FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Kentoffio, K Berkowitz, SA Atlas, SJ Oo, SA Percac-Lima, S AF Kentoffio, Katherine Berkowitz, Seth A. Atlas, Steven J. Oo, Sarah A. Percac-Lima, Sanja TI Use of maternal health services: comparing refugee, immigrant and US-born populations SO MATERNAL AND CHILD HEALTH JOURNAL LA English DT Article DE Refugees; Immigrants; Maternal health; Health services access ID PRENATAL-CARE; INSURANCE-COVERAGE; WASHINGTON-STATE; RISK; WOMEN AB Objectives To determine use of recommended maternal healthcare services among refugee and immigrant women in a setting of near-universal insurance coverage. Methods Refugee women age >= 18 years, who arrived in the US from 2001 to 2013 and received care at the same Massachusetts community health center, were matched by age, gender, and date of care initiation to Spanish-speaking immigrants and US-born controls. The primary outcome was initiation of obstetrical care within the first trimester (12 weeks gestation). Secondary outcomes were number of obstetrical visits and attending a postpartum visit. Results We included 375 women with 763 pregnancies (women/pregnancies: 53/116 refugee, 186/368 immigrant, 136/279 control). More refugees (20.6 %) and immigrants (15.0 %) had their first obstetric visit after 12 weeks gestation than controls (6.0 %, p < 0.001). In logistic regression models adjusted for age, education, insurance, BMI, and median census tract household income, both refugee (odds ratio [OR] 4.58, 95 % confidence interval [CI] 1.73-12.13) and immigrant (OR 2.21, 95 % CI 1.00-4.84) women had delayed prenatal care initiation. Refugees had fewer prenatal visits than controls (median 12 vs. 14, p < 0.001). Refugees (73.3 %) and immigrant (78.3 %) women were more likely to have postpartum care (controls 54.8 %, p < 0.001) with differences persisting after adjustment (refugee [OR 2.00, 95 % CI 1.04-3.83] and immigrant [OR 2.79, 95 % CI 1.72-4.53]). Conclusions for Practice Refugee and immigrant women had increased risk for delayed initiation of prenatal care, but greater use of postpartum visits. Targeted outreach may be needed to improve use of beneficial care. C1 [Kentoffio, Katherine] Massachusetts Gen Hosp, Dept Med, 55 Fruit St, Boston, MA 02114 USA. [Berkowitz, Seth A.; Atlas, Steven J.; Percac-Lima, Sanja] Massachusetts Gen Hosp, Div Gen Internal Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. [Berkowitz, Seth A.; Percac-Lima, Sanja] Massachusetts Gen Hosp, Ctr Diabet, 50 Staniford St, Boston, MA 02114 USA. [Oo, Sarah A.] Massachusetts Gen Hosp, Ctr Community Hlth Improvement, 101 Merrimac St, Boston, MA 02114 USA. [Oo, Sarah A.; Percac-Lima, Sanja] Massachusetts Gen Hosp, Chelsea HealthCare Ctr, 151 Everett Ave, Chelsea, MA 02150 USA. RP Percac-Lima, S (reprint author), Massachusetts Gen Hosp, Div Gen Internal Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA.; Percac-Lima, S (reprint author), Massachusetts Gen Hosp, Ctr Diabet, 50 Staniford St, Boston, MA 02114 USA.; Percac-Lima, S (reprint author), Massachusetts Gen Hosp, Chelsea HealthCare Ctr, 151 Everett Ave, Chelsea, MA 02150 USA. EM kkentoffio@partners.org; saberkowitz@mgh.harvard.edu; satlas@partners.org; soo@partners.org; spercaclima@mgh.harvard.edu OI Berkowitz, Seth/0000-0003-1030-4297 NR 36 TC 0 Z9 0 U1 5 U2 5 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 DEC PY 2016 VL 20 IS 12 SI SI BP 2494 EP 2501 DI 10.1007/s10995-016-2072-3 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EI2FJ UT WOS:000392301800011 PM 27447794 ER PT J AU Patel, NV Mian, M Stafford, RJ Nahed, BV Willie, JT Gross, RE Danish, SF AF Patel, Nitesh V. Mian, Matthew Stafford, R. Jason Nahed, Brian V. Willie, Jon T. Gross, Robert E. Danish, Shabbar F. TI Laser Interstitial Thermal Therapy Technology, Physics of Magnetic Resonance Imaging Thermometry, and Technical Considerations for Proper Catheter Placement During Magnetic Resonance Imaging-Guided Laser Interstitial Thermal Therapy SO NEUROSURGERY LA English DT Article DE Brain tumors; Laser therapy; LITT; MRg-LITT ID TEMPORAL-LOBE EPILEPSY; INITIAL-EXPERIENCE; TISSUE-DAMAGE; ABLATION; AMYGDALOHIPPOCAMPOTOMY; DOSIMETRY; SURGERY AB Laser-induced thermal therapy has become a powerful tool in the neurosurgical armamentarium. The physics of laser therapy are complex, but a sound understanding of this topic is clinically relevant, as many centers have incorporated it into their treatment algorithm, and educated patients are demanding consideration of its use for their disease. Laser ablation has been used for a wide array of intracranial lesions. Laser catheter placement is guided by stereotactic planning; however, as the procedure has popularized, the number of ways in which the catheter can be inserted has also increased. There are many technical nuances for laser placement, and, to date, there is not a clear understanding of whether any one technique is better than the other. In this review, we describe the basic physics of magnetic resonance-guided laser-induced thermal therapy and describe the several common techniques for accurate Visualase laser catheter placement in a stepwise fashion. C1 [Patel, Nitesh V.] Rutgers State Univ, New Jersey Med Sch, Dept Neurosurg, Newark, NJ USA. [Patel, Nitesh V.; Danish, Shabbar F.] Rutgers Canc Inst New Jersey, Sect Neurosurg, New Brunswick, NJ USA. [Mian, Matthew; Nahed, Brian V.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA USA. [Stafford, R. Jason] Univ Texas MD Anderson Canc Ctr, Dept Imaging Phys, Houston, TX USA. [Willie, Jon T.; Gross, Robert E.] Emory Univ Hosp, Dept Neurosurg, 1364 Clifton Rd NE, Atlanta, GA 30322 USA. RP Patel, NV (reprint author), Rutgers State Univ, New Jersey Med Sch, Dept Neurosurg, New Brunswick, NJ 08902 USA. EM patel236@njms.rutgers.edu FU Medtronic; MRI Interventions FX Dr Danish has received honoraria from Medtronic for educational series/workshops. Drs Gross and Willie serve as consultants to and have received research grants from Medtronic and MRI Interventions and receive compensation for these services. Medtronic and MRI Interventions develop products related to the research described in this presentation. The terms of this arrangement have been reviewed and approved by Emory University in accordance with its conflict of interest policies. The other authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. NR 22 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0148-396X J9 NEUROSURGERY JI Neurosurgery PD DEC PY 2016 VL 79 IS 6 SU S BP S8 EP S16 DI 10.1227/NEU.0000000000001440 PG 9 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA EI6PB UT WOS:000392616700003 PM 27861321 ER PT J AU Baish, JW Kunert, C Padera, TP Munn, LL AF Baish, James W. Kunert, Christian Padera, Timothy P. Munn, Lance L. TI Synchronization and Random Triggering of Lymphatic Vessel Contractions SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID SMOOTH-MUSCLE-CELLS; NITRIC-OXIDE; MESENTERIC LYMPHATICS; SARCOPLASMIC-RETICULUM; TRANSMURAL PRESSURE; RESISTANCE VESSELS; DYNAMICS; STRESS; MODEL; ENDOTHELIUM AB The lymphatic system is responsible for transporting interstitial fluid back to the bloodstream, but unlike the cardiovascular system, lacks a centralized pump-the heart-to drive flow. Instead, each collecting lymphatic vessel can individually contract and dilate producing unidirectional flow enforced by intraluminal check valves. Due to the large number and spatial distribution of such pumps, high-level coordination would be unwieldy. This leads to the question of how each segment of lymphatic vessel responds to local signals that can contribute to the coordination of pumping on a network basis. Beginning with elementary fluid mechanics and known cellular behaviors, we show that two complementary oscillators emerge from i) mechanical stretch with calcium ion transport and ii) fluid shear stress induced nitric oxide production (NO). Using numerical simulation and linear stability analysis we show that the newly identified shear-NO oscillator shares similarities with the well-known Van der Pol oscillator, but has unique characteristics. Depending on the operating conditions, the shear-NO process may i) be inherently stable, ii) oscillate spontaneously in response to random disturbances or iii) synchronize with weak periodic stimuli. When the complementary shear-driven and stretch-driven oscillators interact, either may dominate, producing a rich family of behaviors similar to those observed in vivo. C1 [Baish, James W.] Bucknell Univ, Dept Biomed Engn, Lewisburg, PA 17837 USA. [Kunert, Christian; Padera, Timothy P.; Munn, Lance L.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Kunert, Christian; Padera, Timothy P.; Munn, Lance L.] Harvard Med Sch, Boston, MA USA. [Kunert, Christian] Amgen Inc, Cambridge, MA USA. RP Baish, JW (reprint author), Bucknell Univ, Dept Biomed Engn, Lewisburg, PA 17837 USA. EM baish@bucknell.edu OI Padera, Timothy/0000-0002-3453-9384 FU National Institutes of Health [R01-HL149285, R21-AI097745, DP2-OD008780, R01-HL128168] FX This work was funded by National Institutes of Health Grants R01-HL149285 (to LLM), R21-AI097745 and DP2-OD008780 (to TPP), and R01-HL128168 (to JWB, TPP, LLM) nih.gov. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 47 TC 0 Z9 0 U1 2 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-734X EI 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD DEC PY 2016 VL 12 IS 12 AR e1005231 DI 10.1371/journal.pcbi.1005231 PG 23 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA EH9XT UT WOS:000392126000021 PM 27935958 ER PT J AU Jo, U Cai, W Wang, JW Kwon, Y D'Andrea, AD Kim, H AF Jo, Ukhyun Cai, Winson Wang, Jingming Kwon, Yoojin D'Andrea, Alan D. Kim, Hyungjin TI PCNA-Dependent Cleavage and Degradation of SDE2 Regulates Response to Replication Stress SO PLOS GENETICS LA English DT Article ID DNA-DAMAGE RESPONSE; CROSS-LINK REPAIR; GENOMIC INSTABILITY; UBIQUITIN LIGASE; TRANSLESION SYNTHESIS; BINDING MOTIF; POLYMERASE ETA; DVC1 C1ORF124; P97 ADAPTER; CRL4(CDT2) AB Maintaining genomic integrity during DNA replication is essential for cellular survival and for preventing tumorigenesis. Proliferating cell nuclear antigen (PCNA) functions as a processivity factor for DNA replication, and posttranslational modification of PCNA plays a key role in coordinating DNA repair against replication-blocking lesions by providing a platform to recruit factors required for DNA repair and cell cycle control. Here, we identify human SDE2 as a new genome surveillance factor regulated by PCNA interaction. SDE2 contains an N-terminal ubiquitin-like (UBL) fold, which is cleaved at a diglycine motif via a PCNA-interacting peptide (PIP) box and deubiquitinating enzyme activity. The cleaved SDE2 is required for negatively regulating ultraviolet damage-inducible PCNA monoubiquitination and counteracting replication stress. The cleaved SDE2 products need to be degraded by the CRL4(CDT2) ubiquitin E3 ligase in a cell cycle-and DNA damage-dependent manner, and failure to degrade SDE2 impairs S phase progression and cellular survival. Collectively, this study uncovers a new role for CRL4(CDT2) in protecting genomic integrity against replication stress via regulated proteolysis of PCNA-associated SDE2 and provides insights into how an integrated UBL domain within linear polypeptide sequence controls protein stability and function. C1 [Jo, Ukhyun; Cai, Winson; Wang, Jingming; Kwon, Yoojin; Kim, Hyungjin] SUNY Stony Brook, Dept Pharmacol Sci, Stony Brook, NY 11794 USA. [D'Andrea, Alan D.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [D'Andrea, Alan D.] Dana Farber Canc Inst, Ctr DNA Damage & Repair, Boston, MA 02115 USA. RP Kim, H (reprint author), SUNY Stony Brook, Dept Pharmacol Sci, Stony Brook, NY 11794 USA. EM hyungjin.kim@stonybrook.edu FU Research Foundation at SUNY Stony Brook; Cancer Center; Alexandrine and Alexander L. Sinsheimer Fund; Concern Foundation; US National Institutes of Health [2R01HL52725] FX This work was supported by: The Research Foundation at SUNY Stony Brook and the Cancer Center (to HK); The Alexandrine and Alexander L. Sinsheimer Fund (to HK); The Concern Foundation (to HK); and The US National Institutes of Health (2R01HL52725) (to ADD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 58 TC 0 Z9 0 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD DEC PY 2016 VL 12 IS 12 AR e1006465 DI 10.1371/journal.pgen.1006465 PG 26 WC Genetics & Heredity SC Genetics & Heredity GA EI0CD UT WOS:000392138700019 PM 27906959 ER PT J AU Shi, JX Park, JH Duan, JB Berndt, ST Moy, W Yu, K Song, L Wheeler, W Hua, X Silverman, D Garcia-Closas, M Hsiung, CA Figueroa, JD Cortessis, VK Malats, N Karagas, MR Vineis, P Chang, IS Lin, DX Zhou, BS Seow, A Matsuo, K Hong, YC Caporaso, NE Wolpin, B Jacobs, E Petersen, GM Klein, AP Li, DH Risch, H Sanders, AR Hsu, L Schoen, RE Brenner, H Stolzenberg-Solomon, R Gejman, P Lan, Q Rothman, N Amundadottir, LT Landi, MT Levinson, DF Chanock, SJ Chatterjee, N AF Shi, Jianxin Park, Ju-Hyun Duan, Jubao Berndt, Sonja T. Moy, Winton Yu, Kai Song, Lei Wheeler, William Hua, Xing Silverman, Debra Garcia-Closas, Montserrat Hsiung, Chao Agnes Figueroa, Jonine D. Cortessis, Victoria K. Malats, Nuria Karagas, Margaret R. Vineis, Paolo Chang, I-Shou Lin, Dongxin Zhou, Baosen Seow, Adeline Matsuo, Keitaro Hong, Yun-Chul Caporaso, Neil E. Wolpin, Brian Jacobs, Eric Petersen, Gloria M. Klein, Alison P. Li, Donghui Risch, Harvey Sanders, Alan R. Hsu, Li Schoen, Robert E. Brenner, Hermann Stolzenberg-Solomon, Rachael Gejman, Pablo Lan, Qing Rothman, Nathaniel Amundadottir, Laufey T. Landi, Maria Teresa Levinson, Douglas F. Chanock, Stephen J. Chatterjee, Nilanjan CA MGS Mol Genetics Schizophrenia GWA GAME-ON TRICL Transdisciplinary Re PRACTICAL PRostate Canc Assoc Grp PanScan Consortium GAME-ON ELLIPSE Consortium TI Winner's Curse Correction and Variable Thresholding Improve Performance of Polygenic Risk Modeling Based on Genome-Wide Association Study Summary-Level Data SO PLOS GENETICS LA English DT Article ID BODY-MASS INDEX; SUSCEPTIBILITY LOCI; HUMAN HEIGHT; PARTITIONING HERITABILITY; PSYCHIATRIC-DISORDERS; INCREASES ACCURACY; GENETIC-VARIATION; COMMON VARIANTS; CANCER RISK; PREDICTION AB Recent heritability analyses have indicated that genome-wide association studies (GWAS) have the potential to improve genetic risk prediction for complex diseases based on polygenic risk score (PRS), a simple modelling technique that can be implemented using summary-level data from the discovery samples. We herein propose modifications to improve the performance of PRS. We introduce threshold-dependent winner's-curse adjustments for marginal association coefficients that are used to weight the single-nucleotide polymorphisms (SNPs) in PRS. Further, as a way to incorporate external functional/annotation knowledge that could identify subsets of SNPs highly enriched for associations, we propose variable thresholds for SNPs selection. We applied our methods to GWAS summary-level data of 14 complex diseases. Across all diseases, a simple winner's curse correction uniformly led to enhancement of performance of the models, whereas incorporation of functional SNPs was beneficial only for selected diseases. Compared to the standard PRS algorithm, the proposed methods in combination led to notable gain in efficiency (25-50% increase in the prediction R-2) for 5 of 14 diseases. As an example, for GWAS of type 2 diabetes, winner's curse correction improved prediction R-2 from 2.29% based on the standard PRS to 3.10% (P = 0.0017) and incorporating functional annotation data further improved R-2 to 3.53% (P = 2x10(-5)). Our simulation studies illustrate why differential treatment of certain categories of functional SNPs, even when shown to be highly enriched for GWAS-heritability, does not lead to proportionate improvement in genetic risk-prediction because of non-uniform linkage disequilibrium structure. C1 [Shi, Jianxin; Berndt, Sonja T.; Yu, Kai; Song, Lei; Hua, Xing; Silverman, Debra; Garcia-Closas, Montserrat; Figueroa, Jonine D.; Caporaso, Neil E.; Stolzenberg-Solomon, Rachael; Lan, Qing; Rothman, Nathaniel; Amundadottir, Laufey T.; Chanock, Stephen J.; Chatterjee, Nilanjan] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Park, Ju-Hyun] Dongguk Univ, Dept Stat, Seoul, South Korea. [Duan, Jubao; Gejman, Pablo] Univ Chicago, North Shore Univ Hlth Syst, Pritzker Sch Med, Ctr Psychiat Genet,Dept Psychiat & Behav Sci,Res, Evanston, IL USA. [Moy, Winton] Northern Illinois Univ, Dept Stat, De Kalb, IL USA. [Wheeler, William] Informat Management Serv Inc, Rockville, MD USA. [Hsiung, Chao Agnes] Natl Hlth Res Inst, Inst Populat Hlth Sci, Miaoli, Taiwan. [Figueroa, Jonine D.] Univ Edinburgh, Sch Med, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland. [Cortessis, Victoria K.] Univ Southern Calif, USC Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA. [Cortessis, Victoria K.] Univ Southern Calif, USC Keck Sch Med, Dept Obstet & Gynecol, Los Angeles, CA USA. [Cortessis, Victoria K.] Univ Southern Calif, USC Keck Sch Med, Norris Comprehens Canc Ctr, Los Angeles, CA USA. [Malats, Nuria] Spanish Natl Canc Res Ctr CNIO, Genet & Mol Epidemiol Grp, Madrid, Spain. [Karagas, Margaret R.] Dartmouth Coll, Geisel Sch Med, Hanover, NH 03755 USA. [Vineis, Paolo] Human Genet Fdn, Turin, Italy. [Vineis, Paolo] Imperial Coll London, MRC, PHE Ctr Environm & Hlth, Sch Publ Hlth, London, England. [Chang, I-Shou] Natl Hlth Res Inst, Natl Inst Canc Res, Zhunan, Taiwan. [Lin, Dongxin] Chinese Acad Med Sci, Canc Inst & Hosp, Dept Etiol & Carcinogenesis, Beijing, Peoples R China. [Lin, Dongxin] Peking Union Med Coll, Beijing, Peoples R China. [Lin, Dongxin] Chinese Acad Med Sci, Canc Inst & Hosp, State Key Lab Mol Oncol, Beijing, Peoples R China. [Zhou, Baosen] China Med Univ, Sch Publ Hlth, Dept Epidemiol, Shenyang, Peoples R China. [Seow, Adeline] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore. [Matsuo, Keitaro] Aichi Canc Ctr, Res Inst, Div Mol Med, Chikusa Ku, Nagoya, Aichi, Japan. [Hong, Yun-Chul] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea. [Wolpin, Brian] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Wolpin, Brian] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Wolpin, Brian] Harvard Med Sch, Boston, MA USA. [Jacobs, Eric] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Petersen, Gloria M.] Mayo Clin, Dept Hlth Sci Res, Div Epidemiol, Rochester, MN USA. [Klein, Alison P.; Chatterjee, Nilanjan] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Klein, Alison P.] Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Li, Donghui] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX 77030 USA. [Hsu, Li] Yale Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT USA. [Hsu, Li] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Schoen, Robert E.] Univ Pittsburgh, Med Ctr, Dept Med & Epidemiol, Pittsburgh, PA USA. [Brenner, Hermann] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Brenner, Hermann] German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany. [Brenner, Hermann] Natl Ctr Tumor Dis NCT, Heidelberg, Germany. [Brenner, Hermann] German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany. [Levinson, Douglas F.] Stanford Univ, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. [Chatterjee, Nilanjan] Johns Hopkins Univ, Dept Biostat, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. RP Shi, JX; Chatterjee, N (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA.; Chatterjee, N (reprint author), Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA.; Chatterjee, N (reprint author), Johns Hopkins Univ, Dept Biostat, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. EM Jianxin.Shi@nih.gov; nilanjan@jhu.edu RI Brenner, Hermann/B-4627-2017 OI Brenner, Hermann/0000-0002-6129-1572 FU NIH Intramural Research program; NIH [U19 CA148127]; National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services [U01 CA137088, R01 CA059045]; Regional Council of Pays de la Loire; Groupement des Entreprises Francaises dans la Lutte contre le Cancer (GEFLUC); Association Anne de Bretagne Genetique; Ligue Regionale Contre le Cancer (LRCC); National Institutes of Health [R01 CA60987, R01 CA48998, P01 CA 055075, UM1 CA167552, R01 137178, R01 CA151993, P50 CA127003, UM1 CM 86107, R01 CM 37178, P01 CA87969, R01 CA042182, R37 CA54281, P01 CA033619, R01 CA63464, U01 CA074783, R01 CA076366, K05 CA154337]; German Research Council (Deutsche Forschungsgemeinschaft) [BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1]; German Federal Ministry of Education and Research [01KH0404, 01ER0814]; Ontario Research Fund; Canadian Institutes of Health Research; Ontario Institute for Cancer Research; Ontario Ministry of Research and Innovation; National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C] FX The research was supported by the NIH Intramural Research program. The TRICL Consortium was supported by NIH grant U19 CA148127. Funding for GECCO consortium: National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services (U01 CA137088; R01 CA059045). ASTERISK: a Hospital Clinical Research Program (PHRC) and supported by the Regional Council of Pays de la Loire, the Groupement des Entreprises Francaises dans la Lutte contre le Cancer (GEFLUC), the Association Anne de Bretagne Genetique and the Ligue Regionale Contre le Cancer (LRCC). COLO2&3: National Institutes of Health (R01 CA60987). DACHS: German Research Council (Deutsche Forschungsgemeinschaft, BR 1704/6-1, BR 1704/6-3, BR 1704/6-4 and CH 117/1-1), and the German Federal Ministry of Education and Research (01KH0404 and 01ER0814). DALS: National Institutes of Health (R01 CA48998 to M. L. Slattery). HPFS is supported by the National Institutes of Health (P01 CA 055075, UM1 CA167552, R01 137178, R01 CA151993 and P50 CA127003), NHS by the National Institutes of Health (UM1 CM 86107, R01 CM 37178, P01 CA87969, R01 CA151993 and P50 CA127003) and PHS by the National Institutes of Health (R01 CA042182). MEC: National Institutes of Health (R37 CA54281, P01 CA033619, and R01 CA63464). OFCCR: National Institutes of Health, through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783); see CCFR section above. Additional funding toward genetic analyses of OFCCR includes the Ontario Research Fund, the Canadian Institutes of Health Research, and the Ontario Institute for Cancer Research, through generous support from the Ontario Ministry of Research and Innovation. PMH: National Institutes of Health (R01 CA076366 to P.A. Newcomb). VITAL: National Institutes of Health (K05 CA154337). WHI: The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 60 TC 1 Z9 1 U1 5 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD DEC PY 2016 VL 12 IS 12 AR e1006493 DI 10.1371/journal.pgen.1006493 PG 24 WC Genetics & Heredity SC Genetics & Heredity GA EI0CD UT WOS:000392138700036 PM 28036406 ER PT J AU Su, MY Fisher, DE AF Su, Mack Y. Fisher, David E. TI Immunotherapy in the Precision Medicine Era: Melanoma and Beyond SO PLOS MEDICINE LA English DT Editorial Material ID IMMUNE CHECKPOINT BLOCKADE; METASTATIC MELANOMA; UNTREATED MELANOMA; CTLA-4 BLOCKADE; TUMOR MICROENVIRONMENT; BRAF INHIBITION; T-CELLS; CANCER; IPILIMUMAB; NIVOLUMAB C1 [Su, Mack Y.; Fisher, David E.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Dermatol, Cutaneous Biol Res Ctr, Boston, MA 02115 USA. RP Fisher, DE (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Dermatol, Cutaneous Biol Res Ctr, Boston, MA 02115 USA. EM dfisher3@mgh.harvard.edu FU NIH [5P01 CA163222, 5R01 AR043369-19, T32GM007753]; Melanoma Research Alliance; Dr. Miriam and Sheldon G. Adelson Medical Research Foundation FX The authors gratefully acknowledge support from NIH grants 5P01 CA163222, 5R01 AR043369-19, and T32GM007753, and grants from the Melanoma Research Alliance, and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 0 Z9 0 U1 2 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1549-1676 J9 PLOS MED JI PLos Med. PD DEC PY 2016 VL 13 IS 12 AR e1002196 DI 10.1371/journal.pmed.1002196 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA EI0DJ UT WOS:000392142400009 PM 27959922 ER PT J AU Chen, XJ Al-Sheikh, M Chan, CK Hariri, AH Abraham, P Lalezary, M Lin, SG Sadda, S Sarraf, D AF Chen, Xuejing Al-Sheikh, Mayss Chan, Clement K. Hariri, Amir H. Abraham, Prema Lalezary, Maziar Lin, Steven G. Sadda, Srinivas Sarraf, David TI TYPE 1 VERSUS TYPE 3 NEOVASCULARIZATION IN PIGMENT EPITHELIAL DETACHMENTS ASSOCIATED WITH AGE-RELATED MACULAR DEGENERATION AFTER ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY A Prospective Study SO RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES LA English DT Article; Proceedings Paper CT 4th Annual International Retinal Imaging Symposium (IRIS) CY MAR 17, 2016 CL Univ Calif, Los Angeles, Los Angeles, CA HO Univ Calif, Los Angeles DE aflibercept; age-related macular degeneration; imaging; intravitreal injection; optical coherence tomography; pigment epithelial detachment; retinal angiomatous proliferation; type 1 neovascularization; type 3 neovascularization; vascular endothelial growth factor ID OPTICAL COHERENCE TOMOGRAPHY; INTRAVITREAL AFLIBERCEPT; VISUAL-ACUITY; CHOROIDAL NEOVASCULARIZATION; ANATOMICAL OUTCOMES; TREATMENT RESPONSE; RANIBIZUMAB; EYES; MACULOPATHY; SUBANALYSIS AB Purpose: To evaluate the response to aflibercept therapy for Type 1 and Type 3 neovascularization in pigment epithelial detachments associated with treatment-naive, neovascular age-related macular degeneration. Methods: In this multicentered, prospective study, eligible eyes underwent an intravitreal aflibercept injection protocol for 12 months. Visual acuity and morphologic features of the pigment epithelial detachments were compared at baseline and follow-up intervals between eyes with Type 1 versus Type 3 neovascularization. Results: Thirty-six eyes were analyzed. At 12 months, Type 1 lesions showed a 4.5 +/- 23 Early Treatment of Diabetic Retinopathy Study letter improvement (P = 0.1665) versus a 14 +/- 11 (P = 0.0072) letter improvement with Type 3 lesions. Both Type 1 and 3 eyes showed a significant decrease in pigment epithelial detachment size, subretinal fluid, and subretinal hyperreflective material; however, Type 3 eyes had a greater reduction in pigment epithelial detachment size and subretinal hyperreflective material, as well as a reduction in central retinal thickness. Type 1 eyes required an average of 1.636 (range, 1-4) injections to resolve fluid, which was greater than Type 3 eyes, which required an average of 1.143 (range, 1-2) injections (P = 0.0251). Conclusion: Intravitreal aflibercept injections were efficacious for pigment epithelial detachments, but baseline and follow-up anatomical and functional outcomes differed in Type 1 versus Type 3 neovascularization. The better response of Type 3 eyes with fewer injections suggests that differentiation of the neovascularization subtype at the initial diagnosis may allow for a more tailored, optimal therapy. C1 [Chen, Xuejing; Al-Sheikh, Mayss; Sarraf, David] Univ Calif Los Angeles, David Geffen Sch Med, Dept Ophthalmol, Stein Eye Inst, Los Angeles, CA 90095 USA. [Al-Sheikh, Mayss; Hariri, Amir H.; Sadda, Srinivas] Univ Calif Los Angeles, David Geffen Sch Med, Dept Ophthalmol, Doheny Eye Inst, Los Angeles, CA 90095 USA. [Chan, Clement K.; Lalezary, Maziar; Lin, Steven G.] Southern Calif Desert Retina Consultants, Palm Desert, CA USA. [Chan, Clement K.] Loma Linda Univ, Inst Eye, Dept Ophthalmol, Loma Linda, CA 92350 USA. [Abraham, Prema] Black Hills Reg Eye Inst, Rapid City, SD USA. [Sarraf, David] Greater Los Angeles Vet Affairs Healthcare Syst, Dept Ophthalmol, Los Angeles, CA USA. RP Sarraf, D (reprint author), Univ Calif Los Angeles, Retinal Disorders & Ophthalm Genet Div, Stein Eye Inst, 100 Stein Plaza, Los Angeles, CA 90095 USA. EM dsarraf@ucla.edu FU Regeneron; Genentech; NEI; Acucela; Ophthotech; Sequenom; Allergan; Theratechnologies; Juvenile Diabetes Research Foundation; Pfizer; Schering-Plough; Thrombogenics; Ophthotect; Optovue; Optos; Carl Zeiss Meditec FX Supported by a research grant from Regeneron. No support was received from the NIH, Wellcome Trust, or HHMI. C. K. Chan receives research support from Genentech, NEI, Acucela, Ophthotech, Sequenom, Regeneron, Allergan, and Theratechnologies. P. Abraham receives research support from Allergan, Genentech, NEI, Juvenile Diabetes Research Foundation, Ophthotech, Pfizer, Schering-Plough, and Thrombogenics. M. Lalezary and S. G. Lin receive research support from Allergan, Acucela, Regeneron, Genentech, Ophthotect, and NEI. D. Sarraf has research grants from Regeneron, Genentech, and Optovue. S. Sadda is a consultant for Optos, Carl Zeiss Meditec, Allergan, Genentech, Regeneron, Bayer, Novartis, and Iconic and receives research support from Optos, Carl Zeiss Meditec, Allergan, and Genentech. X. Chen, M. Al-Sheikh, and A. H. Hariri have no financial disclosures. NR 34 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0275-004X EI 1539-2864 J9 RETINA-J RET VIT DIS JI Retin.-J. Retin. Vitr. Dis. PD DEC PY 2016 VL 36 IS 12 SU 1 BP S50 EP S64 PG 15 WC Ophthalmology SC Ophthalmology GA EH7IP UT WOS:000391946700006 PM 28005663 ER PT J AU Falavarjani, KG Scott, AW Wang, K Han, IC Chen, XJ Klufas, M Hubschman, JP Schwartz, SD Sadda, SR Sarraf, D Tsui, I AF Falavarjani, Khalil Ghasemi Scott, Adrienne W. Wang, Kang Han, Ian C. Chen, Xuejing Klufas, Michael Hubschman, Jean-Pierre Schwartz, Steven D. Sadda, Srinivas R. Sarraf, David Tsui, Irena TI CORRELATION OF MULTIMODAL IMAGING IN SICKLE CELL RETINOPATHY SO RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES LA English DT Article; Proceedings Paper CT 4th Annual International Retinal Imaging Symposium (IRIS) CY MAR 17, 2016 CL Univ Calif, Los Angeles, Los Angeles, CA HO Univ Calif, Los Angeles DE ischemic index; optical coherence tomography angiography; retinal imaging; sickle cell retinopathy; spectral domain optical coherence tomography; ultra-wide-field fluorescein angiography ID OPTICAL COHERENCE TOMOGRAPHY; ANGIOGRAPHY; DISEASE; HEMOGLOBINOPATHIES AB Purpose: To correlate macular findings on spectral domain optical coherence tomography (SDOCT) and optical coherence tomography angiography (OCTA) with quantitative ischemic index calculations on ultra-wide-field fluorescein angiography (UWFFA) in patients with sickle cell retinopathy. Methods: In this retrospective case series, SDOCT, OCTA, and UWFFA images of patients with sickle cell retinopathy were evaluated. Eyes were staged based on the Goldberg classification of proliferative sickle cell retinopathy. Focal areas of macular thinning were assessed on SDOCT, macular vessel density was derived from OCTA, and peripheral ischemic index was calculated from UWFFA. Results: Eighteen eyes of 10 patients were included. Mean age was 36.8 +/- 16.8 years, and 6 patients (11 eyes) were SS, 3 patients (5 eyes) were SC, and 1 patient (2 eyes) was Sb thalassemia in hemoglobin electrophoresis. Abnormal macular findings included inner retinal atrophy in 11 eyes (61%) on SDOCT, vascular remodeling and nonperfusion in the superficial and deep retinal capillary plexus in 12 eyes (67%) on OCTA, and macular microvascular abnormalities in 9 eyes (50%) on UWFFA. Sickle cell retinopathy Stage I was identified in 4 eyes (22.2%), Stage II in 8 eyes (44.4%), and Stage III in 6 eyes (33.3%). Mean ischemic index was 14.1 +/- 9.1%. Ischemic index was significantly correlated with hemoglobinopathy subtype (23.7 +/- 9.8%, 9.3 +/- 5.4%, and 16.3 +/- 3.2%, for SC, SS, and Sb thalassemia disease, respectively), stage of sickle cell retinopathy (22.5 +/- 9.2%, 12.5 +/- 4.9%, and 4.5 +/- 0.73% for Stages III, II, and I, respectively), and presence of retinal thinning on SDOCT (17.4 +/- 9.7% vs. 8.8 +/- 5.1%, respectively). Conclusion: Multimodal imaging can provide a more complete description of the microvascular and structural alterations associated with sickle retinopathy. The correlation between the severity of peripheral nonperfusion and stage and subtype of retinopathy suggests that UWF imaging may be a useful tool in the evaluation of these patients. C1 [Falavarjani, Khalil Ghasemi; Wang, Kang; Chen, Xuejing; Klufas, Michael; Hubschman, Jean-Pierre; Schwartz, Steven D.; Sadda, Srinivas R.; Sarraf, David; Tsui, Irena] Univ Calif Los Angeles, David Geffen Sch Med, Dept Ophthalmol, Los Angeles, CA 90095 USA. [Falavarjani, Khalil Ghasemi] Iran Univ Med Sci, Rassoul Akram Hosp, Eye Res Ctr, Tehran, Iran. [Scott, Adrienne W.; Han, Ian C.] Johns Hopkins Sch Med, Wilmer Eye Inst, Baltimore, MD USA. [Sarraf, David] Greater Los Angeles VA Healthcare Ctr, Los Angeles, CA USA. RP Tsui, I (reprint author), Jules Stein Eye Inst, 100 Stein Plaza, Los Angeles, CA 90095 USA. EM itsui@jsei.ucla.edu FU Optos; Genentech; Allergan; Carl Zeiss Meditec; Regeneron; Optovue FX S. R. Sadda is a consultant for Optos, Genentech, and Allergan and receives research support from Optos, Genentech, Allergan, and Carl Zeiss Meditec. D. Sarraf receives research grant from Genentech, Regeneron, and Optovue. The remaining authors have no financial/conflicting interests to disclose. NR 18 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0275-004X EI 1539-2864 J9 RETINA-J RET VIT DIS JI Retin.-J. Retin. Vitr. Dis. PD DEC PY 2016 VL 36 IS 12 SU 1 BP S111 EP S117 PG 7 WC Ophthalmology SC Ophthalmology GA EH7IP UT WOS:000391946700012 ER PT J AU Haug, SJ Wong, RW Day, S Choudhry, N Sneed, S Prasad, P Read, S McDonald, RH Agarwal, A Davis, J Sarraf, D AF Haug, Sara J. Wong, Robert W. Day, Shelley Choudhry, Netan Sneed, Scott Prasad, Pradeep Read, Sarah McDonald, Richard H. Agarwal, Anita Davis, Janet Sarraf, David TI DIDANOSINE RETINAL TOXICITY SO RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES LA English DT Article; Proceedings Paper CT 4th Annual International Retinal Imaging Symposium (IRIS) CY MAR 17, 2016 CL Univ Calif, Los Angeles, Los Angeles, CA HO Univ Calif, Los Angeles DE toxic retinopathy; HIV; didanosine retinal toxicity ID HUMAN-IMMUNODEFICIENCY-VIRUS; MITOCHONDRIAL-DNA; OPHTHALMOPLEGIA; DIDEOXYINOSINE; ZIDOVUDINE; THERAPY; LESIONS; ADULTS AB Purpose: To report nine new cases of retinal degeneration secondary to didanosine toxicity and to summarize the previously reported cases in the literature. Methods: This was a multicenter, retrospective, observational case study from seven institutions. Medical records of patients who demonstrated well-demarcated severe midperipheral chorioretinal degeneration and who were previously treated with didanosine therapy were collected and the following information was reviewed: age, gender, medical history, detailed medication history including current and previous antiretroviral use, ocular and retinal examination findings, and multimodal imaging findings with optical coherence tomography, fundus photography, wide-field fundus autofluorescence, and wide-field fluorescein angiography. When available, findings with electrophysiology testing and automated perimetry were also collected and reviewed. A literature review was also performed to collect all reported cases of chorioretinal degeneration secondary to didanosine toxicity. Results: Nine patients were identified who had findings consistent with peripheral retinal toxicity secondary to didanosine use. Eight of the 9 patients were men, and the median age was 54 years at the time of presentation (mean: 55 years, range, 42-71 years). Snellen distance acuity ranged from 20/20 to 20/32. At least three of the cases in the series demonstrated progression of the peripheral retinal pigment epithelium and photoreceptor atrophy despite didanosine cessation. A review of the literature revealed 10 additional cases of didanosine toxicity. Seven of the 10 cases were in men (70%), and the average age was 26 years with a wide range (2-54 years). Chorioretinal findings were very similar to this cohort. Conclusion: Herein, we report the largest series of nine cases of peripheral chorioretinal degeneration secondary to didanosine toxicity in adults. When combined with the cases in the literature, 19 cases of didanosine toxicity, 4 of which occurred in children, were collected and analyzed. Three of the new cases presented showed clear progression of degeneration despite didanosine cessation. Newer nucleoside reverse transcriptase inhibitors may potentiate mitochondrial DNA damage and lead to continued chorioretinal degeneration. C1 [Haug, Sara J.; McDonald, Richard H.] West Coast Retina Med Grp, San Francisco, CA USA. [Wong, Robert W.; Day, Shelley] Austin Retina Associates, Austin, TX USA. [Choudhry, Netan] Herzig Eye Inst, Toronto, ON, Canada. [Sneed, Scott] Associated Retinal Consultants PC, Royal Oak, MI USA. [Prasad, Pradeep; Sarraf, David] Univ Calif Los Angeles, Stein Eye Inst, Retinal Disorders & Ophthalm Genet Div, Los Angeles, CA USA. [Read, Sarah; Davis, Janet] Univ Miami, Bascom Palmer Eye Inst, Miami, FL USA. [Agarwal, Anita] Vanderbilt Univ, Vanderbilt Eye Inst, 221 Kirkland Hall, Nashville, TN 37235 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, Stein Eye Inst, Retinal Disorders & Ophthalm Genet Div, 100 Stein Plaza, Los Angeles, CA 90095 USA. EM dsarraf@ucla.edu FU Allergan; Genentech; Regeneron; Optovue FX Dr. Sarraf has research grants from Allergan, Genentech, Regeneron and Optovue, is a consultant for Genentech and Optovue, and is a paid speaker for Optovue. None of the authors have any financial/conflicting interests to disclose. NR 16 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0275-004X EI 1539-2864 J9 RETINA-J RET VIT DIS JI Retin.-J. Retin. Vitr. Dis. PD DEC PY 2016 VL 36 IS 12 SU 1 BP S159 EP S167 PG 9 WC Ophthalmology SC Ophthalmology GA EH7IP UT WOS:000391946700017 PM 28005674 ER PT J AU Pichi, F Srvivastava, SK Chexal, S Lembo, A Lima, LH Neri, P Saitta, A Chhablani, J Albini, TA Nucci, P Freund, KB Chung, H Lowder, CY Sarraf, D AF Pichi, Francesco Srvivastava, Sunil K. Chexal, Saradha Lembo, Andrea Lima, Luiz H. Neri, Piergiorgio Saitta, Andrea Chhablani, Jay Albini, Thomas A. Nucci, Paolo Freund, K. Bailey Chung, Hyewon Lowder, Careen Y. Sarraf, David TI EN FACE OPTICAL COHERENCE TOMOGRAPHY AND OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY OF MULTIPLE EVANESCENT WHITE DOT SYNDROME New Insights Into Pathogenesis SO RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES LA English DT Article; Proceedings Paper CT 4th Annual International Retinal Imaging Symposium (IRIS) CY MAR 17, 2016 CL Univ Calif, Los Angeles, Los Angeles, CA HO Univ Calif, Los Angeles DE MEWDS; en face OCT; OCT angiography ID INDOCYANINE GREEN ANGIOGRAPHY; FUNDUS AUTOFLUORESCENCE; CHOROIDAL THICKNESS; OUTER; UVEITIS; INNER AB Purpose: To localize the various levels of abnormalities in multiple evanescent white dot syndrome by comparing "en face" optical coherence tomography (OCT) and OCT angiography with various conventional imaging modalities. Methods: In this retrospective case series, multimodal imaging was performed in 9 retinal centers on 36 patients with multiple evanescent white dot syndrome and included widefield fundus autofluorescence (FAF), fluorescein angiography (FA), and indocyanine green angiography, and B-scan and "en face" C-scan enhanced depth imaging and spectral domain OCT. Optical coherence tomography angiography was also performed at the level of the superficial and deep retinal capillary plexus and choroid. Results: Multiple evanescent white dot syndrome lesions were more numerous and more easily detectable with FA and FAF. Two types of lesions were identified with FAF, FA, and indocyanine green angiography: larger widely scattered "spots" (approximately 200 mu in diameter) that were hyperfluorescent with FA, hyperautofluorescent with FAF, and hyporeflective in indocyanine green angiography, representing abnormalities primarily at the retinal pigment epithelium/photoreceptor junction; and punctate "dots" (less than 100 m in diameter) that were hyperfluorescent with FA, hyperautofluorescent, or isoautofluorescent with FAF, and hypofluorescent with indocyanine green angiography and that localized to the outer nuclear layer. These lesions colocalized with "en face" OCT. The larger confluent "spots" were hyporeflective and colocalized to the level of the ellipsoid zone, whereas smaller hyperreflective "dots" colocalized to the outer nuclear layer. The location of the "dots" in the outer nuclear layer was further confirmed by structural spectral domain optical coherence tomography which showed coalescence of the dots into hyperreflective lines extending from the external limiting membrane to the outer plexiform layer in certain cases. Optical coherence tomography angiography analysis of the retinal microvasculature and choriocapillaris and choroid were entirely unremarkable in 100% of our patients. Conclusion: By combining multimodal imaging, the authors propose that multiple evanescent white dot syndrome is primarily the result of inflammation at the outer photoreceptor level leading to a "photoreceptoritis" and causing loss of the inner and outer segments. Its evanescent nature suggests that the photoreceptor cell bodies remain intact ensuring complete recovery of the photoreceptor inner and outer segments in most cases, compatible with the clinical course of spontaneous resolution of white spots and dots. C1 [Pichi, Francesco; Lembo, Andrea; Nucci, Paolo] Univ Eye Clin, San Giuseppe Hosp, Milan, Italy. [Pichi, Francesco; Srvivastava, Sunil K.; Lowder, Careen Y.] Cleveland Clin Fdn, Cole Eye Inst, 9500 Euclid Ave, Cleveland, OH 44195 USA. [Chexal, Saradha] Retina Consultants Austin, Austin, TX USA. [Lima, Luiz H.] Fed Univ Sao Paulo UNIFESP, Sao Paulo, Brazil. [Neri, Piergiorgio; Saitta, Andrea] Polytech Univ Marche, Eye Clin, Ocular Immunol Serv, Ancona, Italy. [Chhablani, Jay] LV Prasad Eye Inst, Smt Kanuri Santhamma Retina Vitreous Ctr, Hyderabad, Andhra Pradesh, India. [Albini, Thomas A.] Univ Miami, Miller Sch Med, Bascom Palmer Eye Inst, Miami, FL 33136 USA. [Freund, K. Bailey] Vitreous Retina Macula Consultants New York, New York, NY USA. [Chung, Hyewon] Konkuk Univ, Sch Med, Dept Ophthalmol, Seoul, South Korea. [Sarraf, David] Univ Calif Los Angeles, Stein Eye Inst, Los Angeles, CA USA. [Sarraf, David] Greater Los Angeles VA Healthcare Ctr, Los Angeles, CA USA. RP Pichi, F (reprint author), Cleveland Clin, Cole Eye Inst, 9500 Euclid Ave, Cleveland, OH 44106 USA. EM ilmiticopicchio@gmail.com FU Macula Foundation Inc, New York, NY FX Supported by the Macula Foundation Inc, New York, NY. NR 37 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0275-004X EI 1539-2864 J9 RETINA-J RET VIT DIS JI Retin.-J. Retin. Vitr. Dis. PD DEC PY 2016 VL 36 IS 12 SU 1 BP S178 EP S188 PG 11 WC Ophthalmology SC Ophthalmology GA EH7IP UT WOS:000391946700019 PM 28005676 ER PT J AU Su, D Lin, S Phasukkijwatana, N Chen, XJ Tan, A Freund, KB Sarraf, D AF Su, Daniel Lin, Shawn Phasukkijwatana, Nopasak Chen, Xuejing Tan, Anna Freund, K. Bailey Sarraf, David TI AN UPDATED STAGING SYSTEM OF TYPE 3 NEOVASCULARIZATION USING SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY SO RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES LA English DT Article; Proceedings Paper CT 4th Annual International Retinal Imaging Symposium (IRIS) CY MAR 17, 2016 CL Univ Calif, Los Angeles, Los Angeles, CA HO Univ Calif, Los Angeles DE age-related macular degeneration; intraretinal neovascularization; optical coherence tomography; pigment epithelial detachment; retinal angiomatous proliferation; staging system; Type 3 neovascularization; vascular endothelial growth factor ID RETINAL ANGIOMATOUS PROLIFERATION; OCCULT CHOROIDAL NEOVASCULARIZATION; MACULAR DEGENERATION; CLINICOPATHOLOGICAL CORRELATION; HYPERREFLECTIVE FOCI; ANGIOGRAPHY; SUBTYPES; EYE; OCT; ASSOCIATION AB Purpose: To comprehensively investigate spectral domain optical coherence tomography features associated with Type 3 neovascularization and determine the prevalence of each feature and to develop an updated staging system for Type 3 neovascularization based on spectral domain optical coherence tomography findings. Methods: The authors retrospectively analyzed 34 eyes with new-onset Type 3 neovascularization. Spectral domain optical coherence tomography images at onset of Type 3 neovascularization, immediately after the first injection, and at the final quiescent visit were analyzed for the presence of specific optical coherence tomography features. In addition, when available, optical coherence tomography images from the visit before onset were studied. Results: Among 18 eyes with preonset optical coherence tomography, 77.8% had preexisting intraretinal hyperreflective foci (precursor lesion). In the same group of eyes, 44.4% and 27.8% exhibited outer plexiform layer disruption and outer plexiform layer downward deflection, respectively. At the onset of detectable Type 3 neovascularization, all 34 eyes demonstrated a hyperreflective focus with cystoid macular edema and 85.3% exhibited disruption of the retinal pigment epithelium. Serous pigment epithelial detachment and subretinal fluid were present in 67.6% and 23.5% of eyes at onset, respectively. The rate of cystoid macular edema decreased from 100% to 17.6% after a single injection. At the final quiescent visit, focal atrophy at the site of Type 3 lesions, as evidenced by outer retinal and retinal pigment epithelium disruption developed in 88.2% and 52.9% of eyes, respectively. Conclusion: An updated staging system of Type 3 lesions was developed based on spectral domain optical coherence tomography findings. A precursor stage consists of a punctate hyperreflective focus in the outer retina. The subtle detection of associated outer plexiform layer disruption and downward deflection may indicate that this precursor lesion is more likely to progress to an active Type 3 neovascular lesion. Stage 1 consists of a larger intraretinal hyperreflective lesion associated with cystoid macular edema but without outer retinal disruption. Stage 2 is notable for outer retinal disruption that occurs with retinal pigment epithelium disruption in most of the cases. Stage 3 is defined by an intraretinal hyperreflective lesion that extends through the retinal pigment epithelium to vascularize a drusenoid pigment epithelial detachment creating a serous component of the pigment epithelial detachment. C1 [Su, Daniel; Lin, Shawn; Phasukkijwatana, Nopasak; Chen, Xuejing; Sarraf, David] Univ Calif Los Angeles, Stein Eye Inst, Los Angeles, CA USA. [Tan, Anna] Singapore Eye Ctr, Singapore, Singapore. [Tan, Anna] Singapore Eye Res Inst, Singapore, Singapore. [Tan, Anna; Freund, K. Bailey] Vitreous Retina Macula Consultants New York, New York, NY USA. [Tan, Anna; Freund, K. Bailey] Manhattan Eye Ear & Throat Hosp, LuEsther T Mertz Retinal Res Ctr, New York, NY 10021 USA. [Freund, K. Bailey] NYU, Dept Ophthalmol, Sch Med, 550 1St Ave, New York, NY 10016 USA. [Sarraf, David] Greater Los Angeles Vet Adm Healthcare Ctr, Los Angeles, CA USA. [Sarraf, David] Kaiser Permanente, Dept Ophthalmol, Woodland Hills, CA USA. RP Sarraf, D (reprint author), UCLA Geffen Sch Med, Stein Eye Inst, Retinal Disorders & Ophthalm Genet Div, 100 Stein Plaza, Los Angeles, CA 90095 USA. EM dsarraf@ucla.edu FU Macula Foundation, Inc, New York, NY; Allergan; Genentech; Optovue; Regeneron FX Supported by the Macula Foundation, Inc, New York, NY.; K. B. Freund is a consultant for Genentech, Optovue, Optos, Bayer Healthcare, and Heidelberg Engineering. D. Sarraf is a consultant for Genentech and Optovue and receives research funding from Allergan, Genentech, Optovue and Regeneron. The remaining authors have no conflicting interests to disclose. NR 32 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0275-004X EI 1539-2864 J9 RETINA-J RET VIT DIS JI Retin.-J. Retin. Vitr. Dis. PD DEC PY 2016 VL 36 IS 12 SU 1 BP S40 EP S49 PG 10 WC Ophthalmology SC Ophthalmology GA EH7IP UT WOS:000391946700005 PM 28005662 ER PT J AU Fu, AZ Tsai, HT Haque, R Yood, MU Van Den Eeden, SK Cassidy-Bushrow, AE Zhou, YJ Keating, NL Smith, MR Aaronson, DS Potosky, AL AF Fu, Alex Z. Tsai, Huei-Ting Haque, Reina Yood, Marianne Ulcickas Van Den Eeden, Stephen K. Cassidy-Bushrow, Andrea E. Zhou, Yingjun Keating, Nancy L. Smith, Matthew R. Aaronson, David S. Potosky, Arnold L. TI Use of androgen deprivation therapy as salvage treatment after primary therapy for clinically localized prostate cancer SO WORLD JOURNAL OF UROLOGY LA English DT Article DE Androgen deprivation therapy; Salvage treatment; Localized prostate cancer ID ANTIGEN DOUBLING TIME; RADICAL PROSTATECTOMY; MEN; RADIOTHERAPY; OUTCOMES; FAILURE; RISK; PROGRESSION; IMMEDIATE; PATTERNS AB Purpose The optimal use of androgen deprivation therapy as salvage treatment (sADT) for men after initial prostatectomy or radiotherapy for clinically localized prostate cancer is undefined. We describe patterns of sADT use and investigate clinical and sociodemographic characteristics of insured men who received sADT versus surveillance in managed care settings. Methods Using comprehensive electronic health records and cancer registry data from three integrated health plans, we identified all men with newly diagnosed clinically localized prostate cancer between 1995 and 2009 who received either prostatectomy (n = 16,445) or radiotherapy (n = 19,531) as their primary therapy. We defined sADT based on the timing of ADT following primary therapy and stage of cancer. We fit Cox proportional hazard models to identify sociodemographic characteristics and clinical factors associated with sADT. Results With a median follow-up of 6 years (range 2-15 years), 13 % of men who underwent primary prostatectomy or radiotherapy received sADT. After adjusting for selected covariates, sADT was more likely to be used in men who were older (e.g., HR 1.70, 95 % CI 1.48-1.96 or HR 1.33, 95 % CI 1.17-1.52 for age 70+ relative to age 35-59 for primary prostatectomy or radiotherapy, respectively), were African-American, had a short PSA doubling time, had a higher pre-treatment risk of progression, had more comorbidities, and received adjuvant ADT for initial disease. Conclusions In men with localized prostate cancer in community practice initially treated with prostatectomy or radiotherapy, sADT after primary treatment was more frequent for men at greater risk of death from prostate cancer, consistent with practice guidelines. C1 [Fu, Alex Z.; Tsai, Huei-Ting; Zhou, Yingjun; Potosky, Arnold L.] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, 3300 Whitehaven St NW,Suite 4100, Washington, DC 20007 USA. [Haque, Reina] Kaiser Permanente Southern Calif, Pasadena, CA USA. [Yood, Marianne Ulcickas] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Van Den Eeden, Stephen K.; Aaronson, David S.] Kaiser Permanente Northern Calif, Oakland, CA USA. [Cassidy-Bushrow, Andrea E.] Henry Ford Hosp, Detroit, MI 48202 USA. [Keating, Nancy L.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Keating, Nancy L.] Harvard Med Sch, Boston, MA USA. [Smith, Matthew R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Fu, AZ (reprint author), Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, 3300 Whitehaven St NW,Suite 4100, Washington, DC 20007 USA. EM zf54@georgetown.edu FU National Cancer Institute [R01CA142934, RC1CA146238, P30CA051008] FX This study was supported by Grant Nos. R01CA142934, RC1CA146238, and P30CA051008 from the National Cancer Institute. NR 30 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0724-4983 EI 1433-8726 J9 WORLD J UROL JI World J. Urol. PD DEC PY 2016 VL 34 IS 12 BP 1611 EP 1619 DI 10.1007/s00345-016-1823-5 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA EI2KU UT WOS:000392316900002 PM 27084777 ER PT J AU Fazio, SB Demasi, M Farren, E Frankl, S Gottlieb, B Hoy, J Johnson, A Kasper, J Lee, P McCarthy, C Miller, K Morris, J O'Hare, K Rosales, R Simmons, L Smith, B Treadway, K Goodell, K Ogur, B AF Fazio, Sara B. Demasi, Monica Farren, Erin Frankl, Susan Gottlieb, Barbara Hoy, Jessica Johnson, Amanda Kasper, Jill Lee, Patrick McCarthy, Claire Miller, Kathe Morris, Juliana O'Hare, Kitty Rosales, Rachael Simmons, Leigh Smith, Benjamin Treadway, Katherine Goodell, Kristen Ogur, Barbara TI Blueprint for an Undergraduate Primary Care Curriculum SO ACADEMIC MEDICINE LA English DT Article ID MEDICAL-EDUCATION REFORM; POPULATION HEALTH; DECISION-MAKING; STUDENTS; COMMUNITY; PERFORMANCE; COMPETENCE; EXPERIENCE; ROTATIONS; CLERKSHIP AB In light of the increasing demand for primary care services and the changing scope of health care, it is important to consider how the principles of primary care are taught in medical school. While the majority of schools have increased students' exposure to primary care, they have not developed a standardized primary care curriculum for undergraduate medical education. In 2013, the authors convened a group of educators from primary care internal medicine, pediatrics, family medicine, and medicine-pediatrics, as well as five medical students to create a blueprint for a primary care curriculum that could be integrated into a longitudinal primary care experience spanning undergraduate medical education and delivered to all students regardless of their eventual career choice. The authors organized this blueprint into three domains: care management, specific areas of content expertise, and understanding the role of primary care in the health care system. Within each domain, they described specific curriculum content, including longitudinality, generalism, central responsibility for managing care, therapeutic alliance/communication, approach to acute and chronic care, wellness and prevention, mental and behavioral health, systems improvement, interprofessional training, and population health, as well as competencies that all medical students should attain by graduation. The proposed curriculum incorporates important core features of doctoring, which are often affirmed by all disciplines but owned by none. The authors argue that primary care educators are natural stewards of this curriculum content and can ensure that it complements and strengthens all aspects of undergraduate medical education. C1 [Fazio, Sara B.; Frankl, Susan] Beth Israel Deaconess Med Ctr, Dept Internal Med, 330 Brookline Ave, Boston, MA 02215 USA. [Fazio, Sara B.; Demasi, Monica; Frankl, Susan; Gottlieb, Barbara; Hoy, Jessica; Lee, Patrick; McCarthy, Claire; Miller, Kathe; Rosales, Rachael; Simmons, Leigh; Treadway, Katherine; Ogur, Barbara] Harvard Med Sch, Boston, MA USA. [Demasi, Monica] Cambridge Hlth Alliance, Populat Hlth Family Med, Boston, MA USA. [Farren, Erin] Harvard Med Sch, Ctr Primary Care, Boston, MA USA. [Gottlieb, Barbara; Hoy, Jessica; O'Hare, Kitty] Brigham & Womens Hosp, Dept Internal Med, 75 Francis St, Boston, MA 02115 USA. [Johnson, Amanda] Univ Calif San Francisco, Sch Med, Dept Internal Med, San Francisco, CA USA. [Kasper, Jill; O'Hare, Kitty] Harvard Med Sch, Dept Pediat, Boston, MA USA. [Lee, Patrick] Cambridge Hlth Alliance, Dept Internal Med, Boston, MA USA. [McCarthy, Claire] Boston Childrens Hosp, Dept Pediat, Boston, MA USA. [Miller, Kathe] Cambridge Hlth Alliance, Populat Med Family Med, Boston, MA USA. [Morris, Juliana] Univ Calif San Francisco, Sch Med, Dept Family & Community Med, San Francisco, CA USA. [Simmons, Leigh; Treadway, Katherine] Massachusetts Gen Hosp, Dept Internal Med, Boston, MA 02114 USA. [Smith, Benjamin] Ft Collins Family Med Residency, Ft Collins, CO USA. [Goodell, Kristen] Harvard Med Sch, Innovat Med Educ Family Med, Ctr Primary Care, Boston, MA USA. [Ogur, Barbara] Cambridge Hlth Alliance, Med, Dept Internal Med, Boston, MA USA. RP Fazio, SB (reprint author), Beth Israel Deaconess Med Ctr, Dept Internal Med, 330 Brookline Ave, Boston, MA 02215 USA. EM sfazio@bidmc.harvard.edu NR 58 TC 0 Z9 0 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1040-2446 EI 1938-808X J9 ACAD MED JI Acad. Med. PD DEC PY 2016 VL 91 IS 12 BP 1628 EP 1637 DI 10.1097/ACM.0000000000001302 PG 10 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA EH7NL UT WOS:000391959600040 ER PT J AU Iyasere, CA Baggett, M Romano, J Jena, A Mills, G Hunt, DP AF Iyasere, Christiana A. Baggett, Meridale Romano, Jordan Jena, Anupam Mills, Gabrielle Hunt, Daniel P. TI Beyond Continuing Medical Education: Clinical Coaching as a Tool for Ongoing Professional Development SO ACADEMIC MEDICINE LA English DT Editorial Material ID CARE AB Problem For most physicians, the period of official apprenticeship ends with the completion of residency or fellowship, yet the acquisition of expertise requires ongoing opportunities to practice a given skill and obtain structured feedback on one's performance. Approach In July 2013, the authors developed a clinical coaching pilot program to provide early-career hospitalists with feedback from a senior clinical advisor (SCA) at Massachusetts General Hospital. A Hospital Medicine Unit-wide retreat was held to help design the SCA role and obtain faculty buy-in. Twelve SCAs were recruited from hospitalists with more than five years of experience; each served as a clinical coach to 28 early-career hospitalists during the pilot. Clinical narratives and programmatic surveys were collected from SCAs and early-career hospitalists. Outcomes Of 25 responding early-career hospitalists, 23 (92%) rated the SCA role as useful to very useful, 20 (80%) reported interactions with the SCA led to at least one change in their diagnostic approach, and 13 (52%) reported calling fewer subspecialty consults as a result of guidance from the SCA. In response to questions about professional development, 18 (72%) felt more comfortable as an independent physician following their interactions with the SCA, and 19 (76%) thought the interactions improved the quality of care they delivered. Next Steps To better understand the impact and generalizability of clinical coaching, a larger, longitudinal study is required to look at patient and provider outcomes in detail. Further refinement of the SCA role to meet faculty needs is needed and could include faculty development. C1 [Iyasere, Christiana A.; Baggett, Meridale; Romano, Jordan] Harvard Med Sch, Boston, MA USA. [Iyasere, Christiana A.; Baggett, Meridale] Massachusetts Gen Hosp, Dept Med, Inpatient Clinician Educator Resident Teaching Se, Boston, MA 02114 USA. [Romano, Jordan; Jena, Anupam] Massachusetts Gen Hosp, Dept Med, Hosp Med Grp, Boston, MA 02114 USA. [Jena, Anupam] Harvard Med Sch, Dept Hlth Care Policy, Boston, MA USA. [Jena, Anupam] Natl Bur Econ Res, Cambridge, MA 02138 USA. [Mills, Gabrielle] Massachusetts Gen Hosp, Dept Med, Internal Residency Program, Boston, MA 02114 USA. [Hunt, Daniel P.] Emory Univ, Sch Med, Atlanta, GA USA. [Hunt, Daniel P.] Emory Univ, Sch Med, Div Hosp Med, Atlanta, GA USA. RP Iyasere, CA (reprint author), Massachusetts Gen Hosp, Clinician Educator Serv, 50 Staniford St,Suite 503b, Boston, MA 02114 USA. EM ciyasere@partners.org FU Office of the Director, National Institutes of Health [1DP5OD017897-01] FX A. Jena reports funding from the Office of the Director, National Institutes of Health (Dr. Jena, National Institutes of Health Early Independence Award, grant 1DP5OD017897-01). NR 10 TC 2 Z9 2 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1040-2446 EI 1938-808X J9 ACAD MED JI Acad. Med. PD DEC PY 2016 VL 91 IS 12 BP 1647 EP 1650 DI 10.1097/ACM.0000000000001131 PG 4 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA EH7NL UT WOS:000391959600043 ER PT J AU Gooding, HC McCarty, C Millson, R Jiang, HY Armstrong, E Leichtner, AM AF Gooding, Holly C. McCarty, Caitlin Millson, Rebecca Jiang, Hungyu Armstrong, Elizabeth Leichtner, Alan M. TI The Boston Children's Hospital Academy: Development and Initial Assessment of a Hospital-Based Teaching Academy SO ACADEMIC MEDICINE LA English DT Editorial Material ID EDUCATORS AB Problem Medical education academies play an important role in the recognition and career advancement of educators. However, hospital-based clinical faculty have unique professional development needs that may not be met by medical-school-based academies. Approach The Boston Children's Hospital Academy was founded in 2008 to serve the needs of its clinician-educators. It was open to junior faculty scholars and to senior faculty scholars and mentors, including interprofessional educators. To maintain membership, individuals must propose and work toward an education project or serve as a project mentor. In 2012, a survey was sent to all members, and annual project reports were reviewed to assess the academy's impact. Outcomes Sixty-five members completed the survey. The majority agreed that the academy created a community of educators, provided opportunities for networking and scholarship, contributed to their personal identity as an educator, and led to recognition by their chief. Projects addressed curriculum development, faculty development, learner assessment, program assessment, and resource development. They largely focused on graduate medical education and on patient safety and quality. During their tenure in the academy (mean length of membership = 2.4 years), members produced an average of 4.4 education presentations and 1.9 education publications, and 11 members were promoted. Next Steps A hospital-based academy provides opportunities for interprofessional faculty development. Next steps include increasing interprofessional membership, wider dissemination of members' successes, better integration with the hospital's mission, specifically regarding graduate medical education and patient safety, and additional evaluation of the academy's impact on project completion and members' accomplishments. C1 [Gooding, Holly C.; Millson, Rebecca; Leichtner, Alan M.] Boston Childrens Hosp, 300 Longwood Ave, Boston, MA 02115 USA. [Gooding, Holly C.] Harvard Med Sch, Pediat & Med, Boston, MA USA. [McCarty, Caitlin] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Jiang, Hungyu] Boston Childrens Hosp, Clin Res Ctr, Boston, MA USA. [Armstrong, Elizabeth; Leichtner, Alan M.] Harvard Med Sch, Pediat, Boston, MA USA. RP Gooding, HC (reprint author), Boston Childrens Hosp, 300 Longwood Ave, Boston, MA 02115 USA. EM holly.gooding@childrens.harvard.edu NR 8 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1040-2446 EI 1938-808X J9 ACAD MED JI Acad. Med. PD DEC PY 2016 VL 91 IS 12 BP 1651 EP 1654 DI 10.1097/ACM.0000000000001095 PG 4 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA EH7NL UT WOS:000391959600044 ER PT J AU Cohen, B Roth, M Marron, JM Gray, SW Geller, DS Hoang, B Gorlick, R Janeway, KA Gill, J AF Cohen, Barrie Roth, Michael Marron, Jonathan M. Gray, Stacy W. Geller, David S. Bang Hoang Gorlick, Richard Janeway, Katherine A. Gill, Jonathan TI Pediatric Oncology Provider Views on Performing a Biopsy of Solid Tumors in Children with Relapsed or Refractory Disease for the Purpose of Genomic Profiling SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID CANCER; CHILDHOOD; MEDICINE AB Background. Patients with relapsed and refractory solid tumors have a poor prognosis. Recent advances in genomic technology have made it feasible to screen tumors for actionable mutations, with the anticipation that this may provide benefit to patients. Methods. Pediatric oncologists were emailed an anonymous 34- question survey assessing their willingness to offer a rebiopsy to patients with relapsed disease for the purpose of tumor genomic profiling. They were presented with two scenarios evaluating morbidity and invasiveness of the procedures using the clinical examples of medulloblastoma and Ewing sarcoma. Results. A total of 195 pediatric oncologists responded to the questionnaire. Morbidity and invasiveness of the procedure demonstrated significant differences in provider willingness to refer their patients for rebiopsy. The pretest probability was a major variable influencing provider willingness to offer a rebiopsy. Respondents were more likely to offer a rebiopsy if the likelihood was high that the results would have an impact on clinical management than if the biopsy was for histologic confirmation alone (mean 89 vs. 56 %; p = 0.017). Compared with the rate of a rebiopsy for histologic confirmation, significantly fewer providers were willing to offer a rebiopsy if they were led to believe the likelihood of finding an actionable mutation was low (mean 45 vs. 56 %; p = 0.021). Conclusion. The scenario showed that the pretest probability of finding an actionable mutation was influential in determining provider willingness to offer a rebiopsy for the purpose of tumor genomic profiling. Further research is warranted to evaluate the benefit of tumor genomic profiling in terms of patient outcomes. C1 [Cohen, Barrie; Roth, Michael; Gorlick, Richard; Gill, Jonathan] Childrens Hosp Montefiore, Albert Einstein Coll Med, Div Pediat Hematol Oncol & Blood & Marrow Cell Tr, Bronx, NY 10467 USA. [Marron, Jonathan M.; Janeway, Katherine A.] Dana Farber Boston Childrens Canc & Blood Disorde, Dept Pediat Oncol, Boston, MA USA. [Gray, Stacy W.] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA USA. [Gray, Stacy W.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Geller, David S.; Bang Hoang] Montefiore Med Ctr, Dept Orthopaed Surg, 111 E 210th St, Bronx, NY 10467 USA. [Geller, David S.; Bang Hoang] Childrens Hosp Montefiore, Albert Einstein Coll Med, Bronx, NY USA. [Gorlick, Richard] Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10467 USA. RP Gill, J (reprint author), Childrens Hosp Montefiore, Albert Einstein Coll Med, Div Pediat Hematol Oncol & Blood & Marrow Cell Tr, Bronx, NY 10467 USA. EM jgill@montefiore.org NR 15 TC 0 Z9 0 U1 1 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 DEC PY 2016 VL 23 SU 5 BP S990 EP S997 DI 10.1245/s10434-016-5453-3 PG 8 WC Oncology; Surgery SC Oncology; Surgery GA EH1FK UT WOS:000391508800068 PM 27459981 ER PT J AU Villani, V Mahadevan, KK Ligorio, M Fernandez-del Castillo, C Ting, DT Sabbatino, F Zhang, I Vangel, M Ferrone, S Warshaw, AL Lillemoe, KD Wargo, J Deshpande, V Ferrone, CR AF Villani, Vincenzo Mahadevan, Krishnan K. Ligorio, Matteo Fernandez-del Castillo, Carlos Ting, David T. Sabbatino, Francesco Zhang, Irene Vangel, Mark Ferrone, Soldano Warshaw, Andrew L. Lillemoe, Keith D. Wargo, Jennifer Deshpande, Vikram Ferrone, Cristina R. TI Phosphorylated Histone H3 (PHH3) Is a Superior Proliferation Marker for Prognosis of Pancreatic Neuroendocrine Tumors SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID ENDOCRINE TUMORS; MITOTIC RATE; SURVIVAL; MITOSIS; NEOPLASMS; LESIONS; INDEX; KI-67 AB Background. The staging of pancreatic neuroendocrine tumors (PNETs) is continuously evolving. Mitotic count, as measured by hematoxylin and eosin (H&E) or Ki67 labeling index (Ki67LI), is the best predictor of disease biology. However, both of these methods have several limitations. Phosphorylated histone H3 (PHH3), a novel mitotic marker, is potentially more accurate and easier to evaluate. This study aimed to evaluate the prognostic impact of PHH3 on patients with PNETs. Methods. Clinicopathologic data and paraffin-embedded tissue were evaluated for 100 of the 247 PNET patients whose tumors were resected between 1998 and 2010. Mitotic counts were analyzed on H& E-, Ki67-, and PHH3-stained slides by two independent pathologists. Kaplan-Meier curves, log-rank tests, Cox regression models, and time-dependent receiver operative characteristics (ROC) curves were used to evaluate the prognostic power of these markers. An internal data cross-validation was performed to select the best cutoff. Results. Of the 100 PNET patients resected, 53 were men. The median age of the patients was 59 years (range 19-96 years). The median follow-up period was 68 months (range 3-186 months). The median time for evaluation of an H&E- or PHH3-stained slide was 3 min, relative to 15 min for Ki67. The findings showed H&E, Ki67, and PHH3 all to be excellent predictors of disease-specific survival (DSS). However, PHH3 was superior to H&E and Ki67 in predicting both disease-free survival (DFS) (p = 0.006) and DSS (p = 0.001). Evaluation of the PHH3 mitotic count showed 7 mitoses per 10 high-power fields (HPFs) to be the optimal cutoff for differentiating between low-and high-risk PNET patients. Conclusions. PHH3 is a better predictor of both DFS and DSS than H&E or Ki67 in PNET. In addition, PHH3 appears to be both easier to interpret and more accurate when compared to current prognostic markers. C1 [Villani, Vincenzo; Ligorio, Matteo; Fernandez-del Castillo, Carlos; Sabbatino, Francesco; Ferrone, Soldano; Warshaw, Andrew L.; Lillemoe, Keith D.; Ferrone, Cristina R.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Boston, MA USA. [Mahadevan, Krishnan K.; Deshpande, Vikram] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Boston, MA USA. [Ting, David T.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Boston, MA USA. [Sabbatino, Francesco] Univ Salerno, Dept Med & Surg, Salerno, Italy. [Zhang, Irene] Harvard Med Sch, Program Med, Boston, MA USA. [Vangel, Mark] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Wargo, Jennifer] Univ Texas MD Anderson Canc Ctr, Dept Surg, Houston, TX 77030 USA. RP Ferrone, CR (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Boston, MA USA. EM cferrone@mgh.harvard.edu OI Ting, David/0000-0002-3261-2322 FU American-Italian Cancer Foundation; Centro per la Comunicazione e la Ricerca of the Collegio Ghislieri of Pavia FX The Loeffler Family and other generous patients provided philanthropic support for this study. Matteo Ligorio is the recipient of American-Italian Cancer Foundation Post-Doctoral Fellowship. Vincenzo Villani is the recipient of a Research Fellowship from the Centro per la Comunicazione e la Ricerca of the Collegio Ghislieri of Pavia. NR 24 TC 1 Z9 1 U1 0 U2 0 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 DEC PY 2016 VL 23 SU 5 BP S609 EP S617 DI 10.1245/s10434-016-5171-x PG 9 WC Oncology; Surgery SC Oncology; Surgery GA EH1FK UT WOS:000391508800012 PM 27020585 ER PT J AU Chaudhury, S Arlington, L Brenan, S Kairuki, AK Meda, AR Isangula, KG Mponzi, V Bishanga, D Thomas, E Msemo, G Azayo, M Molinier, A Nelson, BD AF Chaudhury, Sumona Arlington, Lauren Brenan, Shelby Kairuki, Allan Kaijunga Meda, Amunga Robson Isangula, Kahabi G. Mponzi, Victor Bishanga, Dunstan Thomas, Erica Msemo, Georgina Azayo, Mary Molinier, Alice Nelson, Brett D. TI Cost analysis of large-scale implementation of the 'Helping Babies Breathe' newborn resuscitation-training program in Tanzania SO BMC HEALTH SERVICES RESEARCH LA English DT Article DE Activity-based costing; Cost-analysis; Helping Babies Breathe; Newborn resuscitation; Resuscitation-training; Low-income countries; Tanzania; Low-resource setting; Resource-poor setting ID DEVELOPING-COUNTRIES; PERINATAL-MORTALITY; RATES; STILLBIRTH AB Background: Helping Babies Breathe (HBB) has become the gold standard globally for training birth-attendants in neonatal resuscitation in low-resource settings in efforts to reduce early newborn asphyxia and mortality. The purpose of this study was to do a first-ever activity-based cost-analysis of at-scale HBB program implementation and initial follow-up in a large region of Tanzania and evaluate costs of national scale-up as one component of a multi-method external evaluation of the implementation of HBB at scale in Tanzania. Methods: We used activity-based costing to examine budget expense data during the two-month implementation and follow-up of HBB in one of the target regions. Activity-cost centers included administrative, initial training (including resuscitation equipment), and follow-up training expenses. Sensitivity analysis was utilized to project cost scenarios incurred to achieve countrywide expansion of the program across all mainland regions of Tanzania and to model costs of program maintenance over one and five years following initiation. Results: Total costs for the Mbeya Region were $202,240, with the highest proportion due to initial training and equipment (45.2%), followed by central program administration (37.2%), and follow-up visits (17.6%). Within Mbeya, 49 training sessions were undertaken, involving the training of 1,341 health providers from 336 health facilities in eight districts. To similarly expand the HBB program across the 25 regions of mainland Tanzania, the total economic cost is projected to be around $4,000,000 (around $600 per facility). Following sensitivity analyses, the estimated total for all Tanzania initial rollout lies between $2,934,793 to $4,309,595. In order to maintain the program nationally under the current model, it is estimated it would cost $2,019,115 for a further one year and $5,640,794 for a further five years of ongoing program support. Conclusion: HBB implementation is a relatively low-cost intervention with potential for high impact on perinatal mortality in resource-poor settings. It is shown here that nationwide expansion of this program across the range of health provision levels and regions of Tanzania would be feasible. This study provides policymakers and investors with the relevant cost-estimation for national rollout of this potentially neonatal life-saving intervention. C1 [Chaudhury, Sumona; Brenan, Shelby] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Chaudhury, Sumona; Brenan, Shelby] Harvard TH Chan Sch Publ Hlth, Dept Global Hlth, Boston, MA 02115 USA. [Arlington, Lauren; Kairuki, Allan Kaijunga; Meda, Amunga Robson; Isangula, Kahabi G.; Nelson, Brett D.] MassGen Hosp Children, Div Global Hlth, Boston, MA 02114 USA. [Mponzi, Victor; Bishanga, Dunstan; Thomas, Erica] Jhpiego, Dar Es Salaam, Tanzania. [Msemo, Georgina; Azayo, Mary] Minist Hlth & Social Welf, Dar Es Salaam, Tanzania. [Molinier, Alice] Childrens Investment Fund Fdn, London W1S 2FT, England. [Nelson, Brett D.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Nelson, Brett D.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Nelson, Brett D.] Harvard Med Sch, Boston, MA 02115 USA. RP Chaudhury, S (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.; Chaudhury, S (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Global Hlth, Boston, MA 02115 USA. EM sumona@mail.harvard.edu OI Chaudhury, Sumona/0000-0002-8412-4734 FU Children's Investment Fund Foundation, London, United Kingdom FX The Children's Investment Fund Foundation, London, United Kingdom NR 27 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6963 J9 BMC HEALTH SERV RES JI BMC Health Serv. Res. PD DEC 1 PY 2016 VL 16 AR 681 DI 10.1186/s12913-016-1924-2 PG 10 WC Health Care Sciences & Services SC Health Care Sciences & Services GA EH6KQ UT WOS:000391882300001 PM 27908286 ER PT J AU Roh, MR AF Roh, M. R. TI The SCAR (Scar Cosmesis Assessment and Rating) scale: new evaluation method for postoperative scars SO BRITISH JOURNAL OF DERMATOLOGY LA English DT Editorial Material C1 [Roh, M. R.] Harvard Med Sch, Massachusetts Gen Hosp, Wellman Ctr Photomed, Dept Dermatol, Boston, MA 02115 USA. [Roh, M. R.] Yonsei Univ, Coll Med, Cutaneous Biol Res Inst, Dept Dermatol, Seoul, South Korea. RP Roh, MR (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Wellman Ctr Photomed, Dept Dermatol, Boston, MA 02115 USA.; Roh, MR (reprint author), Yonsei Univ, Coll Med, Cutaneous Biol Res Inst, Dept Dermatol, Seoul, South Korea. EM karenroh@yuhs.ac NR 7 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-0963 EI 1365-2133 J9 BRIT J DERMATOL JI Br. J. Dermatol. PD DEC PY 2016 VL 175 IS 6 BP 1151 EP 1152 DI 10.1111/bjd.14989 PG 2 WC Dermatology SC Dermatology GA EH5NZ UT WOS:000391821300055 PM 27996133 ER PT J AU Farhad, H Staziaki, PV Addison, D Coelho, OR Shah, RV Mitchell, RN Szilveszter, B Abbasi, SA Kwong, RY Scherrer-Crosbie, M Hoffmann, U Jerosch-Herold, M Neilan, TG AF Farhad, Hoshang Staziaki, Pedro V. Addison, Daniel Coelho-Filho, Otavio R. Shah, Ravi V. Mitchell, Richard N. Szilveszter, Balint Abbasi, Siddique A. Kwong, Raymond Y. Scherrer-Crosbie, Marielle Hoffmann, Udo Jerosch-Herold, Michael Neilan, Tomas G. TI Characterization of the Changes in Cardiac Structure and Function in Mice Treated With Anthracyclines Using Serial Cardiac Magnetic Resonance Imaging SO CIRCULATION-CARDIOVASCULAR IMAGING LA English DT Article DE anthracyclines; cardiotoxicity; doxorubicin; magnetic resonance imaging; myocardium ID MYOCARDIAL EXTRACELLULAR VOLUME; LEFT-VENTRICULAR DYSFUNCTION; CONGESTIVE-HEART-FAILURE; METASTATIC BREAST-CANCER; OF-NUCLEAR-CARDIOLOGY; DOXORUBICIN CARDIOTOXICITY; EJECTION FRACTION; RADIONUCLIDE ANGIOCARDIOGRAPHY; CARDIOMYOPATHY; CHEMOTHERAPY AB Background Anthracyclines are cardiotoxic; however, there are limited data characterizing the serial changes in cardiac structure and function after anthracyclines. The aim of this study was to use cardiac magnetic resonance to characterize anthracycline-induced cardiotoxicity in mice. Methods and Results This was a longitudinal cardiac magnetic resonance and histological study of 45 wild-type male mice randomized to doxorubicin (n=30, 5 mg/kg of doxorubicin/week for 5 weeks) or placebo (n=15). A cardiac magnetic resonance was performed at baseline and at 5, 10, and 20 weeks after randomization. Measures of primary interest included left ventricular ejection fraction, myocardial edema (multiecho short-axis spin-echo acquisition), and myocardial fibrosis (Look-Locker gradient echo). In doxorubicin-treated mice versus placebo, there was an increase in myocardial edema at 5 weeks (T2 values of 32 4 versus 21 3 ms; P<0.05), followed by a reduction in left ventricular ejection fraction (54 6 versus 63 +/- 5%; P<0.05) and an increase in myocardial fibrosis (extracellular volume of 0.34 +/- 0.03 versus 0.27 +/- 0.03; P<0.05) at 10 weeks. There was a strong association between the early (5 weeks) increase in edema and the subacute (10 weeks) increase in fibrosis (r=0.90; P<0.001). Both the increase in edema and fibrosis predicted the late doxorubicin-induced mortality in mice (P<0.001). Conclusions Our data suggest that, in mice, anthracycline-induced cardiotoxicity is associated with an early increase in cardiac edema and a subsequent increase in myocardial fibrosis. The early increase in edema and subacute increase in fibrosis are strongly linked and are both predictive of late mortality. C1 [Farhad, Hoshang; Shah, Ravi V.; Abbasi, Siddique A.; Kwong, Raymond Y.] Harvard Med Sch, Brigham & Womens Hosp, Noninvas Cardiovasc Imaging Program, Boston, MA USA. [Farhad, Hoshang; Shah, Ravi V.; Abbasi, Siddique A.; Kwong, Raymond Y.] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Cardiovasc Div, Boston, MA USA. [Mitchell, Richard N.] Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, Boston, MA USA. [Jerosch-Herold, Michael] Harvard Med Sch, Brigham & Womens Hosp, Dept Radiol, Boston, MA USA. [Coelho-Filho, Otavio R.] State Univ Campinas UNICAMP, Fac Med Sci, Campinas, SP, Brazil. [Staziaki, Pedro V.; Addison, Daniel; Szilveszter, Balint; Hoffmann, Udo; Neilan, Tomas G.] Harvard Med Sch, Massachusetts Gen Hosp, Cardiac MR PET CT Program, Div Radiol, Boston, MA USA. Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA USA. RP Neilan, TG (reprint author), Massachusetts Gen Hosp, Cardiooncol Program, 165 Cambridge St, Boston, MA 02114 USA.; Neilan, TG (reprint author), Massachusetts Gen Hosp, Cardiac MR PET CT Program, Div Cardiol, 165 Cambridge St, Boston, MA 02114 USA.; Neilan, TG (reprint author), Massachusetts Gen Hosp, Dept Radiol, 165 Cambridge St, Boston, MA 02114 USA. EM tneilan@mgh.harvard.edu FU American Heart Association [12FTF12060588] FX Dr Neilan is supported by an American Heart Association Fellow to Faculty Grant (12FTF12060588). NR 48 TC 1 Z9 1 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1941-9651 EI 1942-0080 J9 CIRC-CARDIOVASC IMAG JI Circ.-Cardiovasc. Imaging PD DEC PY 2016 VL 9 IS 12 AR e003584 DI 10.1161/CIRCIMAGING.115.003584 PG 8 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA EH5OO UT WOS:000391822800001 ER PT J AU Singh, P Emami, H Subramanian, S Maurovich-Horvat, P Marincheva-Savcheva, G Medina, HM Abdelbaky, A Alon, A Shankar, SS Rudd, JHF Fayad, ZA Hoffmann, U Tawakol, A AF Singh, Parmanand Emami, Hamed Subramanian, Sharath Maurovich-Horvat, Pal Marincheva-Savcheva, Gergana Medina, Hector M. Abdelbaky, Amr Alon, Achilles Shankar, Sudha S. Rudd, James H. F. Fayad, Zahi A. Hoffmann, Udo Tawakol, Ahmed TI Coronary Plaque Morphology and the Anti-Inflammatory Impact of Atorvastatin A Multicenter F-18-Fluorodeoxyglucose Positron Emission Tomographic/Computed Tomographic Study SO CIRCULATION-CARDIOVASCULAR IMAGING LA English DT Article DE atherosclerosis; carotid artery; coronary artery disease; inflammation; positron emission tomography ID C-REACTIVE PROTEIN; ATHEROSCLEROTIC DISEASE; CARDIOVASCULAR EVENTS; CAROTID PLAQUE; ARTERY CALCIUM; STATIN THERAPY; INFLAMMATION; ANGIOGRAPHY; RISK; PET AB Background Nonobstructive coronary plaques manifesting high-risk morphology (HRM) associate with an increased risk of adverse clinical cardiovascular events. We sought to test the hypothesis that statins have a greater anti-inflammatory effect within coronary plaques containing HRM. Methods and Results In this prospective multicenter study, 55 subjects with or at high risk for atherosclerosis underwent F-18-fluorodeoxyglucose positron emission tomographic/computed tomographic imaging at baseline and after 12 weeks of treatment with atorvastatin. Coronary arterial inflammation (F-18-fluorodeoxyOucose uptake, expressed as target-to background ratio) was assessed in the left main coronary artery (LMCA). While blinded to the PET findings, contrast enhanced computed tomographic angiography was performed to characterize the presence of HRM (defined as noncalcified or partially calcified plaques) in the LMCA. Arterial inflammation (target-to-background ratio) was higher in LMCA segments with HRM than those without HRM (mean +/- SEM: 1.95 +/- 0.43 versus 1.67 +/- 0.32 for LMCA with versus without HRM, respectively; P=0.04). Moreover, atorvastatin treatment for 12 weeks reduced target-to-background ratio more in LMCA segments with HRM than those without HRM (12 week-baseline target-to-background ratio [95% confidence interval]: 0.18 [-0.35 to 0.004] versus 0.09 [-0.06 to 0.26]; P=0.02). Furthermore, this relationship between coronary plaque morphology and change in LMCA inflammatory activity remained significant after adjusting for baseline low density lipoprotein and statin dose (beta=-0.27; P=0.038). Conclusions In this first study to evaluate the impact of statins on coronary inflammation, we observed that the anti-inflammatory impact of statins is substantially greater within coronary plaques that contain HRM features. These findings suggest an additional mechanism by which statins disproportionately benefit individuals with more advanced atherosclerotic disease. C1 [Singh, Parmanand] New York Presbyterian Hosp, Div Cardiol, New York, NY USA. [Singh, Parmanand] Weill Cornell Med Coll, New York, NY USA. [Emami, Hamed; Subramanian, Sharath; Maurovich-Horvat, Pal; Marincheva-Savcheva, Gergana; Abdelbaky, Amr; Hoffmann, Udo; Tawakol, Ahmed] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Div Cardiac Imaging, Boston, MA 02114 USA. [Tawakol, Ahmed] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Div Cardiol, Boston, MA 02114 USA. [Tawakol, Ahmed] Harvard Med Sch, Boston, MA USA. [Maurovich-Horvat, Pal] Semmelweis Univ, MTA SE Cardiovasc Imaging Res Grp, Budapest, Hungary. [Medina, Hector M.] Fdn Cardioinfantil, Bogota, Colombia. [Alon, Achilles; Shankar, Sudha S.] Merck & Co Inc, Kenilworth, NJ USA. [Rudd, James H. F.] Univ Cambridge, Div Cardiovasc Med, Cambridge CB2 1TN, England. [Fayad, Zahi A.] Icahn Sch Med Mt Sinai, Translat & Mol Imaging Inst, New York, NY 10029 USA. RP Tawakol, A (reprint author), Massachusetts Gen Hosp, 165 Cambridge St,Suite 400, Boston, MA 02114 USA. EM atawakol@mgh.harvard.edu FU National Heart, Lung, and Blood Institute of the National Institutes of Health [5T32 HL076136]; Marian Foundation; National Institute for Health Research Cambridge Biomedical Research Centre; British Heart Foundation; Wellcome Trust FX Dr Singh received support from the National Heart, Lung, and Blood Institute of the National Institutes of Health (5T32 HL076136) and Marian Foundation. Dr Rudd is partly supported by the National Institute for Health Research Cambridge Biomedical Research Centre, the British Heart Foundation, and the Wellcome Trust. NR 30 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 1941-9651 EI 1942-0080 J9 CIRC-CARDIOVASC IMAG JI Circ.-Cardiovasc. Imaging PD DEC PY 2016 VL 9 IS 12 AR e004195 DI 10.1161/CIRCIMAGING.115.004195 PG 9 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA EH5OO UT WOS:000391822800002 ER PT J AU Perez, DL Young, SS King, JN Guarino, AJ Dworetzky, BA Flaherty, A Chemali, Z Caplan, D Dickerson, BC AF Perez, David L. Young, Sigrid S. King, Julie N. Guarino, Anthony J. Dworetzky, Barbara A. Flaherty, Alice Chemali, Zeina Caplan, David Dickerson, Bradford C. TI Preliminary Predictors of Initial Attendance, Symptom Burden, and Motor Subtype in a US Functional Neurological Disorders Clinic Population SO COGNITIVE AND BEHAVIORAL NEUROLOGY LA English DT Article DE functional neurological disorder; conversion disorder; psychogenic non-epileptic seizures; functional movement disorder; functional weakness ID PSYCHOGENIC NONEPILEPTIC SEIZURES; MOVEMENT-DISORDERS; CONVERSION DISORDER; SOMATOFORM DISORDERS; CHRONIC PAIN; PSYCHIATRISTS; DIAGNOSIS; WEAKNESS; PERSPECTIVE; UNAWARENESS AB Background and Objective: Although many patients present with functional neurological symptoms (FNS), few US clinics offer specialized FNS care, and data on clinic attendees remain limited. We determined predictors of initial attendance, symptom burden, and FNS subtype in the first patients referred to our Functional Neurological Disorders Clinic for suspected FNS. Methods: We reviewed the charts of 62 consecutive patients (46 women, 16 men). Regression analyses investigated predictors of keeping the first scheduled clinic appointment. For the 49 patients who did keep that appointment, regression analyses examined neuropsychiatric factors associated with symptom burden and motor FNS subtypes. Results: The odds of not keeping the first appointment were 10.4 times greater for patients referred from the emergency department than from other sources. The patients who kept their appointment reported a symptom burden that was significantly associated with a past FNS-related emergency department visit and a diagnosis of another medically unexplained somatic syndrome. The number of FNS findings on neurological examination also correlated with a history of an FNS-related emergency department visit. Patients with psychogenic non-epileptic seizures reported cognitive complaints and prior psychiatric hospitalizations significantly more often than did patients with other FNS. One fourth of all patients had two or more motor FNS. Conclusions: In our FNS cohort, patients were less likely to keep an initial clinic appointment if they were referred from the emergency department than from other sources. Patients with psychogenic non-epileptic seizures were more likely to report cognitive symptoms and past psychiatric hospitalizations than patients with other FNS. C1 [Perez, David L.; Young, Sigrid S.; King, Julie N.; Chemali, Zeina; Caplan, David] Massachusetts Gen Hosp, Cognit Behav Neurol Unit, Boston, MA 02114 USA. [Flaherty, Alice] Massachusetts Gen Hosp, Movement Disorders Unit, Boston, MA 02114 USA. [Dickerson, Bradford C.] Massachusetts Gen Hosp, Dept Neurol, Frontotemporal Disorders Unit, Boston, MA 02114 USA. [Perez, David L.; Chemali, Zeina] Massachusetts Gen Hosp, Dept Psychiat, Neuropsychiat Unit, Boston, MA 02114 USA. [Guarino, Anthony J.] Massachusetts Gen Hosp, Inst Hlth Profess, Boston, MA 02114 USA. [Dworetzky, Barbara A.] Harvard Med Sch, Brigham & Womens Hosp, Dept Neurol, Edward B Bromfield Epilepsy Program, Boston, MA USA. RP Caplan, D (reprint author), Massachusetts Gen Hosp, Dept Neurol, 149 13th St, Charlestown, MA 02129 USA.; Caplan, D (reprint author), Massachusetts Gen Hosp, Dept Psychiat, 149 13th St, Charlestown, MA 02129 USA. EM dlperez@partners.org NR 51 TC 0 Z9 0 U1 4 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1543-3633 EI 1543-3641 J9 COGN BEHAV NEUROL JI Cogn. Behav. Neurol. PD DEC PY 2016 VL 29 IS 4 BP 197 EP 205 DI 10.1097/WNN.0000000000000106 PG 9 WC Behavioral Sciences; Clinical Neurology SC Behavioral Sciences; Neurosciences & Neurology GA EH4CS UT WOS:000391719200004 PM 27984257 ER PT J AU Miller, JJ Wen, PY AF Miller, Julie J. Wen, Patrick Y. TI Emerging targeted therapies for glioma SO EXPERT OPINION ON EMERGING DRUGS LA English DT Review DE Glioblastoma; low grade glioma; signal transduction; receptor tyrosine kinase; Epidermal Growth Factor Receptor (EGFR); Phosphoinositide-3-Kinase (PI3K); mammalian Target of Rapamycin (mTOR); angiogenesis; cyclin-dependent kinase; isocitrate dehydrogenase (IDH); targeted therapy; precision medicine ID NEWLY-DIAGNOSED GLIOBLASTOMA; PHASE-II TRIAL; GROWTH-FACTOR; RECURRENT GLIOBLASTOMA; MALIGNANT GLIOMAS; GENOMIC ANALYSIS; GRADE GLIOMAS; LUNG-CANCER; TUMORS; TEMOZOLOMIDE AB Introduction: Gliomas are the most common malignant primary brain tumors in adults. Despite aggressive treatment with surgery, radiation and chemotherapy, these tumors are incurable and invariably recur. Molecular characterization of these tumors in recent years has advanced our understanding of gliomagenesis and offered an array of pathways that can be specifically targeted. Areas covered: The most commonly dysregulated signaling pathways found in gliomas will be discussed, as well as the biologic importance of these disrupted pathways and how each may contribute to tumor development. Our knowledge regarding these pathways are most relevant to Grade IV glioma/glioblastoma, but we will also discuss genomic categorization of low grade glioma. Further, drugs targeting single pathways, which have undergone early phase clinical trials will be reviewed, followed by an in depth discussion of emerging treatments on the horizon, which will include inhibitors of Epidermal Growth Factor Receptor (EGFR) and receptor tyrosine kinases, Phosphoinositide-3-Kinase (PI3K), angiogenesis, cell cycle and mutant Isocitrate Dehydrogenase (IDH) mutations. Expert opinion: Results from single agent targeted therapy trials have been modest. Lack of efficacy may stem from a combination of poor blood brain barrier penetration, the genetically heterogeneous make-up of the tumors and the emergence of resistance mechanisms. These factors can be overcome by rational drug design that capitalizes on ways to target critical pathways and limits upregulation of redundant pathways. C1 [Miller, Julie J.] Massachusetts Gen Hosp, Dana Farber Canc Inst, Boston, MA 02114 USA. [Wen, Patrick Y.] Dana Farber Brigham Canc Ctr, Dept Neurol, Div Neurooncol, Ctr Neurooncol, Boston, MA 02215 USA. [Wen, Patrick Y.] Harvard Med Sch, Boston, MA 02115 USA. RP Wen, PY (reprint author), Dana Farber Brigham Canc Ctr, Dept Neurol, Div Neurooncol, Ctr Neurooncol, Boston, MA 02215 USA.; Wen, PY (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM pwen@partners.org FU Dana-Farber Cancer Institute; John Fountas Brain Tumor Research Fund; Massachusetts General Hospital; Paul Calabresi Career Development Award for Clinical Oncology [K12CA090354] FX This paper was funded by the Dana-Farber Cancer Institute, the John Fountas Brain Tumor Research Fund, Massachusetts General Hospital and JJ Miller received research support from the Paul Calabresi Career Development Award for Clinical Oncology (K12CA090354). NR 72 TC 0 Z9 0 U1 7 U2 7 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1472-8214 EI 1744-7623 J9 EXPERT OPIN EMERG DR JI Expert Opin Emerg. Drugs PD DEC PY 2016 VL 21 IS 4 BP 441 EP 452 DI 10.1080/14728214.2016.1257609 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EH6SV UT WOS:000391905100008 PM 27809598 ER PT J AU Wandling, MW Hungness, ES Pavey, ES Stulberg, JJ Schwab, B Yang, AD Shapiro, MB Bilimoria, KY Ko, CY Nathens, AB AF Wandling, Michael W. Hungness, Eric S. Pavey, Emily S. Stulberg, Jonah J. Schwab, Ben Yang, Anthony D. Shapiro, Michael B. Bilimoria, Karl Y. Ko, Clifford Y. Nathens, Avery B. TI Nationwide Assessment of Trends in Choledocholithiasis Management in the United States From 1998 to 2013 SO JAMA SURGERY LA English DT Article ID BILE-DUCT STONES; COMMON; EXPLORATION; TRIAL AB IMPORTANCE There are currently 2 widely accepted treatment strategies for patients presenting to the hospital with choledocholithiasis. However, the rate of use for each strategy in the United States has not been evaluated, and their trends over time have not been described. Furthermore, an optimal management strategy for choledocholithiasis has yet to be defined. OBJECTIVE To evaluate secular trends in the management of choledocholithiasis in the United States and to compare hospital length of stay between patients with choledocholithiasis treated with endoscopic retrograde cholangiopancreatography with laparoscopic cholecystectomy (ERCP+LC) vs laparoscopic common bile duct exploration with laparoscopic cholecystectomy (LCBDE+LC). DESIGN, SETTING, AND PARTICIPANTS In this cohort study, we studied patients with a primary diagnosis of choledocholithiasis that were included in the National Inpatient Sample between 1998 and 2013 from a representative sample of acute care hospitals in the United States. Patients with cholangitis or pancreatitis were excluded. MAIN OUTCOMES AND MEASURES Unadjusted and risk-adjusted median hospital length of stay. RESULTS Of the 37 207 patients included in our analysis, 36 0 48 (96.9%) were treated with ERCP+LC and 1159 (3.1%) were treated with LCBDE+LC. The mean (SD) age of patients treated with ERCP+LC was 50.7 (21.1) years and was 51.9 (20.9) years for those treated with LCBDE+LC; 25 788 (69.3%) were female. Analysis of the National Inpatient Sample data indicates that there are an average of 26 158 patients with choledocholithiasis admitted in the United States each year. The overall use of CBDE for patients with choledocholithiasis decreased from 39.8% of admissions in 1998 to 8.5% in 2013 (P < .001). A decrease was also seen for open CBDE (30.6% vs 5.5%; P < .001) and laparoscopic CBDE (9.2% vs 3.0%; P < .001) independently. Rates of management with LCBDE+LC decreased from 5.3% to 1.5% (P < .001), while rates of ERCP+LC increased from 52.8% to 85.7% (P < .001). The unadjusted median hospital length of stay was shorter for patients treated with LCBDE+LC than for those treated with ERCP+LC (3.0 vs 4.0 days; P < .001). After risk-adjustment, the median length of stay remained 0.5 days shorter for patients treated with LCBDE+LC than with ERCP+LC (3.5 vs 4.0 days; P < .001). CONCLUSIONS AND RELEVANCE This study highlights the marked decline in the use of both open and laparoscopic CBDE in the United States as well as the benefit to the length of stay LCBDE+LC has over ERCP+LC. Despite a persistent need for CBDE and the potential benefits of LCBDE+LC over ERCP+LC for managing choledocholithiasis, if current trends continue, CBDE may be at risk of disappearing from the surgical armamentarium. C1 [Wandling, Michael W.; Hungness, Eric S.; Pavey, Emily S.; Stulberg, Jonah J.; Schwab, Ben; Yang, Anthony D.; Shapiro, Michael B.; Bilimoria, Karl Y.] Northwestern Univ, Feinberg Sch Med, Dept Surg, 251E Huron St,Ste 3-150, Chicago, IL 60611 USA. [Wandling, Michael W.; Pavey, Emily S.; Stulberg, Jonah J.; Yang, Anthony D.; Bilimoria, Karl Y.] Northwestern Univ, Feinberg Sch Med, Surg Outcomes & Qual Improvement Ctr, Chicago, IL USA. [Wandling, Michael W.; Stulberg, Jonah J.; Yang, Anthony D.; Bilimoria, Karl Y.] Northwestern Univ, Feinberg Sch Med, Ctr Healthcare Studies, Chicago, IL USA. [Wandling, Michael W.; Bilimoria, Karl Y.; Ko, Clifford Y.] Amer Coll Surg, Div Res & Optimal Patient Care, Chicago, IL USA. [Ko, Clifford Y.] Univ Calif Los Angeles, Dept Surg, Los Angeles, CA 90024 USA. [Ko, Clifford Y.] VA Greater Los Angeles Healthcare Syst, Dept Surg, Los Angeles, CA USA. [Nathens, Avery B.] Univ Toronto, Dept Surg, Sunnybrook Hlth Sci Ctr, Toronto, ON, Canada. RP Wandling, MW (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Surg, 251E Huron St,Ste 3-150, Chicago, IL 60611 USA. EM m-wandling@northwestern.edu FU National Institute of General Medical Sciences of the National Institutes of Health [F32GM113513]; Department of Surgery at the Northwestern University Feinberg School of Medicine FX Research reported in this publication was supported by grant F32GM113513 from the National Institute of General Medical Sciences of the National Institutes of Health and by the Department of Surgery at the Northwestern University Feinberg School of Medicine. NR 11 TC 1 Z9 1 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6254 EI 2168-6262 J9 JAMA SURG JI JAMA Surg. PD DEC PY 2016 VL 151 IS 12 BP 1125 EP 1130 DI 10.1001/jamasurg.2016.2059 PG 6 WC Surgery SC Surgery GA EH1VQ UT WOS:000391556100008 PM 27556900 ER PT J AU Massarweh, NN Kougias, P Wilson, MA AF Massarweh, Nader N. Kougias, Panagiotis Wilson, Mark A. TI Complications and Failure to Rescue After Inpatient Noncardiac Surgery in the Veterans Affairs Health System SO JAMA SURGERY LA English DT Article ID QUALITY IMPROVEMENT PROGRAM; SURGICAL-CARE; AMERICAN-COLLEGE; HOSPITAL PARTICIPATION; MEDICARE BENEFICIARIES; PRIVATE-SECTOR; OLDER PATIENTS; OF-CARE; ASSOCIATION; OUTCOMES AB IMPORTANCE The quality of surgical care in the Veterans Health Administration improved markedly in the 1990s after implementation of the Veterans Affairs (VA) National Surgical Quality Improvement Program (now called the VA Surgical Quality Improvement Program). Although there have been many recent evaluations of surgical care in the private sector, to date, a contemporary global evaluation has not been performed within the VA health system. OBJECTIVE To provide a contemporaneous report of noncardiac postoperative outcomes in the VA health system during the past 15 years. DESIGN, SETTING, AND PARTICIPANTS A retrospective cohort study was conducted using data from the VA Surgical Quality Improvement Program among veterans who underwent inpatient general, vascular, thoracic, genitourinary, neurosurgical, orthopedic, or spine surgery from October 1, 1999, through September 30, 2014. MAIN OUTCOMES AND MEASURES Rates of 30-day morbidity, mortality, and failure to rescue (FTR) over time. RESULTS Among 704 901 patients (mean [SD] age, 63.7 [11.8] years; 676 750 [96%] male) undergoing noncardiac surgical procedures at 143 hospitals, complications occurred in 97 836 patients (13.9%), major complications occurred in 66 816 (9.5%), FTR occurred in 12 648 of the 97 836 patients with complications (12.9%), FTR after major complications occurred in 12 223 of the 66 816 patients with major complications (18.3%), and 18 924 patients (2.7%) died within 30 days of surgery. There were significant decreases from 2000 to 2014 in morbidity (8202 of 59 421 [13.8%] vs 3368 of 32 785 [10.3%]), major complications (5832 of 59 421 [9.8%] vs 2284 of 32 785 [7%]), FTR (1445 of 8202 [17.6%] vs 351 of 3368 [10.4%]), and FTR after major complications (1388 of 5832 [23.8%] vs 343 of 2284 [15%]) (trend test, P<.001 for all). Although there were no clinically meaningful differences in rates of complications and major complications across hospital risk-adjusted mortality quintiles (any complications: lowest quintile, 20 945 of 147 721 [14.2%] vs highest quintile, 18 938 of 135 557 [14%]; major complications: lowest quintile, 14 044 of 147 721 [9.5%] vs highest quintile, 12 881 of 135 557 [9.5%]), FTR rates (any complications: lowest quintile, 2249 of 20 945 [10.7%] vs highest quintile, 2769 of 18 938 [14.6%]; major complications: lowest quintile, 2161 of 14 044 [15.4%] vs highest quintile, 2663 of 12 881 [20.7%]) were significantly higher with increasing quintile (P<.001). However, across hospital quintiles, there were significant decreases in morbidity (20.6%-29.9% decrease; trend test, P<.001 for all) and FTR (29.2%-50.6% decrease; trend test, P<.001 for all) during the study period. After hierarchical modeling, the odds of postoperative mortality, FTR, and FTR after a major complication were approximately 40% to 50% lower in the most recent study year compared with 15 years ago (P<.001 for all). CONCLUSIONS AND RELEVANCE For the past 15 years, morbidity, mortality, and FTR have improved within the VA health system. Other integrated health systems providing a high volume of surgical care for their enrollees may benefit by critically evaluating the system-level approaches of the VA health system to surgical quality improvement. C1 [Massarweh, Nader N.; Kougias, Panagiotis] Michael E DeBakey VA Med Ctr, Vet Affairs Hlth Serv, Res & Dev Ctr Innovat Qual, Houston, TX USA. [Massarweh, Nader N.; Kougias, Panagiotis] Baylor Coll Med, Michael E DeBakey Dept Surg, 2002 Holcombe Blvd,Operat Care Line 112, Houston, TX 77030 USA. [Wilson, Mark A.] Vet Affairs Pittsburgh Healthcare Syst, Dept Surg, Pittsburgh, PA USA. RP Massarweh, NN (reprint author), Baylor Coll Med, Michael E DeBakey Dept Surg, 2002 Holcombe Blvd,Operat Care Line 112, Houston, TX 77030 USA. EM massarwe@bcm.edu FU Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development [CIN 13-413]; Department of Veterans Affairs, Center for Innovations in Quality, Effectiveness and Safety; Michael E. DeBakey Veterans Affairs Medical Center seed grant FX This study is based on work supported by grant CIN 13-413 from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, and the Center for Innovations in Quality, Effectiveness and Safety and a Michael E. DeBakey Veterans Affairs Medical Center seed grant (Dr Massarweh). NR 28 TC 1 Z9 1 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6254 EI 2168-6262 J9 JAMA SURG JI JAMA Surg. PD DEC PY 2016 VL 151 IS 12 BP 1157 EP 1165 DI 10.1001/jamasurg.2016.2920 PG 9 WC Surgery SC Surgery GA EH1VQ UT WOS:000391556100015 PM 27653498 ER PT J AU Mull, HJ Rosen, AK Pizer, SD Itani, KMF AF Mull, Hillary J. Rosen, Amy K. Pizer, Steven D. Itani, Kamal M. F. TI Association Between Postoperative Admission and Location of Hernia Surgery: A Matched Case-Control Study in the Veterans Administration SO JAMA SURGERY LA English DT Letter ID CENTERS C1 [Mull, Hillary J.; Rosen, Amy K.] VA Boston Healthcare Syst, Ctr Healthcare Org & Implementat Res, Boston, MA USA. [Mull, Hillary J.; Rosen, Amy K.; Itani, Kamal M. F.] Boston Univ, Sch Med, Dept Surg, Boston, MA 02118 USA. [Pizer, Steven D.] Dept Vet Affairs, Hlth Care Financing & Econ, Boston, MA USA. [Pizer, Steven D.] Northeastern Univ, Boston, MA 02115 USA. [Itani, Kamal M. F.] VA Boston Healthcare Syst, Dept Surg, Boston, MA USA. [Itani, Kamal M. F.] Harvard Med Sch, Boston, MA USA. RP Mull, HJ (reprint author), VA Boston Healthcare Syst, Ctr Healthcare Org & Implementat, 150 S Huntington Ave,152M, Boston, MA 02130 USA. EM hillary.mull@va.gov FU VA Health Services Research and Development Service [CDA13-270] FX This research was supported by grant CDA13-270 from the VA Health Services Research and Development Service (Dr Mull). NR 4 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6254 EI 2168-6262 J9 JAMA SURG JI JAMA Surg. PD DEC PY 2016 VL 151 IS 12 BP 1187 EP 1190 DI 10.1001/jamasurg.2016.3113 PG 5 WC Surgery SC Surgery GA EH1VQ UT WOS:000391556100024 PM 27682221 ER PT J AU Ko, SJ Kuo, B Kim, SK Lee, H Kim, J Han, G Kim, J Kim, SY Jang, S Son, J Kim, M Lee, H Yeo, I Joo, KR Park, JW AF Ko, Seok-Jae Kuo, Braden Kim, Seul-Ki Lee, Hyangsook Kim, Jinsung Han, Gajin Kim, Juyeon Kim, Song-Yi Jang, Seungwon Son, Jiyoung Kim, Minji Lee, Hyejung Yeo, Inkwon Joo, Kwang Ro Park, Jae-Woo TI Individualized Acupuncture for Symptom Relief in Functional Dyspepsia: A Randomized Controlled Trial SO JOURNAL OF ALTERNATIVE AND COMPLEMENTARY MEDICINE LA English DT Article DE acupuncture; alternative therapy; CAM ID IRRITABLE-BOWEL-SYNDROME; GASTROINTESTINAL DISORDERS; MANUAL ACUPUNCTURE; NONULCER DYSPEPSIA; SHAM ACUPUNCTURE; CLINICAL-TRIALS; SLOW WAVES; ELECTROACUPUNCTURE; EPIDEMIOLOGY; EFFICACY AB Objectives: This study was implemented to evaluate the effect of individualized acupuncture treatment (AT) on functional dyspepsia (FD). Methods: A randomized, waitlist-controlled, two-center trial was performed. Seventy-six patients with FD were enrolled in the trial with partially individualized AT in a more realistic clinical setting performed twice a week for 15 minutes a session over 4 weeks. The participants were randomly allocated to a group receiving 8 sessions of AT for 4 weeks or a waitlist control group. After 4 consecutive weeks, the AT group was followed up without AT and the control group received the identical AT. The proportion of responders with adequate symptom relief, Nepean Dyspepsia Index (NDI), FD-related quality of life, Beck Depression Inventory, State-Trait Anxiety Inventory, Acupuncture Belief Scale, and acupuncture credibility test were assessed. Results: After the first 4 weeks, the proportion of responders significantly improved (59% in AT group [n = 37] versus 3% in control group [n = 39]; p < 0.001). The difference was no longer significant at 8 weeks, at which point the waitlist control group showed similar improvement after receiving AT (68% in the AT group versus 79% in the control group). Total NDI scores were significantly reduced in the AT group compared with the waitlist group (p = 0.03). Among NDI items, discomfort (p = 0.01), burning (p = 0.02), fullness after eating (p = 0.02), and burping (p = 0.02) were significantly improved in the AT group compared with the control group. No significant differences were observed between groups in other secondary variables. Conclusion: Individualized AT adequately relieves symptoms in patients with FD, and this effect may persist up to 8 weeks. C1 [Ko, Seok-Jae; Kim, Seul-Ki; Kim, Jinsung; Han, Gajin; Kim, Juyeon; Jang, Seungwon; Son, Jiyoung; Kim, Minji; Park, Jae-Woo] Kyung Hee Univ, Coll Korean Med, Dept Gastroenterol, 26 Kyungheedae Ro, Seoul 130701, South Korea. [Kuo, Braden] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Neurointestinal Hlth, Dept Gastroenterol, Boston, MA USA. [Lee, Hyangsook; Kim, Song-Yi; Lee, Hyejung] Kyung Hee Univ, Acupuncture & Meridian Sci Res Ctr, Coll Korean Med, Seoul, South Korea. [Yeo, Inkwon] Sookmyung Womens Univ, Dept Stat, Seoul, South Korea. [Joo, Kwang Ro] Kyung Hee Univ, Sch Med, Dept Gastroenterol, Seoul, South Korea. RP Park, JW (reprint author), Kyung Hee Univ, Coll Korean Med, Dept Gastroenterol, 26 Kyungheedae Ro, Seoul 130701, South Korea. EM pjw2907@khu.ac.kr OI LEE, HYANGSOOK/0000-0002-1107-9389 FU National Research Foundation of Korea grant - Korean government (Ministry of Science, ICT & Future Planning) [2005-0049404] FX This work was supported by the National Research Foundation of Korea grant funded by the Korean government (Ministry of Science, ICT & Future Planning) (no. 2005-0049404). NR 38 TC 0 Z9 0 U1 1 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1075-5535 EI 1557-7708 J9 J ALTERN COMPLEM MED JI J. Altern. Complement Med. PD DEC PY 2016 VL 22 IS 12 BP 997 EP 1006 DI 10.1089/acm.2016.0208 PG 10 WC Integrative & Complementary Medicine SC Integrative & Complementary Medicine GA EH1ER UT WOS:000391506900009 PM 27732083 ER PT J AU Takeuchi, K Arthanari, H Wagner, G AF Takeuchi, Koh Arthanari, Haribabu Wagner, Gerhard TI Perspective: revisiting the field dependence of TROSY sensitivity SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE TROSY; Aromatic TROSY; Sensitivity; N-15 detection; C-13 detection; Field dependence; CSA ID RELAXATION-OPTIMIZED SPECTROSCOPY; NITROGEN-DETECTED TROSY; HETERONUCLEAR CORRELATION; PERDEUTERATED PROTEINS; NMR-SPECTROSCOPY; RESONANCE; DEUTERATION; ASSIGNMENT; RESOLUTION AB The discovery of the TROSY effect (Pervushin et al. in Proc Natl Acad Sci USA 94:12366-12371, 1997) for reducing transverse relaxation and line sharpening through selecting pathways in which dipole-dipole and CSA Hamiltonians partially cancel each other had a tremendous impact on solution NMR studies of macromolecules. Together with the methyl TROSY (Tugarinov and Kay in J Biomol NMR 28:165-172, 2004) it enabled structural and functional studies of significantly larger systems. The optimal field strengths for TROSY have been estimated to be on spectrometers operating around 900 MHz (21.14 T) for the H-1(N) TROSY (Pervushin et al. in Proc Natl Acad Sci USA 94:12366-12371, 1997) while the aromatic C-13 (C-13(aro)) TROSY is posited to be optimal at around 600 MHz (14.09 T) (Pervushin et al. in J Am Chem Soc 120:6394-6400, 1998b; Pervushin in Q Rev Biophys 33:161-197, 2000). The initial rational was based on the consideration of where the quadratic B-0 field dependences of the TROSY relaxation rates reach a minimum. For sensitivity consideration, however, it is interesting to estimate which field strengths yield the tallest peaks. Recent studies of N-15-detected TROSYs suggested that maximal peak heights are expected at 1.15 GHz (27.01 T) although the slowest relaxation rates or longest transverse relaxation times T-2 are indeed expected around 900 MHz (21.14 T) (Takeuchi in J Biomol NMR 63:323-331, 2015; Takeuchi et al. in J Biomol NMR 64:143-151, 2016). This was based on the fact that the heights of Lorentzian lines are proportional to B (o) (3/2) * T-2 (B-o). Thus, multiplying the parabolic T-2(B-o) dependence with the increasing function of B (o) (3/2) shifts the maxima of peak-height field dependence from the T-2 maximum at 900 MHz to higher fields. Moreover, besides shifting the peak height maximum for N-15 TROSY, this analysis yields estimates for optimal peak heights for H-1(N) detected TROSY to 1.5 GHz, and to 900 MHz for C-13-detected (CaroTROSY)-C-13 as is detailed below. To our knowledge, this aspect of field dependence of TROSY sensitivity has not been in the attention of the NMR community but may affect perspectives of NMR at ultra-high fields. C1 [Takeuchi, Koh] Natl Inst Adv Ind Sci & Technol, Mol Profiling Res Ctr Drug Discovery, Tokyo 1350064, Japan. [Takeuchi, Koh] Japan Sci & Technol Agcy, PRESTO, Tokyo 1350064, Japan. [Arthanari, Haribabu] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Arthanari, Haribabu; Wagner, Gerhard] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RP Wagner, G (reprint author), Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. EM gerhard_wagner@hms.harvard.edu OI Wagner, Gerhard/0000-0002-2063-4401 FU National Institute of Health [GM047467, EB002026]; PREST, JST FX This study was supported by the National Institute of Health (Grant GM047467 and EB002026). This work was partially supported by PREST, JST to KT. NR 26 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0925-2738 EI 1573-5001 J9 J BIOMOL NMR JI J. Biomol. NMR PD DEC PY 2016 VL 66 IS 4 BP 221 EP 225 DI 10.1007/s10858-016-0075-4 PG 5 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA EH9FI UT WOS:000392076700001 PM 27866370 ER PT J AU Vo, LC Snyder, C McCracken, C McDougle, CJ McCracken, JT Aman, MG Tierney, E Arnold, LE Levi, D Kelleman, M Carroll, D Morrissey, J Vitiello, B Scahill, L AF Vo, Lan Chi Snyder, Christopher McCracken, Courtney McDougle, Christopher J. McCracken, James T. Aman, Michael G. Tierney, Elaine Arnold, L. Eugene Levi, Daniel Kelleman, Michael Carroll, Deirdre Morrissey, John Vitiello, Benedetto Scahill, Lawrence TI No Apparent Cardiac Conduction Effects of Acute Treatment with Risperidone in Children with Autism Spectrum Disorder SO JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY LA English DT Article DE risperidone; electrocardiogram; QTc; autism spectrum disorder; cardiac conduction ID PERVASIVE DEVELOPMENTAL DISORDERS; ABERRANT BEHAVIOR CHECKLIST; QT INTERVAL; ANTIPSYCHOTIC TREATMENT; ADOLESCENTS; RISK; DRUG; SCHIZOPHRENIA; ARIPIPRAZOLE; MEDICATIONS AB Objectives: Risperidone is approved for the treatment of serious behavioral problems in children with autism spectrum disorder (ASD). This study examined the effects of risperidone on cardiac conduction in children with ASD. Methods: Data were collected from an 8-week, five-site trial conducted by the Research Units on Pediatric Psychopharmacology Autism Network. Children (age 5-17 years) were randomly assigned to risperidone (n = 49) or placebo (n = 52) under double-blind conditions. Risperidone was superior to placebo in reducing serious behavioral problems. A standard 12-lead, electrocardiogram (ECG) was obtained in most subjects at screening and week 8. A pediatric electrophysiologist blind to treatment assignment reviewed all available ECGs for readability, abnormalities, and cardiac conduction parameters, including QTc. The electrophysiologist measurements were compared to machine readings. A second blinded electrophysiologist examined all available ECGs for abnormalities and a 20% random sample for QTc. Results: Of the 101 randomized subjects in the trial, complete pretreatment and week 8 data were available on 65 subjects (placebo n = 30; risperidone n = 35). The electrophysiologist did not identify any cardiac conduction adverse effects of risperidone and there was no difference in mean change on the QTc compared to placebo. The Bland-Altman plot showed a systematic bias in QTc measurements by the electrophysiologist and machine. Machine readings produced higher values than the electrophysiologist for shorter QTc intervals and machine scoring was lower than electrophysiologist readings for longer QTc values (p = 0.001). Two electrophysiologists had overall percent agreements of 82.9% (95% CI: 76.3 to 89.6) on qualitative assessment and 88.6% (95% CI: 79.3 to 98.0) on QTc interval. Conclusion: Using conventional doses during acute treatment in children with ASD and serious behavioral problems, there was no difference in the mean change in QTc between risperidone and placebo. Compared to the electrophysiologist, the machine readings may miss elevated QTc measurements. C1 [Vo, Lan Chi] Emory Univ, Sch Med, Dept Psychiat, Atlanta, GA 30322 USA. [Snyder, Christopher] Rainbow Babies & Childrens Hosp, Div Pediat Cardiol, Univ Hosp, 2101 Adelbert Rd, Cleveland, OH 44106 USA. [McCracken, Courtney; Kelleman, Michael] Childrens Hosp Atlanta, Atlanta, GA USA. [McCracken, Courtney; Kelleman, Michael] Emory Univ, Sch Med, Atlanta, GA USA. [McDougle, Christopher J.] Harvard Med Sch, Massachusetts Gen Hosp, Lurie Ctr Autism, Boston, MA USA. [McCracken, James T.] Univ Calif Los Angeles, Div Child Psychiat, Los Angeles, CA USA. [Aman, Michael G.; Arnold, L. Eugene] Ohio State Univ, Nisonger Ctr, Columbus, OH 43210 USA. [Tierney, Elaine] Kennedy Krieger Inst, Baltimore, MD USA. [Levi, Daniel; Morrissey, John] Univ Calif Los Angeles, Mattel Childrens Hosp, Los Angeles, CA USA. [Carroll, Deirdre] Yale Univ, Sch Med, Yale Child Study Ctr, New Haven, CT USA. [Vitiello, Benedetto] NIMH, Bethesda, MD 20892 USA. [Scahill, Lawrence] Emory Univ, Sch Med, Marcus Autism Ctr, 1920 Briarcliff Rd, Atlanta, GA 30329 USA. RP Scahill, L (reprint author), Emory Univ, Sch Med, Marcus Autism Ctr, 1920 Briarcliff Rd, Atlanta, GA 30329 USA. EM lawrence.scahill@emory.edu FU National Institute of Mental Health [N01MH70009, N01MH70010, N01MH70001, N01MH80011, R25MH101079]; National Institutes of Health [M01 RR00750, M01 RR00052, M01 RR00034, M01 RR06022]; National Center for Advancing Translational Sciences of the National Institutes of Health [UL1 TR000454]; Marcus Foundation; Children's Hospital Trust Fund FX Supported by contracts from the National Institute of Mental Health (N01MH70009, to Dr. Scahill; N01MH70010, to Dr. J. McCracken; N01MH70001, to Dr. McDougle; and N01MH80011, to Dr. Aman). General Clinical Research Center grants from the National Institutes of Health (M01 RR00750, to Indiana University; M01 RR00052, to Johns Hopkins University; M01 RR00034, to Ohio State University; and M01 RR06022, to Yale University). The project was the National Center for Advancing Translational Sciences of the National Institutes of Health UL1 TR000454 (Emory University) as well as the Marcus Foundation and the Children's Hospital Trust Fund. Dr. Vo has received training support from the National Institute of Mental Health (R25MH101079) to Emory University. NR 41 TC 0 Z9 0 U1 3 U2 3 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1044-5463 EI 1557-8992 J9 J CHILD ADOL PSYCHOP JI J. Child Adolesc. Psychopharmacol. PD DEC PY 2016 VL 26 IS 10 BP 900 EP 908 DI 10.1089/cap.2016.0090 PG 9 WC Pediatrics; Pharmacology & Pharmacy; Psychiatry SC Pediatrics; Pharmacology & Pharmacy; Psychiatry GA EH5TT UT WOS:000391836500006 PM 27726426 ER PT J AU Japuntich, SJ Luberto, CM Streck, JM Rigotti, NA Temel, J Lanuti, M Dresler, C Zallen, JP Davies, D Park, ER AF Japuntich, Sandra J. Luberto, Christina M. Streck, Joanna M. Rigotti, Nancy A. Temel, Jennifer Lanuti, Michael Dresler, Carolyn Zallen, Jennifer P. Davies, Diane Park, Elyse R. TI Integrating tobacco treatment into thoracic oncology settings: Lessons learned SO JOURNAL OF HEALTH PSYCHOLOGY LA English DT Article DE cancer; intervention; lung cancer; methodology; smoking cessation ID CELL LUNG-CANCER; QUALITY-OF-LIFE; 2ND PRIMARY CANCERS; SMOKING-CESSATION; SOCIAL SUPPORT; NECK-CANCER; DIAGNOSIS; DEPENDENCE; HEAD; GUIDELINES AB Clinical practice guidelines recommend tobacco treatment for all cancer patients. However, little is known about how to integrate tobacco treatment into cancer care. The results of our pilot study of an evidence-based tobacco treatment integrated into a thoracic oncology clinic demonstrated good feasibility and efficacy, providing an opportunity to inform future tobacco treatment integration efforts. Here, we describe the process of intervention development, clinic integration, patient identification, and patient enrollment. We report on the intervention content and delivery, patterns of quitting for participants in the tobacco treatment group, and changes in smoking-related psychosocial variables. Clinical implications and suggestions for future research are discussed. C1 [Japuntich, Sandra J.; Luberto, Christina M.; Streck, Joanna M.; Rigotti, Nancy A.; Temel, Jennifer; Lanuti, Michael; Zallen, Jennifer P.; Davies, Diane; Park, Elyse R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Luberto, Christina M.; Rigotti, Nancy A.; Temel, Jennifer; Park, Elyse R.] Harvard Med Sch, Boston, MA USA. [Japuntich, Sandra J.] VA Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA USA. [Zallen, Jennifer P.] Georgetown Univ, Washington, DC 20057 USA. [Dresler, Carolyn] Arkansas Dept Hlth, Little Rock, AR 72205 USA. [Japuntich, Sandra J.] Boston Univ, Sch Med, Boston, MA 02215 USA. RP Luberto, CM (reprint author), Massachusetts Gen Hosp, Dept Behav Med, 1 Bowdoin Sq,7th Floor, Boston, MA 02114 USA. EM cluberto@partners.org FU National Cancer Institute (NCI) [R03CA130722-01]; Pfizer; Massachusetts General Hospital Ladies Visiting Committee; US Department of Veterans Affairs Clinical Sciences Research and Development Service Career Development Award [1IK2CX000918-01A1] FX This work was supported by the National Cancer Institute (NCI R03CA130722-01; Park), Pfizer (Investigator Initiated Research Grant which provided the study medication), and the Massachusetts General Hospital Ladies Visiting Committee. Dr. Japuntich's time was supported in part by the US Department of Veterans Affairs Clinical Sciences Research and Development Service Career Development Award (1IK2CX000918-01A1). 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 33 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1359-1053 EI 1461-7277 J9 J HEALTH PSYCHOL JI J. Health Psychol. PD DEC PY 2016 VL 21 IS 12 BP 2813 EP 2823 DI 10.1177/1359105315587136 PG 11 WC Psychology, Clinical SC Psychology GA EH0PH UT WOS:000391465700005 PM 26044717 ER PT J AU Southey, MC Goldgar, DE Winqvist, R Pylkas, K Couch, F Tischkowitz, M Foulkes, WD Dennis, J Michailidou, K van Rensburg, EJ Heikkinen, T Nevanlinna, H Hopper, JL Dork, T Claes, KBM Reis, J Teo, ZL Radice, P Catucci, I Peterlongo, P Tsimiklis, H Odefrey, FA Dowty, JG Schmidt, MK Broeks, A Hogervorst, FB Verhoef, S Carpenter, J Clarke, C Scott, RJ Fasching, PA Haeberle, L Ekici, AB Beckmann, MW Peto, J dos-Santos-Silva, I Fletcher, O Johnson, N Bolla, MK Sawyer, EJ Tomlinson, I Kerin, MJ Miller, N Marme, F Burwinkel, B Yang, RX Guenel, P Truong, T Menegaux, F Sanchez, M Bojesen, S Nielsen, SF Flyger, H Benitez, J Zamora, MP Perez, JIA Menendez, P Anton-Culver, H Neuhausen, S Ziogas, A Clarke, CA Brenner, H Arndt, V Stegmaier, C Brauch, H Bruning, T Ko, YD Muranen, TA Aittomaki, K Blomqvist, C Bogdanova, NV Antonenkova, NN Lindblom, A Margolin, S Mannermaa, A Kataja, V Kosma, VM Hartikainen, JM Spurdle, AB Wauters, E Smeets, D Beuselinck, B Floris, G Chang-Claude, J Rudolph, A Seibold, P Flesch-Janys, D Olson, JE Vachon, C Pankratz, VS McLean, C Haiman, CA Henderson, BE Schumacher, F Le Marchand, L Kristensen, V Alnaes, GG Zheng, W Hunter, DJ Lindstrom, S Hankinson, SE Kraft, P Andrulis, I Knight, JA Glendon, G Mulligan, AM Jukkola-Vuorinen, A Grip, M Kauppila, S Devilee, P Tollenaar, RAEM Seynaeve, C Hollestelle, A Garcia-Closas, M Figueroa, J Chanock, SJ Lissowska, J Czene, K Darabi, H Eriksson, M Eccles, DM Rafiq, S Tapper, WJ Gerty, SM Hooning, MJ Martens, JWM Collee, JM Tilanus-Linthorst, M Hall, P Li, JM Brand, JS Humphreys, K Cox, A Reed, MWR Luccarini, C Baynes, C Dunning, AM Hamann, U Torres, D Ulmer, HU Rudiger, T Jakubowska, A Lubinski, J Jaworska, K Durda, K Slager, S Toland, AE Ambrosone, CB Yannoukakos, D Swerdlow, A Ashworth, A Orr, N Jones, M Gonzalez-Neira, A Pita, G Alonso, MR Alvarez, N Herrero, D Tessier, DC Vincent, D Bacot, F Simard, J Dumont, M Soucy, P Eeles, R Muir, K Wiklund, F Gronberg, H Schleutker, J Nordestgaard, BG Weischer, M Travis, RC Neal, D Donovan, JL Hamdy, FC Khaw, KT Stanford, JL Blot, WJ Thibodeau, S Schaid, DJ Kelley, JL Maier, C Kibel, AS Cybulski, C Cannon-Albright, L Butterbach, K Park, J Kaneva, R Batra, J Teixeira, MR Kote-Jarai, Z Al Olama, AA Benlloch, S Renner, SP Hartmann, A Hein, A Ruebner, M Lambrechts, D Van Nieuwenhuysen, E Vergote, I Lambretchs, S Doherty, JA Rossing, MA Nickels, S Eilber, U Wang-Gohrke, S Odunsi, K Sucheston-Campbell, LE Friel, G Lurie, G Killeen, JL Wilkens, LR Goodman, MT Runnebaum, I Hillemanns, PA Pelttari, LM Butzow, R Modugno, F Edwards, RP Ness, RB Moysich, KB du Bois, A Heitz, F Harter, P Kommoss, S Karlan, BY Walsh, C Lester, J Jensen, A Kjaer, SK Hogdall, E Peissel, B Bonanni, B Bernard, L Goode, EL Fridley, BL Vierkant, RA Cunningham, JM Larson, MC Fogarty, ZC Kalli, KR Liang, D Lu, KH Hildebrandt, MAT Wu, XF Levine, DA Dao, F Bisogna, M Berchuck, A Iversen, ES Marks, JR Akushevich, L Cramer, DW Schildkraut, J Terry, KL Poole, EM Stampfer, M Tworoger, SS Bandera, EV Orlow, I Olson, SH Bjorge, L Salvesen, HB van Altena, AM Aben, KKH Kiemeney, LA Massuger, LFAG Pejovic, T Bean, Y Brooks-Wilson, A Kelemen, LE Cook, LS Le, ND Grski, B Gronwald, J Menkiszak, J Hogdall, CK Lundvall, L Nedergaard, L Engelholm, SA Dicks, E Tyrer, J Campbell, I McNeish, I Paul, J Siddiqui, N Glasspool, R Whittemore, AS Rothstein, JH McGuire, V Sieh, W Cai, H Shu, XO Teten, RT Sutphen, R McLaughlin, JR Narod, SA Phelan, CM Monteiro, AN Fenstermacher, D Lin, HY Permuth, JB Sellers, TA Chen, YA Tsai, YY Chen, ZH Gentry-Maharaj, A Gayther, SA Ramus, SJ Menon, U Wu, AH Pearce, CL Van den Berg, D Pike, MC Dansonka-Mieszkowska, A Plisiecka-Halasa, J Moes-Sosnowska, J Kupryjanczyk, J Pharoah, PDP Song, HL Winship, I Chenevix-Trench, G Giles, GG Tavtigian, SV Easton, DF Milne, RL AF Southey, Melissa C. Goldgar, David E. Winqvist, Robert Pylkas, Katri Couch, Fergus Tischkowitz, Marc Foulkes, William D. Dennis, Joe Michailidou, Kyriaki van Rensburg, Elizabeth J. Heikkinen, Tuomas Nevanlinna, Heli Hopper, John L. Doerk, Thilo Claes, Kathleen B. M. Reis-Filho, Jorge Teo, Zhi Ling Radice, Paolo Catucci, Irene Peterlongo, Paolo Tsimiklis, Helen Odefrey, Fabrice A. Dowty, James G. Schmidt, Marjanka K. Broeks, Annegien Hogervorst, Frans B. Verhoef, Senno Carpenter, Jane Clarke, Christine Scott, Rodney J. Fasching, Peter A. Haeberle, Lothar Ekici, Arif B. Beckmann, Matthias W. Peto, Julian dos-Santos-Silva, Isabel Fletcher, Olivia Johnson, Nichola Bolla, Manjeet K. Sawyer, Elinor J. Tomlinson, Ian Kerin, Michael J. Miller, Nicola Marme, Federik Burwinkel, Barbara Yang, Rongxi Guenel, Pascal Therese Truong Menegaux, Florence Sanchez, Marie Bojesen, Stig Nielsen, Sune F. Flyger, Henrik Benitez, Javier Pilar Zamora, M. Arias Perez, Jose Ignacio Menendez, Primitiva Anton-Culver, Hoda Neuhausen, Susan Ziogas, Argyrios Clarke, Christina A. Brenner, Hermann Arndt, Volker Stegmaier, Christa Brauch, Hiltrud Bruening, Thomas Ko, Yon-Dschun Muranen, Taru A. Aittomaki, Kristiina Blomqvist, Carl Bogdanova, Natalia V. Antonenkova, Natalia N. Lindblom, Annika Margolin, Sara Mannermaa, Arto Kataja, Vesa Kosma, Veli-Matti Hartikainen, Jaana M. Spurdle, Amanda B. Wauters, Els Smeets, Dominiek Beuselinck, Benoit Floris, Giuseppe Chang-Claude, Jenny Rudolph, Anja Seibold, Petra Flesch-Janys, Dieter Olson, Janet E. Vachon, Celine Pankratz, Vernon S. McLean, Catriona Haiman, Christopher A. Henderson, Brian E. Schumacher, Fredrick Le Marchand, Loic Kristensen, Vessela Alnaes, Grethe Grenaker Zheng, Wei Hunter, David J. Lindstrom, Sara Hankinson, Susan E. Kraft, Peter Andrulis, Irene Knight, Julia A. Glendon, Gord Mulligan, Anna Marie Jukkola-Vuorinen, Arja Grip, Mervi Kauppila, Saila Devilee, Peter Tollenaar, Robert A. E. M. Seynaeve, Caroline Hollestelle, Antoinette Garcia-Closas, Montserrat Figueroa, Jonine Chanock, Stephen J. Lissowska, Jolanta Czene, Kamila Darabi, Hatef Eriksson, Mikael Eccles, Diana M. Rafiq, Sajjad Tapper, William J. Gerty, Sue M. Hooning, Maartje J. Martens, John W. M. Collee, J. Margriet Tilanus-Linthorst, Madeleine Hall, Per Li, Jingmei Brand, Judith S. Humphreys, Keith Cox, Angela Reed, Malcolm W. R. Luccarini, Craig Baynes, Caroline Dunning, Alison M. Hamann, Ute Torres, Diana Ulmer, Hans Ulrich Ruediger, Thomas Jakubowska, Anna Lubinski, Jan Jaworska, Katarzyna Durda, Katarzyna Slager, Susan Toland, Amanda E. Ambrosone, Christine B. Yannoukakos, Drakoulis Swerdlow, Anthony Ashworth, Alan Orr, Nick Jones, Michael Gonzalez-Neira, Anna Pita, Guillermo Rosario Alonso, M. Alvarez, Nuria Herrero, Daniel Tessier, Daniel C. Vincent, Daniel Bacot, Francois Simard, Jacques Dumont, Martine Soucy, Penny Eeles, Rosalind Muir, Kenneth Wiklund, Fredrik Gronberg, Henrik Schleutker, Johanna Nordestgaard, Borge G. Weischer, Maren Travis, Ruth C. Neal, David Donovan, Jenny L. Hamdy, Freddie C. Khaw, Kay-Tee Stanford, Janet L. Blot, William J. Thibodeau, Stephen Schaid, Daniel J. Kelley, Joseph L. Maier, Christiane Kibel, Adam S. Cybulski, Cezary Cannon-Albright, Lisa Butterbach, Katja Park, Jong Kaneva, Radka Batra, Jyotsna Teixeira, Manuel R. Kote-Jarai, Zsofia Al Olama, Ali Amin Benlloch, Sara Renner, Stefan P. Hartmann, Arndt Hein, Alexander Ruebner, Matthias Lambrechts, Diether Van Nieuwenhuysen, Els Vergote, Ignace Lambretchs, Sandrina Doherty, Jennifer A. Rossing, Mary Anne Nickels, Stefan Eilber, Ursula Wang-Gohrke, Shan Odunsi, Kunle Sucheston-Campbell, Lara E. Friel, Grace Lurie, Galina Killeen, Jeffrey L. Wilkens, Lynne R. Goodman, Marc T. Runnebaum, Ingo Hillemanns, Peter A. Pelttari, Liisa M. Butzow, Ralf Modugno, Francesmary Edwards, Robert P. Ness, Roberta B. Moysich, Kirsten B. du Bois, Andreas Heitz, Florian Harter, Philipp Kommoss, Stefan Karlan, Beth Y. Walsh, Christine Lester, Jenny Jensen, Allan Kjaer, Susanne Kruger Hogdall, Estrid Peissel, Bernard Bonanni, Bernardo Bernard, Loris Goode, Ellen L. Fridley, Brooke L. Vierkant, Robert A. Cunningham, Julie M. Larson, Melissa C. Fogarty, Zachary C. Kalli, Kimberly R. Liang, Dong Lu, Karen H. Hildebrandt, Michelle A. T. Wu, Xifeng Levine, Douglas A. Dao, Fanny Bisogna, Maria Berchuck, Andrew Iversen, Edwin S. Marks, Jeffrey R. Akushevich, Lucy Cramer, Daniel W. Schildkraut, Joellen Terry, Kathryn L. Poole, Elizabeth M. Stampfer, Meir Tworoger, Shelley S. Bandera, Elisa V. Orlow, Irene Olson, Sara H. Bjorge, Line Salvesen, Helga B. van Altena, Anne M. Aben, Katja K. H. Kiemeney, Lambertus A. Massuger, Leon F. A. G. Pejovic, Tanja Bean, Yukie Brooks-Wilson, Angela Kelemen, Linda E. Cook, Linda S. Le, Nhu D. Grski, Bohdan Gronwald, Jacek Menkiszak, Janusz Hogdall, Claus K. Lundvall, Lene Nedergaard, Lotte Engelholm, Svend Aage Dicks, Ed Tyrer, Jonathan Campbell, Ian McNeish, Iain Paul, James Siddiqui, Nadeem Glasspool, Rosalind Whittemore, Alice S. Rothstein, Joseph H. McGuire, Valerie Sieh, Weiva Cai, Hui Shu, Xiao-Ou Teten, Rachel T. Sutphen, Rebecca McLaughlin, John R. Narod, Steven A. Phelan, Catherine M. Monteiro, Alvaro N. Fenstermacher, David Lin, Hui-Yi Permuth, Jennifer B. Sellers, Thomas A. Chen, Y. Ann Tsai, Ya-Yu Chen, Zhihua Gentry-Maharaj, Aleksandra Gayther, Simon A. Ramus, Susan J. Menon, Usha Wu, Anna H. Pearce, Celeste L. Van den Berg, David Pike, Malcolm C. Dansonka-Mieszkowska, Agnieszka Plisiecka-Halasa, Joanna Moes-Sosnowska, Joanna Kupryjanczyk, Jolanta Pharoah, Paul D. P. Song, Honglin Winship, Ingrid Chenevix-Trench, Georgia Giles, Graham G. Tavtigian, Sean V. Easton, Doug F. Milne, Roger L. CA kConFab Investigators Australian Ovarian Canc Study Grp TI PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID BREAST-CANCER; PROSTATE-CANCER; OVARIAN-CANCER; BRCA2-INTERACTING PROTEIN; SUSCEPTIBILITY LOCI; FAMILY REGISTRY; GENE; MUTATIONS; BRCA1; METAANALYSIS AB Background The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. Methods We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. Results For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1x10-5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9x10-8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p=0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. Conclusions This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important. C1 [Southey, Melissa C.; Teo, Zhi Ling; Tsimiklis, Helen; Odefrey, Fabrice A.] Univ Melbourne, Genet Epidemiol Lab, Dept Pathol, Melbourne, Vic 3010, Australia. [Goldgar, David E.; Tavtigian, Sean V.] Huntsman Canc Inst, Salt Lake City, UT USA. [Winqvist, Robert; Pylkas, Katri] Univ Oulu, Lab Canc Genet & Tumor Biol, Canc & Translat Med Res Unit, Nordlab Oulu, Oulu, Finland. [Winqvist, Robert; Pylkas, Katri] Univ Oulu, Bioctr Oulu, Oulu, Finland. [Couch, Fergus; Thibodeau, Stephen; Cunningham, Julie M.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Tischkowitz, Marc] Univ Cambridge, Dept Med Genet, Cambridge, England. 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[Liang, Dong] Texas Southern Univ, Coll Pharm & Hlth Sci, Houston, TX USA. [Lu, Karen H.] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA. [Hildebrandt, Michelle A. T.; Wu, Xifeng] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Levine, Douglas A.; Dao, Fanny; Bisogna, Maria] Mem Sloan Kettering Canc Ctr, Dept Surg, Gynecol Serv, 1275 York Ave, New York, NY 10021 USA. [Berchuck, Andrew] Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC USA. [Iversen, Edwin S.] Duke Univ, Dept Stat Sci, Durham, NC USA. [Marks, Jeffrey R.] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. [Akushevich, Lucy; Schildkraut, Joellen] Duke Canc Inst, Canc Prevent Detect & Control Res Program, Durham, NC USA. [Cramer, Daniel W.; Terry, Kathryn L.] Brigham & Womens Hosp, Obstet & Gynecol Epidemiol Ctr, 75 Francis St, Boston, MA 02115 USA. [Poole, Elizabeth M.; Stampfer, Meir; Tworoger, Shelley S.] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Poole, Elizabeth M.; Stampfer, Meir; Tworoger, Shelley S.] Harvard Med Sch, Boston, MA USA. [Poole, Elizabeth M.; Tworoger, Shelley S.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Bandera, Elisa V.] State Univ New Jersey, Rutgers Canc Inst New Jersey, Canc Prevent & Control Program, New Brunswick, NJ USA. [Orlow, Irene; Olson, Sara H.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, 1275 York Ave, New York, NY 10021 USA. [Bjorge, Line; Salvesen, Helga B.] Haukeland Univ Horpital, Dept Gynecol & Obstet, Bergen, Norway. [Bjorge, Line; Salvesen, Helga B.] Univ Bergen, Dept Clin Sci, Ctr Canc Biomarkers, Bergen, Norway. [van Altena, Anne M.; Massuger, Leon F. A. G.] Radboud Univ Nijmegen, Med Ctr, Dept Gynaecol, Nijmegen, Netherlands. [Aben, Katja K. H.; Kiemeney, Lambertus A.] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Nijmegen, Netherlands. [Aben, Katja K. H.] Netherlands Comprehens Canc Org, Utrecht, Netherlands. [Aben, Katja K. H.] Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Portland, OR 97201 USA. [Pejovic, Tanja; Bean, Yukie] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. [Brooks-Wilson, Angela] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC, Canada. [Brooks-Wilson, Angela] Simon Fraser Univ, Dept Biomed Physiol & Kinesiol, Burnaby, BC, Canada. [Kelemen, Linda E.] Med Univ South Carolina, Dept Publ Hlth Sci, Coll Med, Charleston, SC USA. [Kelemen, Linda E.] Med Univ South Carolina, Hollings Canc Ctr, Charleston, SC USA. [Cook, Linda S.] Univ New Mexico, Dept Internal Med, Div Epidemiol & Biostat, Albuquerque, NM 87131 USA. [Le, Nhu D.] BC Canc Agcy, Canc Control Res, Vancouver, BC, Canada. [Grski, Bohdan; Gronwald, Jacek] Pomeranian Med Univ, Dept Genet & Pathol, Int Hereditary Canc Ctr, Szczecin, Poland. [Menkiszak, Janusz] Pomeranian Med Univ, Dept Gynecol Surg & Gynecol Oncol Adults & Adoles, Szczecin, Poland. [Lundvall, Lene] Univ Copenhagen, Rigshosp, Gyn Clin, Copenhagen, Denmark. [Nedergaard, Lotte] Univ Copenhagen, Rigshosp, Dept Pathol, Copenhagen, Denmark. [Engelholm, Svend Aage] Univ Copenhagen, Rigshosp, Dept Oncol, Copenhagen, Denmark. [Dicks, Ed; Tyrer, Jonathan; Pharoah, Paul D. P.; Song, Honglin] Univ Cambridge, Dept Oncol, Strangeways Res Lab, Cambridge, England. [Campbell, Ian] Peter MacCallum Canc Ctr, Div Res, Canc Genet Lab, St Andrews Pl, East Melbourne, Australia. [McNeish, Iain] Univ Glasgow, Wolfson Wohl Canc Res Ctr, Beatson Inst Canc Res, Inst Canc Sci, Glasgow, Lanark, Scotland. [Paul, James] Beatson West Scotland Canc Ctr, Canc Res UK Clin Trials Unit, 1053 Great Western Rd, Glasgow G12 0YN, Lanark, Scotland. [Siddiqui, Nadeem; Glasspool, Rosalind] Glasgow Royal Infirm, Dept Gynaecol Oncol, Glasgow, Lanark, Scotland. [Whittemore, Alice S.; Rothstein, Joseph H.; McGuire, Valerie; Sieh, Weiva] Stanford Univ, Sch Med, Dept Hlth Res & Policy Epidemiol, Stanford, CA 94305 USA. [Teten, Rachel T.; Sutphen, Rebecca] Univ S Florida, Coll Med, Epidemiol Ctr, Tampa, FL USA. [McLaughlin, John R.] Publ Hlth Ontario, Toronto, ON, Canada. [Narod, Steven A.] Univ Toronto, Womens Coll, Res Inst, Toronto, ON, Canada. [Phelan, Catherine M.; Monteiro, Alvaro N.; Permuth, Jennifer B.; Sellers, Thomas A.; Tsai, Ya-Yu] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL USA. [Fenstermacher, David; Lin, Hui-Yi; Chen, Y. Ann; Chen, Zhihua] H Lee Moffitt Canc Ctr & Res Inst, Dept Biostat & Bioinformat, Tampa, FL USA. [Gentry-Maharaj, Aleksandra; Menon, Usha] UCL, Inst Womens Hlth, Womens Canc, London, England. [Gayther, Simon A.; Ramus, Susan J.; Wu, Anna H.; Pearce, Celeste L.; Van den Berg, David; Pike, Malcolm C.] Univ Southern Calif, Norris Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA. [Pike, Malcolm C.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, 1275 York Ave, New York, NY 10021 USA. [Dansonka-Mieszkowska, Agnieszka; Plisiecka-Halasa, Joanna; Moes-Sosnowska, Joanna; Kupryjanczyk, Jolanta] Maria Sklodowska Curie Mem Canc Ctr, Dept Pathol & Lab Diagnost, Warsaw, Poland. [Dansonka-Mieszkowska, Agnieszka; Plisiecka-Halasa, Joanna; Moes-Sosnowska, Joanna; Kupryjanczyk, Jolanta] Inst Oncol, Warsaw, Poland. [Winship, Ingrid] Univ Melbourne Hlth, Dept Med, Melbourne, Vic, Australia. [Winship, Ingrid] Royal Melbourne Hosp, Melbourne, Vic 3050, Australia. [Giles, Graham G.; Milne, Roger L.] Canc Council Victoria, Cancer Epidemiol Ctr, Melbourne, Vic, Australia. RP Southey, MC (reprint author), Univ Melbourne, Genet Epidemiol Lab, Dept Pathol, Melbourne, Vic 3010, Australia. EM msouthey@unimelb.edu.au RI Hein, Alexander/F-6999-2010; Gronwald, Jacek/A-4576-2017; Menkiszak, Janusz/I-4036-2014; Jansen van Rensburg, Elizabeth (Lizette)/B-9104-2011; Hartikainen, Jaana/E-6256-2015; salvesen, Helga/C-1187-2017; Knight, Julia/A-6843-2012; Brooks-Wilson, Angela/E-9399-2012; Bruning, Thomas/G-8120-2015; Brenner, Hermann/B-4627-2017; Peissel, Bernard/E-8187-2017; Dork, Thilo/J-8620-2012; OI Dunning, Alison Margaret/0000-0001-6651-7166; Winship, Ingrid/0000-0001-8535-6003; Arndt, Volker/0000-0001-9320-8684; Hein, Alexander/0000-0003-2601-3398; Gronwald, Jacek/0000-0002-3643-2871; salvesen, Helga/0000-0002-4438-8831; Brooks-Wilson, Angela/0000-0003-1009-6408; Bruning, Thomas/0000-0001-9560-5464; Brenner, Hermann/0000-0002-6129-1572; Peissel, Bernard/0000-0001-9233-3571; Yannoukakos, Drakoulis/0000-0001-7509-3510 FU European Community [223175 (HEALTH-F2-2009-223175)]; Cancer Research UK [C1287/A10118, C1287/A 10710, C12292/A11174, C5047/A8384, C5047/A15007, C5047/A10692, CRUK C8197/A10123]; National Institutes of Health [CA128978]; Post-Cancer GWAS initiative [1 U19 CA 148537]; Department of Defense [W81XWH-10-1-0341]; Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer; Komen Foundation for the Cure; Breast Cancer Research Foundation; Ovarian Cancer Research Fund; Susan G Komen FX Funding for the iCOGS infrastructure came from: the European Community's Seventh Framework Programme under grant agreement no 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C5047/A8384, C5047/A15007, C5047/A10692, CRUK C8197/A10123), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (No. 1 U19 CA 148537-the GAME-ON initiative), the Department of Defense (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, the Ovarian Cancer Research Fund and Susan G Komen (WF). NR 35 TC 4 Z9 4 U1 11 U2 11 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 DEC PY 2016 VL 53 IS 12 BP 800 EP 811 DI 10.1136/jmedgenet-2016-103839 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA EH0MC UT WOS:000391457200003 PM 27595995 ER PT J AU Postmus, I Warren, HR Trompet, S Arsenault, BJ Avery, CL Bis, JC Chasman, DI de Keyser, CE Deshmukh, HA Evans, DS Feng, QP Li, XH Smit, RAJ Smith, AV Sun, FG Taylor, KD Arnold, AM Barnes, MR Barratt, BJ Betteridge, J Boekholdt, SM Boerwinkle, E Buckley, BM Chen, YDI de Craen, AJM Cummings, SR Denny, JC Dube, MP Durrington, PN Eiriksdottir, G Ford, I Guo, XQ Harris, TB Heckbert, SR Hofman, A Hovingh, GK Kastelein, JJP Launer, LJ Liu, CT Liu, YM Lumley, T McKeigue, PM Munroe, PB Neil, A Nickerson, DA Nyberg, F O'Brien, E O'Donnell, CJ Post, W Poulter, N Vasan, RS Rice, K Rich, SS Rivadeneira, F Sattar, N Sever, P Shaw-Hawkins, S Shields, DC Slagboom, PE Smith, NL Smith, JD Sotoodehnia, N Stanton, A Stott, DJ Stricker, BH Sturmer, T Uitterlinden, AG Wei, WQ Westendorp, RGJ Whitsel, EA Wiggins, KL Wilke, RA Ballantyne, CM Colhoun, HM Cupples, LA Franco, OH Gudnason, V Hitman, G Palmer, CNA Psaty, BM Ridker, PM Stafford, JM Stein, CM Tardif, JC Caulfield, MJ Jukema, JW Rotter, JI Krauss, RM AF Postmus, Iris Warren, Helen R. Trompet, Stella Arsenault, Benoit J. Avery, Christy L. Bis, Joshua C. Chasman, Daniel I. de Keyser, Catherine E. Deshmukh, Harshal A. Evans, Daniel S. Feng, QiPing Li, Xiaohui Smit, Roelof A. J. Smith, Albert V. Sun, Fangui Taylor, Kent D. Arnold, Alice M. Barnes, Michael R. Barratt, Bryan J. Betteridge, John Boekholdt, S. Matthijs Boerwinkle, Eric Buckley, Brendan M. Chen, Y-D Ida de Craen, Anton J. M. Cummings, Steven R. Denny, Joshua C. Dube, Marie Pierre Durrington, Paul N. Eiriksdottir, Gudny Ford, Ian Guo, Xiuqing Harris, Tamara B. Heckbert, Susan R. Hofman, Albert Hovingh, G. Kees Kastelein, John J. P. Launer, Leonore J. Liu, Ching-Ti Liu, Yongmei Lumley, Thomas McKeigue, Paul M. Munroe, Patricia B. Neil, Andrew Nickerson, Deborah A. Nyberg, Fredrik O'Brien, Eoin O'Donnell, Christopher J. Post, Wendy Poulter, Neil Vasan, Ramachandran S. Rice, Kenneth Rich, Stephen S. Rivadeneira, Fernando Sattar, Naveed Sever, Peter Shaw-Hawkins, Sue Shields, Denis C. Slagboom, P. Eline Smith, Nicholas L. Smith, Joshua D. Sotoodehnia, Nona Stanton, Alice Stott, David J. Stricker, Bruno H. Sturmer, Til Uitterlinden, Andre G. Wei, Wei-Qi Westendorp, Rudi G. J. Whitsel, Eric A. Wiggins, Kerri L. Wilke, Russell A. Ballantyne, Christie M. Colhoun, Helen M. Cupples, L. Adrienne Franco, Oscar H. Gudnason, Vilmundur Hitman, Graham Palmer, Colin N. A. Psaty, Bruce M. Ridker, Paul M. Stafford, Jeanette M. Stein, Charles M. Tardif, Jean-Claude Caulfield, Mark J. Jukema, J. Wouter Rotter, Jerome I. Krauss, Ronald M. TI Meta-analysis of genome-wide association studies of HDL cholesterol response to statins SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID DENSITY-LIPOPROTEIN CHOLESTEROL; TRANSFER PROTEIN GENE; CORONARY ATHEROSCLEROSIS; CARDIOVASCULAR EVENTS; LOWERING RESPONSE; LDL CHOLESTEROL; ATORVASTATIN; DISEASE; RISK; LIPIDS AB Background In addition to lowering low density lipoprotein cholesterol (LDL-C), statin therapy also raises high density lipoprotein cholesterol (HDL-C) levels. Interindividual variation in HDL-C response to statins may be partially explained by genetic variation. Methods and results We performed a meta-analysis of genome-wide association studies (GWAS) to identify variants with an effect on statin-induced high density lipoprotein cholesterol (HDL-C) changes. The 123 most promising signals with p<1x10(-4) from the 16 769 statin-treated participants in the first analysis stage were followed up in an independent group of 10 951 statin-treated individuals, providing a total sample size of 27 720 individuals. The only associations of genome-wide significance (p<5x10(-8)) were between minor alleles at the CETP locus and greater HDL-C response to statin treatment. Conclusions Based on results from this study that included a relatively large sample size, we suggest that CETP may be the only detectable locus with common genetic variants that influence HDL-C response to statins substantially in individuals of European descent. Although CETP is known to be associated with HDL-C, we provide evidence that this pharmacogenetic effect is independent of its association with baseline HDL-C levels. C1 [Postmus, Iris; Trompet, Stella; de Craen, Anton J. M.] Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, Leiden, Netherlands. [Warren, Helen R.; Barnes, Michael R.; Munroe, Patricia B.; Shaw-Hawkins, Sue; Caulfield, Mark J.] Queen Mary Univ London, Dept Clin Pharmacol, William Harvey Res Inst, Barts & London Sch Med & Dent, London EC1M 6BQ, England. [Warren, Helen R.; Barnes, Michael R.; Munroe, Patricia B.; Shaw-Hawkins, Sue; Caulfield, Mark J.] Queen Mary Univ London, Barts NIHR Cardiovasc Biomed Res Unit, London EC1M 6BQ, England. [Trompet, Stella; Smit, Roelof A. J.; Jukema, J. Wouter] Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands. [Arsenault, Benoit J.; Dube, Marie Pierre; Tardif, Jean-Claude] Univ Montreal, Montreal Heart Inst, Montreal, PQ, Canada. [Avery, Christy L.; Sturmer, Til; Whitsel, Eric A.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Bis, Joshua C.; Lumley, Thomas; Sotoodehnia, Nona; Wiggins, Kerri L.; Psaty, Bruce M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Chasman, Daniel I.; Ridker, Paul M.] Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA. [Chasman, Daniel I.] Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [de Keyser, Catherine E.; Hofman, Albert; Stricker, Bruno H.; Uitterlinden, Andre G.; Franco, Oscar H.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Deshmukh, Harshal A.; Colhoun, Helen M.; Palmer, Colin N. A.] Univ Dundee, Ninewells Hosp & Med Sch, Med Res Inst, Dundee, Scotland. [Evans, Daniel S.; Cummings, Steven R.] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. [Feng, QiPing] Vanderbilt Univ, Dept Clin Pharmacol, 221 Kirkland Hall, Nashville, TN 37235 USA. [Li, Xiaohui; Taylor, Kent D.; Chen, Y-D Ida; Guo, Xiuqing; Rotter, Jerome I.] Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA USA. [Li, Xiaohui; Taylor, Kent D.; Chen, Y-D Ida; Guo, Xiuqing; Rotter, Jerome I.] Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90509 USA. [Li, Xiaohui; Taylor, Kent D.; Chen, Y-D Ida; Guo, Xiuqing; Rotter, Jerome I.] Harbor UCLA Med Ctr, Dept Med, Torrance, CA 90509 USA. [Smith, Albert V.; Eiriksdottir, Gudny; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Smith, Albert V.; Gudnason, Vilmundur] Univ Iceland, Dept Med, Reykjavik, Iceland. [Sun, Fangui; Liu, Ching-Ti; Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Arnold, Alice M.; Rice, Kenneth] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Barratt, Bryan J.] AstraZeneca Res & Dev, Personalised Healthcare & Biomarkers, Alderley Pk, England. [Betteridge, John] Univ Coll London Hosp, London, England. [Boekholdt, S. Matthijs] Acad Med Ctr, Dept Cardiol, Amsterdam, North Holland, Netherlands. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Human Genet Ctr, Houston, TX 77030 USA. [Buckley, Brendan M.] Univ Coll Cork, Dept Pharmacol & Therapeut, Western Rd, Cork, Ireland. [Denny, Joshua C.; Wei, Wei-Qi] Vanderbilt Univ, Dept Biomed Informat, 221 Kirkland Hall, Nashville, TN 37235 USA. [Denny, Joshua C.; Stein, Charles M.] Vanderbilt Univ, Dept Med, Nashville, TN USA. [Durrington, Paul N.] Univ Manchester, Sch Biosci, Cardiovasc Res Grp, Manchester, Lancs, England. [Ford, Ian] Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland. [Harris, Tamara B.; Launer, Leonore J.] NIA, Lab Epidemiol, Demog, Biometry,NIH, Bethesda, MD 20892 USA. [Heckbert, Susan R.; Smith, Nicholas L.; Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Heckbert, Susan R.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Heckbert, Susan R.; Smith, Nicholas L.; Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Hofman, Albert; Uitterlinden, Andre G.] Netherlands Consortium Hlth Ageing, Leiden, Netherlands. [Hovingh, G. Kees; Kastelein, John J. P.] Acad Med Ctr, Dept Vasc Med, Amsterdam, North Holland, Netherlands. [Liu, Yongmei] Wake Forest Sch Med, Div Publ Hlth Sci, Dept Epidemiol & Prevent, Winston Salem, NC USA. [Lumley, Thomas] Univ Auckland, Dept Stat, Auckland, New Zealand. [McKeigue, Paul M.] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [Neil, Andrew] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Churchill Hosp, Oxford, England. [Nickerson, Deborah A.; Smith, Joshua D.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Nyberg, Fredrik] AstraZeneca Gothenburg, Med Evidence & Observat Res, Molndal, Sweden. [Nyberg, Fredrik] Univ Gothenburg, Unit Occupat & Environm Med, Gothenburg, Sweden. [O'Brien, Eoin; Shields, Denis C.] Univ Coll Dublin, Conway Inst, Dublin 4, Ireland. [O'Donnell, Christopher J.; Cupples, L. Adrienne] NHLBI, Framingham Heart Study, Framingham, MA USA. [O'Donnell, Christopher J.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Cardiol Div, Boston, MA USA. [O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Bldg 10, Bethesda, MD 20892 USA. [Post, Wendy] Johns Hopkins Univ, Dept Cardiol, Baltimore, MD USA. [Poulter, Neil; Sever, Peter] Imperial Coll London, Int Ctr Circulatory Hlth, London, England. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Sect Prevent Med & Epidemiol, Framingham, MA USA. [Vasan, Ramachandran S.] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. [Rivadeneira, Fernando; Stricker, Bruno H.; Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Sattar, Naveed] Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland. [Shields, Denis C.] Univ Coll Dublin, Sch Med & Med Sci, Dublin, Ireland. [Slagboom, P. Eline] Leiden Univ, Med Ctr, Dept Mol Epidemiol, Leiden, Netherlands. [Smith, Nicholas L.] Seattle Epidemiol Res & Informat Ctr, Dept Vet Affairs, Off Res & Dev, Seattle, WA USA. [Sotoodehnia, Nona] Univ Washington, Harborview Med Ctr, Div Cardiol, 325 9Th Ave, Seattle, WA 98104 USA. [Stanton, Alice] Royal Coll Surgeons Ireland, Mol & Cellular Therapeut, Dublin, Ireland. [Stanton, Alice] Beaumont Hosp, Dublin, Ireland. [Stott, David J.] Univ Glasgow, Fac Med, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland. [Stricker, Bruno H.] Inspectorate Hlth Care, The Hague, Netherlands. [Westendorp, Rudi G. J.] Univ Copenhagen, Ctr Hlth Ageing, Dept Publ Hlth, Copenhagen, Denmark. [Whitsel, Eric A.] Univ N Carolina, Dept Med, Chapel Hill, NC USA. [Wilke, Russell A.] Sanford Healthcare, Dept Internal Med, Sioux Falls, SD USA. [Wilke, Russell A.] Univ South Dakota, Dept Med, Sioux Falls, SD USA. [Ballantyne, Christie M.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Colhoun, Helen M.] Univ Dundee, Dept Publ Hlth, Dundee, Scotland. [Hitman, Graham] Queen Mary Univ London, Barts & London Sch Med & Dent, London, England. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Stafford, Jeanette M.] Wake Forest Sch Med, Div Publ Hlth Sci, Dept Biostat Sci, Winston Salem, NC USA. [Stein, Charles M.] Vanderbilt Univ, Dept Pharmacol, Nashville, TN USA. [Jukema, J. Wouter] Durrer Ctr Cardiogenet Res, Amsterdam, Netherlands. [Jukema, J. Wouter] Interuniv Cardiol Inst Netherlands, Utrecht, Netherlands. [Krauss, Ronald M.] Childrens Hosp Oakland, Res Inst, Dept Atherosclerosis Res, Oakland, CA 94609 USA. RP Krauss, RM (reprint author), Childrens Hosp Oakland, Res Inst, 5700 Martin Luther King Jr Way, Oakland, CA 94609 USA. EM rkrauss@chori.org RI Palmer, Colin/C-7053-2008; OI Palmer, Colin/0000-0002-6415-6560; Colhoun, Helen/0000-0002-8345-3288; Dube, Marie-Pierre/0000-0001-8442-4393 FU Bristol-Myers Squibb, USA; European Union [HEALTH-F2-2009-223004]; Netherlands Consortium for Healthy Ageing [NGI: 05060810]; Pfizer USA; National Institutes for Health Research (NIHR); NIHR Biomedical Research Centre at Imperial College; International Centre for Circulatory Health Charity; Medical Research Council [G952010]; Pfizer; Diabetes UK [07/0003525]; Department of Health; National Institutes of Health from the National Heart, Lung, and Blood Institute [U19 HL069757]; National Center for Advancing Translational Sciences [UL1TR000124, 2 UL1 TR000445]; NIH [N01-AG-1-2100]; NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); National Heart, Lung and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, R01HL59367, R01HL086694]; National Human Genome Research Institute [U01HG004402, U01-HG04603]; National Institutes of Health [HHSN268200625226C, UL1RR025005, HHSN268200782096C]; NIH Roadmap for Medical Research; National Center for Research Resources [UL1 RR024975]; National Institute of General Medical Sciences [RC2-GM092318]; NHLBI [HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, HL085251, HL073410, HL068986]; National Institute on Aging (NIA) [R01AG023629]; National Center for Advancing Translational Sciences, CTSI [UL1TR000124]; National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) [DK063491]; National Heart Lung and Blood Institute of the National Institutes of Health; Boston University School of Medicine [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 [N01AG62101, N01AG62103, N01AG62106, 1R01AG032098-01A1]; Intramural Research Program of the NIH, National Institute on Aging; National Heart, Lung and Blood Institute (NHLBI); Clinical Translational Science Institute [UL1RR033176]; Erasmus Medical Center; Erasmus University Rotterdam; Netherlands Organization for Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly; Ministry of Education, Culture and Science; Ministry of Health Welfare and Sports; European Commission; Municipality of Rotterdam; Netherlands Genomics Initiative (NGI) Netherlands Organization for Scientific Research (NOW) [050-060-810]; AstraZeneca; Wellcome Trust [084727/Z/08/Z, 085475/Z/08/Z, 085475/B/08/Z]; EU IMI-SUMMIT programme; [N01 HC-95159]; [N01-HC-95160]; [N01-HC-95161]; [N01-HC-95162]; [N01-HC-95163]; [N01-HC-95164]; [N01-HC-95165]; [N01-HC-95166]; [N01-HC-95167]; [N01-HC-95168]; [N01-HC-95169]; [RR-024156] FX PROSPER/PHASE: The Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trial was supported by an investigator initiated grant from Bristol-Myers Squibb, USA. The study was conducted, analysed and reported independently of the company. The GWAS project PHASE has received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement HEALTH-F2-2009-223004. A part of the genotyping was funded by The Netherlands Consortium for Healthy Ageing (NGI: 05060810). Professor Dr J W Jukema is an established clinical investigator of The Netherlands Heart Foundation (2001 D 032). ASCOT: The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) trial was funded by an investigator initiated grant from Pfizer USA. The study was investigator-led and was conducted, analysed and reported independently of the company. The Genome-wide Association Scan was funded by the National Institutes for Health Research (NIHR) as part of the portfolio of translational research of the NIHR Biomedical Research Unit at Barts and the NIHR Biomedical Research Centre at Imperial College, the International Centre for Circulatory Health Charity and the Medical Research Council through G952010. CARDS: The authors thank the other investigators, the staff and the participants of the CARDS study. A full list of CARDS investigators can be found in original CARDS paper. 38 CARDS was funded by grants to the Universities of London and Manchester by Pfizer, Diabetes UK and the Department of Health. PARC: This research was supported by the National Institutes of Health: grant U19 HL069757 from the National Heart, Lung, and Blood Institute; and grant UL1TR000124 from the National Center for Advancing Translational Sciences. TNT: The TNT study was funded by Pfizer, who also provided support for genotyping. AGES: This study has been funded by NIH contract N01-AG-1-2100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association) and the Althingi (the Icelandic Parliament). The study is approved by the Icelandic National Bioethics Committee, VSN: 00-063. The researchers are indebted to the participants for their willingness to participate in the study. ARIC: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. BioVU: BioVU receives support through the National Center for Research Resources UL1 RR024975, which is now the National Center for Advancing Translational Sciences, 2 UL1 TR000445. Genotyping was supported via grant U01-HG04603 from the National Human Genome Research Institute and RC2-GM092318 from the National Institute of General Medical Sciences.; CHS: This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612 and R01HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data were supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Framingham HS: The Framingham Heart Study work was supported by the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine (contract no. N01-HC-25195), its contract with Affymetrix, Inc for genotyping services (contract no. N02-HL-6-4278) and based upon analyses by Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted using 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. Also supported by R01HL103612 (PI Psaty, subcontract PI, Vasan). Health ABC: The Health ABC study was supported by NIA contracts N01AG62101, N01AG62103 and N01AG62106. The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and 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, National Institute on Aging. HVH: This Heart and Vascular Health Study research was supported by NHLBI grants HL085251, HL073410, HL085251 and HL068986. MESA: The Multi-Ethnic Study of Atherosclerosis (MESA) and MESA SNP Health Association Resource (SHARe) are conducted and supported by the National Heart, Lung and Blood Institute (NHLBI) in collaboration with MESA investigators. Support is provided by grants and contracts N01 HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169 and RR-024156. Additional funding was supported in part by the Clinical Translational Science Institute grant UL1RR033176 and is now at the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124. The authors thank the other investigators in the Pharmarcogenetics Working Group, the staff and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org.; Rotterdam Study: The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University Rotterdam; the Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly; the Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sports; the European Commission and Municipality of Rotterdam. This work was supported by the Netherlands Genomics Initiative (NGI) Netherlands Organization for Scientific Research (NOW; 050-060-810). JUPITER: Genetic analysis in JUPITER was supported by a research grant from AstraZeneca to DC and PM. GoDARTS: We are grateful to all the participants who took part in this study, to the general practitioners, to the Scottish School of Primary Care for their help in recruiting the participants, and to the whole team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The Wellcome Trust provides support for Wellcome Trust UK Type 2 Diabetes Case Control Collection (GoDARTS) and informatics support is provided by the Chief Scientist Office. The Wellcome Trust funds the Scottish Health Informatics Programme, provides core support for the Wellcome Trust Centre for Human Genetics in Oxford and funds the Wellcome Trust Case Control Consortium 2. This research was specifically funded by Diabetes UK (07/0003525) and the Wellcome Trust (084727/Z/08/Z, 085475/Z/08/Z, 085475/B/08/Z). Genotyping of the GoDARTS samples (sample 2) was also funded as part of the EU IMI-SUMMIT programme. NR 38 TC 1 Z9 1 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 EI 1468-6244 J9 J MED GENET JI J. Med. Genet. PD DEC PY 2016 VL 53 IS 12 BP 835 EP + DI 10.1136/jmedgenet-2016-103966 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA EH0MC UT WOS:000391457200007 PM 27587472 ER PT J AU Jackson, EA El Khoudary, SR Crawford, SL Matthews, K Joffe, H Chae, C Thurston, RC AF Jackson, Elizabeth A. El Khoudary, Samar R. Crawford, Sybil L. Matthews, Karen Joffe, Hadine Chae, Claudia Thurston, Rebecca C. TI Hot Flash Frequency and Blood Pressure: Data from the Study of Women's Health Across the Nation SO JOURNAL OF WOMENS HEALTH LA English DT Article ID AMERICAN-HEART-ASSOCIATION; CARDIOVASCULAR-DISEASE; MENOPAUSAL TRANSITION; POSTMENOPAUSAL WOMEN; PHYSICAL-ACTIVITY; HORMONE-THERAPY; MIDLIFE WOMEN; POPULATION; SYMPTOMS; FLUSHES AB Background: Vasomotor symptoms (VMS) are highly prevalent among midlife women and have been associated with subclinical cardiovascular disease (CVD). However, the association between VMS frequency and risk factors such as hypertension (HTN) remains unclear. Materials and Methods: We examined VMS frequency and blood pressure (BP) among 2839 participants of the Study of Women's Health Across the Nation (SWAN), a multiethnic, prospective, study of women enrolled from seven U.S. sites between November 1995 and October 1997. Women were age 42-52, with no history of CVD, and not postmenopausal at baseline. VMS was defined by the number of days a woman reported VMS over the 2-week period before each annual visit. Frequent VMS was defined as >= 6 days of VMS; less frequent VMS was defined 1-5 days of symptoms with asymptomatic women the reference group. BP was measured at each visit in addition to demographic and clinic factors. Results: At baseline, 298 women reported frequent VMS, 794 less frequent VMS and 1747 no VMS. More frequent baseline VMS was associated with higher BP. Compared to no VMS, baseline VMS was associated with HTN (odds ratio [OR] 1.47, 95% confidence interval [CI]; 1.14-1.88 for infrequent VMS, and OR 1.40, (95% CI; 0.97-2.02 for frequent VMS). Risk for incident pre-HTN or HTN during follow-up was increased among women with frequent VMS (hazard ratio of 1.39, 95% CI; 1.09-1.79) after adjustment for multiple covariates. Conclusion: Women with VMS may be more likely to develop HTN compared to women without VMS. Further research related to VMS including frequency of symptoms is warranted. C1 [Jackson, Elizabeth A.] Univ Michigan, Cardiovasc Med, Ann Arbor, MI 48109 USA. [El Khoudary, Samar R.; Matthews, Karen; Thurston, Rebecca C.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Crawford, Sybil L.] Univ Massachusetts, Div Prevent & Behav Med, Worcester, MA 01605 USA. [Matthews, Karen; Thurston, Rebecca C.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [Joffe, Hadine] Brigham & Womens Hosp, Dept Psychiat, 75 Francis St, Boston, MA 02115 USA. [Joffe, Hadine] Harvard Med Sch, Dept Psychosocial Oncol & Palliat Care, Dana Farber Canc Inst, Boston, MA USA. [Chae, Claudia] Massachusetts Gen Hosp, Dept Internal Med, Div Cardiol, Boston, MA 02114 USA. RP Jackson, EA (reprint author), Univ Michigan Hlth Syst, Cardiovasc Med, 24 Frank Lloyd Wright Dr,Suite 3700, Ann Arbor, MI 48106 USA. EM lisjacks@umich.edu FU National Institutes of Health (NIH), DHHS, through the National Institute on Aging (NIA); National Institute of Nursing Research (NINR); NIH Office of Research on Women's Health (ORWH) [U01NR004061, U01AG012505, U01AG012535, U01AG012531, U01AG 012539, U01AG012546, U01AG012553, U01AG012554, U01AG012495] FX The SWAN has grant support from the National Institutes of Health (NIH), DHHS, through the National Institute on Aging (NIA), the National Institute of Nursing Research (NINR) and the NIH Office of Research on Women's Health (ORWH) (Grants U01NR004061; U01AG012505, U01AG012535, U01AG012531, U01AG 012539, U01AG012546, U01AG012553, U01AG012554, U01AG012495). The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the NIA, NINR, ORWH, or the NIH. NR 31 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 EI 1931-843X J9 J WOMENS HEALTH JI J. Womens Health PD DEC PY 2016 VL 25 IS 12 BP 1204 EP 1209 DI 10.1089/jwh.2015.5670 PG 6 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA EH1DA UT WOS:000391502600005 PM 27404767 ER PT J AU Aguado, JM Silva, JT Samanta, P Singh, N AF Aguado, Jose M. Tiago Silva, Jose Samanta, Palash Singh, Nina TI Tuberculosis and Transplantation SO MICROBIOLOGY SPECTRUM LA English DT Article ID STEM-CELL TRANSPLANT; MULTIDRUG-RESISTANT TUBERCULOSIS; IMMUNE RECONSTITUTION SYNDROME; SOLID-ORGAN TRANSPLANTATION; BONE-MARROW-TRANSPLANTATION; CORD BLOOD TRANSPLANTATION; GAMMA RELEASING ASSAY; MYCOBACTERIUM-TUBERCULOSIS; RISK-FACTORS; PULMONARY TUBERCULOSIS AB Mycobacterium tuberculosis is a major opportunistic pathogen in transplant recipients. Compared to that in the general population, the frequency of tuberculosis (TB) is 10 to 40 times higher in hematopoietic stem cell transplant (HSCT) recipients and 20 to 74 times higher in solid-organ transplant (SOT) recipients. Transplant recipients with TB are also more likely to develop disseminated disease, have longer time to definitive diagnosis, require more invasive diagnostic procedures, and experience greater anti-TB treatment-related toxicity than the general population. Specific risk factors for TB in SOT recipients include previous exposure to M. tuberculosis (positive tuberculin skin tests and/or residual TB lesions in pretransplant chest X ray) and the intensity of immunosuppression (use of antilymphocyte antibodies, type of basal immunosuppression, and intensification of immunosuppressive therapy for allograft rejection). Risk factors in HSCT recipients are allogeneic transplantation from an unrelated donor; chronic graft-versus-host disease treated with corticosteroids; unrelated or mismatched allograft; pretransplant conditioning using total body irradiation, busulfan, or cyclophosphamide; and type and stage of primary hematological disorder. Transplant recipients with evidence of prior exposure to M. tuberculosis should receive treatment appropriate for latent TB infection. Optimal management of active TB disease is particularly challenging due to significant drug interactions between the anti-TB agents and the immunosuppressive therapy. In this chapter, we address the epidemiology, clinical presentation, diagnostic considerations, and management strategies for TB in SOT and HSCT recipients. C1 [Aguado, Jose M.; Tiago Silva, Jose] Univ Hosp 12 Octubre, Infect Dis Unit, Madrid 28041, Spain. [Samanta, Palash; Singh, Nina] Univ Pittsburgh, Infect Dis Sect, Med Ctr, Pittsburgh, PA 15213 USA. [Singh, Nina] VA Pittsburgh Healthcare Syst, Pittsburgh, PA 15240 USA. [Singh, Nina] Univ Pittsburgh, Pittsburgh, PA 15240 USA. RP Aguado, JM (reprint author), Univ Hosp 12 Octubre, Infect Dis Unit, Madrid 28041, Spain. EM jaguadog1@gmail.com NR 126 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA EI 2165-0497 J9 MICROBIOL SPECTR JI Microbiol. Spectr. PD DEC PY 2016 VL 4 IS 6 AR UNSP TNMI7-0005-2016 DI 10.1128/microbiolspec.TNMI7-0005-2016 PG 14 WC Microbiology SC Microbiology GA EI1AU UT WOS:000392208200033 ER PT J AU Katiyar, SK AF Katiyar, Santosh K. TI Emerging Phytochemicals for the Prevention and Treatment of Head and Neck Cancer SO MOLECULES LA English DT Review DE head and neck cancer; epidermal growth factor receptor; phytochemical; cell migration; tumor growth ID SQUAMOUS-CELL CARCINOMA; NF-KAPPA-B; SEED PROANTHOCYANIDINS INHIBIT; GROWTH-FACTOR RECEPTOR; GREEN TEA POLYPHENOLS; EPITHELIAL-MESENCHYMAL TRANSITION; IN-VIVO INHIBITION; GRAPE SEEDS; DNA-REPAIR; TUMOR-GROWTH AB Despite the development of more advanced medical therapies, cancer management remains a problem. Head and neck squamous cell carcinoma (HNSCC) is a particularly challenging malignancy and requires more effective treatment strategies and a reduction in the debilitating morbidities associated with the therapies. Phytochemicals have long been used in ancient systems of medicine, and non-toxic phytochemicals are being considered as new options for the effective management of cancer. Here, we discuss the growth inhibitory and anti-cell migratory actions of proanthocyanidins from grape seeds (GSPs), polyphenols in green tea and honokiol, derived from the Magnolia species. Studies of these phytochemicals using human HNSCC cell lines from different sub-sites have demonstrated significant protective effects against HNSCC in both in vitro and in vivo models. Treatment of human HNSCC cell lines with GSPs, (-)-epigallocatechin-3-gallate (EGCG), a polyphenolic component of green tea or honokiol reduced cell viability and induced apoptosis. These effects have been associated with inhibitory effects of the phytochemicals on the epidermal growth factor receptor (EGFR), and cell cycle regulatory proteins, as well as other major tumor-associated pathways. Similarly, the cell migration capacity of HNSCC cell lines was inhibited. Thus, GSPs, honokiol and EGCG appear to be promising bioactive phytochemicals for the management of head and neck cancer. C1 [Katiyar, Santosh K.] Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL 35216 USA. [Katiyar, Santosh K.] Univ Alabama Birmingham, Nutr & Obes Res Ctr, Birmingham, AL 35216 USA. [Katiyar, Santosh K.] Birmingham Vet Affairs Med Ctr, Birmingham, AL 35233 USA. RP Katiyar, SK (reprint author), Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL 35216 USA.; Katiyar, SK (reprint author), Univ Alabama Birmingham, Nutr & Obes Res Ctr, Birmingham, AL 35216 USA.; Katiyar, SK (reprint author), Birmingham Vet Affairs Med Ctr, Birmingham, AL 35233 USA. EM skatiyar@uab.edu FU National Cancer Institute/NIH [CA183869]; Veterans Administration [1I01BX001410] FX The work reported from the author's laboratory was supported by the funds from the National Cancer Institute/NIH (CA183869) and Veterans Administration Merit Review Award (1I01BX001410) to S.K.K. The content of this article does not necessarily reflect the views or policies of the funding agencies. Thanks to the staff members in the Author's laboratory for their outstanding contributions in the HNSCC studies. NR 82 TC 0 Z9 0 U1 3 U2 3 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 1420-3049 J9 MOLECULES JI Molecules PD DEC PY 2016 VL 21 IS 12 AR 1610 DI 10.3390/molecules21121610 PG 13 WC Chemistry, Organic SC Chemistry GA EI0CQ UT WOS:000392140100005 ER PT J AU Pal, HC Katiyar, SK AF Pal, Harish C. Katiyar, Santosh K. TI Cryptolepine, a Plant Alkaloid, Inhibits the Growth of Non-Melanoma Skin Cancer Cells through Inhibition of Topoisomerase and Induction of DNA Damage SO MOLECULES LA English DT Article DE cryptolepine; skin cancer; topoisomerase; DNA damage; cell cycle; apoptosis ID DEPENDENT PROTEIN-KINASE; CYTOCHROME-C RELEASE; NF-KAPPA-B; IN-VITRO; MELANOMA-CELLS; CYCLE ARREST; SYNTHETIC CRYPTOLEPINE; INDUCED APOPTOSIS; P53; ACTIVATION AB Topoisomerases have been shown to have roles in cancer progression. Here, we have examined the effect of cryptolepine, a plant alkaloid, on the growth of human non-melanoma skin cancer cells (NMSCC) and underlying mechanism of action. For this purpose SCC-13 and A431 cell lines were used as an in vitro model. Our study reveals that SCC-13 and A431 cells express higher levels as well as activity of topoisomerase (Topo I and Topo II) compared with normal human epidermal keratinocytes. Treatment of NMSCC with cryptolepine (2.5, 5.0 and 7.5 mu M) for 24 h resulted in marked decrease in topoisomerase activity, which was associated with substantial DNA damage as detected by the comet assay. Cryptolepine induced DNA damage resulted in: (i) an increase in the phosphorylation of ATM/ATR, BRCA1, Chk1/Chk2 and gamma H2AX; (ii) activation of p53 signaling cascade, including enhanced protein expressions of p16 and p21; (iii) downregulation of cyclin-dependent kinases, cyclin D1, cyclin A, cyclin E and proteins involved in cell division (e.g., Cdc25a and Cdc25b) leading to cell cycle arrest at S-phase; and (iv) mitochondrial membrane potential was disrupted and cytochrome c released. These changes in NMSCC by cryptolepine resulted in significant reduction in cell viability, colony formation and increase in apoptotic cell death. C1 [Pal, Harish C.; Katiyar, Santosh K.] Univ Alabama Birmingham, Dept Dermatol, Birmingham, AL 35294 USA. [Katiyar, Santosh K.] Univ Alabama Birmingham, Environm Hlth Sci, Birmingham, AL 35294 USA. [Katiyar, Santosh K.] Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL 35294 USA. [Katiyar, Santosh K.] Birmingham Vet Affairs Med Ctr, Birmingham, AL 35294 USA. RP Pal, HC; Katiyar, SK (reprint author), Univ Alabama Birmingham, Dept Dermatol, Birmingham, AL 35294 USA.; Katiyar, SK (reprint author), Univ Alabama Birmingham, Environm Hlth Sci, Birmingham, AL 35294 USA.; Katiyar, SK (reprint author), Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL 35294 USA.; Katiyar, SK (reprint author), Birmingham Vet Affairs Med Ctr, Birmingham, AL 35294 USA. EM hcpal@uab.edu; skatiyar@uab.edu FU Veterans Administration Merit Review Award [1I01BX001410] FX This work was financially supported by the funds from Veterans Administration Merit Review Award (1I01BX001410 to S.K.K.). The content of this publication does not necessarily reflect the views or policies of the funding sources. The funding agency had no roles in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 55 TC 0 Z9 0 U1 2 U2 2 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 1420-3049 J9 MOLECULES JI Molecules PD DEC PY 2016 VL 21 IS 12 AR 1758 DI 10.3390/molecules21121758 PG 18 WC Chemistry, Organic SC Chemistry GA EI0CQ UT WOS:000392140100152 ER PT J AU Thunshelle, C Hamblin, MR AF Thunshelle, Connor Hamblin, Michael R. TI Transcranial Low-Level Laser (Light) Therapy for Brain Injury SO PHOTOMEDICINE AND LASER SURGERY LA English DT Review DE traumatic brain injury; photobiomodulation; stroke; low-level laser therapy; brain disorders ID CYTOCHROME-C-OXIDASE; TERM NEUROLOGICAL DEFICITS; ACUTE ISCHEMIC-STROKE; NEAR-INFRARED LIGHT; NITRIC-OXIDE; CORTICAL-NEURONS; EMBOLIC STROKES; DOSE-RESPONSE; IR RADIATION; IRRADIATION AB Background: Low-level laser therapy (LLLT) or photobiomodulation (PBM) is a possible treatment for brain injury, including traumatic brain injury (TBI). Methods: We review the fundamental mechanisms at the cellular and molecular level and the effects on the brain are discussed. There are several contributing processes that have been proposed to lead to the beneficial effects of PBM in treating TBI such as stimulation of neurogenesis, a decrease in inflammation, and neuroprotection. Both animal and clinical trials for ischemic stroke are outlined. A number of articles have shown how transcranial LLLT (tLLLT) is effective at increasing memory, learning, and the overall neurological performance in rodent models with TBI. Results: Our laboratory has conducted three different studies on the effects of tLLLT on mice with TBI. The first studied pulsed against continuous laser irradiation, finding that 10 Hz pulsed was the best. The second compared four different wavelengths, discovering only 660 and 810 nm to have any effectiveness, whereas 732 and 980 nm did not. The third looked at varying regimens of daily laser treatments (1, 3, and 14 days) and found that 14 laser applications was excessive. We also review several studies of the effects of tLLLT on neuroprogenitor cells, brain-derived neurotrophic factor and synaptogenesis, immediate early response knockout mice, and tLLLT in combination therapy with metabolic inhibitors. Conclusions: Finally, some clinical studies in TBI patients are covered. C1 [Thunshelle, Connor] Harvard Univ, Cambridge, MA USA. [Thunshelle, Connor; Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, BAR414,40 Blossom St, Boston, MA 02114 USA. [Hamblin, Michael R.] Harvard Med Sch, Dept Dermatol, Boston, MA USA. [Hamblin, Michael R.] Harvard Mit Div Hlth Sci & Technol, Cambridge, MA USA. RP Hamblin, MR (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, BAR414,40 Blossom St, Boston, MA 02114 USA. EM hamblin@helix.mgh.harvard.edu FU U.S. NIH [R01AI050875] FX MRH was supported by U.S. NIH grant R01AI050875. NR 72 TC 0 Z9 0 U1 4 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1549-5418 EI 1557-8550 J9 PHOTOMED LASER SURG JI Photomed. Laser Surg. PD DEC PY 2016 VL 34 IS 12 BP 587 EP 598 DI 10.1089/pho.2015.4051 PG 12 WC Surgery SC Surgery GA EH5ZN UT WOS:000391852000002 PM 28001759 ER PT J AU Naeser, MA Martin, PI Ho, MD Krengel, MH Bogdanova, Y Knight, JA Yee, MK Zafonte, R Frazier, J Hamblin, MR Koo, BB AF Naeser, Margaret A. Martin, Paula I. Ho, Michael D. Krengel, Maxine H. Bogdanova, Yelena Knight, Jeffrey A. Yee, Megan K. Zafonte, Ross Frazier, Judith Hamblin, Michael R. Koo, Bang-Bon TI Transcranial, Red/Near-Infrared Light-Emitting Diode Therapy to Improve Cognition in Chronic Traumatic Brain Injury SO PHOTOMEDICINE AND LASER SURGERY LA English DT Article DE traumatic brain injury; TBI; photobiomodulation; PBM; TBI treatment; cognitive dysfunction; light-emitting diodes; LED; postconcussion syndrome; sports head injury; PTSD; LLLT ID POSTTRAUMATIC-STRESS-DISORDER; LEVEL LASER THERAPY; COLLEGIATE FOOTBALL PLAYERS; DEFAULT MODE NETWORK; INTRINSIC CONNECTIVITY NETWORKS; CONTROLLED CORTICAL IMPACT; ALTERED WORKING-MEMORY; DIFFUSE AXONAL INJURY; FUNCTIONAL CONNECTIVITY; HEAD-INJURY AB Objective: We review the general topic of traumatic brain injury (TBI) and our research utilizing transcranial photobiomodulation (tPBM) to improve cognition in chronic TBI using red/near-infrared (NIR) light-emitting diodes (LEDs) to deliver light to the head. tPBM improves mitochondrial function increasing oxygen consumption, production of adenosine triphosphate (ATP), and improving cellular energy stores. Nitric oxide is released from the cells increasing regional blood flow in the brain. Review of published studies: In our previously published study, 11 chronic TBI patients with closed-head TBI caused by different accidents (motor vehicle accident, sports-related, improvised explosive device blast injury) and exhibiting long-lasting cognitive dysfunction received 18 outpatient treatments (Monday, Wednesday, Friday for 6 weeks) starting at 10 months to 8 years post-TBI. LED therapy is nonthermal, painless, and noninvasive. An LED-based device classified as nonsignificant risk (FDA cleared) was used. Each LED cluster head (5.35 cm diameter, 500mW, 22.2 mW/cm(2)) was applied for 9 min 45 sec (13 J/cm(2)) using 11 locations on the scalp: midline from front-to-back hairline and bilaterally on frontal, parietal, and temporal areas. Testing was performed before and after transcranial LED (tLED; at 1 week, 1 month, and at 2 months after the 18th treatment) and showed significant improvements in executive function and verbal memory. There were also fewer post-traumatic stress disorder (PTSD) symptoms reported. Ongoing studies: Ongoing, current studies involve TBI patients who have been treated with tLED using either 26 J/cm(2) per LED location on the head or treated with intranasal only (iLED) using red (633 nm) and NIR (810 nm) diodes placed into the nostrils. The NIR iLED is hypothesized to deliver photons to the hippocampus, and the red 633 nm iLED is believed to increase melatonin. Results have been similar to the previously published tLED study. Actigraphy sleep data showed increased time asleep (on average one additional hour per night) after the 18th tLED or iLED treatment. LED treatments may be performed in the home. Sham-controlled studies with veterans who have cognitive dysfunction from Gulf War Illness, blast TBI, and TBI/PTSD are currently ongoing. C1 [Naeser, Margaret A.; Martin, Paula I.; Ho, Michael D.; Krengel, Maxine H.; Bogdanova, Yelena; Knight, Jeffrey A.; Yee, Megan K.] VA Boston Healthcare Syst 12A, 150 So Huntington Ave, Boston, MA 02130 USA. [Naeser, Margaret A.; Martin, Paula I.; Ho, Michael D.; Krengel, Maxine H.; Yee, Megan K.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Bogdanova, Yelena; Knight, Jeffrey A.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Knight, Jeffrey A.] VA Boston Healthcare Syst, Behav Sci Div, Natl Ctr PTSD, Boston, MA USA. [Zafonte, Ross] Harvard Med Sch, Dept Phys Med & Rehabil, Boston, MA USA. [Zafonte, Ross] Harvard Med Sch, Dept Dermatol, Boston, MA USA. [Zafonte, Ross] Spaulding Rehabil Hosp, Charlestown, MA USA. [Frazier, Judith] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hamblin, Michael R.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Hamblin, Michael R.] Spaulding Rehabil Hosp, TBI Res Program, Charlestown, MA USA. [Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Hamblin, Michael R.] Harvard Mit Div Hlth Sci & Technol, Cambridge, MA USA. [Koo, Bang-Bon] Boston Univ, Ctr Biomed Imaging, Boston, MA 02215 USA. RP Naeser, MA (reprint author), VA Boston Healthcare Syst 12A, 150 So Huntington Ave, Boston, MA 02130 USA. EM mnaeser@bu.edu RI Knight, Julia/A-6843-2012 FU PTSD; Army Medical Department Advanced Medical Technology Initiative FX Additional pilot clinical studies with tLED are being carried out at the VA Boston Healthcare System. Dr. Jeffrey Knight at the National Center for PTSD has received VA funding to carry out a pilot study using real versus sham tLED to see whether PBM can reduce symptoms of PTSD and improve cognitive function in veterans who had suffered TBI. Dr. Yelena Bogdanova is conducting a similar study of real versus sham tLED and iLED to improve sleep and cognition in veterans who have sustained TBI. Dr. Margaret Naeser is conducting a trial with VA funding to test whether real versus sham tLED and iLED can improve cognitive function in veterans suffering from Gulf War Illness. Dr. Carole Palumbo is testing the ability of tLED and iLED applied to active duty soldiers who have suffered blast TBI with funding from the Army Medical Department Advanced Medical Technology Initiative. Dr. Palumbo is an investigator at the U.S. Army Institute of Environmental Medicine. NR 131 TC 0 Z9 0 U1 3 U2 3 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1549-5418 EI 1557-8550 J9 PHOTOMED LASER SURG JI Photomed. Laser Surg. PD DEC PY 2016 VL 34 IS 12 BP 610 EP 626 DI 10.1089/pho.2015.4037 PG 17 WC Surgery SC Surgery GA EH5ZN UT WOS:000391852000004 PM 28001756 ER PT J AU Hoehle, LP Phillips, KM Bergmark, RW Caradonna, DS Gray, ST Sedaghat, AR AF Hoehle, Lloyd P. Phillips, Katie M. Bergmark, Regan W. Caradonna, David S. Gray, Stacey T. Sedaghat, Ahmad R. TI Symptoms of chronic rhinosinusitis differentially impact general health-related quality of life SO RHINOLOGY LA English DT Article DE chronic rhinosinusitis; quality of life; sinonasal symptoms; SNOT-22; EQ5D ID ENDOSCOPIC SINUS SURGERY; SINONASAL OUTCOME TEST; ADULT CHRONIC RHINOSINUSITIS; ALLERGIC RHINITIS; DYSFUNCTION; MANAGEMENT; VALIDITY; SNOT-20; DISEASE; ASTHMA AB Background:The degree to which different sinonasal symptoms contribute to the overall quality of life (QOL) detriment in chronic rhinosinusitis (CRS) patients remains unknown. In this study we sought to characterize the effect of different CRS symptoms on the general health-related QOL in patients. Methodology: We performed a prospective cross-sectional study of 131 adult patients with CRS. Sinonasal symptoms were evaluated using the 22-item Sinonasal Outcomes Test (SNOT-22) and general health-related QOL was evaluated using the EuroQol 5-Dimensional general health-related QOL survey (EQ5D) and visual analog scale (EQ5D-VAS). Health utility values (HUV) were determined using responses to the EQ5D. SNOT-22 scores were broken down into subdomain scores for sleep, nasal, otologic/facial pain and emotional function symptoms. Results: The otologic/facial pain subdomain score consistently had the largest impact on EQ5D-VAS and HUV. After otologic/facial pain, the sleep subdomain score had the second largest effect while the nasal subdomain score had the least impact on general health-related QOL. Conclusions: Different types of CRS symptoms most prominently otologic/facial pain and sleep-related symptoms and their underlying pathophysiologic mechanisms may differentially affect the general health-related QOL detriment associated with CRS. These findings raise the possibility that treatment of the various symptoms associated with CRS may lead to differential improvement in general-health related QOL. C1 [Hoehle, Lloyd P.; Phillips, Katie M.; Bergmark, Regan W.; Gray, Stacey T.; Sedaghat, Ahmad R.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. [Hoehle, Lloyd P.; Phillips, Katie M.; Bergmark, Regan W.; Caradonna, David S.; Gray, Stacey T.; Sedaghat, Ahmad R.] Harvard Med Sch, Dept Otolaryngol, Boston, MA USA. [Caradonna, David S.; Sedaghat, Ahmad R.] Beth Israel Deaconess Med Ctr, Div Otolaryngol, Boston, MA 02215 USA. [Sedaghat, Ahmad R.] Boston Childrens Hosp, Dept Otolaryngol & Commun Enhancement, Boston, MA USA. RP Sedaghat, AR (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. EM ahmad_sedaghat@meei.harvard.edu NR 34 TC 1 Z9 1 U1 1 U2 1 PU INT RHINOLOGIC SOC PI UTRECHT PA UNIV MEDICAL CENTER UTRECHT, RM G05 127, DEPT OTORHINOL, HEIDELBERGLAAN 100, 3584 CX UTRECHT, NETHERLANDS SN 0300-0729 J9 RHINOLOGY JI Rhinology PD DEC PY 2016 VL 54 IS 4 BP 316 EP 322 DI 10.4193/Rhino16.211 PG 7 WC Otorhinolaryngology SC Otorhinolaryngology GA EH8SU UT WOS:000392043400006 PM 27665614 ER PT J AU Vaduganathan, M Patel, NK Lubitz, SA Neilan, TG Dudzinski, DM AF Vaduganathan, Muthiah Patel, Nilay K. Lubitz, Steven A. Neilan, Tomas G. Dudzinski, David M. TI A "Malignant" Arrhythmia: Cardiac Metastasis and Ventricular Tachycardia SO TEXAS HEART INSTITUTE JOURNAL LA English DT Editorial Material C1 [Vaduganathan, Muthiah; Patel, Nilay K.] Massachusetts Gen Hosp, Dept Med, GRB 730,55 Fruit St, Boston, MA 02114 USA. [Lubitz, Steven A.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Neilan, Tomas G.; Dudzinski, David M.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. RP Vaduganathan, M (reprint author), Massachusetts Gen Hosp, Dept Med, GRB 730,55 Fruit St, Boston, MA 02114 USA. EM muthu@md.northwestern.edu FU NHLBI NIH HHS [K23 HL114724] NR 2 TC 0 Z9 0 U1 0 U2 0 PU TEXAS HEART INST PI HOUSTON PA PO BOX 20345, HOUSTON, TX 77225-0345 USA SN 1526-6702 J9 TEX HEART I J JI Tex. Heart Inst. J. PD DEC PY 2016 VL 43 IS 6 BP 558 EP 559 DI 10.14503/THIJ-15-5189 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EH0MY UT WOS:000391459400022 PM 28100983 ER PT J AU Zaugg, TL Thielman, EJ Griest, S Henry, JA AF Zaugg, Tara L. Thielman, Emily J. Griest, Susan Henry, James A. TI Subjective Reports of Trouble Tolerating Sound in Daily Life versus Loudness Discomfort Levels SO AMERICAN JOURNAL OF AUDIOLOGY LA English DT Article ID TINNITUS AB Purpose: A retrospective analysis of tonal and speech loudness discomfort levels (LDLs) relative to a subjective report of sound tolerance (SRST) was performed to explore the relation between the 2 commonly used clinical measures. Method: Tonal LDLs and SRST were measured for 139 U.S. military veterans who were recruited into a study providing intervention for tinnitus. Spearman's rank correlation coefficients were computed to assess the relation between the tonal and speech LDLs and the SRST. Results: Only weak correlations were found between tonal LDLs and SRST and between speech LDLs and SRST. Conclusion: If LDLs ratings of SRST measured the same phenomenon, the measures would be strongly negatively correlated. The weak correlations found between the measures suggest that LDLs do not accurately represent a patient's ability to tolerate sound in daily life. C1 [Zaugg, Tara L.; Thielman, Emily J.; Griest, Susan; Henry, James A.] VA Portland Hlth Care Syst, Natl Ctr Rehabilitat Auditory Res, Rehabil Res & Dev Serv, US Dept Vet Affairs, Portland, OR USA. [Griest, Susan; Henry, James A.] Oregon Hlth & Sci Univ, Dept Otolaryngol Head & Neck Surg, Portland, OR 97201 USA. RP Zaugg, TL (reprint author), VA Portland Hlth Care Syst, Natl Ctr Rehabilitat Auditory Res, Rehabil Res & Dev Serv, US Dept Vet Affairs, Portland, OR USA. EM tara.zaugg@va.gov NR 11 TC 0 Z9 0 U1 0 U2 0 PU AMER SPEECH-LANGUAGE-HEARING ASSOC PI ROCKVILLE PA 2200 RESEARCH BLVD, #271, ROCKVILLE, MD 20850-3289 USA SN 1059-0889 EI 1558-9137 J9 AM J AUDIOL JI Am. J. Audiol. PD DEC PY 2016 VL 25 IS 4 BP 359 EP 363 DI 10.1044/2016_AJA-15-0034 PG 5 WC Audiology & Speech-Language Pathology; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Otorhinolaryngology GA EG9QK UT WOS:000391394100004 PM 27768802 ER PT J AU Hwang, WL Hwang, KL Miyamoto, DT AF Hwang, William L. Hwang, Katie L. Miyamoto, David T. TI The promise of circulating tumor cells for precision cancer therapy SO BIOMARKERS IN MEDICINE LA English DT Review DE cancer; circulating tumor cells (CTCs); precision therapy; predictive marker; prognostic marker ID METASTATIC BREAST-CANCER; RESISTANT PROSTATE-CANCER; EPITHELIAL-MESENCHYMAL TRANSITION; LUNG-CANCER; COLORECTAL-CANCER; PERIPHERAL-BLOOD; PROGNOSTIC VALUE; CLINICAL-SIGNIFICANCE; PANCREATIC-CANCER; RADIATION-THERAPY AB The rapidly growing array of therapeutic options in cancer requires informative biomarkers to guide the rational selection and precision application of appropriate therapies. Circulating biomarkers such as circulating tumor cells have immense potential as noninvasive, serial 'liquid biopsies' that may be more representative of the complete spectrum of a patient's individual malignancy than spatially and temporally restricted tumor biopsies. In this review, we discuss the current state-of-the-art in the isolation and molecular characterization of circulating tumor cells as well as their utility in a wide range of clinical applications such as prognostics, treatment monitoring and identification of novel therapeutic targets and resistance mechanisms to enable real-time adjustments in the clinical management of cancer. C1 [Hwang, William L.; Miyamoto, David T.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Hwang, William L.; Hwang, Katie L.; Miyamoto, David T.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Hwang, Katie L.] Harvard Med Sch, Med Scientist Training Program, Boston, MA 02115 USA. RP Miyamoto, DT (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA.; Miyamoto, DT (reprint author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. EM dmiyamoto@mgh.harvard.edu FU Department of Defense; Prostate Cancer Foundation; NIH [T32G007753] FX This work was supported by the Department of Defense (DT Miyamoto), Prostate Cancer Foundation (DT Miyamoto) and NIH T32G007753 Training Grant (KL Hwang). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 174 TC 0 Z9 0 U1 4 U2 4 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1752-0363 EI 1752-0371 J9 BIOMARK MED JI Biomark. Med. PD DEC PY 2016 VL 10 IS 12 BP 1269 EP 1285 DI 10.2217/bmm-2016-0192 PG 17 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EG8OZ UT WOS:000391317900010 PM 27924634 ER PT J AU Kroenke, K AF Kroenke, Kurt TI Somatic Symptoms Deserve Our Attention SO FAMILIES SYSTEMS & HEALTH LA English DT Editorial Material ID ILLNESS; DISEASE; BURDEN C1 [Kroenke, Kurt] US Dept Vet Affairs, Hlth Serv Res & Dev Ctr Hlth Informat & Commun, Indianapolis, IN USA. [Kroenke, Kurt] Indiana Univ Sch Med, Dept Med, Indianapolis, IN 46202 USA. RP Kroenke, K (reprint author), Regenstrief Inst Inc, Room 221,1101 West 10th St, Indianapolis, IN 46202 USA. EM kkroenke@regenstrief.org NR 10 TC 1 Z9 1 U1 0 U2 0 PU EDUCATIONAL PUBLISHING FOUNDATION-AMERICAN PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST, NE, WASHINGTON, DC 20002-4242 USA SN 1091-7527 EI 1939-0602 J9 FAM SYST HEALTH JI Fam. Syst. Health PD DEC PY 2016 VL 34 IS 4 BP 330 EP 333 DI 10.1037/fsh0000236 PG 4 WC Health Care Sciences & Services; Family Studies; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Family Studies; Public, Environmental & Occupational Health GA EG9IW UT WOS:000391373300004 PM 27977289 ER PT J AU Fuchs, CH Haradhvala, N Evans, DR Nash, JM Weisberg, RB Uebelacker, LA AF Fuchs, Cara H. Haradhvala, Natasha Evans, Daniel R. Nash, Justin M. Weisberg, Risa B. Uebelacker, Lisa A. TI Implementation of an Acceptance- and Mindfulness-Based Group for Depression and Anxiety in Primary Care: Initial Outcomes SO FAMILIES SYSTEMS & HEALTH LA English DT Article DE primary care; integrated health care; group visits; depression; anxiety ID RANDOMIZED CONTROLLED-TRIAL; COGNITIVE-BEHAVIOR THERAPY; COLLABORATIVE CARE; SELF-MANAGEMENT; DISORDERS; ACCEPTABILITY; IMPROVEMENT; IMPAIRMENT; SEVERITY; MODELS AB Introduction: Depression and anxiety disorders are highly prevalent among primary care patients. Group visits provide a way of delivering interventions to multiple patients at the same time. Group visits for depression and anxiety present an opportunity to expand the reach of behavioral health services for primary care patients. The goal of the current study was to evaluate the implementation of an acceptance and mindfulness-based group for primary care patients with depression and anxiety. Methods: Adult family medicine patients with Patient Health Questionnaire-9 (PHQ-9) and/or Generalized Anxiety Disorder Scale-7 (GAD-7) scores >5 were eligible for the group. The group was held biweekly in the family medicine practice with rolling enrollment. The PHQ-9 and GAD-7 were administered at every visit, and changes in depression and anxiety symptoms were analyzed using multilevel modeling. We evaluated feasibility, acceptability/satisfaction, penetration, and sustainability. Results: Over the course of 19 months, 50 patients were referred to the group, and 29 enrolled. The median number of visits attended was four among those who attended more than one group visit. Results revealed that depression and anxiety symptoms decreased significantly over the first four visits attended (d = -.26 and -.19, respectively). Patients who attended more than one group reported high satisfaction. The group was sustainable after the research funding ended; however, penetration was low. Discussion: A rolling enrollment group for patients with depression and anxiety that utilized mindfulness- and acceptance-based treatment principles is feasible to implement in a primary care setting but is not without challenges. Recommendations for ways to enhance implementation and future research are provided. C1 [Fuchs, Cara H.; Evans, Daniel R.; Nash, Justin M.; Weisberg, Risa B.; Uebelacker, Lisa A.] Brown Univ, Warren Alpert Med Sch, Providence, RI 02912 USA. [Fuchs, Cara H.] Brigham & Womens Hosp, Dept Psychiat, 850 Boylston St, Chestnut Hill, MA 02467 USA. [Fuchs, Cara H.] Harvard Med Sch, Boston, MA USA. [Haradhvala, Natasha] Washington Univ, Dept Psychol & Brain Sci, St Louis, MO 63130 USA. [Evans, Daniel R.; Uebelacker, Lisa A.] Butler Hosp, Psychosocial Res Grp, Providence, RI 02906 USA. [Weisberg, Risa B.] VA Boston Healthcare Syst, Boston, MA USA. RP Fuchs, CH (reprint author), Brigham & Womens Hosp, Dept Psychiat, 850 Boylston St, Chestnut Hill, MA 02467 USA. EM chfuchs@partners.org FU Rhode Island Foundation FX This study was funded by a grant from the Rhode Island Foundation. NR 30 TC 0 Z9 0 U1 15 U2 15 PU EDUCATIONAL PUBLISHING FOUNDATION-AMERICAN PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST, NE, WASHINGTON, DC 20002-4242 USA SN 1091-7527 EI 1939-0602 J9 FAM SYST HEALTH JI Fam. Syst. Health PD DEC PY 2016 VL 34 IS 4 BP 386 EP 395 DI 10.1037/fsh0000237 PG 10 WC Health Care Sciences & Services; Family Studies; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Family Studies; Public, Environmental & Occupational Health GA EG9IW UT WOS:000391373300010 PM 27977290 ER PT J AU Chuang, GS Farinelli, W Christiani, DC Herrick, RF Lee, NCY Avram, MM AF Chuang, Gary S. Farinelli, William Christiani, David C. Herrick, Robert F. Lee, Norman C. Y. Avram, Mathew M. TI Gaseous and Particulate Content of Laser Hair Removal Plume SO JAMA DERMATOLOGY LA English DT Article ID ELECTROCAUTERY SMOKE; ULTRAFINE PARTICLES; SURGICAL SMOKE; AIR-POLLUTION; LUNG-CANCER; AMBIENT AIR; MUTAGENICITY; IRRADIATION; EVACUATOR; MORTALITY AB IMPORTANCE Potentially harmful chemicals are released when tissues are vaporized. Laser hair removal (LHR) causes heating and often vaporization of hairs, producing both a signature malodorous plume and visible particulates. OBJECTIVE To characterize the chemical composition and quantify the ultrafine particle content of the plume generated during LHR. DESIGN, SETTING, AND PARTICIPANTS In the laser center of a large academic hospital, discarded terminal hairs from the trunk and extremities were collected from 2 adult volunteers. The hair samples were sealed in glass gas chromatography chambers and treated with a laser. The laser plume was analyzed by gas chromatography-mass spectrometry (GC-MS). During LHR treatment, two 6-L negative pressure canisters were used to capture 30 seconds of laser plume, and a portable condensation particle counter was used to measure ultrafine particulates (<1 mu m). Ultrafine particle concentrations were measured within the treatment room, within the waiting room, and outside the building. MAIN OUTCOMES AND MEASURES The chemical content of the laser plume was analyzed with GC-MS and screened for aerosolized toxins using Environmental Protection Agency-certified methods. The ambient concentration of ultrafine particles during LHR was measured by condensation particle counters. RESULTS Analysis with GC-MS identified 377 chemical compounds. Sixty-two of these compounds, of which 13 are known or suspected carcinogens and more than 20 are known environmental toxins, exhibited strong absorption peaks. During LHR, the portable condensation particle counters documented an 8-fold increase compared with the ambient room baseline level of ultrafine particle concentrations (ambient room baseline, 15 300 particles per cubic centimeter [ppc]; LHR with smoke evacuator, 129 376 ppc), even when a smoke evacuator was in close proximity (5.0 cm) to the procedure site. When the smoke evacuator was turned off for 30 seconds, there was a more than 26-fold increase in particulate count compared with ambient baseline levels (ambient baseline, 15 300 ppc; LHR without smoke evacuator for 30 seconds, 435 888 ppc). CONCLUSIONS AND RELEVANCE These findings establish the concern that the burning-hair plume often present during LHR should be considered a biohazard, warranting the use of smoke evacuators, good ventilation, and respiratory protection, especially for health care workers with prolonged exposure to LHR plume. C1 [Chuang, Gary S.; Farinelli, William; Avram, Mathew M.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Dermatol, Wellman Ctr Photomed, Boston, MA USA. [Chuang, Gary S.] Univ Calif Los Angeles, David Geffen Sch Med, Div Dermatol, 100 Med Plaza,Ste 216, Los Angeles, CA 90095 USA. [Christiani, David C.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Boston, MA USA. [Christiani, David C.; Herrick, Robert F.] Harvard Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA. [Lee, Norman C. Y.] Boston Univ, Dept Chem, Chem Instrumentat Ctr, 590 Commonwealth Ave, Boston, MA 02215 USA. RP Chuang, GS (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Div Dermatol, 100 Med Plaza,Ste 216, Los Angeles, CA 90095 USA. EM gary.s.chuang@gmail.com NR 25 TC 1 Z9 1 U1 2 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6068 EI 2168-6084 J9 JAMA DERMATOL JI JAMA Dermatol. PD DEC PY 2016 VL 152 IS 12 BP 1320 EP 1326 DI 10.1001/jamadermatol.2016.2097 PG 7 WC Dermatology SC Dermatology GA EG8FR UT WOS:000391291900004 PM 27385074 ER PT J AU Shrime, MG AF Shrime, Mark G. TI The Right to Look Human-Head and Neck Surgery in Low- and Middle-Income Countries The Chris O'Brien Memorial Lecture SO JAMA OTOLARYNGOLOGY-HEAD & NECK SURGERY LA English DT Editorial Material ID COST-EFFECTIVENESS; WORLDWIDE; DISEASES C1 [Shrime, Mark G.] Harvard Med Sch, Program Global Surg & Social Change, 641 Huntington Ave,Ste 411, Boston, MA 02115 USA. [Shrime, Mark G.] Massachusetts Eye & Ear Infirm, Off Global Surg & Hlth, Boston, MA 02114 USA. RP Shrime, MG (reprint author), Harvard Med Sch, Program Global Surg & Social Change, 641 Huntington Ave,Ste 411, Boston, MA 02115 USA. EM shrime@mail.harvard.edu NR 10 TC 0 Z9 0 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6181 EI 2168-619X J9 JAMA OTOLARYNGOL JI JAMA Otolaryngol-Head Neck Surg. PD DEC PY 2016 VL 142 IS 12 BP 1143 EP 1144 DI 10.1001/jamaoto.2016.3086 PG 2 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA EH0QC UT WOS:000391467800001 PM 27812700 ER PT J AU Fryd, AS Van Stan, JH Hillman, RE Mehta, DD AF Fryd, Amanda S. Van Stan, Jarrad H. Hillman, Robert E. Mehta, Daryush D. TI Estimating Subglottal Pressure From Neck-Surface Acceleration During Normal Voice Production SO JOURNAL OF SPEECH LANGUAGE AND HEARING RESEARCH LA English DT Article ID AERODYNAMIC PARAMETERS; FUNDAMENTAL-FREQUENCY; VOCAL HYPERFUNCTION; DOSE MEASURES; AIR-FLOW; PHONATION; VIBRATION; ACCELEROMETER; EFFICIENCY; INTENSITY AB Purpose: The purpose of this study was to evaluate the potential for estimating subglottal air pressure using a neck-surface accelerometer and to compare the accuracy of predicting subglottal air pressure relative to predicting acoustic sound pressure level (SPL). Method: Indirect estimates of subglottal pressure (P-sg') were obtained from 10 vocally healthy speakers during loud-to-soft repetitions of 3 different /p/-vowel gestures (/pa/, /pi/, /pu/) at 3 pitch levels in the modal register. Intraoral air pressure, neck-surface acceleration, and radiated acoustic pressure were recorded, and the root-mean-square amplitude of the acceleration signal was correlated with P-sg' and SPL. Results: The coefficient of determination between accelerometer level and P-sg' was high when data were pooled from all vowel and pitch contexts for each participant (r(2) = .68-.93). These relationships were stronger than corresponding relationships between accelerometer level and SPL (r(2) = .46-.81). The average 95% prediction interval for estimating Psg' using accelerometer level was +/- 2.53 cm H2O, ranging from +/- 1.70 to +/- 3.74 cm H2O across participants. Conclusions: Accelerometer signal amplitude correlated more strongly with P-sg' than with SPL. Future work is warranted to investigate the robustness of the relationship in nonmodal voice qualities, individuals with voice disorders, and accelerometer-based ambulatory monitoring of subglottal pressure. C1 [Fryd, Amanda S.; Van Stan, Jarrad H.; Hillman, Robert E.; Mehta, Daryush D.] MGH Inst Hlth Profess, Commun Sci & Disorders, Charlestown, MA 02129 USA. [Fryd, Amanda S.; Van Stan, Jarrad H.; 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, Dept Surg, Boston, MA 02115 USA. [Hillman, Robert E.] Harvard Med Sch, Surg & Hlth Sci & Technol, Boston, MA USA. RP Mehta, DD (reprint author), MGH Inst Hlth Profess, Commun Sci & Disorders, Charlestown, MA 02129 USA.; Mehta, DD (reprint author), Massachusetts Gen Hosp, Ctr Laryngeal Surg & Voice Rehabil, Boston, MA 02114 USA.; Mehta, DD (reprint author), Harvard Med Sch, Dept Surg, Boston, MA 02115 USA. EM daryush.mehta@alum.mit.edu FU Voice Health Institute; National Institute on Deafness and Other Communication Disorders [R33 DC011588] FX This work was supported by Voice Health Institute and National Institute on Deafness and Other Communication Disorders Grant R33 DC011588 (awarded to Robert E. Hillman). Contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. The authors thank J. T. Heaton for scientific discussions and feedback on earlier versions of the manuscript. Portions of this work were presented in the Master's thesis of the first author (Fryd, 2015). NR 54 TC 0 Z9 0 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 DEC PY 2016 VL 59 IS 6 BP 1335 EP 1345 DI 10.1044/2016_JSLHR-S-15-0430 PG 11 WC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation SC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation GA EG9SY UT WOS:000391401000014 PM 27959974 ER PT J AU Misch, EA Safdar, N AF Misch, Elizabeth Ann Safdar, Nasia TI Updated guidelines for the diagnosis and management of aspergillosis SO JOURNAL OF THORACIC DISEASE LA English DT Article ID LIVER-TRANSPLANT RECIPIENTS; INFECTIOUS-DISEASES SOCIETY; INVASIVE FUNGAL-INFECTIONS; GALACTOMANNAN ANTIGEN; SERUM GALACTOMANNAN; ANTIFUNGAL THERAPY; AZOLE RESISTANCE; TRIAL; RISK; COMBINATION C1 [Misch, Elizabeth Ann; Safdar, Nasia] Univ Wisconsin, Dept Med, 5th Floor,1685 Highland Ave, Madison, WI 53705 USA. [Safdar, Nasia] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. RP Misch, EA (reprint author), Univ Wisconsin, Dept Med, 5th Floor,1685 Highland Ave, Madison, WI 53705 USA. EM eamisch@medicine.wisc.edu FU Veteran's Administration-Patient Safety Center of Inquiry FX This work is supported by a Veteran's Administration-funded Patient Safety Center of Inquiry (N Safdar). NR 20 TC 0 Z9 0 U1 2 U2 2 PU PIONEER BIOSCIENCE PUBL CO PI HONG KONG PA 9A GOLD SHINE TOWER, 346-348 QUEEN'S RD CENTRAL, SHEUNG WAN, HONG KONG, 00000, PEOPLES R CHINA SN 2072-1439 EI 2077-6624 J9 J THORAC DIS JI J. Thorac. Dis. PD DEC PY 2016 VL 8 IS 12 BP E1771 EP E1776 DI 10.21037/jtd.2016.12.76 PG 6 WC Respiratory System SC Respiratory System GA EG6SD UT WOS:000391175400055 PM 28149638 ER PT J AU Steensma, DP AF Steensma, David P. TI Good riddance to the term "refractory anemia" in myelodysplastic syndromes SO LEUKEMIA RESEARCH LA English DT Article DE WHO classification; Myelodysplastic syndromes; Cornelius Packard Rhodes; Refractory anemia; Disease classification; Puerto Rico; Racism; Medical ethics ID WORLD-HEALTH-ORGANIZATION; MYELOID NEOPLASMS; CLASSIFICATION; 1930S AB The term "refractory anemia" was used in 1937 by Cornelius Parker Rhoads to describe patients whose anemia did not improve after treatment with liver extract or iron salts, and this term has been used to denote patients with certain subtypes of myelodysplastic syndromes (MDS) since the 1976 and 1982 French-American-British (FAB) classifications of acute leukemias and MDS. In 2016, the World Health Organization (WHO) proposed elimination of "refractory anemia" in a more general proposal for reclassification of myeloid neoplasia. A scandal relating to Dr. Rhoads' possibly unethical medical experiments on anemic patients in Puerto Rico in 1931 and a racially offensive letter he wrote during that period prompted an international incident and Congressional-level inquiry. This dark history, as well as continued terminological problems with refractory anemia, suggest that this hoary term has indeed worn out its usefulness. This article reviews the history of "refractory anemia" and evolution in its use over the past 80 years. Rhoads' personal history, the potentially confusing nature of "refractory anemia", and the fact that it is possible none of the 100 patients Rhoads described in 1937 actually had MDS all support the new WHO reclassification proposal to eliminate this term. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Steensma, David P.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Steensma, David P.] Harvard Med Sch, 450 Brookline Ave,Dana 2037, Boston, MA 02215 USA. RP Steensma, DP (reprint author), Harvard Med Sch, 450 Brookline Ave,Dana 2037, Boston, MA 02215 USA.; Steensma, DP (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave,Dana 2037, Boston, MA 02215 USA. EM David_Steensma@DFCLHARVARD.EDU NR 31 TC 0 Z9 0 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 EI 1873-5835 J9 LEUKEMIA RES JI Leuk. Res. PD DEC PY 2016 VL 51 BP 22 EP 26 DI 10.1016/j.leukres.2016.10.007 PG 5 WC Oncology; Hematology SC Oncology; Hematology GA EG6UG UT WOS:000391181200005 PM 27776290 ER PT J AU Zhou, ES Bober, SL Nekhlyudov, L Hu, JC Kantoff, PW Recklitis, CJ AF Zhou, Eric S. Bober, Sharon L. Nekhlyudov, Larissa Hu, Jim C. Kantoff, Philip W. Recklitis, Christopher J. TI Physical and emotional health information needs and preferences of long-term prostate cancer survivors SO PATIENT EDUCATION AND COUNSELING LA English DT Article DE Prostate cancer; Survivorship; Information needs; Treatment side effects; Sexual function; Emotional health ID QUALITY-OF-LIFE; RANDOMIZED-CONTROLLED-TRIAL; BEHAVIORAL STRESS-MANAGEMENT; SEXUALITY INTERVENTION; PSYCHOSOCIAL CARE; CLINICAL-TRIAL; FOLLOW-UP; MEN; SUPPORT; DELIVERY AB Objective: Many men diagnosed with prostate cancer (PC) will experience physical and psychosocial late effects of treatment. Their interest/preferences for receiving information about addressing common sequelae is not well understood. We examined long-term PC survivors' level of interest, whether this differed based upon symptomatology, and their preferred coping information source. Methods: N = 615 PC survivors (3-8 years post-diagnosis) completed a survey on physical and psychological health and their information interests and preferences related to late effects of cancer treatment. Results: Over half of PC survivors reported interest in information about late effects of treatment or sexual health, while approximately a quarter were interested in emotional health information. Survivors preferred to receive information about late effects of treatment from their oncologists, sexual health information from their primary care providers (PCP), oncologist, or written/online resources, and emotional health information from their PCP. Information needs were more commonly reported among men with poorer domain-specific health functioning. Conclusion: Long-term PC survivors report significant interest in receiving information about their physical, sexual, and emotional health. Practice implications: Medical providers caring for these men should inquire about survivors' information needs and future intervention efforts should consider who delivers the information, dependent upon the type of dysfunction reported. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Zhou, Eric S.; Bober, Sharon L.; Nekhlyudov, Larissa; Recklitis, Christopher J.] Dana Farber Canc Inst, Perini Family Survivors Ctr, 450 Brookline Ave, Boston, MA 02215 USA. [Zhou, Eric S.; Bober, Sharon L.; Nekhlyudov, Larissa; Recklitis, Christopher J.] Harvard Med Sch, Dept Pediat, 25 Shattuck St, Boston, MA 02215 USA. [Hu, Jim C.] Weill Cornell Med Ctr, Dept Urol, 1300 York Ave, New York, NY 10017 USA. [Kantoff, Philip W.] Mem Sloan Kettering Canc Ctr, Dept Med, 600 Third Ave, New York, NY 10017 USA. RP Zhou, ES (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM eric_zhou@dfci.harvard.edu; sharon_bober@dfci.harvard.edu; larissa_nekhlyudov@dfci.harvard.edu; jch9011@med.cornell.edu; kantoff@mskcc.org; christopher_recklitis@dfci.harvard.edu FU American Foundation for Suicide Prevention [PRG-1-10-156] FX This research was generously funded by a research grant from the American Foundation for Suicide Prevention (PRG-1-10-156) awarded to Christopher J. Recklitis, PhD, MPH. NR 51 TC 0 Z9 0 U1 5 U2 5 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 DEC PY 2016 VL 99 IS 12 BP 2049 EP 2054 DI 10.1016/j.pec.2016.07.017 PG 6 WC Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary SC Public, Environmental & Occupational Health; Social Sciences - Other Topics GA EG7JM UT WOS:000391223200018 PM 27439668 ER PT J AU Ando, M Sunaguchi, N Shimao, D Pan, A Yuasa, T Mori, K Suzuki, Y Jin, G Kim, JK Lim, JH Seo, SJ Ichihara, S Ohura, N Gupta, R AF Ando, Masami Sunaguchi, Naoki Shimao, Daisuke Pan, Adam Yuasa, Tetsuya Mori, Kensaku Suzuki, Yoshifumi Jin, Ge Kim, Jong-Ki Lim, Jae-Hong Seo, Seung-Jun Ichihara, Shu Ohura, Norihiko Gupta, Rajiv TI Dark-Field Imaging: Recent developments and potential clinical applications SO PHYSICA MEDICA-EUROPEAN JOURNAL OF MEDICAL PHYSICS LA English DT Article DE X-ray dynamical diffraction; Monochromator; Laue angle analyzer; Refraction contrast; Phase contrast; Medical imaging; Human soft tissue; Breast cancer; Articular cartilage; Artery damage; Synchrotron radiation; High contrast; High spatial resolution ID CONTRAST COMPUTED-TOMOGRAPHY; X-RAY INTERFEROMETER; PENDELLOSUNG FRINGES; DYNAMICAL THEORY; DIFFRACTION; RECONSTRUCTION; TOMOSYNTHESIS; PRINCIPLES; BREAST; MRI AB This paper describes an X-ray phase contrast imaging technique using analyzer-based optics called X-ray Dark-Field Imaging that has been under development for the past 10 years. We describe the theory behind XDFI, the X-ray optics required for implementing it in practice, and algorithms used for 2D, 2.5D, and 3D image reconstruction. The XDFI optical chain consists of an asymmetrically cut, Bragg-type monochromator-collimator that provides a planar monochromatic X-ray beam, a positioning stage for the specimens, a Laue-case angle analyzer, and one or two cameras to capture the dark and bright field images. We demonstrate the soft-tissue discrimination capabilities of XDFI by reconstructing images with absorption and phase contrast. By using a variety of specimens such as breast tissue with cancer, joints with articular cartilage, ex-vivo human eye specimen, and others, we show that refraction-based contrast derived from XDFI is more effective in characterizing anatomical features, articular pathology, and neoplastic disease than conventional absorption-based images. For example, XDFI of breast tissue can discriminate between the normal and diseased terminal duct lobular unit, and between invasive and in-situ cancer. The final section of this paper is devoted to potential future developments to enable clinical and histo-pathological applications of this technique. (C) 2016 Published by Elsevier Ltd on behalf of Associazione Italiana di Fisica Medica. C1 [Ando, Masami] Tokyo Univ Sci, Res Inst Sci & Engn, Noda, Chiba 2788510, Japan. [Sunaguchi, Naoki] Gunma Univ, Grad Sch Engn, Kiryu, Gunma 3768515, Japan. [Shimao, Daisuke] Hokkaido Univ Sci, Dept Radiol Technol, Sapporo, Hokkaido 0068585, Japan. [Pan, Adam] MIT, Dept Hlth Sci & Technol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Yuasa, Tetsuya] Yamagata Univ, Grduate Sch Engn & Sci, Yonezawa, Yamagata 9928510, Japan. [Mori, Kensaku] Nagoya Univ, Grad Sch Informat Sci, Dept Media Sci, Nagoya, Aichi 4648601, Japan. [Suzuki, Yoshifumi; Jin, Ge] Kyushu Inst Technol, Grad Sch Engn, Kitakyushu, Fukuoka 8048550, Japan. [Kim, Jong-Ki; Seo, Seung-Jun] Catholic Univ Daegu, Sch Med, Biomed Engn & Radiol, Daegu 705034, South Korea. [Lim, Jae-Hong] Pohang Accelerator Lab, Ind Technol Convergence Ctr, Pohang 790834, Gyeongbuk, South Korea. [Ichihara, Shu] Nagoya Med Ctr, Dept Pathol, Clin Res Ctr, Nagoya, Aichi 4600001, Japan. [Ohura, Norihiko] Kyorin Univ Hosp, Dept Plast Surg, Shinkawa 6-20-2, Mitaka, Tokyo 1810013, Japan. [Gupta, Rajiv] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Gupta, Rajiv] Harvard Med Sch, Boston, MA 02114 USA. RP Ando, M (reprint author), Tokyo Univ Sci, Res Inst Sci & Engn, Noda, Chiba 2788510, Japan. EM msm-ando@rs.noda.tus.ac.jp FU Monbusho for Scientific Research [26286079, 15H01129] FX The authors would like to thank Professor Koichi Mori at IPU for unlimited access to his bone sample, Masaki Sakai and Yuki Nakao for their assistance in data acquisition of femoral artery and frog, respectively as well as Kazuki Matsui, Megumi Yokoyama and Mayumi Kataoka for their assistance in preparation of medical specimens for pathology. Grant-in-Aid from Monbusho for Scientific Research with entitled number of 26286079 and for Specially Promoted Research with entitled number of 15H01129 is highly appreciated. Machine time has been allotted by the Program Advisory Board at Photon Factory with 2015G597, 2013G731, 2012G562, 2012G558, 2012G106 to whom the authors would like to acknowledge. Another machine time has been allotted by the Program Advisory Board at Pohang Light Source with 2014-3rd-6C-006, 2014-1st-6C-010 to whom the authors also would like to acknowledge. NR 44 TC 0 Z9 0 U1 5 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1120-1797 EI 1724-191X J9 PHYS MEDICA JI Phys. Medica PD DEC PY 2016 VL 32 IS 12 BP 1801 EP 1812 DI 10.1016/j.ejmp.2016.11.103 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EF8RR UT WOS:000390597500045 PM 28024847 ER PT J AU Lee, SW Fallegger, F Casse, BDF Fried, SI AF Lee, Seung Woo Fallegger, Florian Casse, Bernard D. F. Fried, Shelley I. TI Implantable microcoils for intracortical magnetic stimulation SO SCIENCE ADVANCES LA English DT Article ID DEEP BRAIN-STIMULATION; CENTRAL-NERVOUS-SYSTEM; ELECTRICAL MICROSTIMULATION; SUBTHALAMIC NUCLEUS; INDIRECT ACTIVATION; NEURAL STIMULATION; CORTICAL-NEURONS; VISUAL-CORTEX; MOTOR CORTEX; CELLS AB Neural prostheses that stimulate the neocortex have the potential to treat a wide range of neurological disorders. However, the efficacy of electrode-based implants remains limited, with persistent challenges that include an inability to create precise patterns of neural activity as well as difficulties in maintaining response consistency over time. These problems arise from fundamental limitations of electrodes as well as their susceptibility to implantation and have proven difficult to overcome. Magnetic stimulation can address many of these limitations, but coils small enough to be implanted into the cortex were not thought strong enough to activate neurons. We describe a new microcoil design and demonstrate its effectiveness for both activating cortical neurons and driving behavioral responses. The stimulation of cortical pyramidal neurons in brain slices in vitro was reliable and could be confined to spatially narrow regions (<60 mu m). The spatially asymmetric fields arising from the coil helped to avoid the simultaneous activation of passing axons. In vivo implantation was safe and resulted in consistent and predictable behavioral responses. The high permeability of magnetic fields to biological substances may yield another important advantage because it suggests that encapsulation and other adverse effects of implantation will not diminish coil performance over time, as happens to electrodes. These findings suggest that a coil-based implant might be a useful alternative to existing electrode-based devices. The enhanced selectivity of microcoil-based magnetic stimulation will be especially useful for visual prostheses as well as for many brain-computer interface applications that require precise activation of the cortex. C1 [Lee, Seung Woo; Fried, Shelley I.] Boston Vet Affairs Healthcare Syst, Boston, MA 02130 USA. [Lee, Seung Woo; Fried, Shelley I.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Fallegger, Florian; Casse, Bernard D. F.] Xerox Co, Palo Alto Res Ctr, Palo Alto, CA 94304 USA. RP Fried, SI (reprint author), Boston Vet Affairs Healthcare Syst, Boston, MA 02130 USA.; Fried, SI (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. EM Fried.Shelley@mgh.harvard.edu FU Veterans Administration-Rehabilitation Research and Development Service [1I01RX001663]; National Eye Institute [R01-EY023651]; National Institute for Neurological Disease and Stroke [U01-NS099700]; Rappaport Foundation FX This work was supported by the Veterans Administration-Rehabilitation Research and Development Service (1I01RX001663), the National Eye Institute (R01-EY023651), the National Institute for Neurological Disease and Stroke (U01-NS099700), and the Rappaport Foundation. NR 58 TC 1 Z9 1 U1 1 U2 1 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 2375-2548 J9 SCI ADV JI Sci. Adv. PD DEC PY 2016 VL 2 IS 12 AR e1600889 DI 10.1126/sciadv.1600889 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EG7XC UT WOS:000391268800008 PM 27957537 ER PT J AU Wijesinghe, RE Cho, NH Park, K Jeon, M Kim, J AF Wijesinghe, Ruchire Eranga Cho, Nam Hyun Park, Kibeom Jeon, Mansik Kim, Jeehyun TI Bio-Photonic Detection and Quantitative Evaluation Method for the Progression of Dental Caries Using Optical Frequency-Domain Imaging Method SO SENSORS LA English DT Article DE optical frequency domain imaging (OFDI); optical coherence tomography; dental caries; demineralization; Bio-photonic detection ID COHERENCE TOMOGRAPHY; ENAMEL DEMINERALIZATION; ARTIFICIAL CARIES; LESIONS; MICRORADIOGRAPHY; MICROHARDNESS; RESTORATIONS; DISEASE; RANGE AB The initial detection of dental caries is an essential biomedical requirement to barricade the progression of caries and tooth demineralization. The objective of this study is to introduce an optical frequency-domain imaging technique based quantitative evaluation method to calculate the volume and thickness of enamel residual, and a quantification method was developed to evaluate the total intensity fluctuation in depth direction owing to carious lesions, which can be favorable to identify the progression of dental caries in advance. The cross-sectional images of the ex vivo tooth samples were acquired using 1.3 mu m spectral domain optical coherence tomography system (SD-OCT). Moreover, the advantages of the proposed method over the conventional dental inspection methods were compared to highlight the potential capability of OCT. As a consequence, the threshold parameters obtained through the developed method can be used as an efficient investigating technique for the initial detection of demineralization. C1 [Wijesinghe, Ruchire Eranga; Park, Kibeom; Jeon, Mansik; Kim, Jeehyun] Kyungpook Natl Univ, Coll IT Engn, Sch Elect Engn, 80 Daehak Ro, Daegu 41566, South Korea. [Cho, Nam Hyun] Massachusetts Eye & Ear Infirm, Eaton Peabody Labs, 243 Charles St, Boston, MA 02114 USA. [Cho, Nam Hyun] Harvard Med Sch, Dept Otol & Laryngol, 243 Charles St, Boston, MA 02114 USA. RP Jeon, M (reprint author), Kyungpook Natl Univ, Coll IT Engn, Sch Elect Engn, 80 Daehak Ro, Daegu 41566, South Korea. EM eranga@knu.ac.kr; namhyun_cho@meei.harvard.edu; pepl10@knu.ac.kr; msjeon@knu.ac.kr; jeehk@knu.ac.kr FU Industrial Strategic Technology Development Program [10047943]; "Development of Micro-Surgical Apparatus Based on 3D Tomographic Operating Microscope" program; Ministry of Trade, Industry and Energy (MI, Korea) [10047943]; BK21 Plus project - Ministry of Education, Korea [21A20131600011] FX This research was supported by the Industrial Strategic Technology Development Program, Grant No. 10047943; the "Development of Micro-Surgical Apparatus Based on 3D Tomographic Operating Microscope" program, funded by the Ministry of Trade, Industry and Energy (MI, Korea, No. 10047943). This study was also supported by the BK21 Plus project funded by the Ministry of Education, Korea (21A20131600011). NR 36 TC 0 Z9 0 U1 1 U2 1 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 1424-8220 J9 SENSORS-BASEL JI Sensors PD DEC PY 2016 VL 16 IS 12 AR 2076 DI 10.3390/s16122076 PG 12 WC Chemistry, Analytical; Electrochemistry; Instruments & Instrumentation SC Chemistry; Electrochemistry; Instruments & Instrumentation GA EG8JM UT WOS:000391303000096 ER PT J AU Gaissert, H AF Gaissert, Henning TI Diaphragm Season SO THORACIC AND CARDIOVASCULAR SURGEON LA English DT Editorial Material C1 [Gaissert, Henning] Massachusetts Gen Hosp, Dept Thorac Surg, Blake 1570,55 Fruit St, Boston, MA 02114 USA. RP Gaissert, H (reprint author), Massachusetts Gen Hosp, Dept Thorac Surg, Blake 1570,55 Fruit St, Boston, MA 02114 USA. EM HGAISSERT@PARTNERS.ORG NR 1 TC 0 Z9 0 U1 0 U2 0 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0171-6425 EI 1439-1902 J9 THORAC CARDIOV SURG JI Thorac. Cardiovasc. Surg. PD DEC PY 2016 VL 64 IS 8 BP 620 EP 620 DI 10.1055/s-0036-1595813 PG 1 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA EG8AT UT WOS:000391278700002 PM 27960202 ER PT J AU Gaissert, H Wilcox, SR AF Gaissert, Henning Wilcox, Susan R. TI Diaphragmatic Dysfunction after Thoracic Operations SO THORACIC AND CARDIOVASCULAR SURGEON LA English DT Review DE diaphragm; myasthenia; respiratory failure; thymoma; neuromuscular disease ID CONTROLLED MECHANICAL VENTILATION; RESPIRATORY MUSCLE STRENGTH; EATON MYASTHENIC SYNDROME; INTENSIVE-CARE-UNIT; PHRENIC-NERVE; PERIOPERATIVE MANAGEMENT; TRANSSTERNAL THYMECTOMY; NEUROMUSCULAR BLOCKADE; LUNG-FUNCTION; GRAVIS AB The perioperative management of diaphragmatic weakness and phrenic nerve dysfunction is complex, due to varied etiologies and clinical presentations. The factors leading to diaphragmatic weakness may culminate after the operation with transient or persistent respiratory failure. This review discusses diaphragmatic disorders and postoperative respiratory failure caused by unilateral or bilateral diaphragmatic impairment. The origins of neuromuscular weakness involving the diaphragm are diverse, and often lie within the domains of different medical specialties, with only a portion of the condition related to surgical intervention. Consideration of underlying etiologies for any individual patient requires thorough multidisciplinary review. The most important clinical scenarios compounding diaphragmatic weakness, including acute myasthenic states, persistent neuromuscular blockade, and surgical injury to the phrenic nerve or diaphragm, are accessible to attentive surgeons. Awareness of the signs and symptoms of undiagnosed weakness, preoperative pursuit of its diagnosis, knowledge of surgical alternatives to phrenic nerve resection, and cooperative skills in the multidisciplinary management of myasthenia all are crucial to improve patient outcomes. C1 [Gaissert, Henning] Massachusetts Gen Hosp, Dept Surg, Blake 1570 55 Fruit St, Boston, MA 02114 USA. [Wilcox, Susan R.] Med Univ South Carolina, Div Pulm Crit Care Allergy & Sleep Med, Div Emergency Med, Charleston, SC 29425 USA. RP Gaissert, H (reprint author), Massachusetts Gen Hosp, Dept Surg, Blake 1570 55 Fruit St, Boston, MA 02114 USA. EM hgaissert@partners.org NR 68 TC 0 Z9 0 U1 0 U2 0 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0171-6425 EI 1439-1902 J9 THORAC CARDIOV SURG JI Thorac. Cardiovasc. Surg. PD DEC PY 2016 VL 64 IS 8 BP 621 EP 630 DI 10.1055/s-0036-1595816 PG 10 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA EG8AT UT WOS:000391278700003 PM 27888814 ER PT J AU Daginawala, N Qin, H Lerner, L Jati, A AF Daginawala, Naznin Qin, Huang Lerner, Lori Jati, Anupma TI Ectopic dysplastic kidney SO APPLIED RADIOLOGY LA English DT Article ID PELVIC KIDNEY C1 [Daginawala, Naznin] Boston Univ, Med Ctr, Dept Radiol, Boston, MA 02118 USA. [Qin, Huang] VA Boston Healthcare Syst, Dept Pathol, Boston, MA USA. [Lerner, Lori] VA Boston Healthcare Syst, Dept Urol, Boston, MA USA. [Jati, Anupma] VA Boston Healthcare Syst, Dept Radiol, Boston, MA USA. RP Daginawala, N (reprint author), Boston Univ, Med Ctr, Dept Radiol, Boston, MA 02118 USA. NR 7 TC 0 Z9 0 U1 0 U2 0 PU ANDERSON PUBLISHING, INC PI SCOTCH PLAINS PA 180 GLENSIDE AVE, SCOTCH PLAINS, NJ 07076 USA SN 0160-9963 EI 1879-2898 J9 APPL RADIOL JI Appl. Radiol. PD DEC PY 2016 VL 45 IS 12 BP 28 EP 30 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EG2TV UT WOS:000390897900005 ER PT J AU O'Donnell, PV Eapen, M Horowitz, MM Logan, BR DiGilio, A Brunstein, C Fuchs, EJ Flowers, MED Salit, R Raj, K Pagliuca, A Bradstock, K Granata, A Castagna, L Furst, S Blaise, D AF O'Donnell, P. V. Eapen, M. Horowitz, M. M. Logan, B. R. DiGilio, A. Brunstein, C. Fuchs, E. J. Flowers, M. E. D. Salit, R. Raj, K. Pagliuca, A. Bradstock, K. Granata, A. Castagna, L. Furst, S. Blaise, D. TI Comparable outcomes with marrow or peripheral blood as stem cell sources for hematopoietic cell transplantation from haploidentical donors after non-ablative conditioning: a matched-pair analysis SO BONE MARROW TRANSPLANTATION LA English DT Letter ID VERSUS-HOST-DISEASE; POSTTRANSPLANTATION CYCLOPHOSPHAMIDE; BONE-MARROW; HEMATOLOGIC MALIGNANCIES; UNRELATED DONORS; TRIALS C1 [O'Donnell, P. V.; Flowers, M. E. D.; Salit, R.] Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA. [O'Donnell, P. V.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Eapen, M.; Horowitz, M. M.; Logan, B. R.; DiGilio, A.] Med Coll Wisconsin, Div Hematol & Oncol, Milwaukee, WI 53226 USA. [Brunstein, C.] Univ Minnesota, Blood & Marrow Transplant Program, Minneapolis, MN USA. [Fuchs, E. J.] Johns Hopkins Univ, Sydney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Raj, K.] Guys & St Thomas Hosp NHS Hosp Fdn Trusts, London, England. [Raj, K.; Pagliuca, A.] Kings Coll Hosp London, Dept Haematol Med, London, England. [Bradstock, K.] Westmead Hosp, Dept Hematol, Westmead, NSW, Australia. [Granata, A.; Furst, S.; Blaise, D.] Aix Marseille Univ, Inst Paoli Calmettes, Ctr Res Cancerol CRCM, Dept Hematol,UM105,Inserm U1068,CNRS UMR7258, Marseille, France. [Castagna, L.] Ist Clin Humanitas, Humanitas Canc Ctr, Dept Hematol, Rozzano, Italy. RP O'Donnell, PV (reprint author), Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA.; O'Donnell, PV (reprint author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. EM pvodonnell@mgh.harvard.edu OI Castagna, Luca/0000-0002-6239-7387 FU NCI NIH HHS [P01 CA018029, U24 CA076518]; NHLBI NIH HHS [U01 HL069294] NR 15 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 EI 1476-5365 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD DEC PY 2016 VL 51 IS 12 BP 1599 EP 1601 DI 10.1038/bmt.2016.215 PG 3 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA EG0YY UT WOS:000390759600011 PM 27526284 ER PT J AU Basman, C Agrawal, PR McRee, C Saravolatz, L Chen-Scarabelli, C Scarabelli, TM AF Basman, Craig Agrawal, Pratik R. McRee, Chad Saravolatz, Louis Chen-Scarabelli, Carol Scarabelli, Tiziano M. TI Diagnostic Approach to Myocarditis Mimicking Myocardial Infarction at Initial Presentation SO CARDIOLOGY RESEARCH LA English DT Article DE Myocarditis; Cardiac MRI; Endomyocardial biopsy ID VIRAL MYOCARDITIS; DILATED CARDIOMYOPATHY; BIOPSY AB We present a case of a 35-year-old male patient with a 12-hour history of sudden-onset, crushing chest pain and associated complaints of profuse diaphoresis, nausea and vomiting. The patient was transferred to our institution from an outside hospital for evaluation and possible emergent catheterization. Left heart catheterization was conclusive for normal coronary arteries and a ventriculogram revealed a left ventricular ejection fraction of approximately 45%. Due to a suspicion of myocarditis based on clinical history, pertinent serology tests were ordered, which were found to be negative. Cardiac magnetic resonance on delayed enhancement imaging showed typical sub-epicardial enhancement in a pattern most consistent with myocarditis. The patient was eventually diagnosed with myocarditis and discharged home later, without needing a myocardial biopsy. We present and discuss here the indications of myocardial biopsy and compare the relative utility of cardiac magnetic resonance imaging in formulating the diagnosis of myocarditis. C1 [Basman, Craig; Agrawal, Pratik R.; Saravolatz, Louis; Scarabelli, Tiziano M.] Wayne State Univ, Sch Med, St John Hosp & Med Ctr, Detroit, MI USA. [McRee, Chad; Scarabelli, Tiziano M.] Univ Alabama Birmingham, Med Ctr, Birmingham, AL 35294 USA. [Chen-Scarabelli, Carol; Scarabelli, Tiziano M.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. RP Scarabelli, TM (reprint author), Wayne State Univ, Sch Med, Ctr Heart & Vessel Preclin Studies, Detroit, MI 48202 USA. EM tscarabelli@hotmail.com NR 15 TC 0 Z9 0 U1 1 U2 1 PU ELMER PRESS INC PI QUEBEC PA 9160 BOUL LEDUC, BUREAU 410, BROSSARD, QUEBEC, J4Y 0E3, CANADA SN 1923-2829 EI 1923-2837 J9 CARDIOL RES JI Cardiol. Res. PD DEC PY 2016 VL 7 IS 6 BP 209 EP 213 DI 10.14740/cr485w PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EG3JA UT WOS:000390938700004 PM 28197294 ER PT J AU Batur, P Schwarz, EB Walsh, JME Johnson, KM AF Batur, Pelin Schwarz, Eleanor Bimla Walsh, Judith M. E. Johnson, Kay M. TI Women's health 2016: An update for internists SO CLEVELAND CLINIC JOURNAL OF MEDICINE LA English DT Review ID URINARY-TRACT-INFECTION; RANDOMIZED-CONTROLLED-TRIAL; ORAL-CONTRACEPTIVE USE; REPRODUCTIVE FACTORS; PROSPECTIVE COHORT; CANCER; MORTALITY; FRACTURE; RISK; OSTEOPOROSIS AB Internists are called upon on a daily basis to address a range of women's health issues. Staying up to date with the evidence in this wide field can be challenging. This article reviews important studies published in 2015 and early 2016 pertinent to urinary tract infection, osteoporosis, ovarian cancer screening, and contraception. C1 [Batur, Pelin] Cleveland Clin, Primary Care Womens Hlth, Cleveland, OH USA. [Batur, Pelin] Case Western Reserve Univ, Cleveland Clin Lerner, Coll Med, Cleveland, OH USA. [Batur, Pelin] Cleveland Clin, Journal Med, Cleveland, OH USA. [Schwarz, Eleanor Bimla] Univ Calif Davis, Med, Davis, CA 95616 USA. [Walsh, Judith M. E.] Univ Calif San Francisco, Ctr Excellence Womens Hlth, Div Gen Internal Med, San Francisco, CA 94143 USA. [Johnson, Kay M.] Univ Washington, Sch Med, VA Puget Sound Hlth Care Syst, Div Gen Internal Med,Med, Seattle, WA 98195 USA. RP Batur, P (reprint author), Independence Family Hlth Ctr, 5001 Rockside Rd,Crown Ctr II, Independence, CA 44131 USA. EM baturp@ccf.org NR 48 TC 0 Z9 1 U1 2 U2 2 PU CLEVELAND CLINIC PI CLEVELAND PA 9500 EUCLID AVE, CLEVELAND, OH 44106 USA SN 0891-1150 EI 1939-2869 J9 CLEV CLIN J MED JI Clevel. Clin. J. Med. PD DEC PY 2016 VL 83 IS 12 BP 905 EP 913 DI 10.3949/ccjm.83a.16098 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA EG3ER UT WOS:000390927100008 PM 27938517 ER PT J AU Donnellan, E Phelan, D McCarthy, CP Collier, P Desai, M Griffin, B AF Donnellan, Eoin Phelan, Dermot McCarthy, Clan P. Collier, Patrick Desai, Milind Griffin, Brian TI Radiation-induced heart disease: A practical guide to diagnosis and management SO CLEVELAND CLINIC JOURNAL OF MEDICINE LA English DT Review ID CORONARY-ARTERY-DISEASE; INSPIRATION BREATH-HOLD; HODGKIN LYMPHOMA; MEDIASTINAL IRRADIATION; CARDIAC-DISEASE; CONSTRICTIVE PERICARDITIS; CARDIOVASCULAR-DISEASE; AMERICAN-SOCIETY; CHILDHOOD-CANCER; MITRAL CURTAIN AB Radiation-induced heart disease (RIHD) is a recognized late sequela of chest radiotherapy for conditions such as breast cancer and lymphoma and can involve any cardiac structure. Consensus guidelines from the European Association of Cardiovascular Imaging and the American Society of Echocardiography stress the importance of regular screening for the cardiac effects of radiotherapy. However, a gulf remains between these guidelines and clinical practice. C1 [Donnellan, Eoin] Cleveland Clin, Dept Internal Med, Cleveland, OH 44106 USA. [Donnellan, Eoin; Collier, Patrick; Desai, Milind] Case Western Reserve Univ, Cleveland Clin, Lerner Coll Med, Cleveland, OH 44106 USA. [Phelan, Dermot] Cleveland Clin, Inst Heart & Vasc, Dept Cardiovasc Med, Sports Cardiol, Cleveland, OH 44195 USA. [McCarthy, Clan P.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Phelan, Dermot; Collier, Patrick; Desai, Milind] Cleveland Clin, Inst Heart & Vasc, Dept Cardiovasc Med, J1-5,9500 Euclid Ave, Cleveland, OH 44195 USA. [Griffin, Brian] Cleveland Clin, Inst Heart & Vasc, Dept Cardiovasc Med, Sect Cardiovasc Imaging, Cleveland, OH 44195 USA. [Griffin, Brian] Cleveland Clin, Inst Heart & Vasc, Cleveland, OH 44195 USA. RP Phelan, D (reprint author), Cleveland Clin, Inst Heart & Vasc, Dept Cardiovasc Med, J1-5,9500 Euclid Ave, Cleveland, OH 44195 USA. EM pheland@ccf.org NR 59 TC 0 Z9 0 U1 2 U2 2 PU CLEVELAND CLINIC PI CLEVELAND PA 9500 EUCLID AVE, CLEVELAND, OH 44106 USA SN 0891-1150 EI 1939-2869 J9 CLEV CLIN J MED JI Clevel. Clin. J. Med. PD DEC PY 2016 VL 83 IS 12 BP 914 EP 922 DI 10.3949/ccjm.83a.15104 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA EG3ER UT WOS:000390927100009 PM 27938516 ER PT J AU Guo, BQ McMillan, BJ Blacklow, SC AF Guo, Bingqian McMillan, Brian J. Blacklow, Stephen C. TI Structure and function of the Mind bomb E3 ligase in the context of Notch signal transduction SO CURRENT OPINION IN STRUCTURAL BIOLOGY LA English DT Article ID UBIQUITIN LIGASE; INTRACELLULAR MOTIFS; DELTA; DEGRADATION; ENDOCYTOSIS; ACTIVATION; MECHANISM; PROMOTES; REVEALS; LIGANDS AB The Notch signaling pathway has a critical role in cell fate determination and tissue homeostasis in a variety of different lineages. In the context of normal Notch signaling, the Notch receptor of the 'signal-receiving' cell is activated in trans by a Notch ligand from a neighboring 'signal-sending' cell. Genetic studies in several model organisms have established that ubiquitination of the Notch ligand, and its regulated endocytosis, is essential for transmission of this activation signal. In mammals, this ubiquitination step is dependent on the protein Mind bomb 1 (Mib1), a large multi-domain RING-type E3 ligase, and its direct interaction with the intracellular tails of Notch ligand molecules. Here, we discuss our current understanding of Mind bomb structure and mechanism in the context of Notch signaling and beyond. C1 [Guo, Bingqian; McMillan, Brian J.; Blacklow, Stephen C.] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [McMillan, Brian J.] Broad Inst, Ctr Dev Therapeut, Cambridge, MA 02142 USA. [Blacklow, Stephen C.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. RP Blacklow, SC (reprint author), Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA.; Blacklow, SC (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. EM stephen_blacklow@hms.harvard.edu FU NIH [R01 CA092433, P01 CA119070] FX We thank Thomas Klein and members of the Blacklow laboratory for helpful discussions. This work is supported by NIH grants R01 CA092433 and P01 CA119070, Project 3 (to SCB). NR 37 TC 1 Z9 1 U1 1 U2 1 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-440X EI 1879-033X J9 CURR OPIN STRUC BIOL JI Curr. Opin. Struct. Biol. PD DEC PY 2016 VL 41 BP 38 EP 45 DI 10.1016/j.sbi.2016.05.012 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EG3TJ UT WOS:000390967300007 PM 27285058 ER PT J AU Tsui, JI Williams, EC Green, PK Berry, K Su, F Ioannou, GN AF Tsui, Judith I. Williams, Emily C. Green, Pamela K. Berry, Kristin Su, Feng Ioannou, George N. TI Alcohol use and hepatitis C virus treatment outcomes among patients receiving direct antiviral agents SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Hepatitis c treatment; Direct antiviral agents; AUDIT-C ID OF-VETERANS-AFFAIRS; HEPATOCELLULAR-CARCINOMA; UNITED-STATES; VIRAL-HEPATITIS; NATIONAL-HEALTH; LIVER-DISEASE; USE DISORDERS; PRIMARY-CARE; AUDIT-C; INFECTION AB Background: It is unclear whether alcohol use negatively impacts HCV treatment outcomes in the era of direct antiviral agents (DAAs). We aimed to evaluate the associations between current levels of drinking and treatment response among persons treated for HCV with DAAs in the national Veterans Affairs (VA) healthcare system. Methods: We identified patients who initiated HCV DAAs over 18 months (1/1/14-6/30/15) and had documented alcohol screening with the Alcohol Use Disorders Identification Test Consumption (AUDIT-C) questionnaire within one year prior to initiating therapy. DAAs included: sofosbuvir (SOF), ledipasvir/sofosbuvir (LDV/SOF) or ombitasvir-paritaprevir-ritonavir, and dasabuvir (PrOD). AUDIT-C scores were categorized as 0 (abstinence), 1-3 (low-level drinking) and 4-12 (unhealthy drinking) in men or 0, 1-2 and 3-12 in women. Results: Among 17,487 patients who initiated DAAs, 15,151 (87%) completed AUDIT-C screening: 10,387 (68.5%) were categorized as abstinent, 3422 (22.6%) as low-level drinking and 1342 (8.9%) as unhealthy drinking. There were no significant differences in sustained virologic response (SVR) rates between abstinent (SVR 91%; 95% CI: 91-92%), low-level drinking (SVR 93%; 95% CI 92-94%) or unhealthy drinking (SVR 91%; 95% 89-92) categories in univariable analysis or in multivariable logistic regression models. However, after imputing missing SVR data, unhealthy drinkers were less likely to achieve SVR in multivariable analysis (AOR 0.75, 95% CI 0.60-0.92). Conclusion: Absolute SVR rates were uniformly high among all persons regardless of alcohol use, with only minor differences in those who report unhealthy drinking, which supports clinical guidelines that do not recommend excluding persons with alcohol use. Published by Elsevier Ireland Ltd. C1 [Tsui, Judith I.] Gen Internal Med, Seattle, WA USA. [Williams, Emily C.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Williams, Emily C.; Green, Pamela K.; Berry, Kristin; Ioannou, George N.] Hlth Serv Res & Dev, Seattle, WA USA. [Williams, Emily C.] Vet Affairs Puget Sound Hlth Care Syst, Ctr Innovat Veteran Cent Value Driven Care COIN, Seattle, WA USA. [Su, Feng; Ioannou, George N.] Vet Affairs Puget Sound Hlth Care Syst, Div Gastroenterol Med, Seattle, WA USA. [Su, Feng; Ioannou, George N.] Univ Washington, Seattle, WA 98195 USA. RP Ioannou, GN (reprint author), Vet Affairs Puget Sound Hlth Care Syst, Gastroenterol, S-111 Gastro 1660 S Columbian Way, Seattle, WA 98108 USA. EM georgei@medicine.washington.edu NR 44 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD DEC 1 PY 2016 VL 169 BP 101 EP 109 DI 10.1016/j.drugalcdep.2016.10.021 PG 9 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA EG3SO UT WOS:000390965200016 PM 27810652 ER PT J AU Saadi, A Patenaude, B Mateen, FJ AF Saadi, Altaf Patenaude, Bryan Mateen, Farrah J. TI Quality of life in epilepsy-31 inventory (QOLIE-31) scores: A global comparison SO EPILEPSY & BEHAVIOR LA English DT Review DE Quality of life; Epilepsy; Seizure; Global health; Asia; Africa ID RECEIVING ANTIEPILEPTIC DRUGS; RANDOMIZED CONTROLLED-TRIAL; PSYCHOMETRIC PROPERTIES; SEIZURE SEVERITY; PEOPLE; VERSION; ADULTS; DETERMINANTS; ASSOCIATION; RELIABILITY AB Quality of life is a pragmatic endpoint for understanding the experience of people with epilepsy (PWE) in low and middle-income countries (LMICs), where > 80% of PWE reside. However, the literature is bereft of QOL in epilepsy (QOLIE) studies among LMICs and knowledge of the variation in QOLIE globally. We therefore performed a Medline search of original research studies using the quality of life in epilepsy-31 inventory (QOLIE-31) in a recent fifteen-year period (2000-2015). Each of the 194 countries listed by the World Health Organization (WHO) was individually included as search terms. Differences in QOLIE were tested across WHO world regions and World Bank country income group classifications. Sixteen percent of all countries (n = 31) reported on 7255 individuals, including only 8 LMICs. The global mean QOLIE-31 score was 59.8 (standard deviation (SD): 8.0), with a range from 42.1 (SD: 4.1) in the Russian Federation to 82 (SD: 32.8) in Canada. There was a statistically significant difference seen in the QOLIE-31 score by world region and income category, with lower country income level associated with worse QOL (test for trend, p < 0.0001). There exists substantial global variation in QOLIE, and country income level may play a role. Understanding what contributes to international differences in QOLIE can help reduce disparities in QOL among PWE worldwide. (C) 2016 Elsevier Inc. All rights reserved. C1 [Saadi, Altaf] Massachusetts Gen Hosp, Partners Neurol Residency, 55 Fruit St,WACC 8-835, Boston, MA 02114 USA. [Saadi, Altaf] Brigham & Womens Hosp, 55 Fruit St,WACC 8-835, Boston, MA 02114 USA. [Patenaude, Bryan] Harvard TH Chan Sch Publ Hlth, Boston, MA USA. [Mateen, Farrah J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Saadi, Altaf; Mateen, Farrah J.] Harvard Med Sch, Boston, MA USA. RP Saadi, A (reprint author), Massachusetts Gen Hosp, Partners Neurol Residency, 55 Fruit St,WACC 8-835, Boston, MA 02114 USA.; Saadi, A (reprint author), Brigham & Womens Hosp, 55 Fruit St,WACC 8-835, Boston, MA 02114 USA. EM asaadi@partners.org; bryanpatenaude@gmail.com; fmateen@partners.org FU Global Challenges Canada - Government of Canada [338-04]; Thrasher Research Fund FX We are grateful for funding from Global Challenges Canada (338-04), funded by the Government of Canada, and the Thrasher Research Fund. We thank Miss Emma Wolper for her assistance with retrieving articles. NR 50 TC 0 Z9 0 U1 6 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1525-5050 EI 1525-5069 J9 EPILEPSY BEHAV JI Epilepsy Behav. PD DEC PY 2016 VL 65 BP 13 EP 17 DI 10.1016/j.yebeh.2016.09.032 PG 5 WC Behavioral Sciences; Clinical Neurology; Psychiatry SC Behavioral Sciences; Neurosciences & Neurology; Psychiatry GA EG3XB UT WOS:000390976900003 PM 27838562 ER PT J AU Olsson, KM Channick, R AF Olsson, Karen M. Channick, Richard TI Pregnancy in pulmonary arterial hypertension SO EUROPEAN RESPIRATORY REVIEW LA English DT Review ID 2015 ESC/ERS GUIDELINES; CESAREAN DELIVERY; HEART-DISEASE; MANAGEMENT; ANESTHESIA; CONTRACEPTION; EPOPROSTENOL; DIAGNOSIS; OUTCOMES; PATIENT AB Despite advanced therapies, maternal mortality in women with pulmonary arterial hypertension (PAH) remains high in pregnancy and is especially high during the post-partum period. However, recent data indicates that morbidity and mortality during pregnancy and after birth have improved for PAH patients. The current European Society of Cardiology/European Respiratory Society guidelines recommend that women with PAH should not become pregnant. Therefore, the risks associated with pregnancy must be emphasised and counselling offered to women at the time of PAH diagnosis and to women with PAH who become pregnant. Early termination should be discussed. Women who choose to continue with their pregnancy should be treated at specialised pulmonary hypertension centres with experience in managing PAH during and after pregnancy. C1 [Olsson, Karen M.] Hannover Med Sch, Hannover, Germany. [Channick, Richard] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. RP Olsson, KM (reprint author), Hannover Med Sch, Dept Resp Med, Carl Neuberg Str 1, D-30625 Hannover, Germany. EM Olsson.karen@mh-hannover.de FU Actelion Pharmaceuticals Ltd (Allschwil, Switzerland) FX The authors would like to thank Anna Chapman (nspm Ltd, Meggen, Switzerland) for medical writing assistance funded by Actelion Pharmaceuticals Ltd (Allschwil, Switzerland). NR 42 TC 1 Z9 1 U1 1 U2 1 PU EUROPEAN RESPIRATORY SOC JOURNALS LTD PI SHEFFIELD PA 442 GLOSSOP RD, SHEFFIELD S10 2PX, ENGLAND SN 0905-9180 EI 1600-0617 J9 EUR RESPIR REV JI Eur. Respir. Rev. PD DEC 1 PY 2016 VL 25 IS 142 BP 431 EP 437 DI 10.1183/16000617.0079-2016 PG 7 WC Respiratory System SC Respiratory System GA EG3AU UT WOS:000390916700009 PM 27903665 ER PT J AU Kaltenbach, T Soetikno, R AF Kaltenbach, Tonya Soetikno, Roy TI How to Create and Deliver an Effective Presentation SO GASTROENTEROLOGY LA English DT Editorial Material C1 [Kaltenbach, Tonya] Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, Dept Med,Dept Clin Med, Div Gastroenterol, San Francisco, CA 94143 USA. [Soetikno, Roy] Stanford Grad Sch Business, Stanford, CA USA. RP Kaltenbach, T (reprint author), Univ Calif San Francisco, San Francisco Vet Affair Med Ctr, Dept Med, Div Gastroenterol,Clin Med, 4150 Clement St VA111B,Bldg 203,2A-67, San Francisco, CA 94121 USA. EM endoresection@me.com NR 3 TC 0 Z9 0 U1 1 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD DEC PY 2016 VL 151 IS 6 BP 1058 EP 1060 DI 10.1053/j.gastro.2016.10.009 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EG3OV UT WOS:000390955500011 PM 27765689 ER PT J AU Shouval, DS Biswas, A Kang, YH Griffith, AE Konnikova, L Mascanfroni, ID Redhu, NS Frei, SM Field, M Doty, AL Goldsmith, JD Bhan, AK Loizides, A Weiss, B Yerushalmi, B Yanagi, T Lui, X Quintana, FJ Muise, AM Klein, C Horwitz, BH Glover, SC Bousvaros, A Snapper, SB AF Shouval, Dror S. Biswas, Amlan Kang, Yu Hui Griffith, Alexandra E. Konnikova, Liza Mascanfroni, Ivan D. Redhu, Naresh S. Frei, Sandra M. Field, Michael Doty, Andria L. Goldsmith, Jeffrey D. Bhan, Atul K. Loizides, Anthony Weiss, Batia Yerushalmi, Baruch Yanagi, Tadahiro Lui, Xiuli Quintana, Francisco J. Muise, Aleixo M. Klein, Christoph Horwitz, Bruce H. Glover, Sarah C. Bousvaros, Athos Snapper, Scott B. TI Interleukin 1 beta Mediates Intestinal Inflammation in Mice and Patients With Interleukin 10 Receptor Deficiency SO GASTROENTEROLOGY LA English DT Article DE VEOIBD; Treg Cell; Ubiquitination; Caspase-1 ID SPONTANEOUS COLITIS; BOWEL-DISEASE; ACTIVATION; MACROPHAGES; CELLS AB Interleukin 10 receptor (IL10R)-deficient mice develop spontaneous colitis and, similarly, patients with loss-of-function mutations in IL10R develop severe infantonset inflammatory bowel disease. Loss of IL10R signaling in mouse and human macrophages is associated with increased production of interleukin 1 beta. We demonstrated that innate immune production of IL1 beta mediates colitis in IL10R-deficient mice. Transfer of II1r1(-/-) CD4(+) T cells into Rag1(-/-) /II10rb(-/-) mice reduced the severity of their colitis (compared to mice that received CD4(+) T cells that express IL1R), accompanied by decreased production of interferon gamma, tumor necrosis factor-alpha, and IL17A. In macrophages from mice without disruption of IL10R signaling or from healthy humans (controls), incubation with IL10 reduced canonical activation of the inflammasome and production of IL1 beta through transcriptional and post-translational regulation of NLRP3. Lipopolysaccharide and adenosine triphosphate stimulation of macrophages from Il10rb(-/-) mice or IL10R-deficient patients resulted in increased production of IL1 beta. Moreover, in human IL10R-deficient macrophages, lipopolysaccharide stimulation alone triggered IL1 beta secretion via non-canonical, caspase 8-dependent activation of the inflammasome. We treated 2 IL10R-deficient patients with severe and treatment-refractory infant-onset inflammatory bowel disease with the IL1-receptor antagonist anakinra. Both patients had marked clinical, endoscopic, and histologic responses after 4-7 weeks. This treatment served as successful bridge to allogeneic hematopoietic stem cell transplantation in 1 patient. Our findings indicate that loss of IL10 signaling leads to intestinal inflammation, at least in part, through increased production of IL1 by innate immune cells, leading to activation of CD4(+) T cells. Agents that block IL1 signaling might be used to treat patients with inflammatory bowel disease resulting from IL10R deficiency. C1 [Shouval, Dror S.; Biswas, Amlan; Kang, Yu Hui; Griffith, Alexandra E.; Redhu, Naresh S.; Frei, Sandra M.; Field, Michael; Bousvaros, Athos; Snapper, Scott B.] Boston Childrens Hosp, Div Gastroenterol Hepatol & Nutr, Boston, MA USA. [Shouval, Dror S.; Biswas, Amlan; Kang, Yu Hui; Konnikova, Liza; Mascanfroni, Ivan D.; Redhu, Naresh S.; Frei, Sandra M.; Goldsmith, Jeffrey D.; Bhan, Atul K.; Quintana, Francisco J.; Horwitz, Bruce H.; Bousvaros, Athos; Snapper, Scott B.] Harvard Med Sch, Boston, MA USA. [Shouval, Dror S.; Weiss, Batia] Edmond & Lily Safra Childrens Hosp, Sheba Med Ctr, Div Pediat Gastroenterol & Nutr, Tel Hashomer, Israel. [Shouval, Dror S.; Weiss, Batia] Tel Aviv Univ, Sackler Fac Med, Tel Aviv, Israel. [Konnikova, Liza] Brigham & Womens Hosp, Div Newborn Med, Boston, MA USA. [Mascanfroni, Ivan D.; Quintana, Francisco J.] Brigham & Womens Hosp, Ann Romney Ctr Neurol Dis, Boston, MA USA. [Doty, Andria L.] Univ Florida, Dept Med, Div Gastroenterol Hepatol & Nutr, Gainesville, FL USA. [Goldsmith, Jeffrey D.] Boston Childrens Hosp, Dept Pathol, Boston, MA USA. [Bhan, Atul K.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Loizides, Anthony] Childrens Hosp Montefiore, Div Gastroenterol & Nutr, Bronx, NY USA. [Yerushalmi, Baruch] Soroka Univ, Med Ctr, Pediat Gastroenterol Unit, Beer Sheva, Israel. [Yerushalmi, Baruch] Ben Gurion Univ Negev, Fac Hlth Sci, Beer Sheva, Israel. [Yanagi, Tadahiro] Kurume Univ, Sch Med, Dept Pediat, Kurume, Fukuoka, Japan. [Lui, Xiuli] Univ Florida, Dept Pathol Immunol & Lab Med, Gainesville, FL USA. [Muise, Aleixo M.] Hosp Sick Children, Inflammatory Bowel Dis Ctr, Toronto, ON, Canada. [Muise, Aleixo M.] Hosp Sick Children, Res Inst, Cell Biol Program, Toronto, ON, Canada. [Muise, Aleixo M.] Univ Toronto, Hosp Sick Children, Div Gastroenterol Hepatol & Nutr, Dept Pediat, Toronto, ON, Canada. [Muise, Aleixo M.] Univ Toronto, Inst Med Sci, Toronto, ON, Canada. [Muise, Aleixo M.] Univ Toronto, Dept Biochem, Toronto, ON, Canada. [Klein, Christoph] Ludwig Maximilians Univ Munchen, Dr Von Hauner Childrens Hosp, Munich, Germany. [Horwitz, Bruce H.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Snapper, Scott B.] Brigham & Womens Hosp, Div Gastroenterol, Boston, MA 02115 USA. RP Snapper, SB (reprint author), Boston Childrens Hosp, Div Gastroenterol, 300 Longwood Ave,Enders Bldg 670, Boston, MA 02115 USA. EM Scott.Snapper@childrens.harvard.edu FU Crohn's and Colitis Foundation of America (CCFA); CCFA Career Development Award; National Institutes of Health (NIH) KO1 award [K01DK109026]; A*STAR National Science Scholarship (Singapore); NIH [DK034854]; Helmsley Charitable Trust; Translational Investigator Service at Boston Children's Hospital; Wolpow Family Chair in IBD Treatment and Research FX Dror S. Shouval is a recipient of a Research Fellowship Award Grant from the Crohn's and Colitis Foundation of America (CCFA). Amlan Biswas is recipient of CCFA Career Development Award and National Institutes of Health (NIH) KO1 award (K01DK109026). Yu Hui Kang is a recipient of an A*STAR National Science Scholarship (Singapore). Scott B. Snapper is supported by NIH Grant DK034854, the Helmsley Charitable Trust, the Translational Investigator Service at Boston Children's Hospital, and the Wolpow Family Chair in IBD Treatment and Research. NR 17 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 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD DEC PY 2016 VL 151 IS 6 BP 1100 EP 1104 DI 10.1053/j.gastro.2016.08.055 PG 5 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EG3OV UT WOS:000390955500024 PM 27693323 ER PT J AU Yamaguchi, J Mino-Kenudson, M Liss, AS Chowdhury, S Wang, TC Fernandez-del Castillo, C Lillemoe, KD Warshaw, AL Thayer, SP AF Yamaguchi, Junpei Mino-Kenudson, Mari Liss, Andrew S. Chowdhury, Sanjib Wang, Timothy C. Fernandez-del Castillo, Carlos Lillemoe, Keith D. Warshaw, Andrew L. Thayer, Sarah P. TI Loss of Trefoil Factor 2 From Pancreatic Duct Glands Promotes Formation of Intraductal Papillary Mucinous Neoplasms in Mice SO GASTROENTEROLOGY LA English DT Article DE Pancreatic Tumorigenesis; Carcinogenesis; Gene Regulation; PanIN ID MITOCHONDRIAL-DNA MUTATIONS; CANCER CELL-LINES; STEM-CELLS; GENE-EXPRESSION; GROWTH-FACTOR; K-RAS; PROGRESSION; CLASSIFICATION; INFLAMMATION; METAPLASIA AB BACKGROUND & AIMS: Little is known about the origin of pancreatic intraductal papillary mucinous neoplasms (IPMN). Pancreatic duct glands (PDGs) are gland-like outpouches budding off the main pancreatic ducts that function as a progenitor niche for the ductal epithelium; they express gastric mucins and have characteristics of side-branch IPMNs. We investigated whether PDGs are a precursor compartment for IPMNs and the role of Trefoil factor family 2 (TFF2)-a protein expressed by PDGs and the gastric mucosa that are involved in epithelial repair and tumor suppression. METHODS: We obtained pancreatectomy specimens from 20 patients with chronic pancreatitis, 13 with low-grade side-branch IPMNs, and 15 patients with PDAC; histologically normal pancreata were used as controls (n = 18). Samples were analyzed by immunohistochemistry to detect TFF1 and TFF2 and cell proliferation. We performed mitochondrial DNA mutational mapping studies to determine the cell lineage and fate of PDG cells. Pdx1-Cre; LSL-KRAS(G12D) (KC) mice were bred with TFF2-knockout mice to generate KC/Tff2(-/-) and KC/Tff2(+/-) mice. Pancreata were collected and histologically analyzed for formation of IPMN, pancreatic intraepithelial neoplasias, and PDAC, in addition to proliferation and protein expression. Human pancreatic ductal epithelial cells and PDAC cell lines were transfected with vectors to overexpress or knock down TFF2 or SMAD4. RESULTS: Histologic analysis of human samples revealed gastric-type IPMN to comprise 2 molecularly distinct layers: a basal crypt segment that expressed TFF2 and overlying papillary projections. Proliferation occurred predominantly in the PDG-containing basal segments. Mitochondrial mutation mapping revealed a 97% match between the profiles of proliferating PDG cells and their overlying nonproliferative IPMN cells. In contrast to KC mice, 2-month-old KC/Tff2(+/-) and KC/Tff2(-/-) mice developed prominent papillary structures in the duct epithelium with cystic metaplasia of the PDG, which resembled human IPMN; these expressed gastric mucins (MUC5AC and MUC6), but not the intestinal mucin MUC2. KC/TFF2-knockout mice developed a greater number and higher grade of pancreatic intraepithelial neoplasias than KC mice, and 1 mouse developed an invasive adenocarcinoma. Expression of TFF2 reduced proliferation of PDAC cells 3-fold; this effect required up-regulation and activation of SMAD4. We found expression of TFF2 to be down-regulated in human PDAC by hypermethylation of its promoter. CONCLUSIONS: In histologic analyses of human IPMNs, we found PDGs to form the basal segment and possibly serve as a progenitor compartment. TFF2 has tumor-suppressor activity in the mouse pancreas and prevents formation of mucinous neoplasms. C1 [Yamaguchi, Junpei; Liss, Andrew S.; Fernandez-del Castillo, Carlos; Lillemoe, Keith D.; Warshaw, Andrew L.; Thayer, Sarah P.] Massachusetts Gen Hosp, Dept Surg, Andrew L Warshaw Inst Pancreat Canc Res, Boston, MA 02114 USA. [Mino-Kenudson, Mari] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Chowdhury, Sanjib; Thayer, Sarah P.] Univ Nebraska Med Ctr, Div Surg Oncol, Omaha, NE USA. [Chowdhury, Sanjib; Thayer, Sarah P.] Univ Nebraska Med Ctr, Fred & Pamela Buffett Canc Ctr, Omaha, NE USA. [Wang, Timothy C.] Columbia Univ, Med Ctr, Div Digest & Liver Dis, New York, NY USA. [Wang, Timothy C.] Columbia Univ, Med Ctr, Irving Canc Res Ctr, New York, NY USA. RP Thayer, SP (reprint author), Fred & Pamela Buffett Canc Ctr, 986345 Univ Nebraska Med Ctr, Omaha, NE 68198 USA.; Thayer, SP (reprint author), Div Surg Oncol, 986345 Univ Nebraska Med Ctr, Omaha, NE 68198 USA. EM sarah.thayer@unmc.edu FU Warshaw Institute for Pancreatic Cancer Research; [7P01CA117969-07] FX This work was supported in part by 7P01CA117969-07 (SPT) and the Warshaw Institute for Pancreatic Cancer Research (Sarah P. Thayer, Andrew S. Liss, Junpei Yamaguchi). NR 38 TC 0 Z9 0 U1 1 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD DEC PY 2016 VL 151 IS 6 BP 1232 EP + DI 10.1053/j.gastro.2016.07.045 PG 23 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EG3OV UT WOS:000390955500036 PM 27523981 ER PT J AU Young, MJ Pham, J AF Young, Michael J. Pham, Julien TI Improving the electronic nexus between generalists and specialists: A public health imperative? SO HEALTHCARE-THE JOURNAL OF DELIVERY SCIENCE AND INNOVATION LA English DT Article DE Econsults; Access to care; Specialists; Care-coordination; Underserved ID E-CONSULTATION SERVICE; PRIMARY-CARE PROVIDERS; DISPARITIES; COMMUNICATION; INFORMATION; PHYSICIANS; REFERRALS; ACCESS; SYSTEM; IMPACT AB Recent changes in healthcare delivery and payment policy have precipitated interest among healthcare providers across the U.S. seeking innovative strategies to achieve higher quality, lower cost care through improved resource-utilization. One dimension of healthcare delivery with distinctive potential for improvement is care coordination between primary care and specialist providers. Optimizing the nexus between PCPs and specialists through innovations including eConsultation platforms portends reductions in unnecessary referrals and testing, and may help align incentives to promote high-value care. Opportunities and challenges surrounding effective and versatile operationalization of such technologies are assessed, focusing on specific public health needs of access and utilization. C1 [Young, Michael J.] Harvard Med Sch, Massachusetts Gen Hosp, 260 Longwood Ave, Boston, MA USA. [Pham, Julien] Dorchester House Community Hlth Ctr, Boston, MA USA. RP Young, MJ (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, 260 Longwood Ave, Boston, MA USA. EM michael.young@mgh.harvard.edu NR 40 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2213-0764 EI 2213-0772 J9 HEALTHCARE JI HealthCare PD DEC PY 2016 VL 4 IS 4 BP 302 EP 306 DI 10.1016/j.hjdsi.2016.10.002 PG 5 WC Health Care Sciences & Services SC Health Care Sciences & Services GA EG3BI UT WOS:000390918300012 PM 27939171 ER PT J AU Abramson, JS AF Abramson, Jeremy S. TI The Spectrum of Double Hit Lymphomas SO HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA LA English DT Article DE Double-hit lymphomas; Double-expressing lymphomas; High grade B-cell lymphoma; MYC; BCL2 ID B-CELL LYMPHOMA; NON-HODGKIN-LYMPHOMA; CLINICAL PRESENTATION; MYC REARRANGEMENT; BURKITT-LYMPHOMA; GERMINAL CENTER; FEATURES; PROGNOSIS; RITUXIMAB; TRANSLOCATIONS AB Double-hit lymphomas (DHLs) characterize a unique subset of B-cell non Hodgkin lymphomas. DHL typically presents in older adults with high-risk clinical features. This entity carries a significantly inferior prognosis compared with typical cases of diffuse large B-cell lymphoma; however, emerging literature can identify discrete clinical features within DHL that are associated with a favorable prognosis. Emerging literature is also demonstrating that intensive upfront treatment strategies may improve outcome. Diagnosis, prognostication, and management of DHL are reviewed, as well as potential future directions incorporating novel biologically targeted therapies. Finally, double-expressing lymphomas (DELs) will be discussed and contrasted with DHL. C1 [Abramson, Jeremy S.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc, Ctr Lymphoma, 55 Fruit St,Yawkey 9A, Boston, MA 02114 USA. RP Abramson, JS (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc, Ctr Lymphoma, 55 Fruit St,Yawkey 9A, Boston, MA 02114 USA. EM jabramson@mgh.harvard.edu NR 37 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0889-8588 EI 1558-1977 J9 HEMATOL ONCOL CLIN N JI Hematol. Oncol. Clin. North Am. PD DEC PY 2016 VL 30 IS 6 BP 1239 EP + DI 10.1016/j.hoc.2016.07.005 PG 12 WC Oncology; Hematology SC Oncology; Hematology GA EG3UW UT WOS:000390971200008 PM 27888878 ER PT J AU Zabetian, CP AF Zabetian, Cyrus P. TI The Clinical Profile of GBA-Related Lewy Body Disorders SO JAMA NEUROLOGY LA English DT Editorial Material ID PARKINSONS-DISEASE; GLUCOCEREBROSIDASE MUTATIONS; METAANALYSIS; MULTICENTER; RISK C1 [Zabetian, Cyrus P.] Vet Affairs Puget Sound Hlth Care Syst, GRECC S-182,1660 S Columbian Way, Seattle, WA 98108 USA. [Zabetian, Cyrus P.] Univ Washington, Sch Med, Dept Neurol, Seattle, WA USA. RP Zabetian, CP (reprint author), Vet Affairs Puget Sound Hlth Care Syst, GRECC S-182,1660 S Columbian Way, Seattle, WA 98108 USA. EM zabetian@u.washington.edu NR 15 TC 0 Z9 0 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6149 EI 2168-6157 J9 JAMA NEUROL JI JAMA Neurol. PD DEC 1 PY 2016 VL 73 IS 12 BP 1403 EP 1404 DI 10.1001/jamaneurol.2016.2546 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA EG5ZB UT WOS:000391122200009 PM 27723881 ER PT J AU Boulouis, G van Etten, ES Charidimou, A Auriel, E Morotti, A Pasi, M Haley, KE Brouwers, HB Ayres, AM Vashkevich, A Jessel, MJ Schwab, KM Viswanathan, A Greenberg, SM Rosand, J Goldstein, JN Gurol, ME AF Boulouis, Gregoire van Etten, Ellis S. Charidimou, Andreas Auriel, Eitan Morotti, Andrea Pasi, Marco Haley, Kellen E. Brouwers, H. Bart Ayres, Alison M. Vashkevich, Anastasia Jessel, Michael J. Schwab, Kristin M. Viswanathan, Anand Greenberg, Steven M. Rosand, Jonathan Goldstein, Joshua N. Gurol, M. Edip TI Association of Key Magnetic Resonance Imaging Markers of Cerebral Small Vessel Disease With Hematoma Volume and Expansion in Patients With Lobar and Deep Intracerebral Hemorrhage SO JAMA NEUROLOGY LA English DT Article ID CORTICAL SUPERFICIAL SIDEROSIS; ANGIOGRAPHY SPOT SIGN; WHITE-MATTER LESIONS; ACTIVATED FACTOR-VII; AMYLOID ANGIOPATHY; MICROBLEEDS; LEUKOARAIOSIS; BURDEN; RISK AB IMPORTANCE Hematoma expansion is an important determinant of outcome in spontaneous intracerebral hemorrhage (ICH) due to small vessel disease (SVD), but the association between the severity of the underlying SVD and the extent of bleeding at the acute phase is unknown to date. OBJECTIVE To investigate the association between key magnetic resonance imaging (MRI) markers of SVD (as per the Standards for Reporting Vascular Changes on Neuroimaging [STRIVE] guidelines) and hematoma volume and expansion in patients with lobar or deep ICH. DESIGN, SETTING, AND PARTICIPANTS Analysis of data collected from 418 consecutive patients admitted with primary lobar or deep ICH to a single tertiary care medical center between January 1, 2000, and October 1, 2012. Data were analyzed on March 4, 2016. Participants were consecutive patients with computed tomographic images allowing ICH volume calculation and MRI allowing imaging markers of SVD assessment. MAIN OUTCOMES AND MEASURES The ICH volumes at baseline and within 48 hours after symptom onset were measured in 418 patients with spontaneous ICH without anticoagulant therapy, and hematoma expansion was calculated. Cerebral microbleeds, cortical superficial siderosis, and white matter hyperintensity volume were assessed on MRI. The associations between these SVD markers and ICH volume, as well as hematoma expansion, were investigated using multivariable models. RESULTS This study analyzed 254 patients with lobar ICH (mean [SD] age, 75 [11] years and 140 [55.1%] female) and 164 patients with deep ICH (mean [SD] age 67 [14] years and 71 [43.3%] female). The presence of cortical superficial siderosis was an independent variable associated with larger ICH volume in the lobar ICH group (odds ratio per quintile increase in final ICH volume, 1.49; 95% CI, 1.14-1.94; P = .004). In multivariable models, the absence of cerebral microbleeds was associated with larger ICH volume for both the lobar and deep ICH groups (odds ratios per quintile increase in final ICH volume, 1.41; 95% CI, 1.11-1.81; P = .006 and 1.43; 95% CI, 1.04-1.99; P = .03; respectively) and with hematoma expansion in the lobar ICH group (odds ratio, 1.70; 95% CI, 1.07-2.92; P = .04). The white matter hyperintensity volumes were not associated with either hematoma volume or expansion. CONCLUSIONS AND RELEVANCE In patients admitted with primary lobar or deep ICH to a single tertiary care medical center, the presence of cortical superficial siderosis was an independent variable associated with larger lobar ICH volume, and the absence of cerebral microbleeds was associated with larger lobar and deep ICHs. The absence of cerebral microbleeds was independently associated with more frequent hematoma expansion in patients with lobar ICH. We provide an analytical framework for future studies aimed at limiting hematoma expansion. C1 [Boulouis, Gregoire; van Etten, Ellis S.; Charidimou, Andreas; Auriel, Eitan; Morotti, Andrea; Pasi, Marco; Haley, Kellen E.; Brouwers, H. Bart; Ayres, Alison M.; Vashkevich, Anastasia; Jessel, Michael J.; Schwab, Kristin M.; Viswanathan, Anand; Greenberg, Steven M.; Rosand, Jonathan; Goldstein, Joshua N.; Gurol, M. Edip] Harvard Med Sch, Hemorrhag Stroke Res Program, Dept Neurol, Massachusetts Gen Hosp,Stroke Res Ctr, Zero Emerson Pl,Ste 3B, Boston, MA 02114 USA. [van Etten, Ellis S.] Leiden Univ, Med Ctr, Dept Neurol, Leiden, Netherlands. [Brouwers, H. Bart] Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Dept Neurosurg, Heidelberglaan, Utrecht, Netherlands. [Goldstein, Joshua N.] Harvard Med Sch, Massachusetts Gen Hosp, Div Neurocrit Care & Emergency Neurol, Zero Emerson Pl,Ste 3B, Boston, MA 02114 USA. RP Goldstein, JN (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Div Neurocrit Care & Emergency Neurol, Zero Emerson Pl,Ste 3B, Boston, MA 02114 USA. EM jgoldstein@partners.org FU National Institutes of Health [K23-NS083711, R01-AG026484, R01-NS073344]; J. William Fulbright Scholarship; Monahan Foundation Biomedical Research Grant FX This work was supported by grants K23-NS083711 (Dr Gurol), R01-AG026484 (Dr Greenberg), and R01-NS073344 (Dr Rosand) from the National Institutes of Health. Dr Boulouis was supported by a J. William Fulbright Scholarship and a Monahan Foundation Biomedical Research Grant. NR 36 TC 1 Z9 1 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6149 EI 2168-6157 J9 JAMA NEUROL JI JAMA Neurol. PD DEC 1 PY 2016 VL 73 IS 12 BP 1440 EP 1447 DI 10.1001/jamaneurol.2016.2619 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA EG5ZB UT WOS:000391122200015 PM 27723863 ER PT J AU Miller, EC Gatollari, HJ Too, G Boehme, AK Leffert, L Elkind, MSV Willey, JZ AF Miller, Eliza C. Gatollari, Hajere J. Too, Gloria Boehme, Amelia K. Leffert, Lisa Elkind, Mitchell S. V. Willey, Joshua Z. TI Risk of Pregnancy-Associated Stroke Across Age Groups in New York State SO JAMA NEUROLOGY LA English DT Article ID ISCHEMIC-STROKE; UNITED-STATES; POSTPARTUM PERIOD; PREECLAMPSIA; PUERPERIUM; OUTCOMES; HOSPITALIZATIONS; MECHANISMS; INFECTION; DISORDERS AB IMPORTANCE Older age is associated with increased risk of pregnancy-associated stroke (PAS). Data are limited on age-specific incidence ratios of PAS compared with stroke risk in nonpregnant women. OBJECTIVES To assess the risk of stroke by age group in pregnant and postpartum women compared with their nonpregnant contemporaries and to compare risk factors across age groups in the exposed (pregnant/postpartum) and unexposed (nonpregnant) populations. DESIGN, SETTING, AND PARTICIPANTS International Classification of Diseases, Ninth Revision, billing codes from the calendar year 2003-2012 New York State Department of Health inpatient database and population data were used to identify all women aged 12 to 55 years with cerebrovascular events, including transient ischemic attack, ischemic and hemorrhagic stroke, cerebral venous thrombosis, and nonspecified PAS. The cumulative incidence of PAS per 100 000 pregnant/postpartum women vs nonpregnancy-associated stroke (NPAS) per 100 000 women in age cohorts of 24 years or younger, 25 to 34, 35 to 44, and 45 years or older was calculated. Risk factors between groups were compared using logistic regression models. The study included data from calendar years 2003 through 2012. Data analysis was performed from July 11, 2015, to July 16, 2016. EXPOSURES Pregnancy, including the postpartum period up to 6 weeks after delivery. MAIN OUTCOMES AND MEASURES Incidence risk ratios (IRRs) for stroke per age cohort, defined as cumulative risk of stroke in the exposed population divided by cumulative risk of stroke in the unexposed population, were determined, and stroke risk factors and mortality were compared between populations. RESULTS There were 19 146 women hospitalized with stroke during the study period; 797 of the women were pregnant/post partum. The overall median (interquartile range) age of the women was 31 (25-35) years in those with PAS and 48 (41-52) years in those with NPAS. The incidence of PAS in women aged 12 to 24 years was 14 events per 100 000 pregnant/postpartum women vs NPAS incidence of 6.4 per 100 000 nonpregnant women (IRR, 2.2; 95% CI, 1.9-2.6); for ages 25 to 34 years, 21.2 per 100 000 vs 13.5 per 100 000 (IRR, 1.6; 95% CI, 1.4-1.7); for ages 35 to 44 years, 33 per 100 000 vs 31 per 100 000 (IRR, 1.1; 95% CI, 0.9-1.2); and for ages 45 to 55 years, 46.9 per 100 000 vs 73.7 per 100 000 (IRR, 0.6; 95% CI, 0.3-1.4). PAS accounted for 18% of strokes in women younger than 35 years vs 1.4% of strokes in women aged 35 to 55 years. Women in the NPAS group vs the PAS group had more vascular risk factors, including chronic hypertension (age <35 years: 437 [15.7%] vs 60 [9.8%], P < .001; age 35-55 years: 7573 [48.6%] vs 36 [19.3%], P < .001), diabetes (age < 35 years: 103 [3.7%] vs 9 [1.5%], P = .002; age 35-55 years: 2618 [16.8%] vs 12 [6.4%], P < .001), and active smoking (age < 35 years: 315 [11.3%] vs 29 [4.8%], P < .001; age 35-55 years: 2789 [17.9%] vs 10 [5.3%], P < .001); and had higher mortality (age < 35 years: 288 [11.3%] vs 37 [6.5%], P < .001; age 35-55 years: 2121 [13.4%] vs 14 [6.1%], P < .001). CONCLUSIONS AND RELEVANCE Younger women, but not older women, have an increased stroke risk during pregnancy and post partum compared with their nonpregnant contemporaries. These results suggest that pregnancy does not increase the risk of stroke in older women. C1 [Miller, Eliza C.; Boehme, Amelia K.; Elkind, Mitchell S. V.; Willey, Joshua Z.] Columbia Univ, Dept Neurol, Coll Phys & Surg, 710 W 168th St,14th Floor, New York, NY 10032 USA. [Gatollari, Hajere J.; Boehme, Amelia K.; Elkind, Mitchell S. V.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, 710 W 168th St,14th Floor, New York, NY 10032 USA. [Too, Gloria] Columbia Univ, Dept Obstet & Gynecol, 710 W 168th St,14th Floor, New York, NY 10032 USA. [Leffert, Lisa] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Miller, EC (reprint author), Columbia Univ, Neurol Inst New York, Dept Neurol, Coll Phys & Surg, 710 W 168th St,14th Floor, New York, NY 10032 USA. EM ecm2137@cumc.columbia.edu FU National Institute of Neurological Disorders and Stroke (NINDS) National Institutes of Health (NIH) training grant [T32 NS007153-31]; NIH; NIH NINDS grant [K23 073104]; Heartware Incorporated FX Dr Boehme is supported by National Institute of Neurological Disorders and Stroke (NINDS) National Institutes of Health (NIH) training grant T32 NS007153-31. Dr Elkind receives funding from NIH; compensation for providing consultative services for Biotelemetry/Cardionet, BMS-Pfizer Partnership, Boehringer-Ingelheim, and Sanofi-Regeneron; provides paid expert witness testimony for Merck/Organon related to Nuvaring and stroke and BMS-Sanofi related to Plavix and stroke; receives financial compensation as a member of the National, Founders Affiliate, and New York City chapter boards of the American Heart Association/American Stroke Association; and receives royalties from UpToDate for chapters related to cryptogenic stroke and hemicraniectomy. Dr Willey has received funds from NIH NINDS grant K23 073104 and is a paid consultant for Heartware Incorporated. No other disclosures were reported. NR 39 TC 0 Z9 0 U1 4 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6149 EI 2168-6157 J9 JAMA NEUROL JI JAMA Neurol. PD DEC 1 PY 2016 VL 73 IS 12 BP 1461 EP 1467 DI 10.1001/jamaneurol.2016.3774 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA EG5ZB UT WOS:000391122200018 PM 27775757 ER PT J AU Brown, RJ Araujo-Vilar, D Cheung, PT Dunger, D Garg, A Jack, M Mungai, L Oral, EA Patni, N Rother, KI von Schnurbein, J Sorkina, E Stanley, T Vigouroux, C Wabitsch, M Williams, R Yorifuji, T AF Brown, Rebecca J. Araujo-Vilar, David Cheung, Pik To Dunger, David Garg, Abhimanyu Jack, Michelle Mungai, Lucy Oral, Elif A. Patni, Nivedita Rother, Kristina I. von Schnurbein, Julia Sorkina, Ekaterina Stanley, Takara Vigouroux, Corinne Wabitsch, Martin Williams, Rachel Yorifuji, Tohru TI The Diagnosis and Management of Lipodystrophy Syndromes: A Multi-Society Practice Guideline SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID FAMILIAL PARTIAL LIPODYSTROPHY; CONGENITAL GENERALIZED LIPODYSTROPHY; LEPTIN-REPLACEMENT THERAPY; SEVERE INSULIN-RESISTANCE; FATTY LIVER-DISEASE; HUTCHINSON-GILFORD PROGERIA; BASE-LINE CHARACTERISTICS; ENCODING LAMIN A/C; OF-THE-LITERATURE; NONALCOHOLIC STEATOHEPATITIS AB Objective: Lipodystrophy syndromes are extremely rare disorders of deficient body fat associated with potentially serious metabolic complications, including diabetes, hypertriglyceridemia, and steatohepatitis. Due to their rarity, most clinicians are not familiar with their diagnosis and management. This practice guideline summarizes the diagnosis and management of lipodystrophy syndromes not associated with HIV or injectable drugs. Participants: Seventeen participants were nominated by worldwide endocrine societies or selected by the committee as content experts. Funding was via an unrestricted educational grant from Astra Zeneca to the Pediatric Endocrine Society. Meetings were not open to the general public. Evidence: A literature review was conducted by the committee. Recommendations of the committee were graded using the system of the American Heart Association. Expert opinion was used when published data were unavailable or scarce. Consensus Process: The guideline was drafted by committee members and reviewed, revised, and approved by the entire committee during group meetings. Contributing societies reviewed the document and provided approval. Conclusions: Lipodystrophy syndromes are heterogeneous and are diagnosed by clinical phenotype, supplemented by genetic testing in certain forms. Patients with most lipodystrophy syndromes should be screened for diabetes, dyslipidemia, and liver, kidney, and heart disease annually. Diet is essential for the management of metabolic complications of lipodystrophy. Metreleptin therapy is effective for metabolic complications in hypoleptinemic patients with generalized lipodystrophy and selected patients with partial lipodystrophy. Other treatments not specific for lipodystrophy may be helpful as well (eg, metformin for diabetes, and statins or fibrates for hyperlipidemia). Oral estrogens are contraindicated. C1 [Brown, Rebecca J.; Rother, Kristina I.] NIDDK, NIH, Bldg 10 CRC,Room 6-5942,10 Ctr Dr, Bethesda, MD 20892 USA. [Araujo-Vilar, David] Univ Santiago de Compostela, Dept Med, Santiago De Compostela 15782, Spain. [Cheung, Pik To] Univ Hong Kong, Dept Paediat & Adolescent Med, Hong Kong, Hong Kong, Peoples R China. [Dunger, David] Univ Cambridge, Dept Paediat, Cambridge CB2 0QQ, England. [Dunger, David] Univ Cambridge, Metab Res Labs Wellcome Trust, Med Res Council,Inst Metab Sci,MRC Epidemiol Unit, Natl Inst Hlth Res,Cambridge Comprehens Biomed Re, Cambridge CB2 0QQ, England. [Garg, Abhimanyu] UT Southwestern Med Ctr, Div Nutr & Metab Dis, Dept Internal Med, Dallas, TX 75390 USA. [Garg, Abhimanyu] UT Southwestern Med Ctr, Ctr Human Nutr, Dallas, TX 75390 USA. [Jack, Michelle] Univ Sydney, Northern Clin Sch, Royal North Shore Hosp, St Leonards, NSW 2126, Australia. [Mungai, Lucy] Univ Nairobi, Dept Paediat & Child Hlth, Nairobi 00100, Kenya. [Oral, Elif A.] Univ Michigan Med Sch & Hlth Syst, Brehm Ctr Diabet, Ann Arbor, MI 48109 USA. [Oral, Elif A.] Univ Michigan Med Sch & Hlth Syst, Dept Internal Med, Div Metab Endocrinol & Diabet, Ann Arbor, MI 48109 USA. [Patni, Nivedita] UT Southwestern Med Ctr, Div Pediat Endocrinol, Dept Pediat, Dallas, TX 75390 USA. [von Schnurbein, Julia; Wabitsch, Martin] Univ Ulm, Dept Pediat & Adolescent Med, Div Pediat Endocrinol & Diabet, D-89075 Ulm, Germany. [Sorkina, Ekaterina] Moscow MV Lomonosov State Univ, Endocrinol Res Ctr, Clamp Technol Lab, Moscow 119991, Russia. [Sorkina, Ekaterina] Moscow MV Lomonosov State Univ, Med Sci Educ Ctr Lomonosov, Mol Endocrinol Lab, Moscow 119991, Russia. [Stanley, Takara] Massachusetts Gen Hosp, Pediat Endocrine Unit, Boston, MA 02115 USA. [Stanley, Takara] Massachusetts Gen Hosp, Program Nutr Metab, Boston, MA 02115 USA. [Stanley, Takara] Harvard Med Sch, Boston, MA 02115 USA. [Vigouroux, Corinne] Univ Paris 06, Univ Pierre & Marie Curie,St Antoine Hosp, Sorbonne Univ,Inst Cardiometab & Nutr,AP HP,Mol B, Inserm Unite Mixte Rech Sante 938,St Antoine Res, F-75012 Paris, France. [Williams, Rachel] Cambridge Univ Hosp NHS Trust, Dept Paediat Endocrinol, Cambridge CB2 0QQ, England. [Yorifuji, Tohru] Osaka City Gen Hosp, Childrens Med Ctr, Div Pediat Endocrinol & Metab, Osaka 5340021, Japan. RP Brown, RJ (reprint author), NIDDK, NIH, Bldg 10 CRC,Room 6-5942,10 Ctr Dr, Bethesda, MD 20892 USA. EM brownrebecca@niddk.nih.gov OI Sorkina, Ekaterina/0000-0001-7006-0664 FU Pediatric Endocrine Society from AstraZeneca; intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health [RO1-DK088114, RO1-DK105448, RO1-DK101941]; Sopha Fund for Lipodystrophy Research at the University of Michigan; Russian Science Foundation [14-35-00026] FX This practice guideline was sponsored and organized by the Pediatric Endocrine Society via au unrestricted education grant from AstraZeneca. Individual authors were supported by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health Grants RO1-DK088114, RO1-DK105448, and RO1-DK101941; the Sopha Fund for Lipodystrophy Research at the University of Michigan, and Grant 14-35-00026 of the Russian Science Foundation. NR 114 TC 1 Z9 1 U1 2 U2 2 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD DEC PY 2016 VL 101 IS 12 BP 4500 EP 4511 DI 10.1210/jc.2016-2466 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EG3NE UT WOS:000390951000002 PM 27710244 ER PT J AU Stewart, PM Biller, BMK Marelli, C Gunnarsson, C Ryan, MP Johannsson, G AF Stewart, Paul M. Biller, Beverly M. K. Marelli, Claudio Gunnarsson, Candace Ryan, Michael P. Johannsson, Gudmundur TI Exploring Inpatient Hospitalizations and Morbidity in Patients With Adrenal Insufficiency SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID GLUCOCORTICOID REPLACEMENT THERAPY; ADDISONS-DISEASE; PREMATURE MORTALITY; INCREASING PREVALENCE; COHORT; HYPOPITUITARISM; POPULATION; CORTISOL; CRISIS; RISK AB Context: Patients with adrenal insufficiency (AI) (primary AI [PAI], secondary AI due to a pituitary disorder [PIT] and congenital adrenal hyperplasia [CAH]) have reduced life expectancy; however, the underlying explanation remains unknown. Objective: To evaluate characteristics, comorbidities, and hospitalizations in AI patients. Design: Retrospective observational. Setting and Population: Using a United States-based national payer database comprising of more than 108 million members, strict inclusion criteria including diagnostic codes and steroid prescription records were used to identify 10 383 adults with AI; 1014 with PAI, 8818 with PIT, and 551 with CAH. Patients were matched 1: 1 to controls, based on age (+/- 5 y), gender, insurance, and region and followed for more than 12 months. Intervention: None. Main Outcome Measures: Demographic variables, comorbidities (diabetes mellitus [DM] types 1 and 2, depression, anxiety, hyperlipidemia, hypertension) and hospitalization incidence. Results: Compared with controls, patients with AI had higher odds of DM, hypertension, hyperlipidaemia, depression, and anxiety, ranging from an odds ratio (OR) of 1.51 for hyperlipidaemia in PAI to 3.85 for DM in CAH. Odds of having DM (OR, 3.85; 95% confidence interval, 2.52-5.90) or anxiety (OR, 2.99; 95% confidence interval, 2.02-4.42) compared with controls were highest in CAH, whereas depression was highest in PAI and PIT (OR, 2.40 and 2.55). ORs of hyperlipidaemia and hypertension (OR, 1.98 and 2.24) were highest in the PIT cohort. Inpatient admissions were more frequent in PAI (4.64: 1; P <.0001) and PIT (4.00: 1; P <.0001) than controls; infection was the most common cause for admission. Conclusion: Patients with AI carry a significant metabolic and psychiatric burden, with higher risk of comorbidities and hospital admissions than matched controls. C1 [Stewart, Paul M.] Univ Leeds, Sch Med, Leeds LS2 9NL, W Yorkshire, England. [Biller, Beverly M. K.] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA USA. [Marelli, Claudio] Shire, CH-6300 Zug, Switzerland. [Gunnarsson, Candace; Ryan, Michael P.] CTI Clinical Trial & Consulting Serv Inc, Cincinnati, OH 45212 USA. [Johannsson, Gudmundur] Univ Goteborg, Sahlgrenska Acad, Inst Med, Dept Internal Med & Clin Nutr, SE-41345 Gothenburg, Sweden. [Johannsson, Gudmundur] Sahlgrens Univ Hosp, Dept Endocrinol, SE-41345 Gothenburg, Sweden. RP Stewart, PM (reprint author), Univ Leeds, Med, Room 7-08,Worsley Bldg,Clarendon Way, Leeds LS2 9NL, W Yorkshire, England. EM p.m.stewart@leeds.ac.uk FU Shire FX This work was supported by Shire. NR 43 TC 0 Z9 0 U1 5 U2 5 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD DEC PY 2016 VL 101 IS 12 BP 4843 EP 4850 DI 10.1210/jc.2016-2221 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EG3NE UT WOS:000390951000038 PM 27623069 ER PT J AU Admon, L Haefner, JK Kolenic, GE Chang, T Davis, MM Moniz, MH AF Admon, Lindsay Haefner, Jessica K. Kolenic, Giselle E. Chang, Tammy Davis, Matthew M. Moniz, Michelle H. TI Recruiting Pregnant Patients for Survey Research: A Head to Head Comparison of Social Media-Based Versus Clinic-Based Approaches SO JOURNAL OF MEDICAL INTERNET RESEARCH LA English DT Article DE pregnant women; surveys and questionnaires; methods; social media ID HEALTH RESEARCH; FACEBOOK; WOMEN; SITE AB Background: Recruiting a diverse sample of pregnant women for clinical research is a challenging but crucial task for improving obstetric services and maternal and child health outcomes. Objective: To compare the feasibility and cost of recruiting pregnant women for survey research using social media-based and clinic-based approaches. Methods: Advertisements were used to recruit pregnant women from the social media website Facebook. In-person methods were used to recruit pregnant women from the outpatient clinic of a large, tertiary care center. In both approaches, potential respondents were invited to participate in a 15-minute Web-based survey. Each recruitment method was monitored for 1 month. Using bivariate statistics, we compared the number, demographic characteristics, and health characteristics of women recruited and the cost per completed survey for each recruitment method. Results: The social media-based approach recruited 1178 women and the clinic-based approach recruited 219 women. A higher proportion of subjects recruited through social media identified as African American (29.4%, 207/705 vs 11.2%, 20/179), reported household incomes 10,000 patients) may allow the identification of common genes contributing to risk, and whole exome or genome sequencing may enable the identification of genetic risk and causal mutations in cohorts and well-characterized families. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Hopfner, Franziska; Kuhlenbaeumer, Gregor; Deuschl, Guenther] Univ Hosp Schleswig Holstein, Dept Neurol, Kiel, Germany. [Haubenberger, Dietrich; Galpern, Wendy R.; Gwinn, Katrina; Van't Veer, Ashlee; White, Samantha; Hallett, Mark] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Bhatia, Kailash] UCL, Inst Neurol, Sobell Dept Motor Neurosci & Movement Disorders, London WC1E 6BT, England. [Adler, Charles H.] Mayo Clin, Coll Med, Scottsdale, AZ USA. [Eidelberg, David] Feinstein Inst Med Res, Manhasset, NY USA. [Ondo, William] Methodist Neurol Inst, Houston, TX USA. [Stebbins, Glenn T.] Rush Univ, Dept Neurol Sci, Med Ctr, Chicago, IL 60612 USA. [Tanner, Caroline M.] Univ Calif San Francisco, Parkinsons Dis Res Educ & Clin Ctr, San Francisco Vet Affairs Med Ctr, San Francisco, CA 94143 USA. [Tanner, Caroline M.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Helmich, Rick C.] Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Dept Neurol, Nijmegen, Netherlands. [Lenz, Fred A.] Johns Hopkins Univ, Sch Med, Dept Neurosurg, Hopkins Hosp, Baltimore, MD 21205 USA. [Sillitoe, Roy V.] Baylor Coll Med, Dept Pathol & Immunol, Dept Neurosci, Program Dev Biol, Houston, TX 77030 USA. [Vaillancourt, David] Univ Florida, Dept Biomed Engn, Ctr Movement Disorders & Neurorestorat, Dept Appl Physiol & Kinesiol, Gainesville, FL USA. [Vitek, Jerrold L.] Univ Minnesota, Sch Med, Dept Neurol, Minneapolis, MN 55455 USA. [Louis, Elan D.] Yale Univ, Dept Neurol, Dept Chron Dis Epidemiol, Ctr Neuroepidemiol & Clin Neurol Res,Yale Sch Med, New Haven, CT USA. [Shill, Holly A.] Barrow Neurol Inst, Dept Neurol, Phoenix, AZ 85013 USA. [Frosch, Matthew P.] Massachusetts Gen Hosp, CS Kubik Lab Neuropathol, Boston, MA 02114 USA. [Foroud, Tatiana] Indiana Univ Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46202 USA. [Singleton, Andrew] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Testa, Claudia M.] Virginia Commonwealth Univ, Parkinsons & Movement Disorders Ctr, Richmond, VA USA. [Testa, Claudia M.] Virginia Commonwealth Univ, Dept Neurol, Richmond, VA USA. [Elble, Rodger] Southern Illinois Univ, Sch Med, Dept Neurol, Springfield, IL USA. RP Haubenberger, D (reprint author), NINDS, Intramural Res Program, NIH, 9000 Rockville Pike,Bldg 10,Rm 6-5700, Bethesda, MD 20892 USA. EM dietrich.haubenberger@nih.gov RI Helmich, Rick/R-6333-2016; OI Helmich, Rick/0000-0003-4035-6573; Gwinn, Katrina/0000-0002-8277-651X FU National Institute of Neurological Disorders and Stroke FX National Institute of Neurological Disorders and Stroke NR 91 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8020 EI 1873-5126 J9 PARKINSONISM RELAT D JI Parkinsonism Relat. Disord. PD DEC PY 2016 VL 33 BP 27 EP 35 DI 10.1016/j.parkreldis.2016.10.002 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA EG0SR UT WOS:000390743000004 PM 27769649 ER PT J AU Wills, AMA Elm, JJ Ye, R Chou, KL Parashos, SA Hauser, RA Bodis-Wollner, I Hinson, VK Christine, CW Schneider, JS AF Wills, Anne-Marie A. Elm, Jordan J. Ye, Rong Chou, Kelvin L. Parashos, Sotirios A. Hauser, Robert A. Bodis-Wollner, Ivan Hinson, Vanessa K. Christine, Chadwick W. Schneider, Jay S. CA NINDS NET-PD Investigators TI Cognitive function in 1736 participants in NINDS Exploratory Trials in PD Long-term Study-1 SO PARKINSONISM & RELATED DISORDERS LA English DT Article DE Cognitive impairment; Parkinson's disease; SCOPA-COG; SDMT; MCI ID PARKINSONS-DISEASE PATIENTS; QUALITY-OF-LIFE; CLINICAL-TRIAL; SCOPA-COG; IMPAIRMENT; PREDICTORS; DEMENTIA; COHORT; DIAGNOSIS; EDUCATION AB Introduction: Clinical cohort studies suggest that mild cognitive impairment (MCI) is common in early Parkinson's disease (PD). The objectives of this paper were to describe cognitive function in a large clinical trial of early treated PD patients at baseline and over time using two brief cognitive screening tests. Methods: In total 1741 participants were enrolled in the NINDS Exploratory Trials in Parkinson's disease (NET-PD) Long-term Study-1 (LS-1). The Symbol Digit Modalities Test (SDMT) was collected annually. The SCales for Outcomes in PArkinson's disease-COGnition (SCOPA-COG) was collected at baseline and at year 5. The trial was stopped early based on a planned interim analysis after half the cohort completed 5 years of follow-up. The median length of follow-up was 4 years (range 3-6 years). Predictors of cognitive change were examined using cross sectional (baseline) and longitudinal multivariable linear regression. Results: The mean (SD) change from baseline to 5 years was -1.9 (5.1) for the SCOPA-COG and 2.1 (11.1) for the SDMT. Age and baseline UPDRS motor scores were associated with a more rapid decline in SDMT scores and 5 year SCOPA-COG scores. Male gender was associated with more rapid decline in SDMT. Self reported income was a novel predictor of baseline cognitive function, even adjusted for educational status, although not significantly associated with change over time. Conclusion: This large prospective cohort study demonstrated mild cognitive decline in early treated Parkinson's disease. The study identified income level as a novel predictor of cognitive function. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Wills, Anne-Marie A.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Boston, MA USA. [Elm, Jordan J.] Med Univ South Carolina, Div Biostat & Epidemiol, Charleston, SC 29425 USA. [Ye, Rong] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA. [Chou, Kelvin L.] Univ Michigan, Dept Neurol, Ann Arbor, MI USA. [Chou, Kelvin L.] Univ Michigan, Dept Neurosurg, Ann Arbor, MI 48109 USA. [Parashos, Sotirios A.] Struthers Parkinsons Ctr, Golden, MN USA. [Hauser, Robert A.] Univ S Florida, Dept Neurol, USF Hlth Byrd Parkinsons Dis & Movement Disorders, Tampa, FL 33620 USA. [Hauser, Robert A.] Univ S Florida, Dept Mol Pharmacol & Physiol, USF Hlth Byrd Parkinsons Dis & Movement Disorders, Tampa, FL USA. [Bodis-Wollner, Ivan] Suny Downstate Med Ctr, Dept Neurol, Brooklyn, NY 11203 USA. [Bodis-Wollner, Ivan] Suny Downstate Med Ctr, Dept Ophthalmol, Brooklyn, NY 11203 USA. [Hinson, Vanessa K.] Med Univ South Carolina, Dept Neurol, Charleston, SC 29425 USA. [Christine, Chadwick W.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Schneider, Jay S.] Thomas Jefferson Univ, Dept Pathol Anat & Cell Biol, Philadelphia, PA 19107 USA. RP Wills, AMA (reprint author), Massachusetts Gen Hosp, Dept Neurol, Wang ACC Rm 715,55 Fruit St, Boston, MA 02114 USA. EM awills@partners.org FU National Institute of Neurologic Disorders and Stroke [U01NS043127, U01NS043128, U10NS44415-44555] FX The NET-PD LS-1 Trial Investigators were supported, in part, by grants U01NS043127, U01NS043128, and U10NS44415-44555 from the National Institute of Neurologic Disorders and Stroke. NR 38 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8020 EI 1873-5126 J9 PARKINSONISM RELAT D JI Parkinsonism Relat. Disord. PD DEC PY 2016 VL 33 BP 127 EP 133 DI 10.1016/j.parkreldis.2016.10.005 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA EG0SR UT WOS:000390743000019 PM 27743701 ER PT J AU Lunsford, C Grindle, G Salatin, B Dicianno, BE AF Lunsford, Christopher Grindle, Garrett Salatin, Benjamin Dicianno, Brad E. TI Innovations With 3-Dimensional Printing in Physical Medicine and Rehabilitation: A Review of the Literature SO PM&R LA English DT Review ID FOOT ORTHOSES; MASS CUSTOMIZATION; PROSTHETIC SOCKETS; DESIGN; MANUFACTURE; TECHNOLOGY; VALIDATION; SCAFFOLDS; STIFFNESS; ACCURACY AB Created more than 30 years ago, 3-dimensional printing (3DP) has recently seen a meteoric rise in interest within medicine, and the field of Physical Medicine and Rehabilitation is no exception. Also called additive manufacturing (AM), the recent increase in the use of 3DP is likely due to lower-cost printers as well as breakthroughs in techniques and processing. This thematic narrative review serves to introduce the rehabilitation professional to 3DP technology and how it is being applied to orthoses, prostheses, and assistive technology (AT). The basics of the technology, as well as the benefits and challenges of using it within the rehabilitation framework, are described. Proponents of the technology suggest that 3DP offers not only a better way to make devices, but a better way to make improved devices. However, the strength of this claim has not been properly tested by the current literature. This narrative review evaluates the evidence and provides a discussion of possible implications for the rehabilitation professional. C1 [Lunsford, Christopher; Grindle, Garrett; Dicianno, Brad E.] Univ Pittsburgh, Sch Med, Dept Phys Med & Rehabil, Div Pediat Rehabil Med, 6425 Penn Ave,Suite 400,Off 4115, Pittsburgh, PA 15206 USA. [Grindle, Garrett; Dicianno, Brad E.] VA Pittsburgh Healthcare Syst, Human Engn Res Labs, Pittsburgh, PA USA. [Salatin, Benjamin] McGuire Vet Hosp, Dept Phys Med & Rehabil, Assist Technol Program, Richmond, VA USA. RP Dicianno, BE (reprint author), Univ Pittsburgh, Sch Med, Dept Phys Med & Rehabil, Div Pediat Rehabil Med, 6425 Penn Ave,Suite 400,Off 4115, Pittsburgh, PA 15206 USA.; Dicianno, BE (reprint author), VA Pittsburgh Healthcare Syst, Human Engn Res Labs, Pittsburgh, PA USA. EM dicianno@pitt.edu OI Dicianno, Brad/0000-0003-0738-0192 NR 56 TC 0 Z9 0 U1 11 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1934-1482 EI 1934-1563 J9 PM&R JI PM&R PD DEC PY 2016 VL 8 IS 12 BP 1201 EP 1212 DI 10.1016/j.pmrj.2016.07.003 PG 12 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA EG5LS UT WOS:000391085900009 PM 27424769 ER PT J AU Homma, S Beermann, ML Yu, B Boyce, FM Miller, JB AF Homma, Sachiko Beermann, Mary Lou Yu, Bryant Boyce, Frederick M. Miller, Jeffrey Boone TI Nuclear bodies reorganize during myogenesis in vitro and are differentially disrupted by expression of FSHD-associated DUX4 SO SKELETAL MUSCLE LA English DT Article DE DUX4; FUS; Facioscapulohumeral muscular dystrophy; Myotube; Nucleoli; PML bodies; SC35 speckles; TDP-43 ID FACIOSCAPULOHUMERAL MUSCULAR-DYSTROPHY; AMYOTROPHIC-LATERAL-SCLEROSIS; SKELETAL-MUSCLE; CELL-DEATH; DISEASE; PROTEIN; TDP-43; GENE; NEURODEGENERATION; PATHOGENESIS AB Background: Nuclear bodies, such as nucleoli, PML bodies, and SC35 speckles, are dynamic sub-nuclear structures that regulate multiple genetic and epigenetic processes. Additional regulation is provided by RNA/DNA handling proteins, notably TDP-43 and FUS, which have been linked to ALS pathology. Previous work showed that mouse cell line myotubes have fewer but larger nucleoli than myoblasts, and we had found that nuclear aggregation of TDP-43 in human myotubes was induced by expression of DUX4-FL, a transcription factor that is aberrantly expressed and causes pathology in facioscapulohumeral dystrophy (FSHD). However, questions remained about nuclear bodies in human myogenesis and in muscle disease. Methods: We examined nucleoli, PML bodies, SC35 speckles, TDP-43, and FUS in myoblasts and myotubes derived from healthy donors and from patients with FSHD, laminin-alpha-2-deficiency (MDC1A), and alpha-sarcoglycan-deficiency (LGMD2D). We further examined how these nuclear bodies and proteins were affected by DUX4-FL expression. Results: We found that nucleoli, PML bodies, and SC35 speckles reorganized during differentiation in vitro, with all three becoming less abundant in myotube vs. myoblast nuclei. In addition, though PML bodies did not change in size, both nucleoli and SC35 speckles were larger in myotube than myoblast nuclei. Similar patterns of nuclear body reorganization occurred in healthy control, MDC1A, and LGMD2D cultures, as well as in the large fraction of nuclei that did not show DUX4-FL expression in FSHD cultures. In contrast, nuclei that expressed endogenous or exogenous DUX4-FL, though retaining normal nucleoli, showed disrupted morphology of some PML bodies and most SC35 speckles and also co-aggregation of FUS with TDP-43. Conclusions: Nucleoli, PML bodies, and SC35 speckles reorganize during human myotube formation in vitro. These nuclear body reorganizations are likely needed to carry out the distinct gene transcription and splicing patterns that are induced upon myotube formation. DUX4-FL-induced disruption of some PML bodies and most SC35 speckles, along with co-aggregation of TDP-43 and FUS, could contribute to pathogenesis in FSHD, perhaps by locally interfering with genetic and epigenetic regulation of gene expression in the small subset of nuclei that express high levels of DUX4-FL at any one time. C1 [Homma, Sachiko; Beermann, Mary Lou; Yu, Bryant; Miller, Jeffrey Boone] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Boyce, Frederick M.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Miller, Jeffrey Boone] Boston Univ, Sch Med, Dept Neurol, Neuromuscular Biol & Dis Grp, 700 Albany St, Boston, MA 02118 USA. RP Miller, JB (reprint author), Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA.; Miller, JB (reprint author), Boston Univ, Sch Med, Dept Neurol, Neuromuscular Biol & Dis Grp, 700 Albany St, Boston, MA 02118 USA. EM millerjb@bu.edu FU NIH [R01AR060328, R01AR062587]; Muscular Dystrophy Association [216422]; Association Francaise contre les Myopathies [18248]; FSH Society; Undergraduate Research Opportunity Program at Boston University; Boston University Clinical and Translational Science Institute - National Center for Advancing Translational Sciences at the NIH [1UL1TR001430]; German Ministry of Education and Research (BMBF, Bonn, Germany) [01GM0601] FX This work was supported by grants from the NIH (R01AR060328 to J.B.M. and R01AR062587 to Peter L. Jones with a subcontract to J.B.M.); the Muscular Dystrophy Association (#216422 to J.B.M.); the Association Francaise contre les Myopathies (#18248 to J.B.M.); the FSH Society (to S.H.); the Undergraduate Research Opportunity Program at Boston University (to B.Y.); and funding for imaging from the Boston University Clinical and Translational Science Institute which is supported by the National Center for Advancing Translational Sciences at the NIH (1UL1TR001430). The Muscle Tissue Culture Collection (MTCC) at the University of Munich is part of the German network on muscular dystrophies (MD-NET, service structure S1, 01GM0601) funded by the German Ministry of Education and Research (BMBF, Bonn, Germany). MTCC is a partner of Eurobiobank (www.eurobiobank.org) and TREAT-NMD (www.treat-nmd.eu). Funders had no role in design or implementation of the study. NR 63 TC 0 Z9 0 U1 4 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2044-5040 J9 SKELET MUSCLE JI Skeletal Muscle PD DEC 1 PY 2016 VL 6 AR 42 DI 10.1186/s13395-016-0113-7 PG 16 WC Cell Biology SC Cell Biology GA EG9TT UT WOS:000391403100001 PM 27906075 ER PT J AU Wang, F Lee, OEK Feng, F Vitiello, MV Wang, WD Benson, H Fricchione, GL Denninger, JW AF Wang, Fang Lee, Othelia Eun-Kyoung Feng, Fan Vitiello, Michael V. Wang, Weidong Benson, Herbert Fricchione, Gregory L. Denninger, John W. TI The effect of meditative movement on sleep quality: A systematic review SO SLEEP MEDICINE REVIEWS LA English DT Review DE Meditative movement; Sleep quality; Systematic review ID RANDOMIZED CONTROLLED-TRIAL; TAI-CHI EXERCISE; OLDER-ADULTS; CANCER SURVIVORS; OF-LIFE; YOGA; INSOMNIA; FIBROMYALGIA; SYMPTOMS; WOMEN AB The purpose of this systematic review was to identify and assess evidence related to the efficacy of meditative movement (MM) on sleep quality: We conducted a comprehensive review of relevant studies drawn from English and Chinese databases. Only randomized controlled trials (RCTs) reporting outcomes of the effects of MM (tai chi, qi gong, and yoga) on sleep quality were taken into consideration. Twenty-seven RCTs fulfilled our inclusion criteria and formed the basis for this review. Due to clinical heterogeneity, no meta-analysis was performed. Seventeen studies received a Jadad score of >= 3 and were considered high-quality studies. Findings of the 17 studies showed that MM has beneficial effects for various populations on a range of sleep measures. Improvement in sleep quality was reported in the majority of studies and was often accompanied by improvements in quality of life, physical performance, and depression. However, studies to date generally have significant methodological limitations. Additional RCTs with rigorous research designs focusing on sleep quality or insomnia and testing specific hypotheses are needed to clearly establish the efficacy of MM in improving sleep quality and its potential use as an intervention for various populations. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Wang, Fang; Feng, Fan; Wang, Weidong] China Acad Chinese Med Sci, Guangan Men Hosp, Dept Psychol, Beijing, Peoples R China. [Lee, Othelia Eun-Kyoung] Univ N Carolina, Sch Social Work, Charlotte, NC 28223 USA. [Vitiello, Michael V.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Benson, Herbert; Fricchione, Gregory L.; Denninger, John W.] Massachusetts Gen Hosp, Benson Henry Inst Mind Body Med, Boston, MA USA. RP Wang, WD (reprint author), China Acad Chinese Med Sci, Guangan Men Hosp, Dept Psychol, Beijing, Peoples R China. EM prof_ww2005@hotmail.com OI Wang, Weidong/0000-0003-4712-3692 FU China Academy of Chinese Medical Sciences [ZZ0708078] FX Research was funded by the following project: Exploration Project of China Academy of Chinese Medical Sciences (grant number ZZ0708078 grant name Clinical Observation on the Effect of Traditional Chinese Medicine Psychotherapy to Insomnia with Estazolam). NR 42 TC 3 Z9 3 U1 12 U2 12 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 1087-0792 EI 1532-2955 J9 SLEEP MED REV JI Sleep Med. Rev. PD DEC PY 2016 VL 30 BP 43 EP 52 DI 10.1016/j.smrv.2015.12.001 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EG3TV UT WOS:000390968500005 PM 26802824 ER PT J AU Sepucha, KR Breslin, M Graffeo, C Carpenter, CR Hess, EP AF Sepucha, Karen R. Breslin, Maggie Graffeo, Charles Carpenter, Christopher R. Hess, Erik P. TI State of the Science: Tools and Measurement for Shared Decision Making SO ACADEMIC EMERGENCY MEDICINE LA English DT Article; Proceedings Paper CT Academic Emergency Medicine Consensus Conference on Shared Decision Making in the Emergency Department - Development of a Policy-Relevant Patient-Centered Research Agenda CY MAY 10, 2016 CL New Orleans, LA ID EMERGENCY-DEPARTMENT; RANDOMIZED-TRIAL; PATIENT AUTONOMY; HEALTH LITERACY; CARE; AID; RESUSCITATION; PARTICIPATION; INSTRUMENTS; IMPROVEMENT AB Shared decision making (SDM) has been advocated as an approach to selecting medical tests and treatments for many situations. The goal of SDM is to ensure that patients are well informed, are meaningfully involved in decisions, and receive treatments that meet their goals and preferences. There is considerable evidence about the tools used to promote SDM, called patient decision aids, and many different measures have been developed to assess the impact of SDM. However, fairly little is known about the applicability of the tools and measures in the emergency department (ED) setting. This article builds on insights from two keynote lectures presented at the 2016 Academic Emergency Medicine Consensus Conference discussing the state of the science for measurement of SDM and the design of patient decision aids to promote SDM conversations and highlights some key areas for further research to advance SDM in the ED. (C) 2016 by the Society for Academic Emergency Medicine C1 [Sepucha, Karen R.] Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. [Breslin, Maggie; Hess, Erik P.] Mayo Clin, Knowledge & Evaluat Res Unit, Rochester, MN 55905 USA. [Breslin, Maggie] Sch Visual Arts, New York, NY 10010 USA. [Graffeo, Charles] Eastern Virginia Med Sch, Dept Emergency Med, Norfolk, VA 23501 USA. [Carpenter, Christopher R.] Washington Univ, Sch Med, Div Emergency Med, St Louis, MO USA. [Hess, Erik P.] Mayo Clin, Dept Emergency Med, Div Emergency Med Res, Rochester, MN 55905 USA. [Hess, Erik P.] Mayo Clin, Dept Hlth Sci Res, Div Healthcare Policy & Res, Rochester, MN 55905 USA. RP Hess, EP (reprint author), Mayo Clin, Knowledge & Evaluat Res Unit, Rochester, MN 55905 USA.; Hess, EP (reprint author), Mayo Clin, Dept Emergency Med, Div Emergency Med Res, Rochester, MN 55905 USA.; Hess, EP (reprint author), Mayo Clin, Dept Hlth Sci Res, Div Healthcare Policy & Res, Rochester, MN 55905 USA. EM hess.erik@mayo.edu NR 37 TC 0 Z9 0 U1 7 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1069-6563 EI 1553-2712 J9 ACAD EMERG MED JI Acad. Emerg. Med. PD DEC PY 2016 VL 23 IS 12 BP 1325 EP 1331 DI 10.1111/acem.13071 PG 7 WC Emergency Medicine SC Emergency Medicine GA EF8ES UT WOS:000390562300003 PM 27770488 ER PT J AU Barrett, TW Rising, KL Bellolio, MF Hall, MK Brody, A Dodd, KW Grieser, M Levy, PD Raja, AS Self, WH Weingarten, G Hess, EP Hollander, JE AF Barrett, Tyler W. Rising, Kristin L. Bellolio, M. Fernanda Hall, M. Kennedy Brody, Aaron Dodd, Kenneth W. Grieser, Mira Levy, Phillip D. Raja, Ali S. Self, Wesley H. Weingarten, Gail Hess, Erik P. Hollander, Judd E. TI The 2016 Academic Emergency Medicine Consensus Conference, "Shared Decision Making in the Emergency Department: Development of a Policy-relevant Patient-centered Research Agenda" Diagnostic Testing Breakout Session Report SO ACADEMIC EMERGENCY MEDICINE LA English DT Article; Proceedings Paper CT Academic Emergency Medicine Consensus Conference on Shared Decision Making in the Emergency Department - Development of a Policy-Relevant Patient-Centered Research Agenda CY MAY 10, 2016 CL New Orleans, LA ID ROUTINE CLINICAL-PRACTICE; HEALTH LITERACY; PULMONARY-EMBOLISM; COMPUTED-TOMOGRAPHY; RHEUMATOID-ARTHRITIS; RANDOMIZED-TRIAL; HEAD TRAUMA; ENCOUNTER; CHOICE; AIDS AB Diagnostic testing is an integral component of patient evaluation in the emergency department (ED). Emergency clinicians frequently use diagnostic testing to more confidently exclude worst-case diagnoses rather than to determine the most likely etiology for a presenting complaint. Increased utilization of diagnostic testing has not been associated with reductions in disease-related mortality but has led to increased overall healthcare costs and other unintended consequences (e.g., incidental findings requiring further workup, unnecessary exposure to ionizing radiation or potentially nephrotoxic contrast). Shared decision making (SDM) presents an opportunity for clinicians to discuss the benefits and harms associated with diagnostic testing with patients to more closely tailor testing to patient risk. This article introduces the challenges and opportunities associated with incorporating SDM into emergency care by summarizing the conclusions of the diagnostic testing group at the 2016 Academic Emergency Medicine Consensus Conference on SDM. Three primary domains emerged: 1) characteristics of a condition or test appropriate for SDM, 2) critical elements of and potential barriers to SDM discussions on diagnostic testing, and 3) financial aspects of SDM applied to diagnostic testing. The most critical research questions to improve engagement of patients in their acute care diagnostic decisions were determined by consensus. (C) 2016 by the Society for Academic Emergency Medicine C1 [Barrett, Tyler W.; Self, Wesley H.] Vanderbilt Univ, Med Ctr, Dept Emergency Med, Nashville, TN 37232 USA. [Rising, Kristin L.; Hollander, Judd E.] Thomas Jefferson Univ Hosp, Dept Emergency Med, Philadelphia, PA 19107 USA. [Bellolio, M. Fernanda; Hess, Erik P.] Mayo Clin, Dept Emergency Med, Rochester, MN USA. [Hall, M. Kennedy] Univ Washington, Div Emergency Med, Seattle, WA 98195 USA. [Brody, Aaron; Levy, Phillip D.] Wayne State Univ, Dept Emergency Med, Detroit, MI USA. [Dodd, Kenneth W.] Hennepin Cty Med Ctr, Dept Emergency Med, Minneapolis, MN 55415 USA. [Grieser, Mira] Patient Ctr Outcomes Res Inst, Addressing Dispar, Washington, DC USA. [Raja, Ali S.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Raja, Ali S.] Harvard Med Sch, Boston, MA USA. RP Barrett, TW (reprint author), Vanderbilt Univ, Med Ctr, Dept Emergency Med, Nashville, TN 37232 USA. EM tyler.barrett@vanderbilt.edu FU NHLBI NIH HHS [R01 HL127215]; NIDDK NIH HHS [P01 DK043881]; NIGMS NIH HHS [K23 GM110469]; NIMHD NIH HHS [R01 MD005849] NR 53 TC 0 Z9 0 U1 6 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1069-6563 EI 1553-2712 J9 ACAD EMERG MED JI Acad. Emerg. Med. PD DEC PY 2016 VL 23 IS 12 BP 1354 EP 1361 DI 10.1111/acem.13050 PG 8 WC Emergency Medicine SC Emergency Medicine GA EF8ES UT WOS:000390562300008 PM 27404959 ER PT J AU Castaneda-Guarderas, A Glassberg, J Grudzen, CR Ngai, KM Samuels-Kalow, ME Shelton, E Wall, SP Richardson, LD AF Castaneda-Guarderas, Ana Glassberg, Jeffrey Grudzen, Corita R. Ngai, Ka Ming Samuels-Kalow, Margaret E. Shelton, Erica Wall, Stephen P. Richardson, Lynne D. TI Shared Decision Making With Vulnerable Populations in the Emergency Department SO ACADEMIC EMERGENCY MEDICINE LA English DT Article; Proceedings Paper CT Academic Emergency Medicine Consensus Conference on Shared Decision Making in the Emergency Department - Development of a Policy-Relevant Patient-Centered Research Agenda CY MAY 10, 2016 CL New Orleans, LA ID SICKLE-CELL-DISEASE; HEALTH-CARE; MANAGEMENT DECISIONS; TRANSGENDER PERSONS; SAFETY NET; DISPARITIES; RACE; HOMELESS; EXPERIENCES; PHYSICIANS AB The emergency department (ED) occupies a unique position within the healthcare system, serving as a safety net for vulnerable patients, regardless of their race, ethnicity, religion, country of origin, sexual orientation, socioeconomic status, or medical diagnosis. Shared decision making (SDM) presents special challenges when used with vulnerable population groups. The differing circumstances, needs, and perspectives of vulnerable groups invoke issues of provider bias, disrespect, judgmental attitudes, andlack of cultural competence, as well as patient mistrust and the consequences of their social and economic disenfranchisement. A research agenda that includes community-engaged approaches, mixed-methods studies, and cost-effectiveness analyses is proposed to address the following questions: 1) What are the best processes/formats for SDM among racial, ethnic, cultural, religious, linguistic, social, or otherwise vulnerable groups who experience disadvantage in the healthcare system? 2) What organizational or systemic changes are needed to support SDM in the ED whenever appropriate? 3) What competencies are needed to enable emergency providers to consider patients' situation/context in an unbiased way? 4) How do we teach these competencies to students and residents? 5) How do we cultivate these competencies in practicing emergency physicians, nurses, and other clinical providers who lack them? The authors also identify the importance of using accurate, group-specific data to inform risk estimates for SDM decision aids for vulnerable populations and the need for increased ED-based care coordination and transitional care management capabilities to create additional care options that align with the needs and preferences of vulnerable populations. (C) 2016 by the Society for Academic Emergency Medicine C1 [Castaneda-Guarderas, Ana] Aventura Hosp & Med Ctr, Dept Emergency Med, Miami, FL USA. [Castaneda-Guarderas, Ana] Mayo Clin, Dept Emergency Med, Rochester, MN USA. [Castaneda-Guarderas, Ana] Mayo Clin, Knowledge & Evaluat Res Unit, Rochester, MN USA. [Glassberg, Jeffrey; Ngai, Ka Ming; Richardson, Lynne D.] Icahn Sch Med Mt Sinai, Dept Emergency Med, New York, NY 10029 USA. [Glassberg, Jeffrey; Richardson, Lynne D.] Icahn Sch Med Mt Sinai, Ctr Hlth Equ & Community Engaged Res, Dept Populat Hlth Sci & Policy, New York, NY 10029 USA. [Glassberg, Jeffrey] Icahn Sch Med Mt Sinai, Dept Med, Div Hematol & Med Oncol, New York, NY 10029 USA. [Richardson, Lynne D.] Icahn Sch Med Mt Sinai, Dept Populat Hlth Sci & Policy, New York, NY 10029 USA. [Grudzen, Corita R.; Wall, Stephen P.] NYU, Dept Emergency Med, New York, NY USA. [Grudzen, Corita R.; Wall, Stephen P.] NYU, Dept Populat Hlth, New York, NY USA. [Samuels-Kalow, Margaret E.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Shelton, Erica] Johns Hopkins Univ, Dept Emergency Med, Baltimore, MD USA. [Wall, Stephen P.] Bellevue Hosp Ctr, New York, NY 10016 USA. RP Richardson, LD (reprint author), Icahn Sch Med Mt Sinai, Dept Emergency Med, New York, NY 10029 USA.; Richardson, LD (reprint author), Icahn Sch Med Mt Sinai, Ctr Hlth Equ & Community Engaged Res, Dept Populat Hlth Sci & Policy, New York, NY 10029 USA.; Richardson, LD (reprint author), Icahn Sch Med Mt Sinai, Dept Populat Hlth Sci & Policy, New York, NY 10029 USA. EM lynne.richardson@mountsinai.org OI Wall, Stephen/0000-0003-3965-5074; Grudzen, Corita/0000-0003-3039-8497 FU Agency for Healthcare Research and Quality AHRQ [1R13HS024172-01]; NIMHD NIH HHS [1R13MD010171-01] NR 63 TC 0 Z9 0 U1 10 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1069-6563 EI 1553-2712 J9 ACAD EMERG MED JI Acad. Emerg. Med. PD DEC PY 2016 VL 23 IS 12 BP 1410 EP 1416 DI 10.1111/acem.13134 PG 7 WC Emergency Medicine SC Emergency Medicine GA EF8ES UT WOS:000390562300015 PM 27860022 ER PT J AU Kuter, DJ AF Kuter, David J. TI What is the role of novel thrombopoietic agents in the management of acute leukemia? SO BEST PRACTICE & RESEARCH CLINICAL HAEMATOLOGY LA English DT Article DE Eltrombopag; Leukemia; rHuMGDF; Romiplostim; Thrombopoietin; Supportive care; TPO; MDS ID ACUTE MYELOID-LEUKEMIA; RECEPTOR AGONIST; DOUBLE-BLIND; MYELODYSPLASTIC SYNDROME; ELTROMBOPAG; THROMBOCYTOPENIA; ROMIPLOSTIM; PLACEBO; PROLIFERATION; CHEMOTHERAPY AB The role of novel thrombopoietic agents in the management of acute leukemia is a tale of two molecules, romiplostim and eltrombopag. Both are thrombopoietin (TPO) receptor agonists with somewhat different mechanisms of action. Romiplostim is a peptide TPO receptor agonist that activates the TPO receptor by binding to it just like TPO. Eltrombopag is a nonpeptide TPO receptor agonist that activates the TPO receptor by binding to the transmembrane domain. Both TPO receptor agonists increase platelet counts in healthy humans and in those with immune thrombocytopenia. This review focuses on the potential these agents may have in supportive care of patients with acute leukemia. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Kuter, David J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Kuter, David J.] Harvard Med Sch, Boston, MA 02114 USA. RP Kuter, DJ (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA.; Kuter, DJ (reprint author), Harvard Med Sch, Boston, MA 02114 USA. EM dkuter@mgh.harvard.edu FU BMS; Protalix; Rigel FX BMS, Protalix, Rigel. NR 22 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 1521-6926 EI 1532-1924 J9 BEST PRACT RES CL HA JI Best Pract. Res. Clin. Haematol. PD DEC PY 2016 VL 29 IS 4 BP 372 EP 378 DI 10.1016/j.beha.2016.10.013 PG 7 WC Hematology SC Hematology GA EF7IR UT WOS:000390503800011 PM 27890262 ER PT J AU Yu, JX East, JE Kaltenbach, T AF Yu, Jessica X. East, James E. Kaltenbach, Tonya TI Surveillance of patients with inflammatory bowel disease SO BEST PRACTICE & RESEARCH IN CLINICAL GASTROENTEROLOGY LA English DT Article DE Inflammatory bowel disease; Chromoendoscopy; Image-enhanced endoscopy; Colorectal cancer; Dysplasia; Colonoscopy; Surveillance; SCENIC ID INTERNATIONAL CONSENSUS STATEMENT; ENDOSCOPIC SUBMUCOSAL DISSECTION; PRIMARY SCLEROSING CHOLANGITIS; POPULATION-BASED COHORT; ULCERATIVE-COLITIS; COLONOSCOPIC SURVEILLANCE; COLORECTAL NEOPLASIA; DETECTING DYSPLASIA; TARGETED BIOPSIES; GRADE DYSPLASIA AB Patients with inflammatory bowel disease involving the colon are at increased risk for developing colorectal cancer. Colonoscopy surveillance is important to identify and treat IBD associated dysplasia. The SCENIC consensus provides evidence-based recommendations for optimal surveillance and management of dysplasia in IBD. Chromoendoscopy, with the surface application of dyes to enhance mucosal visualization, is the superior endoscopic surveillance strategy to detect dysplasia. Most dysplasia is visible, and can be endoscopically resected. Future studies should determine the effect of new surveillance strategies on the incidence of CRC and mortality in patients with IBD. Published by Elsevier Ltd. C1 [Yu, Jessica X.] Stanford Univ, Med Ctr, Div Gastroenterol & Hepatol, Stanford, CA 94305 USA. [East, James E.] Univ Oxford, John Radcliffe Hosp, Translat Gastroenterol Unit, Oxford, England. [Kaltenbach, Tonya] Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, 4150 Clement St VA111B,Bldg 203,2A-67, San Francisco, CA 94121 USA. RP Kaltenbach, T (reprint author), Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, 4150 Clement St VA111B,Bldg 203,2A-67, San Francisco, CA 94121 USA. EM endoresection@me.com NR 47 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 1521-6918 EI 1532-1916 J9 BEST PRACT RES CL GA JI Best Pract. Res. Clin. Gastroenterol. PD DEC PY 2016 VL 30 IS 6 BP 949 EP 958 DI 10.1016/j.bpg.2016.10.014 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EG1WY UT WOS:000390826100010 PM 27938789 ER PT J AU Mallen-St Clair, J Alani, M Wang, MB Srivatsan, ES AF Mallen-St Clair, Jon Alani, Mustafa Wang, Marilene B. Srivatsan, Eri S. TI Human papillomavirus in oropharyngeal cancer: The changing face of a disease SO BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER LA English DT Review DE Oropharyngeal squamous cell carcinoma (OPSCC); Human papillomavirus; Chemo-radiation therapy; Immune therapy; HPV vaccines; Check point inhibitors ID SQUAMOUS-CELL CARCINOMA; HPV-ASSOCIATED HEAD; MINOR CAPSID PROTEIN; NECK-CANCER; MOLECULAR-BIOLOGY; ADVANCED MELANOMA; HEPARAN-SULFATE; GENE-EXPRESSION; NEGATIVE HEAD; INFECTION AB The last decade has brought about an unexpected rise in oropharyngeal squamous cell carcinoma (OPSCC) primarily in white males from the ages of 40-55 years, with limited exposure to alcohol and tobacco. This subset of squamous cell carcinoma (SCC) has been found to be associated with human papillomavirus infection (HPV). Other Head and Neck Squamous Cell carcinoma (HNSCC) subtypes include oral cavity, hypopharyngeal, nasopharyngeal, and laryngeal SCC which tend to be HPV negative. HPV associated oropharyngeal cancer has proven to differ from alcohol and tobacco associated oropharyngeal carcinoma in regards to the molecular pathophysiology, presentation, epidemiology, prognosis, and improved response to chemoradiation therapy. Given the improved survival of patients with HPV associated SCC, efforts to de-intensify treatment to decrease treatment related morbidity are at the forefront of clinical research. This review will focus on the important differences between HPV and tobacco related oropharyngeal cancer. We will review the molecular pathogenesis of HPV related oropharyngeal cancer with an emphasis on new paradigms for screening and treating this disease. Published by Elsevier B.V. C1 [Mallen-St Clair, Jon; Wang, Marilene B.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Head & Neck Surg, Los Angeles, CA 90073 USA. [Alani, Mustafa] Univ Calif Los Angeles, Sch Dent, Los Angeles, CA 90073 USA. [Wang, Marilene B.; Srivatsan, Eri S.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. [Wang, Marilene B.; Srivatsan, Eri S.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90073 USA. RP Srivatsan, ES (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, VAGLAHS, Dept Surg, Los Angeles, CA 90073 USA. EM esrivats@g.ucla.edu FU VAGLAHS; West Los Angeles Surgical Education Research Center; UCLA Academic Senate grant; Veterans Administration, Washington, D.C. [1101BX000194-01] FX The study was supported by funds from VAGLAHS, West Los Angeles Surgical Education Research Center, UCLA Academic Senate grants (M. B. Wang), and Merit grant from the Veterans Administration, Washington, D.C. (1101BX000194-01) (E. S. Srivatsan). NR 94 TC 3 Z9 3 U1 7 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-419X EI 0006-3002 J9 BBA-REV CANCER JI Biochim. Biophys. Acta-Rev. Cancer PD DEC PY 2016 VL 1866 IS 2 BP 141 EP 150 DI 10.1016/j.bbcan.2016.07.005 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Oncology SC Biochemistry & Molecular Biology; Biophysics; Oncology GA EF9AU UT WOS:000390623900001 PM 27487173 ER PT J AU Ren, F Shen, J Shi, HR Hornicek, FJ Kan, QC Duan, ZF AF Ren, Fang Shen, Jacson Shi, Huirong Hornicek, Francis J. Kan, Quancheng Duan, Zhenfeng TI Novel mechanisms and approaches to overcome multidrug resistance in the treatment of ovarian cancer SO BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER LA English DT Review DE Ovarian cancer; Multidrug resistance (MDR); Cancer stem cells (CSCs); Non-coding RNA (ncRNA); Autophagy; Tumor heterogeneity (TH) ID LONG NONCODING RNA; CELL ADHESION MOLECULE; MODULATES CISPLATIN SENSITIVITY; TUMOR-INITIATING CELLS; STEM-CELLS; IN-VITRO; PACLITAXEL RESISTANCE; DRUG-RESISTANCE; P-GLYCOPROTEIN; ACQUIRED-RESISTANCE AB Ovarian cancer remains the leading cause of gynecological cancer-related mortality despite the advances in surgical techniques and chemotherapy drugs over the past three decades. Multidrug resistance (MDR) to chemotherapy is the major cause of treatment failure. Previous research has focused mainly on strategies to reverse MDR by targeting the MDR1 gene encoded P-glycoprotein (Pgp) with small molecular compound inhibitors. However, prior Pgp inhibitors have shown very limited clinical success because these agents have relatively low potency and high toxicity. Therefore, identification of more specific and potent new inhibitors would be useful. In addition, emerging evidence suggests that cancer stem cells (CSCs), deregulated non-coding RNA (ncRNA), autophagy, and tumor heterogeneity also contribute significantly to drug sensitivity/resistance in ovarian cancer. This review summarizes these novel mechanisms of MDR and evaluates several new concepts to overcome MDR in the treatment of ovarian cancer. These new strategies include overcoming MDR with more potent and specific Pgp inhibitors, targeting CSCs and ncRNA, modulating autophagy signaling pathway, and targeting tumor heterogeneity. (C) 2016 Elsevier B.V. All rights reserved. C1 [Ren, Fang; Shi, Huirong; Kan, Quancheng; Duan, Zhenfeng] Zhengzhou Univ, Affiliated Hosp 1, Dept Gynecol Oncol, 1 Jianshe East Rd, Zhengzhou 450052, Peoples R China. [Ren, Fang; Shen, Jacson; Hornicek, Francis J.; Duan, Zhenfeng] Massachusetts Gen Hosp, Dept Orthopaed Surg, Sarcoma Biol Lab, 55 Fruit St,Jackson 1115, Boston, MA 02114 USA. [Ren, Fang; Shen, Jacson; Hornicek, Francis J.; Duan, Zhenfeng] Harvard Med Sch, 55 Fruit St,Jackson 1115, Boston, MA 02114 USA. RP Kan, QC; Duan, ZF (reprint author), Zhengzhou Univ, Affiliated Hosp 1, Dept Gynecol Oncol, 1 Jianshe East Rd, Zhengzhou 450052, Peoples R China. EM qckan19632012@163.com; zduan@mgh.harvard.edu FU Joint Research Fund devoted to clinical pharmacy and precision medicine; National Natural Science Foundation of China [81402266, 81372875]; Gattegno fund; Wechsler fund; China Scholarship Council FX This work was supported by a Joint Research Fund devoted to clinical pharmacy and precision medicine (Z.D and Q.K). Support has also been provided by the National Natural Science Foundation of China (No.: 81402266 and 81372875), the Gattegno and Wechsler funds. Dr. Ren is supported by a scholarship from the China Scholarship Council. The authors thank Carol A. Trahan for assistance with editing the manuscript. NR 111 TC 1 Z9 1 U1 20 U2 20 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-419X EI 0006-3002 J9 BBA-REV CANCER JI Biochim. Biophys. Acta-Rev. Cancer PD DEC PY 2016 VL 1866 IS 2 BP 266 EP 275 DI 10.1016/j.bbcan.2016.10.001 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Oncology SC Biochemistry & Molecular Biology; Biophysics; Oncology GA EF9AU UT WOS:000390623900011 PM 27717733 ER PT J AU Erpenbeck, L Chowdhury, CS Zsengeller, ZK Gallant, M Burke, SD Cifuni, S Hahn, S Wagner, DD Karumanchi, SA AF Erpenbeck, Luise Chowdhury, Chanchal Sur Zsengeller, Zsuzsanna K. Gallant, Maureen Burke, Suzanne D. Cifuni, Stephen Hahn, Sinuhe Wagner, Denisa D. Karumanchi, S. Ananth TI PAD4 Deficiency Decreases Inflammation and Susceptibility to Pregnancy Loss in a Mouse Model SO BIOLOGY OF REPRODUCTION LA English DT Article DE angiogenesis; inflammation; NETs; placenta; preeclampsia ID NEUTROPHIL EXTRACELLULAR TRAPS; MYOCARDIAL ISCHEMIA/REPERFUSION INJURY; DEEP-VEIN THROMBOSIS; TYROSINE KINASE 1; ANTIPHOSPHOLIPID ANTIBODIES; CHROMATIN DECONDENSATION; INNATE IMMUNITY; PREECLAMPSIA; MICE; CONTRIBUTE AB Inflammation is thought to play a critical role in the pathogenesis of placentation disorders such as recurrent miscarriages, growth restriction, and preeclampsia. Recently, neutrophil extracellular traps (NETs) have emerged as a potential mechanism for promoting inflammation in both infectious and noninfectious disorders. To investigate a pathogenic role for NETs in placentation disorders, we studied a model of antiangiogenic factor-mediated pregnancy loss in wild-type (WT) mice and in mice deficient in peptidylarginine deiminase 4 (Padi4(-/-)) that are unable to form NETs. Overexpression of soluble fms-like tyrosine kinase 1 (sFlt-1), an antiangiogenic protein that is pathogenically linked with abnormal placentation disorders during early gestation, resulted in pregnancy loss and large accumulation of neutrophils and NETs in WT placentas. Interestingly, sFlt-1 overexpression in Padi4(-/-) mice resulted in dramatically lower inflammatory and thrombotic response, which was accompanied by significant reduction in pregnancy losses. Inhibition of NETosis may serve as a novel target in disorders of impaired placentation. C1 [Erpenbeck, Luise; Chowdhury, Chanchal Sur; Gallant, Maureen; Cifuni, Stephen; Wagner, Denisa D.] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA USA. [Zsengeller, Zsuzsanna K.; Burke, Suzanne D.; Karumanchi, S. Ananth] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Zsengeller, Zsuzsanna K.; Burke, Suzanne D.; Karumanchi, S. Ananth] Beth Israel Deaconess Med Ctr, Dept Obstet, Boston, MA 02215 USA. [Zsengeller, Zsuzsanna K.; Burke, Suzanne D.; Karumanchi, S. Ananth] Beth Israel Deaconess Med Ctr, Dept Gynecol, Boston, MA 02215 USA. [Zsengeller, Zsuzsanna K.; Burke, Suzanne D.; Karumanchi, S. Ananth] Harvard Med Sch, Boston, MA USA. [Chowdhury, Chanchal Sur; Hahn, Sinuhe] Univ Basel Hosp, Dept Biomed, Lab Prenatal Med, Basel, Switzerland. [Wagner, Denisa D.] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA USA. [Wagner, Denisa D.] Harvard Med Sch, Dept Pediat, Boston, MA USA. RP Erpenbeck, L (reprint author), Univ Med Ctr Gottingen UMG, Dept Dermatol Venereol & Allergol, Robert Koch Str 40, D-37075 Gottingen, Germany. EM luise.erpenbeck@med.uni-goettingen.de FU National Institutes of Health/National Heart, Lung, and Blood Institute [R01HL102101]; Nationale Akademie der Wissenschaften Leopoldina fellowship; Howard Hughes Medical Institute funds; University Women's Hospital, Basel FX Supported by National Institutes of Health/National Heart, Lung, and Blood Institute grant R01HL102101 to D.D.W.; the Nationale Akademie der Wissenschaften Leopoldina fellowship to L.E.; Howard Hughes Medical Institute funds to S.A.K.; and the Research Fund of the University Women's Hospital, Basel, to C.s.C. NR 56 TC 0 Z9 0 U1 1 U2 1 PU SOC STUDY REPRODUCTION PI MADISON PA 1691 MONROE ST,SUITE # 3, MADISON, WI 53711-2021 USA SN 0006-3363 EI 1529-7268 J9 BIOL REPROD JI Biol. Reprod. PD DEC 1 PY 2016 VL 95 IS 6 AR 132 DI 10.1095/biolreprod.116.140293 PG 11 WC Reproductive Biology SC Reproductive Biology GA EG1PJ UT WOS:000390804400019 PM 28007693 ER PT J AU Kim, TS Park, HS Jang, SJ Song, JW Cho, HS Kim, S Bouma, BE Kim, JW Oh, WY AF Kim, Tae Shik Park, Hyun-Sang Jang, Sun-Joo Song, Joon Woo Cho, Han Saem Kim, Sunwon Bouma, Brett E. Kim, Jin Won Oh, Wang-Yuhl TI Single cardiac cycle three-dimensional intracoronary optical coherence tomography SO BIOMEDICAL OPTICS EXPRESS LA English DT Article ID CORONARY-ARTERY MICROSCOPY; FRACTIONAL FLOW RESERVE; IMAGING IN-VIVO; INTRAVASCULAR ULTRASOUND; CLINICAL-APPLICATION; HEARTBEAT OCT; HIGH-SPEED; ACQUISITION; SCAFFOLDS; 3D AB While high-speed intracoronary optical coherence tomography (OCT) provides three-dimensional (3D) visualization of coronary arteries in vivo, imaging speeds remain insufficient to avoid motion artifacts induced by heartbeat, limiting the clinical utility of OCT. In this paper, we demonstrate development of a high-speed intracoronary OCT system (frame rate: 500 frames/s, pullback speed: 100 mm/s) along with prospective electrocardiogram (ECG) triggering technology, which enabled volumetric imaging of long coronary segments within a single cardiac cycle (70 mm pullback in 0.7 s) with minimal cardiac motion artifact. This technology permitted detailed visualization of 3D architecture of the coronary arterial wall of a swine in vivo and fine structure of the implanted stent. (C) 2016 Optical Society of America C1 [Kim, Tae Shik; Park, Hyun-Sang; Cho, Han Saem; Oh, Wang-Yuhl] Korea Adv Inst Sci & Technol, Dept Mech Engn, 291 Daehak Ro, Daejeon, South Korea. [Kim, Tae Shik; Park, Hyun-Sang; Jang, Sun-Joo; Cho, Han Saem; Oh, Wang-Yuhl] Korea Adv Inst Sci & Technol, KI Hlth Sci & Technol, 291 Daehak Ro, Daejeon, South Korea. [Jang, Sun-Joo] Korea Adv Inst Sci & Technol, Grad Sch Med Sci & Engn, 291 Daehak Ro, Daejeon, South Korea. [Jang, Sun-Joo; Kim, Sunwon; Bouma, Brett E.] Harvard Med Sch, Boston, MA 02114 USA. [Jang, Sun-Joo; Kim, Sunwon; Bouma, Brett E.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Song, Joon Woo; Kim, Jin Won] Korea Univ, Guro Hosp, Ctr Cardiovasc, 80 Guro Dong, Seoul, South Korea. [Cho, Han Saem] Korea Res Inst Stand & Sci, Ctr Med Metrol, 267 Gajeong Ro, Daejeon, South Korea. RP Oh, WY (reprint author), Korea Adv Inst Sci & Technol, Dept Mech Engn, 291 Daehak Ro, Daejeon, South Korea.; Oh, WY (reprint author), Korea Adv Inst Sci & Technol, KI Hlth Sci & Technol, 291 Daehak Ro, Daejeon, South Korea. EM woh1@kaist.ac.kr FU National Research Foundation of Korea [2010-0017465, 2012R1A2A2A04046108]; Ministry of Health and Welfare of Korea [HI15C0001]; National Institutes of Health [P41 EB015903] FX This study was supported by the National Research Foundation of Korea (grant 2010-0017465 and grant 2012R1A2A2A04046108), the Ministry of Health and Welfare of Korea (grant HI15C0001), and the National Institutes of Health (grant P41 EB015903). NR 25 TC 0 Z9 0 U1 2 U2 2 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 2156-7085 J9 BIOMED OPT EXPRESS JI Biomed. Opt. Express PD DEC 1 PY 2016 VL 7 IS 12 BP 4847 EP 4858 DI 10.1364/BOE.7.004847 PG 12 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA EF7DQ UT WOS:000390490700002 PM 28018710 ER PT J AU Lu, Y Bernabeu, MO Lammer, J Cai, CC Jones, ML Franco, CA Aiello, LP Sun, JK AF Lu, Yang Bernabeu, Miguel O. Lammer, Jan Cai, Charles C. Jones, Martin L. Franco, Claudio A. Aiello, Lloyd Paul Sun, Jennifer K. TI Computational fluid dynamics assisted characterization of parafoveal hemodynamics in normal and diabetic eyes using adaptive optics scanning laser ophthalmoscopy SO BIOMEDICAL OPTICS EXPRESS LA English DT Article ID COHERENCE TOMOGRAPHY ANGIOGRAPHY; BLOOD-FLOW-VELOCITY; FLUORESCEIN ANGIOGRAPHY; HUMAN RETINA; IN-VIVO; RETINOPATHY; VISCOSITY; MICROVASCULATURE; MICROCIRCULATION; CAPILLARIES AB Diabetic retinopathy (DR) is the leading cause of visual loss in working-age adults worldwide. Previous studies have found hemodynamic changes in the diabetic eyes, which precede clinically evident pathological alterations of the retinal microvasculature. There is a pressing need for new methods to allow greater understanding of these early hemodynamic changes that occur in DR. In this study, we propose a noninvasive method for the assessment of hemodynamics around the fovea (a region of the eye of paramount importance for vision). The proposed methodology combines adaptive optics scanning laser ophthalmoscopy and computational fluid dynamics modeling. We compare results obtained with this technique with in vivo measurements of blood flow based on blood cell aggregation tracking. Our results suggest that parafoveal hemodynamics, such as capillary velocity, wall shear stress, and capillary perfusion pressure can be noninvasively and reliably characterized with this method in both healthy and diabetic retinopathy patients. (C) 2016 Optical Society of America C1 [Lu, Yang; Cai, Charles C.; Aiello, Lloyd Paul; Sun, Jennifer K.] Joslin Diabet Ctr, Beetham Eye Inst, Boston, MA 02215 USA. [Lu, Yang] Harvard Med Sch, Boston, MA USA. [Bernabeu, Miguel O.] Univ Edinburgh, Usher Inst, Med Informat Ctr, Edinburgh, Midlothian, Scotland. [Lammer, Jan] Med Univ Vienna, Dept Ophthalmol & Optometry, Vienna, Austria. [Jones, Martin L.] Francis Crick Inst, Electron Microscopy Sci Technol Platform, London, England. [Franco, Claudio A.] Univ Lisbon, Fac Med, Inst Mol Med, Lisbon, Portugal. [Aiello, Lloyd Paul; Sun, Jennifer K.] Harvard Med Sch, Dept Ophthalmol, Boston, MA 02115 USA. RP Sun, JK (reprint author), Joslin Diabet Ctr, Beetham Eye Inst, Boston, MA 02215 USA.; Sun, JK (reprint author), Harvard Med Sch, Dept Ophthalmol, Boston, MA 02115 USA. EM jennifer.sun@joslin.harvard.edu OI Jones, Martin/0000-0003-0994-5652 FU National Eye Institute [1R01EY0-24702-01, 2R44EY-16295-04A1]; Juvenile Diabetes Research Foundation [2-SRA-2014-264-M-R, 17-2011-359]; Eleanor Chesterman Beatson Childcare Ambassador Program Foundation Grant; Massachusetts Lions Eye Research Fund; UK Consortium on Mesoscale Engineering Sciences (UKCOMES) [EP/L00030X/1] FX National Eye Institute (1R01EY0-24702-01, 2R44EY-16295-04A1); Juvenile Diabetes Research Foundation (2-SRA-2014-264-M-R, 17-2011-359); Eleanor Chesterman Beatson Childcare Ambassador Program Foundation Grant; Massachusetts Lions Eye Research Fund; UK Consortium on Mesoscale Engineering Sciences (UKCOMES)(EP/L00030X/1). NR 41 TC 0 Z9 0 U1 4 U2 4 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 2156-7085 J9 BIOMED OPT EXPRESS JI Biomed. Opt. Express PD DEC 1 PY 2016 VL 7 IS 12 BP 4958 EP 4973 DI 10.1364/BOE.7.004958 PG 16 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA EF7DQ UT WOS:000390490700010 PM 28078170 ER PT J AU Ostadhadi, S Foroutan, A Momeny, M Norouzi-Javidan, A Azimi, E Kordjazy, N Dehpour, AR AF Ostadhadi, Sattar Foroutan, Arash Momeny, Majid Norouzi-Javidan, Abbas Azimi, Ehsan Kordjazy, Nastaran Dehpour, Ahmad Reza TI Evidence for the involvement of nitric oxide in cholestasis-induced itch associated response in mice SO BIOMEDICINE & PHARMACOTHERAPY LA English DT Article DE Itch; Cholestasis; Nitric oxide (NO); Inducible nitric oxide synthase (iNOS); Mice ID ATOPIC-DERMATITIS; BILIARY-CIRRHOSIS; NO/CGMP PATHWAY; SWIMMING TEST; RATS; PRURITUS; SYNTHASE; SEROTONIN; OPIOIDS; NITRATE AB Cholestasis is a major systemic disorder associated with distressing pruritus (itch). Nitric oxide (NO) is a neurotransmitter, assumed to be involved in pruritus. Based on over-production of NO in cholestatic liver diseases, this project aimed to investigate involvement of NO in cholestasis-related itch in mice. To achieve this, cholestasis was induced by bile duct ligation (BDL). Our results showed that BDL mice elicited significant itch on fifth and seventh day after the procedure. This scratching behavior was inhibited by intraperitoneal (IP) treatment of mice with non-selective NOS inhibitor N-nitro-L-arginine methyl ester (L-NAME; 3 mg/kg) and inducible NOS (iNOS) inhibitor aminoguanidine (AG; 100 mg/kg). The inhibitory effects of L-NAME and AG were reversed by pretreatment with L-arginine (100 mg/kg). Administration of L-NAME, AG and L-arginine per se, in BDL and SHAM mice did not produce scratching behaviors. In addition, intradermal injection of L-arginine at dose of 300 nmol/site significantly increased itch in BDL mice. Furthermore, nitrite levels in skin and serum of BDL animals significantly increased after 7 d of operation and administration of NOS inhibitors decreased this enhancement. L-arginine injection reversed the effects of NOS inhibitors on reduction of nitrite levels in the skin and serum of BDL mice. Finally, cutaneous iNOS expression increased in BDL mice 7 d after surgery. Taken together, our study showed for the first time that BDL, as a model of acute cholestasis in rodents, induces NO over-production by activating NOS enzymes, especially iNOS, which contribute to pruritus. (C) 2016 Elsevier Masson SAS. All rights reserved. C1 [Ostadhadi, Sattar; Norouzi-Javidan, Abbas; Dehpour, Ahmad Reza] Univ Tehran Med Sci, Neurosci Inst, Brain & Spinal Cord Injury Res Ctr, Tehran, Iran. [Ostadhadi, Sattar; Foroutan, Arash; Momeny, Majid; Kordjazy, Nastaran; Dehpour, Ahmad Reza] Univ Tehran Med Sci, Sch Med, Dept Pharmacol, POB 13145-784, Tehran, Iran. [Foroutan, Arash; Kordjazy, Nastaran; Dehpour, Ahmad Reza] Univ Tehran Med Sci, Expt Med Res Ctr, Tehran, Iran. [Foroutan, Arash] Univ Tehran Med Sci, Fac Pharm, Tehran, Iran. [Momeny, Majid] Univ Tehran Med Sci, Sch Med, Shariati Hosp, Hematol Oncol & Stem Cell Transplantat Res Ctr, Tehran, Iran. [Azimi, Ehsan] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA USA. RP Dehpour, AR (reprint author), Univ Tehran Med Sci, Sch Med, Dept Pharmacol, POB 13145-784, Tehran, Iran. EM dehpoura@sina.tums.ac.ir FU Iran National Science Foundation [92001565] FX This work was supported by a grant from Iran National Science Foundation. Grant number: 92001565. NR 50 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0753-3322 EI 1950-6007 J9 BIOMED PHARMACOTHER JI Biomed. Pharmacother. PD DEC PY 2016 VL 84 BP 1367 EP 1374 DI 10.1016/j.biopha.2016.10.068 PG 8 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA EF6JU UT WOS:000390438100159 PM 27802897 ER PT J AU Shaw, AM Hall, KAA Rosenfield, E Timpano, KR AF Shaw, A. M. Hall, K. A. Arditte Rosenfield, E. Timpano, K. R. TI Body dysmorphic disorder symptoms and risk for suicide: The role of depression SO BODY IMAGE LA English DT Article DE Body dysmorphic disorder; Suicide risk; Thwarted belongingness; Perceived burdensomeness; Depression ID INTERPERSONAL-PSYCHOLOGICAL THEORY; ACQUIRED CAPABILITY; INDIVIDUALS; ANXIETY; VALIDATION; BEHAVIOR; ADULTS AB Body dysmorphic disorder (BDD) is associated with elevated suicidality. Little is known about why BDD patients are at increased risk. The interpersonal-psychological theory of suicide (IPTS) could clarify suicidality in BDD, and theorizes that perceived burdensomeness and thwarted belongingness lead to suicidal desire, while an acquired capability for suicide is necessary to attempt suicide. No study has investigated how BDD symptoms relate to IPTS constructs or mediators of the relationship between BDD and suicidality. Individuals (N=235) enrolled in Amazon.com's Mechanical Turk (MTurk), who had appearance concerns, completed questionnaires about BDD, depression, eating pathology, and suicide risk. MTurk is an online data collection platform in which participants complete surveys for payment. BDD symptoms predicted suicidal desire, but not acquired capability for suicide. Depression mediated the relationship between BDD and suicidal desire. Research should examine how fluctuations in BDD affect suicide risk. Replication in a clinical sample may inform treatments for BDD. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Shaw, A. M.; Rosenfield, E.; Timpano, K. R.] Univ Miami, Coral Gables, FL 33124 USA. [Shaw, A. M.] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. [Hall, K. A. Arditte] VA Boston Healthcare Syst, Natl Ctr Posttraumat Stress Disorder, Boston, MA USA. RP Timpano, KR (reprint author), Univ Miami, Dept Psychol, POB 248185, Coral Gables, FL 33124 USA. EM ashmarieshaw@gmail.com; kimarditte@gmail.com; liza.rosenfield@gmail.com; kiaratimpano@gmail.com OI Timpano, Kiara/0000-0002-0665-8722 NR 38 TC 0 Z9 0 U1 6 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1740-1445 EI 1873-6807 J9 BODY IMAGE JI Body Image PD DEC PY 2016 VL 19 BP 169 EP 174 DI 10.1016/j.bodyim.2016.09.007 PG 6 WC Psychology, Clinical; Psychiatry; Psychology, Multidisciplinary SC Psychology; Psychiatry GA EG0KI UT WOS:000390721300021 PM 27760403 ER PT J AU Frosch, ZAK Abel, GA AF Frosch, Zachary A. K. Abel, Gregory A. TI Assessing Quality of Care for the Myelodysplastic Syndromes SO CURRENT HEMATOLOGIC MALIGNANCY REPORTS LA English DT Review DE Myelodysplastic syndromes; Quality of health care; Quality indicators; Access and evaluation; Quality of life; Patient-centered care ID FINANCIAL INCENTIVES; PATTERNS; CANCER; GOALS; LIFE; MDS; END AB Measuring the quality of care for patients with chronic cancers is difficult, especially for heterogeneous malignancies such as the myelodysplastic syndromes (MDS). Recent work suggests that improvements may be needed in the quality of diagnostic, treatment, and end-of-life care for patients with these syndromes. Moreover, rigorous assessment of factors that are necessary to deliver high-quality care such as preferred method of decision-making and pre-treatment quality of life are often overlooked. Finally, a key component of quality care is that it is received equitably across different patient populations, yet several recent studies suggest that there are financial, educational, race-ethnic, and age-related barriers to equitable MDS care. C1 [Frosch, Zachary A. K.] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Abel, Gregory A.] Dana Farber Canc Inst, Div Populat Sci, 450 Brookline Ave, Boston, MA 02215 USA. [Abel, Gregory A.] Dana Farber Canc Inst, Ctr Leukemia, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. RP Abel, GA (reprint author), Dana Farber Canc Inst, Div Populat Sci, 450 Brookline Ave, Boston, MA 02215 USA.; Abel, GA (reprint author), Dana Farber Canc Inst, Ctr Leukemia, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM gregory_abel@dfci.harvard.edu NR 38 TC 0 Z9 0 U1 0 U2 0 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1558-8211 EI 1558-822X J9 CURR HEMATOL MALIG R JI Curr. Hematol. Malig. Rep. PD DEC PY 2016 VL 11 IS 6 BP 402 EP 407 DI 10.1007/s11899-016-0343-0 PG 6 WC Oncology; Hematology SC Oncology; Hematology GA EG4HQ UT WOS:000391004900002 PM 27562670 ER PT J AU Brierley, CK Steensma, DP AF Brierley, Charlotte K. Steensma, David P. TI Targeting Splicing in the Treatment of Myelodysplastic Syndromes and Other Myeloid Neoplasms SO CURRENT HEMATOLOGIC MALIGNANCY REPORTS LA English DT Review DE Splicing; Myelodysplastic syndromes; SF3B1; E7107; Targeted therapy ID PRE-MESSENGER-RNA; CLONAL HEMATOPOIESIS; RING SIDEROBLASTS; INTRON RETENTION; SRSF2 MUTATIONS; SOLID TUMORS; OPEN-LABEL; IN-VIVO; PHASE-I; CANCER AB Genome sequencing of primary cells from patients with myelodysplastic syndromes (MDS) led to the identification of recurrent heterozygous mutations in gene encoding components of the spliceosome, the cellular machinery which processes pre-messenger RNA (mRNA) to mature mRNA during gene transcription. Splicing mutations are mutually exclusive with one another and collectively represent the most common mutation class in MDS, occurring in approximately 60% of patients overall and more than 80% of those with ring sideroblasts. Evidence from animal models suggests that homozygous splicing mutations are lethal, and that in heterozygously mutated models, any further disruption of splicing triggers apoptosis and cell death. MDS cells with spliceosome mutations are thus uniquely vulnerable to therapies targeting splicing, which may be tolerated by healthy cells. The spliceosome is emerging as a novel therapeutic target in MDS and related myeloid neoplasms, with the first clinical trial of a splicing modulator opening in 2016. C1 [Brierley, Charlotte K.] Oxford Univ Hosp NHS Trust, Churchill Hosp, Dept Haematol, Old Rd, Oxford OX3 7LE, England. [Steensma, David P.] Dana Farber Canc Inst, Dept Med Oncol, Div Hematol Malignancies, Adult Leukemia Program, D2037,450 Brookline Ave, Boston, MA 02215 USA. [Steensma, David P.] Harvard Med Sch, 25 Shattuck St, Boston, MA 02115 USA. RP Steensma, DP (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Div Hematol Malignancies, Adult Leukemia Program, D2037,450 Brookline Ave, Boston, MA 02215 USA.; Steensma, DP (reprint author), Harvard Med Sch, 25 Shattuck St, Boston, MA 02115 USA. EM Charlotte.Brierley@new.ox.ac.uk; David_Steensma@DFCI.HARVARD.EDU NR 61 TC 0 Z9 0 U1 2 U2 2 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1558-8211 EI 1558-822X J9 CURR HEMATOL MALIG R JI Curr. Hematol. Malig. Rep. PD DEC PY 2016 VL 11 IS 6 BP 408 EP 415 DI 10.1007/s11899-016-0344-z PG 8 WC Oncology; Hematology SC Oncology; Hematology GA EG4HQ UT WOS:000391004900003 PM 27492253 ER PT J AU Nickolich, M El-Jawahri, A LeBlanc, TW AF Nickolich, Myles El-Jawahri, Areej LeBlanc, Thomas W. TI Palliative and End-of-Life Care in Myelodysplastic Syndromes SO CURRENT HEMATOLOGIC MALIGNANCY REPORTS LA English DT Review DE Palliative care; End-of-life care; Myelodysplastic syndromes; Quality of life ID RANDOMIZED CONTROLLED-TRIAL; TUMOR ONCOLOGY SPECIALISTS; PROGNOSTIC SCORING SYSTEM; ACUTE MYELOID-LEUKEMIA; OLDER PATIENTS; HEMATOLOGIC MALIGNANCIES; ADVANCED CANCER; QUALITY; OUTCOMES; MDS AB A growing literature demonstrates that MDS is associated with significant impairments in overall quality of life. Given the poor prognosis for many patients with MDS, and the considerable morbidities associated with this disease, there is a critical need to address palliative and end-of-life care needs in this population. However, palliative and end-of-life care issues are under-represented in the MDS literature. In this article, we highlight a growing body of literature that demonstrates unmet palliative and end-of-life care needs in hematologic malignancies, including MDS, and highlight opportunities for further research and quality improvement initiatives to address unmet needs in MDS care. C1 [Nickolich, Myles] Duke Univ, Sch Med, Dept Med, Div Hematol, Durham, NC 27706 USA. [Nickolich, Myles] Duke Univ, Sch Med, Dept Med, Div Med Oncol, Durham, NC 27706 USA. [Nickolich, Myles] Duke Univ, Sch Med, Dept Med, Div Hematol Malignancies & Cellular Therapy, Durham, NC 27706 USA. [El-Jawahri, Areej] Massachusetts Gen Hosp, Boston, MA 02114 USA. [LeBlanc, Thomas W.] Duke Univ, Sch Med, Duke Canc Inst, Durham, NC USA. [LeBlanc, Thomas W.] DUMC, Box 2715, Durham, NC 27710 USA. RP LeBlanc, TW (reprint author), Duke Univ, Sch Med, Duke Canc Inst, Durham, NC USA.; LeBlanc, TW (reprint author), DUMC, Box 2715, Durham, NC 27710 USA. EM thomas.leblanc@duke.edu NR 53 TC 0 Z9 0 U1 0 U2 0 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1558-8211 EI 1558-822X J9 CURR HEMATOL MALIG R JI Curr. Hematol. Malig. Rep. PD DEC PY 2016 VL 11 IS 6 BP 434 EP 440 DI 10.1007/s11899-016-0352-z PG 7 WC Oncology; Hematology SC Oncology; Hematology GA EG4HQ UT WOS:000391004900006 PM 27704467 ER PT J AU Pemmaraju, N Gupta, V Thompson, MA Lane, AA AF Pemmaraju, Naveen Gupta, Vikas Thompson, Michael A. Lane, Andrew A. TI Social Media and Internet Resources for Patients with Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) SO CURRENT HEMATOLOGIC MALIGNANCY REPORTS LA English DT Review DE Social media; Twitter; BPDCN; Disease-specific hashtag; Rare disease; #BPDCN ID INTERLEUKIN-3 RECEPTOR; LEUKEMIC PRESENTATION; HEALTH-CARE; TWITTER; COMMUNICATION; ONCOLOGY; THERAPY; TRANSPLANTATION; DIAGNOSIS; EDUCATION AB The incorporation of Internet resources and the use of social media among patients, clinicians, advocates, and researchers in the field of hematology and oncology are growing in importance. Utilization of online information sharing is rising, especially among those involved in rare blood cancer fields, which have generally featured a paucity of reliable, updated information. In particular, blastic plasmacytoid dendritic cell neoplasm (BPDCN), an uncommon, but highly aggressive hematologic malignancy, is one example of a cancer with limited information readily available to the general public. The infrequent incidence of BPDCN, the challenges in recognizing the disease and making a clinico-pathologic diagnosis, and the lack of standard therapies are some of the reasons accounting for the dearth of expert opinion, scientific publications and discussion, and accessibility of online information for patients. This article highlights social media and Internet sources available for patients and other healthcare stakeholders in the field of BPDCN and discusses our efforts to increase awareness and propagation of BPDCN electronic resources, including the founding of an online Twitter community, #BPDCN. C1 [Pemmaraju, Naveen] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Unit 428,POB 301402, Houston, TX 77230 USA. [Gupta, Vikas] Princess Margaret Canc Ctr, Elizabeth & Tony Comper MPN Program, Toronto, ON, Canada. [Thompson, Michael A.] Aurora Hlth Care, Aurora Res Inst, Milwaukee, WI USA. [Lane, Andrew A.] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA. RP Pemmaraju, N (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Unit 428,POB 301402, Houston, TX 77230 USA. EM npemmaraju@mdanderson.org FU MD Anderson Cancer Center Support Grant [P30 CA016672]; Healthcare Hashtags (@ healthhashtags) Project FX This research is supported in part by the MD Anderson Cancer Center Support Grant P30 CA016672. The authors thank Dr Matthew Katz and the creators of the Cancer Ontology Tag (CTO) Program for their example and inspiration, and the founders and members of Symplur. com, including Audun Utengen and the Healthcare Hashtags (@ healthhashtags) Project for their continued analysis and support. NR 37 TC 0 Z9 0 U1 0 U2 0 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1558-8211 EI 1558-822X J9 CURR HEMATOL MALIG R JI Curr. Hematol. Malig. Rep. PD DEC PY 2016 VL 11 IS 6 BP 462 EP 467 DI 10.1007/s11899-016-0340-3 PG 6 WC Oncology; Hematology SC Oncology; Hematology GA EG4HQ UT WOS:000391004900010 PM 27492117 ER PT J AU Tata, PR Rajagopal, J AF Tata, Purushothama Rao Rajagopal, Jayaraj TI Cellular plasticity: 1712 to the present day SO CURRENT OPINION IN CELL BIOLOGY LA English DT Article ID EPITHELIAL STEM-CELL; PROSTATE-CANCER; HAIR FOLLICLE; IN-VIVO; DROSOPHILA TESTIS; PROGENITOR CELLS; HEART REGENERATION; ORGANOID CULTURES; MURINE PROSTATE; ALVEOLAR CELLS AB Cell identity is a fundamental feature of cells. Tissues are often organized into cellular hierarchies characterized by progressive differentiation and developmental commitment. However, it is been historically evident that the cells of many organisms of various phyla, especially in the context of injury, exhibit remarkable plasticity in terms of their ability to convert into other cell types. Recent modern studies, using genetic lineage tracing, have demonstrated that many mature functional cells retain a potential to undergo lineage reversion (dedifferentiation) or to convert into cells of other more distant lineages (transdifferentiation) following injury. Similarly, mimicking progenitor cell transdetermination, stem cells can interconvert. These forms of plasticity may be essential for organismal survival, and are likely part and parcel of regeneration. C1 [Tata, Purushothama Rao; Rajagopal, Jayaraj] Massachusetts Gen Hosp, Ctr Regenerat Med, 185 Cambridge St, Boston, MA 02114 USA. [Tata, Purushothama Rao; Rajagopal, Jayaraj] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Tata, Purushothama Rao; Rajagopal, Jayaraj] Massachusetts Gen Hosp, Div Pulm & Crit Care Med, Dept Internal Med, Boston, MA 02114 USA. [Rajagopal, Jayaraj] Massachusetts Gen Hosp Children, Pediat Pulm Med, Boston, MA 02114 USA. [Rajagopal, Jayaraj] Massachusetts Eye & Ear, Div Otol & Laryngol, Boston, MA 02114 USA. RP Rajagopal, J (reprint author), Massachusetts Gen Hosp, Ctr Regenerat Med, 185 Cambridge St, Boston, MA 02114 USA.; Rajagopal, J (reprint author), Harvard Stem Cell Inst, Cambridge, MA 02138 USA.; Rajagopal, J (reprint author), Massachusetts Gen Hosp, Div Pulm & Crit Care Med, Dept Internal Med, Boston, MA 02114 USA.; Rajagopal, J (reprint author), Massachusetts Gen Hosp Children, Pediat Pulm Med, Boston, MA 02114 USA.; Rajagopal, J (reprint author), Massachusetts Eye & Ear, Div Otol & Laryngol, Boston, MA 02114 USA. EM jrajagopal@mgh.harvard.edu FU NIH [R01HL116756, R01HL118185, K99HL127181] FX J.R. is a New York Stem Cell Foundation Robertson Investigator and a Maroni Research Scholar at MGH and a member of the Ludwig Cancer Institute at Harvard Medical School. We thank all the members of the Rajagopal Laboratory for constructive comments. This research was supported by grants from the NIH (R01HL116756, R01HL118185 to J.R., K99HL127181 to P.R.T.). We apologize to the myriad authors whose work we could not include in this brief conceptual review. NR 90 TC 2 Z9 2 U1 6 U2 6 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0955-0674 EI 1879-0410 J9 CURR OPIN CELL BIOL JI Curr. Opin. Cell Biol. PD DEC PY 2016 VL 43 BP 46 EP 54 DI 10.1016/j.ceb.2016.07.005 PG 9 WC Cell Biology SC Cell Biology GA EG0PB UT WOS:000390733600008 PM 27485353 ER PT J AU Saha, D Wakimoto, H Rabkin, SD AF Saha, Dipongkor Wakimoto, Hiroaki Rabkin, Samuel D. TI Oncolytic herpes simplex virus interactions with the host immune system SO CURRENT OPINION IN VIROLOGY LA English DT Article ID NF-KAPPA-B; NATURAL CYTOTOXICITY RECEPTORS; TYPE-1 US11 PROTEIN; DENDRITIC CELLS; I INTERFERON; T-CELLS; GLIOBLASTOMA VIROTHERAPY; PRODUCTIVE INFECTION; GENE-EXPRESSION; INNATE IMMUNITY AB Oncolytic viruses (OVs), like oncolytic herpes simplex virus (oHSV), are genetically engineered to selectively replicate in and kill cancer cells, while sparing normal cells. Initial OV infection, cell death, and subsequent OV propagation within the tumor microenvironment leads to a cascade of host responses (innate and adaptive), reflective of natural anti-viral immune responses. These host virus interactions are critical to the balance between OV activities, anti-viral immune responses limiting OV, and induction of anti-tumor immunity. The host response against oHSV is complex, multifaceted, and modulated by the tumor microenvironment and immunosuppression. As a successful pathogen, HSV has multiple mechanisms to evade such host responses. In this review, we will discuss these mechanisms and HSV evasion, and how they impact oHSV therapy. C1 [Rabkin, Samuel D.] Massachusetts Gen Hosp, Brain Tumor Res Ctr, Dept Neurosurg, Boston, MA 02114 USA. Harvard Med Sch, Boston, MA USA. RP Rabkin, SD (reprint author), Massachusetts Gen Hosp, Brain Tumor Res Ctr, Dept Neurosurg, Boston, MA 02114 USA. EM rabkin@mgh.harvard.edu FU NIH [RO1CA160762]; Thomas A. Pappas Chair in Neurosciences FX This work was supported in part by a grant from NIH, RO1CA160762, and the Thomas A. Pappas Chair in Neurosciences. NR 90 TC 1 Z9 1 U1 7 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1879-6257 J9 CURR OPIN VIROL JI Curr. Opin. Virol. PD DEC PY 2016 VL 21 BP 26 EP 34 DI 10.1016/j.coviro.2016.07.007 PG 9 WC Virology SC Virology GA EF7MA UT WOS:000390512500006 PM 27497296 ER PT J AU Criscitiello, C Curigliano, G Burstein, HJ Wong, S Esposito, A Viale, G Giuliano, M Veronesi, U Santangelo, M Golshan, M AF Criscitiello, C. Curigliano, G. Burstein, H. J. Wong, S. Esposito, A. Viale, G. Giuliano, M. Veronesi, U. Santangelo, M. Golshan, M. TI Breast conservation following neoadjuvant therapy for breast cancer in the modern era: Are we losing the opportunity? SO EJSO LA English DT Review DE Breast cancer; Breast conserving surgery; Neoadjuvant therapy; Mastectomy ID PATHOLOGICAL COMPLETE RESPONSE; SURGICAL ADJUVANT BREAST; RANDOMIZED PHASE-3 TRIAL; PROJECT PROTOCOL B-27; SYSTEMIC THERAPY; PREOPERATIVE CHEMOTHERAPY; INDUCTION CHEMOTHERAPY; CONSERVING SURGERY; PLUS TRASTUZUMAB; CLINICAL-TRIAL AB The main rationale for neoadjuvant therapy for breast cancer is to provide effective systemic treatment while surgically down-staging the cancer. This down-staging was initially to convert inoperable patients to operable and later to increase rates of breast conservation in patients initially deemed mastectomy only candidates. Unexpectedly, in recent neoadjuvant trials lower rates of breast conservation have been observed than in past decades, despite remarkable advances in systemic therapies, which have increased pathologic complete response rates. These results point to factors aside from response and eligibility for breast conservation that may lead surgeons and/or patients to recommend and choose mastectomy. Here, we aim to examine the surgical benefits offered by the modern era neoadjuvant therapy and explore factors that have contributed to this decrease in breast conservation rates. If the main benefit of neoadjuvant therapy is to increase the opportunity for breast conservation, then our review suggests that to optimize less invasive surgical approaches, we will need to address both surgeon and patient-level variables and biases that may be limiting our ability to identify patients appropriate for less aggressive options. As an oncology community, we must be aware of the surgical overtreatment of breast cancer, especially in a time where systemic therapies have remarkably improved outcomes and responses. (C) 2016 Elsevier Ltd, BASO similar to The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved. C1 [Criscitiello, C.; Curigliano, G.; Esposito, A.; Viale, G.; Veronesi, U.] European Inst Oncol, Div Expt Therapeut, Via G Ripamonti 435, Milan, Italy. [Burstein, H. J.] Dana Farber Canc Inst, Dept Breast Oncol, 450 Brookline Ave, Boston, MA 02115 USA. [Wong, S.] McGill Hosp, Dept Surg, Boston, MA USA. [Giuliano, M.] Univ Federico II, Dept Clin Med & Surg, Corso Umberto 1 40, Naples, Italy. [Santangelo, M.] Univ Federico II, Dept Adv Biomed Sci, Gen Surg, Corso Umberto 1 40, Naples, Italy. [Golshan, M.] Brigham & Womens Hosp, Dept Surg, 75 Francis St, Boston, MA 02115 USA. [Golshan, M.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Criscitiello, C (reprint author), Via Ripamonti 435, I-20141 Milan, Italy. EM carmen.criscitiello@ieo.it; giuseppe.curigliano@ieo.it; hal_burstein@dfci.harvard.edu; smw930@mail.harvard.edu; angela.esposito@ieo.it; giuliaviale@aim.com; m.giuliano@unina.it; umberto.veronesi@ieo.it; misantan@unina.it; mgolshan@partners.org NR 47 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0748-7983 EI 1532-2157 J9 EJSO-EUR J SURG ONC JI EJSO PD DEC PY 2016 VL 42 IS 12 BP 1780 EP 1786 DI 10.1016/j.ejso.2016.10.011 PG 7 WC Oncology; Surgery SC Oncology; Surgery GA EF7IK UT WOS:000390503100003 PM 27825710 ER PT J AU Smith, MR Antonarakis, ES Ryan, CJ Berry, WR Shore, ND Liu, G Alumkal, JJ Higano, CS Maneval, EC Bandekar, R de Boer, CJ Yu, MK Rathkopf, DE AF Smith, Matthew R. Antonarakis, Emmanuel S. Ryan, Charles J. Berry, William R. Shore, Neal D. Liu, Glenn Alumkal, Joshi J. Higano, Celestia S. Maneval, Edna Chow Bandekar, Rajesh de Boer, Carla J. Yu, Margaret K. Rathkopf, Dana E. TI Phase 2 Study of the Safety and Antitumor Activity of Apalutamide (ARN-509), a Potent Androgen Receptor Antagonist, in the High-risk Nonmetastatic Castration-resistant Prostate Cancer Cohort SO EUROPEAN UROLOGY LA English DT Article DE Antitumor activity; Apalutamide; Castration-resistant prostate; cancer; Safety ID METASTASIS-FREE SURVIVAL; PLACEBO-CONTROLLED TRIAL; MEN; ENZALUTAMIDE; CHEMOTHERAPY; ANTIANDROGEN; DENOSUMAB; ANTIGEN AB Background: Apalutamide is a potent androgen receptor (AR) antagonist that targets the AR ligand-binding domain and prevents AR nuclear translocation, DNA binding, and transcription of AR gene targets. Objective: To evaluate the activity and safety of apalutamide in patients with high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC). Design, setting, and participants: We conducted a multicenter phase 2 study of nmCRPC patients with a high risk for progression (prostate-specific antigen [PSA] > 8 ng/ml or PSA doubling time [PSA DT] < 10 mo). Intervention: Patients received 240 mg/d apalutamide while continuing on androgen-deprivation therapy. Outcome measurements and statistical analysis: Primary end point was 12-wk PSA response (Prostate Cancer Working Group 2 criteria). Secondary end points included safety, time to PSA progression (TTPP), and metastasis-free survival (MFS). Results and limitations: A total of 51 patients were enrolled; four patients with metastatic disease were excluded from the efficacy analysis. Patient characteristics included median age, 71 yr; Eastern Cooperative Oncology Group performance status 0 (76%); Gleason score <= 7 (57%); median PSA 10.7 ng/ml; and PSA DT <= 10 mo (45%). At median follow-up of 28.0 mo, 18 patients (35%) remained in the study. Overall, 89% of patients had >= 50% PSA decline at 12 wk. Median TTPP was 24.0 mo (95% confidence interval [CI], 16.3 mo-not reached [NR]); median MFS was NR (95% CI, 33.4 mo-NR). Most of the patients discontinued study treatment (n = 33) due to disease progression (n = 11 [22%]) or adverse events (AEs) (n = 9 [18%]). The most common AE was fatigue (any grade, n = 31 [61%]) although grade >= 3 fatigue was uncommon (n = 2 [4%]). These represent the first apalutamide nmCRPC patient clinical data. Conclusions: In high-risk nmCRPC patients, apalutamide was safe with robust activity based on durable PSA responses and disease control. Patient summary: Antitumor activity and the safety of apalutamide in patients with nonmetastatic castration-resistant prostate cancer support continued development in this setting. (C) 2016 European Association of Urology. Published by Elsevier B.V. C1 [Smith, Matthew R.] Massachusetts Gen Hosp, Ctr Canc, Yawkey 7030,55 Fruit St, Boston, MA 02114 USA. [Smith, Matthew R.] Harvard Med Sch, Boston, MA USA. [Antonarakis, Emmanuel S.] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Ryan, Charles J.] UCSF Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA. [Berry, William R.] Canc Ctr North Carolina, Raleigh, NC USA. [Shore, Neal D.] Carolina Urol Res Ctr, Myrtle Beach, SC USA. [Liu, Glenn] Univ Wisconsin, Carbone Canc Ctr, Madison, WI USA. [Alumkal, Joshi J.] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. [Higano, Celestia S.] Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle, WA 98195 USA. [Maneval, Edna Chow] Aragon Pharmaceut, San Diego, CA USA. [Bandekar, Rajesh] Janssen Res & Dev, Spring House, PA USA. [de Boer, Carla J.] Janssen Biol BV, Leiden, Netherlands. [Yu, Margaret K.] Janssen Res & Dev, Los Angeles, CA USA. [Rathkopf, Dana E.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Rathkopf, Dana E.] Weill Cornell Med Coll, New York, NY USA. RP Smith, MR (reprint author), Massachusetts Gen Hosp, Ctr Canc, Yawkey 7030,55 Fruit St, Boston, MA 02114 USA. EM smith.matthew@mgh.harvard.edu FU Aragon Pharmaceuticals, Inc.; Janssen Research Development; Janssen Global Services, LLC FX This study was funded by Aragon Pharmaceuticals, Inc. and supported by Janssen Research & Development. The sponsors were involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, and approval of the manuscript. Janssen Research & Development, LLC, is performing work on behalf of Aragon. Writing assistance was funded by Janssen Global Services, LLC. NR 21 TC 2 Z9 2 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 EI 1873-7560 J9 EUR UROL JI Eur. Urol. PD DEC PY 2016 VL 70 IS 6 BP 963 EP 970 DI 10.1016/j.eururo.2016.04.023 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA EF8FA UT WOS:000390563100024 PM 27160947 ER PT J AU Bjonnes, AC Saxena, R Welt, CK AF Bjonnes, Andrew C. Saxena, Richa Welt, Corrine K. TI Relationship between polycystic ovary syndrome and ancestry in European Americans SO FERTILITY AND STERILITY LA English DT Article DE European; genetics; population stratification; waist:hip ratio ID GENOME-WIDE ASSOCIATION; GENETIC ANCESTRY; DIAGNOSTIC-CRITERIA; AFRICAN-AMERICANS; ADMIXTURE MAP; WOMEN; POPULATIONS; PREVALENCE; STRATIFICATION; FEATURES AB Objective: To determine whether European Americans with polycystic ovary syndrome (PCOS) exhibit genetic differences associated with PCOS status and phenotypic features. Design: Case-control association study in European Americans. Setting: Academic center. Subject(s): Women with PCOS diagnosed with the use of the National Institutes of Health criteria (n = 532) and control women with regular menstrual cycles and no evidence of hyperandrogenism (n = 432). Intervention(s): Blood was drawn for measurement of sex steroids, metabolic parameters, and genotyping. Main Outcome Measure(s): Associations among PCOS status, phenotype, and genetic background identified with the use of principal component analysis. Result(s): Principal component analysis identified five principal components (PCs). PC1 captured northwest-to-southeast European genetic variation and was associated with PCOS status. Acanthosis was associated with southern European ancestry, and larger waist: hip ratio was associated with northern European ancestry. PC2 was associated with east-to-west European genetic variation and cholesterol levels. Conclusion(s): These data provide evidence for genetic influence based on European ethnicity in women with PCOS. There is also evidence for a genetic component in the phenotypic features of PCOS within a mixed European population. The data point to the need to control for population stratification in genetic studies in women of mixed European ethnicity. They also emphasize the need for better studies of PCOS prevalence and phenotype as a function of genetic background. (C) 2016 by American Society for Reproductive Medicine. C1 [Bjonnes, Andrew C.; Saxena, Richa] Massachusetts Gen Hosp, Dept Anesthesia, Ctr Human Genet Res, Boston, MA 02114 USA. [Welt, Corrine K.] Univ Utah, Div Endocrinol Metab & Diabet, 15 N 2030 E, Salt Lake City, UT 84112 USA. RP Welt, CK (reprint author), Univ Utah, Div Endocrinol Metab & Diabet, 15 N 2030 E, Salt Lake City, UT 84112 USA. EM cwelt@genetics.utah.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [R01HD065029]; Harvard Clinical and Translational Science Center [1 UL1 RR025758]; National Center for Research Resources; American Diabetes Association [1-10-CT-57] FX Supported by award no. R01HD065029 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, award no. 1 UL1 RR025758, Harvard Clinical and Translational Science Center, from the National Center for Research Resources, and award no. 1-10-CT-57 from the American Diabetes Association. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Center for Research Resources, National Institutes of Health, or American Diabetes Association. NR 34 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD DEC PY 2016 VL 106 IS 7 BP 1772 EP 1777 DI 10.1016/j.fertnstert.2016.08.033 PG 6 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA EF9RU UT WOS:000390668400034 PM 27666562 ER PT J AU Hurley, BP Eaton, AD Zimmermann, C Delaney, B AF Hurley, Bryan P. Eaton, Alex D. Zimmermann, Cindi Delaney, Bryan TI Polarized monolayer cultures of human intestinal epithelial cell lines exposed to intractable proteins - In vitro hazard identification studies SO FOOD AND CHEMICAL TOXICOLOGY LA English DT Article DE Intractable proteins; Intestinal epithelial cells; Cytotoxicity ID PHASEOLUS-VULGARIS LECTINS; GENETICALLY-MODIFIED CROPS; SAFETY ASSESSMENT; PLANT-LECTINS; CACO-2; PERMEABILITY; BINDING; RAT; ACTIVATION; TOXICOLOGY C1 [Hurley, Bryan P.; Eaton, Alex D.] Massachusetts Gen Hosp, Mucosal Immunol & Biol Res Ctr, 55 Fruit St,Jackson 1402, Boston, MA 02114 USA. [Hurley, Bryan P.] Harvard Med Sch, Dept Pediat, Boston, MA USA. [Zimmermann, Cindi; Delaney, Bryan] DuPont Pioneer, 8325 NW 62ndAvenue, Johnston, IA 50131 USA. RP Hurley, BP (reprint author), Massachusetts Gen Hosp, Mucosal Immunol & Biol Res Ctr, 55 Fruit St,Jackson 1402, Boston, MA 02114 USA. EM bphurley@partners.org FU DuPont Pioneer FX These studies were conducted at MGH under contract research that was funded by DuPont Pioneer. BPH and AE are employees of MGH while CZ and BD are employees of DuPont Pioneer. NR 33 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-6915 EI 1873-6351 J9 FOOD CHEM TOXICOL JI Food Chem. Toxicol. PD DEC PY 2016 VL 98 BP 262 EP 268 DI 10.1016/j.fct.2016.11.006 PN B PG 7 WC Food Science & Technology; Toxicology SC Food Science & Technology; Toxicology GA EF7JH UT WOS:000390505400019 PM 27832974 ER PT J AU Pereira, TA Syn, WK Pereira, FEL Lambertucci, JR Secor, WE Diehl, AM AF Pereira, Thiago Almeida Syn, Wing-Kin Pereira, Fausto E. L. Lambertucci, Jose Roberto Secor, William Evan Diehl, Anna Mae TI Serum osteopontin is a biomarker of severe fibrosis and portal hypertension in human and murine schistosomiasis mansoni SO INTERNATIONAL JOURNAL FOR PARASITOLOGY LA English DT Article DE Osteopontin; Schistosomiasis mansoni; Liver fibrosis; Portal hypertension; Biomarker ID IMMUNE-RESPONSES; PATHOLOGICAL SYNDROMES; CBA/J MICE; INFECTIONS; IMMUNOPATHOGENESIS; IMMUNOREGULATION; ACTIVATION; CELLS AB Schistosomiasis is a major cause of fibrosis and portal hypertension. The reason 4-10% of infected subjects develops hepatosplenic schistosomiasis remains unclear. Chronically infected male CBA/J mice reproduce the dichotomic forms of human schistosomiasis. Most mice (80%) develop moderate splenomegaly syndrome (similar to hepatointestinal disease in humans) and 20% present severe hypersplenomegaly syndrome (analogous to human hepatosplenic disease). We demonstrated that the profibrogenic molecule osteopontin discriminates between mice with severe and mild disease and could be a novel morbidity biomarker in murine and human schistosomiasis. Failure to downregulate osteopontin during the chronic phase may explain why hepatosplenic subjects develop severe fibrosis. (C) 2016 Published by Elsevier Ltd on behalf of Australian Society for Parasitology. C1 [Pereira, Thiago Almeida; Diehl, Anna Mae] Duke Univ, Med Ctr, Dept Med, Div Gastroenterol, Durham, NC 27710 USA. [Pereira, Thiago Almeida; Lambertucci, Jose Roberto] Univ Fed Minas Gerais, Fac Med, Lab Doencas Infecciosas & Parasitarias, Dept Clin Med, Belo Horizonte, MG, Brazil. [Pereira, Thiago Almeida] NIAID, Immunopathogesis Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Syn, Wing-Kin] Fdn Liver Res, Inst Hepatol, Liver Regenerat & Repair Res Grp, London, England. [Syn, Wing-Kin] Med Univ South Carolina, Div Gastroenterol & Hepatol, Charleston, SC 29425 USA. [Syn, Wing-Kin] Ralph H Johnson Vet Affairs Med Ctr, Gastroenterol Sect, Charleston, SC USA. [Pereira, Fausto E. L.] Univ Fed Espirito Santo, Nucleo Doengas Infecciosas, Vitoria, ES, Spain. [Secor, William Evan] Ctr Dis Control & Prevent, Atlanta, GA USA. RP Diehl, AM (reprint author), Duke Univ, Med Ctr, Dept Med, Duke Liver Ctr,Div Gastroenterol, 905 S LaSalle St,GSRB1 Snyderman Bldg,Suite 1073, Durham, NC 27710 USA. EM diehl004@mc.duke.edu FU National Institutes of Health (NIH), USA [R01-DK-077794]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), USA; Duke University Endowment, USA; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico, Ministry of Science, Technology and Innovation of Brazil (CNPq); Fundacao de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG), Brazil FX We thank Mr Carl Stone for administrative support. This work was supported by: National Institutes of Health (NIH), USA (grant number R01-DK-077794 (to AMD); Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), USA (to TAP)); the Duke University Endowment, USA (the Florence McAlister Professorship) (to AMD), the Conselho Nacional de Desenvolvimento Cientifico e Tecnologico, Ministry of Science, Technology and Innovation of Brazil (CNPq) (to TAP, FEP and JRL); and Fundacao de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG), Brazil (to JRL). NR 25 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 0020-7519 EI 1879-0135 J9 INT J PARASITOL JI Int. J. Parasit. PD DEC PY 2016 VL 46 IS 13-14 BP 829 EP 832 DI 10.1016/j.ijpara.2016.08.004 PG 4 WC Parasitology SC Parasitology GA EG0ML UT WOS:000390726800001 PM 27729270 ER PT J AU Karatasakis, A Danek, BA Karmpaliotis, D Alaswad, K Jaffer, FA Yeh, RW Patel, M Bahadorani, JN Lombardi, WL Wyman, RM Granthami, JA Kandzari, DE Lembo, NJ Doing, AH Toma, C Moses, J Kirtane, AJ Parikh, MA Ali, ZA SantiagoGarcia Kalsaria, P Karacsonyi, J Alame, AJ Thompson, CA Banerjee, S Brilakis, ES AF Karatasakis, Aris Danek, Barbara A. Karmpaliotis, Dimitri Alaswad, Khaldoon Jaffer, Farouc A. Yeh, Robert W. Patel, Mitul Bahadorani, John N. Lombardi, William L. Wyman, R. Michael Granthami, J. Aaron Kandzari, David E. Lembo, Nicholas J. Doing, Anthony H. Toma, Catalin Moses, JeffreyW. Kirtane, Ajay J. Parikh, Manish A. Ali, Ziad A. SantiagoGarcia Kalsaria, Pratik Karacsonyi, Judit Alame, Aya J. Thompson, Craig A. Banerjee, Subhash Brilakis, Emmanouil S. TI Comparison of various scores for predicting success of chronic total occlusion percutaneous coronary intervention SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE Chronic total occlusion; Percutaneous coronary intervention; Procedural success; Complications; Techniques; Outcomes ID MULTICENTER US REGISTRY; BYPASS GRAFT-SURGERY; PROCEDURAL OUTCOMES; HYBRID APPROACH; ANGIOGRAPHIC SUCCESS; SCORING SYSTEM; CTO REGISTRY; INSIGHTS; IMPACT; REVASCULARIZATION AB Background: Various scoring systems have been developed to predict the technical outcome and procedural efficiency of chronic total occlusion (CTO) percutaneous coronary intervention (PCI). Methods: We examined the predictive capacity of 3 CTO PCI scores (Clinical and Lesion-related [CL], Multicenter CTO registry in Japan [J-CTO] and Prospective Global Registry for the Study of Chronic Total Occlusion Intervention [PROGRESS CTO] scores) in 664 CTO PCIs performed between 2012 and 2016 at 13 US centers. Results: Technical success was 88% and the retrograde approach was utilized in 41%. Mean CL, J-CTO and PROGRESS CTO scores were 3.9 +/- 1.9, 2.6 +/- 1.2 and 1.4 +/- 1.0, respectively. All scores were inversely associated with technical success (p < 0.001 for all) and had moderate discriminatory capacity (area under the curve 0.691 for the CL score, 0.682 for the J-CTO score and 0.647 for the PROGRESS CTO score [p = non-significant for pairwise comparisons]). The difference in technical success between the minimum and maximum CL score strata was the highest (32%, vs. 15% for J-CTO and 18% for PROGRESS CTO scores). All scores tended to perform better in antegrade-only procedures and correlated significantly with procedure time and fluoroscopy dose; the CL score also correlated significantly with contrast utilization. Conclusions: CL, J-CTO and PROGRESS CTO scores perform moderately in predicting technical outcome of CTO PCI, with better performance for antegrade-only procedures. All scores correlate with procedure time and fluoroscopy dose, and the CL score also correlates with contrast utilization. Published by Elsevier Ireland Ltd. C1 [Karatasakis, Aris; Danek, Barbara A.; Kalsaria, Pratik; Karacsonyi, Judit; Alame, Aya J.; Banerjee, Subhash; Brilakis, Emmanouil S.] VA North Texas Hlth Care Syst, Dallas, TX USA. [Karatasakis, Aris; Danek, Barbara A.; Kalsaria, Pratik; Karacsonyi, Judit; Alame, Aya J.; Banerjee, Subhash; Brilakis, Emmanouil S.] Univ Texas Southwestern Med Ctr, Dallas, TX USA. [Karmpaliotis, Dimitri; Moses, JeffreyW.; Kirtane, Ajay J.; Parikh, Manish A.; Ali, Ziad A.] Columbia Univ, New York, NY USA. [Alaswad, Khaldoon] Henry Ford Hosp, Detroit, MI 48202 USA. [Jaffer, Farouc A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Jaffer, Farouc A.; Yeh, Robert W.] Harvard Med Sch, Boston, MA USA. [Yeh, Robert W.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Patel, Mitul; Bahadorani, John N.] VA San Diego Healthcare Syst, La Jolla, CA USA. [Patel, Mitul; Bahadorani, John N.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Lombardi, William L.] Univ Washington, Seattle, WA 98195 USA. [Wyman, R. Michael] Torrance Mem Med Ctr, Torrance, CA USA. [Granthami, J. Aaron] St Lukes Mid Amer Heart Inst, Kansas City, MO USA. [Kandzari, David E.; Lembo, Nicholas J.] Piedmont Heart Inst, Atlanta, GA USA. [Doing, Anthony H.] Med Ctr Rockies, Loveland, CO USA. [Toma, Catalin] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [SantiagoGarcia] Minneapolis VA Hlth Care Syst, Minneapolis, MN USA. [SantiagoGarcia] Univ Minnesota, Minneapolis, MN USA. [Thompson, Craig A.] Boston Sci, Natick, MA USA. RP Brilakis, ES (reprint author), Dallas VA Med Ctr 111A, 4500 South Lancaster Rd, Dallas, TX 75216 USA. EM esbrilakis@gmail.com NR 29 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD DEC 1 PY 2016 VL 224 BP 50 EP 56 DI 10.1016/j.ijcard.2016.08.317 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EF6WH UT WOS:000390471300010 PM 27611917 ER PT J AU Vegter, EL Schmitter, D Hagemeijer, Y Ovchinnikova, ES van der Harst, P Teerlink, JR O'Connor, CM Metra, M Davison, BA Bloomfield, D Cotter, G Cleland, JG Givertz, MM Ponikowski, P van Veldhuisen, DJ van der Meer, P Berezikov, E Voors, AA Khan, MAF AF Vegter, Eline L. Schmitter, Daniela Hagemeijer, Yanick Ovchinnikova, Ekaterina S. van der Harst, Pim Teerlink, John R. O'Connor, Christopher M. Metra, Marco Davison, Beth A. Bloomfield, Daniel Cotter, Gad Cleland, John G. Givertz, Michael M. Ponikowski, Piotr van Veldhuisen, Dirk J. van der Meer, Peter Berezikov, Eugene Voors, Adriaan A. Khan, Mohsin A. F. TI Use of biomarkers to establish potential role and function of circulating microRNAs in acute heart failure SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE Acute heart failure; Circulating microRNAs; Biomarkers; Correlation analysis; Pathways ID CARDIAC-HYPERTROPHY; BREAST-CANCER; GALECTIN-3; FIBROSIS; CARDIOMYOPATHY; ASSOCIATION; ROLOFYLLINE; MACROPHAGES; PROGRESSION; EXPRESSION AB Background: Circulating microRNAs (miRNAs) emerge as potential heart failure biomarkers. We aimed to identify associations between acute heart failure (AHF)-specific circulating miRNAs and well-known heart failure biomarkers. Methods: Associations between 16 biomarkers predictive for 180 day mortality and the levels of 12 AHF-specific miRNAs were determined in 100 hospitalized AHF patients, at baseline and 48 hours. Patients were divided in 4 pre-defined groups, based on clinical parameters during hospitalization. Correlation analyses between miRNAs and biomarkers were performed and complemented by miRNA target prediction and pathway analysis. Results: No significant correlations were found at hospital admission. However, after 48 hours, 7 miRNAs were significantly negatively correlated to biomarkers indicative for a worse clinical outcome in the patient group with the most unfavorable in-hospital course (n = 21); miR-16-5p was correlated to C-reactive protein (R = -0.66, p-value = 0.0027), miR-106a-5p to creatinine (R = -0.68, p-value = 0.002), miR-223-3p to growth differentiation factor 15 (R = -0.69, p-value = 0.0015), miR-652-3p to soluble ST-2 (R = -0.77, p-value < 0.001), miR-199a-3p to procalcitonin (R = -0.72, p-value < 0.001) and galectin-3 (R = -0.73, p-value < 0.001) and miR-18a-5p to procalcitonin (R = -0.68, p-value = 0.002). MiRNA target prediction and pathway analysis identified several pathways related to cardiac diseases, which could be linked to some of the miRNA-biomarker correlations. Conclusions: The majority of correlations between circulating AHF-specific miRNAs were related to biomarkers predictive for a worse clinical outcome in a subgroup of worsening heart failure patients at 48 hours of hospitalization. The selective findings suggest a time-dependent effect of circulating miRNAs and highlight the susceptibility to individual patient characteristics influencing potential relations between miRNAs and biomarkers. (C) 2016 The Authors. Published by Elsevier Ireland Ltd. C1 [Vegter, Eline L.; Hagemeijer, Yanick; Ovchinnikova, Ekaterina S.; van der Harst, Pim; van Veldhuisen, Dirk J.; van der Meer, Peter; Voors, Adriaan A.; Khan, Mohsin A. F.] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Hanzepl 1, NL-9713 GZ Groningen, Netherlands. [Schmitter, Daniela] Momentum Res Inc, Hagmattstr 17, CH-4123 Allschwil, Switzerland. [Ovchinnikova, Ekaterina S.; Berezikov, Eugene] Univ Groningen, Univ Med Ctr Groningen, European Res Inst Biol Ageing, Antonius Deusinglaan 1, NL-9713 AV Groningen, Netherlands. [Teerlink, John R.] Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, San Francisco, CA 94143 USA. [O'Connor, Christopher M.] Inova Heart & Vasc Inst, Falls Church, VA USA. [Metra, Marco] Univ Brescia, Dept Med & Surg Specialties Radiol Sci & Publ Hlt, Cardiol, Brescia, Italy. [Davison, Beth A.; Cotter, Gad] Momentum Res, Durham, NC USA. [Bloomfield, Daniel] Merck Res Labs, Rahway, NY USA. [Cleland, John G.] Imperial Coll, Royal Brompton Hosp, Natl Heart & Lung Inst, London, England. [Cleland, John G.] Imperial Coll, Harefield Hosp, Natl Heart & Lung Inst, London, England. [Givertz, Michael M.] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA USA. [Ponikowski, Piotr] Med Univ, Clin Mil Hosp, Wroclaw, Poland. RP Voors, AA (reprint author), Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Hanzepl 1, NL-9713 GZ Groningen, Netherlands. EM a.a.voors@umcg.nl OI Hagemeijer, Yanick/0000-0001-6036-3741 NR 55 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD DEC 1 PY 2016 VL 224 BP 231 EP 239 DI 10.1016/j.ijcard.2016.09.010 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EF6WH UT WOS:000390471300044 PM 27661412 ER PT J AU O'Sullivan, JF Neylon, A McGorrian, C Blake, GJ AF O'Sullivan, John F. Neylon, Antoinette McGorrian, Catherine Blake, Gavin J. TI miRNA-93-5p and other miRNAs as predictors of coronary artery disease and STEMI SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE Plasma microRNA; Myocardial infarction; Stable coronary artery disease ID ACUTE MYOCARDIAL-INFARCTION; CIRCULATING MICRORNAS; CARDIOVASCULAR-DISEASE; HEART-FAILURE; EXPRESSION; SIGNATURE; RISK; BIOMARKERS; MIR-146A; ATHEROSCLEROSIS AB Background: MicroRNAs (miRNAs), small non-coding RNAs, have been implicated as regulators of all mediators of atherosclerosis, and some reports have suggested increased levels in coronary artery disease (CAD) and acute myocardial infarction (AMI). However, the potential of miRNAs as biomarkers or predictors of disease remains to be established. Methods: We designed a study comprising 150 patients (50 Control, 50 Stable CAD, and 50 ST Elevation Myocardial Infarction (STEMI)), and measured plasma miRNAs in each. We then determined the ability of differential miRNAs, adjusting for Framingham Heart Study (FHS) risk factors, to discriminate between CAD vs Control, and STEMI vs Control. Results: Three miRNAs (miR15a-5p, miR16-5p, and miR93-5p) were significantly increased in Stable CAD vs Control groups and one (miR146a-5p) was significantly decreased in Stable CAD vs Control. One miRNA - miR499a-5p - was significantly increased in the STEMI group compared to Controls. After adjustment for FHS risk factors, miR93-5p levels remained an independent predictor of the presence of CAD (Odds Ratio [OR]= 8.76, P = 0.002). All 4 miRNAs improved discriminatory power for CAD over FHS alone in ROC analysis. Similarly, after adjustment for risk factors miR499-5p remained an independent predictor of STEMI (OR = 3.03, P = 0.001) and improved discriminatory power for STEMI in ROC analyses. Conclusion: We identified 4 miRNAs that were differentially expressed among stable CAD and control patients, and 1 miRNA that was elevated in STEMI patients vs controls. MiR93-5p was the strongest predictor of CAD after adjustment for traditional risk factors, suggesting potential diagnostic utility. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [O'Sullivan, John F.] Harvard Med Sch, Massachusetts Gen Hosp, Cardiovasc Res Ctr, Div Cardiol,Dept Med, Boston, MA USA. [O'Sullivan, John F.] Heart Res Inst, Newtown, NSW 2042, Australia. [O'Sullivan, John F.] Univ Sydney, Charles Perkins Ctr, 3E85,Johns Hopkins Dr, Sydney, NSW 2006, Australia. [O'Sullivan, John F.; Neylon, Antoinette; McGorrian, Catherine; Blake, Gavin J.] Mater Misericordiae Univ Hosp, Dept Cardiol, Eccles St, Dublin 7, Ireland. [McGorrian, Catherine; Blake, Gavin J.] Univ Coll Dublin, Dublin, Ireland. RP O'Sullivan, JF (reprint author), Univ Sydney, Charles Perkins Ctr, 3E85,Johns Hopkins Dr, Sydney, NSW 2006, Australia. EM john.jos.osullivan@gmail.com NR 45 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD DEC 1 PY 2016 VL 224 BP 310 EP 316 DI 10.1016/j.ijcard.2016.09.016 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EF6WH UT WOS:000390471300057 PM 27665403 ER PT J AU Brubaker, K Nelson, BD McPherson, H Ahn, R Oguttu, M Burke, TF AF Brubaker, Kathryn Nelson, Brett D. McPherson, Heather Ahn, Roy Oguttu, Monica Burke, Thomas F. TI Qualitative study of the role of men in maternal health in resource-limited communities in western Kenya SO INTERNATIONAL JOURNAL OF GYNECOLOGY & OBSTETRICS LA English DT Article DE Community health workers; Developing countries; Male involvement; Male role; Maternal health; Maternal mortality; Perceptions; Reproductive health ID MALE INVOLVEMENT; CARE; UGANDA; DELIVERY AB Objective: To better understand the beliefs of men and women in western Kenya regarding the appropriate role of men in maternal health and to identify barriers to greater involvement. Methods: Between June 1 and July 31, 2014, a cross-sectional qualitative study enrolled lay men, lay women, and community health workers from Kisumu and Nyamira counties in western Kenya. Semi-structured focus group discussions were conducted and qualitative approaches were utilized to analyze the transcripts and identify common themes. Results: In total, 134 individuals participated in 18 focus group discussions. Participants discussed the role of men and a general consensus was recorded that it was a man's duty to protect women during pregnancy. When discussing obstacles to male involvement, female participants highlighted gender dynamics and male participants raised financial limitations. Conclusion: There was considerable discrepancy between how men described their roles and how they actually behaved, although educated men appeared to describe themselves as performing more supportive behaviors compared with male participants with less education. It is suggested that interventions aimed at increasing male involvement should incorporate the existing culturally sanctioned roles men perform as a foundation upon which to build, rather than attempting to construct roles that oppose prevailing norms. (C) 2016 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. C1 [Brubaker, Kathryn; Nelson, Brett D.; McPherson, Heather; Ahn, Roy; Burke, Thomas F.] Massachusetts Gen Hosp, Dept Emergency Med, Div Global Hlth & Human Rights, 125 Nashua St Suite 910, Boston, MA 02114 USA. [Brubaker, Kathryn; Nelson, Brett D.; Burke, Thomas F.] Harvard Med Sch, Boston, MA USA. [Oguttu, Monica] Kisumu Med & Educ Trust, Kisumu, Kenya. [Burke, Thomas F.] Harvard TH Chan Sch Publ Hlth, Boston, MA USA. RP Nelson, BD (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, Div Global Hlth & Human Rights, 125 Nashua St Suite 910, Boston, MA 02114 USA. EM brett.d.nelson@gmail.com OI Nelson, Brett/0000-0002-5049-1798 FU Ujenzi Charitable Trust; Harvard Medical School FX The present study was funded by Ujenzi Charitable Trust and Harvard Medical School. The authors would like to thank Caleb Okelo for his critical help with study recruitment and translation. NR 15 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0020-7292 EI 1879-3479 J9 INT J GYNECOL OBSTET JI Int. J. Gynecol. Obstet. PD DEC PY 2016 VL 135 IS 3 BP 245 EP 249 DI 10.1016/j.ijgo.2016.06.015 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EG1WK UT WOS:000390824200002 PM 27591051 ER PT J AU Kassick, ME Chinbuah, MA Serpa, M Mazia, G Tang, AM Sagoe-Moses, I Taylor, M Dwomo-Fokuo, A Salifu, N Arhinful, DK Engmann, C Burke, TF Cofie, P Nelson, BD AF Kassick, Megan E. Chinbuah, Margaret A. Serpa, Magdalena Mazia, Goldy Tang, Alice M. Sagoe-Moses, Isabella Taylor, Mira Dwomo-Fokuo, Adoma Salifu, Nihad Arhinful, Daniel K. Engmann, Cyril Burke, Thomas F. Cofie, Patience Nelson, Brett D. TI Evaluating a novel neonatal-care assessment tool among trained delivery attendants in a resource-limited setting SO INTERNATIONAL JOURNAL OF GYNECOLOGY & OBSTETRICS LA English DT Article DE Birth attendant; Essential care for every baby; Essential newborn care; Ghana; Inter-rater reliability; Neonatal mortality; Newborn health; Objective structured clinical examination ID RESUSCITATION SKILLS; PROGRAM; IMPACT AB Objective: To validate a novel objective structured clinical examination (OSCE) tool for assessing neonatal care skills among delivery attendants trained as part of the Essential Care for Every Baby (ECEB) program and to assess ECEB training effectiveness. Methods: Between August 1 and September 30, 2015, a cross-sectional study enrolled ECEB-trained healthcare providers who attended deliveries from the Brong Ahafo and Eastern regions of Ghana. Participants completed a previously developed 21-item OSCE tool that assessed neonatal-care competency. Participant performance was scored independently by regional trainers and national master trainers. The inter-rater scoring reliability was assessed using the Cohen kappa coefficient and performance was compared across participant characteristics. Results: The study enrolled 57 trained delivery attendants from 12 district hospitals. Inter-rater agreement was perfect (kappa 1.00) or almost perfect (kappa 0.81-0.99) for nine OSCE items, substantial (kappa 0.61-0.80) or moderate (kappa 0.41-0.60) for 11 items, and fair (kappa 0.21-0.40) for one item. Differences in OSCE-item performance were recorded based on participants' regions, facility type, age, and education level (P<0.05). Conclusions: In a resource-limited setting, the OSCE tool demonstrated substantial reliability and ECEB-trained healthcare practitioners exhibited satisfactory performance. The OSCE tool could be useful in similar settings and could have potential for up-scaled use in assessing neonatal-management skills. (C) 2016 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. C1 [Kassick, Megan E.; Burke, Thomas F.; Nelson, Brett D.] Massachusetts Gen Hosp, Dept Emergency Med, Div Global Hlth & Human Rights, 125 Nashua St,Suite 910, Boston, MA 02114 USA. [Chinbuah, Margaret A.; Serpa, Magdalena; Mazia, Goldy; Engmann, Cyril; Cofie, Patience] PATH, Accra, Ghana. [Tang, Alice M.] Tufts Univ, Sch Med, Dept Publ Hlth & Community Med, Boston, MA 02111 USA. [Sagoe-Moses, Isabella; Taylor, Mira; Dwomo-Fokuo, Adoma; Salifu, Nihad] Ghana Hlth Serv, Accra, Ghana. [Arhinful, Daniel K.] Noguchi Mem Inst Med Res, Accra, Ghana. [Nelson, Brett D.] Massachusetts Gen Hosp, Dept Pediat, Div Global Hlth, Boston, MA 02114 USA. [Engmann, Cyril] Univ Washington, Dept Pediat, Div Neonatal Perinatal Med, Seattle, WA 98195 USA. [Burke, Thomas F.; Nelson, Brett D.] Harvard Med Sch, Boston, MA USA. RP Nelson, BD (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, Div Global Hlth & Human Rights, 125 Nashua St,Suite 910, Boston, MA 02114 USA. EM brett.d.nelson@gmail.com OI Nelson, Brett/0000-0002-5049-1798 FU Children's Investment Fund Foundation, UK FX The present newborn survival training program and its evaluation were funded by the Children's Investment Fund Foundation, UK. NR 20 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0020-7292 EI 1879-3479 J9 INT J GYNECOL OBSTET JI Int. J. Gynecol. Obstet. PD DEC PY 2016 VL 135 IS 3 BP 285 EP 289 DI 10.1016/j.ijgo.2016.06.014 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EG1WK UT WOS:000390824200011 PM 27599603 ER PT J AU Burke, TF Nelson, BD Kandler, T Altawil, Z Rogo, K Imbamba, J Odenyo, S Pinder, L Lozo, S Guha, M Eckardt, MJ AF Burke, Thomas F. Nelson, Brett D. Kandler, Taylor Altawil, Zaid Rogo, Khama Imbamba, Javan Odenyo, Stella Pinder, Leeya Lozo, Svjetlana Guha, Moytrayee Eckardt, Melody J. TI Evaluation of a ketamine-based anesthesia package for use in emergency cesarean delivery or emergency laparotomy when no anesthetist is available SO INTERNATIONAL JOURNAL OF GYNECOLOGY & OBSTETRICS LA English DT Article DE Anesthesia; Cesarean delivery; Emergency surgery; Ketamine; Laparotomy; Low-resource setting; Maternal health; Maternal mortality; Task shifting ID INDUCTION; SECTION AB Objective: To assess the safety of a ketamine-based rescue anesthesia package to support emergency cesarean delivery and emergency laparotomy when no anesthetist was available. Methods: A prospective case-series study was conducted at seven sub-county hospitals in western Kenya between December 10, 2013, and January 20, 2016. Non-anesthetist clinicians underwent 5 days of training in the Every Second Matters-Ketamine (ESM-Ketamine) program. A database captured preoperative, intraoperative, and postoperative details of all surgeries in which ESM-Ketamine was used. The primary outcome measure was the ability of ESM-Ketamine to safely support emergency operative procedures. Results: Non-anesthetist providers trained on ESM-Ketamine supported 83 emergency cesarean deliveries and 26 emergency laparotomies. Ketamine was administered by 10 nurse-midwives and six clinical officers. Brief oxygen desaturations (<92% for <30 s) were recorded among 5 (4.6%) of the 109 patients. Hallucinations occurred among 9 (8.3%) patients. No serious adverse events related to the use of ESM-Ketamine were recorded. Conclusion: The ESM-Ketamine package can be safely used by trained non-anesthetist providers to support emergency cesarean delivery and emergency laparotomy when no anesthetist is available. (C) 2016 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. C1 [Burke, Thomas F.; Nelson, Brett D.; Kandler, Taylor; Altawil, Zaid; Pinder, Leeya; Lozo, Svjetlana; Guha, Moytrayee; Eckardt, Melody J.] Massachusetts Gen Hosp, Dept Emergency Med, Div Global Hlth & Human Rights, 125 Nashua St,Suite 910, Boston, MA 02114 USA. [Burke, Thomas F.; Nelson, Brett D.] Harvard Med Sch, Boston, MA USA. [Burke, Thomas F.; Pinder, Leeya; Lozo, Svjetlana] Harvard TH Chan Sch Publ Hlth, Dept Global Hlth & Populat, Boston, MA USA. [Rogo, Khama; Imbamba, Javan; Odenyo, Stella; Pinder, Leeya; Lozo, Svjetlana] Sagam Community Hosp, Luanda, Kenya. [Rogo, Khama] Kenya Obstet & Gynaecol Soc, Nairobi, Kenya. RP Burke, TF (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, Div Global Hlth & Human Rights, 125 Nashua St,Suite 910, Boston, MA 02114 USA. EM tfburke@partners.org OI Nelson, Brett/0000-0002-5049-1798 FU Ujenzi Charitable Trust; US Agency for International Development; Government of Norway; Bill & Melinda Gates Foundation; Grand Challenges Canada; UK Government; Saving Lives at Birth FX The Every Second Matters Ketamine program is supported by the Ujenzi Charitable Trust and the Saving Lives at Birth partners, which include the US Agency for International Development, the Government of Norway, the Bill & Melinda Gates Foundation, Grand Challenges Canada, and the UK Government. The present manuscript was prepared by faculty from Massachusetts General Hospital and Harvard Medical School, and does not necessarily reflect the views of the funding bodies. NR 15 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0020-7292 EI 1879-3479 J9 INT J GYNECOL OBSTET JI Int. J. Gynecol. Obstet. PD DEC PY 2016 VL 135 IS 3 BP 295 EP 298 DI 10.1016/j.ijgo.2016.06.024 PG 4 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EG1WK UT WOS:000390824200013 PM 27614787 ER PT J AU Lee, SJ Logan, B Westervelt, P Cutler, C Woolfrey, A Khan, SP Waller, EK Maziarz, RT Wu, J Shaw, BE Confer, D Horowitz, MM Anasetti, C AF Lee, Stephanie J. Logan, Brent Westervelt, Peter Cutler, Corey Woolfrey, Ann Khan, Shakila P. Waller, Edmund K. Maziarz, Richard T. Wu, Juan Shaw, Bronwen E. Confer, Dennis Horowitz, Mary M. Anasetti, Claudio TI Comparison of Patient-Reported Outcomes in 5-Year Survivors Who Received Bone Marrowvs Peripheral Blood Unrelated Donor Transplantation Long-term Follow-up of a Randomized Clinical Trial SO JAMA ONCOLOGY LA English DT Article ID QUALITY-OF-LIFE; HEMATOPOIETIC-CELL TRANSPLANTATION; VERSUS-HOST-DISEASE; PSYCHOLOGICAL DISTRESS; FUNCTIONAL STATUS; HEALTH; CANCER; SCALE AB IMPORTANCE Bone marrow or peripheral blood from unrelated donors may be used for hematopoietic cell transplantation. Information about the relative success of transplantation with these 2 graft sources would help physicians and patients choose between them. OBJECTIVE To compare patient-reported outcomes between patients randomized to receive 1 of 2 graft types for unrelated donor transplantation. DESIGN, SETTING, AND PARTICIPANTS This follow-up of a randomized clinical trial included English-or Spanish-speaking patients 16 years or older participating in a multicenter randomized clinical trial of unrelated donor bone marrow (BM) vs peripheral blood (PB) (N = 551) in hematopoietic cell transplantation for hematologic neoplasms. Patient-reported outcomes were collected from patients at enrollment and 0.5,1,2, and 5 years after transplantation. INTERVENTIONS Unrelated donor BM or PB hematopoietic cell transplantation. MAIN OUTCOMES AND MEASURES Functional Assessment of Cancer Therapy-Bone Marrow Transplant, Mental Health Inventory, occupational functioning, Lee Chronic Graft-vs-Host Disease Symptom Scale. RESULTS At 5 years after transplantation, 102 BMand 93 PB participants were alive and eligible for assessment (age >= 40 years or older: 104 [53.5%] male: 101 [51.8%]). The mean (SE) Mental Health Inventory PsychologicalWell-Being scores (78.9 [1.7] vs 72.2 [1.9]; P =.01; higher better) and Lee chronic graft-vs-host disease symptom scores (13.1 [1.5] vs 19.3 [1.6]; P =.004; lower better) were significantly better for BMrecipients, adjusting for baseline scores and missing data. Recipients of BM were also more likely to be working full or part-time than recipients of PB (odds ratio, 1.5; 95% CI, 1.2-2.0; P =.002), adjusting for work status before transplantation. With a median follow-up of 73 months (range, 30-121 months) for survivors, no differences in survival (40% vs 39%; P =.84), relapse (32% vs 29%; P =.47), or treatment-related mortality (29% vs 32%; P =.44) between BM and PB were observed. CONCLUSIONS AND RELEVANCE Recipients of unrelated donor BM had better psychological well-being, less burdensome chronic GVHD symptoms, and were more likely to return to work than recipients of PB at 5 years after transplantation. Bone marrow should be the standard of care for these types of transplant procedures. C1 [Lee, Stephanie J.] Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA. [Logan, Brent] Med Coll Wisconsin, Div Biostat, Milwaukee, WI 53226 USA. [Westervelt, Peter] Washington Univ, Sch Med, Dept Med, Div Oncol, St Louis, MO USA. [Cutler, Corey] Harvard Med Sch, Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA USA. [Cutler, Corey] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA. [Woolfrey, Ann] Fred Hutchinson Canc Res Ctr, Transplantat Biol Dept, Div Clin Res, Seattle, WA USA. [Khan, Shakila P.] Mayo Clin, Div Pediat Hematol Oncol, Rochester, MN USA. [Waller, Edmund K.] Emory Univ, Dept Hematol & Med Oncol, Winship Canc Inst, Atlanta, GA 30322 USA. [Maziarz, Richard T.] Oregon Hlth & Sci Univ, Adult Blood & Marrow Stem Cell Transplant Program, Knight Canc Inst, Portland, OR 97201 USA. [Wu, Juan] Emmes Corp, Rockville, MD USA. [Shaw, Bronwen E.; Horowitz, Mary M.] Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Confer, Dennis] Natl Marrow Donor Program, Minneapolis, MN USA. [Anasetti, Claudio] H Lee Moffitt Canc Ctr & Res Inst, Dept Blood & Marrow Transplantat, Tampa, FL USA. RP Lee, SJ (reprint author), Canc Res Ctr, D5-290,POB 19024, Seattle, WA 98109 USA. EM sjlee@fhcrc.org FU National Heart, Lung, and Blood Institute [U10HL069294]; Department of the Navy, Office of Naval Research; National Marrow Donor Program; National Cancer Institute FX Support for this study was provided by grant U10HL069294 from the National Heart, Lung, and Blood Institute and the National Cancer Institute to support the Blood and Marrow Transplant Clinical Trials Network and the Department of the Navy, Office of Naval Research, and the National Marrow Donor Program. Enrollment support was provided by DKMS Germany. NR 22 TC 1 Z9 1 U1 2 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2374-2445 J9 JAMA ONCOL JI JAMA Oncol. PD DEC 1 PY 2016 VL 2 IS 12 BP 1583 EP 1589 DI 10.1001/jamaoncol.2016.2520 PG 7 WC Oncology SC Oncology GA EF8TG UT WOS:000390601900012 PM 27532508 ER PT J AU Nishino, M Giobbie-Hurder, A Hatabu, H Ramaiya, NH Hodi, S AF Nishino, Mizuki Giobbie-Hurder, Anita Hatabu, Hiroto Ramaiya, Nikhil H. Hodi, Stephen TI Incidence of Programmed Cell Death 1 Inhibitor-Related Pneumonitis in Patients With Advanced Cancer A Systematic Review and Meta-analysis SO JAMA ONCOLOGY LA English DT Review ID LONG-TERM SAFETY; ADVANCED MELANOMA; LUNG-CANCER; ADVERSE EVENTS; UNTREATED MELANOMA; RECEIVING NIVOLUMAB; METASTATIC MELANOMA; ANTI-PD-1 ANTIBODY; CLINICAL ACTIVITY; PD-1 BLOCKADE AB IMPORTANCE Programmed cell death 1 (PD-1) inhibitor-related pneumonitis is a rare but clinically serious and potentially life-threatening adverse event. Little is known about its incidence across different tumor types and treatment regimens. OBJECTIVE To compare the incidence of PD-1 inhibitor-related pneumonitis among different tumor types and therapeutic regimens. DATA SOURCES A PubMed search through November 10, 2015, and a review of references from relevant articles. For the PubMed search, the following keywords or corresponding Medical Subject Heading terms were used: nivolumab, pembrolizumab, and PD-1 inhibitor. STUDY SELECTION Twenty-six original articles of PD-1 inhibitor trial results were identified. Among them, 20 studies of melanoma, non-small cell lung cancer (NSCLC), or renal cell carcinoma (RCC) were eligible for ameta-analysis. DATA EXTRACTION AND SYNTHESIS The data were extracted by 1 primary reviewer and then independently reviewed by 2 secondary reviewers following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Comparisons of the incidence were based on marginal, exact generalized linear models with generalized estimating equations. MAIN OUTCOMES AND MEASURES Incidence of all-grade and grade 3 or higher pneumonitis and pneumonitis-related deaths. RESULTS Twenty studies of single-tumor-type trials of PD-1 inhibitor (12 melanoma studies, 5 NSCLC studies, and 3 RCC studies) (a total of 4496 unique patients) were included in the meta-analysis. The overall incidence of pneumonitis during PD-1 inhibitor monotherapy was 2.7%(95% CI, 1.9%-3.6%) for all-grade and 0.8%(95% CI, 0.4%-1.2%) for grade 3 or higher pneumonitis. The incidence was higher in NSCLC for all-grade (4.1% vs 1.6%; P =.002) and grade 3 or higher pneumonitis (1.8% vs 0.2%; P <.001) compared with melanoma. The incidence in RCC was higher than in melanoma for all-grade pneumonitis (4.1% vs 1.6%; P <.001) but not for grade 3 or higher pneumonitis. Four pneumonitis-related deaths were observed in patients with NSCLC in the monotherapy group. Pneumonitis was more frequent during combination therapy than monotherapy for all-grade (6.6% vs 1.6%; P <.001) and grade 3 or higher pneumonitis (1.5% vs 0.2%; P =.001) in melanoma, with 1 pneumonitis-related death during combination therapy. Multivariable analyses demonstrated higher odds of pneumonitis in NSCLC for all-grade (odds ratio [OR], 1.43; 95% CI, 1.08-1.89; P =.005) and grade 3 or higher pneumonitis (OR, 2.85; 95% CI, 1.60-5.08; P <.001) and in RCC for all-grade pneumonitis (OR, 1.59; 95% CI, 1.32-1.92; P <.001) compared with melanoma. The combination therapy had significantly higher odds than monotherapy for all-grade (OR, 2.04; 95% CI, 1.69-2.50; P <.001) and grade 3 or higher pneumonitis (OR, 2.86; 95% CI, 1.79-4.35; P <.001). CONCLUSIONS AND RELEVANCE The incidence of PD-1 inhibitor-related pneumonitiswas higher in NSCLC and RCC and during combination therapy. These findings contribute to enhance awareness among clinicians and support further investigations to meet the clinical needs. C1 [Nishino, Mizuki; Hatabu, Hiroto; Ramaiya, Nikhil H.] Brigham & Womens Hosp, Dept Radiol, 75 Francis St, Boston, MA 02115 USA. [Nishino, Mizuki; Hatabu, Hiroto; Ramaiya, Nikhil H.] Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02115 USA. [Giobbie-Hurder, Anita] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Hodi, Stephen] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Hodi, Stephen] Dana Farber Canc Inst, Dept Med, Boston, MA 02115 USA. [Hodi, Stephen] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. RP Nishino, M (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02115 USA. EM mizuki_nishino@dfci.harvard.edu FU National Cancer Institute [5K23CA157631, 1K23CA157631] FX This study was supported by grants 5K23CA157631 and 1K23CA157631 from the National Cancer Institute (Dr Nishino). NR 45 TC 2 Z9 2 U1 2 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2374-2445 J9 JAMA ONCOL JI JAMA Oncol. PD DEC 1 PY 2016 VL 2 IS 12 BP 1607 EP 1616 DI 10.1001/jamaoncol.2016.2453 PG 10 WC Oncology SC Oncology GA EF8TG UT WOS:000390601900015 PM 27540850 ER PT J AU Nipp, RD Moy, B AF Nipp, Ryan D. Moy, Beverly TI No Conflict, No Interest SO JAMA ONCOLOGY LA English DT Editorial Material ID ONCOLOGY C1 [Nipp, Ryan D.; Moy, Beverly] Massachusetts Gen Hosp, Ctr Canc, 55 Fruit St,Yawkey 9A, Boston, MA 02114 USA. RP Moy, B (reprint author), Massachusetts Gen Hosp, Ctr Canc, 55 Fruit St,Yawkey 9A, Boston, MA 02114 USA. EM bmoy@mgh.harvard.edu NR 6 TC 2 Z9 2 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 DEC 1 PY 2016 VL 2 IS 12 BP 1631 EP 1632 DI 10.1001/jamaoncol.2016.2726 PG 3 WC Oncology SC Oncology GA EF8TG UT WOS:000390601900019 PM 27560041 ER PT J AU Aerts, HJWL AF Aerts, Hugo J. W. L. TI The Potential of Radiomic-Based Phenotyping in PrecisionMedicine A Review SO JAMA ONCOLOGY LA English DT Review ID CELL LUNG-CANCER; COMPUTER-AIDED DETECTION; PHASE-III TRIAL; PROGNOSTIC-SIGNIFICANCE; SCREENING MAMMOGRAPHY; 1ST-LINE TAXANE/CARBOPLATIN; PULMONARY ADENOCARCINOMA; AUTOMATED DETECTION; VOLUME MEASUREMENT; TEXTURAL FEATURES AB IMPORTANCE Advances in genomics have led to the recognition that tumors are populated by distinct genotypic subgroups that drive tumor development and progression. The spatial and temporal heterogeneity of solid tumors has been a critical barrier to the development of precision medicine approaches because the standard approach to tumor sampling, often invasive needle biopsy, is unable to fully capture the spatial state of the tumor. Image-based phenotyping, which represents quantification of the tumor phenotype through medical imaging, is a promising development for precision medicine. OBSERVATIONS Medical imaging can provide a comprehensive macroscopic picture of the tumor phenotype and its environment that is ideally suited to quantifying the development of the tumor phenotype before, during, and after treatment. As a noninvasive technique, medical imaging can be performed at low risk and inconvenience to the patient. The semantic features approach to tumor phenotyping, accomplished by visual assessment of radiologists, is compared with a computational radiomic approach that relies on automated processing of imaging assays. Together, these approaches capture important information for diagnostic, prognostic, and predictive purposes. CONCLUSIONS AND RELEVANCE Although imaging technology is already embedded in clinical practice for diagnosis, staging, treatment planning, and response assessment, the transition of these computational methods to the clinic has been surprisingly slow. This review outlines the promise of these novel technologies for precision medicine and the obstacles to clinical application. C1 [Aerts, Hugo J. W. L.] Harvard Med Sch, Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA USA. [Aerts, Hugo J. W. L.] Harvard Med Sch, Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiol, Boston, MA USA. RP Aerts, HJWL (reprint author), Harvard Inst Med, Dana Farber Canc Inst, Dept Radiat Oncol, Ste HIM 343,77 Ave Louis Pasteur, Boston, MA 02115 USA.; Aerts, HJWL (reprint author), Harvard Inst Med, Dana Farber Canc Inst, Dept Radiol, Ste HIM 343,77 Ave Louis Pasteur, Boston, MA 02115 USA. EM hugo_aerts@dfci.harvard.edu RI Aerts, Hugo/P-6350-2015 OI Aerts, Hugo/0000-0002-2122-2003 FU National Institutes of Health [U01CA190234, U24CA194354] FX This study was supported by awards U01CA190234 and U24CA194354 from the National Institutes of Health. NR 76 TC 2 Z9 2 U1 5 U2 5 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 DEC 1 PY 2016 VL 2 IS 12 BP 1636 EP 1642 DI 10.1001/jamaoncol.2016.2631 PG 7 WC Oncology SC Oncology GA EF8TG UT WOS:000390601900020 PM 27541161 ER PT J AU Donovan, NJ Okereke, OI Vannini, P Amariglio, RE Rentz, DM Marshall, GA Johnson, KA Sperling, RA AF Donovan, Nancy J. Okereke, Olivia I. Vannini, Patrizia Amariglio, Rebecca E. Rentz, Dorene M. Marshall, Gad A. Johnson, Keith A. Sperling, Reisa A. TI Association of Higher Cortical Amyloid Burden With Loneliness in Cognitively Normal Older Adults SO JAMA PSYCHIATRY LA English DT Article ID PITTSBURGH-COMPOUND-B; ALZHEIMERS-DISEASE; DEPRESSIVE SYMPTOMS; SOCIAL NETWORKS; ALAMEDA COUNTY; FOLLOW-UP; DECLINE; RISK; HEALTH; POPULATION AB IMPORTANCE Emotional and behavioral symptoms in cognitively normal older people may be direct manifestations of Alzheimer disease (AD) pathophysiology at the preclinical stage, prior to the onset of mild cognitive impairment. Loneliness is a perceived state of social and emotional isolation that has been associated with cognitive and functional decline and an increased risk of incident AD dementia. We hypothesized that loneliness might occur in association with elevated cortical amyloid burden, an in vivo research biomarker of AD. OBJECTIVE To determine whether cortical amyloid burden is associated with greater loneliness in cognitively normal older adults. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional analyses using data from the Harvard Aging Brain Study of 79 cognitively normal, community-dwelling participants. A continuous, aggregate measure of cortical amyloid burden, determined by Pittsburgh Compound B-positron emission tomography (PiB-PET), was examined in association with loneliness in linear regression models adjusting for age, sex, apolipoprotein E epsilon 4 (APOE epsilon 4), socioeconomic status, depression, anxiety, and social network (without and with the interaction of amyloid and APOEe4). We also quantified the association of high amyloid burden (amyloid-positive group) to loneliness (lonely group) using logistic regression, controlling for the same covariates, with the amyloid-positive group and the lonely group, each composing 32% of the sample (n = 25). MAIN OUTCOMES AND MEASURES Loneliness, as determined by the 3-item UCLA Loneliness Scale (possible range, 3-12, with higher score indicating greater loneliness). RESULTS The 79 participants included 43 women and 36 men with a mean (SD) age of 76.4 (6.2) years. Mean (SD) cortical amyloid burden via PiB-PET was 1.230 (0.209), and the mean (SD) UCLA-3 loneliness score was 5.3 (1.8). Twenty-two (28%) had positive APOE epsilon 4 carrier status, and 25 (32%) were in the amyloid-positive group with cortical PiB distribution volume ratio greater than 1.2. Controlling for age, sex, APOEe4, socioeconomic status, depression, anxiety, and social network, we found that higher amyloid burden was significantly associated with greater loneliness: compared with individuals in the amyloid-negative group, those in the amyloid-positive group were 7.5-fold (95% CI, 1.7-fold to 34.0-fold) more likely to be classified as lonely than nonlonely (beta = 3.3, partial r = 0.4, P = .002). Furthermore, the association of high amyloid burden and loneliness was stronger in APOE epsilon 4 carriers than in noncarriers. CONCLUSIONS AND RELEVANCE We report a novel association of loneliness with cortical amyloid burden in cognitively normal older adults, suggesting that loneliness is a neuropsychiatric symptom relevant to preclinical AD. This work will inform new research into the neural underpinnings and disease mechanisms involved in loneliness and may enhance early detection and intervention research in AD. C1 [Donovan, Nancy J.; Vannini, Patrizia; Amariglio, Rebecca E.; Rentz, Dorene M.; Marshall, Gad A.; Johnson, Keith A.; Sperling, Reisa A.] Harvard Med Sch, Brigham & Womens Hosp, Ctr Alzheimer Res & Treatment, 221 Longwood Ave,BL 104H, Boston, MA 02215 USA. [Donovan, Nancy J.; Vannini, Patrizia; Amariglio, Rebecca E.; Rentz, Dorene M.; Marshall, Gad A.; Johnson, Keith A.; Sperling, Reisa A.] Harvard Med Sch, Brigham & Womens Hosp, Ctr Alzheimer Res & Treatment, Dept Neurol, Boston, MA 02215 USA. [Donovan, Nancy J.; Vannini, Patrizia; Amariglio, Rebecca E.; Rentz, Dorene M.; Marshall, Gad A.; Johnson, Keith A.; Sperling, Reisa A.] Brigham & Womens Hosp, Harvard Med Sch, Dept Psychiat, Boston, MA USA. [Donovan, Nancy J.; Okereke, Olivia I.; Rentz, Dorene M.] Brigham & Womens Hosp, Harvard Med Sch, Dept Psychiat, Boston, MA USA. [Donovan, Nancy J.] Massachusetts Gen Hosp, Harvard Med Sch, Dept Psychiat, Boston, MA USA. [Amariglio, Rebecca E.; Rentz, Dorene M.; Marshall, Gad A.; Johnson, Keith A.; Sperling, Reisa A.] Massachusetts Gen Hosp, Harvard Med Sch, Dept Neurol, Boston, MA USA. [Johnson, Keith A.] Massachusetts Gen Hosp, Harvard Med Sch, Dept Radiol, Boston, MA USA. RP Donovan, NJ (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Ctr Alzheimer Res & Treatment, 221 Longwood Ave,BL 104H, Boston, MA 02215 USA. EM njdonovan@partners.org RI Okereke, Olivia/R-9934-2016 FU National Institute of Aging (NIA) [R03 AG045080, R01 AG027435, K24 AG035007]; Harvard Medical School Department of Psychiatry Dupont-Warren Fellowship and Livingston Award; Harvard Aging Brain Study (NIA) [P01 AG036694, R01 AG037497]; Muriel Silberstein Alzheimer's Disease Research Fund FX This study was supported by the National Institute of Aging (NIA) grants R03 AG045080 (Dr Donovan), R01 AG027435 (Dr Sperling), and K24 AG035007 (Dr Sperling); the Harvard Medical School Department of Psychiatry Dupont-Warren Fellowship and Livingston Award (Dr Donovan); and the Harvard Aging Brain Study (NIA grants P01 AG036694 [Drs Sperling and Johnson] and R01 AG037497 [Dr Sperling]); and the Muriel Silberstein Alzheimer's Disease Research Fund (Dr Donovan). NR 63 TC 1 Z9 1 U1 8 U2 8 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-622X EI 2168-6238 J9 JAMA PSYCHIAT JI JAMA Psychiatry PD DEC 1 PY 2016 VL 73 IS 12 BP 1230 EP 1237 DI 10.1001/jamapsychiatry.2016.2657 PG 8 WC Psychiatry SC Psychiatry GA EF9RH UT WOS:000390666900006 PM 27806159 ER PT J AU Seidman, LJ Shapiro, DI Stone, WS Woodberry, KA Ronzio, A Cornblatt, BA Addington, J Bearden, CE Cadenhead, KS Cannon, TD Mathalon, DH McGlashan, TH Perkins, DO Tsuang, MT Walker, EF Woods, SW AF Seidman, Larry J. Shapiro, Daniel I. Stone, William S. Woodberry, Kristen A. Ronzio, Ashley Cornblatt, Barbara A. Addington, Jean Bearden, Carrie E. Cadenhead, Kristin S. Cannon, Tyrone D. Mathalon, Daniel H. McGlashan, Thomas H. Perkins, Diana O. Tsuang, Ming T. Walker, Elaine F. Woods, Scott W. TI Association of Neurocognition With Transition to Psychosis Baseline Functioning in the Second Phase of the North American Prodrome Longitudinal Study SO JAMA PSYCHIATRY LA English DT Article ID CONSENSUS COGNITIVE BATTERY; CLINICAL HIGH-RISK; CALGARY DEPRESSION SCALE; ULTRA-HIGH RISK; MULTIPLE IMPUTATION; BIPOLAR DISORDER; SCHIZOPHRENIA; DEFICITS; IMPAIRMENT; YOUTH AB IMPORTANCE Neurocognition is a central characteristic of schizophrenia and other psychotic disorders. Identifying the pattern and severity of neurocognitive functioning during the "near-psychotic," clinical high-risk (CHR) state of psychosis is necessary to develop accurate risk factors for psychosis and more effective and potentially preventive treatments. OBJECTIVES To identify core neurocognitive dysfunctions associated with the CHR phase, measure the ability of neurocognitive tests to predict transition to psychosis, and determine if neurocognitive deficits are robust or explained by potential confounders. DESIGN, SETTING, AND PARTICIPANTS In this case-control study across 8 sites, baseline neurocognitive data were collected from January 2009 to April 2013 in the second phase of the North American Prodrome Longitudinal Study (NAPLS 2). The dates of analysis were August 2015 to August 2016. The setting was a consortium of 8 university-based, outpatient programs studying the psychosis prodrome in North America. Participants were 264 healthy controls (HCs) and 689 CHR individuals, aged 12 to 35 years. MAIN OUTCOMES AND MEASURES Neurocognitive associations with transition to psychosis and effects of medication on neurocognition. Nineteen neuropsychological tests and 4 factors derived from factor analysis were used: executive and visuospatial abilities, verbal abilities, attention and working memory abilities, and declarative memory abilities. RESULTS This study included 264 HCs (137 male and 127 female) and 689 CHR participants (398 male and 291 female). In the HCs, 145 (54.9%) were white and 119 (45.1%) were not, whereas 397 CHR participants (57.6%) were white and 291 (42.3%) were not. In the HCs, 45 (17%) were of Hispanic origin, whereas 127 CHR participants (18.4%) were of Hispanic origin. The CHR individuals were significantly impaired compared with HCs on attention and working memory abilities and declarative memory abilities. The CHR converters had large deficits in attention and working memory abilities and declarative memory abilities (Cohen d, approximately 0.80) compared with controls and performed significantly worse on these dimensions than nonconverters (Cohen d, 0.28 and 0.48, respectively). These results were not accounted for by general cognitive ability or medications. In Cox proportional hazards regression, time to conversion in those who transitioned to psychosis was significantly predicted by high verbal (premorbid) abilities (beta = 0.40; hazard ratio [HR], 1.48; 95% CI, 1.08-2.04; P = .02), impaired declarative memory abilities (beta = -0.87; HR, 0.42; 95% CI, 0.31-0.56; P < .001), age (beta = -0.10; HR, 0.90; 95% CI, 0.84-0.97; P = .003), site, and a combined score of unusual thought content or delusional ideas and suspiciousness or persecutory ideas items (beta = 0.44; HR, 1.56; 95% CI, 1.36-1.78; P < .001). CONCLUSIONS AND RELEVANCE Neurocognitive impairment, especially in attention and working memory abilities and declarative memory abilities, is a robust characteristic of CHR participants, especially those who later develop psychosis. Interventions targeting the enhancement of neurocognitive functioning are warranted in this population. C1 [Seidman, Larry J.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Psychiat, 75 Fenwood Rd,Room 542, Boston, MA 02115 USA. [Seidman, Larry J.] Massachusetts Gen Hosp, Harvard Med Sch, Dept Psychiat, Boston, MA USA. [Cornblatt, Barbara A.] Zucker Hillside Hosp, Dept Psychiat, New York, NY USA. [Addington, Jean] Univ Calgary, Dept Psychiat, Calgary, AB, Canada. [Bearden, Carrie E.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA USA. [Bearden, Carrie E.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA USA. [Cadenhead, Kristin S.] Univ Calif San Diego, Dept Psychiat, San Diego, CA USA. [Cannon, Tyrone D.] Yale Univ, Dept Psychol, New Haven, CT USA. [Cannon, Tyrone D.; McGlashan, Thomas H.; Woods, Scott W.] Yale Univ, Dept Psychiat, New Haven, CT USA. [Mathalon, Daniel H.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Mathalon, Daniel H.] San Francisco Vet Affairs, Med Ctr, San Francisco, CA USA. [Perkins, Diana O.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Walker, Elaine F.] Emory Univ, Dept Psychol, Atlanta, GA USA. [Walker, Elaine F.] Emory Univ, Dept Psychiat, Atlanta, GA USA. RP Seidman, LJ (reprint author), Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Psychiat, 75 Fenwood Rd,Room 542, Boston, MA 02115 USA. EM lseidman@bidmc.harvard.edu FU National Institute of Mental Health [U01 MH081928, P50 MH080272, R01 MH096027, U01 MH081857, U01 MH081984, P50 MH066286, R01 MH60720, U01 MH082022, K24 MH76191, U01 MH081902, U01 MH082004, U01 MH081988]; Commonwealth of Massachusetts [SCDMH82101008006]; National Center for Research Resources [UL1RR025758, M01RR01032, P41RR14075] FX This study was supported by grants U01 MH081928, P50 MH080272, and R01 MH096027 from the National Institute of Mental Health and by grant SCDMH82101008006 from the Commonwealth of Massachusetts (Dr Seidman), as well as by the following grants from the National Institute of Mental Health: grant U01 MH081857 (Dr Cornblatt); grant U01 MH081984 (Dr Addington); grant P50 MH066286 (Prodromal Core) (Dr Bearden); grants R01 MH60720, U01 MH082022, and K24 MH76191 (Dr Cadenhead); grant U01 MH081902 (Dr Cannon); grant U01 MH082004 (Dr Perkins); grant U01 MH081988 (Dr Walker); and grant U01 MH082022 (Dr Woods). This study was also supported by Clinical Translational Science Award UL1RR025758 and General Clinical Research Center Grant M01RR01032 from the National Center for Research Resources to Harvard University at Beth Israel Deaconess Medical Center and by grant P41RR14075 from the National Center for Research Resources. NR 73 TC 2 Z9 2 U1 5 U2 5 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-622X EI 2168-6238 J9 JAMA PSYCHIAT JI JAMA Psychiatry PD DEC 1 PY 2016 VL 73 IS 12 BP 1239 EP 1248 DI 10.1001/jamapsychiatry.2016.2479 PG 10 WC Psychiatry SC Psychiatry GA EF9RH UT WOS:000390666900008 PM 27806157 ER PT J AU Cappel, D Hall, ML Lenselink, EB Beuming, T Qi, J Bradner, J Sherman, W AF Cappel, Daniel Hall, Michelle Lynn Lenselink, Eelke B. Beuming, Thijs Qi, Jun Bradner, James Sherman, Woody TI Relative Binding Free Energy Calculations Applied to Protein Homology Models SO JOURNAL OF CHEMICAL INFORMATION AND MODELING LA English DT Article ID HIV-1 REVERSE-TRANSCRIPTASE; DRUG-LIKE MOLECULES; INDUCED FIT DOCKING; FORCE-FIELD; LEAD OPTIMIZATION; NONNUCLEOSIDE INHIBITORS; SCORING FUNCTIONS; ACCURATE DOCKING; REPLICA EXCHANGE; TYK2 INHIBITORS AB A significant challenge and potential high-value application of computer-aided drug design is the accurate prediction of protein ligand binding affinities. Free energy perturbation (FEP) using molecular dynamics (MD) sampling is among the most suitable approaches to achieve accurate binding free energy predictions, due to the rigorous statistical framework of the methodology, correct representation of the energetics, and thorough treatment of the important degrees of freedom in the system (including explicit waters). Recent advances in sampling methods and force fields coupled with vast increases in computational resources have made FEP a viable technology to drive hit-to-lead and lead optimization, allowing for more efficient cycles of medicinal chemistry and the possibility to explore much larger chemical spaces. However, previous FEP applications have focused on systems with high resolution crystal structures of the target as starting points something that is not always available in drug discovery projects. As such, the ability to apply FEP on homology models would greatly expand the domain of applicability of FEP in drug discovery. In this work we apply a particular implementation of FEP, called FEP+, on congeneric ligand series binding to four diverse targets: a kinase (Tyk2), an epigenetic bromodomain (BRD4), a transmembrane GPCR (A(2A)), and a protein protein interaction interface (BCL-2 family protein MCL-1). We apply FEP+ using both crystal structures and homology models as starting points and find that the performance using homology models is generally on a par with the results when using crystal structures. The robustness of the calculations to structural variations in the input models can likely be attributed to the conformational sampling in the molecular dynamics simulations, which allows the modeled receptor to adapt to the "real" conformation for each ligand in the series. This work exemplifies the advantages of using all-atom simulation methods with full system flexibility and offers promise for the general application of FEP to homology models, although additional validation studies should be performed to further understand the limitations of the method and the scenarios where FEP will work best. C1 [Cappel, Daniel] Schrodinger GmbH, Dynamostr 13, D-68165 Mannheim, Germany. [Hall, Michelle Lynn; Beuming, Thijs; Sherman, Woody] Schrodinger Inc, 120 W 45th St, New York, NY 10036 USA. [Lenselink, Eelke B.] Leiden Univ, Div Med Chem, Leiden Acad Ctr Drug Res, NL-2333 CC Leiden, Netherlands. [Qi, Jun; Bradner, James] Harvard Med Sch, Dept Med, Dana Farber Canc Inst, Dept Med Oncol, 360 Longwood Ave,LC 2210, Boston, MA 02215 USA. [Hall, Michelle Lynn] Moderna Therapeut, 200 Technol Sq, Cambridge, MA 02139 USA. [Bradner, James] Novartis Inst BioMed Res, 250 Massachusetts Ave, Cambridge, MA 02139 USA. RP Cappel, D (reprint author), Schrodinger GmbH, Dynamostr 13, D-68165 Mannheim, Germany. EM daniel.cappel@schrodinger.com OI Cappel, Daniel/0000-0002-8460-7867 NR 76 TC 0 Z9 0 U1 11 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1549-9596 EI 1549-960X J9 J CHEM INF MODEL JI J. Chem Inf. Model. PD DEC PY 2016 VL 56 IS 12 BP 2388 EP 2400 DI 10.1021/acs.jcim.6b00362 PG 13 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications SC Pharmacology & Pharmacy; Chemistry; Computer Science GA EG1ZM UT WOS:000390832900012 PM 28024402 ER PT J AU Mihlstin, M Juzych, MS Kromrei, HT Hwang, FS Yin, J AF Mihlstin, Melanie Juzych, Mark S. Kromrei, Heidi T. Hwang, Frank S. Yin, Jia TI Resident Compliance With the American Academy of Ophthalmology Preferred Practice Patterns for Primary Open-Angle Glaucoma Suspect SO JOURNAL OF GLAUCOMA LA English DT Article DE American Academy of Ophthalmology Preferred Practice Patterns; primary open-angle glaucoma suspect; resident compliance ID CARE; CONFORMANCE; PROGRESSION AB Purpose:To study resident compliance with the American Academy of Ophthalmology (AAO) Preferred Practice Patterns (PPPs) for primary open-angle glaucoma suspect (POAGS) in a resident ophthalmology clinic.Patients and Methods:Two hundred charts were selected for analysis of adult patients with the International Classification of Diseases diagnosis code for POAGS during their initial visit between November 2, 2010 and May 6, 2014 at the Kresge Eye Institute resident clinic. Electronic medical records of clinic visits for POAGS patients were evaluated for documentation and compliance with 17 elements of AAO PPPs.Results:The overall mean compliance was 73.8% for all charts (n=200), 74.4% for first-year residents (n=53), 74.5% for second-year residents (n=38), and 73.3% for third-year residents (n=109). Documentation rates were high (>90%) for 9 elements, which included most elements of physical examination and history. Documentation of ocular history, central corneal thickness, gonioscopy, optic nerve head and retinal nerve fiber layer analysis, and visual field ranged from 40% to 80%. Documentation was lowest for patient education elements which ranged from 0% to 10%. Compliance was not significantly different (P>0.05) between residents or between different resident years for any element.Conclusions:Residents' compliance was high for most elements of the PPPs for POAGS. We identified elements with poor compliance especially regarding patient education. Adherence to AAO PPPs can be a helpful method of assessing resident performance. C1 [Mihlstin, Melanie; Juzych, Mark S.; Hwang, Frank S.; Yin, Jia] Wayne State Univ, Sch Med, Kresge Eye Inst, Dept Ophthalmol, 4717 St Antoine Blvd, Detroit, MI 48201 USA. [Kromrei, Heidi T.] Detroit Educ & Res, Detroit Med Ctr, Detroit, MI USA. [Yin, Jia] Harvard Med Sch, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA USA. RP Yin, J (reprint author), Wayne State Univ, Sch Med, Kresge Eye Inst, Dept Ophthalmol, 4717 St Antoine Blvd, Detroit, MI 48201 USA. EM jyin@med.wayne.edu FU Research to Prevent Blindness, New York, NY FX Supported by Research to Prevent Blindness, New York, NY, unrestricted funding to the Kresge Eye Institute. NR 19 TC 0 Z9 0 U1 5 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1057-0829 EI 1536-481X J9 J GLAUCOMA JI J. Glaucoma PD DEC PY 2016 VL 25 IS 12 BP 963 EP 967 DI 10.1097/IJG.0000000000000548 PG 5 WC Ophthalmology SC Ophthalmology GA EG1FM UT WOS:000390777600009 PM 27898580 ER PT J AU Mello, S Tan, ASL AF Mello, Susan Tan, Andy S. L. TI Who's Responsible? Media Framing of Pediatric Environmental Health and Mothers' Perceptions of Accountability SO JOURNAL OF HEALTH COMMUNICATION LA English DT Article ID INFORMATION-SEEKING; PUBLIC-HEALTH; CHILDRENS HEALTH; BISPHENOL-A; CANCER; NEWS; BEHAVIORS; COVERAGE; ONLINE; COMMUNICATION AB How the media frames issues of environmental health may affect mothers' views of who is responsible for addressing environmental risks to pediatric health and, ultimately, their protective behaviors. This article describes how information-oriented media sources attribute responsibility for such risks and examines associations between mothers' routine media exposure, or scanning, and perceptions of responsibility. First, a content analysis was conducted on a sample of 474 media stories (i.e., Associated Press, parenting magazines, and websites) about childhood exposure to environmental chemicals over a 6-month period (September 2012-February 2013). We found that media stories attributed responsibility most frequently to parents, though significant differences were observed across media sources, such that websites focused more on parents and general news more on government agencies and manufacturers. Next, we conducted an online survey of mothers (N=819) and revealed that website scanning during the prior 6months was significantly associated with perceived personal responsibility, even after we adjusted for potential confounders. Scanning general news was also significantly associated with perceived government and manufacturer responsibility. Understanding media framing of these issues highlights opportunities for health communicators to offset pressure placed on mothers by encouraging greater social and policy support in and exposure to certain media. C1 [Mello, Susan] Northeastern Univ, Dept Commun Studies, 350 Huntington Ave, Boston, MA 02115 USA. [Tan, Andy S. L.] Dana Farber Canc Inst, Populat Sci Div, Ctr Community Based Res, Boston, MA 02115 USA. [Tan, Andy S. L.] Harvard Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA USA. RP Mello, S (reprint author), Northeastern Univ, Dept Commun Studies, 350 Huntington Ave, Boston, MA 02115 USA. EM s.mello@neu.edu FU University of Pennsylvania's Annenberg School for Communication; Wharton Risk Management and Decision Processes Center; National Cancer Institute-funded Center of Excellence in Cancer Communication at the Annenberg School [P50-CA095856-05, P20-CA-095856] FX We acknowledge support from the University of Pennsylvania's Annenberg School for Communication, the Wharton Risk Management and Decision Processes Center, and the National Cancer Institute-funded Center of Excellence in Cancer Communication at the Annenberg School (P50-CA095856-05 and P20-CA-095856). NR 79 TC 0 Z9 0 U1 8 U2 8 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1081-0730 EI 1087-0415 J9 J HEALTH COMMUN JI J. Health Commun. PD DEC PY 2016 VL 21 IS 12 BP 1217 EP 1226 DI 10.1080/10810730.2016.1240267 PG 10 WC Communication; Information Science & Library Science SC Communication; Information Science & Library Science GA EF6BQ UT WOS:000390415100002 PM 27858529 ER PT J AU Resnick, CM Vakilian, PM Kaban, LB Peacock, ZS AF Resnick, Cory M. Vakilian, Pouya M. Kaban, Leonard B. Peacock, Zachary S. TI Quantifying the Effect of Temporomandibular Joint Intra-Articular Steroid Injection on Synovial Enhancement in Juvenile Idiopathic Arthritis SO JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Article ID RHEUMATOID-ARTHRITIS; CORTICOSTEROID INJECTIONS; DISEASE-ACTIVITY; FOLLOW-UP; CHILDREN; EROSIONS; MEMBRANE; EFFICACY; SAFETY; WRIST AB Purpose: To quantify the effect of intra-articular steroid injections (IASIs) on temporomandibular joint (TMJ) synovitis in children with juvenile idiopathic arthritis (JIA) using gadolinium-enhanced magnetic resonance imaging (MRI). Materials and Methods: The present study was a retrospective study of children with JIA who had undergone TMJ IASIs at Boston Children's Hospital. The patients were included if they had undergone contrast-enhanced MRI both before and after IASI and if the pre-IASI MRI had demonstrated synovitis (enhancement ratio [ER] > 1.55). Patients with TMJ pathology or pain unrelated to JIA or a history of facial trauma were excluded. The predictor variables were age, gender, JIA subtype, exposure to medications for arthritis, and a family history of autoimmune disease. The primary outcome variablewas the ER. Additional outcome variables included patient-reported pain and the maximal incisal opening (MIO). Results: Twenty-nine subjects (83% female) with a total of 50 injected TMJs were included. The average age at JIA diagnosis and at IASI was 6.8 +/- 1.7 years and 12.1 +/- 1.9 years, respectively. The mean follow-up period was 22.9 +/- 4.3 months (range 5 to 48). The ER decreased in all injected joints, with a mean reduction of 1.05 +/- 1.01 (P < .001). The post-IASI ER was less than the normal threshold (1.55) in 18% of the injected TMJs. IASI was associated with an elimination of pain in 89% of the subjects (P < .001) and in augmentation of the MIO by 5.8 +/- 2.6 mm (P < .001). Conclusions: In children with JIA and TMJ synovitis, TMJ IASI was associated with a reduction in synovial enhancement, decreased pain, and an increased MIO. Only 18% of injected joints, however, experienced complete resolution of synovitis. These results support the use of IASI in the management of the pain and dysfunction associated with TMJ synovitis. Further study is required to determine the efficacy of IASI in limiting inflammation and future joint destruction. (C) 2016 American Association of Oral and Maxillofacial Surgeons C1 [Resnick, Cory M.] Boston Childrens Hosp, Dept Plast & Oral Surg, 300 Longwood Ave, Boston, MA 02115 USA. [Resnick, Cory M.] Harvard Sch Dent Med, Oral & Maxillofacial Surg, Boston, MA USA. [Vakilian, Pouya M.; Kaban, Leonard B.; Peacock, Zachary S.] Harvard Sch Dent Med, Boston, MA USA. [Kaban, Leonard B.; Peacock, Zachary S.] Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Boston, MA 02114 USA. RP Resnick, CM (reprint author), Boston Childrens Hosp, Dept Plast & Oral Surg, 300 Longwood Ave, Boston, MA 02115 USA. EM cory.resnick@childrens.harvard.edu NR 28 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0278-2391 EI 1531-5053 J9 J ORAL MAXIL SURG JI J. Oral Maxillofac. Surg. PD DEC PY 2016 VL 74 IS 12 BP 2363 EP 2369 DI 10.1016/j.joms.2016.06.189 PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA EG2DA UT WOS:000390851900011 PM 27474460 ER PT J AU Graves, LL Bukata, SV Aghazadehsanai, N Chang, TI Garrett, NR Friedlander, AH AF Graves, Lindsay L. Bukata, Susan V. Aghazadehsanai, Nona Chang, Tina I. Garrett, Neal R. Friedlander, Arthur H. TI Patients Receiving Parenteral Bisphosphonates for Malignant Disease and Having Developed an Atypical Femoral Fracture Are at Risk of Concomitant Osteonecrosis of the Jaw: An Evidence-Based Review SO JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Review ID FEMUR FRACTURES; BREAST-CANCER AB Purpose: The risk of developing concomitant medication-related osteonecrosis of the jaw (MRONJ) in patients who have sustained an atypical femoral fracture (AFF) in association with parental administration of a bisphosphonate osteoclastic inhibitor medication for malignant disease is unclear. Published data were searched to determine the prevalence of these concomitant adverse medication events, if any. Materials and Methods: A systematic review of published case series in the PubMed database was undertaken to ascertain the prevalence of patients having a concomitant history of AFF and MRONJ. The data were analyzed to provide prevalence rates of these events from the literature. Results: Two case series were identified that delineated the risk (25 and 33%, respectively) of concomitant development of MRONJ and AFF in recipients of parenteral bisphosphonate medication administered for malignant disease. Conclusion: The published data suggest that approximately 30% of patients receiving parenteral bisphosphonates and having sustained an AFF could develop comorbid MRONJ. Published by Elsevier Inc on behalf of the American Association of Oral and Maxillofacial Surgeons C1 [Graves, Lindsay L.; Aghazadehsanai, Nona] Vet Affairs Greater Los Angeles Healthcare Syst, Oral & Maxillofacial Surg Dent Serv, Los Angeles, CA USA. [Bukata, Susan V.] Univ Calif Los Angeles, Med Ctr, Dept Orthopaed Surg, Los Angeles, CA 90024 USA. [Chang, Tina I.] Vet Affairs Greater Los Angeles Healthcare Syst, Res Fellowship & Inpatient Oral & Maxillofacial S, Los Angeles, CA USA. [Chang, Tina I.; Friedlander, Arthur H.] Univ Calif Los Angeles, Sch Dent, Dept Oral & Maxillofacial Surg, Los Angeles, CA USA. [Garrett, Neal R.] Univ Calif Los Angeles, Sch Dent, Div Adv Prosthodont, Los Angeles, CA 90024 USA. [Friedlander, Arthur H.] Vet Affairs Greater Los Angeles Healthcare Syst, Grad Med Educ, Los Angeles, CA USA. [Friedlander, Arthur H.] Ronald Reagan UCLA Med Ctr, Hosp Dent Serv, Qual Assurance, Los Angeles, CA USA. RP Friedlander, AH (reprint author), 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM Arthur.Friedlander@va.gov NR 19 TC 0 Z9 0 U1 2 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0278-2391 EI 1531-5053 J9 J ORAL MAXIL SURG JI J. Oral Maxillofac. Surg. PD DEC PY 2016 VL 74 IS 12 BP 2403 EP 2408 DI 10.1016/j.joms.2016.06.003 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA EG2DA UT WOS:000390851900017 PM 27376180 ER PT J AU Fox, AB Smith, BN Vogt, D AF Fox, Annie B. Smith, Brian N. Vogt, Dawne TI THE RELATIONSHIP BETWEEN ANTICIPATED STIGMA AND WORK FUNCTIONING FOR INDIVIDUALS WITH DEPRESSION SO JOURNAL OF SOCIAL AND CLINICAL PSYCHOLOGY LA English DT Article DE anticipated stigma; workplace functioning; absenteeism; presenteeism; depression ID PERFORMANCE QUESTIONNAIRE HPQ; HEALTH-ORGANIZATION HEALTH; MENTAL-ILLNESS; PRIMARY-CARE; EMPLOYEES; WORKPLACE; DISCLOSURE; DISORDERS; DIAGNOSES; MANAGERS AB Although symptoms of depression are likely the greatest contributing factor to decreased productivity and work functioning, anticipated stigma may also have a direct and indirect impact on workplace functioning. Using a sample of veterans with a history of depression (N = 240) who were participating in a longitudinal study of work and family functioning, we used path analyses to test the direct and indirect relationships between anticipated stigma, depressive symptoms, and three work outcomes: absenteeism, presenteeism, and global work functioning. Anticipated stigma was directly associated with increased absenteeism and decreased global work functioning, and was indirectly associated with presenteeism and overall work functioning through the exacerbation of depressive symptoms. These findings suggest that anticipated stigma has important implications for work functioning. Consequently, employer efforts to improve the overall health and well-being of their employees should also include efforts to decrease the stigma of mental illness in the workplace. C1 [Fox, Annie B.; Smith, Brian N.; Vogt, Dawne] VA Boston Healthcare Syst, Womens Hlth Sci Div, Natl Ctr PTSD, Boston, MA USA. [Smith, Brian N.; Vogt, Dawne] Boston Univ, Sch Med, Boston, MA 02215 USA. RP Fox, AB (reprint author), VA Boston Healthcare Syst, Natl Ctr PTSD 116B 3, 150 South Huntington Ave, Boston, MA 02130 USA. EM anniebfox@gmail.com FU Department of Veterans Affairs, Health Services Research and Development Service [DHI 09-086, IIR 12-345] FX This study was supported by Department of Veterans Affairs, Health Services Research and Development Service grants ("Validation of Modified DRRI Scales in a National Sample of OEF/OIF Veterans," Project DHI 09-086, Dawne Vogt, Principal Investigator and "Work and Family Functioning Work and Family Functioning in Women Veterans: Implications for VA Service Use" Project IIR 12-345, Principal Investigators Dawne Vogt and Brian N. Smith). The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. NR 32 TC 0 Z9 0 U1 10 U2 10 PU GUILFORD PUBLICATIONS INC PI NEW YORK PA 370 SEVENTH AVE, SUITE 1200, NEW YORK, NY 10001-1020 USA SN 0736-7236 J9 J SOC CLIN PSYCHOL JI J. Soc. Clin. Psychol. PD DEC PY 2016 VL 35 IS 10 BP 883 EP 897 PG 15 WC Psychology, Clinical; Psychology, Social SC Psychology GA EF8EC UT WOS:000390560500005 ER PT J AU McGuire, CM Harrington, E Anderson, A Krisch, MJ AF McGuire, Christina M. Harrington, Edward, Jr. Anderson, Ashira Krisch, Maria J. TI Methodology for Removing Dihalomethane Carryover from Solid-Phase Microextraction Fibers SO LC GC NORTH AMERICA LA English DT Article ID HALOGENATED ORGANIC-COMPOUNDS; GAS-CHROMATOGRAPHY; DRINKING-WATER; TRIHALOMETHANES; SPECTROMETRY; HALOCARBONS; SYSTEM; IODINE; GC AB Solid-phase microextraction (SPME) in conjunction with gas chromatography-mass spectrometry (GC-MS) is a simple and effective way to sample analytes. Ordinarily the coated fiber is rid of compounds during desorption in the GC system, allowing for the analysis of a new sample. Carryover of the analyte between samples, however, is a problem with many chemicals. Our data show that heating the fiber in a high-temperature injection port for only 2 min between runs prevents carryover. The short heating between samples improves the linearity of the peak area versus concentration relationship over four orders of magnitude of concentration, with a limit of detection below 10(-7) M in every case. Although carryover is an acknowledged problem with SPME fibers, such short conditioning steps are rarely considered as a means to eliminate it. This study suggests that they should be evaluated as an option. C1 [McGuire, Christina M.] Tufts Univ, Sackler Sch Grad Biomed Sci, Boston, MA 02111 USA. [Harrington, Edward, Jr.] Massachusetts Gen Hosp, Ctr Transplantat Sci, Boston, MA 02114 USA. [Anderson, Ashira] Mercersburg Acad, Mercersburg, PA USA. [Krisch, Maria J.] Trinity Coll, Dept Chem, Hartford, CT 06106 USA. RP Krisch, MJ (reprint author), Trinity Coll, Dept Chem, Hartford, CT 06106 USA. EM chem.krisch@gmail.com FU Camille and Henry Dreyfus Foundation; Research Corporation Cottrell College Science Award; Trinity College Student Research Program; Frank Fellowship at Trinity College FX The authors are grateful for a Camille and Henry Dreyfus Foundation Faculty Start-up grant, and a Research Corporation Cottrell College Science Award for equipment funding. We acknowledge student funding from the Trinity College Student Research Program and the Frank Fellowship at Trinity College. NR 30 TC 0 Z9 0 U1 1 U2 1 PU ADVANSTAR COMMUNICATIONS INC PI DULUTH PA 131 W 1ST STREET, DULUTH, MN 55802 USA SN 1527-5949 EI 1939-1889 J9 LC GC N AM JI LC GC N. AM. PD DEC PY 2016 VL 34 IS 12 BP 916 EP 925 PG 10 WC Chemistry, Analytical SC Chemistry GA EG2AJ UT WOS:000390835200006 ER PT J AU Arbel, Y Wu, H AF Arbel, Yael Wu, Hao TI A Neurophysiological examination of quality of learning in a feedback-based learning task SO NEUROPSYCHOLOGIA LA English DT Article DE Feedback related negativity; Declarative learning; Feedback processing; Event related potentials ID ANTERIOR CINGULATE CORTEX; MEDIAL FRONTAL-CORTEX; ERROR-DETECTION; BRAIN POTENTIALS; NEURAL SYSTEM; NEGATIVITY; PERFORMANCE; ERP; LOCALIZATION; INFORMATION AB The efficiency with which one processes external feedback contributes to the speed and quality of one's learning. Previous findings that the feedback related negativity (FRN) event related potential (ERP) is modulated by learning outcomes suggested that this ERP reflects the extent to which feedback is used by the learner to improve performance. To further test this suggestion, we measured whether the FRN and the fronto-central positivity (FCP) that follows it are modulated by learning slopes, and as a function of individual differences in learning outcomes. Participants were tasked with learning names (non-words) of 42 novel objects in a two choice feedback-based visual learning task. The items were divided into three sets of 14 items, each presented in five learning blocks and a sixth test block. Individual learning slopes based on performance on the task, as well as FRN and FCP slopes based on positive and negative feedback related activation in each block were created for 53 participants. Our data pointed to an interaction between slopes of the FRN elicited by negative feedback and learning slopes, such that a sharper decrease in the amplitude of the FRN to negative feedback was associated with sharper learning slopes. We further examined the predictive power of the FRN and FCP elicited in the training blocks on the learning outcomes as measured by performance on the test blocks. We found that small FRN to negative feedback, large FRN to positive feedback, and large FCP to negative feedback in the first training block predicted better learning outcomes. These results add to the growing evidence that the processes giving rise to the FRN and FCP are sensitive to individual differences in the extent to which feedback is used for learning. C1 [Arbel, Yael] Massachusetts Gen Hosp, Dept Commun Sci & Disorders, Inst Hlth Profess, Boston, MA 02114 USA. [Wu, Hao] Boston Coll, Dept Psychol, Chestnut Hill, MA 02167 USA. RP Arbel, Y (reprint author), Massachusetts Gen Hosp, Dept Commun Sci & Disorders, Inst Hlth Profess, Boston, MA 02114 USA. EM yarbel@mghihp.edu FU MGH Institute of Health Professions, Boston, MA, United States [300259] FX This study was funded by a Faculty Research Fellowship from the MGH Institute of Health Professions, Boston, MA, United States (Grant no. 300259) to Yael Arbel. NR 55 TC 1 Z9 1 U1 10 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3932 EI 1873-3514 J9 NEUROPSYCHOLOGIA JI Neuropsychologia PD DEC PY 2016 VL 93 BP 13 EP 20 DI 10.1016/j.neuropsychologia.2016.10.001 PN A PG 8 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA EG0LC UT WOS:000390723300002 PM 27713069 ER PT J AU Hershenberg, R Mavandadi, S Baddeley, J Libet, J AF Hershenberg, Rachel Mavandadi, Shahrzad Baddeley, Jenna Libet, Julian TI Capitalization in distressed couples: A pilot study and outline for future research SO PERSONAL RELATIONSHIPS LA English DT Article ID SHARING POSITIVE EVENTS; THINGS GO RIGHT; INTERPERSONAL BENEFITS; RELATIONSHIP SATISFACTION; BEHAVIORAL ACTIVATION; MARITAL SATISFACTION; MOTIVATED COGNITION; SELF-ESTEEM; GOOD-NEWS; RESPONSES AB Capitalizationseeking support when good things happenis linked to healthy couple functioning but has never been studied in distressed couples. We examined whether perceptions of capitalization and traditional social support related to couples' satisfaction prior to, and following, couples' therapy at a Veteran Affairs Medical Center. Perceptions of capitalization and traditional social support were associated yet distinct. Not all distressed couples had poor perceptions of support, and greater perceived support related to greater satisfaction at treatment entry. Relationship satisfaction was higher posttreatment for individuals whose partners reported providing them with greater capitalization support prior to treatment. We focus our discussion on the development of systematic research to investigate how capitalization may promote adaptive processes in vulnerable couples. C1 [Hershenberg, Rachel; Mavandadi, Shahrzad] Corporal Michael J Crescenz VA Med Ctr, Philadelphia, PA USA. [Hershenberg, Rachel; Mavandadi, Shahrzad] Univ Penn, Philadelphia, PA 19104 USA. [Baddeley, Jenna; Libet, Julian] Ralph H Johnson VA Med Ctr, Charleston, SC USA. [Baddeley, Jenna; Libet, Julian] Med Univ South Carolina, Columbia, SC USA. RP Hershenberg, R (reprint author), Emory Univ, 12 Executive Pk Dr NE, Atlanta, GA 30329 USA. EM Rachel.Hershenberg@emory.edu FU VISN 4 Mental Illness Research, Education, and Clinical Center, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA FX This paper was prepared with the support of the VISN 4 Mental Illness Research, Education, and Clinical Center, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA. NR 43 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1350-4126 EI 1475-6811 J9 PERS RELATIONSHIP JI Pers. Relat. PD DEC PY 2016 VL 23 IS 4 BP 684 EP 697 DI 10.1111/pere.12154 PG 14 WC Communication; Psychology, Social SC Communication; Psychology GA EF8FQ UT WOS:000390564800004 ER PT J AU Salmon, AB Kim, G Liu, C Wren, JD Georgescu, C Richardson, A Levine, RL AF Salmon, Adam B. Kim, Geumsoo Liu, Chengyu Wren, Jonathan D. Georgescu, Constantin Richardson, Arlan Levine, Rodney L. TI Effects of transgenic methionine sulfoxide reductase A (MsrA) expression on lifespan and age-dependent changes in metabolic function in mice SO REDOX BIOLOGY LA English DT Article DE Redox; Oxidative stress; Longevity; Metabolism; Proteostasis ID PROTEINS; DISEASE; CELLS; OVEREXPRESSION; LOCALIZATION; PROTEOSTASIS; OXIDATION; RESIDUES; MAMMALS AB Mechanisms that preserve and maintain the cellular proteome are associated with long life and healthy aging. Oxidative damage is a significant contributor to perturbation of proteostasis and is dealt with by the cell through regulation of antioxidants, protein degradation, and repair of oxidized amino acids. Methionine sulfoxide reductase A (MsrA) repairs oxidation of free-and protein-bound methionine residues through enzymatic reduction and is found in both the cytosol and the mitochondria. Previous studies in Drosophila have shown that increasing expression of MsrA can extend longevity. Here we test the effects of increasing MsrA on longevity and healthy aging in two transgenic mouse models. We show that elevated expression of MsrA targeted specifically to the cytosol reduces the rate of age-related death in female mice when assessed by Gompertz analysis. However, neither cytosolic nor mitochondrial MsrA overexpression extends lifespan when measured by log-rank analysis. In mice with MsrA overexpression targeted to the mitochondria, we see evidence for improved insulin sensitivity in aged female mice. With these and our previous data, we conclude that the increasing MsrA expression in mice has differential effects on aging and healthy aging that are dependent on the target of its subcellular localization. C1 [Salmon, Adam B.] South Texas Vet Hlth Care Syst, Geriatr Res Educ & Clin Ctr, San Antonio, TX USA. [Salmon, Adam B.] Univ Texas Hlth Sci Ctr San Antonio, Sam & Ann Barshop Inst Longev & Aging Studies, San Antonio, TX 78229 USA. [Salmon, Adam B.] Univ Texas Hlth Sci Ctr San Antonio, Dept Mol Med, San Antonio, TX 78229 USA. [Kim, Geumsoo; Levine, Rodney L.] NHLBI, Biochem Lab, Bldg 3, Bethesda, MD 20892 USA. [Liu, Chengyu] NHLBI, Transgen Core, Bldg 10, Bethesda, MD 20892 USA. [Wren, Jonathan D.; Georgescu, Constantin] Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, 825 NE 13th St, Oklahoma City, OK 73104 USA. [Richardson, Arlan] Univ Oklahoma, Hlth Sci Ctr, Reynolds Oklahoma Ctr Aging, Oklahoma City, OK USA. [Richardson, Arlan] Oklahoma City VA Med Ctr, Oklahoma City, OK USA. RP Salmon, AB (reprint author), UTHSCSA, 15355 Lambda Dr, San Antonio, TX 78245 USA.; Levine, RL (reprint author), NIH, Bldg 50 Room 2351, Bethesda, MD 20892 USA. EM salmona@uthscsa.edu; rlevine@nih.gov RI Levine, Rodney/D-9885-2011 FU National Institute of Health [R01AG050797]; American Federation of Aging Research; American Heart Association [15BGIA23220016]; Geriatric Research, Education and Clinical Center of the South Texas Veterans Health Care System; Intramural Research Program of the National, Heart, Lung, and Blood Institute FX The authors have no potential conflicts of interest to disclose. The laboratory of ABS is supported by a grant from the National Institute of Health (R01AG050797), a grant from the American Federation of Aging Research, a grant from the American Heart Association (15BGIA23220016) and the Geriatric Research, Education and Clinical Center of the South Texas Veterans Health Care System. Body composition was measured through the San Antonio Nathan Shock Center Healthspan and Functional Assessment core facility (P30AG013319). Statistical analysis of lifespan was performed by the Discovery Bioinformatics Core of the Oklahoma Nathan Shock Center (P30AG050911). The work of KM, CL, and RLL was supported by the Intramural Research Program of the National, Heart, Lung, and Blood Institute. This material is the result of work supported with resources and the use of facilities at South Texas Veterans Health Care System, San Antonio, Texas. The contents do not necessarily represent the views of the U.S. Department of Veterans Affairs or the United States Government. NR 30 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2213-2317 J9 REDOX BIOL JI Redox Biol. PD DEC PY 2016 VL 10 BP 251 EP 256 DI 10.1016/j.redox.2016.10.012 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA EF8SD UT WOS:000390598800026 PM 27821326 ER PT J AU Fong, ZV Fernandez-del Castillo, C AF Fong, Zhi Ven Fernandez-del Castillo, Carlos TI Intraductal Papillary Mucinous Neoplasm of the Pancreas SO SURGICAL CLINICS OF NORTH AMERICA LA English DT Article DE Intraductal papillary mucinous neoplasm; Pancreas; Biology; Clinical management ID INTERNATIONAL-CONSENSUS-GUIDELINES; OUTCOMES FOLLOWING-RESECTION; DUCTAL ADENOCARCINOMA; REMNANT PANCREAS; ENDOSCOPIC ULTRASONOGRAPHY; DIFFERENTIAL-DIAGNOSIS; SURGICAL-MANAGEMENT; PREDICTIVE FACTORS; CYSTIC NEOPLASMS; RISK-ASSESSMENT AB The incidence of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas has been rising in the past two decades, driven mainly by the widespread use of cross-sectional imaging. IPMNs are intraductal mucin-producing neoplasms that involve the main pancreatic duct or its side branches and lack the ovarian stroma typically seen in mucinous cystic neoplasms. The International Association of Pancreatology released consensus guidelines in 2006 and 2012 providing clinical algorithms based on IPMN features and risk of malignancy. In this article, we review the different classifications of IPMNs, their natural history, and clinical management and address recent controversies in the literature. C1 [Fong, Zhi Ven; Fernandez-del Castillo, Carlos] Harvard Med Sch, Dept Surg, Massachusetts Gen Hosp, 15 Parkman St, Boston, MA 02114 USA. RP Fernandez-del Castillo, C (reprint author), Massachusetts Gen Hosp, Dept Surg, 15 Parkman St, Boston, MA 02114 USA. EM cfernandez@partners.org NR 75 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 0039-6109 EI 1558-3171 J9 SURG CLIN N AM JI Surg. Clin.-North Am. PD DEC PY 2016 VL 96 IS 6 BP 1431 EP + DI 10.1016/j.suc.2016.07.009 PG 17 WC Surgery SC Surgery GA EG0NW UT WOS:000390730500016 PM 27865286 ER PT J AU Grottkau, BE Hui, Z Saha, SK Bardeesy, NM Pang, Y AF Grottkau, B. E. Hui, Z. Saha, S. K. Bardeesy, N. M. Pang, Y. TI 3d Bioprinting Cancer Tissues for Drug Development and Personalized Cancer Therapy SO TISSUE ENGINEERING PART A LA English DT Meeting Abstract CT TERMIS - Americas Conference and Exhibition CY DEC 11-14, 2016 CL San Diego, CA SP TERMIS C1 [Grottkau, B. E.; Hui, Z.; Pang, Y.] Massachusetts Gen Hosp, Orthopaed, Boston, MA 02114 USA. [Saha, S. K.; Bardeesy, N. M.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. NR 0 TC 0 Z9 0 U1 8 U2 8 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3341 EI 1937-335X J9 TISSUE ENG PT A JI Tissue Eng. Part A PD DEC PY 2016 VL 22 SU 1 MA 517 BP S134 EP S135 PG 2 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA EF8HF UT WOS:000390569200505 ER PT J AU Hui, Z Ma, D Pang, Y Grottkau, B AF Hui, Z. Ma, D. Pang, Y. Grottkau, B. TI Bioprint Injectable MSC Micro-tissues Repairing Cartilage Defects SO TISSUE ENGINEERING PART A LA English DT Meeting Abstract CT TERMIS - Americas Conference and Exhibition CY DEC 11-14, 2016 CL San Diego, CA SP TERMIS C1 [Hui, Z.; Ma, D.; Pang, Y.; Grottkau, B.] Massachusetts Gen Hosp, Orthopaed, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3341 EI 1937-335X J9 TISSUE ENG PT A JI Tissue Eng. Part A PD DEC PY 2016 VL 22 SU 1 MA 315 BP S83 EP S83 PG 1 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA EF8HF UT WOS:000390569200311 ER PT J AU Chapuy, CI Aguad, MD Nicholson, RT AuBuchon, JP Cohn, CS Delaney, M Fung, MK Unger, M Doshi, P Murphy, MF Dumont, LJ Kaufman, RM AF Chapuy, Claudia I. Aguad, Maria D. Nicholson, Rachel T. AuBuchon, James P. Cohn, Claudia S. Delaney, Meghan Fung, Mark K. Unger, Meredith Doshi, Parul Murphy, Michael F. Dumont, Larry J. Kaufman, Richard M. CA DARA-DTT Study Grp BEST Collaborat TI International validation of a dithiothreitol (DTT)-based method to resolve the daratumumab interference with blood compatibility testing SO TRANSFUSION LA English DT Article ID PATIENTS RECEIVING DARATUMUMAB; MULTIPLE-MYELOMA; MONOTHERAPY; THERAPY AB BACKGROUNDDaratumumab (DARA) consistently interferes with routine blood bank serologic testing by directly binding to CD38 expressed on reagent red blood cells (RBCs). Treating RBCs with dithiothreitol (DTT) eliminates the DARA interference. We conducted an international, multicenter, blinded study aimed at validating the DTT method for use by blood bank laboratories worldwide. STUDY DESIGN AND METHODSPaired plasma sample unknowns were sent to 25 participating blood bank laboratories. Sample 1 was spiked with DARA only (10 mu g/mL), and Sample 2 with DARA plus a clinically significant RBC antibody (anti-D [n=6], anti-Fy(a) [n=9], or anti-s [n=10]). Sites were instructed to perform an antibody screen with and without DTT-treated RBCs and to use a DTT-treated RBC panel for antibody identification. Qualitative data about the DTT method were collected by online survey. The primary outcome was the proportion of study sites able to identify the antibody unknown in the presence of DARA. RESULTSAll sites observed the DARA interference with the antibody screen. The DARA interference was seen with all testing methods (gel, tube, or solid phase). Using the DTT method, 25 of 25 sites (100%) successfully identified the antibody unknown in the presence of DARA. Feedback on the DTT method was positive, with 17 of 19 (90%) sites responding to the survey indicating that they planned to use the DTT method to test clinical samples from DARA-treated patients. CONCLUSIONThe DTT method is robust and reproducible and can be implemented by transfusion services worldwide to help provide safe blood products to patients treated with DARA. C1 [Chapuy, Claudia I.] St Elizabeths Med Ctr, Dana Farber Canc Inst, Boston, MA USA. [Aguad, Maria D.; Kaufman, Richard M.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Nicholson, Rachel T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [AuBuchon, James P.] Bloodworks Northwest, Seattle, WA USA. [Cohn, Claudia S.] Univ Minnesota, Minneapolis, MN USA. [Delaney, Meghan] Univ Washington, Seattle Childrens Hosp, Bloodworks Northwest, Seattle, WA 98195 USA. [Fung, Mark K.] Univ Vermont, Med Ctr, Burlington, VT USA. [Unger, Meredith] Janssen Inc, Raritan, NJ USA. [Doshi, Parul] Janssen Res & Dev, Spring House, PA USA. [Murphy, Michael F.] NHS Blood & Transplant, Oxford, England. [Dumont, Larry J.] Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 USA. [Dumont, Larry J.] Dartmouth Hitchcock Med Ctr, Hanover, NH USA. RP Kaufman, RM (reprint author), Brigham & Womens Hosp, Blood Bank, Amory 260,75 Francis St, Boston, MA 02115 USA. EM rmkaufman@partners.org RI Dumont, Larry/B-3994-2011 OI Dumont, Larry/0000-0002-1715-0748 FU Janssen, Inc. FX Janssen, Inc. provided both research funding and daratumumab. NR 15 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD DEC PY 2016 VL 56 IS 12 BP 2964 EP 2972 DI 10.1111/trf.13789 PG 9 WC Hematology SC Hematology GA EF8KS UT WOS:000390578300011 PM 27600566 ER PT J AU Rouse, CE Eckert, LO Wylie, BJ Lyell, DJ Jeyabalan, A Kochhar, S McElrath, TF AF Rouse, Caroline E. Eckert, Linda O. Wylie, Blair J. Lyell, Deirdre J. Jeyabalan, Arundhathi Kochhar, Sonali McElrath, Thomas F. CA Brighton Collaboration Preeclampsi TI Hypertensive disorders of pregnancy: Case definitions & guidelines for data collection, analysis, and presentation of immunization safety data SO VACCINE LA English DT Article DE Preeclampsia; Hypertension in pregnancy; Adverse event; Immunization; Guidelines; Case definition ID LOW PLATELET COUNT; INFLUENZA VACCINE; PREECLAMPSIA; ECLAMPSIA; MANAGEMENT; PATHOPHYSIOLOGY; PROTEINURIA; STATEMENT; HEMOLYSIS; QUALITY C1 [Rouse, Caroline E.; McElrath, Thomas F.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Eckert, Linda O.] Univ Washington, Seattle, WA 98195 USA. [Wylie, Blair J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Lyell, Deirdre J.] Stanford Univ, Stanford, CA 94305 USA. [Jeyabalan, Arundhathi] Univ Pittsburgh, Pittsburgh, PA USA. [Kochhar, Sonali] Global Healthcare Consulting, Delhi, India. RP McElrath, TF (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM contact@brightoncollaboration.org FU Bill and Melinda Gates Foundation FX The authors are grateful for the support and helpful comments provided by the Brighton Collaboration (Jan Bonhoeffer, Jorgen Bauwens) and the reference group (see https://brightoncollaboration.org/public/what-we-do/setting-standards/ca se-definitions/groups.html for reviewers), as well as other experts consulted as part of the process. Finally, we would like to thank the members of the ISPE Special Interest Group in Vaccines (VAX SIG) for the review of, constructive comments on. Brighton Collaboration would like to acknowledge The Global Alignment of Immunization Safety Assessment in Pregnancy (GAIA) Project, funded by the Bill and Melinda Gates Foundation. NR 29 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD DEC 1 PY 2016 VL 34 IS 49 SI SI BP 6069 EP 6076 DI 10.1016/j.vaccine.2016.03.038 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA EF7MP UT WOS:000390514000010 PM 27426628 ER PT J AU Davarpanah, AH Kambadakone, A Holalkere, NS Guimaraes, AR Hahn, PF Lee, SI AF Davarpanah, Amir H. Kambadakone, Avinash Holalkere, Nagaraj S. Guimaraes, Alexander R. Hahn, Peter F. Lee, Susanna I. TI Diffusion MRI of uterine and ovarian masses: identifying the benign lesions SO ABDOMINAL RADIOLOGY LA English DT Article DE Pelvic neoplasms; Magnetic resonance imaging; Diffusion-weighted imaging; Apparent diffusion coefficient ID UPPER ABDOMINAL ORGANS; WEIGHTED MRI; ENDOMETRIAL CANCER; CERVICAL-CANCER; ADNEXAL MASSES; DIAGNOSIS; UTERUS; BODY AB Purpose: The purpose of the study was to assess the diagnostic performance of qualitative and quantitative diffusion-weighted imaging (DWI) in differentiating benign from malignant ovarian and uterine masses. Materials and methods: Institutional review board approval was obtained for this HIPAA-compliant retrospective study, with waiver of informed consent. DWI MRIs of 222 women acquired over 1.5 years were evaluated. Reference standard was pathology or follow-up imaging. For qualitative assessment, two radiologists independently reviewed DWI and apparent diffusion coefficient (ADC) images for diffusion restriction. Differences were resolved by consensus. For quantitative assessment, a single reader measured ADC values. Readers were blinded to the reference standard. Results: 222 lesions, 121 ovarian (99 benign and 22 malignant) and 101 uterine (54 benign and 47 malignant), were included. Final diagnosis was established with pathology in 129 (58%) or with imaging follow-up in 93 (42%). Mean (range) follow-up interval was 27 (13-48) months. Qualitative assessment yielded sensitivity (ratio, 95% CI), specificity, PPV and NPV of 100% (22/22, 85-100), 68% (68/99, 58-76), 41% (22/54, 27-54), and 100% (68/68, 94-100) for ovarian and 94% (44/47, 83-98), 91% (49/54, 80-96), 90% (44/49, 78-95) and 94% (49/52, 84-98) for uterine malignancies. ADC (mean +/- SD) between benign ovarian [(1.11 +/- 0.76) x 10(-3) mm(2)/s] vs. malignant [(0.71 +/- 0.26) x 10(-3) mm(2)/s] lesions was significantly different (p < 0.001). ADC cutoff value of 1.55 x 10(-3) mm(2)/s for ovarian lesions resulted in 99.9% confidence for the absence of malignancy. ADC (mean +/- SD) of benign uterine [(0.64 +/- 0.38) x 10(-3) mm(2)/s] vs. malignant [(0.68 +/- 0.19) x 10(-3) mm(2)/s] lesions was not significantly different (P < 0.54). Conclusions: Quantitative and qualitative DWI assessment can be used to confidently characterize a subset of ovarian lesions as benign. With uterine lesions, although DWI is useful in differentiating benign from malignant lesions, the technique does not allow for definitive quantitative characterization. C1 [Davarpanah, Amir H.; Kambadakone, Avinash; Hahn, Peter F.; Lee, Susanna I.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St,White 270, Boston, MA 02114 USA. [Holalkere, Nagaraj S.] Boston Univ, Med Ctr, Dept Radiol, Boston, MA 02118 USA. [Guimaraes, Alexander R.] Oregon Hlth & Sci Univ, Dept Radiol, Portland, OR 97201 USA. RP Davarpanah, AH (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St,White 270, Boston, MA 02114 USA. EM adavarpanah@mgh.harvard.edu NR 25 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 2366-004X EI 2366-0058 J9 ABDOM RADIOL JI Abdom. Radiol. PD DEC PY 2016 VL 41 IS 12 BP 2466 EP 2475 DI 10.1007/s00261-016-0909-2 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EF0XW UT WOS:000390050600020 PM 27660280 ER PT J AU Park, KJ Braschi-Amirfarzan, M DiPiro, PJ Giardino, AA Jagannathan, JP Howard, SA Shinagare, AB Krajewski, KM AF Park, Kye Jin Braschi-Amirfarzan, Marta DiPiro, Pamela J. Giardino, Angela A. Jagannathan, Jyothi P. Howard, Stephanie A. Shinagare, Atul B. Krajewski, Katherine M. TI Multimodality imaging of locally recurrent and metastatic cervical cancer: emphasis on histology, prognosis, and management SO ABDOMINAL RADIOLOGY LA English DT Article DE Local recurrence; Metastasis; Cervical cancer; Histologic subtypes ID SQUAMOUS-CELL CARCINOMA; MOLECULAR TARGETED THERAPY; GYNECOLOGIC-ONCOLOGY-GROUP; PELVIC INSUFFICIENCY FRACTURES; LYMPH-NODE METASTASES; RADICAL HYSTERECTOMY; UTERINE CERVIX; EARLY-STAGE; PULMONARY METASTASECTOMY; NEUROENDOCRINE CARCINOMA AB The management of recurrent and metastatic cervical cancer is evolving in concert with the available advanced imaging techniques and molecular targeted therapy. The purpose of this review is to provide an overview of imaging and treatment of cervical cancer patients with locoregional recurrence and metastatic disease, with emphasis on characteristic patterns of spread based on histology (squamous cell carcinoma and other subtypes), prognostic factors, diagnosis, and treatment response assessment, as well as updated therapeutic options. C1 [Park, Kye Jin] Univ Ulsan, Dept Radiol, Coll Med, Asan Med Ctr, 86 Asanbyeongwon Gil, Seoul 138736, South Korea. [Park, Kye Jin] Univ Ulsan, Res Inst Radiol, Coll Med, Asan Med Ctr, 86 Asanbyeongwon Gil, Seoul 138736, South Korea. [Braschi-Amirfarzan, Marta; DiPiro, Pamela J.; Giardino, Angela A.; Jagannathan, Jyothi P.; Howard, Stephanie A.; Shinagare, Atul B.; Krajewski, Katherine M.] Harvard Med Sch, Dana Farber Canc Inst, Dept Imaging, 450 Brookline Ave, Boston, MA 02215 USA. [Braschi-Amirfarzan, Marta; DiPiro, Pamela J.; Giardino, Angela A.; Jagannathan, Jyothi P.; Howard, Stephanie A.; Shinagare, Atul B.; Krajewski, Katherine M.] Harvard Med Sch, Brigham & Womens Hosp, Dept Radiol, 75 Francis St, Boston, MA 02115 USA. RP Krajewski, KM (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Dept Imaging, 450 Brookline Ave, Boston, MA 02215 USA.; Krajewski, KM (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Dept Radiol, 75 Francis St, Boston, MA 02115 USA. EM kmkrajewski@partners.org NR 89 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 2366-004X EI 2366-0058 J9 ABDOM RADIOL JI Abdom. Radiol. PD DEC PY 2016 VL 41 IS 12 BP 2496 EP 2508 DI 10.1007/s00261-016-0825-5 PG 13 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EF0XW UT WOS:000390050600023 PM 27357415 ER PT J AU Cheng, LN Li, SA Wang, JH Yu, YM Chen, Q AF Cheng, Linna Li, Shu-Ang Wang, Jia-huai Yu, Yamei Chen, Qiang TI Protein production, crystallization and preliminary crystallographic analysis of the four N-terminal immunoglobulin domains of Down syndrome cell adhesion molecule 1 (vol F71, pg 775, 2015) SO ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY COMMUNICATIONS LA English DT Correction DE Dscam1; RNA splicing; homophilic dimer; horseshoe configuration; crystallization; corrigendum C1 [Cheng, Linna; Li, Shu-Ang; Yu, Yamei; Chen, Qiang] Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Chengdu 610041, Peoples R China. [Cheng, Linna; Li, Shu-Ang; Yu, Yamei; Chen, Qiang] Sichuan Univ, West China Hosp, Ctr Canc, Chengdu 610041, Peoples R China. [Cheng, Linna; Li, Shu-Ang; Yu, Yamei; Chen, Qiang] Collaborat Innovat Ctr Biotherapy, Chengdu 610041, Peoples R China. [Wang, Jia-huai] Harvard Med Sch, Dept Med Oncol, Dana Farber Canc Inst, 450 Brookline Ave,Smith 1036B, Boston, MA 02215 USA. [Wang, Jia-huai] Harvard Med Sch, Dept Canc Biol, Dana Farber Canc Inst, 450 Brookline Ave,Smith 1036B, Boston, MA 02215 USA. RP Yu, YM; Chen, Q (reprint author), Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Chengdu 610041, Peoples R China.; Yu, YM; Chen, Q (reprint author), Sichuan Univ, West China Hosp, Ctr Canc, Chengdu 610041, Peoples R China.; Yu, YM; Chen, Q (reprint author), Collaborat Innovat Ctr Biotherapy, Chengdu 610041, Peoples R China. EM yamei_yu@scu.edu.cn; qiang_chen@scu.edu.cn NR 1 TC 0 Z9 0 U1 0 U2 0 PU INT UNION CRYSTALLOGRAPHY PI CHESTER PA 2 ABBEY SQ, CHESTER, CH1 2HU, ENGLAND SN 2053-230X J9 ACTA CRYSTALLOGR F JI Acta Crystallogr. F-Struct. Biol. Commun. PD DEC PY 2016 VL 72 BP 911 EP 911 DI 10.1107/S2053230X16017817 PN 12 PG 1 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA EF4QL UT WOS:000390317000009 PM 27917840 ER PT J AU Huen, AC Marathi, A Nam, PK Wells, A AF Huen, Arthur C. Marathi, Archana Nam, Peter K. Wells, Alan TI CXCL11 Expression by Keratinocytes Occurs Transiently Between Reaching Confluence and Cellular Compaction SO ADVANCES IN WOUND CARE LA English DT Article DE wound healing; hemokine signaling; contact inhibition; CXCR3; CXCL11; keratinocyte ID KIDNEY EPITHELIAL-CELLS; WOUND REPAIR; INTERMEDIATE-FILAMENTS; DESMOSOME FORMATION; HYPER-ADHESION; MICE LACKING; SKIN; MATURATION; CALPAIN; DIFFERENTIATION AB Objective: To investigate whether differentiation or cellular confluence is responsible for CXCL11 expression patterns in re-epithelialization. Approach:In vitro model systems of re-epithelialization using the HaCaT keratinocyte cell line were utilized in monitoring expression of differentiation markers, including desmoplakin and various cytokeratins while evaluating for an association with chemokine CXCL11 expression. Results: CXCL11 expression was elevated in sparse culture with peak expression near the time of confluence. This somewhat followed the accumulation of desmoplakin in detergent-insoluble pool of proteins. However, in postconfluent, despite continued accumulation of desmoplakin within cells, CXCL11 expression decreased to baseline levels. This biphasic pattern was also seen in low calcium culture, an environment that inhibits keratinocyte differentiation and accumulation of desmosomal proteins. Highest CXCL11-expressing areas best correlated with newly confluent areas within culture expressing basal keratin 14, but also activated keratin 6. Innovation: Achievement of a threshold cellular density induces cell signaling cascade through CXCR3 that, in addition to other undiscovered pathways, can progress cutaneous wounds from the proliferative into the remodeling phases of cutaneous wound healing. Conclusion: These results suggest that the achievement of confluence with increased cellular density by migrating keratinocytes at the wound edge triggers expression of CXCL11. Since CXCR3 stimulation in endothelial cells results in apoptosis and causes neovascular pruning, whereas stimulation of CXCR3 in fibroblasts results decreased motility and cellular contraction, we speculate that CXCL11 expression by epidermal cells upon achieving cellular confluence could be the source of CXCR3 stimulation in the dermis ushering a transition from proliferative to remodeling phases of wound healing. C1 [Huen, Arthur C.; Marathi, Archana; Nam, Peter K.] Univ Pittsburgh, Dept Dermatol, VA Pittsburgh Hlth Syst, McGowan Inst Regenerat Med, Pittsburgh, PA 15260 USA. [Wells, Alan] Univ Pittsburgh, VA Pittsburgh Hlth Syst, McGowan Inst Regenerat Med, Dept Pathol, Pittsburgh, PA USA. RP Huen, AC (reprint author), Univ Pittsburgh, Dept Dermatol, Med Arts Bldg,3708 Fifth Ave,Fifth Floor, Pittsburgh, PA 15213 USA. EM huenac@upmc.edu FU NIH [GM63569, GM69668, K08 GM095917-04] FX This work was supported by grants from NIH (GM63569, GM69668, and K08 GM095917-04). The authors thank members of the Wells Laboratory for constructive comments and suggestions. The VA Pittsburgh Health System provided support in kind. None of the authors has any conflicts of interest in terms of the materials included herein. NR 39 TC 0 Z9 0 U1 1 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 2162-1918 EI 2162-1934 J9 ADV WOUND CARE JI Adv. Wound Care PD DEC PY 2016 VL 5 IS 12 BP 517 EP 526 DI 10.1089/wound.2015.0680 PG 10 WC Dermatology SC Dermatology GA EF5YT UT WOS:000390406700001 PM 28078185 ER PT J AU Espinoza, SE Wang, CP Tripathy, D Clement, SC Schwenke, DC Banerji, MA Bray, GA Buchanan, TA Henry, RR Kitabchi, AE Mudaliar, S Stentz, FB Reaven, PD DeFronzo, RA Musi, N AF Espinoza, Sara E. Wang, Chen-pin Tripathy, Devjit Clement, Stephen C. Schwenke, Dawn C. Banerji, Mary Ann Bray, George A. Buchanan, Thomas A. Henry, Robert R. Kitabchi, Abbas E. Mudaliar, Sunder Stentz, Frankie B. Reaven, Peter D. DeFronzo, Ralph A. Musi, Nicolas TI Pioglitazone is equally effective for diabetes prevention in older versus younger adults with impaired glucose tolerance SO AGE LA English DT Article DE Geriatrics; Diabetes; Prevention; Endocrinology ID INSULIN-SECRETION; CONTROLLED-TRIAL; FASTING GLUCOSE; MELLITUS; RISK; METFORMIN; ACT; METAANALYSIS; POPULATION; CANCER AB To determine the efficacy of pioglitazone to prevent type 2 diabetes in older compared to younger adults with pre-diabetes. Six hundred two participants with impaired glucose tolerance (IGT) were randomized in double blind fashion to placebo or pioglitazone for diabetes prevention in the ACT NOW study (NEJM 364:1104-1115, 2011). Cox proportional hazard regression was used to compare time to development of diabetes over a mean of 2 years between older (ae61 years) and younger participants. We compared effects of pioglitazone versus placebo on metabolic profiles, inflammatory markers, adipokines, beta cell function (disposition index), insulin sensitivity (Matsuda index), and body composition by ANOVA. Diabetes incidence was reduced by 85 % in older and 69 % in younger subjects (p = 0.41). beta cell function (disposition index) increased by 35.0 % in the older and 26.7 % in younger subjects (p = 0.83). Insulin sensitivity (Matsuda index) increased by 3.07 (5.2-fold) in older and by 2.54 (3.8-fold) in younger participants (p = 0.58). Pioglitazone more effectively increased adiponectin in older versus younger subjects (22.9 +/- 3.2 mu g/mL [2.7-fold] vs. 12.7 +/- 1.4 mu g/mL [2.2-fold], respectively; p = 0.04). Younger subjects tended to have a greater increase in whole body fat mass compared to older subjects (3.6 vs. 3.1 kg; p = 0.061). Younger and older subjects had similar decreases in bone mineral density (0.018 +/- 0.0071 vs. 0.0138 +/- 0.021 g/cm(2)). Younger and older pre-diabetic adults taking pioglitazone had similar reductions in conversion to diabetes and older adults had similar or greater improvements in metabolic risk factors, demonstrating that pioglitazone is useful in preventing diabetes in older adults. C1 [Espinoza, Sara E.; Wang, Chen-pin; Musi, Nicolas] Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst Longev & Aging Studies, 7703 Floyd Curl Dr, San Antonio, TX 78223 USA. [Espinoza, Sara E.; Wang, Chen-pin; Musi, Nicolas] South Texas Vet Hlth Care Syst, Geriatr Res Educ & Clin Ctr, 7400 Merton Minter Blvd, San Antonio, TX 78229 USA. [Tripathy, Devjit; DeFronzo, Ralph A.; Musi, Nicolas] Univ Texas Hlth Sci Ctr San Antonio, Texas Diabet Inst, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. [Tripathy, Devjit; DeFronzo, Ralph A.] South Texas Vet Hlth Care Syst, 7400 Merton Minter Blvd, San Antonio, TX 78229 USA. [Clement, Stephen C.] Georgetown Univ, Dept Med, Div Endocrinol & Metab, 3700 O St NW, Washington, DC 20057 USA. [Schwenke, Dawn C.] Arizona State Univ, Tempe, AZ 85281 USA. [Banerji, Mary Ann] Suny Downstate Med Ctr, Dept Med, Div Endocrinol, 450 Clarkson Ave, Brooklyn, NY 11203 USA. [Bray, George A.] Louisiana State Univ, Pennington Biomed Res Ctr, Baton Rouge, LA 70803 USA. [Buchanan, Thomas A.] Univ Southern Calif, Dept Med, Div Endocrinol & Diabet, Los Angeles, CA USA. [Henry, Robert R.; Mudaliar, Sunder] Univ Calif San Diego, Dept Med, Div Endocrinol & Metab, 9500 Gilman Dr, La Jolla, CA 92093 USA. [Kitabchi, Abbas E.; Stentz, Frankie B.] Univ Tennessee, Hlth Sci Ctr, Dept Med, Div Endocrinol Diabet & Metab, 920 Court Ave, Memphis, TN 38163 USA. [Reaven, Peter D.] Phoenix Vet Affairs Hlth Care Syst, 650 E Indian Sch Rd, Phoenix, AZ 85012 USA. RP Espinoza, SE; Musi, N (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst Longev & Aging Studies, 7703 Floyd Curl Dr, San Antonio, TX 78223 USA. EM espinozas2@uthscsa.edu; musi@uthscsa.edu FU Takeda Pharmaceuticals; General Clinical Research Center (GCRC) at the University of Tennessee Health Science Center [MO1-RR-00221]; National Institutes of Health Clinical and Translational Science Award [UL1TR000130]; South Texas Veterans Health Care System-Audie Murphy Division; GCRC at the University of Southern California Keck School of Medicine [MO1-RR-00043]; Veterans Affairs institution in Phoenix; Veterans Affairs institution in San Diego; South Texas Veterans Health Care System FX This study is supported by an investigator-initiated and unrestricted research grant from Takeda Pharmaceuticals and grants from the General Clinical Research Center (GCRC) at the University of Tennessee Health Science Center (MO1-RR-00221), the National Institutes of Health Clinical and Translational Science Award UL1TR000130 to the University of Southern California, and the South Texas Veterans Health Care System-Audie Murphy Division and the GCRC at the University of Southern California Keck School of Medicine (MO1-RR-00043) and by the Veterans Affairs institutions in Phoenix and San Diego, which contributed their resources and the use of their facilities. Sara Espinoza, Nicolas Musi, Devjit Tripathy, and Ralph A. DeFronzo are supported, in part, by the South Texas Veterans Health Care System. NR 31 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0161-9152 EI 1574-4647 J9 AGE JI Age PD DEC PY 2016 VL 38 IS 5-6 BP 485 EP 493 DI 10.1007/s11357-016-9946-6 PG 9 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA EF1CK UT WOS:000390062500011 PM 27585671 ER PT J AU Hirsch, JA Leslie-Mazwi, TM Nicola, GN Bhargavan-Chatfield, M Seidenwurm, DJ Silva, E Manchikanti, L AF Hirsch, J. A. Leslie-Mazwi, T. M. Nicola, G. N. Bhargavan-Chatfield, M. Seidenwurm, D. J. Silva, E. Manchikanti, L. TI PQRS and the MACRA: Value-Based Payments Have Moved from Concept to Reality SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Editorial Material ID INTERVENTIONAL PAIN MANAGEMENT; QUALITY REPORTING SYSTEM; SUSTAINABLE GROWTH-RATE; HEALTH-CARE; NEUROINTERVENTIONALISTS; PRIMER C1 [Hirsch, J. A.; Leslie-Mazwi, T. M.] Massachusetts Gen Hosp, Dept Neuroendovasc Imaging, GRB 2-241,55 Fruit St, Boston, MA 02114 USA. [Hirsch, J. A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Leslie-Mazwi, T. M.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Nicola, G. N.] Hackensack Radiol Grp, River Edge, NJ USA. [Bhargavan-Chatfield, M.] Amer Coll Radiol, Reston, VA USA. [Seidenwurm, D. J.] Sutter Med Grp, Dept Radiol, Sacramento, CA USA. [Silva, E.] South Texas Radiol Grp, San Antonio, TX USA. [Manchikanti, L.] Pain Management Ctr, Paducah, KY USA. RP Leslie-Mazwi, TM (reprint author), Massachusetts Gen Hosp, Dept Neuroendovasc Imaging, GRB 2-241,55 Fruit St, Boston, MA 02114 USA. EM tleslie-mazwi@mgh.harvard.edu NR 28 TC 1 Z9 1 U1 4 U2 4 PU AMER SOC NEURORADIOLOGY PI DENVILLE PA PO BOX 3000, DENVILLE, NJ 07834-9349 USA SN 0195-6108 EI 1936-959X J9 AM J NEURORADIOL JI Am. J. Neuroradiol. PD DEC PY 2016 VL 37 IS 12 BP 2195 EP 2200 DI 10.3174/ajnr.A4936 PG 6 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA EF1KD UT WOS:000390082800005 PM 27659194 ER PT J AU Ackermann, C Andronikou, S Saleh, MG Laughton, B Alhamud, AA van der Kouwe, A Kidd, M Cotton, MF Meintjes, EM AF Ackermann, C. Andronikou, S. Saleh, M. G. Laughton, B. Alhamud, A. A. van der Kouwe, A. Kidd, M. Cotton, M. F. Meintjes, E. M. TI Early Antiretroviral Therapy in HIV-Infected Children Is Associated with Diffuse White Matter Structural Abnormality and Corpus Callosum Sparing SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; NERVOUS-SYSTEM MYELINATION; POSITIVE CHILDREN; MOTION CORRECTION; HUMAN INFANCY; SOUTH-AFRICA; TENSOR MRI; SPIN-ECHO; BRAIN; ADOLESCENCE AB BACKGROUND AND PURPOSE: Fractional anisotropy in the frontal white matter, corpus callosum, and internal capsule is abnormal in human immunodeficiency virus-positive (HIV+) adults. We describe the distribution and nature of white matter abnormalities in a cohort of children who started antiretroviral therapy within the first year of life and the benefit of early treatment by using DTI measures (fractional anisotropy and mean, axial, and radial diffusion). MATERIALS AND METHODS: DTI was performed on children in a neurodevelopmental substudy from the Children with HIV Early Antiretroviral trial. Voxel-based group comparisons were obtained to determine regions where fractional anisotropy and mean diffusion differed between HIV+ and uninfected children. Associations of DTI parameters with the timing of antiretroviral therapy initiation were examined. RESULTS: Thirty-nine HIV+ children (15 boys; mean age, 5.4 years) and 13 controls (5 boys; mean age, 5.7 years) were scanned. Two clusters with lower fractional anisotropy and 7 clusters with increased mean diffusion were identified in the HIV+ group, with symmetric distribution predominantly due to increased radial diffusion, suggestive of decreased myelination. Corticospinal tracts rather than the corpus callosum were predominantly involved. Children on early-interrupted antiretroviral therapy had lower fractional anisotropy compared with those receiving continuous treatment. CONCLUSIONS: HIV+ children at 5 years of age have white matter abnormalities measured by fractional anisotropy, despite early antiretroviral therapy, suggesting that early antiretroviral therapy does not fully protect the white matter from either peripartum or in utero infection. In contrast to adults, the corticospinal tracts are predominantly involved rather than the corpus callosum, possibly due to early antiretroviral therapy. Continuous early antiretroviral therapy can limit white matter damage. C1 [Ackermann, C.] Univ Stellenbosch, Dept Radiodiag, Tygerberg, South Africa. [Laughton, B.; Cotton, M. F.] Univ Stellenbosch, Dept Paediat & Child Hlth, Tygerberg, South Africa. [Kidd, M.] Univ Stellenbosch, Fac Med & Hlth Sci, Tygerberg, South Africa. [Kidd, M.] Univ Stellenbosch, Ctr Stat Consultat, Tygerberg, South Africa. [Andronikou, S.] Univ Bristol, Clin Res & Imaging Ctr, Bristol, Avon, England. [Andronikou, S.] Bristol Royal Hosp Children, Dept Paediat Radiol, Bristol, Avon, England. [Saleh, M. G.; Alhamud, A. A.; Meintjes, E. M.] Univ Cape Town, MRC, Med Imaging Res Unit, Dept Human Biol, Cape Town, South Africa. [van der Kouwe, A.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. RP Ackermann, C (reprint author), Kanonnier Crescent 27, ZA-7530 Cape Town, South Africa. EM ca@sun.ac.za FU Harry Crossley Foundation; South African Medical Research Council; National Research Foundation [CPR20110614000019421]; South African National Research Foundation/Department of Science and Technology South African Research Chairs Initiative; National Institute of Allergy and Infectious Diseases through the Comprehensive International Program of Research on AIDS network [U19 A153217]; National Institutes of Health [R01 HD071664, R21MH096559] FX This work was supported by grants from the Harry Crossley Foundation, the South African Medical Research Council, the National Research Foundation grant CPR20110614000019421, the South African National Research Foundation/Department of Science and Technology South African Research Chairs Initiative, the National Institute of Allergy and Infectious Diseases through the Comprehensive International Program of Research on AIDS network, grant U19 A153217, and the National Institutes of Health R01 HD071664 and R21MH096559. NR 52 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC NEURORADIOLOGY PI DENVILLE PA PO BOX 3000, DENVILLE, NJ 07834-9349 USA SN 0195-6108 EI 1936-959X J9 AM J NEURORADIOL JI Am. J. Neuroradiol. PD DEC PY 2016 VL 37 IS 12 BP 2363 EP 2369 DI 10.3174/ajnr.A4921 PG 7 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA EF1KD UT WOS:000390082800031 PM 27538904 ER PT J AU Beckman, JA Goldfine, AB Leopold, JA Creager, MA AF Beckman, Joshua A. Goldfine, Allison B. Leopold, Jane A. Creager, Mark A. TI Ebselen does not improve oxidative stress and vascular function in patients with diabetes: a randomized, crossover trial SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE endothelial function; type 2 diabetes mellitus; type 1 diabetes mellitus; oxidative stress ID ENDOTHELIUM-DEPENDENT VASODILATION; CORONARY-ARTERY-DISEASE; SMOOTH-MUSCLE-CELLS; MEDIATED VASODILATION; BRACHIAL-ARTERY; MELLITUS; DYSFUNCTION; ATHEROSCLEROSIS; SUPPLEMENTATION; MICROANGIOPATHY AB Oxidative stress is a key driver of vascular dysfunction in diabetes mellitus. Ebselen is a glutathione peroxidase mimetic. A single-site, randomized, double-masked, placebo-controlled, crossover trial was carried out in 26 patients with type 1 or type 2 diabetes to evaluate effects of high-dose ebselen (150 mg po twice daily) administration on oxidative stress and endothelium-dependent vasodilation. Treatment periods were in random order of 4 wk duration, with a 4-wk washout between treatments. Measures of oxidative stress included nitrotyrosine, plasma 8-isoprostanes, and the ratio of reduced to oxidized glutathione. Vascular ultrasound of the brachial artery and plethysmographic measurement of blood flow were used to assess flow-mediated and methacholine-induced endothelium-dependent vasodilation of conduit and resistance vessels, respectively. Ebselen administration did not affect parameters of oxidative stress or conduit artery or forearm arteriolar vascular function compared with placebo treatment. There was no difference in outcome by diabetes type. Ebselen, at the dose and duration evaluated, does not improve the oxidative stress profile, nor does it affect endothelium-dependent vasodilation in patients with diabetes mellitus. C1 [Beckman, Joshua A.] Vanderbilt Univ, Med Ctr, Cardiovasc Div, Nashville, TN USA. [Goldfine, Allison B.] Joslin Diabet Ctr, Clin Behav & Outcomes Res, Boston, MA 02215 USA. [Leopold, Jane A.] Brigham & Womens Hosp, Cardiovasc Div, 75 Francis St, Boston, MA 02115 USA. [Creager, Mark A.] Dartmouth Hitchcock Med Ctr, Heart & Vasc Ctr, Lebanon, NH 03766 USA. RP Beckman, JA (reprint author), Div Cardiovasc, 1215 21st Ave South,MCE 5472, Nashville, TN 37215 USA. EM Joshua.a.beckman@vanderbilt.edu OI Beckman, Joshua/0000-0001-8332-8439 FU National Institutes of Health [K23 HL-04169, P30 DK-036836] FX This study was supported by National Institutes of Health Grants K23 HL-04169 and P30 DK-036836. NR 39 TC 0 Z9 0 U1 2 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 EI 1522-1539 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD DEC PY 2016 VL 311 IS 6 BP H1431 EP H1436 DI 10.1152/ajpheart.00504.2016 PG 6 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA EF1XL UT WOS:000390118400010 PM 27765750 ER PT J AU Berdichevsky, Y Saponjian, Y Park, KI Roach, B Pouliot, W Lu, K Swiercz, W Dudek, FE Staley, KJ AF Berdichevsky, Yevgeny Saponjian, Yero Park, Kyung-Il Roach, Bonnie Pouliot, Wendy Lu, Kimberly Swiercz, Waldemar Dudek, F. Edward Staley, Kevin J. TI Staged anticonvulsant screening for chronic epilepsy SO ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY LA English DT Article ID SPONTANEOUS RECURRENT SEIZURES; SELECTIVE COX-2 INHIBITION; INDUCED STATUS EPILEPTICUS; HIPPOCAMPAL SLICE; RAT MODEL; IN-VITRO; POSTTRAUMATIC EPILEPTOGENESIS; PHARMACORESISTANT EPILEPSY; CYCLOOXYGENASE-2 INHIBITOR; ANTIEPILEPTIC DRUGS AB ObjectiveCurrent anticonvulsant screening programs are based on seizures evoked in normal animals. One-third of epileptic patients do not respond to the anticonvulsants discovered with these models. We evaluated a tiered program based on chronic epilepsy and spontaneous seizures, with compounds advancing from high-throughput in vitro models to low-throughput in vivo models. MethodsEpileptogenesis in organotypic hippocampal slice cultures was quantified by lactate production and lactate dehydrogenase release into culture media as rapid assays for seizure-like activity and cell death, respectively. Compounds that reduced these biochemical measures were retested with in vitro electrophysiological confirmation (i.e., second stage). The third stage involved crossover testing in the kainate model of chronic epilepsy, with blinded analysis of spontaneous seizures after continuous electrographic recordings. ResultsWe screened 407 compound-concentration combinations. The cyclooxygenase inhibitor, celecoxib, had no effect on seizures evoked in normal brain tissue but demonstrated robust antiseizure activity in all tested models of chronic epilepsy. InterpretationThe use of organotypic hippocampal cultures, where epileptogenesis occurs on a compressed time scale, and where seizure-like activity and seizure-induced cell death can be easily quantified with biomarker assays, allowed us to circumvent the throughput limitations of in vivo chronic epilepsy models. Ability to rapidly screen compounds in a chronic model of epilepsy allowed us to find an anticonvulsant that would be missed by screening in acute models. C1 [Berdichevsky, Yevgeny] Lehigh Univ, Dept Elect & Comp Engn, Bethlehem, PA 18015 USA. [Berdichevsky, Yevgeny] Lehigh Univ, Bioengn Program, Bethlehem, PA 18015 USA. [Saponjian, Yero; Swiercz, Waldemar; Staley, Kevin J.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02129 USA. [Saponjian, Yero; Swiercz, Waldemar; Staley, Kevin J.] Harvard Med Sch, Boston, MA 02129 USA. [Park, Kyung-Il] Seoul Natl Univ Hosp, Dept Neurol, Healthcare Syst Gangnam Ctr, Seoul 06236, South Korea. [Roach, Bonnie; Pouliot, Wendy; Dudek, F. Edward] Univ Utah, Sch Med, Dept Neurosurg, Salt Lake City, UT 84108 USA. [Lu, Kimberly] Boston Univ, Sch Med, Boston, MA 02119 USA. RP Staley, KJ (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02129 USA. EM Staley.Kevin@mgh.harvard.edu FU NINDS [NS072258, NS086364, NS077908] FX This work was supported by NINDS grants NS072258, NS086364, and NS077908. NR 58 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2328-9503 J9 ANN CLIN TRANSL NEUR JI Ann. Clin. Transl. Neurol. PD DEC PY 2016 VL 3 IS 12 BP 908 EP 923 DI 10.1002/acn3.364 PG 16 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EF8GH UT WOS:000390566700002 PM 28097203 ER PT J AU Godlove, J Gulati, T Dichter, B Chang, E Ganguly, K AF Godlove, Jason Gulati, Tanuj Dichter, Ben Chang, Edward Ganguly, Karunesh TI Muscle synergies after stroke are correlated with perilesional high gamma SO ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY LA English DT Article ID HUMAN SENSORIMOTOR CORTEX; MOVEMENT; HUMANS; ORGANIZATION; PRIMITIVES; ECOG AB Movements can be factored into modules termed muscle synergies. After stroke, abnormal synergies are linked to impaired movements; however, their neural basis is not understood. In a single subject, we examined how electrocorticography signals from the perilesional cortex were associated with synergies. The measured synergies contained a mix of both normal and abnormal patterns and were remarkably similar to those described in past work. Interestingly, we found that both normal and abnormal synergies were correlated with perilesional high gamma. Given the link between high gamma and cortical spiking, our results suggest that perilesional spiking may organize synergies after stroke. C1 [Godlove, Jason; Gulati, Tanuj; Ganguly, Karunesh] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Godlove, Jason; Gulati, Tanuj; Ganguly, Karunesh] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [Dichter, Ben; Chang, Edward] Univ Calif San Francisco, Dept Neurol Surg, 505 Parnassus Ave,M-779, San Francisco, CA 94143 USA. [Dichter, Ben; Chang, Edward] Univ Calif San Francisco, Dept Physiol, San Francisco, CA 94143 USA. [Dichter, Ben; Chang, Edward] Univ Calif San Francisco, Ctr Integrat Neurosci, San Francisco, CA 94158 USA. RP Chang, E (reprint author), Univ Calif San Francisco, Dept Neurol Surg, 505 Parnassus Ave,M-779, San Francisco, CA 94143 USA.; Ganguly, K (reprint author), Univ Calif San Francisco, Dept Neurol, 1700 Owens St, San Francisco, CA 94158 USA. EM edward.chang@ucsf.edu; karunesh.ganguly@ucsf.edu FU American Heart Association; Doris Duke Charitable Foundation [2013101]; National Institutes of Health through the NIH Director's New Innovator Award Program [1 DP2 HD087955-01]; NIH [R01-DC012379, U01-NS098971]; The New York Stem Cell Foundation FX This work was supported by a fellowship award from the American Heart Association (T. G.). This work was also supported by Grant 2013101 from the Doris Duke Charitable Foundation. This work was also funded by the National Institutes of Health through the NIH Director's New Innovator Award Program, grant number 1 DP2 HD087955-01.; This work was supported by NIH grants R01-DC012379 and U01-NS098971 (EFC). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. EFC is a New York Stem Cell Foundation - Robertson Investigator. This research was supported by The New York Stem Cell Foundation. NR 20 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2328-9503 J9 ANN CLIN TRANSL NEUR JI Ann. Clin. Transl. Neurol. PD DEC PY 2016 VL 3 IS 12 BP 956 EP 961 DI 10.1002/acn3.368 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EF8GH UT WOS:000390566700007 PM 28097208 ER PT J AU Jacobs, JP Shahian, DM Prager, RL Edwards, FH McDonald, D Han, JM D'Agostino, RS Jacobs, ML Kozower, BD Badhwar, V Thourani, VH Gaissert, HA Fernandez, FG Wright, CD Paone, G Cleveland, JC Brennan, JM Dokholyan, RS Brothers, L Vemulapalli, S Habib, RH O'Brien, SM Peterson, ED Grover, FL Patterson, GA Bavaria, JE AF Jacobs, Jeffrey P. Shahian, David M. Prager, Richard L. Edwards, Fred H. McDonald, Donna Han, Jane M. D'Agostino, Richard S. Jacobs, Marshall L. Kozower, Benjamin D. Badhwar, Vinay Thourani, Vinod H. Gaissert, Henning A. Fernandez, Felix G. Wright, Cameron D. Paone, Gaetano Cleveland, Joseph C., Jr. Brennan, J. Matthew Dokholyan, Rachel S. Brothers, Leo Vemulapalli, Sreekanth Habib, Robert H. O'Brien, Sean M. Peterson, Eric D. Grover, Frederick L. Patterson, G. Alexander Bavaria, Joseph E. TI The Society of Thoracic Surgeons National Database 2016 Annual Report SO ANNALS OF THORACIC SURGERY LA English DT Article ID ADULT CARDIAC-SURGERY; CARDIOTHORACIC SURGERY; PATIENT SAFETY; UPDATE; QUALITY; OUTCOMES; RISK AB The art and science of outcomes analysis, quality improvement, and patient safety continue to evolve, and cardiothoracic surgery leads many of these advances. The Society of Thoracic Surgeons (STS) National Database is one of the principal reasons for this leadership role, as it provides a platform for the generation of knowledge in all of these domains. Understanding these topics is a professional responsibility of all cardiothoracic surgeons. Therefore, beginning in January 2016, The Annals of Thoracic Surgery began publishing a monthly series of scholarly articles on outcomes analysis, quality improvement, and patient safety. This article provides a summary of the status of the STS National Database as of October 2016 and summarizes the articles about the STS National Database that appeared in The Annals of Thoracic Surgery 2016 series, "Outcomes Analysis, Quality Improvement, and Patient Safety." (C) 2016 by The Society of Thoracic Surgeons C1 [Jacobs, Jeffrey P.; Jacobs, Marshall L.] Johns Hopkins Univ, Sch Med, Dept Surg, Div Cardiac Surg, Baltimore, MD 21205 USA. [Jacobs, Jeffrey P.; Jacobs, Marshall L.] Johns Hopkins All Childrens Hosp, Johns Hopkins All Childrens Heart Inst, Dept Surg, Div Cardiovasc Surg, St Petersburg, FL USA. [Jacobs, Jeffrey P.; Jacobs, Marshall L.] Johns Hopkins All Childrens Hosp, Johns Hopkins All Childrens Heart Inst, Dept Surg, Div Cardiovasc Surg, Tampa, FL USA. [Jacobs, Jeffrey P.; Jacobs, Marshall L.] Johns Hopkins All Childrens Hosp, Johns Hopkins All Childrens Heart Inst, Dept Surg, Div Cardiovasc Surg, Orlando, FL USA. [Jacobs, Jeffrey P.; Jacobs, Marshall L.] Florida Hosp Children, St Petersburg, FL USA. [Jacobs, Jeffrey P.; Jacobs, Marshall L.] Florida Hosp Children, Tampa, FL USA. [Jacobs, Jeffrey P.; Jacobs, Marshall L.] Florida Hosp Children, Orlando, FL USA. [Shahian, David M.; Gaissert, Henning A.; Wright, Cameron D.] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. [Prager, Richard L.] Univ Michigan, Ann Arbor, MI 48109 USA. [Edwards, Fred H.] Univ Florida, Coll Med, Jacksonville, FL USA. [McDonald, Donna; Han, Jane M.; Habib, Robert H.] Soc Thorac Surg, Chicago, IL USA. [D'Agostino, Richard S.] Lahey Hosp & Med Ctr, Burlington, MA USA. [Kozower, Benjamin D.] Univ Virginia, Charlottesville, VA USA. [Badhwar, Vinay] West Virginia Univ, Div Cardiothorac Surg, Morgantown, WV USA. [Thourani, Vinod H.; Fernandez, Felix G.] Emory Univ, Atlanta, GA 30322 USA. [Paone, Gaetano] Henry Ford Hosp, Detroit, MI 48202 USA. [Cleveland, Joseph C., Jr.; Grover, Frederick L.] Univ Colorado, Sch Med, Aurora, CO USA. [Brennan, J. Matthew; Dokholyan, Rachel S.; Brothers, Leo; Vemulapalli, Sreekanth; O'Brien, Sean M.; Peterson, Eric D.] Duke Univ, Duke Clin Res Inst, Durham, NC USA. [Patterson, G. Alexander] Washington Univ, Sch Med, St Louis, MO USA. [Bavaria, Joseph E.] Univ Penn, Div Cardiovasc Surg, Philadelphia, PA 19104 USA. RP Jacobs, JP (reprint author), Johns Hopkins All Childrens Hosp, Johns Hopkins All Childrens Heart Inst, 601 Fifth St S,Ste 607, St Petersburg, FL 33701 USA.; Jacobs, JP (reprint author), Florida Hosp Children, 601 Fifth St S,Ste 607, St Petersburg, FL 33701 USA. EM jeffjacobs@jhmi.edu NR 19 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 0003-4975 EI 1552-6259 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD DEC PY 2016 VL 102 IS 6 BP 1790 EP 1797 DI 10.1016/j.athoracsur.2016.10.015 PG 8 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA EE4CA UT WOS:000389548100045 PM 27847042 ER PT J AU Mookhoek, A Krishnan, K Chitsaz, S Kuang, HD Ge, L Schoof, PH Bogers, AJJC Takkenberg, JJM Tseng, EE AF Mookhoek, Aart Krishnan, Kapil Chitsaz, Sam Kuang, Heide Ge, Liang Schoof, Paul H. Bogers, Ad J. J. C. Takkenberg, Johanna J. M. Tseng, Elaine E. TI Biomechanics of Failed Pulmonary Autografts Compared With Normal Pulmonary Roots SO ANNALS OF THORACIC SURGERY LA English DT Article ID ROSS PROCEDURE; MECHANICAL-PROPERTIES; AORTIC-VALVE; COLD-STORAGE; REOPERATIONS; OPERATION; ADULTS; DEGENERATION; REPLACEMENT; EXPERIENCE AB Background. Progressive dilatation of pulmonary autografts after the Ross operation may reflect inadequate remodeling of the native pulmonary root to adapt to systemic circulation. Understanding the biomechanics of autograft root dilatation may aid designing strategies to prevent dilatation. We have previously characterized normal human pulmonary root material properties; however, the mechanical properties of failed autografts are unknown. In this study, failed autograft roots explanted during reoperation were acquired, and their material properties were determined. Methods. Failed pulmonary autograft specimens were obtained from patients undergoing reoperation after the Ross operation. Fresh human native pulmonary roots were obtained from the transplant donor network as controls. Biaxial stretch testing was performed to determine tissue mechanical properties. Tissue stiffness was determined at patient-specific physiologic stresses at pulmonary pressures. Results. Nonlinear stress-strain response was present in both failed autografts and normal pulmonary roots. Explanted pulmonary autografts were less stiff than were their native pulmonary root counterparts at 8 mm Hg (134 +/- 42 vs 175 +/- 49 kPa, respectively) (p = 0.086) and 25 mm Hg (369 +/- 105 vs 919 +/- 353 kPa, respectively) (p = 0.006). Autograft wall stiffness at both 8 and 25 mm Hg was not correlated with age at the Ross procedure (p = 0.898 and p = 0.813, respectively) or with time in the systemic circulation (p = 0.609 and p = 0.702, respectively). Conclusions. Failed pulmonary autografts retained nonlinear response to mechanical loading typical of healthy human arterial tissue. Remodeling increased wall thickness but decreased wall stiffness in failed autografts. Increased compliance may explain progressive autograft root dilatation in autograft failures. (C) 2016 by The Society of Thoracic Surgeons C1 Erasmus Univ, Med Ctr, Dept Cardiothorac Surg, Rotterdam, Netherlands. Univ Calif San Francisco, Med Ctr, Dept Surg, San Francisco, CA USA. San Francisco VA Med Ctr, San Francisco, CA USA. Univ Texas Houston, Dept Med, Div Cardiol, Houston, TX USA. Univ Utrecht, Med Ctr, Dept Pediat Cardiothorac Surg, Utrecht, Netherlands. RP Tseng, EE (reprint author), UCSF, Med Ctr, Div Cardiothorac Surg, 500 Parnassus Ave,Ste 405W,Box 0118, San Francisco, CA 94143 USA. EM elaine.tseng@ucsfmedctr.org NR 33 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 DEC PY 2016 VL 102 IS 6 BP 1996 EP 2002 DI 10.1016/j.athoracsur.2016.05.010 PG 7 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA EE4CA UT WOS:000389548100073 PM 27457832 ER PT J AU Nauta, FJH Tolenaar, JL Patel, HJ Appoo, JJ Tsai, TT Desai, ND Montgomery, DG Mussa, FF Upchurch, GR Fattori, R Hughes, GC Nienaber, CA Isselbacher, EM Eagle, KA Trimarchi, S AF Nauta, Foeke J. H. Tolenaar, Jip L. Patel, Himanshu J. Appoo, Jehangir J. Tsai, Thomas T. Desai, Nimesh D. Montgomery, Daniel G. Mussa, Firas F. Upchurch, Gilbert R. Fattori, Rosella Hughes, G. Chad Nienaber, Christoph A. Isselbacher, Eric M. Eagle, Kim A. Trimarchi, Santi CA Int Registry Acute Aortic TI Impact of Retrograde Arch Extension in Acute Type B Aortic Dissection on Management and Outcomes SO ANNALS OF THORACIC SURGERY LA English DT Article ID INTERNATIONAL REGISTRY; FALSE LUMEN; THROMBOSIS; REPAIR; STILL AB Background. Optimal management of acute type B aortic dissection with retrograde arch extension is controversial. The effect of retrograde arch extension on operative and long-term mortality has not been studied and is not incorporated into clinical treatment pathways. Methods. The International Registry of Acute Aortic Dissection was queried for all patients presenting with acute type B dissection and an identifiable primary intimal tear. Outcomes were stratified according to management for patients with and without retrograde arch extension. Kaplan-Meier survival curves were constructed. Results. Between 1996 and 2014, 404 patients (mean age, 63.3 +/- 13.9 years) were identified. Retrograde arch extension existed in 67 patients (16.5%). No difference in complicated presentation was noted (36.8% vs 31.7%, p = 0.46), as defined by limb or organ malperfusion, coma, rupture, and shock. Patients with or without retrograde arch extension received similar treatment, with medical management in 53.7% vs 56.5% (p = 0.68), endovascular treatment in 32.8% vs 31.1% (p = 0.78), open operation in 11.9% vs 9.5% (p = 0.54), or hybrid approach in 1.5% vs 3.0% (p = 0.70), respectively. The in-hospital mortality rate was similar for patients with (10.7%) and without (10.4%) retrograde arch extension (p = 0.96), and 5-year survival was also similar at 78.3% and 77.8%, respectively (p = 0.27). Conclusions. The incidence of retrograde arch dissection involves approximately 16% of patients with acute type B dissection. In the International Registry of Acute Aortic Dissection, this entity seems not to affect management strategy or early and late death. (C) 2016 by The Society of Thoracic Surgeons C1 [Nauta, Foeke J. H.] Univ Milan, Policlin San Donato Ist Ricovero & Cura Caratter, Thorac Aort Res Ctr, Piazza Malan 2, I-20097 Milan, Italy. Univ Michigan Hlth Syst, Cardiovasc Ctr, Ann Arbor, MI USA. St Antonius Hosp, Vasc Surg, Nieuwegein, Netherlands. Univ Calgary, Libin Cardiovasc Inst, Div Cardiac Surg, Calgary, AB, Canada. Hosp Univ Penn, Cardiac Surg, 3400 Spruce St, Philadelphia, PA 19104 USA. Columbia Univ, Med Ctr, Vasc Surg, New York, NY USA. Univ Virginia, Heart & Vasc Ctr, Charlottesville, VA USA. Univ Hosp S Orsola, Vasc Surg, Bologna, Italy. Duke Univ, Med Ctr, Div Cardiovasc Surg, Durham, NC USA. Royal Brompton Hosp, Cardiol & Aort Ctr, London, England. Massachusetts Gen Hosp, Thorac Aort Ctr, Boston, MA 02114 USA. RP Nauta, FJH (reprint author), Univ Milan, Policlin San Donato Ist Ricovero & Cura Caratter, Thorac Aort Res Ctr, Piazza Malan 2, I-20097 Milan, Italy. EM foekenauta@gmail.com FU W.L. Gore & Associates, Inc; Medtronic; Terumo; Varbedian Aortic Research Fund; Hewlett Foundation; Mardigian Foundation; University of Michigan Faculty Group Practice FX Drs Patel and Appoo disclose a financial relationship with W.L. Gore & Associates, Inc; Dr Eagle with W.L. Gore & Associates, Inc, Medtronic, and Terumo; and Dr Trimarchi with W.L. Gore & Associates, Inc, and Medtronic.; IRAD is generously supported by W.L. Gore & Associates, Inc, Medtronic, Varbedian Aortic Research Fund, Hewlett Foundation, Mardigian Foundation, University of Michigan Faculty Group Practice, Terumo, and Ann and Bob Aikens. NR 18 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-4975 EI 1552-6259 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD DEC PY 2016 VL 102 IS 6 BP 2036 EP 2043 DI 10.1016/j.athoracsur.2016.05.013 PG 8 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA EE4CA UT WOS:000389548100078 PM 27424469 ER PT J AU Wells, JM Estepar, RSJ McDonald, MLN Bhatt, SP Diaz, AA Bailey, WC Jacobson, FL Dransfield, MT Washko, GR Make, BJ Casaburi, R van Beek, EJR Hoffman, EA Sciurba, FC Crapo, JD Silverman, EK Hersh, CP AF Wells, J. Michael Estepar, Raul San Jose McDonald, Merry-Lynn N. Bhatt, Surya P. Diaz, Alejandro A. Bailey, William C. Jacobson, Francine L. Dransfield, Mark T. Washko, George R. Make, Barry J. Casaburi, Richard van Beek, Edwin J. R. Hoffman, Eric A. Sciurba, Frank C. Crapo, James D. Silverman, Edwin K. Hersh, Craig P. CA COPDGene Investigators TI Clinical, physiologic, and radiographic factors contributing to development of hypoxemia in moderate to severe COPD: a cohort study SO BMC PULMONARY MEDICINE LA English DT Article ID OBSTRUCTIVE PULMONARY-DISEASE; QUALITY-OF-LIFE; OXYGEN-THERAPY; HEART-FAILURE; PULSE OXIMETRY; ACUTE EXACERBATIONS; RESTING HYPOXEMIA; HIGH-ALTITUDE; GAS-EXCHANGE; EMPHYSEMA AB Background: Hypoxemia is a major complication of COPD and is a strong predictor of mortality. We previously identified independent risk factors for the presence of resting hypoxemia in the COPDGene cohort. However, little is known about characteristics that predict onset of resting hypoxemia in patients who are normoxic at baseline. We hypothesized that a combination of clinical, physiologic, and radiographic characteristics would predict development of resting hypoxemia after 5-years of follow-up in participants with moderate to severe COPD Methods: We analyzed 678 participants with moderate-to-severe COPD recruited into the COPDGene cohort who completed baseline and 5-year follow-up visits and who were normoxic by pulse oximetry at baseline. Development of resting hypoxemia was defined as an oxygen saturation <= 88% on ambient air at rest during follow-up. Demographic and clinical characteristics, lung function, and radiographic indices were analyzed with logistic regression models to identify predictors of the development of hypoxemia. Results: Forty-six participants (7%) developed resting hypoxemia at follow-up. Enrollment at Denver (OR 8.30, 95% CI 3.05-22.6), lower baseline oxygen saturation (OR 0.70, 95% CI 0.58-0.85), self-reported heart failure (OR 6.92, 95% CI 1.56-30.6), pulmonary artery (PA) enlargement on computed tomography (OR 2.81, 95% CI 1.17-6.74), and prior severe COPD exacerbation (OR 3.31, 95% CI 1.38-7.90) were independently associated with development of resting hypoxemia. Participants who developed hypoxemia had greater decline in 6-min walk distance and greater 5-year decline in quality of life compared to those who remained normoxic at follow-up. Conclusions: Development of clinically significant hypoxemia over a 5-year span is associated with comorbid heart failure, PA enlargement and severe COPD exacerbation. Further studies are needed to determine if treatments targeting these factors can prevent new onset hypoxemia. C1 [Wells, J. Michael; Bhatt, Surya P.; Bailey, William C.; Dransfield, Mark T.] Univ Alabama Birmingham, Div Pulm Allergy & Crit Care Med, Birmingham, AL 35294 USA. [Wells, J. Michael; Bhatt, Surya P.; Bailey, William C.; Dransfield, Mark T.] Univ Alabama Birmingham, Lung Hlth Ctr, Birmingham, AL 35294 USA. [Wells, J. Michael; Dransfield, Mark T.] Birmingham VA Med Ctr, Birmingham, AL 35233 USA. [Estepar, Raul San Jose; Jacobson, Francine L.] Brigham & Womens Hosp, Dept Radiol, 75 Francis St, Boston, MA 02115 USA. [McDonald, Merry-Lynn N.; Silverman, Edwin K.; Hersh, Craig P.] Harvard Med Sch, Brigham & Womens Hosp, Channing Div Network Med, Boston, MA USA. [Diaz, Alejandro A.; Washko, George R.] Brigham & Womens Hosp, Div Pulm Med, 75 Francis St, Boston, MA 02115 USA. [Make, Barry J.; Crapo, James D.] Natl Jewish Hlth, Div Pulm Crit Care & Sleep Med, Denver, CO USA. [Casaburi, Richard] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Rehabil Clin Trials Ctr, Torrance, CA 90509 USA. [van Beek, Edwin J. R.] Univ Edinburgh, Dept Radiol, Edinburgh, Midlothian, Scotland. [Hoffman, Eric A.] Univ Iowa, Dept Radiol, Iowa City, IA 52242 USA. [Sciurba, Frank C.] Univ Pittsburgh, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA USA. [Wells, J. Michael] 1900 Univ Blvd,THT 422, Birmingham, AL 35294 USA. RP Wells, JM (reprint author), Univ Alabama Birmingham, Div Pulm Allergy & Crit Care Med, Birmingham, AL 35294 USA.; Wells, JM (reprint author), Univ Alabama Birmingham, Lung Hlth Ctr, Birmingham, AL 35294 USA.; Wells, JM (reprint author), Birmingham VA Med Ctr, Birmingham, AL 35233 USA.; Wells, JM (reprint author), 1900 Univ Blvd,THT 422, Birmingham, AL 35294 USA. EM jmwells@uabmc.edu FU COPD Foundation; [R01HL089897]; [R01HL089856]; [NIH/NHLBI K08HL1123940]; [R01HL116931]; [R01HL116473]; [K01HL118714]; [R01HL094635]; [R01HL125583] FX R01HL089897 and R01HL089856 (to COPDGene); NIH/NHLBI K08HL1123940 (to JMW); R01HL116931, R01HL116473 (RSJE); K01HL118714 (to AAD); R01HL094635, R01HL125583 (CPH). The COPDGene (R) project is also supported by the COPD Foundation through contributions made to an Industry Advisory Board comprised of AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Pfizer, Siemens and Sunovion. NR 57 TC 0 Z9 0 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2466 J9 BMC PULM MED JI BMC Pulm. Med. PD DEC 1 PY 2016 VL 16 AR 169 DI 10.1186/s12890-016-0331-0 PG 9 WC Respiratory System SC Respiratory System GA EF3DM UT WOS:000390204700001 PM 27903260 ER PT J AU Daianu, M Mendez, MF Baboyan, VG Jin, Y Melrose, RJ Jimenez, EE Thompson, PM AF Daianu, Madelaine Mendez, Mario F. Baboyan, Vatche G. Jin, Yan Melrose, Rebecca J. Jimenez, Elvira E. Thompson, Paul M. TI An advanced white matter tract analysis in frontotemporal dementia and early-onset Alzheimer's disease SO BRAIN IMAGING AND BEHAVIOR LA English DT Article DE Early-onset Alzheimer's disease; Behavioral variant frontotemporal dementia; Diffusion tensor imaging (DTI); Tract analysis; White matter ID AMYOTROPHIC-LATERAL-SCLEROSIS; MILD COGNITIVE IMPAIRMENT; BEHAVIORAL VARIANT; IN-VIVO; DIFFUSION MRI; HUMAN BRAIN; DISCONNECTION SYNDROMES; DISCONNEXION SYNDROMES; NETWORK CONNECTIVITY; MULTIPLE-SCLEROSIS AB Cortical and subcortical nuclei degenerate in the dementias, but less is known about changes in the white matter tracts that connect them. To better understand white matter changes in behavioral variant frontotemporal dementia (bvFTD) and early-onset Alzheimer's disease (EOAD), we used a novel approach to extract full 3D profiles of fiber bundles from diffusion-weighted MRI (DWI) and map white matter abnormalities onto detailed models of each pathway. The result is a spatially complex picture of tract-by-tract microstructural changes. Our atlas of tracts for each disease consists of 21 anatomically clustered and recognizable white matter tracts generated from whole-brain tractography in 20 patients with bvFTD, 23 with age-matched EOAD, and 33 healthy elderly controls. To analyze the landscape of white matter abnormalities, we used a point-wise tract correspondence method along the 3D profiles of the tracts and quantified the pathway disruptions using common diffusion metrics - fractional anisotropy, mean, radial, and axial diffusivity. We tested the hypothesis that bvFTD and EOAD are associated with preferential degeneration in specific neural networks. We mapped axonal tract damage that was best detected with mean and radial diffusivity metrics, supporting our network hypothesis, highly statistically significant and more sensitive than widely studied fractional anisotropy reductions. From white matter diffusivity, we identified abnormalities in bvFTD in all 21 tracts of interest but especially in the bilateral uncinate fasciculus, frontal callosum, anterior thalamic radiations, cingulum bundles and left superior longitudinal fasciculus. This network of white matter alterations extends beyond the most commonly studied tracts, showing greater white matter abnormalities in bvFTD versus controls and EOAD patients. In EOAD, network alterations involved more posterior white matter - the parietal sector of the corpus callosum and parahipoccampal cingulum bilaterally. Widespread but distinctive white matter alterations are a key feature of the pathophysiology of these two forms of dementia. C1 [Daianu, Madelaine; Baboyan, Vatche G.; Jin, Yan; Thompson, Paul M.] Univ Southern Calif, Mark & Mary Stevens Inst Neuroimaging & Informat, Imaging Genet Ctr, Marina Del Rey, CA 90292 USA. [Daianu, Madelaine; Thompson, Paul M.] Univ Calif Los Angeles, Sch Med, Dept Neurol, Los Angeles, CA 90024 USA. [Mendez, Mario F.; Jimenez, Elvira E.] Univ Calif Los Angeles, Dept Neurol, Behav Neurol Program, Los Angeles, CA 90024 USA. [Thompson, Paul M.] Univ Southern Calif, Dept Neurol Psychiat Radiol Engn Pediat & Ophthal, Los Angeles, CA USA. [Melrose, Rebecca J.] VA Greater Los Angeles Healthcare Syst, Brain Behav & Aging Res Ctr, Los Angeles, CA USA. [Melrose, Rebecca J.] Univ Calif Los Angeles, Sch Med, Dept Psychiat, Los Angeles, CA 90024 USA. [Melrose, Rebecca J.] Univ Calif Los Angeles, Sch Med, Dept Biobehav Sci, Los Angeles, CA USA. RP Thompson, PM (reprint author), Univ Southern Calif, Mark & Mary Stevens Inst Neuroimaging & Informat, Imaging Genet Ctr, Marina Del Rey, CA 90292 USA.; Thompson, PM (reprint author), Univ Calif Los Angeles, Sch Med, Dept Neurol, Los Angeles, CA 90024 USA.; Thompson, PM (reprint author), Univ Southern Calif, Dept Neurol Psychiat Radiol Engn Pediat & Ophthal, Los Angeles, CA USA. EM pthomp@usc.edu FU NIBIB [R01 EB008281, R01 EB008432]; NIA; NIMH; National Library of Medicine [AG016570, AG040060, EB01651, MH097268, LM05639]; NIH [5R01 AG034499-05]; NIH Institutes contributing to the Big Data to Knowledge (BD2K) Initiative [U54 EB020403] FX Algorithm development and image analysis for this study were funded, in part, by grants to PT from the NIBIB (R01 EB008281, R01 EB008432) and by the NIA, NIBIB, NIMH, and the National Library of Medicine (AG016570, AG040060, EB01651, MH097268, LM05639 to PT). Data collection and sharing for this project was funded by NIH Grant 5R01 AG034499-05. This work was also supported in part by a Consortium grant (U54 EB020403) from the NIH Institutes contributing to the Big Data to Knowledge (BD2K) Initiative and R01 EB008432. NR 88 TC 5 Z9 5 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1931-7557 EI 1931-7565 J9 BRAIN IMAGING BEHAV JI Brain Imaging Behav. PD DEC PY 2016 VL 10 IS 4 BP 1038 EP 1053 DI 10.1007/s11682-015-9458-5 PG 16 WC Neuroimaging SC Neurosciences & Neurology GA EF0LC UT WOS:000390015900010 PM 26515192 ER PT J AU Makris, N Rathi, Y Mouradian, P Bonmassar, G Papadimitriou, G Ing, WI Yeterian, EH Kubicki, M Eskandar, EN Wald, LL Fan, QY Nummenmaa, A Widge, AS Dougherty, DD AF Makris, Nikolaos Rathi, Yogesh Mouradian, Palig Bonmassar, Giorgio Papadimitriou, George Ing, Wingkwai I. Yeterian, Edward H. Kubicki, Marek Eskandar, Emad N. Wald, Lawrence L. Fan, Qiuyun Nummenmaa, Aapo Widge, Alik S. Dougherty, Darin D. TI Variability and anatomical specificity of the orbitofrontothalamic fibers of passage in the ventral capsule/ventral striatum (VC/VS): precision care for patient-specific tractography-guided targeting of deep brain stimulation (DBS) in obsessive compulsive disorder (OCD) SO BRAIN IMAGING AND BEHAVIOR LA English DT Article DE Diffusion tensor imaging; Diffusion tractography; Connectome; Obsessive-compulsive disorder (OCD); Deep brain stimulation (DBS); Tractography-guided DBS ID HUMAN CEREBRAL-CORTEX; THALAMIC MEDIODORSAL NUCLEUS; SURFACE-BASED ANALYSIS; RHESUS-MONKEY; PREFRONTAL CORTEX; CORTICAL CONNECTIONS; FRONTAL-LOBE; DIFFUSION TRACTOGRAPHY; MACAQUE MONKEYS; MEDIAL PULVINAR AB Deep Brain Stimulation (DBS) is a neurosurgical procedure that can reduce symptoms in medically intractable obsessive-compulsive disorder (OCD). Conceptually, DBS of the ventral capsule/ventral striatum (VC/VS) region targets reciprocal excitatory connections between the orbitofrontal cortex (OFC) and thalamus, decreasing abnormal reverberant activity within the OFC-caudate-pallidal-thalamic circuit. In this study, we investigated these connections using diffusion magnetic resonance imaging (dMRI) on human connectome datasets of twenty-nine healthy young-adult volunteers with two-tensor unscented Kalman filter based tractography. We studied the morphology of the lateral and medial orbitofrontothalamic connections and estimated their topographic variability within the VC/VS region. Our results showed that the morphology of the individual orbitofrontothalamic fibers of passage in the VC/VS region is complex and inter-individual variability in their topography is high. We applied this method to an example OCD patient case who underwent DBS surgery, formulating an initial proof of concept for a tractography-guided patient-specific approach in DBS for medically intractable OCD. This may improve on current surgical practice, which involves implanting all patients at identical stereotactic coordinates within the VC/VS region. C1 [Makris, Nikolaos; Rathi, Yogesh; Mouradian, Palig; Bonmassar, Giorgio; Papadimitriou, George; Ing, Wingkwai I.; Kubicki, Marek; Eskandar, Emad N.; Wald, Lawrence L.; Fan, Qiuyun; Nummenmaa, Aapo; Widge, Alik S.; Dougherty, Darin D.] Massachusetts Gen Hosp, Athinoula Martinos Ctr Biomed Imaging, Ctr Morphometr Anal, Dept Psychiat, Bldg 149,13th St, Charlestown, MA 02129 USA. [Makris, Nikolaos; Rathi, Yogesh; Mouradian, Palig; Bonmassar, Giorgio; Papadimitriou, George; Ing, Wingkwai I.; Kubicki, Marek; Eskandar, Emad N.; Wald, Lawrence L.; Fan, Qiuyun; Nummenmaa, Aapo; Widge, Alik S.; Dougherty, Darin D.] Massachusetts Gen Hosp, Athinoula Martinos Ctr Biomed Imaging, Ctr Morphometr Anal, Dept Neurol, Bldg 149,13th St, Charlestown, MA 02129 USA. [Makris, Nikolaos; Rathi, Yogesh; Mouradian, Palig; Bonmassar, Giorgio; Papadimitriou, George; Ing, Wingkwai I.; Kubicki, Marek; Eskandar, Emad N.; Wald, Lawrence L.; Fan, Qiuyun; Nummenmaa, Aapo; Widge, Alik S.; Dougherty, Darin D.] Massachusetts Gen Hosp, Athinoula Martinos Ctr Biomed Imaging, Ctr Morphometr Anal, Dept Neurosurg, Bldg 149,13th St, Charlestown, MA 02129 USA. [Makris, Nikolaos; Rathi, Yogesh; Mouradian, Palig; Bonmassar, Giorgio; Papadimitriou, George; Ing, Wingkwai I.; Kubicki, Marek; Eskandar, Emad N.; Wald, Lawrence L.; Fan, Qiuyun; Nummenmaa, Aapo; Widge, Alik S.; Dougherty, Darin D.] Massachusetts Gen Hosp, Athinoula Martinos Ctr Biomed Imaging, Ctr Morphometr Anal, Dept Radiol, Bldg 149,13th St, Charlestown, MA 02129 USA. [Makris, Nikolaos; Rathi, Yogesh; Kubicki, Marek] Harvard Med Sch, Brigham & Womens Hosp, Dept Psychiat, Psychiat Neuroimaging Lab, Boston, MA 02115 USA. [Makris, Nikolaos] Harvard Med Sch, McLean Hosp, McLean Imaging Ctr, Boston, MA 02115 USA. [Makris, Nikolaos] Boston Univ, Sch Med, Dept Anat & Neurobiol, Boston, MA 02118 USA. [Yeterian, Edward H.] Colby Coll, Dept Psychol, Waterville, ME 04901 USA. [Widge, Alik S.] MIT, Picower Inst Learning & Memory, 77 Massachusetts Ave, Cambridge, MA 02139 USA. RP Makris, N (reprint author), Massachusetts Gen Hosp, Athinoula Martinos Ctr Biomed Imaging, Ctr Morphometr Anal, Dept Psychiat, Bldg 149,13th St, Charlestown, MA 02129 USA.; Makris, N (reprint author), Massachusetts Gen Hosp, Athinoula Martinos Ctr Biomed Imaging, Ctr Morphometr Anal, Dept Neurol, Bldg 149,13th St, Charlestown, MA 02129 USA.; Makris, N (reprint author), Massachusetts Gen Hosp, Athinoula Martinos Ctr Biomed Imaging, Ctr Morphometr Anal, Dept Neurosurg, Bldg 149,13th St, Charlestown, MA 02129 USA.; Makris, N (reprint author), Massachusetts Gen Hosp, Athinoula Martinos Ctr Biomed Imaging, Ctr Morphometr Anal, Dept Radiol, Bldg 149,13th St, Charlestown, MA 02129 USA.; Makris, N (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Dept Psychiat, Psychiat Neuroimaging Lab, Boston, MA 02115 USA.; Makris, N (reprint author), Harvard Med Sch, McLean Hosp, McLean Imaging Ctr, Boston, MA 02115 USA.; Makris, N (reprint author), Boston Univ, Sch Med, Dept Anat & Neurobiol, Boston, MA 02118 USA. EM nikos@cma.mgh.harvard.edu FU NIH, NIBIB [R21EB016449]; NIH [5 UO1 MH 093765-05]; NIMH [RO1MH097979, R01 MH102377]; Colby College Research Fund [01 2836]; Medtronic; Cyberonics; Roche; Eli Lilly and Company FX This study was supported, in part, by grants from: NIH, NIBIB R21EB016449 (NM and GB); from NIH, 5 UO1 MH 093765-05 (LW, QF and AN); from NIMH, RO1MH097979 (YR); from NIMH, R01 MH102377 (MK and NM); from Colby College Research Fund 01 2836 (EY); from Medtronic, Cyberonics, Roche and Eli Lilly and Company (DD). NR 74 TC 3 Z9 3 U1 3 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1931-7557 EI 1931-7565 J9 BRAIN IMAGING BEHAV JI Brain Imaging Behav. PD DEC PY 2016 VL 10 IS 4 BP 1054 EP 1067 DI 10.1007/s11682-015-9462-9 PG 14 WC Neuroimaging SC Neurosciences & Neurology GA EF0LC UT WOS:000390015900011 PM 26518214 ER PT J AU del Re, EC Konishi, J Bouix, S Blokland, GAM Mesholam-Gately, R Goldstein, J Kubicki, M Wojcik, J Pasternak, O Seidman, L Petryshen, T Hirayasu, Y Niznikiewicz, M Shenton, M McCarley, R AF del Re, Elisabetta C. Konishi, Jun Bouix, Sylvain Blokland, Gabriella A. M. Mesholam-Gately, Raquelle I. Goldstein, Jill Kubicki, Marek Wojcik, Joanne Pasternak, Ofer Seidman, Larry J. Petryshen, Tracey Hirayasu, Yoshio Niznikiewicz, Margaret Shenton, Martha E. McCarley, Robert W. TI Enlarged lateral ventricles inversely correlate with reduced corpus callosum central volume in first episode schizophrenia: association with functional measures SO BRAIN IMAGING AND BEHAVIOR LA English DT Article DE Schizophrenia; Ventricles; Corpus callosum; Neurodevelopment; Multi-atlas brain masking; FreeSurfer ID ONSET SCHIZOPHRENIA; LONGITUDINAL MRI; HIGH-RISK; BRAIN; METAANALYSIS; ABNORMALITIES; MORPHOLOGY; ILLNESS; HEALTH; SIZE AB The lateral and third ventricles, as well as the corpus callosum (CC), are known to be affected in schizophrenia. Here we investigate whether abnormalities in the lateral ventricles (LVs), third ventricle, and corpus callosum are related to one another in first episode schizophrenia (FESZ), and whether such abnormalities show progression over time. Nineteen FESZ and 19 age- and handedness-matched controls were included in the study. MR images were acquired on a 3-Tesla MRI at baseline and similar to 1.2 years later. FreeSurfer v.5.3 was employed for segmentation. Two-way or univariate ANCOVAs were used for statistical analysis, where the covariate was intracranial volume. Group and gender were included as between-subjects factors. Percent volume changes between baseline and follow-up were used to determine volume changes at follow-up. Bilateral LV and third ventricle volumes were significantly increased, while central CC volume was significantly decreased in patients compared to controls at baseline and at follow-up. In FESZ, the bilateral LV volume was also inversely correlated with volume of the central CC. This inverse correlation was not present in controls. In FESZ, an inverse correlation was found between percent volume increase from baseline to follow-up for bilateral LVs and lesser improvement in the Global Assessment of Functioning score. Significant correlations were observed for abnormalities of central CC, LVs and third ventricle volumes in FESZ, suggesting a common neurodevelopmental origin in schizophrenia. Enlargement of ventricles was associated with less improvement in global functioning over time. C1 [del Re, Elisabetta C.; Konishi, Jun; Niznikiewicz, Margaret; McCarley, Robert W.] Brockton Div, Dept Psychiat, VA Boston Healthcare Syst, Lab Neurosci, Brockton, MA USA. [del Re, Elisabetta C.; Konishi, Jun] Harvard Med Sch, Boston, MA 02115 USA. [del Re, Elisabetta C.; Konishi, Jun; Bouix, Sylvain; Kubicki, Marek; Pasternak, Ofer; Shenton, Martha E.] Brigham & Womens Hosp, Dept Psychiat, Psychiat Neuroimaging Lab, Boston, MA USA. [del Re, Elisabetta C.; Konishi, Jun; Niznikiewicz, Margaret; McCarley, Robert W.] VA Boston Healthcare Syst, Brockton Div, Brockton, MA USA. [Blokland, Gabriella A. M.; Petryshen, Tracey] Massachusetts Gen Hosp, Psychiat & Neurodevelopmental Genet Unit, Ctr Human Genet Res, Boston, MA USA. [Blokland, Gabriella A. M.; Seidman, Larry J.; Petryshen, Tracey] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA USA. [Mesholam-Gately, Raquelle I.; Wojcik, Joanne; Seidman, Larry J.] Beth Israel Deaconess Med Ctr, Massachusetts Mental Hlth Ctr Div Publ Psychiat, Dept Psychiat, Boston, MA USA. [Goldstein, Jill] Brigham & Womens Hosp, Connors Ctr Womens Hlth & Gender Biol, 75 Francis St, Boston, MA 02115 USA. [Goldstein, Jill] Harvard Med Sch, Dept Psychiat & Med, Boston, MA USA. [Hirayasu, Yoshio] Yokohama City Univ, Grad Sch Med, Dept Psychiat, Yokohama, Kanagawa, Japan. [Shenton, Martha E.] Brigham & Womens Hosp, Dept Radiol, Boston, MA USA. RP del Re, EC (reprint author), Brockton Div, Dept Psychiat, VA Boston Healthcare Syst, Lab Neurosci, Brockton, MA USA.; del Re, EC (reprint author), Harvard Med Sch, Boston, MA 02115 USA.; del Re, EC (reprint author), Brigham & Womens Hosp, Dept Psychiat, Psychiat Neuroimaging Lab, Boston, MA USA.; del Re, EC (reprint author), VA Boston Healthcare Syst, Brockton Div, Brockton, MA USA. EM elisabetta_delre@hms.harvard.edu OI Blokland, Gabriella/0000-0003-0566-444X FU Boston Center for Intervention Development and Applied Research (Boston CIDAR) [P50 MH080272]; National Institutes of Health [R01 MH40799, R01MH092380]; Commonwealth Research Center [SCDMH82101008006]; Clinical Translational Science Award from the National Center for Research Resources [UL1RR025758] FX This study was conducted in part by the P50 MH080272 Boston Center for Intervention Development and Applied Research (Boston CIDAR; RWM PI, MES, LJS, RI-M-G, JG, TLP), entitled: "Longitudinal Assessment and Monitoring of Clinical Status and Brain Function in Adolescents and Adults." This work was also supported in part by R01 MH40799 (RWM) and R01MH092380 (TLP) from National Institutes of Health, by the Commonwealth Research Center (SCDMH82101008006, LJS), and by a Clinical Translational Science Award UL1RR025758 to Harvard University and Beth Israel Deaconess Medical Center from the National Center for Research Resources (LJS). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 53 TC 0 Z9 0 U1 7 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1931-7557 EI 1931-7565 J9 BRAIN IMAGING BEHAV JI Brain Imaging Behav. PD DEC PY 2016 VL 10 IS 4 BP 1264 EP 1273 DI 10.1007/s11682-015-9493-2 PG 10 WC Neuroimaging SC Neurosciences & Neurology GA EF0LC UT WOS:000390015900031 PM 26678596 ER PT J AU Bahcall, M Sim, T Paweletz, CP Patel, JD Alden, RS Kuang, Y Sacher, AG Kim, ND Lydon, CA Awad, MM Jaklitsch, MT Sholl, LM Janne, PA Oxnard, GR AF Bahcall, Magda Sim, Taebo Paweletz, Cloud P. Patel, Jyoti D. Alden, Ryan S. Kuang, Yanan Sacher, Adrian G. Kim, Nam Doo Lydon, Christine A. Awad, Mark M. Jaklitsch, Michael T. Sholl, Lynette M. Jaenne, Pasi A. Oxnard, Geoffrey R. TI Acquired METD1228V Mutation and Resistance to MET Inhibition in Lung Cancer SO CANCER DISCOVERY LA English DT Article ID TYROSINE KINASE; ACTIVATING MUTATIONS; EGFR T790M; PHASE-III; SOMATIC MUTATIONS; PLUS ERLOTINIB; CELL CARCINOMA; DOUBLE-BLIND; AMPLIFICATION; CRIZOTINIB AB Amplified and/or mutated MET can act as both a primary oncogenic driver and as a promoter of tyrosine kinase inhibitor (TKI) resistance in non-small cell lung cancer (NSCLC). However, the landscape of MET-specific targeting agents remains underdeveloped, and understanding of mechanisms of resistance to MET TKIs is limited. Here, we present a case of a patient with lung adenocarcinoma harboring both a mutation in EGFR and an amplification of MET, who after progression on erlotinib responded dramatically to combined MET and EGFR inhibition with savolitinib and osimertinib. When resistance developed to this combination, a new MET kinase domain mutation, D1228V, was detected. Our in vitro findings demonstrate that MET D1228V induces resistance to type I MET TKIs through impaired drug binding, while sensitivity to type II MET TKIs is maintained. Based on these findings, the patient was treated with erlotinib combined with cabozantinib, a type II MET inhibitor, and exhibited a response. SIGNIFICANCE: With several structurally distinct MET inhibitors undergoing development for treatment of NSCLC, it is critical to identify mechanism-based therapies for drug resistance. We demonstrate that an acquired METD1228V mutation mediates resistance to type I, but not type II, MET inhibitors, having therapeutic implications for the clinical use of sequential MET inhibitors. C1 [Bahcall, Magda; Alden, Ryan S.; Sacher, Adrian G.; Lydon, Christine A.; Awad, Mark M.; Jaenne, Pasi A.; Oxnard, Geoffrey R.] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02115 USA. [Sim, Taebo] Korea Inst Sci & Technol, Chem Kinom Res Ctr, Seoul, South Korea. [Sim, Taebo] Korea Univ, KU KIST Grad Sch Converging Sci & Technol, Seoul, South Korea. [Paweletz, Cloud P.; Kuang, Yanan; Jaenne, Pasi A.] Dana Farber Canc Inst, Belfer Ctr Appl Canc Sci, Boston, MA 02115 USA. [Patel, Jyoti D.] Univ Chicago, Dept Med, 5841 S Maryland Ave, Chicago, IL 60637 USA. [Kim, Nam Doo] Daegu Gyeongbuk Med Innovat Fdn, Daegu, South Korea. [Awad, Mark M.; Jaenne, Pasi A.; Oxnard, Geoffrey R.] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Awad, Mark M.; Jaklitsch, Michael T.; Sholl, Lynette M.; Jaenne, Pasi A.; Oxnard, Geoffrey R.] Harvard Med Sch, Boston, MA USA. [Jaklitsch, Michael T.] Brigham & Womens Hosp, Dept Surg, 75 Francis St, Boston, MA 02115 USA. [Sholl, Lynette M.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. RP Janne, PA; Oxnard, GR (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM pasi_janne@dfci.harvard.edu; geoffrey_oxnard@dfci.harvard.edu FU NCI of the NIH [R01-CA135257]; Stading-Younger Cancer Research Foundation; Phi Bets Psi Sorority Trust; Creative/Challenging Research Program of the National Research Foundation of Korea (NRF) [2011-0028676]; Cammarata Family Foundation Fund; James B. Gillen Thoracic Oncology Research Fund; Harold and Gail Kirstein Lung Cancer Research Fund FX The study was supported by the NCI of the NIH (R01-CA135257), Stading-Younger Cancer Research Foundation, the Phi Bets Psi Sorority Trust, the Creative/Challenging Research Program (2011-0028676) of the National Research Foundation of Korea (NRF), the Cammarata Family Foundation Fund, the James B. Gillen Thoracic Oncology Research Fund, and the Harold and Gail Kirstein Lung Cancer Research Fund. NR 39 TC 1 Z9 1 U1 3 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2159-8274 EI 2159-8290 J9 CANCER DISCOV JI Cancer Discov. PD DEC PY 2016 VL 6 IS 12 BP 1334 EP 1341 DI 10.1158/2159-8290.CD-16-0686 PG 8 WC Oncology SC Oncology GA EF3VL UT WOS:000390252900022 PM 27694386 ER PT J AU Kwak, EL Ahronian, LG Siravegna, G Mussolin, B Borger, DR Godfrey, JT Jessop, NA Clark, JW Blaszkowsky, LS Ryan, DP Lennerz, JK Iafrate, AJ Bardelli, A Hong, TS Corcoran, RB Borger, DR Jessop, NA AF Kwak, Eunice L. Ahronian, Leanne G. Siravegna, Giulia Mussolin, Benedetta Borger, Darrell R. Godfrey, Jason T. Jessop, Nicholas A. Clark, Jeffrey W. Blaszkowsky, Lawrence S. Ryan, David P. Lennerz, Jochen K. Iafrate, A. John Bardelli, Alberto Hong, Theodore S. Corcoran, Ryan B. Borger, Darrell R. Jessop, Nicholas A. TI Molecular Heterogeneity and Receptor Coamplification Drive Resistance to Targeted Therapy in MET-Amplified Esophagogastric Cancer (vol 5, pg 1271, 2015) SO CANCER DISCOVERY LA English DT Correction C1 [Kwak, Eunice L.; Ahronian, Leanne G.; Godfrey, Jason T.; Clark, Jeffrey W.; Blaszkowsky, Lawrence S.; Ryan, David P.; Hong, Theodore S.; Corcoran, Ryan B.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Kwak, Eunice L.; Ahronian, Leanne G.; Godfrey, Jason T.; Clark, Jeffrey W.; Blaszkowsky, Lawrence S.; Ryan, David P.; Corcoran, Ryan B.] Harvard Med Sch, Dept Med, Boston, MA USA. [Siravegna, Giulia; Mussolin, Benedetta; Bardelli, Alberto] Univ Turin, Dept Oncol, Turin, Italy. [Siravegna, Giulia; Mussolin, Benedetta; Bardelli, Alberto] IRCCS, Candiolo Canc Inst FPO, Turin, Italy. [Borger, Darrell R.; Jessop, Nicholas A.; Lennerz, Jochen K.; Iafrate, A. John] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Borger, Darrell R.; Jessop, Nicholas A.; Lennerz, Jochen K.; Iafrate, A. John] Harvard Med Sch, Boston, MA USA. [Hong, Theodore S.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA USA. RP Kwak, EL (reprint author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2159-8274 EI 2159-8290 J9 CANCER DISCOV JI Cancer Discov. PD DEC PY 2016 VL 6 IS 12 BP 1402 EP 1402 DI 10.1158/2159-8290.CD-16-1271 PG 1 WC Oncology SC Oncology GA EF3VL UT WOS:000390252900027 ER PT J AU Li, YC Lu, ZY Huang, Y Lopes-Virella, MF Virella, G AF Li, Yanchun Lu, Zhongyang Huang, Yan Lopes-Virella, Maria F. Virella, Gabriel TI F(ab ')(2) fragments of anti-oxidized LDL IgG attenuate vascular inflammation and atherogenesis in diabetic LDL receptor-deficient mice SO CLINICAL IMMUNOLOGY LA English DT Article DE Atherosclerosis; Inflammation; Phagocytosis; Low-density lipoprotein; Oxidized LDL; Oxidized LDL antibody ID LOW-DENSITY-LIPOPROTEIN; IMMUNE-COMPLEXES; ATHEROSCLEROTIC LESIONS; INSULIN-RESISTANCE; HUMAN MACROPHAGES; IN-VITRO; AGE-LDL; CELLS; OXLDL; ACTIVATION AB Considerable evidence is available supporting the atherogenic role of immune complexes (IC) formed by modified forms of LDL and their corresponding antibodies in humans and other species. In this study, we assessed the effect of IgG F(ab')(2) fragments of murine anti-mouse oxLDL, which binds oxLDL forming IC that cannot interact with Fc gamma receptors, on the development of atherosclerosis in diabetic LDL receptor-deficient (LDLR-/-) mice. Immunohistochemical study showed that treatment with the F(ab')(2) fragments for 8 weeks significantly reduced the content of macrophages and interleukin 6 expression in atherosclerotic lesions. Furthermore, histological study showed that treatment with the same F(ab')(2) fragments significantly reduced atherosclerotic lesions in diabetic LDLR-/- mice. Taken together, this study demonstrated for the first time that F(ab')(2) fragments of anti-oxLDL IgG inhibited vascular inflammation and atherogenesis in diabetic LDLR-/- mice and uncovered a possible new avenue for therapy in patients at high risk to progress to cardiovascular complications. (C) 2016 Published by Elsevier Inc. C1 [Li, Yanchun; Huang, Yan; Lopes-Virella, Maria F.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29401 USA. [Li, Yanchun; Lu, Zhongyang; Huang, Yan; Lopes-Virella, Maria F.] Dept Med, Div Endocrinol Diabet & Med Genet, Charleston, SC USA. [Virella, Gabriel] Med Univ South Carolina, Dept Microbiol & Immunol, 173 Ashley Ave,MSC 509,Room 203, Charleston, SC 29425 USA. RP Virella, G (reprint author), Med Univ South Carolina, Dept Microbiol & Immunol, 173 Ashley Ave,MSC 509,Room 203, Charleston, SC 29425 USA. EM virellag@musc.edu FU Merit Review Grant from Biomedical Laboratory Research and Development Program of U.S. Department of Veterans Affairs [BX002281] FX This work was supported by Merit Review Grant from the Biomedical Laboratory Research and Development Program of the U.S. Department of Veterans Affairs (BX002281) (To M. F. L). NR 36 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 EI 1521-7035 J9 CLIN IMMUNOL JI Clin. Immunol. PD DEC PY 2016 VL 173 BP 50 EP 56 DI 10.1016/j.clim.2016.07.020 PG 7 WC Immunology SC Immunology GA EE8GR UT WOS:000389864200007 PM 27455858 ER PT J AU Harel, EV Tennyson, RL Fava, M Bar, M AF Harel, Eiran Vadim Tennyson, Robert Langley Fava, Maurizio Bar, Moshe TI Linking major depression and the neural substrates of associative processing SO COGNITIVE AFFECTIVE & BEHAVIORAL NEUROSCIENCE LA English DT Article DE Depression; Context; Parahippocampus; Associations; Entorhinal; Rumination ID BOLD SENSITIVITY LOSSES; HUMAN PREFRONTAL CORTEX; UNIPOLAR DEPRESSION; ENTORHINAL CORTEX; COGNITIVE CONTROL; DENTATE GYRUS; HIPPOCAMPAL SUBFIELDS; SELECTIVE ATTENTION; PROACTIVE BRAIN; POSITIVE AFFECT AB It has been proposed that mood correlates with the breadth of associative thinking. Here we set this hypothesis to the test in healthy and depressed individuals. Generating contextual associations engages a network of cortical regions including the parahippocampal cortex (PHC), retrosplenial complex, and medial prefrontal cortex. The link between mood, associative processing, and its underlying cortical infrastructure provides a promising avenue for elucidating the mechanisms underlying the cognitive impairments in major depressive disorder (MDD). The participants included 15 nonmedicated individuals with acute major depressive episodes and 15 healthy matched controls. In an fMRI experiment, participants viewed images of objects that were either strongly or weakly associated with a specific context (e.g., a beach chair vs. a water bottle) while rating the commonality of each object. Analyses were performed to examine the brain activation and structural differences between the groups. Consistent with our hypothesis, controls showed greater activation of the contextual associations network than did depressed participants. In addition, PHC structural volume was correlated with ruminative tendencies, and the volumes of the hippocampal subfields were significantly smaller in depressed participants. Surprisingly, depressed participants showed increased activity in the entorhinal cortex (ERC), as compared with controls. We integrated these findings within a mechanistic account linking mood and associative thinking and suggest directions for the future. C1 [Harel, Eiran Vadim] Tel Aviv Univ, Sackler Fac Med, Beer Yaakov Mental Hlth Ctr, Tel Aviv, Israel. [Tennyson, Robert Langley] Univ Washington, Dept Anthropol, Seattle, WA 98195 USA. [Tennyson, Robert Langley] Univ Washington, Ctr Studies Demog & Ecol, Seattle, WA 98195 USA. [Fava, Maurizio] Massachusetts Gen Hosp, Div Clin Res, Res Inst, Boston, MA 02114 USA. [Bar, Moshe] Bar Ilan Univ, Gonda Ctr Brain Res, Ramat Gan, Israel. RP Harel, EV (reprint author), Tel Aviv Univ, Sackler Fac Med, Beer Yaakov Mental Hlth Ctr, Tel Aviv, Israel. EM eiranharel@gmail.com FU National Institutes of Health [R01MH084940]; Israeli Center of Research Excellence in Cognition [51/11] FX This work was supported by National Institutes of Health Grant No. R01MH084940, and by the Israeli Center of Research Excellence in Cognition, Grant No. 51/11, both awarded to M.B. We thank the staff at the Depression Clinical and Research Program of the Massachusetts General Hospital for their skilled assistance in patient recruitment. E.V.H., R.L.T., and M.B. report no biomedical financial interests or potential conflicts of interest. For a list of lifetime disclosures for M.F., please see http://mghcme.org/faculty/faculty-detail/maurizio_fava. NR 74 TC 1 Z9 1 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1530-7026 EI 1531-135X J9 COGN AFFECT BEHAV NE JI Cogn. Affect. Behav. Neurosci. PD DEC PY 2016 VL 16 IS 6 BP 1017 EP 1026 DI 10.3758/s13415-016-0449-9 PG 10 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA EF0MJ UT WOS:000390019200004 PM 27553369 ER PT J AU Hinck, AP Mueller, TD Springer, TA AF Hinck, Andrew P. Mueller, Thomas D. Springer, Timothy A. TI Structural Biology and Evolution of the TGF-beta Family SO COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY LA English DT Article ID BONE-MORPHOGENETIC-PROTEIN; GROWTH-FACTOR-BETA; REPULSIVE GUIDANCE MOLECULE; VON-WILLEBRAND-FACTOR; LIGAND-BINDING DOMAIN; HEREDITARY HEMORRHAGIC TELANGIECTASIA; RECEPTOR EXTRACELLULAR DOMAIN; ACTIVATES LATENT TGF-BETA-1; STRUCTURE ANALYSIS REVEALS; CRIPTO CFC DOMAIN AB We review the evolution and structure of members of the transforming growth factor beta (TGF-beta) family, antagonistic or agonistic modulators, and receptors that regulate TGF-beta signaling in extracellular environments. The growth factor (GF) domain common to all family members and many of their antagonists evolved from a common cystine knot growth factor (CKGF) domain. The CKGF superfamily comprises six distinct families in primitive metazoans, including the TGF-beta and Dan families. Compared with Wnt/Frizzled and Notch/Delta families that also specify body axes, cell fate, tissues, and other families that contain CKGF domains that evolved in parallel, the TGF-beta family was the most fruitful in evolution. Complexes between the prodomains and GFs of the TGF-beta family suggest a new paradigm for regulating GF release by conversion from closed- to open-arm procomplex conformations. Ternary complexes of the final step in extracellular signaling show how TGF-beta GF dimers bind type I and type II receptors on the cell surface, and enable understanding of much of the specificity and promiscuity in extracellular signaling. However, structures suggest that when GFs bind repulsive guidance molecule (RGM) family coreceptors, type I receptors do not bind until reaching an intracellular, membrane-enveloped compartment, blurring the line between extra- and intracellular signaling. Modulator protein structures show how structurally diverse antagonists including follistatins, noggin, and members of the chordin family bind GFs to regulate signaling; complexes with the Dan family remain elusive. Much work is needed to understand how these molecular components assemble to form signaling hubs in extracellular environments in vivo. C1 [Hinck, Andrew P.] Univ Pittsburgh, Sch Med, Dept Biol Struct, Pittsburgh, PA 15260 USA. [Mueller, Thomas D.] Univ Wurzburg, Dept Plant Physiol & Biophys, Julius von Sachs Inst, D-97082 Wurzburg, Germany. [Springer, Timothy A.] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Springer, Timothy A.] Boston Childrens Hosp, Div Hematol, Dept Med, Boston, MA 02115 USA. [Springer, Timothy A.] Harvard Med Sch, Dept Biol Chem & Pharmacol, Boston, MA 02115 USA. RP Springer, TA (reprint author), Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA.; Springer, TA (reprint author), Boston Childrens Hosp, Div Hematol, Dept Med, Boston, MA 02115 USA.; Springer, TA (reprint author), Harvard Med Sch, Dept Biol Chem & Pharmacol, Boston, MA 02115 USA. EM timothy.springer@childrens.harvard.edu FU National Institutes of Health (NIH) [AR067288, CA210920]; NIH [GM58670, CA054174]; Deutsche Forschungsgemeinschaft (DFG) [MU1095/3-2, MU1095/5-1] FX T.A.S. is deeply grateful to Dr. Li-Zhi Mi for help with Figures 1 to 3 and is supported by National Institutes of Health (NIH) Grants AR067288 and CA210920. A.P.H is supported by NIH grants GM58670 and CA054174. T.D.M. is supported by Deutsche Forschungsgemeinschaft (DFG) grants MU1095/3-2 and MU1095/5-1. NR 243 TC 3 Z9 3 U1 5 U2 5 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1943-0264 J9 CSH PERSPECT BIOL JI Cold Spring Harbor Perspect. Biol. PD DEC PY 2016 VL 8 IS 12 AR a022103 DI 10.1101/cshperspect.a022103 PG 51 WC Cell Biology SC Cell Biology GA EF5JX UT WOS:000390367600002 ER PT J AU Martin, JD Fukumura, D Duda, DG Boucher, Y Jain, RK AF Martin, John D. Fukumura, Dai Duda, Dan G. Boucher, Yves Jain, Rakesh K. TI Reengineering the Tumor Microenvironment to Alleviate Hypoxia and Overcome Cancer Heterogeneity SO COLD SPRING HARBOR PERSPECTIVES IN MEDICINE LA English DT Article ID INTERSTITIAL FLUID PRESSURE; ADVANCED PANCREATIC-CANCER; TO-MESENCHYMAL TRANSITION; ANTI-ANGIOGENIC THERAPY; CELL LUNG-CANCER; ANGIOTENSIN SYSTEM INHIBITORS; HUMAN BREAST-CANCER; GROWTH-FACTOR-BETA; STEM-LIKE CELLS; SOLID TUMORS AB Solid tumors consist of cancer cells and stromal cells, including resident and transiting immune cells-all ensconced in an extracellular matrix (ECM)-nourished by blood vessels and drained by lymphatic vessels. The microenvironment constituents are abnormal and heterogeneous in morphology, phenotype, and physiology. Such irregularities include an inefficient tumor vascular network comprised of leaky and compressed vessels, which impair blood flowand oxygen delivery. Low oxygenation in certain tumor regions-or focal hypoxia-is a mediator of cancer progression, metastasis, immunosuppression, and treatment resistance. Thus, repairing an abnormal and heterogeneous microenvironment-and hypoxia in particular-can significantly improve treatments of solid tumors. Here, we summarize two strategies to reengineer the tumor microenvironment (TME)-vessel normalization and decompression-that can alleviate hypoxia. In addition, we discuss how these two strategies alone and in combination with each other-or other therapeutic strategies-may overcome the challenges posed by cancer heterogeneity. C1 [Jain, Rakesh K.] Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Labs, Boston, MA 02114 USA. Harvard Med Sch, Boston, MA 02114 USA. RP Jain, RK (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Labs, Boston, MA 02114 USA. EM jain@steele.mgh.harvard.edu FU National Institutes of Health [P01-CA080124, P50CA165962, R01CA126642, R35CA197743, R21 CA173518, R01 CA098706, R01-CA096915, S10-RR027070, R01-CA159258]; NCI/Federal Share Proton Beam Program Income; Department of Defense (DoD) Breast Cancer Research Innovator Award [W81XWH-10-1-0016]; Lustgarten Foundation; Pancreatic Cancer Action Network-AACR Innovative Grants; American Cancer Society Research Scholar Award; Warshaw Institute for Pancreatic Cancer Research; Ophthotech; SPARC; SynDevRx; XTuit; Medlmmune; Roche; Merrimack Pharmaceutical; HealthCare Pharmaceutical FX The authors thank Meenal Datta, Dr. Vikash Chauhan, and Dr. Kamila Naxerova for insightful input and Dr. Giorgio Seano for assistance in preparing Figure 2. This research is supported by the National Institutes of Health Grants P01-CA080124 (to R.K.J., Y.B., D.G.D., and D.E), P50CA165962, R01CA126642, and R35CA197743 (to R.K.J.), R21 CA173518 and R01 CA098706 (to YB.), R01-CA096915 and S10-RR027070 (to D.E), R01-CA159258 (to D.G.D.), and NCI/Federal Share Proton Beam Program Income (to R.K.J. and D.E); by the Department of Defense (DoD) Breast Cancer Research Innovator Award W81XWH-10-1-0016 (to R.K.J.); the Lustgarten Foundation (to R.K.J.); Pancreatic Cancer Action Network-AACR Innovative Grants (to YB.); American Cancer Society Research Scholar Award (to D.G.D.); and Warshaw Institute for Pancreatic Cancer Research (to D.G.D. and D.F.). R.K.J. received consultant fees from Ophthotech, SPARC, SynDevRx, and XTuit. R.K.J. owns equity in Enlight, Ophthotech, SynDevRx, and XTuit and serves on the Board of Directors of XTuit and the Boards of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund, and Tekla World Healthcare Fund. R.K.J. received grants from Medlmmune and Roche; D.G.D. received grants from Merrimack and HealthCare Pharmaceuticals. Y.B. served as consultant for Xtuit. NR 245 TC 1 Z9 1 U1 10 U2 10 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 2157-1422 J9 CSH PERSPECT MED JI Cold Spring Harb. Perspect. Med. PD DEC PY 2016 VL 6 IS 12 AR a027094 DI 10.1101/cshperspect.a027094 PG 24 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EF5KM UT WOS:000390369100006 ER PT J AU Groth, JB Kao, SY Briet, MC Stankovic, KM AF Groth, Jane Bjerg Kao, Shyan-Yuan Briet, Martijn C. Stankovic, Konstantina M. TI Hepatocyte Nuclear Factor-4 Alpha in Noise-Induced Cochlear Neuropathy SO DEVELOPMENTAL NEUROBIOLOGY LA English DT Article DE noise-induced hearing loss; temporary threshold shift; gene expression; molecular pathways; hepatocyte nuclear factor 4 alpha; aging; cochlear neuropathy ID INDUCED HEARING-LOSS; TEMPORARY THRESHOLD SHIFT; FACTOR-KAPPA-B; RAT COCHLEA; INNER-EAR; NERVE DEGENERATION; MAMMALIAN COCHLEA; OXIDATIVE STRESS; GUINEA-PIG; C-JUN AB Noise-induced hearing loss (NIHL) is a problem of profound clinical significance and growing magnitude. Alarmingly, even moderate noise levels, previously assumed to cause only temporary shifts in auditory thresholds ("temporary" NIHL), are now known to cause cochlear synaptopathy and subsequent neuropathy. To uncover molecular mechanisms of this neuropathy, a network analysis of genes reported to have significantly altered expression after temporary threshold shift-inducing noise exposure was performed. The transcription factor Hepatocyte Nuclear Factor-4 alpha (HNF4 alpha), which had not previously been studied in the context of cochlear response to noise, was identified as a hub of a top-ranking network. Hnf4 alpha expression and localization using quantitative RT-PCR and in situ hybridization, respectively, were described in adolescent and adult mice exposed to neuropathic noise levels in adolescence. Iso-forms alpha 3 and alpha 12 in the cochlea were also identified. At every age examined, Hnf4 alpha mRNA expression in the cochlear apex was similar to expression in the base. Hnf4 alpha expression was evident in select cochlear cells, including spiral ganglion neurons (SGNs) and hair cells, and was significantly upregulated from 6 to 70 weeks of age, especially in SGNs. This age-related Hnf4 alpha upregulation was inhibited by neuropathic noise exposure in adolescence. Hnf4 alpha silencing with shRNA transfection into auditory neuroblast cells (VOT-33) reduced cell viability, as measured with the MTT assay, suggesting that Hnf4 alpha may be involved in SGN survival. Our results motivate future studies of HNF4 alpha in cochlear pathophysiology, especially because HNF4 alpha mutations and polymorphisms are associated with human diseases that may include hearing loss. (C) 2016 Wiley Periodicals, Inc. C1 [Groth, Jane Bjerg; Kao, Shyan-Yuan; Briet, Martijn C.; Stankovic, Konstantina M.] Massachusetts Eye & Ear Infirm, Eaton Peabody Labs, Boston, MA 02114 USA. [Groth, Jane Bjerg; Kao, Shyan-Yuan; Briet, Martijn C.; Stankovic, Konstantina M.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. [Groth, Jane Bjerg; Stankovic, Konstantina M.] Harvard Med Sch, Dept Otol & Laryngol, Boston, MA 02115 USA. [Groth, Jane Bjerg] Univ Copenhagen, Dept Biomed Sci, DK-2200 Copenhagen, Denmark. [Briet, Martijn C.] Leiden Univ, Dept Otorhinolaryngol, Med Ctr, NL-2333 ZA Leiden, Netherlands. [Stankovic, Konstantina M.] Harvard Med Sch, Program Speech & Hearing Biosci & Technol, Boston, MA 02115 USA. RP Stankovic, KM (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Labs, Boston, MA 02114 USA.; Stankovic, KM (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA.; Stankovic, KM (reprint author), Harvard Med Sch, Dept Otol & Laryngol, Boston, MA 02115 USA.; Stankovic, KM (reprint author), Harvard Med Sch, Program Speech & Hearing Biosci & Technol, Boston, MA 02115 USA. EM konstantina_stankovic@meei.harvard.edu FU DoD grant [W81XWH-15-1-0472]; NIDCD [K08 DC010419]; Bertarelli Foundation; Nancy Sayles Day Foundation; Lauer Tinnitus Research Center; Aase & Ejnar Danielsen's Foundation FX Contract grant sponsor: DoD grant; contract grant number: W81XWH-15-1-0472 (KMS).; Contract grant sponsor: NIDCD; contract grant number: K08 DC010419 (KMS).; Contract grant sponsors: Grants from Bertarelli Foundation (KMS), Nancy Sayles Day Foundation (KMS), Lauer Tinnitus Research Center (KMS), and Aase & Ejnar Danielsen's Foundation (JBJ). NR 46 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1932-8451 EI 1932-846X J9 DEV NEUROBIOL JI Dev. Neurobiol. PD DEC PY 2016 VL 76 IS 12 BP 1374 EP 1386 DI 10.1002/dneu.22399 PG 13 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA EF0II UT WOS:000390008700006 PM 27112738 ER PT J AU Garvey, WT AF Garvey, W. Timothy TI Ablation of the Duodenal Mucosa as a Strategy for Glycemic Control in Type 2 Diabetes: Role of Nutrient Signaling or Simple Weight Loss SO DIABETES CARE LA English DT Editorial Material ID Y GASTRIC BYPASS; GLUCAGON-LIKE PEPTIDE-1; RANDOMIZED CONTROLLED-TRIAL; OBESE-PATIENTS; BARIATRIC SURGERY; INSULIN SENSITIVITY; SLEEVE GASTRECTOMY; GLUCOSE-TRANSPORT; CLINICAL-TRIAL; MELLITUS C1 [Garvey, W. Timothy] Univ Alabama Birmingham, Dept Nutr Sci, Birmingham, AL 35294 USA. [Garvey, W. Timothy] Birmingham VA Med Ctr, Birmingham, AL 35233 USA. RP Garvey, WT (reprint author), Univ Alabama Birmingham, Dept Nutr Sci, Birmingham, AL 35294 USA.; Garvey, WT (reprint author), Birmingham VA Med Ctr, Birmingham, AL 35233 USA. EM garveyt@uab.edu FU NIDDK NIH HHS [R01 DK038765, P30 DK079626] NR 28 TC 1 Z9 1 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD DEC PY 2016 VL 39 IS 12 BP 2108 EP 2110 DI 10.2337/dc16-1611 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EG1IF UT WOS:000390785000013 PM 27879354 ER PT J AU Weinger, K de Groot, M Cefalu, WT AF Weinger, Katie de Groot, Mary Cefalu, William T. TI Psychosocial Research and Care in Diabetes: Altering Lives by Understanding Attitudes SO DIABETES CARE LA English DT Editorial Material ID DEPRESSION; ADULTS; METAANALYSIS C1 [Weinger, Katie] Harvard Med Sch, Joslin Diabet Ctr, Boston, MA USA. [Weinger, Katie] Harvard Med Sch, Dept Psychiat, Boston, MA USA. [de Groot, Mary] Indiana Univ, Sch Med, Div Endocrinol & Metab, Dept Med, Indianapolis, IN 46204 USA. [Cefalu, William T.] Louisiana State Univ, Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. RP Cefalu, WT (reprint author), Louisiana State Univ, Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. EM cefaluwt@pbrc.edu FU NCCIH NIH HHS [P50 AT002776]; NIDDK NIH HHS [R18 DK092765]; NIGMS NIH HHS [U54 GM104940] NR 19 TC 1 Z9 1 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD DEC PY 2016 VL 39 IS 12 BP 2122 EP 2125 DI 10.2337/dc16-2056 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EG1IF UT WOS:000390785000016 PM 27879357 ER PT J AU Rajagopalan, H Cherrington, AD Thompson, CC Kaplan, LM Rubino, F Mingrone, G Becerra, P Rodriguez, P Vignolo, P Caplan, J Rodriguez, L Neto, MPG AF Rajagopalan, Harith Cherrington, Alan D. Thompson, Christopher C. Kaplan, Lee M. Rubino, Francesco Mingrone, Geltrude Becerra, Pablo Rodriguez, Patricia Vignolo, Paulina Caplan, Jay Rodriguez, Leonardo Galvao Neto, Manoel P. TI Endoscopic Duodenal Mucosal Resurfacing for the Treatment of Type 2 Diabetes: 6-Month Interim Analysis From the First-in-Human Proof-of-Concept Study SO DIABETES CARE LA English DT Article ID GASTRIC-INHIBITORY POLYPEPTIDE; JEJUNAL BYPASS-SURGERY; BETA-CELL FUNCTION; INSULIN SENSITIVITY; HIGH-FAT; ESOPHAGEAL EPITHELIUM; GLUCOSE-HOMEOSTASIS; GLYCEMIC CONTROL; SECRETION; RATS AB OBJECTIVE To assess procedural safety and glycemic indices at 6 months in a first-in-human study of duodenal mucosal resurfacing (DMR), a novel, minimally invasive, upper endoscopic procedure involving hydrothermal ablation of the duodenal mucosa, in patients with type 2 diabetes and HbA(1c) >= 7.5% (58 mmol/mol) on one or more oral antidiabetic agents. RESEARCH DESIGN AND METHODS Using novel balloon catheters, DMR was conducted on varying lengths of duodenum in anesthetized patients at a single medical center. RESULTS A total of 39 patients with type 2 diabetes (screening HbA(1c) 9.5% [80 mmol/mol]; BMI 31 kg/m(2)) were treated and included in the interimefficacy analysis: 28 had a long duodenal segment ablated (LS; similar to 9.3 cm treated) and 11 had a short segment ablated (SS; similar to 3.4 cm treated). Overall, DMR was well tolerated with minimal gastrointestinal symptoms postprocedure. Three patients experienced duodenal stenosis treated successfully by balloon dilation. HbA(1c) was reduced by 1.2% at 6 months in the full cohort (P < 0.001). More potent glycemic effects were observed among the LS cohort, who experienced a 2.5% reduction in mean HbA(1c) at 3months postprocedure vs. 1.2% in the SS group (P < 0.05) and a 1.4% reduction at 6 months vs. 0.7% in the SS group (P = 0.3). This occurred despite net medication reductions in the LS cohort between 0 and 6 months. Among LS patients with a screening HbA(1c) of 7.5-10% (58-86 mmol/mol) and on stable antidiabetic medications postprocedure, HbA(1c) was reduced by 1.8% at 6 months (P < 0.01). CONCLUSIONS Single-procedure DMR elicits a clinically significant improvement in hyperglycemia in patients with type 2 diabetes in the short-term, with acceptable safety and tolerability. Long-term safety, efficacy, and durability and possible mechanisms of action require further investigation. C1 [Rajagopalan, Harith; Caplan, Jay] Fractyl Labs Inc, Waltham, MA 02453 USA. [Cherrington, Alan D.] Vanderbilt Univ, Med Ctr, 221 Kirkland Hall, Nashville, TN 37235 USA. [Thompson, Christopher C.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Kaplan, Lee M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Rubino, Francesco] Kings Coll London, London, England. [Mingrone, Geltrude] Univ Cattolica Sacro Cuore, Rome, Italy. [Becerra, Pablo; Rodriguez, Patricia; Vignolo, Paulina; Rodriguez, Leonardo] CCO Clin Ctr Diabet Obes & Reflux, Santiago, Chile. [Galvao Neto, Manoel P.] Gastro Obeso Ctr, Sao Paulo, Brazil. [Galvao Neto, Manoel P.] Florida Int Univ, Miami, FL 33199 USA. RP Rajagopalan, H (reprint author), Fractyl Labs Inc, Waltham, MA 02453 USA. EM harith@fractyl.com FU Fractyl Laboratories, Inc. FX Funding for this study was provided by Fractyl Laboratories, Inc. NR 34 TC 2 Z9 2 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD DEC PY 2016 VL 39 IS 12 BP 2254 EP 2261 DI 10.2337/dc16-0383 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EG1IF UT WOS:000390785000033 PM 27519448 ER PT J AU Skupien, J Warram, JH Smiles, AM Stanton, RC Krolewski, AS AF Skupien, Jan Warram, James H. Smiles, Adam M. Stanton, Robert C. Krolewski, Andrzej S. TI Patterns of Estimated Glomerular Filtration Rate Decline Leading to End-Stage Renal Disease in Type 1 Diabetes SO DIABETES CARE LA English DT Article ID RECIPROCAL SERUM CREATININE; CLINICAL-TRIALS; KIDNEY-DISEASE; BLOOD-PRESSURE; GFR DECLINE; NEPHROPATHY; PROGRESSION; RISK; MICROALBUMINURIA; PROTEINURIA AB OBJECTIVE The patterns of estimated glomerular filtration rate (eGFR) decline to end-stage renal disease (ESRD) in patients with type 1 diabetes has not been conclusively described. Decline could be linearly progressive to ESRD but with a variable rate. Conversely, decline may be linear but interrupted by periods of plateaus or improvements. RESEARCH DESIGN AND METHODS This observational study included 364 patients with type 1 diabetes attending the Joslin Clinic who developed ESRD between 1991 and 2013. We retrieved serum creatinine measurements from clinic visits or research examinations up to 24 years (median 6.7 years) preceding the onset of ESRD. Using serial measurements of serum creatinine to estimate renal function (eGFR), we used regression-based spline methods and a data smoothing approach to characterize individual trajectories of eGFR over time for the 257 patients with five or more data points. RESULTS The rate of eGFR decline per year ranged widely, from 272 to 22 mL/min/1.73 m(2) (median -8.5). The trajectories, as characterized with linear regression-based spline models, were linear or nearly so for 87% of patients, accelerating for 6%, and decelerating for 7%. Smoothed trajectories evaluated by a Bayesian approach did not significantly depart from a linear fit in 76%. CONCLUSIONS The decline of eGFR in type 1 diabetes is predominantly linear. Deviations from linearity are small, with little effect on the expected time of ESRD. A single disease process most likely underlies renal decline from its initiation and continues with the same intensity to ESRD. Linearity of renal decline suggests using slope reduction as the measure of effectiveness of interventions to postpone ESRD. C1 [Skupien, Jan; Warram, James H.; Smiles, Adam M.; Stanton, Robert C.; Krolewski, Andrzej S.] Joslin Diabet Ctr, Div Res, 1 Joslin Pl, Boston, MA 02215 USA. [Skupien, Jan; Warram, James H.; Smiles, Adam M.; Stanton, Robert C.; Krolewski, Andrzej S.] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. [Skupien, Jan] Jagiellonian Univ, Coll Med, Dept Metab Dis, Krakow, Poland. [Stanton, Robert C.] Harvard Med Sch, Renal Div, Beth Israel Deaconess Med Ctr, Boston, MA USA. RP Skupien, J; Krolewski, AS (reprint author), Joslin Diabet Ctr, Div Res, 1 Joslin Pl, Boston, MA 02215 USA.; Skupien, J; Krolewski, AS (reprint author), Harvard Med Sch, Dept Med, Boston, MA 02115 USA.; Skupien, J (reprint author), Jagiellonian Univ, Coll Med, Dept Metab Dis, Krakow, Poland. EM jan.skupien@uj.edu.pl; andrzej.krolewski@joslin.harvard.edu FU JDRF [3-2009-397, 17-2013-8]; National Institutes of Health [DK41526] FX This project was supported through JDRF fellowship grant 3-2009-397 (J.S.) and research grant 17-2013-8 (A.S.K.) and National Institutes of Health grant DK41526 (A.S.K.). NR 39 TC 0 Z9 0 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD DEC PY 2016 VL 39 IS 12 BP 2262 EP 2269 DI 10.2337/dc16-0950 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EG1IF UT WOS:000390785000034 PM 27647852 ER PT J AU Hamdy, O Barakatun-Nisak, MY AF Hamdy, Osama Barakatun-Nisak, Mohd-Yusof TI Nutrition in Diabetes SO ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA LA English DT Article DE Medical nutrition therapy; Nutrition; Diet; Glycemic index; Diabetes ID LOW-GLYCEMIC INDEX; AMERICAN-HEART-ASSOCIATION; POSTPRANDIAL BLOOD-GLUCOSE; RANDOMIZED CLINICAL-TRIAL; LIFE-STYLE INTERVENTION; CARDIOVASCULAR-DISEASE; VITAMIN-D; DIETARY-PROTEIN; WEIGHT-LOSS; SCIENTIFIC STATEMENT AB Medical nutrition therapy (MNT) is a key component of diabetes management. The importance of balancing macronutrients, reducing carbohydrate load, lowering glycemic index, and implementing an overall healthy dietary pattern are emerging as better approaches for MNT in diabetes. Recent research points to improved glycemic control, reduction in body weight, and improvement in many cardiovascular risk factors when these approaches are provided by registered dietitians or health care providers. This review article discusses the current evidence about the role of sensible nutrition in diabetes management. Specific eating plans for weight reduction and for patients with type 1 diabetes are also discussed. C1 [Hamdy, Osama] Harvard Med Sch, Joslin Diabet Ctr, Dept Endocrinol, One Joslin Pl, Boston, MA 02481 USA. [Barakatun-Nisak, Mohd-Yusof] Harvard Med Sch, Joslin Diabet Ctr, Boston, MA 02215 USA. [Barakatun-Nisak, Mohd-Yusof] Univ Putra Malaysia, Fac Med & Hlth Sci, Dept Nutr & Dietet, Serdang, Selangor 43400, Malaysia. RP Hamdy, O (reprint author), Harvard Med Sch, Joslin Diabet Ctr, Dept Endocrinol, One Joslin Pl, Boston, MA 02481 USA. EM Osama.hamdy@joslin.harvard.edu NR 100 TC 0 Z9 0 U1 22 U2 22 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0889-8529 EI 1558-4410 J9 ENDOCRIN METAB CLIN JI Endocrinol. Metabol. Clin. North Amer. PD DEC PY 2016 VL 45 IS 4 BP 799 EP + DI 10.1016/j.ecl.2016.06.010 PG 20 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EF2VY UT WOS:000390184900006 PM 27823606 ER PT J AU Segal, AR Vootla, T Beaser, RS AF Segal, Alissa R. Vootla, Tejaswi Beaser, Richard S. TI Insulin Making Sense of Current Options SO ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA LA English DT Article DE Insulin; Glargine U-300; Insulin degludec; Basaglar; Lispro U-200; Afrezza; Regular U-500; Insulin therapy ID TO-TARGET TRIAL; TYPE-2 DIABETES-MELLITUS; RANDOMIZED CONTROLLED-TRIAL; HUMAN REGULAR U-500; GLARGINE 300 U/ML; PEPTIDE-1 RECEPTOR AGONIST; FIXED-RATIO COMBINATION; GLUCOSE-LOWERING DRUGS; ACTING BASAL INSULIN; BETA-CELL FUNCTION AB Newer insulin products have advanced the evolution of insulin replacement options to more accurately mimic natural insulin action. There are new, modified, and concentrated insulins; administration devices calibrated for both increased concentrations and administration accuracy to improve adherence and safety; and inhaled insulin. There are new combinations of longer-acting basal insulin and rapid-acting insulin or glucagon like protein-1 receptor agonists. Existing insulin replacement designs and methods can be updated using these tools to improve efficacy and safety. Individualized decisions to use them should be based on patient physiologic needs, self-care ability, comorbidities, and cost considerations. C1 [Segal, Alissa R.] MCPHS Univ, Dept Pharm Practice, 179 Longwood Ave, Boston, MA 02115 USA. [Segal, Alissa R.; Vootla, Tejaswi; Beaser, Richard S.] Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA. RP Segal, AR (reprint author), MCPHS Univ, Dept Pharm Practice, 179 Longwood Ave, Boston, MA 02115 USA.; Segal, AR (reprint author), Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA. EM alissa.segal@mcphs.edu NR 139 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 0889-8529 EI 1558-4410 J9 ENDOCRIN METAB CLIN JI Endocrinol. Metabol. Clin. North Amer. PD DEC PY 2016 VL 45 IS 4 BP 845 EP + DI 10.1016/j.ecl.2016.06.009 PG 31 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EF2VY UT WOS:000390184900008 PM 27823608 ER PT J AU Khazai, NB Hamdy, O AF Khazai, Natasha B. Hamdy, Osama TI Inpatient Diabetes Management in the Twenty-First Century SO ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA LA English DT Article DE Inpatient diabetes management; Inpatient insulin management; Hospital; Diabetes; Hyperglycemia; Corticosteroids; Enteral and parenteral nutrition; Insulin pump ID CRITICALLY-ILL PATIENTS; INTENSIVE INSULIN THERAPY; GLUCOCORTICOID-INDUCED HYPERGLYCEMIA; CONTINUOUS ENTERAL NUTRITION; BONE-MARROW-TRANSPLANTATION; RANDOMIZED CONTROLLED-TRIAL; HOSPITALIZED-PATIENTS; GLYCEMIC CONTROL; SUBCUTANEOUS INSULIN; PARENTERAL-NUTRITION AB In hospitalized patients, both hyperglycemia and hypoglycemia have been associated with poor outcomes. During the inpatient period, hyperglycemia has been associated with increased risk of infection, cardiovascular events, and mortality. It is also associated with longer length of hospital stay. Hypoglycemia has also been associated with an increased risk of mortality. Therefore, current evidence supports avoidance of both conditions among hospitalized patients whether they are admitted to critical care units or noncritical care units. C1 [Khazai, Natasha B.; Hamdy, Osama] Joslin Diabet Ctr, One Joslin Pl, Boston, MA 02215 USA. RP Khazai, NB (reprint author), Joslin Diabet Ctr, One Joslin Pl, Boston, MA 02215 USA. EM natasha.khazai@joslin.harvard.edu NR 72 TC 0 Z9 0 U1 4 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0889-8529 EI 1558-4410 J9 ENDOCRIN METAB CLIN JI Endocrinol. Metabol. Clin. North Amer. PD DEC PY 2016 VL 45 IS 4 BP 875 EP + DI 10.1016/j.ecl.2016.06.013 PG 21 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EF2VY UT WOS:000390184900009 PM 27823609 ER PT J AU Toschi, E Wolpert, H AF Toschi, Elena Wolpert, Howard TI Utility of Continuous Glucose Monitoring in Type 1 and Type 2 Diabetes SO ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA LA English DT Article DE Technology; Type 1 diabetes mellitus; Type 2 diabetes mellitus; Continuous glucose monitoring ID GLYCEMIC CONTROL; CONTROLLED-TRIAL; PUMP THERAPY; INSULIN; MANAGEMENT; SYSTEM; HYPOGLYCEMIA; REDUCTION; DECISIONS; PANCREAS AB A consensus conference of the American Association of Clinical Endocrinologists and American College of Endocrinology held in February 2016 advocated expanding the use of continuous glucose monitoring (CGM) in the management of diabetes. Based on the data described in this paper, CGM use is shown to improve glucose control and reduce hypoglycemic events, and therefore has the potential to reduce the risk of acute and chronic complications of diabetes. Likely, all of the above would not only improve the quality of life and life expectancy of people with diabetes, but would also have a positive impact on health-related cost. C1 [Toschi, Elena; Wolpert, Howard] Joslin Diabet Ctr, Adult Sect, One Joslin Pl, Boston, MA 02215 USA. RP Toschi, E (reprint author), Joslin Diabet Ctr, Adult Sect, One Joslin Pl, Boston, MA 02215 USA. EM elena.toschi@joslin.harvard.edu NR 39 TC 1 Z9 1 U1 13 U2 13 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0889-8529 EI 1558-4410 J9 ENDOCRIN METAB CLIN JI Endocrinol. Metabol. Clin. North Amer. PD DEC PY 2016 VL 45 IS 4 BP 895 EP + DI 10.1016/j.ecl.2016.06.003 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EF2VY UT WOS:000390184900010 PM 27823610 ER PT J AU Mitri, J Gabbay, R AF Mitri, Joanna Gabbay, Robert TI Understanding Population Health Through Diabetes Population Management SO ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA LA English DT Article DE Population health; Population management; Chronic disease; Diabetes ID CHRONIC CARE MODEL; MEDICAL HOME; GLYCEMIC CONTROL; INTERVENTION; IMPROVEMENT; QUALITY; PAYMENT; ADULTS; GOALS AB A chronic and progressive illness, diabetes requires early diagnosis, effective coordination of care, and self-management to stem its progression. Population health management strategies hold promise to improve outcomes by focusing on reducing the frequency of acute and chronic complications of chronic disease, lowering the cost per service through an integrated care delivery team approach, and promoting patient engagement. This will ultimately result in a better patient experience. The chronic care model targets fragmentation of our health care delivery system and provides a framework for effective care of diabetes and other chronic diseases. C1 [Mitri, Joanna; Gabbay, Robert] Joslin Diabet Ctr, Lipid Clin, Adult Diabet, 1 Joslin Pl,239, Boston, MA 02215 USA. RP Mitri, J (reprint author), Joslin Diabet Ctr, Lipid Clin, Adult Diabet, 1 Joslin Pl,239, Boston, MA 02215 USA. EM Joanna.mitri@joslin.harvard.edu NR 28 TC 0 Z9 0 U1 4 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0889-8529 EI 1558-4410 J9 ENDOCRIN METAB CLIN JI Endocrinol. Metabol. Clin. North Amer. PD DEC PY 2016 VL 45 IS 4 BP 933 EP + DI 10.1016/j.ecl.2016.06.006 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EF2VY UT WOS:000390184900013 PM 27823613 ER PT J AU Archer, NK Adappa, ND Palmer, JN Cohen, NA Harro, JM Lee, SK Miller, LS Shirtliff, ME AF Archer, Nathan K. Adappa, Nithin D. Palmer, James N. Cohen, Noam A. Harro, Jan M. Lee, Steven K. Miller, Lloyd S. Shirtliff, Mark E. TI Interleukin-17A (IL-17A) and IL-17F Are Critical for Antimicrobial Peptide Production and Clearance of Staphylococcus aureus Nasal Colonization SO INFECTION AND IMMUNITY LA English DT Article ID BETA-DEFENSIN 3; HUMAN BETA-DEFENSIN-3; INNATE IMMUNITY; MOUSE BETA-DEFENSIN-14; BACTERIAL-INFECTION; HUMAN KERATINOCYTES; INDUCIBLE PEPTIDE; HUMAN LUNG; EXPRESSION; SKIN AB Approximately 20% of the population is persistently colonized by Staphylococcus aureus in the nares. Th17-like immune responses mediated by the interleukin-17 (IL-17) family of cytokines and neutrophils are becoming recognized as relevant host defense mechanisms for resolution of S. aureus mucocutaneous infections. Since antimicrobial peptides are regulated by the IL-17 cytokines, we sought to determine the role of IL-17 cytokines in production of antimicrobial peptides in a murine model of S. aureus nasal carriage. We discovered that nasal tissue supernatants have antistaphylococcal activity, and mice deficient in both IL-17A and IL-17F lost the ability to clear S. aureus nasal colonization. IL-17A was found to be sufficient for nasal mBD-3 production ex vivo and was required for CRAMP, mBD-3, and mBD-14 expression in response to S. aureus colonization in vivo. These data were confirmed in a clinical study of nasal secretions in which elevated levels of the human forms of these antimicrobial peptides were found in nasal secretions from healthy human subjects when they were colonized with S. aureus but not in secretions from noncolonized subjects. Together, these data provide evidence for the importance of IL-17A regulation of antimicrobial peptides and IL-17F in the clearance of S. aureus nasal carriage. C1 [Archer, Nathan K.; Harro, Jan M.; Shirtliff, Mark E.] Univ Maryland, Sch Dent, Dept Microbial Pathogenesis, Baltimore, MD 21201 USA. [Archer, Nathan K.] Univ Maryland, Mol Microbiol & Immunol Program, Grad Program Life Sci, Baltimore, MD 21201 USA. [Archer, Nathan K.; Lee, Steven K.; Miller, Lloyd S.] Johns Hopkins Univ, Sch Med, Dept Dermatol, Baltimore, MD 21205 USA. [Adappa, Nithin D.; Palmer, James N.; Cohen, Noam A.] Univ Penn, Sch Med, Perelman Sch Med, Dept Otorhinolaryngol Head & Neck Surg, Philadelphia, PA 19104 USA. [Cohen, Noam A.] Philadelphia Vet Affairs Med Ctr, Surg Serv, Philadelphia, PA USA. [Cohen, Noam A.] Monell Chem Senses Ctr, 3500 Market St, Philadelphia, PA 19104 USA. [Shirtliff, Mark E.] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. RP Shirtliff, ME (reprint author), Univ Maryland, Sch Dent, Dept Microbial Pathogenesis, Baltimore, MD 21201 USA.; Shirtliff, ME (reprint author), Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. EM MShirtliff@umaryland.edu OI Cohen, Noam/0000-0002-9462-3932 FU HHS \ NIH \ National Institute of Allergy and Infectious Diseases (NIAID) [R01AI069568] FX This work, including the efforts of Mark E. Shirtliff, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (R01AI069568). NR 53 TC 0 Z9 0 U1 8 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD DEC PY 2016 VL 84 IS 12 BP 3575 EP 3583 DI 10.1128/IAI.00596-16 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA EF2BG UT WOS:000390128700030 PM 27736775 ER PT J AU Musuuza, JS Hundt, AS Zimbric, M Carayon, P Safdar, N AF Musuuza, Jackson S. Hundt, Ann Schoofs Zimbric, Michele Carayon, Pascale Safdar, Nasia TI Standardizing Direct Observation for Assessing Compliance to a Daily Chlorhexidine Bathing Protocol Among Hospitalized Patients SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Editorial Material ID INFECTIONS C1 [Musuuza, Jackson S.] Univ Wisconsin, Inst Clin & Translat Res, Madison, WI USA. [Musuuza, Jackson S.; Safdar, Nasia] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. [Hundt, Ann Schoofs; Carayon, Pascale] Univ Wisconsin, Ctr Qual & Prod Improvement, Madison, WI USA. [Zimbric, Michele; Safdar, Nasia] Univ Wisconsin, Dept Med, Sch Med & Publ Hlth, Div Infect Dis, Madison, WI USA. [Carayon, Pascale; Safdar, Nasia] Univ Wisconsin, Dept Ind & Syst Engn, Madison, WI USA. RP Safdar, N (reprint author), 5138 UWMF Centennial Bldg,1685 Highland Ave, Madison, WI 53705 USA. EM ns2@medicine.wisc.edu FU AHRQ HHS [R18 HS024039] NR 10 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0899-823X EI 1559-6834 J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD DEC PY 2016 VL 37 IS 12 BP 1516 EP 1518 DI 10.1017/ice.2016.214 PG 3 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA EF5DW UT WOS:000390351900023 PM 27677927 ER PT J AU Lin, J Wang, F Weiner, RB DeLuca, JR Wasfy, MM Berkstresser, B Lewis, GD Hutter, AM Picard, MH Baggish, AL AF Lin, Jeffrey Wang, Francis Weiner, Rory B. DeLuca, James R. Wasfy, Meagan M. Berkstresser, Brant Lewis, Gregory D. Hutter, Adolph M., Jr. Picard, Michael H. Baggish, Aaron L. TI Blood Pressure and LV Remodeling Among American-Style Football Players SO JACC-CARDIOVASCULAR IMAGING LA English DT Article DE athlete's heart syndrome; hypertension; left ventricular function; left ventricular hypertrophy ID PRESERVED EJECTION FRACTION; LEFT-VENTRICULAR MASS; HEART-FAILURE; CARDIOVASCULAR MORTALITY; SPECKLE-TRACKING; LEAGUE PLAYERS; HYPERTENSION; PREVALENCE; DISEASE; IMPACT AB OBJECTIVES This study sought to determine the relationships among American-style football (ASF) participation, acquired left ventricular (LV) hypertrophy, and LV systolic function as assessed using contemporary echocardiographic parameters. BACKGROUND Participation in ASF has been associated with development of hypertension and LV hypertrophy. To what degree these processes impact LV function is unknown. METHODS This was a prospective, longitudinal cohort study evaluating National Collegiate Athletic Association Division I football athletes stratified by field position (linemen: n = 30; vs. nonlinemen, n = 57) before and after a single competitive season, using transthoracic echocardiography. LV systolic function was measured using complementary parameters of global longitudinal strain (GLS) (using 2-dimensional speckle-tracking) and ejection fraction (EF) (2-dimensional biplane). RESULTS ASF participation was associated with field position-specific increases in systolic blood pressure (SBP) (a Delta SBP of 10 +/- 8 mm Hg in linemen vs. a Delta SBP of 3 +/- 7 mm Hg in nonlinemen; p < 0.001) and an overall increase in incident LV hypertrophy (pre-season = 8% vs. post-season = 25%, p < 0.05). Linemen who developed LV hypertrophy had concentric geometry (9 of 11 [82%]) with decreased GLS (Delta = -1.1%; p < 0.001), whereas nonlinemen demonstrated eccentric LV hypertrophy (8 of 10 [80%]) with increased GLS (Delta = +1.4%; p < 0.001). In contrast, LV ejection fraction in the total cohort, stratified by field position, was not significantly affected by ASF participation. Among the total cohort, lineman field position, post-season weight, SBP, average LV wall thickness, and relative wall thickness were all independent predictors of post-season GLS. CONCLUSIONS ASF participation at a lineman field position may lead to a form of sport-related myocardial remodeling that is pathologic rather than adaptive. Future study will be required to determine if targeted efforts to control blood pressure, minimize weight gain, and to include an element of aerobic conditioning in this subset of athletes may attenuate this process and translate into tangible downstream health benefits. (C) 2016 by the American College of Cardiology Foundation. C1 [Baggish, Aaron L.] Massachusetts Gen Hosp, Cardiovasc Performance Program, 55 Fruit St,Yawkey Suite 5B, Boston, MA 02114 USA. RP Baggish, AL (reprint author), Massachusetts Gen Hosp, Cardiovasc Performance Program, 55 Fruit St,Yawkey Suite 5B, Boston, MA 02114 USA. EM abaggish@partners.org NR 36 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 1936-878X EI 1876-7591 J9 JACC-CARDIOVASC IMAG JI JACC-Cardiovasc. Imag. PD DEC PY 2016 VL 9 IS 12 BP 1368 EP 1376 DI 10.1016/j.jcmg.2016.07.013 PG 9 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA EF4LC UT WOS:000390295800001 ER PT J AU Nuckols, TK Keeler, E Morton, SC Anderson, L Doyle, B Booth, M Shanman, R Grein, J Shekelle, P AF Nuckols, Teryl K. Keeler, Emmett Morton, Sally C. Anderson, Laura Doyle, Brian Booth, Marika Shanman, Roberta Grein, Jonathan Shekelle, Paul TI Economic Evaluation of Quality Improvement Interventions for Bloodstream Infections Related to Central Catheters A Systematic Review SO JAMA INTERNAL MEDICINE LA English DT Review ID CARE-ASSOCIATED INFECTIONS; CENTRAL VENOUS CATHETER; HEALTH-CARE; PATIENT SAFETY; COST-EFFECTIVENESS; PREVENTION; IMPACT; UNIT; METAANALYSIS; STRATEGIES AB IMPORTANCE Although quality improvement (QI) interventions can reduce central-line-associated bloodstream infections (CLABSI) and catheter-related bloodstream infections (CRBSI), their economic value is uncertain. OBJECTIVE To systematically review economic evaluations of QI interventions designed to prevent CLABSI and/or CRBSI in acute care hospitals. EVIDENCE REVIEW A search of Ovid MEDLINE, Econlit, Centre for Reviews & Dissemination, New York Academy of Medicine's Grey Literature Report, Worldcat, prior systematic reviews (January 2004 to July 2016), and IDWeek conference abstracts (2013-2016), was conducted from 2013 to 2016. We included English-language studies of any design that evaluated organizational or structural changes to prevent CLABSI or CRBSI, and reported program and infection-related costs. Dual reviewers assessed study design, effectiveness, costs, and study quality. For each eligible study, we performed a cost-consequences analysis from the hospital perspective, estimating the incidence rate ratio (IRR) and incremental net savings. Unadjusted weighted regression analyses tested predictors of these measures, weighted by catheter-days per study per year. FINDINGS Of 505 articles, 15 unique studies were eligible, together representing data from 113 hospitals. Thirteen studies compared Agency for Healthcare Research and Quality-recommended practices with usual care, including 7 testing insertion checklists. Eleven studies were based on uncontrolled before-after designs, 1 on a randomized controlled trial, 1 on a time-series analysis, and 2 on modeled estimates. Overall, the weighted mean IRR was 0.43 (95% CI, 0.35-0.51) and incremental net savings were $1.85 million (95% CI, $1.30 million to $2.40 million) per hospital over 3 years (2015 US dollars). Each $100 000-increase in program cost was associated with $315 000 greater savings (95% CI, $166 000-$464 000; P<.001). Infections and net costs declined when hospitals already used checklists or had baseline infection rates of 1.7 to 3.7 per 1000 catheter-days. Study quality was not associated with effectiveness or costs. CONCLUSIONS AND RELEVANCE Interventions related to central venous catheters were, on average, associated with 57% fewer bloodstream infections and substantial savings to hospitals. Larger initial investments may be associated with greater savings. Although checklists are now widely used and infections have started to decline, additional improvements and savings can occur at hospitals that have not yet attained very low infection rates. C1 [Nuckols, Teryl K.; Anderson, Laura; Grein, Jonathan] Cedars Sinai Med Ctr, 8700 Beverly Dr,Becker 113, Los Angeles, CA 90048 USA. [Nuckols, Teryl K.; Keeler, Emmett; Booth, Marika; Shanman, Roberta; Shekelle, Paul] RAND Corp, Santa Monica, CA USA. [Morton, Sally C.] Virginia Tech, Coll Sci, Blacksburg, VA USA. [Anderson, Laura] Univ Calif Los Angeles, Jonathan & Karin Fielding Sch Publ Hlth, Los Angeles, CA USA. [Doyle, Brian; Shekelle, Paul] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RP Nuckols, TK (reprint author), Cedars Sinai Med Ctr, 8700 Beverly Dr,Becker 113, Los Angeles, CA 90048 USA. EM teryl.nuckols@cshs.org FU Agency for Healthcare Research and Quality FX This work was supported by the Agency for Healthcare Research and Quality. NR 77 TC 1 Z9 1 U1 10 U2 10 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD DEC 1 PY 2016 VL 176 IS 12 BP 1843 EP 1854 DI 10.1001/jamainternmed.2016.6610 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA EF3WN UT WOS:000390255700022 PM 27775764 ER PT J AU Lakin, JR Robinson, MG Bernacki, RE Powers, BW Block, SD Cunningham, R Obermeyer, Z AF Lakin, Joshua R. Robinson, Margaret G. Bernacki, Rachelle E. Powers, Brian W. Block, Susan D. Cunningham, Rebecca Obermeyer, Ziad TI Estimating 1-Year Mortality for High-Risk Primary Care Patients Using the "Surprise" Question SO JAMA INTERNAL MEDICINE LA English DT Letter C1 [Lakin, Joshua R.; Bernacki, Rachelle E.; Block, Susan D.] Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, 450 Brookline Ave,D-216A, Boston, MA 02215 USA. [Lakin, Joshua R.; Bernacki, Rachelle E.] Brigham & Womens Hosp, Ariadne Labs, 75 Francis St, Boston, MA 02115 USA. [Lakin, Joshua R.; Bernacki, Rachelle E.] Harvard Sch Publ Hlth, Boston, MA USA. [Robinson, Margaret G.; Powers, Brian W.; Obermeyer, Ziad] Brigham & Womens Hosp, Dept Emergency Med, 75 Francis St, Boston, MA 02115 USA. [Powers, Brian W.] Harvard Med Sch, Francis Weld Peabody Soc, Boston, MA USA. [Block, Susan D.] Brigham & Womens Hosp, Dept Psychiat, 75 Francis St, Boston, MA 02115 USA. [Cunningham, Rebecca] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Obermeyer, Ziad] Harvard Med Sch, Dept Emergency Med, Boston, MA USA. [Obermeyer, Ziad] Harvard Med Sch, Dept Hlth Care Policy, Boston, MA USA. RP Lakin, JR (reprint author), Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, 450 Brookline Ave,D-216A, Boston, MA 02215 USA. EM jlakin@partners.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 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD DEC 1 PY 2016 VL 176 IS 12 BP 1863 EP 1865 DI 10.1001/jamainternmed.2016.5928 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA EF3WN UT WOS:000390255700028 PM 27695853 ER PT J AU Harrison, KL Adrion, ER Ritchie, CS Sudore, RL Smith, AK AF Harrison, Krista L. Adrion, Emily R. Ritchie, Christine S. Sudore, Rebecca L. Smith, Alexander K. TI Low Completion and Disparities in Advance Care Planning Activities Among Older Medicare Beneficiaries SO JAMA INTERNAL MEDICINE LA English DT Letter C1 [Harrison, Krista L.; Ritchie, Christine S.; Sudore, Rebecca L.; Smith, Alexander K.] Univ Calif San Francisco, Div Geriatr, San Francisco, CA 94143 USA. [Harrison, Krista L.; Sudore, Rebecca L.; Smith, Alexander K.] San Francisco VA Med Ctr, San Francisco, CA USA. [Adrion, Emily R.] Univ Michigan, Ctr Healthcare Outcomes & Policy, Ann Arbor, MI 48109 USA. RP Harrison, KL (reprint author), Univ Calif San Francisco, Sch Med, Div Geriatr, 4150 Clement St VA181G, San Francisco, CA 94121 USA. EM krista.harrison@ucsf.edu FU AHRQ HHS [T32 HS000053]; NIA NIH HHS [T32 AG000212, K23 AG040772] NR 5 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD DEC 1 PY 2016 VL 176 IS 12 BP 1872 EP 1875 DI 10.1001/jamainternmed.2016.6751 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA EF3WN UT WOS:000390255700033 PM 27802496 ER PT J AU Rosenberg, AR Wolfe, J Wiener, L Lyon, M Feudtner, C AF Rosenberg, Abby R. Wolfe, Joanne Wiener, Lori Lyon, Maureen Feudtner, Chris TI Ethics, Emotions, and the Skills of Talking About Progressing Disease With Terminally Ill Adolescents A Review SO JAMA PEDIATRICS LA English DT Review ID OF-LIFE CARE; PEDIATRIC PALLIATIVE CARE; ADVANCED CANCER; PROGNOSTIC DISCLOSURE; YOUNG-ADULTS; BAD-NEWS; CHILDREN; PARENTS; END; COMMUNICATION AB Importance:For clinicians caring for adolescent patients living with progressive, life-threatening illness, discussions regarding prognosis, goals of care, and treatment options can be extremely challenging. While clinicians should respect and help to facilitate adolescents' emerging autonomy, they often must also work with parents' wishes to protect patients from the emotional distress of hearing bad news. Observations:We reviewed the ethical justifications for and against truth-telling, and we considered the published ethical and practice guidance, as well as the perspectives of patients, parents, and clinicians involved in these cases. We also explored particular challenges with respect to the cultural context, timing, and content of conversations at the end of adolescents' lives. In most cases, clinicians should gently but persistently engage adolescents directly in conversations about their disease prognosis and corresponding hopes, worries, and goals. These conversations need to occur multiple times, allowing significant time in each discussion for exploration of patient and family values. While truth-telling does not cause the types of harm that parents and clinicians may fear, discussing this kind of difficult news is almost always emotionally distressing. We suggest some "phrases that help" when clinicians strive to deepen understanding and facilitate difficult conversations with adolescents, parents, and other family members. Conclusions and Relevance:The pediatrician's opportunities to engage in difficult conversations about poor prognosis may be rare, but such conversations can be crucial. These discussions affect how patients live at the end of their lives, how they die, and how their families go on. Improved understanding of basic principles of communication, as well as augmented understanding of patient, family, and clinician perspectives may better enable us to navigate these important conversations. C1 [Rosenberg, Abby R.] Seattle Childrens Hosp, Canc & Blood Disorders Ctr, 4800 Sand Point Way NE,M-S MB-8-501, Seattle, WA 98145 USA. [Rosenberg, Abby R.] Seattle Childrens Res Inst, Treuman Katz Ctr Pediat Bioeth, Seattle, WA USA. [Rosenberg, Abby R.] Univ Washington, Sch Med, Dept Pediat, Seattle, WA 98195 USA. [Wolfe, Joanne] Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, Boston, MA 02115 USA. [Wolfe, Joanne] Boston Childrens Hosp, Dept Med, Boston, MA USA. [Wolfe, Joanne] Harvard Med Sch, Boston, MA USA. [Wiener, Lori] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Lyon, Maureen] Childrens Res Inst, Childrens Natl Hlth Syst, Ctr Translat Sci, Washington, DC USA. [Lyon, Maureen] George Washington Univ, Sch Med & Hlth Sci, Washington, DC 20052 USA. [Feudtner, Chris] Childrens Hosp Philadelphia, Pediat Adv Care Team, Philadelphia, PA 19104 USA. [Feudtner, Chris] Childrens Hosp Philadelphia, Dept Med Eth, Philadelphia, PA 19104 USA. [Feudtner, Chris] Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Feudtner, Chris] Univ Penn, Dept Med Eth, Perelman Sch Med, Philadelphia, PA 19104 USA. [Feudtner, Chris] Univ Penn, Dept Hlth Policy, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Rosenberg, AR (reprint author), Seattle Childrens Hosp, Canc & Blood Disorders Ctr, 4800 Sand Point Way NE,M-S MB-8-501, Seattle, WA 98145 USA. EM abby.rosenberg@seattlechildrens.org FU National Institutes of Health [KL2TR000421, L40 CA170049]; Intramural Research Program of the National Cancer Institute FX This work was supported in part by grants KL2TR000421 and L40 CA170049 from the National Institutes of Health (Dr Rosenberg) and the Intramural Research Program of the National Cancer Institute (Dr Wiener). NR 68 TC 0 Z9 0 U1 8 U2 8 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6203 EI 2168-6211 J9 JAMA PEDIATR JI JAMA Pediatr. PD DEC 1 PY 2016 VL 170 IS 12 BP 1216 EP 1223 DI 10.1001/jamapediatrics.2016.2142 PG 8 WC Pediatrics SC Pediatrics GA EF3WZ UT WOS:000390256900023 PM 27749945 ER PT J AU Szalda, D Schwartz, L Schapira, MM Jacobs, L Kim, E Vachani, C Metz, J Hill-Kayser, C AF Szalda, Dava Schwartz, Lisa Schapira, Marilyn M. Jacobs, Linda Kim, Esther Vachani, Carolyn Metz, James Hill-Kayser, Christine TI Internet-Based Survivorship Care Plans for Adult Survivors of Childhood Cancer: A Pilot Study SO JOURNAL OF ADOLESCENT AND YOUNG ADULT ONCOLOGY LA English DT Article DE survivorship; pediatric; care plans; internet ID HEALTH-CARE; MEDICAL-CARE; KNOWLEDGE; PREFERENCES; ADOLESCENT; PREDICTORS AB Survivorship care plans (SCPs) provide health information to survivors and providers. An existing internet-based SCP generator was adapted to incorporate guidelines for adult survivors of pediatric leukemia and lymphoma. Survivors created an SCP online and completed a survey. Survivors (N=30) took an average of 10 minutes to complete the SCP. The majority (95%) found the platform easy to use, would recommend it to others (85%), and intended to share SCP with their healthcare team (90%). Thus, a patient-generated internet-based SCP for adult survivors of childhood cancer may be a feasible tool to improve consistency of information for survivors and their providers. C1 [Szalda, Dava; Schwartz, Lisa; Schapira, Marilyn M.; Jacobs, Linda; Hill-Kayser, Christine] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Szalda, Dava; Schwartz, Lisa; Schapira, Marilyn M.; Jacobs, Linda; Kim, Esther; Metz, James; Hill-Kayser, Christine] Univ Penn, Philadelphia, PA 19104 USA. [Szalda, Dava; Schapira, Marilyn M.; Jacobs, Linda; Vachani, Carolyn; Metz, James; Hill-Kayser, Christine] Abramson Canc Ctr, Philadelphia, PA USA. [Schapira, Marilyn M.] Philadelphia VA Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. RP Szalda, D (reprint author), Childrens Hosp Philadelphia, Abramson Canc Ctr Survivorship Program, 3016 Colket Translat Res Bldg,3501 Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM szaldad@email.chop.edu NR 20 TC 0 Z9 0 U1 1 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 2156-5333 EI 2156-535X J9 J ADOLESC YOUNG ADUL JI J. Adolesc. Young Adult Oncol. PD DEC PY 2016 VL 5 IS 4 BP 351 EP 354 DI 10.1089/jayao.2016.0026 PG 4 WC Oncology SC Oncology GA EF3RN UT WOS:000390242200007 PM 27258823 ER PT J AU Gaggin, HK Belcher, AM Gandhi, PU Ibrahim, NE Januzzi, JL AF Gaggin, Hanna K. Belcher, Arianna M. Gandhi, Parul U. Ibrahim, Nasrien E. Januzzi, James L., Jr. TI Serial Echocardiographic Characteristics, Novel Biomarkers and Cachexia Development in Patients with Stable Chronic Heart Failure SO JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH LA English DT Letter DE Heart failure; Cachexia; Biomarkers; Outcomes ID NATRIURETIC-PEPTIDE AB Little is known regarding objective predictors of cachexia affecting patients with heart failure (HF). We studied 108 stable chronic systolic HF patients with serial echocardiography and biomarker measurements over 10 months. Cachexia was defined as weight loss >= 5 % from baseline or final BMI < 20 kg/m(2); 18.5 % developed cachexia. While there were no significant differences in baseline or serial echocardiographic measures in those developing cachexia, we found significant differences in baseline amino-terminal pro-B type natriuretic peptide (NT-proBNP), highly sensitive troponin I, sST2, and endothelin-1. Baseline log NT-proBNP (hazard ratio (HR) = 2.57, p = 0.004) and edema (HR = 3.36, p = 0.04) were predictive of cachexia in an adjusted analysis. When serial measurement of biomarkers was considered, only percent time with NT-proBNP >= 1000 pg/mL was predictive of cachexia. Thus, a close association exists between baseline and serial measurement of NT-proBNP and HF cachexia. C1 [Gaggin, Hanna K.; Belcher, Arianna M.; Ibrahim, Nasrien E.; Januzzi, James L., Jr.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Gaggin, Hanna K.; Januzzi, James L., Jr.] Harvard Clin Res Inst, Boston, MA 02215 USA. [Gandhi, Parul U.] VA Connecticut Healthcare Syst, West Haven, CT USA. [Gandhi, Parul U.] Yale Univ, Sch Med, New Haven, CT USA. RP Januzzi, JL (reprint author), Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA.; Januzzi, JL (reprint author), Harvard Clin Res Inst, Boston, MA 02215 USA. EM jjanuzzi@mgh.harvard.edu NR 8 TC 0 Z9 0 U1 4 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1937-5387 EI 1937-5395 J9 J CARDIOVASC TRANSL JI J. Cardiovasc. Transl. Res. PD DEC PY 2016 VL 9 IS 5-6 BP 429 EP 431 DI 10.1007/s12265-016-9710-4 PG 3 WC Cardiac & Cardiovascular Systems; Medicine, Research & Experimental SC Cardiovascular System & Cardiology; Research & Experimental Medicine GA EF0LN UT WOS:000390017000004 PM 27631883 ER PT J AU Fujisaka, S Ussar, S Clish, C Devkota, S Dreyfuss, JM Sakaguchi, M Soto, M Konishi, M Softic, S Altindis, E Li, N Gerber, G Bry, L Kahn, CR AF Fujisaka, Shiho Ussar, Siegfried Clish, Clary Devkota, Suzanne Dreyfuss, Jonathan M. Sakaguchi, Masaji Soto, Marion Konishi, Masahiro Softic, Samir Altindis, Emrah Li, Ning Gerber, Georg Bry, Lynn Kahn, C. Ronald TI Antibiotic effects on gut microbiota and metabolism are host dependent SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID DIET-INDUCED OBESITY; NF-KAPPA-B; INSULIN SENSITIVITY; BILE-ACIDS; HIGH-FAT; INTESTINAL MICROBIOTA; EPITHELIAL-CELLS; LIPID-METABOLISM; ADIPOSE-TISSUE; IMMUNE-SYSTEM AB Interactions of diet, gut microbiota, and host genetics play important roles in the development of obesity and insulin resistance. Here, we have investigated the molecular links between gut microbiota, insulin resistance, and glucose metabolism in 3 inbred mouse strains with differing susceptibilities to metabolic syndrome using diet and antibiotic treatment. Antibiotic treatment altered intestinal microbiota, decreased tissue inflammation, improved insulin signaling in basal and stimulated states, and improved glucose metabolism in obesity- and diabetes-prone C57BL/6J mice on a highfat diet (HFD). Many of these changes were reproduced by the transfer of gut microbiota from antibiotic-treated donors to germ-free or germ-depleted mice. These physiological changes closely correlated with changes in serum bile acids and levels of the antiinflammatory bile acid receptor Takeda G protein-coupled receptor 5 (TGR5) and were partially recapitulated by treatment with a TGR5 agonist. In contrast, antibiotic treatment of HFD-fed, obesity-resistant 129S1 and obesity-prone 129S6 mice did not improve metabolism, despite changes in microbiota and bile acids. These mice also failed to show a reduction in inflammatory gene expression in response to the TGR5 agonist. Thus, changes in bile acid and inflammatory signaling, insulin resistance, and glucose metabolism driven by an HFD can be modified by antibiotic-induced changes in gut microbiota; however, these effects depend on important interactions with the host's genetic background and inflammatory potential. C1 [Fujisaka, Shiho; Ussar, Siegfried; Sakaguchi, Masaji; Soto, Marion; Konishi, Masahiro; Softic, Samir; Altindis, Emrah; Kahn, C. Ronald] Joslin Diabet Ctr, Sect Integrat Physiol & Metab, Boston, MA 02215 USA. [Fujisaka, Shiho; Ussar, Siegfried; Devkota, Suzanne; Dreyfuss, Jonathan M.; Sakaguchi, Masaji; Soto, Marion; Konishi, Masahiro; Softic, Samir; Altindis, Emrah; Kahn, C. Ronald] Harvard Med Sch, Boston, MA USA. [Ussar, Siegfried] Helmholtz Zentrum Munchen, Inst Diabet & Obes, Neuherberg, Germany. [Ussar, Siegfried] German Ctr Diabet Res DZD, Munich, Germany. [Clish, Clary] Broad Inst MIT & Harvard, Cambridge, MA USA. [Devkota, Suzanne] Joslin Diabet Ctr, Sect Pathophysiol & Mol Pharmacol, Boston, MA 02215 USA. [Dreyfuss, Jonathan M.] Joslin Diabet Ctr, Bioinformat Core, Boston, MA 02215 USA. [Dreyfuss, Jonathan M.] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. [Softic, Samir] Boston Childrens Hosp, Boston, MA USA. [Li, Ning; Gerber, Georg; Bry, Lynn] Brigham & Womens Hosp, Dept Pathol, Ctr Clin & Translat Metagen, 75 Francis St, Boston, MA 02115 USA. RP Kahn, CR (reprint author), Joslin Diabet Ctr, One Joslin Pl, Boston, MA 02215 USA. EM C.Ronald.Kahn@joslin.harvard.edu OI Ussar, Siegfried/0000-0001-7575-0920; Dreyfuss, Jonathan/0000-0001-7242-3991 FU NIH [R01DK031036, R01DK033201, P30DK036836, P30DK034854]; Mary K. Iacocca Professorship; NICHD [K-12-HD000850]; Sunstar Foundation Postdoctoral Fellowship; iMed; Helmholtz Initiative on Personalized Medicine; German Center for Diabetes Research (DZD) FX We thank Christie Penniman, Vladimir Yeliseyev, Luxue Deng, and Hui Pan for their technical assistance. This work was supported by grants from the NIH (R01DK031036 and R01DK033201, to CRK); a Mary K. Iacocca Professorship (to CRK); and K-12-HD000850 from NICHD (to SS). SF was supported by a Sunstar Foundation Postdoctoral Fellowship. SU was supported by iMed, the Helmholtz Initiative on Personalized Medicine, and the German Center for Diabetes Research (DZD). The authors also thank the Joslin DRC Bioinformatics Core (NIH grant P30DK036836); as the Joslin Animal Physiology Core; the Joslin Flow Cytometry Core; the Joslin Specialized Assay Core; and the Brigham and Women's Hospital, Harvard Digestive Diseases Center for Clinical and Translational Metagenomics (NIH grant P30DK034854) for their core support. NR 48 TC 0 Z9 0 U1 14 U2 14 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 2015 MANCHESTER RD, ANN ARBOR, MI 48104 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD DEC 1 PY 2016 VL 126 IS 12 BP 4430 EP 4443 DI 10.1172/JCI86674 PG 14 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EF2CK UT WOS:000390131900008 PM 27775551 ER PT J AU Garraway, LA AF Garraway, Levi A. TI Believe the miracles: of biomedical science and human suffering SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Editorial Material C1 [Garraway, Levi A.] Harvard Med Sch, Dana Farber Canc Inst, 450 Brookline Ave,Dana Bldg 1542, Boston, MA 02215 USA. RP Garraway, LA (reprint author), Harvard Med Sch, Dana Farber Canc Inst, 450 Brookline Ave,Dana Bldg 1542, Boston, MA 02215 USA. EM levi_garraway@dfci.harvard.edu NR 4 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 2015 MANCHESTER RD, ANN ARBOR, MI 48104 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD DEC 1 PY 2016 VL 126 IS 12 BP 4716 EP 4722 DI 10.1172/JCI90893 PG 7 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EF2CK UT WOS:000390131900029 PM 27906693 ER PT J AU Zhu, P Zhang, YM Yin, X Zhang, XH Wang, F Zhang, JJ Yan, W Xi, Y Wan, JB Kang, JX Zou, ZQ Bu, SZ AF Zhu, Pan Zhang, Yuan-Ming Yin, Xuan Zhang, Xiao-Hong Wang, Feng Zhang, Jin-Jie Yan, Wang Xi, Yang Wan, Jian-Bo Kang, Jing-Xuan Zou, Zu-Quan Bu, Shi-Zhong TI Endogenously synthesized n-3 polyunsaturated fatty acids in fat-1 transgenic mice suppress B16F10 melanoma lung metastasis by impairing mesenchymal to epithelial transition SO JOURNAL OF FUNCTIONAL FOODS LA English DT Article DE Fat-1; n-3 polyunsaturated fatty acids; Mesenchymal to epithelial transition; Lipid mediators; IL-1 beta; Melanoma ID RESOLUTION LIPID MEDIATORS; BREAST-CANCER; INFLAMMATION; CELLS; OBESITY; GROWTH; OMEGA-3-FATTY-ACIDS; MECHANISMS; RESOLVIN; IMPACT AB Malignant melanoma is an aggressive cancer of neuroectodermal origin. The mechanisms of n-3 polyunsaturated fatty acids (PUFAs) against melanoma metastasis are not clear. Here fat-1 and wild type (WT) mice were injected with B16F10 melanoma cells via the tail vein to establish lung metastasis model. Endogenous n-3 PUFAs were associated with a reduction in grossly visible pulmonary metastases and outgrowth through inhibition of mesenchymal to epithelial transition (MET), which was characterized by decreased expression of epithelial markers E-cadherin and ZO-1, and increased expression of mesenchymal marker vimentin in tumour tissues from fat-1 mice compared with WT controls. In addition, n-3 PUFA-mediated inhibition of MET may have been associated, in part, with the: (i) formation of n-3 PUFA-derived lipid mediators and (ii) decreased expression of mature IL-10 and p-NF-kappa B, and enhanced expression of superoxide dismutase-1. These results suggest that n-3 PUFAs exert their antitumourigenic activities, in part, via their anti-inflammatory properties. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Zhu, Pan; Zhang, Yuan-Ming; Zhang, Xiao-Hong; Xi, Yang; Zou, Zu-Quan; Bu, Shi-Zhong] Ningbo Univ, Sch Med, 818 Fenghua Rd, Ningbo 315211, Zhejiang, Peoples R China. [Yin, Xuan] First Peoples Hosp Hangzhou, Dept Nutr, Hangzhou 310006, Zhejiang, Peoples R China. [Wang, Feng] Lihuili Hosp, Clin Lab, Ningbo 315040, Zhejiang, Peoples R China. [Zhang, Jin-Jie] Ningbo Univ, Maritime Fac, Ningbo 315211, Zhejiang, Peoples R China. [Yan, Wang] Second Hosp Ningbo, Neurosurg Dept, Ningbo 315010, Zhejiang, Peoples R China. [Wan, Jian-Bo] Univ Macau, Inst Chinese Med Sci, State Key Lab Qual Res Chinese Med, Macau 519000, Peoples R China. [Kang, Jing-Xuan] Massachusetts Gen Hosp, Lab Lipid Med & Technol, Boston, MA 02114 USA. [Kang, Jing-Xuan] Harvard Med Sch, Boston, MA 02114 USA. RP Zou, ZQ; Bu, SZ (reprint author), Ningbo Univ, Sch Med, 818 Fenghua Rd, Ningbo 315211, Zhejiang, Peoples R China. EM zouzuquan@nbu.edu.cn; bushizhong@nbu.edu.cn FU Fang Runhua Fund of Hong Kong; K.C. Wong Magna Fund of Ningbo University; National Science Foundation of China [81172660, 81370165, 81673163, 31201284]; Scientific Innovation Team Project of Ningbo [2014B82002, 2016C51001]; Natural Science Foundation of Zhejiang [LY14H260001, LY15C200008]; Medical and Health Technology Development Program of Zhejiang [2014kya198]; Natural Science Foundation of Ningbo [2015A610222]; Department of Education of Zhejiang [Y200908119]; Science Foundation of Ningbo University [XKL14D2101]; Application of Public Welfare Technology (Experimental Animals) of Zhejiang [2016C37120] FX This study was partly sponsored by the Fang Runhua Fund of Hong Kong, the K.C. Wong Magna Fund of Ningbo University, the National Science Foundation of China (grant nos. 81172660, 81370165, 81673163 and 31201284), the Scientific Innovation Team Project of Ningbo (grant nos. 2014B82002 and 2016C51001), the Natural Science Foundation of Zhejiang (grant nos. LY14H260001 and LY15C200008), the project of Medical and Health Technology Development Program of Zhejiang (grant no. 2014kya198), the Natural Science Foundation of Ningbo (grant nos. 2015A610222), the project of the Department of Education of Zhejiang (grant no. Y200908119), the Science Foundation of Ningbo University (grant no. XKL14D2101) and the project of the Application of Public Welfare Technology (Experimental Animals) of Zhejiang (grant no. 2016C37120). NR 38 TC 0 Z9 0 U1 5 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1756-4646 J9 J FUNCT FOODS JI J. Funct. Food. PD DEC PY 2016 VL 27 BP 483 EP 490 DI 10.1016/j.jff.2016.10.006 PG 8 WC Food Science & Technology SC Food Science & Technology GA EF2UB UT WOS:000390180000042 ER PT J AU Ettner, SL Harwood, JM Thalmayer, A Ong, MK Xu, HY Bresolin, MJ Wells, KB Tseng, CH Azocar, F AF Ettner, Susan L. Harwood, Jessica M. Thalmayer, Amber Ong, Michael K. Xu, Haiyong Bresolin, Michael J. Wells, Kenneth B. Tseng, Chi-Hong Azocar, Francisca TI The Mental Health Parity and Addiction Equity Act evaluation study: Impact on specialty behavioral health utilization and expenditures among "carve-out" enrollees SO JOURNAL OF HEALTH ECONOMICS LA English DT Article DE Behavioral health; Parity; Utilization; Expenditures; Insurance benefits ID INTERRUPTED TIME-SERIES; USE DISORDER TREATMENT; INSURANCE PARITY; REGRESSION-ANALYSIS; FEDERAL-EMPLOYEES; SUBSTANCE-ABUSE; SERVICES; MEDICAID; PLANS AB Interrupted time series with and without controls was used to evaluate whether the federal Mental Health Parity and Addiction Equity Act (MHPAEA) and its Interim Final Rule increased the probability of specialty behavioral health treatment and levels of utilization and expenditures among patients receiving treatment. Linked insurance claims, eligibility, plan and employer data from 2008 to 2013 were used to estimate segmented regression analyses, allowing for level and slope changes during the transition (2010) and post-MHPAEA (2011-2013) periods. The sample included 1,812,541 individuals ages 27-64 (49,968,367 person-months) in 10,010 Optum "carve-out" plans. Two-part regression models with Generalized Estimating Equations were used to estimate expenditures by payer and outpatient, intermediate and inpatient service use. We found little evidence that MHPAEA increased utilization significantly, but somewhat more robust evidence that costs shifted from patients to plans. Thus the primary impact of MHPAEA among carve-out enrollees may have been a reduction in patient financial burden. (C) 2016 Elsevier B.V. All rights reserved. C1 [Ettner, Susan L.; Harwood, Jessica M.; Ong, Michael K.; Xu, Haiyong; Tseng, Chi-Hong] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Gen Internal Med & Hlth Serv Res, 911 Broxton Plaza, Los Angeles, CA 90024 USA. [Ettner, Susan L.] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Dept Hlth Policy & Management, Los Angeles, CA USA. [Thalmayer, Amber; Bresolin, Michael J.; Azocar, Francisca] Optum, United Hlth Grp, Minnetonka, MN USA. [Ong, Michael K.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Wells, Kenneth B.] Univ Calif Los Angeles, Dept Psychiat, Neuropsychiat Inst, Los Angeles, CA USA. RP Ettner, SL (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Gen Internal Med & Hlth Serv Res, 911 Broxton Plaza, Los Angeles, CA 90024 USA. EM settner@mednet.ucla.edu FU National Institute on Drug Abuse [1R01DA032619-01] FX We gratefully acknowledge support for this study from the National Institute on Drug Abuse (1R01DA032619-01), data from Optum (R), United Health Group, and helpful comments from seminar participants at the Virginia Commonwealth University, the University of Minnesota-Minneapolis, the University of Toronto, and the University of California, Los Angeles. We would like to thank Rosalie Pacula, Ph.D., and Susan Ridgely, J.D., for providing information on state parity mandates for treatment of mental illness and substance use disorders through a RAND subcontract. We would also like to thank Brent Bolstrom and Nghi Ly from Optum (R), United Health Group, for the extraction, preparation and delivery of data to UCLA. The academic team members analyzed all data independently and retained sole authority over all publication-related decisions throughout the course of the study. NR 27 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-6296 EI 1879-1646 J9 J HEALTH ECON JI J. Health Econ. PD DEC PY 2016 VL 50 BP 131 EP 143 DI 10.1016/j.jhealeco.2016.09.009 PG 13 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA EF7HN UT WOS:000390500800011 PM 27736705 ER PT J AU Palma, TH Harth-Chu, EN Scott, J Stipp, RN Boisvert, H Salomao, MF Theobaldo, JD Possobon, RF Nascimento, LC McCafferty, JW Faller, L Duncan, MJ Mattos-Graner, RO AF Palma, Thais H. Harth-Chu, Erika N. Scott, Jodie Stipp, Rafael N. Boisvert, Heike Salomao, Mariana F. Theobaldo, Jessica D. Possobon, Rosana F. Nascimento, Leandro C. McCafferty, Jonathan W. Faller, Lina Duncan, Margaret J. Mattos-Graner, Renata O. TI Oral cavities of healthy infants harbour high proportions of Streptococcus salivarius strains with phenotypic and genotypic resistance to multiple classes of antibiotics SO JOURNAL OF MEDICAL MICROBIOLOGY LA English DT Article ID VIRIDANS GROUP STREPTOCOCCI; ANTIMICROBIAL SUSCEPTIBILITY; GENETIC ELEMENTS; HIGH-RATES; PNEUMONIAE; MACROLIDE; BACTERIA; MICROBIOTA; PENICILLIN; FLORA AB Emerging antibiotic resistance in the oropharyngeal microbiota, of which Streptococcus salivarius is a prominent species, represents a challenge for treating paediatric populations. In this study, we investigated the role of Streptococcus salivarius as a reservoir for antibiotic resistance genes (ARG) in the oral microbiota by analysing 95 Streptococcus salivarius isolates from 22 healthy infants (2-16 months of age). MICs of penicillin G, amoxicillin, erythromycin, tetracycline, doxycycline and streptomycin were determined. ARG profiles were assessed in a subset of 21 strains by next-generation sequencing of genomes, followed by searches of assembled reads against the Comprehensive Antibiotic Resistance Database. Strains resistant to erythromycin, penicillins and tetracyclines were isolated from 83.3, 33.3 and 16.6 %, respectively, of infants aged 2 to 8 months with no prior antibiotic treatment. These percentages were 100.0, 66.6 and 50.0 %, by 13 to 16 months of age. ARG or polymorphisms associated with antibiotic resistance were the most prevalent and involved genes for macrolide efflux (mel, mefA/E and macB), ribosomal protection [erm(B), tet(M) and tet(O)] and beta-lactamase-like proteins. Phylogenetically related strains showing multidrug-resistant phenotypes harboured multidrug efflux ARG. Polymorphic genes associated with antibiotic resistance to drugs affecting DNA replication, folate synthesis, RNA/protein synthesis and regulators of antibiotic stress responses were detected. These data imply that Streptococcus salivarius strains established during maturation of the oral microbiota harbour a diverse array of functional ARG, even in the absence of antibiotic selective pressures, highlighting a potential role for this species in shaping antibiotic susceptibility profiles of oropharyngeal communities. C1 [Palma, Thais H.; Harth-Chu, Erika N.; Stipp, Rafael N.; Theobaldo, Jessica D.; Mattos-Graner, Renata O.] Univ Estadual Campinas, Dept Oral Diag, Sao Paulo, Brazil. [Scott, Jodie; Boisvert, Heike; McCafferty, Jonathan W.; Faller, Lina; Duncan, Margaret J.] Forsyth Inst, Dept Microbiol, Cambridge, MA USA. [Salomao, Mariana F.] Univ Estadual Campinas, Piracicaba Dent Sch, Sao Paulo, Brazil. [Possobon, Rosana F.] Univ Estadual Campinas, Cepae Res & Dent Care Ctr Special Needs Patients, Piracicaba Dent Sch, Sao Paulo, Brazil. [Nascimento, Leandro C.] Univ Estadual Campinas, Lab Genom & Gene Express LGE, Sao Paulo, Brazil. RP Mattos-Graner, RO (reprint author), Univ Estadual Campinas, Dept Oral Diag, Sao Paulo, Brazil. EM rmgraner@fop.unicamp.br FU Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2012/51832-3, 2015/12940-3]; CAPES; FAPESP [2011/09761-9, 2013/06820-0, 2010/06785-1, 2010/06786-8, 2009/50547-0]; CAPES-PNPD; US National Institutes of Health [R01 DE24308, R03-DE023129]; Forsyth Institute Bioinformatics Core FX This study was supported by the Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP, protocol 2012/51832-3 and 2015/12940-3). T. H. P. was supported by CAPES and FAPESP (protocol 2011/09761-9 and 2013/06820-0). M. F. and J. D. T. were supported by FAPESP (protocol 2010/06785-1 and 2010/06786-8). E. N. H. C. was supported by FAPESP (protocol 2009/50547-0) and CAPES-PNPD (2013). J. S. and M. J. D. were supported by the US National Institutes of Health Grant R01 DE24308; H. B. was supported by the US National Institutes of Health Grant R03-DE023129. J. M. and L. F. were supported by The Forsyth Institute Bioinformatics Core. NR 58 TC 0 Z9 0 U1 5 U2 5 PU MICROBIOLOGY SOC PI LONDON PA CHARLES DARWIN HOUSE, 12 ROGER ST, LONDON WC1N 2JU, ERKS, ENGLAND SN 0022-2615 EI 1473-5644 J9 J MED MICROBIOL JI J. Med. Microbiol. PD DEC PY 2016 VL 65 BP 1456 EP 1464 DI 10.1099/jmm.0.000377 PN 12 PG 9 WC Microbiology SC Microbiology GA EF5YC UT WOS:000390404900015 PM 27902365 ER PT J AU Schlimgen, R Howard, J Wooley, D Thompson, M Baden, LR Yang, OO Christiani, DC Mostoslavsky, G Diamond, DV Duane, EG Byers, K Winters, T Gelfand, JA Fujimoto, G Hudson, TW Vyas, JM AF Schlimgen, Ryan Howard, John Wooley, Dawn Thompson, Maureen Baden, Lindsey R. Yang, Otto O. Christiani, David C. Mostoslavsky, Gustavo Diamond, David V. Duane, Elizabeth Gilman Byers, Karen Winters, Thomas Gelfand, Jeffrey A. Fujimoto, Gary Hudson, T. Warner Vyas, Jatin M. TI Risks Associated With Lentiviral Vector Exposures and Prevention Strategies SO JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; VIVO GENE DELIVERY; IN-VIVO; THERAPY; DISEASE; CELLS; TRANSMISSION; PROPHYLAXIS; ACTIVATION; SETTINGS AB Lentiviral vectors (LVVs) are powerful genetic tools that are being used with greater frequency in biomedical laboratories and clinical trials. Adverse events reported from initial clinical studies provide a basis for risk assessment of occupational exposures, yet many questions remain about the potential harm that LVVs may cause. We review those risks and provide a framework for principal investigators, Institutional Biosafety Committees, and occupational health professionals to assess and communicate the risks of exposure to staff. We also provide recommendations to federal research and regulatory agencies for tracking LVV exposures to evaluate long-term outcomes. U.S. Food and Drug Administration approved antiviral drugs for HIV have theoretical benefits in LVV exposures, although evidence to support their use is currently limited. If treatment is appropriate, we recommend a 7-day treatment with an integrase inhibitor with or without a reverse transcriptase inhibitor within 72hours of exposure. C1 [Schlimgen, Ryan] Partners HealthCare, Boston, MA USA. [Howard, John] NIOSH, Washington, DC USA. [Wooley, Dawn] Wright State Univ, Detroit, MI USA. [Thompson, Maureen] Emory Univ, Atlanta, GA 30322 USA. [Baden, Lindsey R.; Byers, Karen] Dana Farber Canc Inst, Boston, MA 02115 USA. [Baden, Lindsey R.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Baden, Lindsey R.; Christiani, David C.; Gelfand, Jeffrey A.; Vyas, Jatin M.] Harvard Med Sch, Boston, MA USA. [Yang, Otto O.; Hudson, T. Warner] Univ Calif Los Angeles, Los Angeles, CA USA. [Christiani, David C.; Gelfand, Jeffrey A.; Vyas, Jatin M.] Massachusetts Gen Hosp, 55 Fruit St,GRJ 5-504, Boston, MA 02114 USA. [Christiani, David C.] Harvard TH Chan Sch Publ Hlth, Boston, MA USA. [Mostoslavsky, Gustavo] Boston Univ, Sch Med, Boston, MA 02118 USA. [Diamond, David V.] MIT, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Winters, Thomas] Occupat & Environm Hlth Network, Boston, MA USA. RP Vyas, JM (reprint author), Massachusetts Gen Hosp, 55 Fruit St,GRJ 5-504, Boston, MA 02114 USA. EM jvyas@partners.org FU Eagleson Institute FX The conference and preparation of this manuscript was supported in part by an unrestricted grant from the Eagleson Institute. NR 29 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1076-2752 EI 1536-5948 J9 J OCCUP ENVIRON MED JI J. Occup. Environ. Med. PD DEC PY 2016 VL 58 IS 12 BP 1159 EP 1166 DI 10.1097/JOM.0000000000000879 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA EF3QE UT WOS:000390238500003 PM 27930472 ER PT J AU Jensen, RJ AF Jensen, Ralph J. TI Effects of Antipsychotic Drugs Haloperidol and Clozapine on Visual Responses of Retinal Ganglion Cells in a Rat Model of Retinitis Pigmentosa SO JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS LA English DT Article DE retinal ganglion cells; retinitis pigmentosa; antipsychotic drugs ID RABBIT RETINA; RECEPTORS; ANTAGONIST AB Purpose: In the P23H rat model of retinitis pigmentosa, the dopamine D2 receptor antagonists sulpiride and eticlopride appear to improve visual responses of retinal ganglion cells (RGCs) by increasing light sensitivity of RGCs and transforming abnormal, long-latency ON-center RGCs into OFF-center cells. Antipsychotic drugs are believed to mediate their therapeutic benefits by blocking D2 receptors. This investigation was conducted to test whether haloperidol (a typical antipsychotic drug) and clozapine (an atypical antipsychotic drug) could similarly alter the light responses of RGCs in the P23H rat retina. Methods: Extracellular recordings were made from RGCs in isolated P23H rat retinas. Responses of RGCs to flashes of light were evaluated before and during bath application of a drug. Results: Both haloperidol and clozapine increased light sensitivity of RGCs on average by approximate to 0.3 log unit. For those ON-center RGCs that exhibit an abnormally long-latency response to the onset of a small spot of light, both haloperidol and clozapine brought out a short-latency OFF response and markedly reduced the long-latency ON response. The selective serotonin 5-HT2A antagonist MDL 100907 had similar effects on RGCs. Conclusions: The effects of haloperidol on light responses of RGCs can be explained by its D2 receptor antagonism. The effects of clozapine on light responses of RGCs on the other hand may largely be due to its 5-HT2A receptor antagonism. Overall, the results suggest that antipsychotic drugs may be useful in improving vision in patients with retinitis pigmentosa. C1 [Jensen, Ralph J.] VA Boston Healthcare Syst, Mail Stop 151E,150 South Huntington Ave, Boston, MA 02130 USA. RP Jensen, RJ (reprint author), VA Boston Healthcare Syst, Mail Stop 151E,150 South Huntington Ave, Boston, MA 02130 USA. EM ralph.jensen@va.gov NR 18 TC 0 Z9 0 U1 3 U2 3 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1080-7683 EI 1557-7732 J9 J OCUL PHARMACOL TH JI J. Ocular Pharmacol. Ther. PD DEC PY 2016 VL 32 IS 10 BP 685 EP 690 DI 10.1089/jop.2016.0102 PG 6 WC Ophthalmology; Pharmacology & Pharmacy SC Ophthalmology; Pharmacology & Pharmacy GA EF5ZG UT WOS:000390408000009 PM 27788033 ER PT J AU Martin, VJ Leonard, MM Fiechtner, L Fasano, A AF Martin, Victoria J. Leonard, Maureen M. Fiechtner, Lauren Fasano, Alessio TI Transitioning From Descriptive to Mechanistic Understanding of the Microbiome: The Need for a Prospective Longitudinal Approach to Predicting Disease SO JOURNAL OF PEDIATRICS LA English DT Editorial Material ID INFLAMMATORY-BOWEL-DISEASE; BIRTH-WEIGHT INFANTS; NECROTIZING ENTEROCOLITIS; INTESTINAL MICROBIOTA; FECAL MICROBIOTA; GUT MICROBIOTA; CELIAC-DISEASE; CROHNS-DISEASE; FOOD ALLERGY; CHILDHOOD OBESITY C1 [Martin, Victoria J.; Leonard, Maureen M.; Fiechtner, Lauren; Fasano, Alessio] Massachusetts Gen Hosp Children, Dept Pediat Gastroenterol & Nutr, Boston, MA USA. RP Fasano, A (reprint author), Massachusetts Gen Hosp, Massachusetts Gen Hosp Children, 175 Cambridge St,CPZS-574, Boston, MA 02114 USA. EM afasano@mgh.harvard.edu FU NIDDK NIH HHS [R01 DK104344] NR 83 TC 0 Z9 0 U1 3 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD DEC PY 2016 VL 179 BP 240 EP 248 DI 10.1016/j.jpeds.2016.08.049 PG 9 WC Pediatrics SC Pediatrics GA EF0PD UT WOS:000390027100048 PM 27634626 ER PT J AU Kimball, AB Luger, T Gottlieb, A Puig, L Kaufmann, R Nikai, E Zhu, BJ Edson-Heredia, E Carlier, H Lin, CY Goldblum, O Yosipovitch, G AF Kimball, Alexandra B. Luger, Thomas Gottlieb, Alice Puig, Luis Kaufmann, Roland Nikai, Enkeleida Zhu, Baojin Edson-Heredia, Emily Carlier, Hilde Lin, Chen-Yen Goldblum, Orin Yosipovitch, Gil TI Impact of ixekizumab on psoriasis itch severity and other psoriasis symptoms: Results from 3 phase III psoriasis clinical trials SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article DE itch; itch numeric rating scale; patient-reported outcomes; psoriasis; skin appearance; bothersomeness; skin pain ID SEVERE PLAQUE PSORIASIS; QUALITY-OF-LIFE; DISEASE SEVERITY; PRURITUS; QUESTIONNAIRE; MODERATE AB Background: Itch is a prevalent symptom of psoriasis that impacts quality of life. Objective: We sought to describe improvements in itch severity, skin pain, and bothersomeness of skin appearance caused by psoriasis among patients who received ixekizumab, etanercept, or placebo in three 12 -week, phase III clinical trials (UNCOVER -1, -2, and -3). Methods: The itch numeric rating scale evaluated psoriasis itch severity in all 3 trials. Skin pain was assessed by skin pain visual analog scale. Bothersomeness because of redness/discoloration, thickness, and scaling/flaking was assessed with the Psoriasis Skin Appearance Bothersomeness instrument. Psoriasis skin appearance bothersomeness and skin pain were assessed at baseline and week 12; itch numeric rating scale score was assessed at baseline and weeks 1, 2, 4, 8, and 12. Results: Patients who received ixekizumab demonstrated statistically significant improvements (P <.001) in itch severity, reduction in skin pain, and degree of bothersomeness compared with those who received etanercept or placebo. Clinically meaningful improvements in itch severity were achieved as early as week 1. Limitations: Longer -term evaluations of psoriasis symptom improvement with ixekizumab treatment are needed. Conclusion: After treatment with ixekizumab, patients reported fast, significant, and clinically meaningful improvements in itch severity and other psoriasis -related symptoms such as skin pain and skin appearance bothersomeness. C1 [Kimball, Alexandra B.] Massachusetts Gen Hosp, 50 Staniford St,24, Boston, MA 02114 USA. [Kimball, Alexandra B.] Harvard Med Sch, 50 Staniford St,24, Boston, MA 02114 USA. [Luger, Thomas] Univ Munster, Dept Dermatol, Munster, Germany. [Gottlieb, Alice] Tufts Med Ctr, Boston, MA USA. [Puig, Luis] Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, E-08193 Barcelona, Spain. [Kaufmann, Roland] Goethe Univ, Frankfurt, Germany. [Nikai, Enkeleida] Eli Lilly & Co, Brussels, Belgium. [Zhu, Baojin; Edson-Heredia, Emily; Carlier, Hilde; Lin, Chen-Yen; Goldblum, Orin] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Yosipovitch, Gil] Temple Univ, Philadelphia, PA 19122 USA. RP Kimball, AB (reprint author), Massachusetts Gen Hosp, 50 Staniford St,24, Boston, MA 02114 USA.; Kimball, AB (reprint author), Harvard Med Sch, 50 Staniford St,24, Boston, MA 02114 USA. EM akimball@mgh.harvard.edu FU Eli Lilly and Company FX Funding for this study was provided by Eli Lilly and Company. NR 14 TC 1 Z9 1 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD DEC PY 2016 VL 75 IS 6 BP 1156 EP 1161 DI 10.1016/j.jaad.2016.07.034 PG 6 WC Dermatology SC Dermatology GA EF0QX UT WOS:000390032000027 PM 27692498 ER PT J AU Kini, V Weiner, RB McCarthy, FH Wiegers, SE Kirkpatrick, JN AF Kini, Vinay Weiner, Rory B. McCarthy, Fenton H. Wiegers, Susan E. Kirkpatrick, James N. TI Association of Liability Concerns with Decisions to Order Echocardiography and Cardiac Stress Tests with Imaging SO JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY LA English DT Article DE Echocardiography; Cardiac stress tests; Malpractice; Liability ID APPROPRIATE USE CRITERIA; HEART-FAILURE; MALPRACTICE; CARE; PHYSICIANS; MEDICARE; RISK; CARDIOLOGISTS; QUALITY; CLAIMS AB Background: Professional societies have made efforts to curb overuse of cardiac imaging and decrease practice variation by publishing appropriate use criteria. However, little is known about the impact of physicianlevel determinants such as liability concerns and risk aversion on decisions to order testing. Methods: A web-based survey was administered to cardiologists and general practice physicians affiliated with two academic institutions. The survey consisted of four clinical scenarios in which appropriate use criteria rated echocardiography or stress testing as "may be appropriate.'' Respondents' degree of liability concerns and risk aversion were measured using validated tools. The primary outcome variable was tendency to order imaging, calculated as the average likelihood to order an imaging test across the clinical scenarios (1 = very unlikely, 6 = very likely). Linear regression models were used to evaluate the association between tendency to order imaging and physician characteristics. Results: From 420 physicians invited to participate, 108 complete responses were obtained (26% response rate, 54% cardiologists). There was no difference in tendency to order imaging between cardiologists and general practice physicians (3.46 [95% CI, 3.12-3.81] vs 3.15 [95% CI, 2.79-3.51], P =.22). On multivariate analysis, a higher degree of liability concerns was the only significant predictor of decisions to order imaging (mean difference in tendency to order imaging, 0.36; 95% CI, 0.09-0.62; P =.01). Conclusion: In clinical situations in which performance of cardiac imaging is rated as "may be appropriate'' by appropriate use criteria, physicians with higher liability concerns ordered significantly more testing than physicians with lower concerns. C1 [Kini, Vinay] Hosp Univ Penn, Div Cardiovasc Med, 3400 Spruce St, Philadelphia, PA 19104 USA. [McCarthy, Fenton H.] Hosp Univ Penn, Div Cardiovasc Surg, 3400 Spruce St, Philadelphia, PA 19104 USA. [Weiner, Rory B.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Wiegers, Susan E.] Temple Univ, Lewis Katz Sch Med, Div Cardiovasc Med, Philadelphia, PA 19122 USA. [Kirkpatrick, James N.] Univ Washington, Sch Med, Div Cardiovasc Med, Seattle, WA USA. RP Kini, V (reprint author), Hosp Univ Penn, Cardiol, 3400 Spruce St, Philadelphia, PA 19104 USA. EM vinay.kini@uphs.upenn.edu NR 33 TC 1 Z9 1 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0894-7317 J9 J AM SOC ECHOCARDIOG JI J. Am. Soc. Echocardiogr. PD DEC PY 2016 VL 29 IS 12 BP 1155 EP + DI 10.1016/j.echo.2016.08.014 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EF0TG UT WOS:000390038300004 PM 27639813 ER PT J AU Juraschek, SP Choi, HK Tang, O Appel, LJ Miller, ER AF Juraschek, Stephen P. Choi, Hyon K. Tang, Olive Appel, Lawrence J. Miller, Edgar R., III TI Opposing effects of sodium intake on uric acid and blood pressure and their causal implication SO JOURNAL OF THE AMERICAN SOCIETY OF HYPERTENSION LA English DT Article DE Hypertension; sodium; trial; uric acid ID ISCHEMIC-HEART-DISEASE; CARDIOVASCULAR MORTALITY; SALT-SENSITIVITY; DIETARY-SODIUM; ESSENTIAL-HYPERTENSION; RISK-FACTORS; FOLLOW-UP; MENDELIAN RANDOMIZATION; INDEPENDENT MECHANISM; DASH-SODIUM AB Reducing uric acid is hypothesized to lower blood pressure, although evidence is inconsistent. In this ancillary of the DASH Sodium trial, we examined whether sodium-induced changes in serum uric acid (SUA) were associated with changes in blood pressure. One hundred and three adults with prestage or stage 1 hypertension were randomly assigned to receive either the DASH diet or a control diet (typical of the average American diet) and were fed each of the three sodium levels (low, medium, and high) for 30 days in random order. Body weight was kept constant. SUA was measured at baseline and following each feeding period. Participants were 55% women and 75% black. Mean age was 52 (SD, 10) years, and mean SUA at baseline was 5.0 (SD, 1.3) mg/dL. Increasing sodium intake from low to high reduced SUA (-0.4 mg/dL; P <.001) but increased systolic (4.3 mm Hg; P <.001) and diastolic blood pressure (2.3 mm Hg; P <.001). Furthermore, changes in SUA were independent of changes in systolic (P =.15) and diastolic (P =.63) blood pressure, regardless of baseline blood pressure, baseline SUA, and randomized diet, as well as sodium sensitivity. Although both SUA and blood pressure were influenced by sodium, a common environmental factor, their effects were in opposite directions and were unrelated to each other. These findings do not support a consistent causal relationship between SUA and BP. Copyright (C) 2016 American Society of Hypertension. All rights reserved. C1 [Juraschek, Stephen P.; Tang, Olive; Appel, Lawrence J.; Miller, Edgar R., III] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Juraschek, Stephen P.; Tang, Olive; Appel, Lawrence J.; Miller, Edgar R., III] Johns Hopkins Univ, Sch Med, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. [Choi, Hyon K.] Harvard Med Sch, Massachusetts Gen Hosp, Gout & Crystal Arthropathy Ctr, Boston, MA USA. RP Juraschek, SP (reprint author), Johns Hopkins Med Inst, 2024 East Monument St,Suite 1-500, Baltimore, MD 21205 USA. EM spj@jhmi.edu FU National Heart, Lung, and Blood Institute [U01-HL57173, U01-HL57114, U01-HL57190, U01-HL57139, K08 HL03857-01, U01-HL57156]; General Clinical Research Center Program of the National Center for Research Resources [M01-RR02635, M01-RR00722] FX Supported by cooperative agreements and grants from the National Heart, Lung, and Blood Institute (U01-HL57173, to Brigham and Women's Hospital; U01-HL57114, to Duke University; U01-HL57190, to Pennington Biomedical Research Institute; U01-HL57139 and K08 HL03857-01, to Johns Hopkins University; and U01-HL57156, to Kaiser Permanente Center for Health Research) and by the General Clinical Research Center Program of the National Center for Research Resources (M01-RR02635, to Brigham and Women's Hospital, and M01-RR00722, to Johns Hopkins University). NR 54 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 1933-1711 EI 1878-7436 J9 J AM SOC HYPERTENS JI J. Am. Soc. Hypertens. PD DEC PY 2016 VL 10 IS 12 BP 939 EP 946 DI 10.1016/j.jash.2016.10.012 PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA EF4KA UT WOS:000390293000006 PM 27938853 ER PT J AU Cambria, RP Conrad, MF AF Cambria, Richard P. Conrad, Mark F. TI Thoracic endovascular aneurysm repair for uncomplicated type B dissection SO JOURNAL OF VASCULAR SURGERY LA English DT Editorial Material ID ACUTE AORTIC DISSECTION; INTERNATIONAL REGISTRY; MEDICAL-MANAGEMENT; TRIAL; IRAD C1 [Cambria, Richard P.; Conrad, Mark F.] Massachusetts Gen Hosp, Thorac Aort Ctr, Div Vasc & Endovasc Surg, Boston, MA 02114 USA. RP Cambria, RP (reprint author), Massachusetts Gen Hosp, Thorac Aort Ctr, Div Vasc & Endovasc Surg, Boston, MA 02114 USA. NR 13 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 DEC PY 2016 VL 64 IS 6 BP 1558 EP 1559 DI 10.1016/j.jvs.2016.08.002 PG 2 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA EF0VI UT WOS:000390044000002 PM 27871488 ER PT J AU McPhee, JT Madenci, A Raffetto, J Martin, M Gupta, N AF McPhee, James T. Madenci, Arin Raffetto, Joseph Martin, Michelle Gupta, Naren TI Contemporary comparison of aortofemoral bypass to alternative inflow procedures in the Veteran population SO JOURNAL OF VASCULAR SURGERY LA English DT Article ID AORTOILIAC OCCLUSIVE DISEASE; ABDOMINAL AORTIC-ANEURYSM; FEMORAL ENDARTERECTOMY; RECONSTRUCTION; OUTCOMES; METAANALYSIS; QUALITY; PROGRAM; REPAIR; CARE AB Objective: Multiple vascular inflow reconstruction options exist for claudication, including aortofemoral bypass (AFB) and alternative inflow procedures (AIPs) such as femoral reconstruction with iliac stents, and femoral-femoral, iliofemoral, and axillofemoral bypass. Contemporary multi-institution comparison of these techniques is lacking. Methods: The Veterans Affairs Surgical Quality Improvement Project (VASQIP) national database (2005-2013) was used to compare AFB vs AIP in a propensity-matched analysis. Primary outcome was mortality at 30 and 90 days. Secondary outcomes included rates of postoperative complications. Multivariable regression assessed the adjusted effect of inflow procedure type on mortality. Results: A matched cohort of 748 claudicant patients (373 AFB, 375 AIP) was identified. The AFB and AIP groups had similar mean age (59.9 vs 60.8 years; P=.30), gender (P=.51), race (P=.52), recent smoking (79.1% vs 76.5%; P=.43), history of coronary artery disease (14.8% vs 14.7%; P>.99), chronic obstructive pulmonary disease (18.8% vs 18.4%; P=.92), renal insufficiency (5.9% vs 6.1%; P>.99), and diabetes (22% vs 20%; P=.53), and American Society of Anesthesiologists Physical Status Classification (P=.41). The AFB group had longer mean operative time (4.9 vs 3.5 hours; P<.0001), more senior resident assistants (72.4% vs 61.1%; P<.0001), and greater mean red blood cell transfusion (1.1 vs 0.12 units; P<.0001). AFB and AIP had similar rates of outflow bypass (1.9% vs 1.3%; P=.58) and outflow endovascular interventions (0.54% vs 1.6%; P=.29). AFB trended toward a higher rate of mortality at 30 days postoperatively (2.7% vs 0.8%; P=.06), but by 90 days, the crude mortality rates were similar for the two (2.9% vs 2.1%; P=.5). AFB had higher rates of pneumonia (5.9% vs 0.8%; P<.001), deep vein thrombosis/pulmonary embolism (1.3% vs 0%; P=.03), postoperative transfusion (2.7% vs 0.53%; P=.02), and urinary tract infection (3.5% vs 0.8%; P=.01), but similar rates of myocardial infarction (1.6% vs 0.8%; P=.34), stroke (0.8% vs 0%; P=.12), wound complications (13.1% vs 12.8%; P=.91), renal failure (1.1% vs 0.3%; P=.22), graft failure (1.3% vs 1.1%; P=.75), and return to the operating room (12.9% vs 9.6%; P=.17). Multivariable analysis showed AFB was not independently associated with mortality (odds ratio [OR], 0.48; 95% confidence interval [CI], 0.1-3.0). Significant factors included age (OR, 1.2; 95% CI, 1.1-1.4), postoperative renal insufficiency (OR, 2.5; 95% CI, 1.6-4.0), and unplanned reintubation (OR, 35.5; 95% CI, 3.1-399). Conclusions: For claudicant patients with inflow disease, AFB has higher rates of 30-day complications and a trend toward higher mortality; however by 90 days postoperatively, the two procedure types have similar rates of mortality. C1 [McPhee, James T.; Raffetto, Joseph; Martin, Michelle; Gupta, Naren] Vet Affairs Boston Healthcare Syst, Div Vasc Surg, West Roxbury, MA USA. [McPhee, James T.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Madenci, Arin] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Madenci, Arin; Raffetto, Joseph; Martin, Michelle; Gupta, Naren] Harvard Med Sch, Boston, MA USA. RP McPhee, JT (reprint author), VA Boston Healthcare Syst, 1400 VFW Pkwy, West Roxbury, MA 02132 USA. EM james.mcphee@va.gov NR 17 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 DEC PY 2016 VL 64 IS 6 BP 1660 EP 1666 DI 10.1016/j.jvs.2016.05.081 PG 7 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA EF0VI UT WOS:000390044000018 PM 27462000 ER PT J AU Barshes, NR Flores, E Belkin, M Kougias, P Armstrong, DG Mills, JL AF Barshes, Neal R. Flores, Everardo Belkin, Michael Kougias, Panos Armstrong, David G. Mills, Joseph L., Sr. TI The accuracy and cost-effectiveness of strategies used to identify peripheral artery disease among patients with diabetic foot ulcers SO JOURNAL OF VASCULAR SURGERY LA English DT Article ID CRITICAL LIMB ISCHEMIA; ANKLE-BRACHIAL INDEX; SKIN PERFUSION-PRESSURE; INTERNATIONAL-WORKING-GROUP; TOE BLOOD-PRESSURE; OCCLUSIVE DISEASE; PHYSICAL-EXAMINATION; DIAGNOSTIC UTILITY; VASCULAR-DISEASE; MANAGEMENT AB Background: Patients with diabetic foot ulcers (DFUs) should be evaluated for peripheral artery disease (PAD). We sought to estimate the overall diagnostic accuracy for various strategies that are used to identify PAD in this population. Methods: A Markov model with probabilistic and deterministic sensitivity analyses was used to simulate the clinical events in a population of 10,000 patients with diabetes. One of 14 different diagnostic strategies was applied to those who developed DFUs. Baseline data on diagnostic accuracy of individual noninvasive tests were based on a meta-analysis of previously reported studies. The overall sensitivity and cost-effectiveness of the 14 strategies were then compared. Results: The overall sensitivity of various combinations of diagnostic testing strategies ranged from 32.6% to 92.6%. Cost-effective strategies included ankle-brachial indices for all patients; skin perfusion pressures (SPPs) or toebrachial indices (TBIs) for all patients; and SPPs or TBIs to corroborate normal pulse examination findings, a strategy that lowered leg amputation rates by 36%. Strategies that used noninvasive vascular testing to investigate only abnormal pulse examination results had low overall diagnostic sensitivity and were weakly dominated in cost-effectiveness evaluations. Population prevalence of PAD did not alter strategy ordering by diagnostic accuracy or cost-effectiveness. Conclusions: TBIs or SPPs used uniformly or to corroborate a normal pulse examination finding are among the most sensitive and cost-effective strategies to improve the identification of PAD among patients presenting with DFUs. These strategies may significantly reduce leg amputation rates with only modest increases in cost. C1 [Barshes, Neal R.; Kougias, Panos; Mills, Joseph L., Sr.] Baylor Coll Med, Michael E DeBakey Dept Surg, Div Vasc Surg & Endovasc Therapy, Houston, TX 77030 USA. [Flores, Everardo] Texas Tech Univ Hlth Sci Ctr, Paul L Foster Sch Med, El Paso, TX USA. [Belkin, Michael] Brigham & Womens Hosp, Dept Surg, Div Vasc & Endovasc Surg, 75 Francis St, Boston, MA 02115 USA. [Armstrong, David G.] Univ Arizona, Coll Med, Dept Surg, SALSA, Tucson, AZ USA. RP Barshes, NR (reprint author), Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Michael E DeBakey Dept Surg, Div Vasc & Endovasc Surg,Surg, 2002 Holcombe Blvd,OCL 112, Houston, TX 77030 USA. EM nbarshes@bcm.tmc.edu OI Mills, Joseph/0000-0002-4955-4384 NR 53 TC 0 Z9 0 U1 3 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD DEC PY 2016 VL 64 IS 6 BP 1682 EP + DI 10.1016/j.jvs.2016.04.056 PG 12 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA EF0VI UT WOS:000390044000021 PM 27575813 ER PT J AU Corey, MR Ergul, EA Cambria, RP Patel, VI Lancaster, RT Kwolek, CJ Conrad, MF AF Corey, Michael R. Ergul, Emel A. Cambria, Richard P. Patel, Virendra I. Lancaster, R. Todd Kwolek, Christopher J. Conrad, Mark F. TI The presentation and management of aneurysms of the pancreaticoduodenal arcade SO JOURNAL OF VASCULAR SURGERY LA English DT Article ID VISCERAL ARTERY ANEURYSMS; ASSOCIATION; PSEUDOANEURYSMS; OCCLUSION; OUTCOMES; STENOSIS AB Objective: Gastroduodenal artery aneurysms (GDAAs) and pancreaticoduodenal artery aneurysms (PDAAs) are uncommon lesions associated, however, with a significant risk of rupture. This study describes the clinical presentation, associated imaging findings, and operative strategies for these aneurysms. Methods: The records of all patients with GDAAs or PDAAs identified through an institutional database by axial imaging between 1994 and 2014 were retrospectively reviewed. Data on presenting symptoms, comorbid conditions, imaging findings, and outcomes after operative intervention were collected and examined. Results: We identified 11 GDAAs and 25 PDAAs in 35 patients. Mean size of the GDAAs was 31.1mm(range, 10-60 mm) and mean size of the PDAAs was 19.1 mm (range, 10-48 mm). At presentation, 13 aneurysms (36%) were symptomatic and seven aneurysms (19.4%) were ruptured. Median size of ruptured aneurysms was 20 mm (range, 10-60 mm). On axial imaging, 24 aneurysms (67%) were associated with a severe stenosis or occlusion of the celiac axis origin, and 11 aneurysms (31%) were thought to be associated with compression of the celiac axis in the setting of median arcuate ligament syndrome. Twenty-four aneurysms (67%) underwent repair. Of these aneurysms, 18 (75%) were successfully managed with primary endovascular repair (coil embolization with or without celiac stent), whereas endovascular therapy failed in two (8%) and required open repair. Four aneurysms (17%) were treated with primary open repair. Overall 30-day morbidity and mortality after aneurysm repair were 29% and 4%, respectively. Conclusions: GDAAs and PDAAs are uncommon lesions that are often associated with a celiac axis stenosis/occlusion leading to altered hemodynamics in the pancreaticoduodenal arcade. These aneurysms are prone to rupture regardless of size, and intervention is accordingly recommended for all aneurysms upon recognition. Despite the concordant celiac axis obstruction and concern for maintenance of hepatic circulation, endovascular repair of these aneurysms is generally successful and should be considered as the initial operative approach. C1 [Corey, Michael R.; Ergul, Emel A.; Cambria, Richard P.; Patel, Virendra I.; Lancaster, R. Todd; Kwolek, Christopher J.; Conrad, Mark F.] Massachusetts Gen Hosp, Dept Surg, Div Vasc & Endovasc Surg, Boston, MA 02114 USA. RP Conrad, MF (reprint author), 15 Parkman St,WACC 440, Boston, MA 02114 USA. EM mconrad@partners.org NR 18 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 DEC PY 2016 VL 64 IS 6 BP 1734 EP 1740 DI 10.1016/j.jvs.2016.05.067 PG 7 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA EF0VI UT WOS:000390044000029 PM 27871496 ER PT J AU Lievens, S Van der Heyden, J Masschaele, D De Ceuninck, L Petta, I Gupta, S De Puysseleyr, V Vauthier, V Lemmens, I De Clercq, DJH Defever, D Vanderroost, N De Smet, AS Eyckerman, S Van Calenbergh, S Martens, L De Bosscher, K Libert, C Hill, DE Vidal, M Tavernier, J AF Lievens, Sam Van der Heyden, Jose Masschaele, Delphine De Ceuninck, Leentje Petta, Ioanna Gupta, Surya De Puysseleyr, Veronic Vauthier, Virginie Lemmens, Irma De Clercq, Dries J. H. Defever, Dieter Vanderroost, Nele De Smet, Anne-Sophie Eyckerman, Sven Van Calenbergh, Serge Martens, Lennart De Bosscher, Karolien Libert, Claude Hill, David E. Vidal, Marc Tavernier, Jan TI Proteome-scale Binary Interactomics in Human Cells SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Article ID SMALL-MOLECULE; GLUCOCORTICOID-RECEPTOR; INTERACTION NETWORK; MAMMALIAN-CELLS; TARGET; DEGRADATION; EXPRESSION; TAMOXIFEN; REVERSINE; COMPLEX AB Because proteins are the main mediators of most cellular processes they are also prime therapeutic targets. Identifying physical links among proteins and between drugs and their protein targets is essential in order to understand the mechanisms through which both proteins themselves and the molecules they are targeted with act. Thus, there is a strong need for sensitive methods that enable mapping out these biomolecular interactions. Here we present a robust and sensitive approach to screen proteome-scale collections of proteins for binding to proteins or small molecules using the well validated MAPPIT (Mammalian Protein-Protein Interaction Trap) and MASPIT (Mammalian Small Molecule-Protein Interaction Trap) assays. Using high-density reverse transfected cell microarrays, a close to proteome-wide collection of human ORF clones can be screened for interactors at high throughput. The versatility of the platform is demonstrated through several examples. With MAPPIT, we screened a 15k ORF library for binding partners of RNF41, an E3 ubiquitin protein ligase implicated in receptor sorting, identifying known and novel interacting proteins. The potential related to the fact that MAPPIT operates in living human cells is illustrated in a screen where the protein collection is scanned for interactions with the glucocorticoid receptor (GR) in its unliganded versus dexamethasone-induced activated state. Several proteins were identified the interaction of which is modulated upon ligand binding to the GR, including a number of previously reported GR interactors. Finally, the screening technology also enables detecting small molecule target proteins, which in many drug discovery programs represents an important hurdle. We show the efficiency of MASPIT-based target profiling through screening with tamoxifen, a first-line breast cancer drug, and reversine, an investigational drug with interesting dedifferentiation and antitumor activity. In both cases, cell microarray screens yielded known and new potential drug targets highlighting the utility of the technology beyond fundamental biology. C1 [Lievens, Sam; Van der Heyden, Jose; Masschaele, Delphine; De Ceuninck, Leentje; Petta, Ioanna; Gupta, Surya; De Puysseleyr, Veronic; Vauthier, Virginie; Lemmens, Irma; Defever, Dieter; Vanderroost, Nele; De Smet, Anne-Sophie; Eyckerman, Sven; Martens, Lennart; De Bosscher, Karolien; Tavernier, Jan] VIB, Ctr Med Biotechnol, Ghent, Belgium. [Lievens, Sam; Van der Heyden, Jose; Masschaele, Delphine; De Ceuninck, Leentje; Petta, Ioanna; Gupta, Surya; De Puysseleyr, Veronic; Vauthier, Virginie; Lemmens, Irma; Defever, Dieter; Vanderroost, Nele; De Smet, Anne-Sophie; Eyckerman, Sven; Martens, Lennart; De Bosscher, Karolien; Tavernier, Jan] Univ Ghent, Dept Biochem, Ghent, Belgium. [De Clercq, Dries J. H.; Van Calenbergh, Serge] Univ Ghent, Med Chem Lab, Ghent, Belgium. [Petta, Ioanna; Libert, Claude] VIB, Inflammat Res Ctr, Ghent, Belgium. [Petta, Ioanna; Libert, Claude] Univ Ghent, Dept Biomed Mol Biol, Ghent, Belgium. [Hill, David E.; Vidal, Marc] Dana Farber Canc Inst, CCSB, Boston, MA 02115 USA. [Hill, David E.; Vidal, Marc] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Hill, David E.; Vidal, Marc] Harvard Med Sch, Dept Genet, Boston, MA USA. [Lievens, Sam] Orionis Biosci, Ghent, Belgium. [Vauthier, Virginie] UPMC, Sorbonne Univ, INSERM, Ctr Rech St Antoine, Paris, France. [De Clercq, Dries J. H.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [De Clercq, Dries J. H.] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA USA. RP Tavernier, J (reprint author), Univ Ghent VIB, Albert Baertsoenkaai 3, B-9000 Ghent, Belgium. EM jan.tavernier@vib-ugent.be FU Belgian government (Interuniversity Attraction Poles Project) [P6/36]; Fund for Scientific Research - Flanders (FWO-V Project) [G.0864.10]; NIH [U01 HG001715]; ERC [340941] FX This work was supported by grants from the Belgian government (Interuniversity Attraction Poles Project P6/36), the Fund for Scientific Research - Flanders (FWO-V Project G.0864.10) and the NIH (U01 HG001715). J.T. is the recipient of an ERC Advanced Grant (# 340941). NR 54 TC 0 Z9 0 U1 34 U2 34 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 EI 1535-9484 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD DEC PY 2016 VL 15 IS 12 BP 3624 EP 3639 DI 10.1074/mcp.M116.061994 PG 16 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA EF5BV UT WOS:000390346600007 PM 27803151 ER PT J AU Zhang, X AF Zhang, Xi TI Instant Integrated Ultradeep Quantitative-structural Membrane Proteomics Discovered Post-translational Modification Signatures for Human Cys-loop Receptor Subunit Bias SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Article ID PROTEIN-COUPLED RECEPTOR; N-GLYCOSIDASE-F; BETA(2) ADRENERGIC-RECEPTOR; EXCHANGE-MASS-SPECTROMETRY; ASPARAGINE-LINKED GLYCANS; GABA(A) RECEPTOR; CRYSTAL-STRUCTURE; HYDROGEN/DEUTERIUM EXCHANGE; SHOTGUN PROTEOMICS; A RECEPTORS AB Neurotransmitter ligand-gated ion channels (LGICs) are widespread and pivotal in brain functions. Unveiling their structure-function mechanisms is crucial to drive drug discovery, and demands robust proteomic quantitation of expression, post-translational modifications (PTMs) and dynamic structures. Yet unbiased digestion of these modified transmembrane proteinsat high efficiency and peptide reproducibilityposes the obstacle. Targeting both enzyme-substrate contacts and PTMs for peptide formation and detection, we devised flow-and-detergent-facilitated protease and de-PTM digestions for deep sequencing (FDD) method that combined omni-compatible detergent, tandem immobilized protease/PNGase columns, and Cys-selective reduction/alkylation, to achieve streamlined ultradeep peptide preparation within minutes not days, at high peptide reproducibility and low abundance-bias. FDD transformed enzyme-protein contacts into equal catalytic travel paths through enzyme-excessive columns regardless of protein abundance, removed products instantly preventing inhibition, tackled intricate structures via sequential multiple micro-digestions along the flow, and precisely controlled peptide formation by flow rate. Peptide-stage reactions reduced steric bias; low contamination deepened MS/MS scan; distinguishing disulfide from M oxidation and avoiding gain/loss artifacts unmasked protein-endogenous oxidation states. Using a recent interactome of 285-kDa human GABA type A receptor, this pilot study validated FDD platform's applicability to deep sequencing (up to 99% coverage), H/D-exchange and TMT-based structural mapping. FDD discovered novel subunit-specific PTM signatures, including unusual nontop-surface N-glycosylations, that may drive subunit biases in human Cys-loop LGIC assembly and pharmacology, by redefining subunit/ligand interfaces and connecting function domains. C1 [Zhang, Xi] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 32 Fruit St, Boston, MA 02114 USA. [Zhang, Xi] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA USA. RP Zhang, X (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 32 Fruit St, Boston, MA 02114 USA. EM xi.zhang.edu@gmail.com OI Zhang, Xi/0000-0003-2755-7901 FU National Institute of General Medical Sciences [GM 58448]; Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital FX This work was supported in part by the National Institute of General Medical Sciences (GM 58448, K.W.M.) and the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 75 TC 1 Z9 1 U1 2 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 EI 1535-9484 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD DEC PY 2016 VL 15 IS 12 BP 3665 EP 3684 DI 10.1074/mcp.M114.047514 PG 20 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA EF5BV UT WOS:000390346600010 PM 27073180 ER PT J AU Zhu, SY Li, W Liu, JZ Chen, CH Liao, Q Xu, P Xu, H Xiao, TF Cao, ZZ Peng, JY Yuan, PF Brown, M Liu, XLS Wei, WS AF Zhu, Shiyou Li, Wei Liu, Jingze Chen, Chen-Hao Liao, Qi Xu, Ping Xu, Han Xiao, Tengfei Cao, Zhongzheng Peng, Jingyu Yuan, Pengfei Brown, Myles Liu, Xiaole Shirley Wei, Wensheng TI Genome-scale deletion screening of human long non-coding RNAs using a paired-guide RNA CRISPR-Cas9 library SO NATURE BIOTECHNOLOGY LA English DT Article ID HUMAN-CELLS; FUNCTIONAL GENOMICS; CRISPR/CAS9 LIBRARY; ESSENTIAL GENES; ACTIVATION; SYSTEM; DNA; IDENTIFICATION; REPRESSION; CANCER AB CRISPR-Cas9 screens have been widely adopted to analyze coding-gene functions, but high-throughput screening of non-coding elements using this method is more challenging because indels caused by a single cut in non-coding regions are unlikely to produce a functional knockout. A high-throughput method to produce deletions of non-coding DNA is needed. We report a high throughput genomic deletion strategy to screen for functional long non-coding RNAs (IncRNAs) that is based on a lentiviral paired-guide RNA (pgRNA) library. Applying our screening method, we identified 51 IncRNAs that can positively or negatively regulate human cancer cell growth. We validated 9 of 51 IncRNA hits using CRISPR-Cas9-mediated genomic deletion, functional rescue, CRISPR activation or inhibition and gene-expression profiling. Our high-throughput pgRNA genome deletion method will enable rapid identification of functional mammalian non-coding elements. C1 [Zhu, Shiyou; Liu, Jingze; Xu, Ping; Cao, Zhongzheng; Peng, Jingyu; Yuan, Pengfei; Wei, Wensheng] Peking Univ, State Key Lab Prot & Plant Gene Res, Sch Life Sci,Biodynam Opt Imaging Ctr BIOPIC, Beijing Adv Innovat Ctr Genom,Peking Tsinghua Ctr, Beijing, Peoples R China. [Zhu, Shiyou; Liu, Jingze] Peking Univ, Peking Univ Tsinghua Univ Natl Inst Biol Sci Join, Beijing, Peoples R China. [Li, Wei; Chen, Chen-Hao; Liu, Xiaole Shirley] Harvard TH Chan Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Li, Wei; Chen, Chen-Hao; Xiao, Tengfei; Brown, Myles; Liu, Xiaole Shirley] Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02115 USA. [Liao, Qi] Ningbo Univ, Sch Med, Dept Prevent Med, Ningbo, Zhejiang, Peoples R China. [Xu, Han] Broad Inst MIT & Harvard, Cambridge Ctr, Cambridge, MA USA. [Xiao, Tengfei; Brown, Myles] Dana Farber Canc Inst, Dept Med Oncol, Div Mol & Cellular Oncol, Boston, MA USA. [Cao, Zhongzheng] Peking Univ, Acad Adv Interdisciplinary Studies, Beijing, Peoples R China. [Brown, Myles] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Brown, Myles] Harvard Med Sch, Boston, MA USA. RP Wei, WS (reprint author), Peking Univ, State Key Lab Prot & Plant Gene Res, Sch Life Sci,Biodynam Opt Imaging Ctr BIOPIC, Beijing Adv Innovat Ctr Genom,Peking Tsinghua Ctr, Beijing, Peoples R China.; Liu, XLS (reprint author), Harvard TH Chan Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA.; Liu, XLS (reprint author), Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02115 USA. EM xsliu.dfci@gmail.com; wswei@pku.edu.cn FU National Science Foundation of China [NSFC31430025, NSFC31170126, NSFC81471909]; Peking-Tsinghua Center for Life Sciences; NIH grant [U01 CA180980, R01 HG008728]; Claudia Adams Barr Award in Innovative Basic Cancer Research from the Dana-Farber Cancer Institute; Beijing Advanced Innovation Center for Genomics at Peking University FX We acknowledge the staff of the BIOPIC sequencing facility (Peking University) for their assistance, and National Center for Protein Sciences Beijing (Peking University) for help in Fluorescence Activated Cell Sorting. The project was supported by funds from the National Science Foundation of China (NSFC31430025, NSFC31170126, NSFC81471909), Beijing Advanced Innovation Center for Genomics at Peking University, and the Peking-Tsinghua Center for Life Sciences (to VV.W), the NIH grant U01 CA180980 (to X.S.L.), R01 HG008728 (to M.B. and X.S.L.), and the Claudia Adams Barr Award in Innovative Basic Cancer Research from the Dana-Farber Cancer Institute. NR 35 TC 1 Z9 1 U1 15 U2 15 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 EI 1546-1696 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD DEC PY 2016 VL 34 IS 12 BP 1279 EP 1286 DI 10.1038/nbt.3715 PG 8 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA EF2WC UT WOS:000390185300019 PM 27798563 ER PT J AU Love, MI Hogenesch, JB Irizarry, RA AF Love, Michael I. Hogenesch, John B. Irizarry, Rafael A. TI Modeling of RNA-seq fragment sequence bias reduces systematic errors in transcript abundance estimation SO NATURE BIOTECHNOLOGY LA English DT Article ID EXPRESSION; NORMALIZATION; QUANTIFICATION; GENES; READS AB We find that current computational methods for estimating transcript abundance from RNA-seq data can lead to hundreds of false-positive results. We show that these systematic errors stem largely from a failure to model fragment GC content bias. Sample-specific biases associated with fragment sequence features lead to misidentification of transcript isoforms. We introduce alpine, a method for estimating sample-specific bias-corrected transcript abundance. By incorporating fragment sequence features, alpine greatly increases the accuracy of transcript abundance estimates, enabling a fourfold reduction in the number of false positives for reported changes in expression compared with Cufflinks. Using simulated data, we also show that alpine retains the ability to discover true positives, similar to other approaches. The method is available as an R/Bioconductor package that includes data visualization tools useful for bias discovery. C1 [Love, Michael I.; Irizarry, Rafael A.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Love, Michael I.; Irizarry, Rafael A.] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Hogenesch, John B.] Univ Penn, Sch Med, Inst Translat Med & Therapeut, Dept Pharmacol, Philadelphia, PA 19104 USA. RP Irizarry, RA (reprint author), Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA.; Irizarry, RA (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. EM rafa@jimmy.harvard.edu FU NIH [5T32CA009337-35, HG005220]; National Institute of Neurological Disorders and Stroke [5R01NS054794-08]; Defense Advanced Research Projects Agency [DARPA-D12AP00025] FX The authors are grateful for helpful suggestions from Y. Benjamini, W. Huber, N. Lahens, L. Pinello, C. Meyer, R. Petro, Z. Xu, and Y. Li. M.I.L. was supported by NIH grant 5T32CA009337-35. J.B.H. was supported by NIH R01 grant HG005220, the National Institute of Neurological Disorders and Stroke (5R01NS054794-08 to J.B.H.), the Defense Advanced Research Projects Agency (DARPA-D12AP00025, to John Harer, Duke University). R.A.I. was supported by NIH R01 grant HG005220. NR 30 TC 1 Z9 1 U1 6 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 EI 1546-1696 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD DEC PY 2016 VL 34 IS 12 BP 1287 EP 1291 DI 10.1038/nbt.3682 PG 5 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA EF2WC UT WOS:000390185300020 PM 27669167 ER PT J AU Elmer, J Gianakas, JJ Rittenberger, JC Baldwin, ME Faro, J Plummer, C Shutter, LA Wassel, CL Callaway, CW Fabio, A AF Elmer, Jonathan Gianakas, John J. Rittenberger, Jon C. Baldwin, Maria E. Faro, John Plummer, Cheryl Shutter, Lori A. Wassel, Christina L. Callaway, Clifton W. Fabio, Anthony CA Pittsburge Post-Cardiac Arrest TI Group-Based Trajectory Modeling of Suppression Ratio After Cardiac Arrest SO NEUROCRITICAL CARE LA English DT Article DE Cardiac arrest; Anoxic brain injury; Quantitative electroencephalography; Suppression ratio; Prognosis ID THERAPEUTIC HYPOTHERMIA; COMATOSE SURVIVORS; BURST-SUPPRESSION; RESUSCITATION COUNCIL; EPILEPTIFORM ACTIVITY; PROSPECTIVE COHORT; BISPECTRAL INDEX; PROGNOSTIC VALUE; CONTINUOUS EEG; ELECTROENCEPHALOGRAM AB Existing studies of quantitative electroencephalography (qEEG) as a prognostic tool after cardiac arrest (CA) use methods that ignore the longitudinal pattern of qEEG data, resulting in significant information loss and precluding analysis of clinically important temporal trends. We tested the utility of group-based trajectory modeling (GBTM) for qEEG classification, focusing on the specific example of suppression ratio (SR). We included comatose CA patients hospitalized from April 2010 to October 2014, excluding CA from trauma or neurological catastrophe. We used Persyst(A (R))v12 to generate SR trends and used semi-quantitative methods to choose appropriate sampling and averaging strategies. We used GBTM to partition SR data into different trajectories and regression associate trajectories with outcome. We derived a multivariate logistic model using clinical variables without qEEG to predict survival, then added trajectories and/or non-longitudinal SR estimates, and assessed changes in model performance. Overall, 289 CA patients had ae36 h of EEG yielding 10,404 h of data (mean age 57 years, 81 % arrested out-of-hospital, 33 % shockable rhythms, 31 % overall survival, 17 % discharged to home or acute rehabilitation). We identified 4 distinct SR trajectories associated with survival (62, 26, 12, and 0 %, P < 0.0001 across groups) and CPC (35, 10, 4, and 0 %, P < 0.0001 across groups). Adding trajectories significantly improved model performance compared to adding non-longitudinal data. Longitudinal analysis of continuous qEEG data using GBTM provides more predictive information than analysis of qEEG at single time-points after CA. C1 [Elmer, Jonathan; Shutter, Lori A.] Univ Pittsburgh, Dept Crit Care Med, Pittsburgh, PA 15260 USA. [Elmer, Jonathan; Rittenberger, Jon C.; Faro, John; Callaway, Clifton W.] Univ Pittsburgh, Dept Emergency Med, Iroquois Bldg,Suite 400A,3600 Forbes Ave, Pittsburgh, PA 15213 USA. [Gianakas, John J.; Fabio, Anthony] Univ Pittsburgh, Dept Epidemiol, Epidemiol Data Ctr, Pittsburgh, PA 15261 USA. [Baldwin, Maria E.] VA Pittsburgh Healthcare Syst, Dept Neurol, Pittsburgh, PA USA. [Plummer, Cheryl] Univ Pittsburgh, Med Ctr, Div Clin Neurophysiol, Pittsburgh, PA USA. [Shutter, Lori A.] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA. [Shutter, Lori A.] Univ Pittsburgh, Dept Neurosurg, Pittsburgh, PA USA. [Wassel, Christina L.] Univ Vermont, Dept Pathol & Lab Med, Coll Med, Burlington, VT 05405 USA. RP Elmer, J (reprint author), Univ Pittsburgh, Dept Crit Care Med, Pittsburgh, PA 15260 USA.; Elmer, J (reprint author), Univ Pittsburgh, Dept Emergency Med, Iroquois Bldg,Suite 400A,3600 Forbes Ave, Pittsburgh, PA 15213 USA. EM elmerjp@upmc.edu FU NIH [5K12HL109068] FX Dr. Elmer's research time was supported by NIH Grant 5K12HL109068. NR 35 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 DEC PY 2016 VL 25 IS 3 BP 415 EP 423 DI 10.1007/s12028-016-0263-9 PG 9 WC Critical Care Medicine; Clinical Neurology SC General & Internal Medicine; Neurosciences & Neurology GA EE9ZI UT WOS:000389984600011 PM 27033709 ER PT J AU Bick, S Izzy, S Rubin, D Zafar, S Rosenthal, E Eskandar, E AF Bick, Sarah K. B. Izzy, Saef Rubin, Daniel B. Zafar, Sahar F. Rosenthal, Eric S. Eskandar, Emad N. TI Anterior Temporal Lobectomy for Refractory Status Epilepticus in Herpes Simplex Encephalitis SO NEUROCRITICAL CARE LA English DT Article DE HSV encephalitis; Status epilepticus; Temporal lobectomy; Epilepsy ID NEUROSURGICAL TREATMENT; DECOMPRESSIVE CRANIECTOMY; PROGNOSIS; SURGERY AB Herpes simplex virus (HSV) is a common cause of viral encephalitis that can lead to refractory seizures. The primary treatment of HSV encephalitis is with acyclovir; however, surgery sometimes plays a role in obtaining tissue diagnosis or decompression in cases with severe mass effect. We report a unique case in which anterior temporal lobectomy was successfully used to treat refractory status epilepticus in HSV encephalitis. Case report and review of the literature. We report a case of a 60-year-old man with HSV encephalitis, who presented with seizures originating from the right temporal lobe refractory to maximal medical management. Right anterior temporal lobectomy was performed for the purpose of treatment of refractory status epilepticus and obtaining tissue diagnosis, with ultimate resolution of seizures and excellent functional outcome. We suggest that anterior temporal lobectomy should be considered in cases of HSV encephalitis with refractory status epilepticus with clear unilateral origin. C1 [Bick, Sarah K. B.; Eskandar, Emad N.] Massachusetts Gen Hosp, Dept Neurosurg, Wang 021,55 Fruit St, Boston, MA 02114 USA. [Izzy, Saef; Rubin, Daniel B.; Zafar, Sahar F.; Rosenthal, Eric S.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Bick, S (reprint author), Massachusetts Gen Hosp, Dept Neurosurg, Wang 021,55 Fruit St, Boston, MA 02114 USA. EM sbick@partners.org FU SAGE Therapeutics; Andrew David Heitman Neuroendovascular Research Foundation; NIBIB [5U54EB007954-04]; NINDS [5U10NS080369-02]; US Army Medical Research and Materiel Command [W81XWH-08-2-0154]; US Army Research Office; Defense Advanced Research Projects Agency [W911NF-14-2-0045]; Medtronic; Cyberonics FX Dr. Rosenthal receives research support from an institutional contract with SAGE Therapeutics and grant funding from the Andrew David Heitman Neuroendovascular Research Foundation, NIBIB (5U54EB007954-04), NINDS (5U10NS080369-02), and the US Army Medical Research and Materiel Command (W81XWH-08-2-0154). Dr. Eskandar receives grant funding from the US Army Research Office and Defense Advanced Research Projects Agency (W911NF-14-2-0045) and has received research funding from and served on advisory panels for Medtronic and Cyberonics. All other authors report no conflicts of interest. NR 25 TC 0 Z9 0 U1 1 U2 1 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 DEC PY 2016 VL 25 IS 3 BP 458 EP 463 DI 10.1007/s12028-016-0302-6 PG 6 WC Critical Care Medicine; Clinical Neurology SC General & Internal Medicine; Neurosciences & Neurology GA EE9ZI UT WOS:000389984600017 PM 27473208 ER PT J AU Barker, FG Fahlbusch, R Schwartz, TH Wisoff, JH AF Barker, Fred G., II Fahlbusch, Rudolf Schwartz, Theodore H. Wisoff, Jeffrey H. TI Craniopharyngioma: current and emerging treatment modalities SO NEUROSURGICAL FOCUS LA English DT Editorial Material C1 [Barker, Fred G., II] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Fahlbusch, Rudolf] Int Neurosci Inst, Dept Neurosurg, Hannover, Germany. [Schwartz, Theodore H.] Weill Cornell Med Ctr, NewYork Presbyterian, Dept Neurosurg Otolaryngol & Neurosci, New York, NY USA. [Wisoff, Jeffrey H.] NYU Langone Med Ctr, Div Pediat Neurosurg, Dept Neurosurg, New York, NY USA. RP Barker, FG (reprint author), Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 1092-0684 J9 NEUROSURG FOCUS JI Neurosurg. Focus PD DEC PY 2016 VL 41 IS 6 AR E1 DI 10.3171/2016.9.FOCUS16405 PG 1 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA EF1OE UT WOS:000390093400001 PM 27903127 ER PT J AU Martinez-Gutierrez, JC D'Andrea, MR Cahill, DP Santagata, S Barker, FG Brastianos, PK AF Martinez-Gutierrez, Juan Carlos D'Andrea, Megan R. Cahill, Daniel P. Santagata, Sandro Barker, Fred G., II Brastianos, Priscilla K. TI Diagnosis and management of craniopharyngiomas in the era of genomics and targeted therapy SO NEUROSURGICAL FOCUS LA English DT Article DE craniopharyngioma; genomics; BRAF V600E; targeted therapy ID HAIRY-CELL LEUKEMIA; BRAF V600E MUTATION; PAPILLARY CRANIOPHARYNGIOMA; BETA-CATENIN; ADAMANTINOMATOUS CRANIOPHARYNGIOMA; RAPID RESPONSE; GENE-MUTATIONS; SELLAR REGION; VE1 ANTIBODY; CLEFT CYSTS AB Craniopharyngiomas are rare intracranial neoplasms that pose clinical challenges due to their location adjacent to vital structures. The authors have previously shown high mutation rates of BRAF V600E in papillary craniopharyngioma and of CTNNB1 in adamantinomatous craniopharyngioma. These activating driver mutations are potential therapeutic targets, and the authors have recently reported a significant response to BRAF/MEK inhibition in a patient with multiply recurrent PCP. As these targetable mutations warrant prospective research, the authors will be conducting a national National Cancer Institute-sponsored multicenter clinical trial to investigate BRAF/MEK inhibition in the treatment of craniopharyngioma. In this new era of genomic discovery, the treatment paradigm of craniopharyngioma is likely to change. C1 [Martinez-Gutierrez, Juan Carlos; D'Andrea, Megan R.; Brastianos, Priscilla K.] Massachusetts Gen Hosp, Dept Med, Div Hematol & Oncol, Boston, MA 02114 USA. [Martinez-Gutierrez, Juan Carlos; D'Andrea, Megan R.; Brastianos, Priscilla K.] Massachusetts Gen Hosp, Dept Neurol, Div Neurooncol, Boston, MA 02114 USA. [Cahill, Daniel P.; Barker, Fred G., II] Massachusetts Gen Hosp, Dept Neurol Surg, Boston, MA 02114 USA. [Santagata, Sandro] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Martinez-Gutierrez, Juan Carlos] North Shore Med Ctr, Salem, MA USA. RP Brastianos, PK (reprint author), Massachusetts Gen Hosp, Dept Med, 55 Fruit St,YAW 9E, Boston, MA 02114 USA.; Brastianos, PK (reprint author), Harvard Med Sch, 55 Fruit St,YAW 9E, Boston, MA 02114 USA. EM pbrastianos@partners.org NR 43 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 1092-0684 J9 NEUROSURG FOCUS JI Neurosurg. Focus PD DEC PY 2016 VL 41 IS 6 AR E2 DI 10.3171/2016.9.FOCUS16325 PG 6 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA EF1OE UT WOS:000390093400002 PM 27903124 ER PT J AU Moore, DT Rosenheck, RA AF Moore, David Thomas Rosenheck, Robert A. TI Factors Affecting Emergency Department Use by a Chronically Homeless Population SO PSYCHIATRIC SERVICES LA English DT Article ID NEW-YORK-CITY; MENTAL-HEALTH-SERVICES; RISK-FACTORS; RANDOMIZED-TRIAL; FREQUENT USERS; MEDICAL-CARE; ADULTS; VETERANS; ILLNESS; PREDICTORS AB Objective: Homeless adults make extensive use of emergency department (ED) services. This study examined factors associated with moderate and high ED use in a cohort of chronically homeless individuals. Methods: A cross-sectional analysis identified factors related to ED use in a cohort of 755 individuals at 11 sites at entry into the Collaborative Initiative to Help End Chronic Homelessness (CICH). Bivariate analyses identified sociodemographic, housing status, health status, and servicerelated factors associated with moderate and high ED use. Independent risk factors were then identified by using a multivariate multinomial model. Hierarchical regression was used to compare the strengths of association between ED use and blocks of factors composed of sociodemographic, housing, health, and service-related characteristics. Results: In a three-month period, 30% of participants visited the ED one or two times (moderate ED use) and 12% visited three or more times (high-ED use). ED use was most strongly associated with poor health and utilization of other non-ED services and to a lesser extent with housing status. Conclusions: Increased ED utilization was associated with both general medical and psychiatric morbidity and greater use of non-ED services. Thus ED use was related to high need and acuity and was not ameliorated by use of other services. Housing instability and homelessness contributed less robustly to increased ED use. More coordinated services may better address the complex medical, housing, and psychosocial needs of chronically homeless individuals. C1 [Moore, David Thomas; Rosenheck, Robert A.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06520 USA. [Rosenheck, Robert A.] US Dept Vet Affairs, New England Mental Illness Res Educ & Clin Ctr, West Haven, CT USA. RP Moore, DT (reprint author), Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06520 USA. EM david.moore@yale.edu FU Office of Research and Development, Veterans Health Administration; National Institute of Mental Health [5T32MH062994-13]; U.S. Department of Housing and Urban Development; U.S. Department of Health and Human Services; Department of Veterans Affairs FX The Collaborative Initiative to Help End Chronic Homelessness Funder's Group, representing the U.S. Department of Housing and Urban Development, the U.S. Department of Health and Human Services, and the Department of Veterans Affairs, provided support and guidance to this evaluation. This material is also based on work supported by the Office of Research and Development, Veterans Health Administration. Further financial support was provided by training grant 5T32MH062994-13 from the National Institute of Mental Health. The views presented here are those of the authors and do not represent the position of any federal agency or of the United States government. NR 44 TC 0 Z9 0 U1 6 U2 6 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 1075-2730 EI 1557-9700 J9 PSYCHIAT SERV JI Psychiatr. Serv. PD DEC 1 PY 2016 VL 67 IS 12 BP 1340 EP 1347 DI 10.1176/appi.ps.201500526 PG 8 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA EF1ZE UT WOS:000390122900015 PM 27417899 ER PT J AU Al-Mozaini, MA Mansour, MK AF Al-Mozaini, Maha A. Mansour, Michael K. TI Personalized medicine Is it time for infectious diseases? SO SAUDI MEDICAL JOURNAL LA English DT Editorial Material C1 [Al-Mozaini, Maha A.; Mansour, Michael K.] King Faisal Specialized Hosp & Res Ctr, Immunocompromised Host Res Sect, Dept Infect & Immun, Riyadh, Saudi Arabia. [Mansour, Michael K.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Div Infect Dis, Boston, MA USA. RP Mansour, MK (reprint author), Harvard Med Sch, Div Infect Dis, Massachusetts Gen Hosp, Med, Boston, MA 02115 USA. EM mkmansour@mgh.harvard.edu FU NIAID NIH HHS [K08 AI110655] NR 5 TC 0 Z9 0 U1 0 U2 0 PU SAUDI MED J PI RIYADH PA ARMED FORCES HOSPITAL, PO BOX 7897,, RIYADH 11159, SAUDI ARABIA SN 0379-5284 J9 SAUDI MED J JI Saudi Med. J. PD DEC PY 2016 VL 37 IS 12 BP 1309 EP 1311 DI 10.15537/smj.2016.12.16837 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA EF3MH UT WOS:000390228000001 PM 27874145 ER PT J AU Yildirim, M Quinn, KP Kobler, JB Zeitels, SM Georgakoudi, I Ben-Yakar, A AF Yildirim, Murat Quinn, Kyle P. Kobler, James B. Zeitels, Steven M. Georgakoudi, Irene Ben-Yakar, Adela TI Quantitative differentiation of normal and scarred tissues using second-harmonic generation microscopy SO SCANNING LA English DT Article DE hamster cheek pouch; vocal fold scarring; collagen fiber alignment; collagen fiber density; second-harmonic generation microscopy; scar remodeling; image analysis; Fourier transform; ultrafast fiber lasers ID FEMTOSECOND LASER MICROSURGERY; HAMSTER-CHEEK POUCH; VOICE DISORDERS; VOCAL FOLDS; HISTOLOGIC CHARACTERIZATION; MULTIPHOTON MICROSCOPY; COLLAGEN ORGANIZATION; MODEL; PREVALENCE; CARCINOGENESIS AB The aim of this study was to differentiate normal and scarred hamster cheek pouch samples by applying a quantitative image analysis technique for determining collagen fiber direction and density in second-harmonic generation microscopy images. This paper presents a collagen tissue analysis of scarred cheek pouches of four adult male Golden Syrian hamsters as an animal model for vocal fold scarring. One cheek pouch was scarred using an electrocautery unit and the other cheek was used as a control for each hamster. A home-built upright microscope and a compact ultrafast fiber laser were used to acquire depth resolved epi-collected second-harmonic generation images of collagen fibers. To quantify the average fiber direction and fiber density in each image, we applied two-dimensional Fourier analysis and intensity thresholding at five different locations for each control and scarred tissue sample, respectively. The resultant depth-resolved average fiber direction variance for scarred hamster cheek pouches (0.61 +/- 0.03) was significantly lower (p<0.05) than control tissue (0.73 +/- 0.04), indicating increased fiber alignment within the scar. Depth-resolved average voxel density measurements indicated scarred tissues contained greater (p<0.005) fiber density (0.72 +/- 0.09) compared to controls (0.18 +/- 0.03). In the present study, image analysis of both fiber alignment and density from depth-resolved second-harmonic generation images in epi-detection mode enabled the quantification of the increased collagen fiber deposition and alignment typically observed in fibrosis. The epi-detection geometry is the only viable method for in vivo imaging as well as imaging thick turbid tissues. These quantitative endpoints, clearly differentiating between control and scarred hamster cheek pouches, provide an objective means to characterize the extent of vocal fold scarring in vivo in preclinical and clinical research. In particular, this non-invasive method offers advantages for monitoring scar treatments in live animals and following the effects of scarring-related treatments such as application of steroids or drugs targeting pathways involved in fibrosis. SCANNING 38:684-693, 2016. (c) 2016 Wiley Periodicals, Inc. C1 [Yildirim, Murat; Ben-Yakar, Adela] Univ Texas Austin, Dept Mech Engn, 204 East Dean Keeton St,ETC Bldg, Austin, TX 78712 USA. [Quinn, Kyle P.; Georgakoudi, Irene] Tufts Univ, Dept Biomed Engn, Medford, MA 02155 USA. [Quinn, Kyle P.] Univ Arkansas, Dept Biomed Engn, Fayetteville, AR 72701 USA. [Kobler, James B.; Zeitels, Steven M.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Laryngeal Surg & Voice Rehabil, Dept Surg, Boston, MA USA. [Ben-Yakar, Adela] Univ Texas Austin, Dept Biomed Engn, Austin, TX 78712 USA. RP Ben-Yakar, A (reprint author), Univ Texas Austin, Dept Mech Engn, 204 East Dean Keeton St,ETC Bldg, Austin, TX 78712 USA. EM ben-yakar@mail.utexas.edu FU National Science Foundation [IDR: CBET-1014953, CBET-0846868]; Cancer Prevention Research Institute of Texas (CPRIT) [RP130412]; National Institutes of Health [K99EB017723] FX Contract grant sponsor: National Science Foundation; Contract grant number: (IDR: CBET-1014953 and Career Award: CBET-0846868); Contract grant sponsor: Cancer Prevention Research Institute of Texas (CPRIT); Contract grant number: RP130412; Contract grant sponsor: National Institutes of Health; Contract grant number: K99EB017723. NR 64 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0161-0457 EI 1932-8745 J9 SCANNING JI Scanning PD DEC PY 2016 VL 38 IS 6 BP 684 EP 693 DI 10.1002/sca.21316 PG 10 WC Instruments & Instrumentation; Microscopy SC Instruments & Instrumentation; Microscopy GA EF4AP UT WOS:000390267000024 PM 27111090 ER PT J AU Palaganas, JC Brunette, V Winslow, B AF Palaganas, Janice C. Brunette, Veronique Winslow, Betty TI Prelicensure Simulation-Enhanced Interprofessional Education A Critical Review of the Research Literature SO SIMULATION IN HEALTHCARE-JOURNAL OF THE SOCIETY FOR SIMULATION IN HEALTHCARE LA English DT Review DE Health care simulation; Interprofessional education; Literature review ID RESPIRATORY THERAPY STUDENTS; HEALTH-PROFESSIONS EDUCATION; CLINICAL-ASSESSMENT COURSE; HUMAN PATIENT SIMULATION; MEDICAL-STUDENTS; HIGH-FIDELITY; STANDARDIZED PATIENTS; CONTACT THEORY; CARE; TEAM AB This review explores the state of prelicensure interprofessional education (IPE) using simulation-based education (SBE) by examining studies that use SBE for prelicensure IPE through a critical review of the research literature. We focus particularly on studies that included experiential SBE with reported measures and formal IPE with prelicensure participants from at least 2 health care professions. Fifty-four studies met criteria. We explore these studies, providing a compilation of information (e.g., educational, simulation, and research methods used; outcome measures reported; and demographics of learner groups), identifying themes that may affect learning, as well as surfacing challenges and gaps in the field. The quality and rigor of the existing literature is inadequate to confidently determine factors that affect learning through simulation-enhanced IPE. We suggest that more rigorous research criteria be included in future studies and a list of reporting items be provided, where future publications can enhance knowledge to guide best practice in simulation-enhanced IPE. C1 [Palaganas, Janice C.] Harvard Med Sch, Dept Anesthesia Crit Care & Pain Med, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Palaganas, Janice C.] Ctr Med Simulat, Boston, MA 02129 USA. [Brunette, Veronique] Univ Montreal, Sch Med, Ctr Med Simulat, Montreal, PQ, Canada. [Brunette, Veronique] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Winslow, Betty] Loma Linda Univ, Sch Nursing, Loma Linda, CA 92350 USA. RP Palaganas, JC (reprint author), Harvard Med Sch, Dept Anesthesia Crit Care & Pain Med, Massachusetts Gen Hosp, Boston, MA 02115 USA.; Palaganas, JC (reprint author), Ctr Med Simulat, Boston, MA 02129 USA. EM jpalaganas@mgh.harvard.edu NR 106 TC 0 Z9 0 U1 7 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1559-2332 EI 1559-713X J9 SIMUL HEALTHC JI Simul. Healthc. PD DEC PY 2016 VL 11 IS 6 BP 404 EP 418 DI 10.1097/SIH.0000000000000175 PG 15 WC Health Care Sciences & Services SC Health Care Sciences & Services GA EF0PQ UT WOS:000390028600005 PM 27602706 ER PT J AU Shipherd, JC Kauth, MR Matza, A AF Shipherd, Jillian C. Kauth, Michael R. Matza, Alexis TI Nationwide Interdisciplinary E-Consultation on Transgender Care in the Veterans Health Administration SO TELEMEDICINE AND E-HEALTH LA English DT Article DE distance learning; e-health; medical records; telecommunications ID GENDER MINORITY VETERANS AB Background:Veteran's Health Administration (VHA) requires the provision of quality transgender care for the relatively large number of transgender veterans using VHA services.Introduction:The Office of Patient Care Services has taken a multimethod approach to improving provider knowledge and skill for transgender veteran care. However, unique patient-specific questions can arise. Thus, VHA implemented a 3-year feasibility program to determine if nationwide interdisciplinary e-consultation can offer veteran-specific consultation to providers who treat transgender veterans in VHA.Materials and Methods:Launch of this program is described along with use to date, types of questions submitted by providers, and length of time to complete a response in the veteran's electronic medical record.Results:In 17 months, the program responded to 303 e-consults, with consultation provided on the care of 230 unique veterans. Nationwide coverage was achieved 1 year after the launch of the program. Common consult questions have been about medications, including hormones (n=125); primary care concerns (n=97); mental health evaluations (n=63); and psychotherapy (n=18). Consistent with the interdisciplinary model, multiple disciplines typically responded to each consult (x=2.27). Average time to completion of a consult was 5.9 calendar days (range=2.4-7.7 days).Discussion:VHA has established a nationwide interdisciplinary e-consultation program. Additional outreach about the program will be needed if funding is continued.Conclusions:E-consultation on transgender health within VHA is feasible and complements the suite of trainings offered within VHA. Other healthcare organizations may benefit from a similar program. C1 [Shipherd, Jillian C.; Kauth, Michael R.; Matza, Alexis] Vet Hlth Adm, Lesbian Gay Bisexual & Transgender Program, Off Patient Care Serv, Washington, DC USA. [Shipherd, Jillian C.] Natl Ctr PTSD, Womens Hlth Sci Div, Boston, MA USA. [Shipherd, Jillian C.] VA Boston Healthcare Syst, Boston, MA USA. [Shipherd, Jillian C.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Kauth, Michael R.] VA South Cent Mental Illness Res Educ & Clin Ctr, Houston, TX USA. [Kauth, Michael R.] VA HSR&D Ctr Innovat Qual Effectiveness & Safety, Houston, TX USA. [Kauth, Michael R.] Baylor Coll Med, Houston, TX 77030 USA. [Matza, Alexis] Boston VA Res Inst Inc, Boston, MA USA. RP Shipherd, JC (reprint author), VA Boston Healthcare Syst, LGBT Program VHA 116B 3, 150 South Huntington Ave, Boston, MA 02130 USA. EM jillian.shipherd@va.gov NR 14 TC 0 Z9 0 U1 4 U2 4 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 DEC PY 2016 VL 22 IS 12 BP 1008 EP 1012 DI 10.1089/tmj.2016.0013 PG 5 WC Health Care Sciences & Services SC Health Care Sciences & Services GA EF5ZB UT WOS:000390407500006 PM 27159795 ER PT J AU Durisko, C McCue, M Doyle, PJ Dickey, MW Fiez, JA AF Durisko, Corrine McCue, Michael Doyle, Patrick J. Dickey, Michael Walsh Fiez, Julie A. TI A Flexible and Integrated System for the Remote Acquisition of Neuropsychological Data in Stroke Research SO TELEMEDICINE AND E-HEALTH LA English DT Article DE behavioral health; cardiology; cardiovascular disease; telemedicine; telepsychiatry; teleneurology ID COGNITIVE REHABILITATION; TELEHEALTH DELIVERY; CAMPERDOWN PROGRAM; ISCHEMIC-STROKE; TELEREHABILITATION; DEFICITS; APHASIA; INTERNET; TRIAL; CARE AB Background:Neuropsychological testing is a central aspect of stroke research because it provides critical information about the cognitive-behavioral status of stroke survivors, as well as the diagnosis and treatment of stroke-related disorders. Standard neuropsychological methods rely upon face-to-face interactions between a patient and researcher, which creates geographic and logistical barriers that impede research progress and treatment advances.Introduction:To overcome these barriers, we created a flexible and integrated system for the remote acquisition of neuropsychological data (RAND). The system we developed has a secure architecture that permits collaborative videoconferencing. The system supports shared audiovisual feeds that can provide continuous virtual interaction between a participant and researcher throughout a testing session. Shared presentation and computing controls can be used to deliver auditory and visual test items adapted from standard face-to-face materials or execute computer-based assessments. Spoken and manual responses can be acquired, and the components of the session can be recorded for offline data analysis.Materials and Methods:To evaluate its feasibility, our RAND system was used to administer a speech-language test battery to 16 stroke survivors with a variety of communication, sensory, and motor impairments. The sessions were initiated virtually without prior face-to-face instruction in the RAND technology or test battery.Results:Neuropsychological data were successfully acquired from all participants, including those with limited technology experience, and those with a communication, sensory, or motor impairment. Furthermore, participants indicated a high level of satisfaction with the RAND system and the remote assessment that it permits.Conclusions:The results indicate the feasibility of using the RAND system for virtual home-based neuropsychological assessment without prior face-to-face contact between a participant and researcher. Because our RAND system architecture uses off-the-shelf technology and software, it can be duplicated without specialized expertise or equipment. In sum, our RAND system offers a readily available and promising alternative to face-to-face neuropsychological assessment in stroke research. C1 [Durisko, Corrine; Fiez, Julie A.] Univ Pittsburgh, Learning Res & Dev Ctr, 3939 OHara St, Pittsburgh, PA 15260 USA. [McCue, Michael] Univ Pittsburgh, Dept Rehabil Sci & Technol, Pittsburgh, PA USA. [Doyle, Patrick J.; Dickey, Michael Walsh] VA Pittsburgh Healthcare Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA USA. [Doyle, Patrick J.; Dickey, Michael Walsh; Fiez, Julie A.] Univ Pittsburgh, Dept Commun Sci & Disorders, Pittsburgh, PA USA. [Dickey, Michael Walsh; Fiez, Julie A.] Univ Pittsburgh, Dept Psychol, Pittsburgh, PA 15260 USA. [Fiez, Julie A.] Univ Pittsburgh, Ctr Neural Basis Cognit, Pittsburgh, PA USA. RP Fiez, JA (reprint author), Univ Pittsburgh, Learning Res & Dev Ctr, 3939 OHara St, Pittsburgh, PA 15260 USA. EM fiez@pitt.edu FU American Heart Association [AHA-RMT31010862]; National Institute of Deafness and Communication Disorders [NIH R21DC013568A] FX We gratefully acknowledge the support of American Heart Association (AHA-RMT31010862) and the National Institute of Deafness and Communication Disorders (NIH R21DC013568A). NR 55 TC 0 Z9 0 U1 5 U2 5 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 DEC PY 2016 VL 22 IS 12 BP 1032 EP 1040 DI 10.1089/tmj.2015.0235 PG 9 WC Health Care Sciences & Services SC Health Care Sciences & Services GA EF5ZB UT WOS:000390407500010 PM 27214198 ER PT J AU John, SF Aniemeke, E Ha, NP Chong, CR Gu, PH Zhou, JB Zhang, Y Graviss, EA Liu, JO Olaleye, OA AF John, Sarah F. Aniemeke, Emmanuel Ha, Ngan P. Chong, Curtis R. Gu, Peihua Zhou, Jiangbing Zhang, Ying Graviss, Edward A. Liu, Jun O. Olaleye, Omonike A. TI Characterization of 2-hydroxy-1-naphthaldehyde isonicotinoyl hydrazone as a novel inhibitor of methionine aminopeptidases from Mycobacterium tuberculosis SO TUBERCULOSIS LA English DT Article; Proceedings Paper CT 4th Texas Tuberculosis Research Symposium (TTRS) CY JAN 22, 2016 CL Houston Methodist Res Inst Campus, Houston, TX SP Univ Texas, Houston McGovern Med Sch, Qiagen HO Houston Methodist Res Inst Campus DE HIV; TB; Co-infection; Drug screening; Drug interactions; Drug discovery ID IRON CHELATORS; SACCHAROMYCES-CEREVISIAE; STAPHYLOCOCCUS-AUREUS; PEPTIDE DEFORMYLASE; HIV-1 TRANSCRIPTION; ESCHERICHIA-COLI; CELL-GROWTH; RESISTANT; THERAPY; ANALOGS AB Mycobacterium tuberculosis (Mtb) and the Human Immunodeficiency Virus (HIV) pose a major public health threat. The 2015 World Health Organization (WHO) report estimates that one in three HIV deaths is due to Mtb, the causative agent of Tuberculosis (TB). The lethal synergy between these two pathogens leads to a decline in the immune function of infected individuals as well as a rise in morbidity and mortality rates. The deadly interaction between TB and HIV, along with the heightened emergence of drug resistance, drug-drug interactions, reduced drug efficacy and increased drug toxicity, has made the therapeutic management of co-infected individuals a major challenge. Hence, the development of new drug targets and/or new drug leads are imperative for the effective therapeutic management of co-infected patients. Here, we report the characterization of 2-hydroxy-1-naphthaldehyde isonicotinoyl hydrazone (311), a known inhibitor of HIV-1 replication and transcription as a new inhibitor of methionine aminopeptidases (MetAPs) from Mycobacterium tuberculosis: MtMetAP1a and MtMetAP1c. MetAP is a metalloprotease that removes the N-terminal methionine during protein synthesis. The essential role of MetAP in microbes makes it a promising chemotherapeutic target. We demonstrated that 311 is a potent and selective inhibitor of MtMetAP1a and MtMetAP1c. Furthermore, we found that 311 is active against replicating and aged non-growing Mtb at low micromolar concentrations. These results suggest that 311 is a promising lead for the development of novel class of therapeutic agents with dual inhibition of TB and HIV for the treatment of TB-HIV co-infection. (C) 2016 Published by Elsevier Ltd. C1 [John, Sarah F.; Aniemeke, Emmanuel; Olaleye, Omonike A.] Texas Southern Univ, Coll Pharm & Hlth Sci, Dept Pharmaceut Sci, Houston, TX 77004 USA. [Ha, Ngan P.; Graviss, Edward A.] Methodist Hosp, Res Inst, Dept Pathol & Genom Med, 6535 Fannin, Houston, TX 77030 USA. [Chong, Curtis R.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Chong, Curtis R.] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Gu, Peihua; Zhou, Jiangbing; Zhang, Ying] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. [Liu, Jun O.] Johns Hopkins Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA. [Zhou, Jiangbing] Yale Univ, Dept Neurosurg, New Haven, CT 06510 USA. RP Liu, JO (reprint author), Johns Hopkins Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA.; Olaleye, OA (reprint author), Texas Southern Univ, Coll Pharm & Hlth Sci, GH 124, Houston, TX 77004 USA. EM joliu@jhu.edu; olaleyeoa@tsu.edu NR 49 TC 1 Z9 1 U1 0 U2 0 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1472-9792 J9 TUBERCULOSIS JI Tuberculosis PD DEC PY 2016 VL 101 SU S BP S73 EP S77 DI 10.1016/j.tube.2016.09.025 PG 5 WC Immunology; Microbiology; Respiratory System SC Immunology; Microbiology; Respiratory System GA EF5JE UT WOS:000390365700011 PM 27856197 ER PT J AU Judge, RA Zhu, HZ Upadhyay, AK Bodelle, PM Hutchins, CW Torrent, M Marin, VL Yu, WY Vedadi, M Li, FL Brown, PJ Pappano, WN Sun, CH Petros, AM AF Judge, Russell A. Zhu, Haizhong Upadhyay, Anup K. Bodelle, Pierre M. Hutchins, Charles W. Torrent, Maricel Marin, Violeta L. Yu, Wenyu Vedadi, Masoud Li, Fengling Brown, Peter J. Pappano, William N. Sun, Chaohong Petros, Andrew M. TI Turning a Substrate Peptide into a Potent Inhibitor for the Histone Methyltransferase SETD8 SO ACS MEDICINAL CHEMISTRY LETTERS LA English DT Article DE SETDS; HMT; drug design; structure-based drug design; cancer ID COMPETITIVE INHIBITOR; SELECTIVE INHIBITORS; DISCOVERY; METHYLATION; INTEGRITY; PROTEINS; PR-SET7 AB SETD8 is a histone H4-K20 methyltransferase that plays an essential role in the maintenance of genomic integrity during mitosis and in DNA damage repair, making it an intriguing target for cancer research. While some small molecule inhibitors for SETD8 have been reported, the structural binding modes for these inhibitors have not been revealed. Using the complex structure of the substrate peptide bound to SETD8 as a starting point, different natural and unnatural amino acid substitutions were tested, and a potent (K-i 50nM, IC50 0.33 mu M) and selective norleucine containing peptide inhibitor has been obtained. C1 [Judge, Russell A.; Zhu, Haizhong; Upadhyay, Anup K.; Bodelle, Pierre M.; Hutchins, Charles W.; Torrent, Maricel; Marin, Violeta L.; Pappano, William N.; Sun, Chaohong; Petros, Andrew M.] AbbVie Inc, 1 North Waukegan Rd, N Chicago, IL 60064 USA. [Yu, Wenyu; Vedadi, Masoud; Li, Fengling; Brown, Peter J.] Univ Toronto, Struct Genom Consortium, 101 Coll St, Toronto, ON M5G 1L7, Canada. [Yu, Wenyu] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Petros, AM (reprint author), AbbVie Inc, 1 North Waukegan Rd, N Chicago, IL 60064 USA. EM andrew.petros@abbvie.com FU U.S. DOE [DE-AC02-06CH11357] FX X-ray diffraction data were collected at beamline 17-ID in the facilities of the Industrial Macromolecular Crystallography Association Collaborative Access Team (IMCA-CAT) at the Advanced Photon Source. These facilities are supported by the companies of the Industrial Macromolecular Crystallography Association. Use of the Advanced Photon Source, an Office of Science User Facility operated for the U.S. Department of Energy (DOE) Office of Science by Argonne National Laboratory, was supported by the U.S. DOE under Contract No. DE-AC02-06CH11357. NR 27 TC 0 Z9 0 U1 2 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-5875 J9 ACS MED CHEM LETT JI ACS Med. Chem. Lett. PD DEC PY 2016 VL 7 IS 12 BP 1102 EP 1106 DI 10.1021/acsmedchemlett.6b00303 PG 5 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA EE5CK UT WOS:000389622100023 PM 27994746 ER PT J AU Lewis, TA Sykes, DB Law, JM Munoz, B Rustiguel, JK Nonato, MC Scadden, DT Schreiber, SL AF Lewis, Timothy A. Sykes, David B. Law, Jason M. Munoz, Benito Rustiguel, Joane K. Nonato, Maria Cristina Scadden, David T. Schreiber, Stuart L. TI Development of ML390: A Human DHODH Inhibitor That Induces Differentiation in Acute Myeloid Leukemia SO ACS MEDICINAL CHEMISTRY LETTERS LA English DT Article DE AML; DHODH; HoxA9; ML390 ID DIHYDROOROTATE DEHYDROGENASE; RANDOMIZED-TRIAL; GENES; HEMATOPOIESIS; EXPRESSION; BREQUINAR; THERAPY; BINDING; AGENTS; MODE AB Homeobox transcription factor A9 (HoxA9) is overexpressed in 70% of patients diagnosed with acute myeloid leukemia (AML), whereas only a small subset of AML patients respond to current differentiation therapies. A cell line overexpressing HoxA9 was derived from the bone marrow of a lysozyme-GFP mouse. In this fashion, GFP served as an endogenous reporter of differentiation, permitting a high-throughput phenotypic screen against the MLPCN library. Two chemical scaffolds were optimized for activity yielding compound ML390, and genetic resistance and sequencing efforts identified dihydroorotate dehydrogenase (DHODH) as the target enzyme. The DHODH inhibitor brequinar works against these leukemic cells as well. The X-ray crystal structure of ML390 bound to DHODH elucidates ML390s binding interactions. C1 [Lewis, Timothy A.; Law, Jason M.; Munoz, Benito; Schreiber, Stuart L.] Broad Inst, Ctr Sci Therapeut, Cambridge, MA 02142 USA. [Sykes, David B.; Scadden, David T.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Sykes, David B.; Scadden, David T.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Law, Jason M.; Schreiber, Stuart L.] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. [Rustiguel, Joane K.; Nonato, Maria Cristina] Univ Sao Paulo, Sch Pharmaceut Sci, BR-14040903 Sao Paulo, Brazil. [Scadden, David T.] Harvard Univ, Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Scadden, David T.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Schreiber, Stuart L.] Howard Hughes Med Inst, Cambridge, MA 02138 USA. RP Lewis, TA; Schreiber, SL (reprint author), Broad Inst, Ctr Sci Therapeut, Cambridge, MA 02142 USA.; Schreiber, SL (reprint author), Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA.; Schreiber, SL (reprint author), Howard Hughes Med Inst, Cambridge, MA 02138 USA. EM tlewis@broadinstitute.org; stuart_schreiber@harvard.edu RI Nonato, Maria/C-5659-2012; Rustiguel, Joane/B-7909-2009 OI Rustiguel, Joane/0000-0002-0900-7175 FU NIH [1R03DA032471-01]; NIH Molecular Library Program [1 U54 HG005032-1]; Bayer; American Society of Hematology; Alex's Lemonade Stand Foundation; Leukemia and Lymphoma Society; Harvard Catalyst; American Cancer Society Institutional Research Grant; Harvard Stem Cell Institute; Amelia Peabody Charitable Fund; Gerald and Darlene Jordan Chair of Medicine at Harvard University; Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2012/25075-0] FX The authors would like to thank Katrina Maxcy and Alexa Carver at the Massachusetts General Hospital for their technical assistance. The flow cytometry experiments were done with the support of the HSCI-CRM Flow Cytometry Facility. The small-molecule screen was supported by NIH 1R03DA032471-01 and the NIH Molecular Library Program (1 U54 HG005032-1 awarded to S.L.S.). Financial support was provided by Bayer. D.B.S. was supported by grants from the American Society of Hematology, Alex's Lemonade Stand Foundation, the Leukemia and Lymphoma Society, Harvard Catalyst, and The American Cancer Society Institutional Research Grant. D.T.S. was supported by the Harvard Stem Cell Institute as well as the Amelia Peabody Charitable Fund and the Gerald and Darlene Jordan Chair of Medicine at Harvard University. Structural studies were supported by Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP), grant number 2012/25075-0 (to M.C.N.). NR 21 TC 0 Z9 0 U1 3 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-5875 J9 ACS MED CHEM LETT JI ACS Med. Chem. Lett. PD DEC PY 2016 VL 7 IS 12 BP 1112 EP 1117 DI 10.1021/acsmedchemlett.6b00316 PG 6 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA EE5CK UT WOS:000389622100025 PM 27994748 ER PT J AU Xu, QL Wang, YT Xu, JW Sun, ML Tian, HQ Zuo, DY Guan, Q Bao, K Wu, YL Zhang, WG AF Xu, Qile Wang, Yueting Xu, Jingwen Sun, Maolin Tian, Haiqiu Zuo, Daiying Guan, Qi Bao, Kai Wu, Yingliang Zhang, Weige TI Synthesis and Bioevaluation of 3,6-Diaryl-[1,2,4]ltriazolo[4,3-b]Pyridazines as Antitubulin Agents SO ACS MEDICINAL CHEMISTRY LETTERS LA English DT Article DE [1,2,4]Triazolo[4,3-b]pyridazine; combretastatin A-4; tubulin; colchicine binding site; molecular modeling ID COMBRETASTATIN A-4 ANALOGS; BIOLOGICAL EVALUATION; TUBULIN INHIBITORS; ANTICANCER AGENTS; DERIVATIVES; POTENT AB A series of 3,6-diaryl-[1,2,4]triazolo[4,3-b]pyridazines were designed as a class of vinylogous CA-4 analogues. The easily isomerized (Z,E)-butadiene linker of vinylogous CA-4 was replaced by a rigid [1,2,4]triazolo[4,3-b]pyridazine scaffold. Twenty-one target compounds were synthesized and exhibited moderate to potent antiproliferative activity. The compound 4q with a 3-amino-4-methoxyphenyl moiety as the B-ring, comparable to CA-4 (IC50 = 0.009-0.012 PM), displayed the highly active antiproliferative activity against SGC-7901, AS49, and HT-1080 cell lines with IC50 values of 0.014, 0.008, and 0.012 mu M, respectively. Tubulin polymerization experiments indicated that 4q effectively inhibited tubulin polymerization, and immunostaining assay revealed that 4q significantly disrupted tubulin microtubule dynamics. Moreover, cell cycle studies revealed that compound 4q dramatically arrested cell cycle progression at G2/M phase in A549 cells. Molecular modeling studies showed that 4q could bind to the colchicine binding site on microtubules. C1 [Xu, Qile; Wang, Yueting; Sun, Maolin; Tian, Haiqiu; Guan, Qi; Bao, Kai; Zhang, Weige] Shenyang Pharmaceut Univ, Minist Educ, Key Lab Struct Based Drug Design & Discovery, 103 Wenhua Rd, Shenyang 110016, Peoples R China. [Xu, Jingwen; Zuo, Daiying; Wu, Yingliang] Shenyang Pharmaceut Univ, Dept Pharmacol, 103 Wenhua Rd, Shenyang 110016, Peoples R China. [Bao, Kai] Massachusetts Gen Hosp, Dept Radiol, Div Nucl Med & Mol Imaging, Gordon Ctr Med Imaging, Boston, MA 02214 USA. [Bao, Kai] Harvard Med Sch, Boston, MA 02214 USA. RP Zhang, WG (reprint author), Shenyang Pharmaceut Univ, Minist Educ, Key Lab Struct Based Drug Design & Discovery, 103 Wenhua Rd, Shenyang 110016, Peoples R China.; Wu, YL (reprint author), Shenyang Pharmaceut Univ, Dept Pharmacol, 103 Wenhua Rd, Shenyang 110016, Peoples R China. EM yingliang_1016@163.com; zhangweige2000@sina.com FU National Natural Science Foundation of China [81502932]; State Key Laboratory of Natural Medicines and Active Substance [GTZK201603] FX This work was funded by the National Natural Science Foundation of China (81502932) and State Key Laboratory of Natural Medicines and Active Substance (No. GTZK201603). NR 25 TC 0 Z9 0 U1 5 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-5875 J9 ACS MED CHEM LETT JI ACS Med. Chem. Lett. PD DEC PY 2016 VL 7 IS 12 BP 1202 EP 1206 DI 10.1021/acsmedchemlett.6b00252 PG 5 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA EE5CK UT WOS:000389622100041 PM 27994764 ER PT J AU Dichgans, M Wardlaw, J Smith, E Zietemann, V Seshadri, S Sachdev, P Biessels, GJ Fazekas, F Benavente, O Pantoni, L De Leeuw, F Norrving, B Matthews, P Chen, C Mok, V During, M Whiteley, W Shuler, K Alonso, A Black, SE Brayne, C Chabriat, H Cordonnier, C Doubal, F Duzel, E Ewers, M Frayne, R Hachinski, V Ikram, MA Jessen, F Jouvent, E Linn, J O'Brien, J van Oostenbrugge, R Malik, R Mazoyer, B Schmidt, R Sposato, LA Stephan, B Swartz, RH Vernooij, M Viswanathan, A Werring, D Abe, K Allan, L Arba, F Bae, HJ Bath, PMW Bordet, R Breteler, M Choi, S Deary, I DeCarli, C Ebmeier, K Feng, L Greenberg, SM Ihara, M Kalaria, R Kim, S Lim, JS Lindley, RI Mead, G Murray, A Quinn, T Ritchie, C Sacco, R Salman, RA Sprigg, N Sudlow, C Thomas, A van Boxtel, M van der Grond, J van der Lugt, A Yang, YH AF Dichgans, Martin Wardlaw, Joanna Smith, Eric Zietemann, Vera Seshadri, Sudha Sachdev, Perminder Biessels, Geert Jan Fazekas, Franz Benavente, Oscar Pantoni, Leonardo De Leeuw, Frankerik Norrving, Bo Matthews, Paul Chen, Christopher Mok, Vincent Duering, Marco Whiteley, Will Shuler, Kirsten Alonso, Alvaro Black, Sandra E. Brayne, Carol Chabriat, Hugues Cordonnier, Charlotte Doubal, Fergus Duzel, Emrah Ewers, Michael Frayne, Richard Hachinski, Vladimir Ikram, Mohammad Arfan Jessen, Frank Jouvent, Eric Linn, Jennifer O'Brien, John van Oostenbrugge, Robert Malik, Rainer Mazoyer, Bernard Schmidt, Reinhold Sposato, Luciano A. Stephan, Blossom Swartz, Richard H. Vernooij, Meike Viswanathan, Anand Werring, David Abe, Koji Allan, Louise Arba, Francesco Bae, Hee-Joon Bath, Philip M. W. Bordet, Regis Breteler, Monique Choi, Seong Deary, Ian DeCarli, Charles Ebmeier, Klaus Feng, Lei Greenberg, Steven M. Ihara, Masafumi Kalaria, Rajesh Kim, SanYun Lim, Jae-Sung Lindley, Richard I. Mead, Gillian Murray, Alison Quinn, Terry Ritchie, Craig Sacco, Ralph Salman, Rustam Al-Shahi Sprigg, Nikola Sudlow, Cathie Thomas, Alan van Boxtel, Martin van der Grond, Jeroen van der Lugt, Aad Yang, Yuan-Han CA VISTA Collaboration METACOHORTS Consortiums TI METACOHORTS for the study of vascular disease and its contribution to cognitive decline and neurodegeneration: An initiative of the Joint Programme for Neurodegenerative Disease Research SO ALZHEIMERS & DEMENTIA LA English DT Article DE Dementia; Cerebrovascular disease; Small vessel disease; Neurodegeneration; Cohorts; Survey ID WHITE-MATTER HYPERINTENSITIES; STRUCTURAL NETWORK EFFICIENCY; SMALL-VESSEL DISEASE; ALZHEIMERS-DISEASE; PARKINSONIAN SIGNS; STROKE SURVIVORS; GAIT DISORDERS; LACUNAR STROKE; DEMENTIA; IMPAIRMENT AB Dementia is a global problem and major target for health care providers. Although up to 45% of cases are primarily or partly due to cerebrovascular disease, little is known of these mechanisms or treatments because most dementia research still focuses on pure Alzheimer's disease. An improved understanding of the vascular contributions to neurodegeneration and dementia, particularly by small vessel disease, is hampered by imprecise data, including the incidence and prevalence of symptomatic and clinically "silent" cerebrovascular disease, long-term outcomes (cognitive, stroke, or functional), and risk factors. New large collaborative studies with long follow-up are expensive and time consuming, yet substantial data to advance the field are available. In an initiative funded by the Joint Programme for Neurodegenerative Disease Research, 55 international experts surveyed and assessed available data, starting with European cohorts, to promote data sharing to advance understanding of how vascular disease affects brain structure and function, optimize methods for cerebrovascular disease in neurodegeneration research, and focus future research on gaps in knowledge. Here, we summarize the results and recommendations from this initiative. We identified data from over 90 studies, including over 660,000 participants, many being additional to neurodegeneration data initiatives. The enthusiastic response means that cohorts from North America, Australasia, and the Asia Pacific Region are included, creating a truly global, collaborative, data sharing platform, linked to major national dementia initiatives. Furthermore, the revised World Health Organization International Classification of Diseases version 11 should facilitate recognition of vascular-related brain damage by creating one category for all cerebrovascular disease presentations and thus accelerate identification of targets for dementia prevention. (C) 2016 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer's Association. This is an open access article under the CC BY license C1 [Dichgans, Martin; Zietemann, Vera; Duering, Marco; Ewers, Michael; Malik, Rainer] Univ Munich, Klinik Univ Munchen, Inst Stroke & Dementia Res ISD, Munich, Germany. [Dichgans, Martin] DZNE, German Ctr Neurodegenerat Dis, Munich, Germany. [Dichgans, Martin] Munich Cluster Syst Neurol SyNergy, Munich, Germany. [Wardlaw, Joanna] Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh, Midlothian, Scotland. [Smith, Eric] Univ Calgary, Calgary, AB T2N 1N4, Canada. [Seshadri, Sudha] Boston Univ, Boston, MA 02215 USA. [Sachdev, Perminder] Univ New South Wales, Sydney, NSW 2052, Australia. [Biessels, Geert Jan] UMC, Utrecht, Netherlands. [Fazekas, Franz] Graz Univ, Graz, Austria. [Benavente, Oscar] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Pantoni, Leonardo] Azienda Ospedaliero Univ Careggi, Florence, Italy. [De Leeuw, Frankerik] Radboud Univ Nijmegen, Med Ctr, NL-6525 ED Nijmegen, Netherlands. [Norrving, Bo] Lund Univ, S-22100 Lund, Sweden. [Matthews, Paul] Imperial Coll, London, England. [Chen, Christopher] Natl Univ Singapore, Singapore 117548, Singapore. [Mok, Vincent] Chinese Univ Hong Kong, Hong Kong, Hong Kong, Peoples R China. [Whiteley, Will; Shuler, Kirsten] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Alonso, Alvaro] Univ Minnesota, Minneapolis, MN 55455 USA. [Black, Sandra E.] Univ Toronto, Sunnybrook Hlth Sci Ctr, Toronto, ON, Canada. [Brayne, Carol] Univ Cambridge, Cambridge, England. [Chabriat, Hugues; Jouvent, Eric] Univ Paris, Paris, France. [Chabriat, Hugues; Jouvent, Eric] DHU Neurovasc, UMR S 1161 INSERM, F-75205 Paris, France. [Chabriat, Hugues; Jouvent, Eric] Hop Lariboisiere, Dept Neurol, F-75475 Paris, France. [Cordonnier, Charlotte; Bordet, Regis] Univ Lille, INSERM, CHU, U1171 Degenerat & Cascular Cognit Disorders, F-59000 Lille, France. [Doubal, Fergus; Deary, Ian; Mead, Gillian; Ritchie, Craig; Salman, Rustam Al-Shahi; Sudlow, Cathie] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Duzel, Emrah] DZNE Magdeburg, Magdeburg, Germany. [Frayne, Richard] Univ Calgary, Calgary, AB T2N 1N4, Canada. [Hachinski, Vladimir] Rush Univ, Med Ctr, London, ON, Canada. [Ikram, Mohammad Arfan; Vernooij, Meike; van der Lugt, Aad] Erasmus MC, Rotterdam, Netherlands. [Jessen, Frank] Univ Cologne, Cologne, Germany. [Linn, Jennifer] Univ Hosp Dresden, Dresden, Germany. [O'Brien, John] Univ Cambridge, Cambridge, England. [van Oostenbrugge, Robert] Maastricht UMC, Maastricht, Netherlands. [Mazoyer, Bernard] Univ Bordeaux, Bordeaux, France. [Schmidt, Reinhold] Med Univ Graz, Graz, Austria. [Sposato, Luciano A.] Western Univ, London, ON, Canada. [Stephan, Blossom] Univ Newcastle, Callaghan, NSW 2308, Australia. [Swartz, Richard H.] Univ Toronto, Sunnybrook Hlth Sci Ctr, Toronto, ON, Canada. [Viswanathan, Anand; Greenberg, Steven M.] Massachusetts Gen Hosp, Boston, MA USA. [Werring, David] UCL, Neurol Inst, London, England. [Abe, Koji] Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Okayama 7008530, Japan. [Allan, Louise; Kalaria, Rajesh] Newcastle Univ, Newcastle Upon Tyne, Tyne & Wear, England. [Arba, Francesco] Univ Florence, I-50121 Florence, Italy. [Bae, Hee-Joon; Kim, SanYun] Seoul Natl Univ, Bundang Hosp, Seoul 151, South Korea. [Bath, Philip M. W.; Sprigg, Nikola] Univ Nottingham, Nottingham, England. [Breteler, Monique] German Ctr Neurodegenerat Dis DZNE, Berlin, Germany. [Choi, Seong] Inha Univ Hosp, Inchon, South Korea. [DeCarli, Charles] Univ Calif, Berkeley, CA USA. [Ebmeier, Klaus] Univ Oxford, Warneford Hosp, Oxford, England. [Feng, Lei] Natl Univ Singapore, Singapore, Singapore. [Ihara, Masafumi] Nat Cerebral & Cardiovasc Ctr, Suita, Osaka, Japan. [Lim, Jae-Sung] Hallym Univ, Sacred Heart Hosp, Dept Neurol, Anyang, South Korea. [Lindley, Richard I.] Univ Sydney, Sydney, NSW 2006, Australia. [Murray, Alison] Univ Aberdeen, Aberdeen, Scotland. [Quinn, Terry] Univ Glasgow, Glasgow, Lanark, Scotland. [Sacco, Ralph] Miami Univ, Miami, FL USA. [Thomas, Alan] Inst Neurosci, Newcastle, England. [Thomas, Alan] Newcastle Univ, Inst Ageing, Newcastle Upon Tyne, Tyne & Wear, England. [van Boxtel, Martin] Maastricht Univ, Maastricht, Netherlands. [van der Grond, Jeroen] Leiden Univ, Med Ctr, NL-2300 RA Leiden, Netherlands. [Yang, Yuan-Han] Kaohsiung Med Univ Hosp, Taipei, Taiwan. RP Wardlaw, J (reprint author), Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh, Midlothian, Scotland. EM joanna.wardlaw@ed.ac.uk RI Mok, Vincent /N-6421-2015; OI Ebmeier, Klaus/0000-0002-5190-7038 FU Joint Programme for Neurodegenerative Disease (JPND) Research; UK Medical Research Council; Deutsches Zentrum fur Neurodegenerative Erkrankungen (DZNE); Canadian Institutes of Health Research (CIHR); Scottish Funding Council; ZonMW [016.126.351]; Edmond J Safra Foundation and Lily Safra; Imperial College Health Trust BRC; Centre Grant NIH [P30 AG 010129]; EU Horizon SVDs@Target grant [666881] FX The following funders supported the work: Joint Programme for Neurodegenerative Disease (JPND) Research, specifically the UK Medical Research Council, the Deutsches Zentrum fur Neurodegenerative Erkrankungen (DZNE), and the Canadian Institutes of Health Research (CIHR). The Scottish Imaging Network, A Platform for Scientific Excellence (SINAPSE) through the Pools Engagement in Europe (PEER) funding from the Scottish Funding Council. The Therese Pei Fong Chow Research Centre for Prevention of Dementia (in memory of Donald H K Chow). The authors thank the Siemens Foundation, Munich, Germany, for providing the workshop venue and catering. F.-E.D.L. acknowledges VIDI Innovation Grant from ZonMW ref 016.126.351. P.M.M. acknowledges generous support from the Edmond J Safra Foundation and Lily Safra and the Imperial College Health Trust BRC. P.M.W.B. is Stroke Association Professor of Stroke Medicine. C.de.C. acknowledges support from Centre Grant NIH P30 AG 010129. MD, JMW, GJB, RVO acknowledge EU Horizon 2020 SVDs@Target grant agreement No 666881. NR 61 TC 0 Z9 0 U1 7 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1552-5260 EI 1552-5279 J9 ALZHEIMERS DEMENT JI Alzheimers. Dement. PD DEC PY 2016 VL 12 IS 12 BP 1235 EP 1249 DI 10.1016/j.jalz.2016.06.004 PG 15 WC Clinical Neurology SC Neurosciences & Neurology GA EE8GZ UT WOS:000389865000004 ER PT J AU Hanseeuw, BJ Schultz, AP Betensky, RA Sperling, RA Johnson, KA AF Hanseeuw, Bernard J. Schultz, Aaron P. Betensky, Rebecca A. Sperling, Reisa A. Johnson, Keith A. TI Decreased hippocampal metabolism in high-amyloid mild cognitive impairment SO ALZHEIMERS & DEMENTIA LA English DT Article DE Hippocampus; Association cortex; Metabolism; FDG-PET; Amyloid; Mild cognitive impairment; Alzheimer's disease ID ALZHEIMERS-DISEASE SPECTRUM; FDG-PET; GLUCOSE-METABOLISM; MCI; HYPOMETABOLISM; PROGRESSION; ATROPHY; BETA; PIB; BIOMARKERS AB Introduction: Hippocampal volume (HV), cortical metabolism, and thickness are decreased in mild cognitive impairment (MCI). Hippocampal metabolism (BM) studies comparing MCI and clinically normal (CN) elderly gave inconsistent results. As hippocampus is a key region in Alzheimer's disease, we hypothesized that HIVI is specifically decreased in high-amyloid MCI. Methods: Overall, 250 CN and 45 MCI underwent three-dimensional magnetic resonance imaging, fludeoxyglucose-positron emission tomography, and fluorodeoxyglucose-positron emission tomography (PET), and Pittsburgh Compound B (PiB) PET. We investigated the interaction between clinical and amyloid status on BM, HV, cortical metabolism, and thickness using linear models, covarying age, gender, and education. Analyses were conducted with and without correction for multiple comparisons and for partial volume effects. Results: Volume-adjusted HM was decreased in high-amyloid MCI but close to normal in low-amyloid MCI and in high-amyloid CN. Both MCI groups had hippocampal atrophy, although less severe in low-amyloid MCI. High-amyloid CN and high-amyloid MCI had cortical hypometabolism. Discussion: KM is decreased when both cognitive impairment and amyloid are present. (C) 2016 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved. C1 [Hanseeuw, Bernard J.; Schultz, Aaron P.; Sperling, Reisa A.; Johnson, Keith A.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02115 USA. [Hanseeuw, Bernard J.; Schultz, Aaron P.; Sperling, Reisa A.; Johnson, Keith A.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02115 USA. [Hanseeuw, Bernard J.; Schultz, Aaron P.; Sperling, Reisa A.; Johnson, Keith A.] Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Betensky, Rebecca A.] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. RP Hanseeuw, BJ (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02115 USA.; Hanseeuw, BJ (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02115 USA.; Hanseeuw, BJ (reprint author), Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. EM bhanseeuw@mgh.harvard.edu OI Hanseeuw, Bernard/0000-0002-3102-6778 FU Belgian American Education Foundation (BAEF, grant "Plateforme pour l'Education et le Talent"); Saint-Luc Foundation (grant "OEuvre du Calvaire-Malte"); Belgian Neurological Society (BNS, RFYI); National Institutes of Health/National Institute on Aging [R01 AG046396, P01 AG036694, P50 AG00513421]; Harvard NeuroDiscovery Center; Fidelity Biosciences; Alzheimer's Association FX B.J.H. received support from the Belgian American Education Foundation (BAEF, grant "Plateforme pour l'Education et le Talent"), the Saint-Luc Foundation (grant "OEuvre du Calvaire-Malte"), and the Belgian Neurological Society (BNS, RFYI 2013). R.A.S. and K.A.J. have received support from National Institutes of Health/National Institute on Aging (R01 AG046396, P01 AG036694, and P50 AG00513421), Fidelity Biosciences, Harvard NeuroDiscovery Center, and the Alzheimer's Association. R.A.B. received support from National Institutes of Health/National Institute on Aging (P01 AG036694, P50 AG00513421) and the Harvard NeuroDiscovery Center. NR 42 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 1552-5260 EI 1552-5279 J9 ALZHEIMERS DEMENT JI Alzheimers. Dement. PD DEC PY 2016 VL 12 IS 12 BP 1288 EP 1296 DI 10.1016/j.jalz.2016.06.2357 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA EE8GZ UT WOS:000389865000008 PM 27421609 ER PT J AU Abaluck, J Agha, L Kabrhel, C Raja, A Venkatesh, A AF Abaluck, Jason Agha, Leila Kabrhel, Chris Raja, Ali Venkatesh, Arjun TI The Determinants of Productivity in Medical Testing: Intensity and Allocation of Care SO AMERICAN ECONOMIC REVIEW LA English DT Article ID SUSPECTED PULMONARY-EMBOLISM; DEEP-VEIN THROMBOSIS; EMERGENCY-DEPARTMENT; COMPUTED-TOMOGRAPHY; CLINICAL-MODEL; CT ANGIOGRAPHY; HEALTH; RISK; MANAGEMENT AB A large body of research has investigated whether physicians overuse care. There is less evidence on whether, fora fixed level of spending, doctors allocate resources to patients with the highest expected returns. We assess both sources of inefficiency, exploiting variation in rates of negative imaging tests for pulmonaty embolism. We document enormous across-doctor heterogeneity in testing conditional on patient population, which explains the negative relationship between physicians' testing rates and test yields. Furthermore, doctors do not target testing to the highest risk patients, reducing test yields by one-third. Our calibration suggests misallocation is more costly than overuse. C1 [Abaluck, Jason; Venkatesh, Arjun] Yale Univ, 165 Whitney Ave, New Haven, CT 06520 USA. [Abaluck, Jason; Agha, Leila] NBER, Cambridge, MA 02138 USA. [Agha, Leila] Dartmouth Coll, Dept Econ, 6016 Rockefeller Hall, Hanover, NH 03755 USA. [Kabrhel, Chris] Massachusetts Gen Hosp, Dept Emergency Med, Zero Emerson Pl,Suite 3B, Boston, MA 02114 USA. [Kabrhel, Chris; Raja, Ali] Harvard Univ, Cambridge, MA 02138 USA. [Raja, Ali] Massachusetts Gen Hosp, Zero Emerson Pl,Suite 3B, Boston, MA 02114 USA. [Venkatesh, Arjun] Yale New Haven Med Ctr, 20 York St, New Haven, CT 06504 USA. RP Abaluck, J (reprint author), Yale Univ, 165 Whitney Ave, New Haven, CT 06520 USA.; Abaluck, J (reprint author), NBER, Cambridge, MA 02138 USA. EM jason.abaluck@yale.edu; Leila.Agha@dartmouth.edu; ckabrhel@partners.org; asraja@partners.org; arjun.venkatesh@yale.edu FU NIA [T32-AG0000186] FX An earlier draft of this paper circulated under the title "Negative Tests and the Efficiency of Medical Care: What Determines Heterogeneity in Imaging Behavior?" Thanks to Brian Abaluck, Joe Altonji, Joshua Aronson, David Chan, Judy Chevalier, Michael Dickstein, David Dranove, Amy Finkelstein, Howard Forman, Jonathan Gruber, Nathan Hendren, Vivian Ho, Mitch Hoffman, Lisa Kahn, Jon Kolstad, Amanda Kowalski, Danielle Li, Costas Meghir, David Molitor, Fiona Scott-Morton, Blair Parry, Michael Powell, Constana Esteves-Sorenson, Ashley Swanson, Bob Town, and Heidi Williams as well as seminar participants at AIIEC 2012, AEA meeting 2013, Boston University, Cornell, IIEC Montreal, IIIEA 2013, the National Bureau of Economic Research, NIA Dartmouth research meeting, the National Tax Association annual meeting, Northwestern University, Stanford University, University of Houston, and Yale University. Funding for this work was provided by NIA grant T32-AG0000186 to the NBER. The authors declare that they have no relevant or material financial interests that relate to the research described in this paper. NR 33 TC 0 Z9 0 U1 6 U2 6 PU AMER ECONOMIC ASSOC PI NASHVILLE PA 2014 BROADWAY, STE 305, NASHVILLE, TN 37203 USA SN 0002-8282 EI 1944-7981 J9 AM ECON REV JI Am. Econ. Rev. PD DEC PY 2016 VL 106 IS 12 BP 3730 EP 3764 DI 10.1257/aer.20140260 PG 35 WC Economics SC Business & Economics GA EE3AS UT WOS:000389459100004 ER PT J AU Singh, V Rodriguez, AP Thakkar, B Patel, NJ Ghatak, A Badheka, AO Alfonso, CE de Marchena, E Sakhuja, R Inglessis-Azuaje, I Palacios, I Cohen, MG Elmariah, S O'Neill, WW AF Singh, Vikas Rodriguez, Alex P. Thakkar, Badal Patel, Nileshkumar J. Ghatak, Abhijit Badheka, Apurva O. Alfonso, Carlos E. de Marchena, Eduardo Sakhuja, Rahul Inglessis-Azuaje, Ignacio Palacios, Igor Cohen, Mauricio G. Elmariah, Sammy O'Neill, William W. TI Comparison of Outcomes of Transcatheter Aortic Valve Replacement Plus Percutaneous Coronary Intervention Versus Transcatheter Aortic Valve Replacement Alone in the United States SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CLINICAL-OUTCOMES; IMPLANTATION; DISEASE; MANAGEMENT; HOSPITALS; REGISTRY; TRENDS; IMPACT AB TransCatlieter aortic valve replacement (TAVR) with percutaneous coronary intervention (PCI) has emerged as a less-invasive therapeutic option for high surgical risk patients with aortic stenosis and coronary artery disease. The aim of this study was to determine the outcomes of TAVR when performed with PCI during the same hospitalization. We identified patients using the International Classification of Diseases, Ninth Revision, Clinical Modification procedure codes from the Nationwide Inpatient Sample between the years 2011 and 2013. A total of 22,344 TAVRs were performed between 2011 and 2013. Of these, 21,736 (97.3%) were performed without PCI (TAVR group) while 608 (2.7%) along with PCI (TAVR + PCI group). Among the TAVR + PCI group, 69.7% of the patients had single-vessel, 22.2% had 2-vessel, and 1.6% had 3-vessel PCI. Drug-eluting stents were more commonly used than bare-metal stents (72% vs 28%). TAVR + PCI group witnessed significantly higher rates of mortality (10.7% vs 4.6%) and complications: vascular injury requiring surgery (8.2% vs 4.2%), cardiac (25.4% vs 18.6%), respiratory (24.6% vs 16.1%), and infectious (10.7% vs 3.3%), p <0.001% for all, compared with the TAVR group. The :mean length of hospital stay and cost of hospitalization were also significantly higher in the -TAVR + PCI group. The propensity score matched analysis yielded similar results. In conclusion, performing PCI along with TAVR during the same hospital admission is associated with higher mortality, complications, and cost compared with TAVR alone. Patients would perhaps be better served by staged PCI before TAVR. (C) 2016 Published by Elsevier Inc. C1 [Singh, Vikas; Sakhuja, Rahul; Inglessis-Azuaje, Ignacio; Palacios, Igor; Elmariah, Sammy] Harvard Med Sch, Massachusetts Gen Hosp, Cardiol Div, Boston, MA 02115 USA. [Rodriguez, Alex P.; Patel, Nileshkumar J.; Alfonso, Carlos E.; de Marchena, Eduardo; Cohen, Mauricio G.] Univ Miami, Miller Sch Med, Cardiovasc Div, Miami, FL 33136 USA. [Thakkar, Badal] Cleveland Clin, Cardiovasc Div, Cleveland, OH 44106 USA. [Ghatak, Abhijit] Southwest Heart, Cardiol Dept, Las Cruces, NM USA. [Badheka, Apurva O.] Everett Clin, Cardiovasc Div, Everett, WA USA. [O'Neill, William W.] Henry Ford Hosp, Div Cardiol, Detroit, MI 48202 USA. RP Singh, V (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Cardiol Div, Boston, MA 02115 USA. EM vikas.dr.singh@gmail.com OI Cohen, Mauricio/0000-0003-2038-6070 NR 18 TC 0 Z9 0 U1 0 U2 0 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 EI 1879-1913 J9 AM J CARDIOL JI Am. J. Cardiol. PD DEC 1 PY 2016 VL 118 IS 11 BP 1698 EP 1704 DI 10.1016/j.amjcard.2016.08.048 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EE5YS UT WOS:000389686100015 PM 27665205 ER PT J AU Goldfarb, IT Naqvi, M Riley, LE AF Goldfarb, I. T. Naqvi, M. Riley, L. E. TI Initial impact of Zika exposure management in pregnancy SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 43rd Annual Meeting of the Infectious-Diseases-Society-for-Obstetrics-and-Gynecology (ISDOG) CY AUG 11-13, 2016 CL Annapolis, MD SP Infect Dis Soc Obstet & Gynecol C1 [Goldfarb, I. T.; Naqvi, M.; Riley, L. E.] 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 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2016 VL 215 IS 6 MA 19 BP 822 EP 823 PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EE3RM UT WOS:000389514400071 ER PT J AU Mitchell, C Srinivasan, S Zhan, X Wu, M Reed, S Guthrie, K LaCroix, A Fiedler, T Munch, M Liu, C Hoffman, N Blair, I Newton, K Freeman, E Joffe, H Cohen, L Fredricks, D AF Mitchell, C. Srinivasan, S. Zhan, X. Wu, M. Reed, S. Guthrie, K. LaCroix, A. Fiedler, T. Munch, M. Liu, C. Hoffman, N. Blair, I. Newton, K. Freeman, E. Joffe, H. Cohen, L. Fredricks, D. TI Associations between serum estrogen, vaginal microbiota and vaginal glycogen in postmenopausal women SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 43rd Annual Meeting of the Infectious-Diseases-Society-for-Obstetrics-and-Gynecology (ISDOG) CY AUG 11-13, 2016 CL Annapolis, MD SP Infect Dis Soc Obstet & Gynecol C1 [Mitchell, C.] Massachusetts Gen Hosp, Vincent Ctr Reprod Biol, Boston, MA 02114 USA. [Srinivasan, S.; Zhan, X.; Wu, M.; Guthrie, K.; Fiedler, T.; Munch, M.; Liu, C.; Fredricks, D.] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Reed, S.] Univ Washington, Seattle, WA 98195 USA. [LaCroix, A.] Univ Calif San Diego, San Diego, CA 92103 USA. [Hoffman, N.] Univ Penn, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA. [Hoffman, N.] Univ Penn, Dept Lab Med, Philadelphia, PA 19104 USA. [Blair, I.; Freeman, E.] Univ Penn, Philadelphia, PA 19104 USA. [Newton, K.] Grp Hlth Res Inst, Seattle, WA USA. [Joffe, H.] Brigham & Womens Hosp, Dept Psychiat, 75 Francis St, Boston, MA 02115 USA. [Cohen, L.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2016 VL 215 IS 6 MA 1 BP 827 EP 827 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EE3RM UT WOS:000389514400078 ER PT J AU Wepler, M Beloiartsev, A Buswell, MD Panigrahy, D Malhotra, R Buys, ES Radermacher, P Ichinose, F Bloch, DB Zapol, WM AF Wepler, Martin Beloiartsev, Arkadi Buswell, Mary D. Panigrahy, Dipak Malhotra, Rajeev Buys, Emmanuel S. Radermacher, Peter Ichinose, Fumito Bloch, Donald B. Zapol, Warren M. TI Soluble epoxide hydrolase deficiency or inhibition enhances murine hypoxic pulmonary vasoconstriction after lipopolysaccharide challenge SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Article DE hypoxic pulmonary vasoconstriction; endotoxemia; soluble epoxide hydrolase; knockout and inhibition; mice ID ONE-LUNG VENTILATION; EPOXYEICOSATRIENOIC ACIDS; 1,3-DISUBSTITUTED UREAS; VENTRICULAR MYOCYTES; ARTERIAL OXYGENATION; POTENT INHIBITORS; ENDOTOXEMIC MICE; ARACHIDONIC-ACID; CYTOCHROME-P450; INFLAMMATION AB Hypoxic pulmonary vasoconstriction (HPV) is the response of the pulmonary vasculature to low levels of alveolar oxygen. HPV improves systemic arterial oxygenation by matching pulmonary perfusion to ventilation during alveolar hypoxia and is impaired in lung diseases such as the acute respiratory distress syndrome (ARDS) and in experimental models of endotoxemia. Epoxyeicosatrienoic acids (EETs) are pulmonary vasoconstrictors, which are metabolized to less vasoactive dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (sEH). We hypothesized that pharmacological inhibition or a congenital deficiency of sEH in mice would reduce the metabolism of EETs and enhance HPV in mice after challenge with lipopolysaccharide (LPS). HPV was assessed 22 h after intravenous injection of LPS by measuring the percentage increase in the pulmonary vascular resistance of the left lung induced by left mainstem bronchial occlusion (LMBO). After LPS challenge, HPV was impaired in sEH(+/+), but not in sEH(-/-) mice or in sEH(+/+) mice treated acutely with a sEH inhibitor. Deficiency or pharmacological inhibition of sEH protected mice from the LPS-induced decrease in systemic arterial oxygen concentration (PaO2) during LMBO. In the lungs of sEH(-/-) mice, the LPS-induced increase in DHETs and cytokines was attenuated. Deficiency or pharmacological inhibition of sEH protects mice from LPS-induced impairment of HPV and improves the PaO2 after LMBO. After LPS challenge, lung EET degradation and cytokine expression were reduced in sEH(-/-) mice. Inhibition of sEH might prove to be an effective treatment for ventilation-perfusion mismatch in lung diseases such as ARDS. C1 [Wepler, Martin; Beloiartsev, Arkadi; Buswell, Mary D.; Buys, Emmanuel S.; Ichinose, Fumito; Bloch, Donald B.; Zapol, Warren M.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Anesthesia Ctr Crit Care Res, 55 Fruit St,Thier 503, Boston, MA 02114 USA. [Wepler, Martin; Beloiartsev, Arkadi; Buswell, Mary D.; Panigrahy, Dipak; Malhotra, Rajeev; Buys, Emmanuel S.; Ichinose, Fumito; Bloch, Donald B.; Zapol, Warren M.] Harvard Med Sch, 55 Fruit St,Thier 503, Boston, MA 02114 USA. [Panigrahy, Dipak] Beth Israel Deaconess Med Ctr, Vasc Biol Res Ctr, Boston, MA 02215 USA. [Panigrahy, Dipak] Beth Israel Deaconess Med Ctr, Dept Pathol, 330 Brookline Ave, Boston, MA 02215 USA. [Malhotra, Rajeev] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [Malhotra, Rajeev] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Bloch, Donald B.] Massachusetts Gen Hosp, Dept Med, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. [Radermacher, Peter] Univ Klin Ulm, Inst Anasthesiol Pathophysiol & Verfahrensentwick, Ulm, Germany. RP Zapol, WM (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Anesthesia Ctr Crit Care Res, 55 Fruit St,Thier 503, Boston, MA 02114 USA.; Zapol, WM (reprint author), Harvard Med Sch, 55 Fruit St,Thier 503, Boston, MA 02114 USA. EM wzapol@mgh.harvard.edu OI Malhotra, Rajeev/0000-0003-0120-4630 FU German Research Foundation [DFG WE 5471/2]; National Heart, Lung, and Blood Institute [K08HL111210]; NIH [5R01-EY022746, R01DK082971]; LeDucq Foundation; Department of Anesthesia, Critical Care and Pain Medicine at Massachusetts General Hospital FX This work was supported by funds of the German Research Foundation (DFG WE 5471/2-1) (M. Wepler), Grant K08HL111210 from the National Heart, Lung, and Blood Institute (R. Malhotra), NIH Grant 5R01-EY022746 (E. S. Buys), NIH Grant R01DK082971 and the LeDucq Foundation (D. B. Bloch), and funds of the Department of Anesthesia, Critical Care and Pain Medicine at Massachusetts General Hospital (W. M. Zapol). NR 36 TC 0 Z9 0 U1 1 U2 1 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 DEC 1 PY 2016 VL 311 IS 6 BP L1213 EP L1221 DI 10.1152/ajplung.00394.2016 PG 9 WC Physiology; Respiratory System SC Physiology; Respiratory System GA EE5JJ UT WOS:000389642700016 PM 27815261 ER PT J AU Mamuya, FA Cano-Penalver, JL Li, W Puyol, DR Puyol, MR Brown, D de Frutos, S Lu, HAJ AF Mamuya, Fahmy A. Luis Cano-Penalver, Jose Li, Wei Rodriguez Puyol, Diego Rodriguez Puyol, Manuel Brown, Dennis de Frutos, Sergio Lu, Hua Ann Jenny TI ILK and cytoskeletal architecture: an important determinant of AQP2 recycling and subsequent entry into the exocytotic pathway SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE aquaporin-2; integrin-linked kinase; kidney tubular cells; diabetes insipidus ID INTEGRIN-LINKED KINASE; RENAL EPITHELIAL-CELLS; WATER-BALANCE DISORDERS; COLLECTING DUCT; EXTRACELLULAR-MATRIX; APICAL MEMBRANE; PRINCIPAL CELLS; PROTEIN-KINASE; LLC-PK1 CELLS; AQUAPORIN 2 AB Within the past decade tremendous efforts have been made to understand the mechanism behind aquaporin-2 (AQP2) water channel trafficking and recycling, to open a path toward effective diabetes insipidus therapeutics. A recent study has shown that integrin-linked kinase (ILK) conditional-knockdown mice developed polyuria along with decreased AQP2 expression. To understand whether ILK also regulates AQP2 trafficking in kidney tubular cells, we performed in vitro analysis using LLCPK1 cells stably expressing rat AQP2 (LLC-AQP2 cells). Upon treatment of LLC-AQP2 cells with ILK inhibitor cpd22 and ILK-siRNA, we observed increased accumulation of AQP2 in the perinuclear region, without any significant increase in the rate of endocytosis. This perinuclear accumulation did not occur in cells expressing a serine-256-aspartic acid mutation that retains AQP2 in the plasma membrane. We then examined clathrin-mediated endocytosis after ILK inhibition using rhodamine-conjugated transferrin. Despite no differences in overall transferrin endocytosis, the endocytosed transferrin also accumulated in the perinuclear region where it colocalized with AQP2. These accumulated vesicles also contained the recycling endosome marker Rab11. In parallel, the usual vasopressin-induced AQP2 membrane accumulation was prevented after ILK inhibition; however, ILK inhibition did not measurably affect AQP2 phosphorylation at serine-256 or its dephosphorylation at serine-261. Instead, we found that inhibition of ILK increased F-actin polymerization. When F-actin was depolymerized with latrunculin, the perinuclear located AQP2 dispersed. We conclude that ILK is important in orchestrating dynamic cytoskeletal architecture during recycling of AQP2, which is necessary for its subsequent entry into the exocytotic pathway. C1 [Mamuya, Fahmy A.; Li, Wei; Brown, Dennis; Lu, Hua Ann Jenny] Massachusetts Gen Hosp, Dept Med, Div Nephrol, Boston, MA 02114 USA. [Mamuya, Fahmy A.; Li, Wei; Brown, Dennis; Lu, Hua Ann Jenny] Harvard Med Sch, Boston, MA 02114 USA. [Luis Cano-Penalver, Jose; Rodriguez Puyol, Manuel; de Frutos, Sergio] Univ Alcala De Henares, Physiol Unit, Dept Syst Biol, Madrid, Spain. [Luis Cano-Penalver, Jose; Rodriguez Puyol, Diego; Rodriguez Puyol, Manuel; de Frutos, Sergio] Inst Salud Carlos III, Inst Reina Sofia Invest Renal, Madrid, Spain. [Luis Cano-Penalver, Jose; Rodriguez Puyol, Diego; Rodriguez Puyol, Manuel; de Frutos, Sergio] Inst Salud Carlos III, Red Invest Renal REDinREN, Madrid, Spain. [Rodriguez Puyol, Diego] Hosp Principe Asturias, Biomed Res Fdn, Alcala De Henares, Spain. [Rodriguez Puyol, Diego] Hosp Principe Asturias, Dept Nephrol, Alcala De Henares, Spain. RP Lu, HAJ (reprint author), Massachusetts Gen Hosp, Dept Med, Div Nephrol, Boston, MA 02114 USA.; Lu, HAJ (reprint author), Harvard Med Sch, Boston, MA 02114 USA. EM Lu.Hua@mgh.harvard.edu FU Nephcure Foundation; NIH [R21 DK-092619]; ASN Gottschalk Research grant; ECOR/MGH; Boston Area Diabetes and Endocrinology Research Center [NIH DK-57521]; Center for the Study of Inflammatory Bowel Disease [NIH DK-43351]; Spanish National Program for Research, Development and Innovation; Instituto de Salud Carlos III; FEDER funds [PI/11/01630, PI/14/01939, PI/14/02075]; FEDER funds (FEDER funds ISCIII RETIC REDinREN programs) [RD06/0016/0002, RD12/0021/0006]; Spanish Ministerio de Ciencia e Innovacion [SAF 2010-16198, BES 2011-045069] FX The Nephcure Foundation, NIH Grant R21 DK-092619, an ASN Gottschalk Research grant, and ECOR/MGH provided support for this work. The Microscopy Core Facility of the Program in Membrane Biology receives additional support from the Boston Area Diabetes and Endocrinology Research Center (NIH DK-57521) and the Center for the Study of Inflammatory Bowel Disease (NIH DK-43351). Additional material support was from NIH R01 DK-096586 (D. Brown). This work was also supported by grants from the Spanish National Program for Research, Development and Innovation and cofunded by the Instituto de Salud Carlos III and FEDER funds (PI/11/01630, PI/14/01939, PI/14/02075 and FEDER funds ISCIII RETIC REDinREN programs RD06/0016/0002 and RD12/0021/0006) and the Spanish Ministerio de Ciencia e Innovacion (SAF 2010-16198). J. L. Cano-Penalver was supported by a fellowship from the Spanish Ministerio de Ciencia e Innovacion (BES 2011-045069). NR 49 TC 0 Z9 0 U1 1 U2 1 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 DEC 1 PY 2016 VL 311 IS 6 BP F1346 EP F1357 DI 10.1152/ajprenal.00336.2016 PG 12 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA EE5KW UT WOS:000389647100029 PM 27760768 ER PT J AU Brooks, BL Mannix, R Maxwell, B Zafonte, R Berkner, PD Iverson, GL AF Brooks, Brian L. Mannix, Rebekah Maxwell, Bruce Zafonte, Ross Berkner, Paul D. Iverson, Grant L. TI Multiple Past Concussions in High School Football Players: Are There Differences in Cognitive Functioning and Symptom Reporting? SO AMERICAN JOURNAL OF SPORTS MEDICINE LA English DT Article DE child; adolescent; traumatic brain injury; sports; postconcussion syndrome ID TRAUMATIC BRAIN-INJURY; POSTCONCUSSION-LIKE SYMPTOMS; PROFESSIONAL SOCCER PLAYERS; HEAD IMPACT EXPOSURE; BASE-LINE; ELECTROPHYSIOLOGICAL ABNORMALITIES; NEUROPSYCHOLOGICAL PERFORMANCE; NONCLINICAL SAMPLE; SPORT CONCUSSION; 1ST EXPOSURE AB Background: There is increasing concern about the possible long-term effects of multiple concussions, particularly on the developing adolescent brain. Whether the effect of multiple concussions is detectable in high school football players has not been well studied, although the public health implications are great in this population. Purpose: To determine if there are measureable differences in cognitive functioning or symptom reporting in high school football players with a history of multiple concussions. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Participants included 5232 male adolescent football players (mean [SD] age, 15.5 1.2 years) who completed baseline testing between 2009 and 2014. On the basis of injury history, athletes were grouped into 0 (n = 4183), 1 (n = 733), 2 (n = 216), 3 (n = 67), or 4 (n = 33) prior concussions. Cognitive functioning was measured by the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) battery, and symptom ratings were obtained from the Post-Concussion Symptom Scale. Results: There were no statistically significant differences between groups (based on the number of reported concussions) regarding cognitive functioning. Athletes with 3 prior concussions reported more symptoms than did athletes with 0 or 1 prior injury. In multivariate analyses, concussion history was independently related to symptom reporting but less so than developmental problems (eg, attention or learning problems) or other health problems (eg, past treatment for psychiatric problems, headaches, or migraines). Conclusion: In the largest study to date, high school football players with multiple past concussions performed the same on cognitive testing as those with no prior concussions. Concussion history was one of several factors that were independently related to symptom reporting. C1 [Brooks, Brian L.; Mannix, Rebekah; Maxwell, Bruce; Zafonte, Ross; Berkner, Paul D.; Iverson, Grant L.] Colby Coll, Waterville, ME 04901 USA. [Brooks, Brian L.] Alberta Childrens Prov Gen Hosp, Neurosci Program Brain Injury & Rehabil, Calgary, AB, Canada. [Brooks, Brian L.] Univ Calgary, Dept Pediat, Calgary, AB, Canada. [Brooks, Brian L.] Univ Calgary, Dept Clin Neurosci, Calgary, AB, Canada. [Brooks, Brian L.] Univ Calgary, Dept Psychol, Calgary, AB, Canada. [Brooks, Brian L.] Univ Calgary, Alberta Childrens Hosp, Res Inst, Calgary, AB, Canada. [Mannix, Rebekah] Boston Childrens Hosp, Brain Injury Ctr, Div Emergency Med, Boston, MA USA. [Maxwell, Bruce] Colby Coll, Dept Comp Sci, Waterville, ME 04901 USA. [Zafonte, Ross] Harvard Med Sch, Brigham & Womens Hosp, Massachusetts Gen Hosp, Dept Phys Med & Rehabil,Spaulding Rehabil Hosp, Boston, MA USA. [Zafonte, Ross; Iverson, Grant L.] Red Sox Fdn, Boston, MA USA. [Zafonte, Ross; Iverson, Grant L.] Massachusetts Gen Hosp, Home Base Program, Boston, MA 02114 USA. [Berkner, Paul D.] Colby Coll, Hlth Serv & Dept Biol, Waterville, ME 04901 USA. [Iverson, Grant L.] Harvard Med Sch, Dept Phys Med & Rehabil, Boston, MA USA. [Iverson, Grant L.] Spaulding Rehabil Hosp, Boston, MA USA. [Iverson, Grant L.] Massachusetts Gen Hosp Children, Sport Concuss Program, Boston, MA USA. RP Brooks, BL (reprint author), Alberta Childrens Prov Gen Hosp, 2888 Shaganappi Trail NW, Calgary, AB T3B 6A8, Canada. EM brian.brooks@albertahealthservices.ca FU Goldfarb Center for Public Affairs and Civic Engagement at Colby College; Bill and Joan Alfond Foundation; Harvard Integrated Program to Protect and Improve the Health of National Football League Players Association Members; Department of Defense of the Harvard Clinical Consortium Post-traumatic Stress Disorder/Traumatic Brain Injury Study Site (INTRuST) [USAMRMC W81XWH-08-2-0159]; ImPACT Applications Inc; Mooney-Reed Charitable Foundation; [NIH/EKS-NICHD 1 R24 HD065688] FX One or more of the authors has declared the following potential conflict of interest or source of funding: This study was funded by the Goldfarb Center for Public Affairs and Civic Engagement at Colby College and the Bill and Joan Alfond Foundation. B.L.B. receives royalties for the sales of a pediatric forensic textbook and pediatric neuropsychological tests; he has previously received support (in-kind test credits) from a different computerized cognitive test publisher. R.Z. was supported in part by the Harvard Integrated Program to Protect and Improve the Health of National Football League Players Association Members. Funding for R.Z. includes the Improving Outcome Measurement for Medical Rehabilitation Clinical Trials (NIH/EKS-NICHD 1 R24 HD065688) and the Department of Defense (USAMRMC W81XWH-08-2-0159) of the Harvard Clinical Consortium Post-traumatic Stress Disorder/Traumatic Brain Injury Study Site (INTRuST); he is also an investigator on the Football Players Health Study at Harvard University. G.L.I. has been reimbursed by the government, professional scientific bodies, and commercial organizations for discussing or presenting research relating to mild traumatic brain injuries (MTBIs) and sport-related concussions at meetings, scientific conferences, and symposiums; he has a clinical practice in forensic neuropsychology involving patients who have sustained MTBIs (including athletes); he has received honoraria for serving on research panels that provide scientific peer reviews of programs; he is a coinvestigator, collaborator, or consultant on grants relating to MTBIs funded by several organizations; and he has received research support from test publishing companies in the past including ImPACT Applications Inc (not in the past 5 years). R.Z. and G.L.I. acknowledge support from the Mooney-Reed Charitable Foundation. NR 78 TC 0 Z9 0 U1 27 U2 27 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0363-5465 EI 1552-3365 J9 AM J SPORT MED JI Am. J. Sports Med. PD DEC PY 2016 VL 44 IS 12 BP 3243 EP 3251 DI 10.1177/0363546516655095 PG 9 WC Orthopedics; Sport Sciences SC Orthopedics; Sport Sciences GA EE8VS UT WOS:000389905400029 PM 27474382 ER PT J AU Meisel, ZF Metlay, JP Sinnenberg, L Kilaru, AS Grossestreuer, A Barg, FK Shofer, FS Rhodes, KV Perrone, J AF Meisel, Zachary F. Metlay, Joshua P. Sinnenberg, Lauren Kilaru, Austin S. Grossestreuer, Anne Barg, Frances K. Shofer, Frances S. Rhodes, Karin V. Perrone, Jeanmarie TI A Randomized Trial Testing the Effect of Narrative Vignettes Versus Guideline Summaries on Provider Response to a Professional Organization Clinical Policy for Safe Opioid Prescribing SO ANNALS OF EMERGENCY MEDICINE LA English DT Article ID DRUG-MONITORING PROGRAMS; EMERGENCY-DEPARTMENT; BEHAVIOR-CHANGE; PUBLIC-HEALTH; RE-AIM; PRESCRIPTION; FRAMEWORK; INTERVENTIONS; IMPLEMENTATION; DISSEMINATION AB Study objective: Clinical guidelines are known to be underused by practitioners. In response to the challenges of treating pain amid a prescription opioid epidemic, the American College of Emergency Physicians (ACEP) published an evidence-based clinical policy for opioid prescribing in 2012. Evidence-based narratives, an effective method of communicating health information in a variety of settings, offer a novel strategy for disseminating guidelines to physicians and engaging providers with clinical evidence. We compare whether narrative vignettes embedded in the ACEP daily e-newsletter improved dissemination of the clinical policy to ACEP members, and engagement of members with the clinical policy, compared with traditional summary text. Methods: A prospective randomized controlled study, titled Stories to Promote Information Using Narrative trial, was performed. Derived from qualitative interviews with 61 ACEP physicians, 4 narrative vignettes were selected and refined, using a consensus panel of clinical and implementation experts. All ACEP members were then block randomized by state of residence to receive alternative versions of a daily e-mailed newsletter for a total of 24 days during a 9-week period. Narrative newsletters contained a selection of vignettes that referenced opioid prescription dilemmas. Control newsletters contained a selection of descriptive text about the clinical policy, using length and appearance similar to that of the narrative vignettes. Embedded in the newsletters were Web links to the complete vignette or traditional summary text, as well as additional links to the full ACEP clinical policy and a Web site providing assistance with prescription drug monitoring program enrollment. The newsletters were otherwise identical. Outcomes measured were the percentage of subjects who visited any of the Web pages that contained additional guideline-related information and the odds of any unique physician visiting these Web pages during the study. Results: There were 27,592 physicians randomized, and 21,226 received the newsletter during the study period. When each physician was counted once during the study period, there were 509 unique visitors in the narrative group and 173 unique visitors in the control group (4.8% versus 1.6%; difference 3.2%; 95% confidence interval [CI] 2.7% to 3.7%). There were 744 gross visits from the e-newsletter to any of the 3 Web pages in the narrative group compared with 248 in the control group (7.0% versus 2.3%; odds ratio 3.2; 95% CI 2.7 to 3.6). During the study, the odds ratio of any physician in the narrative group visiting one of the 3 informational Web sites compared with the control group was 3.1(95% CI 2.6 to 3.6). Conclusion: Among a national sample of emergency physicians, narrative vignettes outperformed traditional guideline text in promoting engagement with an evidence-based clinical guideline related to opioid prescriptions. C1 [Meisel, Zachary F.; Sinnenberg, Lauren; Grossestreuer, Anne; Shofer, Frances S.; Perrone, Jeanmarie] Leonard Davis Inst Hlth Econ, Perelman Sch Med, Ctr Emergency Care Policy Res, Philadelphia, PA 19104 USA. [Perrone, Jeanmarie] Leonard Davis Inst Hlth Econ, Perelman Sch Med, Div Med Oncol, Philadelphia, PA 19104 USA. [Meisel, Zachary F.; Rhodes, Karin V.] Leonard Davis Inst Hlth Econ, Perelman Sch Med, Dept Emergency Med, Philadelphia, PA 19104 USA. [Barg, Frances K.] Univ Penn, Dept Family Med, Philadelphia, PA 19104 USA. [Barg, Frances K.] Univ Penn, Dept Anthropol, Philadelphia, PA 19104 USA. [Rhodes, Karin V.] Northshore Long Isl Jewish Hosp, Dept Emergency Med, New Hyde Pk, NY USA. [Kilaru, Austin S.] Highland Hosp, Dept Emergency Med, Oakland, CA USA. [Metlay, Joshua P.] Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. RP Meisel, ZF (reprint author), Leonard Davis Inst Hlth Econ, Perelman Sch Med, Ctr Emergency Care Policy Res, Philadelphia, PA 19104 USA. EM zfm@wharton.upenn.edu FU Agency for Healthcare Research and Quality [5R18HS021956]; National Institutes of Health Career Development in Comparative Effectiveness Research award [1KM1CA156715] FX By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org). The authors have stated that no such relationships exist and provided the following details: Funded by the Agency for Healthcare Research and Quality (5R18HS021956) and National Institutes of Health Career Development in Comparative Effectiveness Research award (1KM1CA156715). NR 40 TC 0 Z9 0 U1 3 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD DEC PY 2016 VL 68 IS 6 BP 719 EP 728 DI 10.1016/j.annemergmed.2016.03.007 PG 10 WC Emergency Medicine SC Emergency Medicine GA ED9BJ UT WOS:000389164800014 PM 27133392 ER PT J AU Thomas, LE Czuczman, AD Marill, KA AF Thomas, Lisa E. Czuczman, Amanda D. Marill, Keith A. TI Additional Observations About the Diagnostic Approach to Patients With Headache and Possible Subarachnoid Hemorrhage SO ANNALS OF EMERGENCY MEDICINE LA English DT Letter ID LUMBAR PUNCTURE; TRUE C1 [Thomas, Lisa E.] Univ Maryland, Upper Chesapeake Med Ctr, Dept Emergency Med, Bel Air, MD 21014 USA. [Czuczman, Amanda D.] Beverly Hosp, Dept Emergency Med, Beverly, MA USA. [Marill, Keith A.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA USA. RP Thomas, LE (reprint author), Univ Maryland, Upper Chesapeake Med Ctr, Dept Emergency Med, Bel Air, MD 21014 USA. NR 5 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 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD DEC PY 2016 VL 68 IS 6 BP 786 EP 787 PG 2 WC Emergency Medicine SC Emergency Medicine GA ED9BJ UT WOS:000389164800035 PM 27894638 ER PT J AU Guihan, M Sohn, MW Bauman, WA Spungen, AM Powell-Cope, GM Thomason, SS Collins, JF Bates-Jensen, BM AF Guihan, Marylou Sohn, Min-Woong Bauman, William A. Spungen, Ann M. Powell-Cope, Gail M. Thomason, Susan S. Collins, Joseph F. Bates-Jensen, Barbara M. TI Difficulty in Identifying Factors Responsible for Pressure Ulcer Healing in Veterans With Spinal Cord Injury SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article DE Pressure ulcer; Rehabilitation; Spinal cord injuries; Veterans ID NEUROPATHIC FOOT ULCERS; SURROGATE END-POINTS; RISK-FACTORS; MONITORING TOOL; HELP-SEEKING; WOUND AREA; IMPAIRMENT; PREVALENCE; PREDICTORS; DURATION AB Objective: To identify characteristics associated with pressure ulcer (PrU) healing for individuals with spinal cord injury (SCI). Design: Secondary analysis of a large clinical trial's data for healing PrUs in individuals with SCI; prospective Delphi process was conducted with SCI and/or PrU experts. Setting: Spinal cord injury centers. Participants: There were 629 screening and 162 treatment participants (N=791); 185 SCI clinicians/national PrU/wound care experts participated in the Delphi process. Interventions: None. Main Outcome Measure: PrU healing of 50% and 100% at weeks 4 and 12. Results: Poisson regression models using the top Delphi-recommended factors found that only ulcer stage consistently predicted 50% and 100% healing at weeks 4 and 12. Additionally, ischial/perineal location was associated with 33% higher likelihood of 50% healing at week 4. Patient noncompliance with treatment recommendations, the top-ranked Delphi factor, did not predict healing at week 4 or 12. Expanded models found that at week 4, baseline PrU size, PrU stage IV, PrU pain, and American Spinal Injury Association grade A significantly predicted 100% healing, while at week 12, only PrU stage (IV) significantly predicted 100% healing. Significant predictors of 50% healing at week 4 included baseline PrU size, stage, ischial/perianal location body mass index >30kg/m(2), foul odor, and signs of infection. At week 12, PrU duration, paraplegia predicted 50% healing. SCI center identifiers consistently showed 2- to 5-fold variation in predicting 50% PrU healing at weeks 4 and 12. Conclusions: Delphi panel-recommended factors (eg, patient compliance) did not predict PrU healing. Reducing center-level variability in wound healing by learning from best practices should be a health system goal. PrU healing in SCI is still poorly understood, and future studies should focus on as yet unidentified or underappreciated factors. Published by Elsevier Inc. on behalf of the American Congress of Rehabilitation Medicine C1 [Guihan, Marylou; Bates-Jensen, Barbara M.] Edward Hines Jr VA Hosp, Spinal Cord Injury Qual Enhancement Res Initiat, Hines, IL USA. [Guihan, Marylou] Northwestern Univ, Feinberg Sch Med, Dept Phys Med & Rehabil, Chicago, IL USA. [Sohn, Min-Woong] Univ Virginia, Sch Med, Publ Hlth Sci, Charlottesville, VA USA. [Bauman, William A.; Spungen, Ann M.] James J Peters Vet Adm Med Ctr, Natl Ctr Med Consequences Spinal Cord Injury, Vet Adm Rehabil Res & Dev, Bronx, NY USA. [Bauman, William A.; Spungen, Ann M.] Icahn Sch Med Mt Sinai, Dept Med & Rehabil Med, New York, NY 10029 USA. [Powell-Cope, Gail M.; Thomason, Susan S.] Ctr Innovat Disabil & Rehabil Res, Tampa, FL USA. [Powell-Cope, Gail M.] Univ S Florida, Sch Nursing, Tampa, FL USA. [Collins, Joseph F.] Perry Point Vet Adm Med Ctr, Cooperat Studies Program Coordinating Ctr, Perry Point, MD USA. [Bates-Jensen, Barbara M.] Univ Calif Los Angeles, Sch Nursing, Los Angeles, CA USA. [Bates-Jensen, Barbara M.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA USA. RP Guihan, M (reprint author), Edward Hines Jr Vet Adm Hosp 151H, Box 5000,5000 S 5th Ave, Hines, IL 60141 USA. EM Marylou.guihan@va.gov FU Department of Veterans Affairs, Office of Research and Development, Health Services Research and Development Service, Quality Enhancement Research Initiative [RRP-11-376] FX Supported by the Department of Veterans Affairs, Office of Research and Development, Health Services Research and Development Service, Quality Enhancement Research Initiative (grant no. RRP-11-376). NR 36 TC 0 Z9 0 U1 5 U2 5 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0003-9993 EI 1532-821X J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD DEC PY 2016 VL 97 IS 12 BP 2085 EP 2094 DI 10.1016/j.apmr.2016.05.025 PG 10 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA EE7GM UT WOS:000389783900008 PM 27373743 ER PT J AU Pyne, JM Constans, JI Wiederhold, MD Gibson, DP Kimbrell, T Kramer, TL Pitcock, JA Han, XT Williams, DK Chartrand, D Gevirtz, RN Spira, J Wiederhold, BK McCraty, R McCune, TR AF Pyne, Jeffrey M. Constans, Joseph I. Wiederhold, Mark D. Gibson, Douglas P. Kimbrell, Timothy Kramer, Teresa L. Pitcock, Jeffery A. Han, Xiaotong Williams, D. Keith Chartrand, Don Gevirtz, Richard N. Spira, James Wiederhold, Brenda K. McCraty, Rollin McCune, Thomas R. TI Heart rate variability: Pre-deployment predictor of post-deployment PTSD symptoms SO BIOLOGICAL PSYCHOLOGY LA English DT Article DE Post traumatic stress disorder (PTSD); military; risk factors; combat stress; prediction; longitudinal; heart rate variability ID POSTTRAUMATIC-STRESS-DISORDER; CARDIAC VAGAL TONE; SYMPATHOVAGAL BALANCE; VIETNAM VETERANS; COMBAT VETERANS; SELF-REGULATION; RISK-FACTORS; IRAQ; HEALTH; US AB Heart rate variability is a physiological measure associated with autonomic nervous system activity. This study hypothesized that lower pre-deployment HRV would be associated with higher post-deployment post-traumatic stress disorder (PTSD) symptoms. Three-hundred-forty-three Army National Guard soldiers enrolled in the Warriors Achieving Resilience (WAR) study were analyzed. The primary outcome was PTSD symptom severity using the PTSD Checklist Military version (PCL) measured at baseline, 3- and 12-month post-deployment. Heart rate variability predictor variables included: high frequency power (HF) and standard deviation of the normal cardiac inter-beat interval (SDNN). Generalized linear mixed models revealed that the pre-deployment PCL*ln(HF) interaction term was significant (p < 0.0001). Pre-deployment SDNN was not a significant predictor of post-deployment PCL. Covariates included age, pre-deployment PCL, race/ethnicity, marital status, tobacco use, childhood abuse, pre-deployment traumatic brain injury, and previous combat zone deployment. Pre-deployment heart rate variability predicts post-deployment PTSD symptoms in the context of higher pre-deployment PCL scores. Published by Elsevier B.V. C1 [Pyne, Jeffrey M.; Kimbrell, Timothy; Pitcock, Jeffery A.; Han, Xiaotong] Cent Arkansas Vet Healthcare Syst, Ctr Mental Hlth Outcomes Res, North Little Rock, AR 72114 USA. [Pyne, Jeffrey M.; Constans, Joseph I.; Kimbrell, Timothy; Han, Xiaotong] Cent Arkansas Vet Healthcare Syst, South Cent Mental Illness Educ & Clin Ctr, North Little Rock, AR 72114 USA. [Pyne, Jeffrey M.; Kramer, Teresa L.; Han, Xiaotong] Univ Arkansas Med Sci, Coll Med, Dept Psychiat, Div Hlth Serv Res, Little Rock, AR 72205 USA. [Constans, Joseph I.] Southeastern Louisiana Vet Hlth Care Syst 629 11F, POB 61011, New Orleans, IA 70161 USA. [Constans, Joseph I.] Tulane Univ, New Orleans, LA 70118 USA. [Wiederhold, Mark D.; Wiederhold, Brenda K.] Virtual Real Med Ctr, 9565 Waples St,Suite 200, San Diego, CA 92121 USA. [Gibson, Douglas P.] Virginia Army Natl Guard, Off State Surgeon, BLDG 1310,Ft Pickett, Blackstone, VA 23824 USA. [Williams, D. Keith] Univ Arkansas Med Sci, Dept Biostat, Little Rock, AR 72205 USA. [Chartrand, Don] Ease Interactive Inc, San Diego, CA USA. [Gevirtz, Richard N.] Alliant Int Univ, 10455 Pomerado Rd, San Diego, CA 92131 USA. [Spira, James] Univ Hawaii, Sch Med, US Dept Vet Affairs, Natl Ctr PTSD, Honolulu, HI 96819 USA. [Spira, James] Univ Hawaii, Sch Med, Dept Psychiat, Honolulu, HI 96819 USA. [McCraty, Rollin] Inst HeartMath, 14700 West Pk Ave, Boulder Creek, CA 95006 USA. RP Pyne, JM (reprint author), 2200 Ft Roots Dr 152-NLR, North Little Rock, AR USA. EM jmpyne@uams.edu FU Military Operational Medical Research Program [PT074626]; South Central Mental Illness and Research Educational and Clinical Center (MIRECC); National Institutes of Health [P20 GM103425-09, UL1TR000039, KL2TR000063] FX This work was supported by grants from the Military Operational Medical Research Program (PT074626), South Central Mental Illness and Research Educational and Clinical Center (MIRECC), and National Institutes of Health (P20 GM103425-09, UL1TR000039, KL2TR000063). NR 62 TC 0 Z9 0 U1 10 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-0511 EI 1873-6246 J9 BIOL PSYCHOL JI Biol. Psychol. PD DEC PY 2016 VL 121 BP 91 EP 98 DI 10.1016/j.biopsycho.2016.10.008 PN A PG 8 WC Psychology, Biological; Behavioral Sciences; Psychology; Psychology, Experimental SC Psychology; Behavioral Sciences GA EE3SK UT WOS:000389518500011 PM 27773678 ER PT J AU Barroso-Sousa, R Paes, FR Vaz-Luis, I Batista, RB Costa, RB Losk, K Camuso, K Metzger-Filho, O Hughes, ME Bunnell, CA Goishan, M Winer, EP Lin, NU AF Barroso-Sousa, Romualdo Paes, Flavia Rocha Vaz-Luis, Ines Batista, Rafael Borges Costa, Rafael Brant Losk, Katya Camuso, Kristen Metzger-Filho, Otto Hughes, Melissa E. Bunnell, Craig A. Goishan, Mehra Winer, Eric P. Lin, Nancy U. TI Variation in the use of granulocyte-colony stimulating factor for dose dense paclitaxel: A single institution retrospective study SO BREAST LA English DT Article DE Dose-dense chemotherapy; Paclitaxel; Colony stimulating factors ID BREAST-CANCER; ADJUVANT THERAPY; CHEMOTHERAPY; TRIALS; WOMEN; METAANALYSIS; LEUKEMIA; SUPPORT AB Introduction: The necessity of using granulocyte-colony stimulating factor (G-CSF) during dose-dense (DD) paclitaxel (T) after doxorubicin and cyclophosphamide (AC) is unclear. Methods: This was a retrospective cohort study including patients with stage I-III breast cancer treated at Dana-Farber Cancer Institute with adjuvant DD-ACT between January 2011 and December 2013. Descriptive analyses evaluating patterns of G-CSF utilization during T were performed. Results: Overall, 156 patients were treated with DD-ACT by 26 providers. The majority of patients (135, 87%) received at least one dose of G-CSF during T (group 1), 17% of these patients received it in only one cycle and 48% received it in all four cycles. Reasons for omitting G-CSF included high baseline absolute neutrophil count and pain. Twenty-one (13%) patients did not receive any G-CSF during T (group 2). Respectively, 94% and 90% of patients completed the treatment in groups 1 and 2. There were no cases of treatment cessation due to neutropenia. Six percent of patients in group 1 had at least one treatment delay. There were no treatment delays reported in group 2. Variation in the use of G-CSF by provider and by patient was found, with 11 providers choosing not to use G-CSF in at least one patient. Conclusions: We identified substantial variation in the use of G-CSF within the practice. However, omission of G-CSF was not associated with treatment delays or adverse events. Prospective studies are warranted to formally test whether routine G-CSF is necessary during dose-dense T therapy. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Barroso-Sousa, Romualdo; Vaz-Luis, Ines; Losk, Katya; Camuso, Kristen; Metzger-Filho, Otto; Hughes, Melissa E.; Bunnell, Craig A.; Winer, Eric P.; Lin, Nancy U.] Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. [Paes, Flavia Rocha; Batista, Rafael Borges; Costa, Rafael Brant] Oncoclin Brasil, Rua Maranhao 569-4, BR-01240001 Sao Paulo, Brazil. [Goishan, Mehra] Dana Farber Brigham & Womens Canc Ctr, Dept Surg, 75 Francis St, Boston, MA 02115 USA. RP Lin, NU (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,Yawkey 1237, Boston, MA 02215 USA. EM nancy_li@dfci.harvard.edu FU National Comprehensive Cancer Network (NCCN) Opportunities for Improvement grant FX This initiative was supported in part by the National Comprehensive Cancer Network (NCCN) Opportunities for Improvement grant. NR 23 TC 0 Z9 0 U1 1 U2 1 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0960-9776 EI 1532-3080 J9 BREAST JI Breast PD DEC PY 2016 VL 30 BP 136 EP 140 DI 10.1016/j.breast.2016.09.013 PG 5 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA EE2CG UT WOS:000389390700022 PM 27721193 ER PT J AU Danek, BA Karatasakis, A Karmpaliotis, D Alaswad, K Jaffer, FA Yeh, RW Patel, MP Bahadorani, J Lombardi, WL Wyman, RM Grantham, JA Kandzari, DE Lembo, NJ Doing, AH Toma, C Moses, JW Kirtane, AJ Ali, ZA Parikh, M Garcia, S Nguyen-Trong, PK Karacsonyi, J Alame, AJ Kalsaria, P Thompson, C Banerjee, S Brilakis, ES AF Danek, Barbara A. Karatasakis, Aris Karmpaliotis, Dimitri Alaswad, Khaldoon Jaffer, Farouc A. Yeh, Robert W. Patel, Mitul P. Bahadorani, John Lombardi, William L. Wyman, R. Michael Grantham, J. Aaron Kandzari, David E. Lembo, Nicholas J. Doing, Anthony H. Toma, Catalin Moses, Jeffrey W. Kirtane, Ajay J. Ali, Ziad A. Parikh, Manish Garcia, Santiago Phuong-Khanh Nguyen-Trong Karacsonyi, Judit Alame, Aya J. Kalsaria, Pratik Thompson, Craig Banerjee, Subhash Brilakis, Emmanouil S. TI Effect of Lesion Age on Outcomes of Chronic Total Occlusion Percutaneous Coronary Intervention: Insights From a Contemporary US Multicenter Registry SO CANADIAN JOURNAL OF CARDIOLOGY LA English DT Article ID ARTERY-BYPASS GRAFT; HYBRID APPROACH; PROCEDURAL OUTCOMES; DURATION; FAILURE; SURGERY; ANGIOPLASTY; EFFICACY; SUCCESS AB Background: We sought to determine the effect of lesion age on procedural techniques and outcomes of chronic total occlusion (CTO) percutaneous coronary intervention (PCI). Methods: We examined the characteristics and outcomes of 394 CTO PCIs with data on lesion age, performed between 2012 and 2016 at 11 experienced US centres. Results: Mean patient age was 66 +/- 10 years and 85.6% of the patients were men. Overall technical and procedural success rates were 90.1% and 87.5%, respectively. A major adverse cardiovascular event (MACE) occurred in 16 patients (4.1%). Mean and median lesion ages were 43 +/- 62 months and 12 months (interquartile range, 3-64 months), respectively. Patients were stratified into tertiles according to lesion age (3-5, 5-36.3, and > 36.3 months). Older lesion age was associated with older patient age (68 +/- 8 vs 65 +/- 10 vs 64 +/- 11 years; P = 0.009), previous coronary artery bypass grafting (62% vs 42% vs 30%; P < 0.001), and moderate/severe calcification (75% vs 53% vs 59%; P = 0.001). Older lesions more often required use of the retrograde approach and antegrade dissection/re-entry for successful lesion crossing. There was no difference in technical (87.8% vs 89.6% vs 93.0%; P = 0.37) or procedural (86.3% vs 87.4% vs 89.0%; P = 0.80) success, or the incidence of MACE (3.1% vs 3.0% vs 6.3%; P = 0.31) for older vs younger occlusions. Conclusions: Older CTO lesions exhibit angiographic complexity and more frequently necessitate the retrograde approach or antegrade dissection/re-entry. Older CTOs can be recanalized with high technical and procedural success and acceptable MACE rates. Lesion age appears unlikely to be a significant determinant of CTO PCI success. C1 [Danek, Barbara A.; Karatasakis, Aris; Phuong-Khanh Nguyen-Trong; Karacsonyi, Judit; Alame, Aya J.; Kalsaria, Pratik; Banerjee, Subhash; Brilakis, Emmanouil S.] VA North Texas Hlth Care Syst, Dallas, TX USA. [Danek, Barbara A.; Karatasakis, Aris; Phuong-Khanh Nguyen-Trong; Karacsonyi, Judit; Alame, Aya J.; Kalsaria, Pratik; Banerjee, Subhash; Brilakis, Emmanouil S.] Univ Texas Southwestern Med Ctr Dallas, Dallas, TX 75390 USA. [Karmpaliotis, Dimitri; Moses, Jeffrey W.; Kirtane, Ajay J.; Ali, Ziad A.; Parikh, Manish] Henry Ford Hosp, Detroit, MI 48202 USA. [Alaswad, Khaldoon] Columbia Univ, New York, NY USA. [Jaffer, Farouc A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Yeh, Robert W.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Patel, Mitul P.; Bahadorani, John] VA San Diego Healthcare Syst, La Jolla, CA USA. [Patel, Mitul P.; Bahadorani, John] Univ Calif San Diego, La Jolla, CA 92093 USA. [Lombardi, William L.] PeaceHlth St Joseph Med Ctr, Bellingham, WA USA. [Wyman, R. Michael] Torrance Mem Med Ctr, Torrance, CA USA. [Grantham, J. Aaron] Mid Amer Heart Inst, Kansas City, MO USA. [Kandzari, David E.; Lembo, Nicholas J.] Piedmont Heart Inst, Atlanta, GA USA. [Doing, Anthony H.] Med Ctr Rockies, Loveland, CO USA. [Toma, Catalin] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Garcia, Santiago] Minneapolis VA Hlth Care Syst, Minneapolis, MN USA. [Garcia, Santiago] Univ Minnesota, Minneapolis, MN USA. [Thompson, Craig] Boston Sci, Natick, MA USA. RP Brilakis, ES (reprint author), Dallas VA Med Ctr, 111A,4500 South Lancaster Rd, Dallas, TX 75216 USA. EM esbrilakis@gmail.com OI Danek, Barbara/0000-0002-7607-4204; Parikh, Manish/0000-0002-8612-5407 FU Clinical and Translational Science Award (CTSA) National Institutes of Health grant [UL1-RR024982] FX Supported by Clinical and Translational Science Award (CTSA) National Institutes of Health grant UL1-RR024982. NR 27 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0828-282X EI 1916-7075 J9 CAN J CARDIOL JI Can. J. Cardiol. PD DEC PY 2016 VL 32 IS 12 BP 1433 EP 1439 DI 10.1016/j.cjca.2016.04.007 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EE3WC UT WOS:000389529800015 PM 27476986 ER PT J AU Beaudoin, J Singh, JP Szymonifka, J Zhou, Q Levine, RA Januzzi, JL Truong, QA AF Beaudoin, Jonathan Singh, Jagmeet P. Szymonifka, Jackie Zhou, Qing Levine, Robert A. Januzzi, James L. Truong, Quynh A. TI Novel Heart Failure Biomarkers Predict Improvement of Mitral Regurgitation in Patients Receiving Cardiac Resynchronization Therapy-The BIOCRT Study SO CANADIAN JOURNAL OF CARDIOLOGY LA English DT Article ID LEFT-VENTRICULAR DYSFUNCTION; SOLUBLE ST2; BASE-LINE; CARDIOVASCULAR OUTCOMES; GALECTIN-3; TRIAL; ECHOCARDIOGRAPHY; REDUCTION; MORTALITY; FIBROSIS AB Background: Cardiac resynchronization therapy (CRT) improves mitral regurgitation (MR) in a subset of patients. We hypothesized that biomarkers (amino-terminal pro-B type natriuretic peptide, high-sensitivity troponin I, galectin-3 [gal-3], and soluble ST2) might predict MR response after CRT. Methods: We measured levels of biomarkers during CRT implantation in 132 patients with a subsequent 2-year follow-up. MR was graded as no-trace, mild, moderate, or severe at baseline and at 6 months. Results: In patients with baseline at least mild MR, 56% had improvement at 6 months, with lower 2-year mortality vs patients without improvement (0% vs 18%; P = 0.002). At baseline, patients with MR improvement had lower high-sensitivity troponin I and gal-3 levels compared with those without improvement (19 vs 40 pg/L; P = 0.01; 14 vs 18 ng/mL; P = 0.007). In multivariable analyses, higher log-transformed gal-3 (odds ratio, 0.15; 95% confidence interval, 0.04-0.65; P = 0.01) remained an independent predictor for MR nonimprovement. Levels of pro-B type natriuretic peptide and soluble ST2 were lower at follow-up in patients with MR improvement (potentially reflecting reduced myocardial stretch and stress) without reaching statistical significance. Conclusions: Higher galectin levels at the time of CRT implantation are associated with MR nonresponse. C1 [Beaudoin, Jonathan] Univ Laval, Inst Univ Cardiol & Pneumol Quebec, Quebec City, PQ, Canada. [Beaudoin, Jonathan; Singh, Jagmeet P.; Zhou, Qing; Levine, Robert A.; Januzzi, James L.] Harvard Med Sch, Massachusetts Gen Hosp, Div Cardiol, Boston, MA USA. [Singh, Jagmeet P.] Harvard Med Sch, Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA USA. [Szymonifka, Jackie; Truong, Quynh A.] New York Presbyterian Hosp, Dalio Inst Cardiovasc Imaging, New York, NY USA. [Szymonifka, Jackie; Truong, Quynh A.] Weill Cornell Med Coll, New York, NY USA. RP Beaudoin, J (reprint author), Inst Univ Cardiol & Pneumol Quebec, 2725 Chemin St Foy, Quebec City, PQ G1V 4G5, Canada. EM jonathan.beaudoin@criucpq.ulaval.ca FU NIH/NHLBI [K23HL098370]; NIH [L30HL093896]; Fonds de recherche du Quebec - Sante FX This study was supported by NIH/NHLBI K23HL098370. Dr Truong received support from the NIH L30HL093896. Dr Beaudoin is supported by Fonds de recherche du Quebec - Sante. The reagents/assays were provided and performed by Siemens Healthcare Diagnostics Inc, BG Medicine, and Critical Diagnostics. NR 30 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0828-282X EI 1916-7075 J9 CAN J CARDIOL JI Can. J. Cardiol. PD DEC PY 2016 VL 32 IS 12 BP 1478 EP 1484 DI 10.1016/j.cjca.2016.05.013 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EE3WC UT WOS:000389529800021 PM 27527259 ER PT J AU Huang, TY Tworoger, SS Hecht, JL Rice, MS Sood, AK Kubzansky, LD Poole, EM AF Huang, Tianyi Tworoger, Shelley S. Hecht, Jonathan L. Rice, Megan S. Sood, Anil K. Kubzansky, Laura D. Poole, Elizabeth M. TI Association of Ovarian Tumor beta(2)-Adrenergic Receptor Status with Ovarian Cancer Risk Factors and Survival SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID BETA-BLOCKERS; URINARY CATECHOLAMINES; INDIVIDUAL-DIFFERENCES; DEPRESSIVE SYMPTOMS; NOREPINEPHRINE; STRESS; ANXIETY; IMPACT; EPIDEMIOLOGY; DISORDER AB Background: The beta(2)-adrenergic signaling pathway mediates the effects of chronic stress on ovarian cancer progression in mouse models. The relevance of this pathway to human ovarian cancer remains unknown. Methods: We assessed tumor expression of beta(2)-adrenergic receptor (ADRB2) using tissue microarrays in 237 ovarian cancer cases from the Nurses' Health Studies (NHS/NHSII). Competing risks Cox regression was used to evaluate whether associations of reproductive, hormonal, and psychosocial factors with ovarian cancer risk differed by ADRB2. We also examined the association between tumor ADRB2 expression and ovarian cancer survival. Results: Forty-five (19%) cases were positive for ADRB2 staining. High levels of anxiety symptoms were positively associated with ADRB2-positive tumors (HR, 2.59; 95% confidence interval [CI], 1.15-5.84) but not with ADRB2-negative tumors (HR, 1.16; 95% CI, 0.81-1.66; P-heterogeneity = 0.07). We observed similar results for depression. No associations were observed for job strain, caregiving stress, or widowhood for either positive or negative ADRB2 status. Lifetime ovulatory years were more strongly associated with ADRB2-positive tumors (HR per 5 years, 1.60; 95% CI, 1.15-2.21) compared with ADRB2-negative tumors (HR, 1.11; 95% CI, 0.96-1.27; P-heterogeneity = 0.04). Significant heterogeneity by ADRB2 was also observed for parity (P-heterogeneity = 0.01), oral contraceptive use (P-heterogeneity = 0.03), and age at menopause (P-heterogeneity = 0.04). Tumor expression of ADRB2 was not associated with ovarian cancer mortality (HR, 1.05; 95% CI, 0.69-1.59). Conclusions: Several stress-and ovulation-related factors were differentially associated with ovarian tumors responsive to beta(2)-adrenergic signaling. Impact: Replication in larger studies is warranted to confirm the role of b2-adrenergic signaling in ovarian cancer etiology. Cancer Epidemiol Biomarkers Prev; 25(12); 1587-94. (C) 2016 AACR. C1 [Huang, Tianyi; Tworoger, Shelley S.; Poole, Elizabeth M.] Brigham & Womens Hosp, Channing Div Network Med, Dept Med, Boston, MA USA. [Huang, Tianyi; Tworoger, Shelley S.; Poole, Elizabeth M.] Harvard Med Sch, Boston, MA USA. [Huang, Tianyi] Harvard TH Chan Sch Publ Hlth, Dept ment Nutr, Boston, MA USA. [Tworoger, Shelley S.] Harvard T H Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Hecht, Jonathan L.] Beth Israel DeaconessMed Ctr, Dept Pathol, Boston, MA USA. [Hecht, Jonathan L.] Harvard Med Sch, Boston, MA USA. [Rice, Megan S.] Massachusetts Gen Hosp, Dept Med, Clin & Translat Epidemiol Unit, Boston, MA USA. [Sood, Anil K.] MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX USA. [Kubzansky, Laura D.] Harvard TH Chan Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA USA. RP Huang, TY (reprint author), Brigham & Womens Hosp, Channing Div Network Med, Dept Med, Boston, MA USA.; Huang, TY (reprint author), Harvard Med Sch, Boston, MA USA.; Huang, TY (reprint author), Harvard TH Chan Sch Publ Hlth, Dept ment Nutr, Boston, MA USA.; Huang, TY (reprint author), ScD 181 Longwood Ave 4th Fl, Boston, MA 02215 USA. EM tih541@mail.harvard.edu FU DoD OCRP award [W81XWH-13-1-0493]; NCI [R01 CA163451, R01 CA109298]; NIH [UM1 CA186107, P01 CA87969, UM1 CA176726] FX E.M. Poole was supported by a DoD OCRP award (W81XWH-13-1-0493). S.S. Tworoger was supported by a grant from NCI (R01 CA163451). A.K. Sood received a grant from NCI (R01 CA109298). The Nurses' Health Studies were supported by grants from the NIH (UM1 CA186107, P01 CA87969, UM1 CA176726). NR 42 TC 0 Z9 0 U1 5 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD DEC PY 2016 VL 25 IS 12 BP 1587 EP 1594 DI 10.1158/1055-9965.EPI-16-0534 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA EE6FL UT WOS:000389704300006 PM 27587791 ER PT J AU Rand, KA Song, C Dean, E Serie, DJ Curtin, K Sheng, X Hu, DL Huff, CA Bernal-Mizrachi, L Tomasson, MH Ailawadhi, S Singhal, S Pawlish, K Peters, ES Bock, CH Stram, A Van den Berg, DJ Edlund, CK Conti, DV Zimmerman, T Hwang, AE Huntsman, S Graff, J Nooka, A Kong, YF Pregja, SL Berndt, SI Blot, WJ Carpten, J Casey, G Chu, L Diver, WR Stevens, VL Lieber, MR Goodman, PJ Hennis, AJM Hsing, AW Mehta, J Kittles, RA Kolb, S Klein, EA Leske, C Murphy, AB Nemesure, B Neslund-Dudas, C Strom, SS Vij, R Rybicki, BA Stanford, JL Signorello, LB Witte, JS Ambrosone, CB Bhatti, P John, EM Bernstein, L Zheng, W Olshan, AF Hu, JJ Ziegler, RG Nyante, SJ Bandera, EV Birmann, BM Ingles, SA Press, MF Atanackovic, D Glenn, MJ Cannon-Albright, LA Jones, B Tricot, G Martin, TG Kumar, SK Wolf, JL Halverson, SLD Rothman, N Brooks-Wilson, AR Rajkumar, SV Kolonel, LN Chanock, SJ Slager, SL Severson, RK Janakiraman, N Terebelo, HR Brown, EE De Roos, AJ Mohrbacher, AF Colditz, GA Giles, GG Spinelli, JJ Chiu, BC Munshi, NC Anderson, KC Levy, J Zonder, JA Orlowski, RZ Lonial, S Camp, NJ Vachon, CM Ziv, E Stram, DO Hazelett, DJ Haiman, CA Cozen, W AF Rand, Kristin A. Song, Chi Dean, Eric Serie, Daniel J. Curtin, Karen Sheng, Xin Hu, Donglei Huff, Carol Ann Bernal-Mizrachi, Leon Tomasson, Michael H. Ailawadhi, Sikander Singhal, Seema Pawlish, Karen Peters, Edward S. Bock, Cathryn H. Stram, Alex Van den Berg, David J. Edlund, Christopher K. Conti, David V. Zimmerman, Todd Hwang, Amie E. Huntsman, Scott Graff, John Nooka, Ajay Kong, Yinfei Pregja, Silvana L. Berndt, Sonja I. Blot, William J. Carpten, John Casey, Graham Chu, Lisa Diver, W. Ryan Stevens, Victoria L. Lieber, Michael R. Goodman, Phyllis J. Hennis, Anselm J. M. Hsing, Ann W. Mehta, Jayesh Kittles, Rick A. Kolb, Suzanne Klein, Eric A. Leske, Cristina Murphy, Adam B. Nemesure, Barbara Neslund-Dudas, Christine Strom, Sara S. Vij, Ravi Rybicki, Benjamin A. Stanford, Janet L. Signorello, Lisa B. Witte, John S. Ambrosone, Christine B. Bhatti, Parveen John, Esther M. Bernstein, Leslie Zheng, Wei Olshan, Andrew F. Hu, Jennifer J. Ziegler, Regina G. Nyante, Sarah J. Bandera, Elisa V. Birmann, Brenda M. Ingles, Sue A. Press, Michael F. Atanackovic, Djordje Glenn, Martha J. Cannon-Albright, Lisa A. Jones, Brandt Tricot, Guido Martin, Thomas G. Kumar, Shaji K. Wolf, Jeffrey L. Halverson, Sandra L. Deming Rothman, Nathaniel Brooks-Wilson, Angela R. Rajkumar, S. Vincent Kolonel, Laurence N. Chanock, Stephen J. Slager, Susan L. Severson, Richard K. Janakiraman, Nalini Terebelo, Howard R. Brown, Elizabeth E. De Roos, Anneclaire J. Mohrbacher, Ann F. Colditz, Graham A. Giles, Graham G. Spinelli, John J. Chiu, Brian C. Munshi, Nikhil C. Anderson, Kenneth C. Levy, Joan Zonder, Jeffrey A. Orlowski, Robert Z. Lonial, Sagar Camp, Nicola J. Vachon, Celine M. Ziv, Elad Stram, Daniel O. Hazelett, Dennis J. Haiman, Christopher A. Cozen, Wendy TI A Meta-analysis of Multiple Myeloma Risk Regions in African and European Ancestry Populations Identifies Putatively Functional Loci SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID GENOME-WIDE ASSOCIATION; UNDETERMINED SIGNIFICANCE; MONOCLONAL GAMMOPATHY; LOS-ANGELES; VARIANTS; SITES; GENOTYPES; PATTERNS; 7P15.3; TARGET AB Background: Genome-wide association studies (GWAS) in European populations have identified genetic risk variants associated with multiple myeloma. Methods: We performed association testing of common variation in eight regions in 1,318 patients with multiple myeloma and 1,480 controls of European ancestry and 1,305 patients with multiple myeloma and 7,078 controls of African ancestry and conducted a meta-analysis to localize the signals, with epigenetic annotation used to predict functionality. Results: We found that variants in 7p15.3, 17p11.2, 22q13.1 were statistically significantly (P < 0.05) associated with multiple myeloma risk in persons of African ancestry and persons of European ancestry, and the variant in 3p22.1 was associated in European ancestry only. In a combined African ancestry-European ancestry meta-analysis, variation in five regions (2p23.3, 3p22.1, 7p15.3, 17p11.2, 22q13.1) was statistically significantly associated with multiple myeloma risk. In 3p22.1, the correlated variants clustered within the gene body of ULK4. Correlated variants in 7p15.3 clustered around an enhancer at the 30 end of the CDCA7L transcription termination site. A missense variant at 17p11.2 (rs34562254, Pro251Leu, OR, 1.32; P = 2.93 x 10(-7)) in TNFRSF13B encodes a lymphocyte-specific protein in the TNF receptor family that interacts with the NF-kB pathway. SNPs correlated with the index signal in 22q13.1 cluster around the promoter and enhancer regions of CBX7. Conclusions: We found that reported multiple myeloma susceptibility regions contain risk variants important across populations, supporting the use of multiple racial/ethnic groups with different underlying genetic architecture to enhance the localization and identification of putatively functional alleles. Impact: A subset of reported risk loci for multiple myeloma has consistent effects across populations and is likely to be functional. Cancer Epidemiol Biomarkers Prev; 25(12); 1609-18. (C) 2016 AACR. C1 [Rand, Kristin A.; Song, Chi; Sheng, Xin; Van den Berg, David J.; Edlund, Christopher K.; Conti, David V.; Hwang, Amie E.; Kong, Yinfei; Casey, Graham; Lieber, Michael R.; Ingles, Sue A.; Press, Michael F.; Mohrbacher, Ann F.; Stram, Daniel O.; Haiman, Christopher A.; Cozen, Wendy] Univ Southern Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Rand, Kristin A.; Song, Chi; Sheng, Xin; Van den Berg, David J.; Edlund, Christopher K.; Conti, David V.; Hwang, Amie E.; Kong, Yinfei; Casey, Graham; Lieber, Michael R.; Ingles, Sue A.; Press, Michael F.; Mohrbacher, Ann F.; Stram, Daniel O.; Haiman, Christopher A.; Cozen, Wendy] Univ Southern Calif, Norris Comprehens Canc Ctr, Topping Tower,1441 Eastlake Ave,Room 4451A, Los Angeles, CA 90033 USA. [Dean, Eric] Sutter Hlth, Oakland, CA USA. [Serie, Daniel J.; Ailawadhi, Sikander] Mayo Clin Jacksonville, 4500 San Pablo Rd, Jacksonville, FL 32224 USA. [Curtin, Karen; Atanackovic, Djordje; Glenn, Martha J.; Cannon-Albright, Lisa A.; Jones, Brandt; Camp, Nicola J.] Univ Utah, Sch Med, Salt Lake City, UT USA. [Hu, Donglei; Huntsman, Scott; Martin, Thomas G.; Wolf, Jeffrey L.; Ziv, Elad] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Huff, Carol Ann] Johns Hopkins Univ, Johns Hopkins Sch Med, Baltimore, MD USA. [Bernal-Mizrachi, Leon; Nooka, Ajay; Lonial, Sagar] Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. [Tomasson, Michael H.; Vij, Ravi; Colditz, Graham A.] Washington Univ, Sch Med, Alvin J Siteman Canc Ctr, St Louis, MO USA. [Singhal, Seema; Mehta, Jayesh; Murphy, Adam B.] Northwestern Univ, Robert H Lurie Canc Ctr, Chicago, IL 60611 USA. [Pawlish, Karen] New Jersey Dept Hlth, New Jersey State Canc Registry, Trenton, NJ USA. [Peters, Edward S.] Louisiana State Univ, Sch Publ Hlth, New Orleans, LA USA. [Bock, Cathryn H.; Pregja, Silvana L.; Severson, Richard K.; Zonder, Jeffrey A.] Wayne State Univ, Sch Med, Karmanos Canc Inst, Detroit, MI USA. [Bock, Cathryn H.; Pregja, Silvana L.; Severson, Richard K.; Zonder, Jeffrey A.] Wayne State Univ, Sch Med, Dept Oncol, Detroit, MI USA. [Stram, Alex] Genom Hlth Inc, Redwood City, CA USA. [Zimmerman, Todd; Chiu, Brian C.] Univ Chicago, Chicago, IL 60637 USA. [Graff, John; Bandera, Elisa V.] Rutgers State Univ, Rutgers Robert Wood Johnson Med Sch, New Brunswick, NJ USA. [Berndt, Sonja I.; Ziegler, Regina G.; Rothman, Nathaniel; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, US NIH, Bethesda, MD 20892 USA. [Blot, William J.; Zheng, Wei; Halverson, Sandra L. Deming] Int Epidemiol Inst, Rockville, MD USA. [Blot, William J.] Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, Div Epidemiol, Nashville, TN 37212 USA. [Carpten, John] Translat Genom Res Inst, Phoenix, AZ USA. [Chu, Lisa; John, Esther M.] Canc Prevent Inst Calif, Fremont, CA USA. [Chu, Lisa; Hsing, Ann W.; John, Esther M.] Stanford Univ, Sch Med, Palo Alto, CA 94304 USA. [Chu, Lisa; Hsing, Ann W.; John, Esther M.] Stanford Canc Inst, Palo Alto, CA USA. [Diver, W. Ryan; Stevens, Victoria L.] Amer Canc Soc, Atlanta, GA 30329 USA. [Goodman, Phyllis J.] SWOG Stat Ctr, Seattle, WA USA. [Hennis, Anselm J. M.; Leske, Cristina; Nemesure, Barbara] SUNY Stony Brook, Stony Brook, NY 11794 USA. [Hennis, Anselm J. M.] Univ West Indies, Chron Dis Res Ctr, Bridgetown, Barbados. [Hennis, Anselm J. M.] Univ West Indies, Fac Med Sci, Bridgetown, Barbados. [Kittles, Rick A.] Univ Arizona, Dept Surg, Tucson, AZ USA. [Kolb, Suzanne; Stanford, Janet L.; Bhatti, Parveen] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Klein, Eric A.] Cleveland Clin, Glickman Urol & Kidney Inst, Cleveland, OH 44106 USA. [Neslund-Dudas, Christine; Rybicki, Benjamin A.; Janakiraman, Nalini] Henry Ford Hosp, Detroit, MI 48202 USA. [Strom, Sara S.; Orlowski, Robert Z.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Signorello, Lisa B.; Birmann, Brenda M.] Harvard Univ, Harvard Sch Publ Hlth, Boston, MA 02115 USA. [Witte, John S.] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA. [Ambrosone, Christine B.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Bernstein, Leslie] City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Div Canc Etiol, Duarte, CA USA. [Olshan, Andrew F.; Nyante, Sarah J.] Univ N Carolina, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Olshan, Andrew F.; Nyante, Sarah J.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC USA. [Hu, Jennifer J.] Univ Miami, Miller Sch Med, Sylvester Comprehens Canc Ctr, Miami, FL 33136 USA. [Hu, Jennifer J.] Univ Miami, Miller Sch Med, Dept Epidemiol & Publ Hlth, Miami, FL 33136 USA. [Tricot, Guido] Univ Iowa, Iowa City, IA USA. [Kumar, Shaji K.; Rajkumar, S. Vincent; Slager, Susan L.; Vachon, Celine M.] Mayo Clin, Rochester, MN USA. [Brooks-Wilson, Angela R.; Spinelli, John J.] BC Canc Agcy, Vancouver, BC, Canada. [Kolonel, Laurence N.] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. [Terebelo, Howard R.] Providence Hosp, Southfield, MI 48037 USA. [Brown, Elizabeth E.] Univ Alabama Birmingham, Birmingham, AL USA. [De Roos, Anneclaire J.] Drexel Univ, Sch Publ Hlth, Philadelphia, PA 19104 USA. [Giles, Graham G.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Giles, Graham G.] Univ Melbourne, Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia. [Giles, Graham G.] Monash Univ, Melbourne, Vic, Australia. [Spinelli, John J.] Univ British Columbia, Sch Populat & Publ Hlth, Vancouver, BC, Canada. [Munshi, Nikhil C.; Anderson, Kenneth C.] Harvard Univ, Harvard Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Levy, Joan] Multiple Myeloma Res Fdn, Norwalk, CT USA. [Hazelett, Dennis J.] Cedars Sinai Med Ctr, Ctr Bioinformat & Computat Biol, Los Angeles, CA 90048 USA. RP Cozen, W (reprint author), Univ Southern Calif, Norris Comprehens Canc Ctr, Topping Tower,1441 Eastlake Ave,Room 4451A, Los Angeles, CA 90033 USA.; Haiman, CA (reprint author), USC Norris Comprehens Canc Ctr, Harlyne Norris Res Tower,1450 Biggy St,Room 1504, Los Angeles, CA 90033 USA.; Hazelett, DJ (reprint author), Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, 8700 Beverly Blvd, Los Angeles, CA 90048 USA. EM Dennis.Hazelett@csmc.edu; haiman@usc.edu; wcozen@usc.edu RI Brooks-Wilson, Angela/E-9399-2012 OI Brooks-Wilson, Angela/0000-0003-1009-6408 FU National Cancer Institute at the NIH [1R01CA134786, 2P50CA100707, Myeloma SPORE 2P50CA100707 Project, R01CA152336, R01CA134674, P50 CA142509, R01CA184464, R21CA155951, R25CA76023, R01CA186646, U54CA118948, P30CA13148, R21CA191896, K24CA169004]; Leukemia Lymphoma Society [LLS 6067-090]; American Cancer Society [IRG60-001-47]; Steve and Nancy Grand Multiple Myeloma Translational Initiative; National Cancer Institute Surveillance Epidemiology and End Results Population-based Registry Program, NIH, Department of Health and Human Services [N01-PC-35139]; HHSN [261201300021I, N01PC-2013 00021, HHSN261201000026C]; National Program of Cancer Registries of the Centers for Disease Control and Prevention [5U58DP003931-02, 1U58DP000807-01]; Huntsman Cancer Institute (HCI); HCI Cancer Center Support grant [P30 CA42014]; USC Norris Comprehensive Cancer Center Core grant from the National Cancer Institute [P30CA014089]; California Department of Health Services [103885]; NIH [CA63464, CA54281, CA1326792, CA148085, HG004726, CA056678, CA082664, CA092579, ES011126]; Intramural Research Program of the Division of Cancer Epidemiology and Genetics, NCI, NIH; Cancer Research Fund [99- 00524V10258, 9712013]; University of California [98-00924V]; Department of Health Services Cancer Research Program; NCI, NIH, Department of Health and Human Services [N01-PC-35139]; Fred Hutchinson Cancer Research Center; Intramural Program of the National Human Genome Research Institute; Public Health Service from the National Cancer Institute [U10 CA37429, UM1 CA182883]; Vanderbilt-Ingram Cancer Center [CA68485]; Department of Defense Breast Cancer Research Program Era of Hope Scholar Award [W81XWH-08-1-0383]; Norris Foundation [P01-CA151135, U19-CA148065]; MEC (NIH) [R01-CA63464, R37-CA54281, UM1-CA164973]; CARE (National Institute for Child Health and Development) [NO1-HD-3-3175, K05 CA136967]; WCHS [U.S. Army Medical Research and Material Command (USAMRMC)] [DAMD-17-01-0-0334]; WCHS [NIH] [R01-CA100598]; WCHS [Breast Cancer Research Foundation]; SFBCS (NIH) [R01-CA77305]; SFBCS (United States Army Medical Research Program) [DAMD17-96-6071]; NC-BCFR (NIH) [U01-CA69417]; CBCS (NIH Specialized Program of Research Excellence in Breast Cancer) [P50-CA58223]; Center for Environmental Health and Susceptibility National Institute of Environmental Health Sciences, NIH [P30-ES10126]; PLCO (Intramural Research Program, National Cancer Institute, NIH); NBHS (National Institutes of Health) [R01-CA100374]; WFBC (NIH) [R01-CA73629]; National Cancer Institute, NIH [RFA-CA-06-503]; [CA68578]; [ES007784]; [DAMD W81XWH-07-1-0645]; [CA140388]; [CA88164]; [CA127298] FX This study was supported by the National Cancer Institute at the NIH (1R01CA134786 to W. Cozen and Christopher A. Haiman; 2P50CA100707 to K.C. Anderson; Myeloma SPORE 2P50CA100707 Project 6 to K.C. Anderson, W. Cozen, and D.V. Conti; R01CA152336 and R01CA134674 to N. J. Camp; P50 CA142509 and R01CA184464 to R. Z. Orlowski; R21CA155951, R25CA76023, R01CA186646, U54CA118948 Project 3 and P30CA13148 (seed grant) to E. E. Brown; and R21CA191896 and K24CA169004 to E. Ziv). The study also received support from the Leukemia Lymphoma Society (LLS 6067-090) to N. J. Camp, the American Cancer Society (IRG60-001-47) to E. E. Brown, and the Steve and Nancy Grand Multiple Myeloma Translational Initiative to E. Ziv. Data collection from the cancer registries was supported by the National Cancer Institute Surveillance Epidemiology and End Results Population-based Registry Program, NIH, Department of Health and Human Services, under contracts N01-PC-35139 (to USC for Los Angeles County), HHSN 261201300021I, N01PC-2013 00021 (to the New Jersey State Cancer Registry), and HHSN261201000026C (to the Utah Cancer Registry). Additional support for collection of incident multiple myeloma patient data was obtained from the Utah State Department of Health and the University of Utah, the Utah Population Database (UPDB) and the Utah Cancer Registry (UCR), the National Program of Cancer Registries of the Centers for Disease Control and Prevention (5U58DP003931-02 to the New Jersey State Cancer Registry and 1U58DP000807-01 to the California Cancer Registry), the Huntsman Cancer Institute (HCI) and the HCI Cancer Center Support grant, P30 CA42014 and by the USC Norris Comprehensive Cancer Center Core grant P30CA014089 from the National Cancer Institute. The collection of patients used in this publication was supported in part by the California Department of Health Services as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885. AAPC studies: The MEC is supported by NIH grants CA63464, CA54281, CA1326792, CA148085, and HG004726. Genotyping of the PLCO samples was funded by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, NCI, NIH. LAAPC was funded by grant 99- 00524V10258 from the Cancer Research Fund, under Interagency Agreement # 9712013 (University of California contract # 98-00924V) with the Department of Health Services Cancer Research Program. Cancer incidence data for the MEC and LAAPC studies have been collected by the Los Angeles Cancer Surveillance Program of the University of Southern California with Federal funds from the NCI, NIH, Department of Health and Human Services, under Contract No. N01-PC-35139, and the California Department of Health Services as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885, and grant number 1U58DP000807-3 from the Centers for Disease Control and Prevention. KCPCS was supported by NIH grants CA056678, CA082664, and CA092579, with additional support from the Fred Hutchinson Cancer Research Center and the Intramural Program of the National Human Genome Research Institute. MDA was supported by grants, CA68578, ES007784, DAMD W81XWH-07-1-0645, and CA140388. CaP Genes was supported by CA88164 and CA127298. SELECT was funded in part by Public Health Service grants U10 CA37429 (C.D. Blanke) and UM1 CA182883 (I. M. Thompson/C.M. Tangen) from the National Cancer Institute. GECAP was supported by NIH grant ES011126.; SCCS sample preparation was conducted at the Epidemiology Biospecimen Core Lab that is supported in part by the Vanderbilt-Ingram Cancer Center (CA68485).; AABC studies: AABC was supported by a Department of Defense Breast Cancer Research Program Era of Hope Scholar Award to CAH (W81XWH-08-1-0383), the Norris Foundation, P01-CA151135 and U19-CA148065. Each of the participating studies was supported by the following grants: MEC (NIH grants R01-CA63464, R37-CA54281 and UM1-CA164973); CARE (National Institute for Child Health and Development grant NO1-HD-3-3175, K05 CA136967); WCHS [U.S. Army Medical Research and Material Command (USAMRMC) grant DAMD-17-01-0-0334, the NIH grant R01-CA100598, and the Breast Cancer Research Foundation]; SFBCS (NIH grant R01-CA77305 and United States Army Medical Research Program grant DAMD17-96-6071); NC-BCFR (NIH grant U01-CA69417); CBCS (NIH Specialized Program of Research Excellence in Breast Cancer, grant number P50-CA58223, and Center for Environmental Health and Susceptibility National Institute of Environmental Health Sciences, NIH, grant number P30-ES10126); PLCO (Intramural Research Program, National Cancer Institute, NIH); NBHS (National Institutes of Health grant R01-CA100374); WFBC (NIH grant R01-CA73629). The Breast Cancer Family Registry (BCFR) was supported by the National Cancer Institute, NIH under RFA-CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry and Principal Investigators. NR 38 TC 0 Z9 0 U1 5 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD DEC PY 2016 VL 25 IS 12 BP 1609 EP 1618 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA EE6FL UT WOS:000389704300009 PM 27587788 ER PT J AU Awad, MM Jones, RE Liu, HY Lizotte, PH Ivanova, EV Kulkarni, M Herter-Sprie, GS Liao, XY Santos, AA Bittinger, MA Keogh, L Koyama, S Almonte, C English, JM Barlow, J Richards, WG Barbie, DA Bass, AJ Rodig, SJ Hodi, FS Wucherpfennig, KW Janne, PA Sholl, LM Hammerman, PS Wong, KK Bueno, R AF Awad, Mark M. Jones, Robert E. Liu, Hongye Lizotte, Patrick H. Ivanova, Elena V. Kulkarni, Meghana Herter-Sprie, Grit S. Liao, Xiaoyun Santos, Abigail A. Bittinger, Mark A. Keogh, Lauren Koyama, Shohei Almonte, Christina English, Jessie M. Barlow, Julianne Richards, William G. Barbie, David A. Bass, Adam J. Rodig, Scott J. Hodi, F. Stephen Wucherpfennig, Kai W. Janne, Pasi A. Sholl, Lynette M. Hammerman, Peter S. Wong, Kwok-Kin Bueno, Raphael TI Cytotoxic T Cells in PD-L1-Positive Malignant Pleural Mesotheliomas Are Counterbalanced by Distinct Immunosuppressive Factors SO CANCER IMMUNOLOGY RESEARCH LA English DT Article ID ADAPTIVE IMMUNE RESISTANCE; LUNG-CANCER; TUMOR MICROENVIRONMENT; SUPPRESSOR-CELLS; OVARIAN-CANCER; BREAST-CANCER; PD-1 BLOCKADE; NIVOLUMAB; EXHAUSTION; MELANOMA AB PD-L1 immunohistochemical staining does not always predict whether a cancer will respond to treatment with PD-1 inhibitors. We sought to characterize immune cell infiltrates and the expression of T-cell inhibitor markers in PD-L1-positive and PD-L1-negative malignant pleural mesothelioma samples. We developed a method for immune cell phenotyping using flow cytometry on solid tumors that have been dissociated into single-cell suspensions and applied this technique to analyze 43 resected malignant pleural mesothelioma specimens. Compared with PD-L1-negative tumors, PD-L1-positive tumors had significantly more infiltrating CD45(+) immune cells, a significantly higher proportion of infiltrating CD3(+) T cells, and a significantly higher percentage of CD3(+) cells displaying the activated HLA-DR+/CD38(+) phenotype. PD-L1-positive tumors also had a significantly higher proportion of proliferating CD8(+) T cells, a higher fraction of FOXP3(+)/CD4(+) Tregs, and increased expression of PD-1 and TIM-3 on CD4(+) and CD8(+) T cells. Double-positive PD-1(+)/TIM-3(+) CD8(+) T cells were more commonly found on PD-L1-positive tumors. Compared with epithelioid tumors, sarcomatoid and biphasic mesothelioma samples were significantly more likely to be PD-L1 positive and showed more infiltration with CD3(+) T cells and PD-1(+)/TIM-3(+) CD8(+) T cells. Immunologic phenotypes in mesothelioma differ based on PD-L1 status and histologic subtype. Successful incorporation of comprehensive immune profiling by flow cytometry into prospective clinical trials could refine our ability to predict which patients will respond to specific immune checkpoint blockade strategies. (C) 2016 AACR. C1 [Awad, Mark M.; Jones, Robert E.; Liu, Hongye; Lizotte, Patrick H.; Ivanova, Elena V.; Kulkarni, Meghana; Herter-Sprie, Grit S.; Santos, Abigail A.; Bittinger, Mark A.; Keogh, Lauren; Koyama, Shohei; Almonte, Christina; English, Jessie M.; Barbie, David A.; Bass, Adam J.; Hodi, F. Stephen; Wucherpfennig, Kai W.; Janne, Pasi A.; Hammerman, Peter S.; Wong, Kwok-Kin] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Awad, Mark M.; Santos, Abigail A.; Barbie, David A.; Janne, Pasi A.; Hammerman, Peter S.; Wong, Kwok-Kin] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02115 USA. [Awad, Mark M.; Liao, Xiaoyun; Barlow, Julianne; Richards, William G.; Barbie, David A.; Bass, Adam J.; Rodig, Scott J.; Hodi, F. Stephen; Wucherpfennig, Kai W.; Janne, Pasi A.; Sholl, Lynette M.; Hammerman, Peter S.; Wong, Kwok-Kin; Bueno, Raphael] Harvard Med Sch, Boston, MA USA. [Jones, Robert E.; Liu, Hongye; Lizotte, Patrick H.; Ivanova, Elena V.; Kulkarni, Meghana; Herter-Sprie, Grit S.; Bittinger, Mark A.; Keogh, Lauren; Koyama, Shohei; Almonte, Christina; English, Jessie M.; Janne, Pasi A.; Wong, Kwok-Kin] Dana Farber Canc Inst, Belfer Ctr Appl Sci, Boston, MA 02115 USA. [Liao, Xiaoyun; Rodig, Scott J.; Sholl, Lynette M.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Barlow, Julianne; Richards, William G.; Bueno, Raphael] Brigham & Womens Hosp, Dept Surg, 75 Francis St, Boston, MA 02115 USA. [Barlow, Julianne; Richards, William G.; Bueno, Raphael] Brigham & Womens Hosp, Div Thorac Surg, 75 Francis St, Boston, MA 02115 USA. RP Wong, KK (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM kwok-kin_wong@dfci.harvard.edu OI Lizotte, Patrick/0000-0001-9510-0036 NR 48 TC 1 Z9 1 U1 2 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2326-6066 EI 2326-6074 J9 CANCER IMMUNOL RES JI Cancer Immunol. Res. PD DEC PY 2016 VL 4 IS 12 BP 1038 EP 1048 DI 10.1158/2326-6066.CIR-16-0171 PG 11 WC Oncology; Immunology SC Oncology; Immunology GA EE6FA UT WOS:000389702900006 PM 27856426 ER PT J AU Zhou, F Xu, YY Shi, J Lan, X Zou, XP Wang, L Huang, Q AF Zhou, Fan Xu, Yuanyuan Shi, Jiong Lan, Xing Zou, Xiaoping Wang, Lei Huang, Qin TI Expression profile of E-cadherin, estrogen receptors, and P53 in early-onset gastric cancers SO CANCER MEDICINE LA English DT Article DE Early-onset gastric cancer (EOGC); E-cadherin; estrogen receptors (ERs); P53 ID GENETIC PREDISPOSITION; GERMLINE MUTATIONS; PROGNOSTIC ROLE; YOUNG-PATIENTS; CARCINOMAS; SURVIVAL; OVEREXPRESSION; CONTRIBUTE; FEATURES; PROTEIN AB Early-onset gastric cancer (EOGC) is predominant in females, diffuse histology, and hereditary pattern. Germline mutation of CDH1 and p53 has been reported previously and female dominance was speculated to be associated with estrogen and its receptors. Expression of E-cadherin, estrogen receptor alpha (ER alpha), estrogen receptor beta (ER beta), and p53 in EOGC remains unclear, which was the focus of this study, to assess clinical significance of their expression in EOGC. The expression of E-cadherin, ER alpha, ER beta, and p53 in tumors and normal tissues from surgically resected EOGCs was assessed by immunohistochemistry (n = 139) and Western blot (n = 7) methods, respectively. The expression in tumor tissues was significantly higher for ER alpha, ER beta, and p53, but lower for E-cadherin, compared to uninvolved mucosa. Positive staining of ER beta and p53 was more frequently observed in younger patients with advanced TNM stages. For -E-cadherin, significant correlation was observed between the immunopositivity and TNM stages IA+ IB. P53-negative patients had significantly better outcomes than p53-positive patients. Significant association between expression of -E-cadherin and histologic types was found in familial, but not in sporadic, EOGC. In conclusion, our results demonstrated E-cadherin may have a role in initiation of EOGC and positive ER beta and p53 expression may partially explained early-onset and tumor progression of EOGC. C1 [Zhou, Fan; Xu, Yuanyuan; Zou, Xiaoping; Wang, Lei] Nanjing Univ, Dept Gastroenterol, Drum Tower Hosp, Sch Med, Nanjing, Jiangsu, Peoples R China. [Shi, Jiong; Huang, Qin] Nanjing Univ, Dept Pathol, Drum Tower Hosp, Sch Med, Nanjing, Jiangsu, Peoples R China. [Lan, Xing] Xuzhou Med Univ, Xuzhou, Jiangsu, Peoples R China. [Huang, Qin] VA Boston Healthcare Syst, Dept Pathol, Boston, MA 02130 USA. [Huang, Qin] Harvard Med Sch, Boston, MA 02115 USA. RP Huang, Q (reprint author), VA Boston Healthcare Syst, Dept Pathol, Boston, MA 02130 USA.; Huang, Q (reprint author), Harvard Med Sch, Boston, MA 02115 USA.; Wang, L (reprint author), Nanjing Univ, Sch Med, Drum Tower Hosp, Nanjing, Jiangsu, Peoples R China. EM wang128zb@gmail.com; qinhuang0122@hotmail.com FU Nanjing Scientific Technology and Development Project (Nanjing, China) [201402032] FX This work was supported by Nanjing Scientific Technology and Development Project 201402032 (Nanjing, China). NR 37 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2045-7634 J9 CANCER MED-US JI Cancer Med. PD DEC PY 2016 VL 5 IS 12 BP 3403 EP 3411 DI 10.1002/cam4.931 PG 9 WC Oncology SC Oncology GA EE7YK UT WOS:000389841200005 PM 27781410 ER PT J AU Driscoll, DR Karim, SA Sano, M Gay, DM Jacob, W Yu, J Mizukami, Y Gopinathan, A Jodrell, DI Evans, TRJ Bardeesy, N Hall, MN Quattrochi, BJ Klimstra, DS Barry, ST Sansom, OJ Lewis, BC Morton, JP AF Driscoll, David R. Karim, Saadia A. Sano, Makoto Gay, David M. Jacob, Wright Yu, Jun Mizukami, Yusuke Gopinathan, Aarthi Jodrell, Duncan I. Evans, T. R. Jeffry Bardeesy, Nabeel Hall, Michael N. Quattrochi, Brian J. Klimstra, David S. Barry, Simon T. Sansom, Owen J. Lewis, Brian C. Morton, Jennifer P. TI mTORC2 Signaling Drives the Development and Progression of Pancreatic Cancer SO CANCER RESEARCH LA English DT Article ID DUCTAL ADENOCARCINOMA; ONCOGENIC KRAS; COMPLEX 2; PTEN-LOSS; RICTOR; MICE; ACTIVATION; PATHWAY; TUMORIGENESIS; INHIBITION AB mTOR signaling controls several critical cellular functions and is deregulated in many cancers, including pancreatic cancer. To date, most efforts have focused on inhibiting the mTORC1 complex. However, clinical trials of mTORC1 inhibitors in pancreatic cancer have failed, raising questions about this therapeutic approach. We employed a genetic approach to delete the obligate mTORC2 subunit Rictor and identified the critical times during which tumorigenesis requires mTORC2 signaling. Rictor deletion resulted in profoundly delayed tumorigenesis. Whereas previous studies showed most pancreatic tumors were insensitive to rapamycin, treatment with a dual mTORC1/2 inhibitor strongly suppressed tumorigenesis. In late-stage tumor-bearing mice, combined mTORC1/2 and PI3K inhibition significantly increased survival. Thus, targeting mTOR may be a potential therapeutic strategy in pancreatic cancer. (C) 2016 AACR. C1 [Driscoll, David R.; Yu, Jun; Quattrochi, Brian J.; Lewis, Brian C.] Univ Massachusetts, Sch Med, Dept Mol Cell & Canc Biol, Worcester, MA USA. [Karim, Saadia A.; Gay, David M.; Evans, T. R. Jeffry; Sansom, Owen J.; Morton, Jennifer P.] CRUK Beatson Inst, Switchback Rd, Glasgow G61 1BD, Lanark, Scotland. [Sano, Makoto] Nihon Univ, Dept Pathol & Microbiol, Sch Med, Tokyo, Japan. [Jacob, Wright; Evans, T. R. Jeffry; Sansom, Owen J.; Morton, Jennifer P.] Univ Glasgow, Inst Canc Sci, Glasgow, Lanark, Scotland. [Mizukami, Yusuke; Bardeesy, Nabeel] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Gopinathan, Aarthi; Jodrell, Duncan I.] CRUK Cambridge Inst, Cambridge, England. [Hall, Michael N.] Univ Basel, Biozentrum, Basel, Switzerland. [Klimstra, David S.] Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA. [Barry, Simon T.] AstraZeneca, Macclesfield, Cheshire, England. [Lewis, Brian C.] Univ Massachusetts, Sch Med, Ctr Canc, Worcester, MA USA. RP Sansom, OJ (reprint author), CRUK Beatson Inst, Switchback Rd, Glasgow G61 1BD, Lanark, Scotland.; Lewis, BC (reprint author), Univ Massachusetts, Sch Med, 364 Plantat St,LRB 521, Worcester, MA 01605 USA. EM o.sansom@beatson.gla.ac.uk; Brian.Lewis@umassmed.edu FU Cancer Research UK [11650, A12481, A18076, A11650]; NCI NIH HHS [F30 CA168063, R01 CA155784] NR 55 TC 1 Z9 1 U1 3 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 1 PY 2016 VL 76 IS 23 BP 6911 EP 6923 DI 10.1158/0008-5472.CAN-16-0810 PG 13 WC Oncology SC Oncology GA EE2SX UT WOS:000389435800017 PM 27758884 ER PT J AU Horn, T Ferretti, S Ebel, N Tam, A Ho, S Harbinski, F Farsidjani, A Zubrowski, M Sellers, WR Schlegel, R Porter, D Morris, E Wuerthner, J Jeay, S Greshock, J Halilovic, E Garraway, LA Caponigro, G Lehaar, J AF Horn, Thomas Ferretti, Stephane Ebel, Nicolas Tam, Angela Ho, Samuel Harbinski, Fred Farsidjani, Ali Zubrowski, Matthew Sellers, William R. Schlegel, Robert Porter, Dale Morris, Erick Wuerthner, Jens Jeay, Sebastien Greshock, Joel Halilovic, Ensar Garraway, Levi A. Caponigro, Giordano Lehar, Joseph TI High-Order Drug Combinations Are Required to Effectively Kill Colorectal Cancer Cells SO CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR RECEPTOR; MEK INHIBITION; ACQUIRED-RESISTANCE; NEGATIVE FEEDBACK; RAF; ACTIVATION; MELANOMA; MODELS; KRAS; FLUOROURACIL AB Like classical chemotherapy regimens used to treat cancer, targeted therapies will also rely upon polypharmacology, but tools are still lacking to predict which combinations of molecularly targeted drugs may be most efficacious. In this study, we used image-based proliferation and apoptosis assays in colorectal cancer cell lines to systematically investigate the efficacy of combinations of two to six drugs that target critical oncogenic pathways. Drug pairs targeting key signaling pathways resulted in synergies across a broad spectrum of genetic backgrounds but often yielded only cytostatic responses. Enhanced cytotoxicity was observed when additional processes including apoptosis and cell cycle were targeted as part of the combination. In some cases, where cell lines were resistant to paired and tripled drugs, increased expression of antiapoptotic proteins was observed, requiring a fourth-order combination to induce cytotoxicity. Our results illustrate how high-order drug combinations are needed to kill drug-resistant cancer cells, and they also show how systematic drug combination screening together with a molecular understanding of drug responses may help define optimal cocktails to overcome aggressive cancers. (C) 2016 AACR. C1 [Horn, Thomas; Tam, Angela; Zubrowski, Matthew; Schlegel, Robert; Porter, Dale; Morris, Erick; Greshock, Joel; Halilovic, Ensar; Caponigro, Giordano; Lehar, Joseph] Novartis Inst Biomed Res, Translat Clin Oncol, Cambridge, MA 02139 USA. [Ferretti, Stephane; Ebel, Nicolas; Wuerthner, Jens; Jeay, Sebastien] Novartis Inst Biomed Res, Oncol Dis Area, Basel, Switzerland. [Ho, Samuel; Farsidjani, Ali; Sellers, William R.] Novartis Inst Biomed Res, Oncol Dis Area, Cambridge, MA USA. [Harbinski, Fred] Novartis Inst Biomed Res, Dev & Mol Pathways, Cambridge, MA USA. [Garraway, Levi A.] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA. RP Lehaar, J (reprint author), Novartis Inst Biomed Res, Translat Clin Oncol, Cambridge, MA 02139 USA.; Caponigro, G (reprint author), Novartis Inst BioMed Res, 250 Massachusetts Ave, Cambridge, MA 02139 USA. EM giordano.caponigro@novartis.com; lehar@google.com NR 50 TC 1 Z9 1 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 1 PY 2016 VL 76 IS 23 BP 6950 EP 6963 DI 10.1158/0008-5472.CAN-15-3425 PG 14 WC Oncology SC Oncology GA EE2SX UT WOS:000389435800020 PM 27659046 ER PT J AU Ingle, JN Xie, F Ellis, MJ Goss, PE Shepherd, LE Chapman, JAW Chen, BE Kubo, M Furukawa, Y Momozawa, Y Stearns, V Pritchard, KI Barman, P Carlson, EE Goetz, MP Weinshilboum, RM Kalari, KR Wang, LW AF Ingle, James N. Xie, Fang Ellis, Matthew J. Goss, Paul E. Shepherd, Lois E. Chapman, Judith-Anne W. Chen, Bingshu E. Kubo, Michiaki Furukawa, Yoichi Momozawa, Yukihide Stearns, Vered Pritchard, Kathleen I. Barman, Poulami Carlson, Erin E. Goetz, Matthew P. Weinshilboum, Richard M. Kalari, Krishna R. Wang, Liewei TI Genetic Polymorphisms in the Long Noncoding RNA MIR2052HG Offer a Pharmacogenomic Basis for the Response of Breast Cancer Patients to Aromatase Inhibitor Therapy SO CANCER RESEARCH LA English DT Article ID TRANSCRIPTION FACTOR FOXO3A; ESTROGEN-RECEPTOR-ALPHA; DNA-SEQUENCING DATA; ENDOCRINE RESISTANCE; LEVEL METAANALYSIS; RANDOMIZED-TRIALS; GENOME; ASSOCIATION; MECHANISMS; EXPRESSION AB Genetic risks in breast cancer remain only partly understood. Here, we report the results of a genome-wide association study of germline DNA from 4,658 women, including 252 women experiencing a breast cancer recurrence, who were entered on the MA. 27 adjuvant trial comparing the aromatase inhibitors (AI) anastrozole and exemestane. Single-nucleotide polymorphisms (SNP) of top significance were identified in the gene encoding MIR2052HG, a long noncoding RNA of unknown function. Heterozygous or homozygous individuals for variant alleles exhibited a similar to 40% or similar to 63% decrease, respectively, in the hazard of breast cancer recurrence relative to homozygous wild-type individuals. Functional genomic studies in lymphoblastoid cell lines and ER alpha-positive breast cancer cell lines showed that expression from MIR2052HG and the ESR1 gene encoding estrogen receptor-alpha (ER alpha) was induced by estrogen and AI in a SNP-dependent manner. Variant SNP genotypes exhibited increased ER alpha binding to estrogen response elements, relative to wild-type genotypes, a pattern that was reversed by AI treatment. Further, variant SNPs were associated with lower expression of MIR2052HG and ER alpha. RNAi-mediated silencing of MIR2052HG in breast cancer cell lines decreased ER alpha expression, cell proliferation, and anchor-age-independent colony formation. Mechanistic investigations revealed that MIR2052HG sustained ER alpha levels both by promoting AKT/FOXO3-mediated ESR1 transcription and by limiting ubiquitin-mediated, proteasome-dependent degradation of ER alpha. Taken together, our results define MIR2052HS as a functionally polymorphic gene that affects risks of breast cancer recurrence in women treated with AI. More broadly, our results offer a pharmacogenomic basis to understand differences in the response of breast cancer patients to AI therapy. (C) 2016 AACR. C1 [Ingle, James N.; Goetz, Matthew P.] Mayo Clin, Div Med Oncol, Rochester, MN USA. [Xie, Fang; Weinshilboum, Richard M.; Wang, Liewei] Mayo Clin, Dept Mol Pharmacol & Expt Therapeut, Div Clin Pharmacol, Rochester, MN USA. [Ellis, Matthew J.] Baylor Breast Ctr, Houston, TX USA. [Goss, Paul E.] Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Shepherd, Lois E.; Chapman, Judith-Anne W.; Chen, Bingshu E.] Canadian Canc Trials Grp, Kingston, ON, Canada. [Kubo, Michiaki; Momozawa, Yukihide] RIKEN, Ctr Integrat Med Sci, Yokohama, Kanagawa, Japan. [Furukawa, Yoichi] Univ Tokyo, Tokyo, Japan. [Stearns, Vered] Johns Hopkins Sch Med, Baltimore, MD USA. [Pritchard, Kathleen I.] Univ Toronto, Sunnybrook Odette Reg Canc Ctr, Toronto, ON, Canada. [Barman, Poulami; Carlson, Erin E.; Kalari, Krishna R.] Mayo Clin, Dept Hlth Sci Res, Div Biomed Stat & Informat, Rochester, MN USA. RP Ingle, JN (reprint author), Mayo Clin, 200 First St SW,GO 19 460RES, Rochester, MN 55905 USA. EM ingle.james@mayo.edu FU NCI NIH HHS [P50 CA116201, R01 CA196648, U10 CA077202]; NIGMS NIH HHS [U01 GM061388, U19 GM061388] NR 50 TC 0 Z9 0 U1 3 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 1 PY 2016 VL 76 IS 23 BP 7012 EP 7023 DI 10.1158/0008-5472.CAN-16-1371 PG 12 WC Oncology SC Oncology GA EE2SX UT WOS:000389435800025 PM 27758888 ER PT J AU Hayashi, A Fukuda, S Mahara, K Hei, S Onoue, T Kado, Y Nagata, Y Iwataki, M Otani, K Miyamoto, T Oginosawa, Y Sonoda, S Eto, M Nishimura, Y Takanashi, S Levine, RA Otsuji, Y AF Hayashi, Atsushi Fukuda, Shota Mahara, Keitaro Hei, Soshi Onoue, Takeshi Kado, Yuichiro Nagata, Yasufumi Iwataki, Mai Otani, Kyoko Miyamoto, Tetsu Oginosawa, Yasushi Sonoda, Shinjo Eto, Masataka Nishimura, Yosuke Takanashi, Shuichiro Levine, Robert A. Otsuji, Yutaka TI Left Atrial Remodeling in Segmental vs. Global Mitral Valve Prolapse - Three-Dimensional Echocardiography SO CIRCULATION JOURNAL LA English DT Article DE Echocardiography; Left atrium; Mitral valve ID POSTERIOR LEAFLET; REGURGITATION; SEVERITY; REPAIR; SIZE; DETERMINANTS; ANNULOPLASTY; MORTALITY; ANNULUS; SHAPE AB Background: Segmental and global mitral valve prolapse (MVP) comprise 2 representative phenotypes in this syndrome. While mitral regurgitation (MR) severity is a major factor causing left atrial (LA) remodeling in MVP, prominent mitral valve (MV) annulus dilatation in global MVP may specifically cause inferiorly predominant LA remodeling. We compared MV annulus and LA geometry in patients with segmental and global MVP. Methods and Results: LA volume as well as inferior, middle, and superior LA cross-sectional areas (CSA) were measured on 3-D echocardiography in 20 controls, in 40 patients with segmental MVP, and in 18 with global MVP. On multivariate analysis, MR severity was primarily associated with LA dilatation in segmental MVP (P<0.001), while MV annular dilatation was primarily associated with LA dilatation in global MVP (P<0.001). Although there was no regional predominance in LA dilatation in segmental MVP, inferior predominance of LA dilatation was significant in global MVP (increase in inferior, middle, and superior LA-CSA relative to mean of the controls: +220 +/- 70% vs. +171 +/- 55% vs. + 137 +/- 37%, P<0.001). Conclusions: LA remodeling in segmental and global MVP is considerably different regarding its association with MR volume or MV annular dilatation and its regional predominance. While MR volume may mainly contribute to LA remodeling in segmental MVP, MV annular dilatation seems to have an important role in LA remodeling in global MVP. C1 [Hayashi, Atsushi; Fukuda, Shota; Hei, Soshi; Onoue, Takeshi; Nagata, Yasufumi; Iwataki, Mai; Miyamoto, Tetsu; Oginosawa, Yasushi; Sonoda, Shinjo; Otsuji, Yutaka] Univ Occupat & Environm Hlth, Sch Med, Dept Internal Med 2, Kitakyushu, Fukuoka, Japan. [Kado, Yuichiro; Eto, Masataka; Nishimura, Yosuke] Univ Occupat & Environm Hlth, Sch Med, Dept Cardiovasc Surg, Kitakyushu, Fukuoka, Japan. [Otani, Kyoko] Univ Occupat & Environm Hlth, Sch Med, Dept Lab & Transfus Med, Kitakyushu, Fukuoka, Japan. [Mahara, Keitaro] Sakakibara Heart Inst, Dept Cardiol, Fuchu, Tokyo, Japan. [Takanashi, Shuichiro] Sakakibara Heart Inst, Dept Cardiovasc Surg, Fuchu, Tokyo, Japan. [Levine, Robert A.] Harvard Med Sch, Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Boston, MA USA. RP Otsuji, Y (reprint author), Univ Occupat & Environm Hlth, Dept Internal Med 2, Sch Med, Yahatanishi Ku, 1-1 Iseigaoka, Kitakyushu, Fukuoka 8078555, Japan. EM otsujiy@med.uoeh-u.ac.jp OI Mahara, Keitaro/0000-0002-4514-0088 FU Japan Society of the Promotion of Science [15K10226, 15K01346] FX S.F., K.M., M.E., Y. Nishimura, S.T. and Y. Otsuji were supported by Grants-in-aid for Scientific Research from the Japan Society of the Promotion of Science (15K10226 for S.F., K.M., M.E., Y. Nishimura, S.T. and Y. Otsuji, and 15K01346 for Y. Otsuji). NR 26 TC 0 Z9 0 U1 0 U2 0 PU JAPANESE CIRCULATION SOC PI TOYKO PA 18TH FLOOR IMPERIAL HOTEL TOWER, 1-1-1 UCHISAIWAI-CHO CHIYODA-KU, TOYKO, 100-0011, JAPAN SN 1346-9843 EI 1347-4820 J9 CIRC J JI Circ. J. PD DEC PY 2016 VL 80 IS 12 BP 2533 EP 2540 DI 10.1253/circj.CJ-16-0694 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EE0IW UT WOS:000389258800020 PM 27829586 ER PT J AU Beyaz, S Yilmaz, OH AF Beyaz, Semir Yilmaz, Omer H. TI Molecular Pathways: Dietary Regulation of Stemness and Tumor Initiation by the PPAR-delta Pathway SO CLINICAL CANCER RESEARCH LA English DT Article ID ACTIVATED-RECEPTOR-DELTA; ACID-BINDING PROTEIN; BETA/DELTA AGONIST; FATTY-ACIDS; PROLIFERATOR; CANCER; OBESITY; CELLS; METABOLISM; GROWTH AB Peroxisome proliferator-activated receptor delta (PPAR-delta) is a nuclear receptor transcription factor that regulates gene expression during development and disease states, such as cancer. However, the precise role of PPAR-delta during tumorigenesis is not well understood. Recent data suggest that PPAR-delta may have context-specific oncogenic and tumor-suppressive roles depending on the tissue, cell-type, or diet-induced physiology in question. For example, in the intestine, pro-obesity diets, such as a high-fat diet (HFD), are associated with increased colorectal cancer incidence. Interestingly, many of the effects of an HFD in the stem and progenitor cell compartment are driven by a robust PPAR-delta program and contribute to the early steps of intestinal tumorigenesis. Importantly, the PPAR-delta pathway or its downstream mediators may serve as therapeutic intervention points or biomarkers in colon cancer that arise in patients who are obese. Although potent PPAR-delta agonists and antagonists exist, their clinical utility may be enhanced by uncovering how PPAR-delta mediates tumorigenesis in diverse tissues and cell types as well as in response to diet. (C) 2016 AACR. C1 [Beyaz, Semir; Yilmaz, Omer H.] MIT, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Beyaz, Semir; Yilmaz, Omer H.] MIT, Dept Biol, Cambridge, MA USA. [Beyaz, Semir] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA USA. [Beyaz, Semir] Harvard Med Sch, Harvard Stem Cell Inst, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA USA. [Yilmaz, Omer H.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Yilmaz, Omer H.] Harvard Med Sch, Boston, MA USA. RP Yilmaz, OH (reprint author), MIT, 500 Main St, Cambridge, MA 02142 USA. EM ohyilmaz@mit.edu FU V Foundation V Scholar Award; Sidney Kimmel Scholar Award; Pew-Stewart Trust Scholar Award; Kathy and Curt Marble Cancer Research Fund; American Federation of Aging Research; [NIHR00 AG045144] FX This work was supported by the NIHR00 AG045144, V Foundation V Scholar Award, the Sidney Kimmel Scholar Award, the Pew-Stewart Trust Scholar Award, Kathy and Curt Marble Cancer Research Fund, and American Federation of Aging Research (to O.H. Yilmaz). NR 60 TC 1 Z9 1 U1 5 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 DEC 1 PY 2016 VL 22 IS 23 BP 5636 EP 5641 DI 10.1158/1078-0432.CCR-16-0775 PG 6 WC Oncology SC Oncology GA EE2TS UT WOS:000389438100004 PM 27702819 ER PT J AU Braun, DA Burke, KP Van Allen, EM AF Braun, David A. Burke, Kelly P. Van Allen, Eliezer M. TI Genomic Approaches to Understanding Response and Resistance to Immunotherapy SO CLINICAL CANCER RESEARCH LA English DT Review ID IMMUNE CHECKPOINT BLOCKADE; CELL LUNG-CANCER; PD-1 BLOCKADE; METASTATIC MELANOMA; UNTREATED MELANOMA; ANTITUMOR IMMUNITY; CTLA-4 BLOCKADE; ANTI-PD-1 THERAPY; HIGH-THROUGHPUT; UP-REGULATION AB Immunotherapy has led to a paradigm shift in the treatment of some malignancies, providing long-term, durable responses for patients with advanced cancers. However, such therapy has benefited only a subset of patients, with some patients failing to respond to treatment at all and others achieving a limited response followed by tumor progression. Understanding factors contributing to an effective response and further elucidating mechanisms of resistance will be crucial as these therapies are applied more broadly. Genomics-based approaches have significantly advanced the study of response and resistance to immunotherapy in general, and to immune checkpoint blockade more specifically. Here, we review how genomic and transcriptomic approaches have identified both somatic and germline positive correlates of response, including high mutational/neoantigen load and low intratumoral heterogeneity, among others. The genomic analysis of resistant tumors has additionally identified crucial factors involved in resistance to immune checkpoint blockade, including loss of PTEN and upregulation of other immune checkpoints. Overall, the continued use of genomic techniques at the point of care, combined with appropriate functional studies, would ideally lead to a better understanding of why certain patients respond to immune-based therapies, allowing clinicians to identify the subset of patients likely to benefit from such therapy, and potentially providing insight into how other therapies may be added in combination to increase the number of patients who may benefit from immunotherapy. (C) 2016 AACR. C1 [Braun, David A.; Burke, Kelly P.; Van Allen, Eliezer M.] Harvard Med Sch, Dana Farber Canc Inst, Med Oncol, Boston, MA USA. [Braun, David A.] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Van Allen, Eliezer M.] MIT & Harvard, Broad Inst, Canc Program, Cambridge, MA USA. [Van Allen, Eliezer M.] Dana Farber Canc Inst, Ctr Canc Precis Med, Boston, MA 02115 USA. RP Van Allen, EM (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM eliezerm_vanallen@dfci.harvard.edu FU Kure It-AACR Research Grant for Immunotherapy for Kidney Cancer, BroadIgnite; BroadNext10 FX This work supported by the Kure It-AACR Research Grant for Immunotherapy for Kidney Cancer, BroadIgnite, and BroadNext10. NR 75 TC 1 Z9 1 U1 4 U2 4 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 DEC 1 PY 2016 VL 22 IS 23 BP 5642 EP 5650 DI 10.1158/1078-0432.CCR-16-0066 PG 9 WC Oncology SC Oncology GA EE2TS UT WOS:000389438100005 PM 27698000 ER PT J AU Stover, EH Konstantinopoulos, PA Matulonis, UA Swisher, EM AF Stover, Elizabeth H. Konstantinopoulos, Panagiotis A. Matulonis, Ursula A. Swisher, Elizabeth M. TI Biomarkers of Response and Resistance to DNA Repair Targeted Therapies SO CLINICAL CANCER RESEARCH LA English DT Review ID HOMOLOGOUS RECOMBINATION DEFICIENCY; NEGATIVE BREAST-CANCER; SEROUS OVARIAN-CANCER; DOUBLE-STRAND BREAK; POLY(ADP-RIBOSE) POLYMERASE INHIBITORS; TUMOR-INFILTRATING LYMPHOCYTES; ADVANCED SOLID TUMORS; GERM-CELL TUMORS; SYNTHETIC LETHALITY; GENOMIC INSTABILITY AB Drugs targeting DNA damage repair (DDR) pathways are exciting new agents in cancer therapy. Many of these drugs exhibit synthetic lethality with defects in DNA repair in cancer cells. For example, ovarian cancers with impaired homologous recombination DNA repair show increased sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. Understanding the activity of different DNA repair pathways in individual tumors, and the correlations between DNA repair function and drug response, will be critical to patient selection for DNA repair targeted agents. Genomic and functional assays of DNA repair pathway activity are being investigated as potential biomarkers of response to targeted therapies. Furthermore, alterations in DNA repair function generate resistance to DNA repair targeted agents, and DNA repair states may predict intrinsic or acquired drug resistance. In this review, we provide an overview of DNA repair targeted agents currently in clinical trials and the emerging biomarkers of response and resistance to these agents: genetic and genomic analysis of DDR pathways, genomic signatures of mutational processes, expression of DNA repair proteins, and functional assays for DNA repair capacity. We review biomarkers that may predict response to selected DNA repair targeted agents, including PARP inhibitors, inhibitors of the DNA damage sensors ATM and ATR, and inhibitors of nonhomologous end joining. Finally, we introduce emerging categories of drugs targeting DDR and new strategies for integrating DNA repair targeted therapies into clinical practice, including combination regimens. Generating and validating robust biomarkers will optimize the efficacy of DNA repair targeted therapies and maximize their impact on cancer treatment. C1 [Stover, Elizabeth H.; Konstantinopoulos, Panagiotis A.; Matulonis, Ursula A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Swisher, Elizabeth M.] Univ Washington, 1959 NE Pacific St, Seattle, WA 98195 USA. RP Swisher, EM (reprint author), Univ Washington, 1959 NE Pacific St, Seattle, WA 98195 USA. EM swishere@uw.edu FU Department of Defense (DoD) [OC093426, OC140632, OC120506]; OCRFA Program Project Grant; V Foundation Translational Research Award; Stand Up To Cancer-Ovarian Cancer Research Fund Alliance-National Ovarian Cancer Coalition Dream Team Translational Research Grant [SU2C-AACR-DT16-15]; American Association for Cancer Research; scientific partner of SU2C FX This work was supported by Department of Defense (DoD) grants OC093426 and DoD OC140632 (to P.A. Konstantinopoulos), DoD OC120506 (to E.M. Swisher), OCRFA Program Project Grant (to P.A. Konstantinopoulos), and a V Foundation Translational Research Award (to E.M. Swisher). Research also supported by a Stand Up To Cancer-Ovarian Cancer Research Fund Alliance-National Ovarian Cancer Coalition Dream Team Translational Research Grant (grant number: SU2C-AACR-DT16-15). Stand Up To Cancer is a program of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the scientific partner of SU2C (to E.M. Swisher, U.A. Matulonis, and P.A. Konstantinopoulos). NR 93 TC 1 Z9 1 U1 14 U2 14 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 DEC 1 PY 2016 VL 22 IS 23 BP 5651 EP 5660 DI 10.1158/1078-0432.CCR-16-0247 PG 10 WC Oncology SC Oncology GA EE2TS UT WOS:000389438100006 PM 27678458 ER PT J AU Raje, NS Faber, EA Richardson, PG Schiller, G Hohl, RJ Cohen, AD Forero, A Carpenter, S Nguyen, TS Conti, I Kaiser, CJ Cronier, DM Wooldridge, JE Anderson, KC AF Raje, Noopur S. Faber, Edward A., Jr. Richardson, Paul G. Schiller, Gary Hohl, Raymond J. Cohen, Adam D. Forero, Andres Carpenter, Susan Nguyen, Tuan S. Conti, Ilaria Kaiser, Christopher J. Cronier, Damien M. Wooldridge, James E. Anderson, Kenneth C. TI Phase 1 Study of Tabalumab, a Human Anti-B-Cell Activating Factor Antibody, and Bortezomib in Patients with Relapsed/Refractory Multiple Myeloma SO CLINICAL CANCER RESEARCH LA English DT Article ID NON-HODGKIN-LYMPHOMA; PROTEASOME INHIBITOR BORTEZOMIB; MONOCLONAL-ANTIBODY; DEXAMETHASONE; APRIL; BAFF; EXPRESSION; SURVIVAL; GROWTH; TRIAL AB Purpose: Tabalumab, a human mAb that neutralizes B-cell-activating factor (BAFF), demonstrated antitumor activity in xenograft models of multiple myeloma. Here we report on a phase I study of relapsed/refractory multiple myeloma patients in which the primary objective was to identify a tolerable and potentially efficacious dose of tabalumab when combined with bortezomib. Experimental Design: Forty-eight patients were enrolled; 20 to the dose-escalation cohort, and 28 to cohort expansion in which a dose of 100 mg of tabalumab was evaluated. All patients had received either prior bortezomib or an immunomodulatory drug; the median number of prior therapies was 3. Bortezomib was administered intravenously on days 1, 4, 8, and 11 of a 21-day schedule. Tabalumab was given every 21 days for 3 cycles, then every 42 days thereafter. Results: The most common grade 3/4 toxicities included thrombocytopenia, neutropenia, pneumonia, and peripheral sensory neuropathy. There were no dose-limiting toxicities, and the maximum tolerated dose was not reached. Pharmacokinetic data suggested serum exposure increased in a greater than dose-proportional manner up to a dose of 100 mg. Out of 46 evaluable patients, 20 had confirmed responses. The median time to progression (9 patients censored) was 4.8 months, and the median response duration (4 patients censored) was 7.2 months. Conclusions: A dose of 100 mg tabalumab in combination with bortezomib was well tolerated and active and is currently under further investigation. (C) 2016 AACR. C1 [Raje, Noopur S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Faber, Edward A., Jr.] Univ Nebraska, Med Ctr, Omaha, NE USA. [Richardson, Paul G.; Anderson, Kenneth C.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Schiller, Gary] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Hohl, Raymond J.] Univ Iowa Hosp & Clin, Iowa City, IA 52242 USA. [Cohen, Adam D.] Fox Chase Canc Ctr, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Forero, Andres] Univ Alabama Birmingham, Birmingham, AL USA. [Carpenter, Susan; Nguyen, Tuan S.; Conti, Ilaria; Kaiser, Christopher J.; Cronier, Damien M.; Wooldridge, James E.] Eli Lilly & Co, Indianapolis, IN 46285 USA. RP Raje, NS (reprint author), Massachusetts Gen Hosp, MGH Canc Ctr, 55 Fruit St, Boston, MA 02114 USA. EM NRAJE@mgh.harvard.edu FU Eli Lilly and Company FX This study was supported by funding from Eli Lilly and Company. NR 44 TC 1 Z9 1 U1 2 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD DEC 1 PY 2016 VL 22 IS 23 BP 5688 EP 5695 DI 10.1158/1078-0432.CCR-16-0201 PG 8 WC Oncology SC Oncology GA EE2TS UT WOS:000389438100010 PM 27287072 ER PT J AU Infante, JR Cassier, PA Gerecitano, JF Witteveen, PO Chugh, R Ribrag, V Chakraborty, A Matano, A Dobson, JR Crystal, AS Parasuraman, S Shapiro, GI AF Infante, Jeffrey R. Cassier, Philippe A. Gerecitano, John F. Witteveen, Petronella O. Chugh, Rashmi Ribrag, Vincent Chakraborty, Abhijit Matano, Alessandro Dobson, Jason R. Crystal, Adam S. Parasuraman, Sudha Shapiro, Geoffrey I. TI A Phase I Study of the Cyclin-Dependent Kinase 4/6 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas SO CLINICAL CANCER RESEARCH LA English DT Article ID ADVANCED BREAST-CANCER; PALBOCICLIB; TRIAL AB Purpose: Ribociclib (an oral, highly specific cyclin-dependent kinase 4/6 inhibitor) inhibits tumor growth in preclinical models with intact retinoblastoma protein (Rb+). This first-in-human study investigated the MTD, recommended dose for expansion (RDE), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of ribociclib in patients with Rb+ advanced solid tumors or lymphomas. Experimental Design: Patients received escalating doses of ribociclib (3-weeks-on/1-week-off or continuous). Dose escalation was guided by a Bayesian Logistic Regression Model with overdose control principle. Results: Among 132 patients, 125 received ribociclib 3-weeks-on/1-week-off and 7 were dosed continuously. Nine dose-limiting toxicities were observed among 70 MTD/RDE evaluable patients during cycle 1, most commonly neutropenia (n = 3) and thrombocytopenia (n = 2). The MTD and RDE were established as 900 and 600 mg/day 3-weeks-on/1-week-off, respectively. Common treatment-related adverse events were (all-grade; grade 3/4) neutropenia (46%; 27%), leukopenia (43%; 17%), fatigue (45%; 2%), and nausea (42%; 2%). Asymptomatic Fridericia's corrected QT prolongation was specific to doses >= 600 mg/day (9% of patients at 600 mg/day; 33% at doses >600 mg/day). Plasma exposure increases were slightly higher than dose proportional; mean half-life at the RDE was 32.6 hours. Reduced Ki67 was observed in paired skin and tumor biopsies, consistent with ribociclib-mediated antiproliferative activity. There were 3 partial responses and 43 patients achieved a best response of stable disease; 8 patients were progression-free for >6 months. Conclusions: Ribociclib demonstrated an acceptable safety profile, dose-dependent plasma exposure, and preliminary signs of clinical activity. Phase I-III studies of ribociclib are under way in various indications. (C) 2016 AACR. C1 [Infante, Jeffrey R.] Sarah Cannon Res Inst, Tennessee Oncol PLLC, 250 25th Ave North,Suite 200, Nashville, TN 37203 USA. [Cassier, Philippe A.] Ctr Leon Berard, Lyon, France. [Gerecitano, John F.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Witteveen, Petronella O.] Univ Med Ctr Utrecht, Ctr Canc, Utrecht, Netherlands. [Chugh, Rashmi] Univ Michigan, Ann Arbor, MI 48109 USA. [Ribrag, Vincent] Inst Gustave Roussy, Villejuif, France. [Chakraborty, Abhijit; Dobson, Jason R.; Crystal, Adam S.; Parasuraman, Sudha] Novartis Inst BioMed Res, Cambridge, MA USA. [Matano, Alessandro] Novartis Pharma AG, Basel, Switzerland. [Shapiro, Geoffrey I.] Dana Farber Canc Inst, Boston, MA USA. RP Infante, JR (reprint author), Sarah Cannon Res Inst, Tennessee Oncol PLLC, 250 25th Ave North,Suite 200, Nashville, TN 37203 USA. EM jinfante@tnonc.com FU Novartis Pharmaceuticals Corporation FX This study was sponsored by Novartis Pharmaceuticals Corporation, which also provided support for third-party writing assistance. NR 17 TC 0 Z9 0 U1 5 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 DEC 1 PY 2016 VL 22 IS 23 BP 5696 EP 5705 DI 10.1158/1078-0432.CCR-16-1248 PG 10 WC Oncology SC Oncology GA EE2TS UT WOS:000389438100011 PM 27542767 ER PT J AU Lipton, A Smith, MR Fizazi, K Stopeck, AT Henry, D Brown, JE Shore, ND Saad, F Spencer, A Zhu, L Warner, DJ AF Lipton, Allan Smith, Matthew R. Fizazi, Karim Stopeck, Alison T. Henry, David Brown, Janet E. Shore, Neal D. Saad, Fred Spencer, Andrew Zhu, Li Warner, Douglas J. TI Changes in Bone Turnover Marker Levels and Clinical Outcomes in Patients with Advanced Cancer and Bone Metastases Treated with Bone Antiresorptive Agents SO CLINICAL CANCER RESEARCH LA English DT Article ID RESISTANT PROSTATE-CANCER; SKELETAL-RELATED EVENTS; QUALITY-OF-LIFE; LONG-TERM EFFICACY; ZOLEDRONIC ACID; BREAST-CANCER; DOUBLE-BLIND; MULTIPLE-MYELOMA; SOLID TUMORS; LUNG-CANCER AB Purpose: Bone antiresorptive agents can significantly reduce bone turnover markers (BTM) in patients with advanced cancer. We evaluated association of changes in BTMs with overall survival (OS), disease progression (DP), and disease progression in bone (DPB) in patients with advanced cancer and bone metastases following denosumab or zoledronic acid treatment. Experimental Design: This is an integrated analysis of patient-level data from three identically designed, blinded, phase III trials with patients randomized to subcutaneous denosumab or intravenous zoledronic acid. Levels of the BTMs urinary N-telopeptide (uNTx) and serum bone-specific alkaline phosphatase (sBSAP) measured at study entry and month 3 were analyzed. OS, DP, and DPB were compared in patients with BTMs >= median versus < median based on month 3 assessments. Results: uNTx levels >= the median of 10.0 nmol/mmol at month 3 were associated with significantly reduced OS compared with levels < median (HR for death, 1.85; P < 0.0001). sBSAP levels >= median of 12.6 ng/mL were associated with significantly reduced OS compared with levels < median (HR, 2.44; P < 0.0001). uNTx and sBSAP levels >= median at month 3 were associated with significantly greater risk of DP (HR, 1.31; P < 0.0001 and HR, 1.71; P < 0.0001, respectively) and DPB (HR, 1.11; P = 0.0407 and HR, 1.27; P < 0.0001, respectively). Conclusions: BTM levels >= median after 3 months of bone antiresorptive treatment were associated with reduced OS and increased risk of DP and DPB. Assessment of uNTx and sBSAP levels after bone antiresorptive therapy may add to identification of patients at risk for worse clinical outcomes. (C) 2016 AACR. C1 [Lipton, Allan] Penn State Canc Inst, Div Hematol Oncol, Hershey, PA USA. [Smith, Matthew R.] Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02114 USA. [Fizazi, Karim] Univ Paris Sud, Inst Gustave Roussy, Dept Canc Med, Villejuif, France. [Stopeck, Alison T.] Stony Brook Canc Ctr, Dept Internal Med, Stony Brook, NY USA. [Henry, David] Penn Hosp, Joan Karnell Canc Ctr, Dept Med, Philadelphia, PA 19107 USA. [Brown, Janet E.] Univ Sheffield, Expt Canc Med Ctr, Acad Unit Clin Oncol, Sheffield, S Yorkshire, England. [Shore, Neal D.] Carolina Urol Res Ctr, Myrtle Beach, SC USA. [Saad, Fred] Univ Montreal, Ctr Hosp, Dept Surg, Montreal, PQ, Canada. [Spencer, Andrew] Monash Univ, Dept Clin Haematol, Melbourne, Vic, Australia. [Zhu, Li] Amgen Inc, Global Biostat Sci, Thousand Oaks, CA 91320 USA. [Warner, Douglas J.] Amgen Inc, Clin Dev, Thousand Oaks, CA 91320 USA. RP Lipton, A (reprint author), Penn State Univ, Hershey Med Ctr, 500 Univ Dr,Suite CH46, Hershey, PA 17033 USA. EM alipton@hmc.psu.edu FU Amgen Inc. FX This work was supported by Amgen Inc. NR 46 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD DEC 1 PY 2016 VL 22 IS 23 BP 5713 EP 5721 DI 10.1158/1078-0432.CCR-15-3086 PG 9 WC Oncology SC Oncology GA EE2TS UT WOS:000389438100013 PM 27140926 ER PT J AU Jeselsohn, R Barry, WT Migliaccio, I Biagioni, C Zhao, J De Tribolet-Hardy, J Guarducci, C Bonechi, M Laing, N Winer, EP Brown, M Di Leo, A Malorni, L AF Jeselsohn, Rinath Barry, William T. Migliaccio, Ilenia Biagioni, Chiara Zhao, Jin De Tribolet-Hardy, Jonas Guarducci, Cristina Bonechi, Martina Laing, Naomi Winer, Eric P. Brown, Myles Di Leo, Angelo Malorni, Luca TI TransCONFIRM: Identification of a Genetic Signature of Response to Fulvestrant in Advanced Hormone Receptor-Positive Breast Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR RECEPTOR; ESTROGEN-RECEPTOR; POSTMENOPAUSAL WOMEN; CELL-PROLIFERATION; TAMOXIFEN RESISTANCE; AROMATASE INHIBITORS; ACQUIRED-RESISTANCE; SIGNALING PATHWAYS; 1ST-LINE TREATMENT; POOR-PROGNOSIS AB Purpose: Fulvestrant is an estrogen receptor (ER) antagonist and an approved treatment for metastatic estrogen receptor-positive (ER+) breast cancer. With the exception of ER levels, there are no established predictive biomarkers of response to single-agent fulvestrant. We attempted to identify a gene signature of response to fulvestrant in advanced breast cancer. Experimental Design: Primary tumor samples from 134 patients enrolled in the phase III CONFIRM study of patients with metastatic ER+ breast cancer comparing treatment with either 250 mg or 500 mg fulvestrant were collected for genome-wide transcriptomic analysis. Gene expression profiling was performed using Affymetrix microarrays. An exploratory analysis was performed to identify biologic pathways and new signatures associated with response to fulvestrant. Results: Pathway analysis demonstrated that increased EGF pathway and FOXA1 transcriptional signaling is associated with decreased response to fulvestrant. Using a multivariate Cox model, we identified a novel set of 37 genes with an expression that is independently associated with progression-free survival (PFS). TFAP2C, a known regulator of ER activity, was ranked second in this gene set, and high expression was associated with a decreased response to fulvestrant. The negative predictive value of TFAP2C expression at the protein level was confirmed by IHC. Conclusions: Weidentified biologic pathways and a novel gene signature in primary ER+ breast cancers that predicts for response to treatment in the CONFIRM study. These results suggest potential new therapeutic targets and warrant further validation as predictive biomarkers of fulvestrant treatment in metastatic breast cancer. (C) 2016 AACR. C1 [Jeselsohn, Rinath; Barry, William T.; Winer, Eric P.; Brown, Myles] Dana Farber Canc Inst, Susan F Smith Ctr Womens Canc, Boston, MA 02115 USA. [Jeselsohn, Rinath; Zhao, Jin; De Tribolet-Hardy, Jonas; Brown, Myles] Dana Farber Canc Inst, Ctr Funct Caner Epigenet, Boston, MA 02115 USA. [Barry, William T.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Migliaccio, Ilenia; Biagioni, Chiara; Guarducci, Cristina; Bonechi, Martina; Di Leo, Angelo; Malorni, Luca] Hosp Prato, Ist Toscano Tumori, Translat Res Unit, Prato, Italy. [Biagioni, Chiara; Di Leo, Angelo; Malorni, Luca] Ist Toscano Tumori, Sandro Pitigliani Med Oncol Unit, Prato, Italy. [Laing, Naomi] Astra Zeneca Pharmaceut, Macclesfield, Cheshire, England. RP Jeselsohn, R; Brown, M (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,D730, Boston, MA 02215 USA. EM rinath_jeseloshn@dfci.harvard.edu; myles_brown@dfci.harvard.edu FU Susan F. Smith Center for Women's Cancers; Susan G. Komen for the Cure; NCI grant SPORE Career Development Award [P50CA168504] FX This study was supported in part by the Susan F. Smith Center for Women's Cancers and by grants from Susan G. Komen for the Cure (to M. Brown) and NCI grant P50CA168504 SPORE Career Development Award (to R. Jeselsohn). NR 54 TC 1 Z9 1 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD DEC 1 PY 2016 VL 22 IS 23 BP 5755 EP 5764 DI 10.1158/1078-0432.CCR-16-0148 PG 10 WC Oncology SC Oncology GA EE2TS UT WOS:000389438100018 PM 27185372 ER PT J AU Niessner, H Schmitz, J Tabatabai, G Schmid, AM Calaminus, C Sinnberg, T Weide, B Eigentler, TK Garbe, C Schittek, B Quintanilla-Fend, L Bender, B Mai, M Praetorius, C Beissert, S Schackert, G Muders, MH Meinhardt, M Baretton, GB Dummer, R Flaherty, K Pichler, BJ Kulms, D Westphal, D Meier, F AF Niessner, Heike Schmitz, Jennifer Tabatabai, Ghazaleh Schmid, Andreas M. Calaminus, Carsten Sinnberg, Tobias Weide, Benjamin Eigentler, Thomas K. Garbe, Claus Schittek, Birgit Quintanilla-Fend, Leticia Bender, Benjamin Mai, Marion Praetorius, Christian Beissert, Stefan Schackert, Gabriele Muders, Michael H. Meinhardt, Matthias Baretton, Gustavo B. Dummer, Reinhard Flaherty, Keith Pichler, Bernd J. Kulms, Dagmar Westphal, Dana Meier, Friedegund TI PI3K Pathway Inhibition Achieves Potent Antitumor Activity in Melanoma Brain Metastases In Vitro and In Vivo SO CLINICAL CANCER RESEARCH LA English DT Article ID ADVANCED SOLID TUMORS; KINASE INHIBITOR; DOSE-ESCALATION; PHASE-2 TRIAL; OPEN-LABEL; SURVIVAL; GLIOBLASTOMA; BUPARLISIB; PLEKHA5; PROTEIN AB Purpose: Great advances have recently been made in treating patients with metastatic melanoma. However, existing therapies are less effective on cerebral than extracerebral metastases. This highlights the potential role of the brain environment on tumor progression and drug resistance and underlines the need for "brain-specific" therapies. We previously showed that the PI3K-AKT survival pathway is hyperactivated in brain but not extracerebral melanoma metastases and that astrocyte-conditioned medium activates AKT in melanoma cells in vitro. We therefore tested the PI3K inhibitor buparlisib as an antitumor agent for melanoma brain metastases. Experimental Design and Results: Buparlisib inhibited AKT activity, decreased proliferation, and induced apoptosis in metastatic melanoma cell lines and short-term brain melanoma cells, irrespective of their BRAF and NRAS mutation status. In addition, buparlisib inhibited hyperactivated AKT and induced apoptosis in melanoma cells that were stimulated with astrocyte-conditioned medium. The growth of tumors induced by injecting human BRAF- and NRAS-mutant metastatic melanoma cells into the brain of mice was significantly inhibited by buparlisib. Conclusions: These results emphasize the value of targeting the PI3K pathway as a strategy to develop drugs for melanoma brain metastases. (C) 2016 AACR. C1 [Niessner, Heike; Sinnberg, Tobias; Weide, Benjamin; Eigentler, Thomas K.; Garbe, Claus; Schittek, Birgit] Eberhard Karls Univ Tubingen, Univ Tubingen Hosp, Dept Dermatol, Tubingen, Germany. [Schmitz, Jennifer; Schmid, Andreas M.; Calaminus, Carsten] Eberhard Karls Univ Tubingen, Univ Tubingen Hosp, Dept Preclin Imaging & Radiopharmacy, Werner Siemens Imaging Ctr, Tubingen, Germany. [Tabatabai, Ghazaleh] Univ Hosp Tubingen, Hertie Inst Clin Brain Res, Interdisciplinary Div Neuro Oncol, Tubingen, Germany. [Tabatabai, Ghazaleh] Eberhard Karls Univ Tubingen, Hertie Inst Clin Brain Res, Interdisciplinary Div Neuro Oncol, Tubingen, Germany. [Tabatabai, Ghazaleh] Neuro Oncol Ctr Tubingen, Comprehens Canc Ctr Tubingen Stuttgart, Tubingen, Germany. [Tabatabai, Ghazaleh] Eber hard Karls Univ, Ctr Personalized Med, Tubingen, Germany. [Tabatabai, Ghazaleh] German Canc Consortium DKTK, DKFZ Partner Site, Tubingen, Germany. [Quintanilla-Fend, Leticia] Eberhard Karls Univ Tubingen, Univ Hosp Tubingen, Dept Pathol, Tubingen, Germany. [Bender, Benjamin] Eberhard Karls Univ Tubingen, Univ Hosp Tubingen, Dept Diagnost & Intervent Neuroradiol, Tubingen, Germany. [Mai, Marion; Praetorius, Christian; Beissert, Stefan; Kulms, Dagmar; Westphal, Dana] Med Fac & Univ Hosp Carl Gustav Carus, Dept Dermatol, Dresden, Germany. [Mai, Marion; Praetorius, Christian; Kulms, Dagmar; Westphal, Dana] Ctr Regenerat Therapies Dresden, DFG Res Ctr & Cluster Excellence, Dresden, Germany. [Schackert, Gabriele] Med Facul & Univ Hosp Carl Gustav Carus, Dept Neurosurg, Dresden, Germany. [Muders, Michael H.; Meinhardt, Matthias; Baretton, Gustavo B.] Med Fac & Univ Hosp Carl Gustav Carus, Dept Pathol, Dresden, Germany. [Dummer, Reinhard] Univ Zurich Hosp, Dept Dermatol, Zurich, Switzerland. [Flaherty, Keith] Harvard Med Sch, Massachusetts Gen Hosp Canc Ctr, Boston, MA USA. [Westphal, Dana; Meier, Friedegund] Nation Ctr Tumor Dis NCT, Partner Site Dresden, Germany. RP Meier, F (reprint author), Univ Dresden, Fetscherstr 74, D-01307 Dresden, Germany. EM Friedegund.Meier@uniklinikum-dresden.de RI Weide, Benjamin/N-3698-2013; OI Schmid, Andreas/0000-0001-6483-8759; Eigentler, Thomas/0000-0003-0019-2770 FU German Research Foundation [SFB 773]; Novartis; University of Tubingen; Federal Ministry of Education and Research [FKZ 031A423B]; German Cancer Aid [110210]; National Center for Cancer/NCT Program and Infrastructure Grant FX This work was supported by the German Research Foundation (SFB 773; F. Meier, H. Niessner, B. Schittek, and G. Tabatabai), Novartis (F. Meier, H. Niessner), the University of Tubingen (fortuene, H. Niessner; Demonstratorprojekt, G. Tabatabai), the Federal Ministry of Education and Research (FKZ 031A423B; C. Praetorius, D. Kulms), the German Cancer Aid (110210; B. Schittek), and the National Center for Cancer/NCT Program and Infrastructure Grant (F. Meier, M.H. Muders). NR 27 TC 3 Z9 3 U1 14 U2 14 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 DEC 1 PY 2016 VL 22 IS 23 BP 5818 EP 5828 DI 10.1158/1078-0432.CCR-16-0064 PG 11 WC Oncology SC Oncology GA EE2TS UT WOS:000389438100024 PM 27307593 ER PT J AU Al-Mamun, MM Sarker, SK Qadri, SK Shirin, T Mohammad, QD LaRocque, R Karlsson, EK Saha, N Asaduzzaman, M Qadri, F Mannoor, MK AF Al-Mamun, Md Mahfuz Sarker, Suprovath Kumar Qadri, Syeda Kashfi Shirin, Tahmina Mohammad, Quazi Deen LaRocque, Regina Karlsson, Elinor K. Saha, Narayan Asaduzzaman, Muhammad Qadri, Firdausi Mannoor, Md Kaiissar TI Examination of Huntington's disease with atypical clinical features in a Bangladeshi family tree SO CLINICAL CASE REPORTS LA English DT Article DE Atypical clinical features; Bangladeshi family tree; CAG repeat; Huntington's disease; mutation ID TRINUCLEOTIDE REPEAT EXPANSION; PHENOTYPIC VARIATION; ONSET; DEMENTIA; CHOREA; INSTABILITY; LENGTH; GENE; AGE AB Atypical manifestation of Huntington's disease (HD) could inform ongoing research into HD genetic modifiers not present in the primarily European populations studied to date. This work demonstrates that expanding HD genetic testing into under-resourced healthcare settings can benefit both local communities and ongoing research into HD etiology and new therapies. C1 [Al-Mamun, Md Mahfuz; Sarker, Suprovath Kumar; Qadri, Firdausi; Mannoor, Md Kaiissar] Inst Developing Sci & Hlth Initiat IDESHI, Dhaka 1212, Bangladesh. [Qadri, Syeda Kashfi] KK Womens & Childrens Hosp, Singapore, Singapore. [Shirin, Tahmina] Inst Epidemiol Dis Control & Res, Dept Virol, Dhaka, Bangladesh. [Mohammad, Quazi Deen] Natl Inst Neurosci & Hosp, Dept Neurol, Dhaka, Bangladesh. [LaRocque, Regina] Massachusetts Gen Hosp, Dept Med, Div Infect Dis, Boston, MA 02114 USA. [Karlsson, Elinor K.] Univ Massachusetts, Sch Med, Broad Inst, Cambridge, MA USA. [Saha, Narayan] Natl Inst Neurosci & Hosp, Pediat Neurol, Dhaka, Bangladesh. [Asaduzzaman, Muhammad; Qadri, Firdausi] Int Ctr Diarrheal Dis Res, Ctr Vaccine Sci, Dhaka, Bangladesh. RP Mannoor, MK (reprint author), Inst Developing Sci & Hlth Initiat IDESHI, Dhaka 1212, Bangladesh. EM kaiissar@ideshi.org OI Asaduzzaman, Muhammad/0000-0001-9048-7980 NR 20 TC 0 Z9 0 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2050-0904 J9 CLIN CASE REP JI Clin. Case Rep. PD DEC PY 2016 VL 4 IS 12 BP 1191 EP 1194 DI 10.1002/ccr3.743 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA EE1KI UT WOS:000389339900026 PM 27980761 ER PT J AU Sonpavde, G Pond, GR Di Lorenzo, G Buonerba, C Rozzi, A Lanzetta, G Necchi, A Giannatempo, P Raggi, D Matsumoto, K Choueiri, TK Mullane, S Niegisch, G Albers, P Lee, JL Kitamura, H Kume, H Bellmunt, J AF Sonpavde, G. Pond, G. R. Di Lorenzo, G. Buonerba, C. Rozzi, A. Lanzetta, G. Necchi, A. Giannatempo, P. Raggi, D. Matsumoto, K. Choueiri, T. K. Mullane, S. Niegisch, G. Albers, P. Lee, J. L. Kitamura, H. Kume, H. Bellmunt, J. TI Impact of Prior Platinum-Based Therapy on Patients Receiving Salvage Systemic Treatment for Advanced Urothelial Carcinoma SO CLINICAL GENITOURINARY CANCER LA English DT Article DE Chemotherapy; Overall survival; Prior platinum therapy; Salvage; Urothelial carcinoma ID TRANSITIONAL-CELL CARCINOMA; CISPLATIN-BASED CHEMOTHERAPY; PHASE-II TRIAL; SINGLE-AGENT GEMCITABINE; 1ST-LINE TREATMENT; CANCER; PACLITAXEL; DOCETAXEL; COMBINATION; UNFIT AB Prior platinum-versus non-platinum-based chemotherapy did not affect survival after controlling for major prognostic factors in patients receiving salvage systemic chemotherapy for advanced urothelial carcinoma. Exposure to prior platinum therapy should not be required for the inclusion of patients in trials of salvage systemic therapy. Background: Trials of salvage therapy for advanced urothelial carcinoma have required prior platinum-based therapy. This practice requires scrutiny because non-platinum-based first-line therapy may be offered to cisplatin-ineligible patients. Patients and Methods: Data of patients receiving salvage systemic chemotherapy were collected. Data on prior first-line platinum exposure were required in addition to treatment-free interval, hemoglobin, Eastern Cooperative Oncology Group performance status, albumin, and liver metastasis status. Cox proportional hazard regression was used to evaluate their association with overall survival (OS) after accounting for salvage single-agent or combination chemotherapy. Results: Data were obtained from 455 patients previously exposed to platinum-based therapy and 37 not exposed to platinum. In the group exposed to prior platinum therapy, salvage therapy consisted of a single agent taxane (n = 184) or a taxane-containing combination chemotherapy (n = 271). In the group not exposed to prior platinum therapy, salvage therapy consisted of taxane or vinflunine (n = 20), 5-fluorouracil (n = 1), taxane-containing combination chemotherapy (n = 12), carboplatin-based combinations (n = 2), and cisplatin-based combinations (n = 2). The median OS for the prior platinum therapy group was 7.8 months (95% confidence interval, 7.0, 8.1), and for the group that had not received prior platinum therapy was 9.0 months (95% confidence interval, 6.0, 11.0; P = .50). In the multivariable analysis, prior platinum therapy versus no prior platinum exposure did not confer an independent impact on OS (hazard ratio, 1.10; 95% confidence interval, 0.75, 1.64; P = .62). Conclusion: Prior platinum-versus non-platinum-based chemotherapy did not have a prognostic impact on OS after accounting for major prognostic factors in patients receiving salvage systemic chemotherapy for advanced urothelial carcinoma. Lack of prior platinum therapy should not disqualify patients from inclusion onto trials of salvage therapy. (C) 2016 Elsevier Inc. All rights reserved. C1 [Sonpavde, G.] UAB Comprehens Canc Ctr, 1802 6th Ave S,NP2540B, Birmingham, AL 35294 USA. [Pond, G. R.] McMaster Univ, Hamilton, ON, Canada. [Di Lorenzo, G.] Univ Federico II, Naples, Italy. [Buonerba, C.] Ctr Riferimento Oncol Basilicata IRCCS, Rionero In Vulture, Italy. [Rozzi, A.; Lanzetta, G.] Ist Neurotraumatol Italiano, Grottaferrata, Italy. [Necchi, A.; Giannatempo, P.; Raggi, D.] Fdn IRCCS Ist Nazl Tumori, Milan, Italy. [Matsumoto, K.] Kitasato Univ, Sch Med, Sagamihara, Kanagawa, Japan. [Choueiri, T. K.; Mullane, S.; Bellmunt, J.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Choueiri, T. K.; Mullane, S.; Bellmunt, J.] Harvard Med Sch, Boston, MA USA. [Niegisch, G.; Albers, P.] Heinrich Heine Univ, Fac Med, Dusseldorf, Germany. [Lee, J. L.] Asan Med Ctr, Seoul, South Korea. [Kitamura, H.] Sapporo Med Univ, Sch Med, Sapporo, Hokkaido, Japan. [Kume, H.] Tokyo Univ Hosp, Tokyo, Japan. RP Sonpavde, G (reprint author), UAB Comprehens Canc Ctr, 1802 6th Ave S,NP2540B, Birmingham, AL 35294 USA. EM gsonpavde@uabmc.edu NR 23 TC 0 Z9 0 U1 2 U2 2 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1558-7673 EI 1938-0682 J9 CLIN GENITOURIN CANC JI Clin. Genitourin. Cancer PD DEC PY 2016 VL 14 IS 6 BP 494 EP 498 DI 10.1016/j.clgc.2016.05.001 PG 5 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA EE4EP UT WOS:000389555400004 PM 27262369 ER PT J AU Motwani, SS Herlitz, L Monga, D Jhaveri, KD Lam, AQ AF Motwani, Shveta S. Herlitz, Leal Monga, Divya Jhaveri, Kenar D. Lam, Albert Q. TI Paraprotein-Related Kidney Disease: Glomerular Diseases Associated with Paraproteinemias SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID CHAIN DEPOSITION DISEASE; MONOCLONAL IGG DEPOSITS; THROMBOTIC THROMBOCYTOPENIC PURPURA; CHRONIC LYMPHOCYTIC-LEUKEMIA; PRIMARY SYSTEMIC AMYLOIDOSIS; STEM-CELL TRANSPLANTATION; MYELOMA CAST NEPHROPATHY; ISOLATED C3 DEPOSITS; OF-THE-LITERATURE; LIGHT-CHAIN AB Paraproteins are monoclonal Igs that accumulate in blood as a result of abnormal excess production. These circulating proteins cause a diversity of kidney disorders that are increasingly being comanaged by nephrologists. In this review, we discuss paraprotein-related diseases that affect the glomerulus. We provide a broad overview of diseases characterized by nonorganized deposits, such as monoclonal Ig deposition disease (MIDD), proliferative GN with monoclonal Ig deposits (PGNMID), and C3 glomerulopathy, as well as those characterized by organized deposits, such as amyloidosis, immunotactoid glomerulopathy, fibrillary GN, and cryoglobulinemic GN, and rarer disorders, such as monoclonal crystalline glomerulopathies, paraprotein related thrombotic microangiopathies, and membranous-like glomerulopathy with masked IgGtc deposits. This review will provide the nephrologist with an up to date understanding of these entities and highlight the areas of deficit in evidence and future lines of research. C1 [Motwani, Shveta S.; Lam, Albert Q.] Brigham & Womens Hosp, Dept Med, Div Renal Med, 75 Francis St, Boston, MA 02115 USA. [Motwani, Shveta S.; Lam, Albert Q.] Dana Farber Canc Inst, Adult Survivorship Program, Boston, MA 02115 USA. [Herlitz, Leal] Cleveland Clin, Dept Pathol, Cleveland, OH 44106 USA. [Monga, Divya] Univ Mississippi, Med Ctr, Dept Med, Div Nephrol, Jackson, MS 39216 USA. [Jhaveri, Kenar D.] Northwell Hlth, Hofstra Northwell Sch Med, Div Kidney Dis & Hypertens, Great Neck, NY USA. RP Lam, AQ (reprint author), Harvard Inst Med, Room 574B,4 Blackfan Circle, Boston, MA 02115 USA. EM aqlam@partners.org NR 118 TC 2 Z9 2 U1 0 U2 0 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 EI 1555-905X J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD DEC PY 2016 VL 11 IS 12 BP 2260 EP 2272 DI 10.2215/CJN.02980316 PG 13 WC Urology & Nephrology SC Urology & Nephrology GA EE3OF UT WOS:000389498200024 PM 27526706 ER PT J AU Beitler, JR Malhotra, A Thompson, BT AF Beitler, Jeremy R. Malhotra, Atul Thompson, B. Taylor TI Ventilator-induced Lung Injury SO CLINICS IN CHEST MEDICINE LA English DT Article DE Ventilator-induced lung injury; Acute lung injury; Acute respiratory distress syndrome; Mechanical ventilation; Respiratory mechanics ID RESPIRATORY-DISTRESS-SYNDROME; END-EXPIRATORY PRESSURE; RANDOMIZED CONTROLLED-TRIAL; ALVEOLAR EPITHELIAL-CELLS; TIDAL-VOLUME VENTILATION; DEFORMATION-INDUCED INJURY; HIGH-FREQUENCY OSCILLATION; INDUCED LIPID TRAFFICKING; MEMBRANE STRESS FAILURE; CANINE PULMONARY-EDEMA AB Prevention of ventilator-induced lung injury (VILI) can attenuate multiorgan failure and improve survival in at-risk patients. Clinically significant VILI occurs from volutrauma, barotrauma, atelectrauma, biotrauma, and shear strain. Differences in regional mechanics are important in VILI pathogenesis. Several interventions are available to protect against VILI. However, most patients at risk of lung injury do not develop VILI. VILI occurs most readily in patients with concomitant physiologic insults. VILI prevention strategies must balance risk of lung injury with untoward side effects from the preventive effort, and may be most effective when targeted to subsets of patients at increased risk. C1 [Beitler, Jeremy R.; Malhotra, Atul] Univ Calif San Diego, Div Pulm & Crit Care Med, 200 West Arbor Dr 8409, San Diego, CA 92103 USA. [Thompson, B. Taylor] Massachusetts Gen Hosp, Div Pulm & Crit Care Med, 55 Fruit St,Cox 201, Boston, MA 02114 USA. RP Beitler, JR (reprint author), Univ Calif San Diego, Div Pulm & Crit Care Med, 200 West Arbor Dr 8409, San Diego, CA 92103 USA. EM jbeitler@ucsd.edu FU National Institutes of Health [K24-HL132105, T32-HL007633, U01-HL123009] FX All authors have received funding support from the National Institutes of Health (K24-HL132105; T32-HL007633; U01-HL123009). NR 131 TC 1 Z9 1 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 0272-5231 EI 1557-8216 J9 CLIN CHEST MED JI Clin. Chest Med. PD DEC PY 2016 VL 37 IS 4 BP 633 EP + DI 10.1016/j.ccm.2016.07.004 PG 15 WC Respiratory System SC Respiratory System GA EE7IF UT WOS:000389788400004 PM 27842744 ER PT J AU Etherton, MR Wu, O Rost, NS AF Etherton, Mark R. Wu, Ona Rost, Natalia S. TI Recent Advances in Leukoaraiosis: White Matter Structural Integrity and Functional Outcomes after Acute Ischemic Stroke SO CURRENT CARDIOLOGY REPORTS LA English DT Review DE Leukoaraiosis; Ischemic stroke; Stroke recovery ID SMALL VESSEL DISEASE; BRAIN-BARRIER PERMEABILITY; MILD COGNITIVE IMPAIRMENT; DIFFUSION-TENSOR MRI; INTRACEREBRAL HEMORRHAGE; RISK-FACTORS; UNSELECTED COHORT; VASCULAR-DISEASE; LACUNAR STROKE; ROTTERDAM SCAN AB Leukoaraiosis, a radiographic marker of cerebral small vessel disease detected on T2-weighted brain magnetic resonance imaging (MRI) as white matter hyperintensity (WMH), is a key contributor to the risk and severity of acute cerebral ischemia. Prior investigations have emphasized the pathophysiology of WMH development and progression; however, more recently, an association between WMH burden and functional outcomes after stroke has emerged. There is growing evidence that WMH represents macroscopic injury to the white matter and that the extent of WMH burden on MRI influences functional recovery in multiple domains following acute ischemic stroke (AIS). In this review, we discuss the current understanding of WMH pathogenesis and its impact on AIS and functional recovery. C1 [Etherton, Mark R.; Wu, Ona; Rost, Natalia S.] Harvard Med Sch, Boston, MA USA. [Etherton, Mark R.; Rost, Natalia S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Etherton, Mark R.; Wu, Ona; Rost, Natalia S.] Massachusetts Gen Hosp, J Philip Kistler Stroke Res Ctr, 175 Cambridge St,Suite 300, Boston, MA 02114 USA. [Wu, Ona] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, Charlestown, MA USA. RP Rost, NS (reprint author), Harvard Med Sch, Boston, MA USA.; Rost, NS (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA.; Rost, NS (reprint author), Massachusetts Gen Hosp, J Philip Kistler Stroke Res Ctr, 175 Cambridge St,Suite 300, Boston, MA 02114 USA. EM nrost@partners.org FU National Institutes of Health [P50NS051343, R01NS082285, R01NS086905, NIBIB P41EB015896]; NIH-NINDS [R01NS082285, R01NS086905] FX Ona Wu is supported in part by the National Institutes of Health (P50NS051343, R01NS082285, R01NS086905, and NIBIB P41EB015896). Natalia S. Rost is supported by the NIH-NINDS R01NS082285 and R01NS086905. NR 100 TC 1 Z9 1 U1 3 U2 3 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 DEC PY 2016 VL 18 IS 12 AR 123 DI 10.1007/s11886-016-0803-0 PG 13 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EE8RM UT WOS:000389893400007 PM 27796861 ER PT J AU Wang, XC Lockhart, SM Rathjen, T Albadawi, H Sorensen, D O'Neill, BT Dwivedi, N Preil, SR Beck, HC Dunwoodie, SL Watkins, MT Rasmussen, LM Rask-Madsen, C AF Wang, Xuanchun Lockhart, Samuel M. Rathjen, Thomas Albadawi, Hassan Sorensen, Ditte O'Neill, Brian T. Dwivedi, Nishant Preil, Simone R. Beck, Hans Christian Dunwoodie, Sally L. Watkins, Michael T. Rasmussen, Lars Melholt Rask-Madsen, Christian TI Insulin Downregulates the Transcriptional Coregulator CITED2, an Inhibitor of Proangiogenic Function in Endothelial Cells SO DIABETES LA English DT Article ID NEOVASCULARIZATION IN-VIVO; GROWTH-FACTOR EXPRESSION; NITRIC-OXIDE SYNTHASE; INDUCIBLE FACTOR-I; DIABETES-MELLITUS; SKELETAL-MUSCLE; GENE-EXPRESSION; RETINAL NEOVASCULARIZATION; METABOLIC SYNDROME; ANGIOGENESIS AB In patients with atherosclerotic complications of diabetes, impaired neovascularization of ischemic tissue in the myocardium and lower limb limits the ability of these tissues to compensate for poor perfusion. We identified 10 novel insulin-regulated genes, among them Adm, Cited2, and Ctgf, which were downregulated in endothelial cells by insulin through FoxO1. CBP/p300-interacting transactivator with ED-rich tail 2 (CITED2), which was downregulated by insulin by up to 54%, is an important negative regulator of hypoxia-inducible factor (HIF) and impaired HIF signaling is a key mechanism underlying the impairment of angiogenesis in diabetes. Consistent with impairment of vascular insulin action, CITED2 was increased in cardiac endothelial cells from mice with diet-induced obesity and from db/db mice and was 3.8-fold higher in arterial tissue from patients with type 2 diabetes than control subjects without diabetes. CITED2 knockdown promoted endothelial tube formation and endothelial cell proliferation, whereas CITED2 overexpression impaired HIF activity in vitro. After femoral artery ligation, induction of an endothelial-specific HIF target gene in hind limb muscle was markedly upregulated in mice with endothelial cell deletion of CITED2, suggesting that CITED2 can limit HIF activity in vivo. We conclude that vascular insulin resistance in type 2 diabetes contributes to the upregulation of CITED2, which impairs HIF signaling and endothelial proangiogenic function. C1 [Wang, Xuanchun; Lockhart, Samuel M.; Rathjen, Thomas; Sorensen, Ditte; O'Neill, Brian T.; Dwivedi, Nishant; Rask-Madsen, Christian] Joslin Diabet Ctr, Boston, MA 02215 USA. [Wang, Xuanchun; Lockhart, Samuel M.; Rathjen, Thomas; Sorensen, Ditte; O'Neill, Brian T.; Dwivedi, Nishant; Rask-Madsen, Christian] Harvard Med Sch, Boston, MA 02115 USA. [Wang, Xuanchun] Fudan Univ, Huashan Hosp, Shanghai, Peoples R China. [Lockhart, Samuel M.] Queens Univ Belfast, Belfast, Antrim, North Ireland. [Rathjen, Thomas] Novo Nordisk AS, Malov, Denmark. [Albadawi, Hassan; Watkins, Michael T.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Sorensen, Ditte] Univ Southern Denmark, Odense, Denmark. [Sorensen, Ditte] Danish Diabet Acad, Odense, Denmark. [Preil, Simone R.; Beck, Hans Christian; Rasmussen, Lars Melholt] Odense Univ Hosp, Ctr Individualized Med Arterial Dis CIMA, Odense, Denmark. [Dunwoodie, Sally L.] Victor Chang Cardiac Res Inst, Sydney, NSW, Australia. [Dunwoodie, Sally L.] Univ New South Wales, Fac Med, St Vincents Clin Sch, Sydney, NSW, Australia. [Dunwoodie, Sally L.] Univ Sydney, Sch Mol Biosci, Sydney, NSW, Australia. RP Rask-Madsen, C (reprint author), Joslin Diabet Ctr, Boston, MA 02215 USA.; Rask-Madsen, C (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM christian.rask-madsen@joslin.harvard.edu FU National Natural Science Foundation of China [81370936]; Shanghai Pujiang Program [16PJ1401700]; Non-Clinical Open Funding Programme from the Diabetes Research and Wellness Foundation; Danish Diabetes Academy; Novo Nordisk Foundation; National Institute of Diabetes and Digestive and Kidney Diseases [K08DK100543]; Danish Council for Independent Research; National Cancer Institute [R21CA185196]; Pilot and Feasibility grant from the Diabetic Complications Consortium - National Institute of Diabetes and Digestive and Kidney Diseases [U24 DK076169] FX X.W. received grants from the National Natural Science Foundation of China (81370936) and the Shanghai Pujiang Program (16PJ1401700). S.M.L. was supported by a Non-Clinical Open Funding Programme from the Diabetes Research and Wellness Foundation. D.S. was supported by a research grant from the Danish Diabetes Academy, which in turn receives funding from the Novo Nordisk Foundation. B.T.O. was supported by National Institute of Diabetes and Digestive and Kidney Diseases grant K08DK100543. L.M.R. was supported by grants from the Danish Council for Independent Research and the Novo Nordisk Foundation. C.R.-M. is supported by National Cancer Institute grant R21CA185196 and a Pilot and Feasibility grant from the Diabetic Complications Consortium supported by National Institute of Diabetes and Digestive and Kidney Diseases grant U24 DK076169. NR 50 TC 1 Z9 1 U1 1 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD DEC PY 2016 VL 65 IS 12 BP 3680 EP 3690 DI 10.2337/db16-0001 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EE0RA UT WOS:000389285400019 ER PT J AU Chen, BH Hivert, MF Peters, MJ Pilling, LC Hogan, JD Pham, LM Harries, LW Fox, CS Bandinelli, S Dehghan, A Hernandez, DG Hofman, A Hong, J Joehanes, R Johnson, AD Munson, PJ Rybin, DV Singleton, AB Uitterlinden, AG Ying, S Melzer, D Levy, D van Meurs, JBJ Ferrucci, L Florez, JC Dupuis, J Meigs, JB Kolaczyk, ED AF Chen, Brian H. Hivert, Marie-France Peters, Marjolein J. Pilling, Luke C. Hogan, John D. Pham, Lisa M. Harries, Lorna W. Fox, Caroline S. Bandinelli, Stefania Dehghan, Abbas Hernandez, Dena G. Hofman, Albert Hong, Jaeyoung Joehanes, Roby Johnson, Andrew D. Munson, Peter J. Rybin, Denis V. Singleton, Andrew B. Uitterlinden, Andre G. Ying, Saixia Melzer, David Levy, Daniel van Meurs, Joyce B. J. Ferrucci, Luigi Florez, Jose C. Dupuis, Josee Meigs, James B. Kolaczyk, Eric D. CA Magic Investigators TI Peripheral Blood Transcriptomic Signatures of Fasting Glucose and Insulin Concentrations SO DIABETES LA English DT Article ID GENOME-WIDE ASSOCIATION; HUMAN SKELETAL-MUSCLE; TYPE-2 DIABETES SUSCEPTIBILITY; INFLUENCING GLYCEMIC TRAITS; EAST ASIANS; LOCI; IDENTIFICATION; EXPRESSION; RESISTANCE; VARIANTS AB Genome-wide association studies (GWAS) have successfully identified genetic loci associated with glycemic traits. However, characterizing the functional significance of these loci has proven challenging. We sought to gain insights into the regulation of fasting insulin and fasting glucose through the use of gene expression microarray data from peripheral blood samples of participants without diabetes in the Framingham Heart Study (FHS) (n = 5,056), the Rotterdam Study (RS) (n = 723), and the InCHIANTI Study (Invecchiare in Chianti) (n = 595). Using a false discovery rate q <0.05, we identified three transcripts associated with fasting glucose and 433 transcripts associated with fasting insulin levels after adjusting for age, sex, technical covariates, and complete blood cell counts. Among the findings, circulating IGF2BP2 transcript levels were positively associated with fasting insulin in both the FHS and RS. Using 1000 Genomes-imputed genotype data, we identified 47,587 cis-expression quantitative trait loci (eQTL) and 6,695 trans-eQTL associated with the 433 significant insulin-associated transcripts. Of note, we identified a trans-eQTL (rs592423), where the A allele was associated with higher IGF2BP2 levels and with fasting insulin in an independent genetic meta-analysis comprised of 50,823 individuals. We conclude that integration of genomic and transcriptomic data implicate circulating IGF2BP2 mRNA levels associated with glucose and insulin homeostasis. C1 [Chen, Brian H.; Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Translat Gerontol Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Chen, Brian H.; Fox, Caroline S.; Joehanes, Roby; Johnson, Andrew D.; Levy, Daniel; Dupuis, Josee] NHLBI, Framingham Heart Study, Framingham, MA USA. [Chen, Brian H.; Fox, Caroline S.; Joehanes, Roby; Johnson, Andrew D.; Levy, Daniel] NHLBI, Populat Sci Branch, Div Intramural Res, Bldg 10, Bethesda, MD 20892 USA. [Hivert, Marie-France] Harvard Med Sch, Dept Populat Med, Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Hivert, Marie-France; Florez, Jose C.] Massachusetts Gen Hosp, Dept Med, Diabet Res Ctr, Boston, MA 02114 USA. [Hivert, Marie-France] Univ Sherbrooke, Dept Med, Sherbrooke, PQ, Canada. [Peters, Marjolein J.; Uitterlinden, Andre G.; van Meurs, Joyce B. J.] Erasmus Univ, Med Ctr Rotterdam, Dept Internal Med, Rotterdam, Netherlands. [Peters, Marjolein J.; Uitterlinden, Andre G.; van Meurs, Joyce B. J.] Netherlands Consortium Hlth Aging, Netherlands Genom Initiat, Leiden, Netherlands. [Peters, Marjolein J.; Uitterlinden, Andre G.; van Meurs, Joyce B. J.] Netherlands Consortium Hlth Aging, Netherlands Genom Initiat, Rotterdam, Netherlands. [Pilling, Luke C.; Melzer, David] Univ Exeter, Sch Med, Inst Biomed & Clin Sci, Epidemiol & Publ Hlth Grp, Exeter, Devon, England. [Hogan, John D.; Pham, Lisa M.; Kolaczyk, Eric D.] Boston Univ, Program Bioinformat, Boston, MA 02215 USA. [Harries, Lorna W.] Univ Exeter, Sch Med, Inst Biomed & Clin Sci, Exeter, Devon, England. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Rehabil Unit, Florence, Italy. [Dehghan, Abbas; Hofman, Albert; Uitterlinden, Andre G.] Erasmus Univ, Med Ctr Rotterdam, Dept Epidemiol, Rotterdam, Netherlands. [Hernandez, Dena G.; Singleton, Andrew B.] NIA, Lab Neurogenet, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Hong, Jaeyoung; Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Joehanes, Roby] Harvard Med Sch, Hebrew SeniorLife, Boston, MA USA. [Munson, Peter J.; Ying, Saixia] NIH, Math & Stat Comp Lab, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. [Rybin, Denis V.] Boston Univ, Data Coordinating Ctr, Boston, MA 02215 USA. [Florez, Jose C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Florez, Jose C.; Meigs, James B.] Broad Inst, Metab Program, Cambridge, MA 02142 USA. [Florez, Jose C.; Meigs, James B.] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Florez, Jose C.; Meigs, James B.] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. [Meigs, James B.] Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. [Kolaczyk, Eric D.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. RP Kolaczyk, ED (reprint author), Boston Univ, Program Bioinformat, Boston, MA 02215 USA.; Meigs, JB (reprint author), Broad Inst, Metab Program, Cambridge, MA 02142 USA.; Meigs, JB (reprint author), Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.; Meigs, JB (reprint author), Harvard Med Sch, Dept Med, Boston, MA 02115 USA.; Meigs, JB (reprint author), Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA.; Kolaczyk, ED (reprint author), Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. EM jmeigs@partners.org; kolaczyk@bu.edu FU European Commission [HEALTH-F2-2008-201865, GEFOS, HEALTH-F2-2008 35627, TREAT-OA 200800]; Netherlands Organisation for Scientific Research [175.010.2005.011, 911-03-012]; Research Institute for Diseases in the Elderly [014-93-015, RIDE2]; Netherlands Genomics Initiative/Netherlands Consortium for Healthy Ageing [050-060-810]; Netherlands Organisation for Scientific Research VIDI grant [917103521]; Erasmus University Medical Center Rotterdam; Erasmus University; Netherlands Organisation for Health Research and Development; Research Institute for Diseases in the Elderly; Netherlands Ministry of Education, Culture and Science; Netherlands Ministry for Health, Welfare and Sports; European Commission (DG XII); Municipality of Rotterdam FX This work was funded by the European Commission (HEALTH-F2-2008-201865, GEFOS, HEALTH-F2-2008 35627, and TREAT-OA 200800), the Netherlands Organisation for Scientific Research (175.010.2005.011 and 911-03-012), the Research Institute for Diseases in the Elderly (014-93-015, RIDE2), the Netherlands Genomics Initiative/Netherlands Consortium for Healthy Ageing (050-060-810), and Netherlands Organisation for Scientific Research VIDI grant (917103521). The RS is funded by Erasmus University Medical Center Rotterdam and Erasmus University; Netherlands Organisation for Health Research and Development; the Research Institute for Diseases in the Elderly; the Netherlands Ministry of Education, Culture and Science; the Netherlands Ministry for Health, Welfare and Sports; the European Commission (DG XII); and the Municipality of Rotterdam.; The FHS is funded by the National Institutes of Health (NIH) contract N01-HC-25195. The laboratory work for this investigation was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH. The analytical component of this project was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, and the Center for Information Technology, NIH. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster (https://hpc.nih.gov/) and Helix Systems (http://helix.nih.gov) at the NIH. L.M.P., J.D., J.B.M., and E.D.K. were partially supported by NIH grant R01 DK078616. J.B.M. is partly supported by NIH grant K24 DK080140.; This research was supported in part by the Intramural Research Program, National Institute on Aging, NIH (Z01-AG000947 and Z01-AG000185). The InCHIANTI 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 National Institute on Aging (contracts 263 MD 9164 and 263 MD 821336). L.W.H. was funded by a grant from the U.K. Medical Research Council (MR/J006777/1). NR 42 TC 0 Z9 0 U1 2 U2 2 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD DEC PY 2016 VL 65 IS 12 BP 3794 EP 3804 DI 10.2337/db16-0470 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EE0RA UT WOS:000389285400029 PM 27625022 ER PT J AU Hoerster, KD Wilson, S Nelson, KM Reiber, GE Masheb, RM AF Hoerster, Katherine D. Wilson, Sarah Nelson, Karin M. Reiber, Gayle E. Masheb, Robin M. TI Diet quality is associated with mental health, social support, and neighborhood factors among Veterans SO EATING BEHAVIORS LA English DT Article DE Veterans; Diet quality; Ecological framework ID PHYSICAL-ACTIVITY; OVERWEIGHT; BEHAVIORS; DISEASE; RELIABILITY; DEPRESSION; MILITARY; PATTERNS; VALIDITY; SCALES AB United States Veterans have a higher prevalence of overweight and related chronic conditions compared to the general population. Although diet is a primary and modifiable contributor to these conditions, little is known about factors influencing diet quality among Veterans. The goal of this study is to examine individual, social environment, and physical environment correlates of general diet quality among Veterans. Study participants (N = 653) received care at an urban VA Medical Center in Seattle, WA and completed a mailed survey in 2012 and 2013. Diet quality was assessed with Starting the Conversation, an instrument that measures consumption of unhealthy snacks, fast food, desserts, sugar-sweetened beverages, and fats; fruits and vegetables; and healthy proteins. Variables significantly (p < 0.05) associated with diet quality in bivariate analyses were included in a multivariate regression. In the multivariate model, higher level of depressive symptom severity (Diff = 0.05; CI = 0.01, 0.09; p = 0.017); not having others eat healthy meals with the Veteran (Diff = -0.81; CI = -1.5, -0.1; p = 0.022); and reduced availability of low-fat foods in neighborhood stores where the Veteran shops (Diff = -0.37; CI = -0.6, -0.2; p < 0.001) were associated with poorer diet quality. Consistent with prior research in the general population, this study identified multiple domains associated with Veterans' diet quality, including psychological comorbidity, the social environment, and the physical environment. Findings from this study suggest that interventions aimed at mental health, social support, and neighborhood access to healthy foods are needed to improve Veteran diet quality. Published by Elsevier Ltd. C1 [Hoerster, Katherine D.; Nelson, Karin M.; Reiber, Gayle E.] VA Puget Sound Healthcare Syst, Seattle Div, Res & Dev Serv, 1660 South Columbian Way,S-152, Seattle, WA 98108 USA. [Hoerster, Katherine D.] Univ Washington, Dept Psychiat & Behav Sci, 1959 NE Pacific St, Seattle, WA 98195 USA. [Wilson, Sarah] Vet Affairs Midatlantic Mental Illness Res Educ &, 508 Fulton St, Durham, NC 27705 USA. [Wilson, Sarah] Durham Vet Affairs Med Ctr, 508 Fulton St, Durham, NC 27705 USA. [Nelson, Karin M.] VA Puget Sound Healthcare Syst, Gen Internal Med Serv, 1660 South Columbian Way, Seattle, WA 98108 USA. [Nelson, Karin M.] Univ Washington, Dept Med, 1959 NE Pacific St, Seattle, WA 98195 USA. [Reiber, Gayle E.] Univ Washington, Dept Hlth Serv & Epidemiol, Sch Publ Hlth, 1959 NE Pacific St, Seattle, WA 98195 USA. [Masheb, Robin M.] VA Connecticut Healthcare Syst, 950 Campbell Ave, West Haven, CT 06516 USA. [Masheb, Robin M.] Yale Sch Med, 301 Cedar St, New Haven, CT 06520 USA. RP Hoerster, KD (reprint author), VA Puget Sound Healthcare Syst, Seattle Div, Res & Dev Serv, 1660 South Columbian Way,S-152, Seattle, WA 98108 USA. EM Katherine.Hoerster@va.gov; Sarah.Wilson@duke.edu; Karin.Nelson@va.gov; greiber@uw.edu; Robin.Masheb@yale.edu FU VA Puget Sound Healthcare System (VAPS); VAPS Mental Illness Research, Education, and Clinical Center; VAPS Health Services Research and Development Center of Excellence; VA CDA [HSRD-12-263]; Department of Veterans Affairs Office of Academic Affiliations Advanced Fellowship Program in Mental Illness Research and Treatment FX This is the result of work supported by resources from VA Puget Sound Healthcare System (VAPS). Funding was provided by VAPS Mental Illness Research, Education, and Clinical Center and VAPS Health Services Research and Development Center of Excellence. Dr. Hoerster is supported by VA CDA HSR&D-12-263. Dr. Wilson was supported by the Department of Veterans Affairs Office of Academic Affiliations Advanced Fellowship Program in Mental Illness Research and Treatment. Funding sources had no involvement in design, collection, analysis, or interpretation of data, writing the manuscript, nor the decision to submit the manuscript for publication. NR 32 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1471-0153 EI 1873-7358 J9 EAT BEHAV JI Eat. Behav. PD DEC PY 2016 VL 23 BP 168 EP 173 DI 10.1016/j.eatbeh.2016.10.003 PG 6 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA EF0EZ UT WOS:000389999800031 PM 27816854 ER PT J AU Caballero, AE AF Caballero, A. Enrique TI GLP-1 ANALOGUES FOR THE TREATMENT OF TYPE 2 DIABETES IN LATINOS/HISPANICS SO ENDOCRINE PRACTICE LA English DT Editorial Material ID NON-HISPANIC WHITES; INSULIN-RESISTANCE ATHEROSCLEROSIS; AFRICAN-AMERICANS; EXENATIDE; SAFETY; EFFICACY; PATIENT C1 [Caballero, A. Enrique] Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA. RP Caballero, AE (reprint author), Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA. EM enrique.caballero@joslin.harvard.edu NR 18 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CLINICAL ENDOCRINOLOGISTS PI JACKSONVILLE PA 245 RIVERSIDE AVENUE, STE 200, JACKSONVILLE, FL 32202 USA SN 1530-891X EI 1934-2403 J9 ENDOCR PRACT JI Endocr. Pract. PD DEC PY 2016 VL 22 IS 12 BP 1459 EP 1461 DI 10.4158/EP161593.CO PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EE7ZF UT WOS:000389843300015 PM 27929679 ER PT J AU Klug, TE Rusan, M Fuursted, K Ovesen, T Jorgensen, AW AF Klug, T. E. Rusan, M. Fuursted, K. Ovesen, T. Jorgensen, A. W. TI A systematic review of Fusobacterium necrophorum-positive acute tonsillitis: prevalence, methods of detection, patient characteristics, and the usefulness of the Centor score SO EUROPEAN JOURNAL OF CLINICAL MICROBIOLOGY & INFECTIOUS DISEASES LA English DT Review ID A STREPTOCOCCAL PHARYNGITIS; REAL-TIME PCR; PERITONSILLAR ABSCESS; SORE THROAT; EPIDEMIOLOGY; INFECTION; SMOKING AB The purpose of this study was to review the current evidence for an association between Fusobacterium necrophorum (FN) and acute tonsillitis (AT), to assess the prevalence of FN in AT, to identify the better FN detection method, and to characterize the clinical characteristics of FN-positive patients with uncomplicated AT. A systematic literature search was conducted in the PubMed, EMBASE, and SweMed+ databases for studies reporting on the recovery rates of FN in patients with AT. A total of 498 unique records were identified. Eleven studies were included in a qualitative synthesis and six studies were included in a meta-analysis. Considerable heterogeneity (I-2 = 60 %) and risk of bias and confounders was found among the studies, though a subset of studies (prospective) had lower heterogeneity and higher study quality. FN was recovered significantly more frequently from patients (21.2 %) compared to healthy controls (7.6 %) (p < 0.001). FN recovery rates were similar between culture-based studies (20.3 %) and studies using polymerase chain reaction (PCR) methodology (22.2 %) (p = 0.462). The typical FN-positive AT patient was a smoking young (15-25 years) male presenting with tonsillar exudates and a Centor score of 2 or higher. A clear association between FN and AT was found. FN is likely to be a significant and prevalent pathogen in AT, especially in teenagers and young adults. However, no evidence for causality between FN and AT has been established and it is unexplored if timely antibiotic therapy directed against FN accelerates the resolution of symptoms and decreases the risk of complications. C1 [Klug, T. E.; Rusan, M.] Aarhus Univ Hosp, Dept Otorhinolaryngol Head & Neck Surg, NBG, Bldg 10 Noerrebrogade 44, DK-8000 Aarhus C, Denmark. [Rusan, M.] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Fuursted, K.] Statens Serum Inst, Dept Microbiol & Infect Control, DK-2300 Copenhagen S, Denmark. [Ovesen, T.] Hosp Unit West, Dept Otorhinolaryngol Head & Neck Surg, Aarhus, Denmark. [Jorgensen, A. W.] Aalborg Univ Hosp, Dept Otorhinolaryngol Head & Neck Surg, Aalborg, Denmark. RP Klug, TE (reprint author), Aarhus Univ Hosp, Dept Otorhinolaryngol Head & Neck Surg, NBG, Bldg 10 Noerrebrogade 44, DK-8000 Aarhus C, Denmark. EM tejsehlersklug@hotmail.com NR 26 TC 0 Z9 0 U1 4 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0934-9723 EI 1435-4373 J9 EUR J CLIN MICROBIOL JI Eur. J. Clin. Microbiol. Infect. Dis. PD DEC PY 2016 VL 35 IS 12 BP 1903 EP 1912 DI 10.1007/s10096-016-2757-y PG 10 WC Infectious Diseases; Microbiology SC Infectious Diseases; Microbiology GA EE8QR UT WOS:000389891300002 PM 27568201 ER PT J AU Yachimski, P Hur, C AF Yachimski, Patrick Hur, Chin TI Endoscopic therapy versus surgery for T1 colon cancer: defining model clinical practice SO GASTROINTESTINAL ENDOSCOPY LA English DT Editorial Material C1 [Yachimski, Patrick] Vanderbilt Univ, Med Ctr, Div Gastroenterol Hepatol & Nutr, 221 Kirkland Hall, Nashville, TN 37235 USA. [Hur, Chin] Harvard Med Sch, Inst Technol Assessment, Boston, MA USA. [Hur, Chin] Harvard Med Sch, Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA USA. RP Yachimski, P (reprint author), Vanderbilt Univ, Med Ctr, Div Gastroenterol Hepatol & Nutr, 221 Kirkland Hall, Nashville, TN 37235 USA. OI Hur, Chin/0000-0002-2819-7576 NR 6 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 0016-5107 EI 1097-6779 J9 GASTROINTEST ENDOSC JI Gastrointest. Endosc. PD DEC PY 2016 VL 84 IS 6 BP 995 EP 996 DI 10.1016/j.gie.2016.05.047 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EE4YN UT WOS:000389611900018 PM 27855802 ER PT J AU Kaltenbach, T McQuaid, KR Soetikno, R AF Kaltenbach, Tonya McQuaid, Kenneth R. Soetikno, Roy TI Outcomes of colitis-associated dysplasia after referral from the community to a tertiary center Response SO GASTROINTESTINAL ENDOSCOPY LA English DT Letter ID INFLAMMATORY-BOWEL-DISEASE C1 [Kaltenbach, Tonya; McQuaid, Kenneth R.] Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, San Francisco, CA 94143 USA. [Soetikno, Roy] Duke Natl Univ Singapore, Singapore Gen Hosp, Singapore, Singapore. RP Kaltenbach, T (reprint author), Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, San Francisco, CA 94143 USA. NR 5 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 0016-5107 EI 1097-6779 J9 GASTROINTEST ENDOSC JI Gastrointest. Endosc. PD DEC PY 2016 VL 84 IS 6 BP 1079 EP 1080 DI 10.1016/j.gie.2016.09.004 PG 4 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EE4YN UT WOS:000389611900060 PM 27855796 ER PT J AU Mandelker, D Schmidt, RJ Ankala, A Gibson, KM Bowser, M Sharma, H Duffy, E Hegde, M Santani, A Lebo, M Funke, B AF Mandelker, Diana Schmidt, Ryan J. Ankala, Arunkanth Gibson, Kristin McDonald Bowser, Mark Sharma, Himanshu Duffy, Elizabeth Hegde, Madhuri Santani, Avni Lebo, Matthew Funke, Birgit TI Navigating highly homologous genes in a molecular diagnostic setting: a resource for clinical next-generation sequencing SO GENETICS IN MEDICINE LA English DT Article DE homology; mappability; next-generation sequencing; pseudogene; whole-exome sequencing ID LABORATORY STANDARDS; PSEUDOGENES; ALIGNMENT AB PURPOSE: Next-generation sequencing (NGS) is now routinely used to interrogate large sets of genes in a diagnostic setting. Regions of high sequence homology continue to be a major challenge for short-read technologies and can lead to false-positive and false-negative diagnostic errors. At the scale of whole-exome sequencing (WES), laboratories may be limited in their knowledge of genes and regions that pose technical hurdles due to high homology. We have created an exome-wide resource that catalogs highly homologous regions that is tailored toward diagnostic applications. METHODS: This resource was developed using a mappability-based approach tailored to current Sanger and NGS protocols. RESULTS: Gene-level and exon-level lists delineate regions that are difficult or impossible to analyze via standard NGS. These regions are ranked by degree of affectedness, annotated for medical relevance, and classified by the type of homology (within-gene, different functional gene, known pseudogene, uncharacterized noncoding region). Additionally, we provide a list of exons that cannot be analyzed by short-amplicon Sanger sequencing. CONCLUSION: This resource can help guide clinical test design, supplemental assay implementation, and results interpretation in the context of high homology. C1 [Mandelker, Diana; Schmidt, Ryan J.; Lebo, Matthew] Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, Boston, MA USA. [Ankala, Arunkanth] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA USA. [Gibson, Kristin McDonald; Santani, Avni] Childrens Hosp Philadelphia, Div Genom Diagnost, Philadelphia, PA 19104 USA. [Bowser, Mark; Sharma, Himanshu; Duffy, Elizabeth; Lebo, Matthew; Funke, Birgit] Partners HealthCare Personalized Med, Mol Med Lab, Cambridge, MA 02139 USA. [Hegde, Madhuri] Emory Univ, Sch Med, Emory Genet Lab, Atlanta, GA USA. [Funke, Birgit] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02115 USA. [Mandelker, Diana] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. [Gibson, Kristin McDonald] Invitae Corp, Med Genet, San Francisco, CA USA. RP Funke, B (reprint author), Partners HealthCare Personalized Med, Mol Med Lab, Cambridge, MA 02139 USA.; Funke, B (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02115 USA. EM bfunke@partners.org OI Lebo, Matthew/0000-0002-9733-5207; Sharma, Himanshu/0000-0001-7133-6327; McDonald Gibson, Kristin/0000-0002-3297-2002 NR 19 TC 0 Z9 0 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1098-3600 EI 1530-0366 J9 GENET MED JI Genet. Med. PD DEC PY 2016 VL 18 IS 12 BP 1282 EP 1289 DI 10.1038/gim.2016.58 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA EE4HU UT WOS:000389563700017 PM 27228465 ER PT J AU Cho, LP Manuel, M Catalano, P Lee, L Damato, AL Cormack, RA Buzurovic, I Bhagwat, M O'Farrell, D Devlin, PM Viswanathan, AN AF Cho, Linda P. Manuel, Matthias Catalano, Paul Lee, Larissa Damato, Antonio L. Cormack, Robert A. Buzurovic, Ivan Bhagwat, Mandar O'Farrell, Desmond Devlin, Phillip M. Viswanathan, Akila N. TI Outcomes with volume-based dose specification in CT-planned high-dose-rate brachytherapy for stage I-II cervical carcinoma: A 10-year institutional experience SO GYNECOLOGIC ONCOLOGY LA English DT Article DE CT-guided; High-dose-rate; Brachytherapy; Cervical cancer; Radiation oncology; Prognostic factors ID RATE INTRACAVITARY BRACHYTHERAPY; IMAGE-GUIDED BRACHYTHERAPY; CANCER BRACHYTHERAPY; COMPUTED-TOMOGRAPHY; CONSENSUS GUIDELINES; RADIATION-THERAPY; SOCIETY; RECOMMENDATIONS; CHEMOTHERAPY; ONCOLOGY AB Objective. To determine prognostic factors for progression-free survival (PFS) and overall survival (OS) for stage I-II cervical-cancer patients treated using computed-tomography (CT)-planned high-dose-rate (HDR) intracavitary brachytherapy (BT). Methods. A total of 150 patients were treated for Stage I-II cervical cancer using CT -planned BT between 4/2004 and 10/2014. Of these, 128 were eligible for inclusion. Kaplan-Meier local control (LC), pelvic control (PC), overall survival (OS), and PFS estimates were calculated. Results. After a median follow-up of 30 months, the 2-year LC rate was 96%, PFS was 88%, and OS was 88%. Overall, 18 patients (14%) experienced any recurrence (AR), 8 had distant recurrence only and 10 had a combination of local, pelvic, regional, and distant recurrence. No patients had LR only. A prognostic factor for AR was tumor size >4 cm (p = 0.01). Patients with tumors >4 cm were 3.3 times more likely to have AR than those with tumors cm (hazard ratio [FIR] = 3.3; 95% confidence interval [CI] 128-9.47). Point A was 85% of prescription for tumors < 4 cm and decreased approximately 3% over 5 fractions compared to 90% of prescription for tumors > 4 cm that decreased approximately 4% over 5 fractions. Two patients (2%) experienced grade 2 late toxicity. There were no acute or late grade >= 3 toxicities. Conclusion. CT-planned BT resulted in excellent local control and survival. Large tumor size was associated with an increased risk of recurrence outside the radiation field and worse PFS and OS. A volume-optimized plan treated a smaller area than a point A standard plan for patients with Stage I-II cervical cancer that have received chemoradiation. Given the outstanding LC achieved with modem therapy including chemoradiation, HDR, and image-based BT, further efforts to combat spread outside the radiation field with novel therapies are warranted. (C) 2016 Elsevier Inc. All rights reserved. C1 [Cho, Linda P.; Manuel, Matthias; Catalano, Paul; Lee, Larissa; Damato, Antonio L.; Cormack, Robert A.; Buzurovic, Ivan; Bhagwat, Mandar; O'Farrell, Desmond; Devlin, Phillip M.; Viswanathan, Akila N.] Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St,ASB1-L2, Boston, MA 02115 USA. [Cho, Linda P.; Manuel, Matthias; Catalano, Paul; Lee, Larissa; Damato, Antonio L.; Cormack, Robert A.; Buzurovic, Ivan; Bhagwat, Mandar; O'Farrell, Desmond; Devlin, Phillip M.; Viswanathan, Akila N.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Lee, Larissa; Damato, Antonio L.; Cormack, Robert A.; Buzurovic, Ivan; Devlin, Phillip M.; Viswanathan, Akila N.] Harvard Med Sch, Boston, MA USA. [Catalano, Paul] Harvard TH Chan Sch Publ Hlth, Boston, MA USA. [Viswanathan, Akila N.] Johns Hopkins Med, Dept Radiat Oncol & Mol Radiat Sci, 401 North Broadway, Baltimore, MD 21287 USA. RP Viswanathan, AN (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St,ASB1-L2, Boston, MA 02115 USA.; Viswanathan, AN (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA.; Viswanathan, AN (reprint author), Johns Hopkins Med, Dept Radiat Oncol & Mol Radiat Sci, 401 North Broadway, Baltimore, MD 21287 USA. EM lcho7@jhu.edu; anv@jhu.edu OI /0000-0001-9632-3434 FU NIH [CA167800]; Epstein Family Fund; St. Laurent Family Fund; Boerner Family Fund FX Dr. Viswanathan receives support from NIH CA167800. We wish to thank nursing (Mary Consalvo, Katie Duggan, Una Randall, Regina Tsanotellis), therapists (Susan Finucane, Erin Randazzo, Marianne Weiler), surgical technician (Alecia Ofiong), physics planning staff (Ivan Buzurovic, Mandar Bhagwat and Desmond O'Farrell), anesthesiologists (Drs. Eileen Lynch and Nada Hart), Barbara Silver and all of the staff working with us over the past decade that made this project feasible. Research support was provided by the Epstein, St. Laurent and Boerner Family Funds. NR 34 TC 0 Z9 0 U1 1 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD DEC PY 2016 VL 143 IS 3 BP 545 EP 551 DI 10.1016/j.ygyno.2016.09.017 PG 7 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA ED9EO UT WOS:000389173200017 PM 27720445 ER PT J AU Campbell, G Hagan, T Gilbertson-White, S Houze, M Donovan, H AF Campbell, Grace Hagan, Teresa Gilbertson-White, Stephanie Houze, Martin Donovan, Heidi TI Cancer and treatment-related symptoms are associated with mobility disability in women with ovarian cancer: A cross-sectional study SO GYNECOLOGIC ONCOLOGY LA English DT Article DE Ovarian cancer; Symptom assessment; Physical function; Mobility; Disability ID UNITED-STATES; EDUCATIONAL-ATTAINMENT; SURVIVORS; LIFE; CHEMOTHERAPY; NEUROPATHY; CARE; POPULATION; INVENTORY; BURDEN AB Objective. To examine the prevalence of symptbm-related mobility disability and identify specific symptoms and other factors associated with mobility disability among a national sample of ovarian cancer (OC) survivors. Methods. Descriptive, correlational secondary analysis of a National Ovarian Cancer Coalition mailed survey of women with a history of OC (n = 713). We used the Symptom Representation Questionnaire (SRQ), the MD Anderson Symptom Inventory (MDASI) Interference Scale, and medical and demographic information to determine prevalence of symptom-related mobility disability. We constructed a multiple linear regression model to determine the relative contributions of specific "symptoms and other factors to mobility disability. Results. A majority of the sample (60.0%) reported symptom-related mobility disability. Independent predictors included: > one comorbidity 0.112, p = 0.001), active OC = 0.111, p = 0.037), abdominal bloating ((3 = 0.097,p = 0.006), fatigue (I3 = 0.314,p < 0.001 Mack of appetite ((3 = 0.072,p = 0.045), numbness/tingling ((3 = 0.134, p < 0.001), and pain 03 = 0.194, p < 0.001). The model explained 41.5% of the variance in symptom related mobility disability (R2 = 0.415). Unexpectedly, age ((3 = 0.028, p = 0.412) and current chemotherapy (( = 0.107, p = 0.118) were not significant predictors. Conclusions. Symptom-related mobility disability is common among women with OC and is associated with medical comorbidities, abdominal bloating,'fatigue, lack of appetite, numbness/tingling, and pain. Longitudinal research should clarify the relationship of these symptoms to mobility disability and determine whether effective symptom management minimizes disability. (C) 2016 Elsevier Inc. All rights reserved. C1 [Campbell, Grace; Houze, Martin; Donovan, Heidi] Univ Pittsburgh, Sch Nursing, 336 Victoria Bldg,3500 Victoria St, Pittsburgh, PA 15261 USA. [Hagan, Teresa] Harvard Med Sch, Massachusetts Gen Hosp, Yawkey Ctr, 55 Fruit St, Boston, MA 02114 USA. [Gilbertson-White, Stephanie] Univ Iowa, Coll Nursing, 50 Newton Rd,444 Coll Nursing Bldg, Iowa City, IA 52242 USA. RP Campbell, G (reprint author), Univ Pittsburgh, Sch Nursing, Dept Acute Tertiary Care, 336 Victoria Bldg,3500 Victoria St, Pittsburgh, PA 15261 USA. EM gbc3@pitt.edu; thagan@mgh.harvard.edu; stephanie-gilbertson-white@uiowa.edu; houzemartin@gmail.com; donovanh@pitt.edu FU [F31 NR07556]; [T32 NR11972] FX The original data collection was funded by F31 NR07556 (Donovan); analysis was supported by T32 NR11972 (Campbell; Hagan). The funding agencies had no involvement 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 38 TC 0 Z9 0 U1 3 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD DEC PY 2016 VL 143 IS 3 BP 578 EP 583 DI 10.1016/j.ygyno.2016.09.013 PG 6 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA ED9EO UT WOS:000389173200022 PM 27653982 ER PT J AU Shafrir, AL Rice, MS Gupta, M Terry, KL Rosner, BA Tamimi, RM Hecht, JL Tworoger, SS AF Shafrir, Amy L. Rice, Megan S. Gupta, Mamta Terry, Kathryn L. Rosner, Bernard A. Tamimi, Rulla M. Hecht, Jonathan L. Tworoger, Shelley S. TI The association between reproductive and hormonal factors and ovarian cancer by estrogen-alpha and progesterone receptor status SO GYNECOLOGIC ONCOLOGY LA English DT Article ID BREAST-CANCER; RISK-FACTORS; NURSES HEALTH; EXPRESSION; CELL; CARCINOMA; PATHWAYS; SUBTYPES; MARKERS AB Objective. We assessed the association between reproductive and hormonal factors and ovarian cancer incidence characterized by estrogen receptor-alpha (ER alpha) and progesterone receptor (PR) status. Methods. Tissue microarrays were used to assess ERa and PR expression among 197 Nurses' Health Study (NHS), 42 NHSII and 76 New England Case-Control Study (NECC) ovarian cancer cases. NHS/NHSII cases were matched to up to 4 controls (n = 954) on diagnosis date and birth year. NECC controls (n = 725) were frequency matched on age. Cases were considered receptor positive if of tumor cells stained positive. Associations by ER alpha and PR status were assessed using polytomous logistic regression. p-Value for heterogeneity was calculated using a likelihood ratio test. Results. 45% of ovarian tumors were PR( +), 78% were ERa (+) and 45% were ER alpha(+)/PR(+), while 22% were ER alpha(-)/PR(-). Postmenopausal status was associated with an increased risk of PR(-) tumors (OR: 2.07; 95%CI: 1.15-3.75; p-heterogeneity = 0.01) and age at natural menopause was inversely associated with PR(-) tumors (OR, per 5 years: 0.77; 95%CI: 0.61-0.96; p-het = 0.01). Increasing duration of postmenopause was differentially associated by PR status (p-het = 0.0009). Number of children and tubal ligation were more strongly associated with ERa(-) versus ER alpha (+) tumors (p-het = 0.002 and 0.05, respectively). No differential associations were observed for oral contraceptive or hormone therapy use. Conclusions. Postmenopausal women have an increased risk of developing PR(-) ovarian tumors compared to premenopausal women. The associations observed for ovarian cancer differ from those seen for breast cancer suggesting that the biology for tumor development through ERa and PR pathways may differ. (C) 2016 Elsevier Inc. All rights reserved. C1 [Shafrir, Amy L.; Terry, Kathryn L.; Tamimi, Rulla M.; Tworoger, Shelley S.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave, Boston, MA USA. [Shafrir, Amy L.; Rice, Megan S.; Rosner, Bernard A.; Tamimi, Rulla M.; Tworoger, Shelley S.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 181 Longwood Ave, Boston, MA USA. [Shafrir, Amy L.; Rice, Megan S.; Rosner, Bernard A.; Tamimi, Rulla M.; Tworoger, Shelley S.] Harvard Med Sch, 181 Longwood Ave, Boston, MA USA. [Rice, Megan S.] Massachusetts Gen Hosp, Dept Med, Clin & Translat Epidemiol Unit, 55 Fruit St, Boston, MA USA. [Gupta, Mamta; Hecht, Jonathan L.] Beth Israel Deaconess Med Ctr, Dept Pathol, 330 Brookline Ave, Boston, MA 02215 USA. [Gupta, Mamta; Hecht, Jonathan L.] Harvard Med Sch, 330 Brookline Ave, Boston, MA USA. [Terry, Kathryn L.] Brigham & Womens Hosp, Dept Obstet & Gynecol, Obstet & Gynecol Epidemiol Ctr, 221 Longwood Ave, Boston, MA USA. [Terry, Kathryn L.] Harvard Med Sch, 221 Longwood Ave, Boston, MA USA. [Rosner, Bernard A.] Harvard TH Chan Sch Publ Hlth, Dept Biostat, 677 Huntington Ave, Boston, MA USA. RP Shafrir, AL (reprint author), Harvard TH Chan Sch Publ Hlth, 677 Huntington Ave,9th Floor, Boston, MA 02115 USA. EM amy.shafrir@mail.harvard.edu FU National Institutes of Health [P01 CA87969, UM1 CA186107, UM1 CA176726, R01-CA54419, P50-CA105009]; Department of Defense [W81XWH-10-1-02802]; National Institute of Child Health and Human Development, National Institutes of Health [T32 HD060454]; Cancer Epidemiology Training Program [NIH T32CA09001] FX We would like to thank the participants and staff of the Nurses' Health Study and Nurses' Health Study II 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, WY. This project was supported by the National Institutes of Health (P01 CA87969, UM1 CA186107, UM1 CA176726, R01-CA54419, P50-CA105009) and the Department of Defense (W81XWH-10-1-02802). Amy Shafrir was supported by Training Grant T32 HD060454 in Reproductive, Perinatal and Pediatric Epidemiology from the National Institute of Child Health and Human Development, National Institutes of Health. Amy Shafrir and Megan Rice were supported by the Cancer Epidemiology Training Program (NIH T32CA09001). The authors assume full responsibility for the study design, analyses and interpretation of these data. NR 40 TC 0 Z9 0 U1 3 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD DEC PY 2016 VL 143 IS 3 BP 628 EP 635 DI 10.1016/j.ygyno.2016.09.024 PG 8 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA ED9EO UT WOS:000389173200030 PM 27720231 ER PT J AU Massaro, A Giugliano, RP Norrving, B Oto, A Veltkamp, R AF Massaro, Ayrton Giugliano, Robert P. Norrving, Bo Oto, Ali Veltkamp, Roland TI Overcoming global challenges in stroke prophylaxis in atrial fibrillation: The role of non-vitamin K antagonist oral anticoagulants SO INTERNATIONAL JOURNAL OF STROKE LA English DT Review DE Stroke; atrial fibrillation; anticoagulation; non-VKA oral anticoagulants ID CHRONIC KIDNEY-DISEASE; NET CLINICAL BENEFIT; CANADIAN CARDIOVASCULAR SOCIETY; RHYTHM ASSOCIATION SURVEY; ACUTE ISCHEMIC-STROKE; STAGE RENAL-DISEASE; EURO HEART SURVEY; COST-EFFECTIVENESS; ANTITHROMBOTIC THERAPY; ELDERLY-PATIENTS AB Atrial fibrillation is the world's most common sustained cardiac arrhythmia and is associated with a significantly increased risk of stroke. The global burden of atrial fibrillation is rising, commensurate with the ageing population. Well-controlled vitamin K antagonist-based anticoagulation has been shown to reduce the risk of stroke secondary to atrial fibrillation by two-thirds. However, patients with atrial fibrillation have frequently been denied anticoagulation because of a variety of perceived risks related to bleeding, falls, chronological age, and poor compliance. Even when vitamin K antagonists are used, maximum benefit and safety are only delivered when high quality control of therapy (TTR>70%) is achieved, which has proven remarkably difficult in many health-care systems and amongst many patient groups. The non-vitamin K antagonist oral anticoagulants (NOACs) offer solutions to many of the challenges of achieving widespread, safe, and effective anticoagulation for stroke prophylaxis in atrial fibrillation, yet their uptake into routine clinical practice remains variable. The evidence supporting their more widespread use to overcome the challenges of stroke prophylaxis for atrial fibrillation is reviewed in this article. C1 [Massaro, Ayrton] Hosp Sirio Libanes, Dept Neurol, Sao Paulo, Brazil. [Massaro, Ayrton] Pontificia Univ Catolica Rio Grande do Sul, Brain Inst Rio Grande do Sul BraIns, Neurovasc Res Unit, Porto Alegre, RS, Brazil. [Giugliano, Robert P.] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, TIMI Study Grp,Cardiovasc Div, Boston, MA USA. [Norrving, Bo] Lund Univ, Neurol Sect, Dept Clin Neurosci BN, Lund, Sweden. [Oto, Ali] Hacettepe Univ, Dept Cardiol, Fac Med, Ankara, Turkey. [Veltkamp, Roland] Heidelberg Univ, Dept Neurol, Heidelberg, Germany. RP Massaro, A (reprint author), Hosp Sirio Libanes, Dept Neurol, Sao Paulo, Brazil. EM ayrton.massaro@gmail.com FU Daiichi Sankyo Europe FX Financial support for editorial assistance was provided by Daiichi Sankyo Europe. Daiichi Sankyo Europe had no influence on the preparation, content, or decision to submit the manuscript. The authors have not received any payment for the writing of this manuscript. NR 139 TC 0 Z9 0 U1 5 U2 5 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1747-4930 EI 1747-4949 J9 INT J STROKE JI Int. J. Stroke PD DEC PY 2016 VL 11 IS 9 BP 950 EP 967 DI 10.1177/1747493016660106 PG 18 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA ED9PU UT WOS:000389205800004 PM 27703066 ER PT J AU Ko, FC Martins, JS Reddy, P Bragdon, B Hussein, AI Gerstenfeld, LC Demay, MB AF Ko, Frank C. Martins, Janaina S. Reddy, Pooja Bragdon, Beth Hussein, Amira I. Gerstenfeld, Louis C. Demay, Marie B. TI Acute Phosphate Restriction Impairs Bone Formation and Increases Marrow Adipose Tissue in Growing Mice SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE BONE HISTOMORPHOMETRY; DISORDERS OF CALCIUM AND PHOSPHATE METABOLISM; BONE-FAT INTERACTIONS ID MESENCHYMAL STEM-CELLS; OSTEOGENIC DIFFERENTIATION; ADIPOGENIC DIFFERENTIATION; PRECURSOR CELLS; FOXC2; HYPOPHOSPHATEMIA; ANGIOGENESIS; RICKETS; NOTCH; OSTEOCLASTOGENESIS AB Phosphate plays a critical role in chondrocyte maturation and skeletal mineralization. Studies examining the consequences of dietary phosphate restriction in growing mice demonstrated not only the development of rickets, but also a dramatic decrease in bone accompanied by increased marrow adipose tissue (MAT). Thus studies were undertaken to determine the effects of dietary phosphate restriction on bone formation and bone marrow stromal cell (BMSC) differentiation. Acute phosphate restriction of 28-day-old mice profoundly inhibited bone formation within 48 hours. It also resulted in increased mRNA expression of the early osteolineage markers Sox9 and Runt-related transcription factor 2 (Runx2), accompanied by decreased expression of the late osteolineage markers Osterix and Osteocalcin in BMSCs and osteoblasts, suggesting that phosphate restriction arrests osteoblast differentiation between Runx2 and Osterix. Increased expression of PPAR and CEBP, key regulators of adipogenic differentiation, was observed within 1 week of dietary phosphate restriction and was followed by a 13-fold increase in MAT at 3 weeks of phosphate restriction. In vitro phosphate restriction did not alter BMSC osteogenic or adipogenic colony formation, implicating aberrant paracrine or endocrine signaling in the in vivo phenotype. Because BMP signaling regulates the transition between Runx2 and Osterix, this pathway was interrogated. A dramatic decrease in pSmad1/5/9 immunoreactivity was observed in the osteoblasts of phosphate-restricted mice on day 31 (d31) and d35. This was accompanied by attenuated expression of the BMP target genes Id1, KLF10, and Foxc2, the latter of which promotes osteogenic and angiogenic differentiation while impairing adipogenesis. A decrease in expression of the Notch target gene Hey1, a BMP-regulated gene that governs angiogenesis, was also observed in phosphate-restricted mice, in association with decreased metaphyseal marrow vasculature. Whereas circulating phosphate levels are known to control growth plate maturation and skeletal mineralization, these studies reveal novel consequences of phosphate restriction in the regulation of bone formation and osteoblast differentiation. (c) 2016 American Society for Bone and Mineral Research. C1 [Ko, Frank C.; Martins, Janaina S.; Reddy, Pooja; Demay, Marie B.] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Ko, Frank C.; Martins, Janaina S.; Demay, Marie B.] Harvard Med Sch, Boston, MA USA. [Bragdon, Beth; Hussein, Amira I.; Gerstenfeld, Louis C.] Boston Univ, Sch Med, Dept Orthopaed Surg, Boston, MA 02118 USA. RP Demay, MB (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Endocrine Unit, 50 Blossom St,Thier 1101, Boston, MA 02114 USA. EM demay@helix.harvard.edu FU NIH [R01-AR061376, T32-DK007028]; MGH Center for Skeletal Research [NIH P30-AR066261] FX This work was funded by NIH R01-AR061376 and T32-DK007028. It was also supported by the MGH Center for Skeletal Research (NIH P30-AR066261). NR 37 TC 2 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0884-0431 EI 1523-4681 J9 J BONE MINER RES JI J. Bone Miner. Res. PD DEC PY 2016 VL 31 IS 12 BP 2204 EP 2214 DI 10.1002/jbmr.2891 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EE2WF UT WOS:000389445100017 PM 27324177 ER PT J AU Orr, NM Boxer, RS Dolansky, MA Allen, LA Forman, DE AF Orr, Nicole M. Boxer, Rebecca S. Dolansky, Mary A. Allen, Larry A. Forman, Daniel E. TI Skilled Nursing Facility Care for Patients With Heart Failure: Can We Make It "Heart Failure Ready?" SO JOURNAL OF CARDIAC FAILURE LA English DT Review DE Skilled nursing facility; post-acute care; heart failure; transitions; systems of care; policy ID EMERGENCY-DEPARTMENT VISITS; RANDOMIZED CONTROLLED-TRIAL; TRANSITIONAL CARE; HOSPITAL READMISSIONS; POST-ACUTE; CARDIAC REHABILITATION; DISCHARGE SUMMARIES; 30-DAY READMISSION; CLINICAL-OUTCOMES; HOME RESIDENTS AB Skilled nursing facilities (SNFs) have emerged as an integral component of care for older adults with heart failure (HF). Despite their prominent role, poor clinical outcomes for the medically complex patients with HF managed in SNFs are common. Barriers to providing quality care include poor transitional care during hospital-to-SNF and SNF-to-community discharges, lack of HF training among SNF staff, and a lack of a standardized care process among SNF facilities. Although no evidence-based practice standards have been established, various measures and tools designed to improve HF management in SNFs are being investigated. In this review, we discuss the challenges of HF care in SNFs as well as potential targets and recommendations that can help improve care with respect to transitions, HF management within SNFs, and modifiable factors within facilities. Policy considerations that might help catalyze improvements in SNF-based HF management are also discussed. C1 [Orr, Nicole M.] Tufts Med Ctr, Div Cardiol & CardioVasc Ctr, Boston, MA USA. [Orr, Nicole M.] Postacute Cardiol Care, Wellesley, MA USA. [Boxer, Rebecca S.] Eastern Colorado Denver Vet Assoc GRECC, Denver, CO USA. [Boxer, Rebecca S.; Allen, Larry A.] Univ Colorado, Sch Med, Aurora, CO USA. [Dolansky, Mary A.] Frances Payne Bolton Sch Nursing, Cleveland, OH USA. [Forman, Daniel E.] Univ Pittsburgh, Med Ctr, Geriatr Cardiol Sect, Pittsburgh, PA USA. [Forman, Daniel E.] VA Pittsburgh Healthcare Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA USA. RP Orr, NM (reprint author), 95 Chapel St,Suite 2C, Norwood, MA 02062 USA. EM non@postacutecardiologycare.com FU NIA [P30 AG024827, 1R56AG051637-01A1]; PCORI [IH-1304678]; VA Office of Rehabilitation Research and Development [F0834-R] FX Dr. Forman is supported in part by NIA grants P30 AG024827 and 1R56AG051637-01A1, PCORI grant IH-1304678, and VA Office of Rehabilitation Research and Development grant F0834-R. NR 65 TC 0 Z9 0 U1 6 U2 6 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1071-9164 EI 1532-8414 J9 J CARD FAIL JI J. Card. Fail. PD DEC PY 2016 VL 22 IS 12 BP 1004 EP 1014 DI 10.1016/j.cardfail.2016.10.009 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EE4IL UT WOS:000389565400010 PM 27769909 ER PT J AU Schopfer, DW Forman, DE AF Schopfer, David W. Forman, Daniel E. TI Growing Relevance of Cardiac Rehabilitation for an Older Population With Heart Failure SO JOURNAL OF CARDIAC FAILURE LA English DT Review DE Old age; heart failure; multimorbidity; frailty; disability; cardiac rehabilitation ID PRESERVED EJECTION FRACTION; RANDOMIZED CONTROLLED-TRIALS; FRAIL ELDERLY-PATIENTS; PHYSICAL-ACTIVITY; SKELETAL-MUSCLE; CARDIOVASCULAR-DISEASE; MYOCARDIAL-INFARCTION; EXERCISE CAPACITY; THERAPEUTIC INTERVENTIONS; PULMONARY-REHABILITATION AB Cardiac rehabilitation (CR) is a comprehensive lifestyle program that can have particular benefit for older patients with heart failure (HF). Prevalence of HF is increasingly common among older adults. Mounting effects of cardiovascular risk factors in older age as well as the added effects of geriatric syndromes such as multimorbidity, frailty, and sedentariness contribute to the high incidence of HF as well as to management difficulty. CR can play a decisive role in improving function, quality of life, symptoms, morbidity, and mortality, and also address the idiosyncratic complexities of care that often arise in old age. Unfortunately, the current policies and practices regarding CR for patients with HF are limited to HF with reduced ejection fraction and do not extend to HF with preserved ejection fraction, which is likely undercutting its full potential to improve care for today's aging population. Despite the strong rationale for CR on important clinical outcomes, it remains underused, particularly among older patients with HF. In this review, we discuss both the potential and the limitations of contemporary CR for older adults with HF. C1 [Schopfer, David W.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Schopfer, David W.] San Francisco VA Med Ctr, Dept Med, San Francisco, CA USA. [Forman, Daniel E.] Univ Pittsburgh, Med Ctr, Sect Geriatr Cardiol, 3471 Fifth Ave, Pittsburgh, PA 15213 USA. [Forman, Daniel E.] VA Pittsburgh Healthcare Syst, Geriatr Res & Clin Ctr, Pittsburgh, PA USA. [Forman, Daniel E.] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. RP Forman, DE (reprint author), Univ Pittsburgh, Med Ctr, Sect Geriatr Cardiol, 3471 Fifth Ave, Pittsburgh, PA 15213 USA. EM formand@pitt.edu FU National Center for Advancing Translational Sciences of the NIH [KL2TR000143]; NIA [P30 AG024827, 1R56AG051637-01A1]; PCORI [IH-1304678]; VA Rehabilitation Research and Development grant [F0834-R] FX Dr. Schopfer is supported by the National Center for Advancing Translational Sciences of the NIH under Award Number KL2TR000143. Dr. Forman is supported in part by NIA grants P30 AG024827 and 1R56AG051637-01A1, PCORI grant IH-1304678, and VA Rehabilitation Research and Development grant F0834-R. NR 90 TC 0 Z9 0 U1 4 U2 4 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1071-9164 EI 1532-8414 J9 J CARD FAIL JI J. Card. Fail. PD DEC PY 2016 VL 22 IS 12 BP 1015 EP 1022 DI 10.1016/j.cardfail.2016.10.010 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EE4IL UT WOS:000389565400011 PM 27769907 ER PT J AU Gutner, CA Suvak, MK Sloan, DM Resick, PA AF Gutner, Cassidy A. Suvak, Michael K. Sloan, Denise M. Resick, Patricia A. TI Does Timing Matter? Examining the Impact of Session Timing on Outcome SO JOURNAL OF CONSULTING AND CLINICAL PSYCHOLOGY LA English DT Article DE treatment outcome; session timing; posttraumatic stress disorder; cognitive processing therapy; prolonged exposure ID POSTTRAUMATIC-STRESS-DISORDER; COGNITIVE-PROCESSING THERAPY; RANDOMIZED CONTROLLED-TRIAL; ADMINISTERED PTSD SCALE; PROLONGED EXPOSURE; RAPE VICTIMS; VETERANS; CLINICS; DROPOUT; PSYCHOTHERAPY AB Objective: First-line treatments for posttraumatic stress disorder (PTSD) are often implemented twice per week in efficacy trials. However, there is considerable variability in the frequency of treatment sessions (e. g., once per week or twice per week) in clinical practice. Moreover, clients often cancel or reschedule treatment sessions, leading to even greater variability in treatment session timing. The goal of the current study is to investigate the impact of PTSD treatment session frequency on treatment outcome. Method: One hundred thirty-six women (M-age = 32.16 [ SD = 9.90]) with PTSD were randomized to receive cognitive processing therapy or prolonged exposure. PTSD symptom outcome was measured using the Clinician-Administered PTSD Scale, and session frequency and consistency were measured using dates of treatment session attendance. Session frequency was operationalized using average days between session, and consistency was defined by the standard deviation of the number of days between treatment sessions. Results: Piecewise growth curve modeling revealed that higher average days between sessions was associated with significantly smaller PTSD symptom reduction, with more frequent sessions yielding greater PTSD symptom reduction (p < .001, d = .82). Higher consistency was also associated with significantly greater PTSD symptom reduction (p < .01, d = .48). The substantially larger effect size for frequency suggests that average days between treatment sessions impacts treatment outcome more than consistency. Follow-up analyses revealed a longer time interval between Sessions 4 and 5 was associated with smaller reductions in PTSD treatment outcome. Conclusions: More frequent scheduling of sessions may maximize PTSD treatment outcomes. C1 [Gutner, Cassidy A.] VA Boston Healthcare Syst, Natl Ctr PTSD, Womens Hlth Sci Div, Boston, MA USA. [Gutner, Cassidy A.; Sloan, Denise M.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02215 USA. [Suvak, Michael K.] Suffolk Univ, Dept Psychol, Boston, MA 02114 USA. [Sloan, Denise M.] VA Boston Healthcare Syst, Natl Ctr PTSD, Behav Sci Div, Boston, MA USA. [Resick, Patricia A.] Duke Univ, Dept Psychiat, Durham, NC 27706 USA. RP Gutner, CA (reprint author), 150 S Huntington Ave 116B-3, Boston, MA 02130 USA. EM cassidy.gutner@va.gov FU National Institute of Mental Health [NIH-1 R01-MH51509, NIH-2 R01-MH51509, 1K23MH103396-01A1] FX This work was supported by National Institute of Mental Health Grant NIH-1 R01-MH51509 and National Institute of Mental Health Grant NIH-2 R01-MH51509 awarded to Patricia A. Resick while at the University of Missouri-St. Louis. Dr. Gutner was supported by a National Institute of Mental Health grant (1K23MH103396-01A1). NR 39 TC 0 Z9 0 U1 4 U2 4 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 DEC PY 2016 VL 84 IS 12 BP 1108 EP 1115 DI 10.1037/ccp0000120 PG 8 WC Psychology, Clinical SC Psychology GA EE0XX UT WOS:000389304500007 PM 27213491 ER PT J AU Creed, TA Frankel, SA German, RE Green, KL Jager-Hyman, S Taylor, KP Adler, AD Wolk, CB Stirman, SW Waltman, SH Williston, MA Sherrill, R Evans, AC Beck, AT AF Creed, Torrey A. Frankel, Sarah A. German, Ramaris E. Green, Kelly L. Jager-Hyman, Shari Taylor, Kristin P. Adler, Abby D. Wolk, Courtney B. Stirman, Shannon W. Waltman, Scott H. Williston, Michael A. Sherrill, Rachel Evans, Arthur C. Beck, Aaron T. TI Implementation of Transdiagnostic Cognitive Therapy in Community Behavioral Health: The Beck Community Initiative SO JOURNAL OF CONSULTING AND CLINICAL PSYCHOLOGY LA English DT Article DE cognitive therapy; implementation; community mental health; competency; fidelity ID ORGANIZATIONAL SOCIAL-CONTEXT; MENTAL-HEALTH; COST-EFFECTIVENESS; PSYCHOLOGICAL TREATMENTS; PSYCHOMETRIC PROPERTIES; ANXIETY DISORDERS; RANDOMIZED-TRIAL; SERVICES; DEPRESSION; MODEL AB Objective: Progress bringing evidence-based practice (EBP) to community behavioral health (CBH) has been slow. This study investigated feasibility, acceptability, and fidelity outcomes of a program to implement transdiagnostic cognitive therapy (CT) across diverse CBH settings, in response to a policy shift toward EBP. Method: Clinicians (n = 348) from 30 CBH programs participated in workshops and 6 months of consultation. Clinician retention was examined to assess feasibility, and clinician feedback and attitudes were evaluated to assess implementation acceptability. Experts rated clinicians' work samples at baseline, mid-, and end-of-consultation with the Cognitive Therapy Rating Scale (CTRS) to assess fidelity. Results: Feasibility was demonstrated through high program retention (i. e., only 4.9% of clinicians withdrew). Turnover of clinicians who participated was low (13.5%) compared to typical CBH turnover rates, even during the high-demand training period. Clinicians reported high acceptability of EBP and CT, and self-reported comfort using CT improved significantly over time. Most clinicians (79.6%) reached established benchmarks of CT competency by the final assessment point. Mixed-effects hierarchical linear models indicated that CTRS scores increased significantly from baseline to the competency assessment (p < .001), on average by 18.65 points. Outcomes did not vary significantly between settings (i.e., outpatient vs. other). Conclusions: Even clinicians motivated by policy-change rather than self-nomination may feasibly be trained to deliver a case-conceptualization driven EBP with high levels of competency and acceptability. C1 [Creed, Torrey A.; Frankel, Sarah A.; German, Ramaris E.; Green, Kelly L.; Jager-Hyman, Shari; Taylor, Kristin P.; Adler, Abby D.; Waltman, Scott H.; Williston, Michael A.; Sherrill, Rachel; Beck, Aaron T.] Univ Penn, Dept Psychiat, Perelman Sch Med, 3535 Market St Room 2029, Philadelphia, PA 19104 USA. [Green, Kelly L.] Corporal Michael J Crescenz Vet Adm Med Ctr, Philadelphia, PA USA. [Wolk, Courtney B.] Univ Penn, Perelman Sch Med, Ctr Mental Hlth Policy & Serv Res, Philadelphia, PA 19104 USA. [Stirman, Shannon W.] Vet Adm Boston Healthcare Syst, Womens Hlth Sci Div, Natl Ctr Posttraumat Stress Disorder, Boston, MA USA. [Evans, Arthur C.] Philadelphia Dept Behav Hlth & Intellectual disAb, Philadelphia, PA USA. RP Creed, TA (reprint author), Univ Penn, Dept Psychiat, Perelman Sch Med, 3535 Market St Room 2029, Philadelphia, PA 19104 USA. EM tcreed@mail.med.upenn.edu OI Creed, Torrey/0000-0003-0860-2498 FU Philadelphia Department of Behavioral Health and Intellectual disAbility Services; National Institute of Mental Health [T32 MH083745-03, F32-MH-103955] FX We thank the Philadelphia Department of Behavioral Health and Intellectual disAbility Services, the research assistants and the Beck Community Initiative instructors at the Aaron T. Beck Psychopathology Research Center, and the clinicians, administrators, and people in recovery whose participation in training and feedback allowed us to refine the Beck Community Initiative. Funding for this project was supported by the Philadelphia Department of Behavioral Health and Intellectual disAbility Services and by Grants T32 MH083745-03 and F32-MH-103955 from the National Institute of Mental Health. NR 64 TC 0 Z9 0 U1 8 U2 8 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 DEC PY 2016 VL 84 IS 12 BP 1116 EP 1126 DI 10.1037/ccp0000105 PG 11 WC Psychology, Clinical SC Psychology GA EE0XX UT WOS:000389304500008 PM 27379492 ER PT J AU Rousseau, LA Liu, SW Bhatia, K Miller, ES AF Rousseau, Lauren A. Liu, Shan W. Bhatia, Kriti Miller, Emily S. TI SUDDEN WEAKNESS IN A YOUNG HEALTHY MAN SO JOURNAL OF EMERGENCY MEDICINE LA English DT Article ID THYROTOXIC PERIODIC PARALYSIS; GUILLAIN-BARRE-SYNDROME C1 [Rousseau, Lauren A.; Liu, Shan W.; Miller, Emily S.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Liu, Shan W.; Bhatia, Kriti; Miller, Emily S.] Harvard Med Sch, Dept Emergency Med, Boston, MA 02115 USA. [Bhatia, Kriti] Brigham & Womens Hosp, Dept Emergency Med, 75 Francis St, Boston, MA 02115 USA. RP Miller, ES (reprint author), Massachusetts Gen Hosp, Harvard Med Sch, Dept Emergency Med, Zero Emerson Pl,Suite 3B, Boston, MA 02118 USA. NR 19 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0736-4679 EI 1090-1280 J9 J EMERG MED JI J. Emerg. Med. PD DEC PY 2016 VL 51 IS 6 BP 725 EP 728 PG 4 WC Emergency Medicine SC Emergency Medicine GA EE3XQ UT WOS:000389535500023 PM 27658553 ER PT J AU Hebert, PL Hernandez, SE AF Hebert, Paul L. Hernandez, Susan E. TI Providing Patient-Centered Care to Veterans of All Races: Challenges and Evidence of Success SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Editorial Material ID QUALITY-OF-CARE; BLACK PATIENTS; HEALTH SYSTEM; MEDICAL HOME; IMPLEMENTATION; ASSOCIATIONS; DISPARITIES; HOSPITALS C1 [Hebert, Paul L.; Hernandez, Susan E.] VA Puget Sound Hlth Care Syst, VA HSR&D Ctr Innovat Patient Ctr & Value Driven H, Seattle, WA 98108 USA. [Hebert, Paul L.] Univ Washington, Sch Publ Hlth, Dept Hlth Serv, Seattle, WA 98195 USA. RP Hebert, PL (reprint author), VA Puget Sound Hlth Care Syst, VA HSR&D Ctr Innovat Patient Ctr & Value Driven H, Seattle, WA 98108 USA. EM Paul.Hebert2@VA.gov NR 11 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 DEC PY 2016 VL 31 IS 12 BP 1412 EP 1414 DI 10.1007/s11606-016-3866-0 PG 3 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA EE5DX UT WOS:000389626600004 PM 27704365 ER PT J AU Walker, RJ Egede, LE AF Walker, Rebekah J. Egede, Leonard E. TI Rationing of Care: Conceptual Ambiguity and Transparency in Data Collection and Synthesis SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Editorial Material ID HEALTH-CARE C1 [Walker, Rebekah J.; Egede, Leonard E.] Ralph H Johnson Vet Affairs Med Ctr, HEROIC, Charleston, SC USA. [Walker, Rebekah J.; Egede, Leonard E.] Med Univ South Carolina, Ctr Hlth Dispar Res, Charleston, SC 29425 USA. [Walker, Rebekah J.; Egede, Leonard E.] Med Univ South Carolina, Div Gen Internal Med & Geriatr, Dept Med, Charleston, SC USA. RP Egede, LE (reprint author), Med Univ South Carolina, Ctr Hlth Dispar Res, Charleston, SC 29425 USA. EM egedel@musc.edu NR 9 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD DEC PY 2016 VL 31 IS 12 BP 1415 EP 1416 DI 10.1007/s11606-016-3801-4 PG 2 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA EE5DX UT WOS:000389626600005 PM 27435252 ER PT J AU Jones, AL Mor, MK Cashy, JP Gordon, AJ Haas, GL Schaefer, JH Hausmann, LRM AF Jones, Audrey L. Mor, Maria K. Cashy, John P. Gordon, Adam J. Haas, Gretchen L. Schaefer, James H., Jr. Hausmann, Leslie R. M. TI Racial/Ethnic Differences in Primary Care Experiences in Patient-Centered Medical Homes among Veterans with Mental Health and Substance Use Disorders SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE patient-centered medical home; health care experience; race and ethnicity; mental health services ID ETHNIC-DIFFERENCES; PATIENTS ASSESSMENTS; DIAGNOSTIC PATTERNS; DISPARITIES; SATISFACTION; QUALITY; AFFAIRS; ILLNESS; ACCESS; RACE/ETHNICITY AB Patient-Centered Medical Homes (PCMH) may be effective in managing care for racial/ethnic minorities with mental health and/or substance use disorders (MHSUDs). How such patients experience care in PCMH settings is relatively unknown. We aimed to examine racial/ethnic differences in experiences with primary care in PCMH settings among Veterans with MHSUDs. We used multinomial regression methods to estimate racial/ethnic differences in PCMH experiences reported on a 2013 national survey of Veterans Affairs patients. Veterans with past-year MHSUD diagnoses (n = 65,930; 67 % White, 20 % Black, 11 % Hispanic, 1 % American Indian/Alaska Native[AI/AN], and 1 % Asian/Pacific Island[A/PI]). Positive and negative experiences from the Consumer Assessment of Healthcare Providers and Systems (CAHPS) PCMH Survey. Veterans with MHSUDs reported the lowest frequency of positive experiences with access (22 %) and the highest frequency of negative experiences with self-management support (30 %) and comprehensiveness (16 %). Racial/ethnic differences (as compared to Whites) were observed in all seven healthcare domains (p values < 0.05). With access, Blacks and Hispanics reported more negative (Risk Differences [RDs] = 2 .0;3.6) and fewer positive (RDs = -2 .3;-2.3) experiences, while AI/ANs reported more negative experiences (RD = 5.7). In communication, Blacks reported fewer negative experiences (RD = -1.3); AI/ANs reported more negative (RD = 3.6) experiences; and AI/ANs and APIs reported fewer positive (RD = -6.5, -6.7) experiences. With office staff, Hispanics reported fewer positive experiences (RDs = -3.0); AI/ANs and A/PIs reported more negative experiences (RDs = 3.4; 3.7). For comprehensiveness, Blacks reported more positive experiences (RD = 3.6), and Hispanics reported more negative experiences (RD = 2.7). Both Blacks and Hispanics reported more positive (RDs = 2.3; 4.2) and fewer negative (RDs = -1.8; -1.9) provider ratings, and more positive experiences with decision making (RDs = 2.4; 3.0). Blacks reported more positive (RD = 3.9) and fewer negative (RD = -5.1) experiences with self-management support. In a national sample of Veterans with MHSUDs, potential deficiencies were observed in access, self-management support, and comprehensiveness. Racial/ethnic minorities reported worse experiences than Whites with access, comprehensiveness, communication, and office staff helpfulness/courtesy. C1 Vet Affairs Pittsburgh Healthcare Syst, VA Ctr Hlth Equity Res & Promot, Pittsburgh, PA USA. [Jones, Audrey L.] VA Pittsburgh Healthcare Syst, Ctr Hlth Equity Res & Promot CHERP, Pittsburgh, PA 15240 USA. [Mor, Maria K.] Univ Pittsburgh, Sch Publ Hlth, Dept Biostat, Pittsburgh, PA USA. [Gordon, Adam J.; Hausmann, Leslie R. M.] Univ Pittsburgh, Sch Med, Dept Med, Div Gen Internal Med, Pittsburgh, PA USA. [Haas, Gretchen L.] Vet Affairs Pittsburgh Healthcare Syst, VISN4 Mental Illness Res Educ & Clin Ctr, Pittsburgh, PA USA. [Haas, Gretchen L.] Univ Pittsburgh, Sch Med, Det Psychiat, Pittsburgh, PA USA. [Schaefer, James H., Jr.] Dept Vet Affairs Off Analyt & Business Intelligen, Durham, NC USA. RP Jones, AL (reprint author), VA Pittsburgh Healthcare Syst, Ctr Hlth Equity Res & Promot CHERP, Univ Dr 151C,Bldg 30, Pittsburgh, PA 15240 USA. EM Audrey.Jones3@va.gov FU VA Office of Academic Affiliations Associated Health Professions Post-doctoral Fellow in Health Services Research at the Center for Health Equity Research and Promotion (CHERP) at the VA Pittsburgh Healthcare System; Department of Veterans Affairs VISN4 CHERP Competitive Research Pilot Program [LIP 72-081] FX Dr. Jones is supported as a VA Office of Academic Affiliations Associated Health Professions Post-doctoral Fellow in Health Services Research at the Center for Health Equity Research and Promotion (CHERP) at the VA Pittsburgh Healthcare System. The work reported here was supported by the Department of Veterans Affairs VISN4 CHERP Competitive Research Pilot Program (LIP 72-081). The contents of this article do not represent the views of the Department of Veterans Affairs or the United States Government. NR 52 TC 2 Z9 2 U1 7 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD DEC PY 2016 VL 31 IS 12 BP 1435 EP 1443 DI 10.1007/s11606-016-3776-1 PG 9 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA EE5DX UT WOS:000389626600008 PM 27325318 ER PT J AU Shah, SJ Cronin, P Hong, CS Hwang, AS Ashburner, JM Bearnot, BI Richardson, CA Fosburgh, BW Kimball, AB AF Shah, Sachin J. Cronin, Patrick Hong, Clemens S. Hwang, Andrew S. Ashburner, Jeffrey M. Bearnot, Benjamin I. Richardson, Calvin A. Fosburgh, Blair W. Kimball, Alexandra B. TI Targeted Reminder Phone Calls to Patients at High Risk of No-Show for Primary Care Appointment: A Randomized Trial SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE access to care; applied informatics; primary care redesign; behavior change; population health ID NON-ATTENDANCE; ACCOUNTABLE CARE; HEALTH-CARE; MISSED APPOINTMENTS; IMPLEMENTATION INTENTIONS; TELEPHONE REMINDERS; IMPROVE ATTENDANCE; RATES; SYSTEMS; ORGANIZATIONS AB No-shows, or missed appointments, are a problem for many medical practices. They result in fragmented care and reduce access for all patients. To determine whether telephone reminder calls targeted to patients at high risk of no-show can reduce no-show rates. Single-center randomized controlled trial. A total of 2247 primary care patients in a hospital-based primary care clinic at high risk of no-show (> 15 % risk) for their appointment in 7 days. Seven days prior to their appointment, intervention arm patients were placed in a calling queue to receive a reminder phone call from a patient service coordinator. Coordinators were trained to engage patients in concrete planning. All patients received an automated phone call (usual care). Primary outcome was no-show rate. Secondary outcomes included arrival rate, cancellation rate, reschedule rate, time to cancellation, and change in revenue. The no-show rate in the intervention arm (22.8 %) was significantly lower (absolute risk difference -6.4 %, p < 0.01, 95 % CI [-9.8 to -3.0 %]) than that in the control arm (29.2 %). Arrival, cancellation, and reschedule rates did not differ significantly. In the intervention arm, rescheduling and cancellations occurred further in advance of the appointment (mean difference, 0.35 days; 95 % CI [0.07-0.64]; p = 0.01). Reimbursement did not differ significantly. A phone call 7 days prior to an appointment led to a significant reduction in no-shows and increased reimbursement among patients at high risk of no-show. The use of targeted interventions may be of interest to practices taking on increased accountability for population health. C1 [Shah, Sachin J.; Hwang, Andrew S.; Ashburner, Jeffrey M.; Bearnot, Benjamin I.; Fosburgh, Blair W.] Massachusetts Gen Hosp, Div Gen Internal Med, Dept Med, Boston, MA 02114 USA. [Shah, Sachin J.; Hwang, Andrew S.; Ashburner, Jeffrey M.; Bearnot, Benjamin I.; Fosburgh, Blair W.; Kimball, Alexandra B.] Harvard Med Sch, Boston, MA USA. [Shah, Sachin J.; Richardson, Calvin A.; Kimball, Alexandra B.] Massachusetts Gen Hosp, Massachusetts Gen Physicians Org, 50 Staniford St 940-J, Boston, MA 02114 USA. [Cronin, Patrick] Massachusetts Gen Hosp, Comp Sci Lab, Dept Med, Boston, MA 02114 USA. [Hong, Clemens S.] Los Angeles Cty Dept Hlth Serv, Los Angeles, CA USA. [Kimball, Alexandra B.] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. RP Shah, SJ (reprint author), Massachusetts Gen Hosp, Massachusetts Gen Physicians Org, 50 Staniford St 940-J, Boston, MA 02114 USA. EM sshah@mgh.harvard.edu FU Massachusetts General Hospital Physician Organization FX Sachin J. Shah and Patrick Cronin had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. This study was funded internally by the Massachusetts General Hospital Physician Organization and the Internal Medicine Associates. Partial results of the study were published in abstract and poster form at the Society for General Internal Medicine national conference in 2014. Patrick Cronin has a financial stake in SRG Technology as of October 4, 2015. He did not have a financial stake while executing the study or analysis. All other authors declare that they do not have a conflict of interest. NR 57 TC 1 Z9 1 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD DEC PY 2016 VL 31 IS 12 BP 1460 EP 1466 DI 10.1007/s11606-016-3813-0 PG 7 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA EE5DX UT WOS:000389626600011 PM 27503436 ER PT J AU Wong, ES Rosland, AM Fihn, SD Nelson, KM AF Wong, Edwin S. Rosland, Ann-Marie Fihn, Stephan D. Nelson, Karin M. TI Patient-Centered Medical Home Implementation in the Veterans Health Administration and Primary Care Use: Differences by Patient Comorbidity Burden SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE patient-centered medical home; multiple chronic conditions ID LOCAL-AREA UNEMPLOYMENT; SERVICES; COST; ASSOCIATION; PRINCIPLES; BURNOUT; DEMAND; ACCESS AB The patient-centered medical home (PCMH) model has several components to improve care for patients with high comorbidity, including greater access to face-to-face primary care. We examined whether high-comorbidity patients had larger increases in primary care provider (PCP) visits attributable to PCMH implementation in a large integrated health system relative to other patients enrolled in primary care. This longitudinal study examined a 1 % random sample of 9.3 million patients enrolled in the Veterans Health Administration (VHA) at any time between 2003 and 2013. Face-to-face visits with PCPs per quarter were identified through VHA administrative data. Comorbidity was measured using the Gagne index and patients with a weighted score of 2 were defined as high comorbidity. We applied interrupted time-series models to estimate marginal changes in PCP visits attributable to PCMH implementation. Differences in marginal changes were calculated across comorbidity groups (high vs. low). Analyses were stratified by age group to account for Medicare eligibility. Among age 65+ patients, PCMH was associated with greater PCP visits starting four and ten quarters following implementation for high- and low-comorbidity patients, respectively. Changes were larger for high-comorbidity patients (eight to 11 greater visits per 1000 patients per quarter). Among patients age < 65, PCMH was associated with greater visits for high-comorbidity patients starting eight quarters following implementation, but fewer visits for low-comorbidity patients in all quarters. The difference in visit changes across groups ranged from 18 to 67 visits per 1000 patients per quarter. Increases in PCP visits attributable to PCMH were greater among patients with higher comorbidity. Health systems implementing PCMH should account for population-level comorbidity burden when planning for PCMH-related changes in PCP utilization. C1 [Wong, Edwin S.; Nelson, Karin M.] Ctr Veteran Ctr & Value Driven Care, VA Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. [Wong, Edwin S.; Nelson, Karin M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Rosland, Ann-Marie] VHA Ann Arbor Healthcare Syst, Ctr Clin Management Res, Ann Arbor, MI USA. [Rosland, Ann-Marie] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Fihn, Stephan D.] Vet Hlth Adm, Off Analyt & Business Intelligence, Seattle, WA USA. [Nelson, Karin M.] Univ Washington, Dept Med, Seattle, WA 98195 USA. RP Wong, ES (reprint author), Ctr Veteran Ctr & Value Driven Care, VA Puget Sound Hlth Care Syst, 1660 S Columbian Way,MS S-152, Seattle, WA 98108 USA. EM edwin.wong@va.gov FU Veterans Health Administration Patient Aligned Care Team Demonstration Laboratory Coordination Center [XVA-61-041]; VA Health Services Research and Development Career Development Award [VA HSRD CDA 13-024]; VA HSRD CDA [10-209] FX This study was funded by the Veterans Health Administration Patient Aligned Care Team Demonstration Laboratory Coordination Center (XVA-61-041). Dr. Wong is supported by a VA Health Services Research and Development Career Development Award (VA HSR&D CDA 13-024). Dr. Rosland is supported by VA HSR&D CDA 10-209. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs, the University of Washington, the University of Michigan or the United States Government. The authors thank the deputy editor and three reviewers for their helpful comments. NR 27 TC 1 Z9 1 U1 4 U2 4 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 DEC PY 2016 VL 31 IS 12 BP 1467 EP 1474 DI 10.1007/s11606-016-3833-9 PG 8 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA EE5DX UT WOS:000389626600012 PM 27503440 ER PT J AU Thorp, J Dattalo, M Ghanem, K Christmas, C AF Thorp, Jonathon Dattalo, Melissa Ghanem, Khalil G. Christmas, Colleen TI Implementation of 2011 Duty Hours Regulations through a Workload Reduction Strategy and Impact on Residency Training SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE duty hour changes; ACGME; admission numbers; workload reduction; workload compression ID INTERNAL-MEDICINE RESIDENTS; PATIENT-CENTERED CARE; EXAMINATION PERFORMANCE; PROGRAM DIRECTORS; SLEEP DURATION; ASSOCIATION; REFORM; CONTINUITY; MORTALITY; EDUCATION AB Training programs have implemented the 2011 ACGME duty hour regulations (DHR) using "workload compression" (WLC) strategies, attempting to fit similar clinical responsibilities into fewer working hours, or workload reduction (WLR) approaches, reducing the number of patient encounters per trainee. Many have expressed concern that these strategies could negatively impact patient care and learner outcomes. This study evaluates the medical knowledge and clinical impact of a WLR intervention in a single institution. Nonrandomized intervention study with comparison to a historical control study among 58 PGY-1 internal medicine trainees in the 2 years after duty hour implementation [exposure cohort (EC), 7/1/2011-6/30/2013], compared to 2 years before implementation [comparison cohort (CC), 7/1/2009-6/30/2011]. Process outcomes were average inpatient encounters, average new inpatient admissions, and average scheduled outpatient encounters per PGY-1 year. Performance outcomes included trainee inpatient and outpatient days on service, In-Training Examination (ITE) scores as an objective surrogate of medical knowledge, Case-Mix Index (CMI), and quality of care measures (30-day readmission rate, 30-day mortality rate, and average length of stay). Baseline characteristics and average numbers of inpatient encounters per PGY-1 class were similar between the EC and CC. However, the EC experienced fewer new inpatient admissions (157.47 +/- 40.47 vs. 181.72 +/- 25.45; p < 0.01), more outpatient encounters (64.80 +/- 10.85 vs. 56.98 +/- 6.59; p < 0.01), and had similar ITE percentiles (p = 0.58). Patients of similar complexity cared for by the EC also had a greater reduction in readmissions (21.21 % to 19.08 %; p < 0.01) than the hospital baseline (12.07 to 11.14 %; p < 0.01). Our WLR resulted in a small decrease in the average number of new inpatient admissions and an increase in outpatient encounters. ITE and care quality outcomes were maintained or improved. While there is theoretical concern that reducing PGY-1 inpatient admissions volumes may negatively impact education and clinical care measures, this study found no evidence of such a trade-off. C1 [Thorp, Jonathon; Ghanem, Khalil G.; Christmas, Colleen] Johns Hopkins Univ, Sch Med, Johns Hopkins Bayview Med Ctr, 5200 Eastern Ave,Mason F Lord Bldg Ctr Tower,2nd, Baltimore, MD 21218 USA. [Dattalo, Melissa] William S Middleton Mem Vet Adm Med Ctr, Geriatr Res Educ & Clin Ctr, Madison, WI USA. [Dattalo, Melissa] Univ Wisconsin Madison, Div Geriatr & Gerontol, Madison, WI USA. RP Christmas, C (reprint author), Johns Hopkins Univ, Sch Med, Johns Hopkins Bayview Med Ctr, 5200 Eastern Ave,Mason F Lord Bldg Ctr Tower,2nd, Baltimore, MD 21218 USA. EM cchristm@jhmi.edu NR 30 TC 2 Z9 2 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD DEC PY 2016 VL 31 IS 12 BP 1475 EP 1481 DI 10.1007/s11606-016-3840-x PG 7 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA EE5DX UT WOS:000389626600013 PM 27514539 ER PT J AU Tobey, M AF Tobey, Matthew TI Capsule Commentary on Winkelman et al., Health Insurance Trends and Access to Behavioral Healthcare Among Justice-Involved Individuals-United States, 2008-2014 SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Editorial Material C1 [Tobey, Matthew] Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. RP Tobey, M (reprint author), Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. EM mltobey@partners.org NR 4 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 DEC PY 2016 VL 31 IS 12 BP 1510 EP 1510 DI 10.1007/s11606-016-3864-2 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA EE5DX UT WOS:000389626600024 PM 27624176 ER PT J AU Ray, A Jones, D Palamara, K Overland, M Steinberg, KP AF Ray, Alaka Jones, Danielle Palamara, Kerri Overland, Maryann Steinberg, Kenneth P. TI Improving Ambulatory Training in Internal Medicine: X plus Y (or Why Not?) SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE medical education; ambulatory training; resident continuity clinic; outpatient education; clinic scheduling ID EDUCATION; RESIDENCY AB The Accreditation Council for Graduate Medical Education (ACGME) requirement that internal medicine residents spend one-third of their training in an ambulatory setting has resulted in programmatic innovation across the country. The traditional weekly half-day clinic model has lost ground to the block or "X + Y" clinic model, which has gained in popularity for many reasons. Several disadvantages of the block model have been reported, however, and residency programs are caught between the threat of old and new challenges. We offer the perspectives of three large residency programs (University of Washington, Emory University, and Massachusetts General Hospital) that have successfully navigated scheduling challenges in our individual settings without implementing the block model. By sharing our innovative non-block models, we hope to demonstrate that programs can and should create the solution that fits their individual needs. C1 [Ray, Alaka; Palamara, Kerri] Harvard Med Sch, Massachusetts Gen Hosp, 15 Parkman St,Wang 635, Boston, MA 02114 USA. [Jones, Danielle] Emory Univ, Sch Med, Atlanta, GA USA. [Overland, Maryann; Steinberg, Kenneth P.] Univ Washington, Sch Med, Seattle, WA USA. RP Ray, A (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, 15 Parkman St,Wang 635, Boston, MA 02114 USA. EM aray2@partners.org NR 7 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD DEC PY 2016 VL 31 IS 12 BP 1519 EP 1522 DI 10.1007/s11606-016-3808-x PG 4 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA EE5DX UT WOS:000389626600026 PM 27439977 ER PT J AU Brondfield, S Dhaliwal, G AF Brondfield, Sam Dhaliwal, Gurpreet TI Giant Inguinoscrotal Hernia SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Editorial Material C1 [Brondfield, Sam] Univ Calif San Francisco, Dept Med, 505 Parnassus Ave Rm 987, San Francisco, CA 94143 USA. [Dhaliwal, Gurpreet] San Francisco VA Med Ctr, Dept Med, San Francisco, CA 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 3 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD DEC PY 2016 VL 31 IS 12 BP 1537 EP 1537 DI 10.1007/s11606-016-3710-6 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA EE5DX UT WOS:000389626600029 PM 27154730 ER PT J AU Lans, A Janssen, SJ Ring, D AF Lans, Amanda Janssen, Stein J. Ring, David TI Off-Hour Surgery Among Orthopedic Subspecialties at an Urban, Quaternary-Care, Level 1 Trauma Center SO JOURNAL OF HAND SURGERY-AMERICAN VOLUME LA English DT Article DE Trauma; after hour; emergency; fracture; resources ID PERIOPERATIVE COMPLICATIONS; FRACTURES; CHILDREN; CALL; ROOM AB Purpose We sought to determine and quantify which subspecialties of orthopedic surgeons are operating off hours in an urban, quaternary-care, level 1 trauma center. Materials and methods We used our clinical registry to identify 43,211 orthopedic surgeries performed between January 2008 and December 2011. Our outcome measures were the number and proportion of off-hour surgeries performed as well as the number and proportion of off-hours per subspecialty. The denominators were the total number of surgeries and the total number of surgical hours worked per subspecialty. Subspecialties based on the primary surgeon who performed the surgery were arthroplasty, foot and ankle, hand, pediatrics, shoulder, spine, sports, orthopedic trauma, and orthopedic oncology. Results A total of 2,431 (5.6%) surgeries were off-hours; the overall ratio of off-hour to on hour surgeries was 1 to 17. There was a difference in the proportion of off-hour surgeries performed among orthopedic subspecialties: trauma (ratio, 1:5) and pediatric specialists (ratio, 1:5) had the lowest ratio, and shoulder (ratio, 1:152) and sports (ratio, 1:98) specialists the highest. The total number of surgical hours among all specialties was 59,026; of these hours, 3,833 (6.5%) were off-hour. The ratio of off-hour to on-hour surgical hours was 1 to 14. There was a difference in proportion of hours worked off-hour among orthopedic subspecialties; the ratios were greatest for trauma (1:5) and hand (1:5) specialists and the least for shoulder (1:157) and sports (1:92) specialists. Seven percent of hand surgery cases were off-hour, and 16% of the total surgical hours worked by hand surgeons were off-hour. Conclusions In an urban, academic, level 1 trauma and microvascular replantation regional referral hospital, there is a large difference in off-hour surgical volume and duration among orthopedic subspecialties: trauma, pediatric, and hand surgeons performed more off-hour work than their colleagues, with hand and pediatric surgeons the most likely to be working at night. Copyright (C) 2016 by the American Society for Surgery of the Hand. All rights reserved. C1 [Lans, Amanda; Janssen, Stein J.; Ring, David] Massachusetts Gen Hosp, Dept Orthoped Surg, Hand Serv, Boston, MA 02114 USA. RP Ring, D (reprint author), Univ Texas Austin, Dell Med Sch, Dept Surg & Periopetat Care, 1400 Barbara Jordan Blvd,Suite 1-114AC MC R1800, Austin, TX 78723 USA. EM david.ring@austin.utexas.edu OI Ring, David/0000-0002-6506-4879 NR 15 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0363-5023 EI 1531-6564 J9 J HAND SURG-AM JI J. Hand Surg.-Am. Vol. PD DEC PY 2016 VL 41 IS 12 BP 1153 EP 1158 DI 10.1016/j.jhsa.2016.09.017 PG 6 WC Orthopedics; Surgery SC Orthopedics; Surgery GA EE7GW UT WOS:000389784900007 PM 28029391 ER PT J AU Madaras-Kelly, KJ Burk, M Caplinger, C Bohan, JG Neuhauser, MM Goetz, MB Zhang, R Cunningham, FE AF Madaras-Kelly, Karl J. Burk, Muriel Caplinger, Christina Bohan, Jefferson G. Neuhauser, Melinda M. Goetz, Matthew Bidwell Zhang, Rongping Cunningham, Francesca E. CA Pneumonia Duration Therapy Medica TI Total Duration of Antimicrobial Therapy in Veterans Hospitalized With Uncomplicated Pneumonia: Results of a National Medication Utilization Evaluation SO JOURNAL OF HOSPITAL MEDICINE LA English DT Article ID COMMUNITY-ACQUIRED PNEUMONIA; CLOSTRIDIUM-DIFFICILE INFECTION; ANTIBIOTIC USE; DISEASES-SOCIETY; UNITED-STATES; CARE; STEWARDSHIP; METAANALYSIS; GUIDELINES; MANAGEMENT AB OBJECTIVE: Practice guidelines recommend the shortest duration of antimicrobial therapy appropriate to treat uncomplicated pneumonia be prescribed to reduce the emergence of resistant pathogens. A national evaluation was conducted to assess the duration of therapy for pneumonia. DESIGN: Retrospective medication utilization evaluation. SETTING: Thirty Veterans Affairs medical centers. PATIENTS: Inpatients discharged with a diagnosis of pneumonia. MEASUREMENTS: A manual review of electronic medical records of inpatients discharged with uncomplicated community-acquired pneumonia (CAP) or healthcare-associated pneumonia (HCAP) was conducted. Appropriate CAP therapy duration was defined as at least 5 days, and up to 3 additional days beginning the first day the patient achieved clinical stability criteria; the appropriate HCAP therapy duration was defined as 8 days. The duration of antimicrobial therapy for intravenous (IV) and oral (PO) inpatient administration, PO therapy dispensed upon discharge, Clostridium difficile infection (CDI), hospital readmission, and death rates were measured. RESULTS: Of 3881 pneumonia admissions, 1739 met inclusion criteria (CAP [n = 1195]; HCAP [n = 544]). Overall, 13.9% of patients (CAP [6.9%], HCAP [29.0%]) received therapy duration consistent with guideline recommendations. The median (interquartile range) days of therapy were 4 days (3-6 days), 1 day (0-3 days), and 6 days (4-8 days) for inpatient IV, inpatient PO, and outpatient PO antimicrobials, respectively. CDI was rare but more common in patients who received therapy duration consistent with guidelines. Therapy duration was not associated with the readmission or mortality rate. CONCLUSIONS: Antimicrobials were commonly prescribed for a longer duration than guidelines recommend. The majority of excessive therapy was completed upon discharge, identifying the need for strategies to curtail unnecessary use postdischarge. (C) 2016 Society of Hospital Medicine C1 [Madaras-Kelly, Karl J.] Vet Affairs Med Ctr, Serv Pharm, Meridian, ID USA. [Madaras-Kelly, Karl J.] Idaho State Univ, Coll Pharm, Dept Pharm Practice, Meridian, ID USA. [Burk, Muriel; Zhang, Rongping; Cunningham, Francesca E.] Hines VA, Ctr Medicat Safety, Hines, IL USA. [Burk, Muriel; Neuhauser, Melinda M.; Cunningham, Francesca E.] Hines VA, VA Pharm Benefits Management Serv, Hines, IL USA. [Caplinger, Christina; Bohan, Jefferson G.] Vet Affairs Med Ctr, Serv Pharm, Boise, ID USA. [Goetz, Matthew Bidwell] VA Greater Los Angeles Hlth Care Syst, Infect Dis Sect, Los Angeles, CA USA. [Goetz, Matthew Bidwell] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. RP Madaras-Kelly, KJ (reprint author), Vet Affairs Med Ctr, T111,500 West Ft St, Boise, ID 83713 USA. EM karl.madaras-kelly2@va.gov NR 38 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1553-5592 EI 1553-5606 J9 J HOSP MED JI J. Hosp. Med. PD DEC PY 2016 VL 11 IS 12 BP 832 EP 839 DI 10.1002/jhm.2648 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA EE2NB UT WOS:000389420100003 PM 27527659 ER PT J AU Noelle, RJ Roy, M Shepherd, DM Stamenkovic, I Ledbetter, JA Aruffo, A AF Noelle, Randolph J. Roy, Meenakshi Shepherd, David M. Stamenkovic, Ivan Ledbetter, Jeffrey A. Aruffo, Alejandro TI A 39-kDa protein on activated helper T cells binds CD40 and transduces the signal for cognate activation of B cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MONOCLONAL-ANTIBODY; LYMPHOCYTES-T; ANTIGEN; PROLIFERATION; ADHESION; RECEPTOR; LYMPHOKINES; EXPRESSION; IMMUNOGLOBULIN; INTERLEUKIN-4 AB CD40 is a B-cell surface molecule that has been shown to induce B-cell growth upon ligation with monoclonal antibodies. This report shows that triggering via CD40 is essential for the activation of resting B cells by helper T cells (T-h). A soluble fusion protein of CD40 and human immunoglobulin, CD40-Ig, inhibited the induction of B-cell cycle entry, proliferation, and differentiation by activated T(h)1 and T(h)2. The ligand for CD40 was identified as a 39-kDa membrane protein that was selectively expressed on activated T-h. A monoclonal antibody specific for the 39-kDa protein inhibited CD40-Ig binding and also inhibited the activation of B cells by T-h. These data indicate that the 39-kDa membrane protein expressed on activated T-h is a binding protein for CD40 and functions to transduce the signal for T-h-dependent B-cell activation. C1 [Noelle, Randolph J.; Roy, Meenakshi; Shepherd, David M.] Danmouth Med Sch, Dept Microbiol, One Med Ctr Dr, Lebanon, NH 03756 USA. [Ledbetter, Jeffrey A.; Aruffo, Alejandro] Bristol Myers Squibb Pharmaceut Res Inst, Seattle, WA 98121 USA. [Stamenkovic, Ivan] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Noelle, RJ (reprint author), Danmouth Med Sch, Dept Microbiol, One Med Ctr Dr, Lebanon, NH 03756 USA. FU National Institutes of Health [AI26296, GM37767, GM43257] FX Thanks are extended to Robert Peach for assistance in the production of the CD40-Ig protein. This work was supported in part by National Institutes of Health Grants AI26296 and GM37767 to R.J.N. and GM43257 to I.S. NR 28 TC 0 Z9 0 U1 3 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD DEC 1 PY 2016 VL 197 IS 11 BP 4195 EP 4199 PG 5 WC Immunology SC Immunology GA EE5HB UT WOS:000389635300005 PM 27864550 ER PT J AU van Haren, SD Dowling, DJ Foppen, W Christensen, D Andersen, P Reed, SG Hershberg, RM Baden, LR Levy, O AF van Haren, Simon D. Dowling, David J. Foppen, Willemina Christensen, Dennis Andersen, Peter Reed, Steven G. Hershberg, Robert M. Baden, Lindsey R. Levy, Ofer TI Age-Specific Adjuvant Synergy: Dual TLR7/8 and Mincle Activation of Human Newborn Dendritic Cells Enables Thl Polarization SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TOLL-LIKE RECEPTORS; INNATE IMMUNITY; CYTOKINE PRODUCTION; VACCINE ADJUVANTS; LECTIN RECEPTORS; SYK KINASE; IN-VITRO; T-CELLS; DC-SIGN; RESPONSES AB Due to functionally distinct cell-mediated immunity, newborns and infants are highly susceptible to infection with intracellular pathogens. Indeed, neonatal Ag-presenting dendritic cells (DCs) demonstrate impaired Thl responses to many candidate adjuvants, including most TLR agonists (TLRAs). Combination adjuvantation systems may provide enhanced immune activation but have typically been developed without regard to the age of the target population. We posited that distinct combinations of TLRAs and C-type lectin receptor agonists may enhance Thl responses of newborn DCs. TLRA/C-type lectin receptor agonist combinations were screened for enhancement of TNF production by human newborn and adult monocyte-derived DCs cultured in 10% autologous plasma or in newborn cord, infant, adult, and elderly whole blood. Monocyte-derived DC activation was characterized by targeted gene expression analysis, caspase-1 and NF-kappa B studies, cytokine multiplex and naive autologous CD4(+) T cell activation. Dual activation of newborn DCs via the C-type lectin receptor, macrophage-inducible C-type lectin (trehalose-6,6dibehenate), and TLR7/8 (R848) greatly enhanced caspase-1 and NF-kappa B activation, Thl polarizing cytokine production and autologous Thl polarization. Combined activation via TLR4 (glycopyranosyl lipid adjuvant aqueous formulation) and Dectin-1 (beta-glucan peptide) acted synergistically in newborns and adults, but to a lesser extent. The degree of synergy varied dramatically with age, and was the greatest in newborns and infants with less synergy in adults and elders. Overall, combination adjuvant systems demonstrate markedly different immune activation with age, with combined DC activation via Macrophage inducible C-type lectin and TLR7/8 representing a novel approach to enhance the efficacy of early-life vaccines. C1 [van Haren, Simon D.; Dowling, David J.; Foppen, Willemina; Levy, Ofer] Boston Childrens Hosp, Dept Med, Div Infect Dis, 300 Longwood Ave, Boston, MA 02115 USA. [van Haren, Simon D.; Andersen, Peter; Reed, Steven G.; Baden, Lindsey R.; Levy, Ofer] Boston Childrens Hosp, Div Infect Dis, Precis Vaccines Program, Boston, MA 02115 USA. [van Haren, Simon D.; Dowling, David J.; Foppen, Willemina; Levy, Ofer] Harvard Med Sch, Boston, MA 02115 USA. [Christensen, Dennis; Andersen, Peter] Staten Serum Inst, Dept Infect Dis Immunol, DK-2300 Copenhagen, Denmark. [Reed, Steven G.] Infect Dis Res Inst, Seattle, WA 98102 USA. [Hershberg, Robert M.] VentiRx Pharmaceut Inc, Seattle, WA 98101 USA. [Baden, Lindsey R.] Harvard Med Sch, Brigham & Womens Hosp, Div Infect Dis, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Levy, O (reprint author), Boston Childrens Hosp, Dept Med, Div Infect Dis, 300 Longwood Ave, Boston, MA 02115 USA. EM ofer.levy@childrens.harvard.edu OI van Haren, Simon/0000-0002-1791-0161 FU Boston Children's Hospital Department of Medicine [OPPGH5284]; Bill & Melinda Gates Foundation [OPP1035192]; National Institutes of Health [1R01AI100135-01, 3R01AI067353-05S1]; National Institute of Allergy and Infectious Diseases Adjuvant Discovery Program [HHSN272201400052C]; U01 award on Molecular Mechanisms of Combination Adjuvants [U01AI124284-01]; Early Career Award from the Thrasher Research Fund; VentiRx Pharmaceuticals; 3M Drug Delivery Systems; MedImmune; Crucell (Johnson Johnson); Shire FX O.L.'s laboratory is supported by a Boston Children's Hospital Department of Medicine award to the Precision Vaccines Program, Global Health (OPPGH5284), and Grand Challenges Explorations (OPP1035192) awards from the Bill & Melinda Gates Foundation and by National Institutes of Health Grants 1R01AI100135-01 and 3R01AI067353-05S1 and the National Institute of Allergy and Infectious Diseases Adjuvant Discovery Program, Contract No. HHSN272201400052C as well as a U01 award on Molecular Mechanisms of Combination Adjuvants (U01AI124284-01). S.D.v.H. was supported by an Early Career Award from the Thrasher Research Fund. The Levy Laboratory has also received sponsored research support from VentiRx Pharmaceuticals, 3M Drug Delivery Systems, MedImmune, Crucell (Johnson & Johnson), and Shire. NR 60 TC 2 Z9 2 U1 3 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD DEC 1 PY 2016 VL 197 IS 11 BP 4413 EP 4424 DI 10.4049/jimmunol.1600282 PG 12 WC Immunology SC Immunology GA EE5HB UT WOS:000389635300028 PM 27793997 ER PT J AU Hirsch, JA Chandra, RV Pampati, V Barr, JD Brook, AL Manchikanti, L AF Hirsch, Joshua A. Chandra, Ronil V. Pampati, Vidsysagar Barr, John D. Brook, Allan L. Manchikanti, Laxmaiah TI Analysis of vertebral augmentation practice patterns: a 2016 update SO JOURNAL OF NEUROINTERVENTIONAL SURGERY LA English DT Article ID OSTEOPOROTIC SPINAL FRACTURES; INTERVENTIONAL PAIN MANAGEMENT; MANAGING CHRONIC PAIN; COMPRESSION FRACTURES; PERCUTANEOUS VERTEBROPLASTY; MEDICARE POPULATION; CONSERVATIVE TREATMENT; BALLOON KYPHOPLASTY; NEUROINTERVENTIONAL SURGERY; NEUROLOGICAL SURGEONS AB Objective To evaluate procedure utilization patterns for vertebroplasty and kyphoplasty in the US Medicare population from 2004 to 2014. Methods The analysis was performed using the Centers for Medicare and Medicaid Services database of specialty utilization files for the fee for service (FFS) Medicare population. Results The FFS Medicare population increased by 28% with an annual increase of 2.5% from 2004 to 2014. Utilization of vertebroplasty procedures decreased by 63% with an average annual decrease of 9.5% from 2004 to 2014 per 100 000 FFS Medicare beneficiaries. During the same time period, kyphoplasty procedures decreased by a total of 10%, with an average annual decrease of 1.3%. For augmentation generally (combined vertebroplasty/kyphoplasty data) there was thus an overall decrease in the rate per 100 000 Medicare population of 32% from 2004 to 2014, with an average annual decrease of 4.8%. The majority of vertebroplasty procedures were performed by radiologists whereas the majority of kyphoplasties were performed by orthopedic surgeons and neurosurgeons. Conclusions There has been a significant decline in vertebroplasty and kyphoplasty procedures in the FFS Medicare population between 2004 and 2014. C1 [Hirsch, Joshua A.] Harvard Med Sch, Massachusetts Gen Hosp, Neuroendovasc Program, Boston, MA 02114 USA. [Hirsch, Joshua A.] Harvard Med Sch, Massachusetts Gen Hosp, NeuroIntervent Spine Serv, Boston, MA 02114 USA. [Chandra, Ronil V.] Monash Univ, Monash Med Ctr, Monash Imaging, Intervent Neuroradiol Serv,Dept Med, Melbourne, Vic, Australia. [Chandra, Ronil V.] Monash Univ, Monash Med Ctr, Monash Imaging, Intervent Neuroradiol Serv,Dept Surg, Melbourne, Vic, Australia. [Pampati, Vidsysagar] Univ Louisville, Pain Management Ctr Paducah, Paducah, KY USA. [Barr, John D.] UT Southwestern Med Ctr, Dept Radiol, Dallas, TX USA. [Barr, John D.] UT Southwestern Med Ctr, Dept Neurol Surg, Dallas, TX USA. [Brook, Allan L.] Albert Einstein Coll Med, Montefiore Med Ctr, New York, NY USA. [Manchikanti, Laxmaiah] Univ Louisville, Pain Management Ctr Paducah, Louisville, KY USA. RP Hirsch, JA (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Neuroendovasc Program, Boston, MA 02114 USA.; Hirsch, JA (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, NeuroIntervent Spine Serv, Boston, MA 02114 USA. EM Hirsch@snisonline.org FU Merit/DFine; Medtronic FX JAH has an ongoing consulting relationship with Medtronic and in the past 36 months consulted for Carefusion. Both companies make products for vertebral augmentation. JB: shareholder in Medtronic and Stryker; research support from Merit/DFine and Medtronic. NR 42 TC 0 Z9 0 U1 2 U2 2 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1759-8478 EI 1759-8486 J9 J NEUROINTERV SURG JI J. NeuroInterventional Surg. PD DEC PY 2016 VL 8 IS 12 BP 1299 EP + DI 10.1136/neurintsurg-2016-012767 PG 7 WC Neuroimaging; Surgery SC Neurosciences & Neurology; Surgery GA EE0DU UT WOS:000389244700025 ER PT J AU Roalf, DR Moore, TM Wolk, DA Arnold, SE Mechanic-Hamilton, D Rick, J Kabadi, S Ruparel, K Chen-Plotkin, AS Chahine, LM Dahodwala, NA Duda, JE Weintraub, DA Moberg, PJ AF Roalf, David R. Moore, Tyler M. Wolk, David A. Arnold, Steven E. Mechanic-Hamilton, Dawn Rick, Jacqueline Kabadi, Sushila Ruparel, Kosha Chen-Plotkin, Alice S. Chahine, Lama M. Dahodwala, Nabila A. Duda, John E. Weintraub, Daniel A. Moberg, Paul J. TI Defining and validating a short form Montreal Cognitive Assessment (s-MoCA) for use in neurodegenerative disease SO JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY LA English DT Article ID MINI-MENTAL-STATE; IMPAIRMENT HARMONIZATION STANDARDS; STROKE-CANADIAN STROKE; SCREENING INSTRUMENTS; PARKINSONS-DISEASE; NEUROPSYCHOLOGICAL BATTERY; NEUROLOGICAL DISORDERS; NATIONAL INSTITUTE; LINE ORIENTATION; PRIMARY-CARE AB Introduction Screening for cognitive deficits is essential in neurodegenerative disease. Screening tests, such as the Montreal Cognitive Assessment (MoCA), are easily administered, correlate with neuropsychological performance and demonstrate diagnostic utility. Yet, administration time is too long for many clinical settings. Methods Item response theory and computerised adaptive testing simulation were employed to establish an abbreviated MoCA in 1850 well-characterised community-dwelling individuals with and without neurodegenerative disease. Results 8 MoCA items with high item discrimination and appropriate difficulty were identified for use in a short form (s-MoCA). The s-MoCA was highly correlated with the original MoCA, showed robust diagnostic classification and cross-validation procedures substantiated these items. Discussion Early detection of cognitive impairment is an important clinical and public health concern, but administration of screening measures is limited by time constraints in demanding clinical settings. Here, we provide as-MoCA that is valid across neurological disorders and can be administered in approximately 5 min. C1 [Roalf, David R.; Moore, Tyler M.; Mechanic-Hamilton, Dawn; Kabadi, Sushila; Ruparel, Kosha; Weintraub, Daniel A.; Moberg, Paul J.] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Wolk, David A.; Arnold, Steven E.; Chen-Plotkin, Alice S.; Chahine, Lama M.; Dahodwala, Nabila A.; Duda, John E.; Weintraub, Daniel A.; Moberg, Paul J.] Univ Penn, Dept Neurol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Wolk, David A.; Arnold, Steven E.; Mechanic-Hamilton, Dawn; Moberg, Paul J.] Univ Penn, Perelman Sch Med, Alzheimers Dis Ctr, Philadelphia, PA 19104 USA. [Rick, Jacqueline; Weintraub, Daniel A.] Univ Penn, Perelman Sch Med, Udall Ctr Parkinsons Res, Philadelphia, PA 19104 USA. [Duda, John E.; Weintraub, Daniel A.] Philadelphia VA Med Ctr, Parkinsons Dis Res Educ & Clin Ctr PADRECC, Philadelphia, PA USA. RP Roalf, DR (reprint author), Hosp Univ Penn, Brain Behav Lab, Dept Psychiat, Neuropsychiat Sect, 10th Floor,Gates Bldg, Philadelphia, PA 19104 USA. EM roalf@upenn.edu FU NIA NIH HHS [K23 AG034236, P30 AG010124]; NIMH NIH HHS [K01 MH102609]; NINDS NIH HHS [P50 NS053488, U01 NS082134] NR 46 TC 2 Z9 2 U1 7 U2 7 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-3050 EI 1468-330X J9 J NEUROL NEUROSUR PS JI J. Neurol. Neurosurg. Psychiatry PD DEC PY 2016 VL 87 IS 12 BP 1303 EP 1310 DI 10.1136/jnnp-2015-312723 PG 8 WC Clinical Neurology; Psychiatry; Surgery SC Neurosciences & Neurology; Psychiatry; Surgery GA EE3FH UT WOS:000389472700250 PM 27071646 ER PT J AU Nourbakhsh, B Graves, J Casper, TC Lulu, S Waldman, A Belman, A Greenberg, B Weinstock-Guttman, B Aaen, G Tillema, JM Hart, J Ness, J Rubin, J Krupp, L Gorman, M Benson, L Rodriguez, M Chitnis, T Rose, J Barcellos, L Waubant, E AF Nourbakhsh, Bardia Graves, Jennifer Casper, T. Charles Lulu, Sabeen Waldman, Amy Belman, Anita Greenberg, Benjamin Weinstock-Guttman, Bianca Aaen, Gregory Tillema, Jan-Mendelt Hart, Janace Ness, Jayne Rubin, Jennifer Krupp, Lauren Gorman, Mark Benson, Leslie Rodriguez, Moses Chitnis, Tanuja Rose, John Barcellos, Lisa Waubant, Emmanuelle CA Network of Pediatric Multiple Scle TI Dietary salt intake and time to relapse in paediatric multiple sclerosis SO JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY LA English DT Article ID EPSTEIN-BARR-VIRUS; SODIUM-INTAKE; CELLS; PROGRESS; DISEASE AB Background Salt intake was reported to be associated with increased clinical and MRI activity in adult patients with relapsing-remitting multiple sclerosis (MS). Objective To determine if salt intake is associated with time to relapse in patients with paediatric-onset MS. Methods Paediatric-onset MS and patients with clinically isolated syndrome (CIS) within 4 years of disease onset were recruited from 15 paediatric MS centres in the USA as part of a case-control study. Patients with available prospective relapse data subsequent to enrolment were included in this project. Dietary sodium intake was assessed by self-report questionnaire using the validated Block Kids Food Screener. Cox proportional-hazards regression models were employed to determine the association of sodium density, excess sodium intake and sodium density tertiles with time to relapse following study enrolment, adjusting for several confounders. Results 174 relapsing-remitting MS/ CIS patients were included in this analysis (mean age of 15.0 years, and 64.9% females). Median duration of follow-up was 1.8 years. In an unadjusted analysis, density of daily sodium intake was not associated with time to relapse, and patients with excess sodium intake had no decrease in time to relapse as compared with patients with nonexcess sodium intake. The multivariable analysis demonstrated that patients in the medium and high tertile of sodium density had a HR of 0.69 (95% CI 0.37 to 1.30, p= 0.25) and 1.37 (95% CI 0.74 to 2.51, p= 0.32) compared with patients in the lowest tertile, respectively. Conclusions Higher salt intake was not associated with decreased time to relapse in patients with paediatric-onset MS. C1 [Nourbakhsh, Bardia; Graves, Jennifer; Lulu, Sabeen; Hart, Janace; Waubant, Emmanuelle] UCSF Reg Paediat MS Ctr, San Francisco, CA USA. [Casper, T. Charles] Univ Utah, Dept Paediat, Salt Lake City, UT USA. [Waldman, Amy] Univ Penn, Dept Neurol, Philadelphia, PA 19104 USA. [Belman, Anita] SUNY Stony Brook, Dept Neurol, Stony Brook, NY 11794 USA. [Greenberg, Benjamin] UT Southwestern, Dept Neurol, Dallas, TX USA. [Weinstock-Guttman, Bianca] SUNY Buffalo, Jacobs Neurol Inst, Paediat MS Ctr, Buffalo, NY USA. Loma Linda Univ, Dept Child Neurol, Loma Linda, CA 92350 USA. [Tillema, Jan-Mendelt] Mayo Clin, Dept Neurol, Rochester, MN USA. [Ness, Jayne] Alabama Paediat MS Ctr, Birmingham, AL USA. [Rubin, Jennifer] Northwestern Feinberg Sch Med, Dept Paediat Neurol, Chicago, IL USA. [Krupp, Lauren] NYU, Dept Neurol, New York, NY 10016 USA. [Gorman, Mark; Benson, Leslie; Chitnis, Tanuja] Massachusetts Gen Hosp, Partners Paediat MS Ctr, Boston, MA 02114 USA. [Rose, John] Univ Utah, Dept Neurol, Salt Lake City, UT USA. [Barcellos, Lisa] Univ Calif Berkeley, Dept Epidemiol, Berkeley, CA USA. RP Nourbakhsh, B (reprint author), Univ Calif San Francisco, Dept Neurol, 675 Nelson Rising Lane,Room 221F,POB 3206, San Francisco, CA 94158 USA. EM bardia.nourbakhsh@ucsf.edu FU NINDS NIH HHS [R01 NS071463] NR 16 TC 2 Z9 2 U1 1 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-3050 EI 1468-330X J9 J NEUROL NEUROSUR PS JI J. Neurol. Neurosurg. Psychiatry PD DEC PY 2016 VL 87 IS 12 BP 1350 EP 1353 DI 10.1136/jnnp-2016-313410 PG 4 WC Clinical Neurology; Psychiatry; Surgery SC Neurosciences & Neurology; Psychiatry; Surgery GA EE3FH UT WOS:000389472700256 PM 27343226 ER PT J AU Lewis, RF AF Lewis, Richard F. TI Vestibular implants studied in animal models: clinical and scientific implications SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Review DE vestibular system; vertigo; prosthesis; implant; ataxia ID SEMICIRCULAR CANAL AFFERENTS; VESTIBULOOCULAR REFLEX; ELECTRICAL-STIMULATION; EYE-MOVEMENTS; SQUIRREL-MONKEY; RHESUS-MONKEYS; HAIR-CELLS; HEAD TURNS; PROSTHESIS; ADAPTATION AB Damage to the peripheral vestibular system can result in debilitating postural, perceptual, and visual symptoms. A potential new treatment for this clinical problem is to replace some aspects of peripheral vestibular function with an implant that senses head motion and provides this information to the brain by stimulating branches of the vestibular nerve. In this review I consider animal studies performed at our institution over the past 15 years, which have helped elucidate how the brain processes information provided by a vestibular (semicircular canal) implant and how this information could be used to improve the problems experienced by patients with peripheral vestibular damage. C1 [Lewis, Richard F.] Harvard Med Sch, Dept Otolaryngol, Boston, MA USA. [Lewis, Richard F.] Harvard Med Sch, Dept Neurol, Boston, MA USA. [Lewis, Richard F.] Massachusetts Eye & Ear Infirm, Jenks Vestibular Physiol Lab, Boston, MA 02114 USA. RP Lewis, RF (reprint author), Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. EM richard_lewis@meei.harvard.edu FU National Institute on Deafness and Other Communication Disorders [DC-006909, DC-008362, DC-13069, DC-003066, DC-008167]; EU [225929] FX This work was funded by National Institute on Deafness and Other Communication Disorders Grants DC-006909, DC-008362, and DC-13069 to R. F. Lewis and DC-003066 and DC-008167 to Daniel Merfeld. Additional funding was provided by EU Contract 225929 ("CLONS"). NR 59 TC 0 Z9 0 U1 3 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 EI 1522-1598 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD DEC PY 2016 VL 116 IS 6 BP 2777 EP 2788 DI 10.1152/jn.00601.2016 PG 12 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA EE5LF UT WOS:000389648300028 PM 27760820 ER PT J AU Ma, JT Jacques, PF Meigs, JB Fox, CS Rogers, GT Smith, CE Hruby, A Saltzman, E McKeown, NM AF Ma, Jiantao Jacques, Paul F. Meigs, James B. Fox, Caroline S. Rogers, Gail T. Smith, Caren E. Hruby, Adela Saltzman, Edward McKeown, Nicola M. TI Sugar-Sweetened Beverage but Not Diet Soda Consumption Is Positively Associated with Progression of Insulin Resistance and Prediabetes SO JOURNAL OF NUTRITION LA English DT Article DE sugar-sweetened beverages; diet soda; insulin resistance; HOMA-IR; prediabetes ID CARDIOMETABOLIC RISK-FACTORS; RANDOMIZED CONTROLLED-TRIAL; SOFT DRINK CONSUMPTION; CORONARY-HEART-DISEASE; METABOLIC SYNDROME; CARDIOVASCULAR-DISEASE; GLYCEMIC INDEX; AGED ADULTS; FRUIT JUICE; MEN AB Background: Previous studies have shown an inconsistent relation between habitual beverage consumption and insulin resistance and prediabetes. Objective: The objective of the present study was to test the hypothesis that the consumption of sugar-sweetened beverages (SSBs), rather than diet soda, is associated with long-term progression of insulin resistance and the development of prediabetes. Methods: We analyzed the prospective association between cumulative mean consumption of SSBs or diet soda and incident prediabetes (n = 1685) identified across a median of 14 y of follow-up in participants [mean +/- SD age: 51.9 +/- 9.2 y; 59.6% women; mean +/- SD body mass index (BMI; kg/m(2)): 26.3 +/- 4.4] of the Framingham Offspring cohort. The prospective association between beverage consumption and change in homeostasis model assessment of insulin resistance (HOMA-IR; n = 2076) over 7 y was also analyzed. The cumulative mean consumption of SSBs and diet soda was estimated by using food-frequency questionnaires. Multivariable Cox proportional hazards models and linear regression models were implemented to estimate the HRs of incident prediabetes and change in HOMA-IR, respectively. Results: After adjustment for multiple potential confounders, including baseline BMI, we observed that SSB intake was positively associated with incident prediabetes (P-trend < 0.001); the highest SSB consumers (>3 servings/wk; median: 6 servings/wk) had a 46% higher risk of developing prediabetes than did the SSB nonconsumers (HR: 1.46; 95% CI: 1.16, 1.83). Higher SSB intake was also associated with a greater increase in HOMA-IR (P-trend = 0.006). No prospective associations were observed between diet soda intake and risk of prediabetes (P-trend = 0.24) or changes in HOMA-IR (P-trend = 0.25). These associations were similar after additional adjustment for change in BMI. Conclusion: Regular SSB intake, but not diet soda intake, is associated with a greater increase in insulin resistance and a higher risk of developing prediabetes in a group of middle-aged adults. C1 [Ma, Jiantao; Jacques, Paul F.; Rogers, Gail T.; Hruby, Adela; McKeown, Nicola M.] Tufts Univ, USDA, Human Nutr Res Ctr Aging, Nutr Epidemiol Lab, Boston, MA 02111 USA. [Smith, Caren E.] Tufts Univ, USDA, Human Nutr Res Ctr Aging, Nutr & Genom Lab, Boston, MA 02111 USA. [Saltzman, Edward] Tufts Univ, USDA, Human Nutr Res Ctr Aging, Energy Metab Lab, Boston, MA 02111 USA. [Meigs, James B.] Harvard Med Sch, Dept Med, Div Gen Internal Med, Boston, MA USA. [Meigs, James B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Fox, Caroline S.] NHLBI, Framingham Heart Study, Populat Sci Branch, Framingham, MA USA. RP McKeown, NM (reprint author), Tufts Univ, USDA, Human Nutr Res Ctr Aging, Nutr Epidemiol Lab, Boston, MA 02111 USA. EM nicola.mckeown@tufts.edu FU NIH/National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195]; Boston University School of Medicine; USDA (USDA) [58-1950-0-014] FX Supported by the NIH/National Heart, Lung, and Blood Institute's Framingham Heart Study (contract N01-HC-25195), the Boston University School of Medicine, and the USDA (USDA agreement 58-1950-0-014). NR 38 TC 0 Z9 0 U1 5 U2 5 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 EI 1541-6100 J9 J NUTR JI J. Nutr. PD DEC PY 2016 VL 146 IS 12 BP 2544 EP 2550 DI 10.3945/jn.116.234047 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA EE2CP UT WOS:000389391600015 PM 27934644 ER PT J AU Bauman, JR Piotrowska, Z Muzikansky, A Gallagher, E Scribner, E Temel, B Sequist, LV Heist, RS Temel, JS AF Bauman, Jessica R. Piotrowska, Zofia Muzikansky, Alona Gallagher, Emily Scribner, Emily Temel, Brandon Sequist, Lecia V. Heist, Rebecca S. Temel, Jennifer S. TI End-of-Life Care in Patients with Metastatic Lung Cancer Harboring Epidermal Growth Factor Receptor Mutations SO JOURNAL OF PALLIATIVE MEDICINE LA English DT Article ID PROSPECTIVE COHORT; CHEMOTHERAPY; AGGRESSIVENESS; PLACE; NSCLC AB Background/Objective: Patients with metastatic nonsmall cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations benefit from improved survival and quality of life with EGFR-directed therapy. We sought to explore if these improvements in cancer care impacted the delivery of end-of-life (EOL) care in this population. Design: We retrospectively reviewed medical records of patients cared for at our institution with the diagnosis of metastatic EGFR-mutant NSCLC who died by January 2015. Results: Sixty-one patients were included. The majority of patients were female (68%), white or Asian (97%), and never or minimal smokers (76%). Forty-two out of fifty-eight patients (72%) received chemotherapy within 30 days of death. Forty-one out of sixty-one patients (67%) had a hospital admission within 30 days of death. EOL outcomes were known for 53 patients. Of these, 34 (64%) patients enrolled on hospice. The median length of stay on hospice was 6 days (range 0-206). Thirty-three (62%) patients died at home with hospice services or at an inpatient hospice facility. Eighteen patients (34%) died in the hospital. Conclusion: Patients with metastatic NSCLC harboring EGFR mutations had high rates of chemotherapy use and hospital admissions in the last month of life, and many died in the hospital. Hospital admissions near the EOL and short admissions to hospice are indicators of poor quality EOL care and are likely a result of prolonged chemotherapy administration in this population. Thus, current healthcare delivery models may be insufficient to provide comprehensive EOL care for patients with EGFR mutations. C1 [Bauman, Jessica R.] Fox Chase Canc Ctr, 333 Cottman Ave, Philadelphia, PA 19111 USA. [Piotrowska, Zofia; Muzikansky, Alona; Gallagher, Emily; Scribner, Emily; Temel, Brandon; Sequist, Lecia V.; Heist, Rebecca S.; Temel, Jennifer S.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. RP Bauman, JR (reprint author), Fox Chase Canc Ctr, 333 Cottman Ave, Philadelphia, PA 19111 USA. EM jessica.bauman@fccc.edu NR 15 TC 0 Z9 0 U1 7 U2 7 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 DEC PY 2016 VL 19 IS 12 BP 1316 EP 1319 DI 10.1089/jpm.2016.0180 PG 4 WC Health Care Sciences & Services SC Health Care Sciences & Services GA EE2OD UT WOS:000389423200016 PM 27626514 ER PT J AU Gerak, LR Collins, GT France, CP AF Gerak, Lisa R. Collins, Gregory T. France, Charles P. TI Effects of Lorcaserin on Cocaine and Methamphetamine Self-Administration and Reinstatement of Responding Previously Maintained by Cocaine in Rhesus Monkeys SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID RECEPTOR AGONISTS; REINFORCING EFFICACY; SQUIRREL-MONKEYS; SEEKING BEHAVIOR; 5-HT2C RECEPTORS; RATS; NICOTINE; ACTIVATION; FOOD AB Stimulant abuse is a serious public health issue for which there is no effective pharmacotherapy. The serotonin(2C) [5-hydroxytryptamine(2C) (5-HT2C)] receptor agonist lorcaserin decreases some abuse-related effects of cocaine in monkeys and might be useful for treating stimulant abuse. The current study investigated the effectiveness of lorcaserin to reduce self-administration of either cocaine or methamphetamine and cocaine-induced reinstatement of extinguished responding. Four rhesus monkeys responded under a progressive-ratio (PR) schedule in which the response requirement increased after each cocaine infusion (32-320 mu g/kg/infusion). A separate group of four monkeys responded under a fixed-ratio (FR) schedule for cocaine (32 mu g/kg/infusion) and reinstatement of extinguished responding was examined following administration of noncontingent infusions of cocaine (0.1-1 mg/kg) that were combined with response-contingent presentations of the drug-associated stimuli. Finally, three monkeys responded under a FR schedule for methamphetamine (0.32-100 mu g/kg/infusion). Lorcaserin (3.2 mg/kg) significantly decreased the final ratio completed (i.e., decreased break point) in monkeys responding under the PR schedule and reduced the reinstatement of responding for drug-associated stimuli following a noncontingent infusion of cocaine; these effects did not appear to change when lorcaserin was administered daily. The same dose of lorcaserin decreased responding for methamphetamine in two of the three monkeys, and the effect was maintained during daily lorcaserin administration; larger doses given acutely (10-17.8 mg/kg) significantly decreased responding for methamphetamine, although that effect was not sustained during daily lorcaserin administration. Together, these results indicate that lorcaserin might be effective in reducing cocaine and methamphetamine abuse and cocaine relapse at least in some individuals. C1 [Gerak, Lisa R.; Collins, Gregory T.; France, Charles P.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, 7703 Floyd Dr,Mail Code 7764, San Antonio, TX 78229 USA. [France, Charles P.] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Collins, Gregory T.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. RP France, CP (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, 7703 Floyd Dr,Mail Code 7764, San Antonio, TX 78229 USA. EM france@uthscsa.edu FU National Institutes of Health National Institute on Drug Abuse [U01 DA034992, K05 DA017918]; Welch Foundation [AQ-0039] FX This study was supported by the National Institutes of Health National Institute on Drug Abuse [Grants U01 DA034992 and K05 DA017918] and by the Welch Foundation [Grant AQ-0039]. NR 20 TC 0 Z9 0 U1 11 U2 11 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 EI 1521-0103 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD DEC 1 PY 2016 VL 359 IS 3 BP 383 EP 391 DI 10.1124/jpet.116.236307 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EE4WH UT WOS:000389605800001 PM 27650954 ER PT J AU Salameh, TS Shah, GN Price, TO Hayden, MR Banks, WA AF Salameh, Therese S. Shah, Gul N. Price, Tulin O. Hayden, Melvin R. Banks, William A. TI Blood-Brain Barrier Disruption and Neurovascular Unit Dysfunction in Diabetic Mice: Protection with the Mitochondrial Carbonic Anhydrase Inhibitor Topiramate SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID MOUSE CEREBRAL PERICYTES; METABOLIC SYNDROME; PHARMACOLOGICAL INHIBITION; SYNAPTIC PLASTICITY; ALZHEIMERS-DISEASE; OXIDATIVE STRESS; RATS; PERMEABILITY; MELLITUS; INSULIN AB All forms of diabetes mellitus are characterized by chronic hyperglycemia, resulting in the development of a number of microvascular and macrovascular pathologies. Diabetes is also associated with changes in brain microvasculature, leading to dysfunction and ultimately disruption of the blood-brain barrier (BBB). These changes are correlated with a decline in cognitive function. In diabetes, BBB damage is associated with increased oxidative stress and reactive oxygen species. This occurs because of the increased oxidative metabolism of glucose caused by hyperglycemia. Decreasing the production of bicarbonate with the use of a mitochondrial carbonic anhydrase inhibitor (mCAi) limits oxidative metabolism and the production of reactive oxygen species. In this study, we have demonstrated that 1) streptozotocin-induced diabetes resulted in BBB disruption, 2) ultrastructural studies showed a breakdown of the BBB and changes to the neurovascular unit (NVU), including a loss of brain pericytes and retraction of astrocytes, the two cell types that maintain the BBB, and 3) treatment with topiramate, a mCAi, attenuated the effects of diabetes on BBB disruption and ultrastructural changes in the neurovascular unit. C1 [Salameh, Therese S.; Banks, William A.] Vet Affairs Puget Sound Hlth Care Syst, Educ & Clin Ctr, Geriatr Res, Seattle, WA USA. [Salameh, Therese S.; Banks, William A.] Univ Washington, Div Gerontol & Geriatr Med, Dept Med, Seattle, WA USA. [Shah, Gul N.; Price, Tulin O.] St Louis Univ, Sch Med, Div Endocrinol, Dept Internal Med, St Louis, MO USA. [Hayden, Melvin R.] Univ Missouri, Dept Internal Med, Div Endocrinol Diabet & Metab, Columbia, MO USA. [Hayden, Melvin R.] Univ Missouri, Diabet & Cardiovasc Res Lab, Columbia, MO USA. RP Banks, WA (reprint author), VAPSHCS, 810A-1,1660 S Columbian Way, Seattle, WA 98108 USA. EM wabanks1@uw.edu FU National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [RO1 DK083485]; Department of Veterans Affairs FX This work was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant RO1 DK083485] and the Department of Veterans Affairs. NR 34 TC 0 Z9 0 U1 3 U2 3 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 EI 1521-0103 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD DEC 1 PY 2016 VL 359 IS 3 BP 452 EP 459 DI 10.1124/jpet.116.237057 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EE4WH UT WOS:000389605800008 PM 27729477 ER PT J AU Brink, JA AF Brink, James A. TI Building a Better Mousetrap Through Team Training SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Editorial Material C1 [Brink, James A.] Massachusetts Gen Hosp, 55 Fruit St,FND 216, Boston, MA 02114 USA. RP Brink, JA (reprint author), Massachusetts Gen Hosp, 55 Fruit St,FND 216, Boston, MA 02114 USA. EM jabrink@partners.org NR 3 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD DEC PY 2016 VL 13 IS 12 BP 1405 EP 1406 DI 10.1016/j.jacr.2016.09.042 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EE4HF UT WOS:000389562200001 PM 27916105 ER PT J AU Simpson, L Khati, NJ Deshmukh, SP Dudiak, KM Harisinghani, MG Henrichsen, TL Meyer, BJ Nyberg, DA Poder, L Shipp, TD Zelop, CM Glanc, P AF Simpson, Lynn Khati, Nadia J. Deshmukh, Sandeep P. Dudiak, Kika M. Harisinghani, Mukesh G. Henrichsen, Tara L. Meyer, Benjamin J. Nyberg, David A. Poder, Liina Shipp, Thomas D. Zelop, Carolyn M. Glanc, Phyllis TI ACR Appropriateness Criteria Assessment of Fetal Well-Being SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Article DE Fetal well-being; antenatal testing; Appropriateness Criteria ID INTRAUTERINE GROWTH RESTRICTION; BIOPHYSICAL PROFILE SCORE; MYOCARDIAL PERFORMANCE INDEX; HIGH-RISK PREGNANCIES; AMNIOTIC-FLUID INDEX; UMBILICAL ARTERY; ANTEPARTUM SURVEILLANCE; CEREBRAL REDISTRIBUTION; DOPPLER ULTRASOUND; PERINATAL OUTCOMES AB Although there is limited evidence that antepartum testing decreases the risk for fetal death in low-risk pregnancies, women with high risk factors for stillbirth should undergo antenatal fetal surveillance. The strongest evidence supporting antepartum testing pertains to pregnancies complicated by intrauterine fetal growth restriction secondary to uteroplacental insufficiency. The main ultrasound-based modalities to determine fetal health are the biophysical profile, modified biophysical profile, and duplex Doppler velocimetry. In patients at risk for cardiovascular compromise, fetal echocardiography may also be indicated to ensure fetal well-being. Although no single antenatal test has been shown to be superior, all have high negative predictive values. Weekly or twice-weekly fetal testing has become the standard practice in high-risk pregnancies. The timing for the initiation of assessments of fetal well-being should be tailored on the basis of the risk for stillbirth and the likelihood of survival with intervention. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (the RAND/UCLA Appropriateness Method and the Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances in which evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. C1 [Simpson, Lynn] Columbia Univ, Med Ctr, New York, NY USA. [Simpson, Lynn; Shipp, Thomas D.; Glanc, Phyllis] Amer Congress Obstetricians & Gynecologists, Washington, DC USA. [Khati, Nadia J.] George Washington Univ Hosp, Washington, DC USA. [Deshmukh, Sandeep P.; Henrichsen, Tara L.] Thomas Jefferson Univ Hosp, Philadelphia, PA 19107 USA. [Dudiak, Kika M.] Mayo Clin, Rochester, MN USA. [Harisinghani, Mukesh G.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Meyer, Benjamin J.] Northwestern Univ, Prentice Hosp, Chicago, IL 60611 USA. [Nyberg, David A.] Old Vicarage, Worcester Pk, England. [Poder, Liina] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Shipp, Thomas D.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Zelop, Carolyn M.] Valley Hosp, Ridgewood, NJ USA. [Zelop, Carolyn M.] NYU, Sch Med, New York, NY USA. [Glanc, Phyllis] Sunnybrook Hlth Sci Ctr, Bayview Campus, Toronto, ON, Canada. RP Simpson, L (reprint author), Columbia Univ, Med Ctr, Dept Obstet & Gynecol, New York, NY 10032 USA. EM publications@acr.org NR 75 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD DEC PY 2016 VL 13 IS 12 BP 1483 EP 1493 DI 10.1016/j.jacr.2016.08.028 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EE4HF UT WOS:000389562200019 PM 28029583 ER PT J AU Moriarity, AK Hawkins, CM Geis, JR Dreyer, KJ Kamer, AP Khandheria, P Morey, J Whi, J Wiggins, RH Itri, JN AF Moriarity, Andrew K. Hawkins, C. Matthew Geis, J. Raymond Dreyer, Keith J. Kamer, Aaron P. Khandheria, Paras Morey, Jose Whi, James Wiggins, Richard H., III Itri, Jason N. TI Meaningful Peer Review in Radiology: A Review of Current Practices and Potential Future Directions SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Article DE Peer review; quality improvement; feedback; RADPEER; diagnostic error; human performance ID QUALITY-ASSURANCE; IMPROVEMENT; SYSTEM; PERCEPTIONS; CONSENSUS; FACULTY AB The current practice of peer review within radiology is well developed and widely implemented compared with other medical specialties. However, there are many factors that limit current peer review practices from reducing diagnostic errors and improving patient care. The development of "meaningful peer review" requires a transition away from compliance toward quality improvement, whereby the information and insights gained facilitate education and drive systematic improvements that reduce the frequency and impact of diagnostic error. The next generation of peer review requires significant improvements in IT functionality and integration, enabling features such as anonyrnization, adjudication by multiple specialists, categorization and analysis of errors, tracking, feedback, and easy export into teaching files and other media that require strong partnerships with vendors. In this article, the authors assess various peer review practices, with focused discussion on current limitations and future needs for meaningful peer review in radiology. C1 [Moriarity, Andrew K.] Adv Radiol Serv PC, 3264 North Evergreen Dr, Grand Rapids, MI 49525 USA. [Moriarity, Andrew K.] Michigan State Univ, Coll Human Med, Div Radiol & Biomed Imaging, Grand Rapids, MI USA. [Hawkins, C. Matthew] Emory Univ, Sch Med, Dept Radiol & Imaging Sci, Atlanta, GA USA. [Geis, J. Raymond] Adv Med Imaging Consultants PC, Aurora, CO USA. [Geis, J. Raymond] Univ Colorado, Sch Med, Ft Collins, CO USA. [Dreyer, Keith J.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Kamer, Aaron P.] Indiana Univ Sch Med, Dept Radiol, Indianapolis, IN 46202 USA. [Khandheria, Paras] South Texas Radiol Grp, San Antonio, TX USA. [Morey, Jose] Univ Virginia Hlth Syst, Charlottesville, VA USA. [Morey, Jose] US Dept Vet Affairs, Hampton, VA USA. [Whi, James] Scottsdale Hlth Partners, Phoenix, AZ USA. [Whi, James] Univ Arizona, Coll Med, Dept Internal Med, Phoenix, AZ USA. [Whi, James] Univ Arizona, Coll Med, Dept Biomed Informat, Phoenix, AZ USA. [Wiggins, Richard H., III] Univ Utah, Hlth Sci Ctr, Dept Radiol, Salt Lake City, UT USA. [Itri, Jason N.] Univ Virginia, Dept Radiol & Med Imaging, Charlottesville, VA USA. RP Moriarity, AK (reprint author), Adv Radiol Serv PC, 3264 North Evergreen Dr, Grand Rapids, MI 49525 USA. EM andymoriarity@gmail.com NR 34 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD DEC PY 2016 VL 13 IS 12 BP 1519 EP 1524 DI 10.1016/j.jacr.2016.08.005 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EE4HF UT WOS:000389562200026 PM 28233533 ER PT J AU Gunn, AJ Tuttle, MC Flores, EJ Mangano, MD Bennett, SE Sahani, DV Choy, G Boland, GW AF Gunn, Andrew J. Tuttle, Mitch C. Flores, Efren J. Mangano, Mark D. Bennett, Susan E. Sahani, Dushyant V. Choy, Garry Boland, Giles W. TI Differing Interpretations of Report Terminology Between Primary Care Physicians and Radiologists SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Article DE Radiology reporting; practice improvement; informatics; referring physicians; report terminology ID REFERRING PHYSICIANS; COMMUNICATION; CLINICIAN; CERTAINTY AB Purpose: The lexicons of the radiologist and the referring physician may not be synonymous, which could cause confusion with radiology reporting. To further explore this possibility, we surveyed radiologists and primary care physicians (PCPs) regarding their respective interpretations of report terminology. Methods: A survey was distributed to radiologists and PCPs through an internal listserv. Respondents were asked to provide an interpretation of the statistical likelihood of the presence of metastatic disease based upon the terminology used within a hypothetical radiology report. Ten common modifying terms were evaluated. Potential responses for the statistical likelihoods included 0%-25%, 26%-50%, 51%-75%, 76%-99%, and 100%. Differences between the groups were evaluated using either a chi(2) test or Fisher exact test, as appropriate. Results: The phrases "diagnostic for metastatic disease" and "represents metastatic disease" were selected by a high percentage of both groups as conferring a 100% likelihood of "true metastatic disease." The phrases "cannot exclude metastatic disease" and "may represent metastatic disease" were selected by a high proportion of both groups as conferring a 0% likelihood of "true metastatic disease." Radiologists assigned a higher statistical likelihood to the terms "diagnostic for metastatic disease" (P = .016), "represents metastatic disease" (P = .004), "suspicious for metastatic disease" (P = .04), "consistent with metastatic disease" (P < .0001), and "compatible with metastatic disease" (P = .003). Conclusion: A qualitative agreement among radiologists and PCPs exists concerning the significance of the evaluated terminology, although radiologists assigned a higher statistical likelihood than PCPs for several phrases. C1 [Gunn, Andrew J.] Washington Univ, Mallinckrodt Inst Radiol, Sch Med St Louis, Div Vasc & Intervent Radiol, 510 S Kingshighway Blvd, St Louis, MO 63110 USA. [Tuttle, Mitch C.] Washington Univ, Mallinckrodt Inst Radiol, Sch Med St Louis, St Louis, MO USA. [Flores, Efren J.] Massachusetts Gen Hosp, Dept Radiol, Div Emergency Radiol & Teleradiol, Boston, MA USA. [Flores, Efren J.; Mangano, Mark D.; Bennett, Susan E.; Sahani, Dushyant V.; Choy, Garry; Boland, Giles W.] Harvard Med Sch, Boston, MA USA. [Mangano, Mark D.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Bennett, Susan E.; Choy, Garry] Massachusetts Gen Hosp, Dept Internal Med, Boston, MA 02114 USA. [Sahani, Dushyant V.; Boland, Giles W.] Massachusetts Gen Hosp, Div Abdominal Imaging & Intervent, Boston, MA 02114 USA. RP Gunn, AJ (reprint author), Washington Univ, Mallinckrodt Inst Radiol, Sch Med St Louis, Div Vasc & Intervent Radiol, 510 S Kingshighway Blvd, St Louis, MO 63110 USA. EM ajgunnmd@gmail.com NR 25 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD DEC PY 2016 VL 13 IS 12 BP 1525 EP 1529 DI 10.1016/j.jacr.2016.07.016 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EE4HF UT WOS:000389562200027 PM 27595196 ER PT J AU Pallera, A Altman, JK Berman, E Abboud, CN Bhatnagar, B Curtin, P DeAngelo, DJ Gotlib, J Hagelstrom, RT Hobbs, G Jagasia, M Kantarjian, HM Kropf, P Metheny, L Moore, JO Ontiveros, E Purev, E Quiery, A Reddy, VVB Rose, MG Shah, NP Smith, BD Snyder, DS Sweet, KL Tibes, R Yang, DT Gregory, K Sundar, H Deininger, M Radich, JP AF Pallera, Arnel Altman, Jessica K. Berman, Ellin Abboud, Camille N. Bhatnagar, Bhavana Curtin, Peter DeAngelo, Daniel J. Gotlib, Jason Hagelstrom, R. Tanner Hobbs, Gabriela Jagasia, Madan Kantarjian, Hagop M. Kropf, Patricia Metheny, Leland Moore, Joseph O. Ontiveros, Evelena Purev, Enkhtsetseg Quiery, Albert Reddy, Vishnu V. B. Rose, Michal G. Shah, Neil P. Smith, B. Douglas Snyder, David S. Sweet, Kendra L. Tibes, Raoul Yang, David T. Gregory, Kristina Sundar, Hema Deininger, Michael Radich, Jerald P. TI NCCN Guidelines (R) Insights Chronic Myeloid Leukemia, Version 1.2017 Featured Updates to the NCCN Guidelines SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Article ID CHRONIC MYELOGENOUS LEUKEMIA; TYROSINE KINASE INHIBITORS; STEM-CELL TRANSPLANTATION; CHILDRENS ONCOLOGY GROUP; CHRONIC-PHASE; MOLECULAR RESPONSE; IMATINIB MESYLATE; ALPHA-INTERFERON; CML PATIENTS; SUCCESSFUL PREGNANCIES AB The NCCN Guidelines for Chronic Myeloid Leukemia (CML) provide recommendations for the management of chronic-phase and advanced-phase CML in adult patients. The median age of disease onset is 67 years. However, because CML occurs in all age groups, clinical care teams should be prepared to address issues relating to fertility and pregnancy with patients who are of reproductive age at the time of diagnosis. CML is relatively rare in children and there are no evidence-based recommendations for the management of CML in pediatric population. These NCCN Guidelines Insights discuss special considerations for the management of CML during pregnancy and for the management of CML in the pediatric population. C1 [Pallera, Arnel] Univ Tennessee, St Jude Childrens Res Hosp, Hlth Sci Ctr, Knoxville, TN 37996 USA. [Altman, Jessica K.] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Evanston, IL 60208 USA. [Berman, Ellin] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Abboud, Camille N.] Barnes Jewish Hosp, Siteman Canc Ctr, St Louis, MO 63110 USA. [Abboud, Camille N.] Washington Univ, Sch Med, St Louis, MO 63130 USA. [Bhatnagar, Bhavana] Ohio State Univ, Ctr Comprehens Canc, James Canc Hosp, Columbus, OH 43210 USA. [Bhatnagar, Bhavana] Solove Res Inst, Columbus, OH USA. [Curtin, Peter] Univ Calif San Diego, Moores Canc Ctr, San Diego, CA USA. [DeAngelo, Daniel J.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Gotlib, Jason] Stanford Canc Inst, Stanford, CA USA. [Hagelstrom, R. Tanner] Fred & Pamela Buffett Canc Ctr, Omaha, NE USA. [Hobbs, Gabriela] Massachusetts Gen Hosp, Canc Ctr, Boston, MA 02114 USA. [Jagasia, Madan] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Kantarjian, Hagop M.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Kropf, Patricia] Fox Chase Canc Ctr, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Metheny, Leland] Univ Hosp Seidman Canc Ctr, Case Comprehens Canc Ctr, Cleveland, OH USA. [Metheny, Leland] Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44106 USA. [Moore, Joseph O.] Duke Canc Inst, Durham, NC USA. [Ontiveros, Evelena] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Purev, Enkhtsetseg] Univ Colorado, Canc Ctr, Boulder, CO 80309 USA. [Quiery, Albert] Univ Michigan, Comprehens Canc Ctr, Ann Arbor, MI 48109 USA. [Reddy, Vishnu V. B.] Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL 35294 USA. [Rose, Michal G.] Smilow Canc Hosp, Yale Canc Ctr, New Haven, CT USA. [Shah, Neil P.] UCSF, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA. [Smith, B. Douglas] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD USA. [Snyder, David S.] City Hope Comprehens Canc Ctr, Duarte, CA USA. [Sweet, Kendra L.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Tibes, Raoul] Mayo Clin, Canc Ctr, Rochester, MN USA. [Yang, David T.] Univ Wisconsin, Carbone Canc Ctr, Madison, WI 53706 USA. [Gregory, Kristina; Sundar, Hema] Natl Comprehens Canc Network, Hollywood, FL USA. [Deininger, Michael] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT 84112 USA. [Radich, Jerald P.] Fred Hutchinson Canc Res Ctr, Seattle Canc Care Alliance, 1124 Columbia St, Seattle, WA 98104 USA. RP Pallera, A (reprint author), Univ Tennessee, St Jude Childrens Res Hosp, Hlth Sci Ctr, Knoxville, TN 37996 USA. FU AstraZeneca; Bayer Healthcare Pharmaceuticals Inc.; Bristol-Myers Squibb; Clovis Oncology; Foundation Medicine; Genentech; Novartis Oncology; Otsuka America Pharmaceutical, Inc.; Seattle Genetics, Inc.; Takeda Oncology; Actelion Pharmaceuticals US, Inc.; Astellas; Medivation, Inc. FX This activity is supported by educational grants from AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Bristol-Myers Squibb, Clovis Oncology, Foundation Medicine, Genentech, Novartis Oncology, Otsuka America Pharmaceutical, Inc., Seattle Genetics, Inc., and Takeda Oncology; support provided by Actelion Pharmaceuticals US, Inc.; and by an independent educational grant from Astellas and Medivation, Inc. NR 69 TC 0 Z9 0 U1 2 U2 2 PU HARBORSIDE PRESS PI COLD SPRING HARBOR PA 37 MAIN ST, COLD SPRING HARBOR, NY 11724 USA SN 1540-1405 EI 1540-1413 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD DEC PY 2016 VL 14 IS 12 BP 1505 EP 1512 PG 8 WC Oncology SC Oncology GA EE9QU UT WOS:000389962100004 PM 27956535 ER PT J AU Losk, K Vaz-Luis, I Camuso, K Batista, R Lloyd, M Tukenmez, M Golshan, M Lin, NU Bunnell, CA AF Losk, Katya Vaz-Luis, Ines Camuso, Kristen Batista, Rafael Lloyd, Max Tukenmez, Mustafa Golshan, Mehra Lin, Nancy U. Bunnell, Craig A. TI Factors Associated With Delays in Chemotherapy Initiation Among Patients With Breast Cancer at a Comprehensive Cancer Center SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Article ID ADJUVANT CHEMOTHERAPY; DATA-BASE; SURVIVAL; TIME; RECONSTRUCTION; MASTECTOMY; THERAPY; IMPACT; MORTALITY; AMERICAN AB Background: National guidelines endorse time-dependent quality metrics for breast cancer care. We examined factors associated with delays in chemotherapy initiation at an NCI-Designated Comprehensive Cancer Center. Patients and Methods: We identified 523 patients who received postoperative adjuvant chemotherapy between January 2011 and December 2013 at our center. We defined 28 days from last definitive surgery (LDS) to chemotherapy as the target time frame, and an unacceptable delay in chemotherapy initiation (UCD) as greater than 42 days from LDS. Multivariate regression models were used to identify factors associated with UCD and the impact of Oncotype DX testing in patients with hormone receptor (HR) positive breast cancer. Results: Median days between LDS and chemotherapy initiation was 34 (interquartile range, 15), with 30% of patients starting within 28 days of LDS and 26.9% having UCD. Tumor characteristics such as subtype and stage affected UCD; patients with HR-positive or HER2-positive tumors were more likely to be delayed compared with those with triple-negative breast cancer. Patients with stage I disease, those undergoing mastectomy with or without immediate reconstruction, and those whose pathology sign-out was greater than 10 days postoperatively were more likely to be delayed. A higher proportion of UCD was found in HR-positive patients (31%) for whom Oncotype DX testing was ordered compared with those in whom it was not ordered (20%). Conclusions: This study provides insight into subpopulations that may be at risk to experience delays in chemotherapy initiation, directing interventions to improve the timeliness of care. C1 [Losk, Katya; Vaz-Luis, Ines; Lloyd, Max; Lin, Nancy U.; Bunnell, Craig A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Camuso, Kristen] Dana Farber Canc Inst, Qual & Patient Safety, Boston, MA 02115 USA. [Batista, Rafael] Oncoclinicas, Sao Paulo, Brazil. [Tukenmez, Mustafa] Istanbul Med Sch, Dept Gen Surg, Istanbul, Turkey. [Golshan, Mehra] Brigham & Womens Hosp, Dept Surg, Dana Farber Canc Inst, 75 Francis St, Boston, MA 02115 USA. RP Bunnell, CA (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM craig_bunnell@dfci.harvard.edu FU NCCN FX The authors have disclosed that they have no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors. This initiative was supported in part by the NCCN Opportunities for Improvement grant. NR 27 TC 0 Z9 0 U1 1 U2 1 PU HARBORSIDE PRESS PI COLD SPRING HARBOR PA 37 MAIN ST, COLD SPRING HARBOR, NY 11724 USA SN 1540-1405 EI 1540-1413 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD DEC PY 2016 VL 14 IS 12 BP 1519 EP 1526 PG 8 WC Oncology SC Oncology GA EE9QU UT WOS:000389962100005 PM 27956536 ER PT J AU Abdel-Misih, SRZ Wei, L Benson, AB Cohen, S Lai, L Skibber, J Wilkinson, N Weiser, M Schrag, D Bekaii-Saab, T AF Abdel-Misih, Sherif R. Z. Wei, Lai Benson, Al B., III Cohen, Steven Lai, Lily Skibber, John Wilkinson, Neal Weiser, Martin Schrag, Deborah Bekaii-Saab, Tanios TI Neoadjuvant Therapy for Rectal Cancer Affects Lymph Node Yield and Status Without Clear Implications on Outcome: The Case for Eliminating a Metric and Using Preoperative Staging to Guide Therapy SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Article ID COLON-CANCER; COLORECTAL-CANCER; CHEMORADIOTHERAPY; NUMBER; SURVIVAL; IMPACT; CHEMORADIATION; CARCINOMA; RETRIEVAL; HARVEST AB Background: Nodal status has long been considered pivotal to oncologic care, staging, and management. This has resulted in the establishment of rudimentary metrics regarding adequate lymph node yield in colon and rectal cancers for accurate cancer staging. In the era of neoadjuvant treatment, the implications of lymph node yield and status on patient outcomes remains unclear. Patient and Methods: This study included 1,680 patients with locally advanced rectal cancer from the NCCN prospective oncology database stratified into 3 groups based on preoperative therapy received: no neoadjuvant therapy, neoadjuvant chemoradiation, and neoadjuvant chemotherapy. Clinicopathologic characteristics and survival were compared between the groups, with univariate and multivariate analyses undertaken. Results: The clinicopathologic characteristics demonstrated statistically significant differences and heterogeneity among the 3 groups. The neoadjuvant chemoradiation group demonstrated the statistically lowest median lymph node yield (n=15) compared with 17 and 18 for no-neoadjuvant and neoadjuvant chemotherapy, respectively (P<.0001). Neoadjuvant treatment did impact survival, with chemoradiation demonstrating increased median overall survival of 42.7 compared with 37.3 and 26.6 months for neoadjuvant chemotherapy and noneoadjuvant therapy, respectively (P<.0001). Patients with a yield of fewer than 12 lymph nodes had improved median overall survival of 43.3 months compared with 36.6 months in patients with 12 or more lymph nodes (P=.009). Multivariate analysis demonstrated that neither node yield nor status were predictors for overall survival. Discussion: This analysis reiterates that nodal yield in rectal cancer is multifactorial, with neoadjuvant therapy being a significant factor. Node yield and status were not significant predictors of overall survival. A nodal metric may not be clinically relevant in the era of neoadjuvant therapy, and guidelines for perioperative therapy may need reconsideration. C1 [Abdel-Misih, Sherif R. Z.] Ohio State Univ, Div Surg Oncol, Wexner Med Ctr, Arthur G James Canc Hosp, Columbus, OH 43210 USA. [Wei, Lai] Ohio State Univ, Ctr Biostat, Wexner Med Ctr, Columbus, OH 43210 USA. [Benson, Al B., III] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. [Cohen, Steven] Fox Chase Canc Ctr, Dept Hematol Oncol, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Lai, Lily] City Hope Comprehens Canc Ctr, Duarte, CA USA. [Skibber, John] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Wilkinson, Neal] Kalispell Reg Healthcare Specialists, Kalispell Reg Healthcare, Kalispell, MT USA. [Weiser, Martin] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Schrag, Deborah] Dana Farber Canc Inst, Boston, MA 02115 USA. [Bekaii-Saab, Tanios] Mayo Clin, Ctr Canc, Depaartment Med, Div Hematol Oncol, Phoenix, AZ USA. RP Abdel-Misih, SRZ (reprint author), 320 West 10th Ave,M256 Starling Loving Hall, Columbus, OH 43210 USA. EM sherif.abdel-misih@osumc.edu FU NCI NIH HHS [P30 CA008748] NR 24 TC 0 Z9 0 U1 2 U2 2 PU HARBORSIDE PRESS PI COLD SPRING HARBOR PA 37 MAIN ST, COLD SPRING HARBOR, NY 11724 USA SN 1540-1405 EI 1540-1413 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD DEC PY 2016 VL 14 IS 12 BP 1528 EP 1534 PG 7 WC Oncology SC Oncology GA EE9QU UT WOS:000389962100006 PM 27956537 ER PT J AU Mesa, R Jamieson, C Bhatia, R Deininger, MW Gerds, AT Gojo, I Gotlib, J Gundabolu, K Hobbs, G Klisovic, RB Kropf, P Mohan, SR Oh, S Padron, E Podoltsev, N Pollyea, DA Rampal, R Rein, LAM Scott, B Snyder, DS Stein, BL Verstovsek, S Wadleigh, M Wang, ES Bergman, MA Gregory, KM Sundar, H AF Mesa, Ruben Jamieson, Catriona Bhatia, Ravi Deininger, Michael W. Gerds, Aaron T. Gojo, Ivana Gotlib, Jason Gundabolu, Krishna Hobbs, Gabriela Klisovic, Rebecca B. Kropf, Patricia Mohan, Sanjay R. Oh, Stephen Padron, Eric Podoltsev, Nikolai Pollyea, Daniel A. Rampal, Raajit Rein, Lindsay A. M. Scott, Bart Snyder, David S. Stein, Brady L. Verstovsek, Srdan Wadleigh, Martha Wang, Eunice S. Bergman, Mary Anne Gregory, Kristina M. Sundar, Hema TI Myeloproliferative Neoplasms, Version 2.2017 SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Article ID STEM-CELL TRANSPLANTATION; INTERNATIONAL-WORKING-GROUP; SYMPTOM ASSESSMENT FORM; ACUTE MYELOID-LEUKEMIA; PROGNOSTIC SCORING SYSTEM; WORLD-HEALTH-ORGANIZATION; TREATMENT IWG-MRT; QUALITY-OF-LIFE; ESSENTIAL THROMBOCYTHEMIA MYELOFIBROSIS; CYTOGENETIC-RISK CATEGORIZATION AB Myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET) are a group of heterogeneous disorders of the hematopoietic system collectively known as Philadelphia chromosome negative myeloproliferative neoplasms (MPNs). The diagnosis and the management of patients with MPNs have evolved since the identification of mutations that activate the JAK pathway (JAK2, CALR, and MPL mutations) and the development of targeted therapies has resulted in significant improvements in disease-related symptoms and quality of life. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnostic workup of MPN (MF, PV, and ET), risk stratification, treatment, and supportive care strategies for the management of MF. C1 [Mesa, Ruben] Mayo Clin, Ctr Canc, Rochester, MN 55905 USA. [Jamieson, Catriona] Univ Calif San Diego, Moores Canc Ctr, San Diego, CA USA. [Bhatia, Ravi] Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL 35294 USA. [Deininger, Michael W.] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT 84112 USA. [Gerds, Aaron T.] Univ Hosp Seidman Canc Ctr, Case Comprehens Canc Ctr, Cleveland, OH USA. [Gerds, Aaron T.] Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44106 USA. [Gojo, Ivana] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD USA. [Gotlib, Jason] Stanford Canc Inst, Stanford, CA USA. [Gundabolu, Krishna] Fred & Pamela Buffett Canc Ctr, Omaha, NE USA. [Hobbs, Gabriela] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Klisovic, Rebecca B.] Ohio State Univ, Ctr Comprehens Canc, James Canc Hosp, Columbus, OH 43210 USA. [Klisovic, Rebecca B.] Solove Res Inst, Columbus, OH USA. [Kropf, Patricia] Fox Chase Canc Ctr, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Mohan, Sanjay R.] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Oh, Stephen] Barnes Jewish Hosp, Siteman Canc Ctr, St Louis, MO 63110 USA. [Oh, Stephen] Washington Univ, Sch Med, St Louis, MO 63130 USA. [Padron, Eric] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Podoltsev, Nikolai] Smilow Canc Hosp, Yale Canc Ctr, New Haven, CT USA. [Pollyea, Daniel A.] Univ Colorado, Ctr Canc, Boulder, CO 80309 USA. [Rampal, Raajit] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Rein, Lindsay A. M.] Duke Canc Inst, Durham, NC USA. [Scott, Bart] Fred Hutchinson Canc Res Ctr, Seattle Canc Care Alliance, 1124 Columbia St, Seattle, WA 98104 USA. [Snyder, David S.] City Hope Comprehens Canc Ctr, Duarte, CA USA. [Stein, Brady L.] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Evanston, IL 60208 USA. [Verstovsek, Srdan] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Wadleigh, Martha] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Wang, Eunice S.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. RP Mesa, R (reprint author), Mayo Clin, Ctr Canc, Rochester, MN 55905 USA. FU NCI NIH HHS [P30 CA016672] NR 148 TC 0 Z9 0 U1 0 U2 0 PU HARBORSIDE PRESS PI COLD SPRING HARBOR PA 37 MAIN ST, COLD SPRING HARBOR, NY 11724 USA SN 1540-1405 EI 1540-1413 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD DEC PY 2016 VL 14 IS 12 BP 1572 EP 1611 PG 40 WC Oncology SC Oncology GA EE9QU UT WOS:000389962100011 PM 27956542 ER PT J AU Fisher, BT Vendetti, N Bryan, M Prasad, PA Localio, AR Damianos, A Coffin, SE Bell, LM Walsh, TJ Gross, R Zaoutis, TE AF Fisher, Brian T. Vendetti, Neika Bryan, Matthew Prasad, Priya A. Localio, A. Russell Damianos, Andreas Coffin, Susan E. Bell, Louis M. Walsh, Thomas J. Gross, Robert Zaoutis, Theoklis E. TI Central Venous Catheter Retention and Mortality in Children With Candidemia: A Retrospective Cohort Analysis SO JOURNAL OF THE PEDIATRIC INFECTIOUS DISEASES SOCIETY LA English DT Article DE candidemia; central catheter; mortality; pediatrics ID BLOOD-STREAM INFECTIONS; PEDIATRIC-PATIENTS; RISK-FACTORS; INVASIVE CANDIDIASIS; UNITED-STATES; EPIDEMIOLOGY; POPULATION; OUTCOMES; THERAPY; ADULTS AB Background. Candidemia causes significant morbidity and mortality among children. Removal of a central venous catheter (CVC) is often recommended for adults with candidemia to reduce persistent and metastatic infection. Pediatric-specific data on the impact of CVC retention are limited. Methods. A retrospective cohort study of inpatients <19 years with candidemia at the Children's Hospital of Philadelphia between 2000 and 2012 was performed. The final cohort included patients that had a CVC in place at time of blood culture and retained their CVC at least 1 day beyond the blood culture being positive. A structured data collection instrument was used to retrieve patient data. A discrete time failure model, adjusting for age and the complexity of clinical care before onset of candidemia, was used to assess the association of CVC retention and 30-day all-cause mortality. Results. Two hundred eighty-five patients with candidemia and a CVC in place at the time of blood culture were identified. Among these 285 patients, 30 (10%) died within 30 days. Central venous catheter retention was associated with a significant increased risk of death on a given day (odds ratio, 2.50; 95% confidence interval, 1.06-5.91). Conclusions. Retention of a CVC was associated with an increased risk of death after adjusting for age and complexity of care at candidemia onset. Although there is likely persistence of unmeasured confounding, given the strong association between catheter retention and death, our data suggest that early CVC removal should be strongly considered. C1 [Fisher, Brian T.; Vendetti, Neika; Damianos, Andreas; Coffin, Susan E.; Bell, Louis M.; Zaoutis, Theoklis E.] Childrens Hosp Philadelphia, Div Infect Dis, Philadelphia, PA 19104 USA. [Bryan, Matthew; Localio, A. Russell; Bell, Louis M.] Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA. [Fisher, Brian T.; Vendetti, Neika; Localio, A. Russell; Coffin, Susan E.; Zaoutis, Theoklis E.] Childrens Hosp Philadelphia, Ctr Pediat Clin Effectiveness, Philadelphia, PA 19104 USA. [Fisher, Brian T.; Bryan, Matthew; Localio, A. Russell; Coffin, Susan E.; Gross, Robert; Zaoutis, Theoklis E.] Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Prasad, Priya A.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Walsh, Thomas J.] New York Presbyterian Hosp, Weill Cornell Med Ctr, Transplantat Oncol Infect Dis, New York, NY USA. [Gross, Robert] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. RP Fisher, BT (reprint author), Childrens Hosp Philadelphia, Div Infect Dis, CHOP North, 34th & Civ Ctr Blvd,Suite 1515, Philadelphia, PA 19104 USA. EM fisherbria@email.chop.edu NR 19 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 2048-7193 EI 2048-7207 J9 J PEDIATR INFECT DIS JI J. Pediatr. Infect. Dis. Soc. PD DEC PY 2016 VL 5 IS 4 BP 403 EP 408 DI 10.1093/jpids/piv048 PG 6 WC Infectious Diseases SC Infectious Diseases GA EE8EA UT WOS:000389856800008 PM 26407279 ER PT J AU Bohnen, JD Chang, DC Ramly, EP Olufajo, OA Le, RT Kaafarani, HMA Yeh, DD King, DR Fagenholz, PJ Butler, KL Askari, R Salim, A Velmahos, GC de Moya, M AF Bohnen, Jordan D. Chang, David C. Ramly, Elie P. Olufajo, Olubode A. Le, Ryan T. Kaafarani, Haytham M. A. Yeh, Daniel Dante King, David R. Fagenholz, Peter J. Butler, Kathryn L. Askari, Reza Salim, Ali Velmahos, George C. de Moya, Marc TI Low baseline (pre-injury) blood pressure predicts inpatient mortality in elderly trauma patients: A bi-institutional study SO JOURNAL OF TRAUMA AND ACUTE CARE SURGERY LA English DT Article; Proceedings Paper CT 46th Annual Meeting of the Western-Trauma-Association CY FEB 28-MAR 04, 2016 CL CA SP Western Trauma Assoc DE Trauma mortality; blood pressure; elderly; electronic health records; big data ID US ADULT-POPULATION; PREHOSPITAL HYPOTENSION; BRAIN-INJURY; FALLS; HYPERTENSION; ASSOCIATION; HEMORRHAGE; OUTCOMES; SPRINT; RISK AB OBJECTIVE: The relationship between baseline (i.e., pre-injury) blood pressure and trauma outcomes in elderly patients is unknown. We therefore aimed to identify the independent impact of baseline systolic blood pressure (SBP) on inpatient mortality among elderly trauma patients. METHODS: The 2004 to 2014 trauma registries of two Level I Trauma Centers were linked to electronic health records then reviewed to identify patients >= 65 years old with available baseline vital signs. Baseline SBP was defined as mean outpatient SBP within 2 years before injury. Trauma SBP was defined as first SBP reading after presentation for trauma. Baseline and Trauma SBP were classified as Low (<110 mm Hg), Normal (110-139 mm Hg), or High (>= 140 mm Hg). Logistic multivariable regression models were constructed to assess the independent impact of Baseline SBP on inpatient mortality, controlling for demographics, comorbidities, injury mechanism/severity, and Trauma SBP. RESULTS: Of 37,494 patient admissions, 4,233 met inclusion criteria. Median age was 81 years; 63.6% were female. Mortality was 5.39%. In unadjusted analyses, mortality rates were 11.01%, 5.28%, and 4.52% in the Low, Normal, and High Baseline SBP groups, respectively (p = 0.001). In multivariable analyses, patients with Low Baseline SBP had significantly increased mortality risk [OR 3.19 (95% CI 1.62-6.26), p = 0.001] compared to patients with Normal Baseline SBP, in particular when they presented with Low Trauma SBP (< 110 mm Hg) [OR 6.14 (2.17-17.36), p = 0.001] or Normal Trauma SBP (110-139 mm Hg) [OR 3.87 (1.43-10.45), p = 0.008]. The mortality risk associated with Low Baseline SBP was particularly elevated among patients with a pre-existing diagnosis of hypertension [OR 4.78 (1.97-11.62), p = 0.001]. CONCLUSION: Low baseline pre-injury SBP is independently associated with more than a threefold increase in inpatient mortality among elderly trauma patients and a fivefold increase in mortality risk among patients with pre-existing hypertension. Given that blood pressure control in the elderly offers a long-term survival advantage, the paradoxical finding of decreased survival after trauma warrants further investigation. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved. C1 [Bohnen, Jordan D.; Ramly, Elie P.; Le, Ryan T.; Kaafarani, Haytham M. A.; Yeh, Daniel Dante; King, David R.; Fagenholz, Peter J.; Butler, Kathryn L.; Velmahos, George C.; de Moya, Marc] Massachusetts Gen Hosp, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA 02114 USA. Harvard Med Sch, Boston, MA USA. [Chang, David C.; Kaafarani, Haytham M. A.] Massachusetts Gen Hosp, Codman Ctr Clin Effectiveness Surg, Boston, MA 02114 USA. [Ramly, Elie P.] Oregon Hlth & Sci Univ, Dept Surg, Portland, OR 97201 USA. [Olufajo, Olubode A.; Askari, Reza; Salim, Ali] Brigham & Womens Hosp, Div Trauma Burn & Surg Crit Care, 75 Francis St, Boston, MA 02115 USA. RP Bohnen, JD (reprint author), Massachusetts Gen Hosp, Dept Surg, 165 Cambridge St,Suite 810, Boston, MA 02114 USA. EM jbohnen@partners.org NR 25 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 2163-0755 EI 2163-0763 J9 J TRAUMA ACUTE CARE JI J. Trauma Acute Care Surg. PD DEC PY 2016 VL 81 IS 6 BP 1142 EP 1149 DI 10.1097/TA.0000000000001144 PG 8 WC Critical Care Medicine; Surgery SC General & Internal Medicine; Surgery GA EE0BH UT WOS:000389237900021 PM 27244581 ER PT J AU Tran, TLN Brasel, KJ Karmy-Jones, R Rowell, S Schreiber, MA Shatz, DV Albrecht, RM Cohen, MJ DeMoya, MA Biffl, WL Moore, EE Namias, N AF Tran, Thai Lan N. Brasel, Karen J. Karmy-Jones, Riyad Rowell, Susan Schreiber, Martin A. Shatz, David V. Albrecht, Roxie M. Cohen, Mitchell J. DeMoya, Marc A. Biffl, Walter L. Moore, Ernest E. Namias, Nicholas TI Western Trauma Association Critical Decisions in Trauma: Management of pelvic fracture with hemodynamic instability-2016 updates SO JOURNAL OF TRAUMA AND ACUTE CARE SURGERY LA English DT Article ID ENDOVASCULAR BALLOON OCCLUSION; HEMORRHAGE CONTROL; TORSO HEMORRHAGE; RING FRACTURES; RESUSCITATION; INJURIES; PACKING; AORTA; COAGULOPATHY; STABILITY C1 [Tran, Thai Lan N.; Namias, Nicholas] Univ Miami, Miami, FL USA. [Tran, Thai Lan N.; Namias, Nicholas] Jackson Mem Hosp, Miami, FL 33136 USA. [Brasel, Karen J.; Rowell, Susan; Schreiber, Martin A.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Karmy-Jones, Riyad] Legacy Hlth Syst, Vancouver, WA USA. [Shatz, David V.] Univ Calif Davis, Sacramento, CA 95817 USA. [Albrecht, Roxie M.] Univ Oklahoma, Oklahoma City, OK USA. [Cohen, Mitchell J.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [DeMoya, Marc A.] Harvard Univ, Boston, MA 02115 USA. [DeMoya, Marc A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Biffl, Walter L.] Univ Hawaii, Honolulu, HI 96822 USA. [Biffl, Walter L.] Queens Med Ctr, Honolulu, HI USA. [Moore, Ernest E.] Univ Colorado, Denver, CO 80202 USA. [Moore, Ernest E.] Denver Hlth, Denver, CO USA. RP Namias, N (reprint author), Univ Miami, Miller Sch Med, Div Trauma & Surg Crit Care, POB 016960 D-40, Miami, FL 33101 USA. EM nnamias@miami.edu NR 40 TC 1 Z9 1 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 2163-0755 EI 2163-0763 J9 J TRAUMA ACUTE CARE JI J. Trauma Acute Care Surg. PD DEC PY 2016 VL 81 IS 6 BP 1171 EP 1174 DI 10.1097/TA.0000000000001230 PG 4 WC Critical Care Medicine; Surgery SC General & Internal Medicine; Surgery GA EE0BH UT WOS:000389237900026 PM 27537512 ER PT J AU Deng, J Mitsuki, Y Shen, GM Ray, JC Cicala, C Arthos, J Dustin, ML Hioe, CE AF Deng, Jing Mitsuki, Yu-ya Shen, Guomiao Ray, Jocelyn C. Cicala, Claudia Arthos, James Dustin, Michael L. Hioe, Catarina E. TI HIV Envelope gp120 Alters T Cell Receptor Mobilization in the Immunological Synapse of Uninfected CD4 T Cells and Augments T Cell Activation SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; VIROLOGICAL SYNAPSES; MONOCLONAL-ANTIBODIES; TYPE-1 INFECTION; DENDRITIC CELLS; STOP SIGNAL; MICROCLUSTERS; BINDING; ENV; SUBSETS AB HIV is transmitted most efficiently from cell to cell, and productive infection occurs mainly in activated CD4 T cells. It is postulated that HIV exploits immunological synapses formed between CD4 T cells and antigen-presenting cells to facilitate the targeting and infection of activated CD4 T cells. This study sought to evaluate how the presence of the HIV envelope (Env) in the CD4 T cell immunological synapse affects synapse formation and intracellular signaling to impact the downstream T cell activation events. CD4 T cells were applied to supported lipid bilayers that were reconstituted with HIV Env gp120, anti-T cell receptor (anti-TCR) monoclonal antibody, and ICAM-1 to represent the surface of HIV Env-bearing antigen-presenting cells. The results showed that the HIV Env did not disrupt immunological synapse formation. Instead, the HIV Env accumulated with TCR at the center of the synapse, altered the kinetics of TCR recruitment to the synapse and affected synapse morphology over time. The HIV Env also prolonged Lck phosphorylation at the synapse and enhanced TCR-induced CD69 upregulation, interleukin-2 secretion, and proliferation to promote virus infection. These results suggest that HIV uses the immunological synapse as a conduit not only for selective virus transmission to activated CD4 T cells but also for boosting the T cell activation state, thereby increasing its likelihood of undergoing productive replication in targeted CD4 T cells. IMPORTANCE There are about two million new HIV infections every year. A better understanding of how HIV is transmitted to susceptible cells is critical to devise effective strategies to prevent HIV infection. Activated CD4 T cells are preferentially infected by HIV, although how this is accomplished is not fully understood. This study examined whether HIV co-opts the normal T cell activation process through the so-called immunological synapse. We found that the HIV envelope is recruited to the center of the immunological synapse together with the T cell receptor and enhances the T cell receptor-induced activation of CD4 T cells. Heightened cellular activation promotes the capacity of CD4 T cells to support productive HIV replication. This study provides evidence of the exploitation of the normal immunological synapse and T cell activation process by HIV to boost the activation state of targeted CD4 T cells and promote the infection of these cells. C1 [Deng, Jing; Dustin, Michael L.] NYU, Sch Med, Skirball Inst Biomol Med, New York, NY USA. [Deng, Jing; Shen, Guomiao; Dustin, Michael L.] NYU, Sch Med, Dept Pathol, New York, NY USA. [Mitsuki, Yu-ya; Hioe, Catarina E.] Icahn Sch Med Mt Sinai, Div Infect Dis, New York, NY 10029 USA. [Ray, Jocelyn C.; Cicala, Claudia; Arthos, James] NIAID, Immunoregulat Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Dustin, Michael L.] Univ Oxford, Nuffield Dept Orthopaed Rheumatol & Musculoskelet, Kennedy Inst Rheumatol, Headington, England. [Hioe, Catarina E.] James J Peters Vet Affairs Med Ctr, Res Serv, Bronx, NY 10468 USA. RP Hioe, CE (reprint author), Icahn Sch Med Mt Sinai, Div Infect Dis, New York, NY 10029 USA.; Hioe, CE (reprint author), James J Peters Vet Affairs Med Ctr, Res Serv, Bronx, NY 10468 USA. EM catarina.hioe@mssm.edu FU U.S. Department of Veterans Affairs (VA); HHS \ NIH \ National Institute of Allergy and Infectious Diseases (NIAID) [AI093210, AI100151, AI102740, AI043542] FX This work, including the efforts of Catarina E. Hioe, was funded by U.S. Department of Veterans Affairs (VA) (Research Career Scientist Award). This work, including the efforts of Catarina E. Hioe, was funded by U.S. Department of Veterans Affairs (VA) (Merit Review Award). This work, including the efforts of Catarina E. Hioe, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (AI093210). This work, including the efforts of Catarina E. Hioe, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (AI100151). This work, including the efforts of Catarina E. Hioe, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (AI102740). This work, including the efforts of Michael L. Dustin, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (AI043542). NR 65 TC 0 Z9 0 U1 4 U2 4 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 DEC PY 2016 VL 90 IS 23 BP 10513 EP 10526 DI 10.1128/JVI.01532-16 PG 14 WC Virology SC Virology GA EE8VL UT WOS:000389904500007 PM 27630246 ER PT J AU Neal, JW Dahlberg, SE Wakelee, HA Aisner, SC Bowden, M Huang, Y Carbone, DP Gerstner, GJ Lerner, RE Rubin, JL Owonikoko, TK Stella, PJ Steen, PD Khalid, AA Ramalingam, SS AF Neal, Joel W. Dahlberg, Suzanne E. Wakelee, Heather A. Aisner, Seena C. Bowden, Michaela Huang, Ying Carbone, David P. Gerstner, Gregory J. Lerner, Rachel E. Rubin, Jerome L. Owonikoko, Taofeek K. Stella, Philip J. Steen, Preston D. Khalid, Ahmed Ali Ramalingam, Suresh S. CA ECOG-ACRIN 1512 Investigators TI Erlotinib, cabozantinib, or erlotinib plus cabozantinib as second-line or third-line treatment of patients with EGFR wild-type advanced non-small-cell lung cancer (ECOG-ACRIN 1512): a randomised, controlled, open-label, multicentre, phase 2 trial SO LANCET ONCOLOGY LA English DT Article ID MET AMPLIFICATION; III TRIAL; DOCETAXEL; CHEMOTHERAPY; RESISTANCE; INHIBITORS; THERAPY; AXL AB Background Erlotinib is approved for the treatment of all patients with advanced non-small-cell lung cancer (NSCLC), but is most active in the treatment of EGFR mutant NSCLC. Cabozantinib, a small molecule tyrosine kinase inhibitor, targets MET, VEGFR, RET, ROS1, and AXL, which are implicated in lung cancer tumorigenesis. We compared the efficacy of cabozantinib alone or in combination with erlotinib versus erlotinib alone in patients with EGFR wild-type NSCLC. Methods This three group, randomised, controlled, open-label, multicentre, phase 2 trial was done in 37 academic and community oncology practices in the USA. Patients were eligible if they had received one or two previous treatments for advanced non-squamous, EGFR wild-type, NSCLC. Patients were stratified by performance status and line of therapy, and randomly assigned using permuted blocks within strata to receive open-label oral daily dosing of erlotinib (150 mg), cabozantinib (60 mg), or erlotinib (150 mg) and cabozantinib (40 mg). Imaging was done every 8 weeks. At the time of radiographic progression, there was optional crossover for patients in either single-drug group to receive combination treatment. The primary endpoint was to compare progression-free survival in patients given erlotinib alone versus cabozantinib alone, and in patients given erlotinib alone versus the combination of erlotinib plus cabozantinib. We assessed the primary endpoint in the per-protocol population, which was defined as all patients who were eligible, randomly assigned, and received at least one dose of treatment. The safety analysis population included all patients who received study treatment irrespective of eligibility. This trial is registered with ClinicalTrials.gov, number NCT01708954. Findings Between Feb 7, 2013, and July 1, 2014, we enrolled and randomly assigned 42 patients to erlotinib treatment, 40 patients to cabozantinib treatment, and 43 patients to erlotinib plus cabozantinib treatment, of whom 111 (89%) in total were included in the primary analysis (erlotinib [n= 38], cabozantinib [n= 38], erlotinib plus cabozantinib [n= 35]). Compared with erlotinib alone (median 1.8 months [95% CI 1.7-2.2]), progression-free survival was significantly improved in the cabozantinib group (4.3 months [3.6-7.4]; hazard ratio [HR] 0.39, 80% CI 0.27-0.55; one-sided p= 0.0003) and in the erlotinib plus cabozantinib group (4.7 months [2.4-7.4]; HR 0.37, 0.25-0.53; one-sided p= 0.0003). Among participants included in the safety analysis of the erlotinib (n= 40), cabozantinib (n= 40), and erlotinib plus cabozantinib (n= 39) groups, the most common grade 3 or 4 adverse events were diarrhoea (three [8%] cases in the erlotinib group vs three [8%] in the cabozantinib group vs 11 [28%] in the erlotinib plus cabozantinib group), hypertension (none vs ten [25%] vs one [3%]), fatigue (five [13%] vs six [15%] vs six [15%]), oral mucositis (none vs four [10%] vs one [3%]), and thromboembolic event (none vs three [8%] vs two [5%]). One death due to respiratory failure occurred in the cabozantinib group, deemed possibly related to either drug, and one death due to pneumonitis occurred in the erlotinib plus cabozantinib group, deemed related to either drug or the combination. Interpretation Despite its small sample size, this trial showed that, in patients with EGFR wild-type NSCLC, cabozantinib alone or combined with erlotinib has clinically meaningful, superior efficacy to that of erlotinib alone, with additional toxicity that was generally manageable. Cabozantinib-based regimens are promising for further investigation in this patient population. C1 [Neal, Joel W.; Wakelee, Heather A.] Stanford Canc Inst, Stanford, CA 94305 USA. [Dahlberg, Suzanne E.; Bowden, Michaela; Huang, Ying] Dana Farber Canc Inst, Boston, MA 02115 USA. [Aisner, Seena C.] Rutgers Canc Inst New Jersey, Newark, NJ USA. [Carbone, David P.] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Gerstner, Gregory J.] Illinois CancerCare Peoria, Peoria, IL USA. [Lerner, Rachel E.] Pk Nicollet Clin, St Louis Pk, MN USA. [Rubin, Jerome L.] Community Hosp Monterey Peninsula, Monterey, CA USA. [Owonikoko, Taofeek K.; Ramalingam, Suresh S.] Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. [Stella, Philip J.] St Joseph Mercy Hosp, Ann Arbor, MI 48104 USA. [Steen, Preston D.] Roger Maris Canc Ctr, Fargo, ND USA. [Khalid, Ahmed Ali] Charleston Area Med Ctr, Charleston, WV USA. RP Neal, JW (reprint author), Stanford Canc Inst, Stanford, CA 94305 USA. EM jwneal@stanford.edu FU ECOG-ACRIN Cancer Research Group, National Cancer Institute of the National Institutes of Health FX ECOG-ACRIN Cancer Research Group, National Cancer Institute of the National Institutes of Health. NR 29 TC 0 Z9 0 U1 5 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD DEC PY 2016 VL 17 IS 12 BP 1661 EP 1671 DI 10.1016/S1470-2045(16)30561-7 PG 11 WC Oncology SC Oncology GA EE3YG UT WOS:000389537700035 PM 27825638 ER PT J AU Gettinger, SN Bazhenova, LA Langer, CJ Salgia, R Gold, KA Rosell, R Shaw, AT Weiss, GJ Tugnait, M Narasimhan, NI Dorer, DJ Kerstein, D Rivera, VM Clackson, T Haluska, FG Camidge, DR AF Gettinger, Scott N. Bazhenova, Lyudmila A. Langer, Corey J. Salgia, Ravi Gold, Kathryn A. Rosell, Rafael Shaw, Alice T. Weiss, Glen J. Tugnait, Meera Narasimhan, Narayana I. Dorer, David J. Kerstein, David Rivera, Victor M. Clackson, Timothy Haluska, Frank G. Camidge, David Ross TI Activity and safety of brigatinib in ALK-rearranged non-small-cell lung cancer and other malignancies: a single-arm, open-label, phase 1/2 trial SO LANCET ONCOLOGY LA English DT Article ID CRIZOTINIB-RESISTANT; DOSE PROPORTIONALITY; BRAIN METASTASES; TYROSINE KINASE; CHEMOTHERAPY; EXPERIENCE; INHIBITORS; MUTATIONS; CERITINIB; ALECTINIB AB Background Anaplastic lymphoma kinase (ALK) gene rearrangements are oncogenic drivers of non-small-cell lung cancer (NSCLC). Brigatinib (AP26113) is an investigational ALK inhibitor with potent preclinical activity against ALK mutants resistant to crizotinib and other ALK inhibitors. We aimed to assess brigatinib in patients with advanced malignancies, particularly ALK-rearranged NSCLC. Methods In this ongoing, single-arm, open-label, phase 1/2 trial, we recruited patients from nine academic hospitals or cancer centres in the USA and Spain. Eligible patients were at least 18 years of age and had advanced malignancies, including ALK-rearranged NSCLC, and disease that was refractory to available therapies or for which no curative treatments existed. In the initial dose-escalation phase 1 stage of the trial, patients received oral brigatinib at total daily doses of 30-300 mg (according to a standard 3 + 3 design). The phase 1 primary endpoint was establishment of the recommended phase 2 dose. In the phase 2 expansion stage, we assessed three oral once-daily regimens: 90 mg, 180 mg, and 180 mg with a 7 day lead-in at 90 mg; one patient received 90 mg twice daily. We enrolled patients in phase 2 into five cohorts: ALK inhibitor-naive ALK-rearranged NSCLC (cohort 1), crizotinib-treated ALK-rearranged NSCLC (cohort 2), EGFR(T790M)-positive NSCLC and resistance to one previous EGFR tyrosine kinase inhibitor (cohort 3), other cancers with abnormalities in brigatinib targets (cohort 4), and crizotinib-naive or crizotinib-treated ALK-rearranged NSCLC with active, measurable, intracranial CNS metastases (cohort 5). The phase 2 primary endpoint was the proportion of patients with an objective response. Safety and activity of brigatinib were analysed in all patients in both phases of the trial who had received at least one dose of treatment. This trial is registered with ClinicalTrials.gov, number NCT01449461. Findings Between Sept 20, 2011, and July 8, 2014, we enrolled 137 patients (79 [58%] with ALK-rearranged NSCLC), all of whom were treated. Dose-limiting toxicities observed during dose escalation included grade 3 increased alanine aminotransferase (240 mg daily) and grade 4 dyspnoea (300 mg daily). We initially chose a dose of 180 mg once daily as the recommended phase 2 dose; however, we also assessed two additional regimens (90 mg once daily and 180 mg once daily with a 7 day lead-in at 90 mg) in the phase 2 stage. Four (100% [95% CI 40-100]) of four patients in cohort 1 had an objective response, 31 (74% [58-86]) of 42 did in cohort 2, none (of one) did in cohort 3, three (17% [4-41]) of 18 did in cohort 4, and five (83% [36-100]) of six did in cohort 5. 51 (72% [60-82]) of 71 patients with ALK-rearranged NSCLC with previous crizotinib treatment had an objective response (44 [62% (50-73)] had a confirmed objective response). All eight crizotinib-naive patients with ALK-rearranged NSCLC had a confirmed objective response (100% [63-100]). Three (50% [95% CI 12-88]) of six patients in cohort 5 had an intracranial response. The most common grade 3-4 treatment-emergent adverse events across all doses were increased lipase concentration (12 [9%] of 137), dyspnoea (eight [6%]), and hypertension (seven [5%]). Serious treatment-emergent adverse events (excluding neoplasm progression) reported in at least 5% of all patients were dyspnoea (ten [7%]), pneumonia (nine [7%]), and hypoxia (seven [5%]). 16 (12%) patients died during treatment or within 31 days of the last dose of brigatinib, including eight patients who died from neoplasm progression. Interpretation Brigatinib shows promising clinical activity and has an acceptable safety profile in patients with crizotinib-treated and crizotinib-naive ALK-rearranged NSCLC. These results support its further development as a potential new treatment option for patients with advanced ALK-rearranged NSCLC. A randomised phase 2 trial in patients with crizotinib-resistant ALK-rearranged NSCLC is prospectively assessing the safety and efficacy of two regimens assessed in the phase 2 portion of this trial (90 mg once daily and 180 mg once daily with a 7 day lead-in at 90 mg). C1 [Gettinger, Scott N.] Yale Canc Ctr, Yale Sch Med, New Haven, CT 06520 USA. [Bazhenova, Lyudmila A.; Gold, Kathryn A.] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. [Langer, Corey J.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Salgia, Ravi] City Hope Natl Med Ctr, Dept Med Oncol & Therapeut Res, Duarte, CA USA. [Rosell, Rafael] Germans Trias & Pujol Hlth Sci Inst & Hosp, Catalan Inst Oncol, Badalona, Spain. [Shaw, Alice T.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Weiss, Glen J.] Canc Treatment Ctr Amer, Western Reg Med Ctr, Goodyear, AZ USA. [Tugnait, Meera; Narasimhan, Narayana I.; Dorer, David J.; Kerstein, David; Rivera, Victor M.; Clackson, Timothy; Haluska, Frank G.] ARIAD Pharmaceut, Cambridge, MA USA. [Camidge, David Ross] Univ Colorado, Ctr Canc, Aurora, CO USA. RP Gettinger, SN (reprint author), Yale Canc Ctr, Yale Sch Med, New Haven, CT 06520 USA. EM scott.gettinger@yale.edu FU ARIAD Pharmaceuticals FX ARIAD Pharmaceuticals. NR 30 TC 10 Z9 10 U1 5 U2 5 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 DEC PY 2016 VL 17 IS 12 BP 1683 EP 1696 DI 10.1016/S1470-2045(16)30392-8 PG 14 WC Oncology SC Oncology GA EE3YG UT WOS:000389537700037 PM 27836716 ER PT J AU Bhagra, A Tierney, DM Sekiguchi, H Soni, NJ AF Bhagra, Anjali Tierney, David M. Sekiguchi, Hiroshi Soni, Nilam J. TI Point-of-Care Ultrasonography for Primary Care Physicians and General Internists SO MAYO CLINIC PROCEEDINGS LA English DT Review ID HAND-CARRIED ULTRASOUND; RIGHT ATRIAL PRESSURE; INFERIOR VENA-CAVA; LEFT-VENTRICULAR FUNCTION; CENTRAL VENOUS-PRESSURE; DEEP-VEIN THROMBOSIS; LUNG ULTRASOUND; DIAGNOSTIC-ACCURACY; BEDSIDE ULTRASOUND; CARDIAC ULTRASOUND AB Point-of-care ultrasonography (POCUS) is a safe and rapidly evolving diagnostic modality that is now utilized by health care professionals from nearly all specialties. Technological advances have improved the portability of equipment, enabling ultrasound imaging to be executed at the bedside and thereby allowing internists to make timely diagnoses and perform ultrasound-guided procedures. We reviewed the literature on the POCUS applications most relevant to the practice of internal medicine. The use of POCUS can immediately narrow differential diagnoses by building on the clinical information revealed by the traditional physical examination and refining clinical decision making for further management. We describe 2 common patient scenarios (heart failure and sepsis) to highlight the impact of POCUS performed by internists on efficiency, diagnostic accuracy, resource utilization, and radiation exposure. Using POCUS to guide procedures has been found to reduce procedure-related complications, along with costs and lengths of stay associated with these complications. Despite several undisputed advantages of POCUS, barriers to implementation must be considered. Most importantly, the utility of POCUS depends on the experience and skills of the operator, which are affected by the availability of training and the cost of ultrasound devices. Additional system barriers include availability of templates for documentation, electronic storage for image archiving, and policies and procedures for quality assurance and billing. Integration of POCUS into the practice of internal medicine is an inevitable change that will empower internists to improve the care of their patients at the bedside. (C) 2016 Mayo Foundation for Medical Education and Research C1 [Bhagra, Anjali] Mayo Clin, Dept Med, Div Gen Internal Med, Rochester, MN USA. [Sekiguchi, Hiroshi] Mayo Clin, Dept Med, Div Pulm & Crit Care Med, Rochester, MN USA. [Tierney, David M.] Abbott NorthWeast Hosp, Med Educ Dept, Minneapolis, MN USA. [Soni, Nilam J.] Univ Texas San Antonio, Hlth Sci Ctr, South Texas Vet Hlth Care Syst, Sect Hosp Med, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. Univ Texas San Antonio, Hlth Sci Ctr, Div Pulm Dis & Crit Care Med, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. RP Bhagra, A (reprint author), Mayo Clin, Div Gen Internal Med, 200 First St SW, Rochester, MN 55905 USA. EM bhagra.anjali@mayo.edu NR 136 TC 0 Z9 0 U1 8 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0025-6196 EI 1942-5546 J9 MAYO CLIN PROC JI Mayo Clin. Proc. PD DEC PY 2016 VL 91 IS 12 BP 1811 EP 1827 DI 10.1016/j.mayocp.2016.08.023 PG 17 WC Medicine, General & Internal SC General & Internal Medicine GA EE3YW UT WOS:000389539500018 PM 27825617 ER PT J AU Steensma, DP Kyle, RA AF Steensma, David P. Kyle, Robert A. TI Hendrik van Deventer: Dutch Obstetrician and Orthopedist SO MAYO CLINIC PROCEEDINGS LA English DT Editorial Material C1 [Steensma, David P.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Kyle, Robert A.] Mayo Clin, Rochester, MN USA. RP Steensma, DP (reprint author), Dana Farber Canc Inst, Boston, MA 02215 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 0025-6196 EI 1942-5546 J9 MAYO CLIN PROC JI Mayo Clin. Proc. PD DEC PY 2016 VL 91 IS 12 BP E171 EP E171 DI 10.1016/j.mayocp.2016.10.017 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA EE3YW UT WOS:000389539500004 PM 27916164 ER PT J AU Naidoo, U AF Naidoo, Uma TI Learning more about food, mental health, and menopause SO MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY LA English DT Editorial Material ID DEPRESSION; PATTERNS C1 [Naidoo, Uma] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02115 USA. [Naidoo, Uma] Cambridge Sch Culinary Arts, Cambridge, MA 02140 USA. RP Naidoo, U (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02115 USA.; Naidoo, U (reprint author), Cambridge Sch Culinary Arts, Cambridge, MA 02140 USA. NR 10 TC 0 Z9 0 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1072-3714 EI 1530-0374 J9 MENOPAUSE JI Menopause-J. N. Am. Menopause Soc. PD DEC PY 2016 VL 23 IS 12 BP 1275 EP 1276 DI 10.1097/GME.0000000000000792 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EE0HC UT WOS:000389254000004 PM 27824683 ER PT J AU Hickey, M Schoenaker, DAJM Joffe, H Mishra, GD AF Hickey, Martha Schoenaker, Danielle A. J. M. Joffe, Hadine Mishra, Gita D. TI Depressive symptoms across the menopause transition: findings from a large population-based cohort study SO MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY LA English DT Article DE CESD-10; Depressive symptoms; Latent class analysis; Menopause ID NATIONAL COMORBIDITY SURVEY; WOMENS HEALTH; NATURAL MENOPAUSE; HORMONE-THERAPY; LIFETIME PREVALENCE; MAJOR DEPRESSION; MIDLIFE; MOOD; DISCONTINUATION; ONSET AB Objective: The aim of the study was to describe the trajectories of depressive symptoms in a large population-based cohort of midaged women, and to examine the associations of current and changing reproductive stage with depressive symptoms over time. Methods: Prospective, population-based cohort study of 13,715 women aged 45 to 50 years followed up for over 15 years (Australian Longitudinal Study on Women's Health). Nearly 6,000 women provided complete data for this study. Menopause status was determined from questionnaires about hysterectomy, oophorectomy, hormone therapy, and menstrual patterns. Depressive symptoms were measured using the Center for Epidemiologic Studies Depression scale (CESD-10). Results: Latent class analysis indicated four distinct profiles of CESD-10 scores over 15 years: stable low (80.0%), increasing (9.0%), decreasing (8.5%), and stable high (2.5%). Those with "increasing'' depressive symptoms were more likely to have had bilateral salpingo-oophorectomy or be perimenopausal at baseline compared with women in the "stable low'' group. Depressive symptoms were higher in perimenopausal women, (higher CESD-10 score of 0.19, 95% CI 0.02, 0.31), after hysterectomy alone (0.53, 95% CI 0.31, 0.74), bilateral salpingo-oophorectomy with/without hysterectomy (0.85, 95% CI 0.58, 1.12), hormone therapy users (0.19, 95% CI 0.01, 0.36), and after starting or stopping hormone therapy compared with postmenopausal women (adjusted for sociodemographic factors, vasomotor symptoms, health behaviors, and history of depression diagnosis or treatment). Conclusions: Depressive symptoms follow distinct trajectories across the menopause transition. Most women have stable symptoms, but around 9% have increasing symptoms and a similar proportion (8.5%) decreasing symptoms. Increasing depressive symptoms were independent of vasomotor symptoms but were associated with oophorectomy and stopping or starting hormone therapy. A large number of women were excluded due to missing data, and thus the results should be interpreted with caution. C1 [Hickey, Martha] Univ Melbourne, Royal Womens Hosp, Dept Obstet & Gynaecol, Melbourne, Vic, Australia. [Schoenaker, Danielle A. J. M.; Mishra, Gita D.] Univ Queensland, Sch Publ Hlth, Ctr Longitudinal & Life Course Res, Herston, Qld, Australia. [Joffe, Hadine] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA USA. [Joffe, Hadine] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA USA. [Joffe, Hadine] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. RP Hickey, M (reprint author), Univ Melbourne, Royal Womens Hosp, Dept Obstet & Gynaecol, Level 7,Locked Bag 300, Parkville, Vic 3052, Australia. EM hickeym@unimelb.edu.au FU Australian Commonwealth Department of Health; National Health and Medical Research Council (NHMRC) Practitioner Fellowship Award [APP1058935]; Australian Research Council (ARC) Future Fellowship [FT120100812] FX The Australian Longitudinal Study on Women's Health is funded by the Australian Commonwealth Department of Health. M.H. was supported by an National Health and Medical Research Council (NHMRC) Practitioner Fellowship Award (APP1058935). G.M. was supported by an Australian Research Council (ARC) Future Fellowship (FT120100812). NR 38 TC 1 Z9 1 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1072-3714 EI 1530-0374 J9 MENOPAUSE JI Menopause-J. N. Am. Menopause Soc. PD DEC PY 2016 VL 23 IS 12 BP 1287 EP 1293 DI 10.1097/GME.0000000000000712 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EE0HC UT WOS:000389254000006 PM 27552471 ER PT J AU McCurry, SM LaCroix, AZ Mitchell, C AF McCurry, Susan M. LaCroix, Andrea Z. Mitchell, Caroline TI Improving Sleep and Vaginal Health in Symptomatic Midlife Women Evidence from the MsFLASH Trials SO MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY LA English DT Meeting Abstract CT 27th Annual Meeting of the North-American-Menopause-Society CY OCT 05-08, 2016 CL Orlando, FL SP N Amer Menopause Soc C1 [McCurry, Susan M.] Univ Washington, Seattle, WA 98195 USA. [LaCroix, Andrea Z.] Univ Calif San Diego, San Diego, CA 92103 USA. [Mitchell, Caroline] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1072-3714 EI 1530-0374 J9 MENOPAUSE JI Menopause-J. N. Am. Menopause Soc. PD DEC PY 2016 VL 23 IS 12 BP 1365 EP 1366 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA EE0HC UT WOS:000389254000025 ER PT J AU Coy, S Du, ZM Sheu, SH Woo, T Rodriguez, FJ Kieran, MW Santagata, S AF Coy, Shannon Du, Ziming Sheu, Shu-Hsien Woo, Terri Rodriguez, Fausto J. Kieran, Mark W. Santagata, Sandro TI Distinct patterns of primary and motile cilia in Rathke's cleft cysts and craniopharyngioma subtypes SO MODERN PATHOLOGY LA English DT Article ID BRAF V600E MUTATIONS; PAPILLARY CRANIOPHARYNGIOMA; ADAMANTINOMATOUS CRANIOPHARYNGIOMA; TRANSCRIPTION FACTORS; PANCREATIC-CANCER; CELLS; LESIONS; CILIOGENESIS; EXPRESSION; IDENTIFICATION AB Cilia are highly conserved organelles, which serve critical roles in development and physiology. Motile cilia are expressed in a limited range of tissues, where they principally regulate local extracellular fluid dynamics. In contrast, primary cilia are expressed by many vertebrate cell types during interphase, and are intimately involved in the cell cycle and signal transduction. Notably, primary cilia are essential for vertebrate hedgehog pathway activity. Improved detection of motile cilia may assist in the diagnosis of some pathologic entities such as Rathke's cleft cysts, whereas characterizing primary cilia in neoplastic tissues may implicate cilia-dependent signaling pathways as critical for tumorigenesis. We show that immunohistochemistry for the nuclear transcription factor FOXJ1, a master regulator of motile ciliogenesis, robustly labels the motile ciliated epithelium of Rathke's cleft cysts. FOXJ1 expression discriminates Rathke's cleft cysts from entities in the sellar/suprasellar region with overlapping histologic features such as craniopharyngiomas. Co-immunohistochemistry for FOXJ1 and markers that highlight motile cilia such as acetylated tubulin (TUBA4A) and the small GTPase ARL13B further enhance the ability to identify diagnostic epithelial cells. In addition to highlighting motile cilia, ARL13B immunohistochemistry also robustly highlights primary cilia in formalin-fixed paraffin-embedded sections. Primary cilia are present throughout the neoplastic epithelium of adamantinomatous craniopharyngioma, but are limited to basally oriented cells near the fibrovascular stroma in papillary craniopharyngioma. Consistent with this differing pattern of primary ciliation, adamantinomatous craniopharyngiomas express significantly higher levels of SHH, and downstream targets such as PTCH1 and GLI2, compared with papillary craniopharyngiomas. In conclusion, motile ciliated epithelium can be readily identified using immunohistochemistry for FOXJ1, TUBA4A, and ARL13B, facilitating the diagnosis of Rathke's cleft cysts. Primary cilia can be identified by 'ARL13B immunohistochemistry in routine pathology specimens. The widespread presence of primary cilia in adamantinomatous craniopharyngioma implicates cilia-dependent hedgehog signaling in the pathogenesis of adamantinomatous craniopharyngioma. C1 [Coy, Shannon; Du, Ziming; Woo, Terri; Santagata, Sandro] Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, Boston, MA USA. [Sheu, Shu-Hsien; Santagata, Sandro] Harvard Med Sch, Boston Childrens Hosp, Dept Pathol, Boston, MA USA. [Rodriguez, Fausto J.] Johns Hopkins Univ, Dept Pathol, Baltimore, MD USA. [Kieran, Mark W.] Harvard Med Sch, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA USA. [Santagata, Sandro] Harvard Med Sch, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA USA. [Santagata, Sandro] Harvard Med Sch, Ludwig Ctr Harvard, Boston, MA USA. RP Santagata, S (reprint author), Brigham & Womens Hosp, Div Neuropathol, Dept Pathol, 75 Francis St,Amory 3, Boston, MA 02115 USA. EM ssantagata@bics.bwh.harvard.edu FU NCI Cancer Center [NIH 5 P30 CA06516]; Jared Branfman Sunflowers for Life Fund for Pediatric Brain and Spinal Cancer Research; Ludwig Center at Harvard FX We thank members of the Santagata lab for helpful discussions, Christopher Crum for advice on marker development, and Marian Slaney, Karen Bryan, and Sebastian Valentin for technical assistance with tissue processing. This study was supported by the Jared Branfman Sunflowers for Life Fund for Pediatric Brain and Spinal Cancer Research (SS) and the Ludwig Center at Harvard (SS). We thank Dana-Farber/Harvard Cancer Center in Boston, MA, USA, for the use of the Specialized Histopathology Core, which provided tissue imaging services. DanaFarber/Harvard Cancer Center is supported in part by an NCI Cancer Center Support Grant # NIH 5 P30 CA06516. NR 49 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD DEC PY 2016 VL 29 IS 12 BP 1446 EP 1459 DI 10.1038/modpathol.2016.153 PG 14 WC Pathology SC Pathology GA EE2CL UT WOS:000389391200001 PM 27562488 ER PT J AU Alam, M Bouillez, A Tagde, A Ahmad, R Rajabi, H Maeda, T Hiraki, M Suzuki, Y Kufe, D AF Alam, Maroof Bouillez, Audrey Tagde, Ashujit Ahmad, Rehan Rajabi, Hasan Maeda, Takahiro Hiraki, Masayuki Suzuki, Yozo Kufe, Donald TI MUC1-C Represses the Crumbs Complex Polarity Factor CRB3 and Downregulates the Hippo Pathway SO MOLECULAR CANCER RESEARCH LA English DT Article ID BREAST-CANCER CELLS; BETA-CATENIN; TRANSCRIPTION FACTOR; WNT/BETA-CATENIN; MONOCLONAL-ANTIBODY; SIGNALING PATHWAYS; ONCOPROTEIN; ACTIVATION; INHIBITION; GROWTH AB Apical-basal polarity and epithelial integrity are maintained in part by the Crumbs (CRB) complex. The C-terminal subunit of MUC1 (MUC1-C) is a transmembrane protein that is expressed at the apical border of normal epithelial cells and aberrantly at high levels over the entire surface of their transformed counterparts. However, it is not known whether MUC1-C contributes to this loss of polarity that is characteristic of carcinoma cells. Here it is demonstrated that MUC1-C downregulates expression of the Crumbs complex CRB3 protein in triple-negative breast cancer ( TNBC) cells. MUC1-C associates with ZEB1 on the CRB3 promoter and represses CRB3 transcription. Notably, CRB3 activates the core kinase cassette of the Hippo pathway, which includes LATS1 and LATS2. In this context, targeting MUC1-C was associated with increased phosphorylation of LATS1, consistent with activation of the Hippo pathway, which is critical for regulating cell contact, tissue repair, proliferation, and apoptosis. Also shown is that MUC1-C-mediated suppression of CRB3 and the Hippo pathway is associated with dephosphorylation and activation of the oncogenic YAP protein. In turn, MUC1-C interacts with YAP, promotes formation of YAP/beta-catenin complexes, and induces the WNT target gene MYC. These data support a previously unrecognized pathway in which targetingMUC1-C inTNBC cells (i) induces CRB3 expression, (ii) activates the CRB3-driven Hippo pathway, (iii) inactivates YAP, and thereby (iv) suppresses YAP/b-catenin-mediated induction of MYC expression. (C) 2016 AACR. C1 [Alam, Maroof; Bouillez, Audrey; Tagde, Ashujit; Ahmad, Rehan; Rajabi, Hasan; Maeda, Takahiro; Hiraki, Masayuki; Suzuki, Yozo; Kufe, Donald] Harvard Med Sch, Dana Farber Canc Inst, 450 Brookline Ave,Dana 830, Boston, MA 02215 USA. [Ahmad, Rehan] King Saud Univ, Coll Med, Riyadh, Saudi Arabia. [Suzuki, Yozo] Osaka Police Hosp, Dept Gastroenterol Surg, Osaka, Japan. RP Kufe, D (reprint author), Harvard Med Sch, Dana Farber Canc Inst, 450 Brookline Ave,Dana 830, Boston, MA 02215 USA. EM donald_kufe@dfci.harvard.edu FU National Cancer Institute of the NIH [CA97098, CA166480]; Lung Cancer Research Foundation FX Research reported in this publication was supported by the National Cancer Institute of the NIH under award numbers CA97098 and CA166480 and the Lung Cancer Research Foundation. NR 51 TC 1 Z9 1 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1541-7786 EI 1557-3125 J9 MOL CANCER RES JI Mol. Cancer Res. PD DEC PY 2016 VL 14 IS 12 BP 1266 EP 1276 DI 10.1158/1541-7786.MCR-16-0233 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA EE5GE UT WOS:000389632700010 PM 27658423 ER PT J AU Pasternak, A Sideridis, G Fragala-Pinkham, M Glanzman, AM Montes, J Dunaway, S Salazar, R Quigley, J Pandya, S O'Riley, S Greenwood, J Chiriboga, C Finkel, R Tennekoon, G Martens, WB McDermott, MP Fournier, H Madabusi, L Harrington, T Cruz, RE Lamarca, NM Videon, NM De Vivo, DC Darras, BT AF Pasternak, Amy Sideridis, Georgios Fragala-Pinkham, Maria Glanzman, Allan M. Montes, Jacqueline Dunaway, Sally Salazar, Rachel Quigley, Janet Pandya, Shree O'Riley, Susan Greenwood, Jonathan Chiriboga, Claudia Finkel, Richard Tennekoon, Gihan Martens, William B. McDermott, Michael P. Fournier, Heather (Szelag) Madabusi, Lavanya Harrington, Timothy Cruz, Rosangel E. Lamarca, Nicole M. Videon, Nancy M. De Vivo, Darryl C. Darras, Basil T. CA Muscle Study Grp MSG Pediat Neuromuscular Clin Res TI RASCH ANALYSIS OF THE PEDIATRIC EVALUATION OF DISABILITY INVENTORY-COMPUTER ADAPTIVE TEST (PEDI-CAT) ITEM BANK FOR CHILDREN AND YOUNG ADULTS WITH SPINAL MUSCULAR ATROPHY SO MUSCLE & NERVE LA English DT Article DE capacity measures; caregiver-reported outcome measures; computer adaptive testing; Pediatric Evaluation of Disability Inventory-Computer Adaptive Test; Rasch analysis; spinal muscular atrophy ID FUNCTIONAL MOTOR SCALE; QUALITY-OF-LIFE; CLINICAL-TRIALS; CEREBRAL-PALSY; PERFORMANCE; CAPABILITY; CAPACITY; DISEASE; RESPONSIVENESS; ADOLESCENTS AB Introduction: In this study we evaluated the suitability of a caregiver-reported functional measure, the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDI-CAT), for children and young adults with spinal muscular atrophy (SMA). Methods: PEDI-CAT Mobility and Daily Activities domain item banks were administered to 58 caregivers of children and young adults with SMA. Rasch analysis was used to evaluate test properties across SMA types. Results: Unidimensional content for each domain was confirmed. The PEDI-CAT was most informative for type III SMA, with ability levels distributed close to 0.0 logits in both domains. It was less informative for types I and II SMA, especially for mobility skills. Item and person abilities were not distributed evenly across all types. Conclusions: The PEDI-CAT may be used to measure functional performance in SMA, but additional items are needed to identify small changes in function and best represent the abilities of all types of SMA. C1 [Pasternak, Amy; Quigley, Janet; Greenwood, Jonathan] Boston Childrens Hosp, Dept Phys Therapy & Occupat Therapy Serv, 300 Longwood Ave, Boston, MA USA. [Sideridis, Georgios] Harvard Med Sch, Boston Childrens Hosp, Dept Med, Clin Res Ctr, Boston, MA USA. [Sideridis, Georgios] Harvard Med Sch, Boston Childrens Hosp, Div Dev Med, Boston, MA USA. [Fragala-Pinkham, Maria] Franciscan Hosp Children, Res Ctr Children Special Hlth Care Needs, Brighton, MA USA. [Glanzman, Allan M.] Childrens Hosp Philadelphia, Dept Phys Therapy, Philadelphia, PA 19104 USA. [Montes, Jacqueline; Dunaway, Sally] Columbia Univ, Med Ctr, Dept Rehabil & Regenerat Med, New York, NY USA. [Montes, Jacqueline; Dunaway, Sally; Salazar, Rachel; Chiriboga, Claudia; Cruz, Rosangel E.; Lamarca, Nicole M.; De Vivo, Darryl C.] Columbia Univ, Dept Neurol, Med Ctr, New York, NY USA. [Pandya, Shree; Martens, William B.; McDermott, Michael P.] Univ Rochester, Dept Neurol, Rochester, NY USA. [O'Riley, Susan] Massachusetts Gen Hosp, Dept Phys & Occupat Therapy, Boston, MA 02114 USA. [Finkel, Richard] Nemours Childrens Hosp, Dept Pediat, Orlando, FL USA. [Tennekoon, Gihan; Videon, Nancy M.] Childrens Hosp Philadelphia, Dept Neurol, Philadelphia, PA 19104 USA. [Tennekoon, Gihan; Videon, Nancy M.] Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA. [McDermott, Michael P.] Univ Rochester, Dept Biostat & Computat Biol, New York, NY USA. [Fournier, Heather (Szelag); Madabusi, Lavanya; Harrington, Timothy; Darras, Basil T.] Harvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA USA. RP Pasternak, A (reprint author), Boston Childrens Hosp, Dept Phys Therapy & Occupat Therapy Serv, 300 Longwood Ave, Boston, MA USA. EM amy.pasternak@childrens.harvard.edu FU Spinal Muscular Atrophy Foundation FX The project was supported by the Spinal Muscular Atrophy Foundation. NR 40 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0148-639X EI 1097-4598 J9 MUSCLE NERVE JI Muscle Nerve PD DEC PY 2016 VL 54 IS 6 BP 1097 EP 1107 DI 10.1002/mus.25164 PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA EE5DO UT WOS:000389625300019 PM 27121348 ER PT J AU Munoz-Fontela, C Mandinova, A Aaronson, SA Lee, SW AF Munoz-Fontela, Cesar Mandinova, Anna Aaronson, Stuart A. Lee, Sam W. TI Emerging roles of p53 and other tumour-suppressor genes in immune regulation SO NATURE REVIEWS IMMUNOLOGY LA English DT Review ID NF-KAPPA-B; SYSTEMIC-LUPUS-ERYTHEMATOSUS; NONHEMATOPOIETIC CANCER-CELLS; FAS-MEDIATED APOPTOSIS; LEUKOCYTE MARKER CD43; TOLL-LIKE RECEPTOR-3; INFLUENZA-A VIRUS; AUTOIMMUNE-DISEASES; ANTITUMOR IMMUNITY; DENDRITIC-CELL AB Tumour-suppressor genes are indispensable for the maintenance of genomic integrity. Recently, several of these genes, including those encoding p53, PTEN, RB1 and ARF, have been implicated in immune responses and inflammatory diseases. In particular, the p53 tumour-suppressor pathway is involved in crucial aspects of tumour immunology and in homeostatic regulation of immune responses. Other studies have identified roles for p53 in various cellular processes, including metabolism and stem cell maintenance. Here, we discuss the emerging roles of p53 and other tumour-suppressor genes in tumour immunology, as well as in additional immunological settings, such as virus infection. This relatively unexplored area could yield important insights into the homeostatic control of immune cells in health and disease and facilitate the development of more effective immunotherapies. Consequently, tumour-suppressor genes are emerging as potential guardians of immune integrity. C1 [Munoz-Fontela, Cesar] Leibniz Inst Expt Virol, Heinrich Pette Inst, Martinistr 52, D-20251 Hamburg, Germany. [Mandinova, Anna; Lee, Sam W.] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Bldg 149 13th St, Charlestown, MA 02129 USA. [Mandinova, Anna; Lee, Sam W.] Harvard Med Sch, Bldg 149 13th St, Charlestown, MA 02129 USA. [Mandinova, Anna] Harvard Stem Cell Inst, 7 Divin Ave, Cambridge, MA 02138 USA. [Mandinova, Anna; Lee, Sam W.] Broad Inst Harvard & MIT, 7 Cambridge Ctr, Cambridge, MA 02142 USA. [Aaronson, Stuart A.] Mt Sinai Sch Med, Dept Oncol Sci, One Gustave L Levy Pl, New York, NY 10029 USA. RP Lee, SW (reprint author), Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Bldg 149 13th St, Charlestown, MA 02129 USA.; Lee, SW (reprint author), Harvard Med Sch, Bldg 149 13th St, Charlestown, MA 02129 USA.; Lee, SW (reprint author), Broad Inst Harvard & MIT, 7 Cambridge Ctr, Cambridge, MA 02142 USA.; Aaronson, SA (reprint author), Mt Sinai Sch Med, Dept Oncol Sci, One Gustave L Levy Pl, New York, NY 10029 USA. EM stuart.aaronson@mssm.edu; swlee@mgh.harvard.edu FU Breast Cancer Research Foundation; MGH ECOR; [1RO1CA195534]; [1R01CA203552]; [PO1CA80058] FX The authors thank the members of the Lee laboratory for their helpful discussions. This work is supported by the grants 1RO1CA195534, 1R01CA203552, PO1CA80058, MGH ECOR funding, and the Breast Cancer Research Foundation. NR 191 TC 2 Z9 2 U1 15 U2 15 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1733 EI 1474-1741 J9 NAT REV IMMUNOL JI Nat. Rev. Immunol. PD DEC PY 2016 VL 16 IS 12 BP 741 EP 750 DI 10.1038/nri.2016.99 PG 10 WC Immunology SC Immunology GA ED8PX UT WOS:000389134500009 PM 27667712 ER PT J AU Sati, P Oh, J Constable, RT Evangelou, N Guttmann, CRG Henry, RG Klawiter, EC Mainero, C Massacesi, L McFarland, H Nelson, F Ontaneda, D Rauscher, A Rooney, WD Samaraweera, APR Shinohara, RT Sobel, RA Solomon, AJ Treaba, CA Wuerfel, J Zivadinov, R Sicotte, NL Pelletier, D Reich, DS AF Sati, Pascal Oh, Jiwon Constable, R. Todd Evangelou, Nikos Guttmann, Charles R. G. Henry, Roland G. Klawiter, Eric C. Mainero, Caterina Massacesi, Luca McFarland, Henry Nelson, Flavia Ontaneda, Daniel Rauscher, Alexander Rooney, William D. Samaraweera, Amal P. R. Shinohara, Russell T. Sobel, Raymond A. Solomon, Andrew J. Treaba, Constantina A. Wuerfel, Jens Zivadinov, Robert Sicotte, Nancy L. Pelletier, Daniel Reich, Daniel S. CA NIAMS Cooperative TI The central vein sign and its clinical evaluation for the diagnosis of multiple sclerosis: a consensus statement from the North American Imaging in Multiple Sclerosis Cooperative SO NATURE REVIEWS NEUROLOGY LA English DT Review ID WHITE-MATTER LESIONS; CERVICAL-SPINAL CORD; MS LESIONS; 7 TESLA; BRAIN-LESIONS; PREDICT CONVERSION; PARENCHYMAL VEINS; MCDONALD CRITERIA; HIGH-RESOLUTION; FLAIR-ASTERISK AB Over the past few years, MRI has become an indispensable tool for diagnosing multiple sclerosis (MS). However, the current MRI criteria for MS diagnosis have imperfect sensitivity and specificity. The central vein sign (CVS) has recently been proposed as a novel MRI biomarker to improve the accuracy and speed of MS diagnosis. Evidence indicates that the presence of the CVS in individual lesions can accurately differentiate MS from other diseases that mimic this condition. However, the predictive value of the CVS for the development of clinical MS in patients with suspected demyelinating disease is still unknown. Moreover, the lack of standardization for the definition and imaging of the CVS currently limits its clinical implementation and validation. On the basis of a thorough review of the existing literature on the CVS and the consensus opinion of the members of the North American Imaging in Multiple Sclerosis (NAIMS) Cooperative, this article provides statements and recommendations aimed at helping radiologists and neurologists to better understand, refine, standardize and evaluate the CVS in the diagnosis of MS. C1 [Sati, Pascal; McFarland, Henry; Reich, Daniel S.] NINDS, Translat Neuroradiol Sect, NIH, 10 Ctr Dr MSC 1400,Bldg 10 Room 5C103, Bethesda, MD 20892 USA. [Oh, Jiwon] Univ Toronto, St Michaels Hosp, Toronto, ON, Canada. [Oh, Jiwon] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. [Constable, R. Todd] Yale Univ, Dept Diagnost Radiol, New Haven, CT 06510 USA. [Evangelou, Nikos; Samaraweera, Amal P. R.] Univ Nottingham, Dept Clin Neurosci, Nottingham, England. [Guttmann, Charles R. G.] Harvard Med Sch, Brigham & Womens Hosp, Dept Radiol, Ctr Neurol Imaging, Boston, MA USA. [Henry, Roland G.] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [Klawiter, Eric C.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Boston, MA USA. [Mainero, Caterina; Treaba, Constantina A.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA USA. [Massacesi, Luca] Univ Florence, Dept Neurosci Psychol Drug Res & Child Hlth, Florence, Italy. [Nelson, Flavia] Univ Texas Hlth Sci Ctr Houston, Multiple Sclerosis Res Grp, Dept Neurol, Houston, TX 77030 USA. [Ontaneda, Daniel] Cleveland Clin Fdn, Mellen Ctr MS Treatment & Res, 9500 Euclid Ave, Cleveland, OH 44195 USA. [Rauscher, Alexander] Univ British Columbia, Dept Pediat, Div Neurol, UBC MRI Res Ctr, Vancouver, BC, Canada. [Rooney, William D.] Oregon Hlth & Sci Univ, Adv Imaging Res Ctr, Portland, OR 97201 USA. [Shinohara, Russell T.] Univ Penn, Dept Biostat & Epidemiol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Sobel, Raymond A.] Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA. [Solomon, Andrew J.] Univ Vermont, Coll Med, Dept Neurol Sci, Burlington, VT USA. [Wuerfel, Jens] Univ Basel Hosp, Med Image Anal Ctr, Basel, Switzerland. [Zivadinov, Robert] SUNY Buffalo, Buffalo Neuroimaging Anal Ctr, Dept Neurol, Buffalo, NY USA. [Sicotte, Nancy L.] Cedars Sinai Med Ctr, Dept Neurol, Los Angeles, CA 90048 USA. [Pelletier, Daniel] Univ Southern Calif, Multiple Sclerosis Ctr, Dept Neurol, Keck Sch Med, Los Angeles, CA USA. RP Sati, P (reprint author), NINDS, Translat Neuroradiol Sect, NIH, 10 Ctr Dr MSC 1400,Bldg 10 Room 5C103, Bethesda, MD 20892 USA. EM satip@ninds.nih.gov FU Race to Erase Multiple Sclerosis; Intramural Research Program of the National Institute of Neurological Disorders and Stroke FX The authors would like to thank Christina J. Azevedo, Michael G. Dwyer, Leorah Freeman, Christoph Juchem, Shannon Kolind, Naila Makhani, Govind Nair, Nico Papinutto, Haochang Shou, Daniel Schwartz, Ferdinand Schweser, Elizabeth Sweeney, Ian Tagge, Shahamat Tauhid and Subhash Tummala for their participation in, and contribution to, the group workshop at the NAIMS meeting in Los Angeles. Matthew Schindler is acknowledged for helpful suggestions. The authors also acknowledge Rohit Bakshi, Peter Calabresi, Ciprian Crainiceanu and Jack Simon for their contribution as NAIMS members. The authors, on behalf of the NAIMS Cooperative, would also like to thank the Race to Erase Multiple Sclerosis for financial support, and Joel Arnold, Aracely Delgadillo, and Liz Seares for helping with organization of the NAIMS meeting. This research was supported in part by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke. NR 67 TC 0 Z9 0 U1 6 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4758 EI 1759-4766 J9 NAT REV NEUROL JI Nat. Rev. Neurol. PD DEC PY 2016 VL 12 IS 12 BP 714 EP 722 DI 10.1038/nrneurol.2016.166 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA EE6PP UT WOS:000389735000006 PM 27834394 ER PT J AU Chmelik, E Emtman, R Borisovskaya, A Borson, S AF Chmelik, Elizabeth Emtman, Reiko Borisovskaya, Anna Borson, Soo TI Communication in dementia care SO NEURODEGENERATIVE DISEASE MANAGEMENT LA English DT Article DE communication; dementia; prognosis ID NURSING-HOME PLACEMENT; PALLIATIVE CARE; COGNITIVE IMPAIRMENT; HOSPITAL ADMISSIONS; ALZHEIMERS-DISEASE; CAREGIVERS; DIAGNOSIS; PEOPLE; FAMILIES; SERVICES AB Dementia is a progressive neurodegenerative illness that affects a growing number of older adults in our country. We discuss ways to improve the management of persons with dementia within current healthcare models. Specifically, we argue that structured communication at regular intervals is essential for dementia care at all phases of illness. We emphasize the need for a single healthcare provider to take on a central role in organizing communication between patient, family and other healthcare providers in the outpatient setting. We also emphasize the need for healthcare providers to begin conversations about prognosis, care transitions and end of life early while balancing these difficult conversations with a hopeful attitude of realistic optimism that the disease can be managed. C1 [Chmelik, Elizabeth; Borisovskaya, Anna] VA Puget Sound Healthcare Syst, Seattle, WA 98108 USA. [Chmelik, Elizabeth; Emtman, Reiko; Borisovskaya, Anna; Borson, Soo] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Borson, Soo] Univ Minnesota, Dept Neurol, Minneapolis, MN 55455 USA. RP Chmelik, E (reprint author), VA Puget Sound Healthcare Syst, Seattle, WA 98108 USA.; Chmelik, E (reprint author), Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. EM Elizabeth.chmelik@va.gov NR 40 TC 0 Z9 0 U1 4 U2 4 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1758-2024 EI 1758-2032 J9 NEURODEGENER DIS MAN JI Neurodegener. Dis. Manag. PD DEC PY 2016 VL 6 IS 6 BP 479 EP 490 DI 10.2217/nmt-2016-0019 PG 12 WC Clinical Neurology SC Neurosciences & Neurology GA EE7BD UT WOS:000389768200005 PM 27855537 ER PT J AU Ahveninen, J Chang, WT Huang, S Keil, B Kopco, N Rossi, S Bonmassar, G Witzel, T Polimeni, JR AF Ahveninen, Jyrki Chang, Wei-Tang Huang, Samantha Keil, Boris Kopco, Norbert Rossi, Stephanie Bonmassar, Giorgio Witzel, Thomas Polimeni, Jonathan R. TI Intracortical depth analyses of frequency-sensitive regions of human auditory cortex using 7T fMRI SO NEUROIMAGE LA English DT Article ID HUMAN CEREBRAL-CORTEX; SURFACE-BASED ANALYSIS; PRIMARY VISUAL-CORTEX; TONOTOPIC ORGANIZATION; HUMAN-BRAIN; LAMINAR SPECIFICITY; BLOOD OXYGENATION; MACAQUE MONKEYS; SPIN-ECHO; NEUROIMAGING PARADIGMS AB Despite recent advances in auditory neuroscience, the exact functional organization of human auditory cortex (AC) has been difficult to investigate. Here, using reversals of tonotopic gradients as the test case, we examined whether human ACs can be more precisely mapped by avoiding signals caused by large draining vessels near the pial surface, which bias blood-oxygen level dependent (BOLD) signals away from the actual sites of neuronal activity. Using ultra-high field (7T) fMRI and cortical depth analysis techniques previously applied in visual cortices, we sampled 1 mm isotropic voxels from different depths of AC during narrow-band sound stimulation with biologically relevant temporal patterns. At the group level, analyses that considered voxels from all cortical depths, but excluded those intersecting the pial surface, showed (a) the greatest statistical sensitivity in contrasts between activations to high vs. low frequency sounds and (b) the highest inter-subject consistency of phase-encoded continuous tonotopy mapping. Analyses based solely on voxels intersecting the pial surface produced the least consistent group results, even when compared to analyses based solely on voxels intersecting the white-matter surface where both signal strength and within-subject statistical power are weakest. However, no evidence was found for reduced within-subject reliability in analyses considering the pial voxels only. Our group results could, thus, reflect improved inter-subject correspondence of high and low frequency gradients after the signals from voxels near the pial surface are excluded. Using tonotopy analyses as the test case, our results demonstrate that when the major physiological and anatomical biases imparted by the vasculature are controlled, functional mapping of human ACs becomes more consistent from subject to subject than previously thought. (C) 2016 Elsevier Inc. All rights reserved. C1 [Ahveninen, Jyrki; Chang, Wei-Tang; Huang, Samantha; Keil, Boris; Kopco, Norbert; Rossi, Stephanie; Bonmassar, Giorgio; Witzel, Thomas; Polimeni, Jonathan R.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Keil, Boris] Mittelhessen Univ Appl Sci, Life Sci Engn, Inst Med Phys & Radiat Protect, Giessen, Germany. [Kopco, Norbert] Safarik Univ, Inst Comp Sci, Kosice, Slovakia. [Kopco, Norbert] Boston Univ, Hearing Res Ctr, Boston, MA 02215 USA. [Polimeni, Jonathan R.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Ahveninen, J (reprint author), MGH MIT HMS Martinos Ctr, Bldg 149 13th St, Charlestown, MA 02129 USA. EM jyrki@nmr.mgh.harvard.edu FU NIH [R21DC014134, R01MH083744, R01HD040712, R01NS037462, R01EB019437, K01 EB011498]; National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health; [S10RR023401]; [S10RR019307]; [S10RR021110]; [S10RR023043]; [S10RR019371]; [S10OD010364] FX This work was supported by NIH awards R21DC014134, R01MH083744, R01HD040712, R01NS037462, R01EB019437, and K01 EB011498. This research was carried out at the Athinoula A. Martinos Center for Biomedical Imaging at the Massachusetts General Hospital, using resources provided by the Center for Functional Neuroimaging Technologies, P41EB015896, a P41 Biotechnology Resource Grant supported by the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health. The research environment was additionally supported by Shared Instrumentation Grants S10RR019371, S10RR023401, S10RR019307, S10RR021110, S10RR023043, S10RR019371, and S10OD010364. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 114 TC 0 Z9 0 U1 6 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD DEC PY 2016 VL 143 BP 116 EP 127 DI 10.1016/j.neuroimage.2016.09.010 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA EE5XN UT WOS:000389683000011 PM 27608603 ER PT J AU Ganis, G Bridges, D Hsu, CW Schendan, HE AF Ganis, Giorgio Bridges, David Hsu, Chun-Wei Schendan, Haline E. TI Is anterior N2 enhancement a reliable electrophysiological index of concealed information? SO NEUROIMAGE LA English DT Article DE Event-related potentials; N2; Concealed information; Deception; Cognitive control ID BRAIN POTENTIALS; MEMORY DETECTION; SKIN-CONDUCTANCE; P300; RECOGNITION; SIMILARITY; DECEPTION; COMPLEX; TASK; FMRI AB Concealed information tests (CITs) are used to determine whether an individual possesses information about an item of interest. Event-related potential (ERP) measures in CITs have focused almost exclusively on the P3b component, showing that this component is larger when lying about the item of interest (probe) than telling the truth about control items (irrelevants). Recent studies have begun to examine other ERP components, such as the anterior N2, with mixed results. A seminal CIT study found that visual probes elicit a larger anterior N2 than irrelevants (Gamer and Berti, 2010) and suggested that this component indexes cognitive control processes engaged when lying about probes. However, this study did not control for potential intrinsic differences among the stimuli: the same probe and irrelevants were used for all participants, and there was no control condition composed of uninformed participants. Here, first we show that the N2 effect found in the study by Gamer and Berti (2010) was in large part due to stimulus differences, as the effect observed in a concealed information condition was comparable to that found in two matched control conditions without any concealed information (Experiments 1 and 2). Next, we addressed the issue of the generality of the N2 findings by counterbalancing a new set of stimuli across participants and by using a control condition with uninformed participants (Experiment 3). Results show that the probe did not elicit a larger anterior N2 than the irrelevants under these controlled conditions. These findings suggest that caution should be taken in using the N2 as an index of concealed information in CITs. Furthermore, they are a reminder that results of CIT studies (not only with ERPs) performed without stimulus counterbalancing and suitable control conditions may be confounded by differential intrinsic properties of the stimuli employed. (C) 2016 Elsevier Inc. All rights reserved. C1 [Ganis, Giorgio; Bridges, David; Hsu, Chun-Wei; Schendan, Haline E.] Univ Plymouth, Sch Psychol, Portland Sq, Plymouth PL4 8AA, Devon, England. [Ganis, Giorgio; Bridges, David; Hsu, Chun-Wei; Schendan, Haline E.] Univ Plymouth, Cognit Inst, Plymouth, Devon, England. [Ganis, Giorgio] Harvard Med Sch, Dept Radiol, Boston, MA 02115 USA. [Ganis, Giorgio] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. RP Ganis, G (reprint author), Univ Plymouth, Sch Psychol, Portland Sq, Plymouth PL4 8AA, Devon, England. EM giorgio.ganis@plymouth.ac.uk FU Research Executive Agency European Union, Seventh Framework Programme (FP7), Marie Curie Career Integration Grant [CIG09-GA-2011-293850-CoND]; Research Executive Agency European Union FP7 Marie Curie Initial Training Networks (ITN) Innovative Doctoral Programme (IDP): COGNOVO [FP7-PEOPLE-ITN-604764] FX Research supported by Research Executive Agency European Union, Seventh Framework Programme (FP7), Marie Curie Career Integration Grant: CIG09-GA-2011-293850-CoND, and by the Research Executive Agency European Union FP7 Marie Curie Initial Training Networks (ITN) FP7-PEOPLE-2013-ITN-604764 Innovative Doctoral Programme (IDP): COGNOVO. The funding sources had 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 article for publication. NR 34 TC 0 Z9 0 U1 1 U2 1 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 DEC PY 2016 VL 143 BP 152 EP 165 DI 10.1016/j.neuroimage.2016.08.042 PG 14 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA EE5XN UT WOS:000389683000014 PM 27570109 ER PT J AU Puonti, O Iglesias, JE Van Leemput, K AF Puonti, Oula Eugenio Iglesias, Juan Van Leemput, Koen TI Fast and sequence-adaptive whole-brain segmentation using parametric Bayesian modeling SO NEUROIMAGE LA English DT Article DE MRI; Segmentation; Atlases; Parametric models; Bayesian modeling ID MULTI-ATLAS SEGMENTATION; MR-IMAGES; UNIFIED FRAMEWORK; TISSUE CLASSIFICATION; MAXIMUM-LIKELIHOOD; MUTUAL-INFORMATION; LABEL PROPAGATION; REGISTRATION; PARCELLATION; ALGORITHM AB Quantitative analysis of magnetic resonance imaging (MRI) scans of the brain requires accurate automated segmentation of anatomical structures. A desirable feature for such segmentation methods is to be robust against changes in acquisition platform and imaging protocol. In this paper we validate the performance of a segmentation algorithm designed to meet these requirements, building upon generative parametric models previously used in tissue classification. The method is tested on four different datasets acquired with different scanners, field strengths and pulse sequences, demonstrating comparable accuracy to state-of-the-art methods on T1-weighted scans while being one to two orders of magnitude faster. The proposed algorithm is also shown to be robust against small training datasets, and readily handles images with different MRI contrast as well as multi-contrast data. (C) 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license. C1 [Puonti, Oula; Van Leemput, Koen] Tech Univ Denmark, Dept Appl Math & Comp Sci, Bldg 321, DK-2800 Lyngby, Denmark. [Eugenio Iglesias, Juan] Basque Ctr Cognit Brain & Language BCBL, San Sebastian 20009, Gipuzkoa, Spain. [Van Leemput, Koen] Harvard Med Sch, Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, 149 13th St, Charlestown, MA 02129 USA. [Eugenio Iglesias, Juan] UCL, Dept Med Phys & Biomed Engn, Gower St, London WC1E 6BT, England. RP Puonti, O (reprint author), Tech Univ Denmark, Dept Appl Math & Comp Sci, Bldg 321, DK-2800 Lyngby, Denmark. EM oupu@dtu.dk OI Puonti, Oula/0000-0003-3186-244X FU NIH NCRR [P41-RR14075, 1S10RR023043]; NIBIB [R01EB013565]; Lundbeck foundation [R141-2013-13117]; Technical University of Denmark; Gipuzkoako Foru Aldundia (Fellows Gipuzkoa Program); European Union's Horizon Research and innovation program under the Marie Sklodowska-Curie grant [654911]; Spanish Ministry of Economy and Competetiveness (MINECO) [TEC2014-51882-P] FX This research was supported by the NIH NCRR (P41-RR14075, 1S10RR023043), NIBIB (R01EB013565), the Lundbeck foundation (R141-2013-13117) and financial contributions from the Technical University of Denmark. JEI acknowledges financial support from the Gipuzkoako Foru Aldundia (Fellows Gipuzkoa Program), the European Union's Horizon 2020 Research and innovation program under the Marie Sklodowska-Curie grant agreement No 654911, as well as from the Spanish Ministry of Economy and Competetiveness (MINECO, TEC2014-51882-P). NR 76 TC 0 Z9 0 U1 2 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD DEC PY 2016 VL 143 BP 235 EP 249 DI 10.1016/j.neuroimage.2016.09.011 PG 15 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA EE5XN UT WOS:000389683000021 PM 27612647 ER PT J AU Zhou, IY Guo, YK Igarashi, T Wang, Y Mandeville, E Chan, ST Wen, LY Vangel, M Lo, EH Ji, XM Sun, PZ AF Zhou, Iris Yuwen Guo, Yingkun Igarashi, Takahiro Wang, Yu Mandeville, Emiri Chan, Suk-Tak Wen, Lingyi Vangel, Mark Lo, Eng H. Ji, Xunming Sun, Phillip Zhe TI Fast diffusion kurtosis imaging (DKI) with Inherent COrrelation-based Normalization (ICON) enhances automatic segmentation of heterogeneous diffusion MRI lesion in acute stroke SO NMR IN BIOMEDICINE LA English DT Article DE acute stroke; diffusion kurtosis imaging (DKI); Inherent COrrelation-based Normalization (ICON); K-means clustering; mean diffusivity (MD); relaxation-normalized mean kurtosis (RNMK) ID ACUTE ISCHEMIC-STROKE; NON-GAUSSIAN DIFFUSION; CEREBRAL-ISCHEMIA; FOCAL ISCHEMIA; HUMAN BRAIN; MAGNETIZATION-TRANSFER; APPARENT DIFFUSION; DWI MISMATCH; RODENT MODEL; TISSUE AB Diffusion kurtosis imaging (DKI) has been shown to augment diffusion-weighted imaging (DWI) for the definition of irreversible ischemic injury. However, the complexity of cerebral structure/composition makes the kurtosis map heterogeneous, limiting the specificity of kurtosis hyperintensity to acute ischemia. We propose an Inherent COrrelation-based Normalization (ICON) analysis to suppress the intrinsic kurtosis heterogeneity for improved characterization of heterogeneous ischemic tissue injury. Fast DKI and relaxation measurements were performed on normal (n = 10) and stroke rats following middle cerebral artery occlusion (MCAO) (n = 20). We-evaluated the correlations between mean kurtosis (MK), mean diffusivity (MD) and fractional anisotropy (FA) derived from the fast DKI sequence and relaxation rates R-1 and R-2, and found a highly significant correlation between MK and R-1 (p < 0.001). We showed that ICON analysis suppressed the intrinsic kurtosis heterogeneity in normal cerebral tissue, enabling automated tissue segmentation in an animal stroke model. We found significantly different kurtosis and diffusivity lesion volumes: 147 +/- 59 and 180 +/- 66 mm(3), respectively (p = 0.003, paired t-test). The ratio of kurtosis to diffusivity lesion volume was 84% +/- 19% (p < 0.001, one-sample t-test). We found that relaxation-normalized MK (RNMK), but not MD, values were significantly different between kurtosis and diffusivity lesions (p < 0.001, analysis of variance). Our study showed that fast DKI with ICON analysis provides a promising means of demarcation of heterogeneous DWI stroke lesions. C1 [Zhou, Iris Yuwen; Guo, Yingkun; Igarashi, Takahiro; Wang, Yu; Chan, Suk-Tak; Wen, Lingyi; Vangel, Mark; Sun, Phillip Zhe] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, 149 13 St,Rm 2301, Charlestown, MA 02129 USA. [Zhou, Iris Yuwen; Guo, Yingkun; Igarashi, Takahiro; Wang, Yu; Mandeville, Emiri; Chan, Suk-Tak; Wen, Lingyi; Vangel, Mark; Lo, Eng H.; Sun, Phillip Zhe] Harvard Med Sch, 149 13 St,Rm 2301, Charlestown, MA 02129 USA. [Guo, Yingkun; Wen, Lingyi] Sichuan Univ, Dept Radiol, West China Univ Hosp 2, Chengdu, Sichuan, Peoples R China. [Wang, Yu; Ji, Xunming] Capital Med Univ, Xuanwu Hosp, China Amer Joint Neurosci Inst, Beijing, Peoples R China. [Mandeville, Emiri; Lo, Eng H.] Massachusetts Gen Hosp, Dept Radiol & Neurol, Neuroprotect Res Lab, Charlestown, MA USA. RP Sun, PZ (reprint author), Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, 149 13 St,Rm 2301, Charlestown, MA 02129 USA.; Sun, PZ (reprint author), Harvard Med Sch, 149 13 St,Rm 2301, Charlestown, MA 02129 USA. EM pzhesun@mgh.harvard.edu OI Zhou, Iris Yuwen/0000-0002-4351-7398 FU National Natural Science Foundation of China [81471721]; National Basic Research Program of China [2011CB70780420]; National Institute of Neurological Disorders and Stroke, National Institute of Health [1R21NS085574, 1R01NS083654] FX This study was supported in part by grants from the National Natural Science Foundation of China (81471721, Y.G.), National Basic Research Program of China (2011CB70780420, X.J.) and the National Institute of Neurological Disorders and Stroke, National Institute of Health (1R21NS085574 and 1R01NS083654, P.Z.S.). The authors would like to thank Ms Nicole Eusemann for editorial assistance. NR 64 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0952-3480 EI 1099-1492 J9 NMR BIOMED JI NMR Biomed. PD DEC PY 2016 VL 29 IS 12 BP 1670 EP 1677 DI 10.1002/nbm.3617 PG 8 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA ED8SK UT WOS:000389141000001 PM 27696558 ER PT J AU Valkovic, L Chmelik, M Meyerspeer, M Gagoski, B Rodgers, CT Krssak, M Andronesi, OC Trattnig, S Bogner, W AF Valkovic, Ladislav Chmelik, Marek Meyerspeer, Martin Gagoski, Borjan Rodgers, Christopher T. Krssak, Martin Andronesi, Ovidiu C. Trattnig, Siegfried Bogner, Wolfgang TI Dynamic P-31-MRSI using spiral spectroscopic imaging can map mitochondrial capacity in muscles of the human calf during plantar flexion exercise at 7 T SO NMR IN BIOMEDICINE LA English DT Article DE dynamic P-31-MRS; high energy phosphate; MRSI; skeletal muscle; spiral spectroscopic imaging; ultra-high field ID MAGNETIC-RESONANCE-SPECTROSCOPY; PHOSPHOCREATINE RECOVERY KINETICS; HUMAN GASTROCNEMIUS-MUSCLE; HUMAN SKELETAL-MUSCLE; LOWER LEG MUSCLES; P-31 NMR; LOCALIZED P-31-MRS; SURFACE COIL; IN-VIVO; MRI AB Phosphorus MRSI (P-31-MRSI) using a spiral-trajectory readout at 7 T was developed for high temporal resolution mapping of the mitochondrial capacity of exercising human skeletal muscle. The sensitivity and localization accuracy of the method was investigated in phantoms. In vivo performance was assessed in 12 volunteers, who performed a plantar flexion exercise inside a whole-body 7 T MR scanner using an MR-compatible ergometer and a surface coil. In five volunteers the knee was flexed (-60 degrees) to shift the major workload from the gastrocnemii to the soleus muscle. Spiral-encoded MRSI provided 16-25 times faster mapping with a better point spread function than elliptical phase-encoded MRSI with the same matrix size. The inevitable trade-off for the increased temporal resolution was a reduced signal-to-noise ratio, but this was acceptable. The phosphocreatine (PCr) depletion caused by exercise at 0 degrees knee angulation was significantly higher in both gastrocnemii than in the soleus (i.e. 64.8 +/- 19.6% and 65.9 +/- 23.6% in gastrocnemius lateralis and medialis versus 15.3 +/- 8.4% in the soleus). Spiral-encoded P-31-MRSI is a powerful tool for dynamic mapping of exercising muscle oxidative metabolism, including localized assessment of PCr concentrations, pH and maximal oxidative flux with high temporal and spatial resolution. C1 [Valkovic, Ladislav; Chmelik, Marek; Meyerspeer, Martin; Krssak, Martin; Trattnig, Siegfried; Bogner, Wolfgang] Med Univ Vienna, High Field MR Ctr, Vienna, Austria. [Valkovic, Ladislav; Chmelik, Marek; Krssak, Martin; Trattnig, Siegfried; Bogner, Wolfgang] Med Univ Vienna, Dept Biomed Imaging & Image Guided Therapy, Vienna, Austria. [Valkovic, Ladislav; Chmelik, Marek; Krssak, Martin; Trattnig, Siegfried; Bogner, Wolfgang] Christian Doppler Lab Clin Mol MR Imaging, Vienna, Austria. [Valkovic, Ladislav] Slovak Acad Sci, Inst Measurement Sci, Dept Imaging Methods, Bratislava, Slovakia. [Rodgers, Christopher T.] Univ Oxford, Oxford Ctr Clin Magnet Resonance Res OCMR, Oxford, England. [Meyerspeer, Martin] Med Univ Vienna, Ctr Med Phys & Biomed Engn, Vienna, Austria. [Gagoski, Borjan] Boston Childrens Hosp, Fetal Neonatal Neuroimaging & Dev Sci Ctr, Boston, MA USA. [Krssak, Martin] Med Univ Vienna, Dept Internal Med 3, Div Endocrinol & Metab, Vienna, Austria. [Andronesi, Ovidiu C.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA USA. RP Bogner, W (reprint author), Med Univ Vienna, High Field MR Ctr, Vienna, Austria. EM wolfgang.bogner@meduniwien.ac.at OI Valkovic, Ladislav/0000-0003-2567-3642; Bogner, Wolfgang/0000-0002-0130-3463 FU Christian Doppler Society-Clinical Molecular MR Imaging (MOLIMA); OeNB Jubilaeumsfond [15363, 15455, 16133]; Austrian Science Fund FWF [I1743-B13]; Slovak Grant Agency (VEGA) [2/0013/14]; Slovak Grant Agency (APVV) [0431-12]; Sir Henry Dale Fellowship from the Wellcome Trust; Royal Society [098436/Z/12/Z] FX This work was supported by the Christian Doppler Society-Clinical Molecular MR Imaging (MOLIMA to S.T.), by the OeNB Jubilaeumsfond (Grant 15363 to M.K., 15455 to L.V. and 16133 to W.B.), by the Austrian Science Fund FWF (Grant I1743-B13 to M.M.), by the Slovak Grant Agency (VEGA Grant 2/0013/14 and APVV Grant 0431-12) and by a Sir Henry Dale Fellowship from the Wellcome Trust and the Royal Society (Grant 098436/Z/12/Z to C.T.R.). NR 57 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0952-3480 EI 1099-1492 J9 NMR BIOMED JI NMR Biomed. PD DEC PY 2016 VL 29 IS 12 BP 1825 EP 1834 DI 10.1002/nbm.3662 PG 10 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA ED8SK UT WOS:000389141000016 PM 27862510 ER PT J AU Mingos, M Howard, S Giacalone, N Kozono, D Jacene, H AF Mingos, Mark Howard, Stephanie Giacalone, Nicholas Kozono, David Jacene, Heather TI Systemic Immune Response to Vaccination on FDG-PET/CT SO NUCLEAR MEDICINE AND MOLECULAR IMAGING LA English DT Article DE FDG; FDG-PET/CT; Vaccine; Spleen; Lung cancer; Immunization ID AXILLARY LYMPH-NODE; CARCINOMA AB A patient with newly diagnosed right lung cancer had transient F-18-fluorodeoxyglucose (FDG)-avid left axillary lymph nodes and intense splenic FDG uptake on positron emission tomography (PET)/computed tomography (CT). History revealed that the patient received a left-sided influenza vaccine 2-3 days before the examination. Although inflammatory FDG uptake in ipsilateral axillary nodes is reported, to our knowledge, this is the first report of visualization of the systemic immune response in the spleen related to the influenza vaccination on FDG-PET/CT. The history, splenic uptake and time course on serial FDG-PET/CT helped to avoid a false-positive interpretation for progressing lung cancer and alteration of the radiation therapy plan. C1 [Mingos, Mark; Howard, Stephanie; Jacene, Heather] Dana Farber Canc Inst, Dept Imaging, 450 Brookline Ave, Boston, MA 02215 USA. [Mingos, Mark; Howard, Stephanie; Jacene, Heather] Brigham & Womens Hosp, Dept Radiol, 450 Brookline Ave, Boston, MA 02215 USA. [Giacalone, Nicholas; Kozono, David] Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. RP Jacene, H (reprint author), Dana Farber Canc Inst, Dept Imaging, 450 Brookline Ave, Boston, MA 02215 USA.; Jacene, H (reprint author), Brigham & Womens Hosp, Dept Radiol, 450 Brookline Ave, Boston, MA 02215 USA. EM hjacene@partners.org NR 14 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1869-3474 EI 1869-3482 J9 NUCL MED MOLEC IMAG JI NUCL. MED. MOLEC. IMAG. PD DEC PY 2016 VL 50 IS 4 BP 358 EP 361 DI 10.1007/s13139-015-0385-6 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EE7ZG UT WOS:000389843400013 PM 27994693 ER PT J AU Sachdeva, MM Jakobiec, FA Stagner, AM Papakostas, A Eliott, D AF Sachdeva, Mira M. Jakobiec, Frederick A. Stagner, Anna M. Papakostas, Athanasios Eliott, Dean TI Clinical and Ultrastructural Studies of Epiretinal Pigmentary Deposits after Retinectomy with Silicone Oil SO OPHTHALMOLOGY LA English DT Article ID SEVERE PROLIFERATIVE VITREORETINOPATHY; LONG-ACTING GAS; RELAXING RETINOTOMY; EYES; IMMUNOPATHOLOGY; VITRECTOMY; MEMBRANE; VACUOLES; OUTCOMES AB Purpose: Large relaxing retinectomies have become increasingly used in the repair of retinal detachment related to proliferative vitreoretinopathy (PVR). Retinectomies expose the retinal pigment epithelium (RPE) to the vitreous cavity; the direct effects of silicone oil on the RPE are only beginning to be understood. Design: Retrospective case series. Participants: Twelve patients noted to develop pigmented epiretinal deposits at regularly scheduled follow-up visits after repair of complex retinal detachments using silicone oil tamponade and retinectomy. Methods: Epiretinal pigment deposits were characterized clinically by wide-field color photography, fundus autofluorescence imaging, and spectral-domain optical coherence tomography (SD OCT). At the time of silicone oil removal, the pigmented membranes were preserved in fixative and analyzed by light microscopy/immunostaining or electron microscopy for histologic characterization. Main Outcome Measures: Not applicable. Results: We describe the development of diffuse preretinal pigmentary deposits in 12 eyes after surgery for complicated PVR detachments using retinectomies with oil, with an average onset of 3.2 months postoperatively. These pigment clumps produced a striking leopard-spot pattern on fundus autofluorescence imaging. Histopathologic and ultrastructural analysis of these epiretinal proliferations peeled at the time of silicone oil removal revealed RPE cells with intracellular silicone oil droplets, singly dispersed membrane-bound melanin granules, glial tissue (1 case), and a fibrous stroma. Conclusions: Although in vitro studies have suggested that RPE cells can phagocytose emulsified oil droplets, this report represents the first in vivo documentation by electron microscopy of this phenomenon in patients. These findings underscore that direct contact with silicone oil may affect the behavior of the RPE, which may be clinically relevant in patients who have undergone large relaxing retinectomies with silicone oil tamponade for PVR-related retinal detachments. (C) 2016 by the American Academy of Ophthalmology C1 [Sachdeva, Mira M.; Papakostas, Athanasios; Eliott, Dean] Massachusetts Eye & Ear Infirm, Harvard Med Sch, Dept Ophthalmol, Retina Serv, Boston, MA 02114 USA. [Jakobiec, Frederick A.; Stagner, Anna M.] Massachusetts Eye & Ear Infirm, Harvard Med Sch, David G Cogan Lab Ophthalm Pathol, Boston, MA 02114 USA. RP Eliott, D (reprint author), Massachusetts Eye & Ear Infirm, Retina Div, Ophthalmol, 243 Charles St,12th Floor, Boston, MA 02114 USA. EM Dean_Eliott@meei.harvard.edu FU Ocata Therapeutics; Neurotech FX D.E.: Consultant - Acucela, Alcon, Alimera, Allergan, Avalanche, Dutch Ophthalmic, MacuLogix, Ophthotech, Santen, and Thrombogenics; Grants - Ocata Therapeutics and Neurotech. NR 25 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 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD DEC PY 2016 VL 123 IS 12 BP 2595 EP 2602 DI 10.1016/j.ophtha.2016.08.049 PG 8 WC Ophthalmology SC Ophthalmology GA EE3YZ UT WOS:000389539900027 PM 27769586 ER PT J AU De Gasperi, R Graham, ZA Harlow, LM Bauman, WA Qin, WP Cardozo, CP AF De Gasperi, Rita Graham, Zachary A. Harlow, Lauren M. Bauman, William A. Qin, Weiping Cardozo, Christopher P. TI The Signature of MicroRNA Dysregulation in Muscle Paralyzed by Spinal Cord Injury Includes Downregulation of MicroRNAs that Target Myostatin Signaling SO PLOS ONE LA English DT Article ID MESSENGER-RNA EXPRESSION; EMBRYONIC STEM-CELLS; SKELETAL-MUSCLE; GENE-EXPRESSION; ATROPHY; CITED2; MIR-145; PROTEIN; MICE; MASS AB Spinal cord injury (SCI) results in muscle atrophy, reduced force generation and an oxidative-to-glycolytic fiber type shift. The mechanisms responsible for these alterations remain incompletely understood. To gain new insights regarding mechanisms involved in deterioration of muscle after SCI, global expression profiles of miRs in paralyzed gastrocnemius muscle were compared between sham-operated (Sham) and spinal cord-transected (SCI) rats. Ingenuity Pathways Analysis of the altered miRs identified signaling via insulin, IGF-1, integrins and TGF-beta as being significantly enriched for target genes. By qPCR, miRs 23a, 23b, 27b, 145, and 206, were downregulated in skeletal muscle 56 days after SCI. Using FISH, miR-145, a miR not previously implicated in the function of skeletal muscle, was found to be localized to skeletal muscle fibers. One predicted target of miR-145 was Cited2, a transcriptional regulator that modulates signaling through NF-KB, Smad3 and other transcription factors. The 3' UTR of Cited2 mRNA contained a highly conserved miR-145 seed sequence. Luciferase reporter assays confirmed that miR-145 interacts with this seed sequence. However, Cited2 protein levels were similar between Sham and SCI groups, indicating a biochemical interaction that was not involved in the context of adaptations after SCI. Taken together, the findings indicate dysregulation of several highly expressed miRs in skeletal muscle after SCI and suggest that reduced expression of miR-23a, 145 and 206 may have roles in alteration in skeletal muscle mass and insulin responsiveness in muscle paralyzed by upper motor neuron injuries. C1 [De Gasperi, Rita; Graham, Zachary A.; Harlow, Lauren M.; Bauman, William A.; Qin, Weiping; Cardozo, Christopher P.] James J Peters Med Ctr, VA RR&D Serv Natl Ctr Med Consequences Spinal Cor, Bronx, NY 10468 USA. [De Gasperi, Rita] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Graham, Zachary A.; Bauman, William A.; Qin, Weiping; Cardozo, Christopher P.] Icahn Sch Med Mt Sinai, Dept Med, New York, NY 10029 USA. [Bauman, William A.; Cardozo, Christopher P.] Icahn Sch Med Mt Sinai, Dept Rehabil Med, New York, NY 10029 USA. [Cardozo, Christopher P.] Icahn Sch Med Mt Sinai, Dept Pharmacol Sci, New York, NY 10029 USA. [De Gasperi, Rita] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA. RP Cardozo, CP (reprint author), James J Peters Med Ctr, VA RR&D Serv Natl Ctr Med Consequences Spinal Cor, Bronx, NY 10468 USA.; Cardozo, CP (reprint author), Icahn Sch Med Mt Sinai, Dept Med, New York, NY 10029 USA.; Cardozo, CP (reprint author), Icahn Sch Med Mt Sinai, Dept Rehabil Med, New York, NY 10029 USA.; Cardozo, CP (reprint author), Icahn Sch Med Mt Sinai, Dept Pharmacol Sci, New York, NY 10029 USA. EM chris.cardozo@mssm.edu FU VA Rehabilitation and Research Development Grant [B9212C] FX VA Rehabilitation and Research Development Grant B9212C to WAB. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; Funding was provided by Veterans Affairs RR&D Service National Center Grant B9212-C to W.A.B. NR 63 TC 0 Z9 0 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 1 PY 2016 VL 11 IS 12 AR e0166189 DI 10.1371/journal.pone.0166189 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA EE3JC UT WOS:000389482700018 PM 27907012 ER PT J AU Sluss, PM AF Sluss, Patrick M. TI Point-of-Care Pregnancy Testing SO POINT OF CARE LA English DT Review DE diagnosis; human chorionic gonadotropin; monitoring; point-of-care testing; preeclampsia; pregnancy ID HUMAN CHORIONIC-GONADOTROPIN; GESTATIONAL-TROPHOBLASTIC-DISEASES; ANTIBODY INTERFERENCE; BETA-SUBUNIT; HCG; IMMUNOASSAYS; DIAGNOSIS; ORIGIN; ASSAYS; ART C1 [Sluss, Patrick M.] Harvard Med Sch, Boston, MA USA. [Sluss, Patrick M.] Massachusetts Gen Hosp, Special Chem Pathol Core Labs, GRB 554,55 Fruit St, Boston, MA 02114 USA. RP Sluss, PM (reprint author), Massachusetts Gen Hosp, Special Chem Pathol Core Labs, GRB 554,55 Fruit St, Boston, MA 02114 USA. EM Sluss.patrick@mgh.harvard.edu NR 45 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1533-029X EI 1533-0303 J9 POINT CARE JI Point Care PD DEC PY 2016 VL 15 IS 4 BP 164 EP 171 DI 10.1097/POC.0000000000000112 PG 8 WC Medical Laboratory Technology SC Medical Laboratory Technology GA EE5WT UT WOS:000389679300007 ER PT J AU Sluss, PM AF Sluss, Patrick M. TI Three Wishes for the Future of Point-of-Care Testing SO POINT OF CARE LA English DT Editorial Material ID ANTI-MULLERIAN HORMONE; OVARIAN RESERVE MARKERS; MASS-SPECTROMETRY; AMH; ESTRADIOL; WOMEN; SERUM; ASSAY; CHROMATOGRAPHY; MEN C1 [Sluss, Patrick M.] Harvard Med Sch, Boston, MA USA. [Sluss, Patrick M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Sluss, PM (reprint author), Massachusetts Gen Hosp, Special Chem Pathol Serv, GRB 554,55 Fruit St, Boston, MA 02114 USA. EM Sluss.patrick@mgh.harvard.edu NR 19 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1533-029X EI 1533-0303 J9 POINT CARE JI Point Care PD DEC PY 2016 VL 15 IS 4 BP 172 EP 175 DI 10.1097/POC.0000000000000116 PG 4 WC Medical Laboratory Technology SC Medical Laboratory Technology GA EE5WT UT WOS:000389679300008 ER PT J AU Hansoti, B Kellogg, DS Aberle, SJ Broccoli, MC Feden, J French, A Little, CM Moore, B Sabato, J Sheets, T Weinberg, R Elmes, P Kang, C AF Hansoti, Bhakti Kellogg, Dylan S. Aberle, Sara J. Broccoli, Morgan C. Feden, Jeffrey French, Arthur Little, Charles M. Moore, Brooks Sabato, Joseph, Jr. Sheets, Tara Weinberg, R. Elmes, Pat Kang, Christopher TI Preparing Emergency Physicians for Acute Disaster Response: A Review of Current Training Opportunities in the US SO PREHOSPITAL AND DISASTER MEDICINE LA English DT Review DE disaster training; education; emergency physician ID HEALTH-CARE WORKERS; CORE COMPETENCES; PUBLIC-HEALTH; PREPAREDNESS; MEDICINE AB Study Objective: This study aimed to review available disaster training options for health care providers, and to provide specific recommendations for developing and delivering a disaster-response-training program for non-disaster-trained emergency physicians, residents, and trainees prior to acute deployment. Methods: A comprehensive review of the peer-reviewed and grey literature of the existing training options for health care providers was conducted to provide specific recommendations. Results: A comprehensive search of the Pubmed, Embase, Web of Science, Scopus, and Cochrane databases was performed to identify publications related to courses for disaster preparedness and response training for health care professionals. This search revealed 7,681 unique titles, of which 53 articles were included in the full review. A total of 384 courses were found through the grey literature search, and many of these were available online for no charge and could be completed in less than six hours. The majority of courses focused on management and disaster planning; few focused on clinical care and acute response. Conclusion: There is need for a course that is targeted toward emergency physicians and trainees without formal disaster training. This course should be available online and should utilize a mix of educational modalities, including lectures, scenarios, and virtual simulations. An ideal course should focus on disaster preparedness, and the clinical and nonclinical aspects of response, with a focus on an all-hazards approach, including both terrorism-related and environmental disasters. C1 [Hansoti, Bhakti; Kellogg, Dylan S.; Broccoli, Morgan C.] Johns Hopkins Univ, Dept Emergency Med, Baltimore, MD 21218 USA. [Aberle, Sara J.] Mayo Clin, Emergency Med, Rochester, MN USA. [Feden, Jeffrey] Brown Univ, Emergency Med, Providence, RI 02912 USA. [French, Arthur] VA Puget Sound Hlth Care Syst, Emergency Med, Seattle Div, Seattle, WA USA. [Little, Charles M.] Univ Colorado, Emergency Med, Denver, CO 80202 USA. [Moore, Brooks] Emory Univ, Emergency Med, Atlanta, GA 30322 USA. [Sabato, Joseph, Jr.] Univ Florida, Emergency Med, Gainesville, FL USA. [Sheets, Tara] Baylor Coll Med, Emergency Med, Houston, TX 77030 USA. [Weinberg, R.] MIT, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Elmes, Pat] ACEP, Irving, TX USA. [Kang, Christopher] Madigan Army Med Ctr, Emergency Med, Tacoma, WA 98431 USA. RP Hansoti, B (reprint author), Johns Hopkins Univ, Dept Emergency Med, Baltimore, MD 21218 USA. EM bhakti.hansoti@gmail.com OI Hansoti, Bhakti/0000-0003-0188-9764 NR 28 TC 0 Z9 0 U1 5 U2 5 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1049-023X EI 1945-1938 J9 PREHOSPITAL DISASTER JI Prehospital Disaster Med. PD DEC PY 2016 VL 31 IS 6 BP 643 EP 647 DI 10.1017/S1049023X16000820 PG 5 WC Emergency Medicine SC Emergency Medicine GA EE6DK UT WOS:000389698700011 PM 27640891 ER PT J AU Ricq, EL Hooker, JM Haggarty, SJ AF Ricq, Emily L. Hooker, Jacob M. Haggarty, Stephen J. TI Toward development of epigenetic drugs for central nervous system disorders: Modulating neuroplasticity via H3K4 methylation SO PSYCHIATRY AND CLINICAL NEUROSCIENCES LA English DT Review DE chromatin; drug discovery; epigenetics; histone lysine methylation; neuropsychiatric disorder ID LSD1 HISTONE DEMETHYLASE; PLURIPOTENT STEM-CELLS; OF-FUNCTION VARIANTS; DE-NOVO MUTATIONS; GENE-EXPRESSION; TRANSCRIPTIONAL REPRESSION; NEURAL DEVELOPMENT; PREFRONTAL CORTEX; HUMAN BRAIN; NEUROPSYCHIATRIC DISORDERS AB The mammalian brain dynamically activates or silences gene programs in response to environmental input and developmental cues. This neuroplasticity is controlled by signaling pathways that modify the activity, localization, and/or expression of transcriptional-regulatory enzymes in combination with alterations in chromatin structure in the nucleus. Consistent with this key neurobiological role, disruptions in the fine-tuning of epigenetic and transcriptional regulation have emerged as a recurrent theme in studies of the genetics of neurodevelopmental and neuropsychiatric disorders. Furthermore, environmental factors have been implicated in the increased risk of heterogeneous, multifactorial, neuropsychiatric disorders via epigenetic mechanisms. Aberrant epigenetic regulation of gene expression thus provides an attractive unifying model for understanding the complex risk architecture of mental illness. Here, we review emerging genetic evidence implicating dysregulation of histone lysine methylation in neuropsychiatric disease and outline advancements in small-molecule probes targeting this chromatin modification. The emerging field of neuroepigenetic research is poised to provide insight into the biochemical basis of genetic risk for diverse neuropsychiatric disorders and to develop the highly selective chemical tools and imaging agents necessary to dissect dynamic transcriptional-regulatory mechanisms in the nervous system. On the basis of these findings, continued advances may lead to the validation of novel, disease-modifying therapeutic targets for a range of disorders with aberrant chromatin-mediated neuroplasticity. C1 [Ricq, Emily L.] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. [Ricq, Emily L.; Hooker, Jacob M.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Ricq, Emily L.; Haggarty, Stephen J.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Human Genet Res, Dept Neurol,Chem Neurobiol Lab, 185 Cambridge St, Boston, MA 02114 USA. [Ricq, Emily L.; Haggarty, Stephen J.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Human Genet Res, Dept Psychiat,Chem Neurobiol Lab, 185 Cambridge St, Boston, MA 02114 USA. RP Haggarty, SJ (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Ctr Human Genet Res, Dept Neurol,Chem Neurobiol Lab, 185 Cambridge St, Boston, MA 02114 USA.; Haggarty, SJ (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Ctr Human Genet Res, Dept Psychiat,Chem Neurobiol Lab, 185 Cambridge St, Boston, MA 02114 USA. EM shaggarty@mgh.harvard.edu FU US National Institutes of Health [R01DA028301, R01MH095088]; Consortium for Frontotemporal Dementia Research/Bluefield Project FX We thank members of the Haggarty and Hooker laboratories for their constructive feedback and discussion on the topic. We acknowledge financial support from the US National Institutes of Health (R01DA028301, R01MH095088), and Consortium for Frontotemporal Dementia Research/Bluefield Project. NR 139 TC 1 Z9 1 U1 6 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1323-1316 EI 1440-1819 J9 PSYCHIAT CLIN NEUROS JI Psychiatry Clin. Neurosci. PD DEC PY 2016 VL 70 IS 12 BP 536 EP 550 DI 10.1111/pcn.12426 PG 15 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA EE9LE UT WOS:000389947200001 PM 27485392 ER PT J AU Hess, DR AF Hess, Dean R. TI Pulse Oximetry: Beyond S-po2 SO RESPIRATORY CARE LA English DT Article DE breathing frequency; carboxyhentoglobin; fluid responsiveness; methemoglobin; oxygen saturation; pulse oximetry; pulsus paradoxus ID PLETHYSMOGRAPHIC WAVE-FORM; FLUID RESPONSIVENESS; CO-OXIMETRY; PHOTOPLETHYSMOGRAM DPOP; NONINVASIVE MEASUREMENT; RESPIRATORY CHANGES; CLINICAL-USE; CARBOXYHEMOGLOBIN; HEMOGLOBIN; PARADOXUS AB Newer pulse oximetry technology is available that uses multiple wavelengths of light and is thereby able to measure more than 2 forms of hemoglobin, including carboxyhemoglobin (SpCO), methemoglobin (SpMet), and total hemoglobin (SpHb). Several studies have shown relatively low bias, but poor precision, for SpCO compared with HbCO. Evaluations of SpMet have been conducted primarily in normal subjects. Clinical evaluations of SpHb suggest that it might not yet be accurate enough to make transfusion decisions. Respiratory waveform variability of the pulse oximeter plethysmogram might be useful to assess pulsus paradoxus in patients with airway obstruction; it might also be used to measure the breathing frequency. The change in pulse pressure over the respiratory cycle has been used to assess fluid responsiveness in mechanically ventilated patients, and similarly, the pulse oximetry plethysmogram waveform amplitude variability might be used to assess fluid responsiveness. However, there are limitations to this approach, and it remains to be determined how well it can be applied clinically using existing pulse oximetry technology. The pulse oximeter signal is probably useful for applications beyond Spo,. However, the current technology is not mature, and improvements are necessary. With technology improvements, the use of pulse oximetry to detect SpCO, SpMet, SpHb, pulsus paradoxus, breathing frequency, and fluid responsiveness is likely to improve in the future. C1 [Hess, Dean R.] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. [Hess, Dean R.] Northeastern Univ, Boston, MA 02115 USA. RP Hess, DR (reprint author), Massachusetts Gen Hosp, Resp Care Serv, Ellison 401,55 Fruit St, Boston, MA 02114 USA. EM dhess@partners.org NR 48 TC 0 Z9 0 U1 4 U2 4 PU DAEDALUS ENTERPRISES INC PI IRVING PA 9425 N MAC ARTHUR BLVD, STE 100, IRVING, TX 75063-4706 USA SN 0020-1324 EI 1943-3654 J9 RESP CARE JI Respir. Care PD DEC PY 2016 VL 61 IS 12 BP 1671 EP 1680 DI 10.4187/respcare.05208 PG 10 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA EE2FK UT WOS:000389398900015 PM 27899542 ER PT J AU Imber, DAE Pirrone, M Zhang, CS Fisher, DF Kacmarek, RM Berra, L AF Imber, David A. E. Pirrone, Massimiliano Zhang, Changsheng Fisher, Daniel F. Kacmarek, Robert M. Berra, Lorenzo TI Respiratory Management of Perioperative Obese Patients SO RESPIRATORY CARE LA English DT Review DE obesity; mechanical ventilation; PEEP; recruitment maneuver; atelectasis; noninvasive ventilation ID END-EXPIRATORY PRESSURE; RANDOMIZED CONTROLLED-TRIAL; POSITIVE-AIRWAY-PRESSURE; INTRAOPERATIVE VENTILATORY STRATEGIES; BODY-MASS-INDEX; GENERAL-ANESTHESIA; HYPOVENTILATION SYNDROME; MECHANICAL VENTILATION; BARIATRIC SURGERY; LUNG-FUNCTION AB With a rising incidence of obesity in the United States, anesthesiologists are faced with a larger volume of obese patients coming to the operating room as well as obese patients with ever-larger body mass indices (BMIs). While there are many cardiovascular and endocrine issues that clinicians must take into account when caring for the obese patient, one of the most prominent concerns of the anesthesiologist in the perioperative setting should be the status of the lung. Because the pathophysiology of reduced lung volumes in the obese patient differs from that of the ARDS patient, the best approach to keeping the obese patient's lung open and adequately ventilated during mechanical ventilation is unique. Although strong evidence and research are lacking regarding how to best ventilate the obese surgical patient, we aim with this review to provide an assessment of the small amount of research that has been conducted and the pathophysiology we believe influences the apparent results. We will provide a basic overview of the anatomy and pathophysiology of the obese respiratory system and review studies concerning pre-, intra-, and postoperative respiratory care. Our focus in this review centers on the best approach to keeping the lung recruited through the prevention of compression atelectasis and the maintaining of physiological lung volumes. We recommend the use of PEEP via noninvasive ventilation (NIV) before induction and endotracheal intubation, the use of both PEEP and periodic recruitment maneuvers during mechanical ventilation, and the use of PEEP via NIV after extubation. It is our hope that by studying the underlying mechanisms that make ventilating obese patients so difficult, future research can be better tailored to address this increasingly important challenge to the field of anesthesia. C1 [Imber, David A. E.; Pirrone, Massimiliano; Zhang, Changsheng; Berra, Lorenzo] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Imber, David A. E.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Pirrone, Massimiliano] Univ Milan, Dipartimento Anestesiol Terapia Intens & Sci Derm, Milan, Italy. [Zhang, Changsheng] Chinese Peoples Liberat Army Gen Hosp, Anesthesia & Operat Ctr, Beijing, Peoples R China. [Fisher, Daniel F.; Kacmarek, Robert M.] Massachusetts Gen Hosp, Dept Resp Care, Boston, MA 02114 USA. [Kacmarek, Robert M.; Berra, Lorenzo] Harvard Med Sch, Boston, MA USA. RP Berra, L (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. EM lberra@mgh.harvard.edu NR 73 TC 0 Z9 0 U1 4 U2 4 PU DAEDALUS ENTERPRISES INC PI IRVING PA 9425 N MAC ARTHUR BLVD, STE 100, IRVING, TX 75063-4706 USA SN 0020-1324 EI 1943-3654 J9 RESP CARE JI Respir. Care PD DEC PY 2016 VL 61 IS 12 BP 1681 EP 1692 DI 10.4187/respcare.04732 PG 12 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA EE2FK UT WOS:000389398900016 PM 27624632 ER PT J AU Gaspari, R Weekes, A Adhikari, S Noble, VE Nomura, JT Theodoro, D Woo, M Atkinson, P Blehar, D Brown, SM Caffery, T Douglass, E Fraser, J Haines, C Lam, S Lanspa, M Lewis, M Liebmann, O Limkakeng, A Lopez, F Platz, E Mendoza, M Minnigan, H Moore, C Novik, J Rang, L Scruggs, W Raio, C AF Gaspari, Romolo Weekes, Anthony Adhikari, Srikar Noble, Vicki E. Nomura, Jason T. Theodoro, Daniel Woo, Michael Atkinson, Paul Blehar, David Brown, Samuel M. Caffery, Terrell Douglass, Emily Fraser, Jacqueline Haines, Christine Lam, Samuel Lanspa, Michael Lewis, Margaret Liebmann, Otto Limkakeng, Alexander Lopez, Fernando Platz, Elke Mendoza, Michelle Minnigan, Hal Moore, Christopher Novik, Joseph Rang, Louise Scruggs, Will Raio, Christopher TI Emergency department point-of-care ultrasound in out-of-hospital and in-ED cardiac arrest SO RESUSCITATION LA English DT Article DE Cardiac arrest; Ultrasound; Resuscitation ID PREDICT RESUSCITATION OUTCOMES; CARDIOPULMONARY-RESUSCITATION; LIFE-SUPPORT; SURVIVAL; SONOGRAPHY; ECHOCARDIOGRAPHY; DURATION; REGISTRY AB Background: Point-of-care ultrasound has been suggested to improve outcomes from advanced cardiac life support (ACLS), but no large studies have explored how it should be incorporated into ACLS. Our aim was to determine whether cardiac activity on ultrasound during ACLS is associated with improved survival. Methods: We conducted a non-randomized, prospective, protocol-driven observational study at 20 hospitals across United States and Canada. Patients presenting with out-of-hospital arrest or in-ED arrest with pulseless electrical activity or asystole were included. An ultrasound was performed at the beginning and end of ACLS. The primary outcome was survival to hospital admission. Secondary outcomes included survival to hospital discharge and return of spontaneous circulation. Findings: 793 patients were enrolled, 208 (26.2%) survived the initial resuscitation, 114 (14.4%) survived to hospital admission, and 13 (1.6%) survived to hospital discharge. Cardiac activity on US was the variable most associated with survival at all time points. On multivariate regression modeling, cardiac activity was associated with increased survival to hospital admission (OR 3.6, 2.2-5.9) and hospital discharge (OR 5.7, 1.5-21.9). No cardiac activity on US was associated with non-survival, but 0.6% (95% CI 0.3-2.3) survived to discharge. Ultrasound identified findings that responded to non-ACLS interventions. Patients with pericardial effusion and pericardiocentesis demonstrated higher survival rates (15.4%) compared toall others (1.3%). Conclusion: Cardiac activity on ultrasound was the variable most associated with survival following cardiac arrest. Ultrasound during cardiac arrest identifies interventions outside of the standard ACLS algorithm. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Gaspari, Romolo; Blehar, David; Mendoza, Michelle] Univ Massachusetts, Sch Med, Worcester, MA USA. [Weekes, Anthony; Lewis, Margaret] Carolinas Med Ctr, Charlotte, NC 28203 USA. [Adhikari, Srikar] Univ Arizona, Tucson, AZ USA. [Noble, Vicki E.; Douglass, Emily] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Nomura, Jason T.] Christiana Care Hlth Syst, Newark, DE USA. [Theodoro, Daniel] Washington Univ, Sch Med, St Louis, MO USA. [Woo, Michael] Univ Ottawa, Ottawa, ON, Canada. [Atkinson, Paul; Fraser, Jacqueline] Dalhousie Univ, St John, NB, Canada. [Brown, Samuel M.; Lanspa, Michael] Intermt Med Ctr, Salt Lake City, UT USA. [Brown, Samuel M.; Lanspa, Michael] Univ Utah, Salt Lake City, UT USA. [Caffery, Terrell] LSU Hlth Sci Ctr, Baton Rouge, LA USA. [Haines, Christine; Raio, Christopher] North Shore Univ Hosp, Manhasset, NY USA. [Lam, Samuel] Advocate Christ Med Ctr, Chicago, IL USA. [Liebmann, Otto] Brown Univ, Providence, RI 02912 USA. [Limkakeng, Alexander; Lopez, Fernando] Duke Univ, Sch Med, Durham, NC USA. [Platz, Elke] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Minnigan, Hal] Indiana Univ, Indianapolis, IN 46204 USA. [Moore, Christopher] Yale Univ, Sch Med, New Haven, CT USA. [Novik, Joseph] NYU, Bellevue Hosp, New York, NY USA. [Rang, Louise] Kingston Gen Hosp, Kingston, ON, Canada. [Scruggs, Will] Castle Hosp, Kailua, HI USA. RP Gaspari, R (reprint author), UMASS Mem Med Ctr, Dept Emergency Med, Worcester, MA 01655 USA. EM Romolo.Gaspari@umassmemorial.org OI Gaspari, Romolo/0000-0002-8411-0308; Brown, Samuel/0000-0003-1206-6261 NR 29 TC 0 Z9 0 U1 9 U2 9 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0300-9572 J9 RESUSCITATION JI Resuscitation PD DEC PY 2016 VL 109 BP 33 EP 39 DI 10.1016/j.resuscitation.2016.09.018 PG 7 WC Critical Care Medicine; Emergency Medicine SC General & Internal Medicine; Emergency Medicine GA EE3QX UT WOS:000389512100014 PM 27693280 ER PT J AU Amorim, E Rittenberger, JC Zheng, JJ Westover, MB Baldwin, ME Callaway, CW Popescu, A AF Amorim, Edilberto Rittenberger, Jon C. Zheng, Julia J. Westover, M. Brandon Baldwin, Maria E. Callaway, Clifton W. Popescu, Alexandra CA Post Cardiac Arrest Service TI Continuous EEG monitoring enhances multimodal outcome prediction in hypoxic-ischemic brain injury SO RESUSCITATION LA English DT Article DE Cardiac arrest; Prognosis; EEG; Status epilepticus; Burst-suppression; EEG background reactivity ID TARGETED TEMPERATURE MANAGEMENT; ILLNESS SEVERITY SCORE; CARDIAC-ARREST; THERAPEUTIC HYPOTHERMIA; STATUS EPILEPTICUS; CLINICAL EXAMINATION; COMATOSE SURVIVORS; CONSORTIUM ROC; RESUSCITATION; ASSOCIATION AB Objective: Hypoxic brain injury is the largest contributor to disability and mortality after cardiac arrest. We aim to identify electroencephalogram (EEG) characteristics that can predict outcome on cardiac arrest patients treated with targeted temperature management (TTM). Methods: We retrospectively examined clinical, EEG, functional outcome at discharge, and in-hospital mortality for 373 adult subjects with return of spontaneous circulation after cardiac arrest. Poor outcome was defined as a Cerebral Performance Category score of 3-5. Pure suppression-burst (SB) was defined as SB not associated with status epilepticus (SE), seizures, or generalized periodic discharges. Results: In-hospital mortality was 68.6% (N = 256). Presence of both unreactive EEG background and SE was associated with a positive predictive value (PPV) of 100% (95% confidence interval: 0.96-1) and a false-positive rate (FPR) of 0% (95% CI: 0-0.11) for poor functional outcome. A prediction model including demographics data, admission exam, presence of status epilepticus, pure SB, and lack of EEG reactivity had an area under the curve of 0.92 (95% CI: 0.87-0.95) for poor functional outcome prediction, and 0.96 (95% CI: 0.94-0.98) for in-hospital mortality. Presence of pure SB (N = 87) was confounded by anesthetics use in 83.9% of the cases, and was not an independent predictor of poor functional outcome, having a FPR of 23% (95% CI: 0.19-0.28). Conclusions: An unreactive EEG background and SE predicted poor functional outcome and in-hospital mortality in cardiac arrest patients undergoing TTM. Prognostic value of pure SB is confounded by use of sedative agents, and its use on prognostication decisions should be made with caution. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Amorim, Edilberto; Westover, M. Brandon] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Amorim, Edilberto] Brigham & Womens Hosp, Dept Neurol, 75 Francis St, Boston, MA 02115 USA. [Rittenberger, Jon C.; Callaway, Clifton W.] Univ Pittsburgh, Dept Emergency Med, Iroquois Bldg,Suite 400A,3600 Forbes Ave, Pittsburgh, PA 15261 USA. [Zheng, Julia J.] Univ Pittsburgh, Dept Neurosci, Pittsburgh, PA USA. [Baldwin, Maria E.; Popescu, Alexandra] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA. RP Rittenberger, JC (reprint author), Univ Pittsburgh, Dept Emergency Med, Iroquois Bldg,Suite 400A,3600 Forbes Ave, Pittsburgh, PA 15261 USA. EM eamorim@mgh.harvard.edu; rittjc@upmc.edu FU National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH); NIH Roadmap for Medical Research [K12 RR024154]; National Association of EMS Physicians/Zoll EMS Resuscitation Research Fellowship; NIH-NINDS [1K23NS090900]; Andrew David Heitman Neuroendovascular Research Fund; Rappaport Foundation; NHLBI Resuscitation Outcomes Consortium [5U01 HL077871] FX J.C.R. is supported by the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research (K12 RR024154), and by an unrestricted grant from the National Association of EMS Physicians/Zoll EMS Resuscitation Research Fellowship. M.B.W. has received support from NIH-NINDS (1K23NS090900), the Andrew David Heitman Neuroendovascular Research Fund, and the Rappaport Foundation. C.W.C. received support from the NHLBI Resuscitation Outcomes Consortium (5U01 HL077871). JCR received travel and honoraria from CR Bard for presentation at 2015 Asia TTM Master's Course. NR 32 TC 2 Z9 2 U1 4 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0300-9572 J9 RESUSCITATION JI Resuscitation PD DEC PY 2016 VL 109 BP 121 EP 126 DI 10.1016/j.resuscitation.2016.08.012 PG 6 WC Critical Care Medicine; Emergency Medicine SC General & Internal Medicine; Emergency Medicine GA EE3QX UT WOS:000389512100025 PM 27554945 ER PT J AU Shah, S Kimberly, WT AF Shah, Shreyansh Kimberly, W. Taylor TI Today's Approach to Treating Brain Swelling in the Neuro Intensive Care Unit SO SEMINARS IN NEUROLOGY LA English DT Article DE brain swelling; cerebral edema; diagnosis; treatment ID MIDDLE CEREBRAL-ARTERY; ELEVATED INTRACRANIAL-PRESSURE; SEVERE HEAD-INJURY; INTRACEREBRAL HEMORRHAGE; HYPERTONIC SALINE; ISCHEMIC-STROKE; MALIGNANT EDEMA; INFARCTION; TRIAL; HYPERTENSION AB Brain swelling is an urgent clinical problem that frequently accompanies ischemic stroke, brain hemorrhage; and traumatic brain injury; it increases morbidity and mortality associated with them. It occurs due to failure of membrane transporters and leakage of the blood brain barrier (BBB), resulting in combination of cytotoxic, ionic, and vasogenic edema. Currently, decompressive craniectomy and osmotherapy are the mainstays of management, but these therapies do not halt the underlying molecular cascade leading to brain swelling. Recent advances in the molecular underpinnings of cerebral edema have opened up possibilities of newer targeted therapeutic options. Here the authors outline the current approach for rapid diagnosis and intervention to reduce mortality and morbidity associated with brain swelling. C1 [Shah, Shreyansh; Kimberly, W. Taylor] Massachusetts Gen Hosp, Dept Neurol, Div Neurocrit Care & Emergency Neurol, Lunder 644,55 Fruit St, Boston, MA 02114 USA. RP Kimberly, WT (reprint author), Massachusetts Gen Hosp, Dept Neurol, Div Neurocrit Care & Emergency Neurol, Lunder 644,55 Fruit St, Boston, MA 02114 USA. EM wtkimberly@mgh.harvard.edu FU NIH [K23NS076597]; AHA [14GRNT19060044]; Remedy Pharmaceuticals, Inc. FX Dr. Kimberly has received research grants from NIH K23NS076597, AHA 14GRNT19060044, and Remedy Pharmaceuticals, Inc. NR 66 TC 0 Z9 0 U1 1 U2 1 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0271-8235 EI 1098-9021 J9 SEMIN NEUROL JI Semin. Neurol. PD DEC PY 2016 VL 36 IS 6 BP 502 EP 507 DI 10.1055/s-0036-1592109 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA EE0PT UT WOS:000389282100005 PM 27907954 ER PT J AU von Kummer, R Mori, E Truelsen, T Jensen, JKS Gronning, BA Fiebach, JB Lovblad, KO Pedraza, S Romero, JM Chabriat, H Chang, KC Davalos, A Ford, GA Grotta, J Kaste, M Schwamm, LH Shuaib, A Albers, GW AF von Kummer, Ruediger Mori, Etsuro Truelsen, Thomas Jensen, Jens-Kristian S. Gronning, Bjorn A. Fiebach, Jochen B. Lovblad, Karl-Olof Pedraza, Salvador Romero, Javier M. Chabriat, Hugues Chang, Ku-Chou Davalos, Antoni Ford, Gary A. Grotta, James Kaste, Markku Schwamm, Lee H. Shuaib, Ashfaq Albers, Gregory W. CA DIAS-4 Investigators TI Desmoteplase 3 to 9 Hours After Major Artery Occlusion Stroke The DIAS-4 Trial (Efficacy and Safety Study of Desmoteplase to Treat Acute Ischemic Stroke) SO STROKE LA English DT Article DE brain ischemia; cerebral arteries; goals; intracranial hemorrhage; stroke ID ONSET; THROMBECTOMY AB Background and Purpose-The DIAS-3 trial (Efficacy and Safety Study of Desmoteplase to Treat Acute Ischemic Stroke [phase 3]) did not demonstrate a significant clinical benefit of desmoteplase administered 3 to 9 hours after stroke in patients with major artery occlusion. We present the results of the prematurely terminated DIAS-4 trial together with a post hoc pooled analysis of the concomitant DIAS-3, DIAS-4, and DIAS-J (Japan) trials to better understand the potential risks and benefits of intravenous desmoteplase for the treatment of ischemic stroke in an extended time window. Methods-Ischemic stroke patients with occlusion/high-grade stenosis in major cerebral arteries were randomly assigned to intravenous treatment with desmoteplase (90 mu g/kg) or placebo. The primary outcome was modified Rankin Scale (mRS) score of 0 to 2 at day 90. Safety assessments included mortality, symptomatic intracranial hemorrhage, and other serious adverse events. Results-In DIAS-4, 52 of 124 (41.9%) desmoteplase-treated and 46 of 128 (35.9%) placebo-treated patients achieved an mRS score of 0 to 2 (odds ratio, 1.45; 95% confidence interval, 0.79; 2.64; P=0.23) with equal mortality, frequency of symptomatic intracranial hemorrhage, and other serious adverse events in both the treatment arms. In the pooled analysis, mRS score of 0 to 2 was achieved by 184 of 376 (48.9%) desmoteplase-treated versus 171 of 381 (44.9%) placebo-treated patients (odds ratio, 1.33; 95% confidence interval, 0.95; 1.85; P=0.096). Treatment with desmoteplase was safe and increased the recanalization rate (107/217 [49.3%] versus 85/222 [38.3%]; odds ratio, 1.59; 95% confidence interval, 1.08-2.35; P=0.019). Recanalization was associated with favorable outcomes (mRS 0-2) at day 90 in both the treatment arms. Conclusions-Late treatment with intravenous 90 mu g/kg desmoteplase is safe, increases arterial recanalization, but does not significantly improve functional outcome at 3 months. C1 [von Kummer, Ruediger] Tech Univ Dresden, Univ Klinikum Carl Gustav Carus, Dresden, Germany. [Mori, Etsuro] Tohoku Univ, Grad Sch Med, Sendai, Miyagi, Japan. [Truelsen, Thomas; Jensen, Jens-Kristian S.; Gronning, Bjorn A.] H Lundbeck & Co AS, Valby, Denmark. [Fiebach, Jochen B.] Charite, Ctr Stroke Res Berlin, Berlin, Germany. [Lovblad, Karl-Olof] Univ Geneva, CH-1211 Geneva 4, Switzerland. [Pedraza, Salvador] UDG, Hosp Dr Josep Trueta, C IDIBGI, Girona, Spain. [Romero, Javier M.] Harvard Med Sch, Dept Radiol, Boston, MA USA. [Chabriat, Hugues] Univ Paris 07, Hop Lariboisiere, AP HP, Dept Neurol, Paris, France. [Chabriat, Hugues] DHU NeuroVasc, INSERM, U1161, Paris, France. [Chang, Ku-Chou] Chang Gung Univ, Kaohsiung Chang Gung Mem Hosp, Dept Neurol, Taoyuan, Taiwan. [Davalos, Antoni] Univ Autonoma Barcelona, Hosp Germans Trias & Pujol, Dept Neurosci, Barcelona, Spain. [Ford, Gary A.] Oxford Univ Hosp, Oxford, England. [Ford, Gary A.] Univ Oxford, Div Med Sci, Oxford OX1 2JD, England. [Grotta, James] Mem Hermann Hosp, Houston, TX USA. [Kaste, Markku] Univ Helsinki, Helsinki Univ Hosp, Dept Neurol, Clin Neurosci, FIN-00014 Helsinki, Finland. [Schwamm, Lee H.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Boston, MA USA. [Schwamm, Lee H.] Harvard Med Sch, Massachusetts Gen Hosp, Stroke Serv, Boston, MA USA. [Shuaib, Ashfaq] Univ Alberta, Edmonton, AB, Canada. [Albers, Gregory W.] Stanford Univ, Med Ctr, Palo Alto, CA 94304 USA. RP von Kummer, R (reprint author), Univ Klinikum Carl Gustav Carus, Inst Diagnost & Intervent Neuroradiol, Fetscherstr 74, D-01307 Dresden, Germany. EM ruediger.vonkummer@uniklinikum-dresden.de RI Chabriat, Hugues/G-5699-2010; OI Chabriat, Hugues/0000-0001-8436-6074; Kaste, Markku/0000-0001-6557-6412 FU H. Lundbeck A/S FX This study was supported by H. Lundbeck A/S. NR 13 TC 0 Z9 0 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD DEC PY 2016 VL 47 IS 12 BP 2880 EP 2887 DI 10.1161/STROKEAHA.116.013715 PG 8 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA EE2ON UT WOS:000389424200015 PM 27803391 ER PT J AU Lyden, P Weymer, S Coffey, C Cudkowicz, M Berg, S O'Brien, S Fisher, M Haley, EC Khatri, P Saver, J Levine, S Levy, H Rymer, M Wechsler, L Jadhav, A McNeil, E Waddy, S Pryor, K AF Lyden, Patrick Weymer, Sara Coffey, Chris Cudkowicz, Merit Berg, Samantha O'Brien, Sarah Fisher, Marc Haley, E. Clarke Khatri, Pooja Saver, Jeff Levine, Steven Levy, Howard Rymer, Marilyn Wechsler, Lawrence Jadhav, Ashutosh McNeil, Elizabeth Waddy, Salina Pryor, Kent TI Selecting Patients for Intra-Arterial Therapy in the Context of a Clinical Trial for Neuroprotection SO STROKE LA English DT Article DE activated protein C; clinical trial; neuroprotective agents; thrombectomy; thrombolysis ID ACUTE ISCHEMIC-STROKE; ACTIVATED PROTEIN-C; TISSUE-PLASMINOGEN ACTIVATOR; INTRAVENOUS THROMBOLYSIS; ANTICOAGULANT ACTIVITY; ENDOVASCULAR TREATMENT; REPERFUSION INJURY; RANDOMIZED-TRIALS; CEREBRAL-ISCHEMIA; ANIMAL-MODELS AB Background and Purpose-The advent of intra-arterial neurothrombectomy (IAT) for acute ischemic stroke opens a potentially transformative opportunity to improve neuroprotection studies. Combining a putative neuroprotectant with recanalization could produce more powerful trials but could introduce heterogeneity and adverse event possibilities. We sought to demonstrate feasibility of IAT in neuroprotectant trials by defining IAT selection criteria for an ongoing neuroprotectant clinical trial. Methods-The study drug, 3K3A-APC, is a pleiotropic cytoprotectant and may reduce thrombolysis-associated hemorrhage. The NeuroNEXT trial NN104 (RHAPSODY) is designed to establish a maximally tolerated dose of 3K3A-APC. Each trial site provided their IAT selection criteria. An expert panel reviewed site criteria and published evidence. Finally, the trial leadership designed IAT selection criteria. Results-Derived selection criteria reflected consistency among the sites and comparability to published IAT trials. A protocol amendment allowing IAT (and relaxed age, National Institutes of Health Stroke Scale, and time limits) in the RHAPSODY trial was implemented on June 15, 2015. Recruitment before and after the amendment improved from 8 enrolled patients (601 screened, 1.3%) to 51 patients (821 screened, 6.2%; odds ratio [95% confidence limit] of 4.9 [2.3-10.4]; P<0.001). Gross recruitment was 0.11 patients per site month versus 0.43 patients per site per month, respectively, before and after the amendment. Conclusions-It is feasible to include IAT in a neuroprotectant trial for acute ischemic stroke. Criteria are presented for including such patients in a manner that is consistent with published evidence for IAT while still preserving the ability to test the role of the putative neuroprotectant. C1 [Lyden, Patrick] Cedars Sinai Med Ctr, Dept Neurol, Los Angeles, CA 90048 USA. [Weymer, Sara; Levy, Howard; Pryor, Kent] ZZ Biotech LLC, Houston, TX USA. [Coffey, Chris; O'Brien, Sarah] Univ Iowa, Dept Biostat, Iowa City, IA USA. [Cudkowicz, Merit; Berg, Samantha] Massachusetts Gen Hosp, Neurol Clin Res Inst, Boston, MA 02114 USA. [Fisher, Marc] Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA 02215 USA. [Haley, E. Clarke] Univ Virginia, Dept Neurol, Charlottesville, VA USA. [Khatri, Pooja] Univ Cincinnati, Dept Neurol & Rehabil Med, Cincinnati, OH 45221 USA. [Saver, Jeff] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. [Levine, Steven] Suny Downstate Med Ctr, Dept Neurol, Brooklyn, NY 11203 USA. [Rymer, Marilyn] Univ Kansas Hosp, Dept Neurol, Kansas City, MO USA. [Wechsler, Lawrence; Jadhav, Ashutosh] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15260 USA. [McNeil, Elizabeth; Waddy, Salina] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Weymer, Sara] Fate Therapeut, San Diego, CA USA. [McNeil, Elizabeth] Biogen, Cambridge, MA USA. RP Lyden, P (reprint author), Dept Neurol, 127 S San Vicente Blvd,AHSP A6417, Los Angeles, CA 90048 USA. EM lydenp@cshs.org FU National Institutes of Neurological Disorders and Stroke [U01NS088312]; National Institutes of Neurological Disorders and Stroke (Clinical Coordinating Center) [U01NS077179]; National Institutes of Neurological Disorders and Stroke (Data Coordinating Center) [U01NS077352] FX This study was funded by the National Institutes of Neurological Disorders and Stroke (U01NS088312). The NeuroNEXT Network is supported by the National Institutes of Neurological Disorders and Stroke (Clinical Coordinating Center: U01NS077179; Data Coordinating Center: U01NS077352). NR 39 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD DEC PY 2016 VL 47 IS 12 BP 2979 EP 2985 DI 10.1161/STROKEAHA.116.013881 PG 7 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA EE2ON UT WOS:000389424200029 PM 27803392 ER PT J AU Ali, SF Siddiqui, K Ay, H Silverman, S Singhal, A Viswanathan, A Rost, N Lev, M Schwamm, LH AF Ali, Syed F. Siddiqui, Khawja Ay, Hakan Silverman, Scott Singhal, Aneesh Viswanathan, Anand Rost, Natalia Lev, Michael Schwamm, Lee H. TI Baseline Predictors of Poor Outcome in Patients Too Good to Treat With Intravenous Thrombolysis SO STROKE LA English DT Article DE infarction; mortality; skilled nursing facility; stroke; thrombolytic therapy ID TISSUE-PLASMINOGEN ACTIVATOR; ACUTE ISCHEMIC-STROKE; RAPIDLY IMPROVING SYMPTOMS; MILD; MORTALITY; THERAPY; REASONS; TRIALS AB Background and Purpose-Several studies have reported poor outcomes in patients too good to treat with intravenous thrombolysis because of mild or rapidly improving symptoms. We sought to determine baseline clinical and imaging predictors of poor outcome in these patients. Methods-Among 3950 consecutive stroke admissions (2009-2015) in our local Get With the Guidelines-Stroke database, 632 patients presented <= 4.5 hours and did not receive tissue-type plasminogen activator, with 380 of 632 (60.1%) being too good to treat. Univariate and multivariable analyses explored the clinical and imaging features associated with poor outcome (defined as not being discharged to home) in these 380 cases. Results-Among these 380 cases, only 68% were discharged home; the other 25% to inpatient rehabilitation, 4% to a skilled nursing facility, and 3% expired or were discharged to hospice. Patients with poor outcome were older, were more often Hispanic, had more vascular risk factors, and had higher median National Institutes of Health Stroke Scale. Imaging characteristics associated with poor outcomes included large or multifocal infarction and poor collaterals. In multivariable analysis, only age, initial National Institutes of Health Stroke Scale, and infarct location were independently associated with poor outcome. Conclusions-Approximately one third of patients deemed too good for intravenous tissue-type plasminogen activator are unable to be discharged directly to home. Given the current safety profile of intravenous tissue-type plasminogen activator, our results suggest that the concept of being too good to treat should be re-examined with an emphasis on the features associated with poor outcome identified in our study. If replicated, these findings could be incorporated into tissue-type plasminogen activator decision-making algorithms. C1 [Ali, Syed F.; Siddiqui, Khawja; Ay, Hakan; Silverman, Scott; Singhal, Aneesh; Viswanathan, Anand; Rost, Natalia; Lev, Michael; Schwamm, Lee H.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Schwamm, LH (reprint author), Harvard Med Sch, Dept Neurol, MGH Neurol, 55 Fruit St ACC720, Boston, MA 02114 USA. EM LSCHWAMM@mgh.harvard.edu FU NINDS FX Dr Schwamm reports being the principal investigator of an investigator-initiated study of extended-window intravenous thrombolysis funded by the NINDS (clinicaltrials.gov/show/NCT01282242) for which Genentech provides alteplase free of charge to the Massachusetts General Hospital, as well as supplemental per-patient payments to participating sites; serving as chair of the American Heart Association/American Stroke Association Get With the Guidelines-stroke clinical work group; serving as a stroke systems consultant to the Massachusetts Department of Public Health; and serving as a scientific consultant regarding trial design and conduct to Lundbeck (International Steering Committee; DIAS-3, DIAS-4 trials [Safety and Efficacy of Desmoteplase Given 3-9 h After Ischaemic Stroke in Patients With Occlusion or High-Grade Stenosis in Major Cerebral Arteries]), Penumbra (Data and Safety Monitoring Committee, Separator 3D trial), and Medtronic (Victory AF [Atrial Fibrillation], REACT AF, and Stroke AF trials). The other authors report no conflicts. NR 20 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD DEC PY 2016 VL 47 IS 12 BP 2986 EP 2992 DI 10.1161/STROKEAHA.116.014871 PG 7 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA EE2ON UT WOS:000389424200030 PM 27834750 ER PT J AU Nishijima, Y Akamatsu, Y Yang, SY Lee, CC Baran, U Song, SZ Wang, RK Tominaga, T Liu, JL AF Nishijima, Yasuo Akamatsu, Yosuke Yang, Shih Yen Lee, Chih Cheng Baran, Utku Song, Shaozhen Wang, Ruikang K. Tominaga, Teiji Liu, Jialing TI Impaired Collateral Flow Compensation During Chronic Cerebral Hypoperfusion in the Type 2 Diabetic Mice SO STROKE LA English DT Article DE anastomosis; arteriogenesis; carotid occlusive disease; CCAO; doppler OCT; vascular remodeling ID CAROTID-ARTERY OCCLUSION; PENETRATING ARTERIOLES; STROKE; REACTIVITY; RISK; HYPERTENSION; CIRCULATION; ANGIOGRAPHY; MECHANISM; STENOSIS AB Background and Purpose-The presence of collaterals is associated with a reduced risk of stroke and transient ischemic attack in patients with steno-occlusive carotid artery disease. Although metabolic syndrome negatively impacts collateral status, it is unclear whether and to what extent type 2 diabetes mellitus affects cerebral collateral flow regulation during hypoperfusion. Methods-We examined the spatial and temporal changes of the leptomeningeal collateral flow and the flow dynamics of the penetrating arterioles in the distal middle cerebral artery and anterior cerebral artery branches over 2 weeks after unilateral common carotid artery occlusion (CCAO) using optical coherent tomography in db/+ and db/db mice. We also assessed the temporal adaptation of the circle of Willis after CCAO by measuring circle of Willis vessel diameters. Results-After unilateral CCAO, db/db mice exhibited diminished leptomeningeal collateral flow compensation compared with db/+ mice, which coincided with a reduced dilation of distal anterior cerebral artery branches, leading to reduced flow not only in pial vessels but also in penetrating arterioles bordering the distal middle cerebral artery and anterior cerebral artery. However, no apparent cell death was detected in either strain of mice during the first week after CCAO. db/db mice also experienced a more severe early reduction in the vessel diameters of several ipsilateral main feeding arteries in the circle of Willis, in addition to a delayed post-CCAO adaptive response by 1 to 2 weeks, compared with db/+ mice. Conclusions-Type 2 diabetes mellitus is an additional risk factor for hemodynamic compromise during cerebral hypoperfusion, which may increase the severity and the risk of stroke or transient ischemic attack. C1 [Nishijima, Yasuo; Akamatsu, Yosuke; Yang, Shih Yen; Lee, Chih Cheng; Liu, Jialing] Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, Dept Neurol Surg, 1700 Owens St, San Francisco, CA 94158 USA. [Nishijima, Yasuo; Akamatsu, Yosuke; Tominaga, Teiji] Tohoku Univ, Grad Sch Med, Dept Neurosurg, Aoba Ku, Sendai, Miyagi, Japan. [Baran, Utku; Song, Shaozhen; Wang, Ruikang K.] Univ Washington, Dept Bioengn, Dept Ophthalmol, Seattle, WA USA. RP Liu, JL (reprint author), Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, Dept Neurol Surg, 1700 Owens St, San Francisco, CA 94158 USA. EM jialing.liu@ucsf.edu OI Baran, Utku/0000-0002-7740-4252 FU National Institutes of Health (NIH) [R01 NS071050]; Veterns Affairs merit award [I01RX000655, I01BX003335] FX This work was supported by National Institutes of Health (NIH) grant R01 NS071050 (Dr Liu) and Veterns Affairs merit award I01RX000655 and I01BX003335 (Dr Liu). NR 28 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD DEC PY 2016 VL 47 IS 12 BP 3014 EP 3021 DI 10.1161/STROKEAHA.116.014882 PG 8 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA EE2ON UT WOS:000389424200034 PM 27834741 ER PT J AU van Rooden, S van Opstal, AM Labadie, G Terwindt, GM Wermer, MJH Webb, AG Middelkoop, HAM Greenberg, SM van der Grond, J van Buchem, MA AF van Rooden, Sanneke van Opstal, Anna M. Labadie, Gerda Terwindt, Gisela M. Wermer, Marieke J. H. Webb, Andrew G. Middelkoop, Huub A. M. Greenberg, Steven M. van der Grond, Jeroen van Buchem, Mark A. TI Early Magnetic Resonance Imaging and Cognitive Markers of Hereditary Cerebral Amyloid Angiopathy SO STROKE LA English DT Article DE cerebral amyloid angiopathy; cognition; hemorrhage; magnetic resonance imaging; siderosis ID DUTCH TYPE; HEMORRHAGE; LESIONS AB Background and Purpose-Early markers for cerebral amyloid angiopathy are largely unknown. We aimed to identify which magnetic resonance imaging (MRI) (performed at 7 and 3T) and cognitive markers are an early sign in (pre) symptomatic subjects with hereditary cerebral hemorrhage with amyloidosis-Dutch type. Methods-Twenty-seven DNA-proven Dutch-type mutation carriers (15 symptomatic and 12 presymptomatic) (mean age of 45.9 years) and 33 controls (mean age of 45.6 years) were included. 7T and 3T MRI was performed, cerebral amyloid angiopathy and small-vessel disease type MRI markers were estimated, and cognitive performance was assessed. Univariate general linear modeling analysis was used to assess the association between MRI markers and cognitive performance on the one hand and on the other, mutation status, adjusted for age, sex, and education. Results-In symptomatic patients, all established cerebral amyloid angiopathy MRI markers (microbleeds, intracerebral hemorrhages, subarachnoid hemorrhages, superficial siderosis, microinfarcts, volume of white matter hyperintensities, and dilated perivascular spaces in centrum semiovale) were increased compared with controls (P< 0.05). In presymptomatic subjects, the prevalence of microinfarcts and median volume of white matter hyperintensities were increased in comparison to controls (P< 0.05). Symptomatic patients performed worse on all cognitive domains, whereas presymptomatic subjects did not show differences in comparison with controls (P< 0.05). Conclusions-White matter hyperintensities and microinfarcts are more prevalent among presymptomatic subjects and precede cognitive and neuropsychiatric symptoms and intracerebral hemorrhages. C1 [van Rooden, Sanneke; van Opstal, Anna M.; Webb, Andrew G.; van der Grond, Jeroen; van Buchem, Mark A.] Leiden Univ, Med Ctr, CJ Gorter Ctr High Field MRI, Leiden, Netherlands. [van Rooden, Sanneke; van Opstal, Anna M.; Labadie, Gerda; Webb, Andrew G.; van der Grond, Jeroen; van Buchem, Mark A.] Leiden Univ, Med Ctr, Dept Radiol, C3-Q,POB 9600, Leiden 2300, Netherlands. [Terwindt, Gisela M.; Wermer, Marieke J. H.; Middelkoop, Huub A. M.] Leiden Univ, Med Ctr, Dept Neurol, Leiden, Netherlands. [Greenberg, Steven M.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP van der Grond, J (reprint author), Leiden Univ, Med Ctr, Dept Radiol, C3-Q,POB 9600, Leiden 2300, Netherlands. EM j.van_der_Grond@lumc.nl FU NIH [R01 NS070834] FX This work was supported by NIH (R01 NS070834). NR 8 TC 2 Z9 2 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD DEC PY 2016 VL 47 IS 12 BP 3041 EP 3044 DI 10.1161/STROKEAHA.116.014418 PG 4 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA EE2ON UT WOS:000389424200039 PM 27834748 ER PT J AU Henwood, PC Mackenzie, DC Rempell, JS Douglass, E Dukundane, D Liteplo, AS Leo, MM Murray, AF Vaillancourt, S Dean, AJ Lewiss, RE Rulisa, S Krebs, E Rao, AKR Rudakemwa, E Rusanganwa, V Kyanmanywa, P Noble, VE AF Henwood, Patricia C. Mackenzie, David C. Rempell, Joshua S. Douglass, Emily Dukundane, Damas Liteplo, Andrew S. Leo, Megan M. Murray, Alice F. Vaillancourt, Samuel Dean, Anthony J. Lewiss, Resa E. Rulisa, Stephen Krebs, Elizabeth Rao, A. K. Raja Rudakemwa, Emmanuel Rusanganwa, Vincent Kyanmanywa, Patrick Noble, Vicki E. TI Intensive point-of-care ultrasound training with long-term follow-up in a cohort of Rwandan physicians SO TROPICAL MEDICINE & INTERNATIONAL HEALTH LA English DT Article DE ultrasound; global health; Rwanda; curriculum; education ID SETTINGS AB objective We delivered a point-of-care ultrasound training programme in a resource-limited setting in Rwanda, and sought to determine participants' knowledge and skill retention. We also measured trainees' assessment of the usefulness of ultrasound in clinical practice. methods This was a prospective cohort study of 17 Rwandan physicians participating in a point-ofcare ultrasound training programme. The follow-up period was 1 year. Participants completed a 10day ultrasound course, with follow-up training delivered over the subsequent 12 months. Trainee knowledge acquisition and skill retention were assessed via observed structured clinical examinations (OSCEs) administered at six points during the study, and an image-based assessment completed at three points. results Trainees reported minimal structured ultrasound education and little confidence using point-of-care ultrasound before the training. Mean scores on the image-based assessment increased from 36.9% (95% CI 32-41.8%) before the initial 10-day training to 74.3% afterwards (95% CI 69.4-79.2; P < 0.001). The mean score on the initial OSCE after the introductory course was 81.7% (95% CI 78-85.4%). The mean OSCE performance at each subsequent evaluation was at least 75%, and the mean OSCE score at the 58-week follow up was 84.9% (95% CI 80.9-88.9%). conclusions Physicians providing acute care in a resource-limited setting demonstrated sustained improvement in their ultrasound knowledge and skill 1 year after completing a clinical ultrasound training programme. They also reported improvements in their ability to provide patient care and in job satisfaction. C1 [Henwood, Patricia C.; Rempell, Joshua S.] Brigham & Womens Hosp, Dept Emergency Med, 75 Francis St, Boston, MA 02115 USA. [Henwood, Patricia C.; Mackenzie, David C.; Rempell, Joshua S.; Douglass, Emily; Dukundane, Damas; Leo, Megan M.; Murray, Alice F.; Vaillancourt, Samuel; Dean, Anthony J.; Lewiss, Resa E.; Rao, A. K. Raja; Noble, Vicki E.] Point Of Care Ultrasound Resource Ltd Environm, Boston, MA USA. [Mackenzie, David C.] Maine Med Ctr, Dept Emergency Med, Portland, OR USA. [Dukundane, Damas; Rulisa, Stephen] Univ Teaching Hosp Kigali, Kigali, Rwanda. [Liteplo, Andrew S.; Noble, Vicki E.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Leo, Megan M.; Murray, Alice F.] Boston Med Ctr, Dept Emergency Med, Boston, MA USA. [Vaillancourt, Samuel] St Michaels Hosp, Dept Emergency Med, Toronto, ON, Canada. [Dean, Anthony J.] Univ Penn, Dept Emergency Med, Philadelphia, PA 19104 USA. [Lewiss, Resa E.] Univ Colorado, Dept Emergency Med, Denver, CO 80202 USA. [Krebs, Elizabeth] Duke Univ, Med Ctr, Dept Emergency Med, Durham, NC USA. [Rudakemwa, Emmanuel] King Faisal Specialist Hosp & Res Ctr, Kigali, Rwanda. [Rusanganwa, Vincent] Minist Hlth, Kigali, Rwanda. [Kyanmanywa, Patrick] Univ Rwanda, Butare, Rwanda. RP Mackenzie, DC (reprint author), Maine Med Ctr, Dept Emergency Med, 22 Bramhall St, Portland, ME 04102 USA. EM DMackenzie@mmc.org FU Republic of Rwanda Ministry of Health; International Foundation FX We gratefully acknowledge support from Dr. Agnes Binagwaho, Minister of Health of Rwanda; the Republic of Rwanda Ministry of Health; study participants and their hospital site administrators; and PURE volunteer trainers. The work was supported by unrestricted grants from the International Foundation and Philips, and equipment loaned by FUJIFILM SonoSite. NR 21 TC 0 Z9 0 U1 1 U2 1 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 DEC PY 2016 VL 21 IS 12 BP 1531 EP 1538 DI 10.1111/tmi.12780 PG 8 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA EE1KZ UT WOS:000389341700006 PM 27758005 ER PT J AU Ayers, JI Diamond, J Sari, A Fromholt, S Galaleldeen, A Ostrow, LW Glass, JD Hart, PJ Borchelt, DR AF Ayers, Jacob I. Diamond, Jeffrey Sari, Adriana Fromholt, Susan Galaleldeen, Ahmad Ostrow, Lyle W. Glass, Jonathan D. Hart, P. John Borchelt, David R. TI Distinct conformers of transmissible misfolded SOD1 distinguish human SOD1-FALS from other forms of familial and sporadic ALS SO ACTA NEUROPATHOLOGICA LA English DT Article DE Amyotrophic lateral sclerosis; Superoxide dismutase-1; Prion; Strains; sALS; fALS ID AMYOTROPHIC-LATERAL-SCLEROSIS; PRION-LIKE PROPAGATION; MOTOR-NEURON DISEASE; SUPEROXIDE-DISMUTASE; MUTANT SOD1; WILD-TYPE; TRANSGENIC MICE; AGGREGATION; SCRAPIE; STRAINS AB Evidence of misfolded wild-type superoxide dismutase 1 (SOD1) has been detected in spinal cords of sporadic ALS (sALS) patients, suggesting an etiological relationship to SOD1-associated familial ALS (fALS). Given that there are currently a number of promising therapies under development that target SOD1, it is of critical importance to better understand the role of misfolded SOD1 in sALS. We previously demonstrated the permissiveness of the G85R-SOD1:YFP mouse model for MND induction following injection with tissue homogenates from paralyzed transgenic mice expressing SOD1 mutations. This prompted us to examine whether WT SOD1 can self-propagate misfolding of the G85R-SOD1:YFP protein akin to what has been observed with mutant SOD1. Using the G85R-SOD1:YFP mice, we demonstrate that misfolded conformers of recombinant WT SOD1, produced in vitro, induce MND with a distinct inclusion pathology. Furthermore, the distinct pathology remains upon successive passages in the G85R-SOD1:YFP mice, strongly supporting the notion for conformation-dependent templated propagation and SOD1 strains. To determine the presence of a similar misfolded WT SOD1 conformer in sALS tissue, we screened homogenates from patients diagnosed with sALS, fALS, and non-ALS disease in an organotypic spinal cord slice culture assay. Slice cultures from G85R-SOD1:YFP mice exposed to spinal homogenates from patients diagnosed with ALS caused by the A4V mutation in SOD1 developed robust inclusion pathology, whereas spinal homogenates from more than 30 sALS cases and various controls failed. These findings suggest that mutant SOD1 has prion-like attributes that do not extend to SOD1 in sALS tissues. C1 [Ayers, Jacob I.; Diamond, Jeffrey; Sari, Adriana; Fromholt, Susan; Borchelt, David R.] Univ Florida, Dept Neurosci, Ctr Translat Res Neurodegenerat Dis, Box 100159, Gainesville, FL 32610 USA. [Borchelt, David R.] Univ Florida, McKnight Brain Inst, SantaFe HealthCare Alzheimers Dis Res Ctr, Gainesville, FL 32610 USA. [Galaleldeen, Ahmad; Hart, P. John] St Marys Univ, Dept Biol Sci, San Antonio, TX 78228 USA. [Galaleldeen, Ahmad] Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, San Antonio, TX 78229 USA. [Galaleldeen, Ahmad] Univ Texas Hlth Sci Ctr San Antonio, Xray Crystallog Core Lab, San Antonio, TX 78229 USA. [Ostrow, Lyle W.] Johns Hopkins Univ, Dept Neurol, Sch Med, Baltimore, MD 21205 USA. [Glass, Jonathan D.] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA. [Hart, P. John] South Texas Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Dept Vet Affairs, San Antonio, TX 78229 USA. RP Ayers, JI (reprint author), Univ Florida, Dept Neurosci, Ctr Translat Res Neurodegenerat Dis, Box 100159, Gainesville, FL 32610 USA. EM jayers.123ja@ufl.edu FU St. Mary's University Research Grant; Biaggini Research Program; NIH [S10OD020026]; National Institutes of Neurological Disease and Stroke [1R01NA092788-01]; Packard Center for ALS Research at Johns Hopkins University; Target ALS Multicenter Post-mortem Tissue Core FX We would like to thank the patients and family members who contributed tissue to the study; Drs. B. Giasson and J. Lewis for donating mouse tissue for the study; and Dr. C. Janus for his help on statistical analysis. A. G. was supported by St. Mary's University Research Grant and the Biaggini Research Program. This work was supported by an NIH Shared Instrumentation Grant (S10OD020026), a grant from the National Institutes of Neurological Disease and Stroke (1R01NA092788-01), and the Packard Center for ALS Research at Johns Hopkins University. Collection and characterization of human tissues provided by Johns Hopkins were funded by the Target ALS Multicenter Post-mortem Tissue Core. NR 40 TC 1 Z9 1 U1 5 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-6322 EI 1432-0533 J9 ACTA NEUROPATHOL JI Acta Neuropathol. PD DEC PY 2016 VL 132 IS 6 BP 827 EP 840 DI 10.1007/s00401-016-1623-4 PG 14 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA EC1DX UT WOS:000387844900005 PM 27704280 ER PT J AU Zhang, MM Papakostas, TD Malcolm, AW Ancell, KK Biscotti, CV Gragoudas, ES Daniels, AB AF Zhang, Matthew M. Papakostas, Thanos D. Malcolm, Arnold W. Ancell, Kristin K. Biscotti, Charles V. Gragoudas, Evangelos S. Daniels, Anthony B. TI Multiple simultaneous choroidal melanomas arising in the same eye: globe salvage by radiotherapy SO ACTA OPHTHALMOLOGICA LA English DT Article ID MALIGNANT-MELANOMA; UVEAL MELANOMAS; MUTATION; BAP1 AB PurposeMultiple choroidal melanomas arising in the same eye is a very rare entity, usually leading ophthalmologists to entertain other diagnoses. Historically, the only available treatment reported for this rare entity was enucleation. In this study we demonstrate in a series of patients with multiple simultaneous choroidal melanomas that eye salvage is possible using a variety of radiotherapy techniques. ObservationsBoth patients presented with two simultaneous choroidal melanomas in one eye. The first patient was only 30years old and presented with two largely amelanotic tumours with large exudative retinal detachment. Cytology from fine needle aspiration biopsies from both tumours with immunohistochemistry confirmed two separate melanomas. Sequential radioactive iodine plaque brachytherapy led to regression of both tumours. The second, older patient's two tumours both had the typical appearance of choroidal melanoma and he underwent proton beam irradiation to the entire field leading to tumour regression. ConclusionsMultiple choroidal melanomas can rarely arise simultaneously in the same eye, and despite their variable appearance, a definitive diagnosis can be aided by cytology and immunohistochemistry in atypical-appearing cases. While all other previously reported cases have necessitated enucleation, we demonstrate that globe salvage is possible using either proton beam irradiation to the entire tumour field, or with sequential radioactive plaque brachytherapy. C1 [Zhang, Matthew M.; Daniels, Anthony B.] Vanderbilt Univ, Med Ctr, Vanderbilt Eye Inst, Dept Ophthalmol, Nashville, TN 37232 USA. [Papakostas, Thanos D.; Gragoudas, Evangelos S.] Harvard Med Sch, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA USA. [Malcolm, Arnold W.; Daniels, Anthony B.] Vanderbilt Univ, Med Ctr, Dept Radiat Oncol, Nashville, TN USA. [Malcolm, Arnold W.; Ancell, Kristin K.; Daniels, Anthony B.] Vanderbilt Univ, Med Ctr, Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Ancell, Kristin K.] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA. [Biscotti, Charles V.] Cleveland Clin, Dept Anat Pathol, Cleveland, OH 44106 USA. [Daniels, Anthony B.] Vanderbilt Univ, Dept Canc Biol, 221 Kirkland Hall, Nashville, TN 37235 USA. RP Daniels, AB (reprint author), Vanderbilt Eye Inst, 2311 Pierce Ave, Nashville, TN 37205 USA. EM anthony.b.daniels@vanderbilt.edu NR 11 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1755-375X EI 1755-3768 J9 ACTA OPHTHALMOL JI Acta Ophthalmol. PD DEC PY 2016 VL 94 IS 8 BP E799 EP E802 DI 10.1111/aos.13034 PG 4 WC Ophthalmology SC Ophthalmology GA ED1AR UT WOS:000388576400031 PM 27079925 ER PT J AU Junnila, M Laaksonen, I Eskelinen, A Pulkkinen, P Havelin, LI Furnes, O Fenstad, AM Pedersen, AB Overgaard, S Karrholm, J Garellick, G Malchau, H Makela, KT AF Junnila, Mika Laaksonen, Inari Eskelinen, Antti Pulkkinen, Pekka Havelin, Leif Ivar Furnes, Ove Fenstad, Anne Marie Pedersen, Alma B. Overgaard, Soren Karrholm, Johan Garellick, Goran Malchau, Henrik Makela, Keijo T. TI Implant survival of the most common cemented total hip devices from the Nordic Arthroplasty Register Association database SO ACTA ORTHOPAEDICA LA English DT Article ID ELITE-PLUS STEM; FOLLOW-UP; RADIOSTEREOMETRIC ANALYSIS; 10-YEAR SURVIVAL; FEMORAL STEM; RISK-FACTORS; FAILURE RATE; SPECTRON EF; REVISION; REPLACEMENTS AB Background and purpose According to previous Nordic Arthroplasty Register Association (NARA) data, the 10-year implant survival of cemented total hip arthroplasties (THAs) is 94% in patients aged 65-74 and 96% in patients aged 75 or more. Here we report a brand-level comparison of cemented THA based on the NARA database, which has not been done previously.Patients and methods We determined the rate of implant survival of the 9 most common cemented THAs in the NARA database. We used Kaplan-Meier analysis with 95% CI to study implant survival at 10 and 15 years, and Cox multiple regression to assess survival and hazard ratios (HRs), with revision for any reason as endpoint and with adjustment for age, sex, diagnosis, and femoral head material.Results Spectron EF THA (89.9% (CI: 89.3-90.5)) and Elite THA (89.8% (CI: 89.0-90.6)) had the lowest 10-year survivorship. Lubinus (95.7% survival, CI: 95.5-95.9), MS 30 (96.6%, CI: 95.8-97.4), and C-stem THA (95.8%, CI: 94.8-96.8) had a 10-year survivorship of at least 95%. Lubinus (revision risk (RR)=0.77, CI: 0.73-0.81), Muller (RR =0.83, CI: 0.70-0.99), MS-30 (RR =0.73, CI: 0.63-0.86), C-stem (RR =0.70, CI: 0.55-0.90), and Exeter Duration THA (RR =0.84, CI: 0.77-0.90) had a lower risk of revision than Charnley THA, the reference implant.Interpretation The Spectron EF THA and the Elite THA had a lower implant survival than the Charnley, Exeter, and Lubinus THAs. Implant survival of the Muller, MS 30, CPT, and C-stem THAs was above the acceptable limit for 10-year survival. C1 [Junnila, Mika; Laaksonen, Inari; Makela, Keijo T.] Turku Univ Hosp, Dept Orthopaed & Traumatol, Turku, Finland. [Eskelinen, Antti] Coxa Hosp Joint Replacement, Tampere, Finland. [Pulkkinen, Pekka] Univ Helsinki, Dept Publ Hlth, Helsinki, Finland. [Havelin, Leif Ivar; Furnes, Ove; Fenstad, Anne Marie] Haukeland Hosp, Dept Orthopaed Surg, Bergen, Norway. [Havelin, Leif Ivar; Furnes, Ove] Univ Bergen, Dept Clin Med, Bergen, Norway. [Pedersen, Alma B.] Aarhus Univ Hosp, Competence Ctr Clin Epidemiol & Biostat, Dept Clin Epidemiol, Aarhus, Denmark. [Overgaard, Soren] Odense Univ Hosp, Dept Orthopaed Surg & Traumatol, Odense, Denmark. [Overgaard, Soren] Univ Southern Denmark, Inst Clin Res, Odense, Denmark. [Pedersen, Alma B.; Overgaard, Soren] Aarhus Univ Hosp, Dept Clin Epidemiol, Aarhus, Denmark. [Karrholm, Johan; Garellick, Goran; Malchau, Henrik] Sahlgrens Univ Hosp, Dept Orthopaed, Inst Surg Sci, Gothenburg, Sweden. [Malchau, Henrik] Massachusetts Gen Hosp, Harris Orthopaed Lab, Boston, MA 02114 USA. [Malchau, Henrik] Harvard Med Sch, Dept Orthopaed Surg, Boston, MA USA. RP Junnila, M (reprint author), Turku Univ Hosp, Dept Orthopaed & Traumatol, Turku, Finland. EM mika.junnila@tyks.fi NR 40 TC 0 Z9 0 U1 3 U2 3 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 1745-3674 EI 1745-3682 J9 ACTA ORTHOP JI Acta Orthop. PD DEC PY 2016 VL 87 IS 6 BP 546 EP 553 DI 10.1080/17453674.2016.1222804 PG 8 WC Orthopedics SC Orthopedics GA ED3OG UT WOS:000388757800003 PM 27550058 ER PT J AU Mounessa, J Buntinx-Krieg, T Qin, R Dunnick, CA Dellavalle, RP AF Mounessa, Jessica Buntinx-Krieg, Talayesa Qin, Rosie Dunnick, Cory A. Dellavalle, Robert P. TI Primary and Secondary Chemoprevention of Malignant Melanoma SO AMERICAN JOURNAL OF CLINICAL DERMATOLOGY LA English DT Review ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; POLYPODIUM-LEUCOTOMOS EXTRACT; NONMELANOMA SKIN-CANCER; TOPICAL TRETINOIN; DYSPLASTIC NEVI; WOMENS HEALTH; PRIMARY PREVENTION; CLINICAL-TRIAL; ATYPICAL NEVI; RISK AB The incidence of malignant melanoma (MM) continues to rise in the United States. While sun protection and full body skin examinations remain the mainstay of preventative care, chemoprevention of the deadly disease has become an increasingly popular field of study. In this focused review, we discuss current findings and analyze the risks and benefits of various agents investigated for the primary and secondary chemoprevention of MM. Such agents include topical retinoids, vitamins, and supplements, Polypodium leucotomas extracts, non-steroidal anti-inflammatory agents (NSAIDs), statins, sunscreens, and field therapy with topical imiquimod for primary and secondary chemoprevention. We further identify a need for expanded high quality human research on the topic. C1 [Mounessa, Jessica] SUNY Stony Brook, Sch Med, 101 Nicolls Rd, Stony Brook, NY 11794 USA. [Mounessa, Jessica; Dunnick, Cory A.; Dellavalle, Robert P.] Univ Colorado Hosp, Dept Dermatol, 1665 Aurora Ct, Aurora, CO 80045 USA. [Buntinx-Krieg, Talayesa] Univ Cent Florida, Coll Med, 6850 Lake Nona Blvd, Orlando, FL 32827 USA. [Qin, Rosie] Univ San Diego, Dept Med, 9500 Gilman Dr, La Jolla, CA 92093 USA. [Dunnick, Cory A.; Dellavalle, Robert P.] Denver VA Med Ctr, Dept Dermatol, 1055 Clermont St 165, Denver, CO 80220 USA. RP Dellavalle, RP (reprint author), Univ Colorado Hosp, Dept Dermatol, 1665 Aurora Ct, Aurora, CO 80045 USA.; Dellavalle, RP (reprint author), Denver VA Med Ctr, Dept Dermatol, 1055 Clermont St 165, Denver, CO 80220 USA. EM Robert.Dellavalle@ucdenver.edu NR 63 TC 0 Z9 0 U1 3 U2 3 PU ADIS INT LTD PI NORTHCOTE PA 5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND SN 1175-0561 EI 1179-1888 J9 AM J CLIN DERMATOL JI Am. J. Clin. Dermatol. PD DEC PY 2016 VL 17 IS 6 BP 625 EP 634 DI 10.1007/s40257-016-0221-5 PG 10 WC Dermatology SC Dermatology GA EC0WO UT WOS:000387822500007 PM 27665299 ER PT J AU Dhakal, S Advani, R Ballas, LK Dabaja, BS Flowers, CR Ha, CS Hoppe, BS Mendenhall, NP Metzger, ML Plastaras, JP Roberts, KB Shapiro, R Smith, SM Terezakis, SA Winkfield, KM Younes, A Constine, LS AF Dhakal, Sughosh Advani, Ranjana Ballas, Leslie K. Dabaja, Bouthaina S. Flowers, Christopher R. Ha, Chul S. Hoppe, Bradford S. Mendenhall, Nancy P. Metzger, Monika L. Plastaras, John P. Roberts, Kenneth B. Shapiro, Ronald Smith, Sonali M. Terezakis, Stephanie A. Winkfield, Karen M. Younes, Anas Constine, Louis S. TI ACR Appropriateness Criteria (R) Hodgkin Lymphoma-Favorable Prognosis Stage I and II SO AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS LA English DT Article DE appropriateness criteria; Hodgkin lymphoma; combined modality therapy ID POSITRON-EMISSION-TOMOGRAPHY; INVOLVED-FIELD RADIOTHERAPY; COMBINED-MODALITY THERAPY; COLLABORATIVE BRITISH COHORT; RADIATION-THERAPY; 2ND MALIGNANCY; NODE RADIOTHERAPY; CONSOLIDATION RADIATION; EUROPEAN ORGANIZATION; RANDOMIZED-TRIALS AB This topic addresses the treatment of newly diagnosed patients with favorable prognosis stage I and II Hodgkin lymphoma. In most cases, combined modality therapy (chemotherapy followed by involved site radiation therapy) constitutes the current standard of care. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. By combining the most recent medical literature and expert opinion, this revised guideline can aid clinicians in the appropriate use of combined modality therapy for favorable prognosis stage I and II Hodgkin lymphoma. Increasing information about the late effects of treatment has led to attempts to decrease toxicity by using less chemotherapy (decreased duration and/or intensity or different agents) and less radiation therapy (reduced volume and/or dose) while maintaining excellent efficacy. C1 [Dhakal, Sughosh; Constine, Louis S.] Univ Rochester, Med Ctr, Rochester, NY 14627 USA. [Younes, Anas] Amer Soc Clin Oncol, Mem Sloan Kettering Canc Ctr, New York, NY USA. [Advani, Ranjana] Amer Soc Clin Oncol, Stanford Canc Ctr, Stanford, CA USA. [Ballas, Leslie K.] Univ Southern Calif, Keck Sch Med, Los Angeles, CA USA. [Dabaja, Bouthaina S.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Ha, Chul S.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Flowers, Christopher R.] Emory Univ, Amer Soc Clin Oncol, Atlanta, GA 30322 USA. [Hoppe, Bradford S.] Univ Florida, Proton Therapy Inst, Jacksonville, FL USA. [Mendenhall, Nancy P.] Univ Florida, Gainesville, FL USA. [Metzger, Monika L.] St Jude Childrens Res Hosp, Amer Soc Clin Oncol, 332 N Lauderdale St, Memphis, TN 38105 USA. [Plastaras, John P.] Univ Penn Hlth Syst, Philadelphia, PA USA. [Roberts, Kenneth B.] Yale Univ, Sch Med, New Haven, CT USA. [Shapiro, Ronald] Indiana Univ Sch Med, Richard L Roudebush VA Med Ctr, Indianapolis, IN 46202 USA. [Smith, Sonali M.] Univ Chicago, Amer Soc Hematol, Chicago, IL 60637 USA. [Terezakis, Stephanie A.] Johns Hopkins Univ Hosp, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21287 USA. [Winkfield, Karen M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Dhakal, S (reprint author), Amer Coll Radiol, 1891 Preston White Dr, Reston, VA 20191 USA. EM sughosh_dhakal@urmc.rochester.edu RI Flowers, Christopher/F-1953-2010 OI Flowers, Christopher/0000-0002-9524-3990 FU PROCURE; US Oncology; Novartis; J J; Curis FX B.S.H.: "Travel expenses paid by PROCURE for a talks on using proton therapy for thoracic malignancies at a symposium in AZ. Travel expenses paid by US Oncology for a talk on using proton therapy for thoracic malignancies at a symposium in TX." A.Y.: "Research Support: Novartis, J & J, Curis Honorarium: Bayer, BMS, Cegene, Incyte, Janssen, Sanofi, Seattle Genetics, Takeda Millenium." C.R.F.: Optum RX-consultant. The other authors declare no conflicts of interest. NR 67 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0277-3732 EI 1537-453X J9 AM J CLIN ONCOL-CANC JI Am. J. Clin. Oncol.-Cancer Clin. Trials PD DEC PY 2016 VL 39 IS 6 BP 535 EP 544 DI 10.1097/COC.0000000000000331 PG 10 WC Oncology SC Oncology GA ED8YT UT WOS:000389157500001 PM 27643717 ER PT J AU Ye, JC Tucker, NR Weng, LC Clauss, S Lubitz, SA Ellinor, PT AF Ye, Jiangchuan Tucker, Nathan R. Weng, Lu-Chen Clauss, Sebastian Lubitz, Steven A. Ellinor, Patrick T. TI A Functional Variant Associated with Atrial Fibrillation Regulates PITX2c Expression through TFAP2a SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID AP-2 TRANSCRIPTION FACTORS; RISK; GENE; PATHWAY; LOCUS; CARDIOMYOCYTE; ENHANCERS; APOPTOSIS; DATABASE; CITED2 AB The most significantly associated genetic locus for atrial fibrillation (AF) is in chromosomal region 4q25, where four independent association signals have been identified. Although model-system studies suggest that altered PITX2c expression might underlie the association, the link between specific variants and the direction of effect on gene expression remains unknown for all four signals. In the present study, we analyzed the AF-associated region most proximal to PITX2 at 4q25. First, we identified candidate regulatory variants that might confer AF risk through a combination of mammalian conservation, DNase hypersensitivity, and histone modification from ENCODE and the Roadmap Epigenomics Project, as well as through in vivo analysis of enhancer activity in embryonic zebrafish. Within candidate regions, we then identified a single associated SNP, rs2595104, which displayed dramatically reduced enhancer activity with the AF risk allele. CRISPR-Cas9-mediated deletion of the rs2595104 region and editing of the rs2595104 risk allele in human stem-cell-derived cardiomyocytes resulted in diminished PITX2c expression in comparison to that of the non-risk allele. This differential activity was mediated by activating enhancer binding protein 2 alpha (TFAP2a), which bound robustly to the non-risk allele at rs2595104, but not to the risk allele, in cardiomyocytes. In sum, we found that the AF-associated SNP rs2595104 altered PITX2c expression via interaction with TFAP2a. Such a pathway could ultimately contribute to AF susceptibility at the PITX2 locus associated with AF. C1 [Ye, Jiangchuan; Tucker, Nathan R.; Weng, Lu-Chen; Clauss, Sebastian; Lubitz, Steven A.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. [Ye, Jiangchuan; Tucker, Nathan R.; Weng, Lu-Chen; Clauss, Sebastian; Lubitz, Steven A.; Ellinor, Patrick T.] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA 02142 USA. RP Ellinor, PT (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA.; Ellinor, PT (reprint author), Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA 02142 USA. EM ellinor@mgh.harvard.edu FU NIH [T32HL007208, 1RO1HL092577, 1K24HL105780]; European Union [PIOF-GA-2012-328352]; German Centre for Cardiovascular Research (DZHK); Doris Duke Charitable Foundation Clinical Scientist Development Award [2014105]; NIH NHLBI Career Development Award [K23HL114724]; American Heart Association [13EIA14220013]; Fondation Leducq [14CVD01]; Broad Institute from Bayer HealthCare; George L. Nardi, MD, Memorial Research Fund FX N.R.T. was supported by an institutional training grant from the NIH (T32HL007208) and by the George L. Nardi, MD, Memorial Research Fund. S.C. received funding from the People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme (FP7/2007-2013) under Research Executive Agency grant agreement PIOF-GA-2012-328352 and was supported by the German Centre for Cardiovascular Research (DZHK) (81X2600210 and 81X2600204). S.A.L. was supported by a Doris Duke Charitable Foundation Clinical Scientist Development Award (2014105) and an NIH NHLBI Career Development Award (K23HL114724). This work was supported by grants from the NIH to P.T.E. (1RO1HL092577 and 1K24HL105780). P.T.E. was also supported by an Established Investigator Award from the American Heart Association (13EIA14220013) and by the Fondation Leducq (14CVD01). P.T.E. is the principal investigator on a grant at the Broad Institute from Bayer HealthCare. NR 48 TC 0 Z9 0 U1 2 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD DEC 1 PY 2016 VL 99 IS 6 BP 1281 EP 1291 DI 10.1016/j.ajhg.2016.10.001 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA ED8VI UT WOS:000389148600004 PM 27866707 ER PT J AU Baker, TE Chang, G AF Baker, Tanya E. Chang, Grace TI The use of auricular acupuncture in opioid use disorder: A systematic literature review SO AMERICAN JOURNAL ON ADDICTIONS LA English DT Review ID SUBSTANCE USE DISORDERS; DETOXIFICATION TREATMENT; WITHDRAWAL SYMPTOMS; DRUG-DEPENDENCE; CLINICAL-TRIALS; ADDICTION; COMPLEMENTARY; METAANALYSIS; MORTALITY; METHADONE AB Background and ObjectivesOpioid use disorder (OUD) is a chronic disease with significant personal, societal, and public health consequences. Even for the minority who receive the most effective evidence-based treatments, morbidity, and mortality remain significant. These facts, along with the recovery movement calling for individualized, holistic, culturally sensitive care, have led to the exploration of adjunctive interventions including acupuncture. Despite hundreds of international trials, however, there is a lack of consensus regarding its efficacy in OUD due in large part to methodological issues of trials to date. In response to these issues, the National Acupuncture Detoxification Association (NADA) developed an operationalized manual auricular acupuncture protocol that has since become the most widely used in the US. This systematic review is the first to focus explicitly on randomized trials utilizing the NADA protocol as a complementary intervention to address OUD. MethodsThe methods utilized to identify studies for inclusion are based on a 2009 protocol developed by the Cochrane Collaboration. ResultsFour trials met inclusion criteria. Despite methodological issues, results indicate that while the NADA protocol may not be effective in reducing acute opiate craving or withdrawal, it may be effectively utilized as an adjunctive treatment to increase treatment retention and decrease methadone detoxification and maintenance dosages in OUD. Conclusion and Scientific SignificanceIncorporation of the NADA protocol into existing evidence-based treatment approaches may facilitate recovery and, through its impact on treatment retention and completion, indirectly impact morbidity, and mortality in individuals with OUD. Given the limitations of the current review, conclusions are tentative and directions for future research are discussed. (Am J Addict 2016;25:592-602) C1 [Baker, Tanya E.; Chang, Grace] Vet Affairs Boston Healthcare Syst, Dept Psychiat, Brockton, MA USA. [Chang, Grace] Harvard Med Sch, Boston, MA USA. RP Baker, TE (reprint author), VA Boston Healthcare Syst, 940 Belmont St 116-A, Brockton, MA 02301 USA. EM tanya.baker3@va.gov FU Veterans Affairs Boston Healthcare System; Office of Academic Affiliations; Department of Veterans Affairs FX This material is the result of work supported with resources and the use of facilities at the Veterans Affairs Boston Healthcare System. 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.; The Boston VA Healthcare System Psychiatric-Mental Health Nurse Practitioner Residency Program (PMHNPRP) is supported by the Office of Academic Affiliations and the Department of Veterans Affairs. The authors acknowledge the mentorship of Dr. Sherley Belizaire DNP, PMHNP-BC, FNP-BC, Director of PMHNPRP, Boston VAMC. NR 43 TC 1 Z9 1 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1055-0496 EI 1521-0391 J9 AM J ADDICTION JI Am. J. Addict. PD DEC PY 2016 VL 25 IS 8 BP 592 EP 602 DI 10.1111/ajad.12453 PG 11 WC Substance Abuse SC Substance Abuse GA EC6TV UT WOS:000388270500001 PM 28051842 ER PT J AU Treister, R Trudeau, JJ Van Inwegen, R Jones, JK Katz, NP AF Treister, Roi Trudeau, Jeremiah J. Van Inwegen, Richard Jones, Judith K. Katz, Nathaniel P. TI Development and feasibility of the misuse, abuse, and diversion drug event reporting system (MADDERS (R)) SO AMERICAN JOURNAL ON ADDICTIONS LA English DT Article ID CLINICAL-TRIALS; CHRONIC PAIN; RECOMMENDATIONS; INSTRUMENTS AB Background and ObjectivesInappropriate use of analgesic drugs has become increasingly pervasive over the past decade. Currently, drug abuse potential is primarily assessed post-marketing; no validated tools are available to assess this potential in phase II and III clinical trials. This paper describes the development and feasibility testing of a Misuse, Abuse, and Diversion Drug Event Reporting System (MADDERS), which aims to identify potentially abuse-related events and classify them according to a recently developed classification scheme, allowing the quantification of these events in clinical trials. MethodsThe system was initially conceived and designed with input from experts and patients, followed by field-testing to assess its feasibility and content validity in both completed and ongoing clinical trials. ResultsThe results suggest that MADDERS is a feasible system with initial validity. It showed higher rates of the triggering events in subjects taking medications with known abuse potential than in patients taking medications without abuse potential. Additionally, experts agreed on the classification of most abuse-related events in MADDERS. Discussion and ConclusionsMADDERS is a new systematic approach to collect information on potentially abuse-related events in clinical trials and classify them. The system has demonstrated feasibility for implementation. Additional research is ongoing to further evaluate its validity. Scientific SignificanceCurrently, there are no validated tools to assess drug abuse potential during clinical trials. Because of its ease of implementation, its systematic approach, and its preliminary validation results, MADDERS could provide such a tool for clinical trials. (Am J Addict 2016;25:641-651) C1 [Treister, Roi] Massachusetts Gen Hosp, Dept Neurol, Boston, MA USA. [Treister, Roi] Harvard Med Sch Boston, Boston, MA USA. [Treister, Roi; Van Inwegen, Richard; Katz, Nathaniel P.] Analges Solut, 232 Pond St Natick, Natick, MA 01760 USA. [Trudeau, Jeremiah J.] Boehringer Ingelheim GmbH & Co KG, Ridgefield, CT USA. [Jones, Judith K.] Degge Grp, Fairfax, VA USA. [Jones, Judith K.] Georgetown Univ, Sch Med, Washington, DC USA. [Jones, Judith K.] Univ Michigan, Sch Publ Hlth, Ann Arbor, MI 48109 USA. [Katz, Nathaniel P.] Tufts Univ, Boston, MA 02111 USA. RP Katz, NP (reprint author), Analges Solut, 232 Pond St Natick, Natick, MA 01760 USA. EM nkatz@analgesicsolutions.com FU GW Pharmaceuticals FX We acknowledge valuable feedback about MADDERS and its validation during discussions at an ACTTION meeting, "Recommendations for Quantifying Abuse-Related Events in Clinical Trials," held June 27-28, 2013, in Washington, DC. In addition, we thank the following experts for content review and adjudications: Drs. Roger Weiss (Harvard Medical School), Richard Dart (Rocky Mountain Poison and Drug Center), Jennifer Sharpe Potter (UT Health Science Center San Antonio), and Ajay Wasan (University of Pittsburg Medical School). Review and input from Drs. Gil Sperings (MedVadis), Steven Wright (Analgesic Solutions), and Steve Passik (Vanderbilt Medical School) are also gratefully acknowledged. We also thank GW Pharmaceuticals for the use of their data and continued support. NR 16 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1055-0496 EI 1521-0391 J9 AM J ADDICTION JI Am. J. Addict. PD DEC PY 2016 VL 25 IS 8 BP 641 EP 651 DI 10.1111/ajad.12459 PG 11 WC Substance Abuse SC Substance Abuse GA EC6TV UT WOS:000388270500008 PM 28051840 ER PT J AU Nourmahnad, A Stern, AT Hotta, M Stewart, DS Ziemba, AM Szabo, A Forman, SA AF Nourmahnad, Anahita Stern, Alex T. Hotta, Mayo Stewart, Deirdre S. Ziemba, Alexis M. Szabo, Andrea Forman, Stuart A. TI Tryptophan and Cysteine Mutations in M1 Helices of alpha 1 beta 3 gamma 2L gamma-Aminobutyric Acid Type A Receptors Indicate Distinct Intersubunit Sites for Four Intravenous Anesthetics and One Orphan Site SO ANESTHESIOLOGY LA English DT Article ID PROPOFOL BINDING-SITE; GABA(A) RECEPTOR; TRANSMEMBRANE DOMAIN; GENERAL-ANESTHETICS; NEUROACTIVE STEROIDS; ETOMIDATE BINDING; DIRECT ACTIVATION; SUBUNIT; MODULATION; ANALOG AB Background: gamma-Aminobutyric acid type A (GABA(A)) receptors mediate important effects of intravenous general anesthetics. Photolabel derivatives of etomidate, propofol, barbiturates, and a neurosteroid get incorporated in GABA(A) receptor transmembrane helices M1 and M3 adjacent to intersubunit pockets. However, photolabels have not been consistently targeted at heteromeric alpha beta gamma receptors and do not form adducts with all contact residues. Complementary approaches may further define anesthetic sites in typical GABA(A) receptors. Methods: Two mutation-based strategies, substituted tryptophan sensitivity and substituted cysteine modification-protection, combined with voltage-clamp electrophysiology in Xenopus oocytes, were used to evaluate interactions between four intravenous anesthetics and six amino acids in M1 helices of alpha 1, beta 3, and gamma 2L GABA(A) receptor subunits: two photolabeled residues, alpha 1M236 and beta 3M227, and their homologs. Results: Tryptophan substitutions at alpha 1M236 and positional homologs beta 3L231 and gamma 2L246 all caused spontaneous channel gating and reduced gamma-aminobutyric acid EC50. Substituted cysteine modification experiments indicated etomidate protection at alpha 1L232C and alpha 1M236C, R-5-allyl-1-methyl-5-(m-trifluoromethyl-diazirinylphenyl) barbituric acid protection at beta 3M227C and beta 3L231C, and propofol protection at alpha 1M236C and beta 3M227C. No alphaxalone protection was evident at the residues the authors explored, and none of the tested anesthetics protected gamma 2I242C or gamma 2L246C. Conclusions: All five intersubunit transmembrane pockets of GABA(A) receptors display similar allosteric linkage to ion channel gating. Substituted cysteine modification and protection results were fully concordant with anesthetic photolabeling at alpha 1M236 and beta 3M227 and revealed overlapping noncongruent sites for etomidate and propofol in beta(+)-alpha(-) interfaces and R-5-allyl-1-methyl-5-(m-trifluoromethyl-diazirinylphenyl) barbituric acid and propofol in alpha(+)-beta(-) and gamma(+)-beta(-) interfaces. The authors' results identify the alpha(+)-gamma(-) transmembrane interface as a potentially unique orphan modulator site. C1 [Nourmahnad, Anahita; Hotta, Mayo] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Jackson 444,55 Fruit St, Boston, MA 02114 USA. [Nourmahnad, Anahita; Hotta, Mayo] Univ Southern Calif, Keck Sch Med, Los Angeles, CA USA. [Ziemba, Alexis M.] Rensselaer Polytech Inst, Dept Biomed Engn, Troy, NY 12180 USA. RP Forman, SA (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Jackson 444,55 Fruit St, Boston, MA 02114 USA. EM saforman@partners.org FU National Institutes of Health, Bethesda, Maryland [GM089745, GM058448] FX Supported in part by grants (GM089745 and GM058448) from the National Institutes of Health, Bethesda, Maryland. NR 42 TC 2 Z9 2 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-3022 EI 1528-1175 J9 ANESTHESIOLOGY JI Anesthesiology PD DEC PY 2016 VL 125 IS 6 BP 1144 EP 1158 DI 10.1097/ALN.0000000000001390 PG 15 WC Anesthesiology SC Anesthesiology GA ED8QC UT WOS:000389135000014 PM 27753644 ER PT J AU Naoum, EE Oh, LS Levine, WC AF Naoum, Emily E. Oh, Luke S. Levine, Wilton C. TI Images in Anesthesiology: Skin Mottling after Induction SO ANESTHESIOLOGY LA English DT Editorial Material C1 [Naoum, Emily E.; Levine, Wilton C.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Oh, Luke S.] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. RP Naoum, EE (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. EM enaoum@partners.org NR 3 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-3022 EI 1528-1175 J9 ANESTHESIOLOGY JI Anesthesiology PD DEC PY 2016 VL 125 IS 6 BP 1219 EP 1219 DI 10.1097/ALN.0000000000001216 PG 1 WC Anesthesiology SC Anesthesiology GA ED8QC UT WOS:000389135000024 PM 27845984 ER PT J AU Miloslavsky, EM Lu, N Unizony, S Choi, HK Merkel, PA Seo, P Spiera, R Langford, CA Hoffman, GS Kallenberg, CGM St Clair, EW Tchao, NK Fervenza, F Monach, PA Specks, U Stone, JH AF Miloslavsky, Eli M. Lu, Na Unizony, Sebastian Choi, Hyon K. Merkel, Peter A. Seo, Philip Spiera, Robert Langford, Carol A. Hoffman, Gary S. Kallenberg, Cees G. M. St Clair, E. William Tchao, Nadia K. Fervenza, Fernando Monach, Paul A. Specks, Ulrich Stone, John H. TI Myeloperoxidase-Antineutrophil Cytoplasmic Antibody (ANCA)-Positive and ANCA-Negative Patients With Granulomatosis With Polyangiitis (Wegener's) Distinct Patient Subsets SO ARTHRITIS & RHEUMATOLOGY LA English DT Article ID CHURG-STRAUSS-SYNDROME; MICROSCOPIC POLYANGIITIS; SYSTEMIC VASCULITIDES; POLYARTERITIS-NODOSA; CONSENSUS CONFERENCE; CLASSIFICATION; JAPAN; NOMENCLATURE; POPULATION; PREVALENCE AB Objective. To examine the relationship of antineutrophil cytoplasmic antibody (ANCA) type and ANCA-associated vasculitis (AAV) diagnosis with demographic features, disease manifestations, and clinical outcomes. We focused on patients who account for the differences between ANCA type and disease type classifications: antimyeloperoxidase (MPO)-ANCA-positive and ANCA-negative patients with granulomatosis with polyangiitis (Wegener's) (GPA). Methods. We performed a pooled analysis of the Wegener's Granulomatosis Etanercept Trial and the Rituximab in ANCA-Associated Vasculitis trial comparing patients with MPO-ANCA-positive GPA and patients with ANCA-negative GPA to patients with proteinase 3 (PR3)-ANCA-positive GPA and patients with MPO-ANCA-positive microscopic polyangiitis (MPA). Results. Of the 365 patients analyzed, 273 (75%) had PR3-ANCA-positive GPA, 33 (9%) had MPO-ANCA-positive GPA, 15 (4%) had ANCA-negative GPA, and 44 (12%) had MPO-ANCA-positive MPA. MPO-ANCA-positive GPA patients were younger at diagnosis compared to MPO-ANCA-positive MPA patients (53 versus 61 years; P=0.02). Their disease manifestations and rates of relapse were similar to those of PR3-ANCA-positive GPA patients. Relapse was more frequent in MPO-ANCA-positive GPA patients than in patients with MPO-ANCA-positive MPA at trial entry as well as at 12 and 18 months. ANCA-negative patients with GPA had lower Birmingham Vasculitis Activity Score for Wegener's Granulomatosis scores at trial entry than PR3-ANCA-positive patients with GPA (4.5 versus 7.7; P < 0.01), primarily because of a lower prevalence of renal involvement. Conclusion. We were unable to demonstrate important clinical differences between MPO-ANCA-positive and PR3-ANCA-positive patients with GPA. C1 [Miloslavsky, Eli M.; Lu, Na; Unizony, Sebastian; Choi, Hyon K.; Stone, John H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Merkel, Peter A.] Univ Penn, Philadelphia, PA 19104 USA. [Seo, Philip] Johns Hopkins Univ, Baltimore, MD USA. [Spiera, Robert] Hosp Special Surg, 535 E 70th St, New York, NY 10021 USA. [Langford, Carol A.; Hoffman, Gary S.] Cleveland Clin Fdn, 9500 Euclid Ave, Cleveland, OH 44195 USA. [Kallenberg, Cees G. M.] Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands. [St Clair, E. William] Duke Univ, Sch Med, Durham, NC USA. [Tchao, Nadia K.] Immune Tolerance Network, San Francisco, CA USA. [Fervenza, Fernando; Specks, Ulrich] Mayo Clin, Rochester, MN USA. [Monach, Paul A.] Boston Univ, Boston, MA 02215 USA. RP Stone, JH (reprint author), Massachusetts Gen Hosp, Rheumatol Unit, Yawkey 2C,55 Fruit St, Boston, MA 02114 USA. EM jhstone@partners.org FU Amgen; Genentech; Biogen Idec; Eli Lilly; MedImmune; GlaxoSmithKline FX The Wegener's Granulomatosis Etanercept trial was funded in part by Amgen. The Rituximab in ANCA-Associated Vasculitis trial was funded in part by Genentech and Biogen Idec.r Dr. Miloslavsky has received consulting fees (less than $10,000) and research support from Genentech. Dr. Kallenberg has received consulting fees from Eli Lilly, MedImmune, and GlaxoSmithKline (less than $10,000 each). Dr. St. Clair has received research support from Biogen Idec. Dr. Monach has received consulting fees from Genentech (less than $10,000). Dr. Specks has received consulting fees from Genentech (less than $10,000). Dr. Stone has received consulting fees (less than $10,000) and research support from Genentech. NR 30 TC 3 Z9 3 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2326-5191 EI 2326-5205 J9 ARTHRITIS RHEUMATOL JI Arthritis Rheumatol. PD DEC PY 2016 VL 68 IS 12 BP 2945 EP 2952 DI 10.1002/art.39812 PG 8 WC Rheumatology SC Rheumatology GA ED8XE UT WOS:000389153400016 PM 27428559 ER PT J AU Castelino, FV Bain, G Pace, VA Black, KE George, L Probst, CK Goulet, L Lafyatis, R Tager, AM AF Castelino, Flavia V. Bain, Gretchen Pace, Veronica A. Black, Katharine E. George, Leaya Probst, Clemens K. Goulet, Lance Lafyatis, Robert Tager, Andrew M. TI An Autotaxin/Lysophosphatidic Acid/Interleukin-6 Amplification Loop Drives Scleroderma Fibrosis SO Arthritis & Rheumatology LA English DT Article ID LYSOPHOSPHATIDIC ACID PRODUCTION; LYSOPHOSPHOLIPASE-D ACTIVITY; SYSTEMIC-SCLEROSIS; PULMONARY-FIBROSIS; AUTOTAXIN; SKIN; RECEPTOR; INTERLEUKIN-6; INVOLVEMENT; IL-6 AB Objective. We previously implicated the lipid mediator lysophosphatidic acid (LPA) as having a role in dermal fibrosis in systemic sclerosis (SSc). The aim of this study was to identify the role of the LPA-producing enzyme autotaxin (ATX), and to connect the ATX/LPA and interleukin-6 (IL-6) pathways in SSc. Methods. We evaluated the effect of a novel ATX inhibitor, PAT-048, on fibrosis and IL-6 expression in the mouse model of bleomycin-induced dermal fibrosis. We used dermal fibroblasts from SSc patients and control subjects to evaluate LPA-induced expression of IL-6, and IL-6-induced expression of ATX. We next evaluated whether LPA-induced ATX expression is dependent on IL-6, and whether baseline IL-6 expression in fibroblasts from SSc patients is dependent on ATX. Finally, we compared ATX and IL-6 expression in the skin of patients with SSc and healthy control subjects. Results. PAT-048 markedly attenuated bleomycin-induced dermal fibrosis when treatment was initiated before or after the development of fibrosis. LPA stimulated expression of IL-6 in human dermal fibroblasts, and IL-6 stimulated fibroblast expression of ATX, connecting the ATX/LPA and IL-6 pathways in an amplification loop. IL-6 knockdown abrogated LPA-induced ATX expression in fibroblasts, and ATX inhibition attenuated IL-6 expression in fibroblasts and the skin of bleomycin-challenged mice. Expression of both ATX and IL-6 was increased in SSc skin, and LPA-induced IL-6 levels and IL-6-induced ATX levels were increased in fibroblasts from SSc patients compared with controls. Conclusion. ATX is required for the development and maintenance of dermal fibrosis in a mouse model of bleomycin-induced SSc and enables 2 major mediators of SSc fibrogenesis, LPA and IL-6, to amplify the production of each other. Our results suggest that concurrent inhibition of these 2 pathways may be an effective therapeutic strategy for dermal fibrosis in SSc. C1 [Castelino, Flavia V.; Pace, Veronica A.; Black, Katharine E.; George, Leaya; Probst, Clemens K.; Tager, Andrew M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Castelino, Flavia V.; Pace, Veronica A.; Black, Katharine E.; George, Leaya; Probst, Clemens K.; Tager, Andrew M.] Harvard Med Sch, Boston, MA USA. [Bain, Gretchen; Goulet, Lance] PharmAkea, San Diego, CA USA. [Lafyatis, Robert] Boston Univ, Boston, MA 02215 USA. RP Castelino, FV; Tager, AM (reprint author), Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, 149 13th St,Room 8301, Charlestown, MA 02129 USA. EM fcastelino@mgh.harvard.edu; amtager@mgh.harvard.edu FU NIH [K08-AR-062592, R01-HL-095732]; Scleroderma Foundation; Scleroderma Research Foundation; Sanofi; Genentech; PharmAkea FX Dr. Castelino's work was supported by the NIH (grant K08-AR-062592) and a Scleroderma Foundation grant. Dr. Tager's work was supported by the NIH (grant R01-HL-095732) and a Scleroderma Research Foundation grant.; Dr. Lafyatis has received consulting fees from Sanofi and Genentech (less than $10,000 each). Dr. Tager has received consulting fees from PharmAkea (less than $10,000). NR 43 TC 0 Z9 0 U1 2 U2 2 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 DEC PY 2016 VL 68 IS 12 BP 2964 EP 2974 DI 10.1002/art.39797 PG 11 WC Rheumatology SC Rheumatology GA ED8XE UT WOS:000389153400018 PM 27390295 ER PT J AU Juraschek, SP Gelber, AC Choi, HK Appel, LJ Miller, ER AF Juraschek, Stephen P. Gelber, Allan C. Choi, Hyon K. Appel, Lawrence J. Miller, Edgar R., III TI Effects of the Dietary Approaches to Stop Hypertension (DASH) Diet and Sodium Intake on Serum Uric Acid SO Arthritis & Rheumatology LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; VITAMIN-C SUPPLEMENTATION; PURINE-RICH FOODS; BLOOD-PRESSURE; SYSTOLIC HYPERTENSION; PROSPECTIVE COHORT; RENAL EXCRETION; RISK-FACTOR; GOUT; URATE AB Objective. Randomized trial data guiding dietary recommendations to lower serum uric acid (UA), the etiologic precursor of gout, are scarce. We undertook this study to examine the effects of the Dietary Approaches to Stop Hypertension (DASH) diet (a well-established diet that lowers blood pressure) and levels of sodium intake on serum UA. Methods. We conducted an ancillary study of a randomized, crossover feeding trial in 103 adults with prehypertension or stage I hypertension. Participants were randomly assigned to receive either the DASH diet or a control diet (typical of the average American diet) and were further fed low, medium, and high levels of sodium for 30 days, each in random order. Body weight was kept constant. Serum UA levels were measured at baseline and following each feeding period. Results. Trial participants were 55% women and 75% black with a mean +/- SD age of 51.5 +/- 9.7 years and a mean +/- SD serum UA level of 5.0 +/- 1.3 mg/dl. The DASH diet reduced serum UA (-0.35 mg/dl [95% confidence interval (95% CI) -0.65, -0.05], P = 0.02), with a higher effect (-1.29 mg/dl [95% CI -2.50, -0.08]) among participants (n = 8) with a baseline serum UA level of >= 7 mg/dl. Increasing sodium intake from the low level decreased serum UA during the medium sodium intake period (-0.3 mg/dl [95% CI -0.5, -0.2], P < 0.001) and during the high sodium intake period (-0.4 mg/dl [ 95% CI -0.6, -0.3], P < 0.001). Conclusion. The DASH diet lowered serum UA, and this effect was greater among participants with hyperuricemia. Moreover, we found that higher sodium intake decreased serum UA, which enhances our knowledge of urate pathophysiology and risk factors for hyperuricemia. C1 [Juraschek, Stephen P.; Gelber, Allan C.; Appel, Lawrence J.; Miller, Edgar R., III] Johns Hopkins Univ, Baltimore, MD USA. [Choi, Hyon K.] Harvard Med Sch, Boston, MA USA. [Choi, Hyon K.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Juraschek, SP (reprint author), Johns Hopkins Med Inst, 2024 East Monument St,Suite 1-500, Baltimore, MD 21205 USA. EM spj@jhmi.edu FU NIH (National Heart, Lung, and Blood Institute) [U01-HL-57173, U01-HL-57114, U01-HL-57190, U01-HL-57139, K08-HL-03857-01, U01-HL57156]; General Clinical Research Center Program of the National Center for Research Resources [M01-RR-02635, M01-RR-00722]; NIH (National Institute of Diabetes and Digestive and Kidney Diseases) [T32-DK-007732-20] FX Supported by the NIH (National Heart, Lung, and Blood Institute grant U01-HL-57173 to Brigham and Women's Hospital, grant U01-HL-57114 to Duke University, grant U01-HL-57190 to Pennington Biomedical Research Institute, grants U01-HL-57139 and K08-HL-03857-01 to Johns Hopkins University, and grant U01-HL57156 to Kaiser Permanente Center for Health Research) and the General Clinical Research Center Program of the National Center for Research Resources (grant M01-RR-02635 to Brigham and Women's Hospital and grant M01-RR-00722 to Johns Hopkins University). Dr. Juraschek's work was supported by the NIH (Renal Disease Epidemiology Training grant T32-DK-007732-20 from the National Institute of Diabetes and Digestive and Kidney Diseases). NR 52 TC 1 Z9 1 U1 9 U2 9 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 DEC PY 2016 VL 68 IS 12 BP 3002 EP 3009 DI 10.1002/art.39813 PG 8 WC Rheumatology SC Rheumatology GA ED8XE UT WOS:000389153400022 PM 27523583 ER PT J AU Caulfield, MD Zhu, DC McAuley, JD Servatius, RJ AF Caulfield, Meghan D. Zhu, David C. McAuley, J. Devin Servatius, Richard J. TI Cerebellar Response to Familiar and Novel Stimuli: An fMRI Study SO BEHAVIORAL NEUROSCIENCE LA English DT Article DE cerebellum; faces; scenes; familiar; novel ID INTRINSIC FUNCTIONAL CONNECTIVITY; POSTERIOR CINGULATE CORTEX; VERBAL WORKING-MEMORY; RECOGNITION MEMORY; PREFRONTAL CORTEX; SEX-DIFFERENCES; NEURAL SYSTEMS; MOTOR; NETWORKS; FACES AB Historically known for its key contribution to motor behavior, the cerebellum continues to break boundaries. Researchers have demonstrated the cerebellum also plays a role in learning, memory, and more recent evidence for contributions in language, attention, working memory, emotions, and social processes. Here, we present a study that adds to the list of nonmotor processes of the cerebellum. We used images of faces and outdoor scenes to examine the cerebellar response to familiar and novel stimuli. Participants were familiarized with a subset of stimuli, and then underwent functional MRI (fMRI) where they were presented with the previously stimuli and new stimuli while making "old" and "new" judgment. In a familiar versus novel contrast, familiar stimuli (faces and scenes combined) activated bilateral regions of the cerebellum including I-IV, V, VI, Crus I, and Crus II. When separated by type, familiar faces had greater activation of bilateral I-IV than novel faces. These results demonstrate the cerebellar role in determining familiarity and contribute to continuing research supporting cerebellar contributions to nonmotor processes. C1 [Caulfield, Meghan D.; Servatius, Richard J.] Stress & Motivated Behav Inst, E Orange, NJ USA. [Caulfield, Meghan D.] Kessler Fdn, 1199 Pleasant Valley Way, W Orange, NJ 07052 USA. [Caulfield, Meghan D.] Lafayette Coll, Dept Psychol, Easton, PA USA. [Zhu, David C.] Michigan State Univ, Dept Radiol, E Lansing, MI 48824 USA. [Zhu, David C.; McAuley, J. Devin] Michigan State Univ, Dept Psychol, E Lansing, MI 48824 USA. [Servatius, Richard J.] US Dept Vet Affairs, Vet Affairs Med Ctr, Syracuse, NY USA. RP Caulfield, MD (reprint author), Kessler Fdn, 1199 Pleasant Valley Way, W Orange, NJ 07052 USA. EM meghandcaulfield@gmail.com FU Stress and Motivated Behavior Institute; U.S. Department of Veterans Affairs; Graduate School of Biomedical Sciences; Department of Radiology at Michigan State University; Department of Psychology at Michigan State University FX This work was partially supported by the Stress and Motivated Behavior Institute, the U.S. Department of Veterans Affairs, the Foundations Fellowship of the Graduate School of Biomedical Sciences, and the Departments of Radiology and Psychology at Michigan State University. Scan support was provided by the Michigan State University Radiology Pilot Scan Program. We thank Scarlett Doyle for scanning support and Elizabeth Wieland for assistance in participant recruitment and data collection. We thank Glenn Wylie, Catherine Myers, and Elizabeth Tricomi for key input in early stages of this study. NR 62 TC 1 Z9 1 U1 1 U2 1 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0735-7044 EI 1939-0084 J9 BEHAV NEUROSCI JI Behav. Neurosci. PD DEC PY 2016 VL 130 IS 6 BP 585 EP 592 DI 10.1037/bne0000173 PG 8 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA ED3ID UT WOS:000388741900006 PM 27854447 ER PT J AU Zeidan, AM Davidoff, AJ Long, JB Hu, X Wang, R Ma, XM Gross, CP Abel, GA Huntington, SF Podoltsev, NA Hajime, U Prebet, T Gore, SD AF Zeidan, Amer M. Davidoff, Amy J. Long, Jessica B. Hu, Xin Wang, Rong Ma, Xiaomei Gross, Cary P. Abel, Gregory A. Huntington, Scott F. Podoltsev, Nikolai A. Hajime, Uno Prebet, Thomas Gore, Steven D. TI Comparative clinical effectiveness of azacitidine versus decitabine in older patients with myelodysplastic syndromes SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE myelodysplastic syndromes; comparative clinical effectiveness; hypomethylating agents; azacitidine; decitabine ID UNITED-STATES; PHASE-III; MEDICARE POPULATION; LEUKEMIA GROUP; RISK; CANCER; REGIMENS; OUTCOMES; REGISTRY; THERAPY AB The hypomethylating agents (HMAs) azacitidine and decitabine are both approved for treatment of myelodysplastic syndromes (MDS) in the USA. In Europe, decitabine is not approved due to lack of survival advantage in randomized trials. The two drugs have not been compared in clinical trials. We identified patients diagnosed with MDS between 2004 and 2011 from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database in the USA who received 10 doses of either HMA. We estimated survival from HMA initiation with Kaplan-Meier methods and used multivariate Cox proportional hazards models to adjust for covariates. Analyses controlled for histological subtype and we conducted a subset analysis limited to patients with refractory anaemia with excess blasts (RAEB). In 2025 HMA-treated patients, median survival was 15months with no difference in survival based on the HMA received in adjusted analysis (decitabine versus azacitidine, hazard ratio=106, 95% confidence interval: 094-119, P=037). For RAEB patients (n=523), median survival was 12months, with no significant difference based on HMA received. No significant survival difference was found between azacitidine and decitabine in patients with MDS, including RAEB. Importantly, population-based survival of azacitidine-treated RAEB patients was substantially shorter than in the AZA-001 clinical trial (11 versus 245months). C1 [Zeidan, Amer M.; Huntington, Scott F.; Podoltsev, Nikolai A.; Prebet, Thomas; Gore, Steven D.] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT USA. [Zeidan, Amer M.; Davidoff, Amy J.; Long, Jessica B.; Hu, Xin; Wang, Rong; Ma, Xiaomei; Gross, Cary P.; Huntington, Scott F.; Gore, Steven D.] Yale Univ, Canc Outcomes Publ Policy & Effectiveness Res COP, New Haven, CT USA. [Davidoff, Amy J.] Yale Univ, Sch Publ Hlth, Dept Hlth Policy & Management, New Haven, CT USA. [Wang, Rong; Ma, Xiaomei] Yale Univ, Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT USA. [Abel, Gregory A.; Hajime, Uno] Dana Farber Canc Inst, Div Populat Sci, Dept Med Oncol, Boston, MA 02115 USA. RP Zeidan, AM (reprint author), Yale Univ, Dept Internal Med, Sect Hematol, 333 Cedar St,POB 208028, New Haven, CT 06520 USA. EM amer.zeidan@yale.edu FU Dennis Cooper Hematology Young Investigator Award; National Cancer Institute [P30 CA016359]; American Cancer Society Research Scholar Award; California Department of Public Health; National Cancer Institute (NCI)'s Surveillance, Epidemiology and End Results (SEER) Program [N01-PC-35136, N01-PC-35139, N02-PC-15105]; Centers for Disease Control and Prevention's National Program of Cancer Registries [U55/CCR921930-02] FX The results of this study were presented in part at the American Society of Hematology (ASH) Annual Meeting in Orlando, FL, December 5-8, 2015. This research was partly funded by the Dennis Cooper Hematology Young Investigator Award (AZ), a P30 CA016359 from the National Cancer Institute (XM), and an American Cancer Society Research Scholar Award (GAA). The collection of the California cancer incidence data used in this study was supported by the California Department of Public Health as part of the state-wide cancer reporting programme mandated by California Health and Safety Code Section103885; the National Cancer Institute (NCI)'s Surveillance, Epidemiology and End Results (SEER) Program under contract N01-PC-35136 awarded to the Northern California Cancer Center, contract N01-PC-35139 awarded to the University of Southern California, and contract N02-PC-15105 awarded to the Public Health Institute; and the Centers for Disease Control and Prevention's National Program of Cancer Registries, under agreement #U55/CCR921930-02 awarded to the Public Health Institute. The ideas and opinions expressed herein are those of the author(s) and endorsement by the State of California, Department of Public Health, the National Cancer Institute, and the Centers for Disease Control and Prevention or their Contractors and Subcontractors is not intended nor should be inferred. The authors acknowledge the efforts of the Applied Research Program, National Cancer Institute; the Office of Research, Development and Information, Centers for Medicare and Medicaid Services; Information Management Services, Inc.; and the SEER Program tumor registries in the creation of the SEER-Medicare database. The interpretation and reporting of the SEER-Medicare data are the sole responsibility of the authors. NR 25 TC 1 Z9 1 U1 3 U2 3 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 DEC PY 2016 VL 175 IS 5 BP 829 EP 840 DI 10.1111/bjh.14305 PG 12 WC Hematology SC Hematology GA ED8SF UT WOS:000389140500007 PM 27650975 ER PT J AU Herrera, AF Kim, HT Kong, KA Faham, M Sun, H Sohani, AR Alyea, EP Carlton, VE Chen, YB Cutler, CS Ho, VT Koreth, J Kotwaliwale, C Nikiforow, S Ritz, J Rodig, SJ Soiffer, RJ Antin, JH Armand, P AF Herrera, Alex F. Kim, Haesook T. Kong, Katherine A. Faham, Malek Sun, Heather Sohani, Aliyah R. Alyea, Edwin P. Carlton, Victoria E. Chen, Yi-Bin Cutler, Corey S. Ho, Vincent T. Koreth, John Kotwaliwale, Chitra Nikiforow, Sarah Ritz, Jerome Rodig, Scott J. Soiffer, Robert J. Antin, Joseph H. Armand, Philippe TI Next-generation sequencing-based detection of circulating tumour DNA After allogeneic stem cell transplantation for lymphoma SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE lymphomas; minimal residual disease; stem cell transplantation; chronic lymphocytic leukaemia; non-Hodgkin lymphoma ID MINIMAL RESIDUAL DISEASE; CHRONIC LYMPHOCYTIC-LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; NON-HODGKIN-LYMPHOMA; BONE-MARROW-TRANSPLANTATION; POLYMERASE-CHAIN-REACTION; REDUCED-INTENSITY; CONDITIONING REGIMENS; CLL3X TRIAL; RELAPSE AB Next-generation sequencing (NGS)-based circulating tumour DNA (ctDNA) detection is a promising monitoring tool for lymphoid malignancies. We evaluated whether the presence of ctDNA was associated with outcome after allogeneic haematopoietic stem cell transplantation (HSCT) in lymphoma patients. We studied 88 patients drawn from a phase 3 clinical trial of reduced-intensity conditioning HSCT in lymphoma. Conventional restaging and collection of peripheral blood samples occurred at pre-specified time points before and after HSCT and were assayed for ctDNA by sequencing of the immunoglobulin or T-cell receptor genes. Tumour clonotypes were identified in 87% of patients with adequate tumour samples. Sixteen of 19 (84%) patients with disease progression after HSCT had detectable ctDNA prior to progression at a median of 37months prior to relapse/progression. Patients with detectable ctDNA 3months after HSCT had inferior progression-free survival (PFS) (2-year PFS 58% vs. 84% in ctDNA-negative patients, P=0033). In multivariate models, detectable ctDNA was associated with increased risk of progression/death (Hazard ratio 39, P=0003) and increased risk of relapse/progression (Hazard ratio 108, P=00006). Detectable ctDNA is associated with an increased risk of relapse/progression, but further validation studies are necessary to confirm these findings and determine the clinical utility of NGS-based minimal residual disease monitoring in lymphoma patients after HSCT. C1 [Herrera, Alex F.] City Hope Med Ctr, Dept Hematol & Hematopoiet Cell Transplantat, Duarte, CA USA. [Kim, Haesook T.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Kong, Katherine A.; Faham, Malek; Carlton, Victoria E.; Kotwaliwale, Chitra] Adaptive Biotechnol Corp, San Francisco, CA USA. [Sun, Heather; Rodig, Scott J.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Sohani, Aliyah R.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Alyea, Edwin P.; Cutler, Corey S.; Ho, Vincent T.; Koreth, John; Nikiforow, Sarah; Ritz, Jerome; Soiffer, Robert J.; Antin, Joseph H.; Armand, Philippe] Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA 02115 USA. [Chen, Yi-Bin] Massachusetts Gen Hosp, Div Bone Marrow Transplantat, Boston, MA 02114 USA. RP Armand, P (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM parmand@partners.org FU Conquer Cancer Foundation/ASCO Young Investigator Award; National Cancer Institute of the National Institutes of Health [NIH 2K12CA001727-21]; ASH Scholar Award; ASCO Career Development Award; ASBMT/Genentech Young Investigator Award; Dunkin' Donuts Rising Star award; National Institutes of Health [R01CA183559-03, P01CA142106, R01CA183559, R01CA183560] FX We would like to thank the patients who participated in the clinical trial and their families, as well as the nursing and research staff involved in the study. This study would not have been possible without the dedication of Doreen Hearsey and the staff of the Dana-Farber Cancer Institute Pasquarello Tissue Bank. We would like to thank the Ted and Eileen Pasquarello Research Fund and the Jock and Bunny Adams Education and Research Fund. A.F.H was supported by a Conquer Cancer Foundation/ASCO Young Investigator Award and by the National Cancer Institute of the National Institutes of Health under award number NIH 2K12CA001727-21. The content is solely the responsibility of A.F.H. and does not necessarily represent the official views of the National Institutes of Health. P.A. was supported by an ASH Scholar Award, an ASCO Career Development Award, an ASBMT/Genentech Young Investigator Award, and a Dunkin' Donuts Rising Star award for this work. H.T.K was supported by National Institutes of Health award, R01CA183559-03. This work was also supported by National Institutes of Health awards P01CA142106, R01CA183559, and R01CA183560. NR 43 TC 0 Z9 0 U1 6 U2 6 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 DEC PY 2016 VL 175 IS 5 BP 841 EP 850 DI 10.1111/bjh.14311 PG 10 WC Hematology SC Hematology GA ED8SF UT WOS:000389140500008 PM 27711974 ER PT J AU Jurczyszyn, A Nahi, H Avivi, I Gozzetti, A Niesvizky, R Yadlapati, S Jayabalan, DS Robak, P Pika, T Andersen, KT Rasche, L Madry, K Woszczyk, D Razny, M Usnarska-Zubkiewicz, L Knopinska-Posluszny, W Wojciechowska, M Guzicka-Kazimierczak, R Joks, M Grosicki, S Ciepluch, H Rymko, M Vesole, DH Castillo, JJ AF Jurczyszyn, Artur Nahi, Hareth Avivi, Irit Gozzetti, Alessandro Niesvizky, Ruben Yadlapati, Sujitha Jayabalan, David S. Robak, Pawel Pika, Tomas Andersen, Kristian T. Rasche, Leo Madry, Krzysztof Woszczyk, Dariusz Razny, Malgorzata Usnarska-Zubkiewicz, Lidia Knopinska-Posluszny, Wanda Wojciechowska, Malgorzata Guzicka-Kazimierczak, Renata Joks, Monika Grosicki, Sebastian Ciepluch, Hanna Rymko, Marcin Vesole, David H. Castillo, Jorge J. TI Characteristics and outcomes of patients with multiple myeloma aged 21-40years versus 41-60years: a multi-institutional case-control study SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE myeloma; young; survival; outcomes; transplantation ID POPULATION; SURVIVAL; PATTERNS AB We compared the outcomes of multiple myeloma (MM) patients aged 21-40 and 41-60years in the novel agent era. This case-control study included 1089 patients between 2000 and 2015. Cases and controls were matched for sex, International Staging System (ISS) stage and institution. There were 173 patients in the younger group and 916 patients in the older group. Younger patients presented with a higher incidence of lytic lesions (82% vs. 72%; P=004) and high-risk cytogenetic abnormalities (83% vs. 68%; P=0007), but lower rate of elevated lactate dehydrogenase (21% vs. 44%; P<0001). Five- and 10-year overall survival (OS) in younger versus older patients was 83% vs. 67% and 56% vs. 39%, respectively (P<0001). Similar results were seen when studying the subset of 780 patients who underwent autologous transplantation. Younger patients with ISS stage 1 had a better OS than older patients (P<0001). There was no survival difference between younger and older patients with ISS stage 2 or 3. Younger MM patients, aged 21-40years, treated in the era of novel agents have a better OS than their counterparts aged 41-60years, but the survival advantage observed in younger patients was lost in more advanced stages of MM. C1 [Jurczyszyn, Artur] Jagiellonian Univ, Coll Med, Dept Haematol, 17 Kopernika Str, PL-31501 Krakow, Poland. [Nahi, Hareth] Karolinska Univ Hosp, Stockholm, Sweden. [Avivi, Irit] Tel Aviv Med Ctr & Sch Med, Tel Aviv, Israel. [Gozzetti, Alessandro] Azienda Osped Univ Senese, Siena, Italy. [Niesvizky, Ruben; Yadlapati, Sujitha; Jayabalan, David S.] Weill Cornell Med Coll, New York, NY USA. [Robak, Pawel] Med Univ Lodz, Copernicus Mem Hosp, Dept Haematol, Lodz, Poland. [Pika, Tomas] Univ Hosp Olomouc, Olomouc, Czech Republic. [Andersen, Kristian T.] Vejle Hosp, Dept Med, Vejle, Denmark. [Rasche, Leo] UAMS Myeloma Inst, Little Rock, AR USA. [Madry, Krzysztof] Med Univ Warsaw, Warsaw, Poland. [Woszczyk, Dariusz] State Hosp, Dept Haematol, Opole, Poland. [Razny, Malgorzata] State Hosp, Dept Haematol, Krakow, Poland. [Usnarska-Zubkiewicz, Lidia] Wroclaw Med Univ, Wroclaw, Poland. [Knopinska-Posluszny, Wanda] Warmia & Masuria Oncol Ctr, Minist Interior Hosp Olsztyn, Olsztyn, Poland. [Wojciechowska, Malgorzata] State Hosp, Dept Haematol, Olsztyn, Poland. [Guzicka-Kazimierczak, Renata] Pomeranian Med Univ, Szczecin, Poland. [Joks, Monika] Poznan Univ Med Sci, Dept Haematol & Bone Marrow Transplantat, Poznan, Poland. [Grosicki, Sebastian] Med Univ Silesia, Sch Publ Hlth, Dept Canc Prevent, Katowice, Poland. [Ciepluch, Hanna] Copernicus Reg Oncol Ctr, Gdansk, Poland. [Rymko, Marcin] Dist Hosp Torun, Dept Haematol, Torun, Poland. [Vesole, David H.] Hackensack Univ Med Ctr, John Theurer Canc Ctr, Hackensack, NJ USA. [Castillo, Jorge J.] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA USA. RP Jurczyszyn, A (reprint author), Jagiellonian Univ, Coll Med, Dept Haematol, 17 Kopernika Str, PL-31501 Krakow, Poland. EM mmjurczy@cyf-kr.edu.pl OI nahi, hareth/0000-0003-4711-5094; Castillo, Jorge/0000-0001-9490-7532 NR 15 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1048 EI 1365-2141 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD DEC PY 2016 VL 175 IS 5 BP 884 EP 891 DI 10.1111/bjh.14328 PG 8 WC Hematology SC Hematology GA ED8SF UT WOS:000389140500013 PM 27682187 ER PT J AU Tata, PR Rajagopal, J AF Tata, Purushothama Rao Rajagopal, Jayaraj TI Regulatory Circuits and Bi-directional Signaling between Stem Cells and Their Progeny SO Cell Stem Cell LA English DT Editorial Material ID DYNAMICS; NICHE AB Feedback signals from daughter cells to stem cells are well studied and known to provide important feedback cues. Emerging evidence shows that stem cells also send feedforward signals to their progeny. Complex circuits involving both negative and positive feedback and feedforward signals likely contribute to robust tissue maintenance and regeneration. C1 [Tata, Purushothama Rao; Rajagopal, Jayaraj] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Tata, Purushothama Rao; Rajagopal, Jayaraj] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Tata, Purushothama Rao; Rajagopal, Jayaraj] Massachusetts Gen Hosp, Dept Internal Med, Div Pulm & Crit Care Med, Boston, MA 02114 USA. [Rajagopal, Jayaraj] Massachusetts Gen Hosp Children, Pediat Pulm Med, Boston, MA 02114 USA. [Rajagopal, Jayaraj] Massachusetts Eye & Ear, Div Otol & Laryngol, Boston, MA 02114 USA. [Tata, Purushothama Rao] Duke Univ, Sch Med, Dept Cell Biol, Durham, NC 27710 USA. RP Rajagopal, J (reprint author), Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA.; Rajagopal, J (reprint author), Harvard Stem Cell Inst, Cambridge, MA 02138 USA.; Rajagopal, J (reprint author), Massachusetts Gen Hosp, Dept Internal Med, Div Pulm & Crit Care Med, Boston, MA 02114 USA.; Rajagopal, J (reprint author), Massachusetts Gen Hosp Children, Pediat Pulm Med, Boston, MA 02114 USA.; Rajagopal, J (reprint author), Massachusetts Eye & Ear, Div Otol & Laryngol, Boston, MA 02114 USA. EM jrajagopal@mgh.harvard.edu NR 10 TC 1 Z9 1 U1 2 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 EI 1875-9777 J9 CELL STEM CELL JI Cell Stem Cell PD DEC 1 PY 2016 VL 19 IS 6 BP 686 EP 689 DI 10.1016/j.stem.2016.11.009 PG 4 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA EE3GD UT WOS:000389474900007 PM 27912089 ER PT J AU Aranda-Orgilles, B Saldana-Meyer, R Wang, E Trompouki, E Fassl, A Lau, S Mullenders, J Rocha, PP Raviram, R Guillamot, M Sanchez-Diaz, M Wang, K Kayembe, C Zhang, N Amoasii, L Choudhuri, A Skok, JA Schober, M Reinberg, D Sicinski, P Schrewe, H Tsirigos, A Zon, LI Aifantis, I AF Aranda-Orgilles, Beatriz Saldana-Meyer, Ricardo Wang, Eric Trompouki, Eirini Fassl, Anne Lau, Stephanie Mullenders, Jasper Rocha, Pedro P. Raviram, Ramya Guillamot, Maria Sanchez-Diaz, Maria Wang, Kun Kayembe, Clarisse Zhang, Nan Amoasii, Leonela Choudhuri, Avik Skok, Jane A. Schober, Markus Reinberg, Danny Sicinski, Piotr Schrewe, Heinrich Tsirigos, Aristotelis Zon, Leonard I. Aifantis, Iannis TI MED12 Regulates HSC-Specific Enhancers Independently of Mediator Kinase Activity to Control Hematopoiesis SO Cell Stem Cell LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; ACUTE MYELOID-LEUKEMIA; HUMAN CDK8 SUBCOMPLEX; GENOME-WIDE ANALYSIS; STEM-CELLS; UBIQUITIN LIGASE; GENE-EXPRESSION; TRANSCRIPTIONAL REGULATORS; CHROMATIN ARCHITECTURE; TUMOR-SUPPRESSOR AB Hematopoietic-specific transcription factors require coactivators to communicate with the general transcription machinery and establish transcriptional programs that maintain hematopoietic stem cell (HSC) self-renewal, promote differentiation, and prevent malignant transformation. Mediator is a large coactivator complex that bridges enhancer-localized transcription factors with promoters, but little is known about Mediator function in adult stem cell self-renewal and differentiation. We show that MED12, a member of the Mediator kinase module, is an essential regulator of HSC homeostasis, as in vivo deletion of Med12 causes rapid bone marrow aplasia leading to acute lethality. Deleting other members of the Mediator kinase module does not affect HSC function, suggesting kinase-independent roles of MED12. MED12 deletion destabilizes P300 binding at lineage-specific enhancers, resulting in H3K27Ac depletion, enhancer de-activation, and consequent loss of HSC stemness signatures. As MED12 mutations have been described recently in blood malignancies, alterations in MED12-dependent enhancer regulation may control C1 [Aranda-Orgilles, Beatriz; Wang, Eric; Lau, Stephanie; Mullenders, Jasper; Guillamot, Maria; Sanchez-Diaz, Maria; Wang, Kun; Kayembe, Clarisse; Zhang, Nan; Tsirigos, Aristotelis; Aifantis, Iannis] NYU, Sch Med, Laura & Isaac Perlmutter Canc Ctr, Dept Pathol, New York, NY 10016 USA. [Aranda-Orgilles, Beatriz; Wang, Eric; Lau, Stephanie; Mullenders, Jasper; Guillamot, Maria; Sanchez-Diaz, Maria; Wang, Kun; Kayembe, Clarisse; Zhang, Nan; Tsirigos, Aristotelis; Aifantis, Iannis] NYU, Sch Med, Helen L & Martin S Kimmel Ctr Stem Cell Biol, New York, NY 10016 USA. [Saldana-Meyer, Ricardo; Reinberg, Danny] NYU, Howard Hughes Med Inst, Sch Med, New York, NY 10016 USA. [Saldana-Meyer, Ricardo; Reinberg, Danny] NYU, Dept Biochem & Mol Pharmacol, Sch Med, New York, NY 10016 USA. [Trompouki, Eirini] Max Planck Inst Immunobiol & Epigenet, Dept Cellular & Mol Immunol, D-79108 Freiburg, Germany. [Fassl, Anne; Sicinski, Piotr] Harvard Med Sch, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Fassl, Anne; Sicinski, Piotr] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. [Rocha, Pedro P.; Raviram, Ramya; Skok, Jane A.] NYU, Sch Med, Dept Pathol, New York, NY 10016 USA. [Amoasii, Leonela] Univ Texas Southwestern Med Ctr Dallas, Dept Mol Biol, Dallas, TX 75390 USA. [Choudhuri, Avik; Zon, Leonard I.] Harvard Med Sch, Stem Cell Program, Childrens Hosp Boston, Boston, MA 02115 USA. [Choudhuri, Avik; Zon, Leonard I.] Harvard Med Sch, Div Hematol Oncol, Boston, MA 02115 USA. [Choudhuri, Avik; Zon, Leonard I.] Howard Hughes Med Inst, Boston, MA 02115 USA. [Schober, Markus] NYU, Helen L & Martin S Kimmel Ctr Stem Cell Biol, Ronald O Perelman Dept Dermatol, Perlmutter Canc Ctr,Sch Med, New York, NY 10016 USA. [Schober, Markus] NYU, Helen L & Martin S Kimmel Ctr Stem Cell Biol, Dept Cell Biol, Perlmutter Canc Ctr,Sch Med, New York, NY 10016 USA. [Schrewe, Heinrich] Max Planck Inst Mol Genet, Dept Dev Genet, D-14195 Berlin, Germany. [Tsirigos, Aristotelis] NYU, Sch Med, Ctr Hlth Informat & Bioinformat, New York, NY 10016 USA. RP Aifantis, I (reprint author), NYU, Sch Med, Laura & Isaac Perlmutter Canc Ctr, Dept Pathol, New York, NY 10016 USA.; Aifantis, I (reprint author), NYU, Sch Med, Helen L & Martin S Kimmel Ctr Stem Cell Biol, New York, NY 10016 USA. EM iannis.aifantis@nyumc.org OI Tsirigos, Aristotelis/0000-0002-7512-8477; Skok, Jane/0000-0002-4145-1516; Zhang, Nan/0000-0002-4134-7911 FU NYU GTC (NIH) [P30CA016087-30]; NYU Proteomics Resource Center (Cancer Center Support Grant) [P30CA016087]; Immunohistochemistry and Histopathology and Immunohistochemistry cores [P30CA016087]; Cytometry and Cell Sorting facility at NYU [P30CA016087]; NIH [RO1CA133379, RO1CA105129, RO1CA149655, 5RO1CA173636, 1RO1CA194923, R01 CA190509]; Leukemia and Lymphoma Society (LLS TRP Program); NYSTEM program of the New York State Health Department [NYSTEM-N11G-255]; Feodor Lynen Fellowship from the Humboldt-Foundation; Deutsche Jose Carreras Leukamie-Stiftung e.V. FX We thank all members of the I. A. lab for useful discussions; A. Heguy and the NYU GTC (NIH grant P30CA016087-30) for expertise with sequencing experiments and library preparation; Dr. B. Ueberheide at the NYU Proteomics Resource Center (Cancer Center Support Grant P30CA016087) for mass spectrometry experiments; Igor Dolgarev, Harris Lazaris, and Yixiao Gong for helpful bioinformatic discussions and protocols; and The High Performance Computing Facility of the NYU Center of Health Informatics and Bioinformatics. We thank the Immunohistochemistry and Histopathology and Immunohistochemistry cores and the Cytometry and Cell Sorting facility at NYU (both supported by the Cancer Center Support Grant P30CA016087). We thank E.N. Olson and R. Bassel-Duby at the University of Texas Southwestern Medical Center for kindly providing the Med13Flox/Flox mice. We thank Dr. S. Heimfeld in Fred Hutchinson Cancer Research Center for providing human CD34+ cells (Core Center of Excellence NIDDK Grant DK56465), Dr. Chris Vakoc for the RN2-Cas9 line, and Professor L. Carlsson (University of Umea) for the HPC-7 cells. The I. A. lab is supported by the NIH (RO1CA133379, RO1CA105129, RO1CA149655, 5RO1CA173636, 1RO1CA194923, and R01 CA190509 to P.S.), the Leukemia and Lymphoma Society (LLS TRP Program), and the NYSTEM program of the New York State Health Department (NYSTEM-N11G-255). B.A.-O. was supported by the Feodor Lynen Fellowship from the Humboldt-Foundation and the Deutsche Jose Carreras Leukamie-Stiftung e.V. NR 56 TC 1 Z9 1 U1 5 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 EI 1875-9777 J9 CELL STEM CELL JI Cell Stem Cell PD DEC 1 PY 2016 VL 19 IS 6 BP 784 EP 799 DI 10.1016/j.stem.2016.08.004 PG 16 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA EE3GD UT WOS:000389474900015 PM 27570068 ER PT J AU Lee, JJ Pedley, A Marqusee, E Sutherland, P Hoffmann, U Massaro, JM Fox, CS AF Lee, Jane J. Pedley, Alison Marqusee, Ellen Sutherland, Patrice Hoffmann, Udo Massaro, Joseph M. Fox, Caroline S. TI Thyroid function and cardiovascular disease risk factors in euthyroid adults: a cross-sectional and longitudinal study SO CLINICAL ENDOCRINOLOGY LA English DT Article ID BODY-MASS INDEX; WEIGHT-LOSS; ADIPOSE-TISSUE; FREE-THYROXINE; SERUM TSH; FREE T4; METABOLIC SYNDROME; HORMONE LEVELS; HEART-DISEASE; ASSOCIATION AB Objective and designWe explored the cross-sectional and longitudinal associations of thyroid function within the normal range with cardiovascular disease (CVD) risk factors and adiposity measures. Patients and measurementsA total of 3483 (504% women) participants for the cross-sectional CVD study and 1630 (412% women) participants for the cross-sectional body composition substudy were drawn from the Framingham Third Generation Exam 1; 2912 participants (501% women) for the longitudinal CVD study and 713 participants (359% women) for the longitudinal body composition substudy were drawn from the Framingham Third Generation Exams 1-2. Thyroid function was assessed by thyrotropin [thyroid-stimulating hormone (TSH)] and free thyroxine (fT4) concentrations within the reference range at Exam 1. The associations between thyroid function and CVD risk factors were modelled via multivariable-adjusted regression models. Multivariable adjustment included age, sex, current smoking, postmenopausal status and BMI. ResultsCross-sectionally, higher TSH concentration was associated with increased odds of hypertriglyceridaemia [odds ratio (OR)=110], and higher BMI ( = 019 kg/m(2)), total cholesterol ( = 005 mmol/l), triglycerides ( = 00006 mmol/l) and subcutaneous adipose tissue (SAT) volume ( = 388 cm(3)) (all P < 005). Cross-sectionally, fT4 was inversely associated with metabolic and adiposity-related CVD risk factors, including obesity (OR = 117), hypertriglyceridaemia (OR = 109), BMI ( = 042 kg/m(2)), total cholesterol ( = 005 mmol/l), triglycerides ( = 00002 mmol/l), visceral adipose tissue (VAT) volume ( = -207 cm(3)) and attenuation (017 HU) and VAT/SAT ratio ( = -001) (all P < 005). However, during 61 years of follow-up, baseline TSH and fT4 levels were not longitudinally associated with CVD risk factors and adiposity measures. ConclusionsThyroid function within the normal range is cross-sectionally, but not longitudinally, associated with CVD risk factors and adiposity measures. C1 [Lee, Jane J.; Pedley, Alison; Sutherland, Patrice; Fox, Caroline S.] Populat Studies Branch, Framingham Heart Study, Div Intramural Res, Natl Heart Lung & Blood Inst, Framingham, MA USA. [Marqusee, Ellen] Brigham & Womens Hosp, Div Endocrinol, Boston, MA USA. [Marqusee, Ellen] Harvard Med Sch, Boston, MA USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Massaro, Joseph M.] Boston Univ, Dept Biostat, Boston, MA 02215 USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol, 75 Francis St, Boston, MA 02115 USA. [Fox, Caroline S.] Harvard Med Sch, Boston, MA USA. RP Fox, CS (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov FU National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195] FX This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (contract N01-HC-25195). NR 34 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0300-0664 EI 1365-2265 J9 CLIN ENDOCRINOL JI Clin. Endocrinol. PD DEC PY 2016 VL 85 IS 6 BP 932 EP 941 DI 10.1111/cen.13124 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA EC1DU UT WOS:000387844500015 PM 27256825 ER PT J AU Kisiel, JB Konijeti, GG Piscitello, AJ Chandra, T Goss, TF Ahlquist, DA Farraye, FA Ananthakrishnan, AN AF Kisiel, John B. Konijeti, Gauree G. Piscitello, Andrew J. Chandra, Tarun Goss, Thomas F. Ahlquist, David A. Farraye, Francis A. Ananthakrishnan, Ashwin N. TI Stool DNA Analysis is Cost-Effective for Colorectal Cancer Surveillance in Patients With Ulcerative Colitis SO Clinical Gastroenterology and Hepatology LA English DT Article DE ICER; QALY; Cost Benefit Analysis; Inflammatory Bowel Diseases ID INFLAMMATORY-BOWEL-DISEASE; CONSENSUS STATEMENT; COLON-CANCER; DYSPLASIA; MORTALITY; RISK; CARE; MANAGEMENT; NEOPLASIA; CHROMOENDOSCOPY AB BACKGROUND & AIMS: Patients with chronic ulcerative colitis are at increased risk for colorectal neoplasia (CRN). Surveillance by white-light endoscopy (WLE) or chromoendoscopy may reduce risk of CRN, but these strategies are underused. Analysis of DNA from stool samples (sDNA) can detect CRN with high levels of sensitivity, but it is not clear if this approach is cost-effective. We simulated these strategies for CRN detection to determine which approach is most cost-effective. METHODS: We adapted a previously published Markov model to simulate the clinical course of chronic ulcerative colitis, the incidence of cancer or dysplasia, and costs and benefits of care with 4 surveillance strategies: (1) analysis of sDNA and diagnostic chromoendoscopy for patients with positive results, (2) analysis of sDNA with diagnostic WLE for patients with positive results, (3) chromoendoscopy with targeted collection of biopsies, or (4) WLE with random collection of biopsies. Costs were based on 2014 Medicare reimbursement. The primary outcome was the incremental cost-effectiveness ratio (incremental cost/incremental difference in quality adjusted life-years) compared with no surveillance and a willingness-to-pay threshold of $50,000. RESULTS: All strategies fell below the willingness-to-pay threshold at 2-year intervals. Incremental cost-effectiveness ratios were $16,362 per quality-adjusted life-year for sDNA analysis with diagnostic chromoendoscopy; $18,643 per quality-adjusted life-year for sDNA analysis with diagnostic WLE; $23,830 per quality-adjusted life-year for chromoendoscopy alone; and $27,907 per quality-adjusted life-year for WLE alone. In sensitivity analyses, sDNA analysis with diagnostic chromoendoscopy was more cost-effective than chromoendoscopy alone, up to a cost of $1135 per sDNA test. sDNA analysis remained cost-effective at all rates of compliance; when combined with diagnostic chromoendoscopy, this approach was preferred over chromoendoscopy alone, when the specificity of the sDNA test for CRN was >65%. CONCLUSIONS: Based on a Markov model, surveillance for CRN is cost-effective for patients with chronic ulcerative colitis. Analysis of sDNA with chromoendoscopies for patients with positive results was more cost-effective than chromoendoscopy or WLE alone. C1 [Kisiel, John B.; Ahlquist, David A.] Mayo Clin, Div Gastroenterol & Hepatol, Rochester, MN USA. [Konijeti, Gauree G.] Scripps Clin, Div Gastroenterol, La Jolla, CA 92037 USA. [Konijeti, Gauree G.] Scripps Translat Sci Inst, La Jolla, CA USA. [Piscitello, Andrew J.; Chandra, Tarun] EmpiraQA LLC, Long Grove, IL USA. [Goss, Thomas F.] Boston Healthcare Associates, Boston, MA USA. [Farraye, Francis A.] Boston Univ, Sch Med, Boston Med Ctr, Ctr Digest Disorders,Sect Gastroenterol, Boston, MA 02118 USA. [Ananthakrishnan, Ashwin N.] Massachusetts Gen Hosp, Div Gastroenterol & Hepatol, Boston, MA 02114 USA. [Ananthakrishnan, Ashwin N.] Harvard Med Sch, Boston, MA USA. RP Kisiel, JB (reprint author), 200 First St SW, Rochester, MN 55902 USA. EM kisiel.john@mayo.edu FU Maxine and Jack Zarrow Family Foundation of Tulsa Oklahoma; Paul Calabresi Program in Clinical-Translational Research [NCI CA90628]; National Institutes of Health [NCATS TR001112]; Carol M. Gatton endowment for Digestive Diseases Research; Exact Sciences (Madison, WI) FX This study was made possible by grants (to JBK) from the Maxine and Jack Zarrow Family Foundation of Tulsa Oklahoma and the Paul Calabresi Program in Clinical-Translational Research (NCI CA90628). Additional support was provided by a National Institutes of Health KL2 grant (NCATS TR001112, to GGK). Additional partial support was provided by the Carol M. Gatton endowment for Digestive Diseases Research. Additional funding was provided by Exact Sciences (Madison, WI). NR 33 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 1542-3565 EI 1542-7714 J9 CLIN GASTROENTEROL H JI Clin. Gastroenterol. Hepatol. PD DEC PY 2016 VL 14 IS 12 BP 1778 EP 1787 DI 10.1016/j.cgh.2016.07.018 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EE0QD UT WOS:000389283100017 PM 27464589 ER PT J AU Sharaiha, RZ Tyberg, A Khashab, MA Kumta, NA Karia, K Nieto, J Siddiqui, UD Waxman, I Joshi, V Benias, PC Darwin, P DiMaio, CJ Mulder, CJ Friedland, S Forcione, DG Sejpal, DV Gonda, TA Gress, FG Gaidhane, M Koons, A DeFilippis, EM Salgado, S Weaver, KR Poneros, JM Sethi, A Ho, S Kumbhari, V Singh, VK Tieu, AH Parra, V Likhitsup, A Womeldorph, C Casey, B Jonnalagadda, SS Desai, AP Carr-Locke, DL Kahaleh, M Siddiqui, AA AF Sharaiha, Reem Z. Tyberg, Amy Khashab, Mouen A. Kumta, Nikhil A. Karia, Kunal Nieto, Jose Siddiqui, Uzma D. Waxman, Irving Joshi, Virendra Benias, Petros C. Darwin, Peter DiMaio, Christopher J. Mulder, Christopher J. Friedland, Shai Forcione, David G. Sejpal, Divyesh V. Gonda, Tamas A. Gress, Frank G. Gaidhane, Monica Koons, Ann DeFilippis, Ersilia M. Salgado, Sanjay Weaver, Kristen R. Poneros, John M. Sethi, Amrita Ho, Sammy Kumbhari, Vivek Singh, Vikesh K. Tieu, Alan H. Parra, Viviana Likhitsup, Alisa Womeldorph, Craig Casey, Brenna Jonnalagadda, Sreeni S. Desai, Amit P. Carr-Locke, David L. Kahaleh, Michel Siddiqui, Ali A. TI Endoscopic Therapy With Lumen-apposing Metal Stents Is Safe and Effective for Patients With Pancreatic Walled-off Necrosis SO Clinical Gastroenterology and Hepatology LA English DT Article DE ERCP; Pancreatic Necrosis; Pancreatitis; Stents; Necrosectomy ID PERIPANCREATIC FLUID COLLECTIONS; ULTRASOUND-GUIDED DRAINAGE; REPORTING RISK-FACTORS; NECROTIZING PANCREATITIS; ADVERSE EVENTS; NECROSECTOMY; EXPERIENCE AB BACKGROUND & AIMS: Endoscopic ultrasound-guided transmural drainage and necrosectomy have become the standard treatment for patients with pancreatic walled-off necrosis (WON). Lumen-apposing metal stents (LAMS) have shown success in the management of pancreatic fluid collections. However, there are few data on their specific roles in management of WON. We investigated the efficacy and safety of LAMS in treatment of WON. METHODS: We performed a retrospective multicenter case series of 124 patients with WON who underwent endoscopic transmural drainage by using LAMS at 17 tertiary care centers from January 2014 through May 2015. Patients underwent endoscopic ultrasound-guided cystogastrostomy or cystoenterostomy with placement of an LAMS into the WON collection. At the discretion of the endoscopist, we performed direct endoscopic necrosectomy, irrigation with hydrogen peroxide, and/or nasocystic drain placement. We performed endoscopic retrograde cholangiopancreatography with pancreatic duct stent placement when indicated. Concomitant therapies included direct endoscopic debridement (n = 78), pancreatic duct stent placement for leak (n = 19), hydrogen peroxide-assisted necrosectomy (n = 38), and nasocystic irrigation (n = 22). We collected data for a median time of 4 months (range, 1-34 months) after the LAMS placement. The primary outcomes were rates of technical success (successful placement of the LAMS), clinical success (resolution of WON, on the basis of image analysis, without need for further intervention via surgery or interventional radiology), and adverse events. RESULTS: The median size of the WON was 9.5 cm (range, 4-30 cm). Eight patients had 2 LAMS placed for multiport access, all with technical success (100%). Clinical success was achieved in 107 patients (86.3%) after 3 months of follow-up. Thirteen patients required a percutaneous drain, and 3 required a surgical intervention to manage their WON. The stents remained patent in 94% of patients (117 of 124) and migrated in 5.6% of patients (7 of 124). The median number of endoscopic interventions was 2 (range, 1-9 interventions). CONCLUSIONS: On the basis of a retrospective analysis of 124 patients, endoscopic therapy of WON by using LAMS is safe and effective. Creation of a large and sustained cystogastrostomy or cystoenterostomy tract is effective in the drainage and treatment of WON. C1 [Sharaiha, Reem Z.; Tyberg, Amy; Kumta, Nikhil A.; Karia, Kunal; Gaidhane, Monica; DeFilippis, Ersilia M.; Salgado, Sanjay; Weaver, Kristen R.; Parra, Viviana; Desai, Amit P.; Kahaleh, Michel] Weill Cornell Med Ctr, Gastroenterol & Hepatol, New York, NY USA. [Khashab, Mouen A.; Kumbhari, Vivek; Singh, Vikesh K.; Tieu, Alan H.] Johns Hopkins Med Inst, Gastroenterol & Hepatol, Baltimore, MD 21205 USA. [Siddiqui, Uzma D.; Waxman, Irving; Koons, Ann] Univ Chicago Med & Biol Sci, CERT, Chicago, IL USA. [Gonda, Tamas A.; Gress, Frank G.; Poneros, John M.; Sethi, Amrita] Columbia Univ, Med Ctr, Gastroenterol & Hepatol, New York, NY USA. [Friedland, Shai] Stanford Hosp & Clin, Gastroenterol & Hepatol, Palo Alto, CA USA. [Joshi, Virendra] Ochsner Hlth Syst, Gastroenterol & Hepatol, New Orleans, LA USA. [Benias, Petros C.; Carr-Locke, David L.] Beth Israel Mt Sinai, Gastroenterol & Hepatol, New York, NY USA. [Darwin, Peter] Univ Maryland, Gastroenterol & Hepatol, Baltimore, MD 21201 USA. [Siddiqui, Ali A.] Jefferson Univ, Gastroenterol & Hepatol, Philadelphia, PA USA. [DiMaio, Christopher J.] Mt Sinai Med Ctr, Gastroenterol & Hepatol, New York, NY 10029 USA. [Ho, Sammy] Montefiore, Gastroenterol & Hepatol, New York, NY USA. [Forcione, David G.; Casey, Brenna] Harvard Med Sch, Massachusetts Gen Hosp, Gastroenterol & Hepatol, Boston, MA USA. [Mulder, Christopher J.; Womeldorph, Craig] Brooke Army Med Ctr, Gastroenterol & Hepatol, Ft Sam Houston, TX 78234 USA. [Sejpal, Divyesh V.] North Shore Long Isl Jewish Hlth Syst, Gastroenterol & Hepatol, New York, NY USA. [Likhitsup, Alisa; Jonnalagadda, Sreeni S.] Univ Missouri Kansas City, Gastroenterol & Hepatol, Kansas City, MO USA. [Nieto, Jose] Borland Groover Clin, Dept Gastroenterol & Hepatol, Jacksonville, FL USA. RP Sharaiha, RZ (reprint author), Weill Cornell Med Coll, Div Gastroenterol & Hepatol, 1305 York Ave,Fourth Floor, New York, NY 10021 USA. EM rzs9001@med.cornell.edu OI Nieto, Jose/0000-0003-2465-3033; Gaidhane, Monica/0000-0001-6773-7080 FU Boston Scientific; Xlumena FX These authors disclose the following: Mouen A. Khashab, Michel Kahaleh, David L. Carr-Locke, and Jose Nieto have received financial support from Boston Scientific and Xlumena. The remaining authors disclose no conflicts. NR 21 TC 2 Z9 2 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1542-3565 EI 1542-7714 J9 CLIN GASTROENTEROL H JI Clin. Gastroenterol. Hepatol. PD DEC PY 2016 VL 14 IS 12 BP 1797 EP 1803 DI 10.1016/j.cgh.2016.05.011 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA EE0QD UT WOS:000389283100019 PM 27189914 ER PT J AU Trusheim, MR Shrier, AA Antonijevic, Z Beckman, RA Campbell, RK Chen, C Flaherty, KT Loewy, J Lacombe, D Madhavan, S Selker, HP Esserman, LJ AF Trusheim, M. R. Shrier, A. A. Antonijevic, Z. Beckman, R. A. Campbell, R. K. Chen, C. Flaherty, K. T. Loewy, J. Lacombe, D. Madhavan, S. Selker, H. P. Esserman, L. J. TI PIPELINEs: Creating Comparable Clinical Knowledge Efficiently by Linking Trial Platforms SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID OF-CONCEPT TRIALS; NO GO DECISIONS; I-SPY 2; DRUG DEVELOPMENT; STRATIFIED MEDICINE; BREAST-CANCER; PREDICTIVE BIOMARKERS; ADAPTIVE DESIGNS; IMPLEMENTATION; HETEROGENEITY AB Adaptive, seamless, multisponsor, multitherapy clinical trial designs executed as large scale platforms, could create superior evidence more efficiently than single-sponsor, single-drug trials. These trial PIPELINEs also could diminish barriers to trial participation, increase the representation of real-world populations, and create systematic evidence development for learning throughout a therapeutic life cycle, to continually refine its use. Comparable evidence could arise from multiarm design, shared comparator arms, and standardized endpoints-aiding sponsors in demonstrating the distinct value of their innovative medicines; facilitating providers and patients in selecting the most appropriate treatments; assisting regulators in efficacy and safety determinations; helping payers make coverage and reimbursement decisions; and spurring scientists with translational insights. Reduced trial times and costs could enable more indications, reduced development cycle times, and improved system financial sustainability. Challenges to overcome range from statistical to operational to collaborative governance and data exchange. C1 [Trusheim, M. R.; Shrier, A. A.] MIT, Ctr Biomed Innovat, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Shrier, A. A.] Riptide Management, Cambridge, MA USA. [Antonijevic, Z.] Amgen Inc, Thousand Oaks, CA USA. [Beckman, R. A.] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. [Beckman, R. A.; Madhavan, S.] Georgetown Univ, Med Ctr, Innovat Ctr Biomed Informat, Washington, DC 20007 USA. [Campbell, R. K.] Brown Univ, Providence, RI 02912 USA. [Chen, C.] Merck & Co Inc, Philadelphia, PA USA. [Flaherty, K. T.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Loewy, J.] DataForeThought, Winchester, MA USA. [Lacombe, D.] EORTC, Brussels, Belgium. [Selker, H. P.] Tufts Med Ctr, Boston, MA USA. [Selker, H. P.] Tufts Univ, Inst Clin Res & Hlth Policy Studies, Boston, MA 02111 USA. [Selker, H. P.] Tufts Clin & Translat Sci Inst, Boston, MA USA. [Esserman, L. J.] Univ Calif San Francisco, Med Ctr, Carol Franc Buck Breast Care Ctr, San Francisco, CA 94143 USA. RP Trusheim, MR (reprint author), MIT, Ctr Biomed Innovat, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM Trusheim@MIT.edu NR 116 TC 2 Z9 2 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD DEC PY 2016 VL 100 IS 6 BP 713 EP 729 DI 10.1002/cpt.514 PG 17 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EC0RY UT WOS:000387809600023 PM 27643536 ER PT J AU Akhbari, M Shamsollahi, MB Sayadi, O Armoundas, AA Jutten, C AF Akhbari, Mahsa Shamsollahi, Mohammad B. Sayadi, Omid Armoundas, Antonis A. Jutten, Christian TI ECG segmentation and fiducial point extraction using multi hidden Markov model SO COMPUTERS IN BIOLOGY AND MEDICINE LA English DT Article DE Electrocardiogram (ECG); Hidden Markov model (HMM); MultiHMM; Segmentation; Fiducial point (FP) extraction ID T-WAVE DELINEATION; SIGNAL ANALYSIS; GIBBS SAMPLER; CLASSIFICATION; DATABASE; EVENTS AB In this paper, we propose a novel method for extracting fiducial points (FPs) of electrocardiogram (ECG) signals. We propose the use of multi hidden Markov model (MultiHMM) as opposed to the traditional use of Classic HMM. In the MultiHMM method, each segment of an ECG beat is represented by a separate ergodic continuous density HMM. Each HMM has different state number and is trained separately. In the test step, the log likelihood of two consecutive HMMs is compared and a path is estimated, which shows the correspondence of each part of the ECG signal to the HMM with the maximum log-likelihood. Fiducial points are estimated from the obtained path. For performance evaluation, the Physionet QT database and a Swine ECG database are used and the proposed method is compared with the Classic HMM and a method based on partially collapsed Gibbs sampler (PCGS). In our evaluation using the QT database, we also compare the results with low-pass differentiation, hybrid feature extraction algorithm, a method based on the wavelet transform and three HMM-based approaches. For the Swine database, the root mean square error (RMSE) values, across all FPs for MultiHMM, Classic HMM and PCGS methods are 13, 21 and 40 ms, respectively and the MultiHMM exhibits smaller error variability than other methods. For the QT database, RMSE values for MultiHMM, Classic HMM, Wavelet and PCGS methods are 10, 17, 26 and 38 ms, respectively. Our results demonstrate that our proposed MultiHMM approach outperforms other benchmark methods that exist in the literature; therefore can be used in practical ECG fiducial point extraction. C1 [Akhbari, Mahsa; Shamsollahi, Mohammad B.] Sharif Univ Technol, Dept Elect Engn, BiSIPL, Tehran, Iran. [Akhbari, Mahsa; Jutten, Christian] GIPSA Lab, Grenoble, France. [Jutten, Christian] Inst Univ Frantace, Paris, France. [Sayadi, Omid; Armoundas, Antonis A.] Harvard Med Sch, Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. RP Akhbari, M (reprint author), Sharif Univ Technol, Dept Elect Engn, BiSIPL, Tehran, Iran. EM akhbari.mahsa@gmail.com; mbshams@sharif.edu; sayadi.omid@mgh.harvard.edu; aarmoundas@partners.org; christian.jutten@gipsa-lab.grenoble-inp.fr FU French Embassy; [ERC-2012-AdG-320684-CHESS] FX This work has been partly supported by the Ph.D. scholarship of the French Embassy and the European Project ERC-2012-AdG-320684-CHESS. NR 50 TC 1 Z9 1 U1 7 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0010-4825 EI 1879-0534 J9 COMPUT BIOL MED JI Comput. Biol. Med. PD DEC 1 PY 2016 VL 79 BP 21 EP 29 DI 10.1016/j.compbiomed.2016.09.004 PG 9 WC Biology; Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Computer Science; Engineering; Mathematical & Computational Biology GA EE0UP UT WOS:000389294700003 PM 27744177 ER PT J AU Hinton, DE Barlow, DH Reis, R de Jong, J AF Hinton, Devon E. Barlow, David H. Reis, Ria de Jong, Joop TI A Transcultural Model of the Centrality of "Thinking a Lot" in Psychopathologies Across the Globe and the Process of Localization: A Cambodian Refugee Example SO CULTURE MEDICINE AND PSYCHIATRY LA English DT Article DE "Thinking too much"; "Thinking a lot"; Rumination; Idioms of distress; Cross-cultural psychiatry; Cultural concepts of distress ID POSTTRAUMATIC-STRESS-DISORDER; REPETITIVE NEGATIVE THINKING; CULTURAL SYNDROMES; SPIRIT POSSESSION; PTSD; EXPERIENCES; TOO; PREVALENCE; RUMINATION; CHILDHOOD AB We present a general model of why "thinking a lot" is a key presentation of distress in many cultures and examine how "thinking a lot" plays out in the Cambodian cultural context. We argue that the complaint of "thinking a lot" indicates the presence of a certain causal network of psychopathology that is found across cultures, but that this causal network is localized in profound ways. We show, using a Cambodian example, that examining "thinking a lot" in a cultural context is a key way of investigating the local bio-cultural ontology of psychopathology. Among Cambodian refugees, a typical episode of "thinking a lot" begins with ruminative-type negative cognitions, in particular worry and depressive thoughts. Next these negative cognitions may induce mental symptoms (e.g., poor concentration, forgetfulness, and "zoning out") and somatic symptoms (e.g., migraine headache, migraine-like blurry vision such as scintillating scotomas, dizziness, palpitations). Subsequently the very fact of "thinking a lot" and the induced symptoms may give rise to multiple catastrophic cognitions. Soon, as distress escalates, in a kind of looping, other negative cognitions such as trauma memories may be triggered. All these processes are highly shaped by the Cambodian socio-cultural context. The article shows that Cambodian trauma survivors have a locally specific illness reality that centers on dynamic episodes of "thinking a lot," or on what might be called the "thinking a lot" causal network. C1 [Hinton, Devon E.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Anxiety & Traumat, Stress Disorders, One Bowdoin Sq,6th Floor, Boston, MA 02114 USA. [Barlow, David H.] Boston Univ, Ctr Anxiety & Related Disorders, Boston, MA 02215 USA. [Reis, Ria] Leiden Univ, Med Ctr, Leiden, Netherlands. [Reis, Ria; de Jong, Joop] Univ Amsterdam, Amsterdam Inst Social Sci Res, Amsterdam, Netherlands. [Reis, Ria] Univ Cape Town, Childrens Inst, Sch Child & Adolescent Hlth, Cape Town, South Africa. [de Jong, Joop] Boston Univ, Sch Med, Boston, MA 02118 USA. RP Hinton, DE (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Ctr Anxiety & Traumat, Stress Disorders, One Bowdoin Sq,6th Floor, Boston, MA 02114 USA. EM devon_hinton@hms.harvard.edu NR 57 TC 0 Z9 0 U1 5 U2 5 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0165-005X EI 1573-076X J9 CULT MED PSYCHIAT JI Cult. Med. Psychiatr. PD DEC PY 2016 VL 40 IS 4 BP 570 EP 619 DI 10.1007/s11013-016-9489-4 PG 50 WC Anthropology; Psychiatry; Social Sciences, Biomedical SC Anthropology; Psychiatry; Biomedical Social Sciences GA ED4OA UT WOS:000388827800003 PM 27085706 ER PT J AU Sarma, A Scott, NS AF Sarma, Amy Scott, Nandita S. TI Aspirin Use in Women: Current Perspectives and Future Directions SO CURRENT ATHEROSCLEROSIS REPORTS LA English DT Review DE Aspirin; Women; Prevention; Pregnancy; Pre-eclampsia ID LOW-DOSE ASPIRIN; SERVICES TASK-FORCE; CARDIOVASCULAR-DISEASE EVENTS; PRIMARY PREVENTION; UNITED-STATES; RECOMMENDATION STATEMENT; POSTMENOPAUSAL WOMEN; SECONDARY PREVENTION; DIABETES-MELLITUS; PREECLAMPSIA AB Purpose of Review This review examines the recent literature on the use of low-dose aspirin (LDA) for primary and secondary prevention of cardiovascular disease in women, use of LDA for pre-eclampsia prevention in pregnancy, and the underutilization of aspirin therapy in women as compared to men. Recent Findings While men and women should not differ with respect to aspirin use for secondary prevention, its role in primary prevention remains unclear for both sexes, with particular uncertainty in women. Reflective of this are conflicting recommendations in current guidelines for primary prevention and thus investigations of primary prevention aspirin use are ongoing and will play an important role in elucidating its efficacy. While there is significant heterogeneity in studies to date of LDA for pre-eclampsia prevention, based on recent meta-analyses suggesting promising results, guidelines now recommend initiation in high risk women after the 12th week of gestation. Finally, studies consistently reveal that aspirin therapy is underutilized in women as compared to men, suggesting a need to better educate physicians and the general public about its use in women. Summary Further research is needed to better elucidate the role of aspirin in women for primary prevention of cardiovascular disease and for pre-eclampsia in high risk pregnant women. In addition, further investigation into the factors that lead to the current underutilization of aspirin in women are required in order to ensure that patients of both sexes are optimally treated, with the goal of improving cardiovascular outcomes in all patients. C1 [Sarma, Amy; Scott, Nandita S.] Massachusetts Gen Hosp, Dept Cardiol, 55 Fruit St, Boston, MA 02114 USA. RP Scott, NS (reprint author), Massachusetts Gen Hosp, Dept Cardiol, 55 Fruit St, Boston, MA 02114 USA. EM nsscott@mgh.harvard.edu NR 58 TC 0 Z9 0 U1 2 U2 2 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1523-3804 EI 1534-6242 J9 CURR ATHEROSCLER REP JI Curr. Atheroscleros. Rep. PD DEC PY 2016 VL 18 IS 12 AR 74 DI 10.1007/s11883-016-0630-1 PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA ED3CK UT WOS:000388726700005 PM 27807733 ER PT J AU Horton, MB Silva, PS Cavallerano, JD Aiello, LP AF Horton, Mark B. Silva, Paolo S. Cavallerano, Jerry D. Aiello, Lloyd Paul TI Clinical Components of Telemedicine Programs for Diabetic Retinopathy SO CURRENT DIABETES REPORTS LA English DT Review DE Teleophthalmology; Telemedicine; Diabetes mellitus; Diabetic retinopathy ID NONMYDRIATIC FUNDUS CAMERA; RETINAL IMAGING-SYSTEM; EYE CARE; SCREENING-PROGRAM; DIGITAL IMAGE; PUPIL SIZE; COLOR-PHOTOGRAPHY; SLIDE FILM; OPHTHALMOSCOPY; SPECIFICITY AB Diabetic retinopathy is a leading cause of new-onset vision loss worldwide. Treatments supported by large clinical trials are effective in preserving vision, but many persons do not receive timely diagnosis and treatment of diabetic retinopathy, which is typically asymptomatic when most treatable. Telemedicine evaluation to identify diabetic retinopathy has the potential to improve access to care, but there are no universal standards regarding camera choice or protocol for ocular telemedicine. We review the literature regarding the impact of imaging device, number and size of retinal images, pupil dilation, type of image grader, and diagnostic accuracy on telemedicine assessment for diabetic retinopathy. Telemedicine assessment of diabetic retinopathy has the potential to preserve vision, but further development of telemedicine specific technology and standardization of operations are needed to better realize its potential. C1 [Horton, Mark B.] Joslin Vis Network, Indian Hlth Serv Teleophthalmol Program, Phoenix, AZ USA. [Silva, Paolo S.; Cavallerano, Jerry D.; Aiello, Lloyd Paul] Joslin Diabet Ctr, Beetham Eye Inst, Boston, MA 02215 USA. [Silva, Paolo S.; Cavallerano, Jerry D.; Aiello, Lloyd Paul] Harvard Med Sch, Dept Ophthalmol, Boston, MA USA. RP Horton, MB (reprint author), Joslin Vis Network, Indian Hlth Serv Teleophthalmol Program, Phoenix, AZ USA. EM mark.horton@ihs.gov FU Optos FX Mark B. Horton, Paolo S. Silva, and Jerry D. Cavallerano declare that they have no conflict of interest. Lloyd Paul Aiello reports nonfinancial support from Optos, and Optos has loaned Joslin Diabetes Center imaging equipment. NR 100 TC 1 Z9 1 U1 1 U2 1 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1534-4827 EI 1539-0829 J9 CURR DIABETES REP JI Curr. Diabetes Rep. PD DEC PY 2016 VL 16 IS 12 AR 129 DI 10.1007/s11892-016-0813-8 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA ED3CZ UT WOS:000388728200011 PM 27796779 ER PT J AU Horton, MB Silva, PS Cavallerano, JD Aiello, LP AF Horton, Mark B. Silva, Paolo S. Cavallerano, Jerry D. Aiello, Lloyd Paul TI Operational Components of Telemedicine Programs for Diabetic Retinopathy SO CURRENT DIABETES REPORTS LA English DT Review DE Teleophthalmology; Telemedicine; Diabetes mellitus; Diabetic retinopathy ID RETINAL IMAGING TECHNOLOGY; COST-EFFECTIVENESS; ECONOMIC-ANALYSIS; EYE CARE; FUNDUS PHOTOGRAPHY; SCREENING-PROGRAM; HEALTH-CARE; SYSTEM; TELEOPHTHALMOLOGY; OUTCOMES AB Diabetic retinopathy is a leading cause of new-onset vision loss worldwide. Treatments supported by large clinical trials are effective in preserving vision, but many persons do not receive timely diagnosis and treatment of diabetic retinopathy, which is typically asymptomatic when most treatable. Telemedicine evaluation to identify diabetic retinopathy has the potential to improve access to care and improve outcomes, but incomplete implementation of published standards creates a risk to program utility and sustainability. In a prior article, we reviewed the literature regarding the impact of imaging device, number and size of retinal images, pupil dilation, type of image grader, and diagnostic accuracy on telemedicine assessment for diabetic retinopathy. This article reviews the literature regarding the impact of automated image grading, cost effectiveness, program standards, and quality assurance (QA) on telemedicine assessment of diabetic retinopathy. Telemedicine assessment of diabetic retinopathy has the potential to preserve vision, but greater attention to development and implementation of standards is needed to better realize its potential. C1 [Horton, Mark B.] Joslin Vis Network, Indian Hlth Serv Teleophthalmol Program, Phoenix, AZ USA. [Silva, Paolo S.; Cavallerano, Jerry D.; Aiello, Lloyd Paul] Joslin Diabet Ctr, Beetham Eye Inst, Boston, MA 02215 USA. [Silva, Paolo S.; Cavallerano, Jerry D.; Aiello, Lloyd Paul] Harvard Med Sch, Dept Ophthalmol, Boston, MA USA. RP Horton, MB (reprint author), Joslin Vis Network, Indian Hlth Serv Teleophthalmol Program, Phoenix, AZ USA. EM mark.horton@ihs.gov FU Optos FX Lloyd Paul Aiello reports non-financial support from Optos; and Optos has loaned Joslin Diabetes Center imaging equipment. NR 59 TC 0 Z9 0 U1 1 U2 1 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1534-4827 EI 1539-0829 J9 CURR DIABETES REP JI Curr. Diabetes Rep. PD DEC PY 2016 VL 16 IS 12 AR 128 DI 10.1007/s11892-016-0814-7 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA ED3CZ UT WOS:000388728200010 PM 27796778 ER PT J AU Song, BJ Aiello, LP Pasquale, LR AF Song, Brian J. Aiello, Lloyd Paul Pasquale, Louis R. TI Presence and Risk Factors for Glaucoma in Patients with Diabetes SO CURRENT DIABETES REPORTS LA English DT Review DE Glaucoma; Diabetes mellitus; Diabetic retinopathy; Epidemiology; Risk factors ID OPEN-ANGLE GLAUCOMA; PROTEIN-KINASE-C; ENDOTHELIAL GROWTH-FACTOR; NORMAL-TENSION GLAUCOMA; RETINAL GANGLION-CELLS; CEREBROSPINAL-FLUID PRESSURE; RETROGRADE AXONAL-TRANSPORT; SYSTEMIC BLOOD-PRESSURE; VISUAL-FIELD DEFECTS; BEAVER DAM EYE AB Diabetes mellitus represents a growing international public health issue with a near quadrupling in its worldwide prevalence since 1980. Though it has many known microvascular complications, vision loss from diabetic retinopathy is one of the most devastating for affected individuals. In addition, there is increasing evidence to suggest that diabetic patients have a greater risk for glaucoma as well. Though the pathophysiology of glaucoma is not completely understood, both diabetes and glaucoma appear to share some common risk factors and pathophysiologic similarities with studies also reporting that the presence of diabetes and elevated fasting glucose levels are associated with elevated intraocular pressure-the primary risk factor for glaucomatous optic neuropathy. While no study has completely addressed the possibility of detection bias, most recent epidemiologic evidence suggests that diabetic populations are likely enriched with glaucoma patients. As the association between diabetes and glaucoma becomes better defined, routine evaluation for glaucoma in diabetic patients, particularly in the telemedicine setting, may become a reasonable consideration to reduce the risk of vision loss in these patients. C1 [Song, Brian J.; Pasquale, Louis R.] Harvard Med Sch, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. [Aiello, Lloyd Paul] Harvard Med Sch, Joslin Diabet Ctr, Beetham Eye Inst, 1 Joslin Pl, Boston, MA 02115 USA. [Pasquale, Louis R.] Brigham & Womens Hosp, Channing Div Network Med, 181 Longwood Ave, Boston, MA 02215 USA. RP Song, BJ (reprint author), Harvard Med Sch, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM Brian_Song@meei.harvard.edu FU Harvard Vision Clinical Scientist Development Program through the National Institute of Health (Bethesda, MD) [5K12 EY016335]; Harvard Glaucoma Center of Excellence (Boston, MA); Massachusetts Lions Eye Research Fund (Belmont, MA) FX Supported in part by the Harvard Vision Clinical Scientist Development Program through the National Institute of Health Grant 5K12 EY016335 (Bethesda, MD), the Harvard Glaucoma Center of Excellence (Boston, MA), and the Massachusetts Lions Eye Research Fund (Belmont, MA). NR 224 TC 0 Z9 0 U1 6 U2 6 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1534-4827 EI 1539-0829 J9 CURR DIABETES REP JI Curr. Diabetes Rep. PD DEC PY 2016 VL 16 IS 12 AR 124 DI 10.1007/s11892-016-0815-6 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA ED3CZ UT WOS:000388728200006 PM 27766584 ER PT J AU Turner, AP Alschuler, KN Hughes, AJ Beier, M Haselkorn, JK Sloan, AP Ehde, DM AF Turner, Aaron P. Alschuler, Kevin N. Hughes, Abbey J. Beier, Meghan Haselkorn, Jodie K. Sloan, Alicia P. Ehde, Dawn M. TI Mental Health Comorbidity in MS: Depression, Anxiety, and Bipolar Disorder SO CURRENT NEUROLOGY AND NEUROSCIENCE REPORTS LA English DT Review DE Multiple sclerosis; Depression; Anxiety; Bipolar disorder ID QUALITY-OF-LIFE; COGNITIVE-BEHAVIORAL THERAPY; MULTIPLE-SCLEROSIS PATIENTS; RANDOMIZED CONTROLLED-TRIAL; MAJOR DEPRESSION; INJECTION ANXIETY; PHYSICAL-ACTIVITY; SOCIAL SUPPORT; MOOD DISORDER; PSYCHIATRIC MORBIDITY AB Among individuals with multiple sclerosis (MS), mental health comorbidities play a significant role in contributing to secondary disability and detracting from quality of life. This review examines current evidence surrounding three mental health issues of particular relevance to MS: depression, anxiety, and bipolar disorder. We review what is known of the prevalence, correlates, screening mechanisms, and current treatment of each issue and provide recommendations for future areas of research. C1 [Turner, Aaron P.; Haselkorn, Jodie K.; Sloan, Alicia P.] VA Puget Sound Hlth Care Syst, Rehabil Care Serv, 1660 S Columbian Way, Seattle, WA 98108 USA. [Turner, Aaron P.; Alschuler, Kevin N.; Haselkorn, Jodie K.; Ehde, Dawn M.] Univ Washington, Dept Rehabil Med, Seattle, WA 98195 USA. [Alschuler, Kevin N.] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. [Hughes, Abbey J.; Beier, Meghan] Johns Hopkins Univ, Dept Phys Med & Rehabil, Baltimore, MD USA. [Haselkorn, Jodie K.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. RP Turner, AP (reprint author), VA Puget Sound Hlth Care Syst, Rehabil Care Serv, 1660 S Columbian Way, Seattle, WA 98108 USA.; Turner, AP (reprint author), Univ Washington, Dept Rehabil Med, Seattle, WA 98195 USA. EM Aaron.Turner@va.gov NR 144 TC 0 Z9 0 U1 16 U2 16 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 DEC PY 2016 VL 16 IS 12 AR 106 DI 10.1007/s11910-016-0706-x PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA ED4IU UT WOS:000388812100005 PM 27848174 ER PT J AU Dayton, TL Jacks, T Vander Heiden, MG AF Dayton, Talya L. Jacks, Tyler Vander Heiden, Matthew G. TI PKM2, cancer metabolism, and the road ahead SO EMBO REPORTS LA English DT Review DE cancer metabolism; glycolysis; PKM2; pyruvate kinase ID PYRUVATE-KINASE M2; PROTEIN-KINASE; TUMOR-CELLS; NUCLEAR TRANSLOCATION; RAT-LIVER; ALLOSTERIC REGULATION; HORMONAL-REGULATION; ISOFORM EXPRESSION; LUNG-CANCER; AMINO-ACID AB A major metabolic aberration associated with cancer is a change in glucose metabolism. Isoform selection of the glycolytic enzyme pyruvate kinase has been implicated in the metabolic phenotype of cancer cells, and specific pyruvate kinase isoforms have been suggested to support divergent energetic and biosynthetic requirements of cells in tumors and normal tissues. PKM2 isoform expression has been closely linked to embryogenesis, tissue repair, and cancer. In contrast, forced expression of the PKM1 isoform has been associated with reduced tumor cell proliferation. Here, we discuss the role that PKM2 plays in cells and provide a historical perspective for how the study of PKM2 has contributed to understanding cancer metabolism. We also review recent studies that raise important questions with regard to the role of PKM2 in both normal and cancer cell metabolism. C1 [Dayton, Talya L.; Jacks, Tyler; Vander Heiden, Matthew G.] MIT, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Dayton, Talya L.; Jacks, Tyler; Vander Heiden, Matthew G.] MIT, Dept Biol, Cambridge, MA 02139 USA. [Jacks, Tyler] MIT, Howard Hughes Med Inst, Cambridge, MA USA. [Vander Heiden, Matthew G.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Vander Heiden, MG (reprint author), MIT, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Vander Heiden, MG (reprint author), MIT, Dept Biol, Cambridge, MA 02139 USA. EM mvh@mit.edu FU NCI NIH HHS [R01 CA168653] NR 78 TC 0 Z9 0 U1 12 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1469-221X EI 1469-3178 J9 EMBO REP JI EMBO Rep. PD DEC PY 2016 VL 17 IS 12 BP 1721 EP 1730 DI 10.15252/embr.201643300 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA EE1GQ UT WOS:000389329400010 PM 27856534 ER PT J AU Post, KE Flanagan, J AF Post, Kathryn E. Flanagan, Jane TI Web based survivorship interventions for women with breast cancer: An integrative review SO European Journal of Oncology Nursing LA English DT Review DE Breast cancer; Survivorship; Intervention; Web-based ID RANDOMIZED CONTROLLED-TRIAL; CARE PLANS; POSTTREATMENT CARE; SELF-MANAGEMENT; HEALTH-CARE; FOLLOW-UP; NEEDS; EDUCATION; SERVICES; THERAPY AB Purpose: Breast cancer survivors' experience a range of negative sequelae post-treatment including depression, anxiety, physical side effects from treatment, sexuality concerns and decreased quality of life. Survivorship care is recommended by the IOM to meet the post treatment needs of survivors but implementation is variable and barriers to delivery such as time and resource restraints have been identified. Web-based interventions may be a way to overcome some barriers to providing quality survivorship care that is efficacious, cost efficient and convenient. The purpose of this integrative review is to summarize and synthesize the current research on web-based interventions for breast cancer survivorship care and evaluate the data to determine potential implications for practice. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used to guide this integrative review. Key search terms included breast cancer, survivor, intervention, Web, internet and technology. Articles evaluating web-based survivorship interventions (n = 405) for early stage breast cancer patients who completed active therapy were included. Results: Fifteen studies met inclusion criteria: six randomized controlled trials, six survey based studies, one qualitative study, one retrospective chart review and one mixed methods study. Studies evaluating cognitive behavioral therapy provided the strongest data. Other studies evaluated exercise and lifestyle interventions, symptom management programs and pilot/exploratory work. Findings suggest that web based survivorship interventions are feasible and acceptable to breast cancer survivors. Conclusions: Web-based survivorship interventions have the potential to meet the needs of breast cancer survivors while possibly overcoming some of the documented barriers to survivorship care implementation. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Post, Kathryn E.; Flanagan, Jane] Boston Coll, William F Connell Sch Nursing, 140 Commonwealth Ave, Chestnut Hill, MA 02467 USA. [Post, Kathryn E.; Flanagan, Jane] Massachusetts Gen Hosp, 140 Commonwealth Ave, Chestnut Hill, MA 02467 USA. RP Post, KE (reprint author), Boston Coll, William F Connell Sch Nursing, 140 Commonwealth Ave, Chestnut Hill, MA 02467 USA. EM postk@bc.edu; jane.flanagan@bc.edu NR 50 TC 0 Z9 0 U1 5 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1462-3889 EI 1532-2122 J9 EUR J ONCOL NURS JI Eur. J. Oncol. Nurs. PD DEC PY 2016 VL 25 BP 90 EP 99 DI 10.1016/j.ejon.2016.10.004 PG 10 WC Oncology; Nursing SC Oncology; Nursing GA ED9EH UT WOS:000389172500013 PM 27865259 ER PT J AU Bittner, DO Arnold, M Klinghammer, L Schuhbaeck, A Hell, MM Muschiol, G Gauss, S Lell, M Uder, M Hoffmann, U Achenbach, S Marwan, M AF Bittner, Daniel O. Arnold, Martin Klinghammer, Lutz Schuhbaeck, Annika Hell, Michaela M. Muschiol, Gerd Gauss, Soeren Lell, Michael Uder, Michael Hoffmann, Udo Achenbach, Stephan Marwan, Mohamed TI Contrast volume reduction using third generation dual source computed tomography for the evaluation of patients prior to transcatheter aortic valve implantation SO EUROPEAN RADIOLOGY LA English DT Article DE Heart valve prosthesis implantation; Transcatheter aortic valve implantation (TAVI); Low contrast agent; Computed tomography; Aortography ID PROSPECTIVE RANDOMIZED-TRIAL; EXPERT CONSENSUS DOCUMENT; CT CORONARY-ANGIOGRAPHY; REDUCED IODINE LOAD; REPLACEMENT; NEPHROPATHY; OUTCOMES; DISEASE; ACCURACY; STENOSIS AB Chronic renal failure is common in patients referred for transcatheter aortic valve implantation (TAVI). CT angiography is recommended and provides crucial information prior to TAVI. We evaluated the feasibility of a reduced contrast volume protocol for pre-procedural CT imaging. Forty consecutive patients were examined with prospectively ECG-triggered high-pitch spiral acquisition using a novel third-generation dual-source CT system; 38 ml contrast agent was used. Image quality was graded on a visual scale (1-4). Contrast attenuation was measured at the level of the aortic root and at the iliac bifurcation. Mean patient age was 82 +/- 6 years (23 males; 58 %). Mean attenuation/average image quality was 285 +/- 60 HU/1.5 at the aortic annulus compared to 289 +/- 74 HU/1.8 at the iliac bifurcation (p = 0.77/p = 0.29). Mean estimated effective radiation dose was 2.9 +/- 0.3 mSv. A repeat acquisition was necessary in one patient due to image quality. Out of the 35 patients who underwent TAVI, 31 (89 %) patients had no or mild aortic regurgitation. Thirty-two (91 %) patients were discharged successfully. Pre-procedural CTA with a total of 38 ml contrast volume is feasible and clinically useful, using third-generation dual-source CT, allowing comprehensive imaging for procedural success. aEuro cent Reduction of contrast agent volume is crucial in patients with chronic renal failure. aEuro cent Novel third-generation computed tomography helps to reduce contrast agent volume. aEuro cent Pre-procedural CT allows comprehensive imaging for procedural success before heart valve implantation. aEuro cent A low-contrast CT protocol is feasible for pre-procedural TAVI planning. C1 [Bittner, Daniel O.; Arnold, Martin; Klinghammer, Lutz; Schuhbaeck, Annika; Hell, Michaela M.; Muschiol, Gerd; Gauss, Soeren; Achenbach, Stephan; Marwan, Mohamed] Friedrich Alexander Univ Erlangen Nurnberg FAU, Univ Hosp Erlangen, Dept Internal Med Cardiol 2, Ulmenweg 18, D-91054 Erlangen, Germany. [Bittner, Daniel O.; Hoffmann, Udo] Harvard Med Sch, Massachusetts Gen Hosp, Cardiac MR PET CT Program, Boston, MA 02115 USA. [Lell, Michael; Uder, Michael] Friedrich Alexander Univ Erlangen Nurnberg FAU, Univ Hosp Erlangen, Dept Radiol, Erlangen, Germany. RP Bittner, DO (reprint author), Friedrich Alexander Univ Erlangen Nurnberg FAU, Univ Hosp Erlangen, Dept Internal Med Cardiol 2, Ulmenweg 18, D-91054 Erlangen, Germany.; Bittner, DO (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Cardiac MR PET CT Program, Boston, MA 02115 USA. EM daniel.bittner@uk-erlangen.de FU Siemens Healthcare; Abbott Vascular; German government [01EX1012B] FX The scientific guarantor of this publication is Dr. med. Mohamed Marwan. The authors of this manuscript declare relationships with the following companies: Stephan Achenbach has received research grants from Siemens Healthcare and Abbott Vascular. Mohamed Marwan has received Speaker honoraria from Siemens Healthcare and Edwards Lifesciences. Lutz Klinghammer kindly provided statistical advice for this manuscript and has significant statistical expertise. This project was supported by the German government (01EX1012B, 'Spitzencluster' Medical Valley EMN, Bundesministerium fur Bildung und Forschung). NR 28 TC 0 Z9 0 U1 4 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0938-7994 EI 1432-1084 J9 EUR RADIOL JI Eur. Radiol. PD DEC PY 2016 VL 26 IS 12 BP 4497 EP 4504 DI 10.1007/s00330-016-4320-8 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EC0SJ UT WOS:000387810700034 PM 26995206 ER PT J AU Veld, J Vossen, JA Bernstein, KD Halpern, EF Torriani, M Bredella, MA AF Veld, Joyce Vossen, Josephina A. Bernstein, Karen De Amorim Halpern, Elkan F. Torriani, Martin Bredella, Miriam A. TI Adipose tissue and muscle attenuation as novel biomarkers predicting mortality in patients with extremity sarcomas SO EUROPEAN RADIOLOGY LA English DT Article DE Computed tomography (CT); Adipose tissue attenuation; Muscle attenuation; Hounsfield Units; Sarcoma ID SKELETAL-MUSCLE; COMPUTED-TOMOGRAPHY; BODY-COMPOSITION; CANCER-PATIENTS; INSULIN-RESISTANCE; WEIGHT-LOSS; ALL-CAUSE; SARCOPENIA; CACHEXIA; OUTCOMES AB To assess CT-attenuation of abdominal adipose tissue and psoas muscle as predictors of mortality in patients with sarcomas of the extremities. Our study was IRB approved and HIPAA compliant. The study group comprised 135 patients with history of extremity sarcoma (mean age: 53 +/- 17 years) who underwent whole body PET/CT. Abdominal subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and psoas muscle attenuation (HU) was assessed on non-contrast, attenuation-correction CT. Clinical information including survival, tumour stage, sarcoma type, therapy and pre-existing comorbidities were recorded. Cox proportional hazard models were used to determine longitudinal associations between adipose tissue and muscle attenuation and mortality. There were 47 deaths over a mean follow-up period of 20 +/- 17 months. Higher SAT and lower psoas attenuation were associated with increased mortality (p = 0.03 and p = 0.005, respectively), which remained significant after adjustment for age, BMI, sex, tumor stage, therapy, and comorbidities (p = 0.002 and p = 0.02, respectively). VAT attenuation was not associated with mortality. Attenuation of SAT and psoas muscle, assessed on non-contrast CT, are predictors of mortality in patients with extremity sarcomas, independent of other established prognostic factors, suggesting that adipose tissue and muscle attenuation could serve as novel biomarkers for mortality in patients with sarcomas. aEuro cent CT-attenuation of adipose tissue and muscle predict mortality in sarcoma patients aEuro cent CT-attenuation predicts mortality independent of established prognostic factors aEuro cent Patients with sarcomas often undergo CT for staging or surveillance aEuro cent Adipose tissue and muscle attenuation could serve as biomarkers for mortality. C1 [Veld, Joyce; Vossen, Josephina A.; Torriani, Martin; Bredella, Miriam A.] Massachusetts Gen Hosp, Dept Radiol, Div Musculoskeletal Imaging & Intervent, Yawkey 6E,55 Fruit St, Boston, MA 02114 USA. [Veld, Joyce; Vossen, Josephina A.; Bernstein, Karen De Amorim; Torriani, Martin; Bredella, Miriam A.] Harvard Med Sch, Yawkey 6E,55 Fruit St, Boston, MA 02114 USA. [Bernstein, Karen De Amorim] Massachusetts Gen Hosp, Dept Radiat Oncol, Francis H Burr Proton Therapy Ctr, 55 Fruit St, Boston, MA 02114 USA. [Halpern, Elkan F.] Massachusetts Gen Hosp, Inst Technol Assessment, 101 Merrimac St, Boston, MA 02114 USA. [Halpern, Elkan F.] Harvard Med Sch, 101 Merrimac St, Boston, MA 02114 USA. RP Bredella, MA (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Musculoskeletal Imaging & Intervent, Yawkey 6E,55 Fruit St, Boston, MA 02114 USA.; Bredella, MA (reprint author), Harvard Med Sch, Yawkey 6E,55 Fruit St, Boston, MA 02114 USA. EM joyceveld1@gmail.com; josephina.vossen@gmail.com; kbernstein@mgh.harvard.edu; ehalpern@mgh.harvard.edu; mtorriani@mgh.harvard.edu; mbredella@mgh.harvard.edu NR 39 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0938-7994 EI 1432-1084 J9 EUR RADIOL JI Eur. Radiol. PD DEC PY 2016 VL 26 IS 12 BP 4649 EP 4655 DI 10.1007/s00330-016-4306-6 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EC0SJ UT WOS:000387810700052 PM 26960539 ER PT J AU von Witzleben, A Goerttler, LT Lennerz, J Weissinger, S Kornmann, M Mayer-Steinacker, R von Baer, A Schultheiss, M Moller, P Barth, TFE AF von Witzleben, Adrian Goerttler, Lukas T. Lennerz, Jochen Weissinger, Stephanie Kornmann, Marko Mayer-Steinacker, Regine von Baer, Alexandra Schultheiss, Markus Moeller, Peter Barth, Thomas F. E. TI In chordoma, metastasis, recurrences, Ki-67 index, and a matrix-poor phenotype are associated with patients' shorter overall survival SO EUROPEAN SPINE JOURNAL LA English DT Article DE Chordoma; Histological parameters and subtyping; Overall survival ID SKULL BASE CHORDOMAS; IMMUNOHISTOCHEMICAL EXPRESSION; PROGNOSTIC VALUE; NEUROBLASTOMA; CLASSIFICATION; LYMPHOMA; PATTERNS; THERAPY; CELLS; P53 AB To establish a chordoma tissue cohort (n = 43) and to correlate localization, size, metastasis, residual disease (R-status), recurrences, histological subtype, matrix content, and Ki-67 proliferation index with patients' overall survival (OS). We used routine histopathology supplemented by immunohistochemistry. In our patient cohort (median age 69 years, range 17 to 84 years) the median OS was 8.25 years. 24 chordomas were localized in the sacrum, 6 in lumbar vertebrae, 7 in thoracic and cervical vertebrae, 5 were limited to the clivus, and one was localized in the nasal septum. Ten patients had metastases, with pulmonary, nodal, and hepatic involvement. 23 patients had recurrent disease. 23 chordomas were classified as 'not otherwise specified' (NOS). Besides NOS, we found the following differentiation patterns: renal cell cancer like in six cases, chondroid in four cases, hepatoid differentiation in three cases, and anaplastic morphology in six cases. Ki-67 index of ae10 %, presence of metastasis, and the low content of extracellular matrix were statistically linked to poor OS (p < 0.05). The matrix-poor phenotype had a higher Ki-67 index (p < 0.05). Furthermore, presence of metastasis was associated with a higher Ki-67 index in the primary lesion, a positive resection margin, and multiple recurrences (p < 0.05 each). We propose to include these parameters in the final pathologic report of the resected chordoma. C1 [von Witzleben, Adrian; Goerttler, Lukas T.; Weissinger, Stephanie; Moeller, Peter; Barth, Thomas F. E.] Univ Ulm, Inst Pathol, M23,Albert Einstein Allee 11, D-89081 Ulm, Germany. [Lennerz, Jochen] Massachusetts Gen Hosp, Dept Pathol, Boston, MA USA. [Kornmann, Marko] Univ Ulm, Dept Gen & Visceral Surg, Ulm, Germany. [Mayer-Steinacker, Regine] Univ Ulm, Dept Internal Med 3, Ulm, Germany. [von Baer, Alexandra; Schultheiss, Markus] Univ Ulm, Dept Trauma Surg, Ulm, Germany. RP Moller, P (reprint author), Univ Ulm, Inst Pathol, M23,Albert Einstein Allee 11, D-89081 Ulm, Germany. EM adrian.von-witzleben@uni-ulm.de; peter.moeller@uniklinik-ulm.de NR 24 TC 4 Z9 4 U1 1 U2 1 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 DEC PY 2016 VL 25 IS 12 BP 4016 EP 4024 DI 10.1007/s00586-015-4242-1 PG 9 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA EE0KY UT WOS:000389265000021 PM 26399506 ER PT J AU Avci, P Freire, F Banvolgyi, A Mylonakis, E Wikonkal, NM Hamblin, MR AF Avci, Pinar Freire, Fernanda Banvolgyi, Andras Mylonakis, Eleftherios Wikonkal, Norbert M. Hamblin, Michael R. TI Sodium ascorbate kills Candida albicans in vitro via iron-catalyzed Fenton reaction: importance of oxygenation and metabolism SO FUTURE MICROBIOLOGY LA English DT Article DE ascorbate; Candida albicans; hydroxyl radicals; oxidative stress; vitamin C ID VITAMIN-C; AMPHOTERICIN-B; CELL-DEATH; INVASIVE CANDIDIASIS; ACID; CANCER; MECHANISMS; PATHOGENICITY; EPIDEMIOLOGY; TRANSITION AB Aim: Ascorbate can inhibit growth and even decrease viability of various microbial species including Candida albicans. However the optimum conditions and the mechanism of action are unclear. Materials/methodology: Candida albicans shaken for 90 min in a buffered solution of ascorbate (90 mM) gave a 5-log reduction of cell viability, while there was no killing without shaking, in growth media with different carbon sources or at 4 degrees C. Killing was inhibited by the iron chelator 2,2'-bipyridyl. Hydroxyphenyl fluorescein probe showed the intracellular generation of hydroxyl radicals. Results/conclusion: Ascorbate-mediated killing of C. albicans depends on oxygenation and metabolism, involves iron-catalyzed generation of hydroxyl radicals via Fenton reaction and depletion of intracellular NADH. Ascorbate could serve as a component of a topical antifungal therapy. C1 [Avci, Pinar; Freire, Fernanda; Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Avci, Pinar; Hamblin, Michael R.] Harvard Med Sch, Dept Dermatol, Boston, MA 02115 USA. [Avci, Pinar; Banvolgyi, Andras; Wikonkal, Norbert M.] Semmelweis Univ, Dept Dermatol Venerol & Dermatooncol, H-1085 Budapest, Hungary. [Freire, Fernanda] Univ Estadual Paulista UNESP, Inst Sci & Technol, Dept Biosci & Oral Diag, BR-12245000 Sao Paulo, Brazil. [Mylonakis, Eleftherios] Brown Univ, Rhode Isl Hosp, Div Infect Dis, Warren Alpert Med Sch, Providence, RI 02912 USA. [Hamblin, Michael R.] Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Hamblin, MR (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA.; Hamblin, MR (reprint author), Harvard Med Sch, Dept Dermatol, Boston, MA 02115 USA.; Wikonkal, NM (reprint author), Semmelweis Univ, Dept Dermatol Venerol & Dermatooncol, H-1085 Budapest, Hungary.; Hamblin, MR (reprint author), Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02139 USA. EM wikonkal@gmail.com; hamblin@helix.mgh.harvard.edu FU US NIH [R01AI050875] FX Funded by US NIH grant R01AI050875. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 45 TC 0 Z9 0 U1 3 U2 3 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1746-0913 EI 1746-0921 J9 FUTURE MICROBIOL JI Future Microbiol. PD DEC PY 2016 VL 11 IS 12 BP 1535 EP 1547 DI 10.2217/fmb-2016-0063 PG 13 WC Microbiology SC Microbiology GA ED2LM UT WOS:000388676400006 PM 27855492 ER PT J AU Chen, Q Rosen, AK Borzecki, A Shwartz, M AF Chen, Qi Rosen, Amy K. Borzecki, Ann Shwartz, Michael TI Using Harm-Based Weights for the AHRQ Patient Safety for Selected Indicators Composite (PSI-90): Does It Affect Assessment of Hospital Performance and Financial Penalties in Veterans Health Administration Hospitals? SO HEALTH SERVICES RESEARCH LA English DT Article DE Patient safety; performance assessment; hospital profiling; composite measures ID ECOLOGICAL-CORRELATIONS; INDIVIDUALS; MORTALITY; BEHAVIOR; PSIS AB Objective. To assess whether hospital profiles for public reporting and pay-for-performance, measured by the Agency for Healthcare Research and Quality (AHRQ) Patient Safety for Selected Indicators (PSI-90) composite measure, were affected by using the recently developed harm-based weights. Data Sources/Study Setting. Retrospective analysis of 2012-2014 data from the Veterans Health Administration (VA). Study Design. The AHRQ PSI software (v5.0) was applied to obtain the original volume-based PSI-90 scores for 132 acute-care hospitals. We constructed a modified PSI-90 using the harm-based weights developed by AHRQ. We compared hospital profiles for public reporting and pay-for-performance between these two PSI-90s and assessed patterns in these changes. Principal Findings. The volume-based and the harm-based PSI-90s were strongly correlated (r = 0.67, p < .0001). The use of the harm-based PSI-90 had a relatively small impact on public reporting (i.e., 5 percent hospitals changed categorization), but it had a much larger impact on pay-for-performance (e.g., 15 percent of hospitals would have faced different financial penalties under the Medicare Hospital-Acquired Condition Reduction Program). Because of changes in weights of specific PSIs, hospital profile changes occurred systematically. Conclusions. Use of the harm-based weights in PSI-90 has the potential to significantly change payments under pay-for-performance programs. Policy makers should carefully develop transition plans for guiding hospitals through changes in any quality metrics used for pay-for-performance. C1 [Chen, Qi] CHOIR, 150 S Huntington Ave, Boston, MA 02130 USA. [Rosen, Amy K.; Shwartz, Michael] VA Boston Healthcare Syst, CHOIR, Boston, MA USA. [Rosen, Amy K.] Boston Univ, Sch Med, Dept Surg, Boston, MA 02118 USA. [Borzecki, Ann] Bedford VA Med Ctr, CHOIR, Bedford, MA USA. [Borzecki, Ann] Boston Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA USA. [Borzecki, Ann] Boston Univ, Sch Med, Dept Internal Med, Boston, MA 02118 USA. [Shwartz, Michael] Boston Univ, Sch Management, Dept Operat & Technol Management, Boston, MA 02215 USA. RP Chen, Q (reprint author), CHOIR, 150 S Huntington Ave, Boston, MA 02130 USA. EM qc2112@bu.edu FU VA National Center for Patient Safety, Patient Safety Center of Inquiry on Measurement to Advance Patient Safety (MAPS) [XVA 68-023] FX This work was funded by the VA National Center for Patient Safety, Patient Safety Center of Inquiry on Measurement to Advance Patient Safety (MAPS) #XVA 68-023, PI Rosen. NR 20 TC 1 Z9 1 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0017-9124 EI 1475-6773 J9 HEALTH SERV RES JI Health Serv. Res. PD DEC PY 2016 VL 51 IS 6 BP 2140 EP 2157 DI 10.1111/1475-6773.12596 PG 18 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA ED8UP UT WOS:000389146700006 PM 27891603 ER PT J AU Werner, RM Skira, M Konetzka, RT AF Werner, Rachel M. Skira, Meghan Konetzka, R. Tamara TI An Evaluation of Performance Thresholds in Nursing Home Pay-for-Performance SO HEALTH SERVICES RESEARCH LA English DT Article DE Performance-based thresholds; quality of care; pay-for-performance; nursing home quality; long-term care ID RESIDENT ASSESSMENT INSTRUMENT; QUALITY; CARE; PAYMENT; MDS AB Objective. Performance thresholds are commonly used in pay-for-performance (P4P) incentives, where providers receive a bonus payment for achieving a prespecified target threshold but may produce discontinuous incentives, with providers just below the threshold having the strongest incentive to improve and providers either far below or above the threshold having little incentive. We investigate the effect of performance thresholds on provider response in the setting of nursing home P4P. Data Sources. The Minimum Data Set (MDS) and Online Survey, Certification, and Reporting (OSCAR) datasets. Study Setting and Design. Difference-in-differences design to test for changes in nursing home performance in three states that implemented threshold-based P4P (Colorado, Georgia, and Oklahoma) versus three comparator states (Arizona, Tennessee, and Arkansas) between 2006 and 2009. Principal Findings. We find that those farthest below the threshold (i.e., the worst-performing nursing homes) had the largest improvements under threshold-based P4P while those farthest above the threshold worsened. This effect did not vary with the percentage of Medicaid residents in a nursing home. Conclusions. Threshold-based P4P may provide perverse incentives for nursing homes above the performance threshold, but we do not find evidence to support concerns about the effects of performance thresholds on low-performing nursing homes. C1 [Werner, Rachel M.] Univ Penn, Perelman Sch Med, Div Gen Internal Med, 1204 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. [Werner, Rachel M.] Crescenz VAMC, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Skira, Meghan] Univ Georgia, Terry Coll Business, Dept Econ, Athens, GA 30602 USA. [Konetzka, R. Tamara] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. RP Werner, RM (reprint author), Univ Penn, Perelman Sch Med, Div Gen Internal Med, 1204 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM rwerner@upenn.edu FU National Institute on Aging [R01-AG034182, K24-AG047908] FX This research was supported by grant R01-AG034182 from the National Institute on Aging. Rachel Werner is supported in part by grant K24-AG047908, also from the National Institute on Aging. NR 24 TC 1 Z9 1 U1 5 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0017-9124 EI 1475-6773 J9 HEALTH SERV RES JI Health Serv. Res. PD DEC PY 2016 VL 51 IS 6 BP 2282 EP 2304 DI 10.1111/1475-6773.12467 PG 23 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA ED8UP UT WOS:000389146700013 PM 26932527 ER PT J AU Schiff, GD Nieva, HR Griswold, P Leydon, N Ling, J Biondolillo, M Singer, SJ AF Schiff, Gordon D. Nieva, Harry Reyes Griswold, Paula Leydon, Nicholas Ling, Judy Biondolillo, Madeleine Singer, Sara J. TI Addressing Ambulatory Safety and Malpractice: The Massachusetts PROMISES Project SO HEALTH SERVICES RESEARCH LA English DT Editorial Material ID CENTERED MEDICAL HOME; ADVERSE DRUG EVENTS; PRACTICE TRANSFORMATION; DIAGNOSTIC ERRORS; PATIENT SAFETY; CARE; CLAIMS C1 [Schiff, Gordon D.; Nieva, Harry Reyes] Brigham & Womens Hosp, Div Gen Internal Med & Primary Care, 1620 Tremont St,BC 3, Boston, MA 02120 USA. [Schiff, Gordon D.; Nieva, Harry Reyes; Singer, Sara J.] Harvard Med Sch, Boston, MA 02115 USA. [Griswold, Paula] Massachusetts Coalit Prevent Med Errors, Burlington, MA USA. [Leydon, Nicholas; Ling, Judy; Biondolillo, Madeleine] Bur Hlth Care Safety & Qual, Massachusetts Dept Publ Hlth, Boston, MA USA. [Leydon, Nicholas] North Shore Med Ctr, Boston, MA USA. [Singer, Sara J.] Harvard TH Chan Sch Publ Hlth, Boston, MA USA. [Singer, Sara J.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. RP Schiff, GD (reprint author), Brigham & Womens Hosp, Div Gen Internal Med & Primary Care, 1620 Tremont St,BC 3, Boston, MA 02120 USA.; Schiff, GD (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM gschiff@partners.org OI Reyes Nieva, Harry/0000-0001-7774-2561 FU Agency for Healthcare Research and Quality [R18HS019508] FX Supported by grant number R18HS019508 from the Agency for Healthcare Research and Quality. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Agency for Healthcare Research and Quality. NR 18 TC 2 Z9 2 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0017-9124 EI 1475-6773 J9 HEALTH SERV RES JI Health Serv. Res. PD DEC PY 2016 VL 51 SU S3 BP 2634 EP 2641 DI 10.1111/1475-6773.12621 PG 8 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA ED8UL UT WOS:000389146300015 PM 27892623 ER PT J AU Barth, K Blasche, R Neisser, A Bramke, S Frank, JA Kasper, M AF Barth, K. Blaesche, R. Neisser, A. Bramke, S. Frank, J. A. Kasper, M. TI P2X7R-dependent regulation of glycogen synthase kinase 3 beta and claudin-18 in alveolar epithelial type I cells of mice lung SO HISTOCHEMISTRY AND CELL BIOLOGY LA English DT Article DE Mouse lung; Knockout; P2X7 receptor; GSK-3 beta; beta-catenin; claudin-18 ID JUNCTIONAL ADHESION MOLECULE; BARRIER FUNCTION; P2X(7) RECEPTORS; BETA-CATENIN; EXPRESSION; INJURY; FIBROSIS; PROTEIN; SIGNAL AB The purinergic receptor P2X7 represents an ATP-gated ionotropic receptor with a selective localization in alveolar epithelial type I cells of the lung. Despite the involvement of the receptor in inflammatory processes of the lung, it is not established whether this receptor plays a specific role in the alveolar epithelial cell biology. There is evidence that P2X7 receptor influences Wnt/beta-catenin signalling pathways in alveolar epithelial cells under conditions of injury. Here, we investigated the expression of GSK-3 beta, a potent protein kinase involved in alveolar epithelial barrier functions, and of tight junction molecules occludin, claudin-4 and claudin-18 in wild-type and P2X7(-/-) mice. Western blot analysis, immunohistochemistry and quantitative real-time RT-PCR revealed a remarkable increase in claudin-18 mRNA and protein in lungs of P2X7(-/-) mice animals. Furthermore, alveolar epithelial cells from P2X7(-/-) animals showed decreased levels of GSK-3 beta protein and its inactive form GSK-3 beta (pS9). Conversely, claudin-18 knockout mice exhibited decreased P2X7 mRNA transcript abundance as measured by mRNA expression microarray and quantitative PCR. Our data are consistent with the hypothesis that P2X7R contributes to alveolar epithelial barrier function through effects on GSK-3 beta. Furthermore, these data suggest a potential reciprocal regulation of claudin-18 and P2X7R in the alveolar epithelium. C1 [Barth, K.; Blaesche, R.; Neisser, A.; Bramke, S.; Kasper, M.] Tech Univ Dresden, Med Fac Carl Gustav Carus, Inst Anat, Fetscherstr 74, D-01307 Dresden, Germany. [Frank, J. A.] Univ Calif San Francisco, San Francisco VA Med Ctr, 4150 Clement St,Box 111D, San Francisco, CA 94121 USA. RP Kasper, M (reprint author), Tech Univ Dresden, Med Fac Carl Gustav Carus, Inst Anat, Fetscherstr 74, D-01307 Dresden, Germany. EM michael.kasper@tu-dresden.de NR 34 TC 1 Z9 1 U1 4 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0948-6143 EI 1432-119X J9 HISTOCHEM CELL BIOL JI Histochem. Cell Biol. PD DEC PY 2016 VL 146 IS 6 BP 757 EP 768 DI 10.1007/s00418-016-1499-3 PG 12 WC Cell Biology; Microscopy SC Cell Biology; Microscopy GA EC0ST UT WOS:000387811700012 PM 27663455 ER PT J AU Shih, AR Deshpande, V Ferry, JA Zukerberg, L AF Shih, Angela R. Deshpande, Vikram Ferry, Judith A. Zukerberg, Lawrence TI Clinicopathological characteristics of systemic mastocytosis in the intestine SO HISTOPATHOLOGY LA English DT Article DE mast cells; mastocytosis; systemic mastocytosis ID MUCOSAL MAST-CELLS; GASTROINTESTINAL-TRACT; DISEASE AB AimsGastrointestinal (GI) involvement by systemic mastocytosis (SM) presents with non-specific symptoms, and pathological diagnosis can be difficult when a subtle mast cell infiltrate is present. The aim of this study was to characterize the clinicopathological features in diagnostically challenging cases. Methods and resultsSeven patients with GI biopsies showing an atypical mast cell infiltrate were identified, including three consultation cases in which mast cells were initially overlooked. Clinicopathological characteristics were evaluated. Biopsies showed involvement of the large bowel (n = 5), small bowel (n = 1) or both (n = 1) by a wide morphological spectrum of mast cells, including: bland spindle cells; small cells with irregular nuclei; and medium-sized monotonous cells with abundant pale cytoplasm. The patterns of mucosal involvement included: a polypoid mast cell aggregate (n = 1); a confluent subepithelial band of mast cells (n = 3); and multifocal aggregates of mast cells (n = 3). There were admixed eosinophils with a noticeable lack of plasma cells. Mast cells in all cases showed strong positive staining for CD117 and CD25. All patients fulfilled the World Health Organization (WHO) criteria for SM. On follow-up in four cases, none had progression of disease. ConclusionsAtypical mast cell infiltrates in the intestine are often subtle and can easily be overlooked. Clues to diagnosis include lamina propria expansion by monotonous cells with pale cytoplasm, admixed eosinophils, and the absence of crypt distortion or significant plasmacytic infiltrate. Although most patients with GI involvement by SM are symptomatic, a subset remain asymptomatic, and the absence of clinical suspicion of mast cell disease adds to the difficulty in making a diagnosis of SM. C1 [Shih, Angela R.; Deshpande, Vikram; Ferry, Judith A.; Zukerberg, Lawrence] Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St,Warren 2, Boston, MA 02114 USA. RP Shih, AR (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St,Warren 2, Boston, MA 02114 USA. EM ashih1@partners.org NR 16 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0309-0167 EI 1365-2559 J9 HISTOPATHOLOGY JI Histopathology PD DEC PY 2016 VL 69 IS 6 BP 1021 EP 1027 DI 10.1111/his.13033 PG 7 WC Cell Biology; Pathology SC Cell Biology; Pathology GA EC7DO UT WOS:000388296200014 PM 27391777 ER PT J AU Laffey, JG Bellani, G Pham, T Fan, E Madotto, F Bajwa, EK Brochard, L Clarkson, K Esteban, A Gattinoni, L van Haren, F Heunks, LM Kurahashi, K Laake, JH Larsson, A McAuley, DF McNamee, L Nin, N Qiu, HB Ranieri, M Rubenfeld, GD Thompson, BT Wrigge, H Slutsky, AS Pesenti, A AF Laffey, John G. Bellani, Giacomo Pham, Tai Fan, Eddy Madotto, Fabiana Bajwa, Ednan K. Brochard, Laurent Clarkson, Kevin Esteban, Andres Gattinoni, Luciano van Haren, Frank Heunks, Leo M. Kurahashi, Kiyoyasu Laake, Jon Henrik Larsson, Anders McAuley, Daniel F. McNamee, Lia Nin, Nicolas Qiu, Haibo Ranieri, Marco Rubenfeld, Gordon D. Thompson, B. Taylor Wrigge, Hermann Slutsky, Arthur S. Pesenti, Antonio CA LUNG SAFE Investigators ESICM Trials Grp TI Potentially modifiable factors contributing to outcome from acute respiratory distress syndrome: the LUNG SAFE study SO INTENSIVE CARE MEDICINE LA English DT Article DE Acute respiratory distress syndrome; Positive end-expiratory pressure; Patient outcome; Driving pressure; Peak inspiratory pressure ID INTENSIVE-CARE UNITS; VENTILATOR-INDUCED LUNG; CO-2 REMOVAL; INJURY; MORTALITY; EPIDEMIOLOGY; WITHDRAWAL; PULMONARY; METAANALYSIS; COUNTRIES AB Purpose: To improve the outcome of the acute respiratory distress syndrome (ARDS), one needs to identify potentially modifiable factors associated with mortality. Methods: The large observational study to understand the global impact of severe acute respiratory failure (LUNG SAFE) was an international, multicenter, prospective cohort study of patients with severe respiratory failure, conducted in the winter of 2014 in a convenience sample of 459 ICUs from 50 countries across five continents. A pre-specified secondary aim was to examine the factors associated with outcome. Analyses were restricted to patients (93.1 %) fulfilling ARDS criteria on day 1-2 who received invasive mechanical ventilation. Results: 2377 patients were included in the analysis. Potentially modifiable factors associated with increased hospital mortality in multivariable analyses include lower PEEP, higher peak inspiratory, plateau, and driving pressures, and increased respiratory rate. The impact of tidal volume on outcome was unclear. Having fewer ICU beds was also associated with higher hospital mortality. Non-modifiable factors associated with worsened outcome from ARDS included older age, active neoplasm, hematologic neoplasm, and chronic liver failure. Severity of illness indices including lower pH, lower PaO2/FiO(2) ratio, and higher non-pulmonary SOFA score were associated with poorer outcome. Of the 578 (24.3 %) patients with a limitation of life-sustaining therapies or measures decision, 498 (86.0 %) died in hospital. Factors associated with increased likelihood of limitation of life-sustaining therapies or measures decision included older age, immunosuppression, neoplasia, lower pH and increased non-pulmonary SOFA scores. Conclusions: Higher PEEP, lower peak, plateau, and driving pressures, and lower respiratory rate are associated with improved survival from ARDS. C1 [Laffey, John G.] St Michaels Hosp, Keenan Res Ctr Biomed Sci, Dept Anesthesia, Toronto, ON, Canada. [Laffey, John G.] St Michaels Hosp, Keenan Res Ctr Biomed Sci, Dept Crit Care Med, Toronto, ON, Canada. [Laffey, John G.] Univ Toronto, Interdept Div Crit Care Med, Dept Anesthesia, Toronto, ON, Canada. [Laffey, John G.] Univ Toronto, Interdept Div Crit Care Med, Dept Physiol, Toronto, ON, Canada. [Bellani, Giacomo] Univ Milano Bicocca, Sch Med & Surg, Monza, Italy. [Bellani, Giacomo] San Gerardo Hosp, Dept Emergency & Intens Care, Monza, Italy. [Pham, Tai] Hop Univ Est Parisien, Grp Hosp, AP HP, Hop Tenon,Unite Reanimat Med Chirurg,Pole Thorax, Paris, France. [Pham, Tai] Univ Paris Diderot, Sorbonne Paris Cite, ECSTRA Team, UMR 1153,Inserm, Paris, France. [Pham, Tai] Univ Paris Est Creteil, INSERM, UMR 915, Creteil, France. [Fan, Eddy] Mt Sinai Hosp, Univ Hlth Network, Dept Med, Toronto, ON, Canada. [Fan, Eddy; Brochard, Laurent; Rubenfeld, Gordon D.; Slutsky, Arthur S.] Univ Toronto, Interdept Div Crit Care Med, Toronto, ON, Canada. [Fan, Eddy] Univ Toronto, Inst Hlth Policy Management & Evaluat, Toronto, ON, Canada. [Madotto, Fabiana] Univ Milano Bicocca, Sch Med & Surg, Res Ctr Publ Hlth, Monza, Italy. [Bajwa, Ednan K.; Thompson, B. Taylor] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Div Pulm & Crit Care Unit, Boston, MA USA. [Brochard, Laurent; Slutsky, Arthur S.] St Michaels Hosp, Li Ka Shing Knowledge Inst, Keenan Res Ctr, Toronto, ON, Canada. [Clarkson, Kevin] Natl Univ Ireland, Galway Univ Hosp, Dept Anaesthesia, Galway, Ireland. [Esteban, Andres; Nin, Nicolas] Hosp Univ Getafe, CIBER Enfermedades Resp, Madrid, Spain. [Gattinoni, Luciano] Univ Med Gottingen, Dept Anesthesiol Emergency & Intens Care Med, Robert Koch Str 40, D-37073 Gottingen, Germany. [van Haren, Frank] Australian Natl Univ, Canberra Hosp, Intens Care Unit, Canberra, ACT, Australia. [Heunks, Leo M.] Radboud Univ Nijmegen, Dept Intens Care Med, Med Ctr, Nijmegen, Netherlands. [Kurahashi, Kiyoyasu] Yokohama City Univ, Med Ctr, Dept Anesthesiol, Kanagawa, Japan. [Laake, Jon Henrik] Oslo Univ Hosp, Med Ctr, Rikshosp, Div Crit Care,Dept Anaesthesiol, Oslo, Norway. [Larsson, Anders] Uppsala Univ, Dept Surg Sci, Sect Anesthesiol & Intens Care, Uppsala, Sweden. [McAuley, Daniel F.; McNamee, Lia] Queens Univ Belfast, Wellcome Wolfson Inst Expt Med, Belfast & Reg Intens Care Unit, Ctr Expt Med,Royal Victoria Hosp, Grosvenor Rd, Belfast, Antrim, North Ireland. [Qiu, Haibo] Southeast Univ, Sch Med, Nanjing Zhongda Hosp, Dept Crit Care Med, Nanjing 210009, Jiangsu, Peoples R China. [Ranieri, Marco] SAPIENZA Univ ROMA, Policlin Umberto I, Dipartimento Anestesia & Rianimaz, Viale Policlin 155, I-00161 Rome, Italy. [Rubenfeld, Gordon D.] Sunnybrook Hlth Sci Ctr, Program Trauma Emergency & Crit Care, Toronto, ON, Canada. [Wrigge, Hermann] Univ Leipzig, Dept Anesthesiol & Intens Care Med, D-04103 Leipzig, Germany. [Slutsky, Arthur S.] Univ Toronto, Dept Med, Toronto, ON, Canada. [Pesenti, Antonio] Fdn IRCCS Ca Granda Osped Maggiore Policlin, Dipartimento Anestesia Rianimaz & Emergenza Urg, Toronto, ON, Canada. [Pesenti, Antonio] Univ Milan, Dipartimento Fisiopatol Med Chirurg & Trapianti, Milan, Italy. RP Laffey, JG (reprint author), St Michaels Hosp, Keenan Res Ctr Biomed Sci, Dept Anesthesia, Toronto, ON, Canada.; Laffey, JG (reprint author), St Michaels Hosp, Keenan Res Ctr Biomed Sci, Dept Crit Care Med, Toronto, ON, Canada.; Laffey, JG (reprint author), Univ Toronto, Interdept Div Crit Care Med, Dept Anesthesia, Toronto, ON, Canada.; Laffey, JG (reprint author), Univ Toronto, Interdept Div Crit Care Med, Dept Physiol, Toronto, ON, Canada. EM laffeyj@smh.ca OI Van Haren, Frank/0000-0001-8037-4229 FU European Society of Intensive Care Medicine (ESICM), Brussels, Belgium; St Michael's Hospital, Toronto, Canada; University of Milan-Bicocca, Monza, Italy FX This work was funded and supported by the European Society of Intensive Care Medicine (ESICM), Brussels, Belgium, by St Michael's Hospital, Toronto, Canada, and by the University of Milan-Bicocca, Monza, Italy. NR 27 TC 3 Z9 3 U1 3 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0342-4642 EI 1432-1238 J9 INTENS CARE MED JI Intensive Care Med. PD DEC PY 2016 VL 42 IS 12 BP 1865 EP 1876 DI 10.1007/s00134-016-4571-5 PG 12 WC Critical Care Medicine SC General & Internal Medicine GA EC1EL UT WOS:000387846500006 PM 27757516 ER PT J AU Cellamare, M Milstein, M Ventz, S Baudin, E Trippa, L Mitnick, CD AF Cellamare, M. Milstein, M. Ventz, S. Baudin, E. Trippa, L. Mitnick, C. D. TI Bayesian adaptive randomization in a clinical trial to identify new regimens for MDR-TB: the endTB trial SO INTERNATIONAL JOURNAL OF TUBERCULOSIS AND LUNG DISEASE LA English DT Article; Proceedings Paper CT 1st Global Pediatric Multidrug Resistant Tuberculosis (MDR-TB Clinical) Trials Landscape Meeting CY JUN 17, 2016 CL Washington, DC DE MDR-TB; clinical trial; Bayesian adaptive randomization ID MULTIDRUG-RESISTANT TUBERCULOSIS; PROGRESSION-FREE SURVIVAL; STANDARDIZED TREATMENT; TREATMENT OUTCOMES; GLIOBLASTOMA; METAANALYSIS; BEDAQUILINE; DELAMANID; DESIGNS; TMC207 AB BACKGROUND: Evidence-based optimization of treatment for multidrug-resistant tuberculosis (MDR-TB), including integration of new drugs, is urgent. Such optimization would benefit from efficient trial designs requiring fewer patients. Implementation of such innovative designs could accelerate improvements in and access to MDR-TB treatment. OBJECTIVE: To describe the application, advantages, and challenges of Bayesian adaptive randomization in a Phase III non-inferiority trial of MDR-TB treatment. DESIGN: endTB is the first Phase III non-inferiority trial of MDR-TB treatment to use Bayesian adaptive randomization. METHODS: We present a simulation study with assumptions for treatment response at 8, 39, and 73 weeks after randomization, on which sample size calculations are based. We show differences between Bayesian adaptive randomization and balanced randomization designs in sample size and number of patients exposed to ineffective regimens. RESULTS: With 750 participants, 27% fewer than required by balanced randomization, the study had 80% power to detect up to two (of five) novel treatment regimens that are non-inferior (margin 12%) to the control (70% estimated efficacy) at 73 weeks post randomization. Comparing Bayesian adaptive randomization to balanced randomization, up to 25% more participants would receive non-inferior regimens. CONCLUSION: Bayesian adaptive randomization may expose fewer participants to ineffective treatments and enhance the efficiency of MDR-TB treatment trials. C1 [Cellamare, M.] Univ Roma La Sapienza, Dept Stat Sci, Rome, Italy. [Milstein, M.; Mitnick, C. D.] Harvard Med Sch, Dept Global Hlth & Social Med, 641 Huntington Ave, Boston, MA 02115 USA. [Milstein, M.] Northeastern Univ, Bouve Coll Hlth Sci, Boston, MA 02115 USA. [Ventz, S.] Univ Rhode Isl, Dept Comp Sci & Stat, Kingston, RI USA. [Ventz, S.; Trippa, L.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Ventz, S.; Trippa, L.] Harvard TH Chan Sch Publ Hlth, Boston, MA USA. [Baudin, E.] Epictr Medecins Sans Frontieres, Dept Clin Res, Paris, France. [Mitnick, C. D.] Partners Hlth, Boston, MA USA. [Mitnick, C. D.] Brigham & Womens Hosp, Div Global Hlth Equ, 75 Francis St, Boston, MA 02115 USA. RP Mitnick, CD (reprint author), Harvard Med Sch, Dept Global Hlth & Social Med, 641 Huntington Ave, Boston, MA 02115 USA. EM Carole_Mitnick@luns.harvard.edu NR 27 TC 2 Z9 2 U1 1 U2 1 PU INT UNION AGAINST TUBERCULOSIS LUNG DISEASE (I U A T L D) PI PARIS PA 68 BOULEVARD SAINT-MICHEL,, 75006 PARIS, FRANCE SN 1027-3719 EI 1815-7920 J9 INT J TUBERC LUNG D JI Int. J. Tuberc. Lung Dis. PD DEC PY 2016 VL 20 IS 12 SU 2 BP S8 EP S12 DI 10.5588/ijtld.16.0066 PG 5 WC Infectious Diseases; Respiratory System SC Infectious Diseases; Respiratory System GA ED9DU UT WOS:000389171200003 PM 28240566 ER PT J AU Okello, S Asiimwe, SB Kanyesigye, M Muyindike, WR Boum, Y Mwebesa, BB Haberer, JE Huang, Y Williams, K Burdo, TH Tracy, RP Bangsberg, DR Mocello, AR Martin, JN Hunt, PW Siedner, MJ AF Okello, Samson Asiimwe, Stephen B. Kanyesigye, Michael Muyindike, Winnie R. Boum, Yap, II Mwebesa, Bosco B. Haberer, Jessica E. Huang, Yong Williams, Kenneth Burdo, Tricia H. Tracy, Russell P. Bangsberg, David R. Mocello, A. Rain Martin, Jeffrey N. Hunt, Peter W. Siedner, Mark J. TI D-Dimer Levels and Traditional Risk Factors Are Associated With Incident Hypertension Among HIV-Infected Individuals Initiating Antiretroviral Therapy in Uganda SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE D-dimer; immune activation; hypertension; antiretroviral therapy; Africa ID T-CELL-ACTIVATION; MICROBIAL TRANSLOCATION; BLOOD-PRESSURE; IMMUNE ACTIVATION; CARDIOVASCULAR-DISEASE; TRYPTOPHAN CATABOLISM; KYNURENINE PATHWAY; NAIVE PATIENTS; INFLAMMATION; PREVALENCE AB Objectives: We sought to describe blood pressure (BP) changes after antiretroviral therapy (ART) initiation and evaluate the association of markers of inflammation with incident hypertension in a cohort of HIV-infected individuals in Uganda. Methods: We used mixed effects linear regression to model changes in systolic BP over time among a cohort of HIV-infected individuals initiating ART in Uganda. After exclusion of participants with preexisting hypertension, we identified participants with normal BP throughout follow-up (controls) and those with elevated BP on >= 3 consecutive visits (cases). Before ART initiation, participants had testing for interleukin 6, kynurenine/tryptophan ratio, lipopolysaccharide, soluble CD14, soluble CD163, and D-dimer and those with viral suppression at 6 months during ART had repeat tests. We fit logistic regression models to estimate associations between biomarkers and risk of incident hypertension. Results: In the entire cohort, systolic BP increased by 9.6 mm Hg/yr (95% CI: 7.3 to 11.8) in the first 6 months of ART, then plateaued. Traditional factors: male gender (adjusted odds ratio (AOR) 2.76, 95% CI: 1.34 to 5.68), age (AOR 1.09, 95% CI: 1.04 to 1.13), overweight (AOR 4.48, 95% CI: 1.83 to 10.97), and a CD4 count,100 cells (AOR 3.08, 95% CI: 1.07 to 8.89) were associated with incident hypertension. After adjusting for these, D-dimer levels at month 6 were inversely associated with incident hypertension (AOR 0.61, 95% CI: 0.37 to 0.99). Although not significant, similar associations were seen with sCD14 and kynurenine/tryptophan ratio. Conclusion: BP increases early after ART initiation in Ugandans. Traditional risk factors, rather than immune activation, were associated with incident hypertension in this population. C1 [Okello, Samson; Kanyesigye, Michael; Muyindike, Winnie R.; Mwebesa, Bosco B.] Mbarara Univ Sci & Technol, Dept Internal Med, POB 1410, Mbarara, Uganda. [Okello, Samson] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Asiimwe, Stephen B.; Mocello, A. Rain; Martin, Jeffrey N.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Boum, Yap, II] Epictr Mbarara Res Ctr, Mbarara, Uganda. [Haberer, Jessica E.; Bangsberg, David R.; Siedner, Mark J.] Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02114 USA. [Haberer, Jessica E.; Bangsberg, David R.; Siedner, Mark J.] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. [Huang, Yong] Univ Calif San Francisco, Sch Pharm, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA. [Williams, Kenneth; Burdo, Tricia H.] Boston Coll, Dept Biol, Chestnut Hill, MA 02167 USA. [Tracy, Russell P.] Univ Vermont, Dept Pathol & Lab Med, Burlington, VT USA. [Bangsberg, David R.] Harvard TH Chan Sch Publ Hlth, Dept Global Hlth & Populat, Boston, MA USA. [Hunt, Peter W.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. RP Okello, S (reprint author), Mbarara Univ Sci & Technol, Dept Internal Med, POB 1410, Mbarara, Uganda. EM okello.samson@must.ac.ug OI Okello, Samson/0000-0001-7377-6094 FU National Institute of Health [R01 MH054907, K23 MH099916, R56AI100765, R21AI078774, U01 AI069919, UM1 CA181255]; Doris Duke Charitable Foundation [2008047]; Sullivan Family Foundation; Canada-Africa Prevention Trials (CAPT) network FX Supported by the National Institute of Health (R01 MH054907, K23 MH099916, R56AI100765, R21AI078774, U01 AI069919, UM1 CA181255), Doris Duke Charitable Foundation (Clinical Scientist Development Award 2008047), the Sullivan Family Foundation, and the Canada-Africa Prevention Trials (CAPT) network. The funders had no role in study design, conduct, data analysis, or manuscript production. NR 43 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD DEC 1 PY 2016 VL 73 IS 4 BP 396 EP 402 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA ED7LB UT WOS:000389044800007 PM 27171743 ER PT J AU Sharma, A Ma, YF Scherzer, R Wheeler, AL Cohen, M Gustafson, DR Keating, SM Yin, MT Tien, PC AF Sharma, Anjali Ma, Yifei Scherzer, Rebecca Wheeler, Amber L. Cohen, Mardge Gustafson, Deborah R. Keating, Sheila M. Yin, Michael T. Tien, Phyllis C. TI Association of Adipokines With Bone Mineral Density in HIV-Infected and HIV-Uninfected Women SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE bone mineral density; adipokine; body composition; HIV ID INTERAGENCY HIV; SERUM LEPTIN; OLDER WOMEN; FAT MASS; ADIPONECTIN; MEN; LIPOATROPHY; POPULATION; MEDIATORS; INSULIN AB Background: HIV infection is associated with low bone mineral density (BMD) and alterations in adipokines, which may mediate the relationship between fat and bone. Objective: To evaluate the relationship of adiponectin and leptin with BMD in HIV-infected and uninfected women. Methods: We measured BMD over 5 years at the lumbar spine, total hip (TH), and femoral neck (FN) using dual-energy X-ray absorptiometry in 318 HIV-infected and 122 HIV-uninfected participants of the multicenter Women's Interagency HIV Study (WIHS). Total adiponectin and leptin were assayed on stored sera. Multivariable linear mixed models assessed the effects of adipokines and HIV status on BMD. Results: HIV-infected women had higher adiponectin (median 6.2 vs. 5.6 mg/mL,) but lower leptin (11.7 vs. 19.8 ng/mL) levels at baseline (both P, 0.05) compared with HIV-uninfected women. HIV infection was associated with lower BMD at the lumbar spine (20.074 g/cm(2)), FN (20.049 g/cm(2)), and TH (20.047 g/cm(2)) (all P, 0.05) after adjusting for demographic, behavioral, and metabolic factors. HIV infection remained associated with lower BMD at each site, with little change in the effect sizes after additional adjustment for adiponectin or leptin. Among HIV-infected women, higher adiponectin was associated with lower TH BMD (20.025 g/cm(2) per 10-fold increase, P = 0.035), whereas higher leptin was associated with higher BMD at FN (+ 0.027 g/cm(2) per 10-fold increase, P = 0.005) and TH (+ 0.019 g/cm(2), P = 0.028). After multivariable adjustment, the adipokines showed little association with BMD at any site (P>0.8 for adiponectin; P>0.2 for leptin). Conclusions: Alterations in serum adiponectin and leptin do not explain low BMD in HIV-infected women. C1 [Sharma, Anjali] Albert Einstein Coll Med, Dept Med, 1300 Morris Pk Ave,Block Bldg 305, Bronx, NY 10461 USA. [Ma, Yifei] Univ Calif San Francisco, Dept Pediat, San Francisco, CA USA. [Scherzer, Rebecca; Tien, Phyllis C.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Wheeler, Amber L.; Tien, Phyllis C.] San Francisco VA Med Ctr, Dept Med, San Francisco, CA USA. [Cohen, Mardge] John H Stroger Jr Hosp Cook Cty, Dept Med, Chicago, IL USA. [Gustafson, Deborah R.] Suny Downstate Med Ctr, Dept Neurol, Brooklyn, NY 11203 USA. [Keating, Sheila M.] Blood Syst Res Inst, San Francisco, CA USA. [Yin, Michael T.] Columbia Univ, Dept Med, New York, NY USA. RP Sharma, A (reprint author), Albert Einstein Coll Med, 1300 Morris Pk Ave,Block Bldg 305, Bronx, NY 10461 USA. EM anjali.sharma@einstein.yu.edu FU National Institute of Allergy and Infectious Diseases (NIAID); Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Cancer Institute (NCI); National Institute on Drug Abuse (NIDA); National Institute on Mental Health (NIMH); National Institute of Dental and Craniofacial Research (NIDCR); National Institute on Alcohol Abuse and Alcoholism (NIAAA); National Institute on Deafness and other Communication Disorders (NIDCD); NIH Office of Research on Women's Health; National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health [K23AR06199301]; National Institute of Allergy and Infectious Diseases [R01AI087176, K24AI108516] FX The Women's Interagency HIV Study (WIHS) is funded primarily by the National Institute of Allergy and Infectious Diseases (NIAID), with additional cofunding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Cancer Institute (NCI), the National Institute on Drug Abuse (NIDA), and the National Institute on Mental Health (NIMH). Targeted supplemental funding for specific projects is also provided by the National Institute of Dental and Craniofacial Research (NIDCR), the National Institute on Alcohol Abuse and Alcoholism (NIAAA), the National Institute on Deafness and other Communication Disorders (NIDCD), and the NIH Office of Research on Women's Health. WIHS data collection is also supported by UL1-TR000004 (UCSF CTSA) and UL1-TR000454 (Atlanta CTSA). Research reported in this publication was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under award number K23AR06199301 (AS), and National Institute of Allergy and Infectious Diseases R01AI087176 and K24AI108516 (PCT). NR 26 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD DEC 1 PY 2016 VL 73 IS 4 BP 433 EP 437 PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA ED7LB UT WOS:000389044800012 PM 27792683 ER PT J AU Bengtson, AM Pence, BW Gaynes, BN Quinlivan, EB Heine, AD O'Donnell, JK Crane, HM Mathews, WC Moore, RD Westreich, D O'Cleirigh, C Christopoulos, K Mimiaga, MJ Mugavero, MJ AF Bengtson, Angela M. Pence, Brian W. Gaynes, Bradley N. Quinlivan, E. Byrd Heine, Amy D. O'Donnell, Julie K. Crane, Heidi M. Mathews, W. Christopher Moore, Richard D. Westreich, Daniel O'Cleirigh, Conall Christopoulos, Katerina Mimiaga, Matthew J. Mugavero, Michael J. TI Improving Depression Among HIV-Infected Adults: Transporting the Effect of a Depression Treatment Intervention to Routine Care SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE depression; HIV; generalizability; transportability; depression treatment ID INTERNATIONAL NEUROPSYCHIATRIC INTERVIEW; HUMAN-IMMUNODEFICIENCY-VIRUS; STAR-ASTERISK-D; TARGET POPULATIONS; CLINICAL-PRACTICE; DSM-IV; OUTCOMES; ADHERENCE; METAANALYSIS; TRIALS AB Background: Depression affects 20%-30% of people with HIV. Randomized controlled trials (RCTs) have demonstrated the effectiveness of interventions to improve depression among HIV-infected adults, but typically have highly selected populations which may limit generalizability. Inverse probability of sampling weights (IPSW) is a recently proposed method to transport (or standardize) findings from RCTs to a specific external target population. Methods: We used IPSW to transport the 6-month effect of the Measurement-Based Care (MBC) intervention on depression from the SLAM DUNC trial to a population of HIV-infected, depressed adults in routine care in the United States between 2010 and 2014. Results: In the RCT, MBC was associated with an improvement in depression at 6 months of 3.6 points on the Hamilton Depression Rating scale [95% confidence interval (CI): 25.9 to 21.3]. When IPSW were used to standardize results from the trial to the target population, the intervention effect was attenuated by 1.2 points (mean improvement 2.4 points; 95% CI: 26.1 to 1.3). Conclusions: If implemented among HIV-infected, depressed adults in routine care, MBC may be less effective than in the RCT but can still be expected to reduce depression. Attenuation of the intervention effect among adults in routine care reflects the fact that the trial enrolled a larger proportion of individuals for whom the intervention was more effective. Given the burden of depression among HIV-infected adults, more effective interventions to improve depression are urgently needed. However, examining the transportability of trial findings is essential to understand whether similar effects can be expected if interventions are scaled-up. C1 [Bengtson, Angela M.; Pence, Brian W.; O'Donnell, Julie K.; Westreich, Daniel] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Gaynes, Bradley N.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Quinlivan, E. Byrd; Heine, Amy D.] Univ N Carolina, Div Infect Dis, Chapel Hill, NC USA. [Crane, Heidi M.] Univ Washington, Div Allergy & Infect Dis, Seattle, WA 98195 USA. [Mathews, W. Christopher] Univ Calif San Diego, Dept Med, San Diego, CA 92103 USA. [Moore, Richard D.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [O'Cleirigh, Conall] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Christopoulos, Katerina] Univ Calif San Francisco, Sch Med, San Francisco, CA USA. [Mimiaga, Matthew J.] Brown Univ, Sch Publ Hlth, Dept Epidemiol, Providence, RI 02912 USA. [Mimiaga, Matthew J.] Brown Univ, Sch Publ Hlth, Dept Behav & Social Sci, Providence, RI 02912 USA. [Mimiaga, Matthew J.] Brown Univ, Inst Community Hlth Promot, Providence, RI 02912 USA. [Mimiaga, Matthew J.] Fenway Hlth, Fenway Inst, Boston, MA USA. [Mugavero, Michael J.] Univ Alabama Birmingham, Div Infect Dis, Birmingham, AL USA. RP Bengtson, AM (reprint author), Gillings Sch Global Publ Hlth, Dept Epidemiol, 2101 McGavran Greenberg Hall, Chapel Hill, NC 27599 USA. EM abengtso@live.unc.edu FU National Institutes of Health [R01MH086362, R01MH100970, R24AI067039, T32AI007001]; Centers for AIDS Research at Duke; University of North Carolina at Chapel Hill; University of Alabama at Birmingham [P30-AI50410, P30-AI064518, P30-AI027767]; National Institutes of Health Office of the Director; Eunice Kennedy Shriver National Institute of Child Health and Human Development [DP2-HD-08-4070] FX Supported by the National Institutes of Health (Grant numbers R01MH086362, R01MH100970, R24AI067039, and T32AI007001) and the Centers for AIDS Research at Duke, University of North Carolina at Chapel Hill, and University of Alabama at Birmingham (Grant numbers P30-AI50410, P30-AI064518, and P30-AI027767). D.W. was supported by the National Institutes of Health Office of the Director and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Grant number DP2-HD-08-4070). NR 41 TC 0 Z9 0 U1 13 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD DEC 1 PY 2016 VL 73 IS 4 BP 482 EP 488 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA ED7LB UT WOS:000389044800018 PM 27668804 ER PT J AU Jayakumar, A Savic, RM Everett, CK Benator, D Alland, D Heilig, CM Weiner, M Friedrich, SO Martinson, NA Kerrigan, A Zamudio, C Goldberg, SV Whitworth, WC Davis, JL Nahid, P AF Jayakumar, A. Savic, R. M. Everett, C. K. Benator, D. Alland, D. Heilig, C. M. Weiner, M. Friedrich, S. O. Martinson, N. A. Kerrigan, A. Zamudio, C. Goldberg, S. V. Whitworth, W. C. Davis, J. L. Nahid, P. TI Xpert MTB/RIF Assay Shows Faster Clearance of Mycobacterium tuberculosis DNA with Higher Levels of Rifapentine Exposure SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID PULMONARY TUBERCULOSIS; BIOMARKER AB The Xpert MTB/RIF assay is both sensitive and specific as a diagnostic test. Xpert also reports quantitative output in cycle threshold (C-T) values, which may provide a dynamic measure of sputum bacillary burden when used longitudinally. We evaluated the relationship between Xpert C-T trajectory and drug exposure during tuberculosis (TB) treatment to assess the potential utility of Xpert C-T for treatment monitoring. We obtained serial sputum samples from patients with smear-positive pulmonary TB who were consecutively enrolled at 10 international clinical trial sites participating in study 29X, a CDC-sponsored Tuberculosis Trials Consortium study evaluating the tolerability, safety, and antimicrobial activity of rifapentine at daily doses of up to 20 mg/kg of body weight. Xpert was performed at weeks 0, 2, 4, 6, 8, and 12. Longitudinal C-T data were modeled using a nonlinear mixed effects model in relation to rifapentine exposure (area under the concentration-time curve [AUC]). The rate of change of C-T was higher in subjects receiving rifapentine than in subjects receiving standard-dose rifampin. Moreover, rifapentine exposure, but not assigned dose, was significantly associated with rate of change in C-T (P = 0.02). The estimated increase in C-T slope for every additional 100 mu g . h/ml of rifapentine drug exposure (as measured by AUC) was 0.11 C-T/week (95% confidence interval [CI], 0.05 to 0.17). Increasing rifapentine exposure is associated with a higher rate of change of Xpert C-T, indicating faster clearance of Mycobacterium tuberculosis DNA. These data suggest that the quantitative outputs of the Xpert MTB/RIF assay may be useful as a dynamic measure of TB treatment response. C1 [Jayakumar, A.; Everett, C. K.; Nahid, P.] Univ Calif San Francisco, Div Pulm & Crit Care Med, San Francisco, CA 94143 USA. [Savic, R. M.] Univ Calif San Francisco, Sch Pharm, San Francisco, CA 94143 USA. [Benator, D.] Washington DC VA Med Ctr, Washington, DC USA. [Benator, D.] George Washington Univ, Washington, DC USA. [Alland, D.] Rutgers New Jersey Med Sch, Newark, NJ USA. [Heilig, C. M.; Goldberg, S. V.; Whitworth, W. C.] Ctr Dis Control & Prevent, Div TB Eliminat, Atlanta, GA USA. [Weiner, M.] Vet Adm Med Ctr, San Antonio, TX USA. [Weiner, M.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Friedrich, S. O.] Univ Stellenbosch, Fac Med & Hlth Sci, DST NRF Ctr Excellence Biomed TB Res, Div Med Physiol,MRC Ctr TB Res, Tygerberg, South Africa. [Martinson, N. A.] Univ Witwatersrand, MRC Soweto Matlosana Collaborating Ctr HIV AIDS &, Perinatal HIV Res Unit PHRU, Johannesburg, South Africa. [Kerrigan, A.] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Zamudio, C.] Univ Peruana Cayetano Heredia, Lima, Peru. [Davis, J. L.] Yale Sch Publ Hlth, New Haven, CT USA. RP Nahid, P (reprint author), Univ Calif San Francisco, Div Pulm & Crit Care Med, San Francisco, CA 94143 USA. EM pnahid@ucsf.edu OI Heilig, Charles/0000-0003-1075-1310 FU HHS \ National Institutes of Health (NIH) [5T32HL007185-37, AI097005]; HHS \ NIH \ National Institute of Allergy and Infectious Diseases (NIAID) [R01AI104589]; HHS \ Centers for Disease Control and Prevention (CDC) FX This work, including the efforts of Archana Jayakumar, was funded by HHS vertical bar National Institutes of Health (NIH) (5T32HL007185-37). This work, including the efforts of Charles K. Everett, was funded by HHS vertical bar National Institutes of Health (NIH) (AI097005). This work, including the efforts of Payam Nahid, was funded by HHS vertical bar NIH vertical bar National Institute of Allergy and Infectious Diseases (NIAID) (R01AI104589). This work, including the efforts of Debra Benator, Charles M. Heilig, Marc Weiner, Neil Martinson, AmyKerrigan, Carlos Zamudio, Stefan V. Goldberg, William C. Whitworth, and Payam Nahid, was funded by HHS vertical bar Centers for Disease Control and Prevention (CDC). NR 19 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 EI 1098-660X J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD DEC PY 2016 VL 54 IS 12 BP 3028 EP 3033 DI 10.1128/JCM.01313-16 PG 6 WC Microbiology SC Microbiology GA ED9RF UT WOS:000389209600029 PM 27733634 ER PT J AU Moyo, S Mohammed, T Wirth, KE Prague, M Bennett, K Holme, MP Mupfumi, L Sebogodi, P Moraka, NO Boleo, C Maphorisa, CN Seraise, B Gaseitsiwe, S Musonda, RM van Widenfelt, E Powis, KM Gaolathe, T Tchetgen, EJT Makhema, JM Essex, M Lockman, S Novitsky, V AF Moyo, Sikhulile Mohammed, Terence Wirth, Kathleen E. Prague, Melanie Bennett, Kara Holme, Molly Pretorius Mupfumi, Lucy Sebogodi, Philemon Moraka, Natasha O. Boleo, Corretah Maphorisa, Comfort N. Seraise, Boitumelo Gaseitsiwe, Simani Musonda, Rosemary M. van Widenfelt, Erik Powis, Kathleen M. Gaolathe, Tendani Tchetgen, Eric J. Tchetgen Makhema, Joseph M. Essex, Max Lockman, Shahin Novitsky, Vladimir TI Point-of-Care Cepheid Xpert HIV-1 Viral Load Test in Rural African Communities Is Feasible and Reliable SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID RESOURCE-LIMITED SETTINGS; ANTIRETROVIRAL THERAPY; SOUTH-AFRICA; WHOLE-BLOOD; SCALE-UP; ASSAY; PLASMA; RNA; QUANTIFICATION; CHALLENGES AB Routine monitoring of HIV-1 RNA or viral load (VL) in patients on antiretroviral therapy (ART) is important, but there are multiple impediments to VL testing in resource-constrained settings. An accurate point-of-care (POC) HIV-1 VL test could alleviate many of these challenges. We compared the performance of the Cepheid Xpert HIV-1 VL assay against the laboratory-based Abbott m2000sp/m2000rt assay (Abbott assay). ART-naive individuals participating in the Botswana Combination Prevention Project in 20 communities provided EDTA-blood specimens during household surveys. Both the POC Xpert HIV-1 VL and Abbott assays were performed on specimens sampled from 277 individuals. We found a high correlation between the Xpert HIV-1 VL and Abbott assay results (r(2) = 0.92; P < 0.001). The overall mean difference in the HIV-1 RNA values obtained by Xpert HIV-1 VL assay and Abbott assay was 0.34 log(10) copies/ml (95% confidence interval [CI], 0.26 to 0.40 log(10) copies/ml) (P < 0.001). Using a clinically relevant level of 1,000 copies/ml as a threshold, agreement was 90.6% (95% CI, 87.9 to 93.1%), with a sensitivity of 98.6% (95% CI, 97.2 to 100%). The two methods agreed on their detectability of HIV-1 RNA (>40 copies/ml) at 97.1% (95% CI, 95.5 to 98.7%), with a sensitivity of 99.6% (95% CI, 97.2 to 100%). The POC Cepheid Xpert HIV-1 VL assay showed high agreement and accuracy with a laboratory-based method of HIV-1 RNA testing. The POC Xpert HIV-1 VL assay tended to overestimate HIV-1 VL, although the difference was below a clinically relevant threshold of 0.5 log(10) copies/ml. The POC Cepheid Xpert HIV-1 VL assay is a promising tool for monitoring patients on ART in southern Africa. C1 [Moyo, Sikhulile; Mohammed, Terence; Holme, Molly Pretorius; Mupfumi, Lucy; Sebogodi, Philemon; Moraka, Natasha O.; Boleo, Corretah; Maphorisa, Comfort N.; Seraise, Boitumelo; Gaseitsiwe, Simani; Musonda, Rosemary M.; van Widenfelt, Erik; Powis, Kathleen M.; Gaolathe, Tendani; Makhema, Joseph M.; Essex, Max; Lockman, Shahin; Novitsky, Vladimir] Botswana Harvard AIDS Inst Partnership, Gaborone, Botswana. [Moyo, Sikhulile] Univ Stellenbosch, Div Med Virol, Fac Med & Hlth Sci, Tygerberg, South Africa. [Wirth, Kathleen E.; Tchetgen, Eric J. Tchetgen] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Wirth, Kathleen E.; Gaseitsiwe, Simani; Musonda, Rosemary M.; van Widenfelt, Erik; Powis, Kathleen M.; Makhema, Joseph M.; Essex, Max; Lockman, Shahin; Novitsky, Vladimir] Harvard TH Chan Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA USA. [Prague, Melanie; Holme, Molly Pretorius; Tchetgen, Eric J. Tchetgen] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Bennett, Kara] Bennett Stat Consulting Inc, Ballston Lake, NY USA. [Powis, Kathleen M.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Powis, Kathleen M.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Lockman, Shahin] Brigham & Womens Hosp, Div Infect Dis, Boston, MA USA. RP Moyo, S (reprint author), Botswana Harvard AIDS Inst Partnership, Gaborone, Botswana.; Moyo, S (reprint author), Univ Stellenbosch, Div Med Virol, Fac Med & Hlth Sci, Tygerberg, South Africa. EM sikhulilemoyo@gmail.com OI Moyo, Sikhulile/0000-0003-3821-4592 FU U.S. President's Emergency Plan for AIDS Relief (PEPFAR) [U01 GH000447]; Wellcome Trust DELTAS Initiatives/Sub-Saharan Africa Network for TB/HIV Research Excellence (SANTHE) [107752/Z/15/Z]; U.S. President's Emergency Plan for AIDS Relief (PEPFAR) through the Centers for Disease Control and Prevention (CDC) [U01 GH000447] FX This work, including the efforts of Sikhulile Moyo, Terence Mohammed, Kathleen E. Wirth, Melanie Prague, Kara Bennett, Molly P. Holme, Natasha O. Moraka, Corettah Boleo, Comfort N. Maphorisa, Boitumelo Seraise, Simani Gaseitsiwe, Rosemary Musonda, Erik van Widenfelt, Kathleen M. Powis, Tendani Gaolathe, Eric J. Tchetgen Tchetgen, Joseph Makhema, M. Essex, Shahin Lockman, Vlad Novitsky, Lucy Mupfumi, and Philemon Sebogodi, was funded by U.S. President's Emergency Plan for AIDS Relief (PEPFAR) (U01 GH000447). This work, including the efforts of Simani Gaseitsiwe and Natasha O. Moraka, was funded by Wellcome Trust DELTAS Initiatives/Sub-Saharan Africa Network for TB/HIV Research Excellence (SANTHE) (107752/Z/15/Z).; This study was supported by the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) through the Centers for Disease Control and Prevention (CDC) under the terms of cooperative agreement U01 GH000447. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the CDC. The funders had no role in the study design, data collection, analysis, interpretation, writing, or submission of the manuscript for publication. NR 32 TC 1 Z9 1 U1 3 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 EI 1098-660X J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD DEC PY 2016 VL 54 IS 12 BP 3050 EP 3055 DI 10.1128/JCM.01594-16 PG 6 WC Microbiology SC Microbiology GA ED9RF UT WOS:000389209600032 PM 27733636 ER PT J AU Kwak, SY Yamakoshi, Y Simmer, JP Margolis, HC AF Kwak, S. Y. Yamakoshi, Y. Simmer, J. P. Margolis, H. C. TI MMP20 Proteolysis of Native Amelogenin Regulates Mineralization In Vitro SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE amelogenesis; amorphous calcium phosphate; dental enamel; enamel matrix proteins; hydroxyapatite; crystal growth ID CALCIUM-PHOSPHATE FORMATION; IMPERFECTA PHENOTYPE; ENAMEL FORMATION; MICE DISPLAY; PROTEIN; APATITE; MMP-20; MATRIX; BIOMINERALIZATION; PHOSPHORYLATION AB Recent studies have shown that native phosphorylated full-length porcine amelogenin (P173) and its predominant cleavage product (P148) can inhibit spontaneous calcium phosphate formation in vitro by stabilizing an amorphous calcium phosphate (ACP) precursor phase. Since full-length amelogenin undergoes proteolysis by matrix metalloproteinase 20 (MMP20, enamelysin) soon after secretion, the present study was conducted to assess the effect of amelogenin proteolysis on calcium phosphate formation. Calcium and phosphate were sequentially added to protein solutions without and with added MMP20 (ratio = 200: 1) under physiological-like conditions of ionic strength (163 mM) in 50 mM Tris-HCl (pH 7.4) at 37 degrees C. Protein degradation with time was assessed by gel-electrophoresis, and mineral products formed were characterized by transmission electron microscopy (TEM). MMP20 was found to cleave P173 to primarily generate P148, along with P162, P46-148, and P63/64-148. In sharp contrast, MMP20 did not cleave P148. In addition, the formation of well-aligned bundles of enamel-like hydroxyapatite (HA) crystals was promoted in the presence of P173 with added MMP20, while only ACP particles were seen in the absence of MMP20. Although P148 was found to have a somewhat lower capacity to stabilize ACP and prevent HA formation compared with P173 in the absence of MMP20, essentially no HA formation was observed in the presence of somewhat higher concentrations of P148 regardless of MMP20 addition, due to the lack of observed protein proteolysis. Present findings suggest that ACP transformation to ordered arrays of enamel crystals may be regulated in part by the proteolysis of full-length native amelogenin, while the predominant amelogenin degradation product in developing enamel (e.g., P148) primarily serves to prevent uncontrolled mineral formation during the secretory stage of amelogenesis. C1 [Kwak, S. Y.; Margolis, H. C.] Forsyth Inst, Dept Appl Oral Sci, Ctr Biomineralizat, 245 First St, Cambridge, MA 02142 USA. [Kwak, S. Y.; Margolis, H. C.] Harvard Sch Dent Med, Dept Dev Biol, Boston, MA USA. [Yamakoshi, Y.] Tsurumi Univ, Sch Dent Med, Dept Biochem & Mol Biol, Yokohama, Kanagawa, Japan. [Simmer, J. P.] Univ Michigan, Sch Dent, Dept Biol & Mat Sci, Ann Arbor, MI 48109 USA. RP Margolis, HC (reprint author), Forsyth Inst, Dept Appl Oral Sci, Ctr Biomineralizat, 245 First St, Cambridge, MA 02142 USA. EM hmargolis@forsyth.org FU National Institutes of Dental and Craniofacial Research (NIDCR) [R01-DE023091] FX This study was supported by National Institutes of Dental and Craniofacial Research (NIDCR) grant R01-DE023091 (HCM). The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article. NR 37 TC 0 Z9 0 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-0345 EI 1544-0591 J9 J DENT RES JI J. Dent. Res. PD DEC PY 2016 VL 95 IS 13 BP 1511 EP 1517 DI 10.1177/0022034516662814 PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA ED4WB UT WOS:000388851500011 PM 27558264 ER PT J AU Allie, E Bain, A Bowen, K Cashman, L Clauson, K Devoe-Morris, J D'Hondt, N Edwards, A Fouts, B Galante, D Gaskins, K Haley, W Haydon-Greatting, S Kent, D Kowalski, A Leal, S Mcadam-Marx, C O'Keefe, S Peeples, M Ponzo, S Runge, A Tesell, M Trodden, D Williams, E Winter, B Yu-Isenberg, K Cantrell, S Carden, MJ Delauder, E Lanham, A O'Connor, A Oh, S Richardson, T Veeder, J AF Allie, Edward Bain, Amanda Bowen, Kevin Cashman, Lisa Clauson, Kevin Devoe-Morris, Jameeka D'Hondt, Nancy Edwards, Anita Fouts, Brandy Galante, Dominic Gaskins, Kendra Haley, Wenni Haydon-Greatting, Starlin Kent, Daniel Kowalski, Aaron Leal, Sandra Mcadam-Marx, Carrie O'Keefe, Sandra Peeples, Malinda Ponzo, Stephanie Runge, Ava Tesell, Mark Trodden, Daniel Williams, Erica Winter, Bradly Yu-Isenberg, Kristina Cantrell, Susan Carden, Mary Jo Delauder, Emily Lanham, Ashley O'Connor, Amy Oh, Susan Richardson, Terry Veeder, Julia TI AMCP Partnership Forum: Navigating Innovations in Diabetes Care SO Journal of Managed Care & Specialty Pharmacy LA English DT Article AB New developments that provide opportunities to enhance cost-effective diabetes care include advances in the pharmacologic treatment of diabetes, new drug delivery devices, innovations in patient management strategies, contracting strategies that incentivize effective interventions, and mobile health technologies. Payers must carefully consider the utility of these advances when making coverage decisions and designing benefits. To engage national stakeholders in a discussion about how to utilize innovations in diabetes care to optimize patient outcomes, the Academy of Managed Care Pharmacy organized the Partnership Forum on Navigating Innovations in Diabetes Care in Arlington, Virginia, on July 19-20, 2016. The forum explored current trends and advances in diabetes treatments and engaged in discussions about how organizations can leverage these emerging options to develop strategies that improve coordination of care and patient outcomes, while managing limited health resources. Additionally, stakeholders were tasked with identifying gaps in evidence that hinder decision making around novel therapies and other advances that are of direct relevance to managed care organizations. Copyright (C) 2016, Academy of Managed Care Pharmacy. All rights reserved. C1 [Allie, Edward; Richardson, Terry] Steward Hlth Care Network, Pharm & Wellness, Dedham, MA 02026 USA. [Bain, Amanda] Ohio State Univ Hlth Plan, Pharm & Care Management, Columbus, OH USA. [Bowen, Kevin] Hlth Outcomes Researcher, Prime Therapeut, Memphis, TN USA. [Cashman, Lisa] Medlmpact Healthcare, Clin Formulary, San Diego, CA USA. [Clauson, Kevin] Lipscomb Univ, Nashville, TN USA. [Devoe-Morris, Jameeka] WellCare Hlth Plans, Clin Pharmacist, Tampa, FL USA. [D'Hondt, Nancy] St John Providence Hosp & Med Ctr, Clin Pharmacist & Diabet Educator, Detroit, MI USA. [Edwards, Anita] Gateway Hlth Plan, Pittsburgh, PA USA. [Fouts, Brandy] OmedaRx, Clin Pharm Consultant, Specialty Medicat, Delaware, OH USA. [Gaskins, Kendra] Amer Med Grp Associat, Natl Hlth Campaigns, Alexandria, VA USA. [Haley, Wenni] Dexcom, San Diego, CA USA. [Haydon-Greatting, Starlin] Illinois Pharmacists Associat, Clin Programs, Springfield, IL USA. [Kent, Daniel] Grp Hlth, Specialty Clin Pharm Programs, Seattle, WA USA. [Kowalski, Aaron] Juvenile Diabet Res Fdn, New York, NY USA. [Leal, Sandra] SinfoniaRx, Innovat, Tucson, AZ USA. [Mcadam-Marx, Carrie] Univ Utah, Coll Pharm, Salt Lake City, UT USA. [O'Keefe, Sandra] Massachusetts Gen Hosp, Dis Management Qual Improvement, Boston, MA 02114 USA. [Peeples, Malinda] WellDoc, Clin Advocacy, Bangalore, Karnataka, India. [Ponzo, Stephanie] Merck & Co Inc, Managed Care, Kenilworth, NJ USA. [Runge, Ava] DiaTribe Fdn, Columbus, OH USA. [Tesell, Mark] Univ Massachusetts, Med Sch Clin Pharm Serv, Clin Consultant Pharmacist Team Lead, Amherst, MA 01003 USA. [Trodden, Daniel] Insulet Corp, Milford, MA USA. [Williams, Erica] Dexcom, Natl Account Execut, San Diego, CA USA. [Winter, Bradly] Intermountain Healthcare, Ambulatory Care Clin Pharmacist, Salt Lake City, UT USA. [Yu-Isenberg, Kristina] Evidence Generat & Analyt Intarcia Therapeutics, Boston, MA USA. RP Richardson, T (reprint author), Steward Hlth Care Network, Pharm & Wellness, Dedham, MA 02026 USA. EM trichardson@amcp.org FU Boehringer Ingelheim; Lilly; Dexcom; Insulet Corporation; Intarcia Therapeutics; Merck FX The AMCP Partnership Forum on Navigating Innovations in Diabetes Care and the development of this proceedings document were supported by Boehringer Ingelheim, Lilly, Dexcom, Insulet Corporation, Intarcia Therapeutics, and Merck. NR 17 TC 0 Z9 0 U1 2 U2 2 PU ACAD MANAGED CARE PHARMACY PI ALEXANDRIA PA 100 N PITT ST, 400, ALEXANDRIA, VA 22314-3134 USA SN 2376-0540 EI 2376-1032 J9 J MANAG CARE SPEC PH JI J. Manag. Care Spec. Pharm. PD DEC PY 2016 VL 22 IS 12 BP 1369 EP 1375 PG 7 WC Health Care Sciences & Services; Pharmacology & Pharmacy SC Health Care Sciences & Services; Pharmacology & Pharmacy GA ED9FG UT WOS:000389175000001 ER PT J AU Kesselheim, JC Najita, J Morley, D Bair, E Joffe, S AF Kesselheim, Jennifer C. Najita, Julie Morley, Debra Bair, Elizabeth Joffe, Steven TI Ethics knowledge of recent paediatric residency graduates: the role of residency ethics curricula SO JOURNAL OF MEDICAL ETHICS LA English DT Article ID EDUCATION; PROFESSIONALISM; CERTIFICATION; CONSULTANTS; CHALLENGES; PROGRAM AB Objective To evaluate the relationship between recently trained paediatricians' ethics knowledge and exposure to a formal ethics or professionalism curriculum during residency. Methods We conducted a cross-sectional survey of recently trained paediatricians which included a validated 23-item instrument called the Test of Residents' Ethics Knowledge for Pediatrics. The sample included paediatricians who completed medical school in 2006-2008, whose primary specialty was paediatrics or a paediatric subspecialty, and who completed paediatric residency training in 2010-2011. This sample was stratified based on residency programme variables: presence of a formal curriculum in ethics or professionalism, programme size and American Board of Pediatrics certifying exam passage rate. Paediatricians were randomly selected from each stratum for survey participation. Results Among the 370 responding paediatricians (55%), the mean knowledge score was 17.3 (SD 2.2) out of a possible 23. Presence of a formal curriculum in ethics and/or professionalism was not significantly associated with knowledge. Knowledge was lowest on items about parental requests for a child to undergo genetic testing (2 items, 44% and 85% incorrect), preserving patient confidentiality over email (55% incorrect), decision-making regarding life-sustaining technologies (61% incorrect), and decision-making principles such as assent and parental permission (2 items, 47% and 49% incorrect). Conclusions This study highlights several areas in which paediatricians' knowledge may be low and that are amenable to targeted educational interventions. These findings should prompt discussion and research among ethicists and educators about how ethics and professionalism curricula can more consistently influence paediatricians' knowledge. C1 [Kesselheim, Jennifer C.] Harvard Med Sch, Dana Farber Boston Childrens Canc & Blood Disorde, Boston, MA USA. [Najita, Julie] Harvard TH Chan Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA USA. [Najita, Julie] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Morley, Debra; Bair, Elizabeth] Dana Farber Canc Inst, Dept Populat Sci, Boston, MA 02115 USA. [Joffe, Steven] Univ Penn, Perelman Sch Med, Dept Med Eth & Hlth Policy, Philadelphia, PA 19104 USA. [Joffe, Steven] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. RP Kesselheim, JC (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,D1107, Boston, MA 02215 USA. EM Jennifer_kesselheim@dfci.harvard.edu FU Genzyme/Sanofi FX JCK received financial compensation to serve on a data safety monitoring board for Genzyme/Sanofi until November 2012. NR 34 TC 0 Z9 0 U1 9 U2 9 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0306-6800 EI 1473-4257 J9 J MED ETHICS JI J. Med. Ethics PD DEC PY 2016 VL 42 IS 12 BP 809 EP 814 DI 10.1136/medethics-2016-103625 PG 6 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA ED6PG UT WOS:000388977100011 PM 27884969 ER PT J AU O'Neill, AF Qin, L Wen, PY de Groot, JF Van den Abbeele, AD Yap, JT AF O'Neill, Allison F. Qin, Lei Wen, Patrick Y. de Groot, John F. Van den Abbeele, Annick D. Yap, Jeffrey T. TI Demonstration of DCE-MRI as an early pharmacodynamic biomarker of response to VEGF Trap in glioblastoma SO JOURNAL OF NEURO-ONCOLOGY LA English DT Article DE DCE-MRI; VEGF; Glioblastoma; Angiogenesis ID ENDOTHELIAL GROWTH-FACTOR; APPARENT DIFFUSION-COEFFICIENT; CONTRAST-ENHANCED MRI; HIGH-GRADE GLIOMAS; BRAIN-TUMORS; RECURRENT GLIOBLASTOMA; BEVACIZUMAB TREATMENT; HISTOGRAM ANALYSIS; MALIGNANT GLIOMA; LIVER METASTASES AB Glioblastoma (GBM) is an incurable brain tumor characterized by the expression of pro-angiogenic cytokines. A recent phase II clinical trial studied VEGF Trap in adult patients with temozolomide-resistant GBM. We sought to explore changes in [F-18]Fluorodeoxyglucose positron emission tomography (FDG-PET) or magnetic resonance imaging (MRI) in trial participants correlating these changes with disease response. FDG-PET and MRI images obtained before and after the first dose of VEGF Trap were spatially co-registered. Regions of interest on each image slice were combined to produce a volume of interest representative of the entire tumor. Percent and absolute changes in maximum FDG-avidity, mean apparent diffusion coefficient (ADC), K-trans, and Ve were calculated per lesion. Among the 12 participants that underwent dynamic contrast enhanced MRI (DCE-MRI), there were large, statistically significant reductions in K-trans and Ve (median difference = -41.8 %, p < 0.02 and -42.6 %, p < 0.04, respectively). In contrast, there were no significant reductions in ADC or FDG-PET SUVmax values. DCE-MRI is a useful measure of early pharmacodynamic effects of VEGF Trap on tumor vasculature. The absence of significant changes in FDG-PET and DW-MRI suggest that the early pharmacodynamic effects are specific to tumor perfusion and/or permeability and do not directly inhibit metabolism or induce cell death. DCE-MRI in conjunction with standard imaging may be promising for the identification of anti-angiogenic effects in this patient population with this therapeutic target. Further studies are needed to evaluate the relationship between DCE-MRI response and clinical outcome. C1 [O'Neill, Allison F.] Harvard Med Sch, Boston Childrens Hosp, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. [Qin, Lei; Van den Abbeele, Annick D.] Dana Farber Canc Inst, Dept Imaging, Boston, MA 02115 USA. [Qin, Lei; Van den Abbeele, Annick D.] Dana Farber Canc Inst, Ctr Biomed Imaging Oncol, Boston, MA 02115 USA. [Qin, Lei; Van den Abbeele, Annick D.] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Qin, Lei; Van den Abbeele, Annick D.] Harvard Med Sch, Dana Farber Harvard Canc Ctr, Tumor Imaging Metr Core, Boston, MA 02215 USA. [Wen, Patrick Y.] Harvard Med Sch, Dana Farber Canc Inst, Brigham & Womens Hosp, Ctr Neurooncol, Boston, MA 02215 USA. [de Groot, John F.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Yap, Jeffrey T.] Univ Utah, Huntsman Canc Inst, Dept Radiol, Ctr Quantitat Canc Imaging, Salt Lake City, UT 84112 USA. RP O'Neill, AF (reprint author), Harvard Med Sch, Boston Childrens Hosp, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. EM allison_oneill@dfci.harvard.edu NR 48 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X EI 1573-7373 J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD DEC PY 2016 VL 130 IS 3 BP 495 EP 503 DI 10.1007/s11060-016-2243-5 PG 9 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA ED6FE UT WOS:000388950700012 PM 27576699 ER PT J AU Pan, E Supko, JG Kaley, TJ Butowski, NA Cloughesy, T Jung, J Desideri, S Grossman, S Ye, XB Park, DM AF Pan, Edward Supko, Jeffrey G. Kaley, Thomas J. Butowski, Nicholas A. Cloughesy, Timothy Jung, Jinkyu Desideri, Serena Grossman, Stuart Ye, Xiaobu Park, Deric M. TI Phase I study of RO4929097 with bevacizumab in patients with recurrent malignant glioma SO JOURNAL OF NEURO-ONCOLOGY LA English DT Article DE Glioma; Notch; Gamma secretase; Bevacizumab; Clinical trial ID GAMMA-SECRETASE INHIBITOR; ADVANCED SOLID TUMORS; CANCER STEM-CELLS; BREAST-CANCER; NOTCH; ACTIVATION; PATHWAY; HIF-1-ALPHA; LUNG; ANGIOGENESIS AB Antiangiogenic therapies for malignant gliomas often result in transient response, and recurrent disease is characterized by adoption of invasive and hypoxic phenotype. The notch signaling pathway is activated in gliomas, and augments cell migration and hypoxic response. Here we report a clinical study of the combination of bevacizumab and RO4929097, an inhibitor of the notch signaling cascade. A phase I clinical trial was conducted through the Adult Brain Tumor Consortium in subjects with recurrent malignant glioma. Primary objectives were to assess safety and to define the maximum tolerated dose of RO4929097 in combination with bevacizumab. Secondary objectives were to determine overall survival, progression free survival, radiographic response, pharmacokinetic evaluation, and tissue biomarker analysis. Thirteen subjects were enrolled. Of the three subjects treated with the highest dose of RO4929097, one grade 3 toxicity and one grade 2 toxicity were observed. Definitive maximum tolerated dose of RO4929097 in combination with bevacizumab was not identified due to manufacturer's decision to halt drug production. 2 of 12 evaluable subjects demonstrated radiographic response; one subject experienced CR and the second PR. The median overall survival was 10.9 months with a median progression-free survival of 3.7 months. Two subjects remained free of disease progression at 6 months from treatment initiation. PK evaluation did not identify clinically significant drug-drug interactions. All analyzed tissue specimens revealed activation of notch signaling. Combination of RO4929097 and bevacizumab was well-tolerated. Given the compelling scientific rationale, additional studies of antiangiogenic and notch signaling inhibitors should be considered. C1 [Pan, Edward] UT Southwestern Med Ctr, Simmons Comprehens Canc Ctr, Dept Med, Dallas, TX 75390 USA. [Supko, Jeffrey G.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Kaley, Thomas J.] Mem Sloan Kettering Canc Ctr, Dept Neurol, 1275 York Ave, New York, NY 10021 USA. [Butowski, Nicholas A.] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA USA. [Cloughesy, Timothy] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA. [Jung, Jinkyu; Park, Deric M.] NCI, Neurooncol Branch, CCR, NIH, Bethesda, MD 20892 USA. [Desideri, Serena; Grossman, Stuart; Ye, Xiaobu] Johns Hopkins Univ, Sidney Kimmel Canc Ctr, Baltimore, MD USA. RP Pan, E (reprint author), UT Southwestern Med Ctr, Simmons Comprehens Canc Ctr, Dept Med, Dallas, TX 75390 USA.; Park, DM (reprint author), NCI, Neurooncol Branch, CCR, NIH, Bethesda, MD 20892 USA. EM Edward.Pan@UTSouthwestern.edu; deric.park@nih.gov FU [CA UM1 137443] FX CA UM1 137443 awarded to ABTC. NR 35 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X EI 1573-7373 J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD DEC PY 2016 VL 130 IS 3 BP 571 EP 579 DI 10.1007/s11060-016-2263-1 PG 9 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA ED6FE UT WOS:000388950700020 PM 27826680 ER PT J AU Griessenauer, CJ Ogilvy, CS Foreman, PM Chua, MH Harrigan, MR Stapleton, CJ Patel, AB He, L Fusco, MR Mocco, J Winkler, PA Patel, AS Thomas, AJ AF Griessenauer, Christoph J. Ogilvy, Christopher S. Foreman, Paul M. Chua, Michelle H. Harrigan, Mark R. Stapleton, Christopher J. Patel, Aman B. He, Lucy Fusco, Matthew R. Mocco, J. Winkler, Peter A. Patel, Apar S. Thomas, Ajith J. TI Pipeline Embolization Device for small paraophthalmic artery aneurysms with an emphasis on the anatomical relationship of ophthalmic artery origin and aneurysm SO JOURNAL OF NEUROSURGERY LA English DT Article DE Pipeline Embolization Device; ophthalmic artery; aneurysm; occlusion; patency; vision; outcome; vascular disorders ID INTRACRANIAL ANEURYSMS; ENDOVASCULAR TREATMENT; PARACLINOID ANEURYSMS; NATURAL-HISTORY; SEGMENT; EXPERIENCE; OUTCOMES; COHORT AB OBJECTIVE Contemporary treatment for paraophthalmic artery aneurysms includes flow diversion utilizing the Pipeline Embolization Device (PED). Little is known, however, about the potential implications of-the anatomical relationship of the ophthalmic artery (OA) origin and aneurysm, especially in smaller aneurysms. METHODS Four major academic institutions in the United States provided data on small paraophthalmic aneurysms (<= 7 mm) that were treated with PED between 2009 and 2015. The anatomical relationship of OA origin and aneurysm, radiographic outcomes of aneurysm occlusion, and patency of the OA were assessed using digital subtraction angiography. OA origin was classified as follows: Type 1, OA separate from the aneurysm; Type 2, OA from the aneurysm neck; and Type 3, OA from the aneurysm dome. Clinical outcome was assessed using the modified Rankin Scale, and visual deficits were categorized as transient or permanent. RESULTS The cumulative number of small paraophthalmic aneurysms treated with PED between 2009 and 2015 at the 4 participating institutions was 69 in 52 patients (54.1 +/- 13.7 years of age) with a male-to-female ratio of 1:12. The distribution of OA origin was 72.5% for Type 1, 17.4% for Type 2, and 10.1% for Type 3. Radiographic outcome at the last follow-up (median 11.5 months) was available for 54 aneurysms (78.3%) with complete, near-complete, and incomplete occlusion rates of 81.5%, 5.6%, and 12.9%, respectively. Two aneurysms (3%) resulted in transient visual deficits, and no patient experienced a permanent visual deficit. At the last follow-up, the OA was patent in 96.8% of treated aneurysms. Type 3 OA origin was associated with a lower rate of complete aneurysm occlusion (p = 0.0297), demonstrating a trend toward visual deficits (p = 0.0797) and a lower rate of OA patency (p = 0.0783). CONCLUSIONS Pipeline embolization treatment of small paraophthalmic aneurysms is safe and effective. An aneurysm where the OA arises from the aneurysm dome may be associated with lower rates of aneurysm occlusion, OA patency, and higher rates of transient visual deficits. C1 [Griessenauer, Christoph J.; Ogilvy, Christopher S.; Patel, Apar S.; Thomas, Ajith J.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Neurosurg Serv, 110 Francis St,Ste 3B, Boston, MA 02215 USA. [Chua, Michelle H.] Harvard Med Sch, Boston, MA USA. [Stapleton, Christopher J.; Patel, Aman B.] Harvard Med Sch, Dept Neurosurg, Massachusetts Gen Hosp, Boston, MA USA. [Foreman, Paul M.; Harrigan, Mark R.] Univ Alabama Birmingham, Dept Neurosurg, Birmingham, AL USA. [He, Lucy; Fusco, Matthew R.] Vanderbilt Univ, Dept Neurosurg, 221 Kirkland Hall, Nashville, TN 37235 USA. [Mocco, J.] Dept Neurosurg, New York, NY USA. [Winkler, Peter A.] Paracelsus Med Univ, Dept Neurosurg, Salzburg, Austria. RP Griessenauer, CJ (reprint author), Harvard Med Sch, Beth Israel Deaconess Med Ctr, Neurosurg Serv, 110 Francis St,Ste 3B, Boston, MA 02215 USA. EM christoph.griessenauer@gmail.com FU Blockade Medical; Stryker; Data Safety Monitoring Board of the SCENT FX Dr. Mocco is a consultant for Lazurus Effect, Reverse Medical, Pulsar, Edge Therapeutics, and Medina and has a financial relationship with Blockade Medical. Dr. Thomas has a financial relationship with Stryker and a nonfinancial relationship with the Data Safety Monitoring Board of the SCENT flow diverter trial. NR 21 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 0022-3085 EI 1933-0693 J9 J NEUROSURG JI J. Neurosurg. PD DEC PY 2016 VL 125 IS 6 BP 1352 EP 1359 DI 10.3171/2015.12.JNS152499 PG 8 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA ED3XY UT WOS:000388783000004 PM 26943842 ER PT J AU Boasso, AM Steenkamp, MM Larson, JL Litz, BT AF Boasso, Alyssa M. Steenkamp, Maria M. Larson, Jonathan L. Litz, Brett T. TI Posttraumatic stress symptoms across the deployment cycle: A latent transition analysis SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE PTSD; Latent transition analysis; Active-duty military ID PTSD SYMPTOMS; PSYCHOMETRIC PROPERTIES; DISORDER; VETERANS; TRAJECTORIES; AFGHANISTAN; IRAQ; RESILIENCE; DEPRESSION; WAR AB Our objective was to examine symptom-level changes in the course in posttraumatic stress disorder (PTSD) across the deployment cycle among combat-exposed Marines, and to determine the degree to which combat exposure and post-deployment stressor exposure predicted PTSD symptom profile transitions. We examined PTSD symptoms in a cohort of U.S. Marines (N = 892) recruited for the Marine Resiliency Study (MRS). Marines deployed as one battalion infantry unit to Afghanistan in 2010 and were assessed pre-deployment and one, five, and eight months post-deployment. We employed latent transition analysis (LTA) to examine Marines' movement across PTSD symptom profiles, determined by latent class analysis (LCA). LCAs revealed a 3-class solution one month pre-deployment, a 4-class solution at five months post-deployment, and a 3-class solution at eight months post-deployment. LTA revealed notable movement between classes over time, which depended chiefly on pre-deployment symptom presentation. Marines who reported few pre-deployment symptoms either maintained these low levels or returned to low levels by eight months. Marines who reported a moderate number of symptoms at pre-deployment had variable outcomes; 50% had reductions by eight months, and those who reported numbing symptoms at five months post-deployment tended to report more symptoms at eight months. Marines who reported more PTSD symptoms prior to deployment retained more symptoms eight months post-deployment. Combat exposure and post-deployment stressor exposure predicted profile transitions. Examining transitions between latent class membership over time revealed prognostic information about Marines' eight-month PTSD outcomes. The extent of pre-deployment PTSD symptoms was particularly informative of likely PTSD outcomes. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Boasso, Alyssa M.; Larson, Jonathan L.] Massachusetts Vet Epidemiol Res & Informat Ctr, VA Boston Healthcare Syst, Boston, MA USA. [Steenkamp, Maria M.] NYU, Langone Sch Med, New York, NY 10003 USA. [Litz, Brett T.] Boston Univ, Sch Med, Massachusetts Vet Epidemiol Res & Informat Ctr, VA Boston Healthcare Syst, Boston, MA 02215 USA. RP Boasso, AM (reprint author), 800 Boylston St,Suite 1475,14th Floor, Boston, MA 02199 USA. EM alyssa.boasso@gmail.com FU VA Health Service Research and Development [SDR 09-0128]; U.S. Marine Corps and Navy Bureau of Medicine and Surgery FX The authors acknowledge the Marine Resiliency Study (MRS) team who made this work possible. This study was funded by VA Health Service Research and Development (SDR 09-0128) and by the U.S. Marine Corps and Navy Bureau of Medicine and Surgery. NR 36 TC 0 Z9 0 U1 6 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 DEC PY 2016 VL 83 BP 54 EP 60 DI 10.1016/j.jpsychires.2016.08.002 PG 7 WC Psychiatry SC Psychiatry GA ED8CW UT WOS:000389100600008 PM 27566139 ER PT J AU Ehlers, CL Kim, C Gilder, DA Stouffer, GM Caetano, R Yehuda, R AF Ehlers, Cindy L. Kim, Corinne Gilder, David A. Stouffer, Gina M. Caetano, Raul Yehuda, Rachel TI Lifetime history of traumatic events in a young adult Mexican American sample: Relation to substance dependence, affective disorder, acculturation stress, and PTSD SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Mexican American; PTSD; Substance dependence; Trauma ID NATIONAL-COMORBIDITY-SURVEY; R PSYCHIATRIC-DISORDERS; ALCOHOL SURVEY HABLAS; INDIAN RESERVATION POPULATIONS; POSTTRAUMATIC-STRESS; UNITED-STATES; MENTAL-HEALTH; EPIDEMIOLOGIC SURVEY; HOLOCAUST SURVIVORS; ANXIETY DISORDERS AB Mexican Americans comprise one of the most rapidly growing populations in the United States, and within this population, trauma and post-traumatic stress disorder (PTSD) are associated with physical and mental health problems. Therefore, efforts to delineate factors that may uniquely contribute to increased likelihood of trauma, PTSD, and substance use disorders over the lifetime in Mexican Americans are important to address health disparities and to develop treatment and prevention programs. Six hundred fourteen young adults (age 18-30 yrs) of Mexican American heritage, largely second generation, were recruited from the community and assessed with the Semi-Structured Assessment for the Genetics of Alcoholism and an acculturation stress scale. More males (51.2%) reported experiencing traumas than females (41.1%), however, a larger proportion of females received a PTSD diagnosis (15%) than males (8%). Alcohol dependence and affective disorders, but not anxiety disorders, antisocial disorders, nicotine, marijuana, or stimulant dependence, were significantly comorbid with PTSD. Endorsing higher levels of acculturation stress was also significantly associated with both trauma exposure and a diagnosis of PTSD. Logistic regression revealed that female gender, having an affective disorder, alcohol dependence, higher levels of acculturation stress, and lower levels of education were all predictors of PTSD status. Additionally, alcohol dependence generally occurred after the PTSD diagnosis in early adulthood in this high risk population. These studies suggest that treatment and prevention efforts should particularly focus on young adult second generation Mexican American women with higher levels of acculturation stress, who may be at higher risk for PTSD, affective disorder, and alcohol dependence following trauma exposure. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Ehlers, Cindy L.; Kim, Corinne; Gilder, David A.; Stouffer, Gina M.] Scripps Res Inst, Mol & Cellular Neurosci Dept, La Jolla, CA 92037 USA. [Caetano, Raul] Pacific Inst Res & Evaluat, Prevent Res Ctr, Oakland, CA USA. [Yehuda, Rachel] Mt Sinai Sch Med, James J Peters Vet Affairs Med Ctr, Bronx, NY USA. [Yehuda, Rachel] Mt Sinai Sch Med, Traumat Stress Studies Div, Dept Psychiat, Bronx, NY USA. RP Ehlers, CL (reprint author), Scripps Res Inst, 10550 North Torrey Pines Rd,SP30-1501, La Jolla, CA 92037 USA. EM cindye@scripps.edu FU National Institutes of Health (NIH) from the National Institute on Alcoholism and Alcohol Abuse (NIAAA) [AA006420] FX This research was supported by grants from the National Institutes of Health (NIH), from the National Institute on Alcoholism and Alcohol Abuse (NIAAA) grant AA006420 (CLE), the NIAAA, 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 82 TC 0 Z9 0 U1 7 U2 7 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 DEC PY 2016 VL 83 BP 79 EP 85 DI 10.1016/j.jpsychires.2016.08.009 PG 7 WC Psychiatry SC Psychiatry GA ED8CW UT WOS:000389100600011 PM 27569652 ER PT J AU Horn, SR Pietrzak, RH Schechter, C Bromet, EJ Katz, CL Reissman, DB Kotov, R Crane, M Harrison, DJ Herbert, R Luft, BJ Moline, JM Stellman, JM Udasin, IG Landrigan, PJ Zvolensky, MJ Southwick, SM Feder, A AF Horn, Sarah R. Pietrzak, Robert H. Schechter, Clyde Bromet, Evelyn J. Katz, Craig L. Reissman, Dori B. Kotov, Roman Crane, Michael Harrison, Denise J. Herbert, Robin Luft, Benjamin J. Moline, Jacqueline M. Stellman, Jeanne M. Udasin, Iris G. Landrigan, Philip J. Zvolensky, Michael J. Southwick, Steven M. Feder, Adriana TI Latent typologies of posttraumatic stress disorder in World Trade Center responders SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Posttraumatic stress disorder (PTSD); World Trade Center (WTC); Latent class analysis (LCA); Typologies ID CENTER RESCUE; POLICE RESPONDERS; COMBAT VETERANS; CENTER DISASTER; SOCIAL SUPPORT; PTSD SYMPTOMS; RISK-FACTORS; LIFE EVENTS; BEHAVIORAL ACTIVATION; DISSOCIATIVE-SUBTYPE AB Posttraumatic stress disorder (PTSD) is a debilitating and often chronic psychiatric disorder. Following the 9/11/2001 World Trade Center (WTC) attacks, thousands of individuals were involved in rescue, recovery and clean-up efforts. While a growing body of literature has documented the prevalence and correlates of PTSD in WTC responders, no study has evaluated predominant typologies of PTSD in this population. Participants were 4352 WTC responders with probable WTC-related DSM-IV PTSD. Latent class analyses were conducted to identify predominant typologies of PTSD symptoms and associated correlates. A 3-class solution provided the optimal representation of latent PTSD symptom typologies. The first class, labeled "High-Symptom (n = 1,973, 45.3%)," was characterized by high probabilities of all PTSD symptoms. The second class, "Dysphoric (n = 1,371, 31.5%)," exhibited relatively high probabilities of emotional numbing and dysphoric arousal (e.g., sleep disturbance). The third class, "Threat (n = 1,008, 23.2%)," was characterized by high probabilities of re-experiencing, avoidance and anxious arousal (e.g., hypervigilance). Compared to the Threat class, the Dysphoric class reported a greater number of life stressors after 9/11/2001 (OR = 1.06). The High-Symptom class was more likely than the Threat class to have a positive psychiatric history before 9/11/2001 (OR = 1.7) and reported a greater number of life stressors after 9/11/2001 (OR = 1.1). The High-Symptom class was more likely than the Dysphoric class, which was more likely than the Threat class, to screen positive for depression (83% > 74% > 53%, respectively), and to report greater functional impairment (High-Symptom > Dysphoric [Cohen d = 0.19], Dysphoric > Threat [Cohen d = 0.24]). These results may help inform assessment, risk stratification, and treatment approaches for PTSD in WTC and disaster responders. (C) 2016 Elsevier Ltd. All rights reserved. C1 [Horn, Sarah R.; Katz, Craig L.; Feder, Adriana] Icahn Sch Med, Dept Psychiat, New York, NY USA. [Pietrzak, Robert H.; Southwick, Steven M.] VA Connecticut Healthcare Syst, US Dept Vet Affairs, Natl Ctr Posttraumat Stress Disorder, West Haven, CT USA. [Pietrzak, Robert H.; Southwick, Steven M.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Schechter, Clyde] Yeshiva Univ, Albert Einstein Coll Med, Dept Family & Social Med, Bronx, NY USA. [Bromet, Evelyn J.] SUNY Stony Brook, Dept Psychiat, Stony Brook, NY 11794 USA. [Reissman, Dori B.] NIOSH, Washington, DC USA. [Crane, Michael; Herbert, Robin; Landrigan, Philip J.] Icahn Sch Med Mt Sinai, Dept Prevent Med, New York, NY 10029 USA. [Harrison, Denise J.] NYU, Sch Med, Dept Environm Med, New York, NY USA. [Harrison, Denise J.] NYU, Sch Med, Dept Populat Hlth, New York, NY USA. [Luft, Benjamin J.] SUNY Stony Brook, Div Infect Dis, Dept Med, Stony Book, NY USA. [Moline, Jacqueline M.] Hofstra North Shore Long Isl Jewish Sch Med, Dept Occupat Med Epidemiol & Prevent, Great Neck, NY USA. [Stellman, Jeanne M.] Columbia Univ, Mailman Sch Publ Hlth, Dept Hlth Policy & Management, New York, NY 10027 USA. [Udasin, Iris G.] UMDNJ, Robert Wood Johnson Med Sch, Dept Environm & Occupat Med, Piscataway, NJ USA. [Zvolensky, Michael J.] Univ Houston, Dept Psychol, Houston, TX 77004 USA. RP Horn, SR (reprint author), Icahn Sch Med Mt Sinai, Dept Psychiat, One Gustave L Levy Pl,Box 1230, New York, NY 10029 USA. EM shorn@uoregon.edu FU CDC/National Institute for Occupational Safety and Health (NIOSH) [200-2011-41919] FX This work was supported by the CDC/National Institute for Occupational Safety and Health (NIOSH) (A.F., R.H.P. and S.M.S., research contract # 200-2011-41919). The CDC/NIOSH did not contribute to study design; data collection, analysis or interpretation; writing of the report; or decision to submit the manuscript for publication. NR 75 TC 0 Z9 0 U1 15 U2 15 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 DEC PY 2016 VL 83 BP 151 EP 159 DI 10.1016/j.jpsychires.2016.08.018 PG 9 WC Psychiatry SC Psychiatry GA ED8CW UT WOS:000389100600020 PM 27623049 ER PT J AU Triantafyllou, C Polimeni, JR Keil, B Wald, LL AF Triantafyllou, Christina Polimeni, Jonathan R. Keil, Boris Wald, Lawrence L. TI Coil-to-Coil Physiological Noise Correlations and Their Impact on Functional MRI Time-Series Signal-to-Noise Ratio SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE 7T; physiological noise; array coils; fMRI; SNR; 32Channel coil; noise covariance ID IMAGES; OPTIMIZATION; ARRAY AB Purpose: Physiological nuisance fluctuations ("physiological noise") are a major contribution to the time-series signal-to-noise ratio (tSNR) of functional imaging. While thermal noise correlations between array coil elements have a well-characterized effect on the image Signal to Noise Ratio (SNR0), the element-to-element covariance matrix of the time-series fluctuations has not yet been analyzed. We examine this effect with a goal of ultimately improving the combination of multichannel array data. Theory and Methods: We extend the theoretical relationship between tSNR and SNR0 to include a time-series noise covariance matrix Psi(t), distinct from the thermal noise covariance matrix Psi(0), and compare its structure to Psi(0) and the signal coupling matrix SSH formed from the signal intensity vectors S. Results: Inclusion of the measured time-series noise covariance matrix into the model relating tSNR and SNR0 improves the fit of experimental multichannel data and is shown to be distinct from Psi(0) or SSH. Conclusion: Time-series noise covariances in array coils are found to differ from Psi(0) and more surprisingly, from the signal coupling matrix SSH. Correct characterization of the time-series noise has implications for the analysis of time-series data and for improving the coil element combination process. (C) 2016 International Society for Magnetic Resonance in Medicine C1 [Triantafyllou, Christina] Siemens Healthcare GmbH, 2 Allee Roethelheimpk, D-91052 Erlangen, Germany. [Polimeni, Jonathan R.; Keil, Boris; Wald, Lawrence L.] Harvard Med Sch, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, Charlestown, MA USA. [Wald, Lawrence L.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Triantafyllou, C (reprint author), Siemens Healthcare GmbH, 2 Allee Roethelheimpk, D-91052 Erlangen, Germany. EM christina.triantafyllou@siemens.com FU NIH [P41-EB015896, K01-EB011498, S10-RR023401, S10-RR021110, S10-RR023043] FX Grant sponsor: NIH; Grant numbers: P41-EB015896, K01-EB011498, S10-RR023401, S10-RR021110, S10-RR023043. NR 19 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD DEC PY 2016 VL 76 IS 6 BP 1708 EP 1719 DI 10.1002/mrm.26041 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA ED8NC UT WOS:000389127200007 PM 26756964 ER PT J AU Tian, QY Rokem, A Folkerth, RD Nummenmaa, A Fan, QY Edlow, BL Mcnab, JA AF Tian, Qiyuan Rokem, Ariel Folkerth, Rebecca D. Nummenmaa, Aapo Fan, Qiuyun Edlow, Brian L. Mcnab, Jennifer A. TI Q-Space Truncation and Sampling in Diffusion Spectrum Imaging SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE diffusion spectrum imaging; q-space truncation and sampling; Gibbs ringing artifacts; aliasing artifacts; ex vivo imaging; high b-value ID HUMAN CONNECTOME PROJECT; ASCENDING AROUSAL SYSTEM; POSTMORTEM HUMAN BRAINS; STATE FREE PRECESSION; FIBER PATHWAYS; STRUCTURAL INFORMATION; FIELD-GRADIENT; MRI; OPTIMIZATION; TRACTOGRAPHY AB Purpose: To characterize the q-space truncation and sampling on the spin-displacement probability density function (PDF) in diffusion spectrum imaging (DSI). Methods: DSI data were acquired using the MGH-USC connectome scanner (G(max) = 300 mT/m) with b(max) = 30,000 s/mm(2), 17 x 17 x 17, 15 x 15 x 15 and 11 x 11 x 11 grids in ex vivo human brains and b(max) = 10,000 s/mm(2), 11 x 11 x 11 grid in vivo. An additional in vivo scan using b(max) = 7,000 s/mm(2), 11 x 11 x 11 grid was performed with a derated gradient strength of 40 mT/m. PDFs and orientation distribution functions (ODFs) were reconstructed with different q-space filtering and PDF integration lengths, and from down-sampled data by factors of two and three. Results: Both ex vivo and in vivo data showed Gibbs ringing in PDFs, which becomes the main source of artifact in the subsequently reconstructed ODFs. For down-sampled data, PDFs interfere with the first replicas or their ringing, leading to obscured orientations in ODFs. Conclusion: The minimum required q-space sampling density corresponds to a field-of-view approximately equal to twice the mean displacement distance (MDD) of the tissue. The 11 x 11 x 11 grid is suitable for both ex vivo and in vivo DSI experiments. To minimize the effects of Gibbs ringing, ODFs should be reconstructed from unfiltered q-space data with the integration length over the PDF constrained to around the MDD. (C) 2016 International Society for Magnetic Resonance in Medicine C1 [Tian, Qiyuan] Stanford Univ, Dept Elect Engn, Stanford, CA 94305 USA. [Tian, Qiyuan; Mcnab, Jennifer A.] Stanford Univ, Dept Radiol, Richard M Lucas Ctr Imaging, Stanford, CA 94305 USA. [Rokem, Ariel] Stanford Univ, Dept Psychol, Stanford, CA USA. [Folkerth, Rebecca D.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Nummenmaa, Aapo; Fan, Qiuyun; Edlow, Brian L.] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA USA. [Edlow, Brian L.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Tian, QY (reprint author), Stanford Univ, Dept Elect Engn, Richard M Lucas Ctr Imaging, 1201 Welch Rd, Stanford, CA 94305 USA. EM qytian@stanford.edu FU National Institutes of Health [NCRR P41RR14075, NIBIB R01EB006847, NIBIB R00EB015445, NIMH/NIBIB U01MH093765, NEI F32 EY022294, NINDS R25NS065743]; National Science Foundation [BCS1228397]; Canadian Institute of Health Research; Oxford-Stanford Big Data in Biomedicine Seed Grant; Stanford Radiology Angel Funds; Center for Integration of Medicine and Innovative Technology; American Academy of Neurology; American Brain Foundation; Stanford Institute of Neuro-Innovation and Translational Neurosciences, Stanford Neurosciences Institute FX Grant sponsor: National Institutes of Health; Grant numbers: NCRR P41RR14075, NIBIB R01EB006847, NIBIB R00EB015445, NIMH/NIBIB U01MH093765, NEI F32 EY022294, NINDS R25NS065743; Grant sponsor: National Science Foundation; Grant number: BCS1228397; Grant sponsor: Canadian Institute of Health Research, Oxford-Stanford Big Data in Biomedicine Seed Grant, Stanford Radiology Angel Funds, Center for Integration of Medicine and Innovative Technology, American Academy of Neurology and American Brain Foundation, Stanford Institute of Neuro-Innovation and Translational Neurosciences, Stanford Neurosciences Institute. NR 68 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD DEC PY 2016 VL 76 IS 6 BP 1750 EP 1763 DI 10.1002/mrm.26071 PG 14 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA ED8NC UT WOS:000389127200011 PM 26762670 ER PT J AU Saleh, MG Near, J Alhamud, A Robertson, F van der Kouwe, AJW Meintjes, EM AF Saleh, Muhammad G. Near, Jamie Alhamud, Alqadafi Robertson, Frances van der Kouwe, Andre J. W. Meintjes, Ernesta M. TI Reproducibility of macromolecule suppressed GABA measurement using motion and shim navigated MEGA-SPECIAL with LCModel, jMRUI and GANNET SO MAGNETIC RESONANCE MATERIALS IN PHYSICS BIOLOGY AND MEDICINE LA English DT Article DE GABA; H-1-MRS; Edited GABA analysis; Motion correction; Magnetic field correction ID MAGNETIC-RESONANCE-SPECTROSCOPY; GAMMA-AMINOBUTYRIC-ACID; TEST-RETEST RELIABILITY; PROTON MR SPECTROSCOPY; IN-VIVO MEASUREMENT; REAL-TIME MOTION; BRAIN GABA; SENSORIMOTOR CORTEX; SPECTRAL QUALITY; 3 TESLA AB Measuring the pure form of GABA has become increasingly important because of its association with behaviour and certain pathologies. The aim of this study was to assess the reproducibility of GABA measurements using a shim and motion navigated MEGA-SPECIAL sequence with LCModel, jMRUI and GANNET software. Motion and shim navigated MEGA-SPECIAL scans were acquired in 20 healthy subjects. Two acquisitions were performed for each of two regions: the anterior cingulate (ACC) and medial-parietal (PAR) cortices. Absolute GABA concentration () and GABA-to-Creatine ratio (GABA/Cr) were quantified using the three software packages. Using the within-subject coefficient of variation (CVws) as an index, reproducibility for both GABA(H20) and GABA/Cr ranged from 13 to 22 % in the ACC and 13 to 18 % in PAR using the three software packages. Based on CVws, GABA concentrations in both the ACC and PAR are reproducible using a shim and motion navigated MEGA-SPECIAL sequence with any of the three software packages, thus demonstrating the ability to quantify the pure form of GABA using these software in studies relating GABA to pathology and healthy behaviour. C1 [Saleh, Muhammad G.; Alhamud, Alqadafi; Robertson, Frances; Meintjes, Ernesta M.] Univ Cape Town, Dept Human Biol, MRC UCT Med Imaging Res Unit, Cape Town, Western Cape, South Africa. [Near, Jamie] McGill Univ, Douglas Mental Hlth Univ Inst, Montreal, PQ, Canada. [Near, Jamie] McGill Univ, Dept Psychiat, Montreal, PQ, Canada. [van der Kouwe, Andre J. W.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Saleh, Muhammad G.] Johns Hopkins Univ, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD 21218 USA. RP Saleh, MG (reprint author), Univ Cape Town, Dept Human Biol, MRC UCT Med Imaging Res Unit, Cape Town, Western Cape, South Africa.; Saleh, MG (reprint author), Johns Hopkins Univ, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD 21218 USA. EM mgsaleh7@gmail.com FU South African Research Chairs Initiative of the National Research Foundation and Department of Science and Technology (NRF-DST); National Institutes of Health (NIH) [R01HD071664]; South African Medical Research Council (MRC) FX Support was provided by the South African Research Chairs Initiative of the National Research Foundation and Department of Science and Technology (NRF-DST), National Institutes of Health (NIH) Grant R01HD071664 and the South African Medical Research Council (MRC). NR 56 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0968-5243 EI 1352-8661 J9 MAGN RESON MATER PHY JI Magn. Reson. Mat. Phys. Biol. Med. PD DEC PY 2016 VL 29 IS 6 BP 863 EP 874 DI 10.1007/s10334-016-0578-8 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EE0LZ UT WOS:000389268000008 PM 27393351 ER PT J AU Copeland, LA Finley, EP Bollinger, MJ Amuan, ME Pugh, MJV AF Copeland, Laurel A. Finley, Erin P. Bollinger, Mary J. Amuan, Megan E. Pugh, Mary Jo V. TI Comorbidity Correlates of Death Among New Veterans of Iraq and Afghanistan Deployment SO MEDICAL CARE LA English DT Article DE Afghan campaign; comorbidity; Iraq war; mortality; veterans ID POLYTRAUMA-CLINICAL-TRIAD; TRAUMATIC BRAIN-INJURY; ADMINISTRATIVE DATA; PTSD; PAIN AB Background:Veterans of the wars in Iraq and Afghanistan who receive care in the Veterans Health Administration (VA) have high disease burden. Distinct comorbidity patterns have been shown to be differentially associated with adverse outcomes, including death. This study determined correlates of 5-year mortality.Materials and Methods:VA demographic, military, homelessness, and clinical measures informed this retrospective analysis. Previously constructed comorbidity classifications over 3 years of care were entered into a Cox proportional hazards model of death.Results:There were 164,933 veterans in the cohort, including African Americans (16%), Hispanics (11%), and whites (65%). Most were in their 20s at baseline (60%); 12% were women; 4% had attempted suicide; 4% had been homeless. Having clustered disorders of pain, posttraumatic stress disorder, and traumatic brain injury was associated with death [hazard ratio (HR)=2.0]. Mental disorders including substance abuse were similarly associated (HR=2.1). Prior suicide attempt (HR=2.2) or drug overdose (HR=3.0) considerably increased risk of death over 5 years.Conclusions:As congressional actions such as Veterans Choice Act offer more avenues to seek care outside of VA, coordination of care, and suicide prevention outreach for recent veterans may require innovative approaches to preserve life. C1 [Copeland, Laurel A.] UT Hlth Sci Ctr San Antonio, Ctr Appl Hlth Res, Cent Texas Vet Hlth Care Syst, San Antonio, TX USA. [Copeland, Laurel A.] UT Hlth Sci Ctr San Antonio, Ctr Appl Hlth Res, Baylor Scott & White Hlth, Dept Med, San Antonio, TX USA. [Copeland, Laurel A.] UT Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX USA. [Finley, Erin P.; Bollinger, Mary J.; Pugh, Mary Jo V.] UT Hlth Sci Ctr San Antonio, South Texas Vet Hlth Care Syst, San Antonio, TX USA. [Finley, Erin P.; Pugh, Mary Jo V.] UT Hlth Sci Ctr San Antonio, Div Clin Epidemiol, Dept Med, San Antonio, TX USA. [Bollinger, Mary J.] UT Hlth Sci Ctr San Antonio, Dept Epidemiol & Biostat, San Antonio, TX USA. [Amuan, Megan E.] VA New England Hlth Care Syst, Bedford, MA USA. RP Pugh, MJV (reprint author), South Texas Vet Hlth Care Syst, 7400 Merton Minter 11c6, San Antonio, TX 78229 USA. EM maryjo.pugh2@va.gov OI Pugh, Mary Jo/0000-0003-4196-7763; Copeland, Laurel/0000-0002-9478-0209; Finley, Erin/0000-0003-4497-7721 FU South Texas Veterans Healthcare System/Audie L. Murphy Division; Edith Nourse Rogers VA Memorial Hospital FX The authors thank South Texas Veterans Healthcare System/Audie L. Murphy Division and the Edith Nourse Rogers VA Memorial Hospital. NR 16 TC 0 Z9 0 U1 4 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0025-7079 EI 1537-1948 J9 MED CARE JI Med. Care PD DEC PY 2016 VL 55 IS 12 BP 1078 EP 1081 DI 10.1097/MLR.0000000000000588 PG 4 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA ED6JW UT WOS:000388962900010 PM 27367868 ER PT J AU Henao-Martinez, AF Gross, L Mcnair, B McCollister, B DeSanto, K Montoya, JG Shapiro, L Beckham, JD AF Henao-Martinez, Andres F. Gross, Lilyana Mcnair, Bryan McCollister, Bruce DeSanto, Kristen Montoya, Jose G. Shapiro, Leland Beckham, J. David TI Risk Factors for Cryptococcal Meningitis: A Single United States Center Experience SO MYCOPATHOLOGIA LA English DT Article DE Cryptococcal antigen; Cryptococcal meningitis; Cryptococcus neoformans; Fungemia; HIV; Risk factors ID ORGAN TRANSPLANT RECIPIENTS; PULMONARY CRYPTOCOCCOSIS; CLINICAL-FEATURES; HIV-INFECTION; MORTALITY; DISEASE; SMOKING AB Cryptococcal meningitis carries a high mortality. Further understanding of immune suppression factors associated with neuroinvasive infection will improve risk stratification and enhance early diagnosis and treatment with antifungal therapy. The aim of the study was to corroborate established or find novel clinical predictors for cryptococcal meningitis. We performed a matched case-control study of Cryptococcus infection in immunocompromised patients with or without cryptococcal meningitis. Data of all patients with a diagnosis of cryptococcal disease were collected at University of Colorado Hospital between 2000 and 2015 (n = 51). Thirty patients were diagnosed with cryptococcal meningitis. We built a logistic regression model for risk factors associated with cryptococcal meningitis. The single-predictor univariate model found that a positive blood culture, positive serum cryptococcal antigen, current malignancy, and headaches were significantly associated with cryptococcal meningitis (p = 0.02). In the adjusted multivariate model, central nervous system disease was significantly associated with a diagnosis of HIV infection (OR 24.45, 95 % CI 1.62-350.37; p = 0.022) and a positive serum cryptococcal antigen test (OR 42.92, 95 % CI 3.26-555.55; p = 0.0055). In patients with HIV infection or a positive serum cryptococcal antigen, the pretest probability of neuroinvasive Cryptococcus infection is increased and an aggressive diagnostic evaluation should be conducted to exclude infection and consider empiric therapy. C1 [Henao-Martinez, Andres F.; McCollister, Bruce; Beckham, J. David] Univ Colorado Denver, Div Infect Dis, Dept Med, 12700 E 19th Ave,Mail Stop B168, Aurora, CO 80045 USA. [Gross, Lilyana; Mcnair, Bryan] Colorado Sch Publ Hlth, Dept Biostat & Informat, Aurora, CO USA. [DeSanto, Kristen] Univ Colorado Denver, Hlth Sci Lib, Aurora, CO USA. [Montoya, Jose G.] Stanford Univ, Med Ctr, Div Infect Dis & Geog Med, Palo Alto, CA 94304 USA. [Shapiro, Leland] Denver Vet Affairs Med Ctr, Div Infect Dis, Dept Med, 1055 Clermont St,Box 111L, Denver, CO 80220 USA. RP Henao-Martinez, AF (reprint author), Univ Colorado Denver, Div Infect Dis, Dept Med, 12700 E 19th Ave,Mail Stop B168, Aurora, CO 80045 USA. EM andres.henaomartinez@ucdenver.edu; Lilyana.Gross@ucdenver.edu FU University of Colorado Neurosciences Institute; NINDS [1R01NS097729] FX No funding agencies had any role in the preparation, review, or approval of this manuscript. We thank Daniela Garcia for her help in reviewing the manuscript. The views expressed in this article are those of the authors and do not necessarily represent the views of the University of Colorado Denver or Stanford University Medical Center. J.D.B receives research support from the University of Colorado Neurosciences Institute and NINDS 1R01NS097729. NR 30 TC 0 Z9 0 U1 3 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0301-486X EI 1573-0832 J9 MYCOPATHOLOGIA JI Mycopathologia PD DEC PY 2016 VL 181 IS 11-12 BP 807 EP 814 DI 10.1007/s11046-016-0048-x PG 8 WC Mycology SC Mycology GA ED6KM UT WOS:000388964500004 PM 27502502 ER PT J AU Moynihan, KD Opel, CF Szeto, GL Tzeng, A Zhu, EF Engreitz, JM Williams, RT Rakhra, K Zhang, MH Rothschilds, AM Kumari, S Kelly, RL Kwan, BH Abraham, W Hu, K Mehta, NK Kauke, MJ Suh, H Cochran, JR Lauffenburger, DA Wittrup, KD Irvine, DJ AF Moynihan, Kelly D. Opel, Cary F. Szeto, Gregory L. Tzeng, Alice Zhu, Eric F. Engreitz, Jesse M. Williams, Robert T. Rakhra, Kavya Zhang, Michael H. Rothschilds, Adrienne M. Kumari, Sudha Kelly, Ryan L. Kwan, Byron H. Abraham, Wuhbet Hu, Kevin Mehta, Naveen K. Kauke, Monique J. Suh, Heikyung Cochran, Jennifer R. Lauffenburger, Douglas A. Wittrup, K. Dane Irvine, Darrell J. TI Eradication of large established tumors in mice by combination immunotherapy that engages innate and adaptive immune responses SO NATURE MEDICINE LA English DT Article ID T-CELL IMMUNITY; DENDRITIC CELLS; CANCER-IMMUNOTHERAPY; METASTATIC MELANOMA; MYELOID COMPARTMENT; BREAST-CANCER; ANTIGEN; ANTIBODY; THERAPY; REGRESSION AB Checkpoint blockade with antibodies specific for cytotoxic T lymphocyte-associated protein (CTLA)-4 or programmed cell death 1 (PDCD1; also known as PD-1) elicits durable tumor regression in metastatic cancer, but these dramatic responses are confined to a minority of patients. This suboptimal outcome is probably due in part to the complex network of immunosuppressive pathways present in advanced tumors, which are unlikely to be overcome by intervention at a single signaling checkpoint. Here we describe a combination immunotherapy that recruits a variety of innate and adaptive immune cells to eliminate large tumor burdens in syngeneic tumor models and a genetically engineered mouse model of melanoma; to our knowledge tumors of this size have not previously been curable by treatments relying on endogenous immunity. Maximal antitumor efficacy required four components: a tumor-antigen-targeting antibody, a recombinant interleukin-2 with an extended half-life, anti-PD-1 and a powerful T cell vaccine. Depletion experiments revealed that CD8(+) T cells, cross-presenting dendritic cells and several other innate immune cell subsets were required for tumor regression. Effective treatment induced infiltration of immune cells and production of inflammatory cytokines in the tumor, enhanced antibody-mediated tumor antigen uptake and promoted antigen spreading. These results demonstrate the capacity of an elicited endogenous immune response to destroy large, established tumors and elucidate essential characteristics of combination immunotherapies that are capable of curing a majority of tumors in experimental settings typically viewed as intractable. C1 [Moynihan, Kelly D.; Opel, Cary F.; Szeto, Gregory L.; Tzeng, Alice; Zhu, Eric F.; Rakhra, Kavya; Zhang, Michael H.; Rothschilds, Adrienne M.; Kumari, Sudha; Kelly, Ryan L.; Kwan, Byron H.; Abraham, Wuhbet; Mehta, Naveen K.; Kauke, Monique J.; Suh, Heikyung; Lauffenburger, Douglas A.; Wittrup, K. Dane; Irvine, Darrell J.] MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Moynihan, Kelly D.; Szeto, Gregory L.; Tzeng, Alice; Rothschilds, Adrienne M.; Kelly, Ryan L.; Kwan, Byron H.; Hu, Kevin; Mehta, Naveen K.; Lauffenburger, Douglas A.; Wittrup, K. Dane; Irvine, Darrell J.] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Moynihan, Kelly D.; Szeto, Gregory L.; Lauffenburger, Douglas A.; Irvine, Darrell J.] Ragon Inst Massachusetts Gen Hosp Massachusetts I, Cambridge, MA USA. [Opel, Cary F.; Zhu, Eric F.; Kauke, Monique J.; Wittrup, K. Dane] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Engreitz, Jesse M.] MIT, Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Engreitz, Jesse M.] Broad Inst MIT & Harvard Univ, Cambridge, MA USA. [Williams, Robert T.] MIT, Dept Biol, Cambridge, MA USA. [Cochran, Jennifer R.] Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA. [Cochran, Jennifer R.] Stanford Univ, Dept Chem Engn, Stanford, CA 94305 USA. [Cochran, Jennifer R.] Stanford Canc Inst, Stanford, CA USA. [Irvine, Darrell J.] MIT, Dept Mat Sci & Engn, Cambridge, MA 02139 USA. [Irvine, Darrell J.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Szeto, Gregory L.; Zhang, Michael H.] Univ Maryland, Dept Chem Biochem & Environm Engn, Baltimore, MD 21201 USA. RP Wittrup, KD; Irvine, DJ (reprint author), MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Wittrup, KD; Irvine, DJ (reprint author), MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Irvine, DJ (reprint author), Ragon Inst Massachusetts Gen Hosp Massachusetts I, Cambridge, MA USA.; Wittrup, KD (reprint author), MIT, Dept Chem Engn, Cambridge, MA 02139 USA.; Irvine, DJ (reprint author), MIT, Dept Mat Sci & Engn, Cambridge, MA 02139 USA.; Irvine, DJ (reprint author), Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. EM wittrup@mit.edu; djirvine@mit.edu OI Szeto, Gregory/0000-0001-7604-1333 FU Koch Institute from the National Cancer Institute [P30-CA14051]; US National Institutes of Health (NIH) [CA174795]; Koch Institute for Integrative Cancer Research; Dana Farber-Harvard Cancer Center (DF-HCC); V Foundation; Ragon Institute; Fannie and John Hertz Foundation Fellowship; NSF Graduate Research Fellowships; NIGMS-NIH Interdepartmental Biotechnology Training Program (NIH) [T32GM008334]; Siebel Scholarship; NIH; Ruth L. Kirschstein National Research Service Award [CA180586] FX This work was supported in part by the Koch Institute Support (core) grant P30-CA14051 from the National Cancer Institute, the US National Institutes of Health (NIH) grant CA174795 (K.D.W.), the Bridge Project partnership between the Koch Institute for Integrative Cancer Research and the Dana Farber-Harvard Cancer Center (DF-HCC) (D.J.I.), the V Foundation (D.J.I.) and the Ragon Institute (D.J.I.). K.D.M. and J.M.E. are supported by the Fannie and John Hertz Foundation Fellowship; K.D.M., C.F.O., J.M.E., B.H.K. and E.F.Z. are supported by NSF Graduate Research Fellowships; A.M.R. is supported by the NIGMS-NIH Interdepartmental Biotechnology Training Program (NIH #T32GM008334); A.T. is supported by the Siebel Scholarship; and G.L.S. was supported by the NIH with a Ruth L. Kirschstein National Research Service Award (CA180586). We thank T.C. Wu (Johns Hopkins University) for kindly providing the TC-1 tumor cells, D. Sabatini (Whitehead Institute) for providing the Cas9 constructs and G. Dranoff (Dana-Farber Cancer Institute) for providing the DD-Her2/neu and B16-OVA cells. We thank M. Ghebremichael (Ragon Institute of MGH, MIT and Harvard) for helpful statistical advice. We thank the Koch Institute Swanson Biotechnology Center for technical support, specifically the applied therapeutics and wholeanimal imaging core facility, the histology and the flow cytometry core facilities. D.J.I. is an investigator of the Howard Hughes Medical Institute. NR 64 TC 5 Z9 5 U1 23 U2 23 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 DEC PY 2016 VL 22 IS 12 BP 1402 EP + DI 10.1038/nm.4200 PG 12 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA EE4CI UT WOS:000389549000017 PM 27775706 ER PT J AU Osuna, CE Lim, SY Deleage, C Griffin, BD Stein, D Schroeder, LT Omange, RW Best, K Luo, M Hraber, PT Andersen-Elyard, H Ojeda, EFC Huang, S Vanlandingham, DL Higgs, S Perelson, AS Estes, JD Safronetz, D Lewis, MG Whitney, JB AF Osuna, Christa E. Lim, So-Yon Deleage, Claire Griffin, Bryan D. Stein, Derek Schroeder, Lukas T. Omange, Robert Were Best, Katharine Luo, Ma Hraber, Peter T. Andersen-Elyard, Hanne Ojeda, Erwing Fabian Cardozo Huang, Scott Vanlandingham, Dana L. Higgs, Stephen Perelson, Alan S. Estes, Jacob D. Safronetz, David Lewis, Mark G. Whitney, James B. TI Zika viral dynamics and shedding in rhesus and cynomolgus macaques SO NATURE MEDICINE LA English DT Article ID NATURAL-KILLER-CELLS; WEST NILE VIRUS; SEXUAL TRANSMISSION; DENGUE VIRUS; INFECTION; BRAZIL; MOSQUITOS; OUTBREAK; SERUM; EXPRESSION AB Infection with Zika virus has been associated with serious neurological complications and fetal abnormalities. However, the dynamics of viral infection, replication and shedding are poorly understood. Here we show that both rhesus and cynomolgus macaques are highly susceptible to infection by lineages of Zika virus that are closely related to, or are currently circulating in, the Americas. After subcutaneous viral inoculation, viral RNA was detected in blood plasma as early as 1 d after infection. Viral RNA was also detected in saliva, urine, cerebrospinal fluid (CSF) and semen, but transiently in vaginal secretions. Although viral RNA during primary infection was cleared from blood plasma and urine within 10 d, viral RNA was detectable in saliva and seminal fluids until the end of the study, 3 weeks after the resolution of viremia in the blood. The control of primary Zika virus infection in the blood was correlated with rapid innate and adaptive immune responses. We also identified Zika RNA in tissues, including the brain and male and female reproductive tissues, during early and late stages of infection. Re-infection of six animals 45 d after primary infection with a heterologous strain resulted in complete protection, which suggests that primary Zika virus infection elicits protective immunity. Early invasion of Zika virus into the nervous system of healthy animals and the extent and duration of shedding in saliva and semen underscore possible concern for additional neurologic complications and nonarthropod-mediated transmission in humans. C1 [Osuna, Christa E.; Lim, So-Yon; Whitney, James B.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Ctr Virol & Vaccine Res, Boston, MA USA. [Deleage, Claire; Estes, Jacob D.] Frederick Natl Lab Canc Res, Leidos Biomed Res, Frederick, MD USA. [Griffin, Bryan D.; Stein, Derek; Schroeder, Lukas T.; Omange, Robert Were; Luo, Ma; Safronetz, David] Natl Microbiol Lab, Winnipeg, MB, Canada. [Best, Katharine; Hraber, Peter T.; Ojeda, Erwing Fabian Cardozo; Perelson, Alan S.] Los Alamos Natl Lab, Los Alamos, NM USA. [Andersen-Elyard, Hanne; Lewis, Mark G.] Bioqual, Rockville, MD USA. [Huang, Scott; Vanlandingham, Dana L.; Higgs, Stephen] Kansas State Univ, Biosecur Res Inst, Manhattan, KS 66506 USA. [Whitney, James B.] Ragon Inst Massachusetts Gen Hosp Massachusetts I, Cambridge, MA 02139 USA. RP Whitney, JB (reprint author), Harvard Med Sch, Beth Israel Deaconess Med Ctr, Ctr Virol & Vaccine Res, Boston, MA USA.; Whitney, JB (reprint author), Ragon Inst Massachusetts Gen Hosp Massachusetts I, Cambridge, MA 02139 USA. EM jwhitne2@bidmc.harvard.edu OI Osuna, Christa/0000-0003-2761-2456; Hraber, Peter/0000-0002-2920-4897 FU National Cancer Institute ( NIH Contract) [HHSN261200800001E]; NIH [AI028433, OD0110995]; Public Health Agency of Canada FX We thank B. Finneyfrock, Z. Pippin, A. Dodson and A. Cook for their expert animal husbandry and care, and J. Guedj for suggestions about the model simulations. CD38 antibodies were obtained from the NIH Nonhuman Primate Reagent Resource supported by HHSN272200900037C and OD010976. The data presented in this study are tabulated in the main paper and in the supplementary materials. This work was supported in part by federal funds from the National Cancer Institute ( NIH Contract HHSN261200800001E). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products or organizations imply endorsement by the US Government. A.S.P. acknowledges support from NIH grants AI028433 and OD0110995. D.S. acknowledges support from the Public Health Agency of Canada. NR 54 TC 8 Z9 8 U1 11 U2 11 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 DEC PY 2016 VL 22 IS 12 BP 1448 EP + DI 10.1038/nm.4206 PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA EE4CI UT WOS:000389549000022 PM 27694931 ER PT J AU Jarret, A McFarland, AP Horner, SM Kell, A Schwerk, J Hong, M Badil, S Joslyn, RC Baker, DP Carrington, M Hagedorn, CH Gale, M Savan, R AF Jarret, Abigail McFarland, Adelle P. Horner, Stacy M. Kell, Alison Schwerk, Johannes Hong, MeeAe Badil, Samantha Joslyn, Rochelle C. Baker, Darren P. Carrington, Mary Hagedorn, Curt H. Gale, Michael, Jr. Savan, Ram TI Hepatitis-C-virus-induced microRNAs dampen interferon-mediated antiviral signaling SO NATURE MEDICINE LA English DT Article ID GENOME-WIDE ASSOCIATION; RECEPTOR MESSENGER-RNA; GENETIC-VARIATION; HCV INFECTION; IFN THERAPY; III IFN; EXPRESSION; IL28B; LIVER; ALPHA AB Hepatitis C virus (HCV) infects 200 million people globally, and 60-80% of cases persist as a chronic infection that will progress to cirrhosis and liver cancer in 2-10% of patients(1-3). We recently demonstrated that HCV induces aberrant expression of two host microRNAs (miRNAs), miR-208b and miR-499a-5p, encoded by myosin genes in infected hepatocytes(4). These miRNAs, along with AU-rich-element-mediated decay, suppress IFNL2 and IFNL3, members of the type III interferon (IFN) gene family, to support viral persistence. In this study, we show that miR-208b and miR-499a-5p also dampen type I IFN signaling in HCV-infected hepatocytes by directly down-regulating expression of the type I IFN receptor chain, IFNAR1. Inhibition of these miRNAs by using miRNA inhibitors during HCV infection increased expression of IFNAR1. Additionally, inhibition rescued the antiviral response to exogenous type I IFN, as measured by a marked increase in IFN-stimulated genes and a decrease in HCV load. Treatment of HCV-infected hepatocytes with type I IFN increased expression of myosins over HCV infection alone. Since these miRNAs can suppress type III IFN family members, these data collectively define a novel cross-regulation between type I and III IFNs during HCV infection. C1 [Jarret, Abigail; McFarland, Adelle P.; Horner, Stacy M.; Kell, Alison; Schwerk, Johannes; Hong, MeeAe; Badil, Samantha; Joslyn, Rochelle C.; Gale, Michael, Jr.; Savan, Ram] Univ Washington, Dept Immunol, Seattle, WA 98195 USA. [Baker, Darren P.] Biogen Idec Inc, Cambridge, MA USA. [Carrington, Mary] Frederick Natl Lab Canc Res, Canc & Inflammat Program, Expt Immunol Lab, Leidos Biomed Res Frederick, Frederick, MD USA. [Carrington, Mary] Ragon Inst Massachusetts Gen Hosp Massachusetts I, Boston, MA USA. [Hagedorn, Curt H.] Univ Arkansas Med Sci, Dept Med, Little Rock, AR 72205 USA. [Hagedorn, Curt H.] Univ Arkansas Med Sci, Genet Program, Little Rock, AR 72205 USA. [Hagedorn, Curt H.] Cent Arkansas Vet Healthcare Syst, Little Rock, AR USA. [McFarland, Adelle P.] Univ Washington, Dept Microbiol, Mol & Cellular Biol Program, Seattle, WA 98195 USA. [Horner, Stacy M.] Duke Univ, Med Ctr, Ctr Virol, Dept Mol Genet & Microbiol, Durham, NC USA. [Baker, Darren P.] Sanofi Genzyme, Cambridge, MA USA. RP Savan, R (reprint author), Univ Washington, Dept Immunol, Seattle, WA 98195 USA. EM savanram@uw.edu FU NIAID NIH HHS [R01 AI108765] NR 41 TC 0 Z9 0 U1 5 U2 5 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 DEC PY 2016 VL 22 IS 12 BP 1475 EP + DI 10.1038/nm.4211 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA EE4CI UT WOS:000389549000026 PM 27841874 ER PT J AU Catassi, C Fasano, A AF Catassi, Carlo Fasano, Alessio TI Tempters and Gluten-Free Diet SO NUTRIENTS LA English DT Editorial Material ID SENSITIVITY C1 [Catassi, Carlo] Univ Politecn Marche, Dept Pediat, I-60121 Ancona, Italy. [Fasano, Alessio] MassGen Hosp Children, Pediat Gastroenterol & Nutr, Boston, MA 02129 USA. RP Catassi, C (reprint author), Univ Politecn Marche, Dept Pediat, I-60121 Ancona, Italy.; Fasano, A (reprint author), MassGen Hosp Children, Pediat Gastroenterol & Nutr, Boston, MA 02129 USA. EM c.catassi@univpm.it; AFASANO@mgh.harvard.edu NR 7 TC 0 Z9 0 U1 7 U2 7 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 2072-6643 J9 NUTRIENTS JI Nutrients PD DEC PY 2016 VL 8 IS 12 AR 786 DI 10.3390/nu8120786 PG 2 WC Nutrition & Dietetics SC Nutrition & Dietetics GA ED8TP UT WOS:000389144100035 ER PT J AU Richmond, TK Dunn, EC Milliren, CE Evans, CR Subramanian, SV AF Richmond, Tracy K. Dunn, Erin C. Milliren, Carly E. Evans, Clare Rosenfeld Subramanian, S. V. TI Disentangling Overlapping Influences of Neighborhoods and Schools on Adolescent Body Mass Index SO Obesity LA English DT Article ID PHYSICAL-ACTIVITY; SOCIAL ENVIRONMENTS; OBESITY; ASSOCIATIONS; INTERVENTION; PREVALENCE; CHILDHOOD; CHILDREN; HEALTH; LEVEL AB Objective: To compare the simultaneous influence of schools and neighborhoods on adolescent body mass index (BMI). Methods: Analyzing data from a nationally representative sample of adolescents in grades 7 to 12 (n = 18,200), cross-classified multilevel modeling was used to examine the fixed and random effects of individuals, schools, and neighborhoods on adolescent BMI. Additionally, the ability of school and neighborhood demographics to explain racial/ethnic disparities in BMI was assessed. Results: There were 18,200 students nested in 128 schools and 2,259 neighborhoods, with 2,757 unique combinations of schools and neighborhoods. In girls, schools (v(ojk) = 0.18, CI: 0.06-0.33) contributed twice that of neighborhoods (u(ojk) = 0.08, CI: 0.01-0.20) to the variance in BMI, while in males, schools (u(ojk) = 0.15, CI: 0.05-0.30) and neighborhoods (v(ojk) = 0.16, CI: 0.05-0.31) had similar contributions. The interaction of the neighborhood and school random effects contributed significantly to the variance of male and female BMI. Characteristics of neighborhoods and schools explained a large portion of the racial/ethnic disparity in female BMI. Conclusions: In an analysis of a nationally representative sample including multiple racial and ethnic groups, the BMI variance of adolescent females was associated with schools more than neighborhoods. In males, there was no difference in school or neighborhood association with BMI. C1 [Richmond, Tracy K.] Boston Childrens Hosp, Dept Med, Div Adolescent Med, Boston, MA 02115 USA. [Dunn, Erin C.] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Ctr Human Genet Res, Boston, MA 02114 USA. [Dunn, Erin C.] Harvard Med Sch, Dept Psychiat, Boston, MA USA. [Dunn, Erin C.] Broad Inst Harvard & MIT, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Milliren, Carly E.] Boston Childrens Hosp, Dept Med, Clin Res Ctr, Boston, MA USA. [Evans, Clare Rosenfeld; Subramanian, S. V.] Harvard Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA USA. RP Richmond, TK (reprint author), Boston Childrens Hosp, Dept Med, Div Adolescent Med, Boston, MA 02115 USA. EM tracy.k.richmond@gmail.com FU NIH [NICHD K01 HD058042]; Robert Wood Johnson Investigator Award in Health Policy Research FX TKR was funded by the NIH Career Development award (NICHD K01 HD058042). SVS is supported by the Robert Wood Johnson Investigator Award in Health Policy Research. NR 24 TC 0 Z9 0 U1 4 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD DEC PY 2016 VL 24 IS 12 BP 2570 EP 2577 DI 10.1002/oby.21672 PG 8 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA ED8VH UT WOS:000389148500020 PM 27863090 ER PT J AU Morse, LR Nguyen, N Battaglino, RA Guarino, AJ Gagnon, DR Zafonte, R Garshick, E AF Morse, L. R. Nguyen, N. Battaglino, R. A. Guarino, A. J. Gagnon, D. R. Zafonte, R. Garshick, E. TI Wheelchair use and lipophilic statin medications may influence bone loss in chronic spinal cord injury: findings from the FRASCI-bone loss study SO OSTEOPOROSIS INTERNATIONAL LA English DT Article DE Osteoporosis; Rehabilitation medicine; Spinal cord injury; Statin ID CARDIOVASCULAR-DISEASE RISK; HYPERCHOLESTEROLEMIC POSTMENOPAUSAL WOMEN; RANDOMIZED CONTROLLED-TRIAL; COA REDUCTASE INHIBITORS; MINERAL DENSITY; FRACTURE RISK; CANDIDATE BIOMARKER; SIMVASTATIN; PARAPLEGIA; OSTEOPOROSIS AB We identified a protective bone effect at the knee with lipophilic statin use in individuals with chronic spinal cord injury. Lipophilic statin users gained bone at the knee compared to non-users and wheelchair users lost bone compared to walkers. Ambulation and or statins may be effective osteogenic interventions in chronic spinal cord injury (SCI). SCI increases the risk of osteoporosis and low-impact fractures, particularly at the knee. However, during the chronic phase of SCI, the natural history and factors associated with longitudinal change in bone density remain poorly characterized. In this study, we prospectively assessed factors associated with change in bone density over a mean of 21 months in 152 men and women with chronic SCI. A mixed model procedure with repeated measures was used to assess predictors of change in bone mineral density (PROC MIXED) at the distal femur and proximal tibia. Factors with a p value of < 0.10 in the univariate mixed models, as well as factors that were deemed clinically significant (gender, age, and walking status), were assessed in multivariable models. Factors with a p value of ae0.05 were included in the final model. We found no association between bone loss and traditional osteoporosis risk factors, including age, gender, body composition, or vitamin D level or status (normal or deficient). In both crude and fully adjusted models, wheelchair users lost bone compared to walkers. Similarly, statin users gained bone compared to nonusers. The statin finding is supported by reports in the general population where statin use has been associated with a reduction in bone loss and fracture risk. Our results suggest that both walking and statins may be effective osteogenic therapies to mitigate bone loss and prevent osteoporosis in chronic SCI. Our findings also suggest that loss of mechanical loading and/or neuronal factors contribute more to disuse osteoporosis than traditional osteoporosis risk factors. C1 [Morse, L. R.] Craig Rehabil Hosp, Rocky Mt Reg Spinal Injury Syst, Englewood, CO 80113 USA. [Morse, L. R.; Battaglino, R. A.] Univ Colorado, Sch Med, Aurora, CO 80045 USA. [Nguyen, N.; Zafonte, R.] Spaulding Rehabil Hosp, Spaulding Harvard SCI Model Syst Ctr, Boston, MA USA. [Guarino, A. J.] Massachusetts Gen Hosp, Inst Hlth Profess, Boston, MA 02114 USA. [Gagnon, D. R.] Boston Univ, Sch Publ Hlth, VA Cooperat Studies Program, VA Boston Healthcare Syst,Dept Biostat, Boston, MA USA. [Zafonte, R.] Harvard Med Sch, Dept PMR, Boston, MA USA. [Garshick, E.] VA Boston Healthcare Syst, Med Serv, Pulm Allergy Sleep & Crit Care Med Sect, Boston, MA USA. [Garshick, E.] Harvard Med Sch, Brigham & Womens Hosp, Channing Div Network Med, Boston, MA USA. RP Morse, LR (reprint author), Craig Rehabil Hosp, Rocky Mt Reg Spinal Injury Syst, Englewood, CO 80113 USA.; Morse, LR (reprint author), Univ Colorado, Sch Med, Aurora, CO 80045 USA. EM leslie.morse@ucdenver.edu FU National Institute of Arthritis and Musculoskeletal and Skin Diseases [1R01AR059270-01]; National Institute on Disability, Independent Living, and Rehabilitation Research (NIDILRR) [90SI5007-01-02]; Office of Research and Development, Rehabilitation Research and Development [B6618R, RX-000792-01A2]; Massachusetts Veterans Epidemiology Research and Information Center, Cooperative Studies Program, Department of Veterans Affairs FX Leslie Morse, Nguyen Nguyen, Ricardo Battaglino, A J Guarino, David Gagnon, Ross Zafonte, and Eric Garshick declare that they have no conflict of interest. This study received support from: The National Institute of Arthritis and Musculoskeletal and Skin Diseases [1R01AR059270-01], National Institute on Disability, Independent Living, and Rehabilitation Research (NIDILRR 90SI5007-01-02), The Office of Research and Development, Rehabilitation Research and Development [Merit Review Grant B6618R and RX-000792-01A2], and The Massachusetts Veterans Epidemiology Research and Information Center, Cooperative Studies Program, Department of Veterans Affairs. NR 41 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0937-941X EI 1433-2965 J9 OSTEOPOROSIS INT JI Osteoporosis Int. PD DEC PY 2016 VL 27 IS 12 BP 3503 EP 3511 DI 10.1007/s00198-016-3678-4 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA ED6GI UT WOS:000388953700011 PM 27412619 ER PT J AU Qin, W Zhao, W Li, X Peng, Y Harlow, LM Li, J Qin, Y Pan, J Wu, Y Ran, L Ke, HZ Cardozo, CP Bauman, WA AF Qin, W. Zhao, W. Li, X. Peng, Y. Harlow, L. M. Li, J. Qin, Y. Pan, J. Wu, Y. Ran, L. Ke, H. Z. Cardozo, C. P. Bauman, W. A. TI Mice with sclerostin gene deletion are resistant to the severe sublesional bone loss induced by spinal cord injury SO OSTEOPOROSIS INTERNATIONAL LA English DT Article DE Bone formation; Bone mineral density; Mechanical unloading; Sclerostin; Spinal cord injury; Trabecular bone volume ID RAT MODEL; TARGETED DELETION; NERVOUS-SYSTEM; OSTEOPOROSIS; MARROW; MASS; DIFFERENTIATION; STRENGTH; ANTIBODY; DENSITY AB Bone loss after spinal cord injury (SCI) is rapid, severe, and refractory to interventions studied to date. Mice with sclerostin gene deletion are resistant to the severe sublesional bone loss induced by SCI, further indicating pharmacological inhibition of sclerostin may represent a promising novel approach to this challenging medical problem. The bone loss secondary to spinal cord injury (SCI) is associated with several unique pathological features, including the permanent immobilization, neurological dysfunction, and systemic hormonal alternations. It remains unclear how these complex pathophysiological changes are linked to molecular alterations that influence bone metabolism in SCI. Sclerostin is a key negative regulator of bone formation and bone mass. We hypothesized that sclerostin could function as a major mediator of bone loss following SCI. To test this hypothesis, 10-week-old female sclerostin knockout (SOST KO) and wild type (WT) mice underwent complete spinal cord transection or laminectomy (Sham). At 8 weeks after SCI, substantial loss of bone mineral density was observed at the distal femur and proximal tibia in WT mice but not in SOST KO mice. By mu CT, trabecular bone volume of the distal femur was markedly decreased by 64 % in WT mice after SCI. In striking contrast, there was no significant reduction of bone volume in SOST KO/SCI mice compared with SOST KO/sham. Histomorphometric analysis of trabecular bone revealed that the significant reduction in bone formation rate following SCI was observed in WT mice but not in SOST KO mice. Moreover, SCI did not alter osteoblastogenesis of marrow stromal cells in SOST KO mice. Our findings demonstrate that SOST KO mice were protected from the major sublesional bone loss that invariably follows SCI. The evidence indicates that sclerostin is an important mediator of the marked sublesional bone loss after SCI, and that pharmacological inhibition of sclerostin may represent a promising novel approach to this challenging clinical problem. C1 [Qin, W.; Zhao, W.; Peng, Y.; Harlow, L. M.; Qin, Y.; Pan, J.; Cardozo, C. P.; Bauman, W. A.] Natl Ctr Med Consequences SCI, James J Peters VA Med Ctr, 130 West Kingsbridge Roa, Bronx, NY 10468 USA. [Qin, W.; Wu, Y.; Cardozo, C. P.; Bauman, W. A.] Icahn Sch Med Mt Sinai, Dept Med, New York, NY 10029 USA. [Cardozo, C. P.; Bauman, W. A.] Icahn Sch Med Mt Sinai, Rehabil Med, New York, NY USA. [Cardozo, C. P.] Icahn Sch Med Mt Sinai, Pharmacol & Syst Therapeut, New York, NY USA. [Li, X.] Amgen Inc, Thousand Oaks, CA USA. [Li, J.] Indiana Univ Purdue Univ, Indianapolis, IN USA. [Wu, Y.; Ran, L.] Dalian Med Univ, Inst Gene Engn Anim Models Human Dis, Dalian, Peoples R China. [Ke, H. Z.] UCB Pharma, Slough, Berks, England. RP Qin, W (reprint author), Natl Ctr Med Consequences SCI, James J Peters VA Med Ctr, 130 West Kingsbridge Roa, Bronx, NY 10468 USA.; Qin, W (reprint author), Icahn Sch Med Mt Sinai, Dept Med, New York, NY 10029 USA. EM weiping.qin@mssm.edu FU Veterans Health Administration, Rehabilitation Research, and Development Service [5I01RX001313, 5I01RX000687, B9212-C, B2020-C]; Ministry of Science and Technology PRC grant [2014DFA32120]; Natural Science Foundation of China (NSFC) [81471000] FX This work was supported by the Veterans Health Administration, Rehabilitation Research, and Development Service (grants 5I01RX001313 and 5I01RX000687 to WQ; B9212-C and B2020-C to WAB). Ministry of Science and Technology PRC grant 2014DFA32120 and the Natural Science Foundation of China (NSFC) grant 81471000 to YW. Amgen Inc. provided SOST KO mice. Authors' roles: CPC, HK, XL, WAB, and WQ were responsible for study design and data analysis. YP, LH, WZ, JL, YQ, YW, LR, and WQ conducted the bone biology study. Jay Cao performed microCT analysis. The manuscript was written by WZ and WQ and was revised and approved by all authors. WQ takes responsibility for the integrity of the data analysis. NR 52 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0937-941X EI 1433-2965 J9 OSTEOPOROSIS INT JI Osteoporosis Int. PD DEC PY 2016 VL 27 IS 12 BP 3627 EP 3636 DI 10.1007/s00198-016-3700-x PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA ED6GI UT WOS:000388953700024 PM 27436301 ER PT J AU Kohli, P Naik, AN Farhood, Z Ong, AA Nguyen, SA Soler, ZM Schlosser, RJ AF Kohli, Preeti Naik, Akash N. Farhood, Zachary Ong, Adrian A. Nguyen, Shaun A. Soler, Zachary M. Schlosser, Rodney J. TI Olfactory Outcomes after Endoscopic Sinus Surgery for Chronic Rhinosinusitis: A Meta-analysis SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Review DE olfaction; smell; sinus surgery; chronic rhinosinusitis; sinusitis; meta-analysis ID OF-LIFE OUTCOMES; NASAL POLYPOSIS; DISEASE SEVERITY; IMPROVEMENT; SMELL; DYSFUNCTION; IRRIGATION; PREDICTORS; DISORDERS; IMPACT AB Objective. To use combined pre- and postsurgical olfactory outcomes to assess the impact of endoscopic sinus surgery on chronic rhinosinusitis-related olfactory impairment. Data Sources. CINAHL, Cochrane, OVID, EMBASE, PubMed, and SCOPUS. Each database was searched from inception up to October 2015. Review Methods. Studies were included that reported subjective or objective olfactory data in chronic rhinosinusitis patients before and after endoscopic sinus surgery. Results. Thirty-one studies were used in the meta-analysis. Weighted mean differences of olfactory measures demonstrated significant improvement in mixed CRS patients (those with and without polyps) through visual analog scales (20.83, P=.001), altered taste/smell item on Sinonasal Outcome Test (21.32, P <. 00001), 40-item Smell Identification Test (3.49, P =.0010), and Sniffin' Sticks identification (0.34, P =.03). Chronic rhinosinusitis mixed patients demonstrated nonsignificant improvements via Sniffin' Sticks threshold (1.60, P =.16) and Brief Smell Identification Test (0.20, P =.32). When separated, polyp patients and dysosmic patients experienced the highest levels of olfactory improvement. Polyp patients improved by 7.87 (P =.006) on the 40-item Smell Identification test, 11.54 (P <. 0001) with the Sniffin' Sticks total score, and 2.57 (P <. 00001) through Sniffin' Sticks identification. Dysosmic patients improved by 5.75 via the 40-item Smell Identification Test (P =.0001). Conclusion. Endoscopic sinus surgery improves nearly all subjective and objective measures of olfaction in chronic rhinosinusitis patients. Patients with nasal polyposis or preoperative olfactory dysfunction improve to a greater degree. C1 [Kohli, Preeti; Naik, Akash N.; Farhood, Zachary; Ong, Adrian A.; Nguyen, Shaun A.; Soler, Zachary M.; Schlosser, Rodney J.] Med Univ South Carolina, Dept Otolaryngol Head & Neck Surg, 135 Rutledge Ave,MSC 550, Charleston, SC 29425 USA. [Schlosser, Rodney J.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. RP Kohli, P (reprint author), Med Univ South Carolina, Dept Otolaryngol Head & Neck Surg, 135 Rutledge Ave,MSC 550, Charleston, SC 29425 USA. EM pkohli89@gmail.com FU National Institute on Deafness and Other Communication Disorders of the National Institutes of Health [R03 DC013651-01] FX National Institute on Deafness and Other Communication Disorders of the National Institutes of Health (R03 DC013651-01; principal investigator: Z.M.S.). NR 61 TC 0 Z9 0 U1 2 U2 2 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 DEC PY 2016 VL 155 IS 6 BP 936 EP 948 DI 10.1177/0194599816664879 PG 13 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA ED8UN UT WOS:000389146500005 PM 27576679 ER PT J AU Creighton, F Bergmark, R Emerick, K AF Creighton, Francis Bergmark, Regan Emerick, Kevin TI Drainage Patterns to Nontraditional Nodal Regions and Level IIB in Cutaneous Head and Neck Malignancy SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Article; Proceedings Paper CT AAO-HNSF Annual Meeting and OTO EXPO CY SEP 27-30, 2015 CL Dallas, TX SP AAO, HNSF DE cutaneous head and neck malignancy; lymphatic drainage patterns; sentinel lymph node biopsy ID SQUAMOUS-CELL CARCINOMA; LYMPHATIC DRAINAGE; SUBLEVEL IIB; MELANOMA; LYMPHOSCINTIGRAPHY; METASTASIS; DISSECTION; BIOPSY; SITES AB Objectives. (1) Determine the frequency of nontraditional sentinel lymph node (SLN) locations in cutaneous head and neck malignancy and (2) determine the frequency of level IIB SLNs in cutaneous head and neck malignancy. Design. Case series with chart review. Setting. Tertiary academic hospital. Subjects and Methods. In total, 145 consecutive sentinel lymph node biopsy (SLNB) specimens for cutaneous head and neck malignancies were reviewed from 2007 to 2015. Nodal regions were categorized into levels I to V, parotid, external jugular (EJ), perifacial, suboccipital, and postauricular regions. Primary locations were divided into scalp, forehead, cheek, ear, neck, nose, periocular, and lip. Frequencies of sentinel lymph node (SLN) locations for each primary location were determined. Results. Parotid, EJ, perifacial, suboccipital, postauricular, and level IIB lymph SLNs were identified as nontraditional lymph node regions at risk in head and neck cutaneous malignancy. EJ SLNs were present in over 15% of all cases and over 25% of periocular and cheek lesions. Perifacial SLNs were frequently present in nose and lip lesions. Suboccipital and postauricular nodes were only present in scalp lesions. Level II was the most common location for a SLN. In total, 15.9% of all cases involved level IIB. Scalp and ear primary lesions were most likely to drain to level IIB. Conclusions. Nontraditional SLN locations, such as EJ, perifacial, suboccipital, postauricular, and parotid, as well as level IIB, are important sites of drainage for head and neck cutaneous malignancy. Prediction of at-risk lymph node regions is important to help guide SLNBs, elective and completion neck lymphadenectomy and radiation, and long-term observation. C1 [Creighton, Francis; Bergmark, Regan; Emerick, Kevin] Harvard Med Sch, Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA USA. RP Creighton, F (reprint author), Harvard Med Sch, Massachusetts Eye & Ear, ENT Educ Off, 243 Charles St, Boston, MA 02114 USA. EM francis_creighton@meei.harvard.edu NR 21 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0194-5998 EI 1097-6817 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD DEC PY 2016 VL 155 IS 6 BP 1005 EP 1011 DI 10.1177/0194599816662864 PG 7 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA ED8UN UT WOS:000389146500014 PM 27554510 ER PT J AU Brook, CD Maxfield, AZ Stankovic, K Metson, RB AF Brook, Christopher D. Maxfield, Alice Z. Stankovic, Konstantina Metson, Ralph B. TI The Impact of Angiotensin-Modulating Antihypertensives on Time Interval to Revision Surgery for Nasal Polyps SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Article DE chronic rhinosinusitis; nasal polyps; asthma; periostin; endoscopic sinus surgery; angiotensin converting enzyme inhibitor; angiotensin receptor blocker ID ENDOSCOPIC SINUS SURGERY; FACTOR-KAPPA-B; CHRONIC RHINOSINUSITIS; MYOCARDIAL-INFARCTION; GENE-EXPRESSION; PERIOSTIN; VALSARTAN; ASTHMA; OSTEOPONTIN; ACTIVATION AB Objective/Hypothesis. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have been shown to suppress expression of periostin, a matricellular protein that is markedly elevated in nasal polyp tissue. The purpose of this study was to determine whether use of these antihypertensive agents affects the time to revision sinus surgery in patients with polyp regrowth. Study Design. Case series with chart review. Setting. Academic medical center. Subjects and Methods. Records were reviewed for 330 patients who underwent >= 2 operations for chronic sinusitis with nasal polyps from April 1987 through August 2015. The time between surgical interventions was compared with patient demographics and clinical characteristics, including use of ACEIs and ARBs. Results. Sixty patients were taking ACEIs or ARBs during the study period, of which 32 had concurrent asthma. The mean interval between polyp operations was 61.0 +/- 45.2 months (range, 2-228.6 months). Among patients with asthma (n = 197), the mean time to revision surgery was prolonged by >2 years for those taking ACEIs or ARBs (81.0 vs 54.5 months, P =.006). A similar impact on time to revision surgery was not observed for nonasthmatics taking these medications (61.0 vs 65.2 months, P =.655). Conclusion. Use of ACEIs and ARBs is associated with an increased time to revision sinus surgery among patients with concurrent nasal polyps and asthma. A possible mechanism of this observed effect is suppression of periostin expression through inhibition of the angiotensin pathway. C1 [Brook, Christopher D.; Maxfield, Alice Z.; Stankovic, Konstantina; Metson, Ralph B.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. [Brook, Christopher D.; Maxfield, Alice Z.; Stankovic, Konstantina; Metson, Ralph B.] Harvard Med Sch, Dept Otolaryngol, Boston, MA USA. RP Brook, CD (reprint author), Boston Univ, Dept Otolaryngol, Med Ctr, 1 Boston Med Ctr Pl,FGH Bldg,4th Floor, Boston, MA 02118 USA. EM chris.brook@bmc.org NR 34 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0194-5998 EI 1097-6817 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD DEC PY 2016 VL 155 IS 6 BP 1046 EP 1052 DI 10.1177/0194599816663924 PG 7 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA ED8UN UT WOS:000389146500021 PM 27554516 ER PT J AU Colwell, AS AF Colwell, Amy S. TI Discussion: Do Prolonged Prophylactic Antibiotics Reduce the Incidence of Surgical-Site Infections in Immediate Prosthetic Breast Reconstruction? SO PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Editorial Material C1 [Colwell, Amy S.] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Colwell, AS (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA 02114 USA. EM acolwell@mgh.harvard.edu NR 5 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0032-1052 EI 1529-4242 J9 PLAST RECONSTR SURG JI Plast. Reconstr. Surg. PD DEC PY 2016 VL 138 IS 6 BP 1150 EP 1151 DI 10.1097/PRS.0000000000002738 PG 2 WC Surgery SC Surgery GA ED7HQ UT WOS:000389033800035 PM 27879579 ER PT J AU Ascherman, JA Zeidler, K Morrison, KA Appel, JZ Berkowitz, RL Castle, J Colwell, A Chun, Y Johnson, D Mohebali, K AF Ascherman, Jeffrey A. Zeidler, Kamakshi Morrison, Kerry A. Appel, James Z. Berkowitz, R. L. Castle, John Colwell, Amy Chun, Yoon Johnson, Debra Mohebali, Khashayar TI Carbon Dioxide-Based versus Saline Tissue Expansion for Breast Reconstruction: Results of the XPAND Prospective, Randomized Clinical Trial SO PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Article ID POSTMASTECTOMY RADIATION; EXPANDER; PATIENT; IMPLANT; COMPLICATIONS; RATES; RISK AB Background: AeroForm is a new type of remote-controlled, needle-free, carbon dioxide-based expander involving a potentially faster method of tissue expansion. Results are presented here from the AirXpanders Patient Activated Controlled Tissue Expander pivotal trial comparing AeroForm to saline tissue expanders. Methods: Women undergoing two-stage breast reconstruction were randomized at 17 U.S. sites in this U.S. Food and Drug Administration-approved investigational device exemption trial. Expansion in the investigational arm was performed by the patient in 10-cc increments up to 30 cc/day of carbon dioxide and in the control arm by the physician with periodic bolus injections of saline. Safety endpoints, expansion and reconstruction times, pain, and satisfaction were assessed. Results: One hundred fifty women were treated: 98 with carbon dioxide expanders (n = 168) and 52 with saline expanders (n = 88). The treatment success rate (all breasts exchanged successfully excluding non-device-related failures) was 96.1 percent for carbon dioxide and 98.8 percent for saline. Median time to full expansion and completion of the second-stage operation was 21.0 and 108.5 days (carbon dioxide) versus 46.0 and 136.5 days (saline), respectively, with a similar rate of overall complications. Ease of use for the carbon dioxide expander was rated high by patients (98 percent) and physicians (90 percent). Conclusions: The AirXpanders Patient Activated Controlled Tissue Expander trial results demonstrate that a carbon dioxide-based expander is an effective method of tissue expansion with a similar overall adverse event rate compared to saline expanders, and provides a more convenient and expedient expansion. C1 Columbia Univ, Dept Surg, Div Plast Surg, Med Ctr,New York Presbyterian Hosp, 161 Ft Washington Ave,Suite 511, New York, NY 10032 USA. Plast Surg Ctr, New York, NY USA. Mohebali Plast Surg, Corte Madera, CA USA. Novant Hlth Appel Plast Surg, Charlotte, NC USA. Univ Massachusetts, Mem Med Ctr, Div Plast Surg, Amherst, MA 01003 USA. Massachusetts Gen Hosp, Div Plast Surg, Boston, MA 02114 USA. Harvard Med Sch, Brigham & Womens Faulkner Hosp, Boston, MA USA. RP Ascherman, JA (reprint author), Columbia Univ, Med Ctr, 161 Ft Washington Ave,Suite 511, New York, NY 10032 USA. EM jaa7@cumc.columbia.edu FU Sientra; AirXpanders, Inc. FX Dr. Zeidler is a research support recipient from Sientra. Dr. Colwell is a consultant for Acelity and is on the advisory board for Allergan. Dr. Berkowitz is a speaker for Acelity. Dr. Ascherman is a consultant for AirXpanders, Inc. All investigators received research support from AirXpanders, Inc. NR 23 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0032-1052 EI 1529-4242 J9 PLAST RECONSTR SURG JI Plast. Reconstr. Surg. PD DEC PY 2016 VL 138 IS 6 BP 1161 EP 1170 DI 10.1097/PRS.0000000000002784 PG 10 WC Surgery SC Surgery GA ED7HQ UT WOS:000389033800037 PM 27879582 ER PT J AU Davidson, EH Wang, EW Yu, JY Fernandez-Miranda, JC Wang, DJ Richards, N Miller, M Schuman, JS Washington, KM AF Davidson, Edward H. Wang, Eric W. Yu, Jenny Y. Fernandez-Miranda, Juan C. Wang, Dawn J. Richards, Nikisha Miller, Maxine Schuman, Joel S. Washington, Kia M. TI Total Human Eye Allotransplantation: Developing Surgical Protocols for Donor and Recipient Procedures SO PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Article ID PERFUSED MAMMALIAN EYE; OPTIC-NERVE; OPHTHALMIC ARTERY; MAXILLARY ARTERY; REGENERATION; TRANSPLANTATION; RECOVERY; BRANCHES; SURGERY; ANATOMY AB Background: Vascularized composite allotransplantation of the eye is an appealing, novel method for reconstruction of the nonfunctioning eye. The authors' group has established the first orthotopic model for eye transplantation in the rat. With advancements in immunomodulation strategies together with new therapies in neuroregeneration, parallel development of human surgical protocols is vital for ensuring momentum toward eye transplantation in actual patients. Methods: Cadaveric donor tissue harvest (n = 8) was performed with orbital exenteration, combined open craniotomy, and endonasal approach to ligate the ophthalmic artery with a cuff of paraclival internal carotid artery, for transection of the optic nerve at the optic chiasm and transection of cranial nerves III to VI and the superior ophthalmic vein at the cavernous sinus. Candidate recipient vessels (superficial temporal/internal maxillary/facial artery and superficial temporal/facial vein) were exposed. Vein grafts were required for all anastomoses. Donor tissue was secured in recipient orbits followed by sequential venous and arterial anastomoses and nerve coaptation. Pedicle lengths and calibers were measured. All steps were timed, photographed, video recorded, and critically analyzed after each operative session. Results: The technical feasibility of cadaveric donor procurement and transplantation to cadaveric recipient was established. Mean measurements included optic nerve length (39 mm) and caliber (5 mm), donor artery length (33 mm) and caliber (3 mm), and superior ophthalmic vein length (15 mm) and caliber (0.5 mm). Recipient superficial temporal, internal maxillary artery, and facial artery calibers were 0.8, 2, and 2 mm, respectively; and superior temporal and facial vein calibers were 0.8 and 2.5 mm, respectively. Conclusion: This surgical protocol serves as a benchmark for optimization of technique, large-animal model development, and ultimately potentiating the possibility of vision restoration transplantation surgery. C1 Univ Pittsburgh, Dept Plast Surg, Sch Med, 3550 Terrace St Scaife Hall,Suite 668, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Dept Otolaryngol, Sch Med, 3550 Terrace St Scaife Hall,Suite 668, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Dept Ophthalmol, Sch Med, 3550 Terrace St Scaife Hall,Suite 668, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Dept Neurosurg, Sch Med, 3550 Terrace St Scaife Hall,Suite 668, Pittsburgh, PA 15261 USA. VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. RP Washington, KM (reprint author), Univ Pittsburgh, Dept Plast Surg, 3550 Terrace St Scaife Hall,Suite 668, Pittsburgh, PA 15261 USA. EM washingtonkm@upmc.edu FU NEI NIH HHS [R01 EY013178] NR 28 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0032-1052 EI 1529-4242 J9 PLAST RECONSTR SURG JI Plast. Reconstr. Surg. PD DEC PY 2016 VL 138 IS 6 BP 1297 EP 1308 DI 10.1097/PRS.0000000000002821 PG 12 WC Surgery SC Surgery GA ED7HQ UT WOS:000389033800050 PM 27879599 ER PT J AU Eberlin, KR Bojovic, B AF Eberlin, Kyle R. Bojovic, Branko TI Discussion: Total Human Eye Allotransplantation: Developing Surgical Protocols for Donor and Recipient Procedures SO PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Editorial Material ID TRANSPLANTATION; ARTERY; FACE C1 [Eberlin, Kyle R.; Bojovic, Branko] Harvard Med Sch, Massachusetts Gen Hosp, Div Plast & Reconstruct Surg, 15 Parkman St, Boston, MA 02114 USA. RP Eberlin, KR (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Div Plast & Reconstruct Surg, Wang Ambulatory Care Ctr 435, Boston, MA 02114 USA. EM keberlin@mgh.harvard.edu NR 6 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0032-1052 EI 1529-4242 J9 PLAST RECONSTR SURG JI Plast. Reconstr. Surg. PD DEC PY 2016 VL 138 IS 6 BP 1309 EP 1310 DI 10.1097/PRS.0000000000002822 PG 2 WC Surgery SC Surgery GA ED7HQ UT WOS:000389033800051 PM 27879600 ER PT J AU Achebe, MO Parnes, A AF Achebe, Maureen Okam Parnes, Aric TI Preface SO PRIMARY CARE LA English DT Editorial Material C1 [Achebe, Maureen Okam] Harvard Med Sch, Dana Farber Canc Inst, Hematol Serv, Brigham & Womens Hosp,Div Hematol, Midcampus 3,75 Francis St, Boston, MA 02115 USA. [Parnes, Aric] Harvard Med Sch, Dana Farber Canc Inst, Brigham & Womens Hosp, Dept Med,Div Hematol, 75 Francis St, Boston, MA 02115 USA. RP Achebe, MO (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Hematol Serv, Brigham & Womens Hosp,Div Hematol, Midcampus 3,75 Francis St, Boston, MA 02115 USA. EM mokam@bwh.harvard.edu; aparnes@partners.org NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0095-4543 EI 1558-299X J9 PRIMARY CARE JI Primary Care PD DEC PY 2016 VL 43 IS 4 BP XV EP XVI DI 10.1016/j.pop.2016.10.001 PG 2 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA EE3QN UT WOS:000389510000002 PM 27866588 ER PT J AU Parnes, A Ravi, A AF Parnes, Aric Ravi, Arvind TI Polycythemia and Thrombocytosis SO PRIMARY CARE LA English DT Article DE Myeloproliferative neoplasms; Polycythemia vera; Essential thrombocytosis; Myelofibrosis; JAK2 mutation ID DEFINED ESSENTIAL THROMBOCYTHEMIA; ORGANIZATION DIAGNOSTIC-CRITERIA; QUALITY-OF-LIFE; MYELOPROLIFERATIVE NEOPLASMS; PEGYLATED INTERFERON-ALPHA-2A; MOLECULAR RESPONSE; PROGNOSTIC-FACTORS; AVAILABLE THERAPY; DISEASE BURDEN; HIGH-RISK AB Myeloproliferative neoplasms (MPNs) are diseases of excess cell proliferation from bone marrow precursors. Two classic MPNs, polycythemia vera (PV) and essential thrombocytosis (ET), are conditions of excess proliferation of red blood cells and platelets, respectively. Although PV and ET involve different cells in the myeloid lineage, their clinical presentations have shared features, consistent with overlapping mutations in growth factor signaling. The management of both diseases involves minimizing the risk of thrombotic and hemorrhagic complications. Both PV and ET can progress to myelofibrosis or acute myeloid leukemia, portending a poor prognosis. MPNs can also present as primary myelofibrosis. C1 [Parnes, Aric] Brigham & Womens Hosp, Div Hematol, 75 Francis St, Boston, MA 02115 USA. [Parnes, Aric; Ravi, Arvind] Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. RP Parnes, A (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM aparnes@partners.org NR 43 TC 0 Z9 0 U1 2 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0095-4543 EI 1558-299X J9 PRIMARY CARE JI Primary Care PD DEC PY 2016 VL 43 IS 4 BP 589 EP + DI 10.1016/j.pop.2016.07.011 PG 18 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA EE3QN UT WOS:000389510000007 PM 27866579 ER PT J AU Castillo, JJ AF Castillo, Jorge J. TI Plasma Cell Disorders SO PRIMARY CARE LA English DT Article DE MGUS; Multiple myeloma; Waldenstrom macroglobulinemia; Amyloidosis; POEMS ID UNDETERMINED SIGNIFICANCE MGUS; ASYMPTOMATIC MULTIPLE-MYELOMA; LIGHT-CHAIN AMYLOIDOSIS; CONSENSUS PANEL RECOMMENDATIONS; INTERNATIONAL STAGING SYSTEM; INDEPENDENT RISK-FACTOR; MONOCLONAL GAMMOPATHY; WALDENSTROM MACROGLOBULINEMIA; AL AMYLOIDOSIS; LONG-TERM AB Plasma cell disorders are benign, premalignant, and malignant conditions characterized by the presence of a monoclonal paraprotein detected in serum or urine. These conditions are biologically, pathologically, and clinically heterogeneous. There have been major advances in the understanding of the biology of these diseases, which are promoting the development of therapies with novel mechanisms of action. Novel agents such as proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies have gained approval in the United States and Europe for the treatment of plasma cell disorders. Such therapies are translating into higher rates of response and survival and better toxicity profiles. C1 [Castillo, Jorge J.] Harvard Med Sch, Dana Farber Canc Inst, Div Hematol Malignancies, 450 Brookline Ave,Mayer 221, Boston, MA 02215 USA. RP Castillo, JJ (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Div Hematol Malignancies, 450 Brookline Ave,Mayer 221, Boston, MA 02215 USA. EM Jorgej_castillo@dfci.harvard.edu OI Castillo, Jorge/0000-0001-9490-7532 FU Abbvie; Gilead; Millennium; Pharmacyclics FX Disclosure Statement: Advisory Board: Pharmacyclics, Alexion. Consultancy: Biogen Idec, Otsuka. Honoraria: Celgene, Janssen. Research Funding: Abbvie, Gilead, Millennium, Pharmacyclics. NR 63 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 0095-4543 EI 1558-299X J9 PRIMARY CARE JI Primary Care PD DEC PY 2016 VL 43 IS 4 BP 677 EP + DI 10.1016/j.pop.2016.07.002 PG 16 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA EE3QN UT WOS:000389510000013 PM 27866585 ER PT J AU Rodrigue, JR Schold, JD Mandelbrot, DA Taber, DJ Phan, V Baliga, PK AF Rodrigue, James R. Schold, Jesse D. Mandelbrot, Didier A. Taber, David J. Van Phan Baliga, Prabhakar K. TI Concern for Lost Income Following Donation Deters Some Patients From Talking to Potential Living Donors SO PROGRESS IN TRANSPLANTATION LA English DT Article DE kidney transplantation; transplant recipients; living donation; kidney donation; costs; barriers ID ORGAN DONATION; KIDNEY DONATION; UNITED-STATES; ATTITUDES; TRANSPLANTATION; DISINCENTIVES; INCENTIVES; SURGEONS; ADULTS AB Context: Some living kidney donors report lost income during recovery from surgery. Little is known about whether concern for living donor's lost income affects the decision to undergo donation evaluation and the willingness of transplant candidates to discuss living kidney donation (LKD) with others. Objective: To examine whether transplant patients were told by potential donors about lost income concerns and whether patients chose not to discuss LKD with others due to lost income concerns. Design, Setting, and Patients: Kidney transplant patients (185 wait-listed candidates, 171 deceased donor recipients, and 100 live donor recipients) at 2 centers completed a questionnaire to assess whether concern about donor's lost income was a consideration in discussion about LKD with others. Results: One-third (32%) were told by a family member/friend that they were willing to donate but were concerned about potential lost income. The majority of those who expressed financial concern (64%) did not initiate donation evaluation. Many patients (42%) chose not to discuss living donation with a family member/friend due to concern about the impact of lost income on the donor. In the multivariable model, lower annual household income was the only statistically significant predictor of both having a potential donor expressing lost income concern and choosing not to talk to someone because of lost income concern. Conclusion: Findings from the current study underscore how concern about income loss for living donors may affect decision-making by both transplant candidates and potential donors. C1 [Rodrigue, James R.] Beth Israel Deaconess Med Ctr, Ctr Transplant Outcomes & Qual Improvement, Transplant Inst, Boston, MA 02215 USA. [Rodrigue, James R.] Harvard Med Sch, Boston, MA USA. [Schold, Jesse D.] Cleveland Clin, Quantitat Hlth Sci, Cleveland, OH 44106 USA. [Mandelbrot, Didier A.] Univ Wisconsin, Dept Med, Madison, WI USA. [Taber, David J.; Van Phan; Baliga, Prabhakar K.] Med Univ South Carolina, Dept Surg, Charleston, SC 29425 USA. [Taber, David J.] Ralph H Johnson VA Med Ctr, Dept Pharm, Charleston, SC USA. RP Rodrigue, JR (reprint author), Beth Israel Deaconess Med Ctr, Transplant Inst, 110 Francis St,7th Floor, Boston, MA 02215 USA. EM jrrodrig@bidmc.harvard.edu FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [R01DK085185, R01DK098727]; Julie Henry Research Fund; Center for Transplant Outcomes and Quality Improvement, The Transplant Institute, Beth Israel Deaconess Medical Center, Boston, MA FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by Award No. R01DK085185 and R01DK098727 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The preparation of this manuscript was also supported, in part, by the Julie Henry Research Fund and the Center for Transplant Outcomes and Quality Improvement, The Transplant Institute, Beth Israel Deaconess Medical Center, Boston, MA. NR 27 TC 0 Z9 0 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1526-9248 EI 2164-6708 J9 PROG TRANSPLANT JI Prog. Transplant. PD DEC PY 2016 VL 26 IS 4 BP 292 EP 298 DI 10.1177/1526924816661332 PG 7 WC Surgery; Transplantation SC Surgery; Transplantation GA ED4XR UT WOS:000388855800002 ER PT J AU Moore, TM Reise, SP Roalf, DR Satterthwaite, TD Davatzikos, C Bilker, WB Port, AM Jackson, CT Ruparel, K Savitt, AP Baron, RB Gur, RE Gur, RC AF Moore, Tyler M. Reise, Steven P. Roalf, David R. Satterthwaite, Theodore D. Davatzikos, Christos Bilker, Warren B. Port, Allison M. Jackson, Chad T. Ruparel, Kosha Savitt, Adam P. Baron, Robert B. Gur, Raquel E. Gur, Ruben C. TI Development of an Itemwise Efficiency Scoring Method: Concurrent, Convergent, Discriminant, and Neuroimaging-Based Predictive Validity Assessed in a Large Community Sample SO PSYCHOLOGICAL ASSESSMENT LA English DT Article DE neurocognitive efficiency; validity; computerized neurocognitive battery; psychometrics; Philadelphia Neurodevelopmental Cohort ID COMPUTERIZED NEUROCOGNITIVE BATTERY; CEREBRAL BLOOD-FLOW; SEX-DIFFERENCES; CORPUS-CALLOSUM; RESPONSE-TIMES; MENTAL ROTATION; WORKING-MEMORY; INDIVIDUAL-DIFFERENCES; COGNITIVE-PSYCHOLOGY; PSYCHOSIS SPECTRUM AB Traditional "paper-and-pencil" testing is imprecise in measuring speed and hence limited in assessing performance efficiency, but computerized testing permits precision in measuring itemwise response time. We present a method of scoring performance efficiency (combining information from accuracy and speed) at the item level. Using a community sample of 9,498 youths age 8-21, we calculated item-level efficiency scores on 4 neurocognitive tests, and compared the concurrent, convergent, discriminant, and predictive validity of these scores with simple averaging of standardized speed and accuracy-summed scores. Concurrent validity was measured by the scores' abilities to distinguish men from women and their correlations with age; convergent and discriminant validity were measured by correlations with other scores inside and outside of their neurocognitive domains; predictive validity was measured by correlations with brain volume in regions associated with the specific neurocognitive abilities. Results provide support for the ability of itemwise efficiency scoring to detect signals as strong as those detected by standard efficiency scoring methods. We find no evidence of superior validity of the itemwise scores over traditional scores, but point out several advantages of the former. The itemwise efficiency scoring method shows promise as an alternative to standard efficiency scoring methods, with overall moderate support from tests of 4 different types of validity. This method allows the use of existing item analysis methods and provides the convenient ability to adjust the overall emphasis of accuracy versus speed in the efficiency score, thus adjusting the scoring to the real-world demands the test is aiming to fulfill. C1 [Moore, Tyler M.; Roalf, David R.; Satterthwaite, Theodore D.; Port, Allison M.; Jackson, Chad T.; Ruparel, Kosha; Savitt, Adam P.; Baron, Robert B.; Gur, Raquel E.; Gur, Ruben C.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Reise, Steven P.] Univ Calif, Dept Psychol, Philadelphia, PA USA. [Davatzikos, Christos] Univ Penn, Sect Biomed Image Anal, Philadelphia, PA 19104 USA. [Bilker, Warren B.] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Gur, Ruben C.] Philadelphia VA Med Ctr, Mental Illness Res Educ & Clin Ctr VISN4, Philadelphia, PA USA. RP Moore, TM (reprint author), Univ Penn, Perelman Sch Med, Brain Behav Lab, 3400 Spruce St,10th Floor Gates Pavil, Philadelphia, PA 19104 USA. EM tymoore@upenn.edu FU NIMH [MH089983, MH019112, MH096891]; Dowshen Program for Neuroscience FX Ruben C. Gur receives royalties from the Brain Resource Centre, Ultimo, New South Wales, Australia, and is an unpaid consultant on the Scientific Advisory Board of Lumosity, San Francisco, California. This work was supported by NIMH Grants MH089983, MH019112, MH096891 and the Dowshen Program for Neuroscience. NR 85 TC 0 Z9 0 U1 9 U2 9 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 1040-3590 EI 1939-134X J9 PSYCHOL ASSESSMENT JI Psychol. Assess. PD DEC PY 2016 VL 28 IS 12 BP 1529 EP 1542 DI 10.1037/pas0000284 PG 14 WC Psychology, Clinical SC Psychology GA EE0ZE UT WOS:000389308700001 PM 26866796 ER PT J AU Gutierrez, PM Pease, J Matarazzo, BB Monteith, LL Hernandez, T Osman, A AF Gutierrez, Peter M. Pease, James Matarazzo, Bridget B. Monteith, Lindsey L. Hernandez, Theresa Osman, Augustine TI Evaluating the Psychometric Properties of the Interpersonal Needs Questionnaire and the Acquired Capability for Suicide Scale in Military Veterans SO PSYCHOLOGICAL ASSESSMENT LA English DT Article DE Interpersonal Needs Questionnaire; Acquired Capability for Suicide Scale; veterans; psychometrics ID TRAUMATIC BRAIN-INJURY; PSYCHOLOGICAL THEORY; CONSTRUCT-VALIDITY; PERCEIVED BURDENSOMENESS; SCREENING-TEST; RISK-FACTORS; MISSING DATA; 2 SAMPLES; RELIABILITY; BEHAVIOR AB Joiner's (2005) interpersonal-psychological theory of suicide (IPTS) has become one of the most frequently studied in the field. Currently there are 2 primary measures designed to assess the 3 main constructs of the theory-the Interpersonal Needs Questionnaire (INQ; Van Orden, Witte, Gordon, Bender, & Joiner, 2008) and the Acquired Capability for Suicide Scale (ACSS; Van Orden et al., 2008). The psychometric properties of these 2 measures were evaluated in a sample of 477 U.S. military veterans. It was determined that the factor structure for both measures is consistent with the underlying theory and that all internal consistency reliability estimates are good. Acceptable convergent validity was found for the INQ, but not for the ACSS. Recommendations for refining the ACSS based on the results of the current analyses are provided. Comparisons of scale performance were made with data from participants with and without a history of 1 or more suicide attempts. Burdensomeness alone and the interaction between thwarted belongingness and burdensomeness were associated with prior suicide attempts. In conclusion, although some refinement may improve performance of the ACSS, both measures are appropriate and psychometrically sound for use in research and clinical applications with veterans of the U.S. military. C1 [Gutierrez, Peter M.; Pease, James; Matarazzo, Bridget B.; Monteith, Lindsey L.; Hernandez, Theresa] Denver Vet Affairs Med Ctr, Rocky Mt Mental Illness Res Educ & Clin Ctr, Denver, CO USA. [Gutierrez, Peter M.; Pease, James; Matarazzo, Bridget B.; Monteith, Lindsey L.] Univ Colorado, Sch Med, Dept Psychiat, Boulder, CO 80309 USA. [Hernandez, Theresa] Univ Colorado, Dept Psychol & Neurosci, Boulder, CO 80309 USA. [Osman, Augustine] Univ Texas San Antonio, Dept Psychol, San Antonio, TX USA. RP Gutierrez, PM (reprint author), Denver Vet Affairs Med Ctr, Rocky Mt Mental Illness Res Educ & Clin Ctr, MIRECC, 1055 Clermont St, Denver, CO 80220 USA. EM peter.gutierrez@va.gov NR 65 TC 0 Z9 0 U1 0 U2 0 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 1040-3590 EI 1939-134X J9 PSYCHOL ASSESSMENT JI Psychol. Assess. PD DEC PY 2016 VL 28 IS 12 BP 1684 EP 1694 DI 10.1037/pas0000310 PG 11 WC Psychology, Clinical SC Psychology GA EE0ZE UT WOS:000389308700015 PM 26998894 ER PT J AU DuBrock, HM Rodriguez-Lopez, JM LeVarge, BL Curry, MP VanderLaan, PA Zsengeller, ZK Pernicone, E Preston, IR Yu, PB Nikolic, I Xu, DH Thadhani, RI Channick, RN Karumanchi, SA AF DuBrock, Hilary M. Rodriguez-Lopez, Josanna M. LeVarge, Barbara L. Curry, Michael P. VanderLaan, Paul A. Zsengeller, Zsuzsanna K. Pernicone, Elizabeth Preston, Ioana R. Yu, Paul B. Nikolic, Ivana Xu, Dihua Thadhani, Ravi I. Channick, Richard N. Karumanchi, S. Ananth TI Macrophage migration inhibitory factor as a novel biomarker of portopulmonary hypertension SO Pulmonary Circulation LA English DT Article DE portopulmonary hypertension; macrophage migration inhibitory factor; biomarker; transpulmonary; pulmonary arterial hypertension ID PULMONARY-HYPERTENSION; LIVER-TRANSPLANTATION; REVEAL REGISTRY; RISK-FACTORS; EXPRESSION; HEMODYNAMICS; PREVALENCE; DIAGNOSIS; CIRRHOSIS; DISEASE AB Portopulmonary hypertension (POPH) is a poorly understood complication of liver disease associated with significant morbidity and mortality. We sought to identify novel biomarkers of POPH disease presence and severity. We performed a prospective, multicenter, case-control study involving patients with liver disease undergoing right heart catheterization. POPH cases were defined as a mean pulmonary arterial pressure (mPAP) >= 25 mmHg and pulmonary vascular resistance (PVR) >240 dynes.s.cm(-5). Plasma samples were collected from the systemic and pulmonary circulation, and antibody microarray was used to identify biomarkers. Characterization and validation of a candidate cytokine, macrophage migration inhibitory factor (MIF), was performed using enzyme-linked immunosorbent assay. Continuous variables were compared using a Mann-Whitney U test and correlated with disease severity using Spearman correlation. MIF levels were elevated in both the systemic and pulmonary circulation in patients with POPH compared with controls (median MIF level [interquartile range] in systemic circulation: 46.68 ng/mL [32.31-76.04] vs. 31.19 ng/mL [26.92-42.17],P = 0.009; in pulmonary circulation: 49.59 ng/mL [35.90-108.80] vs. 37.78 [21.78-45.53], P = 0.002). In patients with POPH, MIF levels were positively correlated with PVR (r = 0.58, P = 0.006) and inversely correlated with cardiac output (r = -0.57, P = 0.007). MIF > 60 ng/mL or tricuspid regurgitation gradient > 50 mmHg had a 92% sensitivity and specificity for the diagnosis of POPH, with a positive predictive value of 86% and a negative predictive value of 96%. MIF is a promising novel biomarker of POPH disease presence and severity in patients with liver disease and portal hypertension. C1 [DuBrock, Hilary M.; LeVarge, Barbara L.; Curry, Michael P.; VanderLaan, Paul A.; Zsengeller, Zsuzsanna K.; Pernicone, Elizabeth; Karumanchi, S. Ananth] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Rodriguez-Lopez, Josanna M.; Xu, Dihua; Thadhani, Ravi I.; Channick, Richard N.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Preston, Ioana R.] Tufts Univ, Med Ctr, Boston, MA 02111 USA. [Yu, Paul B.; Nikolic, Ivana] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. RP DuBrock, HM (reprint author), Mayo Clin, 200 First St SW, Rochester, MN 55905 USA. EM dubrock.hilary@mayo.edu FU National Institutes of Health [T32 5T32HL007893-17]; Howard Hughes Medical Institute FX HMD was supported by an institutional training grant (T32 5T32HL007893-17) from the National Institutes of Health. SAK was supported by funding from the Howard Hughes Medical Institute. NR 32 TC 0 Z9 0 U1 3 U2 3 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 2045-8932 EI 2045-8940 J9 PULM CIRC JI Pulm. Circ. PD DEC PY 2016 VL 6 IS 4 BP 498 EP 507 DI 10.1086/688489 PG 10 WC Cardiac & Cardiovascular Systems; Respiratory System SC Cardiovascular System & Cardiology; Respiratory System GA EE0XS UT WOS:000389303800009 PM 28090291 ER PT J AU Heesters, BA van der Poel, CE Das, A Carroll, MC AF Heesters, Balthasar A. van der Poel, Cees E. Das, Abhishek Carroll, Michael C. TI Antigen Presentation to B Cells SO TRENDS IN IMMUNOLOGY LA English DT Review ID FOLLICULAR DENDRITIC CELLS; SUBCAPSULAR SINUS MACROPHAGES; GERMINAL-CENTERS; LYMPH-NODE; AFFINITY MATURATION; IMMUNE-COMPLEXES; IN-VIVO; RHEUMATOID-ARTHRITIS; ANTIBODY-PRODUCTION; CLONAL SELECTION AB Unlike T cells that recognize digested peptides, B cells recognize their cognate antigen in its native form. The B cell receptor used in recognition can also be secreted to bind to antigens and initiate multiple effector functions such as phagocytosis, complement activation, or neutralization of receptors. While B cells can interact with soluble antigens, it is now clear that the presentation of membrane-bound antigen plays a crucial role in B cell activation, and in particular during affinity-maturation, the process during which high-affinity B cells are selected. In this review we discuss how native antigen is presented to B cells and its impact at several stages of B cell responses. C1 [Heesters, Balthasar A.; van der Poel, Cees E.; Das, Abhishek; Carroll, Michael C.] Harvard Med Sch, Program Cellular & Mol Med, Boston Childrens Hosp, Boston, MA 02115 USA. [Heesters, Balthasar A.; van der Poel, Cees E.; Das, Abhishek; Carroll, Michael C.] Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA. [Heesters, Balthasar A.] Acad Med Ctr, Dept Cell Biol & Histol, NL-1105 AZ Amsterdam, Netherlands. RP Carroll, MC (reprint author), Harvard Med Sch, Program Cellular & Mol Med, Boston Childrens Hosp, Boston, MA 02115 USA.; Carroll, MC (reprint author), Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA. EM michael.carroll@childrens.harvard.edu FU National Institutes of Health [AI039246] FX The authors thank all members of the laboratory of M.C.C. for suggestions and for help with experiments and reading of the manuscript. We acknowledge the valuable assistance of Dr Elisabeth M. Carroll. Supported by National Institutes of Health grant AI039246 to M.C.C. NR 63 TC 1 Z9 1 U1 5 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4906 EI 1471-4981 J9 TRENDS IMMUNOL JI Trends Immunol. PD DEC PY 2016 VL 37 IS 12 BP 844 EP 854 DI 10.1016/j.it.2016.10.003 PG 11 WC Immunology SC Immunology GA EE2ET UT WOS:000389397200005 PM 27793570 ER PT J AU Wang, ZH Navarro-Alvarez, N Shah, JA Zhang, HP Huang, Q Zheng, Q Madsen, JC Sachs, DH Huang, CA Wang, ZR AF Wang, Zhaohui Navarro-Alvarez, Nalu Shah, Jigesh A. Zhang, Huiping Huang, Qi Zheng, Qian Madsen, Joren C. Sachs, David H. Huang, Christene A. Wang, Zhirui TI Porcine Treg depletion with a novel diphtheria toxin-based anti-human CCR4 immunotoxin SO VETERINARY IMMUNOLOGY AND IMMUNOPATHOLOGY LA English DT Article DE Porcine Treg; CCR4; Immunotoxin; Diphtheria toxin; MGH miniature swine ID REGULATORY T-CELLS; MINIATURE SWINE; EXPRESSION; SUPPRESSION; MOLECULES AB Regulatory T cells (Tregs) are known to play an important role in immunoregulation and have been shown to facilitate induction of transplantation tolerance. Chemokine (C-C motif) receptor 4 (CCR4) is expressed on the surface of effector Tregs involved in controlling alloimmune and autoimmune responses. Recently we have developed a novel diphtheria-toxin based anti-human CCR4 immunotoxin for depleting CCR4(+) cells in vivo. In this study, we have demonstrated that the anti-human CCR4 immunotoxin bound to porcine lymphocytes including CD4(+)FoxP3(+) Tregs. Anti-human CCR4 immunotoxin effectively depleted CCR4(+) Foxp3(+) porcine Tregs in vivo. We observed depletion of up to 70-85% of the CCR4(+) Foxp3(+) porcine Tregs in the peripheral blood and 85-91% in the lymph nodes following the anti-human CCR4 immunotoxin treatment in Massachusetts General Hospital (MGH) miniature swine. The depletion lasted for about one week with no significant reduction observed within CCR4(-) cell populations including CD8 alpha(+) T cells, CCR4(-)CD4(+) T cells and B cells. In summary, anti-human CCR4 immunotoxin effectively depleted CCR4(+)Foxp3(+) porcine Tregs in both peripheral blood and lymph nodes. (C) 2016 Elsevier B.V. All rights reserved. C1 [Wang, Zhaohui; Navarro-Alvarez, Nalu; Shah, Jigesh A.; Zhang, Huiping; Huang, Qi; Zheng, Qian; Madsen, Joren C.; Sachs, David H.; Huang, Christene A.; Wang, Zhirui] Massachusetts Gen Hosp, Ctr Transplantat Sci, CNY149-9019,13th St, Boston, MA 02129 USA. [Wang, Zhaohui; Navarro-Alvarez, Nalu; Shah, Jigesh A.; Zhang, Huiping; Huang, Qi; Zheng, Qian; Madsen, Joren C.; Sachs, David H.; Huang, Christene A.; Wang, Zhirui] Harvard Med Sch, Boston, MA USA. [Sachs, David H.] Massachusetts Gen Hosp, Ctr Transplantat Sci, TBRC Labs, Boston, MA 02114 USA. [Madsen, Joren C.] Massachusetts Gen Hosp, Div Cardiac Surg, Boston, MA 02114 USA. [Wang, Zhirui] Massachusetts Gen Hosp, Ctr Transplantat Sci, Bldg 149-6113,13th St, Boston, MA 02129 USA. [Wang, Zhirui] Harvard Med Sch, MGH East, Bldg 149-6113,13th St, Boston, MA 02129 USA. RP Huang, CA (reprint author), Massachusetts Gen Hosp, Ctr Transplantat Sci, CNY149-9019,13th St, Boston, MA 02129 USA.; Huang, CA (reprint author), Harvard Med Sch, MGH East, CNY149-9019,13th St, Boston, MA 02129 USA.; Wang, ZR (reprint author), Massachusetts Gen Hosp, Ctr Transplantat Sci, Bldg 149-6113,13th St, Boston, MA 02129 USA.; Wang, ZR (reprint author), Harvard Med Sch, MGH East, Bldg 149-6113,13th St, Boston, MA 02129 USA. EM cahuang@mgh.harvard.edu; zwang7@mgh.harvard.edu FU NIH/NIAID [R21AI115136, R56AI121254] FX We would like to thank James A. Winter and Sarah Lofgren for technical assistance. We acknowledge NIH/NIAID R21AI115136 (CAH) and R56AI121254 (CAH) for research support and CO6RR020135-01 for construction of the facility utilized for production and maintenance of MGH miniature swine. NR 15 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-2427 EI 1873-2534 J9 VET IMMUNOL IMMUNOP JI Vet. Immunol. Immunopathol. PD DEC PY 2016 VL 182 BP 150 EP 158 DI 10.1016/j.vetimm.2016.10.014 PG 9 WC Immunology; Veterinary Sciences SC Immunology; Veterinary Sciences GA ED8FK UT WOS:000389107200021 PM 27863545 ER PT J AU Xian, Y Hernandez, AF Harding, T Fonarow, GC Bhatt, DL Suter, RE Khan, Y Schwamm, LH Peterson, ED AF Xian, Ying Hernandez, Adrian F. Harding, Tina Fonarow, Gregg C. Bhatt, Deepak L. Suter, Robert E. Khan, Yosef Schwamm, Lee H. Peterson, Eric D. TI Acute management of stroke patients taking non-vitamin K antagonist oral anticoagulants - Addressing Real-world Anticoagulant Management Issues in Stroke (ARAMIS) Registry: Design and rationale SO AMERICAN HEART JOURNAL LA English DT Article ID ACUTE ISCHEMIC-STROKE; TISSUE-PLASMINOGEN ACTIVATOR; HEALTH-CARE PROFESSIONALS; ATRIAL-FIBRILLATION; INTRACEREBRAL HEMORRHAGE; GUIDELINES-STROKE; DABIGATRAN ANTICOAGULATION; INTRAVENOUS THROMBOLYSIS; INTRACRANIAL HEMORRHAGE; RISK SCORE AB Background Non-vitamin K antagonist oral anticoagulants (NOACs, dabigatran, rivaroxaban, apixaban, and edoxaban) have been increasingly used as alternatives to warfarin for stroke prophylaxis in patients with atrial fibrillation. Yet there is substantial lack of information on how patients on NOACs are currently treated when they have an acute ischemic stroke and the best strategies for treating intracerebral hemorrhage for those on chronic anticoagulation with warfarin or a NOAC. These are critical unmet needs for real world clinical decision making in these emergent patients. Methods The ARAMIS Registry is a multicenter cohort study of acute stroke patients who were taking chronic anticoagulation therapy prior to admission and are admitted with either an acute ischemic stroke or intracerebral hemorrhage. Built upon the existing infrastructure of American Heart Association/American Stroke Association Get With the Guidelines Stroke, the ARAMIS Registry will enroll a total of approximately 10,000 patients (5000 with acute ischemic stroke who are taking a NOAC and 5000 with anticoagulation-related intracerebral hemorrhage who are on warfarin or a NOAC). The primary goals of the ARAMIS Registry are to provide a comprehensive picture of current treatment patterns and outcomes of acute ischemic stroke patients on NOACs, as well as anticoagulation-related intracerebral hemorrhage in patients on either warfarin or NOACs. Beyond characterizing the index hospitalization, up to 2500 patients (1250 ischemic stroke and 1250 intracerebral hemorrhage) who survive to discharge will be enrolled in an optional follow-up sub-study and interviewed at 3 and 6 months after discharge to assess longitudinal medication use, downstream care, functional status, and patient-reported outcomes. Conclusion The ARAMIS Registry will document the current state of management of NOAC treated patients with acute ischemic stroke as well as contemporary care and outcome of anticoagulation-related intracerebral hemorrhage. These data will be used to better understand optimal strategies to care for these complex but increasingly common emergent real world clinical challenges. C1 [Xian, Ying; Hernandez, Adrian F.; Harding, Tina; Peterson, Eric D.] Duke Clin Res Inst, Durham, NC USA. [Xian, Ying] Duke Univ, Med Ctr, Dept Neurol, Durham, NC USA. [Bhatt, Deepak L.] Brigham & Womens Hosp, Heart & Vasc Ctr, 75 Francis St, Boston, MA 02115 USA. [Bhatt, Deepak L.] Harvard Med Sch, Boston, MA USA. [Fonarow, Gregg C.] Univ Calif Los Angeles, Div Cardiol, Los Angeles, CA USA. [Suter, Robert E.] Univ Texas Southwestern, Dept Emergency Med, Dallas, TX USA. [Khan, Yosef] Massachusetts Gen Hosp, Amer Heart Assoc, Boston, MA 02114 USA. [Schwamm, Lee H.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Xian, Y (reprint author), Duke Univ, Med Ctr, Dept Neurol, Duke Clin Res Inst, 2400 Pratt St, Durham, NC 27705 USA. EM ying.xian@duke.edu OI Xian, Ying/0000-0002-1237-1162 FU Daiichi Sankyo, Inc.; Genentech, Inc.; Janssen; Janssen Pharmaceutical Companies of Johnson Johnson; Boeringher-Ingelheim; Merck; Bristol-Myers Squib/Sanofi Pharmaceutical Partnership; AHA Pharmaceutical Roundtable FX The ARAMIS registry receives funding from the Daiichi Sankyo, Inc., Genentech, Inc., and Janssen. The Get With The Guidelines-Stroke (GWTG-Stroke) program is provided by the American Heart Association/American Stroke Association. The GWTG-Stroke Program is currently supported in part by a charitable contribution from Janssen Pharmaceutical Companies of Johnson & Johnson. GWTG-Stroke has been funded in the past through support from Boeringher-Ingelheim, Merck, Bristol-Myers Squib/Sanofi Pharmaceutical Partnership, and the AHA Pharmaceutical Roundtable. NR 36 TC 1 Z9 1 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 EI 1097-5330 J9 AM HEART J JI Am. Heart J. PD DEC PY 2016 VL 182 BP 28 EP 35 DI 10.1016/j.ahj.2016.07.023 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA ED8QS UT WOS:000389136600004 PM 27914497 ER PT J AU Blazing, MA Giugliano, RP de Lemos, JA Cannon, CP Tonkin, A Ballantyne, CM Lewis, BS Musliner, TA Tershakovec, AM Lokhnygina, Y White, JA Reist, C McCagg, A Braunwald, E AF Blazing, Michael A. Giugliano, Robert P. de Lemos, James A. Cannon, Christopher P. Tonkin, Andrew Ballantyne, Christie M. Lewis, Basil S. Musliner, Thomas A. Tershakovec, Andrew M. Lokhnygina, Yuliya White, Jennifer A. Reist, Craig McCagg, Amy Braunwald, Eugene TI On-treatment analysis of the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) SO AMERICAN HEART JOURNAL LA English DT Article ID ACUTE CORONARY SYNDROMES; CARDIOVASCULAR OUTCOMES; CLINICAL-TRIALS; STATIN THERAPY; EZETIMIBE; SIMVASTATIN; MONOTHERAPY; RATIONALE; DESIGN AB Background We aimed to determine the efficacy and safety of adding ezetimibe (Ez) to simvastatin (S) in a post-acute coronary syndrome (ACS) population in a prespecified on-treatment analysis. Methods We evaluated 17,706 post-ACS patients from the IMPROVE-IT trial who had low-density lipoprotein cholesterol values between 50 and 125mg/dL andwho received Ez 10mg/d with S 40mg/d (Ez/S) or placebo with simvastatin 40mg/d (P/ S). The primary composite end point was cardiovascular death, myocardial infarction, unstable angina, coronary revascularization >= 30 days postrandomization, or stroke. The on-treatment analysis included patients who received study drug for the duration of the trial or experienced a primary end point or noncardiovascular death within 30 days of drug discontinuation. Results Mean low-density lipoprotein cholesterol values at 1 year were 71 mg/dL for P/S and 54 mg/dL for Ez/S (absolute difference -17 mg/dL = -24%; P < .001). The 7-year Kaplan-Meier estimate of the primary end point occurred in 32.4% in the P/S arm and 29.8% in the Ez/S arm (absolute difference 2.6%; HRadj 0.92 [ 95% CI 0.87-0.98]; P = .01). The absolute treatment effect favoring Ez/S was 30% greater than in the intention-to-treat analysis of IMPROVE-IT. Conclusions This analysis provides additional support for the efficacy and safety of adding Ez to S in this high-risk, post-ACS population. C1 [Blazing, Michael A.; Lokhnygina, Yuliya; White, Jennifer A.; Reist, Craig] Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC USA. [Giugliano, Robert P.; Cannon, Christopher P.; McCagg, Amy; Braunwald, Eugene] TIMI Study Grp, Boston, MA USA. [de Lemos, James A.] Univ Texas Southwestern Med Ctr Dallas, Dallas, TX 75390 USA. [Tonkin, Andrew] Monash Univ, Melbourne, Vic, Australia. [Ballantyne, Christie M.] Baylor Coll Med, Houston, TX 77030 USA. [Ballantyne, Christie M.] Houston Methodist DeBakey Heart & Vasc Ctr, Houston, TX USA. [Lewis, Basil S.] Lady Davis Carmel Med Ctr, Haifa, Israel. [Musliner, Thomas A.; Tershakovec, Andrew M.] Merck & Co Inc, Kenilworth, NJ USA. RP Blazing, MA (reprint author), Duke Univ, Med Ctr, Box 3126, Durham, NC 27710 USA. EM michael.blazing@duke.edu FU Merck Co, Inc. FX This work was supported by Merck & Co, Inc. NR 15 TC 0 Z9 0 U1 2 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 EI 1097-5330 J9 AM HEART J JI Am. Heart J. PD DEC PY 2016 VL 182 BP 89 EP 96 DI 10.1016/j.ahj.2016.09.004 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA ED8QS UT WOS:000389136600011 PM 27914504 ER PT J AU Rodriguez, F Lin, ST Maron, DJ Knowles, JW Virani, SS Heidenreich, PA AF Rodriguez, Fatima Lin, Shoutzu Maron, David J. Knowles, Joshua W. Virani, Salim S. Heidenreich, Paul A. TI Use of high-intensity statins for patients with atherosclerotic cardiovascular disease in the Veterans Affairs Health System: Practice impact of the new cholesterol guidelines SO AMERICAN HEART JOURNAL LA English DT Article ID DENSITY-LIPOPROTEIN-CHOLESTEROL; PERIPHERAL ARTERIAL-DISEASE; CLINICAL-TRIALS; UNITED-STATES; THERAPY; IMPROVEMENT; DISCONTINUATION; DYSLIPIDEMIA; MANAGEMENT; PHYSICIANS AB Background The November 2013 American College of Cardiology/ American Heart Association cholesterol guidelines recommend the use of high-intensity statins for patients with atherosclerotic cardiovascular disease (ASCVD). We sought to determine how these guidelines are being adopted at the Veterans Affairs (VA) Health System and identify treatment gaps. Methods We examined administrative data from the VA 12 months prior to the index dates of April 1, 2013, and after April 1, 2014, to identify patients <= 75 years of age with >= 2 codes for ASCVD. We identified those on high-intensity statin therapy (atorvastatin 40 mg or 80 mg, rosuvastatin 20 mg or 40 mg, and simvastatin 80 mg) during the 6 months after the index date. Results The study sample included 331,927 and 326,759 eligible adults with ASCVD before and after the release of the new guidelines, respectively. Overall, high-intensity statin use increased from 28% to 35% after guideline release. High-intensity statin use was lowest in Hispanics and Native Americans, although all groups showed an increase over time. Among those on low-or moderate-intensity statin therapy, 15.6% were intensified to a high-intensity statin after guideline release. Groups less likely to undergo statin intensification were older adults (odds ratio = 0.78 for each 10-year increase, 95% CI 0.76-0.81), women (odds ratio = 0.86, 95% CI 0.75-0.99), and certain minority groups. Academic teaching hospitals and hospitals on the West Coast were more likely to intensify statins after release of the new guidelines. Conclusions High-intensity statin use increased in the VA following release of the American College of Cardiology/ American Heart Association cholesterol treatment guidelines, although disparities persist for certain patient groups including older adults, women, and certain minority groups. C1 [Rodriguez, Fatima; Maron, David J.; Knowles, Joshua W.; Heidenreich, Paul A.] Stanford Univ, Div Cardiovasc Med, Stanford, CA 94305 USA. [Rodriguez, Fatima; Maron, David J.; Knowles, Joshua W.; Heidenreich, Paul A.] Stanford Univ, Cardiovasc Inst, Stanford, CA 94305 USA. [Lin, Shoutzu; Heidenreich, Paul A.] Vet Affairs Hlth Syst, Palo Alto, CA USA. [Virani, Salim S.] Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. [Virani, Salim S.] Baylor Coll Med, Sect Cardiovasc Res, Houston, TX 77030 USA. RP Heidenreich, PA (reprint author), VA Palo Alto Hlth Care Syst, 3801 Miranda Ave, Palo Alto, CA 94304 USA. EM heiden@stanford.edu NR 35 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 EI 1097-5330 J9 AM HEART J JI Am. Heart J. PD DEC PY 2016 VL 182 BP 97 EP 102 DI 10.1016/j.ahj.2016.09.007 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA ED8QS UT WOS:000389136600012 PM 27914506 ER PT J AU Hsieh, T Vaickus, MH Stein, TD Lussier, BL Kim, J Stepien, DM Duffy, ER Chiswick, EL Remick, DG AF Hsieh, Terry Vaickus, Max H. Stein, Thor D. Lussier, Bethany L. Kim, Jiyoun Stepien, David M. Duffy, Elizabeth R. Chiswick, Evan L. Remick, Daniel G. TI The Role of Substance P in Pulmonary Clearance of Bacteria in Comparative Injury Models SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID TRAUMATIC BRAIN-INJURY; GLASGOW COMA SCALE; HUMAN-NEUTROPHILS; PERMEABILITY; EXPRESSION; SURVIVAL; STRESS; ASTHMA; DAMAGE AB Neural input to the immune system can alter its ability to clear pathogens effectively. Patients suffering mild traumatic brain injury (mTBI) have shown reduced rates of pneumonia and a murine model replicated these findings, with better overall survival of TBI mice compared with sham-injured mice. To further investigate the mechanism of improved host response in TBI mice, this study developed and characterized a mild tail trauma model of similar severity to mild TBI. Both mild tail trauma and TBI induced similar systemic changes that normalized within 48 hours, including release of substance P. Examination of tissues showed that injuries are limited to the target tissue (ie, tail in tail trauma, brain in mTBI). Pneumonia challenge showed that mild TBI mice showed improved immune responses, characterized by the following: i) increased survival, ii) increased pulmonary neutrophil recruitment, iii) increased bacterial clearance, and iv) increased phagocytic cell killing of bacteria compared with tail trauma. Administration of a neurokinin-1-receptor antagonist to block substance P signaling eliminated the improved survival of mTBI mice. Neurokinin-1-receptor antagonism did not alter pneumonia mortality in tail trauma mice. These data show that immune benefits of trauma are specific to mTBI and that tail trauma is an appropriate control for future studies aimed at elucidating the mechanisms of improved innate immune responses in mTBI mice. C1 [Hsieh, Terry; Vaickus, Max H.; Stein, Thor D.; Lussier, Bethany L.; Kim, Jiyoun; Stepien, David M.; Duffy, Elizabeth R.; Chiswick, Evan L.; Remick, Daniel G.] Boston Univ, Sch Med, Dept Pathol & Lab Med, 670 Albany St,4th Floor, Boston, MA 02118 USA. [Stein, Thor D.] VA Boston Healthcare Syst, Boston, MA USA. [Stein, Thor D.] Dept Vet Affairs Med Ctr, Bedford, MA USA. [Stepien, David M.] Univ Michigan, Sch Med, Dept Surg, Sect Plast Surg, Ann Arbor, MI USA. [Duffy, Elizabeth R.] Harvard Med Sch, Boston Childrens Hosp, Boston, MA USA. [Chiswick, Evan L.] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. RP Remick, DG (reprint author), Boston Univ, Sch Med, Dept Pathol & Lab Med, 670 Albany St,4th Floor, Boston, MA 02118 USA. EM remickd@bu.edu FU [R01 GM82962]; [R21 AI112887]; [R01 GM97320]; [T32 HL 007501]; [T32 GM 86308]; [T32 HL 007035]; [T32 AI 007309] FX Supported by grants R01 GM82962, R21 AI112887, R01 GM97320, T32 HL 007501, T32 GM 86308, T32 HL 007035, and T32 AI 007309. NR 29 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9440 EI 1525-2191 J9 AM J PATHOL JI Am. J. Pathol. PD DEC PY 2016 VL 186 IS 12 BP 3236 EP 3245 DI 10.1016/j.ajpath.2016.08.014 PG 10 WC Pathology SC Pathology GA ED8EC UT WOS:000389103800015 PM 27876152 ER PT J AU Villarreal, G Hamner, MB Canive, JM Robert, S Calais, LA Durklaski, V Zhai, YS Qualls, C AF Villarreal, Gerardo Hamner, Mark B. Canive, Jose M. Robert, Sophie Calais, Lawrence A. Durklaski, Valerie Zhai, Yusheng Qualls, Clifford TI Efficacy of Quetiapine Monotherapy in Posttraumatic Stress Disorder: A Randomized, Placebo-Controlled Trial SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID OF-VETERANS-AFFAIRS; DOUBLE-BLIND; 2ND-GENERATION ANTIPSYCHOTICS; PTSD; SYMPTOMS; SCHIZOPHRENIA; COMORBIDITY; MEDICATIONS; AFGHANISTAN; OLANZAPINE AB Objective: This was a 12-week randomized, placebo-controlled trial to assess the efficacy of quetiapine monotherapy in the treatment of posttraumatic stress disorder (PTSD). Method: Eighty patients were randomly assigned to treatment with either quetiapine or placebo. The primary outcome measure was the Clinician-Administered PTSD Scale (CAPS). Secondary efficacy measures included the CAPS subscales, the Davidson Trauma Scale, the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impressions (CGI) scales for severity of Illness and improvement, the Hamilton Depression Rating Scale (HAM-D), and the Hamilton Anxiety Rating Scale (HAM-A). Safety measurements included adverse events, vital signs, the Abnormal Involuntary Movement Scale, the Barnes Akathisia Scale, the Simpson-Angus Scale, and the Arizona Sexual Experiences Scale. Results: After a 1-week placebo run-in, quetiapine was started at a daily dosage of 25 mg and increased to a maximum of 800 mg; the average was 258 mg (range, 50-800 mg). Reductions in CAPS total, re-experiencing, and hyperarousal scores were significantly greater for the quetiapine group than for the placebo group. Greater improvements were also observed for quetiapine in scores on the Davidson Trauma Scale, CGI severity and improvement ratings, PANSS positive symptom and general psychopathology subscales, HAM-A, and HAM-D than for placebo. Adverse events were generally mild and expected based on prior studies of quetiapine in this and other patient population. There were no differences in safety measures between groups. Conclusion: Quetiapine monotherapy was efficacious in the treatment of PTSD. These findings suggest quetiapine as a single agent is effective in treating military PTSD. C1 [Hamner, Mark B.] Raymond G Murphy VA Med Ctr, Behav Hlth Care Line, Albuquerque, NM 87108 USA. Univ New Mexico, Sch Med, Dept Psychiat, Albuquerque, NM 87131 USA. Univ New Mexico, Sch Med, Dept Neurosci, Albuquerque, NM 87131 USA. Biomed Res Inst New Mexico, Albuquerque, NM USA. Med Univ South Carolina, Dept Psychiat & Behav Sci, Charleston, SC 29425 USA. Med Univ South Carolina, Dept Biometry & Biostat, Charleston, SC 29425 USA. Ralph H Johnson VA Med Ctr, Mental Hlth Serv, Charleston, SC USA. RP Hamner, MB (reprint author), Raymond G Murphy VA Med Ctr, Behav Hlth Care Line, Albuquerque, NM 87108 USA. EM hamnermb@musc.edu FU AstraZeneca; Alkermes; Pfizer; Abbott; Bristol-Myers Squibb; Eli Lilly; Forest Laboratories; Janssen; Lundbeck; Organon; Sanofi-Synthlabo FX Funded by an investigator-initiated grant from AstraZeneca to Dr. Hamner.; Dr. Hamner has current research support from Alkermes and Pfizer; he has been the recipient of research grant support or honoraria and/or has served as a consultant for the following pharmaceutical companies: Abbott, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Forest Laboratories, Janssen, Lundbeck, Organon, Otsuka, and Sanofi-Synthlabo Dr. Canive has received research grant support or honoraria and/or has served as a consultant for the following pharmaceutical companies: Abbott, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Organon, Otsuka, and Sanofi-Synthlabo. The other authors report no financial relationships with commercial interests. NR 35 TC 2 Z9 2 U1 3 U2 3 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 DEC PY 2016 VL 173 IS 12 BP 1205 EP 1212 DI 10.1176/appi.ajp.2016.15070967 PG 8 WC Psychiatry SC Psychiatry GA ED7CB UT WOS:000389012200010 PM 27418378 ER PT J AU Guenette, JP Tirumani, H Keraliya, AR Shinagare, AB Ramaiya, NH Jagannathan, JP AF Guenette, Jeffrey P. Tirumani, Harsha Keraliya, Abhishek R. Shinagare, Atul B. Ramaiya, Nikhil H. Jagannathan, Jyothi P. TI MRI Findings in Patients With Leukemia and Positive CSF Cytology: A Single-Institution 5-Year Experience SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE chloroma; CNS; CSF; leukemia; myeloid sarcoma ID CENTRAL-NERVOUS-SYSTEM; ACUTE MYELOID-LEUKEMIA; HEMATOLOGIC MALIGNANCIES; RISK-FACTORS; INVOLVEMENT; DIAGNOSIS; ADULTS; SARCOMA AB OBJECTIVE. The purposes of this study were to describe the spectrum of MRI findings and determine the prognostic role of MRI in adults with acute leukemia with positive CSF cytology. MATERIALS AND METHODS. In this retrospective study of 34 patients (19 women, 15 men; mean age, 51 years; range, 18-72 years) treated for CNS leukemia between 2006 and 2011, 31 (91%) contrast-enhanced brain and 14 (41%) spine MRI studies were reviewed by two radiologists to note patterns of enhancement. Interobserver agreement and correlation of enhancement with outcome were analyzed. RESULTS. MRI showed abnormal findings in 25 patients (74%). Pachymeningeal enhancement (n = 9/31, 29%), leptomeningeal enhancement (n = 6/31, 19%), cranial nerve enhancement (n = 9/31,29%), masslike enhancement (n = 3/31, 10%), and spinal meningeal enhancement (n = 10/14, 71%) were identified. There was strong interobserver agreement (kappa = 0.906). Survival rates were shorter to a statistically significant degree with pachymeningeal enhancement (median, 7 months; interquartile range [IQR], 5-8 months versus median, 26 months; IQR, 15 months to not reached; p = 0.004) and two or more sites of enhancement (median, 8 months; IQR, 3-13 months versus median, 19 months; IQR, 9 months to not reached; p = 0.046). CONCLUSION. Brain or spine MRI examinations (or both) showed abnormal findings in nearly three-fourths of adults with acute leukemia with positive CSF cytology who were imaged for neurologic symptoms. Pachymeningeal enhancement and two or more sites of brain involvement were associated with shorter survival. C1 [Guenette, Jeffrey P.; Tirumani, Harsha; Keraliya, Abhishek R.; Shinagare, Atul B.; Ramaiya, Nikhil H.; Jagannathan, Jyothi P.] Harvard Med Sch, Brigham & Womens Hosp, Dept Radiol, 75 Francis St, Boston, MA 02115 USA. [Tirumani, Harsha; Shinagare, Atul B.; Ramaiya, Nikhil H.; Jagannathan, Jyothi P.] Harvard Med Sch, Dana Farber Canc Inst, Dept Imaging, Boston, MA USA. RP Guenette, JP (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Dept Radiol, 75 Francis St, Boston, MA 02115 USA. EM jpguenette@bwh.harvard.edu FU Radiological Society of North America research grant FX A. B. Shinagare is a recipient of a Radiological Society of North America research grant that began in July 2014. NR 17 TC 0 Z9 0 U1 1 U2 1 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X EI 1546-3141 J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD DEC PY 2016 VL 207 IS 6 BP 1278 EP 1282 DI 10.2214/AJR.16.16221 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA ED2MS UT WOS:000388681400027 PM 27611654 ER PT J AU Agrawal, MD Oliveira, GR Kalva, SP Pinho, DF Arellano, RS Sahani, DV AF Agrawal, Mukta D. Oliveira, George R. Kalva, Sanjeeva P. Pinho, Daniella F. Arellano, Ronald S. Sahani, Dushyant V. TI Prospective Comparison of Reduced-Iodine-Dose Virtual Monochromatic Imaging Dataset From Dual-Energy CT Angiography With Standard-Iodine-Dose Single-Energy CT Angiography for Abdominal Aortic Aneurysm SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE abdominal aortic aneurysm; CT angiography; dual-energy CT; low iodine dose; virtual monochromatic imaging ID COMPUTED-TOMOGRAPHY ANGIOGRAPHY; ENDOVASCULAR REPAIR; INITIAL-EXPERIENCE; CONTRAST MATERIAL; MULTIDETECTOR CT; RANDOMIZED-TRIAL; KEV-SETTINGS; OPTIMIZATION; ENHANCEMENT; ENDOLEAKS AB OBJECTIVE. The purpose of this study was to compare the image quality of reduced-iodine-dose single-source dual-energy CT angiography (CTA) with that of standard-iodine-dose single-energy CTA in examinations of patients with abdominal aortic aneurysm and to assess the effect of the concentration of iodinated contrast medium on intravascular enhancement and image quality of reduced-iodine-dose CTA. SUBJECTS AND METHODS. In a prospective randomized clinical trial, 66 consecutively registered patients with abdominal aortic aneurysm who had previously undergone single-energy CTA (30-37 g I) underwent follow-up CTA at a reduced dose (21-27 g I) of iodinated contrast medium of either 270 mg I/mL (n = 33) or 320 mg I/mL (n = 33). Two readers independently evaluated virtual monochromatic imaging datasets (40-140 keV) and single-energy CTA images for image quality and noise and their preference for optimal energy virtual monochromatic imaging dataset. A value of p < 0.05 was considered statistically significant. RESULTS. All 66 dual-energy CTA examinations were rated diagnostic with mean image quality and image noise scores of 4.8 and 4.5 for reader 1 and 3.8 and 3.4 for reader 2 compared with single-energy CTA results of 4.5 and 4.2 for reader 1 and 4.5 and 4.1 for reader 2. Low-energy virtual monochromatic images (40-60 keV) from reduced-iodine-dose (28%) dual-energy CTA had significantly higher intravascular aortic attenuation (26-185%) and contrast-to-noise ratio (CNR) (20-25%) than standard-iodine-dose single-energy CTA images (p < 0.0001). No significant difference was found between patients who received 270 and those who received 320 mg I/mL with respect to intravascular aortic attenuation (p = 0.6331) or CNR (p = 0.9775). CONCLUSION. Low-energy virtual monochromatic imaging datasets from reduced-iodine (24 g I) single-source dual-energy CTA of the abdomen provide up to 185% higher attenuation and 25% higher CNR than standard-iodine-dose (33.3 g I) single-energy CTA while offering a wide range of energy settings irrespective of the concentration of IV contrast medium used. C1 [Agrawal, Mukta D.] Brigham & Womens Hosp, Dept Radiol, 75 Francis St, Boston, MA 02115 USA. [Oliveira, George R.; Arellano, Ronald S.; Sahani, Dushyant V.] Massachusetts Gen Hosp, Dept Abdominal Imaging & Intervent Radiol, 55 Fruit St,White Bldg,Rm 270, Boston, MA 02114 USA. [Kalva, Sanjeeva P.; Pinho, Daniella F.] Univ Texas Southwestern Med Ctr Dallas, Dept Intervent Radiol, Dallas, TX 75390 USA. RP Sahani, DV (reprint author), Massachusetts Gen Hosp, Dept Abdominal Imaging & Intervent Radiol, 55 Fruit St,White Bldg,Rm 270, Boston, MA 02114 USA. EM dsahani@partners.org FU GE Healthcare FX D. V. Sahani and Massachusetts General Hospital have received a research grant from GE Healthcare. NR 44 TC 1 Z9 1 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 DEC PY 2016 VL 207 IS 6 BP W125 EP W132 DI 10.2214/AJR.15.15814 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA ED2MS UT WOS:000388681400004 PM 27610820 ER PT J AU Koselny, K Green, J DiDone, L Halterman, JP Fothergill, AW Wiederhold, NP Patterson, TF Cushion, MT Rappelye, C Wellington, M Krysan, DJ AF Koselny, Kristy Green, Julianne DiDone, Louis Halterman, Justin P. Fothergill, Annette W. Wiederhold, Nathan P. Patterson, Thomas F. Cushion, Melanie T. Rappelye, Chad Wellington, Melanie Krysan, Damian J. TI The Celecoxib Derivative AR-12 Has Broad-Spectrum Antifungal Activity In Vitro and Improves the Activity of Fluconazole in a Murine Model of Cryptococcosis SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID ACETYL-COA SYNTHETASE; CANDIDA-ALBICANS; FUNGAL-INFECTIONS; SACCHAROMYCES-CEREVISIAE; DRUG-RESISTANCE; YEAST; NEOFORMANS; COMBINATION; MENINGITIS; COENZYME AB Only one new class of antifungal drugs has been introduced into clinical practice in the last 30 years, and thus the identification of small molecules with novel mechanisms of action is an important goal of current anti-infective research. Here, we describe the characterization of the spectrum of in vitro activity and in vivo activity of AR-12, a celecoxib derivative which has been tested in a phase I clinical trial as an anticancer agent. AR-12 inhibits fungal acetyl coenzyme A (acetyl-CoA) synthetase in vitro and is fungicidal at concentrations similar to those achieved in human plasma. AR-12 has a broad spectrum of activity, including activity against yeasts (e.g., Candida albicans, non-albicans Candida spp., Cryptococcus neoformans), molds (e.g., Fusarium, Mucor), and dimorphic fungi (Blastomyces, Histoplasma, and Coccidioides) with MICs of 2 to 4 mu g/ml. AR-12 is also active against azole- and echinocandin-resistant Candida isolates, and subinhibitory AR-12 concentrations increase the susceptibility of fluconazole- and echinocandin-resistant Candida isolates. Finally, AR-12 also increases the activity of fluconazole in a murine model of cryptococcosis. Taken together, these data indicate that AR-12 represents a promising class of small molecules with broad-spectrum antifungal activity. C1 [Koselny, Kristy; Green, Julianne; DiDone, Louis; Halterman, Justin P.; Wellington, Melanie; Krysan, Damian J.] Univ Rochester, Dept Pediat, Rochester, NY 14611 USA. [Krysan, Damian J.] Univ Rochester, Dept Immunol Microbiol, Rochester, NY 14611 USA. [Fothergill, Annette W.; Wiederhold, Nathan P.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78229 USA. [Patterson, Thomas F.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Patterson, Thomas F.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. [Cushion, Melanie T.] Univ Cincinnati, Coll Med, Dept Internal Med, Cincinnati, OH USA. [Rappelye, Chad] Ohio State Univ, Dept Microbiol, Columbus, OH 43210 USA. RP Krysan, DJ (reprint author), Univ Rochester, Dept Pediat, Rochester, NY 14611 USA. EM damian_krysan@urmc.rochester.edu FU HHS \ National Institutes of Health (NIH) [1R01AI097142, 5K12HD068373, HHS272201000018I] FX This work, including the efforts of Damian J. Krysan, was funded by HHS vertical bar National Institutes of Health (NIH) (1R01AI097142). This work, including the efforts of Julianne Green, was funded by HHS vertical bar National Institutes of Health (NIH) (5K12HD068373). This work, including the efforts of Thomas F. Patterson, was funded by HHS vertical bar National Institutes of Health (NIH) (HHS272201000018I). NR 55 TC 1 Z9 1 U1 3 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD DEC PY 2016 VL 60 IS 12 BP 7115 EP 7127 DI 10.1128/AAC.01061-16 PG 13 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA ED7QO UT WOS:000389064300012 PM 27645246 ER PT J AU Duan, Q Xiao, Y Zhu, LY Liu, ZZ Mao, XX Zhou, ZX Liao, CN Cai, JX Huang, FL Liu, ZH Zeng, J Xia, K Chang, C Qi, J Chen, ZH Huang, H Yang, TL AF Duan, Qiong Xiao, Yi Zhu, Lingyan Liu, Zhenzhen Mao, Xiaoxiao Zhou, Zhengxiang Liao, Chaonan Cai, Jinxing Huang, Fulian Liu, Zehao Zeng, Jian Xia, Ke Chang, Cheng Qi, Jun Chen, Zihua Huang, He Yang, Tianlun TI BET bromodomain is a novel regulator of TAZ and its activity SO BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS LA English DT Article DE Bromodomain and extra-terminal; domain protein (BET); TAZ; beta-Catenin; Colon cancer ID HIPPO PATHWAY; COLORECTAL-CANCER; PROTEIN BRD4; STEM-CELL; P-TEFB; INHIBITION; YAP/TAZ; GROWTH; TRANSCRIPTION; SENSITIVITY AB Transcriptional coactivator with PDZ-binding motif (TAZ) is a key transcriptional mediator of Hippo signaling that has been recently reported to mediate Wnt-activated transcription and serve as a component to suppress canonical Wnt/beta-catenin activity. The Bromodomain and Extra-terminal domain (BET) family of proteins can recognize the acetylated lysine chain on histones and plays a critical role in transcriptional regulation. However, the mechanisms underlying transcriptional repression by the BET bromodomain are poorly understood. Here, we found that BET bromodomain inhibition upregulated TAZ protein and its transcriptional output, independent of its well-established role as a mediator of Hippo and Wnt signaling. Additionally, JQ1, a synthetic BET inhibitor, suppressed Wnt/beta-catenin activity by upregulating TAZ. Although JQ1 upregulated TAZ, which is known to promote cell proliferation, it drastically suppressed the growth of colon cancer cells by inducing cell cycle arrest. Collectively, our study identified an unexpected transcriptional repression function of the BET bromodomain and a novel mechanism for TAZ upregulation. (C) 2016 Elsevier B.V. All rights reserved. C1 [Duan, Qiong; Xiao, Yi; Liu, Zhenzhen; Mao, Xiaoxiao; Zhou, Zhengxiang; Xia, Ke; Yang, Tianlun] Cent S Univ, Xiangya Hosp, Div Cardiovasc, 87 Xiangya Rd, Changsha 410078, Hunan, Peoples R China. [Zhu, Lingyan] Nanchang Univ, Affiliated Hosp 1, Dept Endocrinol, Nanchang, Peoples R China. [Mao, Xiaoxiao] Harvard Med Sch, Brigham & Womens Hosp, Div Cardiovasc, Boston, MA USA. [Liao, Chaonan; Cai, Jinxing; Huang, He] Cent S Univ, Xiangya Sch Med, Dept Histol & Embryol, 172 Tongzipo Rd, Changsha 410008, Hunan, Peoples R China. [Huang, Fulian] Cent S Univ, Xiangya Sch Med, Dept Anat & Neurosci, Changsha, Hunan, Peoples R China. [Liu, Zehao] Cent S Univ, Xiangya Hosp, Div Endocrinol, Changsha, Hunan, Peoples R China. [Zeng, Jian] Yiyang Cent Hosp, Dept Thorac Surg, Yiyang, Peoples R China. [Chang, Cheng] MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Qi, Jun] Harvard Med Sch, Dept Med Oncol, Dana Farber Canc Inst, Boston, MA USA. [Chen, Zihua] Cent S Univ, Xiangya Hosp, Dept Gen Surg, 87 Xiangya Rd, Changsha 410078, Hunan, Peoples R China. [Huang, He] Xinjiang Med Univ, Affiliated Hosp 2, Digest Canc Lab, Urumqi 830063, Peoples R China. RP Yang, TL (reprint author), Cent S Univ, Xiangya Hosp, Div Cardiovasc, 87 Xiangya Rd, Changsha 410078, Hunan, Peoples R China.; Huang, H (reprint author), Cent S Univ, Xiangya Sch Med, Dept Histol & Embryol, 172 Tongzipo Rd, Changsha 410008, Hunan, Peoples R China.; Chen, ZH (reprint author), Cent S Univ, Xiangya Hosp, Dept Gen Surg, 87 Xiangya Rd, Changsha 410078, Hunan, Peoples R China. EM zihuac@outlook.com; huanghe@csu.edu.cn; tianluny@163.com FU National Natural Science Foundation of China [81370320, 81570334, 81141068, 31571241]; Xiangya Eminent Doctor Project [013]; Zijing Foundation [2014-0016] FX We are grateful to Dr. Weihong Tan for critically reading the manuscript. We thank Fan Xia for excellent technical support and Xiong Xiao for assistance with image editing. This work was supported by the National Natural Science Foundation of China (81370320, 81570334 (TL Yang), and 81141068, 31571241(H Huang)), Xiangya Eminent Doctor Project #013 (TL Yang), and the Zijing Foundation (2014-0016) (Q Duan). NR 47 TC 1 Z9 1 U1 10 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1874-9399 EI 0006-3002 J9 BBA-GENE REGUL MECH JI Biochim. Biophys. Acta-Gene Regul. Mech. PD DEC PY 2016 VL 1859 IS 12 BP 1527 EP 1537 DI 10.1016/j.bbagrm.2016.10.001 PG 11 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA ED8FH UT WOS:000389106900005 PM 27717711 ER PT J AU Kharfan-Dabaja, MA Kumar, A Hamadani, M Stilgenbauer, S Ghia, P Anasetti, C Dreger, P Montserrat, E Perales, MA Alyea, EP Awan, FT Ayala, E Barrientos, JC Brown, JR Castro, JE Furman, RR Gribben, J Hill, BT Mohty, M Moreno, C O'Brien, S Pavletic, SZ Pinilla-Ibarz, J Reddy, NM Sorror, M Bredeson, C Carpenter, P Savani, BN AF Kharfan-Dabaja, Mohamed A. Kumar, Ambuj Hamadani, Mehdi Stilgenbauer, Stephan Ghia, Paolo Anasetti, Claudio Dreger, Peter Montserrat, Emili Perales, Miguel-Angel Alyea, Edwin P. Awan, Farrukh T. Ayala, Ernesto Barrientos, Jacqueline C. Brown, Jennifer R. Castro, Januario E. Furman, Richard R. Gribben, John Hill, Brian T. Mohty, Mohamad Moreno, Carol O'Brien, Susan Pavletic, Steven Z. Pinilla-Ibarz, Javier Reddy, Nishitha M. Sorror, Mohamed Bredeson, Christopher Carpenter, Paul Savani, Bipin N. TI Clinical Practice Recommendations for Use of Allogeneic Hematopoietic Cell Transplantation in Chronic Lymphocytic Leukemia on Behalf of the Guidelines Committee of the American Society for Blood and Marrow Transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Chronic lymphocytic leukemia; Allogeneic hematopoietic cell transplantation; BCR inhibitors; BCL-2 inhibitors ID RICHTER-SYNDROME; REDUCED-INTENSITY; FLOW-CYTOMETRY; 17P DELETION; FOLLOW-UP; MUTATIONAL STATUS; PERIPHERAL-BLOOD; BONE-MARROW; SINGLE-ARM; CLL AB We sought to establish clinical practice recommendations to redefine the role of allogeneic hematopoietic cell transplantation (allo-HCT) for patients with chronic lymphocytic leukemia (CLL) in an era of highly active targeted therapies. We performed a systematic review to identify prospective randomized controlled trials comparing allo-HCT against novel therapies for treatment of CLL at various disease stages. In the absence of such data, we invited physicians with expertise in allo-HCT and/or CLL to participate in developing these recommendations. We followed the Grading of Recommendations Assessment, Development and Evaluation methodology. For standard-risk CLL we recommend allo-HCT in the absence of response or if there is evidence of disease progression after B cell receptor (BCR) inhibitors. For high-risk CLL an allo-HCT is recommended after failing 2 lines of therapy and showing an objective response to BCR inhibitors or to a clinical trial. It is also recommended for patients who fail to show an objective response or progress after BCR inhibitors and receive BCL-2 inhibitors, regardless of whether an objective response is achieved. For Richter transformation, we recommend allo-HCT upon demonstration of an objective response to anthracycline-based chemotherapy. A reduced-intensity conditioning regimen is recommended whenever indicated. These recommendations high-light the rapidly changing treatment landscape of CLL. Newer therapies have disrupted prior paradigms, and allo-HCT is now relegated to later stages of relapsed or refractory CLL. (C) 2016 American Society for Blood and Marrow Transplantation. C1 [Kharfan-Dabaja, Mohamed A.; Anasetti, Claudio; Ayala, Ernesto] H Lee Moffitt Canc Ctr & Res Inst, Dept Blood & Marrow Transplantat, Tampa, FL USA. [Kharfan-Dabaja, Mohamed A.; Anasetti, Claudio; Ayala, Ernesto; Pinilla-Ibarz, Javier] Univ S Florida, Morsani Coll Med, Dept Oncol Sci, Tampa, FL USA. [Kumar, Ambuj] Univ S Florida, Coll Med, Program Comparat Effectiveness Res, Tampa, FL USA. [Hamadani, Mehdi] Med Coll Wisconsin, Div Hematol Oncol, Milwaukee, WI 53226 USA. [Stilgenbauer, Stephan] Univ Ulm, Internal Med 3, Ulm, Germany. [Ghia, Paolo] IRCCS San Raffaele Hosp, Dept Oncohaematol, Milan, Italy. [Ghia, Paolo] IRCCS San Raffaele Hosp, Div Expt Oncol, Milan, Italy. [Ghia, Paolo] Univ Vita Salute San Raffaele, Milan, Italy. [Dreger, Peter] Heidelberg Univ, Dept Med 5, Heidelberg, Germany. [Montserrat, Emili] Univ Barcelona, Hosp Clin Barcelona, Dept Hematol, Barcelona, Spain. [Perales, Miguel-Angel] Mem Sloan Kettering Canc Ctr, Dept Med, Adult Bone Marrow Transplant Serv, 1275 York Ave, New York, NY 10021 USA. [Alyea, Edwin P.; Brown, Jennifer R.] Dana Farber Canc Inst, Med Oncol, Boston, MA 02115 USA. [Awan, Farrukh T.] Ohio State Univ, Ctr Comprehens Canc, Dept Internal Med, Div Hematol, Columbus, OH 43210 USA. [Barrientos, Jacqueline C.] Hofstra Northwell Sch Med, CLL Res & Treatment Program, New Hyde Pk, NY USA. [Castro, Januario E.] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. [Furman, Richard R.] Weill Cornell Med Coll, Div Hematol Oncol, New York, NY USA. [Gribben, John] Queen Mary Univ London, John Vane Canc Ctr, Barts Canc Inst, Charterhouse Sq, London, England. [Hill, Brian T.] Cleveland Clin, Dept Hematol & Med Oncol, Taussig Canc Inst, Cleveland, OH 44106 USA. [Mohty, Mohamad] Univ Paris 06, St Antoine Hosp, Dept Haematol, Paris, France. [Mohty, Mohamad] INSERM, UMRs938, Paris, France. [Moreno, Carol] Hosp Santa Creu St Pau, Barcelona, Spain. [O'Brien, Susan] Univ Calif Irvine, Chao Family Comprehens Canc Ctr, Orange, CA 92668 USA. [Pavletic, Steven Z.] NCI, NIH, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. [Pinilla-Ibarz, Javier] H Lee Moffitt Canc Ctr & Res Inst, Dept Malignant Hematol, Tampa, FL USA. [Reddy, Nishitha M.; Savani, Bipin N.] Vanderbilt Univ, Sch Med, Dept Med, Div Hematol Oncol, Nashville, TN 37212 USA. [Sorror, Mohamed; Carpenter, Paul] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. [Sorror, Mohamed; Carpenter, Paul] Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA. [Bredeson, Christopher] Ottawa Hosp, Blood & Marrow Transplant Program, Ottawa, ON, Canada. [Bredeson, Christopher] Ottawa Hosp Res Inst, Ottawa, ON, Canada. RP Kharfan-Dabaja, MA (reprint author), H Lee Moffitt Canc Ctr & Res Inst, Dept Blood & Marrow Transplantat, 12902 Magnolia Dr,FOB 3, Tampa, FL 33612 USA. EM Mohamed.Kharfan-Dabaja@Moffitt.org FU Takeda Oncology; Sanofi; Otsuka; AbbVie; Amgen; Boehringer-Ingelheim; Celgene; Genentech; Genzyme; Gilead; GlaxoSmithKline; Janssen; Mundipharma; Novartis; Pharmacyclics; Hoffmann La-Roche; GSK; Roche; Acerta; TG Therapeutics; Regeneron; ProNAi FX The authors have nothing to disclose. Conflict of interest statement: M.H.: Research funding by Takeda Oncology, Sanofi, and Otsuka; Honoraria from Celgene; Consultancy by Medimmune, Pharmacyclics and Cellerant. S.S.: Honoraria for consultancy, research support, and travel support from AbbVie, Amgen, Boehringer-Ingelheim, Celgene, Genentech, Genzyme, Gilead, GlaxoSmithKline, Janssen, Mundipharma, Novartis, Pharmacyclics, Hoffmann La-Roche, and Sanofi. P.G.: Advisory board for AbbVie, Adaptive Biotechnologies, Gilead, Janssen, Pharmacyclics, and Roche; Research funding from Gilead, GSK, and Roche. P.D.: Research support from Janssen and and Gilead; Honoraria for speaker and advisory board services from Janssen, Gilead, Novartis, and Roche. F.T.A.: Advisory boards for Gilead and Novartis Oncology. J.G.: Honoraria from Janssen, Roche/Genentech, Abbie, Pharmacyclics, Gilead, and Celgene. B.T.H.: Advisory boards for Pharmacyclics and Gilead; Research funding from Abbvie. M.M.: Honoraria for speaking engagements and research support from Janssen. S.O.: Consultant for Amgen, Celgene, and GSK; Advisory board for CLL Global Research Foundation; Research support from Acerta, TG Therapeutics, Regeneron, Gilead, Pharmacyclics, and ProNAi. J.P.-I.: Consultant for Janssen, Gilead, Pharmacyclics, Abbvie, and Celgene; Speaker Bureau for TEVA, Pharmacyclics, and Gilead. N.M.R.: Advisory boards of AbbVie and Gilead. All other authors report no conflicts of interest. NR 76 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD DEC PY 2016 VL 22 IS 12 BP 2117 EP 2125 DI 10.1016/j.bbmt.2016.09.013 PG 9 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA ED8CM UT WOS:000389099600003 PM 27660167 ER PT J AU DeFilipp, Z Chen, YB AF DeFilipp, Zachariah Chen, Yi-Bin TI Strategies and Challenges for Pharmacological Maintenance Therapies after Allogeneic Hematopoietic Cell Transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Review DE Maintenance; Allogeneic; Transplantation; Pre-emptive ID ACUTE MYELOID-LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; VERSUS-HOST-DISEASE; RISK MYELODYSPLASTIC SYNDROMES; CHROMOSOME-POSITIVE LEUKEMIA; INTERNAL TANDEM DUPLICATION; IMPROVES CLINICAL-OUTCOMES; ACUTE MYELOGENOUS LEUKEMIA; MINIMAL RESIDUAL DISEASE; LOW-DOSE AZACITIDINE AB Disease relapse is a major barrier to successful allogeneic hematopoietic cell transplantation (HCT). Maintenance therapy administered after HCT is a promising strategy to attempt to reduce relapse and improve overall survival. However, many questions and challenges remain regarding this approach, including which patients should receive maintenance therapy, which agents should be used, what the ideal duration of therapy is, and what effect specific agents will have on toxicities, immunological reconstitution and graft-versus-host disease. Clinical trials are ongoing, which should help begin to address some of these issues and it is imperative that the transplantation community continues to collaborate in such trials to best answer these questions. (C) 2016 American Society for Blood and Marrow Transplantation. C1 [DeFilipp, Zachariah; Chen, Yi-Bin] Harvard Med Sch, Massachusetts Gen Hosp, Blood & Marrow Transplant Program, Yawkey 9E-9052,55 Fruit St, Boston, MA 02114 USA. RP Chen, YB (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Blood & Marrow Transplant Program, Yawkey 9E-9052,55 Fruit St, Boston, MA 02114 USA. EM ychen6@partners.org FU Millennium; Bayer; Incyte; Seattle Genetics FX Z.D. declares no relevant conflicts of interest. Y.-B.C. has received consulting fees from Millennium, Bayer, Incyte, and Seattle Genetics. NR 59 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 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD DEC PY 2016 VL 22 IS 12 BP 2134 EP 2140 DI 10.1016/j.bbmt.2016.08.021 PG 7 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA ED8CM UT WOS:000389099600005 PM 27567491 ER PT J AU Onibokun, O Boatin, A Diouf, K AF Onibokun, Oluwatosin Boatin, Adeline Diouf, Khady TI The Role of Minimally Invasive Gynecologic Surgery in Sub Saharan Africa SO CURRENT OBSTETRICS AND GYNECOLOGY REPORTS LA English DT Article DE Africa; Laparoscopy; Gynecology; Minimally invasive; Surgery; Challenges ID LAPAROSCOPIC SURGERY; DIAGNOSTIC LAPAROSCOPY; DEVELOPING-COUNTRIES; ECTOPIC PREGNANCY; UTERINE LEIOMYOMA; EXPERIENCE; MANAGEMENT; HYSTERECTOMY; PROGRAMS; OUTCOMES AB Minimally invasive gynecologic surgery (MIGS) is now firmly established in developed countries where there has been a trend away from traditional open surgery towards laparoscopy given proven benefits of faster recovery time and better cosmesis for patients. However, this same trend has not been observed in regions like sub Saharan Africa (SSA) where resources are limited. Lack of human and material resources, need for technological support, and challenges with training have been postulated as major limitations for wide spread introduction and expansion of MIGS in SSA. Nonetheless, a few institutions in sub Saharan Africa have been able to surmount these challenges to develop MIGS in SSA. This paper reviews the current state of minimally invasive surgery in sub Saharan Africa. We review the role and benefits of expanding minimally invasive surgery in sub Saharan Africa with a focus on management of gynecologic conditions. Finally, we review the challenges associated with MIGS in SSA and provide recommendations on the way forward. There are several published studies on the successful development of minimally invasive surgery in sub -Saharan Africa with similar benefits of shorter hospital stay, quicker recovery, and better cosmesis for patients. These studies also report the challenges with human and material resources and training. There is a large role and need for expansion of minimally invasive surgery in sub Saharan Africa. The challenges of lack of resources, personnel, and training can be surmountable through ingenuity, modeling based on experiences from other low to middle income countries and commitment to the advancement of MIGS for the benefit of women's health globally. C1 [Onibokun, Oluwatosin; Diouf, Khady] Brigham & Womens Hosp, Dept Obstet & Gynecol, 75 Francis St, Boston, MA 02215 USA. [Onibokun, Oluwatosin; Boatin, Adeline] Massachusetts Gen Hosp, Dept Obstet & Gynecol, 55 Fruit St, Boston, MA 02114 USA. RP Onibokun, O (reprint author), Brigham & Womens Hosp, Dept Obstet & Gynecol, 75 Francis St, Boston, MA 02215 USA.; Onibokun, O (reprint author), Massachusetts Gen Hosp, Dept Obstet & Gynecol, 55 Fruit St, Boston, MA 02114 USA. EM Oluwatosin.onibokun@gmail.com NR 58 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 2161-3303 J9 CURR OBSTET GYNECOL JI CURR. OBSTET. GYNECOL. REP. PD DEC PY 2016 VL 5 IS 4 BP 333 EP 340 DI 10.1007/s13669-016-0184-9 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA ED5YO UT WOS:000388930200008 ER PT J AU Riggio, S Jagoda, A AF Riggio, Silvana Jagoda, Andy TI Concussion and its neurobehavioural sequelae SO INTERNATIONAL REVIEW OF PSYCHIATRY LA English DT Article DE Concussion; mild traumatic brain injury; post-concussive syndrome; head computed tomography; neuropsychologic testing ID TRAUMATIC BRAIN-INJURY; POSTTRAUMATIC-STRESS-DISORDER; CHRONIC PAIN; PSYCHIATRIC-DISORDERS; HEAD-INJURY; ASSOCIATION; SYMPTOMS; RISK; CLASSIFICATION; ADOLESCENTS AB A concussion results from a force to the brain that results in a transient loss of connectivity within the brain. Sport psychiatrists are increasingly called to be part of the concussion team and need to be prepared to manage issues related to concussion and its behavioural sequelae. Objectively, the best evidence available suggests that deficits in attention and/or in balance are the most reliable objective findings that a concussion has occurred. Prognosis after a concussion is generally very good, although a sub-set of patients that are yet well defined seem pre-disposed to delayed recovery. Neither head CT nor MRI are sufficiently sensitive to diagnose the type of injuries that pre-dispose patients to the neurobehavioural sequelae that have been associated with a concussion; confounding this is the finding that many of these signs and symptoms associated with concussion occur in other types of non-head injuries. Brain biomarkers and functional MRI ( fMRI) hold promise in both diagnosis and prognosis of concussion, but are still research tools without validated clinical utility at this time. Finally, neurocognitive testing holds promise as a diagnostic criterion to demonstrate injury but, unfortunately, these tests are also limited in their prognostic utility and are of limited value. C1 [Riggio, Silvana] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Riggio, Silvana] Icahn Sch Med Mt Sinai, Dept Neurol, New York, NY 10029 USA. [Riggio, Silvana] James J Peters Vet Adm, Dept Psychiat, Bronx, NY USA. [Jagoda, Andy] Icahn Sch Med Mt Sinai, Dept Emergency Med, New York, NY 10029 USA. RP Riggio, S (reprint author), Mt Sinai, Dept Psychiat, One Gustave Levy Pl, New York, NY 10029 USA. EM silvana.riggio@mssm.edu NR 37 TC 0 Z9 0 U1 7 U2 7 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND SN 0954-0261 EI 1369-1627 J9 INT REV PSYCHIATR JI Int. Rev. Psych. PD DEC PY 2016 VL 28 IS 6 SI SI BP 579 EP 586 DI 10.1080/09540261.2016.1220927 PG 8 WC Psychiatry SC Psychiatry GA ED1HM UT WOS:000388595900007 PM 27671123 ER PT J AU Chiotos, K Vendetti, N Zaoutis, TE Baddley, J Ostrosky-Zeichner, L Pappas, P Fisher, BT AF Chiotos, Kathleen Vendetti, Neika Zaoutis, Theoklis E. Baddley, John Ostrosky-Zeichner, Luis Pappas, Peter Fisher, Brian T. TI Comparative effectiveness of echinocandins versus fluconazole therapy for the treatment of adult candidaemia due to Candida parapsilosis: a retrospective observational cohort study of the Mycoses Study Group (MSG-12) SO JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY LA English DT Article ID INFECTIOUS-DISEASES SOCIETY; INVASIVE CANDIDIASIS; IMPACT; EPIDEMIOLOGY; MANAGEMENT; OUTCOMES; AMERICA; UPDATE AB Objectives: A polymorphism in the gene encoding beta-1,3-glucan synthase, the target of the echinocandin class of antifungals, results in increased in vitro MICs of the echinocandins. This has resulted in controversy surrounding use of the echinocandins for treatment of Candida parapsilosis candidaemia. We aimed to compare 30 day mortality in adults with C. parapsilosis candidaemia treated with echinocandins versus fluconazole. Methods: This is a retrospective observational cohort study. We used the Premier Perspective Database to identify adult patients with C. parapsilosis candidaemia treated with only fluconazole or only an echinocandin as definitive therapy. The primary outcome was 30 day mortality. Propensity scores were derived to estimate the probability the patient would have received either an echinocandin or fluconazole. Inverse probability of treatment weighting (IPTW) was used in a weighted logistic regression to calculate odds of 30 day mortality. Results: There were 307 unique patients with C. parapsilosis candidaemia. One hundred and twenty-six (41%) received fluconazole and 181 (59%) received an echinocandin. Age, gender, race, year of admission, need for ICU resources in the week prior to candidaemia onset, and receipt of vasopressors on the day of candidaemia onset were included in the propensity score model used to calculate inverse probability of treatment weights. Weighted logistic regression demonstrated no difference in 30 day mortality between patients receiving an echinocandin as compared with fluconazole (OR 0.82, 95% CI 0.33-2.07). Conclusions: Our result supports the 2016 IDSA invasive candidiasis guidelines, which no longer clearly favour treatment with fluconazole over an echinocandin for C. parapsilosis candidaemia. C1 [Chiotos, Kathleen; Vendetti, Neika; Zaoutis, Theoklis E.; Fisher, Brian T.] Childrens Hosp Philadelphia, Div Infect Dis, Abramson Res Bldg,Room 1202,34th & Civ Ctr Blvd, Philadelphia, PA 19104 USA. [Chiotos, Kathleen] Childrens Hosp Philadelphia, Div Crit Care Med, Philadelphia, PA 19104 USA. [Chiotos, Kathleen; Vendetti, Neika; Zaoutis, Theoklis E.; Fisher, Brian T.] Childrens Hosp Philadelphia, Ctr Pediat Clin Effectiveness, Philadelphia, PA 19104 USA. [Zaoutis, Theoklis E.; Fisher, Brian T.] Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Baddley, John; Pappas, Peter] Univ Alabama Birmingham, Div Infect Dis, Birmingham, AL USA. [Baddley, John] Birmingham Vet Affairs Med Ctr, Med Serv, Birmingham, AL USA. [Ostrosky-Zeichner, Luis] Univ Texas Med Sch, Div Infect Dis, Houston, TX USA. RP Chiotos, K (reprint author), Childrens Hosp Philadelphia, Div Infect Dis, Abramson Res Bldg,Room 1202,34th & Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM chiotosk@email.chop.edu FU National Institutes of Health [T32HD060550] FX This work was supported by the National Institutes of Health (T32HD060550 to K. C.). NR 15 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-7453 EI 1460-2091 J9 J ANTIMICROB CHEMOTH JI J. Antimicrob. Chemother. PD DEC PY 2016 VL 71 IS 12 BP 3536 EP 3539 DI 10.1093/jac/dkw305 PG 4 WC Infectious Diseases; Microbiology; Pharmacology & Pharmacy SC Infectious Diseases; Microbiology; Pharmacology & Pharmacy GA ED4HT UT WOS:000388809300032 PM 27494929 ER PT J AU Balog, J Mehta, SL Vemuganti, R AF Balog, Justin Mehta, Suresh L. Vemuganti, Raghu TI Mitochondrial fission and fusion in secondary brain damage after CNS insults SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Review DE Apoptosis; fission; fusion; mitochondria; neuroprotection ID DYNAMIN-RELATED PROTEIN-1; OUTER-MEMBRANE PERMEABILIZATION; DOMINANT OPTIC ATROPHY; TRANSIENT CEREBRAL-ISCHEMIA; ALPHA-SYNUCLEIN; CELL-DEATH; ALZHEIMERS-DISEASE; PARKINSONS-DISEASE; OXIDATIVE STRESS; REACTIVE OXYGEN AB Mitochondria are dynamically active organelles, regulated through fission and fusion events to continuously redistribute them across axons, dendrites, and synapses of neurons to meet bioenergetics requirements and to control various functions, including cell proliferation, calcium buffering, neurotransmission, oxidative stress, and apoptosis. However, following acute or chronic injury to CNS, altered expression and function of proteins that mediate fission and fusion lead to mitochondrial dynamic imbalance. Particularly, if the fission is abnormally increased through pro-fission mediators such as Drp1, mitochondrial function will be impaired and mitochondria will become susceptible to insertion of proapototic proteins. This leads to the formation of mitochondrial transition pore, which eventually triggers apoptosis. Thus, mitochondrial dysfunction is a major promoter of neuronal death and secondary brain damage after an insult. This review discusses the implications of mitochondrial dynamic imbalance in neuronal death after acute and chronic CNS insults. C1 [Balog, Justin; Mehta, Suresh L.; Vemuganti, Raghu] Univ Wisconsin, Dept Neurol Surg, 600 Highland Ave, Madison, WI 53792 USA. [Vemuganti, Raghu] Univ Wisconsin, Neurosci Training Program, Madison, WI USA. [Vemuganti, Raghu] Univ Wisconsin, Cellular & Mol Pathol Training Program, Madison, WI USA. [Mehta, Suresh L.; Vemuganti, Raghu] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. RP Vemuganti, R (reprint author), Univ Wisconsin, Dept Neurol Surg, 600 Highland Ave, Madison, WI 53792 USA. EM vemuganti@neurosurgery.wisc.edu FU NIH [NS082957, NS083007, NS095192]; VA Merit Review Grant [I01BX002985] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The study was supported by NIH grants NS082957, NS083007, NS095192 and VA Merit Review Grant I01BX002985. NR 147 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0271-678X EI 1559-7016 J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD DEC PY 2016 VL 36 IS 12 BP 2022 EP 2033 DI 10.1177/0271678X16671528 PG 12 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA ED8RI UT WOS:000389138200002 PM 27677674 ER PT J AU Balmana, J Digiovanni, L Gaddam, P Walsh, MF Joseph, V Stadler, ZK Nathanson, KL Garber, JE Couch, FJ Offit, K Robson, ME Domchek, SM AF Balmana, Judith Digiovanni, Laura Gaddam, Pragna Walsh, Michael F. Joseph, Vijai Stadler, Zsofia K. Nathanson, Katherine L. Garber, Judy E. Couch, Fergus J. Offit, Kenneth Robson, Mark E. Domchek, Susan M. TI Conflicting Interpretation of Genetic Variants and Cancer Risk by Commercial Laboratories as Assessed by the Prospective Registry of Multiplex Testing SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CLINVAR PUBLIC ARCHIVE; BREAST-CANCER; CHEK2; SUSCEPTIBILITY; RECOMMENDATIONS; METAANALYSIS; MUTATIONS; GENOMICS; PROTEIN; I157T AB Purpose Massively parallel sequencing allows simultaneous testing of multiple genes associated with cancer susceptibility. Guidelines are available for variant classification; however, interpretation of these guidelines by laboratories and providers may differ and lead to conflicting reporting and, potentially, to inappropriate medical management. We describe conflicting variant interpretations between Clinical Laboratory Improvement Amendments-approved commercial clinical laboratories, as reported to the Prospective Registry of Multiplex Testing (PROMPT), an online genetic registry. Methods Clinical data and genetic testing results were gathered from 1,191 individuals tested for inherited cancer susceptibility and self-enrolled in PROMPT between September 2014 and October 2015. Overall, 518 participants (603 genetic variants) had a result interpreted by more than one laboratory, including at least one submitted to ClinVar, and these were used as the final cohort for the current analysis. Results Of the 603 variants, 221 (37%) were classified as a variant of uncertain significance (VUS), 191 (32%) as pathogenic, and 34 (6%) as benign. The interpretation differed among reporting laboratories for 155 (26%). Conflicting interpretations were most frequently reported for CHEK2 and ATM, followed by RAD51C, PALB2, BARD1, NBN, and BRIP1. Among all participants, 56 of 518 (11%) had a variant with conflicting interpretations ranging from pathogenic/likely pathogenic to VUS, a discrepancy that may alter medical management. Conclusions Conflicting interpretation of genetic findings from multiplex panel testing used in clinical practice is frequent and may have implications for medical management decisions. (C) 2016 by American Society of Clinical Oncology C1 [Balmana, Judith] Hosp Valle De Hebron, Barcelona, Spain. [Balmana, Judith] Univ Autonoma Barcelona, Barcelona, Spain. [Digiovanni, Laura; Nathanson, Katherine L.; Domchek, Susan M.] Univ Penn, Philadelphia, PA USA. [Gaddam, Pragna; Walsh, Michael F.; Joseph, Vijai; Stadler, Zsofia K.; Offit, Kenneth; Robson, Mark E.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Gaddam, Pragna; Walsh, Michael F.; Joseph, Vijai; Stadler, Zsofia K.; Offit, Kenneth; Robson, Mark E.] Weill Cornell Med Coll, New York, NY USA. [Garber, Judy E.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Couch, Fergus J.] Mayo Clin, Rochester, MN USA. RP Balmana, J (reprint author), Univ Autonoma Barcelona, Barcelona, Spain.; Balmana, J (reprint author), Hosp Valle De Hebron, Dept Med Oncol, Paseo Vall dHebron 119-129, Barcelona 08035, Spain.; Balmana, J (reprint author), Vall dHebron Inst Oncol, Paseo Vall dHebron 119-129, Barcelona 08035, Spain. EM jbalmana@vhio.net FU Sociedad Espanola de Oncologia Medica; Robert and Kate Niehaus Center for Inherited Cancer Genomics at Memorial Sloan Kettering Cancer Center; Breast Cancer Research Foundation; Susan G. Komen Foundation FX J.B. is a recipient of an award by Sociedad Espanola de Oncologia Medica. This project was supported also by the Robert and Kate Niehaus Center for Inherited Cancer Genomics at Memorial Sloan Kettering Cancer Center (M.E.R., M.F.W., K.O.), the Breast Cancer Research Foundation (S.M.D., M.E.R., K.O., F.C., J.G.), and the Susan G. Komen Foundation (S.M.D.). We thank Myriad, Ambry, Invitae, GeneDx, Color Genomics, Pathway Genomics, and Quest Diagnostics for their active collaboration with PROMPT NR 24 TC 4 Z9 4 U1 5 U2 5 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD DEC 1 PY 2016 VL 34 IS 34 BP 4071 EP + DI 10.1200/JCO.2016.68.4316 PG 10 WC Oncology SC Oncology GA ED5YM UT WOS:000388929900005 PM 27621404 ER PT J AU Gadgeel, SM Shaw, AT Govindan, R Gandhi, L Socinski, MA Camidge, DR De Petris, L Kim, DW Chiappori, A Moro-Sibilot, DL Duruisseaux, M Crino, L De Pas, T Dansin, E Tessmer, A Yang, JCH Han, JY Bordogna, W Golding, S Zeaiter, A Ou, SHI AF Gadgeel, Shirish M. Shaw, Alice T. Govindan, Ramaswamy Gandhi, Leena Socinski, Mark A. Camidge, D. Ross De Petris, Luigi Kim, Dong-Wan Chiappori, Alberto Moro-Sibilot, Denis L. Duruisseaux, Michael Crino, Lucio De Pas, Tommaso Dansin, Eric Tessmer, Antje Yang, James Chih-Hsin Han, Ji-Youn Bordogna, Walter Golding, Sophie Zeaiter, Ali Ou, Sai-Hong Ignatius TI Pooled Analysis of CNS Response to Alectinib in Two Studies of Pretreated Patients With ALK-Positive Non-Small-Cell Lung Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID BRAIN METASTASES; CRIZOTINIB; CERITINIB; RESISTANCE; DISEASE; SAFETY AB Purpose Alectinib has shown activity in the CNS in phase I and II studies. To further evaluate this activity, we pooled efficacy and safety data from two single-arm phase II studies (NP28761 and NP28673; ClinicalTrials.gov identifiers: NCT01871805 and NCT01801111, respectively) in patients with ALK-positive non-small-cell lung cancer (NSCLC). Patients and Methods Both studies included patients with ALK-positive NSCLC who had previously received crizotinib; all patients received alectinib 600 mg twice per day. The primary end point in both studies was independent review committee (IRC)-assessed objective response rate (ORR; by Response Evaluation Criteria in Solid Tumors [ RECIST] version 1.1). Additional end points (all by IRC) included CNS ORR (CORR), CNS disease control rate (CDCR), and CNS duration of response (CDOR). Results One hundred thirty-six patients had baseline CNS metastases (60% of the overall study populations); 50 patients (37%) had measurable CNS disease at baseline. Ninety-five patients (70%) had prior CNS radiotherapy; 55 patients completed the CNS radiotherapy more than 6 months before starting alectinib. Median follow-up time was 12.4 months (range, 0.9 to 19.7 months). For patients with baseline measurable CNS disease, IRC CORR was 64.0% (95% CI, 49.2% to 77.1%), CDCR was 90.0% (95% CI, 78.2% to 96.7%), and median CDOR was 10.8 months (95% CI, 7.6 to 14.1 months). For patients with measurable and/or nonmeasurable baseline CNS disease, IRC CORR was 42.6% (95% CI, 34.2% to 51.4%), CDCR was 85.3% (95% CI, 78.2% to 90.8%), and median CDOR was 11.1 months (95% CI, 10.3 months to not evaluable). CORR was 35.8% (95% CI, 26.2% to 46.3%) for patients with prior radiotherapy (n = 95) and 58.5% (95% CI, 42.1% to 73.7%) for patients without prior radiotherapy (n = 41). As previously reported, alectinib was well tolerated, regardless of baseline CNS disease. Conclusion Alectinib showed good efficacy against CNS metastases, in addition to systemic activity, in crizotinib-refractory ALK-positive NSCLC. (C) 2016 by American Society of Clinical Oncology C1 [Gadgeel, Shirish M.] Wayne State Univ, Karmanos Canc Inst, Detroit, MI 48202 USA. [Shaw, Alice T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Gandhi, Leena] Dana Farber Canc Inst, Boston, MA 02115 USA. [Govindan, Ramaswamy] Washington Univ, Sch Med, St Louis, MO USA. [Socinski, Mark A.] Univ Pittsburgh, Pittsburgh, PA USA. [Camidge, D. Ross] Univ Colorado, Ctr Canc, Denver, CO 80262 USA. [Chiappori, Alberto] H Lee Moffitt Canc Ctr & Res Inst, Thorac Oncol, Tampa, FL USA. [Ou, Sai-Hong Ignatius] Univ Calif Irvine, Orange, CA 92668 USA. [De Petris, Luigi] Karolinska Inst, Stockholm, Sweden. [Kim, Dong-Wan] Seoul Natl Univ Hosp, Seoul, South Korea. [Han, Ji-Youn] Natl Canc Ctr, Lung Canc Ctr, Goyang, South Korea. [Moro-Sibilot, Denis L.] Serv Pneumol, Grenoble, France. [Duruisseaux, Michael] CHU Grenoble, Grenoble, France. [Dansin, Eric] Ctr Oscar Lambret, Lille, France. [Crino, Lucio] Santa Maria Misericordia Hosp, Perugia, Italy. [De Pas, Tommaso] European Inst Oncol, Milan, Italy. [Tessmer, Antje] Evangel Lungenklin Berlin, Berlin, Germany. [Yang, James Chih-Hsin] Natl Taiwan Univ, Grad Inst Oncol, Taipei, Taiwan. [Yang, James Chih-Hsin] Natl Taiwan Univ, Canc Res Ctr, Taipei, Taiwan. [Bordogna, Walter; Golding, Sophie; Zeaiter, Ali] F Hoffmann La Roche, Basel, Switzerland. RP Gadgeel, SM (reprint author), Wayne State Univ, Karmanos Canc Inst, Detroit, MI 48202 USA. EM gadgeels@karmanos.org RI Duruisseaux, Michael/D-8371-2017 OI Duruisseaux, Michael/0000-0003-1495-0966 FU F. Hoffmann-La Roche FX We thank all the NP28761 and NP28673 investigators, their patients, and their families. Third-party medical writing support, under the direction of the authors, was provided by Rhiannon Owen of Gardiner-Caldwell Communications and was funded by F. Hoffmann-La Roche. NR 28 TC 5 Z9 5 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD DEC 1 PY 2016 VL 34 IS 34 BP 4079 EP + DI 10.1200/JCO.2016.68.4639 PG 10 WC Oncology SC Oncology GA ED5YM UT WOS:000388929900006 PM 27863201 ER PT J AU Daud, AI Wolchok, JD Robert, C Hwu, WJ Weber, JS Ribas, A Hodi, FS Joshua, AM Kefford, R Hersey, P Joseph, R Gangadhar, TC Dronca, R Patnaik, A Zarour, H Roach, C Toland, G Lunceford, JK Li, XN Emancipator, K Dolled-Filhart, M Kang, SP Ebbinghaus, S Hamid, O AF Daud, Adil I. Wolchok, Jedd D. Robert, Caroline Hwu, Wen-Jen Weber, Jeffrey S. Ribas, Antoni Hodi, F. Stephen Joshua, Anthony M. Kefford, Richard Hersey, Peter Joseph, Richard Gangadhar, Tara C. Dronca, Roxana Patnaik, Amita Zarour, Hassane Roach, Charlotte Toland, Grant Lunceford, Jared K. Li, Xiaoyun Nicole Emancipator, Kenneth Dolled-Filhart, Marisa Kang, S. Peter Ebbinghaus, Scot Hamid, Omid TI Programmed Death-Ligand 1 Expression and Response to the Anti-Programmed Death 1 Antibody Pembrolizumab in Melanoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID UNTREATED MELANOMA; LUNG-CANCER; IPILIMUMAB; PD-1; SAFETY; STIMULATION; NIVOLUMAB; ANTI-PD-1; BLOCKADE; CRITERIA AB Purpose Expression of programmed death-ligand 1 (PD-L1) is a potential predictive marker for response and outcome after treatment with anti-programmed death 1 (PD-1). This study explored the relationship between anti-PD-1 activity and PD-L1 expression in patients with advanced melanoma who were treated with pembrolizumab in the phase Ib KEYNOTE-001 study (clinical trial information: NCT01295827). Patients and Methods Six hundred fifty-five patients received pembrolizumab10 mg/kg once every 2 weeks or once every 3 weeks, or 2 mg/kg once every 3 weeks. Tumor response was assessed every 12 weeks per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by independent central review. Primary outcome was objective response rate. Secondary outcomes included progression-free survival (PFS) and overall survival (OS). Membranous PD-L1 expression in tumor and tumor-associated immune cells was assessed by a clinical trial immunohistochemistry assay (22C3 antibody) and scored on a unique melanoma (MEL) scale of 0 to 5 by one of three pathologists who were blinded to clinical outcome; a score >= 2 (membranous staining in >= 1% of cells) was considered positive. Results Of 451 patients with evaluable PD-L1 expression, 344 (76%) had PD-L1-positive tumors. Demographic and staging variables were equally distributed among PD-L1-positive and -negative patients. An association between higher MEL score and higher response rate and longer PFS (hazard ratio, 0.76; 95% CI, 0.71 to 0.82) and OS (hazard ratio, 0.76; 95% CI, 0.69 to 0.83) was observed (P < .001 for each). Objective response rate was 8%, 12%, 22%, 43%, 57%, and 53% for MEL 0, 1, 2, 3, 4, and 5, respectively. Conclusion PD-L1 expression in pretreatment tumor biopsy samples was correlated with response rate, PFS, and OS; however, patients with PD-L1-negative tumors may also achieve durable responses. (C) 2016 by American Society of Clinical Oncology C1 [Daud, Adil I.] Univ Calif San Francisco, 1600 Divisadero St,Room A741,Box 1770, San Francisco, CA 94143 USA. [Ribas, Antoni] Univ Calif Los Angeles, Los Angeles, CA USA. [Hamid, Omid] Angeles Clin & Res Inst, Los Angeles, CA USA. [Roach, Charlotte; Toland, Grant] Dako North Amer, Carpinteria, CA USA. [Wolchok, Jedd D.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Hwu, Wen-Jen] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Patnaik, Amita] South Texas Accelerated Res Therapeut, San Antonio, TX USA. [Weber, Jeffrey S.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Joseph, Richard] Mayo Clin, Jacksonville, FL 32224 USA. [Hodi, F. Stephen] Dana Farber Canc Inst, Boston, MA 02115 USA. [Gangadhar, Tara C.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Zarour, Hassane] Univ Pittsburgh, Pittsburgh, PA USA. [Dronca, Roxana] Mayo Clin, Rochester, MN USA. [Lunceford, Jared K.; Li, Xiaoyun Nicole; Emancipator, Kenneth; Dolled-Filhart, Marisa; Kang, S. Peter; Ebbinghaus, Scot] Merck & Co Inc, Kenilworth, NJ USA. [Robert, Caroline] Gustave Roussy, Villejuif, France. [Robert, Caroline] Univ Paris Sud, Villejuif, France. [Joshua, Anthony M.] Princess Margaret Canc Ctr, Toronto, ON, Canada. [Kefford, Richard] Westmead Hosp, Crown Princess Mary Canc Ctr, Westmead, NSW, Australia. [Kefford, Richard] Melanoma Inst Australia, Wollstonecraft, NSW, Australia. [Kefford, Richard] Macquarie Univ, N Ryde, NSW 2109, Australia. [Kefford, Richard; Hersey, Peter] Univ Sydney, Sydney, NSW, Australia. RP Daud, AI (reprint author), Univ Calif San Francisco, 1600 Divisadero St,Room A741,Box 1770, San Francisco, CA 94143 USA. EM adaud@medicine.ucsf.edu FU Merck Co FX Supported by Merck & Co. NR 38 TC 14 Z9 14 U1 10 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 DEC 1 PY 2016 VL 34 IS 34 BP 4102 EP + DI 10.1200/JCO.2016.67.2477 PG 12 WC Oncology SC Oncology GA ED5YM UT WOS:000388929900009 PM 27863197 ER PT J AU Loehrer, AP Song, ZR Haynes, AB Chang, DC Hutter, MM Mullen, JT AF Loehrer, Andrew P. Song, Zirui Haynes, Alex B. Chang, David C. Hutter, Matthew M. Mullen, John T. TI Impact of Health Insurance Expansion on the Treatment of Colorectal Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 69th Annual Cancer Symposium of the Society-of-Surgical-Oncology CY MAR 02-05, 2016 CL Boston, MA SP Soc Surg Oncol ID DIFFERENCE-IN-DIFFERENCES; UNITED-STATES; RACIAL DISPARITIES; COLON-CANCER; RISK-FACTORS; CARE REFORM; MASSACHUSETTS; MORTALITY; PATTERNS; SURVIVAL AB Purpose Colorectal cancer is the third most common cancer and the third leading cause of cancer deaths in the United States. Lack of insurance coverage has been associated with more advanced disease at presentation, more emergent admissions at time of colectomy, and lower survival relative to privately insured patients. The 2006 Massachusetts health care reform serves as a unique natural experiment to assess the impact of insurance expansion on colorectal cancer care. Methods We used the Hospital Cost and Utilization Project State Inpatient Databases to identify patients with colorectal cancer with government-subsidized or self-pay (GSSP) or private insurance admitted to a hospital between 2001 and 2011 in Massachusetts (n = 17,499) and three control states (n = 144,253). Difference-in-differencesmodels assessed the impact of the 2006 Massachusetts coverage expansion on resection of colorectal cancer, controlling for confounding factors and secular trends. Results Before the 2006 Massachusetts reform, government-subsidized or self-pay patients had significantly lower rates of resection for colorectal cancer compared with privately insured patients in both Massachusetts and the control states. The Massachusetts insurance expansion was associated with a 44% increased rate of resection (rate ratio = 1.44; 95% CI, 1.23 to 1.68; P < .001), a 6.21 percentage point decreased probability of emergent admission (95% CI, 211.88 to20.54; P = .032), and an 8.13 percentage point increased probability of an elective admission (95% CI, 1.34 to 14.91; P = .019) compared with the control states. Conclusion The 2006 Massachusetts health care reform, a model for the Affordable Care Act, was associated with increased rates of resection and decreased probability of emergent resection for colorectal cancer. Our findings suggest that insurance expansion may help improve access to care for patients with colorectal cancer. (C) 2016 by American Society of Clinical Oncology C1 [Loehrer, Andrew P.; Song, Zirui; Haynes, Alex B.; Chang, David C.; Hutter, Matthew M.; Mullen, John T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Loehrer, AP (reprint author), Massachusetts Gen Hosp, Codman Ctr Clin Effectiveness Surg, 165 Cambridge St,Suite 403, Boston, MA 02114 USA. EM aloehrer@partners.org NR 41 TC 0 Z9 0 U1 6 U2 6 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD DEC 1 PY 2016 VL 34 IS 34 BP 4110 EP + DI 10.1200/JCO.2016.68.5701 PG 9 WC Oncology SC Oncology GA ED5YM UT WOS:000388929900010 PM 27863191 ER PT J AU Tung, NM Garber, JE AF Tung, Nadine M. Garber, Judy E. TI Multigene Panels to Evaluate Hereditary Cancer Risk: Reckless or Relevant? Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID BREAST; MUTATIONS; BRCA1; OVARIAN C1 [Tung, Nadine M.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Tung, Nadine M.; Garber, Judy E.] Harvard Med Sch, Boston, MA 02115 USA. [Garber, Judy E.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Tung, NM (reprint author), Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA.; Tung, NM (reprint author), Harvard Med Sch, Boston, MA 02115 USA. NR 13 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD DEC 1 PY 2016 VL 34 IS 34 BP 4187 EP + DI 10.1200/JCO.2016.69.1022 PG 3 WC Oncology SC Oncology GA ED5YM UT WOS:000388929900022 PM 27551137 ER PT J AU Ribi, K Bernhard, J Luo, W Regan, MM Fleming, GF Francis, PA AF Ribi, Karin Bernhard, Jurg Luo, Weixiu Regan, Meredith M. Fleming, Gini F. Francis, Prudence A. TI Quality of Life Effects of Ovarian Suppression in the Suppression of Ovarian Function Trial Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID PREMENOPAUSAL BREAST-CANCER; PATIENT-REPORTED OUTCOMES; ADJUVANT EXEMESTANE; ENDOCRINE TREATMENT; WOMEN; TAMOXIFEN C1 [Ribi, Karin; Bernhard, Jurg] Int Breast Canc Study Grp, Coordinating Ctr, Bern, Switzerland. [Bernhard, Jurg] Inselspital Bern, Univ Hosp Bern, Bern, Switzerland. [Luo, Weixiu; Regan, Meredith M.] Dana Farber Canc Inst, Int Breast Canc Study Grp, Ctr Stat, Boston, MA 02115 USA. [Regan, Meredith M.] Harvard Med Sch, Boston, MA USA. [Fleming, Gini F.] Univ Chicago, Med Ctr, Chicago, IL 60637 USA. [Fleming, Gini F.] Alliance Clin Trials Oncol, Chicago, IL USA. [Francis, Prudence A.] Univ Melbourne, St Vincents Hosp, Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [Francis, Prudence A.] Univ Newcastle, Newcastle, NSW, Australia. RP Ribi, K (reprint author), Int Breast Canc Study Grp, Coordinating Ctr, Bern, Switzerland. NR 11 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD DEC 1 PY 2016 VL 34 IS 34 BP 4189 EP + DI 10.1200/JCO.2016.69.4158 PG 3 WC Oncology SC Oncology GA ED5YM UT WOS:000388929900025 PM 27621403 ER PT J AU Kawakami, A Fisher, DE AF Kawakami, Akinori Fisher, David E. TI Bioinformatic Analysis of Gene Expression for Melanoma Treatment SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Editorial Material ID METASTATIC MELANOMA AB Bioinformatic analysis of genome-wide gene expression allows us to characterize cells, including melanomas. Gene expression profiles have been generated in various stages of melanomas and analyzed by researchers in unique ways. Lauss et al. compared their melanoma subtypes with those of The Cancer Genome Atlas Network and found consistency between the two studies. C1 [Kawakami, Akinori; Fisher, David E.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Dermatol, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. RP Fisher, DE (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Dermatol, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. EM dfisher3@partners.org FU NCI NIH HHS [P01 CA163222]; NIAMS NIH HHS [R01 AR043369] NR 10 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD DEC PY 2016 VL 136 IS 12 BP 2342 EP 2344 DI 10.1016/j.jid.2016.09.011 PG 3 WC Dermatology SC Dermatology GA ED2KP UT WOS:000388673500012 PM 27884291 ER PT J AU Shasha, D Karel, D Angiuli, O Greenblatt, A Ghebremichael, M Yu, X Porichis, F Walker, BD AF Shasha, David Karel, Dan Angiuli, Olivia Greenblatt, Adam Ghebremichael, Musie Yu, Xu Porichis, Filippos Walker, Bruce D. TI Elite controller CD8(+) T cells exhibit comparable viral inhibition capacity, but better sustained effector properties compared to chronic progressors SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE HIV control; polyfunctionality; apoptosis; IL-15 ID VIRUS TYPE-1 INFECTION; HIV-1 INFECTION; PERFORIN EXPRESSION; FUNCTIONAL PROFILE; IMMUNE-RESPONSES; PROLIFERATION; REPLICATION; SURVIVAL; VIREMIA; IL-15 AB Mechanisms modulating HIV-specific CD8+ T cell-mediated viral inhibition are not well defined. To delineate features of effective control, we compared the ability of CD8(+) T cells from HIV ECs and CPs to inhibit HIV ex vivo. ECs showed superior inhibition compared to HAART-treated or untreated CPs in a typical VIA in which CD8(+) T cells are rested 3 d before use (P = 0.025). In contrast, comparable antiviral activity was observed in freshly thawed cells. Rested CD8(+) T cells underwent apoptosis with preferential loss of HIV-specific cells. EC CD8(+) T cells showed greater capacity to sustain polyfunctionality ex vivo compared with those of CPs, and incubation of CD8(+) T cells with IL-15 augmented inhibition. These results indicate that superior ex vivo inhibition of viral replication by CD8(+) T cells from ECs is associated with enhanced retention of functional qualities and that in vitro antiviral function is enhanced by IL-15. C1 Massachusetts Gen Hosp, Ragon Inst, MIT, Boston, MA 02114 USA. Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. RP Porichis, F; Walker, BD (reprint author), Ragon Inst MGH MIT & Harvard, 400 Technol Sq, Cambridge, MA 02139 USA. EM fporichis@mgh.harvard.edu; bwalker@mgh.harvard.edu FU U.S. NIH National Institute of Allergy and Infectious Diseases [AI30914] FX This work was supported by U.S. NIH National Institute of Allergy and Infectious Diseases Grant AI30914. The authors thank laboratory manager Dr. Alicja Piechocka-Trocha for her thorough contribution to this project. NR 49 TC 0 Z9 0 U1 1 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 EI 1938-3673 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD DEC PY 2016 VL 100 IS 6 BP 1425 EP 1433 DI 10.1189/jlb.4A0915-422R PG 9 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA ED1GN UT WOS:000388593000020 PM 27406996 ER PT J AU Lang, M Treister, R Oaklander, AL AF Lang, Magdalena Treister, Roi Oaklander, Anne Louise TI Diagnostic value of blood tests for occult causes of initially idiopathic small-fiber polyneuropathy SO JOURNAL OF NEUROLOGY LA English DT Article DE Sensory polyneuropathy; Skin biopsy; Nerve biopsy; Autonomic-function testing; Immunity; Cost effectiveness ID DISTAL SYMMETRIC POLYNEUROPATHY; PRACTICE PARAMETER EVALUATION; IMPAIRED GLUCOSE-TOLERANCE; SENSORY NEUROPATHY; SKIN BIOPSY; CELIAC-DISEASE; UNITED-STATES; ELECTRODIAGNOSTIC MEDICINE; PERIPHERAL NEUROPATHIES; MONOCLONAL GAMMOPATHY AB Small-fiber polyneuropathy (SFPN) causes non-specific symptoms including chronic pain, cardiovascular, gastrointestinal, and sweating complaints. Diagnosis is made from history and exam in patients with known risk factors such as diabetes, but objective test confirmation is recommended for patients without known risks. If tests confirm SFPN, and it is "initially idiopathic" (iiSFPN), screening for occult causes is indicated. This study's aim was to evaluate the 21 widely available, recommended blood tests to identify the most cost-effective ones and to learn about occult causes of iiSFPN. Records were reviewed from all 213 patients with SFPN confirmed by distal-leg skin biopsy, nerve biopsy, or autonomic-function testing in our academic center during 2013. We determined the prevalence of each abnormal blood-test result (ABTR) in the iiSFPN cohort, compared this to population averages, and measured the costs of screening subjects to obtain one ABTR. Participants were 70 % female and aged 43.0 +/- 18.6 years. High erythrocyte sedimentation rate (ESR) and antinuclear antibody (ANA; aeyen1:160 titer) were most common, each present in 28 % of subjects. The ABTR aeyen3 x more prevalent in iiSFPN than in the total population were high ESR, high ANA, low C3, and Sjogren's and celiac autoantibodies. Together, these suggest the possibility of a specific association between iiSFPN and dysimmunity. ABTR identifying diabetes, prediabetes, and hypertriglyceridemia were less common in iiSFPN than in the population and thus were not associated with iiSFPN here. The six most cost-effective iiSFPN-associated blood tests-ESR, ANA, C3, autoantibodies for Sjogren's and celiac, plus thyroid-stimulating hormone-had estimated cost of $99.57/person and 45.6 % probability of obtaining one abnormal result. Angiotensin-converting enzyme was elevated in 45 %, but no patients had sarcoidosis, so this test was futile here. C1 [Lang, Magdalena; Treister, Roi; Oaklander, Anne Louise] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, 275 Charles St Warren Bldg 310, Boston, MA 02114 USA. [Oaklander, Anne Louise] Massachusetts Gen Hosp, Dept Pathol Neuropathol, Boston, MA 02114 USA. RP Oaklander, AL (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, 275 Charles St Warren Bldg 310, Boston, MA 02114 USA.; Oaklander, AL (reprint author), Massachusetts Gen Hosp, Dept Pathol Neuropathol, Boston, MA 02114 USA. EM aloaklander@mgh.harvard.edu FU Department of Defense [GW093049, GW130109]; National Institutes of Health [K24NS9892, R01NS093653]; Bradley foundation FX This work was supported in part by research grants from the Department of Defense (GW093049 and GW130109), the National Institutes of Health (K24NS9892 and R01NS093653), and the Bradley foundation. We thank Heather Downs BS, Kate O'Neil BS, and Xiaolei Liu MD for assistance with data collection, Stuart Lerman MBA for providing Medicare costs, and Gary Zirpoli PhD for biostatistical advice. Presented in abstract form to the 2015 meetings of the Peripheral Nerve Society and the American Neurological Association. NR 76 TC 0 Z9 0 U1 3 U2 3 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0340-5354 EI 1432-1459 J9 J NEUROL JI J. Neurol. PD DEC PY 2016 VL 263 IS 12 BP 2515 EP 2527 DI 10.1007/s00415-016-8270-5 PG 13 WC Clinical Neurology SC Neurosciences & Neurology GA ED1SP UT WOS:000388625500022 PM 27730378 ER PT J AU Jing, J Dauwels, J Rakthanmanon, T Keogh, E Cash, SS Westover, MB AF Jing, J. Dauwels, J. Rakthanmanon, T. Keogh, E. Cash, S. S. Westover, M. B. TI Rapid annotation of interictal epileptiform discharges via template matching under Dynamic Time Warping SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE EEG; Interictal discharges; Spikes; Graphical user interface; Rapid annotation; Template matching; Dynamic Time Warping ID ARTIFICIAL NEURAL-NETWORKS; AUTOMATIC SPIKE DETECTION; EEG DATA; ELECTROENCEPHALOGRAM; RECOGNITION; SYSTEM; FILTER; RAW AB Background: EEG interpretation relies on experts who are in short supply. There is a great need for automated pattern recognition systems to assist with interpretation. However, attempts to develop such systems have been limited by insufficient expert-annotated data. To address these issues, we developed a system named NeuroBrowser for EEG review and rapid waveform annotation. New methods: At the core of NeuroBrowser lies on ultrafast template matching under Dynamic Time Warping, which substantially accelerates the task of annotation. Results: Our results demonstrate that NeuroBrowser can reduce the time required for annotation of interictal epileptiform discharges by EEG experts by 20-90%, with an average of approximately 70%. Comparison with existing method(s): In comparison with conventional manual EEG annotation, NeuroBrowser is able to save EEG experts approximately 70% on average of the time spent in annotating interictal epileptiform discharges. We have already extracted 19,000+ interictal epileptiform discharges from 100 patient EEG recordings. To our knowledge this represents the largest annotated database of interictal epileptiform discharges in existence. Conclusion: NeuroBrowser is an integrated system for rapid waveform annotation. While the algorithm is currently tailored to annotation of interictal epileptiform discharges in scalp EEG recordings, the concepts can be easily generalized to other waveforms and signal types. (C) 2016 Published by Elsevier B.V. C1 [Jing, J.; Dauwels, J.] Nanyang Technol Univ, Sch Elect & Elect Engn, Res Staff Off 2,S2-B2c-118,50 Nanyang Ave, Singapore 639789, Singapore. [Rakthanmanon, T.] Kasetsart Univ, Dept Comp Engn, Bangkok, Thailand. [Keogh, E.] Univ Calif Riverside, Dept Comp Sci & Engn, Riverside, CA 92521 USA. [Cash, S. S.; Westover, M. B.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Boston, MA USA. RP Jing, J (reprint author), Nanyang Technol Univ, Sch Elect & Elect Engn, Res Staff Off 2,S2-B2c-118,50 Nanyang Ave, Singapore 639789, Singapore. EM jingjin@ntu.edu.sg; justin@dauwels.com; thanawin.r@ku.ac.th; eamonn@cs.ucr.edu; scash@mgh.harvard.edu; mwestover@mgh.harvard.edu FU Singapore Ministry of Education (MOE) Tier 1 grants [M4010982.040, M4011102.040]; NIH-NINDS [K23 NS090900, R01 NS062092]; Rappaport Foundation; Andrew David Heitman Neuroendovascular Research Fund FX This work is supported in part by Singapore Ministry of Education (MOE) Tier 1 grants M4010982.040 and M4011102.040 (J. Jing and J. Dauwels); NIH-NINDS K23 NS090900, Rappaport Foundation, Andrew David Heitman Neuroendovascular Research Fund (M.B. Westover); and NIH-NINDS R01 NS062092 (S.S. Cash). We are grateful to Dr. Andrew James Cole and Dr. Catherine J. Chu at Massachusetts General Hospital for the collaboration and assistance in performing the studies described above. NR 48 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 EI 1872-678X J9 J NEUROSCI METH JI J. Neurosci. Methods PD DEC 1 PY 2016 VL 274 BP 179 EP 190 DI 10.1016/j.jneumeth.2016.02.025 PG 12 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA ED7ZQ UT WOS:000389091800020 PM 26944098 ER PT J AU Iverson, GL Atkins, JE Zafonte, R Berkner, PD AF Iverson, Grant L. Atkins, Joseph E. Zafonte, Ross Berkner, Paul D. TI Concussion History in Adolescent Athletes with Attention-Deficit Hyperactivity Disorder SO JOURNAL OF NEUROTRAUMA LA English DT Article DE adolescents; attention-deficit hyperactivity disorder; concussion; mild traumatic brain injury; surveillance ID TRAUMATIC BRAIN-INJURY; MILD HEAD-INJURY; DEFICIT/HYPERACTIVITY DISORDER; PSYCHIATRIC-ILLNESS; NONFATAL INJURIES; CHILDREN; POPULATION; PREDICTORS; COHORT AB Little is known about the rate of concussions in adolescents with attention-deficit hyperactivity disorder (ADHD). We hypothesized that high school athletes with ADHD would report a greater history of concussion than students without ADHD. A total of 6529 adolescent and young adult student athletes, between the ages of 13 and 19 years (mean, 15.9; standard deviation, 1.3), completed a preseason health survey in 2010. Of those with ADHD, 26.1% reported a history of one or more concussions, compared to 17.1% of those without ADHD (p < 0.00001; odds ratio [OR], 1.71). Stratified by gender, 27.0% of boys with ADHD reported a history of one or more concussions, compared to 20.0% of boys without ADHD (p < 0.004; OR, 1.48), and 23.6% of girls with ADHD reported a history of one or more concussions, compared to 13.6% of girls without ADHD (p < 0.003; OR, 1.97). Of those with ADHD, 9.8% reported a history of two or more concussions, compared to 5.5% of those without ADHD (p < 0.0003; OR, 1.87). Stratified by gender, 10.0% of boys with ADHD reported a history of two or more concussions, compared to 6.7% of boys without ADHD (p < 0.033; OR, 1.54), and 9.1% of girls with ADHD reported a history of two or more concussions, compared to 3.8% of girls without ADHD (p < 0.006; OR, 2.51). In this large-scale, retrospective survey study, boys and girls with ADHD were significantly more likely to report a history of concussion. Additional research is needed to determine whether students with ADHD are more susceptible to injury (i.e., have a lower threshold) or have different recovery trajectories. C1 [Iverson, Grant L.; Zafonte, Ross] Harvard Med Sch, Dept Phys Med & Rehabil, Boston, MA USA. [Iverson, Grant L.; Zafonte, Ross] MassGen Hosp Children Sport Concuss Program, Boston, MA USA. [Iverson, Grant L.; Zafonte, Ross] Red Sox Fdn, Boston, MA USA. [Iverson, Grant L.; Zafonte, Ross] Massachusetts Gen Hosp, Home Base Program, Boston, MA 02114 USA. [Iverson, Grant L.; Zafonte, Ross] Spaulding Rehabil Hosp, Charlestown, MA USA. [Atkins, Joseph E.] Colby Coll, Dept Psychol, Waterville, ME 04901 USA. [Berkner, Paul D.] Colby Coll, Hlth Serv, Waterville, ME 04901 USA. [Berkner, Paul D.] Colby Coll, Dept Biol, Waterville, ME 04901 USA. RP Iverson, GL (reprint author), Harvard Med Sch, Dept Phys Med & Rehabil, Ctr Hlth & Rehabil, 79-96 Thirteenth St, Charlestown, MA 02129 USA. EM giverson@mgh.harvard.edu FU Goldfarb Center for Public Policy; Civic Engagement/Colby College; Bill and Joan Alfond Foundation; Harvard Integrated Program to Protect and Improve the Health of NFLPA Members FX This work was funded, in part, by the Goldfarb Center for Public Policy and Civic Engagement/Colby College and the Bill and Joan Alfond Foundation. R.Z. was supported, in part, by the Harvard Integrated Program to Protect and Improve the Health of NFLPA Members. NR 24 TC 1 Z9 1 U1 10 U2 10 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 DEC 1 PY 2016 VL 33 IS 23 BP 2077 EP 2080 DI 10.1089/neu.2014.3424 PG 4 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA ED2JG UT WOS:000388669800002 PM 25375785 ER PT J AU Zhang, DF Tarabochia, M Janssen, S Ring, D Chen, N AF Zhang, Dafang Tarabochia, Matthew Janssen, Stein Ring, David Chen, Neal TI Risk of Subluxation or Dislocation After Operative Treatment of Terrible Triad Injuries SO JOURNAL OF ORTHOPAEDIC TRAUMA LA English DT Article DE terrible triad injury; elbow fracture-dislocation; elbow instability; elbow subluxation; elbow dislocation ID RADIAL HEAD; ELBOW; FRACTURES; STABILITY; FIXATION; MODEL AB Objective: The management of terrible triad injuries has evolved over the last 2 decades to include routine radial head fixation or replacement, reattachment of the lateral collateral ligament, with or without coronoid fixation. Our objective was to determine the likelihood of and factors associated with subluxation or dislocation after operative treatment of terrible triad injuries among a large group of surgeons using current techniques. Design: Retrospective cohort study. Setting: Two level I trauma centers. Patients/Participants: A total of 107 patients with operatively treated terrible triad injuries from January 2000 to June 2015. Intervention: Review of patient-and surgery-related factors during the first postoperative month. Main Outcome Measurement: Radiographic subluxation of the ulnohumeral joint. Results: One hundred of the 107 patients (93%) treated with open fixation of terrible triad injuries had no radiographic subluxation or redislocation. Two patients (2%) had slight transient radiographic subluxation ("drop sign") that corrected with active exercises within weeks of surgery. Five patients (5%) had persistent radiographic subluxation, 3 treated with a second surgery (3%). When treated within 2 weeks of injury, recurrent subluxation or dislocation after operative fixation of terrible triad injuries was rare (1%), provided that the radial head was replaced and the lateral collateral ligament reattached. Conclusions: Radiographic subluxation is very uncommon with current operative management of terrible triad injuries of the elbow within 2 weeks. Patients treated more than 2 weeks after injury might benefit from ancillary fixation to limit subluxation (ie, cross pinning, external fixation, or internal joint stabilizer). C1 [Zhang, Dafang; Tarabochia, Matthew; Janssen, Stein; Chen, Neal] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. [Zhang, Dafang; Tarabochia, Matthew; Chen, Neal] Harvard Med Sch, Boston, MA USA. [Ring, David] Univ Texas Austin, Dell Med Sch, Austin, TX 78712 USA. RP Zhang, DF (reprint author), Dept Orthopaed Surg, 55 Fruit St, Boston, MA 02114 USA. EM dzhang9@partners.org NR 15 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0890-5339 EI 1531-2291 J9 J ORTHOP TRAUMA JI J. Orthop. Trauma PD DEC PY 2016 VL 30 IS 12 BP 660 EP 663 DI 10.1097/BOT.0000000000000674 PG 4 WC Orthopedics; Sport Sciences SC Orthopedics; Sport Sciences GA ED6CG UT WOS:000388941600012 PM 27479736 ER PT J AU Hang, S Tang, XB Shu, DY Liu, YH Geng, CR Gong, CH Yu, HY Chen, D AF Hang, Shuang Tang, Xiaobin Shu, Diyun Liu, Yuanhao Geng, Changran Gong, Chunhui Yu, Haiyan Chen, Da TI Monte Carlo study of the beam shaping assembly optimization for providing high epithermal neutron flux for BNCT based on D-T neutron generator SO JOURNAL OF RADIOANALYTICAL AND NUCLEAR CHEMISTRY LA English DT Article DE Boron neutron capture therapy; D-T neutron generator; Beam shaping assembly; Deep-seated brain tumor; Dosimetric assessment; MCNP ID CAPTURE THERAPY; BRAIN-TUMORS; DESIGN; BSA; FACILITY; REACTOR; CANCER; HEAD AB In this study, a beam shaping assembly with high epithermal neutron flux output was designed based on a D-T neutron generator using Monte Carlo N-particle Transport Code. D2O-Fe-54 and AlF3-Ni-60 interlayer moderator, efficient multiplier, filters, and reflector were used to improve the neutron beam quality according to the requirements of boron neutron capture therapy while maintaining high flux of epithermal neutron beam. In addition, the dose performance of the beam from our proposed facility was assessed in the Snyder head phantom. The simulation results proved that the proposed neutron beam was applicable to the treatment of deep-seated brain tumor. C1 [Hang, Shuang; Tang, Xiaobin; Shu, Diyun; Liu, Yuanhao; Geng, Changran; Gong, Chunhui; Yu, Haiyan; Chen, Da] Nanjing Univ Aeronaut & Astronaut, Dept Nucl Sci Engn, 29 Yudao St, Nanjing 210016, Jiangsu, Peoples R China. [Tang, Xiaobin; Chen, Da] Jiangsu Higher Educ Inst, Collaborat Innovat Ctr Radiat Med, 29 Yudao St, Nanjing 210016, Jiangsu, Peoples R China. [Geng, Changran] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Tang, XB (reprint author), Nanjing Univ Aeronaut & Astronaut, Dept Nucl Sci Engn, 29 Yudao St, Nanjing 210016, Jiangsu, Peoples R China.; Tang, XB (reprint author), Jiangsu Higher Educ Inst, Collaborat Innovat Ctr Radiat Med, 29 Yudao St, Nanjing 210016, Jiangsu, Peoples R China. EM tangxiaobin@nuaa.edu.cn RI Tang, Xiaobin/I-7601-2014 OI Tang, Xiaobin/0000-0003-3308-0468 FU National Natural Science Foundation of China [11475087]; National Science and Technology Support Program [2015BAI34H00]; Priority Academic Program Development of Jiangsu Higher Education Institutions FX This work was supported by the National Natural Science Foundation of China (Grant No. 11475087), the National Science and Technology Support Program (Grant No. 2015BAI34H00), and the Priority Academic Program Development of Jiangsu Higher Education Institutions. NR 32 TC 0 Z9 0 U1 5 U2 5 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0236-5731 EI 1588-2780 J9 J RADIOANAL NUCL CH JI J. Radioanal. Nucl. Chem. PD DEC PY 2016 VL 310 IS 3 BP 1289 EP 1298 DI 10.1007/s10967-016-5001-4 PG 10 WC Chemistry, Analytical; Chemistry, Inorganic & Nuclear; Nuclear Science & Technology SC Chemistry; Nuclear Science & Technology GA ED1UH UT WOS:000388629900040 ER PT J AU Puram, SV Chow, H Wu, CW Heaton, JT Kamani, D Gorti, G Chiang, FY Dionigi, G Barczynski, M Schneider, R Dralle, H Lorenz, K Randolph, GW AF Puram, Sidharth V. Chow, Harold Wu, Che-Wei Heaton, James T. Kamani, Dipti Gorti, Gautham Chiang, Feng Yu Dionigi, Gianlorenzo Barczynski, Marcin Schneider, Rick Dralle, Henning Lorenz, Kerstin Randolph, Gregory W. TI Posterior cricoarytenoid muscle electrophysiologic changes are predictive of vocal cord paralysis with recurrent laryngeal nerve compressive injury in a canine model SO LARYNGOSCOPE LA English DT Article DE Recurrent laryngeal nerve; injury; endocrine; thyroid surgery; postcricoid; monitoring ID THYROID-SURGERY; THYROARYTENOID MUSCLES; PARATHYROID SURGERY; VAGUS NERVE; ELECTROMYOGRAPHY; IDENTIFICATION; INNERVATION; EXPERIENCE AB Objectives/HypothesisInjury to the recurrent laryngeal nerve (RLN) is a dreaded complication of endocrine surgery. Intraoperative neural monitoring (IONM) has been increasingly utilized to assess the functional status of the RLN. Although the posterior cricoarytenoid muscle (PCA) is innervated by the RLN as the abductor of the larynx, PCA electromyography (EMG) is infrequently recorded during IONM and PCA activity after RLN compressive injury remains poorly characterized. Study DesignSingle-subject prospective animal study. MethodsWe employed a canine model to identify postcricoid EMG correlates of postoperative vocal cord paralysis (VCP). Postcricoid electrode recordings were obtained before and after compressive RLN injury associated with VCP. ResultsNormative postcricoid recordings revealed mean amplitude of 1288 microvolt (V) and latency of 8.2 millisecond (ms) with maximum (1 milliamp [mA]) vagal stimulation, and mean amplitude of 1807 V and latency of 3.5 ms with maximum (1 mA) RLN stimulation. Following injury that was associated with VCP, there was 62.1% decrement in postcricoid EMG amplitude with maximum vagal stimulation and 80% decrement with maximum RLN stimulation. Threshold stimulation of the vagus increased by 23%, and there was a corresponding 42% decrease in amplitude. For RLN stimulation, latency increased by 17.3% following injury, whereas threshold stimulation increased by 61% with 35.5% decrement in EMG amplitude. Thus, if RLN amplitude decreases by 80%, with absolute amplitude of 300 V or less and latency increase of 10%, RLN injury is likely associated with VCP. ConclusionOur results predict postoperative VCP based on postcricoid electromyographic IONM and may guide surgical decision making. Level of EvidenceNA Laryngoscope, 126:2744-2751, 2016 C1 [Puram, Sidharth V.; Chow, Harold; Wu, Che-Wei; Kamani, Dipti; Gorti, Gautham; Randolph, Gregory W.] Harvard Med Sch, Div Thyroid & Parathyroid Surg, Dept Otolaryngol, Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02115 USA. [Heaton, James T.] Harvard Med Sch, Dept Surg, Boston, MA 02115 USA. [Randolph, Gregory W.] Harvard Med Sch, Div Surg Oncol, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Wu, Che-Wei; Chiang, Feng Yu] Kaohsiung Med Univ, Dept Otorhinolaryngol Head & Neck Surg, Kaohsiung Med Univ Hosp, Fac Med,Coll Med, Kaohsiung, Taiwan. [Dionigi, Gianlorenzo] Univ Insubria, Sch Med, Div Surg, Dept Surg Sci & Human Morphol, Varese, Italy. [Barczynski, Marcin] Jagiellonian Univ, Coll Med, Dept Endocrine Surg, Krakow, Poland. [Dralle, Henning; Lorenz, Kerstin] Univ Halle Wittenberg, Dept Gen Visceral & Vasc Surg, Halle, Saale, Germany. RP Randolph, GW (reprint author), Harvard Med Sch, Div Thyroid & Parathyroid Surg, Dept Otolaryngol, Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02115 USA. EM gregory_randolph@meei.harvard.edu FU John and Claire Bertucci Thyroid Research fund FX The John and Claire Bertucci Thyroid Research fund supported this research. The authors have other no funding, financial relationships, or conflicts of interest to disclose. NR 19 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X EI 1531-4995 J9 LARYNGOSCOPE JI Laryngoscope PD DEC PY 2016 VL 126 IS 12 BP 2744 EP 2751 DI 10.1002/lary.25967 PG 8 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA ED1JW UT WOS:000388602600029 PM 27113438 ER PT J AU Taylor-Weiner, A Zack, T O'Donnell, E Guerriero, JL Bernard, B Reddy, A Han, GC AlDubayan, S Amin-Mansour, A Schumacher, SE Litchfield, K Turnbull, C Gabriel, S Beroukhim, R Getz, G Carter, SL Hirsch, MS Letai, A Sweeney, C Van Allen, EM AF Taylor-Weiner, Amaro Zack, Travis O'Donnell, Elizabeth Guerriero, Jennifer L. Bernard, Brandon Reddy, Anita Han, G. Celine AlDubayan, Saud Amin-Mansour, Ali Schumacher, Steven E. Litchfield, Kevin Turnbull, Clare Gabriel, Stacey Beroukhim, Rameen Getz, Gad Carter, Scott L. Hirsch, Michelle S. Letai, Anthony Sweeney, Christopher Van Allen, Eliezer M. . TI Genomic evolution and chemoresistance in germ-cell tumours SO NATURE LA English DT Article ID CARCINOMA IN-SITU; CISPLATIN RESISTANCE; TESTICULAR-TUMORS; SEQUENCING DATA; DNA-DAMAGE; CANCER; MUTATIONS; REVEALS; SAMPLES; QUANTIFICATION AB Germ-cell tumours (GCTs) are derived from germ cells and occur most frequently in the testes(1,2). GCTs are histologically heterogeneous and distinctly curable with chemotherapy(3). Gains of chromosome arm 12p and aneuploidy are nearly universal in GCTs(4-6), but specific somatic genomic features driving tumour initiation, chemosensitivity and progression are incompletely characterized. Here, using clinical whole-exome and transcriptome sequencing of precursor, primary (testicular and mediastinal) and chemoresistant metastatic human GCTs, we show that the primary somatic feature of GCTs is highly recurrent chromosome arm level amplifications and reciprocal deletions (reciprocal loss of heterozygosity), variations that are significantly enriched in GCTs compared to 19 other cancer types. These tumours also acquire KRAS mutations during the development from precursor to primary disease, and primary testicular GCTs (TGCTs) are uniformly wild type for TP53. In addition, by functional measurement of apoptotic signalling (BH3 profiling) of fresh tumour and adjacent tissue(7), we find that primary TGCTs have high mitochondrial priming that facilitates chemotherapy-induced apoptosis. Finally, by phylogenetic analysis of serial TGCTs that emerge with chemotherapy resistance, we show how TGCTs gain additional reciprocal loss of heterozygosity and that this is associated with loss of pluripotency markers (NANOG and POU5F1)(8,9) in chemoresistant teratomas or transformed carcinomas. Our results demonstrate the distinct genomic features underlying the origins of this disease and associated with the chemosensitivity phenotype, as well as the rare progression to chemoresistance. These results identify the convergence of cancer genomics, mitochondrial priming and GCT evolution, and may provide insights into chemosensitivity and resistance in other cancers. C1 [Taylor-Weiner, Amaro; Zack, Travis] Harvard Univ, Div Med Sci, Boston, MA 02115 USA. [Taylor-Weiner, Amaro; Han, G. Celine; Amin-Mansour, Ali; Schumacher, Steven E.; Gabriel, Stacey; Beroukhim, Rameen; Getz, Gad; Carter, Scott L.; Van Allen, Eliezer M. .] Broad Inst MIT & Harvard, Canc Program, Cambridge, MA 02142 USA. [Zack, Travis] Harvard Med Sch, Hlth Sci & Technol, Boston, MA 02115 USA. [O'Donnell, Elizabeth; Guerriero, Jennifer L.; Bernard, Brandon; Han, G. Celine; Beroukhim, Rameen; Letai, Anthony; Sweeney, Christopher; Van Allen, Eliezer M. .] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [O'Donnell, Elizabeth] Massachusetts Gen Hosp, Dept Med Oncol, Boston, MA 02114 USA. [Reddy, Anita] Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA. [AlDubayan, Saud] Boston Childrens Hosp, Div Genet & Genom, Dept Med, Boston, MA 02115 USA. [AlDubayan, Saud] King Saud bin Abdulaziz Univ Hlth Sci, Dept Med, Riyadh, Saudi Arabia. [Schumacher, Steven E.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Litchfield, Kevin; Turnbull, Clare] Inst Canc Res, Div Genet & Epidemiol, Fulham Rd, London SW3 6JB, England. [Litchfield, Kevin; Turnbull, Clare] Queen Mary Univ London, William Harvey Res Inst, Charterhouse Sq, London EC1M 6BQ, England. [Getz, Gad] Massachusetts Gen Hosp, Canc Ctr, Boston, MA 02114 USA. [Getz, Gad] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Carter, Scott L.; Van Allen, Eliezer M. .] Dana Farber Canc Inst, Ctr Canc Precis Med, Boston, MA 02215 USA. [Carter, Scott L.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Carter, Scott L.] Harvard TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Hirsch, Michelle S.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. RP Van Allen, EM (reprint author), Broad Inst MIT & Harvard, Canc Program, Cambridge, MA 02142 USA.; Van Allen, EM (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA.; Van Allen, EM (reprint author), Dana Farber Canc Inst, Ctr Canc Precis Med, Boston, MA 02215 USA. EM eliezerm_vanallen@dfci.harvard.edu FU NIH [U54 HG003067, 1K08 CA188615]; Damon Runyon Clinical Investigator Award; Shawmut Design and Construction Pan Mass Challenge Team; Giovino Jimmy Fund Golf Tournament FX We thank the patients for contributing to this study, and H. Taylor-Weiner for feedback on ES cells. This work was supported by NIH U54 HG003067, NIH 1K08 CA188615 (E.M.V.), Damon Runyon Clinical Investigator Award (E.M.V.), Shawmut Design and Construction Pan Mass Challenge Team (C.S.), and Giovino Jimmy Fund Golf Tournament (C.S.). NR 43 TC 0 Z9 0 U1 15 U2 15 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 DEC 1 PY 2016 VL 540 IS 7631 BP 114 EP + DI 10.1038/nature20596 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ED5UA UT WOS:000388916600059 PM 27905446 ER PT J AU Safikhani, Z El-Hachem, N Smirnov, P Freeman, M Goldenberg, A Birkbak, NJ Beck, AH Aerts, HJWL Quackenbush, J Haibe-Kains, B AF Safikhani, Zhaleh El-Hachem, Nehme Smirnov, Petr Freeman, Mark Goldenberg, Anna Birkbak, Nicolai J. Beck, Andrew H. Aerts, Hugo J. W. L. Quackenbush, John Haibe-Kains, Benjamin TI Consistency in drug response profiling Reply SO NATURE LA English DT Letter ID SENSITIVITY C1 [Safikhani, Zhaleh; Smirnov, Petr; Freeman, Mark; Haibe-Kains, Benjamin] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON M5G 2M9, Canada. [Safikhani, Zhaleh; Haibe-Kains, Benjamin] Univ Toronto, Dept Med Biophys, Toronto, ON M5G 1L7, Canada. [El-Hachem, Nehme] Inst Rech Clin Montreal, Montreal, PQ H2W 1R7, Canada. [Goldenberg, Anna] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Goldenberg, Anna; Haibe-Kains, Benjamin] Univ Toronto, Dept Comp Sci, Toronto, ON M5S 2E4, Canada. [Birkbak, Nicolai J.] Francis Crick Inst, London NW1 1AT, England. [Birkbak, Nicolai J.] UCL, Inst Canc, London WC1E 6BT, England. [Beck, Andrew H.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Beck, Andrew H.; Aerts, Hugo J. W. L.] Harvard Med Sch, Boston, MA 02115 USA. [Aerts, Hugo J. W. L.; Quackenbush, John] Dana Farber Canc Inst, Boston, MA 02115 USA. [Aerts, Hugo J. W. L.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Quackenbush, John] Harvard TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Haibe-Kains, Benjamin] Ontario Inst Canc Res, Toronto, ON M5G 1L7, Canada. RP Haibe-Kains, B (reprint author), Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON M5G 2M9, Canada.; Haibe-Kains, B (reprint author), Univ Toronto, Dept Med Biophys, Toronto, ON M5G 1L7, Canada.; Haibe-Kains, B (reprint author), Univ Toronto, Dept Comp Sci, Toronto, ON M5S 2E4, Canada.; Haibe-Kains, B (reprint author), Ontario Inst Canc Res, Toronto, ON M5G 1L7, Canada. EM bhaibeka@uhnresearch.ca RI Smirnov, Petr/N-9652-2015; Aerts, Hugo/P-6350-2015 OI Aerts, Hugo/0000-0002-2122-2003 NR 11 TC 1 Z9 1 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD DEC 1 PY 2016 VL 540 IS 7631 BP E6 EP E8 DI 10.1038/nature20172 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ED5UA UT WOS:000388916600011 PM 27905416 ER PT J AU Safikhani, Z El-Hachem, N Smirnov, P Freeman, M Goldenberg, A Birkbak, NJ Beck, AH Aerts, HJWL Quackenbush, J Haibe-Kains, B AF Safikhani, Zhaleh El-Hachem, Nehme Smirnov, Petr Freeman, Mark Goldenberg, Anna Birkbak, Nicolai J. Beck, Andrew H. Aerts, Hugo J. W. L. Quackenbush, John Haibe-Kains, Benjamin TI Consistency in large pharmacogenomic studies Reply SO NATURE LA English DT Letter ID ANTICANCER DRUG-SENSITIVITY; LINE GENE-EXPRESSION; CELL-LINES C1 [Safikhani, Zhaleh; Smirnov, Petr; Freeman, Mark; Haibe-Kains, Benjamin] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON M5G 2M9, Canada. [Safikhani, Zhaleh; Haibe-Kains, Benjamin] Univ Toronto, Dept Med Biophys, Toronto, ON M5G 1L7, Canada. [El-Hachem, Nehme] Inst Rech Clin Montreal, Montreal, PQ H2W 1R7, Canada. [Goldenberg, Anna] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Goldenberg, Anna; Haibe-Kains, Benjamin] Univ Toronto, Dept Comp Sci, Toronto, ON M5S 2E4, Canada. [Birkbak, Nicolai J.] UCL, Francis Crick Inst, London NW1 1AT, England. [Birkbak, Nicolai J.] UCL, Inst Canc, London WC1E 6BT, England. [Beck, Andrew H.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Beck, Andrew H.; Aerts, Hugo J. W. L.] Harvard Med Sch, Boston, MA 02115 USA. [Aerts, Hugo J. W. L.; Quackenbush, John] Dana Farber Canc Inst, Boston, MA 02115 USA. [Aerts, Hugo J. W. L.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Quackenbush, John] Harvard Sch Publ Hlth, Boston, MA 02115 USA. [Haibe-Kains, Benjamin] Ontario Inst Canc Res, Toronto, ON M5G 1L7, Canada. RP Haibe-Kains, B (reprint author), Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON M5G 2M9, Canada.; Haibe-Kains, B (reprint author), Univ Toronto, Dept Med Biophys, Toronto, ON M5G 1L7, Canada.; Haibe-Kains, B (reprint author), Univ Toronto, Dept Comp Sci, Toronto, ON M5S 2E4, Canada.; Haibe-Kains, B (reprint author), Ontario Inst Canc Res, Toronto, ON M5G 1L7, Canada. EM bhaibeka@uhnresearch.ca RI Smirnov, Petr/N-9652-2015 NR 15 TC 1 Z9 1 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD DEC 1 PY 2016 VL 540 IS 7631 BP E2 EP E4 DI 10.1038/nature19839 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ED5UA UT WOS:000388916600009 PM 27905430 ER PT J AU Safikhani, Z El-Hachem, N Smirnov, P Freeman, M Goldenberg, A Birkbak, NJ Beck, AH Aerts, HJWL Quackenbush, J Haibe-Kains, B AF Safikhani, Zhaleh El-Hachem, Nehme Smirnov, Petr Freeman, Mark Goldenberg, Anna Birkbak, Nicolai J. Beck, Andrew H. Aerts, Hugo J. W. L. Quackenbush, John Haibe-Kains, Benjamin TI Drug response consistency in CCLE and CGP Reply SO NATURE LA English DT Letter ID SENSITIVITY; CANCER C1 [Safikhani, Zhaleh; Smirnov, Petr; Freeman, Mark; Haibe-Kains, Benjamin] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON M5G 2M9, Canada. [Safikhani, Zhaleh; Haibe-Kains, Benjamin] Univ Toronto, Dept Med Biophys, Toronto, ON M5G 1L7, Canada. [El-Hachem, Nehme] Inst Rech Clin Montreal, Montreal, PQ H2W 1R7, Canada. [Goldenberg, Anna] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Goldenberg, Anna; Haibe-Kains, Benjamin] Univ Toronto, Dept Comp Sci, Toronto, ON M5S 2E4, Canada. [Birkbak, Nicolai J.] UCL, Francis Crick Inst, London NW1 1AT, England. [Beck, Andrew H.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Beck, Andrew H.; Aerts, Hugo J. W. L.] Harvard Med Sch, Boston, MA 02115 USA. [Aerts, Hugo J. W. L.; Quackenbush, John] Dana Farber Canc Inst, Boston, MA 02115 USA. [Aerts, Hugo J. W. L.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Quackenbush, John] Harvard Sch Publ Hlth, Boston, MA 02115 USA. [Haibe-Kains, Benjamin] Ontario Inst Canc Res, Toronto, ON M5G 1L7, Canada. RP Haibe-Kains, B (reprint author), Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON M5G 2M9, Canada.; Haibe-Kains, B (reprint author), Univ Toronto, Dept Med Biophys, Toronto, ON M5G 1L7, Canada.; Haibe-Kains, B (reprint author), Univ Toronto, Dept Comp Sci, Toronto, ON M5S 2E4, Canada.; Haibe-Kains, B (reprint author), Ontario Inst Canc Res, Toronto, ON M5G 1L7, Canada. EM benjamin.haibe.kains@utoronto.ca RI Smirnov, Petr/N-9652-2015 NR 13 TC 1 Z9 1 U1 1 U2 1 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 DEC 1 PY 2016 VL 540 IS 7631 BP E11 EP E12 DI 10.1038/nature20581 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ED5UA UT WOS:000388916600013 PM 27905423 ER PT J AU Majithia, AR Tsuda, B Agostini, M Gnanapradeepan, K Rice, R Peloso, G Patel, KA Zhang, XL Broekema, MF Patterson, N Duby, M Sharpe, T Kalkhoven, E Rosen, ED Barroso, I Ellard, S Kathiresan, S O'Rahilly, S Chatterjee, K Florez, JC Mikkelsen, T Savage, DB Altshuler, D AF Majithia, Amit R. Tsuda, Ben Agostini, Maura Gnanapradeepan, Keerthana Rice, Robert Peloso, Gina Patel, Kashyap A. Zhang, Xiaolan Broekema, Marjoleine F. Patterson, Nick Duby, Marc Sharpe, Ted Kalkhoven, Eric Rosen, Evan D. Barroso, Ines Ellard, Sian Kathiresan, Sekar O'Rahilly, Stephen Chatterjee, Krishna Florez, Jose C. Mikkelsen, Tarjei Savage, David B. Altshuler, David CA UK Monogenic Diabetes Consortium Myocardial Infarction Genetics Con Uk Congenital Lipodystrophy Consor TI Prospective functional classification of all possible missense variants in PPARG SO NATURE GENETICS LA English DT Article ID INSULIN-RESISTANCE; RARE VARIANTS; GAMMA; MUTATIONS; RISK; DIFFERENTIATION; BINDING; DNA AB Clinical exome sequencing routinely identifies missense variants in disease-related genes, but functional characterization is rarely undertaken, leading to diagnostic uncertainty(1,2). For example, mutations in PPARG cause Mendelian lipodystrophy(3,4) and increase risk of type 2 diabetes (T2D)(5). Although approximately 1 in 500 people harbor missense variants in PPARG, most are of unknown consequence. To prospectively characterize PPAR gamma variants, we used highly parallel oligonucleotide synthesis to construct a library encoding all 9,595 possible single-amino acid substitutions. We developed a pooled functional assay in human macrophages, experimentally evaluated all protein variants, and used the experimental data to train a variant classifier by supervised machine learning. When applied to 55 new missense variants identified in population-based and clinical sequencing, the classifier annotated 6 variants as pathogenic; these were subsequently validated by single variant assays. Saturation mutagenesis and prospective experimental characterization can support immediate diagnostic interpretation of newly discovered missense variants in disease-related genes. C1 [Majithia, Amit R.; Tsuda, Ben; Gnanapradeepan, Keerthana; Rice, Robert; Peloso, Gina; Zhang, Xiaolan; Patterson, Nick; Duby, Marc; Sharpe, Ted; Kathiresan, Sekar; Florez, Jose C.; Mikkelsen, Tarjei; Altshuler, David] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [Majithia, Amit R.; Florez, Jose C.; Altshuler, David] Massachusetts Gen Hosp, Dept Med, Diabet Unit, Diabet Res Ctr, Boston, MA 02114 USA. [Majithia, Amit R.; Kathiresan, Sekar; Florez, Jose C.; Altshuler, David] Massachusetts Gen Hosp, Ctr Human Genet, Boston, MA 02114 USA. [Majithia, Amit R.; Rosen, Evan D.; Kathiresan, Sekar; Florez, Jose C.; Altshuler, David] Harvard Med Sch, Dept Med, Boston, MA USA. [Agostini, Maura; Barroso, Ines; O'Rahilly, Stephen; Chatterjee, Krishna; Savage, David B.] Univ Cambridge, Metab Res Labs, Wellcome Trust Med Res Council Inst Metab Sci, Cambridge, England. [Peloso, Gina] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Patel, Kashyap A.; Ellard, Sian] Univ Exeter, Sch Med, Inst Biomed & Clin Sci, Exeter, Devon, England. [Broekema, Marjoleine F.; Kalkhoven, Eric] Univ Med Ctr Utrecht, Mol Canc Res, Utrecht, Netherlands. [Broekema, Marjoleine F.; Kalkhoven, Eric] Univ Med Ctr Utrecht, Ctr Mol Med, Utrecht, Netherlands. [Rosen, Evan D.] Beth Israel Deaconess Med Ctr, Div Endocrinol & Metab, Boston, MA 02215 USA. [Ellard, Sian] Royal Devon & Exeter Natl Hlth Serv Fdn Trust, Dept Mol Genet, Exeter, Devon, England. [Kathiresan, Sekar] Massachusetts Gen Hosp, Dept Med, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Mikkelsen, Tarjei] 10X Genom Inc, Pleasanton, CA USA. [Altshuler, David] Vertex Pharmaceut, Boston, MA USA. RP Majithia, AR (reprint author), Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA.; Majithia, AR (reprint author), Massachusetts Gen Hosp, Dept Med, Diabet Unit, Diabet Res Ctr, Boston, MA 02114 USA.; Majithia, AR (reprint author), Massachusetts Gen Hosp, Ctr Human Genet, Boston, MA 02114 USA.; Majithia, AR (reprint author), Harvard Med Sch, Dept Med, Boston, MA USA. EM amajithia@mgh.harvard.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [1K08DK102877-01, 1R01DK097768-01]; NIH/Harvard Catalyst [1KL2TR001100-01]; Broad Institute; Wellcome Trust [095564, 107064] FX This work was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (1K08DK102877-01, to ARM.; 1R01DK097768-01, to D.A.), NIH/Harvard Catalyst (1KL2TR001100-01, to ARM.), the Broad Institute (SPARC award, to A.R.M. and T.M.), and the Wellcome Trust (095564, to K.C.; 107064, to D.B.S.). NR 26 TC 4 Z9 4 U1 15 U2 15 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 DEC PY 2016 VL 48 IS 12 BP 1570 EP 1575 DI 10.1038/ng.3700 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA ED7BQ UT WOS:000389011100019 PM 27749844 ER PT J AU Cosgrove, BD Mui, KL Driscoll, TP Caliari, SR Mehta, KD Assoian, RK Burdick, JA Mauck, RL AF Cosgrove, Brian D. Mui, Keeley L. Driscoll, Tristan P. Caliari, Steven R. Mehta, Kush D. Assoian, Richard K. Burdick, Jason A. Mauck, Robert L. TI N-cadherin adhesive interactions modulate matrix mechanosensing and fate commitment of mesenchymal stem cells SO NATURE MATERIALS LA English DT Article ID ALPHA-CATENIN; RHO GTPASES; JUNCTIONS; HYDROGELS; CHONDROGENESIS; STIFFNESS; TENSION; YAP/TAZ; GROWTH; RAC AB During mesenchymal development, the microenvironment gradually transitions from one that is rich in cell-cell interactions to one that is dominated by cell-ECM (extracellular matrix) interactions. Because these cues cannot readily be decoupled in vitro or in vivo, how they converge to regulate mesenchymal stem cell (MSC) mechanosensing is not fully understood. Here, we show that a hyaluronic acid hydrogel system enables, across a physiological range of ECM stiffness, the independent co-presentation of the HAVDI adhesive motif from the EC1 domain of N-cadherin and the RGD adhesive motif from fibronectin. Decoupled presentation of these cues revealed that HAVDI ligation (at constant RGD ligation) reduced the contractile state and thereby nuclear YAP/TAZ localization in MSCs, resulting in altered interpretation of ECM stiffness and subsequent changes in downstream cell proliferation and differentiation. Our findings reveal that, in an evolving developmental context, HAVDI/N-cadherin interactions can alter stem cell perception of the stiffening extracellular microenvironment. C1 [Cosgrove, Brian D.; Driscoll, Tristan P.; Mehta, Kush D.; Mauck, Robert L.] Univ Penn, Perelman Sch Med, Dept Orthopaed Surg, McKay Orthopaed Res Lab, Philadelphia, PA 19104 USA. [Cosgrove, Brian D.; Driscoll, Tristan P.; Caliari, Steven R.; Mehta, Kush D.; Burdick, Jason A.; Mauck, Robert L.] Univ Penn, Dept Bioengn, Philadelphia, PA 19104 USA. [Driscoll, Tristan P.; Mauck, Robert L.] Philadelphia VA Med Ctr, Translat Musculoskeletal Res Ctr, Philadelphia, PA 19104 USA. [Assoian, Richard K.] Univ Penn, Perelman Sch Med, Dept Pharmacol, Philadelphia, PA 19104 USA. RP Mauck, RL (reprint author), Univ Penn, Perelman Sch Med, Dept Orthopaed Surg, McKay Orthopaed Res Lab, Philadelphia, PA 19104 USA.; Mauck, RL (reprint author), Univ Penn, Dept Bioengn, Philadelphia, PA 19104 USA.; Mauck, RL (reprint author), Philadelphia VA Med Ctr, Translat Musculoskeletal Res Ctr, Philadelphia, PA 19104 USA. EM lemauck@mail.med.upenn.edu OI Driscoll, Tristan/0000-0002-2426-5551 FU National Institutes of Health [R01 EB008722, R01 HL115553]; Penn Center for Musculoskeletal Disorders [P30 AR050950] FX The authors would like to thank C. McLeod for assistance with atomic force microscopy and curve fitting, C. Rodell for helpful discussions regarding MeHA synthesis and peptide conjugation, and M. Guvendiren for assistance with preliminary studies. This work was funded by the National Institutes of Health (R01 EB008722, R01 HL115553) and the Penn Center for Musculoskeletal Disorders (P30 AR050950). NR 53 TC 2 Z9 2 U1 22 U2 22 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 DEC PY 2016 VL 15 IS 12 BP 1297 EP 1306 DI 10.1038/NMAT4725 PG 10 WC Chemistry, Physical; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Materials Science; Physics GA ED8EI UT WOS:000389104400018 PM 27525568 ER PT J AU Bandyopadhaya, A Tsurumi, A Maura, D Jeffrey, KL Rahme, LG AF Bandyopadhaya, Arunava Tsurumi, Amy Maura, Damien Jeffrey, Kate L. Rahme, Laurence G. TI A quorum-sensing signal promotes host tolerance training through HDAC1-mediated epigenetic reprogramming SO NATURE MICROBIOLOGY LA English DT Article ID PSEUDOMONAS-AERUGINOSA; HOMOSERINE LACTONES; VIRULENCE FACTORS; IMMUNE-SYSTEM; BACTERIAL; INHIBITOR; 2-AMINOACETOPHENONE; PATHOGENESIS; DEFENSE; PATHOGENICITY AB The mechanisms by which pathogens evade elimination without affecting host fitness are not well understood. For the pathogen Pseudomonas aeruginosa, this evasion appears to be triggered by excretion of the quorum-sensing molecule 2-aminoacetophenone, which dampens host immune responses and modulates host metabolism, thereby enabling the bacteria to persist at a high burden level. Here, we examined how 2-aminoacetophenone trains host tissues to become tolerant to a high bacterial burden, without compromising host fitness. We found that 2-aminoacetophenone regulates histone deacetylase 1 expression and activity, resulting in hypo-acetylation of lysine 18 of histone H3 at pro-inflammatory cytokine loci. Specifically, 2-aminoacetophenone induced reprogramming of immune cells occurs via alterations in histone acetylation of immune cytokines in vivo and in vitro. This host epigenetic reprograming, which was maintained for up to 7 days, dampened host responses to subsequent exposure to 2-aminoacetophenone or other unrelated pathogen-associated molecules. The process was found to involve a distinct molecular mechanism of host chromatin regulation. Inhibition of histone deacetylase 1 prevented the immunomodulatory effects of 2-aminoacetophenone. These observations provide the first mechanistic example of a quorum-sensing molecule regulating a host epigenome to enable tolerance of infection. These insights have enormous potential for developing preventive treatments against bacterial infections. C1 [Bandyopadhaya, Arunava; Tsurumi, Amy; Maura, Damien; Rahme, Laurence G.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Bandyopadhaya, Arunava; Tsurumi, Amy; Maura, Damien; Rahme, Laurence G.] Harvard Med Sch, Boston, MA 02114 USA. [Bandyopadhaya, Arunava; Tsurumi, Amy; Maura, Damien; Rahme, Laurence G.] Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. [Bandyopadhaya, Arunava; Tsurumi, Amy; Maura, Damien; Rahme, Laurence G.] Shriners Hosp Children Boston, Boston, MA 02114 USA. [Jeffrey, Kate L.] Harvard Med Sch, Gastrointestinal Unit, Boston, MA 02114 USA. [Jeffrey, Kate L.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA. RP Rahme, LG (reprint author), Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA.; Rahme, LG (reprint author), Harvard Med Sch, Boston, MA 02114 USA.; Rahme, LG (reprint author), Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA 02115 USA.; Rahme, LG (reprint author), Shriners Hosp Children Boston, Boston, MA 02114 USA. EM rahme@molbio.mgh.harvard.edu FU Shriners grant [87100, 85200]; NIH [R33AI105902]; Cystic Fibrosis Foundation [11P0] FX The authors thank S. Mehta and M. Basavappa for their help with the isolation of human primary macrophages and mouse primary macrophages, respectively. The authors thank A. Ballok and A. Power Smith of Write Science Right for editing the manuscript. This work was supported by Shriners grants (nos. 87100 and 85200) and in part by NIH R33AI105902 and Cystic Fibrosis Foundation grant no. CFF# 11P0. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. NR 52 TC 0 Z9 0 U1 18 U2 18 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2058-5276 J9 NAT MICROBIOL JI NAT. MICROBIOL PD DEC PY 2016 VL 1 IS 12 AR 16174 DI 10.1038/NMICROBIOL.2016.174 PG 9 WC Microbiology SC Microbiology GA ED8SC UT WOS:000389140200007 PM 27694949 ER PT J AU Ganna, A Genovese, G Howrigan, DP Byrnes, A Kurki, MI Zekavat, SM Whelan, CW Kals, M Nivard, MG Bloemendal, A Bloom, JM Goldstein, JI Poterba, T Seed, C Handsaker, RE Natarajan, P Magi, R Gage, D Robinson, EB Metspalu, A Salomaall, V Suvisaarill, J Purcell, SM Sklar, P Kathiresan, S Daly, MJ McCarroll, SA Sullivan, PF Palotie, A Esko, T Hultman, CM Neale, BM AF Ganna, Andrea Genovese, Giulio Howrigan, Daniel P. Byrnes, Andrea Kurki, Mitja I. Zekavat, Seyedeh M. Whelan, Christopher W. Kals, Mart Nivard, Michel G. Bloemendal, Alex Bloom, Jonathan M. Goldstein, Jacqueline I. Poterba, Timothy Seed, Cotton Handsaker, Robert E. Natarajan, Pradeep Magi, Reedik Gage, Diane Robinson, Elise B. Metspalu, Andres Salomaall, Veildco Suvisaarill, Jaana Purcell, Shaun M. Sklar, Pamela Kathiresan, Sekar Daly, Mark J. McCarroll, Steven A. Sullivan, Patrick F. Palotie, Aarno Esko, Tonu Hultman, Christina M. Neale, Benjamin M. TI Ultra-rare disruptive and damaging mutations influence educational attainment in the general population SO NATURE NEUROSCIENCE LA English DT Article ID MISSING HERITABILITY; VARIANT ASSOCIATION; INTELLIGENCE AB Disruptive, damaging ultra-rare variants in highly constrained genes are enriched in individuals with neurodevelopmental disorders. In the general population, this class of variants was associated with a decrease in years of education (YOE). This effect was stronger among highly brain-expressed genes and explained more YOE variance than pathogenic copy number variation but less than common variants. Disruptive, damaging ultra-rare variants in highly constrained genes influence the determinants of YOE in the general population. C1 [Ganna, Andrea; Howrigan, Daniel P.; Byrnes, Andrea; Kurki, Mitja I.; Bloemendal, Alex; Bloom, Jonathan M.; Goldstein, Jacqueline I.; Poterba, Timothy; Seed, Cotton; Robinson, Elise B.; Daly, Mark J.; Palotie, Aarno; Neale, Benjamin M.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Ganna, Andrea; Genovese, Giulio; Howrigan, Daniel P.; Byrnes, Andrea; Kurki, Mitja I.; Zekavat, Seyedeh M.; Whelan, Christopher W.; Bloemendal, Alex; Bloom, Jonathan M.; Goldstein, Jacqueline I.; Poterba, Timothy; Seed, Cotton; Handsaker, Robert E.; Natarajan, Pradeep; Robinson, Elise B.; Kathiresan, Sekar; Daly, Mark J.; McCarroll, Steven A.; Esko, Tonu; Neale, Benjamin M.] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Ganna, Andrea; Genovese, Giulio; Howrigan, Daniel P.; Byrnes, Andrea; Kurki, Mitja I.; Whelan, Christopher W.; Bloemendal, Alex; Bloom, Jonathan M.; Goldstein, Jacqueline I.; Poterba, Timothy; Seed, Cotton; Handsaker, Robert E.; Gage, Diane; Robinson, Elise B.; Daly, Mark J.; McCarroll, Steven A.; Palotie, Aarno; Neale, Benjamin M.] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA. [Ganna, Andrea; Sullivan, Patrick F.; Hultman, Christina M.] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Genovese, Giulio; Whelan, Christopher W.; Handsaker, Robert E.; McCarroll, Steven A.] Harvard Med Sch, Dept Genet, Boston, MA USA. [Kurki, Mitja I.; Palotie, Aarno] Univ Helsinki, Inst Mol Med Finland, FIMM, Helsinki, Finland. [Zekavat, Seyedeh M.; Natarajan, Pradeep; Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Zekavat, Seyedeh M.; Natarajan, Pradeep; Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Kals, Mart; Magi, Reedik; Metspalu, Andres; Esko, Tonu] Univ Tartu, Estonian Genome Ctr, Tartu, Estonia. [Kals, Mart] Univ Tartu, Inst Math & Stat, Tartu, Estonia. [Nivard, Michel G.] Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands. [Salomaall, Veildco; Suvisaarill, Jaana] THL Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland. [Purcell, Shaun M.; Sklar, Pamela] Icahn Sch Med Mt Sinai, Dept Psychiat, Div Psychiat Genom, New York, NY 10029 USA. [Purcell, Shaun M.; Sklar, Pamela] Icahn Sch Med Mt Sinai, Inst Genom & Multiscale Biol, New York, NY 10029 USA. [Sullivan, Patrick F.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Sullivan, Patrick F.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. RP Ganna, A (reprint author), Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA.; Ganna, A (reprint author), Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA.; Ganna, A (reprint author), Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA.; Ganna, A (reprint author), Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. EM aganna@broadinstitute.org OI Nivard, Michel/0000-0003-2015-1888; Ganna, Andrea/0000-0002-8147-240X FU Knut and Alice Wallenberg Foundation [2015.0327]; Swedish Research Council [2016-00250]; Royal Netherlands Academy of Science [PAH/6635]; Finnish Foundation for Cardiovascular Research; National Human Genome Research Institute [U54 HG003067, R01 HG006855]; National Institute of Mental Health [1U01MH105666-01, 1R01MH101244-02]; National Institute of Diabetes and Digestive and Kidney Disease [1U54DK105566-02]; Stanley Center for Psychiatric Research; Alexander and Margaret Stewart Trust; National Institutes of Mental Health [R01 MH077139, RC2 MH089905]; Sylvan C. Herman Foundation; EU [692145, 676550, 654248]; Estonian Research Council [IUT20-60]; NIASC; EIT-Health; NIH-BMI Grant [2R0IDK075787-06A1]; EU through the European Regional Development Fund [2014-2020.4.01.15-0012 GENTRANSMED] FX We thank R. Walters for discussions. A.G. is supported by the Knut and Alice Wallenberg Foundation (2015.0327) and the Swedish Research Council (2016-00250). M.G.N. is supported by the Royal Netherlands Academy of Science Professor Award (PAH/6635) to Dorret I. Boomsma. V.S. was supported by the Finnish Foundation for Cardiovascular Research. This study was supported by grants from the National Human Genome Research Institute (U54 HG003067 and R01 HG006855); the National Institute of Mental Health (1U01MH105666-01 and 1R01MH101244-02); the National Institute of Diabetes and Digestive and Kidney Disease (1U54DK105566-02); the Stanley Center for Psychiatric Research; the Alexander and Margaret Stewart Trust; the National Institutes of Mental Health (R01 MH077139 and RC2 MH089905); the Sylvan C. Herman Foundation; EU H2020 grants 692145, 676550 and 654248; Estonian Research Council Grant IUT20-60, NIASC, EIT-Health; NIH-BMI Grant No. 2R0IDK075787-06A1; and by the EU through the European Regional Development Fund (Project No. 2014-2020.4.01.15-0012 GENTRANSMED). NR 19 TC 1 Z9 1 U1 11 U2 11 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 EI 1546-1726 J9 NAT NEUROSCI JI Nat. Neurosci. PD DEC PY 2016 VL 19 IS 12 BP 1563 EP 1565 DI 10.1038/nn.4404 PG 3 WC Neurosciences SC Neurosciences & Neurology GA ED7BY UT WOS:000389011900014 PM 27694993 ER PT J AU Adams, HHH Hibar, DP Chouraki, V Stein, JL Nyquist, PA Renteria, ME Trompet, S Arias-Vasquez, A Seshadri, S Desrivieres, S Beecham, AH Jahanshad, N Wittfeld, K Van der Lee, SJ Abramovic, L Alhusaini, S Amin, N Andersson, M Arfanakis, K Aribisala, BS Armstrong, NJ Athanasiu, L Axelsson, T Beiser, A Bernard, M Bis, JC Blanken, LME Blanton, SH Bohlken, MM Boks, MP Bralten, J Brickman, AM Carmichael, O Chakravarty, MM Chauhan, G Chen, Q Ching, CRK Cuellar-Partida, G Den Braber, A Doan, NT Ehrlich, S Filippi, I Ge, T Giddaluru, S Goldman, AL Gottesman, RF Greven, CU Grimm, O Griswold, ME Guadalupe, T Hass, J Haukvik, UK Hilal, S Hofer, E Hoehn, D Holmes, AJ Hoogman, M Janowitz, D Jia, T Kasperaviciute, D Kim, S Klein, M Kraemer, B Lee, PH Liao, J Liewald, DCM Lopez, LM Luciano, M Macare, C Marquand, A Matarin, M Mather, KA Mattheisen, M Mazoyer, B Mckay, DR McWhirter, R Milaneschi, Y Mirza-Schreiber, N Muetzel, RL Maniega, SM Nho, K Nugent, AC Loohuis, LMO Oosterlaan, J Papmeyer, M Pappa, I Pirpamer, L Pudas, S Puetz, B Rajan, KB Ramasamy, A Richards, JS Risacher, SL Roiz-Santianez, R Rommelse, N Rose, EJ Royle, NA Rundek, T Samann, PG Satizabal, CL Schmaal, L Schork, AJ Shen, L Shin, J Shumskaya, E Smith, AV Sprooten, E Strike, LT Teumer, A Thomson, R Tordesillas-Gutierrez, D Toro, R Trabzuni, D Vaidya, D Van der Grond, J Van der Meer, D Van Donkelaar, MMJ Van Eijk, KR Van Erp, TGM Van Rooij, D Walton, E Westlye, LT Whelan, CD Windham, BG Winkler, AM Woldehawariat, G Wolf, C Wolfers, T Xu, B Yanek, LR Yang, JY Zijdenbos, A Zwiers, MP Agartz, I Aggarwal, NT Almasy, L Ames, D Amouyel, P Andreassen, OA Arepalli, S Assareh, AA Barral, S Bastin, ME Becker, DM Becker, JT Bennett, DA Blangero, J van Bokhoven, H Boomsma, DI Brodaty, H Brouwer, RM Brunner, HG Buckner, RL Buitelaar, JK Bulayeva, KB Cahn, W Calhoun, VD Cannon, DM Cavalleri, GL Chen, C Cheng, CY Cichon, S Cookson, MR Corvin, A Crespo-Facorro, B Curran, JE Czisch, M Dale, AM Davies, GE De Geus, EJC De Jager, PL de Zubicaray, GI Delanty, N Depondt, C DeStefano, AL Dillman, A Djurovic, S Donohoe, G Drevets, WC Duggirala, R Dyer, TD Erk, S Espeseth, T Evans, DA Fedko, I Fernandez, G Ferrucci, L Fisher, SE Fleischman, DA Ford, I Foroud, TM Fox, PT Francks, C Fukunaga, M Gibbs, JR Glahn, DC Gollub, RL Goring, HHH Grabe, HJ Green, RC Gruber, O Gudnason, V Guelfi, S Hansell, NK Hardy, J Hartman, CA Hashimoto, R Hegenscheid, K Heinz, A Le Hellard, S Hernandez, DG Heslenfeld, DJ Ho, BC Hoekstra, PJ Hoffmann, W Hofman, A Holsboer, F Homuth, G Hosten, N Hottenga, JJ Pol, HEH Ikeda, M Ikram, MK Jack, CR Jenldnson, M Johnson, R Jonsson, EG Jukema, JW Kahn, RS Kanai, R Kloszewska, I Knopman, DS Kochunov, P Kwok, JB Lawrie, SM Lemaitre, H Liu, XM Longo, DL Longstreth, WT Lopez, OL Lovestone, S Martinez, O Martinot, JL Mattay, VS McDonald, C McIntosh, AM McMahon, KL McMahon, FJ Mecocci, P Melle, I Meyer-Lindenberg, A Mohnke, S Montgomery, GW Morris, DW Mosley, TH Muhleisen, TW Muller-Myhsok, B Nalls, MA Nauck, M Nichols, TE Niessen, WJ Nothen, MM Nyberg, L Ohi, K Olvera, RL Ophoff, RA Pandolfo, M Paus, T Pausova, Z Penninx, BWJH Pike, GB Potkin, SG Psaty, BM Reppermund, S Rietschel, M Roffman, JL Romanczuk-Seiferth, N Rotter, JI Ryten, M Sacco, RL Sachdev, PS Saykin, AJ Schmidt, R Schofield, PR Sigurdsson, S Simmons, A Singleton, A Sisodiya, SM Smith, C Smoller, JW Soininen, H Srikanth, V Steen, VM Stott, DJ Sussmann, JE Thalamuthu, A Tiemeier, H Toga, AW Traynor, BJ Troncoso, J Turner, JA Tzourio, C Uitterlinden, AG Hernandez, MCV Van der Brug, M Van der Lugt, A Van der Wee, NJA Van Duijn, CM Van Haren, NEM Van't Ent, D Van Tol, MJ Vardarajan, BN Veltman, DJ Vernooij, MW Volzke, H Walter, H Wardlaw, JM Wassink, TH Weale, ME Weinberger, DR Weiner, MW Wen, W Westman, E White, T Wong, TY Wright, CB Zielke, HR Zonderman, AB Deary, IJ DeCarli, C Schmidt, H Martin, NG De Craen, AJM Wright, MJ Launer, LJ Schumann, G Fornage, M Franke, B Debette, S Medland, SE Ikram, MA Thompson, PM AF Adams, Hieab H. H. Hibar, Derrek P. Chouraki, Vincent Stein, Jason L. Nyquist, Paul A. Renteria, Miguel E. Trompet, Stella Arias-Vasquez, Alejandro Seshadri, Sudha Desrivieres, Sylvane Beecham, Ashley H. Jahanshad, Neda Wittfeld, Katharine Van der Lee, Sven J. Abramovic, Lucija Alhusaini, Saud Amin, Najaf Andersson, Micael Arfanakis, Konstantinos Aribisala, Benjamin S. Armstrong, Nicola J. Athanasiu, Lavinia Axelsson, Tomas Beiser, Alexa Bernard, Manon Bis, Joshua C. Blanken, Laura M. E. Blanton, Susan H. Bohlken, Marc M. Boks, Marco P. Bralten, Janita Brickman, Adam M. Carmichael, Owen Chakravarty, M. Mallar Chauhan, Ganesh Chen, Qiang Ching, Christopher R. K. Cuellar-Partida, Gabriel Den Braber, Anouk Doan, Nhat Trung Ehrlich, Stefan Filippi, Irina Ge, Tian Giddaluru, Sudheer Goldman, Aaron L. Gottesman, Rebecca F. Greven, Corina U. Grimm, Oliver Griswold, Michael E. Guadalupe, Tulio Hass, Johanna Haukvik, Unn K. Hilal, Saima Hofer, Edith Hoehn, David Holmes, Avram J. Hoogman, Martine Janowitz, Deborah Jia, Tianye Kasperaviciute, Dalia Kim, Sungeun Klein, Marieke Kraemer, Bernd Lee, Phil H. Liao, Jiemin Liewald, David C. M. Lopez, Lorna M. Luciano, Michelle Macare, Christine Marquand, Andre Matarin, Mar Mather, Karen A. Mattheisen, Manuel Mazoyer, Bernard Mckay, David R. McWhirter, Rebekah Milaneschi, Yuri Mirza-Schreiber, Nazanin Muetzel, Ryan L. Maniega, Susana Munoz Nho, Kwangsik Nugent, Allison C. Loohuis, Loes M. Olde Oosterlaan, Jaap Papmeyer, Martina Pappa, Irene Pirpamer, Lukas Pudas, Sara Puetz, Benno Rajan, Kumar B. Ramasamy, Adaikalavan Richards, Jennifer S. Risacher, Shannon L. Roiz-Santianez, Roberto Rommelse, Nanda Rose, Emma J. Royle, Natalie A. Rundek, Tatjana Saemann, Philipp G. Satizabal, Claudia L. Schmaal, Lianne Schork, Andrew J. Shen, Li Shin, Jean Shumskaya, Elena Smith, Albert V. Sprooten, Emma Strike, Lachlan T. Teumer, Alexander Thomson, Russell Tordesillas-Gutierrez, Diana Toro, Roberto Trabzuni, Daniah Vaidya, Dhananjay Van der Grond, Jeroen Van der Meer, Dennis Van Donkelaar, Marjolein M. J. Van Eijk, Kristel R. Van Erp, Theo G. M. Van Rooij, Daan Walton, Esther Westlye, Lars T. Whelan, Christopher D. Windham, Beverly G. Winkler, Anderson M. Woldehawariat, Girma Wolf, Christiane Wolfers, Thomas Xu, Bing Yanek, Lisa R. Yang, Jingyun Zijdenbos, Alex Zwiers, Marcel P. Agartz, Ingrid Aggarwal, Neelum T. Almasy, Laura Ames, David Amouyel, Philippe Andreassen, Ole A. Arepalli, Sampath Assareh, Amelia A. Barral, Sandra Bastin, Mark E. Becker, Diane M. Becker, James T. Bennett, David A. Blangero, John van Bokhoven, Hans Boomsma, Dorret I. Brodaty, Henry Brouwer, Rachel M. Brunner, Han G. Buckner, Randy L. Buitelaar, Jan K. Bulayeva, Kazima B. Cahn, Wiepke Calhoun, Vince D. Cannon, Dara M. Cavalleri, Gianpiero L. Chen, Christopher Cheng, Ching -Yu Cichon, Sven Cookson, Mark R. Corvin, Aiden Crespo-Facorro, Benedicto Curran, Joanne E. Czisch, Michael Dale, Anders M. Davies, Gareth E. De Geus, Eco J. C. De Jager, Philip L. de Zubicaray, Greig I. Delanty, Norman Depondt, Chantal DeStefano, Anita L. Dillman, Allissa Djurovic, Srdjan Donohoe, Gary Drevets, Wayne C. Duggirala, Ravi Dyer, Thomas D. Erk, Susanne Espeseth, Thomas Evans, Denis A. Fedko, Iryna Fernandez, Guillen Ferrucci, Luigi Fisher, Simon E. Fleischman, Debra A. Ford, Ian Foroud, Tatiana M. Fox, Peter T. Francks, Clyde Fukunaga, Masaki Gibbs, J. Raphael Glahn, David C. Gollub, Randy L. Goring, Harald H. H. Grabe, Hans J. Green, Robert C. Gruber, Oliver Gudnason, Vilmundur Guelfi, Sebastian Hansell, Narelle K. Hardy, John Hartman, Catharina A. Hashimoto, Ryota Hegenscheid, Katrin Heinz, Andreas Le Hellard, Stephanie Hernandez, Dena G. Heslenfeld, Dirk J. Ho, Beng-Choon Hoekstra, Pieter J. Hoffmann, Wolfgang Hofman, Albert Holsboer, Florian Homuth, Georg Hosten, Norbert Hottenga, Jouke-Jan Pol, Hilleke E. Hulshoff Ikeda, Masashi Ikram, M. Kamran Jack, Clifford R., Jr. Jenldnson, Mark Johnson, Robert Jonsson, Erik G. Jukema, J. Wouter Kahn, Rene S. Kanai, Ryota Kloszewska, Iwona Knopman, David S. Kochunov, Peter Kwok, John B. Lawrie, Stephen M. Lemaitre, Herve Liu, Xinmin Longo, Dan L. Longstreth, W. T., Jr. Lopez, Oscar L. Lovestone, Simon Martinez, Oliver Martinot, Jean-Luc Mattay, Venkata S. McDonald, Colm McIntosh, Andrew M. McMahon, Katie L. McMahon, Francis J. Mecocci, Patrizia Melle, Ingrid Meyer-Lindenberg, Andreas Mohnke, Sebastian Montgomery, Grant W. Morris, Derek W. Mosley, Thomas H. Muhleisen, Thomas W. Mueller-Myhsok, Bertram Nalls, Michael A. Nauck, Matthias Nichols, Thomas E. Niessen, Wiro J. Noethen, Markus M. Nyberg, Lars Ohi, Kazutaka Olvera, Rene L. Ophoff, Roel A. Pandolfo, Massimo Paus, Tomas Pausova, Zdenka Penninx, Brenda W. J. H. Pike, G. Bruce Potkin, Steven G. Psaty, Bruce M. Reppermund, Simone Rietschel, Marcella Roffman, Joshua L. Romanczuk-Seiferth, Nina Rotter, Jerome I. Ryten, Mina Sacco, Ralph L. Sachdev, Perminder S. Saykin, Andrew J. Schmidt, Reinhold Schofield, Peter R. Sigurdsson, Sigurdur Simmons, Andy Singleton, Andrew Sisodiya, Sanjay M. Smith, Colin Smoller, Jordan W. Soininen, Hindu. Srikanth, Velandai Steen, Vidar M. Stott, David J. Sussmann, Jessika E. Thalamuthu, Anbupalam Tiemeier, Henning Toga, Arthur W. Traynor, Bryan J. Troncoso, Juan Turner, Jessica A. Tzourio, Christophe Uitterlinden, Andre G. Hernandez, Maria C. Valdes Van der Brug, Marcel Van der Lugt, Aad Van der Wee, Nic J. A. Van Duijn, Cornelia M. Van Haren, Neeltje E. M. Van't Ent, Dennis Van Tol, Marie Jose Vardarajan, Badri N. Veltman, Dick J. Vernooij, Meike W. Voelzke, Henry Walter, Henrik Wardlaw, Joanna M. Wassink, Thomas H. Weale, Michael E. Weinberger, Daniel R. Weiner, Michael W. Wen, Wei Westman, Eric White, Tonya Wong, Tien Y. Wright, Clinton B. Zielke, H. Ronald Zonderman, Alan B. Deary, Ian J. DeCarli, Charles Schmidt, Helena Martin, Nicholas G. De Craen, Anton J. M. Wright, Margaret J. Launer, Lenore J. Schumann, Gunter Fornage, Myriam Franke, Barbara Debette, Stephanie Medland, Sarah E. Ikram, M. Arfan Thompson, Paul M. CA Alzheimer's Dis Neuroimaging Initi EPIGEN IMAGEN SYS TI Novel genetic loci underlying human intracranial volume identified through genome-wide association SO NATURE NEUROSCIENCE LA English DT Article ID COMMON VARIANTS; 17Q21.31 MICRODELETION; PARKINSONS-DISEASE; ALZHEIMERS-DISEASE; HEAD CIRCUMFERENCE; BRAIN SIZE; IGF-I; METAANALYSIS; CONSORTIUM; GROWTH AB Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (rho(genetic) = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (N-combined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits. C1 [Adams, Hieab H. H.; Van der Lee, Sven J.; Amin, Najaf; Hofman, Albert; Ikram, M. Kamran; Tiemeier, Henning; Uitterlinden, Andre G.; Van Duijn, Cornelia M.; Vernooij, Meike W.; Ikram, M. Arfan] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Adams, Hieab H. H.; Niessen, Wiro J.; Van der Lugt, Aad; Vernooij, Meike W.; White, Tonya; Ikram, M. Arfan] Erasmus MC, Dept Radiol & Nucl Med, Rotterdam, Netherlands. [Hibar, Derrek P.; Stein, Jason L.; Jahanshad, Neda; Ching, Christopher R. K.; Whelan, Christopher D.; Thompson, Paul M.] Univ Southern Calif, Keck Sch Med, USC Mark & Mary Stevens Neuroimaging & Informat I, Imaging Genet Ctr, Los Angeles, CA USA. [Chouraki, Vincent; Seshadri, Sudha; Beiser, Alexa; Satizabal, Claudia L.; Debette, Stephanie] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Chouraki, Vincent; Amouyel, Philippe] Univ Lille, RID AGE Risk Factors & Mol Determinants Aging Rel, CHU Lille, Inserm,Inst Pasteur Lille, Lille, France. [Chouraki, Vincent; Seshadri, Sudha; Beiser, Alexa; Satizabal, Claudia L.; DeStefano, Anita L.] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Stein, Jason L.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Stein, Jason L.] Univ N Carolina, UNC Neurosci Ctr, Chapel Hill, NC USA. [Nyquist, Paul A.] Johns Hopkins Univ, Dept Neurol, Dept Anesthesia Crit Care Med, Dept Neurosurg, Baltimore, MD 21218 USA. [Renteria, Miguel E.; Cuellar-Partida, Gabriel; Strike, Lachlan T.; Hansell, Narelle K.; Montgomery, Grant W.; Martin, Nicholas G.; Medland, Sarah E.] QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia. [Trompet, Stella; Jukema, J. Wouter] Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands. [Arias-Vasquez, Alejandro; Bralten, Janita; Hoogman, Martine; Klein, Marieke; Shumskaya, Elena; Van Donkelaar, Marjolein M. J.; Wolfers, Thomas; van Bokhoven, Hans; Brunner, Han G.; Franke, Barbara] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Nijmegen, Netherlands. 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[Beecham, Ashley H.; Blanton, Susan H.] Univ Miami, Miller Sch Med, Dept Human Genet, Dr John T Macdonald Fdn, Miami, FL 33136 USA. [Beecham, Ashley H.; Blanton, Susan H.; Sacco, Ralph L.] Univ Miami, Miller Sch Med, John P Hussman Inst Human Gen, Miami, FL 33136 USA. [Wittfeld, Katharine; Hoffmann, Wolfgang] German Ctr Neurodegenerat Dis DZNE Rostock Greifs, Greifswald, Germany. [Wittfeld, Katharine; Janowitz, Deborah; Grabe, Hans J.] Univ Med Greifswald, Dept Psychiat, Greifswald, Germany. [Abramovic, Lucija; Bohlken, Marc M.; Boks, Marco P.; Brouwer, Rachel M.; Cahn, Wiepke; Pol, Hilleke E. Hulshoff; Kahn, Rene S.; Ophoff, Roel A.; Van Haren, Neeltje E. M.] UMC Utrecht, Dept Psychiat, Brain Ctr Rudolf Magnus, Utrecht, Netherlands. [Alhusaini, Saud] McGill Univ, Montreal Neurol Inst, Dept Neurol & Neurosurg, Montreal, PQ, Canada. [Alhusaini, Saud; Whelan, Christopher D.; Cavalleri, Gianpiero L.; Delanty, Norman] Royal Coll Surgeons Ireland, Dublin 2, Ireland. [Andersson, Micael; Pudas, Sara; Nyberg, Lars] Umea Univ, Dept Integrat Med Biol, Umea, Sweden. [Arfanakis, Konstantinos] IIT, Dept Biomed Engn, Chicago, IL 60616 USA. [Arfanakis, Konstantinos; Yang, Jingyun; Aggarwal, Neelum T.; Bennett, David A.; Fleischman, Debra A.] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA. [Arfanakis, Konstantinos] Rush Univ, Med Ctr, Dept Diagnost Radiol & Nucl Med, Chicago, IL 60612 USA. [Aribisala, Benjamin S.; Maniega, Susana Munoz; Royle, Natalie A.; Bastin, Mark E.; Hernandez, Maria C. Valdes; Wardlaw, Joanna M.] Univ Edinburgh, Brain Res Imaging Ctr, Edinburgh, Midlothian, Scotland. [Aribisala, Benjamin S.] Lagos State Univ, Dept Comp Sci, Lagos, Nigeria. [Aribisala, Benjamin S.; Maniega, Susana Munoz; Royle, Natalie A.; Bastin, Mark E.; Hernandez, Maria C. Valdes; Wardlaw, Joanna M.] Univ Edinburgh, Dept Neuroimaging Sci, Scottish Imaging Network, Edinburgh, Midlothian, Scotland. [Armstrong, Nicola J.; Mather, Karen A.; Assareh, Amelia A.; Brodaty, Henry; Reppermund, Simone; Sachdev, Perminder S.; Thalamuthu, Anbupalam; Wen, Wei] Univ New South Wales, Sch Psychiat, Ctr Hlth Brain Ageing, Sydney, NSW, Australia. [Armstrong, Nicola J.] Murdoch Univ, Math & Stat, Perth, WA, Australia. [Athanasiu, Lavinia; Doan, Nhat Trung; Haukvik, Unn K.; Agartz, Ingrid; Andreassen, Ole A.; Jonsson, Erik G.; Melle, Ingrid] Univ Oslo, Inst Clin Med, NORMENT KG Jebsen Ctr, Oslo, Norway. [Athanasiu, Lavinia; Westlye, Lars T.; Andreassen, Ole A.; Espeseth, Thomas; Melle, Ingrid] Oslo Univ Hosp, Div Mental Hlth & Addict, NORMENT KG Jebsen Ctr, Oslo, Norway. [Axelsson, Tomas] Uppsala Univ, Dept Med Sci Mol Med, Uppsala, Sweden. [Axelsson, Tomas] Uppsala Univ, Sci Life Lab, Uppsala, Sweden. [Beiser, Alexa] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Bernard, Manon; Shin, Jean; Pausova, Zdenka] Univ Toronto, Hosp Sick Children, Toronto, ON, Canada. [Bis, Joshua C.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Blanken, Laura M. E.; Muetzel, Ryan L.; Pappa, Irene] Erasmus MC, Generat R Study Grp, Rotterdam, Netherlands. [Blanken, Laura M. E.; Muetzel, Ryan L.; Tiemeier, Henning; White, Tonya] Erasmus MC Sophia Childrens Hosp, Dept Child & Adolescent Psychiat Psychol, Rotterdam, Netherlands. [Brickman, Adam M.; Barral, Sandra; Vardarajan, Badri N.] Columbia Univ, Med Ctr, Taub Inst Res Alzheimers Dis & Aging Brain, New York, NY USA. [Brickman, Adam M.] Columbia Univ, GH Sergievsky Ctr, Med Ctr, New York, NY USA. [Brickman, Adam M.] Columbia Univ, Dept Neurol, Med Ctr, New York, NY USA. [Carmichael, Owen] Pennington Biomed Res Ctr, 6400 Perkins Rd, Baton Rouge, LA 70808 USA. [Chakravarty, M. Mallar] Douglas Mental Hlth Univ Inst, Cerebral Imaging Ctr, Montreal, PQ, Canada. [Chakravarty, M. Mallar] McGill Univ, Dept Psychiat & Biomed Engn, Montreal, PQ, Canada. [Chauhan, Ganesh] Univ Bordeaux, INSERM Unit U1219, Bordeaux, France. [Chen, Qiang; Goldman, Aaron L.; Mattay, Venkata S.; Weinberger, Daniel R.; Debette, Stephanie] Lieber Inst Brain Dev, Baltimore, MD USA. [Ching, Christopher R. K.] Univ Calif Los Angeles, Sch Med, Interdept Neurosci Grad Program, Los Angeles, CA USA. [Den Braber, Anouk; Boomsma, Dorret I.; De Geus, Eco J. C.; Fedko, Iryna; Hottenga, Jouke-Jan; Van't Ent, Dennis] Vrije Univ Amsterdam, Biol Psychol, Neurosci Campus Amsterdam, Amsterdam, Netherlands. [Den Braber, Anouk; Boomsma, Dorret I.; De Geus, Eco J. C.; Fedko, Iryna; Hottenga, Jouke-Jan; Van't Ent, Dennis] Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands. [Ehrlich, Stefan] Tech Univ Dresden, Fac Med, Div Psychol & Social Med & Dev Neurosci, Dresden, Germany. [Ehrlich, Stefan; Holmes, Avram J.; Lee, Phil H.; Buckner, Randy L.; Gollub, Randy L.; Roffman, Joshua L.; Smoller, Jordan W.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Ehrlich, Stefan; Ge, Tian; Gollub, Randy L.] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Filippi, Irina; Lemaitre, Herve; Martinot, Jean-Luc] Univ Paris Sud, Univ Paris Descartes, NSERM Unit Neuroimaging & Psychiat 1000, Paris, France. [Filippi, Irina; Lemaitre, Herve; Martinot, Jean-Luc] Hosp Cochin, AP HP, Maison Solenn Adolescent Psychopathol & Med Dept, Paris, France. [Ge, Tian; Lee, Phil H.; Smoller, Jordan W.] Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Ge, Tian; Lee, Phil H.; De Jager, Philip L.; Gollub, Randy L.; Green, Robert C.; Smoller, Jordan W.] Harvard Med Sch, Boston, MA USA. [Ge, Tian; Lee, Phil H.; Smoller, Jordan W.] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Boston, MA USA. [Giddaluru, Sudheer; Djurovic, Srdjan; Le Hellard, Stephanie; Steen, Vidar M.] Univ Bergen, Dept Clin Sci, NORMENT KG Jebsen Ctr Psychosis Res, N-5020 Bergen, Norway. [Giddaluru, Sudheer; DeStefano, Anita L.; Le Hellard, Stephanie; Steen, Vidar M.] Haukeland Hosp, Ctr Med Genet & Mol Med, Dr Einar Martens Res Grp Biol Psychiat, Bergen, Norway. [Gottesman, Rebecca F.; Mattay, Venkata S.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Greven, Corina U.; Richards, Jennifer S.; Rommelse, Nanda; Buitelaar, Jan K.] Karakter Child & Adolescent Psychiat Univ Ctr, Nijmegen, Netherlands. [Greven, Corina U.] Kings Coll London, Med Res Council Social, Genet & Dev Psychiat Ctr, Inst Psychol Psychiat & Neurosci, London, England. [Grimm, Oliver; Meyer-Lindenberg, Andreas; Rietschel, Marcella] Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Mannheim, Germany. [Griswold, Michael E.] Univ Mississippi, Med Ctr, Ctr Biostat & Bioinformat, Jackson, MS 39216 USA. [Guadalupe, Tulio; Fisher, Simon E.; Francks, Clyde] Max Planck Inst Psycholinguist, Language & Genet Dept, Nijmegen, Netherlands. [Guadalupe, Tulio] Int Max Planck Res Sch Language Sci, Nijmegen, Netherlands. [Hass, Johanna; Walton, Esther] Tech Univ Dresden, Fac Med, Dept Child & Adolescent Psychiat, Dresden, Germany. [Haukvik, Unn K.; Agartz, Ingrid] Diakonhjemmet Hosp, Dept Res & Dev, Oslo, Norway. [Hilal, Saima; Chen, Christopher; Ikram, M. Kamran] Natl Univ Singapore, Dept Pharmacol, Singapore, Singapore. [Hilal, Saima; Chen, Christopher; Ikram, M. Kamran] Natl Univ Hlth Syst, Mem Aging & Cognit Ctr, Singapore, Singapore. [Hofer, Edith; Pirpamer, Lukas; Schmidt, Reinhold] Med Univ Graz, Clin Div Neurogeriatr, Dept Neurol, Graz, Austria. [Hofer, Edith] Med Univ Graz, Inst Med Informat Stat & Documentat, Graz, Austria. [Hoehn, David; Mirza-Schreiber, Nazanin; Puetz, Benno; Saemann, Philipp G.; Czisch, Michael; Holsboer, Florian; Mueller-Myhsok, Bertram] Max Planck Inst Psychiat, Dept Translat Res Psychiat, Munich, Germany. [Holmes, Avram J.] Yale Univ, Dept Psychol, New Haven, CT USA. [Kasperaviciute, Dalia; Matarin, Mar; Sisodiya, Sanjay M.] UCL, Inst Neurol, London, England. [Kasperaviciute, Dalia; Matarin, Mar; Sisodiya, Sanjay M.] Epilepsy Soc, Gerrards Cross, Bucks, England. [Kasperaviciute, Dalia] Imperial Coll London, Dept Med, London, England. [Nho, Kwangsik; Risacher, Shannon L.; Shen, Li; Saykin, Andrew J.] Indiana Univ, Sch Med, Ctr Neuroimaging Radiol & Imaging Sci, Indianapolis, IN USA. [Kim, Sungeun; Nho, Kwangsik; Shen, Li; Foroud, Tatiana M.] Indiana Univ, Sch Med, Ctr Computat Biol & Bioinformat, Indianapolis, IN USA. [Kim, Sungeun; Nho, Kwangsik; Risacher, Shannon L.; Shen, Li; Saykin, Andrew J.] Indiana Univ, Sch Med, Indiana Alzheimer Dis Ctr, Indianapolis, IN USA. [Kraemer, Bernd; Gruber, Oliver] Heidelberg Univ, Dept Gen Psychiat, Sect Expt Psychopathol & Neuroimaging, Heidelberg, Germany. [Lee, Phil H.] Harvard Med Sch, Massachusetts Gen Hosp, Lurie Ctr Autism, Lexington, MA USA. [Liao, Jiemin; Cheng, Ching -Yu; Ikram, M. Kamran; Wong, Tien Y.] Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore. [Liewald, David C. M.; Lopez, Lorna M.; Luciano, Michelle; Maniega, Susana Munoz; Royle, Natalie A.; Bastin, Mark E.; McIntosh, Andrew M.; Hernandez, Maria C. Valdes; Wardlaw, Joanna M.; Deary, Ian J.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol Psychol, Edinburgh, Midlothian, Scotland. [Marquand, Andre; Shumskaya, Elena; Zwiers, Marcel P.] Radboud Univ Nijmegen, Donders Ctr Cognit Neuroimaging, Nijmegen, Netherlands. [Matarin, Mar; Ramasamy, Adaikalavan; Trabzuni, Daniah; Gibbs, J. Raphael; Guelfi, Sebastian; Hardy, John; Hernandez, Dena G.; Ryten, Mina] UCL Inst Neurol, Reta Lila Weston Inst, London, England. [Matarin, Mar; Ramasamy, Adaikalavan; Trabzuni, Daniah; Gibbs, J. Raphael; Guelfi, Sebastian; Hardy, John; Hernandez, Dena G.; Ryten, Mina] UCL Inst Neurol, Dept Mol Neurosci, London, England. [Mattheisen, Manuel] Aarhus Univ, Dept Biomed, Aarhus, Denmark. [Mattheisen, Manuel] iPSYCH, Lundbeck Fdn Initiat Integrat Psychiat Res, Aarhus, Denmark. [Mattheisen, Manuel] iPSYCH, Lundbeck Fdn Initiat Integrat Psychiat Res, Copenhagen, Denmark. [Mattheisen, Manuel] Aarhus Univ, iSEQ, Ctr Integrated Sequencing, Aarhus, Denmark. [Mazoyer, Bernard] UMR5296 Univ Bordeaux, CNRS, CEA, Bordeaux, France. [Mckay, David R.; Sprooten, Emma; Winkler, Anderson M.; Glahn, David C.] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. [Mckay, David R.; Sprooten, Emma; Glahn, David C.] Olin Neuropsychiat Res Ctr, Hartford, CT USA. [McWhirter, Rebekah] Univ Tasmania, Menzies Inst Med Res, Hobart, Tas, Australia. [Milaneschi, Yuri] VU Univ Med Ctr GGZ Geest, EMGO Inst Hlth & Care Res, Dept Psychiat, Amsterdam, Netherlands. [Milaneschi, Yuri] VU Univ Med Ctr GGZ Geest, Neurosci Campus Amsterdam, Amsterdam, Netherlands. [Nugent, Allison C.; Woldehawariat, Girma; Cannon, Dara M.; Drevets, Wayne C.; Liu, Xinmin; McMahon, Francis J.] NIMH, Exp Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Loohuis, Loes M. Olde; Ophoff, Roel A.] Univ Calif Los Angeles, Ctr Neurobehav Genet, Los Angeles, CA USA. [Oosterlaan, Jaap] Vrije Univ Amsterdam, Dept Clin Neuropsychol, Amsterdam, Netherlands. [Papmeyer, Martina; Sprooten, Emma; Lawrie, Stephen M.; McIntosh, Andrew M.; Sussmann, Jessika E.] Univ Edinburgh, Royal Edinburgh Hosp, Div Psychiat, Edinburgh, Midlothian, Scotland. [Papmeyer, Martina] Univ Bern, Univ Hosp Psychiat, Translat Res Ctr, Div Syst Neurosci Psychopathol, CH-3012 Bern, Switzerland. [Pappa, Irene] Erasmus Univ, Sch Pedag & Educ Sci, Rotterdam, Netherlands. [Rajan, Kumar B.; Aggarwal, Neelum T.; Evans, Denis A.] Rush Univ, Med Ctr, Rush Inst Healthy Aging, Chicago, IL 60612 USA. [Ramasamy, Adaikalavan; Ryten, Mina; Weale, Michael E.] Kings Coll London, Dept Med & Mol Genet, London, England. [Ramasamy, Adaikalavan] Univ Oxford, Jenner Inst Labs, Oxford, England. [Roiz-Santianez, Roberto; Crespo-Facorro, Benedicto] Univ Cantabria IDIVAL, Sch Med, Dept Med & Psychiat, Univ Hosp Marques de Valdecilla, Santander, Spain. [Roiz-Santianez, Roberto; Tordesillas-Gutierrez, Diana; Crespo-Facorro, Benedicto] CIBERSAM Ctr Invest Biomed Red Salud Med, Santander, Spain. [Rose, Emma J.; Corvin, Aiden] Trinity Coll Dublin, Psychosis Res Grp, Dept Psychiat, Dublin, Ireland. [Rose, Emma J.; Corvin, Aiden] Trinity Coll Dublin, Trinity Translat Med Inst, Dublin, Ireland. [Royle, Natalie A.; Bastin, Mark E.; Hernandez, Maria C. Valdes; Wardlaw, Joanna M.] Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh, Midlothian, Scotland. [Rundek, Tatjana; Sacco, Ralph L.; Wright, Clinton B.] Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA. [Rundek, Tatjana; Sacco, Ralph L.; Wright, Clinton B.] Univ Miami, Miller Sch Med, Dept Epidemiol & Publ Hlth Sci, Miami, FL 33136 USA. [Schmaal, Lianne] Orygen, Melbourne, Vic, Australia. [Schmaal, Lianne] Univ Melbourne, Ctr Youth Mental Hlth, Melbourne, Vic, Australia. [Schmaal, Lianne; Penninx, Brenda W. J. H.; Veltman, Dick J.] Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, Neurosci Campus Amsterdam, Amsterdam, Netherlands. [Schork, Andrew J.] Univ Calif San Diego, Dept Neurosci, Multimodal Imaging Lab, San Diego, CA 92103 USA. [Schork, Andrew J.] Univ Calif San Diego, Dept Cognit Sci, San Diego, CA 92103 USA. [Smith, Albert V.; Gudnason, Vilmundur; Sigurdsson, Sigurdur] Iceland Heart Assoc, Kopavogur, Iceland. [Smith, Albert V.; Gudnason, Vilmundur] Univ Iceland, Fac Med, Reykjavik, Iceland. [Sprooten, Emma] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Strike, Lachlan T.; Hansell, Narelle K.; Wright, Margaret J.] Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia. [Teumer, Alexander; Hoffmann, Wolfgang; Voelzke, Henry] Univ Med Greifswald, Inst Community Med, Greifswald, Germany. [Thompson, Paul M.] Univ Western Sydney, Sch Comp Engn & Math, Parramatta, NSW, Australia. [Tordesillas-Gutierrez, Diana] Valdecilla Biomed Res Inst IDIVAL, Neuroimaging Unit, Technol Facil, Santander, Cantabria, Spain. [Toro, Roberto] Inst Pasteur, Paris, France. [Trabzuni, Daniah] King Faisal Specialist Hosp & Res Ctr, Dept Genet, Riyadh, Saudi Arabia. [Vaidya, Dhananjay; Yanek, Lisa R.; Becker, Diane M.] Johns Hopkins Univ, Sch Med, Dept Med, GeneSTAR Res Ctr, Baltimore, MD 21205 USA. [Van der Grond, Jeroen] Leiden Univ, Med Ctr, Dept Radiol, Leiden, Netherlands. [Van der Meer, Dennis; Van Rooij, Daan; Hartman, Catharina A.; Hoekstra, Pieter J.] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands. [Van Eijk, Kristel R.] UMC Utrecht, Human Neurogenet Unit, Brain Ctr Rudolf Magnus, Utrecht, Netherlands. [Van Erp, Theo G. M.; Potkin, Steven G.] Univ Calif Irvine, Dept Psychiat & Human Behav, Irvine, CA 92717 USA. [Westlye, Lars T.; Espeseth, Thomas] Univ Oslo, Dept Psychol, NORMENT KG Jebsen Ctr, Oslo, Norway. [Windham, Beverly G.; Mosley, Thomas H.] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Winkler, Anderson M.; Jenldnson, Mark; Jonsson, Erik G.; Nichols, Thomas E.] Univ Oxford, FMRIB Ctr, Oxford, England. [Wolf, Christiane] Univ Wurzburg, Dept Psychiat Psychosomat & Psychotherapy, Wurzburg, Germany. [Yang, Jingyun; Aggarwal, Neelum T.; Bennett, David A.] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. [Zijdenbos, Alex] Biospect Inc, Montreal, PQ, Canada. [Agartz, Ingrid] Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, Stockholm, Sweden. [Almasy, Laura; Blangero, John; Curran, Joanne E.; Duggirala, Ravi; Dyer, Thomas D.; Goring, Harald H. H.] Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, Edinburg, TX USA. [Almasy, Laura; Blangero, John; Curran, Joanne E.; Duggirala, Ravi; Dyer, Thomas D.; Goring, Harald H. H.] Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, Edinburg, TX USA. [Almasy, Laura; Blangero, John; Curran, Joanne E.; Duggirala, Ravi; Dyer, Thomas D.; Goring, Harald H. H.] Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, San Antonio, TX USA. [Almasy, Laura] Univ Penn, Dept Genet, Perelman Sch Med, Philadelphia, PA 19104 USA. [Almasy, Laura] Childrens Hosp Philadelphia, Dept Biomed & Hlth Informat, Philadelphia, PA 19104 USA. [Ames, David] Royal Melbourne Hosp, Natl Ageing Res Inst, Melbourne, Vic, Australia. [Ames, David] Univ Melbourne, Acad Unit Psychiat Old Age, Melbourne, Vic, Australia. [Arepalli, Sampath; Cookson, Mark R.; Dillman, Allissa; Gibbs, J. Raphael; Hernandez, Dena G.; Nalls, Michael A.; Singleton, Andrew; Traynor, Bryan J.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Becker, James T.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. [Becker, James T.] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA. [Becker, James T.] Univ Pittsburgh, Dept Psychol, Pittsburgh, PA 15260 USA. [Brodaty, Henry] UNSW, Dementia Collaborat Res Ctr Assessment & Better, Sydney, NSW, Australia. [Brunner, Han G.] Maastricht Univ, Med Ctr, Dept Clin Genet, Maastricht, Netherlands. [Buckner, Randy L.] Harvard Univ, Dept Psychol, Ctr Brain Sci, 33 Kirkland St, Cambridge, MA 02138 USA. [Bulayeva, Kazima B.; Wong, Tien Y.] Dagestan State Univ, Dept Evolut & Genet, Makhachkala, Dagestan, Russia. [Calhoun, Vince D.] Mind Res Network, Albuquerque, NM USA. [Calhoun, Vince D.] LBERI, Albuquerque, NM USA. [Calhoun, Vince D.] Univ New Mexico, Dept ECE, Albuquerque, NM 87131 USA. [Cannon, Dara M.; McDonald, Colm; Muhleisen, Thomas W.] Natl Univ Ireland Galway, Ctr Neuroimaging & Cognit Genom NICOG, NCBES Galway Neurosci Ctr, Coll Med Nursing & Hlth Sci,Clin Neuroimaging Lab, Galway, Ireland. [Cheng, Ching -Yu; Ikram, M. Kamran] Duke NUS Grad Med Sch, Acad Med Res Inst, Singapore, Singapore. [Cheng, Ching -Yu; Wong, Tien Y.] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore, Singapore. [Cichon, Sven] Univ Basel, Dept Biomed, Div Med Genet, Basel, Switzerland. [Cichon, Sven; Noethen, Markus M.] Univ Bonn, Inst Human Genet, Bonn, Germany. [Cichon, Sven; Muhleisen, Thomas W.] Res Ctr Julich, Inst Neurosci & Med INM1, Julich, Germany. [Dale, Anders M.] Univ Calif San Diego, Ctr Multimodal Imaging & Genet, San Diego, CA 92103 USA. [Dale, Anders M.] Univ Calif San Diego, Dept Neurosci, San Diego, CA 92103 USA. [Dale, Anders M.] Univ Calif San Diego, Dept Radiol, San Diego, CA 92103 USA. [Dale, Anders M.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Dale, Anders M.] Univ Calif San Diego, Dept Cognit Sci, San Diego, CA 92103 USA. [Davies, Gareth E.] Avera Inst Human Genet, Sioux Falls, SD USA. [Davies, Gareth E.] Brigham & Womens Hosp, Dept Neurol, Program Translat NeuroPsychiat Gen, 75 Francis St, Boston, MA 02115 USA. [Davies, Gareth E.] Brigham & Womens Hosp, Dept Psychiat, 75 Francis St, Boston, MA 02115 USA. [Davies, Gareth E.] Harvard Med Sch, Boston, MA USA. [Davies, Gareth E.; De Jager, Philip L.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [De Jager, Philip L.] Broad Inst, Cambridge, MA USA. [de Zubicaray, Greig I.] Queensland Univ Technol, Fac Hlth, Brisbane, Qld, Australia. [de Zubicaray, Greig I.] Queensland Univ Technol, Inst Hlth & Biomed Innovat, Brisbane, Qld, Australia. [Delanty, Norman] Beaumont Hosp, Div Neurol, Dublin 9, Ireland. [Depondt, Chantal; Pandolfo, Massimo] Univ Libre Bruxelles, Hop Erasme, Dept Neurol, Brussels, Belgium. [Djurovic, Srdjan] Oslo Univ Hosp, Dept Med Genet, Oslo, Norway. [Donohoe, Gary; Morris, Derek W.] Natl Univ Ireland Galway, Cognit Genet & Cognit Therapy Grp, Neuroimaging Cognit & Genom Ctr NICOG, Galway, Ireland. [Donohoe, Gary; Morris, Derek W.] Natl Univ Ireland Galway, NCBES Galway Neurosci Ctr, Sch Psychol, Galway, Ireland. [Donohoe, Gary; Morris, Derek W.] Natl Univ Ireland Galway, Discipline Biochem, Galway, Ireland. [Donohoe, Gary; Morris, Derek W.] Trinity Coll Dublin, Dept Psychiat, Neuropsychiat Genet Res Grp, Dublin 8, Ireland. [Donohoe, Gary; Morris, Derek W.] Trinity Coll Dublin, Inst Psychiat, Dublin 8, Ireland. [Drevets, Wayne C.] Janssen Res & Dev LLC, Titusville, NJ USA. [Erk, Susanne; Heinz, Andreas; Mohnke, Sebastian; Romanczuk-Seiferth, Nina; Walter, Henrik] Charite, CCM, Dept Psychiat & Psychotherapy, Berlin, Germany. [Ferrucci, Luigi] NIA, Intramural Res Program, Baltimore, MD 21224 USA. [Fleischman, Debra A.] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. [Fleischman, Debra A.] Rush Univ, Med Ctr, Dept Behav Sci, Chicago, IL 60612 USA. [Ford, Ian] Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland. [Foroud, Tatiana M.; Saykin, Andrew J.] Indiana Univ, Sch Med, Med & Mol Genet, Indianapolis, IN USA. [Fox, Peter T.; Olvera, Rene L.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Fukunaga, Masaki] Natl Inst Physiol Sci, Div Cerebral Integrat, Aichi, Japan. [Green, Robert C.] Brigham & Womens Hosp, Dept Med, Div Genet, 75 Francis St, Boston, MA 02115 USA. [Hashimoto, Ryota; Ohi, Kazutaka] Osaka Univ, Grad Sch Med, Dept Psychiat, Osaka, Japan. [Hashimoto, Ryota] Osaka Univ, United Grad Sch Child Dev, Mol Res Ctr Childrens Mental Dev, Osaka, Japan. [Hegenscheid, Katrin; Hosten, Norbert] Univ Med Greifswald, Inst Diagnost Radiol & Neuroradiol, Greifswald, Germany. [Hernandez, Dena G.] German Ctr Neurodegenerat Dis DZNE, Tubingen, Germany. [Heslenfeld, Dirk J.] Vrije Univ Amsterdam, Dept Psychol, Amsterdam, Netherlands. [Ho, Beng-Choon] Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA. [Holsboer, Florian] HMNC Brain Hlth, Munich, Germany. [Homuth, Georg] Univ Med Greifswald, Interfac Inst Genet & Funct Gen, Greifswald, Germany. [Ikeda, Masashi] Fujita Hlth Univ, Sch Med, Dept Psychiat, Toyoake, Aichi, Japan. [Jack, Clifford R., Jr.] Mayo Clin, Dept Radiol, Rochester, MN USA. [Johnson, Robert; Zielke, H. Ronald] Univ Maryland, Sch Med, NICHD Brain & Tissue Bank Dev Disorders, Baltimore, MD 21201 USA. [Kanai, Ryota] Univ Sussex, Sch Psychol, Brighton, E Sussex, England. [Kanai, Ryota] UCL, Inst Cognit Neurosci, London, England. [Kanai, Ryota] Araya Brain Imaging, Dept Neuroinformat, Tokyo, Japan. [Kloszewska, Iwona] Med Univ Lodz, Lodz, Poland. [Knopman, David S.] Mayo Clin, Dept Neurol, Rochester, MN USA. [Kochunov, Peter] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Dept Psychiat, Baltimore, MD 21201 USA. [Kwok, John B.; Schofield, Peter R.] Neurosci Res Australia, Sydney, NSW, Australia. [Kwok, John B.; Schofield, Peter R.] UNSW, Sch Med Sci, Sydney, NSW, Australia. [Liu, Xinmin] Columbia Univ, Med Ctr, New York, NY USA. [Longo, Dan L.] NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. [Longstreth, W. T., Jr.] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. [Longstreth, W. T., Jr.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Lopez, Oscar L.] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA. [Lopez, Oscar L.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. [Lovestone, Simon] Univ Oxford, Dept Psychiat, Oxford, England. [Lovestone, Simon] Kings Coll London, NIHR Dementia Biomed Res Unit, London, England. [Martinez, Oliver; DeCarli, Charles] Univ Calif Davis, Dept Neurol, Imaging Dementia & Aging IDeA Lab, Sacramento, CA 95817 USA. [Martinez, Oliver; DeCarli, Charles] Univ Calif Davis, Ctr Neurosci, Sacramento, CA 95817 USA. [Mattay, Venkata S.] Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. [McMahon, Katie L.; Wright, Margaret J.] Univ Queensland, Ctr Adv Imaging, Brisbane, Qld, Australia. [Mecocci, Patrizia] Univ Perugia, Dept Med, Sect Gerontol & Geriatr, Perugia, Italy. [Mueller-Myhsok, Bertram] Munich Cluster Syst Neurol SyNergy, Munich, Germany. [Mueller-Myhsok, Bertram] Univ Liverpool, Inst Translat Med, Liverpool, Merseyside, England. [Nauck, Matthias] Univ Med Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany. [Nauck, Matthias] German Ctr Cardiovasc Res DZHK eV, Partner Site Greifswald, Berlin, Germany. [Nichols, Thomas E.] Univ Warwick, Dept Stat, Coventry, W Midlands, England. [Nichols, Thomas E.] Univ Warwick, Warwick Mfg Grp, Coventry, W Midlands, England. [Niessen, Wiro J.] Erasmus MC, Dept Med Informat, Rotterdam, Netherlands. [Niessen, Wiro J.] Delft Univ Technol, Fac Sci Appl, Delft, Netherlands. [Noethen, Markus M.] Univ Bonn, Life & Brain Ctr, Dept Genom, Bonn, Germany. [Paus, Tomas] Univ Toronto, Rotman Res Inst, Toronto, ON, Canada. [Paus, Tomas] Univ Toronto, Dept Psychol, Toronto, ON M5S 1A1, Canada. [Paus, Tomas] Univ Toronto, Dept Psychiat, Toronto, ON M5S 1A1, Canada. [Paus, Tomas] Child Mind Inst, New York, NY USA. [Pausova, Zdenka] Univ Toronto, Dept Phys, Toronto, ON, Canada. [Pausova, Zdenka] Univ Toronto, Dept Nutr Sci, Toronto, ON, Canada. [Pike, G. Bruce] Univ Calgary, Dept Radiol, Calgary, AB, Canada. [Pike, G. Bruce] Univ Calgary, Dept Clin Neurosci, Calgary, AB, Canada. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Med, Seattle, WA USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Res Inst, Grp Hlth, Seattle, WA USA. [Reppermund, Simone] UNSW Med, Sch Psychiat, Dept Dev Disabil Neuropsychiat, Kensington, NSW, Australia. [Rotter, Jerome I.] Univ Calif Los Angeles, Med Ctr, Ilnst Translat Genom & Populat Sci, Los Angeles Biomed Res Inst & Pediat Harbor, Torrance, CA 90509 USA. [Sacco, Ralph L.; Wright, Clinton B.] Univ Miami, Miller Sch Med, Evelyn F McKnight Brain Inst, Miami, FL 33136 USA. [Sachdev, Perminder S.] Prince Wales Hosp, Neuropsychiat Inst, Sydney, NSW, Australia. [Simmons, Andy] Kings Coll London, Inst Psychiat, Dept Neuroimaging, London, England. [Simmons, Andy] Kings Coll London, Biomed Res Ctr Mental Hlth, London, England. [Simmons, Andy] Kings Coll London, Biomed Res Unit Dementia, London, England. [Smith, Colin] Univ Edinburgh, Acad Dept Neuropathol, Ctr Clin Brain Sci, MRC Edinburgh Brain Bank, Edinburgh, Midlothian, Scotland. [Soininen, Hindu.] Univ Eastern Finland, Inst Clin Med Neurol, Kuopio, Finland. [Soininen, Hindu.] Kuopio Univ Hosp, Neuroctr Neurol, Kuopio, Finland. [Srikanth, Velandai] Peninsula Hlth & Monash Univ, Dept Med, Melbourne, Vic, Australia. [Stott, David J.] Univ Glasgow, Fac Med, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland. [Toga, Arthur W.] Univ Southern Calif, Keck Sch Med, Inst Neuroimaging & Informat, Lab Neuro Imaging, Los Angeles, CA USA. [Troncoso, Juan] Johns Hopkins Univ, Brain Resource Ctr, Baltimore, MD USA. [Turner, Jessica A.] Georgia State Univ, Atlanta, GA 30303 USA. [Tzourio, Christophe] Univ Bordeaux, Institute Neurodegenerat Disorders, CEA, CNRS,UMR 5293, Bordeaux, France. [Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Van der Brug, Marcel] Genentech Inc, San Francisco, CA 94080 USA. [Van der Wee, Nic J. A.] Leiden Univ, Med Ctr, Dept Psychiat, Leiden, Netherlands. [Van der Wee, Nic J. A.] Leiden Univ, Med Ctr, Leiden Inst Brain & Cognit, Leiden, Netherlands. [Van Tol, Marie Jose] Univ Groningen, Univ Med Ctr Groningen, Neuroimaging Ctr, Groningen, Netherlands. [Wassink, Thomas H.] Univ Iowa, Dept Psychiat, Carver Coll Med, Iowa City, IA 52242 USA. [Weinberger, Daniel R.] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. [Weinberger, Daniel R.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Weinberger, Daniel R.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. [Weinberger, Daniel R.] Johns Hopkins Univ, Sch Med, Inst Med Genet, Baltimore, MD USA. [Weiner, Michael W.] Univ Calif San Francisco, San Francisco VA Med Ctr, Ctr Imaging Neurodegenerat Dis, San Francisco, CA 94143 USA. [Westman, Eric] Karolinska Inst, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden. [Zonderman, Alan B.] NIA, Lab Epidemiol & Populat Sci, NIH, Bethesda, MD 20892 USA. [Schmidt, Helena] Med Univ Graz, Inst Mol Biol & Biochem, Graz, Austria. [De Craen, Anton J. M.] Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, Leiden, Netherlands. [Launer, Lenore J.] NIA, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med & Human Genet Ctr, Houston, TX 77030 USA. [Debette, Stephanie] Bordeaux Univ Hosp, Dept Neurol, Bordeaux, France. [Ikram, M. Arfan] Erasmus MC, Dept Neurol, Rotterdam, Netherlands. [Andersson, Micael; Pudas, Sara; Nyberg, Lars] Umea Univ, Umea Ctr Funct Brain Imaging, Umea, Sweden. RP Ikram, MA (reprint author), Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.; Ikram, MA (reprint author), Erasmus MC, Dept Radiol & Nucl Med, Rotterdam, Netherlands.; Thompson, PM (reprint author), Univ Southern Calif, Keck Sch Med, USC Mark & Mary Stevens Neuroimaging & Informat I, Imaging Genet Ctr, Los Angeles, CA USA.; Ikram, MA (reprint author), Erasmus MC, Dept Neurol, Rotterdam, Netherlands. EM m.a.ikram@erasmusmc.nl; pthomp@usc.edu RI Zwiers, Marcel/D-2968-2009; McMahon, Katie/C-6440-2009; Cuellar Partida, Gabriel/C-6686-2017; Fernandez, Guillen/B-3771-2009; Tzourio, christophe/B-4015-2009; Simmons, Andrew/B-8848-2008; Hardy, John/C-2451-2009; Franke, Barbara/D-4836-2009; Meyer-Lindenberg, Andreas/H-1076-2011; Thomson, Russell/H-5653-2012; Hansell, Narelle/A-4553-2016 OI Adams, Hieab/0000-0003-3687-2508; Rose, Emma/0000-0001-5365-4794; Zonderman, Alan B/0000-0002-6523-4778; Vaidya, Dhananjay/0000-0002-7164-1601; Beiser, Alexa/0000-0001-8551-7778; Westlye, Lars T./0000-0001-8644-956X; de Geus, Eco/0000-0001-6022-2666; Kanai, Ryota/0000-0002-0186-2687; McIntosh, Andrew/0000-0002-0198-4588; Zwiers, Marcel/0000-0001-5483-2935; McMahon, Katie/0000-0002-6357-615X; Cuellar Partida, Gabriel/0000-0001-7648-4097; Fernandez, Guillen/0000-0002-5522-0604; Desrivieres, Sylvane/0000-0002-9120-7060; Cavalleri, Gianpiero/0000-0002-9802-0506; Pudas, Sara/0000-0001-9512-3289; Westman, Eric/0000-0002-3115-2977; Arfanakis, Konstantinos/0000-0001-9705-597X; Jonsson, Erik/0000-0001-8368-6332; Tzourio, christophe/0000-0002-6517-2984; Simmons, Andrew/0000-0003-2306-5811; Franke, Barbara/0000-0003-4375-6572; Meyer-Lindenberg, Andreas/0000-0001-5619-1123; Thomson, Russell/0000-0003-4949-4120; Hansell, Narelle/0000-0002-8229-9741 FU National Heart, Lung and Blood Institute [HL105756]; National Institute on Aging [AG033193]; NIH Institute, NIBIB [U54 EB020403]; NIH Institute, NCI [U54 EB020403]; NIH [N01-AG-1-2100, 271201200022C, R01MH62873, K99MH102357, R01 HD050735, P30AG10161, RF1AG15819, R01AG17917, R01AG30146, R01AG40039, 5R01AG037212]; NIA Intramural Research Program; Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); ADNI (National Institutes of Health Grant) [U01 AG024904]; DOD ADNI (Department of Defense) [W81XWH-12-2-0012]; National Institute on Aging; National Institute of Biomedical Imaging and Bioengineering; lzheimer's Association; Alzheimer's Drug Discovery Foundation; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics, N.V.; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Synarc Inc.; Takeda Pharmaceutical Company; Canadian Institutes of Health Research; EU; Kuopio University Hospital; National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201100005C, HSN268201100006C, HSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL70825, R01HL087641, R01HL59367, R01HL086694]; National Human Genome Research Institute [U01HG004402]; National Institutes of Health (NIH) [HHSN268200625226C, R01D0042157-01A, MH081802, 1RC2 MH089951, 1RC2 MH089995]; component of the NIH and NIH Roadmap for Medical Research [UL1RR025005]; NIH R01 grant [NS087541]; Austrian Science Fund (FWF) [1904]; Medical University of Graz; Steiermarkische Krankenanstalten Gesellschaft; Knut and Alice Wallenberg (KAW) foundation; Torsten and Ragnar Soderbergs Foundation; HelseVest RHF [911554]; Brain Research Imaging Centre Edinburgh, a center in the Scottish Funding Council Scottish Imaging Network-A Platform for Scientific Excellence (SINAPSE) Collaboration; National Alliance for Research on Schizophrenia and Depression (NARSAD) Independent Investigator Award; Health Foundation Clinician Scientist Fellowship; European Community [602450, 278948, 602805, 643051]; Biobanking and Biomolecular Resources Research Infrastructure (Netherlands) (BBMRI-NL); Hersenstichting Nederland; Netherlands Organization for Scientific Research (NWO); NWO Gravitation grant 'Language in Interaction'; ERC [268800-NEUROSCHEMA]; ENIGMA Consortium from the BD2K Initiative of a cross-NIH partnership [U54 EB020403]; Center for Brain Science Neuroinformatics Research Group; Athinoula A. Martinos Center for Biomedical Imaging; Center for Human Genetic Research; NIMH [K99 MH101367, R01-MH079799, K24MH094614, K01MH099232]; National Institute of Health [AG033193, AG011101, AG030146, AG008122, AG054076, AG049607, AG010129, NS017950, U01AG49505]; International Alzheimer's Association [NIRP-14-302587]; National Medical Research Council, Singapore [0796/2003, IRG07nov013, IRG09nov014, STaR/0003/2008, CG/SERI/2010]; Biomedical Research Council, Singapore [09/1/35/19/616]; National Medical Research Council, Singapore (NMRC/CG/NUHS) [R-184-006-184-511]; Singapore Ministry of Health's National Medical Research Council [NMRC/CSA/038/2013]; Wellcome Trust [084730, 082604/2/07/Z]; University College London (UCL)/University College London Hospitals (UCLH) NIHR Biomedical Research Centre/Specialist Biomedical Research Centres (CBRC/SBRC) [114]; European Union Marie Curie Reintegration; UK NIHR [08-08-SCC]; Comprehensive Local Research Network (CLRN) Flexibility and Sustainability Funding (FSF) [CEL1300]; Big Lottery Fund; Wolfson Trust; Epilepsy Society; UK Department of Health's NIHR Biomedical Research Centres funding scheme; Science Foundation Ireland [08/RFP/GEN1538]; Netherlands Organization for Scientific Research NWO [MW904-61-193, 400-07-080, MagW 480-04-004, 51.02.060, 668.772]; European Research Council [ERC-230374]; High Potential Grant Utrecht University; NWO Brain and Cognition [433-09-220]; Neuroscience Campus Amsterdam; NHLBI [HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, R01HL130114, R01 HL105756]; National Institute on Aging (NIA) [R01AG023629, R01AG15928, R01AG20098, R01AG027002, R01AG05133, R01AG027058]; National Center for Advancing Translational Sciences, CTSI grant [UL1TR000124]; National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) [DK063491]; Brainwave-the Irish Epilepsy Association; Epilepsy Research UK [F1206]; European Commission [018947 (LSHG-CT-2006-01947), 223004]; European Community's Seventh Framework Programme (FP7) by the European Commission under the programme "Quality of Life and Management of the Living Resources" of 5th Framework Programme [HEALTH-F4-2007-201413, QLG2-CT-2002-01254]; Netherlands Organization for Scientific Research; Russian Foundation for Basic Research [NWO-RFBR 047.017.043]; Netherlands Brain Foundation [F2013(1)-28, 15F07[2]27]; National Heart, Lung and Blood Institute's Framingham Heart Study [HHSN2682015000011]; ZonMw [TOP 40-00812-98-11021, 916.13.054]; National Institute of Neurological Disorders and Stroke [R01NS062059]; National Heart, Lung, and Blood Institute [U01 HL72518, HL097698]; National Institutes of Health/National Center for Research Resources [M01-RR000052]; National Institute of Mental Health [MH0708143, MH078111, MH083824]; Research Facilities Improvement Program from the National Center for Research Resources, NIH [C06 RR13556, C06 RR017515]; Swedish Research Council [K2007-62X-15077-04-1, K2008-62P-20597-01-3, K2010-62X-15078-07-2, K2012-61X-15078-09-3]; Stockholm County Council; Karolinska Institutet; Knut and Alice Wallenberg Foundation; HUBIN project; Swedish Research Council; European Union [602450, LSHM-CT-2007-037286, 603016]; Innovative Medicine Initiative Project EU-AIMS [115300-2]; Medical Research Council Programme Grant "Developmental pathways into adolescent substance abuse" [93558]; NIHR-biomedical Research Center "Mental Health": Swedish Research Council FORMAS; German Federal Ministry for Education and Research BMBF (Forschungsnetz AERIAL) [eMED SysAlc 01ZX1311A, 1EV0711]; US National Institutes of Health (Axon); US National Institutes of Health (Testosterone); US National Institutes of Health (Mental Health during Adolescence); US National Institutes of Health [MH085772-01A1]; French MILDECA; Fondation pour la Recherche Medicale; Brain & Cognition Excellence Program of the Netherlands Organization for Scientific Research (NWO) [433-09-229]; Netherlands Organization for Scientific Research (NWO) [016.130.669]; Research into Ageing programme grant; Age UK-Disconnected Mind project; UK Medical Research Council (MRC); Scottish Funding Council through the SINAPSE Collaboration; Row Fogo Charitable Trust; UK Biotechnology and Biological Sciences Research Council (BBSRC) [MRC MR/K026992/1]; UK MRC; BBSRC [BB/F019394/1]; Innovation-Oriented Research Program on Genomics (SenterNovem) [IGE05007]; Netherlands Consortium for Healthy Ageing [050-060-810]; Department of Energy [DE-FG02-08ER64581]; German Federal Ministry of Education and Research (BMBF) through the Integrated Genome Research Network (IG) MooDS (Systematic Investigation of the Molecular Causes of Major Mood Disorders and Schizophrenia) unde (NGFNplus) [01GS08144, 01GS08147, 01GS08148]; German Federal Ministry of Education and Research (BMBF) through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders) under e:Med Programme [01ZX1314A, 01ZX1314C, 01ZX1314G]; Exzellenz-Stiftung of the Max Planck Society; Federal Ministry of Education and Research (BMBF) [FKZ 01GS0481]; Bergen Research Foundation; University of Bergen; Dr. Einar Martens Fund; K.G. Jebsen Foundation; Research Council of Norway; Netherlands Organization for Scientific Research [10-000-1002]; Center for Medical Systems Biology (CSMB, NWO Genomics); Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL); VU University's Institutes for Health and Care Research (EMGO+); University Medical Center Groningen; Leiden University Medical Center; Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health; BiG Grid; Dutch e-Science Grid - NWO; NWO Large Investment Grant [1750102007010]; Radboud University Nijmegen Medical Center; University Medical Center Groningen and Accare; VU University Amsterdam; NIMH Intramural Research Program [ZIAMH002810, Z01MH002792, Z01MH002790]; Intramural Research Program of the NIH, National Institute on Aging; NHMRC/Australian Research Council Strategic Award [401162]; NHMRC [R01 HD050735, 1045325, 310667, 401184, 525453, 568940, 389875, 486682, 1009064, 1061457]; Commonwealth Scientific and Industrial Research Organisation Flagship Collaboration Fund Grant; Australian Government - Dementia Collaborative Research Centre (DCRC), UNSW; Alzheimer's Australia Dementia Research Foundation; Japanese Ministry of Health, Labor and Welfare; Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT) KAKENHI; Scientific Research on Innovative Areas (Comprehensive Brain Science Network); Brain Sciences Project of the Center for Novel Science Initiatives (CNSI); National Institutes of Natural Sciences (NINS); Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS) from Japan Agency for Medical Research and development, AMED; Instituto de Salud Carlos III [FIS00/3095, 01/3129, PI020499, PI060507, PI10/00183, PI14/00639]; SENY Fundacio Research Grant [CI 2005-0308007]; Fundacion Marques de Valdecilla [API07/011]; Carlos III Health Institute [CA12/00312]; Bristol-Myers Squibb; Netherlands Heart Foundation [2001 D 032]; Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging) [050-060-810]; Autism Speaks; Australian Research Council [FT0991634]; National Health and Medical Research Council (NHMRC), Australia [1103623, 619667]; Translational Genomics Research Institute; Netherlands Organisation of Scientific Research NWO [175.010.2005.011, 911-03-012]; Research Institute for Diseases in the Elderly [014-93-015, RIDE2]; Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) [050-060-810]; Erasmus Medical Center; Erasmus University, Rotterdam; Netherlands Organization for the Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly (RIDE); Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; European Commission (DG XII); Municipality of Rotterdam; Dutch Technology Foundation STW, NWO; Ministry of Economic Affairs; European Research Council (ERC) under the European Union's Horizon research and innovation programme [678543]; Joint Programme - Neurodegenerative Disease Research working group on High-Dimensional Research in Alzheimer's Disease (ZonMW) [733051031]; Van Leersum Grant of the Royal Netherlands Academy of Arts and Sciences; Heart and Stroke Foundation of Quebec; Canadian Foundation for Innovation; Tanenbaum Chair in Population Neuroscience at the Rotman Research Institute, University of Toronto; German Federal Ministry of Education and Research; German Ministry of Cultural Affairs; Social Ministry of the Federal State of Mecklenburg-West Pomerania [01ZZ9603, 01ZZ0103, 01ZZ0403]; network 'Greifswald Approach to Individualized Medicine (GANI_MED)' - Federal Ministry of Education and Research [03IS2061A]; Federal Ministry of Education and Research [03ZIK012]; Siemens Healthcare, Erlangen, Germany; Federal State of Mecklenburg-West Pomerania; Australian National Health and Medical Research Council (NHMRC) Program [350833, 568969]; National Health and Medical Research Council of Australia (NHMRC) [403000, 491109, 606543]; Wicking Dementia Education and Research Centre; Heart Foundation Future Leader Fellowship [100089]; Caisse Nationale Maladie des Travailleurs Salaries; Direction Generale de la Sante; Mutuelle Generale de l'Education Nationale (MGEN); Institut de la Longevite; Conseil Regionaux of Aquitaine; Conseil Regionaux of Bourgogne; Fondation de France; Ministry of Research INSEAM Programme "Cohortes et collections de donnees biologiques"; Fondation Leducq; Research Council of Norway [213837, 223273, 229129]; South-East Norway Health Authority [2013-123]; KG Jebsen Foundation; Netherlands Organization for Health Research and Development ZonMW [917.46.370, 908-02-123]; French National Foundation on Alzheimer's disease and related disorders; LABEX (laboratory of excellence program investment for the future) DISTALZ grant; Inserm; Institut Pasteur de Lille; University de Lille 2; Lille University Hospital; Medical Research Council [503480]; Alzheimer's Research UK [503176]; German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) [01G10102, 01G10711, 01G10420]; NIH/NIA grant [R01 AG033193, U01 AG032984, U24 AG021886, U01 AG016976]; NIA [AG081220]; AGES [N01-AG-12100]; Icelandic Heart Association; Erasmus University; Alzheimer's Association [ADGC-10-196728]; [NWO/SPI 56-464-14192]; [MH59490] FX CHARGE: Infrastructure for the CHARGE Consortium is supported in part by the National Heart, Lung and Blood Institute grant HL105756 and for the neuroCHARGE phenotype working group through the National Institute on Aging grant AG033193.; ENIGMA: ENIGMA was supported in part by a Consortium grant (U54 EB020403 to PMT) from the NIH Institutes contributing to the Big Data to Knowledge (BD2K) Initiative, including the NIBIB and NCI.; Age, Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik): This study has been funded by NIH contracts N01-AG-1-2100 and 271201200022C, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The study was approved by the Icelandic National Bioethics Committee, VSN: 00-063. The researchers are indebted to the participants for their willingness to participate in the study.; Alzheimer's Disease Neuroimaging Initiative (ADNI): Data collection and sharing for this project was funded by the ADNI (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the Alzheimer's Association; Alzheimer's Drug Discovery Foundation; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics, N.V.; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research provides funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (http://www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory of Neuro Imaging at the University of Southern California.; ANM: AddNeuroMed was funded through the EU FP6 programme. HS: Academy of Finland, Research Council for Health, 258081, UEFBrain, University of Eastern Finland, VTR funding Kuopio University Hospital.; Atherosclerosis Risk In Communities Study (ARIC): The Atherosclerosis Risk in Communities study was performed as a collaborative study supported by National Heart, Lung, and Blood Institute (NHLBI) contracts (HHSN268201100005C, HSN268201100006C, HSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL70825, R01HL087641, R01HL59367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health (NIH) contract HHSN268200625226C. Infrastructure was partly supported by grant no. UL1RR025005, a component of the NIH and NIH Roadmap for Medical Research. This project was also supported by NIH R01 grant NS087541 to M.F.; Austrian Stroke Prevention Study Family (ASPS-Fam): The ASPS-Fam is funded by the Austrian Science Fund (FWF) project 1904, the Medical University of Graz and the Steiermarkische Krankenanstalten Gesellschaft.; BETULA: This sample collection was supported by a Wallenberg Scholar grant from the Knut and Alice Wallenberg (KAW) foundation and a grant from Torsten and Ragnar Soderbergs Foundation to Lars Nyberg. S.l.H. was supported by a grant from HelseVest RHF (grant 911554).; Bipolar Family Study (BFS): The Bipolar Family Study wishes to thank the Scottish Mental Health Research Network for research assistant support, the Brain Research Imaging Centre Edinburgh, a center in the Scottish Funding Council Scottish Imaging Network-A Platform for Scientific Excellence (SINAPSE) Collaboration, for image acquisition and the Wellcome Trust Clinical Research Facility for genotyping. Genotyping was supported by the National Alliance for Research on Schizophrenia and Depression (NARSAD) Independent Investigator Award (to A.M.M.), and data collection was supported by the Health Foundation Clinician Scientist Fellowship. The research leading to these results also receives funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreements #602450 (IMAGEMEND) and ongoing support from the Wellcome Trust (Ref 104036/Z/14/Z).; Brain Imaging Genetics (BIG): This work makes use of the BIG database, first established in Nijmegen, The Netherlands, in 2007. This resource is now part of Cognomics (http://www.cognomics.nl), a joint initiative by researchers of the Donders Centre for Cognitive Neuroimaging, the Human Genetics and Cognitive Neuroscience Departments of the Radboud University Medical Center and the Max Planck Institute for Psycholinguistics in Nijmegen. The Board of the Cognomics Initiative consists of B. Franke, S. Fisher, G. Fernandez, P. Hagoort, H. Brunner, J. Buitelaar, H. van Bokhoven and D. Norris. The Cognomics Initiative has received supported from the participating departments and centers and from external grants, that is, the Biobanking and Biomolecular Resources Research Infrastructure (Netherlands) (BBMRI-NL), the Hersenstichting Nederland, and the Netherlands Organization for Scientific Research (NWO). The research leading to these results also receives funding from the NWO Gravitation grant 'Language in Interaction', the European Community's Seventh Framework Programme (FP7/2007-.2013) under grant agreements no 602450 (IMAGEMEND), no 278948 (TACTICS), and no 602805 (Aggressotype), as well as from the European Community's Horizon 2020 programme under grant agreement no 643051 (MiND) and from ERC-2010-AdG 268800-NEUROSCHEMA. In addition, the work was supported by a grant for the ENIGMA Consortium (grant number U54 EB020403) from the BD2K Initiative of a cross-NIH partnership. We wish to thank all persons who kindly participated in the BIG research.; Brain Genomics Superstruct Project (GSP): Data were provided in part by the Brain Genomics Superstruct Project of Harvard University and the Massachusetts General Hospital, with support from the Center for Brain Science Neuroinformatics Research Group, the Athinoula A. Martinos Center for Biomedical Imaging, and the Center for Human Genetic Research. 20 individual investigators at Harvard and MGH generously contributed data to GSP. This work is supported by NIMH grants K99 MH101367 (P.H.L.), R01-MH079799 (J.W.S.), K24MH094614 (J.W.S.) and K01MH099232 (A.J.H.).; Brainscale and NTR-Adults: We would like to thank all twin participants from the Netherlands Twin Register. The NTR-adult and Brainscale studies were supported by the Netherlands Organization for Scientific Research NWO [MW904-61-193 (E.d.G. and D.B.), MaGW-nr: 400-07-080 (D. V't E.), MagW 480-04-004 (D.B.), (51.02.060 (H.H.), 668.772 (D.B. and H.H.); NWO/SPI 56-464-14192 (D.B.), the European Research Council (ERC-230374) (D.B.), High Potential Grant Utrecht University (H.H.), NWO Brain and Cognition 433-09-220 (H.H.) and the Neuroscience Campus Amsterdam.; Cardiovascular Health Study (CHS): This research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, and R01HL130114 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629, R01AG15928, R01AG20098, R01AG027002, R01AG05133, and R01AG027058 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at http://CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.; CHAP: This research was funded by grants from the National Institute of Health (AG011101 and AG030146) and the International Alzheimer's Association (NIRP-14-302587). DNA samples were collected during clinical evaluations and population interviews, and analyzed at the Broad Institute.; Epidemiology of Dementia in Singapore (EDIS): The Singapore Malay Eye Study (SiMES) and the Singapore Chinese Eye. Study (SCES) are funded by National Medical Research Council (grants 0796/2003, IRG07nov013, IRG09nov014, STaR/0003/2008 and CG/SERI/2010) and Biomedical Research Council (grants 09/1/35/19/616), Singapore. The Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore provided services for genotyping. The Epidemiology of Dementia in Singapore study is supported by the National Medical Research Council, Singapore (NMRC/CG/NUHS/2010, grant no. R-184-006-184-511). M.K.I. received additional funding from the Singapore Ministry of Health's National Medical Research Council (NMRC/CSA/038/2013).; EPIGEN: Work from the London Cohort was supported by research grants from the Wellcome Trust (grant 084730 to S.M.S.), University College London (UCL)/University College London Hospitals (UCLH) NIHR Biomedical Research Centre/Specialist Biomedical Research Centres (CBRC/SBRC) (grant 114 to S.M.S.), the European Union Marie Curie Reintegration (to M. Matarin and S.M.S.), the UK NIHR (08-08-SCC), the Comprehensive Local Research Network (CLRN) Flexibility and Sustainability Funding (FSF) (grant CEL1300 to S.M.S.), The Big Lottery Fund, the Wolfson Trust and the Epilepsy Society. This work was undertaken at UCLH/UCL, which received a proportion of funding from the UK Department of Health's NIHR Biomedical Research Centres funding scheme. Work from the Royal College of Surgeons in Ireland was supported by research grants from the Science Foundation Ireland (Research Frontiers Programme award 08/RFP/GEN1538) and Brainwave-the Irish Epilepsy Association. M. Matarin is funded by Epilepsy Research UK (grant F1206).; Erasmus Rucphen Family study (ERF) The ERF study as a part of EUROSPAN (European Special Populations Research Network) was supported by European Commission FP6 STRP grant number 018947 (LSHG-CT-2006-01947) and also received funding from the European Community's Seventh Framework Programme (FP7/2007-2013)/grant agreement HEALTH-F4-2007-201413 by the European Commission under the programme "Quality of Life and Management of the Living Resources" of 5th Framework Programme (no. QLG2-CT-2002-01254). High-throughput analysis of the ERF data was supported by joint grant from Netherlands Organization for Scientific Research and the Russian Foundation for Basic Research (NWO-RFBR 047.017.043). We are grateful to all study participants and their relatives, general practitioners and neurologists for their contributions and to P. Veraart for her help in genealogy, J. Vergeer for the supervision of the laboratory work and P. Snijders for his help in data collection. N. Amin is supported by the Netherlands Brain Foundation (project number F2013(1)-28). The ERF study genome-wide array data and phenotype data (age and gender) is archived in European Genome-Phenome Database (EGA). The study is archived in the DAC named Erasmus Rucphen Family Study with the accession code: EGAS00001001134. Researchers who wish to use other phenotypic data of the Erasmus Rucphen Family Study must seek approval from the management team of the Erasmus Rucphen Family study. They are advised to contact Cornelia van Duijn (c.vanduijn@erasmusmc.nl).; Framingham Heart Study (FHS): This work was supported by the dedication of the Framingham Study participants, the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. HHSN2682015000011), and by grants from the National Institute of Health (AG008122, AG054076, AG049607, AG033193, AG010129, NS017950, and U01AG49505).; Generation R: The Generation R Study is conducted by the Erasmus Medical Centre in close collaboration with the Municipal Health Service Rotterdam area, and the Stichting Trombosedienst & Artsenlaboratorium Rijnmond (STAR), Rotterdam. We gratefully acknowledge the contribution of general practitioners, hospitals, midwives and pharmacies in Rotterdam. Additional support for neuroimaging came from ZonMw TOP 40-00812-98-11021.; GeneSTAR: GeneSTAR was supported by grants from the National Institute of Neurological Disorders and Stroke (R01NS062059), the National Heart, Lung, and Blood Institute (U01 HL72518, HL097698) and the National Institutes of Health/National Center for Research Resources (M01-RR000052) to the Johns Hopkins General Clinical Research Center. We would like to thank the participants and families of GeneSTAR and our dedicated staff for all their sacrifices.; GOBS: We acknowledge the ultimate source of our data, the Mexican American community of San Antonio and surrounding areas. Financial support for this study was provided by grants from the National Institute of Mental Health MH0708143 (D.C. Glahn), MH078111 (J. Blangero) and MH083824 (D.C. Glahn and J. Blangero). Theoretical development of SOLAR is supported by MH59490 (J. Blangero). This investigation was conducted, in part, in facilities constructed with support from Research Facilities Improvement Program grant numbers C06 RR13556 and C06 RR017515 from the National Center for Research Resources, NIH. Some of this work was performed at Texas Biomedical Research Institute, where J. Blangero began this investigator-initiated competitively publicly funded work.; HUBIN: This study was financed by the Swedish Research Council (K2007-62X-15077-04-1, K2008-62P-20597-01-3. K2010-62X-15078-07-2, K2012-61X-15078-09-3), the regional agreement on medical training and clinical research between Stockholm County Council and the Karolinska Institutet, the Knut and Alice Wallenberg Foundation, and the HUBIN project. Genotyping was performed by the SNP&SEQ Technology Platform in Uppsala. The platform is part of Science for Life Laboratory at Uppsala University and supported as a national infrastructure by the Swedish Research Council.; IMAGEN: IMAGEN was supported by the European Union-funded FP6 Integrated Project IMAGEN (Reinforcement-related behavior in normal brain function and psychopathology) (LSHM-CT-2007-037286), the FP7 projects IMAGEMEND (602450) and MATRICS (603016), and the Innovative Medicine Initiative Project EU-AIMS (115300-2), the Medical Research Council Programme Grant "Developmental pathways into adolescent substance abuse" (93558), as well as the NIHR-biomedical Research Center "Mental Health": Further support was provided by the Swedish Research Council FORMAS, and the German Federal Ministry for Education and Research BMBF (eMED SysAlc 01ZX1311A; Forschungsnetz AERIAL; 1EV0711) and the US National Institutes of Health (Axon, Testosterone and Mental Health during Adolescence; MH085772-01A1), and grants from the French MILDECA and from the Fondation pour la Recherche Medicale.; IMpACT: This study was funded by a grant from the Brain & Cognition Excellence Program of the Netherlands Organization for Scientific Research (NWO, grant 433-09-229) and in part by the Netherlands Brain Foundation (grant number, 15F07[2]27). B. Franke is supported by a Vici grant from the Netherlands Organization for Scientific Research (NWO; grant no 016.130.669). The research leading to these results also receives funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreements no 602450 (IMAGEMEND), no 278948 (TACTICS), and no 602805 (Aggressotype) as well as from the European Community's Horizon 2020 programme under grant agreement no 643051 (MiND). In addition, the work was supported by a grant for the ENIGMA Consortium (grant number U54 EB020403) from the BD2K Initiative of a cross-NIH partnership.; LBC1936: We thank the LBC1936 participants and the members of the LBC1936 research team who collected and collated the phenotypic and genotypic data. This work was undertaken as part of the Cross Council and University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology (CCACE; http://www.ccace.ed.ac.uk). This work was supported by a Research into Ageing programme grant (to I.J.D.) and the Age UK-funded Disconnected Mind project (http://www.disconnectedmind.ed.ac.uk; to I.J.D. and J.M.W.), with additional funding from the UK Medical Research Council (MRC; to I.J.D., J.M.W. and M.E.B.). J.M.W. is supported by the Scottish Funding Council through the SINAPSE Collaboration (http://www.sinapse.ac.uk). M.V.M. is supported by the Row Fogo Charitable Trust. CCACE (MRC MR/K026992/1) is funded by the UK Biotechnology and Biological Sciences Research Council (BBSRC) and the UK MRC. Genotyping was supported by a grant from the BBSRC (BB/F019394/1).The image acquisition and analysis was performed at the Brain Research Imaging Centre, University of Edinburgh (http://www.bric.ed.ac.uk).; Leiden Longevity Study (LLS): The Leiden Longevity Study was supported by a grant from the Innovation-Oriented Research Program on Genomics (SenterNovem IGE05007) and the Netherlands Consortium for Healthy Ageing (grant number 050-060-810).; Mind Clinical Imaging Consortium (MCIC): Data used in the preparation of this work were obtained from the Mind Clinical Imaging Consortium database through the Mind Research Network (http://www.mrn.org). The MCIC project was supported by the Department of Energy under Award Number DE-FG02-08ER64581. MCIC is the result of efforts of co-investigators from University of Iowa, University of Minnesota, University of New Mexico, and Massachusetts General Hospital.; MooDS: The establishment of the MooDS sample was funded by the German Federal Ministry of Education and Research (BMBF) through the Integrated Genome Research Network (IG) MooDS (Systematic Investigation of the Molecular Causes of Major Mood Disorders and Schizophrenia; grant 01GS08144 to M.M. Nothen and S. Cichon, grant 01GS08147 to J. Rietschel and A. Meyer-Lindenberg and grant 01GS08148 to A. Heinz), under the auspices of the National Genome Research Network plus (NGFNplus), and through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders), under the auspices of the e:Med Programme (grant 01ZX1314A to M.M. Nothen, grant 01ZX1314C to H. Walter, grant 01ZX1314G to M. Rietschel).; MPIP: The MPIP Munich Morphometry Sample comprises images acquired as part of the Munich Antidepressant Response Signature Study and the Recurrent Unipolar Depression (RUD) Case-Control study performed at the MPIP, and control subjects acquired at the Ludwig-Maximilians-University, Munich, Department of Psychiatry. We thank E. Meisenzahl and D. Rujescu for providing MRI and genetic data for inclusion into the MPIP Munich Morphometry sample. We wish to acknowledge A. Olynyik and radiographers R. Schirmer, E. Schreiter, R. Borschke and I. Eidner for image acquisition and data preparation. We thank D.P. Auer for local study management in the initial phase of the RUD study. We are grateful to GlaxoSmithKline for providing the genotypes of the Recurrent Unipolar Depression Case-Control Sample. We thank the staff of the Center of Applied Genotyping (CAGT) for generating the genotypes of the MARS cohort. The study is supported by a grant of the Exzellenz-Stiftung of the Max Planck Society. This work has also been funded by the Federal Ministry of Education and Research (BMBF) in the framework of the National Genome Research Network (NGFN), FKZ 01GS0481.; NCNG: this sample collection was supported by grants from the Bergen Research Foundation and the University of Bergen, the Dr. Einar Martens Fund, the K.G. Jebsen Foundation, the Research Council of Norway, to S.L.H., V.M.S. and T.E.; NESDA: Funding was obtained from the Netherlands Organization for Scientific Research (Geestkracht program grant 10-000-1002); the Center for Medical Systems Biology (CSMB, NWO Genomics), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL), VU University's Institutes for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam, University Medical Center Groningen, Leiden University Medical Center, National Institutes of Health (NIH, R01D0042157-01A, MH081802, Grand Opportunity grants 1RC2 MH089951 and 1RC2 MH089995). Part of the genotyping and analyses were funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health. Computing was supported by BiG Grid, the Dutch e-Science Grid, which is financially supported by NWO.; NeuroIMAGE: The NeuroIMAGE project was supported by NIH Grant R01MH62873 (to S.V. Faraone), NWO Large Investment Grant 1750102007010 (to J. Buitelaar), and by grants from Radboud University Nijmegen Medical Center, University Medical Center Groningen and Accare, and VU University Amsterdam. The work contributing to this result also receives support from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreements no 602450 (IMAGEMEND), no 278948 (TACTICS) and no 602805 (Aggressotype) as well as from the European Community's Horizon 2020 programme under grant agreement no 643051 (MiND). In addition, the work was supported by a grant for the ENIGMA Consortium (grant number U54 EB020403) from the BD2K Initiative of a cross-NIH partnership.; NIMH-IRP: Supported in part by the NIMH Intramural Research Program (ZIAMH002810; Z01MH002792; Z01MH002790).; North American Brain Expression Consortium (NABEC): This research was supported by the Intramural Research Program of the NIH, National Institute on Aging.; Older Australian Twins Study (OATS): We would like to acknowledge and thank the OATS participants, their supporters and respective Research Teams. This work was supported by a number of sources. OATS is supported by the NHMRC/Australian Research Council Strategic Award 401162 and NHMRC Project Grant 1045325 to P. Sachdev and colleagues. OATS was facilitated through access to the Australian Twin Registry, a national research resource supported by the NHMRC Enabling Grant 310667, administered by the University of Melbourne. DNA was extracted by Genetic Repositories Australia, an Enabling Facility supported by the NHMRC Grant 401184. OATS genotyping was partly funded by a Commonwealth Scientific and Industrial Research Organisation Flagship Collaboration Fund Grant. Henry Brodaty is supported by the Australian Government funded Dementia Collaborative Research Centre (DCRC), UNSW. Nicola Armstrong was supported by the NHMRC Project Grant 525453 and Karen Mather is supported by an Alzheimer's Australia Dementia Research Foundation Postdoctoral Fellowship and the NHMRC Capacity Building Grant 568940.; Osaka: This study was supported, in part, by research grants from the Japanese Ministry of Health, Labor and Welfare; the Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT) KAKENHI and Scientific Research on Innovative Areas (Comprehensive Brain Science Network); and the Brain Sciences Project of the Center for Novel Science Initiatives (CNSI), the National Institutes of Natural Sciences (NINS), and the Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS) from Japan Agency for Medical Research and development, AMED.; PAFIP: The PAFIP study was supported by Instituto de Salud Carlos III, FIS00/3095, 01/3129, PI020499, PI060507, PI10/00183, PI14/00639, the SENY Fundacio Research Grant CI 2005-0308007, and the Fundacion Marques de Valdecilla API07/011. PAFIP wish to acknowledge WTCCC2 (Wellcome Trust Case Control Consortium 2) for DNA Genotyping, Valdecilla Biobank for providing the biological samples and associated data included in this study and Idival Neuroimaging Unit for its help in the technical execution of this work. D. Tordesillas-Gutierrez is funded by a contract from the Carlos III Health Institute (CA12/00312).; PROSPER: The PROSPER study was supported by an investigator-initiated grant obtained from Bristol-Myers Squibb. J.W. Jukema is an Established Clinical Investigator of the Netherlands Heart Foundation (grant 2001 D 032). Support for genotyping was provided by the seventh framework program of the European commission (grant 223004) and by the Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging grant 050-060-810).; QTIM: D.P.H., N.J., C.R.K.C. and P.M.T. are supported, in part, by NIH grants R01 NS080655, R01AG040060, R01 EB008432, R01 MH097268, U01 AG024904, R01 MH085667, R01 MH089722, P41 EB015922, and R01 MH094343. R.K.W. is supported by National Science Foundation (BCS-1229450). J.L.S. was supported by the NIMH (K99MH102357) and Autism Speaks. G.Z. is supported by a Future Fellowship (FT0991634) from the Australian Research Council. S.E.M. and G.W.M. are supported by a National Health and Medical Research Council (NHMRC), Australia, Fellowships (1103623, 619667). The QTIM study is supported by grants from NIH (R01 HD050735) and the NHMRC (389875, 486682, 1009064). We thank the twins and siblings for their participation, M. Grace and A. Eldridge for twin recruitment, A. Al Najjar and other radiographers for scanning, K. McAloney and D. Park for research support, and A. Henders and staff for DNA sample processing and preparation.; ROS and MAP: The clinical, genomic, and neuroimaging data for the Religious Orders Study and the Rush Memory and Aging Project was funded by NIH grants P30AG10161, RF1AG15819, R01AG17917, R01AG30146, R01AG40039, and the Translational Genomics Research Institute.; Rotterdam Study: The generation and management of GWAS genotype data for the Rotterdam Study are supported by the Netherlands Organisation of Scientific Research NWO Investments (nr. 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 Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. This research is supported by the Dutch Technology Foundation STW, which is part of the NWO, and which is partly funded by the Ministry of Economic Affairs. This project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement No 678543). Further support was obtained through the Joint Programme - Neurodegenerative Disease Research working group on High-Dimensional Research in Alzheimer's Disease (ZonMW grant number 733051031). MAI is supported by ZonMW grant number 916.13.054. H.H.H.A. is supported by the Van Leersum Grant of the Royal Netherlands Academy of Arts and Sciences.; Saguenay Youth Study (SYS): The Saguenay Youth Study project is funded by the Canadian Institutes of Health Research (T.P., Z.P.), Heart and Stroke Foundation of Quebec (Z.P.), and the Canadian Foundation for Innovation (Z.P.). T.P. is supported by the Tanenbaum Chair in Population Neuroscience at the Rotman Research Institute, University of Toronto.; SHIP and TREND: The SHIP data sets are part of the Community Medicine Research net (CMR) of the University of Greifswald, which is funded by the German Federal Ministry of Education and Research and the German Ministry of Cultural Affairs, as well as by the Social Ministry of the Federal State of Mecklenburg-West Pomerania (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), and the network 'Greifswald Approach to Individualized Medicine (GANI_MED)' funded by the Federal Ministry of Education and Research (grant 03IS2061A). Genome-wide data and MRI scans were 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 oft the Cache Campus Program of the InterSystems GmbH.; Sydney Memory and Ageing Study (Sydney MAS): We would like to thank the Sydney MAS participants, their supporters and respective research teams. Sydney MAS was supported by the Australian National Health and Medical Research Council (NHMRC) Program Grants 350833 and 568969 to P. Sachdev, H. Brodaty and G. Andrews. DNA was extracted by Genetic Repositories Australia, an Enabling Facility supported by the NHMRC Grant 401184. H. Brodaty is supported by the Australian Government funded Dementia Collaborative Research Centre (DCRC), UNSW. N. Armstrong was supported by the NHMRC Project Grant 525453 and K. Mather is supported by an Alzheimer's Australia Dementia Research Foundation Postdoctoral Fellowship. Both S. Reppermund and K. Mather are supported by the NHMRC Capacity Building Grant 568940.; Tasmanian Study of Gait and Cognition (TASCOG): The Tasmanian Study of Gait and Cognition is supported by project grants from the National Health and Medical Research Council of Australia (NHMRC; 403000, 491109, and 606543) and a grant from the Wicking Dementia Education and Research Centre, Hobart. V.S. is supported by a cofunded NHMRC Career Development Fellowship (1061457) and a Heart Foundation Future Leader Fellowship (ID 100089).; Three-City Dijon Study: The Three-City Study is conducted under a partnership agreement among the Institut National de la Sante et de la Recherche Medicale (INSEAM), the Victor Segalen-Bordeaux II University, and Sanofi-Aventis. The Fondation pour la Recherche Medicale funded the preparation and initiation of the study. The Three-City Study is also supported by the Caisse Nationale Maladie des Travailleurs Salaries, Direction Generale de la Sante, Mutuelle Generale de l'Education Nationale (MGEN), Institut de la Longevite, Conseils Regionaux of Aquitaine and Bourgogne, Fondation de France, and Ministry of Research INSEAM Programme "Cohortes et collections de donnees biologiques." Christophe Tzourio and Stephanie Debette are supported by a grant from the Fondation Leducq.; TOP: The study was supported by the Research Council of Norway (#213837, #223273, #229129), South-East Norway Health Authority (#2013-123) and KG Jebsen Foundation. The research leading to these results has received funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement no 602450 (IMAGEMEND).; UMCU: UMCU acknowledgment data: This work was supported by 917.46.370 (H.H.) and 908-02-123 (H.H.) from the Netherlands Organization for Health Research and Development ZonMW.; WHICAP: This study was supported by a grant from the NIH (5R01AG037212). CHARGE consortium: See ref. 40 for the general cognitive function GWAS, and ref. 29 for the white matter lesion GWAS.; IGAP: We thank the International Genomics of Alzheimer's Project (IGAP) for providing summary results data for these analyses. The investigators within IGAP contributed to the design and implementation of IGAP and/or provided data but did not participate in analysis or writing of this report. IGAP was made possible by the generous participation of the control subjects, the patients, and their families. The i-Select chips was funded by the French National Foundation on Alzheimer's disease and related disorders. EADI was supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant, Inserm, Institut Pasteur de Lille, University de Lille 2 and the Lille University Hospital. GERAD was supported by the Medical Research Council (Grant no 503480), Alzheimer's Research UK (Grant no 503176), the Wellcome Trust (Grant no 082604/2/07/Z) and German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) grant no 01G10102, 01G10711, 01G10420. CHARGE was partly supported by the NIH/NIA grant R01 AG033193 and the NIA AG081220 and AGES contract N01-AG-12100, the NHLBI grant R01 HL105756, the Icelandic Heart Association, and the Erasmus Medical Center and Erasmus University. ADGC was supported by the NIH/NIA grants: U01 AG032984, U24 AG021886, U01 AG016976, and the Alzheimer's Association grant ADGC-10-196728. NR 46 TC 0 Z9 0 U1 27 U2 27 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 EI 1546-1726 J9 NAT NEUROSCI JI Nat. Neurosci. PD DEC PY 2016 VL 19 IS 12 BP 1569 EP 1582 DI 10.1038/nn.4398 PG 14 WC Neurosciences SC Neurosciences & Neurology GA ED7BY UT WOS:000389011900016 PM 27694991 ER PT J AU Garfield, AS Shah, BP Burgess, CR Li, MM Li, C Steger, JS Madara, JC Campbell, JN Kroeger, D Scammell, TE Tannous, BA Myers, MG Andermann, ML Krashes, MJ Lowell, BB AF Garfield, Alastair S. Shah, Bhavik P. Burgess, Christian R. Li, Monica M. Li, Chia Steger, Jennifer S. Madara, Joseph C. Campbell, John N. Kroeger, Daniel Scammell, Thomas E. Tannous, Bakhos A. Myers, Martin G., Jr. Andermann, Mark L. Krashes, Michael J. Lowell, Bradford B. TI Dynamic GABAergic afferent modulation of AgRP neurons SO NATURE NEUROSCIENCE LA English DT Article ID BROWN ADIPOSE-TISSUE; DORSOMEDIAL HYPOTHALAMUS; FEEDING CIRCUITS; LEPTIN ACTION; NUCLEUS; HUNGER; PRESSURE; BEHAVIOR; OBESITY; POMC AB Agouti-related peptide (AgRP) neurons of the arcuate nucleus of the hypothalamus (ARC) promote homeostatic feeding at times of caloric insufficiency, yet they are rapidly suppressed by food-related sensory cues before ingestion. Here we identify a highly selective inhibitory afferent to AgRP neurons that serves as a neural determinant of this rapid modulation. Specifically, GABAergic projections arising from the ventral compartment of the dorsomedial nucleus of the hypothalamus (vDMH) contribute to the preconsummatory modulation of ARC(AgRP) neurons. In a manner reciprocal to ARC(AgRP) neurons, ARC-projecting leptin receptor expressing GABAergic vDMH neurons exhibit rapid activation upon availability of food that additionally reflects the relative value of the food. Thus, leptin receptor-expressing GABAergic vDMH neurons form part of the sensory network that relays real-time information about the nature and availability of food to dynamically modulate ARC(AgRP) neuron activity and feeding behavior. C1 [Garfield, Alastair S.; Shah, Bhavik P.; Burgess, Christian R.; Li, Monica M.; Steger, Jennifer S.; Madara, Joseph C.; Campbell, John N.; Andermann, Mark L.; Lowell, Bradford B.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Med, Div Endocrinol Diabet & Metab, Boston, MA 02115 USA. [Garfield, Alastair S.] Univ Edinburgh, Ctr Integrat Physiol, Hugh Robson Bldg, Edinburgh, Midlothian, Scotland. [Li, Chia; Krashes, Michael J.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Li, Chia; Krashes, Michael J.] NIDA, NIH, Baltimore, MD USA. [Kroeger, Daniel; Scammell, Thomas E.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA USA. [Tannous, Bakhos A.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA USA. [Myers, Martin G., Jr.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Myers, Martin G., Jr.] Univ Michigan, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA. [Andermann, Mark L.; Lowell, Bradford B.] Harvard Med Sch, Program Neurosci, Boston, MA USA. [Garfield, Alastair S.; Shah, Bhavik P.] Pfizer, Cardiovasc & Metab Dis, Cambridge, MA 02139 USA. RP Garfield, AS (reprint author), Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Med, Div Endocrinol Diabet & Metab, Boston, MA 02115 USA.; Garfield, AS (reprint author), Univ Edinburgh, Ctr Integrat Physiol, Hugh Robson Bldg, Edinburgh, Midlothian, Scotland.; Garfield, AS (reprint author), Pfizer, Cardiovasc & Metab Dis, Cambridge, MA 02139 USA. EM alastair.garfield@pfizer.com; manderma@bidmc.harvard.edu; michael.krashes@nih.gov; blowell@bidmc.harvard.edu FU University of Edinburgh Chancellor's Fellowship; National Institutes of Health [R01 DK096010, R01 DK089044, R01 DK071051, R01 DK075632, R37 DK053477, P30 DK046200, R01 DK056731, P30 DK057521, F32 DK089710, DP2 DK105570-01, R01 DK109930]; McKnight Foundation; Klarman Family Foundation; Richard and Susan Smith Family Foundation; Pew Scholars Program in Biomedical Sciences; ADA Mentor-Based Fellowship; Davis Family Foundation; AHA postdoctoral fellowship [14POST20100011]; Intramural Research Program of the NIH, The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [DK075087, DK075088]; NIH/NINDS [P30NS045776] FX We thank B. Sabatini and K.W. Huang for assistance with in vivo fiber photometry. We thank Drs. V. Jayaraman, R.A. Kerr, D.S. Kim, L.L. Looger and K. Svoboda and the GENIE Project at Janelia Farm Research Campus, Howard Hughes Medical Institute, for distribution of GCaMP6. This work was supported by the University of Edinburgh Chancellor's Fellowship (A.S.G.); National Institutes of Health grants R01 DK096010 (B.B.L.), R01 DK089044 (B.B.L.), R01 DK071051 (B.B.L.), R01 DK075632 (B.B.L.), R37 DK053477 (B.B.L.), BNORC Transgenic Core P30 DK046200 (B.B.L.), R01 DK056731 (M.J.G.), BADERC Transgenic Core P30 DK057521 (B.B.L.), F32 DK089710 (M.J.K.), DP2 DK105570-01 (M.L.A.) and R01 DK109930 (M.L.A.); the McKnight Foundation (M.L.A.); the Klarman Family Foundation (M.L.A.); the Richard and Susan Smith Family Foundation (M.L.A.); the Pew Scholars Program in Biomedical Sciences (M.L.A.); ADA Mentor-Based Fellowship (B.P.S. and B.B.L.); Davis Family Foundation postdoctoral fellowship award (C.R.B.); and AHA postdoctoral fellowship 14POST20100011 (J.N.C.). This research was supported, in part, by the Intramural Research Program of the NIH, The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK; DK075087, DK075088). The GH Viral vector core facility was funded by NIH/NINDS grant P30NS045776 (B.A.T.) for the preparation of the rabies virus. NR 29 TC 2 Z9 2 U1 5 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 EI 1546-1726 J9 NAT NEUROSCI JI Nat. Neurosci. PD DEC PY 2016 VL 19 IS 12 BP 1628 EP 1635 DI 10.1038/nn.4392 PG 8 WC Neurosciences SC Neurosciences & Neurology GA ED7BY UT WOS:000389011900022 PM 27643429 ER PT J AU Kamaly, N He, JC Ausiello, DA Farokhzad, OC AF Kamaly, Nazila He, John C. Ausiello, Dennis A. Farokhzad, Omid C. TI Nanomedicines for renal disease: current status and future applications SO NATURE REVIEWS NEPHROLOGY LA English DT Review ID PEGYLATED-LIPOSOMAL DOXORUBICIN; GLOMERULAR-BASEMENT-MEMBRANE; CATIONIC MULTILAMELLAR LIPOSOMES; PROTEIN-NANOPARTICLE INTERACTIONS; ACCELERATED BLOOD CLEARANCE; HAFNIUM OXIDE NANOPARTICLES; POLYMER-BASED NANOPARTICLE; MOLECULAR-WEIGHT CHITOSAN; METASTATIC BREAST-CANCER; HUMAN PANCREATIC-CANCER AB Treatment and management of kidney disease currently presents an enormous global burden, and the application of nanotechnology principles to renal disease therapy, although still at an early stage, has profound transformative potential. The increasing translation of nanomedicines to the clinic, alongside research efforts in tissue regeneration and organ-on-a-chip investigations, are likely to provide novel solutions to treat kidney diseases. Our understanding of renal anatomy and of how the biological and physico-chemical properties of nanomedicines (the combination of a nanocarrier and a drug) influence their interactions with renal tissues has improved dramatically. Tailoring of nanomedicines in terms of kidney retention and binding to key membranes and cell populations associated with renal diseases is now possible and greatly enhances their localization, tolerability, and efficacy. This Review outlines nanomedicine characteristics central to improved targeting of renal cells and highlights the prospects, challenges, and opportunities of - nanotechnology-mediated therapies for renal diseases. C1 [Kamaly, Nazila; Farokhzad, Omid C.] Brigham & Womens Hosp, Ctr Nanomed, 75 Francis St, Boston, MA 02115 USA. [Kamaly, Nazila; Farokhzad, Omid C.] Brigham & Womens Hosp, Dept Anaesthesiol, 75 Francis St, Boston, MA 02115 USA. [Kamaly, Nazila; Farokhzad, Omid C.] Harvard Med Sch, 75 Francis St, Boston, MA 02115 USA. [Kamaly, Nazila] Tech Univ Denmark, Dept Micro & Nanotechnol, DK-2800 Lyngby, Denmark. [He, John C.] Icahn Sch Med Mt Sinai, Div Nephrol, Dept Med, 1 Gustave L Levy Pl, New York, NY 10029 USA. [Ausiello, Dennis A.] Massachusetts Gen Hosp, Ctr Assessment Technol & Continuous Hlth, 55 Fruit St, Boston, MA 02114 USA. [Ausiello, Dennis A.] Massachusetts Gen Hosp, Ctr Syst Biol, Program Membrane Biol, 55 Fruit St, Boston, MA 02114 USA. [Ausiello, Dennis A.] Massachusetts Gen Hosp, Div Nephrol, Simches Res Ctr, 55 Fruit St, Boston, MA 02114 USA. [Ausiello, Dennis A.] Harvard Med Sch, Dept Med, 25 Shattuck St, Boston, MA 02114 USA. [Farokhzad, Omid C.] King Abdulaziz Univ, King Fahad Rd, Jeddah 22254, Saudi Arabia. RP Farokhzad, OC (reprint author), Brigham & Womens Hosp, Ctr Nanomed, 75 Francis St, Boston, MA 02115 USA.; Farokhzad, OC (reprint author), Brigham & Womens Hosp, Dept Anaesthesiol, 75 Francis St, Boston, MA 02115 USA.; Farokhzad, OC (reprint author), Harvard Med Sch, 75 Francis St, Boston, MA 02115 USA.; Farokhzad, OC (reprint author), King Abdulaziz Univ, King Fahad Rd, Jeddah 22254, Saudi Arabia. EM ofarokhzad@bwh.harvard.edu OI Kamaly, Nazila/0000-0002-9716-5121 FU NHLBI [HL127464]; NCI [CA151884]; NIBIB [EB015419]; David Koch-Prostate Cancer Foundation Award in Nanotherapeutics; NIH [1R01DK078897, 1R01DK088541, P01-DK-56492]; Chinese 973 fund [2012CB517601] FX O.C.F acknowledges support from the NHLBI HL127464, NCI CA151884, NIBIB EB015419 and the David Koch-Prostate Cancer Foundation Award in Nanotherapeutics. J.C.H is supported by NIH 1R01DK078897, NIH 1R01DK088541, NIH P01-DK-56492, Chinese 973 fund 2012CB517601. NR 300 TC 1 Z9 1 U1 36 U2 36 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-5061 EI 1759-507X J9 NAT REV NEPHROL JI Nat. Rev. Nephrol. PD DEC PY 2016 VL 12 IS 12 BP 738 EP 753 DI 10.1038/nrneph.2016.156 PG 16 WC Urology & Nephrology SC Urology & Nephrology GA ED3DL UT WOS:000388729400005 PM 27795549 ER PT J AU Kertesz, SG Baggett, TP O'Connell, JJ Buck, DS Kushel, MB AF Kertesz, Stefan G. Baggett, Travis P. O'Connell, James J. Buck, David S. Kushel, Margot B. TI Permanent Supportive Housing for Homeless People - Reframing the Debate SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID HEALTH-CARE; COSTS; 1ST C1 [Kertesz, Stefan G.] Birmingham Vet Affairs Med Ctr, Birmingham, AL 35233 USA. [Kertesz, Stefan G.] Univ Alabama Birmingham, Sch Med, Birmingham, AL 35294 USA. [Baggett, Travis P.; O'Connell, James J.] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. [Baggett, Travis P.; O'Connell, James J.] Boston Hlth Care Homeless Program, Boston, MA USA. [Buck, David S.] Baylor Coll Med, Houston, TX 77030 USA. [Buck, David S.] Healthcare Homeless Houston, Houston, TX USA. [Kushel, Margot B.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Kushel, Margot B.] Zuckerberg San Francisco Gen Hosp, San Francisco, CA USA. RP Kertesz, SG (reprint author), Birmingham Vet Affairs Med Ctr, Birmingham, AL 35233 USA.; Kertesz, SG (reprint author), Univ Alabama Birmingham, Sch Med, Birmingham, AL 35294 USA. OI Kertesz, Stefan/0000-0001-6101-8421 NR 5 TC 0 Z9 0 U1 4 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 DEC 1 PY 2016 VL 375 IS 22 BP 2115 EP 2117 DI 10.1056/NEJMp1608326 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA ED7GN UT WOS:000389030400002 PM 27959753 ER PT J AU Mirza, MR Monk, BJ Herrstedt, J Oza, AM Mahner, S Redondo, A Fabbro, M Ledermann, JA Lorusso, D Vergote, I Ben-Baruch, NE Marth, C Madry, R Christensen, RD Berek, JS Dorum, A Tinker, AV du Bois, A Gonzalez-Martin, A Follana, P Benigno, B Rosenberg, P Gilbert, L Rimel, BJ Buscema, J Balser, JP Agarwal, S Matulonis, UA AF Mirza, M. R. Monk, B. J. Herrstedt, J. Oza, A. M. Mahner, S. Redondo, A. Fabbro, M. Ledermann, J. A. Lorusso, D. Vergote, I. Ben-Baruch, N. E. Marth, C. Madry, R. Christensen, R. D. Berek, J. S. Dorum, A. Tinker, A. V. du Bois, A. Gonzalez-Martin, A. Follana, P. Benigno, B. Rosenberg, P. Gilbert, L. Rimel, B. J. Buscema, J. Balser, J. P. Agarwal, S. Matulonis, U. A. CA ENGOT-OV16 NOVA Investigators TI Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID NEGATIVE BREAST-CANCER; BRCA MUTATION CARRIERS; POLY(ADP-RIBOSE) POLYMERASE; SOLID TUMORS; OLAPARIB; TRIAL AB BACKGROUND Niraparib is an oral poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) 1/2 inhibitor that has shown clinical activity in patients with ovarian cancer. We sought to evaluate the efficacy of niraparib versus placebo as maintenance treatment for patients with platinum-sensitive, recurrent ovarian cancer. METHODS In this randomized, double-blind, phase 3 trial, patients were categorized according to the presence or absence of a germline BRCA mutation (gBRCA cohort and non-gBRCA cohort) and the type of non-gBRCA mutation and were randomly assigned in a 2: 1 ratio to receive niraparib (300 mg) or placebo once daily. The primary end point was progression-free survival. RESULTS Of 553 enrolled patients, 203 were in the gBRCA cohort (with 138 assigned to niraparib and 65 to placebo), and 350 patients were in the non-gBRCA cohort (with 234 assigned to niraparib and 116 to placebo). Patients in the niraparib group had a significantly longer median duration of progression-free survival than did those in the placebo group, including 21.0 vs. 5.5 months in the gBRCA cohort (hazard ratio, 0.27; 95% confidence interval [CI], 0.17 to 0.41), as compared with 12.9 months vs. 3.8 months in the non-gBRCA cohort for patients who had tumors with homologous recombination deficiency (HRD) (hazard ratio, 0.38; 95% CI, 0.24 to 0.59) and 9.3 months vs. 3.9 months in the overall non-gBRCA cohort (hazard ratio, 0.45; 95% CI, 0.34 to 0.61; P < 0.001 for all three comparisons). The most common grade 3 or 4 adverse events that were reported in the niraparib group were thrombocytopenia (in 33.8%), anemia (in 25.3%), and neutropenia (in 19.6%), which were managed with dose modifications. CONCLUSIONS Among patients with platinum-sensitive, recurrent ovarian cancer, the median duration of progression-free survival was significantly longer among those receiving niraparib than among those receiving placebo, regardless of the presence or absence of gBRCA mutations or HRD status, with moderate bone marrow toxicity. (Funded by Tesaro; ClinicalTrials.gov number, NCT01847274.) C1 [Mirza, M. R.] Nord Soc Gynecol Oncol, Copenhagen, Denmark. [Mirza, M. R.] Copenhagen Univ Hosp, Rigshosp, Copenhagen, Denmark. [Herrstedt, J.] Univ Southern Denmark, Odense Univ Hosp, Odense, Denmark. [Christensen, R. D.] Univ Southern Denmark, European Network Gynacol Oncol Trial, Odense, Denmark. [Christensen, R. D.] Univ Southern Denmark, Inst Publ Hlth, Res Unit Gen Practice, Odense, Denmark. [Monk, B. J.] Univ Arizona, Phoenix, AZ USA. [Monk, B. J.] Creighton Univ Phoenix, Phoenix, AZ USA. [Monk, B. J.; Buscema, J.] Arizona Oncol Associates, Tucson, AZ USA. [Oza, A. M.] Univ Toronto, Univ Hlth Network, Princess Margaret Canc Ctr, Princess Margaret Consortium, Toronto, ON, Canada. [Tinker, A. V.] British Columbia Canc Agcy, Vancouver, BC, Canada. [Gilbert, L.] McGill Univ, Ctr Hlth, Montreal, PQ, Canada. [Mahner, S.] Arbeitsgemeinschaft Gynakol Onkol, Munich, Germany. [Mahner, S.] Univ Munich, Munich, Germany. [du Bois, A.] Kliniken Essen Mitte, Essen, Germany. [Redondo, A.; Gonzalez-Martin, A.] GEICO, Madrid, Spain. [Redondo, A.] Hosp Univ La Paz, Madrid, Spain. [Gonzalez-Martin, A.] MD Anderson Canc Ctr Madrid, Madrid, Spain. [Fabbro, M.] French Investigator Grp Ovarian & Breast Canc GIN, Montpellier, France. [Fabbro, M.] Inst Canc Montpellier, Montpellier, France. [Follana, P.] GINECO, Nice, France. [Follana, P.] Ctr Antoine Lacassagne, Nice, France. [Ledermann, J. A.] UCL, Natl Inst Canc Res, London, England. [Ledermann, J. A.] UCL, UCL Canc Inst, London, England. [Lorusso, D.] Ist Nazl Tumori, Fdn Ist Ricovero & Cura Carattere Sci, Mario Negri Gynecol Oncol Grp, Multictr Italian Trials Ovarian Canc, Milan, Italy. [Vergote, I.] Luxembourg Gynecol Oncol Grp, Leuven, Belgium. [Vergote, I.] Univ Leuven, Leuven, Belgium. [Ben-Baruch, N. E.] Kaplan Med Ctr, Rehovot, Israel. [Marth, C.] AGO Austria, Innsbruck, Austria. [Marth, C.] Med Univ Innsbruck, Innsbruck, Austria. [Madry, R.] Cent & Eastern European Gynecol Oncol Grp, Poznan, Poland. [Madry, R.] Uniwersytet Med Poznaniu, Poznan, Poland. [Berek, J. S.] Stanford Comprehens Canc Inst, Stanford, CA USA. [Rimel, B. J.] Cedars Sinai Med Ctr, West Hollywood, CA USA. [Dorum, A.] Oslo Univ Hosp, Radiumhosp, Oslo, Norway. [Benigno, B.] Northside Hosp, Atlanta, GA USA. [Rosenberg, P.] Univ Sjukhuset, Linkoping, Sweden. [Balser, J. P.] Veristat, Southborough, MA USA. [Agarwal, S.] Tesaro, Waltham, MA USA. [Matulonis, U. A.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Mirza, MR (reprint author), Copenhagen Univ Hosp, Rigshosp, Dept Oncol, DK-2100 Copenhagen, Denmark. EM mansoor@rh.regionh.dk FU Tesaro; Amgen; Genentech; Roche; AstraZeneca; Myriad Genetics; Merck; Gradalis; Cerulean; Vermillion; ImmunoGen; Pfizer; Bayer; Nu-Cana BioMed; INSYS Therapeutics; GlaxoSmithKline; Verastem; Mateon Therapeutics; Pharmaceutical Product Development; Clovis Oncology; Janssen/Johnson Johnson; Eli Lilly; Merck Sharp Dohme FX Supported by Tesaro.; Dr. Monk reports receiving consulting fees from Amgen, Genentech, Tesaro, Roche, AstraZeneca, Myriad Genetics, Merck, Gradalis, Cerulean, Vermillion, ImmunoGen, Pfizer, Bayer, Nu-Cana BioMed, INSYS Therapeutics, GlaxoSmithKline, Verastem, Mateon Therapeutics (formally OXiGENE), Pharmaceutical Product Development, and Clovis Oncology, lecture fees from Genentech, Janssen/Johnson & Johnson, Roche, AstraZeneca, and Myriad Genetics, and grant support to his institution from Amgen, Eli Lilly, Genentech, Janssen/Johnson & Johnson, Array Biopharma, Tesaro, and Morphotek; Drs. Herrstedt and Matulonis, receiving fees for serving on an advisory board from Tesaro; Dr. Mahner, receiving fees for serving on advisory boards from AstraZeneca, Clovis Oncology, Merck Sharp & Dohme, Roche, and Sensor-Kinesis, consulting fees from Medac Pharma, lecture fees from AstraZeneca, Bayer, Jenapharm, GlaxoSmithKline, Janssen-Cilag, Medac Pharma, Merck Sharp & Dohme, PharmaMar, Roche, and Teva Pharmaceuticals, travel support from AstraZeneca, Bayer, Clovis Oncology, Jenapharm, GlaxoSmithKline, Janssen-Cilag, Medac Pharma, Merck Sharp & Dohme, PharmaMar, Roche, Sensor-Kinesis, and Teva Pharmaceuticals, and grant support from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Janssen-Cilag, Medac Pharma, Merck Sharp & Dohme, PharmaMar, and Roche; Dr. Ledermann, receiving fees for serving on advisory boards from AstraZeneca, Clovis Oncology, Pfizer, Roche, and Merck Sharp & Dohme, lecture fees from AstraZeneca, and serving as a principal investigator in a trial sponsored by Clovis Oncology; Dr. Lorusso, receiving fees for serving on advisory boards from Roche, PharmaMar, and AstraZeneca; Dr. Ben-Baruch, receiving travel support and fees for serving on an advisory board from AstraZeneca and grant support from AstraZeneca and AbbVie; Dr. Tinker, receiving fees for serving on an advisory board and grant support from AstraZeneca; Dr. du Bois, receiving fees for serving on advisory boards from Roche, AstraZeneca, PharmaMar, Merck Sharp & Dohme, and Pfizer; Dr. Gonzalez-Martin, receiving fees for serving on advisory boards from Roche, PharmaMar, AstraZeneca, and Clovis Oncology and lecture fees and travel support from Roche, PharmaMar, and AstraZeneca; Dr. Rimel, receiving fees for serving on advisory boards from AstraZeneca and Genentech and lecture fees from Genentech; Dr. Balser, being an employee of Veristat; and Dr. Agarwal, being an employee of Tesaro. No other potential conflict of interest relevant to this article was reported. NR 13 TC 13 Z9 13 U1 13 U2 13 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 1 PY 2016 VL 375 IS 22 BP 2154 EP 2164 DI 10.1056/NEJMoa1611310 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA ED7GN UT WOS:000389030400007 PM 27717299 ER PT J AU Armstrong-Javors, A Pratt, J Kharasch, S AF Armstrong-Javors, Amy Pratt, Janey Kharasch, Sigmund TI Wernicke Encephalopathy in Adolescents After Bariatric Surgery: Case Report and Review SO PEDIATRICS LA English DT Review ID GASTRIC BYPASS-SURGERY; MORBIDLY OBESE ADOLESCENTS; WEIGHT-LOSS; METAANALYSIS; CHILDREN; PREVALENCE; DEFICIENCY; MANAGEMENT; DIAGNOSIS; BERIBERI AB Roughly 1% of all weight loss surgery is performed in adolescents. There is strong evidence demonstrating significant postsurgical weight loss, improvement in quality of life, and reduction in comorbidities such as hypertension and diabetes. Reports of postoperative complications in adolescents are few because of the small sample size in most series. Despite vitamin supplementation, nutritional deficiencies requiring hospitalization occur occasionally after Roux-en-Y gastric bypass. Wernicke encephalopathy, a triad of ophthalmoplegia, ataxia, and altered mental status, is a serious consequence of thiamine (vitamin B-1) deficiency. Few cases of Wernicke encephalopathy after weight loss surgery have been reported in the literature and even fewer in the pediatric population. Here we describe a teenage girl who develops vomiting after Roux-en-Y gastric bypass and presented with nystagmus, irritability, and ataxia. The clinical presentation, diagnosis, and treatment of Wernicke encephalopathy in adolescents after bariatric surgery are discussed. C1 [Armstrong-Javors, Amy] Massachusetts Gen Hosp, Dept Pediat Neurol, Boston, MA 02114 USA. [Pratt, Janey] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Kharasch, Sigmund] Massachusetts Gen Hosp, Div Pediat Emergency Med, Boston, MA 02114 USA. RP Armstrong-Javors, A (reprint author), Massachusetts Gen Hosp Children, WACC, Dept Pediat Neurol, 55 Fruit St, Boston, MA 02114 USA. EM aarmstrong-javors@partners.org NR 36 TC 0 Z9 0 U1 1 U2 1 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD DEC PY 2016 VL 138 IS 6 AR e20161039 DI 10.1542/peds.2016-1039 PG 5 WC Pediatrics SC Pediatrics GA ED5WX UT WOS:000388924800018 ER PT J AU Ziniel, SI Rosenberg, HN Bach, AM Singer, SJ Antonelli, RC AF Ziniel, Sonja I. Rosenberg, Hannah N. Bach, Ashley M. Singer, Sara J. Antonelli, Richard C. TI Validation of a Parent-Reported Experience Measure of Integrated Care SO PEDIATRICS LA English DT Article ID HEALTH; SAFETY AB OBJECTIVES: The objectives of this study were to design and validate a survey measuring the parents' and caregivers' experiences of integration of their child's care across providers. METHODS: After review of the literature on care coordination and integration, we solicited input regarding care experiences from focus groups of families with children with chronic conditions. These data informed a 95-item pilot survey that included elements from a care integration measure designed for adult care experiences. The survey was then administered to parents of children who had had at least 1 primary care appointment and 2 specialty care appointments in the previous 12 months. Psychometric analyses were used to establish scales through exploratory factor analysis, internal consistency using Cronbach's a, test-retest reliability using Spearman's rank correlation coefficient, and known-group validity according to chi(2) tests. All research activities were institutional review board approved. RESULTS: The pilot survey was completed as either a Web or mail survey by 255 participants. After excluding nonrating or screening questions and items not applicable to a large percentage of participants, 26 experience items were included in the exploratory factor analysis. The final survey contained 19 experience items in 5 scales: access, communication, family impact, care goal creation, and team functioning. Psychometric analyses supported these 5 scales. CONCLUSIONS: This project developed and validated a survey with 19 experience items, plus additional demographic and health needs and usage items. The Pediatric Integrated Care Survey can be used in quality improvement efforts to measure family-reported experience of pediatric care integration. C1 [Ziniel, Sonja I.] Boston Childrens Hosp, Program Patient Safety & Qual, Ctr Patient Safety & Qual Res, Boston, MA USA. [Ziniel, Sonja I.] Boston Childrens Hosp, Dept Med, Div Adolescent & Young Adult Med, Boston, MA USA. [Rosenberg, Hannah N.; Bach, Ashley M.; Antonelli, Richard C.] Boston Childrens Hosp, Dept Med, Div Gen Pediat, Boston, MA USA. [Rosenberg, Hannah N.; Antonelli, Richard C.] Boston Childrens Hosp, Integrated Care Program, Boston, MA USA. [Ziniel, Sonja I.; Antonelli, Richard C.] Harvard Med Sch, Dept Pediat, Boston, MA USA. [Singer, Sara J.] Harvard Med Sch, Dept Med, Boston, MA USA. [Ziniel, Sonja I.] Childrens Hosp Colorado, Pediat Hosp Med, Aurora, CO USA. [Ziniel, Sonja I.] Univ Colorado, Sch Med, Dept Pediat, Aurora, CO USA. [Singer, Sara J.] Harvard TH Chan Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA USA. [Singer, Sara J.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. RP Antonelli, RC (reprint author), Boston Childrens Hosp, 300 Longwood Ave, Boston, MA 02115 USA. EM richard.antonelli@childrens.harvard.edu FU Lucile Packard Foundation for Children's Health [2013-0036] FX All phases of this study were funded by the Lucile Packard Foundation for Children's Health (grant 2013-0036). NR 25 TC 0 Z9 0 U1 1 U2 1 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD DEC PY 2016 VL 138 IS 6 AR e20160676 DI 10.1542/peds.2016-0676 PG 11 WC Pediatrics SC Pediatrics GA ED5WX UT WOS:000388924800010 ER PT J AU Hajjarian, Z Nia, HT Ahn, S Grodzinsky, AJ Jain, RK Nadkarni, SK AF Hajjarian, Zeinab Nia, Hadi Tavakoli Ahn, Shawn Grodzinsky, Alan J. Jain, Rakesh K. Nadkarni, Seemantini K. TI Laser Speckle Rheology for evaluating the viscoelastic properties of hydrogel scaffolds SO SCIENTIFIC REPORTS LA English DT Article ID ATOMIC-FORCE MICROSCOPY; ATHEROSCLEROTIC PLAQUES; PERICELLULAR MATRIX; ARTICULAR-CARTILAGE; BLOOD-COAGULATION; COMPLEX FLUIDS; DRUG-DELIVERY; TISSUE; MICRORHEOLOGY; ELECTROPHORESIS AB Natural and synthetic hydrogel scaffolds exhibit distinct viscoelastic properties at various length scales and deformation rates. Laser Speckle Rheology (LSR) offers a novel, non-contact optical approach for evaluating the frequency-dependent viscoelastic properties of hydrogels. In LSR, a coherent laser beam illuminates the specimen and a high-speed camera acquires the time-varying speckle images. Cross-correlation analysis of frames returns the speckle intensity autocorrelation function, g(2)(t), from which the frequency-dependent viscoelastic modulus, G*(omega), is deduced. Here, we establish the capability of LSR for evaluating the viscoelastic properties of hydrogels over a large range of moduli, using conventional mechanical rheometry and atomic force microscopy (AFM)-based indentation as reference-standards. Results demonstrate a strong correlation between |G*(omega)| values measured by LSR and mechanical rheometry (r = 0.95, p < 10(-9)), and z-test analysis reports that moduli values measured by the two methods are identical (p > 0.08) over a large range (47 Pa - 36 kPa). In addition, |G*(omega)| values measured by LSR correlate well with indentation moduli, E, reported by AFM (r = 0.92, p < 10(-7)). Further, spatially-resolved moduli measurements in micro-patterned substrates demonstrate that LSR combines the strengths of conventional rheology and micro-indentation in assessing hydrogel viscoelastic properties at multiple frequencies and small length-scales. C1 [Hajjarian, Zeinab; Nadkarni, Seemantini K.] Harvard Med Sch, Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02115 USA. [Nia, Hadi Tavakoli; Jain, Rakesh K.] Harvard Med Sch, Massachusetts Gen Hosp, Edwin Steele Lab Tumor Biol, Boston, MA USA. [Ahn, Shawn] Univ Illinois, Dept Elect & Comp Engn, Urbana, IL USA. [Grodzinsky, Alan J.] MIT, Dept Mech Engn, Cambridge, MA 02139 USA. [Grodzinsky, Alan J.] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Grodzinsky, Alan J.] MIT, Dept Elect Engn, Cambridge, MA 02139 USA. RP Nadkarni, SK (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02115 USA. EM snadkarni@mgh.harvard.edu FU NIH [R01 HL 119867] FX This work was supported in part by the NIH grant No. R01 HL 119867. We thank Dr. Calixto Saenz at the HMS Microfabrication Core Facility for his assistance and consultation on fabricating the micro-patterned substrates. NR 58 TC 0 Z9 0 U1 6 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD DEC 1 PY 2016 VL 6 AR 37949 DI 10.1038/srep37949 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ED6QI UT WOS:000388980200001 PM 27905494 ER PT J AU Isik, M Blackwell, TK Berezikov, E AF Isik, Meltem Blackwell, T. Keith Berezikov, Eugene TI MicroRNA mir-34 provides robustness to environmental stress response via the DAF-16 network in C. elegans SO SCIENTIFIC REPORTS LA English DT Article ID CAENORHABDITIS-ELEGANS; GENE-EXPRESSION; TUMOR-SUPPRESSOR; LIFE-SPAN; RNA INTERACTION; CANCER-CELLS; LONGEVITY; APOPTOSIS; DROSOPHILA; PATHWAY AB Diverse stresses and aging alter expression levels of microRNAs, suggesting a role for these posttranscriptional regulators of gene expression in stress modulation and longevity. Earlier studies demonstrated a central role for the miR-34 family in promoting cell cycle arrest and cell death following stress in human cells. However, the biological significance of this response was unclear. Here we show that in C. elegans mir-34 upregulation is necessary for developmental arrest, correct morphogenesis, and adaptation to a lower metabolic state to protect animals against stress-related damage. Either deletion or overexpression of mir-34 lead to an impaired stress response, which can largely be explained by perturbations in DAF-16/FOXO target gene expression. We demonstrate that mir-34 expression is regulated by the insulin signaling pathway via a negative feedback loop between miR-34 and DAF-16/ FOXO. We propose that mir-34 provides robustness to stress response programs by controlling noise in the DAF-16/FOXO-regulated gene network. C1 [Isik, Meltem; Berezikov, Eugene] Hubrecht Inst KNAW, Utrecht, Netherlands. [Isik, Meltem; Berezikov, Eugene] Univ Med Ctr Utrecht, Utrecht, Netherlands. [Isik, Meltem; Blackwell, T. Keith] Harvard Stem Cell Inst, Joslin Diabet Ctr, Boston, MA 02129 USA. [Isik, Meltem; Blackwell, T. Keith] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. [Berezikov, Eugene] Univ Groningen, Univ Med Ctr Groningen, European Res Inst Biol Ageing, Groningen, Netherlands. RP Isik, M; Berezikov, E (reprint author), Hubrecht Inst KNAW, Utrecht, Netherlands.; Isik, M; Berezikov, E (reprint author), Univ Med Ctr Utrecht, Utrecht, Netherlands.; Isik, M (reprint author), Harvard Stem Cell Inst, Joslin Diabet Ctr, Boston, MA 02129 USA.; Isik, M (reprint author), Harvard Med Sch, Dept Genet, Boston, MA 02115 USA.; Berezikov, E (reprint author), Univ Groningen, Univ Med Ctr Groningen, European Res Inst Biol Ageing, Groningen, Netherlands. EM meltem.isik@joslin.harvard.edu; e.berezikov@umcg.nl FU NIH Office of Research Infrastructure Programs [P40 OD010440]; Netherlands Organization for Scientific Research (NWO) [864.07.005]; American Federation of Aging Research (AFAR) fellowship; NIH [R01 GM062891] FX Some strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). This work was supported by a Vidi grant 864.07.005 from the Netherlands Organization for Scientific Research (NWO) to EB, American Federation of Aging Research (AFAR) fellowship to MI and NIH grant R01 GM062891 to TKB. NR 76 TC 0 Z9 0 U1 5 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD DEC 1 PY 2016 VL 6 AR 36766 DI 10.1038/srep36766 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA ED6UF UT WOS:000388991300001 PM 27905558 ER PT J AU Parthasarathy, S Carskadon, MA Jean-Louis, G Owens, J Bramoweth, A Combs, D Hale, L Harrison, E Hart, CN Hasler, BP Honaker, SM Hertenstein, E Kuna, S Kushida, C Levenson, JC Murray, C Pack, AI Pillai, V Pruiksma, K Seixas, A Strollo, P Thosar, SS Williams, N Buysse, D AF Parthasarathy, Sairam Carskadon, Mary A. Jean-Louis, Girardin Owens, Judith Bramoweth, Adam Combs, Daniel Hale, Lauren Harrison, Elizabeth Hart, Chantelle N. Hasler, Brant P. Honaker, Sarah M. Hertenstein, Elisabeth Kuna, Samuel Kushida, Clete Levenson, Jessica C. Murray, Caitlin Pack, Allan I. Pillai, Vivek Pruiksma, Kristi Seixas, Azizi Strollo, Patrick Thosar, Saurabh S. Williams, Natasha Buysse, Daniel TI Implementation of Sleep and Circadian Science: Recommendations from the Sleep Research Society and National Institutes of Health Workshop SO SLEEP LA English DT Article ID POSITIVE AIRWAY PRESSURE; COGNITIVE-BEHAVIORAL THERAPY; RANDOMIZED CONTROLLED-TRIAL; SCHOOL START TIMES; PATIENT-CENTERED OUTCOMES; RISK-TAKING BEHAVIOR; APNEA SYNDROME; PRIMARY-CARE; FOLLOW-UP; CARDIOVASCULAR-DISEASE C1 [Parthasarathy, Sairam; Combs, Daniel] Univ Arizona, UAHS Ctr Sleep & Circadian Sci, Tucson, AZ USA. [Carskadon, Mary A.] Brown Univ, Dept Psychiat & Human Behav, Warren Alpert Med Sch, Providence, RI 02912 USA. [Carskadon, Mary A.] Univ South Australia, Sch Psychol Social Work & Social Policy, Ctr Sleep Res, Adelaide, SA, Australia. [Jean-Louis, Girardin; Seixas, Azizi; Williams, Natasha] NYU, Sch Med, Dept Populat Hlth, New York, NY USA. [Owens, Judith] Boston Childrens Hosp, Boston, MA USA. [Bramoweth, Adam; Buysse, Daniel] VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. [Hale, Lauren] SUNY Stony Brook, Dept Family Populat & Prevent Med, Stony Brook, NY 11794 USA. [Harrison, Elizabeth] Univ San Diego, Ctr Circadian Biol, San Diego, CA 92110 USA. [Hart, Chantelle N.] Temple Univ, Social & Behav Sci & Ctr Obes Res & Educ, Coll Publ Hlth, Philadelphia, PA USA. [Hasler, Brant P.; Levenson, Jessica C.] Univ Pittsburgh, Dept Psychiat, Sch Med, Pittsburgh, PA USA. [Honaker, Sarah M.] Indiana Univ Sch Med, Dept Pediat, Indianapolis, IN 46202 USA. [Hertenstein, Elisabeth] Univ Med Ctr Freiburg, Freiburg, Germany. [Kuna, Samuel; Pack, Allan I.] Univ Penn, Ctr Sleep & Circadian Neurobiol, Philadelphia, PA USA. [Kushida, Clete] Stanford Univ, Palo Alto, CA 94304 USA. [Murray, Caitlin] Loyola Univ Chicago, Dept Psychol, Chicago, IL USA. [Pillai, Vivek] Henry Ford Hlth Syst, Sleep Disorders & Res Ctr, Detroit, MI USA. [Pruiksma, Kristi] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Thosar, Saurabh S.] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. [Thosar, Saurabh S.] Oregon Hlth & Sci Univ, Oregon Inst Occupat Hlth Sci, Portland, OR 97201 USA. RP Parthasarathy, S (reprint author), Univ Arizona, Med, 1501 N Campbell Ave,UAHS Rm 2342D, Tucson, AZ 85724 USA. EM spartha1@email.arizona.edu RI Levenson, Jessica/O-5448-2015; Hasler, Brant/D-5989-2017; OI Hasler, Brant/0000-0002-3123-1106; Jean-Louis, Girardin/0000-0001-6777-2724 FU Sleep Research Society, Darien, IL; Merck; Purdue Pharma; Cereve; Emmi solutions; Philips Respironics; WebMD; CME Outfitters; Astellas; Servier; National Insitutes of Health; National Space Biomedical Research Institute [NCC 9-58, NIH/NHLBI R01 HL125893, NIH/NHLBI 1F32HL131308-01]; NIH/NICHD [HD073352]; NIH/NIA [AG036838]; NIH/NHLBI [HL122460] FX This was not an industry supported study. Funding was provided by the Sleep Research Society, Darien, IL. Dr. Parthasarathy reports grants from NIH/NHLBI (HL095799), grants from Patient Centered Outcomes Research Institute (IHS-1306-02505 and EAIN 3394-UoA), grants from US Department of Defense, grants from NIH (National Cancer Institute; R21CA184920), grants from Johrei Institute, personal fees from American Academy of Sleep Medicine, personal fees from American College of Chest Physicians, non-financial support from National Center for Sleep Disorders Research of the NIH (NHLBI), personal fees from UpToDate Inc., Philips-Respironics, Inc., and Vapotherm, Inc.; grants from Younes Sleep Technologies, Ltd., Niveus Medical Inc., and Philips-Respironics, Inc. outside the submitted work. In addition, Dr. Parthasarathy has a patent UA 14-018 U.S.S.N. 61/884,654; PTAS 502570970 (Home breathing device). The above-mentioned conflicts including the patent are unrelated to the topic of this paper. Dr. Buysse has served as a paid consultant to the following companies, over the past 5 years: Merck, Purdue Pharma, Cereve, Emmi solutions, Philips Respironics, WebMD, CME Outfitters. He has served as a paid speaker at educational conferences for Astellas and Servier. Dr. Buysse receives research grant support from the National Insitutes of Health. Dr. Thosar was supported by National Space Biomedical Research Institute through NCC 9-58, NIH/NHLBI R01 HL125893, NIH/NHLBI 1F32HL131308-01 during the writing of this manuscript. Dr. Hale reports current grant support from NIH/NICHD (HD073352), NIH/NIA (AG036838) and NIH/NHLBI (HL122460) and has served as a consultant to the BoomShop during the writing of this manuscript. Dr. Hale also sits on the Board of the Directors for the National Sleep Foundation and receives an honorarium for her role as Editor of Sleep Health. The other authors have indicated no financial conflicts of interest. NR 198 TC 0 Z9 0 U1 14 U2 14 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0161-8105 EI 1550-9109 J9 SLEEP JI Sleep PD DEC 1 PY 2016 VL 39 IS 12 BP 2061 EP 2075 AR PII sp-00553-16 DI 10.5665/sleep.6300 PG 15 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA ED5ZK UT WOS:000388932700001 PM 27748248 ER PT J AU Ross, DA Ross, MN AF Ross, Donald A. Ross, Miner N. TI Diagnosis and Treatment of C4 Radiculopathy SO SPINE LA English DT Article DE asymptomatic C4 foraminal stenosis; C4 radiculopathy; C4 root block; facet mediated pain ID CERVICAL RADICULOPATHY; VERTEBRAL ARTERY; NECK PAIN; ROOT; INJECTIONS; DERMATOMES; ANATOMY; BLOCKS; C3 AB Study Design.Clinical case series.Objective.This study sought to clarify symptoms, diagnostic criteria, and treatment of C4 radiculopathy, and the role of diagnostic C4 root block in this entity.Summary of Background Data.Although well understood cervical dermatomal/myotomal syndromes have been described for symptoms originating from impingement on the C2, C3, C5, C6, C7, and C8 roots, less has been written about the syndrome(s) associated with the C4 root.Methods.The senior author reviewed surgical records and describes his personal experience with the diagnosis and treatment of C4 radiculopathy.Results.A total of 712 procedures for cervical radiculopathy without myelopathy were reviewed. Among that cohort, 13 procedures involved the C4 root only and five procedures involved two level procedures including the C4 root. Patients described pain as involving the axial cervical region, paraspinal muscles, trapezius muscle, and interscapular region. No patient described pain over the anterior chest wall or radiating distal to the shoulder, one described pain over the medial clavicle. All patients who were offered surgery had a positive response to a diagnostic C4 transforaminal single nerve root block. Thirteen patients underwent posterior foraminotomy (five at two levels) and five patients underwent an anterior discectomy and fusion at C3-4. Mean Oswestry Disability Index score significantly declined; preoperative score 24.3 (range 14-29), postoperative score 9.7 (range 2-18; P=0.003) at 3 months. Mean Short Form-36v2 score significantly increased; preoperative score 34.2 (range 20-40.2), postoperative score 73.7 (range 40.5-88.3, P=0.001) at 3 months.Conclusion.C4 root symptoms overlap those of the C3 and C5 roots and are very similar to facet mediated pain. Asymptomatic C4 foraminal stenosis may be a common imaging finding, it can be difficult to diagnose C4 radiculopathy clinically. Diagnostic C4 root block can make an accurate diagnosis and lead to successful surgical outcomes.Level of Evidence: 4 C1 [Ross, Donald A.] Oregon Hlth & Sci Univ, Dept Neurol Surg, 3303 SW Bond Ave,CH8N, Portland, OR 97239 USA. [Ross, Donald A.] Portland VA Med Ctr, Operat Care Div, Sect Neurol Surg, Portland, OR USA. [Ross, Miner N.] New York Med Coll, New York, NY USA. RP Ross, DA (reprint author), Oregon Hlth & Sci Univ, Dept Neurol Surg, 3303 SW Bond Ave,CH8N, Portland, OR 97239 USA. EM rossdo@ohsu.edu NR 34 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0362-2436 EI 1528-1159 J9 SPINE JI SPINE PD DEC 1 PY 2016 VL 41 IS 23 BP 1790 EP 1794 DI 10.1097/BRS.0000000000001620 PG 5 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA ED3CG UT WOS:000388726300013 PM 27054454 ER PT J AU Nuschke, A Rodrigues, M Wells, AW Sylakowski, K Wells, A AF Nuschke, Austin Rodrigues, Melanie Wells, Albin W. Sylakowski, Kyle Wells, Alan TI Mesenchymal stem cells/multipotent stromal cells (MSCs) are glycolytic and thus glucose is a limiting factor of in vitro models of MSC starvation SO STEM CELL RESEARCH & THERAPY LA English DT Article DE Multipotent stem cells; Mesenchymal stem cells; Glucose metabolism; Nutrient starvation; Stem cell survival ID SERUM DEPRIVATION; DIFFERENTIATION; HYPOXIA; PROLIFERATION; BIOENERGETICS; PLURIPOTENCY; SURVIVAL; CULTURE; NUMBER; GROWTH AB Background: Mesenchymal stem/multipotent stromal cells (MSCs) contribute to tissue repair but are challenged during wound healing when the blood supply is disrupted, thereby limiting nutrient delivery. Survival mechanisms against 'starvation' include autophagy, which we previously found to enhance differentiation efficiency. MSC response to models of in vitro nutrient deprivation are of great interest for improving MSC survival and therapeutic efficacy; however, the rate-limiting nutrients are unknown. Methods: MSC responses to culture nutrient and/or serum deprivations were assessed through light microscopy, cell survival, and measurements of metabolic levels. Glucose uptake was determined through conditioned media analyses over 3 days of culture. The Seahorse XF24 Flux analysis system was used to determine oxygen consumption and extracellular acidification for glycolytic metabolism. MSC autophagic response to these conditions was assessed via immunoblots for LC3-I and LC3-II, markers of autophagosome turnover. Results: We more closely examined limiting nutritional factors to MSC survival in vitro, finding that glucose is rapidly utilized/depleted whereas amino acids and other required nutrients were used sparingly. This finding concurred with metabolic analyses that showed a primarily glycolytic character to the MSCs at steady state. MSC autophagy, previously linked to MSC function through a unique accumulated autophagosome phenotype, also responded quickly to changes in glucose concentration, with drastic LC3-II changes within 24 h of glucose concentration shifts. Conclusions: Our results demonstrated a rapid uptake of glucose in MSC cultures that was due to a highly glycolytic phenotype for the cells; MSC starvation with serum or other nutrients appears to have a less notable effect on the cells. These findings highlight the importance of glucose and glucose metabolism on MSC function. The conditions and cellular responses outlined here may be essential in modeling MSC nutrient deprivation. C1 [Nuschke, Austin; Rodrigues, Melanie; Sylakowski, Kyle; Wells, Alan] Univ Pittsburgh, Dept Pathol, Sch Med, Scaife Hall,3550 Terrace St, Pittsburgh, PA 15261 USA. [Nuschke, Austin; Wells, Alan] Univ Pittsburgh, McGowan Inst Regenerat Med, 450 Technol Dr, Pittsburgh, PA 15219 USA. [Wells, Alan] VA Pittsburgh Hlth Syst, Univ Dr A, Pittsburgh, PA 15261 USA. [Wells, Albin W.] Taylor Allderdice High Sch, 2409 Shady Ave, Pittsburgh, PA 15217 USA. [Rodrigues, Melanie] Stanford Univ, Dept Plast & Reconstruct Surg, Palo Alto, CA 94304 USA. RP Wells, A (reprint author), Univ Pittsburgh, Dept Pathol, Sch Med, Scaife Hall,3550 Terrace St, Pittsburgh, PA 15261 USA.; Wells, A (reprint author), Univ Pittsburgh, McGowan Inst Regenerat Med, 450 Technol Dr, Pittsburgh, PA 15219 USA.; Wells, A (reprint author), VA Pittsburgh Hlth Syst, Univ Dr A, Pittsburgh, PA 15261 USA. EM wellsa@upmc.edu FU NIH [GM063569, GM069668]; [T32s EB001026]; [CA175294] FX This project was supported by NIH grants GM063569 and GM069668, and support to AN from T32s EB001026 and CA175294. NR 21 TC 0 Z9 0 U1 4 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1757-6512 J9 STEM CELL RES THER JI Stem Cell Res. Ther. PD DEC 1 PY 2016 VL 7 AR 179 DI 10.1186/s13287-016-0436-7 PG 9 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA ED7GD UT WOS:000389029300001 PM 27906055 ER PT J AU Wu, JJ Sun, Y Block, TJ Marinkovic, M Zhang, ZL Chen, R Yin, YX Song, JQ Dean, DD Lu, ZD Chen, XD AF Wu, Junjie Sun, Yun Block, Travis J. Marinkovic, Milos Zhang, Zhi-Liang Chen, Richard Yin, Yixia Song, Juquan Dean, David D. Lu, Zhongding Chen, Xiao-Dong TI Umbilical cord blood-derived non-hematopoietic stem cells retrieved and expanded on bone marrow-derived extracellular matrix display pluripotent characteristics SO STEM CELL RESEARCH & THERAPY LA English DT Article DE Umbilical cord blood; CD146-positive cells; Plastic non-adherent cells; Extracellular matrix-adherent cells; Pluripotent stem cells; Extracellular matrix; Three germ layer tissue formation in vivo ID MESENCHYMAL STEM/PROGENITOR CELLS; ADIPOSE-TISSUE; PROGENITOR CELLS; IN-VITRO; EX-VIVO; DIFFERENTIATION; CULTURE; LINES; TRANSPLANTATION; IDENTIFICATION AB Background: Umbilical cord blood (UCB) not only contains hematopoietic stem cells (HSCs), but also nonhematopoietic stem cells (NHSCs) that are able to differentiate into a number of distinct cell types. Based on studies published to date, the frequency of NHSCs in UCB is believed to be very low. However, the isolation of these cells is primarily based on their adhesion to tissue culture plastic surfaces. Methods and results: In the current study, we demonstrate that this approach overlooks some of the extremely immature NHSCs because they lack the ability to adhere to plastic. Using a native extracellular matrix (ECM), produced by bone marrow (BM) stromal cells, the majority of the UCB-NHSCs attached within 4 h. The colony-forming unit fibroblast frequency of these cells was 1.5 x 10(4)/10(8) mononuclear cells, which is at least 4000-fold greater than previously reported for UCB-NHSCs. The phenotype of these cells was fibroblast-like and different from those obtained by plastic adhesion; they formed embryonic body-like clusters that were OCT4-positive and expressed other human embryonic stem cell-related markers. Importantly, when implanted subcutaneously for 8 weeks into immunocompromised mice, these ECM-adherent and expanded NHSCs generated three germ layer-derived human tissues including muscle, fat, blood vessel, bone, gland, and nerve. Moreover, injection of these cells into muscle damaged by cryoinjury significantly accelerated muscle regeneration. Conclusions: These results indicate that UCB may be a virtually unlimited source of NHSCs when combined with isolation and expansion on ECM. NHSCs may be a practical alternative to embryonic stem cells for a number of therapeutic applications. C1 [Wu, Junjie; Sun, Yun; Block, Travis J.; Marinkovic, Milos; Zhang, Zhi-Liang; Chen, Richard; Yin, Yixia; Dean, David D.; Lu, Zhongding; Chen, Xiao-Dong] Univ Texas Hlth Sci Ctr San Antonio, Div Res, Dept Comprehens Dent, San Antonio, TX 78229 USA. [Wu, Junjie] Fourth Mil Med Univ, Sch Stomatol, Dept Orthodont, Xian 710032, Shaanxi, Peoples R China. [Sun, Yun] Shanghai Jiao Tong Univ, Sch Med, Ren Ji Hosp, Ctr Reprod Med, Shanghai 200135, Peoples R China. [Block, Travis J.; Marinkovic, Milos; Dean, David D.] Univ Texas San Antonio, Dept Biomed Engn, San Antonio, TX 78249 USA. [Zhang, Zhi-Liang] Shanghai Jiao Tong Univ, Ren Ji Hosp, Dept Plast Surg, Sch Med, Shanghai, Peoples R China. [Yin, Yixia] Wuhan Univ Technol, Biomed Mat Engn Res Ctr, Wuhan, Peoples R China. [Song, Juquan] Univ Texas Hlth Sci Ctr San Antonio, Dept Surg, San Antonio, TX 78229 USA. [Chen, Xiao-Dong] South Texas Vet Hlth Care Syst, Audie L Murphy Div, Res Serv, San Antonio, TX 78229 USA. RP Lu, ZD; Chen, XD (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Div Res, Dept Comprehens Dent, San Antonio, TX 78229 USA.; Chen, XD (reprint author), South Texas Vet Hlth Care Syst, Audie L Murphy Div, Res Serv, San Antonio, TX 78229 USA. EM xwdlu@yahoo.com; chenx4@uthscsa.edu OI Dean, David/0000-0002-4512-9065 FU University Research Council Grants Program at the University of Texas Health Science Center at San Antonio (UTHSCSA); VA Merit Review [1 I01 BX000580]; UTHSCSA; NIH-NCI [P30 CA54174]; NIH-NIA [P30 AG013319, P01 AG19316] FX This work was supported by the University Research Council Grants Program at the University of Texas Health Science Center at San Antonio (UTHSCSA) (X-DC) and a VA Merit Review (X-DC) (1 I01 BX000580). The funding agencies did not participate in the design of the study, collecting, analyzing or interpreting the data, or writing the manuscript. Confocal images were generated in the Optical Imaging Core Facility which is supported by UTHSCSA, NIH-NCI P30 CA54174 (San Antonio Cancer Institute), NIH-NIA P30 AG013319 (Nathan Shock Center), and NIH-NIA P01 AG19316. NR 51 TC 0 Z9 0 U1 10 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1757-6512 J9 STEM CELL RES THER JI Stem Cell Res. Ther. PD DEC 1 PY 2016 VL 7 AR 176 DI 10.1186/s13287-016-0437-6 PG 14 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA ED7FZ UT WOS:000389028900001 PM 27906056 ER PT J AU Sharr, C Lavigne, J Elsharkawi, IMA Ozonoff, A Baumer, N Brasington, C Cannon, S Crissman, B Davidson, E Florez, JC Kishnani, P Lombardo, A Lyerly, J McDonough, ME Schwartz, A Berrier, KL Sparks, S Stock-Guild, K Toler, TL Vellody, K Voelz, L Skotko, BG AF Sharr, Christianne Lavigne, Jenifer Elsharkawi, Ibrahim M. A. Ozonoff, Al Baumer, Nicole Brasington, Campbell Cannon, Sheila Crissman, Blythe Davidson, Emily Florez, Jose C. Kishnani, Priya Lombardo, Angela Lyerly, Jordan McDonough, Mary Ellen Schwartz, Alison Berrier, Kathryn L. Sparks, Susan Stock-Guild, Kara Toler, Tomi L. Vellody, Kishore Voelz, Lauren Skotko, Brian G. TI Detecting Celiac Disease in Patients with Down Syndrome SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE celiac disease; Down syndrome; Trisomy 21; registry; patient database ID COST-EFFECTIVENESS; UNITED-STATES; PEDIATRIC-GASTROENTEROLOGY; ASYMPTOMATIC CHILDREN; PREVENTING LYMPHOMA; PREVALENCE; DIAGNOSIS; GUIDELINES; POPULATION; HEPATOLOGY AB The main purposes of this undertaking were to determine how often patients with Down syndrome (DS) are screened for celiac disease (CD) across five DS specialty clinics, which symptoms of CD are most often reported to DS specialty providers at these clinics, and, how many individuals were diagnosed with CD by these clinics. This was accomplished by following 663 individuals with DS for 1 year, across five clinics in different states specializing in the comprehensive care of people with DS. Of the 663 participants, 114 individuals were screened for CD at their visit to a DS specialty clinic. Protracted constipation (43.2%) and refractory behavioral problems (23.7%) were symptoms most often reported to DS specialty providers. During the 1 year study period, 13 patients screened positive for CD by serology. Of those, eight underwent duodenal biopsy, and three were diagnosed with CD. We conclude that CD is an important consideration in the comprehensive care of individuals with DS. However, while symptoms are common, diagnoses are infrequent in DS specialty clinics. (C) 2016 Wiley Periodicals, Inc. C1 [Sharr, Christianne; Elsharkawi, Ibrahim M. A.; Florez, Jose C.; McDonough, Mary Ellen; Schwartz, Alison; Toler, Tomi L.; Skotko, Brian G.] Massachusetts Gen Hosp, Dept Pediat, Div Genet, Syndrome Program, Boston, MA 02114 USA. [Lavigne, Jenifer; Brasington, Campbell; Lyerly, Jordan; Sparks, Susan] Carolina Healthcare Syst, Levine Childrens Hosp, Clin Genet, Dept Pediat, Charlotte, NC USA. [Ozonoff, Al; Baumer, Nicole; Davidson, Emily; Florez, Jose C.; Schwartz, Alison; Skotko, Brian G.] Harvard Med Sch, Boston, MA USA. [Ozonoff, Al] Boston Childrens Hosp, Program Patient Safety & Qual, Ctr Patient Safety & Qual Res, Boston, MA USA. [Baumer, Nicole; Davidson, Emily; Lombardo, Angela; Stock-Guild, Kara; Voelz, Lauren] Boston Childrens Hosp, Dept Med, Div Dev Med, Syndrome Program, Boston, MA USA. [Cannon, Sheila; Vellody, Kishore] Univ Pittsburgh, Med Ctr, Childrens Hosp Pittsburgh, Syndrome Ctr Western Pennsylvania, Pittsburgh, PA USA. [Crissman, Blythe; Kishnani, Priya; Berrier, Kathryn L.] Duke Univ, Med Ctr, Div Med Genet, Comprehens Syndrome Program, Durham, NC USA. RP Skotko, BG (reprint author), Massachusetts Gen Hosp, 185 Cambridge St,Room 2222, Boston, MA 02114 USA. EM bskotko@mgh.harvard.edu OI Toler, Tomi/0000-0002-1637-8310 NR 22 TC 0 Z9 0 U1 6 U2 6 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 DEC PY 2016 VL 170 IS 12 BP 3098 EP 3105 DI 10.1002/ajmg.a.37879 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA EC5TL UT WOS:000388199100007 PM 27605215 ER PT J AU Mitra, M Akobirshoev, I Mckee, MM Iezzoni, LI AF Mitra, Monika Akobirshoev, Ilhom Mckee, Michael M. Iezzoni, Lisa I. TI Birth Outcomes Among US Women With Hearing Loss SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID SIGN-LANGUAGE USERS; HARD-OF-HEARING; UNITED-STATES; HEALTH-CARE; HOSPITAL BIRTHS; PRETERM BIRTH; DEAF PATIENTS; ASL USERS; RISK; COMMUNICATION AB Introduction: The purpose of this study is to estimate the national occurrence of deliveries in women with hearing loss and to compare their birth outcomes to women without hearing loss. Methods: This study examined the 2008-2011 Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project in 2015 to compare birth outcomes in women with hearing loss and without. Birth outcomes included preterm birth and low birth weight. Multivariate regression analyses compared birth outcomes between women with and without hearing loss, controlling for maternal age, racial and ethnic identity, type of health insurance, comorbidity, region of hospital, location and teaching status of the hospital, ownership of the hospital, and median household income for mother's ZIP code. Results: Of an estimated 17.9 million deliveries, 10,462 occurred in women with hearing loss. In adjusted regression analyses controlling for demographic characteristics, women with hearing loss were significantly more likely than those without hearing loss to have preterm birth (OR = 1.28, 95% CI = 1.08, 1.52, p<0.001) and low birth weight (OR = 1.43, 95% CI = 1.09, 1.90, p<0.05). Conclusions: This study provides a first examination of the pregnancy outcomes among women with hearing loss in the U.S. This analysis demonstrates significant disparities in birth outcomes between women with and without hearing loss. Understanding and addressing the causes of these disparities is critical to improving pregnancy outcomes among women with hearing loss. (C) 2016 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved. C1 [Mitra, Monika; Akobirshoev, Ilhom] Brandeis Univ, Lurie Inst Disabil Policy, Waltham, MA 02453 USA. [Mckee, Michael M.] Univ Michigan, Dept Family Med, Ann Arbor, MI 48109 USA. [Iezzoni, Lisa I.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. RP Mitra, M (reprint author), Brandeis Univ, Heller Sch Social Policy & Management, Lurie Inst Disabil Policy, 415 South St, Waltham, MA 02453 USA. EM mmitra@brandeis.edu FU Lurie Institute for Disability Policy at the Heller School; National Institute on Disability, Independent Living, and Rehabilitation Research's Advanced Rehabilitation Research Training Program on Health and Functioning of People with Disabilities [90AR5024-01-00] FX Support for this study was provided by the Lurie Institute for Disability Policy at the Heller School for Social Policy and Management at Brandeis University and by the National Institute on Disability, Independent Living, and Rehabilitation Research's Advanced Rehabilitation Research Training Program on Health and Functioning of People with Disabilities, grant # 90AR5024-01-00. NR 65 TC 0 Z9 0 U1 5 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD DEC PY 2016 VL 51 IS 6 BP 865 EP 873 DI 10.1016/j.amepre.2016.08.001 PG 9 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA EC7ZD UT WOS:000388358800004 PM 27687529 ER PT J AU Markmann, JF AF Markmann, J. F. TI Signatures of Tolerance or Immunosuppression? SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Editorial Material ID RENAL-TRANSPLANT TOLERANCE; HUMANS C1 [Markmann, J. F.] Massachusetts Gen Hosp, Dept Surg, Div Transplantat, Boston, MA 02114 USA. RP Markmann, JF (reprint author), Massachusetts Gen Hosp, Dept Surg, Div Transplantat, Boston, MA 02114 USA. EM jmarkmann@partners.org NR 7 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD DEC PY 2016 VL 16 IS 12 BP 3320 EP 3321 DI 10.1111/ajt.13993 PG 2 WC Surgery; Transplantation SC Surgery; Transplantation GA EC5WS UT WOS:000388208600005 ER PT J AU Goedeke, L Wagschal, A Fernandez-Hernando, C Naar, AM AF Goedeke, Leigh Wagschal, Alexandre Fernandez-Hernando, Carlos Naar, Anders M. TI miRNA regulation of LDL-cholesterol metabolism SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS LA English DT Article DE miRNA; LDL; cholesterol; LDLR; lipid; GWAS ID GENOME-WIDE IDENTIFICATION; CORONARY-ARTERY-DISEASE; LIPOPROTEIN SECRETION; ABCA1 EXPRESSION; IN-VIVO; ATHEROSCLEROSIS; HOMEOSTASIS; MIR-33; MICE; RECEPTOR AB In the past decade, microRNAs (miRNAs) have emerged as key regulators of circulating levels of lipoproteins. Specifically, recent work has uncovered the role of miRNAs in controlling the levels of atherogenic low-density lipoprotein LDL (LDL)-cholesterol by post-transcriptionally regulating genes involved in very low-density lipoprotein (VLDL) secretion, cholesterol biosynthesis, and hepatic LDL receptor (LDLR) expression. Interestingly, several of these miRNAs are located in genomic loci associated with abnormal levels of circulating lipids in humans. These findings reinforce the interest of targeting this subset of non-coding RNAs as potential therapeutic avenues for regulating plasma cholesterol and triglyceride (TAG) levels. In this review, we will discuss how these new miRNAs represent potential pre-disposition factors for cardiovascular disease (CVD), and putative therapeutic targets in patients with cardiometabolic disorders. This article is part of a Special Issue entitled: MicroRNAs and lipid/energy metabolism and related diseases edited by Carlos Fernandez-Hernando and Yajaira Suarez. (C) 2016 Elsevier B.V. All rights reserved. C1 [Goedeke, Leigh; Fernandez-Hernando, Carlos] Yale Univ, Sch Med, Vasc Biol & Therapeut Program, Amistad Res Bldg,10 Amistad St,Room 337C, New Haven, CT 06510 USA. [Goedeke, Leigh; Fernandez-Hernando, Carlos] Yale Univ, Sch Med, Integrat Cell Signaling & Neurobiol Metab Program, Comparat Med Sect, Amistad Res Bldg,10 Amistad St,Room 337C, New Haven, CT 06510 USA. [Wagschal, Alexandre; Naar, Anders M.] Massachusetts Gen Hosp, Ctr Canc Res, Bldg 149,13th St, Charlestown, MA 02129 USA. [Wagschal, Alexandre; Naar, Anders M.] Harvard Med Sch, Dept Cell Biol, Boston, MA USA. RP Fernandez-Hernando, C (reprint author), Yale Univ, Sch Med, Amistad Res Bldg,10 Amistad St,Room 337C, New Haven, CT 06510 USA.; Naar, AM (reprint author), Harvard Med Sch, Bldg 149,13th St, Charlestown, MA 02129 USA.; Naar, AM (reprint author), Massachusetts Gen Hosp, Ctr Canc, Bldg 149,13th St, Charlestown, MA 02129 USA. EM carlos.fernandez@yale.edu FU National Institutes of Health [R01DK094184, U54HL119145, R01HL107953, R01HL106063]; Leducq Transatlantic Network in Vascular microRNAs (MIRVAD) FX This work was supported by grants from the National Institutes of Health (R01DK094184 and U54HL119145 to AMN and R01HL107953 and R01HL106063 to CF-H) and The Leducq Transatlantic Network in Vascular microRNAs (MIRVAD) to CF-H. Fig. 1 was generated using the Servier Medical Art illustration resources (http://www.servier.com). We apologize to those whose work could not be cited due to space limitations. NR 54 TC 1 Z9 1 U1 6 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1388-1981 EI 0006-3002 J9 BBA-MOL CELL BIOL L JI Biochim. Biophys. Acta Mol. Cell Biol. Lipids PD DEC PY 2016 VL 1861 IS 12 SI SI BP 2047 EP 2052 DI 10.1016/j.bbalip.2016.03.007 PN B PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA ED0QD UT WOS:000388546100003 PM 26968099 ER PT J AU Powles, T Escudier, B Motzer, RJ Tannir, NM Scheffold, C Aftab, DT Chouieri, TK AF Powles, Thomas Escudier, Bernard Motzer, Robert J. Tannir, Nizar M. Scheffold, Christian Aftab, Dana T. Chouieri, Toni K. TI Clinical outcomes based on MET expression level in METEOR, a randomized phase 3 trial of cabozantinib versus everolimus in advanced renal cell carcinoma (RCC) SO BJU INTERNATIONAL LA English DT Meeting Abstract CT 15th International Kidney Cancer Symposium CY NOV 04-05, 2016 CL Miami, FL C1 [Powles, Thomas] St Bartholomews Hosp, London, England. [Escudier, Bernard] Inst Gustave Roussy, Villejuif, France. [Motzer, Robert J.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Tannir, Nizar M.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Scheffold, Christian; Aftab, Dana T.] Exelixis Inc, San Francisco, CA USA. [Chouieri, Toni K.] Dana Farber Canc Ctr, 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 1464-4096 EI 1464-410X J9 BJU INT JI BJU Int. PD DEC PY 2016 VL 118 SU S5 BP 4 EP 4 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA EC9QC UT WOS:000388478200002 ER PT J AU Brandao, R Mckay, R Lin, X Hamieh, L Kaymakcalan, M Simantov, R Choueiri, T AF Brandao, Raphael Mckay, Rana Lin, Xun Hamieh, Lana Kaymakcalan, Marina Simantov, Roni Choueiri, Toni TI Impact of aspirin (ASA) and non-aspirin nonsteroidal anti-inflammatory drugs (non-ASA NSAIDS) on outcomes in patients (pts) with metastatic renal cell carcinoma (mRCC) SO BJU INTERNATIONAL LA English DT Meeting Abstract CT 15th International Kidney Cancer Symposium CY NOV 04-05, 2016 CL Miami, FL C1 [Brandao, Raphael; Mckay, Rana; Hamieh, Lana; Kaymakcalan, Marina; Choueiri, Toni] Dana Farber Canc Inst, Boston, MA 02115 USA. [Lin, Xun; Simantov, Roni] Pfizer Oncol, New York, NY USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-4096 EI 1464-410X J9 BJU INT JI BJU Int. PD DEC PY 2016 VL 118 SU S5 BP 7 EP 8 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA EC9QC UT WOS:000388478200009 ER PT J AU Lalani, AK Mckay, R Lin, X Simantov, R Kaymakcalan, M Choueiri, T AF Lalani, Aly-Khan Mckay, Rana Lin, Xun Simantov, Ronit Kaymakcalan, Marina Choueiri, Toni TI Proton-pump inhibitors and survival outcomes in patients with metastatic renal cell carcinoma SO BJU INTERNATIONAL LA English DT Meeting Abstract CT 15th International Kidney Cancer Symposium CY NOV 04-05, 2016 CL Miami, FL C1 [Lalani, Aly-Khan; Mckay, Rana; Kaymakcalan, Marina; Choueiri, Toni] Dana Farber Canc Inst, Boston, MA 02115 USA. [Lin, Xun] Pfizer Oncol, San Diego, CA USA. [Simantov, Ronit] Pfizer Oncol, New York, NY 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 1464-4096 EI 1464-410X J9 BJU INT JI BJU Int. PD DEC PY 2016 VL 118 SU S5 BP 7 EP 7 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA EC9QC UT WOS:000388478200008 ER PT J AU Hamieh, L Mckay, R Lin, X Simantov, R Choueiri, T AF Hamieh, Lana Mckay, Rana Lin, Xun Simantov, Ronit Choueiri, Toni TI Characterization of patients with poor risk metastatic renal cell carcinoma (mRCC): results from a pooled clinical trials database SO BJU INTERNATIONAL LA English DT Meeting Abstract CT 15th International Kidney Cancer Symposium CY NOV 04-05, 2016 CL Miami, FL C1 [Hamieh, Lana; Mckay, Rana; Choueiri, Toni] Dana Farber Canc Inst, Boston, MA 02115 USA. [Lin, Xun; Simantov, Ronit] Pfizer Oncol, New York, NY 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 1464-4096 EI 1464-410X J9 BJU INT JI BJU Int. PD DEC PY 2016 VL 118 SU S5 BP 10 EP 10 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA EC9QC UT WOS:000388478200013 ER PT J AU Martini, D Brandao, R Hamieh, L Norton, C Mullane, S Walsh, M Van Allen, E Mckay, R Harshman, L Choueiri, T AF Martini, Dylan Brandao, Raphael Hamieh, Lana Norton, Craig Mullane, Stephanie Walsh, Meghara Van Allen, Eliezer Mckay, Rana Harshman, Lauren Choueiri, Toni TI Outcomes in PD-1/PD-L1 responders who discontinued therapy for immune-related adverse events (irAEs): analysis of nine patients with metastatic renal cell carcinoma (mRCC) SO BJU INTERNATIONAL LA English DT Meeting Abstract CT 15th International Kidney Cancer Symposium CY NOV 04-05, 2016 CL Miami, FL C1 [Martini, Dylan; Brandao, Raphael; Hamieh, Lana; Norton, Craig; Mullane, Stephanie; Walsh, Meghara; Van Allen, Eliezer; Mckay, Rana; Harshman, Lauren; Choueiri, Toni] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-4096 EI 1464-410X J9 BJU INT JI BJU Int. PD DEC PY 2016 VL 118 SU S5 BP 10 EP 11 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA EC9QC UT WOS:000388478200015 ER PT J AU Plimack, ER Motzer, RJ Escudier, B Sharma, P Mcdermott, DF George, S Hammers, HJ Carducci, M Tykodi, SS Sosman, JA Choueiri, TK Donskov, F Gurney, H Gauler, TC Ueda, T Zhao, HY Berghorn, E Wagstaff, J AF Plimack, Elizabeth R. Motzer, Robert J. Escudier, Bernard Sharma, Padmanee Mcdermott, David F. George, Saby Hammers, Hans J. Carducci, Michael Tykodi, Scott S. Sosman, Jeffrey A. Choueiri, Toni K. Donskov, Frede Gurney, Howard Gauler, Thomas C. Ueda, Takeshi Zhao, Huanyu Berghorn, Elmer Wagstaff, John TI Two-year efficacy and safety update from the phase III CheckMate 025 study of nivolumab versus everolimus in patients with advanced renal cell carcinoma (aRCC) SO BJU INTERNATIONAL LA English DT Meeting Abstract CT 15th International Kidney Cancer Symposium CY NOV 04-05, 2016 CL Miami, FL C1 [Plimack, Elizabeth R.] Fox Chase Canc Ctr, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Motzer, Robert J.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Escudier, Bernard] Gustave Roussy, d, Villejuif, Idf, France. [Sharma, Padmanee] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Mcdermott, David F.] Dana Farber Harvard Canc Ctr, Beth Israel Deaconess Med Ctr, Boston, MA USA. [George, Saby] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Hammers, Hans J.; Carducci, Michael] Johns Hopkins Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Tykodi, Scott S.] Univ Washington, Seattle, WA 98195 USA. [Tykodi, Scott S.] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Sosman, Jeffrey A.] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Choueiri, Toni K.] Brigham & Womens Hosp, Dana Farber Canc Inst, 75 Francis St, Boston, MA 02115 USA. [Donskov, Frede] Aarhus Univ Hosp, Aarhus C, Denmark. [Gurney, Howard] Westmead Hosp, Sydney, NSW, Australia. [Gurney, Howard] Macquarie Univ, Sydney, NSW, Australia. [Gauler, Thomas C.] Univ Duisburg Essen, Univ Hosp Essen, Essen, Germany. [Ueda, Takeshi] Chiba Canc Ctr, Chiba, Japan. [Zhao, Huanyu; Berghorn, Elmer] Bristol Myers Squibb, Princeton, NJ USA. [Wagstaff, John] South West Wales Canc Inst, Swansea, W Glam, Wales. [Wagstaff, John] Swansea Univ, Coll Med, Swansea, W Glam, Wales. NR 0 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-4096 EI 1464-410X J9 BJU INT JI BJU Int. PD DEC PY 2016 VL 118 SU S5 BP 11 EP 12 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA EC9QC UT WOS:000388478200016 ER PT J AU De Velasco, G Mckay, RR Lin, X Moreira, RB Simantov, R Choueiri, TK AF De Velasco, Guillermo Mckay, Rana R. Lin, Xun Moreira, Raphel B. Simantov, Ronit Choueiri, Toni K. TI Comprehensive analysis of survival outcomes in non-clear cell renal cell carcinoma patients treated on clinical trials SO BJU INTERNATIONAL LA English DT Meeting Abstract CT 15th International Kidney Cancer Symposium CY NOV 04-05, 2016 CL Miami, FL C1 [De Velasco, Guillermo; Mckay, Rana R.; Moreira, Raphel B.; Choueiri, Toni K.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Lin, Xun; Simantov, Ronit] Pfizer, New York, NY 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 1464-4096 EI 1464-410X J9 BJU INT JI BJU Int. PD DEC PY 2016 VL 118 SU S5 BP 12 EP 12 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA EC9QC UT WOS:000388478200017 ER PT J AU Choueiri, TK Gross-Goupil, M Porta, C Rodriguez, CS Patel, C Neuwirth, R Enke, A Zohren, F Powles, T AF Choueiri, Toni K. Gross-Goupil, Marine Porta, Camillo Suarez Rodriguez, Christina Patel, Chirag Neuwirth, Rachel Enke, Aaron Zohren, Fabian Powles, Thomas TI Phase 2 study of investigational TORC1/2 inhibitor TAK-228 and TAK-228 plus investigational PI3Ka-selective inhibitor TAK-117 versus everolimus in adults with advanced or metastatic clear-cell renal cell carcinoma (ccRCC) that has progressed on VEGF-targeted therapy SO BJU INTERNATIONAL LA English DT Meeting Abstract CT 15th International Kidney Cancer Symposium CY NOV 04-05, 2016 CL Miami, FL C1 [Choueiri, Toni K.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Gross-Goupil, Marine] CHU Bordeaux, Hop St Andre, Bordeaux, France. [Porta, Camillo] IRCCS San Matteo Univ Hosp Fdn, Pavia, Italy. [Suarez Rodriguez, Christina] Vall dHebron Univ Hosp, Barcelona, Spain. [Suarez Rodriguez, Christina] Univ Barcelona, Inst Oncol, Barcelona, Spain. [Patel, Chirag; Neuwirth, Rachel; Enke, Aaron; Zohren, Fabian] Millennium Pharmaceut Inc, Cambridge, MA USA. [Powles, Thomas] St Bartholomews Hosp, London, England. 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 1464-4096 EI 1464-410X J9 BJU INT JI BJU Int. PD DEC PY 2016 VL 118 SU S5 BP 13 EP 14 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA EC9QC UT WOS:000388478200020 ER PT J AU Wood, L Kottschade, L Davies, M Rubin, K Madden, K Dahl, N Brennan, L Walker, D Li, XM Gagnier, P AF Wood, Laura Kottschade, Lisa Davies, Marianne Rubin, Krista Madden, Kathleen Dahl, Nathan Brennan, Laura Walker, Dana Li, Xuemei Gagnier, Paul TI Management of gastrointestinal adverse events (AEs) associated with nivolumab and ipilimumab combination therapy in solid tumors SO BJU INTERNATIONAL LA English DT Meeting Abstract CT 15th International Kidney Cancer Symposium CY NOV 04-05, 2016 CL Miami, FL C1 [Wood, Laura] Cleveland Clin, Ctr Canc, Cleveland, OH 44106 USA. [Kottschade, Lisa; Dahl, Nathan] Mayo Clin, Rochester, MN USA. [Davies, Marianne] Yale Univ, Sch Med, New Haven, CT USA. [Rubin, Krista] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Madden, Kathleen] New York Univ Med Oncol, New York, NY USA. [Brennan, Laura] UC Davis Comprehens Canc Ctr, Sacramento, CA USA. [Walker, Dana; Li, Xuemei] Bristol Myers Squibb Co, New York, NY 10154 USA. [Gagnier, Paul] Bristol Myers Squibb Co, 5 Res Pkwy, Wallingford, CT 06492 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 1464-4096 EI 1464-410X J9 BJU INT JI BJU Int. PD DEC PY 2016 VL 118 SU S5 BP 16 EP 16 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA EC9QC UT WOS:000388478200025 ER PT J AU Rosenthal, K Choueiri, T Motzer, R Ryan, C Obholz, K Hutson, T Rini, B AF Rosenthal, Kristen Choueiri, Toni Motzer, Robert Ryan, Charles Obholz, Kevin Hutson, Thomas Rini, Brian TI Treatment variance between experts and community clinicians: analysis of an online decision tool for renal cell carcinoma (RCC) SO BJU INTERNATIONAL LA English DT Meeting Abstract CT 15th International Kidney Cancer Symposium CY NOV 04-05, 2016 CL Miami, FL C1 [Rosenthal, Kristen; Choueiri, Toni] Dana Farber Canc Inst, Boston, MA 02115 USA. [Motzer, Robert] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Ryan, Charles] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Obholz, Kevin] Clin Care Opt, Reston, GA USA. [Hutson, Thomas] Texas Oncol Baylor Sammons Canc Ctr, Dallas, TX USA. [Rini, Brian] Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44106 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 1464-4096 EI 1464-410X J9 BJU INT JI BJU Int. PD DEC PY 2016 VL 118 SU S5 BP 19 EP 19 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA EC9QC UT WOS:000388478200030 ER PT J AU Hammers, HJ Plimack, ER Infante, JR Rini, BI Mcdermott, DF Lewis, LD Voss, MH Sharma, P Pal, SK Razak, A Kollmannsberger, C Heng, DYC Spratlin, J Mchenry, MB Gagnier, P Amin, A AF Hammers, Hans J. Plimack, Elizabeth R. Infante, Jeffrey R. Rini, Brian I. Mcdermott, David F. Lewis, Lionel D. Voss, Martin H. Sharma, Padmanee Pal, Sumanta K. Razak, Albiruni Kollmannsberger, Christian Heng, Daniel Y. C. Spratlin, Jennifer Mchenry, M. Brent Gagnier, Paul Amin, Asim TI Updated results from a phase I study of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma: the CheckMate 016 study SO BJU INTERNATIONAL LA English DT Meeting Abstract CT 15th International Kidney Cancer Symposium CY NOV 04-05, 2016 CL Miami, FL C1 [Hammers, Hans J.] Johns Hopkins Med Inst, Baltimore, MD 21205 USA. [Plimack, Elizabeth R.] Fox Chase Canc Ctr, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Infante, Jeffrey R.] Tennessee Oncol PLLC, Sarah Cannon Res Inst, Nashville, TN USA. [Rini, Brian I.] Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44106 USA. [Mcdermott, David F.] Dana Farber Harvard Canc Ctr, Beth Israel Deaconess Med Ctr, Boston, MA USA. [Lewis, Lionel D.] Dartmouth Hitchcock Med Ctr, Norris Cotton Canc Ctr, Lebanon, NH 03766 USA. [Voss, Martin H.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Sharma, Padmanee] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Pal, Sumanta K.] City Hope Comprehens Canc Ctr, Duarte, CA USA. [Razak, Albiruni] Princess Margaret Canc Ctr, Toronto, ON, Canada. [Kollmannsberger, Christian] British Columbia Canc Agcy, Vancouver, BC, Canada. [Heng, Daniel Y. C.] Univ Calgary, Tom Baker Canc Ctr, Calgary, AB, Canada. [Spratlin, Jennifer] Univ Alberta, Cross Canc Inst, Edmonton, AB, Canada. [Mchenry, M. Brent; Gagnier, Paul] Bristol Myers Squibb Co, Princeton, NJ USA. [Amin, Asim] Levine Canc Inst, Charlotte, NC 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 1464-4096 EI 1464-410X J9 BJU INT JI BJU Int. PD DEC PY 2016 VL 118 SU S5 BP 20 EP 21 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA EC9QC UT WOS:000388478200033 ER PT J AU Naing, A Pant, S Infante, J Papadopoulos, K Autio, K Wong, D Ott, P Falchook, G Patel, M Whiteside, M Colen, R Bendell, J Bauer, T Janku, F Javle, M Tannir, N Oft, M Chan, I Rasco, D Hong, D Patnaik, A Moore, K Korn, M Van-Vlasselaer, P Brown, G AF Naing, Aung Pant, Shubham Infante, Jeffrey Papadopoulos, Kyriakos Autio, Karen Wong, Deborah Ott, Patrick Falchook, Gerald Patel, Manish Whiteside, Melinda Colen, Rivka Bendell, Johanna Bauer, Todd Janku, Filip Javle, Milind Tannir, Nixar Oft, Martin Chan, Ivan Rasco, Drew Hong, David Patnaik, Amita Moore, Kathen Korn, Michael Van-Vlasselaer, Peter Brown, Gail TI Anti-tumor activity of PEGylated human IL-10 (AM0010) in renal cancer alone and in combination with anti-PD1 SO BJU INTERNATIONAL LA English DT Meeting Abstract CT 15th International Kidney Cancer Symposium CY NOV 04-05, 2016 CL Miami, FL C1 [Naing, Aung; Pant, Shubham; Colen, Rivka; Janku, Filip; Javle, Milind; Tannir, Nixar; Hong, David] MD Anderson Canc Ctr, Houston, TX USA. [Infante, Jeffrey] Sarah Cannon Res Inst Tennessee, Nashville, TN USA. [Papadopoulos, Kyriakos; Patnaik, Amita] START Ctr Canc Care, San Antonio, TX USA. [Autio, Karen] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Wong, Deborah] Univ Calif Los Angeles, Los Angeles, CA USA. [Ott, Patrick] Dana Farber Canc Inst, Boston, MA 02115 USA. [Falchook, Gerald] HealthONE, Sarah Cannon Res Inst, Denver, CO USA. [Patel, Manish] Florida Canc Specialists, Sarah Cannon Res Inst, Denver, CO USA. [Whiteside, Melinda; Oft, Martin; Chan, Ivan; Van-Vlasselaer, Peter; Brown, Gail] ARMO Biosci, Redwood City, CA USA. [Bendell, Johanna; Bauer, Todd] Tennessee Oncol, Nashville, TN USA. [Rasco, Drew] START Ctr Canc Care, San Antonio, TX USA. [Moore, Kathen] Oklahoma Coll Med, Oklahoma City, OK USA. [Korn, Michael] Univ Calif San Francisco, San Francisco, CA 94143 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 1464-4096 EI 1464-410X J9 BJU INT JI BJU Int. PD DEC PY 2016 VL 118 SU S5 BP 25 EP 25 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA EC9QC UT WOS:000388478200041 ER PT J AU Choueiri, TK Rini, BI Cosgriff, T Miyake, H Vogelzang, NJ Kannourakis, G Mariani, M Chiruzzi, C Albiges, L Haanen, JB Larkin, J Atkins, MB Schmidinger, M Magazzu, D Di Pietro, A Motzer, RJ AF Choueiri, Toni K. Rini, Brian I. Cosgriff, Thomas Miyake, Hideaki Vogelzang, Nicholas J. Kannourakis, George Mariani, Mariangela Chiruzzi, Chiara Albiges, Laurence Haanen, John B. Larkin, James Atkins, Michael B. Schmidinger, Manuela Magazzu, Domenico Di Pietro, Alessandra Motzer, Robert J. TI JAVELIN renal 101: a phase 3 study of avelumab in combination with axitinib vs sunitinib as first-line treatment for patients with advanced renal cell carcinoma (aRCC) SO BJU INTERNATIONAL LA English DT Meeting Abstract CT 15th International Kidney Cancer Symposium CY NOV 04-05, 2016 CL Miami, FL C1 [Choueiri, Toni K.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Rini, Brian I.] Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44106 USA. [Cosgriff, Thomas] East Jefferson Hematol Oncol, Metairie, LA USA. [Miyake, Hideaki] Hamamatsu Univ, Sch Med, Hamamatsu, Shizuoka, Japan. [Vogelzang, Nicholas J.] Comprehens Canc Ctr Nevada, Las Vegas, NV USA. [Kannourakis, George] Fiona Elsey Canc Res Inst, Ballarat, Vic, Australia. [Mariani, Mariangela; Chiruzzi, Chiara] Pfizer Inc, Milan, Lombardia, Italy. [Albiges, Laurence] Univ Paris Sud, Gustave Roussy Canc Campus, Villejuif, France. [Haanen, John B.] Netherlands Canc Inst, Amsterdam, Netherlands. [Larkin, James] Royal Marsden NHS Fdn Trust, London, England. [Atkins, Michael B.] Georgetown Lombardi Comprehens Canc Ctr, Washington, DC USA. [Schmidinger, Manuela] Med Univ Vienna, Div Clin Oncol, Vienna, Austria. [Schmidinger, Manuela] Med Univ Vienna, Ctr Comprehens Canc, Vienna, Austria. [Magazzu, Domenico; Di Pietro, Alessandra] Pfizer Inc, Milan, Lombardia, Italy. [Motzer, Robert J.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-4096 EI 1464-410X J9 BJU INT JI BJU Int. PD DEC PY 2016 VL 118 SU S5 BP 29 EP 30 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA EC9QC UT WOS:000388478200049 ER PT J AU Wood, L Davies, M Rubin, K Madden, K Brennan, L Dahl, N Walker, D Gagnier, P Li, XM Kottschade, L AF Wood, Laura Davies, Marianne Rubin, Krista Madden, Kathleen Brennan, Laura Dahl, Nathan Walker, Dana Gagnier, Paul Li, Xuemei Kottschade, Lisa TI Management of endocrinopathies associated with nivolumab and ipilimumab combination therapy in solid tumors SO BJU INTERNATIONAL LA English DT Meeting Abstract CT 15th International Kidney Cancer Symposium CY NOV 04-05, 2016 CL Miami, FL C1 [Wood, Laura] Cleveland Clin, Ctr Canc, Cleveland, OH 44106 USA. [Davies, Marianne] Yale Univ, Sch Med, New Haven, CT USA. [Rubin, Krista] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Madden, Kathleen] NYU, Med Oncol, New York, NY USA. [Brennan, Laura] UC Davis Comprehens Canc Ctr, Sacramento, CA USA. [Dahl, Nathan; Kottschade, Lisa] Mayo Clin, Rochester, MN USA. [Walker, Dana; Li, Xuemei] Bristol Myers Squibb, New York, NY USA. [Gagnier, Paul] Bristol Myers Squibb, Wallingford, CT 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 1464-4096 EI 1464-410X J9 BJU INT JI BJU Int. PD DEC PY 2016 VL 118 SU S5 BP 29 EP 29 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA EC9QC UT WOS:000388478200048 ER PT J AU Rudman, SM Gray, KP Batista, JL Pitt, MJ Giovannucci, EL Harper, PG Loda, M Mucci, LA Sweeney, CJ AF Rudman, Sarah M. Gray, Kathryn P. Batista, Julie L. Pitt, Michael J. Giovannucci, Edward L. Harper, Peter G. Loda, Massimo Mucci, Lorelei A. Sweeney, Christopher J. TI Risk of prostate cancer-specific death in men with baseline metabolic aberrations treated with androgen deprivation therapy for biochemical recurrence SO BJU INTERNATIONAL LA English DT Article DE prostate cancer; metabolic syndrome; hypertension; androgen deprivation therapy; biochemical recurrence; competing risks ID COMPETING RISK; SHORTER TIME; TESTOSTERONE; PREVENTION; TUMORS AB Objectives To investigate the associations of host metabolic factors and metabolic syndrome on prostate cancer-specific death (PCSD) and overall survival (OS) in patients treated with androgen deprivation therapy (ADT) for biochemically recurrent disease. Patients and Methods The analysis included 273 patients with prostate cancer treated with ADT for rising prostate-specific antigen level after surgery or radiotherapy. Patients were assessed for the presence of diabetes, hypertension, dyslipidaemia and obesity before commencing ADT, and Adult Treatment Panel III criteria were used to assess the presence of the composite diagnosis of metabolic syndrome. A competing risks regression model was used to assess associations of time to PCSD with the metabolic conditions, while a multivariable Cox regression model was used to assess associations of OS with metabolic syndrome and metabolic conditions. Results During a median follow-up of 11.6 years, 157 patients (58%) died, of whom 58 (21%) died from prostate cancer. At the start of ADT the median (range) patient age was 74 (46-92) years and the median PSA level was 3.0 ng/mL. Metabolic syndrome was observed in 31% of patients; hypertension (68%) and dyslipidaemia (47%) were the most common metabolic conditions. No association of PCSD and metabolic syndrome status was observed. Patients with hypertension tended to have a higher cumulative incidence of PCSD than those without hypertension (sub-distribution hazard ratio [HR] 1.59, 95% confidence interval [CI] 0.89, 2.84; P = 0.11) although the difference was not statistically significant. Patients with metabolic syndrome had an increased risk of death from all causes (HR 1.56, 95% CI 1.07, 2.29; P = 0.02) when compared with patients without metabolic syndrome, as did patients with hypertension (HR 1.72, 95% CI 1.18, 2.49; P = 0.004). Conclusions No association of PCSD and metabolic syndrome was observed in this cohort of men receiving ADT for biochemically recurrent prostate cancer. Metabolic syndrome was associated with an increased risk of death from all causes and a similar effect was also observed for patients with prostate cancer with hypertension alone. C1 [Rudman, Sarah M.; Harper, Peter G.] Guys & St Thomas NHS Fdn Trust, Dept Oncol, London, England. [Gray, Kathryn P.] Harvard Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA USA. [Batista, Julie L.; Giovannucci, Edward L.; Mucci, Lorelei A.] Harvard Med Sch Boston, Brigham & Womens Hosp, Channing Div Network Med, Dept Med, Boston, MA USA. [Batista, Julie L.; Pitt, Michael J.; Giovannucci, Edward L.; Loda, Massimo; Mucci, Lorelei A.] Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Giovannucci, Edward L.] Harvard Sch Publ Hlth, Dept Nutr, Boston, MA USA. [Giovannucci, Edward L.] Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Boston, MA 02115 USA. [Sweeney, Christopher J.] Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Boston, MA 02115 USA. [Sweeney, Christopher J.] Harvard Med Sch, Boston, MA USA. RP Sweeney, CJ (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, 450 Brookline Ave,D1230, Boston, MA 02215 USA. EM christopher_sweeney@dfci.harvard.edu FU National Cancer Institute at the National Institutes of Health [R01CA133891, P01CA055075, U19CA055075-20]; Prostate Cancer Foundation; National Institutes of Health [5 T32 CA09001-36]; Department of Defense Prostate Cancer Research Program [W81XWH-12-1-0072]; Dana-Farber Cancer Institute A. David Mazzone Award FX We are grateful to the participants and staff of the HPFS for their valuable contributions. In addition, we would like to thank the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA and WY, USA. This work was supported in part by the National Cancer Institute at the National Institutes of Health: [R01CA133891], PI Giovannucci. The HPFS was supported by the National Cancer Institute at the National Institutes of Health [P01CA055075] (PI Willett) and [U19CA055075-20] (PI Willett). L. A. Mucci is supported by the Prostate Cancer Foundation and J. L. Batista is supported in part by a training grant National Institutes of Health 5 T32 CA09001-36, the Department of Defense Prostate Cancer Research Program (W81XWH-12-1-0072), and the Dana-Farber Cancer Institute A. David Mazzone Award. NR 27 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-4096 EI 1464-410X J9 BJU INT JI BJU Int. PD DEC PY 2016 VL 118 IS 6 BP 919 EP 926 DI 10.1111/bju.13428 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA EC9QL UT WOS:000388479100017 PM 26805930 ER PT J AU Overdyk, FJ Dowling, O Newman, S Glatt, D Chester, M Armellino, D Cole, B Landis, GS Schoenfeld, D DiCapua, JF AF Overdyk, Frank J. Dowling, Oonagh Newman, Sheldon Glatt, David Chester, Michelle Armellino, Donna Cole, Brandon Landis, Gregg S. Schoenfeld, David DiCapua, John F. TI Remote video auditing with real-time feedback in an academic surgical suite improves safety and efficiency metrics: a cluster randomised study SO BMJ QUALITY & SAFETY LA English DT Article ID OPERATING-ROOM EFFICIENCY; CHECKLIST; CARE; IMPLEMENTATION; METHODOLOGY AB Importance Compliance with the surgical safety checklist during operative procedures has been shown to reduce inhospital mortality and complications but proper execution by the surgical team remains elusive. Objective We evaluated the impact of remote video auditing with real-time provider feedback on checklist compliance during sign-in, time-out and sign-out and case turnover times. Design, setting Prospective, cluster randomised study in a 23-operating room (OR) suite. Participants Surgeons, anaesthesia providers, nurses and support staff. Exposure ORs were randomised to receive, or not receive, real-time feedback on safety checklist compliance and efficiency metrics via display boards and text messages, followed by a period during which all ORs received feedback. Main outcome(s) and measure(s) Checklist compliance (Pass/Fail) during sign-in, time-out and sign-out demonstrated by (1) use of checklist, (2) team attentiveness, (3) required duration, (4) proper sequence and duration of case turnover times. Results Sign-in, time-out and sign-out PASS rates increased from 25%, 16% and 32% during baseline phase (n=1886) to 64%, 84% and 68% for feedback ORs versus 40%, 77% and 51% for no-feedback ORs (p<0.004) during the intervention phase (n=2693). Pass rates were 91%, 95% and 84% during the all-feedback phase (n=2001). For scheduled cases (n=1406, 71%), feedback reduced mean turnover times by 14% (41.4 min vs 48.1 min, p<0.004), and the improvement was sustained during the all-feedback period. Feedback had no effect on turnover time for unscheduled cases (n=587, 29%). Conclusions and relevance Our data indicate that remote video auditing with feedback improves surgical safety checklist compliance for all cases, and turnover time for scheduled cases, but not for unscheduled cases. C1 [Overdyk, Frank J.; Newman, Sheldon; Glatt, David; DiCapua, John F.] Long Isl Jewish Med Ctr, Hofstra North Shore LIJ Sch Med, Dept Anesthesiol, 270 76th Ave, New Hyde Pk, NY 11040 USA. [Dowling, Oonagh] Hofstra North Shore LIJ Sch Med, Dept Med, Hempstead, NY USA. [Chester, Michelle; Cole, Brandon] Long Isl Jewish Med Ctr, Dept Anesthesiol, New Hyde Pk, NY 11040 USA. [Armellino, Donna] North Shore LIJ Hlth Syst, Dept Anesthesiol, Lake Success, NY USA. [Landis, Gregg S.] Hofstra North Shore LIJ Sch Med, Dept Surg, Hempstead, NY USA. [Schoenfeld, David] Harvard Med Sch, Massachusetts Gen Hosp, Dept Biostat, Ctr Biostat, Boston, MA USA. RP Overdyk, FJ (reprint author), Long Isl Jewish Med Ctr, Hofstra North Shore LIJ Sch Med, Dept Anesthesiol, 270 76th Ave, New Hyde Pk, NY 11040 USA. EM overdykf@icloud.com FU Arrowsight Inc. FX Arrowsight Inc. NR 20 TC 2 Z9 2 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 2044-5415 EI 2044-5423 J9 BMJ QUAL SAF JI BMJ Qual. Saf. PD DEC PY 2016 VL 25 IS 12 BP 947 EP 953 DI 10.1136/bmjqs-2015-004226 PG 7 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA EC7MH UT WOS:000388323100009 PM 26658775 ER PT J AU Bandello, F Corvi, F La Spina, C Benatti, L Querques, L Capuano, V Naysan, J Chen, XJ Sarraf, D Parodi, MB Souied, E Freund, KB Querques, G AF Bandello, Francesco Corvi, Federico La Spina, Carlo Benatti, Lucia Querques, Lea Capuano, Vittorio Naysan, Jonathan Chen, Xuejing Sarraf, David Parodi, Maurizio Battaglia Souied, Eric Freund, K. Bailey Querques, Giuseppe TI Outcomes of intravitreal anti-VEGF therapy in eyes with both neovascular age-related macular degeneration and diabetic retinopathy SO BRITISH JOURNAL OF OPHTHALMOLOGY LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; RANIBIZUMAB PLUS PROMPT; DEFERRED LASER; CHOROIDAL NEOVASCULARIZATION; TRAP-EYE; EDEMA; CLASSIFICATION; SEVERITY; ANCHOR AB Purpose To investigate the outcomes of intravitreal antivascular endothelial growth factor (VEGF) therapy in eyes with both neovascular age-related macular degeneration (AMD) and diabetic retinopathy (DR). Methods Patients from four high-volume referral centres who presented with neovascular AMD and DR, and received intravitreal anti-VEGF therapy, were included. Data retrieved from medical records and multimodal imaging were analysed. Results Forty-one eyes of 38 patients (21 male, 17 female; mean age 78 +/- 8 years) were enrolled. Median follow-up was 28 +/- 19 (12-72) months with a mean of 9.2 +/- 7.4 intravitreal anti-VEGF injections per eye were administrated. Best-corrected visual acuity (BCVA) was 0.5 +/- 0.3 logMAR; it improved significantly at 1 year (0.3 +/- 0.3 logMAR; p=0.02) and returned to baseline values at last follow-up visit (0.6 +/- 0.4 logMAR; p=0.26). Mean central macular thickness (CMT) significantly decreased from 408 +/- 150 mu m to 328 +/- 104 mu m at 1 year (p=0.021) and to 335 +/- 127 mu m at last follow-up visit (p=0.032). The baseline severity of DR was graded as mild non-proliferative DR (NPDR) in 21 (51%) eyes, moderate NPDR in 14 (34%), severe NPDR in 4 (10%) and inactive proliferative DR in 2 (5%). At last follow-up visit, one eye graded as moderate NPDR improved to mild, one eye graded as severe NPDR improved to mild and one eye graded as severe NPDR was inactivated due to panretinal photocoagulation. Conclusions Outcomes analysis of intravitreal anti-VEGF therapy for eyes with both neovascular AMD and DR showed stabilisation of BCVA and reduction of CMT, along with stable or improved DR stage throughout follow-up. C1 [Bandello, Francesco; Corvi, Federico; La Spina, Carlo; Benatti, Lucia; Querques, Lea; Parodi, Maurizio Battaglia; Querques, Giuseppe] Univ Vita Salute San Raffaele, Dept Ophthalmol, IRCCS San Raffaele Sci, Milan, Italy. [Capuano, Vittorio; Souied, Eric; Querques, Giuseppe] Univ Paris Est Creteil, Hop Intercommunal Creteil, Dept Ophthalmol, Creteil, France. [Naysan, Jonathan; Freund, K. Bailey] Vitreous Retina Macula Consultants New York, New York, NY USA. [Naysan, Jonathan; Freund, K. Bailey] NYU, Dept Ophthalmol, Sch Med, 550 1St Ave, New York, NY 10016 USA. [Chen, Xuejing; Sarraf, David] Univ Calif Los Angeles, David Geffen Sch Med, Stein Eye Inst, Dept Ophthalmol, Los Angeles, CA 90095 USA. [Sarraf, David] Greater Los Angeles VA Healthcare Ctr, Los Angeles, CA USA. RP Querques, G (reprint author), Univ Vita Salute, Osped San Raffaele, Dept Ophthalmol, Via Olgettina 60, I-20132 Milan, Italy. EM giuseppe.querques@hotmail.it OI Freund, K. Bailey/0000-0002-7888-9773; Corvi, Federico/0000-0002-2661-5500 NR 31 TC 2 Z9 2 U1 2 U2 2 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0007-1161 EI 1468-2079 J9 BRIT J OPHTHALMOL JI Br. J. Ophthalmol. PD DEC PY 2016 VL 100 IS 12 BP 1611 EP 1616 DI 10.1136/bjophthalmol-2016-308400 PG 6 WC Ophthalmology SC Ophthalmology GA EC7XD UT WOS:000388353500005 PM 26951773 ER PT J AU Chau, NG Haddad, RI AF Chau, Nicole G. Haddad, Robert I. TI Antiangiogenic Agents in Head and Neck Squamous Cell Carcinoma: Tired of Going Solo SO CANCER LA English DT Editorial Material ID PHASE-II TRIAL; TUMOR-GROWTH; BEVACIZUMAB; RECURRENT; CANCER; RADIATION; CETUXIMAB; ANGIOGENESIS; COMBINATION; ERLOTINIB C1 [Chau, Nicole G.; Haddad, Robert I.] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA. RP Haddad, RI (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM robert_haddad@dfci.harvard.edu NR 23 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD DEC 1 PY 2016 VL 122 IS 23 BP 3592 EP 3595 DI 10.1002/cncr.30352 PG 4 WC Oncology SC Oncology GA EC8CH UT WOS:000388367300004 PM 27649273 ER PT J AU Kovtun, KA Chen, MH Braccioforte, MH Moran, BJ D'Amico, AV AF Kovtun, Konstantin A. Chen, Ming-Hui Braccioforte, Michelle H. Moran, Brian J. D'Amico, Anthony V. TI Race and Mortality Risk After Radiation Therapy in Men Treated With or Without Androgen-Suppression Therapy for Favorable-Risk Prostate Cancer SO CANCER LA English DT Article DE androgen-deprivation therapy; brachytherapy; mortality; prostate cancer; race; radiation therapy ID PHASE-III TRIAL; RADICAL PROSTATECTOMY; RANDOMIZED-TRIAL; DEPRIVATION THERAPY; FOLLOW-UP; RADIOTHERAPY; DISEASE AB BACKGROUND: African American (AA) men are more likely than non-AA men to have a comorbid illness that could interact with androgen-deprivation therapy (ADT) and shorten survival. This study assessed the impact that race had on the risk of all-cause mortality (ACM) and other-cause mortality (OCM) among men definitively treated for favorable-risk prostate cancer (PC). METHODS: Between 1997 and 2013, 7252 men with low-risk or favorable intermediate-risk PC were treated with brachytherapy with neoadjuvant ADT (n = 1501) or without neoadjuvant ADT (n = 5751) for a 4-month median duration. Cox and Fine-Gray multivariate regressions were used to analyze whether the risk of ACM and OCM increased among AA men versus non-AA men receiving ADT; adjustments were made for the age at brachytherapy, year of brachytherapy, cardiometabolic comorbidity status, risk group, and ADT treatment propensity score. RESULTS: After a median follow-up of 8.04 years, 869 men (12.0%) died: 48 (5.52%) of PC and 821 (94.48%) of other causes. There was a significant association between AA race and an increased risk of both ACM (adjusted hazard ratio [AHR], 1.77; 95% confidence interval [CI], 1.06-2.94; P = .028) and OCM (AHR, 1.86; 95% CI, 1.08-3.19; P = .024) among AA men versus non-AA men who received ADT but not among those who did not receive ADT (AHR for ACM, 1.33; 95% CI, 0.93-1.91; P = .12; AHR for OCM, 1.39; 95% CI, 0.96-2.02; P = .08). CONCLUSIONS: ADT use may shorten survival in AA men with favorable-risk PC; therefore, its reservation for the treatment of higher risk PC, for which level 1 evidence supports its use, should be considered. (C) 2016 American Cancer Society. C1 [Kovtun, Konstantin A.] Brigham & Womens Hosp, Dana Farber Canc Inst, Harvard Radiat Oncol Program, 75 Francis St, Boston, MA 02115 USA. [Chen, Ming-Hui] Univ Connecticut, Dept Stat, Storrs, CT 06269 USA. [Braccioforte, Michelle H.; Moran, Brian J.] Prostate Canc Fdn Chicago, Westmont, IL USA. [D'Amico, Anthony V.] Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. RP Kovtun, KA (reprint author), Brigham & Womens Hosp, Dana Farber Canc Inst, Harvard Radiat Oncol Program, 75 Francis St, Boston, MA 02115 USA. EM kkovtun@partners.org NR 26 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD DEC 1 PY 2016 VL 122 IS 23 BP 3608 EP 3614 DI 10.1002/cncr.30224 PG 7 WC Oncology SC Oncology GA EC8CH UT WOS:000388367300007 PM 27490845 ER PT J AU Chau, NG Hurwitz, S Mitchell, CM Aserlind, A Grunfeld, N Kaplan, L Hsi, P Bauer, DE Lathan, CS Rodriguez-Galindo, C Tishler, RB Haddad, RI Sallan, SE Bradner, JE French, CA AF Chau, Nicole G. Hurwitz, Shelley Mitchell, Chelsey M. Aserlind, Alexandra Grunfeld, Noam Kaplan, Leah Hsi, Peter Bauer, Daniel E. Lathan, Christopher S. Rodriguez-Galindo, Carlos Tishler, Roy B. Haddad, Robert I. Sallan, Stephen E. Bradner, James E. French, Christopher A. TI Intensive Treatment and Survival Outcomes in NUT Midline Carcinoma of the Head and Neck SO CANCER LA English DT Article DE bromodomain containing 3-nuclear protein in testis (BRD3-NUT); bromodomain containing 4-nuclear protein in testis (BRD4-NUT); head and neck cancer; nuclear protein in testis (NUT) protein; NUT midline carcinoma ID SINONASAL UNDIFFERENTIATED CARCINOMA; UPPER AERODIGESTIVE TRACT; PAROTID-GLAND; BRD-NUT; DIFFERENTIATION; REARRANGEMENT; TRANSLOCATION; ONCOPROTEIN; INHIBITOR; MECHANISM AB BACKGROUND: NUT midline carcinoma is a rare and aggressive genetically characterized subtype of squamous cell carcinoma frequently arising from the head and neck. The characteristics and optimal management of head and neck NUT midline carcinoma (HNNMC) are unclear. METHODS: A retrospective review of all known cases of HNNMC in the International NUT Midline Carcinoma Registry as of December 31, 2014, was performed. Forty-eight consecutive patients were treated from 1993 to 2014, and clinicopathologic variables and outcomes for 40 patients were available for analyses; they composed the largest HNNMC cohort studied to date. Overall survival (OS) and progression-free survival (PFS) according to patient characteristics and treatment were analyzed. RESULTS: This study identified a 5-fold increase in the diagnosis of HNNMC from 2011 to 2014. The median age was 21.9 years (range, 0.1-81.7 years); the male and female proportions were 40% and 60%, respectively; and 86% had bromodomain containing 4-nuclear protein in testis (BRD4-NUT) fusion. The initial treatment was initial surgery with or without adjuvant chemoradiation or adjuvant radiation (56%), initial radiation with or without chemotherapy (15%), or initial chemotherapy with or without surgery or radiation (28%). The median PFS was 6.6 months (range, 4.7-8.4 months). The median OS was 9.7 months (range, 6.6-15.6 months). The 2-year PFS rate was 26% (95% confidence interval [CI], 13%-40%). The 2-year OS rate was 30% (95% CI, 16%-46%). Initial surgery with or without postoperative chemoradiation or radiation (P5.04) and complete resection with negative margins (P5.01) were significant predictors of improved OS even after adjustments for age, tumor size, and neck lymphadenopathy. Initial radiation or chemotherapy and the NUT translocation type were not associated with outcomes. CONCLUSIONS: HNNMC portends a poor prognosis. Aggressive initial surgical resection with or without postoperative chemoradiation or radiation is associated with significantly enhanced survival. Chemotherapy or radiation alone is often inadequate. (C) 2016 American Cancer Society. C1 [Chau, Nicole G.; Bauer, Daniel E.; Lathan, Christopher S.; Haddad, Robert I.; Bradner, James E.] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. [Mitchell, Chelsey M.; Aserlind, Alexandra; Grunfeld, Noam; Kaplan, Leah; Hsi, Peter; French, Christopher A.] Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, 77 Ave Louis Pasteur,New Res Bldg Room 630G, Boston, MA 02115 USA. [Hurwitz, Shelley] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Ctr Clin Invest, Boston, MA USA. [Bauer, Daniel E.; Rodriguez-Galindo, Carlos; Sallan, Stephen E.] Harvard Med Sch, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA USA. [Bauer, Daniel E.; Rodriguez-Galindo, Carlos; Sallan, Stephen E.] Harvard Med Sch, Boston Childrens Hosp, Div Hematol Oncol, Boston, MA USA. [Tishler, Roy B.] Harvard Med Sch, Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA USA. RP Chau, NG (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA.; French, CA (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, 77 Ave Louis Pasteur,New Res Bldg Room 630G, Boston, MA 02115 USA. EM nicole_chau@dfci.harvard.edu; cfrench@partners.org FU National Institutes of Health [2R01CA124633] FX This work was supported by the National Institutes of Health (grant 2R01CA124633 [supplement to Christopher A. French]), which provided partial salary support for the clinical research coordinator (Peter Hsi) and biostatistician (Shelley Hurwitz), and by the International NUT Midline Carcinoma Registry (http://www.nmcregistry.org/), in which all patient data were collected and stored (Nicole G. Chau, Daniel E. Bauer, Christopher S. Lathan, Carlos Rodriguez-Galindo, Stephen E. Sallan, James E. Bradner, and Christopher A. French). The National Institutes of Health did not play a role in the design and conduct of the study; in the collection, management, analysis, and interpretation of the data; in the preparation, review, or approval of the manuscript; or in the decision to submit the manuscript for publication. The members of the International NUT Midline Carcinoma Registry were involved in the design and conduct of the study; in the collection, management, analysis, and interpretation of the data; in the preparation, review, and approval of the manuscript; and in the decision to submit the manuscript for publication. NR 28 TC 0 Z9 0 U1 4 U2 4 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 DEC 1 PY 2016 VL 122 IS 23 BP 3632 EP 3640 DI 10.1002/cncr.30242 PG 9 WC Oncology SC Oncology GA EC8CH UT WOS:000388367300010 PM 27509377 ER PT J AU Jimeno, A Posner, MR Wirth, LJ Saba, NF Cohen, RB Popa, EC Argiris, A Grossmann, KF Sukari, A Wilson, D Zhang, XS Sun, J Glasser, C Attie, KM Sherman, ML Pandya, SS Weiss, J AF Jimeno, Antonio Posner, Marshall R. Wirth, Lori J. Saba, Nabil F. Cohen, Roger B. Popa, Elizabeta C. Argiris, Athanassios Grossmann, Kenneth F. Sukari, Ammar Wilson, Dawn Zhang, Xiaosha Sun, Jade Glasser, Chad Attie, Kenneth M. Sherman, Matthew L. Pandya, Susan S. Weiss, Jared TI A Phase 2 Study of Dalantercept, an Activin Receptor-Like Kinase-1 Ligand Trap, in Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck SO CANCER LA English DT Article DE activin receptor-like kinase 1 (ALK1); angiogenesis; bone morphogenetic protein 9 (BMP9); dalantercept. squamous cell carcinoma of the head and neck (SCCHN) ID INAPPROPRIATE ANTIDIURETIC-HORMONE; CANCER STATISTICS; TUMOR-GROWTH; ANGIOGENESIS; HYPONATREMIA; EXPRESSION; THERAPIES; SECRETION; ALK1 AB BACKGROUND: Patients with platinum-refractory, recurrent or metastatic squamous cell carcinoma of the head and neck (RM-SCCHN) have limited options. Activin receptor-like kinase 1 (ALK1) is a type I receptor of the transforming growth factor beta superfamily expressed on activated endothelial cells. Dalantercept is an ALK1 receptor fusion protein that acts as a ligand trap to block signaling through ALK1 and inhibits stages of angiogenesis involved in blood vessel maturation and stabilization. In a phase 1 study, dalantercept demonstrated clinical activity in patients with RM-SCCHN. The objective of the current study was to evaluate the activity of dalantercept in RM-SCCHN. METHODS: Forty-six patients received dalantercept at doses of 80mg (n = 2), 0.6mg/kg (n = 13), or 1.2mg/kg (n = 31) subcutaneously every 3 weeks. The primary endpoint was the overall response rate according to Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). Secondary endpoints included progression-free survival and overall survival, safety and tolerability, and pharmacokinetic and pharmacodynamic assessments. RESULTS: Forty patients were evaluable for response (13 who received dalantercept 0.6mg/kg and 27 who received dalantercept 1.2mg/kg). The overall response rate was 5% (n = 2), and 35% of patients had stable disease; 44% of patients who received 1.2mg/kg and 30.8% of those who received 0.6mg/kg achieved disease control (partial response or stable disease). The median progression-fee survival was 1.4 months (95% confidence interval, 1.3-2.2 months), and the median overall survival was 7.1 months (95% confidence interval, 5.5-11.1 months). Drug-related adverse events (>15%) were anemia, fatigue, peripheral edema, headache, and hyponatremia. CONCLUSIONS: In an unselected, heavily pretreated population of patients with RM-SCCHN, dalantercept monotherapy resulted in a favorable safety profile but only modest dose-dependent activity, and it did not meet the primary efficacy objective of the study. (C) 2016 American Cancer Society. C1 [Jimeno, Antonio] Univ Colorado, Ctr Canc, Dept Med, Aurora, CO USA. [Jimeno, Antonio] Univ Colorado, Ctr Canc, Dept Otolaryngol, Aurora, CO USA. [Jimeno, Antonio] Gates Ctr Regenerat Med, Aurora, CO USA. [Posner, Marshall R.] Icahn Sch Med Mt Sinai, Dept Med, New York, NY 10029 USA. [Posner, Marshall R.] Icahn Sch Med Mt Sinai, Dept Otolaryngol, New York, NY 10029 USA. [Wirth, Lori J.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Saba, Nabil F.] Emory Univ, Winship Canc Inst, Dept Hematol & Med Oncol, Atlanta, GA 30322 USA. [Cohen, Roger B.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Popa, Elizabeta C.] Cornell Univ, Dept Med, Joan & Sanford I Weill Cornell Med Coll, New York, NY 10021 USA. [Argiris, Athanassios] Univ Texas Hlth Sci Ctr San Antonio, Inst Drug Dev, Dept Med, San Antonio, TX 78229 USA. [Grossmann, Kenneth F.] Huntsman Canc Inst, Dept Internal Med, Salt Lake City, UT USA. [Sukari, Ammar] Wayne State Univ, Karmanos Canc Ctr, Detroit, MI USA. [Wilson, Dawn; Zhang, Xiaosha; Sun, Jade; Glasser, Chad; Attie, Kenneth M.; Sherman, Matthew L.; Pandya, Susan S.] Acceleron Pharma, Cambridge, MA USA. [Weiss, Jared] Univ N Carolina, Dept Hematol & Oncol, Chapel Hill, NC USA. RP Jimeno, A (reprint author), Univ Colorado, Ctr Canc, Med Oncol & Otolaryngol, 12801 East 1seventh Ave,Room L18-8101B, Aurora, CO 80045 USA.; Jimeno, A (reprint author), Univ Colorado Denver, Sch Med, Gates Ctr Regenerat Med, 12801 East 1seventh Ave,Room L18-8101B, Aurora, CO 80045 USA. EM antonio.jimeno@ucdenver.edu FU Acceleron Pharma FX This study was supported by Acceleron Pharma. NR 25 TC 1 Z9 1 U1 1 U2 1 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 DEC 1 PY 2016 VL 122 IS 23 BP 3641 EP 3649 DI 10.1002/cncr.30317 PG 9 WC Oncology SC Oncology GA EC8CH UT WOS:000388367300011 PM 27648727 ER PT J AU Camargo, CA Davis, KJ Andrews, EB Stempel, DA Schatz, M AF Camargo, Carlos A., Jr. Davis, Kourtney J. Andrews, Elizabeth B. Stempel, David A. Schatz, Michael TI Pharmacoepidemiological Study of Long-Acting beta-agonist/Inhaled Corticosteroid Therapy and Asthma Mortality: Clinical Implications SO CLINICAL DRUG INVESTIGATION LA English DT Article ID INHALED CORTICOSTEROIDS; EXACERBATIONS; POPULATION; SALMETEROL; BURDEN; SYSTEM; CARE AB The increased risk of asthma mortality in association with long-acting beta(2)-agonist (LABA) monotherapy is well documented but the risk associated with LABA plus inhaled corticosteroid (ICS) therapy remains unclear. We assessed the feasibility of a large pharmacoepidemiological study to compare the effect of combined LABA + ICS therapy with non-LABA maintenance therapy on the risk of asthma mortality. This observational retrospective study used electronic data from ten US data partners to construct a cohort of patients with persistent asthma (defined as: four or more asthma maintenance medication dispensings in 12 months and a code diagnosis of asthma). Asthma deaths were determined by linking patient data with the National Death Index. From 5,881,438 asthma patients, a cohort of 994,627 met the criteria for persistent asthma and provided 2.4 million person-years of follow-up. The total number of deaths was 278 with only three of these occurring after incident exposure to an asthma maintenance medication. The overall pooled asthma mortality rate, standardized by age and data partner, was 1.16 [95 % confidence interval (CI) 0.98-1.34] per 10,000 person-years; crude mortality rates (per 10,000 person-years) increased with age and were higher in female individuals (1.34; 95 % CI 1.15-1.55) than in male individuals (0.92; 95 % CI 0.74-1.12). Despite a cohort size of almost 1 million asthma patients, the asthma mortality risk associated with combined LABA + ICS therapy could not be determined. This study showed that very few patients with persistent asthma have asthma-related deaths, and confirmed that those who die are more likely to be older and female. C1 [Camargo, Carlos A., Jr.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Emergency Med, 125 Nashua St,Suite 920, Boston, MA 02114 USA. [Davis, Kourtney J.] GlaxoSmithKline R& D, Real World Evidence, Collegeville, PA USA. [Andrews, Elizabeth B.] RTI Hlth Solut, Res Triangle Pk, NC USA. [Stempel, David A.] US Med Affairs, GlaxoSmithKline, Res Triangle Pk, NC USA. [Schatz, Michael] Kaiser Permanente, San Diego, CA USA. RP Camargo, CA (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Emergency Med, 125 Nashua St,Suite 920, Boston, MA 02114 USA. EM ccamargo@partners.org FU GlaxoSmithKline (GSK) [WEUSRTP4942]; GSK FX The study was conducted by RTI Health Solutions with financial support from GlaxoSmithKline (GSK) (Protocol WEUSRTP4942). Editorial support was received in the form of draft manuscript development, collating of author comments, and copy-editing, which was provided by Kate Hollingworth of Continuous Improvement Ltd. This support was funded by GSK. NR 24 TC 1 Z9 1 U1 1 U2 1 PU ADIS INT LTD PI NORTHCOTE PA 5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND SN 1173-2563 EI 1179-1918 J9 CLIN DRUG INVEST JI Clin. Drug Invest. PD DEC PY 2016 VL 36 IS 12 BP 993 EP 999 DI 10.1007/s40261-016-0448-1 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA EC5IO UT WOS:000388168300002 PM 27581247 ER PT J AU Connelly, C Cicuto, T Leavitt, J Petty, A Litman, A Margolis, HC Gerdon, AE AF Connelly, Christopher Cicuto, Thomas Leavitt, Jason Petty, Alexander Litman, Amy Margolis, Henry C. Gerdon, Aren E. TI Dynamic interactions of amelogenin with hydroxyapatite surfaces are dependent on protein phosphorylation and solution pH SO COLLOIDS AND SURFACES B-BIOINTERFACES LA English DT Article DE Amelogenin; Phosphorylation; Hydroxyapatite; Quartz crystal microbalance; Adsorption ID QUARTZ-CRYSTAL MICROBALANCE; ATOMIC-FORCE MICROSCOPY; MATRIX DERIVATE PROTEIN; SOLID-STATE NMR; CALCIUM-PHOSPHATE; ENAMEL MATRIX; IN-VITRO; PORCINE AMELOGENIN; LIGHT-SCATTERING; ADSORPTION AB Amelogenin, the predominant extracellular matrix protein secreted by ameloblasts, has been shown to be essential for proper tooth enamel formation. In this study, amelogenin adsorption to hydroxyapatite (HAP) surfaces, a prototype for enamel mineral, has been studied using a quartz crystal microbalance (QCM) to interrogate effects of protein phosphorylation and solution pH. Dynamic flow-based experiments were conducted at pH 7.4 and 8.0 using native phosphorylated porcine amelogenin (P173) and recombinant non-phosphorylated porcine amelogenin (rP172). Loading capacities (mu mol/m(2)) on HAP surfaces were calculated under all conditions and adsorption affinities (K-ad) were calculated when Langmuir isotherm conditions appeared to be met. At pH 8.0, binding characteristics were remarkably similar for the two proteins. However, at pH 7.4 a higher affinity and lower surface loading for the phosphorylated P173 was found compared to any other set of conditions. This suggests that phosphorylated P173 adopts a more extended conformation than non-phosphorylated full-length amelogenin, occupying a larger footprint on the HAP surface. This surface-induced structural difference may help explain why P173 is a more effective inhibitor of spontaneous HAP formation in vitro than rP172. Differences in the viscoelastic properties of P173 and rP172 in the adsorbed state were also observed, consistent with noted differences in HAP binding. These collective findings provide new insight into the important role of amelogenin phosphorylation in the mechanism by which amelogenin regulates enamel crystal formation. (C) 2016 Elsevier B.V. All rights reserved. C1 [Connelly, Christopher; Cicuto, Thomas; Leavitt, Jason; Petty, Alexander; Gerdon, Aren E.] Emmanuel Coll, Dept Chem & Phys, Boston, MA 02115 USA. [Litman, Amy; Margolis, Henry C.] Forsyth Inst, Ctr Biomineralizat, Dept Appl Oral Sci, Cambridge, MA 02142 USA. RP Gerdon, AE (reprint author), Emmanuel Coll, Dept Chem & Phys, Boston, MA 02115 USA. EM gerdoar@emmanuel.edu FU NIH [DE016376-05S1, DE023091] FX This study was supported in part by NIH Grants DE016376-05S1 (HCM and AEG) and DE023091 (HCM). NR 57 TC 0 Z9 0 U1 6 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0927-7765 EI 1873-4367 J9 COLLOID SURFACE B JI Colloid Surf. B-Biointerfaces PD DEC 1 PY 2016 VL 148 BP 377 EP 384 DI 10.1016/j.colsurfb.2016.09.010 PG 8 WC Biophysics; Chemistry, Physical; Materials Science, Biomaterials SC Biophysics; Chemistry; Materials Science GA EC6LV UT WOS:000388248500043 PM 27632699 ER EF