chancellors Distinguished Chair in Biomedical Sciences Professorship; Libyan-North American Scholarship program; Kansas University-School of Medicine; Smith Intellectual and Developmental Disabilities Research Center [HD02528]; K-INBRE Bioinformatics Core, NIH [P20 RR016475] FX This study was supported in part by grants from 2014 Breast Cancer Research Foundation-AACR, NIH/NCI 1R21CA185460-01 and Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health P20 GM103418 (FB); by the NCI Early Detection Research Network (U01 CA084955 to JRM and U01CA113916 to AKG), and by the Komen Foundation (BCTR0603000) to TAF. The authors also acknowledge support from The University of Kansas Cancer Center (P30 CA168524). AKG was funded by the Chancellors Distinguished Chair in Biomedical Sciences Professorship. HE was supported by the Libyan-North American Scholarship program. We would like to acknowledge the University of Kansas Cancer Center Biospecimen Repository Core Facility staff for helping obtain human specimens. We thank the Kansas University Medical Center-Genomics Core for generating the array and sequencing data sets. The Genomics Core is supported by the Kansas University-School of Medicine and the Smith Intellectual and Developmental Disabilities Research Center (HD02528). Data analysis is supported by the K-INBRE Bioinformatics Core, NIH grant number P20 RR016475. NR 41 TC 4 Z9 5 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-542X EI 1465-5411 J9 BREAST CANCER RES JI Breast Cancer Res. PD SEP 17 PY 2015 VL 17 AR 128 DI 10.1186/s13058-015-0630-z PG 21 WC Oncology SC Oncology GA CR4EF UT WOS:000361283900002 PM 26384318 ER PT J AU Chen, P Guven, S Usta, OB Yarmush, ML Demirci, U AF Chen, Pu Gueven, Sinan Usta, Osman Berk Yarmush, Martin L. Demirci, Utkan TI Biotunable Acoustic Node Assembly of Organoids SO ADVANCED HEALTHCARE MATERIALS LA English DT Article ID FARADAY WAVES; REGENERATIVE MEDICINE; MICROSCALE HYDROGELS; BONE REGENERATION; HEPATOCYTES; CHALLENGES; PATTERNS; LIVER; FILMS C1 [Chen, Pu; Gueven, Sinan; Demirci, Utkan] Stanford Univ, Bioacoust MEMS Med BAMM Lab, Canary Ctr Stanford Early Canc Detect, Dept Radiol,Sch Med, Palo Alto, CA 94304 USA. [Usta, Osman Berk; Yarmush, Martin L.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Engn Med, Boston, MA 02114 USA. [Usta, Osman Berk; Yarmush, Martin L.] Shriners Hosp Children, Boston, MA 02114 USA. [Yarmush, Martin L.] Rutgers State Univ, Dept Biomed Engn, Piscataway, NJ 08854 USA. RP Demirci, U (reprint author), Stanford Univ, Bioacoust MEMS Med BAMM Lab, Canary Ctr Stanford Early Canc Detect, Dept Radiol,Sch Med, Palo Alto, CA 94304 USA. EM utkan@stanford.edu RI Chen, Pu/B-9795-2011 OI Chen, Pu/0000-0002-6857-2211 FU NIH [R21-HL112114, 1R01EB015776, R15HL115556, 4UH3TR000503-03, 2P41EB002503-11, NS069375]; National Science Foundation under NSF [1150733]; Shrine Fellowship from Shriners Hospitals for Children [84202] FX P.C. and S.G. contributed equally to this work. The authors would like to acknowledge NIH R21-HL112114, 1R01EB015776, R15HL115556, 4UH3TR000503-03, and 2P41EB002503-11. This material is based in part upon work supported by the National Science Foundation under NSF CAREER Award No. 1150733 and Shrine Fellowship #84202 (for O.B.U.) from the Shriners Hospitals for Children. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation. Authors acknowledge Stanford Neuroscience Microscopy Service facility, which is supported by NIH NS069375. U.D. is a founder of, and has an equity interest in: i) DxNow Inc., a company that is developing microfluidic and imaging technologies for point-of-care diagnostic solutions, and ii) Koek Biotech, a company that is developing microfluidic IVF technologies for clinical solutions. U.D.'s interests were viewed and managed by the Brigham and Women's Hospital and Partners HealthCare in accordance with their conflict-of-interest policies. Correspondence and requests for materials should be addressed to U.D. NR 38 TC 5 Z9 5 U1 3 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2192-2640 EI 2192-2659 J9 ADV HEALTHC MATER JI Adv. Healthc. Mater. PD SEP 16 PY 2015 VL 4 IS 13 BP 1937 EP 1943 DI 10.1002/adhm.201500279 PG 7 WC Engineering, Biomedical; Nanoscience & Nanotechnology; Materials Science, Biomaterials SC Engineering; Science & Technology - Other Topics; Materials Science GA DA4EG UT WOS:000367752300003 PM 26149464 ER PT J AU Si, Y Kim, S Cui, XQ Zheng, L Oh, SJ Anderson, T AlSharabati, M Kazamel, M Volpicelli-Daley, L Bamman, MM Yu, SH King, PH AF Si, Ying Kim, Soojin Cui, Xiangqin Zheng, Lei Oh, Shin J. Anderson, Tina AlSharabati, Mohammad Kazamel, Mohamed Volpicelli-Daley, Laura Bamman, Marcas M. Yu, Shaohua King, Peter H. TI Transforming Growth Factor Beta (TGF-beta) Is a Muscle Biomarker of Disease Progression in ALS and Correlates with Smad Expression SO PLOS ONE LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; SKELETAL-MUSCLE; TRANSCRIPTION FACTORS; SIGNALING PATHWAY; MOTONEURONS; REGENERATION; ACTIVATION; CELLS; BONE; MASS AB We recently identified Smads1, 5 and 8 as muscle biomarkers in human ALS. In the ALS mouse, these markers are elevated and track disease progression. Smads are signal transducers and become activated upon receptor engagement of ligands from the TGF-beta superfamily. Here, we sought to characterize ligands linked to activation of Smads in ALS muscle and their role as biomarkers of disease progression. RNA sequencing data of ALS muscle samples were mined for TGF-beta superfamily ligands. Candidate targets were validated by qRT-PCR in a large cohort of human ALS muscle biopsy samples and in the G93A SOD1 mouse. Protein expression was evaluated by Western blot, ELISA and immunohistochemistry. C2C12 muscle cells were used to assess Smad activation and induction. TGF-beta 1, 2 and 3 mRNAs were increased in ALS muscle samples compared to controls and correlated with muscle strength and Smads1, 2, 5 and 8. In the G93A SOD1 mouse, the temporal pattern of TGF-beta expression paralleled the Smads and increased with disease progression. TGF-beta 1 immunoreactivity was detected in mononuclear cells surrounding muscle fibers in ALS samples. In muscle cells, TGF-beta ligands were capable of activating Smads. In conclusion, TGF-beta 1, 2 and 3 are novel biomarkers of ALS in skeletal muscle. Their correlation with weakness in human ALS and their progressive increase with advancing disease in the ALS mouse suggest that they, as with the Smads, can track disease progression. These ligands are capable of upregulating and activating Smads and thus may contribute to the Smad signaling pathway in ALS muscle. C1 [Si, Ying; Kim, Soojin; Zheng, Lei; Oh, Shin J.; Anderson, Tina; AlSharabati, Mohammad; Kazamel, Mohamed; Volpicelli-Daley, Laura; King, Peter H.] Univ Alabama Birmingham, Dept Neurol, Birmingham, AL 35294 USA. [Si, Ying; Zheng, Lei; King, Peter H.] Birmingham VA Med Ctr, Birmingham, AL USA. [Cui, Xiangqin; Yu, Shaohua] Univ Alabama Birmingham, Dept Biostat, Birmingham, AL 35294 USA. [Bamman, Marcas M.; King, Peter H.] Univ Alabama Birmingham, Dept Cell Dev & Integrat Biol, Birmingham, AL USA. [King, Peter H.] Univ Alabama Birmingham, Dept Genet, Birmingham, AL USA. RP King, PH (reprint author), Univ Alabama Birmingham, Dept Neurol, UAB Stn, Birmingham, AL 35294 USA. EM phking@uabmc.edu OI Cui, Xiangqin/0000-0003-0621-9313 FU United States Department of Veterans Affairs Biomedical Laboratory Research and Development Program Merit Review [BX001148]; National Institute of Neurological Disorders [NS064133, R21NS081743, R21NS085497]; National Center for Medical Rehabilitation Research [R01HD084124] FX Funded by the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Program Merit Review BX001148 (http://www.research.va.gov/services/blrd/), National Institute of Neurological Disorders NS064133, R21NS081743, R21NS085497 (http://www.ninds.nih.gov/), and National Center for Medical Rehabilitation Research R01HD084124 (https://www.nichd.nih.gov/about/org/ncmrr/Pages/overview.aspx). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 38 TC 1 Z9 2 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 SEP 16 PY 2015 VL 10 IS 9 AR e0138425 DI 10.1371/journal.pone.0138425 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CR8NH UT WOS:000361610200106 PM 26375954 ER PT J AU Garay, CD Dreyfuss, JM Galagan, JE AF Garay, Christopher D. Dreyfuss, Jonathan M. Galagan, James E. TI Metabolic modeling predicts metabolite changes in Mycobacterium tuberculosis SO BMC SYSTEMS BIOLOGY LA English DT Article ID DRUG-RESISTANT TUBERCULOSIS; FLUX-BALANCE ANALYSIS; CONSTRAINT-BASED ANALYSIS; ESCHERICHIA-COLI; HYPOXIC RESPONSE; CHOLESTEROL-METABOLISM; TRANSCRIPTION FACTOR; 2-COMPONENT SYSTEM; REGULATORY NETWORK; FATTY-ACIDS AB Background: Mycobacterium tuberculosis (MTB) is the causal agent of the disease tuberculosis (TB). Metabolic adaptations are thought to be critical to the survival of MTB during pathogenesis. Computational tools that can be used to study MTB metabolism in silico and prioritize resource-intensive experimental work could significantly accelerate research. Results: We have developed E-Flux-MFC, an enhancement of our original E-Flux method that enables the prediction of changes in the production of external and internal metabolites corresponding to gene expression measurements. We have used this method to simulate the changes in the metabolic state of Mycobacterium tuberculosis (MTB). We have validated the accuracy of E-Flux-MFC for predicting changes in lipids and metabolites during a hypoxia time course using previously published metabolomics and transcriptomics data. We have further validated the accuracy of the method for predicting changes in MTB lipids following the deletion and induction of two well-studied transcription factors (TFs). We have applied the method to predict the metabolic impact of the induction of each of the approximately 180 MTB TFs using a previously generated and publically available expression data set. Conclusions: E-flux-MFC can be used to study global changes in MTB metabolites from gene expression data associated with environmental and genetic perturbations. The application of this method to a data set of MTB TF perturbations provides a resource for studying the large number of TFs whose functions remain unknown. Most TFs impact metabolites indirectly through the propagation of gene expression changes through the regulatory network rather than through their direct regulons. E-Flux-MFC is also applicable to any organism for which accurate metabolic models are available. C1 [Garay, Christopher D.; Dreyfuss, Jonathan M.; Galagan, James E.] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. [Dreyfuss, Jonathan M.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Galagan, James E.] Boston Univ, Grad Program Bioinformat, Boston, MA 02215 USA. [Galagan, James E.] Natl Emerging Infect Dis Labs, Boston, MA 02118 USA. RP Galagan, JE (reprint author), Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. EM jgalag@bu.edu OI Dreyfuss, Jonathan/0000-0001-7242-3991 FU Federal funds from the National Institute of Allergy and Infectious Diseases National Institute of Health, Department of Health and Human Services [HHSN272200800059C] FX The authors gratefully acknowledge Jeremy Zucker, Matthew Peterson, Elham Azizi and Ed Reznik for help in discussing this project. This work was supported in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases National Institute of Health, Department of Health and Human Services, under Contract No. HHSN272200800059C. NR 112 TC 0 Z9 0 U1 1 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1752-0509 J9 BMC SYST BIOL JI BMC Syst. Biol. PD SEP 16 PY 2015 VL 9 AR 57 DI 10.1186/s12918-015-0206-7 PG 16 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA CR4EB UT WOS:000361283500002 PM 26377923 ER PT J AU Schendan, HE Ganis, G AF Schendan, Haline E. Ganis, Giorgio TI Top-down modulation of visual processing and knowledge after 250 ms supports object constancy of category decisions SO FRONTIERS IN PSYCHOLOGY LA English DT Article DE category decision; categorization; identification; recognition; object constancy; visual perception; event-related potentials; knowledge memory ID INFERIOR TEMPORAL CORTEX; EVENT-RELATED POTENTIALS; OSCILLATORY BRAIN ACTIVITY; PRIMATE PREFRONTAL CORTEX; HUMAN FACE PERCEPTION; NEUROPHYSIOLOGICAL EVIDENCE; SPATIOTEMPORAL DYNAMICS; RAPID CATEGORIZATION; NATURAL SCENES; RECOGNITION MEMORY AB People categorize objects more slowly when visual input is highly impoverished instead of optimal. While bottom-up models may explain a decision with optimal input, perceptual hypothesis testing (PHI) theories implicate top-down processes with impoverished input. Brain mechanisms and the time course of PHI are largely unknown. This event-related potential study used a neuroimaging paradigm that implicated prefrontal cortex in top down modulation of occipitotemporal cortex. Subjects categorized more impoverished and less impoverished real and pseudo objects. PHI theories predict larger impoverishment effects for real than pseudo objects because top-down processes modulate knowledge only for real objects, but different PHI variants predict different timing. Consistent with parietal prefrontal PHI variants, around 250 ms, the earliest impoverished real object interaction started on an N3 complex, which reflects interactive cortical activity for object cognition. N3 impoverishment effects localized to both prefrontal and occipitotemporal cortex for real objects only. The N3 also showed knowledge effects by 230 ms that localized to occipitotemporal cortex. Later effects reflected (a) word meaning in temporal cortex during the N400, (b) internal evaluation of prior decision and memory processes and secondary higher-order memory involving anterotemporal parts of a default mode network during posterior positivity (P600), and (c) response related activity in posterior cingulate during an anterior slow wave (SW) after 700 ms. Finally, response activity in supplementary motor area during a posterior SW after 900 ms showed impoverishment effects that correlated with RTs. Convergent evidence from studies of vision, memory, and mental imagery which reflects purely top-down inputs, indicates that the N3 reflects the critical top-down processes of PHI. A hybrid multiple-state interactive, PHI and decision theory best explains the visual constancy of object cognition. C1 [Schendan, Haline E.; Ganis, Giorgio] Univ Plymouth, Cognit Inst, Sch Psychol, Plymouth PL4 8AA, Devon, England. [Ganis, Giorgio] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Ganis, Giorgio] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. RP Schendan, HE (reprint author), Univ Plymouth, Sch Psychol, Plymouth PL4 8AA, Devon, England. EM halina.schendan@plymouth.aa.uk OI Ganis, Giorgio/0000-0001-6175-2618 FU Tufts University FX This project was completed in the School of Psychology at the University of Plymouth. Additional research support from Tufts University. HS and GG designed and set-up the experiment. HS assisted with testing and directed the plan for data acquisition and analyses, supervised data collection, analyzed some data, prepared tables and figures, and wrote the manuscript. GG contributed to manuscript preparation. Emily A. Slocombe (ES) collected the data. The authors are grateful to ES also for assisting with some data analyses, Emily Newman for assisting ES with analyses, and Lisa C. Lucia and Stephen M. Maher for assistance with data collection. NR 156 TC 2 Z9 2 U1 2 U2 11 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-1078 J9 FRONT PSYCHOL JI Front. Psychol. PD SEP 16 PY 2015 VL 6 AR 1289 DI 10.3389/fpsyg.2015.01289 PG 34 WC Psychology, Multidisciplinary SC Psychology GA CR7WB UT WOS:000361561400001 PM 26441701 ER PT J AU Lee, S Allendorfer, JB Gaston, TE Griffis, JC Hernando, KA Knowlton, RC Szaflarski, JP Hoef, LWV AF Lee, Seongtaek Allendorfer, Jane B. Gaston, Tyler E. Griffis, Joseph C. Hernando, Kathleen A. Knowlton, Robert C. Szaflarski, Jerzy P. Hoef, Lawrence W. Ver TI White matter diffusion abnormalities in patients with psychogenic non-epileptic seizures SO BRAIN RESEARCH LA English DT Article DE Psychogenic non-epileptic seizures (PNES); Diffusion tensor imaging (DTI); Tract-based spatial statistics (TBSS); Uncinate fasciculus (UF); Superior temporal gyrus (STG) ID UNCINATE FASCICULUS; FRACTIONAL ANISOTROPY; ICTAL SPECT; VIDEO-EEG; EPILEPSY; DISCONNECTION; CONNECTIVITY; DISSOCIATION; INTEGRITY; DIAGNOSIS AB The purpose of this study was to conduct a preliminary investigation of the white matter characteristics in patients with psychogenic non-epileptic seizures (PNES). Diffusion Tensor Imaging (DTI) data were collected at 3 T in 16 patients with PNES and 16 age- and sex-matched healthy controls (HC). All patients with PNES had their diagnosis confirmed via video/EEG monitoring; HCs had no comorbid neurological or psychiatric conditions. DTI indices including fractional anisotropy (FA), and mean diffusivity (MD) were calculated and compared between patients with PNES and HCs using Tract-Based Spatial Statistics (TBSS). Significantly higher FA values were observed in patients with PNES in the left corona radiata, left internal and external capsules, left superior temporal gyms, as well as left uncinate fasciculus (UP) (P < 0.05; corrected for multiple comparisons). There was no significant change in other indices between patients with PNES and HCs. These findings suggest that patients with PNES have significantly altered white matter structural connectivity when compared to age- and sex-matched HCs. These abnormalities are present in left hemispheric regions associated with emotion regulation and motor pathways. While the relationship between the pathophysiology of PNES and these abnormalities is not entirely clear, this work provides an initial basis to guide future prospective studies. (C) 2015 Elsevier B.V. All rights reserved. C1 [Lee, Seongtaek; Hoef, Lawrence W. Ver] Univ Alabama Birmingham, Dept Biomed Engn, Birmingham, AL 35294 USA. [Allendorfer, Jane B.; Gaston, Tyler E.; Szaflarski, Jerzy P.; Hoef, Lawrence W. Ver] Univ Alabama Birmingham, Dept Neurol, Birmingham, AL 35294 USA. [Griffis, Joseph C.] Univ Alabama Birmingham, Dept Psychol, Birmingham, AL 35294 USA. [Hernando, Kathleen A.] Univ Alabama Birmingham, Sch Publ Hlth, Birmingham, AL 35294 USA. [Knowlton, Robert C.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Hoef, Lawrence W. Ver] Birmingham VA Med Ctr, Neurol Serv, Birmingham, AL 35294 USA. RP Hoef, LWV (reprint author), Univ Alabama Birmingham, Dept Biomed Engn, Suite 312,1719 6th Ave South, Birmingham, AL 35294 USA. EM lverhoef@uab.edu OI Lee, Seongtaek/0000-0001-8954-6103 NR 49 TC 10 Z9 10 U1 2 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 EI 1872-6240 J9 BRAIN RES JI Brain Res. PD SEP 16 PY 2015 VL 1620 BP 169 EP 176 DI 10.1016/j.brainres.2015.04.050 PG 8 WC Neurosciences SC Neurosciences & Neurology GA CR2LZ UT WOS:000361162800014 PM 25979311 ER PT J AU Goldman, JG Weintraub, D AF Goldman, Jennifer G. Weintraub, Daniel TI Advances in the Treatment of Cognitive Impairment in Parkinson's Disease SO MOVEMENT DISORDERS LA English DT Review DE cholinesterase inhibitor; clinical trials; dementia; executive function; mild cognitive impairment ID TRANSCRANIAL MAGNETIC STIMULATION; RANDOMIZED CONTROLLED-TRIAL; DEEP BRAIN-STIMULATION; ALZHEIMERS ASSOCIATION WORKGROUPS; PLACEBO-CONTROLLED TRIAL; LONG-TERM SAFETY; PHASE-III TRIAL; LEWY BODIES; NEUROPSYCHIATRIC SYMPTOMS; DOUBLE-BLIND AB Cognitive impairment in Parkinson's disease (PD) is a frequent complication, with significant interindividual variability in clinical symptoms, severity, timing, and neural substrates. Recent studies have focused not only on understanding PD dementia, but also mild cognitive impairment in PD, which may represent a prodromal stage for dementia. In recent years, there have been important advances regarding clinical characterizations, definitions, associated biomarkers, and risk factors for both mild cognitive impairment in PD and PD dementia. However, there is a paucity of effective therapies for cognitive impairment in PD, whether for mild symptoms or for moderate to severe dementia. At present, only rivastigmine is U.S. Food and Drug Administration approved for PD dementia, an indication received nearly a decade ago. Given the frequency of PD cognitive impairment and its substantial impact on both patients and families, the lack of available and effective treatments represents a striking gap in the field, especially when compared to the large number of available therapies for PD motor symptoms and complications. Improved symptomatic therapies, as well as potential disease-modifying agents, for PD cognitive impairment are needed. Most therapeutic trials for PD dementia and mild cognitive impairment in PD have focused on drugs developed for and tested in Alzheimer's disease, such as cholinesterase inhibitors and the N-methyl-D-aspartate receptor antagonist, memantine, though recent and ongoing trials examine the effects of pharmacological agents affecting other neurotransmitters, as well as nonpharmacological therapies, including mental and physical exercise and neurostimulation. This review summarizes the design and outcomes of trials for PD cognitive impairment published since 2013 and highlights future therapeutic research opportunities and challenges. (c) 2015 International Parkinson and Movement Disorder Society C1 [Goldman, Jennifer G.] Rush Univ, Med Ctr, Dept Neurol Sci, Sect Parkinson Dis & Movement Disorders, Chicago, IL 60612 USA. [Weintraub, Daniel] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Weintraub, Daniel] Univ Penn, Dept Neurol, Philadelphia, PA 19104 USA. [Weintraub, Daniel] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. RP Goldman, JG (reprint author), Rush Univ, Med Ctr, Dept Neurol Sci, 1725 West Harrison St,Suite 755, Chicago, IL 60612 USA. EM Jennifer_Goldman@rush.edu NR 95 TC 10 Z9 12 U1 11 U2 28 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 EI 1531-8257 J9 MOVEMENT DISORD JI Mov. Disord. PD SEP 15 PY 2015 VL 30 IS 11 SI SI BP 1471 EP 1489 DI 10.1002/mds.26352 PG 19 WC Clinical Neurology SC Neurosciences & Neurology GA CW0AX UT WOS:000364652400005 PM 26297863 ER PT J AU Shoamanesh, A Yan, SQ Charidimou, A AF Shoamanesh, Ashkan Yan, Shenqiang Charidimou, Andreas TI New cerebral microbleeds and mechanism of post-thrombolysis remote intracerebral hemorrhage: "red meets white" revisited SO FRONTIERS IN NEUROLOGY LA English DT Editorial Material DE acute stroke; cerebral microbleeds; cerebral small vessel disease; cerebral amyloid angiopathy; intracerebral hemorrhage; thrombolysis ID METAANALYSIS; STROKE; RISK C1 [Shoamanesh, Ashkan] McMaster Univ, Populat Hlth Res Inst, Hamilton, ON, Canada. [Yan, Shenqiang] Zhejiang Univ, Affiliated Hosp 2, Sch Med, Dept Neurol, Hangzhou 310003, Zhejiang, Peoples R China. [Charidimou, Andreas] UCL Inst Neurol, London, England. [Charidimou, Andreas] Harvard Univ, Ctr Stroke Res, Massachusetts Gen Hosp, Sch Med,Hemorrhag Stroke Res Program,Dept Neurol, Boston, MA 02115 USA. RP Shoamanesh, A (reprint author), McMaster Univ, Populat Hlth Res Inst, Hamilton, ON, Canada. EM Ashkan.Shoamanesh@phri.ca; andreas.charidimou.09@ucl.ac.uk OI Yan, Shenqiang/0000-0001-6425-0672 NR 15 TC 3 Z9 3 U1 0 U2 1 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-2295 J9 FRONT NEUROL JI Front. Neurol. PD SEP 15 PY 2015 VL 6 AR 203 DI 10.3389/fneur.2015.00203 PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA CV0HO UT WOS:000363931400001 PM 26441822 ER PT J AU Haas, NB Manola, J Ky, B Flaherty, KT Uzzo, RG Kane, CJ Jewett, M Wood, L Wood, CG Atkins, MB Dutcher, JJ Wilding, G DiPaola, RS AF Haas, Naomi B. Manola, Judith Ky, Bonnie Flaherty, Keith T. Uzzo, Robert G. Kane, Christopher J. Jewett, Michael Wood, Lori Wood, Christopher G. Atkins, Michael B. Dutcher, Janice J. Wilding, George DiPaola, Robert S. TI Effects of Adjuvant Sorafenib and Sunitinib on Cardiac Function in Renal Cell Carcinoma Patients without Overt Metastases: Results from ASSURE, ECOG 2805 SO CLINICAL CANCER RESEARCH LA English DT Article ID BREAST-CANCER; HEART-FAILURE; DOUBLE-BLIND; TRASTUZUMAB; CARDIOTOXICITY; TRIAL; BEVACIZUMAB; CHEMOTHERAPY; INHIBITION; RISK AB Purpose: Sunitinib and sorafenib are used widely in the treatment of renal cell carcinoma (RCC). These agents are associated with a significant incidence of cardiovascular (CV) dysfunction and left ventricular ejection fraction (LVEF) declines, observed largely in the metastatic setting. However, in the adjuvant population, the CV effects of these agents remain unknown. We prospectively defined the incidence of cardiotoxicity among resected, high-risk RCC patients treated with these agents. Experimental Design: Sunitinib, sorafenib, or placebo was administered for up to 12 months in patients with high-risk, resected RCC. LVEF was measured by multigated acquisition (MUGA) scans at standard intervals. Additional CV adverse events were reported according to NCI Common Terminology Criteria for Adverse Events (CTCAE). Results: Among 1,943 patients randomized, 1,599 had at least 1 post-baseline MUGA. Within 6 months, 21 patients (1.3%) experienced a cardiac event, defined as an LVEF decline from baseline that was >15% and below the institutional lower limit of normal. Nine of 513 patients (1.8%) were on sunitinib, 7 of 508 (1.4%) on sorafenib, and 5 of 578 (0.9%) on placebo (P = 0.28 and 0.56 comparing sunitinib and sorafenib to placebo, respectively). With dose interruption or adjustment, 16 of the 21 recovered their LVEF to >50%. The incidence of symptomatic heart failure, arrhythmia, or myocardial ischemia did not differ among groups. Conclusions: In the adjuvant setting, we prospectively define low incidence of cardiotoxicity with sunitinib and sorafenib. These findings may be related to close CV monitoring, or potentially to fewer CV comorbidities in our nonmetastatic population. (C)2015 AACR. C1 [Haas, Naomi B.; Ky, Bonnie; Flaherty, Keith T.] Univ Penn, Philadelphia, PA 19104 USA. [Manola, Judith] Dana Farber Canc Inst, Boston, MA 02115 USA. [Uzzo, Robert G.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Kane, Christopher J.] Univ Calif San Diego, San Diego, CA 92103 USA. [Jewett, Michael] Univ Toronto, Toronto, ON, Canada. [Wood, Lori] Queen Elizabeth 2 Hlth Sci Ctr, Halifax, NS, Canada. [Wood, Lori] Dalhousie Univ, Halifax, NS, Canada. [Wood, Christopher G.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Atkins, Michael B.] Beth Israel Deaconess Med Ctr, Boston, MA USA. [Dutcher, Janice J.] New York Med Coll, Our Lady Mercy Canc Ctr, Bronx, NY USA. [Wilding, George] Univ Wisconsin, Carbone Canc Ctr, Madison, WI USA. [DiPaola, Robert S.] Rutgers Canc Inst New Jersey, New Brunswick, NJ USA. RP Haas, NB (reprint author), Univ Penn, 3400 Spruce St, Philadelphia, PA 19104 USA. EM Naomi.haas@uphs.upenn.edu FU Public Health Service Grants [CA180820, CA180794, CA180867, CA180821, CA31946, CA077202, CA180863, CCSRI021039, CA32102, CA105409]; National Cancer Institute, National Institutes of Health; Department of Health and Human Services; Pfizer FX This study was coordinated 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, CA180821, CA31946, CA077202, CA180863, CCSRI021039, CA32102, CA105409, and from the National Cancer Institute, National Institutes of Health, and the Department of Health and Human Services. Its content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute. The cardiac substudy was supported by Pfizer. NR 22 TC 7 Z9 7 U1 2 U2 3 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 SEP 15 PY 2015 VL 21 IS 18 BP 4048 EP 4054 DI 10.1158/1078-0432.CCR-15-0215 PG 7 WC Oncology SC Oncology GA CU2CN UT WOS:000363329900006 PM 25967143 ER PT J AU Benson, DM Cohen, AD Jagannath, S Munshi, NC Spitzer, G Hofmeister, CC Efebera, YA Andre, P Zerbib, R Caligiuri, MA AF Benson, Don M., Jr. Cohen, Adam D. Jagannath, Sundar Munshi, Nikhil C. Spitzer, Gary Hofmeister, Craig C. Efebera, Yvonne A. Andre, Pascale Zerbib, Robert Caligiuri, Michael A. TI A Phase I Trial of the Anti-KIR Antibody IPH2101 and Lenalidomide in Patients with Relapsed/Refractory Multiple Myeloma SO CLINICAL CANCER RESEARCH LA English DT Article ID NATURAL-KILLER-CELL; MONOCLONAL GAMMOPATHIES; PLUS DEXAMETHASONE; TUMOR-CELLS; BONE-MARROW; CYTOTOXICITY; ACTIVATION; RECEPTORS; THERAPY; ENHANCE AB Purpose: Natural killer (NK) cells may play an important role in the immune response to multiple myeloma; however, multiple myeloma cells express killer immunoglobulin-like receptor (KIR) ligands to prevent NK cell cytotoxicity. Lenalidomide can expand and activate NK cells in parallel with its direct effects against multiple myeloma; however, dexamethasone may impair these favorable immunomodulatory properties. IPH2101, a first-in-class antiinhibitory KIR antibody, has acceptable safety and tolerability in multiple myeloma as a single agent. The present work sought to characterize lenalidomide and IPH2101 as a novel, steroid-sparing, dual immune therapy for multiple myeloma. Experimental Design: A phase I trial enrolled 15 patients in three cohorts. Lenalidomide was administered per os at 10 mg on cohort 1 and 25 mg on cohorts 2 and 3 days 1 to 21 on a 28-day cycle with IPH2101 given intravenously on day 1 of each cycle at 0.2 mg/kg in cohort 1, 1 mg/kg in cohort 2, and 2 mg/kg in cohort 3. No corticosteroids were utilized. The primary endpoint was safety, and secondary endpoints included clinical activity, pharmacokinetics (PK), and pharmacodynamics (PD). Results: The biologic endpoint of full KIR occupancy was achieved across the IPH2101 dosing interval. PD and PK of IPH2101 with lenalidomide were similar to data from a prior single-agent IPH2101 trial. Five serious adverse events (SAE) were reported. Five objective responses occurred. No autoimmunity was seen. Conclusions: These findings suggest that lenalidomide in combination with antiinhibitory KIR therapy warrants further investigation in multiple myeloma as a steroid-sparing, dual immune therapy. (C)2015 AACR. C1 [Benson, Don M., Jr.; Hofmeister, Craig C.; Efebera, Yvonne A.; Caligiuri, Michael A.] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Cohen, Adam D.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Jagannath, Sundar] Mt Sinai Sch Med, New York, NY USA. [Munshi, Nikhil C.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Munshi, Nikhil C.] Harvard Univ, Sch Med, Boston VA Healthcare Syst, Boston, MA USA. [Spitzer, Gary] St Francis Hosp, Greenville, SC USA. [Andre, Pascale; Zerbib, Robert] Innate Pharma, Marseille, France. RP Benson, DM (reprint author), Ohio State Univ, Div Hematol, Ctr Comprehens Canc, B310 Starling Loving Hall,320 West 10th Ave, Columbus, OH 43210 USA. EM Don.benson@osumc.edu RI Hofmeister, Craig/E-3256-2011; Efebera, Yvonne/E-3012-2011 OI Hofmeister, Craig/0000-0003-4816-1607; FU National Cancer Institute [P01 CA095426] FX This study was supported by the National Cancer Institute grant P01 CA095426 (to D.M. Benson Jr and M.A. Caligiuri). NR 32 TC 22 Z9 23 U1 2 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 SEP 15 PY 2015 VL 21 IS 18 BP 4055 EP 4061 DI 10.1158/1078-0432.CCR-15-0304 PG 7 WC Oncology SC Oncology GA CU2CN UT WOS:000363329900007 PM 25999435 ER PT J AU Metelo, AM Noonan, H Iliopoulos, O AF Metelo, Ana Martins Noonan, Haley Iliopoulos, Othon TI HIF2a inhibitors for the treatment of VHL disease SO ONCOTARGET LA English DT Editorial Material DE hypoxia; VHL; HIF2a inhibitors; renal cancer ID CANCER; GENE C1 [Iliopoulos, Othon] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. [Iliopoulos, Othon] Harvard Univ, Sch Med, Charlestown, MA USA. RP Iliopoulos, O (reprint author), Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. EM oiliopoulos@partners.org FU NCI NIH HHS [R01 CA160458] NR 7 TC 3 Z9 3 U1 1 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 SEP 15 PY 2015 VL 6 IS 27 BP 23036 EP 23037 DI 10.18632/oncotarget.4564 PG 2 WC Oncology; Cell Biology SC Oncology; Cell Biology GA CT9SU UT WOS:000363157700001 PM 26325097 ER PT J AU Ecker, BL Paulson, EC Datta, J Jeganathan, AN Aarons, C Kelz, RR Mahmoud, NN AF Ecker, Brett L. Paulson, Emily C. Datta, Jashodeep Jeganathan, Arjun N. Aarons, Cary Kelz, Rachel R. Mahmoud, Najjia N. TI Lymph Node Identification Following Neoadjuvant Therapy in Rectal Cancer: A Stage-Stratified Analysis using the Surveillance, Epidemiology, and End Results (SEER)-Medicare Database SO JOURNAL OF SURGICAL ONCOLOGY LA English DT Article DE rectal cancer; lymph node staging; neoadjuvant therapy; survival; SEER ID PREOPERATIVE CHEMORADIOTHERAPY; COLORECTAL-CANCER; GASTRIC-CANCER; IMPACT; RADIOTHERAPY; SURVIVAL; RADIOCHEMOTHERAPY; CHEMOTHERAPY; GUIDELINES; RADIATION AB Background and Objectives: Neoadjuvant chemoradiation (nCRT) for rectal adenocarcinoma reduces lymph node (LN) identification following surgical resection. We sought to evaluate the relationship between LN identification following nCRT and disease-specific survival (DSS), stratified by pathologic stage. Methods: The SEER-Medicare database (2000-2009) was queried for 1,216 pathologic stage I-III rectal cancer patients who underwent nCRT followed by curative-intent resection. Cox regressions evaluated the association between pathologic stage and DSS for LN cut-points from >= 2 up to >= 12 LNs. Results: Extent of LN identification did not influence DSS in ypStage I or ypStage III disease; in particular, the 12 LN cut-point was not associated with DSS for ypStage I (HR 1.29, P = 0.51) or ypStage III (HR 1.08, P = 0.42) patients. In ypStage II patients, actuarial survival improved continually with increasing lymph node identification up to >= 12 LNs. The 5 LN cut-point was associated with the greatest reduction of risk of cancer death (HR 0.56, P = 0.006), with decreasing magnitudes of survival benefit associated with nodal counts beyond 5 LN. The 12 LN cut-point was not associated with DSS in ypStage II patients (HR 0.67, P = 0.07). Conclusion: The association between DSS and LN identification is a dynamic outcome that varies by pathologic stage, with unique prognostic significance for ypStage II patients. (c) 2015 Wiley Periodicals, Inc. C1 [Ecker, Brett L.; Paulson, Emily C.; Datta, Jashodeep; Jeganathan, Arjun N.; Aarons, Cary; Kelz, Rachel R.; Mahmoud, Najjia N.] Univ Penn, Dept Surg, Philadelphia, PA 19104 USA. [Paulson, Emily C.] Vet Affairs Med Ctr, Dept Surg, Philadelphia, PA USA. RP Mahmoud, NN (reprint author), Hosp Univ Penn, 3400 Spruce St,4 Silverstein, Philadelphia, PA 19104 USA. EM Najjia.Mahmoud@uphs.upenn.edu NR 24 TC 1 Z9 1 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-4790 EI 1096-9098 J9 J SURG ONCOL JI J. Surg. Oncol. PD SEP 15 PY 2015 VL 112 IS 4 BP 415 EP 420 DI 10.1002/jso.23991 PG 6 WC Oncology; Surgery SC Oncology; Surgery GA CT2VN UT WOS:000362662900014 PM 26250884 ER PT J AU Aydogan, F Mallory, MA Tukenmez, M Sagara, Y Ozturk, E Ince, Y Celik, V Akca, T Golshan, M AF Aydogan, Fatih Mallory, Melissa Anne Tukenmez, Mustafa Sagara, Yasuaki Ozturk, Erkan Ince, Yavuz Celik, Varol Akca, Tamer Golshan, Mehra TI A Low Cost Training Phantom Model for Radio-Guided Localization Techniques in Occult Breast Lesions SO JOURNAL OF SURGICAL ONCOLOGY LA English DT Article DE breast; radio-guided localization; training; phantom model ID WIRE LOCALIZATION; CANCER; BIOPSY; ROLL; METAANALYSIS; SIMULATOR; SURGERY AB Radio-guided localization (RGL) for identifying occult breast lesions has been widely accepted as an alternative technique to other localization methods, including those using wire guidance. An appropriate phantom model would be an invaluable tool for practitioners interested in learning the technique of RGL prior to clinical application. The aim of this study was to devise an inexpensive and reproducible training phantom model for RGL. We developed a simple RGL phantom model imitating an occult breast lesion from inexpensive supplies including a pimento olive, a green pea and a turkey breast. The phantom was constructed for a total cost of less than $20 and prepared in approximately 10 min. After the first model's construction, we constructed approximately 25 additional models and demonstrated that the model design was easily reproducible. The RGL phantom is a time-and cost-effective model that accurately simulates the RGL technique for non-palpable breast lesions. Future studies are warranted to further validate this model as an effective teaching tool. (c) 2015 Wiley Periodicals, Inc. C1 [Aydogan, Fatih; Mallory, Melissa Anne; Tukenmez, Mustafa; Sagara, Yasuaki; Golshan, Mehra] Harvard Univ, Sch Med, Dana Farber Brigham & Womens Hosp, Womens Canc Ctr, Boston, MA 02215 USA. [Aydogan, Fatih; Celik, Varol] Istanbul Univ, Cerrahpasa Med Sch, Dept Surg, Breast Div, Istanbul, Turkey. [Tukenmez, Mustafa] Istanbul Univ, Istanbul Med Sch, Dept Surg, Istanbul, Turkey. [Ozturk, Erkan] Gulhane Mil Med Acad, Dept Surg, Ankara, Turkey. [Ozturk, Erkan] Sch Med, Ankara, Turkey. [Ince, Yavuz] Koc Med Sch, Istanbul, Turkey. [Akca, Tamer] Mersin Univ, Fac Med, Dept Gen Surg, Mersin, Turkey. RP Aydogan, F (reprint author), Harvard Univ, Sch Med, Dana Farber Brigham & Womens Hosp, Womens Canc Ctr, 450 Brookline Ave,Yawkey 1441, Boston, MA 02215 USA. EM faydoganmd@gmail.com FU NIH [R25CA089017]; Turkish Anti-Cancer Foundation FX Grant sponsor: NIH; Grant number: R25CA089017; Grant sponsor: Turkish Anti-Cancer Foundation. NR 19 TC 2 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-4790 EI 1096-9098 J9 J SURG ONCOL JI J. Surg. Oncol. PD SEP 15 PY 2015 VL 112 IS 4 BP 449 EP 451 DI 10.1002/jso.23984 PG 3 WC Oncology; Surgery SC Oncology; Surgery GA CT2VN UT WOS:000362662900020 PM 26250621 ER PT J AU Ye, SQ Cheng, B Lip, GYH Buchsbaum, R Sacco, RL Levin, B Di Tullio, MR Qian, M Mann, DL Pullicino, PM Freudenberger, RS Teerlink, JR Mohr, JP Graham, S Labovitz, AJ Estol, CJ Lok, DJ Ponikowski, P Anker, SD Thompson, JLP Homma, S AF Ye, Siqin Cheng, Bin Lip, Gregory Y. H. Buchsbaum, Richard Sacco, Ralph L. Levin, Bruce Di Tullio, Marco R. Qian, Mm Mann, Douglas L. Pullicino, Patrick M. Freudenberger, Ronald S. Teerlink, John R. Mohr, J. P. Graham, Susan Labovitz, Arthur J. Estol, Conrado J. Lok, Dirk J. Ponikowski, Piotr Anker, Stefan D. Thompson, John L. P. Homma, Shunichi CA WARCEF Investigators TI Bleeding Risk and Antithrombotic Strategy in Patients With Sinus Rhythm and Heart Failure With Reduced Ejection Fraction Treated With Warfarin or Aspirin SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID ATRIAL-FIBRILLATION; ANTICOAGULATED PATIENTS; SUBGROUP ANALYSIS; SCORES; TRIAL; RECLASSIFICATION; CHA(2)DS(2)-VASC; PERFORMANCE; HEMORRHAGE; CHADS(2) AB We sought to assess the performance of existing bleeding risk scores, such as the Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly (HAS-BLED) score or the Outpatient Bleeding Risk Index (OBRI), in patients with heart failure with reduced ejection fraction (HFrEF) in sinus rhythm (SR) treated with warfarin or aspirin. We calculated HAS-BLED and OBRI risk scores for 2,305 patients with HFrEF in SR enrolled in the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction trial. Proportional hazards models were used to test whether each score predicted major bleeding, and comparison of different risk scores was performed using Harell C-statistic and net reclassification improvement index. For the warfarin arm, both scores predicted bleeding risk, with OBRI having significantly greater C-statistic (0.72 vs 0.61; p = 0.03) compared to HAS-BLED, although the net reclassification improvement for comparing OBRI to HAS-BLED was not significant (0.32, 95% confidence interval [CI] -0.18 to 0.37). Performance of the OBRI and HAS-BLED risk scores was similar for (the aspirin arm. For participants with OBRI scores of 0 to 1, warfarin compared with aspirin reduced ischemic stroke (hazard ratio [HR] 0.51, 95% CI 0.26 to 0.98, p = 0.042) without significantly increasing major bleeding (HR 1.24, 95% CI 0.66 to 2.30, p = 0.51). For those with OBRI score of there was a trend for reduced ischemic stroke with warfarin compared to aspirin (HR 0.56, 95% CI 0.27 to 1.15, p = 0.12),"but major bleeding was increased (HR 4.04, 95% CI 1.99 to 8.22, p <0.001). In conclusion, existing bleeding risk, scores can identify bleeding risk in patients with HFrEF in SR and could be tested for potentially identifying patients with a favorable risk/benefit profile for antithrombotic therapy with warfarin. (C) 2015 Elsevier Inc. All rights reserved. C1 [Ye, Siqin; Di Tullio, Marco R.; Homma, Shunichi] Columbia Univ, Dept Med, Med Ctr, Div Cardiol, New York, NY 10027 USA. [Mohr, J. P.] Columbia Univ, Dept Neurol, Med Ctr, New York, NY USA. [Cheng, Bin; Buchsbaum, Richard; Levin, Bruce; Qian, Mm; Thompson, John L. P.] Columbia Univ, Mailman Sch Publ Hlth, Dept Biostat, New York, NY USA. [Lip, Gregory Y. H.] Univ Birmingham, City Hosp, Ctr Cardiovasc Sci, Birmingham, W Midlands, England. [Sacco, Ralph L.] Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA. [Mann, Douglas L.] Washington Univ, Dept Med, St Louis, MO USA. [Pullicino, Patrick M.] Univ Kent, Kent Inst Med & Hlth Sci, Canterbury, Kent, England. [Freudenberger, Ronald S.] Lehigh Valley Hosp, Dept Med, Div Cardiol, Allentown, PA USA. [Teerlink, John R.] San Francisco VA Med Ctr, Cardiol Sect, San Francisco, CA USA. [Teerlink, John R.] Univ Calif San Francisco, Sch Med, San Francisco, CA USA. [Graham, Susan] SUNY Upstate Med Univ, Dept Med, Div Cardiol, Buffalo, NY USA. [Labovitz, Arthur J.] Univ S Florida, Dept Cardiovasc Med, Tampa, FL USA. [Estol, Conrado J.] Ctr Neurol Tratamiento & Rehabil, Buenos Aires, DF, Argentina. [Lok, Dirk J.] Deventer Hosp, Dept Cardiol, Deventer, Netherlands. [Ponikowski, Piotr] Wroclaw Med Univ, Mil Hosp, Dept Heart Dis, Wroclaw, Poland. [Anker, Stefan D.] Univ Med Ctr Gottingen, Dept Innovat Clin Trials, Gottingen, Germany. RP Ye, SQ (reprint author), Columbia Univ, Dept Med, Med Ctr, Div Cardiol, New York, NY 10027 USA. EM sy2357@cumc.columbia.edu RI Ponikowski, Piotr/O-6454-2015; OI Ponikowski, Piotr/0000-0002-3391-7064; Ye, Siqin/0000-0002-5229-9775 FU National Institute of Neurological Diseases and Stroke [U01-NS-043975, U01-NS-039143] FX The WARCEF trial was supported by Grant U01-NS-043975 (SH) and U01-NS-039143 (JLPT) from the National Institute of Neurological Diseases and Stroke. Warfarin and warfarin placebo were provided by Taro Pharmaceuticals USA, and aspirin and aspirin placebo by Bayer HealthCare. NR 23 TC 4 Z9 4 U1 1 U2 13 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 SEP 15 PY 2015 VL 116 IS 6 BP 904 EP 912 DI 10.1016/j.amjcard.2015.06.016 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CR8ZU UT WOS:000361643800013 PM 26189039 ER PT J AU Pierre, JF Neuman, JC Brill, AL Brar, HK Thompson, MF Cadena, MT Connors, KM Busch, RA Heneghan, AF Cham, CM Jones, EK Kibbe, CR Davis, DB Groblewski, GE Kudsk, KA Kimple, ME AF Pierre, Joseph F. Neuman, Joshua C. Brill, Allison L. Brar, Harpreet K. Thompson, Mary F. Cadena, Mark T. Connors, Kelsey M. Busch, Rebecca A. Heneghan, Aaron F. Cham, Candace M. Jones, Elaina K. Kibbe, Carly R. Davis, Dawn B. Groblewski, Guy E. Kudsk, Kenneth A. Kimple, Michelle E. TI The gastrin-releasing peptide analog bombesin preserves exocrine and endocrine pancreas morphology and function during parenteral nutrition SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE bombesin; gut hormones; pancreas; parenteral nutrition; adjuvant therapy ID DIGESTIVE ENZYME EXPRESSION; PROTEIN-COUPLED RECEPTORS; GLUCAGON-LIKE PEPTIDE-1; GLUCOSE-INTOLERANCE; INSULIN-SECRETION; LYMPHOID-TISSUE; ACINAR-CELLS; RAT PANCREAS; AMINO-ACIDS; BETA-CELLS AB Stimulation of digestive organs by enteric peptides is lost during total parental nutrition (PN). Here we examine the role of the enteric peptide bombesin (BBS) in stimulation of the exocrine and endocrine pancreas during PN. BBS protects against exocrine pancreas atrophy and dysfunction caused by PN. BBS also augments circulating insulin levels, suggesting an endocrine pancreas phenotype. While no significant changes in gross endocrine pancreas morphology were observed, pancreatic islets isolated from BBS-treated PN mice showed a significantly enhanced insulin secretion response to the glucagon-like peptide-1 (GLP-1) agonist exendin-4, correlating with enhanced GLP-1 receptor expression. BBS itself had no effect on islet function, as reflected in low expression of BBS receptors in islet samples. Intestinal BBS receptor expression was enhanced in PN with BBS, and circulating active GLP-1 levels were significantly enhanced in BBS-treated PN mice. We hypothesized that BBS preserved islet function indirectly, through the enteroendocrine cell-pancreas axis. We confirmed the ability of BBS to directly stimulate intestinal enteroid cells to express the GLP-1 precursor preproglucagon. In conclusion, BBS preserves the exocrine and endocrine pancreas functions during PN; however, the endocrine stimulation is likely indirect, through the enteroendocrine cell-pancreas axis. C1 [Davis, Dawn B.; Kudsk, Kenneth A.; Kimple, Michelle E.] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. [Pierre, Joseph F.; Busch, Rebecca A.; Heneghan, Aaron F.; Kudsk, Kenneth A.] Univ Wisconsin, Dept Surg, Sch Med & Publ Hlth, Madison, WI USA. [Brill, Allison L.; Brar, Harpreet K.; Thompson, Mary F.; Cadena, Mark T.; Connors, Kelsey M.; Kibbe, Carly R.; Davis, Dawn B.; Kimple, Michelle E.] Univ Wisconsin, Dept Med, Sch Med & Publ Hlth, Div Endocrinol, Madison, WI USA. [Neuman, Joshua C.; Jones, Elaina K.; Davis, Dawn B.; Groblewski, Guy E.; Kimple, Michelle E.] Univ Wisconsin, Coll Agr & Life Sci, Interdisciplinary Grad Program Nutr Sci, Madison, WI 53706 USA. [Pierre, Joseph F.; Cham, Candace M.] Univ Chicago, Dept Med, Div Gastroenterol Hepatol & Nutr, Chicago, IL 60637 USA. RP Kimple, ME (reprint author), 4148 UW Med Fdn Centennial Bldg,1685 Highland Ave, Madison, WI 53705 USA. EM mkimple@medicine.wisc.edu OI Brill, Allison/0000-0002-5046-3578 FU Biomedical Laboratory Research and Development Service of the VA Office of Research and Development Award [I01BX001672]; American Diabetes Association [1-14-BS-115]; National Institutes of Health (NIH) [DK-102598, DK-070888]; Wisconsin Partnership Program Grant; US Department of Agriculture/HATCH [WIS01583]; University of Chicago Training Grant in Digestive Diseases and Nutrition (NIH) [T32 DK-007074]; University of Wisconsin Institute on Aging (NIH) [T32 AG-000213]; University of Wisconsin Surgical Oncology Research Training Program (NIH) [T32 CA-090217] FX This research is supported by Biomedical Laboratory Research and Development Service of the VA Office of Research and Development Award I01BX001672 (to K. A. Kudsk) and also by American Diabetes Association Grant 1-14-BS-115 (to M. E. Kimple), National Institutes of Health (NIH) Grant DK-102598 (to M. E. Kudsk), a Wisconsin Partnership Program Grant (to D. B. Davis), NIH Grant DK-070888 (to G. E. Groblewski), and US Department of Agriculture/HATCH Grant WIS01583 (to G. E. Groblewski). J. F. Pierre is supported in part by a University of Chicago Training Grant in Digestive Diseases and Nutrition (NIH Grant T32 DK-007074). J. C. Neuman and C. R. Kibbe are supported in part by a training grant from the University of Wisconsin Institute on Aging (NIH Grant T32 AG-000213). R. A. Busch is supported in part by a training grant from the University of Wisconsin Surgical Oncology Research Training Program (NIH Grant T32 CA-090217). NR 63 TC 1 Z9 1 U1 0 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1857 EI 1522-1547 J9 AM J PHYSIOL-GASTR L JI Am. J. Physiol.-Gastroint. Liver Physiol. PD SEP 15 PY 2015 VL 309 IS 6 BP G431 EP G442 DI 10.1152/ajpgi.00072.2015 PG 12 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA CS1IO UT WOS:000361817700004 PM 26185331 ER PT J AU Hwang, VJ Kim, J Rand, A Yang, CZ Sturdivant, S Hammock, B Bell, PD Guay-Woodford, LM Weiss, RH AF Hwang, Vicki J. Kim, Jeffrey Rand, Amy Yang, Chaozhe Sturdivant, Steve Hammock, Bruce Bell, P. Darwin Guay-Woodford, Lisa M. Weiss, Robert H. TI The cpk model of recessive PKD shows glutamine dependence associated with the production of the oncometabolite 2-hydroxyglutarate SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE ARPKD; glutamine; metabolomics; oncometabolite; reprogramming ID POLYCYSTIC KIDNEY-DISEASE; REDUCTIVE CARBOXYLATION; ALPHA-KETOGLUTARATE; IDH2 MUTATIONS; CANCER; CELLS; METABOLISM; D-2-HYDROXYGLUTARATE; HYPOXIA; GROWTH AB Since polycystic kidney disease (PKD) was first noted over 30 years ago to have neoplastic parallels, there has been a resurgent interest in elucidating neoplasia-relevant pathways in PKD. Taking a nontargeted metabolomics approach in the B6(Cg)-Cys1(cpk/)J (cpk) mouse model of recessive PKD, we have now characterized metabolic reprogramming in these tissues, leading to a glutamine-dependent TCA cycle shunt toward total 2-hydroxyglutarate (2-HG) production in cpk compared with B6 wild-type kidney tissue. After confirmation of increased 2-HG expression in immortalized collecting duct cpk cells as well as in human autosomal recessive PKD tissue using targeted analysis, we show that the increase in 2-HG is likely due to glutamine-sourced alpha-ketoglutarate. In addition, cpk cells require exogenous glutamine for growth such that inhibition of glutaminase-1 decreases cell viability as well as proliferation. This study is a demonstration of the striking parallels between recessive PKD and cancer metabolism. Our data, once confirmed in other PKD models, suggest that future therapeutic approaches targeting this pathway, such as using glutaminase inhibitors, have the potential to open novel treatment options for renal cystic disease. C1 [Hwang, Vicki J.; Weiss, Robert H.] Univ Calif Davis, Grad Grp Integrat Genet & Genom, Davis, CA 95616 USA. [Hwang, Vicki J.; Kim, Jeffrey; Weiss, Robert H.] Univ Calif Davis, Dept Internal Med, Div Nephrol, Davis, CA 95616 USA. [Rand, Amy; Hammock, Bruce] Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA. [Hammock, Bruce; Weiss, Robert H.] Univ Calif Davis, Ctr Canc, Davis, CA 95616 USA. [Yang, Chaozhe; Guay-Woodford, Lisa M.] Childrens Natl Hlth Syst, Ctr Translat Sci, Washington, DC USA. [Sturdivant, Steve] Metabolon, Durham, NC USA. [Bell, P. Darwin] Med Univ S Carolina, Dept Med, Div Nephrol, Charleston, SC 29425 USA. [Bell, P. Darwin] Ralph Johnson Vet Affairs Med Ctr, Charleston, SC USA. [Weiss, Robert H.] Sacramento Vet Affairs Med Ctr, Med Serv, Sacramento, CA USA. RP Weiss, RH (reprint author), Univ Calif Davis, Dept Internal Med, Div Nephrol, Genome & Biomed Sci Bldg,Rm 6312,451 Hlth Sci Dr, Davis, CA 95616 USA. EM rhweiss@ucdavis.edu FU National Institutes of Health (NIH) [1R01CA135401-01A1, 1R03CA181837-01, 1R01DK082690-01A1]; Medical Service of the US Department of Veterans Affairs, and Dialysis Clinics; NIEHS [R01 ES002710, P42 ES004699]; UAB Hepato-Renal Fibrocystic Diseases Core Center [P30 DK074038] FX This work was supported by National Institutes of Health (NIH) Grants 1R01CA135401-01A1, 1R03CA181837-01, and 1R01DK082690-01A1, the Medical Service of the US Department of Veterans Affairs, and Dialysis Clinics (all to R. H. Weiss). Partial support was provided by NIEHS R01 ES002710 and NIEHS Superfund Program P42 ES004699 (to. B. D. Hammock), and the UAB Hepato-Renal Fibrocystic Diseases Core Center, P30 DK074038 (to L. Guay-Woodford and P. D. Bell). A. Rand is a fellow of NIH/NIEHS T32 CA108459. NR 34 TC 3 Z9 3 U1 2 U2 7 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X EI 1522-1466 J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD SEP 15 PY 2015 VL 309 IS 6 BP F492 EP F498 DI 10.1152/ajprenal.00238.2015 PG 7 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA CS1KD UT WOS:000361822100003 PM 26155843 ER PT J AU Takaya, S Kuperberg, GR Liu, HS Greve, DN Makris, N Stufflebeam, SM AF Takaya, Shigetoshi Kuperberg, Gina R. Liu, Hesheng Greve, Douglas N. Makris, Nikos Stufflebeam, Steven M. TI Asymmetric projections of the arcuate fasciculus to the temporal cortex underlie lateralized language function in the human brain SO FRONTIERS IN NEUROANATOMY LA English DT Article DE language pathway; cortical projection; structure-function; surface-based; structural connectivity; functional connectivity; MRI; semantic decision ID PROBABILISTIC DIFFUSION TRACTOGRAPHY; SURFACE-BASED ANALYSIS; CORTICAL SURFACE; LOBE EPILEPSY; RESTING BRAIN; CONNECTIVITY; PATHWAYS; ORGANIZATION; NETWORK; MRI AB The arcuate fasciculus (AF) in the human brain has asymmetric structural properties. However, the topographic organization of the asymmetric AF projections to the cortex and its relevance to cortical function remain unclear. Here we mapped the posterior projections of the human AF in the inferior parietal and lateral temporal cortices using surface-based structural connectivity analysis based on diffusion MRI and investigated their hemispheric differences. We then performed the cross-modal comparison with functional connectivity based on resting state functional MRI (fMRI) and task related cortical activation based on fMRI using a semantic classification task of single words. Structural connectivity analysis showed that the left AF connecting to Broca's area predominantly projected in the lateral temporal cortex extending from the posterior superior temporal gyms to the mid part of the superior temporal sulcus and the middle temporal gyms, whereas the right AF connecting to the right homolog of Broca's area predominantly projected to the inferior parietal cortex extending from the mid part of the supramarginal gyrus to the anterior part of the angular gyms. The left-lateralized projection regions of the AF in the left temporal cortex had asymmetric functional connectivity with Broca's area, indicating structure-function concordance through the AF. During the language task, left-lateralized cortical activation was observed. Among them, the brain responses in the temporal cortex and Broca's area that were connected through the left-lateralized AF pathway were specifically correlated across subjects. These results suggest that the human left AF, which structurally and functionally connects the mid temporal cortex and Broca's area in asymmetrical fashion, coordinates the cortical activity in these remote cortices during a semantic decision task. The unique feature of the left AF is discussed in the context of the human capacity for language. C1 [Takaya, Shigetoshi; Kuperberg, Gina R.; Liu, Hesheng; Greve, Douglas N.; Makris, Nikos; Stufflebeam, Steven M.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Takaya, Shigetoshi; Kuperberg, Gina R.; Liu, Hesheng; Greve, Douglas N.; Makris, Nikos; Stufflebeam, Steven M.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Kuperberg, Gina R.] Tufts Univ, Dept Psychol, Medford, MA 02155 USA. [Stufflebeam, Steven M.] Harvard Massachusetts Inst Technol, Div Hlth Sci & Technol, Cambridge, MA USA. RP Takaya, S (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, 149 Thirteenth St, Charlestown, MA 02129 USA. EM shige@nmr.mgh.harvard.edu FU National Institute of Health [R01NS069696, R41EB015896, S10ODRR031599, S10RR021110]; National Science Foundation [NPS-DMS-1042134]; Hehara Memorial Foundation; SNMMI (Wagner-Torizuka Fellowship); department of energy [DE-SC0008430] FX This work was supported by grants from the National Institute of Health (R01NS069696, R41EB015896, S100DRR031599, S10RR021110) and National Science Foundation grant (NPS-DMS-1042134). This study was also partly supported by fellowships from the Hehara Memorial Foundation, the SNMMI (Wagner-Torizuka Fellowship) and a grant from the department of energy (DE-SC0008430). NR 68 TC 2 Z9 2 U1 5 U2 10 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5129 J9 FRONT NEUROANAT JI Front. Neuroanat. PD SEP 15 PY 2015 VL 9 AR 119 DI 10.3389/fnana.2015.00119 PG 12 WC Anatomy & Morphology; Neurosciences SC Anatomy & Morphology; Neurosciences & Neurology GA CR8XA UT WOS:000361636400001 PM 26441551 ER PT J AU Hodkinson, DJ Veggeberg, R Wilcox, SL Scrivani, S Burstein, R Becerra, L Borsook, D AF Hodkinson, Duncan J. Veggeberg, Rosanna Wilcox, Sophie L. Scrivani, Steven Burstein, Rami Becerra, Lino Borsook, David TI Primary Somatosensory Cortices Contain Altered Patterns of Regional Cerebral Blood Flow in the Interictal Phase of Migraine SO PLOS ONE LA English DT Article ID HUMAN BRAIN; ARTERIAL; CORTEX; ALLODYNIA; PAIN; PATHOPHYSIOLOGY; QUESTIONNAIRE; SENSITIZATION; POPULATION; MECHANISMS AB The regulation of cerebral blood flow (CBF) is a complex integrated process that is critical for supporting healthy brain function. Studies have demonstrated a high incidence of alterations in CBF in patients suffering from migraine with and without aura during different phases of attacks. However, the CBF data collected interictally has failed to show any distinguishing features or clues as to the underlying pathophysiology of the disease. In this study we used the magnetic resonance imaging (MRI) technique-arterial spin labeling (ASL)-to non-invasively and quantitatively measure regional CBF (rCBF) in a case-controlled study of interictal migraine. We examined both the regional and global CBF differences between the groups, and found a significant increase in rCBF in the primary somatosensory cortex (S1) of migraine patients. The CBF values in S1 were positively correlated with the headache attack frequency, but were unrelated to the duration of illness or age of the patients. Additionally, 82% of patients reported skin hypersensitivity (cutaneous allodynia) during migraine, suggesting atypical processing of somatosensory stimuli. Our results demonstrate the presence of a disease-specific functional deficit in a known region of the trigemino-cortical pathway, which may be driven by adaptive or maladaptive functional plasticity. These findings may in part explain the altered sensory experiences reported between migraine attacks. C1 [Hodkinson, Duncan J.; Veggeberg, Rosanna; Wilcox, Sophie L.; Scrivani, Steven; Becerra, Lino; Borsook, David] Harvard Univ, Sch Med, Boston Childrens Hosp, Ctr Pain & Brain,Dept Anesthesiol Perioperat & Pa, Boston, MA 02163 USA. [Scrivani, Steven] Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Boston, MA 02114 USA. [Burstein, Rami] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Anesthesia & Crit Care, Boston, MA 02215 USA. [Becerra, Lino; Borsook, David] Harvard Univ, Sch Med, Dept Psychiat, McLean Hosp, Boston, MA 02115 USA. RP Hodkinson, DJ (reprint author), Harvard Univ, Sch Med, Boston Childrens Hosp, Ctr Pain & Brain,Dept Anesthesiol Perioperat & Pa, Boston, MA 02163 USA. EM duncan.hodkinson@childrens.harvard.edu FU National Institutes of Health [RO1 NS073977, K24 NS064050] FX This study was funded by National Institutes of Health (RO1 NS073977 and K24 NS064050). NR 59 TC 2 Z9 2 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 SEP 15 PY 2015 VL 10 IS 9 AR e0137971 DI 10.1371/journal.pone.0137971 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CR8LR UT WOS:000361604400042 PM 26372461 ER PT J AU Smith, D Aherrera, A Lopez, A Neptune, E Winickoff, JP Klein, JD Chen, G Lazarus, P Collaco, JM McGrath-Morrow, SA AF Smith, Dani Aherrera, Angela Lopez, Armando Neptune, Enid Winickoff, Jonathan P. Klein, Jonathan D. Chen, Gang Lazarus, Philip Collaco, Joseph M. McGrath-Morrow, Sharon A. TI Adult Behavior in Male Mice Exposed to E-Cigarette Nicotine Vapors during Late Prenatal and Early Postnatal Life SO PLOS ONE LA English DT Article ID C57BL/6J MICE; SMOKE EXPOSURE; TERATOGENICITY; HYPERACTIVITY; PERFORMANCE; COTININE; ANXIETY; BRAIN; RISK; TIME AB Nicotine exposure has been associated with an increased likelihood of developing attention deficit hyperactivity disorder (ADHD) in offspring of mothers who smoked during pregnancy. The goal of this study was to determine if exposure to E-cigarette nicotine vapors during late prenatal and early postnatal life altered behavior in adult mice. Methods Timed-pregnant C57BL/6J mice were exposed to 2.4% nicotine in propylene glycol (PG) or 0% nicotine/PG once a day from gestational day 15 until delivery. After delivery, offspring and mothers were exposed to E-cigarette vapors for an additional 14 days from postnatal day 2 through 16. Following their last exposure serum cotinine levels were measured in female juvenile mice. Male mice underwent behavioral testing at 14 weeks of age to assess sensorimotor, affective, and cognitive functional domains. Results Adult male mice exposed to 2.4% nicotine/PG E-cigarette vapors had significantly more head dips in the zero maze test and higher levels of rearing activity in the open field test compared to 0% nicotine/ PG exposed mice and untreated controls. In the water maze test after reversal training, the 2.4% nicotine/ PG mice spent more than 25% of time in the new location whereas the other groups did not. Conclusion Adult male mice exhibited increased levels of activity in the zero maze and open field tests when exposed to E-cigarette vapor containing nicotine during late prenatal and early postnatal life. These findings indicate that nicotine exposure from E-cigarettes may cause persistent behavioral changes when exposure occurs during a period of rapid brain growth. C1 [Smith, Dani] Johns Hopkins Univ, Dept Psychol & Brain Sci, Neurogenet & Behav Ctr, Baltimore, MD USA. [Aherrera, Angela; Lopez, Armando; Collaco, Joseph M.; McGrath-Morrow, Sharon A.] Johns Hopkins Univ, Sch Med, Eudowood Div Pediat Resp Sci, Baltimore, MD 21218 USA. [Lopez, Armando; Neptune, Enid] Johns Hopkins Med Inst, Dept Med, Div Pulm & Crit Care Med, Baltimore, MD 21205 USA. [Winickoff, Jonathan P.; Klein, Jonathan D.; Collaco, Joseph M.; McGrath-Morrow, Sharon A.] Amer Acad Pediat, Julius B Richmond Ctr Excellence, Elk Grove Village, IL USA. [Winickoff, Jonathan P.] Massachusetts Gen Hosp, Div Gen Pediat, Boston, MA 02114 USA. [Winickoff, Jonathan P.] Harvard Univ, Sch Med, Boston, MA USA. [Chen, Gang; Lazarus, Philip] Washington State Univ, Dept Pharmacol, Pullman, WA 99164 USA. RP McGrath-Morrow, SA (reprint author), Johns Hopkins Univ, Sch Med, Eudowood Div Pediat Resp Sci, Baltimore, MD 21218 USA. EM smcgrath@jhmi.edu FU Flight Attendant Medical Research Institute; National Institutes of Health, NIH [RHL114800A] FX This work was funded by a Center of Excellence Grant to the American Academy of Pediatrics from the Flight Attendant Medical Research Institute (SAM, JMC, JDK, JPW); and National Institutes of Health, NIH RHL114800A (SAM). NR 29 TC 8 Z9 8 U1 2 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 15 PY 2015 VL 10 IS 9 AR e0137953 DI 10.1371/journal.pone.0137953 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CR8LR UT WOS:000361604400038 PM 26372012 ER PT J AU Lu, FK Basu, S Igras, V Hoang, MP Ji, MB Fu, D Holtom, GR Neel, VA Freudiger, CW Fisher, DE Xie, XS AF Lu, Fa-Ke Basu, Srinjan Igras, Vivien Hoang, Mai P. Ji, Minbiao Fu, Dan Holtom, Gary R. Neel, Victor A. Freudiger, Christian W. Fisher, David E. Xie, X. Sunney TI Label-free DNA imaging in vivo with stimulated Raman scattering microscopy SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE stimulated Raman scattering microscopy; skin cancer; label-free histology; cell division; mitotic rate ID NONMELANOMA SKIN-CANCER; SQUAMOUS-CELL CARCINOMA; LIVING CELLS; WAVELENGTH SELECTION; TUMOR XENOGRAFTS; MOUSE SKIN; SPECTROSCOPY; PROTEIN; MICE; MICROSPECTROSCOPY AB Label-free DNA imaging is highly desirable in biology and medicine to perform live imaging without affecting cell function and to obtain instant histological tissue examination during surgical procedures. Here we show a label-free DNA imaging method with stimulated Raman scattering (SRS) microscopy for visualization of the cell nuclei in live animals and intact fresh human tissues with subcellular resolution. Relying on the distinct Raman spectral features of the carbon-hydrogen bonds in DNA, the distribution of DNA is retrieved from the strong background of proteins and lipids by linear decomposition of SRS images at three optimally selected Raman shifts. Based on changes on DNA condensation in the nucleus, we were able to capture chromosome dynamics during cell division both in vitro and in vivo. We tracked mouse skin cell proliferation, induced by drug treatment, through in vivo counting of the mitotic rate. Furthermore, we demonstrated a label-free histology method for human skin cancer diagnosis that provides comparable results to other conventional tissue staining methods such as H&E. Our approach exhibits higher sensitivity than SRS imaging of DNA in the fingerprint spectral region. Compared with spontaneous Raman imaging of DNA, our approach is three orders of magnitude faster, allowing both chromatin dynamic studies and label-free optical histology in real time. C1 [Lu, Fa-Ke; Ji, Minbiao; Fu, Dan; Holtom, Gary R.; Freudiger, Christian W.; Xie, X. Sunney] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. [Basu, Srinjan] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. [Igras, Vivien; Fisher, David E.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cutaneous Biol Res Ctr,Dept Dermatol, Charlestown, MA 02129 USA. [Hoang, Mai P.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Neel, Victor A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. RP Fisher, DE (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cutaneous Biol Res Ctr,Dept Dermatol, Charlestown, MA 02129 USA. EM dfisher3@mgh.harvard.edu; xie@chemistry.harvard.edu RI Ji, Minbiao/C-7793-2011; Basu, Srinjan/M-7835-2016 OI Ji, Minbiao/0000-0002-9066-4008; Basu, Srinjan/0000-0002-1080-979X FU US Department of Energy's Basic Energy Sciences Program [DE-FG02-09ER16104]; National Institutes of Health (NIH) [1R01EB010244-01]; Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; NIH [P01 CA163222, R01 AR043369, R21 CA175907] FX We thank Dr. X. Ni, Dr. X. Zhang, and Dr. J. Yong for help on the animal experiments; W. Yang for technical assistance on the photo detector; Dr. L. Sang, Dr. L. Kong, Dr. A. J. Golby, and Dr. N. Y. Agar for helpful discussions; and Dr. D. Lando and Dr. P. Purcell for critical reading and editing of the manuscript. This work was supported by grants to X.S.X. from the US Department of Energy's Basic Energy Sciences Program(DE-FG02-09ER16104) and National Institutes of Health (NIH) T-R01 (1R01EB010244-01) and to D.E.F. from the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation and the NIH (P01 CA163222, R01 AR043369, and R21 CA175907). NR 60 TC 21 Z9 21 U1 22 U2 67 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 15 PY 2015 VL 112 IS 37 BP 11624 EP 11629 DI 10.1073/pnas.1515121112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CR5OW UT WOS:000361393700058 PM 26324899 ER PT J AU Suhara, T Hishiki, T Kasahara, M Hayakawa, N Oyaizu, T Nakanishi, T Kubo, A Morisaki, H Kaelin, WG Suematsu, M Minamishima, YA AF Suhara, Tomohiro Hishiki, Takako Kasahara, Masataka Hayakawa, Noriyo Oyaizu, Tomoko Nakanishi, Tsuyoshi Kubo, Akiko Morisaki, Hiroshi Kaelin, William G., Jr. Suematsu, Makoto Minamishima, Yoji Andrew TI Inhibition of the oxygen sensor PHD2 in the liver improves survival in lactic acidosis by activating the Cori cycle SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE hypoxic response; PHD inhibitor; hyperlactatemia; gluconeogenesis; sepsis ID MYOCARDIAL-INFARCTION; SEPTIC SHOCK; HYPOXIA; METABOLISM; LACTATE; INACTIVATION; DISEASE; FAMILY; MOUSE; HIF AB Loss of prolyl hydroxylase 2 (PHD2) activates the hypoxia-inducible factor-dependent hypoxic response, including anaerobic glycolysis, which causes large amounts of lactate to be released from cells into the circulation. We found that Phd2-null mouse embryonic fibroblasts (MEFs) produced more lactate than wild-type MEFs, as expected, whereas systemic inactivation of PHD2 in mice did not cause hyper-lacticacidemia. This unexpected observation led us to hypothesize that the hypoxic response activated in the liver enhances the Cori cycle, a lactate-glucose carbon recycling system between muscle and liver, and thereby decreases circulating lactate. Consistent with this hypothesis, blood lactate levels measured after a treadmill or lactate tolerance test were significantly lower in Phd2-liver-specific knockout (Phd2-LKO) mice than in control mice. An in vivo C-13-labeled lactate incorporation assay revealed that the livers of Phd2-LKO mice produce significantly more glucose derived from C-13-labeled lactate than control mice, suggesting that blockade of PHD2 in the liver ameliorates lactic acidosis by activating gluconeogenesis from lactate. Phd2-LKO mice were resistant to lactic acidosis induced by injection of a lethal dose of lactate, displaying a significant elongation of survival. Moreover, oral administration of a PHD inhibitor improved survival in an endotoxin shock mice model. These data suggest that PHD2 is a potentially novel drug target for the treatment of lactic acidosis, which is a serious and often fatal complication observed in some critically ill patients. C1 [Suhara, Tomohiro; Hishiki, Takako; Kasahara, Masataka; Hayakawa, Noriyo; Oyaizu, Tomoko; Nakanishi, Tsuyoshi; Kubo, Akiko; Suematsu, Makoto; Minamishima, Yoji Andrew] Keio Univ, Sch Med, Dept Biochem, Tokyo 1608582, Japan. [Suhara, Tomohiro; Oyaizu, Tomoko; Morisaki, Hiroshi] Keio Univ, Sch Med, Dept Anesthesiol, Tokyo 1608582, Japan. [Hishiki, Takako; Hayakawa, Noriyo] Keio Univ, Sch Med, Translat Res Ctr, Tokyo 1608582, Japan. [Hishiki, Takako; Hayakawa, Noriyo; Nakanishi, Tsuyoshi; Suematsu, Makoto; Minamishima, Yoji Andrew] Japan Sci & Technol Agcy, Exploratory Res Adv Technol, Suematsu Gas Biol Project, Core Res Evolut Sci & Technol, Tokyo 1608582, Japan. [Hishiki, Takako] Japan Sci & Technol Agcy, Core Res Evolut Sci & Technol, Tokyo 1608582, Japan. [Kasahara, Masataka] Tokyo Dent Coll, Dept Pharmacol, Tokyo 1010061, Japan. [Nakanishi, Tsuyoshi] Shimadzu Co Ltd, MS Business Unit, Kyoto 6048511, Japan. [Kaelin, William G., Jr.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Kaelin, William G., Jr.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA 02215 USA. [Kaelin, William G., Jr.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Kaelin, WG (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. EM william_kaelin@dfci.harvard.edu; gasbiology@keio.jp; yoji_andrew_minamishima@keio.jp RI Suematsu, Makoto/I-8135-2013; Minamishima, Yoji/E-5380-2010 OI Suematsu, Makoto/0000-0002-7165-6336; Minamishima, Yoji/0000-0001-7995-9318 FU Ministry of Education, Culture, Sports, Science and Technology, Japan [23310136, 23659175, 20593966, 24659154, 26111006]; Takeda Science Foundation, Japan FX This study was supported in part by Grants-in-Aid for Scientific Research (B) (23310136 to Y.A.M.), Grant-in-Aid for Exploratory Research (23659175 and 20593966 to Y.A.M., and 24659154 to M.K.), Grant-in-Aid for Scientific Research on Innovative Areas "Oxygen Biology: a new criterion for integrated understanding of life" (26111006 to Y.A.M.) from the Ministry of Education, Culture, Sports, Science and Technology, Japan, and a research grant from Takeda Science Foundation, Japan (to Y.A.M.). M.S. was a leader of the Japan Science and Technology Agency, Exploratory Research for Advanced Technology, Suematsu Gas Biology Project until March 31, 2015. LC/MS-based metabolome analysis was supported by Biobank Japan Project in the Ministry of Education, Culture, Sports, Science and Technology, Japan, under the supervision of T.H., and capillary electrophoresis-mass spectrometry (CE/MS)-based metabolome analysis was supported by the Japan Science and Technology Agency, Core Research for Evolutional Science and Technology, under the supervision of T.H. and Dr. Yasuaki Kabe. NR 33 TC 5 Z9 5 U1 2 U2 11 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 SEP 15 PY 2015 VL 112 IS 37 BP 11642 EP 11647 DI 10.1073/pnas.1515872112 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CR5OW UT WOS:000361393700061 PM 26324945 ER PT J AU Soeda, T Uemura, S Park, SJ Jang, Y Lee, S Cho, JM Kim, SJ Vergallo, R Minami, Y Ong, DS Gao, L Lee, H Zhang, SS Yu, B Saito, Y Jang, IK AF Soeda, Tsunenari Uemura, Shiro Park, Seung-Jung Jang, Yangsoo Lee, Stephen Cho, Jin-Man Kim, Soo-Joong Vergallo, Rocco Minami, Yoshiyasu Ong, Daniel S. Gao, Lei Lee, Hang Zhang, Shaosong Yu, Bo Saito, Yoshihiko Jang, Ik-Kyung TI Incidence and Clinical Significance of Poststent Optical Coherence Tomography Findings One-Year Follow-Up Study From a Multicenter Registry SO CIRCULATION LA English DT Article DE diagnostic imaging; optical coherence tomography; stents ID ELUTING STENT IMPLANTATION; INTRAVASCULAR ULTRASOUND ANALYSIS; MYOCARDIAL-INFARCTION; NATURAL-HISTORY; TISSUE PROLAPSE; HUMAN AUTOPSY; PREDICTORS; RESTENOSIS; PLAQUE; INTERVENTION AB Background Optical coherence tomography (OCT) was recently introduced to optimize percutaneous coronary intervention. However, the exact incidence and significance of poststent OCT findings are unknown. Methods and Results A total of 900 lesions treated with 1001 stents in 786 patients who had postprocedure OCT imaging were analyzed to evaluate the incidence of poststent OCT findings and to identify the OCT predictors for device-oriented clinical end points, including cardiac death, target vessel-related myocardial infarction, target lesion revascularization, and stent thrombosis. Patients were followed up to 1 year. Stent edge dissection was detected in 28.7% of lesions, and incomplete stent apposition was detected in 39.1% of lesions. The incidences of smooth protrusion, disrupted fibrous tissue protrusion, and irregular protrusion were 92.9%, 61.0%, and 53.8%, respectively. Small minimal stent area, defined as a lesion with minimal stent area <5.0 mm(2) in a drug-eluting stent or <5.6 mm(2) in a bare metal stent, was observed in 40.4% of lesions. One-year device-oriented clinical end points occurred in 33 patients (4.5%). Following adjustment, irregular protrusion and small minimal stent area were independent OCT predictors of 1-year device-oriented clinical end points (P=0.003 and P=0.012, respectively). Conclusions Abnormal poststent OCT findings were frequent. Irregular protrusion and small minimal stent area were independent predictors of 1-year device-oriented clinical end points, which were primarily driven by target lesion revascularization. C1 [Soeda, Tsunenari; Vergallo, Rocco; Minami, Yoshiyasu; Ong, Daniel S.; Gao, Lei; Jang, Ik-Kyung] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Soeda, Tsunenari; Uemura, Shiro; Saito, Yoshihiko] Nara Med Univ, Dept Med 1, Kashihara, Nara 634, Japan. [Park, Seung-Jung] Univ Ulsan, Coll Med, Asan Med Ctr, Div Cardiol, Seoul, South Korea. [Jang, Yangsoo] Yonsei Univ, Coll Med, Severance Cardiovasc Hosp, Seoul, South Korea. [Lee, Stephen] Univ Hong Kong, Queen Mary Hosp, Hong Kong, Hong Kong, Peoples R China. [Cho, Jin-Man; Kim, Soo-Joong; Jang, Ik-Kyung] Kyung Hee Univ, Div Cardiol, Seoul, South Korea. [Lee, Hang] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Biostat Ctr, Boston, MA USA. [Zhang, Shaosong; Yu, Bo] Harbin Med Univ, Chinese Minist Educ, Key Lab Myocardial Ischemia, Dept Cardiol,Affiliated Hosp 2, Harbin, Peoples R China. RP Jang, IK (reprint author), Massachusetts Gen Hosp, Div Cardiol, GRB 800,55 Fruit St, Boston, MA 02114 USA. EM yubodr@163.com; ijang@mgh.harvard.edu FU Mr and Mrs Michael Park and Dr John Nam Research Fellowship; Italian Society of Cardiology Award for Research Abroad FX This study was supported by a Mr and Mrs Michael Park and Dr John Nam Research Fellowship grant. Dr Vergallo was funded in part by the 2013 Italian Society of Cardiology Award for Research Abroad. NR 33 TC 11 Z9 12 U1 0 U2 6 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 SEP 15 PY 2015 VL 132 IS 11 BP 1020 EP 1029 DI 10.1161/CIRCULATIONAHA.114.014704 PG 10 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA CR4HW UT WOS:000361293800007 PM 26162917 ER PT J AU Zhang, CA Doherty, JA Burgess, S Hung, RJ Lindstrom, S Kraft, P Gong, J Amos, CI Sellers, TA Monteiro, ANA Chenevix-Trench, G Bickeboller, H Risch, A Brennan, P Mckay, JD Houlston, RS Landi, MT Timofeeva, MN Wang, YF Heinrich, J Kote-Jarai, Z Eeles, RA Muir, K Wiklund, F Gronberg, H Berndt, SI Chanock, SJ Schumacher, F Haiman, CA Henderson, BE Al Olama, AA Andrulis, IL Hopper, JL Chang-Claude, J John, EM Malone, KE Gammon, MD Ursin, G Whittemore, AS Hunter, DJ Gruber, SB Knight, JA Hou, LF Le Marchand, L Newcomb, PA Hudson, TJ Chan, AT Li, L Woods, MO Ahsan, H Pierce, BL AF Zhang, Chenan Doherty, Jennifer A. Burgess, Stephen Hung, Rayjean J. Lindstroem, Sara Kraft, Peter Gong, Jian Amos, Christopher I. Sellers, Thomas A. Monteiro, Alvaro N. A. Chenevix-Trench, Georgia Bickeboeller, Heike Risch, Angela Brennan, Paul Mckay, James D. Houlston, Richard S. Landi, Maria Teresa Timofeeva, Maria N. Wang, Yufei Heinrich, Joachim Kote-Jarai, Zsofia Eeles, Rosalind A. Muir, Ken Wiklund, Fredrik Gronberg, Henrik Berndt, Sonja I. Chanock, Stephen J. Schumacher, Fredrick Haiman, Christopher A. Henderson, Brian E. Al Olama, Ali Amin Andrulis, Irene L. Hopper, John L. Chang-Claude, Jenny John, Esther M. Malone, Kathleen E. Gammon, Marilie D. Ursin, Giske Whittemore, Alice S. Hunter, David J. Gruber, Stephen B. Knight, Julia A. Hou, Lifang Le Marchand, Loic Newcomb, Polly A. Hudson, Thomas J. Chan, Andrew T. Li, Li Woods, Michael O. Ahsan, Habibul Pierce, Brandon L. CA GECCO GAME-ON Network CORECT DRIVE ELLIPSE FOCI TRICL TI Genetic determinants of telomere length and risk of common cancers: a Mendelian randomization study SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENOME-WIDE METAANALYSIS; SHANGHAI WOMENS HEALTH; LUNG-CANCER; PROSTATE-CANCER; OVARIAN-CANCER; SUSCEPTIBILITY LOCI; COLORECTAL-CANCER; CIGARETTE-SMOKING; DNA-DAMAGE; ASSOCIATION AB Epidemiological studies have reported inconsistent associations between telomere length (TL) and risk for various cancers. These inconsistencies are likely attributable, in part, to biases that arise due to post-diagnostic and post-treatment TL measurement. To avoid such biases, we used a Mendelian randomization approach and estimated associations between nine TL-associated SNPs and risk for five common cancer types (breast, lung, colorectal, ovarian and prostate cancer, including subtypes) using data on 51 725 cases and 62 035 controls. We then used an inverse-variance weighted average of the SNP-specific associations to estimate the association between a genetic score representing long TL and cancer risk. The long TL genetic score was significantly associated with increased risk of lung adenocarcinoma (P = 6.3 x 10(-15)), even after exclusion of a SNP residing in a known lung cancer susceptibility region (TERT-CLPTM1L) P = 6.6 x 10(-6)). Under Mendelian randomization assumptions, the association estimate [odds ratio (OR) = 2.78] is interpreted as the OR for lung adenocarcinoma corresponding to a 1000 bp increase in TL. The weighted TL SNP score was not associated with other cancer types or subtypes. Our finding that genetic determinants of long TL increase lung adenocarcinoma risk avoids issues with reverse causality and residual confounding that arise in observational studies of TL and disease risk. Under Mendelian randomization assumptions, our finding suggests that longer TL increases lung adenocarcinoma risk. However, caution regarding this causal interpretation is warranted in light of the potential issue of pleiotropy, and a more general interpretation is that SNPs influencing telomere biology are also implicated in lung adenocarcinoma risk. C1 [Zhang, Chenan; Ahsan, Habibul; Pierce, Brandon L.] Univ Chicago, Dept Publ Hlth Sci, Chicago, IL 60637 USA. [Ahsan, Habibul; Pierce, Brandon L.] Univ Chicago, Ctr Canc Epidemiol & Prevent, Chicago, IL 60637 USA. [Ahsan, Habibul] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Ahsan, Habibul; Pierce, Brandon L.] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Doherty, Jennifer A.] Dartmouth Coll, Epidemiol & Biostat Sect, Geisel Sch Med, Lebanon, NH 03756 USA. [Amos, Christopher I.] Dartmouth Coll, Dept Community & Family Med, Ctr Genom Med, Geisel Sch Med, Lebanon, NH 03756 USA. [Burgess, Stephen] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Al Olama, Ali Amin] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Hung, Rayjean J.] Lunenfeld Tanenbaum Res Inst Mt Sinai Hosp, Toronto, ON, Canada. [Lindstroem, Sara; Kraft, Peter; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Gong, Jian; Malone, Kathleen E.; Newcomb, Polly A.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Sellers, Thomas A.; Monteiro, Alvaro N. A.] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Canc Epidemiol, Tampa, FL 33682 USA. [Chenevix-Trench, Georgia] QIMR Berghofer Med Res Inst, Dept Genet, Brisbane, Qld, Australia. [Bickeboeller, Heike] Univ Gottingen, Univ Med Ctr, Dept Genet Epidemiol, D-37073 Gottingen, Germany. [Risch, Angela] DKFZ, German Canc Res Ctr, Div Epigen & Canc Risk Factors, Heidelberg, Germany. [Risch, Angela] TLRC H, Heidelberg, Germany. [Brennan, Paul; Mckay, James D.; Timofeeva, Maria N.] Int Agcy Res Canc, F-69372 Lyon, France. [Houlston, Richard S.; Wang, Yufei; Kote-Jarai, Zsofia; Eeles, Rosalind A.] Inst Canc Res, Div Genet & Epidemiol, Sutton, Surrey, England. [Landi, Maria Teresa; Berndt, Sonja I.; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, US Publ Hlth Serv, NIH, Bethesda, MD 20892 USA. [Heinrich, Joachim] Helmholtz Zentrum Munchen, Inst Epidemiol 1, German Res Ctr Environm Hlth, Neuherberg, Germany. [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. [Muir, Ken] Univ Warwick, Warwick Med Sch, Coventry CV4 7AL, W Midlands, England. [Muir, Ken] Univ Manchester, Inst Populat Hlth, Manchester, Lancs, England. [Wiklund, Fredrik; Gronberg, Henrik] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Schumacher, Fredrick; Haiman, Christopher A.; Henderson, Brian E.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Andrulis, Irene L.] Univ Toronto, Mt Sinai Hosp, Mol Genet Lab Med & Pathobiol, Toronto, ON M5G 1X5, Canada. [Hopper, John L.] Univ Melbourne, Ctr Biostat & Epidemiol, Melbourne Sch Populat & Global Hlth, Parkville, Vic 3052, Australia. [Chang-Claude, Jenny] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [John, Esther M.] Canc Prevent Inst Calif, Fremont, CA USA. [Gammon, Marilie D.] Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [Ursin, Giske] Kreftregisteret, Canc Registry Norway, Oslo, Norway. [John, Esther M.; Whittemore, Alice S.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Gruber, Stephen B.] Univ So Calif, USC Norris Comprehens Canc Ctr, Los Angeles, CA USA. [Knight, Julia A.] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Ontario Canc Genet Network, Fred A Litwin Ctr Canc Genet, Toronto, ON M5G 1X5, Canada. [Knight, Julia A.] Univ Toronto, Div Epidemiol, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [Knight, Julia A.] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Hou, Lifang] Northwestern Univ, Dept Prevent Med, Chicago, IL 60611 USA. [Le Marchand, Loic] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI USA. [Newcomb, Polly A.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Zhang, Chenan; Hudson, Thomas J.] Ontario Inst Canc Res, Toronto, ON, Canada. [Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Chan, Andrew T.] Harvard Univ, Sch Med, Boston, MA USA. [Chan, Andrew T.] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Li, Li] Case Western Reserve Univ, Dept Family Med & Community Hlth, Cleveland, OH 44106 USA. [Woods, Michael O.] Mem Univ St Johns, Fac Med, Discipline Genet, St Johns, NF, Canada. RP Pierce, BL (reprint author), Univ Chicago, Dept Publ Hlth Sci, 5841 S Maryland Ave MC2000, Chicago, IL 60637 USA. EM brandonpierce@uchicago.edu RI Knight, Julia/A-6843-2012; Hung, Rayjean/A-7439-2013; Andrulis, Irene/E-7267-2013; Risch, Angela/H-2669-2013; OI Eeles, Rosalind/0000-0002-3698-6241; Risch, Angela/0000-0002-8026-5505; Pierce, Brandon/0000-0002-7829-952X; Burgess, Stephen/0000-0001-5365-8760; Houlston, Richard/0000-0002-5268-0242 FU Genetic Associations and Mechanisms in Oncology Network, GAME-ON: Discovery, Biology, and Risk of Inherited Variants in Breast Cancer, DRIVE [U19 CA148065]; Colorectal Transdisciplinary Study, CORECT [U19 CA148107]; Transdisciplinary Research in Cancer of the Lung, TRICL [U19 CA148127]; Follow-up of ovarian cancer genetic association and interaction studies, FOCI [U19 CA148112]; Elucidating Loci Involved in Prostate Cancer Susceptibility, ELLIPSE [U19 CA148537]; Genetics and Epidemiology of Colorectal Cancer Consortium, GECCO: National Cancer Institute, National Institutes of Health, US Department of Health and Human Services [U01 CA137088, R01 CA059045]; National Institute of Health, National Institute on Aging [T32AG000243, P30AG012857]; Cancer Research Foundation Young Investigator Award [R01 ES020506, U01 HG007601]; Wellcome Trust [100114]; NHMRC; University of Cambridge (COAF Open Access block grant) FX This work was supported by the Genetic Associations and Mechanisms in Oncology Network, GAME-ON: Discovery, Biology, and Risk of Inherited Variants in Breast Cancer, DRIVE, PI: D.J.H. (U19 CA148065); Colorectal Transdisciplinary Study, CORECT, PI: S.B.G. (U19 CA148107); Transdisciplinary Research in Cancer of the Lung, TRICL, PI: C.A. (U19 CA148127); Follow-up of ovarian cancer genetic association and interaction studies, FOCI, PI: T.A. S. (U19 CA148112); Elucidating Loci Involved in Prostate Cancer Susceptibility, ELLIPSE, PI: B.E.H. (U19 CA148537); Genetics and Epidemiology of Colorectal Cancer Consortium, GECCO: National Cancer Institute, National Institutes of Health, US Department of Health and Human Services (U01 CA137088, R01 CA059045); National Institute of Health, National Institute on Aging (T32AG000243; P30AG012857) to C.Z.; Cancer Research Foundation Young Investigator Award, R01 ES020506, and U01 HG007601 to BLP; The Wellcome Trust (100114) to S.B.; The NHMRC Senior Principal Research Fellow to G.C.T. Funding to pay the Open Access publication charges for this article was provided by the University of Cambridge (COAF Open Access block grant). NR 69 TC 20 Z9 20 U1 2 U2 16 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD SEP 15 PY 2015 VL 24 IS 18 BP 5356 EP 5366 DI 10.1093/hmg/ddv252 PG 11 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA CR4PE UT WOS:000361317200024 PM 26138067 ER PT J AU Ndhlovu, ZM Kamya, P Mewalal, N Kloverpris, HN Nkosi, T Pretorius, K Laher, F Ogunshola, F Chopera, D Shekhar, K Ghebremichael, M Ismail, N Moodley, A Malik, A Leslie, A Goulder, PJR Buus, S Chakraborty, A Dong, K Ndung'u, T Walker, BD AF Ndhlovu, Zaza M. Kamya, Philomena Mewalal, Nikoshia Kloverpris, Henrik N. Nkosi, Thandeka Pretorius, Karyn Laher, Faatima Ogunshola, Funsho Chopera, Denis Shekhar, Karthik Ghebremichael, Musie Ismail, Nasreen Moodley, Amber Malik, Amna Leslie, Alasdair Goulder, Philip J. R. Buus, Soren Chakraborty, Arup Dong, Krista Ndung'u, Thumbi Walker, Bruce D. TI Magnitude and Kinetics of CD8(+) T Cell Activation during Hyperacute HIV Infection Impact Viral Set Point SO IMMUNITY LA English DT Article ID IMMUNODEFICIENCY VIRUS-INFECTION; ANTIRETROVIRAL THERAPY; IMMUNE-RESPONSES; VIREMIA; EXPRESSION; EXPANSION; ANTIBODY; ESCAPE; AIDS; SEROCONVERSION AB CD8(+) T cells contribute to the control of HIV, but it is not clear whether initial immune responses modulate the viral set point. We screened high-risk uninfected women twice a week for plasma HIV RNA and identified 12 hyperacute infections. Onset of viremia elicited a massive HIV-specific CD8(+) T cell response, with limited bystander activation of non-HIV memory CD8(+) T cells. HIV-specific CD8(+) T cells secreted little interferon-gamma, underwent rapid apoptosis, and failed to upregulate the interleukin-7 receptor, known to be important for T cell survival. The rapidity to peak CD8(+) T cell activation and the absolute magnitude of activation induced by the exponential rise in viremia were inversely correlated with set point viremia. These data indicate that rapid, high magnitude HIV-induced CD8(+) T cell responses are crucial for subsequent immune control of acute infection, which has important implications for HIV vaccine design. C1 [Ndhlovu, Zaza M.; Kamya, Philomena; Mewalal, Nikoshia; Nkosi, Thandeka; Pretorius, Karyn; Laher, Faatima; Ogunshola, Funsho; Ismail, Nasreen; Moodley, Amber; Goulder, Philip J. R.; Ndung'u, Thumbi; Walker, Bruce D.] Univ KwaZulu Natal, Nelson R Mandela Sch Med, Doris Duke Med Res Inst, HIV Pathogenesis Programme, ZA-4001 Durban, South Africa. [Ndhlovu, Zaza M.; Kamya, Philomena; Ghebremichael, Musie; Moodley, Amber; Leslie, Alasdair; Chakraborty, Arup; Dong, Krista; Ndung'u, Thumbi; Walker, Bruce D.] Ragon Inst Massachusetts Gen Hosp Massachusetts I, Cambridge, MA 02139 USA. [Kloverpris, Henrik N.; Chopera, Denis; Leslie, Alasdair; Ndung'u, Thumbi] Univ KwaZulu Natal, Nelson R Mandela Sch Med, KwaZulu Natal Res Inst TB & HIV K RITH, ZA-4001 Durban, South Africa. [Ndung'u, Thumbi] Max Planck Inst Infect Biol, D-10117 Berlin, Germany. [Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Chakraborty, Arup] MIT, Dept Chem Engn, Cambridge, MA 02142 USA. [Malik, Amna; Goulder, Philip J. R.] Univ Oxford, Dept Paediat, Oxford OX1 3SY, England. [Kloverpris, Henrik N.; Buus, Soren] Univ Copenhagen, Dept Immunol & Microbiol, DK-2200 Copenhagen N, Denmark. RP Walker, BD (reprint author), Univ KwaZulu Natal, Nelson R Mandela Sch Med, Doris Duke Med Res Inst, HIV Pathogenesis Programme, ZA-4001 Durban, South Africa. EM bwalker@mgh.harvard.edu FU Bill and Melinda Gates Foundation; Witten Family Foundation; Mark and Lisa Schwartz Foundation; International AIDS Vaccine Initiative (IAVI) [UKZNRSA1001]; NIAID [R37AI067073]; NIH [P30 AI060354]; NIAID, NIH; NCI, NIH; NICHD, NIH; NHLBI, NIH; NIDA, NIH; NIMH, NIH; NIA, NIH; FIC, NIH; OAR, NIH; Howard Hughes Medical Institute; South African Research Chairs Initiative; Collaboration for AIDS Vaccine Discovery FX We would like to thank the FRESH participants, as well as the FRESH and HIV Pathogenesis Programme (HPP) laboratory staff. This work was supported by the Bill and Melinda Gates Foundation and the Collaboration for AIDS Vaccine Discovery, the Witten Family Foundation, Dan and Marjorie Sullivan, the Mark and Lisa Schwartz Foundation, Ursula Brunner, Gary and Loren Cohen, the International AIDS Vaccine Initiative (IAVI) (UKZNRSA1001), the NIAID (R37AI067073), and an NIH funded Center for AIDS Research (P30 AI060354), which is supported by the following NIH Co-Funding and Participating Institutes and Centers: NIAID, NCI, NICHD, NHLBI, NIDA, NIMH, NIA, FIC, and OAR, and the Howard Hughes Medical Institute. Additional funding was received from the South African Research Chairs Initiative. We would like to thank Drs. Alan S. Perelson and Ruy M. Rubeiro for their expert advice on viral growth kinetics calculations, and Dr. Daniel E. Kaufmann, MD for critical reading of the manuscript. NR 50 TC 25 Z9 26 U1 1 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD SEP 15 PY 2015 VL 43 IS 3 BP 591 EP 604 DI 10.1016/j.immuni.2015.08.012 PG 14 WC Immunology SC Immunology GA CR8BE UT WOS:000361575300011 PM 26362266 ER PT J AU Anzueto, A Wise, R Calverley, P Dusser, D Tang, WB Metzdorf, N Dahl, R AF Anzueto, Antonio Wise, Robert Calverley, Peter Dusser, Daniel Tang, Wenbo Metzdorf, Norbert Dahl, Ronald TI The Tiotropium Safety and Performance in Respimat (R) (TIOSPIR (R)) Trial: Spirometry Outcomes SO RESPIRATORY RESEARCH LA English DT Article ID OBSTRUCTIVE PULMONARY-DISEASE; LUNG-FUNCTION; COPD AB Background: Tiotropium Safety and Performance in Respimat (R) (TIOSPIR (R)) compared the safety and efficacy of tiotropium Respimat (R) and tiotropium HandiHaler (R) in patients with chronic obstructive pulmonary disease (COPD). A prespecified spirometry substudy compared the lung function efficacy between treatment groups. Methods: TIOSPIR (R) was a large-scale, long-term (2.3-year), event-driven, randomized, double-blind, parallel-group trial of 17,135 patients with COPD. In the spirometry substudy, trough forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were measured at baseline and every 24 weeks for the duration of the trial. Results: The substudy included 1370 patients who received once-daily tiotropium Respimat (R) 5 mu g (n = 461), 2.5 mu g (n = 464), or tiotropium HandiHaler (R) 18 mu g (n = 445). Adjusted mean trough FEV1 (average 24-120 weeks) was 1.285, 1.258, and 1.295 L in the Respimat (R) 5 mu g, 2.5 mu g, and HandiHaler (R) 18 mu g groups (difference versus HandiHaler (R) [95 % CI]: -10 [-38, 18] mL for Respimat (R) 5 mu g and, -37 [-65, -9] mL for Respimat (R) 2.5 mu g); achieving noninferiority to tiotropium HandiHaler (R) 18 mu g for tiotropium Respimat (R) 5 but not for 2.5 mu g (prespecified analysis). Adjusted mean trough FVC was 2.590, 2.544, and 2.593 L in the Respimat (R) 5 mu g, 2.5 mu g, and HandiHaler (R) 18 mu g groups. The rates of FEV1 decline over 24 to 120 weeks were similar for the three treatment arms (26, 40, and 34 mL/year for the tiotropium Respimat (R) 5-mu g, 2.5-mu g, and HandiHaler (R) 18-mu g groups). The rate of FEV1 decline in GOLD I + II patients was greater than in GOLD III + IV patients (46 vs. 23 mL/year); as well as in current versus ex-smokers, in patients receiving combination therapies at baseline versus not, and in those experiencing an exacerbation during the study versus not. Conclusions: The TIOSPIR (R) spirometry substudy showed that tiotropium Respimat (R) 5 mu g was noninferior to tiotropium HandiHaler (R) 18 mu g for trough FEV1, but Respimat (R) 2.5 mu g was not. Tiotropium Respimat (R) 5 mu g provides similar bronchodilator efficacy to tiotropium HandiHaler (R) 18 mu g with comparable rates of FEV1 decline. The rate of FEV1 decline varied based on disease severity, with a steeper rate of decline observed in patients with moderate airway obstruction. C1 [Anzueto, Antonio] Univ Texas Hlth Sci Ctr San Antonio, Pulm Crit Care, San Antonio, TX 78229 USA. [Anzueto, Antonio] South Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. [Wise, Robert] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Calverley, Peter] Univ Liverpool, Inst Ageing & Chron Dis, Liverpool L69 3BX, Merseyside, England. [Dusser, Daniel] Hop Cochin, Serv Pneumol, F-75674 Paris, France. [Tang, Wenbo] Boehringer Ingelheim Pharmaceut Inc, Ridgefield, CT 06877 USA. [Metzdorf, Norbert] Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany. [Dahl, Ronald] Odense Univ Hosp, DK-5000 Odense, Denmark. RP Anzueto, A (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Pulm Crit Care, 111E,7400 Merton Minter Blvd, San Antonio, TX 78229 USA. EM anzueto@uthscsa.edu FU Boehringer Ingelheim FX This study was funded by Boehringer Ingelheim. Writing assistance was provided by Sarah J. Petit of PAREXEL, funded by Boehringer Ingelheim. Data have been reported in part in the primary data publication [7] and at the CHEST/ACCP congress 2013 [21]. NR 19 TC 3 Z9 4 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-993X EI 1465-9921 J9 RESP RES JI Respir. Res. PD SEP 15 PY 2015 VL 16 AR 107 DI 10.1186/s12931-015-0269-4 PG 9 WC Respiratory System SC Respiratory System GA CR5EH UT WOS:000361362500001 PM 26369563 ER PT J AU Rigotti, NA Wallace, RB AF Rigotti, Nancy A. Wallace, Robert B. TI Using Agent-Based Models to Address "Wicked Problems" Like Tobacco Use: A Report From the Institute of Medicine SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material C1 [Rigotti, Nancy A.] Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. [Wallace, Robert B.] Univ Iowa, Coll Publ Hlth, Dept Epidemiol, Iowa City, IA 52242 USA. RP Rigotti, NA (reprint author), Massachusetts Gen Hosp, Div Gen Internal Med, 50 Staniford St,Room 914, Boston, MA 02114 USA. EM nrigotti@partners.org NR 9 TC 3 Z9 3 U1 2 U2 7 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD SEP 15 PY 2015 VL 163 IS 6 BP 469 EP + DI 10.7326/M15-1567 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA CR5FL UT WOS:000361365900022 PM 26216183 ER PT J AU Moin, T Duru, OK Mangione, CM AF Moin, Tannaz Duru, O. Kenrik Mangione, Carol M. TI Metformin Prescription for Insured Adults With Prediabetes From 2010 to 2012 RESPONSE SO ANNALS OF INTERNAL MEDICINE LA English DT Letter ID DIABETES PREVENTION PROGRAM C1 [Moin, Tannaz] Vet Affairs Greater Los Angeles Hlth Syst, Vet Affairs Hlth Serv Res & Dev Serv, Ctr Study Healthcare Innovat Implementat & Policy, Los Angeles, CA 90073 USA. [Moin, Tannaz; Duru, O. Kenrik; Mangione, Carol M.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Mangione, Carol M.] Univ Calif Los Angeles, Jonathan & Karin Fielding Sch Publ Hlth, Los Angeles, CA USA. RP Moin, T (reprint author), Vet Affairs Greater Los Angeles Hlth Syst, Vet Affairs Hlth Serv Res & Dev Serv, Ctr Study Healthcare Innovat Implementat & Policy, Los Angeles, CA 90073 USA. NR 5 TC 1 Z9 1 U1 0 U2 0 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD SEP 15 PY 2015 VL 163 IS 6 BP 483 EP 483 DI 10.7326/L15-5136-2 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA CR5FL UT WOS:000361365900031 PM 26370017 ER PT J AU Hunter, JE Zepp, JM Gilmore, MJ Davis, JV Esterberg, EJ Muessig, KR Peterson, SK Syngal, S Acheson, LS Wiesner, GL Reiss, JA Goddard, KAB AF Hunter, Jessica Ezzell Zepp, Jamilyn M. Gilmore, Mari J. Davis, James V. Esterberg, Elizabeth J. Muessig, Kristin R. Peterson, Susan K. Syngal, Sapna Acheson, Louise S. Wiesner, Georgia L. Reiss, Jacob A. Goddard, Katrina A. B. TI Universal tumor screening for Lynch syndrome: Assessment of the perspectives of patients with colorectal cancer regarding benefits and barriers SO CANCER LA English DT Article DE hereditary nonpolyposis colorectal cancer (HNPCC); Lynch syndrome; genetic screening; genetic counseling; colorectal neoplasms ID REVISED BETHESDA GUIDELINES; GENETIC TESTING STRATEGIES; REDUCING MORBIDITY; COST-EFFECTIVENESS; HNPCC; RISK; IDENTIFICATION; INDIVIDUALS; MOTIVATIONS; MORTALITY AB BACKGROUNDUniversal tumor screening for Lynch syndrome, the most common form of hereditary colorectal cancer (CRC), has been recommended among all patients newly diagnosed with CRC. However, there is limited literature regarding patient perspectives of tumor screening for Lynch syndrome among patients with CRC who are not selected for screening based on family history criteria. METHODSA total of 145 patients aged 39 to 87 years were administered surveys assessing perceived risk, patient perspectives, and potential benefits of and barriers to tumor screening for Lynch syndrome. Associations between patient-specific and cancer-specific factors and survey responses were analyzed. RESULTSThe majority of participants perceived their risk of developing Lynch syndrome as being low, with 9 participants (6.2%) anticipating an abnormal screening result. However, most participants endorsed the potential benefits of screening for themselves and their families, with 84.8% endorsing 6 benefits and 50.3% endorsing all 8 benefits. Participants also endorsed few potential barriers to screening, with 89.4% endorsing 4 of 9 potential barriers. A common barrier was worry about the cost of additional testing and surveillance, which was endorsed by 54.5% of participants. The level of distress associated with tumor screening for Lynch syndrome, which was very low, was not associated with age or CRC stage. CONCLUSIONSThe results of the current study indicate that patients with CRC overall have a positive attitude toward tumor screening for Lynch syndrome, endorse the benefits of screening, and experience low levels of distress. These findings provide insight into patient attitudes toward tumor screening for Lynch syndrome among unselected patients with CRC to inform educational approaches that assist in patient decision-making and guide the successful implementation of screening programs. Cancer 2015;121:3281-3289. (c) 2015 American Cancer Society. In the current study, perspectives among patients newly diagnosed with colorectal cancer are assessed regarding universal tumor screening for Lynch syndrome. The majority of patients appear to have a positive attitude toward screening and endorse the benefits for themselves and their families, whereas potential barriers include concerns over the cost of additional genetic counseling and testing. C1 [Hunter, Jessica Ezzell; Zepp, Jamilyn M.; Gilmore, Mari J.; Davis, James V.; Esterberg, Elizabeth J.; Muessig, Kristin R.; Reiss, Jacob A.; Goddard, Katrina A. B.] Kaiser Permanente Northwest, Ctr Hlth Res, Portland, OR 97229 USA. [Peterson, Susan K.] Univ Texas MD Anderson Canc Ctr, Dept Behav Sci, Houston, TX 77030 USA. [Syngal, Sapna] Harvard Univ, Sch Med, Div Med Oncol, Dept Med,Dana Farber Canc Inst,Brigham & Womens H, Boston, MA USA. [Acheson, Louise S.] Case Western Reserve Univ, Dept Reprod Biol, Dept Family Med & Community Hlth, Cleveland, OH 44106 USA. [Acheson, Louise S.] Univ Hosp Case, Med Ctr, Cleveland, OH USA. [Wiesner, Georgia L.] Vanderbilt Univ, Vanderbilt Hereditary Canc Program, Dept Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37235 USA. RP Hunter, JE (reprint author), Kaiser Permanente Northwest, Ctr Hlth Res, 3800 N Interstate Ave, Portland, OR 97229 USA. EM Jessica.E.Hunter@kpchr.org FU National Cancer Institute of the National Institutes of Health [5R01CA140377] FX Supported through a grant from the National Cancer Institute of the National Institutes of Health (grant 5R01CA140377 to Dr. Goddard). NR 41 TC 0 Z9 0 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD SEP 15 PY 2015 VL 121 IS 18 BP 3281 EP 3289 DI 10.1002/cncr.29470 PG 9 WC Oncology SC Oncology GA CQ7DN UT WOS:000360763200016 PM 26036338 ER PT J AU Derwall, M Ebeling, A Nolte, KW Weis, J Rossaint, R Ichinose, F Nix, C Fries, M Brucken, A AF Derwall, Matthias Ebeling, Andreas Nolte, Kay Wilhelm Weis, Joachim Rossaint, Rolf Ichinose, Fumito Nix, Christoph Fries, Michael Bruecken, Anne TI Inhaled nitric oxide improves transpulmonary blood flow and clinical outcomes after prolonged cardiac arrest: a large animal study SO CRITICAL CARE LA English DT Article ID MILD THERAPEUTIC HYPOTHERMIA; ISCHEMIA-REPERFUSION INJURY; DECREASES INFARCTION SIZE; VENTRICULAR ASSIST DEVICE; CARDIOPULMONARY-RESUSCITATION; MYOCARDIAL-ISCHEMIA; STROKE MODEL; BRAIN-DAMAGE; GLUCOSE; PIGS AB Introduction: The probability to achieve a return of spontaneous circulation (ROSC) after cardiac arrest can be improved by optimizing circulation during cardiopulomonary resuscitation using a percutaneous left ventricular assist device (iCPR). Inhaled nitric oxide may facilitate transpulmonary blood flow during iCPR and may therefore improve organ perfusion and outcome. Methods: Ventricular fibrillation was electrically induced in 20 anesthetized male pigs. Animals were left untreated for 10 minutes before iCPR was attempted. Subjects received either 20 ppm of inhaled nitric oxide (iNO, n = 10) or 0 ppm iNO (Control, n = 10), simultaneously started with iCPR until 5 hours following ROSC. Animals were weaned from the respirator and followed up for five days using overall performance categories (OPC) and a spatial memory task. On day six, all animals were anesthetized again, and brains were harvested for neurohistopathologic evaluation. Results: All animals in both groups achieved ROSC. Administration of iNO markedly increased iCPR flow during CPR (iNO: 1.81 +/- 0.30 vs Control: 1.64 +/- 0.51 L/min, p < 0.001), leading to significantly higher coronary perfusion pressure (CPP) during the 6 minutes of CPR (25 +/- 13 vs 16 +/- 6 mmHg, p = 0.002). iNO-treated animals showed significantly lower S-100 serum levels thirty minutes post ROSC (0.26 +/- 0.09 vs 0.38 +/- 0.15 ng/mL, p = 0.048), as well as lower blood glucose levels 120-360 minutes following ROSC. Lower S-100 serum levels were reflected by superior clinical outcome of iNO-treated animals as estimated with OPC (3 +/- 2 vs. 5 +/- 1, p = 0.036 on days 3 to 5). Three out of ten iNO-treated, but none of the Control animals were able to successfully participate in the spatial memory task. Neurohistopathological examination of vulnerable cerebral structures revealed a trend towards less cerebral lesions in neocortex, archicortex, and striatum in iNO-treated animals compared to Controls. Conclusions: In pigs resuscitated with mechanically-assisted CPR from prolonged cardiac arrest, the administration of 20 ppm iNO during and following iCPR improved transpulmonary blood flow, leading to improved clinical neurological outcomes. C1 [Derwall, Matthias; Ebeling, Andreas; Rossaint, Rolf; Bruecken, Anne] Univ Hosp RWTH Aachen, Dept Anesthesiol, D-52074 Aachen, Germany. [Nolte, Kay Wilhelm; Weis, Joachim] Univ Hosp RWTH Aachen, Inst Neuropathol, D-52074 Aachen, Germany. [Ichinose, Fumito] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Anesthesia Ctr Crit Care Res, Boston, MA 02114 USA. [Ichinose, Fumito] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Nix, Christoph] Abiomed Europe GmbH, D-52074 Aachen, Germany. [Fries, Michael] St Vincenz Hosp Limburg, Dept Anesthesiol, D-65549 Limburg, Germany. RP Derwall, M (reprint author), Univ Hosp RWTH Aachen, Dept Anesthesiol, Pauwelsstr 30, D-52074 Aachen, Germany. EM mderwall@ukaachen.de RI Weis, Joachim/G-1984-2014 OI Weis, Joachim/0000-0003-3280-6773 FU German Research Foundation (Deutsche Forschungsgemeinschaft) [DE 1685/3-1]; Else Kroner-Fresenius-Foundation [EKFS: 2014_A119]; National Institutes of Health [NIH R01 110378] FX This work was made possible by a grant by the German Research Foundation (Deutsche Forschungsgemeinschaft: DE 1685/3-1) to Matthias Derwall and a grant to Michael Fries by the Else Kroner-Fresenius-Foundation (EKFS: 2014_A119). Fumito Ichinose was supported by the National Institutes of Health grant NIH R01 110378 (Matthias Derwall, Andreas Ebeling, Rolf Rossaint, and Anne Brucken). NR 33 TC 1 Z9 1 U1 1 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1466-609X EI 1364-8535 J9 CRIT CARE JI Crit. Care PD SEP 15 PY 2015 VL 19 AR 328 DI 10.1186/s13054-015-1050-2 PG 10 WC Critical Care Medicine SC General & Internal Medicine GA CR1PM UT WOS:000361097300001 PM 26369409 ER PT J AU Jena, AB Khullar, D Ho, O Olenski, AR Blumenthal, DM AF Jena, Anupam B. Khullar, Dhruv Ho, Oliver Olenski, Andrew R. Blumenthal, Daniel M. TI Sex Differences in Academic Rank in US Medical Schools in 2014 SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID GENDER-DIFFERENCES; PHYSICIAN-RESEARCHERS; CAREER SATISFACTION; WOMEN PHYSICIANS; FACULTY; PRODUCTIVITY; TRENDS; MEN; RESPONSIBILITIES; ADVANCEMENT AB IMPORTANCE The proportion of women at the rank of full professor in US medical schools has not increased since 1980 and remains below that of men. Whether differences in age, experience, specialty, and research productivity between sexes explain persistent disparities in faculty rank has not been studied. OBJECTIVE To analyze sex differences in faculty rank among US academic physicians. DESIGN, SETTING, AND PARTICIPANTS We analyzed sex differences in faculty rank using a cross-sectional comprehensive database of US physicians with medical school faculty appointments in 2014 (91 073 physicians; 9.1% of all US physicians), linked to information on physician sex, age, years since residency, specialty, authored publications, National Institutes of Health (NIH) funding, and clinical trial investigation. We estimated sex differences in full professorship, as well as a combined outcome of associate or full professorship, adjusting for these factors in a multilevel (hierarchical) model. We also analyzed how sex differences varied with specialty and whether differences were more prevalent at schools ranked highly in research. EXPOSURES Physician sex. MAIN OUTCOMES AND MEASURES Academic faculty rank. RESULTS In all, there were 30 464 women who were medical faculty vs 60 609 men. Of those, 3623 women (11.9%) vs 17 354 men (28.6%) had full-professor appointments, for an absolute difference of -16.7%(95% CI, -17.3% to -16.2%). Women faculty were younger and disproportionately represented in internal medicine and pediatrics. The mean total number of publications for women was 11.6 vs 24.8 for men, for a difference of -13.2 (95% CI, -13.6 to -12.7); the mean first-or last-author publications for women was 5.9 vs 13.7 for men, for a difference of -7.8 (95% CI, -8.1 to -7.5). Among 9.1% of medical faculty with an NIH grant, 6.8%(2059 of 30 464) were women and 10.3%(6237 of 60 609) were men, for a difference of -3.5%(95% CI, -3.9% to -3.1%). In all, 6.4% of women vs 8.8% of men had a trial registered on ClinicalTrials.gov, for a difference of -2.4%(95% CI, -2.8% to -2.0%). After multivariable adjustment, women were less likely than men to have achieved full-professor status (absolute adjusted difference in proportion, -3.8%; 95% CI, -4.4% to -3.3%). Sex-differences in full professorship were present across all specialties and did not vary according to whether a physician's medical school was ranked highly in terms of research funding. CONCLUSIONS AND RELEVANCE Among physicians with faculty appointments at US medical schools, there were sex differences in academic faculty rank, with women substantially less likely than men to be full professors, after accounting for age, experience, specialty, and measures of research productivity. C1 [Jena, Anupam B.; Ho, Oliver; Olenski, Andrew R.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Jena, Anupam B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Jena, Anupam B.] Natl Bur Econ Res, Cambridge, MA 02138 USA. [Khullar, Dhruv] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Khullar, Dhruv; Blumenthal, Daniel M.] Harvard Univ, Sch Med, Boston, MA USA. [Blumenthal, Daniel M.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. RP Jena, AB (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, 180 Longwood Ave, Boston, MA 02115 USA. EM jena@hcp.med.harvard.edu FU Office of the Director, National Institutes of Health [1DP5OD017897-01] FX The authors report funding grant 1DP5OD017897-01 Early Independence Award from the Office of the Director, National Institutes of Health (Dr Jena). NR 33 TC 22 Z9 22 U1 0 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD SEP 15 PY 2015 VL 314 IS 11 BP 1149 EP 1158 DI 10.1001/jama.2015.10680 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA CR4EL UT WOS:000361284500026 PM 26372584 ER PT J AU Cox, A Varma, A Barry, J Vertegel, A Banik, N AF Cox, April Varma, Abhay Barry, John Vertegel, Alexey Banik, Naren TI Nanoparticle Estrogen in Rat Spinal Cord Injury Elicits Rapid Anti-Inflammatory Effects in Plasma, Cerebrospinal Fluid, and Tissue SO JOURNAL OF NEUROTRAUMA LA English DT Article DE spinal cord injury; MCP-1; IL-6; GRO-KC; S100 beta; nanoparticle; estrogen; CSF ID TRAUMATIC BRAIN-INJURY; RANDOMIZED CONTROLLED-TRIAL; APOPTOTIC CELL-DEATH; INFLAMMATORY CYTOKINES; CLINICAL-TRIALS; POSTMENOPAUSAL WOMEN; FUNCTIONAL RECOVERY; LOCOMOTOR FUNCTION; RECEPTOR-ALPHA; SEX STEROIDS AB Persons with spinal cord injury (SCI) are in need of effective therapeutics. Estrogen (E2), as a steroid hormone, is a highly pleiotropic agent; with anti-inflammatory, anti-apoptotic, and neurotrophic properties, it is ideal for use in treatment of patients with SCI. Safety concerns around the use of high doses of E2 have limited clinical application, however. To address these concerns, low doses of E2 (25 mu g and 2.5 mu g) were focally delivered to the injured spinal cord using nanoparticles. A per-acute model (6 h after injury) was used to assess nanoparticle release of E2 into damaged spinal cord tissue; in addition, E2 was evaluated as a rapid anti-inflammatory. To assess inflammation, 27-plex cytokine/chemokine arrays were conducted in plasma, cerebrospinal fluid (CSF), and spinal cord tissue. A particular focus was placed on IL-6, GRO-KC, and MCP-1 as these have been identified from CSF in human studies as potential biomarkers in SCI. S100 beta, an additional proposed biomarker, was also assessed in spinal cord tissue only. Tissue concentrations of E2 were double those found in the plasma, indicating focal release. E2 showed rapid anti-inflammatory effects, significantly reducing interleukin (IL)-6, GRO-KC, MCP-1, and S100 beta in one or all compartments. Numerous additional targets of rapid E2 modulation were identified including: leptin, MIP-1 alpha, IL-4, IL-2, IL-10, IFN gamma, tumor necrosis factor-alpha, etc. These data further elucidate the rapid anti-inflammatory effects E2 exerts in an acute rat SCI model, have identified additional targets of estrogen efficacy, and suggest nanoparticle delivered estrogen may provide a safe and efficacious treatment option in persons with acute SCI. C1 [Cox, April; Varma, Abhay; Banik, Naren] Med Univ S Carolina, Dept Neurol & Neurosurg, Charleston, SC 29425 USA. [Barry, John; Vertegel, Alexey] Clemson Univ, Dept Bioengn, Clemson, SC USA. [Banik, Naren] Ralph H Johnson VA Med Ctr, Charleston, SC USA. RP Cox, A (reprint author), Med Univ S Carolina, Dept Neurosci, 96 Jonathan Lucas St,MSC 606, Charleston, SC 29412 USA. EM coxaa@musc.edu FU NIH [NINDS-RO1 NS-31622, NS-45967]; Office of Research and Development, Medical Research Service, Department of Veterans Affairs, at Ralph H. Johnson VA Medical Center, Charleston, SC, the Department of Neurosurgery, MUSC [1IOBX001262]; South Carolina Spinal Cord Injury Research Fund; National Institutes of Health from the Extramural Research Facilities Program of the National Center for Research Resources [C06 RR015455] FX The funding for this project was provided in part by NIH, NINDS-RO1 NS-31622 and NS-45967; also by 1IOBX001262 from the Office of Research and Development, Medical Research Service, Department of Veterans Affairs, at Ralph H. Johnson VA Medical Center, Charleston, SC, the Department of Neurosurgery, MUSC, and South Carolina Spinal Cord Injury Research Fund. This work was conducted in a facility constructed with support from the National Institutes of Health, Grant Number C06 RR015455 from the Extramural Research Facilities Program of the National Center for Research Resources. We would like to acknowledge Dr. Supriti Samantaray and Nakul Thakore for help in organizing this article. NR 67 TC 5 Z9 5 U1 0 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD SEP 15 PY 2015 VL 32 IS 18 BP 1413 EP 1421 DI 10.1089/neu.2014.3730 PG 9 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA CQ8AR UT WOS:000360828900004 PM 25845398 ER PT J AU Bell, SP Orr, NM Dodson, JA Rich, MW Wenger, NK Blum, K Harold, JG Tinetti, ME Maurer, MS Forman, DE AF Bell, Susan P. Orr, Nicole M. Dodson, John A. Rich, Michael W. Wenger, Nanette K. Blum, Kay Harold, John Gordon Tinetti, Mary E. Maurer, Mathew S. Forman, Daniel E. TI What to Expect From the Evolving Field of Geriatric Cardiology SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE aging; cardiovascular disease; geriatrics; quality; training ID AMERICAN-HEART-ASSOCIATION; OLDER-ADULTS; MYOCARDIAL-INFARCTION; PHYSICAL-ACTIVITY; COGNITIVE IMPAIRMENT; HEALTH-BENEFITS; GAIT SPEED; MINI-COG; CARE; FAILURE AB The population of older adults is expanding rapidly, and aging predisposes to cardiovascular disease. The principle of patient-centered care must respond to the preponderance of cardiac disease that now occurs in combination with the complexities of old age. Geriatric cardiology melds cardiovascular perspectives with multimorbidity, polypharmacy, frailty, cognitive decline, and other clinical, social, financial, and psychological dimensions of aging. Although some assume that a cardiologist may instinctively cultivate some of these skills over the course of a career, we assert that the volume and complexity of older cardiovascular patients in contemporary practice warrants a more direct approach to achieve suitable training and a more reliable process of care. We present a rationale and vision for geriatric cardiology as a melding of primary cardiovascular and geriatrics skills, thereby infusing cardiology practice with expanded proficiencies in diagnosis, risks, care coordination, communications, end-of-life, and other competences required to best manage older cardiovascular patients. (C) 2015 by the American College of Cardiology Foundation. C1 [Bell, Susan P.] Vanderbilt Univ, Sch Med, Dept Med, Div Cardiovasc Med, Nashville, TN 37212 USA. [Bell, Susan P.] Vanderbilt Univ, Sch Med, Div Geriatr Med, Ctr Qual Aging, Nashville, TN 37212 USA. [Orr, Nicole M.] Tufts Med Ctr, Div Cardiol, Boston, MA USA. [Orr, Nicole M.] Tufts Med Ctr, Ctr Cardiovasc, Boston, MA USA. [Dodson, John A.] NYU, Sch Med, Dept Med, Leon H Charney Div Cardiol, New York, NY USA. [Rich, Michael W.] Washington Univ, Sch Med, Div Cardiol, St Louis, MO USA. [Wenger, Nanette K.] Emory Univ, Sch Med, Div Cardiol, Atlanta, GA 30322 USA. [Blum, Kay] Amer Coll Cardiol, Geriatr Cardiol Sect, Washington, DC USA. [Harold, John Gordon] Univ Calif Los Angeles, Cedars Sinai Heart Inst, Los Angeles, CA USA. [Harold, John Gordon] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Tinetti, Mary E.] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA. [Tinetti, Mary E.] Yale Univ, Sch Med, Dept Publ Hlth & Epidemiol, New Haven, CT USA. [Maurer, Mathew S.] Columbia Univ, Dept Med, Med Ctr, Div Cardiol, New York, NY USA. [Forman, Daniel E.] Univ Pittsburgh, Med Ctr, Dept Med, Geriatr Cardiol Sect, Pittsburgh, PA USA. [Forman, Daniel E.] VA Pittsburgh Healthcare Syst, Res Educ & Clin Ctr, Pittsburgh, PA USA. RP Forman, DE (reprint author), Univ Pittsburgh, Med Ctr, Sect Geriatr Cardiol, 3471 Fifth Ave,Suite 500, Pittsburgh, PA 15213 USA. EM formand@pitt.edu FU National Institute of Child Health and Human Development [2K12HD043483-11]; Eisenstein's Women's Heart Fund; National Institute on Aging (NIA) grant [U13 AG047008]; John A. Hartford Foundation; NIA [AG045148, AG036778, P30 AG024827]; VA Office of Rehabilitation Research and Development grant [F0834-R] FX Dr. Bell is supported by a grant from the National Institute of Child Health and Human Development (2K12HD043483-11) and the Eisenstein's Women's Heart Fund. Dr. Rich is supported by National Institute on Aging (NIA) grant U13 AG047008. Dr. Tinetti receives funding from the John A. Hartford Foundation for work related to developing a patient goals-directed approach to the care of older adults with multiple chronic conditions; and is supported by an NIA R21 grant (AG045148). Dr. Maurer receives funding from an NIA K24 award (AG036778). Dr. Forman is supported in part by NIA grant P30 AG024827 and VA Office of Rehabilitation Research and Development grant F0834-R. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 47 TC 13 Z9 14 U1 4 U2 7 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 SEP 15 PY 2015 VL 66 IS 11 BP 1286 EP 1299 DI 10.1016/j.jacc.2015.07.048 PG 14 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CQ7XV UT WOS:000360820800012 PM 26361161 ER PT J AU Oleson, BJ McGraw, JA Broniowska, KA Annamalai, M Chen, J Bushkofsky, JR Davis, DB Corbett, JA Mathews, CE AF Oleson, Bryndon J. McGraw, Jennifer A. Broniowska, Katarzyna A. Annamalai, Mani Chen, Jing Bushkofsky, Justin R. Davis, Dawn B. Corbett, John A. Mathews, Clayton E. TI Distinct differences in the responses of the human pancreatic beta-cell line EndoC-beta H1 and human islets to proinflammatory cytokines SO AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY LA English DT Article DE insulinoma; islet; diabetes; nitric oxide; cytokine ID NITRIC-OXIDE SYNTHASE; INSULIN-SECRETING CELLS; CONFERS RESISTANCE; INDUCED INHIBITION; S-NITROSATION; DNA-DAMAGE; RAT ISLETS; ER STRESS; APOPTOSIS; LANGERHANS AB While insulinoma cells have been developed and proven to be extremely useful in studies focused on mechanisms controlling beta-cell function and viability, translating findings to human beta-cells has proven difficult because of the limited access to human islets and the absence of suitable insulinoma cell lines of human origin. Recently, a human beta-cell line, EndoC-beta H1, has been derived from human fetal pancreatic buds. The purpose of this study was to determine whether human EndoC-beta H1 cells respond to cytokines in a fashion comparable to human islets. Unlike most rodent-derived insulinoma cell lines that respond to cytokines in a manner consistent with rodent islets, EndoC-beta H1 cells fail to respond to a combination of cytokines (IL-1, IFN-gamma, and TNF) in a manner consistent with human islets. Nitric oxide, produced following inducible nitric oxide synthase (iNOS) expression, is a major mediator of cytokine-induced human islet cell damage. We show that EndoC-beta H1 cells fail to express iNOS or produce nitric oxide in response to this combination of cytokines. Inhibitors of iNOS prevent cytokine-induced loss of human islet cell viability; however, they do not prevent cytokine-induced EndoC-beta H1 cell death. Stressed human islets or human islets expressing heat shock protein 70 (HSP70) are resistant to cytokines, and, much like stressed human islets, EndoC-beta H1 cells express HSP70 under basal conditions. Elevated basal expression of HSP70 in EndoC-beta H1 cells is consistent with the lack of iNOS expression in response to cytokine treatment. While expressing HSP70, EndoC-beta H1 cells fail to respond to endoplasmic reticulum stress activators, such as thapsigargin. These findings indicate that EndoC-beta H1 cells do not faithfully recapitulate the response of human islets to cytokines. Therefore, caution should be exercised when making conclusions regarding the actions of cytokines on human islets when using this human-derived insulinoma cell line. C1 [Oleson, Bryndon J.; McGraw, Jennifer A.; Broniowska, Katarzyna A.; Corbett, John A.] Med Coll Wisconsin, Dept Biochem, Milwaukee, WI 53226 USA. [Annamalai, Mani; Chen, Jing; Mathews, Clayton E.] Univ Florida, Coll Med, Dept Pathol Immunol & Lab Med, Gainesville, FL USA. [Bushkofsky, Justin R.; Davis, Dawn B.] Univ Wisconsin, Dept Med, Div Endocrinol Diabet & Metab, Madison, WI USA. [Davis, Dawn B.] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. RP Corbett, JA (reprint author), Med Coll Wisconsin, Dept Biochem, 8701 W Watertown Plank Rd, Milwaukee, WI 53226 USA. EM jcorbett@mcw.edu OI Broniowska, Katarzyna/0000-0002-8000-9093 FU National Institutes of Health [DK-083442, DK-074656, UC4 DK-104194, UC4 DK-104167, P01 AI-042288, DK-052194, AI-44458]; United States Department of Veterans Affairs [1101BX001880]; American Diabetes Association (ADA) [1-11-BS-104]; American Health Association [13POST16940076, 14PRE20380585]; University of Wisconsin; Integrated Islet Distribution Program FX This work was supported by grants from the National Institutes of Health (DK-083442 to D. B. Davis; DK-074656, UC4 DK-104194, UC4 DK-104167, and P01 AI-042288 to C. E. Matthews; and DK-052194 and AI-44458 to J. A. Corbett), United States Department of Veterans Affairs (1101BX001880 to D. B. Davis), American Diabetes Association (ADA 1-11-BS-104 to C. E. Mathews), American Health Association 13POST16940076 (to K. A. Broniowska) and 14PRE20380585 (B. J. Oleson), and by support from the University of Wisconsin. Human pancreatic islets were provided by the National Institute of Diabetes and Digestive and Kidney Diseases funded Integrated Islet Distribution Program. This work was performed, in part, using facilities and resources from the William S. Middleton Memorial Veterans Hospital. NR 65 TC 6 Z9 6 U1 2 U2 2 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 SEP 15 PY 2015 VL 309 IS 5 BP R525 EP R534 DI 10.1152/ajpregu.00544.2014 PG 10 WC Physiology SC Physiology GA CQ4BE UT WOS:000360548300010 PM 26084699 ER PT J AU Ikeda, K Marutani, E Hirai, S Wood, ME Whiteman, M Ichinose, F AF Ikeda, Kohei Marutani, Eizo Hirai, Shuichi Wood, Mark E. Whiteman, Matthew Ichinose, Fumito TI Mitochondria-targeted hydrogen sulfide donor AP39 improves neurological outcomes after cardiac arrest in mice SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Article DE Cardiac arrest; Resuscitation; Hydrogen sulfide; Mitochondria ID CARDIOPULMONARY-RESUSCITATION; ISCHEMIA-REPERFUSION; PROTECTS; SURVIVAL; BRAIN; PRESERVATION; HYPOTHERMIA; INJURY; MODEL; DEATH AB Aims: Mitochondria-targeted hydrogen sulfide donor AP39, [(10-oxo-10-(4-(3-thioxo-3H-1,2-dithiol-5yl) phenoxy)decyl) triphenylphosphonium bromide], exhibits cytoprotective effects against oxidative stress in vitro. We examined whether or not AP39 improves the neurological function and long term survival in mice subjected to cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). Methods: Adult C57BL/6 male mice were subjected to 8 min of CA and subsequent CPR. We examined the effects of AP39 (10, 100, 1000 nmol kg(-1)) or vehicle administered intravenously at 2 min before CPR (Experiment 1). Systemic oxidative stress levels, mitochondrial permeability transition, and histological brain injury were assessed. We also examined the effects of AP39 (10, 1000 nmol kg(-1)) or vehicle administered intravenously at 1 min after return of spontaneous circulation (ROSC) (Experiment 2). ROSC was defined as the return of sinus rhythm with a mean arterial pressure >40 mm Hg lasting at least 10 seconds. Results: Vehicle treated mice subjected to CA/CPR had poor neurological function and 10-day survival rate (Experiment 1; 15%, Experiment 2; 23%). Administration of AP39 (100 and 1000 nmol kg-1) 2 min before CPR significantly improved the neurological function and 10-day survival rate (54% and 62%, respectively) after CA/CPR. Administration of AP39 before CPR attenuated mitochondria] permeability transition pore opening, reactive oxygen species generation, and neuronal degeneration after CA/CPR. Administration of AP39 1 min after ROSC at 10 nmol kg(-1), but not at 1000 nmol kg(-1), significantly improved the neurological function and 10-day survival rate (69%) after CA/CPR. Conclusion: The current results suggest that administration of mitochondria-targeted sulfide donor AP39 at the time of CPR or after ROSC improves the neurological function and long term survival rates after CA/CPR by maintaining mitochondrial integrity and reducing oxidative stress. (C) 2015 Elsevier Inc. All rights reserved. C1 [Ikeda, Kohei; Marutani, Eizo; Hirai, Shuichi; Ichinose, Fumito] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Ikeda, Kohei; Marutani, Eizo; Hirai, Shuichi; Ichinose, Fumito] Harvard Univ, Sch Med, Boston, MA USA. [Wood, Mark E.] Univ Exeter, Dept Biosci, Coll Life & Environm Sci, Exeter EX4 4QJ, Devon, England. [Whiteman, Matthew] Univ Exeter, Sch Med, Exeter, Devon, England. RP Whiteman, M (reprint author), Univ Exeter, Sch Med, St Lukes Campus,Magdalen Rd, Exeter EX1 2LU, Devon, England. EM m.whiteman@exeter.ac.uk; fichinose@mgh.harvard.edu RI Whiteman, Matthew/C-6079-2009; OI Whiteman, Matthew/0000-0002-6583-6779; IKEDA, KOHEI/0000-0002-0961-1532; Wood, Mark/0000-0002-2674-6981 FU National Institutes of Health [HL101930] FX This work was supported by a grant from National Institutes of Health (HL101930 to FI). NR 34 TC 6 Z9 6 U1 2 U2 21 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 EI 1089-8611 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD SEP 15 PY 2015 VL 49 BP 90 EP 96 DI 10.1016/j.niox.2015.05.001 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA CP9AY UT WOS:000360187300010 PM 25960429 ER PT J AU Shelton, MA Newman, JT Gu, H Sampson, AR Fish, KN MacDonald, ML Moyer, CE DiBitetto, JV Dorph-Petersen, KA Penzes, P Lewis, DA Sweet, RA AF Shelton, Micah A. Newman, Jason T. Gu, Hong Sampson, Allan R. Fish, Kenneth N. MacDonald, Matthew L. Moyer, Caitlin E. DiBitetto, James V. Dorph-Petersen, Karl-Anton Penzes, Peter Lewis, David A. Sweet, Robert A. TI Loss of Microtubule-Associated Protein 2 Immunoreactivity Linked to Dendritic Spine Loss in Schizophrenia SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Schizophrenia; Microtubule-Associated Protein 2; Dendritic spines; Auditory cortex; Postmortem human tissue; Confocal microscopy ID PRIMARY AUDITORY-CORTEX; MISMATCH NEGATIVITY GENERATION; SUPERIOR TEMPORAL GYRUS; PREFRONTAL CORTEX; PYRAMIDAL NEURONS; HIPPOCAMPAL-FORMATION; PLANUM TEMPORALE; MOOD DISORDERS; HESCHL GYRUS; MAP2 AB BACKGROUND: Microtubule-associated protein 2 (MAP2) is a neuronal protein that plays a role in maintaining dendritic structure through its interaction with microtubules. In schizophrenia (Sz), numerous studies have revealed that the typically robust immunoreactivity (IR) of MAP2 is significantly reduced across several cortical regions. The relationship between MAP2-IR reduction and lower dendritic spine density, which is frequently reported in Sz, has not been explored in previous studies, and MAP2-IR loss has not been investigated in the primary auditory cortex (Brodmann area 41), a site of conserved pathology in Sz. METHODS: Using quantitative spinning disk confocal microscopy in two cohorts of subjects with Sz and matched control subjects (Sz subjects, n = 20; control subjects, n = 20), we measured MAP2-IR and dendritic spine density and spine number in deep layer 3 of BA41. RESULTS: Subjects with Sz exhibited a significant reduction in MAP2-IR. The reductions in MAP2-IR were not associated with neuron loss, loss of MAP2 protein, clinical confounders, or technical factors. Dendritic spine density and number also were reduced in Sz and correlated with MAP2-IR. In 12 (60%) subjects with Sz, MAP2-IR values were lower than the lowest values in control subjects; only in this group were spine density and number significantly reduced. CONCLUSIONS: These findings demonstrate that MAP2-IR loss is closely linked to dendritic spine pathology in Sz. Because MAP2 shares substantial sequence, regulatory, and functional homology with MAP tau, the wealth of knowledge regarding tau biology and the rapidly expanding field of tau therapeutics provide resources for identifying how MAP2 is altered in Sz and possible leads to novel therapeutics. Keywords: Schizophrenia, Microtubule-Associated Protein 2, Dendritic spines, Auditory cortex, Postmortem human tissue, Confocal microscopy C1 [Shelton, Micah A.; Newman, Jason T.; Fish, Kenneth N.; MacDonald, Matthew L.; Moyer, Caitlin E.; DiBitetto, James V.; Dorph-Petersen, Karl-Anton; Lewis, David A.; Sweet, Robert A.] Univ Pittsburgh, Sch Med, Translat Neurosci Program, Pittsburgh, PA USA. [Shelton, Micah A.; Newman, Jason T.; Fish, Kenneth N.; MacDonald, Matthew L.; Moyer, Caitlin E.; Lewis, David A.; Sweet, Robert A.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [Sweet, Robert A.] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15261 USA. [Gu, Hong; Sampson, Allan R.] Univ Pittsburgh, Sch Med, Dept Stat, Pittsburgh, PA USA. [Dorph-Petersen, Karl-Anton] Aarhus Univ, Dept Clin Med, Translat Neuropsychiat Unit, Aarhus, Denmark. [Dorph-Petersen, Karl-Anton] Aarhus Univ, Ctr Stochast Geometry & Adv Bioimaging, Aarhus, Denmark. [Penzes, Peter] Northwestern Univ, Feinberg Sch Med, Dept Physiol, Chicago, IL 60611 USA. [Penzes, Peter] Northwestern Univ, Feinberg Sch Med, Dept Psychiat & Behav Sci, Chicago, IL 60611 USA. [Sweet, Robert A.] VA Pittsburgh Healthcare Syst, Mental Illness Res Educ & Clin Ctr, Pittsburgh, PA USA. RP Sweet, RA (reprint author), Biomed Sci Tower,Room W-1645,3811 OHara St, Pittsburgh, PA 15213 USA. EM sweetra@upmc.edu RI Dorph-Petersen, Karl-Anton/A-9039-2015; Penzes, Peter/L-3987-2016 OI Dorph-Petersen, Karl-Anton/0000-0002-6676-034X; Penzes, Peter/0000-0001-5449-1640 FU National Institutes of Health [DC011499-03, MH16804, MH096985, MH071316, MH097216, MH071533]; University of Pittsburgh Cancer Institute Cancer Biomarker Facility [P30CA047904]; Biomedical Mass Spectrometry Center; Bristol-Myers Squibb; Pfizer FX This work was supported by National Institutes of Health Grant Nos. DC011499-03 (MAS), MH16804 (MLM), MH096985 (KNF), MH071316 and MH097216 (PP), and MH071533 (RAS). The Biomedical Mass Spectrometry Center and University of Pittsburgh Cancer Institute Cancer Biomarker Facility are supported in part by award P30CA047904.; ARS is a statistical consultant to Janssen Pharmaceutical Research and Development LLC. DAL currently receives investigator-initiated research support from Bristol-Myers Squibb and Pfizer and in 2012-2014 served as a consultant in the areas of target identification and validation and new compound development to Autifony, Bristol-Myers Squibb, Concert Pharmaceuticals, and Sunovion. MAS, JTN, HG, KNF, MLM, CEM, JVD, K-AD-P, PP, and RAS report no biomedical financial interests or potential conflicts of interest. NR 68 TC 13 Z9 14 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD SEP 15 PY 2015 VL 78 IS 6 BP 374 EP 385 DI 10.1016/j.biopsych.2014.12.029 PG 12 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA CP5SR UT WOS:000359945000005 PM 25818630 ER PT J AU Zhang, ZD Kil, KE Poutiainen, P Choi, JK Kang, HJ Huang, XP Roth, BL Brownell, AL AF Zhang, Zhaoda Kil, Kun-Eek Poutiainen, Pekka Choi, Ji-Kyung Kang, Hye-Jin Huang, Xi-Ping Roth, Bryan L. Brownell, Anna-Liisa TI Re-exploring the N-phenylpicolinamide derivatives to develop mGlu(4) ligands with improved affinity and in vitro microsomal stability SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Metabotropic glutamate receptor subtype 4; (mGlu(4)); Positive allosteric modulator (PAM); Positron emission tomography (PET); Affinity; Metabolic stability; Structure-affinity relationship (SAR) ID METABOTROPIC GLUTAMATE RECEPTORS; POSITIVE ALLOSTERIC MODULATOR; POSITRON-EMISSION-TOMOGRAPHY; SUBTYPE 4 MGLU(4); PARKINSONS-DISEASE; GROUP-III; MEDIATED MODULATION; PET RADIOTRACER; RODENT MODELS; DISCOVERY AB In recent years, mGlu(4) has received great attention and research effort because of the potential benefits of mGlu(4) activation in treating numerous brain disorders, such as Parkinson's disease (PD). Many positive allosteric modulators of mGlu(4) have been developed. To better understand the role of mGlu(4) in healthy and disease conditions, we are interested in developing an mGlu(4) selective radioligand for in vivo studies. Thus, we had synthesized and studied [C-11]2 as a PET tracer for mGlu(4), which demonstrated some promising features as a PET radioligand as well as the limitation need to be improved. In order to develop an mGlu(4) ligand with enhanced affinity and improved metabolic stability, we have modified, synthesized and evaluated a series of new N-phenylpicolinamide derivatives. The SAR study has discovered a number of compounds with low nM affinity to mGlu(4). The dideuteriumfluoromethoxy modified compound 24 is identified as a very promising mGlu(4) ligand, which has demonstrated enhanced affinity, improved in vitro microsomal stability, good selectivity and good permeability. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Zhang, Zhaoda; Kil, Kun-Eek; Poutiainen, Pekka; Choi, Ji-Kyung; Brownell, Anna-Liisa] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Kang, Hye-Jin; Huang, Xi-Ping; Roth, Bryan L.] Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27514 USA. RP Brownell, AL (reprint author), Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, 149,13th St,Suite 2301, Charlestown, MA 02129 USA. EM abrownell@partners.org RI Roth, Bryan/F-3928-2010 FU National Institute of Mental Health's Psychoactive Drug Screening Program [HHSN-271-2013-00017-C]; Orion Farmos Research Foundation; Kuopio University Foundation; Sigrid Juselius Foundation, Finland; [NIBIB-R01EB012864]; [NIMH-R01MH91684]; [1S10RR029495-01]; [1S10RR026666-01]; [1S10RR023452-01] FX Funding was provided by NIBIB-R01EB012864 and NIMH-R01MH91684 to A.-L.B. Authors would like to acknowledge Supporting Grants for the instrumentation 1S10RR029495-01, 1S10RR026666-01, and 1S10RR023452-01. The mGlu functional data was generously provided by the National Institute of Mental Health's Psychoactive Drug Screening Program, Contract # HHSN-271-2013-00017-C (NIMH PDSP). The NIMH PDSP is Directed by Bryan L. Roth MD, PhD at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscoll at NIMH, Bethesda MD, USA. Financial support for PP from The Orion Farmos Research Foundation, Kuopio University Foundation, and Sigrid Juselius Foundation, Finland is gratefully acknowledged. NR 34 TC 1 Z9 1 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X EI 1464-3405 J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD SEP 15 PY 2015 VL 25 IS 18 BP 3956 EP 3960 DI 10.1016/j.bmcl.2015.07.031 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA CP2ZX UT WOS:000359747700039 PM 26231155 ER PT J AU Kantor, ED Lipworth, L Fowke, JH Giovannucci, EL Mucci, LA Signorello, LB AF Kantor, Elizabeth D. Lipworth, Loren Fowke, Jay H. Giovannucci, Edward L. Mucci, Lorelei A. Signorello, Lisa B. TI Statin Use and Risk of Prostate Cancer: Results From the Southern Community Cohort Study SO PROSTATE LA English DT Article DE African Americans; chemoprevention; epidemiologic studies; prostate cancer; statins ID REDUCED RISK; HEALTH DISPARITIES; BARRETTS-ESOPHAGUS; SERUM-CHOLESTEROL; COLORECTAL-CANCER; FOLLOW-UP; METAANALYSIS; TRIAL; MEN; ASSOCIATION AB BACKGROUND. Epidemiologic studies suggest that statin use may be inversely associated with risk of prostate cancer, but prior studies have focused predominantly on non-Hispanic white populations. METHODS. We evaluated the association between statin use and prostate cancer risk in the Southern Community Cohort Study (SCCS). Study participants were 32,091 men aged 40-79 at baseline, 67% of whom were non-Hispanic black. Between study enrollment (2002-2009) and December 31, 2010, 570 prostate cancer cases were diagnosed, including 324 low-grade cancers (Gleason score <7 or Gleason pattern 3+4) and 107 high-grade cancers (Gleason score >7 or Gleason pattern 4+3). Analyses of overall prostate cancer were conducted using Cox regression and analyses of grade-specific cancer were conducted using competing risks models. RESULTS. Ten percent of non-Hispanic black men and 22% of non-Hispanic white men reported use of statins at study enrollment. As compared to non-use, statin use was associated with a non-significant 14% lower risk of prostate cancer in multivariable models (Hazard Ratio [HR]:0.86; 95% Confidence Interval [CI]: 0.63-1.18). This association was stronger for high-grade cancer (HR: 0.62; 95%CI: 0.30, 1.28) than low-grade cancer (HR:0.98; 95%CI: 0.65-1.48). Results were similar by race/ethnicity (p-interaction: 0.41) and did not vary by history of prostate-specific antigen [PSA] screening (p-interaction: 0.65). CONCLUSIONS. Results suggest no strong association between statin use and prostate cancer risk overall, and further suggest that if a modest protective effect does exist, it does not vary by race/ethnicity and may be restricted to high-grade tumors, although power to detect differences by subgroup was limited. (c) 2015 Wiley Periodicals, Inc. C1 [Kantor, Elizabeth D.; Giovannucci, Edward L.; Mucci, Lorelei A.; Signorello, Lisa B.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Lipworth, Loren; Fowke, Jay H.] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA. [Giovannucci, Edward L.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Mucci, Lorelei A.; Signorello, Lisa B.] Dana Farber Harvard Canc Ctr, Boston, MA USA. RP Kantor, ED (reprint author), Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave, Boston, MA 02115 USA. EM ekantor@hsph.harvard.edu FU Prostate Cancer Foundation; National Cancer Institute [R01CA092447, T32CA009001] FX Grant sponsor: National Cancer Institute; Grant numbers: R01CA092447; T32CA009001; Grant sponsor: Prostate Cancer Foundation. NR 46 TC 4 Z9 4 U1 1 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-4137 EI 1097-0045 J9 PROSTATE JI Prostate PD SEP 15 PY 2015 VL 75 IS 13 BP 1384 EP 1393 DI 10.1002/pros.23019 PG 10 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA CP2MN UT WOS:000359711300005 PM 26012482 ER EF