FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Brazin, KN Mallis, RJ Li, C Keskin, DB Arthanari, H Gao, YW Wu, SL Karger, BL Wagner, G Reinherz, EL AF Brazin, Kristine N. Mallis, Robert J. Li, Chen Keskin, Derin B. Arthanari, Haribabu Gao, Yuanwei Wu, Shiaw-Lin Karger, Barry L. Wagner, Gerhard Reinherz, Ellis L. TI Constitutively Oxidized CXXC Motifs within the CD3 Heterodimeric Ectodomains of the T Cell Receptor Complex Enforce the Conformation of Juxtaposed Segments SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID VON-WILLEBRAND-FACTOR; ANTIGEN RECEPTOR; ALPHA-BETA; NMR DATA; REDOX STATE; ACTIVATION; PROTEIN; THIOREDOXIN; CD3-EPSILON; LYMPHOCYTES AB The CD3 epsilon gamma and CD3 epsilon delta heterodimers along with the CD3 zeta zeta homodimer are the signaling components of the T cell receptor (TCR). These invariant dimers are non-covalently associated on the T cell plasma membrane with a clone-specific (i.e. clonotypic) alpha beta heterodimer that binds its cognate ligand, a complex between a particular antigenic peptide, and an MHC molecule (pMHC). These four TCR dimers exist in a 1:1:1:1 stoichiometry. At the junction between the extracellular and transmembrane domains of each mammalianCD3 epsilon, CD3 gamma, and CD3 delta subunit is a highly conserved CXXC motif previously found to be important for thymocyte and T cell activation. The redox state of each CXXC motif is presently unknown. Here we show using LC-MS and a biotin switch assay that these CXXC segments are constitutively oxidized on resting and activated T cells, consistent with their measured reduction potential. NMR chemical shift perturbation experiments comparing a native oxidized CD3 delta CXXC-containing segment with that of a mutant SXXS-containing CD3 delta segment in LPPG (1-palmitoyl-sn-glycero-3-phospho-(1'-racglycerol) (sodium salt)) micelles show extensive chemical shift differences in residues within the membrane-proximal motif as well as throughout the transmembrane and cytoplasmic domains as a result of the elimination of the native disulfide. Likewise, direct comparison of the native CD3 delta segment in oxidizing and reducing conditions reveals numerous spectral differences. The oxidized CXXC maintains the structure within the membrane-proximal stalk region as well as that of its contiguous transmembrane and cytoplasmic domain, inclusive of the ITAM (immunoreceptor tyrosine-based activation motif) involved in signaling. These results suggest that preservation of the CD3 CXXC oxidized state may be essential for TCR mechanotransduction. C1 [Brazin, Kristine N.; Keskin, Derin B.; Reinherz, Ellis L.] Dana Farber Canc Inst, Lab Immunobiol, Dept Med Oncol, Boston, MA 02115 USA. [Brazin, Kristine N.; Reinherz, Ellis L.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Mallis, Robert J.; Arthanari, Haribabu; Wagner, Gerhard] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Li, Chen; Gao, Yuanwei; Wu, Shiaw-Lin; Karger, Barry L.] Northeastern Univ, Barnett Inst Chem & Biol Anal, Boston, MA 02115 USA. RP Reinherz, EL (reprint author), Dana Farber Canc Inst, Lab Immunobiol, HIM 419,77 Ave Louis Pasteur, Boston, MA 02115 USA. EM ellis_reinherz@dfci.harvard.edu RI Mallis, Robert/A-2270-2015 FU National Institutes of Health Grants [AI100643-01, GM047467, AI375581, P41-EB002026, S10-RR029236, GM15847] FX This work was supported, in whole or in part, by National Institutes of Health Grants AI100643-01 (to E. L. R.), GM047467 (to E. L. R. and G. W.), AI375581, P41-EB002026, and S10-RR029236 (to G. W.) and GM15847 (to B. L. K.). NR 60 TC 7 Z9 7 U1 0 U2 11 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 11 PY 2014 VL 289 IS 27 BP 18880 EP 18892 DI 10.1074/jbc.M114.574996 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AL3WV UT WOS:000339062900022 PM 24849600 ER PT J AU Lee, J Miyazaki, M Romeo, GR Shoelson, SE AF Lee, Jongsoon Miyazaki, Masaya Romeo, Giulio R. Shoelson, Steven E. TI Insulin Receptor Activation with Transmembrane Domain Ligands SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID EPIDERMAL-GROWTH-FACTOR; TYROSINE KINASE; BETA-SUBUNIT; ERYTHROPOIETIN RECEPTOR; CONFORMATIONAL-CHANGES; CRYSTAL-STRUCTURE; POINT MUTATION; SIGNAL-TRANSDUCTION; NEU ONCOGENE; IN-VITRO AB Complementary surfaces are buried when peptide hormones, growth factors, or cytokines bind and activate cellular receptors. Although these extended surfaces provide high affinity and specificity to the interactions, they also present great challenges to the design of small molecules that might either mimic or antagonize the process. We show that the insulin receptor (IR) and downstream signals can be activated by targeting a site outside of its ligand-binding domain. A 24-residue peptide having the IR transmembrane (TM) domain sequence activates IR, but not related growth factor receptors, through specific interactions with the receptor TM domain. Like insulin-dependent activation, IR-TM requires that IR have a competent ATP-binding site and kinase activation loop. IR-TM also activates mutated receptors from patients with severe insulin resistance, which do not respond to insulin. These results show that IR can be activated through a pathway that bypasses its canonical ligand-binding domain. C1 [Lee, Jongsoon; Shoelson, Steven E.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Lee, J (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, One Joslin Pl, Boston, MA 02115 USA. EM jongsoon.lee@joslin.harvard.edu; m.miyazaki@aist.go.jp; steven.shoelson@joslin.harvard.edu RI Miyazaki, Masaya/F-8520-2012 OI Miyazaki, Masaya/0000-0003-4031-7224 FU National Institutes of Health [R21 DK80380, R01 DK45943, R37 DK51729, R01 DK73547, T32 DK007260, P30 DK36836]; American Diabetes Association [RA 110BS97]; Helen and Morton Adler Chair FX This work was supported, in whole or in part, by National Institutes of Health Grants R21 DK80380 (to J. L.), R01 DK45943, R37 DK51729, and R01 DK73547 (to S. E. S.), T32 DK007260 (to G. R. R.), and P30 DK36836 (to Joslin Diabetes Research Center). This work was also supported by American Diabetes Association Grant RA 110BS97 (to J. L.) and the Helen and Morton Adler Chair (to S. E. S.). NR 66 TC 14 Z9 14 U1 4 U2 14 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 11 PY 2014 VL 289 IS 28 BP 19769 EP 19777 DI 10.1074/jbc.M114.578641 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AL7PL UT WOS:000339326800048 PM 24867955 ER PT J AU Barouch, DH Deeks, SG AF Barouch, Dan H. Deeks, Steven G. TI Immunologic strategies for HIV-1 remission and eradication SO SCIENCE LA English DT Review ID CD4(+) T-CELLS; ACTIVE ANTIRETROVIRAL THERAPY; INTERFERON-STIMULATED GENES; PERSISTENT LCMV INFECTION; PLACEBO-CONTROLLED TRIAL; HIGHLY PATHOGENIC SIV; IN-VIVO; NEUTRALIZING ANTIBODIES; ANTIVIRAL THERAPY; RHESUS-MONKEYS AB Antiretroviral therapy (ART) is able to suppress HIV-1 replication indefinitely in individuals who have access to these medications, are able to tolerate these drugs, and are motivated to take them daily for life. However, ART is not curative. HIV-1 persists indefinitely during ART as quiescent integrated DNA within memory CD4(+) T cells and perhaps other long-lived cellular reservoirs. In this Review, we discuss the role of the immune system in the establishment and maintenance of the latent HIV-1 reservoir. A detailed understanding of how the host immune system shapes the size and distribution of the viral reservoir should lead to the development of a new generation of immune-based therapeutics, which may eventually contribute to a curative intervention. C1 [Barouch, Dan H.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Ctr Virol & Vaccine Res, Boston, MA 02215 USA. [Barouch, Dan H.] MIT, Massachusetts Gen Hosp, Ragon Inst, Cambridge, MA 02139 USA. [Barouch, Dan H.] Harvard Univ, Cambridge, MA 02139 USA. [Deeks, Steven G.] Univ Calif San Francisco, San Francisco, CA 94110 USA. RP Barouch, DH (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Ctr Virol & Vaccine Res, Boston, MA 02215 USA. EM dbarouch@bidmc.harvard.edu; sdeeks@php.ucsf.edu FU NIH [AI078526, AI084794, AI095985, AI096040, AI096109, AI100663, OD011170]; Bill and Melinda Gates Foundation [OPP1033091, OPP1040741, OPP1083689]; Ragon Institute of MGH, MIT, and Harvard; Henry M. Jackson Foundation; American Foundation for AIDS Research FX The authors thank B. Walker, N. Michael, J. Kim, M. Robb, R. Geleziunas, M. McCune, R. Sekaly, N. Chomont, and S. Lewin for helpful discussions. The authors acknowledge support from the NIH [AI078526, AI084794, AI095985, AI096040, AI096109 (Delaney AIDS Research Enterprise), AI100663, and OD011170]; the Bill and Melinda Gates Foundation (OPP1033091, OPP1040741, and OPP1083689); the Ragon Institute of MGH, MIT, and Harvard; the Henry M. Jackson Foundation; and the American Foundation for AIDS Research. D. H. B. is a co-inventor on Ad26 vector, mosaic antigen, and Env immunogen patents. S. G. D. has served as an ad hoc consultant for Bristol-Myers Squib, GlaxoSmithKline, and Janssen on HIV cure-related activities. NR 95 TC 61 Z9 63 U1 1 U2 35 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD JUL 11 PY 2014 VL 345 IS 6193 BP 169 EP 174 DI 10.1126/science.1255512 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AL8SS UT WOS:000339409900041 PM 25013067 ER PT J AU Yu, M Bardia, A Aceto, N Bersani, F Madden, MW Donaldson, MC Desai, R Zhu, HL Comaills, V Zheng, ZL Wittner, BS Stojanov, P Brachtel, E Sgroi, D Kapur, R Shioda, T Ting, DT Ramaswamy, S Getz, G Iafrate, AJ Benes, C Toner, M Maheswaran, S Haber, DA AF Yu, Min Bardia, Aditya Aceto, Nicola Bersani, Francesca Madden, Marissa W. Donaldson, Maria C. Desai, Rushil Zhu, Huili Comaills, Valentine Zheng, Zongli Wittner, Ben S. Stojanov, Petar Brachtel, Elena Sgroi, Dennis Kapur, Ravi Shioda, Toshihiro Ting, David T. Ramaswamy, Sridhar Getz, Gad Iafrate, A. John Benes, Cyril Toner, Mehmet Maheswaran, Shyamala Haber, Daniel A. TI Ex vivo culture of circulating breast tumor cells for individualized testing of drug susceptibility SO SCIENCE LA English DT Article ID CANCER; INHIBITOR; IDENTIFICATION; MUTATIONS; DISCOVERY; FAMILY; POTENT; DOMAIN; ALPHA AB Circulating tumor cells (CTCs) are present at low concentrations in the peripheral blood of patients with solid tumors. It has been proposed that the isolation, ex vivo culture, and characterization of CTCs may provide an opportunity to noninvasively monitor the changing patterns of drug susceptibility in individual patients as their tumors acquire new mutations. In a proof-of-concept study, we established CTC cultures from six patients with estrogen receptor-positive breast cancer. Three of five CTC lines tested were tumorigenic in mice. Genome sequencing of the CTC lines revealed preexisting mutations in the PIK3CA gene and newly acquired mutations in the estrogen receptor gene (ESR1), PIK3CA gene, and fibroblast growth factor receptor gene (FGFR2), among others. Drug sensitivity testing of CTC lines with multiple mutations revealed potential new therapeutic targets. With optimization of CTC culture conditions, this strategy may help identify the best therapies for individual cancer patients over the course of their disease. C1 [Yu, Min; Bardia, Aditya; Aceto, Nicola; Bersani, Francesca; Madden, Marissa W.; Donaldson, Maria C.; Desai, Rushil; Zhu, Huili; Comaills, Valentine; Zheng, Zongli; Wittner, Ben S.; Sgroi, Dennis; Shioda, Toshihiro; Ting, David T.; Ramaswamy, Sridhar; Getz, Gad; Iafrate, A. John; Benes, Cyril; Maheswaran, Shyamala; Haber, Daniel A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. [Yu, Min; Haber, Daniel A.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Bardia, Aditya; Shioda, Toshihiro; Ting, David T.; Ramaswamy, Sridhar; Benes, Cyril; Haber, Daniel A.] Harvard Univ, Sch Med, Dept Med, Charlestown, MA 02129 USA. [Zheng, Zongli; Brachtel, Elena; Sgroi, Dennis; Getz, Gad; Iafrate, A. John] Harvard Univ, Sch Med, Dept Pathol, Charlestown, MA 02129 USA. [Zheng, Zongli] Karolinska Insitutet, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Stojanov, Petar; Getz, Gad] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. [Kapur, Ravi; Toner, Mehmet] Harvard Univ, Sch Med, Ctr Bioengn Med, Charlestown, MA 02129 USA. [Toner, Mehmet; Maheswaran, Shyamala] Harvard Univ, Sch Med, Dept Surg, Charlestown, MA 02129 USA. RP Maheswaran, S (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. EM maheswaran@helix.mgh.harvard.edu; haber@helix.mgh.harvard.edu RI zheng, zongli/B-2917-2011 OI zheng, zongli/0000-0003-4849-4903 FU Breast Cancer Research Foundation; Stand Up to Cancer; Wellcome TrustNational Foundation for Cancer Research; NIH [CA129933]; NIBIB [EB008047]; Susan G. Komen for the Cure [KG09042]; National Cancer Institute-MGH Proton Federal Share Program; MGH-Johnson and Johnson Center for Excellence in CTCs; Howard Hughes Medical Institute FX We are grateful to all the patients who participated in this study. We thank Dr. Lecia Sequist for coordinating the clinical studies, A. McGovern, C. Hart, and the Massachusetts General Hospital (MGH) clinical research coordinators P. Spuhler, A. Shah, J. Ciciliano, and V. Pai for bioengineering technical support; R. Milano, K. Lynch, H. Robinson, and M. Liebers for technical support; L. Collins (Beth Israel Deaconess Medical Center) for providing pathological specimens; and L. Libby for mouse studies. N. Aceto is a fellow of the Human Frontiers Science Program, the Swiss National Science Foundation, and the Swiss Foundation for Grants in Biology and Medicine. This work was supported by grants from the Breast Cancer Research Foundation (D. A. H), Stand Up to Cancer (D. A. H., M. T., S. M.), the Wellcome Trust (D. A. H., C. B.), National Foundation for Cancer Research (D. A. H.), NIH CA129933 (D. A. H.), NIBIB EB008047 (M. T., D. A. H.), Susan G. Komen for the Cure KG09042 (S. M.), National Cancer Institute-MGH Proton Federal Share Program (S. M.), the MGH-Johnson and Johnson Center for Excellence in CTCs (M. T., S. M.), and the Howard Hughes Medical Institute (M.Y., D. A. H.). A. J. I. holds equity in, and is a paid consultant for, Enzymatics, Inc. M. T., D. A. H., and the Massachusetts General Hospital have filed for patent protection for the CTC-iChip technology. RNA-Seq reads have been deposited into Gene Expression Omnibus: uncultured CTCs (accession no. GSE51827); the six cultured CTC lines (accession no. GSE55807). NR 26 TC 203 Z9 217 U1 20 U2 164 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD JUL 11 PY 2014 VL 345 IS 6193 BP 216 EP 220 DI 10.1126/science.1253533 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AL8SS UT WOS:000339409900054 PM 25013076 ER PT J AU Carlson, JM Schaefer, M Monaco, DC Batorsky, R Claiborne, DT Prince, J Deymier, MJ Ende, ZS Klatt, NR DeZiel, CE Lin, TH Peng, J Seese, AM Shapiro, R Frater, J Ndung'u, T Tang, JM Goepfert, P Gilmour, J Price, MA Kilembe, W Heckerman, D Goulder, PJR Allen, TM Allen, S Hunter, E AF Carlson, Jonathan M. Schaefer, Malinda Monaco, Daniela C. Batorsky, Rebecca Claiborne, Daniel T. Prince, Jessica Deymier, Martin J. Ende, Zachary S. Klatt, Nichole R. DeZiel, Charles E. Lin, Tien-Ho Peng, Jian Seese, Aaron M. Shapiro, Roger Frater, John Ndung'u, Thumbi Tang, Jianming Goepfert, Paul Gilmour, Jill Price, Matt A. Kilembe, William Heckerman, David Goulder, Philip J. R. Allen, Todd M. Allen, Susan Hunter, Eric TI Selection bias at the heterosexual HIV-1 transmission bottleneck SO SCIENCE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; CLASS-I ALLELES; REPLICATION CAPACITY; DISCORDANT COUPLES; ESCAPE MUTATIONS; VIRAL-LOAD; SEXUAL TRANSMISSION; CHRONIC INFECTION; IMMUNE CONTROL; SH3 DOMAIN AB Heterosexual transmission of HIV-1 typically results in one genetic variant establishing systemic infection. We compared, for 137 linked transmission pairs, the amino acid sequences encoded by non-envelope genes of viruses in both partners and demonstrate a selection bias for transmission of residues that are predicted to confer increased in vivo fitness on viruses in the newly infected, immunologically naive recipient. Although tempered by transmission risk factors, such as donor viral load, genital inflammation, and recipient gender, this selection bias provides an overall transmission advantage for viral quasispecies that are dominated by viruses with high in vivo fitness. Thus, preventative or therapeutic approaches that even marginally reduce viral fitness may lower the overall transmission rates and offer long-term benefits even upon successful transmission. C1 [Carlson, Jonathan M.; DeZiel, Charles E.; Lin, Tien-Ho; Peng, Jian] Microsoft Res, Redmond, WA 98052 USA. [Schaefer, Malinda; Monaco, Daniela C.; Claiborne, Daniel T.; Prince, Jessica; Deymier, Martin J.; Ende, Zachary S.; Klatt, Nichole R.; Hunter, Eric] Emory Univ, Yerkes Natl Primate Res Ctr, Emory Vaccine Ctr, Atlanta, GA 30329 USA. [Batorsky, Rebecca; Seese, Aaron M.; Ndung'u, Thumbi; Allen, Todd M.] Ragon Inst Massachusetts Gen Hosp Massachusetts I, Cambridge, MA 02114 USA. [Shapiro, Roger] Beth Israel Deaconess Med Ctr, Div Infect Dis, Boston, MA 02215 USA. [Frater, John] Univ Oxford, Nuffield Dept Clin Med, Oxford OX1 7BN, England. [Frater, John] Oxford Biomed Res Ctr, Natl Inst Hlth Res, Oxford OX3 7LE, England. [Frater, John] Univ Oxford, Oxford Martin Sch, Oxford OX1 3BD, England. [Ndung'u, Thumbi; Goulder, Philip J. R.] Univ KwaZulu Natal, Nelson R Mandela Sch Med, Doris Duke Med Res Inst, HIV Pathogenesis Programme, ZA-4013 Durban, South Africa. [Ndung'u, Thumbi] Max Planck Inst Infekt Biol, D-10117 Berlin, Germany. [Tang, Jianming; Goepfert, Paul] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Gilmour, Jill] Int AIDS Vaccine Initiat, London SW10 9NH, England. [Gilmour, Jill] Univ London Imperial Coll Sci Technol & Med, London SW10 9NH, England. [Price, Matt A.] Int AIDS Vaccine Initiat, San Francisco, CA 94105 USA. [Price, Matt A.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94105 USA. [Kilembe, William; Allen, Susan; Hunter, Eric] Zambia Emory HIV Res Project, Rwanda Zambia HIV Res Grp, Lusaka, Zambia. [Heckerman, David] Microsoft Res, Los Angeles, CA USA. [Goulder, Philip J. R.] Univ Oxford, Dept Paediat, Oxford OX1 3SY, England. [Allen, Susan; Hunter, Eric] Emory Univ, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. [Allen, Susan] Emory Univ, Rollins Sch Publ Hlth, Dept Global Hlth, Atlanta, GA 30322 USA. RP Carlson, JM (reprint author), Univ Washington, Washington Natl Primate Res Ctr, Dept Pharmaceut, Seattle, WA 98121 USA. EM carlson@microsoft.com; ehunte4@emory.edu RI Allen, Todd/F-5473-2011; OI Tang, Jianming/0000-0003-0137-7486 FU International AIDS Vaccine Initiative; American people through the U.S. Agency for International Development (USAID); Virology Core at the Emory Center for AIDS Research [P30 AI050409]; Yerkes National Primate Research Center through the National Center for Research Resources [2P51RR000165-51, P51RR165]; Office of Research Infrastructure Programs/OD [P51OD11132]; NIAID [P01-AI074415, U01 AI 66454]; Multidisciplinary AIDS Training Grant NIH [T32-AI007387]; Action Cycling Fellowships; South African Department of Science and Technology; National Research Foundation through the South Africa Research Chairs Initiative; Howard Hughes Medical Institute; Victor Daitz Foundation; [R01 AI64060]; [R37 AI51231] FX We thank all the volunteers in Zambia who participated in this study and all the staff at the Zambia Emory HIV Research Project in Lusaka who made this study possible. We would like to thank J. Allen and M. Hurlston for technical assistance and sample management; P. Farmer, Ph.D., for database design and management; and I. Brill, K. Wall, X. Li, C. Lippert, N. Fusi, J. Listgarten, and Z. Brumme for helpful discussions. This study was funded by R01 AI64060 and R37 AI51231 (E. H.) and the International AIDS Vaccine Initiative (to S. A.), and made possible in part by the support of the American people through the U.S. Agency for International Development (USAID). The contents are the responsibility of the study authors and do not necessarily reflect the views of USAID or the U.S. government. This work was also supported, in part, by the Virology Core at the Emory Center for AIDS Research (grant P30 AI050409); the Yerkes National Primate Research Center base grant (2P51RR000165-51) through the National Center for Research Resources P51RR165 and by the Office of Research Infrastructure Programs/OD P51OD11132; NIAID grants P01-AI074415 (T. M. A.) and U01 AI 66454 (R. S.); and Multidisciplinary AIDS Training Grant NIH T32-AI007387 (R. B.). J. P., D. T. C., and M. S. were supported in part by Action Cycling Fellowships. T. N. was supported by the International AIDS Vaccine Initiative, the South African Department of Science and Technology and the National Research Foundation through the South Africa Research Chairs Initiative, by an International Early Career Scientist award from the Howard Hughes Medical Institute, and by the Victor Daitz Foundation. E. H. is a Georgia Eminent Scholar. All viral sequences not previously published have been submitted to GenBank-accession numbers JN014076-JN014465, JQ219842, and KM048382-KM050767. The data reported in this paper are tabulated in the supplementary online material. NR 72 TC 65 Z9 66 U1 4 U2 37 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD JUL 11 PY 2014 VL 345 IS 6193 AR 1254031 DI 10.1126/science.1254031 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AL8SS UT WOS:000339409900043 PM 25013080 ER PT J AU Svoboda, O Stachura, DL Machonova, O Pajer, P Brynda, J Zon, LI Traver, D Bartunek, P AF Svoboda, Ondrej Stachura, David L. Machonova, Olga Pajer, Petr Brynda, Jiri Zon, Leonard I. Traver, David Bartunek, Petr TI Dissection of vertebrate hematopoiesis using zebrafish thrombopoietin SO BLOOD LA English DT Article ID TRANSCRIPTION FACTOR GATA-1; C-MPL; IN-VITRO; ERYTHROID PROGENITORS; DEFINITIVE HEMATOPOIESIS; PLATELET PRODUCTION; SELF-RENEWAL; SWISS-MODEL; STEM-CELLS; RECEPTOR AB In nonmammalian vertebrates, the functional units of hemostasis are thrombocytes. Thrombocytes are thought to arise from bipotent thrombocytic/erythroid progenitors (TEPs). TEPs have been experimentally demonstrated in avian models of hematopoiesis, and mammals possess functional equivalents known as megakaryocyte/erythroid progenitors (MEPs). However, the presence of TEPs in teleosts has only been speculated. To identifyandprospectively isolate TEPs, we identified, cloned, and generated recombinant zebrafish thrombopoietin (Tpo). TpomRNA expanded itga2b:GFP(+) (cd41:GFP(+)) thrombocytes as well as hematopoietic stem and progenitor cells (HSPCs) in the zebrafish embryo. Utilizing Tpo in clonal methylcellulose assays, we describe for the first time the prospective isolation and characterization of TEPs from transgenic zebrafish. Combinatorial use of zebrafish Tpo, erythropoietin, and granulocyte colony stimulating factor (Gcsf) allowed the investigation of HSPCs responsible for erythro-, myelo-, and thrombopoietic differentiation. Utilizing these assays allowed the visualization and differentiation of hematopoietic progenitors ex vivo in real-time with time-lapse and high-throughput microscopy, allowing analyses of their clonogenic and proliferative capacity. These studies indicate that the functional role of Tpo in the differentiation of thrombocytes from HSPCs is well conserved among vertebrate organisms, positing the zebrafish as an excellent model to investigate diseases caused by dysregulated erythro- and thrombo-poietic differentiation. C1 [Svoboda, Ondrej; Machonova, Olga; Pajer, Petr; Brynda, Jiri; Bartunek, Petr] Acad Sci Czech Republic, Inst Mol Genet, Vvi, Dept Cell Differentiat, Prague, Czech Republic. [Stachura, David L.; Traver, David] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA. [Stachura, David L.; Traver, David] Univ Calif San Diego, Sect Cell & Dev Biol, La Jolla, CA 92093 USA. [Zon, Leonard I.] Harvard Univ, Childrens Hosp, Sch Med, Stem Cell Program, Boston, MA 02115 USA. [Zon, Leonard I.] Harvard Univ, Childrens Hosp, Sch Med, Div Hematol Oncol, Boston, MA 02115 USA. [Zon, Leonard I.] Harvard Univ, Sch Med, Howard Hughes Med Inst, Dana Farber Canc Inst,Harvard Stem Cell Inst, Boston, MA 02115 USA. RP Bartunek, P (reprint author), Inst Mol Genet ASCR Vvi, Dept Cell Differentiat, Prague 14220 4, Czech Republic. EM bartunek@img.cas.cz RI Bartunek, Petr/J-3897-2014; Brynda, Jiri/G-2760-2014 OI Bartunek, Petr/0000-0002-6202-7650; FU National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases [K01-DK087814-01A1, R01-DK074482]; Grand Agency of the Charles University [151-43-253108]; Genetic Alliance Resource Partnership [305/10/0953]; Fulbright Scholars award FX Supported by National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases K01-DK087814-01A1 (D.L.S.) and R01-DK074482 (D. T.), Grand Agency of the Charles University 151-43-253108 (O.S.), Genetic Alliance Resource Partnership 305/10/0953 projects, and Fulbright Scholars award (P.B.). NR 49 TC 9 Z9 10 U1 3 U2 12 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUL 10 PY 2014 VL 124 IS 2 BP 220 EP 228 DI 10.1182/blood-2014-03-564682 PG 9 WC Hematology SC Hematology GA AQ2LV UT WOS:000342618600015 PM 24869937 ER PT J AU Hung, CM Calejman, CM Sanchez-Gurmaches, J Li, HW Clish, CB Hettmer, S Wagers, AJ Guertin, DA AF Hung, Chien-Min Calejman, Camila Martinez Sanchez-Gurmaches, Joan Li, Huawei Clish, Clary B. Hettmer, Simone Wagers, Amy J. Guertin, David A. TI Rictor/mTORC2 Loss in the Myf5 Lineage Reprograms Brown Fat Metabolism and Protects Mice against Obesity and Metabolic Disease SO CELL REPORTS LA English DT Article ID MTOR COMPLEX 2; INDUCED INSULIN-RESISTANCE; ADIPOSE-TISSUE; ADIPOCYTE DIFFERENTIATION; UP-REGULATION; PTEN LOSS; GENE; GLUCOSE; RICTOR; PHOSPHORYLATION AB The in vivo functions of mechanistic target of rapamycin complex 2 (mTORC2) and the signaling mechanisms that control brown adipose tissue (BAT) fuel utilization and activity are not well understood. Here, by conditionally deleting Rictor in the Myf5 lineage, we provide in vivo evidence that mTORC2 is dispensable for skeletal muscle development and regeneration but essential for BAT growth. Furthermore, deleting Rictor in Myf5 precursors shifts BAT metabolism to a more oxidative and less lipogenic state and protects mice from obesity and metabolic disease at thermoneutrality. We additionally find that Rictor is required for brown adipocyte differentiation in vitro and that the mechanism specifically requires AKT1 hydrophobic motif phosphorylation but is independent of pan-AKT signaling and is rescued with BMP7. Our findings provide insights into the signaling circuitry that regulates brown adipocytes and could have important implications for developing therapies aimed at increasing energy expenditure as a means to combat human obesity. C1 [Hung, Chien-Min; Calejman, Camila Martinez; Sanchez-Gurmaches, Joan; Li, Huawei; Guertin, David A.] Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA 01605 USA. [Clish, Clary B.] Broad Inst, Cambridge, MA 02142 USA. [Hettmer, Simone; Wagers, Amy J.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Hettmer, Simone; Wagers, Amy J.] Harvard Stem Cell Inst, Dept Stem Cell & Regenerat Biol, Cambridge, MA 01238 USA. [Hettmer, Simone; Wagers, Amy J.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Wagers, Amy J.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02155 USA. [Hettmer, Simone] Childrens Hosp, Div Pediat Hematol Oncol, Medford, MA 02155 USA. RP Guertin, DA (reprint author), Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA 01605 USA. EM david.guertin@umassmed.edu OI Sanchez Gurmaches, Juan/0000-0002-1902-7129 FU NIH [R00CA129613, R01DK094004]; American Diabetes Association [ADA113BS-066]; Pew Charitable Trusts; Charles Hood Foundation FX This work was supported by grants from the NIH (R00CA129613 and R01DK094004), the American Diabetes Association (ADA113BS-066), the Pew Charitable Trusts, and the Charles Hood Foundation (to D. A. G.). We thank Yuefeng Tang, Xiaohao Yao, and Christine Powers for technical assistance, Morris Birnbaum for Akt floxed mice, and Marcus Cooper for the PPAR gamma 2 construct. Metabolic cage studies were performed in the UMass Mouse Phenotype Center (DK09300). NR 51 TC 19 Z9 20 U1 1 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD JUL 10 PY 2014 VL 8 IS 1 BP 256 EP 271 DI 10.1016/j.celrep.2014.06.007 PG 16 WC Cell Biology SC Cell Biology GA AO5RM UT WOS:000341403000024 PM 25001283 ER PT J AU Schwartz, S Mumbach, MR Jovanovic, M Wang, T Maciag, K Bushkin, GG Mertins, P Ter-Ovanesyan, D Habib, N Cacchiarelli, D Sanjana, NE Freinkman, E Pacold, ME Satija, R Mikkelsen, TS Hacohen, N Zhang, F Carr, SA Lander, ES Regev, A AF Schwartz, Schraga Mumbach, Maxwell R. Jovanovic, Marko Wang, Tim Maciag, Karolina Bushkin, G. Guy Mertins, Philipp Ter-Ovanesyan, Dmitry Habib, Naomi Cacchiarelli, Davide Sanjana, Neville E. Freinkman, Elizaveta Pacold, Michael E. Satija, Rahul Mikkelsen, Tarjei S. Hacohen, Nir Zhang, Feng Carr, Steven A. Lander, Eric S. Regev, Aviv TI Perturbation of m6A Writers Reveals Two Distinct Classes of mRNA Methylation at Internal and 5 ' Sites SO CELL REPORTS LA English DT Article ID TUMOR 1-ASSOCIATING PROTEIN; DROSOPHILA-MELANOGASTER; GENE-EXPRESSION; COMPLEX; METHYLTRANSFERASE; DATABASE; SUBUNIT; GENOME; N-6-METHYLADENOSINE; IDENTIFICATION AB N6-methyladenosine (m6A) is a common modification of mRNA with potential roles in fine-tuning the RNA life cycle. Here, we identify a dense network of proteins interacting with METTL3, a component of the methyltransferase complex, and show that three of them (WTAP, METTL14, and KIAA1429) are required for methylation. Monitoring m6A levels upon WTAP depletion allowed the definition of accurate and near single-nucleotide resolution methylation maps and their classification into WTAP-dependent and -independent sites. WTAP-dependent sites are located at internal positions in transcripts, topologically static across a variety of systems we surveyed, and inversely correlated with mRNA stability, consistent with a role in establishing "basal' degradation rates. WTAP-independent sites form at the first transcribed base as part of the cap structure and are present at thousands of sites, forming a previously unappreciated layer of transcriptome complexity. Our data shed light on the proteomic and transcriptional underpinnings of this RNA modification. C1 [Schwartz, Schraga; Mumbach, Maxwell R.; Jovanovic, Marko; Wang, Tim; Maciag, Karolina; Mertins, Philipp; Ter-Ovanesyan, Dmitry; Habib, Naomi; Cacchiarelli, Davide; Sanjana, Neville E.; Satija, Rahul; Mikkelsen, Tarjei S.; Hacohen, Nir; Zhang, Feng; Carr, Steven A.; Lander, Eric S.; Regev, Aviv] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Wang, Tim; Bushkin, G. Guy; Freinkman, Elizaveta; Pacold, Michael E.] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Wang, Tim; Lander, Eric S.; Regev, Aviv] MIT, Dept Biol, Cambridge, MA 02139 USA. [Maciag, Karolina] Harvard Univ, Div Med Sci, Grad Program Immunol, Sch Med, Boston, MA 02115 USA. [Cacchiarelli, Davide; Mikkelsen, Tarjei S.] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Cacchiarelli, Davide; Mikkelsen, Tarjei S.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Pacold, Michael E.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02215 USA. [Hacohen, Nir] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Charlestown, MA 02129 USA. [Zhang, Feng] MIT, McGovern Inst Brain Res, Cambridge, MA 02139 USA. [Zhang, Feng] MIT, Dept Brain & Cognit Sci & Biol Engn, Cambridge, MA 02139 USA. [Lander, Eric S.] Harvard Univ, Dept Syst Biol, Sch Med, Boston, MA 02114 USA. [Regev, Aviv] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Lander, ES (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. EM lander@broadinstitute.org; aregev@broad.mit.edu OI , /0000-0003-0803-4312; Sanjana, Neville/0000-0002-1504-0027; Schwartz, Schraga/0000-0002-3671-9709 FU NHGRI CEGS [P50 HG006193, U54 HG003067]; Broad Institute; NIH; HHMI; European Molecular Biology Organization fellowship; Human Frontier Science Program fellowships; Swiss National Science Foundation for advanced researchers (SNF); Marie Sklodowska-Curie IOF FX This work was supported by NHGRI CEGS P50 HG006193 (A. R.), U54 HG003067 (E. S. L), and Broad Institute Funds. A. R. was supported by an NIH Pioneer Award and HHMI. S. S. was supported by a European Molecular Biology Organization fellowship, and S. S. and D. C. were supported by Human Frontier Science Program fellowships. M.J. was supported by fellowships of the Swiss National Science Foundation for advanced researchers (SNF) and the Marie Sklodowska-Curie IOF. NR 33 TC 81 Z9 87 U1 10 U2 59 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD JUL 10 PY 2014 VL 8 IS 1 BP 284 EP 296 DI 10.1016/j.celrep.2014.05.048 PG 13 WC Cell Biology SC Cell Biology GA AO5RM UT WOS:000341403000026 PM 24981863 ER PT J AU Ma, LN Cui, P Zhu, J Zhang, ZH Zhang, Z AF Ma, Lina Cui, Peng Zhu, Jiang Zhang, Zhihua Zhang, Zhang TI Translational selection in human: more pronounced in housekeeping genes SO BIOLOGY DIRECT LA English DT Article DE Translational selection; Codon usage bias; Expression regulation; Housekeeping gene; Tissue-specific gene ID SYNONYMOUS CODON USAGE; RNA SECONDARY STRUCTURE; ESCHERICHIA-COLI; HUMAN GENOMES; BIAS; EXPRESSION; TRANSCRIPTION; DRIFT; VERTEBRATES; EFFICIENCY AB Background: Translational selection is a ubiquitous and significant mechanism to regulate protein expression in prokaryotes and unicellular eukaryotes. Recent evidence has shown that translational selection is weakly operative in highly expressed genes in human and other vertebrates. However, it remains unclear whether translational selection acts differentially on human genes depending on their expression patterns. Results: Here we report that human housekeeping (HK) genes that are strictly defined as genes that are expressed ubiquitously and consistently in most or all tissues, are under stronger translational selection. Conclusions: These observations clearly show that translational selection is also closely associated with expression pattern. Our results suggest that human HK genes are more efficiently and/or accurately translated into proteins, which will inevitably open up a new understanding of HK genes and the regulation of gene expression. C1 [Ma, Lina; Zhang, Zhihua; Zhang, Zhang] Chinese Acad Sci, CAS Key Lab Genome Sci & Informat, Beijing Inst Genom, Beijing 100101, Peoples R China. [Cui, Peng] King Abdullah Univ Sci & Technol, Div Chem & Life Sci & Engn, Jeddah 239556900, Thuwal, Saudi Arabia. [Zhu, Jiang] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Zhu, Jiang] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Zhang, Z (reprint author), Chinese Acad Sci, CAS Key Lab Genome Sci & Informat, Beijing Inst Genom, 1 Beichen West Rd, Beijing 100101, Peoples R China. EM zhangzhang@big.ac.cn FU National Natural Science Foundation of China [31200978]; "100-Talent Program" of the Chinese Academy of Sciences [Y1SLXb1365]; National Programs for High Technology Research and Development (863 Program) [2012AA020409]; Ministry of Science and Technology of the People's Republic of China FX We thank Dr. Araxi Urrutia for providing constructive comments on this manuscript. We also thank Drs. Jun Yu, Hao Wu, and Gang Wu for their valuable discussions. This work was supported by grants from National Natural Science Foundation of China (Grant No. 31200978 to LM), the "100-Talent Program" of the Chinese Academy of Sciences (Grant No. Y1SLXb1365 to ZhaZ), and National Programs for High Technology Research and Development (863 Program; Grant No. 2012AA020409 to ZhaZ), the Ministry of Science and Technology of the People's Republic of China. NR 47 TC 8 Z9 9 U1 0 U2 13 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6150 J9 BIOL DIRECT JI Biol. Direct PD JUL 10 PY 2014 VL 9 AR 17 DI 10.1186/1745-6150-9-17 PG 11 WC Biology SC Life Sciences & Biomedicine - Other Topics GA AL3GX UT WOS:000339016000002 PM 25011537 ER PT J AU Agam, Y Vangel, M Roffman, JL Gallagher, PJ Chaponis, J Haddad, S Goff, DC Greenberg, JL Wilhelm, S Smoller, JW Manoach, DS AF Agam, Yigal Vangel, Mark Roffman, Joshua L. Gallagher, Patience J. Chaponis, Jonathan Haddad, Stephen Goff, Donald C. Greenberg, Jennifer L. Wilhelm, Sabine Smoller, Jordan W. Manoach, Dara S. TI Dissociable Genetic Contributions to Error Processing: A Multimodal Neuroimaging Study SO PLOS ONE LA English DT Article ID EVENT-RELATED FMRI; OBSESSIVE COMPULSIVE SCALE; DOPAMINE-D4 RECEPTOR GENE; SURFACE-BASED ANALYSIS; HUMAN CEREBRAL-CORTEX; METHYLENETETRAHYDROFOLATE REDUCTASE; ANTERIOR CINGULATE; PARKINSONS-DISEASE; HEALTHY-VOLUNTEERS; PREFRONTAL CORTEX AB Background: Neuroimaging studies reliably identify two markers of error commission: the error-related negativity (ERN), an event-related potential, and functional MRI activation of the dorsal anterior cingulate cortex (dACC). While theorized to reflect the same neural process, recent evidence suggests that the ERN arises from the posterior cingulate cortex not the dACC. Here, we tested the hypothesis that these two error markers also have different genetic mediation. Methods: We measured both error markers in a sample of 92 comprised of healthy individuals and those with diagnoses of schizophrenia, obsessive-compulsive disorder or autism spectrum disorder. Participants performed the same task during functional MRI and simultaneously acquired magnetoencephalography and electroencephalography. We examined the mediation of the error markers by two single nucleotide polymorphisms: dopamine D4 receptor (DRD4) C-521T (rs1800955), which has been associated with the ERN and methylenetetrahydrofolate reductase (MTHFR) C677T (rs1801133), which has been associated with error-related dACC activation. We then compared the effects of each polymorphism on the two error markers modeled as a bivariate response. Results: We replicated our previous report of a posterior cingulate source of the ERN in healthy participants in the schizophrenia and obsessive-compulsive disorder groups. The effect of genotype on error markers did not differ significantly by diagnostic group. DRD4 C-521T allele load had a significant linear effect on ERN amplitude, but not on dACC activation, and this difference was significant. MTHFR C677T allele load had a significant linear effect on dACC activation but not ERN amplitude, but the difference in effects on the two error markers was not significant. Conclusions: DRD4 C-521T, but not MTHFR C677T, had a significant differential effect on two canonical error markers. Together with the anatomical dissociation between the ERN and error-related dACC activation, these findings suggest that these error markers have different neural and genetic mediation. C1 [Agam, Yigal; Roffman, Joshua L.; Goff, Donald C.; Greenberg, Jennifer L.; Wilhelm, Sabine; Smoller, Jordan W.; Manoach, Dara S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Agam, Yigal; Vangel, Mark; Manoach, Dara S.] Harvard Univ, Sch Med, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Gallagher, Patience J.; Chaponis, Jonathan; Haddad, Stephen; Smoller, Jordan W.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA USA. RP Manoach, DS (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA 02115 USA. EM dara@nmr.mgh.harvard.edu FU NIH [F32 MH088081, K24MH094614, R01 MH67720] FX This work was supported in part by NIH grants F32 MH088081 (YA); K24MH094614 (JWS); and R01 MH67720 (DSM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 74 TC 9 Z9 9 U1 1 U2 15 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 10 PY 2014 VL 9 IS 7 AR e101784 DI 10.1371/journal.pone.0101784 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK9RG UT WOS:000338763800038 PM 25010186 ER PT J AU Jim, B Mehta, S Qipo, A Kim, K Cohen, HW Moore, RM He, JC Sharma, S AF Jim, Belinda Mehta, Swati Qipo, Andi Kim, Kwanghee Cohen, Hillel W. Moore, Robert M. He, John C. Sharma, Shuchita TI A Comparison of Podocyturia, Albuminuria and Nephrinuria in Predicting the Development of Preeclampsia: A Prospective Study SO PLOS ONE LA English DT Article ID ANTIANGIOGENIC FACTORS; ANGIOGENIC FACTORS; URINARY-EXCRETION; PROTEINURIA; BIOMARKERS; PREGNANCY; HYPERTENSION; DISEASE; WOMEN AB Preeclampsia, a hypertensive multisystem disease that complicates 5-8% of all pregnancy, is a major cause for maternal and fetal mortality and morbidity. The disease is associated with increased spontaneous and evoked preterm birth and remote cardio-renal disorders in the mother and offspring. Thus the ability to predict the disease should lead to earlier care and decreased morbidity. This has led to fervent attempts to identify early predictive biomarkers and research endeavors that have expanded as we learn more regarding possible causes of the disease. As preeclampsia is associated with specific renal pathology including podocyte injury, early urinary podocyte (podocyturia), or the podocyte specific proteinuria nephrin in the urine (nephrinuria), as well as the more easily measured urinary albumin (albuminuria), have all been suggested as predictive markers. We performed a prospective study recruiting 91 pregnant women (78 of whom were high risk) and studied the predictive ability of these three urinary biomarkers. The subjects were recruited between 15-38 weeks of gestation. Fourteen patients, all in the high-risk obstetric group, developed preeclampsia. The levels of podocyturia, nephrinuria, and albuminuria were variably higher in the high-risk pregnant patients who developed preeclampsia. The sensitivities and specificities for podocyturia were 70% and 43%, for albuminuria were 36% and 96%, and for nephrinuria were 57% and 58%, respectively. Also, abnormal nephrinuria (69%) and podocyturia (38%) were detected in low risk women who had uncomplicated gestations; none of these women exhibited albuminuria. In our study, none of the three urinary markers achieved the minimum predictive values required for clinical testing. The lack of excessive albuminuria, however, may indicate a preeclampsia-free gestation. Given a discrepant literature, further studies with larger sample size should be considered. C1 [Jim, Belinda; Qipo, Andi] Albert Einstein Coll Med, Jacobi Med Ctr, Dept Nephrol Med, Bronx, NY 10467 USA. [Mehta, Swati; He, John C.] James J Peters VA Med Ctr, Dept Nephrol Med, Bronx, NY USA. [Kim, Kwanghee] Providence Alaska Med Ctr, Anchorage, AK USA. [Cohen, Hillel W.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Moore, Robert M.] Albert Einstein Coll Med, Dept Obstet & Gynecol, Jacobi Med Ctr, Bronx, NY 10467 USA. [He, John C.; Sharma, Shuchita] Mt Sinai Sch Med, Dept Nephrol Med, New York, NY USA. RP Jim, B (reprint author), Albert Einstein Coll Med, Jacobi Med Ctr, Dept Nephrol Med, Bronx, NY 10467 USA. EM belindajim286@gmail.com OI Cohen, Hillel/0000-0002-4524-0898 FU CTSA from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH) [1 UL1 TR001073-01, 1 TL1 TR001072-01, 1 KL2 TR001071-01] FX This publication was supported in part by the CTSA Grant 1 UL1 TR001073-01, 1 TL1 TR001072-01, 1 KL2 TR001071-01 from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 22 TC 7 Z9 8 U1 1 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 10 PY 2014 VL 9 IS 7 AR e101445 DI 10.1371/journal.pone.0101445 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK9RG UT WOS:000338763800024 PM 25010746 ER PT J AU Palmyre, A Lee, J Ryklin, G Camarata, T Selig, MK Duchemin, AL Nowak, P Arnaout, MA Drummond, IA Vasilyev, A AF Palmyre, Aurelien Lee, Jeongeun Ryklin, Gennadiy Camarata, Troy Selig, Martin K. Duchemin, Anne-Laure Nowak, Paul Arnaout, M. Amin Drummond, Iain A. Vasilyev, Aleksandr TI Collective Epithelial Migration Drives Kidney Repair after Acute Injury SO PLOS ONE LA English DT Article ID ACUTE-RENAL-FAILURE; ACUTE TUBULAR-NECROSIS; POSTISCHEMIC KIDNEY; CELL-MIGRATION; ZEBRAFISH; MORPHOGENESIS; DISEASE; REGENERATION; NEPHRON; GENES AB Acute kidney injury (AKI) is a common and significant medical problem. Despite the kidney's remarkable regenerative capacity, the mortality rate for the AKI patients is high. Thus, there remains a need to better understand the cellular mechanisms of nephron repair in order to develop new strategies that would enhance the intrinsic ability of kidney tissue to regenerate. Here, using a novel, laser ablation-based, zebrafish model of AKI, we show that collective migration of kidney epithelial cells is a primary early response to acute injury. We also show that cell proliferation is a late response of regenerating kidney epithelia that follows cell migration during kidney repair. We propose a computational model that predicts this temporal relationship and suggests that cell stretch is a mechanical link between migration and proliferation, and present experimental evidence in support of this hypothesis. Overall, this study advances our understanding of kidney repair mechanisms by highlighting a primary role for collective cell migration, laying a foundation for new approaches to treatment of AKI. C1 [Palmyre, Aurelien; Lee, Jeongeun; Camarata, Troy; Duchemin, Anne-Laure; Arnaout, M. Amin; Drummond, Iain A.; Vasilyev, Aleksandr] Massachusetts Gen Hosp, Dept Med, Div Nephrol, Boston, MA 02114 USA. [Selig, Martin K.; Vasilyev, Aleksandr] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Lee, Jeongeun; Ryklin, Gennadiy; Nowak, Paul; Vasilyev, Aleksandr] NYIT COM, Dept Biomed Sci, Old Westbury, NY USA. [Arnaout, M. Amin] Harvard Univ, Sch Med, Dept Dev & Regenerat Biol, Boston, MA USA. [Drummond, Iain A.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. RP Vasilyev, A (reprint author), Massachusetts Gen Hosp, Dept Med, Div Nephrol, Boston, MA 02114 USA. EM avasilye@nyit.edu OI Duchemin, Anne-Laure/0000-0002-2897-0821 FU HSCI Pilot Grant [K08DK082782, R03DK097443]; [DK053093]; [DK071041]; [DK070263]; [DK088327]; [DK48549]; [DK007540] FX K08DK082782, R03DK097443, HSCI Pilot Grant (A. V.); DK053093, DK071041, DK070263 (I. A. D.), and DK088327, DK48549 and DK007540 (M. A. A.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 35 TC 9 Z9 9 U1 2 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 10 PY 2014 VL 9 IS 7 AR e101304 DI 10.1371/journal.pone.0101304 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK9RG UT WOS:000338763800019 PM 25010471 ER PT J AU Rendleman, J Antipin, Y Reva, B Adaniel, C Przybylo, JA Dutra-Clarke, A Hansen, N Heguy, A Huberman, K Borsu, L Paltiel, O Ben-Yehuda, D Brown, JR Freedman, AS Sander, C Zelenetz, A Klein, RJ Shao, YZ Lacher, M Vijai, J Offit, K Kirchhoff, T AF Rendleman, Justin Antipin, Yevgeniy Reva, Boris Adaniel, Christina Przybylo, Jennifer A. Dutra-Clarke, Ana Hansen, Nichole Heguy, Adriana Huberman, Kety Borsu, Laetitia Paltiel, Ora Ben-Yehuda, Dina Brown, Jennifer R. Freedman, Arnold S. Sander, Chris Zelenetz, Andrew Klein, Robert J. Shao, Yongzhao Lacher, Mortimer Vijai, Joseph Offit, Kenneth Kirchhoff, Tomas TI Genetic Variation in DNA Repair Pathways and Risk of Non-Hodgkin's Lymphoma SO PLOS ONE LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; GENOME-WIDE ASSOCIATION; B-CELL LYMPHOMA; TELANGIECTASIA-MUTATED GENE; DOUBLE-STRAND BREAKS; FOLLICULAR LYMPHOMA; ATM MUTATIONS; CANCER SUSCEPTIBILITY; XRCC1 POLYMORPHISMS; CHINESE POPULATION AB Molecular and genetic evidence suggests that DNA repair pathways may contribute to lymphoma susceptibility. Several studies have examined the association of DNA repair genes with lymphoma risk, but the findings from these reports have been inconsistent. Here we provide the results of a focused analysis of genetic variation in DNA repair genes and their association with the risk of non-Hodgkin's lymphoma (NHL). With a population of 1,297 NHL cases and 1,946 controls, we have performed a two-stage case/control association analysis of 446 single nucleotide polymorphisms (SNPs) tagging the genetic variation in 81 DNA repair genes. We found the most significant association with NHL risk in the ATM locus for rs227060 (OR = 1.27, 95% CI: 1.13-1.43, p = 6.77x10(-5)), which remained significant after adjustment for multiple testing. In a subtype-specific analysis, associations were also observed for the ATM locus among both diffuse large B-cell lymphomas (DLBCL) and small lymphocytic lymphomas (SLL), however there was no association observed among follicular lymphomas (FL). In addition, our study provides suggestive evidence of an interaction between SNPs in MRE11A and NBS1 associated with NHL risk (OR = 0.51, 95% CI: 0.34-0.77, p = 0.0002). Finally, an imputation analysis using the 1,000 Genomes Project data combined with a functional prediction analysis revealed the presence of biologically relevant variants that correlate with the observed association signals. While the findings generated here warrant independent validation, the results of our large study suggest that ATM may be a novel locus associated with the risk of multiple subtypes of NHL. C1 [Rendleman, Justin; Adaniel, Christina; Shao, Yongzhao; Kirchhoff, Tomas] NYU, NYU Sch Med, New York, NY 10012 USA. [Antipin, Yevgeniy; Reva, Boris; Przybylo, Jennifer A.; Dutra-Clarke, Ana; Hansen, Nichole; Heguy, Adriana; Huberman, Kety; Borsu, Laetitia; Sander, Chris; Zelenetz, Andrew; Klein, Robert J.; Lacher, Mortimer; Vijai, Joseph; Offit, Kenneth] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Paltiel, Ora; Ben-Yehuda, Dina] Hadassah Hebrew Univ Med Ctr, Jerusalem, Israel. [Brown, Jennifer R.; Freedman, Arnold S.] Harvard Univ, Dana Farber Canc Ctr, Boston, MA 02115 USA. RP Kirchhoff, T (reprint author), NYU, NYU Sch Med, New York, NY 10012 USA. EM Tomas.Kirchhoff@nyumc.org OI Joseph, Vijai/0000-0002-7933-151X; Kirchhoff, Tomas/0000-0002-9055-2364 FU Leukemia and Lymphoma Society [TRP 6202-09]; Lymphoma Foundation; Filomena M. D'Agostino Foundation; Okonow-Lipton Fund; National Institutes of Health [K23 CA115682]; Anbinder Fund FX The study was funded by Translational Research Grant from Leukemia and Lymphoma Society (TRP 6202-09, awarded to Tomas Kirchhoff). Funding support was also provided by the Lymphoma Foundation and the Filomena M. D'Agostino Foundation (both to Kenneth Offit). Further support was also provided by the Okonow-Lipton Fund (Jennifer R. Brown) and the National Institutes of Health (K23 CA115682, Jennifer R. Brown). Jennifer R. Brown is a Scholar of the American Society of Hematology as well as a Scholar in Clinical Research of the Leukemia and Lymphoma Society. MSKCC Sequenom facility is supported by the Anbinder Fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 69 TC 4 Z9 4 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 10 PY 2014 VL 9 IS 7 AR e101685 DI 10.1371/journal.pone.0101685 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK9RG UT WOS:000338763800032 PM 25010664 ER PT J AU Bianchi, G Richardson, PG Anderson, KC AF Bianchi, Giada Richardson, Paul G. Anderson, Kenneth C. TI Best Treatment Strategies in High-Risk Multiple Myeloma: Navigating a Gray Area SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID STEM-CELL TRANSPLANTATION; HIGH-DOSE THERAPY; MULTIPARAMETER FLOW-CYTOMETRY; BORTEZOMIB PLUS DEXAMETHASONE; INTERNATIONAL SCORING SYSTEM; MINIMAL RESIDUAL DISEASE; INDUCTION THERAPY; COMPLETE RESPONSE; RANDOMIZED-TRIAL; AUTOLOGOUS TRANSPLANTATION AB A previously healthy 62-year-old man presented to his primary care physician with a 3-month history of fatigue and unremitting back pain. Physical examination revealed mucosal pallor, point tenderness at T10-T12, and a normal neurologic examination with preserved lower extremity strength and sphincter tone. Laboratory work-up disclosed hemoglobin 10.1 g/dL with mean corpuscular volume of 101 fL and otherwise normal blood cell counts; reticulocytes, 0.98%; stable creatinine, 1.1 mg/dL; calcium, 9.1 mg/dL; albumin, 3.4 g/dL; beta(2)-microglobulin, 5.7 mg/L; lactate dehydrogenase (LDH), 397 IU/L; and normal liver function tests. Bone survey showed lytic lesions at T10, T12, and throughout the axial skeleton and osteopenia. Serum protein electrophoresis (SPEP) demonstrated a 3.5 g/dL monoclonal peak in the gamma region, with monoclonal immunoglobulin G and lambda light chain detected on immunofixation. Serum free light chain (sFLC) ratio was 0.0001. Twenty-four-hour urine protein electrophoresis (UPEP) was normal. Bone marrow biopsy showed 60% infiltration with lambda light chain-restricted plasma cells staining positive for CD138 and CD56 and negative for CD45 by flow cytometry (Fig 1). Congo red stain on bone marrow biopsy and fat pad aspirate was negative for amyloid light-chain deposition. Cytogenetics of the malignant cells identified a t(4; 14) translocation, confirming the diagnosis of high-risk, International Staging System stage III immunoglobulin G lambda multiple myeloma (MM). The patient began treatment with lenalidomide, bortezomib, and dexamethasone (RVD) plus monthly intravenous zoledronic acid therapy. Hehas tolerated therapy well, and the monoclonal protein peak is rapidly declining. He is now referred to discuss indications for autologous stem-cell transplantation (ASCT) and overall prognosis. C1 [Bianchi, Giada; Richardson, Paul G.; Anderson, Kenneth C.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Bianchi, G (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. NR 54 TC 8 Z9 8 U1 3 U2 7 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 10 PY 2014 VL 32 IS 20 BP 2125 EP 2132 DI 10.1200/JCO.2014.55.7900 PG 8 WC Oncology SC Oncology GA AK9EC UT WOS:000338729400004 PM 24888801 ER PT J AU Vaz-Luis, I Ottesen, RA Hughes, ME Mamet, R Burstein, HJ Edge, SB Gonzalez-Angulo, AM Moy, B Rugo, HS Theriault, RL Weeks, JC Winer, EP Lin, NU AF Vaz-Luis, Ines Ottesen, Rebecca A. Hughes, Melissa E. Mamet, Rizvan Burstein, Harold J. Edge, Stephen B. Gonzalez-Angulo, Ana M. Moy, Beverly Rugo, Hope S. Theriault, Richard L. Weeks, Jane C. Winer, Eric P. Lin, Nancy U. TI Outcomes by Tumor Subtype and Treatment Pattern in Women With Small, Node-Negative Breast Cancer: A Multi-Institutional Study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID SMALL LESS-THAN-OR-EQUAL-TO-1 CM; PLUS ADJUVANT CHEMOTHERAPY; FOLLOW-UP; HEART-FAILURE; UNITED-STATES; HER-2 STATUS; NSABP B-31; TRASTUZUMAB; THERAPY; RECURRENCE AB Purpose Treatment decisions for patients with T1a,bN0M0 breast cancer are challenging. We studied the time trends in use of adjuvant chemotherapy and survival outcomes among these patients. Patients and Methods This was a prospective cohort study within the National Comprehensive Cancer Network Database that included 4,113 women with T1a,bN0M0 breast cancer treated between 2000 and 2009. Tumors were grouped by size (T1a, T1b), biologic subtype defined by hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status, and receipt of chemotherapy with or without trastuzumab. Results Median follow-up time was 5.5 years. Eight percent of patients with HR-positive/HER2-negative tumors were treated with chemotherapy. Fifty-two percent of those with HER2-positive or HR-negative/HER2-negative breast cancers received chemotherapy, with an increase over the last decade. Survival outcomes diverged by subtype and size, but the 5-year distant relapse-free survival (DRFS) did not exceed 10% in any subgroup. The 5-year DRFS for patients with T1a tumors untreated with chemotherapy ranged from 93% to 98% (n = 49 to 972), and for patients with T1b tumors, it ranged from 90% to 96% (n = 17 to 2,005). Patients with HR-positive/HER2-negative disease had the best DRFS estimates, and patients with HR-negative/HER2-negative tumors had the lowest. In this observational, nonrandomized cohort study, the 5-year DRFS for treated patients with T1a tumors was 100% for all subgroups (n = 12 to 33), and for patients with T1b tumors, it ranged from 94% to 96% (n = 88 to 241). Conclusion Women with T1a,b tumors have an excellent prognosis without chemotherapy. Size and tumor subtype may identify patients in whom the rate of recurrence justifies consideration of chemotherapy. These patients represent an optimal group for evaluating less toxic adjuvant regimens to maintain efficacy while minimizing short-and long-term risks. C1 [Vaz-Luis, Ines; Hughes, Melissa E.; Burstein, Harold J.; Weeks, Jane C.; Winer, Eric P.; Lin, Nancy U.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Moy, Beverly] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Vaz-Luis, Ines] Inst Mol Med, Lisbon, Portugal. [Ottesen, Rebecca A.; Mamet, Rizvan] City Hope Natl Med Ctr, Duarte, CA USA. [Rugo, Hope S.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Edge, Stephen B.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Edge, Stephen B.] Baptist Canc Ctr, Memphis, TN USA. [Gonzalez-Angulo, Ana M.; Theriault, Richard L.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. RP Lin, NU (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM nlin@partners.org FU Fundacao para a Ciencia e Tecnologia [HMSP-ICS/0004/2011]; National Cancer Institute Specialized Program of Research Excellence in Breast Cancer [NIH P50 CA089393]; National Comprehensive Cancer Network; Breast Cancer Research Foundation; Conquer Cancer Foundation; Susan G. Komen for the Cure FX Supported by Grant No. HMSP-ICS/0004/2011 from Fundacao para a Ciencia e Tecnologia, Grant No. NIH P50 CA089393 from the National Cancer Institute Specialized Program of Research Excellence in Breast Cancer, and by the National Comprehensive Cancer Network, Breast Cancer Research Foundation, Conquer Cancer Foundation, and Susan G. Komen for the Cure. NR 48 TC 49 Z9 51 U1 2 U2 8 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 10 PY 2014 VL 32 IS 20 BP 2142 EP + DI 10.1200/JCO.2013.53.1608 PG 12 WC Oncology SC Oncology GA AK9EC UT WOS:000338729400006 PM 24888816 ER PT J AU de Azambuja, E Procter, MJ van Veldhuisen, DJ Agbor-Tarh, D Metzger-Filho, O Steinseifer, J Untch, M Smith, IE Gianni, L Baselga, J Jackisch, C Cameron, DA Bell, R Leyland-Jones, B Dowsett, M Gelber, RD Piccart-Gebhart, MJ Suter, TM AF de Azambuja, Evandro Procter, Marion J. van Veldhuisen, Dirk J. Agbor-Tarh, Dominique Metzger-Filho, Otto Steinseifer, Jutta Untch, Michael Smith, Ian E. Gianni, Luca Baselga, Jose Jackisch, Christian Cameron, David A. Bell, Richard Leyland-Jones, Brian Dowsett, Mitch Gelber, Richard D. Piccart-Gebhart, Martine J. Suter, Thomas M. TI Trastuzumab-Associated Cardiac Events at 8 Years of Median Follow-Up in the Herceptin Adjuvant Trial (BIG 1-01) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID HER2-POSITIVE BREAST-CANCER; RANDOMIZED CONTROLLED-TRIAL; HEART-FAILURE; CHEMOTHERAPY; CARDIOTOXICITY; THERAPY; ERBB2; PLUS; DOXORUBICIN; PACLITAXEL AB Purpose To document the rate and outcome of trastuzumab-associated cardiac dysfunction in patients following 1 or 2 years of adjuvant therapy. Patients and Methods The Herceptin Adjuvant (HERA) trial is a three-arm, randomized trial comparing 2 years or 1 year of trastuzumab with observation in 5,102 patients with human epidermal growth factor receptor 2 (HER2) -positive early-stage breast cancer. Cardiac function was closely monitored. Eligible patients had left ventricular ejection fraction (LVEF) >= 55% at study entry following neoadjuvant chemotherapy with or without radiotherapy. This 8-year median follow-up analysis considered patients randomly assigned to 2 years or 1 year of trastuzumab or observation. Results The as-treated safety population for 2 years of trastuzumab (n = 1,673), 1 year of trastuzumab (n = 1,682), and observation (n = 1,744) is reported. Cardiac adverse events leading to discontinuation of trastuzumab occurred in 9.4% of patients in the 2-year arm and 5.2% of patients in the 1-year arm. Cardiac death, severe congestive heart failure (CHF), and confirmed significant LVEF decrease remained low in all three arms. The incidence of severe CHF (0.8%, 0.8%, and 0.0%, respectively) and confirmed significant LVEF decrease (7.2%, 4.1%, and 0.9%, respectively) was significantly higher in the 2-year and 1-year trastuzumab arms compared with the observation arm. Severe CHF was the same for 2-year and 1-year trastuzumab. Of patients with confirmed LVEF decrease receiving 2-year trastuzumab, 87.5% reached acute recovery. Of patients with confirmed LVEF decrease receiving 1-year trastuzumab, 81.2% reached acute recovery. Conclusion Long-term assessment at 8-year median follow-up confirms the low incidence of cardiac events for trastuzumab given sequentially after chemotherapy and radiotherapy, and cardiac events were reversible in the vast majority of patients. C1 [de Azambuja, Evandro; Piccart-Gebhart, Martine J.] Inst Jules Bordet, B-1000 Brussels, Belgium. [de Azambuja, Evandro] Breast European Adjuvant Study Team, Brussels, Belgium. [Piccart-Gebhart, Martine J.] Univ Libre Brussels, Brussels, Belgium. [Procter, Marion J.; Agbor-Tarh, Dominique] Frontier Sci Scotland, Kincraig, Kingussie, Scotland. [Cameron, David A.] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Cameron, David A.] Western Gen Hosp, Edinburgh EH4 2XU, Midlothian, Scotland. [Smith, Ian E.] Royal Marsden Hosp, London SW3 6JJ, England. [Smith, Ian E.] Inst Canc Res, London SW3 6JB, England. [Dowsett, Mitch] Royal Marsden Natl Hlth Serv Trust, London, England. [van Veldhuisen, Dirk J.] Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands. [Metzger-Filho, Otto; Gelber, Richard D.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Steinseifer, Jutta] F Hoffmann La Roche & Co Ltd, CH-4002 Basel, Switzerland. [Suter, Thomas M.] Univ Hosp Bern, Inselspital, Swiss Cardiovasc Ctr, CH-3010 Bern, Switzerland. [Untch, Michael] HELIOS Klin, Buch, Germany. [Jackisch, Christian] Klinikum Offenbach, Offenbach, Germany. [Gianni, Luca] San Raffaele Inst, Milan, Italy. [Baselga, Jose] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Bell, Richard] Geelong Hosp, Andrew Love Canc Ctr, Geelong, Vic, Australia. [Leyland-Jones, Brian] Edith Sanford Breast Canc Res Inst, Sioux Falls, SD USA. RP de Azambuja, E (reprint author), Inst Jules Bordet, Blvd Waterloo 121,7th Floor, B-1000 Brussels, Belgium. EM evandro.azambuja@bordet.be RI Steinseifer-Szabo, Jutta/A-2083-2014; Steinseifer-Szabo, Jutta/A-4840-2013 OI Steinseifer-Szabo, Jutta/0000-0002-1358-6245 NR 20 TC 54 Z9 54 U1 2 U2 14 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 10 PY 2014 VL 32 IS 20 BP 2159 EP + DI 10.1200/JCO.2013.53.9288 PG 9 WC Oncology SC Oncology GA AK9EC UT WOS:000338729400008 PM 24912899 ER PT J AU Aizer, A Nguyen, P AF Aizer, Ayal Paul Nguyen TI Omission of Sexual and Gender Minority Patients Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID CANCER C1 [Aizer, Ayal] Harvard Radiat Oncol Program, Boston, MA 02114 USA. [Paul Nguyen] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. RP Aizer, A (reprint author), Harvard Radiat Oncol Program, Boston, MA 02114 USA. NR 5 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 JUL 10 PY 2014 VL 32 IS 20 BP 2184 EP 2184 DI 10.1200/JCO.2014.55.6688 PG 1 WC Oncology SC Oncology GA AK9EC UT WOS:000338729400014 PM 24888805 ER PT J AU Pagani, O Regan, MM Walley, BA Fleming, GF Colleoni, M Lang, I Gomez, HL Tondini, C Burstein, HJ Perez, EA Ciruelos, E Stearns, V Bonnefoi, HR Martino, S Geyer, CE Pinotti, G Puglisi, F Crivellari, D Ruhstaller, T Winer, EP Rabaglio-Poretti, M Maibach, R Ruepp, B Giobbie-Hurder, A Price, KN Bernhard, J Luo, WX Ribi, K Viale, G Coates, AS Gelber, RD Goldhirsch, A Francis, PA AF Pagani, Olivia Regan, Meredith M. Walley, Barbara A. Fleming, Gini F. Colleoni, Marco Lang, Istvan Gomez, Henry L. Tondini, Carlo Burstein, Harold J. Perez, Edith A. Ciruelos, Eva Stearns, Vered Bonnefoi, Herve R. Martino, Silvana Geyer, Charles E., Jr. Pinotti, Graziella Puglisi, Fabio Crivellari, Diana Ruhstaller, Thomas Winer, Eric P. Rabaglio-Poretti, Manuela Maibach, Rudolf Ruepp, Barbara Giobbie-Hurder, Anita Price, Karen N. Bernhard, Juerg Luo, Weixiu Ribi, Karin Viale, Giuseppe Coates, Alan S. Gelber, Richard D. Goldhirsch, Aron Francis, Prudence A. CA TEXT SOFT Investigators Int Breast TI Adjuvant Exemestane with Ovarian Suppression in Premenopausal Breast Cancer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID POSTMENOPAUSAL WOMEN; ENDOCRINE THERAPY; AMERICAN-SOCIETY; FOLLOW-UP; TAMOXIFEN; TRIAL; METAANALYSIS; LETROZOLE; SEQUENCE AB BACKGROUND Adjuvant therapy with an aromatase inhibitor improves outcomes, as compared with tamoxifen, in postmenopausal women with hormone-receptor-positive breast cancer. METHODS In two phase 3 trials, we randomly assigned premenopausal women with hormone-receptor-positive early breast cancer to the aromatase inhibitor exemestane plus ovarian suppression or tamoxifen plus ovarian suppression for a period of 5 years. Suppression of ovarian estrogen production was achieved with the use of the gonadotropin-releasing-hormone agonist triptorelin, oophorectomy, or ovarian irradiation. The primary analysis combined data from 4690 patients in the two trials. RESULTS After a median follow-up of 68 months, disease-free survival at 5 years was 91.1% in the exemestane-ovarian suppression group and 87.3% in the tamoxifen-ovarian suppression group (hazard ratio for disease recurrence, second invasive cancer, or death, 0.72; 95% confidence interval [CI], 0.60 to 0.85; P<0.001). The rate of freedom from breast cancer at 5 years was 92.8% in the exemestane-ovarian suppression group, as compared with 88.8% in the tamoxifen-ovarian suppression group (hazard ratio for recurrence, 0.66; 95% CI, 0.55 to 0.80; P<0.001). With 194 deaths (4.1% of the patients), overall survival did not differ significantly between the two groups (hazard ratio for death in the exemestane-ovarian suppression group, 1.14; 95% CI, 0.86 to 1.51; P = 0.37). Selected adverse events of grade 3 or 4 were reported for 30.6% of the patients in the exemestane-ovarian suppression group and 29.4% of those in the tamoxifen-ovarian suppression group, with profiles similar to those for postmenopausal women. CONCLUSIONS In premenopausal women with hormone-receptor-positive early breast cancer, adjuvant treatment with exemestane plus ovarian suppression, as compared with tamoxifen plus ovarian suppression, significantly reduced recurrence. (Funded by Pfizer and others; TEXT and SOFT ClinicalTrials.gov numbers, NCT00066703 and NCT00066690, respectively.) C1 [Pagani, Olivia] Kantonsspital St Gallen, Breast Ctr, Inst Oncol Southern Switzerland, St Gallen, Switzerland. [Regan, Meredith M.; Bernhard, Juerg] Univ Hosp Inselspital, Bern, Switzerland. [Regan, Meredith M.; Maibach, Rudolf; Ruepp, Barbara; Bernhard, Juerg; Ribi, Karin] Coordinating Ctr, Int Breast Canc Study Grp IBCSG, Bern, Switzerland. [Regan, Meredith M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, IBCSG Stat Ctr, Boston, MA 02115 USA. [Burstein, Harold J.; Winer, Eric P.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Susan F Smith Ctr Womens Canc, Boston, MA 02115 USA. [Giobbie-Hurder, Anita; Luo, Weixiu] Harvard Univ, Sch Med, Dana Farber Canc Inst, IBCSG Stat Ctr, Boston, MA 02115 USA. [Price, Karen N.] Harvard Univ, Sch Med, Dana Farber Canc Inst, IBCSG Stat Ctr,Frontier Sci & Technol Res Fdn, Boston, MA 02115 USA. [Gelber, Richard D.] Harvard Univ, Sch Publ Hlth, Sch Med, IBCSG Stat Ctr,Dana Farber Canc Inst,Frontier Sci, Boston, MA 02115 USA. [Walley, Barbara A.] Tom Baker Canc Clin, Calgary, AB, Canada. [Fleming, Gini F.] Univ Chicago, Med Ctr, Chicago, IL 60637 USA. [Colleoni, Marco] Univ Milan, European Inst Oncol, IBCSG Cent Pathol Ctr, Div Med Senol, Milan, Italy. [Goldhirsch, Aron] European Inst Oncol, Milan, Italy. [Tondini, Carlo] Osped Papa Giovanni XXIII, Bergamo, Italy. [Pinotti, Graziella] Osped Circolo Varese, Varese, Italy. [Pinotti, Graziella] Fdn Macchi, Varese, Italy. [Puglisi, Fabio] Univ Udine, Dept Oncol, Univ Hosp Udine, I-33100 Udine, Italy. [Crivellari, Diana] Ctr Riferimento Oncol, Aviano, Italy. [Lang, Istvan] Natl Inst Oncol, Budapest, Hungary. [Gomez, Henry L.] Inst Nacl Enfermedades Neoplas, Lima, Peru. [Perez, Edith A.] Mayo Clin, Jacksonville, FL 32224 USA. [Ciruelos, Eva] Hosp Univ 12 Octubre, Madrid, Spain. [Stearns, Vered] Johns Hopkins Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Bonnefoi, Herve R.] Univ Bordeaux, Inst Bergonie Comprehens Canc Ctr, INSERM, U916, Bordeaux, France. [Martino, Silvana] Angeles Clin & Res Inst, Santa Monica, CA USA. [Geyer, Charles E., Jr.] Virginia Commonwealth Univ, Sch Med, Massey Canc Ctr, Richmond, VA 23284 USA. [Coates, Alan S.] Univ Sydney, Sydney, NSW 2006, Australia. [Francis, Prudence A.] Univ Melbourne, St Vincents Hosp, Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. RP Pagani, O (reprint author), Osped San Giovanni Bellinzona, Inst Oncol Southern Switzerland, CH-6500 Bellinzona, Switzerland. EM ibcsgcc@ibcsg.org OI Puglisi, Fabio/0000-0003-0573-4938; Gomez, Henry/0000-0003-2660-1843; Earl, Helena/0000-0003-1549-8094; Ciruelos, Eva /0000-0002-2796-1042 FU Pfizer; Ipsen; International Breast Cancer Study Group; National Cancer Institute; Boehringer Ingelheim; Taiho Pharmaceutical; AbbVie; AstraZeneca; Novartis; Roche; Eli Lilly FX Supported by Pfizer, Ipsen, the International Breast Cancer Study Group, and the National Cancer Institute.; Dr. Fleming reports receiving a study drug for investigation in a clinical trial from Corcept Therapeutics; Dr. Colleoni, receiving fees for serving on advisory boards from Boehringer Ingelheim, Taiho Pharmaceutical, AbbVie, and AstraZeneca and consulting and lecture fees from Novartis; Dr. Stearns, receiving grant support from Pfizer and Novartis; Dr. Ruhstaller, receiving travel support and fees for serving on an advisory board from Novartis; and Dr. Viale, receiving fees for serving on advisory boards from Novartis, Roche, and Eli Lilly. No other potential conflict of interest relevant to this article was reported. NR 16 TC 178 Z9 192 U1 6 U2 45 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 10 PY 2014 VL 371 IS 2 BP 107 EP 118 DI 10.1056/NEJMoa1404037 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA AK7YZ UT WOS:000338645500007 PM 24881463 ER PT J AU Venna, N Niles, JL Lev, MH Frosch, MP AF Venna, Nagagopal Niles, John L. Lev, Michael H. Frosch, Matthew P. TI Case 21-2014: A 68-Year-Old Man with a Sudden Onset of Diplopia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID WEGENERS-GRANULOMATOSIS; NEUROLOGICAL INVOLVEMENT; DIAGNOSIS; DISEASE; MANIFESTATIONS; THERAPY; ANCA C1 [Venna, Nagagopal; Frosch, Matthew P.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Niles, John L.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Lev, Michael H.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Frosch, Matthew P.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Venna, Nagagopal] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Niles, John L.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Lev, Michael H.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Frosch, Matthew P.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Venna, N (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. NR 19 TC 0 Z9 0 U1 1 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 10 PY 2014 VL 371 IS 2 BP 162 EP 173 DI 10.1056/NEJMcpc1403308 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA AK7YZ UT WOS:000338645500013 PM 25006723 ER PT J AU Perez, SM Carreno, FR Frazer, A Lodge, DJ AF Perez, Stephanie M. Carreno, Flavia R. Frazer, Alan Lodge, Daniel J. TI Vagal Nerve Stimulation Reverses Aberrant Dopamine System Function in the Methylazoxymethanol Acetate Rodent Model of Schizophrenia SO JOURNAL OF NEUROSCIENCE LA English DT Article DE dopamine; hippocampus; schizophrenia; vagal nerve stimulation ID TREATMENT-RESISTANT DEPRESSION; RAT DORSAL HIPPOCAMPUS; PREFRONTAL CORTEX; ELECTROPHYSIOLOGICAL CHARACTERIZATION; ANTIPSYCHOTIC-DRUGS; EPILEPSY PATIENTS; GENE-EXPRESSION; BRAIN; NOREPINEPHRINE; DEFICITS AB Vagal nerve stimulation (VNS) is an alternative therapy for epilepsy and treatment refractory depression. Here we examine VNS as a potential therapy for the treatment of schizophrenia in the methylozoxymethanol acetate (MAM) rodent model of the disease. We have previously demonstrated that hyperactivity within ventral regions of the hippocampus (vHipp) drives the dopamine system dysregulation in this model. Moreover, by targeting the vHipp directly, we can reverse aberrant dopamine system function and associated behaviors in the MAM model. Although the central effects of VNS have not been completely delineated, positron emission topographic measurements of cerebral blood flow in humans have consistently reported that VNS stimulation induces bilateral decreases in hippocampal activity. Based on our previous observations, we performed in vivo extracellular electrophysiological recordings in MAM-and saline-treated rats to evaluate the effect of chronic (2 week) VNS treatment on the activity of putative vHipp pyramidal neurons, as well as downstream dopamine neuron activity in the ventral tegmental area. Here we demonstrate that chronic VNS was able to reverse both vHipp hyperactivity and aberrant mesolimbic dopamine neuron function in the MAM model of schizophrenia. Additionally, VNS reversed a behavioral correlate of the positive symptoms of schizophrenia. Because current therapies for schizophrenia are far from adequate, with a large number of patients discontinuing treatment due to low efficacy or intolerable side effects, it is important to explore alternative nonpharmacological treatments. These data provide the first preclinical evidence that VNS may be a possible alternative therapeutic approach for the treatment of schizophrenia. C1 [Perez, Stephanie M.; Carreno, Flavia R.; Frazer, Alan; Lodge, Daniel J.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA. [Perez, Stephanie M.; Carreno, Flavia R.; Frazer, Alan; Lodge, Daniel J.] Univ Texas Hlth Sci Ctr San Antonio, Ctr Biomed Neurosci, San Antonio, TX 78229 USA. [Frazer, Alan] South Texas Vet Hlth Care Syst, Audie L Murphy Div, San Antonio, TX 78229 USA. RP Lodge, DJ (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, 7703 Floyd Curl Dr,MC 7764, San Antonio, TX 78229 USA. EM LodgeD@uthscsa.edu RI Lodge, Daniel/K-4740-2014 OI Lodge, Daniel/0000-0002-6772-1748 FU NIH [R01 MH082933, R01 MH090067, F31 MH098564]; Cyberonics; Dey Pharmaceuticals FX This work was supported by NIH Grants R01 MH082933 (A.F.), R01 MH090067 (D.J.L.), and F31 MH098564 (S.M.P.).; S.M.P. and F.R.C. declare no competing financial interests. A.F. has served on advisory boards for Lundbeck, Takeda Pharmaceuticals International, and Eli Lilly; and as a consultant for Dey Pharmaceuticals. Previously, A.F. had received financial compensation as a consultant for Cyberonics and had also obtained grant support from them for a preclinical study. D.J.L. reports receiving consulting fees from Dey Pharmaceuticals. NR 51 TC 6 Z9 6 U1 0 U2 5 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 9 PY 2014 VL 34 IS 28 BP 9261 EP 9267 DI 10.1523/JNEUROSCI.0588-14.2014 PG 7 WC Neurosciences SC Neurosciences & Neurology GA AL5EJ UT WOS:000339156000010 PM 25009259 ER PT J AU Luft, C Freeman, J Elliott, D Al-Tamimi, N Kriston-Vizi, J Heintze, J Lindenschmidt, I Seed, B Ketteler, R AF Luft, Christin Freeman, Jamie Elliott, David Al-Tamimi, Nadia Kriston-Vizi, Janos Heintze, Jacob Lindenschmidt, Ida Seed, Brian Ketteler, Robin TI Application of Gaussia luciferase in bicistronic and non-conventional secretion reporter constructs SO BMC BIOCHEMISTRY LA English DT Article DE Non-conventional secretion; Gaussia luciferase; GGA1; Bicistronic expression; Signal peptide ID TRANS-GOLGI NETWORK; UNCONVENTIONAL PROTEIN SECRETION; AMYLOID-BETA-PEPTIDE; IN-VIVO; CELL-DEATH; BIOLUMINESCENT REPORTER; COMPLEMENTATION ASSAY; PRINCEPS LUCIFERASE; SIGNAL PEPTIDE; EXPORT ROUTES AB Background: Secreted luciferases are highly useful bioluminescent reporters for cell-based assays and drug discovery. A variety of secreted luciferases from marine organisms have been described that harbor an N-terminal signal peptide for release along the classical secretory pathway. Here, we have characterized the secretion of Gaussia luciferase in more detail. Results: We describe three basic mechanisms by which GLUC can be released from cells: first, classical secretion by virtue of the N-terminal signal peptide; second, internal signal peptide-mediated secretion and third, non-conventional secretion in the absence of an N-terminal signal peptide. Non-conventional release of dNGLUC is not stress-induced, does not require autophagy and can be enhanced by growth factor stimulation. Furthermore, we have identified the golgi-associated, gamma adaptin ear containing, ARF binding protein 1 (GGA1) as a suppressor of release of dNGLUC. Conclusions: Due to its secretion via multiple secretion pathways GLUC can find multiple applications as a research tool to study classical and non-conventional secretion. As GLUC can also be released from a reporter construct by internal signal peptide-mediated secretion it can be incorporated in a novel bicistronic secretion system. C1 [Luft, Christin; Freeman, Jamie; Elliott, David; Al-Tamimi, Nadia; Kriston-Vizi, Janos; Heintze, Jacob; Lindenschmidt, Ida; Ketteler, Robin] UCL, MRC, Lab Mol & Cell Biol, London WC1E 6BT, England. [Seed, Brian] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. RP Ketteler, R (reprint author), UCL, MRC, Lab Mol & Cell Biol, Gower St, London WC1E 6BT, England. EM r.ketteler@ucl.ac.uk RI Kriston-Vizi, Janos/L-6021-2013 OI Kriston-Vizi, Janos/0000-0002-0149-145X FU Medical Research Council; BBSRC [BB/J015881/1]; Marie Curie Reintegration FX JKV was supported by the Marie Curie Reintegration grant. We thank Noboru Mizushima for providing inducible ATG5 knockout MEFs. This work was supported by the Medical Research Council and BBSRC (BB/J015881/1). NR 65 TC 4 Z9 4 U1 0 U2 11 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2091 J9 BMC BIOCHEM JI BMC Boichem. PD JUL 9 PY 2014 VL 15 AR 14 DI 10.1186/1471-2091-15-14 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AL4BN UT WOS:000339077900001 PM 25007711 ER PT J AU Teo, AKK Valdez, IA Dirice, E Kulkarni, RN AF Teo, Adrian Kee Keong Valdez, Ivan Achel Dirice, Ercument Kulkarni, Rohit N. TI Comparable Generation of Activin-Induced Definitive Endoderm via Additive Wnt or BMP Signaling in Absence of Serum SO STEM CELL REPORTS LA English DT Article ID EMBRYONIC STEM-CELLS; EFFICIENT DIFFERENTIATION; MOUSE EMBRYO; PLURIPOTENCY; LINEAGE; CULTURE AB There is considerable interest in differentiating human pluripotent stem cells (hPSCs) into definitive endoderm (DE) and pancreatic cells for in vitro disease modeling and cell replacement therapy. Numerous protocols use fetal bovine serum, which contains poorly defined factors to induce DE formation. Here, we compared Wnt and BMP in their ability to cooperate with Activin signaling to promote DE formation in a chemically defined medium. Varying concentrations of WNT3A, glycogen synthase kinase (GSK)-3 inhibitors CHIR99021 and 6-bromoindirubin-3'-oxime (BIO), and BMP4 could independently co-operate with Activin to effectively induce DE formation even in the absence of serum. Overall, CHIR99021 is favored due to its cost effectiveness. Surprisingly, WNT3A was ineffective in suppressing E-CADHERIN/CDH1 and pluripotency factor gene expression unlike GSK-3 inhibitors or BMP4. Our findings indicate that both Wnt and BMP effectively synergize with Activin signaling to generate DE from hPSCs, although WNT3A requires additional factors to suppress the pluripotency program inherent in hPSCs. C1 [Teo, Adrian Kee Keong; Valdez, Ivan Achel; Dirice, Ercument; Kulkarni, Rohit N.] Brigham & Womens Hosp, Joslin Diabet Ctr, Sect Islet Cell & Regenerat Biol, Boston, MA 02215 USA. [Teo, Adrian Kee Keong; Valdez, Ivan Achel; Dirice, Ercument; Kulkarni, Rohit N.] Brigham & Womens Hosp, Dept Med, Boston, MA 02215 USA. [Teo, Adrian Kee Keong; Valdez, Ivan Achel; Dirice, Ercument; Kulkarni, Rohit N.] Harvard Univ, Sch Med, Boston, MA 02215 USA. RP Teo, AKK (reprint author), Brigham & Womens Hosp, Joslin Diabet Ctr, Sect Islet Cell & Regenerat Biol, Boston, MA 02215 USA. EM drainteo@gmail.com; rohit.kulkarni@joslin.harvard.edu RI Teo, Adrian/A-4009-2013 OI Teo, Adrian/0000-0001-5901-7075 FU HSCI/DRC Flow Core [NIH P30DK036836]; Juvenile Diabetes Research Foundation; HSCI Sternlicht Director's Fund; NIH [F31DK098931, RO1 DK 67536, RO1 DK 055523]; HSCI; AstraZeneca FX The hiPSC line used was derived in the Joslin DRC iPS Core Facility (NIH 5 P30 DK036836-27). FACS analysis was supported by the HSCI/DRC Flow Core (NIH P30DK036836). We thank G. Daley, M. D., Ph.D. for CHB8 hESCs. A. K. K. T. is supported by a Juvenile Diabetes Research Foundation postdoctoral fellowship. I. A. V. is supported by a HSCI Sternlicht Director's Fund Award and an NIH F31DK098931 award. R.N.K. is supported by the HSCI, NIH grants RO1 DK 67536 and RO1 DK 055523, and a grant from AstraZeneca. NR 24 TC 8 Z9 8 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2213-6711 J9 STEM CELL REP JI Stem Cell Rep. PD JUL 8 PY 2014 VL 3 IS 1 DI 10.1016/j.stemcr.2014.05.007 PG 10 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA AN8VB UT WOS:000340882100004 PM 25068117 ER PT J AU Chitnis, T Waubant, E AF Chitnis, Tanuja Waubant, Emmanuelle TI B-cell depletion in children with neuroimmunologic conditions The learning curve SO NEUROLOGY LA English DT Editorial Material ID MULTIPLE-SCLEROSIS; RITUXIMAB C1 [Chitnis, Tanuja] Massachusetts Gen Hosp, Partners Pediat Multiple Sclerosis Ctr, Boston, MA 02114 USA. [Waubant, Emmanuelle] Univ Calif San Francisco, Dept Neurol, Benioffs Children Hosp, Reg Pediat MS Ctr, San Francisco, CA 94143 USA. RP Chitnis, T (reprint author), Massachusetts Gen Hosp, Partners Pediat Multiple Sclerosis Ctr, Boston, MA 02114 USA. EM tchitnis@partners.org NR 11 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD JUL 8 PY 2014 VL 83 IS 2 BP 111 EP 112 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA AM8EI UT WOS:000340103400035 PM 24920852 ER PT J AU Auriel, E Edlow, BL Reijmer, YD Fotiadis, P Ramirez-Martinez, S Ni, J Reed, AK Vashkevich, A Schwab, K Rosand, J Viswanathan, A Wu, O Gurol, ME Greenberg, SM AF Auriel, Eitan Edlow, Brian L. Reijmer, Yael D. Fotiadis, Panagiotis Ramirez-Martinez, Sergi Ni, Jun Reed, Anne K. Vashkevich, Anastasia Schwab, Kristin Rosand, Jonathan Viswanathan, Anand Wu, Ona Gurol, M. Edip Greenberg, Steven M. TI Microinfarct disruption of white matter structure A longitudinal diffusion tensor analysis SO NEUROLOGY LA English DT Article ID CEREBRAL AMYLOID ANGIOPATHY; COGNITIVE IMPAIRMENT; LESIONS; BRAIN; MULTICENTER; POPULATION; DEMENTIA; INFARCTS; AUTOPSY; DISEASE AB Objective: To evaluate the local effect of small asymptomatic infarctions detected by diffusion-weighted imaging (DWI) on white matter microstructure using longitudinal structural and diffusion tensor imaging (DTI). Methods: Nine acute to subacute DWI lesions were identified in 6 subjects with probable cerebral amyloid angiopathy who had undergone high-resolution MRI both before and after DWI lesion detection. Regions of interest (ROIs) corresponding to the site of the DWI lesion (lesion ROI) and corresponding site in the nonlesioned contralateral hemisphere (control ROI) were coregistered to the pre- and postlesional scans. DTI tractography was additionally performed to reconstruct the white matter tracts containing the ROIs. DTI parameters (fractional anisotropy [FA], mean diffusivity [MD]) were quantified within each ROI, the 6-mm lesion-containing tract segments, and the entire lesion-containing tract bundle. Lesion/control FA and MD ratios were compared across time points. Results: The postlesional scans (performed a mean 7.1 +/- 4.7 months after DWI lesion detection) demonstrated a decrease in median FA lesion/control ROI ratio (1.08 to 0.93, p = 0.038) and increase in median MD lesion/control ROI ratio (0.97 to 1.17, p = 0.015) relative to the prelesional scans. There were no visible changes on postlesional high-resolution T1-weighted and fluid-attenuated inversion recovery images in 4 of 9 lesion ROIs and small (2-5 mm) T1 hypointensities in the remaining 5. No postlesional changes in FA or MD ratios were detected in the 6-mm lesion-containing tract segments or full tract bundles. Conclusions: Asymptomatic DWI lesions produce chronic local microstructural injury. The cumulative effects of these widely distributed lesions may directly contribute to small-vessel-related vascular cognitive impairment. C1 [Greenberg, Steven M.] Massachusetts Gen Hosp, Dept Neurol, J Philip Kistler Stroke Res Ctr, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Greenberg, SM (reprint author), Massachusetts Gen Hosp, Dept Neurol, J Philip Kistler Stroke Res Ctr, Boston, MA 02114 USA. EM sgreenberg@partners.org RI Gurol, Edip/J-2279-2014 OI Gurol, Edip/0000-0002-2169-4457 FU NIH [R01AG026484, R25NS065743] FX Supported in part by R01AG026484 and R25NS065743 from the NIH. The funding entities had no involvement in study design, data collection, analysis and interpretation, writing of the manuscript, or the decision to submit for publication. NR 30 TC 14 Z9 16 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD JUL 8 PY 2014 VL 83 IS 2 BP 182 EP 188 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA AM8EI UT WOS:000340103400045 PM 24920857 ER PT J AU Karimkhani, C Boyers, LN Margolis, DJ Naghavi, M Hay, RJ Williams, HC Naldi, L Coffeng, LE Weinstock, MA Dunnick, CA Pederson, H Vos, T Murray, CJL Dellavalle, RP AF Karimkhani, Chante Boyers, Lindsay N. Margolis, David J. Naghavi, Mohsen Hay, Roderick J. Williams, Hywel C. Naldi, Luigi Coffeng, Luc E. Weinstock, Martin A. Dunnick, Cory A. Pederson, Hannah Vos, Theo Murray, Christopher J. L. Dellavalle, Robert P. TI Comparing Cutaneous Research Funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases with 2010 Global Burden of Disease Results SO PLOS ONE LA English DT Article ID RESEARCH PRIORITIES; OF-HEALTH; LEPROSY; ASSOCIATION; PSORIASIS AB Importance: Disease burden data helps guide research prioritization. Objective: To determine the extent to which grants issued by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) reflect disease burden, measured by disability-adjusted life years (DALYs) from Global Burden of Disease (GBD) 2010 project. Design: Two investigators independently assessed 15 skin conditions studied by GBD 2010 in the NIAMS database for grants issued in 2013. The 15 skin diseases were matched to their respective DALYs from GBD 2010. Setting: The United States NIAMS database and GBD 2010 skin condition disability data. Main Outcome(s) and Measure(s): Relationship of NIAMS grant database topic funding with percent total GBD 2010 DALY and DALY rank for 15 skin conditions. Results: During fiscal year 2013, 1,443 NIAMS grants were issued at a total value of $424 million. Of these grants, 17.7% covered skin topics. Of the total skin disease funding, 82%(91 grants) were categorized as "general cutaneous research.'' Psoriasis, leprosy, and "other skin and subcutaneous diseases'' (ie; immunobullous disorders, vitiligo, and hidradenitis suppurativa) were over-represented when funding was compared with disability. Conversely, cellulitis, decubitus ulcer, urticaria, acne vulgaris, viral skin diseases, fungal skin diseases, scabies, and melanoma were under-represented. Conditions for which disability and funding appeared well-matched were dermatitis, squamous and basal cell carcinoma, pruritus, bacterial skin diseases, and alopecia areata. Conclusions and Relevance: Degree of representation in NIAMS is partly correlated with DALY metrics. Grant funding was well-matched with disability metrics for five of the 15 studied skin diseases, while two skin diseases were over-represented and seven were under-represented. Global burden estimates provide increasingly transparent and important information for investigating and prioritizing national research funding allocations. C1 [Karimkhani, Chante] Columbia Univ, Coll Phys & Surg, New York, NY USA. [Boyers, Lindsay N.] Georgetown Univ, Sch Med, Washington, DC USA. [Margolis, David J.] Univ Penn, Dept Biostat & Epidemiol & Dermatol, Philadelphia, PA 19104 USA. [Naghavi, Mohsen; Coffeng, Luc E.; Vos, Theo; Murray, Christopher J. L.] Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA. [Hay, Roderick J.] Kings Coll Hosp NHS Trust, Dept Dermatol, London, England. [Williams, Hywel C.] Univ Nottingham, Ctr Evidence Based Dermatol, Nottingham NG7 2RD, England. [Naldi, Luigi] Azienda Osped Papa Giovanni XXIII, Dept Dermatol, Bergamo, Italy. [Weinstock, Martin A.] Vet Affairs Med Ctr, Dermatoepidemiol Unit, Providence, RI USA. [Weinstock, Martin A.] Rode Isl Hosp, Dept Dermatol, Providence, RI USA. [Weinstock, Martin A.] Brown Univ, Dept Dermatol, Providence, RI 02912 USA. [Weinstock, Martin A.] Brown Univ, Dept Epidemiol, Providence, RI 02912 USA. [Dunnick, Cory A.; Dellavalle, Robert P.] Univ Colorado, Dept Dermatol, Aurora, CO 80045 USA. [Dunnick, Cory A.; Dellavalle, Robert P.] Eastern Colorado Hlth Care Syst, Dermatol Serv, US Dept Vet Affairs, Denver, CO USA. [Pederson, Hannah] Univ Colorado, Sch Med, Aurora, CO USA. [Dellavalle, Robert P.] Univ Colorado, Colorado Sch Publ Hlth, Dept Epidemiol, Aurora, CO USA. RP Dellavalle, RP (reprint author), Univ Colorado, Dept Dermatol, Anschutz Med Campus, Aurora, CO 80045 USA. EM robert.dellavalle@ucdenver.edu RI Naldi, Luigi/K-6343-2016 OI Naldi, Luigi/0000-0002-3160-2835 FU Bill and Melinda Gates Foundation; US Department of Veterans Affairs FX This study was supported in part by the Bill and Melinda Gates Foundation (PI: Christoper Murray) and the US Department of Veterans Affairs (salary for Drs. Dellavalle, Dunnick, Weinstock). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 32 TC 5 Z9 5 U1 1 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 8 PY 2014 VL 9 IS 7 AR e102122 DI 10.1371/journal.pone.0102122 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AL6KZ UT WOS:000339242700112 PM 25003335 ER PT J AU Halperin, JL Hankey, GJ Wojdyla, DM Piccini, JP Lokhnygina, Y Patel, MR Breithardt, G Singer, DE Becker, RC Hacke, W Paolini, JF Nessel, CC Mahaffey, KW Califf, RM Fox, KAA AF Halperin, Jonathan L. Hankey, Graeme J. Wojdyla, Daniel M. Piccini, Jonathan P. Lokhnygina, Yuliya Patel, Manesh R. Breithardt, Guenter Singer, Daniel E. Becker, Richard C. Hacke, Werner Paolini, John F. Nessel, Christopher C. Mahaffey, Kenneth W. Califf, Robert M. Fox, Keith A. A. CA ROCKET AF Steering Comm TI Efficacy and Safety of Rivaroxaban Compared With Warfarin Among Elderly Patients With Nonvalvular Atrial Fibrillation in the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) SO CIRCULATION LA English DT Article DE aging; anticoagulant; elderly; hemorrhage; stroke ID ANTICOAGULANT-THERAPY; CLINICAL-PRACTICE; RISK; MANAGEMENT; RATIONALE; SEVERITY; DESIGN AB Background-Nonvalvular atrial fibrillation is common in elderly patients, who face an elevated risk of stroke but difficulty sustaining warfarin treatment. The oral factor Xa inhibitor rivaroxaban was noninferior to warfarin in the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). This prespecified secondary analysis compares outcomes in older and younger patients. Methods and Results-There were 6229 patients (44%) aged >= 75 years with atrial fibrillation and >= 2 stroke risk factors randomized to warfarin (target international normalized ratio=2.0-3.0) or rivaroxaban (20 mg daily; 15 mg if creatinine clearance <50 mL/min), double blind. The primary end point was stroke and systemic embolism by intention to treat. Over 10 866 patient-years, older participants had more primary events (2.57% versus 2.05%/100 patient-years; P=0.0068) and major bleeding (4.63% versus 2.74%/100 patient-years; P<0.0001). Stroke/systemic embolism rates were consistent among older (2.29% rivaroxaban versus 2.85% warfarin per 100 patient-years; hazard ratio=0.80; 95% confidence interval, 0.63-1.02) and younger patients (2.00% versus 2.10%/100 patient-years; hazard ratio=0.95; 95% confidence interval, 0.76-1.19; interaction P=0.313), as were major bleeding rates (>= 75 years: 4.86% rivaroxaban versus 4.40% warfarin per 100 patient-years; hazard ratio >= 1.11; 95% confidence interval, 0.92-1.34; <75 years: 2.69% versus 2.79%/100 patient-years; hazard ratio=0.96; 95% confidence interval, 0.78-1.19; interaction P=0.336). Hemorrhagic stroke rates were similar in both age groups; there was no interaction between age and rivaroxaban response. Conclusions-Elderly patients had higher stroke and major bleeding rates than younger patients, but the efficacy and safety of rivaroxaban relative to warfarin did not differ with age, supporting rivaroxaban as an alternative for the elderly. C1 [Halperin, Jonathan L.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Hankey, Graeme J.] Univ Western Australia, Sch Med & Pharmacol, Perth, WA 6009, Australia. [Wojdyla, Daniel M.; Piccini, Jonathan P.; Lokhnygina, Yuliya; Patel, Manesh R.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. [Breithardt, Guenter] Univ Munster, D-48149 Munster, Germany. [Singer, Daniel E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Singer, Daniel E.] Harvard Univ, Sch Med, Boston, MA USA. [Becker, Richard C.] Univ Cincinnati, Coll Med, Cincinnati, OH USA. [Hacke, Werner] Heidelberg Univ, Heidelberg, Germany. [Paolini, John F.] Cerenis Therapeut, Labege, France. [Nessel, Christopher C.] Janssen Res & Dev, Raritan, NJ USA. [Mahaffey, Kenneth W.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Califf, Robert M.] Duke Univ, Med Ctr, Duke Translat Med Inst, Durham, NC USA. [Fox, Keith A. A.] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Fox, Keith A. A.] Royal Infirm Edinburgh NHS Trust, Edinburgh, Midlothian, Scotland. RP Halperin, JL (reprint author), Mt Sinai Med Ctr, Icahn Sch Med Mt Sinai, Cardiovasc Inst, Box 1030,1 Gustave L Levy Pl, New York, NY 10029 USA. EM jonathan.halperin@mssm.edu RI Hankey, Graeme /H-4968-2014; Mazurov, Vadim/J-9643-2014; Kubica, Jacek/D-6906-2014; Libis, Roman/O-9193-2015; Arkhipov, Mikhail/Q-2316-2015; Urina, Miguel/H-2605-2016; Zadionchenko, Vladimir/A-7445-2016; De Caterina, Raffaele/K-3857-2016 OI Hankey, Graeme /0000-0002-6044-7328; Mazurov, Vadim/0000-0002-0797-2051; Libis, Roman/0000-0003-0130-990X; Urina, Miguel/0000-0001-6003-4622; Zadionchenko, Vladimir/0000-0003-2377-5266; De Caterina, Raffaele/0000-0003-1637-574X FU Johnson & Johnson Pharmaceutical Research and Development (Raritan, NJ); Bayer HealthCare AG (Leverkusen, Germany) FX The ROCKETAF trial was supported by research grants from Johnson & Johnson Pharmaceutical Research and Development (Raritan, NJ) and Bayer HealthCare AG (Leverkusen, Germany). NR 19 TC 52 Z9 56 U1 2 U2 38 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD JUL 8 PY 2014 VL 130 IS 2 BP 138 EP U45 DI 10.1161/CIRCULATIONAHA.113.005008 PG 15 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AK8ZO UT WOS:000338717500009 PM 24895454 ER PT J AU Zhang, X Yu, HW Barrett, LE AF Zhang, Xuan Yu, Hui W. Barrett, Lisa E. TI How does this make you feel ? A comparison of four affect induction procedures SO FRONTIERS IN PSYCHOLOGY LA English DT Article DE affect induction; procedure; self-report; comparison; efficacy ID EMOTIONS NATURAL KINDS; MOOD-INDUCTION; FACIAL EXPRESSIONS; GUIDED IMAGERY; AFFECTIVE PICTURES; AFFECTIVE STATES; SOCIAL JUDGMENT; EVENT VALENCE; CORE AFFECT; EXPERIENCE AB Affect is a fundamental aspect of the human mind. An increasing number of experiments attempt to examine the influence of affect on other psychological phenomena. To accomplish this research, it is necessary to experimentally modify participants' affective states. In the present experiment, we compared the efficacy of four commonly used affect induction procedures. Participants (38 healthy undergraduate students: 18 males) were randomly assigned to either a pleasant or an unpleasant affect induction group, and then underwent four different affect induction procedures: (1) recall of an affectively salient event accompanied by affectively congruent music, (2) script-driven guided imagery, (3) viewing images while listening to affectively congruent music, and (4) posing affective facial actions, body postures, and vocal expressions. All four affect induction methods were successful in inducing both pleasant and unpleasant affective states. The viewing image with music and recall with music procedures were most effective in enhancing positive affect, whereas the viewing image with music procedure was most effective in enhancing negative affect. Implications for the scientific study of affect are discussed. C1 [Zhang, Xuan; Yu, Hui W.] Boston Coll, Dept Psychol, Chestnut Hill, MA 02167 USA. [Zhang, Xuan; Barrett, Lisa E.] Northeastern Univ, Dept Psychol, Boston, MA 02115 USA. [Barrett, Lisa E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Barrett, Lisa E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Martinos Ctr Biomedial Imaging, Boston, MA 02115 USA. RP Barrett, LE (reprint author), Northeastern Univ, Dept Psychol, Boston, MA 02115 USA. EM l.barrett@neu.edu NR 85 TC 2 Z9 2 U1 3 U2 38 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-1078 J9 FRONT PSYCHOL JI Front. Psychol. PD JUL 8 PY 2014 VL 5 DI 10.3389/fpsyg.2014.00689 PG 10 WC Psychology, Multidisciplinary SC Psychology GA AL2HO UT WOS:000338946800001 ER PT J AU Mellios, N Woodson, J Garcia, RI Crawford, B Sharma, J Sheridan, SD Haggarty, SJ Sur, M AF Mellios, Nikolaos Woodson, Jonathan Garcia, Rodrigo I. Crawford, Benjamin Sharma, Jitendra Sheridan, Steven D. Haggarty, Stephen J. Sur, Mriganka TI beta 2-Adrenergic receptor agonist ameliorates phenotypes and corrects microRNA-mediated IGF1 deficits in a mouse model of Rett syndrome SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE let-7f; LIN28A ID CPG-BINDING PROTEIN-2; MECP2 MUTANT MICE; GROWTH-FACTOR-I; CHOLINE SUPPLEMENTATION; NEUROTROPHIC FACTOR; FACTOR EXPRESSION; BDNF EXPRESSION; RAT-BRAIN; CLENBUTEROL; NEURONS AB Rett syndrome is a severe childhood onset neurodevelopmental disorder caused by mutations in methyl-CpG-binding protein 2 (MECP2), with known disturbances in catecholamine synthesis. Here, we show that treatment with the beta 2-adrenergic receptor agonist clenbuterol increases survival, rescues abnormalities in respiratory function and social recognition, and improves motor coordination in young male Mecp2-null (Mecp2(-/y)) mice. Importantly, we demonstrate that short-term treatment with clenbuterol in older symptomatic female heterozygous (Mecp2(-/+)) mice rescues respiratory, cognitive, and motor coordination deficits, and induces an anxiolytic effect. In addition, we reveal abnormalities in a microRNA-mediated pathway, downstream of brain-derived neurotrophic factor that affects insulin-like growth factor 1 (IGF1) expression in Mecp2(-/y) mice, and show that treatment with clenbuterol restores the observed molecular alterations. Finally, cotreatment with clenbuterol and recombinant human IGF1 results in additional increases in survival in male null mice. Collectively, our data support a role for IGF1 and other growth factor deficits as an underlying mechanism of Rett syndrome and introduce beta 2-adrenergic receptor agonists as potential therapeutic agents for the treatment of the disorder. C1 [Mellios, Nikolaos; Woodson, Jonathan; Garcia, Rodrigo I.; Crawford, Benjamin; Sharma, Jitendra; Sheridan, Steven D.; Sur, Mriganka] MIT, Dept Brain & Cognit Sci, Picower Inst Learning & Memory, Cambridge, MA 02139 USA. [Sheridan, Steven D.; Haggarty, Stephen J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res,Dept Neurol, Boston, MA 02114 USA. RP Sur, M (reprint author), MIT, Dept Brain & Cognit Sci, Picower Inst Learning & Memory, E25-618, Cambridge, MA 02139 USA. EM nmellios@mit.edu; msur@mit.edu OI Haggarty, Stephen J./0000-0002-7872-168X FU National Eye Institute Ruth L. Kirschstein Postdoctoral Fellowship [5F32EY020066-03]; National Institutes of Health [MH085802]; Simons Foundation FX We acknowledge Gerald Pho, Showming Kwok, Jorge Castro, Anita Liu, and Arooshi Kumar for data analysis, Bess Rosen for technical assistance, and Travis Emery for assistance in manuscript preparation. This work was supported by National Eye Institute Ruth L. Kirschstein Postdoctoral Fellowship 5F32EY020066-03 (to N.M.), National Institutes of Health Grant MH085802 (to M. S.), and the Simons Foundation (M.S.). NR 56 TC 18 Z9 18 U1 0 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 8 PY 2014 VL 111 IS 27 BP 9947 EP 9952 DI 10.1073/pnas.1309426111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK6CH UT WOS:000338514800057 PM 24958851 ER PT J AU Feeney, ER Chung, RT AF Feeney, Eoin R. Chung, Raymond T. TI Antiviral treatment of hepatitis C SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Review ID GENOTYPE 1 INFECTION; TREATMENT-NAIVE PATIENTS; SUSTAINED VIROLOGICAL RESPONSE; PEGYLATED INTERFERON ALPHA-2A; PREVIOUSLY TREATED PATIENTS; PEGINTERFERON ALPHA-2A; VIRUS-INFECTION; PHASE-2 TRIAL; RANDOMIZED-TRIAL; LIVER-TRANSPLANTATION AB Hepatitis C virus (HCV) infection is a substantial health problem worldwide. Most patients infected with HCV remain chronically infected, with an increased risk of cirrhosis and hepatocellular carcinoma. Although they are associated with toxicities and low sustained viral response rates, interferon alfa and ribavirin have been the mainstay of treatment until recently. New direct acting antivirals, specifically designed to inhibit three viral proteins (the NS3/4A protease, the NS5A protein, and the NS5B RNA dependent RNA polymerase) are now becoming available. The NS3/4A inhibitor simeprevir and NS5B inhibitor sofosbuvir have recently been licensed and can reduce the length of antiviral treatment, improve response rates, and allow for interferon-free regimens for some HCV genotypes. Several other newer direct acting antivirals have shown promise in clinical studies and are likely to be licensed soon. These agents seem to facilitate the use of shortened courses of combination interferon-free therapy, which are associated with high (>95%) sustained response rates and relatively few toxicities. These regimens have also been successful in patients who were previously difficult to treat, including those with cirrhosis, HIV coinfection, and those who have undergone liver transplantation. The high cost of these agents may be the biggest challenge to their implementation worldwide. C1 [Feeney, Eoin R.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Chung, Raymond T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. RP Chung, RT (reprint author), Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. EM RTCHUNG@partners.org OI Feeney, Eoin/0000-0003-4118-4945 FU Harvard University Center for AIDS Research (NIH/NIAID) [5P30AI060354-09]; Abbvie; Gilead Sciences; Mass Biologics; Vertex; NIH [DK098079, DA033541, AI082630] FX ERF: grant support-Harvard University Center for AIDS Research (NIH/NIAID fund 5P30AI060354-09). RTC has received consultancy fees from Abbvie and payment for clinical trials from Gilead Sciences, Mass Biologics, and Vertex; grant support: NIH DK098079, DA033541, and AI082630. NR 87 TC 45 Z9 45 U1 3 U2 28 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1756-1833 J9 BMJ-BRIT MED J JI BMJ-British Medical Journal PD JUL 7 PY 2014 VL 349 AR g3308 DI 10.1136/bmj.g3308 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA AL2YY UT WOS:000338993000001 ER PT J AU Heidt, T Courties, G Dutta, P Sager, HB Sebas, M Iwamoto, Y Sun, Y Da Silva, N Panizzi, P van der Lahn, AM Swirski, FK Weissleder, R Nahrendorf, M AF Heidt, Timo Courties, Gabriel Dutta, Partha Sager, Hendrik B. Sebas, Matt Iwamoto, Yoshiko Sun, Yuan Da Silva, Nicolas Panizzi, Peter van der Lahn, Anja M. Swirski, Filip K. Weissleder, Ralph Nahrendorf, Matthias TI Differential Contribution of Monocytes to Heart Macrophages in Steady-State and After Myocardial Infarction SO CIRCULATION RESEARCH LA English DT Article DE heart; macrophages; monocytes; myocardial infarction ID TISSUE-RESIDENT MACROPHAGES; INFECTIVE ENDOCARDITIS; CARDIAC MACROPHAGES; INFLAMMATION; DISEASE; KINETICS; REVEALS; MICE AB Rationale: Macrophages populate the steady-state myocardium. Previously, all macrophages were thought to arise from monocytes; however, it emerged that, in several organs, tissue-resident macrophages may self-maintain through local proliferation. Objective: Our aim was to study the contribution of monocytes to cardiac-resident macrophages in steady state, after macrophage depletion in CD11b(DTR/+) mice and in myocardial infarction. Methods and Results: Using in vivo fate mapping and flow cytometry, we estimated that during steady state the heart macrophage population turns over in approximate to 1 month. To explore the source of cardiac-resident macrophages, we joined the circulation of mice using parabiosis. After 6 weeks, we observed blood monocyte chimerism of 35.3 +/- 3.4%, whereas heart macrophages showed a much lower chimerism of 2.7 +/- 0.5% (P<0.01). Macrophages self-renewed locally through proliferation: 2.1 +/- 0.3% incorporated bromodeoxyuridine 2 hours after a single injection, and 13.7 +/- 1.4% heart macrophages stained positive for the cell cycle marker Ki-67. The cells likely participate in defense against infection, because we found them to ingest fluorescently labeled bacteria. In ischemic myocardium, we observed that tissue-resident macrophages died locally, whereas some also migrated to hematopoietic organs. If the steady state was perturbed by coronary ligation or diphtheria toxin-induced macrophage depletion in CD11b(DTR/+) mice, blood monocytes replenished heart macrophages. However, in the chronic phase after myocardial infarction, macrophages residing in the infarct were again independent from the blood monocyte pool, returning to the steady-state situation. Conclusions: In this study, we show differential contribution of monocytes to heart macrophages during steady state, after macrophage depletion or in the acute and chronic phase after myocardial infarction. We found that macrophages participate in the immunosurveillance of myocardial tissue. These data correspond with previous studies on tissue-resident macrophages and raise important questions on the fate and function of macrophages during the development of heart failure. C1 [Heidt, Timo; Courties, Gabriel; Dutta, Partha; Sager, Hendrik B.; Sebas, Matt; Iwamoto, Yoshiko; Sun, Yuan; Da Silva, Nicolas; Swirski, Filip K.; Weissleder, Ralph; Nahrendorf, Matthias] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Heidt, Timo; Courties, Gabriel; Dutta, Partha; Sager, Hendrik B.; Sebas, Matt; Iwamoto, Yoshiko; Sun, Yuan; Da Silva, Nicolas; Swirski, Filip K.; Weissleder, Ralph; Nahrendorf, Matthias] Harvard Univ, Sch Med, Boston, MA USA. [Panizzi, Peter] Auburn Univ, Dept Drug Discovery & Dev, Harrison Sch Pharm, Auburn, AL 36849 USA. [van der Lahn, Anja M.] Univ Amsterdam, Acad Med Ctr, Dept Cardiol, NL-1105 AZ Amsterdam, Netherlands. [Weissleder, Ralph] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA USA. RP Nahrendorf, M (reprint author), Massachusetts Gen Hosp, Ctr Syst Biol, Simches Res Bldg,185 Cambridge St, Boston, MA 02114 USA. EM mnahrendorf@mgh.harvard.edu OI Panizzi, Peter/0000-0003-0141-8807 FU German Research Foundation [HE6382/1-1, SA1668/2-1]; American Heart Association [13POST16580004]; National Heart, Lung, and Blood Institute [R01-HL114477, R01-HL095629, R01-HL117829, HHSN268201000044C] FX This work was funded in part by grants from the German Research Foundation (HE6382/1-1 and SA1668/2-1), American Heart Association (13POST16580004), and the National Heart, Lung, and Blood Institute (R01-HL114477, R01-HL095629, R01-HL117829, HHSN268201000044C). NR 21 TC 63 Z9 67 U1 4 U2 29 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD JUL 7 PY 2014 VL 115 IS 2 BP 284 EP 295 DI 10.1161/CIRCRESAHA.115.303567 PG 12 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA AL6VS UT WOS:000339271900010 PM 24786973 ER PT J AU Garner, C Ahn, R Ding, YC Steele, L Stoven, S Green, PH Fasano, A Murray, JA Neuhausen, SL AF Garner, Chad Ahn, Richard Ding, Yuan Chun Steele, Linda Stoven, Samantha Green, Peter H. Fasano, Alessio Murray, Joseph A. Neuhausen, Susan L. TI Genome-Wide Association Study of Celiac Disease in North America Confirms FRMD4B as New Celiac Locus SO PLOS ONE LA English DT Article ID CROHNS-DISEASE; MICROSCOPIC COLITIS; RISK VARIANTS; UNITED-STATES; INFLAMMATION; PREVALENCE; AUTOPHAGY; ANTIGENS; GENES AB We performed a genome-wide association study (GWAS) of 1550 North American celiac disease cases and 3084 controls. Twelve SNPs, distributed across four regions (3p21.31, 4q27, 6q15, 6q25), were significantly associated with disease (p-value < 1.0x10(-7)), and a further seven SNPs, across four additional regions (1q24.3, 10p15.1, 6q22.31, 17q21.32) had suggestive evidence (1.0x10(-7) < p-value < 1.0x10(-6)). This study replicated a previous suggestive association within FRMD4B (3p14.1), confirming it as a celiac disease locus. All four regions with significant associations and two regions with suggestive results (1q24.3, 10p15.1) were known disease loci. The 6q22.31 and 10p11.23 regions were not replicated. A total of 410 SNPs distributed across the eight significant and suggestive regions were tested for association with dermatitis herpetiformis and microscopic colitis. Preliminary, suggestive statistical evidence for association with the two traits was found at chromosomes 3p21.31, 6q15, 6q25, 1q24.3 and 10p11.23, with future studies being required to validate the reported associations. C1 [Garner, Chad; Ahn, Richard] Univ Calif Irvine, Sch Med, Dept Epidemiol, Irvine, CA 92717 USA. [Ding, Yuan Chun; Steele, Linda; Neuhausen, Susan L.] City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Duarte, CA USA. [Green, Peter H.] Columbia Univ, Celiac Dis Ctr, New York, NY USA. [Fasano, Alessio] MassGen Hosp Children, Ctr Celiac Res, Boston, MA USA. [Stoven, Samantha; Murray, Joseph A.] Mayo Clin, Dept Immunol, Div Gastroenterol & Hepatol, Rochester, MN USA. RP Garner, C (reprint author), Univ Calif Irvine, Sch Med, Dept Epidemiol, Irvine, CA 92717 USA. EM cgarner@uci.edu OI Ahn, Richard/0000-0002-9698-2752 FU National Institutes of Health [DK081645, R01 DK057892]; Center for Celiac Research FX SN and CG were funded by National Institutes of Health Grant DK081645 (www.nih.gov). JAM was also supported in part by National Institutes of Health Grant R01 DK057892 (www.nih.gov). AF was supported by funds from the Center for Celiac Research (www.celiacdiseasecenter.columbia.edu). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 26 TC 14 Z9 14 U1 1 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 7 PY 2014 VL 9 IS 7 AR e101428 DI 10.1371/journal.pone.0101428 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK7WB UT WOS:000338637300042 PM 24999842 ER PT J AU Zeidel, ML Hoenig, MP Palevsky, PM AF Zeidel, Mark L. Hoenig, Melanie P. Palevsky, Paul M. TI A New CJASN Series: Renal Physiology for the Clinician SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Editorial Material C1 [Zeidel, Mark L.; Hoenig, Melanie P.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Palevsky, Paul M.] VA Pittsburgh Healthcare Syst, Renal Sect, Pittsburgh, PA USA. [Palevsky, Paul M.] Univ Pittsburgh, Sch Med, Dept Med, Renal Electrolyte Div, Pittsburgh, PA 15213 USA. RP Zeidel, ML (reprint author), Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. EM mzeidel@bidmc.harvard.edu OI Palevsky, Paul/0000-0002-7334-5400 NR 2 TC 1 Z9 1 U1 1 U2 2 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 JUL 7 PY 2014 VL 9 IS 7 BP 1271 EP 1271 DI 10.2215/CJN.10191012 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA AK7NP UT WOS:000338615300019 PM 25002526 ER PT J AU Hoenig, MP Zeidel, ML AF Hoenig, Melanie P. Zeidel, Mark L. TI Homeostasis, the Milieu Interieur, and the Wisdom of the Nephron SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID ADENOSINE-TRIPHOSPHATASE; POTASSIUM-TRANSPORT; METABOLIC-ACIDOSIS; SINGLE TUBULE; KIDNEY; SODIUM; MECHANISMS; PHYSIOLOGY; MUTATIONS; DISEASE AB The concept of homeostasis has been inextricably linked to the function of the kidneys for more than a century when it was recognized that the kidneys had the ability to maintain the "internal milieu" and allow organisms the "physiologic freedom" to move into varying environments and take in varying diets and fluids. Early ingenious, albeit rudimentary, experiments unlocked a wealth of secrets on the mechanisms involved in the formation of urine and renal handling of the gamut of electrolytes, as well as that of water, acid, and protein. Recent scientific advances have confirmed these prescient postulates such that the modern clinician is the beneficiary of a rich understanding of the nephron and the kidney's critical role in homeostasis down to the molecular level. This review summarizes those early achievements and provides a framework and introduction for the new CJASN series on renal physiology. C1 [Hoenig, Melanie P.; Zeidel, Mark L.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Nephrol, Boston, MA 02215 USA. RP Hoenig, MP (reprint author), Beth Israel Deaconess Med Ctr Clin, Dept Med, Div Nephrol, Fa 8-185 Pilgrim Rd, Boston, MA 02215 USA. EM MHoenig@bidmc.harvard.edu NR 71 TC 6 Z9 7 U1 0 U2 6 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 JUL 7 PY 2014 VL 9 IS 7 BP 1272 EP 1281 DI 10.2215/CJN.08860813 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA AK7NP UT WOS:000338615300020 PM 24789550 ER PT J AU Boros, E Karimi, S Kenton, N Helm, L Caravan, P AF Boros, Eszter Karimi, Shima Kenton, Nathaniel Helm, Lothar Caravan, Peter TI Gd(DOTAlaP): Exploring the Boundaries of Fast Water Exchange in Gadolinium-Based Magnetic Resonance Imaging Contrast Agents SO INORGANIC CHEMISTRY LA English DT Article ID ACID GD-COMPLEX; HIGH-RELAXIVITY; LANTHANIDE(III) COMPLEXES; SERUM-ALBUMIN; METAL-COMPLEXES; O-17 NMR; OPTIMIZATION; BINDING; STATE; FIELD AB Here, we describe the synthesis of the single amino acid chelator DOTAlaP and four of its derivatives. The corresponding gadolinium(III) complexes were investigated for their kinetic inertness, relaxometric properties at a range of fields and temperatures, water exchange rate, and interaction with human serum albumin (HSA). Derivatives with one inner-sphere water (q = 1) were determined to have a mean water residency time between 8 and 6 ns in phoshate-buffered saline at 37 degrees C. The corresponding europium complexes were also formed and used to obtain information on the hydration number of the corresponding coordination complexes. Two complexes capable of binding HSA were also synthesized, of which one, Gd(5b), contains no inner-sphere water, while the other derivative, Gd(4b), is a mixture of ca. 15% q = 1 and 85% q = 0. In the presence of HSA, the latter displayed a very short mean water residency time (tau(310)(M) = 2.4 ns) and enhanced relaxivity at intermediate and high fields. The kinetic inertness of Gd(4b) with respect to complex dissociation was decreased compared to its DOTAla analogue but still 100-fold more inert than [Gd(BOPTA)(H2O)](2-). Magnetic resonance imaging in mice showed that Gd(4b) was able to provide 38% better vessel to muscle contrast compared to the clinically used HSA binding agent MS-325. C1 [Boros, Eszter; Kenton, Nathaniel; Caravan, Peter] Harvard Univ, Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging,Sch Med, Charlestown, MA 02129 USA. [Karimi, Shima; Helm, Lothar] Ecole Polytech Fed Lausanne, Lab Chim Inorgan & Bioinorgan, EPFL BCH, CH-1015 Lausanne, Switzerland. RP Caravan, P (reprint author), Harvard Univ, Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging,Sch Med, 149 Thirteenth St,Suite 2301, Charlestown, MA 02129 USA. EM caravan@nmr.mgh.harvard.edu FU National Institute for Biomedical Imaging and Bioengineering (NIBIB Award) [R01EB009062]; National Center for Research Resources [S10OD010650, SI0RR023385, P41RR14075] FX P.C. acknowledges the National Institute for Biomedical Imaging and Bioengineering for funding for this project (NIBIB Award R01EB009062) and the National Center for Research Resources for instrumentation grants (Grants S10OD010650, SI0RR023385, and P41RR14075). E.B. thanks the Swiss National Science Foundation (advanced.postdoc mobility fellowship) for support. NR 47 TC 5 Z9 6 U1 2 U2 25 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0020-1669 EI 1520-510X J9 INORG CHEM JI Inorg. Chem. PD JUL 7 PY 2014 VL 53 IS 13 BP 6985 EP 6994 DI 10.1021/ic5008928 PG 10 WC Chemistry, Inorganic & Nuclear SC Chemistry GA AK9LH UT WOS:000338748100067 PM 24922178 ER PT J AU Rogal, SS Hu, A Bandi, R Shaikh, O AF Rogal, Shari S. Hu, Angela Bandi, Rupal Shaikh, Obaid TI Novel therapy for non-cirrhotic hyperammonemia due to a spontaneous splenorenal shunt SO WORLD JOURNAL OF GASTROENTEROLOGY LA English DT Article DE Splenorenal shunt; Gastric bypass; Hyperammonemia; Encephalopathy ID ENCEPHALOPATHY AB Spontaneous splenorenal shunts in the absence of cirrhosis have rarely been reported as a cause hyperammonemia with encephalopathy. Several closure techniques of such lesions have been described. Here we report a case of a patient with no history of liver disease who developed significant confusion. After an extensive workup, he was found to have hyperammonemia and encephalopathy due to formation of a spontaneous splenorenal shunt. There was no evidence of cirrhosis on biopsy or imaging and no portal hypertension when directly measured. The shunt was 18 mm and too large for embolization so the segment of the splenic vein between the portal vein and the shunt was occluded using an Amplatzer plug. Thus, the superior mesenteric flow was directed entirely to the liver. After interventional radiology closure of the shunt using this technique there was complete resolution of symptoms. The case represents the first report of a successful closure of splenorenal shunt via percutaneous embolization of the splenic vein with an amplatzer plug using a common femoral vein approach. (C) 2014 Baishideng Publishing Group Inc. All rights reserved. C1 [Rogal, Shari S.] Univ Pittsburgh, Med Ctr, Div Gastroenterol Hepatol & Nutr, Pittsburgh, PA 15213 USA. [Hu, Angela] Univ Pittsburgh, Sch Med, Pittsburgh, PA 15213 USA. [Bandi, Rupal] Vet Affairs Pittsburgh Healthcare Syst, Dept Radiol, Pittsburgh, PA 15240 USA. [Shaikh, Obaid] Vet Affairs Pittsburgh Healthcare Syst, Div Gastroenterol, Pittsburgh, PA 15240 USA. RP Rogal, SS (reprint author), Univ Pittsburgh, Med Ctr, Div Gastroenterol Hepatol & Nutr, PUH, 200 Lothrop St,M Level,C Wing, Pittsburgh, PA 15213 USA. EM rogalss@upmc.edu FU Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development FX Supported by Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development NR 6 TC 2 Z9 4 U1 0 U2 2 PU BAISHIDENG PUBLISHING GROUP INC PI PLEASANTON PA 8226 REGENCY DR, PLEASANTON, CA 94588 USA SN 1007-9327 EI 2219-2840 J9 WORLD J GASTROENTERO JI World J. Gastroenterol. PD JUL 7 PY 2014 VL 20 IS 25 BP 8288 EP 8291 DI 10.3748/wjg.v20.i25.8288 PG 4 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AK6EM UT WOS:000338520900038 PM 25009405 ER PT J AU Emori, MM Drapkin, R AF Emori, Megan M. Drapkin, Ronny TI The hormonal composition of follicular fluid and its implications for ovarian cancer pathogenesis SO REPRODUCTIVE BIOLOGY AND ENDOCRINOLOGY LA English DT Review DE Follicular fluid; Ovarian cancer; Hormones ID ANTI-MULLERIAN HORMONE; STIMULATING-HORMONE; LUTEINIZING-HORMONE; FALLOPIAN-TUBE; BREAST-CANCER; SIGNALING PATHWAY; MLLERIAN HORMONE; MOUSE OVARY; CELLS; FOLLICLES AB Ovulation has long been associated with an increased risk in ovarian cancer, yet the underlying molecular mechanisms remain obscure. Two aspects of ovulation have been linked to ovarian cancer pathogenesis. The first is the impact of repetitive tissue injury and repair that occurs with each ovulatory event. The second is the release of follicular fluid that accompanies the follicular rupture and its effect on the ovarian and fallopian tube epithelial cells. Hormones are an important component of follicular fluid, which transiently bathes the ovarian surface and fallopian tube epithelium during ovulation. Much work has been done exploring the role of hormones in fertility, but some, such as estrogen, have also been implicated in the pathogenesis of ovarian and other cancers. Understanding the role of hormones within follicular fluid, as well as how they are altered in disorders which increase ovarian cancer risk, will enhance our ability to assess risk and develop preventative strategies. This review provides an in depth discussion of the logistics of using and studying follicular fluid in ovarian cancer research, and discusses the fluctuations in follicular fluid hormone levels during normal physiological processes versus conditions that increase ovarian cancer risk. C1 [Emori, Megan M.; Drapkin, Ronny] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Drapkin, R (reprint author), Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02115 USA. EM ronny_drapkin@dfci.harvard.edu RI Drapkin, Ronny/E-9944-2016 OI Drapkin, Ronny/0000-0002-6912-6977 FU National Institutes of Health [U01 CA152990, R21 CA156021, P50 CA083636]; Dr. Miriam and Sheldon G Adelson Medical Research Foundation; Honorable Tina Brozman Foundation; Robert and Debra First Fund; Gamel Family Fund FX The authors would like to thank Dr. Daniel Cramer, Dr. Raymond Anchan, and Dr. Kevin Elias for providing valuable insight and helping to edit the manuscript, and Michael Cooper (Cooper Graphics: www.cooper247.com) for medical illustration. This work was supported by grants from the National Institutes of Health (U01 CA152990, R21 CA156021, and P50 CA083636), the Dr. Miriam and Sheldon G Adelson Medical Research Foundation, the Honorable Tina Brozman Foundation, the Robert and Debra First Fund, and the Gamel Family Fund. NR 75 TC 9 Z9 9 U1 2 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1477-7827 J9 REPROD BIOL ENDOCRIN JI Reprod. Biol. Endocrinol. PD JUL 6 PY 2014 VL 12 AR 60 DI 10.1186/1477-7827-12-60 PG 8 WC Endocrinology & Metabolism; Reproductive Biology SC Endocrinology & Metabolism; Reproductive Biology GA AL7DE UT WOS:000339292400001 PM 24997727 ER PT J AU Fu, XJ Zhu, YQ Peng, YB Chen, YS Hu, YP Lu, HX Yu, WR Fang, Y Du, JZ Yao, M AF Fu, Xiu-Jun Zhu, Yun-Qing Peng, Yin-Bo Chen, You-Shuang Hu, Yi-Ping Lu, Hua-Xiang Yu, Wei-Rong Fang, Yong Du, Jian-Zhong Yao, Min TI Enzyme activated photodynamic therapy for methicillin-resistant Staphylococcus aureus infection both inv itro and in vivo SO JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY LA English DT Article DE Methicillin-resistant Staphylococcus aureus; Skin wound infection; Photodynamic therapy; Wound healing ID BACTERIA; STRAINS; MODEL AB In recent years, methicillin-resistant Staphylococcus aureus (MRSA) has become one of the most common multi-drug resistant bacteria in both hospital and community. The aim of this study is to investigate the selective inhibition of MRSA by a modified photosensitizer (LAEtNBS) in vitro and the efficacy of MRSA infection treatment by photodynamic therapy (PDT) with LAEtNBS in vivo. LAEtNBS was synthesized by adding a cationic photosensitizer molecule (EtNBS-COOH) and a quencher molecule to two side chains of cephalosporin, which was then shown to have similar absorption and emission wavelengths with EtNBS-COOH, but suppressed yields of fluorescence quantum and singlet oxygen. The selective inactivation and less phototoxicity of LAEtNBS, compared to that of EtNBS-COOH, were assessed and confirmed by conducting PDT to two Staphylococcus aureus strains and human skin cells at a fluence of 15 J/cm(2) with 640 +/- 10 nm LED light. Furthermore, using mouse skin wound model infected with 10(8) CFU of MRSA, we found that both LAEtNBS and EtNBS-COOH were able to treat MRSA infection and enhance wound repair. However, there was no significant difference in the two photosensitizers that might be due to the environment in vivo. Modification of the photosensitizer will be very beneficial for developing new strategies to treat drug resistant bacterial infection with less harm to host tissue. (C) 2014 Elsevier B.V. All rights reserved. C1 [Fu, Xiu-Jun; Peng, Yin-Bo; Chen, You-Shuang; Hu, Yi-Ping; Lu, Hua-Xiang; Yu, Wei-Rong; Fang, Yong; Yao, Min] Shanghai Jiao Tong Univ, Sch Med, Dept Burns & Plast Surg, Peoples Hosp 3, Shanghai 201900, Peoples R China. [Fu, Xiu-Jun; Peng, Yin-Bo; Chen, You-Shuang; Hu, Yi-Ping; Lu, Hua-Xiang; Yu, Wei-Rong; Fang, Yong; Yao, Min] Shanghai Jiao Tong Univ, Sch Med, Inst Traumat Med, Shanghai 201900, Peoples R China. [Zhu, Yun-Qing; Du, Jian-Zhong] Tongji Univ, Sch Mat Sci & Engn, Shanghai 201804, Peoples R China. [Yao, Min] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed,Dept Dermatol, Boston, MA 02114 USA. RP Yao, M (reprint author), Shanghai Jiao Tong Univ, Sch Med, Dept Burns & Plast Surg, Peoples Hosp 3, 280 Mohe Rd, Shanghai 201900, Peoples R China. EM my058@vip.sina.com RI Zhu, Yunqing/E-4861-2014; Du, Jianzhong/E-5399-2010 OI Zhu, Yunqing/0000-0002-2557-003X; Du, Jianzhong/0000-0003-1889-5669 FU Ph.D. Programs Foundation of Ministry of Education of China [20120073110088]; Doctoral Innovative Fund at the School of Medicine, Shanghai Jiao Tong University [BXJ201238]; National Natural Science Foundation of China [81272113] FX This study was supported partially by a Grant from Ph.D. Programs Foundation of Ministry of Education of China (20120073110088), and a Grant from the Doctoral Innovative Fund at the School of Medicine, Shanghai Jiao Tong University (BXJ201238), and a Grant from the National Natural Science Foundation of China (81272113). NR 25 TC 7 Z9 7 U1 2 U2 34 PU ELSEVIER SCIENCE SA PI LAUSANNE PA PO BOX 564, 1001 LAUSANNE, SWITZERLAND SN 1011-1344 J9 J PHOTOCH PHOTOBIO B JI J. Photochem. Photobiol. B-Biol. PD JUL 5 PY 2014 VL 136 BP 72 EP 80 DI 10.1016/j.jphotobiol.2014.04.016 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AJ7MI UT WOS:000337880400010 PM 24857792 ER PT J AU Bartlett, JD Simmer, JP AF Bartlett, John D. Simmer, James P. TI Kallikrein-related peptidase-4 (KLK4): role in enamel formation and revelations from ablated mice SO FRONTIERS IN PHYSIOLOGY LA English DT Review DE enamel development; MMP20; amelogenin; ameloblastin; enamelin; enamel crystallites; enamel rods ID HYPOMATURATION AMELOGENESIS-IMPERFECTA; DEVELOPING DENTAL ENAMEL; SERINE PROTEINASE 1; ELECTRON-MICROSCOPY; MMP20 MUTATIONS; PORCINE ENAMEL; HUMAN-TEETH; EXPRESSION; MOUSE; MATRIX AB Enamel development occurs in stages. During the secretory stage, a soft protein rich enamel layer is produced that expands to reach its final thickness. During the maturation stage, proteins are removed and the enamel matures into the hardest substance in the body. KLK4 is expressed during the transition from secretory to the maturation stage and its expression continues throughout maturation. KLK4 is a glycosylated chymotrypsin-like serine protease that cleaves enamel matrix proteins prior to their export out of the hardening enamel layer. Mutations in KLK4 can cause autosomal recessive, non-syndromic enamel malformations in humans and mice. Klk4 ablated mice initially have normal-looking teeth with enamel of full thickness. However, the enamel is soft and protein-rich. Three findings are notable from Klk4 ablated mice: first, enamel rods fall from the interrod enamel leaving behind empty holes where the enamel fractures near the underlying dentin surface. Second, the similar to 10,000 crystallites that normally fuse to form a solid enamel rod fail to grow together in the ablated mice and can fall out of the rods. Third, and most striking, the crystallites grow substantially in width and thickness (a- and b-axis) in the ablated mice until they almost interlock. The crystallites grow in defined enamel rods, but interlocking is prevented presumably because too much protein remains. Conventional thought holds that enamel proteins bind specifically to the sides of enamel crystals to inhibit growth in width and thickness so that the thin, ribbon-like enamel crystallites grow predominantly in length. Results from Klk4 ablated mice demonstrate that this convention requires updating. An alternative mechanism is proposed whereby enamel proteins serve to form a mold or support structure that shapes and orients the mineral ribbons as they grow in length. The remnants of this support structure must be removed by KLK4 so that the crystallites can interlock to form fully hardened enamel C1 [Bartlett, John D.] Harvard Univ, Sch Dent Med, Cambridge, MA 02142 USA. [Bartlett, John D.] Forsyth Inst, Dept Mineralized Tissue Biol, Cambridge, MA USA. [Simmer, James P.] Univ Michigan, Sch Dent, Dept Biol & Mat Sci, Ann Arbor, MI 48109 USA. RP Bartlett, JD (reprint author), Harvard Univ, Sch Dent Med, Dept Mineralized Tissue Biol, Forsyth Inst, 245 First St, Cambridge, MA 02142 USA. EM jbartlett@forsyth.org FU National Institute of Dental and Craniofacial Research of the National Institutes of Health [RO1DE016276, R01DE019775] FX Research reported in this publication was supported by the National Institute of Dental and Craniofacial Research of the National Institutes of Health under award numbers RO1DE016276 (John D. Bartlett) and R01DE019775 (James P. Simmer). NR 69 TC 7 Z9 7 U1 0 U2 3 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-042X J9 FRONT PHYSIOL JI Front. Physiol. PD JUL 4 PY 2014 VL 5 AR 240 DI 10.3389/fphys.2014.00240 PG 7 WC Physiology SC Physiology GA AX7AK UT WOS:000347069000001 PM 25071586 ER PT J AU Clark, T Ciccarese, PN Goble, CA AF Clark, Tim Ciccarese, Paolo N. Goble, Carole A. TI Micropublications: a semantic model for claims, evidence, arguments and annotations in biomedical communications SO JOURNAL OF BIOMEDICAL SEMANTICS LA English DT Article DE Argumentation; Annotation; Data citation; Digital abstract; Scientific discourse; Scientific evidence; Methods citation; Research reproducibility; Nanopublications ID INCLUSION-BODY MYOSITIS; ALZHEIMERS-DISEASE; HUMAN MUSCLE; SCIENCE RESEARCH; AMYLOID PROTEIN; FULL-TEXT; INFORMATION; CHALLENGE; SWAN; LOCALIZATION AB Background: Scientific publications are documentary representations of defeasible arguments, supported by data and repeatable methods. They are the essential mediating artifacts in the ecosystem of scientific communications. The institutional "goal" of science is publishing results. The linear document publication format, dating from 1665, has survived transition to the Web. Intractable publication volumes; the difficulty of verifying evidence; and observed problems in evidence and citation chains suggest a need for a web-friendly and machine-tractable model of scientific publications. This model should support: digital summarization, evidence examination, challenge, verification and remix, and incremental adoption. Such a model must be capable of expressing a broad spectrum of representational complexity, ranging from minimal to maximal forms. Results: The micropublications semantic model of scientific argument and evidence provides these features. Micropublications support natural language statements; data; methods and materials specifications; discussion and commentary; challenge and disagreement; as well as allowing many kinds of statement formalization. The minimal form of a micropublication is a statement with its attribution. The maximal form is a statement with its complete supporting argument, consisting of all relevant evidence, interpretations, discussion and challenges brought forward in support of or opposition to it. Micropublications may be formalized and serialized in multiple ways, including in RDF. They may be added to publications as stand-off metadata. An OWL 2 vocabulary for micropublications is available at http://purl.org/mp. A discussion of this vocabulary along with RDF examples from the case studies, appears as OWL Vocabulary and RDF Examples in Additional file 1. Conclusion: Micropublications, because they model evidence and allow qualified, nuanced assertions, can play essential roles in the scientific communications ecosystem in places where simpler, formalized and purely statement-based models, such as the nanopublications model, will not be sufficient. At the same time they will add significant value to, and are intentionally compatible with, statement-based formalizations. We suggest that micropublications, generated by useful software tools supporting such activities as writing, editing, reviewing, and discussion, will be of great value in improving the quality and tractability of biomedical communications. C1 [Clark, Tim; Ciccarese, Paolo N.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Clark, Tim; Ciccarese, Paolo N.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Clark, Tim; Goble, Carole A.] Univ Manchester, Sch Comp Sci, Manchester M13 9PL, Lancs, England. RP Clark, T (reprint author), Massachusetts Gen Hosp, Dept Neurol, 55 Fruit St, Boston, MA 02114 USA. EM tim_clark@harvard.edu OI Clark, Timothy/0000-0003-4060-7360 FU Elsevier Laboratories; Eli Lilly and Company; U.S. National Insitutes of Health; National Institute of General Medical Sciences of the United States National Institutes of Health [GM10331601] FX We are grateful for the support of Elsevier Laboratories, Eli Lilly and Company, the U.S. National Insitutes of Health (through the Neuroscience Information Framework) and anonymous donor foundations, which funded our work at the Massachusetts General Hospital.; Part of this work was conducted using the Protege resource, which is supported by grant GM10331601 from the National Institute of General Medical Sciences of the United States National Institutes of Health. NR 129 TC 4 Z9 4 U1 2 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2041-1480 J9 J BIOMED SEMANT JI J. Biomed. Semant. PD JUL 4 PY 2014 VL 5 AR 28 DI 10.1186/2041-1480-5-28 PG 33 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA AR6RT UT WOS:000343711300001 PM 26261718 ER PT J AU Liu, T Pursnani, A Sharma, UC Vorasettakarnkij, Y Verdini, D Deeprasertkul, P Lee, AM Lumish, H Sidhu, MS Medina, H Danik, S Abbara, S Holmvang, G Hoffmann, U Ghoshhajra, BB AF Liu, Ting Pursnani, Amit Sharma, Umesh C. Vorasettakarnkij, Yongkasem Verdini, Daniel Deeprasertkul, Peerawut Lee, Ashley M. Lumish, Heidi Sidhu, Manavjot S. Medina, Hector Danik, Stephan Abbara, Suhny Holmvang, Godtfred Hoffmann, Udo Ghoshhajra, Brian B. TI Effect of the 2010 task force criteria on reclassification of cardiovascular magnetic resonance criteria for arrhythmogenic right ventricular cardiomyopathy SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Article DE Arrhythmogenic right ventricular cardiomyopathy; 2010 task force criteria; Cardiovascular magnetic resonance ID MYOCARDIAL FIBROSIS; FATTY INFILTRATION; DIAGNOSTIC YIELD; DYSPLASIA; PREVALENCE; DYSPLASIA/CARDIOMYOPATHY; ENHANCEMENT; ANGIOGRAPHY; DEPOSITION; INSIGHTS AB Background: We sought to evaluate the effect of application of the revised 2010 Task Force Criteria (TFC) on the prevalence of major and minor Cardiovascular Magnetic Resonance (CMR) criteria for Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) versus application of the original 1994 TFC. We also assessed the utility of MRI to identify alternative diagnoses for patients referred for ARVC evaluation. Methods: 968 consecutive patients referred to our institution for CMR with clinical suspicion of ARVC from 1995 to 2010, were evaluated for the presence of major and minor CMR criteria per the 1994 and 2010 ARVC TFC. CMR criteria included right ventricle (RV) dilatation, reduced RV ejection fraction, RV aneurysm, or regional RV wall motion abnormalities. When quantitative measures of RV size and function were not available, and in whom abnormal size or function was reported, a repeat quantitative analysis by 2 qualified CMR physicians in consensus. Results: Of 968 patients, 220 (22.7%) fulfilled either a major or a minor 1994 TFC, and 25 (2.6%) fulfilled any of the 2010 TFC criterion. Among patients meeting any 1994 criteria, only 25 (11.4%) met at least one 2010 criterion. All patients who fulfilled a 2010 criteria also satisfied at least one 1994 criterion. Per the 2010 TFC, 21 (2.2%) patients met major criteria and 4 (0.4%) patients fulfilled at least one minor criterion. Eight patients meeting 1994 minor criteria were reclassified as satisfying 2010 major criteria, while 4 patients fulfilling 1994 major criteria were reclassified to only minor or no criteria under the 2010 TFC. Eighty-nine (9.2%) patients had alternative cardiac diagnoses, including 43 (4.4%) with clinically significant potential ARVC mimics. These included cardiac sarcoidosis, RV volume overload conditions, and other cardiomyopathies. Conclusions: Application of the 2010 TFC resulted in reduction of total patients meeting any diagnostic CMR criteria for ARVC from 22.7% to 2.6% versus the 1994 TFC. CMR identified alternative cardiac diagnoses in 9.2% of patients, and 4.4% of the diagnoses were potential mimics of ARVC. C1 [Liu, Ting] China Med Univ, Affiliated Hosp 1, Dept Radiol, Shenyang, Peoples R China. [Liu, Ting; Pursnani, Amit; Sharma, Umesh C.; Vorasettakarnkij, Yongkasem; Verdini, Daniel; Deeprasertkul, Peerawut; Lee, Ashley M.; Lumish, Heidi; Sidhu, Manavjot S.; Medina, Hector; Danik, Stephan; Abbara, Suhny; Holmvang, Godtfred; Hoffmann, Udo; Ghoshhajra, Brian B.] Massachusetts Gen Hosp, Dept Radiol, Cardiac CT MRI PET Program, Boston, MA 02114 USA. [Danik, Stephan] Mt Sinai St Lukes Roosevelt Hosp, Electrophysiol Lab, New York, NY USA. [Abbara, Suhny] Univ Texas Dallas, SW Med Ctr, Dept Radiol, Cardiothorac Imaging Div, Dallas, TX 75235 USA. RP Liu, T (reprint author), China Med Univ, Affiliated Hosp 1, Dept Radiol, Shenyang, Peoples R China. EM tingliu365@gmail.com NR 32 TC 9 Z9 9 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1097-6647 EI 1532-429X J9 J CARDIOVASC MAGN R JI J. Cardiov. Magn. Reson. PD JUL 4 PY 2014 VL 16 AR 47 DI 10.1186/1532-429X-16-47 PG 10 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA AM7QD UT WOS:000340061600001 PM 24996808 ER PT J AU Burns, CG Burns, CE AF Burns, C. Geoffrey Burns, Caroline E. TI A crowning achievement for deciphering coronary origins SO SCIENCE LA English DT Editorial Material ID ENDOTHELIAL-CELLS; ARTERIES; FORM C1 [Burns, C. Geoffrey; Burns, Caroline E.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. [Burns, C. Geoffrey; Burns, Caroline E.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Burns, C. Geoffrey; Burns, Caroline E.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Burns, CG (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. EM cburns6@mgh.harvard.edu NR 13 TC 3 Z9 4 U1 0 U2 6 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD JUL 4 PY 2014 VL 345 IS 6192 BP 28 EP 29 DI 10.1126/science.1256866 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK2XU UT WOS:000338284400032 PM 24994633 ER PT J AU Iversen, L Tu, HL Lin, WC Christensen, SM Abel, SM Iwig, J Wu, HJ Gureasko, J Rhodes, C Petit, RS Hansen, SD Thill, P Yu, CH Stamou, D Chakraborty, AK Kuriyan, J Groves, JT AF Iversen, Lars Tu, Hsiung-Lin Lin, Wan-Chen Christensen, Sune M. Abel, Steven M. Iwig, Jeff Wu, Hung-Jen Gureasko, Jodi Rhodes, Christopher Petit, Rebecca S. Hansen, Scott D. Thill, Peter Yu, Cheng-Han Stamou, Dimitrios Chakraborty, Arup K. Kuriyan, John Groves, Jay T. TI Ras activation by SOS: Allosteric regulation by altered fluctuation dynamics SO SCIENCE LA English DT Article ID SINGLE-MOLECULE; SIGNAL-TRANSDUCTION; ENZYME CATALYSIS; PLASMA-MEMBRANE; HISTONE DOMAIN; SEVENLESS; CELL; PROTEINS; TIME; AUTOINHIBITION AB Activation of the small guanosine triphosphatase H-Ras by the exchange factor Son of Sevenless (SOS) is an important hub for signal transduction. Multiple layers of regulation, through protein and membrane interactions, govern activity of SOS. We characterized the specific activity of individual SOS molecules catalyzing nucleotide exchange in H-Ras. Single-molecule kinetic traces revealed that SOS samples a broad distribution of turnover rates through stochastic fluctuations between distinct, long-lived (more than 100 seconds), functional states. The expected allosteric activation of SOS by Ras-guanosine triphosphate (GTP) was conspicuously absent in the mean rate. However, fluctuations into highly active states were modulated by Ras-GTP. This reveals a mechanism in which functional output may be determined by the dynamical spectrum of rates sampled by a small number of enzymes, rather than the ensemble average. C1 [Iversen, Lars; Tu, Hsiung-Lin; Lin, Wan-Chen; Christensen, Sune M.; Wu, Hung-Jen; Petit, Rebecca S.; Hansen, Scott D.; Kuriyan, John; Groves, Jay T.] Univ Calif Berkeley, Howard Hughes Med Inst, Dept Chem, Berkeley, CA 94720 USA. [Abel, Steven M.; Chakraborty, Arup K.] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Iwig, Jeff; Gureasko, Jodi; Kuriyan, John] Univ Calif Berkeley, Howard Hughes Med Inst, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. [Rhodes, Christopher] Univ Calif Berkeley, Dept Mech Engn, Berkeley, CA 94720 USA. [Thill, Peter; Chakraborty, Arup K.] MIT, Dept Chem, Cambridge, MA 02139 USA. [Yu, Cheng-Han; Groves, Jay T.] Natl Univ Singapore, Mechanobiol Inst, Singapore 117548, Singapore. [Stamou, Dimitrios] Univ Copenhagen, Dept Chem, DK-2100 Copenhagen, Denmark. [Stamou, Dimitrios] Univ Copenhagen, Nanosci Ctr, Copenhagen, Denmark. [Chakraborty, Arup K.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Chakraborty, Arup K.] Ragon Inst Massachusetts Gen Hosp MIT & Harvard, Cambridge, MA 02139 USA. [Chakraborty, Arup K.] MIT, Dept Phys, Cambridge, MA 02139 USA. [Chakraborty, Arup K.] MIT, Inst Med Engn & Sci, Cambridge, MA 02139 USA. [Kuriyan, John; Groves, Jay T.] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Phys Biosci Div, Berkeley, CA 94720 USA. [Kuriyan, John; Groves, Jay T.] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Div Mat Sci, Berkeley, CA 94720 USA. [Groves, Jay T.] Berkeley Educ Alliance Res Singapore, Singapore 138602, Singapore. RP Groves, JT (reprint author), Univ Calif Berkeley, Howard Hughes Med Inst, Dept Chem, Berkeley, CA 94720 USA. EM jtgroves@lbl.gov RI Yu, Cheng-han/K-8732-2013; Iversen, Lars/C-5298-2011; Stamou, Dimitrios/D-5042-2016; OI Iversen, Lars/0000-0002-1314-130X; Stamou, Dimitrios/0000-0001-8456-8995; Christensen, Sune/0000-0001-9650-6660; Wu, Hung-Jen/0000-0003-3082-7431 FU NIH [P01 AI091580]; Danish Council for Independent Research, Natural Sciences; Mechanobiology Institute, National University of Singapore; Berkeley Education Alliance for Research in Singapore FX Major support was provided by NIH P01 AI091580. Additional support was provided by the Danish Council for Independent Research, Natural Sciences (L. I., S. M. C., and D. S.), by the Mechanobiology Institute, National University of Singapore (C.-H.Y. and J.T.G.), and by the Berkeley Education Alliance for Research in Singapore (J.T.G.). L. I., H.-L. T., W.-C. L., and J.T.G. planned and designed the research; H.-L. T. and L. I. performed experiments and analyzed data; S. M. C. and W.-C. L. assisted with experiments; H.-L. T., S. M. C., and H.-J.W. developed algorithms for data analysis; H.-L. T., S. M. A., and P. T. performed stochastic simulations; J.I., J.G., and S. D. H. prepared proteins; C.-H.Y., C. R., and R. S. P. prepared patterned substrates; L. I., H.-L. T., and J.T.G. wrote the manuscript; J.T.G. supervised the project. All authors commented on the manuscript. NR 43 TC 29 Z9 30 U1 9 U2 84 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD JUL 4 PY 2014 VL 345 IS 6192 BP 50 EP 54 DI 10.1126/science.1250373 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AK2XU UT WOS:000338284400045 PM 24994643 ER PT J AU Sanchez, SH Sethi, SS Santos, SL Boockvar, K AF Sanchez, Sadie H. Sethi, Sanjum S. Santos, Susan L. Boockvar, Kenneth TI Implementing medication reconciliation from the planner's perspective: a qualitative study SO BMC HEALTH SERVICES RESEARCH LA English DT Article DE Medication reconciliation; Adverse drug event; Patient safety; Implementation; National patient safety goals AB Background: Medication reconciliation can reduce adverse events associated with prescribing errors at transitions between sites of care. Though a U.S. Joint Commission National Patient Safety Goal since 2006, at present organizations continue to have difficulty implementing it. The objective of this study was to examine medication reconciliation implementation from the perspective of individuals involved in the planning process in order to identify recurrent themes, including facilitators and barriers, that might inform other organizations' planning and implementation efforts. Methods: We performed semi-structured interviews with individuals who had a role in planning medication reconciliation implementation at a large urban academic medical center in the U.S. and its affiliated Veterans Affairs hospital. We queried respondents' perceptions of the implementation process and their experience with facilitators and barriers. Transcripts were coded and analyzed using a grounded theory approach. The themes that emerged were subsequently categorized using the Consolidated Framework for Implementation Research (CFIR). Results: There were 13 respondents, each with one or more organizational roles in quality improvement, information technology, medication safety, and education. Respondents described a resource-and time-intensivemedication reconciliation planning process. The planning teams' membership and functioning were recognized as important factors to a successful planning process. Implementation was facilitated by planners' understanding of the principles of performance improvement, in particular, fitting the new process into the workflow of multiple disciplines. Nevertheless, a need for significant professional role changes was recognized. Staff training was recognized to be an important part of roll-out, but training had several limitations. Planners monitored compliance to help sustain the process, but acknowledged that this did not ensure that medication reconciliation actually achieved its primary goal of reducing errors. Study findings fit multiple constructs in the CFIR model. Conclusions: Study findings suggest that to improve the likelihood of a successful implementation of medication reconciliation, planners should, among other considerations, involve a multidisciplinary planning team, recognize the significant professional role changes that may be needed, and consider devoting resources not just to compliance monitoring but also to monitoring of the process' impact on prescribing. C1 [Sanchez, Sadie H.; Boockvar, Kenneth] Icahn Sch Med Mt Sinai, One Gustave L Levy Pl,Box 1057, New York, NY 10029 USA. [Sethi, Sanjum S.] Boston Univ, Sch Med, Div Cardiol, Boston, MA 02118 USA. [Santos, Susan L.] VA New Jersey Hlth Care Syst, War Related Illness & Injury Study Ctr East Orang, E Orange, NJ 07018 USA. [Santos, Susan L.] Rutgers State Univ, Sch Publ Hlth Piscataway, Piscataway, NJ USA. [Boockvar, Kenneth] James J Peters Vet Affairs Med Ctr, Geriatr Res Educ & Clin Ctr, Bronx, NY 10468 USA. [Boockvar, Kenneth] Jewish Home Lifecare Res Inst Aging, New York, NY USA. RP Boockvar, K (reprint author), Icahn Sch Med Mt Sinai, One Gustave L Levy Pl,Box 1057, New York, NY 10029 USA. EM kenneth.boockvar@mssm.edu OI Boockvar, Kenneth/0000-0003-1165-5558 FU VA Health Services Research and Development [IAB-05-204, REA 08-260]; Greenwall Foundation FX The authors would like to acknowledge the contribution of Liz Rosen (Lehigh University) who helped enter and sort the coded files. This project was supported by VA Health Services Research and Development grants IAB-05-204 and REA 08-260. Dr. Boockvar was supported by the Greenwall Foundation. NR 23 TC 8 Z9 9 U1 2 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6963 J9 BMC HEALTH SERV RES JI BMC Health Serv. Res. PD JUL 4 PY 2014 VL 14 AR 290 DI 10.1186/1472-6963-14-290 PG 10 WC Health Care Sciences & Services SC Health Care Sciences & Services GA V42FM UT WOS:000209599700001 PM 24996538 ER PT J AU Wynn, JK Jahshan, C Green, MF AF Wynn, Jonathan K. Jahshan, Carol Green, Michael F. TI Multisensory integration in schizophrenia: a behavioural and eventrelated potential study SO COGNITIVE NEUROPSYCHIATRY LA English DT Article DE schizophrenia; multisensory integration; ERP; race model ID AUDIOVISUAL INTEGRATION; PROCESSING DEFICITS; RECOGNITION; INFORMATION; SPEECH; FACILITATION; PERSPECTIVE; STIMULI; BINDING; HUMANS AB IntroductionSuccessful processing of multisensory stimuli increases the likelihood of detection or identification of salient, biologically significant events faster and more efficiently than unisensory inputs. Schizophrenia (SZ) patients show deficits in unisensory processing, but it is unclear whether impairments are seen to multisensory stimuli, a process known as multisensory integration (MSI). We used behavioural and event-related potential (ERP) measures to examine MSI in SZ and healthy controls (HC).MethodsThirty-three SZ and 30 HC completed a target detection task with unisensory and multisensory stimuli. Reaction times (RT) were measured while their electroencephalogram (EEG) was recorded. Two auditory (N100 and P200) and visual (P100 and N160) ERPs were examined. MSI was analysed in terms of violations of RT to the race model and by comparing ERPs in the MSI condition to the sum of the unisensory ERPs.ResultsBoth groups showed faster RT in MSI compared to unisensory conditions. SZ had non-significantly fewer violations of the race model compared to HC. SZ had significantly smaller amplitudes to unisensory visual N160 and auditory P100 relative to HC; there were no significant group differences on any ERP measure of MSI.ConclusionsSZ showed relatively intact MSI with subtle (non-significant) differences at the neural and behavioural levels compared to HC. Our results suggest that neural processes associated with MSI are not an additional source of impairment in SZ. C1 [Wynn, Jonathan K.; Jahshan, Carol; Green, Michael F.] VA Greater Los Angeles Healthcare Syst, Mental Illness Res Educ & Clin Ctr, Los Angeles, CA 90073 USA. [Wynn, Jonathan K.; Green, Michael F.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Behav Sci, Los Angeles, CA 90095 USA. RP Wynn, JK (reprint author), VA Greater Los Angeles Healthcare Syst, Mental Illness Res Educ & Clin Ctr, Los Angeles, CA 90073 USA. EM jkwynn@ucla.edu RI Wynn, Jonathan/H-3749-2014; Keil, Julian/I-3337-2016 OI Wynn, Jonathan/0000-0002-1763-8540; Keil, Julian/0000-0003-4195-7397 FU National Institute of Mental Health [MH043292, MH065707, MH091468] FX This work was supported by grants from the National Institute of Mental Health [grant number MH043292], [grant number MH065707] and [grant number MH091468]. NR 44 TC 2 Z9 2 U1 1 U2 10 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1354-6805 EI 1464-0619 J9 COGN NEUROPSYCHIATRY JI Cogn. Neuropsychiatry PD JUL 4 PY 2014 VL 19 IS 4 BP 319 EP 336 DI 10.1080/13546805.2013.866892 PG 18 WC Psychiatry SC Psychiatry GA AE5VW UT WOS:000334058400003 PM 24397788 ER PT J AU Boudreaux, ED Abar, B O'Hea, E Sullivan, AF Cydulka, R Bernstein, SL Camargo, CA AF Boudreaux, Edwin D. Abar, Beau O'Hea, Erin Sullivan, Ashley F. Cydulka, Rita Bernstein, Steven L. Camargo, Carlos A., Jr. TI Cognitive and affective predictors of smoking after a sentinel health event SO PSYCHOLOGY HEALTH & MEDICINE LA English DT Article DE reliability; validity; motivation; tobacco; stage of change; tobacco cessation ID PROBLEMS SCREEN; BEHAVIOR-CHANGE; CESSATION; SEVERITY; MODEL AB Objective: This study examined how smoking-related causal attributions, perceived illness severity, and event-related emotions relate to both intentions to quit and subsequent smoking behavior after an acute medical problem (sentinel event). Methods: Three hundred and seventy-five patients were enrolled from 10 emergency departments (EDs) across the USA and followed for six months. Two saturated, manifest structural equation models were performed: one predicting quit attempts and the other predicting seven-day point prevalence abstinence at 14days, three months, and six months after the index ED visit. Stage of change was regressed onto each of the other predictor variables (causal attribution, perceived illness severity, event-related emotions) and covariates, and tobacco cessation outcomes were regressed on all of the predictor variables and covariates. Results: Non-White race, baseline stage of change, and an interaction between causal attribution and event-related fear were the strongest predictors of quit attempt. In contrast, abstinence at six months was most strongly predicted by baseline stage of change and nicotine dependence. Conclusion: Predictors of smoking behavior after an acute medical illness are complex and dynamic. The relations vary depending on the outcome examined (quit attempts vs. abstinence), differ based on the time that has progressed since the event, and include significant interactions. C1 [Boudreaux, Edwin D.] Univ Massachusetts, Sch Med, Dept Emergency Med, Worcester, MA USA. [Boudreaux, Edwin D.; O'Hea, Erin] Univ Massachusetts, Sch Med, Dept Psychiat, Worcester, MA 01655 USA. [Boudreaux, Edwin D.] Univ Massachusetts, Sch Med, Dept Quantitat Hlth Sci, Worcester, MA USA. [Abar, Beau] Brown Univ, Alpert Med Sch, Brown Ctr Study Children Risk, Providence, RI 02912 USA. [O'Hea, Erin] Stonehill Coll, Dept Psychol, Easton, MA 02357 USA. [Sullivan, Ashley F.; Camargo, Carlos A., Jr.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Cydulka, Rita] Case Western Reserve Univ, Sch Med, Metro Hlth Med Ctr, Dept Emergency Med, Cleveland, OH USA. [Cydulka, Rita] Case Western Reserve Univ, Sch Med, Metro Hlth Med Ctr, Dept Biostat & Epidemiol, Cleveland, OH USA. [Bernstein, Steven L.] Yale Univ, Sch Med, Dept Emergency Med, New Haven, CT USA. RP O'Hea, E (reprint author), Stonehill Coll, Dept Psychol, Easton, MA 02357 USA. EM eohea@stonehill.edu OI Boudreaux, Edwin/0000-0002-3223-6371 FU NIH/NIDA [R21 DA020771, 6/01/07-5/30/09] FX NIH/NIDA [R21 DA020771] Boudreaux (PI) 6/01/07-5/30/09. Multicenter Pilot Studies for ED Tobacco Interventions. To build capacity to carry out a multi-center randomized controlled trial of one or more tobacco interventions initiated in the emergency department. We will do this by using combined qualitative and quantitative methods. NR 12 TC 0 Z9 0 U1 0 U2 8 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1354-8506 EI 1465-3966 J9 PSYCHOL HEALTH MED JI Psychol. Health Med. PD JUL 4 PY 2014 VL 19 IS 4 BP 402 EP 409 DI 10.1080/13548506.2013.832781 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AG0FA UT WOS:000335089500004 PM 24021099 ER PT J AU Liu, KD Wilson, JG Zhuo, HJ Caballero, L McMillan, ML Fang, XH Cosgrove, K Calfee, CS Lee, JW Kangelaris, KN Gotts, JE Rogers, AJ Levitt, JE Wiener-Kronish, JP Delucchi, KL Leavitt, AD McKenna, DH Thompson, BT Matthay, MA AF Liu, Kathleen D. Wilson, Jennifer G. Zhuo, Hanjing Caballero, Lizette McMillan, Melanie L. Fang, Xiaohui Cosgrove, Katherine Calfee, Carolyn S. Lee, Jae-Woo Kangelaris, Kirsten N. Gotts, Jeffrey E. Rogers, Angela J. Levitt, Joseph E. Wiener-Kronish, Jeanine P. Delucchi, Kevin L. Leavitt, Andrew D. McKenna, David H. Thompson, B. Taylor Matthay, Michael A. TI Design and implementation of the START (STem cells for ARDS Treatment) trial, a phase 1/2 trial of human mesenchymal stem/stromal cells for the treatment of moderate-severe acute respiratory distress syndrome SO ANNALS OF INTENSIVE CARE LA English DT Article DE Acute lung injury; Clinical trial; Mesenchymal stem/stromal cell; Pulmonary edema ID ACUTE LUNG INJURY; RANDOMIZED CONTROLLED-TRIAL; BACTERIAL CLEARANCE; STROMAL CELLS; SEPSIS; VENTILATION; MORTALITY; SURVIVAL; MANAGEMENT; SECRETION AB Background: Despite advances in supportive care, moderate-severe acute respiratory distress syndrome (ARDS) is associated with high mortality rates, and novel therapies to treat this condition are needed. Compelling pre-clinical data from mouse, rat, sheep and ex vivo perfused human lung models support the use of human mesenchymal stem (stromal) cells (MSCs) as a novel intravenous therapy for the early treatment of ARDS. Methods: This article describes the study design and challenges encountered during the implementation and phase 1 component of the START (STem cells for ARDS Treatment) trial, a phase 1/2 trial of bone marrow-derived human MSCs for moderate-severe ARDS. A trial enrolling 69 subjects is planned (9 subjects in phase 1, 60 subjects in phase 2 treated with MSCs or placebo in a 2: 1 ratio). Results: This report describes study design features that are unique to a phase 1 trial in critically ill subjects and the specific challenges of implementation of a cell-based therapy trial in the ICU. Conclusions: Experience gained during the design and implementation of the START study will be useful to investigators planning future phase 1 clinical trials based in the ICU, as well as trials of cell-based therapy for other acute illnesses. C1 [Liu, Kathleen D.] Univ Calif San Francisco, Dept Nephrol, San Francisco, CA 94143 USA. [Liu, Kathleen D.; Lee, Jae-Woo; Matthay, Michael A.] Univ Calif San Francisco, Dept Anesthesia, San Francisco, CA 94143 USA. [Wilson, Jennifer G.] Univ Calif San Francisco, Dept Emergency Med, San Francisco, CA 94143 USA. [Wilson, Jennifer G.] Univ Calif San Francisco, Dept Crit Care Med, San Francisco, CA 94143 USA. [Zhuo, Hanjing; Fang, Xiaohui; Matthay, Michael A.] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA. [Caballero, Lizette; McMillan, Melanie L.] Univ Calif San Francisco, Clin Labs, Bone Marrow Ctr, San Francisco, CA 94143 USA. [Cosgrove, Katherine; Thompson, B. Taylor] Massachusetts Gen Hosp, Dept Med, Div Pulm & Crit Care Med, Boston, MA 02114 USA. [Calfee, Carolyn S.; Gotts, Jeffrey E.] Univ Calif San Francisco, Dept Med, Div Pulm & Crit Care Med, San Francisco, CA USA. [Kangelaris, Kirsten N.] Univ Calif San Francisco, Dept Med, Div Hosp Med, San Francisco, CA USA. [Rogers, Angela J.; Levitt, Joseph E.] Stanford Univ, Dept Med, Div Pulm & Crit Care Med, Stanford, CA 94305 USA. [Wiener-Kronish, Jeanine P.] Harvard Univ, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Cambridge, MA 02138 USA. [Delucchi, Kevin L.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Leavitt, Andrew D.] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA. [McKenna, David H.] Univ Minnesota, Dept Lab Med & Pathol, Div Transfus Med, Minneapolis, MN 55455 USA. [Matthay, Michael A.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. RP Liu, KD (reprint author), Univ Calif San Francisco, Dept Nephrol, San Francisco, CA 94143 USA. EM kathleen.liu@ucsf.edu FU UCSF Clinical and Translational Research Institute; National Heart, Lung and Blood Institute; NHLBI [U01 HL10871301]; UCSF T1 Catalyst Program FX We want to thank the UCSF Clinical and Translational Research Institute for funding support and for early discussions that shaped this clinical trial design, and in particular Drs. June Lee and Ruben Rathnasingham as well as the National Heart, Lung and Blood Institute for funding support. We thank Drs. Elizabeth Leininger, Danny McAuley and Eric Seeley for helpful discussions relevant to the IND preparation and protocol design. We thank study coordinators and bone marrow transplant staff at all of the participating sites who have made the study possible. We appreciate the support of the NHLBI U01 HL10871301 grant plus the UCSF T1 Catalyst Program. NR 32 TC 13 Z9 14 U1 0 U2 10 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 2110-5820 J9 ANN INTENSIVE CARE JI Ann. Intensive Care PD JUL 3 PY 2014 VL 4 AR 22 DI 10.1186/s13613-014-0022-z PG 9 WC Critical Care Medicine SC General & Internal Medicine GA AT8EO UT WOS:000345167000001 PM 25593740 ER PT J AU Placke, T Faber, K Nonami, A Putwain, SL Salih, HR Heidel, FH Kramer, A Root, DE Barbie, DA Krivtsov, AV Armstrong, SA Hahn, WC Huntly, BJ Sykes, SM Milsom, MD Scholl, C Frohling, S AF Placke, Theresa Faber, Katrin Nonami, Atsushi Putwain, Sarah L. Salih, Helmut R. Heidel, Florian H. Kraemer, Alwin Root, David E. Barbie, David A. Krivtsov, Andrei V. Armstrong, Scott A. Hahn, William C. Huntly, Brian J. Sykes, Stephen M. Milsom, Michael D. Scholl, Claudia Froehling, Stefan TI Requirement for CDK6 in MLL-rearranged acute myeloid leukemia SO BLOOD LA English DT Article ID DEPENDENT KINASE 6; MIXED-LINEAGE LEUKEMIA; SYNTHETIC LETHAL INTERACTION; MANTLE CELL LYMPHOMA; NF-KAPPA-B; STEM-CELLS; FUSION PROTEINS; THYMOCYTE DEVELOPMENT; CDK4/6 INHIBITION; GENE-EXPRESSION AB Chromosomal rearrangements involving the H3K4 methyltransferase mixed-lineage leukemia (MLL) trigger aberrant gene expression in hematopoietic progenitors and give rise to an aggressive subtype of acute myeloid leukemia (AML). Insights into MLL fusion-mediated leukemogenesis have not yet translated into better therapies because MLL is difficult to target directly, and the identity of the genes downstream of MLL whose altered transcription mediates leukemic transformation are poorly annotated. We used a functional genetic approach to uncover that AML cells driven by MLL-AF9 are exceptionally reliant on the cell-cycle regulator CDK6, but not its functional homolog CDK4, and that the preferential growth inhibition induced by CDK6 depletion is mediated through enhanced myeloid differentiation. CDK6 essentiality is also evident in AML cells harboring alternate MLL fusions and a mouse model of MLL-AF9-driven leukemia and can be ascribed to transcriptional activation of CDK6 by mutant MLL. Importantly, the context-dependent effects of lowering CDK6 expression are closely phenocopied by a small-molecule CDK6 inhibitor currently in clinical development. These data identify CDK6 as critical effector of MLL fusions in leukemogenesis that might be targeted to overcome the differentiation block associated with MLL-rearranged AML, and underscore that cell-cycle regulators may have distinct, noncanonical, and nonredundant functions in different contexts. C1 [Placke, Theresa; Froehling, Stefan] Natl Ctr Tumor Dis, Dept Translat Oncol, D-69120 Heidelberg, Germany. [Placke, Theresa; Froehling, Stefan] German Canc Res Ctr, D-69120 Heidelberg, Germany. [Placke, Theresa; Salih, Helmut R.; Kraemer, Alwin; Froehling, Stefan] German Consortium Translat Canc Res, Heidelberg, Germany. [Faber, Katrin; Scholl, Claudia] Univ Ulm, Dept Internal Med 3, D-89081 Ulm, Germany. [Nonami, Atsushi; Barbie, David A.; Hahn, William C.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Putwain, Sarah L.; Huntly, Brian J.] Univ Cambridge, Cambridge Inst Med Res, Dept Haematol, Cambridge, England. [Putwain, Sarah L.; Huntly, Brian J.] Univ Cambridge, Wellcome Trust Med Res Council, Cambridge Stem Cell Inst, Cambridge, England. [Salih, Helmut R.] Univ Tubingen, Dept Hematol & Oncol, Tubingen, Germany. [Heidel, Florian H.] Univ Magdeburg, Dept Hematol & Oncol, D-39106 Magdeburg, Germany. [Kraemer, Alwin] Heidelberg Univ, German Canc Res Ctr, Clin Cooperat Unit Mol Hematol & Oncol, Heidelberg, Germany. [Kraemer, Alwin] Heidelberg Univ, Dept Internal Med 5, Heidelberg, Germany. [Root, David E.; Barbie, David A.; Hahn, William C.] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA USA. [Krivtsov, Andrei V.; Armstrong, Scott A.] Mem Sloan Kettering Canc Ctr, Leukemia Ctr, Human Oncol & Pathogenesis Program, New York, NY 10021 USA. [Krivtsov, Andrei V.; Armstrong, Scott A.] Mem Sloan Kettering Canc Ctr, Dept Pediat, New York, NY 10021 USA. [Sykes, Stephen M.] Fox Chase Canc Ctr, Immune Cell Dev & Host Def Program, Philadelphia, PA 19111 USA. [Milsom, Michael D.] German Canc Res Ctr, Heidelberg Inst Stem Cell Technol & Expt Med, Heidelberg, Germany. [Milsom, Michael D.] German Canc Res Ctr, Div Stem Cells & Canc, Expt Hematol Grp, Heidelberg, Germany. RP Frohling, S (reprint author), Natl Ctr Tumor Dis, Neuenheimer Feld 460, D-69120 Heidelberg, Germany. EM claudia.scholl@uni-ulm.de; stefan.froehling@nct-heidelberg.de FU German Research Foundation [FR 2113/3-1, FR 2113/4-1]; Heidelberg School of Oncology; BioRN Leading-Edge Cluster "Cell-Based and Molecular Medicine" - German Federal Ministry of Education and Research; Dietmar Hopp Foundation; German Research Foundation FX This work was supported by grants from the German Research Foundation (FR 2113/3-1 and FR 2113/4-1) (S. F.); a fellowship from the Heidelberg School of Oncology (T. P.); the BioRN Leading-Edge Cluster "Cell-Based and Molecular Medicine" funded by the German Federal Ministry of Education and Research, the Dietmar Hopp Foundation (M.D.M.); an Emmy Noether Fellowship from the German Research Foundation (C.S.). NR 59 TC 43 Z9 43 U1 1 U2 7 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUL 3 PY 2014 VL 124 IS 1 BP 13 EP 23 DI 10.1182/blood-2014-02-558114 PG 11 WC Hematology SC Hematology GA AQ2LT UT WOS:000342618300007 PM 24764564 ER PT J AU Mirabello, L Macari, ER Jessop, L Ellis, SR Myers, T Giri, N Taylor, AM McGrath, KE Humphries, JM Ballew, BJ Yeager, M Boland, JF He, J Hicks, BD Burdett, L Alter, BP Zon, L Savage, SA AF Mirabello, Lisa Macari, Elizabeth R. Jessop, Lea Ellis, Steven R. Myers, Timothy Giri, Neelam Taylor, Alison M. McGrath, Katherine E. Humphries, Jessica M. Ballew, Bari J. Yeager, Meredith Boland, Joseph F. He, Ji Hicks, Belynda D. Burdett, Laurie Alter, Blanche P. Zon, Leonard Savage, Sharon A. TI Whole-exome sequencing and functional studies identify RPS29 as a novel gene mutated in multicase Diamond-Blackfan anemia families SO BLOOD LA English DT Article ID PROTEIN STABILITY CHANGES; SUPPORT VECTOR MACHINES; MUTATIONS; ZEBRAFISH; DATABASE; ABNORMALITIES; PREDICTIONS; ACTIVATION; REGULATOR; SELECTION AB Diamond-Blackfan anemia (DBA) is a cancer-prone inherited bone marrow failure syndrome. Approximately half of DBA patients have a germ-line mutation in a ribosomal protein gene. We used whole-exome sequencing to identify disease-causing genes in 2 large DBA families. After filtering, 1 nonsynonymous mutation (p.I31F) in the ribosomal protein S29 (RPS29[AUQ1]) gene was present in all 5 DBA-affected individuals and the obligate carrier, and absent from the unaffected noncarrier parent in 1 DBA family. A second DBA family was found to have a different nonsynonymous mutation (p.I50T) in RPS29. Both mutations are amino acid substitutions in exon 2 predicted to be deleterious and resulted in haploinsufficiency of RPS29 expression compared with wild-type RPS29 expression from an unaffected control. The DBA proband with the p.I31F RPS29 mutation had a pre-ribosomal RNA (rRNA) processing defect compared with the healthy control. Wedemonstrated that both RPS29 mutations failed to rescue the defective erythropoiesis in the rps29(-/-) mutant zebra fish DBA model. RPS29 is a component of the small 40S ribosomal subunit and essential for rRNA processing and ribosome biogenesis. We uncovered a novel DBA causative gene, RPS29, and showed that germ-line mutations in RPS29 can cause a defective erythropoiesis phenotype using a zebra fish model. C1 [Mirabello, Lisa; Jessop, Lea; Myers, Timothy; Giri, Neelam; Ballew, Bari J.; Alter, Blanche P.; Savage, Sharon A.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Macari, Elizabeth R.; Taylor, Alison M.; McGrath, Katherine E.; Humphries, Jessica M.; Zon, Leonard] Childrens Hosp, Stem Cell Program, Boston, MA 02115 USA. [Macari, Elizabeth R.; Taylor, Alison M.; McGrath, Katherine E.; Humphries, Jessica M.; Zon, Leonard] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Macari, Elizabeth R.; Taylor, Alison M.; McGrath, Katherine E.; Humphries, Jessica M.; Zon, Leonard] Dana Farber Canc Inst, Boston, MA 02115 USA. [Ellis, Steven R.] Univ Louisville, Dept Biochem & Mol Biol, Louisville, KY 40292 USA. [Yeager, Meredith; Boland, Joseph F.; He, Ji; Hicks, Belynda D.; Burdett, Laurie] Frederick Natl Lab Canc Res, Canc Genom Res Lab, Leidos Biomed Res, Frederick, MD USA. [Zon, Leonard] Harvard Univ, Sch Med, Boston, MA USA. RP Savage, SA (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Room 6E454, Bethesda, MD 20892 USA. EM savagesh@mail.nih.gov RI Savage, Sharon/B-9747-2015 OI Savage, Sharon/0000-0001-6006-0740 FU Division of Cancer Epidemiology and Genetics, NCI, National Institutes of Health (NIH); Westat Inc. [N02-CP-91026, N02-CP-11019, HHSN261200655001C]; NIH National Heart, Lung, and Blood Institute [T32HL116324, 5U01HL10001-05]; NIH National Institute of Diabetes and Digestive and Kidney Diseases [5P30 DK049216-20]; Diamond Blackfan Anemia Foundation FX This study was funded by the intramural research program of the Division of Cancer Epidemiology and Genetics, NCI, National Institutes of Health (NIH); Westat Inc. (contracts N02-CP-91026, N02-CP-11019, and HHSN261200655001C); the NIH National Heart, Lung, and Blood Institute (training grant T32HL116324) (E. R. M.); NIH National Institute of Diabetes and Digestive and Kidney Diseases (5P30 DK049216-20); NIH National Heart, Lung, and Blood Institute (5U01HL10001-05); and a grant from the Diamond Blackfan Anemia Foundation. NR 44 TC 17 Z9 19 U1 0 U2 7 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUL 3 PY 2014 VL 124 IS 1 BP 24 EP 32 DI 10.1182/blood-2013-11-540278 PG 9 WC Hematology SC Hematology GA AQ2LT UT WOS:000342618300008 PM 24829207 ER PT J AU Claus, R Lucas, DM Ruppert, AS Williams, KE Weng, D Patterson, K Zucknick, M Oakes, CC Rassenti, LZ Greaves, AW Geyer, S Wierda, WG Brown, JR Gribben, JG Barrientos, JC Rai, KR Kay, NE Kipps, TJ Shields, P Zhao, WQ Grever, MR Plass, C Byrd, JC AF Claus, Rainer Lucas, David M. Ruppert, Amy S. Williams, Katie E. Weng, Daniel Patterson, Kara Zucknick, Manuela Oakes, Christopher C. Rassenti, Laura Z. Greaves, Andrew W. Geyer, Susan Wierda, William G. Brown, Jennifer R. Gribben, John G. Barrientos, Jacqueline C. Rai, Kanti R. Kay, Neil E. Kipps, Thomas J. Shields, Peter Zhao, Weiqiang Grever, Michael R. Plass, Christoph Byrd, John C. TI Validation of ZAP-70 methylation and its relative significance in predicting outcome in chronic lymphocytic leukemia SO BLOOD LA English DT Article ID DNA METHYLATION; MUTATION STATUS; CD38 EXPRESSION; SURVIVAL; ABERRATIONS; EVOLUTION; AGREEMENT; IBRUTINIB; DISEASE AB ZAP-70 methylation 223 nucleotides downstream of transcription start (CpG+223) predicts outcome in chronic lymphocytic leukemia (CLL), but its impact relative to CD38 and ZAP-70 expression or immunoglobulin heavy chain variable region (IGHV) status is uncertain. Additionally, standardizing ZAP-70 expression analysis has been unsuccessful. CpG+223 methylation was quantitatively determined in 295 untreated CLL cases using MassARRAY. Impact on clinical outcome vs CD38 and ZAP-70 expression and IGHV status was evaluated. Cases with low methylation (<20%) had significantly shortened time to first treatment (TT) and overall survival (OS) (P<.0001). For TT, low methylation defined a large subset of ZAP-70 protein-negative cases with significantly shortened TT (median, 8.0 vs 3.9 years for high vs low methylation; hazard ratio [HR] = 0.43; 95% confidence interval [CI], 0.25-0.74). Conversely, 16 ZAP-70 protein-positive cases with high methylation had poor outcome (median, 1.1 vs 2.3 years for high vs low methylation; HR=1.62; 95% CI, 0.87-3.03). For OS, ZAP-70 methylation was the strongest risk factor; CD38 and ZAP-70 expression or IGHV status did not significantly improve OS prediction. A pyrosequencing assay was established that reproduced the MassARRAY data (kappa coefficient > 0.90). Thus, ZAP-70 CpG+223 methylation represents a superior biomarker for TT and OS that can be feasibly measured, supporting its use in risk-stratifying CLL. C1 [Claus, Rainer] Univ Freiburg, Med Ctr, Div Hematol Oncol & Stem Cell Transplantat, Freiburg, Germany. [Claus, Rainer; Oakes, Christopher C.; Plass, Christoph] German Canc Res Ctr, Div Epigen & Canc Risk Factors, Heidelberg, Germany. [Lucas, David M.; Ruppert, Amy S.; Williams, Katie E.; Geyer, Susan; Grever, Michael R.; Byrd, John C.] Ohio State Univ, Div Hematol, Columbus, OH 43210 USA. [Weng, Daniel; Shields, Peter] Ohio State Univ, Dept Internal Med, Div Med Oncol, Columbus, OH 43210 USA. [Weng, Daniel; Patterson, Kara; Shields, Peter; Zhao, Weiqiang] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Patterson, Kara; Zhao, Weiqiang] Ohio State Univ, Dept Pathol, Div Hematopathol, Columbus, OH 43210 USA. [Zucknick, Manuela] German Canc Res Ctr, Div Biostat, Heidelberg, Germany. [Rassenti, Laura Z.; Greaves, Andrew W.; Kipps, Thomas J.] Univ Calif San Diego, Div Hematol Oncol, La Jolla, CA 92093 USA. [Rassenti, Laura Z.; Greaves, Andrew W.; Kipps, Thomas J.] Univ Calif San Diego, Moores Canc Ctr, Cent Off, CLL Res Consortium, La Jolla, CA 92093 USA. [Wierda, William G.] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA. [Brown, Jennifer R.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Gribben, John G.] Univ London, Ctr Med Oncol, Barts & London Sch Med, Inst Canc, London, England. [Barrientos, Jacqueline C.; Rai, Kanti R.] North Shore Long Isl Jewish Hlth Syst, Div Hematol Oncol, New Hyde Pk, NY USA. [Kay, Neil E.] Mayo Clin, Div Hematol, Rochester, MN USA. RP Byrd, JC (reprint author), 410 West 12th Ave,Room 455, Columbus, OH 43210 USA. EM john.byrd@osumc.edu RI Zhao, Weiqiang/E-4368-2011; Lucas, David/E-3555-2011; Oakes, Christopher/H-7288-2014; OI Barrientos, Jacqueline/0000-0001-6018-5535 FU German Research Society (DFG); German Cancer Aid [DKH110461]; US National Institutes of Health, National Cancer Institute [PO1 CA101956, P50CA140158, PO1CA95426, PO1 CA81534, 1K12 CA133250, RO1 CA95241]; German Cancer Research Center; German Cancer Consortium; Leukemia & Lymphoma Society; Harry Mangurian Foundation; D. Warren Brown Foundation FX R.C. receives a fellowship from the German Research Society (DFG) and is supported by the German Cancer Aid (Max Eder stipend, DKH110461). C. P. is supported by the US National Institutes of Health, National Cancer Institute grant PO1 CA101956, the German Cancer Research Center, and the German Cancer Consortium. This work was supported by the US National Institutes of Health, National Cancer Institute (grants P50CA140158, PO1CA95426, PO1 CA81534, 1K12 CA133250, and RO1 CA95241), as well as The Leukemia & Lymphoma Society, The Harry Mangurian Foundation, and The D. Warren Brown Foundation. NR 33 TC 25 Z9 25 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUL 3 PY 2014 VL 124 IS 1 BP 42 EP 48 DI 10.1182/blood-2014-02-555722 PG 7 WC Hematology SC Hematology GA AQ2LT UT WOS:000342618300010 PM 24868078 ER PT J AU Shochat, C Tal, N Gryshkova, V Birger, Y Bandapalli, OR Cazzaniga, G Gershman, N Kulozik, AE Biondi, A Mansour, MR Twizere, JC Muckenthaler, MU Ben-Tal, N Constantinescu, SN Bercovich, D Izraeli, S AF Shochat, Chen Tal, Noa Gryshkova, Vitalina Birger, Yehudit Bandapalli, Obul R. Cazzaniga, Giovanni Gershman, Nava Kulozik, Andreas E. Biondi, Andrea Mansour, Marc R. Twizere, Jean-Claude Muckenthaler, Martina U. Ben-Tal, Nir Constantinescu, Stefan N. Bercovich, Dani Izraeli, Shai TI Novel activating mutations lacking cysteine in type I cytokine receptors in acute lymphoblastic leukemia SO BLOOD LA English DT Article ID THYMIC STROMAL LYMPHOPOIETIN; OF-FUNCTION MUTATIONS; TRANSMEMBRANE DOMAIN; ERYTHROPOIETIN RECEPTOR; JAK2; IDENTIFICATION; INTERLEUKIN-7; JUNCTION; CRLF2; IL7R AB Gain-of-function somatic mutations introducing cysteines to either the extracellular or to the transmembrane domain (TMD) in interleukin-7 receptor alpha (IL7R) or cytokine receptor-like factor 2 (CRLF2) have been described in acute lymphoblastic leukemias. Here we report noncysteine in-frame mutations in IL7R and CRLF2 located in a region of the TMD closer to the cytosolic domain. Biochemical and functional assays showed that these are activating mutations conferring cytokine-independent growth of progenitor lymphoid cells in vitro and are transforming in vivo. Protein fragment complementation assays suggest that despite the absence of cysteines, the mechanism of activation is through ligand-independent dimerization. Mutagenesis experiments and ConSurf calculations suggest that the mutations stabilize the homodimeric conformation, positioning the cytosolic kinases in predefined orientation to each other, thereby inducing spontaneous receptor activation independently of external signals. Hence, type I cytokine receptors may be activated in leukemia through 2 types of transmembrane somatic dimerizing mutations. C1 [Shochat, Chen; Tal, Noa; Birger, Yehudit; Gershman, Nava; Izraeli, Shai] Edmond & Lily Safra Children Hosp, Sheba Med Ctr, Childhood Leukemia Res Inst, Ramat Gan, Israel. [Shochat, Chen; Bercovich, Dani] Migal Galilee Biotechnol Ctr, Dept Human Mol Genet, Kiryat Shmona, Israel. [Shochat, Chen; Tal, Noa; Izraeli, Shai] Tel Aviv Univ, Fac Med, IL-69978 Tel Aviv, Israel. [Shochat, Chen; Bercovich, Dani] Tel Hai Acad Coll, Biotechnol Dept, Human Mol Genet Lab, Tel Hai, Israel. [Gryshkova, Vitalina; Constantinescu, Stefan N.] Catholic Univ Louvain, Ludwig Inst Canc Res, B-1200 Brussels, Belgium. [Gryshkova, Vitalina; Constantinescu, Stefan N.] Catholic Univ Louvain, de Duve Inst, B-1200 Brussels, Belgium. [Bandapalli, Obul R.; Kulozik, Andreas E.; Muckenthaler, Martina U.] Heidelberg Univ, Dept Pediat Oncol Hematol & Immunol, Heidelberg, Germany. [Bandapalli, Obul R.; Kulozik, Andreas E.; Muckenthaler, Martina U.] Mol Med Partnership Unit, Heidelberg, Germany. [Cazzaniga, Giovanni; Biondi, Andrea] Univ Milano Bicocca, Osped San Gerardo, Ctr Ric Tettamanti, Clin Pediat, Monza, Italy. [Gershman, Nava] Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, Ramat Gan, Israel. [Mansour, Marc R.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Mansour, Marc R.] UCL, Dept Haematol, Inst Canc, London, England. [Twizere, Jean-Claude] Univ Liege, Interdisciplinary Cluster Appl Genoprote, Lab Prot Signaling & Interact, B-4000 Sart Tilman Par Liege, Belgium. [Ben-Tal, Nir] Tel Aviv Univ, George S Wise Fac Life Sci, Dept Biochem & Mol Biol, IL-69978 Tel Aviv, Israel. RP Izraeli, S (reprint author), Chaim Sheba Med Ctr, IL-52621 Ramat Gan, Israel. EM shai.izraeli@sheba.health.gov.il OI Bandapalli, Obul Reddy/0000-0002-1132-1745; Constantinescu, Stefan/0000-0002-8599-2699 FU Israel Science Foundation Legacy program; Israel Science Foundation iCORE program; Israel Cancer Research Foundation; Swiss Bridge Foundation; USA Israel Binational Science Foundation; Waxman Cancer Research Foundation; William Lawrence and Blanche Hughes Foundation FX This work was supported by Israel Science Foundation Legacy and iCORE programs, the Israel Cancer Research Foundation, Swiss Bridge Foundation, USA Israel Binational Science Foundation, Waxman Cancer Research Foundation, and William Lawrence and Blanche Hughes Foundation. C. S. and N.T. are PhD candidates at Tel Aviv University and this work is submitted in partial fulfillment of the requirement for a PhD. NR 19 TC 11 Z9 12 U1 1 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUL 3 PY 2014 VL 124 IS 1 BP 106 EP 110 DI 10.1182/blood-2013-10-529685 PG 5 WC Hematology SC Hematology GA AQ2LT UT WOS:000342618300017 PM 24787007 ER PT J AU Liu, Y Kretz, CA Maeder, ML Richter, CE Tsao, P Vo, AH Huarng, MC Rode, T Hu, ZL Mehra, R Olson, ST Joung, JK Shavit, JA AF Liu, Yang Kretz, Colin A. Maeder, Morgan L. Richter, Catherine E. Tsao, Philip Vo, Andy H. Huarng, Michael C. Rode, Thomas Hu, Zhilian Mehra, Rohit Olson, Steven T. Joung, J. Keith Shavit, Jordan A. TI Targeted mutagenesis of zebrafish antithrombin III triggers disseminated intravascular coagulation and thrombosis, revealing insight into function SO BLOOD LA English DT Article ID ZINC-FINGER NUCLEASES; VERTEBRATE BLOOD-COAGULATION; INCREASED HEPARIN AFFINITY; AMINO-ACID SUBSTITUTION; POOL ENGINEERING OPEN; REACTIVE-SITE; GENE; DEFICIENCY; MUTATION; VARIANT AB Pathologic blood clotting is a leading cause of morbidity and mortality in the developed world, underlying deep vein thrombosis, myocardial infarction, and stroke. Genetic predisposition to thrombosis is still poorly understood, and we hypothesize that there are many additional risk alleles and modifying factors remaining to be discovered. Mammalian models have contributed to our understanding of thrombosis, but are low throughput and costly. We have turned to the zebrafish, a tool for high-throughput genetic analysis. Using zinc finger nucleases, we show that disruption of the zebrafish antithrombin III (at3) locus results in spontaneous venous thrombosis in larvae. Although homozygous mutants survive into early adulthood, they eventually succumb to massive intracardiac thrombosis. Characterization of null fish revealed disseminated intravascular coagulation in larvae secondary to unopposed thrombin activity and fibrinogen consumption, which could be rescued by both human and zebrafish at3 complementary DNAs. Mutation of the human AT3-reactive center loop abolished the ability to rescue, but the heparin-binding site was dispensable. These results demonstrate overall conservation of AT3 function in zebrafish, but reveal developmental variances in the ability to tolerate excessive clot formation. The accessibility of early zebrafish development will provide unique methods for dissection of the underlying mechanisms of thrombosis. C1 [Liu, Yang; Richter, Catherine E.; Tsao, Philip; Vo, Andy H.; Huarng, Michael C.; Rode, Thomas; Hu, Zhilian; Shavit, Jordan A.] Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA. [Kretz, Colin A.] Univ Michigan, Inst Life Sci, Ann Arbor, MI 48109 USA. [Maeder, Morgan L.; Joung, J. Keith] Massachusetts Gen Hosp, Mol Pathol Unit, Charlestown, MA USA. [Mehra, Rohit] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. [Olson, Steven T.] Univ Illinois, Ctr Mol Biol Oral Dis, Chicago, IL USA. [Joung, J. Keith] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Shavit, Jordan A.] Univ Michigan, Cellular & Mol Biol Program, Ann Arbor, MI 48109 USA. RP Shavit, JA (reprint author), Univ Michigan, Dept Pediat, Room 8301 Med Sci Res Bldg 3,1150 W Med Ctr Dr, Ann Arbor, MI 48109 USA. EM jshavit@umich.edu FU American Heart Association, a Hemostasis and Thrombosis Research Society Mentored Research Award [0675025N]; Eunice Kennedy Shriver National Institute of Child Health and Human Development [HD028820]; National Institutes of Health [R01 GM088040] FX This work was supported by American Heart Association #0675025N, a Hemostasis and Thrombosis Research Society Mentored Research Award, Eunice Kennedy Shriver National Institute of Child Health and Human Development HD028820 (J.A.S.), and National Institutes of Health R01 GM088040 (J.K.J.). Statistical analysis was supported by the Charles Woodson Fund for Clinical Research. NR 64 TC 12 Z9 12 U1 2 U2 8 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUL 3 PY 2014 VL 124 IS 1 BP 142 EP 150 DI 10.1182/blood-2014-03-561027 PG 9 WC Hematology SC Hematology GA AQ2LT UT WOS:000342618300021 PM 24782510 ER PT J AU Mendy, VL Azevedo, MJ Sarpong, DF Rosas, SE Ekundayo, OT Sung, JH Bhuiyan, AR Jenkins, BC Addison, C AF Mendy, Vincent L. Azevedo, Mario J. Sarpong, Daniel F. Rosas, Sylvia E. Ekundayo, Olugbemiga T. Sung, Jung Hye Bhuiyan, Azad R. Jenkins, Brenda C. Addison, Clifton TI The Association between Individual and Combined Components of Metabolic Syndrome and Chronic Kidney Disease among African Americans: The Jackson Heart Study SO PLOS ONE LA English DT Article ID UNITED-STATES; US ADULTS; POPULATION; PREVALENCE; RISK; GUIDELINES AB Introduction: Approximately 26.3 million people in the United States have chronic kidney disease and many more are at risk of developing the condition. The association between specific metabolic syndrome components and chronic kidney disease in African American individuals is uncertain. Methods: Baseline data from 4,933 participants of the Jackson Heart Study were analyzed. Logistic regression models were used to estimate the odds and 95% confidence intervals of chronic kidney disease associated with individual components, metabolic syndrome, the number of components, and specific combinations of metabolic syndrome components. Results: Metabolic syndrome was common with a prevalence of 42.0%. Chronic kidney disease was present in 19.4% of participants. The prevalence of metabolic components was high: elevated blood pressure (71.8%), abdominal obesity (65.8%), low fasting high density lipoprotein cholesterol (37.3%), elevated fasting glucose (32.2%) and elevated triglycerides (16.2%). Elevated blood pressure, triglycerides, fasting blood glucose, and abdominal obesity were significantly associated with increased odds of chronic kidney disease. Participants with metabolic syndrome had a 2.22-fold (adjusted odds ratio (AOR) 2.22; 95% CI, 1.78-2.78) increase in the odds of chronic kidney disease compared to participants without metabolic syndrome. The combination of elevated fasting glucose, elevated triglycerides, and abdominal obesity was associated with the highest odds for chronic kidney disease (AOR 25.11; 95% CI, 6.94-90.90). Conclusion: Metabolic syndrome as well as individual or combinations of metabolic syndrome components are independently associated with chronic kidney disease in African American adults. C1 [Mendy, Vincent L.; Azevedo, Mario J.; Sarpong, Daniel F.; Ekundayo, Olugbemiga T.; Sung, Jung Hye; Bhuiyan, Azad R.] Jackson State Univ, Coll Publ Serv, Sch Hlth Sci, Dept Epidemiol & Biostat, Jackson, MS 39217 USA. [Sarpong, Daniel F.] Jackson State Univ, RTRN Data Coordinating Ctr, Jackson, MS USA. [Rosas, Sylvia E.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Kidney & Hypertens Sect, Boston, MA 02115 USA. [Jenkins, Brenda C.; Addison, Clifton] Jackson State Univ, Jackson Heart Study, Jackson, MS USA. RP Mendy, VL (reprint author), Jackson State Univ, Coll Publ Serv, Sch Hlth Sci, Dept Epidemiol & Biostat, Jackson, MS 39217 USA. EM vinsluther@hotmail.com FU National Heart, Lung, and Blood Institute [HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C]; National Institute on Minority Health and Health Disparities; National Institute on Biomedical Imaging and Bioengineering FX The Jackson Heart Study is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C from the National Heart, Lung, and Blood Institute and the National Institute on Minority Health and Health Disparities, with additional support from the National Institute on Biomedical Imaging and Bioengineering. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 6 Z9 6 U1 1 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 3 PY 2014 VL 9 IS 7 AR e101610 DI 10.1371/journal.pone.0101610 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO3RT UT WOS:000341253400097 PM 24991817 ER PT J AU Sadleir, KR Eimer, WA Kaufman, RJ Osten, P Vassar, R AF Sadleir, Katherine R. Eimer, William A. Kaufman, Randal J. Osten, Pavel Vassar, Robert TI Genetic Inhibition of Phosphorylation of the Translation Initiation Factor eIF2 alpha Does Not Block A beta-Dependent Elevation of BACE1 and APP Levels or Reduce Amyloid Pathology in a Mouse Model of Alzheimer's Disease SO PLOS ONE LA English DT Article ID ADENOASSOCIATED VIRUS VECTORS; UNFOLDED PROTEIN RESPONSE; PRECURSOR PROTEIN; SECRETASE ACTIVITY; PATHOGENIC MUTATION; CLEAVING ENZYME-1; MAMMALIAN-CELLS; TRANSGENIC MICE; UPSTREAM AUGS; SYNAPSE LOSS AB beta-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) initiates the production of beta-amyloid (A beta), the major constituent of amyloid plaques in Alzheimer's disease (AD). BACE1 is elevated similar to 2-3 fold in AD brain and is concentrated in dystrophic neurites near plaques, suggesting BACE1 elevation is A beta-dependent. Previously, we showed that phosphorylation of the translation initiation factor eIF2 alpha de-represses translation of BACE1 mRNA following stress such as energy deprivation. We hypothesized that stress induced by A beta might increase BACE1 levels by the same translational mechanism involving eIF2 alpha phosphorylation. To test this hypothesis, we used three different genetic strategies to determine the effects of reducing eIF2 alpha phosphorylation on A beta-dependent BACE1 elevation in vitro and in vivo: 1) a two-vector adeno-associated virus (AAV) system to express constitutively active GADD34, the regulatory subunit of PP1c eIF2 alpha phosphatase; 2) a non-phosphorylatable eIF2 alpha S51A knockin mutation; 3) a BACE1-YFP transgene lacking the BACE1 mRNA 59 untranslated region (UTR) required for eIF2 alpha translational regulation. The first two strategies were used in primary neurons and 5XFAD transgenic mice, while the third strategy was employed only in 5XFAD mice. Despite very effective reduction of eIF2 alpha phosphorylation in both primary neurons and 5XFAD brains, or elimination of eIF2 alpha-mediated regulation of BACE1-YFP mRNA translation in 5XFAD brains, A beta-dependent BACE1 elevation was not decreased. Additionally, robust inhibition of eIF2 alpha phosphorylation did not block A beta-dependent APP elevation in primary neurons, nor did it reduce amyloid pathology in 5XFAD mice. We conclude that amyloid-associated BACE1 elevation is not caused by translational derepression via eIF2 alpha phosphorylation, but instead appears to involve a post-translational mechanism. These definitive genetic results exclude a role for eIF2 alpha phosphorylation in A beta-dependent BACE1 and APP elevation. We suggest a vicious pathogenic cycle wherein Ab42 toxicity induces peri-plaque BACE1 and APP accumulation in dystrophic neurites leading to exacerbated A beta production and plaque progression. C1 [Sadleir, Katherine R.; Vassar, Robert] Northwestern Univ, Feinberg Sch Med, Dept Cell & Mol Biol, Chicago, IL 60611 USA. [Eimer, William A.] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA USA. [Kaufman, Randal J.] Sanford Burnham Med Res Inst, La Jolla, CA USA. [Osten, Pavel] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. RP Vassar, R (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Cell & Mol Biol, Chicago, IL 60611 USA. EM r-vassar@northwestern.edu FU National Institutes of Health [R01 AG030142]; NIH [DK042394, DK088227, HL052173, 5T32AG00026]; NRSA [F32AG033445]; Northwestern University Cell Imaging Facility; Cancer Center [NCI CA060553] FX This work was supported by the National Institutes of Health R01 AG030142 to Dr. Robert Vassar, NIH grants DK042394, DK088227 and HL052173 to Dr. Randal Kaufman, NRSA F32AG033445 to Dr. Katherine Sadleir, NIH training grant 5T32AG00026 to Dr. Katherine Sadleir, and the Northwestern University Cell Imaging Facility and a Cancer Center Support Grant (NCI CA060553). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. NR 72 TC 13 Z9 13 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 3 PY 2014 VL 9 IS 7 AR e101643 DI 10.1371/journal.pone.0101643 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO3RT UT WOS:000341253400102 PM 24992504 ER PT J AU Lo, JC Ljubicic, S Leibiger, B Kern, M Leibiger, IB Moede, T Kelly, ME Bhowmick, DC Murano, I Cohen, P Banks, AS Khandekar, MJ Dietrich, A Flier, JS Cinti, S Blueher, M Danial, NN Berggren, PO Spiegelman, BM AF Lo, James C. Ljubicic, Sanda Leibiger, Barbara Kern, Matthias Leibiger, Ingo B. Moede, Tilo Kelly, Molly E. Bhowmick, Diti Chatterjee Murano, Incoronata Cohen, Paul Banks, Alexander S. Khandekar, Melin J. Dietrich, Arne Flier, Jeffrey S. Cinti, Saverio Blueher, Matthias Danial, Nika N. Berggren, Per-Olof Spiegelman, Bruce M. TI Adipsin Is an Adipokine that Improves beta Cell Function in Diabetes SO CELL LA English DT Article ID COMPLEMENT FACTOR-D; ADIPOSE-TISSUE; INSULIN-RESISTANCE; MACROPHAGE INFILTRATION; METABOLIC DISEASE; OBESITY; SECRETION; FAILURE; INFLAMMATION; PATHWAY AB A hallmark of type 2 diabetes mellitus (T2DM) is the development of pancreatic beta cell failure, which results in insulinopenia and hyperglycemia. We show that the adipokine adipsin has a beneficial role in maintaining beta cell function. Animals genetically lacking adipsin have glucose intolerance due to insulinopenia; isolated islets from these mice have reduced glucose-stimulated insulin secretion. Replenishment of adipsin to diabetic mice treated hyperglycemia by boosting insulin secretion. We identify C3a, a peptide generated by adipsin, as a potent insulin secretagogue and show that the C3a receptor is required for these beneficial effects of adipsin. C3a acts on islets by augmenting ATP levels, respiration, and cytosolic free Ca2+. Finally, we demonstrate that T2DM patients with b cell failure are deficient in adipsin. These findings indicate that the adipsin/C3a pathway connects adipocyte function to b cell physiology, and manipulation of this molecular switch may serve as a therapy in T2DM. C1 [Lo, James C.; Ljubicic, Sanda; Kelly, Molly E.; Bhowmick, Diti Chatterjee; Cohen, Paul; Banks, Alexander S.; Khandekar, Melin J.; Danial, Nika N.; Spiegelman, Bruce M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Lo, James C.; Ljubicic, Sanda; Kelly, Molly E.; Bhowmick, Diti Chatterjee; Cohen, Paul; Banks, Alexander S.; Khandekar, Melin J.; Danial, Nika N.; Spiegelman, Bruce M.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02215 USA. [Lo, James C.; Cohen, Paul] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Leibiger, Barbara; Leibiger, Ingo B.; Moede, Tilo; Berggren, Per-Olof] Rolf Luft Res Ctr Diabet & Endocrinol, Karolinska Inst, S-17176 Stockholm, Sweden. [Kern, Matthias; Blueher, Matthias] Univ Leipzig, Dept Med, D-04103 Leipzig, Germany. [Murano, Incoronata; Cinti, Saverio] Univ Ancona, Dept Expt & Clin Med, I-60020 Ancona, Italy. [Dietrich, Arne] Univ Leipzig, Dept Surg, D-04103 Leipzig, Germany. [Flier, Jeffrey S.] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Spiegelman, BM (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM bruce_spiegelman@dfci.harvard.edu RI Banks, Alexander/B-4832-2012; OI Banks, Alexander/0000-0003-1787-6925; Moede, Tilo/0000-0002-2045-9244 FU Swiss National Science Foundation postdoctoral fellowship; Swedish Research Council; Family Erling-Persson Foundation; Novo Nordisk Foundation; Stichting af Jochnick Foundation; Strategic Research Program in Diabetes at Karolinska Institutet; Knut and Alice Wallenberg Foundation; DIABAT [HEALTH-F2-2011-278373]; Deutsche Forschungsgemeinschaft "Obesity mechanisms'' [SFB 1052/1, B01]; NIH [DK097303, DK078081, DK031405]; [ERC-2013-AdG 338936-BetaImage] FX We thank Dr. Gregory L. Stahl (Brigham and Women's Hospital) for generously providing Adipsin-/- mice. We are grateful to Drs. Rana Gupta, Shingo Kajimura, Jennifer Estall, Christiane Wrann, Linus Tsai, Susan Bonner-Weir, Pere Puigserver, and Evan Rosen for helpful discussions. We thank Jennifer Hollister-Lock and the Islet Isolation Core at Joslin Diabetes Center for help with islet perfusions. Fluorescence images were acquired in the Confocal and Light Microscopy Core Facility at the Dana-Farber Cancer Institute. S. L. was supported by a Swiss National Science Foundation postdoctoral fellowship. This work was supported by the Swedish Research Council, the Family Erling-Persson Foundation, the Novo Nordisk Foundation, the Stichting af Jochnick Foundation, the Strategic Research Program in Diabetes at Karolinska Institutet, the ERC-2013-AdG 338936-BetaImage, the Knut and Alice Wallenberg Foundation, DIABAT HEALTH-F2-2011-278373 (S. C.), Deutsche Forschungsgemeinschaft the SFB 1052/1: "Obesity mechanisms'' (project B01 to M. B.), and NIH grants DK097303 (J.C.L.), DK078081 (N.N.D.), and DK031405 (B. M. S.). NR 61 TC 37 Z9 38 U1 3 U2 19 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD JUL 3 PY 2014 VL 158 IS 1 BP 41 EP 53 DI 10.1016/j.cell.2014.06.005 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AN9QQ UT WOS:000340943100006 PM 24995977 ER PT J AU Kong, XX Banks, A Liu, T Kazak, L Rao, RR Cohen, P Wang, X Yu, S Lo, JC Tseng, YH Cypess, AM Xue, R Kleiner, S Kang, S Spiegelman, BM Rosen, ED AF Kong, Xingxing Banks, Alexander Liu, Tiemin Kazak, Lawrence Rao, Rajesh R. Cohen, Paul Wang, Xun Yu, Songtao Lo, James C. Tseng, Yu-Hua Cypess, Aaron M. Xue, Ruidan Kleiner, Sandra Kang, Sona Spiegelman, Bruce M. Rosen, Evan D. TI IRF4 Is a Key Thermogenic Transcriptional Partner of PGC-1 alpha SO CELL LA English DT Article ID BROWN ADIPOSE-TISSUE; REGULATORY FACTOR 4; UNCOUPLING PROTEIN GENE; PLASMA-CELL DIFFERENTIATION; INSULIN-RESISTANCE; RECEPTOR-ALPHA; T-CELLS; MACROPHAGE POLARIZATION; ADAPTIVE THERMOGENESIS; ENERGY HOMEOSTASIS AB Brown fat can reduce obesity through the dissipation of calories as heat. Control of thermogenic gene expression occurs via the induction of various coactivators, most notably PGC-1 alpha. In contrast, the transcription factor partner(s) of these cofactors are poorly described. Here, we identify interferon regulatory factor 4 (IRF4) as a dominant transcriptional effector of thermogenesis. IRF4 is induced by cold and cAMP in adipocytes and is sufficient to promote increased thermogenic gene expression, energy expenditure, and cold tolerance. Conversely, knockout of IRF4 in UCP1(+) cells causes reduced thermogenic gene expression and energy expenditure, obesity, and cold intolerance. IRF4 also induces the expression of PGC-1 alpha and PRDM16 and interacts with PGC-1 alpha, driving Ucp1 expression. Finally, cold, beta-agonists, or forced expression of PGC-1 alpha are unable to cause thermogenic gene expression in the absence of IRF4. These studies establish IRF4 as a transcriptional driver of a program of thermogenic gene expression and energy expenditure. C1 [Kong, Xingxing; Liu, Tiemin; Wang, Xun; Kang, Sona; Rosen, Evan D.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Endocrinol, Boston, MA 02215 USA. [Kong, Xingxing; Liu, Tiemin; Wang, Xun; Kang, Sona; Rosen, Evan D.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02215 USA. [Banks, Alexander; Kazak, Lawrence; Rao, Rajesh R.; Cohen, Paul; Lo, James C.; Kleiner, Sandra; Spiegelman, Bruce M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02215 USA. [Banks, Alexander; Kazak, Lawrence; Rao, Rajesh R.; Cohen, Paul; Lo, James C.; Kleiner, Sandra; Spiegelman, Bruce M.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02215 USA. [Yu, Songtao] Northwestern Univ, Childrens Mem Res Ctr, Sch Med, Dept Pediat, Chicago, IL 60614 USA. [Tseng, Yu-Hua; Cypess, Aaron M.; Xue, Ruidan] Harvard Univ, Joslin Diabet Ctr, Sch Med, Sect Integrat Physiol & Metab, Boston, MA 02215 USA. [Rosen, Evan D.] Broad Inst, Cambridge, MA 02142 USA. RP Rosen, ED (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Endocrinol, Boston, MA 02215 USA. EM erosen@bidmc.harvard.edu RI Banks, Alexander/B-4832-2012 OI Banks, Alexander/0000-0003-1787-6925 FU American Heart Association (AHA) postdoctoral fellowship; NIH [R01 DK31405, R01 DK085171] FX The authors gratefully acknowledge Ulf Klein (Columbia University) for the Irf4flox mice. PGC-1 alpha constructs were the gift of Pere Puigserver; other plasmids were from Lisa Madisen and Hongkui Zeng. The Electron Microscopy core of the Beth Israel Deaconess Medical Center (BIDMC) performed the EM analysis. We thank members of the E. D. R. and B. M. S. laboratories, and Saverio Cinti, for helpful discussions and technical advice. This work was funded by an American Heart Association (AHA) postdoctoral fellowship to X. K., NIH R01 DK31405 to B. M. S., and NIH R01 DK085171 to E. D. R. B. M. S. is a founder of and shareholder in Ember Therapeutics, and S. K. is an employee of the Genomics Institute of the Novartis Research Foundation. NR 57 TC 38 Z9 38 U1 3 U2 16 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD JUL 3 PY 2014 VL 158 IS 1 BP 69 EP 83 DI 10.1016/j.cell.2014.04.049 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AN9QQ UT WOS:000340943100008 PM 24995979 ER PT J AU Shao, DD Xue, W Krall, EB Bhutkar, A Piccioni, F Wang, XX Schinzel, AC Sood, S Rosenbluh, J Kim, JW Zwang, Y Roberts, TM Root, DE Jacks, T Hahn, WC AF Shao, Diane D. Xue, Wen Krall, Elsa B. Bhutkar, Arjun Piccioni, Federica Wang, Xiaoxing Schinzel, Anna C. Sood, Sabina Rosenbluh, Joseph Kim, Jong W. Zwang, Yaara Roberts, Thomas M. Root, David E. Jacks, Tyler Hahn, William C. TI KRAS and YAP1 Converge to Regulate EMT and Tumor Survival SO CELL LA English DT Article ID EPITHELIAL-MESENCHYMAL TRANSITION; GENE-EXPRESSION SIGNATURE; HIPPO PATHWAY; ONCOGENIC RAS; C-FOS; TRANSCRIPTIONAL ACTIVITY; CANDIDATE ONCOGENE; CONTACT INHIBITION; CARCINOMA CELLS; GROWTH-CONTROL AB Cancer cells that express oncogenic alleles of RAS typically require sustained expression of the mutant allele for survival, but the molecular basis of this oncogene dependency remains incompletely understood. To identify genes that can functionally substitute for oncogenic RAS, we systematically expressed 15,294 open reading frames in a human KRAS-dependent colon cancer cell line engineered to express an inducible KRAS-specific shRNA. We found 147 genes that promoted survival upon KRAS suppression. In particular, the transcriptional coactivator YAP1 rescued cell viability in KRAS-dependent cells upon suppression of KRAS and was required for KRAS-induced cell transformation. Acquired resistance to Kras suppression in a Kras-driven murine lung cancer model also involved increased YAP1 signaling. KRAS and YAP1 converge on the transcription factor FOS and activate a transcriptional program involved in regulating the epithelial-mesenchymal transition (EMT). Together, these findings implicate transcriptional regulation of EMT by YAP1 as a significant component of oncogenic RAS signaling. C1 [Shao, Diane D.; Krall, Elsa B.; Wang, Xiaoxing; Schinzel, Anna C.; Rosenbluh, Joseph; Kim, Jong W.; Zwang, Yaara; Roberts, Thomas M.; Hahn, William C.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Shao, Diane D.; Krall, Elsa B.; Piccioni, Federica; Wang, Xiaoxing; Schinzel, Anna C.; Rosenbluh, Joseph; Kim, Jong W.; Zwang, Yaara; Root, David E.; Jacks, Tyler; Hahn, William C.] Harvard & MIT, Broad Inst, Cambridge, MA 02142 USA. [Xue, Wen; Bhutkar, Arjun; Sood, Sabina; Jacks, Tyler] Koch Inst Integrat Canc Res, Cambridge, MA 02142 USA. [Jacks, Tyler] MIT, Dept Biol, Cambridge, MA 02139 USA. [Jacks, Tyler] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Jacks, T (reprint author), Harvard & MIT, Broad Inst, Cambridge, MA 02142 USA. EM tjacks@mit.edu; william_hahn@dfci.harvard.edu FU U.S. National Institutes of Health [R01 CA140545, U01 CA176058, P01 CA050661, K99 CA169512, T32 GM007753]; National Cancer Institute [P30-CA14051]; Howard Hughes Medical Institute; Daniel K. Ludwig Fund for Cancer Research; American Association for Cancer Research; Leukemia Lymphoma Society; Svenson Family Foundation; Department of Defense [W81XWH-10-1-0062, W81XWH-12-1-0115]; Hope Funds for Cancer Research [HFCR-11-03-03] FX This project was supported by R01 CA140545 (W.C.H.), U01 CA176058 (W.C.H.), P01 CA050661 (W.C.H. and T.M.R.), K99 CA169512 (W.X.), and T32 GM007753 (D.S.) from the U.S. National Institutes of Health; and Koch Institute Support Grant P30-CA14051 (T.J.) from the National Cancer Institute. Additional support was provided by Howard Hughes Medical Institute (T.J.), Daniel K. Ludwig Fund for Cancer Research (T.J.), American Association for Cancer Research (W.X.), the Leukemia Lymphoma Society (W.X.), the Svenson Family Foundation (J.R.), fellowships W81XWH-10-1-0062 (X.W.) and W81XWH-12-1-0115 (Y.Z.) from the Department of Defense, and fellowship HFCR-11-03-03 from Hope Funds for Cancer Research (E.B.K.). T.M.R. and W.C.H. are consultants for Novartis. NR 59 TC 148 Z9 151 U1 7 U2 67 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD JUL 3 PY 2014 VL 158 IS 1 BP 171 EP 184 DI 10.1016/j.cell.2014.06.004 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AN9QQ UT WOS:000340943100016 PM 24954536 ER PT J AU Li, Y Calvo, SE Gutman, R Liu, JS Mootha, VK AF Li, Yang Calvo, Sarah E. Gutman, Roee Liu, Jun S. Mootha, Vamsi K. TI Expansion of Biological Pathways Based on Evolutionary Inference SO CELL LA English DT Article ID MITOCHONDRIAL CALCIUM UNIPORTER; PROTEOMIC ANALYSIS; COMPLEX; PROTEIN; GENES; GENOMICS; DISEASE; IDENTIFICATION; PREDICTION; TRANSPORT AB The availability of diverse genomes makes it possible to predict gene function based on shared evolutionary history. This approach can be challenging, however, for pathways whose components do not exhibit a shared history but rather consist of distinct "evolutionary modules." We introduce a computational algorithm, clustering by inferred models of evolution (CLIME), which inputs a eukaryotic species tree, homology matrix, and pathway (gene set) of interest. CLIME partitions the gene set into disjoint evolutionary modules, simultaneously learning the number of modules and a tree-based evolutionary history that defines each module. CLIME then expands each module by scanning the genome for new components that likely arose under the inferred evolutionary model. Application of CLIME to similar to 1,000 annotated human pathways and to the proteomes of yeast, red algae, and malaria reveals unanticipated evolutionary modularity and coevolving components. CLIME is freely available and should become increasingly powerful with the growing wealth of eukaryotic genomes. C1 [Li, Yang; Calvo, Sarah E.; Mootha, Vamsi K.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. [Li, Yang; Calvo, Sarah E.; Mootha, Vamsi K.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Li, Yang; Liu, Jun S.] Harvard Univ, Dept Stat, Cambridge, MA 02138 USA. [Calvo, Sarah E.; Mootha, Vamsi K.] Broad Inst, Cambridge, MA 02141 USA. [Gutman, Roee] Brown Univ, Dept Biostat, Providence, RI 02912 USA. [Mootha, Vamsi K.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. RP Liu, JS (reprint author), Harvard Univ, Dept Stat, Cambridge, MA 02138 USA. EM jliu@stat.harvard.edu; vamsi@hms.harvard.edu RI Gutman, Roee/J-2355-2014 OI Gutman, Roee/0000-0001-7095-3016 FU NIH [GM0077465]; National Science Foundations [DMS-1007762, IIS-1017967]; Shenzhen Special Fund for Strategic Emerging Industry grant [ZD201111080127A]; Investigator of the Howard Hughes Medical Institute FX We thank Jagesh Shah for curation of cilia-related genes and Eran Mick and Daniel Arlow for manuscript feedback. This work was supported in part by grants from the NIH (GM0077465 to V.K.M.), National Science Foundations (DMS-1007762 and IIS-1017967 to J.S.L.), and the Shenzhen Special Fund for Strategic Emerging Industry grant (ZD201111080127A to J.S.L.). V.K.M. is an Investigator of the Howard Hughes Medical Institute. NR 45 TC 11 Z9 11 U1 0 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD JUL 3 PY 2014 VL 158 IS 1 BP 213 EP 225 DI 10.1016/j.cell.2014.05.034 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AN9QQ UT WOS:000340943100019 PM 24995987 ER PT J AU Kfoury, Y Mercier, F Scadden, DT AF Kfoury, Youmna Mercier, Francois Scadden, David T. TI SnapShot: The Hematopoietic Stem Cell Niche SO CELL LA English DT Editorial Material ID BONE-MARROW NICHE; LEUKEMIA C1 [Kfoury, Youmna; Mercier, Francois; Scadden, David T.] Harvard Univ, Massachusetts Gen Hosp, Ctr Regenerat Med, Harvard Stem Cell Inst,Dept Stem Cell & Regenerat, Cambridge, MA 02138 USA. RP Kfoury, Y (reprint author), Harvard Univ, Massachusetts Gen Hosp, Ctr Regenerat Med, Harvard Stem Cell Inst,Dept Stem Cell & Regenerat, Cambridge, MA 02138 USA. NR 10 TC 8 Z9 8 U1 1 U2 14 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD JUL 3 PY 2014 VL 158 IS 1 BP 228 EP U252 DI 10.1016/j.cell.2014.06.019 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AN9QQ UT WOS:000340943100022 PM 24995988 ER PT J AU Tsai, SQ Joung, JK AF Tsai, Shengdar Q. Joung, J. Keith TI What's Changed with Genome Editing? SO CELL STEM CELL LA English DT Editorial Material AB Targeted genome editing using engineered nucleases can reliably generate defined genetic mutations, although the range of off-target lesions caused by these techniques is unclear. Recent papers in Cell Stem Cell perform high-coverage whole-genome sequencing to demonstrate the feasibility of obtaining correctly targeted pluripotent stem cell clones with minimal unintended modifications. C1 [Tsai, Shengdar Q.; Joung, J. Keith] Massachusetts Gen Hosp, Mol Pathol Unit, Charlestown, MA 02129 USA. [Tsai, Shengdar Q.; Joung, J. Keith] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Joung, JK (reprint author), Massachusetts Gen Hosp, Mol Pathol Unit, Charlestown, MA 02129 USA. EM jjoung@mgh.harvard.edu NR 7 TC 13 Z9 13 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 EI 1875-9777 J9 CELL STEM CELL JI Cell Stem Cell PD JUL 3 PY 2014 VL 15 IS 1 BP 3 EP 4 DI 10.1016/j.stem.2014.06.017 PG 2 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA AN8TX UT WOS:000340878600002 PM 24996161 ER PT J AU Veres, A Gosis, BS Ding, QR Collins, R Ragavendran, A Brand, H Erdin, S Cowan, CA Talkowski, ME Musunuru, K AF Veres, Adrian Gosis, Bridget S. Ding, Qiurong Collins, Ryan Ragavendran, Ashok Brand, Harrison Erdin, Serkan Cowan, Chad A. Talkowski, Michael E. Musunuru, Kiran TI Low Incidence of Off-Target Mutations in Individual CRISPR-Cas9 and TALEN Targeted Human Stem Cell Clones Detected by Whole-Genome Sequencing SO CELL STEM CELL LA English DT Article ID DISEASE-MODELS; CAS9; SPECIFICITY; NUCLEASES; ENDONUCLEASE; NICKASES; SYSTEMS AB Genome editing has attracted wide interest for the generation of cellular models of disease using human pluripotent stem cells and other cell types. CRISPR-Cas systems and TALENs can target desired genomic sites with high efficiency in human cells, but recent publications have led to concern about the extent to which these tools may cause off-target mutagenic effects that could potentially confound disease-modeling studies. Using CRISPR-Cas9 and TALEN targeted human pluripotent stem cell clones, we performed whole-genome sequencing at high coverage in order to assess the degree of mutagenesis across the entire genome. In both types of clones, we found that off-target mutations attributable to the nucleases were very rare. From this analysis, we suggest that, although some cell types may be at risk for off-target mutations, the incidence of such effects in human pluripotent stem cells may be sufficiently low and thus not a significant concern for disease modeling and other applications. C1 [Veres, Adrian; Gosis, Bridget S.; Ding, Qiurong; Cowan, Chad A.; Musunuru, Kiran] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Veres, Adrian; Gosis, Bridget S.; Ding, Qiurong; Cowan, Chad A.; Musunuru, Kiran] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Veres, Adrian; Cowan, Chad A.; Musunuru, Kiran] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Collins, Ryan; Ragavendran, Ashok; Brand, Harrison; Erdin, Serkan; Talkowski, Michael E.] Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Mol Neurogenet Unit, Boston, MA 02114 USA. [Talkowski, Michael E.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Cowan, Chad A.; Talkowski, Michael E.; Musunuru, Kiran] Broad Inst, Cambridge, MA 02142 USA. [Musunuru, Kiran] Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02115 USA. RP Musunuru, K (reprint author), Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. EM kiranmusunuru@gmail.com RI Erdin, Serkan/B-4988-2008; OI Erdin, Serkan/0000-0001-6587-2625; Collins, Ryan/0000-0003-1268-9995 FU Harvard Presidential Scholars Fund of the Harvard Medical School MD/PhD Program; National Institutes of Health (NIH) [R00-HL098364, R01-HL118744, R01-DK097768, U01-HL100408, R00-MH095867]; Harvard Stem Cell Institute; Harvard University FX This work was supported in part by the Harvard Presidential Scholars Fund of the Harvard Medical School MD/PhD Program (A.V.); grants R00-HL098364 (K.M.), R01-HL118744 (K.M.), R01-DK097768 (K.M. and C.A.C.), U01-HL100408 (C.A.C.), and R00-MH095867 (M.E.T.) from the National Institutes of Health (NIH); the Harvard Stem Cell Institute (K.M.); and Harvard University (Q.D. and K.M.). We thank Vamsee Pillalamarri, Carrie Hanscom, and the staff of the MGH Genomics and Technology Core and NextGen Sequencing Core for technical assistance. NR 21 TC 154 Z9 165 U1 7 U2 61 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 EI 1875-9777 J9 CELL STEM CELL JI Cell Stem Cell PD JUL 3 PY 2014 VL 15 IS 1 BP 27 EP 30 DI 10.1016/j.stem.2014.04.020 PG 4 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA AN8TX UT WOS:000340878600008 PM 24996167 ER PT J AU Beerman, I Seita, J Inlay, MA Weissman, IL Rossi, DJ AF Beerman, Isabel Seita, Jun Inlay, Matthew A. Weissman, Irving L. Rossi, Derrick J. TI Quiescent Hematopoietic Stem Cells Accumulate DNA Damage during Aging that Is Repaired upon Entry into Cell Cycle SO CELL STEM CELL LA English DT Article ID ACUTE MYELOID-LEUKEMIA; BONE-MARROW; INDIVIDUAL CELLS; PROGENITOR CELLS; SELF-RENEWAL; MYELODYSPLASTIC SYNDROMES; TELOMERASE ACTIVITY; IONIZING-RADIATION; GENE-EXPRESSION; COMET ASSAY AB Hematopoietic stem cells (HSCs) maintain homeostasis and regenerate the blood system throughout life. It has been postulated that HSCs may be uniquely capable of preserving their genomic integrity in order to ensure lifelong function. To directly test this, we quantified DNA damage in HSCs and downstream progenitors from young and old mice, revealing that strand breaks significantly accrue in HSCs during aging. DNA damage accumulation in HSCs was associated with broad attenuation of DNA repair and response pathways that was dependent upon HSC quiescence. Accordingly, cycling fetal HSCs and adult HSCs driven into cycle upregulated these pathways leading to repair of strand breaks. Our results demonstrate that HSCs are not comprehensively geno-protected during aging. Rather, HSC quiescence and concomitant attenuation of DNA repair and response pathways underlies DNA damage accumulation in HSCs during aging. These results provide a potential mechanism through which premalignant mutations accrue in HSCs. C1 [Beerman, Isabel; Rossi, Derrick J.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Beerman, Isabel; Rossi, Derrick J.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Beerman, Isabel; Rossi, Derrick J.] Boston Childrens Hosp, Div Hematol Oncol, Program Cellular & Mol Med, Boston, MA 02116 USA. [Seita, Jun; Inlay, Matthew A.; Weissman, Irving L.] Stanford Univ, Sch Med, Inst Stem Cell Biol & Regenerat Med, Stanford, CA 94305 USA. [Inlay, Matthew A.] Univ Calif Irvine, Dept Mol Biol & Biochem, Sue & Bill Gross Stem Cell Res Ctr, Irvine, CA 92697 USA. [Rossi, Derrick J.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Rossi, DJ (reprint author), Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. EM derrick.rossi@childrens.harvard.edu OI Seita, Jun/0000-0002-3008-3615 FU National Institutes of Health [R01CA86065, U01HL099999, R03HL096234, RO1HL107630, R00AG029760, UO1DK072473-01]; Virginia and D.K. Ludwig Fund for Cancer Research; Leona M. and Harry B. Helmsley Charitable Trust; New York Stem Cell Foundation; Harvard Stem Cell Institute; Joint Program in Transfusion Medicine fellowship [5T32HL066987-12] FX The authors would like to sincerely thank Elizabeth Zuo and the Gene Expression Core of the Stanford Protein and Nucleic Acid (PAN) for microarray processing; L. Jerabek and T. Storm for laboratory management; T.J. Naik for technical assistance; A. Mosley, C. Wang, and A. McCarty for animal care; and A. Zguro for animal husbandry and technical assistance as well as all members of the D.J.R. and I.L.W. labs. This work was supported by grants from the National Institutes of Health (R01CA86065 to I. L. W., U01HL099999 to I.L.W., R03HL096234 to I.L.W., RO1HL107630 to D.J.R., R00AG029760 to D.J.R., UO1DK072473-01 to D.J.R.) and the Virginia and D.K. Ludwig Fund for Cancer Research (to I. L. W.), the Leona M. and Harry B. Helmsley Charitable Trust (to D.J.R.), the New York Stem Cell Foundation (to D.J.R.), and the Harvard Stem Cell Institute (to D.J.R.). I.B. received funding from a Joint Program in Transfusion Medicine fellowship (5T32HL066987-12). D.J.R. is a New York Stem Cell Foundation Robertson Investigator. I.L.W. is a member of the scientific advisory board of StemCells, Inc. NR 69 TC 84 Z9 85 U1 4 U2 27 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 EI 1875-9777 J9 CELL STEM CELL JI Cell Stem Cell PD JUL 3 PY 2014 VL 15 IS 1 BP 37 EP 50 DI 10.1016/j.stem.2014.04.016 PG 14 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA AN8TX UT WOS:000340878600010 PM 24813857 ER PT J AU Lu, Y Loh, YH Li, H Cesana, M Ficarro, SB Parikh, JR Salomonis, N Toh, CXD Andreadis, ST Luckey, CJ Collins, JJ Daley, GQ Marto, JA AF Lu, Yu Loh, Yuin-Han Li, Hu Cesana, Marcella Ficarro, Scott B. Parikh, Jignesh R. Salomonis, Nathan Toh, Cheng-Xu Delon Andreadis, Stelios T. Luckey, C. John Collins, James J. Daley, George Q. Marto, Jarrod A. TI Alternative Splicing of MBD2 Supports Self-Renewal in Human Pluripotent Stem Cells SO CELL STEM CELL LA English DT Article ID TRANSCRIPTIONAL REGULATORY CIRCUITRY; PROTEIN-INTERACTION NETWORKS; GENE-EXPRESSION; DNA METHYLATION; SOMATIC-CELLS; DIFFERENTIATION; REVEALS; NURD; HETEROGENEITY; DYNAMICS AB Alternative RNA splicing (AS) regulates proteome diversity, including isoform-specific expression of several pluripotency genes. Here, we integrated global gene expression and proteomic analyses and identified a molecular signature suggesting a central role for AS in maintaining human pluripotent stem cell (hPSC) self-renewal. We demonstrate that the splicing factor SFRS2 is an OCT4 target gene required for pluripotency. SFRS2 regulates AS of the methyl-CpG binding protein MBD2, whose isoforms play opposing roles in maintenance of and reprogramming to pluripotency. Although both MDB2a and MBD2c are enriched at the OCT4 and NANOG promoters, MBD2a preferentially interacts with repressive NuRD chromatin remodeling factors and promotes hPSC differentiation, whereas overexpression of MBD2c enhances reprogramming of fibroblasts to pluripotency. The miR-301 and miR-302 families provide additional regulation by targeting SFRS2 and MDB2a. These data suggest that OCT4, SFRS2, and MBD2 participate in a positive feedback loop, regulating proteome diversity in support of hPSC self-renewal and reprogramming. C1 [Lu, Yu; Ficarro, Scott B.; Marto, Jarrod A.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Lu, Yu; Loh, Yuin-Han; Cesana, Marcella; Ficarro, Scott B.; Daley, George Q.; Marto, Jarrod A.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Lu, Yu; Luckey, C. John] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Loh, Yuin-Han; Cesana, Marcella; Daley, George Q.] Childrens Hosp Boston, Howard Hughes Med Inst, Div Pediat Hematol Oncol, Dept Med, Boston, MA 02115 USA. [Loh, Yuin-Han; Cesana, Marcella; Daley, George Q.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Loh, Yuin-Han; Toh, Cheng-Xu Delon] Natl Univ Singapore, A STAR Inst Mol & Cell Biol, Singapore 138673, Singapore. [Loh, Yuin-Han; Toh, Cheng-Xu Delon] Natl Univ Singapore, Dept Biol Sci, Singapore 138673, Singapore. [Li, Hu; Collins, James J.] Boston Univ, Dept Biomed Engn, Howard Hughes Med Inst, Boston, MA 02215 USA. [Li, Hu; Collins, James J.] Boston Univ, Ctr Synthet Biol, Boston, MA 02215 USA. [Li, Hu; Collins, James J.] Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA. [Li, Hu] Mayo Clin, Dept Mol Pharmacol & Expt Therapeut, Ctr Individualized Med, Rochester, MN 55905 USA. [Ficarro, Scott B.; Parikh, Jignesh R.; Marto, Jarrod A.] Dana Farber Canc Inst, Blais Prote Ctr, Boston, MA 02115 USA. [Parikh, Jignesh R.] Boston Univ, Bioinformat Program, Boston, MA 02115 USA. [Salomonis, Nathan] Gladstone Inst Cardiovasc Dis, San Francisco, CA 94158 USA. [Andreadis, Stelios T.] SUNY Buffalo, Dept Chem & Biol Engn, Buffalo, NY 14260 USA. RP Daley, GQ (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. EM george.daley@childrens.harvard.edu; jarrod_marto@dfci.harvard.edu RI ASTAR, IMCB/E-2320-2012 FU A*STAR Investigator research award; Mayo Clinic Center for Individualized Medicine; Mayo Clinic Center for Regenerative Medicine; Pathology Department of the Brigham and Women's Hospital; National Blood Foundation; Howard Hughes Medical Institute; SysCODE (Systems-based Consortium for Organ Design Engineering); NIH grant [RL1DE019021]; Dana-Farber Cancer Institute; Harvard Stem Cell Institute [P01GM099117]; NIH/NINDS [P01NS047572]; NIGMS [5P50GM099117]; NIH/NHLBI [5RC2HL102815-02]; [T32HL66987-11] FX We thank J. Sahalie for technical assistance, M.W. Lensch for teratoma interpretation, and G. Adelmant for critical reading of the manuscript. Y.-H.L. is supported by the A*STAR Investigator research award. H.L. is supported by Mayo Clinic Center for Individualized Medicine and Mayo Clinic Center for Regenerative Medicine. Generous support for this work was provided (to C.J.L.) by the Pathology Department of the Brigham and Women's Hospital and the National Blood Foundation. J. J. C. is supported by Howard Hughes Medical Institute, SysCODE (Systems-based Consortium for Organ Design & Engineering), and NIH grant RL1DE019021. Generous support for this work was provided (to J. A. M.) by the Dana-Farber Cancer Institute, the Harvard Stem Cell Institute (P01GM099117), and the NIH/NINDS P01NS047572. Y.L. acknowledges support from T32HL66987-11. G.Q.D. is supported by the Howard Hughes Medical Institute and NIGMS 5P50GM099117. G.Q.D., J.J.C., and J.A.M. acknowledge support from NIH/NHLBI 5RC2HL102815-02. G.Q.D. serves on the scientific advisory boards of iPierian, Inc., Verastem, Inc., and MPM Capital. NR 46 TC 29 Z9 30 U1 2 U2 21 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 EI 1875-9777 J9 CELL STEM CELL JI Cell Stem Cell PD JUL 3 PY 2014 VL 15 IS 1 BP 92 EP 101 DI 10.1016/j.stem.2014.04.002 PG 10 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA AN8TX UT WOS:000340878600014 PM 24813856 ER PT J AU Rinne, ST Feemster, LC Collins, BF Au, DH Perkins, M Bryson, CL O'Riordan, TG Liu, CF AF Rinne, Seppo T. Feemster, Laura C. Collins, Bridget F. Au, David H. Perkins, Mark Bryson, Christopher L. O'Riordan, Thomas G. Liu, Chuan-Fen TI Thiazolidinediones and the risk of asthma exacerbation among patients with diabetes: a cohort study SO ALLERGY ASTHMA AND CLINICAL IMMUNOLOGY LA English DT Article DE Thiazolidinediones; Peroxisome proliferator-activated receptors; Glitazones; Asthma; Cohort study ID ACTIVATED-RECEPTOR-GAMMA; OBSTRUCTIVE PULMONARY-DISEASE; MURINE MODEL; PPAR-GAMMA; AIRWAY INFLAMMATION; ALLERGIC INFLAMMATION; AGONIST ROSIGLITAZONE; PIOGLITAZONE; SEVERITY; COSTS AB Background: Thiazolidinediones are oral diabetes medications that selectively activate peroxisome proliferator-activated receptor gamma and have potent anti-inflammatory properties. While a few studies have found improvements in pulmonary function with exposure to thiazolidinediones, there are no studies of their impact on asthma exacerbations. Our objective was to assess whether exposure to thiazolidinediones was associated with a decreased risk of asthma exacerbation. Methods: We performed a cohort study of diabetic Veterans who had a diagnosis of asthma and were taking oral diabetes medications during the period of 10/1/2005 - 9/30/2006. The risk of asthma exacerbations and oral steroid use during 10/1/2006 - 9/30/2007 was compared between patients who were prescribed thiazolidinediones and patients who were on alternative oral diabetes medications. Multivariable logistic regression and negative binomial regression analyses were used to characterize this risk. A sensitivity analysis was performed, restricting our evaluation to patients who were adherent to diabetes therapy. Results: We identified 2,178 patients who were on thiazolidinediones and 10,700 who were not. Exposure to thiazolidinediones was associated with significant reductions in the risk of asthma exacerbation (OR = 0.79, 95% CI, 0.62 - 0.99) and oral steroid prescription (OR = 0.73, 95% CI 0.63 - 0.84). Among patients who were adherent to diabetes medications, there were more substantial reductions in the risks for asthma exacerbation (OR = 0.64, 95% CI 0.47 - 0.85) and oral steroid prescription (OR = 0.68, 95% CI 0.57 - 0.81). Conclusions: Thiazolidinediones may provide a novel anti-inflammatory approach to asthma management by preventing exacerbations and decreasing the use of oral steroids. C1 [Rinne, Seppo T.; Feemster, Laura C.; Collins, Bridget F.; Au, David H.; Perkins, Mark; Bryson, Christopher L.; Liu, Chuan-Fen] VA Puget Sound Hlth Care Syst, Dept Vet Affairs, Hlth Serv Res & Dev, Seattle, WA 98104 USA. [Rinne, Seppo T.; Feemster, Laura C.; Collins, Bridget F.; Au, David H.] Univ Washington, Dept Pulm & Cri Care, Seattle, WA 98195 USA. [Bryson, Christopher L.] Univ Washington, Dept Med, Div Gen Internal Med, Seattle, WA USA. [O'Riordan, Thomas G.] Gilead Sci Inc, Seattle, WA USA. [Liu, Chuan-Fen] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. RP Rinne, ST (reprint author), VA Puget Sound Hlth Care Syst, Dept Vet Affairs, Hlth Serv Res & Dev, 1100 Olive Way Suite 1400, Seattle, WA 98104 USA. EM srinne@uw.edu FU VA HSRD [IIR 07-068-2]; Gilead Sciences Inc FX Research funding for this project was from a VA HSR&D grant (IIR 07-068-2) along with funding from Gilead Sciences Inc. Neither funding source had a role in the study design, analysis, or interpretation. NR 40 TC 3 Z9 3 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1710-1484 EI 1710-1492 J9 ALLERGY ASTHMA CL IM JI Allerg Asthma Clin. Immunol. PD JUL 3 PY 2014 VL 10 AR 34 DI 10.1186/1710-1492-10-34 PG 6 WC Allergy; Immunology SC Allergy; Immunology GA AL3GY UT WOS:000339016100001 PM 25024717 ER PT J AU Friedly, JL Comstock, BA Turner, JA Heagerty, PJ Deyo, RA Sullivan, SD Bauer, Z Bresnahan, BW Avins, AL Nedeljkovic, SS Nerenz, DR Standaert, C Kessler, L Akuthota, V Annaswamy, T Chen, A Diehn, F Firtch, W Gerges, FJ Gilligan, C Goldberg, H Kennedy, DJ Mandel, S Tyburski, M Sanders, W Sibell, D Smuck, M Wasan, A Won, L Jarvik, JG AF Friedly, Janna L. Comstock, Bryan A. Turner, Judith A. Heagerty, Patrick J. Deyo, Richard A. Sullivan, Sean D. Bauer, Zoya Bresnahan, Brian W. Avins, Andrew L. Nedeljkovic, Srdjan S. Nerenz, David R. Standaert, Christopher Kessler, Larry Akuthota, Venu Annaswamy, Thiru Chen, Allen Diehn, Felix Firtch, William Gerges, Frederic J. Gilligan, Christopher Goldberg, Harley Kennedy, David J. Mandel, Shlomo Tyburski, Mark Sanders, William Sibell, David Smuck, Matthew Wasan, Ajay Won, Lawrence Jarvik, Jeffrey G. TI A Randomized Trial of Epidural Glucocorticoid Injections for Spinal Stenosis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID LOW-BACK-PAIN; STEROID INJECTIONS; MEDICARE POPULATION; OLDER-ADULTS; CLINICAL-TRIALS; QUESTIONNAIRE; DISABILITY; EFFICACY; SURGERY; GROWTH AB Background Epidural glucocorticoid injections are widely used to treat symptoms of lumbar spinal stenosis, a common cause of pain and disability in older adults. However, rigorous data are lacking regarding the effectiveness and safety of these injections. Methods In a double-blind, multisite trial, we randomly assigned 400 patients who had lumbar central spinal stenosis and moderate-to-severe leg pain and disability to receive epidural injections of glucocorticoids plus lidocaine or lidocaine alone. The patients received one or two injections before the primary outcome evaluation, performed 6 weeks after randomization and the first injection. The primary outcomes were the score on the Roland-Morris Disability Questionnaire (RMDQ, in which scores range from 0 to 24, with higher scores indicating greater physical disability) and the rating of the intensity of leg pain (on a scale from 0 to 10, with 0 indicating no pain and 10 indicating "pain as bad as you can imagine"). Results At 6 weeks, there were no significant between-group differences in the RMDQ score (adjusted difference in the average treatment effect between the glucocorticoid-lidocaine group and the lidocaine-alone group, -1.0 points; 95% confidence interval [CI], -2.1 to 0.1; P = 0.07) or the intensity of leg pain (adjusted difference in the average treatment effect, -0.2 points; 95% CI, -0.8 to 0.4; P = 0.48). A pre-specified secondary subgroup analysis with stratification according to type of injection (interlaminar vs. transforaminal) likewise showed no significant differences at 6 weeks. Conclusions In the treatment of lumbar spinal stenosis, epidural injection of glucocorticoids plus lidocaine offered minimal or no short-term benefit as compared with epidural injection of lidocaine alone. (Funded by the Agency for Healthcare Research and Quality; ClinicalTrials.gov number, NCT01238536.) C1 [Friedly, Janna L.; Comstock, Bryan A.; Turner, Judith A.; Heagerty, Patrick J.; Sullivan, Sean D.; Bauer, Zoya; Bresnahan, Brian W.; Kessler, Larry; Jarvik, Jeffrey G.] Univ Washington, Comparat Effectiveness Cost & Outcomes Res Ctr, Seattle, WA 98104 USA. [Friedly, Janna L.; Turner, Judith A.; Standaert, Christopher] Univ Washington, Dept Rehabil Med, Seattle, WA 98104 USA. [Comstock, Bryan A.; Heagerty, Patrick J.] Univ Washington, Dept Biostat, Seattle, WA 98104 USA. [Turner, Judith A.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98104 USA. [Bauer, Zoya; Bresnahan, Brian W.; Jarvik, Jeffrey G.] Univ Washington, Dept Radiol, Seattle, WA 98104 USA. [Bresnahan, Brian W.; Kessler, Larry] Univ Washington, Dept Hlth Serv, Seattle, WA 98104 USA. [Deyo, Richard A.] Oregon Hlth & Sci Univ, Dept Family Med, Portland, OR 97201 USA. [Deyo, Richard A.] Oregon Hlth & Sci Univ, Dept Internal Med, Portland, OR 97201 USA. [Deyo, Richard A.] Oregon Hlth & Sci Univ, Dept Publ Hlth, Portland, OR 97201 USA. [Deyo, Richard A.] Oregon Hlth & Sci Univ, Dept Prevent Med, Portland, OR 97201 USA. [Sibell, David] Oregon Hlth & Sci Univ, Dept Anesthesiol, Portland, OR 97201 USA. [Sibell, David] Oregon Hlth & Sci Univ, Dept Perioperat Med, Portland, OR 97201 USA. [Deyo, Richard A.] Oregon Hlth & Sci Univ, Oregon Inst Occupat Hlth Sci, Portland, OR 97201 USA. [Deyo, Richard A.] Kaiser Permanente Ctr Hlth Res, Portland, OR USA. [Avins, Andrew L.] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Chen, Allen] Kaiser Permanente Martinez Med Ctr, Dept Phys Med & Rehabil, Martinez, CA USA. [Firtch, William] Stanford Univ, Med Ctr, Dept Phys Med & Rehabil, Kaiser Permanente Redwood City Med Ctr, Redwood City, CA USA. [Kennedy, David J.; Smuck, Matthew] Stanford Univ, Med Ctr, Dept Phys Med & Rehabil, Redwood City, CA USA. [Goldberg, Harley] Kaiser Permanente San Jose Med Ctr, Spine Care Serv, San Jose, CA USA. [Won, Lawrence] Kaiser Permanente San Jose Med Ctr, Dept Phys Med & Rehabil, San Jose, CA USA. [Tyburski, Mark] Kaiser Permanente Roseville Med Ctr, Dept Phys Med & Rehabil, Roseville, CA USA. [Nedeljkovic, Srdjan S.] Brigham & Womens Hosp, Dept Anesthesiol Perioperat & Pain Med, Boston, MA 02115 USA. [Nedeljkovic, Srdjan S.] Harvard Vanguard Med Associates, Spine Unit, Boston, MA USA. [Gerges, Frederic J.] Massachusetts Gen Hosp, Dept Anesthesiol & Pain Med, St Elizabeths Med Ctr, Boston, MA 02114 USA. [Gilligan, Christopher] Massachusetts Gen Hosp, Ctr Pain Med, Boston, MA 02114 USA. [Nerenz, David R.] Henry Ford Hosp, Neurosci Inst, Detroit, MI 48202 USA. [Mandel, Shlomo] Henry Ford Hlth Syst, Dept Orthoped Surg, Detroit, MI USA. [Sanders, William] Henry Ford Hlth Syst, Dept Radiol, Detroit, MI USA. [Akuthota, Venu] Univ Colorado, Dept Phys Med & Rehabil, Aurora, CO USA. [Annaswamy, Thiru] Dallas Vet Affairs Med Ctr, Dept Phys Med & Rehabil, Dallas, TX USA. [Diehn, Felix] Mayo Clin, Dept Radiol, Rochester, MN USA. [Wasan, Ajay] Univ Pittsburgh, Dept Anesthesiol, Pittsburgh, PA USA. [Wasan, Ajay] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. RP Friedly, JL (reprint author), Univ Washington, Dept Rehabil Med, 325 Ninth Ave, Seattle, WA 98104 USA. EM friedlyj@uw.edu OI Kennedy, David/0000-0001-8061-0287 FU Agency for Healthcare Research and Quality FX Funded by the Agency for Healthcare Research and Quality; ClinicalTrials.gov number, NCT01238536. NR 40 TC 97 Z9 99 U1 1 U2 11 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 3 PY 2014 VL 371 IS 1 BP 11 EP 21 DI 10.1056/NEJMoa1313265 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA AK2RA UT WOS:000338265700005 PM 24988555 ER PT J AU Crosby, J Peloso, GM Auer, PL Crosslin, DR Stitziel, NO Lange, LA Lu, YC Tang, ZZ Zhang, H Hindy, G Masca, N Stirrups, K Kanoni, S Do, R Jun, G Hu, YN Kang, HM Xue, CY Goel, A Farrall, M Duga, S Merlini, PA Asselta, R Girelli, D Olivieri, O Martinelli, N Yin, W Reilly, D Speliotes, E Fox, CS Hveem, K Holmen, OL Nikpay, M Farlow, DN Assimes, TL Franceschini, N Robinson, J North, KE Martin, LW DePristo, M Gupta, N Escher, SA Jansson, JH Van Zuydam, N Palmer, CNA Wareham, N Koch, W Meitinger, T Peters, A Lieb, W Erbel, R Konig, IR Kruppa, J Degenhardt, F Gottesman, O Bottinger, EP O'Donnell, CJ Psaty, BM Ballantyne, CM Abecasis, G Ordovas, JM Melander, O Watkins, H Orho-Melander, M Ardissino, D Loos, RJF McPherson, R Willer, CJ Erdmann, J Hall, AS Samani, NJ Deloukas, P Schunkert, H Wilson, JG Kooperberg, C Rich, SS Tracy, RP Lin, DY Altshuler, D Gabriel, S Nickerson, DA Jarvik, GP Cupples, LA Reiner, AP Boerwinkle, E Kathiresan, S AF Crosby, Jacy Peloso, Gina M. Auer, Paul L. Crosslin, David R. Stitziel, Nathan O. Lange, Leslie A. Lu, Yingchang Tang, Zheng-zheng Zhang, He Hindy, George Masca, Nicholas Stirrups, Kathleen Kanoni, Stavroula Do, Ron Jun, Goo Hu, Youna Kang, Hyun Min Xue, Chenyi Goel, Anuj Farrall, Martin Duga, Stefano Merlini, Pier Angelica Asselta, Rosanna Girelli, Domenico Olivieri, Oliviero Martinelli, Nicola Yin, Wu Reilly, Dermot Speliotes, Elizabeth Fox, Caroline S. Hveem, Kristian Holmen, Oddgeir L. Nikpay, Majid Farlow, Deborah N. Assimes, Themistocles L. Franceschini, Nora Robinson, Jennifer North, Kari E. Martin, Lisa W. DePristo, Mark Gupta, Namrata Escher, Stefan A. Jansson, Jan-Hakan Van Zuydam, Natalie Palmer, Colin N. A. Wareham, Nicholas Koch, Werner Meitinger, Thomas Peters, Annette Lieb, Wolfgang Erbel, Raimund Konig, Inke R. Kruppa, Jochen Degenhardt, Franziska Gottesman, Omri Bottinger, Erwin P. O'Donnell, Christopher J. Psaty, Bruce M. Ballantyne, Christie M. Abecasis, Goncalo Ordovas, Jose M. Melander, Olle Watkins, Hugh Orho-Melander, Marju Ardissino, Diego Loos, Ruth J. F. McPherson, Ruth Willer, Cristen J. Erdmann, Jeanette Hall, Alistair S. Samani, Nilesh J. Deloukas, Panos Schunkert, Heribert Wilson, James G. Kooperberg, Charles Rich, Stephen S. Tracy, Russell P. Lin, Dan-Yu Altshuler, David Gabriel, Stacey Nickerson, Deborah A. Jarvik, Gail P. Cupples, L. Adrienne Reiner, Alex P. Boerwinkle, Eric Kathiresan, Sekar CA Exome Sequencing Project Natl Heart Lung Blood Inst TI Loss-of-Function Mutations in APOC3, Triglycerides, and Coronary Disease SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID APOLIPOPROTEIN C-III; CARDIOVASCULAR-DISEASE; PLASMA TRIGLYCERIDES; RICH LIPOPROTEINS; RARE VARIANTS; HEART-DISEASE; HUMAN EXOMES; DESIGN; ASSOCIATION; PCSK9 AB Background Plasma triglyceride levels are heritable and are correlated with the risk of coronary heart disease. Sequencing of the protein-coding regions of the human genome (the exome) has the potential to identify rare mutations that have a large effect on phenotype. Methods We sequenced the protein-coding regions of 18,666 genes in each of 3734 participants of European or African ancestry in the Exome Sequencing Project. We conducted tests to determine whether rare mutations in coding sequence, individually or in aggregate within a gene, were associated with plasma triglyceride levels. For mutations associated with triglyceride levels, we subsequently evaluated their association with the risk of coronary heart disease in 110,970 persons. Results An aggregate of rare mutations in the gene encoding apolipoprotein C3 (APOC3) was associated with lower plasma triglyceride levels. Among the four mutations that drove this result, three were loss-of-function mutations: a nonsense mutation (R19X) and two splice-site mutations (IVS2+1G -> A and IVS3+1G -> T). The fourth was a missense mutation (A43T). Approximately 1 in 150 persons in the study was a heterozygous carrier of at least one of these four mutations. Triglyceride levels in the carriers were 39% lower than levels in noncarriers (P<1x10(-20)), and circulating levels of APOC3 in carriers were 46% lower than levels in noncarriers (P = 8x10(-10)). The risk of coronary heart disease among 498 carriers of any rare APOC3 mutation was 40% lower than the risk among 110,472 noncarriers (odds ratio, 0.60; 95% confidence interval, 0.47 to 0.75; P = 4x10(-6)). Conclusions Rare mutations that disrupt APOC3 function were associated with lower levels of plasma triglycerides and APOC3. Carriers of these mutations were found to have a reduced risk of coronary heart disease. (Funded by the National Heart, Lung, and Blood Institute and others.) C1 [Crosby, Jacy] Univ Texas Houston, Dept Biostat Bioinformat & Syst Biol, Grad Sch Biomed Sci, Houston, TX USA. [Crosby, Jacy; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Ballantyne, Christie M.; Boerwinkle, Eric] Baylor Coll Med, Houston, TX 77030 USA. [Ballantyne, Christie M.] Methodist DeBakey Heart & Vasc Ctr, Houston, TX USA. [Peloso, Gina M.; Do, Ron; Altshuler, David; Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Peloso, Gina M.; Do, Ron; Altshuler, David; Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Peloso, Gina M.; Do, Ron; Altshuler, David; Kathiresan, Sekar] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Yin, Wu; Reilly, Dermot] Merck Sharp & Dohme Ltd, Boston, MA USA. [Ordovas, Jose M.] Tufts Univ, Nutr & Genom Lab, Jean Mayer USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Peloso, Gina M.; Do, Ron; Farlow, Deborah N.; DePristo, Mark; Gupta, Namrata; Altshuler, David; Gabriel, Stacey; Kathiresan, Sekar] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Auer, Paul L.] Univ Wisconsin, Sch Publ Hlth, Milwaukee, WI 53201 USA. [Crosslin, David R.; Nickerson, Deborah A.; Jarvik, Gail P.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Crosslin, David R.; Jarvik, Gail P.] Univ Washington, Dept Med Med Genet, Seattle, WA 98195 USA. [Reiner, Alex P.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol & Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Kooperberg, Charles; Reiner, Alex P.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA USA. [Stitziel, Nathan O.] Washington Univ, Sch Med, Dept Med, Cardiovasc Div, St Louis, MO 63130 USA. [Stitziel, Nathan O.] Washington Univ, Sch Med, Div Stat Genom, St Louis, MO 63130 USA. [Lange, Leslie A.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Tang, Zheng-zheng; Lin, Dan-Yu] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Franceschini, Nora; North, Kari E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [North, Kari E.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC USA. [Lu, Yingchang; Gottesman, Omri; Bottinger, Erwin P.; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY USA. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY USA. [Zhang, He; Speliotes, Elizabeth; Willer, Cristen J.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Zhang, He; Xue, Chenyi; Speliotes, Elizabeth; Willer, Cristen J.] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Zhang, He; Willer, Cristen J.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Jun, Goo; Hu, Youna; Kang, Hyun Min; Abecasis, Goncalo] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Speliotes, Elizabeth] Univ Michigan, Div Gastroenterol, Ann Arbor, MI 48109 USA. [Abecasis, Goncalo] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Hindy, George; Orho-Melander, Marju] Lund Univ, Dept Clin Sci, Clin Res Ctr, Malmo, Sweden. [Escher, Stefan A.] Lund Univ, Dept Clin Sci, Genet & Mol Epidemiol Unit, Malmo, Sweden. [Melander, Olle] Lund Univ, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden. Malmo Univ Hosp, Malmo, Sweden. [Jansson, Jan-Hakan] Skelleftea Hosp, Dept Med, Skelleftea, Sweden. [Jansson, Jan-Hakan] Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden. [Masca, Nicholas; Samani, Nilesh J.] Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England. [Masca, Nicholas; Samani, Nilesh J.] Natl Inst Hlth Res Leicester, Cardiovasc Biomed Res Unit, Leicester, Leics, England. [Stirrups, Kathleen; Kanoni, Stavroula; Deloukas, Panos] Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med & Dent, London, England. [Goel, Anuj; Farrall, Martin; Watkins, Hugh] Univ Oxford, Radcliffe Dept Med, Div Cardiovasc Med, Wellcome Trust Ctr Human Genet, Oxford, England. [Van Zuydam, Natalie; Palmer, Colin N. A.] Univ Dundee, Ninewells Hosp & Med Sch, Med Res Inst, Dundee DD1 9SY, Scotland. [Wareham, Nicholas; Cupples, L. Adrienne] Addenbrookes Hosp, Med Res Council Epidemiol Unit, Inst Metab Sci, Cambridge, England. [Deloukas, Panos] Wellcome Trust Sanger Inst, Cambridge, England. [Hall, Alistair S.] Univ Leeds, Sch Med, Div Epidemiol, Leeds LS2 9JT, W Yorkshire, England. [Duga, Stefano; Asselta, Rosanna] Univ Milan, Dipartimento Biotecnol Med & Med Traslaz, Milan, Italy. [Merlini, Pier Angelica] Osped Niguarda Ca Granda, Div Cardiol, Milan, Italy. [Girelli, Domenico; Olivieri, Oliviero; Martinelli, Nicola] Univ Verona, Dept Med, Sch Med, I-37100 Verona, Italy. [Ardissino, Diego] Azienda Osped Univ Parma, Div Cardiol, Parma, Italy. [Fox, Caroline S.; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Fox, Caroline S.] Ctr Populat Studies, Framingham, MA USA. [Hveem, Kristian; Holmen, Oddgeir L.] Norwegian Univ Sci & Technol, Nord Trondelag Hlth Study HUNT Res Ctr, Dept Publ Hlth & Gen Practice, N-7034 Trondheim, Norway. [Hveem, Kristian] Levanger Hosp, Levanger, Norway. [Holmen, Oddgeir L.] Univ Trondheim Hosp, St Olav Hosp, Trondheim, Norway. [Nikpay, Majid; McPherson, Ruth] Univ Ottawa, Inst Heart, Div Cardiol, Ottawa, ON, Canada. [Assimes, Themistocles L.] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA. [Robinson, Jennifer] Univ Iowa, Dept Epidemiol, Coll Publ Hlth, Ames, IA USA. [Robinson, Jennifer] Univ Iowa, Dept Med, Coll Publ Hlth, Ames, IA USA. [Martin, Lisa W.] Washington Univ, Sch Med & Hlth Sci, Div Cardiol, Washington, DC USA. [Koch, Werner; Schunkert, Heribert] Deutsch Herzzentrum Munich, Munich, Germany. [Koch, Werner] Tech Univ Munich, Klinikum Rechts Isar, Med Klin, D-80290 Munich, Germany. [Meitinger, Thomas] Tech Univ Munich, Inst Human Genet, D-80290 Munich, Germany. [Koch, Werner; Peters, Annette] German Ctr Cardiovasc Res, Munich, Germany. [Peters, Annette] Helmholtz Zentrum Munchen, Ctr Environm Hlth, Inst Epidemiol 2, Neuherberg, Germany. [Lieb, Wolfgang] Univ Kiel, Inst Epidemiol & Biobank popgen, Kiel, Germany. [Erbel, Raimund] West German Heart Ctr, Dept Cardiol, Essen, Germany. [Konig, Inke R.; Kruppa, Jochen] Univ Lubeck, Univ Klinikum Schleswig Holstein, Inst Med Biometrie & Stat, Lubeck, Germany. [Erdmann, Jeanette] Univ Lubeck, Univ Klinikum Schleswig Holstein, Inst Integrat & Expt Genom, Lubeck, Germany. [Konig, Inke R.; Kruppa, Jochen] Univ Lubeck, Univ Klinikum Schleswig Holstein, Lubeck, Germany. [Erdmann, Jeanette] DZHK German Res Ctr Cardiovasc Res, Lubeck, Germany. [Degenhardt, Franziska] Univ Bonn, Inst Human Genet, Bonn, Germany. [Ordovas, Jose M.] Natl Ctr Cardiovasc Invest, Dept Cardiovasc Epidemiol & Populat Genet, Madrid, Spain. [Ordovas, Jose M.] Inst Madrileno Estudios Avanzados Alimentac, Madrid, Spain. [Deloukas, Panos] King Abdulaziz Univ, Jeddah 21413, Saudi Arabia. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS USA. [Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Gen, Charlottesville, VA USA. [Tracy, Russell P.] Univ Vermont, Dept Pathol, Coll Med, Burlington, VT 05405 USA. [Tracy, Russell P.] Univ Vermont, Dept Biochem, Coll Med, Burlington, VT 05405 USA. RP Kathiresan, S (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, 185 Cambridge St,CPZN 5-252, Boston, MA 02114 USA. EM skathiresan@partners.org RI Erdmann, Jeanette/P-7513-2014; Deloukas, Panos/B-2922-2013; Hindy, George/H-1864-2016; Jarvik, Gail/N-6476-2014; Palmer, Colin/C-7053-2008; Meitinger, Thomas/O-1318-2015; Peters, Annette/A-6117-2011; Martinelli, Nicola/J-5622-2016; Study, GoDARTS/K-9448-2016; Lieb, Wolfgang/C-1990-2012; Jun, Goo/F-1941-2017; OI Martin, Lisa Warsinger/0000-0003-4352-0914; Erdmann, Jeanette/0000-0002-4486-6231; Stitziel, Nathan/0000-0002-4963-8211; Duga, Stefano/0000-0003-3457-1410; Watkins, Hugh/0000-0002-5287-9016; Assimes, Themistocles/0000-0003-2349-0009; Deloukas, Panos/0000-0001-9251-070X; Hindy, George/0000-0002-7257-9299; Jarvik, Gail/0000-0002-6710-8708; Palmer, Colin/0000-0002-6415-6560; Martinelli, Nicola/0000-0001-6465-5119; Jun, Goo/0000-0003-0891-0204; Asselta, Rosanna/0000-0001-5351-0619 FU National Heart, Lung, and Blood Institute FX Funded by the National Heart, Lung, and Blood Institute and others. NR 40 TC 161 Z9 167 U1 4 U2 28 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 3 PY 2014 VL 371 IS 1 BP 22 EP 31 DI 10.1056/NEJMoa1307095 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA AK2RA UT WOS:000338265700006 ER PT J AU Honavar, J Bradley, E Bradley, K Oh, JY Vallejo, MO Kelley, EE Cantu-Medellin, N Doran, S Dell'italia, LJ Matalon, S Patel, RP AF Honavar, Jaideep Bradley, Eddie Bradley, Kelley Oh, Joo Yeun Vallejo, Matthew O. Kelley, Eric E. Cantu-Medellin, Nadiezhda Doran, Stephen Dell'italia, Louis J. Matalon, Sadis Patel, Rakesh P. TI Chlorine gas exposure disrupts nitric oxide homeostasis in the pulmonary vasculature SO TOXICOLOGY LA English DT Article DE Halogen; Lung; Inflammation ID INDUCED LUNG INJURY; EPITHELIAL NA+ CHANNELS; TRAIN DERAILMENT; MURINE MODEL; MICE; INHALATION; MECHANISMS; MITIGATION; HYPERREACTIVITY; SUPEROXIDE AB Exposure to chlorine (Cl-2) gas during industrial accidents or chemical warfare leads to significant airway and distal lung epithelial injury that continues post exposure. While lung epithelial injury is prevalent, relatively little is known about whether Cl-2 gas also promotes injury to the pulmonary vasculature. To determine this, rats were subjected to a sub-lethal Cl-2 gas exposure (400 ppm, 30 min) and then brought back to room air. Pulmonary arteries (PA) were isolated from rats at various times post-exposure and contractile (phenylephrine) and nitric oxide (NO)-dependent vasodilation (acetylcholine and mahmanonoate) responses measured ex vivo. PA contractility did not change, however significant inhibition of NO-dependent vasodilation was observed that was maximal at 24-48 h post exposure. Superoxide dismutase restored NO-dependent vasodilation suggesting a role for increased superoxide formation. This was supported by similar to 2-fold increase in superoxide formation (measured using 2-hydroethidine oxidation to 2-OH-E+) from PA isolated from Cl-2 exposed rats. We next measured PA pressures in anesthetized rats. Surprisingly, PA pressures were significantly (similar to 4 mmHg) lower in rats that had been exposed to Cl-2 gas 24 h earlier suggesting that deficit in NO-signaling observed in isolated PA experiments did not manifest as increased PA pressures in vivo. Administration of the iNOS selective inhibitor 1400W, restored PA pressures to normal in Cl-2 exposed, but not control rats suggesting that any deficit in NO-signaling due to increased superoxide formation in the PA, is offset by increased NO-formation from iNOS. These data indicate that disruption of endogenous NO-signaling mechanisms that maintain PA tone is an important aspect of post-Cl-2 gas exposure toxicity. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Honavar, Jaideep; Bradley, Kelley; Oh, Joo Yeun; Vallejo, Matthew O.; Patel, Rakesh P.] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA. [Bradley, Eddie; Dell'italia, Louis J.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Doran, Stephen; Matalon, Sadis] Univ Alabama Birmingham, Dept Anesthesiol, Birmingham, AL 35294 USA. [Matalon, Sadis; Patel, Rakesh P.] Univ Alabama Birmingham, Ctr Free Rad Biol, Birmingham, AL 35294 USA. [Matalon, Sadis; Patel, Rakesh P.] Univ Alabama Birmingham, Ctr Lung Injury & Repair, Birmingham, AL 35294 USA. [Kelley, Eric E.; Cantu-Medellin, Nadiezhda] Univ Pittsburgh, Dept Anesthesiol, Pittsburgh, PA 15260 USA. [Dell'italia, Louis J.] Birmingham VA Med Ctr, Birmingham, AL USA. RP Patel, RP (reprint author), Univ Alabama Birmingham, Dept Pathol, 901 19th St South,BMR 2,Room 532, Birmingham, AL 35294 USA. EM rakeshp@uab.edu OI Patel, Rakesh/0000-0002-1526-4303 FU CounterACT Program; Office of the Director; National Institute of Environmental Health Sciences [1U01ES023759, 5U01ES015676]; National Institute of Health [T32 HL007457] FX This research was supported by the CounterACT Program, National Institutes of Health, Office of the Director, and the National Institute of Environmental Health Sciences, Grant Numbers 1U01ES023759 and 5U01ES015676 and a fellowship from the National Institute of Health to MOV (T32 HL007457). NR 35 TC 5 Z9 5 U1 0 U2 17 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD JUL 3 PY 2014 VL 321 BP 96 EP 102 DI 10.1016/j.tox.2014.04.005 PG 7 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA AJ7IO UT WOS:000337870600011 PM 24769334 ER PT J AU Reisner, SL White, JM Mayer, KH Mimiaga, MJ AF Reisner, Sari L. White, Jaclyn M. Mayer, Kenneth H. Mimiaga, Matthew J. TI Sexual risk behaviors and psychosocial health concerns of female-to-male transgender men screening for STDs at an urban community health center SO AIDS CARE-PSYCHOLOGICAL AND SOCIO-MEDICAL ASPECTS OF AIDS/HIV LA English DT Article DE sexual risk; transgender; FTM; psychosocial; HIV; STD ID HIV-RELATED RISK; TRANSMITTED INFECTIONS; BISEXUAL WOMEN; SAN-FRANCISCO; NONTRANSGENDER MEN; NEEDS-ASSESSMENT; PUBLIC-HEALTH; PREVALENCE; DISEASE; GENDER AB The sexual health of female-to-male (FTM) transgender men remains understudied. De-identified electronic medical records of 23 FTMs (mean age = 32, 48% racial/ethnic minority) who screened for sexually transmitted diseases (STDs) between July and December 2007 at a Boston, Massachusetts area health center were analyzed. Almost half (48%) were on testosterone and 39% had undergone chest surgery; none had undergone genital reconstruction. The majority (57%) were bisexual, and 30% reported sex with nontransgender males only in the prior three months. One individual was HIV-infected (4.3%) and two (8.7%) had a history of STDs (all laboratory-confirmed). Overall, 26% engaged in sexual risk behavior in the prior three months (i.e., unprotected sex with a nontransgender male, condom breakage, or anonymous sex). The majority (61%) had a DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th Edition) diagnosis (52% depression, 52% anxiety, and 26% adjustment disorder), and regular alcohol use was common (65%). Alcohol use, psychosocial distress histories, and sex with males only (versus with males and females) were associated with sexual risk in the past three months. Transgender men have concomitant psychosocial health vulnerabilities which may contribute to sexual risk behaviors. Future research is needed to understand the myriad social, behavioral, and biological factors that contribute to HIV and STD vulnerability for FTMs. C1 [Reisner, Sari L.; White, Jaclyn M.; Mayer, Kenneth H.; Mimiaga, Matthew J.] Fenway Hlth, Fenway Inst, Boston, MA 02215 USA. [Reisner, Sari L.] Harvard Univ, Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02115 USA. [Mayer, Kenneth H.] Harvard Univ, Beth Israel Deaconess Med Ctr, Dept Med, Sch Med, Boston, MA 02215 USA. [Mimiaga, Matthew J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Mimiaga, Matthew J.] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Reisner, SL (reprint author), Fenway Hlth, Fenway Inst, Boston, MA 02215 USA. EM sreisner@fenwayhealth.org FU NIMH NIH HHS [P30 MH062294, R01 MH094323, T32 MH020031] NR 71 TC 13 Z9 13 U1 6 U2 22 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0954-0121 EI 1360-0451 J9 AIDS CARE JI Aids Care-Psychol. Socio-Med. Asp. Aids-Hiv PD JUL 3 PY 2014 VL 26 IS 7 BP 857 EP 864 DI 10.1080/09540121.2013.855701 PG 8 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychology, Multidisciplinary; Respiratory System; Social Sciences, Biomedical SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychology; Respiratory System; Biomedical Social Sciences GA AG0PY UT WOS:000335118600010 PM 24206043 ER PT J AU Koenig, CJ Wingard, LM Sabee, C Olsher, D Vandergriff, I AF Koenig, Christopher J. Wingard, Leah M. Sabee, Christina Olsher, David Vandergriff, Ilona TI Managing Patient-centered Communication across the Type 2 Diabetes Illness Trajectory: A Grounded Practical Theory of Interactional Sensitivity SO JOURNAL OF APPLIED COMMUNICATION RESEARCH LA English DT Article DE Treatment Decision-making; Type 2 Diabetes; Health Communication; Conversation Analysis; Physician-Patient Interaction; Patient-centered Communication; Grounded Practical Theory ID HEALTH-CARE; TREATMENT RECOMMENDATIONS; PARENT RESISTANCE; INSULIN THERAPY; ATTACHMENT; CONSULTATIONS; CONVERSATION; PATERNALISM; ADHERENCE; DELIVERY AB This article uses the theoretical and methodological framework of Grounded Practical Theory (GPT) to provide a lens for analyzing and interpreting discourse as a situated form of social action in routine Type 2 diabetes visits. Drawing on a total data-set of 400 audio-recorded routine visits, we randomly selected 55 visits for qualitative analysis. In this article, we use Conversation Analysis to document communication techniques, which we in turn use as evidence to ground our claims within the GPT framework. We use two single cases of interaction to analyze communication techniques physicians use when recommending a change from oral medication to insulin. We argue treatment intensification is a key moment in health communication to reflect about patient centeredness because physicians can find themselves in an interactional dilemma: while insulin may effectively help control unstable disease, an insulin recommendation may simultaneously counter patient values and treatment preferences. Our analysis suggests that physicians use what we call interactional sensitivity to balance medical need and patient preferences when making medical decisions by tailoring their communication according to the local situation and the patient's larger illness trajectory. We propose that interactional sensitivity is a type of communication work and a quality of patient-centered communication characterized by the theoretical relationship between tailoring communication to the contingencies of the local interaction and the global illness trajectory. Overall, this article contributes to health communication scholarship by proposing a normative model for reflecting on how physicians negotiate challenging interactions with patients during routine chronic illness visits. C1 [Koenig, Christopher J.] San Francisco Vet Adm Med Ctr, Dept Med, San Francisco, CA 94121 USA. [Koenig, Christopher J.] Univ Calif San Francisco, Philip R Lee Inst Hlth Policy Studies, San Francisco, CA USA. [Wingard, Leah M.; Sabee, Christina] San Francisco State Univ, Dept Commun Studies, San Francisco, CA USA. [Olsher, David] San Francisco State Univ, Dept English, San Francisco, CA USA. [Vandergriff, Ilona] San Francisco State Univ, Dept Foreign Languages & Literatures, San Francisco, CA USA. RP Koenig, CJ (reprint author), San Francisco Vet Adm Med Ctr, Dept Med, 4150 Clement St,111-A1, San Francisco, CA 94121 USA. EM christopher.koenig@ucsf.edu OI Koenig, Christopher J./0000-0003-0884-4120 NR 62 TC 6 Z9 6 U1 0 U2 14 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0090-9882 EI 1479-5752 J9 J APPL COMMUN RES JI J. Appl. Commun. Res. PD JUL 3 PY 2014 VL 42 IS 3 SI SI BP 244 EP 267 DI 10.1080/00909882.2014.911943 PG 24 WC Communication SC Communication GA AH1MA UT WOS:000335883700002 ER PT J AU Dhimolea, E Wadia, PR Murray, TJ Settles, ML Treitman, JD Sonnenschein, C Shioda, T Soto, AM AF Dhimolea, Eugen Wadia, Perinaaz R. Murray, Tessa J. Settles, Matthew L. Treitman, Jo D. Sonnenschein, Carlos Shioda, Toshi Soto, Ana M. TI Prenatal Exposure to BPA Alters the Epigenome of the Rat Mammary Gland and Increases the Propensity to Neoplastic Development SO PLOS ONE LA English DT Article ID IN-UTERO EXPOSURE; BISPHENOL-A EXPOSURE; PERINATAL EXPOSURE; BREAST-CANCER; ENDOCRINE DISRUPTORS; CD-1 MICE; CARCINOGENESIS; CELL; DIETHYLSTILBESTROL; SUSCEPTIBILITY AB Exposure to environmental estrogens (xenoestrogens) may play a causal role in the increased breast cancer incidence which has been observed in Europe and the US over the last 50 years. The xenoestrogen bisphenol A (BPA) leaches from plastic food/beverage containers and dental materials. Fetal exposure to BPA induces preneoplastic and neoplastic lesions in the adult rat mammary gland. Previous results suggest that BPA acts through the estrogen receptors which are detected exclusively in the mesenchyme during the exposure period by directly altering gene expression, leading to alterations of the reciprocal interactions between mesenchyme and epithelium. This initiates a long sequence of altered morphogenetic events leading to neoplastic transformation. Additionally, BPA induces epigenetic changes in some tissues. To explore this mechanism in the mammary gland, Wistar-Furth rats were exposed subcutaneously via osmotic pumps to vehicle or 250 mu g BPA/kg BW/day, a dose that induced ductal carcinomas in situ. Females exposed from gestational day 9 to postnatal day (PND) 1 were sacrificed at PND4, PND21 and at first estrus after PND50. Genomic DNA (gDNA) was isolated from the mammary tissue and immuno-precipitated using anti-5-methylcytosine antibodies. Detection and quantification of gDNA methylation status using the Nimblegen ChIP array revealed 7412 differentially methylated gDNA segments (out of 58207 segments), with the majority of changes occurring at PND21. Transcriptomal analysis revealed that the majority of gene expression differences between BPA- and vehicle-treated animals were observed later (PND50). BPA exposure resulted in higher levels of pro-activation histone H3K4 trimethylation at the transcriptional initiation site of the alpha-lactalbumin gene at PND4, concomitantly enhancing mRNA expression of this gene. These results show that fetal BPA exposure triggers changes in the postnatal and adult mammary gland epigenome and alters gene expression patterns. These events may contribute to the development of pre-neoplastic and neoplastic lesions that manifest during adulthood. C1 [Dhimolea, Eugen; Wadia, Perinaaz R.; Murray, Tessa J.; Treitman, Jo D.; Sonnenschein, Carlos; Soto, Ana M.] Tufts Univ, Sch Med, Dept Anat & Cellular Biol, Boston, MA 02111 USA. [Settles, Matthew L.] Univ Idaho, Inst Bioinformat & Evolutionary Studies, Moscow, ID 83843 USA. [Shioda, Toshi] Massachusetts Gen Hosp, MGH Ctr Canc Res, Charlestown, MA USA. RP Soto, AM (reprint author), Tufts Univ, Sch Med, Dept Anat & Cellular Biol, Boston, MA 02111 USA. EM ana.soto@tufts.edu RI Settles, Matthew/F-2031-2011 OI Settles, Matthew/0000-0002-3424-1086 FU NIH National Institute of Environmental Health Sciences [ES015182, ES018822, ES08314]; Susan G. Komen for Cure [FAS0703860, KG090515]; ArtBeCause Breast Cancer Foundation FX This work was funded by NIH National Institute of Environmental Health Sciences award numbers ES015182, ES018822, ES08314, (AS), Susan G. Komen for Cure (FAS0703860 and KG090515) (TS) and the ArtBeCause Breast Cancer Foundation (PW). The content is solely the responsibility of the authors and does not necessarily represent the official position of the Centers for Disease Control and Prevention, the National Institute of Environmental Health Sciences or the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 57 TC 24 Z9 25 U1 2 U2 15 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 2 PY 2014 VL 9 IS 7 AR e99800 DI 10.1371/journal.pone.0099800 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO5BA UT WOS:000341354100019 PM 24988533 ER PT J AU Gilman, JM Curran, MT Calderon, V Stoeckel, LE Evins, AE AF Gilman, Jodi M. Curran, Max T. Calderon, Vanessa Stoeckel, Luke E. Evins, A. Eden TI Impulsive Social Influence Increases Impulsive Choices on a Temporal Discounting Task in Young Adults SO PLOS ONE LA English DT Article ID ADOLESCENT RISK-TAKING; PROTECTIVE FACTORS; PHYSICAL-ACTIVITY; PEER INFLUENCE; FOOD-INTAKE; REWARDS; NORMS; IMMEDIATE; ALCOHOL; PREVENTION AB Adolescents and young adults who affiliate with friends who engage in impulsive behavior are more likely to engage in impulsive behaviors themselves, and those who associate with prosocial (i.e. more prudent, future oriented) peers are more likely to engage in prosocial behavior. However, it is difficult to disentangle the contribution of peer influence vs. peer selection (i.e., whether individuals choose friends with similar traits) when interpreting social behaviors. In this study, we combined a novel social manipulation with a well-validated delay discounting task assessing impulsive behavior to create a social influence delay discounting task, in which participants were exposed to both impulsive (smaller, sooner or SS payment) and non-impulsive (larger, later or LL payment) choices from their peers. Young adults in this sample, n = 51, aged 18-25 had a higher rate of SS choices after exposure to impulsive peer influence than after exposure to non-impulsive peer influence. Interestingly, in highly susceptible individuals, the rate of non-impulsive choices did not increase after exposure to non-impulsive influence. There was a positive correlation between self-reported suggestibility and degree of peer influence on SS choices. These results suggest that, in young adults, SS choices appear to be influenced by the choices of same-aged peers, especially for individuals who are highly susceptible to influence. C1 [Gilman, Jodi M.; Curran, Max T.; Calderon, Vanessa; Stoeckel, Luke E.; Evins, A. Eden] Harvard Univ, Sch Med, Dept Psychiat, Ctr Addict Med,Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Gilman, JM (reprint author), Harvard Univ, Sch Med, Dept Psychiat, Ctr Addict Med,Massachusetts Gen Hosp, Boston, MA 02115 USA. EM jgilman1@partners.org FU Harvard Medical School Norman E. Zinberg Fellowship in Addiction Psychiatry Research; NIDA [K01 DA034093, K24 DA030443]; Charles A. King Trust; NIH [K23DA032612] FX This work was supported by the Harvard Medical School Norman E. Zinberg Fellowship in Addiction Psychiatry Research (JMG), NIDA K01 DA034093 (JMG), NIDA K24 DA030443 (AEE), the Charles A. King Trust (LES), and NIH K23DA032612 (LES). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 53 TC 7 Z9 7 U1 3 U2 16 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 2 PY 2014 VL 9 IS 7 AR e101570 DI 10.1371/journal.pone.0101570 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO5BA UT WOS:000341354100114 PM 24988440 ER PT J AU Meffert, SM Henn-Haase, C Metzler, TJ Qian, M Best, S Hirschfeld, A McCaslin, S Inslicht, S Neylan, TC Marmar, CR AF Meffert, Susan M. Henn-Haase, Clare Metzler, Thomas J. Qian, Meng Best, Suzanne Hirschfeld, Ayelet McCaslin, Shannon Inslicht, Sabra Neylan, Thomas C. Marmar, Charles R. TI Prospective Study of Police Officer Spouse/Partners: A New Pathway to Secondary Trauma and Relationship Violence? SO PLOS ONE LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; EMERGENCY SERVICES PERSONNEL; MALE VIETNAM VETERANS; COMBAT VETERANS; WAR VETERANS; PSYCHOLOGICAL DISTRESS; PARTNERS PERCEPTIONS; MISSISSIPPI SCALE; MENTAL-HEALTH; PTSD AB Introduction: It has been reported that posttraumatic stress disorder (PTSD) is associated with secondary spouse/partner (S/P) emotional distress and relationship violence. Objective: To investigate the relationships between PTSD, S/P emotional distress and relationship violence among police recruits using a prospective design. Methods: Two hypotheses were tested in 71 S/Ps: (1) Police officer reports of greater PTSD symptoms after 12 months of police service will be associated with greater secondary trauma symptoms among S/Ps; (2) Greater secondary trauma symptoms among S/Ps at 12 months will be associated with S/P reports of greater relationship violence. Methods: 71 police recruits and their S/Ps were assessed at baseline and 12 months after the start of police officer duty. Using linear and logistic regression, we analyzed explanatory variables for 12 month S/P secondary traumatic stress symptoms and couple violence, including baseline S/P variables and couple violence, as well as exposure and PTSD reports from both S/P and officer. Results: S/P perception of officer PTSD symptoms predicted S/P secondary traumatic stress. OS/P secondary trauma was significantly associated with both total couple violence (.34, p = .004) and S/P to officer violence (.35, p = .003). Conclusions: Although results from this relatively small study of young police officers and their S/Ps must be confirmed by larger studies in general populations, findings suggest that S/P perception of PTSD symptoms may play a key role in the spread of traumatic stress symptoms across intimate partner relationships and intimate partner violence in the context of PTSD. C1 [Meffert, Susan M.; Inslicht, Sabra; Neylan, Thomas C.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Metzler, Thomas J.; Hirschfeld, Ayelet; Inslicht, Sabra; Neylan, Thomas C.] San Francisco Vet Adm Med Ctr, Mental Hlth Serv, San Francisco, CA USA. [Henn-Haase, Clare; Qian, Meng; Marmar, Charles R.] NYU, Dept Psychiat, New York, NY 10016 USA. [Best, Suzanne] Lewis & Clark Coll, Grad Sch Educ & Counseling, Portland, OR 97219 USA. [McCaslin, Shannon] Natl Ctr PTSD, Disseminat & Training Div, Palo Alto, CA USA. RP Meffert, SM (reprint author), Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. EM susan.meffert@ucsf.edu OI meffert, susan/0000-0002-5882-7102 FU National Institute of Mental Health [R01 - MH056350-06] FX This research was supported by National Institute of Mental Health Grant (R01 - MH056350-06) to CRM. The funders had no role in the study design, data collection and analysis, decision to publish or preparation of this manuscript. NR 44 TC 0 Z9 0 U1 0 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 2 PY 2014 VL 9 IS 7 AR e100663 DI 10.1371/journal.pone.0100663 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO5BA UT WOS:000341354100036 PM 24987848 ER PT J AU Yamada, T Yang, Y Hemberg, M Yoshida, T Cho, HY Murphy, JP Fioravante, D Regehr, WG Gygi, SP Georgopoulos, K Bonni, A AF Yamada, Tomoko Yang, Yue Hemberg, Martin Yoshida, Toshimi Cho, Ha Young Murphy, J. Patrick Fioravante, Diasynou Regehr, Wade G. Gygi, Steven P. Georgopoulos, Katia Bonni, Azad TI Promoter Decommissioning by the NuRD Chromatin Remodeling Complex Triggers Synaptic Connectivity in the Mammalian Brain SO NEURON LA English DT Article ID AUTISM SPECTRUM DISORDERS; DE-NOVO MUTATIONS; HISTONE DEACETYLASE; NEURAL DEVELOPMENT; MI-2/NURD COMPLEX; BREAST-CANCER; GRANULE CELL; HUMAN GENOME; STEM-CELLS; DIFFERENTIATION AB Precise control of gene expression plays fundamental roles in brain development, but the roles of chromatin regulators in neuronal connectivity have remained poorly understood. We report that depletion of the NuRD complex by in vivo RNAi and conditional knockout of the core NuRD subunit Chd4 profoundly impairs the establishment of granule neuron parallel fiber/Purkinje cell synapses in the rodent cerebellar cortex in vivo. By interfacing genome-wide sequencing of transcripts and ChIP-seq analyses, we uncover a network of repressed genes and distinct histone modifications at target gene promoters that are developmentally regulated by the NuRD complex in the cerebellum in vivo. Finally, in a targeted in vivo RNAi screen of NuRD target genes, we identify a program of NuRD-repressed genes that operate as critical regulators of presynaptic differentiation in the cerebellar cortex. Our findings define NuRD-dependent promoter decommissioning as a developmentally regulated programming mechanism that drives synaptic connectivity in the mammalian brain. C1 [Yamada, Tomoko; Yang, Yue; Cho, Ha Young; Bonni, Azad] Washington Univ, Sch Med, Dept Anat & Neurobiol, St Louis, MO 63110 USA. [Yamada, Tomoko; Yang, Yue; Cho, Ha Young; Fioravante, Diasynou; Regehr, Wade G.; Bonni, Azad] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. [Hemberg, Martin] Childrens Hosp Boston, Dept Ophthalmol, Boston, MA 02115 USA. [Yoshida, Toshimi; Georgopoulos, Katia] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. [Gygi, Steven P.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. RP Bonni, A (reprint author), Washington Univ, Sch Med, Dept Anat & Neurobiol, St Louis, MO 63110 USA. EM bonni@wustl.edu FU NIH [NS041021, AG000222, NS032405, NS007484]; Mathers Foundation; Japan Society for the Promotion of Science; NCI [P30 CA91842]; ICTS/CTSA [UL1TR000448] FX We thank members of the Bonni laboratory for helpful discussions and critical reading of the manuscript. Supported by NIH grant NS041021 (to A. B.), the Mathers Foundation (to A. B.), the Japan Society for the Promotion of Science (to T. Yamada), NIH training grant AG000222 (to Y.Y.), NIH grant NS032405 (to W. G. R.), and NIH training grant NS007484 (to D. F.). We thank the Genome Technology Access Center at Washington University, which is supported by NCI P30 CA91842 to the Siteman Cancer Center and by ICTS/CTSA UL1TR000448. NR 45 TC 22 Z9 22 U1 2 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD JUL 2 PY 2014 VL 83 IS 1 BP 122 EP 134 DI 10.1016/j.neuron.2014.05.039 PG 13 WC Neurosciences SC Neurosciences & Neurology GA AN3HJ UT WOS:000340476800012 PM 24991957 ER PT J AU Chambers, AR Hancock, KE Sen, K Polley, DB AF Chambers, Anna R. Hancock, Kenneth E. Sen, Kamal Polley, Daniel B. TI Online Stimulus Optimization Rapidly Reveals Multidimensional Selectivity in Auditory Cortical Neurons SO JOURNAL OF NEUROSCIENCE LA English DT Article DE auditory cortex; closed-loop; genetic algorithm; online neural characterization; optimization algorithm; sparse coding ID MACAQUE INFEROTEMPORAL CORTEX; RECEPTIVE-FIELDS; SENSORY NEURONS; DESIGN; CAT; REPRESENTATION; TOPOGRAPHY; CODE; VOCALIZATIONS; INFORMATION AB Neurons in sensory brain regions shape our perception of the surrounding environment through two parallel operations: decomposition and integration. For example, auditory neurons decompose sounds by separately encoding their frequency, temporal modulation, intensity, and spatial location. Neurons also integrate across these various features to support a unified perceptual gestalt of an auditory object. At higher levels of a sensory pathway, neurons may select for a restricted region of feature space defined by the intersection of multiple, independent stimulus dimensions. To further characterize how auditory cortical neurons decompose and integrate multiple facets of an isolated sound, we developed an automated procedure that manipulated five fundamental acoustic properties in real time based on single-unit feedback in awake mice. Within several minutes, the online approach converged on regions of the multidimensional stimulus manifold that reliably drove neurons at significantly higher rates than predefined stimuli. Optimized stimuli were cross-validated against pure tone receptive fields and spectrotemporal receptive field estimates in the inferior colliculus and primary auditory cortex. We observed, from midbrain to cortex, increases in both level invariance and frequency selectivity, which may underlie equivalent sparseness of responses in the two areas. We found that onset and steady-state spike rates increased proportionately as the stimulus was tailored to the multidimensional receptive field. By separately evaluating the amount of leverage each sound feature exerted on the overall firing rate, these findings reveal interdependencies between stimulus features as well as hierarchical shifts in selectivity and invariance that may go unnoticed with traditional approaches. C1 [Chambers, Anna R.; Hancock, Kenneth E.; Polley, Daniel B.] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Chambers, Anna R.] Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02115 USA. [Hancock, Kenneth E.; Polley, Daniel B.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Sen, Kamal] Boston Univ, Hearing Res Ctr, Dept Biomed Engn, Boston, MA 02115 USA. RP Chambers, AR (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, 243 Charles St, Boston, MA 02114 USA. EM chamber3@fas.harvard.edu; Daniel_polley@meei.harvard.edu OI Polley, Daniel/0000-0002-5120-2409 FU National Institutes of Health [R01 DC009836, P30 DC05209] FX This work was supported by National Institutes of Health Grant R01 DC009836 to D. B. P. and Grant P30 DC05209. We thank Professors Jennifer Bizley and Stephen David for providing comments on an earlier version of the manuscript and Ross Williamson for providing analysis code and stimuli for the STRF method. NR 63 TC 5 Z9 5 U1 3 U2 11 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 2 PY 2014 VL 34 IS 27 BP 8963 EP 8975 DI 10.1523/JNEUROSCI.0260-14.2014 PG 13 WC Neurosciences SC Neurosciences & Neurology GA AL5DJ UT WOS:000339153400005 PM 24990917 ER PT J AU Caplan, D AF Caplan, David TI Commentary on "The role of domain-general cognitive control in language comprehension" by Fedorenko SO FRONTIERS IN PSYCHOLOGY LA English DT Editorial Material DE executive function; language localization; modularity; language localizer; functional architecture ID WORKING-MEMORY C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Caplan, D (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM dcaplan@partners.org FU NIDCD NIH HHS [R01 DC000942] NR 9 TC 0 Z9 0 U1 1 U2 5 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-1078 J9 FRONT PSYCHOL JI Front. Psychol. PD JUL 2 PY 2014 VL 5 AR 629 DI 10.3389/fpsyg.2014.00629 PG 2 WC Psychology, Multidisciplinary SC Psychology GA AK9KY UT WOS:000338747200001 PM 25071627 ER PT J AU Tsai, TC Jha, AK AF Tsai, Thomas C. Jha, Ashish K. TI Hospital Consolidation, Competition, and Quality Is Bigger Necessarily Better? SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Tsai, Thomas C.; Jha, Ashish K.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Tsai, Thomas C.] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Jha, Ashish K.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Jha, Ashish K.] VA Boston Healthcare Syst, Boston, MA USA. RP Jha, AK (reprint author), Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, 677 Huntington Ave, Boston, MA 02115 USA. EM ajha@hsph.harvard.edu FU NCI NIH HHS [R25 CA092203, R25CA92203] NR 7 TC 11 Z9 11 U1 1 U2 11 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 2 PY 2014 VL 312 IS 1 BP 29 EP 30 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AK0UK UT WOS:000338131100015 PM 25058212 ER PT J AU Zhu, AX Kudo, M Assenat, E Cattan, S Kang, YK Lim, HY Poon, RTP Blanc, JF Vogel, A Chen, CL Dorval, E Peck-Radosavljevic, M Santoro, A Daniele, B Furuse, J Jappe, A Perraud, K Anak, O Sellami, DB Chen, LT AF Zhu, Andrew X. Kudo, Masatoshi Assenat, Eric Cattan, Stephane Kang, Yoon-Koo Lim, Ho Yeong Poon, Ronnie T. P. Blanc, Jean-Frederic Vogel, Arndt Chen, Chao-Long Dorval, Etienne Peck-Radosavljevic, Markus Santoro, Armando Daniele, Bruno Furuse, Junji Jappe, Annette Perraud, Kevin Anak, Oezlem Sellami, Dalila B. Chen, Li-Tzong TI Effect of Everolimus on Survival in Advanced Hepatocellular Carcinoma After Failure of Sorafenib The EVOLVE-1 Randomized Clinical Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID MTOR; BRIVANIB; THERAPY; MICE AB IMPORTANCE Aside from the multikinase inhibitor sorafenib, there are no effective systemic therapies for the treatment of advanced hepatocellular carcinoma. OBJECTIVE To assess the efficacy of everolimus in patients with advanced hepatocellular carcinoma for whom sorafenib treatment failed. DESIGN, SETTING, AND PARTICIPANTS EVOLVE-1 was a randomized, double-blind, phase 3 study conducted among 546 adults with Barcelona Clinic Liver Cancer stage B or C hepatocellular carcinoma and Child-Pugh A liver function whose disease progressed during or after sorafenib or who were intolerant of sorafenib. Patients were enrolled from 17 countries between May 2010 and March 2012. Randomization was stratified by region (Asia vs rest of world) and macrovascular invasion (present vs absent). INTERVENTIONS Everolimus, 7.5 mg/d, or matching placebo, both given in combination with best supportive care and continued until disease progression or intolerable toxicity. Per the 2: 1 randomization scheme, 362 patients were randomized to the everolimus group and 184 patients to the placebo group. MAIN OUTCOMES AND MEASURES The primary end point was overall survival. Secondary end points included time to progression and the disease control rate (the percentage of patients with a best overall response of complete or partial response or stable disease). RESULTS No significant difference in overall survival was seen between treatment groups, with 303 deaths (83.7%) in the everolimus group and 151 deaths (82.1%) in the placebo group (hazard ratio [HR], 1.05; 95% CI, 0.86-1.27; P=.68; median overall survival, 7.6 months with everolimus, 7.3 months with placebo). Median time to progression with everolimus and placebo was 3.0 months and 2.6 months, respectively (HR, 0.93; 95% CI, 0.75-1.15), and disease control rate was 56.1% and 45.1%, respectively (P=.01). The most common grade 3/4 adverse events for everolimus vs placebo were anemia (7.8% vs 3.3%, respectively), asthenia (7.8% vs 5.5%, respectively), and decreased appetite (6.1% vs 0.5%, respectively). No patients experienced hepatitis C viral flare. Based on central laboratory results, hepatitis B viral reactivation was experienced by 39 patients (29 everolimus, 10 placebo); all cases were asymptomatic, but 3 everolimus recipients discontinued therapy. CONCLUSIONS AND RELEVANCE Everolimus did not improve overall survival in patients with advanced hepatocellular carcinoma whose disease progressed during or after receiving sorafenib or who were intolerant of sorafenib. C1 [Zhu, Andrew X.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Kudo, Masatoshi] Kinki Univ, Sch Med, Osaka 589, Japan. [Assenat, Eric] ICM Val dAurelle, Montpellier, France. [Cattan, Stephane] Univ Nord France, Lille, France. [Kang, Yoon-Koo] Univ Ulsan, Coll Med, Asan Med Ctr, Seoul, South Korea. [Lim, Ho Yeong] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Seoul, South Korea. [Poon, Ronnie T. P.] Univ Hong Kong, Queen Mary Hosp, Hong Kong, Hong Kong, Peoples R China. [Blanc, Jean-Frederic] Hop St Andre, Bordeaux, France. [Vogel, Arndt] Hannover Med Sch, Hannover, Germany. [Chen, Chao-Long] Kaohsiung Chang Gung Mem Hosp, Kaohsiung, Taiwan. [Dorval, Etienne] CHRU Tours, Tours, France. [Peck-Radosavljevic, Markus] Med Univ Vienna, Vienna, Austria. [Santoro, Armando] Ist Clin Humanitas, Humanitas Canc Ctr, Rozzano, Italy. [Daniele, Bruno] G Rummo Hosp, Benevento, Italy. [Furuse, Junji] Kyorin Univ, Sch Med, Tokyo, Japan. [Jappe, Annette; Perraud, Kevin; Anak, Oezlem] Novartis Pharmaceut, Basel, Switzerland. [Sellami, Dalila B.] Novartis Pharmaceut, E Hanover, NJ USA. [Chen, Li-Tzong] Natl Hlth Res Inst, Natl Inst Canc Res, Tainan, Taiwan. [Chen, Li-Tzong] Natl Cheng Kung Univ Hosp, Tainan 70428, Taiwan. [Chen, Li-Tzong] Kaohsiung Med Univ, Kaohsiung Med Univ Hosp, Kaohsiung, Taiwan. RP Zhu, AX (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, POB 232,55 Fruit St, Boston, MA 02114 USA. EM azhu@mgh.harvard.edu RI Chen, Li-Tzong/D-2071-2010; Vogel, Arndt/A-8437-2012; OI Kudo, Masatoshi/0000-0002-4102-3474 FU Novartis Pharmaceuticals FX This study was sponsored by Novartis Pharmaceuticals. Medical writing and editorial support in the preparation of the manuscript was provided by Melanie Leiby, PhD, and Dolores Matthews, MEd, of ApotheCom (Yardley, Pennsylvania) and was supported by Novartis Pharmaceuticals. NR 32 TC 109 Z9 116 U1 3 U2 18 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 2 PY 2014 VL 312 IS 1 BP 57 EP 67 DI 10.1001/jama.2014.7189 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA AK0UK UT WOS:000338131100021 PM 25058218 ER PT J AU Blumenthal, KG Shenoy, ES Hurwitz, S Varughese, CA Hooper, DC Banerji, A AF Blumenthal, Kimberly G. Shenoy, Erica S. Hurwitz, Shelley Varughese, Christy A. Hooper, David C. Banerji, Aleena TI Effect of a Drug Allergy Educational Program and Antibiotic Prescribing Guideline on Inpatient Clinical Providers' Antibiotic Prescribing Knowledge SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE LA English DT Article DE Drug; Antibiotic; Penicillin; Cephalosporin; Inpatient; Allergy; Hypersensitivity; Anaphylaxis; Immune-mediated; IgE mediated; Drug allergy; Antibiotic allergy ID IGE-MEDIATED HYPERSENSITIVITY; PENICILLIN ALLERGY; HISTORY; CARE; CEPHALOSPORINS; TOLERABILITY; VANCOMYCIN; MEROPENEM; IMPACT AB BACKGROUND: Inpatient providers have varying levels of knowledge in managing patients with drug and/or penicillin (PCN) allergy. OBJECTIVES: Our objectives were (1) to survey inpatient providers to ascertain their baseline drug allergy knowledge and preparedness in caring for patients with PCN allergy, and (2) to assess the impact of an educational program paired with the implementation of a hospital-based clinical guideline. METHODS: We electronically surveyed 521 inpatient providers at a tertiary care medical center at baseline and again 6 weeks after an educational initiative paired with clinical guideline implementation. The guideline informed providers on drug allergy history taking and antibiotic prescribing for inpatients with PCN or cephalosporin allergy. RESULTS: Of 323 unique responders, 42% (95% CI, 37-48%) reported no prior education in drug allergy. When considering those who responded to both surveys (n = 213), we observed a significant increase in knowledge about PCN skin testing (35% vs 54%; P < .001) and loss of PCN allergy over time (54% vs 80%; P < .0001). Among those who reported attending an educational session (n = 62), preparedness to determine if an allergy was severe significantly improved (77% vs 92%; P = .03). Other areas, including understanding absolute contraindications to receiving a drug again and PCN cross-reactivity with other antimicrobials, did not improve significantly. CONCLUSIONS: Inpatient providers have drug allergy knowledge deficits but are interested in tools to help them care for inpatients with drug allergies. Our educational initiative and hospital guideline implementation were associated with increased PCN allergy knowledge in several crucial areas. To improve care of inpatients with drug allergy, more research is needed to evaluate hospital policies and sustainable educational tools. (C) 2014 American Academy of Allergy, Asthma & Immunology C1 [Blumenthal, Kimberly G.; Banerji, Aleena] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Rheumatol Allergy & Immunol,Dept Med, Boston, MA USA. [Blumenthal, Kimberly G.; Shenoy, Erica S.] Massachusetts Gen Hosp, Med Practice Evaluat Ctr, Boston, MA 02114 USA. [Shenoy, Erica S.; Hooper, David C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Infect Dis,Dept Med, Boston, MA USA. [Shenoy, Erica S.; Varughese, Christy A.; Hooper, David C.] Massachusetts Gen Hosp, Infect Control Unit, Boston, MA 02114 USA. [Hurwitz, Shelley] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. [Varughese, Christy A.] Massachusetts Gen Hosp, Dept Pharm, Boston, MA 02114 USA. RP Blumenthal, KG (reprint author), Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, 55 Fruit St,Cox 201, Boston, MA 02114 USA. EM kblumenthal1@partners.org FU NHLBI NIH HHS [T32 HL116275]; NIAID NIH HHS [K01 AI110524] NR 34 TC 10 Z9 10 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2213-2198 EI 2213-2201 J9 J ALLER CL IMM-PRACT JI J. Allergy Clin. Immunol.-Pract. PD JUL-AUG PY 2014 VL 2 IS 4 BP 407 EP 413 DI 10.1016/j.jaip.2014.02.003 PG 7 WC Allergy; Immunology SC Allergy; Immunology GA CH7GG UT WOS:000354203300007 PM 25017528 ER PT J AU Banerji, A Lax, T Guyer, A Hurwitz, S Camargo, CA Long, ADA AF Banerji, Aleena Lax, Timothy Guyer, Autumn Hurwitz, Shelley Camargo, Carlos A., Jr. Long, Aidan A. TI Management of Hypersensitivity Reactions to Carboplatin and Paclitaxel in an Outpatient Oncology Infusion Center: A 5-Year Review SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE LA English DT Review DE Drug hypersensitivity; Allergy; Desensitization ID RAPID DESENSITIZATION; RISK STRATIFICATION; PROTOCOL; CHEMOTHERAPY; PREVENTION; EXPERIENCE; OUTCOMES; TAXOL AB BACKGROUND: A high incidence of hypersensitivity reactions (HSR) to carboplatin and Taxol is limiting the use of carboplatin and Taxol. OBJECTIVE: We conducted a 5-year study of all patients with HSR to carboplatin or Taxol to better understand the nature of infusion HSR and success or failure of management plans after the initial HSR. METHODS: We performed a retrospective chart review of all safety reports from the Massachusetts General Hospital outpatient chemotherapy infusion center between January 2006 and February 2011. All the patients with HSRs to carboplatin or Taxol were identified and included in the final analysis. We reviewed patient characteristics, clinical symptoms, timing, and treatment of the initial HSR, and determined if the patient was rechallenged despite an initial HSR. RESULTS: We identified 152 patients with HSR to carboplatin (n = 45) or Taxol (n = 107). Carboplatin HSR was less severe than Taxol HSR. When comparing the 2 groups, the patients with carboplatin HSRs more commonly described itchy palms and feet, generalized itch, and general urticaria and/or erythema, whereas patients with Taxol HSR more commonly described facial flushing, back pain, and chest or throat tightness (all P < .05). Among 40 patients with mild-to-moderate carboplatin HSRs, only 7 were rechallenged, and 100% tolerated rechallenge without desensitization. None of the patients with severe carboplatin HSRs (n = 5) were rechallenged. Most patients (75%) with Taxol HSRs were rechallenged, and 91% tolerated rechallenge without desensitization; the patients with a severe HSR to Taxol were less likely to be rechallenged. CONCLUSION: The clinical symptoms and timing of carboplatin HSR are distinct from Taxol HSR. Most patients with carboplatin HSR were not rechallenged, whereas most patients with Taxol HSR were successfully rechallenged. (C) 2014 American Academy of Allergy, Asthma & Immunology C1 [Banerji, Aleena; Lax, Timothy; Guyer, Autumn; Camargo, Carlos A., Jr.; Long, Aidan A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Rheumatol Allergy & Immunol,Dept Med, Boston, MA USA. [Hurwitz, Shelley] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. [Camargo, Carlos A., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA USA. RP Banerji, A (reprint author), Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, 55 Fruit St, Boston, MA 02114 USA. EM abanerji@partners.org FU Shire; Dyax; CSL FX A. Banerji has consultancy fees and grants from Shire, Dyax, and CSL. A. Guyer has received royalties from UpToDate Inc. A. A. Long has received consultancy fees and is on the advisory board for Novartis and Genentech, and has received royalties from UpToDate Inc. The rest of the authors declare that they have no relevant conflicts of interest. NR 25 TC 9 Z9 9 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2213-2198 EI 2213-2201 J9 J ALLER CL IMM-PRACT JI J. Allergy Clin. Immunol.-Pract. PD JUL-AUG PY 2014 VL 2 IS 4 BP 428 EP 433 DI 10.1016/j.jaip.2014.04.010 PG 6 WC Allergy; Immunology SC Allergy; Immunology GA CH7GG UT WOS:000354203300010 PM 25017531 ER PT J AU Walker, MA Slate, N Alejos, A Volpi, S Iyengar, RS Sweetser, D Sims, KB Walter, JE AF Walker, Melissa A. Slate, Nancy Alejos, Alexandra Volpi, Stefano Iyengar, Rajashri S. Sweetser, David Sims, Katherine B. Walter, Jolan E. TI Predisposition to infection and SIRS in mitochondrial disorders: 8 years' experience in an academic center SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE LA English DT Letter ID CRITERIA; CHILDREN C1 [Walker, Melissa A.; Sims, Katherine B.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Slate, Nancy] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Alejos, Alexandra; Iyengar, Rajashri S.; Walter, Jolan E.] Massachusetts Gen Hosp Children, Div Allergy & Immunol, Dept Pediat, Boston, MA 02114 USA. [Volpi, Stefano] Univ Genoa, Dept Pediat, Genoa, Italy. [Sweetser, David] Massachusetts Gen Hosp, Dept Genet, Boston, MA 02114 USA. RP Walter, JE (reprint author), Massachusetts Gen Hosp Children, Div Allergy & Immunol, 275 Cambridge St,5th Floor, Boston, MA 02114 USA. EM jewalter@partners.org RI Volpi, Stefano/O-3717-2014 OI Volpi, Stefano/0000-0002-7129-868X NR 9 TC 5 Z9 5 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2213-2198 EI 2213-2201 J9 J ALLER CL IMM-PRACT JI J. Allergy Clin. Immunol.-Pract. PD JUL-AUG PY 2014 VL 2 IS 4 BP 465 EP U173 DI 10.1016/j.jaip.2014.02.009 PG 5 WC Allergy; Immunology SC Allergy; Immunology GA CH7GG UT WOS:000354203300017 PM 25017538 ER PT J AU Chang, ET Wells, KB Young, AS Stockdale, S Johnson, MD Fickel, JJ Jou, K Rubenstein, LV AF Chang, Evelyn T. Wells, Kenneth B. Young, Alexander S. Stockdale, Susan Johnson, Megan D. Fickel, Jacqueline J. Jou, Kevin Rubenstein, Lisa V. TI The Anatomy of Primary Care and Mental Health Clinician Communication: A Quality Improvement Case Study SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE primary care; mental health; communication; quality improvement; ambulatory care; primary care redesign ID OF-VETERANS-AFFAIRS; RESPECT-DEPRESSION TRIAL; COLLABORATIVE CARE; BEHAVIORAL HEALTH; OUTPATIENT CLINICS; INTEGRATED CARE; UNITED-STATES; MEDICAL HOME; DISORDERS; IMPLEMENTATION AB The high prevalence of comorbid physical and mental illnesses among veterans is well known. Therefore, ensuring effective communication between primary care (PC) and mental health (MH) clinicians in the Veterans Affairs (VA) health care system is essential. The VA's Patient Aligned Care Teams (PACT) initiative has further raised awareness of the need for communication between PC and MH. Improving such communication, however, has proven challenging. To qualitatively understand barriers to PC-MH communication in an academic community-based clinic by using continuous quality improvement (CQI) tools and then initiate a change strategy. An interdisciplinary quality improvement (QI) work group composed of 11 on-site PC and MH providers, administrators, and researchers identified communication barriers and facilitators using fishbone diagrams and process flow maps. The work group then verified and provided context for the diagram and flow maps through medical record review (32 patients who received both PC and MH care), interviews (6 stakeholders), and reports from four previously completed focus groups. Based on these findings and a previous systematic review of interventions to improve interspecialty communication, the team initiated plans for improvement. Key communication barriers included lack of effective standardized communication processes, practice style differences, and inadequate PC training in MH. Clinicians often accessed advice or formal consultation based on pre-existing across-discipline personal relationships. The work group identified collocated collaborative care, joint care planning, and joint case conferences as feasible, evidence-based interventions for improving communication. CQI tools enabled providers to systematically assess local communication barriers and facilitators and engaged stakeholders in developing possible solutions. A locally tailored CQI process focusing on communication helped initiate change strategies and ongoing improvement efforts. C1 [Chang, Evelyn T.; Rubenstein, Lisa V.] Vet Affairs Greater Los Angeles Healthcare Syst, Dept Med, Los Angeles, CA USA. [Chang, Evelyn T.; Young, Alexander S.; Stockdale, Susan; Johnson, Megan D.; Fickel, Jacqueline J.; Rubenstein, Lisa V.] VA Ctr Study Healthcare Innovat Implementat & Pol, North Hills, CA USA. [Wells, Kenneth B.; Rubenstein, Lisa V.] Univ Calif Los Angeles, Dept Hlth Policy & Management, Fielding Sch Publ Hlth, Los Angeles, CA USA. [Wells, Kenneth B.; Young, Alexander S.] Univ Calif Los Angeles, Sch Med, Dept Psychiat & Behav Sci, Los Angeles, CA 90024 USA. [Johnson, Megan D.; Rubenstein, Lisa V.] RAND Corp, Santa Monica, CA USA. [Young, Alexander S.; Johnson, Megan D.; Jou, Kevin] Vet Affairs Greater Los Angeles Healthcare Syst, Dept Psychiat, Los Angeles, CA USA. RP Chang, ET (reprint author), VA Greater Los Angeles Healthcare Syst, Dept GIM 111G, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM evelyn.chang@va.gov FU VA Office of Patient Care Services; VA Office of Academic Affiliations, Health Services Research and Development through the Health Services Fellowship Training Program [TMP 65-020] FX This work was undertaken as part of the Veterans Administration's PACT Demonstration Laboratory initiative, supporting and evaluating VA's transition to a patient-centered medical home. Funding for the PACT Demonstration Laboratory initiative is provided by the VA Office of Patient Care Services.; Funding support provided by VA Office of Academic Affiliations, Health Services Research and Development through the Health Services Fellowship Training Program (TMP 65-020). NR 54 TC 1 Z9 1 U1 1 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 JUL PY 2014 VL 29 SU 2 BP 598 EP 606 DI 10.1007/s11606-013-2731-7 PG 9 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AK3OS UT WOS:000338334700009 ER PT J AU Carbo, N Fontcuberta, M Rodriguez, C Enreig, E Fuster, G Camps, M Gascon, P Casado, FJ Ametller, E Almendro, V AF Carbo, N. Fontcuberta, M. Rodriguez, C. Enreig, E. Fuster, G. Camps, M. Gascon, P. Casado, F. J. Ametller, E. Almendro, V. TI A functional Cav1-Fas interplay as a new mechanism of chemoresistance in colon cancer SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract C1 [Carbo, N.; Fontcuberta, M.; Rodriguez, C.; Camps, M.; Casado, F. J.] Univ Barcelona, Biochem & Mol Biol, Barcelona, Spain. [Enreig, E.; Fuster, G.; Gascon, P.; Ametller, E.] IDIBAPS, Dept Med Oncol Hosp Clin, Barcelona, Spain. [Almendro, V.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RI Gascon, Pere/F-7905-2015; Camps, Marta/F-6557-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD JUL PY 2014 VL 50 SU 5 MA 550 BP S133 EP S133 PG 1 WC Oncology SC Oncology GA CE1RN UT WOS:000351589701129 ER PT J AU Chonghaile, TN Roderick, J Gutierrez, G Kelliher, M Letai, A AF Chonghaile, T. Ni Roderick, J. Gutierrez, G. Kelliher, M. Letai, A. TI BCL-2 dependence in T-cell leukemia is defined by the maturation stage of the clone of origin SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract C1 [Chonghaile, T. Ni] Univ Coll Dublin, Sch Biomol & Biomed Sci, Dublin 2, Ireland. [Roderick, J.; Kelliher, M.] Univ Massachusetts, Sch Med, Canc Biol, Worcester, MA USA. [Gutierrez, G.] Dana Farber Canc Inst, Pediat Oncol, Boston, MA 02115 USA. [Letai, A.] Dana Farber Canc Inst, Med Oncol, Boston, MA 02115 USA. RI Ni Chonghaile, Triona/L-9418-2015 OI Ni Chonghaile, Triona/0000-0002-3041-4031 NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD JUL PY 2014 VL 50 SU 5 MA 715 BP S172 EP S172 PG 1 WC Oncology SC Oncology GA CE1RN UT WOS:000351589701268 ER PT J AU Fernandez, P Fuster, G Mancino, M Zubeldia, A Ametller, E Enreig, E Gascon, P Slovang, H Russnes, H Almendro, V AF Fernandez, P. Fuster, G. Mancino, M. Zubeldia, A. Ametller, E. Enreig, E. Gascon, P. Slovang, H. Russnes, H. Almendro, V. TI Fibroblast crosstalk with anti-Her2 therapies breast cancer resistant clones SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract C1 [Fernandez, P.] Univ Barcelona, Hosp Clin Barcelona, Med Oncol, Fac Med,IDIBAPS, Barcelona, Spain. [Fuster, G.; Mancino, M.; Zubeldia, A.; Ametller, E.; Enreig, E.; Gascon, P.] Hosp Clin Barcelona, Med Oncol, IDIBAPS, Barcelona, Spain. [Slovang, H.; Russnes, H.] Radiumhospitalet, Oslo Univ Hosp, Dept Genet, Inst Canc Res, Oslo, Norway. [Almendro, V.] Dana Farber Canc Inst, Dept Oncol, Boston, MA 02115 USA. RI Gascon, Pere/F-7905-2015 NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD JUL PY 2014 VL 50 SU 5 MA 347 BP S82 EP S83 PG 2 WC Oncology SC Oncology GA CE1RN UT WOS:000351589700302 ER PT J AU Hu, Y Dimitrov, S Wang, H Livingston, D AF Hu, Y. Dimitrov, S. Wang, H. Livingston, D. TI Unexpected cancer-related properties of BRCA1 SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract C1 [Hu, Y.; Dimitrov, S.; Wang, H.; Livingston, D.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Genet & Med, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD JUL PY 2014 VL 50 SU 5 MA 67 BP S17 EP S17 PG 1 WC Oncology SC Oncology GA CE1RN UT WOS:000351589700062 ER PT J AU Patnaik, A Kung, J Wu, J Loda, M Kantoff, P Cantley, LC Balk, S Bubley, G AF Patnaik, A. Kung, J. Wu, J. Loda, M. Kantoff, P. Cantley, L. C. Balk, S. Bubley, G. TI A Phase Ib study of BKM120 combined with abiraterone acetate for castrate-resistant, metastatic prostate cancer SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract C1 [Patnaik, A.; Balk, S.; Bubley, G.] Beth Israel Deaconess Med Ctr, Dana Farber Harvard Canc Ctr, Med Hematol Oncol, Boston, MA 02215 USA. [Kung, J.; Wu, J.] Beth Israel Deaconess Med Ctr, Radiol, Boston, MA 02215 USA. [Loda, M.] Brigham & Womens Hosp, Dana Farber Canc Inst, Pathol, Boston, MA 02115 USA. [Kantoff, P.] Brigham & Womens Hosp, Dana Farber Canc Inst, Med Hematol Oncol, Boston, MA 02115 USA. [Cantley, L. C.] Weill Cornell Med Coll, Ctr Canc, New York, NY USA. RI Cantley, Lewis/D-1800-2014 OI Cantley, Lewis/0000-0002-1298-7653 NR 0 TC 0 Z9 0 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD JUL PY 2014 VL 50 SU 5 MA 708 BP S171 EP S171 PG 1 WC Oncology SC Oncology GA CE1RN UT WOS:000351589701264 ER PT J AU Rovida, E Di Maira, G Cannito, S Tusa, I Paternostro, C Deng, X Dello Sbarba, P Gray, NS Parola, M Marra, F AF Rovida, E. Di Maira, G. Cannito, S. Tusa, I. Paternostro, C. Deng, X. Dello Sbarba, P. Gray, N. S. Parola, M. Marra, F. TI The mitogen-activated protein kinase ERK5 regulates the development and growth of hepatocellular carcinoma SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract C1 [Rovida, E.; Tusa, I.; Dello Sbarba, P.] Univ Florence, DSBSC, Florence, Italy. [Di Maira, G.; Marra, F.] Univ Florence, Dipartimento Med Sperimentale & Clin, Florence, Italy. [Cannito, S.; Paternostro, C.; Parola, M.] Univ Turin, Dipartimento Med & Oncol Sperimentali, Florence, Italy. [Deng, X.; Gray, N. S.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RI Rovida, Elisabetta/F-3565-2015 OI Rovida, Elisabetta/0000-0002-5949-3239 NR 0 TC 0 Z9 0 U1 1 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD JUL PY 2014 VL 50 SU 5 MA 786 BP S189 EP S189 PG 1 WC Oncology SC Oncology GA CE1RN UT WOS:000351589701328 ER PT J AU Rinker, JR Salter, AR Cutter, GR AF Rinker, John R., II Salter, Amber R. Cutter, Gary R. TI Improvement of multiple sclerosis-associated tremor as a treatment effect of natalizunnab SO MULTIPLE SCLEROSIS AND RELATED DISORDERS LA English DT Article DE Multiple sclerosis; Tremor; Neurologic symptoms; Natatizumab; Self-report; Questionnaires ID PLACEBO-CONTROLLED TRIAL; DOUBLE-BLIND; CEREBELLAR TREMOR; ISONIAZID THERAPY; MULTICENTER; DISABILITY; PREVALENCE; SYMPTOMS; CANNABIS; EFFICACY AB Background: Tremor is among the most physically disabling symptoms associated with MS. The effect of MS disease modifying therapies (DMTs) on the severity of MS tremor is unclear. Objective: To compare the change over time in scores reflecting tremor severity between subjects treated with natalizumab and other disease modifying drugs. Methods: Questionnaires were sent to North American Research Committee on MS registrants reporting mild or greater tremor on semiannual updates. Respondents on natalizumab and other MS therapies completed a survey which included tremor-specific scales to indicate tremor severity both currently and when the current therapy was initiated. Differences between natalizumab and non-natalizumab groups were compared using ANOVA. Results: Surveys were returned by 567 registrants, including 202 taking natalizumab. Subjects on natalizumab were more likely to report tremor improvement (29.6%) than those never (15.2%) or previously (14.8%, p=0.0002) on natalizumab. Over a mean recall period of 6.2+4.6 years, the Tremor Related Activities of Daily Living score worsened by 1.8 points among natalizumab-treated subjects, 3.3 points among those previously on natalizumab, and 5.3 points among those who never took natalizumab (p=0.009). Conclusion: Respondents taking natalizumab were more likely to experience tremor improvement than those taking other MS disease modifying therapies. Published by Elsevier B.V. C1 [Rinker, John R., II] Univ Alabama Birmingham, Dept Neurol, Birmingham, AL 35294 USA. [Rinker, John R., II] Birmingham VA Med Ctr, Birmingham, AL 35233 USA. [Salter, Amber R.; Cutter, Gary R.] Univ Alabama Birmingham, Dept Biostat, Birmingham, AL 35294 USA. RP Rinker, JR (reprint author), Univ Alabama Birmingham, Dept Neurol, 1720 7th Ave South,SC 440, Birmingham, AL 35294 USA. EM rinkerj@uab.edu FU Biogen Idec [US-TYS-11-10238] FX This study was funded by an Investigator Initiated Grant/Trial Award from Biogen Idec (US-TYS-11-10238). NR 30 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2211-0348 EI 2211-0356 J9 MULT SCLER RELAT DIS JI Mult. Scler. Relat. Disord. PD JUL PY 2014 VL 3 IS 4 BP 505 EP 512 DI 10.1016/j.msard.2014.04.001 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA CB5KC UT WOS:000349664900013 PM 25877063 ER PT J AU Ambrosio, AJ Suzin, D Palmer, EL Penson, RT AF Ambrosio, Allison J. Suzin, Daphne Palmer, Edwin L. Penson, Richard T. TI Vintafolide (EC145) for the treatment of folate-receptor-alpha positive platinum-resistant ovarian cancer SO EXPERT REVIEW OF CLINICAL PHARMACOLOGY LA English DT Article DE chemotherapy; EC145; EC20; etarfolatide; novel ID PEGYLATED LIPOSOMAL DOXORUBICIN; PHASE-III TRIAL; EPITHELIAL OVARIAN; CLINICAL-TRIAL; FALLOPIAN-TUBE; RECURRENT; CARCINOMA; CHEMOTHERAPY; SURVIVAL; THERAPY AB Seminal advances in the treatment of cancer have been achieved because of drug development in ovarian cancer; notably the developments of platinums and taxanes. However, no new drug has been FDA approved for ovarian cancer since 2006, and the approval of an antiangiogenic agent for ovarian cancer in the US has stalled. Predicting the next breakthrough is a high risk and highly expensive venture. One of the most promising prospects is folate-receptor (FR)-targeted therapy, given the high expression in FR ovarian cancer. We review the development of vintafolide (EC145), a folic acid-desacetylvinblastine conjugate, the predictive utility of a FR-targeted imaging agent, technetium-(99)m-etarfolatide (EC20), the challenges in proving survival advantage, and other approaches to exploiting FR as a target in ovarian cancer. C1 [Ambrosio, Allison J.; Suzin, Daphne; Palmer, Edwin L.; Penson, Richard T.] Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02114 USA. RP Penson, RT (reprint author), Massachusetts Gen Hosp, Div Hematol Oncol, Yawkey 9-064,32 Fruit St, Boston, MA 02114 USA. EM rpenson@partners.org NR 46 TC 5 Z9 5 U1 1 U2 5 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1751-2433 EI 1751-2441 J9 EXPERT REV CLIN PHAR JI Expert Rev. Clin. Pharmacol. PD JUL PY 2014 VL 7 IS 4 BP 443 EP 450 DI 10.1586/17512433.2014.909723 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA CC0JL UT WOS:000350021500008 PM 24742319 ER PT J AU Kohman, RE Han, X Bleier, BS AF Kohman, Richie E. Han, Xue Bleier, Benjamin S. TI Heterotopic Mucosal Engrafting Procedure for Direct Drug Delivery to the Brain in Mice SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Medicine; Issue 89; drug delivery; mucosa membrane; blood-brain barrier; neurosurgery; transnasal; mouse model ID MOLECULAR TROJAN HORSES; NEUROTROPHIC FACTOR; INTRANASAL INSULIN; PARKINSON-DISEASE; BARRIER; TRANSPORT; INFUSION; GDNF AB Delivery of therapeutics into the brain is impeded by the presence of the blood-brain barrier (BBB) which restricts the passage of polar and high molecular weight compounds from the bloodstream and into brain tissue. Some direct delivery success in humans has been achieved via implantation of transcranial catheters; however this method is highly invasive and associated with numerous complications. A less invasive alternative would be to dose the brain through a surgically implanted, semipermeable membrane such as the nasal mucosa that is used to repair skull base defects following endoscopic transnasal tumor removal surgery in humans. Drug transfer though this membrane would effectively bypass the BBB and diffuse directly into the brain and cerebrospinal fluid. Inspired by this approach, a surgical approach in mice was developed that uses a donor septal mucosal membrane engrafted over an extracranial surgical BBB defect. This model has been shown to effectively allow the passage of high molecular weight compounds into the brain. Since numerous drug candidates are incapable of crossing the BBB, this model is valuable for performing preclinical testing of novel therapies for neurological and psychiatric diseases. C1 [Kohman, Richie E.; Han, Xue] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. [Bleier, Benjamin S.] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Otol & Laryngol, Cambridge, MA 02138 USA. RP Kohman, RE (reprint author), Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. EM Kohman@bu.edu FU Mcihael J. Fox Foundation for Parkinson's Research Rapid Response Innovations Awards Program FX This study was funded by the Mcihael J. Fox Foundation for Parkinson's Research 2011 Rapid Response Innovations Awards Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 20 TC 0 Z9 0 U1 0 U2 2 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD JUL PY 2014 IS 89 AR e51452 DI 10.3791/51452 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CB0DR UT WOS:000349296100027 ER PT J AU Tolonen, AC Haas, W AF Tolonen, Andrew C. Haas, Wilhelm TI Quantitative Proteomics Using Reductive Dimethylation for Stable Isotope Labeling SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Chemistry; Issue 89; quantitative proteomics; mass spectrometry; stable isotope; reductive dimethylation; peptide labeling; LC-MS/MS ID QUANTIFICATION; CELL AB Stable isotope labeling of peptides by reductive dimethylation (ReDi labeling) is a method to accurately quantify protein expression differences between samples using mass spectrometry. ReDi labeling is performed using either regular (light) or deuterated (heavy) forms of formaldehyde and sodium cyanoborohydride to add two methyl groups to each free amine. Here we demonstrate a robust protocol for ReDi labeling and quantitative comparison of complex protein mixtures. Protein samples for comparison are digested into peptides, labeled to carry either light or heavy methyl tags, mixed, and co-analyzed by LC-MS/MS. Relative protein abundances are quantified by comparing the ion chromatogram peak areas of heavy and light labeled versions of the constituent peptide extracted from the full MS spectra. The method described here includes sample preparation by reversed-phase solid phase extraction, on-column ReDi labeling of peptides, peptide fractionation by basic pH reversed-phase (BPRP) chromatography, and StageTip peptide purification. We discuss advantages and limitations of ReDi labeling with respect to other methods for stable isotope incorporation. We highlight novel applications using ReDi labeling as a fast, inexpensive, and accurate method to compare protein abundances in nearly any type of sample. C1 [Tolonen, Andrew C.] CEA, DSV, IG, Paris, France. [Tolonen, Andrew C.] CNRS, UMR8030, Evry, France. [Tolonen, Andrew C.] Univ Evry Val dEssonne, Evry, France. [Haas, Wilhelm] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. RP Tolonen, AC (reprint author), CEA, DSV, IG, Paris, France. EM atolonen@genoscope.cns.fr; whaas@mgh.harvard.edu FU CNRS chaire d'excellence FX We thank SP Gygi and GM Church for help and guidance. This work was supported by a CNRS chaire d'excellence to ACT. NR 22 TC 1 Z9 1 U1 2 U2 12 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD JUL PY 2014 IS 89 AR e51416 DI 10.3791/51416 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CB0DR UT WOS:000349296100025 ER PT J AU Zhou, YB Kucik, DF Szalais, AJ Edberg, JC AF Zhou, Yebin Kucik, Dennis F. Szalais, Alexander J. Edberg, Jeffrey C. TI Human Neutrophil Flow Chamber Adhesion Assay SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Immunology; Issue 89; neutrophil adhesion; flow chamber; human umbilical vein endothelial cell (HUVEC); purified ligand ID WALL SHEAR-STRESS; SUSCEPTIBILITY; MOLECULE-1; LFA-1 AB Neutrophil firm adhesion to endothelial cells plays a critical role in inflammation in both health and disease. The process of neutrophil firm adhesion involves many different adhesion molecules including members of the beta(2) integrin family and their counter-receptors of the ICAM family. Recently, naturally occurring genetic variants in both beta(2) integrins and ICAMs are reported to be associated with autoimmune disease. Thus, the quantitative adhesive capacity of neutrophils from individuals with varying allelic forms of these adhesion molecules is important to study in relation to mechanisms underlying development of autoimmunity. Adhesion studies in flow chamber systems can create an environment with fluid shear stress similar to that observed in the blood vessel environment in vivo. Here, we present a method using a flow chamber assay system to study the quantitative adhesive properties of human peripheral blood neutrophils to human umbilical vein endothelial cell ( HUVEC) and to purified ligand substrates. With this method, the neutrophil adhesive capacities from donors with different allelic variants in adhesion receptors can be assessed and compared. This method can also be modified to assess adhesion of other primary cell types or cell lines. C1 [Zhou, Yebin] Univ Alabama Birmingham, Genet & Genom Sci Grad Program, Birmingham, AL USA. [Kucik, Dennis F.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [Kucik, Dennis F.] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL USA. [Kucik, Dennis F.] Univ Alabama Birmingham, Dept Biomed Engn, Birmingham, AL USA. [Szalais, Alexander J.; Edberg, Jeffrey C.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35233 USA. RP Edberg, JC (reprint author), Univ Alabama Birmingham, Dept Med, Birmingham, AL 35233 USA. EM jedberg@uab.edu OI Zhou, Yebin/0000-0002-4410-1909 FU Lupus Research Institute (NY, NY); NIH [P01-AR49084, R21-DA026956, UL1-TR00165] FX This work is sponsored by the Lupus Research Institute (NY, NY), NIH P01-AR49084, NIH R21-DA026956 and NIH UL1-TR00165. We thank Dr. Robert P. Kimberly for his continued support. NR 20 TC 0 Z9 0 U1 0 U2 2 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD JUL PY 2014 IS 89 AR e51410 DI 10.3791/51410 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CB0DR UT WOS:000349296100023 ER PT J AU Shoamanesh, A Romero, JR Kase, CS AF Shoamanesh, Ashkan Romero, Jose R. Kase, Carlos S. TI Spontaneous Cervical Spinal Epidural Hematoma Mimicking Acute Stroke SO CANADIAN JOURNAL OF NEUROLOGICAL SCIENCES LA English DT Article C1 [Shoamanesh, Ashkan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA USA. [Romero, Jose R.; Kase, Carlos S.] Boston Univ, Sch Med, Boston Med Ctr, Dept Neurol, Boston, MA 02118 USA. RP Shoamanesh, A (reprint author), 175 Cambridge St,Suite 300, Boston, MA 02114 USA. EM ashoamanesh@mgh.harvard.edu NR 5 TC 2 Z9 2 U1 1 U2 1 PU CANADIAN JOURNAL NEUROLOGICAL SCIENCES INC PI CALGARY PA 709-7015 MACLEOD TRAIL SW, CALGARY, AB T2H 2K6, CANADA SN 0317-1671 J9 CAN J NEUROL SCI JI Can. J. Neurol. Sci. PD JUL PY 2014 VL 41 IS 4 BP 533 EP 534 DI 10.1017/S0317167100018655 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA AY6CA UT WOS:000347654000027 PM 24878486 ER PT J AU Varon, J Soto-Ruiz, KM Baumann, BM Borczuk, P Cannon, CM Chandra, A Cline, DM Diercks, DB Hiestand, B Hsu, A Jois-Bilowich, P Kaminski, B Levy, P Nowak, RM Schrock, JW Peacock, WF AF Varon, Joseph Soto-Ruiz, Karina M. Baumann, Brigitte M. Borczuk, Pierre Cannon, Chad M. Chandra, Abhinav Cline, David Martin Diercks, Deborah B. Hiestand, Brian Hsu, Amy Jois-Bilowich, Preeti Kaminski, Brian Levy, Phillip Nowak, Richard M. Schrock, Jon W. Peacock, W. Frank TI The Management of Acute Hypertension in Patients With Renal Dysfunction: Labetalol or Nicardipine? SO POSTGRADUATE MEDICINE LA English DT Article DE acute disease; antihypertensive agents/therapeutic use; hypertension/drug therapy; kidney diseases/drug therapy ID UNITED-STATES; CRISES; EMERGENCIES; PREVALENCE; AWARENESS; DIAGNOSIS; AGENTS AB Study Objectives: To compare the safety and efficacy of US Food and Drug Administration (FDA)-recommended doses of labetalol and nicardipine for hypertension (HTN) management in a subset of patients with renal dysfunction (RD). Design: Randomized, open label, multicenter prospective clinical trial. Setting: Thirteen United States tertiary care emergency departments. Patients or Participants: Subgroup analysis of the Evaluation of IV Cardene (Nicardipine) and Labetalol Use in the Emergency Department (CLUE) clinical trial. The subjects were 104 patients with RD (ie, creatinine clearance, < 75 mL/min) who presented to the emergency department with a systolic blood pressure (SBP) >= 180 mmHg on 2 consecutive readings and for whom the emergency physician felt intravenous antihypertensive therapy was desirable. Interventions: The FDA recommended doses of either labetalol or nicardipine for HTN management. Measurements: The number of patients achieving the physician's predefined target SBP range within 30 minutes of treatment. Results: Patients treated with nicardipine were within target range more often than those receiving labetalol (92% vs 78%, P = 0.046). On 6 SBP measures, patients treated with nicardipine were more likely to achieve the target range on either 5 or all 6 readings than were patients treated with labetalol (46% vs 25%, P = 0.024). Labetalol patients were more likely to require rescue medication (27% vs 17%, P = 0.020). Adverse events thought to be related to either treatment group were not reported in the 30-minute active study period, and patients had slower heart rates at all time points after 5 minutes (P < 0.01). Conclusions: In severe HTN with RD, nicardipine-treated patients are more likely to reach a target blood pressure range within 30 minutes than are patients receiving labetalol. Clinical Implications: Within 30 minutes of administration, nicardipine is more efficacious than labetalol for acute blood pressure control in patients with RD. C1 [Varon, Joseph] Univ Texas Med Branch, Dept Emergency Med, Galveston, TX 77555 USA. [Varon, Joseph] Dorrington Med Associates, Galveston, TX USA. [Soto-Ruiz, Karina M.] Texas Childrens Hosp, Baylor Coll Med, Pediat Emergency Med Dept, Houston, TX 77030 USA. [Baumann, Brigitte M.] Cooper Univ Hosp, Dept Emergency Med, Camden, NJ USA. [Borczuk, Pierre] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Cannon, Chad M.] Univ Kansas, Med Ctr, Dept Emergency Med, Kansas City, KS 66103 USA. [Chandra, Abhinav] Kaiser Permanente, Dept Emergency Med, Sacramento, CA USA. [Cline, David Martin; Hiestand, Brian] Wake Forest Baptist Med Ctr, Dept Emergency Med, Winston Salem, NC USA. [Diercks, Deborah B.] Univ Calif Davis, Dept Emergency Med, Davis Med Ctr, Davis, CA 95616 USA. [Hsu, Amy] Cleveland Clin, Dept Cardiovasc Med, Cleveland, OH 44106 USA. [Jois-Bilowich, Preeti] Univ Florida, Coll Med, Dept Emergency Med, Gainesville, FL USA. [Kaminski, Brian] Toledo Hosp, Dept Emergency Med, Toledo, OH USA. [Levy, Phillip] Wayne State Univ, Sch Med, Dept Emergency Med, Detroit, MI USA. [Nowak, Richard M.] Henry Ford Hosp, Dept Emergency Med, Detroit, MI 48202 USA. [Schrock, Jon W.] MetroHlth Med Ctr, Dept Emergency Med, Cleveland, OH USA. [Peacock, W. Frank] Baylor Coll Med, Dept Emergency Med, Ben Taub Gen Hosp, Houston, TX 77030 USA. RP Varon, J (reprint author), 2219 Dorrington St, Houston, TX 77030 USA. EM Joseph.Varon@uth.tmc.edu FU EKR Therapeutics, Inc. FX This study was supported by EKR Therapeutics, Inc. and coordinated by Cleveland Clinic Coordinating Center for Clinical Research. All authors had access to the database and clinical study report and assume responsibility for the completeness and accuracy of this manuscript. NR 21 TC 0 Z9 0 U1 0 U2 1 PU JTE MULTIMEDIA PI WEST CONSHOHOCKEN PA 18 ELIZABETH ST, STE 110, WEST CONSHOHOCKEN, PA 19428 USA SN 0032-5481 EI 1941-9260 J9 POSTGRAD MED JI Postgrad. Med. PD JUL PY 2014 VL 126 IS 4 BP 124 EP 130 DI 10.3810/pgm.2014.07.2790 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA AZ6FH UT WOS:000348313900012 PM 25141250 ER PT J AU Lindley, LC Zhou, WJ Mack, JW Li, XP AF Lindley, Lisa C. Zhou, Wenjun Mack, Jennifer W. Li, Xueping TI Pediatric Hospice and Palliative Care: Designing a Mobile App for Clinical Practice SO CIN-COMPUTERS INFORMATICS NURSING LA English DT Editorial Material ID OF-LIFE CARE; END; RESIDENTS C1 [Lindley, Lisa C.] Univ Tennessee, Coll Nursing, Knoxville, TN 37996 USA. [Zhou, Wenjun] Univ Tennessee, Coll Business Adm, Knoxville, TN USA. [Mack, Jennifer W.] Childrens Hosp Boston, Dana Farber Canc Inst, Ctr Outcomes & Policy Res, Dept Pediat Oncol, Boston, MA USA. [Mack, Jennifer W.] Childrens Hosp Boston, Dana Farber Canc Inst, Ctr Outcomes & Policy Res, Div Populat Sci, Boston, MA USA. [Mack, Jennifer W.] Childrens Hosp Boston, Div Pediat Hematol Oncol, Boston, MA USA. [Li, Xueping] Univ Tennessee, Coll Engn, Knoxville, TN USA. RP Lindley, LC (reprint author), Univ Tennessee, Coll Nursing, Knoxville, TN 37996 USA. OI Zhou, Wenjun/0000-0003-2346-8151; Lindley, Lisa C./0000-0003-2960-7896 FU NINR NIH HHS [K01 NR014490, K01NR014490] NR 11 TC 2 Z9 2 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1538-2931 EI 1538-9774 J9 CIN-COMPUT INFORM NU JI CIN-Comput. Inform. Nurs. PD JUL PY 2014 VL 32 IS 7 BP 299 EP 302 DI 10.1097/CIN.0000000000000084 PG 4 WC Computer Science, Interdisciplinary Applications; Medical Informatics; Nursing SC Computer Science; Medical Informatics; Nursing GA AZ4JE UT WOS:000348186500001 PM 25032671 ER PT J AU Heimrath, OP Kos, Z Belanger, EC Cagiannos, I Morash, C Gerridzen, RG Lavallee, LT Preston, MA Witiuk, K Breau, RH AF Heimrath, Olivier P. Kos, Zuzana Belanger, Eric C. Cagiannos, Ilias Morash, Chris Gerridzen, Ronald G. Lavallee, Luke T. Preston, Mark A. Witiuk, Kelsey Breau, Rodney H. TI Predicting the Gleason sum of a patient with a prostate biopsy core Gleason <= 7 and a prostate biopsy core Gleason >= 8 SO CUAJ-CANADIAN UROLOGICAL ASSOCIATION JOURNAL LA English DT Article ID GROUP PROTOCOL 92-02; PHASE-III TRIAL; ANDROGEN DEPRIVATION; CANCER; CARCINOMA; SPECIMENS; DURATION; GRADES; SCORE AB Introduction: We review a subset of men who had discordant prostate biopsy sums and were treated with radical prostatectomy. Methods: Consecutive patients treated with radical prostatectomy at The Ottawa Hospital between 2000 and 2012 were reviewed. Those with at least 1 prostate biopsy core of Gleason sum >= 8 and at least 1 prostate biopsy core of Gleason sum <= 7 cancer were included. Results: Of the 764 radical prostatectomies, 661 (87%) were eligible for the study and 35 (5%) met inclusion criteria. Of these, only 16 (46%) had prostatectomy Gleason sum of >= 8. When the highest biopsy core was Gleason sum 8 (n = 24), only 7 (29%) had a prostatectomy Gleason sum >= 8. When the highest biopsy core was Gleason 9 (n = 11), 9 (82%) had a prostatectomy Gleason sum >= 8 (relative risk [RR] 2.8; p = 0.004). Patients with clinical T3 tumours were at higher risk of Gleason sum = 8 compared to cT1 patients (RR 3.7; p = 0.008). Patient age (p = 0.89), preoperative prostate-specific antigen (p = 0.34), prostate volume (p = 0.86), number of biopsy cores (p = 0.18), and proportion of biopsy cores with cancer (p = 0.96) were not strongly associated with risk of prostatectomy Gleason sum >= 8. Conclusion: These data should be considered when assigning patients into prognostic risk categories based on prostate biopsy information. Further study to verify our findings using larger samples is warranted. C1 [Heimrath, Olivier P.; Kos, Zuzana; Belanger, Eric C.; Cagiannos, Ilias; Morash, Chris; Gerridzen, Ronald G.; Lavallee, Luke T.; Preston, Mark A.; Breau, Rodney H.] Univ Ottawa, Ottawa, ON K1H 8L6, Canada. [Heimrath, Olivier P.] McGill Univ, Dept Surg, Div Urol, Montreal, PQ H3A 2T5, Canada. [Cagiannos, Ilias; Morash, Chris; Gerridzen, Ronald G.; Lavallee, Luke T.; Breau, Rodney H.] Ottawa Hosp, Dept Surg, Div Urol, Ottawa, ON, Canada. [Kos, Zuzana; Belanger, Eric C.] Ottawa Hosp, Dept Pathol & Lab Med, Div Anat Pathol, Ottawa, ON, Canada. [Preston, Mark A.] Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. [Witiuk, Kelsey; Breau, Rodney H.] Ottawa Hosp, Res Inst, Ottawa, ON, Canada. RP Breau, RH (reprint author), Univ Ottawa, Ottawa Hosp, Res Inst, Div Urol, 501 Smyth Rd, Ottawa, ON K1H 8L6, Canada. EM rbreau@ottawahospital.on.ca NR 15 TC 0 Z9 0 U1 0 U2 0 PU CANADIAN UROLOGICAL ASSOCIATION PI DORVAL PA 185 DORVAL AVENUE, STE 401, DORVAL, QC H9S 5J9, CANADA SN 1911-6470 EI 1920-1214 J9 CUAJ-CAN UROL ASSOC JI CUAJ-Can. Urol. Assoc. J. PD JUL PY 2014 VL 8 IS 7-8 BP E476 EP E480 DI 10.5489/cuaj.1737 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA AY6YP UT WOS:000347708900002 PM 25132892 ER PT J AU Wang, XS AF Wang, Xiaoshan TI Modified generalized method of moments for a robust estimation of polytomous logistic model SO PEERJ LA English DT Article DE Robust statistics; Generalized method of weighted moments; Polytomous logistic model ID GMM ESTIMATORS; SAMPLE PROPERTIES AB The maximum likelihood estimation (MLE) method, typically used for polytomous logistic regression, is prone to bias due to both misclassification in outcome and contamination in the design matrix. Hence, robust estimators are needed. In this study, we propose such a method for nominal response data with continuous covariates. A generalized method of weighted moments (GMWM) approach is developed for dealing with contaminated polytomous response data. In this approach, distances are calculated based on individual sample moments. And Huber weights are applied to those observations with large distances. Mellow-type weights are also used to downplay leverage points. We describe theoretical properties of the proposed approach. Simulations suggest that the GMWM performs very well in correcting contamination-caused biases. An empirical application of the GMWM estimator on data from a survey demonstrates its usefulness. C1 [Wang, Xiaoshan] Forsyth Inst, Dept Clin & Translat Res, Cambridge, MA USA. [Wang, Xiaoshan] Harvard Univ, Sch Dent Med, Dept Oral Hlth Policy & Epidemiol, Cambridge, MA 02138 USA. RP Wang, XS (reprint author), Forsyth Inst, Dept Clin & Translat Res, Cambridge, MA USA. EM xwang@forsyth.org NR 27 TC 0 Z9 0 U1 1 U2 2 PU PEERJ INC PI LONDON PA 341-345 OLD ST, THIRD FLR, LONDON, EC1V 9LL, ENGLAND SN 2167-8359 J9 PEERJ JI PeerJ PD JUL 1 PY 2014 VL 2 AR e467 DI 10.7717/peerj.467 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AY5LG UT WOS:000347612900008 PM 25071990 ER PT J AU Miller, JB Kim, LA Wu, DM Vavvas, DG Eliott, D Husain, D AF Miller, John B. Kim, Leo A. Wu, David M. Vavvas, Demetrios G. Eliott, Dean Husain, Deeba TI Ocriplasmin for Treatment of Stage 2 Macular Holes: Early Clinical Results SO OPHTHALMIC SURGERY LASERS & IMAGING RETINA LA English DT Article ID POSTERIOR VITREOUS DETACHMENT; VITREOMACULAR TRACTION; INTRAVITREAL OCRIPLASMIN; ASSISTED VITRECTOMY; MICROPLASMIN; ADHESION; VITREOLYSIS; INJECTION; PLASMIN; RABBIT AB BACKGROUND AND OBJECTIVE: To review clinical and structural outcomes of ocriplasmin for treatment of stage 2 macular holes. PATIENTS AND METHODS: A retrospective review of the first patients with stage 2 macular holes to be treated with ocriplasmin at Massachusetts Eye and Ear Infirmary. All patients were imaged with spectral-domain optical coherence tomography (SD-OCT). RESULTS: Eight patients with stage 2 macular holes received a single injection of 125 mu g of ocriplasmin. One patient (12.5%) demonstrated macular hole closure. The posterior hyaloid separated from the macula in six eyes (75%). All seven holes that remained open showed enlargement in hole diameters (narrowest, apical, and basal) at 1 week and 1 month. All seven were successfully closed with surgery. Ellipsoid zone disruptions were observed by OCT in four eyes (50%) and persisted throughout follow-up (more than 6 months on average). CONCLUSION: In early clinical results, the authors found a lower macular hole closure rate with ocriplasmin than previously reported. Enlargement was observed in all holes that failed to close with ocriplasmin. The authors found ellipsoid zone disruptions that persisted through 6 months of follow-up after ocriplasmin injection. Further work is needed to investigate the cause for these ellipsoid zone changes. C1 [Miller, John B.; Kim, Leo A.; Wu, David M.; Vavvas, Demetrios G.; Eliott, Dean; Husain, Deeba] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Ophthalmol,Retina Serv, Boston, MA 02114 USA. RP Husain, D (reprint author), Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Retina Serv, 243 Charles St, Boston, MA 02114 USA. EM deeba_husain@meei.harvard.edu FU NEI NIH HHS [K12 EY016335] NR 15 TC 10 Z9 10 U1 1 U2 1 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 2325-8160 EI 2325-8179 J9 OSLI RETINA JI Ophthalmic Surg. Lasers Imag. Retin. PD JUL-AUG PY 2014 VL 45 IS 4 BP 293 EP 297 DI 10.3928/23258160-20140709-05 PG 5 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA AY0OP UT WOS:000347296300004 PM 25037011 ER PT J AU Nicholson, LB Kim, BT Jardon, J Townsend-Pico, W Santos, C Moshfeghi, AA Albini, TA Eliott, D Sobrin, L AF Nicholson, Laura B. Kim, Brian T. Jardon, Javier Townsend-Pico, William Santos, Carmen Moshfeghi, Andrew A. Albini, Thomas A. Eliott, Dean Sobrin, Lucia TI Severe Bilateral Ischemic Retinal Vasculitis Following Cataract Surgery SO OPHTHALMIC SURGERY LASERS & IMAGING RETINA LA English DT Article ID OIL-FILLED EYE; VANCOMYCIN; MANAGEMENT; TOXICITY AB This report describes two cases of severe, bilateral ischemic retinal vasculitis following cataract surgeries at different surgical centers. In both cases, the patient underwent bilateral cataract surgeries, performed 1 week apart for each eye. In the perioperative period following the second of the two surgeries, both patients developed severe, bilateral intraocular inflammation and profound vision loss. The underlying cause of this adverse response remains unknown. The authors suggest that the severe inflammatory reaction could be related to an intraoperative intracameral vancomycin injection. C1 [Nicholson, Laura B.; Eliott, Dean; Sobrin, Lucia] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA USA. [Kim, Brian T.; Moshfeghi, Andrew A.; Albini, Thomas A.] Univ Miami, Miller Sch Med, Bascom Palmer Eye Inst, Dept Ophthalmol, Miami, FL 33136 USA. [Jardon, Javier; Santos, Carmen] Univ Puerto Rico, Sch Med, Dept Ophthalmol, San Juan, PR 00936 USA. [Townsend-Pico, William] Retina Consultants Puerto Rico, San Juan, PR USA. RP Sobrin, L (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM lucia_sobrin@meei.harvard.edu OI Albini, Thomas/0000-0003-2199-9047 NR 8 TC 7 Z9 7 U1 0 U2 1 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 2325-8160 EI 2325-8179 J9 OSLI RETINA JI Ophthalmic Surg. Lasers Imag. Retin. PD JUL-AUG PY 2014 VL 45 IS 4 BP 338 EP 342 DI 10.3928/23258160-20140605-01 PG 5 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA AY0OP UT WOS:000347296300014 PM 25127533 ER PT J AU Smith, RT True, G AF Smith, R. Tyson True, Gala TI Warring Identities: Identity Conflict and the Mental Distress of American Veterans of the Wars in Iraq and Afghanistan SO SOCIETY AND MENTAL HEALTH LA English DT Article DE identity; military health; posttraumatic stress disorder; psychological distress; institutions ID POSTTRAUMATIC-STRESS-DISORDER; US MILITARY; HEALTH; CARE; SUICIDE; ILLNESS; MASCULINITY; SOCIOLOGY; DIAGNOSIS; PERSONNEL AB Drawing from 26 life story interviews of recent American veterans, this paper analyzes the identity struggle faced by soldiers returning from Operation Iraqi Freedom and Operation Enduring Freedom and reentering the civilian world. Instead of examining veterans' problems as a consequence of post-combat mental illnesses such as PTSD and major depression, we analyze the contrast between the participants' identities as soldiers and their identities as civilians. We find that the postwar transition causes adverse mental health effects that stem from contrasts between the military's demands for deindividuation, obedience, chain-of-command, and dissociation and the civilian identity expectations of autonomy, self-advocacy, and being relational. Veterans' reintegration to civilian society is further hindered by a culture that is perceived (by veterans) as having decreased understanding of the soldier/veteran experience itself. These identity conflicts-what we term warring identities-have an important yet understudied effect on veterans' combat-related mental health problems. C1 [Smith, R. Tyson] Brown Univ, Providence, RI 02912 USA. [True, Gala] CHERP, Philadelphia, PA USA. RP Smith, RT (reprint author), Brown Univ, 112 George St,Box 1916, Providence, RI 02912 USA. EM tyson321@gmail.com NR 75 TC 5 Z9 5 U1 2 U2 19 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 2156-8693 EI 2156-8731 J9 SOC MENT HEALTH JI Soc. Ment. Health PD JUL PY 2014 VL 4 IS 2 BP 147 EP 161 DI 10.1177/2156869313512212 PG 15 WC Sociology SC Sociology GA AY3EG UT WOS:000347466700005 ER PT J AU Sanchez-Perez, L Suryadevara, CM Choi, BD Reap, EA Sampson, JH AF Sanchez-Perez, Luis Suryadevara, Carter M. Choi, Bryan D. Reap, Elizabeth A. Sampson, John H. TI Leveraging chemotherapy-induced lymphopenia to potentiate cancer immunotherapy SO ONCOIMMUNOLOGY LA English DT Editorial Material DE chemotherapy; glioblastoma; lymphopenia; immunotherapy; temozolomide ID TEMOZOLOMIDE; GLIOBLASTOMA AB First- line chemotherapy to combat primary malignant brain cancer is often accompanied by lymphopenic immunologic deficiency. Although counterintuitive, chemotherapy-induced lymphopenia can provide excellent host conditioning that may actually be leveraged to potentiate antitumor immunotherapy. We discuss here our preclinical and clinical experiences applying immunotherapy against glioblastoma, the most common and lethal primary malignant brain tumor, as well as the use of immunotherapeutics in the setting of standard-of-care temozolomide chemotherapy. C1 [Sanchez-Perez, Luis; Suryadevara, Carter M.; Reap, Elizabeth A.; Sampson, John H.] Duke Univ, Med Ctr, Dept Surg, Div Neurosurg,Duke Brain Tumor Immunotherapy Prog, Durham, NC 27710 USA. [Suryadevara, Carter M.; Sampson, John H.] Duke Univ, Dept Pathol, Durham, NC 27710 USA. [Sanchez-Perez, Luis; Suryadevara, Carter M.; Reap, Elizabeth A.; Sampson, John H.] Duke Univ, Med Ctr, Preston Robert Tisch Brain Tumor Ctr Duke, Durham, NC 27710 USA. [Choi, Bryan D.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Choi, Bryan D.] Harvard Univ, Sch Med, Boston, MA USA. RP Sampson, JH (reprint author), Duke Univ, Med Ctr, Dept Surg, Div Neurosurg,Duke Brain Tumor Immunotherapy Prog, Durham, NC 27710 USA. EM john.sampson@duke.edu NR 10 TC 1 Z9 1 U1 0 U2 0 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 2162-4011 EI 2162-402X J9 ONCOIMMUNOLOGY JI OncoImmunology PD JUL PY 2014 VL 3 IS 7 AR e944054 DI 10.4161/21624011.2014.944054 PG 3 WC Oncology; Immunology SC Oncology; Immunology GA AX4SH UT WOS:000346921100006 PM 25610727 ER PT J AU Arlehamn, CSL Lewinsohn, D Sette, A Lewinsohn, D AF Arlehamn, Cecilia S. Lindestam Lewinsohn, David Sette, Alessandro Lewinsohn, Deborah TI Antigens for CD4 and CD8 T Cells in Tuberculosis SO COLD SPRING HARBOR PERSPECTIVES IN MEDICINE LA English DT Article ID IMMUNODEFICIENCY-VIRUS-INFECTION; MEDIATED IMMUNE-RESPONSES; MYCOBACTERIUM-BOVIS BCG; VACCINE DEVELOPMENT; PROTECTIVE IMMUNITY; INTERFERON-GAMMA; SECRETED ANTIGENS; ESAT-6 ANTIGEN; IFN-GAMMA; PULMONARY TUBERCULOSIS AB Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis (MTB), represents an important cause of morbidity and mortality worldwide for which an improved vaccine and immunodiagnostics are urgently needed. CD4(+) and CD8(+) T cells play an important role in host defense to TB. Definition of the antigens recognized by these T cells is critical for improved understanding of the immunobiology of TB and for development of vaccines and diagnostics. Herein, the antigens and epitopes recognized by classically HLA class I- and II-restricted CD4(+) and CD8(+) T cells in humans infected with MTB are reviewed. Immunodominant antigens and epitopes have been defined using approaches targeting particular TB proteins or classes of proteins and by genome-wide discovery approaches. Antigens and epitopes recognized by classically restricted CD4(+) and CD8(+) T cells show extensive breadth and diversity in MTB-infected humans. C1 [Arlehamn, Cecilia S. Lindestam; Sette, Alessandro] La Jolla Inst Allergy & Immunol, La Jolla, CA 92037 USA. [Lewinsohn, David; Lewinsohn, Deborah] Oregon Hlth & Sci Univ, Portland, OR 97239 USA. [Lewinsohn, David] Portland VA Med Ctr, Portland, OR 97239 USA. RP Lewinsohn, D (reprint author), Oregon Hlth & Sci Univ, Portland, OR 97239 USA. EM lewinsde@ohsu.edu RI Lewinsohn, David/I-4936-2013; OI Lewinsohn, David/0000-0001-9906-9494; Lindestam Arlehamn, Cecilia/0000-0001-7302-8002 NR 155 TC 11 Z9 11 U1 0 U2 7 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 JUL PY 2014 VL 4 IS 7 AR a018465 DI 10.1101/cshperspect.a018465 PG 15 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AW8NB UT WOS:000346518000006 ER PT J AU Jakobs, TC AF Jakobs, Tatjana C. TI Differential Gene Expression in Glaucoma SO COLD SPRING HARBOR PERSPECTIVES IN MEDICINE LA English DT Article ID OPTIC-NERVE HEAD; RETINAL GANGLION-CELLS; HUMAN TRABECULAR MESHWORK; OPEN-ANGLE GLAUCOMA; ELEVATED INTRAOCULAR-PRESSURE; HUMAN LAMINA-CRIBROSA; NECROSIS-FACTOR-ALPHA; NITRIC-OXIDE SYNTHASE; RETROGRADE AXOPLASMIC-TRANSPORT; LATERAL GENICULATE-NUCLEUS AB In glaucoma, regardless of its etiology, retinal ganglion cells degenerate and eventually die. Although age and elevated intraocularpressure (IOP) are the main risk factors, there are still many mysteries in the pathogenesis of glaucoma. The advent of genome-wide microarray expression screening together with the availability of animal models of the disease has allowed analysis of differential gene expression in all parts of the eye in glaucoma. This review will outline the findings of recent genome-wide expression studies and discuss their commonalities and differences. A common finding was the differential regulation of genes involved in inflammation and immunity, including the complement system and the cytokines transforming growth factor beta (TGF beta) and tumor necrosis factor alpha (TNF alpha). Other genes of interest have roles in the extracellular matrix, cell-matrix interactions and adhesion, the cell cycle, and the endothelin system. C1 Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA 02114 USA. RP Jakobs, TC (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA 02114 USA. EM tatjana_jakobs@meei.harvard.edu OI Jakobs, Tatjana/0000-0002-8104-9206 NR 162 TC 7 Z9 7 U1 0 U2 11 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 JUL PY 2014 VL 4 IS 7 AR a020636 DI 10.1101/cshperspect.a020636 PG 14 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AW8NB UT WOS:000346518000004 PM 24985133 ER PT J AU Morgan, BA AF Morgan, Bruce A. TI The Dermal Papilla: An Instructive Niche for Epithelial Stem and Progenitor Cells in Development and Regeneration of the Hair Follicle SO COLD SPRING HARBOR PERSPECTIVES IN MEDICINE LA English DT Article ID FEATHER TRACT DEVELOPMENT; BETA-CATENIN; TRANSIENT ACTIVATION; PLACODE FORMATION; ADULT EPIDERMIS; SONIC-HEDGEHOG; GROWTH-PHASE; ANAGEN-PHASE; MOUSE SKIN; KAPPA-B AB The dermal papilla (DP) of the hair follicle is both a chemical and physical niche for epithelial progenitor cells that regenerate the cycling portion of the hair follicle and generate the hair shaft. Here, we review experiments that revealed the importance of the DP in regulating the characteristics of the hair shaft and frequency of hair follicle regeneration. More recent work showed that the size of this niche is dynamic and actively regulated and reduction in DP cell number per follicle is sufficient to cause hair thinning and loss. The formation of the DP during follicle neogenesis provides a context to contemplate the mechanisms that maintain DP size and the potential to exploit these processes for hair preservation or restoration. C1 [Morgan, Bruce A.] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02129 USA. [Morgan, Bruce A.] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Boston, MA 02129 USA. RP Morgan, BA (reprint author), Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02129 USA. EM bruce.morgan@cbrc2.mgh.harvard.edu NR 94 TC 11 Z9 12 U1 0 U2 11 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 JUL PY 2014 VL 4 IS 7 AR a015180 DI 10.1101/cshperspect.a015180 PG 14 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AW8NB UT WOS:000346518000007 PM 24985131 ER PT J AU Karlan, BY Thorpe, J Watabayashi, K Drescher, CW Palomares, M Daly, MB Paley, P Hillard, P Andersen, MR Anderson, G Drapkin, R Urban, N AF Karlan, Beth Y. Thorpe, Jason Watabayashi, Kate Drescher, Charles W. Palomares, Melanie Daly, Mary B. Paley, Pam Hillard, Paula Andersen, M. Robyn Anderson, Garnet Drapkin, Ronny Urban, Nicole TI Use of CA125 and HE4 Serum Markers to Predict Ovarian Cancer in Elevated-Risk Women SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID DISTAL FALLOPIAN-TUBE; PROPHYLACTIC SALPINGECTOMY; POSTMENOPAUSAL WOMEN; MUTATION CARRIERS; SEROUS CARCINOMA; HORMONE-THERAPY; PELVIC MASS; ALGORITHM; TIME; OOPHORECTOMY AB Background: Serum markers are used before pelvic imaging to improve specificity and positive predictive value (PPV) of ovarian cancer multimodal screening strategies. Methods: We conducted a randomized controlled pilot trial to estimate surgical PPV of a "2 of 3 tests positive" screening rule, and to compare use of HE4 as a first-line (Arm 1) versus a second-line (Arm 2) screen, in women at high and elevated risk for epithelial ovarian cancer (EOC) at five study sites. Semiannual screening was offered to 208 women ages 25 to 80 years with deleterious BRCA germline mutations and to 834 women ages 35 to 80 years with pedigrees suggesting inherited susceptibility. Annual screening was offered to 130 women ages 45 to 80 years (Risk Group 3) with epidemiologic and serum marker risk factors. Rising marker levels were identified using the parametric empirical Bayes algorithm. Results: Both strategies yielded surgical PPV above 25%. Protocol-indicated surgery was performed in 6 women, identifying two ovarian malignancies and yielding a surgical PPV in both arms combined of 33% (95% confidence interval: 4%-78%), 25% in Arm 1 and 50% in Arm 2. Surgical consultation was recommended for 37 women(26 in Arm 1 and 11 in Arm 2). On the basis of 12 women with at least 2 of 3 tests positive (CA125, HE4, or imaging), an intent-to-treat analysis yielded PPV of 14% in Arm 1 and 20% in Arm 2. Conclusions: Positive screens were more frequent when HE4 was included in the primary screen. Impact: HE4 may be useful as a confirmatory screen when rising CA125 is used alone as a primary screen. (C)2014 AACR. C1 [Karlan, Beth Y.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Palomares, Melanie] City Hope Comprehens Canc Ctr, Duarte, CA USA. [Hillard, Paula] Stanford Univ, Palo Alto, CA 94304 USA. [Thorpe, Jason; Watabayashi, Kate; Drescher, Charles W.; Andersen, M. Robyn; Anderson, Garnet; Urban, Nicole] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Drescher, Charles W.; Paley, Pam] Pacific Gynecol Specialists, Seattle, WA USA. [Daly, Mary B.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Drapkin, Ronny] Dana Farber Canc Ctr, Boston, MA USA. RP Karlan, BY (reprint author), Cedars Sinai Med Ctr, 8700 Beverly Blvd, Los Angeles, CA 90048 USA. EM Beth.Karlan@cshs.org RI Drapkin, Ronny/E-9944-2016 OI Drapkin, Ronny/0000-0002-6912-6977 FU NIH/NCATS [UL1TR000124, SIOP-06-258-01-COUN]; [NCI P50 CA083636]; [NCI U01 CA152637] FX This work was supported by grants NCI P50 CA083636 (to N. Urban), NCI U01 CA152637 (to N. Urban), and NIH/NCATS Grant# UL1TR000124 and SIOP-06-258-01-COUN (to B.Y. Karlan). NR 43 TC 5 Z9 6 U1 0 U2 7 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 JUL PY 2014 VL 23 IS 7 BP 1383 EP 1393 DI 10.1158/1055-9965.EPI-13-1361 PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AT9WE UT WOS:000345273700029 PM 24789859 ER PT J AU Houde, AA Ruchat, SM Allard, C Perron, P Baillargeon, JP St-Pierre, J Gaudet, D Brisson, D Hivert, MF Bouchard, L AF Houde, A. A. Ruchat, S. M. Allard, C. Perron, P. Baillargeon, J. P. St-Pierre, J. Gaudet, D. Brisson, D. Hivert, M. F. Bouchard, L. TI LRP1B and BRD2: new candidate genes in fetal metabolic programming of the newborn exposed to maternal hyperglycemia SO GENOME LA English DT Meeting Abstract C1 [Houde, A. A.; Ruchat, S. M.; Bouchard, L.] Univ Sherbrooke, Dept Biochem, Sherbrooke, PQ J1E 4K8, Canada. [Houde, A. A.; Ruchat, S. M.; Perron, P.; St-Pierre, J.; Gaudet, D.; Brisson, D.; Bouchard, L.] Chicoutimi Hosp, ECOGENE 21, Saguenay, PQ G7H 5H6, Canada. [Houde, A. A.; Ruchat, S. M.; Perron, P.; St-Pierre, J.; Gaudet, D.; Brisson, D.; Bouchard, L.] Chicoutimi Hosp, Lipid Clin, Saguenay, PQ G7H 5H6, Canada. [Allard, C.; Perron, P.; Baillargeon, J. P.; Hivert, M. F.] Univ Sherbrooke, Dept Med, Sherbrooke, PQ J1H 5N4, Canada. [St-Pierre, J.] Chicoutimi Hosp, Dept Pediat, Saguenay Chicoutimi, PQ G7H 5H6, Canada. [Gaudet, D.] Univ Montreal, Fac Med, Dept Med, Montreal, PQ H3H 1P3, Canada. [Hivert, M. F.] Harvard Pilgrim Hlth Care Inst, Dept Populat Med, Boston, MA 02215 USA. [Hivert, M. F.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CANADIAN SCIENCE PUBLISHING, NRC RESEARCH PRESS PI OTTAWA PA 65 AURIGA DR, SUITE 203, OTTAWA, ON K2E 7W6, CANADA SN 0831-2796 EI 1480-3321 J9 GENOME JI Genome PD JUL PY 2014 VL 57 IS 7 BP 376 EP 377 PG 2 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA AU3SF UT WOS:000345533100006 ER PT J AU Knight, EM Gandy, S AF Knight, E. M. Gandy, S. TI Immunomodulation and AD - Down But Not Out SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Article DE Alzheimer's disease; immunotherapy; immunoglobulin; IVIG; oligomer ID AMYLOID-BETA-PEPTIDE; MODERATE ALZHEIMERS-DISEASE; HUMAN INTRAVENOUS IMMUNOGLOBULIN; MOUSE MODEL; SIGNALING PATHWAY; NATURAL OLIGOMERS; HUMAN-ANTIBODIES; IMMUNIZATION; PATHOLOGY; MEMORY AB Alzheimer's disease (AD) is a progressive neurodegenerative disorder and is the most common cause of dementia in the elderly. Interventions that remove existing fibrillar and oligomeric amyloid-beta (A beta) are believed to be essential for the success of any attempt at stabilization of brain function and mitigation of cognitive decline. Many of these strategies have focused on A beta vaccination and administration of anti-A beta antibodies. Both active and passive immunotherapies have been successful in mouse models, but both have had limited effect in clinical trials. Intravenous immunoglobulin (IVIG) has been proposed as a potential treatment for AD following evidence for behavioral benefit in AD models and cognitive benefit in early phase 1 and phase 2 clinical trials. A phase 3 trial IVIG trial failed to meet its primary outcomes. While there was a statistically significant benefit in moderate stage AD patients who carried an APOE epsilon 4 allele, this stabilization of cognition was evident only on neuropsychological examination. No benefit on activities of daily living was evident, therefore failing to qualify AD as a new indication for IVIG. Identifying the biologically active component (s) responsible for the neuropsychological benefit in APOE epsilon 4-positive AD patients could enable the development of a compound with greater potency that would qualify for FDA (US Food and Drug Administration) registration. C1 [Knight, E. M.; Gandy, S.] Icahn Sch Med Mt Sinai, Dept Neurol, New York, NY 10029 USA. [Knight, E. M.; Gandy, S.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Knight, E. M.; Gandy, S.] Icahn Sch Med Mt Sinai, Alzheimers Dis Res Ctr, New York, NY 10029 USA. [Gandy, S.] James J Peters Vet Affairs Med Ctr, Bronx, NY 10468 USA. RP Gandy, S (reprint author), Icahn Sch Med Mt Sinai, Dept Neurol, New York, NY 10029 USA. EM elysse.knight@mssm.edu; samuel.gandy@mssm.edu FU Baxter Pharmaceuticals; Amicus Therapeutics; Constellation Wines FX SG serves on SABs for the Pfizer-Janssen Alzheimer's Immunotherapy Alliance, for Cerora, and for Diagenic. He has received research grant support from Baxter Pharmaceuticals, Amicus Therapeutics, and Constellation Wines. NR 41 TC 4 Z9 4 U1 0 U2 1 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 EI 1573-2592 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD JUL PY 2014 VL 34 SU 1 BP S70 EP S73 DI 10.1007/s10875-014-0039-y PG 4 WC Immunology SC Immunology GA AU3KN UT WOS:000345512100012 PM 24781637 ER PT J AU Doyle, LA Wong, KK Bueno, R Dal Cin, P Fletcher, JA Sholl, LM Kuo, F AF Doyle, Leona A. Wong, Kwok-Kin Bueno, Raphael Dal Cin, Paola Fletcher, Jonathan A. Sholl, Lynette M. Kuo, Frank TI Ewing sarcoma mimicking atypical carcinoid tumor: detection of unexpected genomic alterations demonstrates the use of next generation sequencing as a diagnostic tool SO CANCER GENETICS LA English DT Article DE Next generation sequencing; Ewing; EWSR1; ERG; carcinoid ID GENE-MUTATIONS; EWS GENE; CANCER; SAMPLES; TRANSLOCATION; FUSES; ERG AB Increasingly, tumors are being analyzed for a variety of mutations and other genomic changes, with the goals of guiding personalized therapy and directing patients to appropriate clinical trials based on genotype, as well as identifying previously unknown genomic changes in different tumor types and thereby providing new insights into the pathogenesis of human cancers. Next generation sequencing is a powerful research tool now gaining traction in the clinic. In this report, we demonstrate the utility of next generation sequencing assays in providing diagnostic information when evaluating tumor specimens. This is illustrated by a case previously thought to represent an atypical carcinoid tumor, in which an EWSR1-ERG translocation was detected during next generation sequencing using a hybrid capture approach, leading to a revised diagnosis of Ewing sarcoma. The role of translocation detection in these assays is also discussed. C1 [Doyle, Leona A.; Dal Cin, Paola; Fletcher, Jonathan A.; Sholl, Lynette M.; Kuo, Frank] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Doyle, Leona A.; Bueno, Raphael; Dal Cin, Paola; Fletcher, Jonathan A.; Sholl, Lynette M.; Kuo, Frank] Harvard Univ, Sch Med, Boston, MA USA. [Wong, Kwok-Kin] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Bueno, Raphael] Brigham & Womens Hosp, Dept Thorac Surg, Boston, MA 02115 USA. RP Sholl, LM (reprint author), Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. EM lmsholl@gmail.com OI wong, kwok kin/0000-0001-6323-235X NR 17 TC 5 Z9 5 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2210-7762 EI 2210-7770 J9 CANCER GENET-NY JI Cancer Genet. PD JUL-AUG PY 2014 VL 207 IS 7-8 BP 335 EP 339 DI 10.1016/j.cancergen.2014.08.004 PG 5 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA AT9NU UT WOS:000345254700007 PM 25441687 ER PT J AU Potter, BJ Yeh, RW Pinto, DS AF Potter, Brian J. Yeh, Robert W. Pinto, Duane S. TI Public Reporting of PCI Outcomes: For Better or for Worse SO CURRENT CARDIOLOGY REPORTS LA English DT Article DE Percutaneous coronary intervention; PCI; Public reporting; Healthcare policy ID PERCUTANEOUS CORONARY INTERVENTION; ELEVATION MYOCARDIAL-INFARCTION; ST-SEGMENT-ELEVATION; HOSPITAL CARDIAC-ARREST; QUALITY-OF-CARE; CARDIOGENIC-SHOCK; MORTALITY; IMPACT; IMPROVEMENT; PREDICTION AB Public reporting of PCI outcomes has had a polarizing effect on the cardiology community. The potential benefits of public reporting are many, but a host of unintended consequences have likely mitigated the anticipated positive impact of current reporting systems. In this review, we discuss what the goals of public disclosure are, the limitations of current reporting systems and the resultant unintended consequences. We also offer a perspective on future directions with a view to ensuring the benefits of public reporting while minimizing the risk of unintended consequences. C1 [Potter, Brian J.; Pinto, Duane S.] Beth Israel Deaconess Med Ctr, Cardiovasc Inst, Boston, MA 02215 USA. [Yeh, Robert W.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Pinto, Duane S.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. RP Pinto, DS (reprint author), Beth Israel Deaconess Med Ctr, 185 Pilgrim Rd,Baker 4, Boston, MA 02215 USA. EM dpinto@bidmc.harvard.edu RI Potter, Brian/A-5083-2015 OI Potter, Brian/0000-0002-0316-9026 FU Edwards Lifescience; Astra Zenica; Medicines Company; Medtronic; St. Jude; Abbott; Boston Scientific; Merck; Rox Medical; UpToDate; CRICO; Covidien; BCRI; Jannsen; Lantheus FX Brian J. Potter reports grants from Edwards Lifescience, and personal fees from Astra Zenica.; Duane S. Pinto reports personal fees from Medicines Company, personal fees from Medtronic, personal fees from St. Jude, personal fees from Abbott, personal fees from Boston Scientific, personal fees from Merck, personal fees from Rox Medical, personal fees from UpToDate, personal fees from CRICO, personal fees from Covidien, personal fees from BCRI, personal fees from Jannsen, and personal fees from Lantheus. NR 40 TC 2 Z9 2 U1 1 U2 1 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 JUL PY 2014 VL 16 IS 7 AR 500 DI 10.1007/s11886-014-0500-9 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AT6ZS UT WOS:000345086300003 PM 24893937 ER PT J AU Rajachandran, M Schainfeld, RM AF Rajachandran, Manu Schainfeld, Robert M. TI Medical and Interventional Options to Treat Pulmonary Embolism SO CURRENT CARDIOLOGY REPORTS LA English DT Article DE Pulmonary embolism; Thrombolysis; Venous interventions; Novel oral anticoagulants; IVC filters ID ULTRASOUND-ACCELERATED THROMBOLYSIS; RANDOMIZED CONTROLLED-TRIALS; ACUTE VENOUS THROMBOEMBOLISM; INFERIOR VENA-CAVA; CATHETER; METAANALYSIS; HEPARIN; EMBOLECTOMY; MANAGEMENT; RESOLUTION AB Venous thromboembolism remains one of the most common conditions. Pulmonary embolism carries a mortality rate of over 15 % in the first 3 months after diagnosis. Venous thromboembolism is the fourth leading cause of death in the Western world, and the third leading cause of cardiovascular death trailing myocardial infarction and stroke. This section highlights the medical and interventional options presently available to treat this potentially lethal disease. C1 [Rajachandran, Manu] Mem Hosp, Dept Cardiol, York, PA 17403 USA. [Rajachandran, Manu] UMDNJ Robert Wood Johnson Med Sch, York, PA 17403 USA. [Schainfeld, Robert M.] Massachusetts Gen Hosp, Sect Vasc Med, Div Cardiol, Boston, MA 02114 USA. [Schainfeld, Robert M.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Schainfeld, RM (reprint author), Massachusetts Gen Hosp, Sect Vasc Med, Div Cardiol, Gray Bigelow 800,55 Fruit St, Boston, MA 02114 USA. EM rschainfeld@partners.org NR 40 TC 0 Z9 0 U1 0 U2 1 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 JUL PY 2014 VL 16 IS 7 AR 503 DI 10.1007/s11886-014-0503-6 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AT6ZS UT WOS:000345086300006 PM 24890764 ER PT J AU Blackburn, JS Langenau, DM AF Blackburn, Jessica S. Langenau, David M. TI Zebrafish as a model to assess cancer heterogeneity, progression and relapse SO DISEASE MODELS & MECHANISMS LA English DT Review DE Cancer stem cell; Fluorescence; Intratumoral; Single cell; Targeted therapy; Tumor ID ACUTE LYMPHOBLASTIC-LEUKEMIA; CHRONIC MYELOID-LEUKEMIA; PROPAGATING CELL FREQUENCY; CLONAL EVOLUTION; EMBRYONAL RHABDOMYOSARCOMA; GENOMIC HETEROGENEITY; MOLECULAR EVOLUTION; ACQUIRED-RESISTANCE; PANCREATIC-CANCER; BREAST-CANCER AB Clonal evolution is the process by which genetic and epigenetic diversity is created within malignant tumor cells. This process culminates in a heterogeneous tumor, consisting of multiple subpopulations of cancer cells that often do not contain the same underlying mutations. Continuous selective pressure permits outgrowth of clones that harbor lesions that are capable of enhancing disease progression, including those that contribute to therapy resistance, metastasis and relapse. Clonal evolution and the resulting intratumoral heterogeneity pose a substantial challenge to biomarker identification, personalized cancer therapies and the discovery of underlying driver mutations in cancer. The purpose of this Review is to highlight the unique strengths of zebrafish cancer models in assessing the roles that intratumoral heterogeneity and clonal evolution play in cancer, including transgenesis, imaging technologies, high-throughput cell transplantation approaches and in vivo single-cell functional assays. C1 [Blackburn, Jessica S.; Langenau, David M.] Massachusetts Gen Hosp, Dept Mol Pathol, Charlestown, MA 02129 USA. [Blackburn, Jessica S.; Langenau, David M.] Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA 02129 USA. [Blackburn, Jessica S.; Langenau, David M.] Harvard Stem Cell Inst, Cambridge, MA 02139 USA. RP Langenau, DM (reprint author), Massachusetts Gen Hosp, Dept Mol Pathol, Charlestown, MA 02129 USA. EM dlangenau@mgh.harvard.edu FU Alex's Lemonade Stand Foundation; American Cancer Society; MGH Howard Goodman Fellowship; Leukemia and Lymphoma Society; Massachusetts General Hospital Toteson Fund for Medical Discovery; National Institutes of Health [R24OD016761, 1R01CA154923, 1K99CA181500-01] FX This work is supported by Alex's Lemonade Stand Foundation (D. M. L. and J.S.B.), the American Cancer Society (D. M. L.), the MGH Howard Goodman Fellowship (D. M. L.), the Leukemia and Lymphoma Society (J.S.B.), the Massachusetts General Hospital Toteson Fund for Medical Discovery (J.S.B.), and National Institutes of Health grants R24OD016761 (D. M. L.), 1R01CA154923 (D. M. L.) and 1K99CA181500-01 (J.S.B.). NR 75 TC 17 Z9 18 U1 2 U2 5 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 1754-8403 EI 1754-8411 J9 DIS MODEL MECH JI Dis. Model. Mech. PD JUL PY 2014 VL 7 IS 7 BP 755 EP 762 DI 10.1242/dmm.015842 PG 8 WC Cell Biology; Pathology SC Cell Biology; Pathology GA AT5TA UT WOS:000345003600005 PM 24973745 ER PT J AU Asnani, A Peterson, RT AF Asnani, Aarti Peterson, Randall T. TI The zebrafish as a tool to identify novel therapies for human cardiovascular disease SO DISEASE MODELS & MECHANISMS LA English DT Review DE Cardiovascular; Drug discovery; Zebrafish ID CONGENITAL HEART-DISEASE; HOMEOBOX GENE NKX2-5; VALVE DEVELOPMENT; CARDIOMYOCYTE PROLIFERATION; CARDIAC DYSFUNCTION; MUTATIONS; REGENERATION; SYSTEM; GENOME; VALVULOGENESIS AB Over the past decade, the zebrafish has become an increasingly popular animal model for the study of human cardiovascular disease. Because zebrafish embryos are transparent and their genetic manipulation is straightforward, the zebrafish has been used to recapitulate a number of cardiovascular disease processes ranging from congenital heart defects to arrhythmia to cardiomyopathy. The use of fluorescent reporters has been essential to identify two discrete phases of cardiomyocyte differentiation necessary for normal cardiac development in the zebrafish. These phases are analogous to the differentiation of the two progenitor heart cell populations in mammals, termed the first and second heart fields. The small size of zebrafish embryos has enabled high-throughput chemical screening to identify small-molecule suppressors of fundamental pathways in vasculogenesis, such as the BMP axis, as well as of common vascular defects, such as aortic coarctation. The optical clarity of zebrafish has facilitated studies of valvulogenesis as well as detailed electrophysiological mapping to characterize the early cardiac conduction system. One unique aspect of zebrafish larvae is their ability to oxygenate through diffusion alone, permitting the study of mutations that cause severe cardiomyopathy phenotypes such as silent heart and pickwick(m171), which mimic titin mutations observed in human dilated cardiomyopathy. Above all, the regenerative capacity of zebrafish presents a particularly exciting opportunity to discover new therapies for cardiac injury, including scar formation following myocardial infarction. This Review will summarize the current state of the field and describe future directions to advance our understanding of human cardiovascular disease. C1 [Asnani, Aarti; Peterson, Randall T.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. RP Peterson, RT (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. EM rtpeterson@mgh.harvard.edu FU National Heart, Lung, and Blood Institute [T32HL007208]; National Institutes of Health [1U54NS079201]; American Heart Association [13IRG14600006]; Charles and Ann Sanders MGH Scholar award FX A.A. is supported by Award Number T32HL007208 from the National Heart, Lung, and Blood Institute. R. T. P. is supported by the National Institutes of Health (1U54NS079201), the American Heart Association (13IRG14600006), and by the Charles and Ann Sanders MGH Scholar award. NR 61 TC 29 Z9 32 U1 4 U2 34 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 1754-8403 EI 1754-8411 J9 DIS MODEL MECH JI Dis. Model. Mech. PD JUL PY 2014 VL 7 IS 7 BP 763 EP 767 DI 10.1242/dmm.016170 PG 5 WC Cell Biology; Pathology SC Cell Biology; Pathology GA AT5TA UT WOS:000345003600006 PM 24973746 ER PT J AU Goessling, W North, TE AF Goessling, Wolfram North, Trista E. TI Repairing quite swimmingly: advances in regenerative medicine using zebrafish SO DISEASE MODELS & MECHANISMS LA English DT Review DE Regeneration; Zebrafish; Disease model; Gastrointestinal; Hematovascular ID HEMATOPOIETIC-CELL TRANSPLANTATION; IN-VIVO; BETA-CATENIN; HEART REGENERATION; STEM-CELLS; LIVER DEVELOPMENT; FIN REGENERATION; ADULT ZEBRAFISH; TRANSGENIC ZEBRAFISH; POSITIONAL CLONING AB Regenerative medicine has the promise to alleviate morbidity and mortality caused by organ dysfunction, longstanding injury and trauma. Although regenerative approaches for a few diseases have been highly successful, some organs either do not regenerate well or have no current treatment approach to harness their intrinsic regenerative potential. In this Review, we describe the modeling of human disease and tissue repair in zebrafish, through the discovery of disease-causing genes using classical forward-genetic screens and by modulating clinically relevant phenotypes through chemical genetic screening approaches. Furthermore, we present an overview of those organ systems that regenerate well in zebrafish in contrast to mammalian tissue, as well as those organs in which the regenerative potential is conserved from fish to mammals, enabling drug discovery in preclinical disease-relevant models. We provide two examples from our own work in which the clinical translation of zebrafish findings is either imminent or has already proven successful. The promising results in multiple organs suggest that further insight into regenerative mechanisms and novel clinically relevant therapeutic approaches will emerge from zebrafish research in the future. C1 [Goessling, Wolfram] Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02215 USA. [Goessling, Wolfram; North, Trista E.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Goessling, Wolfram; North, Trista E.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [North, Trista E.] Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. RP Goessling, W (reprint author), Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02215 USA. EM wgoessling@partners.org; tnorth@bidmc.harvard.edu OI Goessling, Wolfram/0000-0001-9972-1569 FU NIH [R01DK098241, R01DK090311] FX T.E.N. is supported by NIH R01DK098241 and W. G by NIH R01DK090311. NR 109 TC 13 Z9 14 U1 1 U2 9 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 1754-8403 EI 1754-8411 J9 DIS MODEL MECH JI Dis. Model. Mech. PD JUL PY 2014 VL 7 IS 7 BP 769 EP 776 DI 10.1242/dmm.016352 PG 8 WC Cell Biology; Pathology SC Cell Biology; Pathology GA AT5TA UT WOS:000345003600007 PM 24973747 ER PT J AU van Ham, TJ Brady, CA Kalicharan, RD Oosterhof, N Kuipers, J Veenstra-Algra, A Sjollema, KA Peterson, RT Kampinga, HH Giepmans, BNG AF van Ham, Tjakko J. Brady, Colleen A. Kalicharan, Ruby D. Oosterhof, Nynke Kuipers, Jeroen Veenstra-Algra, Anneke Sjollema, Klaas A. Peterson, Randall T. Kampinga, Harm H. Giepmans, Ben N. G. TI Intravital correlated microscopy reveals differential macrophage and microglial dynamics during resolution of neuroinflammation SO DISEASE MODELS & MECHANISMS LA English DT Article DE Brain; Intravital microscopy; Leukocytes; Microglia; Neurodegeneration; Zebrafish ID MONOCYTE-DERIVED MACROPHAGES; CENTRAL-NERVOUS-SYSTEM; ADULT ZEBRAFISH BRAIN; IN-VIVO; APOPTOTIC CELLS; ELECTRON-MICROSCOPY; ALZHEIMERS-DISEASE; BLOOD MONOCYTES; CHOROID-PLEXUS; SPINAL-CORD AB Many brain diseases involve activation of resident and peripheral immune cells to clear damaged and dying neurons. Which immune cells respond in what way to cues related to brain disease, however, remains poorly understood. To elucidate these in vivo immunological events in response to brain cell death we used genetically targeted cell ablation in zebrafish. Using intravital microscopy and large-scale electron microscopy, we defined the kinetics and nature of immune responses immediately following injury. Initially, clearance of dead cells occurs by mononuclear phagocytes, including resident microglia and macrophages of peripheral origin, whereas amoeboid microglia are exclusively involved at a later stage. Granulocytes, on the other hand, do not migrate towards the injury. Remarkably, following clearance, phagocyte numbers decrease, partly by phagocyte cell death and subsequent engulfment of phagocyte corpses by microglia. Here, we identify differential temporal involvement of microglia and peripheral macrophages in clearance of dead cells in the brain, revealing the chronological sequence of events in neuroinflammatory resolution. Remarkably, recruited phagocytes undergo cell death and are engulfed by microglia. Because adult zebrafish treated at the larval stage lack signs of pathology, it is likely that this mode of resolving immune responses in brain contributes to full tissue recovery. Therefore, these findings suggest that control of such immune cell behavior could benefit recovery from neuronal damage. C1 [van Ham, Tjakko J.; Kalicharan, Ruby D.; Oosterhof, Nynke; Kuipers, Jeroen; Veenstra-Algra, Anneke; Sjollema, Klaas A.; Kampinga, Harm H.; Giepmans, Ben N. G.] Univ Groningen, Univ Med Ctr Groningen, Dept Cell Biol, NL-9713 AV Groningen, Netherlands. [Brady, Colleen A.; Peterson, Randall T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Charlestown, MA 02129 USA. RP van Ham, TJ (reprint author), Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands. EM T.vanHam@ErasmusMC.nl RI van Ham, Tjakko/A-1989-2015; Giepmans, Ben/R-4564-2016 OI van Ham, Tjakko/0000-0002-2175-8713; Giepmans, Ben/0000-0001-5105-5915 FU Netherlands Organisation for Scientific Research (NOW) [175-010-2009-023]; Netherlands Organization for Health Research and Development (ZonMW) [91111006]; Stichting Technische Wetenschappen (Technology Foundation) (STW) [12718]; ZonMW [VENI] [016.136.150]; Marie Curie Career Integration Grant [322368]; Alzheimer Nederland fellowship [WE.15-2012-01]; Jane Coffin Childs Memorial Fund for Medical Research; UMCG Graduate School Behavioral and Cognitive Neurosciences (BCN); J.K. de Cock stichting FX Most of the work was performed at the UMCG Imaging and Microscopy Center (UMIC), which is sponsored by the Netherlands Organisation for Scientific Research (NOW) [grant number 175-010-2009-023] and the Netherlands Organization for Health Research and Development (ZonMW) [grant number 91111006]. B.N.G.G. received funding from the Stichting Technische Wetenschappen (Technology Foundation) (STW) "Microscopy Valley 12718". This work was sponsored by ZonMW [VENI grant number 016.136.150], a Marie Curie Career Integration Grant [Saving Dying Neurons, 322368] and an Alzheimer Nederland fellowship [grant number WE.15-2012-01] to T.J.v.H. This investigation has been aided by a grant from The Jane Coffin Childs Memorial Fund for Medical Research to C. A. B., and funding from the UMCG Graduate School Behavioral and Cognitive Neurosciences (BCN) and J.K. de Cock stichting to N.O. NR 72 TC 13 Z9 13 U1 0 U2 6 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 1754-8403 EI 1754-8411 J9 DIS MODEL MECH JI Dis. Model. Mech. PD JUL PY 2014 VL 7 IS 7 BP 857 EP 869 DI 10.1242/dmm.014886 PG 13 WC Cell Biology; Pathology SC Cell Biology; Pathology GA AT5TA UT WOS:000345003600015 PM 24973753 ER PT J AU Burger, A Vasilyev, A Tomar, R Selig, MK Nielsen, GP Peterson, RT Drummond, IA Haber, DA AF Burger, Alexa Vasilyev, Aleksandr Tomar, Ritu Selig, Martin K. Nielsen, G. Petur Peterson, Randall T. Drummond, Iain A. Haber, Daniel A. TI A zebrafish model of chordoma initiated by notochord-driven expression of HRASV12 SO DISEASE MODELS & MECHANISMS LA English DT Article DE HRASV12; Cancer; Chordoma; Drug treatment; Rapamycin; Zebrafish ID GROWTH-FACTOR RECEPTOR; TRANSGENIC ZEBRAFISH; SKULL BASE; GENE; TUMORIGENESIS; EFFICACY; TARGET AB Chordoma is a malignant tumor thought to arise from remnants of the embryonic notochord, with its origin in the bones of the axial skeleton. Surgical resection is the standard treatment, usually in combination with radiation therapy, but neither chemotherapeutic nor targeted therapeutic approaches have demonstrated success. No animal model and only few chordoma cell lines are available for preclinical drug testing, and, although no druggable genetic drivers have been identified, activation of EGFR and downstream AKT-PI3K pathways have been described. Here, we report a zebrafish model of chordoma, based on stable transgene-driven expression of HRASV12 in notochord cells during development. Extensive intra-notochordal tumor formation is evident within days of transgene expression, ultimately leading to larval death. The zebrafish tumors share characteristics of human chordoma as demonstrated by immunohistochemistry and electron microscopy. The mTORC1 inhibitor rapamycin, which has some demonstrated activity in a chordoma cell line, delays the onset of tumor formation in our zebrafish model, and improves survival of tumor-bearing fish. Consequently, the HRASV12-driven zebrafish model of chordoma could enable high-throughput screening of potential therapeutic agents for the treatment of this refractory cancer. C1 [Burger, Alexa; Haber, Daniel A.] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. [Burger, Alexa; Haber, Daniel A.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Vasilyev, Aleksandr; Tomar, Ritu; Drummond, Iain A.] Massachusetts Gen Hosp, Div Nephrol, Charlestown, MA 02129 USA. [Vasilyev, Aleksandr; Selig, Martin K.; Nielsen, G. Petur] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Vasilyev, Aleksandr] NYIT COM, Dept Biomed Sci, New York, NY 11568 USA. [Peterson, Randall T.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. [Peterson, Randall T.] Broad Inst, Cambridge, MA 02142 USA. RP Haber, DA (reprint author), Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. EM Haber@helix.mgh.harvard.edu FU Howard Hughes Medical Institute; NIH [R37 CA058596, K08DK082782, R03DK097443, DK053093, DK071041, DK070263]; HSCI Pilot Grant FX This work was supported by the Howard Hughes Medical Institute (A. B. and D. A. H.), NIH grants R37 CA058596 (D. A. H.), K08DK082782, R03DK097443 (A. V.), DK053093, DK071041, DK070263 (I. A. D.), and a HSCI Pilot Grant (A.V.). NR 30 TC 8 Z9 9 U1 0 U2 4 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 1754-8403 EI 1754-8411 J9 DIS MODEL MECH JI Dis. Model. Mech. PD JUL PY 2014 VL 7 IS 7 BP 907 EP 913 DI 10.1242/dmm.013128 PG 7 WC Cell Biology; Pathology SC Cell Biology; Pathology GA AT5TA UT WOS:000345003600019 PM 24311731 ER PT J AU Kelly, CR Ihunnah, C Fischer, M Khoruts, A Surawicz, C Afzali, A Aroniadis, O Barto, A Borody, T Giovanelli, A Gordon, S Gluck, M Hohmann, EL Kao, D Kao, JY McQuillen, DP Mellow, M Rank, KM Rao, K Ray, A Schwartz, MA Singh, N Stollman, N Suskind, DL Vindigni, SM Youngster, I Brandt, L AF Kelly, Colleen R. Ihunnah, Chioma Fischer, Monika Khoruts, Alexander Surawicz, Christina Afzali, Anita Aroniadis, Olga Barto, Amy Borody, Thomas Giovanelli, Andrea Gordon, Shelley Gluck, Michael Hohmann, Elizabeth L. Kao, Dina Kao, John Y. McQuillen, Daniel P. Mellow, Mark Rank, Kevin M. Rao, Krishna Ray, Arnab Schwartz, Margot A. Singh, Namita Stollman, Neil Suskind, David L. Vindigni, Stephen M. Youngster, Ilan Brandt, Lawrence TI Fecal Microbiota Transplant for Treatment of Clostridium difficile Infection in Immunocompromised Patients SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; ULCERATIVE-COLITIS; DIARRHEA; EPIDEMIOLOGY; FIDAXOMICIN; VANCOMYCIN; PROTECTION; GUIDELINES; RISK AB OBJECTIVES: Patients who are immunocompromised (IC) are at increased risk of Clostridium difficile infection (CDI), which has increased to epidemic proportions over the past decade. Fecal microbiota transplantation (FMT) appears effective for the treatment of CDI, although there is concern that IC patients may be at increased risk of having adverse events (AEs) related to FMT. This study describes the multicenter experience of FMT in IC patients. METHODS: A multicenter retrospective series was performed on the use of FMT in IC patients with CDI that was recurrent, refractory, or severe. We aimed to describe rates of CDI cure after FMT as well as AEs experienced by IC patients after FMT. A 32-item questionnaire soliciting demographic and pre- and post-FMT data was completed for 99 patients at 16 centers, of whom 80 were eligible for inclusion. Outcomes included (i) rates of CDI cure after FMT, (ii) serious adverse events (SAEs) such as death or hospitalization within 12 weeks of FMT, (iii) infection within 12 weeks of FMT, and (iv) AEs (related and unrelated) to FMT. RESULTS: Cases included adult (75) and pediatric (5) patients treated with FMT for recurrent (55%), refractory (11%), and severe and/or overlap of recurrent/refractory and severe CDI (34%). In all, 79% were outpatients at the time of FMT. The mean follow-up period between FMT and data collection was 11 months (range 3-46 months). Reasons for IC included: HIV/AIDS (3), solid organ transplant (19), oncologic condition (7), immunosuppressive therapy for inflammatory bowel disease (IBD; 36), and other medical conditions/medications (15). The CDI cure rate after a single FMT was 78%, with 62 patients suffering no recurrence at least 12 weeks post FMT. Twelve patients underwent repeat FMT, of whom eight had no further CDI. Thus, the overall cure rate was 89%. Twelve (15%) had any SAE within 12 weeks post FMT, of which 10 were hospitalizations. Two deaths occurred within 12 weeks of FMT, one of which was the result of aspiration during sedation for FMT administered via colonoscopy; the other was unrelated to FMT. None suffered infections definitely related to FMT, but two patients developed unrelated infections and five had self-limited diarrheal illness in which no causal organism was identified. One patient had a superficial mucosal tear caused by the colonoscopy performed for the FMT, and three patients reported mild, self-limited abdominal discomfort post FMT. Five (14% of IBD patients) experienced disease flare post FMT. Three ulcerative colitis (UC) patients underwent colectomy related to course of UC >100 days after FMT. CONCLUSIONS: This series demonstrates the effective use of FMT for CDI in IC patients with few SAEs or related AEs. Importantly, there were no related infectious complications in these high-risk patients. C1 [Kelly, Colleen R.; Ihunnah, Chioma] Brown Univ, Alpert Med Sch, Womens Med Collaborat, Div Gastroenterol,Brown Alpert Med Sch, Providence, RI 02912 USA. [Fischer, Monika] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Khoruts, Alexander; Rank, Kevin M.] Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. [Surawicz, Christina; Afzali, Anita; Vindigni, Stephen M.] Univ Washington, Sch Med, Seattle, WA USA. [Aroniadis, Olga; Brandt, Lawrence] Montefiore Med Ctr, Albert Einstein Coll Med, Bronx, NY 10467 USA. [Barto, Amy; McQuillen, Daniel P.] Tufts Univ, Sch Med, Lahey Clin Hosp, Burlington, MA USA. [Barto, Amy; McQuillen, Daniel P.] Tufts Univ, Sch Med, Med Ctr, Burlington, MA USA. [Borody, Thomas] Five Dock, Ctr Digest Dis, Sydney, NSW, Australia. [Giovanelli, Andrea; Stollman, Neil] Northern Gastroenterol Consultants Inc, Oakland, CA USA. [Gordon, Shelley] Calif Pacific Med Ctr, San Francisco, CA USA. [Gluck, Michael; Schwartz, Margot A.; Singh, Namita; Youngster, Ilan] Virginia Mason Med Ctr, Seattle, WA 98101 USA. [Hohmann, Elizabeth L.; Youngster, Ilan] Harvard Univ, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Hohmann, Elizabeth L.; Youngster, Ilan] Harvard Univ, Sch Med, Boston Childrens Hosp, Boston, MA USA. [Kao, Dina] Univ Alberta, Edmonton, AB, Canada. [Kao, John Y.; Rao, Krishna] Univ Michigan, Ann Arbor, MI 48109 USA. [Mellow, Mark] Integris Baptist Med Ctr, Oklahoma City, OK USA. [Ray, Arnab] Ochsner Clin Fdn, New Orleans, LA USA. [Suskind, David L.] Seattle Childrens Hosp, Seattle, WA USA. RP Kelly, CR (reprint author), Womens Med Collaborat, Brown Alpert Med Sch, Div Gastroenterol, 146 West River St, Providence, RI 02904 USA. EM colleen_r_kelly@brown.edu OI Singh, Namita/0000-0002-6782-4288; Youngster, Ilan/0000-0001-5233-1213 FU NIH [1R21DK093839-01A1, R21 AI091907] FX NIH 1R21DK093839-01A1; NIH R21 AI091907. NR 40 TC 116 Z9 122 U1 9 U2 38 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 EI 1572-0241 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD JUL PY 2014 VL 109 IS 7 BP 1065 EP 1071 DI 10.1038/ajg.2014.133 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AS7UC UT WOS:000344459100018 PM 24890442 ER PT J AU Murphy, DM Castellanos-Rizaldos, E Makrigiorgos, GM AF Murphy, Derek M. Castellanos-Rizaldos, Elena Makrigiorgos, G. Mike TI Enriching Mutant Sequences by Modulating the Denaturation Time during PCR SO CLINICAL CHEMISTRY LA English DT Letter ID COLD-PCR; MUTATION-DETECTION; ENRICHMENT C1 [Murphy, Derek M.; Castellanos-Rizaldos, Elena; Makrigiorgos, G. Mike] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dana Farber Canc Inst,Dept Radiat Oncol, Boston, MA 02115 USA. RP Makrigiorgos, GM (reprint author), Dana Farber Canc Inst, 75 Francis St, Boston, MA 02115 USA. EM mmakrigiorgos@partners.org FU NCI NIH HHS [R21CA-175542, R21CA-155615] NR 8 TC 0 Z9 0 U1 0 U2 3 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 EI 1530-8561 J9 CLIN CHEM JI Clin. Chem. PD JUL PY 2014 VL 60 IS 7 BP 1014 EP 1016 DI 10.1373/clinchem.2014.221465 PG 3 WC Medical Laboratory Technology SC Medical Laboratory Technology GA AT2QH UT WOS:000344778700020 PM 24799525 ER PT J AU Brown, HE Roffman, JL AF Brown, Hannah E. Roffman, Joshua L. TI Vitamin Supplementation in the Treatment of Schizophrenia SO CNS DRUGS LA English DT Article ID NEGATIVE SYMPTOMS; RISK-FACTOR; ADULT SCHIZOPHRENIA; BIRTH COHORT; D DEFICIENCY; HOMOCYSTEINE; FOLATE; PSYCHOSIS; ACID; METAANALYSES AB This article reviews the current literature addressing the treatment of schizophrenia with vitamin supplementation. It describes the important roles that vitamins play in normal metabolism, and reviews the evidence pertaining to vitamin deficiency and supplementation in patients with schizophrenia. There is mounting evidence suggesting that vitamin supplementation, in particular with folic acid, vitamin B12 and vitamin D, may be important in treatment within certain subgroups of patients. There is a need for larger randomized controlled trials, and further studies examining the incidence of schizophrenia in countries with poor prenatal care and malnutrition, as well as in countries that have adopted mandatory folic acid fortification of grain products, are recommended. C1 [Brown, Hannah E.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Roffman, Joshua L.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA 02129 USA. RP Roffman, JL (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat, CNY-149,149 13th St, Charlestown, MA 02129 USA. EM hebrown@partners.org; jroffman@partners.org FU Pamlab FX Dr. Roffman reports having received research support from Pamlab. No sources of funding were used to assist with the preparation of this manuscript. Dr. Brown has no conflicts of interest to report. NR 46 TC 3 Z9 4 U1 3 U2 15 PU ADIS INT LTD PI NORTHCOTE PA 5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND SN 1172-7047 EI 1179-1934 J9 CNS DRUGS JI CNS Drugs PD JUL PY 2014 VL 28 IS 7 BP 611 EP 622 DI 10.1007/s40263-014-0172-4 PG 12 WC Clinical Neurology; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA AT0FW UT WOS:000344613500003 PM 24846474 ER PT J AU Dilisio, MF AF Dilisio, Matthew F. TI Osteonecrosis Following Short-term, Low-dose Oral Corticosteroids: A Population-based Study of 24 Million Patients SO ORTHOPEDICS LA English DT Article ID INDUCED AVASCULAR NECROSIS; FEMORAL-HEAD; STEROID-THERAPY AB Although the association between chronic, high-dose corticosteroid use and osteonecrosis is well known, the incidence of osteonecrosis following short-term, lowdose steroid taper packs has never been reported across a large population. The goal of this study was to report the incidence and risk of osteonecrosis after methylprednisolone taper pack (MTP) prescriptions in a multicenter electronic medical records database. A commercially available software platform was used to evaluate the records of 24,533,880 patients to determine the incidence of osteonecrosis in patients who had received single or multiple MTP over a 12-year period. This was compared with the incidence of osteonecrosis in patients who had never been prescribed an MTP. Patients with a history of osteonecrosis or prior corticosteroid use were excluded from the study. A total of 98,390 patients were identified who had received a single MTP. One hundred thirty (0.132%; 95% confidence interval [CI], 0.176%-0.283%) of these patients were subsequently diagnosed with osteonecrosis. The incidence of osteonecrosis in patients who had been prescribed 2 or more MTPs was 0.230% (95% CI, 0.176%-0.283%). Compared with the 0.083% incidence of osteonecrosis in the control group that had never been prescribed an MTP, the relative risk of osteonecrosis after the prescription of a single MTP or multiple MTPs was 1.591 and 2.763, respectively, with a statistically significant difference between cohorts (P<.001). Short-term, low-dose oral corticosteroid administration may be associated with a low but statistically significant increased incidence of osteonecrosis when compared with patients who have never been prescribed a steroid product. C1 [Dilisio, Matthew F.] Summa Hlth Syst, Dept Orthopaed Surg, Akron, OH 44310 USA. [Dilisio, Matthew F.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthopaed Surg, Boston, MA USA. RP Dilisio, MF (reprint author), Summa Hlth Syst, Dept Orthopaed Surg, 444 N Main St, Akron, OH 44310 USA. EM dilisiom@gmail.com NR 19 TC 1 Z9 1 U1 0 U2 4 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0147-7447 EI 1938-2367 J9 ORTHOPEDICS JI Orthopedics PD JUL PY 2014 VL 37 IS 7 BP E631 EP E636 DI 10.3928/01477447-20140626-54 PG 6 WC Orthopedics SC Orthopedics GA AT5GL UT WOS:000344972000010 PM 24992058 ER PT J AU Mlinac, M Lees, F Stamm, K Saint, J Mulligan, J AF Mlinac, Michelle Lees, Faith Stamm, Karen Saint, Jill Mulligan, Jessica TI Maintaining Late Life Health Behaviors Comparing Clinician Rating and Self-reported Resilience SO TOPICS IN GERIATRIC REHABILITATION LA English DT Article DE gerontology; goal maintenance; health behavior; resilience ID SPINAL-CORD-INJURY; OLDER-ADULTS; PSYCHOLOGICAL RESILIENCE; POSITIVE EMOTIONS; MENTAL-HEALTH; INDIVIDUALS; ADVERSITY; BACK; AGES AB As part of the SENIOR Project II (Study of Exercise and Nutrition in Older Rhode Islanders), a study investigating strategies for maintaining health behaviors of exercise and nutrition in older adults, self-reported resilience was compared with the rating of a health behavior coach. Older adults who were meeting an exercise and/or fruit and vegetable consumption goal when the study began were contacted twice a year by a health coach to promote continued maintenance of these goals. At completion of the study, coaches assigned participants to 1 of 4 resilience trajectories. Self-reported resilience was then compared with the coaches' rating. Composite resilience scores on the Resilience Scale were not found to be related to ratings at particular time points. Only 1 of the 4 trajectories was significantly different from the others across time, providing limited support for coaches' ratings. There were significant differences among the trajectory groups on subscales of the Resilience Scale (Personal Competence, and Acceptance of Self and Life). It would be worthwhile to compare trajectories with other measures included in SENIOR Project II such as social support, depression, cognition, and functional status to identify any other differences among them. C1 [Mlinac, Michelle] VA Boston Healthcare Syst, Boston, MA 02131 USA. [Lees, Faith; Stamm, Karen; Saint, Jill; Mulligan, Jessica] Univ Rhode Isl, Program Gerontol, Kingston, RI 02881 USA. RP Mlinac, M (reprint author), VA Boston Healthcare Syst, 150 S Huntington Ave, Boston, MA 02131 USA. EM michelle.mlinac@va.gov NR 25 TC 3 Z9 3 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0882-7524 EI 1550-2414 J9 TOP GERIATR REHABIL JI Top. Geriatr. Rehabil. PD JUL-SEP PY 2014 VL 30 IS 3 BP 188 EP 194 DI 10.1097/TGR.0000000000000021 PG 7 WC Gerontology; Rehabilitation SC Geriatrics & Gerontology; Rehabilitation GA AT2AW UT WOS:000344734100007 ER PT J AU Goral, VN Au, SH Faris, RA Yuen, PK AF Goral, Vasiliy N. Au, Sam H. Faris, Ronald A. Yuen, Po Ki TI Microstructured multi-well plate for three-dimensional packed cell seeding and hepatocyte cell culture SO BIOMICROFLUIDICS LA English DT Article ID PERFUSION-CULTURE; LIVER CULTURE; 3D; TISSUE; ARRAY; BIOREACTOR; SYSTEM AB In this article, we present a microstructured multi-well plate for enabling three-dimensional (3D) high density seeding and culture of cells through the use of a standard laboratory centrifuge to promote and maintain 3D tissue-like cellular morphology and cell-specific functionality in vitro without the addition of animal derived or synthetic matrices or coagulants. Each well has microfeatures on the bottom that are comprised of a series of ditches/open microchannels. The dimensions of the microchannels promote and maintain 3D tissue-like cellular morphology and cell-specific functionality in vitro. After cell seeding with a standard pipette, the microstructured multi-well plates were centrifuged to tightly pack cells inside the ditches in order to enhance cell-cell interactions and induce formation of 3D cellular structures during cell culture. Cell-cell interactions were optimized based on cell packing by considering dimensions of the ditches/open microchannels, orientation of the microstructured multi-well plate during centrifugation, cell seeding density, and the centrifugal force and time. With the optimized cell packing conditions, we demonstrated that after 7 days of cell culture, primary human hepatocytes adhered tightly together to form cord-like structures that resembled 3D tissue-like cellular architecture. Importantly, cell membrane polarity was restored without the addition of animal derived or synthetic matrices or coagulants. (c) 2014 AIP Publishing LLC. C1 [Goral, Vasiliy N.; Faris, Ronald A.; Yuen, Po Ki] Corning Inc, Corning, NY 14831 USA. [Au, Sam H.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Charlestown, MA 02129 USA. RP Goral, VN (reprint author), Corning Inc, Corning, NY 14831 USA. EM goralvn@corning.com; yuenp@corning.com NR 27 TC 1 Z9 1 U1 1 U2 5 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 1932-1058 J9 BIOMICROFLUIDICS JI Biomicrofluidics PD JUL PY 2014 VL 8 IS 4 AR 046502 DI 10.1063/1.4892978 PG 7 WC Biochemical Research Methods; Biophysics; Nanoscience & Nanotechnology; Physics, Fluids & Plasmas SC Biochemistry & Molecular Biology; Biophysics; Science & Technology - Other Topics; Physics GA AS4EG UT WOS:000344225400027 PM 25379107 ER PT J AU Hockemeyer, K Janetopoulos, C Terekhov, A Hofmeister, W Vilgelm, A Costa, L Wikswo, JP Richmond, A AF Hockemeyer, K. Janetopoulos, C. Terekhov, A. Hofmeister, W. Vilgelm, A. Costa, Lino Wikswo, J. P. Richmond, A. TI Engineered three-dimensional microfluidic device for interrogating cell-cell interactions in the tumor microenvironment SO BIOMICROFLUIDICS LA English DT Article ID BREAST-CANCER CELLS; IN-VITRO; CULTURE MODEL; 3D; CHEMOKINES; METASTASIS; ANGIOGENESIS; FIBROBLASTS; MIGRATION; GROWTH AB Stromal cells in the tumor microenvironment play a key role in the metastatic properties of a tumor. It is recognized that cancer-associated fibroblasts (CAFs) and endothelial cells secrete factors capable of influencing tumor cell migration into the blood or lymphatic vessels. We developed a microfluidic device that can be used to image the interactions between stromal cells and tumor cell spheroids in a three dimensional (3D) microenvironment while enabling external control of interstitial flow at an interface, which supports endothelial cells. The apparatus couples a 200-mu m channel with a semicircular well to mimic the interface of a blood vessel with the stroma, and the design allows for visualization of the interactions of interstitial flow, endothelial cells, leukocytes, and fibroblasts with the tumor cells. We observed that normal tissue-associated fibroblasts (NAFs) contribute to the "single file" pattern of migration of tumor cells from the spheroid in the 3D microenvironment. In contrast, CAFs induce a rapid dispersion of tumor cells out of the spheroid with migration into the 3D matrix. Moreover, treatment of tumor spheroid cultures with the chemokine CXCL12 mimics the effect of the CAFs, resulting in similar patterns of dispersal of the tumor cells from the spheroid. Conversely, addition of CXCL12 to co-cultures of NAFs with tumor spheroids did not mimic the effects observed with CAF co-cultures, suggesting that NAFs produce factors that stabilize the tumor spheroids to reduce their migration in response to CXCL12. (C) 2014 AIP Publishing LLC. C1 [Hockemeyer, K.; Vilgelm, A.; Richmond, A.] US Dept Vet Affairs, Tennessee Valley Healthcare Syst, Nashville, TN 37212 USA. [Hockemeyer, K.; Janetopoulos, C.; Hofmeister, W.; Wikswo, J. P.; Richmond, A.] Vanderbilt Univ, Vanderbilt Inst Integrat Biosyst Res & Educ, Nashville, TN 37235 USA. [Hockemeyer, K.; Vilgelm, A.; Richmond, A.] Vanderbilt Univ, Sch Med, Dept Canc Biol, Nashville, TN 37232 USA. [Hockemeyer, K.; Janetopoulos, C.] Vanderbilt Univ, Dept Biol Sci, Nashville, TN 37232 USA. [Hockemeyer, K.; Janetopoulos, C.] Vanderbilt Univ, Dept Cell & Dev Biol, Nashville, TN 37232 USA. [Terekhov, A.; Hofmeister, W.; Costa, Lino] Univ Tennessee, Inst Space, Ctr Laser Applicat, Tullahoma, TN 37388 USA. [Hofmeister, W.; Costa, Lino] Univ Tennessee, Dept Mat Sci & Engn, Knoxville, TN 37996 USA. [Wikswo, J. P.] Vanderbilt Univ, Dept Biomed Engn, Nashville, TN 37235 USA. [Wikswo, J. P.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37235 USA. [Wikswo, J. P.] Vanderbilt Univ, Dept Phys & Astron, Nashville, TN 37235 USA. RP Richmond, A (reprint author), US Dept Vet Affairs, Tennessee Valley Healthcare Syst, Nashville, TN 37212 USA. EM ann.richmond@vanderbilt.edu FU TVHS; Department of Veterans Affairs through MERIT; Senior Research Career Scientist Awards; NIH [R01 CA34590, K12-CA90625]; Tennessee Higher Education Commission grant; Vanderbilt Discovery Award; [RO1GM080370] FX We thank Kevin Seale and the team in VIIBRE and SyBBURE for all their support, guidance, and encouragement. We are thankful to Hal Moses and Simon Hayward at Vanderbilt for the human CAF and NAF cultures isolated and cultured from breast tissue. We thank Melody Swartz at the Laboratory of Lymphatic and Cancer Bioengineering, EPFL Institute, Lausanne, Switzerland for her advice and guidance in the initial development of the devices. Thanks to Tammy Sobolik and Linda Horton who provided technical support and guidance. This work was supported by grants from the TVHS and the Department of Veterans Affairs through MERIT and Senior Research Career Scientist Awards to A. R.; NIH grants R01 CA34590 (A. R.) and K12-CA90625 (A. V.); Tennessee Higher Education Commission grant to the Center for Laser Applications at UT Space Institute (W. H.); RO1GM080370 (C.J.) and Vanderbilt Discovery Award (C.J. and W.H.). NR 38 TC 6 Z9 6 U1 6 U2 57 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 1932-1058 J9 BIOMICROFLUIDICS JI Biomicrofluidics PD JUL PY 2014 VL 8 IS 4 AR 044105 DI 10.1063/1.4890330 PG 12 WC Biochemical Research Methods; Biophysics; Nanoscience & Nanotechnology; Physics, Fluids & Plasmas SC Biochemistry & Molecular Biology; Biophysics; Science & Technology - Other Topics; Physics GA AS4EG UT WOS:000344225400010 PM 25379090 ER PT J AU Nicholas, PK Corless, IB Evans, LA AF Nicholas, Patrice K. Corless, Inge B. Evans, Linda A. TI Peripheral Neuropathy in HIV: An Analysis of Evidence-based Approaches SO JANAC-JOURNAL OF THE ASSOCIATION OF NURSES IN AIDS CARE LA English DT Article DE distal sensory peripheral neuropathy; distal sensory polyneuropathy; HIV; peripheral neuropathy; nursing ID DISTAL SENSORY POLYNEUROPATHY; PLACEBO-CONTROLLED TRIAL; ANTIRETROVIRAL THERAPY; SELF-CARE; MANAGEMENT; HIV/AIDS; ACUPUNCTURE; PREVALENCE; BEHAVIORS; INFECTION AB Peripheral neuropathy is a common and vexing symptom for people living with HIV infection (PL WH). Neuropathy occurs in several different syndromes and is identified in the literature as distal sensory polyneuropathy or distal sensory peripheral neuropathy. More recently, the HIV literature has focused on the syndrome as painful HIV-associated sensory neuropathy, addressing the symptom rather than the underlying pathophysiology. Assessment of neuropathy in PLWH is critical and must be incorporated into nursing practice for each visit. Neuropathy has been attributed to the direct effects of HIV, exposure to antiretroviral medications (particularly the nucleoside reverse transcriptase inhibitors), advanced immune suppression, and comorbid tuberculosis infection and exposure to antituberculosis medications. Evidence supports the importance of addressing neuropathy in PLWH with pharmacologic treatment regimens and complementary/alternative approaches. This paper examines the pathophysiology, evidence, and approaches to managing peripheral neuropathy. A case study has been included to illustrate a patient's experience with neuropathy symptoms. Copyright (C) 2014 Association of Nurses in AIDS Care C1 [Nicholas, Patrice K.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Nicholas, Patrice K.; Corless, Inge B.; Evans, Linda A.] Massachusetts Gen Hosp, Inst Hlth Profess, Sch Nursing, Boston, MA 02114 USA. RP Nicholas, PK (reprint author), Brigham & Womens Hosp, Boston, MA 02115 USA. NR 39 TC 0 Z9 0 U1 2 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1055-3290 EI 1552-6917 J9 J ASSOC NURSE AIDS C JI J. Assoc. Nurses Aids Care PD JUL-AUG PY 2014 VL 25 IS 4 BP 318 EP 329 DI 10.1016/j.jana.2014.01.002 PG 12 WC Nursing SC Nursing GA AS7EI UT WOS:000344419700006 PM 24698331 ER PT J AU Theodoroff, SM Schuette, A Griest, S Henry, JA AF Theodoroff, Sarah M. Schuette, Andrew Griest, Susan Henry, James A. TI Individual Patient Factors Associated with Effective Tinnitus Treatment SO JOURNAL OF THE AMERICAN ACADEMY OF AUDIOLOGY LA English DT Article DE Tinnitus; logistic regression; psychoacoustics; treatment ID RETRAINING THERAPY; PSYCHOMETRIC PROPERTIES; CLINICAL-TRIALS; MANAGEMENT; QUESTIONNAIRE; AMPLIFICATION; INVENTORY; DISTRESS; MASKING AB Background: Little is known about patient factors that might influence outcomes of tinnitus interventions. Determining such factors would offer insights into why some individuals benefit from tinnitus intervention whereas others do not. Purpose: The purpose of this study was to evaluate selected patient factors that may be associated with outcomes of tinnitus intervention. Factors studied include demographics, tinnitus characteristics, psychoacoustic tinnitus measures, audiometric data, and overall physical/emotional health status. Research Design: A retrospective analysis was performed on data obtained from a controlled clinical study that compared factors associated with tinnitus relief after tinnitus masking and tinnitus retraining therapy. Study Sample: A total of 126 military veterans participated in this controlled clinical study. Of these, 89 completed outcome measures at both baseline and 12 mo and were included in the present analysis. Data Collection and Analysis: A "responder" to intervention was identified as having a decrease (improvement) of 20 or more points on the Tinnitus Handicap Inventory between baseline and 12 mo. A "nonresponder" did not achieve a 20-point improvement on the Tinnitus Handicap Inventory. Individual patient factors were examined using independent t-tests or chi(2) analysis. A logistic regression model was used to determine how well each factor predicted treatment outcome (responder or nonresponder) while controlling for each of the other factors. Results: Five patient factors were significantly different (p <= 0.05) between responders and nonresponders. Responders tended to (1) be younger in age; (2) have better low-frequency hearing sensitivity; (3) have greater problems with overall hearing; (4) be more likely to have tinnitus for shorter durations; and (5) perceive their tinnitus to be located "in the head" versus "in the ears." A logistic regression was then performed to determine how well each factor predicted the treatment outcome (responder versus nonresponder) while controlling for each of the other factors. Results from the logistic regression revealed two of the five factors, localization of tinnitus and self-report of hearing problems, to be statistically significant. Conclusions: Examining the association of individual patient factors to a specific tinnitus intervention yielded several significant findings. Although these findings are not definitive, they reveal the capability that exists to perform these kinds of analyses to investigate relationships between individual patient characteristics and outcomes of intervention for tinnitus. Prospective research using systematic approaches is needed to identify these relationships that would contribute toward the ability to differentially predict outcomes of various tinnitus interventions. Obtaining this information would lead to more targeted therapy and ultimately more effective intervention. C1 [Theodoroff, Sarah M.; Griest, Susan; Henry, James A.] Natl Ctr Rehabilitat Auditory Res, VA Med Ctr, Vet Affairs VA Rehabil Res & Dev Serv, Portland, OR 97207 USA. [Theodoroff, Sarah M.; Griest, Susan; Henry, James A.] Oregon Hlth & Sci Univ, Dept Otolaryngol Head & Neck Surg, Portland, OR 97201 USA. [Schuette, Andrew] Washington Univ, Div Audiol, St Louis, MO USA. RP Theodoroff, SM (reprint author), Natl Ctr Rehabilitat Auditory Res, Portland VA Med Ctr, 3710 SW US Vet Hosp Rd, Portland, OR 97207 USA. EM sarah.theodoroff@va.gov FU National Institutes of Health National Institute on Deafness and Other Communication Disorders T35 Research Training Grant [DC008764]; VA Rehabilitation Research and Development Service [C2887R, C3214R, F7070S]; National Center for Rehabilitative Auditory Research at the Portland VA Medical Center FX Support for this project was provided by the National Institutes of Health National Institute on Deafness and Other Communication Disorders T35 Research Training Grant (DC008764), and VA Rehabilitation Research and Development Service (C2887R, C3214R, and F7070S). Additional support was provided by the National Center for Rehabilitative Auditory Research at the Portland VA Medical Center. NR 56 TC 0 Z9 0 U1 1 U2 5 PU AMER ACAD AUDIOLOGY PI RESTON PA 11730 PLAZA DR, STE 300, RESTON, VA 20190 USA SN 1050-0545 EI 2157-3107 J9 J AM ACAD AUDIOL JI J. Am. Acad. Audiol. PD JUL-AUG PY 2014 VL 25 IS 7 BP 631 EP 643 DI 10.3766/jaaa.25.7.2 PG 13 WC Audiology & Speech-Language Pathology; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Otorhinolaryngology GA AS0DY UT WOS:000343949700002 PM 25365366 ER PT J AU Batchelor, TT Gerstner, ER Emblem, KE Duda, DG Kalpathy-Cramer, J Snuderl, M Ancukiewicz, M Polaskova, P Pinho, MC Jennings, D Plotkin, SR Chi, AS Eichler, AF Dietrich, J Hochberg, FH Lu-Emerson, C Iafrate, AJ Ivy, SP Rosen, B Loeffler, JS Wen, PY Sorensen, AG Jain, RK AF Batchelor, Tracy T. Gerstner, Elizabeth R. Emblem, Kyrre E. Duda, Dan G. Kalpathy-Cramer, Jayashree Snuderl, Matija Ancukiewicz, Marek Polaskova, Pavlina Pinho, Marco C. Jennings, Dominique Plotkin, Scott R. Chi, Andrew S. Eichler, April F. Dietrich, Jorg Hochberg, Fred H. Lu-Emerson, Christine Iafrate, A. John Ivy, S. Percy Rosen, Bruce Loeffler, Jay S. Wen, Patrick Y. Sorensen, A. Greg Jain, Rakesh K. TI INCREASED PERFUSION DUE TO VASCULAR NORMALIZATION IMPROVES OXYGENATION AND SURVIVAL IN GLIOBLASTOMA PATIENTS TREATED WITH CEDIRANIB WITH OR WITHOUT CHEMORADIATION SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 20th International Conference on Brain Tumor Research and Therapy CY JUL 20-22, 2014 CL CA C1 [Batchelor, Tracy T.; Gerstner, Elizabeth R.; Emblem, Kyrre E.; Duda, Dan G.; Kalpathy-Cramer, Jayashree; Snuderl, Matija; Ancukiewicz, Marek; Polaskova, Pavlina; Pinho, Marco C.; Jennings, Dominique; Plotkin, Scott R.; Chi, Andrew S.; Eichler, April F.; Dietrich, Jorg; Hochberg, Fred H.; Lu-Emerson, Christine; Iafrate, A. John; Ivy, S. Percy; Rosen, Bruce; Loeffler, Jay S.; Wen, Patrick Y.; Sorensen, A. Greg; Jain, Rakesh K.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. OI Snuderl, Matija/0000-0003-0752-0917 NR 0 TC 0 Z9 0 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JUL PY 2014 VL 16 SU 3 DI 10.1093/neuonc/nou206.42 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA AS4IB UT WOS:000344236400043 ER PT J AU Kieran, MW Yao, X Macy, M Leary, S Cohen, K MacDonald, T Allen, J Boklan, J Smith, A Nazemi, K Gore, L Trippett, T DiRenzo, J Narendran, A Perentesis, J Prabhu, S Pinches, N Robison, N Manley, P Chi, S AF Kieran, Mark W. Yao, X. Macy, M. Leary, S. Cohen, K. MacDonald, T. Allen, J. Boklan, J. Smith, A. Nazemi, K. Gore, L. Trippett, T. DiRenzo, J. Narendran, A. Perentesis, J. Prabhu, S. Pinches, N. Robison, N. Manley, P. Chi, S. TI FINAL RESULTS OF A PROSPECTIVE MULTI-INSTITUTIONAL PHASE II STUDY OF EVEROLIMUS (RAD001), AN MTOR INHIBITOR, IN PEDIATRIC PATIENTS WITH RECURRENT OR PROGRESSIVE LOW-GRADE GLIOMA. A POETIC CONSORTIUM TRIAL SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 20th International Conference on Brain Tumor Research and Therapy CY JUL 20-22, 2014 CL CA C1 Dana Farber Canc Inst, Boston, MA USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JUL PY 2014 VL 16 SU 3 DI 10.1093/neuonc/nou208.15 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA AS4IB UT WOS:000344236400096 ER PT J AU Reardon, DA Gokhale, P Ligon, K Liao, XY Rodig, S Zhou, J Win, L Hodi, FS Kohl, NE Freeman, G AF Reardon, David A. Gokhale, Praful Ligon, Keith Liao, Xiaoyun Rodig, Scott Zhou, Jun Win, Lei Hodi, Frank S. Kohl, Nancy E. Freeman, Gordon TI IMMUNE CHECKPOINT BLOCKADE FOR GLIOBLASTOMA: PRECLINICAL ACTIVITY OF SINGLE AGENT AND COMBINATORIAL THERAPY SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 20th International Conference on Brain Tumor Research and Therapy CY JUL 20-22, 2014 CL CA C1 [Reardon, David A.; Gokhale, Praful; Ligon, Keith; Liao, Xiaoyun; Rodig, Scott; Zhou, Jun; Win, Lei; Hodi, Frank S.; Kohl, Nancy E.; Freeman, Gordon] Dana Farber Canc Inst, Boston, MA 02215 USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JUL PY 2014 VL 16 SU 3 DI 10.1093/neuonc/nou206.40 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA AS4IB UT WOS:000344236400041 ER PT J AU Wen, PY Wen, PY Yung, WKA Mellinghoff, IK Ramkissoon, S Alexander, B Rinne, M Colman, H Omuro, AM DeAngelis, LM Gilbert, MR DeGroot, J Cloughesy, TF Lee, EQ Nayak, L Chi, AS Batchelor, T Chang, SM Prados, MD Reardon, DA Ligon, KL AF Wen, Patrick Y. Wen, Patrick Y. Yung, W. K. Alfred Mellinghoff, Ingo K. Ramkissoon, Shakti Alexander, Brian Rinne, Mikael Colman, Howard Omuro, Antonio M. DeAngelis, Lisa M. Gilbert, Mark R. DeGroot, John Cloughesy, Timothy F. Lee, Eudocia Q. Nayak, Lakshmi Chi, Andrew S. Batchelor, Tracy Chang, Susan M. Prados, Michael D. Reardon, David A. Ligon, Keith L. TI PHASE II TRIAL OF THE PHOSPHATIDYINOSITOL-3 KINASE (PI3K) INHIBITOR BUPARLISIB (BKM120) IN RECURRENT GLIOBLASTOMA CONDUCTED BY THE IVY FOUNDATION EARLY PHASE CLINICAL TRIALS CONSORTIUM SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 20th International Conference on Brain Tumor Research and Therapy CY JUL 20-22, 2014 CL CA C1 [Wen, Patrick Y.; Wen, Patrick Y.; Yung, W. K. Alfred; Mellinghoff, Ingo K.; Ramkissoon, Shakti; Alexander, Brian; Rinne, Mikael; Colman, Howard; Omuro, Antonio M.; DeAngelis, Lisa M.; Gilbert, Mark R.; DeGroot, John; Cloughesy, Timothy F.; Lee, Eudocia Q.; Nayak, Lakshmi; Chi, Andrew S.; Batchelor, Tracy; Chang, Susan M.; Prados, Michael D.; Reardon, David A.; Ligon, Keith L.] Dana Farber Canc Inst, Boston, MA USA. RI Gilbert, Mark/J-7494-2016 OI Gilbert, Mark/0000-0003-2556-9722 NR 0 TC 0 Z9 0 U1 0 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JUL PY 2014 VL 16 SU 3 DI 10.1093/neuonc/nou209.20 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA AS4IB UT WOS:000344236400170 ER PT J AU Gulur, P Williams, L Chaudhary, S Koury, K Jaff, M AF Gulur, Padma Williams, Libby Chaudhary, Sanjay Koury, Katharine Jaff, Michael TI Opioid Tolerance - A Predictor of Increased Length of Stay and Higher Readmission Rates SO PAIN PHYSICIAN LA English DT Article DE Opioid tolerance; opioid tolerant patient population; opioid tolerant patients; readmission rates; length of stay ID PAIN AB The increasing use of opioids to manage pain in the United States over the last decade has resulted in a subset of our population developing opioid tolerance. While the management of opioid tolerant patients during acute episodes of care is well known to be a challenge amongst health care providers, there is little in the literature that has studied opioid tolerance as a predictor of outcomes. We conducted a review on all admissions to Massachusetts General Hospital over a period of 6 months, from January 2013 to June 2013, and identified opioid tolerant patients at admission using the FDA definition of opioid tolerance. To compare risk adjusted groups, we placed opioid tolerant patients and control patients into groups determined by expected length of stay of less than 2 days, 2 to 5 days, 5 to 10 days, and greater than 10 days. Opioid tolerant patients were then compared to the control for outcomes measures including observed length of stay and readmission rates. Our results show that all opioid tolerant patients have a significantly longer length of stay and a greater 30 day all cause readmission rate than the control group (P < 0.01). This trend was found in the first 3 risk adjusted groups, but not in the fourth group where expected length of stay was greater than 10 days. The opioid tolerant population is at risk given the poorer outcomes and higher health care costs associated with their care. It is imperative that we identify opportunities for improvement and delineate specific pathways for the care of these patients. C1 [Gulur, Padma; Williams, Libby; Chaudhary, Sanjay; Koury, Katharine; Jaff, Michael] Massachusetts Gen Hosp, Inpatient Pain Serv, Boston, MA 02114 USA. [Gulur, Padma; Williams, Libby; Chaudhary, Sanjay; Koury, Katharine; Jaff, Michael] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Gulur, P (reprint author), Massachusetts Gen Hosp, Inpatient Pain Serv, 15 Parkman St, Boston, MA 02114 USA. EM pgulur@yahoo.com NR 9 TC 5 Z9 5 U1 1 U2 3 PU AM SOC INTERVENTIONAL PAIN PHYSICIANS PI PADUCAH PA 81 LAKEVIEW DR, PADUCAH, KY 42001 USA SN 1533-3159 J9 PAIN PHYSICIAN JI Pain Physician PD JUL-AUG PY 2014 VL 17 IS 4 BP E503 EP E507 PG 5 WC Anesthesiology; Clinical Neurology SC Anesthesiology; Neurosciences & Neurology GA AS7FB UT WOS:000344421500014 PM 25054400 ER PT J AU Manchikanti, L Candido, KD Kaye, AD Boswell, MV Benyamin, RM Falco, FJE Gharibo, CG Hirsch, JA AF Manchikanti, Laxmaiah Candido, Kenneth D. Kaye, Alan D. Boswell, Mark V. Benyamin, Ramsin M. Falco, Frank J. E. Gharibo, Christopher G. Hirsch, Joshua A. TI Randomized Trial of Epidural Injections for Spinal Stenosis Published in The New England Journal of Medicine: Further Confusion Without Clarification SO PAIN PHYSICIAN LA English DT Review DE Chronic low back pain; central spinal stenosis; epidural injections; local anesthetics; steroids; randomized trials; outcomes assessment ID LOW-BACK-PAIN; ESTIMATE REIMBURSEMENT AMOUNTS; INTRADISCAL ELECTROTHERMAL THERAPY; CORRECTNESS TRUMPING EXPERTISE; CLINICAL-PRACTICE GUIDELINES; TYPE-2 DIABETES-MELLITUS; OUTCOMES-RESEARCH-TRIAL; RESTLESS LEGS SYNDROME; STEROID INJECTIONS; DOUBLE-BLIND AB Randomized controlled trials are considered the hallmark of evidence-based medicine. This conveys the idea that up-to-date evidence applied consistently in clinical practice, in combination with clinicians' individual expertise and patients own preference/expectations are enjoined to achieve the best possible outcome. Since its inception in 1990s, evidence-based medicine has evolved in conjunction with numerous changes in the healthcare environment. However, the benefits of evidence-based medicine have not materialized for spinal pain including surgical interventions. Consequently, the debate continues on the efficacy and medical necessity of multiple interventions provided in managing spinal pain. Friedly et al published a randomized controlled trial of epidural glucocorticoid injections for spinal stenosis in the July 2014 edition of the highly prestigious New England Journal of Medicine,. This was accompanied by an editorial from Andersson. This manuscript provided significant sensationalism for the media and confusion for the spine community. This randomized trial of epidural glucocorticoid injections for spinal stenosis and accompanying editorial concluded that epidural injections of glucocorticoids plus lidocaine offered minimal or no short-term benefit as compared with epidural injections of lidocaine alone, with the editorial emphasizing proceeding directly to surgical intervention. In addition media statements by the authors also emphasized the idea that exercise or surgery might be better options for patients suffereing from narrowing of the spinal canal. The interventional pain management community believes that there are severe limitations to this study, manuscript, and accompanying editorial. The design, inclusion criteria, outcomes assessment, analysis of data and interpretation, and conclusions of this trial point to the fact that this highly sophisticated and much publicized randomized trial may not be appropriate and lead to misinformation. The design of the trial was inappropriate with failure to include existing randomized trials, with inclusion criteria that did not incorporate conservative management, or caudal epidural injections. Simultaneously, acute pain patients were included, multilevel stenosis and various other factors were not identified. The interventions included lumbar interlaminar and transforaminal epidural injections with highly variable volumes of medication being injected per patient. Outcomes assessment was not optimal with assessment of the patients at 3 and 6 weeks for a procedure which provides on average 3 weeks of relief and utilizing an instrument which is more appropriately utilized in acute and subacute low back pain. Analysis of the data was hampered by inadequate subgroup analysis leading to inappropriate interpretation. Based on the available data epidural local anesthetic with steroids was clearly superior at 3 weeks and potentially at 6 weeks. Further, both treatments were effective considering the baseline to 3 week and 6 week assessment, appropriate subgroup analysis seems to have yielded significant superiority for interlaminar epidural injections compared to transforaminal epidural injections with local anesthetic with or without steroids specifically with proportion of patients achieving greater than 50% improvement at 3 and 6 week levels. This critical assessment shows that this study suffers from a challenging design, was premised on the exclusion of available high-quality literature, and had inadequate duration of follow-up for an interventional technique with poor assessment criteria and reporting. Finally the analysis and interpretation of data has led to inaccurate and inappropriate conclusions which we do not believe is based on scientific evidence. C1 [Manchikanti, Laxmaiah] Pain Management Ctr Paducah, Paducah, KY USA. [Candido, Kenneth D.] Advocate Illinois Masonic Med Ctr, Chicago, IL USA. [Candido, Kenneth D.] Univ Illinois, Coll Med, Chicago, IL USA. [Kaye, Alan D.] LSU Hlth Sci Ctr, New Orleans, LA USA. [Boswell, Mark V.] Univ Louisville, Dept Anesthesiol & Perioperat Med, Louisville, KY 40292 USA. [Benyamin, Ramsin M.] Millennium Pain Ctr, Bloomington, IL USA. [Benyamin, Ramsin M.] Univ Illinois, Urbana, IL USA. [Falco, Frank J. E.] Mid Atlantic Spine & Pain Phys, Newark, DE USA. [Falco, Frank J. E.] Temple Univ Hosp & Med Sch, Philadelphia, PA 19140 USA. [Gharibo, Christopher G.] NYU Sch Med, NYU Langone Hosp Joint Dis, New York, NY USA. [Hirsch, Joshua A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hirsch, Joshua A.] Harvard Univ, Sch Med, Boston, MA USA. RP Manchikanti, L (reprint author), 2831 Lone Oak Rd, Paducah, KY 42003 USA. EM drlm@thepainmd.com NR 158 TC 26 Z9 27 U1 1 U2 6 PU AM SOC INTERVENTIONAL PAIN PHYSICIANS PI PADUCAH PA 81 LAKEVIEW DR, PADUCAH, KY 42001 USA SN 1533-3159 J9 PAIN PHYSICIAN JI Pain Physician PD JUL-AUG PY 2014 VL 17 IS 4 BP E475 EP E488 PG 14 WC Anesthesiology; Clinical Neurology SC Anesthesiology; Neurosciences & Neurology GA AS7FB UT WOS:000344421500012 PM 25054398 ER PT J AU Manchikanti, L Candido, KD Singh, V Gharibo, CG Boswell, MV Benyamin, RM Falco, FJE Grider, JS Diwan, S Hirsch, JA AF Manchikanti, Laxmaiah Candido, Kenneth D. Singh, Vijay Gharibo, Christopher G. Boswell, Mark V. Benyamin, Ramsin M. Falco, Frank J. E. Grider, Jay S. Diwan, Sudhir Hirsch, Joshua A. TI Epidural Steroid Warning Controversy Still Dogging FDA SO PAIN PHYSICIAN LA English DT Review DE Chronic pain; epidural injections; epidural steroids; local anesthetic; radicular artery; complication ID CERVICAL TRANSFORAMINAL INJECTION; ACTIVE-CONTROL TRIAL; 2-YEAR FOLLOW-UP; LOW-BACK-PAIN; RANDOMIZED CONTROLLED-TRIAL; LUMBAR RADICULAR PAIN; NERVE ROOT BLOCKS; OF-THE-LITERATURE; DIGITAL-SUBTRACTION-ANGIOGRAPHY; MANAGING CHRONIC PAIN AB On April 23, 2014, the Food and Drug Administration (FDA) issued a letter of warning that injection of corticosteroids into the epidural space of the spine may result in rare, but serious adverse events, including "loss of vision, stroke, paralysis, and death." The advisory also advocated that patients should discuss the benefits and risks of epidural corticosteroid injections with their health care professionals, along with the benefits and risks associated with other possible treatments. In addition, the FDA stated that the effectiveness and safety of the corticosteroids for epidural use have not been established, and the FDA has not approved corticosteroids for such use. To raise awareness of the risks of epidural corticosteroid injections in the medical community, the FDA's Safe Use Initiative convened a panel of experts including pain management experts to help define the techniques for such injections with the aim of reducing preventable harm. The panel was unable to reach an agreement on 20 proposed items related to technical aspects of performing epidural injections. Subsequently, the FDA issued the above referenced warning and a notice that a panel will be convened in November 2014. This review assesses the inaccuracies of the warning and critically analyzes the available literature. The literature has been assessed in reference to alternate techniques and an understanding of the risk factors when performing transforaminal epidural injections in the cervical, thoracic, and lumbar regions, ultimately resulting in improved safety. The results of this review show the efficacy of epidural injections, with or without steroids, in a multitude of spinal ailments utilizing caudal, cervical, thoracic, and lumbar interlaminar approaches as well as lumbar transforaminal epidural injections. The evidence also shows the superiority of steroids in managing lumbar disc herniation utilizing caudal and lumbar interlaminar approaches without any significant difference as compared to transforaminal approaches, either with local anesthetic alone or local anesthetic and steroids combined. In conclusion, the authors request that the FDA modify the warning based on the evidence. C1 [Manchikanti, Laxmaiah] Pain Management Ctr Paducah, Paducah, KY USA. [Manchikanti, Laxmaiah] Univ Louisville, Louisville, KY 40292 USA. [Candido, Kenneth D.] Advocate Illinois Masonic Med Ctr, Chicago, IL USA. [Candido, Kenneth D.] Univ Illinois, Coll Med, Chicago, IL USA. [Singh, Vijay] Spine Pain Diagnost Associates, Niagara, WI USA. [Gharibo, Christopher G.] NYU, Sch Med, Langone Hosp Joint Dis, New York, NY USA. [Boswell, Mark V.] Univ Louisville, Dept Anesthesiol & Perioperat Med, Louisville, KY 40292 USA. [Benyamin, Ramsin M.] Millennium Pain Ctr, Bloomington, IL USA. [Benyamin, Ramsin M.] Univ Illinois, Urbana, IL USA. [Falco, Frank J. E.] Mid Atlantic Spine & Pain Phys, Newark, DE USA. [Falco, Frank J. E.] Temple Univ Hosp & Med Sch, Philadelphia, PA 19140 USA. [Grider, Jay S.] Univ Kentucky, UK Healthcare Pain Serv, Lexington, KY USA. [Diwan, Sudhir] Manhattan Spine & Pain Med, New York, NY USA. [Hirsch, Joshua A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Manchikanti, L (reprint author), 2831 Lone Oak Rd, Paducah, KY 42003 USA. EM drlm@thepainmd.com NR 270 TC 22 Z9 24 U1 7 U2 13 PU AM SOC INTERVENTIONAL PAIN PHYSICIANS PI PADUCAH PA 81 LAKEVIEW DR, PADUCAH, KY 42001 USA SN 1533-3159 J9 PAIN PHYSICIAN JI Pain Physician PD JUL-AUG PY 2014 VL 17 IS 4 BP E451 EP E474 PG 24 WC Anesthesiology; Clinical Neurology SC Anesthesiology; Neurosciences & Neurology GA AS7FB UT WOS:000344421500011 PM 25054397 ER PT J AU Manchikanti, L Atluri, S Candido, KD Boswell, MV Simopoulos, TT Grider, JS Falco, FJE Hirsch, JA AF Manchikanti, Laxmaiah Atluri, Sairam Candido, Kenneth D. Boswell, Mark V. Simopoulos, Thomas T. Grider, Jay S. Falco, Frank J. E. Hirsch, Joshua A. TI Zohydro (TM) Approval by Food and Drug Administration: Controversial or Frightening? SO PAIN PHYSICIAN LA English DT Review DE Chronic non-cancer pain; Food and Drug Administration; opioids; Zohydro; misuse; tolerance; addiction; dependency; medical necessity ID CHRONIC NONCANCER PAIN; VITAL SIGNS OVERDOSES; UNITED-STATES; OPIOID ANALGESICS; HEALTH-STATUS; OLDER-ADULTS; DEATHS; ABUSE; BACK; FDA AB The actions and regulations of the Food and Drug Administration (FDA) are crucial to the entire population of the US, specifically the public who take a multitude of drugs and providers who prescribe drugs and devices. Further, the FDA is relevant to investors, specifically in regards to biotech and pharmaceutical companies involved in developing new drugs. The FDA has been criticized for a lack of independence on the one hand and excessive regulatory and expanding authority without evidence and consistency of the actions on the other hand. The FDA approved a single-entity, long-acting, hydrocodone product (Zohydro (TM), Zogenix, San Diego, CA) on October 25, 2013, against the recommendation of the FDA's own appointed scientific advisory panel, which voted 11 to 2 against the approval of Zohydro. Subsequent to the approval, multiple consumer safety organizations, health care agencies, addiction treatment providers, professional organizations, and other groups on the frontline of the opioid addiction epidemic have expressed concern. In addition, the US Congress and various state attorneys general raised serious concerns about the approval of Zohydro, which is highly addictive and may enhance the opioid addiction epidemic. Supporters of Zohydro contend that it is necessary and essential to manage chronic pain and improve functional status with no additional risk. Over the past 15 years, prescriptions for opioids have skyrocketed with the United States consuming more than 84% of the global oxycodone and more than 99% of the hydrocodone supply. The sharp increase in opioid prescribing has led to parallel increases in opioid addiction and overdose deaths, surpassing motor vehicle injuries in the US. Recent studies assessing the trends of medical use and misuse of opioid analgesics from 2000 to 2011 have concluded that the present trend of the continued increase in the medical use of opioid analgesics appears to contribute to increasing misuse, resulting in multiple health consequences, despite numerous regulations enforced by multiple organizations. The approval of Zohydro and its defense from the FDA were based on a misunderstanding of the prevalence of chronic severe disabling pain. Based on inaccurate data from the Institute of Medicine, in part caused by conflicts of interest, 100 million persons have been described to suffer from severe pain - the correct number is 22.6 million. This manuscript analyzes 3 important principles of drug approval and utilization based on safety, efficacy, and medical necessity. Based on the limited literature that the authors were able to review including that which was submitted to the FDA by the manufacturers, it appears the safety, efficacy, and medical necessity were not demonstrated. In fact, the study submitted to the FDA showed a 50% pain improvement in only 48% of the patients in the treatment group and 21% of the patients in the placebo group at 85 day follow-up. This is a statistically significant result but its clinical relevance is unknown. The FDA approval decision occurring against the backdrop of the advisory panel recommendation is concerning and may result in serious consequences in the future. C1 [Manchikanti, Laxmaiah] Pain Management Ctr Paducah, Paducah, KY USA. [Manchikanti, Laxmaiah] Univ Louisville, Louisville, KY 40292 USA. [Atluri, Sairam] Tri State Spine Care Inst, Cincinnati, OH USA. [Candido, Kenneth D.] Advocate Illinois Mason Med Ctr, Chicago, IL USA. [Candido, Kenneth D.] Univ Illinois, Coll Med, Chicago, IL USA. [Boswell, Mark V.] Univ Louisville, Dept Anesthesiol & Perioperat Med, Louisville, KY 40292 USA. [Simopoulos, Thomas T.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Grider, Jay S.] Univ Kentucky, UK Healthcare Pain Serv, Lexington, KY USA. [Falco, Frank J. E.] Mid Atlantic Spine & Pain Phys, Newark, DE USA. [Falco, Frank J. E.] Temple Univ Hosp & Med Sch, Philadelphia, PA 19140 USA. [Hirsch, Joshua A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hirsch, Joshua A.] Harvard Univ, Sch Med, Boston, MA USA. RP Manchikanti, L (reprint author), 2831 Lone Oak Rd, Paducah, KY 42003 USA. EM drlm@thepainmd.com NR 72 TC 22 Z9 22 U1 1 U2 7 PU AM SOC INTERVENTIONAL PAIN PHYSICIANS PI PADUCAH PA 81 LAKEVIEW DR, PADUCAH, KY 42001 USA SN 1533-3159 J9 PAIN PHYSICIAN JI Pain Physician PD JUL-AUG PY 2014 VL 17 IS 4 BP E437 EP E450 PG 14 WC Anesthesiology; Clinical Neurology SC Anesthesiology; Neurosciences & Neurology GA AS7FB UT WOS:000344421500010 PM 25054396 ER PT J AU Williams, BR Blizard, TI Goode, PS Harada, CN Woodby, LL Burgio, KL Sims, RV AF Williams, Beverly R. Blizard, Tracie I. Goode, Patricia S. Harada, Caroline N. Woodby, Lesa L. Burgio, Kathryn L. Sims, Richard V. TI Exploring the affective dimension of the life review process: Facilitators' interactional strategies for fostering personhood and social value among older adults with early dementia SO DEMENTIA-INTERNATIONAL JOURNAL OF SOCIAL RESEARCH AND PRACTICE LA English DT Article DE dementia; emotions; identity; life review; older adults ID EARLY-STAGE DEMENTIA; OF-THE-LITERATURE; ALZHEIMERS-DISEASE; COMMUNICATION STRATEGIES; PSYCHOSOCIAL INTERVENTIONS; SUBJECTIVE EXPERIENCES; PEOPLE; CARE; SELF; IDENTITY AB We employed an auto-ethnography approach to explore the affective dimension of life review sessions with community-dwelling older military veterans with minor cognitive impairment (MCI) and early dementia. Using researchers' analytic memos, we identified facilitators' interactional strategies that fostered the participant's sense of personal identity, dignity and social self-worth. Interaction among participant, caregiver, and facilitators evoked a range of emotional responses, offering a window into the affective world of MCI and early dementia. Positive emotional responses outnumbered negative emotional responses by a ratio of two-to-one in the life review sessions; however, negative emotions were more revelatory of current struggles with declines in health and function. Facilitators utilized two interactional strategies, in particular, to foster personhood and social value of participants: focusing on the participant and creating an empathic connection with the participant. Further work is needed to understand the role of emotions in research interactions and to examine the psychosocial mechanisms through which positive affect functions in promoting identity, personhood and social value among persons with MCI and early dementia. C1 [Williams, Beverly R.; Goode, Patricia S.; Harada, Caroline N.; Woodby, Lesa L.; Burgio, Kathryn L.; Sims, Richard V.] Birmingham Atlanta Geriatr Res Clin & Educ Ctr, Birmingham, AL USA. [Williams, Beverly R.; Blizard, Tracie I.; Goode, Patricia S.; Harada, Caroline N.; Woodby, Lesa L.; Burgio, Kathryn L.; Sims, Richard V.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [Williams, Beverly R.; Woodby, Lesa L.; Sims, Richard V.] Univ Alabama Birmingham, Div Gerontol Geriatr & Palliat Care, Birmingham, AL 35294 USA. [Williams, Beverly R.; Goode, Patricia S.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Harada, Caroline N.; Burgio, Kathryn L.] Univ Alabama Birmingham, Birmingham, AL 35294 USA. RP Williams, BR (reprint author), Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. EM Bwilliams@aging.uab.edu NR 117 TC 1 Z9 1 U1 6 U2 26 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1471-3012 EI 1741-2684 J9 DEMENTIA-LONDON JI Dement.-Int. J. soc. Res. Pract. PD JUL PY 2014 VL 13 IS 4 BP 498 EP 524 DI 10.1177/1471301213478811 PG 27 WC Gerontology SC Geriatrics & Gerontology GA AR7MP UT WOS:000343764200005 PM 24339069 ER PT J AU DePasse, JW Yost, A Carroll, R Santorino, D Ippolito, A Chu, Z Olson, KR AF DePasse, Jacqueline W. Yost, Allison Carroll, Ryan Santorino, Data Ippolito, Andrea Chu, Zen Olson, Kristian R. TI LESS NOISE, MORE HACKING: HOW TO DEPLOY PRINCIPLES FROM MIT'S HACKING MEDICINE TO ACCELERATE HEALTH CARE SO INTERNATIONAL JOURNAL OF TECHNOLOGY ASSESSMENT IN HEALTH CARE LA English DT Editorial Material DE Innovation; Health care; Technology; Hackathon; Medicine AB Medical technology offers enormous potential for scalable medicine-to improve the quality and access in health care while simultaneously reducing cost. However, current medical device innovation within companies often only offers incremental advances on existing products, or originates from engineers with limited knowledge of the clinical complexities. We describe how the Hacking Medicine Initiative, based at Massachusetts Institute of Technology has developed an innovative "healthcare hackathon" approach, bringing diverse teams together to rapidly validate clinical needs and develop solutions. Hackathons are based on three core principles; emphasis on a problem-based approach, cross-pollination of disciplines, and "pivoting" on or rapidly iterating on ideas. Hackathons also offer enormous potential for innovation in global health by focusing on local needs and resources as well as addressing feasibility and cultural contextualization. Although relatively new, the success of this approach is clear, as evidenced by the development of successful startup companies, pioneering product design, and the incorporation of creative people from outside traditional life science backgrounds who are working with clinicians and other scientists to create transformative innovation in health care. C1 [DePasse, Jacqueline W.] Massachusetts Gen Hosp, Dept Internal Med, Boston, MA 02114 USA. [Yost, Allison; Ippolito, Andrea; Chu, Zen] MIT, Cambridge, MA 02139 USA. [Carroll, Ryan] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Pediat Crit Care Med, Cambridge, MA 02138 USA. [Santorino, Data] Mbarara Univ Sci & Technol, Mbarara, Uganda. [Olson, Kristian R.] Massachusetts Gen Hosp, Ctr Global Hlth, Consortium Affordable Med Technol, Boston, MA 02114 USA. RP DePasse, JW (reprint author), Massachusetts Gen Hosp, Dept Internal Med, Boston, MA 02114 USA. EM jwdepasse@partners.org NR 18 TC 3 Z9 3 U1 1 U2 7 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0266-4623 EI 1471-6348 J9 INT J TECHNOL ASSESS JI Int. J. Technol. Assess. Health Care PD JUL PY 2014 VL 30 IS 3 BP 260 EP 264 DI 10.1017/S0266462314000324 PG 5 WC Health Care Sciences & Services; Public, Environmental & Occupational Health; Medical Informatics SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Medical Informatics GA AR9CE UT WOS:000343868000006 PM 25096225 ER PT J AU Lu, MT Tellis, WM Avrin, DE AF Lu, Michael T. Tellis, Wyatt M. Avrin, David E. TI Providing Formal Reports for Outside Imaging and the Rate of Repeat Imaging SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE CT; image sharing; PACS; repeat imaging ID MANDATORY 2ND OPINION; SURGICAL PATHOLOGY; 2ND-OPINION CONSULTATIONS; CANCER CENTER; RADIOLOGY; CARE; CONSEQUENCES; ISSUES; IMAGES; IMPORT AB OBJECTIVE. The purpose of this study is to assess whether providing a formal report for outside imaging reduces repeat imaging. MATERIALS AND METHODS. From January 1, 2006, through December 31, 2011, patients transferred with an abdominal CT from another ("outside") institution that was imported to our institution's PACS within 60 days of the original CT were considered. Repeat imaging was defined as when an abdominal CT performed at another institution was followed by the same study at our institution in the 14 days after import to PACS. The rate of repeat imaging was compared between patients whose outside imaging did and did not receive a formal report from our radiologists. RESULTS. Consecutive patients (n = 10,330) who imported an outside abdominal CT to our PACS were considered. Thirty-six percent (3719/10,330) received a formal report. These patients were 32% less likely than the other patients to undergo repeat imaging (9.4% [350/3719] vs 14% [919/6611]; p < 0.001). The odds of repeat imaging were statistically significantly lower for patients who received a formal report after adjusting for potential confounding variables, including the age of the outside imaging study and the referring specialty (multivariate odds ratio, 0.53; 95% CI, 0.47-0.61; p < 0.001). CONCLUSION. Patients who received a formal report for their outside abdominal CT examinations were less likely to have repeat imaging. Institutions, payers, and policy makers should consider providing and supporting formal reports for outside imaging. C1 [Lu, Michael T.; Tellis, Wyatt M.; Avrin, David E.] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. RP Lu, MT (reprint author), Massachusetts Gen Hosp, Dept Radiol, Cardiac PET MR CT Program, 165 Cambridge St,Ste 400, Boston, MA 02114 USA. EM mlu@mgh.harvard.edu FU American College of Radiology Harvey L. Neiman Health Policy Institute FX This work was supported by a grant from the American College of Radiology Harvey L. Neiman Health Policy Institute. NR 19 TC 3 Z9 3 U1 0 U2 0 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X EI 1546-3141 J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD JUL PY 2014 VL 203 IS 1 BP 107 EP 110 DI 10.2214/AJR.13.10617 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AR2GD UT WOS:000343400900028 PM 24951202 ER PT J AU Pourjabbar, S Singh, S Sharma, A Padole, A Khawaja, RDA Lira, D Kalra, MK AF Pourjabbar, Sarvenaz Singh, Sarabjeet Sharma, Amita Padole, Atul Khawaja, Ranish Deedar Ali Lira, Diego Kalra, Mannudeep K. TI What Is the Minimal Radiation Dose That Can Be Used for Detecting Pleural Effusion? SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE chest CT; pleural effusion detection; radiation dose reduction ID STATISTICAL ITERATIVE RECONSTRUCTION; CHEST CT; IMAGE QUALITY; LUNG; EXPOSURE AB OBJECTIVE. The objective of our study was to assess the effect of radiation dose reduction on the detection of pleural effusions, thickening, and calcifications. MATERIALS AND METHODS. Forty-five human cadavers (mean age at death, 60 +/- 17 [SD] years; male-female ratio, 29:16; mean body mass index, 29 +/- 5.7 [SD] kg/m(2)) were scanned at seven different dose levels (CT Dose Index volume [CTDIvol] = 20, 12, 10, 6, 4, 2, and 0.8 mGy) on a 128-MDCT unit (Definition FLASH). Images were reconstructed at a 3-mm slice thickness and 2-mm increment with filtered back projection (FBP) technique. Two chest radiologists independently reviewed all image series for the detection of pleural effusion, pleural calcification, and adjacent parenchymal opacification from atelectasis or consolidation. Objective image noise was measured at each dose level on the pleural effusion using ImageJ software. Data analysis was performed with the Student t test and kappa test. RESULTS. Pleural effusions were seen in 39 of 45 cadavers on image series acquired at 2-20 mGy. Only 14 of 39 pleural effusions were identified at 0.8 mGy. Pleural effusions were not detected in 25 of 39 cadavers at 0.8 mGy because of photon starvation and increased image noise. Patient size was significantly larger in subjects with undetected pleural effusion than in those with detectable pleural effusion at 0.8 mGy (p < 0.01). Pleural calcifications and thickening (seen at 2-10 mGy images in three of three cadavers) were not identified on 0.8-mGy FBP images. On the other hand, adjacent parenchymal opacification could be assessed at all dose levels. The mean CT numbers of the pleural effusion were significantly lower on 0.8-mGy images than on images obtained at all other dose levels (-21 +/- 55 [SD] vs 17.6 +/- 19 HU, respectively) (p < 0.001). CONCLUSION. Pleural effusions, thickening, and calcifications can be seen on FBP images reconstructed at a CTDIvol as low as 2 mGy (32-cm body phantom). CT at 0.8 mGy may provide suboptimal information on very small pleural effusions, pleural thickening, and calcifications. C1 [Pourjabbar, Sarvenaz; Singh, Sarabjeet; Sharma, Amita; Padole, Atul; Khawaja, Ranish Deedar Ali; Lira, Diego; Kalra, Mannudeep K.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol,Div Thorac Imaging, Boston, MA 02114 USA. RP Pourjabbar, S (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol,Div Thorac Imaging, 55 Fruit St,Founders Rm 202, Boston, MA 02114 USA. EM spourjabbar@partners.org FU Radiological Society of North America (RSNA) Research and Education Foundation FX The study was supported by a grant from the Radiological Society of North America (RSNA) Research and Education Foundation. NR 16 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 JUL PY 2014 VL 203 IS 1 BP 118 EP 122 DI 10.2214/AJR.13.11842 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AR2GD UT WOS:000343400900030 PM 24951204 ER PT J AU Gaddikeri, S McNeeley, MF Wang, CL Bhargava, P Dighe, MK Yeh, MMC Dubinsky, TJ Kolokythas, O Lalwani, N AF Gaddikeri, Santhosh McNeeley, Michael F. Wang, Carolyn L. Bhargava, Puneet Dighe, Manjiri K. Yeh, Matthew M. C. Dubinsky, Theodore Jay Kolokythas, Orpheus Lalwani, Neeraj TI Hepatocellular Carcinoma in the Noncirrhotic Liver SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE cirrhosis; CT; hepatocellular carcinoma; MRI; noncirrhotic liver; risk factors ID RADIOLOGIC-PATHOLOGICAL CORRELATION; C VIRUS-INFECTION; MALIGNANT-TRANSFORMATION; FIBROLAMELLAR CARCINOMA; AFLATOXIN EXPOSURE; CENTRAL SCARS; DISEASE; HEPATITIS; CIRRHOSIS; RESECTION AB OBJECTIVE. Hepatocellular carcinomas (HCCs) that arise in noncirrhotic livers have several histologic and biochemical features that distinguish them from HCCs occurring in the setting of cirrhosis. Because the presentation, management, and prognosis of these entities are distinct, the accurate preoperative characterization of these lesions is of great clinical significance. We review the pathogenesis, imaging appearance, and clinical implications of noncirrhotic HCCs as they pertain to the clinical radiologist. CONCLUSION. HCCs that develop in noncirrhotic patients have distinct etiologic, cytogenetic, histopathologic, and clinical features. Despite a larger tumor burden at the time of HCC diagnosis, noncirrhotic patients with HCC have better overall survival and disease-free survival than cirrhotic patients with HCC. Knowledge of the precise clinical and imaging features of this entity and of other diagnostic considerations for the noncirrhotic liver is essential for improved patient care. C1 [Gaddikeri, Santhosh; McNeeley, Michael F.; Wang, Carolyn L.; Dighe, Manjiri K.; Dubinsky, Theodore Jay; Lalwani, Neeraj] Univ Washington, Dept Radiol, Seattle, WA 98195 USA. [Bhargava, Puneet] VA Puget Sound Hlth Care Syst, Dept Radiol, Seattle, WA USA. [Yeh, Matthew M. C.] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [Kolokythas, Orpheus] Kantonsspital Winterthur, Inst Radiol, Winterthur, Switzerland. RP Lalwani, N (reprint author), Univ Washington, Dept Radiol, 1959 NE Pacific St, Seattle, WA 98195 USA. EM neerajl@uw.edu OI Bhargava, Puneet/0000-0002-3849-9666 NR 62 TC 5 Z9 6 U1 2 U2 5 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X EI 1546-3141 J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD JUL PY 2014 VL 203 IS 1 BP W34 EP W47 DI 10.2214/AJR.13.11511 PG 14 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AR2GD UT WOS:000343400900005 PM 24951228 ER PT J AU Shin, DS Ingraham, CR Dighe, MK Wang, C Vaidya, S Moshiri, M Lall, C Park, JO Bhargava, P AF Shin, David S. Ingraham, Christopher R. Dighe, Manjiri K. Wang, Carolyn Vaidya, Sandeep Moshiri, Mariam Lall, Chandana Park, James O. Bhargava, Puneet TI Surgical Resection of a Malignant Liver Lesion: What the Surgeon Wants the Radiologist to Know SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE hepatic malignancy; hepatocellular carcinoma; liver resection; surgical planning ID PORTAL-VEIN EMBOLIZATION; EARLY HEPATOCELLULAR-CARCINOMA; GD-EOB-DTPA; HEPATIC RESECTION; CLINICAL-EVALUATION; METASTASES; SURVIVAL; CHOLANGIOCARCINOMA; TRANSPLANTATION; MANAGEMENT AB OBJECTIVE. Hepatic malignancy is a common and lethal disease, whether due to a primary tumor or metastasis. There are numerous treatment options available depending on the stage of the disease and medical condition of the patient, including systemic chemotherapy, transcatheter embolization, thermal ablation, and surgical resection. In a subset of patients with liver malignancy, surgical resection can offer the best chance of long-term survival and potentially even cure. This article reviews the major indications and contraindications for resection, basic surgical techniques and terminology, key clinical and imaging preoperative workup, and pertinent interventional oncology procedures in the management of hepatic malignancy. CONCLUSION. Diagnostic and interventional radiology plays an important role in the assessment and treatment of malignant hepatic lesions. Radiologists should be familiar with how surgeons select, work up, and treat candidates for liver resection to provide the most clinically valuable service. C1 [Shin, David S.; Ingraham, Christopher R.; Dighe, Manjiri K.; Wang, Carolyn; Vaidya, Sandeep; Moshiri, Mariam] Univ Washington, Dept Radiol, Sch Med, Seattle, WA 98108 USA. [Lall, Chandana] Univ Calif Irvine, Dept Radiol, Orange, CA 92668 USA. [Park, James O.] Univ Washington, Dept Surg, Sch Med, Seattle, WA 98108 USA. [Bhargava, Puneet] Univ Washington, Dept Radiol, Seattle, WA 98108 USA. [Bhargava, Puneet] VA Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. RP Bhargava, P (reprint author), Univ Washington, Dept Radiol, Mail Box 358280,S-114 Radiol,1660 S Columbian Way, Seattle, WA 98108 USA. EM bhargp@uw.edu OI Bhargava, Puneet/0000-0002-3849-9666 NR 47 TC 6 Z9 6 U1 0 U2 5 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X EI 1546-3141 J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD JUL PY 2014 VL 203 IS 1 BP W21 EP W33 DI 10.2214/AJR.13.11701 PG 13 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AR2GD UT WOS:000343400900004 PM 24951226 ER PT J AU Kimball, AB Leonardi, C Stahle, M Gulliver, W Chevrier, M Fakharzadeh, S Goyal, K Calabro, S Langholff, W Menter, A AF Kimball, A. B. Leonardi, C. Stahle, M. Gulliver, W. Chevrier, M. Fakharzadeh, S. Goyal, K. Calabro, S. Langholff, W. Menter, A. CA PSOLAR Steering Comm TI Demography, baseline disease characteristics and treatment history of patients with psoriasis enrolled in a multicentre, prospective, disease-based registry (PSOLAR) SO BRITISH JOURNAL OF DERMATOLOGY LA English DT Article ID TO-SEVERE PSORIASIS; PHASE-III TRIAL; INTERLEUKIN-12/23 MONOCLONAL-ANTIBODY; QUALITY-OF-LIFE; DOUBLE-BLIND; INFLAMMATORY DISEASES; MEDICAL COMORBIDITY; CLINICAL-FEATURES; PLAQUE PSORIASIS; POPULATION AB Background Psoriasis is associated with several comorbidities and behavioural risk factors. Objectives To evaluate demographic and disease characteristics in patients enrolled in the Psoriasis Longitudinal Assessment and Registry (PSOLAR). Methods PSOLAR is a global, prospective, longitudinal, disease-based registry that includes a postmarketing commitment to evaluate safety in patients with psoriasis. Enrolled patients had to be receiving, or be eligible to receive, conventional systemic or biological agents. Demographic/disease characteristics, medical histories, lifestyle risk factors and previous treatments are collected at enrolment. Efficacy and safety data are collected every 6 months for 8 years, and data are extracted annually. Selected parameters are evaluated by age quartile using post hoc analyses. Results As of 23 August 2012, 11 900 patients were enrolled at 301 sites in North America, Europe and Latin America. Over half of the PSOLAR population (54.7%) is male, with a mean age of 48.6 years and mean body mass index of 30.9 kg m(-2) at enrolment. Mean duration of disease at enrolment was 17.5 years, and mean Physician's Global Assessment score was 2.0. Psoriatic arthritis (35.5%) and cardiovascular diseases (38.2%) were highly prevalent. Diabetes mellitus type II was reported in 11.4% of patients. Depression and anxiety were noted in 14.7% and 11.1% of patients, respectively; 79.0% reported any alcohol use and 56.7% reported smoking or a history of smoking. The occurrence of most comorbidities, including cardiovascular disease and risk factors, increased with age. Conclusions In the PSOLAR population, multiple and age-appropriate comorbidities are associated with psoriasis and may affect the selection of psoriasis treatments. C1 [Kimball, A. B.] Harvard Univ, Sch Med, Boston, MA 02215 USA. [Kimball, A. B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Leonardi, C.] St Louis Univ, St Louis, MO 63103 USA. [Stahle, M.] Karolinska Inst, Stockholm, Sweden. [Gulliver, W.] Mem Univ Newfoundland, St John, NF, Canada. [Gulliver, W.] New Lab Life Sci, St John, NF, Canada. [Chevrier, M.; Fakharzadeh, S.; Goyal, K.; Calabro, S.] Janssen Sci Affairs LLC, Horsham, PA USA. [Langholff, W.] Janssen Res & Dev LLC, Horsham, PA USA. [Menter, A.] Baylor Univ, Med Ctr, Dallas, TX USA. RP Kimball, AB (reprint author), Harvard Univ, Sch Med, Boston, MA 02215 USA. EM harvardskinstudies@partners.org RI Naldi, Luigi/K-6343-2016 OI Naldi, Luigi/0000-0002-3160-2835 NR 53 TC 22 Z9 22 U1 0 U2 4 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 JUL PY 2014 VL 171 IS 1 BP 137 EP 147 DI 10.1111/bjd.13013 PG 11 WC Dermatology SC Dermatology GA AS0YA UT WOS:000344001300024 PM 24684204 ER PT J AU Allweiss, P Brown, DR Chosewood, LC Dorn, JM Dube, S Elder, R Holman, DM Hudson, HL Kimsey, CD Lang, JE Lankford, TJ Li, CY Muirhead, L Neri, A Plescia, M Rodriguez, J Schill, AL Shoemaker, M Sorensen, G Townsend, J White, MC AF Allweiss, Pamela Brown, David R. Chosewood, L. Casey Dorn, Joan M. Dube, Shanta Elder, Randy Holman, Dawn M. Hudson, Heidi L. Kimsey, C. Dexter, Jr. Lang, Jason E. Lankford, Tina J. Li, Chunyu Muirhead, Lisa Neri, Antonio Plescia, Marcus Rodriguez, Juan Schill, Anita L. Shoemaker, Meredith Sorensen, Glorian Townsend, Julie White, Mary C. CA Canc Prevention Workplace Writing TI Cancer Prevention and Worksite Health Promotion: Time to Join Forces SO PREVENTING CHRONIC DISEASE LA English DT Article ID UNITED-STATES; OBESITY; ADULTS; BAD C1 [Allweiss, Pamela] CDC, Div Diabet Translat, Atlanta, GA 30333 USA. [Brown, David R.; Dorn, Joan M.; Kimsey, C. Dexter, Jr.] CDC, Div Nutr Phys Act & Obes, Atlanta, GA 30333 USA. [Chosewood, L. Casey; Hudson, Heidi L.; Schill, Anita L.] NIOSH, Total Worker Hlth Program, CDC, Atlanta, GA USA. [Dube, Shanta] CDC, Off Smoking & Hlth, Atlanta, GA 30333 USA. [Elder, Randy] CDC, Div Epidemiol Anal & Lib Serv, Atlanta, GA 30333 USA. [Holman, Dawn M.; Li, Chunyu; Neri, Antonio; Plescia, Marcus; Rodriguez, Juan; Shoemaker, Meredith; Townsend, Julie; White, Mary C.] CDC, Div Canc Prevent & Control, Atlanta, GA 30333 USA. [Lang, Jason E.] CDC, Div Populat Hlth, Atlanta, GA 30333 USA. [Lankford, Tina J.] CDC, Worklife Wellness Off, Atlanta, GA 30333 USA. [Muirhead, Lisa] Emory Univ, Nell Hodgson Woodruff Sch Nursing, Atlanta, GA 30322 USA. [Sorensen, Glorian] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. RP Holman, DM (reprint author), Ctr Dis Control & Prevent, Div Canc Prevent & Control, 4770 Buford Hwy,MS F76, Atlanta, GA 30341 USA. EM dholman@cdc.gov RI White, Mary C./C-9242-2012 OI White, Mary C./0000-0002-9826-3962 FU CDC, Division of Cancer Prevention and Control FX Support for this essay was provided by CDC, Division of Cancer Prevention and Control. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of CDC. Members of the Cancer Prevention in the Workplace Writing Group (affiliations at time of contribution to the essay) are Pamela Allweiss, MD, MPH, Division of Diabetes Translation, CDC; David R. Brown, PhD, Division of Nutrition, Physical Activity, and Obesity, CDC; L. Casey Chosewood, MD, MPH, Total Worker Health Program, National Institute for Occupational Safety and Health, CDC; Joan M. Dorn, PhD, Division of Nutrition, Physical Activity, and Obesity, CDC; Shanta Dube, PhD, MPH, Office on Smoking and Health, CDC; Randy Elder, PhD, MEd, Division of Epidemiology, Analysis, and Library Services, CDC; Dawn M. Holman, MPH, Division of Cancer Prevention and Control, CDC; Heidi L. Hudson, MPH, Total Worker Health Program, National Institute for Occupational Safety and Health, CDC; C. Dexter Kimsey Jr, PhD, MSEH, Division of Nutrition, Physical Activity, and Obesity, CDC; Jason E. Lang, MPH, MS, Division of Population Health, CDC; Tina J. Lankford, MPH, Work life Wellness Office, CDC; Chunyu Li, PhD, MD, MS, Division of Cancer Prevention and Control, CDC; Lisa Muirhead, DNP, APRN, ANP-BC, Nell Hodgson Woodruff School of Nursing, Emory University, Atlanta, Georgia; Antonio Neri, MD, MPH, Division of Cancer Prevention and Control, CDC; Marcus Plescia, MD, MPH, Division of Cancer Prevention and Control, CDC; Juan Rodriguez, MPH, Division of Cancer Prevention and Control, CDC; Anita L. Schill, PhD, MPH, MA, Total Worker Health Program, National Institute for Occupational Safety and Health, CDC; Meredith Shoemaker, MPH, Division of Cancer Prevention and Control, CDC; Glorian Sorensen, PhD, MPH, Center for Community-Based Research, Dana-Farber Cancer Institute, Boston, Massachusetts; Julie Townsend, MS, Division of Cancer Prevention and Control, CDC; Mary C. White, ScD, Division of Cancer Prevention and Control, CDC, Atlanta, Georgia. NR 36 TC 1 Z9 1 U1 2 U2 6 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1545-1151 J9 PREV CHRONIC DIS JI Prev. Chronic Dis. PD JUL PY 2014 VL 11 AR 140127 DI 10.5888/pcd11.140127 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AR3XJ UT WOS:000343522200017 ER PT J AU Wentzel, JL Mulligan, JK Soler, ZM White, DR Schlosser, RJ AF Wentzel, Jennifer L. Mulligan, Jennifer K. Soler, Zachary M. White, David R. Schlosser, Rodney J. TI Passive smoke exposure in chronic rhinosinusitis as assessed by hair nicotine SO AMERICAN JOURNAL OF RHINOLOGY & ALLERGY LA English DT Article ID SECONDHAND SMOKE; CIGARETTE-SMOKE; TOBACCO-SMOKE; EPITHELIAL-CELLS; NASAL POLYPOSIS; CHILDREN; PREVALENCE; OUTCOMES; ASTHMA; IMPACT AB Background: Prevalence of passive smoke exposure is relatively unknown in chronic rhinosinusitis (CRS). Previous studies have attempted to establish this relationship using subjective, questionnaire-based methodologies to assess smoke exposure, thus introducing the potential for error bias. The purpose of this study was to accurately determine the prevalence of passive smoke exposure in CRS and control patients using hair nicotine levels as a quantitative measure of cigarette smoke exposure. Methods: Hair samples were obtained at time of surgery from 569 patients: 404 undergoing surgery for CRS and 165 controls undergoing surgery for repair of cerebrospinal fluid leak, removal of pituitary tumors, or adenoidectomy from 2007 to 2013. Patient charts were reviewed for reported smoking status. Hair nicotine was quantified using reversed-phase high-performance liquid chromatography. Nonsmoking patients were classified as passive smoke exposed or smoke naive according to the hair nicotine results. Statistical analysis was performed to test for differences in demographic information and smoke exposure prevalence between CRS, CRS subtypes, and controls. Results: The prevalence of passive smoke exposure in CRS as documented by hair nicotine was lower than previously reported subjective estimates. Passive smoke exposure rates were equivalent between those with CRS versus controls and significantly higher in children. Severity of passive smoke exposure was also equivalent between CRS subsets and controls. Annual passive smoke exposure prevalence did not change over time. Conclusion: There is no clear evidence of avoidance of passive smoke exposure in the CRS population compared with controls. Passive smoke exposure also remained stable over time despite recent regional implementation of smoking bans. Given the constancy of exposure, it is critical that the impact of passive smoke on CRS exacerbation, outcomes, and pathophysiology be evaluated in large-scale clinical studies. C1 [Wentzel, Jennifer L.; Mulligan, Jennifer K.; Soler, Zachary M.; White, David R.; Schlosser, Rodney J.] Med Univ S Carolina, Dept Otolaryngol Head & Neck Surg, Charleston, SC 29425 USA. [Mulligan, Jennifer K.] Med Univ S Carolina, Dept Pediat, Charleston, SC 29425 USA. [Mulligan, Jennifer K.; Schlosser, Rodney J.] Ralph H Johnson VA Med Ctr, Ralph H Johnson VA Med Ctr, Charleston, SC USA. RP Mulligan, JK (reprint author), 135 Rutledge Ave,MSC 550, Charleston, SC 29425 USA. EM konopa@musc.edu FU Flight Attendant Medical Research Institute [092401, 113042, 113039]; Department of Veterans Affairs [1 I01 CX000377] FX Funded by grants from the Flight Attendant Medical Research Institute to JK Mulligan (092401), Z Solar (113042), and RJ Schlosser (113039), as well as a Merit-Review Award from the Clinical Sciences Research and Development Program of the Department of Veterans Affairs (1 I01 CX000377). NR 37 TC 6 Z9 6 U1 0 U2 5 PU OCEAN SIDE PUBLICATIONS INC PI PROVIDENCE PA 95 PITMAN ST, PROVIDENCE, RI 02906 USA SN 1945-8924 EI 1945-8932 J9 AM J RHINOL ALLERGY JI Am. J. Rhinol. Allergy PD JUL-AUG PY 2014 VL 28 IS 4 BP 297 EP 301 DI 10.2500/ajra.2014.28.4058 PG 5 WC Otorhinolaryngology SC Otorhinolaryngology GA AQ4FF UT WOS:000342748000010 PM 25197916 ER PT J AU Zrebiec, J AF Zrebiec, John TI A National Study of the Certified Diabetes Educator Implications for Future Certification Examinations SO DIABETES EDUCATOR LA English DT Article AB Purpose The purposes of this national practice analysis conducted by the National Certification Board for Diabetes Educators are to (1) maintain the Certified Diabetes Educator (R) (CDE (R)) examination as a valid measure of knowledge, (2) ensure that the content of certification examinations is related to practice, and (3) define content areas that should be assessed in future certification examinations. Methods The study involved developing a diabetes educator job task list and survey, distributing 5,053 surveys, and analyzing survey responses from a multidisciplinary and geographically representative sample of certified diabetes educators. Results Nine hundred sixty-one surveys were suitable for analysis, with relevant demographic subgroups adequately represented. On the basis of survey data, an examination matrix and a detailed content outline were constructed that will be used by the National Certification Board for Diabetes Educators to develop future examinations. Conclusions Certification examination specifications were developed on the basis of the important job activities certified diabetes educators perform. These test specifications will guide future test development and ensure that the examination has strong content validity and reflects current practice. Future forms of the examination will contain 175 items at specified cognitive levels, with a representative sampling of tasks within 3 core areas from a detailed content outline. C1 [Zrebiec, John] Natl Certificat Board Diabet Educ, Arlington Hts, IL USA. RP Zrebiec, J (reprint author), Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA. EM john.zrebiec@joslin.harvard.edu FU National Certification Board for Diabetes Educators FX This study was funded by the National Certification Board for Diabetes Educators. NR 3 TC 0 Z9 2 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0145-7217 EI 1554-6063 J9 DIABETES EDUCATOR JI Diabetes Educ. PD JUL-AUG PY 2014 VL 40 IS 4 BP 470 EP 475 DI 10.1177/0145721714534783 PG 6 WC Endocrinology & Metabolism; Public, Environmental & Occupational Health SC Endocrinology & Metabolism; Public, Environmental & Occupational Health GA AQ6FU UT WOS:000342906400009 PM 24829269 ER PT J AU Kashiwagi, S Brauns, T Gelfand, J Poznansky, MC AF Kashiwagi, Satoshi Brauns, Timothy Gelfand, Jeffrey Poznansky, Mark C. TI Laser vaccine adjuvants History, progress, and potential SO HUMAN VACCINES & IMMUNOTHERAPEUTICS LA English DT Review DE laser; vaccine adjuvant; near-infrared; influenza; cancer ID ND-YAG LASER; HEAT-SHOCK-PROTEIN; DENDRITIC CELL-MIGRATION; BIPHASIC DOSE-RESPONSE; LEVEL LIGHT THERAPY; HEPATITIS-B-VACCINE; REACTIVE OXYGEN; NITRIC-OXIDE; HUMAN-SKIN; IMMUNE-RESPONSES AB Immunologic adjuvants are essential for current vaccines to maximize their efficacy. Unfortunately, few have been found to be sufficiently effective and safe for regulatory authorities to permit their use in vaccines for humans and none have been approved for use with intradermal vaccines. The development of new adjuvants with the potential to be both efficacious and safe constitutes a significant need in modern vaccine practice. The use of non-damaging laser light represents a markedly different approach to enhancing immune responses to a vaccine antigen, particularly with intradermal vaccination. This approach, which was initially explored in Russia and further developed in the US, appears to significantly improve responses to both prophylactic and therapeutic vaccines administered to the laser-exposed tissue, particularly the skin. Although different types of lasers have been used for this purpose and the precise molecular mechanism(s) of action remain unknown, several approaches appear to modulate dendritic cell trafficking and/or activation at the irradiation site via the release of specific signaling molecules from epithelial cells. The most recent study, performed by the authors of this review, utilized a continuous wave near-infrared laser that may open the path for the development of a safe, effective, low-cost, simple-to-use laser vaccine adjuvant that could be used in lieu of conventional adjuvants, particularly with intradermal vaccines. In this review, we summarize the initial Russian studies that have given rise to this approach and comment upon recent advances in the use of non-tissue damaging lasers as novel physical adjuvants for vaccines. C1 [Kashiwagi, Satoshi; Brauns, Timothy; Gelfand, Jeffrey; Poznansky, Mark C.] Massachusetts Gen Hosp, Dept Med, Div Infect Dis, Vaccine & Immunotherapy Ctr, Charlestown, MA 02114 USA. RP Kashiwagi, S (reprint author), Massachusetts Gen Hosp, Dept Med, Div Infect Dis, Vaccine & Immunotherapy Ctr, Charlestown, MA 02114 USA. EM skashiwagi@mgh.harvard.edu; mpoznansky@partners.org FU Space and Naval Warfare Systems Center Pacific Award [N66001-101-2132]; Bill and Melinda Gates Foundation [OPP1046276]; National Institute of Allergy and Infectious Diseases [R01AI105131] FX We thank Dr R Rox Anderson and Dr Apostolos Doukas (Masachusetts General Hospital), Dr Holger Schluter (HIGHYAG Lasertechnologie GmbH), and Dr Gregory Altschuler (Dental Photonics) for their critical input into our understanding of lasers and their impact in medicine; we thank Dr Michael Hamblin (Masachusetts General Hospital) and Mr Eugene L. Q. Lee (Imperial College London) for their contributions to figures. This material is based upon work supported by Center for Integration of Medicine and Innovative Technology (CIMIT), Defense Advanced Research Projects Agency under Contract No. Space and Naval Warfare Systems Center Pacific Award N66001-101-2132, Bill and Melinda Gates Foundation (Grand Challenges Explorations OPP1046276), The Friends of VIC and National Institute of Allergy and Infectious Diseases grant (R01AI105131). Any opinions, findings and conclusions, or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the Defense Advanced Research Projects Agency. We also would like to acknowledge the additional support of the Edmund C. Lynch Jr. Cancer Fund. NR 174 TC 4 Z9 6 U1 2 U2 13 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 2164-5515 EI 2164-554X J9 HUM VACC IMMUNOTHER JI Human Vaccines Immunother. PD JUL PY 2014 VL 10 IS 7 BP 1892 EP 1907 DI 10.4161/hv.28840 PG 16 WC Biotechnology & Applied Microbiology; Immunology SC Biotechnology & Applied Microbiology; Immunology GA AQ6ED UT WOS:000342901200024 PM 25424797 ER PT J AU Payer, B Lee, JT AF Payer, Bernhard Lee, Jeannie T. TI Coupling of X-Chromosome reactivation with the pluripotent stem cell state SO RNA BIOLOGY LA English DT Editorial Material DE X-chromosome reactivation; epigenetics; pluripotency; reprogramming; stem cells; long noncoding RNA; PRDM14; Xist; Tsix ID PRIMORDIAL GERM-CELLS; INACTIVATION CENTER REGION; DOSAGE COMPENSATION; XIST RNA; CHROMATIN-STRUCTURE; DNA METHYLATION; GROUND-STATE; NONCODING RNA; TSIX RNA; MOUSE AB X-chromosome inactivation (XCI) in female mammals is a dramatic example of epigenetic gene regulation, which entails the silencing of an entire chromosome through a wide range of mechanisms involving noncoding RNAs, chromatin-modifications, and DNA-methylation. While XCI is associated with the differentiated cell state, it is reversed by X-chromosome reactivation (XCR) ex vivo in pluripotent stem cells and in vivo in the early mouse embryo and the germline. Critical in the regulation of XCI vs. XCR is the X-inactivation center, a multigene locus on the X-chromosome harboring several long noncoding RNA genes including, most prominently, Xist and Tsix. These genes, which sit at the top of the XCI hierarchy, are by themselves controlled by pluripotency factors, coupling XCR with the naive pluripotent stem cell state. In this point-of-view article we review the latest findings regarding this intricate relationship between cell differentiation state and epigenetic control of the X-chromosome. In particular, we discuss the emerging picture of complex multifactorial regulatory mechanisms, ensuring both a fine-tuned and robust X-reactivation process. C1 [Payer, Bernhard; Lee, Jeannie T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Howard Hughes Med Inst,Dept Mol Biol,Dept Genet, Boston, MA USA. RP Payer, B (reprint author), CRG, Stem Cells & Canc Programme, Barcelona, Spain. EM bernhard.payer@crg.eu; lee@molbio.mgh.harvard.edu OI Payer, Bernhard/0000-0002-4694-2082 FU Howard Hughes Medical Institute; NIGMS NIH HHS [R37-GM58839, R37 GM058839] NR 110 TC 5 Z9 5 U1 1 U2 7 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1547-6286 EI 1555-8584 J9 RNA BIOL JI RNA Biol. PD JUL PY 2014 VL 11 IS 7 BP 798 EP 807 DI 10.4161/rna.29779 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AQ6EF UT WOS:000342901600006 PM 25137047 ER PT J AU Williams, MV Li, J Hansen, LO Forth, V Budnitz, T Greenwald, JL Howell, E Halasyamani, L Vidyarthi, A Coleman, EA AF Williams, Mark V. Li, Jing Hansen, Luke O. Forth, Victoria Budnitz, Tina Greenwald, Jeffrey L. Howell, Eric Halasyamani, Lakshmi Vidyarthi, Arpana Coleman, Eric A. TI Project BOOST Implementation: Lessons Learned SO SOUTHERN MEDICAL JOURNAL LA English DT Article DE quality improvement; rehospitalization; readmission; mentored implementation; hospital discharge; care transitions ID PATIENTS AFTER-DISCHARGE; QUALITY IMPROVEMENT; HOSPITAL DISCHARGE; MEDICAL PATIENTS; ADVERSE EVENTS; HEALTH-CARE; REHOSPITALIZATION; COLLABORATIVES; TRANSITION; PROGRAM AB Objectives: Enhancing care coordination and reducing hospital readmissions have been a focus of multiple quality improvement (QI) initiatives. Project BOOST (Better Outcomes by Optimizing Safe Transitions) aims to enhance the discharge transition from hospital to home. Previous research indicates that QI initiatives originating externally often face difficulties gaining momentum or effecting lasting change in a hospital. We performed a qualitative evaluation of Project BOOST implementation by examining the successes and failures experienced by six pilot sites. We also evaluated the unique physician mentoring component of this program. Finally, we examined the impact of intensification of the physician mentoring model on adoption of BOOST interventions in two later Illinois cohorts (27 hospitals). Methods: Qualitative analysis of six pilot hospitals used a process of methodological triangulation and analysis of the BOOST enrollment applications, the listserv, and content from telephone interviews. Evaluation of BOOST implementation at Illinois hospitals occurred via mid-year and year-end surveys. Results: The identified common barriers included inadequate understanding of the current discharge process, insufficient administrative support, lack of protected time or dedicated resources, and lack of frontline staff buy-in. Facilitators of implementation included the mentor, a small beginning, teamwork, and proactive engagement of the patient. Notably, hospitals viewed their mentors as essential facilitators of change. Sites consistently commented that the individualized mentoring was extremely helpful and provided significant accountability and stimulated creativity. In the Illinois cohorts, the improved mentoring model showed more complete implementation of BOOST interventions. Conclusions: The implementation of Project BOOST was well received by hospitals, although sites faced substantial barriers consistent with other QI research reports. The unique mentorship element of Project BOOST proved extremely valuable in helping sites overcome their distinctive challenges and identify facilitators for success. The findings from this qualitative study should contribute to future BOOST implementation success and others' efforts to optimize hospital discharge transitions. C1 [Williams, Mark V.] Univ Kentucky, Dept Internal Med, Ctr Hlth Serv Res, Lexington, KY 40536 USA. Northwestern Univ, Feinberg Sch Med, Dept Emergency Med, Div Hosp Med, Chicago, IL 60611 USA. Soc Hosp Med, Philadelphia, PA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. St Joseph Mercy Hosp, Ann Arbor, MI 48104 USA. Duke Natl Univ Singapore, Div Hosp Med, Singapore Hlth Serv, HealthcareLeadership Coll,Grad Med Sch, Singapore, Singapore. Univ Colorado, Div Hlth Care Policy & Res, Denver, CO 80202 USA. RP Williams, MV (reprint author), Univ Kentucky, Dept Internal Med, Ctr Hlth Serv Res, 789 S Limestone St,BPC Room 551, Lexington, KY 40536 USA. EM mark.will@uky.edu FU John A. Hartford Foundation; BlueCross BlueShield of Illinois; Society of Hospital Medicine; Project BOOST FX This work was supported by grant funding from The John A. Hartford Foundation and BlueCross BlueShield of Illinois.; M.V.W. receives honoraria for multiple presentations on care transitions at grand rounds and conferences, honoraria for educational presentations from Quantia Communications Inc, royalties from Elsevier, grant funding from the Society of Hospital Medicine to Northwestern University Feinberg School of Medicine for Project BOOST, and honoraria from the Society of Hospital Medicine for Project BOOST. J.L. receives honoraria for educational presentations for Quantia Communications Inc. L. O. H. receives grant funding from the Society of Hospital Medicine to Northwestern University Feinberg School of Medicine for Project BOOST and honoraria from the Society of Hospital Medicine for Project BOOST. J.L. G. receives salary support for ongoing work on Project BOOST as well as honoraria for speaking on transitions of care at various grand rounds and conferences. NR 35 TC 7 Z9 7 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0038-4348 EI 1541-8243 J9 SOUTH MED J JI South.Med.J. PD JUL PY 2014 VL 107 IS 7 BP 455 EP 465 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA AQ4ZZ UT WOS:000342812700013 PM 25010589 ER PT J AU Abd-El-Barr, MM Chiocca, EA AF Abd-El-Barr, Muhammad M. Chiocca, E. Antonio TI How Much Is Enough? The Question of Extent of Resection in Glioblastoma Multiforme SO WORLD NEUROSURGERY LA English DT Editorial Material DE Extent of resection; GBM; Glioblastoma; Residual; Surgery; Survival; Volumetric ID SURVIVAL; TEMOZOLOMIDE; TUMORS C1 Harvard Univ, Sch Med, Dept Neurosurg, Brigham & Womens Faulkner Hosp,Inst Neurosci, Cambridge, MA 02138 USA. Dana Farber Canc Inst, Ctr Neurooncol, Boston, MA 02115 USA. RP Chiocca, EA (reprint author), Harvard Univ, Sch Med, Cambridge, MA 02138 USA. EM EAChiocca@partners.org NR 10 TC 3 Z9 3 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1878-8750 EI 1878-8769 J9 WORLD NEUROSURG JI World Neurosurg. PD JUL-AUG PY 2014 VL 82 IS 1-2 BP E109 EP E110 DI 10.1016/j.wneu.2014.05.006 PG 2 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA AQ6HM UT WOS:000342911400027 PM 24813127 ER PT J AU Abd-El-Barr, MM Chiocca, EA AF Abd-El-Barr, Muhammad M. Chiocca, E. Antonio TI Who Benefits from Surgery for Brain Metastases? SO WORLD NEUROSURGERY LA English DT Editorial Material DE Breast; Gastrointestinal; Lung; Melanoma; Metastatic brain tumor; Prognosis; Recurrence; Renal; RPA; Surgery; Survival ID PARTITIONING ANALYSIS RPA; THERAPY C1 Harvard Univ, Sch Med, Brigham & Womens Faulkner Hosp, Inst Neurosci,Dept Neurosurg, Cambridge, MA 02138 USA. Dana Farber Canc Inst, Ctr Neurooncol, Cambridge, MA 02138 USA. RP Chiocca, EA (reprint author), Harvard Univ, Sch Med, Cambridge, MA 02138 USA. EM EAChiocca@partners.org NR 10 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1878-8750 EI 1878-8769 J9 WORLD NEUROSURG JI World Neurosurg. PD JUL-AUG PY 2014 VL 82 IS 1-2 BP E115 EP E116 DI 10.1016/j.wneu.2014.03.020 PG 2 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA AQ6HM UT WOS:000342911400029 PM 24636934 ER PT J AU Bi, WL Chiocca, A AF Bi, Wenya Linda Chiocca, E. Antonio TI From Localization to Pathways: The Continuing Evolution of Diffusion Tensor Imaging SO WORLD NEUROSURGERY LA English DT Editorial Material ID FIBER TRACKING; GLIOMAS; TRACTOGRAPHY; RESECTION; SURGERY C1 [Chiocca, E. Antonio] Harvard Univ, Sch Med, Dept Neurosurg, Inst Neurosci, Boston, MA 02138 USA. Brigham & Womens Faulkner Hosp, Dept Neurosurg, Boston, MA USA. Dana Farber Canc Inst, Ctr Neurooncol, Boston, MA 02115 USA. RP Chiocca, EA (reprint author), Harvard Univ, Sch Med, Dept Neurosurg, Inst Neurosci, Boston, MA 02138 USA. EM eachiocca@partners.org NR 8 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1878-8750 EI 1878-8769 J9 WORLD NEUROSURG JI World Neurosurg. PD JUL-AUG PY 2014 VL 82 IS 1-2 BP E47 EP E48 DI 10.1016/j.wneu.2013.08.059 PG 2 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA AQ6HM UT WOS:000342911400006 PM 24017953 ER PT J AU Gross, BA Chiocca, EA AF Gross, Bradley A. Chiocca, E. Antonio TI Low-Grade Gliomas and Quality of Life SO WORLD NEUROSURGERY LA English DT Editorial Material DE Brain tumor; Cognitive function; Low-grade glioma; Quality of life; Seizures ID COGNITIVE FUNCTION; BRAIN-TUMORS; ADULTS; RADIOTHERAPY; CHEMOTHERAPY; RESECTION; SEQUELAE; IMPACT C1 [Chiocca, E. Antonio] Harvard Univ, Sch Med, Brigham & Womens Faulkner Hosp, Inst Neurosci,Dept Neurosurg, Boston, MA 02163 USA. Dana Farber Canc Inst, Ctr Neurooncol, Boston, MA 02115 USA. RP Chiocca, EA (reprint author), Harvard Univ, Sch Med, Brigham & Womens Faulkner Hosp, Inst Neurosci,Dept Neurosurg, Boston, MA 02163 USA. EM EAChiocca@partners.org NR 24 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1878-8750 EI 1878-8769 J9 WORLD NEUROSURG JI World Neurosurg. PD JUL-AUG PY 2014 VL 82 IS 1-2 BP E133 EP E134 DI 10.1016/j.wneu.2014.05.007 PG 2 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA AQ6HM UT WOS:000342911400035 PM 24813129 ER PT J AU Skovrlj, B Haghighi, M Smethurst, ME Caridi, J Bederson, JB AF Skovrlj, Branko Haghighi, Maryam Smethurst, Mark E. Caridi, John Bederson, Joshua B. TI Curvularia Abscess of the Brainstem SO WORLD NEUROSURGERY LA English DT Article DE Brainstem; Curvularia abscess; Fungal central nervous system infection; Phaeohyphomycosis ID CENTRAL-NERVOUS-SYSTEM; INVASIVE PULMONARY ASPERGILLOSIS; WANGIELLA-DERMATITIDIS; CONTAMINATED MARIJUANA; TRANSPLANT RECIPIENT; FUNGAL-INFECTIONS; MELANIN; PHEOHYPHOMYCOSIS; VIRULENCE; SMOKING AB OBJECTIVE: To present a unique case of a brainstem Curvularia fungal infection and review the diagnosis and management of this rare phenomenon. METHODS: A 33-year-old immunocompetent African American male presented with 2 weeks of headache, nausea, and vomiting in a setting of a recent 20-lb weight loss. Neurological examination was positive for multiple cranial nerve palsies, hemisensory loss, and gait instability. Magnetic resonance imaging demonstrated an enhancing medullary lesion. RESULTS: Metastatic and infectious workup revealed a left lung lesion, which on subsequent biopsy was positive for a granuloma yielding no further clues to the etiology of the brainstem lesion. On surgical exploration of the cranial lesion, a puss-filed, encapsulated lesion was encountered that was tightly adherent to the brainstem. Intraoperative biopsy of the lesion capsule was initially negative but on postoperative day 9, fungal hyphae were encountered identified on morphology as Curvularia species. The patient was started on triple antifungal therapy but necessitated a second surgery for lesion debulking and drainage. The patient was discharged home 10 weeks after initial presentation. At the 13-months follow-up the patient is doing very well and his neurological examination continues to improve. CONCLUSIONS: This is the first reported case of a brainstem Curvularia infection. This case highlights the importance of an aggressive surgical and antibiotic therapy in the treatment of central nervous system Curvularia infections. There appears to be a strong relationship between heavy marijuana use and Curvularia infection, producing lung granulomas that may extend to other organs such as the central nervous system of immunocompetent patients. C1 [Skovrlj, Branko; Caridi, John; Bederson, Joshua B.] Mt Sinai Sch Med, Dept Neurosurg, New York, NY 10029 USA. [Haghighi, Maryam] Karolinska Inst, Sch Med, Hagalund, Sweden. [Smethurst, Mark E.] James J Peters VA Med Ctr, Dept Pathol, Bronx, NY USA. RP Skovrlj, B (reprint author), Mt Sinai Sch Med, Dept Neurosurg, New York, NY 10029 USA. EM skovrlj.branko@gmail.com NR 32 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 1878-8750 EI 1878-8769 J9 WORLD NEUROSURG JI World Neurosurg. PD JUL-AUG PY 2014 VL 82 IS 1-2 AR UNSP 241.e9 DI 10.1016/j.wneu.2013.07.014 PG 5 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA AQ6HM UT WOS:000342911400154 PM 23891581 ER PT J AU Tinloy, J Kaul, S Ulbrecht, J Schaefer, E Gabbay, RA AF Tinloy, Jennifer Kaul, Shailja Ulbrecht, Jan Schaefer, Eric Gabbay, Robert A. TI Podiatric Physicians' Perspectives on Their Role in Promoting Self-Care in High-Risk Patients with Diabetes SO JOURNAL OF THE AMERICAN PODIATRIC MEDICAL ASSOCIATION LA English DT Article ID EDUCATION IMPROVES KNOWLEDGE; FOOT PROBLEMS; PREVENTION; PEOPLE; NEUROPATHY; SETTINGS; EFFICACY; BEHAVIOR; ULCERS AB Background: Foot self-care is key in preventing morbidity in high-risk diabetic patients. Motivational interviewing (MI) is an approach to encourage behavior change by patients that can be used in medical settings. The goal was to explore how podiatric physicians promote self-care in such patients and whether they use MI techniques. Methods: We conducted a 19-question online survey of US-based practicing podiatric physicians. Most answers were on a 5-point scale. The MI index was the sum of answers to five relevant questions. Results: Of 843 podiatric physicians, 86% considered foot self-care to be very important for high-risk diabetic patients, and 90% felt that it was their role to discuss foot self-care with them; 49% felt that they had training and were successful in promoting behavior change, but most were definitely (38%) or possibly (46%) interested in learning more. Only 24% of respondents scored at least 15 of 20 on the MI index. Higher MI scores were associated with more face time and more time discussing foot self-care but were not related to podiatric physicians' age, sex, geographic location, percentage of time in surgery, or years in practice. Reported barriers to counseling were lack of reimbursed time and poor patient engagement. Conclusions: Most podiatric physicians view self-care behavior among high-risk diabetic patients and their role in promoting it as very important; most feel already proficient, but only a few demonstrate MI skills; most are willing to learn more. Success in behavioral counseling, such as MI, is likely to require more time and may be encouraged by a move from fee-for-service to outcome-based reimbursement. C1 [Tinloy, Jennifer] Penn State Coll Med, Dept Med, Hershey, PA USA. [Kaul, Shailja; Gabbay, Robert A.] Penn State Coll Med, Penn State Hershey Diabet Inst, Div Endocrinol Diabet & Metab, Hershey, PA USA. [Ulbrecht, Jan] Penn State Univ, Dept Biobehav Hlth, University Pk, PA 16802 USA. [Schaefer, Eric] Penn State Coll Med, Dept Publ Hlth Sci, Hershey, PA USA. RP Gabbay, RA (reprint author), Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA. EM robert.gabbay@joslin.harvard.edu NR 35 TC 1 Z9 1 U1 1 U2 6 PU AMER PODIATRIC MED ASSOC PI BETHESDA PA 9312 OLD GEORGETOWN ROAD, BETHESDA, MD 20814-1621 USA SN 8750-7315 EI 1930-8264 J9 J AM PODIAT MED ASSN JI J. Am. Podiatr. Med. Assoc. PD JUL-AUG PY 2014 VL 104 IS 4 BP 387 EP 393 PG 7 WC Orthopedics SC Orthopedics GA AQ3KG UT WOS:000342690700010 PM 25076083 ER PT J AU Uihlein, AV Finkelstein, JS Lee, H Leder, BZ AF Uihlein, Alexander V. Finkelstein, Joel S. Lee, Hang Leder, Benjamin Z. TI FSH Suppression Does Not Affect Bone Turnover in Eugonadal Men SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID FOLLICLE-STIMULATING-HORMONE; ANDROGEN-DEPRIVATION THERAPY; POSTMENOPAUSAL WOMEN; MENOPAUSAL TRANSITION; SEX STEROIDS; INHIBIN-B; IN-VITRO; MASS; DENSITY; MARKERS AB Context: In vitro and animal studies have reported conflicting results regarding an independent role for FSH in the regulation of bone turnover. Objective: Our objective was to test the hypothesis that suppressing serum FSH while holding serum gonadal steroid levels stable in the eugonadal range will affect biochemical markers of bone metabolism in healthy men. Participants, Design, and Setting: Eugonadal men aged 20 to 50 years participated in this randomized controlled trial at a tertiary care academic teaching hospital. Interventions: Participants received monthly GnRH analog injections to suppress FSH secretion plus daily topical testosterone gel in prespecified doses (intervention group). Controls received matching placebos (control group). Subjects in the intervention group were individually matched with subjects in the control group to ensure that the mean testosterone and estradiol levels (measured every 4 weeks during the 16-week study period) in the 2 groups were similar. Main Outcome Measures: Biochemical markers of bone resorption (serum N-terminal telopeptide and C-terminal telopeptide), bone formation (serum osteocalcin), and FSH were measured at baseline and after 16 weeks of treatment. Results: Serum FSH declined by 2% in the control group and by 60% in the intervention group (P < .0001 for the between-group difference). Despite the substantial suppression of serum FSH in the intervention group, serum N-terminal telopeptide, C-terminal telopeptide, and osteocalcin did not change in the intervention group, nor were any between-group differences observed. Conclusion: When gonadal steroid levels are held constant, short-to midterm suppressio n of FSH does not affect bone turnover in men. FSH does not appear to be a significant regulator of bone metabolism in eugonadal men. C1 [Uihlein, Alexander V.; Finkelstein, Joel S.; Leder, Benjamin Z.] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Lee, Hang] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. RP Uihlein, AV (reprint author), 50 Blossom St,Thier 1051, Boston, MA 02114 USA. EM alexanderuihlein@gmail.com FU National Institutes of Health [R01 AG030545, K24 KD02759, RR-1066] FX This work was supported by National Institutes of Health Grants R01 AG030545, K24 KD02759, and RR-1066. Additional support was provided by AstraZeneca and AbbVie Inc. NR 31 TC 2 Z9 2 U1 0 U2 0 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 JUL PY 2014 VL 99 IS 7 BP 2510 EP 2515 DI 10.1210/jc.2013-3246 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AP8PM UT WOS:000342341000059 PM 24646101 ER PT J AU Kaufmann, M Gallagher, JC Peacock, M Schlingmann, KP Konrad, M DeLuca, HF Sigueiro, R Lopez, B Mourino, A Maestro, M St-Arnaud, R Finkelstein, JS Cooper, DP Jones, G AF Kaufmann, Martin Gallagher, J. Christopher Peacock, Munro Schlingmann, Karl-Peter Konrad, Martin DeLuca, Hector F. Sigueiro, Rita Lopez, Borja Mourino, Antonio Maestro, Miguel St-Arnaud, Rene Finkelstein, Joel S. Cooper, Donald P. Jones, Glenville TI Clinical Utility of Simultaneous Quantitation of 25-Hydroxyvitamin D and 24,25-Dihydroxyvitamin D by LC-MS/MS Involving Derivatization With DMEQ-TAD SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID TANDEM MASS-SPECTROMETRY; VITAMIN-D SUPPLEMENTATION; AFRICAN-AMERICAN WOMEN; D-3; METABOLITES; CYP24A1; PLASMA; SERUM; PHARMACOKINETICS; DEFICIENCY AB Context: The discovery of hypercalcemic diseases due to loss-of-function mutations in 25-hydroxyvitamin D-24-hydroxylase has placed a new demand for sensitive and precise assays for 24,25-dihydroxyvitamin D [24,25-(OH)(2)D]. Objective: We describe a novel liquid chromatography and tandem mass spectrometry-based method involving derivatization with DMEQ-TAD {4-[2-(6,7-dimethoxy-4-methyl-3,4-dihydroquinoxalinyl) ethyl]-1,2,4-triazoline-3,5-dione} to simultaneously assay multiple vitamin D metabolites including 25-hydroxyvitamin D (25-OH-D) and 24,25-(OH)(2)D using 100 mu L of serum with a 5-minute run time. Design: The assay uses a newly synthesized internal standard d(6)-24,25-(OH)(2)D-3 enabling the quantitation of 24,25-(OH)(2)D-3 as well as the determination of the ratio of 25-OH-D-3 to 24,25-(OH)(2)D-3, a physiologically useful parameter. Setting: We report data on more than 1000 normal and disease samples involving vitamin D deficiency or hypercalcemia in addition to studies involving knockout mouse models. Results: The assay showed good correlation with samples from quality assurance schemes for 25-OH-D (25-OH-D-2 and 25-OH-D-3) determination (-2% to -5% bias) and exhibited low inter-and intraassay coefficients of variation (4%-7%) and lower limits of quantitation of 0.25-0.45 nmol/L. In clinical studies, we found a strong correlation between serum levels of 25-OH-D-3 and 24,25(OH)(2)D-3 (r(2) = 0.80) in subjects over a broad range of 25-OH-D-3 values and a marked lack of production of 24,25-(OH)(2)D-3 below 25 nmol/L of 25-OH-D. The ratio of 25-OH-D-3 to 24,25-(OH)(2)D-3, which remained less than 25 in vitamin D-sufficient subjects (serum 25-OH-D < 50 nmol/L) but was greatly elevated (80-100) in patients with idiopathic infantile hypercalcemia. Conclusions: The new method showed good utility in clinical settings involving vitamin D deficiency; supplementation with vitamin D and idiopathic infantile hypercalcemia, as well as in animal models with ablation of selected cytochrome P450-containing enzymes involved in vitamin D metabolism. C1 [Kaufmann, Martin; Jones, Glenville] Queens Univ, Dept Biomed & Mol Sci, Kingston, ON K7L 3N6, Canada. [Gallagher, J. Christopher] Creighton Univ, Sch Med, Bone Metab Unit, Omaha, NE 68131 USA. [Peacock, Munro] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Schlingmann, Karl-Peter; Konrad, Martin] Univ Childrens Hosp, Dept Gen Pediat, D-48149 Munster, Germany. [DeLuca, Hector F.] Univ Wisconsin, Dept Biochem, Madison, WI 53706 USA. [Sigueiro, Rita; Lopez, Borja; Mourino, Antonio; Maestro, Miguel] Univ Santiago de Compostela, Lab Ignacio Ribas, Dept Quim Organ, Santiago De Compostela 15782, Spain. [Sigueiro, Rita] McGill Univ, Shriners Hosp Children Canada, Montreal, PQ H3G 1A6, Canada. [Finkelstein, Joel S.] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Cooper, Donald P.] Waters Corp, Hlth Sci Res, Wilmslow SK9 4AX, Cheshire, England. RP Jones, G (reprint author), Queens Univ, Dept Biomed & Mol Sci, Kingston, ON K7L 3N6, Canada. EM gj1@queensu.ca FU National Institutes on Aging [RO1-AG28168]; US Department of Defense [W81XWH-07-1-201]; Xunta de Galicia [CN2012/074, INCITE08PXIB209130PR]; Spanish Ministry of Education and Innovation [SAF2010-15291]; [UL1RR025761] FX J.C.G. was supported by Grant RO1-AG28168 from the National Institutes on Aging and Grant W81XWH-07-1-201 from the US Department of Defense. M.P. was supported by Grant UL1RR025761. A. M. thanks Xunta de Galicia (Project CN2012/074, Grant INCITE08PXIB209130PR), and the Spanish Ministry of Education and Innovation (Project Grant SAF2010-15291) for financial support. R. S. thanks Xunta de Galicia for an Angeles Alvarino grant. NR 36 TC 28 Z9 28 U1 1 U2 12 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 JUL PY 2014 VL 99 IS 7 BP 2567 EP 2574 DI 10.1210/jc.2013-4388 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AP8PM UT WOS:000342341000066 PM 24670084 ER PT J AU Brown, RS Lombardi, A Hasham, A Greenberg, DA Gordon, J Concepcion, E Hammerstad, SS Lotay, V Zhang, W Tomer, Y AF Brown, Rosalind S. Lombardi, Angela Hasham, Alia Greenberg, David A. Gordon, Joshua Concepcion, Erlinda Hammerstad, Sara S. Lotay, Vaneet Zhang, Weijia Tomer, Yaron TI Genetic Analysis in Young-Age-of-Onset Graves' Disease Reveals New Susceptibility Loci SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID THYROID AUTOIMMUNITY; ASSOCIATION; BTNL2; POLYMORPHISMS; PTPN22; FOXP3; MHC AB Context: Genetic and environmental factors play an essential role in the pathogenesis of Graves' Disease (GD). Children with GD have less exposure time to environmental factors and therefore are believed to harbor stronger genetic susceptibility than adults. Objective: The aim of the study was to identify susceptibility loci that predispose to GD in patients with young-age-of-onset (YAO) GD. Setting and Design: One hundred six patients with YAO GD (onset <30 y) and 855 healthy subjects were studied. Cases and controls were genotyped using the Illumina Infinium Immunochip, designed to genotype 196,524 polymorphisms. Case control association analyses were performed using the PLINK computer package. Ingenuity Pathway Analysis program (QIAGEN) was used to carry out pathway analyses. Results: Immunochip genetic association analysis identified 30 single-nucleotide polymorphisms in several genes that were significantly associated with YAO GD, including major histocompatibility complex class I and class II genes, BTNL2, NOTCH4, TNFAIP3, and CXCR4. Candidate gene analysis revealed that most of the genes previously shown to be associated with adult-onset GD were also associated with YAO GD. Pathway analysis demonstrated that antigen presentation, T-helper cell differentiation, and B cell development were the major pathways contributing to the pathogenesis of YAO GD. Conclusions: Genetic analysis identified novel susceptibility loci in YAO GD adding a new dimension to the understanding of GD etiology. C1 [Brown, Rosalind S.; Gordon, Joshua] Childrens Hosp Boston, Div Endocrinol, Boston, MA 02115 USA. [Lombardi, Angela; Hasham, Alia; Concepcion, Erlinda; Hammerstad, Sara S.; Tomer, Yaron] Icahn Sch Med Mt Sinai, Div Endocrinol, New York, NY 10029 USA. [Greenberg, David A.] Nationwide Childrens Hosp, Battelle Ctr Math Med, Columbus, OH 43210 USA. [Lotay, Vaneet; Zhang, Weijia] Mt Sinai Sch Med, Dept Med Bioinformat Core, New York, NY 10029 USA. [Tomer, Yaron] James J Peters VA Med Ctr, Bronx, NY 10468 USA. RP Tomer, Y (reprint author), Icahn Sch Med Mt Sinai, Div Endocrinol, Box 1055,One Gustave L Levy Pl, New York, NY 10029 USA. EM Yaron.Tomer@mssm.edu FU NIDDK [DK061659, DK067555, DK073681]; Department of Veterans Affairs FX This work was supported in part by Grants DK061659, DK067555, and DK073681 from NIDDK. In addition, this material is based upon work supported in part by the Department of Veterans Affairs. NR 20 TC 6 Z9 6 U1 0 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 JUL PY 2014 VL 99 IS 7 BP E1387 EP E1391 DI 10.1210/jc.2013-4358 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AP8PM UT WOS:000342341000031 PM 24684463 ER PT J AU Bechis, SK Otsetov, AG Ge, RB Olumi, AF AF Bechis, Seth K. Otsetov, Alexander G. Ge, Rongbin Olumi, Aria F. TI Personalized Medicine for the Management of Benign Prostatic Hyperplasia SO JOURNAL OF UROLOGY LA English DT Review DE prostate; prostatic hyperplasia; 5-alpha reductase inhibitors; finasteride; individualized medicine ID URINARY-TRACT SYMPTOMS; ANDROGEN-RECEPTOR; FINASTERIDE; BPH; MEN; CANCER; VOLUME; RISK; SUSCEPTIBILITY; REDUCTION AB Purpose: Benign prostatic hyperplasia affects more than 50% of men by age 60 years, and is the cause of millions of dollars in health care expenditure for the treatment of lower urinary tract symptoms and urinary obstruction. Despite the widespread use of medical therapy, there is no universal therapy that treats all men with symptomatic benign prostatic hyperplasia. At least 30% of patients do not respond to medical management and a subset require surgery. Significant advances have been made in understanding the natural history and development of the prostate, such as elucidating the role of the enzyme 5 alpha-reductase type 2, and advances in genomics and biomarker discovery offer the potential for a more targeted approach to therapy. We review the current understanding of benign prostatic hyperplasia progression as well as the key genes and signaling pathways implicated in the process such as 5 alpha-reductase. We also explore the potential of biomarker screening and gene specific therapies as tools to risk stratify patients with benign prostatic hyperplasia and identify those with symptomatic or medically resistant forms. Materials and Methods: A PubMed (R) literature search of current and past peer reviewed literature on prostate development, lower urinary tract symptoms, benign prostatic hyperplasia pathogenesis, targeted therapy, biomarkers, epigenetics, 5 alpha-reductase type 2 and personalized medicine was performed. An additional Google Scholar (TM) search was conducted to broaden the scope of the review. Relevant reviews and original research articles were examined, as were their cited references, and a synopsis of original data was generated with the goal of informing the practicing urologist of these advances and their implications. Results: Benign prostatic hyperplasia is associated with a state of hyperplasia of the stromal and epithelial compartments, with 5 alpha-reductase type 2 and androgen signaling having key roles in the development and maintenance of the prostate. Chronic inflammation, multiple growth factor and hormonal signaling pathways, and medical comorbidities have complex roles in prostate tissue homeostasis as well as its evolution into the clinical state of benign prostatic hyperplasia. Resistance to medical therapy with finasteride may occur through silencing of the 5 alpha-reductase type 2 gene by DNA methylation, leading to a state in which 30% of adult prostates do not express 5 alpha-reductase type 2. Novel biomarkers such as single nucleotide polymorphisms may be used to risk stratify patients with symptomatic benign prostatic hyperplasia and identify those at risk for progression or failure of medical therapy. Several inhibitors of the androgen receptor and other signaling pathways have recently been identified which appear to attenuate benign prostatic hyperplasia progression and may offer alternative targets for medical therapy. Conclusions: Progressive worsening of lower urinary tract symptoms and bladder outlet obstruction secondary to benign prostatic hyperplasia is the result of multiple pathways including androgen receptor signaling, proinflammatory cytokines and growth factor signals. New techniques in genomics, proteomics and epigenetics have led to the discovery of aberrant signaling pathways, novel biomarkers, DNA methylation signatures and potential gene specific targets. As personalized medicine continues to develop, the ability to risk stratify patients with symptomatic benign prostatic hyperplasia, identify those at higher risk for progression, and seek alternative therapies for those in whom conventional options are likely to fail will become the standard of targeted therapy. C1 [Bechis, Seth K.; Otsetov, Alexander G.; Ge, Rongbin; Olumi, Aria F.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Urol, Boston, MA USA. RP Olumi, AF (reprint author), Massachusetts Gen Hosp, Dept Urol, 55 Fruit St,Yawkey Bldg,Suite 7E, Boston, MA 02114 USA. EM Olumi.Aria@mgh.harvard.edu FU [NIH-R01DK091353] FX Supported by Grant NIH-R01DK091353. NR 47 TC 16 Z9 16 U1 2 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD JUL PY 2014 VL 192 IS 1 BP 16 EP 23 DI 10.1016/j.juro.2014.01.114 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA AP4XG UT WOS:000342082600005 PM 24582540 ER PT J AU Coulter, RWS Kenst, KS Bowen, DJ Scout AF Coulter, Robert W. S. Kenst, Karey S. Bowen, Deborah J. Scout TI NATIONAL INSTITUTES OF HEALTH EFFORTS ON SEXUAL AND GENDER MINORITY HEALTH RESEARCH RESPONSE SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Letter C1 [Coulter, Robert W. S.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Behav & Community Hlth Sci, Pittsburgh, PA 15261 USA. [Kenst, Karey S.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Dispar Solut Ctr, Boston, MA 02114 USA. [Bowen, Deborah J.] Boston Univ, Sch Publ Hlth, Dept Community Hlth Sci, Boston, MA USA. [Scout] CenterLink Community LGBT Ctr, Network LGBT Hlth Equ, Ft Lauderdale, FL USA. RP Coulter, RWS (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, Dept Behav & Community Hlth Sci, 130 DeSoto St, Pittsburgh, PA 15261 USA. EM robert.ws.coulter@gmail.com OI Coulter, Robert/0000-0001-8350-0075 NR 2 TC 0 Z9 0 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD JUL PY 2014 VL 104 IS 7 BP E7 EP E8 DI 10.2105/AJPH.2014.302028 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AP1EM UT WOS:000341809500007 PM 24832436 ER PT J AU Mishra, SV Jethwani, KS AF Mishra, S., V Jethwani, K. S. TI Combating the spread of HIV among Indian migrants SO JOURNAL OF POSTGRADUATE MEDICINE LA English DT Editorial Material ID FEMALE SEX WORKERS; COMMERCIAL SEX; RISK BEHAVIOR; ALCOHOL-USE; MEN C1 [Mishra, S., V] Decimal Fdn, Bombay, Maharashtra, India. [Mishra, S., V] Atlas Corps, Washington, DC USA. [Mishra, S., V; Jethwani, K. S.] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Jethwani, K. S.] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Jethwani, K. S.] Partners Hlth Care, Ctr Connected Hlth, Boston, MA USA. RP Jethwani, KS (reprint author), Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. EM kjethwani@partners.org NR 15 TC 0 Z9 0 U1 0 U2 1 PU MEDKNOW PUBLICATIONS & MEDIA PVT LTD PI MUMBAI PA B-9, KANARA BUSINESS CENTRE, OFF LINK RD, GHAKTOPAR-E, MUMBAI, 400075, INDIA SN 0022-3859 J9 J POSTGRAD MED JI J. Postgrad. Med. PD JUL-SEP PY 2014 VL 60 IS 3 BP 233 EP 234 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AP1SU UT WOS:000341852500004 PM 25272387 ER PT J AU Jude, CM Nayak, NB Patel, MK Deshmukh, M Batra, P AF Jude, Cecilia M. Nayak, Nita B. Patel, Maitraya K. Deshmukh, Monica Batra, Poonam TI Pulmonary Coccidioidomycosis: Pictorial Review of Chest Radiographic and CT Findings SO RADIOGRAPHICS LA English DT Article ID PLEURAL EFFUSION; FUNGAL PNEUMONIAS; NEEDLE-BIOPSY; CALIFORNIA; DIAGNOSIS; IMMUNOCOMPETENT; EXPERIENCE; INFECTION; SPHERULES; SPECTRUM AB Pulmonary coccidioidomycosis is a fungal disease endemic to the desert regions of the southwestern United States, Mexico, Central America, and South America. The incidence of reported disease increased substantially between 1998 and 2011, and the infection is encountered beyond the endemic areas because of a mobile society. The disease is caused by inhalation of spores of Coccidioides species. Individuals at high risk are those exposed to frequent soil aerosolization. The diagnosis is established by direct visualization of mature spherules by using special stains or cultures from biologic specimens. Serologic testing of anticoccidioidal antibodies is used for diagnosis and treatment monitoring. The infection is self-limited in 60% of cases. When the disease is symptomatic, the lung is the primary site of involvement. On the basis of clinical presentation and imaging abnormalities, pulmonary involvement is categorized into acute, disseminated, and chronic forms, each with a spectrum of imaging findings. In patients with acute disease, the most common findings are lobar or segmental consolidation, multifocal consolidation, and nodules. Adenopathy and pleural effusions are also seen, usually in association with parenchymal disease. Disseminated disease is rare and occurs in less than 1% of patients. Pulmonary findings are miliary nodules and confluent parenchymal opacities. Acute respiratory distress syndrome is an infrequent complication of disseminated disease. The acute findings resolve in most patients, with chronic changes developing in approximately 5% of patients. Manifestations of chronic disease include residual nodules, chronic cavities, persistent pneumonia with or without adenopathy, pleural effusion, and regressive changes. Unusual complications of chronic disease are mycetoma, abscess formation, and bronchopleural fistula. Patients in an immunocompromised state, those with diabetes mellitus, pregnant women, and those belonging to certain ethnic groups may show severe, progressive, or disseminated disease. (C) RSNA, 2014 C1 [Jude, Cecilia M.; Patel, Maitraya K.; Deshmukh, Monica] Olive View UCLA Med Ctr, Dept Radiol, Sylmar, CA 91342 USA. [Jude, Cecilia M.; Batra, Poonam] W Los Angeles Vet Affairs Med Ctr, Imaging Serv, Los Angeles, CA USA. [Jude, Cecilia M.; Nayak, Nita B.; Patel, Maitraya K.; Deshmukh, Monica; Batra, Poonam] Univ Calif Los Angeles, David Geffen Sch Med, Dept Radiol Sci, Los Angeles, CA 90095 USA. RP Jude, CM (reprint author), Olive View UCLA Med Ctr, Dept Radiol, 14445 Olive View Dr,2D115, Sylmar, CA 91342 USA. EM mjude@outlook.com NR 50 TC 3 Z9 3 U1 0 U2 2 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0271-5333 J9 RADIOGRAPHICS JI Radiographics PD JUL-AUG PY 2014 VL 34 IS 4 BP 912 EP 925 DI 10.1148/rg.344130134 PG 14 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AP2QA UT WOS:000341917400008 PM 25019431 ER PT J AU Humphreys, BD AF Humphreys, Benjamin D. TI Introduction: Stem Cells and Kidney Regeneration SO SEMINARS IN NEPHROLOGY LA English DT Editorial Material C1 Brigham & Womens Hosp, Dana Farber Canc Inst, Harvard Stem Cell Inst, Boston, MA 02115 USA. RP Humphreys, BD (reprint author), Brigham & Womens Hosp, Dana Farber Canc Inst, Harvard Stem Cell Inst, 75 Francis St, Boston, MA 02115 USA. NR 6 TC 1 Z9 1 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0270-9295 EI 1558-4488 J9 SEMIN NEPHROL JI Semin. Nephrol. PD JUL PY 2014 VL 34 IS 4 BP 349 EP 350 DI 10.1016/j.semnephrol.2014.06.001 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA AP5LF UT WOS:000342120000001 PM 25217263 ER PT J AU Madariaga, MLL Ott, HC AF Madariaga, Maria Lucia L. Ott, Harald C. TI Bioengineering Kidneys for Transplantation SO SEMINARS IN NEPHROLOGY LA English DT Review DE Kidney; bioengineering; organ engineering; perfusion decellularization; transplantation ID PLURIPOTENT STEM-CELLS; ACUTE-RENAL-FAILURE; REGENERATIVE MEDICINE; IN-VIVO; ORGAN-TRANSPLANTATION; BIOARTIFICIAL KIDNEY; EXTRACELLULAR-MATRIX; EPITHELIAL-CELLS; ORTHOTOPIC TRANSPLANTATION; DECELLULARIZED MATRIX AB One in 10 Americans suffers from chronic kidney disease, and close to 90,000 people die each year from causes related to kidney failure. Patients with end-stage renal disease are faced with two options: hemodialysis or transplantation. Unfortunately, the transplantation option is limited because of the shortage of donor organs and the need for immunosuppression. Bioengineered kidney grafts theoretically present a novel solution to both problems. Herein, we discuss the history of bioengineering organs, the current status of bioengineered kidneys, considerations for the future of the field, and challenges to clinical translation. We hope that by integrating principles of tissue engineering, and stem cell and developmental biology, bioengineered kidney grafts will advance the field of regenerative medicine while meeting a critical clinical need. (C) 2014 Elsevier Inc. All rights reserved. C1 [Madariaga, Maria Lucia L.; Ott, Harald C.] Massachusetts Gen Hosp, Dept Surg, Div Thorac Surg, Boston, MA 02114 USA. [Madariaga, Maria Lucia L.; Ott, Harald C.] Harvard Univ, Sch Med, Harvard Stem Cell Inst, Boston, MA 02114 USA. [Madariaga, Maria Lucia L.; Ott, Harald C.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. RP Ott, HC (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Thorac Surg,Dept Surg, 55 Fruit St,Blake 15, Boston, MA 02114 USA. EM hott@mgh.harvard.edu FU International Heart and Lung Transplantation Society; National Heart, Lung, and Blood Institute of the National Institutes of Health [F32HL117540]; National Institutes of Health Director's New Innovator Award [DP2 OD008749-01] FX Supported by a fellowship from the International Heart and Lung Transplantation Society and fellowship award F32HL117540 from the National Heart, Lung, and Blood Institute of the National Institutes of Health (M.L.L.M.), and the kidney regeneration project was supported by the National Institutes of Health Director's New Innovator Award (DP2 OD008749-01 to H.C.O.). NR 98 TC 3 Z9 3 U1 5 U2 32 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0270-9295 EI 1558-4488 J9 SEMIN NEPHROL JI Semin. Nephrol. PD JUL PY 2014 VL 34 IS 4 BP 384 EP 393 DI 10.1016/j.semnephrol.2014.06.005 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA AP5LF UT WOS:000342120000005 PM 25217267 ER PT J AU Jacobsen, HB Reme, SE Sembajwe, G Hopcia, K Stoddard, AM Kenwood, C Stiles, TC Sorensen, G Buxton, OM AF Jacobsen, Henrik B. Reme, Silje Endresen Sembajwe, Grace Hopcia, Karen Stoddard, Anne M. Kenwood, Christopher Stiles, Tore C. Sorensen, Glorian Buxton, Orfeu M. TI Work-Family Conflict, Psychological Distress, and Sleep Deficiency Among Patient Care Workers SO WORKPLACE HEALTH & SAFETY LA English DT Article ID DEMANDS-CONTROL MODEL; FULL-TIME; CARDIOVASCULAR-DISEASE; MAJOR DEPRESSION; JOB STRAIN; PART-TIME; INSOMNIA; HEALTH; ADULTS; PERFORMANCE AB This study examined whether work-family conflict was associated with sleep deficiencies, both cross-sectionally and longitudinally. In this two-phase study, a workplace health survey was completed by a cohort of patient care workers (n = 1,572). Additional data were collected 2 years later from a subsample of the original respondents (n = 102). Self-reported measures included work-family conflict, workplace factors, and sleep outcomes. The participants were 90% women, with a mean age of 41 +/- 11.7 years. At baseline, after adjusting for covariates, higher levels of work-family conflict were significantly associated with sleep deficiency. Higher levels of work-family conflict also predicted sleep insufficiency nearly 2 years later. The first study to determine the predictive association between work-family conflict and sleep deficiency suggests that future sleep interventions should include a specific focus on work-family conflict. C1 [Jacobsen, Henrik B.; Reme, Silje Endresen; Sembajwe, Grace; Hopcia, Karen; Sorensen, Glorian; Buxton, Orfeu M.] Harvard Univ, Sch Publ Hlth, Ctr Work Hlth & Well Being, Boston, MA 02115 USA. [Jacobsen, Henrik B.; Stiles, Tore C.] Norwegian Univ Sci & Technol, N-7491 Trondheim, Norway. [Reme, Silje Endresen] Uni Res, Uni Hlth, Bergen, Norway. [Sembajwe, Grace] CUNY Hunter Coll, Sch Publ Hlth, New York, NY 10021 USA. [Sembajwe, Grace; Sorensen, Glorian] Dana Farber Canc Inst, Boston, MA 02115 USA. [Hopcia, Karen] Univ Illinois, Coll Nursing, Chicago, IL USA. [Stoddard, Anne M.; Kenwood, Christopher] New England Res Inst, Watertown, MA 02172 USA. [Buxton, Orfeu M.] Harvard Univ, Sch Med, Div Sleep Med, Boston, MA USA. [Buxton, Orfeu M.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Buxton, Orfeu M.] Penn State Univ, Dept Behav Hlth, University Pk, PA 16802 USA. RP Jacobsen, HB (reprint author), Norwegian Univ Sci & Technol, Dept Publ Hlth Circulat & Med Imaging, POB 8905 MTFS, N-7491 Trondheim, Norway. EM henrik.b.jacobsen@ntnu.no FU National Institute for Occupational Safety and Health for the Harvard School of Public Health Center for Work, Health and Well-being [U19 OH008861]; Harvard Clinical and Translational Science Center from the National Center for Research Resources [UL1 RR025758-04]; Partners Occupational Health; [HL R01HL107240] FX Supported by a grant from the National Institute for Occupational Safety and Health (U19 OH008861) for the Harvard School of Public Health Center for Work, Health and Well-being, the Harvard Clinical and Translational Science Center (grant UL1 RR025758-04 from the National Center for Research Resources, and additional support was provided by Partners Occupational Health. Dr. Buxton is in part support by HL R01HL107240. NR 46 TC 6 Z9 6 U1 5 U2 15 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 2165-0799 EI 2165-0969 J9 WORKPLACE HEALTH SAF JI Workplace Health Saf. PD JUL PY 2014 VL 62 IS 7 BP 282 EP 291 DI 10.3928/21650799-20140617-04 PG 10 WC Nursing SC Nursing GA AP3FB UT WOS:000341959900003 PM 25000547 ER PT J AU Wollenberg, MS Claesen, J Escapa, IF Aldridge, KL Fischbach, MA Lemon, KP AF Wollenberg, Michael S. Claesen, Jan Escapa, Isabel F. Aldridge, Kelly L. Fischbach, Michael A. Lemon, Katherine P. TI Propionibacterium-Produced Coproporphyrin III Induces Staphylococcus aureus Aggregation and Biofilm Formation SO MBIO LA English DT Article ID EXTRACELLULAR ELECTRON-TRANSFER; COMPLETE GENOME SEQUENCE; NASAL CARRIAGE; HEME-BIOSYNTHESIS; PORPHYRIN PRODUCTION; PERITONEAL-DIALYSIS; HUMAN MICROBIOME; UNITED-STATES; HUMAN SKIN; IN-VIVO AB The majority of bacteria detected in the nostril microbiota of most healthy adults belong to three genera: Propionibacterium, Corynebacterium, and Staphylococcus. Among these staphylococci is the medically important bacterium Staphylococcus aureus. Almost nothing is known about interspecies interactions among bacteria in the nostrils. We observed that crude extracts of cell-free conditioned medium from Propionibacterium spp. induce S. aureus aggregation in culture. Bioassay-guided fractionation implicated coproporphyrin III (CIII), the most abundant extracellular porphyrin produced by human-associated Propionibacterium spp., as a cause of S. aureus aggregation. This aggregation response depended on the CIII dose and occurred during early stationary-phase growth, and a low pH (similar to 4 to 6) was necessary but was not sufficient for its induction. Additionally, CIII induced plasma-independent S. aureus biofilm development on an abiotic surface in multiple S. aureus strains. In strain UAMS-1, CIII stimulation of biofilm depended on sarA, a key biofilm regulator. This study is one of the first demonstrations of a small-molecule-mediated interaction among medically relevant members of the nostril microbiota and the first description of a role for CIII in bacterial interspecies interactions. Our results indicate that CIII may be an important mediator of S. aureus aggregation and/or biofilm formation in the nostril or other sites inhabited by Propionibacterium spp. and S. aureus. IMPORTANCE Very little is known about interspecies interactions among the bacteria that inhabit the adult nostril, including Staphylococcus aureus, a potential pathogen that colonizes about a quarter of adults. We demonstrated that coproporphyrin III (CIII), a diffusible small molecule excreted by nostril-and skin-associated Propionibacterium spp., induces S. aureus aggregation in a manner dependent on dose, growth phase, and pH. CIII also induces S. aureus to form a plasma-independent surface-attached biofilm. This report is the first description of a role for CIII in bacterial interspecies interactions at any human body site and a novel demonstration that nostril microbiota physiology is influenced by small-molecule-mediated interactions. C1 [Wollenberg, Michael S.; Escapa, Isabel F.; Aldridge, Kelly L.; Lemon, Katherine P.] Forsyth Inst, Dept Microbiol, Cambridge, MA 02142 USA. [Wollenberg, Michael S.; Escapa, Isabel F.] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. [Claesen, Jan; Fischbach, Michael A.] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA. [Claesen, Jan; Fischbach, Michael A.] Univ Calif San Francisco, Calif Inst Quantitat Biosci, San Francisco, CA 94143 USA. [Lemon, Katherine P.] Harvard Univ, Div Infect Dis, Boston Childrens Hosp, Sch Med, Boston, MA USA. RP Lemon, KP (reprint author), Forsyth Inst, Dept Microbiol, Cambridge, MA 02142 USA. EM klemon@forsyth.org OI Claesen, Jan/0000-0002-0755-7974 FU NIH through the Forsyth Postdoctoral Training in Oral Health Research [T32 DE007327, DE020751, AI101018, OD007290]; Boston Children's Hospital Career Development Fellowship; Fundacion Ramon Areces Fellowship; Medical Research Program grant from the WM Keck Foundation; David and Lucile Packard Foundation; NIH Human Microbiome Project (HMP), the Common Fund, NIH, DHHS, as part of the HMP FX This work was supported in part by NIH through the Forsyth Postdoctoral Training in Oral Health Research T32 DE007327 (M. S. W.), DE020751 (K. P. L.), AI101018 (K. P. L., M. A. F.), and OD007290 (M. A. F.) and by a Boston Children's Hospital Career Development Fellowship (K. P. L.), a Fundacion Ramon Areces Fellowship (I. F. E.), a Medical Research Program grant from the WM Keck Foundation (M. A. F.), and a Fellowship for Science and Engineering from the David and Lucile Packard Foundation (M. A. F.). Genomic data used to identify KPL strains to the species level were generated in part with U.S. federal funds from the NIH Human Microbiome Project (HMP), the Common Fund, NIH, DHHS, as part of the HMP. NR 63 TC 10 Z9 10 U1 1 U2 21 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD JUL-AUG PY 2014 VL 5 IS 4 AR e01286-14 DI 10.1128/mBio.01286-14 PG 10 WC Microbiology SC Microbiology GA AO8FE UT WOS:000341588100067 PM 25053784 ER PT J AU Cronin, PR Kimball, AB AF Cronin, Patrick R. Kimball, Alexa Boer TI Success of Automated Algorithmic Scheduling in an Outpatient Setting SO AMERICAN JOURNAL OF MANAGED CARE LA English DT Article ID RANDOMIZED-CONTROLLED-TRIAL; NO-SHOW RATES; REMINDER SYSTEMS; ATTENDANCE; ACCESS; OVERBOOKING; TELEPHONE; TIME; INTERVENTION; VACCINATION AB Objective To determine if algorithmically generated double-booking recommendations could increase patient volume per clinical session without increasing the burden on physicians. Study Design A randomized controlled trial was conducted with 519 clinical sessions for 13 dermatologists from December 1, 2011, through March 31, 2012. Methods Sessions were randomly assigned to "Smart-Booking," an algorithm that generates double-booking recommendations using a missed appointment (no-shows + same-day cancellations) predictive model (c-statistic 0.71), or to a control arm where usual booking rules were applied.The primary outcomes were the average number and variance of arrived patients per session, after controlling by physician. In addition, physicians received a survey after each session to quantify how busy they felt during that session. Results 257 sessions were randomized to Smart-Booking and 262 sessions were randomized to control booking. Using a generalized multi-variate linear model, the average number of arrived patients per session was higher in the Smart-Booking intervention arm than the control (15.7 vs 15.2, difference between groups 4.2; 95% CI, 0.08-0.75; P=.014).The variance was also higher in the intervention than control (3.72 vs 3.33, P=.38).The survey response rate was 92% and the physicians reported being similarly busy in each study arm. Conclusions Algorithmically generated double-booking recommendations of dermatology clinical sessions using individual physician assumptions and predictive modeling can increase the number of arrived patients without overburdening physicians, and is likely scalable to other settings. C1 [Cronin, Patrick R.] Massachusetts Gen Hosp, Practice Improvement Div, Boston, MA 02114 USA. [Kimball, Alexa Boer] Harvard Univ, Sch Med, Dept Dermatol, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Cronin, PR (reprint author), 50 Staniford St,7th Fl, Boston, MA 02114 USA. EM prcronin@partners.org FU Massachusetts General Physicians Organization FX Source of Funding: Massachusetts General Physicians Organization. NR 42 TC 4 Z9 4 U1 0 U2 3 PU MANAGED CARE & HEALTHCARE COMMUNICATIONS LLC PI PLAINSBORO PA 666 PLAINSBORO RD, STE 300, PLAINSBORO, NJ 08536 USA SN 1088-0224 J9 AM J MANAG CARE JI Am. J. Manag. Care PD JUL PY 2014 VL 20 IS 7 BP 570 EP 576 PG 7 WC Health Care Sciences & Services; Health Policy & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AO9MI UT WOS:000341679400005 PM 25295403 ER PT J AU Alidina, S Schneider, EC Singer, SJ Rosenthal, MB AF Alidina, Shehnaz Schneider, Eric C. Singer, Sara J. Rosenthal, Meredith B. TI Structural Capabilities in Small- and Medium-Sized Patient-Centered Medical Homes SO AMERICAN JOURNAL OF MANAGED CARE LA English DT Article ID PRIMARY-CARE PRACTICES; QUALITY IMPROVEMENT COLLABORATIVES; HEALTH-CARE; INFRASTRUCTURE; VIRGINIA; MODEL AB Objectives 1) Evaluate structural capabilities associated with the patient-centered medical home (PCMH) model in PCMH pilots in Colorado, Ohio, and Rhode Island; 2) evaluate changes in capabilities over 2 years in the Rhode Island pilot; and 31 evaluate facilitators and barriers to the adoption of capabilities. Study Design We assessed structural capabilities in the 30 pilot practices using a cross-sectional study design and examined changes over 2 years in 5 Rhode Island practices using a pre/post design. Methods We used National Committee for Quality Assurance's Physician Practice Connections Patient-Centered Medical Home (PPC-PCMH) accreditation survey data to measure capabilities. We stratified by high and low performance based on total score and by practice size. We analyzed change from baseline to 24 months for the Rhode Island practices. We analyzed qualitative data from interviews with practice leaders to identify facilitators and barriers to building capabilities. Results On average, practices scored 73 points (out of 100 points) for structural capabilities. High and low performers differed most on electronic prescribing, patient self-management, and care-management standards. Rhode Island practices averaged 42 points at baseline, and reached 90 points by the end of year 2. Some of the key facilitators that emerged were payment incentives, "transformation coaches," learning collaboratives, and data availability supporting performance management and quality improvement. Barriers to improvement included the extent of transformation required, technology shortcomings, slow cultural change, change fatigue, and lack of broader payment reform. Conclusions For these early adopters, prevalence of structural capabilities was high, and performance was substantially improved for practices with initially lower capabilities. We conclude that building capabilities requires payment reform, attention to implementation, and cultural change. C1 [Alidina, Shehnaz; Schneider, Eric C.; Singer, Sara J.; Rosenthal, Meredith B.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Schneider, Eric C.] RAND Corp, Boston, MA USA. [Schneider, Eric C.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Schneider, Eric C.; Singer, Sara J.] Harvard Univ, Sch Med, Boston, MA USA. [Singer, Sara J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Alidina, S (reprint author), 170 Brookline Ave,Apt 330, Boston, MA 02215 USA. EM sha248@mail.harvard.edu FU Commonwealth Fund; Colorado Trust; dissertation grant from the Canada Program; Weatherhead Center for International Affairs; Canadian Federation of University Women FX The research was approved by the institutional review board at the Harvard School of Public Health and financially supported by the Commonwealth Fund and Colorado Trust (Principle Investigator: Dr Rosenthal). Ms. Alidina's effort on this project was supported by a dissertation grant from the Canada Program, Weatherhead Center for International Affairs and the Canadian Federation of University Women. NR 36 TC 2 Z9 2 U1 2 U2 9 PU MANAGED CARE & HEALTHCARE COMMUNICATIONS LLC PI PLAINSBORO PA 666 PLAINSBORO RD, STE 300, PLAINSBORO, NJ 08536 USA SN 1088-0224 J9 AM J MANAG CARE JI Am. J. Manag. Care PD JUL PY 2014 VL 20 IS 7 BP E265 EP U130 PG 22 WC Health Care Sciences & Services; Health Policy & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AO9MI UT WOS:000341679400010 PM 25295546 ER PT J AU Keyhani, S Cheng, EM Ofner, S Williams, LS Halm, EA Bravata, DM AF Keyhani, Salomeh Cheng, Eric M. Ofner, Susan Williams, Linda S. Halm, Ethan A. Bravata, Dawn M. TI The Underuse of Interventions in Veterans With Symptomatic Carotid Stenosis SO AMERICAN JOURNAL OF MANAGED CARE LA English DT Article ID MEDICARE BENEFICIARIES; ARTERY STENOSIS; STROKE CARE; ENDARTERECTOMY; APPROPRIATENESS; TRIAL; OUTCOMES; QUALITY; MULTICENTER; PREVENTION AB Objectives To examine the receipt of carotid intervention among eligible patients post stroke in the Veterans Health Administration (VA). Methods We examined whether veterans admitted to OVA medical center in 2007 with a diagnosis of stroke and who were eligible for intervention, received carotid intervention in a period up to 6 months after their index hospitalization. We also examined whether demographics, comorbid conditions, stroke severity and availability of vascular intervention services were independently associated with receipt of intervention. Results Among the 5721 patients admitted, 253 ischemic stroke patients had evidence of some carotid stenosis and had data on side of stroke available. Among the 200 patients who had at least 50% to 99% stenosis of the carotid artery, 34 (17%) received intervention (95% confidence interval [CI], 11.79%-22.21%). In a multivariable model, black race and past history of diabetes were significantly associated with carotid intervention: An eligible black patient was 6 times more likely to NOT receive intervention compared to patients of other races (adjusted odds ratio [OR] = 6.54; 95% CI, 1.34-31.9), and a patient with diabetes was 3 times more likely to NOT receive intervention (adjusted OR = 3.38; 95% CI, 1.24-9.24) compared to nondiabetics. Stroke severity and availability of vascular surgery services was not associated with receipt of intervention. Conclusions Few patients with symptomatic carotid stenosis who were admitted with stroke to the VA received carotid intervention. Future research should be directed at improving access to this procedure among eligible patients in the VA. C1 [Keyhani, Salomeh] San Francisco VA Med Ctr, HSR&D REAP, San Francisco, CA 94121 USA. [Keyhani, Salomeh] UCSF, Div Gen Internal Med, San Francisco, CA USA. [Cheng, Eric M.] VA Greater Los Angeles Healthcare Syst, Dept Neurol, Los Angeles, CA USA. [Cheng, Eric M.] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA. [Williams, Linda S.] Richard L Roudebush VA Med Ctr, VHA HSR&D Ctr Excellence Implementing Evidence Ba, Indianapolis, IN USA. [Williams, Linda S.] Indiana Univ Sch Med, Indiana Univ Ctr Aging Res, Indianapolis, IN 46202 USA. [Williams, Linda S.] Regenstrief Inst Hlth Care, Indianapolis, IN 46202 USA. [Ofner, Susan] Indiana Univ Sch Med, Dept Biostat, Indianapolis, IN 46202 USA. [Keyhani, Salomeh; Cheng, Eric M.; Ofner, Susan; Williams, Linda S.; Bravata, Dawn M.] VHA HSR&D Stroke Qual Enhancement Res Initiat Pro, Indianapolis, IN USA. [Williams, Linda S.; Bravata, Dawn M.] Indiana Univ Sch Med, Dept Neurol, Indianapolis, IN 46202 USA. [Bravata, Dawn M.] Indiana Univ Sch Med, Dept Internal Med, Indianapolis, IN 46202 USA. [Halm, Ethan A.] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA. [Halm, Ethan A.] Univ Texas SW Med Ctr Dallas, Dept Clin Sci, Dallas, TX 75390 USA. RP Keyhani, S (reprint author), San Francisco VA Med Ctr, 4150 Clement St,111A1, San Francisco, CA 94121 USA. EM salomeh.keyhani@ucsf.edu FU Department of Veterans Affairs, Veterans Health Administration (VHA), Office of Quality and Performance and Health Services Research and Development Service Quality Enhancement Research Initiative [RRP 09484]; VA HSR&D Career Development Award; Career Development Award from NIH/NINDS [K23NS058571] FX The project reported here was supported by the Department of Veterans Affairs, Veterans Health Administration (VHA), Office of Quality and Performance and Health Services Research and Development Service Quality Enhancement Research Initiative (RRP 09484). SK is also supported by a VA HSR&D Career Development Award. EMC is supported by a Career Development Award from NIH/NINDS (K23NS058571). NR 29 TC 0 Z9 0 U1 0 U2 0 PU MANAGED CARE & HEALTHCARE COMMUNICATIONS LLC PI PLAINSBORO PA 666 PLAINSBORO RD, STE 300, PLAINSBORO, NJ 08536 USA SN 1088-0224 J9 AM J MANAG CARE JI Am. J. Manag. Care PD JUL PY 2014 VL 20 IS 7 BP E250 EP E256 PG 7 WC Health Care Sciences & Services; Health Policy & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AO9MI UT WOS:000341679400008 PM 25295544 ER PT J AU Naarding, MA Fernandez, N Kappes, JC Hayes, P Ahmed, T Icyuz, M Edmonds, TG Bergin, P Anzala, O Hanke, T Clark, L Cox, JH Cormier, E Ochsenbauer, C Gilmour, J AF Naarding, Marloes A. Fernandez, Natalia Kappes, John C. Hayes, Peter Ahmed, Tina Icyuz, Mert Edmonds, Tara G. Bergin, Philip Anzala, Omu Hanke, Tomas Clark, Lorna Cox, Josephine H. Cormier, Emmanuel Ochsenbauer, Christina Gilmour, Jill TI Development of a luciferase based viral inhibition assay to evaluate vaccine induced CD8 T-cell responses SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Review DE HIV; Vaccine Clinical trial; CD8 T cells; Viral inhibition assay; Renilla reniformis luciferase; Infectious molecular clones ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACUTE HIV-1 INFECTION; TYPE-1 INFECTION; MOLECULAR CLONES; REPLICATION; LYMPHOCYTES; SUPPRESSION; BREADTH; ENTRY; NEUTRALIZATION AB Emergence of Sly and HIV specific CD8 T cells has been shown to correlate with control of in vivo replication. Poor correlation between IFNI/ ELISPOT responses and in vivo control of the virus has triggered the development of more relevant assays to assess functional HIV-1 specific CD8 T-cell responses for the evaluation and prioritization of new HIV-1 vaccine candidates. We previously established a viral inhibition assay (VIA) that measures the ability of vaccine-induced CD8 T-cell responses to inhibit viral replication in autologous CD4 T cells. In this assay, viral replication is determined by measuring p24 in the culture supernatant. Here we describe the development of a novel VIA, referred to as IMC LucR VIA that exploits replication-competent HIV-1 infectious molecular clones (IMCs) in which the complete proviral genome is strain-specific and which express the Renilla luciferase (LucR) gene to determine viral growth and inhibition. The introduction of the luciferase readout does provide significant improvement of the read out time. In addition to switching to the LucR read out, changes made to the overall protocol resulted in the miniaturization of the assay from a 48 to a 96-well plate format, which preserved sample and allowed for the introduction of replicates. The overall assay time was reduced from 13 to 8 days. The assay has a high degree of specificity, and the previously observed non-specific background inhibition in cells from HIV-1 negative volunteers has been reduced dramatically. Importantly, we observed an increase in positive responses, indicating an improvement in sensitivity compared to the original VIA. Currently, only a limited number of "whole-genome" IMC-LucR viruses are available and our efforts will focus on expanding the panel to better evaluate anti-viral breadth. Overall, we believe the IMC LucR VIA provides a platform to assess functional CD8 T-cell responses in large-scale clinical trial testing, which will enhance the ability to select the most promising HIV-1 vaccine candidates capable of controlling HIV-1 replication in vivo. (C) 2013 The Authors. Published by Elsevier B.V. C1 [Naarding, Marloes A.; Fernandez, Natalia; Hayes, Peter; Bergin, Philip; Clark, Lorna; Cox, Josephine H.; Cormier, Emmanuel; Gilmour, Jill] Univ London Imperial Coll Sci Technol & Med, Int AIDS Vaccine Initiat, Human Immunol Lab, Chelsea & Westminster Hosp, London SW10 9NH, England. [Kappes, John C.; Icyuz, Mert; Edmonds, Tara G.; Ochsenbauer, Christina] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Kappes, John C.] Birmingham Vet Affairs Med Ctr, Res Serv, Birmingham, AL 35233 USA. [Ahmed, Tina; Hanke, Tomas] Univ Oxford, MRC, Human Immunol Unit, Weatherall Inst Mol Med, Oxford, England. [Ahmed, Tina; Hanke, Tomas] Univ Oxford, Jenner Inst Labs, Oxford OX3 7DQ, England. [Anzala, Omu] Kenya AIDS Vaccine Initiat, Nairobi, Kenya. RP Cox, JH (reprint author), Univ London Imperial Coll Sci Technol & Med, Int AIDS Vaccine Initiat, Human Immunol Lab, Chelsea & Westminster Hosp, London SW10 9NH, England. EM jcox@iavi.org OI Bergin, Philip/0000-0001-5522-8350 FU CAVD [OPP1032325]; NIH Center for HIV/AIDS Vaccine Immunology (CHAVI) [U01-AI067854]; CAVD for the CA-VIMC [OPP1032144, 38619]; UAB Center for AIDS Research Virology and Sequencing Cores [NIH P30 AI 27767]; VA through a Career Scientist Award; Merit Review funding; IAVI FX We would like to thank Prof B Walker (Ragon Institute, Boston, USA) for supplying the PBMCs from HIV-1 positive LTNP, and Dr. G Marrow and Dr. R. Lindsay (Development and Design Laboratory, IAVI, NY, USA) for critically reviewing this manuscript. This study was supported by CAVD funding for the CTVIMC, grant number OPP1032325.; CO, JCK, TGE and MI were supported by the NIH Center for HIV/AIDS Vaccine Immunology (CHAVI, U01-AI067854), a subcontract of CAVD funding for the CA-VIMC (grant numbers OPP1032144 and 38619), and through services by the UAB Center for AIDS Research Virology and Sequencing Cores (NIH P30 AI 27767). JCK also received support from the VA through a Career Scientist Award and Merit Review funding.; The International AIDS Vaccine Initiative (IAVI) is a global non-for-profit organization whose mission is to ensure the development of safe, effective, accessible, preventive HIV vaccines for use throughout the world. Founded in 1996, IAVI works with partners in 25 countries to research, design and develop AIDS vaccine candidates. In addition, IAVI conducts policy analyses and serves as an advocate for the AIDS vaccine field. IAVI supports a comprehensive approach to addressing HIV and AIDS that balances the expansion and strengthening of existing HIV-prevention and treatment programs with targeted investments in the design and development of new tools to prevent HIV. IAVI is dedicated to ensuring that a future AIDS vaccine will be available and accessible to all who need it. IAVI relies on the generous donations from governments, private individuals, corporations and foundations to carry out its mission. For more information, see www.iavi.org. NR 44 TC 8 Z9 8 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 EI 1872-7905 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD JUL PY 2014 VL 409 SI SI BP 161 EP 173 DI 10.1016/j.jim.2013.11.021 PG 13 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA AO7QW UT WOS:000341548700017 PM 24291126 ER PT J AU Misra, M Klibanski, A AF Misra, Madhusmita Klibanski, Anne TI Endocrine consequences of anorexia nervosa SO LANCET DIABETES & ENDOCRINOLOGY LA English DT Review ID BONE-MINERAL DENSITY; GROWTH-FACTOR-I; PHYSIOLOGICAL ESTROGEN REPLACEMENT; DISORDERED EATING PSYCHOPATHOLOGY; CORTICOTROPIN-RELEASING HORMONE; GHRELIN SUPPRESSES SECRETION; DWELLING ADOLESCENT GIRLS; REGIONAL BODY-COMPOSITION; BROWN ADIPOSE-TISSUE; NORMAL-WEIGHT WOMEN AB Anorexia nervosa is prevalent in adolescents and young adults, and endocrine changes include hypothalamic amenorrhoea; a nutritionally acquired growth-hormone resistance leading to low concentrations of insulin-like growth factor-1 (IGF-1); relative hypercortisolaemia; decreases in leptin, insulin, amylin, and incretins; and increases in ghrelin, peptide YY, and adiponectin. These changes in turn have harmful effects on bone and might affect neurocognition, anxiety, depression, and the psychopathology of anorexia nervosa. Low bone-mineral density (BMD) is particularly concerning, because it is associated with changes in bone microarchitecture, strength, and clinical fractures. Recovery leads to improvements in many-but not all-hormonal changes, and deficits in bone accrual can persist. Oestrogen-replacement therapy, primarily via the transdermal route, increases BMD in adolescents, although catch-up is incomplete. In adults, oral oestrogen-combined with recombinant human IGF-1 in one study and bisphosphonates in another-increased BMD, but not to the normal range. More studies are necessary to investigate the optimum therapeutic approach in patients with, or recovering from, anorexia nervosa. C1 [Misra, Madhusmita; Klibanski, Anne] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Misra, Madhusmita; Klibanski, Anne] Massachusetts Gen Hosp, Pediat Endocrine Unit, Boston, MA 02114 USA. [Misra, Madhusmita; Klibanski, Anne] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Misra, M (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, 55 Fruit St, Boston, MA 02114 USA. EM mmisra@mgh.harvard.edu FU National Institutes of Health [1 R01 HD060827, 1 K24 HD071843-01A]; Clinical Translational Science Center [5UL1RR025758]; [2 RO1 DK062249.] FX MM is supported by the National Institutes of Health grants 1 R01 HD060827 and 1 K24 HD071843-01A and Clinical Translational Science Center grant 5UL1RR025758, and AK by grant 2 RO1 DK062249. NR 145 TC 35 Z9 35 U1 3 U2 21 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2213-8587 J9 LANCET DIABETES ENDO JI Lancet Diabetes Endocrinol. PD JUL PY 2014 VL 2 IS 7 BP 581 EP 592 DI 10.1016/S2213-8587(13)70180-3 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AP1AW UT WOS:000341799800026 PM 24731664 ER PT J AU Bezawada, N Song, MY Wu, K Mehta, RS Milne, GL Ogino, S Fuchs, CS Giovannucci, EL Chan, AT AF Bezawada, Navya Song, Mingyang Wu, Kana Mehta, Raaj S. Milne, Ginger L. Ogino, Shuji Fuchs, Charles S. Giovannucci, Edward L. Chan, Andrew T. TI Urinary PGE-M Levels Are Associated with Risk of Colorectal Adenomas and Chemopreventive Response to Anti-Inflammatory Drugs SO CANCER PREVENTION RESEARCH LA English DT Article ID PROSTAGLANDIN E-2 METABOLITE; COLON CARCINOGENESIS; BREAST-CANCER; ASPIRIN; INFLAMMATION; BIOMARKER; PREVENTION; REGRESSION; EXPRESSION; NEOPLASIA AB Prostaglandin E-2 (PGE(2)) promotes colorectal carcinogenesis. Overall, systemic PGE(2) production can be assessed by measuring its major metabolite, PGE-M, in urine. We examined the potential role of PGE-M as a biomarker for colorectal adenoma risk and chemopreventive response to anti-inflammatory drugs. We conducted a prospective case-control study nested within the Nurses' Health Study. Among women who previously provided a urine sample, we identified 420 cases diagnosed with colorectal adenoma during follow-up and matched them to 420 endoscopy-negative controls. We measured urinary PGE-M using an LC/MS assay. Compared with women in the lowest quartile of urinary PGE-M, women in the highest quartile had a multivariate OR of 1.40 (95% confidence interval (CI), 0.92-2.14) for any adenoma; 0.91 (95% CI, 0.48-1.72) for low-risk adenoma (solitary adenoma < 1 cm in greatest diameter with tubular/unspecified histology); and 1.66 (95% CI, 1.04-2.67) for high-risk adenoma (adenoma >= 1 cm in greatest diameter and/or tubulovillous, villous or high-grade dysplasia histology or multiple adenomas of any size or histology). Regular use of anti-inflammatory drugs (> 2 standard tablets of aspirin/NSAIDs per week) was associated with a significant reduction in adenoma risk (multivariate OR, 0.61; 95% CI, 0.43-0.87) in women with high baseline PGE-M (quartiles 2-4), but not low PGE-M (quartile 1). Urinary PGE-M is associated with an increased risk of high-risk adenoma. Anti-inflammatory drugs seem to reduce adenoma risk among women with high, but not low PGE-M. Urinary PGE-M may serve as a biomarker to define subsets of the population who may obtain differential chemopreventive benefit from anti-inflammatory drugs. (C)2014 AACR. C1 [Bezawada, Navya] Univ Aberdeen, Aberdeen, Scotland. [Song, Mingyang; Wu, Kana; Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Cambridge, MA 02138 USA. [Song, Mingyang; Ogino, Shuji; Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Cambridge, MA 02138 USA. [Mehta, Raaj S.; Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Ogino, Shuji] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Fuchs, Charles S.; Giovannucci, Edward L.; Chan, Andrew T.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Ogino, Shuji; Fuchs, Charles S.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Milne, Ginger L.] Vanderbilt Univ, Div Clin Pharmacol, Nashville, TN USA. RP Chan, AT (reprint author), Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. EM achan@mgh.harvard.edu RI Song, Mingyang/M-6701-2013; Milne, Ginger/D-7648-2014 OI Song, Mingyang/0000-0002-1324-0316; Milne, Ginger/0000-0003-3890-151X FU U.S. NIH [P01 CA55075, UM1CA167552, P50CA127003, P01CA087969, R01CA151993, R01 CA137178, K24 DK098311] FX This work was supported by U.S. NIH grants P01 CA55075 (to S. Hankinson), UM1CA167552 (W. Willett), P50CA127003 (to C.S. Fuchs), P01CA087969 (to E.L. Giovannucci), R01CA151993 (to S. Ogino), R01 CA137178 (to A.T. Chan), and K24 DK098311 (to A.T. Chan). A. Chan is a Damon Runyon Cancer Research Foundation Clinical Investigator. NR 27 TC 14 Z9 14 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 EI 1940-6215 J9 CANCER PREV RES JI Cancer Prev. Res. PD JUL PY 2014 VL 7 IS 7 BP 758 EP 765 DI 10.1158/1940-6207.CAPR-14-0120 PG 8 WC Oncology SC Oncology GA AO9TM UT WOS:000341700200014 PM 24824037 ER PT J AU Puissant, A Fenouille, N Robert, G Jacquel, A Bassil, CF Colosetti, P Luciano, F Auberger, P AF Puissant, A. Fenouille, N. Robert, G. Jacquel, A. Bassil, C. F. Colosetti, P. Luciano, F. Auberger, P. TI A new posttranslational regulation of REDD1/DDIT4 through cleavage by caspase 3 modifies its cellular function SO CELL DEATH & DISEASE LA English DT Letter ID FEEDBACK-CONTROL; DNA-DAMAGE; REDD1; HYPOXIA; COMPLEX; MTORC1 C1 [Puissant, A.; Bassil, C. F.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Puissant, A.; Bassil, C. F.] Boston Childrens Hosp, Boston, MA USA. [Fenouille, N.] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Robert, G.; Jacquel, A.; Colosetti, P.; Luciano, F.; Auberger, P.] INSERM, U1065, C3M, Team 2, F-06204 Nice, France. [Robert, G.; Jacquel, A.; Colosetti, P.; Luciano, F.; Auberger, P.] Univ Nice Sophia Antipolis, F-06189 Nice, France. [Robert, G.; Jacquel, A.; Colosetti, P.; Luciano, F.; Auberger, P.] Equipe Labellise LNCC 2011 2013, Paris, France. [Auberger, P.] CHU Nice, F-06202 Nice, France. RP Auberger, P (reprint author), INSERM, U1065, C3M, 131 Route St Antoine de Ginestiere,BP 2 3194, F-06204 Nice, France. EM auberger@unice.fr RI PUISSANT, ALEXANDRE/O-9575-2016; AUBERGER, Patrick/G-1491-2013 OI PUISSANT, ALEXANDRE/0000-0002-3997-9282; AUBERGER, Patrick/0000-0002-2481-8275 NR 8 TC 2 Z9 2 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-4889 J9 CELL DEATH DIS JI Cell Death Dis. PD JUL PY 2014 VL 5 AR e1349 DI 10.1038/cddis.2014.291 PG 3 WC Cell Biology SC Cell Biology GA AO8XO UT WOS:000341639300040 PM 25058423 ER PT J AU Knight, AL Yan, XH Hamamichi, S Ajjuri, RR Mazzulli, JR Zhang, MW Daigle, JG Zhang, SY Borom, AR Roberts, LR Lee, SK DeLeon, SM Viollet-Djelassi, C Krainc, D O'Donnell, JM Caldwell, KA Caldwell, GA AF Knight, Adam L. Yan, Xiaohui Hamamichi, Shusei Ajjuri, Rami R. Mazzulli, Joseph R. Zhang, Mike W. Daigle, J. Gavin Zhang, Siyuan Borom, Akeem R. Roberts, Lindsay R. Lee, S. Kyle DeLeon, Susan M. Viollet-Djelassi, Coralie Krainc, Dimitri O'Donnell, Janis M. Caldwell, Kim A. Caldwell, Guy A. TI The Glycolytic Enzyme, GPI, Is a Functionally Conserved Modifier of Dopaminergic Neurodegeneration in Parkinson's Models SO CELL METABOLISM LA English DT Article ID GENE-EXPRESSION CHANGES; DROSOPHILA LIFE-SPAN; CAENORHABDITIS-ELEGANS; ALPHA-SYNUCLEIN; C.-ELEGANS; LONGEVITY; DISEASE; PROTEIN; PROTEOTOXICITY; MUTANTS AB Neurodegenerative diseases represent an increasing burden in our aging society, yet the underlying metabolic factors influencing onset and progression remain poorly defined. The relationship between impaired IGF-1/insulin-like signaling (IIS) and life-span extension represents an opportunity to investigate the interface of metabolism with age-associated neurodegeneration. Using data sets of established DAF-2/IIS-signaling components in Caenorhabditis elegans, we conducted systematic RNAi screens in worms to select for daf-2-associated genetic modifiers of alpha-synuclein misfolding and dopaminergic neurodegeneration, two clinical hallmarks of Parkinson's disease. An outcome of this strategy was the identification of GPI-1/GPI, an enzyme in glucose metabolism, as a daf-2-regulated modifier that acts independent of the downstream cytoprotective transcription factor DAF-16/FOXO to modulate neuroprotection. Subsequent mechanistic analyses using Drosophila and mouse primary neuron cultures further validated the conserved nature of GPI neuroprotection from alpha-synuclein proteotoxicity. Collectively, these results support glucose metabolism as a conserved functional node at the intersection of proteostasis and neurodegeneration. C1 [Knight, Adam L.; Yan, Xiaohui; Hamamichi, Shusei; Ajjuri, Rami R.; Zhang, Mike W.; Daigle, J. Gavin; Zhang, Siyuan; Borom, Akeem R.; Roberts, Lindsay R.; Lee, S. Kyle; DeLeon, Susan M.; O'Donnell, Janis M.; Caldwell, Kim A.; Caldwell, Guy A.] Univ Alabama, Dept Biol Sci, Tuscaloosa, AL 35487 USA. [Caldwell, Kim A.; Caldwell, Guy A.] Univ Alabama Birmingham, Ctr Neurodegenerat & Expt Therapeut, Gregory Fleming James Cyst Fibrosis Res Ctr, Dept Neurol, Birmingham, AL 35294 USA. [Caldwell, Kim A.; Caldwell, Guy A.] Univ Alabama Birmingham, Ctr Neurodegenerat & Expt Therapeut, Gregory Fleming James Cyst Fibrosis Res Ctr, Dept Neurobiol, Birmingham, AL 35294 USA. [Mazzulli, Joseph R.; Krainc, Dimitri] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol,MassGen Inst Neurodegenerat Dis, Charlestown, MA 02129 USA. [Viollet-Djelassi, Coralie] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Knight, Adam L.] Babraham Inst, Cambridge CB22 3AT, England. RP Caldwell, GA (reprint author), Univ Alabama, Dept Biol Sci, Tuscaloosa, AL 35487 USA. EM gcaldwel@ua.edu FU NIH Office of Research Infrastructure Programs [P40 OD010440]; National Institutes of Health [R15 NS075684-01, R15 NS078728] FX We are grateful to all members of the Caldwell and O'Donnell labs for their collegiality and collective teamwork. Special thanks to Laura Berkowitz for her invaluable contributions and Chris Link and Richard Morimoto for the A beta paralysis and Q82::GFP strains, respectively. Some strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). This research was funded by grants from the National Institutes of Health (R15 NS075684-01 to G. A. C. and R15 NS078728 to J.M.O.). Other support came from a Howard Hughes Medical Institute Undergraduate Science Program Grant to The University of Alabama (A. R. B., S. K. L., and S. M. D.), as well as the Parkinson's Support Group of Huntsville (L. R. R.) and the Parkinson's Association of Alabama (A. L. K. and M.W.Z.). NR 42 TC 6 Z9 6 U1 0 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 EI 1932-7420 J9 CELL METAB JI Cell Metab. PD JUL 1 PY 2014 VL 20 IS 1 BP 145 EP 157 DI 10.1016/j.cmet.2014.04.017 PG 13 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA AO5QZ UT WOS:000341401300016 PM 24882066 ER PT J AU Levine, YC Rosenberg, MA Mittleman, M Samuel, M Methachittiphan, N Link, M Josephson, ME Buxton, AE AF Levine, Yehoshua C. Rosenberg, Michael A. Mittleman, Murray Samuel, Michelle Methachittiphan, Nilubon Link, Mark Josephson, Mark E. Buxton, Alfred E. TI B-type natriuretic peptide is a major predictor of ventricular tachyarrhythmias SO HEART RHYTHM LA English DT Article DE NT-proBNP; BNP; Sudden cardiac death; Ventricular arrhythmias; ICD ID IMPLANTABLE CARDIOVERTER-DEFIBRILLATOR; SUDDEN CARDIAC DEATH; REDUCED EJECTION FRACTION; HEART-FAILURE; MYOCARDIAL-INFARCTION; PRIMARY PREVENTION; RISK; TACHYCARDIA; SHOCKS; CARDIOMYOPATHY AB BACKGROUND The cost-effective use of implantable cardioverter-defibrillators (ICDs) for the prevention of sudden cardiac death requires identification of patients at risk for ventricular tachyarrhythmias, not just for total mortality. OBJECTIVE To determine whether N-terminal pro-B-type natriuretic peptide (NT-proBNP) or B-type natriuretic peptide (BNP) are independent predictors of ventricular arrhythmias in patients receiving primary prevention ICDs. METHODS One hundred sixty-one patients with NT-proBNP levels and 403 patients with BNP levels at the time of ICD implantation were retrospectively assessed for the occurrence of first appropriate ICD therapy and mortality. RESULTS In multivariable Cox proportional hazards regression analysis, NT-proBNP or BNP levels in the upper 50th percentile were the strongest predictor of ICD therapy after adjustment for sex, age, left ventricular ejection fraction, New York Heart Association class, history of coronary artery disease, blood urea nitrogen, creatinine clearance, and history of atrial fibrillation (hazard ratio [HR] 5.75, P < .001 for NT-proBNP; HR 3.40, P = .01 for BNP). Patients were divided into quartiles on the basis of NT-proBNP or BNP levels. The adjusted HR for ICD therapy in the highest and second highest quartiles of NT-proBNP levels (HR 12.9, P < .001, and HR 4.6, P = .03, respectively) were higher than the adjusted HR for total mortality in these 2 quartiles (HR 3.4, P = .021 and HR 2.3, P = .13, respectively). Similarly, the adjusted HR for ICD therapy in the highest and second highest quartiles of BNP levels (HR 4.74, P = .01 and HR 2.17, P = .04, respectively) were higher than the adjusted HR for total mortality in these 2 quartiles (HR 3.05, P = .01 and HR 1.07, P = .3, respectively). CONCLUSION In this study, elevated baseline NT-proBNP and BNP levels are independently associated with the risk for ventricular tachyarrhythmias, which significantly exceeds the risk for total mortality, in multivariable analysis. C1 [Levine, Yehoshua C.; Mittleman, Murray; Samuel, Michelle; Josephson, Mark E.; Buxton, Alfred E.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Cardiovasc Div,Dept Med, Boston, MA 02215 USA. [Rosenberg, Michael A.] VA Boston Healthcare Syst, Boston, MA USA. [Methachittiphan, Nilubon; Link, Mark] Tufts Med Ctr, Boston, MA USA. RP Buxton, AE (reprint author), Beth Israel Deaconess Med Ctr, Baker 4,185 Pilgrim Rd, Boston, MA 02215 USA. EM abuxton@bidmc.harvard.edu NR 30 TC 15 Z9 17 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1547-5271 EI 1556-3871 J9 HEART RHYTHM JI Heart Rhythm PD JUL PY 2014 VL 11 IS 7 BP 1109 EP 1116 DI 10.1016/j.hrthm.2014.04.024 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AO6CK UT WOS:000341435900005 PM 24837348 ER PT J AU Josephson, ME Almendral, J Callans, DJ AF Josephson, Mark E. Almendral, Jesus Callans, David J. TI Resetting and entrainment of reentrant ventricular tachycardia associated with myocardial infarction SO HEART RHYTHM LA English DT Article ID EXCITABLE GAP; TRANSIENT ENTRAINMENT; TERMINATION; CIRCUIT; INTERRUPTION; FUSION C1 [Josephson, Mark E.] Beth Israel Deaconess Med Ctr, Div Cardiovasc Med, Boston, MA 02215 USA. [Josephson, Mark E.] Beth Israel Deaconess Med Ctr, Harvard Thorndike Electrophysiol Inst, Boston, MA 02215 USA. [Josephson, Mark E.] Beth Israel Deaconess Med Ctr, Arrhythmia Serv, Boston, MA 02215 USA. [Josephson, Mark E.] Harvard Univ, Sch Med, Boston, MA USA. [Almendral, Jesus] Grp HM Hosp, Cardiac Electrophysiol Lab, Madrid, Spain. [Almendral, Jesus] Univ CEU San Pablo, Madrid, Spain. [Callans, David J.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Callans, David J.] Univ Penn Hlth Syst, Philadelphia, PA USA. RP Josephson, ME (reprint author), Beth Israel Deaconess Med Ctr, Div Cardiovaslcular Med, Boston, MA 02215 USA. EM mjoseph2@bidmc.harvard.edu NR 20 TC 4 Z9 4 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1547-5271 EI 1556-3871 J9 HEART RHYTHM JI Heart Rhythm PD JUL PY 2014 VL 11 IS 7 BP 1239 EP 1249 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AO6CK UT WOS:000341435900026 PM 24681116 ER PT J AU Dahlberg, SE Shapiro, GI Clark, JW Johnson, BE AF Dahlberg, Suzanne E. Shapiro, Geoffrey I. Clark, Jeffrey W. Johnson, Bruce E. TI Evaluation of Statistical Designs in Phase I Expansion Cohorts: The Dana-Farber/Harvard Cancer Center Experience SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID CHRONIC MYELOID-LEUKEMIA; CLINICAL-TRIAL DESIGN; ABL TYROSINE KINASE; ANTICANCER AGENTS; DRUG DEVELOPMENT; LUNG-CANCER; SAFETY; ONCOLOGY; PUBLICATION; ESCALATION AB Background Phase I trials have traditionally been designed to assess toxicity and establish phase II doses with dose-finding studies and expansion cohorts but are frequently exceeding the traditional sample size to further assess end-points in specific patient subsets. The scientific objectives of phase I expansion cohorts and their evolving role in the current era of targeted therapies have yet to be systematically examined. Methods Adult therapeutic phase I trials opened within Dana-Farber/Harvard Cancer Center (DF/HCC) from 1988 to 2012 were identified for sample size details. Statistical designs and study objectives of those submitted in 2011 were reviewed for expansion cohort details. Results Five hundred twenty-two adult therapeutic phase I trials were identified during the 25 years. The average sample size of a phase I study has increased from 33.8 patients to 73.1 patients over that time. The proportion of trials with planned enrollment of 50 or fewer patients dropped from 93.0% during the time period 1988 to 1992 to 46.0% between 2008 and 2012; at the same time, the proportion of trials enrolling 51 to 100 patients and more than 100 patients increased from 5.3% and 1.8%, respectively, to 40.5% and 13.5% (chi(2) test, two-sided P < .001). Sixteen of the 60 trials (26.7%) in 2011 enrolled patients to three or more sub-cohorts in the expansion phase. Sixty percent of studies provided no statistical justification of the sample size, although 91.7% of trials stated response as an objective. Conclusions Our data suggest that phase I studies have dramatically changed in size and scientific scope within the last decade. Additional studies addressing the implications of this trend on research processes, ethical concerns, and resource burden are needed. C1 [Dahlberg, Suzanne E.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Shapiro, Geoffrey I.; Johnson, Bruce E.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Shapiro, Geoffrey I.; Johnson, Bruce E.] Dana Farber Canc Inst, Dept Med, Boston, MA 02215 USA. [Shapiro, Geoffrey I.; Johnson, Bruce E.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Clark, Jeffrey W.] Massachusetts Gen Hosp, Dept Hematol & Oncol, Boston, MA 02114 USA. [Clark, Jeffrey W.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Dahlberg, SE (reprint author), Dana Farber Canc Inst, Dept Biostat & Computat Biol, CLSB 11007,450 Brookline Ave, Boston, MA 02215 USA. EM dahlberg@jimmy.harvard.edu FU Dana Foundation at Dana-Farber Cancer Institute FX This study was supported by the Dana Foundation at Dana-Farber Cancer Institute. NR 47 TC 5 Z9 5 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD JUL PY 2014 VL 106 IS 7 AR dju163 DI 10.1093/jnci/dju163 PG 6 WC Oncology SC Oncology GA AO8WX UT WOS:000341637400025 ER PT J AU Donovan, KA Donovan, HS Cella, D Gaines, ME Penson, RT Plaxe, SC von Gruenigen, VE Bruner, DW Reeve, BB Wenzel, L AF Donovan, Kristine A. Donovan, Heidi S. Cella, David Gaines, Martha E. Penson, Richard T. Plaxe, Steven C. von Gruenigen, Vivian E. Bruner, Deborah Watkins Reeve, Bryce B. Wenzel, Lari TI Recommended Patient-Reported Core Set of Symptoms and Quality-of-Life Domains to Measure in Ovarian Cancer Treatment Trials SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID GYNECOLOGIC-ONCOLOGY-GROUP; PHASE-II TRIAL; FUNCTIONAL-ASSESSMENT; PERITONEAL CANCER; CLINICAL-TRIALS; RECEIVING CHEMOTHERAPY; QUESTIONNAIRE MODULE; MAINTENANCE THERAPY; RECURRENT OVARIAN; RANDOMIZED-TRIAL AB There is no consensus as to what symptoms or quality-of-life (QOL) domains should be measured as patient-reported outcomes (PROs) in ovarian cancer clinical trials. A panel of experts convened by the National Cancer Institute reviewed studies published between January 2000 and August 2011. The results were included in and combined with an expert consensus-building process to identify the most salient PROs for ovarian cancer clinical trials. We identified a set of PROs specific to ovarian cancer: abdominal pain, bloating, cramping, fear of recurrence/disease progression, indigestion, sexual dysfunction, vomiting, weight gain, and weight loss. Additional PROs identified in parallel with a group charged with identifying the most important PROs across cancer types were anorexia, cognitive problems, constipation, diarrhea, dyspnea, fatigue, nausea, neuropathy, pain, and insomnia. Physical and emotional domains were considered to be the most salient domains of QOL. Findings of the review and consensus process provide good support for use of these ovarian cancer-specific PROs in ovarian cancer clinical trials. C1 [Donovan, Kristine A.] H Lee Moffitt Canc Ctr & Res Inst, Support Care Med Dept, Hlth Outcomes & Behav Program, Tampa, FL USA. [Donovan, Heidi S.] Univ Pittsburgh, Sch Nursing, Acute & Tertiary Care Dept, Pittsburgh, PA 15261 USA. [Cella, David] Northwestern Univ, Dept Med Social Sci, Chicago, IL 60611 USA. [Cella, David] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. [Gaines, Martha E.] Univ Wisconsin, Sch Law, Ctr Patient Partnership, Madison, WI 53706 USA. [Penson, Richard T.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Plaxe, Steven C.] Univ Calif San Diego, Dept Reprod Med, Div Gynecol Oncol, San Diego, CA 92103 USA. [von Gruenigen, Vivian E.] Summa Akron City Hosp, Dept Obstet & Gynecol, Div Gynecol Oncol, Akron, OH USA. [Bruner, Deborah Watkins] Emory Univ, Sch Nursing, Atlanta, GA 30322 USA. [Reeve, Bryce B.] Univ N Carolina, Dept Hlth Policy & Management, Chapel Hill, NC USA. [Wenzel, Lari] Univ Calif Irvine, Dept Med, Irvine, CA 92697 USA. RP Wenzel, L (reprint author), Univ Calif Irvine, Sch Med, Dept Med & Publ Hlth, 100 Theory Dr,Suite 110, Irvine, CA 92697 USA. EM lwenzel@uci.edu FU National Cancer Institute FX This work was supported by the National Cancer Institute. NR 35 TC 8 Z9 8 U1 0 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD JUL PY 2014 VL 106 IS 7 AR dju128 DI 10.1093/jnci/dju128 PG 4 WC Oncology SC Oncology GA AO8WX UT WOS:000341637400008 ER PT J AU Raff, GL Chinnaiyan, KM Cury, RC Garcia, MT Hecht, HS Hollander, JE O'Neil, B Taylor, AJ Hoffmann, U AF Raff, Gilbert L. Chinnaiyan, Kavitha M. Cury, Ricardo C. Garcia, Mario T. Hecht, Harvey S. Hollander, Judd E. O'Neil, Brian Taylor, Allen J. Hoffmann, Udo TI SCCT guidelines on the use of coronary computed tomographic angiography for patients presenting with acute chest pain to the emergency department: A Report of the Society of Cardiovascular Computed Tomography Guidelines Committee SO JOURNAL OF CARDIOVASCULAR COMPUTED TOMOGRAPHY LA English DT Article ID ELEVATION MYOCARDIAL-INFARCTION; AMERICAN-HEART-ASSOCIATION; RADIATION-DOSE-REDUCTION; FRACTIONAL FLOW RESERVE; ACUTE CARDIAC ISCHEMIA; TRIPLE-RULE-OUT; STATISTICAL ITERATIVE RECONSTRUCTION; ACR APPROPRIATENESS CRITERIA(R); RANDOMIZED CONTROLLED-TRIAL; TIMI RISK SCORE AB Coronary computed tomography angiography (coronary CTA) is a viable alternative to functional imaging in the assessment of patients presenting with acute chest pain (ACP) to the emergency department (ED). The Society of Cardiovascular Computed Tomography Guidelines Committee was formed to develop recommendations for acquiring, interpreting, and reporting of cardiovascular CT to ensure adequate, safe, and efficient use of this modality. Because of the increasing extension of coronary CTA testing for the evaluation of ACP patients, the Committee has been charged with the development of the present document to assist physicians and technologists. These recommendations were produced as an educational tool for practitioners to improve the diagnostic care of patients presenting with ACP to the ED, in the interest of developing systematic standards of practice for coronary CTA based on the best available data or broad expert consensus. Because of the highly variable nature of medical care, and individual and unique patient presentations and circumstances, approaches to patient selection, preparation, protocol selection, interpretation, or reporting that differ from these guidelines may represent an appropriate variation based on a legitimate assessment of an individual patient's needs. The Society of Cardiovascular Computed Tomography Guidelines Committee makes every effort to avoid any actual or potential conflicts of interest that might arise as a result of an outside relationship or a personal interest of a member of the Guidelines Committee or its Writing Groups. Specifically, all members of both the Guidelines Committee and of Writing Committees are asked to provide disclosure statements of all such relationships that might be perceived as real or potential conflicts of interest relevant to the document topic. The relationships with industry information for Writing Group and Committee members are available in the acknowledgments section of this document. These are reviewed by the Guidelines Committee and will be updated as changes occur. C1 [Raff, Gilbert L.; Chinnaiyan, Kavitha M.] William Beaumont Hosp, Dept Cardiol, Royal Oak, MI 48073 USA. [Cury, Ricardo C.] Baptist Hosp Miami, Miami, FL 33176 USA. [Cury, Ricardo C.] Baptist Cardiac & Vasc Inst, Miami, FL 33176 USA. [Garcia, Mario T.] Albert Einstein Coll Med, Montefiore Med Ctr, New York, NY 10467 USA. [Hecht, Harvey S.] Lenox Hill Heart & Vasc Inst, New York, NY 10075 USA. [Hollander, Judd E.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [O'Neil, Brian] Wayne State Univ, Sch Med, Dept Emergency Med, Detroit, MI 48201 USA. [Taylor, Allen J.] Georgetown Univ Hosp, Washington, DC 20007 USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Raff, GL (reprint author), William Beaumont Hosp, Dept Cardiol, 3601 13 Mile Rd, Royal Oak, MI 48073 USA. EM raff4258@gmail.com OI Hollander, Judd/0000-0002-1318-2785 FU GE Healthcare FX Dr. Ricardo Cury is a Consultant for GE Healthcare, Astellas Pharma, and Heart Flow. Dr. Ricardo Cury also has a research grant from GE Healthcare. Dr. Harvey S. Hecht is a Consultant for Philips Medical Systems and member of Scientific Advisory Board - Arineta. Dr. Judd Hollander is associated with Siemens. Rest of the authors reports no conflicts of interest. NR 118 TC 29 Z9 30 U1 2 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1934-5925 J9 J CARDIOVASC COMPUT JI J. Cardiovasc. Comput. Tomogr. PD JUL-AUG PY 2014 VL 8 IS 4 BP 254 EP 271 DI 10.1016/j.jcct.2014.06.002 PG 18 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA AO4ZS UT WOS:000341350500002 PM 25151918 ER PT J AU Nakazaki, Y Souders, N Koyama, S Harrison, N Thompson, L Hodi, FS Dranoff, G AF Nakazaki, Yukoh Souders, Nicholas Koyama, Shohei Harrison, Nicole Thompson, Liana Hodi, F. Stephen Dranoff, Glenn TI IMMUNOTHERAPY WITH GENE-MODIFIED TUMOR VACCINATION INDUCED ANTAGONISTIC ANTIBODIES TO TUMOR PROMOTING FACTORS. SO JOURNAL OF GENE MEDICINE LA English DT Meeting Abstract CT Bespghan Meeting CT 17th Annual Meeting of the Japan-Society-of-Gene-Therapy (JSGT) CY DEC, 2011 CY JUL 15-17, 2011 CL Ghent, BELGIUM CL Kyushu Univ Sch Med, Fukuoka, JAPAN SP Japan Soc Gene Therapy HO Kyushu Univ Sch Med C1 [Nakazaki, Yukoh; Souders, Nicholas; Koyama, Shohei; Harrison, Nicole; Thompson, Liana; Hodi, F. Stephen; Dranoff, Glenn] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 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 1099-498X EI 1521-2254 J9 J GENE MED JI J. Gene. Med. PD JUL-AUG PY 2014 VL 16 IS 7-8 MA OR-7 BP 221 EP 222 PG 2 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA AO3PI UT WOS:000341244900061 ER PT J AU Fitzsimmons, J Hamoda, HM Swisher, T Terry, D Rosenberger, G Seidman, LJ Goldstein, J Mesholam-Gately, R Petryshen, T Wojcik, J Kikinis, R Kubicki, M AF Fitzsimmons, J. Hamoda, H. M. Swisher, T. Terry, D. Rosenberger, G. Seidman, L. J. Goldstein, J. Mesholam-Gately, R. Petryshen, T. Wojcik, J. Kikinis, R. Kubicki, M. TI Diffusion tensor imaging study of the fornix in first episode schizophrenia and in healthy controls SO SCHIZOPHRENIA RESEARCH LA English DT Article DE First episode schizophrenia; Fornix; Diffusion tensor imaging; Fractional anisotropy; Trace; Axial diffusivity; Radial diffusivity ID ONSET SCHIZOPHRENIA; 1ST-EPISODE SCHIZOPHRENIA; GRAY-MATTER; BRAIN; INTEGRITY; MRI; METAANALYSIS; HIPPOCAMPUS; VOLUME AB Background: The fornix is a compact bundle of white matter fibers that project from the hippocampus to the mamillary bodies and septal nuclei. Its association with memory, as well as with symptoms in schizophrenia, has been reported in chronic schizophrenia. The purpose of this study is to determine whether or not fornix abnormalities are evident at the onset of schizophrenia. Methods: Diffusion tensor imaging (DTI) and DT tractography were used to evaluate the fornix in 21 patients with first episode schizophrenia (16 males/5 females) and 22 healthy controls (13 males/9 females). Groups were matched on age, gender, parental socioeconomic status, education and handedness. Fractional anisotropy (FA), a measure of white matter integrity, radial diffusivity (RD), thought to reflect myelin integrity, trace, a possible marker of atrophy or cell loss, and axial diffusivity (AD), thought to reflect axonal integrity, were averaged over the entire tract extracted by means of DT tractography, and used to investigate fornix abnormalities in first episode schizophrenia compared with healthy controls. Results: Significant group differences were found between first episode patients and controls for FA (p = 0.0001), RD (p = 0.001) and trace (p = 0.006). Conclusion: These findings suggest abnormalities in the fornix in the early stages of schizophrenia, and further suggest that white matter abnormalities, which are apparent in the early course of the disease, may reflect myelin disturbances. (C) 2014 Elsevier B.V. All rights reserved. C1 [Fitzsimmons, J.; Hamoda, H. M.; Swisher, T.; Terry, D.; Rosenberger, G.] Harvard Univ, Sch Med, Dept Psychiat, Psychiat Neuroimaging Lab,Brigham & Womens Hosp, Boston, MA 02115 USA. [Fitzsimmons, J.; Hamoda, H. M.; Swisher, T.; Terry, D.; Rosenberger, G.] Harvard Univ, Sch Med, Dept Radiol, Psychiat Neuroimaging Lab,Brigham & Womens Hosp, Boston, MA 02115 USA. [Hamoda, H. M.] Harvard Univ, Sch Med, Dept Psychiat, Boston Childrens Hosp, Boston, MA 02115 USA. [Rosenberger, G.] Med Univ Innsbruck, Dept Gen Psychiat, A-6020 Innsbruck, Austria. [Seidman, L. J.; Goldstein, J.; Mesholam-Gately, R.; Wojcik, J.] Harvard Univ, Sch Med, Massachusetts Mental Hlth Ctr, Beth Israel Deaconess Med Ctr,Publ Psychiat Div, Boston, MA 02115 USA. [Seidman, L. J.] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Goldstein, J.] Harvard Univ, Sch Med, Dept Med, Brigham & Womens Hosp, Boston, MA USA. [Petryshen, T.] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Boston, MA USA. [Petryshen, T.] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Ctr Human Genet Res, Boston, MA 02114 USA. [Kikinis, R.; Kubicki, M.] Harvard Univ, Sch Med, Dept Radiol, Surg Planning Lab,MRI Div,Brigham & Womens Hosp, Boston, MA 02115 USA. RP Fitzsimmons, J (reprint author), Psychiat Neuroimaging Lab, 1249 Boylston St,3rd Floor, Boston, MA 02215 USA. EM jfitzsimmons@bw.harvard.edu FU T32 Stuart T. Hauser Clinical Research Training Program in Biological and Social Psychiatry; NIH [P50MH080272, R01MH050740]; National Center for Research Resources [UL1RR025758] FX This work was supported, in part, by a T32 Stuart T. Hauser Clinical Research Training Program in Biological and Social Psychiatry (JF), by NIH P50MH080272 (TS, LJS, JG, MK), R01MH050740 (TS, MK), and by a Clinical Translational Science Award UL1RR025758 to Harvard University and Beth Israel Deaconess Medical Center from the National Center for Research Resources (LS). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. NR 32 TC 13 Z9 15 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 EI 1573-2509 J9 SCHIZOPHR RES JI Schizophr. Res. PD JUL PY 2014 VL 156 IS 2-3 BP 157 EP 160 DI 10.1016/j.schres.2014.04.022 PG 4 WC Psychiatry SC Psychiatry GA AO4MM UT WOS:000341313200004 PM 24837684 ER PT J AU Bienz, M Hueber, PA Al-Hathal, N McCormack, M Bhojani, N Trinh, QD Zorn, KC AF Bienz, Marc Hueber, Pierre-Alain Al-Hathal, Naif McCormack, Michael Bhojani, Naeem Trinh, Quoc-Dien Zorn, Kevin C. TI Accuracy of Transrectal Ultrasonography to Evaluate Pathologic Prostate Weight: Correlation With Various Prostate Size Groups SO UROLOGY LA English DT Article ID ASSISTED RADICAL PROSTATECTOMY; DIGITAL RECTAL EXAMINATION; VOLUME ESTIMATION; GLAND VOLUME; ULTRASOUND; OUTCOMES; IMPACT AB OBJECTIVE To report the accuracy of transrectal ultrasonography (TRUS) to measure prostate size before robotic-assisted radical prostatectomy using the prolate ellipsoid formula and its correlation to the weight of the postoperative prostate specimen, for different prostate size groups. METHODS Preoperative prostate size estimated by TRUS and the weight of postoperative prostate specimens were collected from 440 men undergoing robotic-assisted radical prostatectomy. Patients were grouped according to preoperative prostate size: <30, 30-60, 60-80, and >= 80 g. To evaluate accuracy, the mean absolute percentage of error was used. The mean percentage of error was used to indicate whether the estimation of TRUS had a tendency to overestimate or underestimate prostate size. The correlation between both measurements was analyzed for each size group. RESULTS Accuracy of TRUS estimation was associated with increased prostate size. TRUS estimation was more accurate for larger prostates. The mean absolute percentage of error of each group was 38.64% (<30 g), 21.33% (30-60 g), 13.23% (60-80 g), and 14.96% (>= 80 g). Correlation followed a similar size-dependent trend, with a stronger r coefficient for larger prostates: 0.174 (<30 g), 0.327 (30-60 g), 0.457 (60-80 g), and 0.839 (>= 80 g). Interestingly, smaller prostates were underestimated, whereas larger glands (>= 80 g) had a tendency to be overestimated by TRUS. CONCLUSION This study demonstrates that the accuracy of the prolate ellipsoid formula for TRUS varies according to prostate size. Although this formula is fairly accurate for assessing larger prostates, it shows some limitations for smaller prostates. This must be taken into account when evaluating treatment modalities such as transurethral incision of the prostate and brachytherapy. (C) 2014 Elsevier Inc. C1 Univ Montreal, Ctr Hosp, Dept Surg, Div Urol, Montreal, PQ H2X 3J4, Canada. Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Urol Surg, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Surg & Publ Hlth, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Zorn, KC (reprint author), Univ Montreal, Hosp Ctr CHUM, Hop St Luc, Dept Surg,Div Urol, 1058 St Denis St, Montreal, PQ H2X 3J4, Canada. EM zorn.chumurology@gmail.com FU American Medical Systems (AMS) FX K.C.Z. reports receiving personal fees from American Medical Systems (AMS), outside the submitted work. The remaining authors declare that they have no relevant financial interests. NR 19 TC 4 Z9 4 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 EI 1527-9995 J9 UROLOGY JI Urology PD JUL PY 2014 VL 84 IS 1 BP 170 EP 175 DI 10.1016/j.urology.2014.02.022 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA AO5EE UT WOS:000341364900041 PM 24976231 ER PT J AU Walters, EL Reibling, ET Wilber, ST Sullivan, AF Gaeta, TJ Camargo, CA Boudreaux, ED AF Walters, Elizabeth L. Reibling, Ellen T. Wilber, Scott T. Sullivan, Ashley F. Gaeta, Theodore J. Camargo, Carlos A., Jr. Boudreaux, Edwin D. TI Emergency Department Provider Preferences Related to Clinical Practice Guidelines for Tobacco Cessation: A Multicenter Survey SO ACADEMIC EMERGENCY MEDICINE LA English DT Article ID SMOKING-CESSATION; CIGARETTE-SMOKING; HEALTH-INSURANCE; PREVENTIVE CARE; REGULAR SOURCE; UNITED-STATES; PHYSICIANS; INTERVENTION; ADULTS; BEHAVIORS AB Objectives: The objective was to assess current emergency department (ED) provider practices and preferences for tobacco cessation interventions. The ED is an opportune place to initiate smoking cessation interventions. However, little is known about ED provider current practices and preferences for cessation counseling in the ED. Methods: This was a survey of ED providers conducted in 2008-2009 (including physicians, nurse practitioners, physician assistants, and nurses), working at least half-time at 10 U. S. academic EDs, regarding adherence to clinical practice guidelines ("5 As") and preferences for cessation interventions/styles. Data analysis occurred in 2012-2013. Results: The response rate was 64% (800 out of 1,246 completed surveys). Providers reported strongest adherence to asking about patient smoking status, followed by advising, with significant variance by clinical role. Assessing, assisting, and arranging support for patients was low overall. Most frequently used interventions were to provide patients with a list of telephone numbers for stop-smoking counseling (87%), pamphlets on smoking health risks and the benefits of stopping (85%), and referrals to the National Toll-Free Smoker's Quitline (84%). Most providers (80%) were supportive of personally conducting brief (less than 3 minutes) smoking cessation counseling sessions during the ED visit, emphasizing education and encouragement. The least appealing intervention was writing a prescription for nicotine replacement therapies or medications to stop smoking (35%). Conclusions: Interventions most likely to be used were brief and delivered with a positive tone and included referral to external resources. The logical next step is to design and test interventions that ED providers find acceptable. (C) 2014 by the Society for Academic Emergency Medicine C1 [Walters, Elizabeth L.; Reibling, Ellen T.] Loma Linda Univ, Med Ctr, Dept Emergency Med, Loma Linda, CA 92354 USA. [Wilber, Scott T.] Summa Akron City Hosp, Dept Emergency Med, Akron, OH USA. [Sullivan, Ashley F.; Camargo, Carlos A., Jr.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Gaeta, Theodore J.] New York Methodist Hosp, Dept Emergency Med, Brooklyn, NY USA. [Boudreaux, Edwin D.] Univ Massachusetts, Sch Med, Dept Emergency Med, Worcester, MA USA. RP Walters, EL (reprint author), Loma Linda Univ, Med Ctr, Dept Emergency Med, Loma Linda, CA 92354 USA. EM ewalters@llu.edu OI Boudreaux, Edwin/0000-0002-3223-6371 FU NIH/NIDA K23 Research Career Award (EDB) grant [K23-DA-16698]; NIDA R21 [R21-DA-020771] FX The authors acknowledge research funding provided by NIH/NIDA K23 Research Career Award (EDB) grant (K23-DA-16698) and a NIDA R21 (EDB) (R21-DA-020771). The authors do not have any financial disclosures. Dr. Wilber, an associate editor for this journal, had no role in the peer-review process or publication decision for this paper. NR 42 TC 2 Z9 2 U1 0 U2 3 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 JUL PY 2014 VL 21 IS 7 BP 785 EP 793 DI 10.1111/acem.12421 PG 9 WC Emergency Medicine SC Emergency Medicine GA AN5AA UT WOS:000340600200008 PM 25112653 ER PT J AU Chao, SZ Matthews, BR Yokoyama, JS Lai, NB Ong, H Tse, M Yuan, RF Lin, A Kramer, J Yaffe, K Kornak, J Miller, BL Rosen, HJ AF Chao, Steven Z. Matthews, Brandy R. Yokoyama, Jennifer S. Lai, Ngan Betty Ong, Hilary Tse, Marian Yuan, Runfen Frances Lin, Amy Kramer, Joel Yaffe, Kristine Kornak, John Miller, Bruce L. Rosen, Howard J. TI Depressive Symptoms in Chinese-American Subjects with Cognitive Impairment SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE Chinese American; dementia; geriatric depression ID NEUROPSYCHIATRIC SYMPTOMS; ALZHEIMERS-DISEASE; PRIMARY-CARE; ANTIDEPRESSANT USE; OLDER PERSONS; UNITED-STATES; RISK-FACTORS; PREVALENCE; DEMENTIA; SCALE AB Objectives: To compare the prevalence of depressive symptoms and frequency of antidepressant use between a group of elderly Chinese-American subjects with and without cognitive impairment and a group of matched white subjects. A secondary aim was to examine the clinical and demographic predictors of depressive symptoms across these groups. Methods: The study was conducted at an academic neurology subspecialty clinic. This was a caseecontrol study with 140 Chinese-American subjects and 140 demographically and cognitively matched white subjects. In each group, there were 48 cognitively normal and 92 cognitively impaired participants (49 with mild cognitive impairment, 43 with Alzheimer disease). The proportion of individuals with significant depressive symptoms, as indicated by a Geriatric Depression Scale score >= 6 of 15, and frequency of antidepressant use were compared across groups by using c 2 analysis. Factors predicting depressive symptoms, including racial and diagnostic group, age, gender, Mini-Mental State Examination score, level of functional impairment, education level, and medical comorbidities, were assessed by using linear regression analysis. Results: Significant depressive symptoms were more common in cognitively impaired Chinese-American (35%) than cognitively impaired white (15%; chi(2)([1]) = 9.4; p = 0.004) subjects. Chinese-American subjects with cognitive impairment were less likely to be receiving treatment for depression (12%) than white subjects with cognitive impairment (37%; chi(2)([1]) = 15.6; p = 0.002). Racial and diagnostic group, age, level of functional impairment, Mini-Mental State Examination score, and education level were all statistically significant independent predictors of Geriatric Depression Scale score. Conclusions: Elderly Chinese-American subjects with cognitive impairment are at increased risk for unrecognized and untreated depressive symptoms compared with elderly white subjects with cognitive impairment. Education level may contribute to this risk or it may be a surrogate marker for other factors contributing to depressive symptoms in this group. C1 [Chao, Steven Z.] VA Palo Alto Hlth Care Syst, Dept Neurol, Palo Alto, CA USA. [Chao, Steven Z.; Yokoyama, Jennifer S.; Lai, Ngan Betty; Ong, Hilary; Tse, Marian; Yuan, Runfen Frances; Lin, Amy; Kramer, Joel; Miller, Bruce L.; Rosen, Howard J.] Univ Calif San Francisco, Dept Neurol, Memory & Aging Ctr, San Francisco, CA 94143 USA. [Matthews, Brandy R.] Indiana Univ, Sch Med, Dept Neurol, Indiana Alzheimer Dis Ctr, Indianapolis, IN 46202 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA 94143 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Biostat, San Francisco, CA 94143 USA. San Francisco VA Med Ctr, Memory Disorders Clin, San Francisco, CA USA. [Kornak, John] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. RP Rosen, HJ (reprint author), 675 Nelson Rising Ln,Box 1207,Ste 190, San Francisco, CA 94158 USA. EM hrosen@memory.ucsf.edu FU National Institutes of Health/National Institute on Aging [AG023501]; Larry L. Hillblom Foundation FX This work was supported by the National Institutes of Health/National Institute on Aging grant AG023501 (The UCSF Alzheimer's Disease Research Center) and the Larry L. Hillblom Foundation. NR 49 TC 5 Z9 5 U1 2 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD JUL PY 2014 VL 22 IS 7 BP 642 EP 652 DI 10.1016/j.jagp.2012.10.029 PG 11 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA AN9ZX UT WOS:000340969600002 PM 24021225 ER PT J AU Harshman, LC Choueiri, TK Drake, C Hodi, FS AF Harshman, Lauren C. Choueiri, Toni K. Drake, Charles Hodi, F. Stephen, Jr. TI Subverting the B7-H1/PD-1 Pathway in Advanced Melanoma and Kidney Cancer SO CANCER JOURNAL LA English DT Review DE PD-1; PD-L1; antibody; melanoma; kidney cancer; renal cell carcinoma; nivolumab; MK-3475; MPDL3280A ID RENAL-CELL CARCINOMA; PHASE-III TRIAL; HIGH-DOSE INTERLEUKIN-2; T-CELLS; IMPROVED SURVIVAL; PD-L1 EXPRESSION; TARGETED THERAPY; INTERFERON-ALPHA; BRAF INHIBITION; IMMUNE EVASION AB Ligands for inhibitory immune receptors on T cells may be constitutively expressed on tumor cells or host cells in tumor microenvironment as a consequence of adaptive immunity. Programmed death 1 (PD-1) is 1 such receptor on T cells, which functions as a negative regulator of T cell activity. Tumors that up-regulate programmed death ligand 1 (PDL1) (B7-H1) may abrogate the host's effector T cell antitumor response. Higher tumoral PD-L1 expression has been linked with inferior clinical outcomes. Multiple cancers including renal cell cancers (RCCs) and melanomas have relatively high levels of PD-L1 on the cell surface. Early evaluations of antibodies that block the interaction of PD-1 and PD-L1 have shown efficacy and a favorable tolerability profile with notable inflammatory toxicities that are generally manageable. Upward of 30% of RCC patients and 50% of melanoma patients achieve objective responses. Durable responses can occur, even in some patients who have discontinued treatment. The developing investigation of PD-1/PD-L1 pathway-blocking agents in RCC and melanoma will likely alter our approaches to the treatment of these 2 deadly diseases. C1 [Harshman, Lauren C.; Choueiri, Toni K.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Boston, MA 02215 USA. [Drake, Charles] Johns Hopkins Univ, Dept Oncol, Baltimore, MD USA. [Drake, Charles] Johns Hopkins Univ, James Buchanan Brady Urol Inst, Baltimore, MD USA. [Hodi, F. Stephen, Jr.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Melanoma Dis Ctr, Boston, MA 02215 USA. [Hodi, F. Stephen, Jr.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Immunooncol, Boston, MA 02215 USA. RP Harshman, LC (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 450 Brookline Ave,DANA 1230, Boston, MA 02215 USA. EM LaurenC_Harshman@dfci.harvard.edu FU Bristol-Myers Squibb; Janssen; Aduro Biotech; Compugen; Dendreon; Roche/Genentech; Amplimmune; Pfizer; Bavarian Nordic (DSM); NIH FX L. C. H. is member of the ECOG GU Committee and has a major role in developing the proposed perioperative studies discussed in the Future Directions section. She has received compensation as an advisory board member from Bristol-Myers Squibb, Dendreon, Prizer, and Aveo. T. K. C. has received compensation for board membership and consultancy from Pfizer, GSK, Novartis, Bayer, UpToDate, and NCCN. C.D.'s institution receives compensation through grants from Bristol-Myers Squibb, Janssen, and Aduro Biotech; he receives consulting fees or honorarium from Bristol-Myers Squibb, Compugen, Dendreon, and Roche/Genentech and in the past from Amplimmune, Janssen, and Pfizer; he also receives fees from Bavarian Nordic (DSM) for participation in review activities such as data monitoring boards, statistical analyses, endpoint committee, and the like, and from Bristol-Myers Squibb for provision of writing assistance, medicine, equipment, or administrative support; he receives compensation for board membership from Compugen (SAB member); received royalties for formerly licensed patents from Bristol-Myers Squibb and Amplimmune Inc; received payment by Dendreon for development of educational presentations; and has stock options from Compugen. F. S. H. provides nonpaid consultancy to Bristol-Myers Squibb, Merck, and Genentech; his institution receives grants and has grants pending from Bristol-Myers Squibb; he received grants and has grants pending from the NIH and has IP licensed as per institutional policy to Bristol-Myers Squibb. NR 65 TC 9 Z9 9 U1 2 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1528-9117 EI 1540-336X J9 CANCER J JI Cancer J. PD JUL-AUG PY 2014 VL 20 IS 4 BP 272 EP 280 PG 9 WC Oncology SC Oncology GA AN4ZN UT WOS:000340598700007 PM 25098288 ER PT J AU Kim, JH Oh, SJ Ahn, S Chung, DH AF Kim, Ji Hyung Oh, Sae Jin Ahn, Sehee Chung, Doo Hyun TI IFN-gamma-producing NKT cells exacerbate sepsis by enhancing C5a generation via IL-10-mediated inhibition of CD55 expression on neutrophils SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE C5a; IFN-gamma; Neutrophils; NKT cell; Sepsis ID T-CELLS; CYTOKINE REGULATION; SEPTIC PERITONITIS; HOST-DEFENSE; RECEPTOR; IL-10; SHOCK; MICE; INFLAMMATION; COMPLEMENT AB A role for NKT cells has been implicated in sepsis, but themechanism by which NKT cells contribute to sepsis remains unclear. Here, we examinedWT and NKT-cell-deficient mice of C57BL/6 background during cecal ligation and puncture-induced sepsis. The levels of C5a, IFN-gamma, and IL-10 were higher in the serum and peritoneal fluid of WT mice than in those of CD1d(-/-) mice, while the mortality rate was lower in CD1d(-/-) mice than in WT mice. C5a blockade decreased mortality ofWTmice during sepsis, whereas it did not alter that of CD1d(-/-) mice. As assessed by intracellular staining, NKT cells expressed IFN-., while neutrophils expressed IL-10. Upon coculture, IL-10-deficient NKT cells enhanced IL-10 production byWT, but not IFN-.R-deficient, neutrophils. Meanwhile, CD1d(-/-) mice exhibited high CD55 expression on neutrophils during sepsis, whereas those cells from WT mice expressed minimal levels of CD55. Recombinant IL-10 administration into CD1d(-/-) mice reduced CD55 expression on neutrophils. Furthermore, adoptive transfer of sorted WT, but not IFN-.-deficient, NKT cells into CD1d(-/-) mice suppressed CD55 expression on neutrophils, but increased IL-10 and C5a levels. Taken together, IFN-.-producing NKT cells enhance C5a generation via IL-10-mediated inhibition of CD55 expression on neutrophils, thereby exacerbating sepsis. C1 [Kim, Ji Hyung; Oh, Sae Jin; Chung, Doo Hyun] Seoul Natl Univ, Coll Med, Dept Pathol, Seoul 110799, South Korea. [Kim, Ji Hyung; Oh, Sae Jin; Ahn, Sehee; Chung, Doo Hyun] Seoul Natl Univ, Coll Med, Dept Biomed Sci, Lab Immune Regulat, Seoul 110799, South Korea. [Kim, Ji Hyung] Harvard Univ, Childrens Hosp, Dept Microbiol & Immunobiol, Program Cellular & Mol Med,Med Sch, Boston, MA 02115 USA. [Oh, Sae Jin; Chung, Doo Hyun] Seoul Natl Univ, Coll Med, Ischem Hypoxia Inst, Seoul 110799, South Korea. RP Chung, DH (reprint author), Seoul Natl Univ, Coll Med, Dept Pathol, 103 Daehak Ro, Seoul 110799, South Korea. EM doohyun@snu.ac.kr FU National Research Foundation of Korea (NRF) - Korean government (Ministry of Education, Science and Technology) [20120005652] FX The authors would like to thank the members of the Hye Hwa Forum for helpful discussions and the NIAID Tetramer Facility at the National Institutes of Health, USA for providing PBS-57-loaded CD1d tetramers. This work was supported by a grant from the National Research Foundation of Korea (NRF) funded by the Korean government (Ministry of Education, Science and Technology) (20120005652). NR 45 TC 3 Z9 4 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 EI 1521-4141 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD JUL PY 2014 VL 44 IS 7 BP 2025 EP 2035 DI 10.1002/eji.201343937 PG 11 WC Immunology SC Immunology GA AN4UP UT WOS:000340584300018 PM 24723363 ER PT J AU Kociolek, LK Gerding, DN AF Kociolek, Larry K. Gerding, Dale N. TI Is pediatric Clostridium difficile infection associated with prior antibiotic exposure? SO FUTURE MICROBIOLOGY LA English DT Editorial Material DE antibiotics; Clostridium difficile; epidemiology; pediatric; risk factors ID CHANGING EPIDEMIOLOGY; CHILDREN; SURVEILLANCE; PREVENTION; RISK C1 [Kociolek, Larry K.] Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL 60611 USA. [Kociolek, Larry K.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Gerding, Dale N.] US Dept Vet Affairs, Vet Affairs Edward Hines Jr Hosp, Hines, IL 60141 USA. [Gerding, Dale N.] Loyola Univ, Stritch Sch Med, Maywood, IL 60153 USA. RP Kociolek, LK (reprint author), Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL 60611 USA. EM lkociolek@luriechildrens.org OI Kociolek, Larry/0000-0002-8756-3417 NR 20 TC 1 Z9 1 U1 1 U2 1 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 JUL PY 2014 VL 9 IS 7 BP 825 EP 828 DI 10.2217/FMB.14.51 PG 4 WC Microbiology SC Microbiology GA AO1TV UT WOS:000341098600001 PM 25156370 ER PT J AU Minen, MT Tanev, K Friedman, BW AF Minen, Mia T. Tanev, Kaloyan Friedman, Benjamin W. TI Evaluation and Treatment of Migraine in the Emergency Department: A Review SO HEADACHE LA English DT Review DE migraine; emergency department; narcotic; computerized tomography; pharmacology; discharge ID COMPUTED-TOMOGRAPHY; RESCUE THERAPY; ADULT PATIENTS; DOUBLE-BLIND; HEADACHE MANAGEMENT; MAJOR DEPRESSION; AMERICAN-ACADEMY; RANDOMIZED-TRIAL; CLINICAL POLICY; BENIGN HEADACHE AB Head pain is the fifth most common reason for emergency department (ED) visits. It is second only to focal weakness as the most common reason for neurological consultation in the ED. This manuscript reviews how patients with migraine, the most common primary headache disorder for which patients seek medical treatment, are managed in the ED. We discuss existing guidelines for head imaging in patients with migraine, recommended pharmacologic treatments, and current treatment trends. We also review studies evaluating the discharge care of migraine patients in the ED. With the goal of standardizing, streamlining, and optimizing ED-based migraine care, we offer ideas for future research to improve the evaluation, treatment, and discharge care of patients who present to an ED with acute migraine. C1 [Minen, Mia T.] Brigham & Womens Faulkner Hosp, Graham Headache Ctr, Dept Neurol, Boston, MA USA. [Minen, Mia T.; Tanev, Kaloyan] Harvard Univ, Sch Med, Boston, MA USA. [Tanev, Kaloyan] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Friedman, Benjamin W.] Montefiore Med Ctr, Dept Emergency Med, Bronx, NY 10467 USA. [Friedman, Benjamin W.] Albert Einstein Coll Med, Bronx, NY 10467 USA. RP Minen, MT (reprint author), 1153 Ctr St,Suite 4970, Boston, MA 02130 USA. EM minenmd@gmail.com NR 78 TC 2 Z9 2 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0017-8748 EI 1526-4610 J9 HEADACHE JI Headache PD JUL-AUG PY 2014 VL 54 IS 7 BP 1131 EP 1145 DI 10.1111/head.12399 PG 15 WC Clinical Neurology SC Neurosciences & Neurology GA AN5AU UT WOS:000340602200003 PM 24898930 ER PT J AU Eikermann-Haerter, K AF Eikermann-Haerter, Katharina TI Spreading Depolarization May Link Migraine and Stroke SO HEADACHE LA English DT Review DE stroke; spreading depolarization; migraine; aura; familial hemiplegic migraine; cerebral autosomal arteriopathy with subcortical infarcts and leukoencephalopathy ID FAMILIAL HEMIPLEGIC MIGRAINE; PATENT FORAMEN OVALE; ANEURYSMAL SUBARACHNOID HEMORRHAGE; ISCHEMIC NEUROLOGICAL DEFICITS; CERVICAL ARTERY DISSECTION; FOCAL CEREBRAL-ISCHEMIA; BRAIN-INJURY; RISK-FACTORS; CARDIOVASCULAR-DISEASE; PERIINFARCT DEPOLARIZATIONS AB Migraine increases the risk of stroke, particularly in young and otherwise healthy adults. Being the most frequent neurological condition, migraine prevalence is on a par with that of other common stroke risk factors, such as diabetes or hypertension. Several patterns of association have emerged: (1) migraine and stroke share a common association (eg, vasculopathies, patent foramen ovale, or pulmonary A-V malformations); (2) injury to the arterial wall such as acute arterial dissections can present as migraine aura attacks or stroke; (3) strokes rarely develop during a migraine attack, as described for "migrainous stroke." Increasing experimental evidence suggests that cerebral hyperexcitability and enhanced susceptibility to spreading depolarization, the electrophysiologic event underlying migraine, may serve as a mechanism underlying the migraine-stroke association. Mice carrying human vascular or neuronal migraine mutations exhibit an enhanced susceptibility to spreading depolarization while being particularly vulnerable to cerebral ischemia. The severe stroke phenotype in migraine mutant mice can be prevented by suppressing spreading depolarization. If confirmed in the clinical setting, inhibiting spreading depolarization might protect migraineurs at stroke risk as well as decrease attacks of migraine. C1 [Eikermann-Haerter, Katharina] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Neurovasc Res Lab,Dept Radiol, Charlestown, MA USA. RP Eikermann-Haerter, K (reprint author), 149 13th St, Charlestown, MA 02129 USA. EM khaerter@mgh.harvard.edu FU American Heart Association [10SDG2610275]; Massachusetts General Hospital FX This work was supported in part by the American Heart Association (10SDG2610275) and the Massachusetts General Hospital (Claflin Award and Spark Award). NR 111 TC 15 Z9 15 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0017-8748 EI 1526-4610 J9 HEADACHE JI Headache PD JUL-AUG PY 2014 VL 54 IS 7 BP 1146 EP 1157 DI 10.1111/head.12386 PG 12 WC Clinical Neurology SC Neurosciences & Neurology GA AN5AU UT WOS:000340602200004 PM 24913618 ER PT J AU Jordan, JT Plotkin, S Dietrich, J AF Jordan, Justin T. Plotkin, Scott Dietrich, Jorg TI Magnetic Resonance Imaging Observations in Primary Central Nervous System Lymphoma SO JAMA NEUROLOGY LA English DT Editorial Material ID MRI FEATURES C1 [Jordan, Justin T.; Plotkin, Scott; Dietrich, Jorg] Massachusetts Gen Hosp, Dept Neurol, Pappas Ctr Neurooncol, Boston, MA 02114 USA. RP Jordan, JT (reprint author), Massachusetts Gen Hosp, Dept Neurol, Pappas Ctr Neurooncol, 55 Fruit St,Yawkey Bldg,Ste 9E, Boston, MA 02114 USA. EM jtjordan@mgh.harvard.edu NR 4 TC 0 Z9 1 U1 1 U2 3 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 JUL PY 2014 VL 71 IS 7 BP 918 EP 919 DI 10.1001/jamaneurol.2014.70 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA AN3IR UT WOS:000340481200018 PM 24861724 ER PT J AU Scales, CD Lai, JC Dick, AW Hanley, JM van Meijgaard, J Setodji, CM Saigal, CS AF Scales, Charles D., Jr. Lai, Julie C. Dick, Andrew W. Hanley, Jan M. van Meijgaard, Jeroen Setodji, Claude M. Saigal, Christopher S. CA Amer Project TI Comparative Effectiveness of Shock Wave Lithotripsy and Ureteroscopy for Treating Patients With Kidney Stones SO JAMA SURGERY LA English DT Article ID DISTAL URETERAL CALCULI; INSTRUMENTAL VARIABLES; METABOLIC SYNDROME; 2007 GUIDELINE; UNITED-STATES; HEALTH-CARE; MANAGEMENT; NEPHROLITHIASIS; TECHNOLOGY; PREVALENCE AB IMPORTANCE Shock wave lithotripsy (SWL) and ureteroscopy (URS) account for more than 90% of procedural interventions for kidney stones, which affect 1 in 11 persons in the United States. Efficacy data for SWL are more than 20 years old. Advances in URS, along with emerging evidence of reduced efficacy of modern lithotripters, have created uncertainty regarding the comparative effectiveness of these 2 treatment options. OBJECTIVE To compare the effectiveness of SWL and URS to fragment or remove urinary stones in a large private payer cohort. DESIGN, SETTING, AND PARTICIPANTS We performed a retrospective cohort study of privately insured beneficiaries who had an emergency department visit for a kidney stone and subsequently underwent SWL or URS. Using an instrumental variable approach to control for observed and unobserved differences between the 2 groups, we created a bivariate probit model to estimate the probability of repeat intervention following an initial procedure. MAIN OUTCOMES AND MEASURES A second procedure (SWL or URS) within 120 days of an initial intervention to fragment or remove or a kidney stone. RESULTS Following an acute care visit for a kidney stone, 21 937 patients (45.8%) underwent SWL and 25 914 patients (54.2%) underwent URS to fragment or remove the stone. After the initial URS, 4852 patients (18.7%) underwent an additional fragmentation or removal procedure compared with 5186 patients (23.6%) after the initial SWL (P <.001). After adjusting for observed and unobserved variables, the estimated probabilities of repeat intervention were 11.0% (95% CI, 10.9-11.1) following SWL and 0.3% (95% CI, 0.325-0.329) following URS. CONCLUSIONS AND RELEVANCE Among privately insured beneficiaries requiring procedural intervention to remove a symptomatic stone, repeat intervention is more likely following SWL. For the marginal patient (as opposed to the average patient), the probability of repeat intervention is substantially higher. C1 [Scales, Charles D., Jr.] Univ Calif Los Angeles, Robert Wood Johnson Fdn Clin Scholars Program, Los Angeles, CA USA. [Scales, Charles D., Jr.] US Dept Vet Affairs, Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Scales, Charles D., Jr.; Saigal, Christopher S.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Urol, Los Angeles, CA 90095 USA. [Scales, Charles D., Jr.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Lai, Julie C.; Hanley, Jan M.; Saigal, Christopher S.] RAND Corp, Santa Monica, CA USA. [Dick, Andrew W.] RAND Corp, Boston, MA USA. [van Meijgaard, Jeroen] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Dept Hlth Policy & Management, Los Angeles, CA USA. [Setodji, Claude M.] RAND Corp, Pittsburgh, PA USA. RP Scales, CD (reprint author), Duke Univ, Med Ctr, Duke Clin Res Inst, Div Urol Surg, 40 Med Cir,Ste 1570, Durham, NC 27710 USA. EM chuck.scales@duke.edu FU Robert Wood Johnson Foundation Clinical Scholars Program; US Department of Veterans Affairs; National Institute of Diabetes and Digestive and Kidney Diseases [HHSN276201200016C]; National Library of Medicine FX This study was supported by the Robert Wood Johnson Foundation Clinical Scholars Program and the US Department of Veterans Affairs (Dr Scales). The Urologic Diseases in America Project is supported by grant HHSN276201200016C from the National Institute of Diabetes and Digestive and Kidney Diseases and the National Library of Medicine. NR 37 TC 19 Z9 19 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6254 EI 2168-6262 J9 JAMA SURG JI JAMA Surg. PD JUL PY 2014 VL 149 IS 7 BP 648 EP 653 DI 10.1001/jamasurg.2014.336 PG 6 WC Surgery SC Surgery GA AN8DV UT WOS:000340833800007 PM 24839228 ER PT J AU Halperin, F Ding, SA Simonson, DC Panosian, J Goebel-Fabbri, A Wewalka, M Hamdy, O Abrahamson, M Clancy, K Foster, K Lautz, D Vernon, A Goldfine, AB AF Halperin, Florencia Ding, Su-Ann Simonson, Donald C. Panosian, Jennifer Goebel-Fabbri, Ann Wewalka, Marlene Hamdy, Osama Abrahamson, Martin Clancy, Kerri Foster, Kathleen Lautz, David Vernon, Ashley Goldfine, Allison B. TI Roux-en-Y Gastric Bypass Surgery or Lifestyle With Intensive Medical Management in Patients With Type 2 Diabetes Feasibility and 1-Year Results of a Randomized Clinical Trial SO JAMA SURGERY LA English DT Article ID SWEDISH OBESE SUBJECTS; LONG-TERM MORTALITY; BARIATRIC SURGERY; GLUCOSE CONTROL; CARDIOVASCULAR-DISEASE; RISK-FACTORS; INTERVENTION; WEIGHT; MELLITUS; REDUCTION AB IMPORTANCE Emerging data support bariatric surgery as a therapeutic strategy for management of type 2 diabetes mellitus. OBJECTIVE To test the feasibility of methods to conduct a larger multisite trial to determine the long-term effect of Roux-en-Y gastric bypass (RYGB) surgery compared with an intensive diabetes medical and weight management (Weight Achievement and Intensive Treatment [Why WAIT]) program for type 2 diabetes. DESIGN, SETTING, AND PARTICIPANTS A 1-year pragmatic randomized clinical trial was conducted in an academic medical institution. Participants included persons aged 21 to 65 years with type 2 diabetes diagnosed more than 1 year before the study; their body mass index was 30 to 42 (calculated as weight in kilograms divided by height in meters squared) and hemoglobin A(1c) (HbA(1c)) was greater than or equal to 6.5%. All participants were receiving antihyperglycemic medications. INTERVENTIONS RYGB (n = 19) or Why WAIT (n = 19) including 12 weekly multidisciplinary group lifestyle, medical, and educational sessions with monthly follow-up thereafter. MAIN OUTCOMES AND MEASURES Proportion of patients with fasting plasma glucose levels less than 126 mg/dL and HbA(1c) less than 6.5%, measures of cardiometabolic health, and patient-reported outcomes. RESULTS At 1 year, the proportion of patients achieving HbA(1c) below 6.5% and fasting glucose below 126 mg/dL was higher following RYGB than Why WAIT (58% vs 16%, respectively; P = .03). Other outcomes, including HbA(1c), weight, waist circumference, fat mass, lean mass, blood pressure, and triglyceride levels, decreased and high-density lipoprotein cholesterol increased more after RYGB compared with Why WAIT. Improvement in cardiovascular risk scores was greater in the surgical group. At baseline the participants exhibited moderately low self-reported quality-of-life scores reflected by Short Form-36 total, physical health, and mental health, as well as high Impact of Weight on Quality of Life-Lite and Problem Areas in Diabetes health status scores. At 1 year, improvements in Short Form-36 physical and mental health scores and Problem Areas in Diabetes scores did not differ significantly between groups. The Impact of Weight on Quality of Life-Lite score improved more with RYGB and correlated with greater weight loss compared with Why WAIT. CONCLUSIONS AND RELEVANCE In obese patients with type 2 diabetes, RYGB produces greater weight loss and sustained improvements in HbA(1c) and cardiometabolic risk factors compared with medical management, with emergent differences over 1 year. Both treatments improve general quality-of-life measures, but RYGB provides greater improvement in the effect of weight on quality of life. These differences may help inform therapeutic decisions for diabetes and weight loss strategies in obese patients with type 2 diabetes until larger randomized trials are performed. C1 [Halperin, Florencia; Simonson, Donald C.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, Boston, MA 02215 USA. [Panosian, Jennifer; Goebel-Fabbri, Ann; Wewalka, Marlene; Hamdy, Osama; Abrahamson, Martin; Foster, Kathleen; Goldfine, Allison B.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. [Clancy, Kerri; Lautz, David; Vernon, Ashley] Harvard Univ, Sch Med, Brigham & Womens Hosp, Ctr Metab & Bariatr Surg, Boston, MA 02215 USA. RP Goldfine, AB (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Res, One Joslin Pl, Boston, MA 02215 USA. EM allison.goldfine@joslin.harvard.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [RC1-DK086918, R56-DK095451, P30-DKO03836]; Osterreichischer Austausdienst [ICM-2010-02797]; Herbert Graetz Fund FX This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases grants RC1-DK086918, R56-DK095451, and P30-DKO03836; the Marietta Blau grant ICM-2010-02797 from the Osterreichischer Austausdienst; and the Herbert Graetz Fund. Covidien provided funds for the surgical costs of participants with BMI less than 35 who were randomized to undergo surgery; Lifescan, a Division of Johnson & Johnson, provided home glucose monitoring supplies; Nestle Nutrition Inc provided Boost; and Mercodia provided assay materials. NR 41 TC 51 Z9 51 U1 2 U2 6 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 JUL PY 2014 VL 149 IS 7 BP 716 EP 726 DI 10.1001/jamasurg.2014.514 PG 11 WC Surgery SC Surgery GA AN8DV UT WOS:000340833800019 PM 24899464 ER PT J AU Yeh, DD AF Yeh, Daniel Dante TI Glasgow Coma Scale 40 Years Later In Need of Recalibration? SO JAMA SURGERY LA English DT Editorial Material ID INJURY; SCORE C1 [Yeh, Daniel Dante] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Yeh, Daniel Dante] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Yeh, DD (reprint author), Massachusetts Gen Hosp, Dept Surg, 165 Cambridge St,Ste 810, Boston, MA 02114 USA. EM dyeh2@mgh.harvard.edu NR 5 TC 0 Z9 0 U1 0 U2 2 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 JUL PY 2014 VL 149 IS 7 BP 734 EP 734 DI 10.1001/jamasurg.2014.47 PG 1 WC Surgery SC Surgery GA AN8DV UT WOS:000340833800021 PM 24899079 ER PT J AU Kanick, SC Davis, SC Zhao, Y Hasan, T Maytin, EV Pogue, BW Chapman, MS AF Kanick, Stephen Chad Davis, Scott C. Zhao, Yan Hasan, Tayyaba Maytin, Edward V. Pogue, Brian W. Chapman, M. Shane TI Dual-channel red/blue fluorescence dosimetry with broadband reflectance spectroscopic correction measures protoporphyrin IX production during photodynamic therapy of actinic keratosis SO JOURNAL OF BIOMEDICAL OPTICS LA English DT Article DE fluorescence; reflectance; optical spectroscopy; photodynamic therapy; dosimetry; pharmacokinetics; protoporphyrin IX ID BASAL-CELL CARCINOMA; SKIN IN-VIVO; AMINOLEVULINIC-ACID; METHYL AMINOLEVULINATE; SHORT INCUBATION; TOPICAL APPLICATION; OPTICAL-PROPERTIES; ACCUMULATION; MULTICENTER; SCALP AB Dosimetry for aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) photodynamic therapy of actinic keratosis was examined with an optimized fluorescence dosimeter to measure PpIX during treatment. While insufficient PpIX generation may be an indicator of incomplete response, there exists no standardized method to quantitate PpIX production at depths in the skin during clinical treatments. In this study, a spectrometer-based point probe dosimeter system was used to sample PpIX fluorescence from superficial (blue wavelength excitation) and deeper (red wavelength excitation) tissue layers. Broadband white light spectroscopy (WLS) was used to monitor aspects of vascular physiology and inform a correction of fluorescence for the background optical properties. Measurements in tissue phantoms showed accurate recovery of blood volume fraction and reduced scattering coefficient from WLS, and a linear response of PpIX fluorescence versus concentration down to 1.95 and 250 nM for blue and red excitations, respectively. A pilot clinical study of 19 patients receiving 1-h ALA incubation before treatment showed high intrinsic variance in PpIX fluorescence with a standard deviation/mean ratio of > 0.9. PpIX fluorescence was significantly higher in patients reporting higher pain levels on a visual analog scale. These pilot data suggest that patient-specific PpIX quantitation may predict outcome response. (C) The Authors. Published by SPIE under a Creative Commons Attribution 3.0 Unported License. C1 [Kanick, Stephen Chad; Davis, Scott C.; Zhao, Yan; Pogue, Brian W.] Dartmouth Coll, Thayer Sch Engn, Hanover, NH 03755 USA. [Hasan, Tayyaba; Pogue, Brian W.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Maytin, Edward V.] Cleveland Clin, Cleveland, OH 44195 USA. [Pogue, Brian W.; Chapman, M. Shane] Dartmouth Hitchcock Med Ctr, Dermatol Sect, Dept Surg, Lebanon, NH 03766 USA. RP Kanick, SC (reprint author), Dartmouth Coll, Thayer Sch Engn, Hanover, NH 03755 USA. EM stephen.c.kanick@dartmouth.edu FU [P01 CA084203]; [K25 CA164248-01] FX The authors would like to thank Jason R. Gunn for help in optical phantom preparation, Karen L. Sheehan for many clinical measurements with the dosimeter, and Professor Steven L. Jacques (Oregon Health and Science University) for helpful conversations about tissue optics and modeling of light signals. This work was funded by grants P01 CA084203 and K25 CA164248-01. NR 48 TC 13 Z9 14 U1 1 U2 10 PU SPIE-SOC PHOTO-OPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 1083-3668 EI 1560-2281 J9 J BIOMED OPT JI J. Biomed. Opt. PD JUL PY 2014 VL 19 IS 7 AR 075002 DI 10.1117/1.JBO.19.7.075002 PG 15 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA AN3LU UT WOS:000340490400019 PM 24996661 ER PT J AU Perron-Burdick, M Calhoun, A Idowu, D Pressman, A Zaritsky, E AF Perron-Burdick, Misa Calhoun, Amanda Idowu, Dennis Pressman, Alice Zaritsky, Eve TI Minilaparotomy vs Laparoscopic Hysterectomy: Comparison of Length of Hospital Stay SO JOURNAL OF MINIMALLY INVASIVE GYNECOLOGY LA English DT Article DE Hospital stay; Hysterectomy; Laparoscopy; Laparotomy; Length of stay; Minilaparotomy ID BENIGN GYNECOLOGIC DISEASE; QUALITY-OF-LIFE; ABDOMINAL HYSTERECTOMY; VAGINAL HYSTERECTOMY; UTERINE MYOMAS; WOMEN AB Study Objective: To compare length of hospital stay for minilaparotomy vs laparoscopic hysterectomy. Design: Retrospective cohort study (Canadian Task Force classification II-2). Setting: Kaiser Permanente Northern California, a large integrated health care delivery system. Patients: Women >18 years of age undergoing laparoscopic or minilaparotomy hysterectomy because of benign indications from June 2009 through January 2010. Intervention: Hysterectomy via minilaparotomy or laparoscopy. Measurements and Main Results: Medical records were reviewed for outcomes of interest including length of stay and surgical and demographic data. Parametric and non-parametric analyses were used to compare the 2 groups. The study was powered to detect a difference of 8 hours in length of stay. Two hundred sixty-three cases were identified as hysterectomy via minilaparotomy (n = 100) or laparoscopy (n = 163). The laparoscopy group demonstrated a significantly shorter mean (SD) length of stay (19 [14] hours vs 42 [20] hours; p < .001) and less blood loss (126 [140] mL vs 241 [238] mL; p < .001). The minilaparotomy group experienced a shorter procedure time (113 [47] minutes vs 197 [124] minutes; p < .001). There was no difference between the groups insofar as patient morbidity including intraoperative and postoperative complications, emergency visits, readmissions, or repeat operations. Conclusion: Compared with minilaparotomy, laparoscopic hysterectomy is associated with shorter length of hospital stay, longer operating time, and no increased patient morbidity. Published by Elsevier Inc. on behalf of AAGL. C1 [Perron-Burdick, Misa] San Francisco VA Med Ctr, Dept Gen Internal Med, San Francisco, CA 94112 USA. [Perron-Burdick, Misa] Univ Calif San Francisco, Sch Med, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA USA. [Calhoun, Amanda; Idowu, Dennis; Zaritsky, Eve] Kaiser Permanente No Calif, Dept Obstet & Gynecol, San Francisco, CA USA. [Pressman, Alice] Kaiser Permanente No Calif, Div Res, San Francisco, CA USA. [Pressman, Alice] Sutter Hlth Res, San Francisco, CA USA. RP Perron-Burdick, M (reprint author), San Francisco VA Med Ctr, Dept Gen Internal Med, 647 Edinburgh, San Francisco, CA 94112 USA. EM Perron-BurdickM@obgyn.ucsf.edu NR 19 TC 2 Z9 2 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1553-4650 EI 1553-4669 J9 J MINIM INVAS GYN JI J. Mimim. Invasive Gynecol. PD JUL-AUG PY 2014 VL 21 IS 4 BP 619 EP 623 DI 10.1016/j.jmig.2013.12.125 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AN6ED UT WOS:000340686800021 PM 24469276 ER PT J AU Banister, G Bowen-Brady, HM Winfrey, ME AF Banister, Gaurdia Bowen-Brady, Helene M. Winfrey, Marion E. TI USING CAREER NURSE MENTORS TO SUPPORT MINORITY NURSING STUDENTS AND FACILITATE THEIR TRANSITION TO PRACTICE SO JOURNAL OF PROFESSIONAL NURSING LA English DT Article DE Diversity; Mentorship; Mentor; Minority; Workforce development AB The Clinical Leadership Collaborative for Diversity in Nursing was developed through an academe service partnership focused on supporting minority nursing students and facilitating transition to practice. A key program element is mentoring. Students are paired with an experienced, minority clinical nurse or nurse leader from one of the partnering agencies, who helps guide the student throughout the junior and senior year of school and first year of employment. The mentoring component was evaluated through surveys in which mentors and mentees rated one another and offered open-ended comments on the program's impact. Aspects of mentees rated highest by mentors include manner (courteous and professional), ability to communicate and get along with others, preparation for meetings, and fully utilizing their time with mentors. Aspects of mentors rated highest by mentees include warmth, encouragement, and willingness to listen; enthusiasm for nursing and how they sparked the mentee's interest; and clarity regarding expectations for mentees and how they pushed mentees to achieve high standards. In the open-ended comments, mentees consistently identified mentoring as the program's strongest component. Sixty-four minority students have participated to date with a zero rate of attrition and very low job turnover among graduates. (C) 2014 Elsevier Inc. All rights reserved. C1 [Banister, Gaurdia] Massachusetts Gen Hosp, Inst Patient Care, Boston, MA 02114 USA. [Bowen-Brady, Helene M.] Brigham & Womens Faulkner Hosp, Dept Nursing Profess & Practice Dev, Boston, MA USA. [Winfrey, Marion E.] Univ Massachusetts, Coll Nursing & Hlth Sci, Boston, MA 02125 USA. RP Banister, G (reprint author), Massachusetts Gen Hosp, Inst Patient Care, 55 Fruit St FND3, Boston, MA 02114 USA. EM gbanister@partners.org NR 26 TC 3 Z9 3 U1 2 U2 16 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 8755-7223 EI 1532-8481 J9 J PROF NURS JI J. Prof. Nurs. PD JUL-AUG PY 2014 VL 30 IS 4 BP 317 EP 325 DI 10.1016/j.profnurs.2013.11.001 PG 9 WC Nursing SC Nursing GA AO3KP UT WOS:000341228400006 PM 25150417 ER PT J AU Donelan, K Romano, C DesRoches, C Applebaum, S Ward, JRM Schoneboom, BA Hinshaw, AS AF Donelan, Karen Romano, Carol DesRoches, Catherine Applebaum, Sandra Ward, Johanna R. M. Schoneboom, Bruce A. Hinshaw, Ada Sue TI National Surveys of Military Personnel, Nursing Students, and the Public: Drivers of Military Nursing Careers (vol 179, pg 565, 2014) SO MILITARY MEDICINE LA English DT Correction C1 [Donelan, Karen] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. [Romano, Carol; Hinshaw, Ada Sue] Uniformed Serv Univ Hlth Sci, Grad Sch Nursing, Bethesda, MD 20814 USA. [DesRoches, Catherine] Vanderbilt Univ, Ctr Med, Ctr Interdisciplinary Hlth Workforce Studies, Inst Med & Publ Hlth, Nashville, TN 37203 USA. [Applebaum, Sandra] Math Policy Res, Cambridge, MA 02139 USA. [Ward, Johanna R. M.] Harris Interact Inc, New York, NY 10010 USA. [Schoneboom, Bruce A.] US Army, Med Res Inst Chem Def, Aberdeen Proving Ground, MD 21010 USA. RP Donelan, K (reprint author), Massachusetts Gen Hosp, Mongan Inst Hlth Policy, 50 Staniford St,9th floor, Boston, MA 02114 USA. NR 1 TC 0 Z9 0 U1 1 U2 1 PU ASSOC MILITARY SURG US PI BETHESDA PA 9320 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0026-4075 EI 1930-613X J9 MIL MED JI Milit. Med. PD JUL PY 2014 VL 179 IS 7 BP 792 EP 792 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA AN7UN UT WOS:000340806600024 ER PT J AU Wang, J Shah, D Chen, XY Anderson, RR Wu, MX AF Wang, Ji Shah, Dilip Chen, Xinyuan Anderson, R. Rox Wu, Mei X. TI A micro-sterile inflammation array as an adjuvant for influenza vaccines SO NATURE COMMUNICATIONS LA English DT Article ID PLASMACYTOID DENDRITIC CELLS; RANDOMIZED CONTROLLED SAFETY; ANTIGEN PRESENTATION; INTRADERMAL VACCINATION; IMMUNOGENICITY TRIAL; ADAPTIVE IMMUNITY; IMIQUIMOD; RESPONSES; MICROINJECTION; RECRUITMENT AB There is an urgent need of adjuvants for cutaneous vaccination. Here, we report that micro-sterile inflammation induced at inoculation sites can augment immune responses to influenza vaccines in animal models. The inoculation site is briefly illuminated with a handheld, non-ablative fractional laser before the vaccine is intradermally administered, which creates an array of self-healing microthermal zones (MTZs) in the skin. The dying cells in the MTZs send 'danger' signals that attract a large number of antigen-presenting cells, in particular, plasmacytoid dendritic cells (pDCs) around each MTZ forming a micro-sterile inflammation array. A pivotal role for pDCs in the adjuvanticity is ascertained by significant abrogation of the immunity after systemic depletion of pDCs, local application of a TNF-alpha inhibitor or null mutation of IFN regulatory factor7 (IRF7). In contrast to conventional adjuvants that cause persistent inflammation and skin lesions, micro-sterile inflammation enhances efficacy of influenza vaccines, yet with diminished adverse effects. C1 [Wang, Ji; Shah, Dilip; Chen, Xinyuan; Anderson, R. Rox; Wu, Mei X.] Harvard Univ, Massachusetts Gen Hosp, Med Sch HMS, Wellman Ctr Photomed,Dept Dermatol, Boston, MA 02114 USA. [Anderson, R. Rox; Wu, Mei X.] Harvard MIT Div Hlth Sci & Technol HST, Cambridge, MA 02139 USA. RP Wu, MX (reprint author), Harvard Univ, Massachusetts Gen Hosp, Med Sch HMS, Wellman Ctr Photomed,Dept Dermatol, Boston, MA 02114 USA. EM mwu2@partners.org FU National Institutes of Health [AI089779, AI070785, AI097696, DA028378]; Bullock-Wellman Fellowship; A. Ward. Ford. Memorial Grant [NSP0511] FX We would like to thank Margaret Sherwood, Jenny Zhao and Danny Cao for their help in the microscopy and flow cytometry during this project. This work is supported in part by the National Institutes of Health grants AI089779, AI070785, AI097696, and DA028378 (to M.X.W.) and Bullock-Wellman Fellowship and A. Ward. Ford. Memorial Grant NSP0511 (to X.C.). NR 47 TC 4 Z9 4 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JUL PY 2014 VL 5 AR 4447 DI 10.1038/ncomms5447 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AN5IB UT WOS:000340622900039 PM 25033973 ER PT J AU Kitahara, CM Flint, AJ de Gonzalez, AB Bernstein, L Brotzman, M MacInnis, RJ Moore, SC Robien, K Rosenberg, PS Singh, PN Weiderpass, E Adami, HO Anton-Culver, H Ballard-Barbash, R Buring, JE Freedman, DM Fraser, GE Freeman, LEB Gapstur, SM Gaziano, JM Giles, GG Hakansson, N Hoppin, JA Hu, FB Koenig, K Linet, MS Park, Y Patel, AV Purdue, MP Schairer, C Sesso, HD Visvanathan, K White, E Wolk, A Zeleniuch-Jacquotte, A Hartge, P AF Kitahara, Cari M. Flint, Alan J. de Gonzalez, Amy Berrington Bernstein, Leslie Brotzman, Michelle MacInnis, Robert J. Moore, Steven C. Robien, Kim Rosenberg, Philip S. Singh, Pramil N. Weiderpass, Elisabete Adami, Hans Olov Anton-Culver, Hoda Ballard-Barbash, Rachel Buring, Julie E. Freedman, D. Michal Fraser, Gary E. Freeman, Laura E. Beane Gapstur, Susan M. Gaziano, John Michael Giles, Graham G. Hakansson, Niclas Hoppin, Jane A. Hu, Frank B. Koenig, Karen Linet, Martha S. Park, Yikyung Patel, Alpa V. Purdue, Mark P. Schairer, Catherine Sesso, Howard D. Visvanathan, Kala White, Emily Wolk, Alicja Zeleniuch-Jacquotte, Anne Hartge, Patricia TI Association between Class III Obesity (BMI of 40-59 kg/m(2)) and Mortality: A Pooled Analysis of 20 Prospective Studies SO PLOS MEDICINE LA English DT Article ID BODY-MASS INDEX; CARDIOVASCULAR RISK-FACTORS; BASE-LINE CHARACTERISTICS; MORBID-OBESITY; BREAST-CANCER; WEIGHT-LOSS; PHYSICAL-ACTIVITY; UNITED-STATES; PREDICTING MORTALITY; RANDOMIZED-TRIAL AB Background: The prevalence of class III obesity (body mass index [BMI]>= 40 kg/m(2)) has increased dramatically in several countries and currently affects 6% of adults in the US, with uncertain impact on the risks of illness and death. Using data from a large pooled study, we evaluated the risk of death, overall and due to a wide range of causes, and years of life expectancy lost associated with class III obesity. Methods and Findings: In a pooled analysis of 20 prospective studies from the United States, Sweden, and Australia, we estimated sex-and age-adjusted total and cause-specific mortality rates (deaths per 100,000 persons per year) and multivariable-adjusted hazard ratios for adults, aged 19-83 y at baseline, classified as obese class III (BMI 40.0-59.9 kg/m(2)) compared with those classified as normal weight (BMI 18.5-24.9 kg/m(2)). Participants reporting ever smoking cigarettes or a history of chronic disease (heart disease, cancer, stroke, or emphysema) on baseline questionnaires were excluded. Among 9,564 class III obesity participants, mortality rates were 856.0 in men and 663.0 in women during the study period (19762009). Among 304,011 normal-weight participants, rates were 346.7 and 280.5 in men and women, respectively. Deaths from heart disease contributed largely to the excess rates in the class III obesity group (rate differences = 238.9 and 132.8 in men and women, respectively), followed by deaths from cancer (rate differences = 36.7 and 62.3 in men and women, respectively) and diabetes (rate differences = 51.2 and 29.2 in men and women, respectively). Within the class III obesity range, multivariable-adjusted hazard ratios for total deaths and deaths due to heart disease, cancer, diabetes, nephritis/nephrotic syndrome/nephrosis, chronic lower respiratory disease, and influenza/pneumonia increased with increasing BMI. Compared with normal-weight BMI, a BMI of 40-44.9, 45-49.9, 50-54.9, and 55-59.9 kg/m(2) was associated with an estimated 6.5 (95% CI: 5.7-7.3), 8.9 (95% CI: 7.4-10.4), 9.8 (95% CI: 7.4-12.2), and 13.7 (95% CI: 10.5-16.9) y of life lost. A limitation was that BMI was mainly ascertained by self-report. Conclusions: Class III obesity is associated with substantially elevated rates of total mortality, with most of the excess deaths due to heart disease, cancer, and diabetes, and major reductions in life expectancy compared with normal weight. C1 [Kitahara, Cari M.; de Gonzalez, Amy Berrington; Moore, Steven C.; Rosenberg, Philip S.; Freedman, D. Michal; Freeman, Laura E. Beane; Linet, Martha S.; Park, Yikyung; Purdue, Mark P.; Schairer, Catherine; Hartge, Patricia] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Flint, Alan J.; Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Flint, Alan J.; Adami, Hans Olov; Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Bernstein, Leslie] City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Div Canc Etiol, Duarte, CA USA. [Brotzman, Michelle] WESTAT Corp, Rockville, MD 20850 USA. [MacInnis, Robert J.; Giles, Graham G.] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [MacInnis, Robert J.; Giles, Graham G.] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic, Australia. [Robien, Kim] George Washington Univ, Dept Epidemiol & Biostat, Sch Publ Hlth & Hlth Serv, Washington, DC USA. [Singh, Pramil N.] Loma Linda Univ, Sch Publ Hlth, Ctr Hlth Res, Loma Linda, CA 92350 USA. [Weiderpass, Elisabete; Adami, Hans Olov] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Weiderpass, Elisabete] Univ Tromso, Fac Hlth Sci, Dept Community Med, Tromso, Norway. [Weiderpass, Elisabete] Canc Registry Norway, Dept Res, Oslo, Norway. [Weiderpass, Elisabete] Samfundet Folkhalsan, Helsinki, Finland. [Anton-Culver, Hoda] Univ Calif Irvine, Sch Med, Dept Epidemiol, Irvine, CA 92717 USA. [Ballard-Barbash, Rachel] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Buring, Julie E.; Gaziano, John Michael; Sesso, Howard D.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Prevent Med, Boston, MA 02115 USA. [Buring, Julie E.; Gaziano, John Michael; Sesso, Howard D.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Aging, Boston, MA 02115 USA. [Fraser, Gary E.] Loma Linda Univ, Sch Publ Hlth, Dept Epidemiol Biostat & Populat Med, Loma Linda, CA 92350 USA. [Gapstur, Susan M.; Patel, Alpa V.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Gaziano, John Michael] VA Boston Healthcare Syst, Geriatr Res Educ & Clin Ctr, Massachusetts Vet Epidemiol Res & Informat Ctr, Boston, MA USA. [Hakansson, Niclas; Wolk, Alicja] Karolinska Inst, Natl Inst Environm Med, Div Nutr Epidemiol, Stockholm, Sweden. [Hoppin, Jane A.] NIEHS, Epidemiol Branch, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. [Koenig, Karen; Zeleniuch-Jacquotte, Anne] NYU, Sch Med, Dept Populat Hlth, Div Epidemiol, New York, NY USA. [Koenig, Karen; Zeleniuch-Jacquotte, Anne] NYU, Sch Med, Inst Canc, New York, NY USA. [Visvanathan, Kala] Johns Hopkins Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Visvanathan, Kala] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [White, Emily] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. RP Kitahara, CM (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM kitaharac@mail.nih.gov RI Beane Freeman, Laura/C-4468-2015; Purdue, Mark/C-9228-2016; Moore, Steven/D-8760-2016; Weiderpass, Elisabete/M-4029-2016; Kitahara, Cari/R-8267-2016; OI Zeleniuch-Jacquotte, Anne/0000-0001-9350-1303; Park, Yikyung/0000-0002-6281-489X; Beane Freeman, Laura/0000-0003-1294-4124; Purdue, Mark/0000-0003-1177-3108; Moore, Steven/0000-0002-8169-1661; Weiderpass, Elisabete/0000-0003-2237-0128; MacInnis, Robert/0000-0002-1627-5047 FU Intramural Research Program of the National Cancer Institute, National Institutes of Health FX This work was supported in part by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. Certain data were provided by the Vital Statistics Administration, Maryland Department of Health and Mental Hygiene, Baltimore, Maryland. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 59 TC 48 Z9 48 U1 2 U2 33 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 JUL PY 2014 VL 11 IS 7 AR e1001673 DI 10.1371/journal.pmed.1001673 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA AN5FZ UT WOS:000340617400006 PM 25003901 ER PT J AU Salje, H Andrews, JR Deo, S Satyanarayana, S Sun, AY Pai, M Dowdy, DW AF Salje, Henrik Andrews, Jason R. Deo, Sarang Satyanarayana, Srinath Sun, Amanda Y. Pai, Madhukar Dowdy, David W. TI The Importance of Implementation Strategy in Scaling Up Xpert MTB/RIF for Diagnosis of Tuberculosis in the Indian Health-Care System: A Transmission Model SO PLOS MEDICINE LA English DT Article ID DRUG-RESISTANT TUBERCULOSIS; MYCOBACTERIUM-TUBERCULOSIS; PULMONARY TUBERCULOSIS; TREATMENT OUTCOMES; DISEASE; POPULATION; PATIENT; IMPACT; TESTS; URBAN AB Background: India has announced a goal of universal access to quality tuberculosis (TB) diagnosis and treatment. A number of novel diagnostics could help meet this important goal. The rollout of one such diagnostic, Xpert MTB/RIF (Xpert) is being considered, but if Xpert is used mainly for people with HIV or high risk of multidrug-resistant TB (MDR-TB) in the public sector, population-level impact may be limited. Methods and Findings: We developed a model of TB transmission, care-seeking behavior, and diagnostic/treatment practices in India and explored the impact of six different rollout strategies. Providing Xpert to 40% of public-sector patients with HIV or prior TB treatment (similar to current national strategy) reduced TB incidence by 0.2% (95% uncertainty range [UR]: -1.4%, 1.7%) and MDR-TB incidence by 2.4% (95% UR: -5.2%, 9.1%) relative to existing practice but required 2,500 additional MDR-TB treatments and 60 four-module GeneXpert systems at maximum capacity. Further including 20% of unselected symptomatic individuals in the public sector required 700 systems and reduced incidence by 2.1% (95% UR: 0.5%, 3.9%); a similar approach involving qualified private providers (providers who have received at least some training in allopathic or non-allopathic medicine) reduced incidence by 6.0% (95% UR: 3.9%, 7.9%) with similar resource outlay, but only if high treatment success was assured. Engaging 20% of all private-sector providers (qualified and informal [providers with no formal medical training]) had the greatest impact (14.1% reduction, 95% UR: 10.6%, 16.9%), but required >2,200 systems and reliable treatment referral. Improving referrals from informal providers for smear-based diagnosis in the public sector (without Xpert rollout) had substantially greater impact (6.3% reduction) than Xpert scale-up within the public sector. These findings are subject to substantial uncertainty regarding private-sector treatment patterns, patient care-seeking behavior, symptoms, and infectiousness over time; these uncertainties should be addressed by future research. Conclusions: The impact of new diagnostics for TB control in India depends on implementation within the complex, fragmented health-care system. Transformative strategies will require private/informal-sector engagement, adequate referral systems, improved treatment quality, and substantial resources. C1 [Salje, Henrik; Dowdy, David W.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Andrews, Jason R.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Deo, Sarang] Indian Sch Business, Hyderabad, Andhra Pradesh, India. [Satyanarayana, Srinath; Pai, Madhukar] McGill Univ, Dept Epidemiol & Biostat, Montreal, PQ, Canada. [Satyanarayana, Srinath; Pai, Madhukar] McGill Univ, Ctr Hlth, McGill Int TB Ctr, Montreal, PQ, Canada. [Sun, Amanda Y.] Johns Hopkins Sch Med, Baltimore, MD USA. [Pai, Madhukar] McGill Univ, Ctr Hlth, Montreal Chest Inst, Montreal, PQ, Canada. [Dowdy, David W.] Johns Hopkins Univ, Ctr TB Res, Baltimore, MD USA. RP Salje, H (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. EM madhukar.pai@mcgill.ca; ddowdy1@jhmi.edu RI Deo, Sarang/B-5895-2015; Barley, Kamal/F-9579-2011; OI Deo, Sarang/0000-0002-3233-6014; Barley, Kamal/0000-0003-1874-9813; Andrews, Jason/0000-0002-5967-251X; Salje, Henrik/0000-0003-3626-4254 FU Bill & Melinda Gates Foundation [OPP1061487]; Canadian Institutes of Health Research [MOP 123291] FX The project was funded by grants from the Bill & Melinda Gates Foundation (OPP1061487) and Canadian Institutes of Health Research (MOP 123291). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 22 Z9 22 U1 1 U2 6 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 JUL PY 2014 VL 11 IS 7 AR e1001674 DI 10.1371/journal.pmed.1001674 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA AN5FZ UT WOS:000340617400007 PM 25025235 ER PT J AU Su, LB Qi, YJ Zhang, M Weng, MQ Zhang, XC Su, CW Shi, HN AF Su, Libo Qi, Yujuan Zhang, Mei Weng, Meiqian Zhang, Xichen Su, Chienwen Shi, Hai Ning TI Development of Fatal Intestinal Inflammation in MyD88 Deficient Mice Co-infected with Helminth and Bacterial Enteropathogens SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID TOLL-LIKE RECEPTOR-4; CITROBACTER-RODENTIUM; HOST-DEFENSE; MONONUCLEAR PHAGOCYTES; ADAPTIVE IMMUNITY; INDUCED COLITIS; INNATE; CELLS; MACROPHAGES; HOMEOSTASIS AB Infections with intestinal helminth and bacterial pathogens, such as enteropathogenic Escherichia coli, continue to be a major global health threat for children. To determine whether and how an intestinal helminth parasite, Heligomosomoides polygyrus, might impact the TLR signaling pathway during the response to a bacterial enteropathogen, MyD88 knockout and wild-type C57BL/6 mice were infected with H. polygyrus, the bacterial enteropathogen Citrobacter rodentium, or both. We found that MyD88 knockout mice co-infected with H. polygyrus and C. rodentium developed more severe intestinal inflammation and elevated mortality compared to the wild-type mice. The enhanced susceptibility to C. rodentium, intestinal injury and mortality of the co-infected MyD88 knockout mice were found to be associated with markedly reduced intestinal phagocyte recruitment, decreased expression of the chemoattractant KC, and a significant increase in bacterial translocation. Moreover, the increase in bacterial infection and disease severity were found to be correlated with a significant downregulation of antimicrobial peptide expression in the intestinal tissue in co-infected MyD88 knockout mice. Our results suggest that the MyD88 signaling pathway plays a critical role for host defense and survival during helminth and enteric bacterial co-infection. C1 [Su, Libo; Zhang, Xichen] Jilin Univ, Coll Vet Med, Changchun 130023, Jilin, Peoples R China. [Su, Libo; Qi, Yujuan; Zhang, Mei; Weng, Meiqian; Su, Chienwen; Shi, Hai Ning] Massachusetts Gen Hosp, Mucosal Immunol & Biol Res Ctr, Charlestown, MA USA. [Su, Libo; Qi, Yujuan; Zhang, Mei; Weng, Meiqian; Su, Chienwen; Shi, Hai Ning] Harvard Univ, Sch Med, Charlestown, MA USA. [Qi, Yujuan] Qinghai Univ, Sch Med, Xining, Qinghai, Peoples R China. RP Su, LB (reprint author), Jilin Univ, Coll Vet Med, Changchun 130023, Jilin, Peoples R China. EM shiha@helix.mgh.harvard.edu FU R01 [DK 082427]; Clinical Nutrition Research Center at Harvard [P30 DK 40561]; China Scholarship Council FX This work was supported by a R01 (DK 082427 to HNS) and by the Clinical Nutrition Research Center at Harvard (P30 DK 40561). LS and YQ are sponsored by China Scholarship Council. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 3 Z9 3 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD JUL PY 2014 VL 8 IS 7 AR e2987 DI 10.1371/journal.pntd.0002987 PG 13 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA AN4IQ UT WOS:000340551500036 PM 25010669 ER PT J AU Pollack, CE Wang, H Bekelman, JE Weissman, G Epstein, AJ Liao, KJ Dugoff, EH Armstrong, K AF Pollack, Craig Evan Wang, Hao Bekelman, Justin E. Weissman, Gary Epstein, Andrew J. Liao, Kaijun Dugoff, Eva H. Armstrong, Katrina TI Physician Social Networks and Variation in Rates of Complications After Radical Prostatectomy SO VALUE IN HEALTH LA English DT Article DE cancer; claims data; health services; outcomes research ID PATIENT-SHARING NETWORKS; QUALITY-OF-LIFE; ADMINISTRATIVE DATA; HEALTH-CARE; COMMUNITY STRUCTURE; CANCER-TREATMENT; OPINION LEADERS; SURGEON VOLUME; RADIOTHERAPY; HOSPITALS AB Objectives: Variation in care within and across geographic areas remains poorly understood. The goal of this article was to examine whether physician social networks-as defined by shared patients-are associated with rates of complications after radical prostatectomy. Methods: In five cities, we constructed networks of physicians on the basis of their shared patients in 2004-2005 Surveillance, Epidemiology and End Results-Medicare data From these networks, we identified subgroups of urologists who most frequently shared patients with one another. Among men with localized prostate cancer who underwent radical prostatectomy, we used multilevel analysis with generalized linear mixed-effect models to examine whether physician network structure-along with specific characteristics of the network subgroups-was associated with rates of 30 day and late urinary complications, and long-term incontinence after accounting for patient-level sociodemographic, clinical factors, and urologist patient volume. Results: Networks included 2677 men in five cities who underwent radical prostatectomy. The unadjusted rate of 30 day surgical complications varied across network subgroups from an 18.8 percentage-point difference in the rate of complications across network subgroups in city 1 to a 26.9 percentage-point difference in city 5. Large differences in unadjusted rates of late urinary complications and long-term incontinence across subgroups were similarly found. Network subgroup characteristics average urologist centrality and patient racial composition were significantly associated with rates of surgical complications. Conclusions: Analysis of physician networks using Surveillance, Epidemiology and End Results-Medicare data provides insight into observed variation in rates of complications for localized prostate cancer. If validated, such approaches may be used to target future quality improvement interventions. C1 [Pollack, Craig Evan] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Pollack, Craig Evan] Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Pollack, Craig Evan; Wang, Hao] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Pollack, Craig Evan] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Bekelman, Justin E.; Epstein, Andrew J.; Liao, Kaijun; Dugoff, Eva H.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Weissman, Gary] Hosp Univ Penn, Philadelphia, PA 19104 USA. [Armstrong, Katrina] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Pollack, CE (reprint author), Johns Hopkins Sch Med, 2024 East Monument St,Room 2-521, Baltimore, MD 21287 USA. EM cpollac2@jhmi.edu OI DuGoff, Eva/0000-0001-6673-8428 NR 49 TC 4 Z9 4 U1 4 U2 16 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1098-3015 EI 1524-4733 J9 VALUE HEALTH JI Value Health PD JUL PY 2014 VL 17 IS 5 BP 611 EP 618 DI 10.1016/j.jval.2014.04.011 PG 8 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA AO1PE UT WOS:000341084700016 ER PT J AU Beca, F Schmitt, F AF Beca, Francisco Schmitt, Fernando TI Growing Indication for FNA to Study and Analyze Tumor Heterogeneity at Metastatic Sites SO CANCER CYTOPATHOLOGY LA English DT Review DE fine-needle aspiration (FNA); metastases; tumoral heterogeneity ID FINE-NEEDLE-ASPIRATION; BREAST-CANCER METASTASIS; COLORECTAL-CANCER; NEXT-GENERATION; CELLULAR HETEROGENEITY; CYTOLOGICAL SPECIMENS; ONCOGENIC MUTATIONS; KRAS MUTATION; GROWTH-RATES; BRAF AB In routine practice, suspected metastases in patients with cancer are only occasionally biopsied, primarily because of the cost and invasiveness of the procedure. However, biopsies of metastatic lesions can be valuable, not only in confirming the presence of metastatic disease, but also in revealing unsuspected benign disease or secondary malignancies. In addition, such biopsies also allow the assessment of biomarkers that might differ from those on primary tumor cells, and can thereby facilitate selection of the optimal treatment. Because of the increasing recognition of clonal and phenotypic heterogeneity of tumors, we anticipate that in the near future, biopsying of metastatic lesions will constitute a standard-ofcare practice, allowing assessment of molecular differences between the primary tumor and metastatic lesions. In our opinion, fine-needle aspiration is currently the best method for making repeated biopsies to monitor the tumor: it is minimally invasive, safe, and cost effective and can be coupled with modern ancillary techniques. Here we provide an up-todate review of the clinical implications of tumor heterogeneity in metastatic disease and the ancillary molecular techniques used in cytology; we also discuss the role of modern cytology in contemporary diagnosis and management of metastatic cancer. (c) 2014 American Cancer Society. C1 [Beca, Francisco] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Beca, Francisco; Schmitt, Fernando] Univ Porto, IPATIMUP Inst Mol Pathol & Immunol, P-4100 Oporto, Portugal. [Beca, Francisco] Univ Porto, Fac Med, P-4100 Oporto, Portugal. [Schmitt, Fernando] Univ Toronto, Fac Med, Dept Lab Med & Pathobiol, Toronto, ON M5G 2C4, Canada. [Schmitt, Fernando] Univ Hlth Network, Dept Pathol, Toronto, ON, Canada. RP Schmitt, F (reprint author), Univ Toronto, Toronto Gen Hosp, Dept Lab Med & Pathobiol, Fac Med,Univ Hlth Network, 200 Elizabeth St,11E-215B, Toronto, ON M5G 2C4, Canada. EM fernando.schmitt@uhn.ca OI Beca, Francisco/0000-0002-4409-012X FU Fundacao para a Ciancia e Tecnologia (FCT) [FCT: HMSP-ICJ/0006/2012]; FCT FX This work was partially supported by a research grant to Francisco F. de Beca (FCT: HMSP-ICJ/0006/2012) from Fundacao para a Ciancia e Tecnologia (FCT) in the framework of the Harvard Medical School-Portugal Program. IPATIMUP is an Associate Laboratory of the Portuguese Ministry of Science, Technology and Higher Education and is partially supported by the FCT. NR 57 TC 6 Z9 6 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1934-662X EI 1934-6638 J9 CANCER CYTOPATHOL JI Cancer Cytopathol. PD JUL PY 2014 VL 122 IS 7 BP 504 EP 511 DI 10.1002/cncy.21395 PG 8 WC Oncology; Pathology SC Oncology; Pathology GA AN4BA UT WOS:000340531400005 PM 24478259 ER PT J AU Gross, DA Silver, DL AF Gross, David A. Silver, David L. TI Cytosolic lipid droplets: From mechanisms of fat storage to disease SO CRITICAL REVIEWS IN BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Review DE Adipose; endoplasmic reticulum; evolution; diabetes; lipid droplets; lipodystrophy; phospholipid; triglyceride ID HEPATITIS-C VIRUS; HORMONE-SENSITIVE LIPASE; CONGENITAL GENERALIZED LIPODYSTROPHY; COMPARATIVE GENE IDENTIFICATION-58; YEAST SACCHAROMYCES-CEREVISIAE; ANCIENT UBIQUITOUS PROTEIN-1; ADIPOSE TRIGLYCERIDE LIPASE; ENDOPLASMIC-RETICULUM; DIACYLGLYCEROL ACYLTRANSFERASE; TRIACYLGLYCEROL SYNTHESIS AB The lipid droplet (LD) is a phylogenetically conserved organelle. In eukaryotes, it is born from the endoplasmic reticulum, but unlike its parent organelle, LDs are the only known cytosolic organelles that are micellar in structure. LDs are implicated in numerous physiological and pathophysiological functions. Many aspects of the LD has captured the attention of diverse scientists alike and has recently led to an explosion in information on the LD biogenesis, expansion and fusion, identification of LD proteomes and diseases associated with LD biology. This review will provide a brief history of this fascinating organelle and provide some contemporary views of unanswered questions in LD biogenesis. C1 [Gross, David A.; Silver, David L.] Duke NUS Grad Med Sch, Program Cardiovasc & Metab Disorders, Singapore 169857, Singapore. [Gross, David A.] Massachusetts Gen Hosp, Dept Internal Med, Boston, MA 02114 USA. RP Silver, DL (reprint author), Duke NUS Grad Med Sch, 8 Coll Rd, Singapore 169857, Singapore. EM dgross3@partners.org; david.silver@duke-nus.edu.sg OI Silver, David/0000-0002-7289-9890 FU Singapore Ministry of Health's National Medical Research Council [CBRG/0012/2012]; NIH MSTP Training Program [5T32 GM 7288-37] FX This work was supported, in whole or in part, by the Singapore Ministry of Health's National Medical Research Council CBRG/0012/2012 (to D. L. S.) and the NIH MSTP Training Program 5T32 GM 7288-37 (to D. A. G.). The authors report no declarations of interest. NR 215 TC 19 Z9 19 U1 3 U2 36 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1040-9238 EI 1549-7798 J9 CRIT REV BIOCHEM MOL JI Crit. Rev. Biochem. Mol. Biol. PD JUL-AUG PY 2014 VL 49 IS 4 BP 304 EP 326 DI 10.3109/10409238.2014.931337 PG 23 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AN2QG UT WOS:000340429800003 PM 25039762 ER PT J AU Fihn, SD Francis, J Clancy, C Nielson, C Nelson, K Rumsfeld, J Cullen, T Bates, J Graham, GL AF Fihn, Stephan D. Francis, Joseph Clancy, Carolyn Nielson, Christopher Nelson, Karin Rumsfeld, John Cullen, Theresa Bates, Jack Graham, Gail L. TI Insights From Advanced Analytics At The Veterans Health Administration SO HEALTH AFFAIRS LA English DT Article ID VA-CLINICAL-ASSESSMENT; CENTERED MEDICAL HOME; NATIONAL-SURVEY; INFORMATION-TECHNOLOGY; CART PROGRAM; SYSTEM; STRATEGIES; QUALITY; MODELS; RISK AB Health care has lagged behind other industries in its use of advanced analytics. The Veterans Health Administration (VHA) has three decades of experience collecting data about the veterans it serves nationwide through locally developed information systems that use a common electronic health record. In 2006 the VHA began to build its Corporate Data Warehouse, a repository for patient-level data aggregated from across the VHA's national health system. This article provides a high-level overview of the VHA's evolution toward "big data," defined as the rapid evolution of applying advanced tools and approaches to large, complex, and rapidly changing data sets. It illustrates how advanced analysis is already supporting the VHA's activities, which range from routine clinical care of individual patients-for example, monitoring medication administration and predicting risk of adverse outcomes-to evaluating a systemwide initiative to bring the principles of the patient-centered medical home to all veterans. The article also shares some of the challenges, concerns, insights, and responses that have emerged along the way, such as the need to smoothly integrate new functions into clinical workflow. While the VHA is unique in many ways, its experience may offer important insights for other health care systems nationwide as they venture into the realm of big data. C1 [Fihn, Stephan D.] Vet Hlth Adm VHA Off Analyt & Business Intelligen, Washington, DC 20422 USA. [Fihn, Stephan D.] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. [Fihn, Stephan D.] Univ Washington, Sch Med, Dept Hlth Serv, Seattle, WA USA. [Fihn, Stephan D.] Univ Washington, Sch Publ Hlth, Dept Med, Seattle, WA 98195 USA. [Fihn, Stephan D.] Univ Washington, Sch Publ Hlth, Dept Hlth Serv, Seattle, WA 98195 USA. [Francis, Joseph] VHA Off Analyt & Business Intelligence, Washington, DC USA. [Clancy, Carolyn] VHA, Washington, DC USA. [Nielson, Christopher] VHA Off Analyt & Business Intelligence, Reno, NV USA. [Nelson, Karin] Vet Affairs Puget Sound Hlth Care Syst, Hlth Serv Res & Dev Dept, Seattle, WA USA. [Nelson, Karin] Univ Washington, Seattle, WA 98195 USA. [Rumsfeld, John] VHA, Denver, CO USA. [Rumsfeld, John] Univ Colorado, Denver, CO 80202 USA. [Cullen, Theresa] VHA Off Informat & Analyt, Silver Spring, MD USA. [Bates, Jack] Dept Vet Affairs, Off Informat & Technol, North Little Rock, AR USA. [Graham, Gail L.] VHA Off Informat & Analyt, Washington, DC USA. RP Fihn, SD (reprint author), Vet Hlth Adm VHA Off Analyt & Business Intelligen, Washington, DC 20422 USA. EM Stephan.Fihn@va.gov NR 27 TC 20 Z9 20 U1 5 U2 19 PU PROJECT HOPE PI BETHESDA PA 7500 OLD GEORGETOWN RD, STE 600, BETHESDA, MD 20814-6133 USA SN 0278-2715 J9 HEALTH AFFAIR JI Health Aff. PD JUL PY 2014 VL 33 IS 7 BP 1203 EP 1211 DI 10.1377/hlthaff.2014.0054 PG 9 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA AN3FC UT WOS:000340469700014 PM 25006147 ER PT J AU Susarla, SM Peacock, ZS Kaban, LB AF Susarla, Srinivas M. Peacock, Zachary S. Kaban, Leonard B. TI Evaluation and Correction of Facial Asymmetry in the Coronal Plane SO JOURNAL OF CRANIOFACIAL SURGERY LA English DT Article DE Facial asymmetry; occlusal cant; orthognathic surgery ID HEMIFACIAL MICROSOMIA; SURGICAL-CORRECTION; MANDIBULAR HYPOPLASIA; OCCLUSAL CANT; FRONTAL PLANE; CLASSIFICATION; CHILDHOOD AB Correction of a facial asymmetry, manifest as canting of the occlusal, piriform, or intergonial planes, is a challenging problem requiring accurate preoperative evaluation, planning, and operative execution. A lack of understanding and appreciation for the three-dimensional geometry of the asymmetry may result in under-correction or incomplete correction of the deformity. Recent advances in virtual three-dimensional planning have provided surgeons with an additional tool to improve the clinical outcomes for patients with facial asymmetries. This report focuses on the basic geometric relationships that dictate the magnitude of correction and the importance of correlations between model surgery, virtual planning, and intraoperative positioning of the jaws. C1 [Susarla, Srinivas M.] Johns Hopkins Univ Hosp, Dept Plast & Reconstruct Surg, Baltimore, MD 21285 USA. [Peacock, Zachary S.; Kaban, Leonard B.] Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Boston, MA 02114 USA. [Peacock, Zachary S.; Kaban, Leonard B.] Harvard Univ, Sch Dent Med, Dept Oral & Maxillofacial Surg, Cambridge, MA 02138 USA. RP Susarla, SM (reprint author), Johns Hopkins Univ Hosp, Dept Plast Surg, 801 N Caroline St, Baltimore, MD 21285 USA. EM SSUSARL1@JHMI.EDU OI Susarla, Srinivas/0000-0003-0155-8260 NR 18 TC 0 Z9 0 U1 1 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1049-2275 EI 1536-3732 J9 J CRANIOFAC SURG JI J. Craniofac. Surg. PD JUL PY 2014 VL 25 IS 4 BP 1299 EP 1301 DI 10.1097/SCS.0000000000000751 PG 3 WC Surgery SC Surgery GA AN0EZ UT WOS:000340257800081 PM 25006912 ER PT J AU Honda, JR Connick, E MaWhinney, S Chan, ED Flores, SC AF Honda, Jennifer R. Connick, Elizabeth MaWhinney, Samantha Chan, Edward D. Flores, Sonia C. TI Plasma LL-37 correlates with vitamin D and is reduced in human immunodeficiency virus-1 infected individuals not receiving antiretroviral therapy SO JOURNAL OF MEDICAL MICROBIOLOGY LA English DT Article ID D DEFICIENCY; 25-HYDROXYVITAMIN D; HIV; TUBERCULOSIS; ADULTS; WOMEN AB Low levels of the vitamin D-regulated antimicrobial peptide cathelicidin (LL-37) may negatively impact the immune status of human immunodeficiency virus-1 (HIV-1) infected individuals (HIV+). We compared plasma LL-37 levels in healthy controls (HIV) and HIV+ individuals on or off antiretroviral therapies (ARTs) (ART+ and ART-, respectively), and evaluated the relationship between vitamin D and LL-37 levels. In this cross-sectional study, levels of LL-37, 25-hydroxycholecalciferol [25(OH)D-3] and 1,25-dihydroxycholecalciferol [1,25(OH)(2)D-3] were measured from an initial cohort of 18 healthy controls and 10 HIV+/ART- individuals. Because this cohort lacked HIV +/ART + subjects, LL-37 was also quantified from a second cohort of 10 HIV+/ART- and 13 HIV+/ART+ individuals. LL-37 levels were significantly lower in the HIV+/ART- group compared to the healthy controls (P=0.01). A direct relationship was observed between LL-37 and both 25(OH)D-3 and 1,25(OH)(2)D-3. The level of 25(OH)D-3 was predictive of higher LL-37 (P=0.04) and for any given level of 25(OH)D-3, HIV +/ART- subjects averaged 20% lower LL-37 compared to the healthy controls (P=0.045). For any given level of 1,25(OH)(2)D-3, HIV+/ART- subjects averaged 25% lower LL-37 compared to the healthy controls (P=0.018), although 1,25(OH)(2)D-3 was not predictive of higher LL-37 (P=0.28). Finally, LL-37 levels were significantly lower in the HIV+/ART- group compared to the HIV+/ART+ group from the second cohort (P=0.045). Untreated HIV infection may contribute to lower LL-37 levels, independent of vitamin D levels. ART treatment may potentially mitigate this decrease in LL-37 levels. C1 [Honda, Jennifer R.; Flores, Sonia C.] Univ Colorado, Div Pulm Sci & Crit Care Med, Aurora, CO 80045 USA. [Connick, Elizabeth] Univ Colorado, Div Infect Dis, Aurora, CO 80045 USA. [MaWhinney, Samantha] Univ Colorado, Colorado Sch Publ Hlth Biostat & Informat, Aurora, CO 80045 USA. [Chan, Edward D.] Natl Jewish Hlth, Denver, CO 80220 USA. [Chan, Edward D.] Denver Vet Affairs Med Ctr, Denver, CO 80220 USA. RP Honda, JR (reprint author), Univ Colorado, Div Pulm Sci & Crit Care Med, Anschutz Med Campus, Aurora, CO 80045 USA. EM Jennifer.Honda@ucdenver.edu FU National Center for Advancing Translational Sciences at the National Institutes of Health Colorado (CTSI) [UL1 TR000154]; National Heart, Lung, and Blood Institute at the National Institutes of Health; Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado; Colorado HIV-1 Research Training Program through the NRSA NIH Infectious Disease Training Award [T32-AI007447-19]; Tim Gill Endowment for AIDS Research; Pulmonary and Critical Care Medicine Training Award [T32 HL 7085-83] FX We extend our appreciation to all study participants for their enthusiasm and support. This study was supported, in part, by the National Center for Advancing Translational Sciences at the National Institutes of Health Colorado (CTSI grant number UL1 TR000154), and through the National Heart, Lung, and Blood Institute at the National Institutes of Health and institutional funds (Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado) for Dr Sonia Flores. Jennifer R. Honda PhD is supported by the Colorado HIV-1 Research Training Program through the NRSA NIH Infectious Disease (T32-AI007447-19) Training Award, the Tim Gill Endowment for AIDS Research, and the Pulmonary and Critical Care Medicine (T32 HL 7085-83) Training Award. NR 25 TC 3 Z9 3 U1 0 U2 2 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-2615 EI 1473-5644 J9 J MED MICROBIOL JI J. Med. Microbiol. PD JUL PY 2014 VL 63 BP 997 EP 1003 DI 10.1099/jmm.0.070888-0 PN 7 PG 7 WC Microbiology SC Microbiology GA AN3UO UT WOS:000340514400013 PM 24821067 ER PT J AU Lertpiriyapong, K Handt, L Feng, Y Mitchell, TW Lodge, KE Shen, ZL Dewhirst, FE Muthupalani, S Fox, JG AF Lertpiriyapong, Kvin Handt, Laurence Feng, Yan Mitchell, Thomas W. Lodge, Kenneth E. Shen, Zeli Dewhirst, Floyd E. Muthupalani, Sureshkumar Fox, James G. TI Pathogenic properties of enterohepatic Helicobacter spp. isolated from rhesus macaques with intestinal adenocarcinoma SO JOURNAL OF MEDICAL MICROBIOLOGY LA English DT Article ID CYTOLETHAL DISTENDING TOXIN; INFLAMMATORY-BOWEL-DISEASE; CHRONIC IDIOPATHIC COLITIS; MONKEYS MACACA-MULATTA; COLON-CANCER; HEPATICUS INFECTION; CAMPYLOBACTER-CINAEDI; RAG2-DEFICIENT MICE; BACTEREMIA; PYLORI AB Considerable progress has been made in understanding the roles of Helicobacter pylori in inflammation and gastric cancer; however, far less is known about the roles of enterohepatic Helicobacter species (EHS) in carcinogenesis and their zoonotic or pathogenic potential. We determined the prevalence of EHS infection in a cohort of geriatric rhesus monkeys in which intestinal adenocarcinoma (IAC) is common and investigated the association between EHS infection and IAC. The cohort consisted of 36 animals, 14 of which (age 26-35 years) had IAC. Of the 36 rhesus, 35 (97%) were positive for EHS using PCR or bacterial isolation from faeces, colonic or tumour tissues. Only a single rhesus, which had IAC, was negative for EHS by all detection methods. The EHS identified by 16S rRNA sequencing in this study were from three Helicobacter taxa: Helicobacter macacae (previously rhesus monkey taxon 1), Helicobacter sp. rhesus monkey taxon 2, previously described from strain MIT 99-5507, and Helicobacter sp. rhesus monkey taxon 4, related to Helicobacter fennelliae. Thirteen of 14 monkeys with IAC were positive for either H. macacae (7/13, 54%), EHS rhesus monkey taxon 4 (4/13, 31%) or a mixture of the two EHS (2/13, 15%). These results indicate that EHS are prevalent among aged rhesus macaques with IAC. Using Helicobacter genus-specific florescent in situ hybridization, EHS were detected on the surface of colonic epithelia of infected monkeys. All Helicobacter isolates, including H. macacae, effectively adhered to, invaded, and significantly induced proinflammatory genes, including IL-8, IL-6, TNF-alpha and iNOS, while downregulating genes involved in the function of inflammasomes, particularly IL-1 beta, CASPASE-1, NRLP3, NLRP6 and NLRC4 in the human colonic 184 cell line (P<0.0001). These results suggest that EHS may represent an aetiological agent mediating diarrhoea, chronic inflammation, and possibly intestinal cancer in non-human primates, and may play a role in similar disease syndromes in humans. Downregulation of inflammasome function may represent an EHS strategy for long-term persistence in the host and play a role in inducing pathological changes in the host's lower bowel. C1 [Lertpiriyapong, Kvin; Feng, Yan; Shen, Zeli; Muthupalani, Sureshkumar; Fox, James G.] MIT, Div Comparat Med, Cambridge, MA 02139 USA. [Handt, Laurence; Mitchell, Thomas W.; Lodge, Kenneth E.] Merck Res Labs, West Point, PA USA. [Dewhirst, Floyd E.] Forsyth Inst, Dept Microbiol, Cambridge, MA USA. [Dewhirst, Floyd E.] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. RP Fox, JG (reprint author), MIT, Div Comparat Med, Cambridge, MA 02139 USA. EM jgfox@mit.edu FU NIH [T32 RR007036, P30-ES002109, P01-CA26731] FX This study was supported by NIH grants T32 RR007036 (J. G. F.), P30-ES002109 (MIT Center for Environmental Health Sciences) and P01-CA26731. We thank Alyssa Terestre for assisting with manuscript preparation. NR 72 TC 6 Z9 6 U1 1 U2 4 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-2615 EI 1473-5644 J9 J MED MICROBIOL JI J. Med. Microbiol. PD JUL PY 2014 VL 63 BP 1004 EP 1016 DI 10.1099/jmm.0.072462-0 PN 7 PG 13 WC Microbiology SC Microbiology GA AN3UO UT WOS:000340514400014 PM 24696515 ER PT J AU Cooper, DC Trivedi, RB Nelson, KM Reiber, GE Eugenio, EC Beaver, KA Fan, VS AF Cooper, Denise C. Trivedi, Ranak B. Nelson, Karin M. Reiber, Gayle E. Eugenio, Evercita C. Beaver, Kristine A. Fan, Vincent S. TI Antidepressant Adherence and Risk of Coronary Artery Disease Hospitalizations in Older and Younger Adults with Depression SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE depression; antidepressants; adherence; coronary artery disease; hospitalizations ID AMERICAN-HEART-ASSOCIATION; MYOCARDIAL-INFARCTION; VETERANS; MEDICATION; CARE; MORTALITY; POPULATION; PREDICTORS; DISORDERS; ILLNESSES AB OBJECTIVES: To assess whether the relationship between antidepressant adherence and coronary artery disease (CAD) hospitalizations varied between older and younger adults with depression. DESIGN: Retrospective cohort study. SETTING: Department of Veterans Affairs outpatient clinics nationwide. PARTICIPANTS: Chronically depressed individuals (n = 50,261; aged 20-97) who had been prescribed an antidepressant were identified from records indicating an outpatient clinic visit for depression (index depression visit) during fiscal years 2009 and 2010. Individuals were considered chronically depressed if they had had prior depression visits and treatment for depression within the previous 4 months. The sample was age-stratified into younger (<65) and older (>= 65) groups. MEASUREMENTS: After the index depression visit, medication possession ratios were calculated from pharmacy refill data to determine whether participants had 80% or greater adherence to antidepressant refills during a 6-month treatment observation period. International Classification of Diseases, Ninth Revision, codes were used to derive CAD-related hospitalizations during the follow-up period. Mean follow-up was 24 months. Data were analyzed using Cox proportional hazard models. RESULTS: Older participants with 80% or greater antidepressant adherence had 26% lower risk of CAD hospitalizations (hazard ratio = 0.74, 95% confidence interval = 0.60-0.93). Antidepressant adherence was not significantly related to CAD hospitalizations in younger adults. CONCLUSION: Older adults with chronic depression with 80% or greater antidepressant adherence had significantly lower risk of CAD hospitalizations at follow-up than those with less than 80% adherence. These preliminary results suggest that older adults with depression may derive cardiovascular benefits from clinical efforts to increase antidepressant adherence. C1 [Cooper, Denise C.; Nelson, Karin M.; Reiber, Gayle E.; Eugenio, Evercita C.; Beaver, Kristine A.; Fan, Vincent S.] Univ Washington, Vet Affairs Puget Sound Hlth Care Syst, Hlth Serv Res & Dev, Ctr Innovat Vet Centered & Value Driven Care, Seattle, WA 98195 USA. [Cooper, Denise C.; Reiber, Gayle E.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Trivedi, Ranak B.] Stanford Univ, Vet Affairs Palo Alto Hlth Care Syst, Ctr Innovat Implementat, Palo Alto, CA 94304 USA. [Trivedi, Ranak B.] Stanford Univ, Dept Psychiat & Behav Sci, Palo Alto, CA 94304 USA. [Nelson, Karin M.; Fan, Vincent S.] Univ Washington, Dept Med, Seattle, WA USA. RP Cooper, DC (reprint author), VA Puget Sound Hlth Care Syst, HSR & D, 1100 Olive Way,Suite 1400, Seattle, WA 98101 USA. EM cooped2@uw.edu FU VA Quality Enhancement Research Initiative Rapid Response Project [RRP 10-105] FX This study was supported by the VA Quality Enhancement Research Initiative Rapid Response Project (RRP 10-105) (VSF). The views expressed in this article are solely those of the authors and do not necessarily reflect the position or policy of the VA. NR 41 TC 8 Z9 8 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JUL PY 2014 VL 62 IS 7 BP 1238 EP 1245 DI 10.1111/jgs.12849 PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA AN3IX UT WOS:000340482000004 PM 24890000 ER PT J AU Lum, HD Mody, L Levy, CR Ginde, AA AF Lum, Hillary D. Mody, Lona Levy, Cari R. Ginde, Adit A. TI Pandemic Influenza Plans in Residential Care Facilities SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE residential facility; assisted living facility; geriatric; pandemic; influenza ID ASSISTED LIVING FACILITIES; INFECTION PREVENTION; NURSING-HOMES; PREPAREDNESS AB OBJECTIVES: To identify characteristics of residential care facilities (RCFs) associated with having a pandemic influenza plan. DESIGN: Nationally representative, cross-sectional survey. SETTING: RCFs in the United States. PARTICIPANTS: Participating facilities in the 2010 National Survey of RCFs (N = 2,294), representing 31,030 assisted living facilities and personal care homes. MEASUREMENTS: Facility-level characteristics associated with a pandemic influenza plan, including general organization descriptors, staffing, resident services, and immunization practices. RESULTS: Forty-five percent (95% confidence interval (CI) = 43-47%) had a pandemic plan, 14% (95% CI = 13-16%) had a plan in preparation, and 41% (95% CI = 38-43%) had no plan. In the multivariable model, organization characteristics, staffing, and immunization practices were independently associated with the presence of a pandemic preparedness plan. Organization characteristics were larger size (extra large, OR = 3.27, 95% CI = 1.96-5.46; large, OR = 2.60, 95% CI = 1.81-3.75; medium, OR = 1.66, 95% CI = 1.21-2.27 vs small), not-for-profit status (OR = 1.65, 95% CI = 1.31-2.09 vs for profit), and chain affiliation (OR = 1.65, 95% CI = 1.31-2.09 vs nonaffiliated). Staffing characteristics included number of registered nurse hours (<15 minutes, OR = 1.36, 95% CI = 1.07-1.74 vs no hours), any licensed practical nurse hours (OR = 1.47, 95% CI = 1.08-1.99 vs no hours), and at least 75 hours of required training for aides (OR = 1.34, 95% CI = 1.05-1.71 vs < 75 hours). RCFs with high staff influenza vaccination rates (81-100%, OR = 2.12, 95% CI = 1.273.53 vs 0% vaccinated) were also more likely to have a pandemic plan. CONCLUSION: A majority of RCFs lacked a pandemic influenza plan. These facilities were smaller, for-profit, non-chain-affiliated RCFs and had lower staff vaccination rates. These characteristics may help target facilities that need to develop plans to handle a pandemic, or other disasters. C1 [Lum, Hillary D.] Univ Colorado, Sch Med, Div Geriatr Med, Aurora, CO 80045 USA. [Lum, Hillary D.; Levy, Cari R.] Denver Vet Affairs Med Ctr, Denver, CO USA. [Mody, Lona] Univ Michigan, Div Geriatr & Palliat Care Med, Ann Arbor, MI 48109 USA. [Mody, Lona] Vet Affairs Ann Arbor Healthcare Syst, Geriatr Res Educ & Clin Ctr, Ann Arbor, MI USA. [Levy, Cari R.] Univ Colorado, Sch Med, Div Hlth Care Policy & Res, Aurora, CO 80045 USA. [Ginde, Adit A.] Univ Colorado, Sch Med, Dept Emergency Med, Aurora, CO 80045 USA. RP Lum, HD (reprint author), Univ Colorado, Sch Med, Div Geriatr Med, 12631 E 17th Ave,B-179, Aurora, CO 80045 USA. EM hillary.lum@ucdenver.edu RI bebarta, vikhyat/K-3476-2015; Siry, Bonnie/D-7189-2017 FU National Institute on Aging [R01 AG032298, R01 AG41780, R18 HS019979, K23 AG040708]; University of Michigan Claude D. Pepper Older Americans Independence Center Grant [P30 AG024824] FX Dr. Mody was supported by National Institute on Aging Grants R01 AG032298, R01 AG41780, and R18 HS019979 and University of Michigan Claude D. Pepper Older Americans Independence Center Grant P30 AG024824. Dr. Ginde was supported by National Institute on Aging Grant K23 AG040708. NR 19 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JUL PY 2014 VL 62 IS 7 BP 1310 EP 1316 DI 10.1111/jgs.12879 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA AN3IX UT WOS:000340482000013 PM 24852422 ER PT J AU Burke, RE Jones, CD Levy, C Ginde, AA AF Burke, Robert E. Jones, Christine D. Levy, Cari Ginde, Adit A. TI ELECTRONIC COMMUNICATION CAPABILITIES OF RESIDENTIAL CARE FACILITIES AT TIMES OF TRANSITION SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Letter ID SKILLED NURSING FACILITY; EMERGENCY-DEPARTMENT; NETWORK; HOMES C1 [Burke, Robert E.] Denver VA Med Ctr, Hosp Med Sect, Denver, CO 80220 USA. [Burke, Robert E.; Jones, Christine D.] Univ Colorado, Dept Med, Div Gen Internal Med, Denver, CO USA. [Levy, Cari] Univ Colorado, Div Hlth Care Policy & Res, Denver, CO 80202 USA. [Ginde, Adit A.] Univ Colorado, Dept Emergency Med, Denver, CO 80202 USA. RP Burke, RE (reprint author), Denver VA Med Ctr, Hosp Med Sect, Denver, CO 80220 USA. RI bebarta, vikhyat/K-3476-2015 FU NIA NIH HHS [K23AG040708, K23 AG040708] NR 9 TC 2 Z9 2 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JUL PY 2014 VL 62 IS 7 BP 1381 EP 1383 DI 10.1111/jgs.12905 PG 3 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA AN3IX UT WOS:000340482000027 PM 25039508 ER PT J AU Li, H Hsu, HC Wu, Q Yang, P Li, J Luo, B Oukka, M Steele, CH Cua, DJ Grizzle, WE Mountz, JD AF Li, Hao Hsu, Hui-Chen Wu, Qi Yang, PingAr Li, Jun Luo, Bao Oukka, Mohamed Steele, Claude H., III Cua, Daniel J. Grizzle, William E. Mountz, John D. TI IL-23 promotes TCR-mediated negative selection of thymocytes through the upregulation of IL-23 receptor and ROR gamma t SO NATURE COMMUNICATIONS LA English DT Article ID ORPHAN NUCLEAR RECEPTOR; LYMPHOID ORGAN DEVELOPMENT; THYMIC EPITHELIAL-CELLS; BONE-MARROW CHIMERAS; AUTOIMMUNE INFLAMMATION; DENDRITIC CELLS; CUTTING EDGE; ASPERGILLUS-FUMIGATUS; MOLECULE EXPRESSION; CYTOKINE PRODUCTION AB Transient thymic involution is frequently found during inflammation, yet the mode of action of inflammatory cytokines is not well defined. Here we report that interleukin-23 (IL-23) production by the thymic dendritic cells (DCs) promotes apoptosis of the CD4(hi)CD8(hi) double-positive (DP) thymocytes. A deficiency in IL-23 signalling interferes with negative selection in the male D-b/H-Y T-cell receptor (TCR) transgenic mice. IL-23 plus TCR signalling results in significant upregulation of IL-23 receptor (IL-23R) expressed predominantly on CD4(hi)CD8(hi)CD3(+) alpha beta TCR+ DP thymocytes, and leads to ROR gamma t-dependent apoptosis. These results extend the action of IL-23 beyond its peripheral effects to a unique role in TCR-mediated negative selection including elimination of natural T regulatory cells in the thymus. C1 [Li, Hao; Hsu, Hui-Chen; Wu, Qi; Yang, PingAr; Li, Jun; Luo, Bao; Mountz, John D.] Univ Alabama Birmingham, Dept Med, Div Clin Immunol & Rheumatol, Birmingham, AL 35294 USA. [Li, Hao] Univ Alabama Birmingham, Dept Microbiol, Birmingham, AL 35294 USA. [Oukka, Mohamed] Univ Washington, Dept Pediat, Seattle, WA 98195 USA. [Steele, Claude H., III] Univ Alabama Birmingham, Dept Med, Div Pulm Allergy & Crit Care, Birmingham, AL 35294 USA. [Cua, Daniel J.] Merck Res Labs, Palo Alto, CA 94304 USA. [Grizzle, William E.] Univ Alabama Birmingham, Birmingham, AL 35294 USA. [Mountz, John D.] Birmingham VA Med Ctr, Birmingham, AL 35233 USA. RP Hsu, HC (reprint author), Univ Alabama Birmingham, Dept Med, Div Clin Immunol & Rheumatol, Birmingham, AL 35294 USA. EM rheu078@uab.edu; jdmountz@uab.edu RI Li, Hao/N-7406-2015 OI Li, Hao/0000-0002-2171-8826 FU VA Merit Review Grant [1I01BX000600-01]; NIH/NIAID [1AI 071110, ARRA 3RO1AI71110-02S1, 1RO1 AI083705]; Rheumatology Research Foundation; Lupus Research Institute; Arthritis Foundation FX We thank Drs. J. Kolls (Louisiana State University) and Paul Robbins (University of Pittsburgh) for providing AdLacZ and AdIL-23; Dr N. Manley (University of Georgia) for technical support in the TEC sorting; and Dr F. Hunter for review of the manuscript. Flow cytometry and confocal imaging data acquisition were carried out at the UAB Comprehensive Flow Cytometry Core (P30 AR048311 and P30 AI027767) and UAB Analytic Imaging and Immunoreagent Core (P30 AR048311), respectively; BioQuant histomorphometry analysis was carried out at the UAB Center for Metabolic Bone Disease-Histomorphometry and Molecular Analysis Core Laboratory (P30 AR46031). This work is supported by grants from VA Merit Review Grant (1I01BX000600-01), NIH/NIAID (1AI 071110, ARRA 3RO1AI71110-02S1 and 1RO1 AI083705), Rheumatology Research Foundation, Lupus Research Institute, and Arthritis Foundation. NR 65 TC 2 Z9 2 U1 2 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JUL PY 2014 VL 5 AR 4259 DI 10.1038/ncomms5259 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AN5FE UT WOS:000340615000003 PM 25001511 ER PT J AU Rotstein, BH Stephenson, NA Vasdev, N Liang, SH AF Rotstein, Benjamin H. Stephenson, Nickeisha A. Vasdev, Neil Liang, Steven H. TI Spirocyclic hypervalent iodine(III)-mediated radiofluorination of non-activated and hindered aromatics SO NATURE COMMUNICATIONS LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; HETEROAROMATIC IODONIUM SALTS; DIARYLIODONIUM-SALTS; NO-CARRIER; OXIDATIVE FLUORINATION; F-18 FLUORIDE; PET; SELECTIVITY; STABILITY; CHEMISTRY AB Fluorine-18 (t(1/2)=109.7 min) is the most commonly used isotope to prepare radiopharmaceuticals for molecular imaging by positron emission tomography (PET). Nucleophilic aromatic substitution reactions of suitably activated (electron-deficient) aromatic substrates with no-carrier-added [F-18] fluoride ion are routinely carried out in the synthesis of radiotracers in high specific activities. Despite extensive efforts to develop a general F-18-labelling technique for non-activated arenes there is an urgent and unmet need to achieve this goal. Here we describe an effective solution that relies on the chemistry of spirocyclic hypervalent iodine(III) complexes, which serve as precursors for rapid, one-step regioselective radiofluorination with [F-18] fluoride. This methodology proves to be efficient for radiolabelling a diverse range of non-activated functionalized arenes and heteroarenes, including arene substrates bearing electron-donating groups, bulky ortho functionalities, benzylic substituents and meta-substituted electron-withdrawing groups. Polyfunctional molecules and a range of previously elusive F-18-labelled building blocks, compounds and radio-pharmaceuticals are synthesized. C1 [Vasdev, Neil] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Adv Med Imaging Sci,Div Nucl Med & Mol Imagin, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02114 USA. RP Vasdev, N (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Adv Med Imaging Sci,Div Nucl Med & Mol Imagin, 55 Fruit St, Boston, MA 02114 USA. EM vasdev.neil@mgh.harvard.edu; liang.steven@mgh.harvard.edu OI Rotstein, Benjamin/0000-0001-9707-9357 NR 40 TC 45 Z9 45 U1 6 U2 37 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD JUL PY 2014 VL 5 AR 4365 DI 10.1038/ncomms5365 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AN5FI UT WOS:000340615500056 PM 25007318 ER PT J AU Simis, M Bravo, GL Boggio, PS Devido, M Gagliardi, RJ Fregni, F AF Simis, Marcel Bravo, Gabriela L. Boggio, Paulo S. Devido, Michele Gagliardi, Rubens J. Fregni, Felipe TI Transcranial Direct Current Stimulation in de novo Artistic Ability After Stroke SO NEUROMODULATION LA English DT Letter DE Art; neuro-aesthetics; noninvasive brain stimulation; stroke; tDCS ID FRONTOTEMPORAL DEMENTIA; UNAFFECTED HEMISPHERE; EMERGENCE; BRAIN; ART C1 [Simis, Marcel; Bravo, Gabriela L.; Fregni, Felipe] Harvard Univ, Sch Med, Lab Neuromodulat, Dept Phys Med & Rehabil,Spaulding Rehabil Hosp, Boston, MA USA. [Simis, Marcel; Bravo, Gabriela L.; Fregni, Felipe] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Simis, Marcel; Devido, Michele; Gagliardi, Rubens J.] Santa Casa Med Sch, Div Neurol, Sao Paulo, Brazil. [Boggio, Paulo S.] Univ Prebiteriana Mackenzie, Social & Cognit Neurosci Lab, Ctr Hlth & Biol Sci, Sao Paulo, Brazil. [Boggio, Paulo S.] Univ Prebiteriana Mackenzie, Dev Disorders Program, Ctr Hlth & Biol Sci, Sao Paulo, Brazil. RP Fregni, F (reprint author), Spaulding Rehabil Hosp, Lab Neuromodulat, 125 Nashua St 726, Boston, MA 02114 USA. EM fregni.felipe@mgh.harvard.edu RI Boggio, Paulo/K-6272-2012 OI Boggio, Paulo/0000-0002-6109-0447 NR 20 TC 0 Z9 0 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1094-7159 EI 1525-1403 J9 NEUROMODULATION JI Neuromodulation PD JUL PY 2014 VL 17 IS 5 BP 497 EP 501 DI 10.1111/ner.12140 PG 5 WC Medicine, Research & Experimental; Clinical Neurology SC Research & Experimental Medicine; Neurosciences & Neurology GA AN0JJ UT WOS:000340270400027 PM 24320745 ER PT J AU Roby, BB Wilson, MN Raol, N Carter, J Kelley, K Deckard, NA Yoo, ES Dowdall, JR AF Roby, Brianne B. Wilson, Meghan N. Raol, Nikhila Carter, John Kelley, Kanwar Deckard, Nathan A. Yoo, Estelle S. Dowdall, Jayme R. TI Section for Residents and Fellows-in-Training Leaders: Where Are They Now? SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Editorial Material DE residents; fellows; leadership; American Academy of Otolaryngology; AAO-HNSF ID MEDICINE AB The purpose of this study was to examine the experiences of prior governing council (GC) members of the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) Section for Residents and Fellows-in-Training (SRF) and assess the impact of early Academy involvement. A survey was conducted via email on all prior AAO-HNS SRF GC members. The AAO-HNS SRF has elected 52 GC members since its 2003 inception. Each member served an average of 1.5 year-long terms. The mean time since completion of training is 4.1 years. A subspecialty fellowship was pursued in 86%. Fifty-seven percent practice in academic settings, with 3 members advancing to subspecialty division director within their department. More than half (58%) have served on an AAO-HNS committee, and most are frequent attendees of the annual meeting. All prior members felt involvement in the SRF GC was beneficial, enabling them to gain leadership skills and deeper understanding of the specialty. C1 [Roby, Brianne B.] Childrens Hosp & Clin Colorado, Dept Otolaryngol, Aurora, CO 80045 USA. [Wilson, Meghan N.] Louisiana State Univ, Dept Otolaryngol, Hlth Sci Ctr, New Orleans, LA USA. [Raol, Nikhila] Massachusetts Eye & Ear Infirm, Dept Otol & Larynogol, Boston, MA 02114 USA. [Carter, John] Tulane Univ, Dept Otolaryngol, New Orleans, LA 70118 USA. [Kelley, Kanwar] Univ Calif Irvine, Dept Otolaryngol, Irvine, CA USA. [Deckard, Nathan A.] Rowan Univ, Div Otolaryngol, Dept Surg, Cooper Med Sch, Camden, NJ USA. [Yoo, Estelle S.] Nemours duPont Hosp Children, Wilmington, DE USA. [Dowdall, Jayme R.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. RP Roby, BB (reprint author), Childrens Hosp & Clin Colorado, Dept Otolaryngol, 13123 East 16th Ave,Box B455, Aurora, CO 80045 USA. EM brianne.roby@childrenscolorado.org NR 6 TC 0 Z9 0 U1 0 U2 3 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0194-5998 EI 1097-6817 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD JUL PY 2014 VL 151 IS 1 BP 6 EP 9 DI 10.1177/0194599814532904 PG 4 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA AN2YQ UT WOS:000340452400004 PM 24781655 ER PT J AU Remenschneider, AK D'Amico, L Litvack, JR Gray, ST Holbrook, EH Gliklich, R Metson, R AF Remenschneider, Aaron K. D'Amico, Laura Litvack, Jamie R. Gray, Stacey T. Holbrook, Eric H. Gliklich, Richard Metson, Ralph TI Long-Term Outcomes in Sinus Surgery: A New Tool for Measuring Health-Related Quality of Life SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Article DE chronic rhinosinusitis; clinical outcomes; sinus surgery; EQ-5D; utility values; sinusitis ID US ADULT-POPULATION; CHRONIC RHINOSINUSITIS; PROSPECTIVE COHORT; EQ-5D; SCORES; IMPACT; DISEASE; UTILITY; STATES; MODEL AB Objective. The 6-question EuroQol 5-Dimension Health Assessment (EQ-5D) is a widely used, simple instrument that monitors general health-related quality of life (HRQoL) in chronic disease. It has not previously been applied to US patients undergoing endoscopic sinus surgery (ESS). Study Design. Prospective cohort study. Setting. Academic Medical Center. Subjects and Methods. The study population consisted of 267 patients with chronic rhinosinusitis (CRS) who completed 2 disease-specific instruments-the Chronic Sinusitis Survey (CSS) and the Sinonasal Outcomes Test-22 (SNOT-22)-and 1 general health-related quality-of-life instrument-the EQ-5D- before and after ESS for CRS. Baseline scores were compared to those collected 3 and 12 months after surgery and to the general US population. Results. Surveys were completed at all time points by 186 patients, for a response rate of 69.7%. Patients with CRS, when compared to the US population, reported more problems in the domains of pain/discomfort (73.1% vs 40.8%, P < .01), anxiety/depression (50.5% vs 26.4%, P < . 01), and usual activities (30.6% vs 15.0%, P < . 01). One year following ESS, there was a significant decrease in patients who reported problems with pain/discomfort (54.3%, P < .001), anxiety/depression (30.6%, P < . 001), and usual activities (21.5%, P < .01). After surgery, CRS anxiety/depression scores were no different from those of the US general population. Chronic Sinusitis Survey and SNOT-22 scores demonstrated similar postoperative improvements. Conclusion. The EQ-5D assessment provides meaningful general health outcomes data with low patient burden. Application of this instrument demonstrated long-term improvement in the quality of life of patients who undergo sinus surgery. C1 [Remenschneider, Aaron K.; D'Amico, Laura; Gray, Stacey T.; Holbrook, Eric H.; Gliklich, Richard; Metson, Ralph] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. [Remenschneider, Aaron K.; Gray, Stacey T.; Holbrook, Eric H.; Gliklich, Richard; Metson, Ralph] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Litvack, Jamie R.] MedStar Washington Hosp Ctr, Dept Otolaryngol, Washington Vet Affairs Med Ctr, Dept Surg, Washington, DC USA. RP Remenschneider, AK (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. EM aaron_remenschneider@meei.harvard.edu FU Board Committee on Quality of the Massachusetts Eye and Ear Infirmary FX The Board Committee on Quality of the Massachusetts Eye and Ear Infirmary provided financial and clerical support for data collection. NR 34 TC 12 Z9 12 U1 0 U2 1 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 JUL PY 2014 VL 151 IS 1 BP 164 EP 170 DI 10.1177/0194599814529536 PG 7 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA AN2YQ UT WOS:000340452400027 PM 24705224 ER PT J AU Small, EJ Higano, CS Kantoff, PW Whitmore, JB Frohlich, MW Petrylak, DP AF Small, E. J. Higano, C. S. Kantoff, P. W. Whitmore, J. B. Frohlich, M. W. Petrylak, D. P. TI Time to disease-related pain and first opioid use in patients with metastatic castration-resistant prostate cancer treated with sipuleucel-T SO PROSTATE CANCER AND PROSTATIC DISEASES LA English DT Article ID IMMUNOTHERAPY; MEN; SURVIVAL; THERAPY; TRIALS AB BACKGROUND: Sipuleucel-T has demonstrated improved overall survival in patients with metastatic castration-resistant prostate cancer (mCRPC). This analysis examined the effect of sipuleucel-T on time to disease-related pain (TDRP) and time to first use of opioid analgesics (TFOA) in mCRPC using data pooled from three randomized phase III studies in men with asymptomatic or minimally symptomatic mCRPC (D9901 (NCT00005947), D9902A (NCT01133704), D9902B (IMPACT; NCT00065442)). METHODS: Four-hundred and twenty-eight asymptomatic patients were analyzed for TDRP; 737 patients were analyzed for TFOA. Pain status was collected using logs adjudicated by blinded, independent reviewers. Opioid use for cancer-related pain was identified from medically reviewed reports of concomitant medication. Disease-related pain was defined as pain post enrollment. TDRP and TFOA were analyzed using the Kaplan-Meier method and Cox regression. RESULTS: Treatment with sipuleucel-T was not associated with a significant difference in TDRP (hazard ratio (HR) = 0.819; 95% confidence interval (CI): 0.616-1.089; P=0.170; median TDRP 5.6 months for sipuleucel-T and 5.3 months for control, respectively), although 39.3% of sipuleucel-T-treated patients and 18.9% of control patients were pain-free at 12 months. However, there was a significant delay in TFOA with sipuleucel-T (HR = 0.755; 95% CI: 0.579-0.985; P =0.038). Median TFOA for sipuleucel-T was 12.6, and 9.7 months for control, with 50.6% and 43.1% opioid-free at 12 months, respectively. Kapla-Meier curves for both end points began to diverge at 6 months. CONCLUSIONS: Sipuleucel-T was associated with longer TFOA but not significantly longer TDRP. Both end points demonstrated evidence of a delayed treatment effect, consistent with an active immunotherapy. C1 [Small, E. J.] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Higano, C. S.] Univ Washington, Sch Med, Dept Oncol, Seattle, WA USA. [Higano, C. S.] Univ Washington, Sch Med, Dept Urol, Seattle, WA 98195 USA. [Kantoff, P. W.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Whitmore, J. B.; Frohlich, M. W.] Dendreon Corp, Seattle, WA USA. [Petrylak, D. P.] Yale Univ, Smilow Canc Ctr, New Haven, CT USA. RP Small, EJ (reprint author), Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, 1600 Div,3rd Floor, San Francisco, CA 94143 USA. EM smalle@medicine.ucsf.edu FU Dendreon Corporation FX We thank Laura Gibbons, PhD, and Sam Yarwood, PhD, at Complete HealthVizion, UK, for their assistance with writing and revising the draft manuscript, based on discussion and feedback from all authors. Writing assistance was funded by Dendreon Corporation. The authors had full access to the data, participated in reviewing and interpreting the data and paper, read and approved the final version, and had final responsibility for the decision to submit for publication. Primary responsibility for the article lies with the authors. Study design, data collection and statistical analysis were supported and funded by Dendreon Corporation. NR 12 TC 10 Z9 10 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1365-7852 EI 1476-5608 J9 PROSTATE CANCER P D JI Prostate Cancer Prostatic Dis. PD JUL PY 2014 VL 17 IS 3 BP 259 EP 264 DI 10.1038/pcan.2014.21 PG 6 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA AN3UL UT WOS:000340514100008 PM 24957547 ER PT J AU Mahal, BA Aizer, AA Ziehr, DR Hyatt, AS Lago-Hernandez, C Chen, YW Choueiri, TK Hu, JC Sweeney, CJ Beard, CJ D'Amico, AV Martin, NE Trinh, QD Nguyen, PL AF Mahal, B. A. Aizer, A. A. Ziehr, D. R. Hyatt, A. S. Lago-Hernandez, C. Chen, Y-W Choueiri, T. K. Hu, J. C. Sweeney, C. J. Beard, C. J. D'Amico, A. V. Martin, N. E. Trinh, Q-D Nguyen, P. L. TI The association between insurance status and prostate cancer outcomes: implications for the Affordable Care Act SO PROSTATE CANCER AND PROSTATIC DISEASES LA English DT Article ID QUALITY-OF-LIFE; HEALTH-INSURANCE; RADICAL PROSTATECTOMY; MEN; DISPARITIES; ACCESS; MORTALITY; IMPACT; RISK; COMMUNITIES AB BACKGROUND: The Affordable Care Act (ACA) aims to expand health insurance coverage to over 30 million previously uninsured Americans. To help evaluate the potential impact of the ACA on prostate cancer care, we examined the associations between insurance coverage and prostate cancer outcomes among men <65 years old who are not yet eligible for Medicare. METHODS: The Surveillance, Epidemiology and End Results Program was used to identify 85 203 men aged <65 years diagnosed with prostate cancer from 2007 to 2010. Multivariable logistic regression modeled the association between insurance status and stage at presentation. Among men with high-risk disease, the associations between insurance status and receipt of definitive therapy, prostate cancer-specific mortality (PCSM) and all-cause mortality were determined using multivariable logistic, Fine and Gray competing-risks and Cox regression models, respectively. RESULTS: Uninsured patients were more likely to be non-white and come from regions of rural residence, lower median household income and lower education level (P <0.001 for all cases). Insured men were less likely to present with metastatic disease (adjusted odds ratio (AOR) 0.23; 95% confidence interval (CI) 0.20-0.27; P < 0.001). Among men with high-risk disease, insured men were more likely to receive definitive treatment (AOR 2.29; 95% CI 1.81-2.89; P<0.001), and had decreased PCSM (adjusted hazard ratio 0.56; 95% CI 0.31-0.98; P=0.04) and all-cause mortality (adjusted hazard ratio 0.60; 0.39-0.91; P=0.01). CONCLUSIONS: Insured men with prostate cancer are less likely to present with metastatic disease, more likely to be treated if they develop high-risk disease and are more likely to survive their cancer, suggesting that expanding health coverage under the ACA may significantly improve outcomes for men with prostate cancer who are not yet eligible for Medicare. C1 [Mahal, B. A.; Ziehr, D. R.; Lago-Hernandez, C.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Aizer, A. A.] Harvard Radiat Oncol Program, Boston, MA USA. [Hyatt, A. S.; Beard, C. J.; D'Amico, A. V.; Martin, N. E.; Nguyen, P. L.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Hyatt, A. S.; Choueiri, T. K.; Sweeney, C. J.; Beard, C. J.; D'Amico, A. V.; Martin, N. E.; Nguyen, P. L.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA 02115 USA. [Chen, Y-W] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Choueiri, T. K.; Sweeney, C. J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Hu, J. C.] Univ Calif Los Angeles, Med Ctr, Dept Urol, Los Angeles, CA 90024 USA. [Trinh, Q-D] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Urol, Boston, MA 02115 USA. RP Nguyen, PL (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Dana Farber Canc Inst,Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. EM pnguyen@LROC.harvard.edu RI Martin, Neil/E-2193-2014 OI Martin, Neil/0000-0002-8164-8516 FU Prostate Cancer Foundation; Fitz's Cancer Warriors FX This work is supported by David and Cynthia Chapin, the Prostate Cancer Foundation, Fitz's Cancer Warriors, Hugh Simons in honor of Frank and Anne Simons and a grant from an anonymous family foundation. NR 41 TC 8 Z9 8 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1365-7852 EI 1476-5608 J9 PROSTATE CANCER P D JI Prostate Cancer Prostatic Dis. PD JUL PY 2014 VL 17 IS 3 BP 273 EP 279 DI 10.1038/pcan.2014.23 PG 7 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA AN3UL UT WOS:000340514100010 PM 24980272 ER PT J AU Fishman, JA AF Fishman, Jay A. TI Assessment of infectious risk in clinical xenotransplantation: The lessons for clinical allotransplantation SO XENOTRANSPLANTATION LA English DT Editorial Material ID PORCINE ENDOGENOUS RETROVIRUS; MINIATURE SWINE; NO EVIDENCE; RECIPIENTS; IDENTIFICATION; TRANSMISSION; STRATEGIES C1 [Fishman, Jay A.] Massachusetts Gen Hosp, MGH Transplant Ctr, Transplantat Infect Dis & Compromised Host Progra, Boston, MA 02114 USA. [Fishman, Jay A.] Harvard Univ, Sch Med, Boston, MA USA. RP Fishman, JA (reprint author), Massachusetts Gen Hosp, MGH Transplant Ctr, Transplantat Infect Dis & Compromised Host Progra, Boston, MA 02114 USA. EM jfishman@partners.org NR 19 TC 7 Z9 7 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0908-665X EI 1399-3089 J9 XENOTRANSPLANTATION JI Xenotransplantation PD JUL-AUG PY 2014 VL 21 IS 4 BP 307 EP 308 DI 10.1111/xen.12118 PG 2 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA AN3HL UT WOS:000340477000001 PM 25098837 ER PT J AU Ciaranello, AL Leroy, V Rusibamayila, A Freedberg, KA Shapiro, R Engelsmann, B Lockman, S Kelly, KA Dabis, F Walensky, RP AF Ciaranello, Andrea L. Leroy, Valeriane Rusibamayila, Asinath Freedberg, Kenneth A. Shapiro, Roger Engelsmann, Barbara Lockman, Shahin Kelly, Kathleen A. Dabis, Francois Walensky, Rochelle P. TI Individualizing the WHO HIV and infant feeding guidelines: optimal breastfeeding duration to maximize infant HIV-free survival SO AIDS LA English DT Article DE breastfeeding; HIV; infant feeding; mother-to-child transmission; prevention of mother-to-child transmission ID TO-CHILD TRANSMISSION; RESOURCE-LIMITED SETTINGS; SUB-SAHARAN AFRICA; INFECTED MOTHERS; POOLED ANALYSIS; ANTIRETROVIRAL THERAPY; COST-EFFECTIVENESS; POSITIVE MOTHERS; COTE-DIVOIRE; SOUTH-AFRICA AB Objectives:To determine how infant feeding recommendations can maximize HIV-free survival (HFS) among HIV-exposed, uninfected African infants, balancing risks of breast milk-associated HIV infection with setting-specific risks of illness and death associated with replacement feeding.Design:Validated mathematical model of HIV-exposed, uninfected infants, with published data from Africa.Methods:We projected 24-month HFS using combinations of: maternal CD4(+), antiretroviral drug availability, and relative risk of mortality among replacement-fed compared to breastfed infants (RR-RF', range 1.0-6.0). For each combination, we identified the optimal' breastfeeding duration (0-24 months) maximizing HFS. We compared HFS under an individualized' approach, based on the above parameters, to the WHO public health approach' (12 months breastfeeding for all HIV-infected women).Results:Projected HFS was 65-93%. When the value of RR-RF is 1.0, replacement feeding from birth maximized HFS. At a commonly reported RR-RF value (2.0), optimal breastfeeding duration was 3-12 months, depending on maternal CD4(+) and antiretroviral drug availability. As the value of RR-RF increased, optimal breastfeeding duration increased. Compared to the public health approach, an individualized approach improved absolute HFS by less than 1% if RR-RF value was 2.0-4.0, by 3% if RR-RF value was 1.0 or 6.0, and by greater amounts if access to antiretroviral drugs was limited.Conclusion:Tailoring breastfeeding duration to maternal CD4(+), antiretroviral drug availability, and local replacement feeding safety can optimize HFS among HIV-exposed infants. An individualized approach leads to moderate gains in HFS, but only when mortality risks from replacement feeding are very low or very high, or antiretroviral drug availability is limited. The WHO public health approach is beneficial in most resource-limited settings. C1 [Ciaranello, Andrea L.; Freedberg, Kenneth A.; Walensky, Rochelle P.] Massachusetts Gen Hosp, Div Infect Dis, Med Practice Evaluat Ctr, Boston, MA 02114 USA. [Leroy, Valeriane; Dabis, Francois] Univ Bordeaux, ISPED, Bordeaux, France. [Leroy, Valeriane; Dabis, Francois] Ctr INSERM, U897, Bordeaux, France. [Rusibamayila, Asinath; Freedberg, Kenneth A.; Kelly, Kathleen A.; Walensky, Rochelle P.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Freedberg, Kenneth A.; Lockman, Shahin; Walensky, Rochelle P.] Harvard Ctr AIDS Res, Boston, MA USA. [Shapiro, Roger] Beth Israel Deaconess Med Ctr, Div Infect Dis, Boston, MA 02215 USA. [Shapiro, Roger; Lockman, Shahin] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Shapiro, Roger; Lockman, Shahin] Botswana Harvard Sch Publ Hlth, AIDS Inst Partnership HIV Res & Educ, Gaborone, Botswana. [Engelsmann, Barbara] Org Publ Hlth Intervent & Dev, Harare, Zimbabwe. [Lockman, Shahin; Walensky, Rochelle P.] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. RP Ciaranello, AL (reprint author), Massachusetts Gen Hosp, Div Infect Dis, 50 Stanford St,Room 936, Boston, MA 02114 USA. EM aciaranello@partners.org RI Leroy, Valeriane/F-8129-2013 OI Leroy, Valeriane/0000-0003-3542-8616 FU March of Dimes Foundation; Massachusetts General Hospital Executive Committee on Research; National Institutes of Health; National Institute of Allergy and Infectious Disease (NIAID) [K01 AI078754, K24 AI062476, R01 AI058736, R01 AI093269]; Center for AIDS Research [P30 AI060354]; International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT); National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) [UM1AI068632, UM1AI068616]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute of Mental Health (NIMH) FX Funding for this work was provided by the March of Dimes Foundation, the Massachusetts General Hospital Executive Committee on Research, and the National Institutes of Health, including the National Institute of Allergy and Infectious Disease (NIAID) through K01 AI078754 (A. L. C.), K24 AI062476 (K. A. F.), R01 AI058736 (K. A. F., A. R., R. P. W.), R01 AI093269 (R. W.), and the Center for AIDS Research/P30 AI060354 (K. A. F., S. L., R. P. W.), and the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT; K. A. F., A. R., R. P. W.). Overall support for IMPAACT was provided by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) under Award Numbers UM1AI068632 (IMPAACTLOC), UM1AI068616 (IMPAACTSDMC), with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Mental Health (NIMH). NR 61 TC 2 Z9 2 U1 1 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD JUL PY 2014 VL 28 SU 3 BP S287 EP S299 DI 10.1097/QAD.0000000000000337 PG 13 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA AM8XD UT WOS:000340161500009 PM 24991902 ER PT J AU Diekstra, FP Van Deerlin, VM van Swieten, JC Al-Chalabi, A Ludolph, AC Weishaupt, JH Hardiman, O Landers, JE Brown, RH van Es, MA Pasterkamp, RJ Koppers, M Andersen, PM Estrada, K Rivadeneira, F Hofman, A Uitterlinden, AG van Damme, P Melki, J Meininger, V Shatunov, A Shaw, CE Leigh, PN Shaw, PJ Morrison, KE Fogh, I Chio, A Traynor, BJ Czell, D Weber, M Heutink, P de Bakker, PIW Silani, V Robberecht, W van den Berg, LH Veldink, JH AF Diekstra, Frank P. Van Deerlin, Vivianna M. van Swieten, John C. Al-Chalabi, Ammar Ludolph, Albert C. Weishaupt, Jochen H. Hardiman, Orla Landers, John E. Brown, Robert H., Jr. van Es, Michael A. Pasterkamp, R. Jeroen Koppers, Max Andersen, Peter M. Estrada, Karol Rivadeneira, Fernando Hofman, Albert Uitterlinden, Andre G. van Damme, Philip Melki, Judith Meininger, Vincent Shatunov, Aleksey Shaw, Christopher E. Leigh, P. Nigel Shaw, Pamela J. Morrison, Karen E. Fogh, Isabella Chio, Adriano Traynor, Bryan J. Czell, David Weber, Markus Heutink, Peter de Bakker, Paul I. W. Silani, Vincenzo Robberecht, Wim van den Berg, Leonard H. Veldink, Jan H. TI C9orf72 and UNC13A Are Shared Risk Loci for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia: A Genome-Wide Meta-Analysis SO ANNALS OF NEUROLOGY LA English DT Article ID HEREDITARY SPASTIC PARAPLEGIA; LOBAR DEGENERATION; HEXANUCLEOTIDE REPEAT; COGNITIVE IMPAIRMENT; SUSCEPTIBILITY LOCI; ASSOCIATION; ALS; DISEASES; MUTATIONS; VARIANTS AB Objective: Substantial clinical, pathological, and genetic overlap exists between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 inclusions have been found in both ALS and FTD cases (FTD-TDP). Recently, a repeat expansion in C9orf72 was identified as the causal variant in a proportion of ALS and FTD cases. We sought to identify additional evidence for a common genetic basis for the spectrum of ALS-FTD. Methods: We used published genome-wide association studies data for 4,377 ALS patients and 13,017 controls, and 435 pathology-proven FTD-TDP cases and 1,414 controls for genotype imputation. Data were analyzed in a joint meta-analysis, by replicating topmost associated hits of one disease in the other, and by using a conservative rank products analysis, allocating equal weight to ALS and FTD-TDP sample sizes. Results: Meta-analysis identified 19 genome-wide significant single nucleotide polymorphisms (SNPs) in C9orf72 on chromosome 9p21.2 (lowest p = 2.6 x 10(-12)) and 1 SNP in UNC13A on chromosome 19p13.11 (p = 1.0 x 10(-11)) as shared susceptibility loci for ALS and FTD-TDP. Conditioning on the 9p21.2 genotype increased statistical significance at UNC13A. A third signal, on chromosome 8q24.13 at the SPG8 locus coding for strumpellin (p = 3.91 x 10(-7)) was replicated in an independent cohort of 4,056 ALS patients and 3,958 controls (p = 0.026; combined analysis p = 1.01 x 10(-7)). Interpretation: We identified common genetic variants in C9orf72, but in addition in UNC13A that are shared between ALS and FTD. UNC13A provides a novel link between ALS and FTD-TDP, and identifies changes in neurotransmitter release and synaptic function as a converging mechanism in the pathogenesis of ALS and FTD-TDP. C1 [Diekstra, Frank P.; van Es, Michael A.; Koppers, Max; van den Berg, Leonard H.; Veldink, Jan H.] Univ Med Ctr Utrecht, Rudolf Magnus Inst Neurosci, Dept Neurol, NL-3584 CX Utrecht, Netherlands. [Van Deerlin, Vivianna M.] Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA USA. [van Swieten, John C.; Heutink, Peter] Vrije Univ Amsterdam Med Ctr, Sect Med Genom, Dept Clin Genet, Amsterdam, Netherlands. [van Swieten, John C.] Erasmus MC, Dept Neurol, Rotterdam, Netherlands. [Al-Chalabi, Ammar; Shatunov, Aleksey; Shaw, Christopher E.; Leigh, P. Nigel; Fogh, Isabella] Kings Coll London, Inst Psychiat, Med Res Council Ctr Neurodegenerat Res, Dept Clin Neurosci, London WC2R 2LS, England. [Ludolph, Albert C.; Weishaupt, Jochen H.] Univ Ulm, Dept Neurol, D-89069 Ulm, Germany. [Hardiman, Orla] Beaumont Hosp, Dept Neurol, Dublin 9, Ireland. [Hardiman, Orla] Univ Dublin Trinity Coll, Dept Neurol, Dublin 2, Ireland. [Landers, John E.; Brown, Robert H., Jr.] Univ Massachusetts, Sch Med, Dept Neurol, Worcester, MA USA. [Landers, John E.; Brown, Robert H., Jr.] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA USA. [Pasterkamp, R. Jeroen; Koppers, Max] Univ Med Ctr Utrecht, Rudolf Magnus Inst Neurosci, Dept Neurosci & Pharmacol, NL-3584 CX Utrecht, Netherlands. [Andersen, Peter M.] Umea Univ, Dept Pharmacol & Clin Neurosci, Umea, Sweden. [Estrada, Karol; Rivadeneira, Fernando; Hofman, Albert; Uitterlinden, Andre G.] Erasmus Univ, Dept Epidemiol & Biostat, Med Ctr, NL-3000 DR Rotterdam, Netherlands. [van Damme, Philip; Robberecht, Wim] Univ Leuven, Univ Hosp Leuven, Dept Neurol, Leuven, Belgium. [van Damme, Philip; Robberecht, Wim] Flanders Inst Biotechnol, Vesalius Res Ctr, Neurobiol Lab, Leuven, Belgium. [Melki, Judith] INSERM, UMR 986, Paris, France. [Melki, Judith] Univ Paris 11, Bicetre Hosp, Paris, France. [Meininger, Vincent] Univ Paris 06, Salpetriere Hosp, Dept Neurol, Paris, France. [Shaw, Pamela J.] Univ Sheffield, Sheffield Inst Translat Neurosci, Dept Neurosci, Acad Neurol Unit, Sheffield, S Yorkshire, England. [Morrison, Karen E.] Univ Birmingham, Coll Med & Dent, Sch Clin & Expt Med, Birmingham, W Midlands, England. [Morrison, Karen E.] Univ Hosp Birmingham, Div Neurosci, Birmingham, W Midlands, England. [Fogh, Isabella; Silani, Vincenzo] IRCCS Italian Auxol Inst, Dept Neurol, Milan, Italy. [Fogh, Isabella; Silani, Vincenzo] IRCCS Italian Auxol Inst, Neurosci Lab, Milan, Italy. [Chio, Adriano] Univ Turin, Dept Neurosci, Turin, Italy. [Chio, Adriano] City Hosp Hlth & Sci, Turin, Italy. [Traynor, Bryan J.] NIA, Neuromuscular Dis Res Unit, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Traynor, Bryan J.] Johns Hopkins Univ, Dept Neurol, Brain Sci Inst, Baltimore, MD 21218 USA. [Czell, David; Weber, Markus] St Gallen Cantonal Hosp, Neuromuscular Dis Unit, St Gallen, Switzerland. [de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Dept Med Genet, NL-3584 CX Utrecht, Netherlands. [Silani, Vincenzo] Univ Milan, Dino Ferrari Ctr, Dept Pathophysiol & Transplantat, Milan, Italy. RP Veldink, JH (reprint author), Univ Med Ctr Utrecht, Rudolf Magnus Inst Neurosci, Dept Neurol, Heidelberglaan 100, NL-3584 CX Utrecht, Netherlands. EM j.h.veldink@umcutrecht.nl RI Van Damme, Philip/A-6464-2009; de Bakker, Paul/B-8730-2009; Rivadeneira, Fernando/O-5385-2015; OI Van Damme, Philip/0000-0001-6384-0611; de Bakker, Paul/0000-0001-7735-7858; Rivadeneira, Fernando/0000-0001-9435-9441; Koppers, Max/0000-0002-7751-1082; Chio, Adriano/0000-0001-9579-5341; Silani, Vincenzo/0000-0002-7698-3854; Pasterkamp, Jeroen/0000-0003-1631-6440; van Swieten, John /0000-0001-6278-6844; Hardiman, Orla/0000-0003-2610-1291 FU Prinses Beatrix Fonds (Kersten Foundation); VSB Fonds; Netherlands ALS Foundation; J. R. van Dijk, and the Adessium Foundation; Brain Foundation of the Netherlands; Thierry Latran Foundation; Prinses Beatrix Fonds; Netherlands Organization of Scientific Research NWO Investments [175.010.2005.011, 911-03-012]; Research Institute for Diseases in the Elderly [014-93-015]; Netherlands Genomics Initiative/Netherlands Organization for Scientific Research [050-060-810]; European Community [259867]; Erasmus Medical Center; Erasmus University, Rotterdam; Netherlands Organization for Health Research and Development; Research Institute for Diseases in the Elderly; Ministry of Education, Culture, and Science; Ministry for Health, Welfare, and Sports; European Commission (DG XII); Municipality of Rotterdam; German Federal Ministry of Education and Research (network for ALS research [MND-NET]) [01GI0704]; Charcot Foundation for ALS Research; Swabian ALS Registry; Muscular Dystrophy Association (USA); Health Research Board of Ireland; Irish Neurological Association Travel Award; Irish Motor Neuron Disease Research Foundation; Swedish Brain Research Foundation; Hallstens Research Foundation; Swedish Medical Society; Bjorklund Foundation for ALS Research; Swedish Association for the Neurologically Disabled; Swiss ALS Association; University of Leuven (Methusalem); Interuniversity Attraction Poles program of the Belgian Federal Science Policy Office [P6/43]; Associazione Centro Dino Ferrari; Italian Ministry of Health (GWA-SLA, Ricerca Finalizzata) [31]; ALS-FTD, Ricerca Finalizzata [276]; Fondazione Istituto Auxologico Italiano; Italian Health Ministry (Ricerca Sanitaria Finalizzata); Fondazione Vialli e Mauro ONLUS; Federazione Italiana Giuoco Calcio; Association pour la recherche sur la sclerose laterale amyotrophique; Association Reseau SLA Ile de France; ALS Therapy Alliance; Project ALS; Angel Fund; Pierre L. de Bourgknecht ALS Research Foundation; Al-Athel ALS Research Foundation; ALS Family Charitable Foundation; NIH National Institute of Neurological Disorders and Stroke [NS050557, 1R01NS073873]; NIH [AG017586]; Intramural Research Program of the NIH, National Institute on Aging; Research Motor Neurone; Motor Neurone Disease Association UK FX This work was supported by the Prinses Beatrix Fonds (Kersten Foundation), VSB Fonds, the Netherlands ALS Foundation and J. R. van Dijk, and the Adessium Foundation (L.H.v.d.B.). J.H.V. is supported by the Brain Foundation of the Netherlands and the Thierry Latran Foundation. R.J.P. is supported by the Prinses Beatrix Fonds and the Thierry Latran Foundation. The GWAS was funded by the Netherlands Organization of Scientific Research NWO Investments (grants 175.010.2005.011, 911-03-012), the Research Institute for Diseases in the Elderly (014-93-015), and the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research (project number 050-060-810). In addition, the research leading to these results has received funding from the European Community's Health Seventh Framework Program (FP7/2007-2013; grant agreement number 259867). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam; Netherlands Organization for Health Research and Development; the Research Institute for Diseases in the Elderly; the Ministry of Education, Culture, and Science; the Ministry for Health, Welfare, and Sports; the European Commission (DG XII); and the Municipality of Rotterdam. The work was also supported by grants from the German Federal Ministry of Education and Research (01GI0704; network for ALS research [MND-NET]), the Charcot Foundation for ALS Research (A. C. L., J. H. W.), and the Swabian ALS Registry. The Irish study was funded by the Muscular Dystrophy Association (USA), the Health Research Board of Ireland, the Irish Neurological Association Travel Award, and the Irish Motor Neuron Disease Research Foundation. In Sweden, this project was supported by the Swedish Brain Research Foundation, the Hallstens Research Foundation, the Swedish Medical Society, the Bjorklund Foundation for ALS Research, and the Swedish Association for the Neurologically Disabled (P. M. A.). In Switzerland, this study was supported by the Swiss ALS Association. W. R. was supported by grants from the University of Leuven (Methusalem) and the Interuniversity Attraction Poles program P6/43 of the Belgian Federal Science Policy Office. In Italy, this study has been funded by grants from the Associazione Centro Dino Ferrari, Italian Ministry of Health (GWA-SLA, Ricerca Finalizzata 2007, grant number 31 and ALS-FTD, Ricerca Finalizzata 2009, grant number 276; I. F., V. S.), and Fondazione Istituto Auxologico Italiano. Also in Italy, the study was financed by the Italian Health Ministry (Ricerca Sanitaria Finalizzata 2007), Fondazione Vialli e Mauro ONLUS, and Federazione Italiana Giuoco Calcio (A. C.). In France, this study was funded by the Association pour la recherche sur la sclerose laterale amyotrophique and the Association Reseau SLA Ile de France. Support was also provided by the ALS Therapy Alliance, Project ALS, the Angel Fund, the Pierre L. de Bourgknecht ALS Research Foundation, the Al-Athel ALS Research Foundation, the ALS Family Charitable Foundation, and the NIH National Institute of Neurological Disorders and Stroke (NS050557). J. E. L. received funding from the NIH National Institute of Neurological Disorders and Stroke (1R01NS073873). V. M. V. D. was supported by NIH grant AG017586. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging (B.J.T.). O.H. was supported by a grant from Research Motor Neurone. K.E.M. was supported by a grant from Motor Neurone Disease Association UK. NR 38 TC 9 Z9 9 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0364-5134 EI 1531-8249 J9 ANN NEUROL JI Ann. Neurol. PD JUL PY 2014 VL 76 IS 1 BP 120 EP 133 DI 10.1002/ana.24198 PG 14 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AM7JQ UT WOS:000340043200012 PM 24931836 ER PT J AU von Boehmer, H AF von Boehmer, Harald TI The Thymus in Immunity and in Malignancy SO CANCER IMMUNOLOGY RESEARCH LA English DT Article ID T-CELL-RECEPTOR; ALPHA-BETA; LINEAGE COMMITMENT; NEGATIVE SELECTION; ALLELIC EXCLUSION; THYMOCYTES; DIFFERENTIATION; TCR; PROGENITORS; REQUIRES AB The thymus is an essential organ for the generation of the adaptive immune system. By now, the cellular selection events taking place in ongoing life before sexual maturity have been worked out even at the molecular level, and thus thymic lymphocyte development represents one of the best-studied systems in mammalian development. Because thymic lymphocyte development involves ample proliferation and generation of new cells, it is not astonishing that the thymus also represents an organ where malignancy can develop. In this Masters of Immunology primer, the development of lymphocytes and the role of intracellular Notch 1 and cyclins in lymphocytic malignancy are reviewed, offering new therapeutic possibilities. (C) 2014 AACR. C1 [von Boehmer, Harald] Harvard Univ, Sch Med, Boston, MA USA. [von Boehmer, Harald] Dana Farber Canc Inst, Boston, MA 02115 USA. [von Boehmer, Harald] Univ Florida, Gainesville, FL USA. [von Boehmer, Harald] Univ Munich, Munich, Germany. RP von Boehmer, H (reprint author), Haspingerstr 428, A-6100 Seefeld Tirol, Austria. EM Harald_von_Boehmer@dfci.harvard.edu NR 48 TC 8 Z9 8 U1 0 U2 5 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 JUL PY 2014 VL 2 IS 7 BP 592 EP 597 DI 10.1158/2326-6066.CIR-14-0070 PG 6 WC Oncology; Immunology SC Oncology; Immunology GA AM7HG UT WOS:000340035800002 PM 24990239 ER PT J AU Hodi, FS Lawrence, D Lezcano, C Wu, XQ Zhou, J Sasada, T Zeng, WY Giobbie-Hurder, A Atkins, MB Ibrahim, N Friedlander, P Flaherty, KT Murphy, GF Rodig, S Velazquez, EF Mihm, MC Russell, S DiPiro, PJ Yap, JT Ramaiya, N van den Abbeele, AD Gargano, M McDermott, D AF Hodi, F. Stephen Lawrence, Donald Lezcano, Cecilia Wu, Xinqi Zhou, Jun Sasada, Tetsuro Zeng, Wanyong Giobbie-Hurder, Anita Atkins, Michael B. Ibrahim, Nageatte Friedlander, Philip Flaherty, Keith T. Murphy, George F. Rodig, Scott Velazquez, Elsa F. Mihm, Martin C., Jr. Russell, Sara DiPiro, Pamela J. Yap, Jeffrey T. Ramaiya, Nikhil van den Abbeele, Annick D. Gargano, Maria McDermott, David TI Bevacizumab plus Ipilimumab in Patients with Metastatic Melanoma SO CANCER IMMUNOLOGY RESEARCH LA English DT Article ID LYMPHOCYTE-ASSOCIATED ANTIGEN-4; ENDOTHELIAL GROWTH-FACTOR; ANTIBODY BLOCKADE; COLORECTAL-CANCER; PHASE-II; IN-VIVO; TUMOR; CELL; VEGF; CD31 AB Ipilimumab improves survival in advanced melanoma and can induce immune-mediated tumor vasculopathy. Besides promoting angiogenesis, vascular endothelial growth factor (VEGF) suppresses dendritic cell maturation and modulates lymphocyte endothelial trafficking. This study investigated the combination of CTLA4 blockade with ipilimumab and VEGF inhibition with bevacizumab. Patients with metastatic melanoma were treated in four dosing cohorts of ipilimumab (3 or 10 mg/kg) with four doses at 3-week intervals and then every 12 weeks, and bevacizumab (7.5 or 15 mg/kg) every 3 weeks. Forty-six patients were treated. Inflammatory events included giant cell arteritis (n = 1), hepatitis (n = 2), and uveitis (n = 2). On-treatment tumor biopsies revealed activated vessel endothelium with extensive CD8(+) and macrophage cell infiltration. Peripheral blood analyses demonstrated increases in CCR7(+/-)/CD45RO(+) cells and anti-galectin antibodies. Best overall response included 8 partial responses, 22 instances of stable disease, and a disease-control rate of 67.4%. Median survival was 25.1 months. Bevacizumab influences changes in tumor vasculature and immune responses with ipilimumab administration. The combination of bevacizumab and ipilimumab can be safely administered and reveals VEGF-A blockade influences on inflammation, lymphocyte trafficking, and immune regulation. These findings provide a basis for further investigating the dual roles of angiogenic factors in blood vessel formation and immune regulation, as well as future combinations of antiangiogenesis agents and immune checkpoint blockade. (C) 2014 AACR. C1 [Hodi, F. Stephen; Wu, Xinqi; Zhou, Jun; Sasada, Tetsuro; Zeng, Wanyong; Ibrahim, Nageatte; Gargano, Maria] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Giobbie-Hurder, Anita] Dana Farber Canc Inst, Dept Biostat, Boston, MA 02215 USA. [DiPiro, Pamela J.; Yap, Jeffrey T.; Ramaiya, Nikhil; van den Abbeele, Annick D.] Dana Farber Canc Inst, Dept Imaging, Boston, MA 02215 USA. [Lawrence, Donald; Flaherty, Keith T.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Murphy, George F.; Rodig, Scott; Mihm, Martin C., Jr.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Russell, Sara] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Velazquez, Elsa F.] Tufts Univ, Boston, MA 02111 USA. [McDermott, David] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Velazquez, Elsa F.] Miraca Life Sci, Newton, MA USA. [Lezcano, Cecilia] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Atkins, Michael B.] Georgetown Univ, Lombardi Canc Ctr, Washington, DC USA. [Friedlander, Philip] Mt Sinai Med Ctr, New York, NY USA. RP Hodi, FS (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM Stephen_Hodi@dfci.harvard.edu FU NIH [CA143832, 1R012CA158467]; Melanoma Research Alliance; Sharon Crowley Martin Memorial Fund for Melanoma Research; Malcolm and Emily Mac Naught Fund for Melanoma Research at the Dana-Farber Cancer Institute; Genentech/Roche; Bristol-Myers Squibb FX This study was funded by NIH CA143832 (to F.S. Hodi) and 1R012CA158467 (to F.S. Hodi and G.F. Murphy), the Melanoma Research Alliance (to F. S. Hodi), the Sharon Crowley Martin Memorial Fund for Melanoma Research (to F.S. Hodi), and the Malcolm and Emily Mac Naught Fund for Melanoma Research (to F.S. Hodi) at the Dana-Farber Cancer Institute, Genentech/Roche, and Bristol-Myers Squibb. NR 36 TC 118 Z9 122 U1 2 U2 17 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 JUL PY 2014 VL 2 IS 7 BP 632 EP 642 DI 10.1158/2326-6066.CIR-14-0053 PG 11 WC Oncology; Immunology SC Oncology; Immunology GA AM7HG UT WOS:000340035800007 PM 24838938 ER PT J AU Cooper, ZA Juneja, VR Sage, PT Frederick, DT Piris, A Mitra, D Lo, JA Hodi, S Freeman, GJ Bosenberg, MW McMahon, M Flaherty, KT Fisher, DE Sharpe, AH Wargo, JA AF Cooper, Zachary A. Juneja, Vikram R. Sage, Peter T. Frederick, Dennie T. Piris, Adriano Mitra, Devarati Lo, Jennifer A. Hodi, Stephen Freeman, Gordon J. Bosenberg, Marcus W. McMahon, Martin Flaherty, Keith T. Fisher, David E. Sharpe, Arlene H. Wargo, Jennifer A. TI Response to BRAF Inhibition in Melanoma Is Enhanced When Combined with Immune Checkpoint Blockade SO CANCER IMMUNOLOGY RESEARCH LA English DT Article ID CELL CARCINOMA PATIENTS; METASTATIC MELANOMA; T-CELLS; THERAPEUTIC TARGET; ANTI-PD-1 ANTIBODY; ANTITUMOR-ACTIVITY; PD-1 EXPRESSION; UP-REGULATION; CANCER; B7-H1 AB BRAF-targeted therapy results in objective responses in the majority of patients; however, the responses are short lived (similar to 6 months). In contrast, treatment with immune checkpoint inhibitors results in a lower response rate, but the responses tend to be more durable. BRAF inhibition results in a more favorable tumor microenvironment in patients, with an increase in CD8(+) T-cell infiltrate and a decrease in immunosuppressive cytokines. There is also increased expression of the immunomodulatory molecule PDL1, which may contribute to the resistance. On the basis of these findings, we hypothesized that BRAF-targeted therapy may synergize with the PD1 pathway blockade to enhance antitumor immunity. To test this hypothesis, we developed a BRAF(V600E)/Pten(-/-) syngeneic tumor graft immunocompetent mouse model in which BRAF inhibition leads to a significant increase in the intratumoral CD8(+) T-cell density and cytokine production, similar to the effects of BRAF inhibition in patients. In this model, CD8(+) T cells were found to play a critical role in the therapeutic effect of BRAF inhibition. Administration of anti-PD1 or anti-PDL1 together with a BRAF inhibitor led to an enhanced response, significantly prolonging survival and slowing tumor growth, as well as significantly increasing the number and activity of tumor-infiltrating lymphocytes. These results demonstrate synergy between combined BRAF-targeted therapy and immune checkpoint blockade. Although clinical trials combining these two strategies are ongoing, important questions still remain unanswered. Further studies using this new melanoma mouse model may provide therapeutic insights, including optimal timing and sequence of therapy. (C) 2014 AACR. C1 [Cooper, Zachary A.; Wargo, Jennifer A.] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA. [Cooper, Zachary A.; Wargo, Jennifer A.] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA. [Juneja, Vikram R.] Harvard Div Hlth Sci & Technol, Cambridge, England. [Juneja, Vikram R.; Sage, Peter T.] Brigham & Womens Hosp, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. [Juneja, Vikram R.; Sage, Peter T.; Piris, Adriano; Mitra, Devarati; Hodi, Stephen; Freeman, Gordon J.; Flaherty, Keith T.; Fisher, David E.; Sharpe, Arlene H.] Harvard Univ, Sch Med, Boston, MA USA. [Frederick, Dennie T.; Flaherty, Keith T.] Brigham & Womens Hosp, Div Med Oncol, Massachusetts Gen Hosp, Boston, MA USA. [Piris, Adriano] Brigham & Womens Hosp, Div Dermatopathol, Massachusetts Gen Hosp, Boston, MA USA. [Fisher, David E.] Brigham & Womens Hosp, Div Dermatol, Massachusetts Gen Hosp, Boston, MA USA. [Freeman, Gordon J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA. [Sharpe, Arlene H.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Bosenberg, Marcus W.] Yale Univ, Sch Med, Dept Dermatol, New Haven, CT USA. [McMahon, Martin] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA. [McMahon, Martin] Univ Calif San Francisco, Dept Cell & Mol Pharmacol, San Francisco, CA USA. RP Wargo, JA (reprint author), Univ Texas MD Anderson Canc Ctr, 1515 Holcombe Blvd SCT17-6010, Houston, TX 77030 USA. EM jwargo@mdanderson.org OI , /0000-0002-9520-6874; Cooper, Zachary/0000-0003-1059-0940 FU NIH [1K08CA160692-01A1, P30CA016672, P01 CA163222, 5T32HL007627-28]; DF HCC Kidney Cancer SPORE [P50CA101942]; Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; Department of Defense; National Science Foundation Graduate Fellowship; [U54CA163125]; [P01AI056299] FX J.A. Wargo acknowledges NIH grants 1K08CA160692-01A1 and P30CA016672, and from philanthropic support of several families whose lives have been affected by melanoma. J.A. Wargo, A.H. Sharpe, and G.J. Freeman acknowledge support from U54CA163125. A.H. Sharpe and G.J. Freeman acknowledge P01AI056299. A.H. Sharpe and G.J. Freeman also acknowledge support from DF HCC Kidney Cancer SPORE P50CA101942. D.E. Fisher acknowledges support from NIH grant P01 CA163222 and a grant from the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation. P.T. Sage acknowledges support from NIH grant (5T32HL007627-28). V.R. Juneja acknowledges support from the Department of Defense and from a National Science Foundation Graduate Fellowship. NR 45 TC 67 Z9 68 U1 3 U2 14 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 JUL PY 2014 VL 2 IS 7 BP 643 EP 654 DI 10.1158/2326-6066.CIR-13-0215 PG 12 WC Oncology; Immunology SC Oncology; Immunology GA AM7HG UT WOS:000340035800008 PM 24903021 ER PT J AU Elpek, KG Cremasco, V Shen, H Harvey, CJ Wucherpfennig, KW Goldstein, DR Monach, PA Turley, SJ AF Elpek, Kutlu G. Cremasco, Viviana Shen, Hua Harvey, Christopher J. Wucherpfennig, Kai W. Goldstein, Daniel R. Monach, Paul A. Turley, Shannon J. TI The Tumor Microenvironment Shapes Lineage, Transcriptional, and Functional Diversity of Infiltrating Myeloid Cells SO CANCER IMMUNOLOGY RESEARCH LA English DT Article ID GENE-EXPRESSION ANALYSIS; SUPPRESSOR-CELLS; MAMMARY-TUMORS; NEUTROPHIL; MACROPHAGES; HAPTOGLOBIN; HYPOXIA; CANCER; ACTIVATION; INFLAMMATION AB Myeloid cells play important regulatory roles within the tumor environment by directly promoting tumor progression and modulating the function of tumor-infiltrating lymphocytes, and as such, they represent a potential therapeutic target for the treatment of cancer. Although distinct subsets of tumor-associated myeloid cells have been identified, a broader analysis of the complete myeloid cell landscape within individual tumors and also across different tumor types has been lacking. By establishing the developmental and transcriptomic signatures of infiltrating myeloid cells from multiple primary tumors, we found that tumor-associated macrophages (TAM) and tumor-associated neutrophils (TAN), while present within all tumors analyzed, exhibited strikingly different frequencies, gene expression profiles, and functions across cancer types. We also evaluated the impact of anatomic location and circulating factors on the myeloid cell composition of tumors. The makeup of the myeloid compartment was determined by the tumor microenvironment rather than the anatomic location of tumor development or tumor-derived circulating factors. Protumorigenic and hypoxia-associated genes were enriched in TAMs and TANs compared with splenic myeloid-derived suppressor cells. Although all TANs had an altered expression pattern of secretory effector molecules, in each tumor type they exhibited a unique cytokine, chemokine, and associated receptor expression profile. One such molecule, haptoglobin, was uniquely expressed by 4T1 TANs and identified as a possible diagnostic biomarker for tumors characterized by the accumulation of myeloid cells. Thus, we have identified considerable cancer-specific diversity in the lineage, gene expression, and function of tumor-infiltrating myeloid cells. (C) 2014 AACR. C1 [Elpek, Kutlu G.; Cremasco, Viviana; Harvey, Christopher J.; Wucherpfennig, Kai W.; Turley, Shannon J.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Monach, Paul A.] Boston Univ, Sch Med, Boston, MA 02215 USA. [Turley, Shannon J.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA USA. [Shen, Hua; Goldstein, Daniel R.] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT USA. [Shen, Hua; Goldstein, Daniel R.] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT USA. RP Turley, SJ (reprint author), Dana Farber Canc Inst, 44 Binney St,D1440a, Boston, MA 02115 USA. EM shannon_turley@dfci.harvard.edu FU NIH [T32, T32 CA 070083-15, AG028082, AG033049, AI098108, AI101918, ROI DK074500, PO1 AI045757, R21 CA182598]; Cancer Research Institute; American Heart Association [0940006N]; American Cancer Society Research Scholar Grant; Claudia Adams Barr Award for Innovative Cancer Research FX This study was supported by research funding from NIH T32 grant to K.G. Elpek, NIH T32 CA 070083-15 and Postdoctoral Fellowship from the Cancer Research Institute to V. Cremasco, NIH grants (AG028082, AG033049, AI098108, and AI101918) and an Established Investigator Award (0940006N) from American Heart Association to D.R. Goldstein, NIH grants (ROI DK074500, PO1 AI045757, and R21 CA182598), American Cancer Society Research Scholar Grant, and Claudia Adams Barr Award for Innovative Cancer Research to S.J. Turley. NR 37 TC 14 Z9 14 U1 1 U2 4 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 JUL PY 2014 VL 2 IS 7 BP 655 EP 667 DI 10.1158/2326-6066.CIR-13-0209 PG 13 WC Oncology; Immunology SC Oncology; Immunology GA AM7HG UT WOS:000340035800009 PM 24801837 ER PT J AU Shen, JK Cote, GM Choy, E Yang, P Harmon, D Schwab, J Nielsen, GP Chebib, I Ferrone, S Wang, XH Wang, YY Mankin, H Hornicek, FJ Duan, ZF AF Shen, Jacson K. Cote, Gregory M. Choy, Edwin Yang, Pei Harmon, David Schwab, Joseph Nielsen, G. Petur Chebib, Ivan Ferrone, Soldano Wang, Xinhui Wang, Yangyang Mankin, Henry Hornicek, Francis J. Duan, Zhenfeng TI Programmed Cell Death Ligand 1 Expression in Osteosarcoma SO CANCER IMMUNOLOGY RESEARCH LA English DT Article ID BREAST-CANCER PATIENTS; CARCINOMA PATIENTS; POSTOPERATIVE RECURRENCE; HEPATOCELLULAR-CARCINOMA; TUMOR AGGRESSIVENESS; POTENTIAL MECHANISM; PROGNOSTIC-FACTORS; LUNG-CANCER; B7-H1; SAFETY AB Programmed cell death ligand 1 (PDL1, also known as B7H1) is a cell-surface protein that suppresses the cytotoxic CD8(+) T-cell-mediated immune response. PDL1 expression and its clinical relevance in sarcomas are not well understood. Therefore, we sought to measure RNA expression levels for PDL1 in 38 clinically annotated osteosarcoma tumor samples and aimed to determine if PDL1 expression correlates with clinical features and tumor-infiltrating lymphocytes (TIL). Quantitative real-time RT-PCR for PDL1 was optimized in 18 cell lines, of which 5 were osteosarcoma derived. qRT-PCR results were validated via flow cytometry and immunohistochemistry (IHC) in select cell lines. Total RNA was isolated from 38 human osteosarcoma samples for qRT-PCR analysis. Clinical data were sorted, and significance was determined by the Student t test. TILs were examined in patient samples by tissue microarray hematoxylin-eosin staining. We confirmed the constitutive PDL1 mRNA expression in cell lines by qRT-PCR, flow cytometry, and IHC. Across human osteosarcoma samples, PDL1 mRNA gene expression ranged over 4 log (>5,000-fold difference). Relative expression levels were evaluated against clinical factors such as age/gender, metastasis, recurrence, chemotherapy, percentage of necrosis, and survival; no significant associations were identified. The presence of TILs was associated with high PDL1 expression (R-2 = 0.37; P = 0.01). In summary, we developed an RNA-based assay to determine PDL1 expression levels, and we show, for the first time, that high levels of PDL1 are expressed in a subset of osteosarcoma, and PDL1 expression is positively correlated with TILs. Multiple agents targeting PD1/PDL1 are in clinical development, and this may be a novel immunotherapeutic strategy for osteosarcoma clinical trials. (C)2014 AACR. C1 [Shen, Jacson K.; Yang, Pei; Schwab, Joseph; Mankin, Henry; Hornicek, Francis J.; Duan, Zhenfeng] Massachusetts Gen Hosp, Sarcoma Biol Lab, Ctr Sarcoma & Connect Tissue Oncol, Boston, MA 02114 USA. [Cote, Gregory M.; Choy, Edwin; Harmon, David] Massachusetts Gen Hosp, Div Hematol & Oncol, Boston, MA 02114 USA. [Nielsen, G. Petur; Chebib, Ivan] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Ferrone, Soldano; Wang, Xinhui; Wang, Yangyang] Massachusetts Gen Hosp, Dept Surg, Monoclonal Antibody & Immunotherapy Lab, Boston, MA 02114 USA. RP Duan, ZF (reprint author), Massachusetts Gen Hosp, 55 Fruit St,Jackson Bldg Room 1115, Boston, MA 02114 USA. EM zduan@mgh.harvard.edu OI Cote, Gregory/0000-0003-0181-886X FU Gattegno and Wechsler funds; Jennifer Hunter Yates Foundation; Kenneth Stanton Osteosarcoma Research Fund; Sarcoma Foundation of America; Sarcoma SPORE (NCI); NCI/NIH [UO1, CA151452-01]; Academic Enrichment Fund of MGH Orthopedic Surgery FX This work was supported in part by grants from the Gattegno and Wechsler funds. J.K. Shen is supported by the Jennifer Hunter Yates Foundation and the Kenneth Stanton Osteosarcoma Research Fund. Z. Duan is supported, in part, through a grant from Sarcoma Foundation of America, a developmental research award from Sarcoma SPORE (NCI), a grant from NCI/NIH, UO1, CA151452-01, and a grant from an Academic Enrichment Fund of MGH Orthopedic Surgery. NR 37 TC 33 Z9 34 U1 1 U2 11 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 JUL PY 2014 VL 2 IS 7 BP 690 EP 698 DI 10.1158/2326-6066.CIR-13-0224 PG 9 WC Oncology; Immunology SC Oncology; Immunology GA AM7HG UT WOS:000340035800012 PM 24866169 ER PT J AU Collins, SE Saxon, AJ Duncan, MH Smart, BF Merrill, JO Malone, DK Jackson, TR Clifasefi, SL Joesch, J Ries, RK AF Collins, Susan E. Saxon, Andrew J. Duncan, Mark H. Smart, Brian F. Merrill, Joseph O. Malone, Daniel K. Jackson, T. Ron Clifasefi, Seema L. Joesch, Jutta Ries, Richard K. TI Harm reduction with pharmacotherapy for homeless people with alcohol dependence: Protocol for a randomized controlled trial SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE Alcohol dependence; Extended-release naltrexone; Harm reduction; Homelessness; Alcohol treatment ID SUBSTANCE-ABUSE TREATMENT; HOUSING 1ST; ETHYL GLUCURONIDE; USE DISORDERS; BRIEF INTERVENTIONS; CLINICAL-RESEARCH; BEHAVIOR-THERAPY; VIDEO ASSESSMENT; PROBLEM DRINKING; MENTAL-ILLNESS AB Background: Interventions requiring abstinence from alcohol are neither preferred by nor shown to be highly effective with many homeless individuals with alcohol dependence. It is therefore important to develop lower-threshold, patient-centered interventions for this multimorbid and high-utilizing population. Harm-reduction counseling requires neither abstinence nor use reduction and pairs a compassionate style with patient-driven goal-setting. Extended-release naltrexone (XR-NTX), a monthly injectable formulation of an opioid receptor antagonist, reduces craving and may support achievement of harm-reduction goals. Together, harm-reduction counseling and XR-NTX may support alcohol harm reduction and quality-of-life improvement Aims: Study aims include testing: a) the relative efficacy of XR-NTX and harm-reduction counseling compared to a community-based, supportive-services-as-usual control, b) theory-based mediators of treatment effects, and c) treatment effects on publicly funded service costs. Methods: This RCT involves four arms: a) XR-NTX + harm-reduction counseling, b) placebo + harm-reduction counseling, c) harm-reduction counseling only, and d) community-based, supportive-services-as-usual control conditions. Participants are currently/formerly homeless, alcohol dependent individuals (N = 300). Outcomes include alcohol variables (i.e., craving, quantity/frequency, problems and biomarkers), health-related quality of life, and publicly funded service utilization and associated costs. Mediators include 10-point motivation rulers and the Penn Alcohol Craving Scale. XR-NTX and harm-reduction counseling are administered every 4 weeks over the 12-week treatment course. Follow-up assessments are conducted at weeks 24 and 36. Discussion: If found efficacious, XR-NTX and harm-reduction counseling will be well-positioned to support reductions in alcohol-related harm, decreases in costs associated with publicly funded service utilization, and increases in quality of life among homeless, alcohol-dependent individuals. (C) 2014 Elsevier Inc. All rights reserved. C1 [Collins, Susan E.; Duncan, Mark H.; Smart, Brian F.; Joesch, Jutta; Ries, Richard K.] Univ Washington, Harborview Med Ctr, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Saxon, Andrew J.] VA Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. [Saxon, Andrew J.; Clifasefi, Seema L.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Merrill, Joseph O.] Univ Washington, Harborview Med Ctr, Dept Med, Seattle, WA 98195 USA. [Malone, Daniel K.] Downtown Emergency Serv Ctr, Seattle, WA 98104 USA. [Jackson, T. Ron] Evergreen Treatment Serv REACH, Seattle, WA 98134 USA. RP Collins, SE (reprint author), Univ Washington, Harborview Med Ctr, 325 Ninth Ave,Box 359911, Seattle, WA 98195 USA. EM collinss@uw.edu; andrew.saxon@va.gov; mhduncan@uw.edu; smartb@uw.edu; joem@uw.edu; dmalone@desc.org; ronjack@uw.edu; seemac@uw.edu; Jutta.Joesch@kingcounty.gov; rries@uw.edu FU National Institute on Alcohol Abuse and Alcoholism [1R01AA022309-01] FX This research is supported by a research program grant from the National Institute on Alcohol Abuse and Alcoholism (1R01AA022309-01; PI: Collins), and is registered with clinicaltrials.gov (NCT01932801). The active medication and placebo injections are being provided by Alkermes, Inc. Neither NIAAA nor Alkermes, Inc. had a role in the study design; collection, analysis and interpretation of data; writing of the manuscript; or decision to submit this manuscript for publication. NR 102 TC 0 Z9 0 U1 2 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7144 EI 1559-2030 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD JUL PY 2014 VL 38 IS 2 BP 221 EP 234 DI 10.1016/j.cct.2014.05.008 PG 14 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA AN0VF UT WOS:000340301400009 PM 24846619 ER PT J AU Van Houtven, CH Oddone, EZ Hastings, SN Hendrix, C Olsen, M Neelon, B Lindquist, J Weidenbacher, H Boles, J Chapman, J Weinberger, M AF Van Houtven, Courtney Harold Oddone, Eugene Z. Hastings, Susan N. Hendrix, Cristina Olsen, Maren Neelon, Brian Lindquist, Jennifer Weidenbacher, Hollis Boles, Jillian Chapman, Jennifer Weinberger, Morris TI Helping Invested Families Improve Veterans' Experiences Study (HI-FIVES): Study design and methodology SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE Informal care; Skills training; Randomized control trial; Days at home; Health care costs; Depressive symptoms ID RANDOMIZED CONTROLLED-TRIAL; COMMUNITY-BASED SERVICES; QUALITY-OF-LIFE; CARE; CAREGIVERS; DEMENTIA; HOME; INTERVENTION; PROGRAM; METAANALYSIS AB Within the Veterans Health Administration (VHA), the largest integrated health care system in the US, approximately 8.5 million Veteran patients receive informal care. Despite a need for training, half of VHA caregivers report that they have not received training that they deemed necessary. Rigorous study is needed to identify effective ways of providing caregivers with the skills they need. This paper describes the Helping Invested Families Improve Veterans' Experience Study (HI-FIVES), an ongoing randomized controlled trial that is evaluating a skills training program designed to support caregivers of cognitively and/or functionally impaired, community-dwelling Veterans who have been referred to receive additional formal home care services. This two-arm randomized controlled trial will enroll a total of 240 caregiver-patient dyads. For caregivers in the HI-FIVES group, weekly individual phone training occurs for 3 weeks, followed by 4 weekly group training sessions, and two additional individual phone training calls. Caregivers in usual care receive information about the VA Caregiver Support Services Program services, including a hotline number. The primary outcome is the number of days a Veteran patient spends at home in the 12 months following randomization (e.g. not in the emergency department, inpatient or nursing home setting). Secondary outcomes include patient VHA health care costs, patient and caregiver satisfaction with VHA health care, and caregiver depressive symptoms. Outcomes from HI-FIVES have the potential to improve our knowledge of how to maximize the ability to maintain patients safely at home for caregivers while preventing poor mental health outcomes among caregivers. (C) 2014 Published by Elsevier Inc. C1 [Van Houtven, Courtney Harold; Oddone, Eugene Z.; Hastings, Susan N.; Hendrix, Cristina; Olsen, Maren; Neelon, Brian; Lindquist, Jennifer; Weidenbacher, Hollis; Chapman, Jennifer; Weinberger, Morris] Durham VA Med Ctr, Ctr Hlth Serv Res Primary Care, US Dept Vet Affairs, Durham, NC 27705 USA. [Van Houtven, Courtney Harold; Oddone, Eugene Z.; Boles, Jillian] Duke Univ, Dept Med, Med Ctr, Div Gen Internal Med, Durham, NC 27710 USA. [Hastings, Susan N.] Duke Univ, Dept Med, Med Ctr, Div Geriatr, Durham, NC 27710 USA. [Hendrix, Cristina] Duke Univ, Med Ctr, Sch Nursing, Durham, NC 27710 USA. [Olsen, Maren; Neelon, Brian] Duke Univ, Med Ctr, Dept Biostat, Durham, NC 27710 USA. [Weinberger, Morris] Univ N Carolina, Dept Hlth Policy & Management, Gillings Sch Global Publ Hlth, Chapel Hill, NC 27599 USA. [Hastings, Susan N.] Geriatr Res Educ & Clin Ctr, Durham, NC 27705 USA. [Hastings, Susan N.; Hendrix, Cristina] Ctr Study Aging & Human Dev, Durham, NC 27710 USA. RP Van Houtven, CH (reprint author), Durham VA Med Ctr, Ctr Hlth Serv Res Primary Care, 508 Fulton St, Durham, NC 27705 USA. EM courtney.vanhoutven@duke.edu; eugene.oddone@dm.duke.edu; susan.hastings@dm.duke.edu; cristina.hendrix@dm.duke.edu; maren.olsen@dm.duke.edu; brian.neelon@duke.edu; jennifer.lindquist@va.gov; hollis.weidenbacher@va.gov; jillian.boles@dm.duke.edu; jennifer.chapman2@va.gov; mweinber@email.unc.edu FU U.S. Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research and Development Service [IIR 11-345]; U.S. Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Research Career Scientist Program [RCS 91-408] FX This project is supported by, the U.S. Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research and Development Service (IIR 11-345). Dr. Weinberger is supported by the the U.S. Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Research Career Scientist Program (RCS 91-408). We thank the members of the study's advisory board, for excellent input and expertise on the study: Peggy Becker, Thomas Edes, Margaret Kabat, Christy Knight, Jennifer Martindale-Adams, Linda Nichols, Kenneth Shay, Scott Trudeau, and Laura Wray. NR 34 TC 0 Z9 0 U1 2 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7144 EI 1559-2030 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD JUL PY 2014 VL 38 IS 2 BP 260 EP 269 DI 10.1016/j.cct.2014.05.003 PG 10 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA AN0VF UT WOS:000340301400013 PM 24837544 ER PT J AU Nelson, K Drain, N Robinson, J Kapp, J Hebert, P Taylor, L Silverman, J Kiefer, M Lessler, D Krieger, J AF Nelson, Karin Drain, Nathan Robinson, June Kapp, Janet Hebert, Paul Taylor, Leslie Silverman, Julie Kiefer, Meghan Lessler, Dan Krieger, James TI Peer Support for Achieving Independence in Diabetes (Peer-AID): Design, methods and baseline characteristics of a randomized controlled trial of community health worker assisted diabetes self-management support SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE Diabetes self-management; Community health workers ID AFRICAN-AMERICAN WOMEN; QUALITY-OF-LIFE; MEDICATION ADHERENCE; PREDICTIVE-VALIDITY; PHYSICAL-ACTIVITY; CARE UTILIZATION; GLYCEMIC CONTROL; LOW-INCOME; INTERVENTION; ADULTS AB Background & objectives: Community health workers (CHWs) may be an important mechanism to provide diabetes self-management to disadvantaged populations. We describe the design and baseline results of a trial evaluating a home-based CHW intervention. Methods & research design: Peer Support for Achieving Independence in Diabetes (Peer-AID) is a randomized, controlled trial evaluating a home-based CHW-delivered diabetes self-management intervention versus usual care. The study recruited participants from 3 health systems. Change in Al c measured at 12 months is the primary outcome. Changes in blood pressure, lipids, health care utilization, health-related quality of life, self-efficacy and diabetes self-management behaviors at 12 months are secondary outcomes. Results: A total of 1438 patients were identified by a medical record review as potentially eligible, 445 patients were screened by telephone for eligibility and 287 were randomized. Groups were comparable at baseline on socio-demographic and clinical characteristics. All participants were low-income and were from diverse racial and ethnic backgrounds. The mean Al c was 8.9%, mean BMI was above the obese range, and non-adherence to diabetes medications was high. The cohort had high rates of co-morbid disease and low self-reported health status. Although one-third reported no health insurance, the mean number of visits to a physician in the past year was 5.7. Trial results are pending. Conclusions: Peer-AID recruited and enrolled a diverse group of low income participants with poorly controlled type 2 diabetes and delivered a home-based diabetes self-management program. If effective, replication of the Peer-AID intervention in community based settings could contribute to improved control of diabetes in vulnerable populations. Published by Elsevier Inc. C1 [Nelson, Karin; Hebert, Paul; Taylor, Leslie; Silverman, Julie; Kiefer, Meghan] VA Puget Sound Healthcare Syst, Northwest HSR&D Ctr Excellence, Seattle, WA USA. [Nelson, Karin; Silverman, Julie; Kiefer, Meghan] VA Puget Sound Healthcare Syst, Gen Internal Med Serv, Seattle, WA USA. [Nelson, Karin; Hebert, Paul; Silverman, Julie; Kiefer, Meghan; Lessler, Dan; Krieger, James] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. [Nelson, Karin; Krieger, James] Univ Washington, Sch Publ Hlth, Seattle, WA 98195 USA. [Drain, Nathan; Robinson, June; Kapp, Janet; Krieger, James] Publ Hlth Seattle & King Cty, Seattle, WA USA. RP Nelson, K (reprint author), VA Puget Sound Healthcare Syst HSR&D, 1100 Olive Way,Suite 1400, Seattle, WA 98108 USA. EM Karin.Nelson@va.gov FU National Institutes of Health. National Institute of Diabetes and Digestive and Kidney Diseases [5R18DK088072]; Veterans Health Administration (VHA) Diabetes Quality Enhancement Research Initiative [QUERI QLP 92-007] FX National Institutes of Health. National Institute of Diabetes and Digestive and Kidney Diseases. Grant Number 5R18DK088072. Supplemental funding was provided by the Veterans Health Administration (VHA) Diabetes Quality Enhancement Research Initiative (QUERI QLP 92-007) to support Veteran recruitment efforts. NR 56 TC 6 Z9 6 U1 4 U2 14 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7144 EI 1559-2030 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD JUL PY 2014 VL 38 IS 2 BP 361 EP 369 DI 10.1016/j.cct.2014.06.011 PG 9 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA AN0VF UT WOS:000340301400026 PM 24956324 ER PT J AU Piccini, JP Garg, J Patel, MR Lokhnygina, Y Goodman, SG Becker, RC Berkowitz, SD Breithardt, G Hacke, W Halperin, JL Hankey, GJ Nessel, CC Mahaffey, KW Singer, DE Califf, RM Fox, KAA AF Piccini, Jonathan P. Garg, Jyotsna Patel, Manesh R. Lokhnygina, Yuliya Goodman, Shaun G. Becker, Richard C. Berkowitz, Scott D. Breithardt, Guenter Hacke, Werner Halperin, Jonathan L. Hankey, Graeme J. Nessel, Christopher C. Mahaffey, Kenneth W. Singer, Daniel E. Califf, Robert M. Fox, Keith A. A. CA ROCKET AF Investigators TI Management of major bleeding events in patients treated with rivaroxaban vs. warfarin: results from the ROCKET AF trial SO EUROPEAN HEART JOURNAL LA English DT Article DE Factor Xa inhibitor; Bleeding; Atrial fibrillation ID COAGULOPATHY; CONCENTRATE; DABIGATRAN; REVERSAL; PLACEBO AB Aims There are no data regarding management and outcomes of major bleeding events in patients treated with oral factor Xa inhibitors. Methods and results Using data from ROCKET AF, we analysed the management and outcomes of major bleeding overall and according to the randomized treatment. During a median follow-up of 1.9 years, 779 (5.5%) patients experienced major bleeding at a rate of 3.52 events/100 patient-years with a similar event rate in each arm (n = 395 rivaroxaban vs. n = 384 warfarin). The median number of transfused packed red blood cells (PRBC) per episode was similar in both arms [2 (25th, 75th: 2, 4) units]. Overall, few transfusions of whole blood (n = 14), platelets (n = 10), or cryoprecipitate (n = 2) were used. Transfusion of fresh frozen plasma (FFP) was significantly less in the rivaroxaban arm (n = 45 vs. n = 81 units) after adjustment for covariates [odds ratio (OR) 0.43 (95% CI 0.29-0.66); P < 0.0001]. Prothrombin complex concentrates (PCC) were administered less in the rivaroxaban arm (n = 4 vs. n = 9). Outcomes after major bleeding, including stroke or non-central nervous system embolism (4.7% rivaroxaban vs. 5.4% warfarin; HR 0.89; 95% CI 0.42-1.88) and all-cause death (20.4% rivaroxaban vs. 26.1% warfarin; HR 0.69, 95% CI 0.46-1.04) were similar in patients treated with rivaroxaban and warfarin (interaction P = 0.51 and 0.11). Conclusion Among high-risk patients with atrial fibrillation who experienced major bleeding in ROCKET AF, the use of FFP and PCC was less among those allocated rivaroxaban compared with warfarin. However, use of PRBCs and outcomes after bleeding were similar among patients randomized to rivaroxaban or to warfarin. C1 [Piccini, Jonathan P.; Garg, Jyotsna; Patel, Manesh R.; Lokhnygina, Yuliya] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC 27710 USA. [Goodman, Shaun G.] Univ Toronto, St Michaels Hosp, Canadian Heart Res Ctr, Toronto, ON, Canada. [Goodman, Shaun G.] Univ Toronto, St Michaels Hosp, Div Cardiol, Terrence Donnelly Heart Ctr, Toronto, ON, Canada. [Becker, Richard C.] Univ Cincinnati, Div Cardiovasc Hlth & Dis, Cincinnati, OH USA. [Berkowitz, Scott D.] Bayer HealthCare Pharmaceut, Montville, NJ USA. [Breithardt, Guenter] Hosp Univ Munster, Munster, Germany. [Hacke, Werner] Heidelberg Univ, Heidelberg, Germany. [Halperin, Jonathan L.] Mt Sinai Med Ctr, Cardiovasc Inst, New York, NY 10029 USA. [Hankey, Graeme J.] Univ Western Australia, Sch Med & Pharmacol, Crawley, WA 6009, Australia. [Nessel, Christopher C.] Janssen Res & Dev, Raritan, NJ USA. [Mahaffey, Kenneth W.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Singer, Daniel E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Singer, Daniel E.] Harvard Univ, Sch Med, Boston, MA USA. [Califf, Robert M.] Duke Univ, Med Ctr, Duke Translat Med Inst, Durham, NC 27710 USA. [Fox, Keith A. A.] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Fox, Keith A. A.] Royal Infirm Edinburgh NHS Trust, Edinburgh, Midlothian, Scotland. RP Piccini, JP (reprint author), Duke Univ, Med Ctr, Duke Clin Res Inst, POB 17969, Durham, NC 27710 USA. EM jonathan.piccini@duke.edu RI Hankey, Graeme /H-4968-2014 OI Hankey, Graeme /0000-0002-6044-7328 FU Johnson Johnson; Bayer HealthCare FX This work was supported by Johnson & Johnson and Bayer HealthCare. NR 11 TC 39 Z9 40 U1 2 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X EI 1522-9645 J9 EUR HEART J JI Eur. Heart J. PD JUL PY 2014 VL 35 IS 28 BP 1873 EP 1880 DI 10.1093/eurheartj/ehu083 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AM7SI UT WOS:000340068200012 PM 24658769 ER PT J AU Garakani, A Shalenberg, E Burstin, SC Brendel, RW Appel, JM AF Garakani, Amir Shalenberg, Eli Burstin, Samantha C. Brendel, Rebecca Weintraub Appel, Jacob M. TI Voluntary Psychiatric Hospitalization and Patient-Driven Requests for Discharge: A Statutory Review and Analysis of Implications for the Capacity to Consent to Voluntary Hospitalization SO HARVARD REVIEW OF PSYCHIATRY LA English DT Article DE against medical advice (AMA); capacity; involuntary admission; leave; 72-hour letter; sign-out letter; voluntary admission ID CIVIL COMMITMENT; ADMISSION; COMPETENCE; COERCION AB Along with the advances in civil rights protections for psychiatric patients since the 1970s, so-called voluntary inpatient psychiatric admissions have become common. In most U. S. states, however, these voluntary admissions abridge the rights of patients through legal provisions that limit the conditions under which patients can be discharged upon their request. This phenomenon, including variations in the state laws governing requests for discharge from voluntary psychiatric hospitalization, has received little attention in the psychiatry literature. Using Lexis-Nexis, PubMed, and Web of Science, we conducted a review of state laws regarding patients' legal rights to request discharge from voluntary hospitalization. Our hypothesis was that most states would have provisions limiting access to immediate discharge for patients whose psychiatric admission had been voluntary. Our findings from the review indicate that 49 of the 51 jurisdictions (50 states plus the District of Columbia) have provisions about patients requesting discharge from voluntary psychiatric admission. The majority of states employ a 72-hour period in which patients can be held following a request for discharge from hospitalization. As a general rule, after this evaluation period, either the patient must be discharged, or the facility must initiate involuntary commitment proceedings. Given these provisions, we explore the range of clinical admission procedures and whether voluntary admissions are truly voluntary. We also discuss the implications of our analysis for assessing the decisional capacity of patients seeking voluntary psychiatric admission. C1 [Garakani, Amir] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06520 USA. [Garakani, Amir; Appel, Jacob M.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Brendel, Rebecca Weintraub] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Garakani, Amir] Silver Hill Hosp, New Canaan, CT 06840 USA. [Shalenberg, Eli] Visiting Nurse Serv New York, New York, NY USA. [Burstin, Samantha C.] Split Rock Rehabil & Hlth Care Ctr, Bronx, NY USA. [Brendel, Rebecca Weintraub] Massachusetts Gen Hosp, Ctr Law Brain & Behav, Boston, MA 02114 USA. RP Garakani, A (reprint author), Silver Hill Hosp, 208 Valley Rd, New Canaan, CT 06840 USA. EM amir.garakani@mssm.edu NR 20 TC 0 Z9 0 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1067-3229 EI 1465-7309 J9 HARVARD REV PSYCHIAT JI Harv. Rev. Psychiatr. PD JUL-AUG PY 2014 VL 22 IS 4 BP 241 EP 249 DI 10.1097/HRP.0000000000000044 PG 9 WC Psychiatry SC Psychiatry GA AM9HL UT WOS:000340191700005 PM 24983871 ER PT J AU Snyder, ML Darragh, A Flood, JG Jones, J Ropar, K Jarolim, P Melanson, SEF AF Snyder, Marion L. Darragh, Alicia Flood, James G. Jones, Jenny Ropar, Kaitlin Jarolim, Petr Melanson, Stacy E. F. TI Improved Buprenorphine Immunoassay Performance After Urine Treatment with beta-Glucuronidase SO JOURNAL OF ANALYTICAL TOXICOLOGY LA English DT Article ID MASS-SPECTROMETRY; ASSAY AB Buprenorphine (BUP), a semi-synthetic opioid analgesic, is increasingly prescribed for the treatment of chronic pain and opioid dependence. Urine immunoassay screening methods are available for monitoring BUP compliance and misuse; however, these screens may have poor sensitivity or specificity. We evaluated whether the pretreatment of urine with beta-glucuronidase (BG) improves the sensitivity and overall accuracy of three BUP enzyme immunoassays when compared with liquid chromatography-tandem mass spectrometry (LC-MS-MS). Urine samples sent to our laboratories for BUP testing (n = 114) were analyzed before and after BG pretreatment by cloned enzyme donor immunoassay (CEDIA), enzyme immunoassay (EIA) and homogenous EIA (HEIA) immunoassays using a common 5 ng/mL cutoff. Total BUP and norbuprenorphine (NBUP) concentrations were measured by LC-MS-MS as the reference method. Urine BG pretreatment improved EIA, HEIA and CEDIA sensitivities from 70, 82 and 94%, respectively, to 97% for each of the three methods, when compared with LC-MS-MS. While the specificity of the EIA and HEIA remained 100% after BG pretreatment, the specificity of the CEDIA decreased from 74 to 67%. Urine pretreatment with BG is recommended to improve sensitivity of the EIA and HEIA BUP screening methods. C1 [Snyder, Marion L.; Darragh, Alicia; Jones, Jenny] LabSource, Greenville, SC 29607 USA. [Flood, James G.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02114 USA. [Ropar, Kaitlin; Jarolim, Petr; Melanson, Stacy E. F.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol,Clin Labs Div, Boston, MA 02115 USA. RP Melanson, SEF (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol,Clin Labs Div, 75 Francis St,Amory 2, Boston, MA 02115 USA. EM semelanson@partners.org NR 13 TC 0 Z9 0 U1 1 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0146-4760 EI 1945-2403 J9 J ANAL TOXICOL JI J. Anal. Toxicol. PD JUL-AUG PY 2014 VL 38 IS 6 BP 375 EP 379 DI 10.1093/jat/bku045 PG 5 WC Chemistry, Analytical; Toxicology SC Chemistry; Toxicology GA AM7SP UT WOS:000340069000011 PM 24802159 ER PT J AU Yu, EW AF Yu, Elaine W. TI Bone Metabolism After Bariatric Surgery SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Review DE BARIATRIC SURGERY; DXA; BIOCHEMICAL MARKERS OF BONE TURNOVER; OBESITY ID Y GASTRIC BYPASS; X-RAY ABSORPTIOMETRY; VERTICAL-BANDED GASTROPLASTY; POPULATION-BASED COHORT; MORBIDLY OBESE WOMEN; VITAMIN-D DEFICIENCY; BODY-MASS INDEX; MINERAL DENSITY; WEIGHT-LOSS; SLEEVE GASTRECTOMY AB Bariatric surgery is a popular and effective treatment for severe obesity but may have negative effects on the skeleton. This review summarizes changes in bone density and bone metabolism from animal and clinical studies of bariatric surgery, with specific attention to Roux-en-Y gastric bypass (RYGB), adjustable gastric banding (AGB), and sleeve gastrectomy (SG). Skeletal imaging artifacts from obesity and weight loss are also considered. Despite challenges in bone density imaging, the preponderance of evidence suggests that bariatric surgery procedures have negative skeletal effects that persist beyond the first year of surgery, and that these effects vary by surgical type. The long-term clinical implications and current clinical recommendations are presented. Further study is required to determine mechanisms of bone loss after bariatric surgery. Although early studies focused on calcium/vitamin D metabolism and mechanical unloading of the skeleton, it seems likely that surgically induced changes in the hormonal and metabolic profile may be responsible for the skeletal phenotypes observed after bariatric surgery. (C) 2014 American Society for Bone and Mineral Research. C1 Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. RP Yu, EW (reprint author), Massachusetts Gen Hosp, Endocrine Unit, 50 Blossom St,Thier 1051, Boston, MA 02114 USA. EM ewyu@mgh.harvard.edu FU NIH [K23 DK093713] FX This work was supported by NIH grant K23 DK093713 (EWY). NR 136 TC 21 Z9 21 U1 1 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0884-0431 EI 1523-4681 J9 J BONE MINER RES JI J. Bone Miner. Res. PD JUL PY 2014 VL 29 IS 7 BP 1507 EP 1518 DI 10.1002/jbmr.2226 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AN0AO UT WOS:000340243600001 PM 24677277 ER PT J AU Boronat, S Shaaya, EA Auladell, M Thiele, EA Caruso, P AF Boronat, Susana Shaaya, Elias A. Auladell, Maria Thiele, Elizabeth A. Caruso, Paul TI Intracranial Arteriopathy in Tuberous Sclerosis Complex SO JOURNAL OF CHILD NEUROLOGY LA English DT Article DE arteriopathy; intracranial aneurysms; neural crest; tuberous sclerosis complex; vascular ID POLYCYSTIC KIDNEY-DISEASE; CAROTID-ARTERY ANEURYSM; NEURAL CREST; PATIENT; GENE; HAMARTOMAS; INFANT; CHILD AB Arterial aneurysms, mostly aortic and intracranial, have been occasionally reported in patients with tuberous sclerosis complex. Brain magnetic resonance imaging reports of 404 patients with definite and 16 patients with either probable or possible tuberous sclerosis complex were revised for intracranial aneurysms. Among these patients, brain images of 220 patients with definite and 16 with probable or possible tuberous sclerosis complex were reviewed. Intracranial aneurysms were reported in 3 of 404 patients with a definite diagnosis (0.74%) (general population: 0.35%), including 2 children. A fourth intracranial aneurysm was found in a patient with probable tuberous sclerosis complex, who did not have tubers or subependymal nodules but had clinical manifestations related to neural crest derivatives, including lymphangioleiomyomatosis and extrarenal angiomyolipomas. The authors hypothesize that neural crest dysfunction can have a major role in intracranial arteriopathy in tuberous sclerosis complex, as smooth muscle cells in the forebrain vessels are of neural crest origin. C1 [Boronat, Susana; Shaaya, Elias A.; Auladell, Maria; Thiele, Elizabeth A.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Boronat, Susana] Univ Autonoma Barcelona, Vall dHebron Hosp, Dept Pediat Neurol, E-08193 Barcelona, Spain. [Caruso, Paul] Massachusetts Gen Hosp, Dept Neuroradiol, Boston, MA 02114 USA. RP Thiele, EA (reprint author), Massachusetts Gen Hosp, Pediat Epilepsy Program, 175 Cambridge St,Suite 340, Boston, MA 02114 USA. EM ethiele@partners.org FU Herscot Center for Tuberous Sclerosis Complex; National Institutes of Health/National Institute of Neurological Disorders and Stroke [P01 NS024279]; Beca de Ampliacion de Estudios grant from the Carlos III Institute (Spain) FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Herscot Center for Tuberous Sclerosis Complex and the National Institutes of Health/National Institute of Neurological Disorders and Stroke (P01 NS024279). SB is supported by a Beca de Ampliacion de Estudios grant from the Carlos III Institute (Spain). NR 50 TC 2 Z9 3 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0883-0738 EI 1708-8283 J9 J CHILD NEUROL JI J. Child Neurol. PD JUL PY 2014 VL 29 IS 7 BP 912 EP 919 DI 10.1177/0883073813492386 PG 8 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA AM8ZY UT WOS:000340170000005 PM 24056157 ER PT J AU Carbonell, CF Benson, L Rintell, D Prince, J Chitnis, T AF Carbonell, Cristina Fernandez Benson, Leslie Rintell, David Prince, Jefferson Chitnis, Tanuja TI Functional Relapses in Pediatric Multiple Sclerosis SO JOURNAL OF CHILD NEUROLOGY LA English DT Article DE Pediatric multiple sclerosis; functional relapses; children and adolescents ID CHRONIC PHYSICAL ILLNESS; PSYCHOGENIC NONEPILEPTIC SEIZURES; CONVERSION DISORDER; ADOLESCENTS; CHILDREN; METAANALYSIS; SYMPTOMS; ONSET; EXACERBATION; ASSOCIATION AB Multiple sclerosis in children is characterized by more frequent relapses than in adult patients. Diagnosing and treating youth with multiple sclerosis present a number of challenges including differentiating organic relapses from functional symptoms. However, there is no literature describing coexistence of functionality in pediatric multiple sclerosis. Here, we report 2 cases in which inconsistency between clinical history, physical examination, imaging, and atypical disease progression led to suspicion of functional relapses. The purpose of this study is to raise awareness of functional relapses, as prompt recognition can prevent overtreatment and iatrogenic risks in children and adolescents with multiple sclerosis. Underlying psychiatric issues also need to be addressed. C1 [Carbonell, Cristina Fernandez; Benson, Leslie; Rintell, David; Chitnis, Tanuja] Massachusetts Gen Hosp, Dept Child Neurol, Partners Pediat Multiple Sclerosis Ctr, Boston, MA 02114 USA. [Rintell, David; Prince, Jefferson] Massachusetts Gen Hosp, Dept Child Psychiat, Boston, MA 02114 USA. RP Chitnis, T (reprint author), Massachusetts Gen Hosp, Dept Child Neurol, Partners Pediat Multiple Sclerosis Ctr, Boston, MA 02114 USA. EM tchitnis@partners.org FU National MS Society (Regional Pediatric MS Centers of Excellence Award) FX The Partners Pediatric Multiple Sclerosis Center at the Massachusetts General Hospital is supported by the National MS Society (Regional Pediatric MS Centers of Excellence Award). NR 35 TC 1 Z9 1 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0883-0738 EI 1708-8283 J9 J CHILD NEUROL JI J. Child Neurol. PD JUL PY 2014 VL 29 IS 7 BP 943 EP 946 DI 10.1177/0883073813501873 PG 4 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA AM8ZY UT WOS:000340170000010 ER PT J AU Dishion, TJ Kim, H Stormshak, EA O'Neill, M AF Dishion, Thomas J. Kim, Hanjoe Stormshak, Elizabeth A. O'Neill, Maya TI A Brief Measure of Peer Affiliation and Social Acceptance (PASA): Validity in an Ethnically Diverse Sample of Early Adolescents SO JOURNAL OF CLINICAL CHILD AND ADOLESCENT PSYCHOLOGY LA English DT Article ID CONFIRMATORY FACTOR-ANALYSES; MULTITRAIT-MULTIMETHOD DATA; FAMILY CHECK-UP; PROBLEM BEHAVIOR; ANTECEDENTS; CHILDHOOD; CHILDREN; SCHOOL; TESTS; BOYS AB The purpose of this study was to conduct a multiagent-multimethod analysis of the validity of a brief measure of deviant peer affiliations and social acceptance (PASA) in young adolescents. Peer relationships are critical to child and adolescent social and emotional development, but currently available measures are tedious and time consuming. The PASA consists of a youth, parent, and teacher report that can be collected longitudinally to study development and intervention effectiveness. This longitudinal study included 998 middle school students and their families. We collected the PASA and peer sociometrics data in Grade 7 and a multiagent-multimethod construct of deviant peer clustering in Grade 8. Confirmatory factor analyses of the multiagent-multimethod data revealed that the constructs of deviant peer affiliations and social acceptance and rejection were distinguishable as unique but correlated constructs within the PASA. Convergent, discriminant, concurrent, and predictive validity of the PASA was satisfactory, although the acceptance and rejection constructs were highly correlated and showed similar patterns of concurrent validity. Factor invariance was established for mother reports and for father reports. Results suggest that the PASA is a valid and reliable measure of peer affiliation and of social acceptance among peers during the middle school years and provides a comprehensive yet brief assessment of peer affiliations and social acceptance. C1 [Dishion, Thomas J.; Kim, Hanjoe] Arizona State Univ, Dept Psychol, Tempe, AZ 85287 USA. [Dishion, Thomas J.; Stormshak, Elizabeth A.; O'Neill, Maya] Univ Oregon, Child & Family Ctr, Eugene, OR 97403 USA. [O'Neill, Maya] Portland VA Med Ctr, Portland, OR USA. RP Dishion, TJ (reprint author), Arizona State Univ, Dept Psychol, Tempe, AZ 85287 USA. EM dishion@asu.edu FU NIDA NIH HHS [DA07031, DA016110, R01 DA007031, R01 DA016110, R37 DA007031]; NIMH NIH HHS [T32 MH020012, T32MH20012] NR 55 TC 5 Z9 5 U1 19 U2 33 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1537-4416 EI 1537-4424 J9 J CLIN CHILD ADOLESC JI J. Clin. Child Adolesc. Psychol. PD JUL-AUG PY 2014 VL 43 IS 4 BP 601 EP 612 DI 10.1080/15374416.2013.876641 PG 12 WC Psychology, Clinical; Psychology, Developmental SC Psychology GA AM8JM UT WOS:000340120200006 PM 24611623 ER PT J AU Pedersen, ER Myers, US Browne, KC Norman, SB AF Pedersen, Eric R. Myers, Ursula S. Browne, Kendall C. Norman, Sonya B. TI The Role of Alcohol Expectancies in Drinking Behavior among Women with Alcohol Use Disorder and Comorbid Posttraumatic Stress Disorder SO JOURNAL OF PSYCHOACTIVE DRUGS LA English DT Article DE alcohol; expectancies; intimate partner violence; PTSD ID ADDICTION SEVERITY INDEX; SUBSTANCE USE DISORDERS; COLLEGE-STUDENTS; PARTNER VIOLENCE; PTSD CHECKLIST; TRAUMA; SYMPTOMS; QUESTIONNAIRE; ASSOCIATIONS; CHALLENGE AB Understanding how alcohol expectancies relate to alcohol use among individuals with concurrent alcohol use disorder (AUD) and Posttraumatic Stress Disorder (PTSD) is important to understanding and treating this comorbidity. This study examined the role of positive and negative alcohol expectancies and PTSD symptoms in drinking behavior in a comorbid female sample. Participants were women (n = 33; 56% Caucasian) seeking AUD and PTSD treatment in an outpatient community co-occurring disorders program. Hypotheses related to drinking days and alcohol problems outcomes were evaluated using negative binomial hierarchical regression. PTSD symptoms were associated with fewer reported days of alcohol-related problems. Negative expectancies related to negative changes in social behavior associated with drinking days and cognitive and motor impairment associated with problems. Both the general positive expectancies score and specific global positive change subscale were uniquely associated with drinking and alcohol-related problems days after controlling for PTSD symptom severity and negative expectancies scores. Results suggest that both negative and positive expectancies about alcohol's effects are important correlates of drinking behavior among women with AUD and PTSD, with positive expectancies playing a potentially more salient role on use and consequences than symptom severity and negative expectancies. C1 [Pedersen, Eric R.] RAND Corp, Santa Monica, CA USA. [Myers, Ursula S.] SDSU UCSD Joint Doctoral Program Clin Psychol, San Diego, CA USA. [Browne, Kendall C.] VA Puget Sound Hlth Care Syst, Mental Illness Res Educ & Clin Ctr, Seattle, WA USA. [Browne, Kendall C.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Norman, Sonya B.] Natl Ctr PTSD, PTSD Consultat Program, White River Jct, VT USA. [Norman, Sonya B.] VA Ctr Excellence Stress & Mental Hlth, San Diego, CA USA. [Norman, Sonya B.] UCSD Sch Med, San Diego, CA USA. RP Norman, SB (reprint author), VA San Diego Healthcare Syst, 3350 La Jolla Village Dr,MC116B, La Jolla, CA 92161 USA. EM snorman@ucsd.edu FU NIAAA NIH HHS [K23 AA015707] NR 53 TC 2 Z9 2 U1 3 U2 12 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0279-1072 EI 2159-9777 J9 J PSYCHOACTIVE DRUGS JI J. Psychoact. Drugs PD JUL-AUG PY 2014 VL 46 IS 3 BP 178 EP 187 DI 10.1080/02791072.2014.917750 PG 10 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA AM8JW UT WOS:000340121400002 PM 25052876 ER PT J AU Leentjens, AFG Dujardin, K Pontone, GM Starkstein, SE Weintraub, D Martinez-Martin, P AF Leentjens, Albert F. G. Dujardin, Kathy Pontone, Gregory M. Starkstein, Sergio E. Weintraub, Daniel Martinez-Martin, Pablo TI The Parkinson Anxiety Scale (PAS): Development and Validation of a New Anxiety Scale SO MOVEMENT DISORDERS LA English DT Article DE Parkinson's disease; anxiety; rating scale; depression; 'non-motor' symptoms ID HEALTH-STATUS; RATING-SCALES; DISEASE; DEPRESSION; QUALITY; CRITERIA; RELIABILITY; PREVALENCE; DISORDERS; INVENTORY AB Existing anxiety rating scales have limited construct validity in patients with Parkinson's disease (PD). This study was undertaken to develop and validate a new anxiety rating scale, the Parkinson Anxiety Scale (PAS), that would overcome the limitations of existing scales. The general structure of the PAS was based on the outcome of a Delphi procedure. Item selection was based on a canonical correlation analysis and a Rasch analysis of items of the Hamilton Anxiety Rating Scale (HARS) and the Beck Anxiety Inventory (BAI) from a previously published study. Validation was done in a cross-sectional international multicenter study involving 362 patients with idiopathic PD. Patients underwent a single screening session in which the PAS was administered, along with the Hamilton Depression Rating Scale, the HARS, and the BAI. The Mini International Neuropsychiatric Interview was administered to establish Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnoses of anxiety and depressive disorders. The PAS is a 12-item observer or patient-rated scale with three subscales, for persistent, episodic anxiety and avoidance behavior. Properties for acceptability and reliability met predetermined criteria. The convergent and known groups validity was good. The scale has a satisfactory factorial structure. The area under the receiver operating characteristics curve and Youden index of the PAS are higher than that of existing anxiety rating scales. The PAS is a reliable and valid anxiety measure for use in PD patients. It is easy and brief to administer, and has better clinimetric properties than existing anxiety rating scales. The sensitivity to change of the PAS remains to be assessed. (C) 2014 International Parkinson and Movement Disorder Society C1 [Leentjens, Albert F. G.] Maastricht Univ, Med Ctr, Dept Psychiat, NL-6202 AZ Maastricht, Netherlands. [Dujardin, Kathy] Univ Lille, Neurol & Movement Disorders Unit, Med Ctr, Lille, France. [Pontone, Gregory M.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Starkstein, Sergio E.] Univ Western Australia, Sch Psychiat, Fremantle, WA, Australia. [Starkstein, Sergio E.] Fremantle Hosp, Fremantle, WA, Australia. [Weintraub, Daniel] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Weintraub, Daniel] Univ Penn, Dept Neurol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Weintraub, Daniel] Philadelphia Vet Affairs Med Ctr, Parkinsons Dis Res Educ & Clin Ctr, Philadelphia, PA USA. [Martinez-Martin, Pablo] Alzheimer Ctr Reina Sofia Fdn, Alzheimer Dis Res Unit, Madrid, Spain. [Martinez-Martin, Pablo] Alzheimer Ctr Reina Sofia Fdn, CIBERNED, CIEN Fdn, Carlos Inst Hlth 3, Madrid, Spain. RP Leentjens, AFG (reprint author), Maastricht Univ, Med Ctr, Dept Psychiat, POB 5800, NL-6202 AZ Maastricht, Netherlands. EM a.leentjens@np.unimaas.nl FU Michael J. Fox Foundation; Stichting International Parkinson Fonds; France Parkinson; NIH; National Institute on Aging; Acadia Pharmaceuticals; National Health Medical and Research Centre (Australia); Novartis Pharmaceuticals; Department of Veterans Affairs; Alzheimer's Disease Cooperative Study; Parkinson UK; Spanish Official Agency FIS; Spanish Official Agency IMSERSO FX A.F.G.L. has received research grants from the Michael J. Fox Foundation and the Stichting International Parkinson Fonds. K.D. received research support from the Michael J. Fox Foundation and from France Parkinson. G.P. is funded by grants from the NIH and National Institute on Aging, Acadia Pharmaceuticals, and the Michael J. Fox Foundation. S.E.S. is funded by grants from the National Health Medical and Research Centre (Australia) and the Michael J. Fox Foundation. D.W. has received funding from the Michael J. Fox Foundation, NIH, Novartis Pharmaceuticals, Department of Veterans Affairs, and Alzheimer's Disease Cooperative Study. P.M.-M. received grants from the Michael J. Fox Foundation, Parkinson UK, and the Spanish Official Agencies FIS and IMSERSO. NR 33 TC 17 Z9 17 U1 4 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 EI 1531-8257 J9 MOVEMENT DISORD JI Mov. Disord. PD JUL PY 2014 VL 29 IS 8 BP 1035 EP 1043 DI 10.1002/mds.25919 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA AM8AA UT WOS:000340089300013 PM 24862344 ER PT J AU Lim, ET Wurtz, P Havulinna, AS Palta, P Tukiainen, T Rehnstrom, K Esko, T Magi, R Inouye, M Lappalainen, T Chan, YL Salem, RM Lek, M Flannick, J Sim, X Manning, A Ladenvall, C Bumpstead, S Hamalainen, E Aalto, K Maksimow, M Salmi, M Blankenberg, S Ardissino, D Shah, S Horne, B McPherson, R Hovingh, GK Reilly, MP Watkins, H Goel, A Farrall, M Girelli, D Reiner, AP Stitziel, NO Kathiresan, S Gabriel, S Barrett, JC Lehtimaki, T Laakso, M Groop, L Kaprio, J Perola, M McCarthy, MI Boehnke, M Altshuler, DM Lindgren, CM Hirschhorn, JN Metspalu, A Freimer, NB Zeller, T Jalkanen, S Koskinen, S Raitakari, O Durbin, R MacArthur, DG Salomaa, V Ripatti, S Daly, MJ Palotie, A AF Lim, Elaine T. Wuertz, Peter Havulinna, Aki S. Palta, Priit Tukiainen, Taru Rehnstrom, Karola Esko, Tonu Magi, Reedik Inouye, Michael Lappalainen, Tuuli Chan, Yingleong Salem, Rany M. Lek, Monkol Flannick, Jason Sim, Xueling Manning, Alisa Ladenvall, Claes Bumpstead, Suzannah Hamalainen, Eija Aalto, Kristiina Maksimow, Mikael Salmi, Marko Blankenberg, Stefan Ardissino, Diego Shah, Svati Horne, Benjamin McPherson, Ruth Hovingh, Gerald K. Reilly, Muredach P. Watkins, Hugh Goel, Anuj Farrall, Martin Girelli, Domenico Reiner, Alex P. Stitziel, Nathan O. Kathiresan, Sekar Gabriel, Stacey Barrett, Jeffrey C. Lehtimaki, Terho Laakso, Markku Groop, Leif Kaprio, Jaakko Perola, Markus McCarthy, Mark I. Boehnke, Michael Altshuler, David M. Lindgren, Cecilia M. Hirschhorn, Joel N. Metspalu, Andres Freimer, Nelson B. Zeller, Tanja Jalkanen, Sirpa Koskinen, Seppo Raitakari, Olli Durbin, Richard MacArthur, Daniel G. Salomaa, Veikko Ripatti, Samuli Daly, Mark J. Palotie, Aarno CA Sequencing Initiative Suomi TI Distribution and Medical Impact of Loss-of-Function Variants in the Finnish Founder Population SO PLOS GENETICS LA English DT Article ID COMPLEMENTATION GROUP-M; ELONGATION-FACTOR EFTS; CARDIOVASCULAR RISK; MUTATION; DISEASE; GENE; ASSOCIATION; FINLAND; PROFILE; COHORT AB Exome sequencing studies in complex diseases are challenged by the allelic heterogeneity, large number and modest effect sizes of associated variants on disease risk and the presence of large numbers of neutral variants, even in phenotypically relevant genes. Isolated populations with recent bottlenecks offer advantages for studying rare variants in complex diseases as they have deleterious variants that are present at higher frequencies as well as a substantial reduction in rare neutral variation. To explore the potential of the Finnish founder population for studying low-frequency (0.5-5%) variants in complex diseases, we compared exome sequence data on 3,000 Finns to the same number of non-Finnish Europeans and discovered that, despite having fewer variable sites overall, the average Finn has more low-frequency loss-of-function variants and complete gene knockouts. We then used several well-characterized Finnish population cohorts to study the phenotypic effects of 83 enriched loss-of-function variants across 60 phenotypes in 36,262 Finns. Using a deep set of quantitative traits collected on these cohorts, we show 5 associations (p < 5 x 10(-8)) including splice variants in LPA that lowered plasma lipoprotein(a) levels (P = 1.5 x 10(-117)). Through accessing the national medical records of these participants, we evaluate the LPA finding via Mendelian randomization and confirm that these splice variants confer protection from cardiovascular disease (OR = 0.84, P = 3 x 10(-4)), demonstrating for the first time the correlation between very low levels of LPA in humans with potential therapeutic implications for cardiovascular diseases. More generally, this study articulates substantial advantages for studying the role of rare variation in complex phenotypes in founder populations like the Finns and by combining a unique population genetic history with data from large population cohorts and centralized research access to National Health Registers. C1 [Lim, Elaine T.; Tukiainen, Taru; Lek, Monkol; Lindgren, Cecilia M.; MacArthur, Daniel G.; Daly, Mark J.; Palotie, Aarno] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Lim, Elaine T.; Tukiainen, Taru; Esko, Tonu; Chan, Yingleong; Salem, Rany M.; Lek, Monkol; Flannick, Jason; Manning, Alisa; Gabriel, Stacey; Altshuler, David M.; Lindgren, Cecilia M.; Hirschhorn, Joel N.; MacArthur, Daniel G.; Daly, Mark J.; Palotie, Aarno] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Lim, Elaine T.; Tukiainen, Taru; Esko, Tonu; Lek, Monkol; Flannick, Jason; Altshuler, David M.; MacArthur, Daniel G.; Daly, Mark J.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Lim, Elaine T.; Chan, Yingleong] Harvard Univ, Sch Med, Program Biol & Biomed Sci, Boston, MA USA. [Wuertz, Peter; Palta, Priit; Ladenvall, Claes; Groop, Leif; Kaprio, Jaakko; Perola, Markus; Ripatti, Samuli; Palotie, Aarno] Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland. [Wuertz, Peter; Havulinna, Aki S.; Salomaa, Veikko; Ripatti, Samuli] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Wuertz, Peter] Univ Oulu, Inst Hlth Sci, Oulu, Finland. [Palta, Priit; Rehnstrom, Karola; Bumpstead, Suzannah; Barrett, Jeffrey C.; Durbin, Richard; Ripatti, Samuli] Wellcome Trust Sanger Inst, Cambridge, England. [Esko, Tonu; Magi, Reedik; Metspalu, Andres] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia. [Esko, Tonu; Chan, Yingleong; Salem, Rany M.; Hirschhorn, Joel N.] Childrens Hosp Boston, Div Endocrinol, Boston, MA USA. [Esko, Tonu; Chan, Yingleong; Salem, Rany M.; Hirschhorn, Joel N.] Childrens Hosp Boston, Div Genet, Boston, MA USA. [Esko, Tonu; Chan, Yingleong; Salem, Rany M.; Hirschhorn, Joel N.] Childrens Hosp Boston, Ctr Basic & Translat Obes Res, Boston, MA USA. [Inouye, Michael] Univ Melbourne, Dept Pathol, Parkville, Vic 3052, Australia. [Inouye, Michael] Univ Melbourne, Dept Microbiol & Immunol, Parkville, Vic 3052, Australia. [Lappalainen, Tuuli] Stanford Univ, Dept Genet, Stanford, CA 94305 USA. [Lappalainen, Tuuli] Stanford Ctr Computat Evolutionary & Human Gen, Stanford, CA USA. [Sim, Xueling; Boehnke, Michael] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Sim, Xueling; Boehnke, Michael] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Ladenvall, Claes; Groop, Leif] Lund Univ, Skane Univ Hosp, Dept Clin Sci Diabet & Endocrinol, Ctr Diabet, Malmo, Sweden. [Aalto, Kristiina; Maksimow, Mikael] Univ Turku, MediCity, Turku, Finland. [Salmi, Marko; Jalkanen, Sirpa] Univ Turku, Dept Med Microbiol & Immunol, Turku, Finland. [Salmi, Marko; Jalkanen, Sirpa] Natl Inst Hlth & Welf, Turku, Finland. [Blankenberg, Stefan; Zeller, Tanja] Univ Heart Ctr Hamburg, Clin Gen & Intervent Cardiol, Hamburg, Germany. [Blankenberg, Stefan; Zeller, Tanja] DZHK German Ctr Cardiovasc Res, Hamburg, Germany. [Ardissino, Diego] Azienda Osped Univ Parma, Div Cardiol, Parma, Italy. [Shah, Svati] Duke Univ Med Ctr, Dept Med, Durham, NC USA. [Horne, Benjamin] Intermt Med Ctr, Intermt Heart Inst, Salt Lake City, UT USA. [McPherson, Ruth] Univ Ottawa, Inst Heart, Div Cardiol, Ottawa, ON, Canada. [Hovingh, Gerald K.] Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, NL-1105 AZ Amsterdam, Netherlands. [Reilly, Muredach P.] Univ Penn, Cardiovasc Inst, Perelman Sch Med, Philadelphia, PA 19104 USA. [Watkins, Hugh; Goel, Anuj; Farrall, Martin] Univ Oxford, Div Cardiovasc Med, Radcliffe Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England. [Girelli, Domenico] Univ Verona, Sch Med, Dept Med, I-37100 Verona, Italy. [Reiner, Alex P.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Stitziel, Nathan O.] Washington Univ, Sch Med, Dept Med, Cardiovasc Div, St Louis, MO 63110 USA. [Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Lehtimaki, Terho] Univ Tampere, Sch Med, Dept Clin Chem, Fimlab Labs, FIN-33101 Tampere, Finland. [Kaprio, Jaakko; Ripatti, Samuli] Univ Helsinki, Hjelt Inst, Dept Publ Hlth, Helsinki, Finland. [Kaprio, Jaakko] Natl Inst Hlth & Welf, Dept Mental Hlth & Subst Abuse Serv, Helsinki, Finland. [McCarthy, Mark I.] Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England. [McCarthy, Mark I.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [McCarthy, Mark I.] Churchill Hosp, Oxford NIHR Biomed Res Ctr, Oxford OX3 7LJ, England. [Lindgren, Cecilia M.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Freimer, Nelson B.] Univ Calif Los Angeles, Ctr Neurobehav Genet, Semel Inst Neurosci & Human Behav, Los Angeles, CA USA. [Koskinen, Seppo] Natl Inst Hlth & Welf, Dept Hlth Funct Capac & Welf, Helsinki, Finland. [Raitakari, Olli] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland. [Raitakari, Olli] Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku, Finland. [Ripatti, Samuli] Univ Helsinki, Hjelt Inst, Dept Biometry, Helsinki, Finland. [Palotie, Aarno] Massachusetts Gen Hosp, Dept Psychiat, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. RP Lim, ET (reprint author), Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA. EM mjdaly@atgu.mgh.harvard.edu; aarno@broadinstitute.org RI Ripatti, Samuli/H-9446-2014; OI Watkins, Hugh/0000-0002-5287-9016; Ripatti, Samuli/0000-0002-0504-1202; Wurtz, Peter/0000-0002-5832-0221; Durbin, Richard/0000-0002-9130-1006; Palta, Priit/0000-0001-9320-7008; Kaprio, Jaakko/0000-0002-3716-2455; Lappalainen, Tuuli/0000-0002-7746-8109; Magi, Reedik/0000-0002-2964-6011; Esko, Tonu/0000-0003-1982-6569; Stitziel, Nathan/0000-0002-4963-8211; Barrett, Jeffrey/0000-0002-1152-370X FU European Commission [201413 ENGAGE, 242167 SynSys, 261433 BioSHare, 261123 gEUVADIS]; Academy of Finland [251704, 263401, 255847, 251217, 139635, 141054, 265240, 263278, 250422]; Finnish Foundation for Cardiovascular Research; Sigrid Juselius Foundation; Australian National Health and Medical Research Council [637400]; Wellcome Trust [086596/Z/08/Z, 098381]; GoT2D [RC2-DK088389]; GoT2D Wellcome Trust [090367]; T2DGENES NIDDM [U01-DK-085545, DK062370, DK085584, DK088389]; European Union [HEALTH-F2-2011-278913]; European Union [BiomarCaRE]; Estonian Ministry of Science and Education [SF0180142s08]; US National Institute of Health [R01DK075787]; University of Tartu [SP1GVARENG]; European Regional Development Fund [3.2.0304.11-0312]; FP7 grant [313010]; Lung GO Sequencing Project [HL-102923]; WHI Sequencing Project [HL-102924]; Broad GO Sequencing Project [HL-102925]; Seattle GO Sequencing Project [HL-102926]; Heart GO Sequencing Project [HL-103010]; NIH [RC2 HL-102925]; Merck; [NIH/RFA-HL-12-007] FX We acknowledge support and funding from the following grants: the European Commission FP7 projects no. 201413 ENGAGE (to AP), project no. 242167 SynSys (to AP), Health-2010 -projects no. 261433 BioSHare (to AP) and project no. 261123 gEUVADIS (to AP), the Academy of Finland grants no. 251704 and 263401 (to AP), the Finnish Foundation for Cardiovascular Research (to AP), the Sigrid Juselius Foundation (to AP), NIH/RFA-HL-12-007 (to AP), the European Commission Health-2010-project no. 261433 BioSHare (to SR), the Academy of Finland grants no 255847 and no 251217 (to SR), the Finnish Foundation for Cardiovascular Research (to SR), the Sigrid Juselius Foundation (to SR), the Academy of Finland grant #139635 (to VS), the Finnish Foundation for Cardiovascular Research (to VS), the Australian National Health and Medical Research Council Early Career Fellowship no. 637400 (to MI), the Wellcome Trust Research Career Development Fellow 086596/Z/08/Z (to CML), GoT2D RC2-DK088389 (to DMA), GoT2D Wellcome Trust 090367 (to MIM), Wellcome Trust 098381 (to MIM), T2DGENES NIDDM U01-DK-085545 (to MIM), DK062370 (to MB), DK085584 (to MB), DK088389(to MB), Academy of Finland grants 141054, 265240, 263278 (to JK), Academy of Finland grant 250422 (to PW), the European Union's Seventh Framework Programme FP7/2007-2013 [HEALTH-F2-2011-278913, BiomarCaRE], the Targeted Financing from the Estonian Ministry of Science and Education SF0180142s08 (to AMe), the US National Institute of Health R01DK075787 (to JNH, AMe), the Development Fund of the University of Tartu grant SP1GVARENG (to AMe), the European Regional Development Fund to the Centre of Excellence in Genomics (EXCEGEN) grant 3.2.0304.11-0312 (to AMe), and FP7 grant 313010 (to AMe). We thank the GoT2D, T2D-GENES and MIGen ExA groups for providing replication data, as well as the GTEx Consortium and Geuvadis Consortium for the use of the RNA sequencing data, and NHLBI GO Exome Sequencing Project and its ongoing studies which produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the WHI Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926) and the Heart GO Sequencing Project (HL-103010). Exome Chip genotyping in the Myocardial infarction Genetics Exome Array Consortium (MIGen ExA) was supported by NIH RC2 HL-102925 (to SG and DMA) and an investigator-initiated research grant from Merck to SKa. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 78 Z9 78 U1 2 U2 21 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7390 EI 1553-7404 J9 PLOS GENET JI PLoS Genet. PD JUL PY 2014 VL 10 IS 7 AR e1004494 DI 10.1371/journal.pgen.1004494 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA AM5ME UT WOS:000339902600042 PM 25078778 ER PT J AU Makinen, VP Civelek, M Meng, QY Zhang, B Zhu, J Levian, C Huan, TX Segre, AV Ghosh, S Vivar, J Nikpay, M Stewart, AFR Nelson, CP Willenborg, C Erdmann, J Blakenberg, S O'Donnell, CJ Marz, W Laaksonen, R Epstein, SE Kathiresan, S Shah, SH Hazen, SL Reilly, MP Lusis, AJ Samani, NJ Schunkert, H Quertermous, T McPherson, R Yang, X Assimes, TL AF Makinen, Ville-Petteri Civelek, Mete Meng, Qingying Zhang, Bin Zhu, Jun Levian, Candace Huan, Tianxiao Segre, Ayellet V. Ghosh, Sujoy Vivar, Juan Nikpay, Majid Stewart, Alexandre F. R. Nelson, Christopher P. Willenborg, Christina Erdmann, Jeanette Blakenberg, Stefan O'Donnell, Christopher J. Marz, Winfried Laaksonen, Reijo Epstein, Stephen E. Kathiresan, Sekar Shah, Svati H. Hazen, Stanley L. Reilly, Muredach P. Lusis, Aldons J. Samani, Nilesh J. Schunkert, Heribert Quertermous, Thomas McPherson, Ruth Yang, Xia Assimes, Themistocles L. CA Coronary ARtery DIs Genome-Wide TI Integrative Genomics Reveals Novel Molecular Pathways and Gene Networks for Coronary Artery Disease SO PLOS GENETICS LA English DT Article ID EVENTS ILLUMINATE TRIAL; LIPID-LEVEL MANAGEMENT; WIDE ASSOCIATION; HEART-DISEASE; FUNCTIONAL VARIATION; CANDIDATE GENES; EXPRESSION; IDENTIFICATION; ATHEROSCLEROSIS; LOCI AB The majority of the heritability of coronary artery disease (CAD) remains unexplained, despite recent successes of genome-wide association studies (GWAS) in identifying novel susceptibility loci. Integrating functional genomic data from a variety of sources with a large-scale meta-analysis of CAD GWAS may facilitate the identification of novel biological processes and genes involved in CAD, as well as clarify the causal relationships of established processes. Towards this end, we integrated 14 GWAS from the CARDIoGRAM Consortium and two additional GWAS from the Ottawa Heart Institute (25,491 cases and 66,819 controls) with 1) genetics of gene expression studies of CAD-relevant tissues in humans, 2) metabolic and signaling pathways from public databases, and 3) data-driven, tissue-specific gene networks from a multitude of human and mouse experiments. We not only detected CAD-associated gene networks of lipid metabolism, coagulation, immunity, and additional networks with no clear functional annotation, but also revealed key driver genes for each CAD network based on the topology of the gene regulatory networks. In particular, we found a gene network involved in antigen processing to be strongly associated with CAD. The key driver genes of this network included glyoxalase I (GLO1) and peptidylprolyl isomerase I (PPIL1), which we verified as regulatory by siRNA experiments in human aortic endothelial cells. Our results suggest genetic influences on a diverse set of both known and novel biological processes that contribute to CAD risk. The key driver genes for these networks highlight potential novel targets for further mechanistic studies and therapeutic interventions. C1 [Makinen, Ville-Petteri; Meng, Qingying; Levian, Candace; Yang, Xia] Univ Calif Los Angeles, Dept Integrat Biol & Physiol, Los Angeles, CA 90095 USA. [Makinen, Ville-Petteri] South Australian Hlth & Med Res Inst, Adelaide, SA, Australia. [Makinen, Ville-Petteri] Univ Adelaide, Sch Mol & Biomed Sci, Adelaide, SA, Australia. [Civelek, Mete; Lusis, Aldons J.] Univ Calif Los Angeles, David Geffen Sch Med, Div Cardiol, Dept Med, Los Angeles, CA 90095 USA. [Zhang, Bin; Zhu, Jun] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Huan, Tianxiao; O'Donnell, Christopher J.; Kathiresan, Sekar] NHLBI, Framingham Heart Study, Framingham, MA USA. [Segre, Ayellet V.] Broad Inst Harvard & MIT, Cambridge, MA USA. [Ghosh, Sujoy; Vivar, Juan] N Carolina Cent Univ, Dept Cardiovasc & Metab Res, Biomed Biotechnol Res Inst, Durham, NC USA. [Ghosh, Sujoy] Duke NUS Grad Med Sch, Program Cardiovasc & Metab Disorders & Ctr Comput, Singapore, Singapore. [Nikpay, Majid; McPherson, Ruth] Univ Ottawa, Inst Heart, Atherogen Lab, Ottawa, ON, Canada. [Stewart, Alexandre F. R.] Univ Ottawa, Inst Heart, John & Jennifer Ruddy Canadian Cardiovasc Res, Ottawa, ON, Canada. [Nelson, Christopher P.; Samani, Nilesh J.] Univ Leicester, Glenfield Hosp, Dept Cardiovasc Sci, Leicester, Leics, England. [Nelson, Christopher P.; Samani, Nilesh J.] Glenfield Hosp, Natl Inst Hlth Res NIHR, Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England. [Willenborg, Christina; Erdmann, Jeanette] Med Univ Lubeck, Inst Integrat & Expt Genom, D-23538 Lubeck, Germany. [Erdmann, Jeanette] DZHK German Res Ctr Cardiovasc Res, Lubeck, Germany. [Blakenberg, Stefan] Univ Heart Ctr Hamburg, Clin Gen & Intervent Cardiol, Hamburg, Germany. [O'Donnell, Christopher J.; Kathiresan, Sekar] Massachusetts Gen Hosp, Div Cardiol, Ctr Human Genet Res, Boston, MA 02114 USA. [O'Donnell, Christopher J.; Kathiresan, Sekar] Harvard Univ, Sch Med, Boston, MA USA. [Marz, Winfried] Heidelberg Univ, Med Fac Mannheim, Mannheim Inst Publ Hlth Social & Prevent Med, Mannheim, Germany. [Marz, Winfried] Synlab Acad, Mannheim, Germany. [Laaksonen, Reijo] Tampere Univ Hosp, Ctr Sci, Tampere, Finland. [Epstein, Stephen E.] Washington Hosp Ctr, Cardiovasc Res Inst, Washington, DC 20010 USA. [Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Shah, Svati H.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Hazen, Stanley L.] Cleveland Clin, Cleveland, OH 44106 USA. [Reilly, Muredach P.] Univ Penn, Perelman Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Schunkert, Heribert] DZHK German Res Ctr Cardiovasc Res, Munich, Germany. [Schunkert, Heribert] Tech Univ Munich, Deutsch Herzzentrum Munchen, D-80290 Munich, Germany. [Quertermous, Thomas; Assimes, Themistocles L.] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA. RP Makinen, VP (reprint author), Univ Calif Los Angeles, Dept Integrat Biol & Physiol, Los Angeles, CA 90095 USA. EM xyang123@ucla.edu; tassimes@stanford.edu RI Willenborg, Christina/D-2668-2012; Erdmann, Jeanette/P-7513-2014; OI Willenborg, Christina/0000-0001-5217-6882; Makinen, Ville-Petteri/0000-0002-7262-2656; Stewart, Alexandre/0000-0003-2673-9164; Erdmann, Jeanette/0000-0002-4486-6231; GHOSH, SUJOY/0000-0002-7601-165X; Civelek, Mete/0000-0002-8141-0284; Assimes, Themistocles/0000-0003-2349-0009; Kleber, Marcus/0000-0003-0663-7275 FU American Heart Association; Finnish Cultural Foundation Postdoc Pool; Heart and Stroke Foundation of Canada [T-7268]; Canadian Institutes of Health Research [MOP2390941]; Ruth L. Kirschstein National Research Service Award [T32HL69766]; Transatlantic Networks of Excellence Award from Foundation Leducq; NIH-NIDDK [1R21DK088319]; NIH-NIMH [D2P20MD000175-11, R21MH097156-01A1]; NIH-NIA [R01AG046170]; NIH-NCI [R01CA163772]; NIH-NIAID [U01AI111598] FX The study was funded by American Heart Association (VPM, XY, SG), The Finnish Cultural Foundation Postdoc Pool (VPM), Heart and Stroke Foundation of Canada T-7268 (RM), Canadian Institutes of Health Research MOP2390941 (RM), Ruth L. Kirschstein National Research Service Award T32HL69766 (MC), Transatlantic Networks of Excellence Award from Foundation Leducq (MC, AJL, XY), NIH-NIDDK 1R21DK088319 (SG), NIH-NIMH D2P20MD000175-11 (SG), NIH-NIA R01AG046170 (BZ), NIH-NIMH R21MH097156-01A1 (BZ), NIH-NCI R01CA163772 (BZ), and NIH-NIAID U01AI111598-01 (BZ). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 70 TC 49 Z9 49 U1 2 U2 19 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7390 EI 1553-7404 J9 PLOS GENET JI PLoS Genet. PD JUL PY 2014 VL 10 IS 7 AR e1004502 DI 10.1371/journal.pgen.1004502 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA AM5ME UT WOS:000339902600047 PM 25033284 ER PT J AU Traylor, M Makela, KM Kilarski, LL Holliday, EG Devan, WJ Nalls, MA Wiggins, KL Zhao, W Cheng, YC Achterberg, S Malik, R Sudlow, C Bevan, S Raitoharju, E Oksala, N Thijs, V Lemmens, R Lindgren, A Slowik, A Maguire, JM Walters, M Algra, A Sharma, P Attia, JR Boncoraglio, GB Rothwell, PM de Bakker, PIW Bis, JC Saleheen, D Kittner, SJ Mitchell, BD Rosand, J Meschia, JF Levi, C Dichgans, M Lehtimaki, T Lewis, C Markus, HS AF Traylor, Matthew Makela, Kari-Matti Kilarski, Laura L. Holliday, Elizabeth G. Devan, William J. Nalls, Mike A. Wiggins, Kerri L. Zhao, Wei Cheng, Yu-Ching Achterberg, Sefanja Malik, Rainer Sudlow, Cathie Bevan, Steve Raitoharju, Emma Oksala, Niku Thijs, Vincent Lemmens, Robin Lindgren, Arne Slowik, Agnieszka Maguire, Jane M. Walters, Matthew Algra, Ale Sharma, Pankaj Attia, John R. Boncoraglio, Giorgio B. Rothwell, Peter M. Bakker, Paul I. W. de Bis, Joshua C. Saleheen, Danish Kittner, Steven J. Mitchell, Braxton D. Rosand, Jonathan Meschia, James F. Levi, Christopher Dichgans, Martin Lehtimaki, Terho M. Lewis, Cathryn Markus, Hugh S. CA Metastroke Int Stroke Wellcome Trust Case Consortium TI A Novel MMP12 Locus Is Associated with Large Artery Atherosclerotic Stroke Using a Genome-Wide Age-at-Onset Informed Approach SO PLOS GENETICS LA English DT Article ID ISCHEMIC-STROKE; MATRIX METALLOPROTEINASE-12; GENOTYPE IMPUTATION; ATRIAL-FIBRILLATION; LIFETIME RISK; METAANALYSIS; MACROPHAGES; VARIANTS; PLAQUES; STABILITY AB Genome-wide association studies (GWAS) have begun to identify the common genetic component to ischaemic stroke (IS). However, IS has considerable phenotypic heterogeneity. Where clinical covariates explain a large fraction of disease risk, covariate informed designs can increase power to detect associations. As prevalence rates in IS are markedly affected by age, and younger onset cases may have higher genetic predisposition, we investigated whether an age-at-onset informed approach could detect novel associations with IS and its subtypes; cardioembolic (CE), large artery atherosclerosis (LAA) and small vessel disease (SVD) in 6,778 cases of European ancestry and 12,095 ancestry-matched controls. Regression analysis to identify SNP associations was performed on posterior liabilities after conditioning on age-at-onset and affection status. We sought further evidence of an association with LAA in 1,881 cases and 50,817 controls, and examined mRNA expression levels of the nearby genes in atherosclerotic carotid artery plaques. Secondly, we performed permutation analyses to evaluate the extent to which age-at-onset informed analysis improves significance for novel loci. We identified a novel association with an MMP12 locus in LAA (rs660599; p = 2.5x10(-7)), with independent replication in a second population (p = 0.0048, OR(95% CI) = 1.18(1.05-1.32); meta-analysis p = 2.6x10(-8)). The nearby gene, MMP12, was significantly overexpressed in carotid plaques compared to atherosclerosis-free control arteries (p = 1.2x10(-15); fold change = 335.6). Permutation analyses demonstrated improved significance for associations when accounting for age-at-onset in all four stroke phenotypes (p<0.001). Our results show that a covariate-informed design, by adjusting for age-at-onset of stroke, can detect variants not identified by conventional GWAS. C1 [Traylor, Matthew; Kilarski, Laura L.] St Georges Univ London, Stroke & Dementia Res Ctr, London, England. [Makela, Kari-Matti; Raitoharju, Emma; Oksala, Niku; Lehtimaki, Terho] Fimlab Labs, Dept Clin Chem, Tampere, Finland. [Makela, Kari-Matti; Raitoharju, Emma; Oksala, Niku; Lehtimaki, Terho] Univ Tampere, Sch Med, FIN-33101 Tampere, Finland. [Holliday, Elizabeth G.; Maguire, Jane M.; Attia, John R.] Univ Newcastle, Ctr Clin Epidemiol & Biostat, Sch Med & Publ Hlth, Callaghan, NSW 2308, Australia. [Holliday, Elizabeth G.; Maguire, Jane M.; Attia, John R.; Levi, Christopher] Hunter Med Res Inst, New Lambton Hts, NSW, Australia. [Devan, William J.; Rosand, Jonathan] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Devan, William J.; Bakker, Paul I. W. de; Rosand, Jonathan] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [Nalls, Mike A.] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. [Wiggins, Kerri L.; Bis, Joshua C.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Zhao, Wei] Univ Penn, Div Translat Med & Human Genet, Perelman Sch Med, Philadelphia, PA 19104 USA. [Cheng, Yu-Ching; Mitchell, Braxton D.] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Cheng, Yu-Ching; Kittner, Steven J.] Vet Affairs Maryland Hlth Care Syst, Res & Dev Program, Baltimore, MD USA. [Achterberg, Sefanja; Algra, Ale] Univ Med Ctr Utrecht, Dept Neurol & Neurosurg, Brain Ctr Rudolf Magnus, Utrecht, Netherlands. [Malik, Rainer; Dichgans, Martin] Univ Munich, Klinikum Univ Munchen, Inst Stroke & Dementia Res, Munich, Germany. [Sudlow, Cathie] Univ Edinburgh, Div Clin Neurosci, Edinburgh, Midlothian, Scotland. [Sudlow, Cathie] Univ Edinburgh, Insititute Genet & Mol Med, Edinburgh, Midlothian, Scotland. [Bevan, Steve; Markus, Hugh S.] Univ Cambridge, Cambridge, England. [Oksala, Niku] Tampere Univ Hosp, Dept Surg, Tampere, Finland. [Thijs, Vincent; Lemmens, Robin] Katholieke Univ Leuven, Dept Neurosci, Neurobiol Lab, Leuven, Belgium. [Thijs, Vincent; Lemmens, Robin] VIB, Vesalius Res Ctr, Leuven, Belgium. [Thijs, Vincent; Lemmens, Robin] Univ Hosp Leuven, Dept Neurol, Leuven, Belgium. [Lindgren, Arne] Lund Univ, Dept Clin Sci Lund, Lund, Sweden. [Lindgren, Arne] Skane Univ Hosp, Dept Neurol & Rehabil Med, Lund, Sweden. [Slowik, Agnieszka] Jagiellonian Univ, Dept Neurol, Krakow, Poland. [Maguire, Jane M.] Univ Newcastle, Sch Nursing & Midwifery, Callaghan, NSW 2308, Australia. [Maguire, Jane M.; Attia, John R.; Levi, Christopher] Univ Newcastle, Ctr Translat Neurosci & Mental Hlth, Callaghan, NSW 2308, Australia. [Walters, Matthew] Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland. [Algra, Ale; Bakker, Paul I. W. de] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Sharma, Pankaj] Univ London Imperial Coll Sci Technol & Med, Imperial Coll Cerebrovasc Res Unit ICCRU, London, England. [Boncoraglio, Giorgio B.] Fdn Ist Ricovero & Cura & Carattere Sci, Ist Neurol Carlo Besta, Dept Cereberovasc Dis, Milan, Italy. [Rothwell, Peter M.] Univ Oxford, Nuffield Dept Clin Neurosci, Stroke Prevent Res Unit, Oxford, England. [Bakker, Paul I. W. de] Univ Med Ctr, Dept Med Genet, Utrecht, Netherlands. [Bakker, Paul I. W. de] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Genet, Boston, MA 02115 USA. [Saleheen, Danish] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Saleheen, Danish] Ctr Noncommunicable Dis, Karachi, Pakistan. [Meschia, James F.] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. [Dichgans, Martin] Univ Munich, Munich Cluster Syst Neurol SyNergy, Munich, Germany. [M. Lewis, Cathryn] Kings Coll London, Dept Med & Mol Genet, London WC2R 2LS, England. [M. Lewis, Cathryn] Kings Coll London, Social Genet & Dev Psychiat Ctr, London WC2R 2LS, England. RP Traylor, M (reprint author), St Georges Univ London, Stroke & Dementia Res Ctr, London, England. EM mtraylor@sgul.ac.uk RI Thijs, Vincent/C-3647-2009; de Bakker, Paul/B-8730-2009; Boncoraglio, Giorgio/B-8647-2011; Lewis, Cathryn/A-5225-2010 OI Thijs, Vincent/0000-0002-6614-8417; Kilarski, Laura/0000-0003-0645-3134; Traylor, Matthew/0000-0001-6624-8621; Zhao, Wei/0000-0002-8301-9297; Bevan, Steve/0000-0003-0490-6830; Mitchell, Braxton/0000-0003-4920-4744; de Bakker, Paul/0000-0001-7735-7858; Lewis, Cathryn/0000-0002-8249-8476 FU Wellcome Trust, as part of the Wellcome Trust Case Control Consortium 2 project [085475/B/08/Z, 085475/Z/08/Z, WT084724MA]; NIHR Senior Investigator award; NIHR Biomedical Research Centre at Cambridge; National Institutes of Health Research Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust; King's College London; Netherlands Heart Foundation [2005B031]; Dutch Brain Foundation [2008(1).10]; University of Newcastle; Australian National and Medical Health Research Council (NHMRC) [569257]; Australian National Heart Foundation (NHF) [G 04S 1623]; Gladys M Brawn Fellowship scheme; Vincent Fairfax Family Foundation in Australia; Australian NHMRC Fellowship scheme; National Institutes of Health Genes, Environment and Health Initiative (GEI) Grant [U01 HG004436]; GENEVA consortium under GEI; Mid-Atlantic Nutrition and Obesity Research Center [P30 DK072488]; Office of Research and Development, Medical Research Service; Baltimore Geriatrics Research, Education, and Clinical Center of the Department of Veterans Affairs; National Institutes of Health [HHSN268200782096C]; Division of Adult and Community Health, Centers for Disease Control; National Institute of Neurological Disorders and Stroke (NINDS); NIH Office of Research on Women's Health [R01 NS45012, U01 NS069208-01]; NHLBI [R01 HL085251, R01 HL073410]; Intramural Research Program of the National Institute on Aging, NIH project [Z01 AG-000954-06, Z01 AG-000015-50, 2003-078]; NIH-NINDS Grant [R01 NS-42733, R01 NS-39987]; National Institute of Neurological Disorders and Stroke [U01 NS069208]; American Heart Association/Bugher Foundation Centers for Stroke Prevention Research [0775010N]; National Institutes of Health; National Heart, Lung, and Blood Institute's STAMPEED genomics research program [R01 HL087676]; National Center for Research Resources [U54 RR020278]; Italian Ministry of Health [RC 2007/LR6, RC 2008/LR6, RC 2009/LR8, RC 2010/LR8]; Medical Research Council; Stroke Association; Dunhill Medical Trust; National Institute of Health Research (NIHR); NIHR Biomedical Research Centre, Oxford; Wellcome Trust; Binks Trust; German Federal Ministry of Education and Research (BMBF); FP7 European Union project [261123]; Scottish Funding Council; Chief Scientist Office; Vascular Dementia Research Foundation; Medical Research Council [WT095219MA, G1001799]; European Union [201668]; Finnish Foundation of Cardiovascular Research; Finnish Cultural Foundation; Tampere Tuberculosis Foundation; Emil Aaltonen Foundation; Tampere University Hospital Medical Fund [9M048, 9N035]; Foundation of Clinical Chemistry FX The principal funding for this study was provided by the Wellcome Trust, as part of the Wellcome Trust Case Control Consortium 2 project (085475/B/08/Z and 085475/Z/08/Z and WT084724MA). HSM is supported by an NIHR Senior Investigator award and the NIHR Biomedical Research Centre at Cambridge. We acknowledge support from the National Institutes of Health Research Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. The PROMISe Study (The Netherlands) was made possible, in part, by a Complementation Grant to PIWdB from the Biobanking and Biomolecular Resources Research Infrastructure in the Netherlands (BBMRI-NL). SA is supported in part by a grant from the Netherlands Heart Foundation (grant no. 2005B031) and a grant from the Dutch Brain Foundation (project 2008(1).10). The Australian Stroke Genetics Collaboration (ASGC) Australian population control data was derived from the Hunter Community Study. We also thank the University of Newcastle for funding and the men and women of the Hunter region who participated in this study. This research was funded by grants from the Australian National and Medical Health Research Council (NHMRC Project Grant ID: 569257), the Australian National Heart Foundation (NHF Project Grant ID: G 04S 1623), the University of Newcastle, the Gladys M Brawn Fellowship scheme and the Vincent Fairfax Family Foundation in Australia. EGH is supported by the Australian NHMRC Fellowship scheme. The Genetics of Early Onset Stroke (GEOS) Study, Baltimore, USA was supported by the National Institutes of Health Genes, Environment and Health Initiative (GEI) Grant U01 HG004436, as part of the GENEVA consortium under GEI, with additional support provided by the Mid-Atlantic Nutrition and Obesity Research Center (P30 DK072488); and the Office of Research and Development, Medical Research Service, and the Baltimore Geriatrics Research, Education, and Clinical Center of the Department of Veterans Affairs. Genotyping services were provided by the Johns Hopkins University Center for Inherited Disease Research (CIDR), which is fully funded through a federal contract from the National Institutes of Health to the Johns Hopkins University (contract number HHSN268200782096C). Assistance with data cleaning was provided by the GENEVA Coordinating Center (U01 HG 004446; PI Bruce S Weir). Study recruitment and assembly of datasets were supported by a Cooperative Agreement with the Division of Adult and Community Health, Centers for Disease Control and by grants from the National Institute of Neurological Disorders and Stroke (NINDS) and the NIH Office of Research on Women's Health (R01 NS45012, U01 NS069208-01). The Heart and Vascular Health Study (HVH) research reported in this article was funded by NHLBI grants R01 HL085251 and R01 HL073410 The Ischemic Stroke Genetics Study (ISGS)/Siblings With Ischemic Stroke Study (SWISS) study was supported in part by the Intramural Research Program of the National Institute on Aging, NIH project Z01 AG-000954-06. ISGS/SWISS used samples and clinical data from the NIH-NINDS Human Genetics Resource Center DNA and Cell Line Repository (http://ccr.coriell.org/ninds), human subjects protocol numbers 2003-081 and 2004-147. ISGS/SWISS used stroke-free participants from the Baltimore Longitudinal Study of Aging (BLSA) as controls.; The inclusion of BLSA samples was supported in part by the Intramural Research Program of the National Institute on Aging, NIH project Z01 AG-000015-50, human subjects protocol number 2003-078. The ISGS study was funded by NIH-NINDS Grant R01 NS-42733 (JFM, P. I.). The SWISS study was funded by NIH-NINDS Grant R01 NS-39987 (JFM, P. I.). This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the NIH (http://biowulf.nih.gov). The MGH Genes Affecting Stroke Risk and Outcome Study (MGH-GASROS) GASROS was supported by The National Institute of Neurological Disorders and Stroke (U01 NS069208), the American Heart Association/Bugher Foundation Centers for Stroke Prevention Research 0775010N, the National Institutes of Health and National Heart, Lung, and Blood Institute's STAMPEED genomics research program (R01 HL087676) and a grant from the National Center for Research Resources. The Broad Institute Center for Genotyping and Analysis is supported by grant U54 RR020278 from the National Center for Research resources. Milano - Besta Stroke Register Collection and genotyping of the Milan cases within CEDIR were supported by Annual Research Funding of the Italian Ministry of Health (Grant Numbers: RC 2007/LR6, RC 2008/LR6; RC 2009/LR8; RC 2010/LR8). FP6 LSHM-CT-2007-037273 for the PROCARDIS control samples. The Wellcome Trust Case-Control Consortium 2 (WTCCC2) The principal funding for the WTCCC2 stroke study was provided by the Wellcome Trust, as part of the Wellcome Trust Case Control Consortium 2 project (085475/B/08/Z and 085475/Z/08/Z and WT084724MA). The Stroke Association provided additional support for collection of some of the St George's, London cases. The Oxford cases were collected as part of the Oxford Vascular Study which is funded by the Medical Research Council, Stroke Association, Dunhill Medical Trust, National Institute of Health Research (NIHR) and the NIHR Biomedical Research Centre, Oxford. PMR has a Wellcome Trust Senior Investigator Award and an NIHR Senior Investigator Award. The Edinburgh Stroke Study was supported by the Wellcome Trust (clinician scientist award to CS), and the Binks Trust. Sample processing occurred in the Genetics Core Laboratory of the Wellcome Trust Clinical Research Facility, Western General Hospital, Edinburgh. This work was supported by grants received from the German Federal Ministry of Education and Research (BMBF) in the context of the e: Med program (e:AtheroSysMed) and the FP7 European Union project CVgenes@target (261123) to Martin Dichgans. Much of the neuroimaging occurred in the Scottish Funding Council Brain Imaging Research Centre (www.sbirc.ed.ac.uk), Division of Clinical Neurosciences, University of Edinburgh, a core area of the Wellcome Trust Clinical Research Facility and part of the SINAPSE (Scottish Imaging Network - A Platform for Scientific Excellence) collaboration (www.sinapse.ac.uk), funded by the Scottish Funding Council and the Chief Scientist Office. Collection of the Munich cases and data analysis was supported by the Vascular Dementia Research Foundation. This work made use of data and samples generated by the 1958 Birth Cohort (NCDS). Access to these resources was enabled via the 58READIE Project funded by Wellcome Trust and Medical Research Council (grant numbers WT095219MA and G1001799). A full list of the financial, institutional and personal contributions to the development of the 1958 Birth Cohort Biomedical resource is available at http://www2.le.ac.uk/projects/birthcohort.; Tampere Vascular Study (TVS) was supported by the European Union 7th Framework Programme funding for the AtheroRemo project [201668], the Finnish Foundation of Cardiovascular Research (TL), the Finnish Cultural Foundation, the Tampere Tuberculosis Foundation, the Emil Aaltonen Foundation (NO & TL), the Tampere University Hospital Medical Fund (grant 9M048 and 9N035) and the the Foundation of Clinical Chemistry. Immunochip case data for UK, Polish, Belgian, German and Swedish cohorts was genotyped by the Sanger Centre, Cambridge, UK as part of the Wellcome Trust Case Control Consortium 2 project (085475/B/08/Z and 085475/Z/08/Z and WT084724MA), as were the UK and Polish control cohorts. German Control Genotypes was provided through the POPGEN Consortium. Swedish Immunochip Control Samples were provided by the Swedish SLE network and the Uppsala Bioresource. Belgian Immunochip Control Sample Genotypes were provided through the efforts of the International Multiple Sclerosis Genetics Consortium (IMSGC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 55 TC 21 Z9 21 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7390 EI 1553-7404 J9 PLOS GENET JI PLoS Genet. PD JUL PY 2014 VL 10 IS 7 AR e1004469 DI 10.1371/journal.pgen.1004469 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA AM5ME UT WOS:000339902600025 PM 25078452 ER PT J AU Zeng, X Tan, TC Dudzinski, DM Hung, J AF Zeng, Xin Tan, Timothy C. Dudzinski, David M. Hung, Judy TI Echocardiography of the Mitral Valve SO PROGRESS IN CARDIOVASCULAR DISEASES LA English DT Review DE Echocardiography; Mitral valve; Mitral regurgitation; Mitral stenosis ID PULMONARY VENOUS FLOW; TIME 3-DIMENSIONAL ECHOCARDIOGRAPHY; SURFACE-AREA METHOD; PRESSURE HALF-TIME; LEFT-VENTRICULAR DYSFUNCTION; VENA CONTRACTA AREA; DOPPLER-ECHOCARDIOGRAPHY; TRANSESOPHAGEAL ECHOCARDIOGRAPHY; DILATED CARDIOMYOPATHY; ORIFICE AREA AB Echocardiography is the primary imaging modality for assessment of the mitral valve (MV). It provides an accurate and non-invasive tool to assess the morphology, geometry and function of the MV apparatus, which form the basis of the mechanisms and classification of MV disease. This review highlights the mechanistic insights into MV dysfunction by echocardiography and the critical role of echocardiography in the quantitative assessment of the severity of mitral regurgitation and mitral stenosis. (C) 2014 Elsevier Inc. All rights reserved. C1 [Zeng, Xin; Tan, Timothy C.; Dudzinski, David M.; Hung, Judy] Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Boston, MA 02114 USA. RP Hung, J (reprint author), Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Blake 256,55 Fruit St, Boston, MA 02114 USA. EM jhung@partners.org NR 87 TC 3 Z9 3 U1 1 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0033-0620 EI 1873-1740 J9 PROG CARDIOVASC DIS JI Prog. Cardiovasc. Dis. PD JUL-AUG PY 2014 VL 57 IS 1 BP 55 EP 73 DI 10.1016/j.pcad.2014.05.010 PG 19 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AM7UY UT WOS:000340075400007 PM 25081402 ER PT J AU Prabhakar, AM Harvey, HB Platt, JT Brink, JA Oklu, R AF Prabhakar, Anand M. Harvey, H. Benjamin Platt, Judy T. Brink, James A. Oklu, Rahmi TI Engaging Our Patients: Shared Decision Making and Interventional Radiology SO RADIOLOGY LA English DT Editorial Material ID SORAFENIB; HEALTH C1 [Prabhakar, Anand M.; Harvey, H. Benjamin; Brink, James A.; Oklu, Rahmi] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Imaging, Boston, MA 02114 USA. [Oklu, Rahmi] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Intervent Radiol, Boston, MA 02114 USA. [Platt, Judy T.] Boston Univ, Sch Med, Dept Family Med, Boston, MA 02118 USA. RP Oklu, R (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Imaging, 55 Fruit St,GRB 290A, Boston, MA 02114 USA. EM roklu@mgh.harvard.edu NR 19 TC 6 Z9 6 U1 0 U2 1 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD JUL PY 2014 VL 272 IS 1 BP 9 EP 11 DI 10.1148/radiol.14131909 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AM7GU UT WOS:000340034300003 PM 24956045 ER PT J AU Lankowski, AJ Siedner, MJ Bangsberg, DR Tsai, AC AF Lankowski, Alexander J. Siedner, Mark J. Bangsberg, David R. Tsai, Alexander C. TI Impact of Geographic and Transportation-Related Barriers on HIV Outcomes in Sub-Saharan Africa: A Systematic Review SO AIDS AND BEHAVIOR LA English DT Review DE Transportation barriers; Linkage to care; Retention in care; Adherence; Sub-Saharan Africa ID RURAL SOUTH-AFRICA; RECEIVING ANTIRETROVIRAL THERAPY; RESOURCE-LIMITED SETTINGS; FOLLOW-UP; INFECTED PATIENTS; HEALTH-CARE; PREVENTIVE THERAPY; TREATMENT PROGRAMS; TESTING SERVICES; UNIVERSAL ACCESS AB Difficulty obtaining reliable transportation to clinic is frequently cited as a barrier to HIV care in sub-Saharan Africa (SSA). Numerous studies have sought to characterize the impact of geographic and transportation-related barriers on HIV outcomes in SSA, but to date there has been no systematic attempt to summarize these findings. In this systematic review, we summarized this body of literature. We searched for studies conducted in SSA examining the following outcomes in the HIV care continuum: (1) voluntary counseling and testing, (2) pre-antiretroviral therapy (ART) linkage to care, (3) loss to follow-up and mortality, and (4) ART adherence and/or viral suppression. We identified 34 studies containing 52 unique estimates of association between a geographic or transportation-related barrier and an HIV outcome. There was an inverse effect in 23 estimates (44 %), a null association in 26 (50 %), and a paradoxical beneficial impact in 3 (6 %). We conclude that geographic and transportation-related barriers are associated with poor outcomes across the continuum of HIV care. C1 [Lankowski, Alexander J.] Univ Penn, Dept Internal Med, Philadelphia, PA 19104 USA. [Lankowski, Alexander J.] Univ Penn, Dept Pediat, Philadelphia, PA 19104 USA. [Lankowski, Alexander J.; Siedner, Mark J.; Bangsberg, David R.; Tsai, Alexander C.] Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02114 USA. [Bangsberg, David R.] Harvard Univ, Sch Med, Massachusetts Inst Technol, Ragon Inst,Massachusetts Gen Hosp, Cambridge, MA 02138 USA. [Bangsberg, David R.; Tsai, Alexander C.] Mbarara Univ Sci & Technol, Mbarara, Uganda. [Tsai, Alexander C.] Massachusetts Gen Hosp, Chester M Pierce Div Global Psychiat, Dept Psychiat, Boston, MA 02114 USA. RP Lankowski, AJ (reprint author), Massachusetts Gen Hosp, Ctr Global Hlth, 100 Cambridge St,15th Floor, Boston, MA 02114 USA. EM alexlankowski@gmail.com OI Siedner, Mark/0000-0003-3506-842X; Tsai, Alexander/0000-0001-6397-7917 FU FIC NIH HHS [R24 TW007988, R24TW007988]; NIMH NIH HHS [K23 MH096620, K23 MH099916, K23MH096620, K23MH099916, K24 MH087227, K24MH087227] NR 117 TC 27 Z9 27 U1 7 U2 14 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 EI 1573-3254 J9 AIDS BEHAV JI AIDS Behav. PD JUL PY 2014 VL 18 IS 7 BP 1199 EP 1223 DI 10.1007/s10461-014-0729-8 PG 25 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA AM5AO UT WOS:000339867700001 PM 24563115 ER PT J AU Biello, KB Colby, D Closson, E Mimiaga, MJ AF Biello, Katie B. Colby, Donn Closson, Elizabeth Mimiaga, Matthew J. TI The Syndemic Condition of Psychosocial Problems and HIV Risk Among Male Sex Workers in Ho Chi Minh City, Vietnam SO AIDS AND BEHAVIOR LA English DT Article DE HIV; Vietnam; Psychosocial health; Male sex workers; Transactional sex ID HEALTH-PROBLEMS; YOUNG MEN; BEHAVIOR; PREVENTION; PREVALENCE; INFECTION AB In Vietnam, the co-occurrence (i.e., "syndemic'') of psychosocial factors (e.g., depression and substance use) may disproportionately burden male sex workers and increase their HIV risk. A comprehensive survey was conducted among 300 male sex workers in Ho Chi Minh City, Vietnam in 2010. We performed logistic regression to examine the association between the syndemic variable-a count score of the number of five psychosocial conditions endorsed-and unprotected anal sex (UAS) in the past. One-third of participants reported any UAS, and 42 % reported >= 2 psychosocial health problems. In multivariable models, experiencing >= 4 psychosocial health problems was significantly associated with UAS. Every unit increase in number of psychosocial health problems was associated with a 25-30 % increase in odds of UAS. Understanding the syndemic condition and its association with HIV risk among male sex workers in Vietnam may lead to the development of more effective, comprehensive interventions. C1 [Biello, Katie B.; Mimiaga, Matthew J.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Biello, Katie B.; Closson, Elizabeth; Mimiaga, Matthew J.] Fenway Hlth, Fenway Inst, Boston, MA 02215 USA. [Colby, Donn] Harvard Med Sch AIDS Initiat Vietnam HAIVN, Ho Chi Minh City, Vietnam. [Mimiaga, Matthew J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Biello, KB (reprint author), Fenway Hlth, Fenway Inst, 1340 Boylston St, Boston, MA 02215 USA. EM kbiello@fenwayhealth.org OI colby, donn/0000-0003-3931-5926 FU NCRR NIH HHS [UL1 RR025758, 1 UL1 RR 025758-02] NR 26 TC 24 Z9 25 U1 4 U2 10 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 EI 1573-3254 J9 AIDS BEHAV JI AIDS Behav. PD JUL PY 2014 VL 18 IS 7 BP 1264 EP 1271 DI 10.1007/s10461-013-0632-8 PG 8 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA AM5AO UT WOS:000339867700006 PM 24081899 ER PT J AU Irvin, R Wilton, L Scott, H Beauchamp, G Wang, L Betancourt, J Lubensky, M Wallace, J Buchbinder, S AF Irvin, R. Wilton, L. Scott, H. Beauchamp, G. Wang, L. Betancourt, J. Lubensky, M. Wallace, J. Buchbinder, S. TI A Study of Perceived Racial Discrimination in Black Men Who Have Sex with Men (MSM) and Its Association with Healthcare Utilization and HIV Testing SO AIDS AND BEHAVIOR LA English DT Article DE HIV; Black men who have sex with men (MSM); Racial discrimination; Healthcare utilization; HIV testing ID HETEROSEXUAL MEN; UNITED-STATES; RISK; INFECTION; METAANALYSIS; PERCEPTIONS; DISPARITIES; IDENTITY; LATINO; IMPACT AB In HPTN 061, a study of Black men who have sex with men (MSM), we evaluated the association of healthcare-specific racial discrimination with healthcare utilization and HIV testing among 1167 HIV-negative participants. Median age was 38 years, 41 % were uninsured, and 38 % had an annual household income <$ 10,000. Overall, 19 % reported healthcare-specific racial discrimination directed toward family, friend, or self; 61 % saw a healthcare provider in the previous 6 months and 81 % HIV tested within the past year. Healthcare-specific racial discrimination was positively associated with seeing a provider [adjusted odds ratio (AOR) = 1.4 (1.0, 2.0)] and HIV testing [AOR = 1.6 (1.1, 2.4)] suggesting that barriers other than racial discrimination may be driving health disparities related to access to medical care and HIV testing among Black MSM. These results contrast with previous studies, possibly due to measurement or cohort differences, strategies to overcome discrimination, or because of greater exposure to healthcare. C1 [Irvin, R.] Johns Hopkins Univ, Div Infect Dis, Baltimore, MD 21205 USA. [Irvin, R.; Scott, H.; Buchbinder, S.] San Francisco Dept Publ Hlth, San Francisco, CA USA. [Wilton, L.] SUNY Binghamton, Dept Human Dev, Binghamton, NY USA. [Scott, H.] Univ Calif San Francisco, Ctr AIDS Prevent Studies, San Francisco, CA 94143 USA. [Beauchamp, G.; Wang, L.] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98104 USA. [Betancourt, J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Lubensky, M.] San Francisco AIDS Fdn, San Francisco, CA USA. [Wallace, J.] Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Buchbinder, S.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. RP Irvin, R (reprint author), Johns Hopkins Univ, Div Infect Dis, 725 N Wolfe St,Suite 218A, Baltimore, MD 21205 USA. EM rirvin1@jhmi.edu FU NCATS NIH HHS [UL1 TR000454]; NCRR NIH HHS [UL1 RR025008]; NIAID NIH HHS [5U01 AI069418, 3U01 AI069496-03S1, P30 AI050409, P30 AI060354, U01 AI069424, U01 AI069466, UM1 AI068613, UM1 AI068617, UM1 AI068619, UM1 AI069496, 3U01 AI069496-03S2, 3U01 AI069466-03S1, 5U01 AI069466, P30 AI087714, P30 AI094189, U01 AI069418, U01 AI069496, UM1 AI069480] NR 37 TC 11 Z9 11 U1 2 U2 8 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 EI 1573-3254 J9 AIDS BEHAV JI AIDS Behav. PD JUL PY 2014 VL 18 IS 7 BP 1272 EP 1278 DI 10.1007/s10461-014-0734-y PG 7 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA AM5AO UT WOS:000339867700007 PM 24569888 ER PT J AU Jeevanjee, S Penko, J Guzman, D Miaskowski, C Bangsberg, DR Kushel, MB AF Jeevanjee, Sara Penko, Joanne Guzman, David Miaskowski, Christine Bangsberg, David R. Kushel, Margot B. TI Opioid Analgesic Misuse is Associated with Incomplete Antiretroviral Adherence in a Cohort of HIV-Infected Indigent Adults in San Francisco SO AIDS AND BEHAVIOR LA English DT Article DE HIV infections; Medication adherence; Pain; Analgesics; Opioid; Opioid-related disorders; Antiretroviral therapy; Highly active ID INJECTION-DRUG USERS; AMBULATORY AIDS PATIENTS; ASSISTED SELF-INTERVIEWS; CHRONIC NONCANCER PAIN; REPORTED ADHERENCE; THERAPY ADHERENCE; CLINICAL-TRIALS; RISK BEHAVIORS; MANAGEMENT; OUTCOMES AB There is little or no data examining the association between either pain or the use or misuse of opioid analgesic with adherence to antiretroviral medications (ARVs) among HIV-infected adults. We interviewed a community-based cohort of HIV-infected indigent adults prescribed antiretroviral medications (ARVs) quarterly to examine the association between (1) pain, (2) receipt of opioid analgesics, and (3) opioid analgesic misuse with self-reported ARV adherence. Of 281 participants, most (82.5 %) reported severe or moderate pain, half (52.4 %) received a prescription for opioids, and one quarter (24.6 %) misused opioid analgesics. Most (71.9 %) reported >90 % ARV adherence. In a GEE model, neither pain (unadjusted OR 1.14, CI 0.90-1.45) nor prescription of opioid analgesics (unadjusted OR 1.11, CI 0.84-1.49) were significantly associated with ARV adherence. Misuse of opioid analgesics was associated with incomplete adherence (AOR 1.42, CI 1.09-1.86). Individuals who misuse opioid analgesics, like those who use illicit substances, may have difficulty adhering to medication regimens. C1 [Jeevanjee, Sara] Univ Calif San Francisco, San Francisco Gen Hosp, Div Hosp Med, San Francisco, CA 94143 USA. [Penko, Joanne] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Guzman, David; Kushel, Margot B.] Univ Calif San Francisco, San Francisco Gen Hosp, Div Gen Internal Med, San Francisco, CA 94143 USA. [Miaskowski, Christine] Univ Calif San Francisco, Dept Physiol Nursing, Sch Nursing, San Francisco, CA 94143 USA. [Bangsberg, David R.] Harvard Univ, Massachusetts Gen Hosp, MGH Ctr Global Hlth,Med Sch,Harvard Initiat Globa, Dept Global Hlth & Social Med,Ragon Inst MGH,MIT, Boston, MA USA. RP Kushel, MB (reprint author), Univ Calif San Francisco, San Francisco Gen Hosp, Div Gen Internal Med, Box 1364, San Francisco, CA 94143 USA. EM mkushel@medsfgh.ucsf.edu FU NCATS NIH HHS [UL1 TR000004]; NCRR NIH HHS [UL1 RR024131, UL1RR024131]; NIDA NIH HHS [R01 DA022550, R01DA022550]; NIMH NIH HHS [R01MH54907, R01 MH054907] NR 64 TC 8 Z9 8 U1 1 U2 1 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 EI 1573-3254 J9 AIDS BEHAV JI AIDS Behav. PD JUL PY 2014 VL 18 IS 7 BP 1352 EP 1358 DI 10.1007/s10461-013-0619-5 PG 7 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA AM5AO UT WOS:000339867700016 PM 24077929 ER PT J AU Rough, K Dietrich, J Essien, T Grelotti, DJ Bansberg, DR Gray, G Katz, IT AF Rough, Kathryn Dietrich, Janan Essien, Thandekile Grelotti, David J. Bansberg, David R. Gray, Glenda Katz, Ingrid T. TI Whoonga and the Abuse and Diversion of Antiretrovirals in Soweto, South Africa SO AIDS AND BEHAVIOR LA English DT Article DE Antiretroviral diversion; Recreational antiretroviral abuse; Whoonga; Efavirenz; South Africa ID EFAVIRENZ AB Media reports have described recreational use of HIV antiretroviral medication in South Africa, but little has been written about this phenomenon in the scientific literature. We present original, qualitative data from eight semi-structured interviews that characterize recreational antiretroviral use in Soweto, South Africa. Participants reported that antiretrovirals, likely efavirenz, are crushed, mixed with illicit drugs (in a mixture known as whoonga), and smoked. They described medications being stolen from patients and expressed concern that antiretroviral abuse jeopardized the safety of both patients and users. Further studies are needed to understand the prevalence, patterns, and consequences of antiretroviral abuse and diversion. C1 [Rough, Kathryn; Grelotti, David J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Rough, Kathryn; Katz, Ingrid T.] Brigham & Womens Hosp, Div Womens Hlth, Boston, MA 02115 USA. [Dietrich, Janan; Essien, Thandekile; Gray, Glenda] Perinatal HIV Res Unit, Soweto, South Africa. [Bansberg, David R.; Katz, Ingrid T.] Harvard Univ, Sch Med, Boston, MA USA. [Bansberg, David R.; Katz, Ingrid T.] Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02114 USA. [Bansberg, David R.] Massachusetts Gen Hosp, Ragon Inst, Boston, MA 02114 USA. RP Katz, IT (reprint author), Brigham & Womens Hosp, Div Womens Hlth, 1620 Tremont St,3rd Floor BWH, Boston, MA 02115 USA. EM ikatz2@partners.org FU NIAID NIH HHS [P30 AI060354]; NIMH NIH HHS [K23 MH097667] NR 13 TC 5 Z9 5 U1 0 U2 1 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 EI 1573-3254 J9 AIDS BEHAV JI AIDS Behav. PD JUL PY 2014 VL 18 IS 7 BP 1378 EP 1380 DI 10.1007/s10461-013-0683-x PG 3 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA AM5AO UT WOS:000339867700019 PM 24370963 ER PT J AU Kruse, GR Bangsberg, DR Hahn, JA Haberer, JE Hunt, PW Muzoora, C Bennett, JP Martin, JN Rigotti, NA AF Kruse, Gina R. Bangsberg, David R. Hahn, Judith A. Haberer, Jessica E. Hunt, Peter W. Muzoora, Conrad Bennett, John P. Martin, Jeffrey N. Rigotti, Nancy A. TI Tobacco Use Among Adults Initiating Treatment for HIV Infection in Rural Uganda SO AIDS AND BEHAVIOR LA English DT Article DE Tobacco use; Smoking cessation; Socioeconomic status; Resource-limited setting; Antiretroviral treatment initiation ID HUMAN-IMMUNODEFICIENCY-VIRUS; NUTRITION EXAMINATION SURVEY; SERUM COTININE LEVELS; CIGARETTE-SMOKING; ALCOHOL-CONSUMPTION; NATIONAL-HEALTH; AUDIT-C; CESSATION; SMOKERS; AFRICA AB We conducted a longitudinal study of tobacco use among adults initiating antiretroviral therapy (ART) in Mbarara, Uganda where 11 % of men and 3 % of women use tobacco according to the 2011 Demographic and Health Survey. In a prospective cohort, self-reported tobacco use was assessed before starting ART and reassessed every 3-4 months. Plasma cotinine, a nicotine metabolite, was measured in a subset of adults pre-ART to verify self-report. Among 496 subjects, 50 (10 %) reported current tobacco use (20 % of men, 6 % of women). Most (53 %) adults with elevated cotinine levels (>15 ng/mL) reported no tobacco use. By 6 months after ART initiation, 33 % of tobacco users had quit (95 % CI 20-46 %). By 5 years, 64 % quit (95 % CI 47-77 %). Self-reported tobacco use among rural Ugandans starting ART was twice as common as among the local background population and use may be underreported. ART initiation could be an opportunity for tobacco cessation interventions. C1 [Kruse, Gina R.; Haberer, Jessica E.; Rigotti, Nancy A.] Massachusetts Gen Hosp, Dept Med, Div Gen Med, Boston, MA 02114 USA. [Kruse, Gina R.; Rigotti, Nancy A.] Harvard Univ, Sch Med, Boston, MA USA. [Kruse, Gina R.; Rigotti, Nancy A.] Massachusetts Gen Hosp, Dept Med, Tobacco Res & Treatment Ctr, Boston, MA 02114 USA. [Bangsberg, David R.; Haberer, Jessica E.] Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02114 USA. [Bangsberg, David R.; Muzoora, Conrad] Mbarara Univ Sci & Technol, Mbarara, Uganda. [Bangsberg, David R.] MIT, MGH, Ragon Inst, Boston, MA USA. [Bangsberg, David R.] Harvard Univ, Boston, MA 02115 USA. [Hahn, Judith A.; Hunt, Peter W.] Univ Calif San Francisco, Dept Med, San Francisco Gen Hosp, San Francisco, CA USA. [Hahn, Judith A.; Bennett, John P.; Martin, Jeffrey N.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. RP Kruse, GR (reprint author), Massachusetts Gen Hosp, Dept Med, Div Gen Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM gkruse@partners.org FU NCI NIH HHS [R25 CA057711]; NIAAA NIH HHS [K24 AA015287, K24 AA022586]; NIAID NIH HHS [P30 AI-027763, P30 AI027763]; NIMH NIH HHS [K23 MH-079713, K23 MH-079713-03S1, K23 MH079713, K23 MH087228, K24 MH087227, K24 MH87227, R01 MH-054907, R01 MH054907]; PHS HHS [K23 087228, T32HP12706-03-00] NR 47 TC 1 Z9 1 U1 1 U2 3 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 EI 1573-3254 J9 AIDS BEHAV JI AIDS Behav. PD JUL PY 2014 VL 18 IS 7 BP 1381 EP 1389 DI 10.1007/s10461-014-0737-8 PG 9 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA AM5AO UT WOS:000339867700020 PM 24638166 ER PT J AU Darsie, B Shlipak, MG Sarnak, MJ Katz, R Fitzpatrick, AL Odden, MC AF Darsie, Brendan Shlipak, Michael G. Sarnak, Mark J. Katz, Ronit Fitzpatrick, Annette L. Odden, Michelle C. TI Kidney Function and Cognitive Health in Older Adults: The Cardiovascular Health Study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE aging; chronic kidney disease; cognitive function; congestive heart failure; myocardial infarction; prospective study; stroke; successful aging ID SERUM CYSTATIN-C; BODY-COMPOSITION; ELDERLY PERSONS; DISEASE; DECLINE; IMPAIRMENT; CREATININE; RISK; DEMENTIA; PEOPLE AB Recent evidence has demonstrated the importance of kidney function in healthy aging. We examined the association between kidney function and change in cognitive function in 3,907 participants in the Cardiovascular Health Study who were recruited from 4 US communities and studied from 1992 to 1999. Kidney function was measured by cystatin C-based estimated glomerular filtration rate (eGFR(cys)). Cognitive function was assessed using the Modified Mini-Mental State Examination and the Digit Symbol Substitution Test, which were administered up to 7 times during annual visits. There was an association between eGFR(cys) and change in cognitive function after adjustment for confounders; persons with an eGFR(cys) of less than 60 mL/minute/1.73 m(2) had a 0.64 (95% confidence interval: 0.51, 0.77) points/year faster decline in Modified Mini-Mental State Examination score and a 0.42 (95% confidence interval: 0.28, 0.56) points/year faster decline in Digit Symbol Substitution Test score compared with persons with an eGFR(cys) of 90 or more mL/minute/1.73 m(2). Additional adjustment for intermediate cardiovascular events modestly affected these associations. Participants with an eGFR(cys) of less than 60 mL/minute/1.73 m(2) had fewer cognitive impairment-free life-years on average compared with those with eGFR(cys) of 90 or more mL/minute/1.73 m(2), independent of confounders and mediating cardiovascular events (mean difference = -0.44, 95% confidence interval: -0.62, -0.26). Older adults with lower kidney function are at higher risk of worsening cognitive function. C1 [Darsie, Brendan; Odden, Michelle C.] Oregon State Univ, Sch Biol & Populat Hlth Sci, Corvallis, OR 97331 USA. [Shlipak, Michael G.] San Francisco VA Med Ctr, Div Gen Internal Med, San Francisco, CA USA. [Shlipak, Michael G.] Univ Calif San Francisco, Dept Med, Div Gen Internal Med, San Francisco, CA USA. [Shlipak, Michael G.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Sarnak, Mark J.] Tufts Med Ctr, Dept Med, Div Nephrol, Boston, MA USA. [Katz, Ronit] Univ Washington, Kidney Res Grp, Seattle, WA 98195 USA. [Fitzpatrick, Annette L.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Fitzpatrick, Annette L.] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. RP Darsie, B (reprint author), Oregon State Univ, 141B Milam Hall, Corvallis, OR 97331 USA. EM brendan.darsie@gmail.com FU National Heart, Lung, and Blood Institute [HHSN268201200036C, HHSN 268200800007C, N01HC55222, N01HC85079, N01HC 85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, HL080295]; National Institute on Aging [R01AG023629, R01AG027002, K01AG039387]; American Heart Association Western States Affiliate [11CRP7210088] FX This research was supported by the National Heart, Lung, and Blood Institute (contracts HHSN268201200036C, HHSN 268200800007C, N01HC55222, N01HC85079, N01HC 85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086, and grant HL080295), with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided by the National Institute on Aging (grants R01AG023629 and R01AG027002). A full list of principal Cardiovascular Health Study investigators and institutions can be found at http://www.chs-nhlbi.org/PI.htm. M.C.O. is supported by the American Heart Association Western States Affiliate (grant 11CRP7210088) and the National Institute on Aging (grant K01AG039387). NR 36 TC 11 Z9 12 U1 1 U2 7 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUL 1 PY 2014 VL 180 IS 1 BP 68 EP 75 DI 10.1093/aje/kwu102 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AM4FI UT WOS:000339808200010 PM 24844846 ER PT J AU Souter, I Dimitriadis, I Baltagi, LM Meeker, JD Petrozza, JC AF Souter, Irene Dimitriadis, Irene Baltagi, Lina M. Meeker, John D. Petrozza, John C. TI Elevated day 3 follicle-stimulating hormone in younger women: is gonadotropin stimulation/intrauterine insemination a good option? SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE day 3 follicle stimulating hormone; gonadotropins; infertility; intrauterine insemination; ovulation induction ID IN-VITRO FERTILIZATION; CITRATE CHALLENGE TEST; OVARIAN RESERVE TESTS; ASSISTED REPRODUCTIVE TECHNOLOGY; RECURRENT PREGNANCY LOSS; ANTI-MULLERIAN HORMONE; ANTRAL FOLLICLES; PREDICTIVE-VALUE; BASAL MARKERS; INHIBIN-B AB OBJECTIVE: The objective of the study was to determine the fecundity of young women (<35 years) with an elevated day 3 follicle stimulating hormone (FSH) undergoing gonadotropin-stimulation/intrauterine insemination. STUDY DESIGN: This was a retrospective study. The study was conducted at an academic fertility center. A total of 1396 gonadotropin stimulation/intrauterine insemination cycles from 563 women were stratified by day 3 FSH levels (<10 vs >= 10 U/L) and outcomes were compared. Gonadotropin dose, treatment duration, peak estradiol (E-2), number of preovulatory follicles (total, large, and medium size), E-2/follicle, endometrial thickness, spontaneous abortion, clinical and multiple pregnancy rates were measured. The statistics included a Student ttest, a chi(2), regression, and a discrete survival analysis. RESULTS: An elevated day 3 FSH was found in 10.2% of the women, despite favorable age (31.9 +/- 2.5 years). Women with a day 3 FSH of 10 U/L or greater when compared with women with a normal day 3 level required significantly more medication (1058.9 +/- 1106.0 vs 632.7 +/- 477.5 IU, P < .0001) were triggered a day earlier (10.6 +/- 2.4 vs 11.5 +/- 2.9 days, P=.0006) and had E-2 levels (on the day of and the day prior to human chorionic gonadotropin administration) that were significantly higher (529.5 +/- 244.3 vs 450.0 +/- 244.2 and 359.6 +/- 141.7 vs 306.8 +/- 160.9 pg/mL, respectively, P < .05). Clinical pregnancy rates were comparable among the groups (14.6 vs 14%, respectively, P > .05). Spontaneous abortion and multiple pregnancy rates were higher among women with an FSH of 10U/L or greater but not significantly so (27.8% vs 12.0%, 22.2% vs 13.8% for FSH of >= 10 vs FSH < or > 10 U/L, P > .05). CONCLUSION: Women younger than 35 years with an elevated day 3 FSH, when treated aggressively with gonadotropins have pregnancy rates comparable with those of women with a normal baseline FSH. To achieve this outcome, they need higher doses of medication to stimulate the production of a larger preovulatory follicular cohort. C1 [Souter, Irene; Dimitriadis, Irene; Baltagi, Lina M.; Petrozza, John C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Obstet & Gynecol,Div Reprod Endocrinol & Inf, Boston, MA 02115 USA. [Meeker, John D.] Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA. RP Souter, I (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Obstet & Gynecol,Div Reprod Endocrinol & Inf, Boston, MA 02115 USA. OI Meeker, John/0000-0001-8357-5085 NR 45 TC 0 Z9 0 U1 0 U2 4 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 JUL PY 2014 VL 211 IS 1 AR 62.e1 DI 10.1016/j.ajog.2014.01.031 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AM3IW UT WOS:000339747000024 PM 24487006 ER PT J AU Kloke, BP Rae, R Mahr, A Burkhardt, UE Kvistborg, P Britten, CM AF Kloke, Bjoern-Philipp Rae, Richard Mahr, Andrea Burkhardt, Ute E. Kvistborg, Pia Britten, Cedrik M. TI Toward the next waves of cancer immunotherapy: 11th Annual Meeting of the Association for Cancer Immunotherapy (CIMT), Mainz, Germany, May 14-16, 2013 SO CANCER IMMUNOLOGY IMMUNOTHERAPY LA English DT Article DE CIMT 2013; Cancer immunotherapy; Meeting report; Targeted therapies C1 [Kloke, Bjoern-Philipp; Britten, Cedrik M.] Ribol GmbH, D-55131 Mainz, Germany. [Rae, Richard; Britten, Cedrik M.] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Translat Oncol TRON, D-55122 Mainz, Germany. [Mahr, Andrea] Immat Biotechnol GmbH, Tubingen, Germany. [Burkhardt, Ute E.] Dana Farber Canc Inst, Canc Vaccine Ctr, Dept Med Oncol, Boston, MA 02115 USA. [Kvistborg, Pia] Netherlands Canc Inst, Amsterdam, Netherlands. RP Kloke, BP (reprint author), Ribol GmbH, Holderlinstr 8, D-55131 Mainz, Germany. EM bjoern.kloke@ribological.de FU German Research Foundation [BU 3028/1-1]; German Bundesministerium fur Bildung and Forschung (BMBF) [031A018]; Deutsche Forschungsgemeinschaft (DFG) [GZ: HU 852/4-1, AOBJ: 602849]; Wallace Coulter Foundation (Florida, USA) FX The authors would like to thank Dr. Stephen Reece (Mainz, Germany) for carefully proofreading the meeting report. Ute E. Burkhardt acknowledges support from the German Research Foundation (BU 3028/1-1). Selected sessions of the CIMT meeting were made possible due to research grants from the German Bundesministerium fur Bildung and Forschung (BMBF grant: 031A018) and the Deutsche Forschungsgemeinschaft (DFG grant: GZ: HU 852/4-1; AOBJ: 602849). The CIMT-working group CIP receives support for educational activities by the Wallace Coulter Foundation (Florida, USA). NR 0 TC 1 Z9 1 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-7004 EI 1432-0851 J9 CANCER IMMUNOL IMMUN JI Cancer Immunol. Immunother. PD JUL PY 2014 VL 63 IS 7 BP 749 EP 755 DI 10.1007/s00262-013-1495-6 PG 7 WC Oncology; Immunology SC Oncology; Immunology GA AM5CN UT WOS:000339873300009 PM 24190545 ER PT J AU Sousa, CM Kimmelman, AC AF Sousa, Cristovao Marques Kimmelman, Alec C. TI The complex landscape of pancreatic cancer metabolism SO CARCINOGENESIS LA English DT Review ID LUNG ADENOCARCINOMA CELLS; RAS-TRANSFORMED CELLS; TUMOR-SUPPRESSOR GENE; HIGH-FAT DIET; MUTANT K-RAS; DUCTAL ADENOCARCINOMA; GLUTAMINE-METABOLISM; GLUCOSE-METABOLISM; ONCOGENIC KRAS; DNA-DAMAGE AB Pancreatic ductal adenocarcinomas (PDA) are extremely aggressive cancers and currently available therapies are only minimally effective in treating this disease. Tackling this devastating cancer has been a major challenge to the scientific and medical communities, in part due to its intense therapeutic resistance. One of the aspects of this tumor that contributes to its aggressive behavior is its altered cellular metabolism. Indeed, PDA cells seem to possess the ability to adapt their metabolism to the particular environment to which they are exposed, including utilizing diverse fuel sources depending on their availability. Moreover, PDA tumors are efficient at recycling various metabolic substrates through activation of different salvage pathways such as autophagy and macropinocytosis. Together, these diverse metabolic adaptations allow PDA cells to survive and thrive in harsh environments that may lack nutrients and oxygen. Not surprisingly, given its central role in the pathogenesis of this tumor, oncogenic Kras plays a critical role in much of the metabolic reprogramming seen in PDA. In this review, we discuss the metabolic landscape of PDA tumors, including the molecular underpinnings of the key regulatory nodes, and describe how such pathways can be exploited for future diagnostic and therapeutic approaches C1 [Sousa, Cristovao Marques; Kimmelman, Alec C.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Genom Stabil & DNA Repair,Dept Radiat Oncol, Boston, MA 02215 USA. RP Kimmelman, AC (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Genom Stabil & DNA Repair,Dept Radiat Oncol, Boston, MA 02215 USA. EM alec_kimmelman@dfci.harvard.edu FU National Institutes of Health/National Cancer Institute [1R01CA157490]; American Cancer Society [RSG-13-298-01-TBG]; Department of Defense [W81XWH-12-1-0459]; Lustgarten Foundation for Pancreatic Cancer Research FX National Institutes of Health/National Cancer Institute (1R01CA157490); American Cancer Society (RSG-13-298-01-TBG); Department of Defense Discovery Award (W81XWH-12-1-0459); the Lustgarten Foundation for Pancreatic Cancer Research to A.C.K. NR 185 TC 30 Z9 30 U1 3 U2 26 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 EI 1460-2180 J9 CARCINOGENESIS JI Carcinogenesis PD JUL PY 2014 VL 35 IS 7 BP 1441 EP 1450 DI 10.1093/carcin/bgu097 PG 10 WC Oncology SC Oncology GA AM4IB UT WOS:000339816100003 PM 24743516 ER PT J AU Bansal, R Esan, A Hess, D Angel, LF Levine, SM George, T Raoof, S AF Bansal, Ruchi Esan, Adebayo Hess, Dean Angel, Luis F. Levine, Stephanie M. George, Tony Raoof, Suhail TI Mechanical Ventilatory Support in Potential Lung Donor Patients SO CHEST LA English DT Review ID RESPIRATORY-DISTRESS-SYNDROME; LOWER TIDAL VOLUMES; PRESSURE RELEASE VENTILATION; RANDOMIZED CONTROLLED-TRIAL; BRAIN-DEATH; ORGAN DONOR; PROTECTIVE VENTILATION; MANAGEMENT PROTOCOL; TRANSPLANT DONOR; PULMONARY-EDEMA AB Lung transplantation reduces mortality in patients with end-stage lung disease; however, only approximately 21% of lungs from potential donor patients undergo transplantation. A large number of donor lungs become categorized as unsuitable for lung transplantation as a result of lung injury around the time of brain death. Limiting this injury is key to increasing the number of successful lung procurements and subsequent transplants. This narrative review by a working group of pulmonologists, respiratory therapists, and lung transplant specialists elucidates principles of mechanical ventilatory support that can be used to limit lung injury in potential lung donor patients and examines the implementation of protocolized strategies in enhancing the procurement of donor lungs for transplantation. C1 [Bansal, Ruchi; Esan, Adebayo; George, Tony; Raoof, Suhail] New York Methodist Hosp, Div Pulm & Crit Care Med, Brooklyn, NY 11215 USA. [Hess, Dean] Massachusetts Gen Hosp, Resp Care Serv, Boston, MA USA. [Angel, Luis F.; Levine, Stephanie M.] Univ Texas Hlth Sci Ctr San Antonio, Crit Care Med, San Antonio, TX 78229 USA. [Angel, Luis F.; Levine, Stephanie M.] Univ Texas Hlth Sci Ctr San Antonio, Div Pulm, San Antonio, TX 78229 USA. RP Raoof, S (reprint author), New York Methodist Hosp, Pulm & Crit Care Med, 506 Sixth St, Brooklyn, NY 11215 USA. EM suhailraoof@gmail.com NR 38 TC 1 Z9 2 U1 0 U2 2 PU AMER COLL CHEST PHYSICIANS PI GLENVIEW PA 2595 PATRIOT BLVD, GLENVIEW, IL 60026 USA SN 0012-3692 J9 CHEST JI Chest PD JUL PY 2014 VL 146 IS 1 BP 220 EP 227 DI 10.1378/chest.12-2745 PG 8 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA AM3CP UT WOS:000339729800041 PM 25010965 ER PT J AU Paltiel, AD Walensky, RP Freedberg, KA AF Paltiel, A. David Walensky, Rochelle P. Freedberg, Kenneth A. TI Misinterpretation of HIV Preexposure Prophylaxis Findings SO CLINICAL INFECTIOUS DISEASES LA English DT Letter C1 [Paltiel, A. David] Yale Univ, Sch Publ Hlth, Sch Management, New Haven, CT 06520 USA. [Walensky, Rochelle P.; Freedberg, Kenneth A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Paltiel, AD (reprint author), Yale Univ, Sch Publ Hlth, 60 Coll St, New Haven, CT 06520 USA. EM david.paltiel@yale.edu NR 5 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL 1 PY 2014 VL 59 IS 1 DI 10.1093/cid/ciu240 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AM2FL UT WOS:000339665000026 PM 24729554 ER PT J AU Rosell, DR Futterman, SE McMaster, A Siever, LJ AF Rosell, Daniel R. Futterman, Shira E. McMaster, Antonia Siever, Larry J. TI Schizotypal Personality Disorder: A Current Review SO CURRENT PSYCHIATRY REPORTS LA English DT Review DE Schizotypal; Schizophrenia; Personality disorder; Frontal lobe; Temporal lobe; Dopamine; Working memory; Cognition; Social cognition; Affect processing; Magical thinking; Perceptual aberration; Suspiciousness; Paranoia; Social anhedonia ID INDUCED DOPAMINE RELEASE; HIGH-ACTIVITY ALLELE; FOLLOW-UP MRI; CAUDATE-NUCLEUS; WORKING-MEMORY; SCHIZOPHRENIA SPECTRUM; EMPATHIC ACCURACY; LARGE POPULATION; CINGULATE GYRUS; NAIVE PATIENTS AB The study of schizotypal personality disorder (SPD) is important clinically, as it is understudied, challenging to treat, often under-recognized or misdiagnosed, and associated with significant functional impairment. SPD also represents an intermediate schizophrenia-spectrum phenotype, and therefore, can provide a better understanding of the genetics, pathogenesis, and treatment of related psychotic illnesses. In this review we discuss recent findings of SPD related to epidemiology and functional impairment, heritability and genetics, working memory and cognitive impairments, social-affective disturbances, and neurobiology. Additionally, we examine the challenges associated with treating patients with SPD, as well as clinical recommendations. Finally, we address future directions and areas in need of further exploration. C1 [Rosell, Daniel R.; Futterman, Shira E.; McMaster, Antonia; Siever, Larry J.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Rosell, Daniel R.; Futterman, Shira E.; McMaster, Antonia; Siever, Larry J.] James J Peters Vet Affairs Med Ctr, Bronx, NY 10468 USA. RP Siever, LJ (reprint author), James J Peters Vet Affairs Med Ctr, 130 West Kingsbridge Rd,Room 6A-44, Bronx, NY 10468 USA. EM larry.siever@va.gov FU Department of Veterans Affairs; National Institute of Mental Health; Mental Illness Research, Education and Clinical Centers; Mount Sinai FX Daniel R. Rosell has received support for travel and payment from writing or reviewing manuscript from the Department of Veterans Affairs.; Shira E. Futterman has received support from a grant from the National Institute of Mental Health awarded to LJS.; Antonia McMaster has received a support from a grant from the National Institute of Mental Health awarded to LJS.; Larry J. Siever has received grants and travel support from the National Institute of Mental Health and the Department of Veterans Affairs. He also received travel support from the Mental Illness Research, Education and Clinical Centers. Dr. Siever also has receive payment for writing or reviewing manuscripts from the Department of Veterans Affairs, the Mental Illness Research, Education and Clinical Centers, and Mount Sinai. NR 82 TC 14 Z9 14 U1 7 U2 37 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3812 EI 1535-1645 J9 CURR PSYCHIAT REP JI Curr. Psychiatry Rep. PD JUL PY 2014 VL 16 IS 7 AR 452 DI 10.1007/s11920-014-0452-1 PG 12 WC Psychiatry SC Psychiatry GA AM4CZ UT WOS:000339801400001 PM 24828284 ER PT J AU Mela, T Singh, JP AF Mela, Theofanie Singh, Jagmeet P. TI EFFORTLESS S-ICD registry: another step in the right direction SO EUROPEAN HEART JOURNAL LA English DT Editorial Material ID IMPLANTABLE-CARDIOVERTER-DEFIBRILLATOR; EXPERIENCE; RECEIVE C1 [Mela, Theofanie; Singh, Jagmeet P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. RP Singh, JP (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac Arrhythmia Serv, Suite 109,Gray Bldg, Boston, MA 02114 USA. EM jsingh@mgh.harvard.edu NR 11 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X EI 1522-9645 J9 EUR HEART J JI Eur. Heart J. PD JUL PY 2014 VL 35 IS 25 BP 1634 EP 1636 DI 10.1093/eurheartj/ehu155 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AM2GD UT WOS:000339667000006 PM 24780499 ER PT J AU Leow, JJ Martin-Doyle, W Rajagopal, PS Patel, CG Anderson, EM Rothman, AT Cote, RJ Urun, Y Chang, SL Choueiri, TK Bellmunt, J AF Leow, Jeffrey J. Martin-Doyle, William Rajagopal, Padma S. Patel, Chirayu G. Anderson, Erin M. Rothman, Andrew T. Cote, Richard J. Urun, Yuksel Chang, Steven L. Choueiri, Toni K. Bellmunt, Joaquim TI Adjuvant Chemotherapy for Invasive Bladder Cancer: A 2013 Updated Systematic Review and Meta-Analysis of Randomized Trials SO EUROPEAN UROLOGY LA English DT Review DE Muscle-invasive bladder cancer; Adjuvant chemotherapy; Perioperative chemotherapy; Meta-analysis ID INDIVIDUAL PATIENT DATA; RADICAL CYSTECTOMY; NEOADJUVANT CHEMOTHERAPY; PHASE-III; PERIOPERATIVE CHEMOTHERAPY; UROTHELIAL CANCER; CISPLATIN; CARCINOMA; EXPERIENCE; REGRESSION AB Context: The role of adjuvant chemotherapy remains poorly defined for the management of muscle-invasive bladder cancer (MIBC). The last meta-analysis evaluating adjuvant chemotherapy, conducted in 2005, had limited power to fully support its use. Objective: To update the current evidence of the benefit of postoperative adjuvant cisplatin-based chemotherapy compared with control (ie, surgery alone) in patients with MIBC. Evidence acquisition: A comprehensive literature review was performed to identify all randomized controlled trials (RCTs) comparing adjuvant cisplatin-based chemotherapy with control for patients with MIBC. The search included the Medline, Embase, Cochrane Central Register of Controlled Trials databases, and abstracts from the American Society of Clinical Oncology meetings up to May 2013. An updated systematic review and meta-analysis was performed. Evidence synthesis: A total of 945 patients included in nine RCTs (five previously analyzed, one updated, and three new) were examined. For overall survival, the pooled hazard ratio (HR) across all nine trials was 0.77 (95% confidence interval [CI], 0.59-0.99; p = 0.049). For disease-free survival, the pooled HR across seven trials reporting this outcome was 0.66 (95% CI, 0.45-0.91; p = 0.014). This disease-free survival benefit was more apparent among those with positive nodal involvement (p = 0.010). Conclusions: This updated and improved meta-analysis of randomized trials provides further evidence of an overall survival and disease-free survival benefit in patients with MIBC receiving adjuvant cisplatin-based chemotherapy after radical cystectomy. (C) 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved. C1 [Leow, Jeffrey J.; Martin-Doyle, William] Harvard Univ, Harvard Sch Publ Hlth, Boston, MA USA. [Chang, Steven L.] Brigham & Womens Hosp, Ctr Surg & Publ Hlth, Boston, MA USA. [Chang, Steven L.] Brigham & Womens Hosp, Div Urol, Boston, MA USA. [Cote, Richard J.] Univ Miami, Miller Sch Med, Dept Pathol, Miami, FL 33136 USA. [Urun, Yuksel; Bellmunt, Joaquim] Bladder Canc Ctr, Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Bellmunt, Joaquim] Univ Hosp Mar IMIM, Barcelona, Spain. RP Bellmunt, J (reprint author), Dana Farber Brigham & Womens Canc Ctr, Bladder Canc Ctr, Harvard Med Sch, 450 Brookline Ave, Boston, MA 02215 USA. EM Joaquim_Bellmunt@dfci.harvard.edu OI Leow, Jeffrey/0000-0002-6216-1913 NR 44 TC 82 Z9 84 U1 2 U2 11 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 JUL PY 2014 VL 66 IS 1 BP 42 EP 54 DI 10.1016/j.eururo.2013.08.033 PG 13 WC Urology & Nephrology SC Urology & Nephrology GA AM3EY UT WOS:000339736800017 PM 24018020 ER PT J AU Brooks, SA Brannon, AR Parker, JS Fisher, JC Sen, O Kattan, MW Hakimi, AA Hsieh, JJ Choueiri, TK Tamboli, P Maranchie, JK Hinds, P Miller, CR Nielsen, ME Rathmell, WK AF Brooks, Samira A. Brannon, A. Rose Parker, Joel S. Fisher, Jennifer C. Sen, Oishee Kattan, Michael W. Hakimi, A. Ari Hsieh, James J. Choueiri, Toni K. Tamboli, Pheroze Maranchie, Jodi K. Hinds, Peter Miller, C. Ryan Nielsen, Matthew E. Rathmell, W. Kimryn TI ClearCode34: A Prognostic Risk Predictor for Localized Clear Cell Renal Cell Carcinoma SO EUROPEAN UROLOGY LA English DT Article DE Biomarker; ccRCC; Kidney cancer; Renal cell carcinoma; TCGA; Prognosis ID GENE-EXPRESSION; BREAST-CANCER; TUMOR-GROWTH; CLASSIFICATION; THERAPY AB Background: Gene expression signatures have proven to be useful tools in many cancers to identify distinct subtypes of disease based on molecular features that drive pathogenesis, and to aid in predicting clinical outcomes. However, there are no current signatures for kidney cancer that are applicable in a clinical setting. Objective: To generate a signature biomarker for the clear cell renal cell carcinoma (ccRCC) good risk (ccA) and poor risk (ccB) subtype classification that could be readily applied to clinical samples to develop an integrated model for biologically defined risk stratification. Design, setting, and participants: A set of 72 ccRCC sample standards was used to develop a 34-gene classifier (ClearCode34) for assigning ccRCC tumors to subtypes. The classifier was applied to RNA-sequencing data from 380 nonmetastatic ccRCC samples from the Cancer Genome Atlas (TCGA), and to 157 formalin-fixed clinical samples collected at the University of North Carolina. Outcome measurements and statistical analysis: Kaplan-Meier analyses were performed on the individual cohorts to calculate recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). Training and test sets were randomly selected from the combined cohorts to assemble a risk prediction model for disease recurrence. Results and limitations: The subtypes were significantly associated with RFS (p < 0.01), CSS (p < 0.01), and OS (p < 0.01). Hazard ratios for subtype classification were similar to those of stage and grade in association with recurrence risk, and remained significant in multivariate analyses. An integrated molecular/clinical model for RFS to assign patients to risk groups was able to accurately predict CSS above established, clinical risk-prediction algorithms. Conclusions: The ClearCode34-based model provides prognostic stratification that improves upon established algorithms to assess risk for recurrence and death for nonmetastatic ccRCC patients. Patient summary: We developed a 34-gene subtype predictor to classify clear cell renal cell carcinoma tumors according to ccA or ccB subtypes and built a subtype-inclusive model to analyze patient survival outcomes. (C) 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved. C1 [Brooks, Samira A.; Brannon, A. Rose; Parker, Joel S.; Fisher, Jennifer C.; Sen, Oishee; Kattan, Michael W.; Miller, C. Ryan; Nielsen, Matthew E.; Rathmell, W. Kimryn] Univ N Carolina, Lineberger Canc Ctr, Chapel Hill, NC 27599 USA. [Brannon, A. Rose] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Kattan, Michael W.] Cleveland Clin, Dept Quantitat Hlth Sci, Cleveland, OH 44106 USA. [Hakimi, A. Ari; Hsieh, James J.] Mem Sloan Kettering Canc Ctr, Dept Surg, Urol Serv, New York, NY 10021 USA. [Choueiri, Toni K.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA. [Choueiri, Toni K.] Dana Farber Canc Inst, Kidney Canc Ctr, Boston, MA USA. [Maranchie, Jodi K.; Hinds, Peter] Univ Texas Houston, MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Miller, C. Ryan] Univ N Carolina, Dept Pathol, Chapel Hill, NC USA. [Nielsen, Matthew E.] Univ N Carolina, Dept Urol, Chapel Hill, NC USA. [Nielsen, Matthew E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Rathmell, W. Kimryn] Univ N Carolina, Dept Med, Div Hematol & Oncol, Chapel Hill, NC USA. [Rathmell, W. Kimryn] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. RP Rathmell, WK (reprint author), Univ N Carolina, Lineberger Canc Ctr, 450 W Dr,CB 7295, Chapel Hill, NC 27599 USA. EM Rathmell@med.unc.edu RI Miller, Ryan/B-9365-2008; OI Miller, Ryan/0000-0002-0096-8762; Maranchie, Jodi/0000-0002-8534-9468 FU Landon American Association for Cancer Research INNOVATOR grant; National Research Service from the National Institute of Environmental Health Sciences [T32 ES007126]; Howard Hughes Medical Institute Translational Medicine Fellowship; National Cancer Institute of the National Institutes of Health (NIH) [5T32CA160001]; University Cancer Research Fund of the University of North Carolina (UNC) Lineberger Comprehensive Cancer Center; Urology Care Foundation/Astellas Rising Stars in Urology Research FX This work was supported by a Landon American Association for Cancer Research INNOVATOR grant to W.K. Rathmell; National Research Service Award T32 ES007126 from the National Institute of Environmental Health Sciences to S. Brooks; the Howard Hughes Medical Institute Translational Medicine Fellowship to S. Brooks; the National Cancer Institute of the National Institutes of Health (NIH) Award 5T32CA160001 to A.R. Brannon; the University Cancer Research Fund of the University of North Carolina (UNC) Lineberger Comprehensive Cancer Center to M.E. Nielsen; and the Urology Care Foundation/Astellas Rising Stars in Urology Research Award to M.E. Nielsen. NR 25 TC 39 Z9 39 U1 1 U2 6 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 JUL PY 2014 VL 66 IS 1 BP 77 EP 84 DI 10.1016/j.eururo.2014.02.035 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA AM3EY UT WOS:000339736800023 PM 24613583 ER PT J AU Ploussard, G Daneshmand, S Efstathiou, JA Herr, HW James, ND Rodel, CM Shariat, SF Shipley, WU Sternberg, CN Thalmann, GN Kassouf, W AF Ploussard, Guillaume Daneshmand, Siamak Efstathiou, Jason A. Herr, Harry W. James, Nicholas D. Roedel, Claus M. Shariat, Shahrokh F. Shipley, William U. Sternberg, Cora N. Thalmann, George N. Kassouf, Wassim TI Critical Analysis of Bladder Sparing with Trimodal Therapy in Muscle-invasive Bladder Cancer: A Systematic Review SO EUROPEAN UROLOGY LA English DT Review DE Urinary bladder neoplasms; Organ sparing treatments; Outcome assessment; Chemoradiotherapy; Chemotherapy; Radiotherapy; Cystectomy ID TRANSITIONAL-CELL-CARCINOMA; QUALITY-OF-LIFE; SELECTIVE ORGAN PRESERVATION; COMBINED-MODALITY THERAPY; EXTERNAL-BEAM RADIOTHERAPY; LONG-TERM OUTCOMES; PHASE-III TRIAL; RADICAL CYSTECTOMY; TRANSURETHRAL RESECTION; RADIATION-THERAPY AB Context: Aims of bladder preservation in muscle-invasive bladder cancer (MIBC) are to offer a quality-of-life advantage and avoid potential morbidity or mortality of radical cystectomy (RC) without compromising oncologic outcomes. Because of the lack of a completed randomised controlled trial, oncologic equivalence of bladder preservation modality treatments compared with RC remains unknown. Objective: This systematic review sought to assess the modern bladder-preservation treatment modalities, focusing on trimodal therapy (TMT) in MIBC. Evidence acquisition: A systematic literature search in the PubMed and Cochrane databases was performed from 1980 to July 2013. Evidence synthesis: Optimal bladder-preservation treatment includes a safe transurethral resection of the bladder tumour as complete as possible followed by radiation therapy (RT) with concurrent radiosensitising chemotherapy. A standard radiation schedule includes external-beam RT to the bladder and limited pelvic lymph nodes to an initial dose of 40 Gy, with a boost to the whole bladder to 54 Gy and a further tumour boost to a total dose of 64-65 Gy. Radiosensitising chemotherapy with phase 3 trial evidence in support exists for cisplatin and mitomycin C plus 5-fluorouracil. A cystoscopic assessment with systematic rebiopsy should be performed at TMT completion or early after TMT induction. Thus, nonresponders are identified early to promptly offer salvage RC. The 5-yr cancer-specific survival and overall survival rates range from 50% to 82% and from 36% to 74%, respectively, with salvage cystectomy rates of 25-30%. There are no definitive data to support the benefit of using of neoadjuvant or adjuvant chemotherapy. Critical to good outcomes is proper patient selection. The best cancers eligible for bladder preservation are those with low-volume T2 disease without hydronephrosis or extensive carcinoma in situ. Conclusions: A growing body of accumulated data suggests that bladder preservation with TMT leads to acceptable outcomes and therefore may be considered a reasonable treatment option in well-selected patients. Patient summary: Treatment based on a combination of resection, chemotherapy, and radiotherapy as bladder-sparing strategies may be considered as a reasonable treatment option in properly selected patients. (C) 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved. C1 [Ploussard, Guillaume; Kassouf, Wassim] McGill Univ, Dept Surg, Div Urol, Montreal, PQ H3G 1A4, Canada. [Ploussard, Guillaume] St Louis Hosp, AP HP, Dept Urol, Paris, France. [Efstathiou, Jason A.; Shipley, William U.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA USA. [Herr, Harry W.] Mem Sloan Kettering Canc Ctr, Dept Urol, New York, NY 10021 USA. [Shariat, Shahrokh F.] Med Univ Vienna, Dept Urol, Vienna, Austria. [Roedel, Claus M.] Goethe Univ Frankfurt, Dept Radiotherapy & Oncol, D-60054 Frankfurt, Germany. [Sternberg, Cora N.] San Camillo Forlanini Hosp, Dept Med Oncol, Rome, Italy. [James, Nicholas D.] Univ Birmingham, Sch Canc Sci, Birmingham, W Midlands, England. [Thalmann, George N.] Univ Bern, Dept Urol, Bern, Switzerland. [Daneshmand, Siamak] Univ So Calif, Norris Comprehens Canc Ctr, Inst Urol, Los Angeles, CA USA. RP Kassouf, W (reprint author), McGill Univ, Ctr Hlth, Div Urol, Dept Surg, 1650 Cedar Ave,Room L8-315, Montreal, PQ H3G 1A4, Canada. EM wassim.kassouf@muhc.mcgill.ca OI Daneshmand, Siamak/0000-0001-6224-9598 FU Association Francaise d'Urologie; Association pour la Recherche sur le Cancer; Fonds de recherche Sante Quebec FX Wassim Kassouf certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Dr Ploussard is partially funded by the Association Francaise d'Urologie and Association pour la Recherche sur le Cancer. Dr Kassouf is a recipient of a Research Scholar Award from the Fonds de recherche Sante Quebec. NR 122 TC 35 Z9 37 U1 2 U2 6 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 JUL PY 2014 VL 66 IS 1 BP 120 EP 137 DI 10.1016/j.eururo.2014.02.038 PG 18 WC Urology & Nephrology SC Urology & Nephrology GA AM3EY UT WOS:000339736800032 PM 24613684 ER PT J AU Aziz, A May, M Burger, M Palisaar, RJ Trinh, QD Fritsche, HM Rink, M Chun, F Martini, T Bolenz, C Mayr, R Pycha, A Nuhn, P Stief, C Novotny, V Wirth, M Seitz, C Noldus, J Gilfrich, C Shariat, SF Brookman-May, S Bastian, PJ Denzinger, S Gierth, M Roghmann, F AF Aziz, Atiqullah May, Matthias Burger, Maximilian Palisaar, Rein-Jueri Quoc-Dien Trinh Fritsche, Hans-Martin Rink, Michael Chun, Felix Martini, Thomas Bolenz, Christian Mayr, Roman Pycha, Armin Nuhn, Philipp Stief, Christian Novotny, Vladimir Wirth, Manfred Seitz, Christian Noldus, Joachim Gilfrich, Christian Shariat, Shahrokh F. Brookman-May, Sabine Bastian, Patrick J. Denzinger, Stefan Gierth, Michael Roghmann, Florian TI Prediction of 90-day Mortality After Radical Cystectomy for Bladder Cancer in a Prospective European Multicenter Cohort SO EUROPEAN UROLOGY LA English DT Article DE Bladder cancer; Radical cystectomy; 90-day mortality; Nomogram; Outcome ID STANDARDIZED REPORTING METHODOLOGY; PERIOPERATIVE COMPLICATIONS; NOMOGRAMS AB Background: Despite recent improvements, radical cystectomy (RC) is still associated with adverse rates for 90-d mortality. Objective: To validate the performance of the Isbarn nomogram incorporating age and postoperative tumor characteristics for predicting 90-d RC mortality in a multicenter series and to generate a new nomogram based strictly on preoperative parameters. Design, setting, and participants: Data of 679 bladder cancer (BCa) patients treated with RC at 18 institutions in 2011 were prospectively collected, from which 597 patients were eligible for final analysis. Intervention: RC for BCa. Outcome measurements and statistical analysis: An established prediction tool, the Isbarn nomogram, was applied to our cohort. For the purpose of external validation, model discrimination was measured using the receiver operating characteristics-derived area under the curve. Calibration plots examined the relationship between predicted and observed probabilities. Univariable and multivariable logistic regression models were fitted to assess the impact of preoperative characteristics on 90-d mortality. Results and limitations: The 30-, 60-, and 90-d mortality rates in the development cohort (n = 597) were 2.7%, 6.7%, and 9.0%, respectively. The Isbarn nomogram predicted individual 90-d mortality with an accuracy of 68.6%. Our preoperative multivariable model identified age (odds ratio [OR]: 1.052), American Society of Anesthesiologists score (OR: 2.274), hospital volume (OR: 0.982), clinically lymphatic metastases (OR: 4.111), and clinically distant metastases (OR: 7.788) (all p < 0.05) as independent predictors of 90-dmortality (predictive accuracy: 78.8%). Our conclusions are limited by the lack of an external validation of the preoperative model. Conclusions: The Isbarn nomogram was validated with moderate discrimination. Our newly developed model consisting of preoperative characteristics might outperform existing models. Our model might be particularly suitable for preoperative patient counseling. Patient summary: The current report validated an established nomogram predicting 90-d mortality in patients with bladder cancer after radical cystectomy (RC). We developed a new prediction tool consisting of strictly preoperative parameters, thus allowing clinicians an optimal consultation for RC candidates. (C) 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved. C1 [Aziz, Atiqullah; Burger, Maximilian; Fritsche, Hans-Martin; Denzinger, Stefan; Gierth, Michael] Univ Regensburg, Caritas St Josef Med Ctr, Dept Urol, D-93053 Regensburg, Germany. [May, Matthias] St Elisabeth Med Ctr, Dept Urol, Straubing, Germany. [Palisaar, Rein-Jueri; Noldus, Joachim; Roghmann, Florian] Ruhr Univ Bochum, Marienhosp, Dept Urol, Herne, Germany. [Quoc-Dien Trinh] Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Urol Surg, Boston, MA 02115 USA. [Quoc-Dien Trinh] Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Surg & Publ Hlth, Boston, MA 02115 USA. [Rink, Michael; Chun, Felix] Univ Med Ctr Hamburg Eppendorf, Dept Urol, Hamburg, Germany. [Martini, Thomas; Bolenz, Christian] Heidelberg Univ, Mannheim Med Ctr, Dept Urol, Mannheim, Germany. [Mayr, Roman; Pycha, Armin] Cent Hosp Bolzano, Dept Urol, Bolzano, Italy. [Nuhn, Philipp; Stief, Christian; Brookman-May, Sabine] Univ Munich, Dept Urol, Munich, Germany. [Novotny, Vladimir; Wirth, Manfred] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Dept Urol, Dresden, Germany. [Seitz, Christian] Med Univ Vienna, Dept Urol, Vienna, Austria. [Bastian, Patrick J.] Paracelsus Med Ctr Golzheim, Dept Urol, Dusseldorf, Germany. RP Aziz, A (reprint author), Univ Regensburg, Caritas St Josef Med Ctr, Dept Urol, Landshuterstr 65, D-93053 Regensburg, Germany. EM atiqullah.aziz@ukr.de RI Chun, Felix/M-4652-2015; OI Chun, Felix/0000-0001-8486-9536; Keck, Bastian/0000-0002-9287-0630; Buchner, Alexander/0000-0001-7895-7070 NR 29 TC 28 Z9 28 U1 3 U2 11 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 JUL PY 2014 VL 66 IS 1 BP 156 EP 163 DI 10.1016/j.eururo.2013.12.018 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA AM3EY UT WOS:000339736800035 PM 24388438 ER PT J AU Ferrari, G Quackenbush, J Strobeck, J Hu, L Johnson, CK Mak, A Shaw, RE Sayles, K Brizzio, ME Zapolanski, A Grau, JB AF Ferrari, Giovanni Quackenbush, John Strobeck, John Hu, Lan Johnson, Christopher K. Mak, Andrew Shaw, Richard E. Sayles, Kathleen Brizzio, Mariano E. Zapolanski, Alex Grau, Juan B. TI Comparative genome-wide transcriptional analysis of human left and right internal mammary arteries SO GENOMICS LA English DT Article DE Cardiovascular disease; Transcriptome analysis; Genomics; Coronary artery bypass grafting ID SMOOTH-MUSCLE-CELLS; MIGRATION INHIBITORY FACTOR; NF-KAPPA-B; THORACIC ARTERY; CORONARY-ARTERY; SAPHENOUS-VEIN; RADIAL ARTERY; ANGIOGRAPHIC PREDICTORS; CARDIOVASCULAR-DISEASE; ENDOTHELIAL FUNCTION AB In coronary artery bypass grafting (CABG), the combined use of left and right internal mammary arteries (LIMA and RIMA) - collectively known as bilateral IMAs (BIMAs) provides a survival advantage over the use of LIMA alone. However, gene expression in RIMA has never been compared to that in LIMA. Here we report a genome-wide transcriptional analysis of BIMA to investigate the expression profiles of these conduits in patients undergoing CABG. As expected, in comparing the BIMAs to the aorta, we found differences in pathways and processes associated with atherosclerosis, inflammation, and cell signaling - pathways which provide biological support for the observation that BIMA grafts deliver long-term benefits to the patients and protect against continued atherosclerosis. These data support the widespread use of BIMAs as the preferred conduits in CABG. (C) 2014 Elsevier Inc. All rights reserved. C1 [Ferrari, Giovanni; Strobeck, John; Johnson, Christopher K.; Mak, Andrew; Shaw, Richard E.; Sayles, Kathleen; Brizzio, Mariano E.; Zapolanski, Alex; Grau, Juan B.] Valley Columbia Heart Ctr, Ridgewood, NJ 07450 USA. [Ferrari, Giovanni] Univ Penn, Dept Surg, Glenolden, PA 19036 USA. [Quackenbush, John; Hu, Lan] Dana Farber Canc Inst, Ctr Canc Computat Biol, Boston, MA 02215 USA. [Brizzio, Mariano E.; Zapolanski, Alex; Grau, Juan B.] Columbia Univ Coll Phys & Surg, Dept Surg, New York, NY 10032 USA. RP Grau, JB (reprint author), Columbia Univ Coll Phys & Surg, Valley Columbia Heart Ctr, New York, NY 10032 USA. EM jbg2136@cumc.columbia.edu OI Ferrari, Giovanni/0000-0002-8863-2496 FU NCI NIH HHS [U01 CA151118] NR 48 TC 1 Z9 1 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 EI 1089-8646 J9 GENOMICS JI Genomics PD JUL PY 2014 VL 104 IS 1 BP 36 EP 44 DI 10.1016/j.ygeno.2014.04.005 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA AM7CE UT WOS:000340021500005 PM 24858532 ER PT J AU Strazzula, L Pratt, DS Zardas, J Chung, RT Thiim, M Kroshinsky, D AF Strazzula, Lauren Pratt, Daniel S. Zardas, Janet Chung, Raymond T. Thiim, Michael Kroshinsky, Daniela TI Widespread Morbilliform Eruption Associated With Telaprevir Use of Dermatologic Consultation to Increase Tolerability SO JAMA DERMATOLOGY LA English DT Article ID HCV INFECTION; HEPATITIS-C; PEGINTERFERON; RIBAVIRIN AB IMPORTANCE Telaprevir, combined with pegylated interferon alfa and ribavirin, is an efficacious approach to treat hepatitis C virus infection. A morbilliform eruption associated with telaprevir is a common adverse effect experienced by patients. Current guidelines mandate telaprevir discontinuation in any patient with a severe, progressive, or unresponsive cutaneous eruption. OBSERVATIONS Eight patients with a grade 3 (severe) widespread morbilliform eruption associated with telaprevir were referred to dermatology for evaluation and treatment. Each patient received a combination of antihistamines, topical corticosteroids, and thick emollient creams, rendering their eruption tolerable for the duration of treatment. No patients had evidence of a systemic or life-threatening drug reaction, developed a systemic drug eruption, or had to prematurely stop triple therapy secondary to a cutaneous eruption. CONCLUSIONS AND RELEVANCE Patients with an uncomplicated grade 3 (severe) widespread morbilliform eruption associated with telaprevir may be able to continue triple therapy with close monitoring and dermatologic consultation. Given our findings, we propose an additional clinical classification of the telaprevir-associated eruption to better reflect the dermatologic classification of drug eruptions. C1 [Strazzula, Lauren; Kroshinsky, Daniela] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Pratt, Daniel S.; Zardas, Janet; Chung, Raymond T.; Thiim, Michael] Massachusetts Gen Hosp, Dept Gastroenterol, Boston, MA 02114 USA. RP Kroshinsky, D (reprint author), Massachusetts Gen Hosp, Dept Dermatol, 50 Staniford St,Second Floor, Boston, MA 02114 USA. EM dkroshinsky@partners.org FU Vertex; Gilead FX Dr Chung reported serving as a research consultant and receiving research and clinical trial grants from Vertex and Gilead, which were applied to unrelated projects and not used for this study. No other disclosures are reported. NR 13 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 2168-6068 EI 2168-6084 J9 JAMA DERMATOL JI JAMA Dermatol. PD JUL PY 2014 VL 150 IS 7 BP 756 EP 759 DI 10.1001/jamadermatol.2013.9938 PG 4 WC Dermatology SC Dermatology GA AM2BF UT WOS:000339652400015 PM 24718650 ER PT J AU Watanabe, R Teague, JE Fisher, DC Kupper, TS Clark, RA AF Watanabe, Rei Teague, Jessica E. Fisher, David C. Kupper, Thomas S. Clark, Rachael A. TI Alemtuzumab Therapy for Leukemic Cutaneous T-Cell Lymphoma: Diffuse Erythema as a Positive Predictor of Complete Remission SO JAMA DERMATOLOGY LA English DT Letter C1 [Watanabe, Rei; Teague, Jessica E.; Kupper, Thomas S.; Clark, Rachael A.] Brigham & Womens Hosp, Dept Dermatol, Harvard Skin Dis Res Ctr, Boston, MA 02115 USA. [Fisher, David C.; Kupper, Thomas S.] Dana Farber Brigham & Womens Canc Ctr, Cutaneous Lymphoma Program, Boston, MA USA. RP Clark, RA (reprint author), Brigham & Womens Hosp, Dept Dermatol, 221 Longwood Ave,Room 505A, Boston, MA 02115 USA. EM rclark1@partners.org FU NCI NIH HHS [P50 CA093683, P50 CA9368305]; NIAID NIH HHS [R01 AI025082, R01 AI097128]; NIAMS NIH HHS [R01 AR063962, R01 AR065807, R01 AR056720]; NIMH NIH HHS [R03 MH095529]; PHS HHS [R01 A1025082] NR 3 TC 7 Z9 8 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6068 EI 2168-6084 J9 JAMA DERMATOL JI JAMA Dermatol. PD JUL PY 2014 VL 150 IS 7 BP 776 EP 779 DI 10.1001/jamadermatol.2013.10099 PG 5 WC Dermatology SC Dermatology GA AM2BF UT WOS:000339652400023 PM 24760312 ER PT J AU Strazzula, L Das, S Nambudiri, VE Kroshinsky, D AF Strazzula, Lauren Das, Shinjita Nambudiri, Vinod E. Kroshinsky, Daniela TI Fingertip Purpura in a Dental Student: An Unusual Manifestation of Methyl Methacrylate Dermatitis SO JAMA DERMATOLOGY LA English DT Letter ID CONTACT-DERMATITIS C1 [Strazzula, Lauren; Das, Shinjita; Nambudiri, Vinod E.; Kroshinsky, Daniela] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. RP Kroshinsky, D (reprint author), Massachusetts Gen Hosp, Dept Dermatol, 50 Staniford St, Boston, MA 02114 USA. EM dkroshinsky@partners.org NR 6 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 2168-6068 EI 2168-6084 J9 JAMA DERMATOL JI JAMA Dermatol. PD JUL PY 2014 VL 150 IS 7 BP 784 EP 785 DI 10.1001/jamadermatol.2013.8520 PG 3 WC Dermatology SC Dermatology GA AM2BF UT WOS:000339652400028 PM 24847849 ER PT J AU Fung, V Graetz, I Galbraith, A Hamity, C Huang, J Vollmer, WM Hsu, J Wu, AC AF Fung, Vicki Graetz, Ilana Galbraith, Alison Hamity, Courtnee Huang, Jie Vollmer, William M. Hsu, John Wu, Ann Chen TI Financial Barriers to Care Among Low-Income Children With Asthma Health Care Reform Implications SO JAMA PEDIATRICS LA English DT Article ID PATIENT-PHYSICIAN COMMUNICATION; OF-POCKET COSTS; PRESCRIPTION DRUG; INSURANCE-PROGRAM; MEDICATION; BENEFITS; STATES; POPULATION; FAMILIES; SERVICES AB IMPORTANCE The Patient Protection and Affordable Care Act (ACA) includes subsidies that reduce patient cost sharing for low-income families. Limited information on the effects of cost sharing among children is available to guide these efforts. OBJECTIVE To examine the associations between cost sharing, income, and care seeking and financial stress among children with asthma. DESIGN, SETTING, AND PARTICIPANTS A telephone survey in 2012 about experiences during the prior year within an integrated health care delivery system. Respondents included 769 parents of children aged 4 to 11 years with asthma. Of these, 25.9% of children received public subsidies; 21.7% were commercially insured with household incomes at or below 250% of the federal poverty level (FPL) and 18.2% had higher cost-sharing levels for all services (eg, >=$75 for emergency department visits). We classified children with asthma based on (1) current receipt of a subsidy (ie, Medicaid or Children's Health Insurance Program) or potential eligibility for ACA low-income cost sharing or premium subsidies in 2014 (ie, income <= 250%, 251%-400%, or >400% of the FPL) and (2) cost-sharing levels for prescription drugs, office visits, and emergency department visits. We examined the frequency of changes in care seeking and financial stress due to asthma care costs across these groups using logistic regression, adjusted for patient/family characteristics. MAIN OUTCOMES AND MEASURES Switching to cheaper asthma drugs, using less medication than prescribed, delaying/avoiding any office or emergency department visits, and financial stress (eg, cutting back on necessities) because of the costs of asthma care. RESULTS After adjustment, parents at or below 250% of the FPL with lower vs higher cost-sharing levels were less likely to delay or avoid taking their children to a physician's office visit (3.8% vs 31.6%; odds ratio, 0.07 [95% CI, 0.01-0.39]) and the emergency department (1.2% vs 19.4%; 0.05 [0.01-0.25]) because of cost; higher-income parents and those whose children were receiving public subsidies (eg, Medicaid) were also less likely to forego their children's care than parents at or below 250% of the FPL with higher cost-sharing levels. Overall, 15.6% of parents borrowed money or cut back on necessities to pay for their children's asthma care. CONCLUSIONS AND RELEVANCE Cost-related barriers to care among children with asthma were concentrated among low-income families with higher cost-sharing levels. The ACA's low-income subsidies could reduce these barriers for many families, but millions of dependents for whom employer-sponsored family coverage is unaffordable could remain at risk for cost-related problems because of ACA subsidy eligibility rules. C1 [Fung, Vicki; Hsu, John] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. [Fung, Vicki; Hsu, John] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Graetz, Ilana; Hamity, Courtnee; Huang, Jie] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Graetz, Ilana] Univ Tennessee, Hlth Sci Ctr, Dept Prevent Med, Memphis, TN USA. [Galbraith, Alison; Wu, Ann Chen] Harvard Univ, Sch Med, Dept Populat Med, Ctr Child Hlth Care Studies, Boston, MA USA. [Galbraith, Alison; Wu, Ann Chen] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Hamity, Courtnee] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. [Vollmer, William M.] Kaiser Permanente Northwest, Ctr Hlth Res, Portland, OR USA. [Hsu, John] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. RP Fung, V (reprint author), Massachusetts Gen Hosp, Mongan Inst Hlth Policy, 50 Staniford St,Ninth Floor, Boston, MA 02114 USA. EM vfung@mgh.harvard.edu RI Graetz, Ilana/N-1189-2016 OI Graetz, Ilana/0000-0003-3664-5815 FU Agency for Healthcare Research and Quality [R01 HS019669-01] FX This study was funded by grant R01 HS019669-01 from the Agency for Healthcare Research and Quality. NR 46 TC 10 Z9 10 U1 0 U2 7 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 JUL PY 2014 VL 168 IS 7 BP 649 EP 656 DI 10.1001/jamapediatrics.2014.79 PG 8 WC Pediatrics SC Pediatrics GA AL9VV UT WOS:000339492400014 PM 24840805 ER PT J AU Lehavot, K Simpson, TL AF Lehavot, Keren Simpson, Tracy L. TI Trauma, Posttraumatic Stress Disorder, and Depression Among Sexual Minority and Heterosexual Women Veterans SO JOURNAL OF COUNSELING PSYCHOLOGY LA English DT Article DE women veterans; lesbian and bisexual; PTSD; depression; trauma ID MENTAL-HEALTH; FEMALE VETERANS; BISEXUAL ADULTS; CIVILIAN WOMEN; LIFE-SPAN; GULF-WAR; GAY MEN; MILITARY; VICTIMIZATION; ABUSE AB This study examined the impact of various traumas across the life span on screening positive for current posttraumatic stress disorder (PTSD) and depression among heterosexual and sexual minority women veterans. Women veterans were recruited over the Internet (N = 706, 37% lesbian or bisexual) to participate in an anonymous, online survey. We assessed childhood trauma; adult sexual assault and adult physical victimization before, during, and after the military; combat exposure; perceived sexist discrimination during military service; sexual minority military stressors; past-year sexist events; and whether participants screened positive for PTSD or depression. Binary logistic regressions were used to generate odds ratios and 95% confidence intervals for PTSD and depression, stratified by sexual orientation and controlling for demographic characteristics. Lesbian and bisexual women reported higher rates of trauma across the life span, although in some instances (e. g., sexual assault during and after military service, combat exposure), they did not differ from their heterosexual counterparts. Childhood trauma and traumas that occurred during military service added the most variance to both PTSD and depression models. Sexual assault during military service appeared to be especially harmful with respect to screening positive for PTSD for both sexual orientation groups. Results revealed a number of other predictors of mental health status for women veterans, some of which differed by sexual orientation. Findings indicate a significant burden of interpersonal trauma for both heterosexual and lesbian/bisexual women veterans and provide information on the distinct association of various traumas with current PTSD and depression by sexual orientation. C1 [Lehavot, Keren; Simpson, Tracy L.] VA Puget Sound Hlth Care Syst, MIRECC, Seattle, WA USA. [Lehavot, Keren; Simpson, Tracy L.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Simpson, Tracy L.] VA Puget Sound Hlth Care Syst, CESATE, Seattle, WA USA. RP Lehavot, K (reprint author), 1660 South Columbian Way S-116 POC, Seattle, WA 98108 USA. EM klehavot@uw.edu NR 65 TC 8 Z9 8 U1 3 U2 14 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0022-0167 EI 1939-2168 J9 J COUNS PSYCHOL JI J. Couns. Psychol. PD JUL PY 2014 VL 61 IS 3 BP 392 EP 403 DI 10.1037/cou0000019 PG 12 WC Psychology, Educational; Psychology, Applied SC Psychology GA AM2ER UT WOS:000339662800009 PM 25019543 ER PT J AU Lamont, EB Yu, M He, Y Saltz, L Muss, H Zaslavsky, AM AF Lamont, Elizabeth B. Yu, Menggang He, Yulei Saltz, Leonard Muss, Hyman Zaslavsky, Alan M. CA Alliance Clinical Trials Oncology TI Hospital-based health care use correlates with incidence of adverse events among elderly Medicare patients treated in adjuvant chemotherapy trials (Alliance 70802) SO JOURNAL OF GERIATRIC ONCOLOGY LA English DT Article DE Elderly; Cancer; Medicare; Toxicity; Chemotherapy; Health care use; Comparative effectiveness research; Hospitalization; Adjuvant; Colon cancer; Breast cancer ID III COLON-CANCER; BREAST-CANCER; OLDER WOMEN; UNITED-STATES; COST; AGE; TOXICITY; SURVIVAL; CLAIMS; BIAS AB Objective: Medicare claims can be useful in chemotherapy-related comparative effectiveness research (CER) estimating survival, but methods for estimating patients' treatment morbidity are currently lacking. We sought to determine if patients' health care use in the claims is a marker of treatment morbidity. Materials and Methods: For 249 elderly Medicare patients with breast or colon cancer who were treated in two adjuvant clinical trials, we merged patients' National Cancer Institute Common Toxicity Criteria for Adverse Events (CTC AEs) trial data with their contemporaneous Medicare claims. We estimated associations of patients' grade >= 3 CTC AS counts and their use of two types of hospital-based health care in claims (i.e., emergency room (ER) visits and hospitalizations). Results: ER visits and hospitalizations were significantly positively associated with grade >= 3 CTC AS counts incurred by patients during the study. Eight percent of patients without any grade >= 3 CTC AEs had one or more hospitalizations during the observation period compared to 43% of patients with three or more grade >= 3 CTC AEs (p<0.01). Those who were hospitalized at least once had more than three times the rate of grade >= 3 CTC AEs (IRA 3.70, 95% CI: 2.53-5.40) compared to those who were not. With each hospitalization, the daily incidence rate of any grade >= 3 CTC AS more than doubled (IRR 2.10,95% CI: 1.54-2.86). Conclusions: Because hospitalization is strongly associated with clinically significant toxicity it may be a useful outcome for Medicare claim-based CER comparing treatment morbidity for elderly patients receiving different adjuvant chemotherapy regimens. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Lamont, Elizabeth B.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Lamont, Elizabeth B.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Lamont, Elizabeth B.; He, Yulei; Zaslavsky, Alan M.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA USA. [Yu, Menggang] Univ Wisconsin, Dept Biostat & Med Informat, Madison, WI USA. [Saltz, Leonard] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Muss, Hyman] Univ N Carolina, Dept Med, Chapel Hill, NC USA. RP Lamont, EB (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, 180A Longwood Ave, Boston, MA 02115 USA. EM lamont@hcp.med.harvard.edu OI Saltz, Leonard/0000-0001-8353-4670 FU National Cancer Institute [CA132900, CA33601] FX The study was supported by grants from the National Cancer Institute: CA132900 (Lamont) and CA33601 (CALGB Statistics Center). NR 34 TC 1 Z9 1 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1879-4068 EI 1879-4076 J9 J GERIATR ONCOL JI J. Geriatr. Oncol. PD JUL PY 2014 VL 5 IS 3 BP 230 EP 237 DI 10.1016/j.jgo.2014.02.001 PG 8 WC Oncology; Geriatrics & Gerontology SC Oncology; Geriatrics & Gerontology GA AM4WS UT WOS:000339857500002 PM 24594119 ER PT J AU Batista, EL Kantarci, AI Hasturk, H Van Dyke, TE AF Batista, Eraldo L., Jr. Kantarci, Alpdogan I. Hasturk, Hatice Van Dyke, Thomas E. TI Alternative Splicing Generates a Diacylglycerol Kinase alpha Transcript That Acts as a Dominant-Negative Modulator of Superoxide Production in Localized Aggressive Periodontitis SO JOURNAL OF PERIODONTOLOGY LA English DT Article DE Aggressive periodontitis; diacylglycerol kinase; inflammation; neutrophils; phosphoprotein phosphatases; protein kinases ID HUMAN-NEUTROPHILS; JUVENILE PERIODONTITIS; DISEASE; IDENTIFICATION; DECAY; CHEMOTAXIS; METABOLISM; ACTIVATION; EXPRESSION; INHIBITOR AB Background: Diacylglycerol (DAG), levels of which are tightly regulated by diacylglycerol kinases (DGKs), is a lipid mediator linked to key biologic functions. Members of the DGK family undergo alternative splicing, generating the protein diversity necessary to control different intracellular DAG pools. DGKa function is altered in polymorphonuclear neutrophils (PMNs) of patients with localized aggressive periodontitis (LAgP), suggesting a genetic basis. Here, the authors assess DGKa spliced transcripts in human LAgP neutrophils. Methods: In an expression library of a patient with LAgP, PMNs were screened for different DGKa transcripts. Realtime polymerase chain reaction and in vitro expression assays were performed to assess the fate of different transcripts on protein translocation and superoxide production in human leukemia cells (HL-60) and COS-7 cells. Results: A DGKa transcript that lacks exon 10 (DGK alpha Delta 10) and generates a premature stop codon and a truncated protein was identified as being upregulated in LAgP neutrophils. In vitro assays revealed that DGKaD10 translocation occurred even in the absence of important regulatory motifs. Transfection of HL-60 neutrophil-like cells with the DGKaD10 spliced variant induced an increase in the stimulated production of superoxide anion replicating the phenotype of LAgP PMNs. Conclusion: DGKaD10 can act as a dominant-negative transcript that can modulate superoxide production and provides an example of genetic regulation of the inflammatory response that may be relevant to human inflammatory diseases such as LAgP. C1 [Batista, Eraldo L., Jr.] Univ Manitoba, Fac Dent, Dept Diagnost & Surg Sci, Winnipeg, MB, Canada. [Batista, Eraldo L., Jr.] Univ Manitoba, Fac Dent, Dept Oral Biol, Winnipeg, MB, Canada. [Batista, Eraldo L., Jr.; Kantarci, Alpdogan I.; Hasturk, Hatice; Van Dyke, Thomas E.] Boston Univ, Goldman Sch Dent Med, Dept Periodontol & Oral Biol, Boston, MA 02215 USA. [Kantarci, Alpdogan I.; Hasturk, Hatice; Van Dyke, Thomas E.] Forsyth Inst, Ctr Periodontol, Dept Appl Oral Sci, Cambridge, MA USA. RP Van Dyke, TE (reprint author), Ctr Periodontol, Dept Appl Oral Sci, 245 First St, Cambridge, MA 02142 USA. EM tvandyke@forsyth.org FU USPHS [DE15566, DE19938, RR00533]; CAPES Foundation, Brasilia, DF, Brazil FX The authors have no financial affiliation or involvement with any commercial organization with direct financial interest in the subject or materials discussed in this manuscript, nor have any such arrangements existed in the past. Supported by USPHS Grants DE15566, DE19938, and RR00533 (TEVD). ELB was partially supported by CAPES Foundation, Brasilia, DF, Brazil. The authors thank Dr. Victor Jones, previously Department of Periodontology and Oral Biology, Boston University Goldman School of Dental Medicine, Boston, Massachusetts, for his excellent technical assistance. The authors report no conflicts of interest related to this study. NR 36 TC 1 Z9 1 U1 0 U2 2 PU AMER ACAD PERIODONTOLOGY PI CHICAGO PA 737 NORTH MICHIGAN AVENUE, SUITE 800, CHICAGO, IL 60611-2690 USA SN 0022-3492 EI 1943-3670 J9 J PERIODONTOL JI J. Periodont. PD JUL PY 2014 VL 85 IS 7 BP 934 EP 943 DI 10.1902/jop.2013.130468 PG 10 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA AM2MD UT WOS:000339684000016 PM 24171497 ER PT J AU Via, G Hussain, A Wells, M Reardon, R ElBarbary, M Noble, VE Tsung, JW Neskovic, AN Price, S Oren-Grinberg, A Liteplo, A Cordioli, R Naqvi, N Rola, P Poelaert, J Gulic, TG Sloth, E Labovitz, A Kimura, B Breitkreutz, R Masani, N Bowra, J Talmor, D Guarracino, F Goudie, A Wang, XT Chawla, R Galderisi, M Blaivas, M Petrovic, T Storti, E Neri, L Melniker, L AF Via, Gabriele Hussain, Arif Wells, Mike Reardon, Robert ElBarbary, Mahmoud Noble, Vicki E. Tsung, James W. Neskovic, Aleksandar N. Price, Susanna Oren-Grinberg, Achikam Liteplo, Andrew Cordioli, Ricardo Naqvi, Nitha Rola, Philippe Poelaert, Jan Gulic, Tatjana Golob Sloth, Erik Labovitz, Arthur Kimura, Bruce Breitkreutz, Raoul Masani, Navroz Bowra, Justin Talmor, Daniel Guarracino, Fabio Goudie, Adrian Wang Xiaoting Chawla, Rajesh Galderisi, Maurizio Blaivas, Micheal Petrovic, Tomislav Storti, Enrico Neri, Luca Melniker, Lawrence CA Int Liaison Comm Focused Cardiac TI International Evidence-Based Recommendations for Focused Cardiac Ultrasound SO JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY LA English DT Article DE Cardiac sonography; Echocardiography; Cardiac ultrasound; Crit Care echocardiography; Emergency ultrasound; Critical ultrasound; Point-of-care ultrasound; Guideline; RAND; GRADE; Evidence-based medicine ID INFERIOR VENA-CAVA; HAND-CARRIED ULTRASOUND; POINT-OF-CARE; CRITICALLY-ILL PATIENTS; LEFT-VENTRICULAR FUNCTION; EMERGENCY-DEPARTMENT PATIENTS; LIMITED TRANSTHORACIC ECHOCARDIOGRAM; TARGETED NEONATAL ECHOCARDIOGRAPHY; SPONTANEOUSLY BREATHING PATIENTS; CENTRAL VENOUS-PRESSURE AB Background: Focused cardiac ultrasound (FoCUS) is a simplified, clinician-performed application of echocardiography that is rapidly expanding in use, especially in emergency and critical care medicine. Performed by appropriately trained clinicians, typically not cardiologists, FoCUS ascertains the essential information needed in critical scenarios for time-sensitive clinical decision making. A need exists for quality evidence-based review and clinical recommendations on its use. Methods: The World Interactive Network Focused on Critical UltraSound conducted an international, multi-specialty, evidence-based, methodologically rigorous consensus process on FoCUS. Thirty-three experts from 16 countries were involved. A systematic multiple-database, double-track literature search (January 1980 to September 2013) was performed. The Grading of Recommendation, Assessment, Development and Evaluation method was used to determine the quality of available evidence and subsequent development of the recommendations. Evidence-based panel judgment and consensus was collected and analyzed by means of the RAND appropriateness method. Results: During four conferences (in New Delhi, Milan, Boston, and Barcelona), 108 statements were elaborated and discussed. Face-to-face debates were held in two rounds using the modified Delphi technique. Disagreement occurred for 10 statements. Weak or conditional recommendations were made for two statements and strong or very strong recommendations for 96. These recommendations delineate the nature, applications, technique, potential benefits, clinical integration, education, and certification principles for FoCUS, both for adults and pediatric patients. Conclusions: This document presents the results of the first International Conference on FoCUS. For the first time, evidence-based clinical recommendations comprehensively address this branch of point-of-care ultrasound, providing a framework for FoCUS to standardize its application in different clinical settings around the world. C1 [Via, Gabriele] IRCCS Fdn Policlin San Matteo, Serv Anestesia & Rianimaz 1, I-27100 Pavia, Italy. [Hussain, Arif] Minist Natl Guard Hlth, King Abdulaziz Med City, Riyadh, Saudi Arabia. [Wells, Mike] Univ Witwatersrand, Div Emergency Med, Netcare Union Hosp, Emergency Dept, Johannesburg, South Africa. [Reardon, Robert] Univ Minnesota, Hennepin Cty Med Ctr, Sch Med, Dept Emergency Med, Minneapolis, MN 55415 USA. [ElBarbary, Mahmoud] King Saud Univ Hlth Sci, Natl & Gulf Ctr Evidence Based Hlth Practice, Riyadh, Saudi Arabia. [Noble, Vicki E.] Massachusetts Gen Hosp, Dept Emergency Med, Div Emergency Ultrasound, Boston, MA 02114 USA. [Tsung, James W.] Mt Sinai Sch Med, Dept Emergency Med, New York, NY USA. [Tsung, James W.] Mt Sinai Sch Med, Dept Pediat, New York, NY USA. [Neskovic, Aleksandar N.] Univ Belgrade, Fac Med, Univ Clin Hosp Ctr Zemun, Belgrade, Serbia. [Price, Susanna] Royal Brompton Hosp, Adult Intens Care Unit, London SW3 6LY, England. [Oren-Grinberg, Achikam; Talmor, Daniel] Beth Israel Deaconess Med Ctr, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02215 USA. [Oren-Grinberg, Achikam; Talmor, Daniel] Harvard Univ, Sch Med, Boston, MA USA. [Liteplo, Andrew] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Cordioli, Ricardo] Hosp Israelita Albert Einstein, Intens Care Unit, Sao Paulo, Brazil. [Naqvi, Nitha] Royal Brompton Hosp, London SW3 6LY, England. [Rola, Philippe] Santa Cabrini Hosp, Montreal, PQ, Canada. [Poelaert, Jan] Univ Hosp, Dept Anesthesiol & Perioperat Med, Brussels, Belgium. [Gulic, Tatjana Golob] Univ Clin Ctr Maribor, Dept Cardiosurg, Maribor, Slovenia. [Sloth, Erik] Aarhus Univ Hosp, Dept Anaesthesia & Intens Care, Skejby, Denmark. [Labovitz, Arthur] Univ S Florida, Dept Cardiovasc Sci, Tampa, FL USA. [Kimura, Bruce] Scripps Mercy Hosp, Dept Med Educ, San Diego, CA USA. [Breitkreutz, Raoul] Hosp City Frankfurt, Emergency Dept, Frankfurt, Germany. [Masani, Navroz] Univ Wales Hosp, Dept Cardiol, Cardiff CF4 4XW, S Glam, Wales. [Bowra, Justin] Sydney Adventist Hosp, Sidney, BC, Canada. [Guarracino, Fabio] Univ Hosp Pisa, Dept Anaesthesia & Intens Care Med, Pisa, Italy. [Goudie, Adrian] Emergency Dept, Fremantle, WA, Australia. [Wang Xiaoting] Beijing Union Med Coll Hosp, Intens Care Unit, Beijing, Peoples R China. [Chawla, Rajesh] Indraprastha Apollo Hosp, New Delhi, India. [Galderisi, Maurizio] Federico II Univ Hosp, Dept Clin & Expt Med, Lab Echocardiog, Cardioangiol CCU, Naples, Italy. [Blaivas, Micheal] Univ S Carolina, Sch Med, Dept Emergency Med, St Francis Hosp, Columbus, GA USA. [Petrovic, Tomislav] Univ Hosp Avicenne, Bobigny, France. [Storti, Enrico] Osped Niguarda Ca Granda, Intens Care Unit G Bozza, Milan, Italy. [Neri, Luca] Osped Niguarda Ca Granda, AREU EMS Publ Reg Co, Milan, Italy. [Melniker, Lawrence] Cornell Univ, Weill Med Coll, New York Methodist Hosp, Dept Emergency Med, New York, NY 10021 USA. [Melniker, Lawrence] Cornell Univ, Weill Med Coll, Clin Epidemiol Unit, Div Gen Internal Med,Dept Med, New York, NY 10021 USA. RP Via, G (reprint author), IRCCS Fdn Policlin San Matteo, Serv Anestesia & Rianimaz 1, Viale Golgi 2, I-27100 Pavia, Italy. EM gabriele.via@winfocus.org RI Poelaert, Jan/P-9070-2015; OI Tsung, James/0000-0002-4718-8325; Poelaert, Jan/0000-0002-0065-2899; Guarracino, Fabio/0000-0002-2562-0199; Wells, Mike/0000-0002-4520-2007; Galderisi, Maurizio/0000-0003-0311-9069 FU GE Healthcare FX Dr Bowra is a member of the Medical Advisory Board of Signostics Pty Ltd. Dr Neskovic is an advisor to Medtronic and AstraZeneca and has received consultative honoraria from these companies. Dr Neskovic has received honoraria from Merck and research funds from GE Healthcare. Dr Sloth is an uncompensated member of the Medical Advisory Board of GE Vscan and an uncompensated lecturer for Philips. All other members declared no conflict of interest. No direct sponsorship of any kind has been provided by any commercial or industrial source. No honoraria have been given to any of the panel members. NR 300 TC 32 Z9 34 U1 4 U2 19 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 JUL PY 2014 VL 27 IS 7 AR 683. e1 DI 10.1016/j.echo.2014.05.001 PG 33 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AM3CK UT WOS:000339729200004 PM 24951446 ER PT J AU Ting, DT Ryan, DP AF Ting, David T. Ryan, David P. TI The wide gulf between stage III and stage IV colon cancer SO LANCET ONCOLOGY LA English DT Editorial Material ID ADJUVANT CHEMOTHERAPY; COLORECTAL-CANCER; RANDOMIZED-TRIAL; SURVIVAL; FLUOROURACIL; OXALIPLATIN; LEUCOVORIN C1 [Ting, David T.; Ryan, David P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Ting, DT (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM dpryan@mgh.harvard.edu OI Ting, David/0000-0002-3261-2322 NR 9 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD JUL PY 2014 VL 15 IS 8 BP 785 EP 786 DI 10.1016/S1470-2045(14)70272-4 PG 3 WC Oncology SC Oncology GA AM3DS UT WOS:000339733000040 PM 24928084 ER PT J AU Ledermann, J Harter, P Gourley, C Friedlander, M Vergote, I Rustin, G Scott, CL Meier, W Shapira-Frommer, R Safra, T Matei, D Fielding, A Spencer, S Dougherty, B Orr, M Hodgson, D Barrett, JC Matulonis, U AF Ledermann, Jonathan Harter, Philipp Gourley, Charlie Friedlander, Michael Vergote, Ignace Rustin, Gordon Scott, Clare L. Meier, Werner Shapira-Frommer, Ronnie Safra, Tamar Matei, Daniela Fielding, Anitra Spencer, Stuart Dougherty, Brian Orr, Maria Hodgson, Darren Barrett, J. Carl Matulonis, Ursula TI Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial SO LANCET ONCOLOGY LA English DT Article ID POLY(ADP-RIBOSE) POLYMERASE; OPEN-LABEL; MUTATIONS; CARCINOMA; REPAIR; CHEMOTHERAPY; MULTICENTER; INHIBITION; PATTERNS AB Background Maintenance monotherapy with the PARP inhibitor olaparib significantly prolonged progression-free survival (PFS) versus placebo in patients with platinum-sensitive recurrent serous ovarian cancer. We aimed to explore the hypothesis that olaparib is most likely to benefit patients with a BRCA mutation. Methods We present data from the second interim analysis of overall survival and a retrospective, preplanned analysis of data by BRCA mutation status from our randomised, double-blind, phase 2 study that assessed maintenance treatment with olaparib 400 mg twice daily (capsules) versus placebo in patients with platinum-sensitive recurrent serous ovarian cancer who had received two or more platinum-based regimens and who had a partial or complete response to their most recent platinum-based regimen. Randomisation was by an interactive voice response system, stratified by time to progression on penultimate platinum-based regimen, response to the most recent platinum-based regimen before randomisation, and ethnic descent. The primary endpoint was PFS, analysed for the overall population and by BRCA status. This study is registered with ClinicalTrials.gov, number NCT00753545. Findings Between Aug 28, 2008, and Feb 9, 2010, 136 patients were assigned to olaparib and 129 to placebo. BRCA status was known for 131 (96%) patients in the olaparib group versus 123 (95%) in the placebo group, of whom 74 (56%) versus 62 (50%) had a deleterious or suspected deleterious germline or tumour BRCA mutation. Of patients with a BRCA mutation, median PFS was significantly longer in the olaparib group than in the placebo group (11.2 months [95% CI 8.3-not calculable] vs 4.3 months [3.0-5.4]; HR 0.18 [0.10-0.31]; p<0.0001); similar findings were noted for patients with wild-type BRCA, although the difference between groups was lower (7.4 months [5.5-10.3] vs 5.5 months [3.7-5.6]; HR 0.54 [0.34-0.85]; p=0.0075). At the second interim analysis of overall survival (58% maturity), overall survival did not significantly differ between the groups (HR 0.88 [95% CI 0.64-1.21]; p=0.44); similar findings were noted for patients with mutated BRCA (HR 0.73 [0.45-1.17]; p=0.19) and wild-type BRCA (HR 0.99 [0.63-1.55]; p=0.96). The most common grade 3 or worse adverse events in the olaparib group were fatigue (in ten [7%] patients in the olaparib group vs four [3%] in the placebo group) and anaemia (seven [5%] vs one [<1%]). Serious adverse events were reported in 25 (18%) patients who received olaparib and 11 (9%) who received placebo. Tolerability was similar in patients with mutated BRCA and the overall population. Interpretation These results support the hypothesis that patients with platinum-sensitive recurrent serous ovarian cancer with a BRCA mutation have the greatest likelihood of benefiting from olaparib treatment. C1 [Ledermann, Jonathan] UCL, UCL Canc Inst, London W1T 4TJ, England. [Harter, Philipp] Kliniken Essen Mitte, Essen, Germany. [Gourley, Charlie] Univ Edinburgh, Canc Res UK Ctr, MRC Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland. [Friedlander, Michael] Univ New S Wales, Prince Wales Clin Sch, Randwick, NSW, Australia. [Vergote, Ignace] Univ Leuven, Leuven, Belgium. [Rustin, Gordon] Mt Vernon Hosp, Northwood HA6 2RN, Middx, England. [Scott, Clare L.] Royal Melbourne Hosp, Parkville, NSW, Australia. [Meier, Werner] Evangel Krankenhaus, Dusseldorf, Germany. [Shapira-Frommer, Ronnie] Chaim Sheba Med Ctr, IL-52621 Tel Hashomer, Israel. [Safra, Tamar] Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, IL-69978 Tel Aviv, Israel. [Matei, Daniela] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Fielding, Anitra; Spencer, Stuart; Orr, Maria; Hodgson, Darren] AstraZeneca, Macclesfield, Cheshire, England. [Dougherty, Brian; Barrett, J. Carl] AstraZeneca, Waltham, MA USA. [Matulonis, Ursula] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Ledermann, J (reprint author), UCL, UCL Canc Inst, London W1T 4TJ, England. EM j.ledermann@ucl.ac.uk FU AstraZeneca FX AstraZeneca. NR 27 TC 275 Z9 285 U1 9 U2 32 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 JUL PY 2014 VL 15 IS 8 BP 852 EP 861 DI 10.1016/S1470-2045(14)70228-1 PG 10 WC Oncology SC Oncology GA AM3DS UT WOS:000339733000053 PM 24882434 ER PT J AU Sedaghat, AR Wilke, CO Cunningham, MJ Ishman, SL AF Sedaghat, Ahmad R. Wilke, Claus O. Cunningham, Michael J. Ishman, Stacey L. TI Socioeconomic Disparities in the Presentation of Acute Bacterial Sinusitis Complications in Children SO LARYNGOSCOPE LA English DT Article DE Sinusitis; healthcare disparities; orbital cellulitis; brain abscess; pediatrics ID CLINICAL-PRACTICE GUIDELINE; INTRACRANIAL COMPLICATIONS; ORBITAL COMPLICATIONS; HEALTH-INSURANCE; MANAGEMENT; HOSPITALIZATION; CARE; RHINOSINUSITIS; CELLULITIS; INFANTS AB Objectives/Hypothesis: To identify characteristics and disparities associated with presentation of pediatric acute bacterial sinusitis (ABS) complications. Study Design: A cross-sectional study of the 2008 Nationwide Emergency Department Sample database. Methods: A total of 101,660 children 18 years of age or younger diagnosed with ABS, 696 of whom had orbital or intracranial complications, were identified. Patient and hospital-specific characteristics were investigated for association with childhood ABS complications. Results: Orbital and intracranial complications occurred in 0.7% of children with ABS. Such complications were more common in boys (odds ratio [OR]: 1.65, P<.001) and children with chronic rhinosinusitis (OR: 7.89, P<.001), and were associated with presentation to metropolitan teaching (OR: 2.15, P<.001) and nonteaching (OR: 14.39, P<.001) hospitals. Orbital complications were associated with younger age (OR: 0.96, P<.001), whereas intracranial complications were associated with older age (OR: 1.11, P<.001). A dichotomy in socioeconomic background differentiated children with orbital ABS complications from those with intracranial complications. Although orbital complications were associated with higher income (OR: 2.13, P<.001) and private insurance (OR: 1.36, P=.003), intracranial complications were associated with Medicaid (OR: 2.96, P<.001) or no insurance at all (OR: 3.73, P=.001). Conclusions: Socioeconomic disparities exist in presentation of ABS complications in children. Although hinted at by the association with urban/metropolitan hospitals, explicit evidence is provided by association of intracranial complications with markers of low socioeconomic status and poor access to healthcare. Efforts to aid early diagnosis and treatment should target providers in metropolitan areas who treat children of lower socioeconomic status. Such interventions will ideally improve outcomes and limit healthcare costs related to the high morbidity of pediatric ABS complications. C1 [Sedaghat, Ahmad R.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol Head & Neck Surg, Boston, MA 02114 USA. [Cunningham, Michael J.] Boston Childrens Hosp, Dept Otolaryngol & Commun Enhancement, Boston, MA USA. [Sedaghat, Ahmad R.; Cunningham, Michael J.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Wilke, Claus O.] Univ Texas Austin, Dept Integrat Biol, Ctr Computat Biol & Bioinformat, Austin, TX 78712 USA. [Wilke, Claus O.] Univ Texas Austin, Inst Cellular & Mol Biol, Austin, TX 78712 USA. [Ishman, Stacey L.] Cincinnati Childrens Hosp Med Ctr, Div Otolaryngol, Cincinnati, OH 45229 USA. [Ishman, Stacey L.] Cincinnati Childrens Hosp Med Ctr, Div Pulm Med, Cincinnati, OH 45229 USA. Univ Cincinnati, Dept Otolaryngol Head & Neck Surg, Cincinnati, OH USA. RP Sedaghat, AR (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol Head & Neck Surg, 243 Charles St, Boston, MA 02114 USA. EM ahmad_sedaghat@meei.harvard.edu OI Wilke, Claus/0000-0002-7470-9261; Ishman, Stacey/0000-0003-0997-9692 NR 32 TC 12 Z9 12 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X EI 1531-4995 J9 LARYNGOSCOPE JI Laryngoscope PD JUL PY 2014 VL 124 IS 7 BP 1700 EP 1706 DI 10.1002/lary.24492 PG 7 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA AL9SL UT WOS:000339481100047 PM 24338779 ER PT J AU Hohman, MH Hadlock, TA AF Hohman, Marc H. Hadlock, Tessa A. TI Etiology, Diagnosis, and Management of Facial Palsy: 2000 Patients at a Facial Nerve Center SO LARYNGOSCOPE LA English DT Article DE Facial nerve; facial paralysis; facial palsy ID HERPES-SIMPLEX-VIRUS; BELLS-PALSY; SURGICAL-MANAGEMENT; PARALYZED FACE; MUSCLE; REHABILITATION; REANIMATION; SYNKINESIS; OPTION; SYSTEM AB Objectives/Hypothesis: To evaluate the range and incidence of facial palsy etiologies in cases presenting to a tertiary facial nerve center, and to review the broad and evolving spectrum of diagnostic and management approaches to the condition. Study Design: Retrospective chart review. Methods: Records of patients referred for facial weakness between 2003 and 2013 were reviewed for cases of facial palsy. Cases of muscle dysfunction and primary hemifacial spasm were excluded. The remainder were analyzed by age, sex, and diagnosis. Diagnostic and treatment strategies were reviewed. Results: There were 1,989 records that met inclusion criteria. Bell's palsy accounted for 38% of cases, acoustic neuroma resections 10%, cancer 7%, iatrogenic injuries 7%, varicella zoster 7%, benign lesions 5%, congenital palsy 5%, Lyme disease 4%, and other causes 17%. Sixty-one percent of patients were female. Mean age at presentation was 44.5 years (+/- 18.6 years). Diagnoses were revealed primarily by history, though serial physical examinations, radiography, and hematologic testing also contributed. Management strategies included observation, physical therapy, pharmacological therapy, chemodenervation, facial nerve exploration, decompression, repair, and the full array of static and dynamic surgical interventions. Conclusions: Bell's palsy remains the most common facial palsy; females present more often for evaluation. Comprehensive diagnostic investigation is mandatory in atypical cases, and thorough management must be multidisciplinary. The algorithms presented herein outline a single center's approach to the facial palsy patient, providing a framework that clinicians caring for these patients may adapt to their specific settings. C1 [Hohman, Marc H.; Hadlock, Tessa A.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Hohman, Marc H.; Hadlock, Tessa A.] Massachusetts Eye & Ear Infirm, Facial Nerve Ctr, Boston, MA 02114 USA. RP Hadlock, TA (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Div Facial Plast & Reconstruct Surg, 243 Charles St, Boston, MA 02114 USA. EM tessa_hadlock@meei.harvard.edu NR 53 TC 20 Z9 20 U1 3 U2 31 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 JUL PY 2014 VL 124 IS 7 BP E283 EP E293 DI 10.1002/lary.24542 PG 11 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA AL9SL UT WOS:000339481100005 PM 24431233 ER PT J AU Zhang, W Du, JY Jiang, ZD Okimura, T Oda, T Yu, Q Jin, JO AF Zhang, Wei Du, Jiang-Yuan Jiang, Zedong Okimura, Takasi Oda, Tatsuya Yu, Qing Jin, Jun-O TI Ascophyllan Purified from Ascophyllum nodosum Induces Th1 and Tc1 Immune Responses by Promoting Dendritic Cell Maturation SO MARINE DRUGS LA English DT Article DE ascophyllan; dendritic cells; DC maturation; Th1 cells; Tc1 cells ID CROSS-PRESENTATION; IN-VIVO; POLYSACCHARIDE ASCOPHYLLAN; SULFATED POLYSACCHARIDE; ANTIGEN PRESENTATION; CYTOKINE PRODUCTION; T-CELLS; FUCOIDAN; PATHWAYS; INNATE AB Marine-derived sulfated polysaccharides have been shown to possess certain anti-virus, anti-tumor, anti-inflammatory and anti-coagulant activities. However, the in vivo immunomodulatory effects of marine-derived pure compounds have been less well characterized. In this study, we investigated the effect of ascophyllan, a sulfated polysaccharide purified from Ascophyllum nodosum, on the maturation of mouse dendritic cells (DCs) in vitro and in vivo. Ascophyllan induced up-regulation of co-stimulatory molecules and production of pro-inflammatory cytokines in bone marrow-derived DCs (BMDCs). Moreover, in vivo administration of ascophyllan promotes up-regulation of CD40, CD80, CD86, MHC class I and MHC class II and production of IL-6, IL-12 and TNF-alpha in spleen cDCs. Interestingly, ascophyllan induced a higher degree of co-stimulatory molecule up-regulation and pro-inflammatory cytokine production than fucoidan, a marine-derived polysaccharide with well-defined effect for promoting DC maturation. Ascophyllan also promoted the generation of IFN-gamma-producing Th1 and Tc1 cells in the presence of DCs in an IL-12-dependent manner. Finally, myeloid differentiation primary response 88 (MyD88) signaling pathway was essential for DC maturation induced by ascophyllan. Taken together, these results demonstrate that ascophyllan induces DC maturation, and consequently enhances Th1 and Tc1 responses in vivo. This knowledge could facilitate the development of novel therapeutic strategies to combat infectious diseases and cancer. C1 [Zhang, Wei; Du, Jiang-Yuan; Jin, Jun-O] Fudan Univ, Shanghai Med Coll, Shanghai Publ Hlth Clin Ctr, Shanghai 201508, Peoples R China. [Jiang, Zedong; Oda, Tatsuya] Nagasaki Univ, Div Biochem, Fac Fisheries, Nagasaki 8528521, Japan. [Okimura, Takasi] Hayashikane Sangyo Co Ltd, Div Res & Dev, Shimonoseki, Yamaguchi 7508608, Japan. [Oda, Tatsuya] Nagasaki Univ, Grad Sch Sci & Technol, Nagasaki 8528521, Japan. [Yu, Qing] Forsyth Inst, Dept Immunol & Infect Dis, Cambridge, MA 02142 USA. RP Jin, JO (reprint author), Fudan Univ, Shanghai Med Coll, Shanghai Publ Hlth Clin Ctr, Shanghai 201508, Peoples R China. EM weiwei061215@126.com; dujiangyuan@shaphc.org; zdjiang1982@hotmail.com; tokimura@hayashikane.co.jp; t-oda@nagasaki-u.ac.jp; qyu@forsyth.org; junojin1@gmail.com RI Jiang, Zedong/G-1317-2013 OI Jiang, Zedong/0000-0001-7579-3680 FU Shanghai Public Health Clinical Center in Fudan University [RCJJP17] FX We thank the Shanghai Public Health Clinical Center animal facility for maintaining animals. This study was supported by grants from the Shanghai Public Health Clinical Center in Fudan University (RCJJP17). NR 33 TC 13 Z9 14 U1 2 U2 18 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1660-3397 J9 MAR DRUGS JI Mar. Drugs PD JUL PY 2014 VL 12 IS 7 BP 4148 EP 4164 DI 10.3390/md12074148 PG 17 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA AM6QI UT WOS:000339989300022 PM 25026264 ER PT J AU Dienstmann, R Dong, F Borger, D Dias-Santagata, D Ellisen, LW Le, LP Iafrate, AJ AF Dienstmann, Rodrigo Dong, Fei Borger, Darrell Dias-Santagata, Dora Ellisen, Leif W. Le, Long P. Iafrate, A. John TI Standardized decision support in next generation sequencing reports of somatic cancer variants SO MOLECULAR ONCOLOGY LA English DT Review DE Cancer; Genomics; Next-generation sequencing; Report; Variant annotation ID PLECKSTRIN HOMOLOGY DOMAIN; PAN-FGFR INHIBITOR; CELL LUNG-CANCER; LOSS-OF-FUNCTION; MISSENSE MUTATIONS; CLINICAL-TRIAL; GENOME; SENSITIVITY; MELANOMA; TUMORS AB Of hundreds to thousands of somatic mutations that exist in each cancer genome, a large number are unique and non-recurrent variants. Prioritizing genetic variants identified via next generation sequencing technologies remains a major challenge. Many such variants occur in tumor genes that have well-established biological and clinical relevance and are putative targets of molecular therapy, however, most variants are still of unknown significance. With large amounts of data being generated as high throughput sequencing assays enter the clinical realm, there is a growing need to better communicate relevant findings in a timely manner while remaining cognizant of the potential consequences of misuse or overinterpretation of genomic information. Herein we describe a systematic framework for variant annotation and prioritization, and we propose a structured molecular pathology report using standardized terminology in order to best inform oncology clinical practice. We hope that our experience developing a comprehensive knowledge database of emerging predictive markers matched to targeted therapies will help other institutions implement similar programs. (C) 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. C1 [Dienstmann, Rodrigo; Dong, Fei; Dias-Santagata, Dora; Le, Long P.; Iafrate, A. John] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Dienstmann, Rodrigo; Dong, Fei; Dias-Santagata, Dora; Le, Long P.; Iafrate, A. John] Harvard Univ, Sch Med, Mol Pathol Lab, Boston, MA 02114 USA. [Borger, Darrell; Ellisen, Leif W.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Borger, Darrell; Ellisen, Leif W.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Dienstmann, R (reprint author), Sage Bionetworks, Fred Hutchinson Canc Res Ctr, 1100 Fairview N, Seattle, WA 98109 USA. EM rodrigo.dienstmann@sagebase.org FU La Caixa International Program for Cancer Research Education FX R. Dienstmann is a recipient of "La Caixa International Program for Cancer Research & Education". NR 53 TC 16 Z9 16 U1 1 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1574-7891 EI 1878-0261 J9 MOL ONCOL JI Mol. Oncol. PD JUL PY 2014 VL 8 IS 5 BP 859 EP 873 DI 10.1016/j.molonc.2014.03.021 PG 15 WC Oncology SC Oncology GA AM3TE UT WOS:000339774900001 PM 24768039 ER PT J AU Luo, H Zhang, P Huang, H Huang, JL Kao, E Shi, LM He, L Yang, L AF Luo, Heng Zhang, Ping Huang, Hui Huang, Jialiang Kao, Emily Shi, Leming He, Lin Yang, Lun TI DDI-CPI, a server that predicts drug-drug interactions through implementing the chemical-protein interactome SO NUCLEIC ACIDS RESEARCH LA English DT Article ID HUMAN CYTOCHROME-P450; SEROTONIN SYNDROME; DOCKING; SERTRALINE; MECHANISM; TARGETS AB Drug-drug interactions (DDIs) may cause serious side-effects that draw great attention from both academia and industry. Since some DDIs are mediated by unexpected drug-human protein interactions, it is reasonable to analyze the chemical-protein interactome (CPI) profiles of the drugs to predict their DDIs. Here we introduce the DDI-CPI server, which can make real-time DDI predictions based only on molecular structure. When the user submits a molecule, the server will dock user's molecule across 611 human proteins, generating a CPI profile that can be used as a feature vector for the pre-constructed prediction model. It can suggest potential DDIs between the user's molecule and our library of 2515 drug molecules. In cross-validation and independent validation, the server achieved an AUC greater than 0.85. Additionally, by investigating the CPI profiles of predicted DDI, users can explore the PK/PD proteins that might be involved in a particular DDI. A 3D visualization of the drug-protein interaction will be provided as well. C1 [Luo, Heng; Huang, Hui; He, Lin; Yang, Lun] Shanghai Jiao Tong Univ, BioX Inst, Shanghai 200030, Peoples R China. [Luo, Heng] Univ Arkansas Med Sci, Univ Arkansas Little Rock, Little Rock, AR 72204 USA. [Zhang, Ping] IBM Corp, Thomas J Watson Res Ctr, Healthcare Analyt Res Grp, Yorktown Hts, NY 10598 USA. [Huang, Jialiang] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Huang, Jialiang] Harvard Univ, Sch Publ Heath, Boston, MA 02215 USA. [Kao, Emily] Univ Calif Berkeley, Dept Bioengn, Berkeley, CA 94720 USA. [Shi, Leming] Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China. RP Yang, L (reprint author), GlaxoSmithKline Res & Dev Ltd, 709 Swedeland Rd, Philadelphia, PA 19406 USA. EM lun.yang@gmail.com RI Luo, Heng/D-3616-2016 OI Luo, Heng/0000-0001-5192-8878 FU Minwei Meng foundation at Shanghai Jiao Tong University FX Funding for open access charge: Minwei Meng foundation at Shanghai Jiao Tong University. NR 47 TC 11 Z9 11 U1 0 U2 11 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JUL 1 PY 2014 VL 42 IS W1 BP W46 EP W52 DI 10.1093/nar/gku433 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AM2XN UT WOS:000339715000009 PM 24875476 ER PT J AU Choy, E MacConaill, LE Cote, GM Le, LP Shen, JK Nielsen, GP Iafrate, AJ Garraway, LA Hornicek, FJ Duan, ZF AF Choy, Edwin MacConaill, Laura E. Cote, Gregory M. Le, Long P. Shen, Jacson K. Nielsen, Gunnlaugur P. Iafrate, Anthony J. Garraway, Levi A. Hornicek, Francis J. Duan, Zhenfeng TI Genotyping Cancer-Associated Genes in Chordoma Identifies Mutations in Oncogenes and Areas of Chromosomal Loss Involving CDKN2A, PTEN, and SMARCB1 SO PLOS ONE LA English DT Article ID MALIGNANT RHABDOID TUMORS; SKULL BASE CHORDOMAS; CELL LUNG-CANCER; SWI/SNF COMPLEXES; SACRAL CHORDOMAS; INHIBITION; THERAPY; BONE; EZH2; REEXPRESSION AB The molecular mechanisms underlying chordoma pathogenesis are unknown. We therefore sought to identify novel mutations to better understand chordoma biology and to potentially identify therapeutic targets. Given the relatively high costs of whole genome sequencing, we performed a focused genetic analysis using matrix-assisted laser desorption/ionization-time of flight mass spectrometer (Sequenom iPLEX genotyping). We tested 865 hotspot mutations in 111 oncogenes and selected tumor suppressor genes (OncoMap v.3.0) of 45 human chordoma tumor samples. Of the analyzed samples, seven were identified with at least one mutation. Six of these were from fresh frozen samples, and one was from a paraffin embedded sample. These observations were validated using an independent platform using homogeneous mass extend MALDI-TOF (Sequenom hME Genotyping). These genetic alterations include: ALK (A877S), CTNNB1 (T41A), NRAS (Q61R), PIK3CA (E545K), PTEN (R130), CDKN2A (R58*), and SMARCB1 (R40*). This study reports on the largest comprehensive mutational analysis of chordomas performed to date. To focus on mutations that have the greatest chance of clinical relevance, we tested only oncogenes and tumor suppressor genes that have been previously implicated in the tumorigenesis of more common malignancies. We identified rare genetic changes that may have functional significance to the underlying biology and potential therapeutics for chordomas. Mutations in CDKN2A and PTEN occurred in areas of chromosomal copy loss. When this data is paired with the studies showing 18 of 21 chordoma samples displaying copy loss at the locus for CDKN2A, 17 of 21 chordoma samples displaying copy loss at PTEN, and 3 of 4 chordoma samples displaying deletion at the SMARCB1 locus, we can infer that a loss of heterozygosity at these three loci may play a significant role in chordoma pathogenesis. C1 [Choy, Edwin; Cote, Gregory M.] Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02114 USA. [Choy, Edwin; Cote, Gregory M.; Shen, Jacson K.; Hornicek, Francis J.; Duan, Zhenfeng] Massachusetts Gen Hosp, Ctr Sarcoma & Connect Tissue Oncol, Sarcoma Biol Lab, Boston, MA 02114 USA. [MacConaill, Laura E.; Garraway, Levi A.] Harvard Univ, Sch Med, Ctr Canc Genome Discovery, Boston, MA 02115 USA. [MacConaill, Laura E.; Garraway, Levi A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Le, Long P.; Nielsen, Gunnlaugur P.; Iafrate, Anthony J.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Choy, E (reprint author), Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02114 USA. EM echoy@partners.org OI Cote, Gregory/0000-0003-0181-886X FU Jennifer Hunter Yates Foundation; Stephan L. Harris Chordoma Fund; Cassandra Moseley Berry Sarcoma Endowed Fund; Gategno Fund; Wechsler Fund; KL2 Medical Research Investigator Training (MeRIT) grant (National Institutes of Health) [1KL2RR025757-01]; Harvard University FX This project was supported in part by the Jennifer Hunter Yates Foundation, the Stephan L. Harris Chordoma Fund, the Cassandra Moseley Berry Sarcoma Endowed Fund, the Gategno and Wechsler Funds, and the KL2 Medical Research Investigator Training (MeRIT) grant awarded to E.C. through Harvard Catalyst/The Harvard Clinical and Translational Science Center (National Institutes of Health grant 1KL2RR025757-01), and by financial contributions from Harvard University and its affiliated academic health care centers. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 13 Z9 14 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 1 PY 2014 VL 9 IS 7 AR e101283 DI 10.1371/journal.pone.0101283 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AM1UX UT WOS:000339635000083 PM 24983247 ER PT J AU Frederick, DT Fragomeni, RAS Schalck, A Ferreiro-Neira, I Hoff, T Cooper, ZA Haq, R Panka, DJ Kwong, LN Davies, MA Cusack, JC Flaherty, KT Fisher, DE Mier, JW Wargo, JA Sullivan, RJ AF Frederick, Dennie T. Fragomeni, Roberto A. Salas Schalck, Aislyn Ferreiro-Neira, Isabel Hoff, Taylor Cooper, Zachary A. Haq, Rizwan Panka, David J. Kwong, Lawrence N. Davies, Michael A. Cusack, James C. Flaherty, Keith T. Fisher, David E. Mier, James W. Wargo, Jennifer A. Sullivan, Ryan J. TI Clinical Profiling of BCL-2 Family Members in the Setting of BRAF Inhibition Offers a Rationale for Targeting De Novo Resistance sing BH3 Mimetics SO PLOS ONE LA English DT Article ID ACQUIRED-RESISTANCE; METASTATIC MELANOMA; SOLID TUMORS; PHASE-I; POTENTIAL MECHANISM; DOWN-REGULATION; BIM EXPRESSION; V600E MUTATION; HUMAN CANCERS; SURVIVAL AB While response rates to BRAF inhibitiors (BRAFi) are high, disease progression emerges quickly. One strategy to delay the onset of resistance is to target anti-apoptotic proteins such as BCL-2, known to be associated with a poor prognosis. We analyzed BCL-2 family member expression levels of 34 samples from 17 patients collected before and 10 to 14 days after treatment initiation with either vemurafenib or dabrafenib/trametinib combination. The observed changes in mRNA and protein levels with BRAFi treatment led us to hypothesize that combining BRAFi with a BCL-2 inhibitor (the BH3-mimetic navitoclax) would improve outcome. We tested this hypothesis in cell lines and in mice. Pretreatment mRNA levels of BCL-2 negatively correlated with maximal tumor regression. Early increases in mRNA levels were seen in BIM, BCL-XL, BID and BCL2-W, as were decreases in MCL-1 and BCL2A. No significant changes were observed with BCL-2. Using reverse phase protein array (RPPA), significant increases in protein levels were found in BIM and BID. No changes in mRNA or protein correlated with response. Concurrent BRAF (PLX4720) and BCL2 (navitoclax) inhibition synergistically reduced viability in BRAF mutant cell lines and correlated with down-modulation of MCL-1 and BIM induction after PLX4720 treatment. In xenograft models, navitoclax enhanced the efficacy of PLX4720. The combination of a selective BRAF inhibitor with a BH3-mimetic promises to be an important therapeutic strategy capable of enhancing the clinical efficacy of BRAF inhibition in many patients that might otherwise succumb quickly to de novo resistance. C1 [Frederick, Dennie T.; Fragomeni, Roberto A. Salas; Ferreiro-Neira, Isabel; Hoff, Taylor; Cusack, James C.] Massachusetts Gen Hosp, Div Surg Oncol, Boston, MA 02114 USA. [Fragomeni, Roberto A. Salas; Haq, Rizwan; Panka, David J.; Cusack, James C.; Flaherty, Keith T.; Fisher, David E.; Mier, James W.; Sullivan, Ryan J.] Harvard Univ, Sch Med, Boston, MA 02138 USA. [Schalck, Aislyn; Haq, Rizwan; Flaherty, Keith T.; Sullivan, Ryan J.] Massachusetts Gen Hosp, Ctr Canc, Div Med Oncol, Boston, MA USA. [Cooper, Zachary A.; Kwong, Lawrence N.; Davies, Michael A.; Wargo, Jennifer A.] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol & Genom Med, Houston, TX 77030 USA. [Panka, David J.; Mier, James W.] Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Boston, MA 02215 USA. [Fisher, David E.] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. RP Sullivan, RJ (reprint author), Harvard Univ, Sch Med, Boston, MA 02138 USA. EM rsullivan7@partners.org FU MGH; Eugene Michael Egan Translational Research Fund at BIDMC FX Funding Sources for this work include: 1. Internal sundry funds at MGH. 2. The Eugene Michael Egan Translational Research Fund at BIDMC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 12 Z9 12 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 1 PY 2014 VL 9 IS 7 AR e101286 DI 10.1371/journal.pone.0101286 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AM1UX UT WOS:000339635000084 PM 24983357 ER PT J AU Koo, KH Nguyen, HV Gilmore, AK Blayney, JA Kaysen, DL AF Koo, Kelly H. Nguyen, Hong V. Gilmore, Amanda K. Blayney, Jessica A. Kaysen, Debra L. TI Posttraumatic Cognitions, Somatization, and PTSD Severity Among Asian American and White College Women With Sexual Trauma Histories SO PSYCHOLOGICAL TRAUMA-THEORY RESEARCH PRACTICE AND POLICY LA English DT Article DE race; Asian Americans; posttraumatic cognitions; somatization; PTSD ID STRESS-DISORDER; PROCESSING THERAPY; PROLONGED EXPOSURE; EXPERIENCES SURVEY; PROTECTIVE FACTORS; ASSAULT SURVIVORS; INVENTORY PTCI; FEMALE VICTIMS; STUDENTS; HEALTH AB The need for trauma research with monoracial groups such as Asian Americans (AAs) has recently been emphasized to better understand trauma experiences and inform interventions across populations. Given AA cultural contexts, posttraumatic cognitions and somatization may be key in understanding trauma experiences for this group. AA and White American (WA) trauma-exposed college women completed a survey on sexual trauma history, posttraumatic cognitions, somatic symptoms, and PTSD severity. For the overall sample, higher negative cognitions were associated with higher somatization. Asian race was associated with higher negative cognitions, which then predicted higher PTSD. Unexpectedly, WAs more strongly endorsed somatization than AAs. These findings indicate that posttraumatic cognitions may be helpful in understanding relationships between somatization and PTSD severity among those of Asian backgrounds and that the relationship between somatization and PTSD symptoms is culturally complex. C1 [Koo, Kelly H.; Nguyen, Hong V.; Gilmore, Amanda K.] Univ Washington, Dept Psychol, Seattle, WA 98195 USA. [Blayney, Jessica A.; Kaysen, Debra L.] Univ Washington, Seattle, WA 98195 USA. RP Koo, KH (reprint author), San Francisco VA Med Ctr, 4150 Clement St, San Francisco, CA 94121 USA. EM kelly.koo@va.gov FU NIAAA NIH HHS [R21 AA016211] NR 54 TC 4 Z9 4 U1 3 U2 12 PU EDUCATIONAL PUBLISHING FOUNDATION-AMERICAN PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST, NE, WASHINGTON, DC 20002-4242 USA SN 1942-9681 EI 1942-969X J9 PSYCHOL TRAUMA-US JI Psychol. Trauma PD JUL PY 2014 VL 6 IS 4 BP 337 EP 344 DI 10.1037/a0033830 PG 8 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA AM2FD UT WOS:000339664100006 PM 25419439 ER PT J AU McGeary, CA Garcia, HA McGeary, DD Finley, EP Peterson, AL AF McGeary, Cindy A. Garcia, Hector A. McGeary, Donald D. Finley, Erin P. Peterson, Alan L. TI Burnout and Coping: Veterans Health Administration Posttraumatic Stress Disorder Mental Health Providers SO PSYCHOLOGICAL TRAUMA-THEORY RESEARCH PRACTICE AND POLICY LA English DT Article DE burnout; caffeine use; absenteeism; health behaviors; Veterans Health Administration ID OCCUPATIONAL STRESS; GENERAL SURVEY; ABSENTEEISM; EMPLOYEES; NURSES; IRAQ; SATISFACTION; AFGHANISTAN; PERFORMANCE; INVENTORY AB Mental health providers employed specifically by the Veterans Health Administration to treat posttraumatic stress disorder (PTSD) may be at increased risk for burnout due to both organizational and patient care stressors. Usage of caffeine, alcohol, and tobacco products may increase as a means to cope with burnout and stress. This cross-sectional study measured concurrent changes in burnout levels and caffeine, alcohol, and tobacco use as a means to cope with work stressors among a population of Veterans Health Administration mental health providers working within a PTSD specialty clinic. This study consisted of 138 participants, and the sample was mostly female (67%), Caucasian (non-Hispanic; 81%), and married (70%), with a mean age of 44.3 years (SD = 11.2). Participants completed an electronic survey that assessed demographics, absenteeism, and coping behaviors, as well as burnout as measured through the Maslach Burnout Inventory-General Survey (Maslach, Jackson, & Leiter, 1996). The study results revealed a minor predictive relationship between some dimensions of burnout and the use of some negative health behaviors (drinking and caffeine use) to cope with work stress. Burnout scores (i. e., exhaustion) significantly predicted concurrent missed time from work for both physical and emotional health reasons (sick days/mental health days), but tobacco and caffeine use contributed little, and alcohol was not related to burnout at all. In the future, it would be useful to obtain information regarding in-depth health behaviors that include baseline data as well as prospective systematic fluctuations in these behaviors due to work stressors. C1 [McGeary, Cindy A.; McGeary, Donald D.; Peterson, Alan L.] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychol, San Antonio, TX 78229 USA. [Garcia, Hector A.] South Texas Vet Hlth Care Syst, PTSD Clin Team, San Antonio, TX USA. [Garcia, Hector A.] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Finley, Erin P.] South Texas Vet Hlth Care Syst, Res Serv, San Antonio, TX USA. [Finley, Erin P.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. RP McGeary, CA (reprint author), STRONG STAR, 7550 IH-10 West,Suite 1325, San Antonio, TX 78229 USA. EM mcgearyc@uthscsa.edu OI Finley, Erin/0000-0003-4497-7721 NR 37 TC 1 Z9 1 U1 0 U2 14 PU EDUCATIONAL PUBLISHING FOUNDATION-AMERICAN PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST, NE, WASHINGTON, DC 20002-4242 USA SN 1942-9681 EI 1942-969X J9 PSYCHOL TRAUMA-US JI Psychol. Trauma PD JUL PY 2014 VL 6 IS 4 BP 390 EP 397 DI 10.1037/a0036144 PG 8 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA AM2FD UT WOS:000339664100013 ER PT J AU Liong, M Im, H Majmudar, MD Aguirre, AD Sebas, M Lee, H Weissleder, R AF Liong, Monty Im, Hyungsoon Majmudar, Maulik D. Aguirre, Aaron D. Sebas, Matthew Lee, Hakho Weissleder, Ralph TI Magnetic Ligation Method for Quantitative Detection of MicroRNAs SO ADVANCED HEALTHCARE MATERIALS LA English DT Article ID POINT MUTATION DETECTION; ASSAY; AMPLIFICATION; DISEASE; INJURY C1 [Liong, Monty; Im, Hyungsoon; Majmudar, Maulik D.; Aguirre, Aaron D.; Sebas, Matthew; Lee, Hakho; Weissleder, Ralph] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA 02114 USA. [Weissleder, Ralph] Harvard Univ, Dept Syst Biol, Sch Med, Boston, MA 02115 USA. RP Lee, H (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, 185 Cambridge St, Boston, MA 02114 USA. EM hlee@mgh.harvard.edu; rweissleder@mgh.harvard.edu RI Im, Hyungsoon/A-3178-2009 OI Im, Hyungsoon/0000-0002-0626-1346 FU NIH [R01-EB010011, R01-EB00462605A1, T32CA79443, R01-HL113156]; NHLBI [HHSN268201000044C] FX The authors thank P. Dutta, K. Lee, M. McKee, H. Sager, N. Sergeyev, and H. Shao for assistance with the experiments; Y. Fisher-Jeffes for reviewing the manuscript. This work was supported in part by NIH grants R01-EB010011 (R.W.), R01-EB00462605A1 (R.W.), T32CA79443 (R.W.), R01-HL113156 (H. L.), and NHLBI contract HHSN268201000044C (R.W.). NR 33 TC 1 Z9 1 U1 3 U2 21 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2192-2640 EI 2192-2659 J9 ADV HEALTHC MATER JI Adv. Healthc. Mater. PD JUL PY 2014 VL 3 IS 7 BP 1015 EP 1019 DI 10.1002/adhm.201300672 PG 5 WC Engineering, Biomedical; Nanoscience & Nanotechnology; Materials Science, Biomaterials SC Engineering; Science & Technology - Other Topics; Materials Science GA AM0QE UT WOS:000339549900008 PM 24532323 ER PT J AU Chen, Q Hanchate, A Shwartz, M Borzecki, AM Mull, HJ Shin, MH Rosen, AK AF Chen, Qi Hanchate, Amresh Shwartz, Michael Borzecki, Ann M. Mull, Hillary J. Shin, Marlena H. Rosen, Amy K. TI Comparison of the Agency for Healthcare Research and Quality Patient Safety Indicator Rates Among Veteran Dual Users SO AMERICAN JOURNAL OF MEDICAL QUALITY LA English DT Article DE patient safety indicators; quality measurements; patient safety; quality of care; coding variation ID PRESSURE ULCER CARE; IMPROVEMENT PROGRAM; MEDICARE; AFFAIRS; VA AB This study compares rates of I 1 Agency for Healthcare Research and Quality Patient Safety Indicators (PSIs) among 266 203 veteran dual users (ie, those with hospitalizations in both the Veterans Health Administration [VA] and the private sector through Medicare fee-for-service coverage) during 2002 to 2007. PSI risk-adjusted rates were calculated using the PSI software (version 3.1a). Rates of pressure ulcer, central venous catheter-related bloodstream infections, and postoperative sepsis, areas in which the VA has focused quality improvement efforts, were found to be significantly lower in the VA than in the private sector. VA had significantly higher rates for 7 of the remaining 8 PSIs, although the rates of only 2 PSIs (postoperative hemorrhage/hematoma and accidental puncture or laceration) remained higher in the VA after sensitivity analyses were conducted. A better understanding of system-level differences in coding practices and patient severity, poorly documented in administrative data, is needed before conclusions about differences in quality can be drawn. C1 [Chen, Qi; Hanchate, Amresh; Shwartz, Michael; Mull, Hillary J.; Shin, Marlena H.; Rosen, Amy K.] VA Boston Healthcare Syst, COLMR, Boston, MA 02130 USA. [Hanchate, Amresh; Borzecki, Ann M.; Mull, Hillary J.; Rosen, Amy K.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Shwartz, Michael] Boston Univ, Sch Management, Boston, MA 02215 USA. [Borzecki, Ann M.] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Borzecki, Ann M.] Bedford VAMC, Ctr Hlth Qual Outcomes & Econ Res, Bedford, MA USA. RP Chen, Q (reprint author), VA Boston Healthcare Syst, COLMR, 150 S Huntington Ave, Boston, MA 02130 USA. EM qc2112@bu.edu FU VA Health Services Research and Development (HSRD) Service [SDR-07-002] FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: VA Health Services Research and Development (HSR&D) Service, Grant No. SDR-07-002. NR 32 TC 2 Z9 2 U1 1 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1062-8606 EI 1555-824X J9 AM J MED QUAL JI Am. J. Med. Qual. PD JUL-AUG PY 2014 VL 29 IS 4 BP 335 EP 343 DI 10.1177/1062860613499402 PG 9 WC Health Care Sciences & Services SC Health Care Sciences & Services GA AL9KT UT WOS:000339460700009 PM 23969475 ER PT J AU Spatz, C Bricker, P Gabbay, R AF Spatz, Christin Bricker, Patricia Gabbay, Robert TI The Patient-Centered Medical Neighborhood: Transformation of Specialty Care SO AMERICAN JOURNAL OF MEDICAL QUALITY LA English DT Article DE patient-centered medical home; specialty; primary care; health care delivery transformation ID CHRONIC KIDNEY-DISEASE; CONTROLLED-TRIAL; COMMUNICATION; HEALTH; READMISSIONS; PHYSICIANS; QUALITY; SYSTEM; ADULTS; IMPACT AB The growing need for coordinated care of those with medically complex diseases is becoming more important in today's health care system, wherein reimbursement changes are driving methods to improve quality and cost. This article discusses the 6 key processes that, according to the American College of Physicians, define an effective medical neighborhood; the evidence supporting the need for this coordinated system; and pilot medical neighborhood strategies being implemented. C1 [Spatz, Christin] Penn State Milton S Hershey Med Ctr, Hershey, PA USA. [Bricker, Patricia] Penn State Coll Med, Hershey, PA USA. [Gabbay, Robert] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. RP Gabbay, R (reprint author), Joslin Diabet Ctr, One Joslin Pl, Boston, MA 02215 USA. EM robert.gabbay@joslin.harvard.edu NR 35 TC 6 Z9 6 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1062-8606 EI 1555-824X J9 AM J MED QUAL JI Am. J. Med. Qual. PD JUL-AUG PY 2014 VL 29 IS 4 BP 344 EP 349 DI 10.1177/1062860613498812 PG 6 WC Health Care Sciences & Services SC Health Care Sciences & Services GA AL9KT UT WOS:000339460700010 PM 23966551 ER PT J AU Axon, RN Coleman, EA AF Axon, R. Neal Coleman, Eric A. TI What Will It Take to Move the Needle on Hospital Readmissions? SO AMERICAN JOURNAL OF MEDICAL QUALITY LA English DT Editorial Material ID CARE TRANSITIONS; QUALITY C1 [Axon, R. Neal] Ralph H Johnson VAMC, Charleston, SC 29401 USA. [Axon, R. Neal] Med Univ S Carolina, Charleston, SC 29425 USA. [Coleman, Eric A.] Univ Colorado Anschutz Med Campus, Aurora, CO USA. RP Axon, RN (reprint author), Ralph H Johnson VAMC, 109 Bee St,Mail Stop 111, Charleston, SC 29401 USA. EM axon@musc.edu NR 10 TC 1 Z9 1 U1 1 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1062-8606 EI 1555-824X J9 AM J MED QUAL JI Am. J. Med. Qual. PD JUL-AUG PY 2014 VL 29 IS 4 BP 357 EP 359 DI 10.1177/1062860613505196 PG 3 WC Health Care Sciences & Services SC Health Care Sciences & Services GA AL9KT UT WOS:000339460700012 PM 24101682 ER PT J AU Burgess, DJ Taylor, BC Phelan, S Spoont, M van Ryn, M Hausmann, LRM Do, T Gordon, HS AF Burgess, Diana J. Taylor, Brent C. Phelan, Sean Spoont, Michele van Ryn, Michelle Hausmann, Leslie R. M. Do, Tam Gordon, Howard S. TI A Brief Self-Affirmation Study to Improve the Experience of Minority Patients SO APPLIED PSYCHOLOGY-HEALTH AND WELL BEING LA English DT Article DE communication; minority; racial disparities; self-affirmation; stereotype threat ID RANDOMIZED CONTROLLED-TRIAL; HEALTH-CARE PROVIDERS; STEREOTYPE THREAT; POSITIVE-AFFECT; PERCEIVED DISCRIMINATION; VALUES AFFIRMATION; AFRICAN-AMERICANS; ACHIEVEMENT GAP; ETHNIC DISPARITIES; PHYSICAL-ACTIVITY AB Background: There is evidence that Black patients may experience stereotype threat-apprehension about being negatively stereotyped-in healthcare settings, which might adversely affect their behavior in clinical encounters. Recent studies conducted outside of healthcare have shown that a brief self-affirmation intervention, in which individuals are asked to focus on and affirm their valued characteristics and sources of personal pride, can reduce the negative effects of stereotype threat on academic performance and on interpersonal communication. Methods: This randomised controlled trial examined whether a self-affirmation (SA) intervention would decrease the negative effects of stereotype threat (negative mood, lower state self-esteem, greater perceptions of racial discrimination) and increase communication self-efficacy among Black primary care patients. Self-affirmation was induced by having patients complete a 32-item values affirmation questionnaire. Results: Patients in the SA condition had lower levels of performance self-esteem and social self-esteem than patients in the control. There were no differences between the SA and the control groups on negative mood, communication self-efficacy, and perceptions of discrimination. Conclusions: Our SA intervention lowered state self-esteem among Black patients. Future research is needed to determine the type of SA task that is most effective for this population. C1 [Burgess, Diana J.; Taylor, Brent C.; Spoont, Michele; Do, Tam] Minneapolis Vet Affairs Healthcare Syst, Ctr Chron Dis Outcomes Res CCDOR, Minneapolis, MN USA. [Burgess, Diana J.; Taylor, Brent C.; Spoont, Michele] Univ Minnesota, Minneapolis, MN 55455 USA. [Phelan, Sean; van Ryn, Michelle] Mayo Div Hlth Care Policy & Res, Rochester, MN 55904 USA. [Hausmann, Leslie R. M.] Vet Affairs Pittsburgh Healthcare Syst, Ctr Hlth Equity Res & Promot CHERP, Pittsburgh, PA USA. [Hausmann, Leslie R. M.] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Gordon, Howard S.] Jesse Brown Vet Affairs Med Ctr, Chicago, IL 60612 USA. [Gordon, Howard S.] VA Ctr Innovat Complex Chron Healthcare, Hines, IL USA. [Gordon, Howard S.] Univ Illinois, Chicago Coll Med, Chicago, IL 60680 USA. RP Burgess, DJ (reprint author), VA Med Ctr, Ctr Chron Dis Outcomes Res, One Vet Dr 152-2E, Minneapolis, MN 55417 USA. EM diana.burgess@va.gov RI Gordon, Howard/E-4420-2010; Taylor, Brent/A-8069-2009; Burgess, Diana/A-1946-2016 OI Gordon, Howard/0000-0002-6712-5954; Taylor, Brent/0000-0002-2140-8377; NR 49 TC 2 Z9 2 U1 3 U2 18 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1758-0846 EI 1758-0854 J9 APPL PSYCHOL-HLTH WE JI Appl. Psychol.-Health Well Being PD JUL PY 2014 VL 6 IS 2 BP 135 EP 150 DI 10.1111/aphw.12015 PG 16 WC Psychology, Applied SC Psychology GA AL9BF UT WOS:000339433800001 PM 24124121 ER PT J AU Keruakous, AR Sadek, BT Shenouda, MN Niemierko, A Raad, RF Specht, M Smith, BL Taghian, AG AF Keruakous, Amany R. Sadek, Betro T. Shenouda, Mina N. Niemierko, Andrzej Raad, Rita F. Abi Specht, Michelle Smith, Barbara L. Taghian, Alphonse G. TI The impact of isolated tumor cells on loco-regional recurrence in breast cancer patients treated with breast-conserving treatment or mastectomy without post-mastectomy radiation therapy SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Isolated tumor cells (ITC); Breast cancer; Outcome ID LYMPH-NODE INVOLVEMENT; AXILLARY DISSECTION; SENTINEL NODE; METASTASES; CARCINOMA; SURVIVAL; PATTERNS; OUTCOMES; PN0(I+); SIZE AB To compare the outcome of patients with invasive breast cancer, who had isolated tumor cells (ITC) in sentinel lymph nodes, pN0(i+), to patients with histologically negative nodes, pN0. We retrospectively studied 1,273 patients diagnosed with T1-T3 breast cancer from 1999 to 2009. Patients were divided into 2 populations: 807 patients treated with breast-conserving surgery (BCS) and radiotherapy (RT), 85(10.5 %) with pN0(i+) and 722(89.5 %) with pN0. And the other population had 466 patients treated with mastectomy without post-mastectomy radiation therapy (PMRT), 80(17.2 %) with pN0(i+),and 386(82.8 %)with pN0. All patients underwent sentinel node biopsy, and the presence of ITC was determined. Patients with axillary dissection only or neoadjuvant chemotherapy were excluded. Among the 1,273 patients studied; 87.3 % received adjuvant systemic therapy. Kaplan-Meier, Cox regression, and log-rank statistical tests were used. Median patient age was 55.7 years. Median follow-up was 69.5 months. The 5- and 10-year cumulative incidence of Loco-regional recurrence (LRR) for patients treated with BCS and RT was 1.6 and 3.5 % for 85 pN0(i+) patients, and 2.4 and 5 % for 722 pN0 patients, respectively. For patients treated with mastectomy without PMRT, 5- and 10-year LRR rates were 2.8 and 2.8 % for 80 pN0(i+) patients, and 1.8 and 3 % for 386 pN0 patients, respectively. There were no statistically significant differences in LRR (p = 0.9), distant recurrence (p = 0.3) ,and overall survival (p = 0.5) among all groups. On multivariate analysis, ITC were not associated with increased risk of LRR, distant recurrence and overall survival. Grade (p = 0.003) and systemic therapy (p = 0.02) were statistically significantly associated with risk of LRR. Sentinel node ITC have no significant impact on LRR, distant recurrence and overall survival in breast cancer patients. Additional treatments such as axillary dissection, chemotherapy, or regional radiation should not be given solely based on the presence of sentinel node ITC. C1 [Keruakous, Amany R.; Sadek, Betro T.; Shenouda, Mina N.; Niemierko, Andrzej; Raad, Rita F. Abi; Taghian, Alphonse G.] Harvard Univ, Sch Med, Dept Radiat Oncol, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Niemierko, Andrzej] Harvard Univ, Sch Med, Stat Sect, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Specht, Michelle; Smith, Barbara L.] Harvard Univ, Sch Med, Div Surg Oncol, Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Taghian, AG (reprint author), Harvard Univ, Sch Med, Dept Radiat Oncol, Massachusetts Gen Hosp, Cox 3 Bldg,100 Blossom St, Boston, MA 02114 USA. EM ataghian@partners.org RI Sadek, Betro/I-7734-2013 OI Sadek, Betro/0000-0003-0119-7207 NR 22 TC 0 Z9 0 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 EI 1573-7217 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD JUL PY 2014 VL 146 IS 2 BP 365 EP 370 DI 10.1007/s10549-014-3027-2 PG 6 WC Oncology SC Oncology GA AL7QR UT WOS:000339330300014 PM 24952906 ER PT J AU Boeke, CE Eliassen, AH Chen, WDY Cho, EY Holmes, MD Rosner, B Willett, WC Tamimi, RM AF Boeke, Caroline E. Eliassen, A. Heather Chen, Wendy Y. Cho, Eunyoung Holmes, Michelle D. Rosner, Bernard Willett, Walter C. Tamimi, Rulla M. TI Dietary fat intake in relation to lethal breast cancer in two large prospective cohort studies SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Fat; Breast cancer; Mortality; Survival; Cholesterol; Lethal ID CORONARY-HEART-DISEASE; RED MEAT INTAKE; RISK-FACTORS; PROSTATE-CANCER; NURSES HEALTH; PREMENOPAUSAL WOMEN; MOLECULAR SUBTYPES; FOOD-CONSUMPTION; COMPETING RISKS; POOLED ANALYSIS AB Whether fat intake influences risk of developing more aggressive, lethal breast tumors is unknown. We evaluated intakes of total fat, specific types of fat, and cholesterol prior to diagnosis in relation to lethal breast cancer risk in 88,759 women in the Nurses' Health Study (NHS; 1980-2010) and 93,912 women in the Nurses' Health Study II (NHSII; 1991-2010). Diet was assessed every 4 years using a semi-quantitative food frequency questionnaire. Breast cancers were confirmed with pathology reports; deaths were confirmed by next of kin or the National Death Index. We defined lethal cases as women with invasive breast cancer who died of breast cancer. We pooled the cohorts and used multivariable Cox proportional hazards models. We identified 1,529 lethal breast cancer cases (1,279 in NHS and 250 in NHSII). Higher total fat intake was associated with a slightly lower lethal breast cancer risk (top vs. bottom quintile hazard ratio [HR] 0.85; 95 % CI 0.72, 1.01; p trend = 0.05). Specific types of fat were generally not associated with lethal breast cancer risk. For example, compared with those in the lowest quintile of saturated fat intake, those in the highest quintile had a HR of 0.98 (95 % CI 0.75, 1.26; p trend = 0.96). Among women diagnosed with breast cancer, pre-diagnosis fat intake was not associated with survival. Higher pre-diagnosis fat intake was not associated with greater risk of lethal breast cancer in these large prospective cohort studies, consistent with the weight of the evidence against a causal role for fat intake and breast cancer incidence. C1 [Boeke, Caroline E.; Eliassen, A. Heather; Holmes, Michelle D.; Rosner, Bernard; Willett, Walter C.; Tamimi, Rulla M.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Boeke, Caroline E.; Eliassen, A. Heather; Chen, Wendy Y.; Cho, Eunyoung; Holmes, Michelle D.; Rosner, Bernard; Willett, Walter C.; Tamimi, Rulla M.] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Eliassen, A. Heather; Holmes, Michelle D.; Rosner, Bernard; Willett, Walter C.; Tamimi, Rulla M.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Chen, Wendy Y.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Cho, Eunyoung] Brown Univ, Warren Alpert Med Sch, Dept Dermatol, Providence, RI 02903 USA. [Rosner, Bernard] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Willett, Walter C.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. RP Boeke, CE (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave, Boston, MA 02115 USA. EM caroline.boeke@mail.harvard.edu FU Breast Cancer Research Foundation; National Institutes of Health [P01 CA87969, UM1 CA176726, R01 CA 050385]; National Institutes of Health Cancer Epidemiology Training Grant [T32 CA 09001] 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. In addition, this study was approved by the Connecticut Department of Public Health (DPH) Human Investigations Committee. We acknowledge Elizabeth M. Poole and Erica T. Warner for their assistance with this analysis. Certain data used in this publication were obtained from the DPH. This work was supported by the Breast Cancer Research Foundation and the National Institutes of Health (P01 CA87969, UM1 CA176726, R01 CA 050385). Caroline Boeke was funded by the National Institutes of Health Cancer Epidemiology Training Grant T32 CA 09001. NR 46 TC 6 Z9 6 U1 8 U2 24 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 EI 1573-7217 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD JUL PY 2014 VL 146 IS 2 BP 383 EP 392 DI 10.1007/s10549-014-3005-8 PG 10 WC Oncology SC Oncology GA AL7QR UT WOS:000339330300016 PM 24894342 ER PT J AU Gutierrez, A Feng, H Stevenson, K Neuberg, DS Calzada, O Zhou, Y Langenau, DM Look, AT AF Gutierrez, Alejandro Feng, Hui Stevenson, Kristen Neuberg, Donna S. Calzada, Oscar Zhou, Yi Langenau, David M. Look, A. Thomas TI Loss of function tp53 mutations do not accelerate the onset of myc-induced T-cell acute lymphoblastic leukaemia in the zebrafish SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE Myc; Tp53; ARF; tumour suppression; T-cell acute lymphoblastic leukaemia ID ARF TUMOR-SUPPRESSOR; REGULATED TRANSGENIC ZEBRAFISH; P53 MUTATIONS; HOMOZYGOUS DELETIONS; IN-VIVO; GENE; P16(INK4A); MODEL; LYMPHOMAGENESIS; TUMORIGENESIS AB The TP53 tumour suppressor is activated in response to distinct stimuli, including an ARF-dependent response to oncogene stress and an ATM/ATR-dependent response to DNA damage. In human T-cell acute lymphoblastic leukaemia (T-ALL), TP53-dependent tumour suppression is typically disabled via biallelic ARF deletions. In murine models, loss of Arf (Cdkn2a) or Tp53 markedly accelerates the onset of Myc-induced lymphoblastic malignancies. In zebrafish, no ARF ortholog has been identified, but the sequence of ARF is very poorly conserved evolutionarily, making it difficult to exclude the presence of a zebrafish ARF ortholog without functional studies. Here we show that tp53 mutations have no significant influence on the onset of myc-induced T-ALL in zebrafish, consistent with the lack of additional effects of Tp53 loss on lymphomagenesis in Arf-deficient mice. By contrast, irradiation leads to complete T-ALL regression in tp53 wildtype but not homozygous mutant zebrafish, indicating that the tp53-dependent DNA damage response is intact. We conclude that tp53 inactivation has no impact on the onset of myc-induced T-ALL in the zebrafish, consistent with the lack of a functional ARF ortholog linking myc-induced oncogene stress to tp53-dependent tumour suppression. Thus, the zebrafish model is well suited to the study of ARF-independent pathways in T-ALL pathobiology. C1 [Gutierrez, Alejandro; Feng, Hui; Look, A. Thomas] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Gutierrez, Alejandro; Calzada, Oscar; Zhou, Yi; Look, A. Thomas] Harvard Univ, Sch Med, Boston Childrens Hosp, Div Hematol Oncol, Boston, MA USA. [Feng, Hui] Boston Univ, Sch Med, Dept Pharmacol & Expt Therapeut, Canc Ctr,Sect Hematol & Med Oncol, Boston, MA 02118 USA. [Feng, Hui; Stevenson, Kristen] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Zhou, Yi] Harvard Univ, Sch Med, Stem Cell Program, Boston Childrens Hosp, Boston, MA USA. [Langenau, David M.] Massachusetts Gen Hosp, Dept Pathol, Charlestown, MA USA. [Langenau, David M.] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA USA. [Langenau, David M.] Harvard Univ, Sch Med, Harvard Stem Cell Inst, Boston, MA USA. [Langenau, David M.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. RP Look, AT (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Mayer 630450 Brookline Ave, Boston, MA 02215 USA. EM thomas_look@dfci.harvard.edu FU National Institutes of Health, USA [NCI 5P01CA68484, NCI 1K08CA133103, NCI 5R21CA167124]; American Society of Hematology Harold Amos Medical Faculty Development Program; NIH [NCI K99CA134743, K01AR055619, 1RO1CA154923, 1R21CA156056]; American Cancer Society Research Scholar Grant; Leukemia Research Foundation; Alex Lemonade Stand Foundation; Harvard Stem Cell Institute FX This work was supported by grants from the National Institutes of Health, USA (Grant NCI 5P01CA68484 to ATL and grants NCI 1K08CA133103 and NCI 5R21CA167124 to AG), as well as an award from the American Society of Hematology Harold Amos Medical Faculty Development Program (AG). Alejandro Gutierrez is a Research Fellow of the Gabrielle's Angel Foundation for Cancer Research. Hui Feng is supported by NIH grant NCI K99CA134743. David M. Langenau is supported by NIH grants K01AR055619, 1RO1CA154923, and 1R21CA156056, an American Cancer Society Research Scholar Grant, the Leukemia Research Foundation, the Alex Lemonade Stand Foundation, and the Harvard Stem Cell Institute. The authors have no conflicts of interest to disclose. NR 44 TC 3 Z9 3 U1 0 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 JUL PY 2014 VL 166 IS 1 BP 84 EP 90 DI 10.1111/bjh.12851 PG 7 WC Hematology SC Hematology GA AL7UQ UT WOS:000339341700011 PM 24690081 ER PT J AU Martindale, J Swenson, A Coffman, J Newton, AW Lindberg, DM AF Martindale, Jennifer Swenson, Alice Coffman, Jamye Newton, Alice W. Lindberg, Daniel M. CA ExSTRA Investigators TI Recurrent concerns for child abuse: Repeated consultations by a subspecialty child abuse team SO CHILD ABUSE & NEGLECT LA English DT Article DE Abuse; Maltreatment; Child protection; Foster care ID TRAUMATIC BRAIN-INJURY; HEAD TRAUMA; REASONABLE SUSPICION; PHYSICAL ABUSE; PROTECTION AB Physically abused children may be repeatedly reported to child protection services and undergo multiple medical evaluations. Less is known about recurrent evaluations by hospital-based child abuse teams for possible abuse. The objectives of this study were to determine the frequency of repeated consultations by child abuse teams and to describe this cohort in terms of injury pattern, perceived likelihood of abuse, disposition plan, and factors related to repeat consultation. This was a prospectively planned, secondary analysis of data from the Examining Siblings to Recognize Abuse (ExSTRA) research network. Subjects included children younger than 10 years of age who were referred to child abuse subspecialty teams at one of 20 U.S. academic centers. Repeat consultations occurred in 101 (3.5%; 95% CI 2.9-4.2%) of 2890 subjects. The incidence of death was 4% (95% CI 1-9%) in subjects with repeated consults and 3% (95% CI 2-3%) in subjects with single consults. Perceived likelihood of abuse from initial to repeat visit remained low in 33% of subjects, remained high in 24.2% of subjects, went from low to high in 16.5%, and high to low in 26.4% of subjects. Themes identified among the subset of patients suspected of repeated abuse include return to the same environment, failure to comply with a safety plan, and abuse in foster care. Repeated consultation by child abuse specialists occurs for a minority of children. This group of children may be at higher risk of subsequent abuse and may represent an opportunity for quality improvement. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Martindale, Jennifer] SUNY Downstate, Dept Emergency Med, Brooklyn, NY 11203 USA. [Swenson, Alice] Childrens Hosp Wisconsin, Milwaukee, WI 53226 USA. [Coffman, Jamye] Cook Childrens Med Ctr, Ft Worth, TX 76104 USA. [Newton, Alice W.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Lindberg, Daniel M.] Kempe Ctr Prevent & Treatment Child Abuse & Negle, Aurora, CO 80045 USA. [Lindberg, Daniel M.] Univ Colorado, Sch Med, Dept Emergency Med, Aurora, CO 80045 USA. RP Martindale, J (reprint author), SUNY Downstate, Dept Emergency Med, 450 Clarkson Ave,Box 1228, Brooklyn, NY 11203 USA. NR 25 TC 0 Z9 0 U1 1 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2134 EI 1873-7757 J9 CHILD ABUSE NEGLECT JI Child Abuse Negl. PD JUL PY 2014 VL 38 IS 7 BP 1259 EP 1266 DI 10.1016/j.chiabu.2014.03.007 PG 8 WC Family Studies; Psychology, Social; Social Work SC Family Studies; Psychology; Social Work GA AM1YC UT WOS:000339644200013 PM 24726050 ER PT J AU Litwack, SD Mitchell, KS Sloan, D Reardon, AF Miller, M AF Litwack, Scott D. Mitchell, Karen S. Sloan, DeniseM. Reardon, Annemarie F. Miller, Markw. TI Eating disorder symptoms and comorbid psychopathology among male and female veterans SO GENERAL HOSPITAL PSYCHIATRY LA English DT Article DE Binge eating disorder; Bulimia nervosa; Gender; Comorbidity; Veterans ID MENTAL-HEALTH DIAGNOSES; PSYCHIATRIC COMORBIDITY; GENDER-DIFFERENCES; SURVEY-REPLICATION; COMMUNITY SAMPLE; PREVALENCE; SUBTHRESHOLD; AFGHANISTAN; WOMEN; IRAQ AB Objective: Eating disorder (ED) symptoms have gone mostly unexamined among veterans. The current study assessed rates of bulimia nervosa (BN) and binge eating disorder (BED) symptoms and diagnoses and their associations with common comorbidities among male and female veterans. Method: Participants were US military veterans who screened positive for trauma histories and/or a probable Diagnostic and Statistical Manual of Mental Disorders 4th Edition (DSM-IV) posttraumatic stress disorder (PTSD) diagnosis (n=499). Symptoms of PTSD were assessed using the Clinician-Administered PTSD Scale, and symptoms of EDs, mood, and substance use disorders were assessed using the Structured Clinical Interview for the DSM-IV. Results: Lifetime rates of BN and BED diagnoses were comparable to civilian populations, and a considerable range of lifetime and current BN and BED symptoms were identified. In multivariate models, PTSD and depression severity were most consistently associated with BN and BED symptom severity, with depression most strongly associated with EDs for women. Conclusions: Findings highlight the importance of screening for ED symptoms among male and female veterans, particularly those that present with PTSD and depression symptomatology. Future examinations of the temporal order of such relationships and the degree to which ED symptoms and associated symptoms impact veteran functioning are warranted. Published by Elsevier Inc. C1 [Litwack, Scott D.; Mitchell, Karen S.; Sloan, DeniseM.; Reardon, Annemarie F.; Miller, Markw.] VA Boston Healthcare Syst, Boston, MA USA. [Litwack, Scott D.; Mitchell, Karen S.; Sloan, DeniseM.; Miller, Markw.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02215 USA. RP Miller, M (reprint author), VA Boston Healthcare Syst 116B 4, 150 S Huntington Ave, Boston, MA 02130 USA. EM Mark.Miller5@va.gov RI Miller, Mark/G-7322-2011 OI Miller, Mark/0000-0001-6393-8563 FU VA Clinical Science RD award [MHBA-012-10F]; National Institute on Mental Health [RO1MH079806] FX Support for this study was provided by the VA Clinical Science R&D award MHBA-012-10F and the National Institute on Mental Health award RO1MH079806 to Mark W. Miller. Karen S. Mitchell's contribution was supported by K01MH093750. NR 40 TC 10 Z9 10 U1 3 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0163-8343 EI 1873-7714 J9 GEN HOSP PSYCHIAT JI Gen. Hosp. Psych. PD JUL-AUG PY 2014 VL 36 IS 4 BP 406 EP 410 DI 10.1016/j.genhosppsych.2014.03.013 PG 5 WC Psychiatry SC Psychiatry GA AL7RZ UT WOS:000339333800009 PM 24815590 ER PT J AU Richards, AM Januzzi, JL Troughton, RW AF Richards, A. Mark Januzzi, James L., Jr. Troughton, Richard W. TI Natriuretic Peptides in Heart Failure with Preserved Ejection Fraction SO HEART FAILURE CLINICS LA English DT Article DE Heart failure; Cardiac natriuretic peptides; B-type natriuretic peptide; N-terminal prohormone B-type natriuretic peptide; Diagnosis; Prognosis ID LEFT-VENTRICULAR DYSFUNCTION; RANDOMIZED CONTROLLED-TRIAL; EMERGENCY-DEPARTMENT PRIDE; STANDARD MEDICAL THERAPY; SYSTOLIC FUNCTION; DIASTOLIC FUNCTION; EUROPEAN-SOCIETY; PROGNOSTIC VALUE; ELDERLY-PATIENTS; TERMINAL PROBNP AB Timely diagnosis, early introduction of appropriate treatment, accurate risk stratification, and optimal titration of therapy are all key to the management of acute and chronic heart failure (HF). Plasma concentrations of the cardiac natriuretic peptides (NPs) are valuable aids in each of these elements of care. However, most data are derived from cohorts with undifferentiated HF or HF with reduced ejection fraction (HFREF), and the performance and best application of NPs in HF with preserved ejection fraction (HFPEF) is less certain. This review outlines the evidence for use of NPs in the evaluation and management of HFPEF. C1 [Richards, A. Mark] Natl Univ Singapore, Natl Univ Heart Ctr, Cardiovasc Res Inst, Dept Cardiac, Singapore 119228, Singapore. [Richards, A. Mark; Troughton, Richard W.] Univ Otago, Christchurch Heart Inst, Dept Med, Christchurch 8140, New Zealand. [Januzzi, James L., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac Intens Care Unit, Boston, MA 02114 USA. RP Richards, AM (reprint author), Natl Univ Singapore, Natl Univ Heart Ctr, Cardiovasc Res Inst, Dept Cardiac, 1E Kent Ridge Rd,NUHS Tower Block,Level 9, Singapore 119228, Singapore. EM mdcarthu@nus.edu.sg FU Roche Diagnostics; Alere; Critical Diagnostics; Siemens; Thermo Fisher; Singulex; Zensun; Amgen; Novartis; St. Jude Medical FX Professor A.M. Richards is the recipient of speakers honoraria, consultancy fees and/or research grants (in cash or in kind) from Roche Diagnostics, Alere and Critical Diagnostics. Professor J.L. Januzzi is the recipient of speakers honoraria, consultancy fees, and/or research grants from Roche Diagnostics, Siemens, Thermo Fisher, Singulex, Critical Diagnostics, Zensun, Amgen, and Novartis. Professor R.W. Troughton is the recipient of grants and/or speakers honoraria/consulting fees from Roche Diagnostics and St. Jude Medical. NR 48 TC 3 Z9 4 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7136 J9 HEART FAIL CLIN JI Heart Fail. Clin. PD JUL PY 2014 VL 10 IS 3 BP 453 EP + DI 10.1016/j.hfc.2014.04.006 PG 20 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AM0MT UT WOS:000339540400010 PM 24975909 ER PT J AU Maguire, J Lindgren, A Bevan, S Fernandez-Cadenas, I Hankey, G Jern, C Jimenez-Conde, J Lee, JM Levi, C Lemmens, R Rost, N Rosand, J Rothwell, P Strbian, D Sudlow, C Scott, R Sturm, J Thijs, V Tatlisumak, T Woo, D Worrall, B AF Maguire, J. Lindgren, A. Bevan, S. Fernandez-Cadenas, I. Hankey, G. Jern, C. Jimenez-Conde, J. Lee, J-M Levi, C. Lemmens, R. Rost, N. Rosand, J. Rothwell, P. Strbian, D. Sudlow, C. Scott, R. Sturm, J. Thijs, V. Tatlisumak, T. Woo, D. Worrall, B. TI GISCOME - Genetic Influences on Ischaemic Stroke Functional Outcome: A genome wide association study SO INTERNATIONAL JOURNAL OF STROKE LA English DT Meeting Abstract C1 [Maguire, J.; Levi, C.] Hunter Med Res Inst, Newcastle, NSW, Australia. [Maguire, J.; Levi, C.; Scott, R.] Univ Newcastle, Fac Hlth & Med, Newcastle, NSW 2300, Australia. [Lindgren, A.] Lund Univ, Lund, Sweden. [Bevan, S.] Univ Cambridge, Cambridge, England. [Fernandez-Cadenas, I.] Fundacio Docencia & Recerca Mutuaterrassa, Barcelona, Spain. [Fernandez-Cadenas, I.] Vall dHebron Inst Res, Barcelona, Spain. [Hankey, G.] Univ Western Australia, Sch Med & Pharmacol, Perth, WA 6009, Australia. [Hankey, G.] Univ Western Australia, Perth, WA 6009, Australia. [Jern, C.] Univ Gothenburg, Sahlgrenska Acad, Gothenburg, Sweden. [Jimenez-Conde, J.] Univ Autonoma Barcelona, E-08193 Barcelona, Spain. [Jimenez-Conde, J.] Hosp del Mar, IMIM, Dept Neurol, Barcelona, Spain. [Lee, J-M] Washington Univ, Dept Neurol, St Louis, MO USA. [Lemmens, R.; Thijs, V.] KU Leuven Univ Leuven, Expt Neurol Lab Neurobiol, VIB Vesalius Res Ctr, Dept Neurosci, Leuven, Belgium. [Rost, N.] Massachusetts Gen Hosp, J Philip Kistler Stroke Res Ctr, Boston, MA 02114 USA. [Rosand, J.] Broad Inst, Cambridge, MA USA. [Rosand, J.] Harvard Univ, Sch Med, Boston, MA USA. [Rosand, J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Rothwell, P.] Univ Oxford, Oxford, England. [Strbian, D.; Tatlisumak, T.] Univ Helsinki, Cent Hosp, Dept Neurol, Helsinki, Finland. [Sudlow, C.] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Sturm, J.] Gosford Hosp, Dept Neurol, Gosford, NSW, Australia. [Woo, D.] Univ Cincinnati, Cincinnati, OH USA. [Worrall, B.] Univ Virginia, Charlottesville, VA USA. RI Hankey, Graeme /H-4968-2014; Lee, Jin-Moo/K-2024-2015 OI Hankey, Graeme /0000-0002-6044-7328; Lee, Jin-Moo/0000-0002-3979-0906 NR 0 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1747-4930 EI 1747-4949 J9 INT J STROKE JI Int. J. Stroke PD JUL PY 2014 VL 9 SU 1 SI SI BP 23 EP 23 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AM0WR UT WOS:000339568900058 ER PT J AU Posthuma, R Pulliam, SJ Foust-Wright, CE Weinstein, MM Wakamatsu, MM Kaimal, AJ AF Posthuma, R. Pulliam, S. J. Foust-Wright, C. E. Weinstein, M. M. Wakamatsu, M. M. Kaimal, A. J. TI PELVIC FLOOR MUSCLE TRAINING VERSUS RETROPUBIC MIDURETHRAL SLING AS THE INITIAL TREATMENT FOR STRESS URINARY INCONTINENCE: A DECISION ANALYSIS SO INTERNATIONAL UROGYNECOLOGY JOURNAL LA English DT Meeting Abstract C1 [Posthuma, R.; Pulliam, S. J.; Foust-Wright, C. E.; Weinstein, M. M.; Wakamatsu, M. M.; Kaimal, A. J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 3 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 0937-3462 EI 1433-3023 J9 INT UROGYNECOL J JI Int. Urogynecol. J. PD JUL PY 2014 VL 25 SU 1 MA OP 072 BP S150 EP S150 PG 1 WC Obstetrics & Gynecology; Urology & Nephrology SC Obstetrics & Gynecology; Urology & Nephrology GA AL7UZ UT WOS:000339342800143 ER PT J AU Posthuma, RL Pulliam, SJ Berk, TK Foust-Wright, CE Weinstein, MM Wakamatsu, MM Phillippe, M AF Posthuma, R. L. Pulliam, S. J. Berk, T. K. Foust-Wright, C. E. Weinstein, M. M. Wakamatsu, M. M. Phillippe, M. TI ESTRADIOL AND PROGESTERONE MODULATE TOLL-LIKE RECEPTOR 4 IN CULTURED HUMAN BLADDER EPITHELIAL CELLS SO INTERNATIONAL UROGYNECOLOGY JOURNAL LA English DT Meeting Abstract ID MENSTRUAL-CYCLE C1 [Posthuma, R. L.; Pulliam, S. J.; Berk, T. K.; Foust-Wright, C. E.; Weinstein, M. M.; Wakamatsu, M. M.; Phillippe, M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 3 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 0937-3462 EI 1433-3023 J9 INT UROGYNECOL J JI Int. Urogynecol. J. PD JUL PY 2014 VL 25 SU 1 MA OP 013 BP S88 EP S89 PG 2 WC Obstetrics & Gynecology; Urology & Nephrology SC Obstetrics & Gynecology; Urology & Nephrology GA AL7UZ UT WOS:000339342800084 ER PT J AU Swaminathan, SS Oh, DJ Kang, MH Shepard, AR Pang, IH Rhee, DJ AF Swaminathan, Swarup S. Oh, Dong-Jin Kang, Min Hyung Shepard, Allan R. Pang, Iok-Hou Rhee, Douglas J. TI TGF-beta 2-Mediated Ocular Hypertension Is Attenuated in SPARC-Null Mice SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article DE SPARC; matricellular proteins; TGF-beta 2; intraocular pressure ID HUMAN TRABECULAR MESHWORK; LOWER INTRAOCULAR-PRESSURES; GROWTH-FACTOR BETA-2; OPEN-ANGLE GLAUCOMA; AQUEOUS-HUMOR; GENE-TRANSFER; EXTRACELLULAR-MATRIX; OUTFLOW FACILITY; HUMAN EYES; SIGNALING PATHWAY AB PURPOSE. Transforming growth factor-beta 2 (TGF-beta 2) has been implicated in the pathogenesis of primary open-angle glaucoma through extracellular matrix (ECM) alteration among various mechanisms. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein that regulates ECM within the trabecular meshwork (TM), and is highly upregulated by TGF-beta 2. We hypothesized that, in vivo, SPARC is a critical regulatory node in TGF-beta 2-mediated ocular hypertension. METHODS. Empty (Ad. empty) or TGF-beta 2-containing adenovirus (Ad. TGF-beta 2) was injected intravitreally into C57BL6-SV129 WT and SPARC-null mice. An initial study was performed to identify a stable period for IOP measurement under isoflurane. The IOP was measured before injection and every other day for two weeks using rebound tonometry. Additional mice were euthanized at peak IOP for immunohistochemistry. RESULTS. The IOP was stable under isoflurane during minutes 5 to 8. The IOP was significantly elevated in Ad. TGF-beta 2-injected (n = 8) versus Ad. empty-injected WT (n = 8) mice and contralateral uninjected eyes during days 4 to 11 (P < 0.03). The IOPs were not significantly elevated in Ad. TGF-beta 2-injected versus Ad. empty-injected SPARC-null mice. However, on day 8, the IOP of Ad. TGF-beta 2-injected SPARC-null eyes was elevated compared to that of contralateral uninjected eyes (P = 0.0385). Immunohistochemistry demonstrated that TGF-beta 2 stimulated increases in collagen IV, fibronectin, plasminogen activator inhibitor-1 (PAI-1), connective tissue growth factor (CTGF), and SPARC in WT mice, but only PAI-1 and CTGF in SPARC-null mice (P < 0.05). CONCLUSIONS. SPARC is essential to the regulation of TGF-beta 2-mediated ocular hypertension. Deletion of SPARC significantly attenuates the effects of TGF-beta 2 by restricting collagen IV and fibronectin expression. These data provide further evidence that SPARC may have an important role in IOP regulation and possibly glaucoma pathogenesis. C1 [Swaminathan, Swarup S.; Oh, Dong-Jin; Kang, Min Hyung; Rhee, Douglas J.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA USA. [Shepard, Allan R.] Novartis Inst Biomed Res, Ft Worth, TX USA. [Pang, Iok-Hou] Univ N Texas, Hlth Sci Ctr, Dept Pharmaceut Sci, Ft Worth, TX USA. [Pang, Iok-Hou] Univ N Texas, Hlth Sci Ctr, North Texas Eye Res Inst, Ft Worth, TX USA. RP Rhee, DJ (reprint author), Massachusetts Eye & Ear Infirm, Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. EM DougRhee@aol.com FU National Eye Institute [EY 019654-01, EY14104]; Howard Hughes Medical Institute Medical Research Fellowship; Alcon Research FX Supported by National Eye Institute Grants EY 019654-01 (DJR) and EY14104 (MEEI Vision-Core Grant), Howard Hughes Medical Institute Medical Research Fellowship (SSS), and Alcon Research. NR 71 TC 8 Z9 8 U1 0 U2 4 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD JUL PY 2014 VL 55 IS 7 BP 4084 EP 4097 DI 10.1167/iovs.13-12463 PG 14 WC Ophthalmology SC Ophthalmology GA AL9UI UT WOS:000339487000011 PM 24906856 ER PT J AU Matsumoto, H Kataoka, K Tsoka, P Connor, KM Miller, JW Vavvas, DG AF Matsumoto, Hidetaka Kataoka, Keiko Tsoka, Pavlina Connor, Kip M. Miller, Joan W. Vavvas, Demetrios G. TI Strain Difference in Photoreceptor Cell Death After Retinal Detachment in Mice SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article DE retinal detachment; retinal degeneration; photoreceptor death; cell death signaling; neurotrophins ID APOPTOSIS-INDUCING FACTOR; FIBRILLARY ACIDIC PROTEIN; FAS-MEDIATED APOPTOSIS; NERVE GROWTH-FACTOR; MULLER CELLS; EXPERIMENTAL-MODEL; RAT RETINA; MACULAR DEGENERATION; MESSENGER-RNA; TRK RECEPTORS AB PURPOSE. To evaluate the potential for mouse genetic background to effect photoreceptor cell death in response to experimental retinal detachment (RD). METHODS. Retinal detachment was induced in three inbred mouse strains (C57BL/6, BALB/c, and B6129SF2) by subretinal injection of sodium hyaluronate. A time course of photoreceptor cell death was assessed by TUNEL assay. Total photoreceptor cell death was analyzed through comparing the outer nuclear layer (ONL)/inner nuclear layer (INL) ratio 7 days post RD. Western blot analysis or quantitative real-time PCR (qPCR) were performed to assess cell death signaling, expression of endogenous neurotrophin, and levels of apoptosis inhibitors 24 hours after RD. Inflammatory cytokine secretion and inflammatory cell infiltration were quantified by ELISA and immunostaining, respectively. RESULTS. The peak of photoreceptor cell death after RD was at 24 hours in all strains. Photoreceptor cell death as well as monocyte chemoattractant protein 1 and interleukin 6 secretion at 24 hours after RD was the highest in BALB/c, followed in order of magnitude by C57BL/6 and B6129SF2. Conversely, nerve growth factor expression and ONL/INL ratio were the lowest in BALB/c. Apoptosis signaling was higher in C57BL/6, whereas necroptosis signaling was higher in C57BL/6 and BALB/c. Autophagic signaling was higher in BALB/c. X-linked inhibitor of apoptosis (XIAP) and survivin protein levels were lower in C57BL/6 and BALB/c, respectively. Macrophage/microglia infiltration was higher in C57BL/6 and BALB/c at 24 hours after RD. CONCLUSIONS. Photoreceptor cell death after RD was significantly different among the three strains, suggesting the presence of genetic factors that affect photoreceptor cell death after RD. C1 [Matsumoto, Hidetaka; Kataoka, Keiko; Tsoka, Pavlina; Connor, Kip M.; Miller, Joan W.; Vavvas, Demetrios G.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Retina Serv,Angiogenesis Lab,Dept Ophthalmol, Boston, MA USA. RP Vavvas, DG (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM Vavvas@meei.harvard.edu RI Kataoka, Keiko/B-2806-2016; OI Kataoka, Keiko/0000-0002-8795-6536; Connor, Kip/0000-0002-2048-9080; Vavvas, Demetrios/0000-0002-8622-6478 FU Foundation Lions Eye Research Fund; Yeatts Family Foundation; Macula Society Research Grant award; Bausch & Lomb Vitreoretinal Fellowship; Special Scholar Award; Physician Scientist Award; Research to Prevent Blindness Foundation; NIH [R01EY022084-01/S1, NEI R21EY023079-01A1]; NEI [EY014104] FX Supported by Foundation Lions Eye Research Fund (DGV); The Yeatts Family Foundation (DGV, JWM); a 2013 Macula Society Research Grant award (DGV); a Bausch & Lomb Vitreoretinal Fellowship (HM); a Special Scholar Award (KMC), a Physician Scientist Award (DGV), and a unrestricted grant (JWM) from the Research to Prevent Blindness Foundation; NIH R01EY022084-01/S1 (KMC); NEI R21EY023079-01A1 (DGV); and NEI Grant EY014104 (MEEI Core Grant). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Eye Institute or the National Institutes of Health. NR 72 TC 13 Z9 13 U1 0 U2 2 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD JUL PY 2014 VL 55 IS 7 BP 4165 EP 4174 DI 10.1167/iovs.14-14238 PG 10 WC Ophthalmology SC Ophthalmology GA AL9UI UT WOS:000339487000020 PM 24854853 ER PT J AU Al-Moujahed, A Nicolaou, F Brodowska, K Papakostas, TD Marmalidou, A Ksander, BR Miller, JW Gragoudas, E Vavvas, DG AF Al-Moujahed, Ahmad Nicolaou, Fotini Brodowska, Katarzyna Papakostas, Thanos D. Marmalidou, Anna Ksander, Bruce R. Miller, Joan W. Gragoudas, Evangelos Vavvas, Demetrios G. TI Uveal Melanoma Cell Growth Is Inhibited by Aminoimidazole Carboxamide Ribonucleotide (AICAR) Partially Through Activation of AMP-Dependent Kinase SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article DE AMPK; AICAR; melanoma; mTOR ID RIBOSIDE INDUCES APOPTOSIS; PROTON-BEAM IRRADIATION; FATTY-ACID OXIDATION; PROTEIN-KINASE; PROGNOSTIC-FACTORS; CHOROIDAL MELANOMA; OCULAR MELANOMA; ENERGY STATUS; MAPK PATHWAY; CANCER-CELLS AB PURPOSE. To evaluate the effects and mechanism of aminoimidazole carboxamide ribonucleotide (AICAR), an AMP-dependent kinase (AMPK) activator, on the growth of uveal melanoma cell lines. METHODS. Four different cell lines were treated with AICAR (1-4 mM). Cell growth was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay. Cell cycle analysis was conducted by flow cytometry; additionally, expression of cell-cycle control proteins, cell growth transcription factors, and downstream effectors of AMPK were determined by RT-PCR and Western blot. RESULTS. Aminoimidazole carboxamide ribonucleotide inhibited cell growth, induced S-phase arrest, and led to AMPK activation. Aminoimidazole carboxamide ribonucleotide treatment was associated with inhibition of eukaryotic translation initiation factor 4E-BP1 phosphorylation, a marker of mammalian target of rapamycin (mTOR) pathway activity. Aminoimidazole carboxamide ribonucleotide treatment was also associated with downregulation of cyclins A and D, but had minimal effects on the phosphorylation of ribosomal protein S6 or levels of the macroautophagy marker LC3B. The effects of AICAR were abolished by treatment with dipyridamole, an adenosine transporter inhibitor that blocks the entry of AICAR into cells. Treatment with adenosine kinase inhibitor 5-iodotubericidin, which inhibits the conversion of AICAR to its 5'-phosphorylated ribotide 5-aminoimidazole-4-carboxamide-1-D-ribofuranosyl-5'-monophosphate (ZMP; the direct activator of AMPK), reversed most of the growth-inhibitory effects, indicating that some of AICAR's antiproliferative effects are mediated at least partially through AMPK activation. CONCLUSIONS. Aminoimidazole carboxamide ribonucleotide inhibited uveal melanoma cell proliferation partially through activation of the AMPK pathway and downregulation of cyclins A1 and D1. C1 [Al-Moujahed, Ahmad; Brodowska, Katarzyna; Papakostas, Thanos D.; Marmalidou, Anna; Miller, Joan W.; Gragoudas, Evangelos; Vavvas, Demetrios G.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Retina Serv,Angiogenesis Lab,Dept Ophthalmol, Boston, MA 02114 USA. [Nicolaou, Fotini] Massachusetts Gen Hosp, Pediat Surg Labs, Boston, MA 02114 USA. [Ksander, Bruce R.] Harvard Univ, Sch Med, Massachusetts Eye & Ear, Schepens Eye Res Inst,Dept Ophthalmol, Boston, MA 02114 USA. RP Vavvas, DG (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Retina Serv,Angiogenesis Lab,Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. EM vavvas@meei.harvard.edu OI Al Moujahed, Ahmad/0000-0002-5435-8804; Vavvas, Demetrios/0000-0002-8622-6478 FU Research to Prevent Blindness (New York, New York, United States); Physician Scientist Award; Yeatts Family Foundation (Boston, Massachusetts, United States); National Eye Institute (Bethesda, Maryland, United States) [EY014104] FX Supported by grants from Research to Prevent Blindness (New York, New York, United States) Physician Scientist Award (DGV), Yeatts Family Foundation (Boston, Massachusetts, United States; DGV, JWM), and National Eye Institute (Bethesda, Maryland, United States) Grant EY014104 (Massachusetts Ear and Eye Infirmary Core Grant). NR 77 TC 2 Z9 2 U1 0 U2 4 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD JUL PY 2014 VL 55 IS 7 BP 4175 EP 4185 DI 10.1167/iovs.13-12856 PG 11 WC Ophthalmology SC Ophthalmology GA AL9UI UT WOS:000339487000021 PM 24781943 ER PT J AU Scarcelli, G Besner, S Pineda, R Yun, SH AF Scarcelli, Giuliano Besner, Sebastien Pineda, Roberto Yun, Seok Hyun TI Biomechanical Characterization of Keratoconus Corneas Ex Vivo With Brillouin Microscopy SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article DE Brillouin microscopy; keratoconus; corneal biomechanics ID OCULAR RESPONSE ANALYZER; OPTICAL MICROSCOPY; COLLAGEN; STROMA; EYES; ORGANIZATION; ELASTICITY; THICKNESS AB PURPOSE. Loss of corneal strength is a central feature of keratoconus progression. However, it is currently difficult to measure corneal mechanical changes noninvasively. The objective of this study is to evaluate if Brillouin optical microscopy can differentiate the mechanical properties of keratoconic corneas versus healthy corneas ex vivo. METHODS. We obtained eight tissue samples from healthy donor corneas used in Descemet's stripping endothelial keratoplasty (DSEK) and 10 advanced keratoconic corneas from patients undergoing deep anterior lamellar keratoplasty (DALK). Within 2 hours after surgery, a confocal Brillouin microscope using a monochromatic laser at 532 nm was used to map the Brillouin frequency shifts of the corneas. RESULTS. The mean Brillouin shift in the anterior 200 mu m of the keratoconic corneas at the cone was measured to be 7.99 +/- 0.10 GHz, significantly lower than 8.17 +/- 0.06 GHz of the healthy corneas (P < 0.001). The Brillouin shift in the keratoconic corneas decreased with depth from the anterior toward posterior regions with a steeper slope than in the healthy corneas (P < 0.001). Within keratoconic corneas, the Brillouin shift in regions away from the apex of the cone was significantly higher than within the cone region (P < 0.001). CONCLUSIONS. Brillouin measurements revealed notable differences between healthy and keratoconic corneas. Importantly, Brillouin imaging showed that the mechanical loss is primarily concentrated within the area of the keratoconic cone. Outside the cone, the Brillouin shift was comparable with that of healthy corneas. The results demonstrate the potential of Brillouin microscopy for diagnosis and treatment monitoring of keratoconus. C1 [Scarcelli, Giuliano; Besner, Sebastien; Yun, Seok Hyun] Massachusetts Gen Hosp, Wellman Ctr Photomed, Cambridge, MA USA. [Scarcelli, Giuliano; Besner, Sebastien; Yun, Seok Hyun] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Pineda, Roberto] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. [Yun, Seok Hyun] Harvard MIT Hlth Sci & Technol, Cambridge, MA USA. RP Scarcelli, G (reprint author), 65 Landsdowne St, Cambridge, MA 02139 USA. EM scarcelli.giuliano@mgh.harvard.edu; syun@hms.harvard.edu OI scarcelli, giuliano/0000-0002-1736-077X FU Harvard Clinical and Translational Science Center (National Institutes of Health; Bethesda, MD, USA) [UL1-RR025758]; American Society for Laser Medicine and Surgery (Wasau, WI, USA); National Institutes of Health (Bethesda, MD, USA) [P41-EB015903, R21EY023043, K25EB015885]; National Science of Foundation (Washington, DC, USA) [CBET-0853773]; Human Frontier Science Program (Strasbourg, France) FX Supported by grants from Harvard Clinical and Translational Science Center (National Institutes of Health UL1-RR025758; Bethesda, MD, USA), American Society for Laser Medicine and Surgery (Wasau, WI, USA), National Institutes of Health (P41-EB015903, R21EY023043, K25EB015885; Bethesda, MD, USA), National Science of Foundation (CBET-0853773; Washington, DC, USA), and Human Frontier Science Program (Strasbourg, France). NR 41 TC 20 Z9 20 U1 1 U2 15 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD JUL PY 2014 VL 55 IS 7 BP 4490 EP 4495 DI 10.1167/iovs.14-14450 PG 6 WC Ophthalmology SC Ophthalmology GA AL9UI UT WOS:000339487000060 PM 24938517 ER PT J AU Dhaliwal, G AF Dhaliwal, Gurpreet TI Bringing High-Value Care to the Inpatient Teaching Service SO JAMA INTERNAL MEDICINE LA English DT Editorial Material ID CURRICULUM C1 [Dhaliwal, Gurpreet] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Dhaliwal, Gurpreet] San Francisco VA Med Ctr, Med Serv, San Francisco, CA USA. RP Dhaliwal, G (reprint author), San Francisco VA Med Ctr, Med Serv, 4150 Clement St,111, San Francisco, CA 94121 USA. EM gurpreet.dhaliwal@ucsf.edu NR 7 TC 1 Z9 1 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD JUL PY 2014 VL 174 IS 7 BP 1021 EP 1022 DI 10.1001/jamainternmed.2014.2012 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AL9VS UT WOS:000339491700001 PM 24862304 ER PT J AU McCarthy, AM Armstrong, K AF McCarthy, Anne Marie Armstrong, Katrina TI The Role of Testing for BRCA1 and BRCA2 Mutations in Cancer Prevention SO JAMA INTERNAL MEDICINE LA English DT Editorial Material ID RISK-ASSESSMENT; BREAST C1 [McCarthy, Anne Marie; Armstrong, Katrina] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Armstrong, K (reprint author), Massachusetts Gen Hosp, Dept Med, 55 Fruit St,GRB 740, Boston, MA 02114 USA. EM karmstrong6@partners.org FU NCI NIH HHS [U54 CA163313] NR 9 TC 5 Z9 6 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD JUL PY 2014 VL 174 IS 7 BP 1023 EP 1024 DI 10.1001/jamainternmed.2014.1322 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AL9VS UT WOS:000339491700002 PM 24841841 ER PT J AU Joffe, H Guthrie, KA LaCroix, AZ Reed, SD Ensrud, KE Manson, JE Newton, KM Freeman, EW Anderson, GL Larson, JC Hunt, J Shifren, J Rexrode, KM Caan, B Sternfeld, B Carpenter, JS Cohen, L AF Joffe, Hadine Guthrie, Katherine A. LaCroix, Andrea Z. Reed, Susan D. Ensrud, Kristine E. Manson, JoAnn E. Newton, Katherine M. Freeman, Ellen W. Anderson, Garnet L. Larson, Joseph C. Hunt, Julie Shifren, Jan Rexrode, Kathryn M. Caan, Bette Sternfeld, Barbara Carpenter, Janet S. Cohen, Lee TI Low-Dose Estradiol and the Serotonin-Norepinephrine Reuptake Inhibitor Venlafaxine for Vasomotor Symptoms A Randomized Clinical Trial SO JAMA INTERNAL MEDICINE LA English DT Article ID MENOPAUSAL HOT FLASHES; BREAST-CANCER; WOMENS HEALTH; DOUBLE-BLIND; METAANALYSIS; INDEX; 17-BETA-ESTRADIOL; INSTRUMENT; MANAGEMENT; SERTRALINE AB IMPORTANCE Estrogen therapy is the gold standard treatment for hot flashes and night sweats, but some women are unable or unwilling to use it because of associated risks. The serotonin-norepinephrine reuptake inhibitor venlafaxine hydrochloride is used widely as a nonhormonal treatment. While the clinical impression is that serotonin-norepinephrine reuptake inhibitors are less effective than estrogen, these medications have not been simultaneously evaluated in one clinical trial to date. OBJECTIVE To determine the efficacy and tolerability of low-dose oral 17 beta-estradiol and low-dose venlafaxine extended release in alleviating vasomotor symptoms (VMS). DESIGN, SETTING, AND PARTICIPANTS In total, 339 perimenopausal and postmenopausal women with at least 2 bothersome VMS per day (mean, 8.1 per day) were recruited from the community to MsFLASH (Menopause Strategies: Finding Lasting Answers for Symptoms and Health) clinical network sites between December 5, 2011, and October 15, 2012. INTERVENTIONS Participants were randomized to double-blind treatment with low-dose oral 17 beta-estradiol (0.5mg/d) (n = 97), low-dose venlafaxine hydrochloride extended release (75 mg/d) (n = 96), or placebo (n = 146) for 8 weeks. MAIN OUTCOMES AND MEASURES The primary outcome was the mean daily frequency of VMS after 8 weeks of treatment. Secondary outcomes were VMS severity, bother, and interference with daily life. Intent-to-treat analyses compared the change in VMS frequency between each active intervention and placebo and between the 2 active treatments. RESULTS Compared with baseline, the mean VMS frequency at week 8 decreased to 3.9 (95% CI, 2.9-4.9) VMS per day (52.9% reduction) in the estradiol group, to 4.4 (95% CI, 3.5-5.3) VMS per day (47.6% reduction) in the venlafaxine group, and to 5.5 (95% CI, 4.7-6.3) VMS per day (28.6% reduction) in the placebo group. Estradiol reduced the frequency of symptoms by 2.3 more per day than placebo (P < .001), and venlafaxine reduced the frequency of symptoms by 1.8 more per day than placebo (P = .005). The results were consistent for VMS severity, bother, and interference. Low-dose estradiol reduced the frequency of symptoms by 0.6 more per day than venlafaxine (P = .09). Treatment satisfaction was highest (70.3%) for estradiol (P < .001 vs placebo), lowest (38.4%) for placebo, and intermediate (51.1%) for venlafaxine (P = .06 vs placebo). Both interventions were well tolerated. CONCLUSIONS AND RELEVANCE Low-dose oral estradiol and venlafaxine are effective treatments for VMS in women during midlife. While the efficacy of low-dose estradiol may be slightly superior to that of venlafaxine, the difference is small and of uncertain clinical relevance. C1 [Joffe, Hadine; Manson, JoAnn E.; Rexrode, Kathryn M.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Psychiat, Boston, MA 02115 USA. [Joffe, Hadine] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, Boston, MA 02115 USA. [Joffe, Hadine; Shifren, Jan; Cohen, Lee] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02115 USA. [Guthrie, Katherine A.; LaCroix, Andrea Z.; Anderson, Garnet L.; Larson, Joseph C.; Hunt, Julie] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, MsFLASH Data Coordinating Ctr, Seattle, WA 98104 USA. [Reed, Susan D.] Univ Washington, Sch Med, Dept Obstet & Gynecol, Seattle, WA 98195 USA. [Ensrud, Kristine E.] Vet Affairs Hlth Syst, Dept Med, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Ensrud, Kristine E.] Univ Minnesota, Dept Med, Minneapolis, MN 55455 USA. [Newton, Katherine M.] Grp Hlth Res Inst, Seattle, WA USA. [Freeman, Ellen W.] Univ Penn, Perelman Sch Med, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA. [Freeman, Ellen W.] Univ Penn, Perelman Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. [Caan, Bette; Sternfeld, Barbara] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Carpenter, Janet S.] Indiana Univ, Sch Nursing, Indianapolis, IN 46204 USA. RP Joffe, H (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Psychiat, 75 Francis St, Boston, MA 02115 USA. EM hjoffe@partners.org OI Rexrode, Kathryn/0000-0003-3387-8429 FU National Institutes of Health [U01AG032656, U01AG032659, U01AG032669, U01AG032682, U01AG032699, U01AG032700] FX All financial and material support for this study was provided by grants U01AG032656, U01AG032659, U01AG032669, U01AG032682, U01AG032699, and U01AG032700 from the National Institutes of Health as a cooperative agreement issued by the National Institute on Aging. NR 37 TC 41 Z9 42 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD JUL PY 2014 VL 174 IS 7 BP 1058 EP 1066 DI 10.1001/jamainternmed.2014.1891 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA AL9VS UT WOS:000339491700015 PM 24861828 ER PT J AU Moin, T Mangione, CM AF Moin, Tannaz Mangione, Carol M. TI Live vs Electronically Delivered Weight-Loss Interventions Paying for Feasible Interventions SO JAMA INTERNAL MEDICINE LA English DT Editorial Material ID METAANALYSIS C1 [Moin, Tannaz] Vet Affairs Greater Los Angeles Healthcare Syst, Hlth Serv Res & Dev Ctr Study Healthcare Innovat, Los Angeles, CA USA. [Moin, Tannaz; Mangione, Carol M.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Mangione, Carol M.] Univ Calif Los Angeles, Jonathan & Karin Fielding Sch Publ Hlth, Los Angeles, CA 90095 USA. RP Moin, T (reprint author), Care of Gonzalez V, Univ Calif Los Angeles, 911 Broxton Ave,Off 302, Los Angeles, CA 90024 USA. EM tmoin@mednet.ucla.edu FU NCATS NIH HHS [UL1 TR000124, UL1TR000124]; NIA NIH HHS [P30-AG021684, P30 AG021684] NR 7 TC 0 Z9 0 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD JUL PY 2014 VL 174 IS 7 BP 1157 EP 1159 DI 10.1001/jamainternmed.2014.414 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA AL9VS UT WOS:000339491700030 PM 24861172 ER PT J AU Wilcox, ME Wiener-Kronish, JP AF Wilcox, M. Elizabeth Wiener-Kronish, Jeanine P. TI Telemedicine in the Intensive Care Unit Effect of a Remote Intensivist on Outcomes SO JAMA INTERNAL MEDICINE LA English DT Editorial Material ID CRITICALLY-ILL PATIENTS; MORTALITY C1 [Wilcox, M. Elizabeth] Univ Hlth Network, Interdept Div Crit Care, Toronto, ON, Canada. [Wiener-Kronish, Jeanine P.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Wiener-Kronish, JP (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St,GRB 444A, Boston, MA 02114 USA. EM jwiener-kronish@partners.org NR 8 TC 1 Z9 1 U1 1 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD JUL PY 2014 VL 174 IS 7 BP 1167 EP 1169 DI 10.1001/jamainternmed.2014.289 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA AL9VS UT WOS:000339491700032 PM 24819239 ER PT J AU Greysen, SR Garcia, CC Sudore, RL Cenzer, IS Covinsky, KE AF Greysen, S. Ryan Garcia, Carie Chin Sudore, Rebecca L. Cenzer, Irena Stijacic Covinsky, Kenneth E. TI Functional Impairment and Internet Use Among Older Adults: Implications for Meaningful Use of Patient Portals SO JAMA INTERNAL MEDICINE LA English DT Letter ID CARE C1 [Greysen, S. Ryan] Univ Calif San Francisco, Div Hosp Med, San Francisco, CA 94113 USA. [Garcia, Carie Chin] Calif Pacific Med Ctr, Dept Med, San Francisco, CA USA. [Sudore, Rebecca L.; Cenzer, Irena Stijacic; Covinsky, Kenneth E.] San Francisco VA Med Ctr, San Francisco, CA USA. [Sudore, Rebecca L.; Cenzer, Irena Stijacic; Covinsky, Kenneth E.] Univ Calif San Francisco, Div Geriatr Med, San Francisco, CA 94113 USA. RP Greysen, SR (reprint author), Univ Calif San Francisco, Div Hosp Med, 533 Parnassus Ave,POB 0131, San Francisco, CA 94113 USA. EM ryan.greysen@ucsf.edu FU NIA NIH HHS [K24 AG029812, 1K23AG045338-01, 1R01AG045043-01, K23 AG045338, P30 AG044281, R01 AG045043] NR 6 TC 10 Z9 10 U1 1 U2 4 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 JUL PY 2014 VL 174 IS 7 BP 1188 EP 1190 DI 10.1001/jamainternmed.2014.1864 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA AL9VS UT WOS:000339491700039 PM 24839165 ER PT J AU Dudzinski, DM Bhatia, RS Weiner, RB AF Dudzinski, David M. Bhatia, R. Sacha Weiner, Rory B. TI Assessing the Clinical Impact of Appropriate Echocardiograms SO JAMA INTERNAL MEDICINE LA English DT Letter ID TRANSTHORACIC ECHOCARDIOGRAPHY; USE CRITERIA C1 [Dudzinski, David M.; Bhatia, R. Sacha; Weiner, Rory B.] Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Boston, MA 02114 USA. RP Dudzinski, DM (reprint author), Massachusetts Gen Hosp, Cardiac Ultrasound Lab, 55 Fruit St, Boston, MA 02114 USA. EM ddudzinski@partners.org NR 4 TC 2 Z9 2 U1 1 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD JU